Doxycycline: a first-line treatment for bullous pemphigoid?
Authors: Henry J Grantham, Deborah D Stocken, Nick J Reynolds
Journal: The Lancet (2017)

Bullous pemphigoid is the most common autoimmune blistering skin disease, and incidence is on the rise, due at least in part to its association with older age.1Langan SM Smeeth L Hubbard R Fleming KM Smith CJ West J Bullous pemphigoid and pemphigus vulgaris—incidence and mortality in the UK: population based cohort study.BMJ. 2008; 337: a180Crossref PubMed Scopus (461) Google Scholar, 2Ren Z Hsu DY Brieva J et al.Hospitalization, inpatient burden and comorbidities associated with bullous pemphigoid in the USA.Br J Dermatol. 2017; 176: 87-99Crossref PubMed Scopus (76) Google Scholar Treatment of bullous pemphigoid presents a challenge to the clinician, as first-line treatment regimens—either oral corticosteroids or whole body application of super-potent topical steroids—result in substantial morbidity and mortality or present logistical challenges in the elderly.3Schmidt E Zillikens D Pemphigoid diseases.Lancet. 2013; 381: 320-332Summary Full Text Full Text PDF PubMed Scopus (671) Google Scholar Few trials have compared therapies for bullous pemphigoid. A previous landmark study4Joly P Roujeau JC Benichou J et al.A comparison of oral and topical corticosteroids in patients with bullous pemphigoid.N Engl J Med. 2002; 346: 321-327Crossref PubMed Scopus (477) Google Scholar found that whole-body topical application of the super-potent corticosteroid clobetasol propionate was at least as effective as oral prednisone for disease control at 3 weeks (and more effective for extensive disease). Notably, clobetasol proprionate treatment was associated with a significant reduction in mortality over 52 weeks compared with high-dose (1 mg/kg per day) but not medium-dose prednisone (0·5 mg/kg per day). Consistent with dose-dependent systemic absorption of topical steroids, reducing the dose of topical steroids provided a similar degree of disease control but with reduced morbidity and mortality.5Joly P Roujeau JC Benichou J et al.A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study.J Invest Dermatol. 2009; 129: 1681-1687Summary Full Text Full Text PDF PubMed Scopus (185) Google Scholar Tetracyclines have been used in dermatology for some time for their anti-inflammatory properties.6Perret LJ Tait CP Non-antibiotic properties of tetracyclines and their clinical application in dermatology.Australas J Dermatol. 2014; 55: 111-118Crossref PubMed Scopus (39) Google Scholar The only previous study comparing tetracyclines with corticosteroids in bullous pemphigoid was terminated early and the results, although promising, were not statistically significant.7Fivenson DP Breneman DL Rosen GB Hersh CS Cardone S Mutasim D Nicotinamide and tetracycline therapy of bullous pemphigoid.Arch Dermatol. 1994; 130: 753-758Crossref PubMed Scopus (226) Google Scholar In The Lancet, Hywel Williams and colleagues8Williams HC Wojnarowska F Kirtschig G et al.Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial.Lancet. 2017; (published online March 6.)http://dx.doi.org/10.1016/S0140-6736(17)30560-3Google Scholar report the results of the largest multicentre trial comparing oral treatments for bullous pemphigoid; the investigators and participating sites should be congratulated for completing this valuable study. Using a non-inferiority trial design, they tested the hypothesis that 200 mg/day oral doxycycline is not inferior in effectiveness to oral prednisolone (0·5 mg/kg per day) and that doxycycline is less likely to result in severe adverse effects. Participants were allowed to apply up to 30 g per week of potent topical corticosteroids to localised lesions for the first 3 weeks, and after 6 weeks. A high proportion of participants were available for analysis at 6 weeks although, perhaps not unexpectedly, a substantial number dropped out by week 52. Rates of withdrawal were balanced between the two treatment groups. So what were the major findings? The modified intention-to-treat analysis showed that disease control at 6 weeks was achieved by 91% (92 of 101) of participants starting prednisolone compared with 74% (83 of 112) starting doxycycline—an adjusted difference (by baseline severity of bullous pemphigoid and Karnofsky score) of 18·6% (90% CI 11·1–26·1). In terms of safety, this trial underscored the adverse event profile of systemic steroids for bullous pemphigoid: 36% (41 of 113) of participants starting medium-dose oral prednisolone developed a serious adverse event over 52 weeks compared with 18% (22 of 121) of participants starting doxycycline—an adjusted difference of 19·0% (95% CI 7·9–30·1). In agreement with this, and previous studies,5Joly P Roujeau JC Benichou J et al.A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study.J Invest Dermatol. 