Evaluating the cardiometabolic impact of Janus-kinase inhibition: An experimental analysis of Tofacitinib's therapeutic potential in a rodent model.

BACKGROUND

Rheumatoid arthritis (RA) is the most prevalent non-infectious inflammatory disorder, often associated with comorbidities such as cardiovascular alterations and metabolic syndrome. These comorbidities significantly influence RA activity, flare duration, and treatment outcomes. This study investigated the effects of the Janus-kinase (JAK) inhibitor on cardiometabolic alterations in the complete Freund's adjuvant (CFA)-induced RA model combined with metabolic syndrome using ZSF1 rats.

METHODS

Fifty male ZSF1 rats were divided into lean and obese groups with or without CFA-induced arthritis and tofactinib treatment. Inflammation was assessed by paw volume, thermal and mechanical nociceptive testing, and Positron emission tomography (PET) imaging of the tibiotarsal joints using fluorodeoxyglucose ([18F] FDG). Cardiac effects were assessed with [18F] FDG-PET scans of the heart and echocardiography. Key metabolic parameters, including lipid metabolism, glucose homeostasis, blood pressure, and body weight, were recorded, followed by histological and molecular analyses.

RESULTS

CFA-induced arthritis led to increased inflammatory and functional cardiac alterations, while metabolic syndrome further aggravated cardiovascular dysfunction. In obese animals, the tofacitinib treatment partially modulated inflammatory and metabolic alterations, whereas in lean animals, it was associated with subtle structural cardiac changes. JAK inhibition did not consistently reduce myocardial fibrosis across experimental groups. Histological analysis confirmed differential patterns of cardiac remodelling between lean and metabolically diseased animals, with more pronounced structural alterations in the presence of metabolic syndrome.

CONCLUSIONS

Overall, these findings indicate that JAK inhibition exerts context-dependent effects on cardiac remodelling, suggesting that metabolic status is a key determinant of treatment response in inflammatory arthritis-associated cardiometabolic disease.