Oral biopsy in mucous membrane pemphigoid and pemphigus vulgaris with gingival expression: the optimal site. A systematic review and meta-analysis.

PURPOSE: In order to diagnose mucous membrane pemphigoid (MMP) and pemphigus vulgaris (PV) with gingival expression, clinical data must be compared with immunohistochemical data obtained using direct immunofluorescence (DIF). It is therefore essential to carry out a good quality mucosal biopsy for this vital additional test. To date, no study has been able to effectively guide clinicians in their choice of oral site for biopsy to guarantee the efficient contribution of DIF to diagnosis. We propose a systematic review of the literature and a meta-analysis to clarify this issue. MATERIALS AND METHODS: Electronic databases and bibliographies of articles were searched in April 2023. The primary outcome was the rate of DIF + contribution to diagnosis according to the location of the oral site biopsied. RESULTS: 16 studies were included. Gingival biopsies showed a rate of DIF + 100% [97%-100%] p = 0.998 I2 = 0.0% with no heterogeneity for PV, and 90.2% [66.5%-100%] p < 0.001 I2 = 89.6% with high heterogeneity for MMP. For the other oral sites, this rate was 95.7% [87.4%- 100%] p = 0.011 I2 = 73.0% with moderate heterogeneity for PV, and 87.4% [70.1%- 98.7%] p < 0.001 I2 = 92.6% with high heterogeneity for MMP. In addition, meta-regression confirmed the significant association between the appearance of the biopsied mucosa and the rate of DIF + in MMP (p < 0.001), with no influence on residual heterogeneity. CONCLUSION: The nature of the oral mucosa biopsied does not influence the rate of DIF + to diagnosis. The choice of biopsy site should only take into account the characteristics of the clinical picture and the benefit/risk balance of the surgical protocol. The sample must be taken in healthy aeras as close as possible of active lesions: on the gingiva if the MMP and PV are strictly gingival, on the alveolar mucosa if the whole gingiva is altered and on any healthy mucosa if a large number of oral sites are affected. CLINICAL TRIALS: CRD42023392345.

Tissue Remodeling in Ocular Mucous Membrane Pemphigoid.

Purpose: Ocular mucous membrane pemphigoid (OcMMP) is a rare eye disease characterized by relapsing-remitting or persisting long-lasting inflammatory events associated with progressive scarring. Despite long-term immunomodulating therapy, abnormal fibrosis keeps worsening in patients with OcMMP. This study investigates the fibrotic process in patients with OcMMP, as well as the critical role of the epithelium in modulating the local fibrosis. Methods: In this prospective, observational pilot study, patients affected by long-lasting OcMMP were compared with age- and gender-matched healthy controls. Clinical grading was assessed, and conjunctival biopsy and impression cytology were performed. Conjunctival samples were used for quantifying the expression of transcripts regulating the inflammatory and fibrogenic processes. Results: Ocular surface clinical and functional markers worsened in patients with OcMMP with fibrotic disease progression. In more advanced disease stages, both impression cytologies and conjunctival biopsies revealed increased tissue remodeling and profibrotic markers (α-SMA and TGF-ß), and decreased levels of inflammatory markers (I-CAM1, IL-10, and IL-17). Increased epithelial expression of profibrotic markers and histological changes were detected. Conclusions: Chronic OcMMP is characterized by a progressive, aberrant self-sustaining fibrotic process that worsens clinical signs and symptoms. Conjunctival epithelial cells may transdifferentiate into myofibroblast-like phenotypes when chronically exposed to high levels of inflammation, as in the case of OcMMP. Tissue remodeling markers in OcMMP could be used as early diagnostic, prognostic, and therapeutic biomarkers, harvested in a non-invasive and painless procedure such as impression cytologies.

[Refractory esophageal stricture of esophageal mucous membrane pemphigoid after allogeneic hematopoietic stem cell transplantation].

Haploidentical allogeneic hematopoietic stem cell transplantation from her brother was performed on a 41-year-old lady with no prior history of pemphigoid to treat recurrent AML. On day 59 following transplantation, she experienced esophageal stenosis. During immunosuppressive therapy for graft vs. host disease, this condition was controlled with periodic esophageal dilatation (GVHD). Her esophageal stricture, which required periodic dilatation, grew worse after she stopped immunosuppressive therapy because of recurrent AML. The esophageal mucosa was easily hemorrhagic and desquamative. Histologic analysis revealed that the squamous cell layers had been divided. Indirect immunofluorescence was negative for IgG and positive for IgA on the epidermal layers, while direct immunofluorescence showed a linear deposition of IgG on the basement membrane zone. It was determined through immunoblotting utilizing recombinant protein of BP180 C-terminal domain that both IgG and IgA antibodies were present, supporting the diagnosis of mucous membrane pemphigoid with anti-BP180. After allogeneic transplantation, basal epidermal cell destruction by GVHD may result in autoimmune blistering disorders, which expose basement membrane proteins and antigen presentation. A similar mechanism could apply to our situation. For rare GVHD cases, a thorough histological diagnosis is required.

Cutaneous kinase activity correlates with treatment outcomes following PI3K delta inhibition in mice with experimental pemphigoid diseases.

