Janus Kinase and Interleukin-6 Inhibitor-Induced Lipid Modulation and Its Association With Major Adverse Cardiovascular Events in Rheumatoid Arthritis: A Systematic Review of Clinical and Biomarker Evidence.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease associated with increased cardiovascular (CV) risk and alterations in lipid metabolism. Janus kinase inhibitors (JAKi) and interleukin-6 inhibitors (IL-6i) have offered effective control of disease activity; however, their impact on lipid profiles and subsequent CV outcomes has yet to be fully elucidated. This systematic review aimed to evaluate the effects of JAKi and IL-6i on lipid profiles, inflammatory biomarkers, and major adverse cardiovascular events (MACE) in patients with RA. Nineteen peer-reviewed studies published after 2015 were identified that examined the influence of these targeted therapies on laboratory parameters and/or MACE. The findings revealed that both approaches were associated with reductions in erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and high-sensitivity CRP (hsCRP), although the magnitude of change varied substantially. Most studies reported an increase in total cholesterol and low-density lipoprotein cholesterol (LDL-C), often accompanied by modest increases in high-density lipoprotein cholesterol (HDL-C) following treatment. Despite these lipid changes, the incidence of MACE generally remained low. IL-6i therapy showed no significant increase in absolute CV events, whereas some JAKi studies reported numerically higher rates of MACE. These findings suggest that lipid alterations observed with targeted RA therapies may reflect the complex relationship between inflammation and lipid metabolism, often referred to as the "lipid paradox," where systemic inflammation in RA is associated with lower circulating cholesterol levels despite increased CV risk. In this context, the increases in lipid levels observed after effective RA therapy may actually reflect normalization of lipid metabolism rather than necessarily reflecting an increase in CV risk. However, evidence from randomized trials such as the ORAL Surveillance Trial has demonstrated increased MACE risk with tofacitinib in higher-risk populations, and heterogeneity across observational studies limits causal interpretation. Further prospective studies are required to assess whether JAKi and IL-6i-induced lipid modulation actually translates into meaningful differences in CV outcomes. Until additional evidence is available, optimal inflammatory control and guideline-directed lipid management remain essential components of CV risk reduction in RA.