World Workshop on Oral Medicine VI: a systematic review of the treatment of mucous membrane pemphigoid.

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World Workshop on Oral Medicine VI: a systematic review of the treatment of mucous membrane pemphigoid J. Taylor, BDS, MBChB, MFDSRCS,a R. McMillan, BDS, MBChB, MFDSRCS, FDS(OM) RCPS, FHEA,b M. Shephard, BDent (Hons), MBBS (Hons), FRACDS,c J. Setterfield, BDS, DCH, MD, FRCP,d R. Ahmed, MD, DSc, MPA,e M. Carrozzo, MD, DSM (Turin, 1995),f S. Grando, MD, PhD, DSc,g M. Mignogna, MD, DMD,h M. Kuten-Shorrer, DMD,i T. Musbah, BDS,j A. Elia, DDM, MSc (Oral Med),k R. McGowan, MLS,l A.R. Kerr, DDS, MSD,m M.S. Greenberg, DDS, FDS RCS,n T. Hodgson, BDS, FDS RCS (Eng), FGDP (UK),o and D. Sirois, DMD, PhDp Objective. To determine the efficacy and safety of interventions for mucous membrane pemphigoid (MMP). Study Design. We conducted a systematic review from 2003 to 2013 according to the Cochrane Collaboration methodology. Randomized controlled trials (RCTs) or controlled clinical trials and observational studies were included, with diagnosis confirmed by clinical, histopathologic, and immunofluorescence criteria. The primary outcome was lesion remission or healing; several relevant secondary outcomes were also included. Results. In the final analysis, 1 RCT and 32 observational studies were included. The one included RCT with a high risk of bias in multiple domains found limited evidence that pentoxifylline, combined with corticosteroid and cyclophosphamide, was more effective than standard therapy (corticosteroid þ cyclophosphamide alone) for ocular MMP. We summarize here the outcomes from 32 observational studies examining 242 patients across 19 unique treatments. Interventions that show promise include rituximab and intravenous immunoglobulin. Conclusions. This systematic review is the most recent since 2003e2009. There is still lack of high-quality research providing evidence-based MMP treatments. (Oral Surg Oral Med Oral Pathol Oral Radiol 2015;-:1-11)

The following organizations, individuals and companies provided unrestricted financial support for WWOM VI and this study: American Academy of Oral Medicine, European Association of Oral Medicine, anonymous gifts from patients of Dr. David Sirois, New York University College of Dentistry, Biocosmetics, Elsevier, Johnson and Johnson, The Oral Cancer Foundation, and Unilever. a SPR Oral Medicine, University Dental Hospital of Manchester, Higher Cambridge Street, Manchester, UK. b Consultant and Honorary Clinical Teaching Fellow in Oral Medicine and Facial Pain, Eastman Dental Hospital, London, UK. c SPR Oral Medicine, Eastman Dental Hospital, London, UK. d Reader/Honorary Consultant in Dermatology in relation to Oral Disease, Department of Oral Medicine and St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK. e Center For Blistering Diseases, Boston, Massachusetts, USA. f Professor of Oral Medicine, School of Dental Sciences, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, UK. g Professor, Dermatology, School of Medicine, University of California, Irvine, CA 92697, USA. h Head of the Oral Medicine Complex Unit, Department of Neurosciences, Reproductive and Odontostomatological Sciences e Head and Neck Clinical Section, “Federico II” University, Naples, Italy. i Oral Medicine Resident, Harvard School of Dental Medicine, Boston, Massachusetts, USA. j Orofacial Pain Resident, Orofacial Pain Center, University of Kentucky College of Dentistry, Lexington, Kentucky, USA. k Oral Medicine Section, Department of Surgical Sciences, Lingotto Dental School, University of Turin, Turin, Italy. l Research Librarian, Adjunct Assistant Professor, Department of Epidemiology and Health Promotion, New York University College of Dentistry, New York, New York, USA. m Clinical Professor, Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry, New York City, New York, USA.

Mucous membrane pemphigoid (MMP) is a heterogeneous group of chronic, autoimmune, subepithelial blistering diseases that predominantly involve the mucous membranes and occasionally the skin. Although the oral and ocular mucosae are the most common sites n Professor Emeritus, Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. o Consultant in Oral Medicine/Honorary Senior Clinical Lecturer, Divisional Clinical Director, Eastman Dental Hospital, London, UK. p Associate Professor, Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry, New York City, New York, USA. Received for publication Dec 23, 2014; returned for revision Jan 20, 2015; accepted for publication Jan 26, 2015. Ó 2015 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2015.01.024

Statement of Clinical Relevance Mucous membrane pemphigoid (MMP) is a rare, autoimmune blistering disease resulting in multiple, chronic erosions predominantly of oral and ocular mucosae. This systematic review summarizes the evidence supporting MMP treatments and is a valuable resource for clinicians to facilitate clinical decision making. 1

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affected, the nasopharynx, esophagus, larynx, and anogenital region may also be involved.1 Affected persons often experience diagnostic delays despite its relatively characteristic and recognizable presentation of MMP. The presentation varies considerably within the spectrum of MMP in terms of sites of involvement and severity of disease. Tailoring treatment to individual patients is considerably limited by a paucity of highquality clinical trials to demonstrate efficacy of available treatments. Future collaboration between specialized oral medicine clinicians, dermatologists, ophthalmologists, and others working in this field will be essential in developing high-quality clinical trials. The Sixth World Workshop in Oral Medicine sponsored this systematic review of the efficacy and safety of interventions for MMP. Epidemiology MMP is a rare disease, defined as affecting no more than 5 to 7.5 of 10,000 individuals.2 The real incidence of MMP is unclear. It was estimated to be 1.3 to 2.0 per million per year in French and German dermatologic studies. However, ophthalmologic and oral cohorts suggest a higher incidence.3 Women are more often affected than men, the female-to-male ratio being nearly 2:1. MMP mainly occurs in the older population, commonly observed in those between 50 and 80 years of age. Children are only rarely affected. There is no known racial or geographic predilection.1,3 Natural course of disease MMP typically starts with recurring vesicles or bullae affecting either the mucous membranes or the skin. Extraoral lesions exhibit a pronounced tendency to scarring. Many patients have primary oral involvement of gingivae, buccal mucosa, hard and soft palates, tongue, and uncommonly the lower lip. Oral lesions are usually persistent. Fluid-filled blisters develop and then break, leaving raw, painful ulcers that heal slowly over several days to weeks. The severity of the disease is extremely variable, ranging from occasional blisters to continuous severe blistering and ulceration. The most common oral manifestation of MMP is patchy or generalized gingival sloughing with superficial ulcers and erosions,4 a clinical presentation often referred to as desquamative gingivitis, as seen in pemphigus vulgaris and ulcerative lichen planus. The conjunctiva is the second most common site of involvement, with lesions ranging from conjunctival erosions to scarring and progressive cicatrization that may culminate in blindness. In patients without initial ocular involvement, the annual risk for developing eye lesions is 5% over the first 5 years.4,5 Eye involvement usually begins with erythema and symptoms of

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burning, irritation, and excessive tearing. Subconjunctival inflammation and scarring may result in the palpebral conjunctiva fusing with the bulbar conjunctiva, resulting in symblepharon or ankyloblepharon. Shrinkage of conjunctivae may lead to entropion, or inward turning of the lid margin onto the corneal surface, with subsequent trauma from the eyelashes (trichiasis). The combination of entropion and trichiasis may result in blindness.3 Scarring lesions can also involve other mucosae: Scarring of the laryngeal mucosa can result in hoarseness and progressive or sudden asphyxiation; scarring of the esophagus can lead to dysphagia; and scarring of the anogenital mucosa can lead to significant morbidity.1

Pathogenesis MMP is characterized by linear deposition of immunoglobulin G (IgG; 97%), IgA (27%), or C3 (78%) along the epithelial basement membrane zone (BMZ).1,3 Autoantibodies are directed against specific adhesion molecules located in the hemi-desmosomes of basal epidermal keratinocytes and the lamina lucida of the BMZ. MMP lesions are widely believed to be the result of a subepithelial loss of adhesion mediated by autoantibodies, although the underlying molecular mechanisms are largely unknown.4 By use of molecular techniques, at least six autoantigens have been identified: bullous pemphigoid antigen of 180 kDa (BP180/collagen type XV11), bullous pemphigoid antigen of 230 kDa (PB230), both subunits of integrin a6b4, laminin 332 (formerly known as laminin 5), and type VII collagen.6 The C-terminal epitopes on BP180 are predominantly recognized,5 although the NC16a domain is also a recognized target. In the majority of patients with antielaminin 332 reactivity, the a3 chain is targeted.7 Autoantibodies to a6 integrin have been described in patients with oral lesions, although not invariably,5 whereas reactivity against b4 integrin has been associated with ocular involvement.8 Notably, a solid cancer is present in about 30% of patients with antielaminin 332 MMP.9 The pathogenic relevance of some of the above-cited autoantibodies in MMP has yet to be demonstrated in vitro and in vivo. Antibodies to both antilaminin 332 and antiea6b4 integrin induced noninflammatory subepidermal blisters when injected into mice or human skin grafted onto immunocompromised mice or in organ cultures.6 Ultrastructural analysis has demonstrated that blister formation occurs within the lower lamina lucida and lamina densa.4 Experimental models of blister formation suggest that the autoantibodies target the adhesion molecules

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within the basal membrane, interfering with their structural integrity and function. In some lesions, autoantibodies may impair keratinocyte adhesion through steric hindrance or by eliciting a complement-mediated inflammatory reaction at the basement membrane zone. In others, additional amplification factors, including inflammatory cytokines or activated CD4þ T cells, may be necessary to induce the disruption of the basement membrane zone.4 Etiology Genetic and environmental factors have a substantial effect on susceptibility to MMP. There are no known racial or geographic predilections, but there may be an immunogenetic background and an association with the common major histocompatibility complex (MHC) molecules. An increased frequency of the HLA-DR4 allele in patients affected by ocular pemphigoid has been reported.4 Furthermore, a prevalence of HLADQB1* 03:01 (formerly known as DQB1*0301) was first described in patients with pure ocular MMP and then confirmed in all clinical phenotypes.10-13 Very recently, it has been suggested that a genotype of the interleukin 4 receptor A (IL-4RA)-1902 A/A, found in 90% of patients with oral pemphigoid, is associated with a reduced response to IL-4 and it may explain the low likelihood of scarring in this group of patients.14 Recent studies have shown that monozygotic twins are discordant for MMP, which argues against genetic susceptibility as the only major risk factor of the disease.4 A model has been proposed in which relevant portions of the four different peptides derived from BMZ involved in autoimmune response in MMP have potential sites that could be presented by an antigen presenting cell in conjunction with DQB1*03:01 to a T-cell receptor to initiate the process that results in anti-BMZ antibody production.15 The nature and the role of environmental factors remain unclear in most cases. According to the concept of molecular mimicry antibodies to viruses or drugs with structural similarities to an endogenous antigen within the basal membrane zone may cause an autoimmune process. A few cases of MMP triggered by medications, such as methyldopa, clonidine, and penicillamine have been reported. The availability of epithelial basement membrane zone antigens for immune processing may also be influenced by severe mucosal injury, for example, from burns and severe drugs eruptions, such as Steven-Johnson syndrome.1,4 Diagnosis Diagnosis of MMP is based on history and on clinical presentation of a predominantly mucosal disease as well as on the presence of certain immunopathologic features.

