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Die besonderen Charakteristika von Patienten mit bullösem Pemphigoid (BP) mit Schleimhautbeteiligung sind weitgehend unbekannt. Unser Ziel war die Erforschung der klinischen und immunologische Charakteristika von BP-Patienten mit Schleimhautbeteiligung, um Faktoren zu identifizieren, die mit Schleimhautläsionen assoziiert sind.Eine retrospektive Studie, die alle konsekutiven Patienten umfasst, die in den Jahren 2009-2019 in einem tertiären Referenzzentrum mit BP diagnostiziert wurden.Die Studie umfasste 273 Patienten mit BP, von denen 31 (11,4 %) Schleimhautläsionen aufwiesen. Die Mundschleimhaut war die am häufigsten betroffene Schleimhautoberfläche (71,0 %), gefolgt von der Genital- (25,8 %) und der Nasenschleimhaut (22,6 %). Im Vergleich zu anderen Patienten mit BP hatten Patienten mit Schleimhautbeteiligung eine ausgeprägtere palmoplantare Beteiligung (67,7 % vs. 37,2 %; p = 0,001); eine niedrigere Seropositivitätsrate (18,2 % vs. 54.2 %; p = 0,027) und niedrigere Konzentrationen (29,3 ± 64,5 vs. 129,5 ± 304,4 U/ml; p = 0,016) von Anti-BP230-Autoantikörpern; und verminderte periphere Eosinophilenzahlen (760,0 ± 638,6 vs. 1296,3 ± 1013,7; p 0,001). Das Fehlen von Anti-BP230-Autoantikörpern (OR, 5,32; 95 %-Konfidenzintervall [KI], 1,07-26,32; p = 0,026) und das Fehlen von einer peripheren Eosinophilie (OR, 4,31; 95 %-KI, 1,14-16,39; p = 0,021) waren mit dem Vorhandensein einer Schleimhautbeteiligung bei BP assoziiert.Eine Beteiligung der Schleimhäute findet sich in einer nennenswerten Subgruppe von Patienten mit BP und ist assoziiert mit dem Fehlen sowohl von Anti-BP230-Antikörpern als auch von peripherer Eosinophilie.

BACKGROUND AND OBJECTIVES The features of bullous pemphigoid (BP) patients presenting with mucosal lesions are not established. We aimed to elucidate the clinical and immunological features of BP patients with mucosal involvement, and to identify factors associated with mucosal lesions. PATIENTS AND METHODS A retrospective study encompassing all consecutive patients diagnosed with BP throughout the years 2009-2019 in a tertiary referral center. RESULTS The study encompassed 273 patients with BP, of whom 31 (11.4 %) presented with mucosal lesions. The oral mucosa was the most frequently affected mucosal surface (71.0 %), followed by the genital (25.8 %) and the nasal (22.6 %) mucosae. Relative to other patients with BP, patients with mucosal involvement had a more prominent palmoplantar involvement (67.7 % vs. 37.2 %; P = 0.001); lower seropositivity rate (18.2 % vs. 54.2 %; P = 0.027) and lower levels (29.3 ± 64.5 vs. 129.5 ± 304.4 U/ml; P = 0.016) of anti-BP230 autoantibodies; and decreased peripheral eosinophil counts (760.0 ± 638.6 vs. 1296.3 ± 1013.7; P

BACKGROUND The influence of cutaneous cellular infiltration on the phenotype of bullous pemphigoid (BP) remains to be established. OBJECTIVES To evaluate the main histopathological characteristics of patients with BP and to assess the association between the composition of lesional inflammatory infiltrate and the various clinical, immunological and immunopathological aspects of the disease. METHODS Retrospective study encompassing patients diagnosed with BP throughout the years 2009-2020 in a specialized tertiary referral centre. RESULTS The study encompassed 136 patients with BP, of whom 27 (19.9%) demonstrated a cell-poor inflammatory infiltrate in lesional skin specimens. Overall, 78 (57.4%), 71 (52.2%) and 5 (3.7%) specimens were found to include eosinophil-predominant, lymphocyte-predominant and neutrophil-predominant inflammatory infiltrates, respectively. Relative to the remaining patients with BP, those with an eosinophil-predominant inflammatory infiltrate had higher (90.8% vs. 77.2%; P = 0.030) whilst those with a cell-poor inflammatory infiltrate lower (70.3% vs. 88.7%; P = 0.017) seropositivity of anti-BP180 NC16A IgG. The latter subgroup presented with higher prevalence of mucosal involvement (25.9% vs. 8.3%; P = 0.011) and a non-inflammatory clinical phenotype (50.0% vs. 17.1%; P = 0.041). Patients with lymphocyte-predominant inflammatory infiltrate manifested with higher severity BPDAI scores and a lower frequency of the non-inflammatory subtype (11.1% vs. 36.4%; P = 0.035), whilst those with a neutrophilic infiltrate presented with lower mean (SD) levels of anti-BP180 NC16A IgG [269.3 (227.6) vs. 722.7 (1499.6) U/mL; P = 0.003]. CONCLUSIONS Eosinophil-predominance and high cellularity in the lesional inflammatory infiltrate of BP skin are associated with increased seropositivity of anti-BP180 NC16A IgG. Lymphocyte-predominant infiltrates predict a more severe phenotype, pointing towards a pathogenic role of autoreactive lymphocytes.

Bullous pemphigoid (BP) is an autoimmune skin disease, caused by autoantibodies to BP180 and/or BP230. While both these autoantigens are expressed in the entire skin, only some parts of the body become affected. Rare clinical observations indicate that BP may also manifest locally, usually following exposure to triggers. Here, we evaluated the occurrence and potential triggers of localized BP (LBP) in a cohort of 285 BP patients. Medical records of all BP patients hospitalized between 2009 and 2019 were reviewed. In 7/285 BP patients, a localized variant was identified. In 5/7 LBP patients, the disease remained local, while in 2/7 patients, an initial LBP subsequently spread. All cases were preceded by presumptive triggers, including previously described triggers and bacterial infections. Overall, LBP is rare. LBP, however, might be underdiagnosed and should thus be considered in the differential diagnosis, particularly when trigger factors preceded.

