University of Groningen

Hand eczemaChristoffers, Wianda

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.

Document VersionPublisher's PDF, also known as Version of record

Publication date:2014

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):Christoffers, W. (2014). Hand eczema: interventions & contact allergies. [S.n.].

CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Download date: 23-01-2021

134

Chapter

4

135

Drug survival of cyclosporine in the treatment of hand eczema: a multicenter, daily use studyManuscript submitted for publication to JEADV

Wietske Andrea Christoffers1, Klaziena Politiek1, Pieter-Jan Coenraads1, Jorien van der

Schaft2, Marjolein de Bruin-Weller2, Marie-Louise Anna Schuttelaar1

1 Department of Dermatology, University Medical Center Groningen,

University of Groningen, Groningen, the Netherlands2 Department of Dermatology & Allergology, University Medical Center Utrecht,

Utrecht, the Netherlands.

Key words: hand eczema, cyclosporine,

drug survival, vesicular eczema

4chapter

136

AbstractBackground: Hand eczema is a common condition; it is often chronic and can be difficult to

treat. Cyclosporine is used off-label to treat severe hand eczema; however the evidence for

this treatment is scarce.

Objective: To examine the drug survival of cyclosporine in a daily practice cohort of patients

with chronic hand eczema.

Methods: This daily use study included hand eczema patients who were treated with

cyclosporine between 01-06-1999 and 01-06-2014 in two Dutch university hospitals. Patient

and treatment characteristics were retrospectively collected from medical charts. First treat-

ment episodes were analysed by means of Kaplan-Meier drug survival curves and possible

determinants of drug survival were analysed by Cox-regression models.

Results: A total of 102 patients was treated with cyclosporine. The median survival rate

was 0.86 years. The overall drug survival rates after 6 months, 1, 2 and 3 years were 61.7%,

45.2%, 18.6% and 13.9%, respectively. Main reasons for discontinuation were adverse events,

especially early in treatment, and ineffectiveness. After three months a good response to

treatment was recorded in 59.8% of the patients.

Conclusion: Cyclosporine is a valuable treatment option for patients with hand eczema,

especially in patients with recurrent vesicular hand eczema. Moreover, cyclosporine can be

used for longer periods of time without the occurrence of serious adverse events.

4chapter

137

IntroductionHand eczema is a common condition affecting approximately 10% of the population.1

Topical corticosteroids are the mainstay of treatment.2 However, an estimated 3-5% of hand

eczema patients is unresponsive to topical treatment. Various guidelines recommend either

phototherapy and/ or systemic treatment for these patients.3-5 Although, except for one

type of retinoid6-8, the evidence for systemic therapy is limited and head to head trials are

lacking.9-11 Therefore clinicians base their choice of treatment often on clinical experience.

Cyclosporine is a cyclic polypeptide with a potent immunosuppressive effect. It specifically

inhibits the proliferation of T-lymphocytes, without influencing phagocyting cells and without

suppressing hematopoiesis. Cyclosporine is the only registered systemic treatment for

severe atopic dermatitis, but is not registered for the treatment of hand eczema.

In this retrospective daily use study the drug survival of cyclosporine was investigated.

Drug survival is the period of time during which a patient remains on a specific treatment.12

This depends on a combination of factors such as drug effectiveness, occurrence of adverse

events, patient satisfaction and availability of alternative treatments.12,13 If a treatment is

effective, the treatment will be continued, or the patient will discontinue over time due

to disease control. Therefore, drug survival is a useful outcome parameter for treatment

success which can be used retrospectively. In addition, a retrospective clustered Physician’s

Global Assessment (PGA) was used.

The aim of this study was to examine the effectiveness of cyclosporine by means of drug

survival in a daily practice cohort of patients with chronic hand eczema.

Material & MethodsSubjects & treatmentThis retrospective study was conducted at the Dermatology Departments of the University

Medical Center Groningen (UMCG) and the University Medical Center Utrecht (UMCU). To

be included, patients had to fulfill the following criteria: a clinical diagnosis of chronic hand

eczema and treatment with cyclosporine between 01-06-1999 and 01-06-2014 (data-lock). In

the UMCG patients were identified based on the clinical diagnosis and the hematological

monitoring of creatinine, since this is mandatory during cyclosporine treatment. In the

UMCU patients were identified based on the clinical diagnosis combined with prescription

records.

