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.

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.

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.

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.

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.

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.

Diagnostic challenge: Juvenile bullous pemphigoid with a negative BP180 ELISA.

Bullous pemphigoid (BP) is an autoimmune blistering disease primarily affecting the elderly, whereas cases of juvenile BP are rare. Both types of BP are typically mediated by autoantibodies targeting the NC16A region of BP180; however, a small subset of adult patient sera react to other regions of the protein. The incidence of a similar occurrence in juvenile BP is unknown. This case of juvenile BP with a negative BP180 ELISA highlights diagnostic pitfalls that can lead to a delay in the correct diagnosis in the pediatric population.

Successful treatment of infantile refractory bullous pemphigoid with baricitinib.

Infantile bullous pemphigoid (BP) is a rare autoantibody-mediated skin disorder. We report the effective treatment of a 6-month-old infant with BP using baricitinib, a Janus kinase (JAK) inhibitor, after failure with steroids and intravenous immunoglobulin. The patient achieved full remission and discontinued all medications without any relapses. To our knowledge, this is the first case of baricitinib used in an infant with BP.

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.

Fast Itch Relief during Dupilumab Predicts Clinical Efficacy in Bullous Pemphigoid: A Retrospective Cohort Study.

INTRODUCTION: Dupilumab has emerged as a promising treatment option for bullous pemphigoid (BP). Rapid identification of responders could avoid the need for additional immunosuppressive treatments that are associated with increased morbidity and mortality. METHODS: To investigate the course of itch as an early indicator of treatment response, data of 12 BP patients treated with dupilumab at the University Hospital of Zurich were retrospectively evaluated. Disease severity was assessed by bullous pemphigoid disease area index (BPDAI) and pruritus by a numeric rating scale (NRS, 0-10) at baseline; days 1, 3, 14; months 1, 2; and the last follow-up. RESULTS: A total of 8/12 patients (67%) had complete response, and 4/12 patients (33%) had partial response during dupilumab treatment. Notably, a highly significant reduction of pruritus (p < 0.0001) was observed already on day 1 with further improvement at later time points. Moreover, fast relief of itch could predict treatment response with a significant correlation to clinical response on day 14 (Spearman correlation R 0.70, p value 0.025), with a positive but non-significant trend on day 3 (R 0.63, p value 0.091). Additionally, 92% (11/12 patients) were on dupilumab monotherapy at the last follow-up without any concomitant systemic or topical treatment for BP. CONCLUSIONS: The rapid and significant decline in BP-associated pruritus observed with dupilumab correlated significantly with disease remission. Early evaluation of pruritus response could change how BP is treated in the future and avoid additional immunosuppressive treatment in BP.

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.

Perifollicular Melanocyte Regeneration in Bullous Pemphigoid.

Bullous pemphigoid (BP) is an autoimmune skin disorder that causes fluid-filled blisters to appear on various body parts, often preceded by urticaria and pruritis. This case report describes the perifollicular melanocyte regeneration within diseased areas in a skin of color patient with BP. By reviewing the various pathologies that can result in melanocyte destruction and the basic science of melanocyte regeneration, we can better identify and explain this phenomenon to patients and lead to earlier diagnoses. Furthermore, due to the lack of published information on skin conditions in skin of color patients, this report can assist in raising awareness of an atypical BP presentation in the dermatological community.

Reactivity against the BP180 ectodomain in patients with bullous pemphigoid, mucous membrane pemphigoid, multiple sclerosis and Parkinson disease.

The 16th non-collagenous domain (NC16A) of BP180 is the main antigenic target of autoantibodies in bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP). Commercially available assays detect serum autoantibodies against NC16A in the majority of BP (80%-90%) and in approximately 50% of MMP patients. However, a standardized test system for detecting antibodies against other regions of BP180 is still lacking. Moreover, anti-BP180 autoantibodies have been found in neurological conditions such as multiple sclerosis and Parkinson disease. This study aimed at identifying primary epitopes recognized by BP autoantibodies on the BP180 ectodomain. Serum samples of 51 BP and 30 MMP patients both without anti-NC16A reactivity were included along with 44 multiple sclerosis and 75 Parkinson disease sera. Four overlapping His-tagged proteins covering the entire BP180 ectodomain (BP180(ec)1-4) were cloned, expressed, purified and tested for reactivity by immunoblot. IgG antibodies to BP180(ec)3 were detected in 98% of BP, 77% of MMP and 2% of normal human sera. Only weak reactivity was detected for neurological diseases against BP180(ec)1, BP180(ec)2 and BP180(ec)4, in 3%, 11% and 7% of tested multiple sclerosis sera, respectively. 8% of Parkinson disease sera reacted with BP180(ec)2 and 9% with BP180(ec)4. In conclusion, this study successfully identified epitopes recognized by BP autoantibodies outside the NC16A domain in pemphigoid diseases. These findings contribute to a better understanding of the immune response in BP and MMP with potential implications for a future diagnostic assay for NC16A-negative pemphigoid patients.

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.

Revisiting serum storage protocols: assessing the impact of temperature variations on indirect immunofluorescence testing for pemphigus and bullous pemphigoid.

BACKGROUND: Indirect immunofluorescence (IIF) plays a crucial role in the diagnosis of pemphigus and bullous pemphigoid (BP) by detecting the presence of circulating autoantibodies in the serum of patients. The standard serum transportation method requires delivery to laboratories at 2-8 °C within a day and storage at -20 to -80 °C. However, this protocol poses logistical challenges. OBJECTIVES: We conducted a study to assess how temperature variations affect the effectiveness of IIF tests. METHODS: This case-control study analysed 203 serum specimens: 102 from patients with pemphigus and 101 from patients with BP. Specimens were stored at -80 °C (control), 24 °C, and 40 °C for seven days before analysis to investigate variations in IIF titres compared to the control conditions. RESULTS: In pemphigus serum, 95% at 24 °C and 76% at 40 °C showed no titre difference compared to controls. Similarly, 89% of BP serum at 24 °C and 82% at 40 °C matched the control titres. While 57 specimens across both groups experienced reduced titres, the decrease was primarily marginal (one-step reduction in 54 cases, two-step in 3), with no transition from positive to negative results. CONCLUSIONS: Storing serum at 24-40 °C for up to seven days before testing slightly influences IIF outcomes for pemphigus and BP. These findings could prompt a significant revision in the existing strict transport guidelines, ensuring efficient use of resources without sacrificing the accuracy of diagnostic tests.