The association between bullous pemphigoid (BP) and melanoma is yet to be investigated. We aimed to assess assess the bidirectional association between BP and melanoma and to delineate the epidemiological features of patients with both diagnoses. A population-based cohort study was performed comparing BP patients (n = 3924) with age-, sex- and ethnicity-matched control subjects (n = 19,280) with regard to incident cases of melanoma. A case–control design was additionally adopted to estimate the risk of BP in individuals with a preexisting diagnosis of melanoma. The prevalence of preexisting melanoma was higher in patients with BP than in control subjects (1.5% vs. 1.0%, respectively; P = 0.004). A history of melanoma confers a 50% increase in the risk of subsequent BP (OR 1.53; 95% CI 1.14–2.06). This risk was higher among males (OR 1.66; 95% CI 1.09–2.54) and individuals older than 80 years (OR 1.63; 95% CI 1.11–2.38), and persisted after adjustment for multiple putative confounders including PD-1/PDL-1 antagonists (adjusted OR 1.53; 95% CI 1.14–2.06). Conversely, the risk of melanoma among patients with BP was slightly elevated, but did not reach the level of statistical significance (adjusted HR 1.13; 95% CI 0.73–1.74). Patients with a dual diagnosis of BP and melanoma were older at the onset of BP and had lower body mass index. A history of melanoma is associated with a 50% increase in the incidence of subsequent BP. Physicians managing patients with both conditions should be aware of this association. Further research is warranted to reveal the underlying mechanism of these findings.

The association of bullous pemphigoid (BP) with solid malignancies (SM) is a matter of controversy, as previous studies produced inconclusive findings. The aim of this study was to assess the risk of SM among patients with BP and to evaluate whether a history of SM predisposes individuals to develop subsequent BP. A population-based cohort study was performed comparing BP patients (n = 3924) with age-, sex- and race-matched control subjects (n = 19 280) with regard to incident cases of SM. Adjusted hazard ratios (HR) and adjusted odds ratios (OR) were estimated by Cox regression and logistic regression, respectively. The incidence of SM was 13.4 (95% confidence interval [CI], 11.6-15.3) and 14.3 (95% CI, 13.5-15.1) per 1000 person-years among patients with BP and controls, respectively. BP was not associated with an increased risk of SM (adjusted HR, 0.90; 95% CI, 0.77-1.05). Additionally, a history of SM was not related to the risk of subsequent BP (adjusted OR, 1.00; 95% CI, 0.90-1.10). In a stratified analysis, patients with BP had an increased risk of uterine cancer (adjusted HR, 2.56; 95% CI, 1.39-4.72) unlike the 18 remaining analyzed types of SM. Relative to BP patients without SM, those with BP and SM were older, had a male predominance, a higher prevalence of smoking, a higher burden of comorbidities and comparable survival rates. Although patients with BP do not experience an overall increased risk of developing SM, they are more likely to have uterine cancer. Our findings argue against routine extended cancer screening for patients with incident BP, but raise the awareness of uterine cancer among females with BP.

Background: T-helper 2 (Th2)-associated cytokines are involved in the pathogenesis of bullous pemphigoid (BP), an autoimmune skin disease. Increased expression of Th2 cytokines such as interleukin-4 (IL-4), IL-5, IL-6, IL-10, and IL-13 have been observed in serum, skin biopsies and/or blister fluid. This study aimed to uncover a possible association between Th2 cytokine genetic variations and susceptibility to BP.Methods: In a cohort study, blood samples of BP patients and controls were obtained and variations in IL-4 (rs2243250 and rs2070874), IL-4R (rs1805010), IL-5 (rs2069812), IL-6 (rs1800795), IL-10 (rs1800896, rs1800871, and rs1800872), and IL-13 (rs1800925 and rs20541) were genotyped by PCR-RFLP assays. Furthermore, quantitative expression levels of IL-13 gene were evaluated by real-time RT-PCR analysis.Results: Among the studied variations, a significantly higher frequency of the C-allele was observed in IL-13 gene variation (rs1800925) in the healthy individuals than BP patients. This may indicate a protective effect of C-allele on predisposition to BP. Considering individuals carrying polymorphic genotypes compared to wild genotype, the minor G-allele of IL-4R rs1805010 and A-allele of IL-13 rs20541 had a promotive and protective effect, respectively, on predisposing to the development of BP. No significant difference in IL-13 mRNA expression was detected between BP patients and healthy individuals.Conclusions: Our results indicate that IL-13 rs1800925 variation may be a protective genetic marker for the development of BP. Given this preventive effect against BP, therapeutic strategies could potentially be developed interfering with the functions of IL-13 cytokine, which seems to be integral in the pathogenesis of eosinophilic inflammatory disorders, such as BP.

Background and purpose Pemphigus is caused by autoantibodies against desmoglein (Dsg) 1, Dsg3 and/or non-Dsg antigens. Pemphigus vulgaris (PV) is the most common manifestation of pemphigus, with painful erosions on mucous membranes. In most cases, blistering also occurs on the skin, leading to areas of extensive denudation. Despite improvements in pemphigus treatment, time to achieve remission is long, severe adverse events are frequent, and 20% of patients do not respond adequately. Current clinical developments focus exclusively on modulating B cell function or autoantibody half-life. However, topical modulation of PV autoantibody-induced blistering is an attractive target because it could promptly relieve symptoms. Experimental approach To address this issue, we performed an unbiased screen in a complex biological system using 141 small molecule inhibitors from a chemical library. Specifically, we evaluated PV IgG-induced Dsg3 internalization in HaCaT keratinocytes. Validation of the 20 identified compounds was performed using keratinocyte fragmentation assays, as well as a human skin organ culture (HSOC) model. Key results Overall, this approach led to the identification of 4 molecules involved in PV IgG-induced skin pathology: MEK1, TrkA, PI3Kα, and VEGFR2. Conclusion and implications This unbiased screen revealed novel mechanisms by which PV autoantibodies induce blistering in keratinocytes and identified new treatment targets for this severe and potentially life-threatening skin disease.

Background Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are common autoimmune bullous dermatoses (AIBD) characterized by blisters and erosions. Treatment options are limited and often insufficient. Immune checkpoint receptors play critical roles in immune homoeostasis and self- tolerance. Targeting checkpoint receptors is highly efficient in treatment of various cancers, but often also associated with autoimmune side effects. Objectives We therefore aimed to investigate the expression of immune checkpoint receptors in patients with BP and PV. Methods We analysed expression of the checkpoint receptors programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain 3 (Tim-3) and lymphocyte activation gene 3 (Lag-3) in lesional skin of patients with BP and PV compared to healthy control skin as well as the expression patterns of PD-1 and Tim-3 on various infiltrating immune cells in skin sections of AIBD by immunohistochemistry and immunofluorescence. We also measured serum levels of soluble PD-1, Tim-3 and Lag-3 in AIBD patients by ELISA. Results We report on increased expression of PD-1 and Tim-3, but not Lag-3, in lesional skin of patients with BP and PV. Investigating the expression pattern of PD-1 and Tim-3 on different cutaneous immune cells, we observed significant upregulation of PD-1 predominantly on infiltrating CD8 T cells and upregulation of Tim-3 on CD8 T cells as well as macrophages. Conclusions Our results suggest exploring immune checkpoint receptors as novel therapeutic targets using an agonistic approach in autoimmune bullous diseases.

