Pemphigus Vulgaris: Present and Future Therapeutic Strategies.

Pemphigus vulgaris (PV) belongs to the group of autoimmune blistering diseases. PV can affect not only mucous membranes, but also the skin and it is characterized by serum IgG autoantibodies against desmoglein 1 and 3, two major components of desmosomes. The introduction of glucocorticoids improved dramatically the prognosis of patients affected by PV. However, long-term use of high dose corticosteroids and adjuvant steroid-sparing immunosuppressants can lead to several adverse events. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been recently approved as in-label therapy for PV, leading to an improvement of the prognosis and higher remission rate. Furthermore, other anti B-cell therapies and several anti-CD20 biosimilars have been introduced in the clinical practice. We focused on present and future therapeutic approaches in PV. ©2022 Didona et al.

Introduction

Pemphigus vulgaris (PV) belongs to autoimmune blistering diseases and it is characterized by flaccid blisters and erosions, that can involve not only the skin, but also mucous membranes [1]. Three main forms of pemphigus are described: PV, pemphigus foliaceus (PF), and paraneoplastic pemphigus [1-6].

Methods

We conducted a review to identify studies that documented the current therapeutic strategies for pemphigus vulgaris, as well as the future ones. All type of study, in English language, was considered eligible for this review, including case reports and case series. The main search was conducted in the electronic databases of MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to January 2021 using different combinations of the following terms: “pemphigus”, “pemphigus vulgaris”, “treatment” and “therapy”. Additionally, we concluded the manual search by reviewing all relevant citations within the selected and identified articles.

Epidemiology

PV is the most frequent type of pemphigus [1]. It usually affects people between 50–60 years of age [7]. A female to male ratio of 5.0 was reported in the USA [7]. In the American general population, an annual incidence of 4.2/1,000,000 inhabitants was reported, but it was much higher in the Jewish-American population [7]. This is due to the most prominent expression of specific HLA class II genes in PV patients with Jewish background, such as HLA-DRB1*0402 and HLA-DQB1*0503 [7].

Clinical Features of PV

PV usually arises with painful and refractory oral erosions (Figure 1) [1]. Furthermore, other mucous membranes can be affected [1]. Most of patients also develop flaccid skin blisters that rapidly evolve into oozing erosions (Figure 2) [1]. Rarely, pemphigus patients show a clinical and serological transition from PV to PF or conversely. This phenomenon could be due to the epitope spreading, a process of diversification of B- or T-cell responses from the initial dominant epitope to a second one [8].

Figure 1

Large erosions of the oral mucosa.

Figure 2

Multiple erosions on the back of this male patient.

Pathogenesis

Cutaneous desmoglein-1 (Dsg1) can be expressed in the whole epidermis, cutaneous Dsg3 is typically found in the lower epidermis, while in the mucosa Dsg1 and Dsg3 are located in the whole squamous layer, with a higher expression of Dsg3 [9]. Therefore, PV patients who show only anti-Dsg1 immunoglobulin G (IgG) serum antibodies develop only skin blisters, and, in the case of detectable anti-Dsg3 IgG serum antibodies, the clinical phenotype is characterized by erosions or ulcerations of mucosal membranes [10]. Furthermore, the production of both anti-Dsg1 and anti-Dsg3 IgG serum autoantibodies provokes skin and mucosal lesions [10].

Evidence suggests that anti-Dsg1 and anti-Dsg3 autoantibodies are responsible for a loss of cell-cell adhesion between keratinocytes [11,12]. The most important targets for autoantibodies in PV are represented by the extracellular domains of Dsg [13,14]. Further mechanisms can also lead to acantholysis in PV, such as Dsg endocytosis and desmosome disassembly [15,16], and intercellular stretch at non-acantholytic cell layers caused by pathogenic autoantibodies [17,18]. In addition, non-Dsg IgG serum autoantibodies have been reported as important in PV pathogenesis, including those directed against desmocollins, mitochondria, pemphaxin, and alpha-9 acetylcholine receptor [13,19].

Diagnosis of PV

The diagnosis of PV requires not only compatible clinical features, but evidence of pathological features of involved skin and the presence of autoantibodies by direct immunofluorescence microscopy of non-affected skin. Indirect immunofluorescence microscopy, enzyme-linked immunosorbent assay and other techniques have a confirmatory role [5].