ORIGINAL ARTICLE Taylor et al. 3

The most appropriate area to biopsy is the edge of a blister or, in the absence of an intact blister, the area of erythema, erosion, or ulceration and extending also into perilesional tissue.3 Classic histopathologic features, including a subepithelial split with a variable inflammatory cells infiltrate, can also be seen in other oral diseases, such as oral lichen planus and erythema multiforme.3 Direct immunofluorescence (DIF) is essential for diagnosis and typically shows a continuous, linear deposition of IgG, C3, less commonly IgA, or a combination of these along the basement membrane zone.3,6 Standard indirect immunofluorescence (IIF) is usually negative, as serum samples from MMP patients contain antiepithelialeconnective tissue junction autoantibodies at low titers (usually 1:10e1:40) and only in 50% to 80% of cases.6 The use of salt split skin (SSS) IIF studies may increase the sensitivity of this technique. SSS-IIF may reveal binding to the roof (epithelial) or floor (connective tissue) depending on the antigen targeted.3,6 This technique may identify circulating autoantibodies in up to 91% patients for IgG and 64% patients with IgA.16 Connective tissue binding suggests antielaminin 332 reactivity.6 Immunoblotting and immunoprecipitation techniques can help in difficult cases, and target antigen can now be achieved with enzyme-linked immunosorbent assay (ELISA) systems, at least for BP180 and laminin 332.17,18 Prognostic indicators The site of involvement will predict the likelihood of serious sequelae. Pure oral MMP is associated with a relatively low risk of scarring, whereas ocular, nasopharyngeal, esophageal, and laryngeal sites are highly likely to scar with significant associated morbidity. There is evidence suggesting that the presence of both IgG and IgA anti-BMZ antibodies are associated with more severe and persistent disease. Furthermore, the titers of IgG antiBMZ autoantibodies at the initial presentation correlate with disease activity and predict disease severity.16 There is no known correlation between specific BP180 epitopes and disease prognosis. However, there is a well-recognized positive association between antibodies to anti-laminin 332 and an underlying adenocarcinoma in a third of patients,9 although the association of anti-laminin 332 with cancers has been questioned in a recent study.17 There is some evidence to suggest a positive correlation between the extent and severity of oral disease and the titer of IgG to a6-integrin.19 Treatment Treatment of MMP is complex for a number of reasons, including (1) the diversity of pathogenic pathways, (2) rarity of the disease and paucity of randomized


controlled trials (RCTs) or controlled clinical trials (CCTs), (3) complex and variable disease activity and severity, and (4) differential effectiveness of treatments on the most common (oral and ocular) manifestations, including an often intransigent course despite extensive therapeutic efforts. A wide variety of medications have been utilized to treat MMP by disrupting various pathogenic pathways.5 Although systemic corticosteroids (prednisolone 0.5e1.5 mg/kg per day) are effective in achieving rapid control in cases of acute, moderate to severe disease, the adverse effects associated with long-term use limit their value. Immunosuppressant medications, used alone or in combination, include azathioprine, cyclophosphamide, cyclosporine, leflunomide, methotrexate, and mycophenolate mofetil. Biologic agents to reduce autoantibody production include rituximab and intravenous immunoglobulin (IVIg), as well as tumor necrosis factor alpha (TNF-a) inhibitors, such as infliximab, to reduce inflammation. Dapsone and other sulfonamides, as well as cycline antibiotics, have been used extensively in the treatment of MMP. Other medications used to treat MMP that do not share common mechanisms include colchicine, nicotinamide, and pentoxifylline. Topical corticosteroids and calcineurin inhibitors are used extensively and often as single agents for the treatment of MMP. Finally, MMP has been treated with low-energy laser phototherapy and cryotherapy with mixed results. We discuss these current and emerging therapies in greater detail later, with an emphasis on benefiterisk considerations. The single, international, comprehensive expert consensus treatment guidelines published in 200220 continue to influence clinicians’ decision making. Three disease factors influence the choice of medications: site, severity, and rapidity of progression. A summary of the 2002 consensus treatment guidelines is presented in online Supplementary Material Table I, and full details can be found in the publication.20 The guidelines were developed by an international expert panel, but they have not been reviewed and posted at the US Government Agency for Healthcare Research and Quality (AHRQ) National Guideline Clearinghouse. As discussed in the companion paper in this issue of TripleO (McMillan et al., The treatment of pemphigus vulgarisea systematic review), expert opinion and consensus treatment guidelines become important evidence in the absence of directly applicable studies of good quality. We discuss the quality of current evidence in greater detail later.

Objective The objective of this systematic review is to determine the clinical effectiveness and safety of topical and systemic interventions for the treatment of MMP.

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METHODS A systematic review was conducted following a detailed protocol consistent with the methodology of the Cochrane Collaboration. Here we summarize key aspects of the protocol, and additional detailed aspects of the protocol are provided in the online Supplementary Material to this publication. Types of studies RCTs, CCTs, observational studies (e.g., cohort studies, case series, and case reports) whose primary outcome measures were regression or healing of mucosal lesions were included. However, trials were not restricted by primary outcomes alone, and so other measures were considered when relevant to the review (e.g., time to disease control, time to disease relapse, cumulative glucocorticoid dose, and adverse treatment events, including mortality). Types of participants Participants with a diagnosis of MMP confirmed with clinical, histopathologic, and immunofluorescence criteria were included. Patients with a diagnosis of bullous pemphigoid, linear IgA disease, and epidermolysis bullosa aquisita were excluded. Patients with concomitant autoimmune disease or malignancy were also excluded. Participants with drug-induced disease, pediatric cases, and pregnancy cases were included. Types of interventions Active treatment included any preventive, palliative, or curative interventions administered topically or systemically with the aim of treating MMP. Treatments administered for the purpose of treating the sequelae of MMP were excluded. Topical interventions for ocular only disease were also excluded. Types of outcome measures The primary outcome measure assessed was regression or healing of mucosal lesion(s). Secondary outcome measures assessed were (1) time to disease control; (2) time to disease relapse; (3) cumulative glucocorticoid dose; (4) adverse treatment events, including mortality; (5) quality of life; and (6) any other valid prespecified outcome measure. Literature search methods Assisted by a research librarian (RMcG), we searched a number of electronic databases from 2003 to 2013, including (Ovid) Evidence-Based Medicine Reviews (EBMR) e Cochrane Central Register of Controlled


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Trials, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects (DARE), MEDLINE via OVID, EMBASE via OVID, and PubMed. The restriction to the last 10 years was to avoid duplication of effort from previous systematic reviews already conducted on the topic. In addition we searched (1) the bibliographies of included papers and relevant review articles for studies not identified by the search strategies above and (2) for unpublished trials with data (US National Institutes of Health ongoing trials register at www.clinicaltrials.gov and the World Health Organization International Clinical Trials Registry platform at www.who.int/trialssearch). The detailed search strategy is provided in Appendix 1 of the online Supplementary Material. Language The electronic search included all noneEnglish language papers, although papers which did not have an English version were not included in the final selection. Data collection and analysis Selection of studies. The titles and abstracts obtained from the initial electronic searches were independently reviewed for relevance by two authors (JT, RM). Full manuscripts for those studies satisfying the study criteria were obtained. When the data in an abstract were insufficient to determine their status, the full manuscript was obtained and assessed independently by two of the review authors (DS, JT, MK, MS, RM, TM). Disagreements were resolved by discussion or inclusion of a third author to achieve consensus. Data extraction. All studies meeting the inclusion criteria had their characteristics independently extracted by three teams of at least two authors (RM, JT; MS, AE; TM, MK, DS) and recorded and using prespecified pro formata (see online Supplementary Material: Appendix A2). Disagreements among authors were resolved by discussion with a third author and consensus. For RCTs or CCTs, the pro forma was adapted from the Cochrane risk of bias template for RCTs or CCTs,21 and for observational studies, a separate pro forma was based on the STROBE guidelines.22 Missing data. We attempted to contact trial authors, where necessary, for missing data if the study was published from 2003 to date. Methodologic quality assessment (risk of bias) and evidence grading. A two-part risk of bias tool was used to assess the RCTs or CCTs. This assessed eight specific domains (random sequence generation, allocation concealment, blinding of participants, blinding of patient reported outcomes, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and any other risk of bias). Risk of bias for each domain


was assessed as “high,” “low,” or “unclear.” A study with one or more “high” risk of bias judgments for any given domains was deemed overall to have a high risk of bias. Individual studies were graded according to the level of evidence (1þþ [highest], 1þ, 1, 2þþ, 2þ, 2, 3, 4 [lowest]) as reported by the Scottish Intercollegiate Guidelines Network.23 Data synthesis and measures of treatment effect. For RCTs or CCTs, dichotomous outcomes were to be expressed as an estimated effect of an intervention using a risk ratio with 95% confidence intervals (95% CIs). Continuous outcome data was presented using mean differences and 95%CIs. The outcomes reported by observational studies would be described in narrative form, where appropriate. Where possible, quantitative synthesis (meta-analysis) was to be applied to the outcomes of relevant RCTs. Presentation of main results. To facilitate critical appraisal of the evidence, the results are separated into three categories: (1) generalized adult MMP, (2) pediatric and pregnancy MMP, and (3) ocular-only MMP. Results for treatment of adult MMP are reported separately from pediatric and pregnancy MMP because of the significant group differences in disease natural history and treatment response. Similarly, we report ocular-only MMP separately from the other studies because of its unique clinical presentation, risk, and treatment approaches. No studies of generalized adult or pediatric and pregnancy MMP excluded occasional skin lesions; that is, there was no “oral mucosa only” MMP category. RCTs or CCTs and observational studies (case series, case reports) were evaluated separately. Results of our appraisals are presented below in narrative form for each intervention category, and the detailed characteristics of all included studies, including their evidence grades, are presented in the online Supplementary Materials Table II: MMP Interventions. The characteristics of excluded studies are provided in the online Supplementary Material: Appendix A3.

RESULTS Search process and yield Figure 1 illustrates the search process. From an initial set of 465 abstracts identified by the electronic searches and dual-reviewed by two of the authors (RM, JT), 314 (67.5%) were excluded, and 151 were selected for full review by three teams of at least two authors (RM, JT; DS, MKS, TM; MS, AE). Of the 151 manuscripts undergoing full review, 1 was an RCT or a CCT and subsequently included in the analyses; 116 were general MMP observational or descriptive studies, of which 21 were subsequently included in the analyses and 95 excluded; 12 were ocular-only studies, of which 8 were subsequently included in the analysis and 4


OOOO Month 2015 Mucous membrane pemphigoid 465 records identified by electronic database search

314 excluded on basis of title and abstract review

151 included on basis of title / abstract review proceed to full manuscript review

1 RCT / CCT study

1 included

116 general MMP descriptive studies

21 included 95 excluded

12 ocular only descriptive


7 pediatric / pregnancy descriptive


1 RCT/CCT

32 descriptive

15 authoritative publications (systematic review, critical reviews, guidelines) 2 excluded 13 remained as informative & relevant, but not included in analyses

Fig. 1. Literature Search Flowchart.

excluded; 7 were pediatric or pregnancy studies, of which 3 were subsequently included in the analyses and 4 excluded. The remaining 15 papers included a single systematic review and several authoritative reviews and treatment guidelines, of which 2 were excluded and 13 retained as informative and relevant publications but not included in our analyses. The reason for excluding each of the 103 manuscripts that underwent full review but were excluded is provided in the online Supplementary Material Appendix A3. Only one publication was excluded because it was a noneEnglish language paper: a Portuguese case report of MMP with severe esophageal stricture.24 Seven authors (RM, JT, MS, RA, DS, JS, MC) met for 2 days (April 7e8, 2014) during the Sixth World Workshop on Oral Medicine (Orlando, FL) for critical discussion and interpretation of the literature. RCTs or CCTs A single RCT met the inclusion criteria for our review25 (see Figure 2). This study was carried out in Egypt and included 30 patients with ocular cicatricial pemphigoid. Group A (15 patients) were given IV pulsed corticosteroids, cyclophosphamide, and IV pentoxyfylline. Group B (15 patients) were given pulsed IV corticosteroids and cyclophosphamide only. There were 20 “control” healthy patients who had baseline TNF-a blood levels. The control patients did not receive any treatment. The primary outcomes

