European guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology  Part I

This guideline on mucous membrane pemphigoid (MMP) has been elaborated by the Task Force for Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology (EADV) with a contribution of physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline encompassing a systematic review of the literature until June 2019 in the MEDLINE and EMBASE databases. This first part covers methodology, the clinical definition of MMP, epidemiology, MMP subtypes, immunopathological characteristics, disease assessment and outcome scores. MMP describes a group of autoimmune skin and mucous membrane blistering diseases, characterized  Both authors contributed equally.

# Introduction
Mucous membrane pemphigoid (MMP) comprises a group of autoantibody-mediated subepidermal bullous diseases, characterized by a chronic course with predominant involvement of mucous membranes and a tendency to scarring. 1,2 Disease severity varies, ranging from mild/moderate disease with mild gingival inflammation, to severe disease affecting multiple mucosal surfaces. In 2002, a group of experts published a consensus-based guideline for the diagnosis and management of MMP. [bib_ref] The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic..., Chan [/bib_ref] Advances regarding diagnosis and therapeutic options have led to the need for an update of the guideline, an initiative promoted by the European Academy of Dermatology and Venereology (EADV) Task Force for autoimmune bullous diseases (AIBD). The guideline is based on a systematic search and review of the available literature, in combination with a structured consensus process, resulting in a level S3 guideline. The full guideline document with methodology, search strategy, scientific questions and evidence tables is available on the EADV website. It is the fourth guideline initiated by this EADV Task Force, following the guidelines for bullous pemphigoid (BP), 4 pemphigus 5 and dermatitis herpetiformis. [bib_ref] Guidelines for the diagnosis and treatment of dermatitis herpetiformis, Caproni [/bib_ref] 

# Methods

## Guideline committee
The guideline committee was established during the EADV Task Force meeting in Geneva, Switzerland, on 16 September 2017. The committee consisted of members of the EADV taskforce for AIBD, as well as selected specialists familiar with MMP, including dermatologists, ophthalmologists, oral medicine specialists, an otorhinolaryngologist and a pathologist. Several national patient organizations, including the German Pemphigus und approved the final version. Conflict of interest forms were collected during the guideline process and approved by the guideline committee.
Aim, scope and targeted audience of the guideline During the guideline kick-off meeting in Groningen, The Netherlands, on 21 March 2018, the scope and methodology of the guideline and the targeted audience were defined. The aim was to develop a multidisciplinary S3 European guideline, based on both evidence and expert opinion, and useful for all medical specialists who encounter patients with undiagnosed MMP, and treat and/or monitor patients with MMP. In this context, the overall aim is to provide specialists with a diagnostic and therapeutic algorithm. The professionals targeted are healthcare practitioners who may be involved with management of MMP patients in their daily practice. This includes general practitioners, dermatologists, ophthalmologists, otorhinolaryngologists, gynaecologists, urologists, gastroenterologists, dentists, oral medicine specialists and pathologists.

# Guideline methodology
This guideline was developed in line with EDF standard operating procedures and in agreement with the quality criteria of the Appraisal of Guidelines Research & Evaluation II (AGREE II) instrument. [bib_ref] AGREE II: advancing guideline development, reporting and evaluation in health care, Brouwers [/bib_ref] 

## Literature search
During the guideline kick-off meeting, research questions were formulated. Searches were performed per formulated research question. The literature searches were performed in the MED-LINE and EMBASE (OvidSP) databases, published in European languages with no limitations in timeframe. To answer questions regarding management, we used the evidence described in the Cochrane review of Kirtschig et al. [bib_ref] Interventions for mucous membrane pemphigoid and epidermolysis bullosa acquisita, Kirtschig [/bib_ref] and in the systematic review by Taylor et al.that updated the Cochrane search up to 2013. By using exactly the same keywords, we updated the search from 2013 until June 2019 in the MEDLINE, EMBASE (OvidSP) and Cochrane libraries.

## Data screening and extraction, and methodological evaluation
All identified articles were screened for relevance, based on the title and abstract. If the publication appeared relevant, the full text was reviewed. Relevant findings were extracted and summarized in evidence tables. The level of evidence of the selected studies was graded according to the Oxford Centre for Evidence-Based Medicine (OCEBM) 2011. Recommendations were formulated by the guideline working group and were based on evidence and/or expert opinion. The level of the recommendations was determined by examining the individual levels of the evidence [fig_ref] Table 1: Level of recommendation based on level of evidence [/fig_ref].

## Consensus process
All sections with recommendations and tables were discussed within the whole group. Consensus was defined as agreement by at least 80% of the guideline committee. A further meeting took place during the World Dermatology Congress in Milan, in July 2019. During this meeting, several points of consensus were reached regarding the chapters on clinical features and outcome measurements. In a second meeting, during the EADV annual congress in Madrid in October 2019, consensus was reached concerning diagnostics and management.

## Clinical presentation
Clinical definition of mucous membrane pemphigoid MMP is a group of chronic, autoimmune subepithelial blistering diseases predominantly affecting the mucous membranes. MMP should be regarded as a 'disease phenotype' shared by a heterogeneous group of blistering diseases, with antibodies targeting different autoantigens. Involved mucosal areas are generally in close contact with the skin, such as mouth, eyes, nose and anogenital region. Other affected mucosal sites include oesophagus, larynx and pharynx. The skin is almost invariably only mildly affected. Mucosal lesions tend to heal with scarring, with the exception of the oral mucosa, which is relatively spared unless severely affected. In serious cases, according to the involved sites, MMP may result in severe comorbidities, lifethreatening complications and a significant negative impact on quality of life. An overview of possible clinical manifestations according to the affected mucosal site is depicted in [fig_ref] Table 2: Overview of possible clinical signs of mucous membrane pemphigoid per affected mucosal... [/fig_ref].
Over the years, different terminology has been used to describe various forms of MMP, based on antigen or affected mucosal site [fig_ref] Table 3: List of previous and current terminology for mucous membrane pemphigoid [/fig_ref]. MMP is the most appropriate nomenclature for disease in all patients with more than one affected mucous membrane. The following consensus was reached by the guideline group: single-site terms such as ocular MMP and oral MMP, or ocular monosite MMP and oral monosite MMP, should be applied to patients with involvement of only one specific mucosal site, as the disease in such cases may have different characteristics from those with multisite involvement. In MMP patients with several affected mucosal sites, involvement of one site can be highlighted, as follows: MMP with ocular or oral involvement, or MMP with multisite involvement (oral, ocular, anogenital, etc.). The autoantibody reactivity and immunoglobulin class profile should not be considered or specified in the terminology and classification of MMP. Therefore, terms such as IgA-MMP, mucosal-dominant EBA or LAD, or alternatively, MMP-like EBA or MMP-like LAD, should be avoided.
Patients with mild and moderate MMP usually present with lesions limited to the oral mucosa, whereas patients with severe MMP often have additional affected sites: ocular, nasopharyngeal, laryngeal, oesophageal, genital mucosae or skin. [bib_ref] The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic..., Chan [/bib_ref] Differentiating between MMP and BP in patients with both oral and skin lesions may sometimes pose a diagnostic challenge. The definitive classification should take into account the area which is predominantly affected, and is more refractory to treatment, as well as the clinical evolution.

## Recommendations epidemiology
Incidence and prevalence MMP typically occurs in the elderly, with a mean age between 60 and 80 years at the time of diagnosis. Only case reports or small case series of MMP have been reported in childhood. [bib_ref] Early onset childhood cicatricial pemphigoid: a case report and review of the..., Kharfi [/bib_ref] The incidence of MMP is estimated at approximately 1-2 new cases per million people annually in Germany and France. [bib_ref] Prospective analysis of the incidence of autoimmune bullous disorders in Lower Franconia, Bertram [/bib_ref] [bib_ref] Incidence of autoimmune subepidermal blistering dermatoses in a region of Central Germany, Zillikens [/bib_ref] [bib_ref] Incidence and distribution of subepidermal autoimmune bullous skin diseases in three French..., Bernard [/bib_ref] The incidence of ocular MMP is estimated at 0.7-0.8 million in New Zealand and the United Kingdom. [bib_ref] Incidence, presenting features, and diagnosis of cicatrising conjunctivitis in the United Kingdom, Radford [/bib_ref] [bib_ref] Incidence, clinical features and diagnosis of cicatrising conjunctivitis in Australia and New..., Bobba [/bib_ref] In 2014, the calculated prevalence of MMP in Germany was 25 cases/million inhabitants, with a female predominance of 30.52/million, versus 18.37/million. [bib_ref] Incidence and distribution of subepidermal autoimmune bullous skin diseases in three French..., Bernard [/bib_ref] [bib_ref] Prevalence and age distribution of pemphigus and pemphigoid diseases in Germany, Hubner [/bib_ref] [bib_ref] Mucous membrane pemphigoid and pseudopemphigoid, Thorne [/bib_ref] [bib_ref] Incidence and clinical characteristics of ocular involvement in mucous membrane pemphigoid, Hong [/bib_ref] [bib_ref] Spectrum of autoimmune bullous diseases in Iran: a 10-year review, Daneshpazhooh [/bib_ref] [bib_ref] The regibul register: a tool for monitoring the distribution and incidence of..., Loget [/bib_ref] [bib_ref] Laryngeal mucous membrane pemphigoid (MMP): a systematic review and pooled-data analysis, Higgins [/bib_ref] [bib_ref] Development of ocular disease in patients with mucous membrane pemphigoid involving the..., Higgins [/bib_ref] [bib_ref] Bullous pemphigoid, cicatricial pemphigoid, and pemphigus vulgaris. A comparative clinical survey of..., Laskaris [/bib_ref] No geographic or racial predilection has been described.

