2004, vol.22, issues 4, psoriasis
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Dermatol Clin 22 (2004) xiii –xiv
Preface
Psoriasis
Alan Menter, MD Jennifer Cather, MD
Guest Editors
This issue of the Dermatology Clinics reviews in peutic era, with hundreds of thousands of patients
a comprehensive fashion the important features of
psoriasis, of relevance to the practicing dermatolo-
gist. All the authors are acknowledged leaders in the
field, having written extensively on various aspects
of psoriasis.
The initial three articles discuss the genetics of
psoriasis, immunopathogenesis of psoriasis, and the
rationale for the use of biologic therapy based on our
current knowledge of both genetics and immunopa-
thogenesis of this prevalent disease. In addition, the
realization of the significant impact that quality of
life issues play in the lives of our psoriasis patients
warrants a full article. All too often we, as busy der-
matologists, do a cursory clinical evaluation without
discussing the day-to-day impact that this highly
visible and distressful disease has on our patients.
Thereafter, the full range of therapeutic modalities
in psoriasis are covered in multiple articles, starting
with a review of the phototherapy arsenal available
to us in clinical practice, together with a comprehen-
sive review of the major systemic tools available to
the practicing dermatologist, prior to the advent of
biologic therapy.
Biologic therapy of psoriasis has become—as with
other immunomediated diseases such as rheumatoid
arthritis and Crohn’s disease—increasingly important.
Dermatology has ‘‘come lately’’ to the biologic thera-
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doi:10.1016/j.det.2004.05.001
already being treated over the past 5 or 10 years
for the two aforementioned diseases. The promise of
biologics, based on our knowledge of the specific
immunopathogenesis of psoriasis reviewed in this
issue, has allowed biotechnology companies to more
specifically target individual molecules involved in
antigen presentation and T-cell interaction with the
release of individual cytokines, particularly tumor
necrosis factor a, thus allowing for more precise
therapeutic options for the practicing dermatologist.
With the first biologic drug Alefacept, having been
released in January 2003, the second, Efalizumab,
in November 2003, and the third, Etanercept, in
May 2004, it is important for the practicing derma-
tologist to have a full understanding of these agents
and subsequent agents likely to be approved in the
months and years ahead. All these biologic agents are
reviewed in individual articles, again by physicians
experienced both in clinical research as well as in the
subsequent therapy of these individual agents.
In addition to our standard tools and the biologic
agents for psoriasis, other new agents have potential
for adding to our therapeutic armamentarium in the
years ahead. Dermatologists are fully versed in reti-
noid therapy for psoriasis, acne, and other dermato-
ses. With the likely advent of future systemic
retinoids, particularly oral Tazarotene, it is important
s reserved.
A. Menter, J. Cather / Dermatol Clin 22 (2004) xiii–xivxiv
that this be reviewed in full in a separate chapter. In
addition, the systemic form of pimecrolimus has re-
ceived a lot of attention and is likewise discussed.
The next two articles review two important issues
for the practicing dermatologist. First, the realization
that psoriatic arthritis is far more prevalent than we
had once believed. Drs. Ruderman and Mease, two
rheumatologists who are fully conversant with psori-
atic arthritis and its impact on the dermatologist, re-
view psoriatic arthritis in a way that will prove of
great value to the dermatologist in clinical practice.
The next article reviews how we as dermatologists can
integrate all these new drugs, particularly the biologic
agents, into our clinical practices.
Finally, Dr. Griffiths, an acknowledged leader
in investigative and clinical research as well as pso-
riasis therapy, gives a fascinating insight into how
psoriasis research and therapy is likely to evolve in the
years ahead.
We sincerely hope that this issue of the Dermato-
logic Clinics, which is designed to familiarize the
reader with the latest updates in psoriasis, will prove
both interesting and valuable as a ready reference for
practitioners who have an interest in psoriasis.
Alan Menter, MD
Jennifer Cather, MD
Baylor University Medical Center
5310 Harvest Hill Road, Suite 260
Dallas, TX 75230, USA
E-mail addresses: [email protected]
(A. Menter); [email protected] (J. Cather)
Dermatol Clin 22 (2004) 339–347
An update on the genetics of psoriasis
Francesca Capon, PhDa,*, Richard C. Trembath, MB, BS, FRCP, FMedScia,Jonathan N. Barker, MD, FRCP, FRCPathb
aDivision of Medical Genetics, Department of Genetics and Cardiovascular Sciences, University of Leicester, Adrian Building,
University Road, Leicester LE1 7RH, UKbDivision of Skin Sciences, St John’s Institute of Dermatology, St Thomas Hospital, Kings College, London SE1 7EH, UK
The existence of a genetic component to psoriasis traditionally been achieved by genotyping markers
has long been recognized, with repeated observations
of familial clustering [1,2] together with increased
concordance rates among monozygotic twins [3]. The
increase in disease risk among patient siblings ranges
from 4 to 6 [4,5], a relatively low ratio, consistent with
a multifactorial mode of inheritance (Fig. 1). These
observations contribute to the widely held view that
psoriasis is a disorder of complex etiology, requiring
the interaction between environmental triggers and
inherited susceptibility alleles. The dissection of such
an intricate model has proved challenging, necessi-
tating the recruitment of increasingly large patient
resources and the development of specifically de-
signed statistical tools. Despite these difficulties, the
last few years have witnessed significant progress in
the field, leading several research groups to close in on
the major psoriasis-susceptibility genes. It seems
timely to review these advances, while highlighting
the controversies and difficulties still to be faced by
the research community.
Chromosome 6p21 harbors the major psoriasis-
susceptibility locus (psoriasis-susceptibility 1)
Defining the psoriasis-susceptibility 1 interval
The first step in the isolation of a disease gene is the
identification of the chromosomal region (locus) bear-
ing the gene responsible for the disorder. This has
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doi:10.1016/S0733-8635(03)00125-6
* Corresponding author.
E-mail address: [email protected] (F. Capon).
that cover the entire genome and identifying those that
are co-inherited by affected sib pairs more frequently
than the 50% prior expectation. Such genome-wide
scans have now been performed in several extended
patient cohorts and have repeatedly identified a region
of chromosome 6p21 as a contributor to psoriasis
susceptibility (Table 1). This degree of consistency
among genome-scan results in the analyses of complex
disorders is uncommon. Many studies are typically
plagued by poor reproducibility, caused in part by a
number of recognized confounder issues (Table 2).
Hence, the repeated identification of a 6p21 suscepti-
bility locus (psoriasis susceptibility 1 [PSORS1]) in
several independent samples clearly indicates a major
pathogenic role for this region.
Several attempts have been made to refine the
boundaries of the PSORS1 interval, to define a
minimal target region to focus the search for the
6p21 susceptibility genes. These refinement studies
have sought to identify haplotypes (blocks of markers
grouped together on a chromosome) that are trans-
mitted to affected patients more often than expected
by chance. The rationale behind this approach is that
marker alleles lying in close proximity to a mutation
tend to be in linkage disequilibrium with it (ie, they
are very seldom separated from it by recombination
or cross-over events) (Fig. 2). As a consequence,
marker alleles whose frequency is increased in patient
cohorts may be used to highlight the most likely
location of a susceptibility gene (see Fig. 2).
Three studies reported the fine-scale mapping of
the PSORS1 interval and a consensus minimal region
has emerged. The PSORS1 segment is contained
within a 200-kb block of DNA in the class I major
s reserved.
Fig. 1. A modest degree of family clustering is consistent
with a polygenic mode of disease inheritance. Upper pedi-
gree: an individual affected by a dominant monogenic
disorder caused by mutated allele A transmits the disease to
half (50%) of his offspring. Lower pedigree: an individual
affected by a polygenic disorder requiring the presence of
mutated alleles A, B, and C transmits the disease to one
(12.5%) in eight of his offspring. Square, male; circle, fe-
male; filled symbol, affected; empty symbol, unaffected.
Table 2
Major factors affecting the reproducibility of complex trait
genetic analysis
Confounder Example
Genetic heterogeneity Different genes cause the
same disease, in two
unrelated populations
Lack of statistical power The analyzed sample is
too small to detect the
effect of a given locus
Occurrence of phenocopies Part of the patients are
affected by a nonhereditary
form of the disease
Diagnostic criteria Diverse inclusion criteria
have been used in different
studies
Experimental design Different statistical tools
have been used in various
surveys
False-positives Originally published results
were in fact spurious
In-depth treatises of these issues can be found in Refs.
[73,74].
F. Capon et al / Dermatol Clin 22 (2004) 339–347340
histocompatibility complex (MHC) region (Fig. 3)
[6–8]. One study reported a further refinement of the
critical interval, describing a 60-kb minimal suscep-
tibility region [7] (RH1 segment in Fig. 3). This result
has generated some controversy in the field, however,
with a consensus view that the larger 200-kb interval
may not be discounted at this time [9,10]. The RH1
segment was defined by comparing a number of risk
haplotypes, most of which also contained a second
Table 1
Studies implicating the psoriasis-susceptibility 1 region in
psoriasis susceptibility
Authors Sample origin
Nair et al [65] Germany, United States
Trembath et al [49] United Kingdom
Capon et al [71] Italy
Samuelsson et al [72] Sweden
Lee et al [63] Germany
Veal et al [66] United Kingdom
Zhang et al [67] China
Zheng et al [70] China
conserved block, RH2 (see Fig. 3). The definition of
the minimal PSORS1 region was based on the
observation of a single Cw6-negative risk haplotype
bearing RH1 only (see Fig. 3). A collaborative survey
of an extended patient cohort failed to validate this
chromosome as conferring risk, however, pointing to
a more conservative minimal region, including HLA-
C and RH2, together with RH1 (see Fig. 3) [11].
Psoriasis-susceptibility 1 candidate genes
The consensus 200-kb PSORS1 interval contains
several genes, most of which have been investigated
as positional candidates for psoriasis susceptibility.
HLA-C lies at the centromeric end of the interval and
has long been considered a likely psoriasis-suscepti-
bility gene [12]. The HLA-C gene encodes a MHC
class I antigen participating to the process of immune
system self-recognition and self-tolerance [13]. Class
I molecules also stimulate the response against intra-
cellular pathogens, by presenting nonself cytoplasm
peptides to cytotoxic T cells [13]. HLA-C polymor-
phisms have been investigated in a wide range of
populations and a highly significant association be-
tween the HLA-Cw6 allele and psoriasis has been
repeatedly reported [10,12]. Association studies have
also defined the HLA-Cw6 allele as a factor that
predisposes to early onset disease [14,15] and to the
exacerbating action of streptococcal infections
[14,16]. Despite the significance and consistency of
association findings, it is not known whether the
Fig. 2. Linkage disequilibrium as a tool for the fine mapping of disease loci. The analysis of six polymorphisms spanning a
susceptibility interval shows that patients from unrelated families share a core two-marker haplotype (A7–A2). The preservation
of this genomic segment indicates linkage disequilibrium (ie, lack of recombination because of close proximity) between the two
markers and the susceptibility mutation (asterisk). The conserved haplotype (filled bar) defines the minimal region that is most
likely to harbor the disease-susceptibility gene.
F. Capon et al / Dermatol Clin 22 (2004) 339–347 341
HLA-Cw6 antigen participates in the cellular pro-
cesses that lead to the onset of psoriasis. In the
absence of functional data, it remains possible that
the reported association merely reflects HLA-C prox-
imity to an as yet undisclosed susceptibility mutation.
In addition to HLA-C, the consensus PSORS1
region contains seven known genes (see Fig. 3). Of
these, OTF3 and STG have been considered unlikely
candidates, based on the known characteristics of
their protein products. OTF3 encodes a transcription-
al factor playing a major role in embryonic stem cells
lineage commitment [17], whereas STG codes for an
extracellular protein that is only expressed in the
tongue taste buds [18]. The SC1 and SPR1 genes
seem not to show association with psoriasis [19,20],
and SEEK1 has not yet been characterized in terms of
function, expression pattern, or polymorphism con-
tent. In contrast to this group of genes, both HCR and
CDSN have been extensively investigated and have
been seen in independent reports to show association
with psoriasis. HCR (alpha-Helix Coiled coil Rod
homologue) encodes a highly polymorphic, ubiqui-
tously expressed protein of unknown function, which
is up-regulated in psoriatic epidermis [21,22]. An
association between psoriasis and two HCR variants
first reported in the Finnish population [21] has been
confirmed in studies of several ethnic groups [10,22].
The pathogenicity of these variants remains unclear,
however, not least because haplotypes have been
identified that are overtransmitted to affected patients
but lack the HCR risk alleles [23,24]. A collaborative
analysis of an extended patient resource has also been
reported but failed to discriminate whether the asso-
ciation at the HCR variants was caused by their
proximity to HLA-Cw6 or vice versa [10].
The CDSN gene lies at the distal end of the
PSORS1 interval (see Fig. 3) and codes for corneo-
desmosin, a structural protein that participates in the
process of keratinocyte adhesion and desquamation
[25,26]. Homozygous, nonsense CDSN mutations
Fig. 3. The PSORS1 region refinement proposed by Nair et al [7]. The upper diagram shows the 200-kb consensus minimal
region together with the eight known genes contained therein. HLA-C, HCR, and CDSN are highlighted as genes that have
repeatedly been associated with psoriasis. The lower diagram schematizes the PSORS1 risk haplotypes reported by Nair et al [7],
with different line styles symbolizing regions of haplotype divergence. Following to the exclusion of the bottom haplotype, the
minimal region shared by all risk chromosomes expands to include both HLA-C and RH2.
F. Capon et al / Dermatol Clin 22 (2004) 339–347342
have been identified in patients with the rare, auto-
somal-recessive disorder hypotrichosis simplex of the
scalp [27]. The observation of CDSN-specific expres-
sion in cornified squamous epithelia [28], together
with its up-regulation and abnormal degradation in
psoriatic epidermis [29–31], have generated a con-
siderable interest in this gene. The CDSN gene is
highly polymorphic, with 37 sequence variants de-
scribed [32,33]. Association analyses have identified
three variants defining an intragenic haplotype that
confers risk to psoriasis in a wide range of popula-
tions [33–38]. The biologic relevance of these find-
ings has been questioned, however, based on the
argument already put forward against the HCR risk
alleles (ie, that the observed association could be
Fig. 4. Both HLA-C and CDSN risk alleles might be required to c
200-kb consensus PSORS1 minimal region. The lower bars schema
and Capon et al [33]. Risk haplotypes carry both HLA-C and CDS
set of risk SNPs (HLA-C or CDSN only) are neutral.
ascribed to linkage disequilibrium with HLA-Cw6)
[39,40].
How many psoriasis-susceptibility 1 genes?
The controversies surrounding the analysis of can-
didate genes have highlighted the difficulties of
carrying out association studies in a region where ex-
tensive linkage disequilibrium between marker alleles
can act as a major confounder. To unravel the rela-
tionship between the HLA-C, HCR, and CDSN
associations, haplotypes spanning the PSORS1 inter-
val and encompassing these three loci have been
generated (Fig. 4) [24]. To maximize the genetic
resolution of the study single nucleotide polymor-
onfer psoriasis susceptibility. The upper diagram shows the
tize the PSORS1 SNP haplotypes reported by Veal et al [24]
N related risk alleles, whereas chromosomes bearing a single
Table 3
Published non–major histocompatibility complex suscepti-
bility loci
Chromosome
(locus name) Sample origin
1p (PSORS7) United Kingdom [66]
1q (PSORS4)a Italy, United States [4,68]
2pa United States, United Kingdom [4,66]
2q United Kingdom [49]
3q (PSORS5) Sweden [51,72]
4q13a United States, Sweden [4,72]
4q31 China [67]
4q34a (PSORS3) Ireland [64]
6qa United States, Germany [65]
7 United Kingdom [49]
8qa United Kingdom [49]
10qa United States, Germany [65]
F. Capon et al / Dermatol Clin 22 (2004) 339–347 343
phism markers distributed across the interval have
been identified. Single nucleotide polymorphisms
occur at a higher frequency in the genome [41], al-
lowing the construction of more dense genetic maps.
In addition, single nucleotide polymorphisms exhibit
a much lower mutation rate compared with micro-
satellite markers [41] and as such are more suited to
the reconstruction of very ancient haplotypes. The
single nucleotide polymorphism–based dissection of
the PSORS1 interval has identified a major risk
haplotype bearing HLA-C, HCR, and CDSN dis-
ease-associated alleles (cluster E in Fig. 4), together
with a minor risk chromosome (cluster D in Fig. 4)
carrying HLA-C and CDSN risk variants only [24].
These observations have subsequently been repli-
cated in an independent population of northern Indian
descent, where two novel haplotypes (G1 and G2 in
Fig. 4) were identified that carried a single set of
risk alleles and did not show any association with
psoriasis [33]. Taken together, these findings have
prompted the intriguing hypothesis that both HLA-C
and CDSN alleles may contribute to psoriasis sus-
ceptibility. The possibility that multiple genes may
underlie a single susceptibility locus is not a novel
concept in the genetics of common multifactorial
disorders, because compound MHC risk alleles have
already been observed within loci conferring suscep-
tibility to type I diabetes [42] and multiple sclerosis
[43]. It is tempting to speculate that further MHC
genes, lying outside of the minimal PSORS1 interval,
might also contribute to or modify an individual’s
genetic susceptibility. In fact, genetic associations
with psoriasis have been reported for a number of
genes lying proximal to HLA-C. These include the
TAP genes, which encode a heterodimeric complex
delivering antigenic peptides to the endoplasmic
reticulum before the assembly of class I molecules
[44,45], and MICA, which codes for a ligand of the
natural killer cell activating receptor NKG2D [46,47].
Significant associations have also been reported for
polymorphisms of the tumor necrosis factor-beta
gene, which encodes the lymphotoxin alpha cytokine
[45,48].
14qa United Kingdom, United States [4,66]15 Sweden [72]
16qa United States, Germany, Icelandb
[62,65]
17q25a (PSORS2) United States, Germany, Sweden,
China [51,61,65,70,72]
19p13 (PSORS6) Germany, United Kingdom [63]
20pa Germany, United Kingdom, United
States [7,49,65]
a Loci included in the International Psoriasis Genetics
Study [50].b Psoriatic arthritis cohort.
Non–major histocompatibility complex
susceptibility loci: separating the wheat from the
chaff
The non–major histocompatibility complex
contribution to psoriasis susceptibility
The evidence supporting PSORS1 as the major
psoriasis susceptibility locus is by now overwhelm-
ing. PSORS1 accounts for less than 50% of familial
aggregation in psoriasis [49,50], however, hence
other susceptibility loci must contribute to the dis-
order pathogenesis. Genome-wide scans have identi-
fied a number of such non-MHC susceptibility
intervals (Table 3), but the validation of these regions
in independent dataset has proved a challenging task.
Unlike PSORS1, most non-MHC loci have been ob-
served only once and, with the exception of PSORS2,
none of them has been replicated in more than two
populations (see Table 3). The inconsistency of these
findings can be accounted for by confounders that
generally complicate the genetic dissection of com-
plex traits (see Table 2). In the case of psoriasis, the
repeated observation of distinct susceptibility regions
(see Table 3) highlights the likely presence of ge-
netic heterogeneity, well known to affect the repro-
ducibility of localization studies. The small effect of
non-MHC susceptibility loci is also likely to be a
confounder, with undersized patient cohorts lacking
the power to replicate regions of relatively mod-
est effect. Finally, some susceptibility loci might be
unique to the population where they were identified.
F. Capon et al / Dermatol Clin 22 (2004) 339–347344
This might be particularly true for samples originat-
ing from genetic isolates, such as the cohort from
southwest Sweden in which the PSORS5 suscepti-
bility interval has been reported [51].
Possible approaches to locus validation
The positional cloning of a susceptibility gene is a
labor-intensive and costly endeavor, which is unlikely
to be undertaken unless the chromosomal assignment
of the relevant locus is supported by robust statistical
evidence. The validation of non-MHC susceptibility
loci and the identification of regions warranting fur-
ther investigation are essential steps in the dissection
of psoriasis genetics. To achieve these objectives, an
extended clinical resource was recently established
by integrating the patient cohorts from three research
centers [50]. This pooled sample included 942 affect-
ed sib pairs and, being the largest yet analyzed in a
psoriasis genetics study, was expected to have enough
statistical power to validate non-MHC loci. The pa-
tient data set was typed using 53 markers, which
spanned a number of published susceptibility regions
(labeled with an asterisk in Table 3) and statistically
significant evidence was gathered in support of the
10q and 16q loci [50]. Although these results un-
doubtedly warrant a closer scrutiny of the previously
mentioned regions, they cannot be interpreted as a
definite exclusion of all the remaining non-MHC loci.
In fact, it is entirely possible that even a dataset as
large as the Consortium’s may lack the power to
detect a non-MHC locus in the presence of substantial
genetic heterogeneity. This interpretation is consistent
with independent evidence that has emerged from the
analysis of a distinct inflammatory disorder (atopic
eczema). Indeed, genome-wide searches for loci pre-
disposing to childhood atopic dermatitis have identi-
fied four chromosomal regions closely overlapping
with the 1q21, 3q21, 17q25, and 20p psoriasis-
susceptibility intervals [52,53]. Colocalization of loci
predisposing to different inflammatory disorders is
not unusual and it has been hypothesized that a com-
mon set of genes influencing the immune response
may underlie clinically distinct complex diseases
[54]. The possibility that some of the reported colo-
calizations might be coincidental should always be
considered, however, given the broad extension of the
susceptibility regions detected by genome-wide scans
and the occurrence of false-positive findings in these
studies. Nonetheless, the overlap between atopic der-
matitis and psoriasis-susceptibility regions is thought
to underlie a set of common genetic determinants,
because it has been estimated that the likelihood of
identifying four atopic dermatitis loci colocalizing by
chance with an equal number of psoriasis suscepti-
bility intervals is less than 1:100,000 [52]. Another
possible instance of a shared inflammatory locus
is the chromosome 16q susceptibility region, which
also contains the NOD2-CARD15 Crohn’s disease
gene [55,56]. Case-control and family-based studies
have failed to detect an association between the ma-
jor NOD2 risk allele and psoriasis susceptibility
[57–59]. Preliminary data obtained in the Newfound-
land genetic isolate, however, support an association
between a distinct NOD2 variant and psoriatic arthri-
tis [60].
Summary
It will soon be 10 years since Tomfohrde et al [61]
identified the first psoriasis-susceptibility locus
through a genome-wide scan of eight extended Amer-
ican pedigrees. Nine further genome-scans totaling
almost 800 pedigrees have followed [49,51,62–68]
and at least 500 additional families have been ana-
lyzed in follow-up studies of published loci [50,69,
70]. This major research effort has led to considerable
insights as to the genetic basis of psoriasis suscepti-
bility, notwithstanding the inevitable appearance of
contradictory findings. The evidence supporting a
primary role for the PSORS1 locus is now over-
whelming. Remarkably, psoriasis is the only complex
disorder that has been consistently associated with
an HLA-C allele. This indicates that HLA-Cw6 (or
the undiscovered susceptibility variant that may be
in linkage disequilibrium with it) affects the disease
risk by specifically predisposing to psoriasis, rather
than by conferring a generic susceptibility to inflam-
matory disorders.
Dissecting the contribution of non-MHC loci is
proving a somewhat arduous task, because of their
less prominent role and the likely occurrence of
genetic heterogeneity. Unlike PSORS1, several non-
MHC susceptibility intervals overlap with loci pre-
disposing to other inflammatory or autoimmune
diseases. The identification of the genes underlying
these loci may benefit the understanding of clinically
distinct conditions.
The disease model emerging from 10 years of
genetic analyses is, not unexpectedly, a rather elabo-
rate one, where psoriasis-specific determinants are
likely to interact with a potentially large number of
inflammatory loci and environmental triggers. In this
context, the availability of the human genome se-
quence and the establishment of collaborative pa-
tients’ resources are going to prove essential tools
F. Capon et al / Dermatol Clin 22 (2004) 339–347 345
to disentangle the contribution of individual psoria-
sis-susceptibility genes.
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Dermatol Clin 22 (2004) 349–369
Current concepts in the immunopathogenesis of psoriasis
Michelle A. Lowes, MD, PhDa, Wook Lew, MD, PhDb,James G. Krueger, MD, PhDa,*
aRockefeller University, 1230 York Avenue, Box 178, New York, NY 10021, USAbDepartment of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine,
Yongdong Severance Hospital, 146-92 Dogok-Dong, Kangnam-Ku, Seoul, South Korea
Psoriasis vulgaris affects approximately 2% of the therapy used in individuals with psoriasis is cyto-
US population, and although it varies in severity, it
imposes a great burden on those who have this
disease. Psoriasis was initially considered to be a
primary disorder of keratinocytes, with disturbed
epidermal differentiation leading to keratinocyte
hyperproliferation. Now there is much evidence to
support the involvement of the immune system in the
pathogenesis and maintenance of psoriasis, including
roles for CD8+ and CD4+ lymphocytes, dendritic cells
(DCs), monocytes/macrophages, and natural killer
(NK) and natural killer T (NK-T) cells. Keratinocytes
may still play an integral role, responding to the
leukocyte infiltration and cytokine environment.
Novel anti–T-lymphocyte immunotherapies, and
review of the mechanisms of some traditional anti-
psoriatic medications, have confirmed an important
role of the immune system in psoriasis (reviewed in
reference [1]). Therapies aimed at different immune
targets have proved successful, although there is
variability in clinical response between patients,
reflecting the complexity of psoriasis pathogenesis
and redundancy of immune pathways. The first
such treatment used the immunotoxin DAB389IL-2,
which is a fusion protein carrying a cellular toxin to
interleukin 2R (IL-2R)–expressing cells [2]. This
agent blocks proliferation of activated lymphocytes,
and clinical improvement was associated with reduc-
tion in intraepidermal CD3+ and CD8+ T cells,
therefore supporting the role of these cells in dis-
ease pathogenesis. Another important antilymphocyte
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/j.det.2004.03.010
* Corresponding author.
E-mail address: [email protected] (J.G. Krueger).
toxic T-lymphocyte–associated antigen 4-immuno-
globulin (CTLA4-Ig) [3]. Molecules in the B7
family on the surface of antigen-presenting cells
(APCs) normally engage CD28 on T cells, which
delivers costimulatory signals during T-cell activa-
tion, or CTLA4, which delivers a negative signal.
Blocking this interaction with CTLA4-Ig in indi-
viduals with psoriasis showed a dose-dependent
clinical response associated with reduction of cell
activation markers. Other examples of immuno-
biologic mechanisms are discussed and tabulated in
reference [4], and some are also discussed in other
articles in this issue. The current theories of the roles
of components and the potential functions of the
innate and cell-mediated immune system are dis-
cussed, focusing on current concepts of the immuno-
pathogenesis of psoriasis. The role of xenotransplant
and other mouse models, and the contribution of
recent genomic studies, are also outlined in the con-
text of further understanding psoriasis.
Psoriasis as a type 1 T-cell–mediated autoimmune
disease
There is mounting evidence that psoriasis may be a
type 1 T-cell–mediated autoimmune disease, such as
type 1 diabetes or multiple sclerosis. In such type 1
autoimmune diseases, there is characteristic activation
and proliferation of pathogenic antigen-specific CD4+
or CD8+ T cells, and the responsible lymphocytes are
activated type 1 (interferon g [IFN-g�]–producing)
memory cells. Initially, morphologic studies showed
abundant lymphocytes within lesional skin (along
s reserved.
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369350
with characteristic neutrophils), but few monoclonal
antibodies were available to classify these cells fur-
ther. Fig. 1 shows the relevant cell types that have
been described in psoriatic tissue and important in-
flammatory products that are likely to play a role in
disease pathogenesis.
Immunohistochemical analysis of these abundant
lymphocytes in lesional tissue and fluorescence-acti-
vated cell sorting (FACS) of epidermal and dermal
single-cell suspensions reveal patterns consistent with
immunologic memory and specialized tissue homing.
There are abundant CD4+ T cells in psoriatic dermis
and CD8+ T cells in the epidermis [5,6]. Lesional
T cells demonstrate the surface marker cutaneous
lymphocyte antigen (CLA), which allows them to
bind to endothelial P- and E-selectin, facilitating
transmigration across the cutaneous vasculature [7].
Epidermal CD8+ T cells are CXCR3+. CXCR3 is a
chemokine receptor that allows these cells to respond
to epidermal chemokine gradients from keratinocyte-
Fig. 1. Psoriasis as a type 1–mediated disease. CLA+ memory
extravasate across inflamed blood vessels, responding to chemokin
dermis, and CD8+ Tc1 cells are found in the epidermis. Both are abl
augment the psoriatic inflammatory process. Activated DCs play a
within the psoriatic lesion by means of type 1 cytokines IL-12 an
direct and downstream effects of these locally produced cytokines
derived monokine induced by IFN-g (MIG) and IFN
inducible protein 10 (IP-10), and migrate into the
epidermis [8]. Many CD8+ lymphocytes bear the
aEb7 (CD103/b7) integrin, which facilitiates move-
ment into the epidermis by way of keratinocyte
E-cadherin [8,9]. Thus, there is specialization in the
surface phenotype of these cells to encourage their
movement into psoriatic lesional tissue.
Lesional epidermal lymphocytes are persistently
activated, as shown by the following: up-regulation of
CD69, a rapidly induced antigen; CD25, the low-
affinity receptor for IL-2 (a chain); and the major
histocompatibility complex (MHC) class II molecule
HLA-DR [6]. Although a universal and specific pso-
riatic antigen has not yet been determined, there is
oligoclonal expansion of CD8+ T-cell receptor (TCR)
b-chain components within psoriatic lesions, particu-
larly of the complementary determining region 3, or
CDR3. The specific TCR chain that is preferentially
expressed is not the same in all patients [10–12]. Over
T lymphocytes and polymorphonuclear (PMN) leukocytes
e gradients. CD4+ Th1 cells are found predominantly in the
e to produce type 1 cytokines IL-2, IFN-g, and TNF-a, whichrole in T-cell activation both in the draining lymph node and
d IL-23. The phenotype of psoriasis is likely caused by the
and chemokines.
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369 351
time, dominant TCR rearrangements persist in re-
lapsing psoriasis [13]. This finding suggests the pres-
ence of ongoing specific antigen, or at least favorable
conditions for clonal in situ T-cell proliferation. Epi-
dermal and dermal CD8+ cytotoxic T-cell (Tc) clones
also have been developed, some of which release
mediators capable of causing keratinocyte prolifera-
tion [14] or producing IFN-g [15].
T-helper (Th) cell (CD4+) differentiation can be
categorized into a type 1 (IFN-g– and IL-2–produc-
ing) versus type 2 (IL-4– and IL-10–producing)
cytokine pattern (Th1 versus Th2, respectively). Simi-
larly, CD8+ cytotoxic T cells can be functionally dif-
ferentiated into two populations, Tc1 and Tc2, which
secrete these two patterns of cytokines [16]. CD4+ and
CD8+ T cells from psoriatic epidermal and dermal
single-cell suspensions produce a type 1 pattern of
cytokines, specifically IFN-g and IL-2, and small
amounts of type 2 cytokines, IL-4 and IL-10 [17].
Tumor necrosis factor a (TNF-a), a cytokine that may
be produced by many cells during innate and cell-
mediated immune responses, is also increased from
lesional lymphocytes. Essentially all type 1 (IFN-g–producing) T cells cosynthesize TNF-a when acti-
vated. Elaborated cytokines are able to orchestrate
further proliferation of antigen-specific T cells, and
activation of effector and responding cells, such as
CD8+ T cells, macrophages, and keratinocytes.
Patients with psoriasis also demonstrate systemic
type 1 immune deviation (Fig. 2), with two- to
threefold expansion of type 1 T cells producing IFN-
g and IL-2 [17–19].
The specific cytokine milieu can determine the
process of type 1 versus type 2 differentiation. IL-12,
produced by activated DCs, stimulates the production
of a type 1 cytokine pattern. IL-13 leads to the
production of IL-4 and IL-10, a more immunosup-
pressive type 2 pattern that is also associated with
antibody production. There are increased IL-12 and
IL-12R found within psoriatic lesions [20,21], which
may drive type 1 T-cell differentiation. One of the
major stimuli for DCs to produce IL-12 is the ligation
Fig. 2. Immune deviation in psoriasis. In homeostatic conditions, th
than type 2 (T2) cytokines (IL-4, IL-10). In diseases characterized b
In type 2 immune deviations, there are more type 2 cytokines tha
of DC CD40 by the CD40 ligand (CD40L) on CD4+
T cells [22,23]. This sets up a scenario where acti-
vated CD4+ T cells engage DCs by means of a
CD40L–CD40 interaction, resulting in IL-12 pro-
duction by DCs and subsequently driving the pro-
duction of the classic type 1 cytokine, IFN-g.This CD40–CD40L interaction also generates the
production of IL-23 [24], another important, recently
discovered type 1 cytokine. IL-23 is a heterodimer
composed of one of the IL-12 chains (p40) and an
IL-23–specific chain (p19; reviewed in reference
[25]). This cytokine shares many features with IL-12,
such as signal transduction pathways, induction of
IFN-g production, target cell proliferation, and up-
regulation of APC costimulatory function. It acts
primarily on memory CD4+ T cells, however, whereas
IL-12 acts on naıve CD4+ T cells. IL-23 is up-
regulated in psoriasis [26] and may be the key
cytokine driving type 1 T-cell expansion and the
production of IFN-g.The current authors believe that IFN-g is a pivotal
cytokine in the development and maintenance of
psoriatic lesions. Fig. 3 outlines a sequential pathway
of type 1 T-cell activation, release of T-cell–derived
cytokines, and production of several inflammatory
mediators that the authors term the type 1 pathogenic
pathway. IFN-g is produced by effector memory
CD8+ T cells, epidermal Tc1, CD4+ T cells, and NK
and NK-T cells. Psoriatic CD8+ Tc1 cell lines and
clones have been shown to produce heterogeneous
levels of IFN-g [15]. There is also evidence of the
effects of IFN-g at the tissue level in psoriatic lesions:keratinocytes show increased levels of HLA-DR,
intercellular adhesion molecule-1 (ICAM-1) [27],
and CD40 [28]; increased CXCR3 expression on
lymphocytes [8]; and greater levels of keratinocyte-
derived MIG and IP-10 [8]. Furthermore, this cyto-
kine may also increase expression of costimulatory
molecules on DCs [29]. IFN-g potently activates
macrophages and may also induce TNF-a release
from monocytes and macrophages, which acts syner-
gistically with IFN-g in an inflammatory response
ere are more type 1 (T1) cytokines (IL-2, IFN-g, and TNF-a)y a type 1 immune deviation, there are more type 1 cytokines.
n normal.
Fig. 3. Type 1 pathogenic pathway in psoriasis. The current authors have proposed that IL-12 and IL-23, primarily DC-derived
cytokines, stimulate type 1 T cells to produce type 1 cytokines. This has many effects at the gene level, and the resultant products
help explain the phenotype of psoriatic lesions. For some genes there is synergy between IFN-g and TNF-a. GAS, IFN-gactivation sequence; ISRE, IFN-stimulated response element.
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369352
[30]. Endothelial cells are also responsive to IFN-g,up-regulating several adhesion molecules, such as
ICAM-1 and vascular cell adhesion molecule-1
(VCAM-1), which facilitates the complex process of
leukocyte trafficking into tissues. The sum of cyto-
kines and chemokines made in response to IFN-g and
TNF-a (see Fig. 3) can explain many features of the
pathogenic process: angiogenesis and vascular ecta-
sia, T-cell and neutrophil emigration into lesions, and
some components of the psoriatic epidermal response.
There have been several additional observations
regarding the relationship between IFN-g and psoria-
sis. IFN-g receptors in keratinocytes [31] and IFN-gprotein in papillary dermal cells [32] have been
shown to be up-regulated in lesional skin of patients
with psoriasis. Subcutaneous administration of IFN-gfor the treatment of psoriatic arthritis can lead to the
occurrence of punctiform psoriatic foci at the site of
injection [33]. Patients with immunoblastic lymph-
adenopathy-like T-cell lymphoma showed elevated
serum levels of IFN-g and were reported to develop
psoriasis [34]. For treatment of lepromatous leprosy,
delivery of IFN-g resulted in several features present
in psoriatic lesional skin [35]. As mentioned, a type 1
bias toward activated T cells is indicated by the
overexpression of IFN-g in psoriasis, both lesionally
and in the circulating leukocytes [17]. There are also
preliminary data that blocking IFN-g in patients with
psoriasis may give a beneficial clinical effect [36].
Recent gene expression studies by microchip
analysis have begun to elucidate the pattern of cyto-
kines, inflammatory mediators, and transcriptional
factors within psoriatic tissue at the message level
(discussed later). Interpretation of this vast bank of
data is challenging, but the information can be
ordered on the basis of IFN-g responsive genes
(Fig. 4). After type 2 IFN (IFN-g) is produced, it
binds to the IFN-g cell surface receptor, which is
phosphorylated by janus kinase (JAK) 1 and JAK2
enzymes (reviewed in references [37–39]). This
process makes available a recruitment site for an
important transcriptional factor, the signal transducer
and activator of transcription (STAT). Dimers of
STAT-1 form an IFN-g–activated factor (GAF),
translocate to the nucleus, and activate transcription
from IFN-g target gene promoters containing IFN-gactivation sequence (GAS) elements. Thus, STAT-1
production is an important early indicator of IFN-geffects. Other primary response genes include addi-
tional IFN transcription factors and MIG. Down-
stream effects of IFN-g include the secondary
response genes, which may contribute to the devel-
opment of the psoriatic phenotype, such as IL-8 and
IP-10. Type 1 IFNs (IFN-a and IFN-b) are also able
to induce many genes on the IFN-g pathway, particu-
larly the secondary response genes.
APCs are central to the process of antigen-specific
T-cell activation (reviewed in reference [40]). The
first DC described in normal epidermis, but which
can also be found in the dermis, was the Langerhans’
cell (LC). This cell can be identified by surface anti-
gens MHC class I and II, CD1a, langerin, lag, and
Birbeck granules. LCs are extremely efficient at
capturing local antigen, and after activation, they
migrate to local lymph nodes by way of cutaneous
lymphatics. During migration, they mature for in-
Fig. 4. IFN receptor binding and effects. Binding of IFN-g to its receptor causes STAT-1 phosphorylation and dimerization to
form the IFN-g–activating factor (GAF). GAF is able to translocate to the nucleus and bind to IFN-g activation sequence (GAS)
in promoters for translation of IFN primary response genes. Binding of type 1 IFNs (IFN-a or IFN-b) to the type 1 IFN receptor
causes production of IFN-stimulated gene factor 3 (ISGF3), which is composed of STAT1, STAT 2, and IFN regulatory factor 9
(IRF-9, p48). ISRE is able to bind to the ISRE sequence in gene promoters leading to transcription of IFN-g secondary response
genes in the IFN-g pathway. There is cross-talk between these two IFN systems: STAT1 dimers (GAF) can bind IRF-9 and also
activate ISRE (reviewed in Refs. [37–39]).
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369 353
creased antigen presentation to lymphocytes, by up-
regulating MHC class I and II, costimulatory mole-
cules B7.1 and B7.2 (CD80 and CD86, respectively),
and CD83. These mature DCs have the capacity to
stimulate resting and memory T cells, unlike other
nonprofessional APCs, such as monocytes or B cells,
which can only activate memory T cells. Inflamed
epidermis has two additional types of DCs [41]. The
inflammatory dendritic epidermal cell, or IDEC, lacks
Birbeck granules; is positive for CD1a, HLA-DR,
CD11b, CD11c; and expresses costimulatory mole-
cules in situ. More recently, the plasmacytoid den-
dritic cell (PDC or DC2) has been identified in
psoriatic lesional skin. PDCs were increased in epi-
dermal single-cell suspensions of psoriasis compared
with other inflammatory dermatoses or normal skin.
This cell has a characteristic ‘‘plasmacytoid’’ mor-
phology, is CD123+ and CD11c�, and makes large
amounts of type 1 IFN on viral infection or stimula-
tion with CpG motifs within microbial DNA. Mature
activated plasmacytoid DCs are functionally special-
ized to prime a Th2 pattern of cytokine production.
Currently, there exists controversy regarding the
capacity for PDC to produce IL-12 and promote an
IL-12–dependent Th1 response [42].
Other DCs that are located in the dermis are factor
XIIIa+ and called dermal DCs (DDC). Factor XIIIa+
DCs were increased in psoriatic skin [43]. These cells
also have an excellent capacity for antigen capture,
migration, and MHC-restricted presentation to lym-
phocytes. DDCs can be further subdivided into three
subsets: CD1a� CD14�, CD1a+ CD14�, and CD1a�
CD14+ [44]. DCs from psoriatic plaques are able to
present to and activate T cells [44,45], concurrently
producing IL-12 and potentially setting up a local type
1 immune response that is perpetuated rather than self-
limited. Psoriatic-derived DDCs were able to stimu-
late spontaneous T-cell proliferation and increase IL-2
and IFN-g production compared with blood-derived
or normal skin–derived DCs. There was involvement
of HLA-DR, B7, and leukocyte function-associated
antigen 1 (LFA-1). There are also activated macro-
phages in psoriatic tissue [46], which may represent a
source of blood-derived APCs. The presence of ma-
ture epidermal and dermal DCs, defined by CD83,
DC-lysome– associated membrane protein (DC-
LAMP), and CD11c positivity [3], supports the con-
cept of the psoriatic lesion becoming more like
peripheral lymphoid tissue, capable of initiation and
maintenance of inflammation. This concept will be
further discussed later.
The study of the actions and role of DCs in disease
states is complicated because there is no uniform
method for generating sufficient quantities of DCs
for study in vitro, and the relationship between these
DCs derived from blood or bone marrow with in vivo
DCs is not yet fully understood. IFN-g can act to
stimulate uncommitted myeloid immature DCs to
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369354
produce IL-12 and polarize toward Th1 responses
[47]. An alternative method to study cutaneous DCs
is to culture skin biopsy specimens, which yield DC
‘‘crawl outs’’ [45]. In addition, epidermal and dermal
cell suspensions can give rise to DCs suitable for
surface phenotype analysis or functional studies. Al-
though clinicians still have much to learn about the
roles of different DC subsets in the regulation of
normal and pathogenic immune responses, the DC
repertoire in psoriasis is likely to regulate T-cell
activation and clonal expansion by conventional anti-
gen-presenting mechanisms and type 1 T-cell devia-
tion by cytokines such as IL-12 and IL-23 (see Fig. 3).
In addition, DCs are likely to contribute nitric oxide
(NO) to the inflammatory environment, because in-
ducible NO synthetase (iNOS) is highly up-regulated
in activated DCs, and NO even has been postulated as
a psoriasis-triggering factor [48]. Hence, DCs may be
as important in the maintenance of pathogenic immu-
nity in psoriatic plaques as T cells.
Innate immunity in psoriasis
Despite all the evidence reviewed previously, there
are also data to suggest that the innate immune system
is activated in psoriasis and may play an important
contributory role. Cellular and noncellular compo-
nents of primitive innate immunity give an immediate
or very fast proinflammatory cutaneous response to
microbial infection or nonspecific stimuli, such as
trauma [49]. Leukocytes that contribute to innate
immunity possess several types of pattern recognition
receptors (PRRs) that are individually nonpolymor-
phic, as opposed to adaptive responses where these
receptors are individually variable (eg, TCRs). Pro-
inflammatory molecules and cytokines, such as IL-1
and TNF-a, may be released from keratinoyctes,
macrophages, or DCs, activating endothelial cells
and recruiting additional leukocytes to the site of
inflammation. Pathogens are eliminated by mecha-
nisms such as superoxide anion release, defensins,
phagocytosis, and NK-cell killing. Tissue repair in
the skin is associated with additional changes, such
as epidermal hyperplasia and erythema, but these
changes reverse as homeostasis is restored.
TNF-a is an important cytokine of the innate
immune system, and recent beneficial clinical trials
with anti–TNF-a agents [50] point to its considerable
role in psoriasis. This cytokine may be produced by
many cells, including activated keratinocytes, in re-
sponse to nonspecific injury or stimulation. It induces
complex inflammatory cascades, initially by altering
endothelial cell adhesion molecules, causing neutro-
phil and NK-cell recruitment and stimulating produc-
tion of other cytokines by means of the NFkB pathway
[51]. There is convergence of the TNF-a and IFN-gsignaling pathways mediated by a composite GAS/kBpromoter element, leading to induction of regulatory
components of the IFN-g pathway [30].
Introduction of NK cells to an innate cutaneous
immune response provides a back-up system to the
previously mentioned keratinocyte reaction. NK cells
are bonemarrow–derived large granular lymphocytes,
which make up approximately 10% of circulating
peripheral blood lymphocytes, and probably initially
developed as an early host response to viral infection.
NK cells lack CD3 and T-cell receptor proteins but can
be identified by the following surface markers
(reviewed in reference [52]): CD2+, CD16+, CD56+,
CD57+, CD94+, CD158a+, and CD161. Although
there are diverse NK cell activation stimuli, including
IFNs, cytokines such as TNF-a, IL-2, and IL-15,
chemokines, and membrane-bound molecules on sur-
rounding tissues, effector function is tightly regulated.
NK cells possess low-affinity FcgRIII (CD16),
which enables them to perform one of their hallmark
functions, antibody-dependent cellular cytoxicity, to-
ward cells coated with antibody fragments. They do
this by the release of granzyme and perforin. NK cells
also have an additional function of specific NK-cell
cytotoxicity. NK cells can recognize ubiquitous sur-
face molecules on normal cells by means of receptors
known as killing activating receptors, or KARs. If the
target cell possesses MHC molecule, a killing inhibi-
tory receptor (KIR) is engaged and no attack takes
place. In abnormal cells, however, such as some
virally infected cells or tumor cells that lack MHC
molecules, the KIRs are not activated and perforin
and granzyme are released from the NK cell to effect
target cell death. Another important function of NK
cells is the early production of IFN-g, which may
augment immune responses to deal with the inflam-
matory stimulus. Most studies have shown NK cells
to be increased in psoriatic tissue [53,54] and de-
creased in the circulation [55].
An alternative mechanism to cause type 1 T-cell
activation is by the addition of proinflammatory
cytokines from other cells, such as DCs or keratino-
cytes. A recent important observation is that there is a
TCR-independent process whereby IL-12 can syner-
gize with IL-18 or IL-1b to stimulate production of
IFN-g from T cells by activating transcription factor
GAAD45b [56,57]. IL-18, previously known as IFN-
g–inducing factor, can also stimulate NK-cell IFN-gproduction and cytotoxicity. IL-18 and IL-1b can
both be produced by keratinocytes and macrophages,
monocytes, DCs, and T cells [58]. This finding
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369 355
provides a mechanism to explain type 1 T-cell acti-
vation and cytokine release in the absence of TCR
engagement, and NK-cell activation.
A model that encompasses the presence of lym-
phocytes and DCs without antigen-specific TCR en-
gagement would require the activation of DCs
by means of non–antigen-specific mechanisms. This
would lead to release of inflammatory mediators, such
as IL-12, and lymphocyte activation and proliferation.
Recent genomics data suggest that DCs may produce
T-cell–activating IL-2 [59]. DCs do bear PRRs for
microbial antigens, which can lead to lymphocyte acti-
vation. Examples of such receptors include the fol-
lowing: mannose receptors; CD14, which binds LPS;
heat shock protein (HSP) receptors, such as CD91;
and Toll-like receptors (TLRs). Engagement of such
PRR causes DC activation, leading to a cytokine
environment that encourages Th1 or Th2 T-cell de-
velopment, depending on the nature of the stimulus.
TLRs are a recently described set of innate im-
mune receptors first discovered based on their ho-
mology with the Drosophilia melanogaster ortholog
protein, Toll. There are currently 10 described TLRs,
with specific ligands for each one, some having more
than one ligand (reviewed in reference [60]). For
example, the respective binding ligands for TLR2,
TLR3, TLR4, TLR5, and TLR9 are as follows: gram-
positive bacterial components, double-stranded RNA,
lipopolysaccharide, bacterial flagellin, and bacterial
CpG DNA. TLR signaling induces APC activation
and maturation, proinflammatory cytokine produc-
tion, such as TNF-a and IL-6, and increased expres-
sion of costimulatory molecules. Ligation of TLR
may induce a type 1 or type 2 cytokine response,
depending on the stimulus. Engagement of TLRs
may also lead to peptide loading of MHC class II
molecules in DCs, with enhancement of CD4+ T-cell
responses [61].
These TLRs are mainly expressed on professional
APCs and endothelial and epithelial cells. Studies
have revealed different patterns of TLR expression in
normal skin. Keratinocytes constitutively express
TLR1, TLR2, TLR4, and TLR5; DCs and DDCs
demonstrate TLR1 and TLR 4; and DDCs also
express TLR2 [62,63]. In psoriasis, there is increased
basal keratinocyte expression of TLR1, TLR2 is
mainly expressed by DDCs, and TLR4 is found on
epidermal DCs and DDCs with mid–epidermal-layer
keratinocytes displaying cell surface staining [62,63].
The alteration of TLRs in psoriasis points to their
possible role in activating DCs and keratinocytes,
leading to T-cell activation independent of the TCR,
which implies the significance of the innate immune
system in the psoriatic lesion.
HSPs are another conserved innate immune mech-
anism which may be involved in skin inflammation
(reviewed in reference [64]). HSPs are abundant,
intracellular, monoallelic proteins that can bind anti-
genic peptides generated within cells. They then
ligate a common receptor CD91 (a2-macroglobulin
receptor) and other receptors found predominantly on
APCs. This process initiates a cascade of innate
events, the earliest of which may be NFkB activation.
Ligation of HSP receptors then leads to secretion of
proinflammatory cytokines (eg, TNF-a, IL-12, IL-1b,and granulocyte macrophage-colony stimulating fac-
tor), chemokine secretion, production of iNOS and
NO, and DC maturation and migration to local lymph
nodes. HSPs may also chaperone their bound pep-
tides for MCH presentation and cross-presentation
and the generation of CD4+ and CD8+ responses.
HSPs 27, 60, and 70 have been found in psoriatic
epidermis. CD91 and other HSP binding receptors are
present on DDCs and fibroblasts (but not keratino-
cytes) in normal skin. DDCs up-regulate their CD91
expression in psoriatic lesions [63].
Nickoloff [65] has proposed an alternative theory
that the primary psoriatic abnormality is in keratino-
cyte response to injury. Normally, nonspecific cutane-
ous stimuli cause keratinocytes to desquamate and
release the contents of their lamellar bodies (pre-
formed lipid and hydrolytic enzymes), IL-1a and
TNF-a. Overall, there is an effort to repair the epider-
mal barrier and maintain cutaneous homeostasis. In
genetically predisposed patients, however, a psoriatic
plaque develops, which, although disfiguring, pro-
vides ongoing resistance to infection. The current
authors have previously reported numerous molecular
similarities between psoriatic lesional epidermis and
acute healing wounds. One idea that bridges these
views is that leukocyte trafficking into the epidermis
induces direct injury to the basement membrane zone
and desmosomes, triggering an exuberant and unnec-
essary wound-healing reaction [1,66,67].
Is psoriasis a disease caused by overlap of innate
and acquired immunity?
The suggestion that the innate immune system
alone can fully explain psoriasis is probably simplis-
tic because it does not take into account clonal
population of T cells, disease transfer by bone mar-
row transplantation [68], resolution of psoriasis after
bone marrow transplant [69], or the beneficial effects
of anti–T-lymphocyte therapies. Trying to separate
the pathogenesis of psoriasis into the innate or
acquired immune system is therefore somewhat arti-
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369356
ficial, for there is clearly cross-talk between cells,
mediators, and receptors of these two systems.
TLRs and HSPs are innate system components
that may facilitate type 1 cytokine production. CD91
ligation by HSP plus peptide may generate antigen-
specific responses. Several cellular components may
also link these two systems: the NK-T cells because
they possess cell receptors classically linked to both
systems (discussed further later); DCs because they
may be activated in both antigen-specific and non-
antigen-specific ways to bring about T-cell activation
and type 1 cytokine release; and cytokines, such as
IFN-g and TNF-a, which may be produced by
leukocytes of both systems and may be the final
common pathway for the development of psoriatic
lesions. An alternative possible theory to unite these
two systems is that the innate system is responsible
for the initiation of psoriatic lesions, but during this
process, neoautoantigens become exposed and the
acquired system becomes involved to maintain a
newly developed plaque. Alternatively, a bacterial
antigen or superantigen could initiate the psoriatic
response, which becomes self-perpetuating in the face
of the psoriatic cutaneous microenvironment.
NK-T cells are a recently discovered subpopula-
tion of NK cells that may play an important role in
autoimmune diseases. They are called NK-T cells
because they bear NK-cell receptors, such as CD161.
They and a TCR with an invariant and highly
conserved a chain, Va24, and the b chain is usually
Vb11 [70]. NK-T cells can be identified by the
following surface markers: CD3, Va24, CD56,
CD94, and CD161, and represent less than 1/1000 pe-
ripheral blood lymphocytes in healthy individuals.
Gene rearrangement is not required for their dif-
ferentiation or function. These cells specifically
recognize CD1d+ cells presenting a glycosphingo-
lipid antigen, a-galactosyl ceramide (a-GalCer). It isnot yet determined if a-GalCer is the natural ligand
for these cells, but perhaps this or a similar antigen is
unveiled during cutaneous tissue damage. The non-
polymorphic MHC class I molecule CD1d is found in
normal skin on upper level keratinocytes at a low
level of expression [71] and also on dermal DCs [72].
NK-T cells seem to have several functions: per-
forin/granzyme or fas-mediated cell killing, antiviral
properties, and the capability to produce large
amounts of type 1 and type 2 cytokines. NK-T cells
are a heterogeneous population and distinct subsets
have now been identified. In activated lymphocytes
of healthy adults, CD4+ NK-T cells (defined by
a-GalCer loaded CD1d-tetramer+ and Va24+ cells)
can produce type 1 and type 2 cytokines. However,
the CD4� (CD4�CD8� and CD4�CD8+) NK-T cells
only demonstrate a type 1 cytokine profile (IFN-g andTNF-a) [73,74]. These two populations also demon-
strate different chemokine receptors, integrins, and
NK receptor expression patterns. Cell surface markers
now have been identified to distinguish these two
populations of NK-T cells, with IL-18R being present
on type 1 cytokine-producing cells and ST2L
expressed on type 2 cytokine-producing cells [75].
There have been few studies analyzing NK-T cells
in psoriasis. CD161+ cells seem to be increased in
lesional psoriatic tissue [54,71], but these could be
NK, NK-T, or T cells. There may be a decrease [76] or
increase [75] in NK-T cells in the peripheral circula-
tion; this finding may depend on the surface markers
used to classify the NK-T cells (eg, CD3+ CD56+
versus CD161+ Va24+, respectively). It is not yet
possible to determine if an increase in the tissue is
simply caused by a decrease in the circulation. NK-T
cells did increase slightly with various successful
antipsoriatic treatments, although not to control levels,
and in vitro anti–CD3-activated NK-T cells could not
be detected [76]. These authors hypothesized that an
NK-T cell deficiency is a characteristic and intrinsic
abnormality in patients with psoriasis, and that this
deficiency leads to an imbalance in type 1 and type 2
cytokine profiles, with the excessive activation of type
1 responses leading to autoimmunity. Similarly, a
genetically predisposed excessive NK-T cell response
to infection could trigger psoriasis [65].
Increased CD1d expression is also found through-
out the epidermis in psoriatic tissue. In a positive
feedback loop (shown in vitro), IFN-g treatment of
keratinocytes could induce CD1d expression, which
activates NK-T cells and increases IFN-g production
[71]. A CD94/CD161+ NK-T cell line from a patient
with psoriasis (established by IL-2 and superantigen
stimulation) could be cocultured with CD1d+ kerati-
nocytes and give rise to high levels of IFN-g and
IL-13. This process could be inhibited by anti-CD1d
monoclonal antibodies [77]. This production of both
type 1 and type 2 cytokines suggests that this
NK-T cell line was CD4+. It would be helpful to
know the conditions that encourage development of
different cytokine-producing NK-T cells. Further
work is needed to determine whether NK-T cells
defined by strict criteria, such as Va24+ Vb11+,are genuinely increased in psoriasis lesions.
How can the phenotype of chronic psoriasis be
explained?
The usual response of the skin to an antigenic
stimulus is for an immature DC to acquire the antigen
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369 357
through constant sampling of the environment, mi-
grate to the local draining lymph nodes, mature with
up-regulation of costimulatory markers, and activate a
naıve antigen-specific T cell. Depending on factors
such as the cytokine microenvironment, Th1 or Th2
cytokine profiles are produced. Antigen-specific lym-
phocytes clonally expand and develop additional skin
homing receptors, which allow them to bind to selec-
tins (eg, CLA+ binds to E- and P-selectin) for initial
tethering and rolling on cutaneous endothelial cells.
Locally produced chemokines cause up-regulation
of T-cell integrins, such as LFA-1 and very late
antigen-4, or VLA-4, for fixed lymphocyte-endothe-
lial cell adhesion, chemotaxis, and extravasation of
lymphocytes into the dermis. Up-regulation of integ-
rin aeb7 on CD8+ T cells allows them to bind to
E-cadherin on keratinocytes with subsequent infiltra-
tion into epidermis. ICAM-1 is often up-regulated on
activated keratinocytes, which can also interact with
lymphocyte LFA-1. Antigen-specific CD4+ and
CD8+ T cells are finally present in the skin, producing
cytokines and inflammatory mediators, ultimately
leading to antigen eradication.
Fig. 5. Epidermal hyperplasia in psoriasis may result from keratino
The pathways diagram inductive effects of IFN-g and TNF-a on ex
keratinocytes. MIG, IP-10, and I-TAC stimulate intraepidermal tr
disrupts the basement membrane and traumatically severs de
Regenerative epidermal hyperplasia may result from physical inj
from the process of IFN-regulated inward migration of leukocytes
In psoriasis, however, the process becomes a
chronic one. Development of lesions requires initia-
tion and maintenance steps. The classic antigen-
driven process just described may indeed take place,
but until a specific antigen is conclusively defined,
other mechanisms must be explored. And although
antigen may initiate the process, physicians need to
be able to explain the chronicity of psoriatic plaques.
There is some evidence that the skin in psoriasis may
actually behave focally like peripheral lymphoid
tissue, which may be a primary or secondary event.
First, psoriatic blood vessels possess the morphology
and cell surface markers found on lymph node high
endothelial blood vessels (HEVs), such as L-selectin,
CD31, CD34, and peripheral lymph node addressin
[1,78]. Second, lymphoid-organizing chemokines
CCL19 and CCL21, and the Bonzo receptor ligand
(CXCL16) recently have been shown to be elevated
in psoriasis [26]. Such factors may help organize
T-cell/DC infiltrates in secondary lymphoid tissues
and produce ‘‘autoimmune’’ inflammation [79].
Third, there are abundant aggregates of T cells and
mature DCs (CD83+/DC-LAMP+) within psoriatic
cyte injury produced by IFN-regulated leukocyte migration.
pression of adhesion molecules and chemokines in epidermal
afficking of CXCR3+ CD8+ T cells. The inward trafficking
smosomes from adjacent connections on keratinocytes.
ury to the basement membrane or keratinocyte membranes
.
