Current Clinical Trials in Pemphigus and Pemphigoid

Autoimmune bullous dermatoses (AIBDs) are a group of rare chronic inflammatory skin diseases, which clinically manifest as blisters and erosions of the skin and/or mucosa. Immunologically, AIBDs are characterized and caused by autoantibodies targeting adhesion molecules in the skin and mucosa. According to the histological location of the blistering, AIBDs are classified into the following two main subtypes: pemphigus (intraepidermal blistering) and pemphigoid (subepidermal blistering). Most AIBDs were potentially life-threatening diseases before the advent of immunosuppressive drugs, especially systemic steroid therapies, which suppress pathogenic immunological activity. Although there have been recent advancements in the understanding of the pathogenesis of AIBDs, glucocorticosteroids and/or adjuvant immunosuppressive drugs are still needed to control disease activity. However, the long-term use of systemic immunosuppression is associated with major adverse events, including death. Based on the growing understanding of AIBD pathogenesis, novel treatment targets have emerged, some of which are currently being evaluated in clinical trials. Within this article, we review the current clinical trials involving pemphigus and pemphigoid and discuss the rationale that lead to these trials. Overall, we aim to foster insights into translational research in AIBDs to improve patient care

Fcγ Receptor IIB Controls Skin Inflammation in an Active Model of Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita (EBA) is an autoimmune skin blistering disease characterized by IgG autoantibodies (aAb) against type VII collagen (COL7). The mechanisms controlling the formation of such aAbs and their effector functions in the skin tissue are incompletely understood. Here, we assessed whether the inhibitory IgG Fc receptor, FcγRIIB, controls the development of autoimmune skin blistering disease in an active model of EBA. For this purpose, we immunized congenic EBA-susceptible B6.SJL-H2s (B6.s) and B6.s-Fcgr2b−/− mice with the immunodominant vWFA2 region of COL7. B6.s-Fcgr2b−/− mice developed a strong clinical phenotype with 15 ± 3.3% of affected body surface area at week 4. In contrast, the body surface area in B6.s mice was affected to a maximum of 5% at week 6 with almost no disease signs at week 4. Surprisingly, we already found strong but similar COL7-specific serum IgG1 and IgG2b aAb production at week 2. Further, aAb and C3b deposition in the skin of B6.s and B6.s-Fcgr2b−/− mice increased between weeks 2 and 6 after vWFA2 immunization. Importantly, neutrophil skin infiltration and activation was much stronger in B6s-Fcgr2b−/− than in B6.s mice and already present at week 2. Also, the early aAb response in B6.s-Fcgr2b−/− mice was more diverse than in wt B6.s mice. Reactive oxygen species (ROS) release from infiltrating neutrophils play a crucial role as mediator of skin inflammation in EBA. In line, sera from B6.s and B6.s-Fcgr2b−/− mice induced strong ROS release from bone marrow-neutrophils in vitro. In contrast to the antibody-transfer-induced EBA model, individual targeting of FcγRIII or FcγRIV decreased ROS release to 50%. Combined FcγR blocking abrogated ROS release from BM neutrophils. Also, ROS release induced by COL7-specific serum IgG aAbs was significantly higher using BM neutrophils from B6.s-Fcgr2b−/− than from B6.s mice. Together, our findings identified FcγRIIB as a suppressor of skin inflammation in the active EBA model through inhibition of early epitope spreading, protection from strong early neutrophil infiltration to and activation of neutrophils in the skin and suppression of FcγRIII activation by IgG1 aAbs which drive strong ROS release from neutrophils leading to tissue destruction at the dermal-epidermal junction

Dimethylfumarate Impairs Neutrophil Functions

Host defense against pathogens relies on neutrophil activation. Inadequate neutrophil activation is often associated with chronic inflammatory diseases. Neutrophils also constitute a significant portion of infiltrating cells in chronic inflammatory diseases, for example, psoriasis and multiple sclerosis. Fumarates improve the latter diseases, which so far has been attributed to the effects on lymphocytes and dendritic cells. Here, we focused on the effects of dimethylfumarate (DMF) on neutrophils. In vitro, DMF inhibited neutrophil activation, including changes in surface marker expression, reactive oxygen species production, formation of neutrophil extracellular traps, and migration. Phagocytic ability and autoantibody-induced, neutrophil-dependent tissue injury ex vivo was also impaired by DMF. Regarding the mode of action, DMF modulates—in a stimulus-dependent manner-neutrophil activation using the phosphoinositide 3-kinase/Akt-p38 mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 pathways. For in vivo validation, mouse models of epidermolysis bullosa acquisita, an organ-specific autoimmune disease caused by autoantibodies to type VII collagen, were employed. In the presence of DMF, blistering induced by injection of anti-type VII collagen antibodies into mice was significantly impaired. DMF treatment of mice with clinically already-manifested epidermolysis bullosa acquisita led to disease improvement. Collectively, we demonstrate a profound inhibitory activity of DMF on neutrophil functions. These findings encourage wider use of DMF in patients with neutrophil-mediated diseases

