10.5826/dpc.1201a37
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
text/xml
2160-9381
1867
en
Santo Raffaele Mercuri
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
treatment
Pemphigus Vulgaris: Present and Future Therapeutic Strategies
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2022-02-02
2021-07-05
2022-02-02
2022-02-09
e2022037
Dermatol Pract Concept
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
Santo Raffaele Mercuri
2022/02/02
10.5826/dpc.1201a37
e2022037
Unit of Dermatology, IRCCS San Raffaele Hospital, Milan, Italy
2160-9381
treatment
en
e2022037
Ulrichts P, Guglietta A, Dreier T, et al. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J Clin Invest. 2018;128(10):4372-4386. DOI: 10.1172/JCI97911. PMID: 30040076; PMCID: PMC6159959.
Pemphigus Vulgaris: Present and Future Therapeutic Strategies
https://dpcj.org/index.php/dpc/article/download/1867/1458
                   Dermatology Practical & Conceptual


                 Pemphigus Vulgaris: Present and Future
                        Therapeutic Strategies
        Dario Didona1, Giovanni Paolino2, Giovanni Di Zenzo3, Biagio Didona3, Riccardo
                Pampena4, Matteo Riccardo Di Nicola2, Santo Raffaele Mercuri2


1 Department of Dermatology and Allergology, Philipps University, Marburg, Germany
2 Unit of Dermatology, IRCCS San Raffaele Hospital, Milan, Italy
3 IDI-IRCCS, Rome, Italy
4 Centro Oncologico ad Alta Tecnologia Diagnostica-Dermatologica, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Italy



Key words: anti-CD20 antibodies, neonatal Fc receptor (FcRn), pemphigus, rituximab, treatment
Citation: Didona D, Paolino G, Di Zenzo G, Didona B, Pampena R, Di Nicola MR, Mercuri SR. Pemphigus vulgaris: present and future
therapeutic strategies. Dermatol Pract Concept. 2022;12(1): e2022037. DOI: https://doi.org/10.5826/dpc.1201a37
Accepted: August 18, 2021; Published: January 2022
Copyright: ©2022 Didona et al. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted
noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Authorship: All authors have contributed significantly to this publication. DD and GP have equally contributed to the article and share
co-first authorship.
Corresponding author: Matteo Riccardo Di Nicola, Unit of Dermatology, IRCCS San Raffaele Hospital, Milan, Italy.
E-mail: dinicola.matteo@hsr.it




  ABSTRACT             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.




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



Review | Dermatol Pract Concept. 2022;12(1): e2022037                                                                                     1
Methods                                                             Pathogenesis
                                                                    Cutaneous desmoglein-1 (Dsg1) can be expressed in the
We conducted a review to identify studies that documented           whole epidermis, cutaneous Dsg3 is typically found in the
the current therapeutic strategies for pemphigus vulgaris,          lower epidermis, while in the mucosa Dsg1 and Dsg3 are
as well as the future ones. All type of study, in English lan-      located in the whole squamous layer, with a higher expression
guage, was considered eligible for this review, including case      of Dsg3 [9]. Therefore, PV patients who show only anti-Dsg1
reports and case series. The main search was conducted in the       immunoglobulin G (IgG) serum antibodies develop only skin
electronic databases of MEDLINE, EMBASE and Cochrane                blisters, and, in the case of detectable anti-Dsg3 IgG serum
Central Register of Controlled Trials (CENTRAL) from                antibodies, the clinical phenotype is characterized by erosions
inception to January 2021 using different combinations of           or ulcerations of mucosal membranes [10]. Furthermore, the
the following terms: “pemphigus”, “pemphigus vulgaris”,             production of both anti-Dsg1 and anti-Dsg3 IgG serum auto-
“treatment” and “therapy”. Additionally, we concluded the           antibodies provokes skin and mucosal lesions [10].
manual search by reviewing all relevant citations within the            Evidence suggests that anti-Dsg1 and anti-Dsg3 auto-
selected and identified articles.                                   antibodies are responsible for a loss of cell-cell adhesion
                                                                    between keratinocytes [11,12]. The most important targets
Epidemiology                                                        for autoantibodies in PV are represented by the extracellular
PV is the most frequent type of pemphigus [1]. It usually           domains of Dsg [13,14]. Further mechanisms can also lead to
affects people between 50–60 years of age [7]. A female to          acantholysis in PV, such as Dsg endocytosis and desmosome
male ratio of 5.0 was reported in the USA [7]. In the American      disassembly [15,16], and intercellular stretch at non-acantho-
general population, an annual incidence of 4.2/ 1,000,000           lytic cell layers caused by pathogenic autoantibodies [17,18].
inhabitants was reported, but it was much higher in the             In addition, non-Dsg IgG serum autoantibodies have been
Jewish-American population [7]. This is due to the most             reported as important in PV pathogenesis, including those
prominent expression of specific HLA class II genes in PV           directed against desmocollins, mitochondria, pemphaxin, and
patients with Jewish background, such as HLA-DRB1*0402              alpha-9 acetylcholine receptor [13,19].
and HLA-DQB1*0503 [7].
                                                                    Diagnosis of PV
Clinical Features of PV                                             The diagnosis of PV requires not only compatible clinical fea-
PV usually arises with painful and refractory oral erosions         tures, but evidence of pathological features of involved skin
(Figure 1) [1]. Furthermore, other mucous membranes can be          and the presence of autoantibodies by direct immunofluores-
affected [1]. Most of patients also develop flaccid skin blisters   cence microscopy of non-affected skin. Indirect immunoflu-
that rapidly evolve into oozing erosions (Figure 2) [1]. Rarely,    orescence microscopy, enzyme-linked immunosorbent assay
pemphigus patients show a clinical and serological transition       and other techniques have a confirmatory role [5].
from PV to PF or conversely. This phenomenon could be                   The most important pathological feature is the intraepi-
due to the epitope spreading, a process of diversification of       dermal acantholysis [20]. Direct immunofluorescence of
B- or T-cell responses from the initial dominant epitope to a       non-affected skin detects IgG and proteins of complement C3
second one [8].                                                     (C3) on epidermal keratinocytes (Figure 3) [20,21]. Indirect




