new england jurnal rosasea
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n engl j med
352;8
www.nejm.org february
24, 2005
The
new england journal
of
medicine
793
clinical practice
This
Journal
feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the authors clinical recommendations.
Rosacea
Frank C. Powell, F.R.C.P.I.
From the Regional Centre of Dermatology,Mater Misericordiae Hospital, Dublin. Sendreprint requests to Dr. Powell at the Region-al Centre of Dermatology, Mater Misericor-diae Hospital, Eccles St., Dublin 7, Ireland,or at fpowell@eircom.net.
N Engl J Med 2005;352:793-803.
Copyright 2005 Massachusetts Medical Society.
A 47-year-old white woman reports facial redness and flushing. Her eyes are itchy andirritated. She thinks she may have rosacea and is worried that she will have a whiskeynose. On examination, multiple erythematous papules, pustules, and telangiectasiasare observed on a background of erythema of the central portion of her face. Howshould her case be managed?
A constellation of clinical symptoms and signs are included under the broad rubric ofrosacea. These consist of facial flushing, the appearance of telangiectatic vessels andpersistent redness of the face, eruption of inflammatory papules and pustules on thecentral facial convexities, and hypertrophy of the sebaceous glands of the nose, with fi-brosis (rhinophyma).
1
Ocular changes are present in more than 50 percent of patientsand range from mild dryness and irritation with blepharitis and conjunctivitis (commonsymptoms) to sight-threatening keratitis (rare).
2
Patients with rosacea may report in-creased sensitivity of the facial skin
3
and may have dry, flaking facial dermatitis, edemaof the upper face,
4
or persistent granulomatous papulonodules.
5
There is often an over-lapping of clinical features, but in the majority of patients, a particular manifestation ofrosacea dominates the clinical picture. As a useful approach to the guidance of therapy,the disease can thus be classified into four subtypes erythematotelangiectatic (sub-type 1), papulopustular (2), phymatous (3), and ocular (4)
6
with the severity of eachsubtype graded as 1 (mild), 2 (moderate), or 3 (severe).
7
The psychological, social, andoccupational effects of the disease on the patient should also be assessed and factoredinto treatment decisions.
The onset of rosacea usually occurs between the ages of 30 and 50 years.
8
Thecourse of the disease is typically chronic, with remissions and relapses. Some patientsidentify exacerbating factors, particularly in regard to flushing, such as heat, alcohol,sunlight, hot beverages, stress, menstruation, certain medications, and certain foods.
9
Rosacea is more common in women than in men, but men with rosacea are more proneto the development of thickening and distorting phymatous skin changes. Rosacea hasbeen anecdotally reported to be associated with seborrheic dermatitis (this associationis likely), with migraine headaches in women
10
(possible), and with
Helicobacter pylori
in-fection
11
(controversial). A rosacea-like eruption can be induced by the topical applica-tion of fluorinated corticosteroids
12
and tacrolimus ointment
13
to the face. In two Eu-ropean population studies, the prevalence of rosacea was reported to be 1.5 percent
14
and 10 percent,
15
but estimates are complicated by the difficulty of distinguishing be-tween chronic actinic damage and erythematotelangiectatic rosacea. Although rosaceacan occur in all racial and ethnic groups, white persons of Celtic origin are thought to beparticularly prone to the disorder,
16
and it is uncommon in persons with dark skin. Up to30 percent of patients report a family history of rosacea.
17
The common misconception
the clinical problem
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Copyright 2005 Massachusetts Medical Society. All rights reserved.
-
n engl j med
352;8
www.nejm.org february
24
,
2005
The
new england journal
of
medicine
794
Tabl
e 1.
Cla
ssifi
catio
n, F
eatu
res,
and
Tre
atm
ent o
f Ros
acea
.*
Subt
ype
Clin
ical
Fea
ture
sSe
veri
ty
Ther
apeu
tic A
ppro
ach
Com
men
ts
Gra
deFe
atur
es
Eryt
hem
atot
el-
angi
ecta
tic
(sub
type
1)
Pers
iste
nt e
ryth
ema
of th
e ce
ntra
l fac
e.
Flus
hing
; tel
angi
ecta
sias
oft
en p
rese
nt;
easi
ly ir
rita
ted
faci
al s
kin.
Pat
ient
may
re
port
stin
ging
or
burn
ing
of th
e fa
ce
and
have
sym
ptom
s of
ocu
lar r
osac
ea.
Rhi
noph
yma
occa
sion
ally
coe
xist
s.
1 2 3
Occ
asio
nal m
ild fl
ushi
ng; f
aint
per
sist
ent
eryt
hem
a; o
ccas
iona
l tel
angi
ecta
sias
.Fr
eque
nt tr
oubl
esom
e flu
shin
g; m
oder
ate
pers
iste
nt e
ryth
ema;
sev
eral
dis
tinct
tel-
angi
ecta
sias
.Fr
eque
nt s
ever
e flu
shin
g; p
rono
unce
d pe
rsis
-te
nt e
ryth
ema;
pos
sibl
e ed
ema;
man
y pr
omin
ent t
elan
giec
tasi
as.
