Drug Development in Pemphigoid Diseases

Abstract

Despite detailed insights into the pathogenesis of pemphigoid diseases, their treatment still relies on unspecific immunosuppression. Since such treatment contributes significantly to the high patient morbidity and increased mortality, we propose pathways that may facilitate drug development for pemphigoid diseases. With this we aim to foster translational research to develop new treatment strategies for patients with pemphigoid 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. Theme issue: Blistering skin disorders Advances in dermatology and venereology Acta Dermato-Venereologica 113 Drug development in pemphigoid diseases Theme issue: Blistering skin disordersof translational research in this field, which is expected to improve the treatment of patients with PD in the future. New drug approvals, more clinical trials, and personalized and curative treatments are expected.

C5aR2 Deficiency Ameliorates Inflammation in Murine Epidermolysis Bullosa Acquisita by Regulating Fcγ Receptor Expression on Neutrophils

“…Many insights into the pathogenesis of EBA have been gained by the use of animal models (Bieber and Ludwig, 2020;Kasprick et al, 2019;Nishie, 2014). Both antibody transfer and immunization-based animal models have been utilized to discover and define the importance of C5aR1 in the pathogenesis of EBA (Iwata et al, 2015;Mihai et al, 2018;Sitaru et al, 2005).…”

The relevance of complement in pemphigoid diseases: A critical appraisal

“…In a phase I trial, sutimlimab, a humanized monoclonal IgG4 antibody directed against the C1s subunit of human complement component C1, was shown to partially or completely abrogate C3 deposition along the DEJ in BP patients ( 153 ). Nomacopan (formerly known as coversin) is a bifunctional inhibitor of both C5 and leukotriene B4 ( 88 , 154 ). EBA mice treated with coversin were almost completely protected from disease development mainly due to the C5-inhibitory effect of this compound ( 88 ).…”

“…demonstrated in a phase IIa clinical trial that nomacopan successfully reduced the clinical disease severity in BP patients, without any serious adverse event ( 152 ). Furthermore, several other complement-targeting treatments have been developed that so far have not been evaluated in preclinical and clinical settings ( 151 , 154 ).…”

Heat Shock Protein 90 (Hsp90) and Hsp70 as Potential Therapeutic Targets in Autoimmune Skin Diseases

“…Autoimmune bullous diseases (AIBDs) belong to a relatively rare and potentially life-threatening organ-specific group of inflammatory skin diseases characterized by the presence of autoantibodies against various structural proteins of the skin present in desmosomes (e.g., pemphigus vulgaris-PV) and hemidesmosomes (e.g., bullous pemphigoid-BP and epidermolysis bullosa acquisita-EBA), or against epidermal/tissue transglutaminases present in Duhring disease (also known as dermatitis herpetiformis-DH). Despite understanding of the pathophysiology of AIBDs, in which both innate and adaptive mechanisms of the immune response are undoubtedly involved, treatment for this group of diseases remains a challenge, due to frequent relapses after the discontinuation of therapy, numerous side effects associated with using, e.g., corticosteroids, or due to the lack of a fully effective drug [ 67 , 68 , 69 ].…”