drug survival for acitretin and cyclosporine in patients...

UNIVERSITAIR MEDISCH CENTRUM GRONINGEN

Drug survival for acitretin and cyclosporine

in patients with chronic hand eczema

Multicenter long-term daily practice cohort

Student: A.E. Brandsma 1719114

Period: 01-04-2014 to 15-09-2014

Supervisor: Dr. M.L.A. Schuttelaar

Institution: Department of Dermatology, University Medical Center Groningen

Multicentre retrospective study on the daily use of acitretin and cyclosporine for chronic hand eczema 2

1. Abstracts

1.1 Abstract

Background Long-term data on the use of acitretin and cyclosporine in patients with chronic

hand eczema in daily practice are lacking.

Objectives The primary objective was to describe drug survival for acitretin and cyclosporine in

a retrospective long-term multicenter daily practice cohort of patients with chronic hand eczema.

The secondary objective was to identify determinants of drug survival for acitretin and

cyclosporine in general and separately for discontinuation due to adverse events or

ineffectiveness of treatment.

Methods Data of all patients treated with systemic therapy for hand eczema between the 1st of

January 1994 and the 1st of June 2014 were collected. All first treatment episodes of acitretin

and cyclosporine were included. Drug survival was analyzed by Kaplan-Meier survival curves

and split for two reasons for discontinuation: adverse events and ineffectiveness. Determinants of

drug survival were analyzed using univariate Cox regression analysis and multivariate Cox

regression analysis with backward selection.

Results In total, data of 267 patients was collected and 120 patients with a first episode of

acitretin and 102 patients with a first episode of cyclosporine were included. The overall drug

survival of acitretin was 35.4%, 23.2% and 16.3% after 1, 2 and 4 years respectively, with a

median drug survival of 0.5 years. The overall drug survival of cyclosporine was 48.2%, 26.3%

and 13.1% after 1, 2 and 4 years respectively, with a median drug survival of 0.9 years. Reasons

for discontinuation of acitretin were adverse events (37.5%), ineffectiveness (16.7%), both

adverse events and ineffectiveness (5.0%) and other reasons (8.3%). The reasons for

discontinuation of cyclosporine were adverse events (43.1%), ineffectiveness (17.6%) both

adverse events and ineffectiveness (4.9%) and other reasons (2.9%). Patients with a good

response at treatment after 3 months (PGA score 1) had a longer overall drug survival of acitretin

and cyclosporine. Males also had a longer overall drug survival of cyclosporine and patients with

prior immunosuppressive therapy had a shorter overall drug survival of cyclosporine.

Conclusions This is the first daily practice study analyzing drug survival of acitretin and

cyclosporine in the treatment of chronic hand eczema. Drug survival of cyclosporine in

particular, was longer than expected based on previous studies (median 0.9 years). Because no

serious adverse events or complications occurred during this longer treatment, maintenance

therapy with cyclosporine for a longer period should be considered in future treatment of patients

with chronic hand eczema. Most important determinant of longer overall drug survival of

acitretin and cyclosporine was a good response at treatment after 3 months (PGA score 1).


1.2 Samenvatting

Achtergrond Lange termijn data over het gebruik van acitretine en ciclosporine bij patiënten

met chronisch handeczeem in de dagelijkse praktijk ontbreken.

Doel Het primaire doel was drug survival van acitretine en ciclosporine te beschrijven in een

retrospectief lange termijn multicenter cohort van patienten met chronisch hand eczeem uit de

dagelijkse praktijk. Het secondaire doel was determinanten van drug survival in het algemeen te

identificeren en apart voor het staken vanwege bijwerkingen of vanwege ineffectiviteit van de

behandeling.

Methoden Data van alle patiënten die behandeld zijn met systemische therapie vanwege hand

eczeem tussen 1 Januari 1994 en 1 Juni 2014 werd verzameld. Alle eerste behandelepisodes van

acitretine en ciclosporine werden geïncludeerd. Drug survival werd geanalyseerd met behulp van

Kaplan-Meier survival curves en gesplitst voor twee redenen van staken: bijwerkingen en

ineffectiviteit. Determinanten van drug survival werden geanalyseerd door middel van univariate

Cox regressie analyse en multivariate Cox regressie analyse met backward selection.

Resultaten In totaal werden data van 267 patiënten verzameld. Hiervan werden 120 patienten

met een eerste behandelepisode van acitretine en 102 patiënten met een eerste behandelepisode

van ciclosporine geïncludeerd. De cumulatieve algehele drug survival van acitretine was 35,4%,

23,2% en 16,3% na 1, 2 en 4 jaar respectievelijk, met een mediane drug survival van 0,5 jaar. De

cumulatieve algehele drug survival van ciclosporine was 48,2%, 26,3% and 13,1% na 1, 2 en 4

jaar respectievelijk, met een mediane drug survival van 0,9 jaar. Redenen voor staken van

acitretine waren bijwerkingen (37,5%), ineffectiviteit (16,7%), zowel bijwerkingen als

ineffectiviteit (5,0%) en andere redenen (8,3%). Redenen voor staken van ciclosporine waren

bijwerkingen (43,1%), ineffectiviteit (17,6%), zowel bijwerkingen als ineffectiviteit (4,9%) en

andere redenen (2,9%). Patiënten met een goede respons op de behandeling na 3 maanden (PGA

score 1) hadden een langere cumulatieve algehele drug survival van acitretine en ciclosporine.

Mannen hadden een langere cumulatieve algehele drug survival dan vrouwen betreffende

ciclosporine en patiënten die eerder met orale immunosuppressiva waren behandeld hadden een

kortere cumulatieve algehele drug survival van ciclosporine.

Conclusie Dit is de eerste studie uit de dagelijkse praktijk die drug survival van acitretine en

ciclosporine bij patiënten met chronisch hand eczeem beschrijft. Drug survival van met name

ciclosporine bleek langer dan verwacht werd op basis van eerdere literatuur (mediaan 0,9 jaar).

Aangezien er geen ernstige bijwerkingen of complicaties optraden tijdens deze langdurige

behandeling met ciclosporine, zou bij de toekomstige behandeling van chronisch hand eczeem

overwogen moeten worden ciclosporine in onderhoudsdosering voor langere duur te gebruiken.

Belangrijkste determinant van een langere cumulatieve drug survival van acitretine en

ciclosporine was een goede respons op de behandeling na 3 maanden (PGA score 1).


2. Index

1. Abstracts

1.1 Abstract (English) 2

1.2 Samenvatting (Dutch) 3

2. Index 4

3. Introduction

3.1 Background 5

3.2 Objectives and research question 9

4. Materials and Methods 11

5. Results 14

6. Discussion 22

7. Acknowledgements 26

8. References 27


3. Introduction

3.1 Background

Hand eczema is a common disorder of the skin. It often has a chronically relapsing

course, even when contact with potentially damaging allergens and/or irritants has been avoided.

The poor long-term prognosis results in a high social and economic impact for the individual and

the society.1 Although different topical and systemic treatment options exist, the management of

chronic hand eczema is still often unsatisfactory.

Etiology and epidemiology

Among adults in the general population hand eczema has a point prevalence of 4% and a

1-year prevalence up to 10%, depending on whether mild cases are included.2

In all patients with hand eczema, the proportion of chronic severe hand eczema is estimated to be

5-7%.1 The prevalence of hand eczema is higher in specific occupational groups like

hairdressers, cleaners and health care professionals, than in the general population: up to 30%.3

This could be explained by high exposure to wet work and irritants. Several studies found also

higher prevalences of hand eczema among women than among men, which seems to be

explained by different environmental exposure, domestically and occupationally.4

Hand eczema is not a uniform disease and varies in etiology, morphology and severity.

