Citation for published version (APA): Coevorden, A. M. V. (2005). Hand eczema: clinical efficacy of interventions, and burden of disease s.n.

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1 University of Groningen Hand eczema Coevorden, Anthony Marco van IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2005 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Coevorden, A. M. V. (2005). Hand eczema: clinical efficacy of interventions, and burden of disease s.n. Copyright Other 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 the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 CHAPTER 2 OVERVIEW OF THERAPEUTIC STUDIES OF TREATMENTS FOR HAND ECZEMA THE EDEN HAND ECZEMA SURVEY A.M. van Coevorden, P.J. Coenraads, Å. Svensson, J.N. Bouwes Bavinck, T.L. Diepgen, L. Naldi, P. Elsner, H.C. Williams, on behalf of the European Dermato-Epidemiology Network (EDEN) British Journal of Dermatology 2004; 151:

3 Chapter 2 ABSTRACT Hand eczema is a major cause of morbidity and lost earnings. Many interventions ranging from topical corticosteroids to oral ciclosporin are used, but their evidence base and the best methods to assess their efficacy are uncertain. As part of a long-term project to improve standards of design and reporting in hand eczema trials, we sought to describe the prevalent study designs and comment on the quality of reporting of such studies. Electronic databases (Cochrane, Medline, Embase, Pascal, Jicst-Eplus, Amed) were searched from the beginning of 1977 to April 2003 using all possible variants of the term hand in combination with the terms eczema or dermatitis. In addition, four general medical and 17 specialist dermatology journals were hand-searched by pairs of researchers for all possible therapeutic studies. Studies were eligible for inclusion if they dealt with hand eczema as diagnosed by a physician irrespective of the aetiology and if they described the results of a study of a therapeutic intervention in humans. Single case reports and reviews were excluded, but case series and non-randomised studies were considered alongside randomised studies. For each study, two researchers independently assessed the type of study, outcome measures, enrolment criteria, randomisation, masking of interventions, and how losses to follow-up were dealt with. Main outcome measures: Proportion of studies according to type of intervention and study type. Proportion of randomised controlled trials (RCTs) that adequately reported eligibility criteria, randomisation generation and concealment, masking and intention-to-treat analysis. A total of 90 studies reported in 87 papers dealt with 11 different classes of interventions. Around 80% of the studies dealt with just four interventions: ultraviolet light, topical corticosteroids, radiation and systemic immunosuppresives. Of the 90 studies, 44 were case series, 15 were nonrandomised controlled trials, and the remaining 31 were RCTs. Of the 31 RCTs, 16 were parallel (one with cross-over design) and 15 self-controlled. Only 11 of the RCTs adequately reported eligibility criteria. The randomisation method was described in 10, and there was adequate concealment of allocation in eight. Masking the treatment allocation from both the study assessors and patients was done in 11 RCTs, and intention-to-treat analysis was reported in four. Only 13 RCTs were 4 months or longer in duration. No study reported a rationale for the sample size and in only one study had the outcome variable been validated. Most trials in hand eczema are not RCTs. Internally controlled (leftright) studies were common. Based on the poor overall quality of reporting, most RCTs of hand eczema trials are not adequate to guide clinical practice. Future trials of hand eczema should be randomised, using a parallel group or 24

