Pemphigus vulgaris (PV) is an autoimmune blistering disease that involves both mucous membranes as well as the skin and it is characterized by serum immunoglobulin G (IgG) autoantibodies against desmoglein 1 and 3, two major components of desmosomes. 

Glucocorticoids can dramatically improve the prognosis of patients affected by PV. However, the long-term use of high-dose corticosteroids and adjuvant steroid-sparing immunosuppressants can lead to several adverse events like severe infections, secondary impairment of adrenal glands, osteoporosis, hyperglycemia, and hypertension.

Rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, has been recently approved as an in-label therapy for PV, causing an improvement in the prognosis and a loftier remission rate. 

Also, other anti-B-cell therapies and several anti-CD20 biosimilars have been familiarized in clinical practice. 

A recent article illustrated present and future therapeutic approaches in PV.

Current therapies

Corticosteroids: Prednisolone is often given as initial therapy in PV in association with immunosuppressive agents. Still, prednisolone monotherapy is recommended as first-line therapy. 

Azathioprine (AZA): AZA diminishes purine metabolism and obstructs the synthesis of DNA, RNA, and proteins. It also reduces Langerhans cells and monocytes, and the activity of T- and B-lymphocytes. Furthermore, AZA intercepts T-helper-cell-dependent responses of B-cells. 

Mycophenolate mofetil (MMF): MMF suppresses the immune system by selectively blocking inosine monophosphate dehydrogenase, which produces a downregulation of the pathway of purine synthesis in T- and B-cells. Its mode of action makes it a safer corticosteroid-sparing drug compared to other immunosuppressive drugs.

Cyclophosphamide (CYP): CYP is an alkylating prodrug that blocks the release of cytokines and reduces lymphocytic inflammation. It is recommended as a rescue drug, because its administration is described by several adverse events, such as nausea, fatigue, pancytopenia, and alopecia.

RTX: It is a chimeric monoclonal anti-CD20 antibody, and it causes B-cell depletion through different mechanisms like- direct induction of apoptosis; complement-dependent cytotoxicity; antibody-dependent cytotoxicity; antibody-dependent phagocytosis, and trogocytosis.

The optimal RTX dose in PV remains debatable. Two main protocols have been proposed: 2 intravenous infusions of 1000 mg each, separated by 2 weeks (rheumatoid arthritis protocol), and 4 infusions of 500 mg each, every week.

Ofatumumab: Ofatumumab is a fully human anti-CD20 monoclonal antibody employed as therapy in chronic lymphocytic leukemia and in PV patients who develop side effects or loss of response to RTX.

Intravenous immunoglobulin (IVIG): IVIG is used as immunomodulatory therapy for several inflammatory disorders, with the main mechanism of action believed the implementation of degradation of immunoglobulins by binding the neonatal Fc receptor (FcRn). The standard administration schedule is 2 g/kg in 5 days (400 mg/kg/day in 5 days) in that IVIG does not show an immunosuppressive activity. It can be administered along with systemic corticosteroids and other immunosuppressants in recalcitrant PV.

Immunoadsorption (IA): The combination of IA with immunosuppressive therapies is deemed an effective treatment for pemphigus patients with severe activity because IA allows immediate removal of pathogenic autoantibodies. It is believed an effective treatment in patients with severe disease (>30% of the body surface or >25% of genital or oral mucosa) or with involvement of the conjunctiva or esophagus.

Future therapeutic approaches

Chimeric antigen receptor (CAR)-T-cell therapies: CAR-T-cell therapy has been depicted as a promising therapy in hematology. In a PV mouse model, chimeric autoantibody receptor T cells therapy decreased pathogenic IgG antibodies and improved the clinical picture.

Antineonatal FcRn: The FcRn has been shown to play a central role in the homeostasis of IgG. Indeed, the IgG-FcRn complex bypasses the degradation of IgG, causing recycling and release of IgG. It is reported that blocking FcRn can prevent PV from causing acantholysis. 

As PV remains a therapeutic challenge for clinicians, knowledge, and management of multiple therapeutic choices for patients with PV would help in better patient management.

Source: Didona D, Paolino G, Di Zenzo G, et al. Pemphigus vulgaris: present and future therapeutic strategies. Dermatol Pract Concept. 2022;12(1):e2022037.