Fig. 6. Epidermal mononuclear leukocyte trafficking in
psoriasis. Electron micrographs of lesional psoriatic skin
showing mononuclear leukocyte trafficking through the
epidermis (stars), severing desmosomes on adjacent kerati-
nocytes (arrows). This injury, in conjunction with local
inflammatory cytokines, may initiate a pattern of epidermal
repair and hyperplasia.
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369358
lesions that develop spatial arrangements similar to
secondary lymphoid tissue [3]. Keratinocytes may
also play a role in the maintenance of lesions be-
cause once there is an inflammatory cytokine milieu,
keratinocytes up-regulate surface markers such as
ICAM-1 and MHC class II molecules for further sti-
mulation of memory CD8+ and CD4+ T cells. In
addition, keratinocytes may produce inflammatory
cytokines, such as TNF-a, that play a role in DC acti-
vation and maturation. As discussed previously, there
is also persistent T-cell activation in psoriatic tissue
[6], which is able to respond to local, activated APCs.
How do these changes lead to the phenotype of
psoriasis? The major histopathologic features that
need explaining are marked T-cell infiltrate, psoriasi-
form hyperplasia, dilated blood vessels filling the
elongated dermal papillae, increase in mature DCs,
and neutrophil accumulation. An important trigger
for keratinocyte hyperplasia may actually be injury
caused by the passage of lymphocytes through the
epidermis, severing desmosomes as they move
(Fig. 5). Electron micrographs of lesional epidermis
show support for this concept (Fig. 6). As the
desmosomes are disrupted, a pattern of epidermal
repair with keratinocyte hyperplasia may ensue. Oth-
er cytokines may be contributing, such as IL-20
release from dermal macrophages [80], or IFN-g.How does IFN-g contribute to epidermal hyper-
plasia? Conditioned media from CD8+ Tc clones
from psoriatic skin specimens had either proliferative
or antiproliferative effects on keratinocytes, and both
effects were reversed by antiserum to IFN-g [14].
Previous studies, however, have shown that IFN-ghas suppressive in vitro effects on keratinocytes [81].
It is likely that the array of keratinocyte-stimulating
cytokines (Table 1) made in injured skin, such as
transforming growth factor a (TGF-a), amphiregulin,
insulin-like growth factor 1 (IGF-1), and keratinocyte
growth factor (KGF), override any suppressive ef-
fects of IFN-g, resulting in epidermal hyperplasia.
IFN-g may be a key inducer of the overall injury
response pathway, because IFN-g–induced keratino-
cyte production of the chemokines MIG, IP-10,
and IFN-inducible T-cell a chemoattractant (I-TAC)
would set up a chemotactic gradient that regulates
migration of CD8+ T cells bearing CXCR3 into
the epidermis.
The blood vessel changes may be more easily
explained by vascular endothelial cell growth factor
(VEGF) and NO, which cause neovascularization
and dilatation of blood vessels, respectively [82,83].
The most likely candidate for neutrophil chemotaxis
is IL-8, a cytokine that is released by many cells,
including psoriatic keratinoyctes, as an early proin-
flammatory response [84]. There are other cytokines
and inflammatory mediators that may contribute to
the phenotype of psoriasis, which have not been
discussed in this article; these are listed in Table 1.
How do murine models help physicians to
understand the pathogenesis of psoriasis?
There are quite a few ‘‘psoriasis’’ mouse models
with knockouts or overexpression of important epi-
dermal and immune components. One fundamental
problem with these models, however, is that human
epidermis is structurally different to murine, which
Table 1
Changes in cytokines and growth factors with their receptors
in psoriatic lesions
Cytokines and
growth factors/receptors Effect Reference
Inflammatory cytokines
IL-1a +, �, F [101–104]
IL-1b +, � [101–104]
IL-2 + [18,19]
IL-2Ra(CD25) + [21]
IL-6 + [105–108]
IL-7 + [109]
IL-12 + (p40, p70)/
F (p35)
[20,110]
IL-12Rb2 + [21]
IL-15 + [111]
IL-17 + [112]
IL-18 + [58,113]
IL-20/IL-20R +/+ [80,114]
IL-23 + [26]
TNF-a + [115,116]
IFN-g/IFN-gR +/+ [18,19,31,
117,118]
MIF + [119,120]
Inhibitory cytokines
IL-1RII + [121]
IL-1RA +, �, F [121–123]
IL-4 � [18,124]
IL-5 +, F [18,124]
IL-10 F, � [18,110,125]
IL-11 + [106]
IL-13/IL-13R F/+, � [126]
TGF-b +, �, F [127–129]
Hematopoietic cytokines
IL-3 + [124]
GM-CSF + [18,130]
LIF + [131]
OSM + [131]
Chemokines
IL-8/CXCR2 +/+ [26,106,
132–136]
GROa + [26,135–137]
IP-10 + [26,138]
MIG + [26,139]
I-TAC + [26]
MIP3a/CCR6 +/+ [26,140]
RANTES + [141]
MCP-1 + [26,142]
TARC + [8]
MDC + [8,26]
CTACK/CCR10 F, �/+ [26,143]
MIP3b + [26]
SLC + [26]
SDF-1 + [26]
PARC + [26]
Table 1 (continued )
Cytokines and
growth factors/receptors Effect Reference
Chemokines
Bonzo receptor
ligand
+ [26]
ENA-78 + [26]
EMAPII + [26]
HCC-1 � [26]
Keratinocytes/tissue growth factors
TGF-a/amphiregulin/
EGF-R
+/+ [128,144–147]
PDGF-R + [148]
IGF-1R + [149]
KGF/KGF-R +/+ [150]
NGF + [151,152]
bFGF + [153]
Angiogenic factors
VEGF/VEGF-R +/+ [154]
Angiopoitin/tie 2 +/+ [155]
ET-1 + [156]
Angiogenic inhibitors
Thrombospondin � [133]
Abbreviations: bFGF, basic fibroblast growth factor;
CTACK, cutaneous T-cell – attracting chemokine; EGF,
epidermal growth factor; EMAPII, endothelial monocyte–
activating polypeptide II; ENA-78, epithelial cell-derived
neutrophil attractant 78; ET-1, endothelin 1; GM-CSF,
granulocyte machrophage-colony stimulating factor; GRO-
a, growth-regulated oncogenea; HCC-1, hemofiltrate CC
chemokine1; LIF, leukemia inhibitory factor; MCP-1;
monocyte chemoattractant protein 1; MDC, macrophage-
derived chemokine; MIF, migration inhibition factor; MIP,
macrophage inflammatory protein; NGF, nerve growth
factor; OSM, oncostatin M; PARC, pulmonary- and
activation-regulated chemokine; PDGF, platelet-derived
growth factor; R, receptor; RA, receptor antagonist;
RANTES, regulated upon activation normal T expressed
and secreted; SDF-1, stromal cell-derived factor 1; SLC,
secondary lymphoid tissue chemokine; TARC, thymus- and
activation-regulated chemokine; +, increase; �, decrease;F,
no change.
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369 359
makes extrapolation to human skin disease difficult.
In human skin, there is a clear difference in kerati-
nocyte differentiation of the outer root sheath of the
hair follicle and the interfollicular epidermis. Perifol-
licular ‘‘epidermis’’ is keratin 16-positive (K16+) and
connexin 26+, and in effect represents outer root
sheath differentiation, whereas normal interfollicular
epidemis is K16� and connexin 26�. In psoriasis,
interfollicular epidemis changes to become more
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369360
perifollicular-like. But in the mouse, there is less
difference between these two structural areas, and
they are K16�, connexin 26+. Normal murine epi-
dermis is much thinner than normal human interfol-
licular epidermis, with many fewer cell layers.
Clinicians therefore need to be careful describing a
skin lesion in a knockout or transgenic mouse psori-
asis when the murine epidermis already has some
features of this condition, such as connexin 26 posi-
tivity. Another important consideration in the use of
single- or even double-gene manipulations is that
they do not usually reproduce the complete pheno-
type of psoriasis, which is a polygenic disease
[85,86]. Possibly even more important, none of the
transgenic models expresses the primary genes of
psoriasis susceptibility loci and are all downstream
of primary genetic events.
Perhaps the most relevant models are those that
produce regulatory alterations in immune pathways
or other cell growth responses. There is an interesting
murine model of psoriasis: the IFN regulatory factor
2 (IRF-2) knockout mouse [87]. IRF-2 can be in-
duced by IFN-a/b and IFN-g [88] and has a predom-
inantly negative regulatory effect on IFN-a/b–activated IFN-stimulated gene factor 3 (ISGF3).
ISGF3 is a heterotrimer consisting of STAT1, STAT2,
and IFN regulatory factor 9 (IRF-9, p48). Deletion of
the IRF-2 gene caused overexpression of IFN-a/b–inducible genes and led to an erythematous inflam-
matory skin disease with some histopathologic fea-
tures of psoriasis. This includes epidermal acanthosis,
activation of keratinocytes (ICAM-1+), infiltration of
both CD4+ and CD8+ T cells into the basal dermis,
and some CD8+ T cells into the epidermis. There
were additional features not suggestive of psoriasis,
such as alopecia, excoriations leading to ulceration,
and a disorganized muscle layer with associated
fibrosis. Experimental depletion of CD8+ T cells
significantly delayed the onset of skin disease, and
these CD8+ T cells were hyper-responsive to antigen
stimulation, as are psoriatic T cells. There was a
marked polyclonal increase in the population of
memory CD8+ T cells in these mice, and lymphade-
nopathy developed as the skin disease progressed.
Furthermore, not only was there overexpression of
genes usually induced by IFN-a/b by means of
ISGF3 (oligoadenylate synthetase and IRF-7) but
there was also increased cutaneous expression of
genes known to be primarily controlled by IFN-g(MIG and IP-10). The introduction of additional
mutations in IRF-9 in these IRF-2 knockout mice
abrogated the skin disease, genetic overexpression,
and T-cell hyper-responsiveness. Because there is
overlap between the effects of type I and II IFNs,
this model supports the role of overexpression of
IFNs and IFN-related genes in the development of a
psoriasis-like skin disease. In comparison, a study of
transgenic mice with overexpression of epidermal
IFN-g resulted in keratinocyte hyperproliferation,
MHC class II and ICAM-1 induction, and dermal
capillary enlargement. Although there was a dermal
T-cell infiltrate, however, there were no epidermal T
cells [89]. Clinically, there was an ezcematous pro-
cess with hair hypopigmentation and alopecia.
Overexpression of epidermal VEGF (VEGF trans-
genic mouse under-expression of K16 promoter) [86]
led to a psoriatic phenotype at 3 months with wound-
ing (similar to the Koebner phenomenon), or sponta-
neously at 6 months. These mice demonstrated
epidermal hyperplasia with hyperkeratosis, parakera-
tosis, and K6 expression. There was a leukocyte
infiltrate very similar to human psoriasis with neu-
trophil microabscesses within and beneath the stra-
tum corneum, dermal CD4+ T cells, epidermal CD8+
T cells, mast cells, and macrophages. There were
dilated and tortuous dermal papillae blood vessels
with up-regulation of adhesion molecules, such as
ICAM-1, E-selectin, VCAM-1, and platelet-endothe-
lial cell adhesion molecule 1, or PECAM-1. An anti-
VEGF monoclonal antibody (VEGF Trap) was effec-
tive in reversing spontaneous changes of psoriasis
unless the mice developed neutralizing antibodies to
this treatment. High serum levels of E-selectin, a
surrogate marker of disease activity in human disease
and in this K16-VEGF transgenic mouse, were also
reversed by VEGF Trap. Exactly how epidermal
chronic overexpression of a potent angiogenic factor
leads to psoriasis is not yet understood; perhaps it
diffuses to the dermis and primarily creates inflamed
blood vessels, which attract inflammatory leukocytes
and allow cytokine and chemokine changes that lead
to secondary epidermal alterations seen clinically as
psoriasis. VEGF antagonists are obviously an in-
teresting therapeutic modality to investigate further
in patients with psoriasis.
Another useful model to study psoriasis used a
xenotransplant concept, with human skin of varying
clinical types grafted to immunodeficient mice, which
fail to reject it. Initial studies used nude or athymic
mice, which are deficient in T cells. In these mice,
infiltrating human T cells are eliminated from the graft
quite readily. Subacute combined immunodeficiency
(SCID) mice fail to rearrange variable-diversity-join-
ing (VDJ) segments of B- and T-cell receptors, so
these mice lack both humoral and cellular immunity.
SCID mice still make NK and NK-T cells because
these cells do not require TCR gene rearrangement for
their generation. Recombination activating genes
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369 361
(RAG) knockout mice lack the RAG enzyme, which
is responsible for rearranging TCRs, so these mice
also still have NK and NK-T cells. RAG-deficient
knockout mice now have been generated in conjunc-
tion with deletions of murine type I and II IFN
receptor. Human keratome skin biopsy specimens
have been grafted to these immunodeficient mice
from healthy volunteers, nonlesional skin of patients
with psoriasis, or lesional psoriatic skin. These skin
grafts are allowed to heal and then the mice are
injected with activated human leukocytes to determine
the role of the transplanted cells in the initiation and
maintenance of the psoriatic lesion.
The initial nude mice studies demonstrated that
engraftment of psoriatic skin leads to regression of
histologic and immunologic features of psoriasis,
correlating with elimination of infiltrating human T
cells within the psoriatic skin [90]. Boehncke et al
[91] showed that repeated intradermal injections of
staphylococcal superantigen exfoliative toxin into
grafted nonlesional skin from patients with psoriasis,
along with intraperitoneal administration of autolo-
gous peripheral blood mononuclear cells (PBMCs)
stimulated in vitro with the respective superantigen,
were capable of triggering psoriasis.
Nickoloff et al [92] extended these findings and
continued to develop the SCID mouse model with
injection of activated immunocytes into the graft.
Experiments in 1996 showed that IL-2 and staphy-
lococcal superantigen-stimulated, autologous pe-
ripheral blood-derived immunocytes were able to
induce psoriasis in nonlesional skin of patients with
psoriasis [93]. They next showed that psoriasis could
be induced in normal skin with similarly activated but
allogeneic blood-derived psoriatic immunocytes in
three of six patients [94]. Graft versus host disease
would be expected in this context, but this condition
only developed in one of six transplants. In two
patients, the authors looked at the surface markers of
the human cells in the graft and found that many
possessed NK surface markers (CD94, CD158a,
CD158b, NKB1, and CD161) [95]. They next further
characterized the immunocytes: injection of en-
grafted nonlesional psoriatic skin with activated
CD4+ T-cell lines could induce psoriasis in five of
five cases and in none of five cases, with CD8+ T-cell
lines [53]. Cells with NK markers accumulated early
in the lesion. However, it is difficult to appropriately
activate and differentiate epithelial homing CD8+
T cells in vitro. Finally, the authors characterized a
T-cell line from a psoriatic patient that was capable
of initiating psoriasis in a nonlesional psoriatic skin
graft and demonstrated CD4+ NK-T cell markers
(CD94+, CD161+, Va24�, Vb11+) [77]. A Th1 po-
larized cytokine profile was evident in the lesion
(IFN-g and IL-15).
Gilhar et al [96] also performed early experiments
with SCID mice, demonstrating that intradermal or
intravenous injection of autologous lesional T cells
(cultured for 1 month with IL-2, APCs, and keratino-
cytes) were able to maintain psoriatic grafts. This
group wanted to explore induction of psoriasis using
these IL-2–activated T cells rather than superantigen-
stimulated lymphocytes, and they next used beige-
SCID mice, which have less NK-cell activity [97].
The authors cultured PBMCs with IL-2 for 3 weeks
to generate NK and NK-T cell lines (CD56, CD94,
CD158a, CD158b, CD8, CD4, CD3+ CD161+), which
were IFN-g producing and cytotoxic in vitro. Injectionof autologous NK/NK-T cells initiated psoriasis in
nonlesional psoriatic skin. Unlike Nickoloff’s group,
however, they did not find that that injection of
allogeneic T cells caused psoriasis in nonlesional
psoriatic skin or normal grafts; rather, in these con-
ditions, a psoriasiform dermatitis was seen.
Finally, in a new model using RAG and IFN
receptor–deficient mice, nonlesional psoriatic skin
spontaneously converted to psoriasis in 29 of 30 grafts
[98]. There was an absence of circulating human or
mouse lymphocytes, with up-regulation of HLA-DR
and CD91. CD91 ligands were also present (HSP 27
and 70), and CD91+ cells were adjacent to CD91
ligand-positive keratinocytes. There was expression
of NFkB and TNF-a production, and the effect was
abrogated with anti–TNF-a antibodies in eight of
nine mice. Subsequent work showed blockage of this
effect by CD3 antibodies [99], thus this model is also
T-cell dependent. This finding does not rule out an
important role for IFN-g, because human IFN-g may
still be produced by the graft and react with IFN-greceptors present on engrafted human psoriatic skin.
This is an important report because this is the first
experiment to show that psoriasis could develop
spontaneously in grafts of nonlesional psoriatic skin
without injection of exogenous lymphocytes. This
finding suggests that resident immunocytes are able
to proliferate in situ depending on the local environ-
ment to initiate a lesion, and that once skin homing
(CLA+) memory cells have developed, lymphocyte
trafficking may not be required.
What do recent genomics data add?
Three large-scale analyses of psoriatic disease–
associated genes (mRNA expression) have been pub-
lished recently [26,67,100]. These analyses differ
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369362
primarily in their use of various gene chips, with each
study examining an increasingly greater number of
known genes, but also in the samples tested and
approach to analysis. These experiments are not
simple to evaluate because they generate such large
data sets and require specific analytic approaches,
such as hierarchical clustering, nonhierarchical clus-
tering (eg, self-organizing maps [SOMs]), functional
clustering, and principal components analysis (re-
viewed in reference [59]). This line of research will
yield important information and enable further under-
standing about the pathogenesis of skin diseases,
clinical response, and drug mechanisms.
The first study used arrays containing 7000 genes
[67]. An unsupervised cluster analysis approach was
taken, where samples were clustered based on a
hierarchical correlation coefficient (ie, fold change).
Gene expression frequency patterns of normal and
uninvolved skin were grouped together, and they were
clearly different to a separate cluster of expression
patterns of lesional skin. A differential statistical
approach was then taken where average frequency of
gene expression values between uninvolved and
lesional skin were calculated and a paired t test was
performed. Transcript levels that were statistically
different with a confidence level of 95% or greater
were initially identified (426 genes), and this number
was subsequently refined to 159 genes when only
those whose transcript levels differed on average by
twofold or greater were selected. Thus, a disease
classification set for chronic plaque psoriasis was gen-
erated, and these genes could be categorized into di-
verse functional groups. These include transcriptional
regulation, metabolic control, protein processing,
intracellular signaling, cell cycle control, lymphocyte
regulation, and extracellular matrix destruction. Genes
previously known to be differentially expressed in
psoriasis included transcripts such as psoriasin
(S100A7), fatty acid–binding protein (FABP5), elafin
(SKALP, P13), retinoic acid – binding protein
(CRAB2), squamous cell carcinoma antigen (SCCA),
b defensin-2 (DEFB2), keratin 17 (KRT17), and
keratin 16 (KRT16). There were also new genes in
these lists including S100A12 (calgranulin C, EN-
RAGE), matrix metalloproteinases (MMP-12), and
heparin-binding protein 17 (HBP-17). The signifi-
cance of differential expression of many of these
genes will need to be determined in the future.
Findings of expression differences were con-
firmed by performing immunohistochemical analyses
for protein products and reverse transcriptase poly-
merase chain reaction (RT-PCR) on additional sam-
ples where possible. Oestreicher et al [67] next
examined antigen nonspecific gene responses in
delayed-type hypersensitivity (representing T-cell–
driven responses) and in tape stripping (indicative
of active epidermal regeneration) in healthy volun-
teers, and there was some overlap with psoriasis. The
subtraction of overlapping genes from these two
groups and the psoriatic gene set revealed 94 tran-
scripts that were differentially regulated only in
psoriasis, including S100A12 (calgranulin C, EN-
RAGE), RAGE, and GATA3. Finally, the authors
performed similar analyses in samples collected be-
fore, during, and after two immunomodulatory pso-
riasis treatments, comparing expression levels in
lesional skin of the previously identified 159 genes
in responders versus nonresponders. Treatment was
either with the Th2 cytokine IL-11 (which restores
Th1 and Th2 imbalance partially through inhibition
of NFkB nuclear translocation) or cyclosporin A
(which has a T-cell inhibitory effect through blockade
of calcineurin/nuclear factor of activated transmis-
sion IL [NFAT] and p38/JNK signaling pathways).
SOMs were used where the level of expression of
the lesional skin before therapy was normalized to a
value of 1 and the change in expression of the
159 gene set over the course of treatment was
calculated relative to this baseline level. Four patterns
of expression could be identified in responding pa-
tients, with no such change noted for nonresponders.
In responders, gene sets could be observed that
changed (increased or decreased) quickly before
clinical improvement and between rhIL-11 and cyclo-
sporin A treatment. On termination of either treat-
ment, transcripts returned to pretreatment levels. Of
the 41 gene transcripts that increased quickly with
treatment, 12 can be mapped to five of the six known
psoriasis susceptibility loci.
The second study published the same year used
Affymetrix gene chips (Santa Clara, California) with
12,000 known genes and also used gene-clustering
techniques [100]. These authors found a similar
number of differentially expressed gene transcripts
in psoriasis (177 transcripts) compared with normal
skin, independent of demographics or HLA class I
status. These genes were mostly up-regulated, and
approximately 80% had not been described in psori-
asis previously. Some of the 17 genes that showed the
highest level of expression in involved psoriatic skin
were the same as those previously reported and found
in the previously discussed study. The transcript that
showed the greatest increase was transcobalamin
1 (vitamin B12–binding protein), which is found in
mature neutrophils, suggesting an important role for
neutrophil granule proteins. A complete list of genes
in clusters that differentiate involved skin from nor-
mal skin can be found at http://hg.wustl.edu. Several
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369 363
of these genes have been mapped to regions previ-
ously linked to psoriasis susceptibility.
Using the newer Affymetrix chips containing
63,100 oligonucleotides, the third study further ex-
tended the description of psoriatic gene expression
[26]. The authors used two methods of analysis to
detect differentially expressed genes: first, fold
change combined with t tests comparing differences
in psoriasis and nonlesional and normal skin; and
second, K-means clustering to examine for small fold
changes. A total of 1338 genes were identified, and
these also have been reported on the previously
mentioned Web site. These genes were functionally
categorized according to the Gene Ontology database,
demonstrating disruption of immune and inflamma-
tory responses, response to wounding, response to
pests/pathogens, cell proliferation, the JAK-STAT sig-
naling cascade, cell growth or maintenance, and
several metabolic processes such as NO biosynthesis.
There were 131 genes that were significantly dif-
ferentially expressed (PV 0.05; fold change, > 1.2) in
at least one pairwise comparison among the three skin
groups that were involved in immune signaling. These
were subsequently broken down into three groups:
IL-1 cluster of genes (especially IL-1R antagonists),
those involved in T-cell and DC activation, and che-
mokines in psoriasis. Comparing genes that were
elevated in involved psoriatic skin with normal skin
demonstrated many genes indicative of T-cell activa-
tion, including CD47 (general lineage marker for
blood-derived cells), IL-2Ra, IL-2Rb, CD71, CD69,and IL-7R. Leukocyte integrins LFA-1 (CD11a/
CD18) and Mac-1 (CD11b/CD18), and adhesion
molecules E-selectin, P-selectin, and ICAM were
also elevated. There was up-regulation of genes in-
volved in APC function, such as CD163, CD32,
MHC class I and II, CD83, CD53, and CD24.
Comparison of uninvolved versus normal skin also
revealed some interesting expression changes: un-
involved skin showed increased CD4, CD11c (high-
level expression on monocytes, macrophages, and
NK cells), CD86 (costimulatory molecule), and
CD103 (epithelial homing cells), suggesting a low
level of immune activation.
There were 19 chemokines that were elevated in
this study, including lymphoid tissue chemokines
CCL19 and CCL21. Eleven of these chemokines
had not been previously implicated. CCR7 is the
receptor for CCL19 and it was also overexpressed
(by FACS analysis); its usual role is to allow naıve
and central memory T-cell migration across HEVs
found in lymph nodes. Along with prior reports,
these findings provide evidence for the suggestion
that psoriatic skin behaves as secondary lymphoid
tissue, which could sustain chronic T-cell activation
within focal skin regions. Increased CCL18 may
be important for recruiting naıve T cells to skin
draining lymph nodes, and CXC16 (expressed on
CD11c+ DCs) is important for epidermal recruitment
of CD8+ T cells.
Further analysis revealed the importance of the
IFN-g or type 1 pathway, consistent with the current
authors’ hypothesis that this is a key cytokine in
psoriasis. There was increased expression of the IFN-
g transcript, along with primary IFN-g– induciblegenes TRIM22 and STAT-1, and the chemokines
IP-10 and MIG. In fact, more than 5% of elevated
genes (>60) related to IFN signaling were identified
in this study. Finally, large-scale promoter analysis
demonstrated 13 coexpressed gene clusters and
shared transcription factor–binding sites (TFBS),
including the IFN-g–inducible TFBS motif IRF2-
ISRE (IFN-stimulated response element). A recent
review described 200 genes that are considered to be
regulated by IFN-g in various cell types and lines
[37], and in psoriasis, there are 60 IFN-g–regulatedgenes that can be extrapolated from the literature.
This overlap supports the hypothesis that IFN-g is
functional and produced by activated T cells in
psoriasis; however, it is curious that the overlap is
not more complete. There could be several reasons
for this finding: the chronic process of psoriasis may
result in different gene activation than can be found in
a short-term in vitro analysis; direct IFN-g effects in
skin, an organ rather than cell type or line, have not
been studied; and other cytokines may be inducing
the JAK-STAT pathway rather than IFN-g.
Summary
This article has focused on the innate and acquired
immune systems, their overlap, and the role of these
components in the pathogenesis of psoriasis. Recent
data on mouse models have been presented, empha-
sizing xenotransplant models as more representative
of psoriatic lesions than knockouts or transgenic
mice. Finally, a summary of recent genomics data
in psoriasis was discussed to introduce these impor-
tant studies and the data they generate. The authors’
belief of the importance of IFN-g as a pivotal
cytokine in the initiation or maintenance of psoriatic
lesions has been supported with evidence throughout
the article, while acknowledging that TNF-a plays an
important and probably synergistic role. There are
topics that have not been covered but some of these
are done so elsewhere in this issue, such as the
genetics of psoriasis. The role of specific antigens
M.A. Lowes et al / Dermatol Clin 22 (2004) 349–369364
(autoantigens, superantigens, or microbial antigens)
in triggering or maintaining lesional activity is an-
other area that has not been discussed and requires
further experimentation and attention.
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Dermatol Clin 22 (2004) 371–377
From laboratory to clinic: rationale for biologic therapy
Stephanie Mehlis, MDa, Kenneth B. Gordon, MDb,*
aDepartment of Dermatology, Northwestern University Medical School, 675 N. St. Clair Street, Chicago, IL 60611, USAbDivision of Dermatology, Department of Medicine, Loyola University, Stritch School of Medicine, 2160 South First Avenue,
Building 112, Room 342, Maywood, IL 60153, USA
Although topical therapy can be extremely effec- The pathogenesis of psoriasis
tive in cases of limited psoriasis, systemic therapy is
often needed for severe cases to give patients appro-
priate relief. Traditional systemic medications for
psoriasis include systemic retinoids, methotrexate,
cyclosporin, and psoralen plus UVA. All of these
treatments have well-documented side effects, the
frequency of which increases with increasing length
of exposure [1]. Dermatologists have devised meth-
ods including intermittent and rotational strategies to
avoid these side effects [2].
Because psoriasis is a chronic disease, there has
been an increased demand to develop therapies that
can be used for the lifetime of the patient. The
development of new treatments has been facilitated
by advances in immunology and an increased under-
standing of the basic pathophysiology of the disease.
This information, and the advent of genetic engineer-
ing techniques, has led to the creation of new targeted
medicines termed ‘‘biologic therapies’’ that inhibit
the basic pathologic processes while remaining rela-
tively free of interactions with other organ systems.
These treatments are proteins produced by living
organisms to target specific points of the inflamma-
tion cascade, including antibodies against cell surface
markers, cytokines, and adhesion molecules. This
article discusses the pathogenesis of psoriasis, looks
at the immunologic factors that contribute to form-
ing a psoriatic plaque, reviews how novel biologic
therapies are made, and explores how biologics can
target each of these specific parts of the immuno-
logic cascade.
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/S0733-8635(03)00124-4
* Corresponding author.
E-mail address: [email protected] (K.B. Gordon).
The clinical and histolopathologic presentation of
psoriasis is dominated by the obvious changes in the
keratinocyte of the plaque when compared with
uninvolved skin. The clinical scaling and induration
associated with psoriasis can be seen on biopsy as
parakeratosis, acanthosis, and loss of the granular
layer. Keratinocytes proliferate rapidly, with an eight-
fold shortening of the epidermal cell cycle [3].
Additionally, these cells mature abnormally. These
keratinocyte changes are accompanied by an inflam-
matory infiltrate composed primarily of mononuclear
cells and neutrophils. The lymphocytes are primarily
T cells with a predominance of CD4+ T cells in the
dermis and many CD8+ T cells in the epidermis.
Some of the T cells in the epidermis express natural
killer cell markers and are thought to be resident to
the skin. Additionally, activated Langerhans’ cells,
macrophages, and dermal dendritic cells are present
in the psoriatic plaques.
Animal and human models have helped to clarify
the significance of the inflammatory infiltrate in the
development of psoriatic plaques. Most experiments
have focused on the role of these activated T cells and
the cytokines they produce as the driving force for the
induction and maintenance of psoriatic plaques [4,5].
In a model first developed by Wrone-Smith and
Nickoloff [6], symptomless skin (psoriatic patient/
nonindividual skin [PN]) from a psoriatic patient was
transplanted onto an immunodeficient (severe com-
bined immunodeficiency) mouse. T cells from the
same patient were activated in vitro and then injected
into the xenografted skin. In time, the graft became
histologically identical to skin from a plaque of
psoriasis, complete with keratinocyte and vascular
s reserved.
S. Mehlis, K.B. Gordon / Dermatol Clin 22 (2004) 371–377372
changes. This change did not occur in skin from
patients without psoriasis (non-psoriatic patient/non-
involved skin [NN]) or when the T cells were not
activated in vitro. The introduction of activated T cells
was sufficient to induce psoriasis in genetically
susceptible skin [7].
One question this model does not answer is the
role played by local cells in the skin including resi-
dent T cells and antigen-presenting cells (APC). Re-
cently, a model has been identified that addresses this
issue. Boyman et al [8] have identified a novel im-
munodeficient mouse called the AGR mouse. When
susceptible skin is transferred to the mouse, it spon-
taneously develops into a plaque of psoriasis. This
response can be blocked by the addition of medi-
cations that inactivate tumor necrosis factor-alpha
(TNF-a), a cytokine central to the immune process
in psoriasis. What the results of these experiments
suggest is that local cells in the skin, when properly
activated, may be sufficient in themselves to create a
psoriatic plaque without the requirement of inflam-
matory cells being introduced from the circulation.
Moreover, TNF-a is a major cytokine produced by
APC, including dendritic cells and macrophages. The
activation of these inflammatory cells may play a
major role in the early development of lesions.
Additional evidence for the fundamental role of
the inflammatory response, particularly of T cells,
comes from the efficacy of T cell–specific immuno-
modulation in the treatment of psoriasis. Cyclosporin
has immunosuppressive effects by decreasing prolif-
eration and cytokine production of T cells. It was
incidentally noted to improve psoriatic lesions in pa-
tients on cyclosporin after solid organ transplantation
[9]. Further study has definitively proved that this
T cell–specific medication is extremely effective as a
treatment for psoriasis [10]. Psoralen plus UVA and
UVB have also been shown to deplete affected skin
of T cells [11]. Finally, treatment with biologic agents
that decrease the number of effector T cells in
psoriasis (denileukin diftitox and alefacept) has dem-
onstrated efficacy. Further evidence for the critical
role the immune response plays in psoriasis is shown
by a cure of psoriasis after reconstruction of a pa-
tient’s immune system from an allogenic bone mar-
row transplant, and the development of psoriasis in a
patient who had a bone marrow transplant from a
psoriatic donor [12,13]. All of these therapeutic
results help to prove the important role the T cell
plays in the pathogenesis of psoriasis.
T cells can be classified into two major pheno-
types characterized by the cytokines they produce.
Type 1 helper T cells and cytotoxic T cells (Th1 and
Tc1) secrete interleukin (IL)-2, TNF-a, interferon
(IFN)-g, and IL-18, and stimulate cell-mediated im-
munity and T-cell cytotoxicity. IgE-mediated allergic
and mucosal responses are generated from the type 2
T cells (Th2 and Tc2) through release of IL-4, IL-5,
and IL-13. Cytokines released by type 1 reactions
inhibit type 2 reactions and vice versa [14]. The T cell
response in psoriasis is primarily a type 1 reaction.
Skin in psoriatic lesions has increased TNF-a and
IFN-g compared with nonlesional skin [15] and IL-2
has been shown to flare psoriasis. Moreover, circu-
lating T cells of patients with psoriasis have a higher
ratio of IFN-g to IL-4 than normal patients [16].
These data all help to demonstrate that the T cell–
directed immune response in psoriasis is primarily a
type 1 reaction [17].
T cells and psoriasis
Many of the new biologic treatments of psoriasis
have targeted blocking the inflammatory response
of the T cells. To understand how these therapies
work, an analysis of the steps necessary for T cells to
induce a psoriatic plaque must be understood. For
ease of understanding, this complicated process can
be simplified into three basic steps: (1) the initial acti-
vation of T cells, (2) the migration of T cells into the
skin, and (3) reactivation of the memory T cells and
the magnification of the immune cascade by cyto-
kines on various cells in the psoriatic plaque.
Activation of T cells
T cells must be activated by APC. In the skin, the
APC are Langerhans’ cells that are constantly exposed
to infectious and other protein antigens from the
environment. When Langerhans’ cells are exposed
to an antigen and have an appropriate signal to mature,
they display the peptides from these antigens on either
class I (for intracellular antigens) or class II (for
extracellular antigens) major histocompatibility com-
plex. These mature APC migrate out of the skin and
into the skin’s lymphatic system. It is here that a
mature APC binds to a naıve T cell through adhesion
molecules [18]. One of the first interactions between
these cells is the binding of the leukocyte function-
associated antigen 1 (LFA-1) and its two subunits
(CD11a-CD18) to the intracellular adhesion molecule
(ICAM or CD54) on the APC. Additionally, CD2 on
the T cell binds to LFA-3 on the APC to complete the
initial recognition process [19].
Once bound, there must be a process of antigen-
specific recognition, referred to as ‘‘signal 1.’’ The
major histocompatibility complex presents antigens
S. Mehlis, K.B. Gordon / Dermatol Clin 22 (2004) 371–377 373
on the surface of the APC, and T cells sample
these until there is a ‘‘fit’’ between the antigen-spe-
cific T-cell receptor and the major histocompatibility
complex–antigen complex. The major histocompat-
ibility complex I recognizes the CD3-CD8 T-cell
receptor of cytotoxic T cells, whereas major histo-
compatibility complex II recognizes the CD3-CD4 T-
cell receptor of helper T cells [18]. Binding still plays
an important role in this step, because it keeps the
cells together while the T-cell receptor is sampling
the various major histocompatibility complex–anti-
gen complexes.
The third and final step in T-cell activation is
referred to as ‘‘signal 2’’ or co-stimulation. This is a
not an antigen-specific reaction, but it is necessary for
T-cell stimulation. If antigen recognition takes place
without co-stimulation, the T cell does become active.
In fact, in the absence of co-stimulation the T cell is
forced to die through apoptosis or be rendered unre-
sponsive in the future (anergy). One of the most im-
portant co-stimulatory molecules is CD28 on the
T cell. CD28 binds to both CD80 and CD86 on the
APC (molecules that are up-regulated during matu-
ration). The T-cell receptor and CD28 synergistically
make the T cell produce cytokines that promote ac-
tivation, including IFN-g, TNF-a, and IL-2 [20]. If
this response takes place in the presence of IL-12, the
T cell differentiates into a type 1 cell. The activated
T cell also begins to express the high-affinity IL-2
receptor (IL-2R or CD25) and promotes its own ac-
tivation and clonal proliferation though IL-2 [21].
Other important co-stimulatory molecules include
CD2–LFA-3 and CD40L-CD40 [22–24]. Although
it has traditionally been thought that this initial ac-
tivation step takes place in the draining lymph nodes
of the skin, the AGR mouse suggests that this could
also take place with resident T cells in the skin.
Migration of T cells into the skin
After the initial clonal proliferation of T cells in
the lymph node, most of the newly active cells un-
dergo apoptosis. A minority, however, become mem-
ory cells that express markers like CD45RO and
migrate out of the lymph node and into the circulation
and tissues. For these cells to induce lesions of pso-
riasis, they must migrate to the skin and be reacti-
vated locally. This trafficking back into the skin is yet
another multistep process, this time between the T
cell and the endothelium. Perhaps the most important
of these regulators is the cutaneous lymphocyte
antigen. Cutaneous lymphocyte antigen is a skin-
specific adhesion molecule that binds to selectins
including both E-selectin and P-selection [25,26],
molecules that are greatly up-regulated on endothelial
cells during cutaneous inflammation [27]. This cell-
cell interaction slows the memory T cells in the
bloodstream and allows these cells to undergo a sec-
ond adhesion event called adherence [25,26]. Chemo-
kines secreted in the local inflammatory reaction
induce the T cell to increase expression of the integ-
rin molecules LFA-1 and very late antigen-4. These
molecules bind respectively to ICAM and vascular
cell adhesion molecule-1 on the endothelium and
cause the T cell literally to stick to the blood vessel
wall. Finally, a flattening and migration of the T cell
through the blood vessel wall occurs in a process
called diapedesis. From here they follow various
chemotactic molecules into the dermis [28].
There are multiple chemokines that are thought to
play a role in inflammation in psoriasis. Chemokines
were originally described as primary chemoattract-
ants, but have also been found to promote a variety of
other inflammatory functions. Initially, chemokines
help with adhesion and the ‘‘rolling’’ of cells along
the endothelium. They can also have direct effects on
T-cell differentiation by altering cytokine expression
and inflammatory receptors [29]. The major influence
for the secretion of chemokines (by various cells
including endothelial cells, keratinocytes, monocytes,
and Langerhans’ cells) is the synergistic action of
TNF-a and IFN-g from type 1 cells. Endothelial cells
secrete chemokines RANTES and TARC further to
attract more type 1 cells out of the vasculature [30].
The CD8+ cells need to migrate all the way up into
the epidermis. This is accomplished though the inter-
action of the chemokines MIG and IP-10 produced by
epidermal keratinocytes to the CXCR3 receptor. In
fact, CXCR3 CD8 cells are 10 times more likely to be
found in psoriatic plaques than in the peripheral
blood of psoriatic patients [31].
Immune cascade in the skin
The keratinocyte changes of psoriasis are a re-
action to the immune response in the skin initiated by
activated T cells but involving many different types
of inflammatory cells. The T cells are believed to
promote these changes by secreting a variety of cy-
tokines. These cytokines induce the other cells found
in the skin, including epidermal keratinocytes, den-
dritic cells, and macrophages, to produce their own
cytokines. This positive feedback cycle maintains the
chronic psoriatic plaque. The type 1 cytokines induce
ICAM-1, CD40, and major histocompatibility com-
plex II proteins on epidermal keratinocytes. ICAM-1
makes it possible for the T cells to migrate into the
epidermis through LFA-1–ICAM-1 interaction [30].
Table 1
Cytokines and chemokines that play a role in the immunologic cascade of psoriasis
Cytokines and chemokines Produced by Effects
TNF-a [54,55] Type 1 T cells, macrophages,
keratinocytes
Promotes type 1 differentiation of T cells; induces ICAM,
VCAM, and E selectin
IFN-g [29,30] Type 1 T cells Keratinocyte proliferation; increases MHC I and II expression;
Ag presentation attracts macrophages and release of TNFa;induces ICAM, VCAM, and E selectin; inhibits IL-4 (and Th2
expression)
IL-2 [29] Type 1 T cells Promotes CD28-CD80-CD86 interaction and clonal proliferation
of Th1 cells; activates macrophages and Tc1
IL-3 [29] T cells Growth of dendritic cells and macrophages
GM-CSF [29] T cells Activates neutrophils and mononuclear cells
IL-12 [29,56] APC Promotes Th1 differentiation
VEG-F [33,52] Keratinocytes, T cells Promotes angiogenesis
RANTES [29,30] Keratinocytes Induces IL-12; attracts lymphocytes
MIG and IP-10 [29,31] Keratinocytes Increases leukocyte adhesion
IL-8 [51,53] Neutrophils, keratinocytes Attracts lymphocytes and neutrophils; induces vascular response
Abbreviations: APC, antigen-presenting cells; GM-CSF, granulocyte macrophage colony–stimulating factor; ICAM, intra-
cellular adhesion molecule; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; TNF, tumor necrosis
factor; VCAM, vascular cell adhesion molecule; VEG-f, vascular endothelial growth factor.
S. Mehlis, K.B. Gordon / Dermatol Clin 22 (2004) 371–377374
IFN-g produced by the Tc1 cells induces keratinocyte
proliferation and differentiation.
The IFN-g also is a potent stimulator for macro-
phages to release TNF-a. Neutrophils are attracted
into the dermis by the IL-8 chemokine, released by
differentiated keratinocytes as a result of multiple
inflammatory cytokines [32]. Vascular growth and
remodeling seen in psoriasis are likely caused by the
T cell release of vascular endothelial growth factor
[33]. A more extensive list of cytokines and chemo-
kines is provided in Table 1.
Creating a novel biologic therapy
The simplified immunologic cascade described
previously presents a basic understanding of the
different molecules and signals behind the develop-
ment of a psoriatic plaque. Each of these is a potential
target for the new biologic therapies. The develop-
ment of these novel biologics, however, poses a chal-
lenge. After an appropriate target is chosen, whether
it is a cell surface receptor or an extracellular cyto-
kine, it must interact with that target appropriately to
induce the proposed response.
Kohler and Milstein [34] described the first bio-
logic therapies with monoclonal antibodies in 1975.
The spleen of a mouse immunized with a specific
antigen is mixed with human myeloma cells (immor-
tal cells). To ensure that the myeloma cells do not
overgrow the fused cells, only myeloma cells that are
deficient in HGPRT, a crucial enzyme in the prolif-
eration of cells, are mixed in with the mouse spleen
cells. The medium itself does not allow spleen cells to
grow. Myeloma cells cannot reproduce on their own
without HGPRT. Only the hybrid of the myeloma and
spleen cells is able to grow in the medium. This hy-
bridoma is then cloned, and large amounts of mono-
clonal antibodies are produced.
The problem with the use of these monoclonal
antibodies in humans, however, is the potential for
patients to develop immune reactions against the
mouse protein. This reaction manifests itself as hu-
man antimouse antibodies. More recently, methods
have been developed to decrease or eliminate these
reactions by fusing parts of human antibodies with
these mouse antibodies. Chimeric antibodies (drugs
ending with -ximab) take the antigen-binding portion
of mouse antibody and fuse it to a constant region of
human antibody. Humanized antibodies (drugs end-
ing with -umab) use the framework of a human
antibody and selectively place it in small amino acid
sequences from murine antibodies into the variable
region. Fusion proteins (often ending in -cept) are
receptor domains or cell surface markers of human
proteins that are fixed to the constant portion of an
immunoglobulin [35]. For example, if a medication is
needed to block TNF-a, using an antibody that is
bound to the TNF-a receptor blocks the activation of
that receptor.
The rational for synthesizing these proteins with
the constant chain of human immunoglobulin (usu-
ally IgG) is to improve the half-life of the drug. The
drug lasts longer in the circulation if it appears to be a
human immunoglobulin. Organs that clear proteins,
like the spleen and liver, recognize it as foreign if
S. Mehlis, K.B. Gordon / Dermat
most of the antibody is murine. This allows for longer
periods between dosing and easier use for patients.
Targets for biologic therapies
The authors have developed a model, published
previously [36,37], that uses the simplified vision of
the immunopathogenesis of psoriasis to develop four
potential areas as target strategies for biologic im-
munotherapy. Strategy 1 is to decrease selectively
the number of pathogenic T cells. Strategy 2 inhibits
T-cell activation or reactivation in the lymph nodes or
skin. Strategy 3 attempts to alter the cytokine profile
of the effector T cells from type 1 to type 2, a process
called immune deviation. Finally, strategy 4 inac-
tivates specific cytokines that play a major role in
the immunologic cascade of psoriasis. This section
briefly discusses how some of the newer biologics
may fit into this framework.
Strategy 1: targeting pathogenic T cells
Psoriasis is a T-cell –mediated disease. Elimi-
nating pathogenic T cells from the periphery or the
skin should decrease disease activity. One of the first
biologics studied for psoriasis was denileukin difitox,
a fusion protein that combines an enzymatically
active diphtheria toxin with the coding sequence of
IL-2. This protein binds avidly to the IL-2 R and
rapidly gets internalized. The active diphtheria toxin
inhibits protein synthesis and ultimately results in cell
death [38]. It has no effect on any other cells other
than an activated T cell that expresses the high
affinity IL-2 receptor [39]. In clinical trials with this
drug in psoriasis, there was an improvement in
psoriasis, leading researchers to focus on blocking
T cells and their function for biologics [40,41].
Another method of blocking T cells is to induce
apoptosis of the cell itself by surface receptors or
by activating natural killer cells or macrophages to
induce their death. Alefacept, a fusion protein of
LFA-3 and human IgG, works in two separate ways.
First, the LFA-3 portion binds to its match on the
T cell, the CD-2 receptor, blocking co-stimulation.
The constant portion IgG engages the FcgIII receptoron natural killer cell, however, which induces apo-
ptosis by the perforin-granzyme system [42]. It also
reduces the number of activated T cells found in the
circulation, and the response to therapy correlates to
this decrease in the periphery and especially the skin
[42,43].
Strategy 2: blocking T-cell activation
Strategy 2 blocks cell-cell interaction in any of the
three steps outlined in T-cell activation: (1) binding,
(2) antigen-specific activation, and (3) co-stimulation.
It could also target the trafficking of the T cells back
into the skin. Efalizumab is a humanized monoclonal
antibody that binds to the CD11a portion of the LFA-
1 surface molecule found on T cells [44]. By blocking
the interaction with ICAM, efalizumab blocks the
initial binding of T cells to the APC [45], migration
into the skin by ICAM on endothelial cells [46], and
Tc1 adhesion to keratinocytes [45].
Strategy 3: immune deviation away from type 1
T cells
There is an inverse relationship between the bal-
ance of Th1 and Th2 cells. Promoting a Th2 response
by the addition of Th2 cytokines should decrease the
activity of Th1 cells. Several different biologic agents
work to upset the Th1 balance. IL-4 is the primary
cytokine that inhibits the activity of type 1 T cells.
Small studies have demonstrated some efficacy with
acute treatment with recombinant IL-4. IL-10 is an
important Th2 cytokine, and subcutaneous injection
of recombinant IL-10 has been shown to decrease
Th1 cytokines and improve psoriasis [47]. Recombi-
nant IL-11 has similarly induced a Th2 response and
improvement in psoriatic plaques [48].
Although the induction of immune deviation has
traditionally been limited to treatment with type 2
cytokines to down-regulate type 1 cells, very prelim-
inary data from another approach suggest potential
effects with immune deviation. The presence of IL-12
is necessary for type 1 T-cell differentiation. Early
studies suggest a monoclonal antibody directed
against IL-12 could have some efficacy in psoriasis.
By blocking type 1 differentiation, a novel form of
immune deviation in psoriasis, it may be possible to
improve disease.
Strategy 4: inactivating cytokines and chemokines
The final strategy uses antibodies to target inflam-
matory mediators that are still bound to cells or have
been excreted. There are a variety of different cyto-
kines and chemokines implicated in the pathogenesis
of psoriasis, and any of the candidates in Table 1 can
be a potential target. Etanercept is a dimeric fusion
protein that binds to soluble TNF-a to neutralize it
[49]. Infliximab also targets TNF-a. It is a chimeric
antibody that targets both soluble and bound TNF,
and can neutralize the effects of TNF and can also
ol Clin 22 (2004) 371–377 375
S. Mehlis, K.B. Gordon / Dermatol Clin 22 (2004) 371–377376
result in compliment-mediated fixation and antibody-
dependant toxicity of T cells [50]. Other cytokines
that have been targeted include IL-8 [51] and IFN-g.
Summary
Traditional systemic therapy for psoriasis is
limited by either lack of efficacy or the long-term
side effect profile of the medications used. Newer
information about the pathophysiology of the disease
has led to new perspectives on developing novel
techniques for attacking psoriasis. In particular, spe-
cifically targeting the areas in the immunologic
cascade that may be the central drivers for the
development of psoriasis could lead to better therapy.
The techniques of genetic engineering and the tech-
nology to produce bioengineered molecules in large
quantities have given clinicians the ability specifi-
cally to target psoriasis and other inflammatory dis-
eases. These biologic medications truly bridge the gap
between the identification of the pathophysiologic
processes of psoriasis and the treatment of patients
suffering from this disease.
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Dermatol Clin 22 (2004) 379–388
Review of therapy of psoriasis:
the prebiologic armamentarium
David S. Aaronson, MD, Mark Lebwohl, MD*
Mount Sinai School of Medicine, 5 East 98th Street, Box 1048, New York, NY 10029-6574, USA
To appreciate the evolving treatments for psoriasis diflorasone diacetate in optimized base, to the weaker
in the current biologic era, it is important to first
examine traditional therapies. This article reviews the
prebiologic armamentarium and addresses the follow-
ing treatments: (1) topical agents, including topical
corticosteroids, tars, anthralin, vitamin D analogs,
retinoids, and salicylic acid; (2) systemic agents, such
as oral acitretin, methotrexate, and cyclosporine; and
(3) phototherapy with ultraviolet B (UVB) light,
narrowband UVB, and psoralen with ultraviolet A
(PUVA) light.
Topical therapy
Topical therapy is considered the first line in
psoriasis treatment. The various side-effect profiles
of these agents, however, often require their rotation
throughout the course of the disease. The following
sections describe the medicines in this category, their
side effects, and the current data on their efficacy.
Corticosteroids
Corticosteroids persist as the mainstay for the
topical treatment of psoriasis despite the existence
of safer therapies with lesser side effects. Topical
corticosteroids are categorized by the Stoughton-
Cornell classification system, based on the vasocon-
striction of small blood vessels in the upper dermis
[1]. This system ranges from the superpotent class 1
steroids, such as clobetasol, halobetasol propionate,
betamethasone dipropionate in optimized base, and
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/j.det.2004.03.012
* Corresponding author.
E-mail address: [email protected] (M. Lebwohl).
class 7 steroids, such as 1% hydrocortisone. They all
reduce inflammation but vary in strength, vehicle,
and cost. Many forms of topical corticosteroids exist,
including solutions, foams, lotions, creams, emollient
creams, gels, ointments, sprays, and tape.
Topical corticosteroids come with bothersome and
occasionally serious side effects that limit their long-
term use in the treatment of psoriasis, however. The
hypothalamic–pituitary–adrenal axis can be sup-
pressed by medium-potency or stronger topical cor-
ticosteroids. This potential side effect is most
worrisome for children because their ratio of surface
to body mass is increased. Conversely, iatrogenic
Cushing’s syndrome is also a rare potential side effect
of topical corticosteroids. More common side effects
occur locally at the site of topical corticosteroid
application resulting in cutaneous atrophy. This pro-
cess leads to skin fragility and tearing of dermal
connective tissue, which causes irreversible striae.
Telangiectases also arise, which can rupture and form
purpura. These findings are most often seen when
high-potency corticosteroids are used on the face and
intertriginous areas for prolonged periods of time.
One other major complication of topical cortico-
steroids is tachyphylaxis. Tachyphylaxis is defined as
the cessation of therapeutic response to a substance as
treatments with that substance are continued. This
phenomenon is seen scientifically as the reduction
or loss of small vessel vasoconstriction induced by
topical corticosteroids [2]. Clinically, however, it has
been questioned whether tachyphylaxis exists [3]. To
avoid tachyphylaxis and other side effects, Katz et al
[4] demonstrated that a regimen of three applica-
tions of superpotent betamethasone dipropionate over
24 hours per week led to improvement of psoriasis for
up to 6 months in 60% of patients versus 20% of
s reserved.
D.S. Aaronson, M. Lebwohl / Dermatol Clin 22 (2004) 379–388380
patients in the placebo group. This method has been
termed pulse therapy or weekend therapy. Other
methods to limit the side effects from topical cortico-
steroids include the introduction of novel agents,
such as fluticasone propionate, mometasone furoate,
prednicarbate, and tipredane, and novel vehicles, such
as betamethasone valerate in a foam and diflorasone
diacetate in an optimized base in a gel.
Anthralin and tars
Anthralin use has declined in Europe with the
introduction of topical vitamin D analogs for psoria-
sis. Anthralin can be moderately irritating and can
stain skin, clothes, and furniture. Micanol with 1%
anthralin in a new temperature-sensitive vehicle acti-
vated at skin temperature was recently released to
avoid these drawbacks. It only prevents staining of
clothes and furniture, however, not skin. To reduce
skin irritation, short contact regimens of anthralin
have been explored to minimize exposure to the
staining and irritating effects. Despite these efforts,
and the equal efficacy shown for 0.25% to 2%
dithranol cream applied once daily for 30 minutes
versus 3 mg/g of calcitriol ointment twice daily, the
quality of life in the calcitriol group was perceived as
much better [5]. Application of triethanolamine after
removal of anthralin may prevent irritation and stain-
ing of the skin [6].
Topical vitamin D analogs
The vitamin D3 analog calcipotriene was intro-
duced in Europe in the early 1990s in a 0.005%
ointment formulation. Calcipotriene binds to the
vitamin D receptor found in keratinocytes, halting
proliferation and causing terminal differentiation [7].
It is currently used to treat moderate to severe plaque
psoriasis alone, but primarily in combination with
other treatment modalities.
Side effects from vitamin D analogs are minimal
when compared with topical corticosteroids and
anthralin. Vitamin D analogs can cause irritant con-
tact dermatitis, however, particularly on the face and
in intertriginous sites. Yet, they are highly effective in
alleviating psoriasis. Studies suggest that dilution of
calcipotriene with petrolatum, when used on the face
or intertriginous areas, or the addition of superpotent
halobetasol ointment may prevent irritant contact
dermatitis [8,9]. Another side effect, hypercalcemia,
is seen rarely in case reports but is invariably asso-
ciated with excess use over large surface areas [10].
In general, long-term studies of calcipotriene have
shown that it is well tolerated with few adverse
effects [11,12].
Calcipotriene, when compared with topical corti-
costeroids in clinical trials, was shown to be as
effective as class 2 (fluocinonide, 0.05%) but not as
effective as class 1 corticosteroids [13]. In combina-
tion, calcipotriene plus limited application of the
superpotent topical corticosteroid halobetasol worked
better than either one alone, with no incidence of
cutaneous atrophy [14]. Furthermore, a new combi-
nation of calcipotriol and the betamethasone dipropio-
nate ointment used once daily was shown to be more
effective than either one alone in a randomized
double-blind study [15].
These studies led to the examination of combination
preparations containing calcipotriene. Halobetasol
(0.05%) ointment or cream and 5% tar gel (Estargel)
in combination with calcipotriene (0.005%) ointment
remained stable for a minimum of 13 days at room
temperature. One study found, however, that 6% sali-
cylic acid or 12% ammonium lactate lotion inactivated
calcipotriene completely or by more than 30%, respec-
tively [16].
Calcipotriene also has been combined with photo-
therapy. The Canadian Calcipotriol and UVB Study
Group has shown in a multicenter, prospective, ran-
domized, parallel-group, vehicle-controlled, single-
blind study that calcipotriol cream plus twice-weekly
broadband UVB reduced the UVB exposure to
achieve total psoriasis clearance [17]. Narrowband
UVB plus calcipotriol, however, does not improve
psoriatic response when compared with narrowband
UVB alone [18]. Importantly, calcipotriene is not
inactivated by UVB and may increase the minimal
erythema dose [19].
PUVA in combination with calcipotriene also has
been studied. One promising study by Speight and
Farr [20] showed that application of twice-daily
calcipotriene ointment versus placebo to symmetri-
cally located plaques of psoriasis on the same patient
decreased the UVA dose by 26.5% without affecting
time to relapse. This regimen has the advantage of
reducing the long-term skin aging and carcinogenic
effects of UVA. Calcipotriene is inactivated by UVA
and should therefore be applied only after photo-
therapy [21].
Retinoids
Tazarotene is a specific retinoic acid receptor
(RAR) ligand and has no binding activity with the
retinoic X receptor. It specifically binds b and gsubtypes of RAR and is believed to reduce inflam-
mation and cause epidermal differentiation [22,23].
D.S. Aaronson, M. Lebwohl / Derm
Tazarotene is available in gel and cream formulation
at 0.05% and 0.1% concentrations.
Tazarotene was introduced because it is less
irritating when compared with topical application of
nonspecific retinoids and has little of their systemic
effects. Still, its major side effect is cutaneous irrita-
tion, which is worse with the more effective higher
concentration [24]. Like the vitamin D analogs, it
does not cause the more troublesome side effects of
topical corticosteroids.
Efforts have been undertaken to minimize the
irritating nature of retinoids and enhance their action
by combining topical corticosteroids. Tazarotene used
with the topical corticosteroids, 0.1% mometasone
furoate cream (class 4) or 0.05% fluocinonide (class 2),
improved psoriatic plaques with reduced retinoid
dermatitis [25]. Furthermore, a small-scale pilot study
postulated that 0.1% tazarotene can actually reduce
epidermal atrophy induced by 0.05% diflorasone
diacetate ointment [26]. Regimens of 0.1% tazarotene
and the corticosteroids, 0.1% mometasone furoate or
clobetasol ointment, also have shown increased effi-
cacy and decreased side effects compared with either
treatment alone [27,28].
Tazarotene with phototherapy also has been
examined. The addition of tazarotene to UVB quick-
ened psoriasis improvement when compared with
UVB alone but caused increased sensitivity to burn-
ing [29]. There have been recommendations to reduce
UV doses by one third to avoid burning with com-
bination tazarotene [30].
Phototherapy
UV light causes DNA damage to cutaneous
tissue. It also is a proven effective psoriasis treat-
ment. William Goeckerman [31] first introduced
phototherapy at the beginning of the 20th century.
Goeckerman’s regimen consisted of a day and night
crude coal tar bath followed by exposure to a hot
quartz mercury vapor lamp. At that time, patients
only received phototherapy in the inpatient setting.
Ingram [32], who substituted anthralin for crude
coal tar, made an important modification in the
1950s. Levine et al [33] made additional modifica-
tions in the 1970s when they discovered that out-
patient treatment 3 times per week and a clear
lubricating base instead of crude coal tar was as
effective as an equal number of inpatient treatments.
