Bruton tyrosine kinase (Btk) is essential for B cell function. Its role in myeloid cells is less understood. Greater insights into Btk significance in myeloid cells are needed to evaluate its potential as a therapeutic target during the effector phase of antibody-induced autoimmune diseases, where inhibiting autoantibody production suppresses tissue inflammation only after a delay. Such a situation can be observed, for example, in acute flares of pemphigoid diseases, a group of autoimmune blistering skin diseases. We examined the effect of neutrophil-specific Btk gene deficiency and of the Btk inhibitor ibrutinib on disease in the antibody-transfer model of bullous pemphigoid (BP)-like epidermolysis bullosa acquisita (EBA), a model that solely reflects the effector phase. We additionally investigated the effect of Btk inhibitors on responses of neutrophils relevant for autoimmune diseases in vitro. Both neutrophil-specific Btk deficiency and ibrutinib administration, systemic or topical, markedly protected against skin inflammation and disrupted established inflammation. Stimulation of murine neutrophils with immune complexes activated Btk and induced the release of leukotriene B4 (LTB4) and reactive oxygen species (ROS). Btk deficiency abolished LTB4 but not ROS release, indicating distinct signalling pathways regulating LTB4 and ROS following Fcγ receptor activation. Our findings demonstrate that EBA skin inflammation is critically controlled by a Fcγ receptor-Btk-LTB4 axis in neutrophils. This highlights Btk as promising drug target to treat EBA and potentially other antibody-induced autoimmune diseases.

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Understanding IgE-mediated autoimmunity and autoallergy.

Background Bullous pemphigoid (BP) is a common autoimmune subepidermal bullous disease. Dupilumab, an IL-4/IL-13 inhibitor, represents a novel therapeutic approach for BP, but real-world long-term data in super-elderly patients are limited. Methods This retrospective, single-center observational study included super-elderly BP patients (≥80 years) receiving dupilumab monotherapy from September 2022 to September 2024. Disease severity was assessed using BPDAI and NRSP, and BP180 antibody, total IgE, and eosinophil count were monitored over 52 weeks. Results Thirteen patients with mild to moderate BP were enrolled. Ten (76.9%) achieved Complete remission (CR) within a mean of 7.4 weeks. BPDAI and NRSP significantly improved, with BPDAI scores decreased from 16.08 ± 9.00 at baseline to 1.23 ± 1.64 at week 16 and 0.23 ± 0.44 at week 52 (both p < 0.001). BP180 and total IgE also showed significant improvement. Two patients experienced relapse after discontinuing treatment. Comorbidities were generally well managed, though three patients passed away due to worsening comorbidities. One patient experienced mild drowsiness and erythema; no other dupilumab-related adverse events were observed. Conclusion Dupilumab demonstrates significant long-term efficacy and safety in super-elderly BP patients (≥80 years) with mild to moderate disease and multiple comorbidities, offering a promising alternative to traditional therapies.

Bullous pemphigoid is the most common bullous chronic autoimmune skin disease. Recent studies suggest dipeptidyl peptidase-4 inhibitors used in the treatment of type-2 diabetes as possible predisposing agents of bullous pemphigoid. It is thought to be important for primary care physicians, who are the most common referral point of patients and where drug use is examined in detail, to keep in mind that drugs such as dipeptidyl-peptidase-4 inhibitors may cause bullous pemphigoid and to refer to dermatology for early treatment. In this context, a 70-year-old female patient with a diagnosis of type 2 diabetes mellitus presented to our outpatient clinic with pruritic, erythematous bullous lesions diffusely distributed over the body, occurring one week after initiation of a vildagliptin-containing medication. There was no mucosal involvement. The patient initially received treatment with the presumptive diagnoses of allergy and scabies; however, as no improvement was observed, a detailed medical history was obtained. Based on the clinical findings, drug-induced bullous pemphigoid was suspected, and the vildagliptin-containing medication was discontinued. The patient was subsequently referred to the dermatology department. Histopathological examination and direct immunofluorescence findings were consistent with bullous pemphigoid. Following drug withdrawal and a short course of oral corticosteroid therapy, a marked improvement of the lesions was achieved. With this case, we aimed to draw attention to the approach of bullous pemphigoid disease developing as a result of vildagliptin use in a patient with type-2 diabetes who presented to primary care and to increase awareness on this issue.