4 Overview of therapeutic studies of treatments for hand eczema self-controlled design. Research is needed to develop validated and clinically relevant outcome measures. Most of the remaining issues relating to poor quality of existing evidence can be relatively easily dealt with by following the CONSORT guidelines. INTRODUCTION Hand eczema is a common skin disorder affecting more than 1% of the adult population; in several studies the one-year prevalence is almost 10% with considerably higher prevalences among certain occupational groups engaged in wet work such as hairdressers, cooks, domestics, nurses and print workers. 1 2 Hand eczema can be defined simply as an inflammation of the skin of the hands, which includes several clinical subtypes such as pompholyx, vesicular, atopic, endogenous, discoid, acral, irritant, allergic, tylotic and hyperkeratotic eczema. 3 The condition tends to run a chronic relapsing course. Concomitant involvement of the feet is common. Hand eczema can vary from mild involvement of a few fingers to a severe incapacitating and extremely itchy blistering eruption affecting all of the hand and fingers. Chronic hand eczema is characterised by thick scaly skin that gives rise to painful cracks (fissures) over the joints. Hand eczema may be caused by external irritant agents such as soaps and to a much lesser extent, contact allergens such as chromate found in cement. Often the cause is unknown ( endogenous ) or it is atopic hand eczema, or a combination of irritant, allergic and endogenous factors are acting in concert. It has been suggested that the multifactorial origin of hand eczema is responsible for the chronic course of the condition and for its poor response to treatment. Many different therapeutic options are available, with considerable variation in preference among physicians, patients and countries. A recent review of commonly prescribed treatments for hand eczema concluded that there was little evidence for recommending any one treatment over another. 3 This study was undertaken by the European Dermato-Epidemiology Network (EDEN) to survey the quality (internal validity) and generalisability (external validity) of the therapeutic studies on hand eczema published since The aims were to summarise the range of treatments tested, to describe methods used to assess therapeutic efficacy and to assess the quality of those studies found. The overall aim of the survey is to promote a better understanding of the peculiarities of clinical studies in hand eczema and to make recommendations that could help improve the quality of future clinical research on therapeutic studies dealing with hand eczema. 25

5 Chapter 2 METHODS Search strategy All publications, including letters to the editor, comments etcetera over the past 25 years, i.e. from 1977 to mid-2003, describing the results of a therapeutic intervention in humans ( trials ) were considered eligible. Because of the difficulty in ascribing a precise cause to a person with hand eczema, for pragmatic reasons we accepted a diagnosis of hand eczema as made by a physician as acceptable, regardless of the underlying assumed aetiology. Variants of the term eczema such as dermatitis, pompholyx, dyshidrosis, and pulpitis were acceptable, wherever it referred to the hands. To ensure completeness in capturing all possible uncontrolled ( open ) studies, the identification process of eligible publications included hand-searching and searching of electronic databases. We excluded studies that were case reports describing a single case, review articles and studies dealing exclusively with non-clinical outcomes such as transepidermal water loss. Hand-searching was performed on the terms eczema, eczematous, dermatitis, hand, hands, palmoplantar, inflammatory, inflammation for four general medical English-language journals (British Medical Journal, Journal of the American Medical Association, Lancet, New England Journal of Medicine). In addition, 12 English-language dermatological journals, two major German, one major Italian, one major Dutch, and one major French dermatology journal were hand-searched (selected because they were the main journals where clinical trials are published). Table 1 shows the journals that were handsearched. Table 1. Journals that were hand-searched Acta Dermatovenereologica Annales de Dermatologie et Vénéreologie Archives of Dermatological Research Archives of Dermatology British Journal of Dermatology British Medical Journal Clinical and Experimental Dermatology Contact Dermatitis Cutis Dermatology (formerly Dermatologica) Environmental Dermatology Journal of Dermatologic Treatment Journal of Investigative Dermatology Journal of the American Academy of Dermatology Journal of the American Medical Association. 26

6 Overview of therapeutic studies of treatments for hand eczema Table 1. Journals that were hand-searched (continued) Lancet New England Journal of Medicine Hautarzt Giornale Italiano di Dermatologia e Venereologia Nederlands Tijdschrift voor Dermatologie en Venereologie HG-Zeitschrift für Hautkrankheiten The electronic searching process, using all possible variants of the term hand in combination with the terms eczema or dermatitis, identified relevant trials from the following six databases: Cochrane Skin Group Specialised Register and the Cochrane Central Register of Controlled Trials, Medline, Embase, Pascal, Jicst-Eplus and Amed. There was no language restriction on papers retrieved from electronic searches. Data abstraction Eligibility for study inclusion was checked independently by a pair of reviewers. If both reviewers agreed that the study was eligible, they then proceeded to independently record a range of methodological and study quality issues on a standard data abstraction form. Discrepancies were resolved by discussion between the two reviewers, or, if no agreement could be found, by a third reviewer. Where there were duplicate publications of the same trial, the paper with the most relevant data was used. If papers were rejected, the reasons were entered in a separate database. The following items were recorded for each study: publication year, intervention(s) examined, number of patients included and sponsoring by a pharmaceutical company. Papers were classified either as studies lacking internal control (including studies without any explicit control group), studies with external historical controls or as studies with internal control, which included parallel concurrent control studies, self-controlled studies (e.g. leftright hand comparison studies) and crossover studies. Without making any judgement of the appropriateness of the methods, each study was assessed on quality criteria selected a priori by the research team on the basis of their content expertise in hand eczema and from methods used to assess the quality of RCTs used by the Cochrane Collaboration ( Table 2 shows the criteria used for assessment. 27