Fig. 2. Characteristics of included RCT.

were visual acuity, conjunctival inflammation (0e3), dryness, and cicatrization. There were a number of additional secondary outcomes. The study had a high risk of performance bias, reporting bias, and other risk of bias. The two arms had differing treatment schedules and therefore were essentially


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Fig. 3. MMP - number of publications by therapy type.

nonblinded. The outcomes listed were not reported clearly, and no raw data were presented. Statistical comparisons did not compare A with B; instead they compared A before and after and B before and after. No baseline characteristics were provided. Descriptive studies A total of 32 observational studies (21 adult generalized MMP, 8 ocular-only MMP, and 3 pediatric- or pregnancyonly MMP) described outcomes for 242 patients across 19 different treatments for MMP (see Figure 3 and online Supplement Material Table I. The most commonly reported treatments, in decreasing order, were oral corticosteroids, cyclophosphamide, dapsone, and IVIg. Pediatric and pregnancy studies. No pregnancy cases were included. Three studies involved pediatric patients. These were individual case reports26-28 of pediatric MMP, ages ranging from 20 months to 9 years. Combinations of treatments, including corticosteroids, dapsone, topical tacrolimus, and topical cyclosporin, were described. All three cases had a successful outcome. MMP adult studies. Twenty-one studies, with a combined total of 92 patients, looked at various treatments for adult MMP. Ten case series and 11 case reports were included. Online Supplementary Material Table II describes for each of 19 MMP treatments the characteristics and evidence level of the studies that explored those treatments. Figure 3 further summarizes for each of the 19 MMP interventions the number and types of study that explored those interventions. The case series ranged from two participants29 to 25 participants.30 The three largest case series described rituximab,30 prednisone/dapsone/colchicine/

cyclophosphamide,31 and cyclophosphamide.32 These three case series are discussed in further detail below. LE ROUX-VILLET, 2011.30 In this study from France,

25 patients were given a combination of rituximab and immunosuppression (dapsone, sulfasalazine, or both). The outcomes were described on the basis of responders (complete response or partial response) and nonresponders. Of the 25 subjects, 2 patients died, 2 patients were nonresponders, 7 patients had complete remission after the second cycle of rituximab, and the remaining 14 patients were partial responders. The authors stated that rituximab appeared to have rapid and dramatic efficacy in patients with severe, refractory MMP. However, the occurrence of severe infections in patients receiving concomitant conventional immunosuppressants supports the use of rituximab without other immunosuppressants. In the absence of confirmatory studies, rituximab cannot be the first-line drug for MMP. Future prospective studies and registries may be able to accurately evaluate rituximab’s safety profile, an optimal regimen, and its riskebenefit ratio in the setting of severe MMP. CHAIDEMENOS, 2011.31 This retrospective record review from Greece included 15 patients who received a combination of treatments, including prednisone, dapsone, colchicine, azathioprine, and cyclophosphamide. The outcome measure described was “lesion clearance” or “disease improvement.” The authors concluded that colchicine was effective in 8 of 12 cases, with only 1 withdrawal of treatment because of diarrhea as a side effect. Dapsone caused hemolytic anemia in 2 of 3 patients. MUMYANGANGO, 2013.32 This retrospective case series from France included 13 patients. The intervention


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Fig. 4. Summary Treatment Algorithm for MMP.

studied was oral daily cyclophosphamide with adjuvant immunosuppressives, including dapsone with or without sulfasalazine. Primary outcome measure was “active lesion scores.” Four patients remained in complete remission at 6 months after the study; all 4 were also on dapsone. Multiple adverse events were recorded, including lymphopenia in 10 of 15 patients; 6 of these patients had to stop treatment. The authors concluded that cyclophosphamide without corticosteroids had rapid efficacy in patients with severe refractory MMP and that it was safe. Ocular-only studies. There was 1 cohort study,33 5 case series with 734 to 9435 patients, and 2 case reports.36,37 A full list of interventions attempted is summarized in the online Supplementary Material Table II. The cohort study33 from Boston, Massachusetts, included 16 patients with ocularonly MMP. Immunosuppression plus corticosteroids plus IVIg was compared with immunosuppression plus corticosteroids. Group allocation was related to the health insurance provider for each patient (some insurance companies allowed the use of IVIg and others did not). Outcome measures were poorly validated and included a disease activity grade assessed by a nonblinded single

assessor. The authors reported positive results for the intervention group (8 of 8 total control) with a low rate of side effects (minimal in 4 of 8), and a failure in the “control” group (2 of 8 total control) and a high rate of side effects (8 of 8). The largest case series had 94 patients,35 and patients were had a variety of interventions, including cyclophosphamide, oral prednisone, dapsone, mycophenolate mofetil, chlorambucil, and azathioprine. Various ocular outcome measures were reported. The authors reported that treatment with cyclophosphamide and prednisone was strongly associated with the development of ocular remission. Various side effects, including malignancy and infections, were described, and 27 patients stopped treatment because of side effects.34 Eight patients developed malignancy (rate, 0.02/year; 95%CI, 0.01/yeare0.05/year), although in 1 patient, 2 malignancies developed. Of the 9 cases of cancer that occurred, 4 were skin cancers (2 basal cell carcinomas and 2 squamous cell carcinomas), 2 were leukemias, 1 was a breast carcinoma, 1 was a laryngeal squamous cell carcinoma, and 1 was a bladder carcinoma.34


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DISCUSSION Comparison with previous systematic reviews There has been little evidence to guide clinicians on the best treatments for MMP. Although there are several authoritative reviews as well as treatment guidelines for single therapies,38-47 there are only 2 comprehensive, international consensus guidelines,20,48 including the study by Chan et al. (2002)20 published in English. Finally, a single Cochrane Systematic Review on MMP treatment first published in 200349 and last updated in 2009 identified only 2 RCTs with limited evidence for treatment of ocular-only MMP.50 An authoritative review by Di Zenzo et al. (2014)5 summarized the best therapeutic options for MMP. Although not yet published as a systematic review, the same authors5 extended the 2009 Cochrane systematic review by using the same methodology and found the same single RCT we identified with limited evidence for treatment of ocular-only MMP with pentoxifylline25; they also identified 2 RCTs completed in 198650 (earlier than our 2003 cut-off point) exploring (1) cyclophosphamide plus prednisone to prednisone plus placebo and (2) dapsone versus prednisone. The study concluded that MMP involving the eyes responds best to treatment with cyclophosphamide combined with corticosteroids. However, dapsone is effective in mild to moderate disease and is preferred because of its lower side-effect profile compared with cyclophosphamide. The 2003 systematic review by Kirtschig et al.49 concluded that there was some evidence to support the author’s conclusions but high-quality, reliable evidence was lacking. We summarize in the online Supplementary Material Table II the recommendations of the single, international, comprehensive expert consensus treatment guidelines published in 2002.20 Di Zenzo et al. (2014)5 emphasizes the importance of careful risk assessment, particularly when making treatment decisions for mild to moderate MMP, which can be effectively treated with a (potent) topical agent plus one systemic medication. The authors point out the high rates of adverse effects (AEs) and discontinuation of therapy reported in previous studies: cyclophosphamide 77% AE, minocycline 67% discontinuation rate, mycophenolate mofetil 41% AE, and dapsone 14% discontinuation rates. Such rates of complications, and even deaths, have resulted from medications commonly used to treat MMP, and this only emphasizes the need for high-quality RCTs that very carefully characterize initial mucocutaneous lesion activity and disease severity. A significant methodologic limitation adversely affecting the quality of and comparison between clinical trials and observational studies is lack of common, validated methods for assessing disease severity and therapeutic endpoints and outcomes with differentiation


between oral mucosal disease and ocular mucosal disease. A significant advance has just been published (international, expert consensus recommendations for assessing disease activity and therapeutic outcome),51 and, if followed in future studies, it could overcome historical limitations and more accurately allow comparison of treatment efficacy for MMP. In addition to definitions of disease activity, the international expert panel introduces a Pemphigoid Disease Area Index (PDAI) specific to MMP-oral and MMP-ocular. Validation studies of the expert definitions and outcomes measures are already being planned (personal communication). A summary of the consensus recommendations are provided in the online Supplementary Material Table III, and full details can be found in the publication.51 A final point worth emphasizing for MMP is that topical treatments can effectively control mild to moderate disease, especially in the oral cavity. Although no study has explored the technique specifically, a common practice among oral medicine clinicians to enhance the topical treatment of generalized desquamative or erosive gingivitis is the use of a custom-made, soft drug-delivery oral stent covering the gingivae to extend drug contact time and absorption.52 Additionally, there has long been interest in the relationship between dental plaque-associated gingivitis and MMP-associated desquamative or erosive gingivitis. Painful erosive gingivitis often compromises a patient’s effective control of dental plaque with toothbrushing and dental flossing methods. Although not included in this systematic review because the intervention was not the treatment of MMP, an Italian group has recently described case-control differences in periodontal health status due to differences in oral hygiene in patients with MMP compared with healthy controls.53 The same authors then developed a pilot program of periodontal hygiene instruction combined with periodontal therapy and demonstrated significant improvement in periodontal health status and MMP lesion activity.54 Although these preliminary findings have not been replicated, the results suggest that optimal dental hygiene education and control of dental plaqueeassociated gingivitisdeven when painful gingival lesions are presentdwill improve periodontal health and gingival inflammation in patients with MMP and erosive gingivitis lesions. Potential biases in the review process Several studies had incomplete or missing data that we were unable to obtain from the authors. As our review only assessed the published literature, there is a risk of publication bias, as there may be unpublished studies that may provide further useful data. Indeed, a search


(US National Institutes of Health ongoing trials register at www.clinicaltrials.gov and World Health Organization International Clinical Trials Registry platform at www.who.int/trialssearch) for recent and ongoing or recently completed clinical trials did reveal 4 ongoing and recruiting studies, 2 studies not yet recruiting, and 2 completed trials. Of the 2 completed trials, 1 had data (Clinical Trial Evaluating Rituximab in Ocular MMP; 3 patients entered and completed the trial; only baseline data were available for comparison with treatment; and no serious AEs occurred) and the second trial did not have data (naturalistic observational cohort study: no study intervention).

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5. 6. 7.

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CONCLUSIONS There continues to be a paucity of high-quality clinical trials of interventions for MMP. Clinical practice is presently guided by descriptive evidence and expert guidelines published in 2002. Future studies of MMP treatment would be significantly improved by strict adherence to newly published expert recommendations on definitions of disease activity and outcome measures. Presently, research evidence is of insufficient quality to determine the optimal therapies for the treatment of MMP. Interventions that show promise include rituximab and IVIg. We have summarized in Figure 4 a treatment algorithm, adopted from the 2002 guidelines and modified on the basis of the literature published since that time. We emphasize that this algorithm is our summary of current best practices and has not been validated. Further high-quality research would very likely have an important impact on our clinical decision making. For clinicians, this review is a summary of the most recent available evidence, which can be used to guide clinical decision making. The authors would like to gratefully acknowledge the following organizations, individuals and companies that provided unrestricted financial support of WWOM VI: American Academy of Oral Medicine, European Association of Oral Medicine, anonymous gifts from patients of Dr. David Sirois, New York University College of Dentistry, Biocosmetics, Elsevier, Johnson and Johnson, The Oral Cancer Foundation, and Unilever.