## Delay in diagnosis
The diagnosis of MMP is often significantly delayed, ranging from weeks to several years. In a retrospective cohort study of 105 cases, diagnosis was not made until after more than one year. [bib_ref] Bullous pemphigoid, cicatricial pemphigoid, and pemphigus vulgaris. A comparative clinical survey of..., Laskaris [/bib_ref] In a prospective national incidence survey, diagnostic delay lasted approximately 21 months. 14 Stratification per involved site was not possible, due to frequent involvement of multiple sites and lack of solid data.

## Mmp subtypes based on clinical affected site
Multiple mucosal sites can be affected in patients with MMP [fig_ref] Table 2: Overview of possible clinical signs of mucous membrane pemphigoid per affected mucosal... [/fig_ref].
Oral involvement in MMP MMP with oral involvement generally affects the middle-aged and elderly, with a mean age between 54-76 years, and a predilection for Caucasian patients. [bib_ref] Periodontitis in oral pemphigus and pemphigoid: a systematic review of published studies, Jascholt [/bib_ref] [bib_ref] Describing the gingival involvement in a sample of 182 Italian predominantly oral..., Arduino [/bib_ref] Diagnostic delays have been reported, ranging from 2 to 60 months from development of the first symptoms to diagnosis. [bib_ref] Oral mucous membrane pemphigoid and pemphigus vulgaris-a retrospective two-center cohort study, Villa [/bib_ref] In 85% of MMP patients, the oral mucosa is the site of onset, and most frequently involved. Other mucosal sites may be concomitantly involved. [bib_ref] Cicatricial pemphigoid, Ahmed [/bib_ref] [bib_ref] Mucous membrane pemphigoid and oral blistering diseases, Carey [/bib_ref] Oral involvement in MMP usually has a gradual progressive onset, characterized by episodes of spontaneous relapses and remissions, with variable mucosal inflammation and ulcerations. Intraoral sites include the gingiva (80%), buccal mucosa (58%), palate (26%), alveolar ridge (16%), tongue (15%) and lower lip (7%). [bib_ref] Bullous pemphigoid, cicatricial pemphigoid, and pemphigus vulgaris. A comparative clinical survey of..., Laskaris [/bib_ref] [bib_ref] Oral mucous membrane pemphigoid: a clinical study of 100 low-risk cases, Bagan [/bib_ref] [bib_ref] Desquamative gingivitis as only presenting sign of mucous membrane pemphigoid, Vijayan [/bib_ref] Broadly, three oral phenotypes are recognized: pure gingival lesions, extra-gingival lesions or both. Desquamative gingivitis ranges from localized gingival erythema to generalized inflammation with blistering or ulceration. However, desquamative gingivitis may also be observed in pemphigus vulgaris and in oral lichen planus, which need to be excluded. The labial gingiva is always affected, with lingual and palatal gingiva less frequently involved. Extra-gingival lesions appear as erythematous patches, blisters or erosions. During the healing phase, fibrosis may be observable, with development of reticulated, white striations, mimicking lichen planus. [bib_ref] Bullous pemphigoid: a review of its diagnosis, associations and treatment, Bernard [/bib_ref] [bib_ref] Mucous membrane pemphigoid of the oral lichen type: a retrospective analysis of..., Benzaquen [/bib_ref] [bib_ref] Oral involvement in mucous membrane pemphigoid, Gallagher [/bib_ref] The predominant symptoms upon presentation include discomfort, burning, gingival bleeding, mucosal peeling and difficulty in eating. [bib_ref] Describing the gingival involvement in a sample of 182 Italian predominantly oral..., Arduino [/bib_ref] Gingival bleeding often results in suboptimal oral hygiene, with subsequent plaque-related marginal gingivitis, leading to chronic periodontitis as a recognized complication. [bib_ref] Periodontitis in oral pemphigus and pemphigoid: a systematic review of published studies, Jascholt [/bib_ref] Ocular involvement in MMP The average age at diagnosis of ocular monosite and multisite MMP ranges from a mean of 60.4-68.2 years. [bib_ref] Incidence, presenting features, and diagnosis of cicatrising conjunctivitis in the United Kingdom, Radford [/bib_ref] [bib_ref] Mucous membrane pemphigoid and pseudopemphigoid, Thorne [/bib_ref] [bib_ref] Incidence and clinical characteristics of ocular involvement in mucous membrane pemphigoid, Hong [/bib_ref] [bib_ref] Development of ocular disease in patients with mucous membrane pemphigoid involving the..., Higgins [/bib_ref] [bib_ref] Clinical features and in vivo confocal microscopy assessment in 12 patients with..., Long [/bib_ref] [bib_ref] Mucous membrane pemphigoid with ocular involvement: the clinical phenotype and its relationship..., Ong [/bib_ref] [bib_ref] Clinical implications of direct immunofluorescence findings in patients with ocular mucous membrane..., Labowsky [/bib_ref] [bib_ref] Ocular cicatricial pemphigoid: conjunctival biopsy findings and its relationship to ocular's inflammation..., Chiganer [/bib_ref] [bib_ref] Analysis of clinical characteristics of cicatricial pemphigoid in 35 cases, Hui [/bib_ref] [bib_ref] Long-term results of systemic chemotherapy for ocular cicatricial pemphigoid, Foster [/bib_ref] Patients with ocular monosite and multisite involvement seem to be older than those without ocular involvement. [bib_ref] Incidence and clinical characteristics of ocular involvement in mucous membrane pemphigoid, Hong [/bib_ref] [bib_ref] Mucous membrane pemphigoid with ocular involvement: the clinical phenotype and its relationship..., Ong [/bib_ref] Younger patients with MMP with ocular involvement appear to present with more severe ocular and systemic disease and, despite immunosuppression, their disease progresses more rapidly. [bib_ref] Evaluation of mucous membrane pemphigoid with ocular involvement in young patients, Rauz [/bib_ref] An average female proportion of 52% (range 37-81%) has been observed. [bib_ref] Incidence, presenting features, and diagnosis of cicatrising conjunctivitis in the United Kingdom, Radford [/bib_ref] [bib_ref] Mucous membrane pemphigoid and pseudopemphigoid, Thorne [/bib_ref] [bib_ref] Incidence and clinical characteristics of ocular involvement in mucous membrane pemphigoid, Hong [/bib_ref] [bib_ref] Development of ocular disease in patients with mucous membrane pemphigoid involving the..., Higgins [/bib_ref] [bib_ref] Clinical features and in vivo confocal microscopy assessment in 12 patients with..., Long [/bib_ref] [bib_ref] Mucous membrane pemphigoid with ocular involvement: the clinical phenotype and its relationship..., Ong [/bib_ref] [bib_ref] Clinical implications of direct immunofluorescence findings in patients with ocular mucous membrane..., Labowsky [/bib_ref] [bib_ref] Ocular cicatricial pemphigoid: conjunctival biopsy findings and its relationship to ocular's inflammation..., Chiganer [/bib_ref] [bib_ref] Analysis of clinical characteristics of cicatricial pemphigoid in 35 cases, Hui [/bib_ref] [bib_ref] Long-term results of systemic chemotherapy for ocular cicatricial pemphigoid, Foster [/bib_ref] [bib_ref] Diagnostic relevance of direct immunofluorescence in ocular mucous membrane pemphigoid, Mehra [/bib_ref] [bib_ref] Treatment of ocular mucous membrane pemphigoid with immunosuppressive drug therapy, Thorne [/bib_ref] [bib_ref] The effect of treatment and its related side effects in patients with..., Miserocchi [/bib_ref] [bib_ref] Progression of disease in ocular cicatricial pemphigoid, Elder [/bib_ref] [bib_ref] The frequency of other autoimmune disorders in patients with ocular cicatricial pemphigoid, Anzaar [/bib_ref] [bib_ref] Characteristics of patients with ocular cicatricial pemphigoid referred to major tertiary hospital, Goldich [/bib_ref] [bib_ref] Clinical manifestations of mucous membrane pemphigoid in a tertiary center, Mameletzi [/bib_ref] [bib_ref] Evaluation of early and late presentation of patients with ocular mucous membrane..., Williams [/bib_ref] [bib_ref] Ocular cicatricial pemphigoid. Retrospective analysis of risk factors and complications]. Okulares vernarbendes..., Messmer [/bib_ref] The mean duration of symptoms prior to diagnosis of ocular MMP ranges from 225 days to 6.4 years. 14,36,39,52 Mehra et al. reported that the median duration of symptoms until biopsy was longer in cases with ocular involvement than in cases without ocular involvement (2.3 years vs. 1.8 years). [bib_ref] Diagnostic relevance of direct immunofluorescence in ocular mucous membrane pemphigoid, Mehra [/bib_ref] Ocular involvement in MMP commonly presents with symptoms of any non-specific chronic conjunctival inflammation. Many patients initially complain of redness, tearing, burning, decreased vision and foreign body sensation. [bib_ref] Clinical manifestations of mucous membrane pemphigoid in a tertiary center, Mameletzi [/bib_ref] Limbitis occurs in 12-28% of the eyes. [bib_ref] Incidence, presenting features, and diagnosis of cicatrising conjunctivitis in the United Kingdom, Radford [/bib_ref] [bib_ref] Incidence, clinical features and diagnosis of cicatrising conjunctivitis in Australia and New..., Bobba [/bib_ref] [bib_ref] Progression of disease in ocular cicatricial pemphigoid, Elder [/bib_ref] Except for MMP, conjunctivitis with limbitis, without significant corneal involvement, is usually seen only in vernal keratoconjunctivitis. Thus, chronic conjunctivitis with limbitis may be regarded as a distinctive sign of ocular MMP and is associated with more severe disease progression. Infrequently, patients may also present with conjunctival ulceration, swelling and severe hyperaemia. [bib_ref] Chronic progressive conjunctival cicatrisation, Bernauer [/bib_ref] However, these inflammatory signs may be intermittent, relapsing and sometimes minimal, with early clinical signs limited to those of conjunctival cicatrization, often first involving the canthal structures. [bib_ref] Long-term results of systemic chemotherapy for ocular cicatricial pemphigoid, Foster [/bib_ref] [bib_ref] Enigma of ocular cicatricial pemphigoid. A comparative study of clinical and immunological..., Wright [/bib_ref] Furthermore, in late-stage disease, which is often when a definitive diagnosis is made, ocular inflammation may not be the predominant finding. [bib_ref] Incidence, presenting features, and diagnosis of cicatrising conjunctivitis in the United Kingdom, Radford [/bib_ref] Untreated, ocular involvement in MMP eventually destroys the lacrimal gland ductules and meibomian gland orifices, impairing both the aqueous and the oily constituents of the tear film, resulting in secondary dry eye. Eyelid malposition, symblepharon and trichiasis eventually develop and, together with secondary dry eye, chronic limbitis and subsequent limbal stem cell failure, contribute to keratopathy. The latter ultimately results in reduced vision due to corneal epithelial defects, neovascularization or even corneal perforation. [bib_ref] Mucous membrane pemphigoid with ocular involvement: the clinical phenotype and its relationship..., Ong [/bib_ref] [bib_ref] Long-term results of systemic chemotherapy for ocular cicatricial pemphigoid, Foster [/bib_ref] [bib_ref] Clinical manifestations of mucous membrane pemphigoid in a tertiary center, Mameletzi [/bib_ref] Although ocular involvement in MMP can occasionally be unilateral, it is usually bilateral. [bib_ref] The effect of treatment and its related side effects in patients with..., Miserocchi [/bib_ref] [bib_ref] Immunosuppressive therapy for ocular mucous membrane pemphigoid, Saw [/bib_ref] By the time of diagnosis or referral to a tertiary centre, most patients have moderate to severe conjunctival inflammation, with advanced cicatrizing disease and symblepharon formation; this probably reflects the difficulties in diagnosing early ocular MMP. [bib_ref] Incidence, presenting features, and diagnosis of cicatrising conjunctivitis in the United Kingdom, Radford [/bib_ref] [bib_ref] The effect of treatment and its related side effects in patients with..., Miserocchi [/bib_ref] [bib_ref] Characteristics of patients with ocular cicatricial pemphigoid referred to major tertiary hospital, Goldich [/bib_ref] Nasopharyngeal involvement in MMP The frequency of nasal and pharyngeal involvement was at least 35% with a mean age of 60 years as demonstrated in a prospective study of 110 MMP patients. [bib_ref] A prospective study of upper aerodigestive tract manifestations of mucous membrane pemphigoid, Alexandre [/bib_ref] The most common nasal symptoms and signs consist of epistaxis, rhinorrhea, nasal crusting and nasal obstruction. Examination of the nasal mucosa may reveal atrophic rhinitis, erosive and crusted lesions and synechia. [bib_ref] A prospective study of upper aerodigestive tract manifestations of mucous membrane pemphigoid, Alexandre [/bib_ref] [bib_ref] Multiple mucosal involvement in cicatricial pemphigoid, Trimarchi [/bib_ref] [bib_ref] Cicatricial pemphygoid in the upper aerodigestive tract: report of two cases, Freitas [/bib_ref] [bib_ref] Anti-laminin 332 mucous membrane pemphigoid with laryngeal involvement -adjuvant treatment with immunoadsorption..., H Ugel [/bib_ref] [bib_ref] Cicatricial pemphigoid with circulating autoantibodies to beta4 integrin, bullous pemphigoid 180 and..., Leverkus [/bib_ref] [bib_ref] Mucosal morbidity in patients with epidermolysis bullosa acquisita, Luke [/bib_ref] [bib_ref] Cicatricial pemphigoid: report of five cases, Miziara [/bib_ref] [bib_ref] Immunofluorescence serration pattern analysis as a diagnostic criterion in antilaminin-332 mucous membrane..., Terra [/bib_ref] [bib_ref] Mucous membrane pemphigoid: nasal and laryngeal manifestations, Whiteside [/bib_ref] Patients with pharyngeal involvement often complain of pharyngalgia, dysphagia or odynophagia, impaired food intake and coughing. [bib_ref] A prospective study of upper aerodigestive tract manifestations of mucous membrane pemphigoid, Alexandre [/bib_ref] [bib_ref] Mucosal morbidity in patients with epidermolysis bullosa acquisita, Luke [/bib_ref] [bib_ref] Immunofluorescence serration pattern analysis as a diagnostic criterion in antilaminin-332 mucous membrane..., Terra [/bib_ref] [bib_ref] Severe refractory paraneoplastic mucous membrane pemphigoid successfully treated with rituximab, Wittenberg [/bib_ref] [bib_ref] A particular type of cicatricial Pemphigoid with unique IgA deposit, Aounallah [/bib_ref] [bib_ref] Cicatricial pemphigoid of upper digestive and respiratory tracts, Bergstrom [/bib_ref] [bib_ref] Cicatricial pemphigoid in the upper aerodigestive tract: diagnosis and management in severe..., Boedeker [/bib_ref] [bib_ref] Anti-laminin-332 mucous membrane pemphigoid in a 9-year old girl, Kahn [/bib_ref] [bib_ref] Paraneoplastic mucous membrane pemphigoid with ocular and laryngeal involvement, Lambiel [/bib_ref] [bib_ref] Hypopharyngeal presentation of cicatricial pemphigoid: videofluorographic and direct laryngoscopic findings, Murono [/bib_ref] [bib_ref] Assessment and management of laryngeal mucous membrane pemphigoid: our experience in six..., Nash [/bib_ref] Nasopharyngeal involvement may coexist with involvement of the laryngeal mucosa. [bib_ref] Multiple mucosal involvement in cicatricial pemphigoid, Trimarchi [/bib_ref] [bib_ref] Cicatricial pemphigoid with circulating