HLA alleles associated to susceptibility to gliptin-associated bullous pemphigoid in Italian patients.

Bullous pemphigoid (BP), although a rare disease, is the most frequent subepidermal autoimmune disorder. Treatment with gliptins, used for type 2 diabetes, was reported as associated with BP onset. To identify HLA alleles that may reflect a higher susceptibility to BP in the Italian population, we analysed 30 patients affected by idiopathic bullous pemphigoid (IBP) and 86 gliptin-associated BP (GABP) patients. A significant association between HLA-DQB1*03:01 allele and IBP and GABP patients was found. Of note, both IBP and GABP were significantly associated with one of the following haplotypes: DRB1*11:01, DRB3*02:02, DQA1*05:05, DQB1*03:01 or DRB1*11:04, DRB3*02:02, DQA1*05:05 and DQB1*03:01. These data identify, for the first time, potential markers of susceptibility to BP in the Italian population, especially when associated with gliptin intake.

The cardiovascular risk in bullous pemphigoid: Insights from a population-based study.

BACKGROUND: The risk of life-threatening major cardiovascular outcomes among patients with bullous pemphigoid (BP) is inconsistent in the current literature. OBJECTIVE: To evaluate the risk and prognostic outcomes of myocardial infarction (MI), cerebrovascular accident (CVA), peripheral vascular disease (PVD) and pulmonary embolism (PE) in patients with BP. We additionally aimed to explore the influence of different therapeutic approaches on the risk of these outcomes. METHODS: A population-based retrospective cohort study was conducted to compare BP patients (n = 3924) with age-, gender- and ethnicity-matched control subjects (n = 19,280) with regard to incident cases of MI, CVA, PVD and PE. Adjusted hazard ratio (HR) and 95% confidence intervals (CI) were estimated by multivariate Cox regression analysis. Data were retrieved from Clalit Health Services' computerized database. RESULTS: Relative to their matched controls, patients with BP were at an elevated risk of MI (fully-adjusted HR: 1.44; 95% CI: 1.14-1.81; p = 0.002), CVA (fully-adjusted HR: 1.24; 95% CI: 1.06-1.45; p = 0.007), PVD (fully-adjusted HR: 1.60; 95% CI: 1.27-2.03; p = 0.003) and PE (fully-adjusted HR: 1.72; 95% CI: 1.28-2.32; p < 0.008). Patients with BP experienced heightened risk of all-cause mortality in the presence of comorbid MI (fully-adjusted HR: 1.61; 95% CI: 1.44-1.81; p < 0.001), CVA (fully-adjusted HR: 1.70; 95% CI: 1.52-1.89; p < 0.001), PVD (fully-adjusted HR: 1.38; 95% CI: 1.20-1.58; p < 0.001) and PE (fully-adjusted HR: 1.44; 95% CI: 1.10-1.88; p = 0.007). The therapeutic approach utilized to manage BP did not significantly influence the risk of cardiovascular outcomes. CONCLUSIONS: BP is associated with an elevated risk of MI, CVA, PVD, PE and cardiovascular mortality. Primary, secondary and tertiary cardiovascular prevention measures should be implemented among patients with BP.

A Retrospective Comparison of Diagnostic Tools of Bullous Pemphigoid for Elderly Patients.

