Oral mucous membrane pemphigoid: updates in diagnosis and management.

Mucous membrane pemphigoid (MMP) is a rare, immune-mediated, vesiculobullous disease that predominantly affects the oral cavity and conjunctiva. In MMP, autoantibodies are directed against hemidesmosomal proteins in the basement membrane zone, most commonly BP180. Clinical signs and symptoms include gingival desquamation, erosions, and ulcerations. Differential diagnoses include other immune-mediated blistering diseases, such as bullous pemphigoid. Definitive diagnosis is reached through history taking, physical examination, tissue biopsy and/or serology testing. MMP, although not curable, is typically managed with topical or systemic corticosteroids, in addition to immunosuppressive therapies and biologic agents in recalcitrant cases. Untreated MMP can lead to life-threatening complications, such as blindness. As a condition that affects the oral cavity, it is important that dentists understand how to recognise, diagnose and manage the disease.

Two cases of linagliptin-associated bullous pemphigoid resulting in sepsis and endocarditis.

We describe two patients, in their 70s, each presenting to the emergency department, with 6-week histories of progressively developing pruritic bullae. Both individuals had multiple comorbidities, including type 2 diabetes-for which they took linagliptin, chronic kidney disease, hypertension and prosthetic heart valves. Owing to systemic illness and endocarditis secondary to superadded bacterial infections, they both required intensive treatment and prolonged hospital admissions.Despite the beneficial effect of linagliptin on glycaemic control and its reported cardiovascular and renal safety profiles, we add our cases as evidence of the significant risk of developing bullous pemphigoid while taking this medication. Secondary infection of bullous pemphigoid increased the risk of developing endocarditis, particularly among individuals with a medical history of valve replacement surgery. Considering this, we advocate caution when prescribing this medication.

Relationship between bullous pemphigoid and malignancy: A Mendelian randomization study.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease, which primarily affects the elderly. However, the relationship between BP and malignancy remains controversial in traditional observational studies. The aim of this study, which included only European populations, was to assess the potential causative link between BP and 13 types of malignant tumors in a two-sample Mendelian randomization (MR) study. BP was not associated with an increased risk of developing 13 types of malignant tumors. This study did not find a causal relationship between BP and malignant tumors. However, further research is warranted to examine the generalizability of this conclusion in non-European populations.

Bullous pemphigoid and diabetes mellitus: a systematic review and meta-analysis.

We aimed to systematically review and meta-analyze the association between diabetes mellitus (DM) and bullous pemphigoid (BP). Bullous pemphigoid (BP) is a prevalent autoimmune subepidermal blistering disease. Comorbid health conditions like neurological diseases and malignancies have been associated with BP. Growing evidence suggests that type 2 diabetes mellitus (T2DM) may increase the risk of developing BP. This review aims to synthesize this evidence. A systematic literature review was performed using Medline, PubMed, and Scopus in March 2022. Studies exploring the association between BP and DM were included. Data were extracted, and quality was assessed using the Newcastle-Ottawa scale. Meta-analysis was conducted to identify the odds ratio (OR) and 95% confidence intervals (CI) of the association. Seventeen studies were included, most being case-control studies from Europe and Asia. The pooled OR was 2.06 (95% CI: 1.61-2.62), suggesting a significant association between DM and BP. However, strong heterogeneity (I2 = 88%) was observed. Evidence consolidates a significant relationship between DM and BP, potentially due to alterations in the immune system and skin properties caused by diabetes. Strengths of this review include a comprehensive search, rigorous methodology, large sample size, and heterogeneity evaluation. However, varying study quality, potential publication bias, and unaccounted confounding factors present limitations. There is a potential link between T2DM and an increased risk of BP. Further studies are required to understand this association and the underlying mechanisms.

Evaluation of Dry Eye Severity and Ocular Surface Inflammation in Patients with Pemphigus and Pemphigoid.

PURPOSE: To evaluate ocular surface involvement, tear cytokine levels, and histopathological changes in pemphigus and pemphigoid patients. METHODS: A total of 22 patients (15 pemphigus and 7 pemphigoids) and 21 non-diseased controls were enrolled in our study. All participants underwent ocular surface evaluation, which included ocular surface disease index test, slit lamp observation, dry eye-related examination, tear multicytokine analysis, and conjunctival impression cytology. RESULTS: Pemphigus and pemphigoid patients presented much more severe conjunctivochalasis, corneal epithelial defects, corneal opacity, symblepharon   and dry eye. Severe ocular surface squamous metaplasia and a significant increase of tear macrophage inflammatory protein-1beta, tumor necrosis factor-alpha, interleukin (IL)-1ß, IL -6, and IL-8 occurred in pemphigus and pemphigoid patients. CONCLUSIONS: Our results revealed that ocular surface inflammation and dry eye persist in most pemphigus and pemphigoid patients, and do not occur in parallel with the systemic course. Regular ophthalmological examinations and local anti-inflammatory should be provided for pemphigus and pemphigoid patients.