Red
uce
flush
ing
and
redn
ess
and
min
i-m
ize
skin
irri
tatio
n. T
opic
al m
edi-
catio
ns r
ecom
men
ded
for
papu
lo-
pust
ular
ros
acea
are
not
indi
cate
d an
d m
ay c
ause
irri
tatio
n. S
yste
mic
tr
eatm
ents
use
d fo
r pa
pulo
pust
u-la
r ro
sace
a m
ay r
educ
e er
ythe
ma
if si
gnifi
cant
infla
mm
atio
n is
pre
sent
. A
blat
ive
ther
apy
of p
rom
inen
t ves
-se
ls fo
r gr
ade-
2-to
-3 d
isea
se.
Diff
icul
t to
trea
t sat
is-
fact
orily
.
Papu
lopu
stul
ar(s
ubty
pe 2
)Pe
rsis
tent
ery
them
a of
the
cent
ral f
ace;
do
me-
shap
ed e
ryth
emat
ous
papu
les;
sm
all p
ustu
les
surm
ount
som
e pa
p-ul
es. F
lush
ing,
tela
ngie
ctas
ias,
ocu
lar
infla
mm
atio
n, a
nd p
hym
atou
s sk
in
chan
ges
may
be
pres
ent.
1 2 3
Few
pap
ules
or
pust
ules
; mild
per
sist
ent
eryt
hem
a; n
o pl
aque
s.Se
vera
l pap
ules
or
pust
ules
; mod
erat
e pe
rsis
-te
nt e
ryth
ema;
no
plaq
ues.
Man
y or
ext
ensi
ve p
apul
es o
r pu
stul
es; p
ro-
noun
ced
pers
iste
nt e
ryth
ema;
infla
mm
a-to
ry p
laqu
es o
r ed
ema
may
be
pres
ent.
Topi
cal o
r sy
stem
ic m
edic
atio
ns fo
r gr
ade-
1-to
-2 d
isea
se; s
yste
mic
m
edic
atio
ns fo
r gr
ade
3.
Res
pons
e to
trea
tmen
t is
usu
ally
goo
d.
Mai
nten
ance
ther
-ap
y is
usu
ally
re-
quir
ed to
mai
ntai
n re
mis
sion
.
Phym
atou
s(s
ubty
pe 3
)Th
icke
ned
skin
with
pro
min
ent p
ores
. May
af
fect
nos
e (r
hino
phym
a
mos
t com
-m
on ty
pe),
chi
n (g
nath
ophy
ma)
, for
e-he
ad (
met
ophy
ma)
, ear
s (o
toph
yma)
, an
d ey
elid
s (b
leph
arop
hym
a). M
ay
occu
r in
isol
atio
n or
with
oth
er s
kin
chan
ges
of r
osac
ea (
flush
ing,
ery
the-
ma,
ede
ma,
tela
ngie
ctas
ias,
pap
ules
, pu
stul
es in
a n
asal
or
cent
ral-f
acia
l di
stri
butio
n) o
r w
ith o
cula
r ro
sace
a.
1 2 3
For
rhin
ophy
ma:
slig
ht p
uffin
ess
of n
ose;
slig
ht p
rom
inen
ce o
f fol
licul
ar o
rific
es
(pat
ulou
s fo
llicl
es);
no
clin
ical
ly a
ppar
ent
hype
rtro
phy
of c
onne
ctiv
e tis
sue
or s
eba-
ceou
s gl
ands
; no
chan
ge in
nas
al c
onto
ur.
For
rhin
ophy
ma:
bul
bous
nas
al s
wel
ling;
m
oder
atel
y di
late
d pa
tulo
us fo
llicl
es; c
lini-
cally
app
aren
t mild
hyp
ertr
ophy
of t
he s
e-ba
ceou
s gl
ands
or c
onne
ctiv
e tis
sue,
with
ch
ange
in n
asal
con
tour
but
with
out n
od-
ular
com
pone
nt.
For r
hino
phym
a: m
arke
d na
sal s
wel
ling;
larg
e di
late
d fo
llicl
es; d
isto
rtio
n of
nas
al c
on-
tour
due
to h
yper
trop
hy o
f the
seb
aceo
us
glan
ds o
r co
nnec
tive
tissu
e, w
ith n
odul
ar
com
pone
nt.
Rhi
noph
yma
(gra
des
2 an
d 3)
may
re-
spon
d w
ell t
o su
rgic
al o
r la
ser
ther
-ap
y. O
ther
phy
mat
ous
skin
cha
nges
ar
e ve
ry d
iffic
ult t
o tr
eat b
ut m
ay
impr
ove
with
trea
tmen
t of i
nfla
m-
mat
ory
skin
lesi
ons,
if p
rese
nt.
All
phym
atou
s sk
in
chan
ges
are
rare
. Th
e m
ost c
omm
on
form
(rh
inop
hym
a)
occu
rs p
redo
mi-
nant
ly in
men
.
The New England Journal of Medicine Downloaded from nejm.org on September 20, 2015. For personal use only. No other uses without permission.
Copyright 2005 Massachusetts Medical Society. All rights reserved.