BACKGROUND: Older patients who are predisposed to bullous pemphigoid (BP) may exhibit reluctance to undergo skin biopsy due to potential complications. OBJECTIVES: This study aimed to conduct a comparative evaluation among histology, direct immunofluorescence (DIF), and indirect immunofluorescence (IIF) to determine the optimal diagnostic tool in elderly patients. METHODS: A retrospective study was conducted on 841 patients suspected of having BP. All cases were initially classified as BP and non-BP in accordance with the diagnostic criteria. Student's t-test and chi-squared test examined differences between the 2 groups. We evaluated the sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio detected by the 3 tools. We stratified the analysis by age to compare the performance of the diagnostic tools and examined the risk factors associated with BP using logistic regression. RESULTS: Overall, histology exhibited the highest sensitivity (89.4%), while DIF demonstrated the highest specificity (67.1%). In the elderly, the IIF test exhibited the highest specificity (57.5%), the highest positive likelihood ratio (2.047), and the lowest negative likelihood ratio (0.226). Among patients taking Dipeptidyl Peptidase-4 (DPP-4) inhibitors, IIF demonstrated the highest positive likelihood ratio (3.194) and the second-lowest negative likelihood ratio (0.235). CONCLUSIONS: In cases that elderly patients suspected of having BP are reluctant to undergo skin biopsy, IIF demonstrates the optimal diagnostic method due to its highest positive likelihood ratio, the lowest negative likelihood ratio among the 3 diagnostic measures. Moreover, IIF is found to be a more effective tool for detecting BP in patients using DPP-4 inhibitors.

A rare case of cicatricial pemphigoid confined to the scalp with associated photodamage.

We present a case of Brunsting-Perry characterized as an erythematous erosive plaque on photodamaged scalp skin, flaring after a recent prolonged sun exposure. Subsequent progression with blister formation led to the correct diagnosis, highlighting the need to consider cicatricial pemphigoid in eroded lesions without blisters, particularly on photodamaged skin.

Anti-IL-17 monoclonal antibodies and bullous pemphigoid: treatment or causal agents? A case series and review of the literature.

Bullous pemphigoid (BP) is an autoimmune bullous disease, typically affecting the elderly, characterized by the production of autoantibodies directed against structural components of the dermal-epidermal junction. An association between BP and psoriasis has been described several times, but the mechanisms underlying this association have yet to be clearly defined. The pathophysiological mechanism underlying psoriasis may be implicated in the pathogenesis of BP, as psoriasis precedes BP in most cases; in particular, a promoting role has been hypothesized by biologic therapies, which may induce a switch from a T helper 1 (TH1)/TH17-dominant cytokine milieu, typical of patients with psoriasis, to a TH2-dominant one, typical of patients with BP. IL-17 inhibitors, in particular, have also been successfully used to treat BP in patients with psoriasis. The use of these drugs in these patients has been based on in vitro studies. However, cases of new-onset BP or relapses of BP already diagnosed in patients with psoriasis treated with biologic drugs have also been reported, and they occurred mainly in patients on anti-TNF drugs, yet very few cases with anti-IL-17A drugs have been described. We hereby describe two cases of new-onset BP in two patients treated with anti-IL-17 drugs for psoriasis.

Clinical management of bullous pemphigoid-The importance of cytology in diagnosis.

Bullous pemphigoid (BP) is a common immune-mediated blistering disorder with predominant skin involvement and occasionally oral manifestations. Vesiculobullous lesions of the oral mucosa present with similar clinical features, and hence arriving at a clinical diagnosis is aided by a valuable chairside investigation, exfoliative cytology. Cytology done in the present case ruled out pemphigus because of the absence of Tzanck cells in the smear. Biopsy and direct immunofluorescence further confirmed the diagnosis of BP. Treatment initiated with systemic steroids and immunomodulators, along with oral topical application of triamcinolone acetonide resulted in complete remission in 2 months. This case report highlights the role of cytology in the diagnosis of vesiculobullous lesions and management protocol for BP patients presenting with simultaneous skin and oral lesions.

Dyspnea Due to Laryngeal Cicatricial Pemphigoid: A Case Report.

Cicatricial pemphigoid (CP) is a rare, chronic, vesiculobullous disease characteristically affecting the mucous membranes and healing with cicatrization. Laryngeal involvement is rare and leads to airway stenosis. We present a 74-year-old Caucasian woman with CP, affecting the oral cavity, esophagus, lower eyelids, and larynx. Regardless of regular treatment with hydrocortisone and azathioprine, she developed bilateral cicatrization of the aryepiglottic folds and ovoid stenosis of the laryngeal introitus, leading to dyspnea. To avoid tracheostomy, we were able to utilize infraglottic high-frequency jet ventilation under total intravenous anesthesia to perform a CO2 laser supraglottoplasty with sectioning of the aryepiglottic folds. Post-operatively, her dyspnea at rest resolved; there was no progression at the six- and 12-month follow-up, and she was satisfied with the result.