Background and purpose Pemphigus and pemphigoid diseases are characterized and caused predominantly by IgG autoantibodies targeting structural proteins of the skin. Their current treatment relies on general and prolonged immunosuppression that causes severe adverse events, including death. Hence, novel safe and more effective treatments are urgently needed. Due to its' physiological functions, the neonatal Fc receptor (FcRn) has emerged as a potential therapeutic target for pemphigus and pemphigoid, primarily because IgG is protected from proteolysis after uptake into endothelial cells. Thus, blockade of FcRn would reduce circulating autoantibody concentrations. However, long-term effects of pharmacological FcRn inhibition in therapeutic settings of autoimmune diseases are unknown. Experimental approach Therapeutic effects of FcRn blockade were investigated in a murine model of the prototypical autoantibody-mediated pemphigoid disease, epidermolysis bullosa acquisita (EBA). B6.SJL-H2s C3c/1CyJ mice with clinically active disease were randomized to receive either an anti-FcRn monoclonal antibody (4470) or an isotype control over 4 weeks. Key results While clinical disease continued to worsen in isotype control-treated mice, overall disease severity continuously decreased in mice injected with 4470, leading to almost complete remission in over 25% of treated mice. These clinical findings were paralleled by a reduction of autoantibody concentrations. Reduction of autoantibody concentrations, rather than modulating neutrophil activation, was responsible for the observed therapeutic effects. Conclusion and implications The clinical efficacy of anti-FcRn treatment in this prototypical autoantibody-mediated disease encourages further development of anti-FcRn antibodies for clinical use in pemphigoid diseases and potentially in other autoantibody mediated diseases.

Pemphigoid diseases are organ-specific autoimmune diseases of the skin and/or mucous membranes. They are caused by autoantibodies targeting adhesion molecules located at the dermal-epidermal junction. While the diagnostics of pemphigoid diseases and insights into their pathogenesis have improved significantly, the development of novel treatments that are effective and safe remains an unmet medical need. However, numerous pre-clinical studies and early clinical trials have recently been launched. This review summarizes some pathways leading to drug development in pemphigoid diseases, namely: (i) hypothesis-driven drug development; (ii) omics-based drug development; (iii) drug repurposing; (iv) screening-based drug development; and (v) drug development based on careful clinical observations. Ultimately, it is hoped that this will lead to personalized and curative treatments.

Aiping Ma,1,* Lifang Wen,2,* Junping Yin,3 Yi Hu,4 Xiaoyang Yue,3 Jiurong Li,1 Xiaoru Dong,2 Yask Gupta,5 Ralf J Ludwig,5 Susanne Krauss-Etschmann,3,6 Gabriela Riemekasten,7 Frank Petersen,3 Xinhua Yu2,3 1Department of Respiratory Medicine, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 2Xiamen-Borstel Joint Laboratory of Autoimmunity, The Medical College of Xiamen University; 3Priority Area Asthma and Allergy, Research Center Borstel, Airway Research Center North (ARCN), Members of the German Center for Lung Research (DZL), Borstel, Germany; 4Department of Clinical Laboratory, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 5Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany; 6Institute for Experimental Medicine, Christian-Albrechts-Universitaetzu Kiel, Kiel, Germany; 7Department of Rheumatology, University of Lübeck, Lübeck 23538, Germany*These authors contributed equally to this workCorrespondence: Xinhua YuPriority Area Asthma and Allergy, Research Center Borstel, Borstel 23845, GermanyTel +49 453 7188 2520Email xinhuayu@fz-borstel.deBackground: Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease leading to irreversible airflow limitation and is characterized by chronic pulmonary inflammation, obstructive bronchiolitis and emphysema. Etiologically, COPD is mediated by toxic gases and particles, eg, cigarette smoke, while the pathogenesis of the disease is largely unknown. Several lines of evidence indicate a link between COPD and autoimmunity but comprehensive studies are lacking.Methods: By using a protein microarray assaying more than 19,000 human proteins we determined in this study the autoantibody profiles of COPD and non-COPD smokers. The discovery cohort included 5 COPD patients under acute exacerbation (AECOPD) and 5 age- and gender-matched non-COPD smokers. One putative candidate autoantibody, anti-lactoferrin IgG, was further investigated by using immunoblotting with a large validation cohort containing 124 healthy controls, 92 patients with AECOPD and 52 patients with stable COPD.Results: We show that i) autoantigens targeted by autoantibodies with higher titers in COPD patients were enriched in extracellular regions, while those with lower titers in COPD patients were enriched in intracellular compartments. ii) levels of IgG autoantibodies against many neutrophil granule proteins were significantly higher in COPD patients than in non-COPD smokers. Furthermore, increased levels of anti-lactoferrin antibodies in COPD patients were confirmed in a cohort with a large number of samples.Conclusion: The comprehensive autoantibody profiles from COPD patients established in this study demonstrated for the first time a shift in the cellular localization of antigens targeted by autoantibodies in COPD.Keywords: chronic obstructive pulmonary disease, autoimmunity, autoantibody profile, neutrophil granule proteins, lactoferrin

Vb cyclones are major drivers of extreme precipitation and floods in the study area of hydrological Bavaria (Germany). When assessing climate change impacts on Vb cyclones, internal variability of the climate system is an important underlying uncertainty. Here, we employ a 50-member single-model initial-condition large ensemble of a regional climate model to study climate variability and forced change on Vb cyclones. An artificial neural network detects cutoff lows over central Europe, which are associated with extreme precipitation Vb cyclones. Thus, machine learning filters the large ensemble prior to cyclone tracking. Our results show a striking change in Vb seasonality with a strong decrease of Vb cyclones in summer (−52%) and a large increase in spring (+73%) under the Representative Concentration Pathway 8.5. This change exceeds the noise of internal variability and leads to a peak shift from summer to spring. Additionally, we show significant increases in the daily precipitation intensity during Vb cyclones in all seasons.

Pathomechanisms in IgA pemphigus are assumed to rely on Fc-dependent cellular activation by antigen-specific IgA autoantibodies; however, models for the disease and more detailed pathophysiologic data are lacking. In this study, we aimed to establish in vitro models of disease for IgA pemphigus, allowing us to study the effects of the interaction of anti-keratinocyte IgA with cell surface FcαRs. Employing multiple in vitro assays, such as a skin cryosection assay and a human skin organ culture model, in this study, we present mechanistic data for the pathogenesis of IgA pemphigus, mediated by anti–desmoglein 3 IgA autoantibodies. Our results reveal that this disease is dependent on FcαR-mediated activation of leukocytes in the epidermis. Importantly, this cell-dependent pathology can be dose-dependently abrogated by peptide-mediated inhibition of FcαR:IgA-Fc interaction, as confirmed in an additional model for IgA-dependent disease, that is, IgA vasculitis. These data suggest that IgA pemphigus can be modeled in vitro and that IgA pemphigus and IgA vasculitis are FcαR-dependent disease entities that can be specifically targeted in these experimental systems.

