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Pemphigus is a general term for a rare group of autoimmune diseases which result in the formation of blisters on the skin and oral cavity. Although there is no way to prevent autoimmune diseases, some factors may trigger pemphigus initiation in susceptible individuals or be exacerbated in affected patients. Recognition of these triggers, based on the latest studies and experiences is essential and should be updated every few years. In this study, several triggers, including different drugs and treatments, diseases, vaccines, genetic factors, nutrients, micronutrients, pregnancy, stress, and various other triggers have been discussed. Some possible triggers, such as blood antigens and the effect of seasons have also been discussed briefly. Moreover, some protective factors against pemphigus have been reviewed. Considering the molecular mechanism of pemphigus and immune response alteration during this disease, some possible triggers have been suggested and discussed. Although those triggers may be a real threat, more studies are needed to support these hypotheses.

Pemphigus forms a group of rare autoimmune bullous diseases that affect the skin and mucous membranes. This group has a chronic course leading to high morbidity and mortality. It is characterized by the production of pathogenic autoantibodies directed against different proteins of the desmosome, leading histologically to intraepidermal cleavage, and clinically to vesicles and erosions on the epithelium of the mucous membranes and/or the skin. The diagnosis of the subtype of pemphigus is based on clinical features, the level of histologic cleavage, and the identification of the antigens recognized by circulating autoantibodies by immunoserological analyses. The epidemiological features of pemphigus vary considerably in different regions of the world. Observational studies examining comorbidities and associations among patients with pemphigus are scarce and sometimes inconclusive. The prognosis, mortality, and clinical outcomes in pemphigus have undergone dramatic change throughout the years. This review provides a brief overview about the different subtypes of pemphigus: pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, pemphigus herpetiformis, and IgA pemphigus. In addition, it summarizes the most recent understanding of the epidemiology, mortality data, and comorbidities of this group of organ-specific autoimmune diseases.

Desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) expressing the pemphigus vulgaris (PV) autoantigen DSG3 fused to CD137-CD3ζ signaling domains, represent a precision cellular immunotherapy approach for antigen-specific B cell depletion. Here, we present definitive preclinical studies enabling a first-in-human trial of DSG3-CAART for mucosal PV. DSG3-CAART specifically lysed human anti-DSG3 B cells from PV patients and demonstrated activity consistent with a threshold dose in vivo, resulting in decreased target cell burden, decreased serum and tissue-bound autoantibodies, and increased DSG3-CAART engraftment. In a PV active immune model with physiologic anti-DSG3 IgG levels, DSG3-CAART inhibited antibody responses against pathogenic DSG3 epitopes and autoantibody binding to epithelial tissues, leading to clinical and histologic resolution of blisters. DSG3 autoantibodies stimulated DSG3-CAART IFN-γ secretion and homotypic clustering, consistent with an activated phenotype. Toxicology screens using primary human cells and high-throughput membrane proteome arrays did not identify off-target cytotoxic interactions. These preclinical data guided the trial design for DSG3-CAART and may help inform CAART preclinical development for other antibody-mediated diseases.