autoantibodies to beta4 integrin, bullous pemphigoid 180 and..., Leverkus [/bib_ref] [bib_ref] Severe refractory paraneoplastic mucous membrane pemphigoid successfully treated with rituximab, Wittenberg [/bib_ref] [bib_ref] Cicatricial pemphigoid of upper digestive and respiratory tracts, Bergstrom [/bib_ref] [bib_ref] Anti-laminin-332 mucous membrane pemphigoid in a 9-year old girl, Kahn [/bib_ref] [bib_ref] Paraneoplastic mucous membrane pemphigoid with ocular and laryngeal involvement, Lambiel [/bib_ref] [bib_ref] Assessment and management of laryngeal mucous membrane pemphigoid: our experience in six..., Nash [/bib_ref] [bib_ref] A systematic review with pooled analysis of clinical presentation and immunodiagnostic testing..., Amber [/bib_ref] [bib_ref] Case of mucous membrane pemphigoid with immunoglobulin G antibodies to the beta..., Murata [/bib_ref] Clinical signs including erythema, erosions or ulcerations, vesicular lesions and scarring of the pharynx can be seen. [bib_ref] A prospective study of upper aerodigestive tract manifestations of mucous membrane pemphigoid, Alexandre [/bib_ref] [bib_ref] Cicatricial pemphigoid with circulating autoantibodies to beta4 integrin, bullous pemphigoid 180 and..., Leverkus [/bib_ref] [bib_ref] Mucosal morbidity in patients with epidermolysis bullosa acquisita, Luke [/bib_ref] [bib_ref] A particular type of cicatricial Pemphigoid with unique IgA deposit, Aounallah [/bib_ref] [bib_ref] Cicatricial pemphigoid of upper digestive and respiratory tracts, Bergstrom [/bib_ref] [bib_ref] Anti-laminin-332 mucous membrane pemphigoid in a 9-year old girl, Kahn [/bib_ref] [bib_ref] Paraneoplastic mucous membrane pemphigoid with ocular and laryngeal involvement, Lambiel [/bib_ref] [bib_ref] Hypopharyngeal presentation of cicatricial pemphigoid: videofluorographic and direct laryngoscopic findings, Murono [/bib_ref] Laryngeal involvement in MMP The most common symptoms and signs of laryngeal involvement in MMP are dyspnoea and dysphonia. [bib_ref] Assessment and management of laryngeal mucous membrane pemphigoid: our experience in six..., Nash [/bib_ref] However, a proportion of MMP patients with laryngeal involvement are asymptomatic. [bib_ref] Laryngeal mucous membrane pemphigoid (MMP): a systematic review and pooled-data analysis, Higgins [/bib_ref] The supraglottis is the most commonly affected site. Swallowing problems are uncommon. MMP with oesophageal involvement may coexist with laryngeal disease and may require independent investigation and management. In one study, the estimated frequency of MMP with laryngeal involvement was 12.2% of MMP cases, with a prevalence in the general population of one case in 10 million persons. [bib_ref] Laryngeal mucous membrane pemphigoid (MMP): a systematic review and pooled-data analysis, Higgins [/bib_ref] The mean age of patients with laryngeal involvement in MMP is approximately 60 years, with equal gender distribution. Laryngeal involvement can result in severe laryngeal obstruction and become life-threatening, in severe cases sometimes requiring surgical interventions. In one report, tracheostomy was required in 10.5% of the cases. [bib_ref] Laryngeal mucous membrane pemphigoid (MMP): a systematic review and pooled-data analysis, Higgins [/bib_ref] Oesophageal involvement in MMP Oesophageal involvement in MMP has a severe scarring potential and is one of the most lifethreatening complications. Symptomatic oesophageal disease was found in approximately 5% of a cohort of 477 MMP patients and often occurs in combination with involvement of additional mucosal sites. [bib_ref] Oesophageal involvement in 26 consecutive patients with mucous membrane pemphigoid, Zehou [/bib_ref] Dysphagia is usually the first and most common symptom to reveal oesophageal MMP, [bib_ref] Oesophageal involvement in 26 consecutive patients with mucous membrane pemphigoid, Zehou [/bib_ref] but it may also develop several years after onset of the disease. [bib_ref] Successful rituximab treatment of juvenile bullous pemphigoid with esophageal scarring due to..., S Ardy [/bib_ref] Oesophageal webs are thought to represent an early stage of the disease, whereas oesophageal strictures are more likely to represent a more advanced stage, secondary to scarring with fibrosis. [bib_ref] Mucous membrane pemphigoid presenting with isolated esophageal involvement: a case report, Sallout [/bib_ref] Oesophageal stenosis following oesophageal dilation may occur. The development of blisters, bleeding and oedema may interfere with breathing. [bib_ref] Cicatricial pemphigoid: Bullae blossoming before one's eyes, Goedicke [/bib_ref] Tracheal involvement in MMP Although no data exist about the exact frequency of tracheal involvement in MMP, the latter may manifest with dyspnoea, cough, dysphonia and wheezing. There are anecdotal cases of MMP in which tracheal involvement represents the leading clinical feature of the disease. Severe laryngeal involvement may require tracheostomy. [bib_ref] Mucous membrane pemphigoid causing central airway obstruction, Jalil [/bib_ref] Genital and urological involvement in MMP Involvement of the anogenital region can occur, either isolated or with other mucosal sites. [bib_ref] Childhood cicatricial pemphigoid confined to the vulva, Hoque [/bib_ref] [bib_ref] Childhood localized vulvar pemphigoid is a true variant of bullous pemphigoid, Saad [/bib_ref] [bib_ref] Localized childhood vulval pemphigoid treated with tacrolimus ointment, Lebeau [/bib_ref] In two cohorts of MMP patients, genital lesions were observed in 28-38% of the cases. [bib_ref] Mucous membrane pemphigoid: HLA-DQB1*0301 is associated with all clinical sites of involvement..., Setterfield [/bib_ref] [bib_ref] Prevalence and clinical significance of anti-laminin 332 autoantibodies detected by a novel..., Bernard [/bib_ref] Affected patients present with pain and/or pruritus. Examination reveals blisters, vesicles, erosions and ulcers, which may affect the vulvar area and introitus vaginae, glans penis or foreskin. Mucosal adhesions and scarring may occur. Moreover, less specific signs such as erythema, oedema, milia, atrophy and purulent vaginal discharge can be present. Genital involvement in MMP can be misdiagnosed as lichen sclerosus et atrophicus, lichen planus, pemphigus or even sexual abuse. [bib_ref] Childhood cicatricial pemphigoid confined to the vulva, Hoque [/bib_ref] [bib_ref] Localized childhood vulval pemphigoid treated with tacrolimus ointment, Lebeau [/bib_ref] [bib_ref] Vulval cicatricial pemphigoid may mimic lichen sclerosus, Marren [/bib_ref] [bib_ref] Vulvair gelokaliseerd pemfigo d, De Waard [/bib_ref] [bib_ref] Childhood mucous membrane pemphigoid of the oral and genital mucosa, Wentworth [/bib_ref] [bib_ref] Mucous membrane pemphigoid of the Vulva, Goldstein [/bib_ref] [bib_ref] Dermatologic causes of vaginitis: a clinical review, Edwards [/bib_ref] [bib_ref] Localized vulvar pemphigoid in a child misdiagnosed as sexual abuse, Levine [/bib_ref] Distinguishing it from localized vulvar pemphigoid may also pose a challenge. Genital involvement in MMP can be drug-induced or paraneoplastic. [bib_ref] Drug-induced anogenital cicatricial pemphigoid, Van Joost [/bib_ref] [bib_ref] Cicatricial pemphigoid with autoantibodies to laminin 5 (epiligrin) in a patient with..., Lenz [/bib_ref] [bib_ref] Anti-laminin-332 mucous membrane pemphigoid with autoantibodies to a3, b3 and c2 subunits..., Fukuchi [/bib_ref] [bib_ref] Metastatic ovarian carcinoma-associated subepidermal blistering disease with autoantibodies to both the p200..., Mitsuya [/bib_ref] [bib_ref] Bevacizumab associated mucous membrane pemphigoid, Ormond [/bib_ref] Only limited data are available on urological involvement in MMP. Reported signs are recurrent dysuria with negative urine cultures, or meatal stenosis obstructing the flow of urine. [bib_ref] Mucosal involvement in bullous and cicatricial pemphigoid. A clinical and immunopathological study, Venning [/bib_ref] [bib_ref] Cicatricial pemphigoid: a diagnostic problem for the urologist, Ramlogan [/bib_ref] Skin involvement in MMP The skin can be mildly affected in MMP and is encountered in 20-35% of MMP patients. [bib_ref] Mucous membrane pemphigoid and pseudopemphigoid, Thorne [/bib_ref] [bib_ref] Describing the gingival involvement in a sample of 182 Italian predominantly oral..., Arduino [/bib_ref] [bib_ref] Diagnostic relevance of direct immunofluorescence in ocular mucous membrane pemphigoid, Mehra [/bib_ref] [bib_ref] Mucous membrane pemphigoid: HLA-DQB1*0301 is associated with all clinical sites of involvement..., Setterfield [/bib_ref] [bib_ref] Autoantibody profile of a Cohort of 78 Italian patients with mucous membrane..., Cozzani [/bib_ref] [bib_ref] Clinical and immunological studies of 332 japanese patients tentatively diagnosed as anti-BP180-type..., Yasukochi [/bib_ref] [bib_ref] Mucous membrane pemphigoid: a dual circulating antibody response with IgG and IgA..., Setterfield [/bib_ref] In Brunsting-Perry pemphigoid, a variant of MMP, skin lesions present mainly on the head and the neck region consisting of crusts, erosions, blisters and atrophic scars. Mucosal involvement is not always present in this variant. [bib_ref] Brunsting-Perry pemphigoid of the scalp with antibodies against laminin 332, Jedlickova [/bib_ref] [bib_ref] Brunsting-Perry pemphigoid: a case with antigen identification, Chandan [/bib_ref] Generalized skin lesions in MMP have also been reported. [bib_ref] Localized cicatricial pemphigoid of the Brunsting-Perry type with transition into disseminated cicatricial..., Kurzhals [/bib_ref] [bib_ref] Brunsting-Perry pemphigoid: a retrospective case series of a frequently unrecognized condition, Imstepf [/bib_ref] Antigen recognition in MMP BP180 and BP230 BP180 (also termed BP antigen 2 or type XVII collagen) and BP230 (also called BP antigen 1, epithelial isoform) are haemidesmosomal proteins with a molecular weight of 180 and 230 kD. [bib_ref] Structural proteins of the dermalepidermal junction targeted by autoantibodies in pemphigoid diseases, Goletz [/bib_ref] BP180 is a transmembrane collagenous protein, and BP230 is an intracellular protein of the plakin family of cytolinkers. [bib_ref] Structural proteins of the dermalepidermal junction targeted by autoantibodies in pemphigoid diseases, Goletz [/bib_ref] BP180 is the main target antigen in MMP. In addition to the NC16A domain, C-terminal epitopes are also frequently targeted. In a considerable number of MMP patients, IgA reactivity against BP180 is detected, in addition to IgG autoantibodies. So far, although no specific clinical phenotype has been associated with anti-BP180 reactivity, while one report suggested that a combined IgG and IgA-anti-BMZ reactivity is found in patients with a more severe clinical phenotype. 100 BP230 reactivity is less common and is reported in 9% up to 28% of MMP cases. [bib_ref] Prevalence and clinical significance of anti-laminin 332 autoantibodies detected by a novel..., Bernard [/bib_ref] [bib_ref] Autoantibody profile of a Cohort of 78 Italian patients with mucous membrane..., Cozzani [/bib_ref] [bib_ref] IgA autoantibodies in the pemphigoids and linear IgA bullous dermatosis, Horv Ath [/bib_ref] [bib_ref] Diagnostic value of indirect immunofluorescence on sodium chloride-split skin in differential diagnosis..., Ghohestani [/bib_ref] [bib_ref] Analysis of antigens targeted by circulating IgG and IgA antibodies in patients..., Carrozzo [/bib_ref] [bib_ref] Analysis of antigens targeted by circulating IgG and IgA autoantibodies in 50..., Murakami [/bib_ref] Laminin 332 Laminin 332, previously known as epiligrin and laminin 5, is a heterotrimer composed of a3, b3 and c2 subunits, targeted by a subset of MMP patients who usually present with multisite mucosal lesions, with significant association with pharyngo-laryngeal, oro-pharyngo-laryngeal and tracheal involvement. [bib_ref] A systematic review with pooled analysis of clinical presentation and immunodiagnostic testing..., Amber [/bib_ref] [bib_ref] Mucous membrane pemphigoid causing central airway obstruction, Jalil [/bib_ref] [bib_ref] The n-vs. u-serration is a learnable criterion to differentiate pemphigoid from epidermolysis..., Terra [/bib_ref] Type VII Collagen Limited data exist on MMP with reactivity against type VII collagen. A number of case reports describe MMP as associated with circulating anti-type VII collagen. In one series encompassing 78 MMP patients, reactivity with type VII collagen was found in 4% of the cases. The latter appeared to have a higher disease severity score. [bib_ref] Autoantibody profile of a Cohort of 78 Italian patients with mucous membrane..., Cozzani [/bib_ref] The a6 and b4 integrin subunits The a6 and b4 integrin subunits are components of hemidesmosomes, and belong to the integrin family of heterodimeric cell surface adhesion receptors, which is linked to the cytokeratin network via plectin and BP230. [bib_ref] Structural proteins of the dermalepidermal junction targeted by autoantibodies in pemphigoid diseases, Goletz [/bib_ref] [bib_ref] Structure and function of hemidesmosomes: more than simple adhesion complexes, Borradori [/bib_ref] Ahmed et al. reported that antibodies against the integrin a6 subunit are detected in 80-100% of oral MMP cases. [bib_ref] Identification of an epitope within human integrin alpha 6 subunit for the..., Rashid [/bib_ref] [bib_ref] Antigen specificity in subsets of mucous membrane pemphigoid, Rashid [/bib_ref] [bib_ref] Autoantibodies to human alpha6 integrin in patients with oral pemphigoid, Bhol [/bib_ref] These antibodies appear to specifically bind to the extracellular domain of the integrin a6 subunit. [bib_ref] Identification of an epitope within human integrin alpha 6 subunit for the..., Rashid [/bib_ref] In contrast to oral MMP, almost all patients with ocular MMP showed autoantibodies directed against the integrin b4 subunit. [bib_ref] Antigen specificity in subsets of mucous membrane pemphigoid, Rashid [/bib_ref] [bib_ref] The role of antibody to human beta4 integrin in conjunctival basement membrane..., Chan [/bib_ref] [bib_ref] Profile of autoantibody to basement membrane zone proteins in patients with mucous..., Yeh [/bib_ref] Autoantibodies against the integrin b4 subunit bind to the C terminal end of its intracellular domain. [bib_ref] The autoantibodies to alpha 6 beta 4 integrin of patients affected by..., Bhol [/bib_ref] [bib_ref] Identification of ocular cicatricial pemphigoid antibody binding site(s) in human beta4 integrin, Kumari [/bib_ref] In a study encompassing 43 ocular MMP sera, Li et al. [bib_ref] Integrin b4 is a major target antigen in pure ocular mucous membrane..., Li [/bib_ref] reported reactivity with the integrin b4 subunit, BP180, laminin 332 a3 subunit, c2 subunit, b3 subunit and LAD-1 in 62.8%, 58%, 28%, 21%, 21% and 19% of cases, respectively. Furthermore, reactivity to the a6 subunit in the ocular MMP sera was found in only 23.3% for IgG and 18.6% for IgA. [bib_ref] Integrin b4 is a major target antigen in pure ocular mucous membrane..., Li [/bib_ref] Since the presence of anti-a6b4 integrin antibodies in MMP has not been confirmed in independent laboratories, the findings described remain to be validated.

