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Importance: The correlation between serum levels of autoantibodies against bullous pemphigoid (BP) antigens 180 (BP180) and 230 (BP230) with BP disease severity is unclear., Objective: To investigate the correlation of anti-BP180 and anti-BP230 immunoglobulin G (IgG) antibody levels with BP disease severity., Data Sources: A search was performed of the Cochrane Central Register of Controlled Trials, Embase, and PubMed databases from their respective inception to April 11, 2024., Study Selection: Studies evaluating the correlation between serum levels of anti-BP180 or anti-BP230 IgG measured using enzyme-linked immunosorbent assay (ELISA) and disease severity assessed per the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) or BP Disease Area Index (BPDAI) were included. No language or geographic restrictions were imposed. Nearly 0.4% of initially identified studies met the selection criteria., Data Extraction and Synthesis: One researcher extracted data and another researcher confirmed data. The risk of bias was independently assessed by these researchers using the Quality Assessment of Diagnostic Accuracy Studies 2 tool, with discrepancies resolved by discussion with a third researcher. A random-effects model meta-analysis and a subgroup analysis were conducted based on the ELISA kit manufacturers., Main Outcomes and Measures: Pooled correlation coefficients of antibody levels with ABSIS and BPDAI., Results: In all, 14 studies with 1226 participants were analyzed. The risk of bias of included studies was generally low. The meta-analysis found anti-BP180 autoantibody levels showed moderate correlation with objective BPDAI (r = 0.56; 95% CI, 0.46-0.64) at baseline, strong correlation (r = 0.63; 95% CI, 0.39-0.79) at 3-month follow-up, and moderate correlation (r = 0.53; 95% CI, 0.25-0.72) at 6-month follow-up. Anti-BP180 autoantibody levels also showed moderate correlation (r = 0.52; 95% CI, 0.39-0.62) with ABSIS at baseline, strong correlation (r = 0.62; 95% CI, 0.39-0.79) at 3-month follow-up, and moderate correlation (r = 0.53; 95% CI, 0.25-0.72) at 6-month follow-up. By contrast, anti-BP230 autoantibody levels showed no association with objective BPDAI and ABSIS at diagnosis and follow-up. The subgroup analysis found similar results when using different ELISA kits., Conclusions and Relevance: The findings of this systematic review and meta-analysis indicated that anti-BP180 autoantibody levels may serve as an adjunctive tool for monitoring BP disease severity and guiding clinical care for patients with BP.

Background: Dupilumab, a novel therapy targeting the T helper (Th) 2-mediated inflammation, is showing clinical benefits in treating bullous pemphigoid (BP). However, limited research investigated the serum biomarkers that reflect the inflammation alterations throughout the disease course., Objectives: To explore the changes of the serum inflammatory biomarkers under dupilumab therapy in BP and establish their correlations with disease severity and clinical outcomes., Methods: This exploratory study evaluated serum samples from 40 patients with BP at baseline, 30 of these patients following 16-week dupilumab therapy, and 20 senior healthy controls. Serum levels of 29 cytokines and chemokines were quantified using the Magnetic Luminex Assay., Results: Two distinct clusters based on serum inflammatory profiles were identified. The first cluster, characterized by elevated levels of inflammatory activation, exhibited worse disease severity and poorer remission outcomes. Following the 16-week dupilumab therapy regimen, a significant suppression of Th2-mediated inflammation in the serum was observed, alongside a relative upregulation of Th1 responses. Patients treated with adjuvant systemic steroids exhibited an enhanced suppression of B cell activating factor compared to those receiving dupilumab alone. Significant correlations were unveiled between Th2 biomarkers and clinical scores, eosinophil counts, and anti-BP180 immunoglobulin G levels. Baseline levels of CCL18, Periostin, interleukin (IL)-6, and IL-16 constitute an optimal combination to distinguish between inflammatory clusters., Conclusions: Cluster analysis of serum inflammatory biomarkers provided novel insights into the heterogeneity of the inflammation profiles in BP. Baseline levels of CCL18, Periostin, IL-6, IL-16 emerged as effective predictors for disease severity and therapy response to dupilumab., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2024 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

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, T h 2 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 T h 2, eosinophil and coagulation cascade activity may be contributory., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CS has received honoraria from Abbvie, Leo, Pfizer, Miravo, Novartis, UCB, Sanofi/Regeneron unrelated to this work. RGS has received honoraria from Perfuse, Quart Medical, Novartis, Medexus Pharmaceuticals Canada along with Ontario Gov’t Project ECHO Ontario Skin & Wound—Ministry of Health and Micro-credentials—through Ministry of Colleges and Universities and Sault College all unrelated to this work. RSQG, EW, and BW have no conflicts of interest to disclose.

Background: Bullous pemphigoid (BP) is a severe autoimmune sub-epidermal bullous disease. Exosomes are small extracellular vesicles secreted by most cell types. The exosomal membrane proteins are implicated in various biological and pathological pathways. This study aims to explore the potential roles of exosomes in BP pathomechanism., Research Design: We collected plasma samples from 30 BP patients and 31 healthy controls. Nanoparticle tracking analysis (NTA) was used to analyze the size and concentration of exosomes. The immunogold labelling experiment and extracellular vesicle (EV) array were performed to detect the content and distribution of exosomes., Results: The exosomes from both the BP and control groups' plasma were successfully extracted. EV Array showed that CD63 and CD9 levels were significantly higher in the BP group than in the control group ( p  < 0.05). Expression levels of the BP180 NC16A and intracellular domain (ICD) were higher in the anti-BP180 positive group versus the controls ( p  < 0.05). The active BP group exhibits higher CD63 and BP180 ICD protein concentrations than the control or inactive BP groups ( p  < 0.05)., Conclusion: BP180 autoantigen fragments were expressed on the exosomal membrane in BP patients. The BP180 ICD and CD63 on exosomes could potentially be novel biomarkers for monitoring disease activity.

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., (© 2024 The Author(s). Experimental Dermatology published by John Wiley & Sons Ltd.)

