RARE DISEASE
Pemphigus vulgaris
Pemphigus vulgaris
Pemphigus vulgaris
Drug discovery
15
drugs
With orphan designations
Overview
Pemphigus vulgaris is a rare, chronic autoimmune blistering disorder characterized by painful flaccid blisters and erosions affecting mucous membranes (oral/ocular/genital) and skin. Pathogenesis involves IgG autoantibodies targeting desmoglein 1/3, disrupting epidermal adhesion (acantholysis). Diagnosis requires histopathology with suprabasal clefting and direct immunofluorescence showing intercellular IgG/C3 deposits. Untreated cases risk sepsis and dehydration, with mortality historically >90% pre-corticosteroids [1][6][12].
Burden
Morbidity: 89% report impaired eating; 63% have depression/anxiety [6][17]
Mortality: 5-15% with treatment (vs 90% untreated); 3× increased mortality vs general population [6][7][12]
Economic: Median hospitalization cost $26,800 (US); 30% require ICU care for sepsis/fluid loss [14][16]
Critical complications include secondary infections (22.6× sepsis risk) and steroid-related adverse effects (diabetes/osteoporosis). Maintenance therapy achieves remission in 75% at 5 years with rituximab [3][18].
Therapies
First-line: High-dose systemic corticosteroids (0.5-1.5 mg/kg/day prednisone) + rituximab (anti-CD20 monoclonal antibody) [3][6][18]
Adjuvants: Immunosuppressants (azathioprine/mycophenolate), IVIG, plasmapheresis [3][16][18]
Supportive: Antiseptic/analgesic mouthwashes, topical tacrolimus, nutritional support [1][3][16]
Categories: rare skin diseases
Research Papers
1,467 drug discovery papers about Pemphigus vulgaris, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,467 drug discovery papers about Pemphigus vulgaris, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-22 | Unraveling the autoimmune architecture of pemphigus: from B-cell depletion to network-based immune engineering.
Pemphigus encompasses autoimmune blistering diseases driven by autoantibodies to desmosomal proteins. Disruption of keratinocyte adhesion produces acantholysis and epidermal fragility. Anti-CD20 B-cell depletion and IgG lowering strategies have transformed care, but many patients relapse, some variants respond incompletely, and durable drug-independent tolerance remains uncommon across variants. These gaps highlight that pemphigus is not a simple linear B-cell disorder, but an autoantibody disease sustained by a network linking the innate immunity, the adaptive lymphocytes, and the stromal niches. In this review, we focus on pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome, and IgA pemphigus as representative variants within this network. We place these entities within a conceptual type 1, type 2, and type 3 immunity framework and summarize how central and peripheral B-cell tolerance can fail. We further consider current and emerging therapies as partial interventions within this network and outline next-generation strategies that modulate innate circuits, rewire survival pathways, restore antigen-specific regulation, and shift the adaptive autoimmune response toward a more tolerogenic state. Framing pemphigus in this way may help move the field from empiric immunosuppression toward precise immune engineering with the goal of durable immune reset and long-term drug-independent remission.
2026-05-11 | Cyclophosphamide is associated with long-term treatment-free remission in patients with pemphigus.
Pemphigus treatment has seen significant advancements, yet long-term remission remains a challenge. Comparative data on the long-term effectiveness of available therapies are limited. We compared 10-year relapse rates in pemphigus patients treated with azathioprine or cyclophosphamide plus high-dose IV corticosteroids PATIENTS AND METHODS: In this retrospective single-center cohort study, we analyzed 91 patients with pemphigus vulgaris/foliaceus treated between 1985 and 2022. 43 patients received oral azathioprine, 48 received intermittent intravenous and oral cyclophosphamide. All patients also received intermittent high-dose IV corticosteroids for ≥ 1 year. As rituximab became widely available only after 2019, follow-up was insufficient to include it in this analysis. Remission occurred equally quickly in both groups, but patients treated with cyclophosphamide suffered from significantly fewer relapses: 27% of cyclophosphamide patients had ≥ 1 relapse vs. 80.6% with azathioprine (p < 0.001). 70% of cyclophosphamide patients remained relapse-free and were off therapy for an average of 7 years. Aggressive initial immunosuppressive therapy with cyclophosphamide is associated with a significantly lower long-term relapse rate in pemphigus. While routine use is limited by its toxicity, these findings underscore the potential for durable remission and the importance of long-term disease control as a treatment goal.
2026-04-30 | Recurrent Pemphigus Vulgaris with Isolated Nail Involvement
A 67-year-old man presented with a 3-year history of nail changes including discoloration, dystrophy, subungual hyperkeratosis, frayed edges, onycholysis, splitting, pitting, exudation, and paronychia [Figure 1]. No skin or mucosal lesions were observed. The patient had a history of pemphigus vulgaris (PV) 13 years ago, which had resolved after 6 months of treatment with oral prednisone. Histopathological examination of the right ring finger nail bed revealed a suprabasal cleft in the epidermis [Figure 2]. Direct immunofluorescence of proximal nail fold showed a reticulated pattern of intercellular IgG deposition [Figure 3]. The anti-desmoglein 3 antibody level was elevated to > 200 U/mL (ELISA kit, Euroimmun, normal: 0-20U/mL). A diagnosis of recurrent PV was established. The nail lesions resolved within 6 months following treatment with oral minocycline and nicotinamide.Figure 1: Discoloration, dystrophy, subungual hyperkeratosis, frayed edges, onycholysis, ripping, pitting, exudation, and paronychia of the nailsFigure 2: Suprabasal cleft in the epidermis (Hematoxylin and eosin, 200×)Figure 3: Direct immunofluorescence showed a reticulated pattern of intercellular IgG deposition (Fluorescein Isothiocyanate, 200×)Previous studies report nail involvement in 47% to 80% of PV patients [1,2] and in up to 91% of patients with autoimmune blistering diseases.[3] Paronychia is the most common nail manifestation in PV [4,5] and is considered a sign that may precede disease exacerbation.[1,3] Authors’ contributions We confirm that all authors have read and approved the manuscript for submission. All authors meet authorship criteria, and the manuscript represents honest work. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Use of artificial intelligence (AI) The preparation of this manuscript was carried out entirely by the authors without the use of artificial intelligence technologies.
2026-04-27 | Treatment of Canine Pemphigus Foliaceus, Pemphigus Vulgaris and Mucous Membrane Pemphigoid With Oclacitinib: A Retrospective Analysis of 21 Cases.
This study was performed to retrospectively evaluate the efficacy of oclacitinib (OC) (Apoquel; Zoetis) as a treatment option for pemphigus foliaceus (PF), pemphigus vulgaris (PV) and mucous membrane pemphigoid (MMP). To determine if OC can reduce or replace the corticosteroid use in dogs with PF, PV and MMP. There were no animal subjects. Multicentre retrospective study reviewing medical records from two institutions for dogs diagnosed with PF, PV or MMP and prescribed OC between 2014 and 2025. Twenty-one dogs diagnosed with PF, PV or MMP via histopathological results were included. OC alone was effective in eight of 18 PF dogs at a median dose of 0.65 mg/kg/day per os (range 0.5-1.9 mg/kg/day p.o.). Five dogs reached clinical remission, and three reached partial remission. One PV dog and the MMP dog each reached clinical remission with OC alone at 0.7 mg/kg/day and 0.24 mg/kg every other day, respectively. OC was a corticosteroid-sparing agent or adjunctive therapy in seven of 18 PF dogs at a median dose of 0.6 mg/kg/day (range 0.4-2.4 mg/kg/day). One PV dog reached partial remission at OC 1.9 mg/kg/day and prednisone 1.8 mg/kg/day yet died from pancreatitis. OC was ineffective in three of 18 PF dogs at a median dose of 1.0 mg/kg/day p.o. (range 0.9-1.2 mg/kg/day p.o.). Statistical significance was not analysed. OC is an effective sole therapeutic agent or adjunctive therapy in a subset of dogs with PF, PV or MMP. The long-term safety of higher doses of OC is unknown.
2026-04-14 | The role of the dental surgeon in the diagnosis and treatment of pemphigus vulgaris
Pemphigus vulgaris is a low-prevalence autoimmune disorder characterized by vesiculobullous lesions affecting the skin and mucous membranes. Lesions in the oral mucosa can be the initial manifestations of the disease and highlight the importance of the dentist in early diagnosis. The objective of this study is to report a clinical case of pemphigus vulgaris with oral lesions in a 44-year-old female patient with no comorbidities. Intraoral physical examination revealed ulcerated lesions throughout the oral cavity, accompanied by bullous lesions, ulcerations, and crusts on the skin. The patient reported having had the lesions for four months, with no conclusive diagnosis. These lesions made eating difficult and resulted in marked weight loss and the need for hospitalization. During hospitalization, the diagnosis was established by the medical and dental team based on clinical characteristics and medical history, followed by histopathological confirmation. Oral lesions were treated with 0.12% chlorhexidine digluconate mouthwash and laser photobiomodulation, combined with systemic corticosteroid therapy, resulting in significant remission. Therefore, dentists' knowledge of the clinical and histopathological characteristics of pemphigus vulgaris is essential for early diagnosis and effective treatment, promoting patient health and quality of life. Further studies should be conducted to optimize management strategies for oral lesions in patients with pemphigus vulgaris.
proteins
2026-03-13 | IL‑37/IL‑1R8 blocks keratinocyte acantholysis via suppressing ADAM17/EGFR.
Pemphigus vulgaris (PV) is a life‑threatening autoimmune blistering disease characterized by acantholysis (the loss of cell‑cell adhesion of keratinocytes) and the formation of non‑healing suprabasal intraepidermal blisters. The progression of keratinocyte acantholysis in PV is complex. Interleukin‑37 (IL‑37), which functions through receptor binding, exerts a protective role in PV. However, the specific receptor mediating the effect of IL‑37 in PV and the underlying mechanisms remain unclear. The present study found elevated levels of IL‑37, a natural suppressor of innate inflammatory and immune responses, in patients with PV. IL‑37 treatment directly suppressed both acantholysis and apoptosis in keratinocytes. Mechanistic investigations using co‑immunoprecipitation revealed that IL‑37 binds to interleukin‑1 receptor 8 (IL‑1R8). Knockdown of IL‑1R8 (or IL‑18Rα) abolished the inhibitory effects of IL‑37 on acantholysis and apoptosis. Furthermore, the IL‑37/IL‑1R8 complex suppressed epidermal growth factor receptor (EGFR) signaling, and reduced the expression of TNF‑alpha‑converting enzyme (ADAM17). Activation of EGFR using specific agonists reversed the IL‑37‑mediated reduction in acantholysis and apoptosis in HaCaT cells. In conclusion, IL‑37 treatment markedly attenuated keratinocyte dissociation and apoptosis in PV through the IL‑1R8/ADAM17/EGFR pathway. These findings provide novel mechanistic insights into the immunoregulatory functions of IL‑37.
