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.

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.

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.

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.

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.

Use of dupilumab for recalcitrant bullous pemphigoid: A case report.

Bullous pemphigoid is an autoimmune blistering disease affecting the dermo-epidermal junction, most commonly seen in older patients. First-line treatment includes systemic, topical corticosteroids and/or steroid-sparing immunosuppressants. Treatment with these medications may be limited by their safety profile. Dupilumab is a humanized monoclonal antibody targeting interleukin-4 and interleukin-13 cytokines currently indicated for moderate-to-severe atopic dermatitis, severe asthma, chronic rhinosinusitis with nasal polyposis, and moderate-to-severe prurigo nodularis. We report a case of a patient with recalcitrant bullous pemphigoid effectively treated with dupilumab.

Proposal of a modified technique of Nikolsky's sign in oral autoimmune vesiculobullous diseases.

Nikolsky's sign, originally described for skin lesions, presents challenges when applied to the oral mucosa. To address this, a modified Nikolsky's sign has been proposed specifically for the oral mucosa. In this variant, a gentle breath of air from the air syringe embedded in the dental unit is used to inflate a pre-existing collapsed blister (non-induced technique). Alternatively, in the induced technique, a healthy peri-lesion mucosal site is gently scratched with a blunt dental tool, and after a few minutes, air is blown on the same area to inflate any newly formed blister. The sign is considered positive if a blister is raised from the blown surface. The described modified Nikolsky's sign improves the visualization of oral vesicles and blisters in a cost-effective, easy, and minimally invasive manner. Its elicitation can aid in referring patients to specialized tertiary care units.

High throughput screening identifies repurposable drugs for modulation of innate and acquired immune responses.

A balanced immune system is essential to maintain adequate host defense and effective self-tolerance. While an immune system that fails to generate appropriate response will permit infections to develop, uncontrolled activation may lead to autoinflammatory or autoimmune diseases. To identify drug candidates capable of modulating immune cell functions, we screened 1200 small molecules from the Prestwick Chemical Library for their property to inhibit innate or adaptive immune responses. Our studies focused specifically on drug interactions with T cells, B cells, and polymorphonuclear leukocytes (PMNs). Candidate drugs that were validated in vitro were examined in preclinical models to determine their immunomodulatory impact in chronic inflammatory diseases, here investigated in chronic inflammatory skin diseases. Using this approach, we identified several candidate drugs that were highly effective in preclinical models of chronic inflammatory disease. For example, we found that administration of pyrvinium pamoate, an FDA-approved over-the-counter anthelmintic drug, suppressed B cell activation in vitro and halted the progression of B cell-dependent experimental pemphigoid by reducing numbers of autoantigen-specific B cell responses. In addition, in studies performed in gene-deleted mouse strains provided additional insight into the mechanisms underlying these effects, for example, the receptor-dependent actions of tamoxifen that inhibit immune-complex-mediated activation of PMNs. Collectively, our methods and findings provide a vast resource that can be used to identify drugs that may be repurposed and used to promote or inhibit cellular immune responses.

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.

Diagnosis of autoimmune bullous dermatoses: Comparative analysis of immunohistochemical staining using C4d, C3d, IgG, and IgG4 in lesional tissues and perilesional frozen skin samples.

Immunohistochemical staining with immunoglobulins and complements may aid the diagnosis of patients whose clinical and histological findings are consistent with autoimmune bullous dermatoses (AIBD). We aimed to investigate the diagnostic value of immunohistochemical markers in lesional biopsy and perilesional frozen samples in AIBD. We included 136 cases from whom lesional biopsies and perilesional samples for direct immunofluorescence (DIF) examination were collected with a preliminary diagnosis of AIBD between January 2019 and January 2023. All diagnoses were reconfirmed by evaluating the clinical, histopathological, and serological findings and DIF results (C3, IgG, IgA, or IgM positivity compatible with the clinical diagnosis) altogether, although DIF results were considered a priority. After confirming the diagnoses, the samples were categorized as AIBD or the others. The perilesional tissues obtained for DIF simultaneously with skin biopsy and stored at -80 °C were thawed, and FFPE tissues were prepared. We performed immunohistochemical staining (C4d, C3d, IgG, and IgG4) on FFPE tissues of both lesional and perilesional samples. Strong, linear, or granular staining patterns at the dermoepidermal junction or the intraepidermal blistering space were considered positive in line with the diagnosis of the case. Cases other than AIBD were used as negative control tissues to assess the specificity of immunohistochemical markers. Of the 136 cases, 52 were diagnosed with AIBD. In lesional samples, the sensitivity of C4d, C3d, IgG, and IgG4 was 80.6 %, 69.4 %, 75 %, and 5.7 % with corresponding specificity of 100 %, 98.7 %, 89.6 %, and 97.4 %, respectively in pemphigoid diseases compared to a sensitivity of 18.2 %, 9.1 %, 70 %, and 9.1 % and specificity of 98.7 %, 100 %, 89.6 %, and 97.4 %, respectively in pemphigus diseases. In frozen samples, we detected expression in a limited number of cases. The sensitivity of C4d, C3d, IgG, and IgG4 was 8.7 %, 2.2 %, 19.4 %, and 2.2 %, with corresponding specificity of 100 %, 100 %, 98.5 %, and 98.6, respectively. There was a none to slight concordance rate between the IHC results of lesional tissues and perilesional frozen samples. Kappa coefficients for C4d, C3d, IgG, and IgG4 were 0.120 (P = 0.029), 0.111 (P = 0.050), 0.203 (P = 0.003), and - 0.15 (P = 0.846), respectively. Immunohistochemical staining with C4d, C3d, IgG, and IgG4 on biopsy samples collected from lesions may guide the diagnosis of AIBD, thereby eliminating the need for an additional biopsy and accelerating the diagnostic process.

Efficacy and safety of low-dose Interleukin-2 in the treatment of moderate to severe bullous pemphigoid: a single center perspective-controlled trial.

BACKGROUND: Regulatory T cells (Tregs) are reduced in the peripheral blood and skin lesions of bullous pemphigoid (BP) patients. Low-dose IL-2 therapy can stimulate Tregs specifically, suggesting potential for the treatment of BP. OBJECTIVE: To evaluate the response to low-dose IL-2 therapy in the treatment of moderate to severe BP. METHODS: 43 patients with moderate to severe BP were included. The therapy included systemic corticosteroids with initial dose of 0.5mg/kg/d for moderate and 1.0mg/kg/d for severe disease respectively, combined with allowed immunosuppressants for control group, while in addition to the same corticosteroids therapy, IL-2 (half million IU) was administered subcutaneously every other day for treatment group for 8 weeks. The primary outcome was the number of days required to achieve disease control. Secondary outcomes included other clinical responses. RESULTS: The number of days required to achieve disease control with treatment group was (7.60±3.00), which was shorter than in the control group (10.43±3.06) (p=0.008). The total amount of systemic corticosteroids was less and no serious infections were detected in the treatment group. LIMITATIONS: Single center, open-label study with short duration and small size. CONCLUSION: Our trial supports the potential of low-dose IL-2 therapy for patients with moderate to severe BP, which showed earlier treatment responses.

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.

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.