Patients with doubtful hand eczema or psoriasis on the remaining of the body were ex-

cluded. Patients with predominantly atopic dermatitis in which the hands were also involved,

were excluded as well and will be discussed in a separate paper.

Two different dosages schedules were used: step-up and step-down regime. In the step-up

regime the dermatologist starts with a low-intermediate dosage of cyclosporine (≤ 3.5 mg/

4chapter

138

kg/day) and gradually increases the dosages in the following weeks to months, which was

more often used in the UMCG in the past. In the step-down regime the start dosages was

higher (>3.5 mg/kg), and slowly tapered over time, which was more often prescribed in the

UMCU and recently in the UMCG. During treatment with cyclosporine, patients used topical

emollients and/or topical corticosteroids.

Whenever the hand eczema was controlled, the dosage of cyclosporine was gradually

tapered.

Data collectionMedical records were retrospectively analysed with regard to patient characteristics, type of

medication, start and maintenance dosages (<3.5 mg/kg/day or >3.5 mg/kg/day), start and

stop dates, adverse events, laboratory parameters, co-medication, patch tests and contact

sensitizations. Non-naive patients were treated with another systemic agent in the past, such

as acitretin or azathioprine.

Hand eczema was classified according to clinical diagnoses of the Danish Contact Dermatitis

Group: chronic fissured hand eczema, recurrent vesicular hand eczema, hyperkeratotic

palmar eczema, pulpitis, interdigital eczema and nummular hand eczema.3 Retrospective

classification was conducted based on the flow chart of Boonstra et al. in addition to the

doctors diagnosis.14

The effectiveness of treatment was retrospectively assessed after three months of treatment

according to the clustered physician’s global assessment (PGA) score of Hijnen et al.15 This

clustered PGA ranges 1 to 3:

PGA 1: good effect; more than 50% improvement, •PGA 2: moderate effect; patients with less than 50% improvement, •PGA 3: failure of treatment; no improvement or worse.•

Drug survival and statistical analysesData analyses were performed with IBM SPSS Statistics (SPSS, Chicago, IL, USA) for

Windows (version 22.0). Chi squared test and Mann-Whitney U test were used whenever

appropriate.

Duration of drug survival was defined as the number of days which an individual continued

the first treatment episode. Treatment interruptions up to 14 days were allowed and

considered as one continuous treatment episode. Reasons for drug discontinuation were

registered. For each subject only the first treatment episode was analysed.

Drug survival was descriptively analysed using Kaplan-Meier survival curves. Graphpad

prism version 5.04 was used to create Kaplan Meier survival curves. Separate analyses were

conducted for discontinuation in general (a), discontinuation due to adverse events (b) and

due to ineffectiveness (c). In the overall analysis (a), subjects were censored when still active

4chapter

139

at the moment of data lock or when lost to follow-up. In sub analyses (b, c) subjects were

censored for all other reasons than the reason of interest. Subjects that discontinued be-

cause of both adverse events and ineffectiveness were considered to have an event in both

sub analyses (b, c).

In addition, the influence of the following determinants was analysed by univariate Cox-

regression models: gender, age, prior immunosuppressive drugs, dosage, co-medication

and clinical type of hand eczema. Determinants with p-values <0.2 were entered in a

multivariate Cox-regression model. By backward selection, a full model was built to identify

independent determinants which influence the overall drug survival for cyclosporine.

Missing values were excluded from analyses. Determinants with a p-value <0.05 were

considered statistically significant.

ResultsPatient characteristicsA first episode of cyclosporine was prescribed to 102 hand eczema patients, of whom 71

patients were treated in the UMCG and 31 patients in the UMCU. Cyclosporine was

often prescribed to patients with recurrent vesicular hand eczema (64.7%) and 42.2% had a

physician-diagnosed history of atopic dermatitis (Table 1).

n (%)

Male gender 57 (55.9)

Age over 40 years 62 (60.8)

Mean age (SD) 44.7 (±13.7)

Prior oral immunosuppressive drugs 21 (20.6)

At least 1 positive patch test reaction 64 (62.7) (12 missing)

A history of atopic dermatitis 43 (42.2) (1 missing)