2025-10-03 | Taking aim at autoimmunity-Antigen-Fc constructs for mucosal pemphigus hit the mark.
A desmoglein-3 antigen-Fc fusion construct shows promise as a therapeutic in a model of pemphigus vulgaris.
2025-08-27 | Antigen-Fc fusion therapy reduces severity of a model of pemphigus vulgaris without systemic immunosuppression.
Pemphigus vulgaris is a B cell-mediated autoimmune disease characterized by autoantibodies targeting desmoglein-3 (Dsg3), a critical adhesion molecule in epithelial tissues. Current treatments rely on broad immunosuppression, highlighting the need for more targeted therapeutic approaches in pemphigus vulgaris and other autoantibody-driven disorders. We engineered a therapeutic fusion protein consisting of the pathogenic domains of Dsg3 linked to either human immunoglobulin G1 (IgG1) or mouse IgG2a (Dsg3-Fc). In vitro, Dsg3-Fc selectively eliminated Dsg3-autoreactive B cells. In vivo, Dsg3-Fc effectively depleted human B cells expressing patient-derived anti-Dsg3 B cell receptors, even in the presence of circulating autoantibodies. Moreover, Dsg3-Fc inhibited both disease initiation and progression in a polyclonal, active pemphigus vulgaris model in immunocompetent mice. In addition, Dsg3-Fc rapidly neutralized pathogenic autoantibodies without inducing systemic toxicity. These findings demonstrate that targeting pathogenic B cells and neutralizing autoantibodies through autoantigen-Fc fusion proteins may represent a promising therapeutic strategy for pemphigus vulgaris and potentially other autoantibody-mediated diseases without the need for global immunosuppression.
2025-08-20 | Immunoregulatory effects of TPM203 peptide-nanoparticle therapy in pemphigus vulgaris
Journal Article Accepted manuscript Immunoregulatory effects of TPM203 peptide-nanoparticle therapy in pemphigus vulgaris Get access Chuda Rujitharanawong , Chuda Rujitharanawong Department of Dermatology, Columbia University, New York, NY, USADepartment of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand Search for other works by this author on: Oxford Academic Google Scholar Aimee S Payne Aimee S Payne Department of Dermatology, Columbia University, New York, NY, USA Corresponding author: Aimee S. Payne, MD, PhD, Email:[email protected] Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljaf323, https://doi.org/10.1093/bjd/ljaf323 Published: 21 August 2025 Article history Received: 11 August 2025 Accepted: 12 August 2025 Published: 21 August 2025
2025-08-12 | Safety, tolerability, pharmacokinetics and pharmacodynamic effects of desmoglein 3 peptide-coupled tolerizing nanoparticles in pemphigus.
Pemphigus vulgaris (PV) is a CD4+ T-cell-dependent autoantibody-mediated blistering disease associated with human leucocyte antigen (HLA) class II molecules. IgG autoantibodies against the primary autoantigen desmoglein 3 (Dsg3), a desmosomal adhesion protein on epidermal keratinocytes, cause loss of epidermal cell adhesion. To assess the clinical applicability of an innovative nanoparticle platform for the induction of immune tolerance exploiting the natural tolerance potential of liver sinusoidal endothelial cells. An open-label first-in-human study was conducted with TPM203, a mixture of four nanoparticle-coupled immunodominant Dsg3 T-cell peptides. The efficacy and mechanism of action of TPM203 were first tested in a humanized HLA-DRB1*0402-transgenic PV mouse model. In the clinical phase I trial, TPM203 was administered intravenously in patients with PV with no-to-moderate disease activity in single ascending and multiple doses (three doses of TPM203 two weeks apart). Primary endpoints included safety and tolerability. As a secondary endpoint, pharmacokinetics were assessed. Exploratory endpoints comprised changes in Dsg3-specific and bulk T- and B-cell frequencies, anti-Dsg3 IgG levels and autoantibody-induced keratinocyte dissociation. The trial was registered with EudraCT (2019-001727-12). In the PV mouse model, two administrations of TPM203 significantly reduced anti-Dsg3 IgG. On the cellular level, TPM203 led to a significant decrease in CD4+ T cells in the spleen, accompanied by increased frequencies of regulatory T (Treg) cells. In the clinical trial, the 17 patients with PV enrolled across single- and multiple-dose groups did not experience any serious or severe adverse events, or treatment-related PV worsening. Pharmacokinetics confirmed rapid TPM203 clearance from the circulation. Significant TPM203-induced modulations in bulk lymphocyte subsets included an increase in Treg cells, and reductions in T helper 17.1 and CD27+ memory B cells, when dose groups were combined for analysis. Dsg3-specific T cells were found to be significantly reduced at week 8 following single administration of TPM203. Anti-Dsg3 IgG levels trended downward in the three lower single ascending dose groups, while IgG-induced keratinocyte-dissociating capacity was significantly reduced after multiple doses. Administered for the first time in humans, TPM203 was shown to be a safe and well-tolerated nanoparticle-based therapeutic approach with the potential to promote tolerance induction in PV, justifying further clinical development in this and other autoimmune diseases. An author video to accompany this article is available online.
antibodies
2026-07-11 | Case Report: Dupilumab as a corticosteroid-sparing adjunct in severe mucocutaneous pemphigus vulgaris with prior avascular necrosis and chronic kidney disease.
Pemphigus vulgaris is a potentially life-threatening autoimmune blistering disease for which corticosteroid minimization can be difficult when prior steroid toxicity has already occurred. We report a 60-year-old woman with severe mucocutaneous pemphigus vulgaris confirmed by clinical, immunopathologic, and serologic findings, who had previously developed femoral head avascular necrosis during high-dose prednisone therapy and also had advanced chronic kidney disease, hypoalbuminemia, and anemia. Rituximab was discussed as a guideline-supported first-line option; however, after counseling regarding its expected benefits and potential adverse effects, the patient declined rituximab. Therefore, dupilumab was introduced off-label as an adjunctive corticosteroid-minimizing approach together with oral prednisone 30 mg/day and supportive care. The Pemphigus Disease Area Index was 111 during the first treatment week and decreased to 22 by week 6, when disease control was achieved with cessation of new lesions and marked healing of pre-existing erosions. Prednisone was then tapered gradually. Complete re-epithelialization was achieved by approximately month 4 while the patient was receiving oral prednisone 7.5 mg/day, and clinical stability was maintained through month 6 after dupilumab discontinuation at month 4. No adverse events were observed. This case supports the clinical feasibility of dupilumab-assisted corticosteroid minimization in selected patients with pemphigus vulgaris and major treatment-related constraints, while further evidence is needed regarding patient selection, duration of therapy, and long-term relapse risk.
2026-07-07 | RITUXIMAB THERAPY IN PEMPHIGUS VULGARIS: CLINICAL OUTCOMES, SAFETY, AND QUALITY-OF-LIFE ASSESSMENT
Objectives: Pemphigus vulgaris is a chronic autoimmune blistering disorder that affects the skin and mucous membranes, often requiring prolonged immunosuppressive treatment. Although systemic corticosteroids remain effective in controlling disease activity, their long-term use is frequently limited by infections, metabolic adverse effects, steroid dependence, and relapse during dose reduction. Rituximab, an anti-CD20 monoclonal antibody, has emerged as a valuable treatment option, particularly in patients with moderate-to-severe disease, recurrent flares, or poor response to conventional therapy. Methods: The present work was a prospective single-arm interventional study. Sixty patients with clinically, histopathologically, and immunologically confirmed pemphigus vulgaris were enrolled. Rituximab was administered using the rheumatoid arthritis (RA) protocol, 1 g intravenously on Day 1 and Day 14, with standard pre-medication and short-term bridging corticosteroids. Patients were followed at 1, 3, 6, 9, and 12 months. Disease activity was assessed by the pemphigus disease area index (PDAI), and quality of life was assessed by the dermatology life quality index (DLQI). Clinical response definitions were aligned with the 2008 pemphigus consensus statement. Adverse events were graded using Common Terminology Criteria for Adverse Events v5.0, and causality was assessed clinically using the World Health Organization-Uppsala Monitoring Centre approach. Results: The mean age was 40.6±11.8 years. There were 38 females (63.3%) and 22 males (36.7%). Oral mucosal involvement was present in all 60 patients (100.0%), cutaneous lesions in 52 patients (86.7%), and genital mucosal involvement in 18 patients (30.0%). At baseline, 8 patients (13.3%) had mild disease, 20 patients (33.3%) had moderate disease, and 32 patients (53.3%) had severe disease according to PDAI-based severity grouping. The mean PDAI score decreased from 78.6±31.4 at baseline to 8.9±6.2 at 12 months. Mean DLQI score improved from 19.2±5.7 to 3.1±2.6. Disease control was achieved in 6.4±2.1 weeks. Complete remission on minimal therapy was seen in 51 patients (85.0%). Relapse occurred in 12 patients (20.0%), and 10 patients (16.7%) required booster rituximab. Mild infusion reactions occurred in 8 patients (13.3%). Serious infection requiring hospital-based care occurred in 2 patients (3.3%), and no mortality was observed. Conclusion: Rituximab administered by the RA protocol was effective and generally well tolerated in this single-arm cohort. The treatment reduced disease activity, improved quality of life, and supported corticosteroid tapering. Because there was no control group, no prospective trial registration, and limited immunological monitoring, the findings should be interpreted as real-world evidence rather than proof of superiority over other regimens.
2026-05-26 | Examining the association of dipeptidyl peptidase-4 inhibitors with autoimmune blistering disorders in the U.S. Military veterans.
Dipeptidyl peptidase 4 inhibitor (DPP4i) are commonly used for management of diabetes. Although there are reports of increased risk of autoimmune skin blistering disorders (AIBD) with DPP4i, data is scarce. Although the exact mechanism through which DPP4i may cause AIBD is unknown, DPP4i may induce anti-basement membrane zone antibodies. Inhibition of DPP4 enzyme may also result in the recruitment of eosinophils into the dermis. Examine the incidence of AIBD in DPP4i users compared to non-users. This retrospective cohort study included US veterans who initiated either DPP4i or glucagon like-peptide 1 receptor agonist (GLP1-RA) medications, as active comparator, between 2006 to 2021. We formed a propensity score (PS) matched cohort of DPP4i and GLP1-RA users encompassing 46 baseline characteristics. Our primary outcome was the incidence of AIBD, which included bullous pemphigoid (BP) and pemphigus vulgaris (PV) in the PS-matched cohort. The study included 266,315 DPP4i users and 149,183 GLP1-RA users. We propensity score-matched 101,220 pairs of DPP4i and GLP1-RA users without residual imbalances. A total of 154 patients developed AIBD. Of those, 123 were DPP4i users (0.05%) and 31 were GLP1-RA users (0.02%). Use of DPP4i compared to GLP1-RA was associated with increased odds of AIBD (odds ratio [OR]: 1.88, 95% confidence interval [95%CI]: 1.02-3.44, p = 0.0421) and BP (OR: 1.90, 95%CI: 1.14-3.17, p = 0.014) but was not associated with PV (OR: 1.31, 95% CI: 0.65-2.62, p = 0.45). Our study supports existing literature indicating that DPP4i is associated with an increased risk of BP.