The development of hand eczema is multifactorial and is often caused by a combination of

external and endogenous factors. Exposure to irritants (e.g. water and soaps) or mild toxic agents

is a frequent external cause of hand eczema, causing irritant contact dermatitis. Another external

cause is allergic contact dermatitis, which reflects a contact allergy to a specific substance (for

example: nickel). An important endogenous cause of hand eczema is atopic dermatitis. General

population studies have repeatedly found that atopic dermatitis is the most important risk factor

for hand eczema; one third to one half of the patients with hand eczema has atopy.4 Nevertheless,

in many cases of hand eczema, no cause can be found.

Clinical features and diagnosis

Hand eczema is an inflammatory skin disorder, which can be diagnosed clinically in most

cases. Typical symptoms are erythema, infiltration, hyperkeratosis, itching, vesicles, edema,

fissures and erosions. The feet can also be affected. Chronic hand eczema is characterized by

(red) thick scaly skin that gives rise to painful fissures.

Several types of hand eczema can be distinguished, but currently there is no classification

system that is universally accepted. Consensus about a classification system would be an

important step to facilitate more accurate diagnoses and thereby more effectively targeted

therapy.

In 2011, the Danish Contact Dermatitis Group (DCDG) published a guideline for the

diagnosis and treatment of hand eczema and defined a classification system based on etiology

and morphology.5 The morphological (clinical) types of hand eczema are well-defined in this

classification system, allowing us to classify the different types of hand eczema in this

retrospective study. Classification system of the DCDG:

Etiological classification:

1. Irritant contact dermatitis, with or without atopy


Fig. 1. Recurrent

vesicular hand eczema

Fig. 6. Nummular

hand eczema

2. Allergic contact dermatitis, with or without atopy

3. Atopic hand eczema

4. Protein contact dermatitis

A combination of these etiological types is also possible.

Morphological (clinical) classification:

1. Recurrent vesicular hand eczema

2. Hyperkeratotic palmar eczema

3. Chronic fissured hand eczema

4. Pulpitis

5. Interdigital eczema

6. Nummular hand eczema

Since the clinical classification is used in this study, a short explanation with figures, obtained

from the guideline of the DCDG, is displayed below.5

Recurrent vesicular hand eczema: Characterized by recurrent eruptions of vesicles on the palms

and/or on the sides of the fingers (Fig. 1), and possibly also on the palmar aspects of the fingers

and around the fingernails. The eczema may also be present on the plantar aspects of the feet.

Hyperkeratotic palmar eczema: Typical well-demarcated hyperkeratosis on the palms, possibly

extending to the palmar aspects of the fingers. Fissures may be seen. There are no vesicles at any

time. This eczema can also be seen on the plantar aspects of the feet (Fig. 2).

Chronic fissured hand eczema: Dry eczema, usually with scaling and possibly with

hyperkeratotic areas and fissures (Fig. 3). A limited number of vesicles on the palmar aspects of

the hands may be present.

Pulpitis: Hyperkeratotic eczema on the fingertips, possibly with fissures extending

under the nails. Especially the thumbs and middle fingers are involved, but it may affect all

fingers. Vesicles are occasionally present (Fig. 4).

Interdigital eczema: Eczema in the proximal part of the interdigital spaces with erythema and

scaling. Vesicles are rarely seen (Fig. 5).

Nummular hand eczema: Typically located on the dorsal aspects of the hands or fingers.

Nummular, well-circumscribed lesions are present, characterized by erythema, keratosis,

vesicles, and possibly oozing. Frequently secondarily infected with Staphylococcus aureus (Fig.

6).

Fig. 3. Chronic fissured

Fig. 4. Pulpitis Fig. 5. Interdigital

eczema

Fig. 2. Hyperkeratotic palmar eczema


Pathophysiology

Impaired skin barrier function is the most important factor in the development of (hand)

eczema. This skin barrier function protects the skin from external influences, such as irritants and

allergens. Also it prevents loss of water trough the epidermis. Loss of skin barrier function

makes the skin more susceptible for the penetration of irritants and allergens, which will initiate

immunological reactions and inflammation. Skin barrier function can be impaired through a

genetic cause or external factors.

Genetics

A genetic predisposition to produce increased levels of stratum corneum chymotryptic

enzyme is an important cause of loss of skin barrier function. This protease enzyme causes a

premature breakdown of corneodesmosomes, leading to impairment of the epidermal barrier.3

Another genetic predisposition leading to an impaired skin barrier function is the loss-of-

function mutations in the filaggrin gene. Filaggrin is a protein that is responsible for the

mechanical strength of the skin. It constitutes the structural and chemical barrier, maintaining

hydration and homeostasis.6 Furthermore, it aggregates keratin filaments in the stratum corneum.

Individuals carrying this loss-of-function mutations will produce reduced levels of filaggrin and

thus will have an altered skin barrier and therefore be more susceptible to develop contact

dermatitis.

External factors

The epidermal barrier can be damaged by different external factors. For example:

exposure to irritants like water and soap, long-term application of topical steroids and exogenous

proteases from house dust mites and Staphylococcus aureus. Some of these factors can further

increase the levels of stratum corneum chymotryptic enzyme and thereby impair the epidermal

barrier.3

The immune system

Chronic hand eczema is caused by exposure to either irritant or allergic/atopic trigger

factors but the underlying pathological mechanisms are still not fully understood. Both causes

may have similar clinical presentations, but can be differentiated on pathophysiological

grounds.7

Irritant contact dermatitis (ICD) is a non-specific inflammatory dermatitis induced by the

pro-inflammatory properties of chemicals that activate the innate immune system.7 Structural

cells as well as resident cells of the skin immune system are primarily activated and primary pro-

inflammatory cytokines such as TNF-α and IL-1 family members are induced.3 This will mediate

the recruitment of distant subsets of the immune system to the skin, which will induce ICD.

In allergic contact dermatitis (ACD), a delayed-type hypersensitivity response takes

place, with a skin inflammation mediated by hapten-specific T-cells. During an allergic reaction,

resident antigen-presenting cells are activated, which migrate to local draining lymph nodes and

present the allergen to the specific T-cells. These cells differentiate into allergen-specific

memory T-cells and re-circulate. On subsequent contact with the specific allergen, they

extravasate and get in contact with antigen-presenting cells, which present the specific allergen

to the effector memory T-cells. These memory T-cells will produce effector cytokines. Chronic

hand eczema is characterized by a predominance of the production of type 1 effector cytokines

and an excess of IL-4 production.3


Consequences and treatment

Hand eczema is often chronic and may lead to severe impairment of health-related

quality of life, prolonged absence from work, or even loss of job and early retirement.8 In some

countries, chronic hand eczema has been identified as the most expensive occupational

disease.9,10

The management of hand eczema starts with minimizing exposure to irritants and allergic

factors and the correct use of emollients.2 The next step is treatment with topical corticosteroids.

Phototherapy (Ultraviolet B (UVB) and topical psoralen UVA (PUVA)) is widely used as

second-line treatment for patients in whom topical therapy alone has failed, in combination with

topical steroids.2

Topical calcineurin inhibitors also might be an efficacious treatment option for chronic

occupational hand eczema, but more experience with these agents is needed.11

In case of an acute flare or exacerbation of hand eczema, oral corticosteroids can be a

useful treatment. Long-term use of oral corticosteroids is not appropriate as they have serious

adverse events and long-term toxicities such as osteoporosis and an increased infection risk.