Over the years, additional advances in phototherapy
have occurred with the use of systemic and topi-
cal medicines.
Ultraviolet B
Discussion of phototherapy in the more modern
era must first start with broadband UVB. UVB dose
is based on minimal erythema dose or Fitzpatrick skin
types [34]. UVB has enhanced efficacy with a thin-
layer application of clear emollients, such as petrola-
tum and mineral oil, because of improved optical
transmission to the skin [35]. Thick application of
these same emollients and other topical treatments
already discussed can block UVB [36]. Attention
should be paid to agents that block or enhance UVB.
The side effects of UVB are skin burning and
photosensitivity. Unlike UVB in sunlight, evidence
suggests that broadband UVB in phototherapy does
not lead to carcinogenesis [37]. The combination of
UVB with other topical and systemic treatments for
psoriasis has been shown to increase skin burning and
photosensitivity, and with some treatments, actually
reduces the time to relapse. Care must be taken when
combined treatment is considered. The benefits of
combination therapy with calcipotriene or tazarotene,
however, are accelerated efficacy and increased skin
clearing [29,38,39].
Systemic therapy with methotrexate or acitretin in
combination with UVB is another effective treatment
of psoriasis. The addition of a systemic agent reduces
the total cumulative dose of UVB, and conversely,
addition of UVB to systemic therapy reduces drug
dosages [40,41]. The synergy between systemic and
UVB therapy is a critical observation when the side
effects of methotrexate and oral retinoids are consid-
ered. This synergy includes reduction in liver biop-
sies performed for methotrexate and the hair loss,
cheilitis, myalgias, and pyogenic granulomas caused
by oral retinoids.
Psoralen plus ultraviolet A
PUVA is a major treatment of widespread or re-
sistant psoriasis. Psoralen, 8-methoxypsoralen, when
targeted with UVA, causes the formation of pyrimi-
dine dimers and reaches peak cutaneous concentra-
tions between 1 and 4 hours. Pyrimidine dimers lead
to cross-linkage of DNA strands. Cross-linkage of
DNA strands leads to genomic instability and inflam-
matory cell death. Psoralen is typically given orally
2 hours before UVA in a crystalline form (Oxsoralen)
at 0.6 mg/kg or 90 minutes before UVA in an encap-
sulated liquid form (Oxsoralen Ultra) at 0.4mg/kg.
PUVA increases the incidence of squamous cell
carcinoma (SCC) and, to a lesser extent, malignant
melanoma. One study showed that patients treated
with 260 individual PUVA sessions compared with
atol Clin 22 (2004) 379–388 381
D.S. Aaronson, M. Lebwohl / Dermatol Clin 22 (2004) 379–388382
fewer than 170 sessions had an 11-fold increase in
SCC [42]. Male genitalia should be shielded during
UVA exposure because of the tendency to develop
carcinoma in that region [43]. One study reported that
malignant melanoma increased several-fold in indi-
viduals treated with more than 250 PUVA ses-
sions, and that study included individuals treated at
the onset of PUVA therapy with higher doses [44].
Notwithstanding, it is important for all patients re-
ceiving PUVA therapy to have periodic skin exami-
nations to monitor for new lesions.
In addition to cancer, lesser side effects, such as
premature cutaneous aging, nausea, headache, and
burning, can be prominent. It is important to take
psoralen with food to reduce the incidence of nausea,
or particularly sensitive patients can bathe in psoralen
[45,46]. Also, avoidance of sun exposure should be
stressed. Unlike normal sunburn, PUVA-induced
burns appear within 24 hours, but peak around
48 hours. For this reason, PUVA therapy should
never be given 2 days consecutively.
The combination of PUVA therapy plus other
topical agents has been explored to reduce the cumu-
lative dose of UVA. PUVA and corticosteroids have
yielded conflicting results [47,48]. Studies of the
combination of PUVA and anthralin have not been
undertaken, most likely because of the potential for a
UVA-photosensitizing effect. The combination of
PUVA and calcipotriene has met with greater success
and was discussed earlier. It causes quicker clearing
with lower UVA doses than with PUVA alone. The
combination of PUVA and tazarotene gel is not
widely published, but tazarotene may enhance PUVA
with the caveat that tazarotene gel reduces the amount
of UVA necessary [30]. The combination of PUVA
with oral retinoids provides not only synergy but also
a reduction in one another’s side-effect profiles. This
effect is partially brought about through a reduced
need for UVA exposure to achieve the same clearance
of psoriasis [49,50]. The addition of oral retinoids is
termed PUVA-sparing therapy. There has been work
showing that the addition of oral retinoids reduces the
incidence of skin cancers because the development
of UVA-induced skin cancers is dose-dependent
[51–53]. Another systemic agent, methotrexate, also
has been proven effective in combination with PUVA
in the treatment of psoriasis [54]. Yet, methotrexate is
a known risk factor for SCCs and requires liver
function monitoring.
Narrowband ultraviolet B
Narrowband UVB (Tl-01) is a wavelength of ap-
proximately 311 nm that maximizes psoriasis clear-
ance compared with its erythrogenic potential.
Narrowband UVB has the disadvantage of producing
more severe and longer-lasting burns than broadband
UVB, however, and its long-term effect on carcino-
genesis remains unknown. Its overall safety is sus-
pected to be much greater than PUVA.
Narrowband UVB has been proven superior to
broadband UVB [55] and is as effective as or less
effective than PUVA [56,57]. The better safety profile
of narrowband UVB, especially when administered at
an optimized dosage, has led to its increased use over
the last few years. Studies with narrowband UVB in
combination with other agents are underway.
Systemic therapy
Systemic therapy for psoriasis in the prebiologic era
consists of Food and Drug Administration (FDA-)–
approved drugs, such as methotrexate, acitretin, and cy-
closporine, and nonapproved drugs, such as tacrolimus,
mycophenolate mofetil, hydroxyurea, 6-thioguanine,
and sulfasalazine. Typically, these systemic therapies
are used for severe disabling psoriasis or psoriasis
refractory to topical or phototherapeutic modalities.
Methotrexate
Methotrexate was implemented as an effective
treatment of psoriasis back in the 1970s, and at the
present time, remains widely used [58]. It also has
FDA-approved uses for the treatment of neoplastic
and rheumatologic disease. It reversibly inhibits
dihydrofolate reductase, which is an enzyme required
for the reduction of folic acid to tetrahydrofolic acid.
This inhibition limits the quantity of one-carbon units
needed to form purines and transform deoxyuridylate
into thymidylate. Through this mechanism, metho-
trexate prevents the synthesis of DNA and cell
replication. Inflammatory cells and cells with high
turnover, such as hematopoetic and gastrointestinal
cells, are most affected by systemic methotrexate
therapy. It is methotrexate’s effects on these cell types
that cause most of its side effects; most recently,
attention has been drawn to the immunosuppressive
effects of methotrexate. Methotrexate is 50% protein
bound in plasma and primarily excreted by the
kidneys. In addition, it interacts with many other
drugs, making it crucial to get a complete list of pa-
tient medications.
Methotrexate has a multitude of side effects, rang-
ing from benign to life threatening. The most com-
mon side effects are nausea, vomiting, anorexia,
D.S. Aaronson, M. Lebwohl / Dermatol Clin 22 (2004) 379–388 383
stomatitis, macrocytic anemia, and phototoxicity.
Stomatitis and macrocytic anemia can be prevented
with oral folic acid in dosages of 1 to 5 mg daily [59].
Methotrexate phototoxicity is a unique side effect and
has been given the name ‘‘radiation recall,’’ which is
the development of erythema at previous sights of
radiation or sunburns [60].
Methotrexate can also cause fatal seizures, hepa-
totoxicity, renal failure, bone marrow suppression,
and pulmonary fibrosis. Consequently, methotrexate
is contraindicated in patients who have renal or
hepatic impairment or profound bone marrow sup-
pression. It is also necessary to stop methotrexate in
the event of infection or other illness requiring an
intact immune response.
The pulmonary side effects can be deadly. If a
patient complains of new-onset shortness of breath or
cough, methotrexate should be discontinued [61].
Persistent or worsening symptoms should be evalu-
ated with a chest radiograph.
Much like other immunosuppressive drugs, metho-
trexate has been reported to cause lymphoprolifera-
tive disorders. These lymphoproliferative disorders
have disappeared with methotrexate cessation, sug-
gesting possible causality [62,63].
Hepatotoxicity is the most serious long-term side
effect, and how best to monitor patients taking
methotrexate is a topic of much debate. It is well
agreed on, though, that those patients already predis-
posed to cirrhosis of the liver, such as alcoholic,
obese, or diabetic patients, should take methotrexate
with extreme caution or not at all. Roenigk et al [58]
have published guidelines on monitoring patients
taking methotrexate. Patients with hepatic risk factors
should have a liver biopsy after 2 to 4 months of
methotrexate therapy with signs of psoriatic improve-
ment. A biopsy should be repeated after a 1- to 1.5-g
cumulative dose has been reached. Patients with no
hepatic risk factors should have a liver biopsy at a
1–1.5-g cumulative dose and thereafter for every
1.5 g of methotrexate. Previously, a baseline liver bi-
opsy was indicated for every patient starting metho-
trexate. Rheumatologists do not recommend routine
liver biopsy for patients treated with methotrexate for
rheumatoid arthritis (RA), however. Patients with
psoriasis, however, are more likely to have histologic
progression or cirrhosis than patients with RA [64].
There are several confounding factors that may ex-
plain this difference, including use of nonsteroidal
anti-inflammatory medicine and oral steroids, popu-
lation bias, and dosage.
One final contraindication to the administration of
methotrexate is pregnancy. It is a class X drug and
therefore highly teratogenic and known to cause
miscarriages [65]. Methotrexate may also temporarily
affect male fertility. Therefore, methotrexate therapy
should be halted several months before conception,
and all patients should be advised about its deleteri-
ous effects.
Despite numerous side effects and the required
monitoring of toxicity, methotrexate is effective.
Psoriatic arthritis may be most alleviated with metho-
trexate. Methotrexate is also useful for the long-term
management of severe psoriasis, especially the eryth-
rodermic and pustular variants. Newer studies in
comparing the biologics are currently underway.
Retinoids
Retinoids can be applied topically or systemically
to treat psoriasis. Topical retinoids were discussed
previously. Systemic usage is indicated for the treat-
ment of severe psoriasis, including the erythrodermic
and pustular types. There are four FDA-approved
retinoids available, but only three are used in the
treatment of psoriasis. Isotretinoin is useful for acne
and pustular psoriasis in monotherapy [66]. It can
also be combined with PUVA and UVB for enhanced
effects [67,68]. Etretinate and acitretin are the other
two FDA-approved systemic retinoids for the treat-
ment of psoriasis. Acitretin is the active metabolite
of etretinate.
Retinoids are highly teratogenic and persist in
fatty tissue long after they are discontinued. Further-
more, etretinate was withdrawn from the market once
the shorter-lived acitretin was introduced. All women
considering this agent must be warned that retinoids
should not be taken if they plan to become pregnant
while they are taking this medication, or even 3 years
after they discontinue the medicine. Most physicians
expect patients to use some sort of birth control to
prevent accidental pregnancy. Prolongation of reti-
noid teratogenicity may occur if acitretin is taken
with alcohol because it is esterified to longer-lived
etretinate [69]. Therefore, female patients of child-
bearing potential must also cease drinking and be
watchful of over-the-counter medications and foods
containing alcohol.
Acitretin is usually well tolerated at low doses, but
at doses of greater than 50 mg per day, mucocutane-
ous lesions may develop, including hair loss, dry lips,
cheilitis, dry skin, and ‘‘sticky skin’’ (retinoid-type
dermatitis). Elevation of serum lipids and liver func-
tion tests are common. Triglyceride elevation can be
partially negated by use of gemfibrozil or atorvastatin
[70]. No cases of hepatitis have been reported, but
liver function should be monitored. Other concerns
after long-term treatment with retinoids include the
D.S. Aaronson, M. Lebwohl / Dermatol Clin 22 (2004) 379–388384
following: the development of pseudotumor cerebri,
although this is rare and has only been associated
with isotretinoin; osteoporosis [71]; and the develop-
ment of ligamentous calcifications and skeletal ab-
normalities [72].
Despite these minor side effects, acitretin is a
highly effective systemic treatment modality for se-
vere erythrodermic or pustular psoriasis in mono-
therapy or in combination with other treatment
modalities. Plaque and guttate psoriasis are slower
to resolve with acitretin therapy alone. In combina-
tion with PUVA or UVB, however, excellent results
can be achieved with lower doses of UV light
[49,50,73]. One study showed that retinoids may
suppress development of cutaneous malignancies
associated with UVA [74]. Acitretin in combination
with calcipotriol ointment has improved resolution of
psoriatic plaques and reduces total cumulative dose of
acitretin to reach clearance [75].
Cyclosporine
Cyclosporine is an immunosuppressive agent
originally created in the 1970s for the prevention of
kidney transplant rejection. Its mechanism of action
is not completely understood, but cyclosporine is
known to cause inhibition of the antigenic response
of helper T lymphocytes by reducing the production
of interleukin 2 (IL-2) and interferon g (IFN-g). Theoral microemulsion formulation is FDA-approved for
the treatment of psoriasis in doses of up to 4 mg/kg
daily. It is highly effective for all forms of psoriasis
but must be administered by knowledgeable physi-
cians [76,77].
Cyclosporine can cause nephrotoxicity, hyper-
tension, hyperlipidemia, hypomagnesemia, hyper-
kalemia, increased susceptibility to infection, and
malignancy. The risk of malignancy, however, proba-
bly is only increased in those patients who are
undergoing long-term treatment. Skin cancer and
lymphoproliferative disorders have been witnessed
in transplant patients on long-term, high-dosage cyclo-
sporine [78,79]. In patients treated with cyclosporine
for RA for a mean of 1.6 years, but at an average dose
of only 2.6 mg/kg daily, the incidence of malignancy
was no different from that in the control group [80].
A recent report found that a patient treated for
recalcitrant psoriasis with cyclosporine developed a
primary, cutaneous, large T-cell lymphoma that re-
solved clinically and histologically with discontinua-
tion of therapy after 2 months. The lymphoma
recurred 3 years later, however [81].
The nephrotoxicity of cyclosporine is perhaps the
most worrisome side effect of this powerful drug.
Histologic changes consistent with interstitial fibrosis
and renal tubular atrophy have been demonstrated in
individuals treated for more than 2 years [82,83].
Nephrotoxicity is best minimized by maintaining
doses of less than 5mg/kg per day and monitoring
serum creatinine for a change from baseline that is
greater than 30%. Patients must also be monitored
periodically for hypertension, although this common
side effect can be alleviated by the addition of a
calcium channel blocker. It has been suggested that
calcium channel blockers may actually prevent cy-
closporine nephrotoxicity [84]. Hyperlipidemia can
be managed with a statin-type drug. Hyperkalemia
can be avoided through low-potassium diets or the
use of hydrochlorothiazide.
Serum levels of cyclosporine are greatly affected
by numerous medicines. With proper monitoring,
however, cyclosporine dosage can be altered accord-
ingly. Unlike methotrexate and acitretin, cyclosporine
is not teratogenic and is not myelosuppressive [85].
Cyclosporine is a highly effective agent for the
treatment of severe psoriasis. Debate concerning
intermittent versus continuous treatment has resulted
in numerous studies. The use of intermittent cyclo-
sporine is recommended; although it may be less
effective, the added side effects do not warrant con-
tinuous therapy [86,87]. The administration of cyclo-
sporine should stop or be tapered once psoriatic
clearance has occurred.
Tacrolimus (FK506)
Tacrolimus is a macrolide antibiotic used as an
immunosuppressive agent for organ transplant. It is
structurally distinct from cyclosporine but behaves in a
similar manner by suppressing T-lymphocyte activa-
tion. When compared with cyclosporine, it is 100 times
more potent in its ability to inhibit IL-2 and IFN-gsecretion [88,89]. Tacrolimus is not FDA-approved for
psoriasis but is indicated in the treatment of atopic
dermatitis as a topical agent.
Tacrolimus has a side-effect profile similar to
cyclosporine. The monitoring of renal, hematopoetic,
and hepatic function is necessary if a patient is put
on tacrolimus.
A multicenter, double-blind, placebo-controlled
study involving 50 patients with severe recalcitrant
plaque psoriasis demonstrated a significant improve-
ment based on the Psoriasis Area and Severity In-
dex [90]. The reported side effects were not severe.
Greater experience needs to be gained with tacroli-
mus for the treatment of psoriasis. To date, no
comparisons to cyclosporine have been undertaken
in patients with psoriasis.
Dermatol Clin 22 (2004) 379–388 385
Mycophenolate mofetil
Mycophenolate mofetil is an oral immunosup-
pressive agent that is hepatically metabolized to its
biologically active mycophenolic acid. It currently is
FDA-approved for prophylaxis against rejection of
organ transplants. Mycophenolate mofetil has been
used to treat severe psoriasis, with long-term remis-
sion and minimal side effects [90,91]. Its mecha-
nism of action is the noncompetitive inhibition of
inosine monophosphate dehydrogenase, thereby pre-
venting DNA synthesis and cellular proliferation. Its
other non–FDA-approved uses are for the treatment
of bullous pemphigoid, pemphigus vulgaris, and
atopic dermatitis.
Like all immunosuppressive agents, its use must
be monitored. Notably, nephrotoxicity is not asso-
ciated with this drug. There is a risk of increased sus-
ceptibility to infection and malignancy, however [92].
Hydroxyurea
Hydroxyurea is an antimetabolite that is FDA-
approved for the treatment of cancer and sickle cell
anemia. It inhibits ribonucleotide reductase, a crucial
enzyme necessary for the conversion of DNA bases.
Its use in the treatment of severe psoriasis is not
FDA-approved, but it has a three-decade history as a
monotherapy for psoriasis [93,94].
Doses needed to develop psoriatic improvement,
however, cause nearly 50% of patients to experience
bone marrow toxicity. In addition, long-term treat-
ment has been associated with lymphoproliferative
disorders [70]. Mucocutaneous lesions can also arise
as a common side effect.
6-Thioguanine
The agent 6-thioguanine is a purine analog that
inhibits DNA and RNA synthesis by incorporating
into native strands. It is an approved antineoplastic
drug, with a nonapproved indication in the treatment
of severe psoriasis.
Its side effects primarily involve the gastrointes-
tinal tract, but severe myelosuppression can occur. Fur-
thermore, initial trials with 6-thioguanine were limited by
bone marrow toxicity. Silvis and Levine [95] reported
that weekly dosing could achieve similar clearance of
psoriasis with nearly no myelosuppression.
Sulfasalazine
Sulfasalazine is a conjugation of 5-aminosalicylic
acid and sulfapyridine. It is indicated in the use of
D.S. Aaronson, M. Lebwohl /
ulcerative colitis but also has been implemented in
the treatment of psoriatic arthritis. The mechanism of
action is unknown although it is believed to disrupt
prostaglandin synthesis and the arachidonic acid
pathway. Multiple double-blind studies have shown
moderate results in the treatment of psoriatic arthritis.
One study comparing cyclosporine versus sulfasala-
zine in 99 patients through an open, prospective,
randomized, controlled format significantly demon-
strated better results with cyclosporine [96].
Summary
The prebiologic armamentarium discussed in
this article has a significant role in certain patients
for the treatment of psoriasis. With the creation of
the newer ‘‘biologics’’ and their comparatively les-
ser toxicity, however, the treatment of psoriasis is
being re-evaluated.
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2274–82.
Dermatol Clin 22 (2004) 389–395
Quality-of-life issues in psoriasis
Rita Mukhtar, BA, Jane Choi, MD, John Y.M. Koo, MD*
Psoriasis and Phototherapy Treatment Center, Department of Dermatology, University of California,
515 Spruce Street, San Francisco, CA 94118, USA
Although most skin conditions are not life threat- riasis in such terms can be helpful in formulating a
ening, they can strongly affect how patients perceive
and interact with their environment, giving such dis-
eases the potential to alter every aspect of a patient’s
life. There is a common tendency among the general
public, health professionals, and policymakers, how-
ever, to view skin disease as merely a ‘‘cosmetic’’
problem. When it comes to determining morbidity,
more weight is generally assigned to the physical
sequelae of disease, based on the assumption that the
psychosocial impact somehow deserves less attention.
Increasingly, however, studies of psoriasis show
that skin disease has serious consequences for those
afflicted. Psoriasis, as a disease, typically affects the
skin, but as an illness, it can affect a patient’s
relationships, finances, leisure activities, and mental
health. The words of one psoriasis sufferer illustrate
the significance of the disease:
Skin is contact. It is my closest contact with my
surroundings. Expressions of love, etc., revolve
around skin. . . . it is frustrating to have a damper
placed on one’s contact with people. [1]
The visibility of skin gives it a prominent role in
social interactions. One study examining the psycho-
dynamic characteristics of life stressors raises this
issue, suggesting that the skin lesions of psoriasis
might not simply be of biologic significance but carry
psychologic meaning as well [2]. Thinking about pso-
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/j.det.2004.03.016
Conflict of interest: Dr. Koo has been a clinical re-
searcher, consultant, and speaker for Allergan, Amgen,
Biogen, Bristol-Myers Squibb, Centacor, Connetics, Elan,
Fujisawa, Galderma, Genentech, GlaxoSmithKlein, ICN,
Novartis, and Roche.
* Corresponding author.
E-mail address: [email protected] (J.Y.M. Koo).
concept of how a patient might experience the disease.
Although clinicians who care for people with skin
disorders are most likely to be cognizant of some of
the difficulties their patients face, there remains a
notable gap between the patient’s experience of
disease and the dermatologist’s perception thereof.
A comparison of physician and patient responses to
surveys showed significant differences between phy-
sician and patient assessments of patient quality of
life (QOL). Physicians tended to underestimate the
impact of severe skin disease, and overestimate the
impact of mild disease (the authors suggested that
some patients might downplay morbidity as they
become accustomed to having disease) [3]. Similarly,
a survey of members of the National Psoriasis Foun-
dation (NPF) revealed the prevalent view among
patients that physicians fail to appreciate the full
impact psoriasis has on their lives [4,5].
It is, then, the inner world of the patient with
psoriasis to which clinicians need access. Understand-
ing exactly how psoriasis affects the patient is the
purpose of queries about QOL. It has been argued that
QOL assessment is the most important measure of
disease severity because reductions in QOL define the
patient’s actual experience of living with the illness.
The concept of ‘‘quality of life’’ attempts to account
for several dimensions of well-being in an individual.
The domains that are often assessed include physical,
psychologic, social, and general well-being, and cog-
nitive functioning [6]. Health-related QOL (HRQOL)
is more narrowly defined and encompasses those
factors specifically relating to the disease process or
its treatment. In the absence of a permanent cure, as is
the current case with psoriasis, the clinician strives to
reduce the severity of disease with the goal of pre-
venting reduction in QOL [7].
s reserved.
R. Mukhtar et al / Dermatol Clin 22 (2004) 389–395390
Increasingly, QOL is being used as a measurement
tool in the evaluation of health care outcomes [6].
Krueger et al [8] argued that although body surface
area (BSA) is often used to define severity in clinical
trials, such a definition fails to be sensitive to indi-
vidual differences between psoriasis sufferers. De-
pending on which region of the body the psoriasis
affects, a low BSA can correspond with very severe
functional impairment, whereas a higher BSA can
have very little impact on an individual’s day-to-day
life. For example, psoriasis affecting the dominant
hand might receive a low BSA but hinder an indi-
vidual’s ability to perform basic tasks, whereas pso-
riasis affecting a larger region of the body, such as the
back, might not affect functioning as much. Because
it is ultimately the impact of psoriasis on activities of
daily living that matters to patients, QOL becomes a
critical measure of disease severity.
Measuring QOL not only gives clinicians access
to important information about the individual patient,
it also allows for comparisons to be made between
psoriasis and other chronic medical conditions.
Knowing which diseases have the most impact on pa-
tient QOL helps ensure proper allocation of research
and treatment resources. In addition, accurately mea-
suring QOL allows clinicians to assess the efficacy of
new therapies and provides a patient-oriented means
of measuring disease status [9].
Tools for measuring quality of life
As the importance of measuring QOL has been
increasingly recognized, researchers have developed
several instruments to assess the impact of skin dis-
eases, including psoriasis, on patients. These instru-
ments can be divided into generic, specialty-specific,
or disease-specific classes, such that an instrument
might be applicable to patients with any systemic ill-
ness, patients with skin disorders in general, or pa-
tients with only psoriasis. In addition, questionnaires
designed to measure HRQOL are categorized as either
discriminative or evaluative. Discriminative instru-
ments attempt to differentiate between individuals at
one point in time, whereas evaluative instruments are
useful in quantifying change in the same individuals
over time [7]. To be useful, these tools must be valid,
reliable, and responsive to change, meaning that they
actually measure what is intended to be measured,
yield consistent results on repeated use, and are able
to detect clinically meaningful changes [10]. Using
a general measure along with a psoriasis-specific
measure has been recommended to better assess
the full impact of psoriasis on HRQOL [6].
Generic measures that have been used in studies
of psoriasis include the Short Form–36 Health Sur-
vey (SF-36), a commonly used survey developed as
part of the Medical Outcomes Study, which consists
of 36 questions that address eight domains of
HRQOL [11]. These categories can be combined to
create a physical component summary score and a
mental component summary score, with higher scores
indicating better HRQOL [12]. Like the SF-36, sur-
veys such as the UK Sickness Impact Profile (UKSIP),
the Nottingham Health Profile, and the General Health
Questionnaire allow for comparisons to be made
between different diseases but can often be quite long
and time-consuming to complete [7]. Dermatology-
specific tools that have been developed are discussed
in the following sections.
Dermatology Life Quality Index
Finlay and Khan [9] developed the Dermatology
Life Quality Index (DLQI), a 10-item questionnaire
with the aim of creating a simple, compact measure
of QOL applicable to patients with any skin disease.
A Spanish study using a translated version of the
DLQI found it to be generally reliable, valid, and
responsive to change [13]. A pediatric version of the
DLQI also exists [7].
Dermatology Quality-of-Life Scales
Developed from patient-generated items, the Der-
matology Quality-of-Life Scales are intended to
complement the DLQI with more emphasis on the
psychosocial domain of QOL, with a psychosocial
score composed of four subscales of embarrassment,
despair, irritableness, and distress, along with addi-
tional items addressing physical activities and symp-
toms [14].
Next, this article discusses disease-specific assess-
ments that focus on the effects of psoriasis on HRQOL.
Psoriasis Disability Index
The Psoriasis Disability Index (PDI), a 15-item
questionnaire, was developed with patients who have
psoriasis to assess QOL by looking at the following
areas: daily activities, work or school matters, per-
sonal relationships, leisure, and treatment [15]. Pa-
tient scores on the PDI correlate with their scores on
the UKSIP, a general measure of QOL, supporting the
validity of the PDI in measuring QOL [16]. It has
been argued, however, that use of the PDI in the
United States might be limited by the disparity
between the British patients with whom the test was
R. Mukhtar et al / Dermatol Clin 22 (2004) 389–395 391
developed and the typical American patient with
psoriasis, as the differing structures of health care
systems mean that dermatologists in the two countries
have access to different populations. Although der-
matologists in the United States treat many mild to
moderate cases on an outpatient basis, dermatologists
in the United Kingdom have more limited access to
the average patient with psoriasis, instead seeing
more patients on the severe end of the disease
spectrum [5].
Psoriasis Quality-of-Life Questionnaire–12
The Psoriasis Quality-of-Life Questionnaire–12
(PQOL-12) is a 12-item self-administered, disease-
specific, psychometric instrument created to specifi-
cally assess those QOL issues that are most important
to the largest proportion of patients with psoriasis. It
was developed using both nationwide, randomized
psoriasis population samples and multicentered clini-
cal trial subjects [17,18]. The original 41-item, two-
factor domain (psychosocial and physical) version
was created by testing many questions in a sample of
patients with psoriasis drawn from a nationwide
survey [5]. Psychometric analysis showed the origi-
nal PQOL-41 had satisfactory reliability, validity,
and responsiveness to change [19]; however, it was
too lengthy to be practically administered in a
clinical setting and there was some overlap between
its questions.
Therefore, a three-center study to determine va-
lidity and correlation with the Psoriasis Area and
Severity Index (PASI) was conducted. A total of 474
subjects participated who had disease ranging from
mild to severe. As a result of this study, a shortened
version of the questionnaire was developed that
contained only 12 items with one factor/domain.
The PQOL-12, produced by Koo et al [17,18], is a
valid, reliable, and responsive subset of the original
PQOL, with a Cronbach’s a of 0.95 and a mean
interitem correlation of 0.62. Because this instrument
was purposely designed to assess issues that were
scientifically proven to be of most relevance to the
largest population of patients with psoriasis, it shows
a predictable correlation with PASI. Simultaneous
assessment of PASI and PQOL-12 demonstrated that
for every 1-point increase in PASI score, the mean
PQOL-12 score increased by 6 to 11 points. There
was a similar correlation found with BSA measure-
ments and simultaneously administered DLQI sur-
veys. The PQOL-12 takes approximately 5 minutes to
complete and is appropriate to use in both clinical
practice and research. In addition, it can be used
across the spectrum of disease severity.
Physical impact of psoriasis
You have a disgusting body covered by marks and
lesions. You feel like a leper . . . I feel unclean and
sticky. Touching the rash disgusts me. [1]
In Koo’s [5] nationwide population study, psori-
asis sufferers reported that the worst and second
worst things about psoriasis were (1) itching and
scratching and (2) appearance. At least two other
studies reported on the high prevalence of pruritus in
psoriasis, with 76% of sufferers experiencing pruritus
‘‘frequently’’ or ‘‘all the time’’ in one study, and 79%
reporting pruritus in another [4,20]. Itching and skin
soreness have been found to have a negative impact
on the mental component of the SF-36 [21]. Because
of the high prevalence of pruritus and its negative
impact on the QOL of psoriasis sufferers, it has been
suggested that physicians pay more attention to con-
trolling this symptom [22].
In addition, Krueger et al’s [4] survey of the NPF
found that 94% and 71% of patients experienced
scaling and skin redness, respectively, with 39% of
the total group describing involvement of more than
10% of their bodies. The location of these physical
signs affects how the patient feels emotionally, with
more discomfort resulting from the involvement of
the face, scalp, or hands [1]. Messy, sticky, and
malodorous treatments can be physically unappealing
for patients as well [23].
Those individuals with psoriatic arthritis face
additional physical challenges. The NPF’s 1998 sur-
vey reported that roughly two thirds of these patients
have difficulty using their hands, standing for long
periods of time, and ambulating [4].
Mental health impact of psoriasis
I often have a feeling of being inadequate. The
disease brings defeat after defeat. I am ashamed of
being different. [1]
Research has shown that psoriasis has deleterious
effects on an individual’s psychosocial functioning.
In a national study in which 67% of the original
50,000 subjects returned surveys, people with psori-
asis were more likely to feel self-conscious, helpless,
embarrassed, angry, and frustrated than those with-
out psoriasis. Those who considered their psoriasis to
be more severe were more likely to feel uncomfort-
able or apprehensive about their appearance [5].
Patients with psoriasis also report significant levels
of social embarrassment, life disruption, and social
withdrawal [24].
R. Mukhtar et al / Dermatol Clin 22 (2004) 389–395392
In a study of 64 patients with psoriasis, 56%
reported being markedly to extremely anxious and
46% reported moderate to extreme depression during
flares of the disease. During these periods of exacer-
bation, 33% of patients remained housebound, with
15% of patients being essentially housebound even in
between flares [24]. McKenna and Stern [25] fol-
lowed up with 1113 patients who had previously been
enrolled in the long-term psoralen plus ultraviolet A
light, or PUVA, cohort study in 1976. Of those
patients, 44% felt physically unattractive, sexually
undesirable, or both, whereas 29% felt shame or
embarrassment because of their psoriasis. As self-
reported disease severity increases, so does use of
alcohol, cigarettes, tranquilizers, sleeping pills, and
antidepressant drugs [26].
Of particular concern is the increased depression
and suicidal ideation found in patients who have
psoriasis. Psoriasis sufferers have significantly higher
rates of depression and problems with body cathexis
than do control subjects [27]. One small-scale study
found a 37% prevalence of depression in its sample of
psoriasis sufferers, and an association between active
flares of skin lesions and higher stress levels, suggest-
ing that stress might play a causal role in psoriasis
activity and initiate a self-perpetuating cycle of stress,
flare, and subsequently, more stress [28]. Krueger et al
[4] found that in those patients aged 18 to 34 years,
54% reported feeling depressed. Another study found
links between pruritus, sleep difficulties, and depres-
sion, and reported that active suicidal ideation is found
in more than 5% of patients with psoriasis [29].
Similarly, Gupta and Gupta [30] found a 5.5% preva-
lence of acute suicidal ideation and a 9.7% prevalence
of a death wish in patients with psoriasis.
One gets a sense of just how life-altering psoriasis
can be by how much time and money patients would
be willing to invest in a cure. Forty-nine percent of
patients surveyed were willing to spend 2 to 3 hours
each day on treatment if it would result in normal
skin for the rest of the day [31]. In another study,
patients with psoriasis were willing to pay 9% to 14%
of their income each month for a cure, roughly the
same amount patients with asthma were willing to
pay [32].
Social interactions and psoriasis
I want to do many things; I want to be a positive
person and talk to other people. But the psoriasis
stops me from seeking the contact I want with others.
I’m afraid of rejection . . . I feel sort of alone with my
disease . . . I also feel like I want to hide. [1]
Many studies have shown that the shame and
embarrassment patients with psoriasis feel does not
evolve simply out of self-consciousness but from
actual experiences of rejection from others. Krueger
et al [4] found that 40% of those with severe psoriasis
had experienced problems receiving equal service or
treatment in places like hair salons, barbershops,
public pools, and health clubs. In a study of 137
patients with moderate to severe psoriasis, Gupta
et al [33] found that 26.3% of patients with psoriasis
had had an episode in the previous month where
‘‘people made a conscious effort not to touch them.’’
Although these experiences can depend on the pa-
tient’s perception of the social interaction, Ginsburg
and Link [34] reported that 19 of 100 subjects studied
had experienced a total of 50 episodes of frank rejec-
tion from a gym, pool, hairdresser, or job, despite the
fact that many of these patients with psoriasis avoid
these places to begin with for fear of such reactions.
Even in their intimate personal relations, sufferers
are not spared the negative impact of their disease. Of
120 patients with psoriasis surveyed, 40.8% reported
being affected sexually, with a decline in the amount
of sexual activity. These patients reported more joint
pains, somewhat increased severity of disease affect-
ing the groin region, greater scaling, and greater
pruritus severity than psoriasis sufferers who were
not affected sexually. Sixty percent of those affected
attributed the decline in their sexual activity to the
appearance caused by their psoriasis [35].
Patients with psoriasis often respond to difficulties
in social interactions by avoiding them altogether.
They engage in anticipatory and avoidant behavior,
such as not going to a swimming pool, even if they
haven’t experienced rejection previously [29]. The
stress of avoiding negative reactions from others has
a huge impact on the psyche of patients with psori-
asis. Furthermore, stress resulting from anticipating
other people’s reactions to psoriasis has been found to
have more effect on day-to-day QOL than any other
factor taken into consideration, including medical
and health status [36]. This finding has led Lebwohl
and Tan [37] to argue that interventions that can
reduce this fear of negative evaluation can improve
patient QOL.
Several studies have shown that younger patients
with psoriasis are more acutely affected by the
difficulties they face in social interactions than older
patients. Patients aged 18 to 54 years report a greater
impact of psoriasis on the psychosocial aspects of
their lives than do respondents aged 55 years and
older, describing more difficulty in sexual activities,
embarrassment, feelings of being unattractive, and
frustration [4,26]. Gupta and Gupta [38] reported that
R. Mukhtar et al / Dermatol Clin 22 (2004) 389–395 393
patients aged 18 to 45 years have more problems with
appearance, socialization, occupation, and finances
than those older than 45 years. Younger patients also
have been found to be less compliant than older
patients [39]. The increased QOL impact of psoriasis
coupled with poor compliance warrants clinicians
paying particular attention to younger patients, espe-
cially children and adolescents [40].
Seeking social support, expressing emotions, tell-
ing others that psoriasis is not contagious, and en-
dorsing beliefs in the controllability of the disease
lessen the negative impact of psoriasis on QOL [41–
43]. Furthermore, the following have been found to
be significantly associated with a negative impact on
QOL: telling others about psoriasis without address-
ing its noninfectious nature, covering the lesions, and
avoiding people [41].
Financial impact of psoriasis
The only thing you think of is scratching, bathing,
and putting on ointment, then putting on more
ointment, bathing, scratching, and slathering on
ointment yet again. It’s in your head 24 hours a
day. [1]
Psoriasis presents direct costs to the patient and
health care system in terms of treatment and indirect
costs in terms of time lost from work and difficulties
with employment in general. In 1993, the outpatient
cost of psoriasis in the United States was conserva-
tively estimated to be between 1.6 and 3.2 billion
dollars annually. The mean annual direct cost for an
individual patient is estimated at $800 per year [44].
In one study, of the 54% of subjects who were not
working or retired, 34% attributed their employment
status to their psoriasis. Of those who were working,
59.3% had lost a mean of 26 days from work during
the previous year because of their disease [31]. In
addition, patients with severe psoriasis rate the qual-
ity of their work life lower than do control subjects
[44], and 6% report discrimination at work [4]. Men
tend to have greater work-related stresses because of
their psoriasis than do women, reporting more fear of
losing their job and more criticism for taking time off
to go to medical appointments [38]. Psoriasis can, in
fact, be so severe as to make working impossible for
some patients [22].
The financial effects of psoriasis overlap with
other aspects of QOL as well, with one study finding
that unemployed patients suffer from more desqua-
mation than employed patients [21]. Patients with
lower family incomes not only are more affected by
the cost of psoriasis treatment but also spend more
time caring for psoriasis. In addition, they perceive
more interference with work and activities around the
home [44].
How psoriasis compares with other diseases
Using the SF-36 to compare QOL impact between
different conditions, Rapp et al [21] found that
patients with psoriasis report reductions in physical
functioning and mental health comparable to that
seen in patients with cancer, arthritis, hypertension,
heart disease, and diabetes. Furthermore, patients
with psoriasis had among the lowest SF-36 scores
of all groups. Only patients with congestive heart
failure scored lower on the physical component score,
and only patients with depression or chronic lung
disease scored lower on the mental component score
[20]. The negative effects of psoriasis on the physical,
psychologic, and social aspects of life can be worse
than those caused by life-threatening illnesses [22].
For a sense of comparison, 46%, 42%, and 32% of
severe psoriasis sufferers considered it ‘‘better’’ or
‘‘the same’’ to have diabetes, asthma, or bronchitis,
respectively. Of those subjects who happened to
have both psoriasis and the comparative disease,
the percentages rose to 87%, 80%, and 77%, respec-
tively [29].
Summary
A preponderance of evidence clearly shows that
understanding the true impact of psoriasis on patients
requires assessing their QOL. Better QOL tools are
necessary to further reduce the gap that exists between
patient experience and clinician perception of the
illness. Knowing the impact of disease on QOL can
help clinicians and patients when grappling with
treatment options and performing risk–benefit analy-
ses. Using tools like BSA measurements only skim
the surface without really getting to the core of the
illness [45]. HRQOL measurements reveal that psori-
asis sufferers face challenges that demand that psori-
asis be viewed and aggressively treated as a serious
disease. Patients with psoriasis deserve as much
attention from clinicians and policymakers as patients
with other systemic illnesses. It is hoped that such
mindfulness will lead to better treatments and in-
creased public awareness of this noncontagious, dis-
abling disease. This result, in and of itself, might help
ameliorate some of the negative impact of the disease.
R. Mukhtar et al / Dermatol Clin 22 (2004) 389–395394
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Dermatol Clin 22 (2004) 397–406
Phototherapy arsenal in the treatment of psoriasis
Michael Zanolli, MDa,b,*
aDermatology Consultants, PC, 4230 Harding Road, Suite 609 East, Nashville, TN 37205, USAbDivision of Dermatology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
An essential method of treatment for psoriasis tant psoriasis, and can be used with precautions and
vulgaris in the twenty-first century will remain the
option for UVB light therapy and photochemother-
apy. During the last half of the twentieth century, the
use of UVB therapy was one of the mainstays of
treatment for psoriasis. During the last quarter cen-
tury, photochemotherapy in the form of psoralen plus
UVA (PUVA) emerged as one of the most effective
modalities of treatment for psoriasis. Accompanying
the advent of the most recent era of psoriasis with
targeted biologic therapies has been a decline in the
frequency of phototherapy. This does not diminish its
known clinical effects and, because of a better un-
derstanding of photobiology, the therapeutic ap-
proach to treatment of psoriasis with UV light has a
common basis for treatment of psoriasis along with
and in combination with new biologic agents [1].
Individuals affected with psoriasis vulgaris know
the natural effect of sunlight can improve psoriasis in
most cases. This use of limited amounts of natural
sunlight will continue as a practical approach to treat-
ment of psoriasis for patients. Refinement of the
delivery and methods for the most effective wave-
lengths of UV light in treating psoriasis will continue
into the twenty-first century. This is evidenced by the
continued prevalence of the availability of narrow-
band UVB, which has been recognized as more
effective than broadband UVB, in addition to the
devices that deliver the most effective range of UV
light to the skin in a localized manner. The efficacy of
PUVA for the treatment of psoriasis has not been
surpassed by any other form of phototherapy. It still
plays a significant role, especially in extensive resis-
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/j.det.2003.12.003
* Dermatology Consultants, PC, 4230 Harding Road,
Suite 609 East, Nashville, TN 37205.
E-mail address: [email protected]
limitation of total dose with excellent response. The
long-term experience with the use of photochemo-
therapy has been important in helping to understand
potential risks and side effects for that modality. It is
similar to other psoriasis treatments in that caution
must be used when PUVA and other forms of photo-
chemotherapy are used.
Natural phototherapy
Natural sunlight for treatment of psoriasis has
been used throughout the ages, even before the
advent of Westernized medicine. It is common
knowledge, evidenced by experience and observa-
tion, that a vacation to more southern latitudes or to
areas of recreation, such as beaches, tends to help
patients with psoriasis and in many cases contributes
part of an annual practice to help clear up limited thin
plaque-type psoriasis. The closer one is to the equator
and the lower the latitude, there is more energy in the
terrestrial light in UVB range. This is caused by the
angle of incidence of the sun to the earth’s surface.
As such, there are special geographic locations in
the world today that further enhance the effects of UV
light and are frequently used as a therapeutic ap-
proach to treatment. Specifically, the UV light that
reaches the earth’s surface at the Dead Sea, which is
below sea level, is unique in its spectrum [2]. Be-
cause the Dead Sea is below sea level, the terrestrial
light at this location has less of the 290 to 300 nm
wavelengths of light. This slight shift in the spectrum
more toward the mid range of UVB enhances the
ability for a person to incur less sunburning and
obtain more therapeutic UVB as it relates to treatment
of psoriasis. This is very beneficial because of the
known enhanced effects of wavelengths closer to
s reserved.
M. Zanolli / Dermatol Clin 22 (2004) 397–406398
310 to 315 nm. One can consider the Dead Sea to be
more of a natural location for therapeutic UVB
unique in the world. Use of this therapeutic spa and
scientific investigations that have been ongoing for
decades at the Dead Sea attest to this being a very
special place to receive UV light in combination with
the specialized salts found in the Dead Sea. The
remissions obtained and the clearing percentage for
persons attending the spa for 2 to 4 weeks has not
been achieved at any other natural therapeutic resort
for treatment of psoriasis.
Box 1. Broad band UVB protocol byMinimal Erythma Dose (MED)
1) Obtain MED using the followingdoses (mj/cm2): 20, 40, 60, 80,100, 120
2) Start at 70% of MED3) Increase by 20% of MED each
treatment4) Treatment frequency of
3–5X/week
Artificial UVB
Amainstay of therapy for psoriasis during the mid-
portion of the twentieth century was the use of UVB
produced by an artificial light source, either alone or
in combination with other agents. The refinement of
this modality of therapy using either a discontinuous
spectrum from hot quartz lamps or the use of fluores-
cent tubes has gradually evolved and facilitated ease
of use in an office-based setting. The current mainstay
of therapy for office-based UV light is the fluorescent
tube. The fluorescent tube has the benefit of ease of
mass production and depending on the phosphor used
to line the inner surface of the fluorescent tube, can
also have more specific emissions spectrum. The
broad-spectrum fluorescent tubes remain important
and contain a relatively wide range of UV light. They
contain higher-energy, lower-frequency UV light, and
carry a greater potential for a sunburning-type reac-
tion and erythemogenic response.
The availability of narrowband UVB on a com-
mercial scale was made possible because of the
specialized lamps produced by Phillips having the
narrow spectrum between 300 and 313 nm. Because
of their specialized use, however, the production of
these lamps has not been a major emphasis by this
company. The lamps have a relatively shorter work-
ing life of 500 to 1000 hours of operation as com-
pared with the more durable broader-spectrum UVB
lamps that can maintain fairly consistent output with
thousands of hours. This fact requires that the nar-
rowband UVB lamps be replaced more often because
their fluence diminishes with less use as compared
with broad-spectrum UVB lamps.
Traditional broadband UVB therapy
The use of conventional broadband UV light
therapy is dependent on an induction phase during
the initial response with thinning of the psoriatic
plaques and then a variable duration of approximately
15 to 25 treatments before full therapeutic efficacy.
The most efficient approach to treatment with any
UVB protocol for the practitioner is first to determine
the minimal erythema dose (MED), which is depen-
dent on the response a person experiences to that
particular light unit. The determination of the MED
shows a dose response and allows for more precise
and more aggressive therapy with UVB, which facili-
tates more rapid clearing and better final results.
Investigation comparing erythemogenic and sub-
erythemogenic UVB delivery demonstrates that the
more aggressive monotherapy with broadband UVB
produces a quicker response rate and a better overall
response. With that type of approach, however,
patients may experience mild discomfort because of
the pink erythema that is consistently produced by the
advancement of therapy on a daily basis. Patients can
improve while undergoing broadband UVB light
therapy without having to incur the maximal MED
on each visit [3]. It is customary to obtain a MED and
proceed by starting at 70% to 75% MED and in-
creasing by up to 50% of the MED each visit.
Aggressive treatment with UVB therapy is possi-
ble because the maximal erythema reaction of the
effects of UVB on the skin is seen between 12 and
18 hours. Patients demonstrate the reaction on their
return even if treatments are given on consecutive
days. Such an aggressive treatment protocol custom-
arily uses an average of 15 to 25 treatments during
the course of therapy to achieve maximal benefit.
Protocols and approaches to treatment may vary from
region to region and a more simplified and slightly
less aggressive approach to treatment for broadband
UVB is set forth in Box 1.
Narrowband UVB
Narrowband UVB has finally achieved general
recognition in North America as advancement in the
further refinement of UV therapy for treatment of
Box 3. Narrow band UVB protocol byMinimal Erythma Dose (MED)
1) Obtain MED2) Start at 50% of MED3) Increase by 10% of MED each
treatment4) Treatment frequency of
3–4X/week
M. Zanolli / Dermatol Clin 22 (2004) 397–406 399
psoriasis. Before the availability of narrowband UVB
in North America in 1998, Europeans had been using
narrowband UVB with regularity and good success.
The original reports reflecting the efficacy and pref-
erence of narrowband UVB emerged in the mid-
1990s. Comparison trials with right- and left-sided
controls on the same individual demonstrated that
narrowband UVB is more effective than broadband
UVB and eliminated the need to produce erythema at
each visit [4–6].
Delivery of broadband UVB is best initiated with
determination of the MED, as with any UVB treat-
ment. This is especially important because the do-
simetry between the broadband and narrowband is
different and to be able to have a dosage measured in
millijoule per square centimeter, one needs to have
the proper photometers or accurate readings of the
irradiance from the lamps themselves provided by the
manufacturer. This information enables one to deliver
incremental doses just below the range known to
cause erythema for the Fitzpatrick’s skin type deter-
mination of patients being treated. This is important
because the more limited wavelengths of the narrow-
band spectrum emitted by these specialized fluores-
cent tubes require a much higher energy because of
the absence of the more erythemogenic shorter wave-
lengths from 310 nm and below. The dosage range
for the determination of MED by skin type is included
in Box 2. There can certainly be production of ery-
thema using narrowband UVB, and this is also on a
reproducible dose response curve in an individual.
As with any erythema dose response within the
UV range, the higher the skin type, the higher the
average mean of the millijoule per square centimeter
is needed to produce erythema. Each skin type has a
broader range for MED with narrowband UVB than
with broadband UVB, which further illustrates the
importance of determining MED before initiation of a
treatment protocol.
A series of experiments done in the 1990s to
maximize therapeutic benefits of narrowband UVB
shows therapy done three times weekly is essentially
as effective as broadband UVB done five times per
Box 2. Dose range for MED testing fornarrow band UVB
� Six test sites of 1.5 cm2 each� For skin types I–III (mj/cm2): 400,600, 800, 1000, 1200, 1400
� For skin types IV–VI (mj/cm2): 600,800, 1000, 1200, 1400, 1600
week and is certainly more convenient for the patient
[7]. A more aggressive approach that maximizes the
erythemogenic potential of narrowband UVB does
not offer substantial benefit over trying to maximize
the amount of erythema produced at each visit. The
less aggressive approach is certainly preferred by the
patients receiving treatment.
The use of lubricants that help transmit UV light
on top of the skin’s surface and decreases reflectance
from the psoriatic scale is also considered standard
therapy. The protocol for the use of narrowband UVB
in an office-based setting is outlined in Box 3. There
is some variability of the starting dose of narrowband
UVB, either at a more conservative 50% or slightly
more aggressive 70% of the MED. The onset of
erythema following narrowband UVB occurs within
8 to 24 hours.
One of the practical advantages of using limited
narrowband UVB wavelengths delivered to the skin
surface is that phototoxic or photoallergic drug reac-
tions do not occur as frequently as with the broader-
spectrum broadband UV, and with UVA light used
with photochemotherapy. There have been reports of
photoallergic reactions in patients who are receiving
narrowband UVB, but the occurrence of drug reac-
tions while receiving narrowband UVB is uncommon.
Localized UVB
The traditional use of localized delivery of UV
light for treatment of hands and feet has been facili-
tated by the availability of 2- to 3-ft fluorescent tubes
with broadband wavelength. Similar systems are used
for localized bath PUVA therapy with irradiation or
systemic PUVAwith irradiation of just the hands and
feet. The use of UVB for hyperkeratotic thick plaques
on the distal extremities has limited response, and
combination therapy with a systemic retinoid is
frequently used to enhance the efficacy of the treat-
ments. There is more success with the use of systemic
administration of psoralen with localized delivery
of UVA to the hand and feet but this approach also
is enhanced with addition of systemic retinoids to
M. Zanolli / Dermatol Clin 22 (2004) 397–406400
decrease the thickness of the plaques before and
during phototherapy.
The application of localized delivery of laser light
near the optimal wavelength for maximal efficiency
in the treatment of psoriasis led to clinical investiga-
tions regarding the excimer laser for treatment of
psoriasis [8]. Because noninvolved skin is left unir-
radiated, this offers the opportunity to test for the
optimal method of delivery and dose for treatment of
psoriasis without involving the surrounding skin.
Using multiples of the MED when treating psoriasis
has been found to enhance the benefits and therapeu-
tic response to laser light. The durability of the
clearing was also correlated with the more aggressive
treatment using 4x, 6x, and 8x multiples of the MED.
As expected, using multiples of the MED produced
very pronounced effects of marked erythema and
blistering at the sites of delivery, although scarring
at the sites was not observed. Another aspect of this
approach to treatment is the reduction in the number
of treatments needed to achieve the response [9].
Generally 8 to 10 treatments can attain clearing of
plaques. Continued experience with this method of
treatment using multiples of the MED with localized
treatment makes it obvious that certain locations
tolerate a higher dose of UV light, such as the knees
and elbows. In those locations multiples of 6 to 8x
MED should be used as compared with 4 to 6x MED
on more sensitive non-UV hardened skin, such as the
intertriginous skin or buttocks.
The same principles used with the laser-generated
coherent light at 308 nm have been applied to the
localized delivery of broader band UVB generated by
a filamentous light source delivered through optics to
a small spot target area. Less complicated technology
using a high-intensity lamp as the light source has
been developed and brought to the market for treat-
ment of psoriasis and other photoresponsive derma-
toses. The two main devices are being marketed
through Lumenis and Theralight corporations. There
are differences between the coherent light at 308 nm
from the excimer laser and the range of the UVB
delivered by the other localized delivery systems for
UVB. Both light units have the same filamentous light
source, but the Lumenis system, B Clear, transmits the
light through a fiberoptic cable to a very functional
handheld delivery, whereas the Theralight unit uses a
liquid medium in a flexible cable to a cylindrical
pencil-grip type handpiece. The Theralight system
has the ability also to switch to a low-fluence UVA
if localized PUVA is a consideration for therapy.
Basic principles of localized delivery of UVB are
the same as with the excimer laser. First, an MED
needs to be obtained; then, choices for the multiple of
the MED to be used for the site to be treated are se-
lected by the clinician. The actual setting on the
device is very easy to determine on the Lumenis
system, which gives a numerical reading of the actual
dose to be delivered. The Theralight system requires
reference to a chart to set the machine, but follows the
same principles of the multiples of the MED. Once a
phototherapist becomes accustomed to the use of any
of the devices the actual operation becomes routine.
Photochemotherapy
The development of photochemotherapy for treat-
ment of psoriasis comprises a major advance in
therapy and efficacy of treatments for psoriasis
worldwide. For centuries it was known that agents
with photosensitizing compounds in the class of
psoralen drugs could be used for treating vitiligo
and other skin disorders. The discovery, however,
that the ingestion of certain psoralen molecules when
combined with UV light has dramatic effects on
psoriasis improved the effective available treatments
further. These advances were championed primarily
in the United States by Fitzpatrick and Parrish but
also were recognized by European colleagues who
developed the use and protocols for delivery of
PUVA [10]. This therapy generated intense clinical
research during the late 1960s and early 1970s.
One reason that photochemotherapy is so impor-
tant is that the duration of remission following
clearing with PUVA is more durable than with
UVB light. Refinements of photochemotherapy and
improvements in the bioavailability of the chemical
after ingestion help make this therapy one of the
standard treatment options in the arsenal for treatment
of psoriasis. Specifically in North America, 8-me-
thoxypsoralen has been the psoralen used for PUVA
therapy. In Europe this has also been a mainstay but
there has been more use in the recent decade of
5-methoxypsoralen, which has therapeutic efficacy
and fewer gastrointestinal side effects [11].
As with the acceptance of UVB therapy for treat-
ment of psoriasis, the adoption and development of
photochemotherapy occurred because of the observed
beneficial therapeutic effect on people with psoriasis.
The exact mechanisms of the psoralen molecule as it
relates to treatment of psoriasis have not been entirely
clear. In fact, further insights are gained into the
mechanism of action for both UV light and photo-
chemotherapy because of a better understanding of
the pathogenesis of psoriasis. The known effects of
photochemotherapy are dependent on both the availa-
bility of the psoralen molecule at the site of action
Box 4. Precautions in selection of PUVApatients
� Skin types I and II� Previous history of skin cancer� Previous or current immunosuppres-sive therapy
� Cumulative number of previousPUVA treatment >200
M. Zanolli / Dermatol Clin 22 (2004) 397–406 401
and stimulation by wavelengths of UV light within its
absorption peaks. It is known that the psoralen mole-
cule intercalates between DNA base pairs through a
concentration gradient. There is no biochemical inter-
action between the psoralen molecule and DNA itself
without activation or absorption of photons of UV
light. If there is absorption of photons of UV light
there is a photochemical reaction with the psoralen
molecule and a pyrimidine base and DNA cross-links
can occur. For a true cyclobutane ring to form another
photochemical reaction must occur. If a cross-link
does form, this is one of the theoretical reasons for
increased development of squamous cell carcinomas
with repetitive therapy over years.
A second mechanism of action of PUVA therapy
on inflammatory skin disorders is oxygen-dependent
photochemical reactions (ie, reactive oxygen species
are formed when the psoralen molecule absorbs
photons in the presence of oxygen). This type of
oxygen-dependent reaction causes membrane and cell
damage and may be central to the observable effects
of UV light on the skin. It seems that antigen-
presenting cells and T lymphocytes are more sus-
ceptible to these oxygen-dependent reactions than
keratinocytes, and the underlying mechanism of ac-
tion of psoriasis photochemotherapy may be inhibi-
tion of immune activation and immune recruitment
of additional T cells into the skin [12].
Taking this one step further one could speculate
that long-term remissions induced by PUVA may be
caused by depopulating the epidermis of antigen-
presenting cells, natural killer T cells, and cutaneous
lymphocyte antigen (CLA)-positive lymphocytes.
These effects decrease the recruitment of additional
cells and reduce the stimulus for the ongoing pso-
riasis reaction instead of just interfering with the
activation of lymphocytes or cytokine messaging. A
short-term remission is expected if message interfer-
ence occurred. A long-term remission is expected if
the cells stimulating the reaction of T lymphocytes
and immune competent cells in the epidermis and
dermis are reduced in number or eliminated.
The use of PUVA gained more widespread availa-
bility throughout the last quarter of the twentieth
century in North America. It is still a vital tool in
therapy, but the availability of PUVA has declined
over the past decade for two main reasons. First, other
therapies have become available that are potent and
modify the immune system. Examples are the known
effect of the cyclosporine class of drugs and more
recently the biologic protein medications that show
efficacy without the need for specialized equipment
and specialized personnel. The second reason is the
30 years of experience with PUVA and the known
increased risk of squamous cell carcinoma that occurs
especially in fair-skinned individuals with greater
than 250 treatments over time [13]. There have been
reports also of increased risk of melanoma in this
special population by following over three decades a
cohort of patients registered in North America [14].
This group of patients has confounding factors, such
as other treatments for psoriasis including systemic
immunosuppressive therapy and the fact that the early
protocols for PUVA used high-dose PUVA, which is
not done to such a degree today. Nonetheless, now
that these important observations and statistical analy-
sis of a specialized group of patients have been done,
clinicians are better able to use this tool in a way that
is safer and with parameters that help ensure the
overall well-being of patients. Precautions and limi-
tations of the use of PUVA over time are listed
in Box 4.
The delivery of PUVA is more complicated than
UVB therapy even though both must have ocular
protection to prevent corneal burns in the case of
UVB and lens and retinal changes more specifically
with the use of PUVA. PUVA requires additional
protection from any other sources of UVA light for
18 to 24 hours following treatment. In my opinion,
PUVA has been a great success story in preventive
medicine over time because of the awareness of the
potential for ocular side effects and the institution of
standardized protocols and mechanisms for proper
eye protection following a treatment.