7 Chapter 2 Table 2. Criteria used for the assessment Were entry criteria clearly specified? Was there a description of pretreatment variables such as disease severity? Was there a description of the method used to generate the randomisation sequence and subsequent concealment of allocation of the randomisation sequence? Were masking procedures clearly described? What was the duration of the study including follow-up? What efficacy parameters were employed and were these validated? What were the major endpoints? Was a sample size calculation made before the study started? If repeated measurements were done, was an appropriate time-analysis done? Was the analysis presented as an intention-to-treat analysis? Did the main results include confidence intervals? Statistics Simple descriptive statistics were calculated for all parameters used, whereby only the most relevant figures (mostly simple counts) are presented. Statistical analyses were considered for evaluating secular trends in quality, but in hindsight deemed uninformative because of the small numbers. RESULTS A total of 87 papers describing trials of a treatment for hand eczema were identified. Three papers reported two trials, giving a total of 90 trials to be assessed. Four journals Acta Dermatovenereologica (14 papers), British Journal of Dermatology (12), Journal of the American Academy of Dermatology (seven) and Contact Dermatitis (six), accounted for 39 (45%) of all papers. In 26 papers there was evidence of sponsoring, while sponsorship was unclear in 49 studies. Types of study design Table 3 shows that of the 90 trials that were identified, 44 had no explicit control group, three used historical controls, 22 had a parallel control group (of which one had a cross-over design) and 21 were left-right studies. Of the 22 parallel studies, 16 (73%) could be described as an RCT, of the 21 left-right studies 15 (76%) were RCTs. None of the studies reported the rationale of the sample size. 28

8 Overview of therapeutic studies of treatments for hand eczema Table 3. Published hand eczema trials Item Number Papers 87 Trials 90 Uncontrolled trials 45 Self-controlled (left-right) trials 21 Parallel trials 21 Other 3 Total subjects enrolled 2142 RCTs 31 RCTs with patients blinded 18 RCTs with investigators blinded 12 RCTs with patient and investigator blinded 11 RCTs with allocation concealment 8 RCTs reported rationale of sample size 0 Subjects enrolled in RCTs 1175 Description of participants Inclusion or exclusion criteria were described in 42 (47%) trials (12 had inclusion and exclusion criteria, 18 only inclusion criteria and 12 only exclusion criteria). For the 42 controlled (parallel and left-right) trials inclusion and/or exclusion criteria were described in 20. Of the 31 RCTs, 11 had defined inclusion and exclusion criteria. Patch test results were given in 27 (30%) of all trials. In 29 trials patients with diseases other than hand eczema were included (e.g. psoriasis of the hands, palmoplantar dermatoses ); in 10 trials it could not be reconstructed how many participants actually had hand eczema. None of the studies analysed age- and sex-specific therapeutic responses. Since 1977, a total of 2142 patients with hand eczema participated in the trials that were identified: of these 941 participated in a parallel study and 454 in a self controlled study. Most studies included patients with different subtypes of hand eczema; 24 trials were dealing with one specific subtype (11 with dyshidrotic/pompholyx/vesicular, four with constitutional/endogenous, four with hyperkeratotic, two with atopic, and three with other different subtypes). Issues of randomisation, blinding and dropouts Of the 43 trials with a concurrent control group, 31 (72%) could be clearly identified as randomised. A description of the randomisation method was present in three of the 22 parallel studies and in seven of the 21 self-controlled (left-right) trials. Concealment of allocation was adequate in eight of the 43 29

