|The therapeutic use of topical contact sensitizers in benign dermatoses
|Buckley D A, Du Vivier A W
To review the published literature on the therapeutic use of topical sensitizers for alopecia areata (AA) and viral warts.
MEDLINE was searched from 1966 to December 2000, and EMBASE from 1988 to December 2000. The searches were conducted using the MeSH terms 'alopecia areata', 'warts', 'topical immunotherapy' and 'contact sensitizers', and the textwords 'alopecia areata', 'warts', 'topical immunotherapy', 'contact sensitizers', 'diphenylcyclopropenone', 'dinitrochlorobenzene' and 'squaric acid dibutyl ester'. The Cochrane Database of Systematic Reviews, DARE and the NHS HTA (UK) Internet sites were also searched. Additional studies were identified by examining citations from reference lists, and letters were sent to dermatologists requesting information on unpublished studies. Studies published in English, French, Spanish, Italian and German were included. All but one of multiple publications were excluded.
Study designs of evaluations included in the review
Primary studies of all types were included. Single case reports and series of fewer than ten patients were excluded.
Specific interventions included in the review
The intervention were topical applications of diphenylcyclopropenone (DPCP), dinitrochlorobenzene (DNCB) and squaric acid dibutyl ester (SADBE) as sole treatment. Studies using these substances as part of combination treatment were excluded, unless at least one treatment arm used a contact sensitizer alone.
A variety of dosages and frequencies of treatment were used, which are too numerous to report in this abstract; details of the specific treatment regimens were tabulated;.
Participants included in the review
Patients with AA or viral warts. The types of AA were totalis or universalis, greater than 40%, less than 40% and other or mixed. The types of viral warts were common, plantar, plane, periungual and other or mixed.
Outcomes assessed in the review
Studies were excluded if the outcome measures were not adequately defined, i.e. in terms of the numbers showing complete regrowth of terminal scalp hair or the numbers who were completely cleared of warts. The number of patients suffering side-effects was also recorded.
How were decisions on the relevance of primary studies made?
The authors do not state how the papers were selected for the review, or how many of the reviewers performed the selection.
Assessment of study quality
The quality of case series was assessed on the basis of eight criteria.
1. Were the data collected prospectively or retrospectively and could this be assessed?
2. How were the patients selected and how representative is the sample with regard to the population of patients with AA and warts requiring treatment?
3. How well were the patients described?
4. How was any improvement assessed?
5. Were the observers blinded?
6. Were there any control patients?
7. Were the baseline data, outcome data, follow-up and loss to follow-up reported in full, and were all patients accounted for in the analysis?
8. Were side-effects reported in detail?
The authors do not state how the papers were assessed for quality, or how many of the reviewers performed the quality assessment.
The data were extracted by one of the authors following discussion with the UK Cochrane Trial Search Coordinator. The following data were extracted from the studies: study design, participant characteristics, disease characteristics, treatment regimen, withdrawals, symptom relief and adverse effects. Further details are available in the paper.
The percentages of patients with complete clearance of warts or complete regrowth of hair were calculated in relation to the number of individuals entering the study, i.e. on an 'intention to treat' basis (where this was feasible from the available data).
Methods of synthesis
How were the studies combined?
The results from the individual studies were summarised in a table and described narratively, with emphasis on the better quality study designs. The range and median of overall clearance rates were presented in the text. Publication bias was not assessed.
How were differences between studies investigated?
Heterogeneity was not formally assessed.
Results of the review
Treatment of warts: 6 case series using DPCP (551 patients), 5 using SADBE (696 patients), and 15 using DNCB (631 patients) were eligible for inclusion in the review. One of the studies using DNCB was placebo-controlled, in another the control half of the body was treated with acetone, and in two others the control half of the body was left untreated.
Treatment of AA: 15 studies using DPCP (736 patients), 14 using SADBE (676 patients), and 8 using DNCB (264 patients) were eligible for inclusion in the review. Two of the studies were randomised placebo-controlled trials. Half-head studies were common, using half the patient's head as untreated control (n=14), treating half with the irritant sodium lauryl sulphate (n=1), or in one case treating initially only a single patch. The remaining studies were uncontrolled (n=15), had croton oil (n=1), tretinoin (n=1) or topical psoralen UV radiation A (n=1) as control treatment, or used combination treatment with interferon-alpha (n=1). Most of the studies were retrospective.
The overall clearance rates of warts in the included studies ranged from 7 to 100% (median: 62%). The worst results were obtained in studies where the number of applications of treatment was limited, e.g. to 8 weeks. This suggested that treatment for as long as necessary results in higher clearance rates. Some patients treated for a limited duration only cleared after cessation of therapy. Side-effects occurred in 10 to 50% of the individuals but few patients were withdrawn for this reason. Withdrawal due to non-compliance was more common, and was in keeping with the difficulty of attending for multiple appointments.
The overall clearance rates of AA in the included studies ranged from 0 to 70% (median 30%). Side-effects were seen in up to 100% of the patients but subsequent withdrawal was uncommon, suggesting a highly motivated group of patients.
The evidence base for topical immunotherapy of both warts and AA with DPCP, SADBE and DNCB remains poor. Placebo-controlled studies have been unable to demonstrate any significant benefit in AA, but half-body studies have shown a striking advantage of immunotherapy over no treatment. Both types of study were unable to demonstrate a significant benefit in the treatment of warts.
The authors stated their review question and the inclusion criteria clearly. The literature search was adequate and included contacting dermatologists in an attempt to identify grey literature. Publication bias was not assessed.
The quality of the individual studies was systematically assessed. The authors did not describe the decision-making process for selecting the studies, such as how many of the reviewers were involved, whether the studies were examined independently, or whether the reviewers were blinded to source.
Details of the studies were reported thoroughly in tables and supplemented by a narrative discussion. The range and median of the results of the primary studies were reported; the results of better quality studies were described further.
The authors highlighted the poor quality of the primary research in this area, which has a detrimental effect on the findings of the review. However, the authors' conclusions appear justified.
Implications of the review for practice and research
Practice: The authors state that when treating warts with contact sensitizers it seems prudent to restrict treatment to plantar, palmar, periungual and digital sites. In the treatment of AA, it is worth being aware that patients with long duration of disease, extensive disease, young age at onset, a family history of AA, atopy, presence of nail changes and anergy are less likely to respond. It seems appropriate to reserve topical immunotherapy for very highly motivated patients who understand that there is limited evidence of treatment efficacy, and that the treatment can cause side-effects.
Research: The authors did not state any implications for further research.
Buckley D A, Du Vivier A W. The therapeutic use of topical contact sensitizers in benign dermatoses. British Journal of Dermatology 2001; 145(3): 385-405
Subject indexing assigned by NLM
Allergens /therapeutic use; Alopecia Areata /therapy; Cyclopropanes /immunology; Dinitrochlorobenzene /immunology; Female; Humans; Immunotherapy /adverse effects /methods; Irritants /immunology; Male; Warts /therapy
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.