Background: Bullous pemphigoid (BP), the most common subepidermal autoimmune blistering disease, is classically defined by the presence of IgG autoantibodies directed against the hemidesmosomal proteins BP180 (type XVII collagen) and BP230 and the predominance of skin lesions. Several studies have addressed the role of anti-BP180 IgE in patients and experimental models, while data on anti-BP230 IgE are scarce., Objective: To assess anti-BP230 IgE level by ELISA in BP sera and to correlate it with disease severity and clinical characteristics., Methods: BP sera underwent anti-BP230 IgE ELISA and Western blotting against human BP230 fragments., Results: We demonstrate that 36/154 (23%) of BP sera were positive for anti-BP230 IgE. Anti-BP230 IgE levels had no correlation with clinical phenotype or disease activity per se. Interestingly, anti-BP230 IgE was significantly associated with disease activity within individuals during the course of the disease. Additionally, anti-BP230 IgE and total IgE levels showed a significant correlation. Notably, anti-BP230 IgG correlated interindividually with disease activity. By Western blotting, the C-terminal domain of BP230 fragments (C2; amino acids 2024-2349 and C3; amino acids 2326-2649), provided the best serological assay for anti-BP230 IgE detection., Conclusion: As a complementary tool, IgE immunoblotting is recommended to obtain an optimal serological diagnosis, particularly in patients with severe disease without IgG reactivity by BP180- or BP230-specific ELISA. Although the detection of serum anti-BP230 IgE is not of major diagnostic significance, it may be relevant for therapeutic decisions, e.g., for anti-IgE-directed treatment, which has been successfully used in case series of BP., Competing Interests: Declaration of Competing Interest ES has research grants from Euroimmun. ES holds patents with Euroimmun. ES and NvB have a joint research project and a patent pending with Euroimmun. The other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Bullous pemphigoid (BP), the most frequent blistering dermatosis in the elderly, is associated with increased mortality. The severity of BP can be assessed by detecting the anti-BP180 immunoglobulin G (IgG) concentration, but the lab test is not available in many community clinics. BP patients are usually in a hypercoagulable state with increased levels of D-dimer and fibrin degradation products (FDPs). We aimed to evaluate the use of D-dimer and FDPs in assessing BP severity. We compared the levels of plasma D-dimer, plasma FDPs, eosinophil counts, eosinophil cationic protein, and serum anti-BP180 IgG concentration between 48 typical BP patients and 33 Herpes zoster (HZ) patients (control group). Correlational analyses were conducted to determine the relationships between the lab values and common BP severity markers. The plasma D-dimer and FDP levels were higher in BP patients than in HZ controls (D-dimer: 3297 ± 2517 µg/L vs. 569.70 ± 412.40 µg/L; FDP: 9.74 ± 5.88 mg/L vs. 2.02 ± 1.69 mg/L, respectively, P < 0.0001). Significant positive correlations were found between D-dimer/FDP levels and BP severity markers (i.e. anti-BP180 IgG concentration [D-dimer: r = 0.3928, P = 0.0058; FDP: r = 0.4379, P = 0.0019] and eosinophil counts [D-dimer: r = 0.3625, P = 0.0013; FDP: r = 0.2880, P = 0.0472]) in BP patients. We also found an association between FDP and urticaria/erythema lesions (r = 0.3016, P = 0.0372), but no other BPDAI components. In 19 BP patients with complete remission after systemic glucocorticoid treatment, D-dimer and FDP levels decreased post-therapy (D-dimer: 5559 ± 7492 µg/L vs. 1738 ± 1478 µg/L; P < 0.0001; FDP: 11.20 ± 5.88 mg/L vs. 5.13 ± 3.44 mg/L; P = 0.0003), whereas they did not in BP patients with treatment resistant. Plasma D-dimer and FDP are convenient markers to evaluate BP severity assistant on BPDAI and eosinophil counts. FDP is also helpful for inflammatory lesions in BP patients., (© 2021. The Author(s).)

Background: The clinical and immunological profile of patients with dipeptidyl peptidase-4 inhibitor (DPP4i)-associated bullous pemphigoid (BP) is inconsistent in the current literature., Objectives: The aims were to investigate the clinical and immunological features of patients with DPP4i-associated BP and to examine whether there are intraclass differences between different DPP4i agents., Methods: A retrospective cohort study was conducted, including all consecutive patients diagnosed with BP throughout the years 2009-2019 in a tertiary referral center., Results: The study encompassed 273 patients with BP (mean age at diagnosis 79.1 ± 9.9 years), of whom 24 (8.8%) were associated with DPP4i. Sitagliptin was the prescribed agent for 17 patients (70.8%), and vildagliptin was prescribed in seven patients (29.2%). Relative to other patients with BP, patients with DPP4i-associated BP had more prominent truncal involvement (95.8% vs. 73.9%; P = 0.017), greater erosion/blister Bullous Pemphigoid Disease Area Index (BPDAI) subscore (29.8 ± 17.4 vs. 20.6 ± 14.4; P = 0.018), and lower levels of anti-BP180 NC16A (279.2 ± 346.1 vs. 572.2 ± 1352.0 U/ml; P = 0.009) and anti-BP230 (25.5 ± 47.8 vs. 128.6 ± 302.9 U/ml; P = 0.009) antibodies. Relative to patients with sitagliptin-associated BP, those with vildagliptin-associated BP had a lower seropositivity rate (57.1% vs. 94.1%, P = 0.031) and lower levels (96.7 ± 139.0 vs. 354.5 ± 376.5; P = 0.023) of anti-BP180 NC16A antibodies, and tended to present with higher erosion/blister BPDAI subscore (36.3 ± 9.6 vs. 25.8 ± 19.7; P = 0.095)., Conclusions: DPP4i-associated BP is characterized by a more severe blistering and erosive presentation despite lower levels of typically pathogenic antibodies.

iNKT (invariant natural killer T) cells are unconventional immunoregulatory T cells which contribute to B cell maturation, antibody and cytokine production. iNKT cells are implicated in the control of autoimmune inflammation in different disorders. For bullous pemphigoid (BP), the most frequent bullous autoimmune dermatosis, the role of iNKT cells has not yet been studied. We, therefore, aimed at investigating the frequency of iNKT cells in peripheral blood and biopsies from lesional and non-lesional skin from patients with BP and controls. Circulating CD3 + iTCR + iNKT cells were assessed by flow cytometry in peripheral blood from 30 patients with BP and from 29 controls (19 patients with skin tumors and 10 healthy controls). In 34 lesional and 13 non-lesional skin biopsies from BP patients and 17 biopsies from control individuals the number of Vα24 + Vβ11 + iNKT cells was investigated by immunofluorescence staining. BP patients showed a significantly lower frequency of circulating iNKT cells compared to the control group. Patients with severe disseminated blistering tended to display lower iNKT cell numbers than patients with moderate disease severity. In lesional skin of BP patients, an enrichment of iNKT cells was detected compared to skin biopsies from controls. Similarly to control biopsies, non-lesional biopsies of BP patients contained only few iNKT cells. In conclusion, the deficiency of circulating iNKT cells associated with enrichment at the site of cutaneous inflammation suggests that iNKT cells may play a pathophysiologically relevant role in BP.