9 Chapter 2 controlled studies. In 10 of the 22 parallel studies and 10 of the 21 left-right studies both the investigator(s) and the patients were blinded. An intention-totreat analysis was reported in four studies that were all parallel studies. Withdrawals were reported in 35 (39%) trials; in 19 (54%) of these 35 there were more than 10% dropouts and eight studies had more than 20% dropouts. Study duration A duration of the study was not specified in 25 trials (two parallel, three leftright, two historical, and 18 open). A study duration of two months or less was a characteristic of 30 (33%) of all trials; 27 trials lasted more than two months, 20 more than three months and 13 more than four months. Outcome variables and interpretation In 56 trials there was more than one outcome variable, while in seven of these 56 trials a major endpoint was defined. An adequate description of the outcome assessment was present in 48 (53%) of all trials. Change in a scoring system was used as outcome variable in 44 (49%) of all trials; in one trial the scoring systems were validated. The scoring systems were mostly variations of arbitrary numerical scores of the severity of eczema characteristics (such as scaling, redness, vesicles, infiltration, fissures), which are subsequently summed to a total score. Burden of disease was an outcome variable in two trials; both were parallel studies. Patients own assessments were used in 24 trials. Confidence intervals and other measures of variability were presented in 11 studies. Of the 23 studies with repeated measurements, only three had an appropriate timeanalysis. Of all the trials, 77 (86%) stated a positive or promising effect of the treatment that was examined. Treatments The range of treatment modalities that were evaluated could be classified into 11 categories (table 4), ignoring variations in dose, frequency or combinations with other treatments. The majority of the trials (32) dealt with ultravioletirradiation, followed by 13 on corticosteroids. Nine types of treatment of this common disease have over the past 25 years been studied by RCTs in less than 1200 patients. 30

10 Overview of therapeutic studies of treatments for hand eczema Table 4. Treatment categories Nr. of trials RCTs Treatment categories 32 7 UV-irradiation (UVA, UVB, PUVA with oral or topical psoralen) 13 7 Corticosteroids (topical and oral) 5 2 Oral immunosuppressives (ciclosporin, mycophenolatemofetil, methotrexate) 6 6 Radiotherapy 5 0 Retinoids (oral and topical) 1 1 Calcineurin inhibitors (tacrolimus, pimecrolimus) 6 1 Barrier creams and gloves 5 0 Emollients 2 1 Antimicrobial agents 6 3 Metal (e.g. nickel) load reduction (e.g. diet, chelators) 9 3 Other 1 1 The category Other includes a range of 7 occasionally investigated treatments: diaminodiphenylsulfone (DDS), ranitidine, pentoxifylline, iontophoresis, biofeedback, vitamins, urea. Time trends Dividing the time frame from 1977 to 2003 into three subsequent nine-year periods, the distribution of randomised controlled trials was six (five selfcontrolled, one parallel) out of 25 trials for the period , 10 (four selfcontrolled, six parallel) out of 23 trials for the period , and 15 (six self-controlled, 9 parallel) out of 42 trials for the period The proportion of sponsored papers was around 20% in the first two time periods, and increased to 40% in the third time period. Since 1998, i.e. one and a half years after the first publication of the CONSORT statement, 5 there were 30 trials, of which eight were RCTs. Of these eight RCTs, only one had a description of the randomisation method, and this was the only one with both the patients and the outcome assessor blinded. Since the publication in 2001 of the revised version of the CONSORT statement on improving the quality of reports of parallel group randomised trials, 6 seven trials on hand eczema were published. Two of these were RCTs: only one had a parallel group design, and both were unclear on blinding. 31