Background The IL2RB gene encodes the beta subunit of the interleukin-2 (IL2) receptor, which transmits signals from the cytokines IL-2 and IL-15. IL2RB shows constitutive or induced expression on various types of immune cells, including CD4+ T regulatory cells, CD4+ and CD8+ T cells, B cells, and natural killer cells. IL2RB cytoplasmic domain is essential for JAK1/3 signaling. Biallelic loss-of-function variants typically cause autosomal recessive immunodeficiency. Here, we describe a patient with a novel heterozygous splice site variant and severe immune dysregulation. Methods Clinical evaluation and whole exome sequencing were performed. Variant classification followed the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. In silico predictions were used to assess the molecular consequences. Results A 4-year-old girl born to non-consanguineous parents presented with neonatal diabetes requiring insulin-pump therapy (anti-glutamic acid decarboxylase antibodies positive), autoimmune hypothyroidism (anti-thyroglobulin and anti-thyroperoxidase antibodies positive), autoimmune hemolytic anemia (direct Coombs positive), chronic diarrhea consistent with inflammatory bowel disease, and bullous pemphigoid (anti-bullous pemphigoid antibodies positive). This last manifestation was refractory to high-dose intravenous immunoglobulin, corticosteroids, dapsone, and rituximab, with only partial improvement; clinical stabilization was achieved after dupilumab plus palliative care. Whole exome sequencing identified a heterozygous IL2RB splice site variant (c.903+1G&amp;gt;T), absent from gnomAD and classified as likely pathogenic (PVS1, PM2). The variant disrupts the canonical donor site of intron 9, and in silico splicing predictors indicate activation of a cryptic donor site 26 nt upstream in exon 9, generating a frameshift and premature stop codon located within the last exon, thereby predicted to escape nonsense-mediated decay. The predicted truncated protein lacks most of the intracellular domain, likely compromising JAK1/3-mediated signaling. Conclusion This case raises the possibility of a dominant-negative or haploinsufficient mechanism of IL2RB-related disease. Functional studies are needed to confirm the impact on receptor signaling and clarify the inheritance pattern.

Infantile bullous pemphigoid (BP) can be an early manifestation of ZAP-70 deficiency, a rare combined immunodeficiency (CID) characterised by defective T-cell signalling and a propensity to multiple autoimmune manifestations.1 We describe two patients with BP subsequently diagnosed with ZAP-70 deficiency. Case 1: A female neonate presented at 14 days with severe seborrhoeic dermatitis. From 3 months she was repeatedly admitted with severe respiratory infections. Investigations revealed normal full blood count (FBC), but profoundly reduced CD8+ lymphocytes. At 7 months she developed an extensive bullous eruption. Skin biopsy with direct and indirect immunofluorescence confirmed the diagnosis of BP, which was difficult to control and required multiple systemic treatments, including methylprednisolone, dapsone, dupilumab, intravenous immunoglobulin and rituximab. She developed immune-mediated thrombocytopenia and is currently being prepared for bone marrow transplantation (BMT) due to ZAP-70 deficiency. Case 2: A female infant presented at 3 months with bullae of the face and extremities. Skin biopsy with direct and indirect immunofluorescence confirmed BP, which responded to topical corticosteroids and erythromycin. At 9 months she developed recurrent severe respiratory infections requiring ventilation. Laboratory studies showed near-absent CD8+ lymphocytes and confirmed ZAP-70 deficiency. She underwent BMT in June 2024, with no recurrence of blistering. Conclusion: Infantile BP should prompt suspicion of an underlying CID. Assessment of lymphocyte subsets is essential, as ZAP-70 deficiency is characterised by profoundly reduced CD8+ lymphocytes, which may not be apparent on a standard FBC where total lymphocyte numbers can be normal. Early -diagnosis is essential, as BMT offers the only curative -treatment.

Infantile bullous pemphigoid (IBP) usually presents at 3-5 months of age and resolves rapidly with appropriate therapy. Unfortunately, diagnosis and effective treatment are often delayed as in the case reported here. The paediatric dermatology team was called to the emergency department to see a 4-month-old girl with widespread tense vesicles, bullae and patchy erythema. The clinical diagnosis of IBP was confirmed by histology and direct immunofluorescence, and she was treated with erythromycin and prednisolone 0.5 mg/kg/day. Within 2 weeks all lesions were drying up and the steroid was discontinued after 8 weeks with no relapse. This child had first presented to the GP more than 3 weeks previously and as well as 3 GP visits had an admission to a paediatric ward with suspected hand, foot and mouth disease. Photographs were sent to the local dermatology team who advised treatment with flucloxacillin and acyclovir. She returned 2 days after discharge with continuing bullous lesions only to be reassured that it would settle in time. Three days later the GP referred her to Urgent Care and thence to our service. Although the diagnosis is straightforward for paediatric dermatologists, the rarity of IBP means that GPs and others may fail to recognize it and favor more common infectious diagnoses. It is likely that a paediatric dermatologist would recognize immune bullous disease even based on photographs. Faced with an unusual infantile rash, GPs and paediatricians should be encouraged to refer promptly, with photographs, to paediatric dermatologists who need to accommodate such referrals.

