Autoimmune Pemphigus: Latest Advances and Emerging Therapies

Abstract

Pemphigus represents a group of rare and severe autoimmune intra-epidermal blistering diseases affecting the skin and mucous membranes. These painful and debilitating diseases are driven by the production of autoantibodies that are mainly directed against the desmosomal adhesion proteins, desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1). The search to define underlying triggers for anti-Dsg-antibody production has revealed genetic, environmental, and possible vaccine-driven factors, but our knowledge of the processes underlying disease initiation and pathology remains incomplete. Recent studies point to an important role of T cells in supporting auto-antibody production; yet the involvement of the myeloid compartment remains unexplored. Clinical management of pemphigus is beginning to move away from broad-spectrum immunosuppression and towards B-cell-targeted therapies, which reduce many patients' symptoms but can have significant side effects. Here, we review the latest developments in our understanding of the predisposing factors/conditions of pemphigus, the underlying pathogenic mechanisms, and new and emerging therapies to treat these devastating diseases.

Keywords: advance in pemphigus; autoimmune bullous diseases; autoimmunity; pemphigus; pemphigus treatment.

FIGURE 1

Erosions of the alvealor gingiva and attached mucosa (A) and conjuctival involvement with episcleritis (B) in patients with pemphigus vulgaris. Puff pastry-like scales and crusts on the periorbital skin of a patient with pemphigus foliaceus (C). Severe stomatitis crusting and bleeding erosions on the lips that extended beyond the vermilion (D1), severe pseudomembranous conjuctivitis with mucus discharge and eyelid erosions (D2), diffuse lingual erotions (D3) in patient with paraneoplastics pemphigus. Vegetative plaque of pemphigus vegetans on the patient’s occipital scalp (E). Post-pustular crusts with rounded or annular disposition in the trunk and neck in a patient with profuse IgA pemphigus (F). Trunk lesions with annular lesions in a pemphigus herpetiformis patient (G).

FIGURE 2

Mode of action of the pathogenic autoantibodies in pemphigus. (A) Interaction of pathogenic autoantibodies the NH2-terminal of desmosomal protien leading to steric hindrance of trans-Dsg binding. (B) Binding of autoantibodies to desmoglein induce an alteration of cellular signaling affecting components of multiple pathways including p38 MAPK (p38), protien kinase C (PKC) including an internalization of Dsg3. The autoantibodies binding reduce the RhoA activity in the p38MPAK-dependent manner which impact the reorganization of the actin cytoskeleton and drive further loss of desmosomal integrity. Caspace signaling may be activated by signal induced by the binding of autoantibodies to desmoglein by the Fas ligand/receptor pathway including pre-apoptotic caspase signaling. (C) Anti-keratinocyte α-acetycholine receptor (AChR) IgG autoantibodies induce signal causing disassembly of desmosomes, leading to acantholysis and blistering. In PNP, autoantibody binding also seems to inhibit A2ML1 (α-2 microglobulin-like 1) impacting the activation of a protease inhibitor. For a recent in-depth review see Schmitt and Waschke (2021).