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
1,484 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:
1,484 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
2026-09-23 | A Comprehensive Integrative Review of Pemphigus Vulgaris: Modern Pathophysiology and Ayurvedic Management (Visphota)
Pemphigus vulgaris (PV) is a rare, life-threatening autoimmune bullous dermatosis characterized by severe, non-healing erosions and flaccid blisters on the skin and mucous membranes. Modern pathophysiology attributes the disease to immunoglobulin G (IgG) autoantibodies targeting desmogleins (Dsg1 and Dsg3), leading to the loss of intercellular adhesion (acantholysis). While allopathic protocols rely heavily on systemic corticosteroids and immunosuppressants to induce remission, chronic use often leads to severe metabolic, bone, and immunological side effects. Ayurveda conceptualizes PV through the lens of Tridoshaja vitiation with a pronounced Pitta-Kapha dominance, clinically correlating it with Agnivisarpa (spreading erysipelas-like lesions) or Visphota (bullous eruptions), categorized under Rakta Pradoshaja Vikaras (blood-borne pathologies). This article comprehensively reviews the modern immunological landscape and the Ayurvedic pathological framework (Samprapti) of Pemphigus. It emphasizes an integrative management protocol—including Shodhana (purification), Shamana (pacification), Bahya Chikitsa (topical therapies), and Rasayana (immunomodulation)—to improve the quality of life, promote rapid mucosal re-epithelialization, and facilitate corticosteroid-sparing effects.
2026-09-18 | Long-term periodontal stability following palliative management of pemphigus vulgaris: A 5-year case report.
Pemphigus vulgaris (PV) is a chronic autoimmune mucocutaneous disorder that may cause painful oral erosions, mucosal fragility, and impaired oral hygiene, complicating periodontal treatment. This case report describes a staged, minimally traumatic approach to periodontal management in a patient with active PV. A 49-year-old female with active PV and persistent oral and cutaneous lesions despite systemic therapy presented with severe oral pain, gingival bleeding, and difficulty performing oral hygiene. Initial management consisted of a 2-month palliative botanical oral care regimen, gentle plaque-control instructions, and avoidance of mechanical trauma. Pain was assessed using a 10-point Numerical Rating Scale. Following improvement in oral comfort, scaling and root planing were performed, followed by periodontal re-evaluation and maintenance at 3-month intervals. Periodontal parameters were assessed at baseline and 5 years. Pain decreased from 7/10 at baseline to 2/10 after 1 week and 1/10 following initial therapy. Improved oral comfort facilitated oral hygiene and non-surgical periodontal therapy. Periodontal re-evaluation demonstrated reduced probing depths and gingival bleeding. At 5 years, clinically healthy gingival tissues, minimal bleeding on probing, and stable alveolar bone levels were observed. A staged, minimally traumatic approach facilitated periodontal treatment and long-term periodontal stability in this patient with active PV. A staged, minimally traumatic approach can enable safe periodontal therapy in patients with poorly controlled pemphigus vulgaris. Palliative topical therapy may provide palliative symptom relief, improving patient comfort and tolerance to oral hygiene and periodontal treatment. Long-term periodontal stability can be achieved with careful treatment sequencing and regular maintenance, even in patients with persistent mucocutaneous disease. Pemphigus vulgaris is a condition that causes fragile, painful sores in the mouth, making it difficult for patients to eat, brush their teeth, and maintain good oral health. In this case, a patient with poorly controlled disease experienced severe pain and bleeding gums despite medical treatment. A cautious, step-by-step dental approach was used to manage her condition. First, a soothing, non-irritating mouth rinse was prescribed to reduce discomfort and allow the patient to tolerate oral hygiene. After symptoms improved, careful deep cleaning of the teeth and gums was performed, followed by regular maintenance visits every 3 months. The patient showed rapid improvement in comfort within 1 week and was able to eat normally again. Over 5 years, her gums remained stable and healthy with minimal bleeding. This case suggests that a cautious, staged approach can help safely manage gum disease in patients with sensitive oral conditions.