Bullous pemphigoid (BP) is a rare autoimmune blistering disorder in pediatric patients. Although various medications have been implicated as potential triggers, hypersensitivity reactions associated with Rivaroxaban, a direct Factor Xa inhibitor, are rarely documented. We present a case of an 8-year-old male who developed widespread BP after 3 months of Rivaroxaban therapy. Histopathological and immunofluorescence findings confirmed the diagnosis. Discontinuation of Rivaroxaban and administration of systemic corticosteroids led to rapid clinical improvement. This case highlights Rivaroxaban-induced BP as a potential adverse reaction in children and underscores the need for awareness and prompt management of this rare but treatable condition.

Autoimmune blistering diseases (AIBDs), including pemphigus diseases, pemphigoid diseases, linear immunoglobulin A (IgA) bullous dermatosis (LABD), epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (DH), are a group of diseases clinically characterized by erosions and blisters that involve the skin and mucosa. Tumor necrosis factor-alpha (TNF-α), a key inflammatory cytokine, plays a critical role in their pathogenesis. TNF-α inhibitors are used for their immunomodulatory effects but may also induce paradoxical autoimmune blistering. This systematic review aimed to synthesize current evidence on therapeutic and paradoxical effects of TNF-α inhibitors in these diseases. A systematic search of PubMed, Scopus, and Embase was conducted up to March 7th, 2025, following PRISMA guidelines. Studies eligible for inclusion were original human research articles in English reporting therapeutic or paradoxical effects of TNF-α inhibitors, including infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab, on autoimmune bullous diseases. Risk of bias was evaluated using the NIH and Murad et al. assessment tools. A total of 35 studies with 68 patients were included in the treatment application group and 29 studies with 31 subjects were included in the paradoxical reaction group. Infliximab was most frequently associated with favorable outcomes in pemphigus vulgaris (PV), bullous pemphigoid (BP), and EBA, with multiple reports of sustained remission. Etanercept showed partial to complete responses in some cases of PV and BP; however, it was associated with paradoxical induction of BP in several patients. Adalimumab demonstrated therapeutic efficacy in PV and MMP, yet was the most common agent implicated in paradoxical BP and LABD. Paradoxical effects were most often observed in patients treated for non-dermatologic conditions such as rheumatoid arthritis or Crohn's disease. TNF-α inhibitors, particularly infliximab, show therapeutic promise in refractory AIBDs. However, their potential to paradoxically induce blistering diseases,especially with adalimumab and etanercept,necessitates careful patient selection, close monitoring, and individualized risk-benefit assessment.

Bullous pemphigoid is a chronic autoimmune blistering disease characterized by subepidermal blisters and caused by autoantibodies against BP180 and BP230. Although type 2 inflammation is considered relevant to its pathogenesis, the full spectrum of immune dysregulation in BP remains incompletely defined. To comprehensively profile local and systemic inflammatory responses in BP and explore their potential associations with disease severity, clinical features and treatment outcomes. A total of 29 skin biopsies and 27 matched serum samples from patients with bullous pemphigoid, along with samples from 14 healthy controls, were analysed using the Olink Target 96 Inflammation panel. Analyses included principal component analysis, unsupervised clustering, differential expression, gene set enrichment and k-means clustering to define molecular subgroups. Proteomic data were further compared with a publicly available single-cell transcriptomic dataset from bullous pemphigoid skin for external validation. Proteomic analysis revealed distinct inflammatory signatures in bullous pemphigoid skin and sera compared to controls, with 22 and 16 differentially expressed proteins, respectively. CCL13, IL-6, OSM, TNFSF14 and CCL19 were significantly elevated in both compartments. Cutaneous CCL13, expressed mainly by keratinocytes, strongly correlated with the bullous pemphigoid disease activity index score and autoantibody titres. Two molecular skin clusters were identified, with one showing broader, predominantly type 2 inflammatory activation and significantly higher titres of BP180-IgG antibodies. CCL13 was a major driver of cluster separation. Higher baseline serum IL22RA1 levels were observed in non-responder patients at 1-year follow-up. Proteomic findings showed high concordance with transcriptomic data derived from publicly available single-cell RNA sequencing of bullous pemphigoid lesional skin. CCL13 was among the most prominent inflammatory proteins identified in bullous pemphigoid. The emergence of two distinct skin proteomic clusters highlights a biological heterogeneity of bullous pemphigoid, indicating the need for endotype-driven, personalized treatment strategies.