A manageable but frequent side effect of psoralen
is caused by the nausea that the psoralen compound
commonly produces especially with the use of
8-methoxypsoralen. There is a dose-response rela-
tionship with the degree of nausea that occurs and
peak blood levels of the psoralen compound that
occasionally is so pronounced that patients withdraw
from therapy. Management of the nausea is to take
the psoralen exactly the same way at the same time of
day, preferably in the afternoon, and to have a small
bit of food with the psoralen dose [15]. A slight
reduction in the dose can also be attempted; however,
Box 5. PUVA protocol by skin type
1) Dose of 8-MOP = 0.5 mg/kg2) Ingest psoralen 1.5 hours prior to
treatment3) Take psoralen at same time of day
with liquid4) If nausea take psoralen with some
food5) Dose of UVA
Skin type I–III Initial = 2 J/cm2
Skin type IV–VI Initial = 4 J/cm2
Increase by 1 J/cm2 each treatment6) Frequency of treatments 3X/week
M. Zanolli / Dermatol Clin 22 (2004) 397–406402
care must be taken not to reduce the dose below the
therapeutic range.
There is variability from person to person in the
gastrointestinal absorption of the psoralen molecule.
The range for dosing and the timing of dosing should
remain constant for each individual throughout their
particular course of therapy. Although protocols vary
between regions of the country and between conti-
nents, one of the standard protocols is included in
Box 5. Different psoralen molecules have been used
in Europe primarily to reduce the gastrointestinal side
effects while maintaining efficacy. The most widely
used psoralen molecule besides 8-methoxypsoralen is
5-methoxypsoralen. It still has potential to form
cyclobutane rings and with excessive long-term use
is also expected to increase the risk of squamous
cell carcinoma. The efficacy of 5-methoxypsoralen
is approximately that of 8-methoxypsoralen, however,
with much fewer complaints of gastrointestinal
side effects [16]. The 5-methoxypsoralen is not
available in the United States as a commercial prod-
uct, however, and requires clinical trials to demon-
strate its efficacy before approval by the Food and
Drug Administration.
Combination therapy
Phototherapy historically has been used, especially
in this modern era, in combination with both topical
and systemic agents. In fact, it is unusual not to have
some sort of combination therapy in the form of
concomitant topical agents while the patient is un-
dergoing induction and treatment with either UVB
modalities or PUVA. There are myriad combinations
that have been used, with some known to enhance the
therapeutic effect while reducing the dose and total
number of treatments required for response. This
section highlights the best and most common com-
bination therapies to use with phototherapy and
specifies important nuances in understanding the
maximum benefit and the most efficient delivery of
the combinations.
Topical agents plus phototherapy
Patients must understand that certain topical agents
used with phototherapy may either inhibit the effects
of the UV light by blocking UV light at the surface of
the skin and not allowing it to penetrate to the proper
site of action or inactivate the drug through absorption
of UV light. Topical steroids are still the most com-
mon treatment for mild plaque-type psoriasis and can
be used safely in combination with phototherapy.
Although there might be some initial reduction in
the thickness and a more rapid initial response for
plaque-type psoriasis, continued use of the topical
steroids throughout the course of a full therapeutic
regimen with UVB does not necessarily add much
long-term benefit. When superpotent topical cortico-
steroids are used, a regimen of using the initial
treatment for induction followed by tapering and
discontinuation of topical steroids should be used.
This is the most effective approach to combination
treatment and seems to have the best initial benefit.
Calcipotriene with both UVB and PUVA therapy
has also been used. Calcipotriene can enhance photo-
therapy; however, certain precautions must be taken
to ensure that their combined use does not inhibit or
alter the calcipotriene molecule. Specifically, if calci-
potriene is applied immediately before UV light
therapy, inactivation of the molecule may result. To
realize the enhanced effect of this topical combination
with phototherapy, one should deliver the UV light
treatment first and then use the topical agent later that
day or at least 2 hours before treatment [17]. This
helps ensure the modest benefit that might be
obtained with this combination therapy. Topical for-
mulations of retinoids have also been used to help
enhance the effects of UV therapy [18]. As with the
vitamin D derivatives, application should not imme-
diately precede the delivery of the UV light. Caution
should be used when advancing the dose of UVB or
PUVA in this circumstance because of the retinoid
effect on the plaques of psoriasis.
Systemic retinoids plus UV therapy
The best combination therapy with UV light,
whether UVB or PUVA, is with systemic retinoids
Box 6. Retinoids and UV therapy
� Dose of Acitretin and UVB or PUVA10 or 25 mg/day
� Use the retinoid two weeks prior toinitiation of UV therapy
� Obtain MED with UVB treatments� Select a lower skin type determina-tion when using PUVA
� Adding acitretin to an ongoing photo-therapy treatmentReduce the dose of UV light therapy
by 50%Keep the dose of the UV the same for
six treatments
M. Zanolli / Dermatol Clin 22 (2004) 397–406 403
[19]. Various systemic retinoids are used in combi-
nation with UV light therapy, and numerous studies
have demonstrated their positive effects. The treat-
ment rationale for combining retinoids with UV light
is to enable reduction of the total energy delivered to
the skin and enhance the therapeutic regimen by
decreasing the total number of treatments needed.
The approach to such treatment is to initiate
therapy with the retinoid for at least 7 to 14 days to
establish the retinoid effect on the skin and its
modification of psoriatic plaques. The observed effect
of retinoids on plaque-type psoriasis is to reduce the
thickness of the plaque and help reduce scaling
through their inherent mechanisms of helping to
normalize differentiation of the keratinocytes. The
exact effect of retinoids relates to cellular differentia-
tion through impact on retinoid receptors, both local
and circulating. Retinoids probably also have an
effect on the immune mechanisms involved with
psoriasis. This cumulative effect of the retinoids helps
to decrease the thickness of the plaques and the
scaling, allowing the UV therapy to be more effective
and encounter less blocking and scattering of light at
the skin surface. The retinoid effect increases suscep-
tibility to erythema from UVB and makes one more
prone to phototoxic effects from PUVA. It is not a
direct effect from UV light on the retinoid molecule
itself that produces the increased susceptibility to UV
treatment. It is the effect on the skin, primarily the
epidermis, which enhances the UV light combination.
When using a systemic retinoid 2 weeks before
initiation of UV therapy, caution must be used during
the initiation and induction period of phototherapy.
This is another incidence in which determining the
MED before UVB therapy, whether broadband UVB
or narrowband UVB, is very helpful because using
only skin type to determine the dose is not as ac-
curate, and a starting point has to be estimated
without any objective measurement. The dose of
the retinoid can be reduced when combined with
phototherapy as compared with the dose of retinoid
if used only as a monotherapy. A simplified modifi-
cation of the dosage of retinoid when used in com-
bination with UVB or PUVA is contained in Box 6.
Caution must be applied when considering adding a
retinoid to a UV treatment program if a patient has
already received multiple doses of UV light. The
tolerance to UV, whether UVB or PUVA, is decreased
within 1 week of introduction of the retinoid and
unexpected phototoxic reactions may occur even
without increase in the dose of UV light. If a retinoid
is to be introduced to an ongoing protocol for photo-
therapy it is recommended the dose of the UV light
be reduced by 50% at the start of retinoid therapy and
kept at that level for 2 weeks before increasing the
dose of UV light.
Various individual retinoid molecules have been
used in combination with phototherapy. Currently, the
most used retinoid is acitretin [20–22]. The basic
principles for the use of retinoids in conjunction with
phototherapy have been applied to the combination of
acitretin plus narrowband UVB, although there are no
studies that have actually been performed in a pro-
spective manner.
Thirteen-cis-retinoic acid (Accutane) can also be
used in combination with phototherapy, but requires
adhering to the general precautions needed for all the
retinoids and their use. This is especially true with
regard to informed consent and the special precau-
tions necessary for avoidance of pregnancy. There
may be times when 13-cis-retinoic acid is preferred
over acitretin because of the problems with long-term
bioavailability of acitretin metabolites when com-
bined with alcohol. With even minimal ethanol con-
sumption a potential for long-term fat storage of the
teratogenic metabolite occurs, which requires pro-
longed years of strict adherence to contraception.
Other systemic agents and UV therapy
There are other systemic agents that have been
tried and used with phototherapy. Particular features
of some of the more common systemic agents deserve
mention when used in combination. Methotrexate has
frequently been used in combination treatment for
psoriasis [23,24]. Short-term UV light therapy may
be particularly helpful in aborting psoriasis flares,
which can then be brought under control with long-
term use of methotrexate with appropriate monitor-
ing. Methotrexate by itself does not inhibit the
M. Zanolli / Dermatol Clin404
efficacy of UV treatments. In fact, if methotrexate is
used before UV light, some of the same plaque-
thinning benefits realized by retinoids can occur,
helping with the induction of UV light response. It
is more common, however, to have UV light used as
an adjunct to long-term methotrexate treatments.
Early studies show that the combination can be very
helpful with application of routine broadband UVB.
One must prevent a generalized phototoxic reaction
with excessive UV light therapy during the course of
treatment. This is true whether a therapeutic use of
UV light is used or a patient sustains a sunburn
reaction from natural sunlight. This situation can
provoke what is known as a ‘‘recall reaction’’ with
methotrexate and normal doses of light subsequent to
the burn. Although it is an infrequent and unexpected
side effect, if the recall reaction occurs, it may be as a
result of normal doses of therapeutic UV light.
The combination of methotrexate and PUVA has
also been used. This alternative is not considered a
very common treatment choice because of the in-
creased incidence of squamous cell carcinoma known
to occur with long-term PUVA therapy with the
additional relative immunosuppression of methotrex-
ate. Short-term it can be used with caution for very
resistant cases having significant plaque-type pso-
riasis. This is another instance in which methotrex-
ate can be used during the pretreatment phase and
then tapered before induction with PUVA. The ap-
propriate procedure is to limit methotrexate use to
the 1 or 2 months before induction and maintenance
with PUVA.
Another conventional therapy used for resistant
plaque-type psoriasis is cyclosporine. Combination
therapies with cyclosporine should be used very
cautiously because the particular combination of
cyclosporine and PUVA therapy, if used long-term,
leads to increased risk of squamous cell carcinoma
over and above the risk inherent in PUVA itself [25].
Whether broadband or narrowband, UVB combina-
tion therapy with cyclosporine generally should not
be used in the long-term. If there are resistant
plaques, possibly just a short-term course of UV light
therapy should be considered. Of particular concern
here is historical use of PUVA, especially in patients
who had long-term maintenance with PUVA therapy
before the advent of the use of cyclosporine. In this
instance, even use of cyclosporine post-PUVA carries
increased risk of developing or facilitating squamous
cell carcinomas years posttherapy as demonstrated by
the results of long-term follow-up of the PUVA
cohort. Patients having a history of years of PUVA
treatment should be considered to have a relative
contraindication for any follow-up with cyclosporine.
Biologics in combination with UV light
Over the next 2 to 5 years more information about
use of biologic agents with UV light therapy, particu-
larly narrowband UVB, will be available. The regu-
lations regarding phase 2 and phase 3 clinical trials
require that phototherapy be excluded as concomitant
therapy during the clinical trials determining the
dosage, frequency, efficacy, and safety of the biologic
agents that have become part of treatment for psori-
asis over the last 2 years. Small pilot studies are now
starting to appear concerning UV combination treat-
ments with alefacept and etanercept. These initial
reports are few and do not define the nuances of
phototherapy, which may be important for the most
effective and efficient delivery of UVB therapy. The
important factors are whether or not there is change in
the MED with concomitant use of the biologic
treatment and if there is any actual significant en-
hancement of effect in conjunction with UVB therapy.
The general principles underlying combination ther-
apy with UV therapy are to decrease the total dose of
millijoule per square centimeter for an individual and
to decrease the total number of treatments needed to
obtain the desired effect. Subsequent trials will pro-
vide further insights concerning these issues.
Theoretically, there could be great advantage to
the combination therapy with biologics and UV light.
The biologics may have actions that vary from
inhibiting circulating T cells from entering the der-
mis, such as with efalizumab, or decreasing circulat-
ing CD4 lymphocytes, as with alefacept. The use of
narrowband UVB could compliment these effects
through known mechanisms of decreasing CD3 lym-
phocytes in the epidermis [26], thereby having po-
tential for attacking the cutaneous immune system
from the surface of the skin while the biologic agents
act on cells in the circulating CLA, CD45RO+
lymphocyte pool. Although the frequency of office-
based UV light treatment has diminished over the
past 5 years in North America there is great potential
for short-term intermittent combination therapy for
patients who may be on long-term therapy with one
of the new biologic agents.
22 (2004) 397–406
Summary
Ultraviolet light has been the most used and
effective treatment of psoriasis over the centuries.
The beneficial effects of natural sunlight for clearing
of psoriasis on the exposed skin do not depend on
technology or insight into the known pathogenesis of
the disease. In fact, an understanding of the patho-
M. Zanolli / Dermatol Clin 22 (2004) 397–406 405
genesis was not necessary to recommend one of the
traditionally effective treatments of psoriasis with
long-term remissions, as was done with the Goecker-
man therapy for psoriasis in the mid portion of the
twentieth century. Even the current advancements in
therapeutics enjoyed today with the advent of the
biologics and other immunomodulating systemic
agents do not surpass the overall response rate and
duration of remission of the previous standard of
therapy that was had in the 1950s. Refinements in
the delivery of UVB light, the development of photo-
chemotherapy with PUVA, and the more recent
focusing of the spectrum of UVB to the most effec-
tive region between 310 and 313 nm for narrowband
UVB have given clinicians additional options in the
arsenal of therapeutics to attack psoriasis. Further
refinements of the delivery systems for UVB in the
form of lasers and localized delivery through fiber-
optics are beneficial in helping to reduce the overall
exposure of noninvolved skin and permitting more
aggressive doses of UV to the sites of disease while
sparing noninvolved skin.
Enhancement of the different modalities of UVB
and PUVA has been demonstrated with systemic
agents, such as retinoids, but also in combination
with immunosuppressive agents for short-term treat-
ment to hasten the initial response to treatment. The
advent of the biologic agents in treating psoriasis also
introduced the opportunity for combination therapy
and the theoretical advantage of managing T cells and
antigen-presenting cells in the epidermis with UV
light, and activated T cells in the circulation.
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Dermatol Clin 22 (2004) 407–426
Current concepts and review of alefacept in the treatment
of psoriasis
Gerald G. Krueger, MD
Department of Dermatology, 4B454 School Medicine, University of Utah Health Sciences Center, 30 N 1900 E,
Salt Lake City, UT 84132-2409, USA
Alefacept is the first and only biologic agent ap- marker that can be targeted by therapeutic agents.
proved by the US Food and Drug Administration for
the treatment of adult patients with moderate to severe
chronic plaque psoriasis who are candidates for sys-
temic therapy or phototherapy. Several reviews have
been published on alefacept and new treatment options
for psoriasis [1–4]. This article provides updated in-
formation on alefacept with regard to the following:
� Mechanism of action� New data analyses from the psoriasis clinical
program� Rationale and design of two recently completed
pilot studies, one evaluating alefacept/ultraviolet
B (UVB) light combination therapy for psoriasis
and the other investigating the effects of adding
alefacept to methotrexate in patients with active
rheumatoid arthritis (RA)� Description of an ongoing psoriasis study in
which alefacept is used concurrently with other
systemic therapies and phototherapy� Initial findings in patients with psoriatic arthritis
Mechanism of action
Psoriasis is an immune-mediated disease, with
memory T cells playing a key role in disease patho-
genesis [3,5]. The costimulatory molecule CD2 is
highly expressed on activated memory T cells [6–8].
This increased expression of CD2 provides a specific
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/j.det.2004.03.014
Conflict of interest: the author has been a long-term con-
sultant for Biogen and a lead investigator or an investigator
in some of the clinical trials.
E-mail address: [email protected]
Alefacept is a bivalent recombinant fusion protein
composed of the first extracellular domain of lym-
phocyte function-associated antigen 3 (LFA-3) fused
to the hinge, CH2 domain, and CH3 domain of human
IgG1. The results of experiments in vitro and in
rodents have shown that alefacept has a dual mecha-
nism of action. The LFA-3 portion of alefacept binds
to CD2 receptors on T cells, thereby blocking their
natural interaction with LFA-3 on antigen-presenting
cells. The IgG1 portion of alefacept binds to the FcgRreceptor on accessory cells (eg, natural killer [NK]
cells) to cause T-cell apoptosis [9,10]. Cytotoxic
assays have shown the apoptotic effects of alefacept
to be selective for the activated memory T-cell
population [6], presumably because of the CD2 up-
regulation associated with this cell type.
Recent experimentation using mutant LFA-3/IgG1
isoforms and cell depletion or antibody blockade
strategies indicates that alefacept immunomodulation
reflects its ability to mediate cognate interactions
between cells expressing human CD2 and human
CD16 (FcgRIII) [11]. To address the molecular and
structural basis for the mechanisms of action of
alefacept, its signal-inducing properties were investi-
gated in transfected Jurkat cells and in interleukin
2–expanded NK cells, which express both CD2 and
CD16. Alefacept induced the activation of intracel-
lular signaling pathways (eg, phosphorylation of
extracellular signal-regulated kinase, up-regulated ex-
pression of the cell surface activation marker CD25,
and release of granzyme B). The binding of alefacept
to both CD2 and CD16 was required for pharmaco-
logic activity, although most of the signaling was
mediated through CD16. Thus, alefacept acts as an
effector molecule, mediating cognate interactions of
s reserved.
Activation
CD2
CD2
CD16CD16TNF
TNF-R
Apoptosis
Apoptosis
CD2+ target cell
NK cell
Caspase- independent pathway
Caspases
GRANZYME/PERFORIN
Alefacept Alefacept
Fig. 1. Model for the activation of apoptosis of sensitive CD2+ cells by alefacept. The LFA-3 portion of alefacept binds CD2
(eg, T cells), and the IgG1 portion binds CD16 on accessory cells (eg, NK cells). Binding of alefacept to both CD2 and CD16
is necessary for pharmacologic activity. NK cells then secrete granzyme/perforin to induce activated CD2+ target cells to undergo
apoptosis. The apoptotic effects of alefacept are selective for the activated memory T-cell population because of its high level of
CD2 expression. Naıve T-cell, NK-cell, and B-cell counts are not significantly affected by alefacept therapy.
G.G. Krueger / Dermatol Clin 22 (2004) 407–426408
cells expressing CD2 and FcgR to activate FcgR+
cells (eg, CD16+ NK cells). These cells secrete
granzyme/perforin to induce activated CD2+ target
cells (eg, T cells) to undergo apoptosis as measured
by annexin V staining (Fig. 1). The prolonged remis-
sions observed in patients with psoriasis who respond
to alefacept (see ‘‘Duration of response’’ section) are
likely the result of this targeted apoptosis.
Alefacept in chronic plaque psoriasis
The clinical profile of alefacept for the treatment
of psoriasis has been extensively studied. Three
studies provide the primary clinical data: one phase
2 study [12] and two phase 3 studies [13,14]. These
studies consistently showed improvements in psoria-
sis that were superior to placebo, durable (even
following treatment cessation), and associated with
improvements in patients’ quality of life (QOL).
Importantly, the effect of alefacept continued well
into the postdosing period, which provided confirma-
tion of the remittive action of the drug and the
importance of evaluating its effect over time.
The efficacy and pharmacodynamic and QOL
effects of alefacept that are presented in the following
sections are primarily based on the results of the two
multicenter, double-blind, placebo-controlled, paral-
lel-group, phase 3 studies involving 1060 patients with
chronic plaque psoriasis. In the intramuscular (IM)
study, patients were randomized to placebo (n = 168),
alefacept (10 mg; n = 173), or alefacept (15 mg; n =
166) for a single course [14]. In the intravenous bolus
(IV) study, patients were randomized to one of three
cohorts: alefacept (7.5 mg) in courses 1 and 2 (cohort
1, n = 183), alefacept (7.5 mg) in course 1 and placebo
in course 2 (cohort 2, n = 184), or placebo in course 1
and alefacept (7.5 mg) in course 2 (cohort 3, n = 186)
[13]. In both studies, each course consisted of
12 once-weekly injections of the study drug followed
by 12 weeks of observation.
Recent analyses of safety data from the phase 3
studies are also presented. In addition, the tolerability
of alefacept over up to six treatment courses is
reported based on a pooled analysis of all studies in
the alefacept clinical program. The latter sections
describe the rationale and design of a study evaluat-
ing combination treatment with alefacept and UVB,
and the design of an ongoing trial that allows alefa-
cept to be administered concomitantly with other
psoriasis systemic and phototherapies.
Efficacy
The benefits of targeted therapy with alefacept are
evident in the overall response rates for reductions in
0
10
20
30
40
50
60
70
80
28
40
71
56
≥50% PASI Reduction
% P
AS
I Red
uct
ion
≥75% PASI Reduction
1 Course of IV Alefacept
2 Courses of IV Alefacept
Fig. 2. Overall response rates for a �50% reduction in PASI and a �75% reduction in PASI with one and two courses of
IV alefacept. (Data from Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver WP, Ellis CN, for the Alefacept Clinical
Study Group. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses
of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol 2002;47(6):821–33.)
G.G. Krueger / Dermatol Clin 22 (2004) 407–426 409
the baseline Psoriasis Area and Severity Index (PASI)
from the two phase 3 studies (Figs. 2 and 3). With
either IM or IV administration, most patients treated
with a single course of alefacept achieved at least a
50% reduction in PASI (PASI-50), and a second
course of therapy provided further benefit by increas-
ing response rates and prolonging the duration of off-
treatment response [13–15].
The following sections summarize new analyses
regarding the efficacy of alefacept among important
subpopulations of patients who participated in these
0
10
20
30
40
50
60
70
80
69
57
≥50% PASI Reduction
% P
AS
I Red
uct
ion
Fig. 3. Overall response rates for a �50% reduction in PASI an
IM alefacept. (Data from Lebwohl M, Christophers E, Langley R
Clinical Study Group. An international, randomized, double-blind,
patients with chronic plaque psoriasis. Arch Dermatol 2003;139:7
pivotal trials. The results demonstrate that alefacept is
efficacious in a broad spectrum of patients with pso-
riasis and that it provides long-lasting off-treatment
responses, regardless of the route of administration.
Patients with severe disease
At baseline, the severity of psoriasis was defined in
both phase 3 studies according to PASI, body surface
area (BSA) involvement, and Physician Global As-
sessment (PGA). The PASI is based on a formula
encompassing disease severity and extent of lesions,
33
43
≥75% PASI Reduction
1 Course of IM Alefacept
2 Courses of IM Alefacept
d a �75% reduction in PASI with one and two courses of
, Ortonne J-P, Roberts J, Griffiths CEM, for the Alefacept
placebo-controlled phase 3 trial of intramuscular alefacept in
19–27.)
66
3341
29Pat
ien
ts (
%)
Alefacept15 mg IM
(n=44)
Placebo IM(n=43)
Alefacept7.5 mg IV(n=111)
Placebo IV(n=56)
0
20
40
60
80
100
Fig. 4. Percentage of patients who achieved a �50% reduction in PASI at any time during treatment or the follow-up period
(overall response rates) for patients with severe disease at screening (PASI, > 20). Results shown are from the two phase 3
studies of alefacept (course 1 data are presented). (Data from Vaishnaw AK, Ticho B. Alefacept is efficacious in a broad spec-
trum of patients with psoriasis, including those with severe disease. Presented at the 61st Annual Meeting of the American
Academy of Dermatology. San Francisco, March 21–26, 2003.)
G.G. Krueger / Dermatol Clin 22 (2004) 407–426410
weighted by the proportion of BSA involved [16].
Scores range from 0 to 72, with the highest score
reflecting complete erythroderma. A PASI greater than
20 generally has been used to define severe disease.
Patients who participated in the phase 3 studies
had a median baseline PASI ranging from 13.2 to
15.2, and a median baseline BSA involvement of 22%
to 24% [17]1. Based on physician assessment, which
is likely to account for multiple factors (eg, severity,
disability, and psychosocial impact), more than 80%
of patients were considered to have moderate, mod-
erate to severe, or severe disease. Among those with a
screening PASI of greater than 20, more patients
treated with alefacept (15 mg given IM or 7.5 mg
given IV) achieved a 50% or greater reduction in PASI
(PASI-50) during treatment or during the follow-up
period (overall response rate) than those who received
placebo (Fig. 4). Results were similar when psoriasis
severity was defined by a BSA of greater than 30% or
a PGA of moderate or worse.
Prior treatment history and response
In the two phase 3 studies, patients were queried
about their prior therapies for psoriasis and then,
during randomization, stratified according to their
histories of prior systemic or phototherapy [18].
Patients were also asked to classify their responses
to each prior systemic or phototherapy as follows: no
1 Data on file, Biogen, Inc.
change, worsening of disease, or improved. The
treatment groups were well balanced with respect to
prior treatment history; 77% and 78% of patients,
respectively, in the IM and IV studies had received
prior systemic or phototherapy. Substantial percent-
ages of patients reported either no change or wors-
ening of their psoriasis after treatment with prior
therapy. Prior therapies consisted of the following:
cyclosporine (21% and 28% of IM and IV patients,
respectively), psoralen plus ultraviolet A light (PUVA;
26% and 36%), methotrexate (32% and 35%), UVB
(35% and 45%), and retinoids (44% and 50% of
IM and IV).
Regardless of prior treatment history, the percent-
ages of patients who achieved a PASI-50 at any time
during treatment or during the follow-up period were
higher in the alefacept group (15 mg IM or 7.5 mg IV)
than in the placebo group (Fig. 5) [18]. Similar
proportions of treatment-naıve and previously treated
patients had a clinically meaningful response to IM or
IV alefacept. As expected, treatment-naıve patients
had slightly better response rates than patients who
had tried other therapies before enrolling in these
studies. In the alefacept 15-mg IM group, 39% of pa-
tients who reported no change or worsening of disease
during prior systemic or phototherapy achieved a 75%
or greater reduction in PASI (PASI-75) compared with
28% of patients who improved on prior therapy. The
corresponding results in the alefacept 7.5-mg IV group
were 36% and 23%, respectively. Importantly, a sub-
stantial number of patients who had not responded to
0
20
40
60
80
100
60 61
24
Pat
ien
ts (
%)
Alefacept15 mg IM(n=47)
PlaceboIM
(n=46)
Treatment–Naïve Prior Systemic Therapy
Alefacept15 mg IM(n=119)
PlaceboIM
(n=122)
Alefacept7.5 mg IV(n=92)
PlaceboIV
(n=46)
Alefacept7.5 mg IV(n=275)
PlaceboIV
(n=140)
Treatment–Naïve Prior Systemic Therapy
37
24
54
34
55
Fig. 5. Percentage of patients who achieved a �50% reduction in PASI at any time during treatment or the follow-up period
(overall response rates) in treatment-naıve patients and those who received prior systemic psoriasis therapies or phototherapy.
Results shown are from the two phase 3 studies of alefacept (course 1 data are presented). (Data from van de Kerkhof P,
Vaishnaw AK, Kragballe K, Ortonne J-P. Alefacept is efficacious in a broad spectrum of patients with psoriasis. J Eur Acad
Dermatol Venereol 2003;17(Suppl):55.)
G.G. Krueger / Dermatol Clin 22 (2004) 407–426 411
prior therapies responded to alefacept. Furthermore,
patients who reported responding to prior therapies
had a lesser overall response to alefacept. This finding
is not understood and requires future study.
Patients who were refractory to or who had
contraindications to conventional systemic psoriasis
therapies or phototherapy
Data from both phase 3 studies were pooled to
determine whether a single course of alefacept was
effective in the subset of patients who were refractory
to or had contraindications to other systemic psoriasis
therapies or phototherapy [19]. Patients who reported
no change or worsening of disease while on such
treatment were considered to be refractory. The most
common contraindication was a history of hyperten-
sion (21%). Among patients who were refractory to or
had contraindications to one or more systemic psoria-
sis therapies or phototherapy, 53% of alefacept-treated
patients and 26% of placebo-treated patients achieved
a PASI-50 during treatment or the follow-up period.
The corresponding results were 52% versus 25%
among patients who were refractory to or had contra-
indications to two or more systemic psoriasis thera-
pies or phototherapy, and 50% versus 21% among
patients who were refractory to or had contraindica-
tions to three or more systemic therapies or photo-
therapy. The efficacy results were comparable to those
observed among patients who were not refractory and
who had no contraindications to other systemic pso-
riasis therapies or phototherapy.
Duration of response
The remittive effect of alefacept has been demon-
strated following IV administration [13]. Recently,
data from the phase 3 IM study have been analyzed
and confirmed this effect [20]. In the phase 3 IV study,
patients who received alefacept in course 1 and
placebo in course 2 (cohort 2) were observed to de-
termine the duration of their off-treatment response.
Per the prespecified analysis, patients in this cohort
who achieved a PASI-75 after the first dose main-
tained a PASI-50 for a median of more than 7 months
(216 days). In addition to improving PASI response
rates, two courses of alefacept (cohort 1) provided a
longer duration of response compared with a single
course. The median duration of response could not be
determined because more than 50% of the patients
who received two courses of alefacept had maintained
their PASI-50 at the final study endpoint, nearly 1 year
after the first dose.
Patients who completed the phase 3 IM study
were eligible to enroll in a separate double-blind
extension study. Patients treated with 15 mg of
alefacept in the phase 3 study received another course
of alefacept at the same dosage. In this treatment
group, those who achieved a PASI-75 after the first
dose in the phase 3 study maintained a PASI-50 for a
Alefacept 15 mg (n=166) Placebo (n=167)
Study Week
Mea
n C
ou
nt
(cel
ls/µ
l)
CD4+ Memory T Cells
600
500
400
300
200
100
A.
0 12 24
CD4+ Naïve T Cells
Mea
n C
ou
nt
(cel
ls/µ
l)
0 12 24
600
500
400
300
200
100Dosing PeriodDosing Period
Fig. 6. Effects of IM (A) and IV (B) alefacept on circulating CD4+ memory and naıve T cells. Similar results were seen for
circulating CD8+ memory and naıve T cells (data not shown). Results shown are from the two phase 3 studies of alefacept.
(Reprinted from Gordon KB, Vaishnaw A, O’Gorman J, Haney J, Menter A. Treatment of psoriasis with alefacept. Correlation of
clinical improvement with reductions of memory T-cell counts. Arch Dermatol 2003;139:1563–70; with permission; and
Ortonne J-P, Lebwohl M, Griffiths CEM. Alefacept-induced decreases in circulating blood lymphocyte counts correlate with
clinical response in patients with chronic plaque psoriasis. Eur J Dermatol 2003;13(2):117–23; with permission.)
G.G. Krueger / Dermatol Clin 22 (2004) 407–426412
median of approximately 7 months (209 days) [20].
These observations confirm and extend the data that
show the duration of response to alefacept is pro-
longed and provides patients with an extended treat-
ment-free period.
Pharmacodynamics
As expected from its mechanism of action, alefa-
cept reduces total lymphocyte and CD4+ and CD8+ T-
cell counts [21,22]. Reductions are selective for
memory T cells, with relative sparing of naıve T cells
(Fig. 6) and no notable effects on CD19+ B cells or
CD16+/CD56+ NK cells [21,22]. Importantly, there
has been no evidence of a cumulative effect of
alefacept on total lymphocyte count or lymphocyte
subset counts over two courses in the phase 3 IV
study (Fig. 6B) [21]. Fig. 7 shows the effect of five
courses of 7.5 mg of IV alefacept on CD4+ T cells
based on the results of an ongoing retreatment study2.
Mean reductions reached a plateau during course 3,
and reductions for courses 3 through 5 appeared
superimposable. At no time did mean CD4+ T-cell
counts drop below the lower limit of normal (LLN;
400 cells/mL).Because of the drug’s effects on T cells, the
product labeling recommends that CD4+ T-cell counts
2 Data on file, Biogen, Inc.
be monitored weekly during alefacept therapy. Impor-
tantly, as a part of the clinical studies, safety and
tolerability assessments focused on the effect of ale-
facept on immune responses, including infection rates,
malignancies, and the development of antibodies.
Alefacept has not been associated with adverse events
indicative of generalized immunosuppression, and no
opportunistic infections or increased frequency of
malignancies have been reported (see ‘‘Safety and
tolerability’’ section). The selectivity of alefacept for
memory T cells is likely responsible for the lack of
effect on immune responses.
Relationship between memory T-cell reductions and
efficacy
The relationship between the selective targeting of
memory T cells by alefacept and its antipsoriatic
effect was proposed in the phase 2 study and vali-
dated in the phase 3 studies [12,21,22]. In these
studies, the area under the percentage change from
the baseline curve for blood lymphocyte counts over
the dosing interval (EAUC) was calculated for each
patient to relate the cumulative effect of alefacept on
memory T cells with antipsoriatic efficacy [21,22].
Patients were then divided into quartiles (Q) based on
EAUC (Q1 = lowest, Q4 = highest), and the percent-
ages of patients achieving a PASI-50, PASI-75, or
PGA of ‘‘clear’’ or ‘‘almost clear’’ at any time during
the treatment and follow-up periods, without the use
CD4+ Memory T Cells
Course 1 Course 2
Mea
n C
ou
nt
(cel
ls/µ
L)
Study Week
600
500
400
300
200
100
0 12 0 12
0 12 0 12
24 24
B.
CD4+ Naïve T Cells
Course 1 Course 2
Cohort 1, Alefacept (n=154)/Alefacept (n=154)
Cohort 2, Alefacept (n=142)/Placebo (n=139)
Cohort 3, Placebo (n=153)/Alefacept (n=151)
Mea
n C
ou
nt
(cel
ls/µ
L)
600
500
400
300
200
100
Study Week
24 24
Dosing Period Dosing Period
Dosing Period Dosing Period
Fig. 6 (continued ).
G.G. Krueger / Dermatol Clin 22 (2004) 407–426 413
of other psoriasis systemic or phototherapies, were
expressed graphically.
There was a consistent relationship between the
magnitude of change in memory T-cell counts and
probability of response (Fig. 8) [21,22]. Regardless of
the definition of response (PASI-50, PASI-75, or
PGA of ‘‘clear’’ or ‘‘almost clear’’), a greater degree
of reduction in memory T-cell counts was generally
associated with a more favorable clinical outcome
[21,22]. The duration of response to alefacept also
was longer in patients who had more pronounced
reductions in memory T cells [21]. Time-course
analysis revealed that the peak effect of alefacept
on memory T cells occurred during treatment, where-
400
500
600
700
800
1100M
ean
Co
un
t (c
ells
/uL
)
Study Week
900
1000
Course 1 Course 2 Course 3 Course 4 Course 5
0 12 24 0 12 24 0 12 24 0 12 24 0 12 24
Dosing PeriodDosing Period Dosing Period Dosing Period Dosing Period
Fig. 7. Effects of repeat courses of 7.5-mg IV alefacept on circulating CD4+ T cells. Results shown are from an ongoing,
retreatment study. The number of patients at each time point in courses 1 to 4 ranges from 61 to 66. The number of patients
at each time point in course 5 ranges from 19 to 33. (Data on file, Biogen, Inc.)
0
20
40
60
80
100
Pat
ien
ts (
%)
Q2
Q1
Q4
Q3
n=84
Alefacept 10 mg +15 mg IM
40
n=85 n=85
5866
n=85
54
n=92
Alefacept 7.5 mg IV
n=92 n=92
62
n=91
51
33
75
Fig. 8. Percentage of patients who achieved a �50% reduction in PASI at any time during treatment or the follow-up period
(overall response rates) by EAUC of CD4+ memory T cells. Similar results were seen for CD8+ memory T cells (data not shown).
Results shown are from the two phase 3 studies of alefacept (course 1 data are presented). (From Gordon KB, Vaishnaw A,
O’Gorman J, Haney J, Menter A. Treatment of psoriasis with alefacept. Correlation of clinical improvement with reductions
of memory T-cell counts. Arch Dermatol 2003;139:1563–70; with permission; and Ortonne J-P, Lebwohl M, Griffiths CEM.
Alefacept-induced decreases in circulating blood lymphocyte counts correlate with clinical response in patients with chronic
plaque psoriasis. Eur J Dermatol 2003;13(2):117–23; with permission.)
G.G. Krueger / Dermatol Clin 22 (2004) 407–426414
G.G. Krueger / Dermatol Cl
as the peak effect on PASI generally occurred well
after treatment cessation [21,22]. This finding further
suggests that reductions in memory T cells drive the
therapeutic response to alefacept.
The relationship between alefacept-induced T-cell
changes in psoriatic skin and clinical response was
also investigated. Chamian et al [23] reported data
that showed a significant correlation between reduc-
tions in lesional T cells and clinical improvement
with alefacept therapy. The selective targeting of
memory T cells by alefacept was 11 times greater
in skin lesions than in the peripheral circulation.
Although the reduction in T-cell counts in circu-
lation and skin clearly correlate with level and
duration of response, it is common to find patients
who seem to respond without much change in the
number of memory T cells in the circulation. The
same is true for those who do not respond. Clearly, if
a patient experiences significant improvement, there
is a decrease in T cells in skin. It would be beneficial
to know the reason for this discordance, because it
would allow the clinician to more accurately predict
response without performing a skin biopsy.
Pharmacodynamics in subpopulations
In both phase 3 studies of alefacept, analysis of
circulating total lymphocyte and CD4+ and CD8+
T-cell counts in those patients who received alefacept
plus concomitant immunosuppressants (methotrexate,
cyclosporine, prednisone, etanercept, leflunomide,
infliximab, or mycophenolate mofetil) did not reveal
any patterns that suggested an increased risk for
greater reductions in lymphocyte or lymphocyte sub-
set counts [24].
In the alefacept 15-mg IM group, changes in
circulating CD4+ and CD8+ T cells were determined
in patients who were refractory to or had contra-
indications to one or more other systemic psoriasis
therapies or phototherapy [19]. As mentioned previ-
ously, patients who reported no change or worsening
of disease while on such treatment were considered to
be refractory, and the most common contraindication
was a history of hypertension (21%). Analysis
showed that reductions in T cells were consistent
regardless of whether patients were refractory to or
had contraindications to one or more systemic thera-
pies or phototherapy—mean reductions at the time of
maximal effect ranged from 39% to 43% for CD4+ T
cells and from 47% to 53% for CD8+ T cells. These
results were comparable to those observed among
patients who were not refractory to and had no
contraindications to other systemic psoriasis therapies
or phototherapy.
Variability in circulating T cells
In the two phase 3 studies, there was a surprisingly
high degree of variability in circulating levels of
baseline T-cell counts [25]. For example, among
placebo-treated patients across both studies, baseline
CD4+ T-cell counts ranged from 325 to 2573 cells/mL(normal range, 404–1612 cells/mL) and baseline
CD8+ T-cell counts ranged from 110 to 1625 cells/
mL (normal range, 220–1129 cells/mL). In the alefa-
cept 10-mg IM study, the percentages of placebo-
treated patients who had at least one CD4+ T-cell
count below 400, 300, 200, and 100 cells/mL at any
time after the first dose were 8%, 2%, 0%, and 0%,
respectively. The corresponding percentages in the
alefacept 15-mg IM group were 28%, 9%, 2%, and
0%. For CD8+ T cells, 16%, 6%, less than 1%, and 0%
of patients in the placebo IM group and 39%, 23%,
7%, and 2% of patients in the alefacept 15-mg IM
group had counts below 200, 150, 100, and 50 cells/
mL, respectively. Most patients experienced a recovery
in T-cell counts during the treatment-free follow-up
period. At 12 weeks after the last IM dose, in the
10-mg group two (1%) placebo-treated patients had
CD4+ T-cell counts below the LLN, and 14 (9%) had
CD8+ T-cell counts below the LLN. At the same time
point, 11 (7%) patients treated with 15 mg of IM
alefacept had CD4+ T-cell counts below the LLN, and
32 (22%) had CD8+ T-cell counts below the LLN.
Results of the IV study were similar to those of the IM
study. Although these values were below the LLN,
they were not associated with adverse events and, as
noted previously, did not continue to decline with
further administration. These findings suggest that
variability in T-cell counts occurs in patients with
psoriasis regardless of therapy and that T-cell counts
generally recover to normal ranges following alefa-
cept therapy.
Quality of life
In addition to the obvious physical characteristics
of psoriasis, the disease causes significant impairment
in patients’ QOL. A large survey (>17,000 respon-
dents) conducted by the National Psoriasis Foundation
(NPF) found that patients often report difficulty
performing routine activities (eg, sleeping and exer-
cising), interacting with peers and family, making or
keeping friends, and getting a job [26]. Suicide is fre-
quently contemplated. Approximately 50% of patients
with severe psoriasis are not satisfied or only some-
what satisfied with their current treatment. More than
75% of patients with severe psoriasis are frustrated
with the lack of efficacy of their current treatment, and
87% report receiving treatment with topical agents,
which can be time-consuming to administer [26]. A
in 22 (2004) 407–426 415
G.G. Krueger / Dermatol Clin 22 (2004) 407–426416
survey of similar size was recently conducted in Eu-
rope by the European Federation of Psoriasis Patients
Organizations (EUROPSO) [27,28]. The findings of
EUROPSO paralleled those of the NPF.
Further complicating the management of psoriasis
is the lack of correlation between the patient’s per-
ception of their disease intensity and objective mea-
sures of disease severity (eg, BSA, PASI, and PGA),
which do not take into account the effect of psoriasis
on the patient’s QOL [29]. A recent pooled analysis
of baseline data from both phase 3 studies in the
alefacept clinical program yielded interesting results.
The primary QOL instrument used in these trials was
the Dermatology Life Quality Index (DLQI) [30]. At
baseline, the distribution of DLQI varied widely for
any given measure of BSA. That is, patients with
extensive BSA at baseline may have had high or low
DLQI. This was also true for patients with low BSA
at baseline who may have had high or low DLQI. In
addition, there was no correlation between baseline
PASI or PGA and baseline DLQI [29]. These data
underscore the need to address both the physical and
psychologic aspects of psoriasis.
QOL assessments have been included in the phase
2 and 3 studies of alefacept and the data have been
-8
-6
-4
-2
0
1
Mea
n C
han
ge
in D
LQ
I
2 WeeksAfter Last Dose
-4.4
-5.1
-7
-5
-3
-1
12 WeeksAfter Last Dose
2 WeeksAfter Last Dos
≥50% to <75% PASI ≥75%
-2.2 -2.1
-7.2
-2.9
*
*
Fig. 9. Mean change from baseline in DLQI by responder status
improvement in QOL. Results shown are from the phase 3 intram
bined for this analysis). *P < 0.001 versus nonresponders. (Repri
Clinical Study Group. Intramuscular alefacept improves health-rel
Dermatology 2003;206(4):307–15; with permission.)
published [31–33]. In the phase 3 studies, alefacept
significantly improved overall DLQI scores at 2 weeks
after treatment cessation compared with placebo, a
benefit that was largely preserved at 12 weeks after the
last dose [32,33]. Significant improvements over
placebo were also observed for the Dermatology
Quality of Life Scales and the Short Form–36 Health
Survey, a general health survey. The DLQI signifi-
cantly improved in patients who achieved a reduction
in PASI of 50% to less than 75% (Fig. 9); these pa-
tients also experienced visible clinical improvement.
It was not necessary for PASI to be reduced by 75% or
more or for the PGA to be clear or almost clear for
these benefits to be realized. Taken together, the
results of these three studies strongly suggest that
PASI-50 is clinically meaningful for both patients and
physicians. Other observations lend further support to
this conclusion [34]. First, the relationship between
PASI and severity of psoriasis is not linear. There is a
tendency for PASI to underestimate the actual im-
provement in psoriasis because of how the score is
calculated. Second, methotrexate, widely viewed as
an effective therapy for psoriasis, when given in an
aggressive dosing fashion in a small-scale 25-patient
trial, resulted in a PASI-75 in about one fourth of
Nonresponder
Responder
e12 Weeks
After Last Dose2 Weeks
After Last Dose12 Weeks
After Last Dose
PGA "Clear"/"Almost Clear" PASI
-6.6
-2.6
-7.1
-3.1 -2.8
-6.6*
**
at 2 weeks after the last dose. A negative change indicates
uscular study of alefacept (all treatment groups were com-
nted from Finlay AY, Salek MS, Haney J, for the Alefacept
ated quality of life in patients with chronic plaque psoriasis.
G.G. Krueger / Dermatol Cl
patients and a PASI-50 in about two thirds of patients
after 6 months of treatment [35]. Third, clinical
studies have shown that effective therapies for psoria-
sis can be consistently differentiated from placebo at
PASI-50. Fourth, patients who achieve PASI-75 often
choose to defer treatment until their PASI is below 50.
For these and other reasons, it seems that PASI-50
would serve as an effective endpoint when defining a
clinically meaningful response [34].
Safety and tolerability
The data presented in the following sections
demonstrate that alefacept is safe and well tolerated
in a broad spectrum of patients, including those on
concomitant immunosuppressant agents and those
who are refractory to or have contraindications to oth-
er systemic psoriasis therapies or phototherapy. The
incidence of serious adverse events, discontinuations,
infections, malignancies, and antialefacept antibodies
remain low over up to six alefacept courses. In addi-
tion, critical functions of the immune system are
maintained during alefacept therapy.
Table 1
Incidence of adverse events in the first course of the intravenous s
received concomitant immunosuppressants
Alefacept
Adverse event
Received (N = 21)
n (%)
Accidental injury 3 (14)
Pruritus 2 (10)
Allergic reaction 1 (5)
Anxiety 1 (5)
Arthritis 1 (5)
Contact dermatitis 1 (5)
Dizziness 1 (5)
Ear disorder 1 (5)
Gout 1 (5)
Headache 1 (5)
Hyperglycemia 1 (5)
Hypertension 1 (5)
Infectiona 1 (5)
Insomnia 1 (5)
Kidney calculus 1 (5)
Paresthesia 1 (5)
Pharyngitis 1 (5)
Rash 1 (5)
Respiratory disorder 1 (5)
This table lists all adverse events that were reported among alefac
suppressants. Patients may have experienced more than one advera Most episodes were common colds.
Data from Vaishnaw AK, Lee S. Concomitant use of alefacept an
at the 61st Annual Meeting of the American Academy of Dermato
Concomitant use of alefacept and immuno-
suppressants
As new, targeted immunotherapies are being de-
veloped and studied in patients with psoriasis, the
concomitant, sequential, or rotational use of these
agents with older, nonspecific immunosuppressants
is of interest. In the two phase 3 studies of alefacept,
the incidence of adverse events, serious adverse
events, and serious infections during the first course
of 7.5-mg alefacept in the IV study (cohorts 1 and
2 pooled) and 15-mg alefacept in the IM study were
analyzed according to concomitant use and prior use
(within 60 d before the first alefacept dose) of the
following immunosuppressants: methotrexate, cyclo-
sporine, prednisone, etanercept, leflunomide, inflix-
imab, and mycophenolate mofetil [24].
One or more immunosuppressant agents were used
concomitantly by 21 patients (6%) in the 7.5-mg
alefacept IV group and by 4 patients (2%) in the
15-mg alefacept IM group compared with 22 patients
(6%) in the placebo group (IM study and cohort 3 of
IV study pooled) [24]. There were no unusual patterns
of adverse events in the IV study (Table 1) or IM
in 22 (2004) 407–426 417
tudy among alefacept-treated patients who had and had not
Did not receive (N = 346)
n (%)
Placebo (N = 186)
n (%)
70 (20) 30 (16)
37 (11) 16 (9)
1 (<1) 1 (<1)
8 (2) 4 (2)
15 (4) 5 (3)
2 (<1) 3 (2)
16 (5) 6 (3)
2 (<1) 1 (<1)
0 1 (<1)
58 (17) 38 (20)
0 1 (<1)
10 (3) 6 (3)
33 (10) 20 (11)
2 (<1) 7 (4)
2 (<1) 2 (1)
5 (1) 0
51 (15) 23 (12)
3 (<1) 3 (2)
0 0
ept-treated patients who had received concomitant immuno-
se event.
d immunosuppressants in patients with psoriasis. Presented
logy. San Francisco, March 21–26, 2003.
G.G. Krueger / Dermatol Clin 22 (2004) 407–426418
study. The nature of the adverse events was consist-
ent between those patients who had and those who
had not received concomitant immunosuppressants.
Among the four patients in the 15-mg alefacept IM
group who had received concomitant immunosup-
pressants, one patient each reported arthritis, conjunc-
tivitis, diarrhea, eczema, edema, hypercholesteremia,
and insomnia.
Similar results were obtained when adverse events
were analyzed according to use of one or more
immunosuppressants within 60 days before the first
dose of alefacept [24]. A review of the safety data
collected during phase 3 studies of alefacept (admin-
istered by IM and IV injection) suggests that the
frequency and spectrum of adverse events or serious
infections is not altered by concomitant use or prior
use of immunosuppressants. An ongoing study using
combination therapy will address this question more
directly (see ‘‘Ongoing study of alefacept in clinical
practice’’ section for details).
Patients who were refractory to or who had
contraindications to other systemic therapies or
phototherapy
Data from both phase 3 studies of alefacept were
pooled to determined the adverse event profile in the
subset of patients who were considered refractory to or
who had contraindications, as defined previously, to
other systemic psoriasis therapies (cyclosporine,
methotrexate, and retinoids) or phototherapy (PUVA
0
2
4
6
8
10
Aleface
1 2 3
Pat
ien
ts (
%)
n=1359 n=826 n=415
0.50.8
4.1
3.1
1.8
4.9
Fig. 10. Incidence of serious adverse events and discontinuations b
therapy. Results shown are from all studies in the alefacept clinica
or UVB) [36]. Among the 714 patients who were
refractory to or had contraindications to one or more
systemic therapies or phototherapy, the only adverse
event to occur at an incidence of 5% or greater
incidence in the alefacept group compared with the
placebo group was pruritus (15% versus 10%).
Among the 431 patients who were refractory to or
had contraindications to two or more systemic thera-
pies or phototherapy, the following adverse events
were reported at an incidence of 5% or greater in the
alefacept group compared with the placebo group:
pruritus (15% alefacept versus 8% placebo), flu syn-
drome (13% versus 8%), rhinitis (12% versus 6%),
myalgia (6% versus 1%), and injection site pain (5%
versus 0%). Among the 206 patients who were refrac-
tory or had contraindications to three or more systemic
therapies or phototherapy, the following adverse
events occurred at an incidence of 5% or greater in
the alefacept group versus the placebo group: pruritus
(18% versus 11%), accidental injury (17% versus 8%),
and injection site pain (6% versus 0%). The safety
profile of alefacept in patients who were considered
refractory or had contraindications to one or more
other systemic psoriasis therapies or phototherapy was
similar to the safety profile observed in the overall
alefacept-treated patient population.
Multiple courses
Safety and tolerability data were obtained from all
studies evaluating alefacept as a treatment for psoria-
sis. These data were pooled, and the integrated results
pt Course
4 5 6
Discontinuations foradverse events
Serious adverse events
1.5
0.8 0.8
n=133 n=65 n=36
000
ecause of adverse events over multiple courses of alefacept
l program. (Data on file, Biogen, Inc.)
0
20
40
60
80
100
Pat
ien
ts (
%)
CD4+ count ≥250 cells/µL
CD4+ count <250 cells/µL
n=121
63
29 31
4438 39
47
26
44
0
43
n=1238 n=85 n=741 n=28 n=387 n=8 n=125 n=6 n=59 n=1 n=35
33
Alefacept Course
1 2 3 4 5 6
A.
0
20
40
60
80
100
Pat
ien
ts (
%)
CD8+ count ≥100 cells/µL
CD8+ count <100 cells/µL
n=178
40
2730
46
31
47 44
30
42
n=1181 n=155 n=671 n=78 n=337 n=35 n=98 n=20 n=45 n=10 n=26
353336
Alefacept Course1 2 3 4 5 6
B.
Fig. 11. Incidence of infections by circulating CD4+ (A) and CD8+ (B) T-cell counts over multiple courses of alefacept ther-
apy. Results shown are from all studies in the alefacept clinical program. (Data on file, Biogen, Inc.)
G.G. Krueger / Dermatol Clin 22 (2004) 407–426 419
are presented here3. A total of 1359 patients received
at least a single course of alefacept, 826 received at
least two courses, 415 received at least three courses,
133 received at least four courses, 65 received at least
five courses, and 36 received at least six courses.
Adverse events
Alefacept was well tolerated over multiple
courses. Across all alefacept studies, there was no
3 Data on file, Biogen, Inc.
increase in the incidence of serious adverse events or
discontinuations because of adverse events with re-
peated administration of up to six treatment courses
(Fig. 10). There was a tendency for rates of serious
adverse events and discontinuations to decrease with
continued courses of therapy. The percentage of
patients who experienced at least one serious adverse
event ranged from a high of 4.9% in course 1 to a low
of 0% in course 6. The most common serious adverse
events were accidental injury (0.4%, 0.6%, 0.2%, 0%,
0%, and 0% of patients in courses 1 through 6,
respectively) and cholelithiasis (0.2%, 0.5%, 0.2%,
Table 2
Incidence of serious infections by course of alefacept
Alefacept course
Infection
1 (N = 1359)
n (%)
2 (N = 826)
n (%)
3 (N = 415)
n (%)
4 (N = 133)
n (%)
5 (N = 65)
n (%)
6 (N = 36)
n (%)
Cellulitis 3 (0.2) 0 0 0 0 0
Pneumonia 0 2 (0.2) 1 (0.2) 0 0 0
Bacterial infection 2 (0.1) 0 0 0 0 0
Gastroenteritis 2 (0.1) 0 0 0 0 0
Abscess 1 (<0.1) 0 0 0 0 0
Appendicitis 0 0 1 (0.2) 0 0 0
Asthma 1 (<0.1) 0 0 0 0 0
Bronchitis 0 0 1 (0.2) 0 0 0
Burn infection 1 (<0.1) 0 0 0 0 0
Herpes simplex 0 1 (0.1) 0 0 0 0
Postprocedural site
wound infection
0 1 (0.1) 0 0 0 0
Wound infection 0 1 (0.1) 0 0 0 0
Total 10 (0.7) 5 (0.6) 3 (0.7) 0 0 0
Data on file, Biogen, Inc.
G.G. Krueger / Dermatol Clin 22 (2004) 407–426420
0%, 0%, and 0% of patients in courses 1 through 6,
respectively). Discontinuation rates because of adverse
events ranged from 1.8% in course 1 to 0% in courses
5 and 6. Headache (0.2% in course 1, 0% in other
courses), nausea (0.2% in course 1, 0% in other courses),
and herpes zoster (0.07%, 0%, 0.2%, 0.8%, 0%, and 0%
in courses 1 through 6, respectively) were the most
frequent adverse events that resulted in withdrawal.
Table 3
Incidence of malignancies by course of alefacept
Alefacept course
Malignancy
1 (N = 1359)
n (%)
2 (N = 826)
n (%)
Skin carcinoma 11 (0.8) 4 (0.5)
Skin melanoma 2 (0.1) 1 (0.1)
Lung carcinoma 0 1 (0.1)a
Prostatic carcinoma 1 (<0.1) 1 (0.1)
Adenocarcinoma of colon 0 0
Colonic polyps 0 0
Esophageal carcinoma 0 1 (0.1)
Lymphomac 0 1 (0.1)
Renal cell carcinoma 1 (<0.1) 0
Secondary neoplasm of brain 0 1 (0.1)a
Testicular cancer 1 (<0.1) 0
Total 16 (0.7) 9 (1.1)
Data on file, Biogen, Inc.a Same patient was diagnosed with both events.b Same patient was diagnosed with both events.c Two additional cases of lymphoma were diagnosed 5 and 6
Infections
Infections were analyzed by course and circulating
CD4+ (<250 cells/mL and �250 cells/mL) and CD8+
(<100 cells/mL and �100 cells/mL) T-cell counts
(Fig. 11). There was no evidence of an increased risk
of infection over multiple courses of alefacept, nor
was there an association between infections and CD4+
and CD8+ T-cell counts. Infections were generally
3 (N = 415)
n (%)
4 (N = 133)
n (%)
5 (N = 65)
n (%)
6 (N = 36)
n (%)
3 (0.7) 1 (0.8) 1 (1.5) 0
0 0 0 0
1 (0.2) 0 0 0
0 0 0 0
1 (0.2)b 0 0 0
1 (0.2)b 0 0 0
0 0 0 0
0 0 0 0
0 0 0 0
0 0 0 0
0 0 0 0
5 (1.2) 1 (0.8) 1 (1.5) 0
months after alefacept therapy (see text for details).
0
2
4
6
8
10
Pat
ien
ts (
%)
Postbaseline
Baseline
n=1291
0 0 0 0 0 0
1.5
0.8
2.4
n=1268 n=826 n=606 n=415 n=157 n=133n=77 n=65 n=40 n=36 n=14
0.30.7
1.3
Alefacept Course
1 2 3 4 5 6
Fig. 12. Incidence of antibodies to alefacept over multiple courses of therapy. All patients with available data were included in
the analysis. Results shown are from all studies in the alefacept clinical program. (Data on file, Biogen, Inc.)
G.G. Krueger / Dermatol Clin 22 (2004) 407–426 421
mild and responsive to conventional therapy. The vast
majority of episodes were common colds. Serious
infections were experienced by 0.7%, 0.6%, 0.7%,
0%, 0%, and 0% of patients in courses 1 through 6,
respectively. These events are summarized in Table 2.
No cases of opportunistic or unusual infections, tu-
berculosis, or deaths related to infections were ob-
served in patients receiving alefacept.
Malignancies
The percentages of patients (n = 1359) who
developed malignancies were low and did not increase
over multiple courses of alefacept: these percentages
were 1.2%, 1.1%, 1.2%, 0.8%, 1.5%, and 0% in
courses 1 through 6, respectively. No relationship
between malignancies and circulating CD4+ or
CD8+ T-cell counts was observed. The specific
malignancies that were diagnosed are presented in
Table 3, the most common of which was skin carci-
noma (basal and squamous cell carcinomas). The
overall malignancy rate among alefacept-treated
patients was 25.6 per 1000 person-years of exposure4,
which is somewhat less than the corresponding rate in
the general psoriasis population (29.0 per 1000 per-
son-years) [37]. There were three cases of lymphoma
among alefacept-treated patients. A 68-year-old
woman with longstanding psoriasis and previous
exposure to methotrexate and PUVA developed fea-
tures consistent with sporadic B-cell non-Hodgkin’s
lymphoma, without an immunotherapy-related lesion.
4 Data on file, Biogen, Inc.
She had received a total of 20 alefacept injections. A
53-year-old man was diagnosed with Hodgkin’s dis-
ease 6 months after his last dose of alefacept (34 total
doses). Before receiving alefacept, the patient had
been treated with methotrexate for 15 years. The other
case was a 62-year-old man who was diagnosed with
Hodgkin’s disease (stage IV) 5 months after his last
dose of alefacept (24 total doses). The patient had
previously received PUVA and UVB. Two of the three
patients had received significant prior immunother-
apy, which is known to be associated with an in-
creased risk of lymphoma [37,38]. Overall, total
lymphoma (Hodgkin’s and non-Hodgkin’s) occurred
at a rate of 0.53 per 1000 person-years of alefacept
exposure versus 1.6 per 1000 person-years in the
general psoriasis population [37]5.
Immunogenicity
Consistent with its composition as a fully human
fusion protein, the immunogenicity of alefacept was
low in all courses (Fig. 12). The percentage of
patients who tested positive for antialefacept anti-
bodies post baseline was highest during course 1
(2.4%) and lowest during courses 4 through 6 (0%).