Epidermolysis Bullosa Acquisita: The 2019 Update

Epidermolysis bullosa acquisita (EBA) is an orphan autoimmune disease. Patients with EBA suffer from chronic inflammation as well as blistering and scarring of the skin and mucous membranes. Current treatment options rely on non-specific immunosuppression, which in many cases, does not lead to a remission of treatment. Hence, novel treatment options are urgently needed for the care of EBA patients. During the past decade, decisive clinical observations, and frequent use of pre-clinical model systems have tremendously increased our understanding of EBA pathogenesis. Herein, we review all of the aspects of EBA, starting with a detailed description of epidemiology, clinical presentation, diagnosis, and current treatment options. Of note, pattern analysis via direct immunofluorescence microscopy of a perilesional skin lesion and novel serological test systems have significantly facilitated diagnosis of the disease. Next, a state-of the art review of the current understanding of EBA pathogenesis, emerging treatments and future perspectives is provided. Based on pre-clinical model systems, cytokines and kinases are among the most promising therapeutic targets, whereas high doses of IgG (IVIG) and the anti-CD20 antibody rituximab are among the most promising “established” EBA therapeutics. We also aim to raise awareness of EBA, as well as initiate basic and clinical research in this field, to further improve the already improved but still unsatisfactory conditions for those diagnosed with this condition

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

Risk factors and sequelae of epidermolysis bullosa acquisita: A propensity-matched global study in 1,344 patients

Identification of risk factors and sequelae of any given disease is of key importance. For common diseases, primary prevention and disease management are based on this knowledge. For orphan diseases, identification of risk factors and sequelae has been challenging. With the advent of large databases, e.g., TriNetX, this can now be addressed. We used TriNetX to identify risk factors and sequelae of epidermolysis bullosa acquisita (EBA), a severe and orphan autoimmune disease. To date, there is only enigmatic information on EBA comorbidity. We recruited 1,344 EBA patients in the Global Collaborative Network of TriNetX. Using the “explore outcomes” function we identified 55 diagnoses with a different prevalence between EBA and no-EBA patients. We next performed propensity-matched, retrospective cohort studies in which we determined the risk of EBA development following any of the identified 55 diseases. Here, 31/55 diseases were identified as risk factors for subsequent EBA. Importantly, the highest risk for EBA were other chronic inflammatory diseases (CID), especially lupus erythematosus and lichen planus. Lastly, we determined the risk to develop any of the identified diseases after EBA diagnosis. Here, 38/55 diseases were identified as sequelae. Notably, EBA patients showed an increased risk for metabolic and cardiovascular disease, and thrombosis. Furthermore, the risk for CIDs, especially lupus erythematosus and lichen planus, was elevated. These insights into risk factors and sequelae of EBA are not only of clinical relevance, e.g., optimizing cardiovascular disease risk, but in addition, point to shared pathogenetic pathways between EBA and other inflammatory diseases

Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita (EBA) is a rare, but prototypical, organ-specific autoimmune disease, characterized and caused by autoantibodies against type VII collagen (COL7). Mucocutaneous inflammation, blistering, and scarring are the clinical hallmarks of the disease. Treatment of EBA is difficult and mainly relies on general immunosuppression. Hence, novel treatment options are urgently needed. The phosphatidylinositol-3-kinase (PI3K) pathway is a putative target for the treatment of inflammatory diseases, including EBA. We recently discovered LAS191954, an orally available, selective PI3Kδ inhibitor. PI3Kδ has been shown to be involved in B cell and neutrophil cellular functions. Both cell types critically contribute to EBA pathogenesis, rendering LAS191954 a potential drug candidate for EBA treatment. We, here, demonstrate that LAS191954, when administered chronically, dose-dependently improved the clinical phenotype of mice harboring widespread skin lesions secondary to immunization-induced EBA. Direct comparison with high-dose corticosteroid treatment indicated superiority of LAS191954. Interestingly, levels of circulating autoantibodies were unaltered in all groups, indicating a mode of action independent of the inhibition of B cell function. In line with this, LAS191954 also hindered disease progression in antibody transfer-induced EBA, where disease develops dependent on myeloid, but independent of B cells. We further show that, in vitro, LAS191954 dose-dependently impaired activation of human myeloid cells by relevant disease stimuli. Specifically, immune complex-mediated and C5a-mediated ROS release were inhibited in a PI3Kδ-dependent manner. Accordingly, LAS191954 also modulated the dermal–epidermal separation induced in vitro by co-incubation of immune complexes with polymorph nuclear cells, thus pointing to an important role of PI3Kδ in EBA effector functions. Altogether, these results suggest a new potential mechanism for the treatment of EBA and potentially also other autoimmune bullous diseases