Survey: Preferred practice patterns in the diagnosis of mucous membrane pemphigoid amongst cornea specialists.

PURPOSE: To evaluate preferred diagnostic tools and treatment decision-making factors in cases suspicious of mucous membrane pemphigoid (MMP) amongst ophthalmologists and cornea specialists. METHODS: Web-based survey, consisting of 14 multiple choice questions, posted to the Cornea Society Listserv Keranet, the Canadian Ophthalmological Society Cornea Listserv, and the Bowman Club Listserv. RESULTS: One hundred and thirty-eight ophthalmologists participated in the survey. Eighty-six percent (86%) of respondents were cornea trained and practiced in either North America or Europe (83%). Most respondents (72%) routinely perform conjunctival biopsies for all suspicious cases of MMP. For those who do not, fear that biopsy will exacerbate inflammation was the most common reason to defer investigation (47%). Seventy-one percent (71%) performed biopsies from perilesional sites. Ninety-seven percent (97%) ask for direct (DIF) studies and 60% for histopathology in formalin. Most do not recommend biopsy at other non-ocular sites (75%), nor do they perform indirect immunofluorescence for serum autoantibodies (68%). Immune-modulatory therapy is started following positive biopsy results for most (66%), albeit most (62%) would not let a negative DIF influence the choice of starting treatment should there be clinical suspicion of MMP. Differences in practice patterns as they relate to level of experience and geographical location are contrasted to the most up-to-date available guidelines. CONCLUSION: Responses to the survey suggest that there is heterogeneity in certain practice patterns for MMP. Biopsy remains an area of controversy in dictating treatment plans. Identified areas of need should be targeted in future research.

Is it Possible to Obtain Immunofluorescence Data in Formalin-Fixed Paraffin-Embedded Skin Samples for the Diagnosis of Pemphigus Vulgaris and Bullous Pemphigoid.

OBJECTIVE: The gold-standard method for assessment of autoimmune bullous disease is direct/indirect immunofluorescence (IF) examination applied to fresh frozen tissue. Since the sensitivity of IF is greatly reduced in formalin-fixed paraffin-embedded (FFPE) tissues, IF cannot be relied upon in these samples. However, immunohistochemistry with the C4d antibody is a promising marker used as a surrogate for immune complex deposition, in nephropathology practice, and the paraffin IF method is also used as a `salvage` technique when fresh frozen tissue is not available or lacks glomeruli. We aimed to investigate whether it is possible to obtain immunofluorescence data from FFPE tissues diagnosed with bullous pemphigoid (BP) and pemphigus vulgaris (PV) and its relationship with inflammatory parameters in the skin. MATERIAL AND METHODS: Eighty-nine in-house cases with both IgG and C3 positivity by routine immunofluorescence examination were included in the study. Inflammation parameters were evaluated in hematoxylin-eosin sections. Immunofluorescence study with IgG protease digestion and C4d immunohistochemistry were performed. RESULTS: Results of 83 biopsies were obtained by paraffin immunofluorescence with IgG. There were positive reactions in 28 (34%) of these 83 biopsies. Five of the 28 positive results belonged to BP (18%), and 23 were PV (82%). Ten positive results were on lesional skin (36%), and 18 (64%) were on non-lesional skin. In the immunohistochemical study with C4d, 84 biopsy results were obtained. There were positive reactions in 34 (40.4%) of 84 biopsies. Of the 34 positive results, 12 belonged to BP (35.3%) and 22 to PV (64.7%). Again, 22 (64.7%) of 34 positive results belonged to lesional skin, and 12 (35.3%) belonged to non-lesional skin. When both techniques were used together, 44 (54%) of 81 biopsies yielded positive results for at least one of the two studies, while in 37 (46%), both tests showed negative results. CONCLUSION: The sensitivity of both IgG and C4d was less than in the literature, especially in BP-diagnosed biopsies. Positive samples were mostly PV. In conclusion, obtaining immunofluorescence data in FFPE samples is possible and is independent of the related skin being lesional or not, however, negative results should not be relied upon.