2026-08-01 | Wound Repair in a Patient with Pemphigus Vulgaris: A Case Report
Pemphigus vulgaris is a rare autoimmune disease with a prevalence of 0.1-0.5 per 100,000 people that characterized by blisters and acantholysis. Wounds in this disease tend to be extensive and wet, causing skin integrity problems. Research on local therapeutic interventions in pemphigus vulgaris is still limited. The purpose of this report is to determine the patient's response to a combination of wound care interventions with 0.9% NaCl compresses, MEBO ointment, and antibiotic tulle. This report method is a case report with primary and secondary data sources. Primary data is obtained through direct observation of the patient's objective condition, anamnesis, and physical examination. Secondary data was obtained from statements from the patient's family who had provided written consent (informed consent) and the patient's electronic medical records. The patient is a 36-year-old man with a wound scale according to the Pemphigus Disease Area Index 97/120. The patient's wound improved, where the wet wound dried and re-epithelialization occurred after 4 days of treatment with MEBO ointment and antibiotic tulle. In the dry wound, the wound appeared clean of dead skin tissue and soft hemorrhagic crusts after 0.9% NaCl compresses.
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.
proteins
2026-09-08 | The efficacy and safety of intravenous immunoglobulin in pemphigus vulgaris and bullous pemphigoid: a systematic review and meta-analysis.
Autoimmune blistering diseases (AIBDs) encompass various skin conditions that involve the production of autoantibodies that attach to specific antigens found in the skin and mucous membranes. This systematic review examined the efficacy and safety of intravenous immunoglobulin (IVIG) therapy for AIBDs. The search included PubMed, Science Direct, Google Scholar, Wiley, and EBSCO using the following keyword combinations: (Pemphigus Vulgaris OR Bullous Pemphigoid OR Autoimmune Blistering Disease) AND (Intravenous Immunoglobulin OR IVIG) AND (Efficacy OR Long-term Outcomes) AND (Safety OR Adverse Effects OR Quality of Life). Of 617 papers, 12 articles were considered suitable for the systematic review and extracted through the database search. A meta-analysis demonstrated an efficacy of 85.0% (95% confidence interval [CI]: 75.5-92.3, p<0.001) for IVIG therapy in AIBDs. Subgroup analyses showed relapse rates of 18.2% (95% CI: 9.3-27.0, p<0.001) and adverse event rates of 48.0% (95% CI: 28.7-67.3, p<0.001). Rapid clinical responses occurred within 1-4 weeks, with sustained remission lasting up to 44 months. Corticosteroid use was reduced by 76-90%, and autoantibody titers declined significantly. While adverse events were common (26-88% of patients), most were mild, with severe complications (<5%). IVIG is effective for AIBDs, offering rapid control, durable remission, and significant steroid reduction. Standardized protocols for dosing and monitoring are needed, and future research should focus on large-scale trials to confirm long-term benefits.
2026-09-03 | Early disease control, corticosteroid sparing, and relapse-free survival after intravenous immunoglobulin in pemphigus: a single-center retrospective cohort.
Intravenous immunoglobulin (IVIg) is used in refractory pemphigus, but data linking disease activity, corticosteroid reduction, remission, and post-remission durability are limited. To evaluate early clinical response, corticosteroid exposure, post-IVIg complete remission on therapy (CRon), and relapse-free survival (RFS) in pemphigus treated with IVIg before rituximab. In this single-center retrospective cohort study, patients with pemphigus vulgaris or foliaceus treated between 2010 and 2018 were screened. Outcomes were analyzed in those receiving IVIg before rituximab. Mucosal and cutaneous Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and prednisolone exposure, normalized to the initial maximum dose (100%), were assessed. CRon was counted only when first documented after IVIg initiation, and RFS was measured from the CRon date. Missing data were not imputed. Among 100 patients, 37 received IVIg and 36 entered the IVIg-before-rituximab cohort. Prednisolone exposure decreased from 65.59±34.65% at IVIg initiation to 27.55±27.32% at month 6. By month 3, mucosal ABSIS decreased from 17.22±9.17 to 5.96±8.60 and cutaneous ABSIS from 5.00±7.46 to 1.38±2.58 (all p < 0.001). Post-IVIg CRon was documented in 25/36 patients (69.4%). In the primary RFS set (n=21), 10 relapses occurred; RFS was 72.4% at 12 months and 60.8% at 24 months. IVIg use was associated with early disease improvement and reduced corticosteroid exposure. Post-remission control was durable among patients achieving post-IVIg CRon, but RFS estimates are conditional on remission. Because background therapy continued, the independent contribution of IVIg cannot be determined.
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.
antibodies
2026-09-11 | Efficacy and safety of subcutaneous efgartigimod with prednisone in moderate-to-severe pemphigus (ADDRESS): a global, phase III, randomised controlled, double-blind trial.
Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are rare, chronic, potentially life-threatening, immunoglobulin (Ig)G-mediated, autoimmune skin and/or mucosal blistering diseases. Efgartigimod, a human IgG1 antibody Fc fragment, blocks the neonatal Fc receptor, decreasing IgG recycling and reducing both healthy and pathogenic IgG autoantibody levels. To investigate the efficacy, safety and impact of subcutaneous efgartigimod PH20 (co-formulated with recombinant human hyaluronidase PH20) in conjunction with prednisone in the treatment of pemphigus. Adult participants with newly diagnosed or relapsing moderate-to-severe pemphigus were recruited in this phase III, prospective, multicentre, randomised, double-blinded, placebo-controlled study (NCT04598451). Participants were randomised (2 : 1) to weekly subcutaneous efgartigimod PH20 or placebo. Subcutaneous efgartigimod PH20 2000 mg was administered on days 1 and 8, followed by 1000 mg weekly until complete remission on minimal prednisone therapy (CRmin) (≤ 10 mg daily). All participants received concomitant prednisone starting at 0.5 mg kg-1 daily. The primary outcome was the proportion of participants with PV who achieved CRmin by week 30, while receiving minimal prednisone, for ≥ 8 weeks. Pharmacodynamics and safety were also assessed. Overall, 222 participants (PV: n = 190; PF: n = 32) were randomised (subcutaneous efgartigimod PH20: n = 147; placebo: n = 75). The proportions of participants with PV achieving CRmin within 30 weeks were comparable between the subcutaneous efgartigimod PH20 and placebo groups, with no statistically significant difference observed [44/124 (35.5%) vs. 20/66 (30.3%); P = 0.60; odds ratio 1.19 (95% confidence interval 0.60-2.41)]. Total prednisone consumption over time was comparable between groups. Subcutaneous efgartigimod PH20 resulted in rapid reductions from baseline in total IgG and anti--desmoglein-1 and anti-desmoglein-3 autoantibody levels, but these did not translate to improvements in Pemphigus Disease Area Index scores. The rates of adverse events (AEs) in the subcutaneous efgartigimod PH20 and placebo groups were 89.1% (n = 131/147) and 76.0% (n = 57/75), respectively; most were mild to moderate [serious AEs: 12.2% (n = 18/147) and 13.3% (n = 10/75), respectively]. No deaths occurred. Subcutaneous efgartigimod PH20 in combination with systemic corticosteroids did not demonstrate clinical benefit over systemic corticosteroids alone in patients with moderate-to-severe pemphigus at 30 weeks, but it was well tolerated in this patient population.
2026-09-11 | Targeting IL-33 and TSLP: A Novel Approach to Modulate Type 2 and Non-Type 2 Inflammatory Pathways in Pemphigus Vulgaris.
Pemphigus vulgaris (PV) is an autoantibody-mediated blistering disorder in which pathogenic immunoglobulins target epidermal desmoglein proteins, leading to suprabasal acantholysis that manifests clinically as flaccid blisters and mucosal erosions. First-line management typically includes oral corticosteroids as well as B-cell-depleting therapies such as rituximab; however, these and other systemic immunosuppressants carry substantial toxicities and are not suitable for all patients, motivating the search for more targeted, well-tolerated alternatives. Although PV is fundamentally driven by anti-desmoglein autoantibodies, emerging evidence implicates type 2 inflammation as a secondary contributor to disease activity, and epithelial-derived cytokines interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP) have garnered interest as upstream modulators of this axis. Beyond canonical type 2 effects, IL-33 and TSLP can influence a broader inflammatory milieu, including modulating type 17 responses that may also contribute to PV immunopathology. No clinical evidence currently supports IL-33 or TSLP blockade in PV, and it remains to be determined if modulation of this secondary axis could potentially control disease as monotherapy. Nonetheless, given their upstream position in cutaneous immune processes, therapeutic blockade of IL-33 or TSLP warrants investigation in preclinical models and biomarker-informed trials, principally as an adjunct to current autoantibody-directed regimens.