Clinical and demographic characteristics of mucous membrane pemphigoid in India: A retrospective analysis.

Background Mucous membrane pemphigoid (MMP) is a rare subepidermal autoimmune blistering disorder. The clinical and demographic parameters of this disease in Indian patients have not yet been elucidated in detail. Objective We aimed to study the clinical and demographic characteristics, disease course, and treatment aspects of MMP patients. Methods The data for this study were obtained by reviewing the case record forms of patients registered in the Autoimmune Bullous Disease (AIBD) Clinic of the Department of Dermatology, Venereology & Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, a tertiary care centre in India. The diagnosis of MMP was established on the basis of clinical and immune-histopathological features which are consistent with standard diagnostic criteria for the disease. Results A total of 52 patients with MMP registered in the AIBD clinic were included. The mean age at disease onset was 50 years and the average age at presentation was 56 years. Females outnumbered males in the study with a ratio of 1.36:1. The oral and ocular mucosae were the most commonly affected sites (82.6% and 63.4% respectively). Visual difficulty was reported by half the patients (26 of 52 patients). IgG, C3, and IgA deposits were detected on direct immunofluorescence (DIF) in 29, 21, and 11 patients, respectively. Serologic analysis was performed in only 7 of the patients and of these, just 1 exhibited a positive result on multivariant ELISA and epidermal pattern of binding on salt split skin indirect immunofluorescence. Most patients were treated with prednisolone (44 of 52). Steroid-sparing adjuvants were used in combination including cyclophosphamide, azathioprine, methotrexate, dapsone, and colchicine. Rituximab was administered in 7 patients with severe or refractory disease. Limitations This is a retrospective analysis of data available from a clinic registry. In patients with negative direct immunofluorescence on biopsy, the diagnosis was based on clinico-pathologic consensus. Conclusion MMP is not as uncommon in India as the paucity of reports suggest. Visual complications are frequent in Indian MMP patients. A high index of suspicion is required for early diagnosis and appropriate treatment to prevent ocular complications.

High serum total IgE levels correlate with urticarial lesions and IgE deposition in perilesional skin of bullous pemphigoid patients: An observational study.

Background In the pathophysiology of bullous pemphigoid, besides IgG, there has been evidence that supports the role of IgE antibodies. However, there have been no studies to evaluate total serum IgE levels or detect IgE deposits in the skin of Vietnamese patients. Aim To analyse the association between IgE levels in the serum and disease severity as well as eosinophils and IgE basement membrane zone (BMZ) deposition in Vietnamese bullous bullous pemphigoid patients. Methods A single-centre observational research on 35 newly diagnosed and untreated bullous bullous pemphigoid patients. Total serum IgE levels were analysed using enzyme-linked immunosorbent assay (ELISA). For controls, we collected sera of 30 pemphigus patients and 30 elderly patients with pruritus. Perilesional skin biopsies underwent direct immunofluorescence (DIF) staining, with biopsies of pemphigus patients as controls. Results Elevated total serum IgE was observed in 60% of bullous pemphigoid patients, the percentage in the pemphigus group and pruritus group was 20% and 40%, respectively. The mean total serum IgE level among the bullous pemphigoid group was higher than that of the pemphigus group (123.3 ± 102.4 IU/mL vs. 64.3 ± 45.1 IU/mL, p = 0.010). Total serum IgE levels of bullous pemphigoid patients correlated with higher eosinophil counts (r = 0.61; p = 0.018) and urticaria/erythema (U/E) Bullous Pemphigoid Disease Area Index (BPDAI) score (r = 0.50; p = 0.035). Among 35 bullous pemphigoid patients, 5 patients showed positive IgE DIF staining, accounting for 14.3%. Higher serum IgE levels correlated with the deposition of IgE in patients' perilesional skin (p = 0.037). Limitations Due to the rarity of bullous pemphigoid, the effect of the COVID-19 pandemic, and self-treatment issues in Vietnam, we could not recruit a larger number of participants. Conclusions Total serum IgE values correlated with urticarial lesions and IgE deposition in perilesional skin of Vietnamese bullous pemphigoid patients. IgE autoantibodies present in the skin of bullous pemphigoid patients support the role of IgE in bullous pemphigoid pathogenesis.