The most important pathological feature is the intraepidermal acantholysis [20]. Direct immunofluorescence of non-affected skin detects IgG and proteins of complement C3 (C3) on epidermal keratinocytes (Figure 3) [20,21]. Indirect immunofluorescence on monkey esophagus detects a fishnet pattern due to IgG antibodies reactivity to cell membrane of epithelial or epidermal cells [20].

Figure 3

Deposition of IgG and/or C3 on the surface of epidermal keratinocytes detected by direct immunofluorescence. C3 = proteins of complement C3; IgG = Immunoglobulin G.

Current Therapies

Corticosteroids

Prednisolone is usually administered as initial therapy in PV in association with immunosuppressive agents, such as azathioprine (AZA) and mycophenolate mofetil (MMF), or anti-CD20 monoclonal antibodies [1]. In patients with several comorbidities and in those who cannot undergo a therapy with anti-CD20 monoclonal antibodies or immunosuppressive agents, prednisolone as monotherapy is still recommended as first-line therapy [1]. Nevertheless, plenty of side effects have been described after prolonged corticosteroid (CS) therapy, including severe infections, secondary impairment of adrenal glands, osteoporosis, hyperglycemia, and hypertension [1].

AZA

AZA downregulates purine metabolism, and blocks the synthesis of DNA, RNA, and proteins. In addition, AZA causes a reduction of Langerhans cells and monocytes, and reduces the activity of T- and B-lymphocytes [1]. Furthermore, AZA blocks T-helper-cell dependent responses of B-cells [1]. AZA dosage should be adapted to thiopurine-methyltransferase activity, the enzyme responsible for AZA metabolism. Adverse events (AEs) are reported in up to 30% of patients, including nausea, pancreatitis, diarrhea, aphthous stomatitis, and maculopapular rash [1]. Pancytopenia and hepatotoxicity are reported as severe AEs [1].

MMF

MMF leads to a suppression of the immune system by a selective blockade of inosine monophosphate dehydrogenase, that produces a downregulation of the pathway of purine synthesis in T- and B-cells [1]. Because of its mode of action, MMF represents a safer CS-sparing drug compared to other immunosuppressive drugs [1]. Moderate gastrointestinal AEs are frequently reported [1]. In addition, MMF can increase the risk of hematologic malignancies, skin basal cell, and squamous cell carcinoma [1].

Cyclophosphamide

Cyclophosphamide (CYP) is an alkylating prodrug [1]. It is converted in the liver into 2 active metabolites, which cause cell death through the downregulation of DNA replication. CYP blocks the release of cytokines and reduces the lymphocytic inflammation [1]. It is recommended as a rescue drug, since its administration is characterized by several AEs, such as nausea, fatigue, pancytopenia, and alopecia [1]. A severe complication of CYP treatment is hemorrhagic cystitis, which can be avoided with the administration of adequate fluid intake and sodium 2-mercaptoethane sulfonate [1]. CYP administration can cause transitional cell carcinoma of the bladder [1]. In addition, transient or lasting impairment of gonadal function has been reported [1].

Rituximab

Rituximab (RTX) is a chimeric monoclonal anti-CD20 antibody, that targets CD20, a transmembrane receptor, expressed at several stages of the B-cell maturation [22]. RTX causes B-cell depletion through different mechanisms: 1) direct induction of apoptosis; 2) complement-dependent cytotoxicity; 3) antibody-dependent cytotoxicity; 4) antibody-dependent phagocytosis; and 5) trogocytosis [23,24]. The last mechanism is characterized by the elimination of RTX-CD20 complexes by macrophages, that causes cell death by a still unknown mechanism [25].

PV patients on RTX can develop opportunistic infections, such as Pneumocystis jirovecii pneumonia [23], but it is still unclear whether PV on RTX may receive a Pneumocystisjirovecii prophylaxis [26]. Furthermore, reactivation of hepatitis B and C and tuberculosis could be possible [23]. Side effects related to RTX administration are represented mostly by type I allergic reaction and cytokine release syndrome [23]. Furthermore, late AEs include serum sickness and toxic epidermal necrolysis [23,27].