## Aetiology
The exact pathogenesis and factors responsible for the development of MMP are unknown. Pathogenicity of autoantibodies directed to BP180, laminin 332 and type VII collagen have been demonstrated in vitro, and in animal models for BP. However, no animal model reproduces the clinical features of MMP. In dogs, spontaneous onset of MMP has been described. [bib_ref] Clinical and immunological heterogeneity of canine subepidermal blistering dermatoses with antilaminin-332 (laminin-5)..., Olivry [/bib_ref] [bib_ref] Mucous membrane pemphigoid in dogs: a retrospective study of 16 new cases, Tham [/bib_ref] In MMP, genetic susceptibility has also been demonstrated. Several studies have confirmed a link between MMP and HLA class II allele variants, such as HLA-DQB1*0301 or HLA-DRB1*11 in Caucasian MMP patients. [bib_ref] Association of DQw7 (DQB1*0301) with ocular cicatricial pemphigoid, Ahmed [/bib_ref] [bib_ref] HLA alleles in British Caucasians with mucous membrane pemphigoid, H Ubner [/bib_ref] [bib_ref] Common major histocompatibility complex class II markers in clinical variants of cicatricial..., Yunis [/bib_ref] [bib_ref] Genomewide association study identifies GALC as susceptibility gene for mucous membrane pemphigoid, Sadik [/bib_ref] A genome-wide association study found 38 single-nucleotide polymorphisms associated with MMP; these polymorphisms need functional validation. [bib_ref] Genomewide association study identifies GALC as susceptibility gene for mucous membrane pemphigoid, Sadik [/bib_ref] In a few cases, drug-induction of MMP has been described. [bib_ref] Analysis of patients with drug-induced pemphigoid using the Japanese Adverse Drug Event..., Tanaka [/bib_ref] [bib_ref] Mucous membrane pemphigoid and lichenoid reactions after immune checkpoint inhibitors: common pathomechanisms, F Assler [/bib_ref] [bib_ref] Mucous membrane pemphigoid, bullous pemphigoid, and anti-programmed death-1/ programmed death-ligand 1: a..., Zumelzu [/bib_ref] Dipeptidyl peptidase-4 inhibitors may be associated with the induction of MMP. In a cohort of 313 MMP patients, a total of 24 were treated by one dipeptidyl peptidase-4 inhibitor, and 17 had an accountability score, suggesting induction of MMP by the drug. [bib_ref] Gliptin accountability in mucous membrane pemphigoid induction in 24 out of 313..., Gaudin [/bib_ref] Finally, an increasing number of immune check point inhibitor-triggered cases of MMP has recently been reported. [bib_ref] Mucous membrane pemphigoid and lichenoid reactions after immune checkpoint inhibitors: common pathomechanisms, F Assler [/bib_ref] 