Background Pemphigus vulgaris (PV) is a rare autoimmune blistering disease characterized by the development of autoantibodies targeting desmoglein (Dsg) 3, but also against Dsg1 in mucocutaneous disease. Given that existing PV animal models only recapitulate aspects of the disease, we aimed to establish a more comprehensive disease model based on the immunization of mice with PV autoantigen(s). Methods The following immunization strategies were tested: (i) C57Bl/6J, B6.SJL-H2s C3c/1CyJ, DBA2/J, or SJL/J mice were immunized with recombinant murine Dsg3 (mDsg3), (ii) DBA2/J and SJL/J mice were immunized with mDsg3 and additionally injected a single non-blister inducing dose of exfoliative toxin A (ETA), and (iii) DBA2/J and SJL/J mice were immunized with human Dsg (hDsg) 1 and 3. Results Despite the induction of autoantibodies in each immunization protocol, the mice did not develop a clinical phenotype. Tissue-bound autoantibodies were not detected in the skin or mucosa. Circulating autoantibodies did not bind to the native antigen in indirect immunofluorescence microscopy using monkey esophagus as a substrate. Conclusion Immunization with PV autoantigens induced non-pathogenic Dsg1/3 antibodies, but did not cause skin/mucous membrane disease in mice. These findings, confirmed by failure of binding of the induced autoantibodies to their target in the skin, suggest that the autoantibodies which were formed were unable to bind to the conformational epitope present in vivo.

Background Monocyte chemoattractant protein‐1 (MCP‐1) is highly expressed by lymphocytes at skin sites affected by alopecia areata (AA). Variations in MCP‐1 as well as in methylene‐tetrahydrofolate reductase (MTHFR), a key enzyme related to many inflammatory pathologies, have been associated with several autoimmune disorders. This study was designed to test a possible association between MCP‐1 and MTHFR variations and altered expression of their genes and the risk of AA. Methods Blood samples of patients (60) suffering from AA as well as healthy subjects (60) were collected. Gene expression levels of MCP‐1 and MTHFR were evaluated by real‐time reverse‐transcription polymerase chain reaction analysis. Moreover, MCP‐1 rs1024611 (A‐2518G) and MTHFR rs1801133 (C677T) polymorphisms were genotyped by using polymerase chain reaction‐restriction fragment length polymorphism assays. Results In contrast to MCP‐1, the MTHFR gene expression was found to be significantly higher in patients than in controls. Further stratification of the patients revealed that polymorphic genotypes in MCP‐1 (AG + GG) and MTHFR (CT + TT) could significantly alter gene expression levels. Elevation of MCP‐1 expression was significantly associated with the total number of variant MCP‐1 and MTHFR alleles. However, no statistically significant difference was noticed in the genotypic distribution of MCP‐1 and MTHFR variations between patients and controls. Conclusion In summary, despite MCP‐1 rs1024611 and MTHFR rs1801133 variations are not associated with AA risk, they may implicate the disease pathogenesis by influencing MCP‐1 activity., Despite MCP‐1 rs1024611 and MTHFR rs1801133 variations are not associated with AA risk, they may implicate the disease pathogenesis by influencing MCP‐1 activity

BACKGROUND Although bullous pemphigoid (BP), atopic dermatitis (AD), and allergic rhinitis (AR) are associated with shared pathogenic mechanisms the epidemiological relationship between these conditions remains to be investigated. OBJECTIVE To evaluate the bidirectional association of BP with AD and AR. METHODS A population-based retrospective cohort study was performed comparing BP patients (n = 3924) with age-, sex-, and ethnicity-matched control subjects (n = 19,280), with respect to incident cases of AD and AR. A case-control design was additionally adopted to assess the odds of BP in individuals with a preexisting diagnosis of AD and AR. RESULTS The odds of BP was increased after a preexisting diagnosis of AD (fully adjusted odds ratio, 1.76; 95% confidence interval [CI], 1.44-2.15; P < 0.001) and AR (fully adjusted odds ratio, 1.13; 95% CI, 1.01-1.28; P = 0.047). Patients with BP were at an increased risk of subsequent AD (fully adjusted hazard ratio, 2.00; 95% CI, 1.60-2.51; P < 0.001) but not AR (fully adjusted hazard ratio, 1.00; 95% CI, 0.83-1.20; P = 0.997). Compared with other patients with BP, those with BP and comorbid AD and AR were more frequently managed by adjuvant drugs and long-term systemic and topical corticosteroids and had decreased all-cause mortality. CONCLUSIONS A history of AD and AR confers susceptibility to the development of BP. Awareness of this association may be of help for physicians managing patients with these diseases.

Vulval lichen planus (VLP) is a rare, but often chronic, inflammatory disease whose symptoms include genital pain, discomfort, and dyspareunia. The clinical manifestations include erythema, erosions, and scarring. The aim of this study was to longitudinally investigate patient-reported outcomes and clinical findings in patients with VLP. Patients (>18 years) with histologically confirmed VLP were included in the retrospective analysis. Patient demographics, clinical features, symptomatology, quality of life, management, clinical outcomes, and comorbidities associated with VLP were analyzed. Twenty-four patients were identified with a mean (standard deviation [SD]) follow-up time of 19.3 (13.8) months. Classical VLP with glazed erythema was found in seven (29.2%) patients, erosive VLP was present in 15 (62.5%) patients, and hypertrophic VLP in two (8.3%). Seven patients had additional cutaneous involvement, while six patients had both vulval and oral mucosal involvement. The labia minora was the most frequently affected anatomical site (83.3%), followed by the clitoris (58.3%). Scarring lesions were found in 62.5% (n = 15) of patients. All study participants received treatment with potent and/or superpotent topical corticosteroids but 50% required systemic therapy (acitretin, corticosteroids, or hydroxychloroquine). Five (20.8%) patients underwent surgery due to adhesions and scarring resulting from VLP. One patient was diagnosed with a vulval squamous cell carcinoma during long-term follow-up. The mean (SD) Dermatology Life Quality Index score was 8.4 (5.5) at presentation and 8.9 (6.8) at the end of follow-up. In conclusion, VLP was associated with moderate quality of life impairments which persisted despite treatment, suggesting that current treatments for VLP are inadequate.

