Portal de Periódicos da CAPES

Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial

2017; Elsevier BV; Volume: 389; Issue: 10079 Linguagem: Inglês

10.1016/s0140-6736(17)30560-3

1474-547X

Hywel C Williams, Fenella Wojnarowska, Gudula Kirtschig, James Mason, Thomas Godec, Enno Schmidt, Joanne R Chalmers, Margaret Childs, Shernaz Walton, Karen Harman, Anna Chapman, Diane Whitham, Andrew Nunn, Jerry M. Adams, Victoria Akhras, A. Anstey, C.N. Barnard, Hazel Κ. Bell, S. Blackford, E.‐B. Bröcker, A.J. Carmichael, Rúben Coelho, Fiona E. Craig, Kathy J Davies, R Ellis, J.S.C. English, Regine Gläser, Richard Groves, C Günthert, Philip Hampton, N. C. Hepburn, Rainer Hügel, K Hussain, Jackie Ingram, Alison Layton, N. J. Levell, Victor L. Lewis, H Malhomme, A Omerod, Girish K. Patel, Ruth Rallan, Jane Ravenscroft, Henk Santander, Kerstin Steinbrink, Michael Sticherling, C. Abasq Thomas, M Vatve, Nina van Beek, Vanessa Venning, Emma Veysey, Rachel Wachsmuth, Shyamal Wahie, Benjamin Walker, Michael Walsh, J. S. Wee, Michael Westmoreland, G Wong, Adam Ferguson, Indre Verpetinske, Emilia Duarte-Williamson, Fiona Antony, Chris Bower, David J. Gawkrodger, Kathy Taghipour, M. G. S. Dunnill, Alex Waters, W.W. Bottomley, Andrew Wright, Jane Sterling, Adzura Azam, Sam Gibbs, Thomas A. Luger, Ingrid Salvary, Chris Lovell, A. Ilchyshyn, Karen Gibbon, Marinella Nik, R. Charles‐Holmes, Anita Lavery,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

BackgroundBullous pemphigoid is a blistering skin disorder with increased mortality. We tested whether a strategy of starting treatment with doxycycline gives acceptable short-term blister control while conferring long-term safety advantages over starting treatment with oral corticosteroids.MethodsWe did a pragmatic, multicentre, parallel-group randomised controlled trial of adults with bullous pemphigoid (three or more blisters at two or more sites and linear basement membrane IgG or C3). Participants were randomly assigned to doxycycline (200 mg per day) or prednisolone (0·5 mg/kg per day) using random permuted blocks of randomly varying size, and stratified by baseline severity (3–9, 10–30, and >30 blisters for mild, moderate, and severe disease, respectively). Localised adjuvant potent topical corticosteroids (<30 g per week) were permitted during weeks 1–3. The non-inferiority primary effectiveness outcome was the proportion of participants with three or fewer blisters at 6 weeks. We assumed that doxycycline would be 25% less effective than corticosteroids with a 37% acceptable margin of non-inferiority. The primary safety outcome was the proportion with severe, life-threatening, or fatal (grade 3–5) treatment-related adverse events by 52 weeks. Analysis (modified intention to treat [mITT] for the superiority safety analysis and mITT and per protocol for non-inferiority effectiveness analysis) used a regression model adjusting for baseline disease severity, age, and Karnofsky score, with missing data imputed. The trial is registered at ISRCTN, number ISRCTN13704604.FindingsBetween March 1, 2009, and Oct 31, 2013, 132 patients were randomly assigned to doxycycline and 121 to prednisolone from 54 UK and seven German dermatology centres. Mean age was 77·7 years (SD 9·7) and 173 (68%) of 253 patients had moderate-to-severe baseline disease. For those starting doxycycline, 83 (74%) of 112 patients had three or fewer blisters at 6 weeks compared with 92 (91%) of 101 patients on prednisolone, an adjusted difference of 18·6% (90% CI 11·1–26·1) favouring prednisolone (upper limit of 90% CI, 26·1%, within the predefined 37% margin). Related severe, life-threatening, and fatal events at 52 weeks were 18% (22 of 121) for those starting doxycycline and 36% (41 of 113) for prednisolone (mITT), an adjusted difference of 19·0% (95% CI 7·9–30·1), p=0·001.InterpretationStarting 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.FundingNIHR Health Technology Assessment Programme.