Therapeutic Targeting of Gasdermin D-Mediated Pyroptosis to Attenuate Joint Inflammation in Rheumatoid Arthritis
University of Oklahoma
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent joint inflammation and systemic immune activation. Obesity is common among individuals with RA and is associated with increased disease activity, reduced treatment response, and worse functional outcomes. Inflammation in adipose tissue, driven in part by activation of the NLRP3 inflammasome and downstream gasdermin D (GSDMD)-mediated pathways, may contribute to systemic inflammation and RA disease severity. Disulfiram (DSF), an FDA-approved medication for alcohol use disorder, has recently been identified as an inhibitor of GSDMD-mediated inflammatory signaling and pyroptosis. Preclinical studies suggest that DSF reduces inflammasome activation, inflammatory cytokine release, and metabolic dysfunction. This study is a 12-week, randomized, double-blind, placebo-controlled pilot trial designed to evaluate the safety, tolerability, and preliminary efficacy of DSF in overweight and obese adults with active RA despite stable disease-modifying antirheumatic drug (DMARD) therapy. Participants will be randomized to receive either DSF (250 mg daily) or placebo. The primary objective is to assess safety and tolerability. Secondary and exploratory objectives include evaluating the effects of DSF on systemic inflammation, RA disease activity, metabolic parameters, and adipose tissue inflammasome activation. Findings from this study will inform the feasibility and design of larger clinical trials targeting GSDMD-mediated inflammation in RA.
Description
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation, joint destruction, and systemic immune activation. Obesity is highly prevalent among individuals with RA and is associated with increased disease activity, reduced response to therapy, and greater functional impairment. Emerging evidence suggests that adipose tissue inflammation plays a key role in amplifying systemic immune activation in RA. In obesity, macrophage infiltration of adipose tissue leads to activation of the NLRP3 inflammasome, resulting in the production of pro-inflammatory cytokine…
Eligibility
- Age range
- 18–75 years
- Sex
- All
- Healthy volunteers
- No
Inclusion Criteria: Age 18-75 years Body mass index (BMI) ≥25 kg/m² Diagnosis of rheumatoid arthritis (RA) according to ACR/EULAR classification criteria Active disease defined as Clinical Disease Activity Index (CDAI) \>10 Stable disease-modifying antirheumatic drug (DMARD) therapy for ≥3 months prior to enrollment Willingness to abstain from alcohol for the duration of the study Ability and willingness to comply with study procedures \- Exclusion Criteria: Significant liver dysfunction (ALT or AST \>2.5× upper limit of normal) Current or recent alcohol dependence (based on screening, e.g…
Interventions
- DrugPlacebo
Matching placebo will be administered orally once daily for 12 weeks. The placebo will be identical in appearance, packaging, and labeling to disulfiram to maintain blinding.
- DrugDisulfiram (DSF)
Disulfiram will be administered orally at a dose of 250 mg once daily for 12 weeks.
Location
- University of Oklahoma Health CampusOklahoma City, Oklahoma