In the few patients who developed antialefacept anti-
bodies after treatment initiation, antibody titers were
generally low (<1:40) and transient in most patients
and did not increase with sequential sampling and
treatment. Antibody titers were not associated with
immune hypersensitivity reactions.
5 Data on file, Biogen, Inc.
G.G. Krueger / Dermatol Clin 22 (2004) 407–426422
Primary and secondary immune responses
A multicenter, randomized, open-label, parallel-
group study evaluated the effects of alefacept on
primary and secondary immune responses in patients
with chronic plaque psoriasis [39]. Patients were
randomized into two groups: alefacept (n = 23) and
control (n = 23). Antibody responses to the neo-
antigen bacteriophage fX174 and to the recall antigentetanus toxoid and diphtheria were evaluated. There
were no statistically significant differences between
the alefacept and control groups in antibody responses
to either antigen. Mean anti-fX174 titers were com-
parable in the two groups at all time points after the
first and second immunizations [39]. The observed
titers were comparable with those seen in healthy
volunteers after fX174 administration [40–44].
The IgG fraction of total anti-fX174 response at 2
weeks after the second immunization was 54% in the
alefacept group and 48% in the control group, indi-
cating that alefacept does not alter immunologic
memory [39]. No evaluable patient failed to show
an IgG anti-fX174 antibody response. Consistent
with an acquired immune response, antibody titers
rose rapidly after immunization with the recall anti-
gen, tetanus toxoid. The percentage of patients with a
twofold or greater increase in antitetanus titer at
3 weeks after immunization was similar in the alefa-
cept (89%) and control (91%) groups. Thus, a single
course of alefacept does not impair primary or sec-
ondary antibody responses to a neoantigen or memory
responses to a recall antigen.
Concomitant alefacept and ultraviolet B
The combination of alefacept and UVB has the
potential to provide synergistic efficacy with each
agent targeting T cells in a different way, one from
within and one from the surface. It has been hypoth-
esized that this combination might provide a faster
onset of action and longer duration of response than
observed with either agent alone.
The combination of alefacept and either narrow-
band (NB) or broadband (BB) UVB was evaluated in
an open-label study of patients with chronic plaque
psoriasis. Patients (N = f60) were enrolled at two
sites: one in France (NB UVB) [45] and one in the
United States (BB UVB) [46]. All patients received
15 mg of IM alefacept once weekly for 12 weeks.
Patients were randomized (1:1:1) to receive either no
UVB, UVB 3 times per week until clear or for up to 6
weeks, or UVB 3 times per week until clear or for up
to 12 weeks. An observation period of 12 weeks
followed the treatment period. The primary objective
was to determine the safety and tolerability of com-
bination therapy.
Results from both sites have been presented
[45,46]. Alefacept in combination with UVB was well
tolerated; adverse events were similar among patients
who received alefacept monotherapy and patients who
received combination therapy. No opportunistic infec-
tions were reported. Combination therapy seemed to
provide a more rapid onset of effect compared with
alefacept monotherapy. Complete results will be pub-
lished separately.
Ongoing study of alefacept in clinical practice
To understand the best way to manage existing
therapies during a course of alefacept, an international
study is being conducted to reflect what is projected to
be an approach that will be common to the usual
clinical setting [47]. Approximately 400 patients with
chronic plaque psoriasis will be enrolled in this open-
label study in which topical treatments, NB or BB
UVB (2–3 treatments/wk), systemic retinoids, and
prednisone will be permitted as concomitant therapies.
Methotrexate and cyclosporine will be tapered over
the first 4 and 12 weeks of alefacept therapy, respec-
tively. Patients must need systemic therapy, have
normal circulating CD4+ T-cell counts (�300 cells/
mm3 if on a stable dose of prednisone), and be naıve
to alefacept treatment. In each course, 15 mg of IM
alefacept will be administered once weekly for
12 weeks followed by 12 weeks of observation. Pa-
tients may receive up to three treatment courses.
The primary objective of this study is to evaluate
the safety of repeat courses of alefacept [47]. Other
prespecified objectives are to determine the efficacy
of initial and repeat courses of alefacept and the time
to retreatment with alefacept after the first two
courses. The results will provide valuable insight into
the management of other psoriasis therapies when
used concurrently with alefacept.
Alefacept in psoriatic arthritis
Although data are limited, some evidence suggests
that T cells may play a role in the pathogenesis of
psoriatic arthritis (PsA) [48–50]. Therefore, a pro-
spective, single-center, open-label pilot study was
conducted to determine the clinical effect and changes
in the synovium of patients with active PsA treated
with alefacept [51]. Patients (N = 11) had had chronic
plaque psoriasis for 1 year or more and active PsA,
defined as two or more swollen joints and two or more
tender joints. After a 28-day washout phase in which
current treatments were withdrawn, 7.5 mg of IV
alefacept was administered weekly for 12 weeks with
12 weeks of treatment-free observation. No concom-
G.G. Krueger / Dermatol Clin 22 (2004) 407–426 423
itant treatment for PsA was allowed, with the ex-
ception of nonsteroidal anti-inflammatory drugs
(NSAIDs). Clinical assessments, which were per-
formed at baseline, after 4 and 12 weeks of treatment,
and at 16 weeks (ie, 4 wk after the last dose), included
a 30-joint count (28-joint count and both ankles) for
joint swelling and tenderness, physician and patient
assessment of disease activity, morning stiffness, pain
as assessed by a visual analog scale (VAS), serum
concentrations of C-reactive protein (CRP), and PASI.
Serial arthroscopic synovial biopsies of the same
index joint were performed under local anesthesia at
baseline and after 4 and 12 weeks of treatment (knee
joint, n = 7; wrist joint, n = 2; metacarpophalangeal
joint, n = 1; and ankle joint, n = 1).
Alefacept significantly improved the mean swol-
len and tender joint counts, disease activity score
(DAS), VAS, and CRP concentrations from baseline.
The mean PASI was lowered by 13% at 4 weeks,
23% at 12 weeks, and 28% at 16 weeks. Immuno-
histochemical analysis revealed significant decreases
from baseline in the mean number of macrophages in
the synovial sublining at 12 weeks (43% reduction),
CD4+ T cells at 4 and 12 weeks (42% and 59%
reductions, respectively), and CD8+ T cells at 4 and
12 weeks (13% and 60% reductions, respectively).
Patients who fulfilled the DAS response criteria at
12 weeks (n = 6) achieved a greater reduction in
the memory subset of T cells in both synovial tissue
and peripheral blood compared with nonresponders
(n = 5).
The improvement in clinical joint score and skin
psoriasis and changes in synovial tissue after treat-
ment with alefacept support the hypothesis that T-cell
activation plays an important role in PsA.
Alefacept in rheumatoid arthritis
T cells are believed to mediate the painful and
disabling inflammation of synovial tissues observed
in patients with RA [52]. Alefacept may prove to be a
valuable treatment option in RA because studies have
shown that it is the CD4+ memory subset of T cells
that predominate in synovium [52]. A 6-month,
randomized, double-blind, placebo-controlled, pilot
study was conducted to assess the safety, tolerability,
and efficacy trends of alefacept in patients with active
RA despite treatment with methotrexate [53]. IV
alefacept (3.75 mg or 7.5 mg) or placebo (n = 12/
group) was administered weekly for 12 weeks fol-
lowed by 12 weeks of observation. All patients
continued treatment with a stable dose of methotrex-
ate throughout the study. Additional disease-modify-
ing antirheumatic drugs were not allowed, but stable
doses of NSAIDs and corticosteroids (prednisone,
V10 mg/d) were permitted. Efficacy assessments
included swollen and tender joint counts and the
percentages of patients achieving American College
of Rheumatology (ACR) response scores of 20, 50,
and 70.
A total of 36 subjects with severe disease were
randomized into the three treatment arms [53]. Ale-
facept responses were superior to placebo with 58%
and 25% of subjects achieving ACR 20 at 6 months
in the 7.5-mg and 3.75-mg alefacept groups, respec-
tively, as compared with 17% in the placebo group.
ACR 50 and ACR 70 responses were 17% and 8%,
respectively, for each of the alefacept arms at 6
months. Without any further intervention, all subjects
in the 3.75-mg alefacept group who had achieved an
ACR 20 response at 14 weeks maintained this benefit
during the 12-week follow-up period. Alefacept se-
lectively reduced circulating CD4+ and CD8+ T cells,
with a return toward baseline levels during the
follow-up period. The author predicts that because
alefacept and methotrexate were well tolerated and
without identifiable safety concerns in this small
cohort of patients with RA, the combination will
have a similar profile in patients with psoriasis.
Summary
Alefacept is the first biologic agent to be approved
for the treatment of chronic plaque psoriasis. By
selectively targeting the memory T-cell population
involved in the pathogenesis of psoriasis, alefacept
provides durable clinical improvement without gen-
eralized immunosuppression. Moreover, alefacept is a
safe and effective treatment for psoriasis, regardless
of disease severity, prior treatment history, response
to prior therapy, or the presence of contraindications
to other systemic psoriasis therapies or phototherapy.
Patients who respond to alefacept benefit from ex-
tended periods free of disease and its treatments. As
experience with alefacept has grown, the favorable
safety and tolerability profile has been confirmed in
patients who have received up to six courses of ther-
apy. There has been no evidence of an increased risk
for infection or malignancy; no correlation between
rates of infection, malignancy, and circulating CD4+/
CD8+ T-cell counts; and low immunogenicity. Re-
search is ongoing to examine the use of alefacept in
PsA and RA and its use in combination with other
systemic psoriasis therapies and phototherapy.
G.G. Krueger / Dermatol Clin 22 (2004) 407–426424
Acknowledgments
The author expresses appreciation to colleagues
at Biogen for their willingness to provide key data
and interpretation and to Mike McNamara of Scien-
tific Connections for editorial support.
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Dermatol Clin 22 (2004) 427–435
Current concepts and review of efalizumab in the treatment
of psoriasis
Craig L. Leonardi, MDa,b,*
aDepartment of Dermatology, St. Louis University School of Medicine, 1755 S Grand, St. Louis, MO 63104, USAbCentral Dermatology, 1034 South Brentwood Boulevard, Suite 600, St. Louis, MO 63117, USA
Psoriasis is commonly a disease of young adults cal advances in large-scale protein synthesis, has
with an average age of onset of 28 years. Those
individuals with the more severe forms of the disease
are thus faced with the requirement of decades of
therapy using the traditional systemic approaches.
The cumulative toxicities of these therapies, how-
ever, preclude their use in a chronic setting. To reduce
these treatment-related side effects, dermatologists
use various creative strategies in an attempt to control
psoriasis. For example, rotational treatment para-
digms are sometimes used, with the patient moving
from a highly effective to a less effective therapy
possessing a different side-effect profile. Alterna-
tively, combination therapy is sometimes used with
multiple agents at lower doses to reduce the risk of
toxicity. Last, intermittent treatments are also used,
with discontinuation of treatment and subsequent
recurrence of the disease [1]. Many of these patients
therefore have difficulty maintaining uninterrupted
control of their symptoms and thus experience a
significant impact of psoriasis on their lives. Further-
more, widespread dissatisfaction exists with the treat-
ments and with those who prescribe them. There is a
substantial unmet need for effective therapies that can
be safely administered on a long-term basis.
The pathophysiology of psoriasis has been dra-
matically reshaped by recent advances in cellular and
molecular immunology. Physicians now understand
the key role of T cells and their cytokine products in
the pathogenesis of this chronic, inflammatory dis-
ease. This new knowledge, coupled with technologi-
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/j.det.2004.03.015
* Central Dermatology, 1034 South Brentwood
Boulevard, Suite 600, St. Louis, MO 63117.
E-mail address: [email protected]
resulted in the ongoing development of more than
two dozen biologic therapies that target the key steps
in the inflammatory cascade. Efalizumab (Raptiva) is
one of the promising new targeted immunomodula-
tors designed to reduce inflammation in the body. It is
currently the only biologic agent approved by the US
Food and Drug Administration for continuous ad-
ministration to adult patients with moderate to severe
chronic plaque psoriasis.
Mechanism of efalizumab action and evidence of
immunobiologic activity
Efalizumab is a recombinant, humanized, mono-
clonal IgG1 antibody designed to down-regulate
inflammatory processes in the body (Fig. 1). Admin-
istered once weekly by subcutaneous injection, efali-
zumab binds to CD11a, the a subunit of leukocyte
function-associated antigen 1 (LFA-1). There, it dis-
rupts the interaction between LFA-1 and one of its
ligands, intercellular adhesion molecule 1 (ICAM-1).
ICAM-1 is a cell surface molecule that is expressed by
antigen-presenting cells (APCs) and is up-regulated
on both endothelial cells and keratinocytes within
psoriatic plaques [2]. Thus, efalizumab disrupts sev-
eral of the key T-cell–mediated steps involved in the
pathogenesis of psoriasis: it destabilizes the binding
of APCs and T cells, reducing the efficiency of initial
T-cell activation in lymph nodes; it decreases the
trafficking of T cells from the circulation into dermal
and epidermal tissues; and it interferes with the
secondary activation of memory-effector T cells
in the target tissues (Fig. 2). Finally, because CD11a
s reserved.
Fig. 1. Space-filling model of efalizumab. This full-length
IgG1 was originally developed in a murine system. Human
DNA sequences have replaced all but 3% of the original
murine sequences to reduce antigenicity.
C.L. Leonardi / Dermatol Clin 22 (2004) 427–435428
expression is unique to LFA-1, the effects of efalizu-
mab are believed to be confined only to those cells
expressing LFA-1.
Phase 1 and 2 trials have characterized the phar-
macodynamic profile of efalizumab and demonstrated
its clinical activity at the molecular level in patients
with psoriasis. Upon administration by either intra-
venous or subcutaneous routes, efalizumab rapidly
saturates cell surface CD11a on T cells and down-
regulates CD11a expression [3–7]. The effect is
quickly reversed, however, with CD11a levels re-
turning to normal 7 to 10 days following clearance of
efalizumab from the circulation (Fig. 3) [7].
Histologic changes also accompany CD11a satu-
ration and down-modulation. Reduced keratin 16 and
ICAM-1 expression suggest diminished keratinocyte
hyperproliferation and reduced cytokine-mediated
inflammation, respectively. Other findings include
thinning of the psoriatic epidermis, with a restoration
of normal phenotype, and a marked reduction in the
number of dermal and epidermal CD3+ T cells in
lesional skin.
A concomitant increase in the number of circulat-
ing CD3+ lymphocytes suggests that efalizumab
prevents T-cell trafficking from the circulation into
dermal and epidermal tissues. Clinically, a marked re-
duction of erythema, induration, and scaling is noted
early in treatment followed by reduction in the
involved body surface area [5,7].
Phase 3 clinical experience with efalizumab
Efalizumab therapy has been studied in more than
2700 patients. The results from a various large-scale
placebo-controlled and open-label phase 3 trials
demonstrate the rapid change and sustained efficacy
seen in patients with psoriasis. In blinded trials,
the primary endpoint was the percentage of patients
achieving a 75% reduction in their Psoriasis Area
and Severity Index (PASI-75) at 12 weeks as com-
pared with a placebo group. In addition, several
secondary endpoints were also assessed, including
PASI-50 response, Overall Lesion Severity (OLS),
Physicians’ Static Global Assessment, Dermatology
Life Quality Index (DLQI), an Itching scale, and the
Psoriasis Symptom Assessment (PSA) frequency and
severity subscales.
Short-term results
Efalizumab-treated patients experienced quick
onset of action. Following initiation of therapy at
1 mg/kg/week, a statistically significant reduction
in PASI was noted as early as 2 to 4 weeks [8–10].
These changes were most pronounced in the ery-
thema, induration, and scale components of the PASI.
In one trial, 22% of treated patients achieved
PASI-75 after 12 weeks of treatment as compared
with 5% of those who received placebo (P < 0.001)
[8]. At the same time point, 52% of treated patients
achieved a PASI-50 response. Overall, the mean im-
provement in PASI was 51% versus 17% (P < 0.001)
[8]. In a second trial, 27% of efalizumab-treated
patients achieved PASI-75 at 12 weeks as compared
with 4% receiving placebo (P < 0.001). As expected,
significant PASI-50 responses were also noted, with
59% versus 14% (P < 0.001) for the efalizumab and
placebo arms, respectively [10]. In a third blinded,
placebo-controlled trial, 39% versus 2.4% (P < 0.001)
of patients achieved PASI-75 at 12 weeks for treated
versus placebo groups, respectively. The PASI-50
responses seen in this trial were 61% versus 15%
of treated and placebo groups, respectively [11].
These results are summarized in Fig. 4. In addition
to PASI, all other physician-assessed measures of
disease severity achieved statistical significance by
week 12.
This efficacy noted by the investigators was also
paralleled by improvements in patient-reported out-
come measures. Patients periodically evaluated the
extent of their symptoms using an Itching scale and
the bipartite PSA scale, which incorporated symp-
tom frequency and severity subscales. At week 12,
•
•
•
•
MHC
B7 CD28
CD3
Activated APCImmunologic Synapse
Memory T Cell
LFA-1ICAM-1
CD11a
Antigen-Peptide
LFA-3CD4/CD8
TCR
CD2CD40LCD40
Costimulatory Molecules
LFA-1ICAM-1
T-Cell Reactivation, Proliferation, and Cytokine Production
T-CellActivation Signals
Costimulatory Signals
Cytokine production
Keratinocyte hyperproliferation
Inflammatory response
Effector-mediated killing response
A
Fig. 2. Mechanism of action. (A) In binding to CD11a, efalizumab disrupts the interaction of LFA-1 and ICAM-1, interfering
with the activation of T cells as a primary or secondary event. (B) ICAM is expressed by endothelial cells in sites of
inflammation. By disrupting the binding of LFA-1 to ICAM-1, efalizumab interferes with T-cell trafficking from the circula-
tion into the dermis and epidermis. As a consequence, blood lymphocyte counts are increased (but still normal) in efalizumab-
treated patients.
C.L. Leonardi / Dermatol Clin 22 (2004) 427–435 429
150
100
50
0
0 2 4 6 8
Week
Available CD11a binding sites during and after8 weeks of treatment with efalizumab
Per
cent
age
ofP
retr
eatm
ent L
evel
s
No TreatmentTreatment
10 12 14
Fig. 3. Efalizumab rapidly saturates CD11a binding sites on lymphocytes when administered intravenously or by subcutaneous
routes. On discontinuation of therapy, the number of binding sites quickly returns to pretreatment levels.
C.L. Leonardi / Dermatol Clin 22 (2004) 427–435430
improvements were found in the Itching scale (38%
versus �0.2% for placebo, P < 0.001) andin the
frequency (48% versus 18% for placebo, P < 0.001)
and severity (47% versus 17% for placebo, P < 0.001)
of symptoms as assessed by the PSA subscales. The
functional and psychosocial impact of psoriatic symp-
toms on patients’ lives was captured using the DLQI
[14]. Overall DLQI scores at week 12 were signifi-
cantly improved as compared with placebo (47%
versus 14%, P < 0.001) [10]. These data demonstrate
70
Per
cent
of P
atie
nts
60
50
40
30
20
10
0Study 1
(n = 354)Study 2
(n = 556)
Fig. 4. Percentage of patients achieving PASI-75 or PASI-50 in efal
from three placebo-controlled trials are shown. Statistical significan
50 levels as compared with placebo.
that efalizumab improved patient functionality, pa-
tient well-being, and the symptoms most important to
patients with psoriasis, resulting in improved health-
related quality of life.
Intermediate-term results
One of the phase 3 trials showed that prolonging
efalizumab therapy from 12 to 24 weeks improved
Study 3(n = 332)
PASI-50
PASI-75
PASI-50
PASI-75
Efalizumab
Placebo
izumab-treated (1 mg/kg/wk) and placebo groups. The results
ce was achieved in all three trials at both PASI-75 and PASI-
70
*P < 0.001 vs placebo
Placebo(n=187)
Efalizumab1.0 mg/kg/wk
(n=369)
Efalizumab1.0 mg/kg/wk
(n=368)
60
50
40
30
20
10
0
24 Weeks
66.6%
43.8%
58.5%*
26.6%*
13.9%
4.3%
12 Weeks
PASI 75
PASI 50
Per
cent
age
of P
atie
nts
(%)
Fig. 5. Percentage of patients achieving PASI-75 at the primary endpoint (week 12) of a blinded, placebo-controlled trial and also
in an open-label treatment extension to 24 weeks. Significant numbers of patients improved in the 12- to 24-week time period.
C.L. Leonardi / Dermatol Clin 22 (2004) 427–435 431
response rates and maintained clinical responses.
Significant additional improvement was noted,
with 44% and 67% of patients achieving PASI-75
and PASI-50, respectively. These results are shown
in Fig. 5 [10]. As might be expected, the patient-
reported outcome measures were also maintained or
improved throughout this extended dosing period
[15–18].
Long-term results
An ongoing open-label phase 3 trial is examining
the efficacy and safety of patients treated with up to 3
years of continuous efalizumab therapy. To date, this
Main
MMonth 9Month 6Month 30
10
20
30
40
60
70
5041.3%
13.0%
22.4%
56.6% 57
51.7%
First 12 Weeks
24.5%
Per
cent
age
of P
atie
nts (n = 339)
Fig. 6. Percent of patients achieving PASI-75 and PASI-90 during
will last 36 months. The analysis is intent-to-treat with respect to
was carried.
is the longest ongoing trial evaluating the use of a
biologic therapy in patients with psoriasis.
Three hundred and thirty-nine patients entered the
trial and received efalizumab for 3 months. At the end
of this initial dosing period, 290 patients (82%)
achieved either a PASI-50 response or an OLS of
‘‘mild’’ or ‘‘clear’’ and were allowed to continue in
the maintenance phase of the trial for up to 3 years. A
preliminary analysis of this ongoing trial shows
excellent results: at 21 months, 55.9% of patients in
the maintenance period achieved PASI-75. Further-
more, 30% (more than half) of these patients are
PASI-90 responders (Fig. 6) [13]. The clinical re-
sponse of a long-term treatment patient and the
kinetics of his response are shown in Fig. 7. Collect-
tenance Period (ITT* n = 290)PASI 75
PASI 90
Month 21Month 18Month 15onth 12
.2%
25.9%
58.3% 56.2%
29.0%33.4%
55.9%
30.0%
21 months of continuous therapy. This study is ongoing and
entry into the maintenance period and the last observation
Before Treatment Day 84
PASI = 15BSA = 18%
PASI = 0BSA = 0%
A
16
14
12
10
8
6
4
2
0
20
18
1614
12
10
86
BS
A %
42
00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
PASI Score
BSA %
21 22 23 24
PA
SI S
core
Month
B
Fig. 7. (A) Patient response to efalizumab therapy. *Tattoo has been covered to protect patient’s privacy. (B) Reduction in PASI
and body surface area (BSA) in response to continuous efalizumab therapy. By 24 months, the patient maintained complete
control of his psoriasis by weekly subcutaneous injections.
C.L. Leonardi / Dermatol Clin 22 (2004) 427–435432
ively, these results demonstrate that efalizumab rap-
idly controls psoriasis symptoms and also seems to be
an effective long-term maintenance treatment.
Safety
With 2762 patients with psoriasis treated in 13
clinical trials, efalizumab represents the largest evi-
dence base in the psoriasis population for a biologic
therapy. To date, more than 2400 patients have re-
ceived efalizumab for at least 3 months, 904 for up to
6 months, and more than 225 for up to 1 year.
In general, efalizumab has been well tolerated.
Some patients experience acute flulike symptoms
when efalizumab therapy is initiated, however, in-
cluding headache, chills, fever, nausea, and myalgia.
During phase 3 trials, these events most commonly
C.L. Leonardi / Dermatol Clin 22 (2004) 427–435 433
occurred within 48 hours after administration of the
first two doses and were primarily mild to moderate
in severity and well tolerated when a conditioning
dose (0.7 mg/kg) was administered the first time. By
the third and all subsequent doses, the incidence of
these acute adverse events was similar to placebo [8].
In the trials, fewer than 1% of patients withdrew from
efalizumab treatment because of adverse events. The
adverse events that occurred at least 2% more fre-
quently in efalizumab versus placebo groups during the
first 12 weeks of treatment in randomized, placebo-
controlled, double-blind phase 3 trials are summarized
in Table 1.
Patients receiving long-term efalizumab therapy
did not exhibit any increased incidence of adverse
events over time nor did the safety profile change
over time [12,13,19]. To date, there has been no evi-
dence for cumulative toxicity or end-organ damage,
or increased risk of infection or malignancy with
prolonged dosing [13].
Serious adverse reactions occurred infrequently
and included serious infections requiring hospitaliza-
tion (0.3% of efalizumab patients versus 0.1% of
placebo patients), thrombocytopenia with platelet
counts lower then 52,000 (0.3% of patients), and
worsening of psoriasis requiring hospitalization
(0.7% of patients).
As part of the trial design, some patients abruptly
stopped therapy after 12 weeks of treatment. Al-
though most had a gradual recurrence of their disease,
13.8% experienced significant worsening of their
psoriasis and achieved the National Psoriasis Foun-
dation definition of ‘‘rebound’’ (PASI-125 as com-
pared with baseline or emergence of a new psoriasis
morphology within 12 wk on discontinuation of
treatment). An analysis of patients who experienced
Table 1
Adverse events in placebo-controlled study periods reported at a 2
Adverse event Placebo (N = 715)
Headache 159 (22%)
Infectiona 188 (26%)
Chills 32 (4%)
Nausea 51 (7%)
Generalized pain 38 (5%)
Myalgia 35 (5%)
Flu syndrome 29 (4%)
Fever 24 (3%)
Back pain 14 (2%)
Acne 4 (1%)
The most common adverse reactions associated with efalizumab
chills, fever, nausea, and myalgia within 2 days following the firsa Includes diagnosed infections and other nonspecific infection
Data from Raptiva (efalizumab) [package insert]. South San Franc
rebound showed that it was most likely to occur in
those who failed to achieve PASI-50 (ie, nonrespond-
ers). In addition, some patients randomized to receive
placebo also had worsening of their psoriasis and
achieved PASI-125.
Antibodies to efalizumab were predominantly
low-titer, detected in 6.3% (67 of 1063) patients
and clinically irrelevant [20]. To date, the presence
of anti-efalizumab antibodies has not been associated
with changes in efficacy, safety or efalizumab phar-
macodynamics [8].
The combined safety and efficacy profiles suggest
that efalizumab is appropriate for continuous treat-
ment and represents a significant advance not only for
patients with psoriasis but also for the dermatologists
attempting to treat them.
Practical concerns
Given as a once-weekly subcutaneous injection,
patients can self-administer efalizumab at home once
they are trained and have demonstrated competency
in reconstituting the drug, in loading the syringe, and
in administering the injection. Patients receive the
following: a 4-week supply containing four single-
use vials, each containing 125 mg of efalizumab as a
sterile lyophilized powder; preloaded single-use sy-
ringes containing 1.3 mL of sterile water; alcohol
swabs; instructions; and telephone support numbers,
if necessary. The experience from one trial showed
that patients rapidly learned this process and most
found self-administration ‘‘easy’’ or ‘‘very easy’’ [21].
When efalizumab therapy is initiated, a single
0.7-mg/kg subcutaneous conditioning dose is recom-
mended to diminish the incidence and severity of
% or higher rate in efalizumab than placebo groups
Efalizumab (1 mg/kg/wk) (N = 1213)
391 (32%)
350 (29%)
154 (13%)
128 (11%)
122 (10%)
102 (8%)
83 (7%)
80 (7%)
50 (4%)
45 (4%)
were a first-dose reaction complex that included headache,
t two doses.
s (most commonly upper respiratory tract infection).
isco, CA: Genentech, Inc.; 2003.
C.L. Leonardi / Dermatol Clin 22 (2004) 427–435434
acute adverse events. This dose is followed 1 week
later by subcutaneous efalizumab (1 mg/kg/wk), with
no single dose to exceed 200 mg. Patients should be
instructed to rotate the injection sites between the
thigh, abdomen, buttocks, and upper arm with each
dose. Several studies have shown that efalizumab at
1 mg/kg/week is the optimal dose and that increasing
to 2 mg/kg/week or even 4 mg/kg/week is unlikely to
provide additional benefit.
Efalizumab is best used as a continuous therapy
for psoriasis. Because the effects of efalizumab on
T cells are reversible, recurrence of disease is ex-
pected on discontinuation. The rebound phenomenon
is easily avoided by transition to alternative treat-
ments in patients who must permanently stop therapy
or in those who fail to respond.
During therapy, patients should be monitored for
signs and symptoms of thrombocytopenia, and as-
sessment of platelet counts is recommended on ini-
tiating therapy and periodically while receiving
treatment. Efalizumab should be discontinued if
thrombocytopenia occurs.
Because efalizumab is a T-cell modulator, caution
should be exercised in patients with a history of re-
current or chronic infection, and treatment should
be temporarily stopped in patients with clinically
significant infections. Efalizumab should not be rou-
tinely combined with other immunosuppressive thera-
pies without close supervision. The most relevant
circumstance for dermatologists will involve transi-
tion on or off therapy. Additional studies are under-
way to evaluate various entry or exit strategies.
Because the role of efalizumab in the development
of malignancies is not clear, caution should be
exercised in high-risk patients, and treatment should
be discontinued in the event of malignancy. Excep-
tions to this situation might include development
of basal cell carcinoma or cutaneous squamous cell
carcinoma. Until more data have accrued, a conser-
vative approach is recommended.
The safety and efficacy of vaccines administered
to patients receiving efalizumab have not been fully
characterized. An early study assessing the develop-
ment of humoral immunity in response to inocula-
tion with a neoantigen suggested that efalizumab
might decrease immune responses on rechallenge.
Until more data exist, live or live-attenuated vaccines
should be avoided.
Summary
Efalizumab is a new therapeutic option that may
simplify psoriasis management for some patients. It
is approved as a single, once-weekly, subcutaneous
injection for continuous administration in adults with
moderate to severe chronic plaque psoriasis. Continu-
ous therapeutic use, without the need for rotation to
a new therapy or intermittent treatment discontinua-
tion, represents an advance in psoriasis management.
The results of multiple randomized, placebo-con-
trolled, double-blind phase 3 trials have demon-
strated consistent efficacy, and the safety database is
the largest to date of a biologic therapy approved for
psoriasis. In each trial, all efficacy endpoints reached
statistical significance relative to placebo. Efalizumab
is associated with a rapid onset of action, with im-
provement relative to placebo observed as early as 2 to
4 weeks after start of therapy. Patients achieve signif-
icant clinical benefit, as measured both by physician-
and patient-assessed outcomes, and this benefit is
maintained over the course of prolonged treatment
periods. Efalizumab seems to provide rapid, sustain-
able symptom control, which allows patients to return
to their normal activities of daily living.
Biologic therapies, such as efalizumab, are chang-
ing the treatment landscape by offering hope for
improved patient safety and uninterrupted control of
psoriasis. Efalizumab seems to be appropriate for a
wide range of patients, with convenient and well-
tolerated dosing schedules. The efficacy, safety, and
tolerability of prolonged efalizumab therapy demon-
strate the therapeutic value of this new agent in the
management of patients with moderate to severe
chronic plaque psoriasis.
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Dermatol Clin 22 (2004) 437–447
Psoriasis and its treatment with infliximab-mediated tumor
necrosis factor a blockade
Laura Winterfield, MDa, Alan Menter, MDa,b,c,*
aDepartment of Dermatology, University of Texas Southwestern Medical School, Dallas, TX, USAbBaylor University Medical Center, 5310 Harvest Hill Road, Suite 260, Dallas, TX 75230, USA
cTexas Dermatology Associates, Dallas, TX, USA
Psoriasis is a chronic inflammatory skin condi- mately 15% of patients, joint pain presents before
tion, affecting approximately 2% of the US popula-
tion [1–3]. It is seen predominantly in whites ( > 80%
of cases) and occurs equally in men and women, with
a typical onset between the age of 20 and 30 years
[2]. Marked familial aggregation (30%) and a high
concordance rate in monozygotic twins (65%–72%)
indicate the role of a multifactorial genetic predispo-
sition in the emergence of psoriasis [4].
Psoriasis can be triggered in predisposed persons
by several factors, including bacterial infections, in-
flammatory insults, local trauma, psychologic stress,
drugs (eg, lithium, b-blockers, and antimalarial
agents), alcohol, and overexposure to the sun [5–8].
Skin involvement may range from minimal, with
small focal lesions on the elbows, knees, or scalp, to
extensive, with areas on the torso and extremities and,
in rarer instances, whole body involvement. The most
common plaque-type psoriatic lesions are usually
easily recognized by the presence of three cardinal
signs: acanthosis, erythema, and white or silvery
scales. Pruritus and nail dystrophy are frequently
associated. A subset of patients with psoriasis (up to
35%) develop or exhibit a progressive, inflammatory
arthritis (psoriatic arthritis [PsA]), marked by joint
swelling and pain; in most patients (�75%), psoriatic
skin lesions precede such arthritis, whereas in approxi-
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/j.det.2004.03.011
Support for this article was provided by an unrestricted
grant from Centocor, Malvern, Pennsylvania.
* Corresponding author. Baylor UniversityMedical Cen-
ter, 5310 Harvest Hill Road, Suite 260, Dallas, TX 75230.
E-mail address: [email protected]
(A. Menter).
obvious skin lesions [9].
Treatment options for psoriasis vary widely with
respect to mechanism of action, route of administra-
tion, efficacy, and adverse event risk. Minor skin
involvement usually responds well to topical therapy
(eg, corticosteroid-, vitamin D3-, or retinoid-contain-
ing products), and these formulations are associated
with a low risk of troublesome side effects. Such
treatments target local epidermal inflammation and
acanthosis caused by keratinocyte hyperproliferation.
In those patients with a larger area of involved skin
or more severe symptoms, traditional phototherapy,
ultraviolet B, and combined psoralen/long-wave
ultraviolet radiation (PUVA), or systemic therapy,
including oral retinoids, methotrexate, and cyclospor-
ine, is required. These approaches have been shown to
be highly effective in clearing psoriatic lesions [10,11]
but may be associated with side effects, such as
hepatotoxicity (methotrexate) and nephrotoxicity (cy-
closporine) [11,12], teratogenicity and skeletal hyper-
ostosis (oral retinoids) [13], and cancer (PUVA,
cyclosporine) [14,15], which limit their long-term use.
The safety limitations of conventional systemic
treatments, however, and a growing understanding of
the pathogenesis of psoriasis have stimulated intense
interest in inhibiting the immunologic processes that
contribute to the causes of psoriasis.
Tumor necrosis factor in the pathogenesis of
psoriasis
Psoriasis is an immune disease of activated T cells
and an exaggerated inflammatory response in the skin
s reserved.
L. Winterfield, A. Menter / Dermatol Clin 22 (2004) 437–447438
[16]. After passage through the skin’s endothelial
cells, activated T cells secrete type 1 (Th1) cytokines:
interferon l, interleukin 2 (IL-2), IL-6, IL-8, IL-12,
and tumor necrosis factor a (TNF-a) [17]. These
proinflammatory cytokines mediate several biologic
actions, which perpetuate and amplify the inflamma-
tory response, including induction of keratinocyte
proliferation and dermal vascular changes. Because
these cytokines ‘‘drive’’ skin inflammatory reactions
and other immune responses, an emerging therapeutic
strategy is selective deactivation of specific cyto-
kines. As a key contributor to the clinical features
of psoriasis, TNF-a is now considered an important
therapeutic target in drug development.
TNF-a exists as both transmembrane and soluble
proteins. The membrane-bound form of TNF-a is
cleaved by an enzyme to release a soluble circulating
form. Both forms of TNF-a are believed to be
biologically active. The soluble form may be more
potent, however [18]. TNF-a can be produced by
multiple cells of the body, including cells present in
the dermis and epidermis of patients with psoriasis,
such as activated T cells, keratinocytes, and Langer-
hans cells [19].
The concentrations of TNF-a and other inflam-
matory mediators in lesional skin from patients with
Table 1
Correlation between cellular actions of TNF-a and pathogenic me
Cellular action of TNF-a C
Stimulates synthesis of proinflammatory cytokines, such as
IL-1, IL-6, IL-8, and RANTES [74,75]
H
T
I
Activates NFkB, a nuclear transcription factor [74,75,77] D
Stimulates transcription of keratin-6 gene promoter [79] A
Retards progression of keratinocyte cell cycle [85] D
Induces SKALP/elafin gene in keratinocytes [81] E
n
r
Increases type 1 vasoactive intestinal peptide receptor
mRNA in keratinocytes [78]
P
s
Increases plasminogen activator inhibitor type 2, a serine
proteinase inhibitor [84]
P
Stimulates production of ICAM-1 and other adhesion
molecules [73,83]
F
Increases VEGF directly and increases production of
nitric oxide necessary for the induction of VEGF [76,86]
P
v
Decreases E-cadherin expression [82] F
o
i
Increases expression of CD44, a cell surface receptor
for hyaluronate [80]
P
Abbreviation: VEGF, vascular endothelial cell growth factor.
psoriasis are up-regulated [17,20]. Immunolabeling
of TNF-a and its receptors is increased when com-
pared with uninvolved skin. Furthermore, increases in
TNF-a production by monocytes in the blood of
patients with both active and inactive psoriasis cor-
relate with the clinical severity of the psoriasis [21].
Also, the distribution of TNF-a differs between
psoriatic and normal skin. In normal skin, TNF-a is
found mainly in the epidermal basal cell layers and
around eccrine ducts and sebaceous glands. In psori-
atic skin, TNF-a is present throughout all epidermal
layers and upper dermal blood vessels [22].
Through its pleiotropic actions, TNF-a is likely to
be an important stimulus for the events leading to
psoriasis, as summarized in Table 1. The presence of
TNF-a within the dermis recruits macrophages to the
area and induces secretion of other proinflammatory
cytokines and chemokines. The interaction of TNF-awith the vascular endothelium leads to the enhanced
expression of certain adhesion molecules and vascu-
lar endothelial growth factor, which encourages an-
giogenesis and facilitates migration of inflammatory
cells. Finally, the increased production of proinflam-
matory cytokines, which is at least partially triggered
by TNF-a, causes keratinocyte hyperproliferation.
These actions serve to amplify, propagate, and main-
chanisms of psoriasis
orrelation with psoriasis pathogenesis
yperproliferative epithelium; proliferation of keratinocytes;
-cell and neutrophil activation; chemotaxis; increases
CAM-1 mRNA
ecreases in the rate of apoptosis among keratinocytes
ctivates keratinocytes
ecreases the rate of apoptosis among keratinocytes
xpresses a proteinase inhibitor that the keratinocytes of
ormal skin do not express and that is involved in the
egulation of the cutaneous inflammatory process
romotes keratinocyte proliferation and stimulates
ynthesis of proinflammatory cytokines.
rotects cells from apoptosis
acilitates T-cell infiltration into the skin
romotes angiogenesis; with the creation of new blood
essels, T cells have increased access into the epidermis
acilitates Langerhans cell emigration and the initiation
f immune responses against antigens encountered
n epidermis
romotes migration of Langerhans cells from the epidermis
L. Winterfield, A. Menter / Dermatol Clin 22 (2004) 437–447 439
tain the abnormal inflammatory response that is
responsible for psoriasis and serve as the rationale
for use of TNF-a–blocking agents for the treatment
of this disease.
Characterization of infliximab
Infliximab (Remicade; Centocor, Malvern, Penn-
ysylvania) is a TNF-a–blocking agent approved for
treatment of Crohn’s disease and rheumatoid arthritis
(RA). It is a chimeric anti–TNF-a monoclonal anti-
body made by joining the human IgG1 constant
region to a murine-derived antigen-binding variable
region [23]. Infliximab binds with high affinity to
both soluble and transmembrane-bound forms of
TNF-a and, in this manner, inhibits the ability of
TNF-a to bind with its receptors and initiate the
intracellular signaling that leads to gene transcription
and subsequent biologic activity [24,25]. When pres-
ent at molar excess over TNF-a, three infliximab mol-
ecules can bind to each molecule of soluble TNF-a,thereby blocking all receptor binding sites on the
TNF. It does not bind with or inhibit the receptor-
mediated activity of TNF-b or any other known
antigen. The binding of infliximab to TNF-a is
sustained, so that likelihood of dissociation and
subsequent activity of TNF-a is low [26]. Because
of its inhibition of TNF-a activity, infliximab also
indirectly inhibits production of other proinflamma-
tory cytokines, and its combined actions are likely to
cause a reduction in proliferation of keratinocytes
[19,27]. Finally, in vitro evidence indicates that the
binding of infliximab to membrane-bound TNF-aresults in lysis of TNF-producing cells by means of
a complement- or antibody-dependent cell cyto-
toxicity mechanism. Reducing the population of such
Table 2
Randomized, placebo-controlled trials with infliximab
Study Population Treatment
IIS phase 2 [29] Mod to sev
plaque-type psoriasis
Infliximab, 5 mg/
Infliximab, 10 mg
Placebo (n = 11)
IMPACT [28] Active PsA Infliximab, 5 mg/
Placebo (n = 51)
SPIRIT [30] Mod to sev
plaque-type psoriasis
Infliximab, 3 mg/
Infliximab, 5 mg/
Placebo (n = 51)
Abbreviations: IIS, investigated-initiated study; mod, moderate; sea Open-label.b Blinded.
cells could have beneficial clinical effects, but this
finding has not yet been confirmed in vivo [25].
Clinical experience with infliximab
Randomized, controlled clinical trials
An expanding literature documents the efficacy
and safety of infliximab in the treatment of psoriasis.
Clinical experience with infliximab in psoriasis
ranges from randomized, placebo-controlled, dou-
ble-blind trials to open-label studies and case series.
Long-term follow-up studies and analyses of safety
are also beginning to appear, providing important
information about tolerability, safety, and durability
of the beneficial clinical effects seen with infliximab.
Three randomized, placebo-controlled trials of
infliximab that evaluate improvement in psoriasis
have been reported (Table 2) [28–30]. One was an
investigator-initiated study of infliximab in patients
with moderate to severe psoriasis (eg, �5% body
surface area [BSA]) [29]. This trial assigned patients
(N = 33) to receive either 5 mg/kg or 10 mg/kg of
intravenous (IV) infliximab or placebo on weeks 0, 2,
and 6 of the study, and these patients were evaluated
initially until week 10 (eg, the ‘‘induction’’ phase). At
baseline, randomized patients were clinically and
demographically similar across the groups, with a
mean age range of 35 to 51 years and mean Psoriasis
Area and Severity Index (PASI) scores of 20 to 26.
Beginning at week 2 of treatment and continuing
through week 10, decreases in psoriasis severity were
significantly greater with 5 mg/kg or 10 mg/kg of
infliximab than with placebo. At week 10, a reduction
of 75% or greater from the baseline PASI score (eg,
‘‘PASI-75’’ response) was seen in 82% and 73% of
Duration of double-blind
phase (wk)
Extension
phase (wk)
kg (n = 11)
/kg (n = 11)
10 10–26a
kg (n = 50) 16 16–32a
kg (n = 99)
kg (n = 99)
46 10–26b
v, severe.
L. Winterfield, A. Menter / Dermatol Clin 22 (2004) 437–447440
patients given 5 mg/kg or 10 mg/kg doses of IV
infliximab, respectively, whereas only 18% of patients
treated with placebo reached this treatment goal.
The results of evaluation of psoriasis from a larger
investigator-initiated study, the Infliximab Multina-
tional Psoriatic Arthritis Controlled Trial (IMPACT),
support the results of the earlier study [29]. In
IMPACT, 102 patients with PsA who had failed
therapy with at least one traditional disease-modifying
antirheumatic drug (DMARD) were randomized to ei-
ther 5 mg/kg of infliximab or placebo, with infusions
administered at weeks 0, 2, 6, and 14. In addition to
significant improvements in joint signs and symp-
toms, based on American College of Rheumatology
response criteria, patients exhibited significant im-
provements in psoriatic skin involvement. Among
patients with a baseline PASI of 2.5 or greater, these
scores decreased from 8.4 to 1.6 at week 16 with
infliximab treatment [28]. By contrast, PASI scores
worsened for those patients receiving placebo (from
8.4 to 9.3). Approximately 67% of patients random-
ized to infliximab infusions exhibited a 75% decrease
in baseline PASI scores at week 16. Moreover, a
subset of patients (n = 69) who participated in the
IMPACT were receiving concomitant DMARD ther-
apy at baseline; among these patients, 56 received
concomitant methotrexate throughout the 16-week
study period. PASI scores remained largely un-
changed from baseline levels in those patients receiv-
ing methotrexate paired with placebo, indicating that
methotrexate alone did not exert a positive effect on
PASI scores.
The Study of Psoriasis with Infliximab Induction
Therapy (SPIRIT) trial [30] is to be fully reported at
the 62nd annual meeting of the American Academy of
Dermatology, but preliminary analysis noted rapid,
dose-related improvements in psoriatic symptoms.
The SPIRIT trial was a phase 2 multicenter, double-
blind, randomized, placebo-controlled study in pa-
tients (N = 249) with plaque psoriasis affecting 10%
or more of their BSA; individuals were randomized in
a 1:2:2 ratio to either placebo (n = 51), 3 mg/kg of
infliximab (n = 99), or 5 mg/kg of infliximab (n = 99)
infusions and treated at weeks 0, 2, and 6. Concomi-
tant psoriasis therapy was prohibited with the excep-
tion of tar or salicylic acid–containing shampoos
during the study period. PASI assessments, quality-
of-life questionnaires, and physician global ratings
were scheduled every 2 weeks through week 10.
Sustained efficacy of infliximab
Results from extension phases in all three ran-
domized trials of infliximab have been reported and
provide evidence of sustained efficacy (see Table 2).
In the earlier investigator-initiated study, investigators
followed up patients for an additional 16 weeks. At
week 26, 33% and 67% of patients who received
5 mg/kg or 10 mg/kg, respectively, maintained a 75%
improvement in PASI. Individuals were given single
infusions of infliximab if a loss of response occurred
(eg, <50% reduction in baseline PASI score) [31]. At
week 26, 9 (41%) of 22 patients who had received
infliximab during the double-blind phase exhibited a
loss of response and required one or two additional
infliximab infusions. This retreatment largely im-
proved PASI scores but not to the extent seen with
a full induction regimen.
The 34-week (weeks 16–50) open-label extension
of the IMPACT in patients with PsA showed that
intermittent retreatment with infliximab effectively
maintained skin and joint improvements [28]. In-
fusions of 5 mg/kg infliximab (at weeks 16, 18, 22,
30, 38, and 46) were administered to patients who had
initially received either placebo or infliximab during
double-blind infliximab treatment. Twelve (86%) of
14 patients who exhibited a PASI-75 response at
week 16 sustained that level of improvement at week
50. The mean reduction in baseline PASI score was
81% at week 50. Moreover, patients who were
initially given placebo and then switched to inflixi-
mab exhibited skin and joint responses of a similar
magnitude to those who had received infliximab
during the blinded phase of the study.
The SPIRIT trial provided data during weeks 14
to 26 for 198 patients who received no further in-
fliximab treatment after the initial three infusions at
weeks 0, 2, and 6 [32]. At week 26, 14% and 30% in
the 3-mg/kg and 5-mg/kg groups, respectively, main-
tained a 75% improvement in PASI.
Collectively, the results of the extension phases of
the randomized studies demonstrated that the benefit
of infliximab induction treatment persists over time
and is dose dependent, but is variable for individual
subjects. Moreover, the data suggest that infrequent
maintenance dosing may sustain clinically meaning-
ful therapeutic responses for most patients.
Uncontrolled, open-label trials
Six uncontrolled trials of infliximab in patients
with psoriasis or PsA have been reported (Table 3)
[33–38]. These noncomparative trials examined re-
sponse to infliximab therapy among small groups of
patients (N = 6 to 16) with severe psoriasis or PsA
refractory to other systemic therapies. Patients in these
studies had undergone one or more courses of treat-
ment with PUVA or DMARDs, such as methotrexate,
Table 3
Noncomparative trials with infliximab
First author Population N Treatmenta Duration
Antoni [33] All with PsA 10 Infliximab, 5 mg/kg induction and
then intermittently
12 mo
Salvarani [37] All with PsA 16 Infliximab, 3 mg/kg, at 0, 2, 6, 14, 22,
and 30 wk
30 wk
Cauza [34] All with PsA 9 Infliximab, 3 mg/kg, at 0, 2, 6, 14,
and 22 wks
22 wk
Ogilvie [36] All with PsA 6 Infliximab, 5 mg/kg, at 0, 2, and 6 wk 10 wk
Chan [35] 5 with psoriasis; 2 with PsA 7 Infliximab, 5 mg/kg, intermittently 15 mo
Schopf [38] All with psoriasis 8 Infliximab, 5 mg/kg, at 0, 2, and 6 wk 10 wk
a Patients continued stable doses of other antiarthritis/psoriasis drugs.
L. Winterfield, A. Menter / Dermatol Clin 22 (2004) 437–447 441
but continued to exhibit PASI scores indicating sub-
stantial skin involvement. Across these studies, inflix-
imab was administered as an ‘‘induction’’ regimen of
either 3 mg/kg or 5 mg/kg at weeks 0, 2, and 6, and
thereafter on an individualized basis or, in the case of
longer-term studies, on an intermittent schedule. Fur-
thermore, patients were usually maintained on a stable
dose of the pre-existing treatment regimen.
The magnitude and timing of improvements in
psoriatic skin lesions seen in these noncomparative
trials were largely comparable to those observed in the
controlled trials. For example, Antoni et al [33] treated
10 patients with PsA with a 5-mg/kg infliximab
induction regimen and reported an average decrease
of 71% in PASI score at week 10. Likewise, Schopf
et al [38] found that a 5-mg/kg infliximab induction
regimen in eight patients resulted in a mean decrease
of 89% in PASI at week 10. At week 14, 8 weeks
following the last infliximab infusion, PASI scores
were decreased by an average of 66% from baseline.
Maintenance treatment over longer periods seems
to preserve initial treatment response. For instance,
after 44 weeks of intermittent infliximab treatment
(every 8 wk), 8 of the 10 patients in the study
reported by Antoni et al [33] exhibited PASI scores
that decreased by an average of 71.3%. Similarly, in
the largest uncontrolled trial, 16 patients with severe
treatment-refractory PsA, treated with 3-mg/kg in-
fliximab infusions at three consecutive 8-week inter-
vals following an initial induction regimen, continued
to show a robust treatment response. At week 30, PASI
scores were decreased by an average of 86% from
baseline [37]. Quality-of-life instruments showed that
the improvement in skin involvement seen with long-
term infliximab treatment can also have a significant
positive effect on patients’ personal and health-related
quality of life. Among patients repeatedly hospitalized
for severe, recalcitrant psoriasis, those who received
repeated intermittent infusions no longer required
hospitalization and exhibited significant improve-
ments in quality of life, marked by the ability to return
to full-time employment [35].
Thus, the results from these uncontrolled studies
support those of the randomized trials, showing that
infliximab is highly effective for the rapid improve-
ment of severe psoriasis and PsA; furthermore, they
suggest that prudent intermittent treatment seems to be
critical for maintaining clinically relevant responses.
Case series
The first report of the efficacy of infliximab in
treating psoriasis described the case of a 57-year-old
woman who had refractory inflammatory bowel dis-
ease treated with infliximab. Infliximab infusion
dramatically improved the patient’s psoriasis [39].
Since this observation, a growing number of case
reports documenting the use of infliximab for psoria-
sis and PsA have appeared in the literature. They
describe the treatment of patients (a total of 20 cases)
who had longstanding, recalcitrant, or severe disease,
affecting more than 50% of their BSA, including the
face, hands, feet, and scalp [40–49]. In several
instances, patients presented relatively uncommon
types of psoriasis, including pustular, palmoplantar,
and erythrodermic forms [41,43,47,49]. In some
cases, patients had undergone prior treatment with
most available topical, phototherapy, and systemic
approaches, with skin lesions remaining refractory to
therapy. As might be expected, many of these patients
reported impaired quality of life, psychosocial diffi-
culties, and depression [42,49].
In nearly all patients, infliximab treatment con-
sisted of infusions of 3 to 10 mg/kg at weeks 0, 2, and
6, with intermittent maintenance treatments thereafter.
Patients were maintained on pre-existing treatment
regimens, often involving several agents, including
methotrexate, cyclosporin and topical therapies, and
L. Winterfield, A. Menter / Dermatol Clin 22 (2004) 437–447442
nonsteroidal anti-inflammatory drugs for manage-
ment of pain in patients with PsA. With the addition
of infliximab to their treatment regimen, most
patients (16 of 20) exhibited dramatic improvements
in skin involvement. After 4 weeks of treatment
among patients who responded well to infliximab
treatment, lesions were described as reduced in area
and severity, with improvements characterized by a
significant reduction in redness and thickness, and
healing of individual fissures. In some patients, PsA-
related clinical symptoms, such as joint swelling and
tenderness, also improved.
Safety of infliximab
More than 432,000 patients worldwide have re-
ceived single or multiple doses of infliximab. Inflixi-
mab has been approved for use in moderate to severe
or fistulizing Crohn’s disease, refractory to conven-
tional therapies, and for combined use with metho-
trexate in RA, refractory to methotrexate alone.
Therefore, infliximab’s 10-year safety experience
comprises predominantly patients with these condi-
tions. Interpolating the adverse event profile of inflixi-
mab for patients with psoriasis from the safety
database for patients with Crohn’s disease and RA
may skew the analysis. Crohn’s disease and RA are
chronic, debilitating systemic diseases associated
with comorbidities for which patients may also be
receiving other immunosuppressive therapies. Ac-
cordingly, the safety experience in these conditions
may be less favorable than would be anticipated in
patients receiving monotherapy with infliximab for
moderate to severe psoriasis. Alternately, additional
safety issues may be identified with expanded studies
in a new patient population, such as in those with
psoriasis alone.
Safety and tolerability of infliximab in rheumatoid
arthritis and Crohn’s disease
Overall, infliximab has been well tolerated in
controlled clinical trials involving patients with RA
and Crohn’s disease. An integrated safety database
is available that comprises nine open-label and pla-
cebo-controlled clinical trials involving 453 patients
(Crohn’s disease, RA, and ulcerative colitis) who
received at least one dose of infliximab [50]. The
most frequent adverse events reported in 10% or more
of infliximab-treated patients included headache, nau-
sea, and upper respiratory tract infection (URI). Less
frequently reported adverse events included abdomi-
nal pain, pharyngitis, fever, vomiting, coughing, rash,
pain, rhinitis, sinusitis, urinary tract infection, fatigue,
and pruritus. Infection was seen in 21% of patients
given infliximab compared with 11% in those given
placebo. Serious adverse events associated with in-
fliximab have been infrequent. Seven (1.5%) of
453 patients developed a lymphoproliferative disorder
while undergoing infliximab therapy.
A broader analysis, including 913 patients with
RA or Crohn’s disease exposed to infliximab, showed
that the rate of malignancy with infliximab was low
and similar to rates expected in the general population
based on the National Institutes of Health SEER
database [50] Although safety statistics like these
are encouraging, the long-term data still remain in-
sufficient to answer the question of an increased risk
for lymphoproliferative disorders and other malignan-
cies [51]. Continued surveillance of all infliximab-
treated patients is ongoing in an effort to conclusively
define this issue.
In the overall safety database analysis, infusion
reactions, defined as any adverse event occurring
during the infusion period or the 2-hour postinfusion
observation period, were more common among inflixi-
mab-treated patients compared with those receiving
placebo (16% and 6%, respectively) [50]. Among
1207 infliximab infusions, 5% (58 of 1207) were
associated most commonly with nonspecific symp-
toms. Of these reactions, only four (0.03%) were
considered serious; they were characterized by car-
diopulmonary symptoms, such as chest pain, palpita-
tions, hyper- or hypotension, and dyspnea [50]. In
another report [52] documenting the frequency of
infusion reactions to infliximab in 165 consecutive
patients with Crohn’s disease, the overall incidence of
infusion reactions was 6.1% (29 of 479) of infusions,
affecting 9.7% (16 of 165) of patients. Mild, moder-
ate, or severe acute reactions occurred in 3.1% (15 of
479), 1.2% (6 of 479), and 1.0% (5 of 479) of
infliximab infusions, respectively. Typically, symp-
toms improved substantially or resolved completely
after infusion rate adjustments alone or the addition of
treatment with acetaminophen and antihistamines.
Less commonly, steroids or epinephrine was admin-
istered. Pretreatment with these agents may also limit
the reactions.
Safety and tolerability of infliximab in psoriasis
The safety experience for infliximab in patients
with psoriasis is considerably smaller than that in the
integrated analysis of safety in patients with Crohn’s
disease and RA in clinical studies. In the investigator-
initiated study reported by Chaudhari et al [29],
headache was the only adverse event that occurred
more often with infliximab than with placebo. Infu-
sion reactions were seen during the 16-week post-
induction study phase in 4 (14%) of 29 patients treated
L. Winterfield, A. Menter / Dermatol Clin 22 (2004) 437–447 443
with infliximab; these were all considered mild and
transient [31]. Unlike the pattern of adverse events
seen in the integrated analysis of infliximab safety
data [50], the frequency of infection (including cellu-
litis in the placebo group and dental abscess, com-
munity-acquired pneumonia and otitis externa in the
infliximab group) was similar between the placebo
and infliximab groups (infliximab, n = 7; placebo,
n = 6) [29]. This variance may be related to differ-
ences in the patient populations, with respect to
morbidity and history of immunosuppressant use or
the small patient numbers. In the SPIRIT trial, the
most frequent adverse events in infliximab-treated
patients were headache, pruritus, and URI [32]. The
most frequently reported infections were URIs, sinus-
itis, and pharyngitis, the latter two occurring more
frequently in the infliximab-treated groups compared
with placebo. This finding may have been in part
because of the shorter follow-up period in the placebo
group. Similarly, in the IMPACT, the most frequent
adverse events in infliximab-treated patients were
URI, headache, nausea, sinusitis, and rash [53]. One
patient developed an infection of the knee [28]. No
opportunistic infections were reported in any of these
three studies.
Reactivation of latent tuberculosis
Most people infected with Mycobacterium tuber-
culosis contain the initial infection and develop latent
tuberculosis (TB). This state is characterized by evi-
dence of an immune response against the bacterium
(a positive tuberculin skin test [TST]), but no signs of
active infection, including the absence of symptoms
or chest radiograph evidence of disease [54]. The
incidence of a positive TST without signs of active
infection is approximately 1% in non-Latino individ-
uals born in the United States, but may be higher in
other ethnic groups [55]. Serious cases of reactivation
of latent TB (both disseminated and nondisseminated
presentations) have been reported with all TNF-ainhibitors [56–59]. Through February 2003, there
were 537,000 patient years of exposure to infliximab
in the United States and 109 cases of TB reported in
infliximab-treated individuals. Thus, before starting
TNF-a inhibitor therapy, patients should be screened
for latent TB infection with a TST.