2026-08-28 | Pemphigus vulgaris in a pregnant lady with type 1 Diabetes: A case report (Preprint)
UNSTRUCTURED Pemphigus vulgaris is a rare autoimmune blistering disorder involving the skin and mucous membranes. The disease may first develop or worsen during pregnancy, when diagnosis and treatment are complicated by maternal and fetal considerations. We report the case of a 37-year-old gravida 3 para 2 woman with poorly controlled type 1 diabetes mellitus and autoimmune hypothyroidism who developed painful oral and lip lesions at 19 weeks of gestation. The lesions were initially treated as oral candidiasis, herpetic lesions, and idiopathic aphthous ulceration. At 27 weeks, she developed a progressive generalized blistering eruption involving the trunk, extremities, oral mucosa, and genital region. Pemphigoid gestationis with secondary bacterial infection was initially suspected, and she was treated with topical corticosteroids, wound care, antimicrobial therapy, and subsequently low-dose oral prednisone. At 34 weeks and 6 days, she presented in labor after several days of reduced oral intake caused by worsening mucosal disease. She underwent emergency cesarean delivery and developed diabetic ketoacidosis requiring intensive care. A male infant weighing 2400 g was delivered with multiple cutaneous blisters. The neonatal lesions were clinically compatible with transient neonatal pemphigus, began healing during the first week of life, and were managed supportively. Postpartum maternal skin histopathology was interpreted as consistent with pemphigus vulgaris. Progressive disease was treated with systemic corticosteroids, topical therapy, a brief course of mycophenolate mofetil that was discontinued after liver enzyme elevation, and rituximab. Clinical remission was documented at 1-year follow-up. This case emphasizes that persistent painful oral erosions followed by generalized blistering during pregnancy should prompt early investigation for pemphigus vulgaris. In pregnant patients with type 1 diabetes, reduced oral intake, infection, corticosteroid exposure, and peripartum stress may collectively precipitate diabetic ketoacidosis, highlighting the importance of coordinated dermatologic, obstetric, endocrine, and neonatal care.
2026-08-28 | Successful treatment of rituximab-refractory pemphigus vulgaris with Obinutuzumab
Successful treatment of rituximab-refractory pemphigus vulgaris with Obinutuzumab ଝDear Editor, Pemphigus Vulgaris (PV) is an autoimmune blistering disease in which Rituximab (RTX) constitutes the standard first-line therapy for moderate-to-severe disease; however, resistance or hypersensitivity may occur.We report a severe case of RTX-refractory PV demonstrating a rapid clinical response to obinutuzumab.A patient with a 10-year history of PV presented with extensive mucocutaneous erosions.Prior therapies included high-dose systemic corticosteroids, plasmapheresis, cyclophosphamide, mycophenolate sodium, long-term azathioprine, 59 courses of intravenous immunoglobulin, and RTX, which was initially discontinued because of an anaphylactic reaction.RTX was subsequently reintroduced using a desensitization protocol and administered every six months for four years (eight infusions total); however, persistent blistering necessitated additional IVIG courses without clinical benefit.Owing to ongoing disease activity, obinutuzumab was initiated at a dose of 1000 mg on days 1, 8, and 15 with standard premedication.The Pemphigus Disease Area Index (PDAI) score decreased from 73 (activity: 60; damage: 13) at baseline to 21 (activity: 12; damage: 9) at one month and further to 7 (activity: 3; damage: 4) at six months, indicating sustained clinical improvement.The PDAI activity component evaluates active erosions, blisters, or new erythema involving the skin, scalp, and mucous membranes, whereas the damage component is scored separately and records post-inflammatory changes, such as hyperpigmentation or erythema in resolving lesions. 1 To facilitate interpretation, previously proposed PDAI severity thresholds have classified pemphigus as mild, moderate, or severe using different cut-off values.Shimizu et al. defined mild disease as 0---8, moderate disease as 9---24, and severe disease as ≥25, 2 whereas Boulard et al. proposed PDAI cutoff values of 15 and 45 to distinguish moderate, sig-
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.
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
2026-09-23 | A Comprehensive Integrative Review of Pemphigus Vulgaris: Modern Pathophysiology and Ayurvedic Management (Visphota)
Pemphigus vulgaris (PV) is a rare, life-threatening autoimmune bullous dermatosis characterized by severe, non-healing erosions and flaccid blisters on the skin and mucous membranes. Modern pathophysiology attributes the disease to immunoglobulin G (IgG) autoantibodies targeting desmogleins (Dsg1 and Dsg3), leading to the loss of intercellular adhesion (acantholysis). While allopathic protocols rely heavily on systemic corticosteroids and immunosuppressants to induce remission, chronic use often leads to severe metabolic, bone, and immunological side effects. Ayurveda conceptualizes PV through the lens of Tridoshaja vitiation with a pronounced Pitta-Kapha dominance, clinically correlating it with Agnivisarpa (spreading erysipelas-like lesions) or Visphota (bullous eruptions), categorized under Rakta Pradoshaja Vikaras (blood-borne pathologies). This article comprehensively reviews the modern immunological landscape and the Ayurvedic pathological framework (Samprapti) of Pemphigus. It emphasizes an integrative management protocol—including Shodhana (purification), Shamana (pacification), Bahya Chikitsa (topical therapies), and Rasayana (immunomodulation)—to improve the quality of life, promote rapid mucosal re-epithelialization, and facilitate corticosteroid-sparing effects.
