title: Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial.
abstract: Bullous 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.
  
  
  
  We 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.
  
  
  
  Between 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.
  
  
  
  Starting 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.
  
  
  
  NIHR Health Technology Assessment Programme.
authors.affiliation: Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK. Electronic address: hywel.williams@nottingham.ac.uk.
authors.forename: Hywel C
authors.initials: HC
authors.lastname: Williams
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors.forename: Fenella
authors.initials: F
authors.lastname: Wojnarowska
authors.affiliation: Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK; Institute of General Medicine and Interprofessional Care, University of Tübingen, Tübingen, Germany.
authors.forename: Gudula
authors.initials: G
authors.lastname: Kirtschig
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: James
authors.initials: J
authors.lastname: Mason
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Godec
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Enno
authors.initials: E
authors.lastname: Schmidt
authors.affiliation: Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, UK.
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Chalmers
authors.affiliation: Nottingham Clinical Trials Unit, Nottingham Health Science Partners, Nottingham, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Childs
authors.affiliation: Dermatology Department, Hull Royal Infirmary, Hull, UK.
authors.forename: Shernaz
authors.initials: S
authors.lastname: Walton
authors.affiliation: Dermatology Department, Leicester Royal Infirmary, Leicester, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Harman
authors.affiliation: Dermatology Department, Queen Elizabeth Hospital, Greenwich, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Chapman
authors.affiliation: Nottingham Clinical Trials Unit, Nottingham Health Science Partners, Nottingham, UK.
authors.forename: Diane
authors.initials: D
authors.lastname: Whitham
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nunn
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004318:Doxycycline / Q000627:therapeutic use*; D000074099:Equivalence Trials as Topic; D005260:Female; D005858:Germany; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010391:Pemphigoid, Bullous / Q000188:drug therapy*; D011239:Prednisolone / Q000627:therapeutic use*; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D000900:Anti-Bacterial Agents; D005938:Glucocorticoids; D011239:Prednisolone; D004318:Doxycycline