Conflict of interest: none declared.
A systematic review of randomized controlled trials of treatments for inherited forms of epidermolysis bullosa
Article first published online: 26 SEP 2008
© 2008 The Author(s). Journal compilation © 2008 Blackwell Publishing Ltd
Clinical and Experimental Dermatology
Volume 34, Issue 1, pages 20–25, January 2009
How to Cite
Langan, S. M. and Williams, H. C. (2009), A systematic review of randomized controlled trials of treatments for inherited forms of epidermolysis bullosa. Clinical and Experimental Dermatology, 34: 20–25. doi: 10.1111/j.1365-2230.2008.02789.x
- Issue published online: 8 DEC 2008
- Article first published online: 26 SEP 2008
- Accepted for publication 21 December 2007
Background. Many interventions have been described for inherited epidermolysis bullosa (EB), but it is unclear which are beneficial.
Aims. A systematic review of randomized controlled trials (RCTs) was performed to inform practice and highlight research gaps.
Methods. The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and the Cochrane Skin Group specialist library, from inception until 1 April 2007, were searched. Primary outcomes were healing of lesions or prevention of new lesions. Trials were assessed for quality of reporting and data were extracted.
Results. Five randomized double-blind placebo-controlled crossover studies were identified (n = 102). Two studies assessed oral tetracyclines in EB simplex (EBS). In one study (n = 12), 4/6 patients improved and 2/6 deteriorated on a dose of 1500 mg of tetracycline daily; only two patients completed the study. In the second study (n = 21), 6/18 and 7/18 improved on oxytetracycline 1 g and placebo, respectively. Two RCTs assessed topical interventions for EBS: aluminium chloride hexahydrate solution 20% (n = 23) and bufexamac cream 5% (n = 8). Neither showed a benefit over placebo. One RCT of 36 patients with recessive dystrophic EB compared phenytoin with placebo and failed to show any difference in mean lesion counts (difference = 0, 95% CI −11 to 4).
Conclusions. There is no reliable trial evidence for interventions in inherited EB. In future, it may be that gene treatment becomes the best treatment approach for these diseases.
There are three major inherited forms of epidermolysis bullosa (EB): EB simplex (EBS), junctional EB and dystrophic EB, all characterized by varying degrees of skin fragility and blistering. These disorders are associated with a range of complications, reflecting their heterogeneous phenotypes, ranging from localized skin fragility to death in the neonatal period.1 Morbidity includes anaemia, ocular complications leading to blindness, sepsis, and gastrointestinal problems such as oesophageal stenosis and malnutrition. The rates of squamous cell carcinoma are also significantly increased in recessive dystrophic EB, affecting 21.7 and 53% of those aged 25 and 35 years, respectively.1 The prevalence of inherited forms of EB is estimated at around 19 per million population in the USA, and 49 per million in Scotland.1,2 Despite major advances in understanding the genetic basis for these disorders, the scientific basis and evaluation of treatment interventions remain unclear. Many interventions are described for these diseases (summarized in Table 1), but it is unclear which are beneficial.3 Some treatments are directed at wound care, whereas others purport to reduce skin fragility through systemic effects.
|Iron supplements and blood transfusions for anaemia|
|Prevention of trauma|
|Artificial skin substances|
We sought to review systematically the evidence from randomized controlled trials (RCTs) in order to inform clinical practice and to highlight research gaps.
We searched for randomized controlled trials of the inherited forms of EB in the following databases: CENTRAL (The Cochrane Central Register of Controlled Trials), the Cochrane Skin Group specialized register of trials, EMBASE and MEDLINE, from their inception until 01 April 2007. The search terms used are listed in Table 2. Our two primary outcomes were healing of lesions or prevention of new lesions. Only results of RCTs were included in the final analysis. No language restrictions were imposed. An expert in the field was contacted to ensure that no relevant studies were missed. Full copies of the relevant papers were obtained. One author (SL) abstracted data from the retrieved studies. Quality of reporting was assessed by seeing how well randomization and blinding were described and whether all those randomized were included in the final analysis. Heterogeneity of studies prevented meta-analysis, therefore, descriptive results are presented within the tables.