2026-05-25 | NK cell hyperactivation drives macrophage repolarization and limits M2 bias in pemphigus vulgaris.
Macrophages and natural killer (NK) cells are innate immune components proven to be either pathogenic, protective, or both in autoimmune disorders. Nonetheless, the function of macrophages in the pathogenesis of pemphigus vulgaris (PV), an autoimmune skin disorder, is lacking. We aimed to investigate macrophages and their crosstalk with NK cells in PV, with a particular focus on how these interactions influence their functionalities. Flow cytometry and immunofluorescence was utilised to assess macrophage profile along with expression of receptors on NK cells and macrophages. In-vitro macrophage skewing, and NK-macrophage interactions (including F-actin accumulation, activation markers, cytotoxicity, IFNγ and perforin secretion, NOS2, CD86, CD206 expression, phagocytic activity, and arginase activity were examined. NKG2D blocking and related assays were performed to elucidate its role in crosstalk. Expression of NKG2D on NK cells and MICA/B on macrophages was upregulated. CD56+ NK cells and CD68+ macrophages co-localized in lesions. A significant increase in macrophages in both the periphery and lesional skin was observed. Both M1 and M2 macrophages were upregulated in blood, whereas M1 increased and M2 decreased in skin lesions. Macrophages displayed skewing toward an M2 phenotype in vitro. Upon co-culturing, F-actin accumulation increased during interaction. The interaction led to increased activation, cytotoxicity, and IFNγ and perforin secretion in NK cells when M1 stimulation and Dsg3 autoantigen were given. In macrophages, increased expression of iNOS and CD86 and higher phagocytic activity were noted, whereas arginase activity and expression along with CD206 were downregulated. NKG2D blockade on NK cells resulted in partial but significant decrease in NK cells activity including activation, perforin, cytotoxicity and IFNγ release. The reduction were prominent in M1 state. M1 like markers NOS2 and CD86 were reduced and arginase activity non significantly improved under M2 state post blockade. This study helped in comprehending functionally active NK- macrophage axis, where NK cells promote pro inflammatory M1 state, and dysregulate M2 macrophage functionality. NKG2D blockade resulted in partial reversal suggesting its critical, though not elusive, contribution indicating multifactorial crosstalk mechanism. Targeting NK cell activity or promoting M2 functionality could potentially lead to improvements in disease pathogenesis.
2026-04-27 | Common Skin Diseases and Metabolic Syndrome: A Proinflammatory Chemokine Perspective.
Skin diseases frequently coexist with other disorders, such as metabolic syndrome, diabetes mellitus, depression, psoriatic arthritis, and cardiovascular disease. Altered levels of distinct chemokines, like CCL5/RANTES, CXCL12/SDF-1a, CCL7/MCP-3, CCL2/MCP-1, CXCL1/GROa, and the eotaxin family, contribute to the development and/or exacerbation of inflammation, which is a common feature of numerous skin diseases as well as metabolic syndrome. The pathological and molecular connections between chronic inflammatory skin diseases and metabolic syndrome are increasingly recognized as being driven by shared inflammatory pathways, oxidative stress, and adipokine dysregulation. While systemic inflammation acts as a common thread, the precise mechanisms for some conditions remain partially understood. Nevertheless, the exact pathological and molecular connections between skin diseases (i.e., psoriasis, atopic dermatitis, pemphigus vulgaris, acute and chronic spontaneous urticaria, bullous pemphigoid, squamous cell carcinoma, alopecia areata, systemic sclerosis, discoid lupus erythematosus, diffuse large B-cell lymphoma) and metabolic syndrome are not yet fully understood. This narrative review summarizes the robust association between various chronic inflammatory skin diseases and metabolic syndrome in the context of pro-inflammatory chemokines.
cell therapies
2026-06-01 | Severe Pemphigus Vulgaris with Oral and Cutaneous Involvement: A Case Report
Pemphigus vulgaris (PV) is a rare, chronic, and potentially life-threatening autoimmune vesiculobullous disorder characterized by intraepithelial blister formation involving the skin and mucous membranes. It commonly affects individuals in the fifth to seventh decades of life and is associated with significant morbidity due to fluid and protein loss, metabolic disturbances, and secondary infections if left untreated. This report presents the case of a 50-year-old female patient with severe PV who presented with persistent painful oral ulcerations and recurrent cutaneous blisters over a period of three years. The patient had shown an inadequate clinical response to conventional systemic corticosteroid therapy. Due to the chronicity and severity of the condition, the treatment regimen was modified to include combination immunomodulatory therapy along with systemic corticosteroids, which resulted in marked clinical improvement in both oral and cutaneous lesions. This case highlights the importance of early diagnosis, prompt intervention, and individualized therapeutic strategies in the successful management of pemphigus vulgaris. Timely initiation of appropriate treatment can significantly reduce disease-related morbidity and improve the overall quality of life of affected patients.
2026-05-27 | CD19 CAR T Therapy Is Feasible in Patients with Pemphigus Vulgaris Treated Without Lymphodepletion in the RESET-PV Trial.
Lymphodepleting pre-conditioning (LD) is essential for the efficacy of CAR T therapy in hematologic malignancies. However, in the setting of autoimmune diseases (ADs), the contribution of LD for efficacy is unclear. Here, we report on the early safety, efficacy, and correlative data of the first four pemphigus vulgaris (PV) subjects who received resecabtagene autoleucel (rese-cel) a fully human CD19-CAR T cell therapy, without LD in the RESET-PV® trial (NCT04422912), a sub-study of the DesCAARTes trial. Following infusion, pemphigus disease area index (PDAI) scores improved significantly in all subjects. A favorable safety profile was observed with a single episode of grade 1 cytokine release syndrome. Immune-effector-cell-associated neurotoxicity was not observed. Rese-cel expansion was similar in PV subjects as compared to other rese-cel treated AD subjects who received LD. B cell depletion was observed in all PV subjects, with 3 of 4 subjects achieving B cell aplasia. Elevations in serum BAFF were observed, with 3 of 4 subjects achieving levels within the lowest end of the range exhibited in rese-cel treated AD subjects who received LD. Pathogenic PV autoantibodies decreased in 2 of 4 subjects. Together, these preliminary data suggest that LD may not be required for humanized CAR T efficacy in patients with AD.
2026-02-23 | Autoimmune Bullous Diseases: Therapeutic Update.
Autoimmune blistering diseases (AIBDs) are a heterogeneous group of at least a dozen disorders characterized by autoantibodies against structural proteins of desmosomes in the skin and surface-close epithelia in pemphigus and of the dermal-epidermal junction in pemphigoid diseases. Novel disease entities have recently been described. Owing to their relative rarity with annual incidences between below 1 and about 20 new cases per million inhabitants, few randomized controlled trials (RCTs) have been performed. In this review, we summarize the results of recent RCTs and future treatment options for the three most frequent AIBDs, i.e., bullous pemphigoid, pemphigus vulgaris/foliaceus, and mucous membrane pemphigoid. More specifically, RCTs with immunoadsorption, rilzabrutinib, and efgartigimod in pemphigus, as well as dupilumab, benralizumab, mepolizumab, avdoralimab, and efgartigimod in bullous pemphigoid are summarized. The recent US Food and Drug Administration (FDA) approval of the interleukin (IL)-4/IL-13 inhibitor dupilumab for moderate/severe bullous pemphigoid is highlighted. In addition, an overview is given about the current treatment landscape on the basis of national and international guidelines as well the experience of the authors. In all, while licensing of rituximab for pemphigus vulgaris and dupilumab for bullous pemphigoid represents a therapeutic breakthrough, the lack of industry-sponsored RCTs in mucous membrane pemphigoid and the failure of recent RCTs in pemphigus and bullous pemphigoid demonstrate, on the one hand, the high medical need for effective and safe therapies in AIBDs and, on the other hand, the apparent difficulty in finding suitable compounds and appropriate trial designs.
2025-10-22 | Conversion of pathogenic T cells into functionally stabilized Treg cells for antigen-specific immunosuppression in pemphigus vulgaris.
Antigen-specific immunotherapy represents one candidate strategy for treating autoimmune diseases such as pemphigus vulgaris, a skin autoimmune disorder mediated by anti-desmoglein 3 (Dsg3) autoantibodies. We developed a therapeutic strategy by which Dsg3-specific pathogenic autoreactive CD4+ T cells were converted in vitro into functionally stable Foxp3+ regulatory T (Treg) cells, designated stable and functional induced Treg (S/F-iTreg) cells. The conversion was achieved by pharmacological induction of Foxp3 and costimulation-dependent installation of Treg cell-specific epigenetic changes. In an animal model of pemphigus vulgaris, the Dsg3-specific S/F-iTreg cells expanded specifically in the skin-draining lymph nodes through recognition of endogenous Dsg3. They selectively inhibited Dsg3-specific T follicular helper cell and B cell proliferation and, consequently, anti-Dsg3 autoantibody formation, without affecting the total B cell population, thereby mitigating disease progression without inducing systemic immunosuppression. Human S/F-iTreg cells with similar functions could also be efficiently generated from peripheral blood T cells of patients with pemphigus vulgaris. This study demonstrates that pathogenic autoreactive T cells can be converted into disease-specific Treg cells retaining antigen specificity, enabling antigen- and disease-specific treatment of autoimmune disease.
2025-06-05 | Antigen-specific immune responses and microbiota interactions in skin: Insights into autoimmune skin diseases and emerging therapeutic strategies.