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by recruitment of leucocytes into skin and release of damaging enzymes, resulting in epidermal detachment and blister formation. To better understand the role of leukotriene B4 (LTB4) and other inflammatory factors in BP pathophysiology, we conducted microscopic and immunohistochemical analyses of preserved skin biopsy sections and conducted flow cytometry and ELISA analyses of matched blood and blister fluid from BP patients. Neutrophils predominated in BP blister fluid, which also contained monocytes/macrophages and T cells, but few to no eosinophils and B cells. In contrast, BP skin histology showed a different pattern, with abundant neutrophils but eosinophils being the predominant immune cell type. LTB4 pathway and neutrophil activation markers were prevalent in BP skin lesions and strongly associated with perivascular neutrophils. Blister fluid neutrophils, monocytes/macrophages and eosinophils all exhibited increased surface expression of leukotriene A4 hydrolase and neutrophil elastase (P = .002 for both). Blister fluid was also enriched in interleukins (IL)-1α, IL-1β, IL-8, IL-10, IL-18, monocyte colony-stimulating factor (M-CSF) and vascular endothelial growth factor (VEGF). Our findings suggest differential leucocyte recruitment from blood into dermis and from dermis into blister, which correlates with disease activity, and presents potential new treatment opportunities for BP., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: TH17/IL-23 immune axis is considered to be involved in the pathogenesis of autoimmune and chronic inflammatory diseases. Bullous pemphigoid (BP) is the most frequent autoimmune blistering disease, characterized by the presence of autoantibodies against the components of the dermal-epidermal junction. Animal studies and characterization of patient samples point toward a contribution of TH17 cells in BP pathogenesis. However, genetic polymorphisms in the genes of TH17/IL-23 cytokines have not yet been well investigated in BP., Methods: Detection of polymorphisms in IL-17A (rs2275913 and rs3819025), IL-17F (rs2397084 and rs763780), IL-17RA (rs2229151), and IL-23R (rs2201841, rs7530511, rs11209026, and rs10889677) genes were performed following the collection of blood samples and DNA extraction from BP patients and controls. Gene expression of IL-23R was determined by quantitative RT-PCR analysis., Results: The prevalence of IL-23R rs7530511 genotypes and alleles, as well as IL-23R rs2201841 alleles, is significantly different between the BP patients and controls. While the minor C-allele of IL-23R rs7530511 is highly present in the patients, the G-allele distribution of IL-23R rs2201841 is significantly more prevalent in the control individuals compared to the BP patients. Genotypes and alleles of other SNPs in IL-17A, IL-17F, and IL-17RA were similarly distributed in patients and controls., Conclusions: No alteration was found in the gene expression between wild and polymorphic genotypes of IL-23R (rs2201841 and rs7530511) variations, indicating they do not contribute to altering the levels of gene expression in blood. In summary, our data show that the alleles of two SNPs in IL-23R rs2201841 and rs7530511 are associated with BP., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: The current standard in the serologic diagnosis of autoimmune bullous diseases (AIBD) is a multistep procedure sequentially applying different assays. In contrast, the BIOCHIP Mosaic technology combines multiple substrates for parallel analysis by indirect immunofluorescence., Methods: Sera from 749 consecutive, prospectively recruited patients with direct immunofluorescence-positive AIBD from 13 international study centers were analyzed independently and blinded by using (1) a BIOCHIP Mosaic including primate esophagus, salt-split skin, rat bladder, monkey liver, monkey liver with serosa, recombinant BP180 NC16A, and gliadin GAF3X, as well as HEK293 cells expressing recombinant desmoglein 1, desmoglein 3, type VII collagen, and BP230 C-terminus and (2) the conventional multistep approach of the Department of Dermatology, University of Lübeck., Results: In 731 of 749 sera (97.6%), specific autoantibodies could be detected with the BIOCHIP Mosaic, similar to the conventional procedure (725 cases, 96.8%). The Cohen κ for both serologic approaches ranged from 0.84 to 1.00. In 6.5% of sera, differences between the 2 approaches occurred and were mainly attributed to autoantigen fragments not present on the BIOCHIP Mosaic., Limitations: Laminin 332 and laminin γ1 are not represented on the BIOCHIP Mosaic., Conclusions: The BIOCHIP Mosaic is a standardized time- and serum-saving approach that further facilitates the serologic diagnosis of AIBD., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Although T cells are considered as the central component in immune-mediated diseases, supportive evidence has demonstrated that B cells also contribute to the progression of these diseases. B cells are divided into various subsets according to their secreted cytokines. Different B cell subsets play diverse roles in immune-mediated dermatoses. Regulatory B cells (Bregs) are defined functionally by their ability to secrete IL-10, which has been revealed to contribute to immunological tolerance. Drugs that deplete B cells, such as rituximab, are now used for the treatment of several immune-mediated dermatoses. In this review, we present and discuss the current knowledge on the roles of B cells in several immune-mediate dermatoses including psoriasis, pemphigus, bullous pemphigoid, and dermatomyositis, atopic dermatitis., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Regulatory T (Treg) cells play an essential role in peripheral immune tolerance. Bullous pemphigoid (BP) is the most common blistering disease and is caused by autoantibodies to two BP antigens: type XVII collagen and BP230. Recently, we reported that Treg cell dysfunction may cause the production of autoantibodies to BP antigens. Several studies have suggested an association between Treg cells and BP pathogenesis. However, Treg cells are heterogeneous in humans, leading to inconsistent results in previous studies., Objective: To assess functional Treg subsets in BP., Methods: We examined three distinct Treg subsets in conventional BP (cBP) patients before versus after systemic corticosteroid treatment, dipeptidyl peptidase-4 inhibitor-associated BP (DPP-4i-BP) patients, younger controls and older controls., Results: We found that total Treg cells and all Treg cell subsets were increased in cBP patients before treatment and decreased by systemic corticosteroid treatment. In contrast, neither total Treg cells nor all Treg subsets were increased in DPP-4i-BP. Notably, CD45RA - Foxp3 hi effector Treg cells positively correlated with disease severity in cBP, whereas CD45RA + Foxp3 lo naïve Treg cells positively correlated with the disease severity in DPP-4i-BP., Conclusion: These findings suggest that Treg cells are differently involved in the pathogeneses of cBP and DPP-4i-BP., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of coeliac disease (CD). Patients with DH have an elevated risk of development of another autoimmune blistering skin disease, bullous pemphigoid (BP). In this study we investigated whether patients with DH and CD (mean age for both 49 years) have circulating autoantibodies against BP180, the major BP autoantigen. ELISA tests showed that only a few DH (3/46) and CD (2/43) patients had BP180-NC16A IgG autoantibodies. Immunoblotting found that more than half of the DH samples contained IgG autoantibodies against full-length BP180. Epitope mapping with 13 fusion proteins covering the BP180 polypeptide revealed that in DH and CD patients, IgG autoantibodies did not target the NC16A or other epitopes typical of BP but recognized other intracellular and mid-extracellular regions of BP180. None of the analyzed DH and CD patients with either ELISA or immunoblotting positivity had IgG or IgA reactivity against the cutaneous basement membrane in indirect immunofluorescence analysis or skin symptoms characteristic of BP. Although only a minority of middle-aged DH patients had IgG autoantibodies against the immunodominant epitopes of BP180, our results do not exclude the possibility that intermolecular epitope spreading could explain the switch from DH to BP in elderly patients., (Copyright © 2020 Nätynki, Tuusa, Hervonen, Kaukinen, Lindgren, Huilaja, Kokkonen, Salmi and Tasanen.)