Oral retinoids & immunosuppressants

In severe chronic hand eczema, systemic treatment with immunosuppressants or retinoids

can be helpful, but randomized controlled trials (RCTs) on these treatments in hand eczema are

lacking. Choice of treatment is largely based on clinical experience. Compounds that are used

are, acitretin, alitretinoin, azathioprine, cyclosporine methotrexate, mycophenolic acid sodium

and mycophenolate mofetil. Alitretinoin has recently become available as the only approved

systemic treatment option for chronic hand eczema in the Netherlands. In RCTs it was shown

that this agent was well tolerated and in almost half of the patients marked improvement was

seen.12-14 During the last 20 years, cyclosporine and acitretin seem to be the most prescribed in

daily practice.15 This is probably the result of some small studies that were published about the

efficacy of these two compounds in chronic hand eczema and atopic dermatitis.16-19

Oral retinoids have been successfully used since the 1980’s in different dermatological

disorders and have proven to be effective for the treatment of psoriasis, acne and some

genodermatoses.3,20 Some first results about the efficacy in hand eczema were published in 2001

by Thestrup-Pedersen et al. They found a 51% reduction of hyperkeratotic hand eczema after 4

weeks of treatment with acitretin in a RCT of 29 patients.16 Retinoids are vitamin A derivatives

that can be either endogenous physiological or synthetic and they play key regulatory functions

in epidermal growth and differentiation.3 Regular dose is based on experience in other

dermatological diseases and starts with 0.3-0.5 mg/kg/day during 4 weeks.21 Thereafter, 0.5-0.8

mg/kg/day. Response is gradual en requires at least 3 months to reach an optimum. Specific class

effects associated with the use of retinoids are skin reactions (dry skin, dry mucosa, cheilitis),

metabolic effects (elevations in triglycerides and cholesterol) and hepatic effects (elevations in

transaminases and billirubin).

The use of cyclosporine for the treatment of hand eczema is largely based on evidence of

effectiveness in the treatment of atopic dermatitis.17,19 In 2005, a retrospective study was

performed with cyclosporine for patients with atopic dermatitis.17 Seventy-three patients with

severe atopic dermatitis refractory to conventional treatment were included and treated with

cyclosporine. Treatment was successful in 77% of the patients. Granlund et al. performed a

randomized, double-blind study in 1996 to compare cyclosporine and topical bethamethason

treatment in patients with severe chronic hand eczema, resistant to conventional treatment.18


Both treatments improved the hand eczema but between the groups no significant difference was

found. They concluded that low-dose cyclosporine could be useful as an alternative treatment for

severe chronic hand eczema in patients unresponsive to conventional treatment. Cyclosporine is a cyclic polypeptide with a powerful immunosuppressive effect. It was

introduced in the 1980s as a potent immunosuppressive agent, useful in treating organ transplant

patients.17 It decreases the proliferation of T-lymphocytes specifically and reversibly, without

impact on phagocyting cells and without suppressing hematopoësis. Most common adverse

events are nephrotoxicity, hypertension and malignancies such as non-melanoma skin

cancer.19,21,22 Therefore, cyclosporine is preferably used as a short-term crisis intervention, with a

maximum treatment duration of 6 months and dose reduction in case of remission.21 Start dose is

2.5-3mg/kg/day, split in 2 dosages a day. Maximum dose in dermatology is 5mg/kg/day.

Recently several guidelines were published on the treatment of hand eczema.2,5,23,24

Following these guidelines, topical corticosteroids are still the core of treatment for hand

eczema. Furthermore, it is the most frequently prescribed therapy in hand eczema. However, a

number of patients is unresponsive to treatment with topical corticosteroids (estimation 2-4% of

all patients with hand eczema1) and requires systemic therapy. Surprisingly, as described above,

evidence for systemic therapy in chronic hand eczema is poor.

RCTs are the gold standard for proving the efficacy and safety of drugs. However, these

results are perceived to be poorly generalizable into daily clinical practice because of the

difference in study population and domain population in daily practice.25,26 This has previously

been termed as external validity, applicability or generalizability.27 RCTs often have a short

follow-up time. Long-term observational cohort studies are therefore important to obtain data

about long-term safety and effectiveness of therapies.

A measure for treatment success in daily practice is provided by drug survival. Drug

survival is the period of time a patient remains on a specific treatment.28 It is dependent on a

combination of factors such as drug-efficacy, treatment or patient satisfaction, the availability of

other treatment options and the occurrence of severe or disturbing adverse events.28,29

3.2 Objective of the study and research questions

Primary objective of this study was to describe drug survival for acitretin and

cyclosporine in a long-term daily practice cohort of patients with chronic hand eczema.

Secondary objective of this study was to identify determinants of drug survival for acitretin and

cyclosporine in general and separately for discontinuation due to adverse events or

ineffectiveness of therapy. Moreover, we investigated effectiveness of both compounds in

different clinical types of hand eczema. While cyclosporine and acitretin are very different

compounds, they were not compared at every level. To our knowledge, this is the first study on

drug survival for acitretin and cyclosporine treatment in chronic hand eczema.

Research question I:

What is the drug survival of cyclosporine and acitretin for the treatment of patients with chronic

hand eczema?

Research question II:

Which determinants influence the drug survival of acitretin and cyclosporine for the treatment of

patients with chronic hand eczema?


We hypothesized that cyclosporine has a shorter drug survival than acitretin. As

mentioned above, long-term treatment with cyclosporine is avoided in daily practice because of

the association with malignancies such as non-melanoma skin cancer.19,21

Also we hypothesize that determinants such as a good response to treatment and prior oral

immunosuppressive therapy will be important determinants of drug survival.


4. Material and methods

This retrospective multicentre study took place at the department of dermatology at the

Universital Medical Center of Groningen (UMCG) and the Universital Medical Center of

Utrecht (UMCU).

Patients

Data of all patients treated with systemic therapy for hand eczema in the UMCG or

UMCU between the 1st of January 1994 and the 1

st of June 2014 was collected. In the UMCG,

patients were identified by using DBC (Diagnosis Treatment Combination) for different types of

(hand) eczema (tylotic eczema, dyshidrotic eczema, nummular eczema, allergic contact eczema,

pulpitis sicca, irritant contact eczema, eczema hand foot) in combination with the laboratory

parameters creatinine or triglycerides. Serum creatinine or triglycerides are determined in every

patient before starting and during systemic treatment. Both clinical- and outpatients were

included. Since the DBC codes were introduced in 2004, only patients treated after 2004 could

be traced using this method. To identify patients treated with systemic therapy in the period

1994-2003, old hospitalization books were used. All patients who stayed at the dermatology

department were registered in these books, including their diagnosis. Patients were selected by

checking their medical records in medical paper files and electronic files (Poliplus©). In case of

systemic treatment for the purpose of another disease, the patient was excluded.

In the UMCU, patients were identified in a different way. From 1995 all patients with

eczema and systemic therapy were registered by a physician in a separate document. From this

document patients with hand eczema and systemic therapy were selected. In addition, patients

were identified by using the same DBC codes as in the UMCG, in combination with the generic

name or brand of the used systemic drug. This was possible because the UMCU, in contrast with

the UMCG, registered all patients with systemic treatment for eczema from 2006 by DBC and

name of the drug.