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immune-mediated subepithelial blistering entity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;88:56-68. Bruch-Gerharz D, Hertl M, Ruzicka T. Mucous membrane pemphigoid: clinical aspects, immunopathological features and therapy. Eur J Dermatol. 2007;17:191-200. Di Zenzo G, Carrozzo M, Chan LS. Urban legend series: mucous membrane pemphigoid. Oral Dis. 2014;20:35-54. Schmidt E, Zillikens D. Pemphigoid diseases. Lancet. 2013;381: 320-332. Kirtschig G, Marinkovich MP, Burgeson RE, Yancey KB. Antibasement membrane autoantibodies in patients with anti-epiligrin cicatricial pemphigoid bind the alpha subunit of laminin 5. J Invest Dermatol. 1995;105:543-548. Rashid KA, Gurcan HM, Ahmed AR. Antigen specificity in subsets of mucous membrane pemphigoid. J Invest Dermatol. 2006;126:2631-2636. Egan CA, Lazarova Z, Darling TN, Yee C, Coté T, Yancey KB. Anti-epiligrin cicatricial pemphigoid and relative risk for cancer. Lancet. 2001;357:1850-1851. Ahmed AR, Foster S, Zaltas M, et al. Association of DQw7 (DQB1*0301) with ocular cicatricial pemphigoid. Proc Natl Acad Sci U S A. 1991;88:11579-11582. Delgado JC, Turbay D, Yunis EJ, et al. A common major histocompatibility complex class II allele HLA-DQB1* 0301 is present in clinical variants of pemphigoid. Proc Natl Acad Sci U S A. 1996;93:8569-8571. Setterfield J, Theron J, Vaughan RW, et al. Mucous membrane pemphigoid: HLA-DQB1*0301 is associated with all clinical sites of involvement and may be linked to antibasement membrane IgG production. Br J Dermatol. 2001;145:406-414. Carrozzo M, Fasano ME, Broccoletti R, et al. HLA-DQB1 alleles in Italian patients with mucous membrane pemphigoid predominantly affecting the oral cavity. Br J Dermatol. 2001;145: 805-808. Carrozzo M, Dametto E, Fasano ME, et al. Interleukin-4RA gene polymorphism is associated with oral mucous membrane pemphigoid. Oral Dis. 2014;20:275-280. Zakka LR, Reche P, Ahmed AR. Role of MHC Class II genes in the pathogenesis of pemphigoid. Autoimmun Rev. 2011;11:40-47. Setterfield J, Shirlaw PJ, Bhogal BS, Tilling K, Challacombe SJ, Black MM. Cicatricial pemphigoid: serial titres of circulating IgG and IgA antibasement membrane antibodies correlate with disease activity. Br J Dermatol. 1999;140:645-650. Bernard P, Antonicelli F, Bedane C, et al. Prevalence and clinical significance of anti-laminin 332 autoantibodies detected by a novel enzyme-linked immunosorbent assay in mucous membrane pemphigoid. JAMA Dermatol. 2013;149:533-540. Calabresi V, Carrozzo M, Cozzani E, et al. Oral pemphigoid autoantibodies preferentially target BP180 ectodomain. Clin Immunol. 2007;122:207-213. Sami N, Bhol KC, Ahmed AR. Treatment of oral pemphigoid with intravenous immunoglobulin as monotherapy. Long-term follow-up: influence of treatment on antibody titres to human alpha6 integrin. Clin Exp Immunol. 2002;129:533-540. Chan LS, Ahmed AR, Anhalt GJ, et al. The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol. 2002;138:370-379. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)


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statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147:573-577. Scottish Intercollegiate Guidelines Network. SIGN 50dA Guideline Developer’s Handbook. Edinburgh, Scotland: Scottish Intercollegiate Guidelines Network; 2008. Available at: http:// www.sign.ac.uk/pdf/sign50.pdf. Accessed July 9, 2013. do Nascimento Barbosa L, da Silva RS, Verardino GC, Gripp AC, Alves MFGS. Mucous membrane pemphigoid with severe esophageal stricture [translation]. Anais Brasileiros de Dermatologia. 2011;86:565-568. El Darouti MA, Fakhry Khattab MA, Hegazy RA, Hafez DA, Gawdat HI. Pentoxifylline (anti-tumor necrosis factor drug): effective adjuvant therapy in the control of ocular cicatricial pemphigoid. Eur J Ophthalmol. 2011;21:529-537. Kharfi M, Khaled A, Anane R, Fazaa B, Kamoun MR. Early onset childhood cicatricial pemphigoid: a case report and review of the literature. Pediatr Dermatol. 2010;27:119-124. Lebeau S, Mainetti C, Masouye I, Saurat JH, Borradori L. Localized childhood vulval pemphigoid treated with tacrolimus ointment. Dermatology. 2004;208:273-275. Schoeffler A, Roth B, Causeret A, Kanitakis J, Faure M, Claudy A. Vulvar cicatricial pemphigoid of childhood. Pediatr Dermatol. 2004;21:51-53. Lourari S, Herve C, Doffoel-Hantz V, et al. Bullous and mucous membrane pemphigoid show a mixed response to rituximab: experience in seven patients. J Eur Acad Dermatol Venereol. 2011;25:1238-1240. Le Roux-Villet C, Prost-Squarcioni C, Alexandre M, et al. Rituximab for patients with refractory mucous membrane pemphigoid. Arch Dermatol. 2011;147:843-849. Chaidemenos G, Sidiropoulos T, Katsioula P, KoussidouEremondi T. Colchicine in the management of mucous membrane pemphigoid. Dermatol Ther. 2011;24:443-445. Munyangango EM, Le Roux-Villet C, Doan S, et al. Oral cyclophosphamide without corticosteroids to treat mucous membrane pemphigoid. Br J Dermatol. 2013;168:381-390. Letko E, Miserocchi E, Daoud YJ, Christen W, Foster CS, Ahmed AR. A nonrandomized comparison of the clinical outcome of ocular involvement in patients with mucous membrane (cicatricial) pemphigoid between conventional immunosuppressive and intravenous immunoglobulin therapies. Clin Immunol. 2004;111:303-310. Suelves AM, Arcinue CA, Gonzalez-Martin JM, Kruh JN, Foster CS. Analysis of a novel protocol of pulsed intravenous cyclophosphamide for recalcitrant or severe ocular inflammatory disease. Ophthalmology. 2013;120:1201-1209. Thorne JE, Woreta FA, Jabs DA, Anhalt GJ. Treatment of ocular mucous membrane pemphigoid with immunosuppressive drug therapy. Ophthalmology. 2008;115:2146-2152.e1. Galdos M, Etxebarria J. Intravenous immunoglobulin therapy for refractory ocular cicatricial pemphigoid: case report. Cornea. 2008;27:967-969. Prey S, Robert PY, Drouet M, et al. Treatment of ocular cicatricial pemphigoid with the tumour necrosis factor alpha antagonist etanercept. Acta Derm Venereol. 2007;87:74-75. Patel R, Cafardi JM, Patel N, Sami N, Cafardi JA. Tumor necrosis factor biologics beyond psoriasis in dermatology. Expert Opin Biol Ther. 2011;11:1341-1359.

39. O’Neill ID. Biological response modifiers in inflammatory oral mucosal disease. Oral Dis. 2010;16:514-515. 40. Namazi MR. Nicotinamide in dermatology: a capsule summary. Int J Dermatol. 2007;46:1229-1231. 41. Kim EC, Foster CS. Immunomodulatory therapy for the treatment of ocular inflammatory disease: evidence-based medicine recommendations for use. Int Ophthalmol Clin. 2006;46:141-164. 42. Gurcan HM, Ahmed AR. Efficacy of dapsone in the treatment of pemphigus and pemphigoid: analysis of current data. Am J Clin Dermatol. 2009;10:383-396. 43. Gurcan HM, Ahmed AR. Intravenous immunoglobulin treatment in laryngeal pemphigoid. Clin Exp Dermatol. 2009;34:884-886. 44. Gera C, Kumar N, Berry V. Etarnacept JK Sci. 2008;10:151-154. 45. Eskin-Schwartz M, David M, Mimouni D. Mycophenolate mofetil for the management of autoimmune bullous diseases. Immunol Allergy Clin North Am. 2012;32:309-315. 46. Elad S, Epstein JB, Von Bltzingslowen I, Drucker S, Tzach R, Yarom N. Topical immunomodulators for management of oral mucosal conditions, a systematic review. Part II: Miscellaneous agents. Expert Opin Emerg Drugs. 2011;16:183-202. 47. Durrani K, Zakka FR, Ahmed M, Memon M, Siddique SS, Foster CS. Systemic therapy with conventional and novel immunomodulatory agents for ocular inflammatory disease. Surv Ophthalmol. 2011;56:474-510. 48. Diagnosis and therapy of mucous membrane pemphigoid. Results of the 1st International Consensus Conference [translation]. Hautarzt. 2002;53:371-372. 49. Kirtschig G, Murrell D, Wojnarowska F, Khumalo N. Interventions for mucous membrane pemphigoid and epidermolysis bullosa acquisita. Cochrane Database Syst Rev. 2003:CD004056. 50. Foster CS. Cicatricial pemphigoid. Trans Am Ophthalmol Soc. 1986;84:527-663. 51. Murrell DF, Marinovic B, Caux F, et al. Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international panel of experts. J Am Acad Dermatol. 2015;72:168-174. 52. Lee MS, Wakefield PE, Konzelman JL Jr, James WD. Oral insertable prosthetic device as an aid in treating oral ulcers. Arch Dermatol. 1991;127:479-480. 53. Arduino PG, Farci V, D’Aiuto F, et al. Periodontal status in oral mucous membrane pemphigoid: initial results of a case-control study. Oral Dis. 2011;17:90-94. 54. Arduino PG, Lopetuso E, Carcieri P, et al. Professional oral hygiene treatment and detailed oral hygiene instructions in patients affected by mucous membrane pemphigoid with specific gingival localization: a pilot study in 12 patients. Int J Dent Hyg. 2012;10: 138-141. Reprint requests: David Sirois, DMD, PhD Associate Professor, Department of Oral and Maxillofacial Pathology Radiology and Medicine New York University College of Dentistry 380 2nd Avenue Suite 301, New York City NY 10010, USA. [email protected]

ORAL MEDICINE 11.e1 Taylor et al.

APPENDIX A1: MMP Detailed Search String Pemphigoid MEDLINE Search strategy 1. randomized controlled trial.pt. 2. controlled clinical trial.pt. 3. randomized.ab. 4. placebo.ab. 5. clinical trials as topic.sh. 6. randomly.ab. 7. trial.ti. 8. 1 or 2 or 3 or 4 or 5 or 6 or 7 9. humans.sh. 10. 8 and 9 11. exp Pemphigoid/or pemphigoid.mp. 12. 11 and 10 EMBASE Search strategy 1. random$.mp. 2. factorial$.mp.