The skin plays a vital role in serving as a physical and immunologic barrier against external insults while orchestrating complex immune responses. Autoimmune skin diseases including pemphigus, vitiligo, and alopecia areata illustrate the intricate interplay between antigen-specific immunity and tissue-specific pathologies. Pemphigus serves as a model to understand the dynamics of peripheral immune tolerance and the interplay between humoral and cellular autoimmunity, emphasizing the role of regulatory T cells in controlling autoreactive responses. Similarly, vitiligo and alopecia areata highlight the pathological contribution of resident memory CD8+ T cells and IFN-γ signaling, identifying potential therapeutic targets such as the IL-15 signaling pathway to address disease intractability. In addition to autoimmune mechanisms, the skin microbiota profoundly influences local and systemic immune responses. Commensals such as Staphylococcus epidermidis promote homeostasis by regulating barrier integrity, T-cell activation, and wound repair, while dysbiosis exacerbates immune dysregulation. Innovative strategies, including the use of genetically modified microorganisms to stimulate antigen-specific immunity, hold promise for next-generation therapies. This review underscores the significance of antigen-specific immunity in skin diseases and the emerging role of microbiota in modulating immune responses. Future research into these areas is pivotal for advancing targeted therapies and understanding the interconnectedness of skin health and systemic immunity.
other
2024-12-09 | Immunosuppressants in dermatology on vaccine immunogenicity: a prospective cohort study of pemphigus patients in the pandemic.
Both cellular and humoral responses are important for vaccine protection, but recommendations on immunosuppressants in dermatology are largely based on pre-pandemic experiences. This study aimed to investigate the impacts of immunosuppressants on humoral and cellular immunogenicity to COVID-19 vaccinations in pemphigus patients. SARS-CoV-2-naïve pemphigus patients and age-, and sex-matched healthy controls were recruited from multiple tertiary medical centers during 2021-2023. Anti-spike protein-related T-cell responses, antibody titers, and high-parameter cell analysis of the peripheral blood were utilized to investigate the inhibitory effects of immunosuppressants, including rituximab and azathioprine. A total of 32 patients and 120 healthy controls were enrolled. COVID-19 vaccinations spaced at least six months after the last rituximab infusion did not cause a significant difference in anti-viral T-cell or antibody responses between rituximab-naïve and rituximab-treated patients. All pemphigus patients demonstrated improved antibody responses after the third vaccination and none of them suffered from severe COVID-19 illness. Intriguingly, we found that daily dosages of 100 mg or more of azathioprine were linked to significantly decreased anti-viral T-cell responses induced by the vaccination (mean of fold change [SD]; higher azathioprine dosage = 0.70 [0.61] folds vs. lower azathioprine dosage = 2.11 [1.03] folds; p = 0.044). Except for a subset of patients with unrecovered B-cell deficiency, rituximab infusion with proper scheduling of vaccination preserved better anti-viral T-cell responses and did not lead to hindered antibody responses in pemphigus patients. All pemphigus patients benefited from receiving the third booster regardless of B-cell status.
2024-08-29 | shRNA-Targeting Caspase-3 Inhibits Cell Detachment Induced by Pemphigus Vulgaris Autoantibodies in HaCaT Cells.
Pemphigus is an autoimmune disease that affects the skin and mucous membranes, induced by the deposition of pemphigus IgG, which mainly targets desmogleins 1 and 3 (Dsg1 and 3). This autoantibody causes steric interference between Dsg1 and 3 and the loss of cell adhesion, producing acantholysis. This molecule and its cellular effects are clinically reflected as intraepidermal blistering. Pemphigus vulgaris-IgG (PV-IgG) binding involves p38MAPK-signaling-dependent caspase-3 activation. The present work assessed the in vitro effect of PV-IgG on the adherence of HaCaT cells dependent on caspase-3. PV-IgG induced cell detachment and apoptotic changes, as demonstrated by annexin fluorescent assays. The effect of caspase-3 induced by PV-IgG was suppressed in cells pre-treated with caspase-3-shRNA, and normal IgG (N-IgG) as a control had no relevant effects on the aforementioned parameters. The results demonstrated that shRNA reduces caspase-3 expression, as measured via qRT-PCR and via Western blot and immunofluorescence, and increases cell adhesion. In conclusion, shRNA prevented in vitro cell detachment and the late effects of apoptosis induced by PV-IgG on HaCaT cells, furthering our understanding of the molecular role of caspase-3 cell adhesion dependence in pemphigus disease.
2023-07-31 | Plasma Exosomal microRNA Profile Reveals miRNA 148a-3p Downregulation in the Mucosal-Dominant Variant of Pemphigus Vulgaris.
The mucosal-dominant variant of pemphigus vulgaris (MPV) is an autoimmune disease characterized by oral mucosal blistering and circulating pathogenic IgG antibodies against desmoglein 3 (Dsg3), resulting in life-threatening bullae and erosion formation. Recently, microRNAs (miRNAs) have emerged as promising players in the diagnosis and prognosis of several pathological states. For the first time, we have identified a different expression profile of miRNAs isolated from plasma-derived exosomes (P-EVs) of MPV patients positive for antibodies against Dsg3 (Dsg3-positive) compared to healthy controls. Moreover, a dysregulated miRNA profile was confirmed in MPV tissue biopsies. In particular, a strong downregulation of the miR-148a-3p expression level in P-EVs of MPV patients compared to healthy controls was demonstrated. Bioinformatics prediction analysis identifies metalloproteinase-7 (MMP7) as a potential miR-148a-3p target. An in vitro acantholysis model revealed that the miR-148a-3p expression level was dramatically downregulated after treatment with Dsg3 autoantibodies, with a concomitant increase in MMP7 expression. The increased expression of MMP7 leads to the disruption of intercellular and/or extracellular matrix adhesion in an in vitro cellular model of MPV, with subsequent cell dissociation. Overexpression of miR-148a-3p prevented cell dissociation and regressed MMP7 upregulation. Our findings suggest a pivotal role of P-EV cargo in regulating molecular mechanisms involved in MPV pathogenesis and indicate them as potential MPV therapeutic targets.
2022-09-20 | Low SOCS3 expression in CD4+ T cells from pemphigus vulgaris patients enhanced Th1- and Th17-cell differentiation and exacerbated acantholysis via STAT activation.
Pemphigus vulgaris (PV) is a chronic inflammatory autoimmune blistering disease. Aberrant SOCS3/STAT pathway activation is associated with many autoimmune diseases. This study explored the relationship between activation of the SOCS3/STAT pathway and abnormally increased proportions of Th1 and Th17 cells in the peripheral blood of PV patients as well as the effect of CD4+ T cells with abnormal SOCS3/STAT pathway activation on acantholysis. In PV patients, the proportions of Th1 and Th17 cells in peripheral blood, the levels of IFN-γ and IL-17 in serum and the mRNA levels of SOCS3 and STAT1/3 in CD4+ T cells were detected. Then, SOCS3-knockdown primary CD4+ T cells were prepared, and cocultured with HaCaT cells. Finally, after SOCS3 knockdown and coculture, CD4+ T cells were collected, and the proportions of Th1 and Th17 cells, the protein levels of STAT1/3 and p-STAT1/3, and the levels of IFN-γ and IL-17 were measured. After 2 days of coculture, HaCaT cells were collected, inflammatory factors mRNA expression and acantholysis were assessed. In PV patients, the proportions of Th1 (P = 0.016) and Th17 (P = 0.045) cells and the levels of IFN-γ (P = 0.010) were significantly increased. SOCS3 mRNA in CD4+ T cells was significantly decreased (P = 0.008), whereas STAT1 (P = 0.043) and STAT3 (P = 0.004) mRNA were significantly increased. After SOCS3 knockdown, the proportions of Th1 (P < 0.001) and Th17 (P = 0.006) cells, the levels of IFN-γ (P < 0.001) and IL-17 (P = 0.001), and the protein levels of p-STAT1 (P = 0.001) and p-STAT3 (P = 0.003) were significantly increased in the CD4+ T-shSOCS3-1 group. In the coculture system, the proportions of Th1 (P < 0.001) and Th17 (P < 0.001) cells, the levels of IFN-γ (P < 0.001) and IL-17 (P < 0.001), and the number of cell fragments (P < 0.001) were significantly increased in the CD4+ T-shSOCS3-1+HaCaT-PV-IgG group, whereas the protein level of desmoglein3 (Dsg3) was significantly decreased. In addition, PV-IgG significantly increased IFN-γ and IL-6 mRNA in HaCaT cells. Low SOCS3 expression in CD4+ T cells from PV patients leads to overactivation of STAT, which causes CD4+ T cells to overdifferentiate into Th1 and Th17 cells. Additionally, PV-IgG-induced local inflammation in skin lesions, which is mediated by IFN-γ and IL-6, can aggravate this phenomenon. Furthermore, low SOCS3 expression in CD4+ T cells further exacerbates PV-IgG-induced acantholysis. Therefore, upregulating the expression of SOCS3 in CD4+ T cells of PV patients and maintaining the balance of the IFN-γ/STAT1/SOCS3 and IL-6/STAT3/SOCS3 pathways can alleviate acantholysis in patients with PV.
2022-04-21 | Transcriptomic profiling of pemphigus lesion infiltrating mononuclear cells reveals a distinct local immune microenvironment and novel lncRNA regulators
Abstract Pemphigus is an autoimmune skin disease. Ectopic lymphoid-like structures (ELSs) were found to be commonly present in the pemphigus lesions, presumably supporting in situ desmoglein (Dsg)-specific antibody production. Yet functional phenotypes and the regulators of Lymphoid aggregates in pemphigus lesions remain largely unknown. Herein, we used microarray technology to profile the gene expression in skin lesion infiltrating mononuclear cells (SIMC) from pemphigus patients. On top of that, we compared SIMC dataset to peripheral blood mononuclear cells (PBMC) dataset to characterize the unique role of SIMC. Functional enrichment results showed that mononuclear cells in skin lesions and peripheral blood both had over-represented IL-17 signaling pathways while neither was characterized by an activation of type I Interferon signaling pathways. Cell-type identification with relative subsets of known RNA transcripts (CIBERSORT) results showed that naïve natural killer cells (NK cells) were significantly more abundant in pemphigus lesions, and their relative abundance positively correlated with B cells abundance. Meanwhile, plasma cells population highly correlated with type 1 macrophages (M1) abundance. In addition, we also identified a lncRNA LINC01588 which might epigenetically regulate T helper 17 cells (Th17)/regulatory T cells (Treg) balance via the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Here, we provide the first transcriptomic characterization of lesion infiltrating immune cells which illustrates a distinct interplay network between adaptive and innate immune cells. It helps discover new regulators of local immune response, which potentially will provide a novel path forward to further uncover pemphigus pathological mechanisms and develop targeted therapy.
small molecules
2026-07-22 | Unraveling the autoimmune architecture of pemphigus: from B-cell depletion to network-based immune engineering.