Concomitant potent topical corticosteroids 78 (76.5)

Start dosages <3.5 mg/kg/day 50 (49.0) (17 missing)

Morphology

Recurrent vesicular hand eczema • 66 (64.7)

Hyperkeratotic palmar eczema • 15 (14.7)

Chronic fissured dry hand eczema • 12 (11.8)

Nummular hand eczema • 1 (1.0)

Pulpitis • 1 (1.0)

Non classifiable • 7 (6.9)

Table 1 Demographic characteristics of included patients

4chapter

140

Overall drug survival rates of cyclosporineFig. 1 shows the drug survival for cyclosporine in patients with hand eczema. The overall

drug survival rates after 6 months, 1, 2 and 3 years were 61.7%, 45.2%, 18.6% and 13.9%,

respectively. The median survival duration for cyclosporine in hand eczema was 0.86 year

(10.3 months). The treatment duration ranged from 6 days to 13.7 years.

Fig. 1 Cyclosporine drug survival

Determinants of drug survivalTable 2 shows results from the univariate Cox-regression analyses. Potential determinants

associated with the overall drug survival for cyclosporine were: male sex, concomitant use of

potent topical corticosteroids, recurrent vesicular hand eczema, prior oral immunosuppres-

sive medication and at least one positive patch test. The multivariate Cox regression analysis

demonstrated that only male sex was an independent determinant associated with a longer

overall drug survival for cyclosporine (HR 0.536, 95%CI 0.334-0.861). Recurrent vesicular hand

eczema was borderline significant.

Effectiveness based on PGA The majority of the patients (59.8%) showed an improvement in their hand eczema of at least

50% after three months of treatment (PGA1). Gender, age, being naïve, clinical type of hand

eczema and co-medication did not influence PGA score of cyclosporine after three months

(data not shown). In the group of patients with recurrent vesicular hand eczema 66.7%

reached a PGA1 score.

4chapter

141

4chapter

With regards to drug survival, ineffectiveness was a reason to discontinue cyclosporine

treatment in 11.1%, 18.0%, 40.9% and 52.2% of the patients after 6 months, 1, 2 and 3 years,

respectively (Fig. 1c). Twenty three of 102 patients discontinued cyclosporine because of

ineffectiveness (Table 3).

Overall drug-survival Event = discontinuation

Hazard ratio [CI95%]

Increasing age every 5 years 1.015 [0.927-1.113]

Male sex 0.641 [0.412-0.996]*

Atopic dermatitis 0.929 [0.597-1.446] (1 missing)

Positive patch test 1.457 [0.852-2.492] † (12 missing)

Recurrent vesicular hand eczema 0.722 [0.459-1.136] †

Prior oral immunosuppressive drugs 1.453 [0.866-2.436] †

Concomitant potent topical corticosteroids 0.596 [0.354-1.003] †

Start dosage >3.5 mg/kg/day 0.877 [0.535-1.438] (17 missing)

Table 2 Determinants of overall drug survival determined by univariate Cox regression analyses † p<0.2* p< 0.05

n (%)

Status at the moment of data lock

Active• 13 (12.8)

Stop due to ineffectiveness• 18 (17.6)

Stop due to adverse events• 44 (43.1)

Stop due to adverse events & ineffectiveness• 5 (4.9)

Stop due to disease control• 11 (10.8)

Other stop reason (pregnancy wish, non-adherence, other compound)• 3 (2.9)

Lost to follow up• 8 (7.6)

Effectiveness after 3 months15

PGA 1• 61 (59.8)

PGA 2• 20 (19.6)

PGA 3• 16 (15.7)

Missing PGA• 5 (4.9)

Table 3 Treatment characteristics

Adverse events One or more adverse events occurred in 71 patients (69.6%). In 24 patients (23.5%) hyper-

tension was registered, which was a reason to discontinue therapy in 21 patients (Table 4).

142

Eight patients (7.8%) encountered an increase in serum creatinine levels of at least 30%

and six patients discontinued therapy because of this. Gastrointestinal complaints (18.6%)

and headache (18.6%) were the most reported subjective adverse events. In total 49 (48%)

patients discontinued their treatment due to adverse events (Table 3 & Table 4).

