Association of Disease-Modifying Antirheumatic Drugs (DMARDs) with Cardiovascular Diseases: Evidence from a Drug Target Mendelian Randomization Study.

OBJECTIVES

Cardiovascular diseases (CVDs) still represent a major cause of mortality, with inflammation playing a key role in their pathogenesis. Thus, elucidating the possible effects of disease-modifying antirheumatic drugs (DMARDs) on CVD risk in the general population may hold considerable clinical implications.

METHODS

Genetic instruments were employed to proxy the pharmacological effects of seven DMARD classes, including sulfasalazine, cyclosporine, leflunomide, IL-6 inhibitors, TNF-alpha inhibitors, abatacept, rituximab, and JAK inhibitors. To investigate their potential causal associations with 11 CVD outcomes, a comprehensive framework incorporating two-sample Mendelian randomization (TSMR), summary-data-based MR (SMR), and colocalization analysis was developed. Lastly, several sensitivity analyses were undertaken to verify the robustness of our findings.

RESULTS

In the primary TSMR results, sulfasalazine targeting PLA2G1B was linked to reduced risks of heart failure (OR: 0.86, 95% CI: 0.80-0.94), total cholesterol (OR: 0.89, 95% CI: 0.83-0.95), high-density lipoprotein cholesterol (OR: 0.88, 95% CI: 0.82-0.94), and aortic stenosis (OR: 0.72, 95% CI: 0.62-0.84). Sulfasalazine targeting RELB exhibited similar protective associations, whereas RELA exhibited the opposite associations. Moreover, IL-6R was robustly associated with increased risks of atrial fibrillation (OR: 1.29, 95% CI: 1.16-1.44), coronary artery disease (OR: 1.38, 95% CI: 1.23-1.56), myocardial infarction (OR: 1.27, 95% CI: 1.11-1.44), ischemic stroke (OR: 1.34, 95% CI: 1.22-1.48), and aortic stenosis (OR: 1.75, 95% CI: 1.46-2.09). Genetically higher IL-6R expression was associated with increased CVD risk, suggesting that IL-6 inhibition may confer cardiovascular benefit. SMR analysis further validated the associations of RELA, CD80, and IL-6R with one or more cardiovascular phenotypes. Finally, colocalization analyses for IL-6R and RELB provided strong evidence supporting their involvement in multiple CVDs.

CONCLUSION

Overall, this study presents evidence supporting a causal association between DMARDs and several CVDs. Nevertheless, further clinical investigations are necessary to validate our findings.