Pemphigus encompasses autoimmune blistering diseases driven by autoantibodies to desmosomal proteins. Disruption of keratinocyte adhesion produces acantholysis and epidermal fragility. Anti-CD20 B-cell depletion and IgG lowering strategies have transformed care, but many patients relapse, some variants respond incompletely, and durable drug-independent tolerance remains uncommon across variants. These gaps highlight that pemphigus is not a simple linear B-cell disorder, but an autoantibody disease sustained by a network linking the innate immunity, the adaptive lymphocytes, and the stromal niches. In this review, we focus on pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome, and IgA pemphigus as representative variants within this network. We place these entities within a conceptual type 1, type 2, and type 3 immunity framework and summarize how central and peripheral B-cell tolerance can fail. We further consider current and emerging therapies as partial interventions within this network and outline next-generation strategies that modulate innate circuits, rewire survival pathways, restore antigen-specific regulation, and shift the adaptive autoimmune response toward a more tolerogenic state. Framing pemphigus in this way may help move the field from empiric immunosuppression toward precise immune engineering with the goal of durable immune reset and long-term drug-independent remission.
2026-05-11 | Cyclophosphamide is associated with long-term treatment-free remission in patients with pemphigus.
Pemphigus treatment has seen significant advancements, yet long-term remission remains a challenge. Comparative data on the long-term effectiveness of available therapies are limited. We compared 10-year relapse rates in pemphigus patients treated with azathioprine or cyclophosphamide plus high-dose IV corticosteroids PATIENTS AND METHODS: In this retrospective single-center cohort study, we analyzed 91 patients with pemphigus vulgaris/foliaceus treated between 1985 and 2022. 43 patients received oral azathioprine, 48 received intermittent intravenous and oral cyclophosphamide. All patients also received intermittent high-dose IV corticosteroids for ≥ 1 year. As rituximab became widely available only after 2019, follow-up was insufficient to include it in this analysis. Remission occurred equally quickly in both groups, but patients treated with cyclophosphamide suffered from significantly fewer relapses: 27% of cyclophosphamide patients had ≥ 1 relapse vs. 80.6% with azathioprine (p < 0.001). 70% of cyclophosphamide patients remained relapse-free and were off therapy for an average of 7 years. Aggressive initial immunosuppressive therapy with cyclophosphamide is associated with a significantly lower long-term relapse rate in pemphigus. While routine use is limited by its toxicity, these findings underscore the potential for durable remission and the importance of long-term disease control as a treatment goal.
2026-04-30 | Recurrent Pemphigus Vulgaris with Isolated Nail Involvement
A 67-year-old man presented with a 3-year history of nail changes including discoloration, dystrophy, subungual hyperkeratosis, frayed edges, onycholysis, splitting, pitting, exudation, and paronychia [Figure 1]. No skin or mucosal lesions were observed. The patient had a history of pemphigus vulgaris (PV) 13 years ago, which had resolved after 6 months of treatment with oral prednisone. Histopathological examination of the right ring finger nail bed revealed a suprabasal cleft in the epidermis [Figure 2]. Direct immunofluorescence of proximal nail fold showed a reticulated pattern of intercellular IgG deposition [Figure 3]. The anti-desmoglein 3 antibody level was elevated to > 200 U/mL (ELISA kit, Euroimmun, normal: 0-20U/mL). A diagnosis of recurrent PV was established. The nail lesions resolved within 6 months following treatment with oral minocycline and nicotinamide.Figure 1: Discoloration, dystrophy, subungual hyperkeratosis, frayed edges, onycholysis, ripping, pitting, exudation, and paronychia of the nailsFigure 2: Suprabasal cleft in the epidermis (Hematoxylin and eosin, 200×)Figure 3: Direct immunofluorescence showed a reticulated pattern of intercellular IgG deposition (Fluorescein Isothiocyanate, 200×)Previous studies report nail involvement in 47% to 80% of PV patients [1,2] and in up to 91% of patients with autoimmune blistering diseases.[3] Paronychia is the most common nail manifestation in PV [4,5] and is considered a sign that may precede disease exacerbation.[1,3] Authors’ contributions We confirm that all authors have read and approved the manuscript for submission. All authors meet authorship criteria, and the manuscript represents honest work. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Use of artificial intelligence (AI) The preparation of this manuscript was carried out entirely by the authors without the use of artificial intelligence technologies.
2026-04-27 | Treatment of Canine Pemphigus Foliaceus, Pemphigus Vulgaris and Mucous Membrane Pemphigoid With Oclacitinib: A Retrospective Analysis of 21 Cases.
This study was performed to retrospectively evaluate the efficacy of oclacitinib (OC) (Apoquel; Zoetis) as a treatment option for pemphigus foliaceus (PF), pemphigus vulgaris (PV) and mucous membrane pemphigoid (MMP). To determine if OC can reduce or replace the corticosteroid use in dogs with PF, PV and MMP. There were no animal subjects. Multicentre retrospective study reviewing medical records from two institutions for dogs diagnosed with PF, PV or MMP and prescribed OC between 2014 and 2025. Twenty-one dogs diagnosed with PF, PV or MMP via histopathological results were included. OC alone was effective in eight of 18 PF dogs at a median dose of 0.65 mg/kg/day per os (range 0.5-1.9 mg/kg/day p.o.). Five dogs reached clinical remission, and three reached partial remission. One PV dog and the MMP dog each reached clinical remission with OC alone at 0.7 mg/kg/day and 0.24 mg/kg every other day, respectively. OC was a corticosteroid-sparing agent or adjunctive therapy in seven of 18 PF dogs at a median dose of 0.6 mg/kg/day (range 0.4-2.4 mg/kg/day). One PV dog reached partial remission at OC 1.9 mg/kg/day and prednisone 1.8 mg/kg/day yet died from pancreatitis. OC was ineffective in three of 18 PF dogs at a median dose of 1.0 mg/kg/day p.o. (range 0.9-1.2 mg/kg/day p.o.). Statistical significance was not analysed. OC is an effective sole therapeutic agent or adjunctive therapy in a subset of dogs with PF, PV or MMP. The long-term safety of higher doses of OC is unknown.
2026-04-14 | The role of the dental surgeon in the diagnosis and treatment of pemphigus vulgaris
Pemphigus vulgaris is a low-prevalence autoimmune disorder characterized by vesiculobullous lesions affecting the skin and mucous membranes. Lesions in the oral mucosa can be the initial manifestations of the disease and highlight the importance of the dentist in early diagnosis. The objective of this study is to report a clinical case of pemphigus vulgaris with oral lesions in a 44-year-old female patient with no comorbidities. Intraoral physical examination revealed ulcerated lesions throughout the oral cavity, accompanied by bullous lesions, ulcerations, and crusts on the skin. The patient reported having had the lesions for four months, with no conclusive diagnosis. These lesions made eating difficult and resulted in marked weight loss and the need for hospitalization. During hospitalization, the diagnosis was established by the medical and dental team based on clinical characteristics and medical history, followed by histopathological confirmation. Oral lesions were treated with 0.12% chlorhexidine digluconate mouthwash and laser photobiomodulation, combined with systemic corticosteroid therapy, resulting in significant remission. Therefore, dentists' knowledge of the clinical and histopathological characteristics of pemphigus vulgaris is essential for early diagnosis and effective treatment, promoting patient health and quality of life. Further studies should be conducted to optimize management strategies for oral lesions in patients with pemphigus vulgaris.
proteins
2026-03-13 | IL‑37/IL‑1R8 blocks keratinocyte acantholysis via suppressing ADAM17/EGFR.
Pemphigus vulgaris (PV) is a life‑threatening autoimmune blistering disease characterized by acantholysis (the loss of cell‑cell adhesion of keratinocytes) and the formation of non‑healing suprabasal intraepidermal blisters. The progression of keratinocyte acantholysis in PV is complex. Interleukin‑37 (IL‑37), which functions through receptor binding, exerts a protective role in PV. However, the specific receptor mediating the effect of IL‑37 in PV and the underlying mechanisms remain unclear. The present study found elevated levels of IL‑37, a natural suppressor of innate inflammatory and immune responses, in patients with PV. IL‑37 treatment directly suppressed both acantholysis and apoptosis in keratinocytes. Mechanistic investigations using co‑immunoprecipitation revealed that IL‑37 binds to interleukin‑1 receptor 8 (IL‑1R8). Knockdown of IL‑1R8 (or IL‑18Rα) abolished the inhibitory effects of IL‑37 on acantholysis and apoptosis. Furthermore, the IL‑37/IL‑1R8 complex suppressed epidermal growth factor receptor (EGFR) signaling, and reduced the expression of TNF‑alpha‑converting enzyme (ADAM17). Activation of EGFR using specific agonists reversed the IL‑37‑mediated reduction in acantholysis and apoptosis in HaCaT cells. In conclusion, IL‑37 treatment markedly attenuated keratinocyte dissociation and apoptosis in PV through the IL‑1R8/ADAM17/EGFR pathway. These findings provide novel mechanistic insights into the immunoregulatory functions of IL‑37.
2025-10-03 | Taking aim at autoimmunity-Antigen-Fc constructs for mucosal pemphigus hit the mark.
A desmoglein-3 antigen-Fc fusion construct shows promise as a therapeutic in a model of pemphigus vulgaris.
2025-08-27 | Antigen-Fc fusion therapy reduces severity of a model of pemphigus vulgaris without systemic immunosuppression.
Pemphigus vulgaris is a B cell-mediated autoimmune disease characterized by autoantibodies targeting desmoglein-3 (Dsg3), a critical adhesion molecule in epithelial tissues. Current treatments rely on broad immunosuppression, highlighting the need for more targeted therapeutic approaches in pemphigus vulgaris and other autoantibody-driven disorders. We engineered a therapeutic fusion protein consisting of the pathogenic domains of Dsg3 linked to either human immunoglobulin G1 (IgG1) or mouse IgG2a (Dsg3-Fc). In vitro, Dsg3-Fc selectively eliminated Dsg3-autoreactive B cells. In vivo, Dsg3-Fc effectively depleted human B cells expressing patient-derived anti-Dsg3 B cell receptors, even in the presence of circulating autoantibodies. Moreover, Dsg3-Fc inhibited both disease initiation and progression in a polyclonal, active pemphigus vulgaris model in immunocompetent mice. In addition, Dsg3-Fc rapidly neutralized pathogenic autoantibodies without inducing systemic toxicity. These findings demonstrate that targeting pathogenic B cells and neutralizing autoantibodies through autoantigen-Fc fusion proteins may represent a promising therapeutic strategy for pemphigus vulgaris and potentially other autoantibody-mediated diseases without the need for global immunosuppression.