## Associated factors and comorbidities
One retrospective study reported increased incidence of pernicious anaemia in MMP. [bib_ref] Association of autoimmunity and cicatricial pemphigoid: is there an immunogenetic basis?, Nayar [/bib_ref] Other retrospective cohort studies found no increased risk for autoimmune disease compared with healthy controls. [bib_ref] Coexistence of mucous membrane pemphigoid and connective-tissue disease, Malik [/bib_ref] [bib_ref] Oral mucous membrane pemphigoid associated with hypothyroidism: a retrospective study and a..., Siassipour [/bib_ref] In contrast to BP, so far no report indicates an increased association with diseases of the central nervous system. The potential occurrence of malignancies in MMP is also a matter of controversy. [bib_ref] Immunofluorescence serration pattern analysis as a diagnostic criterion in antilaminin-332 mucous membrane..., Terra [/bib_ref] [bib_ref] Prevalence and clinical significance of anti-laminin 332 autoantibodies detected by a novel..., Bernard [/bib_ref] [bib_ref] No association between cicatricial pemphigoid and malignant disease, Nayar [/bib_ref] [bib_ref] Anti-epiligrin cicatricial pemphigoid: clinical findings, immunopathogenesis, and significant associations, Egan [/bib_ref] [bib_ref] Relative risk for cancer in mucous membrane pemphigoid associated with antibodies to..., Letko [/bib_ref] [bib_ref] Relationship between cancer and oral pemphigoid patients with antibodies to alpha6-integrin, Malik [/bib_ref] [bib_ref] A sensitive and specific assay for the serological diagnosis of antilaminin 332..., Goletz [/bib_ref] [bib_ref] Mucous membrane pemphigoidassociated malignancies: case series and a brief overview of the..., Placa [/bib_ref] [bib_ref] Malignancies in pemphigus and pemphigoid diseases, Schulze [/bib_ref] A multicentre retrospective cohort study, which found a malignancy in 11.7% of MMP patients, did not find evidence for an increased rate of malignancy in MMP. [bib_ref] Prevalence and clinical significance of anti-laminin 332 autoantibodies detected by a novel..., Bernard [/bib_ref] Furthermore, MMP patients with antilaminin-332 reactivity also did not show an increased incidence of malignancy. In contrast, in a small retrospective cohort study with anti-laminin 332 MMP, 20% had a malignancy, while in an another retrospective study with 246 MMP patients, 25% of the anti-laminin 332 MMP patients had a malignancy. [bib_ref] A sensitive and specific assay for the serological diagnosis of antilaminin 332..., Goletz [/bib_ref] 