2026-09-18 | Long-term periodontal stability following palliative management of pemphigus vulgaris: A 5-year case report.
Pemphigus vulgaris (PV) is a chronic autoimmune mucocutaneous disorder that may cause painful oral erosions, mucosal fragility, and impaired oral hygiene, complicating periodontal treatment. This case report describes a staged, minimally traumatic approach to periodontal management in a patient with active PV. A 49-year-old female with active PV and persistent oral and cutaneous lesions despite systemic therapy presented with severe oral pain, gingival bleeding, and difficulty performing oral hygiene. Initial management consisted of a 2-month palliative botanical oral care regimen, gentle plaque-control instructions, and avoidance of mechanical trauma. Pain was assessed using a 10-point Numerical Rating Scale. Following improvement in oral comfort, scaling and root planing were performed, followed by periodontal re-evaluation and maintenance at 3-month intervals. Periodontal parameters were assessed at baseline and 5 years. Pain decreased from 7/10 at baseline to 2/10 after 1 week and 1/10 following initial therapy. Improved oral comfort facilitated oral hygiene and non-surgical periodontal therapy. Periodontal re-evaluation demonstrated reduced probing depths and gingival bleeding. At 5 years, clinically healthy gingival tissues, minimal bleeding on probing, and stable alveolar bone levels were observed. A staged, minimally traumatic approach facilitated periodontal treatment and long-term periodontal stability in this patient with active PV. A staged, minimally traumatic approach can enable safe periodontal therapy in patients with poorly controlled pemphigus vulgaris. Palliative topical therapy may provide palliative symptom relief, improving patient comfort and tolerance to oral hygiene and periodontal treatment. Long-term periodontal stability can be achieved with careful treatment sequencing and regular maintenance, even in patients with persistent mucocutaneous disease. Pemphigus vulgaris is a condition that causes fragile, painful sores in the mouth, making it difficult for patients to eat, brush their teeth, and maintain good oral health. In this case, a patient with poorly controlled disease experienced severe pain and bleeding gums despite medical treatment. A cautious, step-by-step dental approach was used to manage her condition. First, a soothing, non-irritating mouth rinse was prescribed to reduce discomfort and allow the patient to tolerate oral hygiene. After symptoms improved, careful deep cleaning of the teeth and gums was performed, followed by regular maintenance visits every 3 months. The patient showed rapid improvement in comfort within 1 week and was able to eat normally again. Over 5 years, her gums remained stable and healthy with minimal bleeding. This case suggests that a cautious, staged approach can help safely manage gum disease in patients with sensitive oral conditions.
2026-08-01 | Wound Repair in a Patient with Pemphigus Vulgaris: A Case Report
Pemphigus vulgaris is a rare autoimmune disease with a prevalence of 0.1-0.5 per 100,000 people that characterized by blisters and acantholysis. Wounds in this disease tend to be extensive and wet, causing skin integrity problems. Research on local therapeutic interventions in pemphigus vulgaris is still limited. The purpose of this report is to determine the patient's response to a combination of wound care interventions with 0.9% NaCl compresses, MEBO ointment, and antibiotic tulle. This report method is a case report with primary and secondary data sources. Primary data is obtained through direct observation of the patient's objective condition, anamnesis, and physical examination. Secondary data was obtained from statements from the patient's family who had provided written consent (informed consent) and the patient's electronic medical records. The patient is a 36-year-old man with a wound scale according to the Pemphigus Disease Area Index 97/120. The patient's wound improved, where the wet wound dried and re-epithelialization occurred after 4 days of treatment with MEBO ointment and antibiotic tulle. In the dry wound, the wound appeared clean of dead skin tissue and soft hemorrhagic crusts after 0.9% NaCl compresses.