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3. crossover$.mp. 4. placebo$.mp. or PLACEBO/ 5. (doubl$ adj blind$).mp. [mp ¼ title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] 6. (singl$ adj blind$).mp. [mp ¼ title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] 7. assign$.mp. 8. volunteer$.mp. or VOLUNTEER/ 9. Crossover Procedure/ 10. Double Blind Procedure/ 11. Randomized Controlled Trial/ 12. Single Blind Procedure/ 13. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 14. exp MUCOUS MEMBRANE PEMPHIGOID/or exp PEMPHIGOID/or pemphigoid.mp. 15. 13 and 14


ORIGINAL ARTICLE Taylor et al. 11.e2

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APPENDIX 2: Mucous Membrane Pemphigoid Electronic data entry Initials of reviewing authors (minimum 2 authors): Study ID: first author surname/year of publication. Summary: Brief description of a few sentences e description of study (numbers of patients/interventions), summary of results

Grade of evidence: (See SIGN documenteDropbox “background” folder/short guide at end of this form.) 1þþ

Methods

Participants

Interventions

Outcomes

Notes

1þ

1

2þþ

2þ

2

3

Study design: RCT (describe either parallel, crossover, split mouth, cluster) Trial ID: Conducted in: (country) Number of centers: Recruitment period: Funding source: Conflicts of interest declared: Sample size calculation undertaken and met: Source of recruitment: Age (overall sample): Mean z years (range ¼ x to y years or SD ¼ years) Age GrA Age GrB Gender (overall sample): x females/y males Gender GrA Gender GrB Inclusion criteria: Exclusion criteria: Number randomized (overall and by group): Number evaluated (overall and by group): Comorbidities: Comparison: Specify treatment(s) and control interventions being compared, mode of administration & duration of interventions GrA (n ¼ ?): GrB (n ¼ ?): GrC (n ¼ ?): Primary outcomes with time of measurement 1. 2. 3. Secondary outcomes with time of measurement 1. 2. 3. Were adverse events reported? Yes/No/Unclear Was a reduction in morbidity reported? Yes/No/Unclear Was quality of life considered? Yes/No/Unclear Were Cost issues considered? Yes/No/Unclear Comparable groups at baseline: Co-interventions: Statistical tests: Anything else noteworthy?:

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Entry

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Judgment (Low risk of bias, high risk of bias, unclear)

Random sequence generation (selection bias)

Support for judgment Quote: Comment: Quote: Comment: Quote: Comment: Quote: Comment: Quote: Comment: Time of assessment: x/y missing from intervention group (provide reasons if stated); x/y missing from control group (provide reasons if stated). Proportions similar/different across groups. Reasons similar/different across groups. e.g., assessments stated in methods do not appear in the results e.g., baseline inequalities

Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) (patient-reported outcomes) Blinding of outcome assessment (detection bias) (clinical outcomes) Incomplete outcome data addressed (attrition bias)

Selective reporting (reporting bias) Any other risk of bias?

Example of a completed “Risk of bias” table for a single study (fictional)

Entry

Judgment (Low risk of bias, high risk of bias, unclear)

Random sequence generation (selection bias)

Low risk

Allocation concealment (selection bias)

High risk

Blinding of participants and personnel (performance bias)

Low risk

Blinding of outcome assessment (detection bias) (patient-reported outcomes) Blinding of outcome assessment (detection bias) (Mortality) Incomplete outcome data addressed (attrition bias)

Low risk

High risk

Selective reporting (reporting bias)

High risk

Low risk

Support for judgment Quote: “Patients were randomly allocated.” Comment: Probably done, since earlier reports from the same investigators clearly describe use of random sequences (Cartwright, 1980). Quote: “.using a table of random numbers.” Comment: Probably not done. Quote: “double blind, double dummy”; “High and low dose tablets or capsules were indistinguishable in all aspects of their outward appearance. For each drug an identically matched placebo was available (the success of blinding was evaluated by examining the drugs before distribution).” Comment: Probably done. Quote: “double blind”. Comment: Probably done. Obtained from medical records; review authors do not believe this will introduce bias. 4 weeks: 17 of 110 missing from intervention group (9 due to “lack of efficacy”); 7 of 113 missing from control group (2 due to “lack of efficacy”). Three rating scales for cognition listed in Methods, but only one (with statistically significant results) is reported.

Data extraction Please list outcome values for all outcomes in the review, and indicate the time of measurementde.g., mean pain score in last six months (treatment duration) measured on VAS scale from 0 to 10; mean ulcer size (mm).



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Results e dichotomous data

Outcome measure

Source of data (Table, Figure, etc.)

GrA

N randomized

N analyzed

GrB

N randomized

N analyzed

Comments e.g., per protocol or ITT analysis; ulcer or patient level data

Results e continuous data

Outcome measure


GrA

Sd/range

N randomized

N analyzed

GrB

Sd/range

N randomized

N analyzed

Comments e.g., per protocol or ITT analysis; ulcer or patient level data

Table. Criteria for judging risk of bias in the ‘Risk of bias’ assessment tool RANDOM SEQUENCE GENERATION Selection bias (biased allocation to interventions) due to inadequate generation of a randomized sequence. Criteria for a judgment of “low risk” of bias

The investigators describe a random component in the sequence generation process such as:

Criteria for the judgment of “high risk” of bias

Referring to a random number table Using a computer random number generator Coin tossing Shuffling cards or envelopes Throwing dice Drawing of lots Minimization*

*Minimization may be implemented without a random element, and this is considered to be equivalent to being random. The investigators describe a nonrandom component in the sequence generation process. Usually, the description would involve some systematic, nonrandom approach, for example: Sequence generated by odd or even date of birth Sequence generated by some rule based on date (or day) of admission Sequence generated by some rule based on hospital or clinic record number Other nonrandom approaches happen much less frequently than the systematic approaches mentioned above and tend to be obvious. They usually involve judgment or some method of nonrandom categorization of participants, for example:

Allocation Allocation Allocation Allocation

by judgment of the clinician by preference of the participant based on the results of a laboratory test or a series of tests by availability of the intervention (continued on next page)


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Table. Continued RANDOM SEQUENCE GENERATION Selection bias (biased allocation to interventions) due to inadequate generation of a randomized sequence. Criteria for the judgment of “unclear risk” of bias

Insufficient information about the sequence generation process to permit judgment of “low risk” or “high risk.”

ALLOCATION CONCEALMENT Selection bias (biased allocation to interventions) due to inadequate concealment of allocations before assignment. Criteria for a judgment of “low risk” of bias


Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: Central allocation (including telephone, web-based and pharmacy-controlled randomization) Sequentially numbered drug containers of identical appearance Sequentially numbered, opaque, sealed envelopes Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: Using an open random allocation schedule (e.g., a list of random numbers) Assignment envelopes were used without appropriate safeguards (e.g., if envelopes were unsealed or nonopaque or not sequentially numbered) Alternation or rotation Date of birth Case record number Any other explicitly unconcealed procedure

Criteria for the judgment of “unclear risk” of bias

Insufficient information to permit judgment of “low risk” or “high risk.” This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgment e for example, if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque, and sealed.

BLINDING OF PARTICIPANTS AND PERSONNEL Performance bias due to knowledge of the allocated interventions by participants and personnel during the study. Criteria for a judgment of “low risk” of bias

Any one of the following: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken


Any one of the following: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding


Any one of the following: Insufficient information to permit judgment of “low risk” or “high risk”; The study did not address this outcome

BLINDING OF OUTCOME ASSESSMENT Detection bias due to knowledge of the allocated interventions by outcome assessors. Criteria for a judgment of “low risk” of bias

Any one of the following: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken (continued on next page)



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Table. Continued BLINDING OF OUTCOME ASSESSMENT Detection bias due to knowledge of the allocated interventions by outcome assessors. Criteria for the judgment of “high risk” of bias

Any one of the following: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding Blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding

Criteria for the judgment of “unclear risk” of bias.

Any one of the following: Insufficient information to permit judgment of “low risk” or “high risk” The study did not address this outcome

INCOMPLETE OUTCOME DATA Attrition bias due to amount, nature or handling of incomplete outcome data. Criteria for a judgment of “low risk” of bias

Any one of the following: No missing outcome data Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias) Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size Missing data have been imputed using appropriate methods


Any one of the following: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size “As-treated” analysis done with substantial departure of the intervention received from that assigned at randomization Potentially inappropriate application of simple imputation


Any one of the following: Insufficient reporting of attrition or exclusions to permit judgment of “low risk” or “high risk” (e.g., number randomized not stated, no reasons for missing data provided) The study did not address this outcome

SELECTIVE REPORTING Reporting bias due to selective outcome reporting. Criteria for a judgment of “low risk” of bias

Any of the following: The study protocol is available and all of the study’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were prespecified (convincing text of this nature may be uncommon) (continued on next page)


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Table. Continued SELECTIVE REPORTING Reporting bias due to selective outcome reporting. Criteria for the judgment of “high risk” of bias

Any one of the following: Not all of the study’s prespecified primary outcomes have been reported One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g., subscales) that were not prespecified One or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect) One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis The study report fails to include results for a key outcome that would be expected to have been reported for such a study


Insufficient information to permit judgment of “low risk” or “high risk.” It is likely that the majority of studies will fall into this category

OTHER BIAS Bias due to problems not covered elsewhere in the table. Criteria for a judgment of “low risk” of bias Criteria for the judgment of “high risk” of bias

The study appears to be free of other sources of bias. There is at least one important risk of bias. For example, the study: Had a potential source of bias related to the specific study design used

or Has been claimed to have been fraudulent

or Had some other problem Criteria for the judgment of “unclear risk” of bias

There may be a risk of bias, but there is either: Insufficient information to assess whether an important risk of bias exists

or Insufficient rationale or evidence that an identified problem will introduce bias

Levels of Evidence 1DD High-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias 1D Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias 1 Meta-analyses, systematic reviews, or RCTs with a high risk of bias 2DD High-quality systematic reviews of case-control or cohort studies. High-quality case-control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal 2D Well-conducted case-control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal 2 Case-control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal 3 Nonanalytic studies (e.g., case reports, case series) 4 Expert opinion WWOM Pemphigus Vulgaris/Mucous membrane pemphigoid Electronic data entry Checklist derived from STROBE checklist for observational studies e http://www.strobe-statement.org



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Initials of reviewing authors (minimum 2 authors): Study ID: surname and year Summary: Brief description of a few sentences e description of study (numbers of patients/interventions), summary of results

Grade of evidence: (See SIGN documenteDropbox “background” folder/short guide at end of this form.) 1þþ

Methods

Participants

Interventions

Outcomes

Bias

1þ

1-

2þþ

2þ

2-

3

Study design: Cohort study, case-control, case series, case report describe type of studyde.g., prospective, retrospective, descriptive (describing observations in single group) or analytical (describing observations between different groups) Trial ID: Conducted in: (country) Number of centers: Recruitment period: Funding source: Conflicts of interest declared: Sample size calculation undertaken and met: Source and method of recruitment of cases: Case inclusion criteria (include diagnostic criteria if any): Case exclusion criteria: Source and method of recruitment of controls: Matching criteria and number of exposed and unexposed (cohort) and number of controls per case (case-control) Age (overall sample): Mean z years (range ¼ x to y years or SD ¼ years) Age cases Age controls Gender (overall sample): x females/y males Gender cases Gender controls Number evaluated (overall and by group): Follow-up period: Comorbidities: Specify treatment(s) and control interventions being compared, mode of administration and duration of interventions: Treatment A (n ¼ ?): Treatment B (n ¼ ?): Primary outcomes with time of measurement 1. 2. 3. Secondary outcomes with time of measurement 1. 2. 3. Were dropouts accounted for?: Were missing data accounted for?: Were adverse events reported? Yes/No/Unclear Was a reduction in morbidity reported? Yes/No/Unclear Was quality of life considered? Yes/No/Unclear Were Cost issues considered? Yes/No/Unclear Describe any efforts to address potential sources of bias: Confounding factors: Statistical tests: Anything else noteworthy?: e.g., the generalizability (external validity) of the results

