Evaluation of Nomacopan for Treatment of Bullous Pemphigoid:A Phase 2a Nonrandomized Controlled Trial

Importance: Bullous pemphigoid is a difficult-to-treat autoimmune blistering skin disease that predominantly affects older adults and is associated with an increased mortality rate. Objective: To examine the safety and therapeutic potential of nomacopan, an inhibitor of leukotriene B4and complement C5, in patients with bullous pemphigoid. Design, Setting, and Participants: This multicenter, single-group, phase 2a nonrandomized controlled trial was conducted in the dermatology departments of universities in the Netherlands and Germany. Participants were enrolled between September 2018 and April 2020. Older adult patients (aged ≥55 years) with mild to moderate, new-onset or relapsing bullous pemphigoid were recruited into the study. Interventions: Patients received nomacopan, 90 mg, subcutaneously on day 1 and 30 mg subcutaneously daily until day 42. Main Outcomes and Measures: The primary end point was the proportion of patients with grade 3 to 5 (severe) adverse events associated or possibly associated with nomacopan. Secondary end points included mean absolute and percentage changes in the Bullous Pemphigoid Disease Area Index (BPDAI) activity score, the BPDAI pruritus score, and the patient-reported outcome measures Dermatology Life Quality Index (DLQI) and Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL). Results: A total of 9 patients (median [range] age, 75 [55-85] years) with bullous pemphigoid were included in the trial, of whom 5 were women (55.6%). No serious adverse events associated with nomacopan were found. The mean (90% CI) BPDAI activity score decreased from 32.0 (8.7) points on day 1 to 19.6 (9.0) points on day 42. Seven of 9 patients (77.8%) responded to nomacopan with a reduction in the BPDAI activity score of at least 8 points between days 1 and 42; in 3 responders, the reduction was 80% or greater. On day 42, the mean (90% CI) BPDAI pruritus score had decreased by 6.8 (4.6) points from 17.6 (4.0) points on day 1. The mean (90% CI) DLQI score decreased from 11.3 (4.2) points at baseline to 6.4 (3.8) points by day 42, and the mean (90% CI) TABQOL score decreased from 14.6 (5.4) points at baseline to 10.3 (5.0) points on day 42. Conclusions and Relevance: Results of this nonrandomized controlled trial suggest that nomacopan can be well tolerated in older patients with bullous pemphigoid and may have therapeutic benefits for suppressing acute flares of this disease. A larger, placebo-controlled randomized clinical trial is warranted to confirm this safety profile and to establish nomacopan as a new therapeutic option for bullous pemphigoid. Trial Registration: ClinicalTrials.gov Identifier: NCT04035733

The relevance of complement in pemphigoid diseases: A critical appraisal

Pemphigoid diseases are autoimmune chronic inflammatory skin diseases, which are characterized by blistering of the skin and/or mucous membranes, and circulating and tissue-bound autoantibodies. The well-established pathomechanisms comprise autoantibodies targeting various structural proteins located at the dermal-epidermal junction, leading to complement factor binding and activation. Several effector cells are thus attracted and activated, which in turn inflict characteristic tissue damage and subepidermal blistering. Moreover, the detection of linear complement deposits in the skin is a diagnostic hallmark of all pemphigoid diseases. However, recent studies showed that blistering might also occur independently of complement. This review reassesses the importance of complement in pemphigoid diseases based on current research by contrasting and contextualizing data from in vitro, murine and human studies

Anti-BP180 Autoantibodies Are Present in Stroke and Recognize Human Cutaneous BP180 and BP180-NC16A

Objective: Current evidence has revealed a significant association between bullous pemphigoid (BP) and neurological diseases (ND), including stroke, but the incidence of BP autoantibodies in patients with stroke has not previously been investigated. Our study aimed to assess BP antigen-specific antibodies in stroke patients.Design: One hundred patients with stroke and 100 matched healthy controls were randomly selected for measurement of anti-BP180/BP230 IgG autoantibodies by enzyme-linked immunosorbent assay (ELISA), salt-split indirect immunofluorescence (IIF), and immunoblotting against human cutaneous BP180 and BP180-NC16A.Results: Anti-BP180 autoantibodies were found in 14 (14.0%) patients with stroke and 5 (5.0%) of controls by ELISA (p < 0.05). Sera from 13 (13.0%) patients with stroke and 3 (3.0%) controls reacted with 180-kDa proteins from human epidermal extract (p < 0.05). 11 (11.0%) of stroke and 2 (2.0%) of control sera recognized the human recombinant full length BP180 and NC16A (p < 0.05). The anti-BP180-positive patients were significantly younger than the negative patients at the time of stroke (p < 0.001).Conclusion: Development of anti-BP180 autoantibodies occurs at a higher frequency after stroke, suggesting BP180 as a relatively common autoantigen after stroke and providing novel insights into BP pathogenesis in aging

BP180-specific IgG is associated with skin adverse events, therapy response and overall survival in non-small cell lung cancer patients treated with checkpoint inhibitors