# Conclusions

## Recommendations

## Outcome measurements
Disease assessment scores for multisite involvement Currently, no published validated scoring methodologies are available for multisite MMP, [bib_ref] A review of scoring systems for ocular involvement in chronic cutaneous bullous..., Lee [/bib_ref] although methodology for oral MMP has recently been validated. [bib_ref] Validation of an Oral Disease Severity Score (ODSS) tool for use in..., Ormond [/bib_ref] The lack of an agreed unified disease severity score, or a means of combining sitespecific severity scores, has hindered interpretation of the few interventional studies in the literature.However, in 2012, an international panel of experts in autoimmune bullous disease proposed a new scoring system: the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI). [bib_ref] Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international..., Murrell [/bib_ref] This was adapted from the validated Pemphigus Disease Area Index (PDAI) and the Bullous Pemphigoid Disease Area Index (BPDAI). [bib_ref] Consensus statement on definitions of disease, end points, and therapeutic response for..., Murrell [/bib_ref] [bib_ref] Reliability and convergent validity of two outcome instruments for pemphigus, Rosenbach [/bib_ref] [bib_ref] The reliability, validity and responsiveness of two disease scores (BPDAI and ABSIS)..., Wijayanti [/bib_ref] MMPDAI is proposed for use in 'milder' forms of MMP and is primarily designed to be used by dermatologists.
A further tool advocated for potential use in MMP is the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS). [bib_ref] Introducing a novel Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) in pemphigus, Pf Utze [/bib_ref] It is based on the amount of body surface area (BSA) involved, and the degree of activity/healing observed in that site. ABSIS scores only skin, oral mucosal sites and genitalia. It has been validated for pemphigus vulgaris but not for MMP. [bib_ref] Introducing a novel Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) in pemphigus, Pf Utze [/bib_ref] In addition, Setterfield et al. published an original multisite methodology, which scored each potential site for the severity of involvement and was applicable to all MMP types, including severe cases. Two studies using this methodology showed an association between disease severity and serum autoantibody isotype upon presentation, followed by a longitudinal study relating sequential titres with disease severity. [bib_ref] Mucous membrane pemphigoid: a dual circulating antibody response with IgG and IgA..., Setterfield [/bib_ref] [bib_ref] Cicatricial pemphigoid: serial titres of circulating IgG and IgA antibasement membrane antibodies..., Setterfield [/bib_ref] The methodology was subsequently used in two cohort studies, although expanded to include a damage score describing the scarring. [bib_ref] Autoantibody profile of a Cohort of 78 Italian patients with mucous membrane..., Cozzani [/bib_ref] [bib_ref] Oral cyclophosphamide without corticosteroids to treat mucous membrane pemphigoid, Munyangango [/bib_ref] Thornhill et al. scored sites including the mouth, eye, nose, genitals and skin as areas of involvement, but not the pharynx and larynx. [bib_ref] An open clinical trial of sulphamethoxypyridazine in the treatment of mucous membrane..., Thornhill [/bib_ref] Further interventional studies have based response to treatment on previously reported observation endpoint definitions. [bib_ref] Consensus statement on definitions of disease, end points, and therapeutic response for..., Murrell [/bib_ref] [bib_ref] Razzaque Ahmed A. Intravenous immunoglobulin therapy in patients with multiple mucosal involvement..., Sami [/bib_ref] [bib_ref] Critical analysis of the use of rituximab in mucous membrane pemphigoid: a..., Shetty [/bib_ref] [bib_ref] Horv ath B. Effectiveness and safety of rituximab in recalcitrant pemphigoid diseases, Lamberts [/bib_ref] These include the early observation end point of control of disease activity, late observation end points of partial remission on minimal therapy, complete remission on minimal therapy or off therapy, and relapse/flare, or the extension of established lesions in a patient who has achieved disease control. Patient-reported pain in the form of a VAS score has also been reported. [bib_ref] Low-level laser therapy for oral mucous membrane pemphigoid, Cafaro [/bib_ref] 

# Conclusions

## Level of evidence 4
No evidence supports a phenotype association with the target autoantigens. Contradictory evidence exists regarding the association between laminin 332 and an underlying malignancy.
In case of anti-laminin 332 reactivity, a tumor search, in particular for solid tumors, may be recommended.