4


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Data extraction Please list outcome values for all outcomes in the review, and indicate the time of measurementde.g., mean pain score in last 6 months (treatment duration) measured on VAS scale from 0 to 10; mean ulcer size (mm). Results e dichotomous data Outcome measure


Case

N enrolled

N analyzed

Control

N enrolled

N analyzed

Comments

N analyzed

Comments

Results e continuous data

Outcome measure

Source of data (Table, Figure Etc.) Case

Standard deviation/range

N Enrolled

N analyzed

Standard Controls deviation/range

N enrolled

Levels of evidence 1DD High-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias 1D Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias 1 - Meta-analyses, systematic reviews, or RCTs with a high risk of bias 2DD High-quality systematic reviews of case-control or cohort studies. High-quality case-control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal

2D Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal 2 Case-control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal 3 Nonanalytic studies (e.g., case reports, case series) 4 Expert opinion



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APPENDIX 3: Excluded studies Generalized adult MMP Citation Arash, 2008 Arduino, 2012 Barbosa, 2011 Boedeker, 2003 Carozzo, 2008 Chandra, 2004 Chehal, 2009 Chiou, 2007 Dainichi, 2005 Dainichi, 2010 Daito, 2008 Daoud, 2005 De, 2008 Do Nascimento Barbosa, 2011 Egan, 2004 Fantasia, 2006 Freitas, 2008 Friedman, 2009 Fukushima, 2008 Gamm, 2006 Giddings, 2009 Gonzalez, 2003 Gurcan, 2007 Hall, 2003 Hanafusa, 2012 Hanawa, 2012 Hayashi, 2009 Hayashi, 2012 Heelan, 2013 Heffernan, 2006 Howell, 2004 Inaoki, 2006 Inoue, 2005 Ion, 2005 Iwata, 2007 John, 2007 Kanjanabuch, 2012 Kanwar, 2006 Kasperkiewicz, 2011 Kavosh, 2007 Khaliq, 2011 Kleber, 2007 Laccheri, 2004 Lugovic, 2007 Malik, 2010 Martin, 2009 Martinez-Sahu, 2010 Masunaga, 2011 McCluskey, 2004 Mignogna, 2007 Motta, 2006 Muller, 2004 Newland, 2003 Nottage, 2013 Ojha, 2007 Oliveira, 2009 Ormond, 2010

Reason for exclusion Insufficient detail regarding diagnosis No intervention Insufficient detail regarding intervention and outcomes Insufficient detail regarding intervention and outcomes Insufficient detail regarding intervention and outcomes No intervention No intervention No intervention Comorbid autoimmune condition Comorbid autoimmune condition Not MMP No intervention No intervention Language other than English Insufficient detail regarding intervention and outcomes No intervention Insufficient detail regarding diagnosis, intervention and outcome Comorbid autoimmune condition Comorbid autoimmune condition Insufficient detail regarding intervention Not MMP Outcome data mixed with other diagnoses Insufficient detail regarding outcomes Insufficient detail regarding diagnosis No intervention No intervention Management of sequelae Insufficient detail regarding intervention and outcomes Outcome data mixed with other diagnoses Insufficient detail regarding diagnosis Insufficient detail regarding outcomes Insufficient detail regarding intervention and outcomes Not MMP Insufficient detail regarding diagnosis and outcome No intervention Insufficient detail regarding diagnosis and outcome Insufficient detail regarding intervention Not MMP Insufficient detail regarding diagnosis and intervention No intervention No intervention No intervention Insufficient detail regarding intervention Insufficient detail regarding diagnosis Comorbid autoimmune condition Not MMP Insufficient detail e letter or abstract Insufficient detail regarding intervention and outcomes Insufficient detail regarding diagnosis Outcome data mixed with other diagnoses Insufficient detail regarding intervention and outcomes No intervention No intervention Insufficient detail regarding diagnosis, intervention and outcome Insufficient detail regarding intervention Insufficient detail regarding diagnosis Insufficient detail e letter or abstract (continued on next page)


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Appendix 3. Continued Generalized adult MMP Orrico, 2010 Pasadhika, 2009 Patel, 2010 Pemberton, 2004 Rauz, 2005 Reganato, 2006 Rodrigues-Tellez, 2010 Ross, 2009 Roufas, 2010 Rourke, 2012 Sanchez, 2004 Sanfilippo, 2003 Saw, 2008 Schulz, 2011 Sezin, 2013 Singh, 2011 Syn, 2004 Thorne, 2005 Uchino, 2007 Van Lingen, 2006 Varughese, 2007 Ward, 2013 Wilkins, 2008 Woo, 2013 Yesudian, 2005 Yilmaz, 2010

No intervention Insufficient detail regarding diagnosis and intervention Insufficient detail e letter or abstract No intervention Insufficient detail regarding diagnosis and intervention No intervention Insufficient detail regarding diagnosis, intervention and outcome Insufficient detail regarding outcomes Insufficient detail regarding intervention and outcomes Insufficient detail regarding outcomes Insufficient detail regarding diagnosis Insufficient detail regarding diagnosis Insufficient detail regarding diagnosis Insufficient detail regarding intervention Insufficient detail regarding intervention and outcomes Insufficient detail regarding intervention and outcomes Insufficient detail regarding intervention and outcomes Outcome data mixed with other diagnoses Insufficient detail regarding intervention Insufficient detail regarding intervention and outcomes Insufficient detail regarding intervention and outcomes Insufficient detail regarding diagnosis, intervention and outcome Insufficient detail regarding diagnosis and intervention Insufficient detail regarding diagnosis and outcome Management of sequelae Insufficient detail regarding outcomes Ocular-only MMP

Citation Cervantes, 2009 Da Costa, 2012 Daniel, 2010 Durrani, 2004 Gangaputra, 2009 Kacmaz, 2010 Papaliodis, 2003 Pujari, 2010

Reason for exclusion Outcome data mixed with other diagnoses Insufficient detail regarding diagnosis and intervention Insufficient detail regarding diagnosis Outcome data mixed with other diagnoses Outcome data mixed with other diagnoses Insufficient detail regarding diagnosis Insufficient detail regarding diagnosis Insufficient detail regarding diagnosis Pediatric/Pregnancy MMP

Citation Hoque, 2006 Iovine, 2008 Lourenco, 2006 Mostafa, 2010 Veysey, 2007

Reason for exclusion Topical skin only Insufficient detail regarding Insufficient detail regarding Insufficient detail regarding Insufficient detail regarding

intervention and outcomes outcomes outcomes intervention and outcomes



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Supplementary Table I. Summary of treatment recommendations from the First International Consensus on mucous membrane pemphigoid (MMP)* Risk class

Criteria (site, severity, rapidity)

High

Ocular, genital or esophageal and/or laryngeal lesions; OR Rapidly progressive disease

Low

Oral mucosa only Or Oral mucosa þ Skin

Treatment SEVERE disease: Prednisone (0.5e1.5 mg/kg/day) plus cyclophosphamide (1e2 mg/kg/day) OR alternative therapies: Azathioprine (1e2 mg/kg/day) (Check thiopurine methyltransferase (TPMT) level before starting. Monitor activity: low level predicts efficacy and potentially severe myelosuppression/adverse events.) OR Mycophenolate mofetil (1e2 g/day in divided doses) MILD Disease: Dapsone (50e200 mg/day) (Check glucose-6-phosphate dehydrogenase (G6PD) level: Deficiency. Increases risk of hemolytic anemia.) OR Sulfamethoxypyridazine (0.5e1 g/day) or sulfapyridine (0.25e1 g/day) (Not universally available.) (Must improve 3 months or begin prednisolone þ immunosuppressive agent.) Moderate to high-dose topical corticosteroid If additional control needed: Add dapsone (50e200 mg/day) or other sulfa drug OR Low dose systemic corticosteroid Tetracycline (1-2 g/d) and nicotinamide (2-2.5 g/d) Consider adjuvants if further control needed: Azathioprine (1-2 mg/kg/day) Mycophenolate mofetil (1-2 g/d in divided doses)

*Chan LS, Ahmed AR, Anhalt GJ, et al. The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol. 2002;138:370-379.


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Supplementary Table II. Mucous membrane pemphigoid (MMP) interventions Intervention/ co-intervention Azathioprine

Colchicine

Corticosteroids e IV

Corticosteroids e oral

Corticosteroids etopical

Study type and number MMP CR-1 Ocular Cohort-1 CS-1 CR-1

MMP CS-1

MMP CR-1 Ocular RCT-1 CS-1

MMP CS-5 CR-5 Ocular RCT-1 Cohort-1 CS-1 CR-1 Pediatric CR-1

MMP CS-3 CR-1

Levels of evidence 3 2 3 3

3

3 1 3

3 3 1 2 3 3 3

3 3

Summary

References

Letko, 2004 e Ocular MMP cohort, high risk MMP CR of bias, variable treatments with (Kennedy, Devillez, et al., 2010) insufficient details, outcome measures used Ocular had questionable validity Cohort Thorne, 2008 e ocular MMP series, oral (Lebeau, Mainetti, et al., 2004) cyclophosphamide and oral prednisolone CS with variable adjuvants including (Thorne, Woreta, et al., 2008) azathioprine (see cyclophosphamide) CR Galdos and Etxebarria, 2008 Chaidemenos, 2011 e series of 15 patients MMP with MMP e treated with prednisone CS 40 mg/day and adjuvants including (Chaidemenos, Sidiropoulos, et al., 2011) colchicine 1 mg/day e complete remission on colchicine in 5 of/12 El-Darouti 2011 e RCT of ocular MMP in MMP CR 30 participants e comparing pulsed CYP (Schumann, Schmidt, et al., 2009) IV/IV methylprednisolone (standard) Ocular versus standard plus IV pentoxyfylline (see RCT cyclophosphamide) (El Darouti, Fakhry Khattab, et al., 2011) Suelves, 2013 e ocular MMP series treated CS with pulsed IV CYP and IV (Suelves, Arcinue, et al., 2013) methylprednisolone (see cyclophosphamide) El-Darouti, 2011 e RCT of ocular MMP in MMP 30 participants e comparing pulsed CYP CS (Segura, Iranzo, et al., 2007; Chaidemenos, IV/IV methylprednisolone (standard) Sidiropoulos, et al., 2011; Doycheva, versus standard plus IV pentoxyfylline. Deuter, et al., 2011; Lourari, Herve, et al., Oral prednisolone used as adjuvant in both 2011; Staines and Hampton, 2012) arms (see cyclophosphamide) CR Letko, 2004 e ocular MMP cohort, high risk (Gunther, Wozel, et al., 2004; Wozniak, of bias, variable treatments with Waszczykowska, et al., 2006; Taverna, insufficient details, outcome measures used Lerner, et al., 2007; Yu, Chong, et al., had questionable validity 2007; Schumann, Schmidt, et al., 2009) Kharfi, 2010 e a case of a 20-month-old boy Ocular with MMP e treated successfully with RCT systemic steroids followed by disease free (El Darouti, Fakhry Khattab, et al., 2011) maintenance on dapsone and topical Cohort (ocular) cyclosporine and oral prednisone (Letko, Miserocchi, et al., 2004) CS (Thorne, Woreta, et al., 2008) CR (Galdos and Etxebarria, 2008) Pediatric CR (Kharfi, Khaled, et al., 2010) Canizares, 2006 e series of 3 patients with MMP CS oral and ocular disease treated with (Canizares, Smith, et al., 2006; Carrozzo, etanercept 25 mg, topical clobetasol and Arduino, et al., 2009; Le Roux-Villet, nystatin Prost-Squarcioni, et al., 2011) Carrozzo, 2009 e open-label uncontrolled Ocular series of 9 MMP patients using CR minocycline e 5 with adjuvant topical (Galdos and Etxebarria, 2008) clobetasol (see minocycline) Le Roux-Villet, 2011 e series of 25 MMP (10 with ocular disease) patients treated with 1e2 cycles rituximab and adjuvants, including dapsone and/or sulfasalazine and topical corticosteroids (see rituximab) (continued on next page)