With regards to drug survival, adverse events were a reason to discontinue treatment with

cyclosporine in 28.6%, 40.8%, 59.1% and 62.2% of the patients after 6 months, 1, 2 and 3

years respectively (Fig. 1b). The patient who used cyclosporine for 13.7 years does not suffer

from any adverse events, though the hand eczema flares whenever the dosages is reduced

and patients refused to discontinue treatment.

DiscussionCyclosporine is a valuable treatment option for patients with hand eczema. Despite the

fact that cyclosporine is not registered for the treatment of hand eczema extensive clinical

experience exists. This is the first study on drug survival of cyclosporine in patients with hand

eczema

Drug survival as outcome parameterAs expected, a substantial number of patients discontinued cyclosporine treatment in

the first months. The majority of these patients discontinued treatment because of insur-

mountable adverse events early in treatment, as represented by the steep curve in Fig. 1b.

Systemic treatments require some time before their effectiveness is established, though

overall cyclosporine is rapid-acting.16 Therefore, a substantial number of drop outs due to

ineffectiveness was expected in the first months of therapy, but not in the first days/weeks:

this is shown by the small plateau, followed by a steep drop in Fig. 1c.

After one year of treatment, few patients discontinued treatment due to adverse events,

and when the drug survival was plotted further then three years (data not shown), none of

the patients dropped out because of adverse events. When patients ‘survived’ the first year

of treatment, the chances of dropping out diminished and drug survival rates up to 13.7

years were even registered. After three years subjects did stop because of ineffectiveness or

disease control, but over time other reasons such as pregnancy wish or non-specific request

of the patient, were more often reasons for discontinuation.

Patients who used cyclosporine for several months were expected to eventually discontinue

treatment because of disease control. However, even after two years of treatment patients

discontinued treatment due to ineffectiveness, though treatment had been effective before.

This might be a result of treatment ineffectiveness after dose reduction. If patients use

cyclosporine for a substantial period of the time, physicians are inclined to taper the

4chapter

143

dosages or patients request a lower dosage out of fear for adverse events. This tapering

may result in a flare of the hand eczema. In addition the chronic and relapsing course of

hand eczema can result in flares without a change is dosages.

In the drug survival analyses, some patients were censored early in treatment. The majority

of these patients was referred back to their local hospital after successful initiation of treat-

ment. Moreover, active users were censored. Including these censored patients would have

resulted in even longer drug survival.

Daily-life versus clinical trialDifference in drop-out rates between clinical trials and daily practice is a well-known

phenomenon.17 Clinical studies investigate the efficacy of a drug under ‘ideal’ study condi-

tions, while daily practice studies investigate the effectiveness of a drug under ‘usual’

conditions. Trial patients are overall ‘perfect’ patients who fulfill strict in- and exclusion

criteria and follow a strict trail protocol towards a fixed end goal. Moreover, trial patients

may be more motivated to continue treatment. Because of this, the internal validity is higher

in clinical trials, but the external validity may be lower compared to daily use studies.

Cyclosporine was first described to treat recalcitrant vesicular hand eczema in 1992.18 In a

small case series by Reitamo et al.11, 6 out of the 7 patients responded moderately to good

to cyclosporine during 2-16 weeks of treatment. Granlund et al. compared cyclosporine A

to topical 0.05% betamethasone-17,21-dipropionate cream in 41 patients with chronic hand

eczema for six weeks: both gave significant improvement, without significant differences

between the groups.10,19 Granlund et al. found a decrease in severity of hand eczema of at

least 50% in half of the patients using cyclosporine.10 These results are in line with our results:

more than half of the patients (59.8%) in our cohort achieved an improvement of at least 50%

of their eczema after three months. The same is true for atopic dermatitis: in a meta-analysis

which included 15 studies on atopic dermatitis, Schmitt et al. found a relative effectiveness

of 55% (95%CI 48-62%) for cyclosporine.16

The study of Granlund and the case series of Reitamo were of short duration and only one

follow-up study was conducted, although the subjects in this follow-up study did not receive

active cyclosporine treatment.20 For cyclosporine the tendency exists to give the drug for

short crisis interventions and to taper as soon as possible. However, the current study

demonstrated a median survival for cyclosporine of 10.3 months. Since long term use data

of cyclosporine in hand eczema do not exist, it is not possible to compare our results to

other studies in hand eczema patients.