-
n engl j med
352;8
www.nejm.org february
24, 2005
clinical practice
795
that both the facial redness and the rhinophyma as-sociated with rosacea are due to excessive alcoholconsumption makes rosacea a socially stigmatizingcondition for many patients.
The diagnosis of rosacea is a clinical one. There isno confirmatory laboratory test. Biopsy is warrantedonly to rule out alternative diagnoses, since histo-pathological findings are not diagnostic.
18
The differential diagnosis and therapy vary ac-cording to subtype (Table 1). Rosacea that is mani-fested predominantly by flushing is difficult to treat,but the condition may improve with the manage-ment of other manifestations and the avoidanceof provoking or triggering factors. Inflammatorychanges in the skin are usually responsive to medi-cal therapies and heal without scarring, whereas tel-angiectasias and phymatous changes often requirelaser or surgical intervention. Ocular rosacea is usu-ally mild and responsive to lid hygiene, tear replace-ment, and topical or systemic antibiotics, but pa-tients with persistent or severe ocular disease shouldbe referred to an ophthalmologist. All patientsshould be advised in regard to protection from cli-matic influences (both heat and cold), avoidanceof factors that trigger or exacerbate flushing or thatirritate the often-sensitive skin, appropriate care ofthe facial skin (Table 2), and a strategy for mainte-nance of remission when the condition improves.The choice of medications, dosages, and durationof therapy is often based on clinical experience.Off-label prescription-drug use is common.
19
subtype 1
Flushing, with persistent central facial erythema(erythematotelangiectatic rosacea), is probably themost common presentation of rosacea.
6
Althoughit has been suggested that rosacea is essentially acutaneous vascular disorder,
20
facial flushing is notalways a feature; patients who report flushing astheir only symptom should not receive a diagnosisof prerosacea, since, in many such patients, ro-sacea never develops. Common causes of flushing(e.g., psychosocial factors or anxiety, food, alcoholor drugs, or menopause) should become apparentwhen a medical history is taken. Prolonged episodesof severe flushing accompanied by sweating, flush-ing that is not limited to the face, and, especially, sys-temic symptoms such as diarrhea, wheezing, head-ache, palpitations, or weakness indicate the need
strategies and evidence
*A
dapt
ed fr
om W
ilkin
et a
l.
6,7
In
gen
eral
, 1 d
enot
es m
ild d
isea
se, 2
mod
erat
e di
seas
e, a
nd 3
sev
ere
dise
ase,
but
gra
des
of s
ever
ity a
re n
ot a
lway
s cl
earl
y de
fined
. Pat
ient
s m
ay h
ave
mor
e th
an o
ne s
ubty
pe, a
nd th
e gr
ade
of s
ever
ity s
houl
d be
ass
esse
d in
eac
h of
thes
e. P
atie
nts
shou
ld a
lso
be a
sked
to g
rade
the
psyc
holo
gica
l, so
cial
, and
occ
upat
iona
l effe
cts
of th
eir d
isea
se o
n a
sim
ilar s
cale
. For
exa
mpl
e,
in g
rade
1 (
mild
), th
e pa
tient
is c
onsc
ious
of t
he c
ondi
tion,
but
it d
oes
not c
ause
em
barr
assm
ent o
r inh
ibit
soci
al fu
nctio
ning
; in
grad
e 2
(mod
erat
e), t
he p
atie
nt is
con
stan
tly a
war
e of
the
rosa
cea
duri
ng s
ocia
l situ
atio
ns a
nd it
regu
larl
y ca
uses
em
barr
assm
ent;
in g
rade
3 (
seve
re),
the
patie
nt is
con
stan
tly th
inki
ng a
bout
the
cond
ition
and
avo
ids
soci
al in
tera
ctio
n be
caus
e of
it. S
uch
grad
ing
on th
e pa
rt o
f the
pat
ient
faci
litat
es e
valu
atio
n of
the
over
all e
ffect
of t
he d
isea
se o
n hi
m o
r he
r an
d gu
ides
ass
essm
ent o
f the
effi
cacy
of t
hera
py.
Ocu
lar
(sub
type
4)
Sens
atio
n of
fore
ign
body
in th
e ey
e; te
l-an
giec
tasi
a an
d er
ythe
ma
of li
d m
ar-
gins
, oft
en w
ith s
calin
g. C
onju
nctiv
al
inje
ctio
n; r
ecur
rent
cha
lazi
on o
r ho
rdeo
lum
. Ker
atiti
s, e
pisc
leri
tis o
r sc
leri
tis, a
nd ir
itis
may
occ
ur, t
houg
h ra
rely
. May
pre
cede
, fol
low
, or
occu
r si
-m
ulta
neou
sly
with
cut
aneo
us c
hang
es.
Bot
h ey
es a
re u
sual
ly a
ffect
ed.
1 2 3
Mild
itch
, dry
ness
, or
gritt
ines
s of
eye
s; fi
ne
scal
ing
of li
d m
argi
ns; t
elan
giec
tasi
a an
d er
ythe
ma
of li
d m
argi
ns; m
ild c
onju
nctiv
al
inje
ctio
n (m
ild c
onge
stio
n of
con
junc
tival
ve
ssel
s).