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Supplementary Table II. Continued Intervention/ co-intervention

Study type and number

Cyclophosphamide MMP CS-3 CR-2 Ocular RCT-1 Cohort-1 CS-2 CR-1

Cyclosporine e topical

Dapsone

Ocular CS-1 Pediatric CR-1

MMP CS-3

Levels of evidence 3 3 1 2 3 3

3 3

3

Summary

References

El-Darouti, 2011 e RCT of ocular MMP in MMP CS 30 participants e comparing pulsed CYP (Segura, Iranzo, et al., 2007; Chaidemenos, IV/methylprednisolone IV (standard) Sidiropoulos, et al., 2011; Munyangango, versus standard plus IV pentoxyfylline. Le Roux-Villet, et al., 2013) Study suggests no significant clinical CR benefit of standard therapy and (Wozniak, Waszczykowska, et al., 2006; pentoxyfylline over standard therapy alone. Yu, Chong, et al., 2007) No drug discontinuation was needed in Ocular either arm due to adverse effects. RCT Letko, 2004 e ocular MMP cohort, high risk (El Darouti, Fakhry Khattab, et al., 2011) of bias, variable treatments with Cohort insufficient details, outcome measures used (Letko, Miserocchi, et al., 2004) had questionable validity CS Segura, 2007 e series of 4 patients with (Thorne, Woreta, et al., 2008; Suelves, MMP, treated with IVIg monotherapy of Arcinue, et al., 2013) with adjuvant IS (including CYP) e (see IVIg) CR Chaidemenos, 2011 e series of 15 patients (Galdos and Etxebarria, 2008) with MMP e treated with prednisone 40 mg/day and adjuvants including oral CYPe complete remission in 1 of 4 using oral CYP Munyangango, 2013 e series of 13 MMP patients treated with oral CYP and adjuvants in 10 of 13 (dapsone/ sulfasalazine) - 7 of 13 achieved complete remission (3 of 5 ocular disease patients). 2 of 13 stopped CYP due to lymphopenia Suleves, 2013 e ocular MMP series treated with pulsed IV CYP and IV methylprednisolone e complete remission in 54 of 65. 12 of 54 required to stop therapy due to adverse effects e 3 of 54 developed malignancy e the most common adverse effects were nausea (29%) and transient lymphopenia (26%) Thorne, 2008 - ocular MMP series, oral cyclophosphamide and oral prednisolone with variable adjuvants, including azathioprine, dapsone, MMF e 58 of 70 patients achieved complete control. Adverse events included hematuria, infection (34 of 70), malignancy (8 of 70 e including 1 bladder carcinoma) Doycheva, 2011 - series of 10 patients with Ocular CS ocular MMP treated with MMF 1 g twice (Doycheva, Deuter, et al., 2011) daily as well as prednisolone and Pediatric cyclosporine A 2% eye drops. 11 of 17 CR eyes with active inflammation at (Kharfi, Khaled, et al., 2010) commencement of therapy showed a reduction in ocular inflammation. Prevention of cicatrization was prevented in 9 eyes of 7 patients. Kharfi, 2010 e a case of a 20-month-old boy with MMP e treated successfully with systemic steroids followed by disease-free maintenance on dapsone and topical (ocular) cyclosporine and oral prednisone Chaidemenos, 2011 e series of 15 patients MMP with MMP e treated with prednisone CS (continued on next page)


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Study type and number CR-2 Ocular Cohort-1 CS-1 CR-1 Pediatric CR-2

Etanercept

IVIg

MMP CS-1 CR-2

MMP CS-2 CR-3 Ocular Cohort-1 CS-1 CR-1

Levels of evidence 3 2e 3 3 3

3 3

3 3 2 3 3

Summary

References

(Chaidemenos, Sidiropoulos, et al., 2011; 40 mg/day and adjuvants including Staines and Hampton, 2012; dapsone e complete remission in 3 of 10 Munyangango, Le Roux-Villet, et al., using dapsone 2013) Staines, 2012 e series of 6 patients with CR MMP treated with combination of MMF, (Yu, Chong, et al., 2007; Gurcan and dapsone and oral prednisolone e all had Ahmed, 2009) complete oral disease control on therapy at Ocular 18 months follow-up Cohort Munyangango, 2013 eseries of 13 MMP (Letko, Miserocchi, et al., 2004) patients treated with oral CYP and CS adjuvants in 10 of 13 (dapsone/ (Thorne, Woreta, et al., 2008) sulfasalazine) e (see cyclophosphamide) CR Letko, 2004 e ocular MMP cohort, high risk (Prey, Robert, et al., 2007) of bias, variable treatments with Pediatric insufficient details, outcome measures used CR had questionable validity (Schoeffler, Roth, et al., 2004; Kharfi, Thorne, 2008 e ocular MMP series, oral Khaled, et al., 2010) cyclophosphamide and oral prednisolone with variable adjuvants including azathioprine, dapsone, MMF e (see cyclophosphamide) Kharfi, 2010 e a case of a 20-month-old boy with MMP e treated successfully with systemic steroids followed by disease-free maintenance on dapsone and topical (ocular) cyclosporine and oral prednisone Schoeffler, 2004 e a 9-year-old girl with vulval MMP. No clinical response was obtained after 4 weeks of topical clobetasol propionate cream e dapsone was then started e complete healing was obtained in 1 month, with persistent remission after tapering dapsone to a dosage as low as 25 mg on alternate days over 1 year. There was no recurrence after discontinuation of the treatment. Adverse events were not discussed. Canizares, 2006 e series of 3 patients with MMP oral and ocular disease treated with CS etanercept 25 mg and topical clobetasol and (Canizares, Smith, et al., 2006) nystatin e 2 of 3 gained partial control and CR 1 of 3 complete control of disease Kennedy, Devillez, et al., 2010 Ocular CR (Canizares, Smith, et al., 2006; Prey, Robert, et al., 2007; Kennedy, Devillez, et al., 2010) Canizares, 2006 e series of 3 MMP patients MMP CS treated with etanercept e 1 case was (Canizares, Smith, et al., 2006; Segura, treated with IVIg unsuccessfully before Iranzo, et al., 2007) etanercept e headaches and hypertension CR were reported with the IVIg therapy (Wozniak, Waszczykowska, et al., 2006; Segura, 2007 e series of 4 patients with Yu, Chong, et al., 2007; Gurcan and MMP, treated with IVIg monotherapy of Ahmed, 2009) with adjuvant IS. 1 of 4 with oral disease Ocular had complete remission after 8 cycles of Cohort monotherapy, 2 of 4 had partial remission (Letko, Miserocchi, et al., 2004) (1 on monotherapy; 1 with oral CS prednisolone and oral CYP) e these 2 (Sami, Letko, et al., 2004) cases had to discontinue therapy due to (continued on next page)



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Levels of evidence

Low level laser therapy

MMP CS-1

3

Methotrexate

Ocular Cohort-1

3

Minocycline

Mycophenolate mofetil

MMP CS-1 Ocular CR-1

MMP CS-2 CR-1 Ocular CS-2

3 3

3 3 3

Summary adverse effects of IVIg. 1 of 4 was a nonresponder despite adjuvant IS therapy Letko, 2004 e ocular MMP cohort, high risk of bias, variable treatments with insufficient details, outcome measures used had questionable validity Sami, 2004 e series of 10 MMP patients with refractory ocular disease treated with IVIg monotherapy. All 10 patients initially demonstrated signs of clinical improvement with IVIg therapy. The total number of IVIg cycles ranged from 20 to 42 (mean, 32), and the total duration of IVIg therapy ranged from 25 to 43 months (mean, 35). 8 of 10 patients who completed the protocol had an improvement in their visual acuity and did not have further progression of subepithelial conjunctival fibrosis. 2 of 10 patients dropped out of the protocol and lost vision e the reasons for dropout were unclear Cafaro, 2012 e series of 3 MMP patients treated with LLLT. 3 patients with MMP e all patients had complete resolution of oral lesions in less than a mean of 10 treatment sessions. Single observer, blinding not stated Letko, 2004 e ocular MMP cohort, high risk of bias, variable treatments with insufficient details, outcome measures used had questionable validity Carrozzo, 2009 e open label, uncontrolled series of 9 MMP patients using minocycline (5 with adjuvant topical clobetasol) e complete remission in 3 of 9, 2 of 9 no response e 5 of 9 patients discontinued minocycline due to adverse effects Chaidemenos, 2011 e series of 15 patients with MMP e treated with prednisone 40 mg/day and adjuvants including MMFe complete remission in 0 of 1 using MMF Staines, 2012 e series of 6 patients with MMP treated with combination of MMF, dapsone and oral prednisolone e all had complete oral disease control on therapy at 18 months follow-up Thorne, 2008 e ocular MMP series, oral cyclophosphamide and oral prednisolone with variable adjuvants, including azathioprine, dapsone, MMF (see cyclophosphamide) Doycheva, 2011 e series of 10 patients with ocular MMP treated with MMF 1 g twice daily as well as prednisolone and cyclosporine A 2% eye drops. 11 of 17 eyes with active inflammation at commencement of therapy showed a reduction in ocular inflammation. Prevention of cicatrization in 9 eyes of 7 patients.

References CR (Galdos and Etxebarria, 2008)

MMP (Cafaro, Broccoletti, et al., 2012)

Ocular (Lebeau, Mainetti, et al., 2004)

MMP CS (Carrozzo, Arduino, et al., 2009) Ocular CR (Galdos and Etxebarria, 2008) MMP CS (Chaidemenos, Sidiropoulos, et al., 2011; Staines and Hampton, 2012) CR (Taverna, Lerner, et al., 2007) Ocular CS (Thorne, Woreta, et al., 2008; Doycheva, Deuter, et al., 2011)

(continued on next page)


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Mycophenolic acid MMP CS-1

Pentoxyfylline

Rituximab

Sulfasalazine

Tacrolimus topical

Levels of evidence 3

Ocular RCT-1

1

MMP CS-2 CR-2

3 3

MMP CS-2

3

MMP CS-1 CR-3 Pediatric CR-1

3 3 3

Summary Marzano, 2006 e MMP series of 2 participants (1 with Brunsting-Perry variant) with a high risk of bias e treated with MPA and adjuvant oral steroids e partial remission 1 of 2, complete remission in 1 of 2 El Darouti, 2011 e RCT of ocular MMP in 30 participants e comparing pulsed CYP IV/methylprednisolone IV (standard) versus standard plus IV pentoxyfylline. Study suggests no significant clinical benefit of standard therapy and pentoxyfylline over standard therapy alone. No drug discontinuation was needed in either arm due to adverse effects. Le Roux-Villet, 2011 e series of 25 MMP (10 with ocular disease) patients treated with 1e2 cycles rituximab and adjuvants, including dapsone and/or sulfasalazine and topical corticosteroids e 17 of 25 in complete remission at 12 weeks after 1 cycle; 9 of 10 ocular patients were clear of disease after mean of 10 weeks. 10 of 25 relapse at mean of 4(range 1e16) months. 2 of 25 died (also on IS medications) Lourari, 2011 e series of 6 MMP patients treated with rituximab with unspecified adjuvant IS e 4 of 6 complete remission on therapy Le Roux-Villet, 2011 e series of 25 MMP (10 with ocular disease) patients treated with 1e2 cycles rituximab and adjuvants, including dapsone and/or sulfasalazine and topical (see rituximab) Munyangango, 2013 e series of 13 MMP patients treated with oral CYP and adjuvants in 10 of 13 (dapsone/ sulfasalazine) e (see cyclophosphamide) Assmann, 2004 e series of 2 refractory oral MMP patients treated with topical tacrolimus e complete remission was achieved - adverse effects were not discussed Lebeau, 2004 e case of an 8-year-old with vulval MMP e responded to topical tacrolimus