Class I phosphoinositide 3-kinases (PI3K) have been implemented in pathogenesis of experimental epidermolysis bullosa acquisita (EBA), an autoimmune skin disease caused by type VII collagen (COL7) autoantibodies. Mechanistically, inhibition of specific PI3K isoforms, namely PI3Kβ or PI3Kδ, impaired immune complex (IC)-induced neutrophil activation, a key prerequisite for EBA pathogenesis. Data unrelated to EBA showed that neutrophil activation is also modulated by PI3Kα and γ, but their impact on the EBA has, so far, remained elusive. To address this and to identify potential therapeutic targets, we evaluated the impact of a panel of PI3K isoform-selective inhibitors (PI3Ki) on neutrophil function in vitro, and in pre-clinical EBA mouse models. We document that distinctive, and EBA pathogenesis-related activation-induced neutrophil in vitro functions depend on distinctive PI3K isoforms. When mice were treated with the different PI3Ki, selective blockade of PI3Kα (alpelisib), PI3Kγ (AS-604850), or PI3Kβ (TGX-221) impaired clinical disease manifestation. When applied topically, only TGX-221 impaired induction of experimental EBA. Ultimately, multiplex kinase activity profiling in the presence of disease-modifying PI3Ki identified unique signatures of different PI3K isoform-selective inhibitors on the kinome of IC-activated human neutrophils. Collectively, we here identify topical PI3Kβ inhibition as a potential therapeutic target for the treatment of EBA.

Drug survival reflects the real-life efficacy and safety of therapeutic agents. Evidence regarding the durability of adjuvant agents in the treatment of pemphigus is sparse. The aims of this study were to investigate the survival of adjuvant agents used to manage patients with pemphigus, and to identify predictors of treatment dropout. A retrospective population-based cohort study was designed to follow patients with pemphigus managed by adjuvant agents. The study population included 436 patients with pemphigus managed by 608 adjuvant agent courses. The highest median drug survival time was observed for rituximab (43.6 months, 95% confidence interval (95% CI) 5.3-81.9), followed by cyclophosphamide (30.5 months; 95% CI 10.5-50.5), azathioprine (22.9 months; 95% CI 15.6-30.2), and mycophenolate mofetil (20.2 months; 95% CI 10.0-30.4). Compared with azathioprine, cyclosporine (adjusted hazard ratio 2.98; 95% CI 1.57-5.62; p = 0.005) and dapsone (adjusted hazard ratio 1.83; 95% CI 1.07-3.15; p = 0.027) were associated with a significantly increased risk of drug discontinuation. To conclude, rituximab, azathioprine, and mycophenolate mofetil demonstrated better durability, whilst dapsone and cyclosporine were associated with low drug survival and high dropout.

Hautveranderungen sind bei chronisch-entzundlichen Erkrankungen haufig und konnen als visueller Marker auf eine systemische Entzundung hinweisen. Hoch pravalente entzundliche Hauterkrankungen, wie die Psoriasis und die atopische Dermatitis, sind aufgrund der systemischen Entzundung mit einer erhohten rheumatischen, metabolischen und kardiovaskularen Komorbiditat assoziiert. Auch der systemische Lupus erythematodes weist ein komplexes klinisches Spektrum auf, welches von hauptsachlich kutanem Befall bis zu kritischer Multiorganmanifestation reicht. Die lokalisierte Sklerodermie kann klinisch von der systemischen Sklerose unterschieden werden und bedarf einer suffizienten Therapie, um bleibenden funktionellen Defekten vorzubeugen. Aus diesem Grund ist das interdisziplinare Management bei diesen Erkrankungen besonders wichtig und zielfuhrend.

In this paper, a two-step automatic change detection chain for rapid flood mapping based on Sentinel-1 Synthetic Aperture Radar (SAR) data is presented. First, a reference image is selected from a set of potential image candidates via a Jensen-Shannon (JS) divergence-based index. Second, saliency detection is applied on log-ratio data to derive the prior probabilities of changed and unchanged classes for initializing the following expectation-maximization (EM) based generalized Gaussian mixture model (GGMM). The saliency-guided GGMM is capable of capturing the primary pixel-based change information and handling highly imbalanced datasets. A fully-connected conditional random field (FCRF) model, which takes long-range pairwise potential connections into account, is integrated to remove the ambiguities of the saliency-guided GGMM and to achieve the final change map. The whole process chain is automatic with an efficient computation. The proposed approach was validated on flood events at the Evros River, Greece and the Wharfe River and Ouse River in York, United Kingdom. Kappa coefficients (k) of 0.9238 and 0.8682 were obtained respectively. The sensitivity analysis underlines the robustness of the proposed approach for rapid flood mapping.

There is strong scientific and social interest to understand the factors leading to extreme events in order to improve the management of risks associated with hazards like droughts. In this study, artificial neural networks are applied to predict the occurrence of a drought in two contrasting European domains, Munich and Lisbon, with a lead time of one month. The approach takes into account a list of 30 atmospheric and soil variables as input parameters from a single-model initial condition large ensemble (CRCM5-LE). The data was produced the context of the ClimEx project by Ouranos with the Canadian Regional Climate Model (CRCM5) driven by 50 members of the Canadian Earth System Model (CanESM2). Drought occurrence was defined using the Standardized Precipitation Index. The best performing machine learning algorithms managed to obtain a correct classification of drought or no drought for a lead time of one month for around 55–60 % of the events of each class for both domains. Explainable AI methods like SHapley Additive exPlanations (SHAP) were applied to gain a better understanding of the trained algorithms. Variables like the North Atlantic Oscillation Index and air pressure one month before the event proved to be of high importance for the prediction. The study showed that seasonality has a high influence on goodness of drought prediction, especially for the Lisbon domain.

There is strong scientific and social interest to understand the factors leading to extreme events in order to improve the management of risks associated with hazards like droughts. Recent events like the summer 2018 drought in Germany already had severe und unexpected impacts, e.g. forest fires and crop failures; in order to increase preparedness robust prediction tools are urgently required. In this study, machine learning methods are applied to predict the occurrence of a drought with lead times of one to three months. The approach takes into account a list of thirty atmospheric and soil variables as predictor input parameters from a single regional climate model initial condition large ensemble (CRCM5-LE). The data was produced the context of the ClimEx project by Ouranos with the Canadian Regional Climate Model (CRCM5) driven by 50 members of the Canadian Earth System Model (CanESM2) for the Bavarian and Quebec domains.Drought occurrence was defined using the Standardized Precipitation Index. The training and test datasets were chosen from the current climatology (1955-2005) for the Munich and Lisbon subdomain within the CRCM5-LE. The best performing machine learning algorithms managed to obtain a correct classification of drought or no drought for a lead time of one month for around 60 % of the events of each class for the both domains. Explainable AI methods like feature importance and shapley values were applied to gain a better understanding of the trained algorithms. Physical variables like the North Atlantic Oscillation Index and air pressure one month before the event proved to be of high importance for the prediction. The study showed that better accuracies can be obtained for the Lisbon domain, due to the stronger influence of the North Atlantic Oscillation Index on Portugal’s climate.