Clinical and immunoserological characteristics of anti-p200 pemphigoid: Comparisons of patients with epitope spreading and non-epitope spreading.

BACKGROUND: Anti-p200 pemphigoid is a rare autoimmune subepidermal blistering disease. Although the phenomenon of epitope spreading has been reported to be common in anti-p200 pemphigoid, the association between its clinical and immunoserological features has yet to be elucidated. OBJECTIVES: Our aim was to compare the clinical and immunoserological characteristics of anti-p200 pemphigoid patients with and without epitope spreading. METHODS: We performed a retrospective cohort study encompassing 30 patients with anti-p200 pemphigoid between January 2015 and December 2022. The clinical and immunoserological characteristics of anti-p200 pemphigoid were analyzed using combined immunoserological assays. RESULTS: Epitope spreading was observed in 11 of 30 patients (36.7%) with anti-p200 pemphigoid. Compared with patients in the non-epitope spreading group, patients in the epitope spreading group showed more heterogeneous clinical presentations (P = 0.018), a higher proportion of mucosal involvement (P = 0.003), higher Bullous Pemphigoid Disease Area Index (BPDAI) scores for skin erosions/blisters (P = 0.018), mucosal erosions/blisters (P = 0.001), activity (P = 0.017) and total scores (P = 0.022), and required a higher initial dose of prednisone for disease control (P = 0.040). CONCLUSIONS: This study supported the idea that anti-p200 pemphigoid was prone to epitope spreading. Anti-p200 pemphigoid patients with epitope spreading are more likely to present heterogeneous clinical phenotypes, frequent mucosal involvement, and a more severe and recalcitrant disease course.

Pembrolizumab therapy in a patient with NSCLC and bullous pemphigoid: A case report.

Immune checkpoint inhibitor (ICI) therapy, which targets programmed cell death protein 1, has demonstrated enhanced survival outcomes in numerous patients with cancer. Historically, individuals with autoimmune diseases have been excluded from clinical trials involving cancer immunotherapies due to concerns about the potential worsening of their underlying autoimmune conditions. In the present case report, a patient with non-small cell lung cancer and bullous pemphigoid (BP) who underwent treatment with the ICI pembrolizumab is described. In this specific clinical case, no severe exacerbation of the underlying autoimmune disease was observed. Contrarily, the patient not only tolerated pembrolizumab well but also experienced amelioration of the BP lesions after the treatment. This case challenges the conventional exclusion criteria for ICI therapy in patients with autoimmune diseases, suggesting the potential safety and efficacy of such treatments in this specific population. However, further investigations and larger-scale studies are warranted to validate these findings and provide a more comprehensive understanding of the implications of ICI therapy in patients with autoimmune comorbidities.

Periodontal and microbiological data in patients with mucous membrane pemphigoid in a French population in 2021-2022: A pilot cross-sectional study.