Congestive heart failure
Experimental evidence has suggested that TNF-amay be implicated in the pathogenesis of heart failure
[60]. Three large-scale clinical trials of TNF-a inhibi-
tors in patients with advanced congestive heart fail-
ure (CHF)—one 150-patient study of infliximab [61]
and two etanercept (a fusion protein directed against
TNF) trials involving a total of 2048 participants
[62]—were prematurely halted for lack of benefit or
adverse outcomes, prompting a warning from the US
Food and Drug Administration about the safety of
these therapies for at-risk patients with RA. In the
trial evaluating infliximab, the combined risk of death
from any cause or hospitalization for heart failure was
increased in the patients randomized to 10 mg/kg of
infliximab relative to placebo (P = 0.043). A similar
picture emerged from the two etanercept trials, which
showed that the effects of the fusion protein were not
different from placebo (P = 0.17 and P = 0.34,
respectively). In support of the observations from
these trials were reports to the MedWatch program
on 47 patients who developed new or worsening CHF
during TNF antagonist therapy. After TNF antagonist
therapy, 38 patients developed new-onset CHF and
9 patients experienced heart failure exacerbation [63].
In contrast to the findings from these three trials
and the MedWatch data, however, an abstract pre-
sented at the 2003 Annual Scientific Meeting of the
American College of Rheumatology indicated that
anti-TNF therapy conferred a cardioprotective effect
in patients with RA [64]. The report examined medi-
cal records of 13,171 patients with RA from the
National Data Bank for Rheumatic Disease over a
period of 2 years and found that among those treated
with anti-TNF therapies, the prevalence rate of CHF
was significantly reduced.
Demyelinating conditions
As TNF-a antagonists have become increasingly
used, there have been several reports of demyelinat-
ing and other central nervous system events in
patients receiving TNF antagonists [65]. Although
the causal relationship between these demyelinating
events and currently available TNF-a antagonists
remains unclear, it seems prudent to avoid use of
TNF-a antagonists in patients with a history of
demyelinating disease.
Formation of anti-infliximab antibodies
All biologic TNF-a inhibitors (eg, infliximab, eta-
nercept, and adalimumab) are ‘‘foreign’’ proteins and
therefore potentially immunogenic [66]. Antibody
data are highly dependent on the sensitivity and
specificity of the assay method used, however, so
comparison of the incidence of antibodies to inflixi-
mab with the incidence of antibodies to other products
may be misleading. Although the clinical relevance of
antibodies to the anti–TNF-a inhibitors is difficult to
define, it is possible that immune responses that
L. Winterfield, A. Menter / Dermatol Clin 22 (2004) 437–447444
develop following treatment with foreign proteins
may limit the efficacy of such treatments and increase
the incidence of adverse events [67].
It has been shown that the development of anti-
bodies to infliximab (ATI) can be reduced by several
approaches, including appropriate dose selection, use
of concomitant immunosuppressive agents, and ad-
ministration of regular maintenance doses. The effect
of dose on antibody formation and concomitant im-
munosuppressive therapy was demonstrated in a
phase 2 RA study evaluating an infliximab induction
regimen of 1 mg/kg, 3 mg/kg, or 10 mg/kg, with and
without methotrexate [68]. With infliximab monother-
apy, 53%, 21%, and 7% of patients with RA exhibited
ATI when treated with 1 mg/kg, 3 mg/kg, and 10 mg/
kg of infliximab, respectively. Antibody titers were
reduced at each dose level with concomitant metho-
trexate to 15%, 7%, and 0%, respectively. The data for
treatment in the absence of immunosuppressant agents
are similar to the results presented for the develop-
ment of ATI in the SPIRIT trial. Following induction
dosing at weeks 0, 2, and 6, 27.5% of patients with
psoriasis receiving 3 mg/kg and 19.5% of patients
receiving 5 mg/kg of infliximab were antibody posi-
tive by week 26 [69]. Furthermore, the titer of ATI
was generally low, with 37 of 38 subjects positive
for antibodies presenting with titers less than or equal
to 1:40.
Regular maintenance dosing with infliximab has
been associated with a reduced incidence of antibody
formation in clinical studies. In a trial in patients with
active Crohn’s disease [70], individuals who received
a single infusion of infliximab showed a 28% inci-
dence of ATI compared with an 8% rate in those
receiving induction and regular maintenance in-
fusions of infliximab. Also, the frequency of ATI in
patients with RA who were administered induction
and maintenance doses of infliximab was 9%, similar
to the rate in patients with Crohn’s disease who re-
ceived maintenance infusions [71]. Additional studies
are ongoing to determine the incidence of ATI in
patients with psoriasis receiving long-term main-
tenance and intermittent treatment.
ATI may influence the frequency of infusion re-
actions [70]. A higher incidence of these events was
seen in Crohn’s disease and RA trials in patients with
ATI compared with those who were antibody nega-
tive or inconclusive for antibodies [70,72]. Most
infusion reactions were mild to moderate in nature,
and there was no correlation with the presence of ATI
and serious infusion reactions in the Crohn’s disease
and RA studies.
The potential for loss of response in conjunction
with ATI is a concern, but regular maintenance
treatment with infliximab seems to sustain response
even in the presence of ATI. For example, in patients
with Crohn’s disease who were administered mainte-
nance treatment, the proportion of subjects achieving
a clinical response after 1 year was similar in anti-
body-positive and antibody-negative subjects [70].
When infliximab is administered intermittently, how-
ever, there is evidence from a cohort of 125 consecu-
tive patients with Crohn’s disease who were treated
‘‘as needed’’ with infliximab that indicates efficacy
may decrease in patients who develop sufficient
concentrations of ATI [72]. Specifically, 36 of
53 patients initially responded well to 5 mg/kg of
infliximab, but among those who developed ATI
(n = 19), 11 (58%) exhibited a loss of response to
infliximab treatment. Moreover, none of the patients
in the trial who exhibited a continued response to
infliximab (n = 21) were ATI positive.
Summary
Evidence that the proinflammatory cytokine
TNF-a plays a major role in the development and
maintenance of psoriasis is the rationale for the use of
anti–TNF-a therapies. Infliximab is a chimeric hu-
man-murine antibody that selectively blocks the ac-
tivity of TNF-a. Randomized, controlled clinical
trials, open-label investigations, and case reports have
shown that infliximab therapy leads to rapid, sub-
stantial improvements in psoriasis lesions that are
among the highest seen with use of the systemic
agents to date. Significant improvement in psoriatic
joint involvement also has been reported. Impor-
tantly, the burden of organ toxicity with biologic
therapy is lower, with no clear indication to date of
hepatotoxicity, nephrotoxicity, skeletal changes, or
teratogenicity that may result from traditional sys-
temic therapies. As with other biologic agents, be-
cause of the relatively short-term (5–10 y) safety
data, it is impossible to be certain at this time about
the increased malignancy risk. Potential concerns
and questions related to the immunosuppressive and
immunogenic properties of infliximab, including in-
creased risk of infection, infusion reactions, and
waning therapeutic response in the psoriasis popula-
tion, are currently being fully examined and charac-
terized in phase 3 trials. The ongoing studies of
infliximab in patients with moderate to severe psoria-
sis will yield a more sophisticated understanding of
the benefits and risks associated with this treatment
option and ultimately determine the role of this
biologic agent in the psoriasis armamentarium.
L. Winterfield, A. Menter / Dermatol Clin 22 (2004) 437–447 445
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Dermatol Clin 22 (2004) 449–459
The treatment of psoriasis and psoriatic arthritis with
etanercept: practical considerations on monotherapy,
combination therapy, and safety
Paul S. Yamauchi, MD, PhDa,b,*, Vivian Gindi, MDa,b,Nicholas J. Lowe, MD, FRCPa,b
aClinical Research Specialists, 2001 Santa Monica Boulevard, Suite 490W, Santa Monica, CA 90404, USAbDivision of Dermatology, University of California at Los Angeles School of Medicine, Los Angeles, CA, USA
Etanercept is a recombinant fusion protein that is cally driven by overproduction of an inflammatory
currently approved by the Food and Drug Adminis-
tration (FDA) for the treatment of rheumatoid arthri-
tis, polyarticular-course juvenile rheumatoid arthritis,
ankylosing spondylitis, psoriatic arthritis, and in
April 2004, approved for the treatment of moderate
to severe plaque psoriasis. Etanercept is manufac-
tured by Amgen under the trade name Enbrel. Eta-
nercept is manufactured by Amgen under the trade
name Enbrel.
Etanercept was first used in human clinical studies
in 1992, and in 1995 the rheumatoid arthritis studies
were initiated. In 1998, etanercept was FDA-
approved for the treatment of rheumatoid arthritis.
Four years later, etanercept became the first FDA-
approved drug for the treatment of psoriatic arthritis.
Of all the biologic agents that are in use or potentially
will be used for the treatment of psoriasis and
psoriatic arthritis, etanercept has the longest track
record for safety data and current evidence supports
the efficacy of etanercept in the treatment of psoriasis
[1,2].
Up to 42% of patients with psoriasis develop
psoriatic arthritis [3]. Both diseases are immunologi-
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/j.det.2003.12.002
* Corresponding author. Clinical Research Specialists,
2001 Santa Monica Boulevard, Suite 490W, Santa Monica,
CA 90404.
E-mail address: [email protected]
(P.S. Yamauchi).
cytokine called tumor necrosis factor-a (TNF-a)[4,5]. Etanercept is a disease-modifying drug by
acting as a soluble TNF-a receptor that competitively
binds to TNF-a. Once bound to etanercept, TNF-ais prevented from binding to cell surface receptors
on target cells and its proinflammatory effects are
thereby blocked.
Role of tumor necrosis factor-A in psoriasis and
psoriatic arthritis
Tumor necrosis factor-a is a proinflammatory
cytokine with a molecular weight of approximately
17 kd. TNF-a is expressed in psoriatic disease mainly
by activated macrophages and monocytes but is also
produced by other cell types found within psoriatic
plaques including dendritic cells, Langerhans’ cells,
and T cells. TNF-a exerts a wide range of biologic
activities that include antiviral properties, growth
regulation of different cell types, and immunomodu-
lation of several signal transduction cascades.
Mechanism of action
One major mechanism of action of TNF-a is the
induction of other inflammatory cytokines, such as
interleukins-1, -2, -6, and -8; granulocyte-macro-
phage colony-stimulating factor; and interferon-g [4].
s reserved.
P.S. Yamauchi et al / Dermatol Clin 22 (2004) 449–459450
Other inflammatory molecules induced by TNF-a,such as prostaglandin and leukotriene synthesis, are
well known to incite bone resorption and cartilage
degradation in arthritis [5,6]. In addition, TNF-astimulates collagenase and matrix metalloproteinase
production by neutrophils and fibroblasts that lead
to tissue and joint damage [5,7].
Tumor necrosis factor-a also stimulates T-cell ad-
hesion to the endothelium through the up-regulation
of adhesion molecules on the surface of endothelial
cells. One report demonstrated the TNF-a–depen-dent up-regulation of intercellular adhesion molecule
type 1, E-selectin, and vascular cell adhesion mole-
cule type 1 on endothelial cells [8]. The induction of
T-cell trafficking into the dermis through adhesion
molecule binding in the vasculature is an important
signaling event in the pathogenesis of psoriasis
There are two major receptor variants for TNF-a:the p55 and p75 receptors. These high-affinity recep-
tors are bound to the surface of the cells, such as
macrophages, lymphocytes, keratinocytes, and endo-
thelial cells, and are composed of the extracellular
binding site for TNF-a, the transmembrane domain,
and the cytoplasmic tail, which is responsible for sig-
nal transduction through the activation of NFkB [9].
In addition, there are soluble receptors for TNF-athat are not membrane-bound that seem to act as
competitive inhibitors for TNF-a binding to cell sur-
face receptors. The activity and levels of these solu-
ble receptors are not sufficient enough, however, to
inhibit the inflammatory cascade caused by TNF-ain disease states, such as psoriasis and psoriatic arthri-
tis [10,11]. Levels of TNF-a receptors are up-regu-
lated in epidermal dendritic cells and keratinocytes
following treatment with TNF-a [12].
Several studies have demonstrated that TNF-a is
implicated in the pathogenesis of psoriasis and pso-
riatic arthritis. TNF-a levels have been shown to be
Fig. 1. Structure o
increased in psoriatic plaques and in the synovial
fluid of patients with active psoriatic arthritis [13,14].
TNF-a concentrations are also increased in the serum
of patients with psoriasis and in suction blisters
induced in psoriatic patients [15]. Furthermore, levels
of TNF-a have been shown to correlate with disease
severity (ie, increasing during worsening of the pso-
riasis and decreasing after effective therapy) [15–18].
Acute-phase reactants, which are elevated in inflam-
matory arthritides, correlate with the expression of
TNF-a in the serum and synovial fluid [19].
Structure and function of etanercept
Because there is significant correlation between
disease activity of psoriasis and psoriatic arthritis and
TNF-a levels, direct antagonism of TNF-a is a
logical treatment modality. Etanercept is a recombi-
nant molecule comprised of the extracellular binding
domain of the TNF-a p75 receptor fused to the Fc
portion of IgG1 molecule (Fig. 1). The molecular
weight of etanercept is 150 kd consisting of 934
amino acids and is almost 10 times larger than
insulin. Etanercept is a fully human dimeric fusion
protein produced by Chinese hamster ovary cells and
functions as a TNF inhibitor by binding to and
inactivating both free and membrane-bound TNF-athereby preventing interactions with its cell surface
receptors. Studies have demonstrated that etanercept
does not induce complement mediated TNF-a cell
lysis in vitro and has very low immunogenicity. The
Fc portion of IgG1 serves to stabilize etanercept and
prolong the median half-life, which is 4.8 days. The
dimeric form of etanercept allows binding to two
TNF-a molecules at an affinity 50 to 1000 times
greater than the naturally occurring soluble mono-
f etanercept.
P.S. Yamauchi et al / Dermatol Clin 22 (2004) 449–459 451
meric form of the TNF-a receptor [20]. This accounts
for the greater inhibitor activity of etanercept than the
natural soluble receptor [21].
Indications, dosage, and usage of etanercept
Etanercept is FDA-approved for the treatment
of rheumatoid arthritis, polyarticular-course juve-
nile rheumatoid arthritis, ankylosing spondylitis,
and psoriatic arthritis, and more recently, moderate
to severe psoriasis.
The dosage of etanercept for adults is 50 mg per
week continuously for rheumatoid arthritis, anky-
losing spondylitis, and psoriatic arthritis. For the
treatment of psoriasis, the initial dosage of etanercept
is 50 mg twice weekly for 12 weeks followed by step-
down dosing to 50 mg weekly continuously. For
pediatric patients with juvenile rheumatoid arthritis
(4 to 17 years), the dosage is 0.8 mg/kg/wk (50 mg
maximum per week). The drug is self-administered
by the patient subcutaneously.
Etanercept is supplied as a sterile, preservative-
free, lyophilized powder for subcutaneous injection
after reconstitution with 1 mL of supplied bacterio-
static water. Each vial contains 25 mg of etanercept
plus stabilizers including 10 mg sucrose, 40 mg man-
nitol, and 1.2 mg tromethamine. At the time of this
writing, etanercept will be available as 50 mg doses
per vial. Etanercept is stored in the refrigerator and
should not be frozen. Reconstituted etanercept is
stable for up to 14 days in the refrigerator. The sup-
plied syringe does not contain any latex.
The frequency of dosing is once or twice a week
depending on the indication. Because etanercept is
supplied as 25-mg doses per vial, for the 50-mg
weekly dosing, patients are instructed to administer
two shots the same day and can be given at the same
time. Alternatively, etanercept can be administered
25 mg twice a week, spaced every three to four days.
For psoriasis, the initial dose is 50 mg twice weekly
for the first 12 weeks and patients administer etaner-
cept as two 25-mg injections twice weekly every three
to four days (four injections per week). The dosage is
then stepped down to 50 mg weekly continuously
(two injections per week). With the advent of the
50-mg vial, the number of injections will be reduced
to half (two shots per week for 12 weeks and then one
shot per week for psoriasis). Pediatric patients can
administer etanercept once a week at 0.8 mg/kg or in
divided doses twice a week at 0.4 mg/kg. The most
common locations for subcutaneous injections are the
abdomen, thighs, and upper arms. To minimize injec-
tion site reactions, patients are instructed to place their
injections at least an inch apart from the prior injection
site or to inject at contralateral sites.
Clinical efficacy in psoriatic arthritis
The safety and efficacy of etanercept were as-
sessed in a phase III randomized, double-blinded,
placebo-controlled study for 24 weeks in 205 patients
with active psoriatic arthritis. Patients were random-
ized equally to receive either etanercept, 25 mg, twice
weekly or placebo twice weekly. Patients with psori-
atic arthritis were between 18 and 70 years of age and
had greater than or equal to three swollen joints and
greater than or equal to three tender joints with one or
more of the following joint diseases: distal interpha-
langeal involvement, polyarticular arthritis, arthritis
mutilans, asymmetric psoriatic arthritis, or ankylosing
spondylitis. These patients also had plaque psoriasis
with a qualifying lesion of greater than or equal to
2 cm in diameter. Patients who were on methotrex-
ate therapy for more than 2 months could continue
the methotrexate if the dose was less than 25 mg
per week.
The primary end point in the study for psoriatic
arthritis was the American College of Rheumatology–
20 definition of improvement as set forth by the FDA.
These guidelines include a 20% improvement in both
tender and swollen joints plus 20% improvement in
three of the following: patient’s pain assessment,
patient’s assessment of disability, physician’s global
assessment, patient’s global assessment, or C-reactive
protein or erythrocyte sedimentation rate.
In those patients with psoriatic arthritis who
received etanercept, the clinical responses were evi-
dent 4 weeks into treatment and were maintained
through the 24 weeks of treatment. At 12 weeks, 59%
of the patients who received etanercept achieved the
American College of Rheumatology–20 response
compared with 15% in the placebo group. The
responses were similar to patients who were or were
not receiving concomitant methotrexate therapy. At
week 12, 62% of patients who received concomitant
etanercept plus methotrexate attained the American
College of Rheumatology–20 response compared
with 58% in the group who received etanercept alone.
In addition, the skin lesions of psoriasis were also
improved with etanercept in this trial, relative to
placebo, as measured by percentages of patients
achieving improvements in the Psoriasis Area and
Severity Index (PASI). Responses increased over
time, and at 24 weeks the proportions of patients
P.S. Yamauchi et al / Dermatol Clin 22 (2004) 449–459452
achieving a 50% or 75% improvement in the PASI
were 47% and 23%, respectively, in the etanercept
group compared with 18% and 3% in the placebo
group, respectively.
Mease et al [2] showed that twice weekly subcu-
taneous injections of etanercept (25 mg) for 12 weeks
resulted in substantial remission of both psoriasis and
psoriatic arthritis. Eighty-seven percent of patients
with psoriatic arthritis had a reduction in their arthri-
tis as measured by the psoriatic arthritis response
criteria versus 23% of placebo patients. The Ameri-
can College of Rheumatology–20 was achieved by
73% of etanercept-treated patients compared with
13% of placebo-treated patients. In addition, 26%
of the etanercept-treated patients achieved a 75%
improvement in the PASI compared with none in
the placebo-treated group. The median PASI im-
provement was 46% in etanercept-treated patients
versus 9% in placebo-treated patients.
Radiographic response
In the phase III psoriatic arthritis study, radio-
graphic changes were also assessed. Radiographs of
the hands and wrists were obtained at baseline and at
months 6 and 12. A modified total sharp score that
included the distal interphalangeal joints was used to
measure the degree of pencil-and-cup deformity, joint
space changes, gross osteolysis, and ankylosis. More
patients in the placebo group exhibited larger magni-
tudes of radiographic worsening compared with the
etanercept-treated group. At the end of 1 year, eta-
nercept inhibited radiographic progression of joint
space narrowing and erosions compared with placebo,
which led to progressive worsening [22].
Clinical efficacy in psoriasis
The phase II and III trials of etanercept as mono-
therapy treatment for chronic plaque psoriasis have
demonstrated significant clearance of psoriatic pla-
ques. The phase II trial was a 24-week, multicentered,
double-blinded, placebo-controlled study in which
112 patients with moderate to severe psoriasis (more
than 10% of their body surface area) who had re-
ceived prior systemic treatment were enrolled. Pa-
tients were randomized to receive 25 mg etanercept
twice a week (N = 55) or placebo (N = 57). At weeks
12 and 24, 30% and 56% of patients who received
etanercept achieved a 75% improvement in the PASI
score, respectively, versus 2% and 5% of the placebo
group at the same time intervals.
The onset of action of etanercept is of moderate
rapidity. After 4 weeks of therapy, there was about an
overall 28% improvement in the PASI score. Almost
40% of the patients attained a PASI 50 improvement
by week 4.
In addition, the Dermatology Life Quality Index
(DLQI) was measured in the phase II trial. The
DLQI is a reliable 10-question survey completed by
the patient that analyzes the impact various skin dis-
eases, such as psoriasis, have on a patient’s quality of
life [23]. Physical and social elements including pain,
itching, occupation and school performance, leisurely
activities, and relationships are measured by the
DLQI. The improvement in the DLQI scores corre-
lated well temporally with the improvement in
PASI scores.
There were two phase III trials conducted for the
treatment of psoriasis with etanercept: the Global
phase III trial and the United States phase III trial
[1]. The Global phase III trial was a 6-month, double-
blinded, multi-centered, placebo controlled study in
which patients were randomized to receive either pla-
cebo (N = 204), etanercept 50 mg weekly (N = 204),
or etanercept 50 mg twice-weekly (N = 203) for
3 months. Thereafter, all patients were crossed-over
to receive etanercept at 50-mg weekly for the next
3 months. The data was adjusted for the intent-to-treat
analysis. At 3 months, 46% of the patients attained a
PASI 75 improvement in the 50-mg twice-weekly
dose compared to 3% in the placebo group. When
the dosage of etanercept at 50 mg twice weekly for
3 months was stepped down to 50 mg weekly for
3 additional months, the improvement was sustained
with 50% of the patients attaining a PASI 75 im-
provement at 6 months.
The phase III trial conducted in the United States
was a double-blinded, multi-centered, placebo-
controlled study divided into 2 parts. In the first
part, patients were randomized to receive placebo
(N = 168), etanercept at 25 mg weekly (N = 169),
50 mg weekly (N = 167), or 50 mg twice weekly
(N = 168) for 6 months. In the placebo group, after
receiving placebo for 3 months, the patients were
crossed over to receive etanercept at 50 mg per week.
The data was adjusted for the intent-to-treat analysis.
At 3 months, 49% of the patients attained a PASI
75 improvement in the 50-mg twice-weekly dose
compared to 4% in the placebo group, 34% at the
50-mg weekly dose, and 14% in the 25-mg weekly
dose. There was continued improvement with longer,
continuous treatment. At 6 months, 59% of the
patients attained the PASI 75 improvement in the
50-mg twice-weekly dose, 44% in the 50-mg weekly
dose, and 25% in the 25-mg weekly dose. Patients in
P.S. Yamauchi et al / Dermatol Clin 22 (2004) 449–459 453
the original placebo group who were crossed over to
receive etanercept at 50-mg weekly at month
3 exhibited improvement of their psoriasis with
33% of them achieving the PASI 75 improvement
— a response rate consistent with that in the 50-mg
once-a-week dose at 3 months (34%).
In the second part of the United States phase III
trial, the abrupt discontinuation and retreatment with
etanercept were evaluated. For all patients who
attained a PASI 75 or greater improvement at any
dose (N = 409), when etanercept was abruptly dis-
continued, the median time to loss of response
(defined as loss of half the of the PASI improvement)
was 85 days. In addition, in the 409 patients observed
during the discontinuation period, there was no con-
version of morphology (pustular psoriasis, erythro-
dermic psoriasis, or unusual morphology), no serious
adverse events or hospitalizations due to withdrawal,
and no study discontinuation due to adverse events.
Only one patient (25 mg once per week of etanercept)
out of the 409 evaluated during the withdrawal phase
had an episode of rebound. When patients were
retreated with etanercept following loss of response,
the PASI 75 response rates after 3 months of re-
treatment with etanercept were similar to PASI 75 re-
sponse rates seen after the initial 3 months of
treatment with etanercept. No significant tachyphi-
laxis with etanercept was evident with repeated treat-
ments. In addition, retreatment with etanercept was
not associated with increased antigenicity or forma-
tion of neutralizing antibodies.
The onset of action with etanercept was rapid in
the phase III trials. The improvement in the PASI
scores was statistically significant over placebo for all
three doses as early as 2 weeks. Higher dosages of
etanercept resulted in faster clearance of the psoriasis.
The DLQI was also assessed in the phase III trial and
improvements in the DLQI correlated well temporally
with the improvement in the PASI scores at all doses
used in the study. Finally, etanercept was well toler-
ated at all dosages with no increased adverse events
evident at the 50-mg twice-weekly dose.
The results of the Global and United States
phase III trials underscore several important points.
There is a dose-dependent response rate with eta-
nercept as evidenced by higher dosages of etaner-
cept exhibiting faster response rates and higher
efficacy. At 6 months, efficacy with step-down dosing
from 50 mg twice weekly to 50 mg weekly was
similar to 50-mg twice-weekly dosing continuously.
Etanercept was not associated with rebound follow-
ing abrupt discontinuation, and retreatment with eta-
nercept resulted in comparable reestablishment of
clinical response. Finally, there was no increased in-
cidence of adverse events evident with higher doses
of etanercept.
Safety: frequently asked questions
Between May 1, 1993, and December 31, 2001,
over 121,000 patients have received etanercept in
controlled clinical trials and in clinical practice. Of
all the biologic agents that are currently in use or
potentially will be used for the treatment of psoriasis
and psoriatic arthritis, etanercept has the longest track
record for safety data.
Injection site reactions
In clinical trials, the adverse event that occurred
more frequently in patients treated with etanercept
over the placebo group was transient injection site
reactions. These injection site reactions typically
occurred 2 to 3 weeks into treatment and consisted
of erythema, pain, itching, or swelling. The mean
duration of the reaction was approximately 3 to 5 days.
A biopsy of an injection site reaction revealed a peri-
vascular lymphohistiocytic reaction in the dermis but
there was no evidence of a panniculitis (author’s per-
sonal observations). Topical steroids, oral antihista-
mines, and compresses are typically used to alleviate
injection site reactions. In the clinical trials, injection
site reactions did not become severe enough to war-
rant discontinuation of etanercept.
Does etanercept increase risk of malignancies?
The long-term safety data in clinical trials show
the incidence of malignancies was not increased in
the etanercept-treated group when compared with the
expected number from the National Cancer Insti-
tute’s database [24]. The expected number of ma-
lignancies was 42 and the observed incidence was
41. There were no predominant types of malig-
nancies observed and a total of five lymphomas
were reported. In postmarketing surveillance
(N = 127,379), the observed number of malignan-
cies was 277 and the expected incidence was 1020.
In addition, a study has demonstrated that lym-
phoma rates are low but increased in patients with
psoriasis [25]. Patients with psoriasis had a 2.95
relative rate of developing lymphoma compared with
those without psoriasis. As a TNF-a inhibitor, how-
ever, there is always the possibility that etanercept
can affect the immune system’s response to cancer
and specific concerns and risks versus benefits should
P.S. Yamauchi et al / Dermatol Clin 22 (2004) 449–459454
be discussed with the patient, especially if there is a
history of malignancy.
Does etanercept increase the risk of serious
infections?
The rates of infection that required hospitalization
or parenteral antibiotic therapy were 0.04 per pt-year
in the etanercept-treated group in clinical trials [24].
This rate is very similar to the total population,
which was 0.03 to 0.09 per pt-year. In postmarketing
surveillance, the reported rate is 0.007 per pt-year.
There have been rare cases of serious infections and
sepsis, which included fatalities when patients were on
etanercept. Patients who are on concurrent immuno-
suppressants, or patients who have serious underlying
medical conditions, such as diabetes, that make them
predisposed to infections may be at increased risk of
infection when administered etanercept and caution
should be exercised when considering etanercept.
Should etanercept be discontinued if an infection
develops?
There are no specific guidelines regarding the
discontinuation of etanercept in patients who develop
an infection and patient situations should be assessed
individually. Patients who develop a new infection
while on etanercept therapy should be closely moni-
tored. In the authors’ opinion, etanercept should not
be administered to patients with sepsis or active
infections, including chronic or localized infections.
Until the infection subsides, etanercept should be
discontinued temporarily.
Is laboratory testing required for patients on
etanercept?
There is no specific laboratory or blood testing
that is required to monitor treatment with etanercept.
No correlation exists with organ toxicity, such as
hepatotoxicity or nephrotoxicity, with etanercept.
There have been rare cases of pancytopenia reported
with the usage of etanercept, however, but a cause
and effect relationship has not been reported. It is up
to the treating physician’s discretion to determine if
laboratory testing is indicated.
Is tuberculin testing required before initiation of
etanercept therapy?
The current guideline is that no specific tuberculin
testing is required before treatment with etanercept.
This is in contrast to other TNF-a antagonists, such as
infliximab and adalimubab, in which tuberculosis
screening is required before initiation of therapy be-
cause of the incidence of complement mediated lysis
of macrophages present in tuberculous granulomas,
which could release mycobacteria systemically and
activate tuberculosis. The incidence of tuberculosis in
121,000 patients who have received etanercept be-
tween May 1, 1992, and December 13, 2001, was
0.02% (N = 20), which was similar to the background
incidence of tuberculosis in the general population.
There has not been a temporal association between the
development of tuberculosis and etanercept therapy. It
is up to the physician’s discretion whether to initiate
purified protein derivative testing for etanercept ther-
apy. Given this regard, however, the use of purified
protein derivative testing might be advisable for
patients undergoing nonselective systemic therapy,
such as methotrexate or cyclosporine.
Can etanercept be administered to patients who test
positive for tuberculosis?
There are no specific recommendations regarding
the use of etanercept in patients with previous posi-
tive testing for tuberculosis. In the clinical trials, there
was no incidence of reactivation of tuberculosis in
patients who were purified protein derivative–posi-
tive. Treatment with etanercept should not be started
in patients with active infections, including chronic
and localized infections. If a patient is purified pro-
tein derivative–positive and the chest radiograph is
negative for radiographic evidence of active tubercu-
losis, then preventative therapy with isoniazid should
be instituted before treatment with etanercept.
Does etanercept cause demyelination disorders?
In postmarketing surveillance, there have been
rare incidences of demyelinating disorders and exacer-
bation of pre-existing multiple sclerosis occurring in
patients treated with etanercept [26]. Cases of trans-
verse myelitis, optic neuritis, and new onset or
exacerbation of seizure disorders have been observed
with etanercept. The causal relationship between
these central nervous disorders and etanercept
remains unclear. Caution should be exercised when
considering etanercept in patients with a history or
family history of multiple sclerosis.
Can etanercept be administered to patients with
congestive heart failure?
There were two large clinical trials that evaluated
the use of etanercept in the treatment of heart failure.
P.S. Yamauchi et al / Dermatol Clin 22 (2004) 449–459 455
These trials were terminated because of lack of
efficacy. The results of one study suggested higher
mortality in patients treated with etanercept com-
pared with placebo but the second trial did not
corroborate these observations.
There have been reports of worsening conges-
tive heart failure and rare instances of new onset
of congestive heart failure without identifiable
precipitating factors in patients treated with eta-
nercept [27]. Caution should be exercised when
using etanercept in patients who have a history of
heart failure.
Does etanercept increase the risk of autoimmunity?
In two trials, the percentage of patients evaluated
for antinuclear antibodies who developed a positive
antinuclear antibodies titer (titer � 1:40) was higher
in patients treated with etanercept (11%) than in
placebo-treated patients (5%) [28,29]. The percent-
age of patients who developed new positive anti–
double stranded DNA antibodies was higher in the
etanercept-treated group (15%) compared with pla-
cebo (4%) [28,29]. There have been rare cases of
drug-induced systemic lupus erythematosus asso-
ciated with etanercept therapy [30].
Can etanercept be given during pregnancy or
breastfeeding?
Etanercept is rated pregnancy category B by the
FDA. No formal studies have been conducted in
pregnant women who have received etanercept. It is
not known if etanercept is excreted in human milk or
absorbed systemically after ingestion. Because many
drugs and immunoglobulins are excreted in human
milk and because of the potential for serious adverse
reactions in nursing infants, a decision should be
made whether to discontinue nursing or to discontin-
ue the drug.
Can immunizations be given during etanercept
treatment?
Most psoriatic patients receiving etanercept were
able to mount effective B-cell immune responses.
Patients on therapy with etanercept may receive con-
current vaccinations, except for live vaccines. There
are no data available on the secondary transmission
of infection by live vaccines in patients receiv-
ing etanercept.
Practical considerations on usage of etanercept
Most psoriatic patients are able to self-administer
etanercept when offered to them. If self-administra-
tion by the patient is not achievable, then a family
member or friend can administer the drug at home.
The nursing staff easily can learn how to teach pa-
tients the technique in administering etanercept. In
addition, specialty pharmacies are now available that
can demonstrate to the patient how to self-inject
etanercept. Because etanercept can be given once a
week, it may be possible for the uncommon patient to
come in weekly to the clinic for injections if home
administration is not achievable. If the patient is truly
needle phobic, then etanercept and other injectable
agents are obviously not possible and other treatment
modalities for psoriasis and psoriatic arthritis must
be used.
Monotherapy dosing of etanercept
Most patients with moderate to severe plaque
psoriasis often exhibit improvement with mono-
therapy step-down dosing of etanercept. Initial clear-
ance of psoriatic plaques can be seen as early as
2 weeks at 50 mg twice weekly. The symptoms of
psoriatic arthritis respond quicker than skin lesions.
Frequently, patients notice a decrease in morning
stiffness, pain, and swelling in their joints as soon
as 2 weeks. It is not uncommon for a patient to state
that the arthritis ‘‘feels better’’ after one injection.
Etanercept is an ideal agent as first-line therapy in the
treatment of psoriasis or psoriatic arthritis because of
its high efficacy, excellent safety profile, and conve-
nience. Once a patient has started a good treatment
regime with etanercept, follow-up visits are con-
ducted every 3 to 4 months.
The maintenance dosage of etanercept for clear-
ance of psoriasis is 50 mg weekly. Some psoriatic
patients can maintain clearance of their psoriasis at
decreased doses of etanercept, such as 25 mg per
week, or even at longer intervals, such as every
10 to 14 days. Other patients develop remission of
their psoriasis for an extended period of time when
etanercept is discontinued. Should the psoriasis re-
lapse at the lower dosages or upon discontinuation,
retreatment with 50 mg weekly of etanercept is
instituted without loss of efficacy as seen in the
clinical trials with retreatment. Etanercept is not
associated with rebound or change or morphology
upon abrupt discontinuation of etanercept. In a mi-
nority of patients, the psoriasis may worsen even at
50-mg weekly dosing etanercept. This can be precipi-
tated by known factors, which worsen psoriasis such
Table 1
Summary of six psoriatic patients treated with etanercept and combination therapy
Patient Age (y) Previous treatment Arthritis
Initial combination therapy
with etanercept
PASI score
before etanercept
After
etanercept Arthritis response
1 (M) 57 UVB, cyclosporine, acitretin, etretinate,
methotrexate, 6-thioguanine
None Methotrexate, 20 mg po weekly 29 10 —
2 (M) 51 UVB, PUVA, methotrexate, cyclosporine Present Cyclosporine, 200 mg po qd 27 14 Improved, major
3 (M) 52 Acitretin, hydroxyurea None Acitretin, 25 mg po qod 28 10 —
Hydroxyurea, 1.5 g po qd
4 (M) 33 PUVA, calcipotriene cream and ointment Present Calcipotriene cream and ointment bid 22 10 Improved, moderate
5 (M) 45 Cyclosporine, acitretin, methotrexate Present Methotrexate, 15 mg po weekly 24 12 Improved, major
6 (F) 55 Methotrexate, acitretin, UVB None Acitretin, 25 mg po qod UVB weekly 14 7 —
P.S.Yamauchiet
al/Derm
atolClin
22(2004)449–459
456
P.S. Yamauchi et al / Dermatol Clin 22 (2004) 449–459 457
as stress or streptococcal throat infections. In these
instances where the psoriasis flares at maintenance
dosages, the dose of etanercept can be increased to
50 mg twice weekly until the psoriasis improves.
Then the dosage can be stepped down to 50 mg
weekly for maintenance control.
In contrast to psoriasis, it is recommended that
patients with psoriatic arthritis be maintained at the
conventional dose of 50 mg per week. Etanercept has
been shown to inhibit radiographic progression of
joint destruction. Any stoppage of etanercept or
lowering the dose may potentially cause further
osteolysis and joint space narrowing. If a patient is
diagnosed with psoriatric arthritis and has moderate
to severe psoriasis, step-down dosing is recommended
to gain quick control of the psoriatric plaques.
Combination therapy with etanercept
Iyer et al [31] reported six cases of patients with
severe recalcitrant psoriasis that was partially resist-
ant to other ongoing systemic agents or phototherapy
whose disease activity showed marked improvement
with the addition of etanercept to the treatment
regime. Three of the patients also had severe psoriatic
arthritis. Table 1 illustrates the improvement in the
disease activity for each of the six patients following
the addition of etanercept to their treatment regime.
When etanercept was combined with other agents,
each of the patient’s psoriasis and those with psori-
atic arthritis became more responsive to treatment
and allowed lower doses of other systemic agents to
be used to limit their side effects. For example,
patient 2 demonstrated a response to cyclosporine,
but the dosage was limited by the development of
medication-related hypertension.
In addition, no additional toxicity was found with
etanercept when added to such agents as methotrex-
ate, hydroxyurea, acitretin, or cyclosporine. None of
these patients developed any serious or opportunis-
tic infections. Addition of etanercept did not poten-
tiate any type of organ toxicity, myelosuppression,
metabolic or lipid abnormalities, hypertension, or
malignancies. No drug interactions with etanercept
were evident.
These case reports underscore two important
points. First, etanercept can be added safely to some
other systemic and topical agents to augment efficacy
and develop more potent combination regimens in
severe recalcitrant cases of psoriasis, at least over a
short-term crisis period. Second, etanercept can play
a role in diminishing the short- and long-term tox-
icities of other systemic medications by allowing
lower doses of these agents to be used while main-
taining disease control. Etanercept is an excellent
choice that can be used in combination therapy for
the treatment of psoriasis.
Etanercept offers a good method to wean and
transition psoriatic patients off of systemic agents.
One prevalent problem with these systemic agents,
such as cyclosporine and methotrexate, is the occur-
rence of rebound and flare-ups on abrupt cessation.
For example, a patient with psoriasis who has attained
good clearance with cyclosporine at 5 mg/kg most
likely rebounds with sudden discontinuation. The
addition of etanercept at 50 mg per week prevents
this from occurring. Because the onset of action for
etanercept is typically evident in about 4 weeks, the
dose of cyclosporine should be held constant for that
period of time. After 4 weeks, the dosage of cyclo-
sporine can slowly be lowered by 50 to 100 mg every
2 to 4 weeks while maintaining the etanercept.
Laboratory monitoring and blood pressure checks
should be performed while on cyclosporine. With
methotrexate, the dosage can be lowered by 2.5 mg
every 2 to 4 weeks after instituting therapy with
etanercept for 4 weeks. There are no specific guide-
lines for transitioning off of systemic agents while on
etanercept but these are some of the methods that the
authors have used.
Summary
It is quite evident the pathogenesis of psoriasis is
modulated by immune-mediated mechanisms that
invoke activated T cells and inflammatory cytokines,
such as TNF-a. Current immunosuppressive systemic
treatments may be effective in controlling psoriasis to
a certain degree but have significant drawbacks, such
as toxicity and relapse of the disease on discontinua-
tion. The advantages of biologic agents are their
greater selectivity in targeting specific pathways in
the inflammatory cascade of psoriasis with a much
higher safety profile. With specific antagonism di-
rected against TNF-a, etanercept has demonstrated
remarkable efficacy in the treatment of psoriasis and
psoriatic arthritis.
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Dermatol Clin 22 (2004) 461–465
Current concepts and review of pimecrolimus in the
treatment of psoriasis
Klaus Wolff, MD, FRCP
Department of Dermatology, University of Vienna, Vienna General Hospital, Waehringer Guertel 18–20, Vienna A-1090, Austria
The ascomycine macrolactam derivative pimecro- systemic treatment of patients with psoriasis. A
limus is a novel inflammatory cytokine-release inhib-
itor [1 – 6] that has a high degree of cytokine
selectivity. The first ascomycine derivative to show
efficacy in a disease was SDZ 281-240, which a
proof-of-concept study showed cleared psoriasis as
effectively as the high-potency corticosteroid clobe-
tasol-17-proprionate when applied topically under
occlusive conditions [7]. Pimecrolimus has been
shown to suppress atopic dermatitis [8,9] and contact
dermatitis [10] when applied topically and psoriasis
when delivered topically under occlusion [11]. A
large-scale experience with pimecrolimus cream has
now accumulated in atopic dermatitis where multi-
center studies proved high efficacy and safety. Studies
in more than 2000 patients confirm that topical
pimecrolimus is suitable for short-and long-term treat-
ment of atopic dermatitis in adults, children, and in-
fants older than 3months [7]. After topical application,
the levels of pimecrolimus in blood remain consis-
tently low and no clinically relevant, drug-related,
systemic adverse events have been reported [12].
When given systemically in animal models with
inflammatory skin disease, pimecrolimus exhibits
high anti-inflammatory activity [1] and a low poten-
tial for systemic immunosuppression [7]. Pimecroli-
mus therefore has been considered for use in the
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/j.det.2004.03.013
Part of this work was supported by a grant from Novartis
AG, Basel, Switzerland. The author has served as a
consultant to Novartis Research Institute, Vienna, Austria;
however, he has no direct financial interest in this subject
matter, neither with Novartis nor with any companies
making competing products.
E-mail address: [email protected]
randomized, double-blind, placebo-controlled proof-
of-concept phase 1/2 study has confirmed the efficacy,
safety, and tolerability of this drug as an oral treat-
ment in psoriasis [13]. Although pimecrolimus is not
yet approved as a systemic drug, the experience
available to date suggests that it might be a novel,
highly effective systemic drug for psoriasis and other
inflammatory skin diseases.
Preclinical profile
Pimecrolimus is a calcineurin inhibitor that selec-
tively targets T cells and mast cell activation in vitro.
It blocks the release of helper T-cell (Th1 and Th2)
cytokines [14] and inhibits the induction of corecep-
tors involved in the accessory cell-dependent acti-
vation of inflammation-mediating T cells [15]. In
addition, it prevents the production of cytokines and
the release of proinflammatory mediators from mast
cells [14,16,17]. In animal models, pimecrolimus is
highly active against skin inflammation after systemic
application. In contrast to cyclosporin and tacrolimus,
pimecrolimus has only a low potential to impair
systemic immune responses [1,6,18,19]. In rats, oral
pimecrolimus is superior to cyclosporin by a factor of
4 and superior to tacrolimus by a factor of more than
2 in the down-regulation of allergic contact dermati-
tis; in mice, oral pimecrolimus is superior to cyclo-
psorin and equal to tacrolimus in inhibiting allergic
contact dermatitis [19]. Although in these animal
models pimecrolimus is highly effective in suppress-
ing the inflammatory response in the elicitation phase
of allergic contact dermatitis, it has no effect on the
s reserved.
K. Wolff / Dermatol Clin 22 (2004) 461–465462
induction phase, which is in contrast to oral cyclo-
sporin or tacrolimus [18]. Also, although the inhibi-
tion of the primary immune response with tacrolimus
and cyclosporin is associated with a decrease in
lymph node weight and cellularity, this effect is not
observed with pimecrolimus [18,19].
Also in contrast to cyclosporin and tacrolimus,
pimecrolimus has a low immunosuppressive effect in
animal models when given systemically. For instance,
the potential of pimecrolimus to suppress a graft-
versus-host reaction is 8 and 66 times less than
tacrolimus and cyclosporin, respectively. This finding
also holds for allogeneic kidney transplantation and
antibody production models [1,6,19].
In summary, it seems that pimecrolimus has a
different profile than other calcineurin inhibitors such
as tacrolimus and cyclosporin. It is equal to or even
more potent than tacrolimus and cyclosporin in
suppressing cutaneous inflammatory responses; in
addition, it interferes only with the elicitation phase
and not with the initiation phase of an immune
response and is far less effective in suppressing a
systemic immune response than tacrolimus or cyclo-
sporin. These findings suggest that oral treatment
with pimecrolimus in humans with inflammatory skin
disease should leave systemic immune surveillance
intact as a natural defense system.
Fig. 1. The clinical efficacy of pimecrolimus is shown for a patient r
Oral pimecrolimus in patients with psoriasis
Clinical efficacy
Pimecrolimus is highly effective in suppressing
psoriasis. In a randomized, double-blind, placebo-
controlled, multiple-rising-dose study, it was shown
that pimecrolimus was highly effective in down-
regulating psoriatic disease activity [13]. Although
there was no change in Psoriasis Area and Severity
Index (PASI) scores in patients taking the placebo or
in patients receiving low doses of pimecrolimus daily
(5 mg, 10 mg, and 20 mg, respectively), there was
clear efficacy in patients receiving 40 mg (20 mg
twice daily) and 60 mg (30 mg twice daily) of
pimecrolimus per day. This improvement involved a
reduction of scaling, erythema, and infiltration of
lesions (Fig. 1), and led to a significant reduction of
patients’ PASI score to an almost complete clearing
of lesions after 4 weeks of treatment. This response
was clearly dose-dependent (Fig. 2). The mean re-
duction of PASI (change from baseline at day 28) was
60% for the 40-mg/day and 75% for the 60-mg/day
patient groups [13]. These results now have been
confirmed by a multicenter study, which reported on
143 patients with moderate to severe chronic plaque
psoriasis and extending over 12 weeks of treatment;
eceiving 30 mg twice daily on day 0 (left) and day 28 (right).
Fig. 2. The clinical efficacy of pimecrolimus as assessed by percentage of PASI change from baseline for the different dose
levels. (From Rappersberger K, Komar M, Ebelin ME, Scott G, Burtin P, Creig G, et al. Pimecrolimus identifies a common
genomic anti-inflammatory profile, is clinically highly effective in psoriasis and is well tolerated. J Invest Dermatol 2002;119:
876–87; with permission.)
K. Wolff / Dermatol Clin 22 (2004) 461–465 463
the median change in PASI from baseline showed a
clear dose-dependent effect and again was greatest
for the 40-mg/day and 60-mg/day groups [20]. At
12 weeks, the median reduction in PASI was 80%
and 58% in the 60-mg and 40-mg groups, respec-
tively, and 43% of patients were clear or almost clear
of disease following 12 weeks of treatment with
60-mg/day dosages [20].
Follow-up and recurrences
In the original study [13], follow-up evaluation
showed recurrence of psoriasis after 8 weeks but no
rebound. In the two highest-dose (40-mg and 60-mg)
patient groups in the multicenter study [20], more
than half of the patients had not experienced disease
relapse 10 weeks after stopping treatment.
Pharmacokinetics
Pharmacokinetics of pimecrolimus reveal rapid
absorption, attainment of steady state after 5 to 10
days, and a linear dose dependency at steady state
[13]. Both Cmax and AUC0–24 increased broadly in
proportion to the dose. Steady state was reached after
days 5 to 10 at daily administrations of 30 mg of
pimecrolimus twice daily, and Cmax and AUC0–24
reached 54.5 ng/mL and 589.9 ng h/mL at steady
state, respectively [13].
Pharmacogenomics
Gene expression analysis identified a common
genomic profile for pimecrolimus in blood cells of
patients with psoriasis [13]. Blood samples subjected
to a gene expression analysis using gene chips for
the survey of more than 7000 genes permitted the
identification of a common genomic profile of pime-
crolimus consisting of approximately 150 genes.
Pimecrolimus strongly down-regulated the expres-
sion of genes associated with the macrolactam target
pathway, cellular activation and proliferation, antigen
presentation and genes related to cellular metabolism,
signal transduction, transcription factors, and inflam-
matory mediators. Genes related to lymphocyte re-
cruitment, chemotaxis, and cellular migration were
also down-regulated, but no significant changes in
T-lymphocyte markers could be detected at the RNA
expression level, suggesting an absence of a systemic
T-cell suppressive effect of the drug. There was also
no change of expression for transforming growth
factor b1–3 and for interleukin 1 (IL-1), IL-2, IL-8,
and IL-10. None of the expression changes in genes
that showed change were clearly related to side
effects or toxicity, and genes associated with apopto-
sis, stress, and enzymatic induction did not change
expression [13].
Tolerability
Pimecrolimus is well tolerated and lacks notable
clinical and laboratory side effects. In the previously
described study [13], there were no clinically notable
and significant changes in physical examination,
blood pressure, heart rate, and ECG throughout the
study. The only consistent side effect recorded was a
transient feeling of warmth on the upper chest occur-
ring about 40 minutes after ingestion of the drug and
K. Wolff / Dermatol Clin 22 (2004) 461–465464
lasting approximately 90 minutes. It did not occur
every time after drug intake, and in 75% of all
patients it did not occur more than 3 times during
28 days of treatment. Furthermore, the sensation of
warmth was not a matter of concern for the patients.
Hematology and blood chemistry analyses re-
vealed no significant changes throughout the study,
and there were no notable changes of kidney func-
tion, such as glomerular filtration rate or renal plasma
flow, and glucose tolerance tests were normal [13].
Tolerability of pimecrolimus has been confirmed in a
multicenter study comprising 243 adult patients with
psoriasis and atopic dermatitis over a treatment period
of 12 weeks [21]. The only adverse effect that
showed a clear dose–effect relationship was the
transient mild to moderate feeling of warmth de-
scribed previously. Headache and common gastro-
intestinal symptoms, such as nausea and dyspepsia,
were the most commonly observed adverse effects,
but these were not significantly increased as com-
pared with placebo-treated patients; this finding was
also true for skin and systemic infections. These data
indicate that pimecrolimus has an excellent safety
profile in short-term treatment (4 wk and 12 wk,
respectively) of patients and is also in line with the
pharmacogenomic profile of pimecrolimus examined
in the original study on this drug [13].
Immunology
Pimecrolimus leaves immunologic parameters
unaffected. Intradermal testing for delayed hypersen-
sitivity reactions to recall antigens showed no signif-
icant changes from pre-to post-treatment testing for
the pimecrolimus-and placebo-treated patients [13].
Flow cytometry analysis of blood lymphocyte sub-
populations revealed no significant differences be-
tween treatment groups and patients taking placebo.
In addition, no consistent or significant changes or
patterns were seen in the proliferation of lymphocytes
or in the patterns of cytokine release before and after
4 weeks of treatment [13]. The absent suppressive
effect on circulating lymphocytes is of considerable
importance because, as discussed later, pimecrolimus
down-regulates T cells in the skin.
Histopathology
Histopathologically and immunopathologically,
pimecrolimus reverses the psoriatic phenotype to
normal [13]. After 4 weeks of treatment, pimecroli-
mus induces an almost complete reversion of psoria-
tic epidermal hyperplasia and a marked reduction of
the inflammatory infiltrate. In addition, it induces the
expression of proliferation-associated keratin-16 and
the proliferating Ki-67+ keratinocytes. Staining pat-
terns of involucrin and filaggrin reverted from that
typical for psoriasis to near that of normal epidermis,
and keratinocyte activation was significantly reduced
or abolished. In contrast to pimecrolimus’ absence of
effect on circulating lymphocytes [13], there was a
significant reduction of CD3+, CD4+, and CD8+
dermal lymphocytes and of CD3+ and CD4+ epider-
mal lymphocytes; importantly, there was no signifi-
cant change in the CD1a+ subpopulation in the
epidermis and dermis, indicating that pimecrolimus
leaves Langerhans cells unchanged [13].
Summary
Although pimecrolimus is approved as a topical
treatment for atopic dermatitis in the United States,
the European Union, and most other Western coun-
tries, it is not yet approved for use as a systemic drug
because phase 2 studies are still ongoing. Nonethe-
less, evidence accumulated to date indicates the
following: it has a genomic profile of broad anti-
inflammatory activity without evidence of toxicity as
evaluated in blood cells, it exhibits excellent clinical
tolerability after 4 and 12 weeks of oral treatment,
and it is highly effective in a concentration-dependent
manner in patients with moderate to severe plaque
psoriasis. The impressive clinical efficacy of pime-
crolimus compares favorably with that of established
systemic treatments for psoriasis, such as psoralen
with ultraviolet A (PUVA), retinoic acid PUVA com-
binations, and cyclosporin [13]. No impairment of
organ function, as assessed by clinical and laboratory
examinations, and no systemic immune suppression
have been noted in the studies performed thus far. In
addition, no viral infections and increase of skin
infections were seen throughout the time patients
were observed [13,21]. These findings harmonize
with the observed gene profiling of the drug, which
showed down-regulation of genes responsible for the
target pathway, inflammation, activation, prolifera-
tion, chemotaxis, and migration of leukocytes but
did not reveal changes in gene expression that might
be linked to treatment-related immune suppression
and toxicity [13]. The findings also seem to verify the
observation in animal models in which pimecrolimus
had high skin-selective, anti-inflammatory activity
and a very low potential for effective systemic im-
mune responses [6].
The efficacy of pimecrolimus in psoriasis and its
short-term safety are encouraging, but it will have to
be determined whether the safety profile of this novel
K. Wolff / Dermatol Clin 22 (2004) 461–465 465
drug continues to be as favorable when it is admin-
istered over longer periods of time. Multicenter trials
are underway to answer these and other questions. The
experience available with this drug to date is unique,
however, and supports the notion that pimecrolimus
may also be effective for other T-cell–mediated skin
diseases. The efficacy of oral pimecrolimus already
has been shown in atopic dermatitis [22].
References
[1] Meingassner JG, Grassberger M, Fahrngruber H,
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[3] Neckermann G, Bavandi A, Meingassner JG. Atopic
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[4] Paul C, Graeber M, Stuetz A. Ascomycins, promising
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[5] Wellington K, Spencer CM. Adis new drug profile:
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[7] Rappersberger K, Meingassner JG, Fialla R, Foedinger
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[8] Van Leent EJM, Graber M, Thurston M, Wagenaar A,
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[10] Queille-Roussel C, Graeber M, Thurston M, Lacha-
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[12] Van Leent EJM, Ebelin ME, Burtin P, Spuls PI, Bos
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[13] Rappersberger K, Komar M, Ebelin ME, Scott G, Bur-
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[14] Grassberger M, Baumruker T, Enz A, Hiestand P,
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[15] Kalthoff FS, Chung J, Grassberger M, Stuetz A. SDZ
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Dermatol Clin 22 (2004) 467–476
Retinoid therapy for psoriasis
Paul S. Yamauchi, MD, PhDa,b, Dalia Rizk, MDa, Nicholas J. Lowe, MDa,b,*
aClinical Research Specialists, 2001 Santa Monica Boulevard, Suite 490W, Santa Monica, CA 90404, USAbDivision of Dermatology, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095-1750, USA
The systemic retinoids possess a remarkable range and is no longer available. The use of topical tazar-
of activities and clinical applications. They are an im-
portant form of therapy for patients with more severe
and resistant types of psoriasis. In general, with plaque
psoriasis, systemic retinoids are used most effectively
in combination with other forms of therapy, such as
phototherapy or other systemic agents. With general-
ized pustular psoriasis, they are effective as mono-
therapy and are frequently helpful for the control of
exfoliative psoriasis.
The Food and Drug and Administration (FDA) in
the United States has approved four derivatives of
systemic retinoids. Isotretinoin, whose main indica-
tion is for cystic acne, has been found to be ineffective
for plaque-type psoriasis as monotherapy treatment
[1]. Clinical responses, however, were observed with
isotretinoin for pustular psoriasis [1] and in conjunc-
tion with phototherapy for psoriasis [2,3]. Bexarotene
is approved for the treatment of cutaneous T-cell
lymphoma. One report showed that bexarotene at
0.5 to 2 mg/kg/d reduced lesions in patients with
moderate to severe psoriasis [4].
Topical retinoids for the treatment of psoriasis was
introduced in the United States in 1997 for the treat-
ment of plaque-type psoriasis. The only FDA-ap-
proved topical retinoid for psoriasis is tazarotene gel
and cream. Topical tazarotene has remained one of
the mainstay treatments for psoriasis.
This article focuses on the treatment of psoriasis
with acitretin, the only systemic retinoid approved for
psoriasis, and also briefly discusses its predecessor,
etretinate, which was replaced by acitretin in 1997
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/S0733-8635(03)00126-8
* Corresponding author. Clinical Research Specialists,
2001 Santa Monica Boulevard, Suite 490W, Santa Monica,
CA 90404.
E-mail address: [email protected] (N.J. Lowe).
otene is also discussed in detail. Combination therapy
of retinoids, both topical and systemic, with photo-
therapy and other therapeutic agents is described. In
addition, new retinoid analogues that are currently
undergoing clinical investigation at the time of prep-
aration of this article are mentioned. Finally, potential
toxicities and adverse effects associated with reti-
noids are discussed.
Chemistry and pharmacology
Fig. 1 shows the chemical structures of acitretin
and etretinate. Acitretin is the principle active metab-
olite of the prodrug, etretinate. They are very similar
to each other except that etretinate is the ethylester
form of acitretin. Because of this modification, how-
ever, under physiologic conditions etretinate is in an
uncharged state and is 50 times more lipophilic than
acitretin, which carries a negative charge [5]. Conse-
quently, etretinate is accumulated in adipose tissue
because of its high lipophilicity as opposed to acitre-
tin, which is not stored in fat. This is the main phar-
macokinetic reason why acitretin has a much shorter
half-life (approximately 50 hours) than etretinate
(approximately 120 days). In light of the highly tera-
togenic effects associated with systemic retinoids (dis-
cussed later) and because of its long half-life and
detection in the serum up to 2 years after discontinu-
ing treatment, etretinate was withdrawn from the
market in 1997 following the introduction of acitretin.
Studies have demonstrated that the concurrent
ingestion of ethanol with acitretin results in the trans-
esterification conversion of acitretin to etretinate [6,7].
Furthermore, higher alcohol consumption was linked
to higher etretinate concentrations. This is clinically
significant because the ingestion of alcohol extends the
s reserved.
Fig. 1. Chemical structures of etretinate (A) and acitretin (B).
P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476468
half-life of acitretin to the same as that of etretinate
because of the enzymatic conversion. There are no data
documenting the spontaneous formation of acitretin
to etretinate in the absence of alcohol consumption.
It is also important to instruct patients that sys-
temic retinoids, including acitretin, have higher ab-
sorption and improved bioavailability when ingested
with food [8].
Fig. 2 illustrates the structure of tazarotene. Min-
imal systemic absorption of tazarotene occurs because
of rapid metabolism in the skin to the active metab-
olite, tazarotenic acid, which is systemically absorbed
and further metabolized. Tazarotenic acid is hydro-
philic and is rapidly metabolized causing no apparent
accumulation within body tissues. More than 99% of
tazarotenic acid is bound to plasma proteins. The
metabolism of tazarotene to tazarotenic acid occurs
through esterase hydrolysis in skin. On conversion,
tazarotenic acid exhibits a half-life of approximately
18 hours in both normal and psoriatic patients.
Mechanism of action
The exact molecular mechanism by which reti-
noids are able to exert their effects on psoriasis is
unknown. It has been demonstrated that acitretin
modulates the cellular differentiation of the epider-
mis, which results in deceased scaling, erythema, and
thickness of the plaques. There is also histologic
evidence that acitretin decreases the thickness of the
stratum corneum and the inflammation in the epider-
mis and dermis that is associated with psoriasis.