Climate change is altering the Earth’s atmospheric circulation and the dynamic drivers of extreme events. Extreme weather events pose a great potential risk to infrastructure and human security. In Montréal (Québec, Canada) long-duration mixed precipitation events (freezing rain and/or ice pellets) are high-impact cold-season hazards and an understanding of how climate change alters their occurrence is of high societal interest.Here, we introduce a two-staged deep learning approach that uses the synoptic-scale drivers of mixed precipitation to identify these extreme events in archived climate model data. The approach is destined for the application on regional climate model (RCM) data over the Montréal area. The dominant dynamic mechanism leading to mixed precipitation in Montréal is pressure-driven channeling of winds along the St. Lawrence river valley. The identification of the synoptic-scale pressure pattern related to pressure-driven channeling is a visual image classification task that is addressed with supervised machine learning. A convolutional neural network (CNN) is trained on the classification of the synoptic-scale pressure patterns by using a large training database derived from an ensemble of the Canadian Regional Climate Model version 5 (CRCM5). The CRCM5 is to our knowledge the only RCM available so far that employs the diagnostic method by Bourgouin to simulate mixed precipitation inline and thus delivers training examples and labels for this supervised classification task.The CNN correctly identifies 90 % of the Bourgouin mixed precipitation cases in the test set. The weak point of the approach is a high type I error, which is enhanced in a second stage by applying a temperature condition. The evaluation on an CRCM5 run driven by ERA-Interim reanalysis reveals a still low precision of 21 % and thus a Matthews correlation coefficient of 0.39. The deep learning approach can be applied to ensembles of regional climate models on the North America grid of the Coordinated Regional Downscaling Experiment (CORDEX-NA).

Clean energy for all, as listed in the United Nation’s SDG7, is a key component for sustainable environmental development. Therefore, it is imperative to uncover the environmental implications of alternative energy technologies. SustainableGAS project simulates different process chains for the substitution of natural gas with renewable energies in the German gas market. The project follows an interdisciplinary approach, taking into account techno-social and environmental variabilities. However, this research highlights the project results from the environmental perspective. So far, a detailed assessment of the environmental costs of alternative gas technologies with a focus on the process of energy transition has remained rare. Although such data constitute key inputs for decision-making, this study helps to bridge a substantial knowledge gap. Competing land-use systems are examined to secure central ecosystem services. To fulfill this obligation, an Integrated Valuation of Ecosystem Services and Trade-offs (InVEST) serves as the modelling tool. InVEST assesses ecosystem services (ES) that are or may be affected by alternative bioenergy technologies. Spatially explicit model results include the water provisioning from the Water Yield Model (WYM), soil erosion and sedimentation described by the Sediment Delivery Ratio (SDR), and nutrient fluxes (N) in response to changing land use are obtained through the Nutrient Delivery Ratio (NDR). The detailed model results are finally extrapolated, which provides a comprehensive image of the environmental impacts associated with bioenergy expansion in Germany from our combination of unique Renewable Gas Plants (RGPs). The final result shows that nutrient load will reduce in southern Germany by the year 2050 compared to the reference state, and biomass use reduced by 46% crops.

BACKGROUND While clustering of bullous pemphigoid (BP) with neuropsychiatric diseases is well-established, the clinical and immunological profile of BP patients with this comorbidity remains to be decisively determined. OBJECTIVES To evaluate the burden of neurological and psychiatric comorbidities among patients with BP and to elucidate the clinical, immunological and immunopathological features of patients with BP and comorbid neuropsychiatric conditions. METHODS We performed a retrospective study encompassing patients diagnosed with BP throughout the years 2009-2020 in a specialized tertiary referral centre. Multivariate logistic regression model was used to identify predictors of neuropsychiatric conditions among patients with BP. RESULTS The study included 273 patients with BP, of whom 123 (45.1%) presented with comorbid neuropsychiatric disease. Compared to the remaining patients with BP (n = 150), those with pre-existing neuropsychiatric diseases demonstrated older mean [standard deviation (SD)] age [81.7 (9.1) vs. 76.9 (10.1); P

Heat shock proteins (Hsp) are constitutive and stress-induced molecules which have been reported to impact innate and adaptive immune responses. Here, we evaluated the role of Hsp70 as a treatment target in the imiquimod-induced, psoriasis-like skin inflammation mouse model and related in vitro assays. We found that immunization of mice with Hsp70 resulted in decreased clinical and histological disease severity associated with expansion of T cells in favor of regulatory subtypes (CD4+FoxP3+/CD4+CD25+ cells). Similarly, anti-Hsp70 antibody treatment led to lowered disease activity associated with down-regulation of pro-inflammatory Th17 cells. A direct stimulating action of Hsp70 on regulatory T cells and its anti-proliferative effects on keratinocytes were confirmed in cell culture experiments. Our observations suggest that Hsp70 may be a promising therapeutic target in psoriasis and potentially other autoimmune dermatoses.

研究グループは、グランザイムBが類天疱瘡疾患の治療標的となることを明らかにしました。難病に指定されている類天疱瘡は全身にかゆみを伴う水膨れができる疾患で、高齢者に多く発症し、無治療では最悪の場合死に至ることがあります。現在の一般的な治療ではステロイドをはじめとした免疫抑制剤を使用しますが、細菌やウイルスに感染しやすくなるなど、場合によっては命に関わる副作用を伴います。また、高齢化社会において患者がより増えていくことが予想され、高齢者ほど免疫抑制剤の副作用リスクが高いため、副作用のほとんどない治療薬の開発が急務となっています。そこで本研究では、類天疱瘡の水膨れの近くに沢山存在することが知られており、その役割が研究されてこなかったグランザイムBに着目しました。3種類の独立した動物モデルを用いた実験により、グランザイムBが類天疱瘡の症状をより重篤にしていることを発見しました。また、グランザイムBの働きを阻害する外用薬が、類天疱瘡の動物モデルの水膨れを治療することがわかりました。さらに、ヒト患者の水膨れの周囲や水膨れの内容液ではグランザイムBが増加していることが本研究でわかりました。今回グランザイムB阻害薬(VTI-1002)の外用が類天疱瘡動物モデルの水膨れを治療することが明らかとなり、それをヒト患者にも用いることができる可能性が期待できます。, Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.