Background and Aims: In the case of mucous membrane pemphigoid with gingival expression (gMMP), the complete healing of the gingiva is generally not achieved despite medical treatment. Therefore, patients' oral comfort is impaired. The dysbiotic periodontal microbiota, generated by a lack of oral hygiene associated with persistent gingival pain, could the immunopathological mechanism to persist. The main objective of this study was to characterize the subgingival microbiota of the gMMP patients, and to highlight a potential link between this microbiological data and the clinical data. Methods: Subgingival biofilm was collected from 15 gMMP patients, medically treated or not, but not receiving periodontal treatment. The usual clinical periodontal parameters were recorded. The biofilm was analyzed by polymerase chain reaction quantitative. The risk factors of severe erosive gingivitis and severe periodontitis were assessed using Chi-square or Fischer's exact test were used. Results: Whatever the medical and periodontal conditions of the patients, the results showed the existence of three main communities of periodontopathic, dysbiotic bacteria. The first including Tannnerella forsythia, Peptostreptococcus micros, Fusobacterium nucleatum, and Campylobacter rectus, was found in 100% of the patients, the second enriched with Treponema denticola in 60% and the third enriched with Porphyromonas gingivalis and Prevotella intermedia in 26%. Furthermore, there was a significant positive link between the duration of gMMP and the severity of erosive gingivitis (p = 0.009), and the loss of deep periodontal tissue (p = 0.04). Conclusion: This pilot study suggests a high periodontal risk in gMMP patients. The pathological processes, autoimmune on the one hand and plaque-induced on the other, may amplify each other. The application of periodontal therapy is therefore necessary in parallel with medical treatment. Nevertheless, further controlled studies are required to validate and complement these preliminary results.

Clinical Characteristics of Ocular Mucous Membrane Pemphigoid: A Systematic Review and Meta-Analysis.

PURPOSE: To synthesize the evidence and generate a combined weighted measure on the frequency of ocular manifestations of mucous membrane pemphigoid (OMMP). METHODS: Systematic literature review and meta-analysis, searching PubMed, Embase, VHL, and Google Scholar. Articles reporting patients with mucous membrane pemphigoid and ocular involvement were included. At least, two reviewers independently and in parallel participated in all the following phases; preliminary screening, full-text review, risk of bias assessment by validated tools, and data extraction. Qualitative analysis and meta-analysis were conducted. This study was previously registered in PROSPERO (CRD42023451844). RESULTS: Thirty-five studies met the inclusion criteria, comprising 1,439 patients and 1,040 eyes summarized in qualitative analysis. Twenty-eight studies were included in the meta-analysis. Ages included ranged from 60.4 to 75 years. Women were reported with more frequency. The mean time for diagnosis was 55.1 months, usually with bilateral ocular disease in 90% (95% CI 78%; 96%). Trichiasis and entropion were the most frequent manifestations in up to 92%, followed by symblepharon and punctate keratitis. Ankyloblepharon, persistent epithelial defects, and visual impairment were less frequent complications. Direct immunofluorescence positivity in conjunctival biopsies was 54% (95% CI 43%; 64%). Extraocular involvement was highly frequent, being oral and skin involvement the most frequently reported. CONCLUSIONS: Our systematic review and meta-analysis evidenced that patients around 60 years of age are the most affected population with a female preponderance, usually with bilateral ocular involvement. Trichiasis and entropion were the most frequent findings; although visual impairment and persistent epithelial defects were less reported, they should not be overlooked in suspected OMMP.

Serum Biomarkers in Bullous Pemphigoid: A Systematic Review.

INTRODUCTION: Bullous pemphigoid (BP) is the most common type of subepidermal blistering disease, usually observed in the elderly population, with a mean age of presentation between 66 and 83 years. BP is a psychosocially ladened disease, with many patients experiencing negative body image, social isolation, and depression. The identification and validation of biomarkers in BP may further the understanding of disease pathogenesis, provide objective measures in assessing efficacy in clinical trials, and identify new targets for targeted therapy. METHODS/RESULTS: Two databases (Medline and Embase) were searched from database inception to September 2023. All published articles reporting on biomarker levels of BP patients in serum compared to healthy controls were included. A total of 877 unique articles were identified, resulting in the inclusion of 62 case-control studies reporting on a total of 1837 patients and 140 unique biomarkers. Biomarkers were categorized into T-cell mediated, B-cell mediated, innate immune system, and coagulation cascade pathway. The most notable biomarkers identified include increases in anti-BP180/230 immunoglobulin (Ig)G/E, total IgE, TNF-α, B-cell activating factor, interleukin-31, eosinophil cationic protein, MMP-9, and coagulation cascade biomarker levels. The results of this review provide the greatest support for a role of anti-BP180/230 autoantibodies, Th2 cells, eosinophils, and the coagulation cascade in the pathogenesis of BP. CONCLUSIONS: The pathogenesis of BP has an underlying autoimmune etiology centred around the production of autoantibodies against BP180/230, but increased Th2, eosinophil and coagulation cascade activity may be contributory.