Cyclosporine is extensively studied in patients with atopic dermatitis and Schmitt et al.

conducted an extensive meta-analysis of 602 atopic dermatitis patients in clinical trials of

cyclosporine.16 Schmitt concluded that the use of cyclosporine was limited by the occurrence

4chapter

144

of adverse events. They calculated the risk of adverse events in patient months (the months

that patients in a study are followed divided by the event of interest) to compare 15 different

studies. In 11% of the patient months serum creatinine levels increased significantly, hyper-

tension occurred in 6% of patient months and gastrointestinal symptoms in 40% of patient

months. Our study found a lower number of increased creatinine levels, hypertension and

gastrointestinal symptoms, but in our cohort adverse events were the major reason for

discontinuation of treatment as well.

AlitretinoinRecently, the retinoid alitretinoin was registered for the European market. In large, well-

conducted, trials 30 mg alitretinoin a day resulted in clear or almost clear hand eczema in

48% of the participants.6-8 However, of the participants with vesicular hand eczema only one

third (33%) achieved clearance or almost clearance, compared to 16% in the placebo group

(based on Physician Global Assessment on a 5-point scale). In our study, cyclosporine gave

a PGA1 score in 59.8% of all patients and in the subgroup of 66 patients with vesicular hand

eczema 66.7% of them achieved a PGA1 score. The clustered PGA score in our retrospec-

tive study is less reliable than the prospective PGA used by Ruzicka et al. However, based on

these results, a head-to-head trial comparing cyclosporine to alitretinoin is highly recom-

mended. Schmitt et al. registered a clinical trial comparing cyclosporine to alitretinoin in all

kinds of hand eczema, but the trial was ended prematurely (clinicaltrials.gov NCT01231854).

Alitretinoin was not included in this daily life study, since it was registered in the Netherlands

only recently (September 2013). Moreover the maximum recommended treatment duration

for alitretinoin is 24 weeks: therefore drug-survival will not be a suitable outcome.

Limitations of the studyThe retrospective nature of this study is one of the major limitations. However, in almost all

medical records start- and stop dates and reasons for discontinuation were registered in

detail and drug survival is reliable even in a retrospective design. With regard to the

effectiveness after three months, a clustered PGA score was used, which had been used for

retrospective analyses more often.15 Moreover, missing information was excluded from

analyses. Selection bias may have occurred: physicians may have been more prone to pre-

scribe for example acitretin in hyperkeratotic hand eczema, and cyclosporine for vesicular

hand eczema based on their own clinical experience. One should take this potential skewed

distribution into consideration when interpreting these results. Moreover, this study included

various tertiary referral patients, who tend to suffer of more recalcitrant eczema. This could

limit the generalizability of this study.

Only the first episode of cyclosporine was analysed in order to prevent further selection

bias and to prevent distortion, because dermatologists may be inclined to re-introduce

4chapter

145

cyclosporine if the first treatment episode was successful

Over the years the attitude of dermatologists towards systemic drugs has changed. In the

past many physicians started with a low dosage cyclosporine for short intervals. Nowadays,

a higher start dosage is more common. Subgroups analyses regarding the start dosages did

not favor a step-up or step-down regime, though these subgroups were relative small and

further studies are warranted.

ConclusionThis study demonstrated that cyclosporine is a valuable treatment option for patients with

severe hand eczema with a long median drug survival of 10.3 months. Cyclosporine is

especially effective in patients with recurrent vesicular hand eczema and should be

considered in this subgroup as one of the first treatment options.

AcknowledgementWe would like to thank Raisa Thybaut and Anna Brandsma for their help with data collection,

Wietske Kievit, Elke de Jong and Juul van den Reek for their support with the statistical

analyses and finally Tanja Vogel for her input in the manuscript.

4chapter

146

ReferencesMeding B, Jarvholm B. Incidence of hand eczema-a population-based retrospective study.1.

J Invest Dermatol 2004:122:873-877.

Soost S, Abdollahnia M, Kostev K, Worm M. Topical therapy of hand eczema - analysis of the 2.

prescription profile from dermatologists in private practice. J Dtsch Dermatol Ges 2012:10:180-184.