The practical implications of complement deposition in direct immunofluorescence (DIF) microscopy and its influence on the disease phenotype are poorly understood. We aimed to investigate whether the presence of complement deposition in DIF microscopy gives rise to differences in the morphological, immunological, and histological characteristics of patients with BP (bullous pemphigoid). We performed a retrospective study encompassing patients with BP in a specialized tertiary referral center. Logistic regression model was utilized to identify variables independently associated with complement deposition. The study included 233 patients with BP, of whom 196 (84.1%) demonstrated linear C3 deposition along the dermal-epidermal junction (DEJ) in DIF analysis. BP patients with C3 deposition had higher mean (SD) levels (645.2 (1418.5) vs. 172.5 (243.9) U/mL, p &lt, 0.001) and seropositivity rate (86.3% vs.64.9%, p = 0.002) of anti-BP180 NC16A and less prevalent neutrophilic infiltrate in lesional skin specimens (29.8% vs. 52.4%, p = 0.041). C3 deposition was found positively associated with the detection of anti-BP180 NC16A autoantibodies (OR, 4.25, 95% CI, 1.38&ndash, 13.05) and inversely associated with the presence of neutrophils in lesional skin (OR, 3.03, 95% CI, 1.09&ndash, 8.33). To conclude, complement deposition influences the immunological and histological features of BP. These findings are in line with experimental data describing the pathogenic role of complement in BP.

International audience; Immunophenotyping on the molecular and cellular level is a central aspect for characterization of patients with inflammatory diseases, both to better understand disease etiopathogenesis and based on this to develop diagnostic and prognostic biomarkers which allow patient stratification and tailor-made treatment strategies. Technology-driven developments have considerably expanded the range of analysis tools. Especially the analysis of adaptive immune responses, often regarded as central though mostly poorly characterized disease drivers, is a major focus of personalized medicine. The identification of the disease-relevant antigens and characterization of corresponding antigen-specific lymphocytes in individual patients benefits significantly from recent developments in cytometry by sequencing and proteomics. The aim of this workshop was to identify the important developments for state-of-the-art immunophenotyping for clinical application and precision medicine. We focused here on recent key developments in analysis of antigen-specific lymphocytes, sequencing, and proteomics approaches, their relevance in precision medicine and the discussion of the major challenges and opportunities for the future.

Background Pemphigoid diseases are a heterogeneous group of autoimmune blistering disorders characterized by predominant deposition of immunoglobulin G or immunoglobulin A autoantibodies against structural proteins of the dermoepidermal junction (DEJ). Sole linear immunoglobulin M (IgM) deposits at the DEJ in pemphigoid diseases have been observed; however, IgM-specific target antigens have not been identified. Objective Characterization of patients with IgM pemphigoid. Methods Skin biopsy specimens and sera from IgM-positive patients were assessed using histopathology, direct and indirect immunofluorescence microscopy, enzyme-linked immunosorbent assays, immunoblotting, cryosection assay, complement fixation test, and internalization assays. Results Tissue-bound linear IgM deposits along the DEJ and circulating IgM autoantibodies against type XVII collagen (Col17) were detected. These circulating IgM autoantibodies showed no complement activating or blister inducing capacity, but the ability of Col17 internalization ex vivo. Limitations Limited number of patients. Conclusion This study provides further evidence for the role of IgM autoantibodies in pemphigoid disease and highlights Col17 as a target antigen in IgM pemphigoid.

Background The burden of Coronavirus disease 2019 (COVID-19) in patients with bullous pemphigoid (BP) and pemphigus is yet to be evaluated. Objective To assess the risk of COVID-19, and COVID-19-associated hospitalization and mortality in patients with BP and pemphigus, and to delineate determinants of severe COVID-19 illness among these patients. Methods A population-based cohort study was performed to compare patients with BP (n=1,845) and pemphigus (n=1,236) with their age-, sex- and ethnicity-matched control subjects regarding COVID-19 and its complications. Results The risk of COVID-19 (HR, 1.12; 95%CI, 0.72-1.73; P=0.691) and COVID-19-associated hospitalization (HR, 1.58; 95%CI, 0.84-2.98; P=0.160) was comparable between patients with BP and controls, whereas the risk of COVID-19-associated mortality was higher among patients with BP (HR, 2.82; 95%CI, 1.15-6.92; P=0.023). The risk of COVID-19 (HR, 0.81; 95%CI, 0.44-1.49; P=0.496), COVID-19-associated hospitalization (HR, 1.41; 95%CI, 0.53-3.76; P=0.499), and COVID-19-associated mortality (HR, 1.33; 95%CI, 0.15-11.92; P=0.789) was similar in patients with pemphigus and their controls. Systemic corticosteroids and immunosuppressants did not predispose COVID-19-positive BP and pemphigus patients to a more severe illness. Limitations Retrospective data collection. Conclusions BP patients experience increased COVID-19-associated mortality and should be monitored closely. Maintaining systemic corticosteroids and immunosuppressive adjuvant agents during the pandemic.is not associated with worse outcomes.

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.

Introduction: Palmoplantar pustular psoriasis (PPPP) is a debilitating inflammatory skin disorder of the palms and soles that poses a high burden on affected patients. Satisfactory treatment response is rarely achieved using current treatment options, little is known about the potential benefit of the PDE4 inhibitor apremilast in the treatment of refractory PPPP patients. We aimed to evaluate the use of apremilast in PPPP patients. Patients and Methods: Six patients, four with severe physician global assessment (PGA) = 3 on a scale of 0-4 and two with very severe (PGA = 4) treatment-refractory PPPP [mean age (years ± SD): 56.2 ± 15.6], were included in this study. Five patients had concomitant psoriatic arthritis (PsA). Prior to apremilast administration, topical corticosteroids, psoralen-UVA and multiple systemic oral and biologic anti-inflammatory treatments were insufficient to improve their skin condition or had to be discontinued due to adverse events. Apremilast (titrated to a maintenance dose of 30 mg 2x/d) was commenced in all patients with clinical follow-up over 18 months. Results: Within the first 4 weeks of treatment, each patient's symptoms improved as assessed by PGA score. At 3 months, four patients had a mild PGA score and two were cleared from PPPP. After 18 months of follow-up, three patients improved from PGA = 3 to PGA = 1 and one patient from PGA = 4 to PGA = 1. Two patients discontinued treatment, one due to a lack of efficacy against PsA and the other to a desire to have a child. However, both patients recorded improvements before discontinuing treatment. Conclusion: Apremilast may be a promising treatment option for refractory and severely affected PPPP patients. Our observation, however, requires further validation.