Chronic blistering at the skin and/or mucous membranes, accompanied by a varying degree of inflammation, is the clinical hallmark of pemphigoid diseases that impose a major medical burden. Pemphigoid diseases are caused by autoantibodies targeting structural proteins of the epithelial basement membrane. One major pathogenic pathway of skin blistering and inflammation is activation of myeloid cells following Fc gamma receptor-dependent binding to the skin-bound immune complexes. This process requires activation of specific kinases, such as PI3Kδ, which have emerged as potential targets for the treatment of pemphigoid diseases. Yet, it is unknown if global cutaneous kinase activity present in lesional pemphigoid disease correlates with therapeutic effects following treatment with a given target-selective kinase inhibitor. To address this, we here first determined the kinase activity in three different mouse models of pemphigoid diseases: Antibody transfer-induced mucous membrane pemphigoid (MMP), antibody transfer-induced epidermolysis bullosa acquisita (EBA) and immunization-induced EBA. Interestingly, the kinome signatures were different among the three models. More specifically, PI3Kδ was within the kinome activation network of antibody transfer-induced MMP and immunization-induced EBA, but not in antibody transfer-induced EBA. Next, the therapeutic impact of the PI3Kδ-selective inhibitor parsaclisib was evaluated in the three model systems. In line with the kinome signatures, parsaclisib had therapeutic effects in antibody transfer-induced MMP and immunization-induced EBA, but not in autoantibody-induced EBA. In conclusion, kinase activation signatures of inflamed skin, herein exemplified by pemphigoid diseases, correlate with the therapeutic outcomes following kinase inhibition, demonstrated here by the PI3Kδ inhibitor parsaclisib.

Anti-Laminin 332-Type Mucous Membrane Pemphigoid.

Anti-laminin (LM) 332-type mucous membrane pemphigoid (MMP) is a rare autoimmune bullous disease and was originally discovered as anti-epiligrin cicatricial pemphigoid. Anti-LM332-type MMP has clinical manifestations similar to those of other types of MMP and can only be distinguished through the detection of circulating autoantibodies against LM332. Our group and others have established a number of immunological methods with varying sensitivity and specificity for detection of anti-LM332 autoantibodies; however, none of the established methods has been widely used for clinical diagnosis. There is currently no unified standard treatment, and it is very difficult to completely cure anti-LM332-type MMP. In addition, an increasing body of evidence suggests that there may be a strong correlation between anti-LM332-type MMP and tumors. In this article, we review the current progression of diagnosis and treatment of anti-LM332-type MMP, as well as the possible correlation between anti-LM332-type MMP and tumors.

Ocular paraneoplastic pemphigoid / Szemészeti érintettséggel járó paraneoplasiás pemphigoid

Paraneoplastic mucous membrane pemphigoid, a rare pemphigoid variant is associated with primary malignancy, and characterised by fulminant progression and frequent ineffectivity of classical systemic immunosuppression. In this paper, the clinical features, diagnostic and therapeutical challenges are presented through three cases. Detailed history and analysis of the immunofluorescent samples help the diagnosis. The therapeutic goal is to prevent the progression with systemic immunosuppressive treatment, which can be contraindicated during the ongoing oncological therapy. In absence of consent in the exact diagnostic criteria and management protocol of this rare condition, consultation with other specialists (ophthalmologist, dermatologist, dentist, ear-nose-throat specialist, immunologist) has high importance in early diagnosis and treatment.

Childhood Vulvar Mucous Membrane Pemphigoid.

BACKGROUND: Autoimmune bullous diseases in childhood are a diagnostic challenge. CASE: We present the case of an 11-year-old girl with recurrent vulvar erosions since early childhood. She had been referred to a child abuse unit under the suspicion of sexual abuse. She responded well to dapsone and topical corticosteroids. SUMMARY AND CONCLUSION: Our review focuses on previously reported cases of pemphigoid (bullous or mucous membrane) in childhood with exclusively genital involvement. We also summarize mucous membrane pemphigoid cases diagnosed during childhood. There seems to be a differentiated form of pemphigoid predominantly affecting girls with exclusively vulvar involvement and with good prognosis. Dermatologic evaluation and a skin biopsy with direct immunofluorescence are key to diagnosing a mucous membrane pemphigoid. Further antigenic studies are needed to nosologically classify the disease properly.

High frequency of upper aerodigestive tract manifestations in mucous membrane pemphigoid.

OBJECTIVE: The objective of this study was to evaluate the frequency of upper aerodigestive tract involvement in patients with mucous membrane pemphigoid associated with desquamative gingivitis. SUBJECTS AND METHODS: Data from 25 patients were collected by retrospective chart review. Their upper aerodigestive had been evaluated using a conventional flexible fiberscope. Oral disease activity was quantified on the basis of the Mucous Membrane Pemphigoid Disease Area Index activity score. RESULTS: Lesions of the upper aerodigestive tract were confirmed in nine symptomatic patients (9/25, 36%), of which five (5/25, 20%) had laryngeal involvement. No lesions were seen in the asymptomatic patients on fiberscope examination. There was a statistically significant difference in the symptoms, high oral disease activity score, and linear IgA deposition on direct immunofluorescence between patients with and without upper aerodigestive tract lesions (p = .001, .001, .002, respectively). CONCLUSION: The high frequency of considerable complications highlights the importance of confirming the presence of upper aerodigestive tract involvement in patients with mucous membrane pemphigoid having desquamative gingivitis. Signs including the presence of symptoms, high oral disease activity score, or linear IgA deposition on direct immunofluorescence might indicate a higher risk of upper aerodigestive tract involvement.