Inhibition of phosphodiesterase-4 significantly decreases oral mucosa lesions in experimental anti-laminin 332 mucous membrane pemphigoid

Mucous membrane pemphigoid (MMP) is characterized by autoantibodies against the dermal-epidermal-junction and a mucosal disease predominating over skin involvement. As the treatment of MMP patients still relies on high-dose corticosteroids, there is an unmet need for new and more specific therapies. Here, we made use of a recently established experimental model that recapitulated major clinical and immunopathological characteristics of human MMP by the injection of IgG against the murine alpha3 chain of laminin 332 (Lam332) into adult mice. In a prophylactic approach, the specific PDE4 inhibitor roflumilast (ROF) led in 2 independent, blinded experiments, to the reduction of oral lesions compared to vehicle-treated mice as quantified by endoscopy (p¼0.029). In contrast, an increase in skin lesions was observed in ROF-treated mice (p<0.0001). In a quasi-therapeutic approach, i.e. when ROF/vehicle was not used until mice had developed first skin lesions, ROF-treated mice showed significantly less oral lesions compared to vehicle-treated mice, while skin lesions did not differ. To investigate the discrepant effect of ROF on oral and skin lesions, a transcriptome analysis of both tissues in ROF- and vehicle-treated anti-Lam332 MMP mice as well as mice injected with normal rabbit IgG was performed. An up-regulation of IL-6 and an impact of CXCL2 were found by Gene Set Enrichment and STRING analysis, respectively, in both the skin and buccal mucosa of vehicle-treated mice. The subsequent incubation of murine keratinocytes with anti-mLam332 IgG resulted in a dose-dependent release of IL-6 and CXCL2, which was inhibited by the addition of ROF. Our data propose IL-6 and CXCL2 as relevant pathogenic factors in MMP and suggest PDE4 inhibition as potential novel treatment options for MMP patients with severe oral lesions

Experimental models for the autoimmune and inflammatory blistering disease, Bullous pemphigoid

Bullous pemphigoid (BP) is a subepidermal skin blistering disease characterized immunohistologically by dermal-epidermal junction (DEJ) separation, an inflammatory cell infiltrate in the upper dermis, and autoantibodies targeted toward the hemidesmosomal proteins BP230 and BP180. Development of an IgG passive transfer mouse model of BP that reproduces these key features of human BP has demonstrated that subepidermal blistering is initiated by anti-BP180 antibodies and mediated by complement activation, mast cell degranulation, neutrophil infiltration, and proteinase secretion. This model is not compatible with study of human pathogenic antibodies, as the human and murine antigenic epitopes are not cross-reactive. The development of two novel humanized mouse models for the first time has enabled study of disease mechanisms caused by BP autoantibodies, and presents an ideal in vivo system to test novel therapeutic strategies for disease management

Prevalence of pemphigus and pemphigoid autoantibodies in the general population

Background: Mucocutaneous blistering is characteristic of autoimmune bullous dermatoses (AIBD). Blisters are caused by autoantibodies directed against structural components of the skin. Hence, detection of specific autoantibodies has become a hallmark for AIBD diagnosis. Studies on prevalence of AIBD autoantibodies in healthy individuals yielded contradictory results. Methods: To clarify this, samples from 7063 blood donors were tested for presence of anti-BP180-NC16A, anti-BP230 and anti-Dsg1/3 IgG by indirect immunofluorescence (IF) microscopy using a biochip. Results: Cumulative prevalence of these autoantibodies was 0.9 % (CI: 0.7-1.1 %), with anti-BP180-NC16A IgG being most prevalent. Validation of IF findings using ELISA confirmed presence of autoantibodies in 7/15 (anti-Dsg1), 6/7 (anti-Dsg3), 35/37 (anti-BP180-NC16A) and 2/3 (anti-BP230) cases. Moreover, in 16 samples, anti-BP180-NC16A autoantibody concentrations exceeded the cut-off for the diagnosis of bullous pemphigoid. Interestingly, these anti-BP180-NC16A autoantibodies from healthy individuals formed immune complexes with recombinant antigen and dose-dependently activated neutrophils in vitro. However, fine-epitope mapping within NC16A showed a different binding pattern of anti-BP180-NC16A autoantibodies from healthy individuals compared to bullous pemphigoid patients, while IgG subclasses were identical. Conclusions: Collectively, we here report a low prevalence of AIBD autoantibodies in a large cohort of healthy individuals. Furthermore, functional analysis shows differences between autoantibodies from healthy donors and AIBD patients

Characterization of the skin microbiota in bullous pemphigoid patients and controls reveals novel microbial indicators of disease

