Pemphigus: Current and Future Therapeutic Strategies

Abstract

Pemphigus encompasses a heterogeneous group of autoimmune blistering diseases, which affect both mucous membranes and the skin. The disease usually runs a chronic-relapsing course, with a potentially devastating impact on the patients' quality of life. Pemphigus pathogenesis is related to IgG autoantibodies targeting various adhesion molecules in the epidermis, including desmoglein (Dsg) 1 and 3, major components of desmosomes. The pathogenic relevance of such autoantibodies has been largely demonstrated experimentally. IgG autoantibody binding to Dsg results in loss of epidermal keratinocyte adhesion, a phenomenon referred to as acantholysis. This in turn causes intra-epidermal blistering and the clinical appearance of flaccid blisters and erosions at involved sites. Since the advent of glucocorticoids, the overall prognosis of pemphigus has largely improved. However, mortality persists elevated, since long-term use of high dose corticosteroids and adjuvant steroid-sparing immunosuppressants portend a high risk of serious adverse events, especially infections. Recently, rituximab, a chimeric anti CD20 monoclonal antibody which induces B-cell depletion, has been shown to improve patients' survival, as early rituximab use results in higher disease remission rates, long term clinical response and faster prednisone tapering compared to conventional immunosuppressive therapies, leading to its approval as a first line therapy in pemphigus. Other anti B-cell therapies targeting B-cell receptor or downstream molecules are currently tried in clinical studies. More intriguingly, a preliminary study in a preclinical mouse model of pemphigus has shown promise regarding future therapeutic application of Chimeric Autoantibody Receptor T-cells engineered using Dsg domains to selectively target autoreactive B-cells. Conversely, previous studies from our group have demonstrated that B-cell depletion in pemphigus resulted in secondary impairment of T-cell function; this may account for the observed long-term remission following B-cell recovery in rituximab treated patients. Likewise, our data support the critical role of Dsg-specific T-cell clones in orchestrating the inflammatory response and B-cell activation in pemphigus. Monitoring autoreactive T-cells in patients may indeed provide further information on the role of these cells, and would be the starting point for designating therapies aimed at restoring the lost immune tolerance against Dsg. The present review focuses on current advances, unmet challenges and future perspectives of pemphigus management.

Keywords: BTK inhibitors; CAAR T-cell; anti-CD 20 antibodies; neonatal Fc receptor (FcRn); pemphigus; rituximab.

Figure 1

Pemphigus vulgaris: (A) Flaccid cutaneous blisters associated with erosions; (B) Multiple erosions of the tongue and of the lips; Paraneoplastic pemphigus: (C) haemorrhagic crusts and erosion of the lips. All the patients gave written informed consent for the publication of the pictures.

Figure 2

Pemphigus vegetans: vegetative lesions and erosions of the groin and genitals.

Figure 3

Pemphigus foliaceus: (A) Scaly and crusted erythematous plaques on the seborrheic areas; (B) Leafy and crusted circumscribed erosion on the back; (C) Scaly erythematous plaques on the seborrheic areas. All the patients gave written informed consent for the publication of the pictures.

Figure 4

Diagnostic of pemphigus: (A) Intraepidermal acantholysis in pemphigus vulgaris; (B) Subcorneal loss of adhesion in pemphigus foliaceus; (C) Reticular binding of IgG in pemphigus vulgaris.

Figure 5

Induction therapy in pemphigus. (A) mild pemphigus; (B) severe pemphigus. AZA, azathioprine; GC, glucocorticoids; MMF, mycophenolate mofetil; moAb, monoclonal antibody.

Figure 6

Maintenance therapy in pemphigus. (A) without anti-CD20 moAb; (B) with anti-CD20 moAb. GC, glucocorticoids; moAb, monoclonal antibody.

Figure 7

Therapy of relapse. (A) with corticosteroids only; (B) systemic corticosteroids combined with anti CD20 moAb; (C) systemic corticosteroids combined with other immunosuppressive agents. moAb, monoclonal antibody.

Figure 8

Mode of action of RTX in pemphigus. RTX induces depletion of B-cells and lymphoid resident memory B-cells by different mechanisms, including direct cell apoptosis, complement-dependent cytotoxicity and antibody-dependent cytotoxicity. The latter consists of the phagocytosis of opsonized B-cells by neutrophils, monocytes and macrophages, which express the Fcγ Receptor. Moreover, RTX significantly decreases T-cell function, by depleting antigen presenting B cells. Patients achieving durable responses have an increased naïve/memory B-cell ratio. Regulatory B-cells (B-regs) and regulatory T-cells (T-regs) are also increased, and are inhibitory on Dsg3-specific memory B-cells. On the contrary, patients with early relapses following B-cell repopulation have a decreased naïve/memory B-cell ratio. Reappearance of auto-reactive, Dsg3-specific T-cells contributes to activation of autoreactive B-cells and subsequent anti-Dsg IgG production.

Figure 9

Emerging therapies targeting auto-reactive B and T-cells in pemphigus. Ofatumumab, veltuzumab, and obinutuzumab are fully human or humanized monoclonal antibodies targeting CD20. Ofatumumab and veltuzumab are class I anti-CD20 monoclonal antibody, with a higher capacity of binding CD20 and inducing complement-dependent cytotoxicity compared to RTX. Obinutuzumab is a class II anti-CD20 monoclonal antibody, that has an increased affinity to the FcγIII receptor, resulting in a more potent antibody-dependent cytotoxicity. Bruton kinase (BTK) inhibitors interfere with B cell activation. BCR signaling induces migration of BTK from the cytosol to the cell membrane, though the interaction with phosphatidylinositol 3,4,5-triphosfate generated by phosphoinositide 3-kinase (PI3K). BTK is activated by Lyn and Syk and then actives downstream molecules including phospholipase C gamma 2 (PLCγ2) and Protein kinase C. The latter in turns activate different pro-inflammatory pathways including mitogen associated protein kinases (MAPK) and Nuclear Factor k B (NFkB). Chimeric autoantibody receptor (CAAR)-T-cells are engineered T-lymphocytes which express Dsg3 ectodomain, which allows recognition and subsequent killing of B-cells targeting Dsg3. Belimumab and atacicept target B-cell derived B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), respectively, which promote differentiation toward autoantibody-producing plasma cells. Inebilizumab is a monoclonal antibody targeting CD19 which is not only expressed on B cells but also plasma cells. Dupilumamb is a monoclonal antibody targeting interleukin (IL-4), which is one the main cytokine produced by T helper 2 cells and T follicular helper cell which induces autoantibody production by autoreactive B-cells.