Background: Paraneoplastic pemphigus (PNP) is a devastating autoimmune multiorgan syndrome associated with autoantibodies against several autoantigens, including the alpha-2-macroglobulin-like-1 (A2ML1). A2ML1 is recognized by up to 70 % of PNP sera. The currently recommended techniques for serological diagnosis of PNP are inadequate to detect anti-A2ML1 antibodies., Objectives: To develop novel assays which allow to easily and reliably detect anti-A2ML1 autoantibodies in PNP sera., Methods: We produced full-length A2ML1 in fusion with enhanced green fluorescent protein (EGFP-A2ML1) in transfected human embryonic kidney 293 T cells. The recombinant protein was used as fluorescent ligand for immunoprecipitation studies. We further developed an enzyme-linked immunosorbent assay (ELISA) by immobilizing EGFP-A2ML1 on 96-well plates., Results: A2ML1-positive PNP sera were able to immunoprecipitate EGFP-A2ML1. Direct measurement of fluorescence in immunoprecipitates correlates with the relative levels of anti-A2ML1 antibodies in the PNP sera. By the novel ELISA, based on the determined best cut-off value, 61 % of the tested 36 PNP sera were A2ML1 positive with a specificity of 88.9 % and a sensitivity of 95 %. The 20 tested normal sera (NHS) were negative, while 2 (10 %) of 20 pemphigus vulgaris and 3 (15 %) of 20 bullous pemphigoid sera showed borderline values., Conclusions: Our novel immunoassays enable rapid stratification of PNP patients. The novel green fluorescent protein-based ELISA utilizing an active eukaryotic A2ML1 is highly sensitive and reliable and, hence, is useful for a better understanding of the immunological background of PNP. This approach may be easily applied for the rapid detection of antibodies to various other antigens., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Bullous pemphigoid (BP) has been associated with dipeptidyl peptidase-4 inhibitors (DPP4i). Clinical features, outcomes, and risk of BP for new DPP4i (linagliptin, saxagliptin, and alopgliptin) are not well established. Comparison of risk of BP appearance for DPP4i and other oral antidiabetic drugs (OADs) such as sodium glucose cotransporter 2 inhibitors has not been studied to date., Objectives: To describe the prevalence, sociodemographic, clinical, and histopathological characteristics, and outcome after drug withdrawal in DPP-4i-associated BP cases from our hospital. To review all Spanish spontaneous notifications of BP where DPP4i or OADs were included as suspected drugs and calculate the reporting odds ratios (RORs)., Methods: A retrospective observational study was performed examining the association between DDP4i and BP. Clinical features and RORs were analyzed. Data from the Spanish Pharmacovigilance System (SEFV) are included., Results: In our center, 28 of 89 patients with BP (31.5%) were under DPP4i treatment; 53.6% were male, and mean age was 80.8 years. BP debuted the first year after DPP4i in 57.2%. BP control was achieved within 3.7 months after drug withdrawal. Regarding SEFV, 22 of 972 spontaneous notifications were related to BP and DPP4i. RORs were superior for DPP4i compared to other OADs. Vildagliptin had the highest ROR., Conclusions: We present the largest DPP4i-induced BP case series in a single center, with a detailed study of the sociodemographic, clinical, and histopathological characteristics of each patient, and their treatment and outcome. Vildagliptin had the highest risk. DPP4i-associated BP does not seem to have specific clinical characteristics., (© 2019 The International Society of Dermatology.)

Background: Bullous pemphigoid (BP) is a common T helper 2- (Th2-) dominated autoimmune blistering skin disease with significant mortality. MicroRNAs (miRNAs), which are endogenous noncoding RNA molecules, have been reported to be potential biomarkers for some autoimmune diseases; however, to date, there exist no reports on serum expression profiles of miRNAs in BP patients., Methods: A RNA quantitative PCR- (qPCR-) based array was conducted on sera from 20 active BP patients and 20 healthy controls for screening of miRNAs. Significantly dysregulated miRNAs were validated with use of qPCR as performed on sera samples of 45 active BP patients and 60 healthy controls. Serum CCL17, anti-BP180, and anti-BP230 levels were measured with use of ELISA., Results: Relative baseline expression levels of serum miR-1291 were significantly upregulated in the 45 BP patients as compared with the 60 healthy controls ( P < 0.001) and significantly decreased in the disease control stage ( n = 13, P = 0.006). In addition, these baseline miR-1291 levels showed a significant positive correlation with the baseline levels of serum CCL17 ( P < 0.001) and anti-BP180 ( n = 38, P = 0.024). Like that observed for miR-1291, baseline levels of serum CCL17 were also significantly elevated in the 45 BP patients compared with the 60 healthy controls ( P < 0.001) and significantly decreased in the disease control stage ( n = 13, P = 0.002). However, for anti-BP180, baseline serum levels were significantly elevated in only 38 of the 45 BP patients and significantly decreased in the disease control stage ( n = 10, P = 0.004)., Conclusions: Relative expression levels of serum miR-1291 can reflect disease activity of BP. miR-1291 may function as an important new serum biomarker for BP., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Li Qiu et al.)