Bur
ning
or s
tingi
ng o
f eye
s; c
rust
ing
or ir
regu
-la
rity
of l
id m
argi
ns, w
ith e
ryth
ema
and
edem
a; d
efin
ite c
onju
nctiv
al h
yper
emia
or
inje
ctio
n; fo
rmat
ion
of c
hala
zion
or
hord
eolu
m.
Pain
, pho
tose
nsiti
vity
, or
blur
red
visi
on; s
e-ve
re li
d ch
ange
s, w
ith lo
ss o
f las
hes;
se-
vere
con
junc
tival
infla
mm
atio
n; c
orne
al
chan
ges,
with
pot
entia
l los
s of
vis
ion;
ep
iscl
eriti
s or
scl
eriti
s; ir
itis.
Topi
cal m
edic
atio
n fo
r gra
de 1
; sys
tem
-ic
med
icat
ion
for
grad
e 2.
Ref
er
patie
nts
with
per
sist
ent g
rade
1
or 2
dis
ease
or
susp
ecte
d gr
ade
3 di
seas
e to
oph
thal
mol
ogis
t.
May
occ
ur in
the
maj
or-
ity o
f ros
acea
cas
es,
but o
ften
not
di-
agno
sed.
Vis
ion-
thre
aten
ing
ocul
ar
infla
mm
atio
n is
ra
re.
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Copyright 2005 Massachusetts Medical Society. All rights reserved.
-
n engl j med
352;8
www.nejm.org february
24
,
2005
The
new england journal
of
medicine
796
for investigations to rule out rare conditions thatmay be characterized by flushing (e.g., the carcinoidsyndrome, pheochromocytoma, or mastocytosis).
21
Telangiectatic vessels are usually prominent onthe cheeks and nose in grades 2 and 3 of subtype 1rosacea (Fig. 1) and contribute to the facial erythe-ma. Erythematotelangiectatic rosacea is difficult todistinguish from the effects of chronic actinic dam-age, which may coexist. Since the management ofthe two conditions is similar, this distinction is notessential for patient care. Erythematotelangiectaticrosacea may occasionally mimic facial contact der-matitis, the butterfly rash of lupus erythematosus,or photosensitivity; if the diagnosis is uncertain,skin biopsies, serologic screening for antinuclearand anticytoplasmic autoantibodies, or other inves-tigations may be indicated.
Subtype 1 rosacea is poorly responsive to treat-ment. The measures outlined in Table 2 are partic-ularly relevant for patients with subtype 1, who of-ten have sensitive, easily irritated skin. There are fewstudies of the effectiveness of medical treatmentsfor flushing in patients with rosacea. Beta-blockersin low doses (e.g., nadolol, 20 to 40 mg daily)
22
aswell as clonidine and spironolactone have been usedto treat flushing in patients with rosacea, but evi-dence from randomized trials is lacking to supportthe effectiveness of these agents. Endoscopic trans-thoracic sympathectomy has been used successfullyto treat socially disabling blushing
23
; however, itsuse as a treatment for rosacea is not recommended,owing to rare but serious complications such aspneumothorax and pulmonary embolism, as wellas postoperative increases in episodes of abnormalsweating.
If the telangiectatic component is prominent, asit is in grade-2-to-3 disease, ablation of vessels bylaser can be helpful. A nonblinded, uncontrolledstudy of 16 patients who had erythematotelangiec-tatic rosacea and were treated with pulsed-dyelaser therapy showed a significant improvement inerythema and quality of life after treatment.
24
Al-though topical and systemic therapies, as outlinedfor papulopustular rosacea below, are often used totreat patients with erythematotelangiectatic rosa-cea, there is little evidence of the efficacy of theseagents. In addition, topical therapy may irritate thesensitive skin of patients with subtype 1 rosacea.
subtype 2
Small, dome-shaped erythematous papules, someof which have tiny surmounting pustules, on the
Table 2. General Nonpharmacologic Guidelines for the Management of Rosacea.
Reassure patients about the benign nature of the disorder and the rarity of rhi-nophyma (particularly in women).
Direct patients to Web sites such as those of the National Rosacea Society (www.rosacea.org) and the American Academy of Dermatology (www.aad.org), where patient-related information can be accessed.
Advise patients to keep a daily diary to identify precipitating or exacerbating factors.
Suggest a daily application of combined ultraviolet-Aprotective and ultravio-let-Bprotective sunscreen (with a sun-protection factor of 15 or greater). Sunscreen may be incorporated into moisturizer or topical medication. Vehicle formulations with dimethicone and cyclomethicone may be less irritating than others. Sun-blocking creams containing titanium dioxide and zinc oxide are usually well tolerated.
Suggest a daily application of soap-free cleansers, silicone facial foundations, and liquid film-forming moisturizers.
Suggest cosmetic coverage of excess redness with brush application; matte-finish, water-soluble facial powder containing inert green pigment helps neutralize erythema.
Advise patients to avoid potentially exacerbating factors:Overly strenuous exercise, hot and humid atmosphere, emotional upset,
alcohol, hot beverages, spicy foods, and large hot meals.Exposure to sun or to intense cold or harsh winds.Perfumed sunscreens or those containing insect repellents.Astringents and scented products containing hydroalcoholic extracts or
sorbic acid.Cleansers containing acetone or alcohol.Abrasive or exfoliant preparations.Vigorous rubbing of the skin.Toners or moisturizers containing glycolic acid.If possible, medications that may exacerbate flushing (e.g., vasodilative
drugs, nicotinic acid and amyl nitrite, calcium-channelblocking agents, and opiates).