Pemphigus represents a group of chronic inflammatory disorders characterized by autoantibodies that target components of desmosomes, leading to the loss of intercellular adhesion between keratinocytes and causing intraepithelial blistering. The pemphigus group consists of four main clinical types with several variants: pemphigus vulgaris (with pemphigus vegetans and pemphigus herpetiformis as variants), pemphigus foliaceus, paraneoplastic pemphigus and IgA pemphigus (with two clinical variants: intraepidermal neutrophilic IgA dermatosis and subcorneal pustular dermatosis). Genetic factors are involved in the pathogenesis, with HLA-DR4 (DRB1*0402) and HLA-DRw6 (DQB1*0503) allele more common in patients with pemphigus vulgaris, HLA class II DRB1*0344 and HLA Cw*1445 correlated with paraneoplastic pemphigus, and HLA-DRB1*04:01, HLA-DRB1*04:06, HLA-DRB1*01:01, HLA-DRB1*14, associated with a higher risk of developing pemphigus foliaceus. Autoantibodies are conducted against structural desmosomal proteins in the skin and mucous membranes, mainly desmogleins, desmocollins and plakins. Cell-mediated immunity may also play a role, especially in paraneoplastic pemphigus. Patients may present erythema, blisters, erosions, and ulcers that may affect the skin, as well as mucosal surfaces of the oral cavity, eyes, nose, leading to severe complaints including pain, dysphagia, and fetor. Oral mucosal postbullous erosive lesions are frequently the first sign of disease in pemphigus vulgaris and in paraneoplastic pemphigus, without skin involvement, making the diagnosis difficult. Treatment options classically include immunosuppressive agents, such as corticosteroids and corticosteroid-sparing agents such as azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate or dapsone. Newer therapies focus on blocking cell signaling events induced by pathogenic autoantibodies and/or targeting specific autoantibodies. The disease evolution is conditioned by the treatment with maximum doses of corticosteroids and the side effects associated with long-term immunosuppressive therapy, which is why patients need a multidisciplinary approach in following the treatment. In this review, we provide a comprehensive overview of the epidemiology, pathophysiology, clinical aspect, diagnosis and management of the main intraepidermal blistering diseases from the pemphigus group.

Clinicians may encounter a variety of skin conditions that present with vesiculobullous lesions in their everyday practice. Pemphigus vulgaris, pemphigus foliaceus, IgA pemphigus, and paraneoplastic pemphigus represent the spectrum of autoimmune bullous dermatoses of the pemphigus family. The pemphigus family of diseases is characterized by significant morbidity and mortality. Considering the risks associated with a delayed diagnosis or misdiagnosis and the potential for overlap in clinical features and treatment, evaluation for suspected pemphigus disease often requires thorough clinical assessment and laboratory testing. Diagnosis is focused on individual biopsies for histopathology and direct immunofluorescence. Additional laboratory methods used for diagnosis include indirect immunofluorescence and enzyme-linked immunosorbent assay. Recent advancements, including anti-CD20 therapy, have improved the efficacy and reduced the morbidity of pemphigus treatment. This contribution presents updates on the pathophysiology, clinical features, diagnostic work-up, and medical management of pemphigus. Improved strategies for diagnosis and clinical assessment are reviewed, and newer treatment options are discussed.

Pemphigus is a group of IgG-mediated autoimmune diseases of stratified squamous epithelia, such as the skin and oral mucosa, in which acantholysis (the loss of cell adhesion) causes blisters and erosions. Pemphigus has three major subtypes: pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus. IgG autoantibodies are characteristically raised against desmoglein 1 and desmoglein 3, which are cell–cell adhesion molecules found in desmosomes. The sites of blister formation can be physiologically explained by the anti-desmoglein autoantibody profile and tissue-specific expression pattern of desmoglein isoforms. The pathophysiological roles of T cells and B cells have been characterized in mouse models of pemphigus and patients, revealing insights into the mechanisms of autoimmunity. Diagnosis is based on clinical manifestations and confirmed with histological and immunochemical testing. The current first-line treatment is systemic corticosteroids and adjuvant therapies, including immunosuppressive agents, intravenous immunoglobulin and plasmapheresis. Rituximab, a monoclonal antibody against CD20 + B cells, is a promising therapeutic option that may soon become first-line therapy. Pemphigus is one of the best-characterized human autoimmune diseases and provides an ideal paradigm for both basic and clinical research, especially towards the development of antigen-specific immune suppression treatments for autoimmune diseases. Pemphigus is an autoimmune disorder characterized by blisters in the oral mucosa and epidermis. Acantholysis (loss of cell adhesion, which results in blisters) is caused by the presence of autoantibodies that target desmosomal proteins, in particular, desmoglein 1 and desmoglein 3.