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.
proteins
2026-09-08 | The efficacy and safety of intravenous immunoglobulin in pemphigus vulgaris and bullous pemphigoid: a systematic review and meta-analysis.
Autoimmune blistering diseases (AIBDs) encompass various skin conditions that involve the production of autoantibodies that attach to specific antigens found in the skin and mucous membranes. This systematic review examined the efficacy and safety of intravenous immunoglobulin (IVIG) therapy for AIBDs. The search included PubMed, Science Direct, Google Scholar, Wiley, and EBSCO using the following keyword combinations: (Pemphigus Vulgaris OR Bullous Pemphigoid OR Autoimmune Blistering Disease) AND (Intravenous Immunoglobulin OR IVIG) AND (Efficacy OR Long-term Outcomes) AND (Safety OR Adverse Effects OR Quality of Life). Of 617 papers, 12 articles were considered suitable for the systematic review and extracted through the database search. A meta-analysis demonstrated an efficacy of 85.0% (95% confidence interval [CI]: 75.5-92.3, p<0.001) for IVIG therapy in AIBDs. Subgroup analyses showed relapse rates of 18.2% (95% CI: 9.3-27.0, p<0.001) and adverse event rates of 48.0% (95% CI: 28.7-67.3, p<0.001). Rapid clinical responses occurred within 1-4 weeks, with sustained remission lasting up to 44 months. Corticosteroid use was reduced by 76-90%, and autoantibody titers declined significantly. While adverse events were common (26-88% of patients), most were mild, with severe complications (<5%). IVIG is effective for AIBDs, offering rapid control, durable remission, and significant steroid reduction. Standardized protocols for dosing and monitoring are needed, and future research should focus on large-scale trials to confirm long-term benefits.
2026-09-03 | Early disease control, corticosteroid sparing, and relapse-free survival after intravenous immunoglobulin in pemphigus: a single-center retrospective cohort.
Intravenous immunoglobulin (IVIg) is used in refractory pemphigus, but data linking disease activity, corticosteroid reduction, remission, and post-remission durability are limited. To evaluate early clinical response, corticosteroid exposure, post-IVIg complete remission on therapy (CRon), and relapse-free survival (RFS) in pemphigus treated with IVIg before rituximab. In this single-center retrospective cohort study, patients with pemphigus vulgaris or foliaceus treated between 2010 and 2018 were screened. Outcomes were analyzed in those receiving IVIg before rituximab. Mucosal and cutaneous Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and prednisolone exposure, normalized to the initial maximum dose (100%), were assessed. CRon was counted only when first documented after IVIg initiation, and RFS was measured from the CRon date. Missing data were not imputed. Among 100 patients, 37 received IVIg and 36 entered the IVIg-before-rituximab cohort. Prednisolone exposure decreased from 65.59±34.65% at IVIg initiation to 27.55±27.32% at month 6. By month 3, mucosal ABSIS decreased from 17.22±9.17 to 5.96±8.60 and cutaneous ABSIS from 5.00±7.46 to 1.38±2.58 (all p < 0.001). Post-IVIg CRon was documented in 25/36 patients (69.4%). In the primary RFS set (n=21), 10 relapses occurred; RFS was 72.4% at 12 months and 60.8% at 24 months. IVIg use was associated with early disease improvement and reduced corticosteroid exposure. Post-remission control was durable among patients achieving post-IVIg CRon, but RFS estimates are conditional on remission. Because background therapy continued, the independent contribution of IVIg cannot be determined.
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.
antibodies
2026-09-11 | Efficacy and safety of subcutaneous efgartigimod with prednisone in moderate-to-severe pemphigus (ADDRESS): a global, phase III, randomised controlled, double-blind trial.
Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are rare, chronic, potentially life-threatening, immunoglobulin (Ig)G-mediated, autoimmune skin and/or mucosal blistering diseases. Efgartigimod, a human IgG1 antibody Fc fragment, blocks the neonatal Fc receptor, decreasing IgG recycling and reducing both healthy and pathogenic IgG autoantibody levels. To investigate the efficacy, safety and impact of subcutaneous efgartigimod PH20 (co-formulated with recombinant human hyaluronidase PH20) in conjunction with prednisone in the treatment of pemphigus. Adult participants with newly diagnosed or relapsing moderate-to-severe pemphigus were recruited in this phase III, prospective, multicentre, randomised, double-blinded, placebo-controlled study (NCT04598451). Participants were randomised (2 : 1) to weekly subcutaneous efgartigimod PH20 or placebo. Subcutaneous efgartigimod PH20 2000 mg was administered on days 1 and 8, followed by 1000 mg weekly until complete remission on minimal prednisone therapy (CRmin) (≤ 10 mg daily). All participants received concomitant prednisone starting at 0.5 mg kg-1 daily. The primary outcome was the proportion of participants with PV who achieved CRmin by week 30, while receiving minimal prednisone, for ≥ 8 weeks. Pharmacodynamics and safety were also assessed. Overall, 222 participants (PV: n = 190; PF: n = 32) were randomised (subcutaneous efgartigimod PH20: n = 147; placebo: n = 75). The proportions of participants with PV achieving CRmin within 30 weeks were comparable between the subcutaneous efgartigimod PH20 and placebo groups, with no statistically significant difference observed [44/124 (35.5%) vs. 20/66 (30.3%); P = 0.60; odds ratio 1.19 (95% confidence interval 0.60-2.41)]. Total prednisone consumption over time was comparable between groups. Subcutaneous efgartigimod PH20 resulted in rapid reductions from baseline in total IgG and anti--desmoglein-1 and anti-desmoglein-3 autoantibody levels, but these did not translate to improvements in Pemphigus Disease Area Index scores. The rates of adverse events (AEs) in the subcutaneous efgartigimod PH20 and placebo groups were 89.1% (n = 131/147) and 76.0% (n = 57/75), respectively; most were mild to moderate [serious AEs: 12.2% (n = 18/147) and 13.3% (n = 10/75), respectively]. No deaths occurred. Subcutaneous efgartigimod PH20 in combination with systemic corticosteroids did not demonstrate clinical benefit over systemic corticosteroids alone in patients with moderate-to-severe pemphigus at 30 weeks, but it was well tolerated in this patient population.
2026-09-11 | Targeting IL-33 and TSLP: A Novel Approach to Modulate Type 2 and Non-Type 2 Inflammatory Pathways in Pemphigus Vulgaris.
Pemphigus vulgaris (PV) is an autoantibody-mediated blistering disorder in which pathogenic immunoglobulins target epidermal desmoglein proteins, leading to suprabasal acantholysis that manifests clinically as flaccid blisters and mucosal erosions. First-line management typically includes oral corticosteroids as well as B-cell-depleting therapies such as rituximab; however, these and other systemic immunosuppressants carry substantial toxicities and are not suitable for all patients, motivating the search for more targeted, well-tolerated alternatives. Although PV is fundamentally driven by anti-desmoglein autoantibodies, emerging evidence implicates type 2 inflammation as a secondary contributor to disease activity, and epithelial-derived cytokines interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP) have garnered interest as upstream modulators of this axis. Beyond canonical type 2 effects, IL-33 and TSLP can influence a broader inflammatory milieu, including modulating type 17 responses that may also contribute to PV immunopathology. No clinical evidence currently supports IL-33 or TSLP blockade in PV, and it remains to be determined if modulation of this secondary axis could potentially control disease as monotherapy. Nonetheless, given their upstream position in cutaneous immune processes, therapeutic blockade of IL-33 or TSLP warrants investigation in preclinical models and biomarker-informed trials, principally as an adjunct to current autoantibody-directed regimens.
2026-08-28 | Pemphigus vulgaris in a pregnant lady with type 1 Diabetes: A case report (Preprint)
UNSTRUCTURED Pemphigus vulgaris is a rare autoimmune blistering disorder involving the skin and mucous membranes. The disease may first develop or worsen during pregnancy, when diagnosis and treatment are complicated by maternal and fetal considerations. We report the case of a 37-year-old gravida 3 para 2 woman with poorly controlled type 1 diabetes mellitus and autoimmune hypothyroidism who developed painful oral and lip lesions at 19 weeks of gestation. The lesions were initially treated as oral candidiasis, herpetic lesions, and idiopathic aphthous ulceration. At 27 weeks, she developed a progressive generalized blistering eruption involving the trunk, extremities, oral mucosa, and genital region. Pemphigoid gestationis with secondary bacterial infection was initially suspected, and she was treated with topical corticosteroids, wound care, antimicrobial therapy, and subsequently low-dose oral prednisone. At 34 weeks and 6 days, she presented in labor after several days of reduced oral intake caused by worsening mucosal disease. She underwent emergency cesarean delivery and developed diabetic ketoacidosis requiring intensive care. A male infant weighing 2400 g was delivered with multiple cutaneous blisters. The neonatal lesions were clinically compatible with transient neonatal pemphigus, began healing during the first week of life, and were managed supportively. Postpartum maternal skin histopathology was interpreted as consistent with pemphigus vulgaris. Progressive disease was treated with systemic corticosteroids, topical therapy, a brief course of mycophenolate mofetil that was discontinued after liver enzyme elevation, and rituximab. Clinical remission was documented at 1-year follow-up. This case emphasizes that persistent painful oral erosions followed by generalized blistering during pregnancy should prompt early investigation for pemphigus vulgaris. In pregnant patients with type 1 diabetes, reduced oral intake, infection, corticosteroid exposure, and peripartum stress may collectively precipitate diabetic ketoacidosis, highlighting the importance of coordinated dermatologic, obstetric, endocrine, and neonatal care.