Figure 1. Erythematotelangiectatic (Subtype 1) Rosacea.
Prominent telangiectasias and erythema of the medial cheek are evident in this example of grade 2 disease. As the erythema subsides, the telangiectasias often become more evident. This patient, who has fair skin and works out-side, reported sensitive, easily irritated skin and frequent flushing.
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n engl j med
352;8
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clinical practice
797
convexities of the central portion of the face, withbackground erythema (Fig. 2), typify papulopustu-lar rosacea.
6
In grade 3 disease, plaques can formfrom the coalescence of inflammatory lesions (Fig.3). Telangiectatic vessels, varying degrees of edema,ocular inflammation, and a tendency to flush arepresent in some patients. The differential diagnosisincludes acne vulgaris, perioral dermatitis, and seb-orrheic dermatitis. Patients with acne vulgaris haveless erythema, are often younger, and have oily skinwith blackheads and whiteheads (comedones), larg-er pustules and nodulocystic lesions, and a tendencyto scarring. In patients with perioral dermatitis, mi-cropustules and microvesicles around the mouth oreyes and dry, sensitive skin may follow the inappro-priate use of topical corticosteroids. Seborrheic der-matitis may accompany rosacea and contribute tothe facial erythema, but it is distinguished from ro-sacea by a prominence of yellowish scaling aroundthe eyebrows and alae nasi, together with trouble-some dandruff.
Management
Systemic or topical antibiotics, or both, are themainstays of therapy for subtype 2 rosacea (Table 3),and the response is often satisfactory (Fig. 4A and4B). Moderate-to-severe (i.e., grade 2 or 3) papulo-pustular rosacea may require systemic therapy toachieve clearance of inflammatory skin lesions,whereas milder (grade 1 and some cases of grade 2)disease can often be treated with topical medica-tions alone.
25
Although data are lacking to supportthe combined use of topical and systemic therapies,many clinicians recommend such a combination forthe treatment of moderate-to-severe disease.
20,25
On the basis of an analysis that pooled data fromtwo randomized trials, van Zuuren and colleaguesconcluded that there was strong evidence of the ef-ficacy of topical metronidazole and azelaic acidcream.
26
Sixty-eight of 90 patients (76 percent)treated with topical metronidazole for eight or nineweeks considered their rosacea to be improved, ascompared with 32 of 84 patients (38 percent) in theplacebo group.
26
Significant reductions in the num-ber of inflammatory lesions and in erythema werereported in two large placebo-controlled, double-blind studies of a 15 percent azelaic acid gel appliedtwice daily.
27
A double-blind, randomized, parallel-group trial involving 251 patients with papulopus-tular rosacea
28
demonstrated the superiority of 15percent azelaic acid gel over 0.75 percent metroni-dazole gel applied twice daily for 15 weeks. In a dou-
Figure 2. Papulopustular (Subtype 2) and Ocular (Subtype 4) Rosacea of Mod-erate Severity.
In this example of grade-2-to-3 disease, the typical distribution of papules and pustules on a background of inflammatory erythema is seen over the con-vexities of the central portion of the face, with sparing of the periocular area. Grade-1-to-2 ocular rosacea (erythema and edema of the upper eyelids) is also present.
Figure 3. Severe Papulopustular Rosacea with Moderate Ocular Involvement.
In this patient with grade 3 papulopustular disease, in-flammatory lesions have coalesced into an erythema-tous plaque below the eye. Note the multiple small, studded pustules on the surface of the plaque and the inflammatory lesions on the lower eyelid (grade 2 ocular rosacea).
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Table 3. Treatment of Papulopustular Rosacea.*
Medication Properties and Actions Dosage and DurationContraindicationsand Side Effects Comments
TopicalMetronidazole (0.75% gel
or cream; 1% cream)Antibacterial; antiinflam-
matory.Applied once or twice dai-
ly. Can be used as ini-tial treatment to clear inflammatory lesions or as indefinite main-tenance therapy after clearance with sys-temic therapy.
Contraindications: women of childbearing age not on oral contraception should use with caution because of possibility of absorption and mutagenic effects.
Side effects: gel preparation may be irritating to skin. Transient watering of eyes may occur when applied to periocular skin.
Gel and cream and both concentra-tions appear to be equally effective.
Azelaic acid(20% cream; 15% gel)
Antibacterial; anti-inflammatory.
Applied twice daily. Can be used as initial or indefinite mainte-nance therapy.
Side effects: may cause mild burning or stinging sensa-tion when applied initially. Pruritus, dryness, or scal-ing can occur. Rarely, con-tact dermatitis or facial edema may occur.
May be used in wom-en of childbearing age and during pregnancy.
10% Sodium sulfaceta-mide and 5% sulfur in cream or lotion. Prep-arations may include 10% urea; sunscreen; green tint.
Antibacterial; keratolytic (sulfur); hydrating (urea).