Some patients were treated with systemic therapy in a local hospital. Those patients were

asked to give consent for requesting information in that hospital by filling in a consent form.

Local hospitals were approached with a signed consent form to supply information concerning

the period of systemic treatment.

Data collection

All patient data were collected in an Access database. The database consisted already of

around 150 patients from the UMCG, identified and selected as described above, and was

supplemented with additional data. Data-lock took place on the 1st

of June, 2014.

Various patient characteristics were recorded such as: age, sex, clinical diagnosis, history

of eczema treatments and comorbidities.

Treatment

Data of the following systemic treatments were collected: cyclosporine, acitretin,

alitretinoin, azathioprine, methotrexate, mycophenolate mofetil and mycophenolic acid sodium.

Treatment episodes were registered for each patient because one patient may have had more than

one episode of systemic treatment. No minimum or maximum duration of therapy was defined.

Treatment interruptions up to 14 days were considered as a continuous treatment episode since

patients might discontinue their treatment for short intervals due to infection or run out of tablets.


Various treatment characteristics were recorded of each treatment episode, such as: type

of agent, duration of therapy, start- and maintenance dose, comedication, treatment response,

subjective and objective adverse events, reason for stopping.

Adverse events

All adverse events that were mentioned during treatment were registered. Blood pressure

and laboratory values such as serum creatinine, triglycerides and cholesterol were checked

before starting systemic treatment and during treatment because of the well-known risk of

developing a rise in these values as an adverse event of acitretin or cyclosporine treatment.

Hypertension was defined as diastolic pressure >90mmHg and systolic pressure >140mmHg.

High creatinine was defined as >30% increase in creatinine level compared to the patient’s

baseline.17 High triglyceride level was defined as a level of >4.6mmol/L12 and high cholesterol

was defined as a level of >6.7mmol/L. Only laboratory parameters mentioned as a reason for

dose reduction or discontinuation of treatment were counted as ‘high’.

Comedication

Concomitant use of topical corticosteroids class III and IV, following the European

classification of topical steroids30, was registered. Also concomitant use of prednisolone, other

immunosuppressive drugs, anti-hypertensive medication, cholesterolinhibitors and antibiotics

was registered, including duration of therapy.

Treatment response

The treatment response was retrospectively determined based on the clustered physician

global assessment (PGA) according to Hijnen et al.17

The PGA is an overall estimation of the

severity of the eczema, based on the quality and extent of lesions relative to the baseline

assessment (before starting systemic treatment). It is defined by a scoring system from 0-5: 0 =

clear, 1 = almost clear, 2 = marked improvement, 3= modest improvement, 4 = no change and 5

= worse. These scores were simplified in the following 3-group classification system:

1. Good response: patients successfully treated, improvement >50% (scores 0-2).

2. Moderate response to therapy: improvement <50% (score 3).

3. No response to therapy or worse (scores 4-5).

The PGA was determined for each patient after approximately 3 months of therapy. This

moment was chosen because it can be assumed that after 3 months of therapy a maintenance

dose is reached.

Drug survival and statistical analysis

In this study we reviewed therapy adherence by survival rates of the two most prescribed

systemic therapies in patients with chronic hand eczema, acitretin and cyclosporine. For each

patient, only the first treatment episode was analyzed. Duration of drug survival was expressed in

the number of days a individual remained on their first treatment with acitretin or cyclosporine.

General characteristics of all treatments were analyzed using the Chi-square test in case

of data with a binominal distribution and the Mann-Whitney U-test in case of continuous

variables. Effectiveness of acitretin and cyclosporine in different clinical types of hand eczema

was analyzed by using the Chi-square test. P-values of <0.05 were considered statistically

significant.


Drug survival was descriptively analyzed by Kaplan-Meier survival curves. Three

‘events’ for drug survival were defined and analyzed separately: (1) discontinuation overall, (2)

discontinuation due to ineffectiveness and (3) discontinuation due to adverse events. Patients

were censored when they were lost to follow-up, in remission at the moment of stop or active

user at the moment of stop. When patients discontinued due to both ineffectiveness and adverse

events, they were considered to have an event in both analyses (2) and (3). When patients

discontinued due to other reasons (e.g. non-compliance), they were considered to have an event

in the overall drug survival analysis, but were censored in the other analyses (2) and (3).

Discontinuation rates were read from the survival curves. Discontinuation due to remission was

classified as a ‘positive event’ and discontinuation to any other reason was classified as a

‘negative event’.

Also several possible determinants of drug survival were analyzed: age, gender, prior

systemic treatment, concomitant use of topical corticosteroids class III and IV, start dose and

clinical diagnosis. Determinants of drug survival were selected by comparing patients on each

potential predictor in an univariate Cox-regression model. Hazard ratio’s >1 indicate a shorter

drug survival, hazard ratio’s <1 indicate a longer drug survival. Determinants that differed

between the two groups with a p-value <0.2 were entered in a multivariate Cox-regression

model. P-values of <0.05 were considered to be statistically significant. By backward selection, a

full model was build. Missing data were excluded from analysis. All data were analyzed with

IBM SPSS Statistics 22.0


5. Results

Characteristics of all systemic treatment episodes

In total data of 267 patients were collected in this retrospective study; 212 patients of the

UMCG and 55 patients of the UMCU. In this group 240 patients received at least one form of

systemic therapy. The remaining 27 patients were screened for systemic therapy but did not start

for different reasons.

The majority of patients received acitretin or cyclosporine (Table 1).Other treatments

include alitretinoin, azathioprine, methotrexate, mycophenolate mofetil and mycophenolic acid

sodium. Most patients had one treatment episode of systemic therapy (n = 115), the maximum

amount of treatment episodes was 9 (mean: 2.1).

Table 1: Numbers of all systemic treatments

Systemic treatment Number of patients Number of treatment

episodes

Acitretin 137 192

Cyclosporine 116 145

Azathioprine 44 52

Methotrexate 39 45

Alitretinoin 29 45

Mycophenolic acid sodium 12 12

Mycophenolate mofetil 3 3

The first treatment episodes of acitretin and cyclosporine were further analyzed.

Characteristic of all first treatment episodes of acitretin and cyclosporine

Patients

In total 120 patients with a first episode of acitretin and 102 patients with a first episode

of cyclosporine were included. Because of missing data, 17 patients with a first episode of

acitretin and 14 patients with a first episode of cyclosporine were excluded. Hyperkeratotic

palmar eczema was the most common clinical diagnosis in these groups together with 91 cases

(41.0%). It also was the most common diagnosis in the acitretin group with 70 cases (58.3%).

Recurrent vesicular hand eczema was the most common morphological diagnosis in the

cyclosporine group with 67 patients (65.7%). An overview of other patient characteristics can be

found in Table 2.

Since acitretin and cyclosporine are very different compounds they were not compared on every

level.


Table 2: General characteristics Median (range), sum (%)

Systemic treatment Acitretin

n=120

Range/% Cyclosporine n=102

Range/%

Median age*(years) at start 54.5 18.6-81.6 45.2 15.4-72.4

Male gender* 43 35.3% 57 55.9%

Clinical diagnosis

1. Recurrent vesicular*

2. Hyperkeratotic palmar*

3. Chronic fissured

4. Pulpitis*

5. Interdigital

6. Nummular 7. Non-classifiable

20

77

7

14

0

0 2

16.7%

64.2%

5.8%

11.7%

0%

0% 1.7%

67

14

12

1

0

1 7

65.7%

13.7%

11.8%

1.0%

0%

1% 6.9%

Centre

1. UMCG*

2. UMCU*

109

11

90.8%

9.2%

71

31

69.6%

30.4% *P < 0.05: Significant difference between acitretin and cyclosporine group. Demonstrated with Chi-square test or

Mann-Whitney U test.