A male neonate was born with blisters on the trunk to a 37-year-old primigravid woman with a past medical history of recurrent, painful, topical steroid-responsive oral blisters. The diagnosis of neonatal pemphigus was made after the neonate and mother were found to have elevated desmoglein 3 (Dsg3) antibodies in conjunction with histopathologic features of pemphigus vulgaris. Interestingly, both neonate and mother also had elevated levels of BP180 antibodies, classically seen in bullous pemphigoid. This case is unique in that it portrays neonatal pemphigus, an already rare condition, complicated by the presence of BP180 antibodies., (© 2019 Wiley Periodicals, Inc.)

Background: Bullous pemphigoid (BP) is a distressing autoimmune bullous disease strongly associated with severe pruritus; however, data concerning pruritus in BP are still scarce. No clinical research evaluating the effect of BP on sleep quality has been conducted., Aim: To evaluate the intensity of pruritus measured by nocturnal wrist movements (NWMs) and the sleep quality in patients with BP using actigraphy in comparison with nonpruritic healthy controls (HCs) with subsequent correlations with an itch visual analogue scale (VAS) as a subjective measure, disease severity [Bullous Pemphigoid Disease Area Index (BPDAI), urticaria/erythema, erosions/blisters] and serum total IgE level., Methods: In total, 31 patients with newly diagnosed BP (mean ± SD age 75.4 ± 12.3 years) and 40 nonpruritic HCs (age 73.5 ± 11.7 years) were recruited. All participants wore a sleep monitor (ActiSleep+) on the dominant wrist., Results: For patients with BP, median VAS score was 5.5 and median BPDAI was 43 (urticaria/erythema BPDAI was 16, erosions/blisters BPDAI was 29). Scratching, defined as bouts of NWMs, was significantly (P < 0.001) more intensive in patients with BP than in controls. Characteristic of BP was that scratching bouts corresponded with the slowest wrist movements. There were no correlations with VAS, BPDAI or total IgE level. Compared with HCs, patients with BP presented significant (P < 0.001) sleep disturbances, as determined by sleep efficiency, waking after sleep onset and average duration of awakening, and these were strongly correlated with urticaria/erythema BPDAI., Conclusion: Nocturnal wrist movements measured by actigraphy are more intensive in patients with BP than in nonpruritic HCs, and characteristically slow movements. Actigraphy method showed very low sleep quality in patients with BP, thus severity of BP has a negative impact on sleep., (© 2019 British Association of Dermatologists.)

Bullous pemphigoid (BP) is an autoantibody-mediated blistering disease that is often associated with neurologic disease. BP antibodies target two epidermal adhesion molecules, known as BP180 and BP230. Homologues to these proteins are found in the brain, and it is hypothesized that neurologic disease leads to the production of autoantibodies that can cross-react with their cutaneous forms. To better understand the link between BP and neurologic disease, we evaluated primary demographic features (age, sex, race, ethnicity, and elapsed time between onset of skin symptoms and BP diagnosis), severity of BP, and IgG and IgE autoantibody levels in BP control individuals and patients with BP with preceding Parkinson disease, dementia, and stroke. The main findings of this study are that patients with BP with preceding neurologic disease have a shorter elapsed time between onset of skin disease and BP diagnosis and that patients with preceding Parkinson disease or dementia, but not stroke, are significantly older than patients with BP without neurologic disease. However, no significant differences in clinical presentation, BP severity scores, or autoantibody (IgG and IgE) responses were observed among the groups. These findings suggest that, despite the age difference, the clinical phenotype of BP is not affected by preceding neurologic disease., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Bullous pemphigoid (BP) autoantibody levels are generally elevated in patients with BP but can be present nonspecifically in patients without BP., Objective: To analyze the clinical findings of patients with elevated BP180 or BP230 autoantibody levels and negative direct immunofluorescence (DIF) study findings., Methods: We retrospectively reviewed records of patients seen at our institution during January 1, 2005-December 31, 2015, who were positive for BP180 or BP230 autoantibodies and had a negative DIF study finding. These patients' demographic characteristics and BP180 and BP230 levels were compared with those of a BP control group who were positive for BP180 or BP230 autoantibodies and had positive DIF study findings., Results: We identified 208 patients with BP autoantibodies but without positive DIF study findings. These patients' mean age and enzyme-linked immunosorbent assay values were significantly lower than those of the control group. Dermatitis was the most common final clinical diagnosis. Of the 208 patients, 41 (19.7%) had at least 2 years' follow-up. Four patients had positive DIF results upon repeating the test and ultimately received pemphigoid diagnoses., Limitations: Retrospective design with limited follow-up., Conclusion: Patients might harbor serum BP autoantibodies in the context of a wide range of dermatoses. Low positive BP180 and BP230 autoantibody levels should not be overinterpreted as evidence for BP in the setting of a negative DIF., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Higher vitamin D status has been associated with symptom improvement and decreased risk of various autoimmune disorders. Our objective was to determine whether higher serum 25-hydroxyvitamin D (25OHD) concentration correlated with less severe first-diagnosed bullous pemphigoid (BP) in older inpatients., Methods: This cross-sectional study was performed from November 2012 to February 2014 among 30 consecutive older inpatients (21 women; mean ± SD, 83 ± 7 years; all Caucasian) with a de novo diagnosis of active BP recruited in the Department of Dermatology of Angers University Hospital, France. The severity of BP was graded clinically on the basis of i) the number of bullae during the first three days of hospitalization (grade 0-4, worse), and ii) the extent of the lesions (grade 0-5, worse)., Results: Sixteen participants had ≤ 5 bullae at the time of diagnosis, 8 had 6-20 bullae, 3 had 20-50 bullae, and 3 had >50 bullae. The lesions were spread over 5 cutaneous areas in 5 participants (17%). The median 25OHD concentration was 23 [IQR, 16-42] nmol/L. Serum 25OHD concentration was inversely correlated with the bullae grade (ρ = - 0.38, p = 0.04) and the lesion extension grade (ρ = - 0.50, p = 0.005)., Conclusions: Higher serum 25OHD concentration correlated with less severe BP prior to initiation of treatment among our sample of older inpatients. This result suggests that vitamin D may be involved in the pathophysiology of BP and could serve as prognostic biomarker of BP., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Anti-hyperglycemic drug dipeptidyl peptidase-IV inhibitors (DPP-4i) have recently been recognized as bullous pemphigoid (BP) inducing drugs. It remains uncertain whether DPP-4i induce BP-IgG autoantibodies before the onset of BP. Objective: To evaluate the effect of DPP-4i in the development of BP-IgG autoantibodies in type 2 diabetes mellitus (T2DM) patients. Methods: A cross-sectional study on 221 DPP-4i (+) and 54 DPP-4i (-) T2DM cases was conducted. BP180 NC16A, BP230, and full-length BP180 ELISAs were used to detect the BP-IgG autoantibodies. We have also statistically analyzed the proportion of age, gender, intake periods of DPP-4i, and hemoglobin A1c level between anti-full-length BP180 IgG-positive and -negative DPP-4i (+) T2DM cases to identify co-founding factors. Results: BP180 NC16A ELISA, BP230 ELISA, and full-length BP180 ELISA were positive in 1.8, 2.2, and 10.9% of DPP-4i (+) T2DM cases, respectively; in contrast, they were positive in 0, 7.4, and 5.6% of DPP-4i (-) T2DM cases, respectively. The odds ratio for the development of BP-IgG autoantibodies detected by full-length BP180 ELISA was 2.070 for DPP-4i (+). There were no significant differences between the genders, intake periods of DPP-4i, nor of hemoglobin A1c levels, the anti-full-length BP180 IgG-positive cases tended to be significantly older than anti-full-length BP180 IgG-negative cases (median 74 vs. 69, p = 0.025) in the DPP-4i (+) T2DM cases. Limitations: We focused the analysis on DPP-4i intake and not on the effects of metformin and other drugs. Conclusion: Exposure to specific DPP-4i may induce the development of anti-full-length BP180 autoantibodies even in T2DM patients without any clinical symptoms of BP. Aging would be a risk factor to develop anti-full-length BP180-IgG autoantibody in DPP-4i (+) T2DM cases.