Menné T, Johansen JD, Sommerlund M, Veien NK, Danish Contact Dermatitis Group. Hand 3.

eczema guidelines based on the Danish guidelines for the diagnosis and treatment of hand ec-

zema. Contact Dermatitis 2011:65:3-12.

Diepgen TL, Elsner P, Schliemann S, Fartasch M, Kollner A, Skudlik C, 4. et al. Guideline on the

management of hand eczema ICD-10 Code: L20. L23. L24. L25. L30. J Dtsch Dermatol Ges

2009:7 Suppl 3:S1-16.

Lynde C, Guenther L, Diepgen TL, Sasseville D, Poulin Y, Gulliver W, 5. et al. Canadian hand

dermatitis management guidelines. J Cutan Med Surg 2010:14:267-284.

Ruzicka T, Larsen FG, Galewicz D, Horvath A, Coenraads PJ, Thestrup-Pedersen K, 6. et al. Oral

alitretinoin (9-cis-retinoic acid) therapy for chronic hand dermatitis in patients refractory to standard

therapy: results of a randomized, double-blind, placebo-controlled, multicenter trial.

Arch Dermatol 2004:140:1453-1459.

Ruzicka T, Lynde CW, Jemec GB, Diepgen T, Berth-Jones J, Coenraads PJ, 7. et al. Efficacy and safety

of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to

topical corticosteroids: results of a randomized, double-blind, placebo-controlled, multicentre trial.

Br J Dermatol 2008:158:808-817.

Bissonnette R, Worm M, Gerlach B, Guenther L, Cambazard F, Ruzicka T, 8. et al. Successful

retreatment with alitretinoin in patients with relapsed chronic hand eczema. Br J Dermatol

2010:162:420-426.

Thestrup-Pedersen K, Andersen KE, Menné T, Veien NK. Treatment of hyperkeratotic dermatitis of 9.

the palms (eczema keratoticum) with oral acitretin. A single-blind placebo-controlled study.

Acta Derm Venereol 2001:81:353-355.

Granlund H, Erkko P, Eriksson E, Reitamo S. Comparison of cyclosporine and topical 10.

betamethasone-17,21-dipropionate in the treatment of severe chronic hand eczema.

Acta Derm Venereol 1996:76:371-376.

Reitamo S, Granlund H. Cyclosporin A in the treatment of chronic dermatitis of the hands. 11.

Br J Dermatol 1994:130:75-78.

Burden AD. Drug survival rates for tumour necrosis factor-alpha antagonists in psoriasis. 12.

Br J Dermatol 2011:164:940-941.

Gniadecki R, Kragballe K, Dam TN, Skov L. Comparison of drug survival rates for adalimumab, 13.

etanercept and infliximab in patients with psoriasis vulgaris. Br J Dermatol 2011:164:1091-1096.

4chapter

147

Boonstra MB, Christoffers WA, Coenraads PJ, Schuttelaar MLA. Patch test results of hand eczema 14.

patients – relation to clinical types. Journal of the European Academy of Dermatology &

Venereology ahead of printing:.

Hijnen DJ, ten Berge O, Timmer-de Mik L, Bruijnzeel-Koomen CA, de Bruin-Weller MS. Efficacy 15.

and safety of long-term treatment with cyclosporin A for atopic dermatitis. J Eur Acad Dermatol

Venereol 2007:21:85-89.

Schmitt J, Schmitt N, Meurer M. Cyclosporin in the treatment of patients with atopic eczema - a 16.

systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2007:21:606-619.

Martin K, Begaud B, Latry P, Miremont-Salame G, Fourrier A, Moore N. Differences between clinical 17.

trials and postmarketing use. Br J Clin Pharmacol 2004:57:86-92.

Petersen CS, Menné T. Cyclosporin A responsive chronic severe vesicular hand eczema. 18.

Acta Derm Venereol 1992:72:436-437.

Granlund H, Erkko P, Reitamo S. Comparison of the influence of cyclosporine and topical 19.

betamethasone-17,21-dipropionate treatment on quality of life in chronic hand eczema.

Acta Derm Venereol 1997:77:54-58.

Granlund H, Erkko P, Reitamo S. Long-term follow-up of eczema patients treated with cyclosporine. 20.

Acta Derm Venereol 1998:78:40-43.

4chapter