2009; 129: 1681-1687Summary Full Text Full Text PDF PubMed Scopus (185) Google Scholar, 7Fivenson DP Breneman DL Rosen GB Hersh CS Cardone S Mutasim D Nicotinamide and tetracycline therapy of bullous pemphigoid.Arch Dermatol. 1994; 130: 753-758Crossref PubMed Scopus (226) Google Scholar treatment-related deaths were greater in the prednisolone group (11 deaths) compared with the doxycycline group (three deaths). So how should these data be interpreted? Some help is provided within the protocol and statistical analysis plan9UK Dermatology Clinical Trials NetworkThe Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) Study.https://www.nottingham.ac.uk/research/groups/cebd/projects/5rareandother/blistertrial.aspxDate: 2015Google Scholar and by an earlier publication from the group that considers, in advance, possible outcomes from this trial.10Bratton DJ Williams HC Kahan BC Phillips PP Nunn AJ When inferiority meets non-inferiority: implications for interim analyses.Clin Trials. 2012; 9: 605-609Crossref PubMed Scopus (11) Google Scholar Additionally, it is important to consider how the trial was powered and how the non-inferiority margins were determined and set.11Rehal S Morris TP Fielding K Carpenter JR Phillips PP Non-inferiority trials: are they inferior? A systematic review of reporting in major medical journals.BMJ Open. 2016; 6: e012594Crossref Scopus (81) Google Scholar, 12Piaggio G Elbourne DR Pocock SJ Evans SJ Altman DG Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement.JAMA. 2012; 308: 2594-2604Crossref PubMed Scopus (808) Google Scholar It appears that the trial was primarily powered to detect a 20% difference in grade 3, 4, and 5 side-effects.9UK Dermatology Clinical Trials NetworkThe Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) Study.https://www.nottingham.ac.uk/research/groups/cebd/projects/5rareandother/blistertrial.aspxDate: 2015Google Scholar Achieving a consensus around the setting of the non-inferiority margin is recognised to be challenging. The authors commendably addressed this in part by undertaking a survey of dermatologists through a national group (the UK Dermatology Clinical Trials Network; appendix p 18Williams HC Wojnarowska F Kirtschig G et al.Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial.Lancet. 2017; (published online March 6.)http://dx.doi.org/10.1016/S0140-6736(17)30560-3Google Scholar).13Taghipour K Mohd Mustapa MF Highet AS Venning VA Kirtschig G The approach of dermatologists in the UK to the treatment of bullous pemphigoid: results of a national survey.Clin Exp Dermatol. 2013; 38: 311-313Crossref PubMed Scopus (10) Google Scholar The results of this survey suggested that UK dermatologists were willing to accept a 25% reduction in effectiveness if this was balanced against a 10% reduction in mortality rate for "tetracycline to have potential as a primary treatment for bullous pemphigoid".13Taghipour K Mohd Mustapa MF Highet AS Venning VA Kirtschig G The approach of dermatologists in the UK to the treatment of bullous pemphigoid: results of a national survey.Clin Exp Dermatol. 2013; 38: 311-313Crossref PubMed Scopus (10) Google Scholar However, it is not entirely clear how the data from the survey fed into the setting of the primary endpoints or if the sample size was sufficient to detect a clinically relevant non-inferiority effectiveness margin. Nevertheless, it seems reasonable to move to a broader definition of adverse events (including grades 3–5) and to increase this rate to 20%. Although guidelines for the reporting of non-inferiority trials are not entirely consistent,11Rehal S Morris TP Fielding K Carpenter JR Phillips PP Non-inferiority trials: are they inferior? A systematic review of reporting in major medical journals.BMJ Open. 2016; 6: e012594Crossref Scopus (81) Google Scholar the non-inferiority margin is often informed by the minimally clinically relevant difference12Piaggio G Elbourne DR Pocock SJ Evans SJ Altman DG Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement.JAMA. 2012; 308: 2594-2604Crossref PubMed Scopus (808) Google Scholar (in this case 25% for effectiveness) such