2026-08-28 | Successful treatment of rituximab-refractory pemphigus vulgaris with Obinutuzumab
Successful treatment of rituximab-refractory pemphigus vulgaris with Obinutuzumab ଝDear Editor, Pemphigus Vulgaris (PV) is an autoimmune blistering disease in which Rituximab (RTX) constitutes the standard first-line therapy for moderate-to-severe disease; however, resistance or hypersensitivity may occur.We report a severe case of RTX-refractory PV demonstrating a rapid clinical response to obinutuzumab.A patient with a 10-year history of PV presented with extensive mucocutaneous erosions.Prior therapies included high-dose systemic corticosteroids, plasmapheresis, cyclophosphamide, mycophenolate sodium, long-term azathioprine, 59 courses of intravenous immunoglobulin, and RTX, which was initially discontinued because of an anaphylactic reaction.RTX was subsequently reintroduced using a desensitization protocol and administered every six months for four years (eight infusions total); however, persistent blistering necessitated additional IVIG courses without clinical benefit.Owing to ongoing disease activity, obinutuzumab was initiated at a dose of 1000 mg on days 1, 8, and 15 with standard premedication.The Pemphigus Disease Area Index (PDAI) score decreased from 73 (activity: 60; damage: 13) at baseline to 21 (activity: 12; damage: 9) at one month and further to 7 (activity: 3; damage: 4) at six months, indicating sustained clinical improvement.The PDAI activity component evaluates active erosions, blisters, or new erythema involving the skin, scalp, and mucous membranes, whereas the damage component is scored separately and records post-inflammatory changes, such as hyperpigmentation or erythema in resolving lesions. 1 To facilitate interpretation, previously proposed PDAI severity thresholds have classified pemphigus as mild, moderate, or severe using different cut-off values.Shimizu et al. defined mild disease as 0---8, moderate disease as 9---24, and severe disease as ≥25, 2 whereas Boulard et al. proposed PDAI cutoff values of 15 and 45 to distinguish moderate, sig-
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.
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.
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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 | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
bispecific humanized IgG4 BCMA-directed CD3 T cell engager antibody | antibodies | FDA | — | Ouro Medicines Ltd. |
resecabtagene autoleucel | cell therapies | FDA | Cabaletta Bio, Inc. | |
afamelanotide | peptides | FDA | Wanbangde Pharmaceutical Group Co., Ltd. | |
Efgartigimod alfa [Vyvgart] | antibodies | EMA | Argenx | |
Autologous Desmoglein 3 (DSG3) Chimeric Autoantibody Receptor-directed (CAAR) T cells | cell therapies | FDA | Cabaletta Bio, Inc. | |
orilanolimab | antibodies | FDA | Alexion Pharmaceuticals, Inc. | |
Rilzabrutinib [PRN1008] | small molecules | EMA | Scendea (NL) B.V. | |
Small Molecule Bruton's Agammaglobulinemia Tyrosine Kinase (BKT) Inhibitor | small molecules | FDA | Principia Biopharma Inc. | |
rituximab [Rituxan(r); MabThera(r)] | antibodies | FDA | Approved | 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 | — | Almirall S.A. |
veltuzumab | antibodies | FDA | — | 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 | — | Almirall S.A. |
Human monoclonal antibody against Fas ligand | antibodies | EMA | — | PinCell S.r.l. |
Mycophenolate mofetil | small molecules | FDA | Hoffman-La Roche, Inc. | |
Desmoglein 3 synthetic peptide (PI-0824) | peptides | FDA | Peptimmune, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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