Bullous pemphigoid and pemphigus constitute two major autoimmune blistering diseases (AIBD) with complicated disease pathomechanisms involving a multitude of cytokines and immunological pathways. The purpose of our literature review of the cytokines and chemokines involved in these AIBDs was to allow for a meta-analysis of studies detailing differential cytokine and chemokine changes in these conditions. Elucidation of inflammatory pathways could lead to more targeted therapies, several of which specific monoclonal antibodies already exist and are used safely for other autoimmune diseases. A systematic review of the Pubmed/Medline database was performed for articles characterizing cytokines/chemokines involved in BP and pemphigus. Further, a meta-analysis was carried out using standardized methods, including assessment for heterogeneity. The results of our analysis demonstrated numerous inflammatory alterations in these AIBDs. Significant alterations included serum levels of IL-5, IL-6, IL-8, IL-17, CCL-17, and CCL-26 in patients with BP, and increased blister fluids levels of IL-5, IL-6, IL-8, CCL11, and TNF-α. Blister fluid levels of IL-1α are decreased in BP. In pemphigus, we identified significantly increased serum levels of IL-10, IL-17, and CCL17. We have additionally summarized all studies excluded from meta-analysis to provide a comprehensive summary of cytokine/chemokine alterations in these two conditions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering skin disease. Two antigens have been identified as targets of circulating autoantibodies (autoAbs) - BP180 and BP230 - with BP180 being a critical transmembrane adhesion protein of basal keratinocytes of the epidermis. The noncollagenous domain 16A (NC16A) of BP180 is the immunodominant epitope in patients with BP, and anti-BP180-NC16A IgG antibodies (Abs) correlate to disease activity. Routine serological testing and follow-up of BP relies on indirect immunofluorescence (IIF) of serum Abs, commonly performed on monkey oesophagus (ME), and/or enzyme-linked immunosorbent assay (ELISA) testing on recombinantly produced fragments of BP180 and BP230 (BP180-NC16A, BP230-C/N)., Objectives: To determine if NC16A epitopes are well represented on ME substrate., Methods: Sera from different BP cohorts were tested by IIF on ME and normal human skin (NHS). To confirm findings, affinity-purified anti-BP180-NC16A/BP230 polyclonal Abs and recombinant anti-BP180-NC16A/BP230 monoclonal antibodies (mAbs) were used., Results: For sensitive detection of BP180-NC16A-specific IgG Abs, sections of NHS are superior to the widely used ME. Confirmation comes from polyclonal affinity-purified anti-BP180-NC16A/BP230 Abs, and by mAbs cloned from a patient with active BP., Conclusions: Use of NHS is preferable over ME in routine IIF testing for BP. These results are of clinical relevance because anti-BP180-NC16A IgG titres are correlated to disease activity and detecting them reliably is important for screening, diagnosis and follow-up of patients with BP., (© 2018 British Association of Dermatologists.)

