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.