2025-08-20 | Immunoregulatory effects of TPM203 peptide-nanoparticle therapy in pemphigus vulgaris
Journal Article Accepted manuscript Immunoregulatory effects of TPM203 peptide-nanoparticle therapy in pemphigus vulgaris Get access Chuda Rujitharanawong , Chuda Rujitharanawong Department of Dermatology, Columbia University, New York, NY, USADepartment of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand Search for other works by this author on: Oxford Academic Google Scholar Aimee S Payne Aimee S Payne Department of Dermatology, Columbia University, New York, NY, USA Corresponding author: Aimee S. Payne, MD, PhD, Email:[email protected] Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljaf323, https://doi.org/10.1093/bjd/ljaf323 Published: 21 August 2025 Article history Received: 11 August 2025 Accepted: 12 August 2025 Published: 21 August 2025
2025-08-12 | Safety, tolerability, pharmacokinetics and pharmacodynamic effects of desmoglein 3 peptide-coupled tolerizing nanoparticles in pemphigus.
Pemphigus vulgaris (PV) is a CD4+ T-cell-dependent autoantibody-mediated blistering disease associated with human leucocyte antigen (HLA) class II molecules. IgG autoantibodies against the primary autoantigen desmoglein 3 (Dsg3), a desmosomal adhesion protein on epidermal keratinocytes, cause loss of epidermal cell adhesion. To assess the clinical applicability of an innovative nanoparticle platform for the induction of immune tolerance exploiting the natural tolerance potential of liver sinusoidal endothelial cells. An open-label first-in-human study was conducted with TPM203, a mixture of four nanoparticle-coupled immunodominant Dsg3 T-cell peptides. The efficacy and mechanism of action of TPM203 were first tested in a humanized HLA-DRB1*0402-transgenic PV mouse model. In the clinical phase I trial, TPM203 was administered intravenously in patients with PV with no-to-moderate disease activity in single ascending and multiple doses (three doses of TPM203 two weeks apart). Primary endpoints included safety and tolerability. As a secondary endpoint, pharmacokinetics were assessed. Exploratory endpoints comprised changes in Dsg3-specific and bulk T- and B-cell frequencies, anti-Dsg3 IgG levels and autoantibody-induced keratinocyte dissociation. The trial was registered with EudraCT (2019-001727-12). In the PV mouse model, two administrations of TPM203 significantly reduced anti-Dsg3 IgG. On the cellular level, TPM203 led to a significant decrease in CD4+ T cells in the spleen, accompanied by increased frequencies of regulatory T (Treg) cells. In the clinical trial, the 17 patients with PV enrolled across single- and multiple-dose groups did not experience any serious or severe adverse events, or treatment-related PV worsening. Pharmacokinetics confirmed rapid TPM203 clearance from the circulation. Significant TPM203-induced modulations in bulk lymphocyte subsets included an increase in Treg cells, and reductions in T helper 17.1 and CD27+ memory B cells, when dose groups were combined for analysis. Dsg3-specific T cells were found to be significantly reduced at week 8 following single administration of TPM203. Anti-Dsg3 IgG levels trended downward in the three lower single ascending dose groups, while IgG-induced keratinocyte-dissociating capacity was significantly reduced after multiple doses. Administered for the first time in humans, TPM203 was shown to be a safe and well-tolerated nanoparticle-based therapeutic approach with the potential to promote tolerance induction in PV, justifying further clinical development in this and other autoimmune diseases. An author video to accompany this article is available online.
antibodies
2026-07-11 | Case Report: Dupilumab as a corticosteroid-sparing adjunct in severe mucocutaneous pemphigus vulgaris with prior avascular necrosis and chronic kidney disease.
Pemphigus vulgaris is a potentially life-threatening autoimmune blistering disease for which corticosteroid minimization can be difficult when prior steroid toxicity has already occurred. We report a 60-year-old woman with severe mucocutaneous pemphigus vulgaris confirmed by clinical, immunopathologic, and serologic findings, who had previously developed femoral head avascular necrosis during high-dose prednisone therapy and also had advanced chronic kidney disease, hypoalbuminemia, and anemia. Rituximab was discussed as a guideline-supported first-line option; however, after counseling regarding its expected benefits and potential adverse effects, the patient declined rituximab. Therefore, dupilumab was introduced off-label as an adjunctive corticosteroid-minimizing approach together with oral prednisone 30 mg/day and supportive care. The Pemphigus Disease Area Index was 111 during the first treatment week and decreased to 22 by week 6, when disease control was achieved with cessation of new lesions and marked healing of pre-existing erosions. Prednisone was then tapered gradually. Complete re-epithelialization was achieved by approximately month 4 while the patient was receiving oral prednisone 7.5 mg/day, and clinical stability was maintained through month 6 after dupilumab discontinuation at month 4. No adverse events were observed. This case supports the clinical feasibility of dupilumab-assisted corticosteroid minimization in selected patients with pemphigus vulgaris and major treatment-related constraints, while further evidence is needed regarding patient selection, duration of therapy, and long-term relapse risk.
2026-07-07 | RITUXIMAB THERAPY IN PEMPHIGUS VULGARIS: CLINICAL OUTCOMES, SAFETY, AND QUALITY-OF-LIFE ASSESSMENT
Objectives: Pemphigus vulgaris is a chronic autoimmune blistering disorder that affects the skin and mucous membranes, often requiring prolonged immunosuppressive treatment. Although systemic corticosteroids remain effective in controlling disease activity, their long-term use is frequently limited by infections, metabolic adverse effects, steroid dependence, and relapse during dose reduction. Rituximab, an anti-CD20 monoclonal antibody, has emerged as a valuable treatment option, particularly in patients with moderate-to-severe disease, recurrent flares, or poor response to conventional therapy. Methods: The present work was a prospective single-arm interventional study. Sixty patients with clinically, histopathologically, and immunologically confirmed pemphigus vulgaris were enrolled. Rituximab was administered using the rheumatoid arthritis (RA) protocol, 1 g intravenously on Day 1 and Day 14, with standard pre-medication and short-term bridging corticosteroids. Patients were followed at 1, 3, 6, 9, and 12 months. Disease activity was assessed by the pemphigus disease area index (PDAI), and quality of life was assessed by the dermatology life quality index (DLQI). Clinical response definitions were aligned with the 2008 pemphigus consensus statement. Adverse events were graded using Common Terminology Criteria for Adverse Events v5.0, and causality was assessed clinically using the World Health Organization-Uppsala Monitoring Centre approach. Results: The mean age was 40.6±11.8 years. There were 38 females (63.3%) and 22 males (36.7%). Oral mucosal involvement was present in all 60 patients (100.0%), cutaneous lesions in 52 patients (86.7%), and genital mucosal involvement in 18 patients (30.0%). At baseline, 8 patients (13.3%) had mild disease, 20 patients (33.3%) had moderate disease, and 32 patients (53.3%) had severe disease according to PDAI-based severity grouping. The mean PDAI score decreased from 78.6±31.4 at baseline to 8.9±6.2 at 12 months. Mean DLQI score improved from 19.2±5.7 to 3.1±2.6. Disease control was achieved in 6.4±2.1 weeks. Complete remission on minimal therapy was seen in 51 patients (85.0%). Relapse occurred in 12 patients (20.0%), and 10 patients (16.7%) required booster rituximab. Mild infusion reactions occurred in 8 patients (13.3%). Serious infection requiring hospital-based care occurred in 2 patients (3.3%), and no mortality was observed. Conclusion: Rituximab administered by the RA protocol was effective and generally well tolerated in this single-arm cohort. The treatment reduced disease activity, improved quality of life, and supported corticosteroid tapering. Because there was no control group, no prospective trial registration, and limited immunological monitoring, the findings should be interpreted as real-world evidence rather than proof of superiority over other regimens.
2026-05-26 | Examining the association of dipeptidyl peptidase-4 inhibitors with autoimmune blistering disorders in the U.S. Military veterans.
Dipeptidyl peptidase 4 inhibitor (DPP4i) are commonly used for management of diabetes. Although there are reports of increased risk of autoimmune skin blistering disorders (AIBD) with DPP4i, data is scarce. Although the exact mechanism through which DPP4i may cause AIBD is unknown, DPP4i may induce anti-basement membrane zone antibodies. Inhibition of DPP4 enzyme may also result in the recruitment of eosinophils into the dermis. Examine the incidence of AIBD in DPP4i users compared to non-users. This retrospective cohort study included US veterans who initiated either DPP4i or glucagon like-peptide 1 receptor agonist (GLP1-RA) medications, as active comparator, between 2006 to 2021. We formed a propensity score (PS) matched cohort of DPP4i and GLP1-RA users encompassing 46 baseline characteristics. Our primary outcome was the incidence of AIBD, which included bullous pemphigoid (BP) and pemphigus vulgaris (PV) in the PS-matched cohort. The study included 266,315 DPP4i users and 149,183 GLP1-RA users. We propensity score-matched 101,220 pairs of DPP4i and GLP1-RA users without residual imbalances. A total of 154 patients developed AIBD. Of those, 123 were DPP4i users (0.05%) and 31 were GLP1-RA users (0.02%). Use of DPP4i compared to GLP1-RA was associated with increased odds of AIBD (odds ratio [OR]: 1.88, 95% confidence interval [95%CI]: 1.02-3.44, p = 0.0421) and BP (OR: 1.90, 95%CI: 1.14-3.17, p = 0.014) but was not associated with PV (OR: 1.31, 95% CI: 0.65-2.62, p = 0.45). Our study supports existing literature indicating that DPP4i is associated with an increased risk of BP.
2026-05-25 | NK cell hyperactivation drives macrophage repolarization and limits M2 bias in pemphigus vulgaris.
Macrophages and natural killer (NK) cells are innate immune components proven to be either pathogenic, protective, or both in autoimmune disorders. Nonetheless, the function of macrophages in the pathogenesis of pemphigus vulgaris (PV), an autoimmune skin disorder, is lacking. We aimed to investigate macrophages and their crosstalk with NK cells in PV, with a particular focus on how these interactions influence their functionalities. Flow cytometry and immunofluorescence was utilised to assess macrophage profile along with expression of receptors on NK cells and macrophages. In-vitro macrophage skewing, and NK-macrophage interactions (including F-actin accumulation, activation markers, cytotoxicity, IFNγ and perforin secretion, NOS2, CD86, CD206 expression, phagocytic activity, and arginase activity were examined. NKG2D blocking and related assays were performed to elucidate its role in crosstalk. Expression of NKG2D on NK cells and MICA/B on macrophages was upregulated. CD56+ NK cells and CD68+ macrophages co-localized in lesions. A significant increase in macrophages in both the periphery and lesional skin was observed. Both M1 and M2 macrophages were upregulated in blood, whereas M1 increased and M2 decreased in skin lesions. Macrophages displayed skewing toward an M2 phenotype in vitro. Upon co-culturing, F-actin accumulation increased during interaction. The interaction led to increased activation, cytotoxicity, and IFNγ and perforin secretion in NK cells when M1 stimulation and Dsg3 autoantigen were given. In macrophages, increased expression of iNOS and CD86 and higher phagocytic activity were noted, whereas arginase activity and expression along with CD206 were downregulated. NKG2D blockade on NK cells resulted in partial but significant decrease in NK cells activity including activation, perforin, cytotoxicity and IFNγ release. The reduction were prominent in M1 state. M1 like markers NOS2 and CD86 were reduced and arginase activity non significantly improved under M2 state post blockade. This study helped in comprehending functionally active NK- macrophage axis, where NK cells promote pro inflammatory M1 state, and dysregulate M2 macrophage functionality. NKG2D blockade resulted in partial reversal suggesting its critical, though not elusive, contribution indicating multifactorial crosstalk mechanism. Targeting NK cell activity or promoting M2 functionality could potentially lead to improvements in disease pathogenesis.