Sequential occurrence of primary cutaneous indeterminate cell histiocytosis after oesophageal cancer and subsequent bullous pemphigoid: a case report.

Aims/Background Indeterminate cell histiocytosis is a rare proliferative histiocytic disease with an unknown aetiology, which shares immunophenotypic features of both Langerhans cells and macrophages. There is a relationship between indeterminate cell histiocytosis and cancer, while there are no reports about indeterminate cell histiocytosis and bullous pemphigoid. In this study, we reported the rare case of a patient with primary cutaneous indeterminate cell histiocytosis who had been diagnosed with oesophagal cancer and later developed bullous pemphigoid. The objective of this clinical case report is to analyse the association between solid tumours and indeterminate cell histiocytosis and focus on the coexistence of indeterminate cell histiocytosis and bullous pemphigoid in a patient with cancer. Case Presentation This study presented the case of a 75-year-old man who exhibited annular erythema lesions of variable size and papules scattered over his chest, abdomen, and limbs, along with four bullae on his thigh, persisting for 1.5 months. The patient also had a 9-month history of oesophageal cancer treated with radical radiotherapy. Histopathology and immunohistochemistry confirmed cutaneous indeterminate cell histiocytosis. Bullae and blisters developed on the lower limbs 38 days after treatment. A diagnosis of bullous pemphigoid was established based on clinical and histopathological features and results of direct immunofluorescence and enzyme-linked immunosorbent assay. Results Histopathological examination of the abdominal lesion revealed an accumulation of mononuclear cells in the dermis, with infiltration of eosinophils and lymphocytes in the superficial dermal layer. The histology of the blister on the thigh indicated the formation of an old subepidermal blister, with slurry and eosinophils present within the blister, and infiltration of eosinophils, lymphocytes, as well as histiocytoid cells in the superficial dermal layer. Immunohistochemical staining was positive for CD1a, S100, and CD68, and negative for CD207. Histopathological examination of blisters and bullae on the lower limbs revealed a subepidermal blister with infiltration of a large number of eosinophils within the blister and the dermis beneath it. Direct immunofluorescence showed that immunoglobulin Gs (IgGs) were linearly deposited in the basal membrane zone. Conclusion The coexistence of oesophageal carcinoma, indeterminate cell histiocytosis, and bullous pemphigoid in a single patient represents a rare case that warrants consideration of possible underlying mechanisms.

Pemphigoid diseases in patients with end-stage kidney diseases: pathogenesis and treatment.

Background: Pemphigoid diseases constitute a group of autoimmune blistering disorders characterized by subepithelial blistering. The association between pemphigoid diseases and both end-stage kidney disease (ESKD) and its treatment is notable. However, there is limited evidence about the management of pemphigoid diseases in patients with ESKD. This systematic review compiled case reports and relevant studies, summarized the underlying mechanisms of pemphigoid diseases in patients with ESKD, and summarized the efficacy of various therapies. Methods: A systematic search of PubMed and Embase was performed for articles published between 1982 to June 2, 2024. Results: Fifty-three case reports and eight relevant studies were included. Triggers for pemphigoids in patients with ESKD included materials used to treat ESKD, immune dysregulation of patients with ESKD, and rejection of renal allograft. Treatment for these patients included removing triggers, as well as administering of corticosteroids, mycophenolate mofetil (MMF), tetracyclines, rituximab, methotrexate, dapsone, azathioprine, cyclosporine, intravenous immunoglobin (IVIG), plasmapheresis, and Janus kinase inhibitors. Conclusion: Removing triggers is the most effective strategy. Despite their suboptimal efficacy, corticosteroids remain the most commonly used agents in this patient population. MMF, tetracyclines, and rituximab are less used but with benefits. There are significant adverse effects associated with methotrexate treatment. Other treatment may also be beneficial and require further investigation. These findings may enable clinicians to optimize the therapeutic approach for these patients.