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

Abstract

This guideline has been initiated by the task force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology, including physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline that systematically reviewed the literature on mucous membrane pemphigoid (MMP) in the MEDLINE and EMBASE databases until June 2019, with no limitations on language. While the first part of this guideline addressed methodology, as well as epidemiology, terminology, aetiology, clinical presentation and outcome measures in MMP, the second part presents the diagnostics and management of MMP. MMP should be suspected in cases with predominant mucosal lesions. Direct immunofluorescence microscopy to detect tissue-bound IgG, IgA and/or complement C3, combined with serological testing for circulating autoantibodies are recommended. In most patients, serum autoantibodies are present only in low levels and in variable proportions, depending on the clinical sites involved. Circulating autoantibodies are determined by indirect IF assays using tissue substrates, or ELISA using different recombinant forms of the target antigens or immunoblotting using different substrates. The major target antigen in MMP is type XVII collagen (BP180), although in 10-25% of patients laminin 332 is recognized. In 25-30% of MMP patients with anti-laminin 332 reactivity, malignancies have been associated. As first-line treatment of mild/moderate MMP, dapsone, methotrexate or tetracyclines and/or topical corticosteroids are recommended. For severe MMP, dapsone and oral or intravenous cyclophosphamide and/or oral corticosteroids are recommended as first-line regimens. Additional recommendations are given, tailored to treatment of single-site MMP such as oral, ocular, laryngeal, oesophageal and genital MMP, as well as the diagnosis of ocular MMP. Treatment recommendations are limited by the complete lack of high-quality randomized controlled trials.

Figure 1

Diagnostic algorithm and work‐up, and diagnostic criteria for mucous membrane pemphigoid. ¹Alternatively or in addition, direct immunoelectron microcopy can be performed. ²A positive DIF from any site is diagnostic for MMP, providing the clinical phenotype at the site that has not been biopsied is consistent with MMP. ³If ocular MMP is suspected, take biopsies from the least inflamed bulbar conjunctiva of both eyes together with another site (buccal mucosa or skin). Also take an additional lesional biopsy for routine histopathology to exclude both ocular surface neoplasia and sarcoid (which may present in the conjunctiva). ⁴Patients with predominant or exclusive IgA deposition could also be classified as having linear IgA disease. ⁵Patients with reactivity with type VII collagen could also be classified as having Epidermolysis Bullosa Acquisita. ⁶On human/primate salt‐split skin. ⁷Commercially available (for IgG antibodies). ⁸Only available in specialized diagnostic centers. ⁹Associated with a malignancy in 25–30% of patients; a tumor search is indicated. ¹⁰A diagnosis of immunopathology unconfirmed ocular monosite MMP can be made by exclusion of the more than 25 other causes of cicatrising conjunctivitis (CC). MMP is the most common cause of CC in most developed countries. Causes of CC, except for sarcoid & surface neoplasia: (i) have a history consistent with another cause of conjunctival disease; (ii) are positive on routine histopathology for neoplasia or sarcoid; or (iii) are DIF+ for another immuno‐bullous disease. If, after initiating appropriate therapy for immunopathology negative ocular monosite MMP, the disease course or response to therapy is not as expected, then this algorithm (both for DIF in ocular cases and serology) should be repeated and alternative diagnoses considered (e.g., severe ocular rosacea which can be difficult to differentiate from ocular MMP. DIF, direct immunofluorescence microscopy; ELISA, enzyme‐linked immuno sorbent assay; IIF, indirect immunofluorescence microscopy; MMP, mucous membrane pemphigoid.

Figure 2

Algorithm for treatment of mucous membrane pemphigoid. CI, contraindication; CS, corticosteroid; CYC, cyclophosphamide; IV, intravenous; IVIg, Intravenous Immunoglobulin; MMF, mycophenolate mofetil; MMP, mucous membrane pemphigoid; TNF, tumour necrosis factor.

Figure 3

Algorithm for systemic treatment of ocular mucous membrane pemphigoid. The complete legend is shown in the Appendix S1.