Treatment characteristics

Reasons for discontinuation

Acitretin

Hundred-eight patients (90%) were naïve for oral immunosuppressive treatment. The

total treatment duration was 106.5 years, with a mean treatment duration of 323.8 days and a

median treatment duration of 144.5 days (interquartile range (IQR):265).

At the moment of data-lock, 4 patients (3.3%) actively used acitretin, 26 patients (21.7%)

discontinued treatment because of a positive event (remission), 81 patients (67,5%) discontinued

treatment because of a negative event and 9 patients (7.5%) were lost to follow-up. The main

reasons for discontinuation of acitretin treatment were adverse events (n=45, 37.5%) and

ineffectiveness (n=20, 16.7%). Six patients (5.0%) discontinued treatment because of both main

reasons. See Table 3.

Cyclosporine

Eighty-one patients (79.4%) were naïve for oral immunosuppressive treatment. The total

treatment duration was 123.3 years, with a mean treatment duration of 441.3 days and a median

treatment duration of 277.0 days (IQR: 439).

At the moment of data-lock, 13 patients (12.8%) actively used cyclosporine, 11 patients (10.8%)

discontinued treatment because of remission, 70 patients (68.6%) discontinued treatment because

of a negative event and 8 patients (7.8%) were lost to follow-up. The main reasons for

discontinuation of cyclosporine treatment were also adverse events (n=44, 43.1%) and

ineffectiveness (n=18, 17.6%). Five patients (4.9%) discontinued treatment because of both main

reasons. An overview of the treatment characteristics of acitretin and cyclosporine treatment can

be found in Table 3.


Table 3: Treatment characteristics

Acitretin

n=120 (%)

Cyclosporine

n=102 (%)

Concomitant use of:

Prednisolone 4 3.3% 13 12.7%

Corticosteroids class III/IV

79 65.8% 78 76.5%

Oral immunosuppressive drugs history:

Prior immunosuppressive drugs 12 10.0% 21 20.6%

Naïve for immunosuppressive drugs 108 90.0% 81 79.4%

Status of use at the moment of data locka

Active 4 3.3% 13 12,8%

Discontinued due to negative event 81 67.5% 70 68.6%

Discontinued due to remission 26 21.7% 11 10.8%

Lost to follow-up 9 7.5% 8 7.8%


Ineffectiveness (non-responsiveness,

unable to reduce dose)

20 16.7% 18 17.6%

Adverse events (=side effects,

infection/fever, drugallergy)

45 37.5% 44 43.1%

Both (loss of efficacy and unable to

reduce dose)

6 5.0% 5 4.9%

Other (non-compliance, malignancy,

pregnancy wish)

10

8.3% 3 2,9%

a Data lock: June 1, 2014

Treatment response

In patients treated with acitretin a good response at treatment after 3 months of therapy

(PGA score 1) was found in 57 cases (47.3%). In 32 cases (26.7%) a moderate response was

found and in 22 cases (18.3%) no response at treatment was found. There were 9 missing values.

In patients treated with cyclosporine a good response after 3 months of therapy (PGA

score 1) was found in 61 patients (59.8%). In 20 patients (19.6%) a moderate response was found

and in 16 patients (15.7%) no response at treatment was found. There were 5 missing values.

Numbers of PGA score for different clinical types of hand eczema can be found in Table 4.


Table 4: PGA scores for different clinical types of hand eczema

Diagnose Acitretin Cyclosporine

n = 120 % n = 102 %

Recurrent vesicular hand

eczema

PGA 1* 7 35.0 45 67.2

PGA 2 7 35.0 12 17.9

PGA 3 6 30.0 9 13.4

Total 20 100.0 66 98.5

Missing 0 0.0 1 1.5

Total 20 100.0 67 100.0

Hyperkeratotic palmar

eczema

PGA 1 39 50.6 5 35.7

PGA 2 18 23.4 3 21.4

PGA 3 11 14.3 2 14.3

Total 68 88.3 10 71.4

Missing 9 11.7 4 28.6

Total 77 100.0 14 100.0

Chronic fissured hand

eczema

PGA 1 3 42.9 7 58.3

PGA 2 3 42.9 3 25.0

PGA 3 1 14.3 2 16.7

Total 7 100.0 12 100.0

Pulpitis PGA 1 8 57.1 1 100.0

PGA 2 3 21.4 0 0.0

PGA 3 3 21.4 0 0.0

Total 14 100.0 1 100.0

Nummulair hand eczema PGA 1 0 0.0 1 100.0

Non-classifiable hand

eczema

PGA 1 1 50.0 2 28.6

PGA 2 0 0.0 2 28.6

PGA 3 1 50.0 3 42.9

Total 2 100.0 7 100.0

*P<0.05: Significant difference in number of patients with PGA score 1 between acitretin and cyclosporine for

recurrent vesicular hand eczema. Demonstrated with Chi-square test.

Adverse events

During the first treatment episodes of acitretin 87/120 patients (73.0%) reported at least

one adverse event. In total 160 adverse events were reported. Most common reported adverse

event was dry mucosa (40.8%).

During the first treatment episode of cyclosporine 71/102 patients (69.6%) reported at

least one adverse event. In total 153 adverse events were reported. Most common adverse event

was hypertension (23.5%). See Table 5.


Table 5: Adverse events during acitretin and cyclosporine treatment

Acitretin Cyclosporine

Adverse event

During

treatmenta

Reason for

discontinuation

During

treatmenta

Reason for

discontinuation

n = 120 (%) n = 81 (%) n = 102 (%) n = 70 (%)

Hypertension (>140/90mmHg) 0 0.0 0 0.0 24 23.5 21 30

Headache 13 10.8 9 11.1 19 18.6 6 8.6

Gastro-intestinal complaints 7 5.8 3 3.7 19 18.6 8 11.4

Tiredness 9 7.5 2 2.5 17 16.7 6 8.6

Musclepain 6 5.0 2 2.5 14 13.7 2 2.9

Neurological symptoms 3 2.5 2 2.5 8 7.8 1 1.4

High creatinine (>30% increase from

baseline) 0 0.0 0 0.0 8 7.8 6 8.6

Malaise 5 4.2 4 4.9 9 8.8 5 7.1

Reduced/blurred vision 7 5.8 2 2.5 1 1.0 1 1.4

Dry mouth/lips 49 40.8 15 18.5 0 0.0 0 0.0

Epistaxis 6 5.0 2 2.5 0 0.0 0 0.0

Hairloss 12 10.0 7 8.6 3 2.9 1 1.4

Rushed feeling/mood changes 4 3.3 3 3.7 0 0.0 0 0.0

High cholesterol >6.6mmol/L 7 5.8 5 6.2 0 0.0 0 0.0

High triglycerides >4.6mmol/L 3 2.5 1 1.2 0 0.0 0 0.0

Other* 29 24.2 19 23.5 13 12.8 7 10.0

*Insomnia, weight gain, physical condition loss, paronchia, shortness of breath, red eyes, gum hyperplasia, edema,

hypertrichosis. aHigh laboratory parameters were only counted when they were reason for dose reduction

Drug survival rates

As shown in Figure 1, 35.4%, 23.2% and 16.3% of the patients still used acitretin for

hand eczema after 1, 2 and 4 years, respectively. The mean survival duration for acitretin was 2.3

[95% confidence interval (CI95%)1.4-3.2] years and the median survival duration 0.5 years.