Figure 1. Large erosions of the oral mucosa.                        Figure 2. Multiple erosions on the back of this male patient.



2                                                                               Review | Dermatol Pract Concept. 2022;12(1): e2022037
                                                                     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 lympho-
                                                                     cytic inflammation [1]. It is recommended as a rescue drug,
Figure 3. Deposition of IgG and/or C3 on the surface of epidermal
keratinocytes detected by direct immunofluorescence. C3 = proteins   since its administration is characterized by several AEs, such
of complement C3; IgG = Immunoglobulin G.                            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
immunofluorescence on monkey esophagus detects a fishnet
                                                                     intake and sodium 2-mercaptoethane sulfonate [1]. CYP
pattern due to IgG antibodies reactivity to cell membrane of
                                                                     administration can cause transitional cell carcinoma of the
epithelial or epidermal cells [20].
                                                                     bladder [1]. In addition, transient or lasting impairment of
                                                                     gonadal function has been reported [1].
Current Therapies
Corticosteroids                                                      Rituximab
Prednisolone is usually administered as initial therapy in           Rituximab (RTX) is a chimeric monoclonal anti-CD20
PV in association with immunosuppressive agents, such as             antibody, that targets CD20, a transmembrane receptor,
azathioprine (AZA) and mycophenolate mofetil (MMF),                  expressed at several stages of the B-cell maturation [22].
or anti-CD20 monoclonal antibodies [1]. In patients with             RTX causes B-cell depletion through different mechanisms:
several comorbidities and in those who cannot undergo a              1) direct induction of apoptosis; 2) complement-dependent
therapy with anti-CD20 monoclonal antibodies or immu-                cytotoxicity; 3) antibody-dependent cytotoxicity; 4) anti-
nosuppressive agents, prednisolone as monotherapy is still           body-dependent phagocytosis; and 5) trogocytosis [23,24].
recommended as first-line therapy [1]. Nevertheless, plenty          The last mechanism is characterized by the elimination of
of side effects have been described after prolonged cortico-         RTX-CD20 complexes by macrophages, that causes cell death
steroid (CS) therapy, including severe infections, secondary         by a still unknown mechanism [25].
impairment of adrenal glands, osteoporosis, hyperglycemia,              PV patients on RTX can develop opportunistic infections,
and hypertension [1].                                                such as Pneumocystis jirovecii pneumonia [23], but it is still
AZA                                                                  unclear whether PV on RTX may receive a Pneumocystisji-
                                                                     rovecii prophylaxis [26]. Furthermore, reactivation of hep-
AZA downregulates purine metabolism, and blocks the syn-
                                                                     atitis B and C and tuberculosis could be possible [23]. Side
thesis of DNA, RNA, and proteins. In addition, AZA causes
                                                                     effects related to RTX administration are represented mostly
a reduction of Langerhans cells and monocytes, and reduces
                                                                     by type I allergic reaction and cytokine release syndrome
the activity of T- and B-lymphocytes [1]. Furthermore, AZA
                                                                     [23]. Furthermore, late AEs include serum sickness and toxic
blocks T-helper-cell dependent responses of B-cells [1]. AZA
                                                                     epidermal necrolysis [23,27].
dosage should be adapted to thiopurine-methyltransferase
                                                                        The optimal RTX dose in PV is still under debate. Two
activity, the enzyme responsible for AZA metabolism. Adverse
                                                                     main protocols have been proposed: 2 intravenous infusions
events (AEs) are reported in up to 30% of patients, includ-
                                                                     of 1000 mg each 2 weeks apart (rheumatoid arthritis proto-
ing nausea, pancreatitis, diarrhea, aphthous stomatitis, and
                                                                     col) and 4 infusions of 500-mg each weekly [23,28]. In 2017,
maculopapular rash [1]. Pancytopenia and hepatotoxicity are
                                                                     a prospective randomized controlled trial that compared
reported as severe AEs [1].
                                                                     RTX combined with CS versus CS alone in patients with
MMF                                                                  newly diagnosed PV showed a significantly higher remis-
MMF leads to a suppression of the immune system by a                 sion rate off-therapy in the RTX cohort [29]. Furthermore,
selective blockade of inosine monophosphate dehydrogenase,           re-treatment with a single RTX dose of 500 mg after 12 and