11 Chapter 2 DISCUSSION Low quality of hand eczema studies This survey has found a wide range of treatment options for hand eczema that have been evaluated in a few small studies. Considering the high prevalence of hand eczema, it is remarkable that the results of RCTs are based on only 1200 patients. Serious limitations in quality of reporting have been found. Poor quality of reporting is strongly related to poor trial quality. 7 8 Only a third of all studies were randomised controlled trials (RCTs) arguably the evidence source that is most likely to reduce the effects of bias if conducted well. Other frequent shortcomings were lack of entry criteria, missing information on randomisation and blinding, no justification of the number of participants and no analysis of dropouts. A range of outcome parameters were presented, most of which were not validated. Internally controlled (left-right) studies were common: these studies show strength in terms of power to obtain a significant results with small participants numbers, but at the expense of problems in interpreting studies that find no difference in effect because of crosscontamination of topical interventions and the possible systemic effects of topical preparations. The fact that 86% of the studies stated a positive or promising effect may point towards publication bias. Only a few papers addressed the issue of blinding and the problems with patient blinding when the therapy has side effects that can be perceived by patients. 9 Although hand eczema has usually a chronically relapsing course, only a small proportion of the studies had a duration of more than four months required to document important data such as duration and frequency of disease relapse. We could not find any evidence that any of the various scoring methods that were used in the trials are relevant to patients, and the interpretation of the changes in scores derived by adding several physical parameters together is obscure even to clinicians. There is currently no consensus on a standard severity scale for hand eczema. A validation of commonly used scoring systems or of simple global ratings using photographic anchors is urgently needed. Duration of remission, the way the disease is brought under control, side effects and simple outcome measures applicable to all patients are preferable. 10 Strengths and limitations of this study This study has used comprehensive methods to search for relevant studies. It is possible that we could have missed important hand eczema studies that were published before 1977, although we did evaluate pre-1977 studies that were identified on the citation lists of eligible studies. We have not formally attempted to pool any of the outcome data, as this is the aim of a Cochrane Skin Group review, which is presented in chapter 4. With 32

12 Overview of therapeutic studies of treatments for hand eczema the exception of a few better quality RCTs, perhaps the most important overall recommendation is to start again. Implications for practice and research There are very few reliable studies to inform clinical practice with regard to the best way of managing hand eczema, especially in the long term. Until such data are forthcoming, physicians will continue to use an array of treatments, many of which will be ineffective or even harmful. The most important conclusion from this study is to conduct high-quality RCTs of people with hand eczema comparing commonly used interventions using simple outcome measures that can be understood by patients and clinicians. Studies need to describe in more detail what they mean by hand eczema. Subgroup analysis on irritant contact, allergic contact and endogenous groups if their data permits, is desirable, although the multifactorial origin of hand eczema and the lack of consensus regarding definitions are serious complications. Studies should be of an adequate duration (greater than 6 months) in order to capture the effect of interventions on long-term disease control as well as short-term relief of symptoms. The deficiencies of poor trial reporting could be rectified overnight if all specialist dermatology journals adopted CONSORT standards. REFERENCES 1. Meding B, Järvholm B. Hand eczema in Swedish adults changes in prevalence between 1983 and J Invest Dermatol 2002; 118: Coenraads PJ, Smit H. Dermatoses. In: McDonald JC, editor. Epidemiology of work related diseases. London: BMJ Books; 2000: McFadden JP. Hand eczema. In: Rycroft RJG, Menné T, Frosch PJ, Lepoittevin JP, editors. Textbook of contact dermatitis. Berlin: Springer; 2001: Coenraads PJ, van Coevorden AM, Diepgen TL. Hand eczema. In: Williams H, Bigby M, Diepgen T, Herxheimer A, Naldi L, Rzany B, editors. Evidence-based dermatology. London: BMJ Books; 2003: Begg CB, Cho M, Eastwood S et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA 1996; 276: Moher D, Schultz KF, Altman G. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001; 357: Huwiler-Muntener K, Juni P, Junker C, Egger M. Quality of reporting of randomized trials as a measure of methodologic quality. JAMA 2002; 287: Juni P, Altman DG, Egger M. Assessing the quality of controlled clinical trials. BMJ 2001; 323:

13 Chapter 2 9. Thestrup-Pedersen K, Andersen K, Menné T, Veien NK. Treatment of hyperkeratotic dermatitis of the palms (eczema keratoticum) with oral acitretin. A single blind placebo-controlled study. Acta Derm Venereol (Stockh) 2001; 81: Wright JG. Evaluating the outcome of treatment: Shouldn t we be asking patients if they are better? J Clin Epidemiol 2000; 53: Granlund H, Erkko P, Eriksson E, Reitamo S. Comparison of cyclosporine and topical betamethasone-17,21-dipropionate in the treatment of severe chronic hand eczema. Acta Derm Venereol 1996; 76: Veien NK, Larsen PO, Thestrup-Pedersen K, Schou G. Long-term, intermittent treatment of chronic hand eczema with mometasone furoate. Br J Dermatol 1999; 140:

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