Also shown in Figure 1, 48.2%, 26.3% and 13.1% of the patients still used cyclosporine

for hand eczema after 1, 2 and 4 years respectively. The mean survival duration for cyclosporine

was 2.5 [CI95% 1.4-3.5] years and the median survival duration 0.9 years.

No significant difference between overall survival duration of acitretin and cyclosporine

was found (p = 0.2132, demonstrated with long-rank analysis).

Survival time (years)

Perc

en

t su

rviv

al

0 1 2 3 40

20

40

60

80

100 Overall survival acitretin

Overall survival cyclosporine

Figure 1: Survival rate (overall) for acitretin and cyclosporine in chronic hand eczema


The drug survival split by reason for discontinuation of acitretin and cyclosporine

(adverse events vs. ineffectiveness of treatment) is shown in Figure 2.

Adverse events were a reason for discontinuation of acitretin in 49.9%, 59.7% and 59.7%

of the patients after 1, 2 and 4 years, respectively. The mean survival duration was 4.5 [CI95%

3.3-5.7] years. The median survival duration was 1.1 years. Ineffectiveness was a reason for

discontinuation of acitretin in 30.8%, 34.6% and 54.2% of the patients after 1, 2 and 4 years

respectively. The mean survival duration was 5.6 [CI95% 3.7-7.4] years. The median survival

duration was 3.6 years.

For cyclosporine adverse events were a reason for discontinuation in 40.8%, 59.1% and

74.8% of the patients after 1, 2 and 4 years, respectively. The mean survival duration was

4.4[CI95% 2.6-6.2] years. The median survival duration was 1.3 years. Ineffectiveness was a

reason for discontinuation of cyclosporine in 18.0%, 40.9% and 52.2% of the patients after 1, 2

and 4 years respectively. The mean survival duration was 6.3[CI95% 3.8-8.8] years. The median

survival duration was 3.0 years.

a) b)


Perc

en

t su

rviv

al

0 1 2 3 40

20

40

60

80

100

Figure 2: Drug survival rate split for reason of discontinuation for a) acitretin b) cyclosporine

Determinants of drug survival

Acitretin

Table 6 shows determinants of acitretin drug survival as determined by univariate Cox

regression analysis. Patients with PGA score 1 had a significant longer overall survival duration.

A higher maintenance dose of acitretin resulted in a significant shorter survival duration.

Multivariate Cox regression analysis with backward modeling showed a PGA score 1 [HR 0.471,

95% CI 0.286-0.776] as independent determinant of longer overall drug survival.

Male sex, prior oral immunosuppressive therapy and PGA score 1 are determinants that

showed a decreased risk of discontinuation due to adverse events. Multivariate Cox regression

analysis showed no independent determinants of a decreased risk for discontinuation due to

adverse events.

Patients with an older age had a decreased risk of discontinuation due to ineffectiveness

of treatment with acitretin. Patients with PGA score 1 had a significant decreased risk of

discontinuation due to ineffectiveness of acitretin and patients with a higher maintenance dose

had a significant increased risk of discontinuation due to ineffectiveness of acitretin. Mulitvariate


Perc

en

t su

rviv

al

0 1 2 3 40

20

40

60

80

100Overall survival

Ineffectiveness

Adverse-events


Cox regression analysis identified PGA score 1 [HR 0.146, 95% CI 0.048-0.439] as independent

determinant of a decreased risk for discontinuation due to ineffectiveness of acitretin treatment.

Table 6: Determinants of acitretin drug survival determined by univariate Cox regression analysis

Overall drug survival,

event = discontinuation

Drug survival, event =

discontinuation due

adverse events


ineffectiveness of therapy

Hazard ratio [CI95%] Hazard ratio [CI95%] Hazard ratio [CI95%]

Older age 0.979 [0.896-1.069]

Sig = 0.633

0.999 [0.892-1.119

Sig =0.988 0.896[0.772-1.039]

Sig = 0.146

Male sex 0.772 [0.481-1.238]

Sig = 0.282 0.650 [0.351-1.201]

Sig = 0.169

0.794 [0.344-1.831]

Sig = 0.588

Prior oral

immunosuppressive

therapy

0.847 [0.389-1.843]

Sig = 0.675 0.368 [0.089-1.517]

Sig = 0.167

1.146 [0.342-3.839]

Sig = 0.825

Concomitant use of

topical corticosteroids

0.828 [0.522-1.313]

Sig = 0.423

0.893 [0.497-1.603]

Sig = 0.705

0.806[0.358-1.815]

Sig = 0.602

Hyperkeratotic hand eczema

1.007 [0.638-1.590] Sig = 0.976

1.142 [0.637-2.045 Sig = 0.656

0.734 [0.333-1.617] Sig = 0.442

PGA score 1a 0.454 [0.285-0.725]

Sig = 0.001 0.606 [0.336-1.092]

Sig =0.096 0.121[0.041-0.357]

Sig = 0.000

Higher maintenance

dose (mg/day)b 1.012 [1.000-1.024]

Sig = 0.048

1.009 [0.993-1.025]

Sig = 0.281 1.025[1.008-1.041]

Sig = 0.003

Data are presented as hazard ratio (95% confidence interval, p-value). Green numbers indicate hazard ratio’s with a

p-value <0.2, red numbers indicate significant hazard ratio’s (p-value <0.05).

Age in 5-year intervals. aMissing values: 9. bMissing values: 18

Cyclosporine

Table 7 shows that males and patients with PGA score 1 had a significant longer overall

drug survival of cyclosporine. Prior oral immunosuppressive therapy was a determinant for

shorter overall drug survival. Concomitant use of topical corticosteroids and vesicular hand

eczema were determinants for a longer drug survival of cyclosporine. Multivariate Cox

regression analysis with backward modeling identified male sex [HR 0.466, 95%CI 0.276-0.784]

and PGA score 1 [HR 0.352, 95%CI 0.213-0.583] as independent determinants of longer overall

drug survival.

Patients with an older age had an increased risk of discontinuation due to adverse events

and patients who used concomitant topical corticosteroids had a decreased risk of discontinuation

due to adverse events. Males and patients with PGA score 1 had a significant decreased risk of

discontinuation due to adverse events. Multivariate Cox regression analysis identified male sex

[HR 0.328, 95%CI 0.180-0.596] and PGA score 1 [HR 0.412, 95%CI 0.225-0.756] as

independent determinants of a decreased risk for discontinuation due to adverse events.

Patients who used oral immunosuppressive drugs before had a significant increased risk

of discontinuation due to ineffectiveness of acitretin treatment. Patients with a PGA score 1 had a

significant decreased risk for discontinuation due to ineffectiveness of cyclosporine treatment.

Multivariate Cox regression analysis showed prior immunosuppressive therapy [HR 3.487,

95%CI 1.457-8.348] as independent determinant of an increased risk for discontinuation due to

ineffectiveness and PGA score 1 [HR 0.204, 95%CI 0.085-0.489] as independent determinant of

a decreased risk for discontinuation due to ineffectiveness of cyclosporine treatment.


