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

Rashid, Hanan; Lamberts, Aniek; Borradori, Luca; Alberti‐Violetti, Silvia; Barry, Robert J.; Caproni, Marzia; Carey, Barbara; Carrozzo, Marco; Caux, F.; Cianchini, Giuseppe; Corrà, Alberto; Diercks, Gilles F.H.; Dikkers, Frederik G.; Zenzo, Giovanni Di; Feliciani, Claudio; Geerling, Gerd; Genovese, Giovanni; Hertl, Michael; Joly, P.; Marzano, Angelo Valerio; Meijer, Joost; Mercadante, Valeria; Murrell, Dédée F.; Ormond, Martyn; Pas, Hendrikus; Patsatsi, Aikaterini; Prost, Cathérine; Rauz, Saaeha; Rhijn, Bram D. van; Roth, Mathias; Schmidt, Enno; Setterfield, Jane; Zambruno, Giovanna; Zillikens, Detlef; Hórvath, Barbara

doi:10.1111/jdv.17397

Cited by 103 publications

(102 citation statements)

References 214 publications

(591 reference statements)

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“…This view is supported by the observation of Bernard and coworkers that mucous membrane pemphigoid patients showed an association of anti-BP230 and anti-laminin 332 autoantibodies, both measured by ELISA ( 33 ). In line with this, the recent European guidelines on diagnosis and management of MMP recommended testing for laminin 332-specific autoantibodies also in cases with negative indirect IF in salt-split skin ( 3 , 4 ).…”

Section: Discussionmentioning

confidence: 88%

“…Patients with anti-laminin 332 MMP cannot be differentiated from other variants of MMP based on clinical appearance. However, identification of MMP patients with laminin 332specific antibodies is essential since 25%-30% of these patients might have a malignancy (3,4,(8)(9)(10)(11)(12)(13)(14). The introduction of the laminin 332-specific biochip mosaic in 2019 provided us with widely available standardized test system for the detection of anti-laminin 332 serum autoantibodies.…”

Section: Discussionmentioning

confidence: 99%

“…Anti-laminin 332 mucous membrane pemphigoid (MMP) is a subepidermal blistering autoimmune disease defined by predominant mucosal lesions and autoantibodies against laminin 332, formerly known as laminin 5 and epilegrin (1)(2)(3)(4). Laminin 332 is a heterotrimer consisting of a3, b3, and g2 chains (5).…”

Section: Introductionmentioning

confidence: 99%

“…The protein is part of the dermal-epidermal junction interacting with integrin a6b4, integrin a3b1, BP180 (type XVII collagen), and type VII collagen (5). Anti-laminin 332 MMP comprises 10%-25% of MMP patients (6,7) and was reported to be associated with malignancies in 25%-30% of patients (3,4,(8)(9)(10)(11)(12)(13)(14). Therefore, a sensitive and specific detection of anti-laminin 332 autoantibodies is of great importance to identify patients at risk of a malignancy and to initiate a tumor search in the anti-laminin 332-reactive MMP patients.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of Two Diagnostic Assays for Anti-Laminin 332 Mucous Membrane Pemphigoid

et al. 2021

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Anti-laminin 332 mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by predominant mucosal lesions and autoantibodies against laminin 332. The exact diagnosis of anti-laminin 332 MMP is important since nearly 30% of patients develop solid cancers. This study compared two independently developed diagnostic indirect immunofluorescence (IF) tests based on recombinant laminin 332 expressed in HEK239 cells (biochip mosaic assay) and the migration trails of cultured keratinocytes rich in laminin 332 (footprint assay). The sera of 54 anti-laminin 332 MMP, 35 non-anti-laminin 332 MMP, and 30 pemphigus vulgaris patients as well as 20 healthy blood donors were analyzed blindly and independently. Fifty-two of 54 and 54/54 anti-laminin 332 MMP sera were positive in the biochip mosaic and the footprint assay, respectively. In the 35 non-anti-laminin 332 MMP sera, 3 were positive in both tests and 4 others showed weak reactivity in the footprint assay. In conclusion, both assays are easy to perform, highly sensitive, and specific, which will further facilitate the diagnosis of anti-laminin 332 MMP.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparison of Two Diagnostic Assays for Anti-Laminin 332 Mucous Membrane Pemphigoid

et al. 2021

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“…Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by autoantibodies against structural proteins of the basal membrane zone of skin and surface-close epithelia and predominant mucosal lesions (1,2). Most frequently, the oral cavity and conjunctivae are affected, in 20% of patients also the skin (3,4).…”