BACKGROUND: Anti-PD1/PD-L1 therapy frequently entails immune-related adverse events (irAEs) and biomarkers to predict irAEs are lacking. While checkpoint inhibitors have been found to re-invigorate T-cells, the relevance of autoantibodies remains elusive. OBJECTIVE: Our aim was to explore whether IgG autoantibodies directed against co-expressed antigens by tumor tissue and healthy skin correlate with skin irAEs and therapy outcome. METHODS: We measured skin-specific IgG via ELISA in non-small cell lung cancer (NSCLC) patients, who received anti-PD1/PD-L1 treatment between July 2015 and September 2017 at the Kantonsspital St. Gallen. Sera were sampled at baseline and during therapy after 8 weeks. RESULTS: Analysis of publicly available tumor expression data revealed that NSCLC and skin co-express BP180, BP230 and type VII collagen. Of 40 recruited patients, 16 (40%) developed a skin irAE. Only elevated anti-BP180 IgG at baseline significantly correlated with the development of skin irAEs (P=.04), therapy response (P=.01) and overall survival (P=.04). LIMITATIONS: The patients were recruited in a single tertiary care center. CONCLUSIONS: Our data suggest that the level of anti-BP180 IgG of NSCLC patients at baseline is associated with better therapy response, overall survival and a higher probability to develop skin irAEs during anti-PD1/PD-L1 treatment

Pathogenic Activation and Therapeutic Blockage of FcαR-Expressing Polymorphonuclear Leukocytes in IgA Pemphigus

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

Blocking soluble Fas Ligand ameliorates pemphigus: PC111 efficacy in ex-vivo human pemphigus models

Pemphigus is a life-threatening, chronic, autoimmune bullous disease affecting both the skin and the mucous membranes. Based on the mainstream concept that blister formation occurs upon binding of autoantibodies to their antigen proteins (desmoglein1, DSG1 and desmoglein3, DSG3), current therapies mostly aim to suppress the immune system. To avoid the severe side effects associated with the chronic use of immunosuppressive treatments, we have developed PC111, a fully human monoclonal antibody targeting human Fas ligand (FasL). We have provided a number of in vitro and in vivo evidences showing that soluble FasL induces keratinocyte apoptosis followed by acantholysis. An anti-murine FasL prevents blister formation in the pemphigus neonatal mouse model. To confirm the mechanism of action (MoA) and the efficacy of PC111 in a human pemphigus context, we used the keratinocyte dissociation assay and two independent Human Skin Organ Cultures (HSOC) pemphigus models. PC111 reduced acantholysis in vitro, as shown by the dose-dependent reduction of fragments in the monolayer cultures. In the first HSOC model, normal human skin was subcutaneously injected with a scFv antibody fragment directed against DSG1 and DSG3, resulting in a severe acantholysis (70-100%) after 24 hours. PC111 inhibited blister formation to around 50% of control. In the second model, normal human skin was injected with a mixture of pemphigus patients’ autoantibodies resulting in a less severe acantholysis (20-30%). PC111 significantly suppressed blister formation to more than 75% up to 72 hours. These results confirm PC111 MoA and demonstrates the efficacy of the anti-FasL antibody also in a pemphigus setting

Numerical simulation of heat transfer in a large room with a working gas infrared emitter

The article presents a new approach to determining the main characteristics of the thermal regime in the buildings and structures heated by the gas infrared emitters, based on the analysis of convective heat transfer in the air and thermal conductivity in the enclosing structures. The authors have considered a mathematical model of turbulent heat transfer in the framework of the standard k-e model under radiant heating conditions. The simulation was carried out for a large room with an approximation to the real operating conditions of an industrial facility. The options for heating an empty room and the room with an object were considered

The gut microbiome in bullous pemphigoid: implications of the gut-skin axis for disease susceptibility

Bullous pemphigoid (BP) is an autoimmune blistering disease that primarily affects the elderly. An altered skin microbiota in BP was recently revealed. Accumulating evidence points toward a link between the gut microbiota and skin diseases; however, the gut microbiota composition of BP patients remains largely underexplored, with only one pilot study to date, with a very limited sample size and no functional profiling of gut microbiota. To thoroughly investigate the composition and function of the gut microbiota in BP patients, and explore possible links between skin conditions and gut microbiota, we here investigated the gut microbiota of 66 patients (81.8% firstly diagnosed) suffering from BP and 66 age-, sex-, and study center-matched controls (CL) with non-inflammatory skin diseases (132 total participants), using 16S rRNA gene and shotgun sequencing data. Decreased alpha-diversity and an overall altered gut microbial community is observed in BP patients. Similar trends are observed in subclassifications of BP patients, including first diagnoses and relapsed cases. Furthermore, we observe a set of BP disease-associated gut microbial features, including reduced Faecalibacterium prausnitzii and greater abundance of pathways related to gamma-aminobutyric acid (GABA) metabolism in BP patients. Interestingly, F. prausnitzii is a well-known microbiomarker of inflammatory diseases, which has been reported to be reduced in the gut microbiome of atopic dermatitis and psoriasis patients. Moreover, GABA plays multiple roles in maintaining skin health, including the inhibition of itching by acting as a neurotransmitter, attenuating skin lesions by balancing Th1 and Th2 levels, and maintaining skin elasticity by increasing the expression of type I collagen. These findings thus suggest that gut microbiota alterations present in BP may play a role in the disease, and certain key microbes and functions may contribute to the link between gut dysbiosis and BP disease activity. Further studies to investigate the underlying mechanisms of the gut-skin interaction are thus clearly warranted, which could aid in the development of potential therapeutic interventions