Tazarotene has multiple effects on keratinocyte
differentiation and proliferation, and inflammation
processes that contribute to psoriasis. In animal mod-
els, topical tazarotene blocks induction of ornithine
Fig. 2. Chemical structure of tazarotene.
decarboxylase activity, which is associated with cell
proliferation and expression. In vitro skin models and
cell cultures have demonstrated tazarotene suppresses
expression of MRP8, a marker of inflammation pres-
ent in high levels in the epidermis of psoriasis patients
and inhibits the formation of hyperkeratotic plaques.
Tazarotene also induces the expression of tazarotene-
induced gene 3, a suppressor gene that may inhibit
epidermal hyperproliferation in treated plaques.
There are two classes of nuclear retinoid recep-
tors that have been identified: the retinoic acid recep-
tor and retinoid X receptor. The retinoic acid receptors
and retinoid X receptors are each composed of three
different subtypes, labeled a, b, and g [9]. Nuclear
retinoid receptors exist as dimers, and retinoic acid
receptors are known to form heterodimers with reti-
noid X receptors [10]. Acitretin has been shown to
activate all three subtypes of retinoic acid receptor,
despite the absence of measurable binding to any of
the subtypes [10]. Tazarotenic acid selectively binds
to retinoic acid receptors and exhibits little affinity for
retinoid X receptors [11]. The function of these
retinoic acid receptor– retinoid X receptor hetero-
dimers is unknown in the skin. Such data indicate
that further studies are necessary to understand the
interaction of acitretin with nuclear receptors.
Monotherapy with systemic retinoids
Several studies have confirmed the efficacy of
acitretin treatment for different types of psoriasis
[12–19]. Pustular forms of psoriasis are more re-
sponsive to systemic retinoid monotherapy than
plaque-type psoriasis, which responds more slowly.
With plaque-type psoriasis, it is possible to enhance
the response to therapy by combining retinoids with
other treatments.
Pustular psoriasis
When acitretin is used as monotherapy for gen-
eralized pustular psoriasis, the initial dose is 25 to
50 mg per day, but higher doses may be required
in some patients. A rapid resolution of generalized
pustular psoriasis is achieved usually within 10 days
P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476 469
of initiating acitretin, which is probably the drug of
first choice for the treatment of this condition.
One advantage with acitretin for pustular psoriasis
over methotrexate is the absence of acute effects on
the peripheral blood count. Methotrexate may occa-
sionally produce acute leukopenia in patients with
generalized pustular psoriasis, which can lead to a
major toxicity risk in these patients. Pustular psoria-
sis leads to rapid proliferation of monocytes in the
S-phase of the cell cycle. Methotrexate, which blocks
DNA synthesis in these cells, may lead to failure of
maturation of cells beyond mitosis that leads to mye-
losuppression [20]. This phenomena is not clinically
evident with acitretin,
After the clearance of pustulation, the psoriasis
can continue to be controlled by reducing the dose of
acitretin (eg, decreasing acitretin at 25 mg per day to
25 mg every other day or to 10 mg per day). Some
patients, however, relapse and develop plaque-type
psoriasis. In such patients, alternative forms of ther-
apy, such as phototherapy, can gradually be instituted
in combination with acitretin. When the psoriasis
improves, the retinoid then can be tapered down.
In women of childbearing age, acitretin should
probably be avoided whenever possible, even for
pustular psoriasis. If acitretin is required, strict birth
control practices must be adhered to and alcohol must
be avoided. In such situations, oral isotretinoin with
its shorter half-life of 10 to 20 hours may be used
as an alternative to control the pustulation. Starting
doses range from 1 to 1.5 mg/kg/d. If necessary,
phototherapy may be initiated to control the psoriasis.
Another situation in which acitretin is effective is
in the treatment of palmoplantar pustular psoriasis,
particularly where there is significant hyperkeratosis
or severe pustulation. Isotretinoin may be used as an
alternative in women who are fertile. Retinoid ther-
apy reduces the degree of hyperkeratosis and pustu-
lation. If monotherapy with acitretin is not achieving
the desired results, then combination with psoralen
plus UVA (PUVA) phototherapy is extremely useful.
Alternatively, hydroxyurea at 500 mg twice a day in
conjunction with acitretin is another way of control-
ling palmoplantar pustular psoriasis.
Exfoliative erythrodermic psoriasis
In exfoliative erythrodermic psoriasis, acitretin is
useful at starting doses of 25 to 50 mg per day. It
is advantageous to use emollients liberally along
with the application of mild topical corticosteroids
(eg, triamcinolone acetonide [0.025% cream or oint-
ment]) under occlusion to achieve more rapid resolu-
tion of psoriasis.
Rarely, patients with severe exfoliative erythro-
dermic psoriasis may need to use a combination of
acitretin with methotrexate. This combination should
only be used rarely and, when it is, only with careful
monitoring of the peripheral blood count and liver
function tests.
Another option for the treatment of exfoliative
psoriasis is to use methotrexate or cyclosporine
therapy to achieve a rapid improvement after which
the methotrexate or cyclosporine dosage is reduced
and low doses of acitretin (10 to 25 mg per day)
are introduced.
Combination therapy for moderate to severe
plaque psoriasis
In patients with severe plaque psoriasis, especially
if the condition is extensive with hyperkeratosis, the
use of a retinoid plus other forms of treatment, par-
ticularly phototherapy, has been shown to be highly
effective. The dose of the retinoid or the amount of
alternative therapy required when used separately can
be reduced if used in combination with each other.
Acitretin and psoralen plus UVA phototherapy
For combination therapy, the optimum dose for
acitretin is 0.3 mg/kg/d, either 2 weeks before starting
phototherapy or at the same time. The increases in
ultraviolet radiation should be more gradual and
cautious than in patients not taking systemic retinoids
because of an increased risk of ultraviolet radiation-
induced erythema. This is not a true photosensitivity,
but probably represents increased epidermal trans-
mission of the ultraviolet radiation because of altered
optical properties of the stratum corneum caused by
the retinoid.
The concomitant use of PUVA with acitretin has
been studied by several investigators [21–27]. Most
patients receiving the combination improve more
quickly than with PUVA or acitretin alone. In addi-
tion, the total number of ultraviolet radiation exposures
can be reduced. Following clearance of psoriasis,
various maintenance regimens may be used. Acitretin
administered in low maintenance doses can be effec-
tive, or acitretin therapy can be stopped and mainte-
nance therapy is undertaken solely with PUVA.
In a double-blinded comparative study, patients
with severe, widespread psoriasis were randomized to
receive either PUVA alone or PUVA in combination
with acitretin [21]. Eighty percent of patients with
PUVA alone demonstrated marked or complete clear-
ing of psoriasis, whereas 96% of patients who re-
P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476470
ceived adjunctive therapy with PUVA plus acitretin
exhibited the same degree of improvement. The mean
cumulative UVA dose given to patients who received
combination therapy was 42% less than that required
for patients who received PUVA alone.
When patients with psoriasis were initially treated
with acitretin at 50 mg per day for 2 weeks followed
by decreasing the amount to 25 mg per day in
conjunction with PUVA for up to 10 weeks, there
was a 40.5% reduction in the total cumulative UVA
dose, a decrease of the overall duration of treatment
by almost 18 days, and a reduction in the number of
PUVA treatments by nearly six sessions, when com-
pared with treatment with PUVA alone [22].
Bath PUVA together with acitretin is another
option for treatment of patents with pustular, plaque-
type, or erythrodermic psoriasis [24]. After 4 weeks of
treatment, patients had greater than a 90% response
rate with no relapse after 3 months.
The safety of PUVA is now of concern because of
the risk of melanoma and nonmelanoma skin cancer.
Whether or not acitretin alters this risk is unknown at
this stage.
Acitretin and UVB phototherapy
Acitretin plus UVB therapy is another combina-
tion form of therapy to treat psoriasis and has been
investigated [28–30]. This option can be used for
those patients who are intolerant of side effects
associated with oral psoralens, such as gastrointesti-
nal toxicity.
Treatment with UVB combined with acitretin at
50 mg per day or placebo resulted in greater clearance
with fewer treatments and smaller amounts of UVB
radiation when acitretin was used compared with
placebo [29]. A 74% improvement in the psoriasis
score was noted in patients treated with acitretin plus
UVB compared with 35% with UVB only. In addi-
tion, in the same study, when only acitretin was used,
there was a 42% reduction in psoriasis. There was a
decrease in the total number of hours of exposure
time to UVB therapy by approximately 6 hours when
acitretin was used to attain clearance compared with
light treatment alone. Another study demonstrated
that when patients with psoriasis were initially treated
with 35 mg per day of acitretin during the first
4 weeks of therapy followed by concomitant therapy
with UVB radiation plus 25 mg per day of acitretin
and compared with the placebo group, there was a
79% decrease in the psoriasis severity index in the
acitretin and UVB group and 35% reduction in the
UVB-only group [28]. In addition, the medium cu-
mulative dose to achieve 75% clinical improvement
was 41.5% lower when acitretin was combined.
Finally, the number of treatments to attain 80% to
100% clearance of psoriatic plaques was decreased
by 5.6 sessions with UVB plus acitretin versus UVB
only [30]. The total UVB dose and minimal erythema
dose was reduced by approximately 20%.
In summary, reasons for combining PUVA or
UVB with systemic retinoids include the following:
1. Better clearance
2. Decreased cumulative ultraviolet doses
3. The number of treatments and duration of PUVA
therapy is reduced
4. The possibility of reduction or cessation of acit-
retin therapy before the occurrence of side ef-
fects, such as hyperlipidemia or alopecia
Combination therapy with other agents
Combination therapy of acitretin with other mo-
dalities other than light therapy can be used to control
psoriasis. Concomitant treatment with acitretin and
topical calcipotriene may help reduce psoriatic pla-
ques better than with either alone [31,32]. In addition,
acitretin at 25 mg per day together with hydroxyurea,
500 mg twice daily, has been effective for some pa-
tients with chronic plaque psoriasis and pustular
psoriasis. When using combination therapy with aci-
tretin and hydroxyurea, the complete blood count
should be carefully monitored.
Combination therapy with immunomodulatory agents
New-generation drugs are being developed that
selectively target key cytokines and receptor mole-
cules on T cells and antigen-presenting cells that
are involved in the pathogenesis of psoriasis. These
immunomodulators are in the form of monoclonal
antibodies or fusion proteins that are administered
as injections either subcutaneously, intramuscularly,
or intravenously.
One biologic agent that is currently on the market
and is FDA-approved for rheumatoid arthritis and
psoriatic arthritis is etanercept. Etanercept is currently
undergoing clinical trials as monotherapy treatment
for psoriasis. Etanercept is a fusion protein that acts as
a soluble tumor necrosis factor and competitively
binds to tumor necrosis factor thereby preventing
tumor necrosis factor from binding to cell surface
receptors on target cells. Because tumor necrosis
factor is involved in the pathogenesis of psoriasis,
through such inhibition, etanercept serves as an anti-
inflammatory agent that is beneficial in the treatment
Fig. 3. Patient with recalcitrant plaque-type psoriasis (A) before and (B) after treatment with 25 mg acitretin each day plus
etanercept, 25 mg twice a week subcutaneously for 8 weeks.
P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476 471
of psoriasis. A recent report demonstrated that com-
bination therapy with etanercept together with various
systemic agents, such as cyclosporine, methotrexate,
acitretin, or hydroxyurea, in patients with severe
recalcitrant psoriasis resulted in marked improvement
and reduction in the PASI score [33]. More impor-
tantly, no added toxicity was seen in these patients
when etanercept was combined with a systemic agent.
Fig. 3 shows a patient with refractory psoriasis who
responded well to combination therapy with 25 mg
per day of acitretin plus twice-weekly 25-mg subcu-
taneous injections of etanercept.
Combination treatment with systemic agents and
immunomodulators underscores the significance of
treating psoriasis in the future. With the advent of
new biologic agents and the existing systemics, this
new approach to combination therapy may provide an
impetus in controlling psoriasis that previously was
difficult to treat.
Other systemic retinoids
Oral tazarotene
An oral form of tazarotene (a topical retinoid
approved for plaque psoriasis and acne) has recently
been developed that is currently not available on the
market during the preparation of this article. Tazar-
otene is converted to its active metabolite, tazarotenic
acid, which has a short elimination half-life of 7 to
12 hours (Allergan, unpublished data).
In a dose escalation study, 181 patients with mod-
erate to severe plaque psoriasis received daily doses
of oral tazarotene (0.4 to 6.3 mg) or placebo (Lowe
et al, submitted for publication). Optimal efficacy
was seen with the 4.2-mg dose. At this dosage, the
body surface area involvement was reduced by 17%
at week 12 and 82% of patients were satisfied or very
satisfied with oral tazarotene. Fig. 4 shows a patient
who had good clearance of psoriatic plaques with oral
tazarotene at 4.2 mg per day by week 12.
The only significant adverse effect noted was chei-
litis at doses of 2.8 mg or higher. There were no other
dose-related adverse events, such as increased liver
function enzymes, hyperlipidemia, or changes in the
hematologic profile. The shorter half-life of oral taza-
rotene may potentially be a useful alternative for sys-
temic retinoid treatment in women of childbearing
age with psoriasis.
Toxicities and adverse reactions associated with
systemic retinoids
Teratogenicity
All systemic retinoids are highly teratogenic with
a pregnancy category of X rated by the FDA. Major
human fetal abnormalities associated with retinoids
include meningomyelocele, meningoencephalocele,
multiple bony malformations, facial dysmorphia, low-
set ears, high palate, decreased cranial volume alter-
ations, and cardiovascular malformations.
Fig. 4. Patient with plaque psoriasis (A) before and (B) after treatment with oral tazarotene, 4.2 mg each day for 12 weeks.
P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476472
In light of its teratogenicity, acitretin must not
be used by women who are pregnant or who intend
to become pregnant during therapy or at any time
for at least 3 years following discontinuation of
therapy. In addition, acitretin must not be used by
women who may not use reliable contraception while
taking acitretin or for at least 3 years following
cessation of treatment. In addition, the current guide-
line states that ethanol must not be ingested by female
patients either during treatment with acitretin or for
2 months after discontinuing acitretin to avoid con-
version into etretinate, which carries a much longer
elimination half-life. This is caused by the trans-
esterification of acitretin to etretinate by ethanol as
previously discussed.
Mucocutaneous toxicity
Mucocutaneous toxicity occurs with all of the
systemic retinoids [34]. The common mucocutaneous
side-effects in order of frequency are cheilitis, skin
peeling, alopecia, xerosis, rhinitis, nail dystrophy,
epistaxis, sticky skin, retinoid dermatitis, and xeroph-
thalmia. Hair loss may occur a few weeks after
initiation of treatment and ceases 6 to 8 weeks after
discontinuation of therapy. In rare cases, chronic hair
loss has occurred. Patients frequently find these
symptoms extremely difficult to accept. Rapid reduc-
tion in retinoid therapy is desirable to reduce the
impact on patients of these toxicity problems. Some
studies have suggested that 800 IU of vitamin E daily
may reduce some of the mucocutaneous effects of
systemic retinoids [35].
Arthralgias and myalgias
Some patients develop muscle pain and myalgias
with or without an elevation of creatine phospho-
kinase. In general, it is wise for patients to avoid
excessive muscle exercising, particularly excessive
weight lifting and contact sports, because these forms
of activity may increase such risks. Arthralgias occur
in a small percentage of patients and disappear on
discontinuation of therapy.
Pseudotumor cerebri
Acitretin and other systemic retinoids have been
associated with cases of pseudotumor cerebri (benign
intracranial hypertension). Such symptoms and signs
include papilledema, severe headaches, nausea and
vomiting, and visual disturbances. If pseudotumor
cerebri is suspected, ophthalmologic evaluation for
papilledema should be conducted and if present, the
retinoid should be discontinued immediately. Oral
retinoids should not be taken with tetracycline or
tetracycline derivatives because of increased risk of
pseudotumor cerebri.
Ophthalmologic effects
Ocular toxicity does not seem to be a major prob-
lem with acitretin, although rare cases of disturbances
of color vision have been recorded. Most of the ocu-
lar symptoms have been mucocutaneous in nature,
such as dry eyes, irritation of eyes, and loss of brow
and lashes. Other side effects, such as blurred vision,
cataracts, decreased night vision, and diplopia, are
much less common.
Skeletal toxicity
There is some concern that long-term high-dose
acitretin therapy is associated with changes that re-
semble diffuse idiopathic skeletal hyperostosis, which
include anterior spinal ligamentous calcification and
the formation of osteophytes and bony bridges. Disk
space narrowing is not evident in diffuse idiopathic
P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476 473
skeletal hyperostosis. There seems to be a cumulative
threshold dose of 25 to 30 g etretinate below which
skeletal toxicity is not seen radiographically.
Psychiatric effects
There are no recorded incidents of suicide or
depression linked to patients on systemic retinoid
therapy for the treatment of psoriasis. There is clearly
a background of depression with some psoriasis
patients but this has not been noted to be aggra-
vated by acitretin (Lowe NJ, unpublished observa-
tions, 2002).
Hyperlipidemia
Hyperlipidemia occurs in approximately 25% to
50% of patients. Occasionally, severe levels reaching
five to eight times the normal value occur, but usually
levels are increased two to three times the normal. The
incidence of pancreatitis or eruptive xanthomas with
increased triglyceride levels is uncommon. In addi-
tion, levels of high-density lipoproteins decrease with
oral retinoids. These abnormal levels are reversible on
cessation of therapy. Patients with an increased tend-
ency to develop hypertriglyceridemia include those
with diabetes mellitus, obesity, increased alcohol in-
take, or a familial history of these conditions. There
are a number of ways to manage hyperlipidemia
including low-fat diets, reduced alcohol intake, physi-
cal activity, the use of polyunsaturated fish-oil supple-
ments, and prescribing lipid-lowering drugs.
Hepatotoxicity
All the systemic retinoids have the potential for
liver toxicity. Elevations of aspartate transaminase
(serum glutamic-oxaloacetic transaminase), alanine
transaminase (serum glutamate pyruvate transami-
nase), g-glutamyltransferase (GGTP), low-density li-
poproteins, and alkaline phosphatase have occurred
in 33% of patients treated with acitretin. During the
clinical trials in the United States for acitretin, 3.8%
of patients had sufficient elevation of liver function
tests that they were discontinued from further treat-
ment. If hepatotoxicity is suspected with acitretin, the
drug should be discontinued and a liver work-up
should be conducted.
Frequency of follow-up
Blood investigations should include a full blood
count; a complete metabolic panel including liver
enzymes; renal function tests; creatine phosphoki-
nase; and a lipid panel including triglycerides, cho-
lesterol, and high-density lipoproteins. In all women
of childbearing age, a monthly pregnancy test must
be conducted. These investigations should be per-
formed initially every 2 weeks while on clearance
doses, reducing to monthly or 2-monthly assessments
depending on the maintenance dose required. There is
presently no requirement for liver biopsy.
Guidelines for the use of systemic retinoids in
psoriasis
The following guidelines apply for the use of sys-
temic retinoids in psoriasis:
1. Acitretin can be prescribed for male patients or
postmenopausal female patients. It is up to the
clinician’s discretion to prescribe acitretin in
women of childbearing age keeping in mind the
strict guidelines associated with acitretin’s
teratogenicity. If there is any suggestion that a
woman desires pregnancy, or suspicion that
adequate birth control methods will not be
practiced, or abstinence from alcohol cannot be
avoided, then acitretin should not be prescribed
to that woman.
2. Careful pretreatment and screening should be
performed to exclude the possibility of hyper-
lipidemia and hepatotoxicity. Risk factors
for hyperlipidemia (diabetes mellitus, obesity)
should be looked for and a history of alco-
hol use and hepatitis should be screened in
every patient.
3. Retinoids should be considered as monother-
apy in generalized pustular psoriasis.
4. Combination therapy of acitretin with PUVA or
UVB is advised in patients with severe plaque
psoriasis and localized palmoplantar psoriasis,
including local pustular psoriasis of the palms
and soles.
5. Combination therapy of acitretin with hy-
droxyurea may be beneficial in some patients
with plaque or pustular psoriasis. In addition,
combination therapy with the retinoids and
the new immunomodulatory biologic agents
may play pivotal roles in the future treatment
of psoriasis.
6. New retinoids, such as oral tazarotene, seem to
have a good safety profile. Longer-term studies
and combination studies with this drug are ea-
gerly awaited.
P.S. Yamauchi et al / Dermatol Clin 22 (2004) 467–476474
Topical tazarotene
There are four formulations for topical tazarotene:
(1) 0.05% gel, (2) 0.1% gel, (3) 0.05% cream, and
(4) 0.1% cream. All four vehicles and strengths can
be used for plaque psoriasis. In general, gels and the
more concentrated strengths tend to have a higher in-
cidence of irritation, pruritus, erythema, stinging, and
desquamation. These side effects are most apparent on
initial applications but alleviate with continuous usage.
In two multicentered, double-blinded, random-
ized, placebo-controlled studies involving 660 pa-
tients, tazarotene gels 0.05% and 0.1% applied once
a day for 3 months were found to be efficacious and
safe for the treatment of plaque psoriasis. The most
profound effect with tazarotene gel was the improve-
ment of plaque elevation [36].
Results of two multicenter studies showed that
topical therapy once daily with tazarotene in a cream
formulation at concentrations of 0.05% or 0.1% was
effective in the treatment of plaque psoriasis [37]. A
total of 1303 patients participated in these random-
ized, double-blinded, placebo-controlled trails in
which tazarotene creams 0.1% and 0.05% or vehi-
cle were applied daily to all psoriatic lesions for
12 weeks followed by a 12-week posttreatment pe-
riod. Tazarotene creams 0.05% and 0.1% were sig-
nificantly more effective than vehicle in terms of
clinical success rates and in reducing the severity of
the clinical signs of plaque psoriasis. Tazarotene
cream 0.1% was generally more effective, although
slightly less well tolerated, than the 0.05% cream.
Both tazarotene concentrations showed good mainte-
nance of therapeutic effect during a 12-week post-
treatment period. Tazarotene creams 0.05% and 0.1%
for the treatment of psoriasis were found to be safe
with acceptable tolerability.
To counteract potential irritation from tazarotene,
topical corticosteroids may be combined to the
lesions. A study showed that application of tazarotene
in the evening and a mid- to high-potency topical
corticosteroids in the morning achieved significantly
greater reductions in scaling, erythema, and overall
lesional severity, and a decreased incidence of adverse
events [38]. Combination therapy by alternating tazar-
otene and high-potency steroids each day significantly
increased the treatment success rate and lowered
incidence of treatment-related adverse effects [39].
Short contact with tazarotene minimizes the local
irritation on the skin. For patients who are beginning
therapy with tazarotene, initial application times of
15 minutes in the evenings and then washing off the
tazarotene decreases the incidence of stinging, burn-
ing, and erythema. As the patient becomes accus-
tomed and more tolerant to tazarotene, application
times are prolonged incrementally until patients can
leave it on overnight.
Combination treatment using tazarotene with ul-
traviolet therapy has become very popular for the
treatment of plaque psoriasis [40–43].The efficacy of
tazarotene reported in clinical trials suggests that this
drug may help to improve the efficacy of photo-
therapy, and perhaps reduce the ultraviolet light
exposure required without introducing additional,
clinically significant problems. Broad or narrow band
UVB plus tazarotene combination achieves greater
reductions in the elevation and scaling of difficult-to-
treat psoriatic plaques than UVB phototherapy alone.
The tazarotene combination therapy also achieved
initial treatment success in less than half the time
needed with phototherapy alone. Combining UVB
phototherapy with tazarotene treatment seems to offer
a valuable therapeutic option that is more efficacious
and faster than UVB phototherapy alone.
Summary
Both systemic and topical retinoids provide an
excellent alternative for the treatment of psoriasis.
Retinoids are generally used as combination therapy
with other treatment modalities, such as phototherapy
or other topical or systemic agents, and can be com-
bined with the newer biologic agents, such as eta-
nercept. Newer retinoids are being developed to treat
psoriasis with the hope of a less toxic side effect
profile. For now, retinoids remain a mainstay for the
treatment of psoriasis.
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Dermatol Clin 22 (2004) 477–486
Psoriatic arthritis: prevalence, diagnosis, and review of
therapy for the dermatologist
Eric M. Ruderman, MD*, Siddharth Tambar, MD
Department of Medicine, Northwestern University Feinberg School of Medicine, 240 East Huron Street, McGaw 2300,
Chicago, IL 60611, USA
Psoriatic arthritis (PsA) is an inflammatory arthri- and Wright [4] have described five different clinical
tis that is commonly associated with psoriasis. Char-
acteristic symptoms of any inflammatory arthritis
include pain and stiffness in affected joints, morning
stiffness lasting longer than 30 minutes, and stiffness
that is accentuated by prolonged rest and relieved
with activity.
Prevalence and presentation of disease
Although psoriasis affects 1% to 3% of the United
States population, it has been reported that 7% to
31% of patients with psoriasis also have PsA [1].
The wide range may relate to the variability in the
populations studied, from community-based cohorts
to referral clinics or hospitalized patients. There is an
equal gender distribution, onset of joint complaints is
typically in the 30s to 50s, and whites have a greater
incidence as compared with African Americans and
Asians. In the United States, the incidence of new
cases is approximately 6 per 100,000, and the preva-
lence is 100 per 100,000 [2,3].
Although previously believed to be a less severe
variant of rheumatoid arthritis (RA), PsA is now
considered a distinct disease process as first described
by Moll and Wright [4]. When compared with RA,
patients with PsA tend to have less tender joints and
less prominent joint effusions. Significant joint de-
struction and pain, however, are still possible. Moll
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/S0733-8635(03)00127-X
* Corresponding author.
E-mail address: [email protected]
(E.M. Ruderman).
patterns of joint involvement:
1. Asymmetric oligoarthritis, where fewer than
five joints are affected in an asymmetric
distribution.
2. Symmetric polyarthritis, in which more than
five joints in a symmetric pattern are in-
volved. This pattern is almost indistinguishable
from RA.
3. Distal arthritis, characterized by distal interpha-
langeal joint involvement.
4. Arthritis mutilans, a destructive arthritis that re-
sults in severe deformities.
5. Spondyloarthropathy, disease affecting the spine
(spondylitis), sacrum-sacroiliac joints (sacro-
iliitis), and hip-shoulder joints with or without
peripheral arthritis.
Studies done since Moll and Wright [4] published
their classification scheme have not found the same
distribution in all patient populations [5]. Further-
more, some patients present with more than one
pattern, and many undergo a change in the pattern
of their arthritis during follow-up [6,7]. One proposed
disease classification is limited to just three patterns:
(1) asymmetric oligoarthritis, (2) symmetric polyar-
thritis, and (3) spondyloarthropathy. Other series
have suggested that nearly all patients fit into the
second pattern [8,9]. Another group has suggested
that the disease is best divided into just two subsets:
peripheral arthritis, and axial (spinal) disease with or
without peripheral arthritis [7]. Oligoarthritis has
been considered the most common initial presenta-
tion, although recent series have questioned this
s reserved.
Box 2. Radiographic features of PsA
Peripheral
Asymmetric distributionDistal interphalyngeal joint
involvementPeriostitisPreservation of bone densityBony ankylosisPencil-in-cup deformities
E.M. Ruderman, S. Tambar / Dermatol Clin 22 (2004) 477–486478
presumption [7,10]. Although rare, isolated distal
interphalangeal (DIP) synovitis and arthritis mutilans
are considered the most specific joint findings in PsA.
The pattern of severity of the joint disease is not
related to the pattern or severity of the skin disease.
In the majoriy of patients, however, skin findings
develop years before the arthritis [11]. At present,
most information on disease patterns is observational.
Current efforts to develop better outcomes measure-
ments in PsA may ultimately produce characteriza-
tions of disease patterns that are more clearly related
to pathogenesis or response to specific therapies.
Axial
Sacroiliitis (may be asymmetrical)Vertebral syndesmophytesIntervertebral ankylosisParavertebral ossification
Diagnosis
Psoriatic arthritis is considered a seronegative
spondyloarthropathy, a group of diseases that in-
cludes ankylosing spondylitis, reactive arthritis or
Reiter’s syndrome, and the arthritis associated with
inflammatory bowel disease. These diseases share a
predilection for asymmetric peripheral arthritis and
axial or spinal involvement. As with other spondy-
loarthropathies, musculoskeletal manifestations of
PsA may also include inflammation at the site of
attachment of tendons and ligaments (enthesitis),
especially at the Achilles tendon insertion and the
insertion of the plantar fascia into the calcaneus.
Dactylitis, also described as a sausage digit, may also
be seen. These digits develop swelling and tenderness
of the entire finger or toe because of inflammation of
the tendons along with the involved joints. Inflam-
matory eye involvement has been observed in up to
one third of patients with PsA [11].
The diagnosis of PsA is based on the clinical
presentation of joint complaints, a history of psoria-
sis, radiographic changes, and a possible family
history of psoriasis. The presence of other arthritis
conditions makes the diagnosis of PsA difficult at
times; a diagnosis of PsA requires the exclusion of
other possible causes of joint symptoms (Box 1).
Confounders include the coexistence of gout and
Box 1. Differential diagnosis of PsA
OsteoarthritisGoutRheumatoid arthritisReactive arthritisAnkylosing spondylitisInflammatory bowel disease–related
arthritis
osteoarthritis in some patients. Gouty arthritis is
commonly seen in association with psoriasis, pre-
sumably related to the hyperuricemia resulting from
rapid skin cell turnover [12]. Osteoarthritis is a
common disease, and in women DIP involvement
with Heberden’s nodes may be mistaken for the DIP
synovitis seen in PsA. The presence of soft tissue
swelling and erythema around the joint may help
to distinguish PsA changes from osteoarthritis.
Finally, RA or another arthritic condition may be
present in a patient who also happens to have
unrelated skin psoriasis.
There are no specific laboratory studies used in
making the diagnosis of PsA. An elevated erythrocyte
sedimentation rate, C-reactive protein, or leukocyto-
sis is seen in one third of patients, consistent with a
nonspecific inflammatory state [13].Thecommon find-
ing of normal acute-phase reactants may help to dis-
tinguish PsA from RA. Although PsA is classically
considered a rheumatoid factor–negative disease,
both antinuclear antibodies and rheumatoid factor
may be present in 10% of patients [5].
There are common and distinct radiographic
changes in PsA (Box 2). In one study, radiographic
damage was found in two thirds of patients at initial
presentation [14]. Bone changes in PsA may be dis-
tinct from the findings in other inflammatory ar-
thropathies, and may include a combination of
erosion and new bone formation in distal joints.
Distinctive radiographic features of PsA include
asymmetric oligoarticular distribution, relative ab-
sence of periarticular osteopenia, involvement of
E.M. Ruderman, S. Tambar / Dermatol Clin 22 (2004) 477–486 479
the DIP joints, and involvement of the sacroiliac
joints [15]. Other changes include joint space loss
with or without ankylosis; destruction of isolated
joints; fluffy periostitis; and lysis of the terminal
phalanges (acro-osteolysis). Pencil-in-cup appearance
of phalanges is also described, and is a combination
of tapering of the middle phalanx and bony pro-
liferation at the base of the distal phalanx. In contrast
to RA, bone density in PsA is usually preserved [16].
Findings in the axial skeleton include para-
vertebral ossification, vertebral syndesmophytes,
asymmetric sacroiliitis, apophyseal sclerosis, and
calcification of the interspinous or anterior ligaments
[15]. Cervical spine findings include intervertebral
disk-space narrowing and ankylosis; both atlantoaxial
fusion and subluxation may be found in the upper
cervical spine. Temporomandibular joint involve-
ment, with condylar erosions and condylar osteolysis,
may occur [17].
MRI may be more sensitive than plain radio-
graphs in documenting the articular, periarticular,
and soft tissue inflammation in PsA [18]. MRI seems
to be especially useful in demonstrating entheseal
changes, such as inflammation and new bone forma-
tion, and may be useful in differentiating an early
spondyloarthropathy from early RA [19,20].
Damage and disability
Opinions differ as to the extent of joint dam-
age and subsequent disability in PsA. Some popula-
tion studies suggest a disease with a relatively
benign course. An evaluation of psoriasis in Olmsted
County, Minnesota, from 1982 through 1991 identi-
fied 66 cases of PsA among 1056 confirmed cases of
psoriasis [3]. During the 10-year follow-up period,
only 3% and 8% of the patients developed erosive
changes on foot and hand radiographs, respectively
[3]. Only 25 patients developed extra-articular mani-
festations of disease, including enthesitis, inflamma-
tory eye disease, and urethritis. A population study in
Finland showed a similar incidence rate of PsA, but
found that 46% of the patients developed erosive
joint disease [21]. The difference may relate to an
ascertainment bias in the Finnish study that limited its
cohort to patients receiving medication for their PsA.
Cohort analyses of referral populations also sug-
gest that PsA is frequently associated with a signifi-
cant amount of erosive arthritis [10,14]. In a study
of 220 patients with PsA seen at a Canadian re-
ferral center, Gladman et al [14] found that 67% of
the patients had erosive disease. The presence of
DIP joint involvement and symmetrical polyarthri-
tis were associated with the most advanced radio-
logic changes in this study. Similarly, Torre Alonso
et al [10] reported on a Spanish cohort of 180 pa-
tients with PsA, 57% of whom had erosive disease
on radiographs.
Although PsA has traditionally been viewed as a
disease with a benign prognosis, radiographic evi-
dence, such as that described previously, indicates
that the disease is more progressive and destructive
than previously thought. In a comparison of radio-
graphic changes in PsA and RA, there was no
significant difference in the severity of damage seen
in hands and feet [22]. Furthermore, both groups had
similar numbers of joints affected by significant
radiologic damage. Although the highest rate of
peripheral joint involvement in PsA seems to be
within 12 months of disease onset, the disease has
been shown to be progressive in terms of the number
of joints affected and the damage to those joints [23].
It has been suggested that possible indicators of poor
prognosis include younger age at onset, extensive
skin involvement, and certain HLA antigens [24].
Although the degree of skin involvement and HLA
type do not demonstrate a consistent impact between
studies, the most reliable factor in determining a poor
prognosis is polyarticular onset of disease. In fact, in
a recent prospective study the only independent risk
factor predictive of erosive and deforming disease
over time was a polyarticular onset of disease [25].
Disability and reduced quality of life in psoriatic
arthritis may be caused by factors other than joint
damage alone. In a recent study comparing 47 pa-
tients with RA and PsA of equivalent duration, the
patients with RA seemed to have greater disease
severity, as suggested both by radiographic damage
and the medication they were taking [26]. Function
and quality of life scores were similar for both
groups, however, leading the authors to suggest that
this finding may have resulted from the additional
burden of skin disease in the PsA patients [26]. In a
separate study, PsA patients reported more limitations
because of emotional problems than a comparison
group of RA patients [27]. This finding is consistent
with the psychosocial disability that has been
reported in connection with psoriasis [28].
In most patients (70%), arthritis symptoms de-
velop years after skin changes present. In 10% to
15%, arthritis precedes psoriasis, yet a significant
family history of psoriasis may help in making the
diagnosis. In 15% of patients the initial presentation
includes arthritis and psoriasis together [11,14]. The
correlation between skin disease and arthritis is
limited; only 35% of patients with PsA note a re-
lationship between the severity of their skin disease
E.M. Ruderman, S. Tambar / Dermatol Clin 22 (2004) 477–486480
and joint activity [14]. With respect to predictors of
future arthritis in patients with isolated psoriasis, nail
involvement is the only clinical feature that identifies
patients with psoriasis who are likely to develop
arthritis [15]. In fact, nail involvement is found in
80% of patients with PsA [29]. Moreover, the only
significant relationship shown between severity of
arthritis and psoriasis has been DIP joint activity and
nail involvement [30].
Disease pathogenesis
The pathogenesis of PsA is unknown, but genetic,
environmental, and immunologic factors all seem
to influence disease susceptibility. Forty percent of
patients with psoriasis or PsA have a first-degree rela-
tive with disease [29]. Individual HLA antigens, found
on the short arm of chromosome 6, have been asso-
ciated with PsA, and may be involved in antigen pre-
sentation, or they may be in linkage disequilibrium
with another disease susceptibility gene. HLA anti-
gens B13, B17, B38, B39, B27, Cw*0602, DR4, and
DR7 have been implicated [29,31,32]. HLA-B7 and
HLA-B27 are found more commonly in patients with
PsA compared with patients with isolated skin pso-
riasis [29]. HLA-B27 itself is actually more common
in the other seronegative spondyloarthropathies, how-
ever, and is only found in approximately 40% of
patients with PsA. HLA-DR4, which is strongly
associated with RA, is also associated with the poly-
articular form of PsA [29]. HLA-B39, -B27, and
-DQw3 have been reported to be associated with
disease progression [33]. Genetic inheritance of genes
other than HLA antigens also may be important. A
separate gene locus on chromosome 16 has also been
associated with PsA, with inheritance from the father
being more strongly associated with developing the
condition when compared with inheritance from the
mother of the same allele [34].
Just as with the inflammatory response seen in
psoriatic skin lesions, immunologic factors have been
implicated within the joint spaces in PsA. T cells
found in plasma and synovium are predominantly
CD8+ cells and are activated, expressing HLA-DR
molecules and interleukin (IL)-2 receptors [35].
These activated cells also secrete multiple proinflam-
matory cytokines and within the synovium there are
elevated levels of tumor necrosis factor (TNF)-a,IL-1, IL-2, and the anti-inflammatory cytokine
IL-10 [36]. The overall milieu results in proliferation
and activation of synovial and epidermal fibroblasts.
At the same time there are increased numbers of
osteoclast precursors, resulting in osteoclastogenesis
and bony erosions [37].
Environmental factors are also believed to play a
role in pathogenesis of PsA. An infectious etiology
has been proposed. Elevated levels of IgG antibody to
the C-terminal of Streptococcus pyogenes M protein
have been found compared with patients with only
skin psoriasis, RA, and controls [38]. Exacerbations
of both psoriasis and PsA have been reported in the
context of HIV infection; however, the viral role in
this situation is not clear [39]. Trauma may also be
involved, similar to the Koebner phenomenon in
which patients may develop psoriasis at site of pre-
vious trauma. Some patients with PsA have reported
a history of trauma before the onset of their dis-
ease [40].
Treatment
Treatment of PsA has generally been similar to
treatment of other types of inflammatory arthritis,
including RA. Physical therapy and other nonmedical
treatments may be useful. Nonsteroidal anti-inflam-
matory drugs have been shown to be effective in PsA
[41,42]. Some authors have raised concern that non-
steroidal anti-inflammatory drugs may exacerbate the
associated skin disease [43,44]. Corticosteroids are
also used, although again there is some concern over
exacerbation of skin disease, particularly after with-
drawal of relatively short courses, and concern that
corticosteroids may cause the skin disease to become
resistant to other therapies [2,44]. Other authors have
suggested that the use of corticosteroids may be an
important risk for the development of PsA in a patient
with psoriasis [45].
Historically, the management of PsA unresponsive
to anti-inflammatory therapy has borrowed from the
disease-modifying antirheumatic drugs commonly
used to treat RA. Injectable gold salts, although
infrequently used at the present time, were one of
the earliest second-line therapies for RA, and clinical
benefit from the use of these agents in PsA has been
reported [46–48]. Similar to the experience in RA,
auranofin, the oral form of gold, seems to be less
effective than the parenteral forms, although it may
be better tolerated [48,49]. Hydroxychloroquine and
other antimalarials have been reported to be effective
in PsA in uncontrolled series, although hydroxy-
chloroquine has been reported to exacerbate skin
disease in some cases [50].
A meta-analysis of 12 clinical trials of various
medications for PsA found statistical benefit relative
to placebo only for intravenous methotrexate, sulfa-
Box 4. American College of Rheumatologyresponse criteria
Both
20% improvement in tender-jointcount
20% improvement in swollen-jointcount
Plus 20% improvement in three of five ofthe following criteria
Patient pain assessment (100 mm vi-sual analog scale)
Patient global assessment (100 mm vi-sual analog scale)
Physician global assessment (100 mmvisual analog scale)
Patient self-assessed function (HealthAssessment Questionnaire or similarinstrument)
Acute-phase reactant value (erythro-cyte sedimentation rate or C-reac-tive protein)
E.M. Ruderman, S. Tambar / Dermatol Clin 22 (2004) 477–486 481
salazine, azathioprine, and etretinate, although study-
related issues limited the interpretation of the results
of the last two [51]. The authors noted a significant
placebo response in all 12 trials, and suggested that
this limits the ability of uncontrolled trials to guide
treatment decisions in PsA.
Despite the issue of placebo response, anecdotal
reports and open series may provide a clue to the
value of a particular therapy by using a variety of
measurements of disease activity. Controlled clinical
trials, however, require predetermined end points,
generally including defined response criteria. The Pso-
riatic Arthritis Response Criteria (PsARC) (Box 3),
developed for use in clinical trials of sulfasalazine, in-
cludes measurements of tender and swollen joints,
and patient and physician assessments of disease
activity [52]. The American College of Rheuma-
tology (ACR) response criteria includes these same
measurements, and adds the elements of pain, func-
tional assessment, and acute-phase reactant levels
(Box 4) [53]. An ACR-20 response indicates 20%
improvement in these measurements of disease activ-
ity. ACR-50 and ACR-70 responses, respectively,
indicate 50% and 70% improvement. Although the
ACR response criteria have been used to evaluate
treatment response in PsA, some have raised concern
that these response criteria may be less reliable in this
disease because of the generally lower sedimentation
rates and lower joint counts. Efforts are currently
underway to develop and validate disease-specific
response criteria in PsA.
Sulfasalazine, originally developed some 50 years
ago for use in treating RA, has been demonstrated
in controlled trials to be effective in PsA. Using the
PsARC, sulfasalazine, 2 g/d, was shown to be statis-
tically more effective than placebo in a multicenter
Box 3. Psoriatic arthritis response criteria
Improvement in at least two of fourcriteria, one of which must be tender- orswollen-joint score
Physician global assessment (� 1 uniton a scale of 0 to 5)
Patient global assessment (� 1 unit ona scale of 0 to 5)
Tender-joint score (� 30%)Swollen-joint score (� 30%)
PlusNo worsening in any criterion
trial in 221 patients [52]. In this same group of pa-
tients, the drug was shown to be more effective for
the management of peripheral arthritis than for axial
disease [54]. In a separate placebo-controlled study of
sulfasalazine, 3 g/d, in 351 patients with spondyloar-
thropathies, the drug was found to be particularly
effective in the subset of patients with PsA [55].
Cyclosporine, frequently used in the treatment of
psoriasis, has been evaluated in the treatment of PsA,
although there are no published double-blind studies
with this agent. Early series described the use of
relatively high doses of cyclosporine, up to 6 mg/kg/d
[56,57]. More recent studies have used lower doses to
reduce toxicity [58,59]. In a prospective, open study
of cyclosporine for psoriasis and PsA, the drug was
clearly more effective for skin disease than for joint
symptoms [58]. A 50% reduction in skin involvement
was achieved within 5 to 6 weeks of initiation of
therapy, whereas a 50% reduction in joint symptoms
took 24 weeks. A prospective, open 1-year compari-
son of cyclosporine and methotrexate for the treat-
ment of PsA demonstrated improvement in multiple
measurements of joint disease activity for both
compounds [60]. Cyclosporine was initially dosed
at 3 mg/kg/d in this trial, then raised as necessary to a
maximum of 5 mg/kg/d; the comparable dose range
E.M. Ruderman, S. Tambar / Dermatol Clin 22 (2004) 477–486482
for methotrexate was 7.5 to 15 mg/wk. In a 24-week
prospective, open study, cyclosporine, 3 mg/kg/d,
was statistically more effective than sulfasalazine,
2 g/d, in reducing pain, the primary end point [59].
Methotrexate, another drug frequently used to
treat psoriasis, was reported to be effective as a par-
enteral therapy for PsA as early as 1964 [61]. A
retrospective analysis of 59 patients treated for up to
11 years with weekly low-dose methotrexate (initially
15 mg/wk) reported response in 43 patients that was
unrelated to the initial severity of disease [62]. The
only placebo-controlled, blinded study of low-dose,
oral methotrexate for the treatment of PsA was
published in 1984, and included 37 patients with
active arthritis that could not be treated successfully
with aspirin or nonsteroidal anti-inflammatory drugs
[63]. Although a variety of arthritis assessments were
evaluated, including grip strength, morning stiffness,
and joint counts, the only variable that statistically
improved compared with placebo was the physician
global assessment [63].
Etretinate, also used to treat psoriatic skin disease,
has been investigated as a therapy for PsA [64,65].
One open-label trial treated 40 patients for up to
24 weeks with etretinate, 50 mg/d, reducing the dose
to 25 mg daily when necessary because of side effects
[65]. Significant improvements were seen in all
measurements of PsA disease activity. Thirty-nine
of the 40 patients had mucocutaneous side effects,
however, including nine in whom these side effects
resulted in discontinuation of therapy. Such toxicity
has limited the acceptance of etretinate as a therapy
for PsA.
Finally, leflunomide, the most recently introduced
antimetabolite for the treatment of RA, has been ex-
amined in PsA [66,67]. This drug, a pyrimidine
synthesis inhibitor, is believed to work by selectively
reducing activated inflammatory cells, particularly
T cells, in inflamed joints. A placebo-controlled study
demonstrated a modest response rate of 58% in the
leflunomide group compared with 38.5% in the
placebo group (again highlighting the placebo re-
sponse in this disease) [67]. There was also a statis-
tically significant improvement in skin lesions in
the leflunomide group. The discontinuation rate was
quite high for both groups in this 24-week study.
In addition to potential differences in efficacy,
there are potential differences in toxicity that must
be evaluated before applying RA therapy to PsA.
This is highlighted in a recently published review that
examined and compared disease-modifying antirheu-
matic drugs treatment courses in disease-modifying
antirheumatic drugs in 104 patients with PsA and
102 patients with RA [68]. Agents used included
parenteral gold, methotrexate, and sulfasalazine.
Patients were treated longer for RA with both gold
and methotrexate (35 versus 12 months and 72 versus
12 months, respectively), whereas the treatment
course for sulfasalazine in PsA was slightly longer
(17 versus 12 months). Although the results did not
show a difference in efficacy for the three drugs in
these two diseases, toxicity was seen more frequently
among the PsA patients. Rash and hematologic dis-
orders were the most common toxicities leading to
discontinuation of therapy in PsA patients treated
with gold, whereas elevated serum transaminases,
hematologic disorders, and infections were the most
common reasons in the methotrexate-treated patients.
The authors comment that these differences in toxic-
ity may limit the applicability of RA therapies to
patients with PsA [68].
Biologic response modifiers
The perceived imbalance between efficacy and
toxicity may be one of the factors that have limited
the widespread use of second-line agents in PsA. Bio-
logic response modifiers may hold the key to revers-
ing this imbalance. Recent studies have demonstrated
both clinical and radiographic improvement in RA
with compounds that block the biologic activity of
TNF-a [69–72]. Experimental evidence has sug-
gested that TNF-a also may play an important role
in the pathogenesis of PsA [36,73]. These findings,
coupled with the clinical experience in RA, have led
to trials of TNF-a antagonists in PsA.
Infliximab, a chimeric monoclonal antibody di-
rected against TNF-a, has been studied as a therapy
for PsA in several small open-label treatment studies
[74–76], and in a larger placebo-controlled trial [77].
A placebo-controlled study of infliximab in 40 pa-
tients with spondyloarthropathies included 13 with
PsA [78]. Regimens studied with this intravenously
administered agent have included loading doses at 0,
2, and 6 weeks, followed by repeated doses every
8 weeks. Doses have ranged from the 3 mg/kg dose
commonly used as the initial dose in RA to 5 mg/kg,
the dose used for the treatment of Crohn’s disease and
ankylosing spondylitis [74,76,78].
Results in all of these studies have been encour-
aging. More than half of the patients in two of the
open-label trials achieved an ACR-70 response after
the loading doses and maintained this response with
ongoing treatment [75,76]. In the spondyloar-
thropathy trial, the primary end points of patient
and physician assessment on a visual analog scale
improved significantly in the treatment group, where-
E.M. Ruderman, S. Tambar / Dermatol Clin 22 (2004) 477–486 483
as the placebo group remained unchanged [78].
Results were seen as early as 2 weeks, and main-
tained through 12 weeks in this short study.
A recently reported double-blind, placebo-con-
trolled trial of infliximab in PsA included 102 patients
with active disease (more than five actively inflamed
joints) [77]. Patients were randomized to receive
5 mg/kg of infliximab or placebo at 0, 2, and 6 weeks,
and then every 8 weeks thereafter. Background ther-
apy with second-line agents, including methotrexate,
was allowed, as was therapy with nonsteroidal anti-
inflammatory drugs and less than 10 mg of pred-
nisone, but the doses were to remain stable. At
16 weeks, the percentage of patients achieving an
ACR-20, -50, and -70 was 69%, 49%, and 29%,
respectively. Only 8% of the placebo-treated patients
achieved an ACR-20, and none reached a higher level
of response. The presence or type of background
therapy did not influence response. Infliximab is
typically used in combination with methotrexate in
the therapy of RA; the addition of methotrexate
seems both to increase efficacy and decrease toxicity
[79,80]. The necessity of combination therapy with
methotrexate in PsA has yet to be determined.
Etanercept is a recombinant fusion protein com-
bining the extracellular portions of two p75 TNF
receptors with the Fc fragment of a human IgG1. This
TNF-a antagonist has been studied for the treatment
of PsA in two placebo-controlled trials [81]. In a
small, single center trial, 60 patients with PsA were
randomized to receive etanercept, 25 mg twice-
weekly (N = 30), or placebo (N = 30) [81]. End
points included the PsARC and the ACR20. After
12 weeks of treatment, 87% of the patients in the
etanercept group met the PsARC compared with 23%
of the patients in the placebo group. An ACR20 was
achieved by 73% of the patients in the etanercept
group compared with 13% in the placebo group.
The results of the single center trial were corrobo-
rated in a large, multicenter trial of etanercept, which
enrolled 205 patients with PsA. In this study, 59% of
etanercept-treated patients achieved an ACR-20 at
12 weeks compared with 15% of placebo-treated
patients. An ACR-50 was achieved by 38% of the
etanercept-treated patients and an ACR-70 by 11%
[82]. This trial also demonstrated that radiographic
progression in the treated group was significantly
reduced when compared with placebo [83]. As in
treatment for RA, the most common treatment-related
adverse events seen with etanercept therapy for PsA
have been injection site reactions.
On the basis of these data, etanercept has become
the first biologic agent approved in the United States
for the treatment of PsA. Registry trials for infliximab
and adalimumab, a fully human anti-TNF antibody
approved for treatment of RA, are currently under-
way. Concern has been raised in clinical practice
about the potential increased risk for infection that
may accompany TNF inhibition, including bacterial
infections and opportunistic and atypical infections,
such as tuberculosis [84–86]. PPD screening before
the initiation of treatment and appropriate vigilance
during treatment are important elements of therapy
with these agents.
Other biologic response modifiers are being stud-
ied in psoriasis and PsA. Alefacept, which modulates
T-cell response by blockade of the IL-2 receptor, has
shown promising results in the treatment of plaque
psoriasis. A small pilot study in PsA has shown that
alefacept improves clinical joint score along with skin
disease [87].
Summary
Psoriatic arthritis is increasingly perceived as a
common disease that causes progressive joint damage
and disability. With earlier recognition and diagnosis,
clinicians have the chance to intervene before signifi-
cant permanent damage has occurred, reducing long-
term disability and enhancing quality of life. With
skin disease typically developing much earlier than
joint disease, dermatologists can play a key role in
identifying the onset of PsA. Dermatologists will
frequently be the first physicians to recognize a
diagnosis of PsA and will need to work closely with
rheumatologists to establish the diagnosis and select
treatments that will address both the skin and the joint
disease. Cooperative management, with input from
both specialties, will result in the most efficient and
effective care for both the skin and joint manifesta-
tions of this disease.
Newer therapeutic agents, such as the TNF-aantagonists and other biologic response modifiers,
offer the potential for improved efficacy without
some of the toxicities that have limited traditional
therapies. However, these agents are not for all
patients. As with the use of these agents in psoriatic
skin disease, the financial cost of these agents is high.
Patients with mild joint symptoms or only a few
involved joints may not require biologic agents to
manage their arthritis, sparing them both the cost and
the potential toxicity. On the other hand, those with
aggressive, destructive disease would benefit from
effective treatment before they develop permanent
joint damage. Ongoing research into the epidemi-
ology and outcomes of PsA can provide insight into
the patient characteristics, such as multiple involved
E.M. Ruderman, S. Tambar / Dermatol Clin 22 (2004) 477–486484
joints, that may be indicators of poor outcomes.
Appropriate patient selection will be critical to ensure
that resources are used wisely on patients who will
benefit, and that those who would benefit the most
are treated appropriately.
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Dermatol Clin 22 (2004) 487–492
Practical considerations in future psoriasis therapies
Christy Riddle, MDa, Melodie Young, MSN, RNb,c,*, Alan Menter, MDa,c
aDepartment of Internal Medicine, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USAbGraduate School of Nursing, The University of Texas at Arlington, Arlington, TX, USA
cTexas Dermatology Associates, 5310 Harvest Hill Road, Suite 260, Dallas, TX 75230, USA
Revolutionary new therapies for psoriasis are psoriasis experts have collaborated to develop bio-
likely to allow dermatologists, even those who con-
sider themselves nonpsoriasis experts, the ability to
provide more targeted treatments that can offer a
significant number of patients the ability to reclaim
their lives. This new frontier in therapy significantly
broadens the choices dermatologists and their patients
have available from which to choose. For decades,
psoriasis therapy has been limited to Goeckerman
treatment, phototherapy, and several systemic drugs
that although effective are limited by toxicities that
frequently precluded long-term maintenance therapy.
It is hoped that the introduction of these new biologic
drugs allows dermatologists to share in the excitement
and enter the psoriasis therapy arena. For the pa-
tient, this means wider access and potentially fewer
risks. As discussed elsewhere in this issue, psoriasis
researchers, pharmaceutical companies, and front-line
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/S0733-8635(03)00128-1
Alan Menter has the following conflicts of interest: (1)
research: Abbott, Allergan, Allermed, Amgen, Astralis, Bio-
gen, Centocor, Connetics, Corixa, Dermik, Dow, Ferndale,
Fujisawa, Galderma, Genzyme, GlaxoSmithKline, Inamed,
Lumenis, Medicis, Novartis, Otsuka, Photocure, Regenera-
tio, Pharma AG, Scirex, Serono, Thermosurgery; and (2) con-
sultancies and honoraria: Allergan, Amgen, Biogen,
Centocor, Genentech, ICN, Novartis, Serono, Thermosur-
gery, Warner-Chilcott. No stock ownership.
Melodie Young has the following conflicts of interest:
Nurse Advisory Boards for Biogen, Fujisawa, and Genen-
tech. Presentations for Allergan, Amgen, Biogen, Fujisawa,
Genentech, Healthpoint, and ICN.
* Corresponding author. Texas Dermatology Associ-
ates, 5310 Harvest Hill Road, Suite 260, Dallas, TX 75230.
E-mail address: [email protected] (M. Young).
logic therapies that directly target specific steps in the
immunopathologic process of psoriasis and other
immune-mediated diseases. Fortuitously, the side ef-
fects and cumulative toxicities in the short-term at
least seem to be less burdensome than those of the
traditional workhorses of psoriasis (ie, methotrexate,
cyclosporine, retinoids, and psoralen plus UVA).
Critical in this revolution is the recognition by the
dermatologist of the value in assisting the psoriasis
sufferer in assessing the impact of this disease on his
or her quality of life. Pain and suffering are obviously
subjective characteristics of any chronic debilitating
disease that do not always correlate with the objective
severity gauged by the treating physician. There are
now validated tools for psoriasis patients to measure
their deficiencies, both physical and emotional [1].
Improvement in individualizing therapy depends on
having the clinician evaluate the impact of psoriasis
on the patient’s quality of life and the value of having
the patient also recognize the physical and emotional
impact or damage sustained from living with psoria-
sis. The Koo-Menter Psoriasis Index (KMPI) is a tool
requiring the input of both the patient and the
clinician and encourages changing the paradigm
whereby a clinician alone decides what is best or
having a patient deny the quality of life issues
inherent in psoriasis and its treatment. This index
provides guidance in deciding on a patient’s eligibil-
ity for a systemic treatment. It legitimizes the
patients’ quality of life concerns, their joint symp-
tomatology, and degree of psoriasis involvement,
thereby allowing the clinician to determine if more
aggressive therapies are warranted. Like rheumatolo-
gists, gastroenterologists, and neurologists who have
had access to new technologic therapies over the past
s reserved.
C. Riddle et al / Dermatol Clin 22 (2004) 487–492488
10 years, dermatologists now have the opportunity to
offer psoriasis patients the hope of clearer skin and
the encouragement of looking forward to a brighter
outlook on life.
This article discusses practical issues that allow
dermatologists the ability to implement the expanding
psoriasis armamentarium into their practices. Individ-
ual dermatologists are faced with an internet-savvy
patient population who will no doubt have many
questions about the new therapies. The increasing
use of direct-to-consumer marketing tools by phar-
maceutical companies also increases patient aware-
ness and interest in biologics. Because the authors
earnestly believe the correct therapy can help psori-
asis patients reclaim their lives, they outline the steps
necessary to integrate these new therapies into busy
dermatology practices. Each practice must decide the
extent to which it will offer currently available and
future systemic and biologic therapies based on
patient demand, support staff, available space, and
the economic considerations unique to that office.
Table 1
Biologics pending approval or currently available for moderate to
Product Approval status Administration
Alefacept Approved for moderate
to severe psoriasis
IM 15 mg each
week for 12 doses,
in-office
Efalizumab Approved for moderate
to severe plaque
psoriasis
1 mg/kg weekly
subcutaneous injection
by the patient
Etanercept Approved for juvenile
and adult rheumatoid
and psoriatic arthritis
and ankylosing
spondylitis, approval
for moderate to severe
plaque psoriasis
imminent
25–50 mg
subcutaneous by the
patient twice weekly
Infliximab Approved for Crohn’s
disease and rheumatoid
arthritis
5 mg/kg IV infusion
in-office at weeks
0, 2, 6, and q
8 weeks thereafter
Adalimumab Approved for
rheumatoid arthritis
40 mg every other
week subcutaneous
Abbreviations: CNS, central nervous system; PASI, Psoriasis Area
Data from Psoriasis for the clinician: a new therapeutics era (the ‘
The available armamentarium
Now and over the next few years, more and more
biologics will be introduced for moderate to severe
plaque psoriasis. The science, clinical efficacy, and
side effect profiles of each of these drugs have been
discussed in detail elsewhere in this issue. This arti-
cle addresses information related to the practical as-
pects of their use. Already approved is alefacept
(Amevive), which is administered in-office only by
the intramuscular injection (IM) route. Efalizumab
(Raptiva) given by subcutaneous weekly injection
was approved at the end of 2003 for treatment of
moderate to severe psoriasis. Biologics available for
other indications but not yet approved for psoriasis
are the tumor necrosis factor-a (TNF-a) antagonistdrugs etanercept (Enbrel), infliximab (Remicade), and
adalimumab (Humira). Enbrel is a subcutaneously
self-administered biologic, currently approved for
psoriatic arthritis, rheumatoid arthritis, juvenile rheu-
matoid arthritis, and ankylosing spondylitis, but ex-
severe plaque psoriasis
Short-term efficacy data Monitoring and side effects
33% obtained PASI
75 at 14 weeks
CD4+ counts weekly
while dosing; chills
s
28% obtained PASI
75 at wk 12
Monitor platelets, flu-like
symptoms, rebound
34% obtained PASI
75 at 12 wk
Optional laboratory
monitoring, injection site
reactions, CNS symptoms
and infections
88% obtained PASI
75 at wk 10
TB testing; VS and infection
monitoring pre-, during, and
postinjection; premedica-
tion: acetaminophen, diphen-
hydramine, and prednisone
53% obtained PASI
75 at week 12
As for above 2 TNF-a agents
and Severity Index; TB, tuberculosis; VS, vital signs.