Applied twice daily. Can be used as initial or indefinite mainte-nance therapy. Cleanser preparation available.
Contraindications: hypersensi-tivity to sulphonamide or sulfur.
Side effects: rarely, systemic hypersensitivity reactions. May cause redness, peel-ing, and dryness of skin.
Sulfur component may help accom-panying seborrhe-ic dermatitis. Sun-screen or tinted preparations may reduce number of topical prepara-tions needed.
Erythromycin (2% solution)
Antibacterial; anti-inflammatory.
Applied twice daily. Can be used as initial or indefinite mainte-nance therapy.
Side effects: local irritation or dryness.
May be used in preg-nancy. Alcohol in solution may re-duce tolerance.
Tretinoin (0.025% cream or lotion; 0.01% gel)
Alters epidermal keratini-zation. May improve photoaging changes.
Applied at night. Can be used as initial or in-definite maintenance therapy.
Contraindications: teratogenic; women of childbearing age not on oral contraceptives should use with caution.
Side effects: Irritating and poorly tolerated by some patients. May cause photo-sensitivity. Use on dam-aged skin and contact with eyes should be avoided.
Theoretically useful for actinically damaged skin (common in rosacea).
SystemicOxytetracycline Antibacterial; antiinflam-
matory.250 to 500 mg twice daily
for 6 to 12 weeks to achieve remission. In-termittent low-dose therapy may prevent relapse.
Contraindications: should be avoided by women who are pregnant, contemplating pregnancy, or lactating and by persons with impaired renal or hepatic function.
Side effects: gastrointestinal upset; candida; photosen-sitivity; benign intracranial hypertension. May reduce effectiveness of oral contra-ceptives. May cause tooth discoloration or enamel hy-poplasia.
Poor absorption if taken with food, milk, or some medi-cations.
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ble-blind study of 103 patients, a lotion containing10 percent sodium sulfacetamide and 5 percent sul-fur reduced inflammatory lesions by 78 percent, ascompared with a reduction of 36 percent in the pla-cebo group.
29
An investigator-blinded study involv-ing 63 patients that compared the combination of10 percent sodium sulfacetamide and 5 percent sul-
fur lotion with 0.75 percent metronidazole showeda significantly greater clearance of lesions amongthe patients treated with sodium sulfacetamide andsulfur.
30
An uncontrolled study showed a reductionin erythema, papules, and pustules in 13 of 15 pa-tients (87 percent) who were treated with topicalerythromycin applied twice daily for four weeks.
31
* Topical treatment alone is usually effective for mild-to-moderate (grade-1-to-2) papulopustular rosacea. Topical metronidazole, combination 10 percent sodium sulfacetamide and 5 percent sulfur, and 15 percent azelaic acid have been approved by the Food and Drug Administration for the treatment of rosacea; however, several other topical medications are used off label. For patients with moderate-to-severe papulopus-tular rosacea (grade 2 to 3), oral medication is usually indicated. These patients may not tolerate topical medications initially, owing to in-flamed skin, but topical therapy may be added as the inflammation subsides and is used to maintain remission after cessation of oral therapy.
Dosage ranges relate to published reports and reflect the lack of uniformity in the approach to the treatment of papulopustular rosacea.
Contraindications and side effects are selected examples rather than a comprehensive summary.
Table 3. (Continued.)*
Medication Properties and Actions Dosage and DurationContraindicationsand Side Effects Comments
Doxycycline Antibacterial; antiinflam-matory.
50 to 100 mg once or twice daily for 6 to 12 weeks.
Same as for oxytetracycline. May be taken with food.
Minocycline Antibacterial; antiinflam-matory.
50 to 100 mg twice daily or sustained-action formulation once dai-ly for 6 to 12 weeks.
Contraindications: pregnancy or lactation. Persons with hepatic impairment should use with caution.
Side effects: gastrointestinal upset (but less than with tetracycline); allergic reac-tions. Hyperpigmentation of the skin may occur. Long-term use should be avoided (hepatic damage or systemic-lupus-erythe-matosuslike syndrome may be induced). Drug in-teractions with antacids, mineral supplements, anti-coagulants.
Randomized, clinical trials to support its use in rosacea are lacking, but clinical impres-sion is of equal efficacy to oxytet-racycline. Unlike oxytetracycline, can be taken with food.
Erythromycin Antibacterial; antiinflam-matory.
250 to 500 mg once or twice daily for 6 to 12 weeks.
Contraindications: severe hepatic impairment.
Side effects: gastrointestinal upset; headache or rash. Drug interactions (many).
Alternative to oxy-tetracycline or minocycline as first-line systemic treatment. Useful if systemic thera-py necessary in oxytetracycline-intolerant or preg-nant or lactating patients.
Metronidazole Antibacterial; antiinflam-matory.
200 mg once or twice dai-ly for 4 to 6 weeks.
Contraindications: pregnant or lactating women should use with caution.
Side effects: gastrointestinal upset; leukopenia; neuro-logic effect (seizures or pe-ripheral neuropathy). Drug interactions with alcohol, anticoagulants, or pheno-barbital.
Side-effect profile lim-its its use to resis-tant cases for short periods.