Section: Introductionmentioning

confidence: 99%

Increased Fibrosis in a Mouse Model of Anti-Laminin 332 Mucous Membrane Pemphigoid Remains Unaltered by Inhibition of Aldehyde Dehydrogenase

et al. 2022

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Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by autoantibodies against the basal membrane zone of skin and surface-close epithelia and predominant mucosal lesions. The oral cavity and conjunctivae are most frequently affected, albeit clinical manifestations can also occur on the skin. MMP-associated lesions outside the oral cavity typically lead to scarring. Mechanisms underlying scarring are largely unknown in MMP and effective treatment options are limited. Herein, we assessed the collagen architecture in tissue samples of an antibody-transfer mouse model of anti-laminin-332 MMP. In MMP mice, increased collagen fibril density was observed in skin and conjunctival lesions compared to mice injected with normal rabbit IgG. The extracellular matrix of MMP skin samples also showed altered post-translational collagen cross-linking with increased levels of both lysine- and hydroxylysine-derived collagen crosslinks supporting the fibrotic phenotype in experimental MMP compared to control animals. In addition, we evaluated a potential anti-fibrotic therapy in experimental anti-laminin-332 MMP using disulfiram, an inhibitor of the aldehyde dehydrogenase (ALDH), which has been implicated in immune-mediated mucosal scarring. In addition, disulfiram also acts as a copper chelator that was shown to block lysyl oxidase activity, an enzyme involved in formation of collagen crosslinks. Topical use of disulfiram (300 μM in 2% [w/v] methocel) did not improve ocular lesions in experimental MMP over the 12-day treatment period in disulfiram-treated mice compared to vehicle-treated mice (n=8/group). Furthermore, C57BL6/J mice (n=8/group) were treated prophylactically with 200 mg/kg p.o. disulfiram or the solvent once daily over a period of 12 days. Systemic treatment did not show any reduction in the severity of oral and ocular lesions in MMP mice, albeit some improvement in skin lesions was observed in disulfiram- vs. vehicle-treated mice (p=0.052). No reduction in fibrosis was seen, as assessed by immunohistochemistry. Whilst blocking of ALDH failed to significantly ameliorate disease activity, our data provide new insight into fibrotic processes highlighting changes in the collagenous matrix and cross-linking patterns in IgG-mediated MMP.

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Characteristics Associated With Refractory Course, Blindness, and Treatment Strategy–Related Outcomes in Patients With Mucous Membrane Pemphigoid

et al. 2023

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ImportanceMucous membrane pemphigoid (MMP) is a rare and heterogeneous subepithelial autoimmune bullous disease with predominant mucosal involvement. Characteristics associated with the disease course and complications are yet to be delineated.ObjectivesTo evaluate characteristics associated with refractory disease course and blindness among patients with MMP and to estimate the association of different treatment strategies with the prognostic outcome.Design, Setting, and ParticipantsA retrospective cohort study of consecutive patients diagnosed with MMP and followed up for more than 1 year from 2007 to 2020 in 2 tertiary referral centers. Data were analyzed from January 1, 2009, to June 30, 2020.Main Outcomes and MeasuresCharacteristics associated with refractory disease course and blindness were evaluated using multivariable logistic regression model.ResultsThe study encompassed 121 patients with MMP (mean [SD] age, 66.0 [14.0] years; 78 (64.5%) were women), of whom 56 (46.3%) followed a refractory course and 13 (10.7%) developed blindness. Anti–LAD-1 IgA (odds ratio [OR], 3.42; 95% CI, 1.11-10.52; P = .03) and anti–dermal-epidermal/epithelial junction (DEJ) IgG (by indirect immunofluorescence on human salt-split skin; OR, 2.92; 95% CI, 1.26-6.78; P = .01) were significantly associated with refractory course. Development of blindness was associated with older age (≥68 years; OR, 6.38; 95% CI, 1.35-30.16; P = .009), initial presentation with bilateral ocular involvement (OR, 7.92; 95% CI, 2.04-30.68; P = .001), and scarring ocular lesions (OR, 5.11; 95% CI, 1.47-17.79; P = .006). However, 4 (30.8%) and 2 (15.4%) of those experiencing blindness had no ocular scarring lesions and unilateral ocular involvement at the onset of their disease, respectively. Patients progressing to blindness were more likely to be treated by 3 or more immunosuppressive/immunomodulatory drugs (OR, 4.07; 95% CI, 1.17-14.14; P = .02) and by cyclophosphamide (OR, 7.64; 95% CI, 2.24-26.09; P &lt; .001). Patients developing blindness and refractory course were more frequently managed by intravenous immunoglobulin (OR, 7.64; 95% CI, 2.24-26.09; P &lt; .001 and OR, 3.47; 95% CI, 1.42-8.45; P = .005, respectively).Conclusions and RelevanceFindings of this cohort study support that patients with MMP with anti–LAD-1 IgA and anti-DEJ IgG reactivity should be carefully monitored. While initial bilateral ocular disease and scarring ocular lesions were associated with blindness, patients initially presenting with unilateral and nonscarring ocular disease may still develop severe vision impairment.

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

Cited by 103 publications

References 214 publications

Comparison of Two Diagnostic Assays for Anti-Laminin 332 Mucous Membrane Pemphigoid

Comparison of Two Diagnostic Assays for Anti-Laminin 332 Mucous Membrane Pemphigoid

Increased Fibrosis in a Mouse Model of Anti-Laminin 332 Mucous Membrane Pemphigoid Remains Unaltered by Inhibition of Aldehyde Dehydrogenase

Characteristics Associated With Refractory Course, Blindness, and Treatment Strategy–Related Outcomes in Patients With Mucous Membrane Pemphigoid

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