that to reject the null hypothesis (and conclude non-inferiority), the trial would need to provide data where the CI does not cross this boundary. However, the authors interpret the 25% difference as a point estimate and extend the non-inferiority margin to 37%—quite a large difference but one that was achievable from recruiting 128 participants per group. Together, this suggests that the trial might have been underpowered for non-inferiority at a clinically relevant difference of effectiveness. Overall, the data look interesting and, for now, we are left with the conclusion that doxycycline is non-inferior to prednisolone in effectiveness at a difference of between 11·1% and 26·1% (as set by a 90% CI). The secondary measures of effectiveness at 6 weeks also supported a difference of more than 30% in favour of prednisolone and the Kaplan-Meier curve of time to change in treatment (appendix p 10)8Williams HC Wojnarowska F Kirtschig G et al.Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial.Lancet. 2017; (published online March 6.)http://dx.doi.org/10.1016/S0140-6736(17)30560-3Google Scholar clearly favours oral prednisolone over doxycycline. It would be interesting to investigate whether any baseline clinical features or biomarkers might differentially predict treatment response. Finally, although the authors aimed to restrict the use of topical corticosteroids for symptomatic relief, we do not know whether the amount applied by both groups was the same. Systemic absorption from topical corticosteroids does occur, and this must be kept in mind when interpreting disease control, morbidity, and mortality. In conclusion, doxycycline is clearly safer than prednisolone for the treatment of bullous pemphigoid and demonstrates a reduced success rate, based on achieving three or fewer blisters, at 6 weeks. The evidence for non-inferiority is subjective, dependent on the definition of the clinically relevant non-inferiority boundary. However, given the natural history of bullous pemphigoid,3Schmidt E Zillikens D Pemphigoid diseases.Lancet. 2013; 381: 320-332Summary Full Text Full Text PDF PubMed Scopus (671) Google Scholar and previous responses to topical treatment alone,4Joly P Roujeau JC Benichou J et al.A comparison of oral and topical corticosteroids in patients with bullous pemphigoid.N Engl J Med. 2002; 346: 321-327Crossref PubMed Scopus (477) Google Scholar, 5Joly P Roujeau JC Benichou J et al.A comparison of two regimens of topical corticosteroids in the treatment of patients with bullous pemphigoid: a multicenter randomized study.J Invest Dermatol. 2009; 129: 1681-1687Summary Full Text Full Text PDF PubMed Scopus (185) Google Scholar it is rational to deduce that doxycycline is at least partly effective. So how will this trial affect the management of bullous pemphigoid in clinical practice? Importantly, the primary endpoint for effectiveness in this trial was at 6 weeks. So it would seem reasonable to introduce doxycycline initially in combination with potent (or super-potent)4Joly P Roujeau JC Benichou J et al.A comparison of oral and topical corticosteroids in patients with bullous pemphigoid.N Engl J Med. 2002; 346: 321-327Crossref PubMed Scopus (477) Google Scholar topical steroids; if control is inadequate, treatment can then be escalated to systemic steroids (although this was not covered in the trial design). An alternative strategy, identified by the authors as a potential future trial, would be to start all patients on prednisolone to gain initial control, and then consider doxycycline as a potential maintenance treatment—with patients randomly assigned to continuation of oral corticosteroids or doxycycline. HJG is an academic foundation doctor based at Newcastle University and the Newcastle upon Tyne Hospitals NHS Foundation Trust. NJR's laboratory and research is supported by the NIHR-Newcastle Biomedical Research Centre. NJR is chair of the UK Translational Research Network in Dermatology which collaborates with the UK Dermatology Clinical Trials Network and director of the Medical Research Council/Engineering and Physical Sciences Research Council (MRC/EPSRC) Newcastle Molecular Pathology Node. DDS declares no competing interests. Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trialStarting patients on doxycycline is non-inferior to standard treatment with oral prednisolone for short-term blister control in bullous pemphigoid and significantly safer in the long-term. Full-Text PDF Open Access