Introduction: Bullous pemphigoid (BP) is the most common autoimmune blistering disease. It predominately afflicts the elderly and is significantly associated with increased mortality. The observation of age-dependent changes in the skin microbiota as well as its involvement in other inflammatory skin disorders suggests that skin microbiota may play a role in the emergence of BP blistering. We hypothesize that changes in microbial diversity associated with BP might occur before the emergence of disease lesions, and thus could represent an early indicator of blistering risk. Objectives: The present study aims to investigate potential relationships between skin microbiota and BP and elaborate on important changes in microbial diversity associated with blistering in BP. Methods: The study consisted of an extensive sampling effort of the skin microbiota in patients with BP and age- and sex-matched controls to analyze whether intra-individual, body site, and/or geographical variation correlate with changes in skin microbial composition in BP and/or blistering status. Results: We find significant differences in the skin microbiota of patients with BP compared to that of controls, and moreover that disease status rather than skin biogeography (body site) governs skin microbiota composition in patients with BP. Our data reveal a discernible transition between normal skin and the skin surrounding BP lesions, which is characterized by a loss of protective microbiota and an increase in sequences matching Staphylococcus aureus, a known inflammation-promoting species. Notably, Staphylococcus aureus is ubiquitously associated with BP disease status, regardless of the presence of blisters. Conclusion: The present study suggests Staphylococcus aureus may be a key taxon associated with BP disease status. Importantly, we however find contrasting patterns in the relative abundances of Staphylococcus hominis and Staphylococcus aureus reliably discriminate between patients with BP and matched controls. This may serve as valuable information for assessing blistering risk and treatment outcomes in a clinical setting

Definitions and outcome measures for bullous pemphigoid: Recommendations by an international panel of experts

Our scientific knowledge of bullous pemphigoid (BP) has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in BP. A major obstacle in sharing multicenter-based evidences for therapeutic efforts is the lack of generally accepted definitions for the clinical evaluation of patients with BP. Common terms and end points of BP are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. These recommendations from the International Pemphigoid Committee represent 2 years of collaborative efforts to attain mutually acceptable common definitions for BP and proposes a disease extent score, the BP Disease Area Index. These items should assist in the development of consistent reporting of outcomes in future BP reports and studies. © 2011 by the American Academy of Dermatology, Inc

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 by a chronic course and by predominant involvement of the mucous membranes, such as the oral, ocular, nasal, nasopharyngeal, anogenital, laryngeal and oesophageal mucosa. MMP patients may present with mono- or multisite involvement. Patients’ autoantibodies have been shown to be predominantly directed against BP180 (also called BPAG2, type XVII collagen), BP230, laminin 332 and type VII collagen, components of junctional adhesion complexes promoting epithelial stromal attachment in stratified epithelia. Various disease assessment scores are available, including the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI), the Autoimmune Bullous Skin disorder Intensity Score (ABSIS), the ‘Cicatrising Conjunctivitis Assessment Tool’ and the Oral Disease Severity Score (ODSS). Patient-reported outcome measurements (PROMs), including DLQI, ABQOL and TABQOL, can be used for assessment of quality of life to evaluate the effectiveness of therapeutic interventions and monitor disease course

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

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

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 by a chronic course and by predominant involvement of the mucous membranes, such as the oral, ocular, nasal, nasopharyngeal, anogenital, laryngeal and oesophageal mucosa. MMP patients may present with mono- or multisite involvement. Patients’ autoantibodies have been shown to be predominantly directed against BP180 (also called BPAG2, type XVII collagen), BP230, laminin 332 and type VII collagen, components of junctional adhesion complexes promoting epithelial stromal attachment in stratified epithelia. Various disease assessment scores are available, including the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI), the Autoimmune Bullous Skin disorder Intensity Score (ABSIS), the ‘Cicatrising Conjunctivitis Assessment Tool’ and the Oral Disease Severity Score (ODSS). Patient-reported outcome measurements (PROMs), including DLQI, ABQOL and TABQOL, can be used for assessment of quality of life to evaluate the effectiveness of therapeutic interventions and monitor disease course

International bullous diseases group: consensus on diagnostic criteria for epidermolysis bullosa acquisita

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a complex autoimmune bullous disease disease with variable clinical presentations and multiple possible diagnostic tests, making an international consensus on the diagnosis of EBA essential. ----- OBJECTIVES: To obtain an international consensus on the clinical and diagnostic criteria for EBA. ----- METHODS: The International Bullous Diseases Group (IBDG) met three times to discuss the clinical and diagnostic criteria for EBA. For the final voting exercise, 22 experts from 14 different countries voted on 50 different items. When > 30% disagreed with a proposal, a discussion was held and re-voting carried out. ----- RESULTS: In total, 48 of 50 proposals achieved consensus after discussion. This included nine diagnostic criteria, which are summarized in a flow chart. The IBDG was unable to determine one procedure that would be applicable worldwide. A limitation of the study is that differential diagnosis of bullous systemic lupus erythematosus has not been addressed. ----- CONCLUSIONS: This first international consensus conference established generally agreed-upon clinical and laboratory criteria defining the clinical classification of and diagnostic testing for EBA. Holding these voting exercises in person with the possibility of discussion prior to voting has advantages in reaching consensus over Delphi exercises with remote voting