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Evidence of the efficacy of oral metronidazoleand tetracycline was also reported by van Zuuren etal.
26
Of 73 patients who were treated with tetracy-cline for four to six weeks, 56 (77 percent) were con-sidered to have improvement, as compared with 28of 79 (35 percent) in the placebo group.
26
Among 14patients treated with 200 mg of metronidazole twicedaily for six weeks, 10 were considered to have im-provement, as compared with 2 of 13 patients (15percent) who received placebo pills.
32
A double-blind trial that compared 200 mg of metronidazoletwice daily with 250 mg of tetracycline twice dailyfor 12 weeks among 40 patients showed that thetwo agents were equally effective.
33
Although bothminocycline and erythromycin are frequently usedin the systemic treatment of rosacea, there are fewdata available on the effectiveness of these agents.On the basis of clinical experience, some investiga-tors have suggested that intermittent low-dose anti-biotic treatment (250 mg of tetracycline on alternatedays) may be as effective as multiple daily doses.
34
An uncontrolled study of 10 patients with moder-ate or severe rosacea that had responded poorly totreatment were prescribed 250 mg of azithromycin
three times per week; moderate or marked improve-ment was observed in all patients after four weeksof therapy.
35
Oral isotretinoin in low doses has been reportedto be effective in the control of rosacea that wasotherwise resistant to treatment, but the ocular andcutaneous drying effects of this agent are poorlytolerated, and its potential for serious adverse ef-fects (including teratogenic effects) contradicts itsuse in routine care. Topical tretinoin has been re-ported to be as effective as oral isotretinoin after 16weeks of treatment
36
and may be helpful in the treat-ment of patients with papulopustular rosacea whoalso have oily skin.
37
Anecdotal reports have suggested that
Cucumissativus
(cucumber), applied in a cooled yogurt paste,is helpful in reducing facial edema of rosacea thatis otherwise resistant to treatment
38
and that facialmassage involving rotatory movements of the fin-gers from the central to the peripheral face may im-prove papulopustular and edematous skin chang-es.
39
However, data that support the effectivenessof either of these treatments are lacking.
Maintenance Therapy
Because relapse occurs in about one quarter of pa-tients within weeks after the cessation of systemictherapy,
40
topical therapy is usually used in an effortto maintain remission.
41
The required duration ofmaintenance therapy is unknown, but a period ofsix months is generally advised.
42
After this time,some patients report that they can keep their skinfree of papulopustular lesions with topical therapyapplied on alternate days or twice weekly, whereasothers require repeated courses of systemic medi-cation.
subtype 3
Phymatous rosacea is uncommon. The most fre-quent phymatous manifestation is rhinophyma(known familiarly as whiskey nose or rum blos-som). In its severe forms (grade 3), rhinophymais a disfiguring condition of the nose resulting fromhyperplasia of both the sebaceous glands and theconnective tissue (Fig. 5). Rhinophyma occursmuch more often in men than in women (approxi-mate ratio, 20:1),
43
and a number of clinicopatho-logic variants have been described.
44
Although rhi-nophyma is often referred to as end-stage rosacea,it may occur in patients with few or no other featuresof rosacea. The diagnosis is usually made on a clin-ical basis, but a biopsy may be necessary to distin-
Figure 4. Response to Treatment in a Patient with Papulopustular Rosacea.
This patient with grade-2-to-3 papulopustular rosacea (Panel A) was given oral antibiotics for six weeks, followed by topical maintenance therapy, as well as continuous application of a sunscreen with a sun-protection factor of 15 or greater. Eight weeks after the initiation of therapy (Panel B), the inflammatory papules and pustules had cleared, although some residual erythema persisted.
A
B
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guish atypical, or nodular, rhinophyma from lupuspernio (sarcoidosis of the nose); basal-cell, squa-mous-cell, and sebaceous carcinomas; angiosarco-ma; and even nasal lymphoma.
45
Data from randomized trials of therapies for rhi-nophyma and long-term follow-up studies of recur-rence rates are lacking. Clinical experience suggeststhat grades 2 and 3 rhinophyma respond well, atleast initially, to surgical excision, electrosurgery, orcarbon dioxidelaser therapy. A case series of 30 pa-tients who were treated with carbon dioxide lasersand followed for one to three years showed goodcosmetic results in almost all the patients.
46
subtype 4
Ocular rosacea is common but often not recog-nized by the clinician.
47
It may precede, follow, oroccur simultaneously with the skin changes typicalof rosacea. In the absence of accompanying skinchanges, ocular rosacea can be difficult to diagnose,and there is no test that will confirm the diagnosis.Patients usually have mild, nonspecific symptoms,such as burning or stinging of the eyes. A sensationof dryness is common, and tear secretion is fre-quently decreased.
48
Mild-to-moderate ocular rosa-cea (including blepharoconjunctivitis, chalazia, andhordeola) occurs frequently, whereas serious (grade3) disease with the potential for visual loss, such asthat which results from keratitis, occurs rarely.