Direct Immunofluorescence Findings and Factors Affecting Conjunctival Biopsy Positivity in Ocular Mucous Membrane Pemphigoid.

PURPOSE: The aim of this study was to describe the direct immunofluorescence (DIF) findings and factors affecting conjunctival biopsy positivity in patients clinically diagnosed with ocular mucous membrane pemphigoid (OMMP). METHODS: This retrospective observational case series included patients with clinical OMMP who underwent conjunctival biopsy for DIF in at least 1 eye between 2018 and 2021 in an institutional setting. The primary outcome measures were association of age and chronic ocular complications with biopsy positivity. RESULTS: Of 61 patients, DIF positivity was seen in 33 (54.1%) clinically suspected cases of OMMP. Of 39 patients who underwent bilateral biopsy, 23 (59%) were positive, of which 12 (52%) were positive in both eyes while 11 (48%) were positive in 1 eye. Of 22 patients who underwent unilateral biopsy, 10 (45%) were positive. Of the 100 biopsied eyes, 45 (45%) were DIF positive. Among the immunoreactants studied, linear deposition of C3 was seen in all 45 positive eyes (100%). Increasing age was significantly associated with higher likelihood of biopsy negativity ( P = 0.032), whereas a greater Sotozono chronic ocular complication score, indicative of disease severity, was associated with low likelihood of biopsy positivity ( P = 0.0042) and lower overall expression of immunoreactants on DIF ( P = 0.0007). CONCLUSIONS: Older patients and patients with more severe ocular surface disease sequelae are likely to have negative DIF results. To optimize the chances of confirming the diagnosis of OMMP by DIF, both eyes should be biopsied early in the disease course. If 1 eye is being biopsied, the less affected eye must be chosen.

From Molecular Insights to Clinical Perspectives in Drug-Associated Bullous Pemphigoid.

Bullous pemphigoid (BP), the most common autoimmune blistering disease, is characterized by the presence of autoantibodies targeting BP180 and BP230 in the basement membrane zone. This leads to the activation of complement-dependent and independent pathways, resulting in proteolytic cleavage at the dermoepidermal junction and an eosinophilic inflammatory response. While numerous drugs have been associated with BP in the literature, causality and pathogenic mechanisms remain elusive in most cases. Dipeptidyl peptidase 4 inhibitors (DPP4i), in particular, are the most frequently reported drugs related to BP and, therefore, have been extensively investigated. They can potentially trigger BP through the impaired proteolytic degradation of BP180, combined with immune dysregulation. DPP4i-associated BP can be categorized into true drug-induced BP and drug-triggered BP, with the latter resembling classic BP. Antineoplastic immunotherapy is increasingly associated with BP, with both B and T cells involved. Other drugs, including biologics, diuretics and cardiovascular and neuropsychiatric agents, present weaker evidence and poorly understood pathogenic mechanisms. Further research is needed due to the growing incidence of BP and the increasing identification of new potential triggers.

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.

Approach to red, scaly eruptions in the older patient.

BACKGROUND: Older patients with a red scaly eruption often present first to a primary care practitioner. A thorough clinical assessment can help delineate between common causes and assist the clinician with the next steps in management. OBJECTIVE: This article discusses the assessment of acute- to subacute-onset erythematous and scaly plaques that are present on multiple body sites in a patient aged >65 years. DISCUSSION: The differential diagnosis of a red, scaly rash in an older patient includes atopic dermatitis, psoriasis, generalised drug eruption, tinea, scabies and non-bullous pemphigoid. Less common causes include subacute cutaneous lupus and mycosis fungoides. If the diagnosis is unclear after clinical assessment, a skin biopsy sent for histopathology, and/or direct immunofluorescence can be very useful. Management requires consideration of physical impairments, carer availability and cost.

[The main autoimmune bullous diseases]. / Les principales maladies bulleuses auto-immunes.

Autoimmune bullous diseases are disorders in which the immune system mistakenly attacks certain molecules that act as "glue" in the various layers of the skin, leading to the formation of bullae or vesicles. A bulla is a liquid-containing lesion over five millimeters in size on the skin or mucous membranes. It forms due to a loss of cohesion between the epidermis and dermis, or between keratinocytes within the epidermis. Diagnosis is based on biopsies, which show the presence of autoantibodies and the depth of skin detachment. A blood test can be used to identify circulating autoantibodies.