Background: DNA extracellular traps (ETs), released by neutrophils (NETs), or eosinophils (EETs), play a pathogenic role in several autoimmune disorders. However, to date, NETs have never been investigated in bullous pemphigoid (BP) with respect to clinical and immunological activities, both at baseline and at time of relapse which have been characterized with specific IL-17 and IL-23 patterns. Objective: We sought to assess whether ETs were associated with BP as well as the relative contribution of IL-17 axis cytokines to NET induction. Methods: Skin biopsy specimens were obtained from 11 patients with BP. Immuno-detection of neutrophils and eosinophils combined to DNA staining allowed us to investigate the in-situ presence of NETs and EETs using confocal scanning microscopy. NETs release was evaluated ex vivo by stimulating polymorphonuclear cells from BP patients with BP biological fluids in presence of IL-17A and IL-23 or of glucocorticoids. Results: At baseline, ETs were observed in BP lesions at the site of dermal-epidermal cleavage. Despite an important infiltrate of eosinophils, ETs were essentially associated with neutrophils in situ and were not related to BP clinical activity at diagnosis. In situ observation of NETs was associated in 6 among 8 patients with serum capacity of NET induction. Notably both blister fluid and sera from BP patients at diagnosis and at time of relapse could induce NET formation ex vivo . In contrast, a longitudinal investigation showed a decrease of NET formation with time of treatment in patients undergoing remission. Mimicking relapse, complementation of sera from BP patients with ongoing remission with either IL-17A or IL-23 increased NET formation. Conversely, IL-17A inhibited NET formation induced by serum from BP patients with relapse supplemented or not with IL-23. Finally, glucocorticoids also inhibited NET formation ex vivo in BP. Conclusion: NET formation is an associated phenomenon with BP. Furthermore, we showed that IL-23 favored NET formation, whereas the effects of IL-17A are environment dependent. Indeed, IL-17A displayed a protective effect on NET formation when associated with IL-23, showing for the first-time differential effects of these two cytokines in BP.

Background: Anti-laminin-γ1 (lam-γ1) pemphigoid, a recently described immunobullous disorder sharing immune serological features of bullous pemphigoid and epidermolysis bullosa acquisita (EBA), is characterized by the detection of serum IgG autoantibodies against the lam-γ1 chain, a 200 kDa heterotrimeric component of the dermal-epidermal junction (DEJ)., Objective: The aim of the study was to develop an easy-to-perform and reliable assay for the serological detection of anti-lam-γ1 IgG autoantibodies. The clinical appearance alone is not sufficient to establish diagnosis of anti-lam-γ1 pemphigoid and rather requires immune serological evidence of (i) IgG reactivity against the dermal portion of salt-split human skin; (ii) exclusion of IgG against other components of the DEJ; and (iii) IgG reactivity with a 200 kDa protein of dermal extracts by immunoblot analysis (IB)., Methods: The sera of 55 patients with anti-lam-γ1 pemphigoid were tested by IB with two recombinant heterotrimers, laminin 111 (lam-111) and laminin 421 (lam-421), as well as with a recombinant lam-γ1 chain monomer. Additionally, a total of 41 control sera from patients with EBA (n = 15), psoriasis vulgaris (PV; n = 14), and healthy controls (HC; n = 12) were tested., Results: Immunoblot analysis revealed a positive reactivity with lam-111 and/or lam-421 in 46/55 (84%) of anti-lam-γ1 pemphigoid sera. Moreover, 8/9 of the initially non-reactive sera were positive with the lam-γ1 monomer, leading to an overall sensitivity of 98.2%. Analyses of 41 control sera with the three lam-γ1 recombinants led to a specificity of 88%. Specifically, 3/15 EBA sera, 1/14 PV serum and 1/12 HC serum reacted with the lam-γ1 monomer while only the 3 EBA sera reacted with lam-421., Conclusions: Here we show a novel two-step IB assay using the two recombinant laminin trimers and lam-γ1 chain monomer for the detection of anti-lam-γ1 serum IgG with high sensitivity and specificity. This assay will facilitate the diagnosis and further characterization of this disease., (© 2018 European Academy of Dermatology and Venereology.)

Background: Bullous pemphigoid (BP) is the most common autoimmune blistering disease. BP180 is the primary autoantigen of BP, and in a portion of BP cases, BP230 is the only target of autoantibodies. Such BP is called BP230-type BP. BP230-type BP tends to show milder clinical phenotypes than conventional BP, but the reason is unclear. The pathogenic roles of autoantibodies and complement activation have been shown in conventional BP, but the distribution of IgG subclasses and the degree of complement deposition in BP230-type BP remain unclear., Objective: To compare the distribution of IgG subclasses and the degree of complement deposition in BP230-type BP with those in conventional BP with autoantibodies to BP180 and BP230 (BP180-BP230-type BP)., Methods: The diagnosis of BP was confirmed by the histopathology of the lesions, the deposition of IgG and complement in the perilesional skin and the presence of circulating autoantibodies to BP180 and BP230. The disease severity was determined by bullous pemphigoid disease area index. The deposition of IgG subclasses and complement deposition were examined by direct immunofluorescence of the perilesional skin in 6 BP230-type BP cases and 11 BP180-BP230-type BP cases., Results: Sixty seven percent of BP230-type BP cases show a mild clinical phenotype. All BP230-type BP cases and 82% of BP180-BP230-type BP cases were found to demonstrate the clear deposition of IgG4 at the basement membrane zone of skin specimens. Notably, the deposition of IgG1 and IgG3 was faint or negative in all of the BP230-type BP cases, whereas they were clearly detected in 91% and 64% of the BP180-BP230-type BP cases, respectively. The deposition of complement C3 tended to be weaker in BP230-type BP than in BP180-BP230-type BP., Conclusion: The mild clinical phenotype of BP230-type BP may correlate with the weaker deposition of IgG1, IgG3 and complement in the skin lesions., (© 2018 European Academy of Dermatology and Venereology.)

Background: Peripheral eosinophilia has been reported in 50-60% of patients with bullous pemphigoid (BP) and correlated positively with disease severity., Objectives: To establish an association of peripheral eosinophilia with the different morphological characteristics of BP., Methods: The study was designed as a case-control study. Diagnosis of BP was grounded on well-established immunopathological criteria. Five age-, sex- and ethnicity-matched controls were randomly selected for each patient with BP., Results: Overall, 225 patients with BP and 1125 control participants were enrolled. A total of 113 (50·2%) patients with BP and 49 (4·4%) controls had pathological peripheral eosinophilia (P < 0·001). An independent association between eosinophil count and the diagnosis of BP was observed [odds ratio 59·9 (per 1000 eosinophil μL -1 increase); P < 0·001]. Patients with BP with eosinophilia were significantly older at presentation (P = 0·003) and had increased palmoplantar involvement (P = 0·005), whereas patients with normal eosinophil counts had greater involvement of mucosal surfaces (P = 0·002) and the head and neck (P = 0·047). Patients with BP with extensive disease had significantly higher eosinophil counts than patients with mild-to-moderate disease (996·5 ± 1052·5 vs. 696·1 ± 962·6 cells μL -1 ; P < 0·001)., Conclusions: Patients with BP with serum eosinophilia were significantly older and had higher palmoplantar involvement. Patients with BP with a normal eosinophil count were younger and presented more frequently with atypical clinical manifestations., (© 2018 British Association of Dermatologists.)

