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.

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 cytokines such as interleukin (IL)-1β and IL-18. These processes contribute to systemic inflammation and may exacerbate RA disease activity.

Gasdermin D (GSDMD) is a critical downstream effector of inflammasome activation. Cleavage of GSDMD by caspase-1 results in pore formation in the cell membrane, enabling the release of inflammatory cytokines and inducing pyroptosis, a lytic form of programmed cell death. While therapies targeting IL-1β have demonstrated limited efficacy in RA, inhibition of GSDMD represents a broader strategy to suppress multiple inflammasome-mediated inflammatory pathways.

Disulfiram (DSF), an FDA-approved medication for alcohol use disorder, has been identified as a potent inhibitor of GSDMD-mediated pore formation. Preclinical studies demonstrate that DSF reduces inflammasome activation, decreases cytokine release, and improves metabolic parameters in models of obesity. These findings support the repurposing of DSF as a novel therapeutic strategy in RA, particularly in patients with obesity.

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. A total of 20 participants aged 18-75 years with body mass index (BMI) ≥25 kg/m² and active disease (Clinical Disease Activity Index [CDAI] >10) will be enrolled and randomized in a 1:1 ratio to receive either DSF (250 mg daily) or placebo. Randomization will be stratified by BMI to ensure balanced allocation.

The primary objective is to assess the safety and tolerability of DSF in this population. Safety assessments will include adverse event monitoring using Common Terminology Criteria for Adverse Events (CTCAE v5.0), laboratory evaluations (including liver function tests), vital signs, and patient-reported outcomes related to neurotoxicity and quality of life.

Secondary and exploratory objectives include evaluation of systemic inflammation, metabolic function, RA disease activity, and adipose tissue biology. Systemic inflammation will be assessed through circulating cytokines (e.g., IL-1β, IL-6, tumor necrosis factor-α) and immune cell profiling using flow cytometry. Metabolic parameters will include fasting glucose, insulin, and insulin resistance (HOMA-IR), as well as body composition assessed by dual-energy X-ray absorptiometry (DEXA) and bioelectrical impedance analysis (BIA). RA disease activity will be evaluated using validated measures including CDAI and DAS28-CRP, along with functional assessments such as the Modified Health Assessment Questionnaire (MDHAQ).

Adipose tissue biopsies will be obtained at baseline and Week 12 to assess inflammasome activation and GSDMD-mediated pathways. Analyses will include evaluation of NLRP3 inflammasome components, caspase-1 activation, GSDMD cleavage, and cytokine release following ex vivo stimulation. These mechanistic studies will provide insight into the biological effects of DSF on adipose tissue inflammation and its relationship to systemic and clinical outcomes.

This pilot study is designed to generate preliminary data on safety, feasibility, and biological activity to inform the design of future larger clinical trials targeting inflammasome-mediated inflammation in RA

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

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Exclusion Criteria:

Significant liver dysfunction (ALT or AST >2.5× upper limit of normal) Current or recent alcohol dependence (based on screening, e.g., AUDIT) Known hypersensitivity to disulfiram or other thiuram derivatives Pregnancy or breastfeeding Severe cardiovascular disease (e.g., myocardial infarction, arrhythmia, coronary occlusion) Severe psychiatric illness (e.g., psychosis, suicidal ideation) Neurologic disorders (e.g., epilepsy, peripheral neuropathy, cerebral damage) Chronic or acute renal disease (e.g., nephritis) Hepatic cirrhosis or hepatic insufficiency Use of contraindicated medications (e.g., metronidazole, phenytoin, paraldehyde, alcohol-containing preparations, warfarin) Other autoimmune diseases or active/chronic infections Diabetes mellitus or hypothyroidism Allergy to topical iodine Any condition that, in the opinion of the investigator, would pose undue risk or interfere with study participation

This is a double-blind study. Participants, investigators, study staff, and outcome assessors will be blinded to treatment assignment. Disulfiram and placebo will be identical in appearance, packaging, and labeling. Randomization codes will be maintained by the investigational pharmacy and will not be accessible to the study team except in the case of a medical emergency requiring unblinding.