|Search strategy for Skin Disorders Specialist Library|
|#1 (epidermolysis bullosa):ti, ab, kw|
|#2 MeSH descriptor epidermolysis bullosa explode all trees|
|#3 MeSH descriptor epidermolysis bullosa Acquisita, this term only|
|#4 (#1 OR #2)|
|#5 (#4 AND NOT #3)|
|Search strategy for MEDLINE|
|1. Randomized controlled trial.pt.|
|2. Controlled clinical trial.pt.|
|3. Randomized controlled trials.sh.|
|4. Random allocation.sh.|
|5. Double blind method.sh.|
|6. Single-blind method.sh.|
|8. Animal/ not human/|
|9. 7 not 8|
|10. Clinical trial.pt.|
|11. exp Clinical trials/|
|12. (clin$ adj25 trial$).ti,ab.|
|13. [(singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)].ti,ab.|
The results of the search strategy are shown in Fig. 1. Five RCTs were identified, with sample size varying from 10 to 36 participants, and involving a total of 102 participants (Table 1).4–8 All five studies were randomized, double-blind, placebo-controlled crossover studies. Four of the five studies incorporated a washout period, which ranged from 1 week to 2 months in duration.5–8
Overall, the quality of study reporting was poor. Four of the five studies did not give the details of how randomization was carried out,4–6,8 and in the study that did, only two of 12 participants completed the study.7 Allocation concealment was not clearly described in any of the studies. In four of the five studies, some of the aspects of blinding were described.4,5,7,8 In three of the studies, the investigators describe the use of creams and tablets of identical appearance.4,5,7 However, it was not clear whether side effects of the intervention might have compromised the resultant blinding. Only two of the studies gave details of the reasons for participants not completing the study.4,8
Sample sizes were very small and the several dropout rates high. None of the studies showed a benefit using active treatment compared with placebo; quantitative data are given where possible in Table 3. Fine et al. compared topical 5% bufexamac (4-n-butoxyphenylacethydroxamic acid) with placebo in an 8-week study (n = 10) and failed to find any reduction in lesions with active treatment.4 Younger et al. assessed the role of topical aluminium hexahydrate in Weber–Cockayne EB in order to reduce sweating, which may in turn reduce blistering (n = 23), and showed no significant difference between treatment groups.5 In the first of two studies examining the role of oral tetracyclines in EBS, Hansen et al. compared oxytetracycline 1 g with placebo with treatment periods of 3 weeks (n = 19),6 and did not demonstrate any superiority over placebo. In the second study, Weiner et al. compared oxytetracycline 1.5 g with placebo (n = 12), but owing to the fact that only two patients completed the whole study, clear conclusions were not possible.7 Finally, Caldwell-Brown et al. evaluated the role of phenytoin in recessive dystrophic EB (n = 36); again no benefit was shown compared with placebo.8
|Author, year||Study participants||Study duration||Intervention||Outcome measures||Results||Quality of reporting||Conclusions||Comments|
|Epidermolysis bullosa simplex|
|Fine, 1988||10 patients (9 W-C, 1 generalized EBS) aged 15–74 years (4 male, 6 female)||8 weeks (4 weeks active and 4 weeks in placebo group)||Bufexamac cream 5% (4-n-butoxyphenyl-acethydroxamic acid) vs. placebo four times daily applied to hands in feet in localized disease and to one arm and leg in the patient with generalized EB. 4 weeks in each group; no washout period||Weekly mean lesion counts. Degree of cutaneous pain. Subjective improvement from baseline||Mean difference in lesion counts was 3.44 (95% CI 11.88–18.76), P = 0.62. Increased lesions in active and placebo in 7 of 8 compliant patients. Pain improved in 4/8 (no difference between treatment), 2/8 worse with placebo.||Randomization and allocation concealment poorly described. Blinding appeared adequate. 2 patients not included in analysis (reduced activity), no drop-outs||No benefit detected using bufexamac cream but statistical power was only 6%. Only 5 of 10 correctly identified the active product||The small sample size and short duration mean that this study does not exclude a benefit from the use of this agent|
|Younger, 1990||23 patients aged 4–63 years (all W-C EBS)||9 weeks (4 weeks treating one side with active, the other with placebo, followed by 1-week washout and 4 weeks on the contralateral side)||Aluminum chloride hexahydrate 20% vs. placebo applied each night to right and left sole. 4 weeks followed by 1-week washout and repeated procedure on the contralateral side||Total and mean blister counts||First month: mean blister count 6.5 both feet. Second month: mean blister count 5.4 and 5.1 for placebo and active sides respectively (NS).||Randomization and allocation concealment poorly described. Blinding appeared adequate. 8 drop-outs, reasons not given. Authors state no AEs||No benefit showed with the use of aluminum hexahydrate 20% compared with placebo||The small sample size and short duration mean that this study does not exclude a benefit from the use of this agent|