Table 7: Determinants of cyclosporine drug survival determined by univariate Cox regression

analysis

Overall drug survival,

event = discontinuation


discontinuation due

adverse events


ineffectiveness of

therapy

Hazard ratio [CI95%] Hazard ratio [CI95%] Hazard ratio [CI95%]

Older age 1.034 [0.938-1.140]

Sig = 0.501 1.109 [0.985-1.248]

Sig = 0.086

0.901 [0.756-1.073]

Sig = 0.242

Male sex 0.610 [0.380-0.979]

Sig = 0.040 0.396 [0.224-0.699]

Sig = 0.001

1.750 [0.648-4.726]

Sig = 0.270

Prior oral immunosuppressive

drugs

1.493 [0.862-2.586] Sig = 0.153

1.160 [0.578-2.328] Sig = 0.677

3.195 [1.364-7.484] Sig = 0.007

Concomitant use of topical corticosteroids

0.665 [0.373-1.186] Sig = 0.167

0.564 [0.291-1.092] Sig = 0.089

1.194 [0.352-4.051] Sig = 0.776

Vesicular hand eczema 0.659 [0.404-1.075]

Sig = 0.095

0.697 [0.388-1.252]

Sig = 0.227

0.652 [0.274-1.551]

Sig = 0.333

PGA score 1a 0.404 [0.247-0.659]

Sig = 0.000 0.478 [0.264-0.863]

Sig = 0.014 0.223 [0.094-0.529]

Sig = 0.001

Low start dose

(≤2.5mg/kg)b

1.063 [0.580-1.948]

Sig = 0.844

0.897 [0.428-1.881]

Sig = 0.774

1.859 [0.673-5.137]

Sig = 0.232

Data are presented as hazard ratio (95% confidence interval, p-value). Green numbers indicate hazard ratio’s with a

p-value <0.2, red numbers indicate significant hazard ratio’s (p-value <0.05).

Age in 5-year intervals. aMissing values: 5. bMissing values: 17


6. Discussion

Acitretin and cyclosporine were the two most prescribed systemic therapies in patients

with chronic hand eczema during the last 20 years in the UMCG and UMCU. This is probably

due to the availability of long-term data on these compounds and their frequent use in other

(dermatological) diseases.19,20

Furthermore, previous studies demonstrated that acitretin and

cyclosporine were effective and safe treatment options in hand eczema and atopic dermatitis.16,17

Drug survival and determinants

The present study is the first one describing drug survival for acitretin and cyclosporine

in patients with chronic hand eczema, based on daily practice data in a 20-year time frame.

Furthermore it provides a detailed analysis of determinants of drug survival for acitretin and

cyclosporine. Previous drug survival analyses were performed to describe daily practice

treatment results of biologicals in patients with rheumatoid arthritis and psoriasis, with a

maximum time frame of 7.5 years.29,31-34

The overall drug survival of acitretin was 35.4%, 23.2% and 16.3% after 1, 2 and 4 years

respectively, with a median drug survival of 0.5 years. The overall drug survival of cyclosporine

was 48.2%, 26.3% and 13.1% after 1, 2 and 4 years respectively, with a median drug survival of

0.9 years. Survival rates of acitretin and cyclosporine showed a relatively short median overall

survival duration (0.5 and 0.9 years, respectively) compared to the mean survival duration (2.3

and 2.5 years, respectively). This indicates that discontinuation of treatment often takes place in

the first year after initiation of treatment. When patients 'survive' this first period, they are likely

to 'survive' for a longer period of time (years). See Figure 1.

Remarkable findings in this present study are the survival rates of cyclosporine. Our

hypothesis that cyclosporine would have a shorter survival duration than acitretin can be

rejected. The survival rates of cyclosporine transcend our expectation. According to recent

guidelines on the use of cyclosporine, it should only be given as a short-term crisis

intervention.21

Furthermore, a systematic review and meta-analysis in 2006 about the efficacy of

cyclosporine in atopic dermatitis reported a maximum active treatment duration of 1 year and

Hijnen et al. reported a mean treatment duration of cyclosporine in atopic dermatitis of 1.3

years.17

According to our results based on a 20-year timeframe, several patients use cyclosporine

for more than 1 year, without the occurrence of serious adverse events during treatment.

Therefore it should be considered to use cyclosporine not only as a short-term crisis intervention,

but also for a longer maintenance period.

Determinants of drug survival depended on the reason for discontinuation (adverse events vs.

ineffectiveness). We found a good response at treatment (PGA score 1) after 3 months of therapy

as independent determinant of longer overall drug survival of both acitretin and cyclosporine. An

explanation for this finding is that patients with a moderate or no response at treatment after 3

months (PGA score 2/3), are likely to discontinue treatment in daily practice, while it is not

plausible that they will have a better response to treatment in a later stage. Male sex was also an

independent determinant of longer overall drug survival of cyclosporine. The reason why women

have shorter times of adherence to treatment can only be a subject of speculation, but this has

been previously reported for patients with psoriasis or psoriatic arthritis.29,33-35

An explanation

can be that women use topical therapies more consequent than men and therefore require shorter


periods of systemic therapy. Also we suggest that women are more prone to develop subjective

adverse events than men and are therefore likely to discontinue treatment earlier.


Reasons for discontinuation of acitretin were adverse events (37.5%), ineffectiveness

(16.7%), both adverse events and ineffectiveness (5.0%) and other reasons (8.3%), such as non-

compliance or pregnancy wish. Reasons for discontinuation of cyclosporine were adverse events

(43.1%), ineffectiveness (17.6%), both adverse events and ineffectiveness (4.9%) and other

reasons, such as non-compliance or pregnancy wish (2.9%).

The occurrence of adverse events was the main reason for discontinuation of acitretin and

cyclosporine. Previous studies showed lower rates of discontinuation of acitretin or cyclosporine

treatment due to adverse events. In a single-blind placebo controlled study by Thestrup-Pedersen

et al. none of the 14 patients discontinued acitretin due to adverse events during 4 weeks of

treatment.16

Other studies report also that adverse events of acitretin treatment are rarely a reason

for discontinuation of treatment.36-38

In a RCT by Haeck et al., patients with severe atopic

dermatitis were treated with cyclosporine for 6 weeks and only 3/26 patients (11.5%)

discontinued cyclosporine treatment due to adverse events.39

Hijnen et al. reported 12/73 patients

(16.4%) discontinued cyclosporine treatment due to adverse events with a mean treatment

duration of 1.3 years.17

The higher rates in our study can be explained by the longer treatment

duration. Because of the longer treatment duration, more time is available for the development of

adverse events. Another explanation might be that patients (and their physicians) who decide to

participate in clinical trials, are highly motivated to complete the trial period, despite of the

occurrence of adverse events.

Dry mucosa is a well-known adverse event of acitretin20

and has previously been reported as

the most reported adverse event during acitretin treatment.16,38

In our study, dry mucosa was also

the most frequently reported adverse event during acitretin treatment (40.8%). Furthermore, dry

mucosa was also the adverse event most frequently leading to discontinuation of acitretin

treatment (18.5%).

Hypertension was the most reported adverse event during cyclosporine treatment (23.5%)

and also the most reported adverse event leading to discontinuation of cyclosporine treatment

(30%). Hypertension is a well-known adverse event during cyclosporine treatment.17,19,21

However, previous studies reported lower rates of the occurrence of hypertension during

cyclosporine treatment. Hijnen et al. found hypertension in 11/73 patients (15.1%)17

, Haeck et al.

found hypertension in 4/55 (7.3%) patients.39

Another well-known adverse event of cyclosporine

is an increase in serum creatinine level.17,19,21

In our study 8/102 patients (7.8%) had an increase

in serum creatinine level above the normal range as an adverse event of cyclosporine treatment.