References MMP CS (Marzano, Dassoni, et al., 2006)

Ocular RCT (El Darouti, Fakhry Khattab, et al., 2011)

MMP CS (Le Roux-Villet, Prost-Squarcioni, et al., 2011; Lourari, Herve, et al., 2011) CR (Taverna, Lerner, et al., 2007; Schumann, Schmidt, et al., 2009)

MMP CS (Munyangango, Le Roux-Villet, et al., 2013) (Le Roux-Villet, Prost-Squarcioni, et al., 2011)

MMP CS (Assmann, Becker, et al., 2004) CR (Gunther, Wozel, et al., 2004; Suresh, Martinez Calixto, et al., 2006; Lee, Blazek, et al., 2011) Pediatric CR (Lebeau, Mainetti, et al., 2004)

Note: Modified from 2002. See the full publication for additional details. Site, severity and rapidity of progression determine risk status and medications. MMP, mucous membrane pemphigoid; ocular, ocular only MMP study; pediatric, pediatric only MMP study; RCT, randomized controlled trial; CCT, controlled clinical trial; cohort, cohort study; CS, case series; CR, case report; CYP, cyclophosphamide; CYP IV, pulsed IV cyclophosphamide; IS, immunosuppressant; IV, intravenous; IVIg, intravenous immunoglobulin; LLLT, low level laser therapy; MMF, mycophenolate mofetil.

Levels of Evidence (SIGN 2008) 1þþ High-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias

1þ Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias


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1 Meta-analyses, systematic reviews, or RCTs with a high risk of bias 2þþ High-quality systematic reviews of case control or cohort studies. High-quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal 2þ Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal 2 Case-control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal 3 Nonanalytic studies (e.g., case reports, case series) 4 Expert opinion References Assmann T, Becker J, Ruzicka T, Megahed M. Topical tacrolimus for oral cicatricial pemphigoid. Clin Exp Dermatol. 2004;29:674-676. Cafaro A, Broccoletti R, Arduino PG. Low-level laser therapy for oral mucous membrane pemphigoid. Lasers Med Sci. 2012;27:1247-1250. Canizares MJ, Smith DI, Conners M, Maverick KJ, Heffernan MP. Successful treatment of mucous membrane pemphigoid with etanercept in 3 patients. Arch Dermatol. 2006;142:1457-1461. Canizares MJ, Smith DI, Conners MS, Maverick KJ, Heffernan MP. Successful treatment of mucous membrane pemphigoid with etanercept in 3 patients. Arch Dermatol. 2006;142:1457-1461. Carrozzo M, Arduino P, Bertolusso G, Cozzani E, Parodi A. Systemic minocycline as a therapeutic option in predominantly oral mucous membrane pemphigoid: a cautionary report. Int J Oral Maxillofac Surg. 2009;38:1071-1076. Chaidemenos G, Sidiropoulos T, Katsioula P, Koussidou-Eremondi T. Colchicine in the management of mucous membrane pemphigoid. Dermatol Ther. 2011;24:443-445. Doycheva D, Deuter C, Blumenstock G, Stuebiger N, Zierhut M. Long-term results of therapy with mycophenolate mofetil in ocular mucous membrane pemphigoid. Ocul Immunol Inflamm. 2011;19:431-438. El Darouti MA, Fakhry Khattab MA, Hegazy A, Hafez DA, Gawdat HI. Pentoxifylline (anti-tumor necrosis factor drug): effective adjuvant therapy in the control of ocular cicatricial pemphigoid. Eur J Ophthalmol. 2011;21:529-537. Galdos M, Etxebarria J. Intravenous immunoglobulin therapy for refractory ocular cicatricial pemphigoid: case report. Cornea. 2008;27:967-969. Gunther C, Wozel G, Meurer M, Pfeiffer C. Topical tacrolimus treatment for cicatricial pemphigoid. J Am Acad Dermatol. 2004;50:325-326.


Gurcan HM, Ahmed AR. Intravenous immunoglobulin treatment in laryngeal pemphigoid. Clin Exp Dermatol. 2009;34:884-886. Kennedy JS, Devillez RL, Henning JS. Recalcitrant cicatricial pemphigoid treated with the anti-TNF-alpha agent etanercept. J Drugs Dermatol. 2010;9:68-70. Kharfi M, Khaled A, Anane R, Fazaa B, Kamoun MR. Early onset childhood cicatricial pemphigoid: a case report and review of the literature. Pediatr Dermatol. 2010;27:119-124. Le Roux-Villet C, Prost-Squarcioni C, Alexandre M, et al. Rituximab for patients with refractory mucous membrane pemphigoid. Arch Dermatol. 2011;147:843-849. Lebeau S, Mainetti C, Masouye I, Saurat JH, Borradori L. Localized childhood vulval pemphigoid treated with tacrolimus ointment. Dermatology. 2004;208:273-275. Lee HY, Blazek C, Beltraminelli H, Borradori L. Oral mucous membrane pemphigoid: complete response to topical tacrolimus. Acta Derm Venereol. 2011;91:604-605. Letko E, Miserocchi E, Daoud YJ, Christen W, Foster CS, Ahmed AR. A nonrandomized comparison of the clinical outcome of ocular involvement in patients with mucous membrane (cicatricial) pemphigoid between conventional immunosuppressive and intravenous immunoglobulin therapies. Clin Immunol. 2004;111:303-310. Lourari S, Herve C, Doffoel-Hantz V, et al. Bullous and mucous membrane pemphigoid show a mixed response to rituximab: experience in seven patients. J Eur Acad Dermatol Venereol. 2011;25:1238-1240. Marzano AV, Dassoni F, Caputo R. Treatment of refractory blistering autoimmune diseases with mycophenolic acid. J Dermatol Treat. 2006;17:370-376. Munyangango EM, Le Roux-Villet C, Doan S, et al. Oral cyclophosphamide without corticosteroids to treat mucous membrane pemphigoid. Br J Dermatol. 2013;168:381-390. Prey S, Robert PY, Drouet M, et al. Treatment of ocular cicatricial pemphigoid with the tumor necrosis factor alpha antagonist etanercept. Acta Dermato-Venereologica. 2007;87:74-75. Sami N, Letko E, Androudi S, Daoud Y, Foster CS, Ahmed AR. Intravenous immunoglobulin therapy in patients with ocular-cicatricial pemphigoid: a long-term follow-up. Ophthalmology. 2004;111:1380-1382. Schoeffler A, Roth B, Causeret A, Kanitakis J, Faure M, Claudy A. Vulvar cicatricial pemphigoid of childhood. Pediatr Dermatol. 2004;21:51-53. Schumann T, Schmidt E, Booken N, Goerdt S, Goebeler M. Successful treatment of mucous membrane pemphigoid with the anti-CD-20 antibody rituximab. Acta Derm Venereol. 2009;89:101-102. Segura S, Iranzo P, Martinez-de Pablo I, Mascaro JM, Jr., Alsina M, Herrero J, Herrero C. High-dose


intravenous immunoglobulins for the treatment of autoimmune mucocutaneous blistering diseases: evaluation of its use in 19 cases. J Am Acad Dermatol. 2007;56:960-967. Scottish Intercollegiate Guidelines Network. SIGN 50 eA Guideline Developer’s Handbook. Revised ed. Edinburgh, Scotland: SIGN; 2011. Available at: http:// www.sign.ac.uk/pdf/sign50.pdf. Accessed July 9, 2013. Staines K, Hampton PJ. Treatment of mucous membrane pemphigoid with the combination of mycophenolate mofetil, dapsone, and prednisolone: a case series. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012; 114:E49-56. Suelves AM, Arcinue CA, Gonzalez-Martin JM, Kruh JN, Foster C. Analysis of a novel protocol of pulsed intravenous cyclophosphamide for recalcitrant or severe ocular inflammatory disease. Ophthalmology. 2013; 120:1201-1209.

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Suresh L, Martinez Calixto LE, Radfar L. Successful treatment of mucous membrane pemphigoid with tacrolimus. Spec Care Dentist. 2006; 26:66-70. Taverna JA, Lerner A, Bhawan J, Demierre MF. Successful adjuvant treatment of recalcitrant mucous membrane pemphigoid with anti-CD20 antibody rituximab. J Drugs Dermatol. 2007; 6:731-732. Thorne JE, Woreta FA, Jabs DA, Anhalt GJ. Treatment of ocular mucous membrane pemphigoid with immunosuppressive drug therapy. Ophthalmology. 2008; 115:2146-2152, e2141. Wozniak K, Waszczykowska E, Hashimoto T, et al. Anti-epiligrin cicatricial pemphigoid initially limited to the upper respiratory tract. Br J Dermatol. 2006; 154:779-781. Yu JT, Chong LY, Lee KC. A recalcitrant case of cicatricial pemphigoid. Hong Kong Med J. 2007; 13:157-160.



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Supplementary Table III. Summary of 2015 International Expert Recommendations of disease* Endpoint observation

Disease activity term

Early

Baseline Control disease activity Control scarring activity End disease consolidation

Intermediate

Transient lesions Nontransient lesions Complete remission Minimal therapy

Minimal adjuvant therapy

Long-term biological therapy Late

Partial remission on minimal therapy Complete remission on minimal therapy Partial remission off therapy Complete remission off therapy Relapse/flare

Definition The day mucous membrane pemphigoid (MMP) therapy is started by doctor Time when new lesions stop forming and established lesions begin to heal The time needed to control scarring progression Time when no new lesions have developed for a minimum of 4 weeks and approximately 80% of lesions have healed New lesions that heal within 1 week or clear without treatment New lesions that do not heal within 1 week Absence of nontransient lesions while patient is receiving more than minimal therapy Dapsone 1.0 mg/kg/day 0.1 mg/kg/day of prednisone (or equivalent) Minocycline 100 mg/day Doxycycline 100 mg/day Lymecycline 300 mg/day Topical corticosteroid once daily, including fluticasone prop. suspension 400 mg/1 day colchicine 500 mg/day Salazopyrin 1 g/day Sulfapyridine 500 mg/day Sulfamethoxypyridazine 500 mg/day Nicotinamide 500 mg/day Azathioprine (1 mg/kg/day) with normal thiopurine S-methyltransferase level Mycophenolate mofetil 500 mg/day Mycophenolic acid 360 mg/day Methotrexate 5 mg/week Cyclosporine 1 mg/kg/day Therapies given intermittently (i.e., rituximab for MMP, or intravenous immunoglobulin (IVIg) monthly) Transient new lesions that heal without scarring 1 week while on minimal therapy for at least 2 months The absence of new or established lesions while the patient is receiving minimal therapy for at least 2 months Presence of transient new lesions that heal within 1 week without treatment while the patient is off all MMP therapy for at least 2 months Absence of new or established lesions while the patient is off all MMP therapy for at least 2 months Appearance of 3 new lesions a month that do not heal within 1 week, or the extension of established lesions in a patient who has achieved disease control

See the full publication for additional details and the Mucous Membrane Pemphigoid Disease Area Index (MM-PDAI) the scoring/assessment of disease activity. *Murrell DF, Marinovic B, Caux F, et al. Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international panel of experts. J Am Acad Dermatol. 2015;72:168-174.

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