|Hansen, 1996||21 participants, mean age 36.6 years (12 men, 9 women)||8 weeks (two 3-week active periods with a 2-week washout period)||Oxytetracycline 1 g daily or placebo for 3 weeks; 2 weeks washout with placebo; followed by a reversal of the treatment for 3 weeks||Lesion counts, physician assessment of improvement (≥ 50%)||6/18 improved with oxytetracycline vs. 7/18 with placebo (P > 0.05)||Randomization, allocation concealment and blinding poorly described. Three drop-outs inadequately described. Authors stated no AEs||No benefit was showed with active treatment.||The authors suggest that the cold summer reduced lesion counts overall and may have masked possible benefit. They also propose that the dose and duration may not have been sufficient|
|Weiner, 2004||12 participants with W-C EB (8 males, 4 females) aged 13–47 years||10 months: 4 months either active or placebo treatment followed by a 2-month washout period||Oxytetracycline 1.5/g daily vs. placebo in 4-month treatment intervals separated by a 2-month washout period||Total lesion counts||Only two patients completed both arms of the study. In these two, lesion counts were reduced with tetracycline, but this was not significant. The authors described no improvement with placebo and improvement in 4/6 on tetracycline but placebo results were not given||Block randomization described. Allocation concealment poorly described. Blinding appeared adequate. Unclear how many were in each treatment group in each arm of the study. Drop-outs (2 completed full trial) and AEs poorly described||Owing to the high drop-out rate, impossible to determine if there was clinical benefit||Authors conclude that trial of high-dose tetracycline may be justified in symptomatic patients; however, the attrition rate precludes definitive conclusions|
|Recessive dystrophic epidermolysis bullosa|
|Caldwell-Brown, 1992||36 patients with recessive dystrophic EB (12 male, 24 female) aged 12 ± 14 years||12–16 months: 4 months at steady-state concentration of phenytoin 8–20 μg/mL with additional time to reach this concentration, and a 2-month washout period||Phenytoin at an initial dose of 5 mg/kg/day until blood concentration reached 8–20 μg/mL and continued at that level for 4 months vs. placebo. There was a 2-month washout, after which the patients received the alternate treatment for an equivalent period||Lesion counts and size of chronic plaques. Investigator global assessment.||22 patients completed both courses of treatment. There was no significant difference between active and placebo in the change in lesion number (7% increase vs. 6% decrease), in the area of the lesions (0.4% decrease vs. 0.2% increase) or in lesion counts within the designated plaques (12% decrease vs. 31% increase)||Randomization and treatment allocation poorly described. Blinding seemed effective. 14 drop-outs. No ITT analysis. Adverse events described (3 patients developed phenytoin toxicity)||Phenytoin showed no benefit over placebo in this study||This study was of good duration with significant phenytoin concentrations.|
Some ongoing clinical trials in EB were identified through searching the UK National Research Register (http://www.nrr.nhs.uk/) and the Dystrophic Epidermolysis Bullosa Research Association (DebRA) UK website (http://www.debra.org.uk/). One study is currently evaluating the use of amitryptyline and topical opiates for pain relief in children with EB, and other trials are exploring the value of ex vivo gene treatment to treat children with recessive dystrophic EB.
The results of this review show that there is a dearth of RCT evidence informing treatment decisions for the inherited forms of EB. None of the studies showed any definitive benefit from the treatment interventions tested.
Strengths and limitations of this review
This systematic review has critically appraised the evidence based on study design and quality, and has included nonEnglish papers. However, some relevant papers may have been missed despite a comprehensive search strategy. All of the studies are hampered by very small numbers of participants, resulting in low statistical power to detect an effect if one exists.
This review highlights the lack of trial evidence to inform the treatment of EB, with the exception of a lack of benefit from the use of phenytoin.8
This review highlights a significant research gap, the need for better reporting and the need for larger trials. There may also be a role for multicentre, international collaborative RCTs. One of the studies described ‘aggressive recruitment’ from the US National EB registry over a period of nearly 1 year. However, they stated that insufficient suitable patients who fulfilled their inclusion criteria were found to participate in the study.7 This highlights the difficulty with recruiting sufficient numbers of patients when a disease is uncommon, even in a large country with a well-established disease registry. There may be a role for patient support groups to aid with design and recruitment. However, it is hoped in the future that successful gene treatment will transform treatment of EB.
We thank Dr Finola Delamere, trials search co-ordinator of the Cochrane skin group for her assistance with the search strategy. We are also indebted to Dr Jo-David Fine for ensuring that we had not omitted any RCTs. Dr Langan is funded by a research grant from the BUPA foundation. Dr Langan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
- 1Epidermolysis Bullosa. Clinical, Epidemiologic, and Laboratory Advances, and the Findings of the National Epidermolysis Registry. Baltimore: John’s. Hopkins University Press, 1999., , , .