Current and Innovated Managements for Autoimmune Bullous Skin Disorders: An Overview

Abstract

Autoimmune bullous skin disorders are a group of disorders characterized by the formation of numerous blisters and erosions on the skin and/or the mucosal membrane, arising from autoantibodies against the intercellular adhesion molecules and the structural proteins. They can be classified into intraepithelial or subepithelial autoimmune bullous dermatoses based on the location of the targeted antigens. These dermatoses are extremely debilitating and fatal in certain cases, depending on the degree of cutaneous and mucosal involvement. Effective treatments should be implemented promptly. Glucocorticoids serve as the first-line approach due to their rapid onset of therapeutic effects and remission of the acute phase. Nonetheless, long-term applications may lead to major adverse effects that outweigh the benefits. Hence, other adjuvant therapies are mandatory to minimize the potential harm and ameliorate the quality of life. Herein, we summarize the current therapeutic strategies and introduce promising therapies for intractable autoimmune bullous diseases.

Keywords: IgA pemphigus; autoimmune bullous dermatoses; bullous pemphigoid; dermatitis herpetiformis; epidermolysis bullosa acquisita; mucous membrane pemphigoid; paraneoplastic pemphigus; pemphigus foliaceus; pemphigus vulgaris.

Figure 1

Mechanisms of the emerging therapies of pemphigus vulgaris. These therapies target anti-Dsg3 B-cells or autoantibodies. ① Ofatumumab and veltuzumab are new second generation monoclonal antibodies targeting CD20 on the surface of B-cells. ② Engineered CAAR-T-cell expressing the Dsg3 ectodomain recognizes and forms cytolytic synapse with the pathognomonic B-cells and subsequently annihilates them. ③ Ibrutinib and rilzabrutinib prohibit the proliferation of B-cells through blocking of the BTK. ④ Ianalumab inhibits the signal transduction of BAFF by binding to its receptor and contributes to depletion of B-cells. ⑤ Efgartigimod and SYNT001 occupy the binding sites of anti-Dsg3 antibodies to the FcRn and accelerate their clearance. ⑥ PolyTregs suppress the adaptive immune cells via inhibitory cytokines and terminate the differentiation of B-cells toward plasma cells. Abbreviations: Dsg3, desmoglein 3; CAAR-T-cell, chimeric autoantibody receptor T-cells; BTK, Bruton tyrosine kinase; BAFF, B-cell activating factor; BAFFR, B-cell activating factor receptor; FcRn, neonatal Fc receptor; PolyTregs, polyclonal regulatory T-cells.

Figure 2

Mechanisms of the emerging therapies of bullous pemphigoid. ① Omalizumab prohibits the adherence of IgE antibodies to the basement membrane proteins BP180 and BP230. ② Avdoralimab blocks the subsequent binding of the C5aR on the mast cells to the complements and deters the process of degranulation. ③ In the upstream, dendritic cells release IL-4 and IL-23 which then activate Th2 and Th17 cells, respectively. Ustekinumab, tildrakizumab and ixekizumab are therefore applied to inhibit the cascade. ④ In the blisters, chemokines result in recruitment of multiple innate and adaptive cells of which eosinophils play the pivotal role. Dupilumab, mepolizumab, and bertilimumab targeting the downstream products of eosinophils (IL-4/IL-13, IL-5 and eotaxin) may reduce further blister formation. ⑤ AKST4290 interacts with the receptor of eotaxin CCR3 causing downregulation of the eosinophils. Abbreviations: IgE, immunoglobulin E; IgG, immunoglobulin G; C5aR, C5a receptor; IL, interleukin; Th, T-helper; CCR3, C-C chemokine receptor 3.