Artificial tears, eyelid hygiene (i.e., cleaning the
lids with warm water twice daily), fucidic acid, andmetronidazole gel applied to lid margins are treat-ments that are frequently used to treat mild ocularrosacea. Systemic antibiotics are often additionallyrequired for grade-2-to-3 disease, although limiteddata are available to support these approaches. In adouble-blind, placebo-controlled trial, 35 patientswith ocular rosacea who received 250 mg of oxytet-racycline twice daily for six weeks had a significant-ly higher rate of remission than did patients whoreceived a placebo (65 percent vs. 28 percent).
49
Inan uncontrolled study of 39 patients with cutane-ous rosacea (28 with ocular symptoms), 100 mg ofdoxycycline daily for 12 weeks improved symp-toms of dryness, itching, blurred vision, and photo-sensitivity.
50
After ocular symptoms subside, themaintenance of lid hygene and the use of artificialtears are usually recommended. However, suchtreatment may be inadequate for moderate-to-severeocular rosacea, and patients with persistent or po-tentially serious ocular symptoms should be re-ferred to an ophthalmologist.
The causes and pathogenesis of rosacea remainpoorly understood.
4,51
Data from randomized, clin-ical trials on the efficacy and optimal duration ofmany of the therapies, including complementarytherapies that are frequently used by patients,
52
arelacking. The possibility of emergence and carriageon the skin of resistant organisms is a concern withregard to the prolonged use of topical and systemicantibiotics.
There are no specific guidelines for the manage-ment of rosacea.
Rosacea is a diagnostic term applied to a spec-trum of changes in the skin and eyes. Until the caus-es and pathogenesis are better understood, the clas-sification of rosacea by its predominant features andgrading according to severity (Table 1) are recom-mended to guide management. The emotional ef-fect of rosacea on the patient must also be consid-ered in the management of this condition, andadvice on improving the cosmetic appearance of theskin is an important aspect of overall care.
areas of uncertainty
guidelines
summary of recommendations
Figure 5. Advanced Rhinophyma (Subtype 3).
In grade 3 rhinophyma, enlargement and distortion of the nose occur, with prominent pores and thickened skin due to hyperplasia of the sebaceous glands and fibrosis of the connective tissue. There is follicular prominence and a distorted nodular appearance. In this patient, the rhinophyma was accompanied by mild papulopustular rosacea, which responded well to topical medications.
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The woman described in the vignette should bereassured that inflammatory papules and pustulesusually respond to therapy and resolve without scar-ring and that rhinophyma rarely develops in wom-en. She should be advised to apply a sunscreen dailythat provides protection against both ultraviolet Aand ultraviolet B irradiation and to avoid using irri-tating topical products. Treatment should be initi-ated with 100 mg of doxycycline or 100 mg of mi-nocycline daily for a period of 6 to 12 weeks. Thisshould be followed by maintenance therapy withazelaic acid, topical metronidazole, or a sodium sul-
facetamidesulfur preparation applied twice dailyfor six months and then gradually discontinued,as outlined above. Laser therapy should be consid-ered for residual, prominent telangiectatic vessels.The oral antibiotic is likely to help the patients oc-ular symptoms, and she should also be advised toclean her eyelids with warm water twice daily andto use artificial tears. Referral to an ophthalmolo-gist should be considered if her ocular symptomspersist.
Dr. Powell reports having received speaking fees from GaldermaLaboratories, Bradley Pharmaceuticals, and Dermik Laboratories.
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sions of rosacea. Arch Dermatol 1998;134:679-83.42. Wilkin JK. Use of topical products formaintaining remission in rosacea. ArchDermatol 1999;135:79-80.43. Roberts JO, Ward CM. Rhinophyma. J RSoc Med 1985;78:678-81.44. Aloi F, Tomasini C, Soro E, Pippione M.The clinicopathologic spectrum of rhinophy-ma. J Am Acad Dermatol 2000;42:468-72.45. Murphy A, OKeane JC, Blayney A, Pow-ell FC. Cutaneous presentation of nasal lym-phoma: a report of two cases. J Am AcadDermatol 1998;38:310-3.
46. el-Azhary RA, Roenigk RK, Wang TD.Spectrum of results after treatment of rhino-phyma with the carbon dioxide laser. MayoClin Proc 1991;66:899-905.47. Kligman AM. Ocular rosacea: currentconcepts and therapy. Arch Dermatol 1997;133:89-90.48. Gudmundsen KJ, ODonnell BF, PowellFC. Schirmer testing for dry eyes in patientswith rosacea. J Am Acad Dermatol 1992;26:211-4.49. Bartholomew RS, Reid BJ, CheesbroughMJ, Macdonald M, Galloway NR. Oxytetra-cycline in the treatment of ocular rosacea:
a double-blind trial. Br J Ophthalmol 1982;66:386-8.50. Quarterman MJ, Johnson DW, AbeleDC, Lesher JL Jr, Hull DS, Davis LS. Ocularrosacea: signs, symptoms, and tear studiesbefore and after treatment with doxycycline.Arch Dermatol 1997;133:49-54.51. Powell FC. Whats going on in rosacea?J Eur Acad Dermatol Venereol 2000;14:351-2.52. Ernst E. The use of complementary ther-apies by dermatological patients: a systemat-ic review. Br J Dermatol 2000;142:857-61.Copyright 2005 Massachusetts Medical Society.
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