Some patients with pemphigus continue to have elevated levels of desmoglein autoantibodies (Dsg Ab) even after achieving remission. Thus, it is crucial to gain a deeper understanding of these patients’ demographics and clinical patterns to improve prognosis, prevent complications, and devise individualized management strategies. This study utilized electronic patient records from a dermatology registry, focusing on PV and PF patients (diagnosed based on clinical and histopathologic diagnosis which included DIF) who achieved complete remission. We analyzed demographic and clinical data, including age, gender, BMI, disease type, lesion onset location, disease duration, test results, anti-desmoglein levels, and previous treatments. For comparative analysis, patients were categorized into two groups based on their Dsg Ab levels (high vs. normal) 3 months post-remission. Of the 80 patients evaluated, 57.5% were female, averaging 48.66 years. Significant gender differences were observed in Dsg Ab1 antibody levels, with males more likely to test sustained positive (P = 0.037), though no such difference was found for Dsg Ab 3 (P = 0.167). No significant differences in age, BMI, or history of other diseases were found between patients with high versus normal Dsg Abs post-recovery. The average time to complete recovery was 27.34 months, with no significant difference in recovery time or relapse rates based on antibody levels. However, there was a notable difference in some variables, including PDAI score, mucosal involvement, the average dose of prednisolone after achieving complete remission and occurrence of infectious complications (only regarding Dsg Ab 3) between the two groups (P < 0.05). The study underscores the heterogeneity in the post-remission course of pemphigus patients regarding the persistence of high Dsg Ab levels in some individuals. These findings emphasize the need for a tailored approach to management and monitoring of patients. Further research into the mechanisms driving these differences could pave the way for more effective treatments and prognostic tools in pemphigus care.

Paraneoplastic pemphigus is a rare autoimmune skin disease that is always associated with a neoplasm. Usually, oral, skin, and mucosal lesions are the earliest manifestations shown by paraneoplastic pemphigus patients. The pathogenesis of paraneoplastic pemphigus is not yet completely understood, although some immunological aspects have been recently clarified. Because of its rarity, several diagnostic criteria have been proposed. Besides, several diagnostic procedures have been used for the diagnosis, including indirect immunofluorescence, direct immunofluorescence, and ELISA. We reviewed the most recent literature, searching on PubMed “paraneoplastic pemphigus”. We included also papers in French, German, and Spanish. We found 613 papers for “paraneoplastic pemphigus”. Among them, 169 were review papers. Because of its varying clinical features, paraneoplastic pemphigus still represents a challenge for clinicians. Furthermore, diagnosis and management of paraneoplastic pemphigus requires close collaboration between physicians, including dermatologist, oncologist, and otorhinolaryngologist.

Pemphigus vegetans (P Veg), the rarest subtype of pemphigus, is characterized by vegetative plaques, primarily affecting intertriginous areas. The most common autoantibodies target desmoglein 3 (Dsg3). A 60-year-old female patient presented with well-demarcated red vegetative plaques on her feet, vulva, and thigh, accompanied by surrounding pustules. Histopathological examination revealed epidermal hyperplasia with significant infiltration of neutrophils and eosinophils in the dermis. Enzyme-linked immunosorbent assay showed elevated anti-Dsg3 antibodies (203.2 U/ml), and immunohistochemical staining confirmed positive expression of anti-Dsg3 IgG antibodies in keratinocytes. The patient was diagnosed with P Veg and achieved remission after treatment with either 900 mg of intravenous spesolimab or oral methylprednisolone.

Secukinumab is a fully human monoclonal antibody that specifically targets and neutralizes interleukin (IL)-17A, a cytokine typically involved in the mucocutaneous defense against pathogens. Despite its favorable safety profile, serious adverse events such as inflammatory bowel disease, oral pemphigoid-like lesions, and lupus erythematosus have been reported. While widely used for psoriasis treatment, cytokine-based therapies carry a potential risk of triggering autoimmune responses. The precise mechanism by which secukinumab induces pemphigus erythematosus remains unclear but may involve immune dysregulation, autoantibody production, microbiota influences, and genetic susceptibility. We report a case of pemphigus erythematosus occurring in a psoriasis patient during secukinumab therapy, which improved after treatment with methylprednisolone sodium succinate injection, leading to clinical symptom resolution. Clinicians should remain vigilant for potential complications and develop individualized management strategies for patients receiving secukinumab.