Eccrine syringofibroadenoma was initially described by Mascaró in 1963 as a possible "eccrine" counterpart of Pinkus fibroepithelioma. Later, Nomura et al, reported a case of bullous pemphigoid associated to syringofibroadenomatous hyperplasia of the palms and soles, suggesting that this entity corresponds to hyperplasia of the eccrine ducts rather than a true neoplasm. There are currently numerous publications that support this hypothesis, describing similar changes induced by different alterations of the papillary dermis, either associated to inflammatory reactions or even neoplastic diseases. Despite the fact that these changes are already well-known, there are very few published cases of this condition in its subungual location. We believe that it is important to highlight this information so dermatologists and pathologists can include it among their differential diagnoses. Histopathological findings can be very subtle, and if not known, they can go unnoticed, leading to a nonspecific diagnosis, creating uncertainty for both the patient and the treating physician.

Bullous pemphigoid (BP), the most prevalent autoimmune blistering skin disorder, has been associated with dipeptidyl peptidase-4 inhibitor (DPP4i) treatment in type 2 diabetic patients. This study aimed to investigate the association of DPP4 gene variants, rs3788979 and rs12617656, with classic BP (cBP)- and DPP4i-associated BP predisposition. Fifty-six (56) unrelated patients with cBP, 32 DPP4i-associated BP patients, 60 healthy controls, and 49 diabetic patients receiving DPP4i were included. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). Statistical analyses were conducted using SPSS software. For rs3788979, the CT+TT genotypes were significantly associated with increased risk of DPP4i-associated BP compared with cBP [(Odds Ratio (OR) = 2.80, 95% Confidence Interval (CI) = 1.07–7.35; p-value = 0.034] and healthy controls (OR = 0.30, 95% CI = 0.13–0.86; p-value = 0.020). The T allele was also enriched in DPP4i-associated BP (OR = 2.57, 95% CI = 1.09–6.07; p-value = 0.027). Additionally, the TC genotype of rs12617656 (OR = 2.29, 95% CI = 1.04–5.03, p-value = 0.039) showed significant association with cBP susceptibility. These findings highlight DPP4 variants as potential BP risk factors, supporting personalized risk assessment prior to initiating gliptin therapy. Large-scale studies are warranted to validate these associations.

Recently, dipeptidyl peptidase4 inhibitors (DPP4i), a group of drugs used for the treatment of diabetes mellitus, have been associated with an increased risk of bullous pemphigoid (BP). Several studies previously found clinical and laboratory differences between patients with gliptin-induced BP and conventional BP, and some authors accept DPP4i-induced BP as a separate entity. In this retrospective study, we aimed to compare clinical and laboratory characteristics, comorbidities, and medications used simultaneously with gliptins in these two groups of BP. Patients with the diagnosis of BP hospitalized in our clinic between 2010 and 2023 were included in this retrospective cross-sectional study. Demographic, clinical, laboratory data, comorbidities, and additional medications were recorded for each patient. Patients were divided into DPP4i-associated and conventional BP groups, and the data were compared between the two groups. A total of 105 patients with BP, of which 11 were DPP4i-associated, were included. There was no statistically significant difference in age, age at onset, gender distribution, lesion distribution, histopathological, and laboratory findings between the two groups. The median use of DPP4i before BP onset was 3months (1-12). Disease and follow-up duration were shorter in the gliptin-associated group. DPP4i-induced patients had a higher frequency of severe disease and presentation with a prebullous phase. Cardiovascular disorders, hypertension, hyperlipidemia, the use of angiotensin receptor blockers (ARB), and statins were significantly higher in the gliptin-using patients. This is one of the first studies to compare demographic, clinical, and laboratory characteristics of patients with gliptin-induced and conventional BP. Our results suggest gliptin-associated BP may present with more severe disease. Hyperlipidemia, ARB, and statin use may be associated with DPP4i-induced BP. Although larger studies are warranted to confirm this association, we believe these findings should be kept in mind while choosing patients to treat with gliptins.

041 Eosinophil-derived neurotoxin and eosinophil cationic protein are key molecules for blister formation in bullous pemphigoid

022 DPP4 and its inhibition has no impact on disease progression and severity in a bullous pemphigoid like mouse model

016 Identification of skin-based therapeutic targets in regular and gliptin-associated bullous pemphigoid via transcriptomics

004 Basophils orchestrate bullous pemphigoid inflammation by promoting myeloid cell networks

055 The immuno-phenotype of immune checkpoint induced Bullous pemphigoid: a cohort study

Bullous pemphigoid triggered by axitinib treatment for clear cell renal carcinoma: A novel cutaneous adverse event