2026-04-27 | Common Skin Diseases and Metabolic Syndrome: A Proinflammatory Chemokine Perspective.
Skin diseases frequently coexist with other disorders, such as metabolic syndrome, diabetes mellitus, depression, psoriatic arthritis, and cardiovascular disease. Altered levels of distinct chemokines, like CCL5/RANTES, CXCL12/SDF-1a, CCL7/MCP-3, CCL2/MCP-1, CXCL1/GROa, and the eotaxin family, contribute to the development and/or exacerbation of inflammation, which is a common feature of numerous skin diseases as well as metabolic syndrome. The pathological and molecular connections between chronic inflammatory skin diseases and metabolic syndrome are increasingly recognized as being driven by shared inflammatory pathways, oxidative stress, and adipokine dysregulation. While systemic inflammation acts as a common thread, the precise mechanisms for some conditions remain partially understood. Nevertheless, the exact pathological and molecular connections between skin diseases (i.e., psoriasis, atopic dermatitis, pemphigus vulgaris, acute and chronic spontaneous urticaria, bullous pemphigoid, squamous cell carcinoma, alopecia areata, systemic sclerosis, discoid lupus erythematosus, diffuse large B-cell lymphoma) and metabolic syndrome are not yet fully understood. This narrative review summarizes the robust association between various chronic inflammatory skin diseases and metabolic syndrome in the context of pro-inflammatory chemokines.
cell therapies
2026-06-01 | Severe Pemphigus Vulgaris with Oral and Cutaneous Involvement: A Case Report
Pemphigus vulgaris (PV) is a rare, chronic, and potentially life-threatening autoimmune vesiculobullous disorder characterized by intraepithelial blister formation involving the skin and mucous membranes. It commonly affects individuals in the fifth to seventh decades of life and is associated with significant morbidity due to fluid and protein loss, metabolic disturbances, and secondary infections if left untreated. This report presents the case of a 50-year-old female patient with severe PV who presented with persistent painful oral ulcerations and recurrent cutaneous blisters over a period of three years. The patient had shown an inadequate clinical response to conventional systemic corticosteroid therapy. Due to the chronicity and severity of the condition, the treatment regimen was modified to include combination immunomodulatory therapy along with systemic corticosteroids, which resulted in marked clinical improvement in both oral and cutaneous lesions. This case highlights the importance of early diagnosis, prompt intervention, and individualized therapeutic strategies in the successful management of pemphigus vulgaris. Timely initiation of appropriate treatment can significantly reduce disease-related morbidity and improve the overall quality of life of affected patients.
2026-05-27 | CD19 CAR T Therapy Is Feasible in Patients with Pemphigus Vulgaris Treated Without Lymphodepletion in the RESET-PV Trial.
Lymphodepleting pre-conditioning (LD) is essential for the efficacy of CAR T therapy in hematologic malignancies. However, in the setting of autoimmune diseases (ADs), the contribution of LD for efficacy is unclear. Here, we report on the early safety, efficacy, and correlative data of the first four pemphigus vulgaris (PV) subjects who received resecabtagene autoleucel (rese-cel) a fully human CD19-CAR T cell therapy, without LD in the RESET-PV® trial (NCT04422912), a sub-study of the DesCAARTes trial. Following infusion, pemphigus disease area index (PDAI) scores improved significantly in all subjects. A favorable safety profile was observed with a single episode of grade 1 cytokine release syndrome. Immune-effector-cell-associated neurotoxicity was not observed. Rese-cel expansion was similar in PV subjects as compared to other rese-cel treated AD subjects who received LD. B cell depletion was observed in all PV subjects, with 3 of 4 subjects achieving B cell aplasia. Elevations in serum BAFF were observed, with 3 of 4 subjects achieving levels within the lowest end of the range exhibited in rese-cel treated AD subjects who received LD. Pathogenic PV autoantibodies decreased in 2 of 4 subjects. Together, these preliminary data suggest that LD may not be required for humanized CAR T efficacy in patients with AD.
2026-02-23 | Autoimmune Bullous Diseases: Therapeutic Update.
Autoimmune blistering diseases (AIBDs) are a heterogeneous group of at least a dozen disorders characterized by autoantibodies against structural proteins of desmosomes in the skin and surface-close epithelia in pemphigus and of the dermal-epidermal junction in pemphigoid diseases. Novel disease entities have recently been described. Owing to their relative rarity with annual incidences between below 1 and about 20 new cases per million inhabitants, few randomized controlled trials (RCTs) have been performed. In this review, we summarize the results of recent RCTs and future treatment options for the three most frequent AIBDs, i.e., bullous pemphigoid, pemphigus vulgaris/foliaceus, and mucous membrane pemphigoid. More specifically, RCTs with immunoadsorption, rilzabrutinib, and efgartigimod in pemphigus, as well as dupilumab, benralizumab, mepolizumab, avdoralimab, and efgartigimod in bullous pemphigoid are summarized. The recent US Food and Drug Administration (FDA) approval of the interleukin (IL)-4/IL-13 inhibitor dupilumab for moderate/severe bullous pemphigoid is highlighted. In addition, an overview is given about the current treatment landscape on the basis of national and international guidelines as well the experience of the authors. In all, while licensing of rituximab for pemphigus vulgaris and dupilumab for bullous pemphigoid represents a therapeutic breakthrough, the lack of industry-sponsored RCTs in mucous membrane pemphigoid and the failure of recent RCTs in pemphigus and bullous pemphigoid demonstrate, on the one hand, the high medical need for effective and safe therapies in AIBDs and, on the other hand, the apparent difficulty in finding suitable compounds and appropriate trial designs.
2025-10-22 | Conversion of pathogenic T cells into functionally stabilized Treg cells for antigen-specific immunosuppression in pemphigus vulgaris.
Antigen-specific immunotherapy represents one candidate strategy for treating autoimmune diseases such as pemphigus vulgaris, a skin autoimmune disorder mediated by anti-desmoglein 3 (Dsg3) autoantibodies. We developed a therapeutic strategy by which Dsg3-specific pathogenic autoreactive CD4+ T cells were converted in vitro into functionally stable Foxp3+ regulatory T (Treg) cells, designated stable and functional induced Treg (S/F-iTreg) cells. The conversion was achieved by pharmacological induction of Foxp3 and costimulation-dependent installation of Treg cell-specific epigenetic changes. In an animal model of pemphigus vulgaris, the Dsg3-specific S/F-iTreg cells expanded specifically in the skin-draining lymph nodes through recognition of endogenous Dsg3. They selectively inhibited Dsg3-specific T follicular helper cell and B cell proliferation and, consequently, anti-Dsg3 autoantibody formation, without affecting the total B cell population, thereby mitigating disease progression without inducing systemic immunosuppression. Human S/F-iTreg cells with similar functions could also be efficiently generated from peripheral blood T cells of patients with pemphigus vulgaris. This study demonstrates that pathogenic autoreactive T cells can be converted into disease-specific Treg cells retaining antigen specificity, enabling antigen- and disease-specific treatment of autoimmune disease.
2025-06-05 | Antigen-specific immune responses and microbiota interactions in skin: Insights into autoimmune skin diseases and emerging therapeutic strategies.
The skin plays a vital role in serving as a physical and immunologic barrier against external insults while orchestrating complex immune responses. Autoimmune skin diseases including pemphigus, vitiligo, and alopecia areata illustrate the intricate interplay between antigen-specific immunity and tissue-specific pathologies. Pemphigus serves as a model to understand the dynamics of peripheral immune tolerance and the interplay between humoral and cellular autoimmunity, emphasizing the role of regulatory T cells in controlling autoreactive responses. Similarly, vitiligo and alopecia areata highlight the pathological contribution of resident memory CD8+ T cells and IFN-γ signaling, identifying potential therapeutic targets such as the IL-15 signaling pathway to address disease intractability. In addition to autoimmune mechanisms, the skin microbiota profoundly influences local and systemic immune responses. Commensals such as Staphylococcus epidermidis promote homeostasis by regulating barrier integrity, T-cell activation, and wound repair, while dysbiosis exacerbates immune dysregulation. Innovative strategies, including the use of genetically modified microorganisms to stimulate antigen-specific immunity, hold promise for next-generation therapies. This review underscores the significance of antigen-specific immunity in skin diseases and the emerging role of microbiota in modulating immune responses. Future research into these areas is pivotal for advancing targeted therapies and understanding the interconnectedness of skin health and systemic immunity.
other
2024-12-09 | Immunosuppressants in dermatology on vaccine immunogenicity: a prospective cohort study of pemphigus patients in the pandemic.
Both cellular and humoral responses are important for vaccine protection, but recommendations on immunosuppressants in dermatology are largely based on pre-pandemic experiences. This study aimed to investigate the impacts of immunosuppressants on humoral and cellular immunogenicity to COVID-19 vaccinations in pemphigus patients. SARS-CoV-2-naïve pemphigus patients and age-, and sex-matched healthy controls were recruited from multiple tertiary medical centers during 2021-2023. Anti-spike protein-related T-cell responses, antibody titers, and high-parameter cell analysis of the peripheral blood were utilized to investigate the inhibitory effects of immunosuppressants, including rituximab and azathioprine. A total of 32 patients and 120 healthy controls were enrolled. COVID-19 vaccinations spaced at least six months after the last rituximab infusion did not cause a significant difference in anti-viral T-cell or antibody responses between rituximab-naïve and rituximab-treated patients. All pemphigus patients demonstrated improved antibody responses after the third vaccination and none of them suffered from severe COVID-19 illness. Intriguingly, we found that daily dosages of 100 mg or more of azathioprine were linked to significantly decreased anti-viral T-cell responses induced by the vaccination (mean of fold change [SD]; higher azathioprine dosage = 0.70 [0.61] folds vs. lower azathioprine dosage = 2.11 [1.03] folds; p = 0.044). Except for a subset of patients with unrecovered B-cell deficiency, rituximab infusion with proper scheduling of vaccination preserved better anti-viral T-cell responses and did not lead to hindered antibody responses in pemphigus patients. All pemphigus patients benefited from receiving the third booster regardless of B-cell status.
