Mechanisms by Which Lipid-Lowering Agents Modulate the Lipid-Inflammation Circuit and Their Stratified Clinical Use in Rheumatic Immune-Mediated Diseases

Rheumatic immune-mediated diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and spondyloarthritis, combine persistent inflammation with increased cardiovascular risk. Inflammation alters lipoprotein production, remodeling, function, and clearance, explaining why low or apparently normal cholesterol concentrations may coexist with accelerated atherosclerosis. Modified lipids can influence nuclear factor-kappa B (NF-κB), the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, and immune-cell signaling, creating a reciprocal lipid-inflammation circuit. This review examines established and emerging lipid-lowering agents, their molecular targets, and the clinical evidence across rheumatic diseases. Particular attention is given to dynamic cholesterol- and sphingolipid-enriched membrane nanodomains, cholesterol homeostasis, and the distinction between experimental immunomodulation and clinical outcomes. Statins have the most developed rheumatic-disease evidence; findings for other agents remain limited or are extrapolated from cardiovascular populations. Clinical use should be stratified by overall cardiovascular risk, low-density lipoprotein cholesterol goals, comorbidities, drug interactions, and tolerability, alongside assessment of rheumatic disease activity. Future studies should distinguish lipid-mediated vascular benefit from drug-specific immune effects using matched lipid-lowering comparators, validated rheumatic outcomes, and cardiovascular endpoints.