Background: Bullous pemphigoid (BP) and asthma both share a pathogenic role of eosinophils and immunoglobulin E (IgE) and favorable response for corticosteroids and omalizumab. However, the association between these conditions is yet to be investigated. We sought to estimate the risk of having BP among patients previously diagnosed with asthma and to characterize patients with coexistent BP and asthma. Methods: Utilizing the dataset of Clalit Health Services, a population-based case-control study was conducted comparing BP patients (n = 3,924) with age-, sex-, and ethnicity-matched control subjects (n = 19,280) regarding the presence of asthma. Logistic regression models were utilized for univariate and multivariate analyses. Results: The prevalence of preceding asthma was higher in patients with BP than in control subjects (11.1 vs. 7.9%, respectively; p < 0.001). A history of asthma was associated with a 50% increase in the risk of BP (OR 1.45; 95% CI 1.30–1.62). The association was not altered greatly after adjusting for demographics (adjusted OR 1.43; 95% CI 1.28–1.61) as well as for demographics and comorbidities (adjusted OR 1.40; 95% CI 1.25–1.57). The average (SD) latency between the diagnosis of asthma and the development of BP was 12.5 (14.7) years. When compared with other patients with BP, those with a dual diagnosis of BP and asthma were older, had higher BMI, and were more frequently managed by corticosteroids and immunosuppressive and immunomodulatory adjuvants. Conclusions: Asthma confers a predisposition to the development of BP. Awareness of this association may be of help for physicians managing patients with BP and asthma. Further research is required to elucidate the mechanism underlying this observation.

Zusammenfassung Die durch SARS-CoV-2 verursachte Pandemie COVID-19 hat weitreichende direkte und indirekte medizinische Folgen. Dazu gehoren sowohl der Verlauf als auch die Behandlung vieler Krankheiten. Es wird immer deutlicher, dass Infektionen mit SARS-CoV-2 erhebliche immunologische Veranderungen verursachen konnen, die insbesondere auch pathogenetisch und/oder therapeutisch relevante Faktoren betreffen. Vor diesem Hintergrund fassen wir hier den aktuellen Wissensstand zur Interaktion von SARS-CoV-2/COVID-19 mit Mediatoren der akuten Phase der Entzundung (TNF, IL-1, IL-6), der Typ-1- und Typ-17-Immunantwort (IL-12, IL-23, IL-17, IL-36), Typ-2-Immunreaktionen (IL-4, IL-13, IL-5, IL-31, IgE), B-Zell-Immunitat, Checkpoint-Regulatoren (PD-1, PD-L1, CTLA4) und Signalwegen, die durch oral applizierte Medikamente moduliert werden (JAK, PDE4, Calcineurin), zusammen. Daruber hinaus diskutieren wir in diesem Zusammenhang die unspezifische Immunmodulation durch Glukokortikosteroide, Methotrexat, Malariamittel, Azathioprin, Dapson, Mycophenolsaure-Derivate und Fumarsaureester sowie angeborene Immunmechanismen neutrophiler Granulozyten. Aus diesen neueren Erkenntnissen leiten wir mogliche Implikationen fur die therapeutische Modulation der genannten immunologischen Mechanismen im Zusammenhang mit SARS-CoV-2/COVID-19 ab. Obwohl naturlich bei Patienten mit immunologisch vermittelten Krankheiten oder immunmodulierenden Therapien gro ss te Vorsicht geboten ist, scheint es, dass viele Behandlungen auch wahrend der COVID-19-Pandemie durchgefuhrt werden konnen; einige scheinen COVID-19 sogar zu lindern.

Background: Ulcerative colitis (UC) is a well-known underlying comorbidity of pyoderma gangrenosum (PG). However, the risk conferred by UC for the subsequent development of PG is yet to be elucidated. We aimed to estimate the magnitude of the association between UC and the subsequent occurrence of PG, which would enable us to assess the odds of PG developing in individuals with a history of UC. Methods: A population-based case-control study was conducted to compare PG patients (n = 302) and age-, sex- and ethnicity-matched control subjects (n = 1,497) regarding the presence of UC. Logistic regression models were utilized for univariate and multivariate analyses. Results: The prevalence of preexisting UC was greater in patients with PG than in controls (7.3 vs. 0.5%; p < 0.001). A 15-fold increase in the odds of PG in individuals with preexisting UC was observed (OR 14.62, 95% CI 6.45–33.18). The greatest risk of developing PG occurred in the first years following the diagnosis of UC (OR 35.50, 95% CI 4.35–289.60), and decreased thereafter to 10.03 (95% CI 1.83–55.03), 6.69 (95% CI 1.49–30.02), and 10.03 (95% CI 1.83–55.03) at 1–5, 5–10, and 10–15 years after the diagnosis of UC, respectively. This association retained its statistical significance following the adjustment for confounding factors (adjusted OR 10.78, 95% CI 4.55–25.52). Patients with both PG and UC were younger and had a lower prevalence of smoking than the remaining patients with PG. Conclusions: UC increases the odds of developing PG by 15-fold, with the highest probability of developing PG occurring within the first year after the diagnosis of UC. Patients with UC may be advised to avoid additional precipitating factors for the development of PG.

Although Crohn's disease (CD) is an established underlying disease in pyoderma gangrenosum (PG), studies comparing patients with PG and controls with respect to the presence of CD are lacking. Consequently, the relative risk imposed by CD for the development of PG is yet to be elucidated.The study aims to quantify the magnitude of the association between CD and subsequent development of PG, thus enabling to evaluate the risk of PG with CD.A matched case-control study was conducted in Israel comparing PG patients (The prevalence of CD was higher in patients with PG than in control subjects (7.0% vs. 0.3%, respectively;CD increases the odds of having PG by 28-folds. Patients with CD should be advised to avoid additional precipitating factors of PG like pathergy and smoking.

Background Although the association of bullous pemphigoid (BP) and psoriasis is well-established, the clinical and immunological features of patients with coexisting BP and psoriasis are yet to be investigated. Objective We aimed to estimate the prevalence of psoriasis amongst patients with BP and to elucidate the clinical and immunological characteristics of BP patients with comorbid psoriasis. Methods A retrospective cohort study including all consecutive patients diagnosed with BP throughout the years 2009-2019 in a tertiary referral centre. Results The study encompassed 273 patients with BP, of whom 11 (4.0%; 95% CI, 2.3-7.1%) had comorbid psoriasis. The onset of psoriasis preceded that of BP in 81.8% of patients by a median (range) latency of 26.5 (5.0-34.0) years. Compared to BP patients without psoriasis, those with BP and comorbid psoriasis were significantly younger at the onset of BP [71.8 (9.3) vs. 79.4 (9.8) years; P = 0.023], had a milder erosive phenotype [erosion/blister BPDAI mean (SD)score; 5 (4.1) vs. 22.3 (15.2); P = 0.025], lower levels of anti-BP180 NC16A serum autoantibodies [236.6 (266.3) vs. 556.2 (1323.6) U/mL; P = 0.008] and a higher prevalence of isolated linear C3 deposits (36.4% vs. 14.1%; P = 0.043) and a lower prevalence of linear immunoglobulin G deposits (36.4% vs. 68.7%; P = 0.025) along the dermal-epidermal junction by direct immunofluorescence microscopy. Conclusions Patients with BP and comorbid psoriasis present at a younger age with milder erosive phenotype and lower levels of pathogenic autoantibodies.