Minocycline/tetracycline is clinically used for the treatment of bullous pemphigoid (BP), and its clinical benefits are superior to those of prednisolone when considering adverse events. Although the clinical benefits of minocycline/tetracycline are well known, its immunosuppressive mechanisms are still unclear. In this study, we investigated the immunomodulatory effects of traditional anti-BP drugs (minocycline, nicotinic acid amide, dexamethasone and cyclosporine) on CD163 + M2 macrophages in vitro, with special focus on the production of CCL18 and CCL22, both of which are produced by CD163 + M2 macrophages in the lesional skin of BP and are increased in the serum of BP patients. Minocycline decreased the production of CCL22, CCL24 and CCL26 as well as CCL2 from M2 macrophages. CCL18 from M2 macrophages was decreased by dexamethasone and cyclosporine, but not decreased by minocycline. These data suggest that the clinical benefit of minocycline is partially explained by its suppressive effects against the production of specific Th2 chemokines from M2 macrophages, which should contribute to the recruitment of Th2 cells and eosinophils in the lesional skin of BP patients., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: The association of bullous pemphigoid (BP) with the use of dipeptidyl-peptidase 4 (DPP-4) inhibitors among patients with diabetes has recently emerged. The risk of developing BP during treatment with new DPP-4 inhibitor agents like linagliptin is yet to be established. The clinical features and the prognostic outcomes of patients with DPP-4 inhibitor-associated BP are yet to be established., Objectives: Primarily to estimate the association between DPP-4 inhibitor exposure and the development of BP, and secondarily to characterize the clinical features and history of patients with DPP-4 inhibitor-associated BP., Design, Setting, and Participants: A retrospective case-control study of the intake of different DPP-4 inhibitor agents and metformin and occurrence of BP among patients with diabetes in a tertiary care referral center for autoimmune bullous diseases in northern Israel. Included were 82 consecutive patients with diabetes and immunopathologically validated BP diagnosed between January 1, 2011, and December 31, 2017, and 328 age-, sex-, and ethnicity-matched control participants with diabetes but without BP., Main Outcomes and Measures: Patients with diabetes and BP and exposure to DPP-4 inhibitors were followed up for a median of 2.0 years and compared with other patients with diabetes and BP who were not exposed to DPP-4 inhibitors regarding clinical and immunological features, laboratory analyses, treatments, and clinical outcomes., Results: Eighty-two patients with BP and 328 age- and sex-matched control participants were enrolled; mean (SD) age, 79.1 (9.1) years; and 44 patients were female (53.7%). Overall, DPP-4 inhibitor intake was associated with a 3-fold increased risk for BP (adjusted odds ratio [OR], 3.2; 95% CI, 1.9-5.4). The adjusted ORs for vildagliptin and linagliptin were 10.7 (95% CI, 5.1-22.4) and 6.7 (95% CI, 2.2-19.7), respectively. The association of DPP-4 inhibitor use with BP was independent of the use of metformin and was stronger among male (OR, 4.46; 95% CI, 2.11-9.40) than female (OR, 1.88; 95%, CI 0.92-3.86) patients and strongest in patients younger than 70 years (OR, 5.59; 95% CI, 1.73-18.01). Patients with DPP-4 inhibitor-associated BP presented with higher mucosal involvement (22.2% vs 6.5%; P = .04) and lower mean (SD) peripheral eosinophil counts (399.8 [508.0] vs 1117.6 [1847.6] cells/μL; P = .01) than those with BP who had not been exposed to DPP-4 inhibitor. Discontinuation of DPP-4 inhibitor treatment was followed by improved clinical outcomes., Conclusions and Relevance: Vildagliptin and, to a lesser extent, linagliptin are associated with an increased risk of BP. This may partly explain the increasing incidence of BP in Israel. Discontinuation of DPP-4 inhibitor treatment in patients with diabetes should be considered when BP is diagnosed.

Background: Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by autoantibodies against the two hemidesmosomal proteins, BP180 (type XVII collagen) and BP230. The multicentre prospective BLISTER (Bullous Pemphigoid Steroids and Tetracyclines) trial randomized 253 patients with BP to compare the benefits and harms between initial treatment with doxycycline or prednisolone., Objectives: To analyse distinct autoantibody profiles for the prediction of the disease course in a well-characterized cohort of BP sera., Methods: One hundred and forty-three patients of the BLISTER trial consented to participate in this serological study. Sera taken at baseline were analysed by (i) indirect immunofluorescence, (ii) anti-BP180 NC16A (16th noncollagenous domain) and anti-BP230 enzyme-linked immunosorbent assay and (iii) immunoblotting with various substrates. Results were then linked with clinical parameters including age, Karnofsky score, number of blisters, related adverse events and mortality., Results: Disease activity correlated with immunoglobulin (Ig)G anti-BP180 levels but not with levels of anti-BP230 IgG and anti-BP180 IgE. High levels of both anti-BP180 IgG and anti-BP230 IgG were associated with a low Karnofsky score. The presence of anti-BP230 IgG was more frequent in older patients. Those with higher total IgE serum levels suffered from fewer adverse events. Higher IgG anti-BP180 levels were associated with an increased 1-year mortality rate., Conclusions: Analysis of the autoantibody profile is not only of diagnostic relevance but may also be helpful in predicting the course of the disease., (© 2018 British Association of Dermatologists.)

The clinical features of bullous pemphigoid are extremely polymorphous. Several atypical forms of bullous pemphigoid have been described, and the diagnosis critically relies on immunopathological findings. We describe three bullous pemphigoid patients characterized by palmoplantar keratoderma, diffused hyperkeratotic cutaneous lesions and extremely high levels of immunoglobulin E serum. The diagnosis of bullous pemphigoid should be taken into account in patients presenting diffused hyperkeratotic cutaneous lesions and palmoplantar keratoderma, even in the absence of blisters. Alteration of the keratinization process, that could occur in patients with genetic mutations in desmosomal and hemidesmosomal genes, may also be due to circulating autoantibodies against hemidesmosomal proteins in these bullous pemphigoid patients., (© 2018 Japanese Dermatological Association.)