The optimal RTX dose in PV is still under debate. Two main protocols have been proposed: 2 intravenous infusions of 1000 mg each 2 weeks apart (rheumatoid arthritis protocol) and 4 infusions of 500-mg each weekly [23,28]. In 2017, a prospective randomized controlled trial that compared RTX combined with CS versus CS alone in patients with newly diagnosed PV showed a significantly higher remission rate off-therapy in the RTX cohort [29]. Furthermore, re-treatment with a single RTX dose of 500 mg after 12 and 18 months was highly effective in achieving a long-term clinical remission [29].

Ofatumumab

Ofatumumab is a fully human anti-CD20 monoclonal antibody used as therapy in chronic lymphocytic leukemia. Its target is represented by another CD20 epitope compared to the one targeted by RTX [30]. Ofatumumab has been used for PV patients who developed side effects or loss of response to RTX [31].

Intravenous Immunoglobulin

Intravenous immunoglobulin (IVIG) is used for immunomodulatory therapy of several inflammatory disorders [32]. The mechanism of action of IVIG is still not completely known, but several modes of action have been proposed [33,34]. However, the main mechanism of action is considered the implementation of degradation of immunoglobulins by binding the neonatal of Fc receptor (FcRn) [33,34]. The standard administration schedule is 2 g/kg in 5 days (400 mg/kg per day in 5 days) must be kept in mind that IVIG does not show an immunosuppressive activity [32,34]. It can be administered in combination with systemic CS and other immunosuppressants in recalcitrant PV [35].

Side effects were not frequently described [36,37]. Early AEs include headache, nausea, fever, tachycardia, malaise, arthralgia, and dyspnea [36,37]. Late-onset AEs include, aseptic meningitis, acute renal failure, thromboembolic events, and pseudohyponatremia [36,37].

Immunoadsorption

Through immunoadsorption (IA) IgG were passively removed from systemic circulation [1]. The combination of IA with immunosuppressive therapies is considered an effective treatment for pemphigus patients with severe activity, because IA allows an immediate removal of pathogenic autoantibodies. Infections are still the most frequently complications [1]. IA is considered 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 [1].

Future Therapeutic Approaches

CAR-T Cell Therapies

Chimeric antigen receptor (CAR)-T-cell therapy has been described as promising therapy in hematology [1]. CAR-T cell therapy is a paradigmatic example of adoptive cell transfer therapy. Indeed, autologous T-cells are modified ex-vivo to express a CAR, which leads to a specific targeting of a particular antigen and elimination of the antigen-expressing cells [38,39].

The CARs are composed of 3 domains: 1) the extracellular domain, which represents the antigen recognition domain; 2) the transmembrane and hinge domain; 3) the one or more intracellular T-cell signaling domains [39]. In 2016, T-cells were modified to express a chimeric autoantibody receptor (CAAR), which was composed by Dsg 3 fused to a CD137-CD3-zeta signaling domains [39]. Desmoglein-3 CAAR-T-cells show a selective cytotoxicity directed to cells with anti-Dsg3 B cell receptors in vitro and destroy Dsg3-specific B-cells in vivo. In a PV mouse model, CAAR-T cells reduced pathogenic IgG antibodies and improved the clinical picture [40].

Anti-Neonatal Fc Receptor (FcRn)

The FcRn is formed by the MHC class I-like heavy chain and the β2-microglobulin light chain [41]. It has played a central role in the homeostasis of IgG. Indeed, the IgG-FcRn complex avoids the degradation of IgG, leading to a recycle and release of IgG [42,43]. In a Knockout Mouse for FcRn, loss of cell-cell adhesion by passive transfer of antibodies against Dsg was not evident [44]. Furthermore, it was reported that blocking FcRn impaired the capability of PV to determine acantholysis [45]. A randomized, double-blind, placebo-controlled study with efgartigimod, a human IgG1-derived Fc fragments bound to FcRn, reported the efficacy of the drug in reducing the IgG titer in up to 75% of patients [46].

Conclusions

PV remains a therapeutic challenge for clinicians. Several therapeutic options are currently available. However, finding a specific treatment for a particular patient is not easy. Therefore, knowledge and management of multiple therapeutic choices for patients with PV play a pivotal role in better patient management.