Review | Dermatol Pract Concept. 2022;12(1): e2022037                                                                             3
18 months was highly effective in achieving a long-term             the transmembrane and hinge domain; 3) the one or more
clinical remission [29].                                            intracellular T-cell signaling domains [39]. In 2016, T-cells
                                                                    were modified to express a chimeric autoantibody receptor
Ofatumumab                                                          (CAAR), which was composed by Dsg 3 fused to a CD137-
Ofatumumab is a fully human anti-CD20 monoclonal anti-              CD3-zeta signaling domains [39]. Desmoglein-3 CAAR-T-cells
body used as therapy in chronic lymphocytic leukemia. Its           show a selective cytotoxicity directed to cells with ­anti-Dsg3 B
target is represented by another CD20 epitope compared to           cell receptors in vitro and destroy Dsg3-specific B-cells in vivo.
the one targeted by RTX [30]. Ofatumumab has been used              In a PV mouse model, CAAR-T cells reduced pathogenic IgG
for PV patients who developed side effects or loss of response      antibodies and improved the clinical picture [40].
to RTX [31].
                                                                    Anti-Neonatal Fc Receptor (FcRn)
Intravenous Immunoglobulin                                          The FcRn is formed by the MHC class I-like heavy chain and
Intravenous immunoglobulin (IVIG) is used for immuno-               the β2-microglobulin light chain [41]. It has played a central
modulatory therapy of several inflammatory disorders [32].          role in the homeostasis of IgG. Indeed, the IgG-FcRn com-
The mechanism of action of IVIG is still not completely             plex avoids the degradation of IgG, leading to a recycle and
known, but several modes of action have been proposed               release of IgG [42,43]. In a Knockout Mouse for FcRn, loss
[33,34]. However, the main mechanism of action is consid-           of cell-cell adhesion by passive transfer of antibodies against
ered the implementation of degradation of immunoglobu-              Dsg was not evident [44]. Furthermore, it was reported that
lins by binding the neonatal of Fc receptor (FcRn) [33,34].         blocking FcRn impaired the capability of PV to determine
The standard administration schedule is 2 g/kg in 5 days            acantholysis [45]. A randomized, double-blind, placebo-con-
(400 mg/kg per day in 5 days) must be kept in mind that IVIG        trolled study with efgartigimod, a human IgG1-derived Fc
does not show an immunosuppressive activity [32,34]. It can         fragments bound to FcRn, reported the efficacy of the drug in
be administered in combination with systemic CS and other           reducing the IgG titer in up to 75% of patients [46].
immunosuppressants in recalcitrant PV [35].
    Side effects were not frequently described [36,37]. Early
                                                                    Conclusions
AEs include headache, nausea, fever, tachycardia, malaise,
arthralgia, and dyspnea [36,37]. Late-onset AEs include, asep-      PV remains a therapeutic challenge for clinicians. Several
tic meningitis, acute renal failure, thromboembolic events,         therapeutic options are currently available. However, finding
and pseudohyponatremia [36,37].                                     a specific treatment for a particular patient is not easy. There-
                                                                    fore, knowledge and management of multiple therapeutic
Immunoadsorption
                                                                    choices for patients with PV play a pivotal role in better
Through immunoadsorption (IA) IgG were passively removed            patient management.
from systemic circulation [1]. The combination of IA with
immunosuppressive therapies is considered an effective treat-
ment for pemphigus patients with severe activity, because IA        References
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Review | Dermatol Pract Concept. 2022;12(1): e2022037                                                                                          5
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