‘biologics’’) beckons. J Am Acad Dermatol 2003;49.
C. Riddle et al / Dermatol Clin 22 (2004) 487–492 489
pecting an indication for plaque psoriasis in 2004.
Infliximab (Remicade) is currently indicated in the
treatment of Crohn’s disease and rheumatoid arthritis
and is administered as an in-office intravenous (IV)
infusion. Adalimumab (Humira) is another subcuta-
neously self-administered TNF-a monoclonal anti-
body approved for rheumatoid arthritis. Both of
these latter drugs are in phase two and three develop-
ment for psoriasis and psoriatic arthritis. Table 1 pro-
vides a summary of the available injectable biologics.
Other systemic therapies under development for
psoriasis include oral pimecrolimus (Elidel) and oral
tazarotene (Tazorac), both familiar to dermatologists
as topical agents used for atopic dermatitis, acne,
and psoriasis.
Staffing requirements
Dermatology nurses in most dermatologic prac-
tices already are familiar with injectable medications,
such as triamcinolone and methotrexate. The addition
of subcutaneously and intramuscularly administered
biologics, such as alefacept, efalizumab, etanercept,
and adalimumab, necessitates only a small amount
of change in the nursing role. Because etanercept,
efalizumab, and adalimumab may be self-injected
each week by the patient, the nurse provides counsel-
ing and instruction at the beginning of treatment and
then assists in managing patients between office visits.
The technique for reconstituting and self-injecting
medications is precise and requires all staff interact-
ing with patients to have extensive training in these
procedures. Thereafter, the nurse is available to an-
swer questions and dispense medications on subse-
Table 2
Suggested codes for biologic therapy
Function Code Allowable
Nurse only CPT 99211 $20–$25 per
Subcutaneous or
intramuscular injection
CPT 90782 $5–$7 per in
Venipuncture CPT 36415 $4–$5
CD4+ evaluation Lab code 83681 $20–$30
IV push CPT 90784 $23
IV infusion up to 1 h CPT code 90780 $45
IV infusion for each
additional h
CPT code 90781 $23
Infliximab J1745 $65.70 per un
Unclassified drugs
for Medicare
J3490 $875 per vial
Unclassified drugs
non-Medicare
J3590 Variable
quent office visits. For IM alefacept, the patient
requires weekly visits with the nurse for drawing
laboratories and drug administration. Registered
nurses (RNs), licensed vocational nurses, and some
medical assistants are trained in IM administration
techniques and can inject IM alefacept. The nurse or
allied health professional monitors the alefacept in-
ventory, procures the drugs from the pharmaceutical
company or contracted pharmacy, and schedules
patients accordingly.
Coding and billing for subcutaneous and IM in-
jectables is consistent with 99,211 level visits ($20 to
$25) if the patient only interacts with a nurse. The
actual injection procedure is billed as Current Proce-
dural Terminology (CPT) code 90,782 ($5 to $7).
Reimbursement for medication obtained from con-
tracted pharmacies or distributors is billed by the
appropriate J-code [2]. Phlebotomy and laboratory
codes may also apply 36,415 ($4 to $5) for venipunc-
ture and 86361 ($20 to $30) for CD4+ evaluation.
Refer to Table 2 for the recommended code use.
Because most dermatology practices do not em-
ployee RNs, starting an infusion center to administer
IV therapies requires the greatest amount of change
in the practice. Qualified staff has to be hired and
trained. Other changes include developing space, ob-
taining necessary equipment, and safety considera-
tions. A RN with infusion therapy experience and
fully trained in the management of potential side ef-
fects becomes a central and irreplaceable part of the
team. His or her role includes procurement of the
drug, patient education, obtaining informed consent,
IV access, documentation, laboratory review, drug
administration, and multiple patient assessments. For-
tunately, codes for reimbursement of these RN ser-
Description
visit Evaluation and teaching
jection If administered by nursing staff
Blood draw
Laboratories obtained and billed from practice
IV administration of a drug, may include access
IV access and administration of a drug
Continuous infusion beyond the first hour
it 10 units per vial
Total per dose
Reimbursed per third-party contract with
each practice
C. Riddle et al / Dermatol Clin 22 (2004) 487–492490
vices are available, but the degree to which they are
covered differs between third-party payers and from
state to state. Billing for IV infusion uses E, M, J,
and CPT codes. CPT level 90,784 level ($21) IV
push or the 90,780 level ($45) up to 1 hour and
90,781 for each additional hour depending on time
requirements for the procedure. When billing for
infliximab, use code J1745 with a Medicare reim-
bursement allowable rate of $65.70 per unit. For
alefacept or other ‘‘unclassified drugs,’’ code J3490
with a Medicare reimbursement allowable of $875 per
vial. For non-Medicare claims for alefacept, code
J34590 with reimbursement varying dependent on
the third-party contract (see Table 2).
Space considerations depend on the individual
office, but a private area with an infusion chair,
writing and work surface, and stool are essential. If
an extra examination room is available it may be
converted easily to an infusion room for daily or
perhaps only once-weekly use, depending on patient
volume. A licensed medical doctor must always be
present when performing infusions.
Infliximab infusions mandate additional changes.
The infusion time for this particular biologic runs
from 1.5 to 3 hours. The patient must also be moni-
tored for an hour afterward for postinfusion reactions.
At least one RN must be present to infuse and monitor
the patients, but a medical assistant or licensed voca-
tional nurse can assist with preparation and monitor-
ing of more than one patient. Also necessary is a
Fig. 1. Tiers of psorias
medical doctor immediately available for evaluation
and management. Advanced cardiac life-support
training is not mandatory, but is encouraged, and each
physician must weigh risks and benefits and malprac-
tice-related issues of advanced cardiac life-support
training. At a minimum, the office must be able to pro-
vide oxygen therapy, diphenhydramine, epinephrine,
and steroids to patients having an infusion reaction. In
this regard, other medicine and surgical subspecialties
have readily embraced these issues and offer derma-
tologists a great deal of published data to simplify this
process [3–5].
Several options are recommended for infusion
space configuration. The best arrangement depends
on the level of psoriasis care each practice wishes to
provide. If feasibility and volume dictate, additional
office space adjacent to the main office can be leased
and remodeled into a freestanding infusion center.
Space dedicated for waiting, reception, charts, and
infusion cubicles requires about 500 to 1000 sq ft.
Fortunately, most committed dermatologists and other
specialists have been able to work within the frame-
work of their existing space or otherwise using a
much smaller amount of space. An 8-ft by 8-ft stall
with one wall curtained satisfies the Health Informa-
tion Portability and Accountability Act guidelines
for patient privacy and allows easy nursing access.
Furniture, a telephone system, computer and monitor-
ing equipment, crash cart, oxygen, and pulse oximeter
are the necessary equipment. Besides the RN with
is care providers.
C. Riddle et al / Dermatol Clin 22 (2004) 487–492 491
Advanced Cardiac Life Support Qualifications, a re-
ceptionist and an infusion billing specialist comprise
the staff [2]. Again, depending on the volume of
patients treated, they may be either full time with
the infusion center or shared with the general derma-
tology practice.
Because so many options are becoming available,
dermatologists have choices to make about the level
of psoriasis care to provide. Many of these newly
indicated drugs can be integrated easily into already
busy practices with only minimal changes in staff
and space. The authors foresee several tiers of pso-
riasis care based on services offered (Fig. 1). The
highest level is a psoriasis center of excellence similar
to the dedicated psoriasis day care centers of the 80s
and 90s. Currently, there are only a handful of centers
in the United States that truly offer expert medical
and nursing care, cutting edge therapy, clinical re-
search, and the full spectrum of traditional modalities
of systemic agents and phototherapy. At these cen-
ters, psoriasis patients have been receiving psoralen
plus UVA or narrow-band phototherapy; systemics,
such as methotrexate, cyclosporine, and etretinate;
second-tier drugs, such as hydroxyurea, 6-thiogua-
nine, and mycophenolate mofetil; and the new bio-
logics. These centers are likewise involved in clinical
trials with biologics seeking psoriasis and psoriatic
arthritis indications. They also may be in trials for
oral pimecrolimus, tazarotene, or other psoriasis ther-
apies, and are intimately involved with patient edu-
cation and advocacy with the National Psoriasis
Foundation and the American Academy of Derma-
tology in physician education. Reaching this level of
excellence requires time, staff, and space dedication
for phototherapy units, an infusion center, patient
education areas, and clinical research.
The next tier, with a lesser expenditure of re-
sources than the center of excellence, is known as a
‘‘psoriasis specialty clinic.’’ This resource allows for
some UV and systemic therapy and biologics, but not
necessarily at the comprehensive scope of the top
tier centers. This is very feasible for medically
oriented dermatologists who wish to take more ini-
tiative in treating their psoriasis patients with moder-
ate to severe disease. In some areas, they are the
referral center for physicians with limited expertise
and interest.
The medical dermatologist who does not wish
routinely to tackle the treatment of severe or moder-
ately affected psoriatic patients makes up the next tier
of care. This level of service provides limited treat-
ment options and does not invest resources in photo-
therapy or extensive offering of all available therapies.
For example, in this third tier, patients may receive the
option of methotrexate or a self-administered biologic,
which requires very little change in practice. It is
hoped that patients will be made aware of the new
sophisticated biologic therapies and provided appro-
priate information, such as literature, web sites, and
National Psoriasis Foundation referrals. Education
and training of staff on the use, effects, provision,
and billing of the new medication is, as in the prior
two tiers, undertaken at this level. The final tier and
the one least likely to provide a range of therapeutic
options for moderate to severe psoriasis is the general
community dermatologist or surgically oriented der-
matologist whose interests lie elsewhere within der-
matology. These physicians likely refer to a colleague
who has the interest, staff, and facilities to offer more
options, expertise, and quality of care to their patients.
Summary
This is an exciting time to be in dermatology, both
medical and nursing, especially for those interested in
helping to change the lives of psoriasis patients. For
too long the pace of new treatment modalities has
crept along with few breakthroughs and minimal
industry support. Now, as biologic therapy becomes
a major focus of research and approval of new drugs
gathers speed, dermatology is challenged to maintain
and even regain its standing in the medical subspe-
cialty arena. For a significant number of psoriasis
patients with recalcitrant disease (not just a tiny
minority) this means fresh hope that sophisticated
new therapies will provide a better quality of life with
potentially fewer side effects than the traditional
weapons. Dermatologists who previously did not
consider themselves psoriasis ‘‘experts’’ but who care
about making a significant difference in patients’
lives now have the opportunity to treat patients they
once referred effectively and safely in their own
offices. This revolution in psoriasis therapy is a chal-
lenging one for the specialty but it is hoped it is one
in which both patients and physicians win qualita-
tively and intellectually.
References
[1] Koo J, Menter A. The Koo-Menter psoriasis instrument
for identifying candidate patients for systemic therapy.
Psoriasis Forum, Summer 2003. p. 6–9.
[2] Craze M, Young M. Integrating biologic therapies into
a dermatology practice: practical and economic consid-
erations. J Am Acad Dermatol 2003;49:S139–42.
C. Riddle et al / Dermatol Clin 22 (2004) 487–492492
[3] Chaudhari U, Romano P, Mulcahy LD, Dooley LT,
Baker DG, Gottlieb AB. Efficacy and safety of inflixi-
mab monotherapy for plaque-type psoriasis: a random-
ized trial. Lancet 2001;357:1842–7.
[4] Lipsky PE, Van der Heijde D, St. Clair W, Furst DE,
Breedveld FC, Kalden JR, et al. Infliximab and metho-
trexate in the treatment of rheumatoid arthritis. N Engl J
Med 2000;343:1594–602.
[5] Cheifetz A, Smedley M, Martin S, Reiter M, Leone G,
Mayer L, et al. The incidence and management of infu-
sion reactions to infliximab: a large center experience.
Am J Gastroenterol 2003;98:1315–24.
Dermatol Clin 22 (2004) 493–499
Psoriasis: future research needs and goals for the
twenty-first century
Christopher E.M. Griffiths, MD, FRCP
The Dermatology Centre, Hope Hospital, Irving Building, Salford, Manchester M6 8HD, UK
Most dermatologists are still involved with the Epidemiology
management of patients with psoriasis. Despite its
ubiquitous presence in outpatient clinics and mo-
nopoly of dwindling inpatient resources, psoriasis
remains an enigma. Few studies have accurately
addressed the prevalence and epidemiology of pso-
riasis outside secondary care. Molecular genetics in-
dicate what has been suspected for some time in that
clinicians are dealing with a continuum of ‘‘psoria-
sis’’ with similar phenotypes. Although no genes that
are specific for psoriasis have been identified it is
only a matter of time before a gene mutation is iden-
tified, perhaps leading to development of an animal
model faithful to the histologic, immunologic, and
clinical features of the disease.
The explosion in new therapies under trial for
psoriasis is a direct consequence of advances in the
understanding of the key pathogenic pathways in
psoriasis. Components of these pathways can be tar-
geted selectively by biologic agents. Despite such
progress clinicians are held back by lack of a good
evidence base for efficacy in that many of the thera-
pies for psoriasis are hindered by paucity of consen-
sus on clinically relevant outcome measures.
This article, inevitably speculative, part philo-
sophic, discusses what I believe are the future needs
in psoriasis research and how achievement of these
goals should lead to a greater understanding of, and
better therapy for, this disease (Table 1).
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/j.det.2003.12.001
E-mail address: [email protected]
Surprisingly, there are few comprehensive epide-
miologic studies of chronic plaque psoriasis. In
Europe and the United States the oft-quoted preva-
lence is 2% of the population [1] with caveats that
Northern Europe (ie, Scandinavia [2]) has a higher
prevalence than Southern Europe and that in China
psoriasis is rarer [3]. In the United Kingdom epide-
miologic surveys are confounded by the fact that not
all people with psoriasis seek medical help and that
only a minority of cases is seen by dermatologists. A
national survey, perhaps along the lines of a census, is
required to examine accurately the prevalence, pref-
erably on a regional basis, but this is dependent on
clinical examination of alleged sufferers. Often peo-
ple who are told they have psoriasis are shown sub-
sequently to have other skin disorders, such as
discoid eczema, dermatitis, and seborrheic dermatitis.
It is my view that the prevalence of chronic plaque
psoriasis is a good deal higher than 2%. In the United
Kingdom newer, better treatments and the promo-
tional awareness campaigns associated with them
probably bring more psoriasis sufferers to the atten-
tion of primary care practitioners. This promotional
bias may mask any real changes that have occurred in
prevalence. As far as can be ascertained there has
been no significant change in prevalence of psoriasis
over the past 20 years unlike atopic dermatitis where
cases have doubled. Prevalence figures for psoriasis
are important for planning of resources for manage-
ment. One of the drawbacks to achieving accurate
prevalence figures is the lack of reliable diagnostic
criteria for psoriasis (diagnosis is made purely on
clinical examination). Clinical diagnosis is acceptable
s reserved.
Table 1
Research needs and goals of psoriasis
Research needs Goals
Enhanced public awareness of psoriasis Increased funds available for research
Health economics studies Make case for burden of disease and economic impact
Identification of genes Animal model
Understanding of pathomechanisms
Gene therapy
Identification of autoantigen Understanding of pathomechanisms
Prevention and vaccination strategies
Investigation of innate immune responses
angiogenesis and Koebner phenomenon
Targets of therapy
Interrogation of the brain-skin axis and
psychosocial disability
Identification of patients who would benefit from
behavioural therapy and who are at risk of
stress-induced relapse
Classification of clinical phenotypes Prediction of prognosis and response to therapy
Outcome measures and trial design Studies relevant to real life management of psoriasis
Academia-industry collaboration Strategic application of research and development
C.E.M. Griffiths / Dermatol Clin 22 (2004) 493–499494
for dermatologists but not necessarily for other
health care personnel. There is no test, other than
skin biopsy, to aid diagnosis for the disease that
is analogous to rheumatoid factor for rheumatoid
arthritis or antinuclear antibodies for systemic lu-
pus erythematosus.
Clinical research is entering a new era, one that
has direct relevance to psoriasis. Modern day clini-
cians are becoming overreliant on diagnostic tests
and as a consequence are starting to lose or place less
value on clinical examination. Chronic plaque pso-
riasis is referred to as a single disease entity but those
working in psoriasis clinics and who see large num-
bers of psoriasis patients know that within this
umbrella definition are subsets of disease with rela-
tively distinct clinical patterns, such as small plaque,
follicular, thin plaque, seborrheic, and so forth [4].
These patterns may relate to prognosis. It is my view
that these patterns are relevant. As an analogy, pen-
guins as a genus are birds that are instantly recog-
nizable to most people. Within the generic definition
of penguin, however, there are different, distinct
species of penguins (Emperor, King, Rockhopper,
and so forth). What is required is for careful pheno-
type classification of psoriasis predicated on clinical
pattern. A diligent clinical research fellow is capable
of performing such an important task. Our dermato-
logic forefathers, such as Willan [5], had only clinical
observation at their disposal and were able to classify
and subclassify dermatologic disease on pattern; it is
beholden on us to recapture these skills. Quite pos-
sibly this phenotype mapping possesses fidelity with
genotype and allows clinic-based prediction of re-
sponse to therapy, prognosis, and so forth.
Genetics
Indubitably most research funding in psoriasis is
spent on immunogenetics: the search for the psoria-
sis genes. There are at least eight psoriasis sus-
ceptibility loci located on different chromosomes.
Psoriasis susceptibility locus-1 [6] close to HLA-
Cw6 [7] is a key determinant of early onset psoriasis
beginning on or before 40 years of age [8] but of itself
is not the psoriasis gene. A combination of genes is
undoubtedly required to reveal the psoriasis pheno-
type after exposure to an environmental trigger, such
as streptococcal pharyngitis or tonsillitis [9]. It is
possible that different families have different permu-
tations of genes and triggers leading to the skin
reaction pattern typical of psoriasis. The elucidation
of genes and gene products in psoriasis is of vital
importance if targeted therapies are to be designed
that may cure or even prevent the disease. Heteroge-
neity of disease probably precludes gene therapy for
the time being. Perhaps the most important conse-
quence of identifying psoriasis genes is the ability to
develop a transgenic animal model for psoriasis. No
such model exists; the nearest is a severe combined
immunodeficient mouse xenografted with biopsies of
human psoriasis [10]. An animal model allows rapid
and economic screening of potential therapeutic
agents. Diseases associated with psoriasis are impor-
C.E.M. Griffiths / Dermatol Clin 22 (2004) 493–499 495
tant clinical signposts to candidate gene approaches;
a good example is Crohn’s disease with its fivefold
increased prevalence of psoriasis [11]. Genes close
to caspase response domain-15 on chromosome 16
(a mutation that confers a 48-fold increased risk to
Crohn’s disease [12]) are attractive candidates for
psoriasis [13] as are other genes of the innate im-
mune response.
Pathomechanisms
The three classic histologic features of psoriasis
are the main subjects of research into pathomecha-
nisms: (1) abnormal epidermal keratinocyte prolife-
ration and differentiation, (2) inflammation, and
(3) angiogenesis. Current research into epidermal
components is in abeyance but if psoriasis is to be
considered an autoimmune disease then the putative
autoantigen is most likely a component of the epi-
dermis, probably an epitope of keratin. Investiga-
tions into this, particularly keratin cross-reactivity
with streptococcal M protein, are important [14].
The inflammatory response whether cellular or cyto-
kine is a critical focus of current research. The past
decade has witnessed detailed investigation of the
acquired immune responses in psoriasis: CD4-CD8 T
[15] cells and the Th1-Th2 cytokine pattern [16]. The
pendulum is starting to swing away from research
into the acquired immune response toward investiga-
tion of the role of the innate immune response in
psoriasis [17]. This is in line with research on other
autoimmune inflammatory diseases, such as Crohn’s
disease and multiple sclerosis. Severe combined im-
munodeficiency mouse xenotransplantation studies
have identified natural killer [18] cells as important
in promulgating the natural killer cell and T-cell ac-
tivity and keratinocyte proliferation, [19], and tumor
necrosis factor-a (TNF-a) [20] indicates the impor-
tance of this immune pathway in psoriasis. The role
of this pathway seems increasingly important with the
discovery of different natural killer cell receptors
[21], abnormalities or deficiencies in which may pro-
mote the inflammatory response. The central role that
TNF-a plays in this inflammatory response is un-
derscored by the efficacy of TNF-a blocking bio-
logics, such as infliximab [22] and etanercept [23], in
psoriasis. On this basis an inappropriate innate im-
mune response in the skin of patients with psoriasis
seems to be an attractive research hypothesis.
Perhaps the most underresearched area of psoria-
sis pathogenesis has been in the field of vascular
biology. Studies 20 years ago showed that changes
in the dermal capillary bed are among the earliest
in the evolution from uninvolved skin to plaque [24].
Research work on angiogenic factors derived from
epidermal keratinocytes, specifically vascular endo-
thelial growth factor (VEGF), have reawakened in-
terest in the vascular component of psoriasis [25]. A
single nucleotide polymorphism of the 405 CC ge-
notype of the VEGF gene confers susceptibility to
severe psoriasis of early onset [26] and a mouse
transgenic for overexpression of VEGF has a psoria-
siform phenotype [27]. The roles of VEGF isoforms
in psoriasis and their reciprocal relationship with
antiangiogenic factors (eg, thrombospondin-1) are a
further area for research, as are receptor-targeted
therapies (ie, anti-VEGF and VEGF-receptor).
Quality of life
There is little doubt that one of the hindrances
to obtaining significant research funding for psoria-
sis is the view (nondermatologic) that the disease is of
low priority, particularly because it has no apprecia-
ble mortality. The specialty of dermatology has only
recently, and belatedly, awoken to this misconcep-
tion. Although dermatologists and patients are well
aware of the psychosocial [28,29] and financial con-
sequences of psoriasis, comparatively little work has
specifically addressed these in an objective, struc-
tured manner. Studies have shown that psoriasis
produces significant impairment in quality of life, in-
deed to a level lower than that produced by diabetes
[30]. The psychosocial disability suffered by psoriasis
patients is immense. Stress caused by living with
psoriasis is the greatest stressor in patients’ lives [28],
so much so that most patients practice avoidance-
coping and automatic vigilance [31]. It is these
elements of psoriasis morbidity that require further
study, particularly the roles that stress and worry may
have on compliance with, and efficacy of, treatment
[32]. Major areas of research are whether self-help
and cognitive behavioral therapy can significantly
improve quality of life and enhance the efficacy of
traditional pharmacologic approaches to treatment.
Few dermatologists have received any form of train-
ing in how to recognize psychologic distress, particu-
larly depression and anxiety in their patients. This is
highly relevant for physicians who deal with chronic
adult medical dermatoses, such as psoriasis, that have
a significant impact on quality of life. Work is
required to assess strategies to improve compliance
and adherence with prescribed therapy coupled with
in-depth assessment of the health economics of
psoriasis care. What is the true burden of disease to
individual, family member, taxpayer, health care
C.E.M. Griffiths / Dermatol Clin 22 (2004) 493–499496
system, and government? Such information is vital to
facilitate informed debate on the economics of treat-
ing these patients, particularly with the seemingly
expensive biologics. Such studies by necessity should
be performed on a country-by-country basis.
Triggers
Revelation of the psoriatic phenotype is the con-
sequence of a confluence of genetic predisposition
and environmental trigger. The triggers are as im-
portant, and probably as protean, as the putative
genetic mutations; however, comparatively little fund-
ing or endeavor is aimed at elucidating the nature of
these environmental triggers. A few triggers are
recognized, such as streptococcal infection, lithium,
Koebner’s phenomenon, and stress, but there is no
clear understanding as to how and in whom such an
exposure eventuates in psoriasis. Take Koebner’s
phenomenon, for example. First described in 1878,
the Koebner or isomorphic response is a characteristic
feature of active psoriasis [33]. There is no under-
standing as to how trauma to the epidermis results in
psoriasis; indeed, few researchers have specifically
addressed this issue. The appearance of psoriasis at
sites of skin trauma or pressure is probably indicative
of epidermal signaling leading to up-regulation or
induction of vascular adhesion molecules allowing
primed T cells to egress into the dermis. Lithium [34],
prescribed for manic depression, and HIV infection
[35] also trigger or exacerbate psoriasis and are
clinical clues to pathogenesis.
Stress is another purported trigger. A study per-
formed in Manchester [36] showed that 60% of
psoriasis patients believed that stress was either a
trigger or an exacerbator of their disease, an observa-
tion familiar to any dermatologist dealing with pso-
riasis patients. Somewhat surprisingly, despite strong
circumstantial evidence, there has not been a detailed
prospective study of whether exacerbations of psoria-
sis are linked to stressful life events.
The ability of neuroendocrine responses to im-
pact on physiology is an area of increasing scientific
interest, and already under intense investigation in
inflammatory bowel disease, rheumatoid arthritis,
and multiple sclerosis [37]. Evidence exists that ex-
perimental psychosocial stress and the real life stress
of final examinations for medical students can impact
significantly on skin physiology, particularly on
the barrier function of the stratum corneum [38,39].
The brain-skin axis or neuroscience of the skin,
particularly as it pertains to psoriasis, is an exciti-
ng and relatively untrodden area of research both
from the standpoint of psychoneuroimmunology and
hypothalamic-pituitary-adrenal axis responses to
stress and the roles of neuropeptides in facilitating
skin inflammation.
Evidence base
An important component of managing a patient
with psoriasis is knowledge of how various treat-
ments compare with each other in terms of efficacy,
side effects, and patient acceptability. Current prac-
tice has not been subject to rigorous evaluation; the
evidence-base movement is only beginning to stimu-
late reflection on how and why clinicians use the
medicines they do for psoriasis management. A
recent survey [40] by the European Dermato-Epide-
miology Network of 226 randomized controlled trials
for psoriasis produced some important information:
only two randomized controlled trials had compared
two or more different systemic therapies (although to
some extent rectified by the recent comparative study
of methotrexate with cyclosporin) [41]; median study
duration was only on the order of 7 weeks (woefully
inadequate in a chronic, life-long disease); less
than 4% of studies considered maintenance of remis-
sion or relapse rates; less than 10% reported patient
preferences; and amazingly 43 different scoring sys-
tems were used to assess outcome.
There is a need to improve the quality of design
and reporting of future psoriasis studies; many
of these issues are addressed in the CONSORT
statement [42] about good practice in designing,
analyzing, and reporting clinical trials. In particular,
placebo-controlled trials should be confined mainly
to early development of new therapies; comparator
studies with standard practice should be performed
before acceptance of new treatments; and more long-
term studies are required to assess remission, relapse,
side-effects, and patient preference. In order that the
results of studies are directly relevant and important
to patients, patients themselves should be consulted
during the design stage [43].
Consensus is desperately needed as to the best
way to assess response of psoriasis to treatment. The
most commonly used measure of psoriasis severity,
the Psoriasis Area and Severity Index [44], a compo-
sition of surface area affected by psoriasis, scaling,
erythema, and plaque thickness, is unwieldy, re-
quires training in its use, and is poor at revealing or
identifying changes in mild-moderate disease. Fur-
thermore, current determinants of disease severity,
such as Psoriasis Area and Severity Index, physi-
cian’s global assessment, and body surface area, are
C.E.M. Griffiths / Dermatol Clin 22 (2004) 493–499 497
physical and take no account of psychosocial dis-
ability (the two do not correlate) [45]. Agreement is
urgently needed to reach consensus on relevant
measures of psoriasis severity, and as a consequence,
relevant outcomes for treatment. For instance, these
should incorporate, in a holistic manner, the other
determinants of psoriasis severity, namely psycho-
social disability and resistance to therapy as exem-
plified by the Salford Psoriasis Index [46].
New therapies
Research into new therapies needs to be collabo-
ration between academia and industry [47]. The era
of biologic therapies is exciting, not only because
there are new selective therapies for psoriasis, but
because the success or failure of such targeted ap-
proaches allows valuable insights into the biologic
pathways critical to the psoriatic process. This is
nothing new. The observation that cyclosporin is a
highly effective therapy for severe psoriasis [48]
finally paved the way to an acceptance that T cells
are central to the psoriatic process and subsequently
the development of a plethora of biologics for this
disease. Two observations from biologics illustrate
the yin and yang of this argument. Anti–TNF-aapproaches, such as infliximab [22] and etanercept
[23], have highlighted the central proinflammatory
role of TNF-a in psoriasis, whereas the nonefficacy
of an anti–E-selectin approach [49] demonstrates that
E-selectin and cutaneous lymphocyte-associated an-
tigen binding may be redundant in psoriasis. The
latter observation of nonefficacy of blocking T-cell
trafficking in psoriasis implies that biologics, proba-
bly those targeting T-cell activation and trafficking,
may be used more effectively and appropriately in
preventing relapse of psoriasis following clearance
with some other entity (ie, cyclosporin). The goal is
to place new therapies strategically and not to judge
solely on ability to induce clearance or remission;
a two-step approach is required.
In all the excitement over systemic biologics
that target T cells and cytokines one must not over-
look other targets and other drugs. Angiogenesis is an
attractive and highly pertinent target in psoriasis; the
field is well developed in cancer and new therapies
for cancer reliant on antiangiogenic approaches (eg,
anti-VEGF) are a logical choice for trials in psoriasis.
Nonbiologics, such as retinoids (eg, tazarotene [50]),
and retinoid-like drugs, such as liarozole [51], an
inhibitor of retinoic acid 4-hydroxylase without the
long-term risks of acitretin, are certainly worth pur-
suing. Other drugs, such as oral pimecrolimus, which
has cyclosporin-like efficacy seemingly without tox-
icity, are promising [52]. In the rush to use more sys-
temics, the place of effective, cosmetically acceptable
topicals should not be ignored.
The inexorable rise of appearance- and procedure-
based dermatology may produce some benefit for
those still involved in adult medical dermatology.
Development of new lasers and application of old
lasers for psoriasis shows some promise in that the
excimer 308-mm UVB laser is effective for small
recalcitrant plaques [53], and pulse dye laser treat-
ment of plaques can result in long-term remission
[54]. This, coupled with photodynamic therapy, may
be an opportunity for procedure-based treatment but
not prevention of psoriasis particularly if stable.
Summary
The research needs and goals for therapy of
psoriasis should be consonant. The research should
identify targets for treatment, may produce an ani-
mal model, and conceivably gene therapy. Therapies
should embrace these observations but need to un-
dergo trials in a way that is relevant to real life (ie, in
comparison with current clinical practice); with long-
term objectives; and with realistic outcome measures.
Research goals should, in no small way, be deter-
mined by the patients themselves working in close
collaboration with scientists, clinicians, and industry.
It is only by this concerted approach that progress can
be made. It should be borne in mind, however, that
serendipity and not reductionism has perhaps been
the greatest driver of change.
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Dermatol Clin 22 (2004) 501–508
Sclerotherapy basics
Margaret E. Parsons, MDa,b,*
aDermatology Consultants of Sacramento, 5340 Elvas Avenue, Suite 600, Sacramento, CA 95819, USAbDepartment of Dermatology, University of California at Davis, Davis, CA, USA
Every day dermatologists see patients with vari- 40% of cases [4]. Leg veins occur less often in the
cosities of the legs. Treatment of these vessels can be
rewarding to both the physician and the patient.
Sclerotherapy can improve the cosmetic appearance
of aberrant blood vessels and greatly benefit symp-
tomatic veins by decreasing pain, burning, and
cramps that many patients describe. Resolution of
larger varicosities can improve the risk of further
venous disease sequelae. Sclerotherapy continues to
be the gold standard in the treatment of lower
extremity small vessel disease. An understanding of
the indications, mechanisms, and treatment manage-
ment is essential. This article reviews the ‘‘basics’’ of
sclerotherapeutic treatment of the smaller vessels.
Varicose and telangiectatic veins affect both men
and women. In the United States, 8.65% of men and
12.9% of women have varicose veins. Telangiectatic
veins are reported at a higher rate of 28.9% of men
and 40.9% of women in the United States [1]. These
vessels can be visually unattractive and may also be
symptomatic. Venous disease contributes to the
changes of stasis dermatitis, pigmentary alteration,
and edema of the lower legs. Even mild venous
disease can cause ‘‘restless legs’’ syndrome and pain
[2]. Sometimes a patient will complain of a single
cluster of veins causing pain [3]. Sclerotherapy can
be very effective in decreasing the pain of varicose
and telangiectatic leg veins [4,5].
Many factors can affect an individual’s predispo-
sition to develop varicose veins. Genetics is believed
to play a major role in the development of leg veins,
and familial incidence has been reported in 15% to
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All right
doi:10.1016/j.det.2004.03.017
* Dermatology Consultants of Sacramento, 5340 Elvas
Avenue, Suite 600, Sacramento, CA 95819.
E-mail address: [email protected]
nonwhite population. Pregnancy also affects the in-
cidence of leg veins, and varicosities increase with
multiple pregnancies. The distensibility of the vessel
wall and increased blood volume during pregnancy
can also increase the formation of new blood vessels
and increase the diameter of existing blood vessels.
Similarly, occupations that require significant walk-
ing, standing, or long periods of sitting can contribute
to blood vessel pooling in the lower extremities and
therefore an increase in varicosities. Nurses, grocery
clerks, and teachers, therefore, are among some of the
patients often presenting with vessels for treatment.
Leg-crossing also can cause development of vessels
in the area of pressure of one leg on another.
Instructing patients about this causal factor can help
decrease further vessels in the area.
Anatomy
It is important to have an understanding of the
vasculature and anatomy of the lower extremities
when doing sclerotherapy. Although this article fo-
cuses on the smaller vessels, it is important to
understand general circulatory patterns. For example,
it has been demonstrated that telangiectasias can
communicate with the deep venous system [6]. The
volume of sclerosant at a treatment session should
therefore be limited to decrease the chance of the
sclerosing solution entering the deeper system where
it may potentially cause deep vein thrombosis [6].
When treating larger vessels, a thorough knowl-
edge of anatomy is essential. The deeper venous
system includes the femoral and popliteal veins,
which are affected by muscular compression. The
channels of connection between the deep and super-
s reserved.
M.E. Parsons / Dermatol Clin 22 (2004) 501–508502
ficial systems are called the perforating veins. They
provide the junction between the saphenous, femoral,
and popliteal systems. These perforating veins allow
for the return flow to the subcutaneous systems [7].
The superficial venous system includes the great
saphenous vein, the accessory saphenous vein, and
the lesser saphenous vein. The reticular and con-
necting branch veins provide for further connection
Box 1. Duffy system of classification
Type 1—telangiectasia ‘‘spider veins’’
0.1 to 1.0 mm in diameterRed to cyanotic in color
Type 1A—telangiectatic matting
Less than 0.2 mm in diameterRed color
Type 1B—communicating telangiectasia
Type 1 veins in direct communicationwith varicose veins of thesaphenous system
Type 2—mixed telangiectatic/varicoseveins
No direct communication with thesaphenous system
Type 3—nonsaphenous varicose veins(reticular)
2 to 8 mm in sizeBlue to blue-green
Type 4—saphenous varicose viens
Usually over 8 mm in diameterBlue to blue-green
From Goldman M. Sclerotherapy: treat-ment of varicose and telangiectatic. Legveins. 2nd edition. St. Louis, MO:Mosby; 1995. Modified from Duffy D.Small vessel sclerotherapy: an overview.In: Callen, et al, editors. Advances indermatology, vol. 3. Chicago: Yearbook;1988; with permission.
throughout the system. When treating larger vessels,
it is important to identify specific flow patterns
occurring in the patient by Doppler or Duplex studies.
It is helpful to understand the different types of
vessels that can be seen with visual examination. This
understanding facilitates knowledge of and planning
of treatment with sclerotherapy, and documenting this
treatment in the chart. A simple description of the
vessels with color and size can be sufficient. The
‘‘Duffy’’ classification is also useful for describing
vessels (Box 1). The diameter of the vessel also helps
determine which solution can be used for injection.
Etiology
Various factors contribute to the pathophysiology
of the development of varicosities. Aging of vessels
plays a major role in the cause of these conditions,
where many of the same factors as in the aging of the
skin are seen. The intima of a blood vessel becomes
thickened, the elastic lamina atrophies, and the ad-
ventitia becomes more fibrous. Because varicosities
usually have endothelial damage as part of their
development, they are therefore susceptible to scle-
rosing. In addition, the varicosities have a fibrosed
adventitia and an atrophic elastic layer accessible to
the sclerosant. Chronic hypertension can lead to
valvular insufficiency and dilatation of the vessels.
Hormonal effects of increased estrogen during preg-
nancy also contribute to distensibility of the blood
vessel wall. Patient history should also include the
patient’s use of hormonal replacement therapy or oral
contraceptive agents, but these are usually a low and
stable dose with minimal, if any, notable effects on
distensibility. Vin et al [8] showed that the effects of
estroprogestogen treatment on superficial venous sys-
tem is dose-dependent. Tamoxifen can also cause an
increase in hypercoaguability and should be noted
during the consultation appointment and reviewed
with the patient. The physical factors of leg-crossing
and tight clothing can play a role by causing focused
pressure in areas, and obesity or pelvic obstruction
from a tumor or lymph node can also cause stress on
the lower extremity vasculature. Valvular incompe-
tence can be caused by a genetic dysfunction or even
a decreased number of valves. Thrombophlebitis is
also related to valvular dysfunction.
Sclerosing agents
The concept and purpose of a sclerosing agent in
the treatment of varicosities is straightforward. Scle-
M.E. Parsons / Dermatol Clin 22 (2004) 501–508 503
rosants are injected into the vessel and affect the
vessel wall by initiating a vein wall injury. If the
injury causes sufficient damage to the vessel wall,
the vessel will be resorbed and fibrosed. The agents
cause some damage to the endothelial cell wall and
also to some of the deeper layers of the vessel wall.
This deeper damage is important to the success of
sclerotherapy and in decreasing the incidence of
recanalization [9].
There are three types of sclerosants: detergents,
osmotic agents, and chemical irritants (Box 2). Deter-
gents interact with the surface lipids of cellular mem-
branes and cause disruption of the endothelial cells.
Detergents are chemicals with polar (hydrophilic) and
nonpolar (hydrophobic) groups. The nonpolar group
of the detergent molecule aligns itself with the cell
membrane of the endothelial cell because the internal
space of the plasma membrane is also nonpolar. This
placement reduces surface tension of the cell mem-
brane, which leads to the disruption of the endothelial
layer. Similarly, detergents can disrupt the deeper
layers of the vessel wall as well. Osmotic agents cause
cellular dehydration by disrupting the water balance
of a cell and thereby causing damage to the cells of the
endothelial level. Osmotic agents also disrupt the
noncellular mural layers of the vessel, decreasing
the chance of recanalization [9]. There is a relation
between the concentration of the sclerosant and the
depth of the vessel wall damage. Chemical irritants,
the last class of sclerosants, have their effect through
various mechanisms to damage the vessel wall.
An ideal sclerosant would clear all veins that were
injected, have no side effects, and be painless to the
Box 2. Sclerosing agent classification
Detergents
Sodium tetradecyl sulfate (Sotradecol)Polidocanol (Aethoxysclerol)Sodium morruhate (Scleromate)Ethanolamine oleate (Ethamolin)
Osmotic agents
Hypertonic salineSaline/dextrose (Sclerodex)
Chemical irritants
Chromated glycerin (Sclermo)Polyiodinated iodine
patient; however, a perfectly ideal sclerosant does not
exist. Therefore, it is important to understand the
good and bad points of each sclerosing agent. There
are three sclerosing agents most commonly used in
the treatment of small vessels: hypertonic saline,
sodium tetradecyl sulfate, and polidocanol. Other
agents are used for some of the larger vessels,
some agents that are no longer used, and there are
other agents that are used outside the United States.
Hypertonic saline comes as a 23.4% solution of
sodium chloride. It is approved by the US Food and
Drug Administration (FDA) for use as an abortificant,
so its use in sclerotherapy is considered ‘‘off-label.’’
It provides for a ‘‘fast-fade’’ of vessels and has a very
low risk of allergenicity. It does sting and cause
discomfort to the patient, however. As a salt solution,
it can cause fluid overload if significant volumes are
used or if many very distal vessels are treated.
Hypertonic saline is caustic enough to cause skin
sloughing at the site of injection in some cases. If
it extravasates, ulceration can occur. If used ap-
propriately, however, it works very well in the treat-
ment of vessels. Appropriate dilution minimizes the
risk of ulceration and telangiectatic matting. For
treating smaller vessels, dilution of the 23.4% sodium
chloride solution with normal saline to an 11.7%
solution is important. In very fine vessels or in
vessels in the ankle area, a solution of approximately
6% sodium chloride may be appropriate. The 23.4%
solution can be used directly in reticular and larger
vessels [10].
Over the years, dilutions with lidocaine and hepa-
rin have been used. A solution of two parts 23.4%
saline and one part 1% lidocaine with epinephrine
(resulting in a 15.6% saline/0.33% lidocaine) solution
has been used. This solution introduces a possible
allergen and another agent that causes stinging,
however. Normal saline can be used for dilution.
Heparin also has been used because it is believed to
decrease the risk of clotting. Its inclusion, however,
again introduces another agent with its own particular
complexities to the mixture, including the risk of
allergenicity [11].
Sodium tetradecyl (Sotradecol) has been widely
used in the United States. In recent years no major
manufacturer has been producing it. It is FDA
approved if a manufacturer meets production guide-
lines. Some smaller companies are currently prepar-
ing the solution. Negative effects include possible
ulceration, pigmentation, and necrosis, and this agent
can be painful in patients with thrombophlebitis. It
also has the potential to induce anaphylaxis. The fol-
lowing appropriate dilutions for vessel size will mini-
mize the potential for side effects: telangiectatic veins
M.E. Parsons / Dermatol Clin 22 (2004) 501–508504
less than 2 mm in diameter (0.1%–0.3% concentra-
tion); varicose veins, 2 to 4 mm (0.5%–1% concen-
tration); and larger ( > 4 mm) varicose veins (1.5%–
3% concentration.)
Polidocanol (also known as Aethoxysclerol) is
currently not FDA approved for use in the United
States, although it has been submitted for such
approval for some years. There is extensive experi-
ence with polidocanol in Australia [12,13], and it is
used in Europe as well. Because it is pain free
(ie, without the stinging caused by saline or Sotrade-
col), it is well liked by patients. It also has decreased
risk of skin sloughing and pigmentation. The agent’s
negative features are the slower fading of treated
vessels and risk of allergic reaction. Because of this
latter risk, a test dose of 0.5% solution should be
injected into a vessel before a treatment session. The
solutions should be diluted appropriately as follows:
0.25% to 0.75% for telangiectasias, 1% for vessels of
1 to 2 mm, and 2% solution for vessels of 2 to 4 mm.
There are total daily dose limitations with polidoca-
nol based on body weight (2 mg/kg/d) and detailed in
the manufacturer’s guidelines [11,14]. Sadick [15] has
shown comparable results between hypertonic saline
and polidocanol.
A solution that is composed of saline (10%),
dextrose (5%), propylene glycol, and phenethyl alco-
hol is manufactured under the brand name Sclerodex.
This substance is not FDA approved, although it is
approved in Canada. It has limited use because it can
only be used in very small vessels, those smaller than
1 mm in diameter. It has the risk of pigmentation, al-
lergenicity, and necrosis. Because there is a decreased
percentage of saline, there may be decreased cramp-
ing during treatment. The manufacturer recommends
a maximum volume of 1 cc at any injection site, with
a total per session of no more than 10 cc [16].
Sodium morrhuate (Scleromate) is an FDA-ap-
proved substance that is currently infrequently used
and is not indicated for use in telangiectasias. It must
be diluted to appropriate concentration. Its many
potential side effects limit its use (eg, necrosis, hyper-
pigmentation, pain, risk of pulmonary embolus, al-
lergenicity, and risk of anaphylaxis) [16].
Ethanolamine oleate (Ethamolin) is of historical
significance in sclerotherapy as one of the first FDA-
approved sclerosing agents. It is not used much now,
however, because it is a viscous solution with a risk
of a hemolytic reaction [11].
Chromated glycerin (Sclermo) has been used in
Europe but is not approved for use by the FDA. It can
be used for telangiectasias and has a low potential of
hyperpigmentation. Only a total of a 0.1-cc prediluted
solution can be used in a single session, and it can be
diluted with lidocaine. Chromated glycerin can be
painful to patients upon injection [11].
Polyiodinated iodine is the most powerful of all
sclerosants and is used in treatment of the sapheno-
femoral junction, a treatment beyond the scope of this
article. It is not FDA approved and can cause necro-
sis. Therefore, it is not appropriate for use in small
vessel sclerotherapy.
Patient history and physical examination
As with all medical and surgical treatments, it is
important to obtain a thorough patient history [17].
There are some contraindications for sclerotherapy.
Pregnancy, a history of hypercoaguability, and allergy
to any agents are very specific contraindications. A
patient with a history of hypercoaguability may be
revealed by history of thrombophlebitis, pulmonary
embolus, deep vein thrombosis, or having a positive
lupus anticoagulant status. Allergy to aspirin, heparin,
and anesthetics can also be important, depending on
the choice of sclerosant. Those patients who have a
history of easy bruising or bleeding, or those patients
who are on aspirin, nonsteroidal anti-inflammatory
drugs (NSAIDs), or vitamin E therapy, have increased
chances of bruising and bleeding with sclerotherapy.
Smokers and those on hormone replacement therapy
or oral contraceptive pills may have an increased risk
of clotting, although these factors are not specific
contraindications. Hormonal therapy has been shown
to have an association with increased telangiectatic
matting [18]. Systemic disease status must be
reviewed and include discussion of the following
conditions: hypertension, congestive heart failure,
diabetes, asthma, and infectious disease. Some of
these conditions can be relative contraindications
because of poor healing and risk of infection. A good
candidate for sclerotherapy is an active patient.
Activity status is also important in posttreatment
counseling because some high-impact activities must
be avoided immediately following sclerotherapy. The
status and results of other leg vein treatments, includ-
ing sclerotherapy, stripping, other surgical treatments,
or laser treatments should be reviewed with the
patient. The dermatologist should also know the
patient’s family history in relation to predisposition
to varicosity development.
It is important to examine the patient from hip to
toe, rather than just a patient’s calf or a similarly
focused area. Examination of the extent of the disease
with which the patient is presenting is important so
that the patient is treated appropriately and so that any
significant underlying venous disease is not over-
M.E. Parsons / Dermatol Clin 22 (2004) 501–508 505
looked. Underlying venous or arterial disease can
result in risks such as emboli or ulceration and lead
to poor results with sclerotherapy treatment. During
examination, it is important to assess if there are just a
few scattered vessels or vessels throughout both legs.
Similarly, the physician should determine if there are
just spider telangiectasias and a few reticular veins
visible or if there are large varicosities visible. The
physician should examine the patient at the inner
upper thigh for any saphenous visibility. Examination
of the patient’s skin for evidence of venous disease,
such as pigmentation, stasis changes, and actinic
damage, may indicate the possibility of poor healing.
As appropriate, an examination for hernias and fascial
defects should be performed. Palpation of arterial
pulses and veins can also assist in examination.
Valsalva maneuvers can assist in checking for poor
venous flow in the groin area. Other physical maneu-
vers include the Perthes’ test, Brodie-Trendelenburg
test, and the percussion/Schwartz test. These modali-
ties are outlined in some of the textbooks on scle-
rotherapy and in an article by Fronek [19].
Lab work to evaluate hypercoaguability or bleed-
ing risks may be appropriate if something in the
patient history suggests further evaluation is war-
ranted. If the vessels are larger than 4 mm in diameter
or if there are significant signs of venous damage,
further evaluation by Doppler (unidirectional or bidi-
rectional), Duplex Ultrasound, or photoplethysmog-
raphy is indicated. These tests evaluate the extent of
venous disease and may indicate that larger vessels
need to be addressed. Excellent discussions of these
modalities are available in textbooks on sclerother-
apy, and training is available at the meetings of the
North American Society of Phlebology.
Materials
A basic sclerotherapeutic set-up can be simple.
The solutions a kit should include are as follows: the
sclerosing agent, normal saline, dilutant in case of
extravasation, and possibly nitroglycerin paste. The
choice between 3-cc syringes and 1-cc syringes is a
personal preference, but locking syringes are recom-
mended. The physician should try both sizes and
decide which is preferable. All syringes should be
well labeled as to what solution they contain and its
percentage strength. Disposable 30-gauge needles are
used for injection, with a larger-gauge needle used for
drawing up solutions. Alcohol wipes are used for
cleansing the area before treatment. It is often easier
to visualize veins in the area after wiping with alcohol.
Cotton balls and tape (paper tape, which is less
irritating, is preferred) are used after injecting for
immediate compression and to cover the bleeding
point of injection. Gloves are to be used as a universal
precaution. The current author was trained to use a
mid-to high-potency topical corticosteroid cream after
injection and before applying the cotton ball and
tape. Although there has not been a study to evaluate
the use of topical corticosteroid cream, patients
seem to find it soothing and it seems to decrease the
slight urticarial focal reaction some get at the site
of injection. Also, it may decrease skin sloughing
at the site of injection by decreasing local inflamma-
tory reaction.
Injection techniques
When injecting the patient with the sclerosant, it is
important to have good lighting and, if needed,
magnification. Injecting the patient with the needle
bevel angled up and with a slight bend at the hub
seems to be the most comfortable for the physician.
Also, with the bevel up, the physician can best judge
where the solution is going. It is important to inject
slowly. Rapid injection can cause extravasation and
increase the risk of telangiectatic matting. If the
needle moves, there is risk of scleroscent getting
out of the vessel, and extravasation is more likely.
Therefore it is important to inject slowly, stop when
there is resistance, and not rush while doing the
procedure. The amount of sclerosant per site ranges
from 0.1 to 0.5 cc. It is recommended to proceed from
proximal to distal sites in larger vessels [20], but the
reality is that, for small vessel sclerotherapy, the
dermatologist usually addresses the vessels that
bother the patient the most. The shin, distal lower
leg near the ankle, and popliteal areas cause more
discomfort and have a somewhat higher risk of
ulceration. Therefore these locations are not a good
place to start a sclerotherapy treatment plan. If a
patient has significant reticular disease, it is usually
recommended that the reticular vessels be treated
first. Dr. David Green has shown some excellent
results in which patients just wanted to treat the
spider telangiectasias and not reticular veins (Ameri-
can Academy of Dermatology session, 1999 annual
meeting). Subsequently, the current author has found
that to be true for her patients. As with all treatments,
documentation is important. Some physicians find
that stamps or predrawn sheets are helpful in docu-
menting leg vein treatment.
If a patient describes burning pain, it is likely that
extravasation is occurring. There is a small group of
patients, however, who have significant pain with
M.E. Parsons / Dermatol Clin 22 (2004) 501–508506
accurate sclerotherapy. If extravasation occurs, the
sclerosant should be diluted with normal saline or 1%
lidocaine to decrease the risk of ulceration. Hyal-
uronidase has been shown to decrease the risk of
extravasation-related ulceration. A dose of 75 units of
hyaluronidase injected into the extravasated area can
be effective in decreasing ulceration [21,22]. There-
fore, it is important to have a syringe filled and ready
with your choice of a countertreatment agent. If a
patient has cramping while the physician is in the
process of injecting, the physician should knead or
massage the area or go on to the other leg for a while.
As discussed, the ankle area has a higher risk
of ulceration and should never be first in a patient’s
treatment plan. It is important to use diluted solution
in this region and only do a small amount of
treatment in the ankle area in a session.
Reticular veins are rewarding to treat. The treat-
ment of reticular veins usually causes less stinging to
the patient. For these vessels, a smaller amount of
sclerosant in each syringe is preferred (eg, 0.5 cc).
This is because when treating reticular vessels, the
physician should draw back on the needle to get a
flash of blood to ensure that he or she is in the vessel.
Once there is flashback, inject slowly. Resistance is
felt when the solution is reaching a valve or tortuosity
and is an indication to stop injecting. Compression
with cotton and tape is done immediately after
removing the needle.
Compression
Compression improves the results of sclerother-
apy and decreases the risk of recanalization, hyper-
pigmentation, phlebitic reactions, and telangiectatic
matting [23,24]. Compression is normally accom-
plished with hose stockings. These stockings are
rated in terms of their compressive ability, with the
common ranges of 12 to 40 mm Hg. Support hose
have a more even and graduated compression than
bandaging or wrapping. Patients who only undergo
spider vessel treatment can wear lighter compression
hose, in the range of 12 to 20 mm Hg. Patients with
reticular vein treatments should wear hose in the 20 to
30 mm Hg range. Hose in the 30 to 40 mm Hg range
may be too strongly compressive if the patient is
lying down much of the day. Overcompression could
be a risk factor for ulceration [25]. Patients are
instructed to put their hose on just after therapy and
ideally before standing at all. They wear the hose
overnight the first night after treatment and then
during the day as well. For spider and small vein
treatment, approximately 5 to 7 days of wearing
compression hose use is appropriate. For reticular
vein treatment, 2 to 3 weeks is preferred. Patients are
advised to be ambulatory, because inactivity can
increase the risk of clotting. They are also advised
to avoid high-impact activity, such as jogging, aero-
bics, and kick-boxing. Patients are also advised that
wearing some level of daily support hose should
improve their lower extremity vessel status. Some
patients find that their legs are less ‘‘tired’’ at the end
of the day and prefer to wear the hose on a regular
basis, which is especially important in occupations
where the patient stands all day [26].
Side effects/complications
Overall, sclerotherapy is a safe and well-tolerated
procedure. There are some areas to be aware of,
however, and it is important to caution patients about
these areas in your consultation appointment and
informed consent.
Bruising at the site of injection can occur and is
more likely if the patient takes aspirin or NSAIDs.
This effect clears with time. Localized urticaria can
occur at the site of injection and seems to be relieved
by the use of topical corticosteroids applied before the
application of dressings and compression hose. The
urticaria is transient and can occur with most agents.
The theory is that it is caused by the irritation of the
endothelial wall of the injected vessel [11]. Many pa-
tients complain of some pain at the time of procedure.
Hyperpigmentation can occur in up to 10% to
30% of vessels but is more likely to occur in vessels
larger than 2 mm [25]. Compression therapy and the
avoidance of tanning decrease this likelihood. Hyper-
pigmentation clears with time or can be managed
with topical tretinoin or hydroquinones, or the physi-
cian’s hyperpigmentation treatment of choice.
Crusting at the site of injection has been reported
up to 10% of the time and is caused by out-leak
of sclerosant.
Telangiectatic matting can also occur, especially if
the sclerosant is injected too quickly and possibly if
the concentration percentage is too strong. Matting
has been shown to occur in up to 15% to 20% of pa-
tients [25,27]. Management with treatment at a future
visit is usually appropriate. Laser or light therapy
may play a role in treatment of vessels that are too
small to inject.
Edema can also occur with sclerotherapy. The
lower part of the leg, particularly the ankle area, is
prone to this side effect. Compression therapy and
caution regarding the volume of sclerosant used in a
session can minimize edema.
M.E. Parsons / Dermatol Clin 22 (2004) 501–508 507
Superficial thrombophlebitis can occur with ves-
sels of 3 to 5 mm and can be managed with
compression, NSAIDs, heat, and sometimes intra-
muscular corticosteroids. Nodular fibrosis can occur
with the larger vessels and needs to be minimized
with compression and managed with reassurance
and time.
Necrosis can be caused by out-leaks of the scle-
rosant, and needle placement issues warrant patience
and caution when sclerosing vessels. Sometimes
dilution with lidocaine, normal saline, or hyaluroni-
dase can minimize necrosis.
Ulcers can occur with injection of sclerosants.
Extravasation or injection into an arteriole can also
lead to ulceration. If extravasation is suspected,
dilution with normal saline, lidocaine, or hyaluroni-
dase can help as previously discussed. Also, if the
physician sees a white blanching suggestive of arte-
riole infiltration, application of topical nitroglycerin
paste at the site may decrease the potential for
ulceration by increasing the microcirculation, which
can flush the sclerosant from the arteriole [28]. If an
ulcer occurs, patience, frequent visits, and good ulcer
care management are important.
Patient management
Before performing sclerotherapy on a patient, it is
important to have a thorough consultation appoint-
ment. During this appointment, details of the patient’s
history are obtained. A standardized form for patients
for sclerotherapy can simplify the history-taking. A
complete examination as previously discussed should
be performed. Risks, benefits, and side effects should
be reviewed with the patient as appropriate for an
informed consent. The patient’s treatment plan can be
reviewed with the patient, helping to ensure realistic
outcomes. It is important to advise patients that
vessels may take up to a month to fade after treat-
ment. The number of sessions will vary with the
extent of the disease, amount of therapy done in each
session, and the rate of success of treatment. Addi-
tional sessions are usually not scheduled until 4 to
6 weeks after therapy. Appropriate compression
hose should be discussed, because the patient will
need these with them at the time of treatment. Patients
are advised that they may need to modify exercise
programs to avoid high-impact activities from 1 to
3 weeks after therapy (1 wk for telangiectasias and up
to 3 wks for reticular veins). Patients are also advised
at consultation to avoid shaving or moisturizing the
24 hours before (or day of) procedure.
A follow-up examination with the patient after
sclerotherapy usually occurs at approximately
1 month, unless they have any problems or questions
and need to be seen sooner. Patients are usually
advised that some vessels may take up to a month
to fully clear after therapy, and further treatment, if
needed, can be planned at that time.
New developments
New areas of discussion in sclerotherapy include
the use of foam sclerosant. Foam is formed by mixing
air with the sclerosant [29,30]. Sclerotherapy is also
being used on vessels of the face, hand, and chest
[31]. These areas are more complex and should be
reviewed with someone experienced in treating these
areas. Laser therapy continues to evolve with new
modalities. Currently, however, laser and light thera-
pies should be considered in patients who do not
tolerate sclerotherapy because of a fear of needles or
failure of previous therapy, or in those who are prone
to telangiectatic matting [32].
Summary
Sclerotherapy is a good procedure to include in
dermatology practice. As with all procedures, the
dermatologist should proctor with a colleague and
learn further details about the procedure before be-
ginning independent practice. Sclerotherapy of small
vessels requires minimal equipment and has a high
satisfaction for both the patient and physician.
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