## Grade of recommendation c

## Level of evidence 4
MMPDAI is a disease-specific severity scoring tool. It has not been validated. Level of evidence 4
ABSIS has been proposed for use in MMP, but it is not disease-specific and has not been validated for use in MMP. (Pfutze 2007).

## Level of evidence 4
Multisite oral mucosal disease scoring tool proposed for MMP [bib_ref] Cicatricial pemphigoid: serial titres of circulating IgG and IgA antibasement membrane antibodies..., Setterfield [/bib_ref] , utilized in further treatment studies (Munyangango 2013, Cozzani 2016), has not been validated.

## Level of evidence 4
No validated comprehensive disease severity scoring tools are available for use in MMP. Interventional study assessing area of involvement, including mouth, eye, nose, genitals and skin [bib_ref] An open clinical trial of sulphamethoxypyridazine in the treatment of mucous membrane..., Thornhill [/bib_ref] , has not been validated.

## Recommendations

## Oral disease assessment
The Oral Disease Severity Score (ODSS) has been proposed as a comprehensive scoring system for the oral lesions of lichen planus, [bib_ref] A scoring system for mucosal disease severity with special reference to oral..., Escudier [/bib_ref] pemphigus vulgaris [bib_ref] An Oral Disease Severity Score validated for use in oral pemphigus vulgaris, Ormond [/bib_ref] and mucous membrane pemphigoid. [bib_ref] Validation of an Oral Disease Severity Score (ODSS) tool for use in..., Ormond [/bib_ref] It was developed from the Setterfield et al. [bib_ref] Mucous membrane pemphigoid: a dual circulating antibody response with IgG and IgA..., Setterfield [/bib_ref] multisite MMP score. The oral aspect of this score was subsequently expanded to become the ODSS, providing a more detailed and sensitive method for detecting subtle changes in disease activity. The ODSS has been independently shown to be a reliable and sensitive tool for oral MMP, [bib_ref] Ocular and oral grading of mucous membrane pemphigoid, Reeves [/bib_ref] and has been validated in a parallel study comparing it with the oral components of MMPDAI, ABSIS and the physician's global assessment score. ODSS was shown to have greater inter-and intra-observer reliability than the other methods.

# Conclusions

## Recommendations

## Ocular disease assessment
None of the scoring systems described above address ocular MMP in enough depth to assess ocular disease activity and progression. These systems have also not been evaluated for the inter-and intra-observer reproducibility of inflammation, scarring and morbidity. Over the last 4 decades, eleven methodologies have been developed specifically to evaluate ocular MMP. However, most of these have focused on evaluation only of conjunctival scarring. [bib_ref] Ocular and oral grading of mucous membrane pemphigoid, Reeves [/bib_ref] [bib_ref] Ocular pemphigoid, Mondino [/bib_ref] [bib_ref] Improved detection of disease progression in ocular cicatricial pemphigoid, Tauber [/bib_ref] [bib_ref] A new method for measuring progression in patients with ocular cicatricial pemphigoid, Rowsey [/bib_ref] [bib_ref] Measurement of fornix depth and area: a novel method of determining the..., Kawakita [/bib_ref] [bib_ref] Validation of a fornix depth measurer: a putative tool for the assessment..., Williams [/bib_ref] One scoring system has also added a simple qualitative grading of conjunctival inflammation, using a 4-point scale, [bib_ref] Oral cyclophosphamide without corticosteroids to treat mucous membrane pemphigoid, Munyangango [/bib_ref] while another system has included this grading for a disease activity index, but excluded scarring and morbidity. [bib_ref] Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international..., Murrell [/bib_ref] Only one system 164 incorporates indices of inflammation (present or absent), as well as another 15 graded indices of scarring and morbidity. Nevertheless, the latter is time-consuming to use, has very limited evaluation of inflammation and has subsequently been used for evaluation of MMP cases in only one case series. [bib_ref] Local interferon alfa-2b for ocular cicatricial pemphigoid, Gillies [/bib_ref] A review of these ocular MMP scoring systems concluded that none met the need for a validated scoring system of the three parameters of inflammation, scarring and morbidity that cause progression in ocular MMP. [bib_ref] A review of scoring systems for ocular involvement in chronic cutaneous bullous..., Lee [/bib_ref] Only two out of the 11 systems available, measuring conjunctival scarring using different quantitative methods, have been validated for inter and intraobserver variability, and compared with another methodology. [bib_ref] Ocular and oral grading of mucous membrane pemphigoid, Reeves [/bib_ref] [bib_ref] Validation of a fornix depth measurer: a putative tool for the assessment..., Williams [/bib_ref] A scoring system called the Cicatrising Conjunctivitis Assessment Tool 166 was developed to meet the requirements identified by Lee et al., and has been validated, by calculation of inter-and intra-observer levels of agreement, for reproducible scoring of the three functional categories of inflammation, scarring and morbidity. Although the validation study was carried out on MMP subjects, it is applicable to all causes of cicatrizing conjunctivitis. It was developed from previously described tools [bib_ref] Mucous membrane pemphigoid with ocular involvement: the clinical phenotype and its relationship..., Ong [/bib_ref] [bib_ref] Ocular cicatricial pemphigoid, Francis [/bib_ref] [bib_ref] New grading system for the evaluation of chronic ocular manifestations in patients..., Sotozono [/bib_ref] and includes the use of a fornix depth measurer (FDM) for scarring assessment. [bib_ref] Validation of a fornix depth measurer: a putative tool for the assessment..., Williams [/bib_ref] 

# Conclusions

## Recommendations
For clinical studies, MMPDAI or ABSIS scoring tools are recommended for use.

## Grade of recommendation d

## Level of evidence 4
ODSS is an oral mucosal disease severity scoring tool, validated for use in lichen planus [bib_ref] A scoring system for mucosal disease severity with special reference to oral..., Escudier [/bib_ref] , pemphigus vulgaris [bib_ref] An Oral Disease Severity Score validated for use in oral pemphigus vulgaris, Ormond [/bib_ref] , and MMP [bib_ref] Validation of an Oral Disease Severity Score (ODSS) tool for use in..., Ormond [/bib_ref]. ODSS was demonstrated to be reliable in MMP.

## (reeves 2012)

## Level of evidence 1
The ODSS and the oral part of both MMPDAI and ABSIS have been validated as disease severity scoring tools for use in oral aspects of MMP.
In monosite and predominantly oral MMP, application of the ODSS may also be considered for clinical studies and daily practice.

## Grade of recommendation b

## Level of evidence 2
Two grading schemes for conjunctival scarring disease, which include disease activity, scarring, and morbidity/loss of vision parameters, are required to fully phenotype ocular MMP and meet an evidence level of B or C. One of these was designed for Stevens-Johnson syndrome [bib_ref] New grading system for the evaluation of chronic ocular manifestations in patients..., Sotozono [/bib_ref] , a disease with a phenotype similar to that of ocular MMP, but the parameters have not been assessed for interand intra-observer variability.

## Level of evidence 2
The Cicatrising Conjunctivitis Assessment Tool tool (Ong 2020) meets all these requirements. It is semi-quantitative, unlike the other tools, which are all qualitative; it has been shown to be comparable to the most comprehensive [bib_ref] New grading system for the evaluation of chronic ocular manifestations in patients..., Sotozono [/bib_ref] and widely used , evaluating scarring only) previous systems. It is ready for use as a phenotyping tool for ocular MMP.
The validated Cicatrising Conjunctivitis Assessment Tool is recommended for disease assessment in ocular MMP.