2024-08-29 | shRNA-Targeting Caspase-3 Inhibits Cell Detachment Induced by Pemphigus Vulgaris Autoantibodies in HaCaT Cells.
Pemphigus is an autoimmune disease that affects the skin and mucous membranes, induced by the deposition of pemphigus IgG, which mainly targets desmogleins 1 and 3 (Dsg1 and 3). This autoantibody causes steric interference between Dsg1 and 3 and the loss of cell adhesion, producing acantholysis. This molecule and its cellular effects are clinically reflected as intraepidermal blistering. Pemphigus vulgaris-IgG (PV-IgG) binding involves p38MAPK-signaling-dependent caspase-3 activation. The present work assessed the in vitro effect of PV-IgG on the adherence of HaCaT cells dependent on caspase-3. PV-IgG induced cell detachment and apoptotic changes, as demonstrated by annexin fluorescent assays. The effect of caspase-3 induced by PV-IgG was suppressed in cells pre-treated with caspase-3-shRNA, and normal IgG (N-IgG) as a control had no relevant effects on the aforementioned parameters. The results demonstrated that shRNA reduces caspase-3 expression, as measured via qRT-PCR and via Western blot and immunofluorescence, and increases cell adhesion. In conclusion, shRNA prevented in vitro cell detachment and the late effects of apoptosis induced by PV-IgG on HaCaT cells, furthering our understanding of the molecular role of caspase-3 cell adhesion dependence in pemphigus disease.
2023-07-31 | Plasma Exosomal microRNA Profile Reveals miRNA 148a-3p Downregulation in the Mucosal-Dominant Variant of Pemphigus Vulgaris.
The mucosal-dominant variant of pemphigus vulgaris (MPV) is an autoimmune disease characterized by oral mucosal blistering and circulating pathogenic IgG antibodies against desmoglein 3 (Dsg3), resulting in life-threatening bullae and erosion formation. Recently, microRNAs (miRNAs) have emerged as promising players in the diagnosis and prognosis of several pathological states. For the first time, we have identified a different expression profile of miRNAs isolated from plasma-derived exosomes (P-EVs) of MPV patients positive for antibodies against Dsg3 (Dsg3-positive) compared to healthy controls. Moreover, a dysregulated miRNA profile was confirmed in MPV tissue biopsies. In particular, a strong downregulation of the miR-148a-3p expression level in P-EVs of MPV patients compared to healthy controls was demonstrated. Bioinformatics prediction analysis identifies metalloproteinase-7 (MMP7) as a potential miR-148a-3p target. An in vitro acantholysis model revealed that the miR-148a-3p expression level was dramatically downregulated after treatment with Dsg3 autoantibodies, with a concomitant increase in MMP7 expression. The increased expression of MMP7 leads to the disruption of intercellular and/or extracellular matrix adhesion in an in vitro cellular model of MPV, with subsequent cell dissociation. Overexpression of miR-148a-3p prevented cell dissociation and regressed MMP7 upregulation. Our findings suggest a pivotal role of P-EV cargo in regulating molecular mechanisms involved in MPV pathogenesis and indicate them as potential MPV therapeutic targets.
2022-09-20 | Low SOCS3 expression in CD4+ T cells from pemphigus vulgaris patients enhanced Th1- and Th17-cell differentiation and exacerbated acantholysis via STAT activation.
Pemphigus vulgaris (PV) is a chronic inflammatory autoimmune blistering disease. Aberrant SOCS3/STAT pathway activation is associated with many autoimmune diseases. This study explored the relationship between activation of the SOCS3/STAT pathway and abnormally increased proportions of Th1 and Th17 cells in the peripheral blood of PV patients as well as the effect of CD4+ T cells with abnormal SOCS3/STAT pathway activation on acantholysis. In PV patients, the proportions of Th1 and Th17 cells in peripheral blood, the levels of IFN-γ and IL-17 in serum and the mRNA levels of SOCS3 and STAT1/3 in CD4+ T cells were detected. Then, SOCS3-knockdown primary CD4+ T cells were prepared, and cocultured with HaCaT cells. Finally, after SOCS3 knockdown and coculture, CD4+ T cells were collected, and the proportions of Th1 and Th17 cells, the protein levels of STAT1/3 and p-STAT1/3, and the levels of IFN-γ and IL-17 were measured. After 2 days of coculture, HaCaT cells were collected, inflammatory factors mRNA expression and acantholysis were assessed. In PV patients, the proportions of Th1 (P = 0.016) and Th17 (P = 0.045) cells and the levels of IFN-γ (P = 0.010) were significantly increased. SOCS3 mRNA in CD4+ T cells was significantly decreased (P = 0.008), whereas STAT1 (P = 0.043) and STAT3 (P = 0.004) mRNA were significantly increased. After SOCS3 knockdown, the proportions of Th1 (P < 0.001) and Th17 (P = 0.006) cells, the levels of IFN-γ (P < 0.001) and IL-17 (P = 0.001), and the protein levels of p-STAT1 (P = 0.001) and p-STAT3 (P = 0.003) were significantly increased in the CD4+ T-shSOCS3-1 group. In the coculture system, the proportions of Th1 (P < 0.001) and Th17 (P < 0.001) cells, the levels of IFN-γ (P < 0.001) and IL-17 (P < 0.001), and the number of cell fragments (P < 0.001) were significantly increased in the CD4+ T-shSOCS3-1+HaCaT-PV-IgG group, whereas the protein level of desmoglein3 (Dsg3) was significantly decreased. In addition, PV-IgG significantly increased IFN-γ and IL-6 mRNA in HaCaT cells. Low SOCS3 expression in CD4+ T cells from PV patients leads to overactivation of STAT, which causes CD4+ T cells to overdifferentiate into Th1 and Th17 cells. Additionally, PV-IgG-induced local inflammation in skin lesions, which is mediated by IFN-γ and IL-6, can aggravate this phenomenon. Furthermore, low SOCS3 expression in CD4+ T cells further exacerbates PV-IgG-induced acantholysis. Therefore, upregulating the expression of SOCS3 in CD4+ T cells of PV patients and maintaining the balance of the IFN-γ/STAT1/SOCS3 and IL-6/STAT3/SOCS3 pathways can alleviate acantholysis in patients with PV.
2022-04-21 | Transcriptomic profiling of pemphigus lesion infiltrating mononuclear cells reveals a distinct local immune microenvironment and novel lncRNA regulators
Abstract Pemphigus is an autoimmune skin disease. Ectopic lymphoid-like structures (ELSs) were found to be commonly present in the pemphigus lesions, presumably supporting in situ desmoglein (Dsg)-specific antibody production. Yet functional phenotypes and the regulators of Lymphoid aggregates in pemphigus lesions remain largely unknown. Herein, we used microarray technology to profile the gene expression in skin lesion infiltrating mononuclear cells (SIMC) from pemphigus patients. On top of that, we compared SIMC dataset to peripheral blood mononuclear cells (PBMC) dataset to characterize the unique role of SIMC. Functional enrichment results showed that mononuclear cells in skin lesions and peripheral blood both had over-represented IL-17 signaling pathways while neither was characterized by an activation of type I Interferon signaling pathways. Cell-type identification with relative subsets of known RNA transcripts (CIBERSORT) results showed that naïve natural killer cells (NK cells) were significantly more abundant in pemphigus lesions, and their relative abundance positively correlated with B cells abundance. Meanwhile, plasma cells population highly correlated with type 1 macrophages (M1) abundance. In addition, we also identified a lncRNA LINC01588 which might epigenetically regulate T helper 17 cells (Th17)/regulatory T cells (Treg) balance via the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Here, we provide the first transcriptomic characterization of lesion infiltrating immune cells which illustrates a distinct interplay network between adaptive and innate immune cells. It helps discover new regulators of local immune response, which potentially will provide a novel path forward to further uncover pemphigus pathological mechanisms and develop targeted therapy.
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Drug Discovery Landscape
15 orphan drug designations for Pemphigus vulgaris, including 1 approved therapy.
15 orphan drug designations for Pemphigus vulgaris, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
bispecific humanized IgG4 BCMA-directed CD3 T cell engager antibody | antibodies | FDA | 2026-08-20 | — | Ouro Medicines Ltd. |
resecabtagene autoleucel | cell therapies | FDA | 2026-03-14 | — | Cabaletta Bio, Inc. |
afamelanotide | peptides | FDA | 2025-10-16 | — | Wanbangde Pharmaceutical Group Co., Ltd. |
Efgartigimod alfa [Vyvgart] | antibodies | EMA | 2022-07-18 | — | Argenx |
Autologous Desmoglein 3 (DSG3) Chimeric Autoantibody Receptor-directed (CAAR) T cells | cell therapies | FDA | 2020-01-28 | — | Cabaletta Bio, Inc. |
orilanolimab | antibodies | FDA | 2018-09-10 | — | Alexion Pharmaceuticals, Inc. |
Rilzabrutinib [PRN1008] | small molecules | EMA | 2017-12-12 | — | Scendea (NL) B.V. |
Small Molecule Bruton's Agammaglobulinemia Tyrosine Kinase (BKT) Inhibitor | small molecules | FDA | 2017-06-29 | — | Principia Biopharma Inc. |
rituximab [Rituxan(r); MabThera(r)] | antibodies | FDA | 2015-02-23 | 2018-06-07 | Genentech, Inc. |
(S)-2-(1-((6-amino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-5-carbonitrile | small molecules | FDA | 2015-01-26 | — | Almirall S.A. |
veltuzumab | antibodies | FDA | 2014-11-17 | — | Immunomedics, Inc. |
2-((1s)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3,4-dihydro-4-oxo-3-phenylpyrrolo(2,1-f)(1,2,4)triazine-5-carbonitrile [LAS191954] | small molecules | EMA | 2014-10-15 | — | Almirall S.A. |
Human monoclonal antibody against Fas ligand | antibodies | EMA | 2012-02-09 | — | PinCell S.r.l. |
Mycophenolate mofetil | small molecules | FDA | 2006-05-26 | — | Hoffman-La Roche, Inc. |
Desmoglein 3 synthetic peptide (PI-0824) | peptides | FDA | 2004-10-26 | — | Peptimmune, Inc. |
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