Novel Therapies for Pemphigus Vulgaris
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LEADING ARTICLE
Novel Therapies for Pemphigus Vulgaris Emily M. Altman1
© Springer Nature Switzerland AG 2020
Abstract Pemphigus vulgaris (PV) is a severe chronic autoimmune blistering disease that affects the skin and mucous membranes. It is characterized by suprabasal acantholysis due to disruption of desmosomal connections between keratinocytes. Autoantibodies against desmosomal cadherins, desmoglein 3 and 1, have been shown to induce disease. Certain human leukocyte antigen (HLA) types and non-HLA foci confer genetic susceptibility. Until the discovery of corticosteroids in the 1950s, PV was 75% fatal. Since then, multiple PV treatments, such as systemic corticosteroids and adjunctive therapy with immunosuppressive medications (mycophenolate mofetil, azathioprine, cyclophosphamide, cyclosporine, methotrexate, gold, and others) have been introduced; however, none have led to long-term remissions and many have undesired adverse effects. Our growing understanding of the pathophysiologic mechanisms in PV is leading to development of new targeted therapies, such as intravenous immunoglobulin, anti-CD20 monoclonal antibodies, inhibitors of Bruton tyrosine kinase and neonatal Fc receptors, and adoptive cellular transfer, that may result in lasting control of this life-threatening disease. Key Points Pemphigus vulgaris is a prototypical autoimmune disease that results from production of autoantibodies that target keratinocyte adherence proteins. New treatment options, from targeting the B cell receptor to manufacturing “hunter” cytotoxic T cells are being developed to combat this severe blistering disease.
1 Introduction Pemphigus vulgaris (PV) is a life-threatening, antibodymediated, autoimmune, blistering disease that affects the skin and mucous membranes. It is characterized by loss of adhesion of epidermal keratinocytes above the basal layer due to disruption of desmosomes and formation of flaccid blisters and erosions. PV has a progressive course, with loss * Emily M. Altman [email protected] 1
Department of Dermatology, University of New Mexico, 1021 Medical Arts Avenue NE, Albuquerque, NM 87102, USA
of body fluids and proteins, and secondary infections, which may lead to sepsis and cardiac failure [1, 2]. Identification of several human leukocyte antigen (HLA) alleles, such as HLA-DRB1*0402 and HLA-DQB1*0503, as risk factors for PV points to genetic susceptibility [3, 4]. The ST18 gene, located outside the major histocompatibility complex (MHC), is significantly associated with PV in a population-specific manner [5–7]. Although disease onset is at approximately 50–60 years of age, PV can occur at any age. PV preferentially affects women, with a female:male ratio of up to 1:1.9 [8]. The pathophysiology of PV most likely involves a combination of autoreactive B cells [9], desmoglein 3 (Dsg3)specific T helper cell (TH)1 and TH2-type CD4 + T cells [10], and decreased function of regulatory T and possibly B lym reg cells) [11–13]. IgG phocytes (T regulatory [ Treg] and B autoantibodies (particularl
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