## Grade of recommendation b

## Otorhinolaryngological disease assessment
None of the scoring systems described above address otorhinolaryngological MMP in enough depth to evaluate and assess either progression of disease in the hypopharynx or larynx, or the effect of interventional studies. These systems have also not been evaluated for the required inter-and intra-observer reproducibility of inflammation, scarring and morbidity. Currently, no validated tool exists for these purposes. However, in a systematic review, Higgins et al. proposed a disease/ damage assessment of laryngeal MMP. [bib_ref] Laryngeal mucous membrane pemphigoid (MMP): a systematic review and pooled-data analysis, Higgins [/bib_ref] Although their proposal has not been validated, it has been referred to in other case series. [bib_ref] Assessment and management of laryngeal mucous membrane pemphigoid: our experience in six..., Nash [/bib_ref] [bib_ref] Monoclonal anti-CD20 antibody therapy in cicatrical pemphigoid with oral and hypopharyngeal involvement..., Wollina [/bib_ref] Conclusions Recommendations Patient-reported outcome measurements PROM use has a positive impact both on diagnosis and treatment, and on the relationship between patients and clinicians. [bib_ref] The impact of measuring patient-reported outcomes in clinical practice: a systematic review..., Valderas [/bib_ref] [bib_ref] Impact of patient-reported outcome measures on routine practice: a structured review, Marshall [/bib_ref] Quality of life (QOL) is increasingly recognized as an important clinical outcome and basis for understanding patient care within the field of dermatology. QOL assessment can be used to evaluate the effectiveness of therapeutic interventions, monitor disease course, and provide a patient-based end point for clinical trials. PROM is an instrument that enables patients to assess their health, without external interpretation. [bib_ref] Standards for patient-reported outcomebased performance measures, Basch [/bib_ref] The clinical manifestations and treatment options available for management of MMP can place a significant burden on everyday life, with physical, economic, social and psychological consequences. [bib_ref] Development of a quality-oflife instrument for autoimmune bullous disease: the Autoimmune Bullous..., Sebaratnam [/bib_ref] Often, however, the QOL burden is independent of objective disease burden and clinical severity. [bib_ref] Development of a quality-oflife instrument for autoimmune bullous disease: the Autoimmune Bullous..., Sebaratnam [/bib_ref] [bib_ref] The development and validation of the treatment of autoimmune bullous disease quality..., Tjokrowidjaja [/bib_ref] A variety of questionnaires and psychometric tools exist to assess QOL in AIBD; these can be categorized as generic, skinspecific or disease-specific. A number of studies have evaluated QOL in AIBD by using generic tools such as the Medical Outcome Study 36-item Short Form (SF-36), [bib_ref] The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item..., Ware [/bib_ref] [bib_ref] Quality of life and pemphigus, Terrab [/bib_ref] [bib_ref] The health impact of pemphigus vulgaris and pemphigus foliaceus assessed using the..., Tabolli [/bib_ref] Activities of Daily Living (ADLs), [bib_ref] An investigation of quality of life (QOL) of pemphigus patients in Japan..., Masahiro [/bib_ref] 12-item General Health Questionnaire (GHQ-12), [bib_ref] Quality-of-life assessment in patients with pemphigus using a minimum set of evaluation..., Paradisi [/bib_ref] [bib_ref] Quality of life and psychological status of patients with pemphigus vulgaris using..., Ghodsi [/bib_ref] Hospital Anxiety and Depression scale (HADS), [bib_ref] The hospital anxiety and depression scale, Zigmond [/bib_ref] [bib_ref] Quality of life, depression, anxiety and loneliness in patients with bullous pemphigoid...., Kouris [/bib_ref] Clinical Depression Questionnaire (CDQ), [bib_ref] The health impact of pemphigus vulgaris and pemphigus foliaceus assessed using the..., Tabolli [/bib_ref] Beck Depression Inventory (BDI), [bib_ref] An inventory for measuring depression, Beck [/bib_ref] [bib_ref] Depression in patients with pemphigus: is it a major concern?, Layegh [/bib_ref] and The Work Productivity and Activity Impairment Questionnaire-Specific Health Problem (WPAIQ-SHP). [bib_ref] The validity and reproducibility of a work productivity and activity impairment instrument, Reilly [/bib_ref] [bib_ref] Loss of work productivity and quality of life in patients with autoimmune..., Heelan [/bib_ref] The literature also mentions several dermatology-specific instruments that evaluate QOL in AIBD, including the Dermatology Life Quality Index (DLQI), Dermatology Quality of Life Scales, Dermatology Specific Quality of Life Instrument, Itchy QOL and Skindex-29. [bib_ref] Dermatology Life Quality Index (DLQI)-a simple practical measure for routine clinical use, Finlay [/bib_ref] [bib_ref] Dermatology quality of life scales-a measure of the impact of skin diseases, Morgan [/bib_ref] [bib_ref] Pemphigus and quality of life, Chee [/bib_ref] [bib_ref] Quality of life in patients with pemphigus receiving adjuvant therapy, Paradisi [/bib_ref] [bib_ref] A pilot quality-of-life instrument for pruritus, Desai [/bib_ref] [bib_ref] Development and validation of a quality of life instrument for cutaneous diseases, Anderson [/bib_ref] [bib_ref] 574 Comparative analysis of quality of life impact in patients with autoimmune..., Alshamekh [/bib_ref] [bib_ref] Skindex, a quality-of-life measure for patients with skin disease: reliability, validity, and..., Chren [/bib_ref] The DLQI is the first validated dermatology-specific QOL instrument. [bib_ref] Dermatology Life Quality Index (DLQI)-a simple practical measure for routine clinical use, Finlay [/bib_ref] [bib_ref] The Dermatology Life Quality Index 1994-2007: a comprehensive review of validation data..., Basra [/bib_ref] Currently, the SF-36 and the DLQI are the most often reported measures for evaluating QOL in AIBD.
The Oral Health Impact Profile (OHIP) [bib_ref] Development and evaluation of the Oral Health Impact Profile, Slade [/bib_ref] is the most common generic instrument used in the field of oral medicine. [bib_ref] The use of quality of life measures in oral medicine: a review..., Ni Riordain [/bib_ref] The OHIP was originally developed with 49 questions across seven domains; a shortened version was subsequently derived with 14 questions, referred to as OHIP- This was developed to provide a comprehensive measure of self-reported dysfunction, discomfort and disability resulting from oral conditions. In oral MMP studies, the Visual Analogue Scale (VAS) is the most commonly used PROM, [bib_ref] An open clinical trial of sulphamethoxypyridazine in the treatment of mucous membrane..., Thornhill [/bib_ref] [bib_ref] Professional oral hygiene treatment and detailed oral hygiene instructions in patients affected..., Arduino [/bib_ref] and its validity and reliability have been well established. [bib_ref] Reliability of the visual analog scale for measurement of acute pain, Bijur [/bib_ref] Further, the Chronic Oral Mucosal Disease Questionnaire (COMDQ)is the first validated specific QOL measure developed in the field of oral medicine to evaluate chronic conditions of the oral mucosa, and has been translated into other languages. The reliability and validity of this tool have also been confirmed. [bib_ref] Reliability and validity of the Chinese version of the chronic oral mucosal..., Li [/bib_ref] [bib_ref] Validity and reliability of the Chronic Oral Mucosal Diseases Questionnaire in a..., Ni Riordain [/bib_ref] [bib_ref] Assessment of quality of life in patients with chronic oral mucosal diseases:..., Rajan [/bib_ref] [bib_ref] Validity and reliability of the persian version of the chronic oral mucosal..., Shirzad [/bib_ref] Finally, the Autoimmune Bullous Disease Quality of Life (ABQOL), a validated 17-item questionnaire, is the only disease-specific tool used for patients with AIBD. [bib_ref] Development of a quality-oflife instrument for autoimmune bullous disease: the Autoimmune Bullous..., Sebaratnam [/bib_ref] [bib_ref] Reliability of the autoimmune bullous disease quality of life (Abqol) questionnaire in..., Sebaratnam [/bib_ref] Its specificity promises to capture the small changes in AIBD which generic tools may miss. The ABQOL can be used to quantify the effect of a patient's AIBD on their QOL, and capture changes in disease status, which may not be apparent during routine clinical review. Treatment of MMP may be associated with a significant risk of medical complications and a severe impact on QOL, an impact which is difficult to differentiate from the burden of the disease itself. The Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL) [bib_ref] The development and validation of the treatment of autoimmune bullous disease quality..., Tjokrowidjaja [/bib_ref] is the first validated patient-centred tool to allow quantitative measurement of treatment-specific impact on QOL in AIBD. 209

## Level of evidence 4
Higgins 2010 proposed a staging system for laryngeal mucous membrane pemphigoid. It quantifies disease severity and provides standardized reporting. This method has not been validated.

## Level of evidence 4
Nash 2017 described a symptomatology scale for laryngeal involvement. This method has not been validated.

## Level of evidence 2
No validated comprehensive disease severity scoring tools are available for use regarding otorhinolaryngological involvement in MMP.
For clinical studies, it is recommended that an otorhinolaryngological version of the MMPDAI scoring tools be validated.

## Grade of recommendation d

# Conclusions
Recommendations
[table] Table 1: Level of recommendation based on level of evidence [/table]
[table] Table 2: Overview of possible clinical signs of mucous membrane pemphigoid per affected mucosal site [/table]
[table] Table 3: List of previous and current terminology for mucous membrane pemphigoid [/table]