Six patients discontinued cyclosporine treatment for this reason. Similar results were found in

previous studies.17,39

An increase of serum creatinine level of more than >30% was reported in

9.6% and 8% of the patients. Furthermore, a feared adverse event of cyclosporine treatment is

the development of malignancies, such as non-melanoma skin cancer.17,19,21

The appearance of

non-melanoma skin cancer or other malignancies was not found in our study population until the

moment of data-lock.


Effectiveness in different clinical subgroups of chronic hand eczema

Besides describing drug survival for the two most prescribed systemic therapies in

chronic hand eczema, also interesting secondary results were found in this study. Although

acitretin and cyclosporine are very different compounds and not easy to compare, we tried to

compare their effectiveness in different clinical subtypes of chronic hand eczema.

In patients with recurrent vesicular hand eczema a significant higher amount of patients

treated with cyclosporine had a good response after 3 months of treatment (PGA score 1) than

patients treated with acitretin. Furthermore, 50.6% of the patients with hyperkeratotic hand

eczema treated with acitretin had a good response after 3 months of treatment compared to

35.7% for patients with hyperkeratotic hand eczema treated with cyclosporine. However, this

difference was not statistically significant. A contributing factor to this can be the small number

of patients with hyperkeratotic hand eczema that was treated with cyclosporine compared to

acitretin (10 and 68 patients, respectively). Acitretin is the first choice for the systemic treatment

of hyperkeratotic hand eczema, mainly because Thestrup-Pedersen found acitretin as an effective

treatment option in the treatment of hyperkeratotic hand eczema (compared to treatment with

placebo).16

Recurrent vesicular hand eczema was the most frequent clinical diagnosis in the patients

treated with cyclosporine. An explanation could be that recurrent vesicular hand eczema seems

to represent the largest clinical subgroup in patients with hand eczema according to a study

performed by Johansen et al. in 2011.40

In this study 557 patients with hand eczema were

classified prospectively and recurrent vesicular hand eczema represented the largest clinical

subgroup with a proportion of 37.7%. However, in our study, hyperkeratotic palmar eczema

represented the largest clinical subgroup in the acitretin group. Selection bias could be an

explanation for this. Due to proven efficacy of acitretin in hyperkeratotic hand eczema, it is

likely that physicians prescribed acitretin in patients with hyperkeratotic hand eczema more

often.

These findings underline the importance of the need for consensus about the

classification of hand eczema to further analyze effectiveness of different systemic therapies in

different clinical subtypes of hand eczema.

Limitations of the study and recommendations for future research

The most important limitation of this study is the retrospective design. Quality of the

results is highly dependent on quality of the medical records. Clinical diagnoses (subgroups)

were not always mentioned in the patients file and needed to be determined retrospectively. PGA

scores were not recorded in the medical files and also needed to be determined retrospectively.

The clustered PGA score of Hijnen et al. facilitated the retrospective classification and therefore

reliability of this value was improved. Furthermore, reliability of the retrospective determination

of PGA score and clinical diagnosis was improved by carrying out these two determinants by

two different researchers and discussing doubtful cases with supervisors. Nevertheless, a

prospective design combined with a uniform scoring system and classification of hand eczema

would improve reliability in future research. Then more valid conclusions can be made about

effectiveness of systemic treatment in relation to the clinical type of hand eczema.

Drug survival depends on a combination of different factors such as drug-efficacy, treatment

or patient satisfaction, the availability of other treatment options and the occurrence of severe or

disturbing adverse events.28,29

It is conceivable that treatment will be more often continued


despite the occurrence of adverse events or a moderate response if no other treatment options are

available. Bias can be introduced since we only selected first treatment episodes of acitretin and

cyclosporine. In addition, the majority of patients with a first treatment episode was naïve for

any immunosuppressive treatment (90% vs. 79.4%). Therefore, drug survival might be shortened

in this patient group due to the availability of other systemic treatment options.

Patients receive treatment based on their own preference and the physicians’ preference,

which at the same time is one of the strengths of daily practice studies as well. During the 20-

year time frame of this study, knowledge about systemic therapies has been improved and

different therapies have been introduced. Also recently in 2013, alitretinoine has become

available as the only approved systemic treatment option for chronic hand eczema in the

Netherlands. These changes influence prescribing behavior and selection bias could have been

subject to this.

In addition to these limitations, it is worth mentioning that the use of daily practice data

strengthened our study results. To be clinical useful, results have to be generalizable to patients

in a daily practice setting. For example, in both psoriasis and psoriatic arthritis, higher response

rates to biologicals were reported in RCTs than in daily practice.41-43

Van der Lem et al. also

investigated the external validity of clinical study results and reported that outcome of treatment

for mild to moderate depression in daily practice seemed less effective compared to results from

RCTs.44

By analyzing daily practice data in our study, results are highly clinical useful.

Several explanations for difference in outcome between daily practice and trial results

can be given. An important difference is patient selection. In clinical trials, patients are selected

using strict inclusion- and exclusion criteria. Unconsciously different patient characteristics can

influence selection (for example a doctors' confidence in therapy adherence of the patient) in

RCTs. Another important factor influencing external validity of RCTs is the limited duration of a

trial. Initial response at treatment is not always a good predictor of long-term treatment response.

Although PGA score 1 was an independent determinant of longer overall drug survival in our

study, also patients with PGA score 2 showed overall drug survival rates of >1 year, which

illustrated this statement. Furthermore, hand eczema is a chronic, relapsing condition which

makes initial response at treatment a less appropriate outcome measure.

Conclusion

In conclusion this is the first long-term daily practice study analyzing drug survival of

acitretin and cyclosporine in the treatment of chronic hand eczema. Drug survival of

cyclosporine in particular, turned out to be longer than expected based on previous studies, with

a median survival duration of 0.9 years. Because no serious adverse events or complications

occurred during this longer treatment period, maintenance therapy with cyclosporine for a longer

period should be considered in future treatment of patients with chronic hand eczema.

The overall drug survival of acitretin and cyclosporine was longer for patients with a good

response at treatment after 3 months of therapy (PGA score 1). The overall drug survival of

cyclosporine was longer in men compared to women and shorter in patients who used prior oral

immunosuppressive therapy. Determinants of drug survival depended on the reason for

discontinuation of acitretin or cyclosporine (adverse events vs. ineffectiveness of therapy).

A uniform scoring system and classification of hand eczema is indispensable to perform a

prospective study on the effectiveness of different systemic therapies in the future.


7. Acknowledgements

Many people have supported me during the past 6 months to realize and fulfill this research

project.

Therefore I would like to thank:

Dr. M.L.A. Schuttelaar for sharing her expertise and having a solution for every problem we

encountered during this study.

Drs. W.A. Christoffers as a daily supervisor for ‘guiding’ me to this past 6 months and

answering any (stupid) question I had.

Drs. T.A. Vogel for her commitment and critical view on this project.

Klaziena Politiek as an expert in ‘drug survival’ for helping me with the statistic part, no matter

which day or time it was.

Carolien Scholten, database manager of the dermatology department, for building a descent

database and helping me to structure the data.

Riël Dijkstra from the medical administration for managing the availability of medical files and

sending consent forms to the patients.

Jorien van der Schaft as MD/PhD in the UMCU for helping me to find my way in the UMCU

and collecting the data.

Raisa Thybaut as a student who went before me, for making me familiar with the database.

Last but not least, my roommates: Aniek, Marjolein, Marrit and Awalia, I would not have made

it without your companionship, good advice, jokes and the pleasant lunch breaks!


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