A Mitochondrial Polymorphism Alters Immune Cell Metabolism and Protects Mice from Skin Inflammation

Several genetic variants in the mitochondrial genome (mtDNA), including ancient polymorphisms, are associated with chronic inflammatory conditions, but investigating the functional consequences of such mtDNA polymorphisms in humans is challenging due to the influence of many other polymorphisms in both mtDNA and the nuclear genome (nDNA). Here, using the conplastic mouse strain B6-mtFVB, we show that in mice, a maternally inherited natural mutation (m.7778G > T) in the mitochondrially encoded gene ATP synthase 8 (mt-Atp8) of complex V impacts on the cellular metabolic profile and effector functions of CD4+ T cells and induces mild changes in oxidative phosphorylation (OXPHOS) complex activities. These changes culminated in significantly lower disease susceptibility in two models of inflammatory skin disease. Our findings provide experimental evidence that a natural variation in mtDNA influences chronic inflammatory conditions through alterations in cellular metabolism and the systemic metabolic profile without causing major dysfunction in the OXPHOS system

C-type lectin receptor expression is a hallmark of neutrophils infiltrating the skin in epidermolysis bullosa acquisita

IntroductionInflammatory epidermolysis bullosa acquisita (EBA) is characterized by a neutrophilic response to anti-type VII collagen (COL7) antibodies resulting in the development of skin inflammation and blistering. The antibody transfer model of EBA closely mirrors this EBA phenotype.MethodsTo better understand the changes induced in neutrophils upon recruitment from peripheral blood into lesional skin in EBA, we performed single-cell RNA-sequencing of whole blood and skin dissociate to capture minimally perturbed neutrophils and characterize their transcriptome.ResultsThrough this approach, we identified clear distinctions between circulating activated neutrophils and intradermal neutrophils. Most strikingly, the gene expression of multiple C-type lectin receptors, which have previously been reported to orchestrate host defense against fungi and select bacteria, were markedly dysregulated. After confirming the upregulation of Clec4n, Clec4d, and Clec4e in experimental EBA as well as in lesional skin from patients with inflammatory EBA, we performed functional studies in globally deficient Clec4e−/− and Clec4d−/− mice as well as in neutrophil-specific Clec4n−/− mice. Deficiency in these genes did not reduce disease in the EBA model.DiscussionCollectively, our results suggest that while the upregulation of Clec4n, Clec4d, and Clec4e is a hallmark of activated dermal neutrophil populations, their individual contribution to the pathogenesis of EBA is dispensable

Reduced Skin Blistering in Experimental Epidermolysis Bullosa Acquisita After Anti-TNF Treatment

Epidermolysis bullosa acquisita (EBA) is a difficult-to-treat subepidermal autoimmune blistering skin disease (AIBD) with circulating and tissue-bound anti-type VII collagen antibodies. Different reports have indicated increased concentration of tumor necrosis factor a (TNF) in the serum and blister fluid of patients with subepidermal AIBD. Furthermore, successful anti-TNF treatment has been reported for individual patients with AIBD. Here we show that in mice, induction of experimental EBA by repeated injections of rabbit anti-mouse type VII collagen antibodies led to increased expression of TNF in skin, as determined by real-time polymerase chain reaction (PCR) and immunohistochemistry. To investigate whether the increased TNF expression is of functional relevance in experimental EBA, we inhibited TNF function using the soluble TNF receptor fusion protein etanercept (Enbrel) or a monoclonal antibody to murine TNF. Interestingly, mice that received either of these treatments showed significantly milder disease progression than controls. In addition, immunohistochemical staining demonstrated reduced numbers of macrophages in lesional skin in mice treated with TNF inhibitors compared with controls. Furthermore, etanercept treatment significantly reduced disease progression in immunization-induced EBA. In conclusion, increased expression of TNF in experimental EBA is of functional relevance, as both the prophylactic blockade of TNF and the therapeutic use of etanercept impaired induction and progression of experimental EBA. Thus, TNF is likely to serve as a new therapeutic target for EBA and AIBDs with a similar pathogenesis