Cardiovascular effects of approved drugs for rheumatoid arthritis

Abstract

The risk of cardiovascular disease is increased in patients with rheumatoid arthritis compared with the general population owing to the influence of traditional and non-traditional risk factors. Inflammation has a pivotal contribution and can accelerate the atherosclerotic process. Although dampening inflammation with DMARDs should theoretically abrogate this process, evidence suggests that these drugs can also promote atherosclerosis directly and indirectly, hence adding to an increased cardiovascular burden. However, the extent and direction of the effects largely differ across drugs. Understanding how these drugs influence endothelial damage and vascular repair mechanisms is key to understanding these outcomes. NSAIDs and glucocorticoids can increase the cardiovascular risk. Conversely, conventional, biologic and targeted DMARDs control inflammation and reduce this risk, although some of these drugs can also aggravate traditional factors or thrombotic events. Given these data, the fundamental objective for clinicians should be disease control, in an individualized approach that considers the most appropriate drug for each patient, taking into account joint and cardiovascular outcomes. This Review provides a comprehensive analysis of the effects of DMARDs and other approved drugs on cardiovascular involvement in rheumatoid arthritis, from a clinical and mechanistic perspective, with a roadmap to inform the research agenda. Various drugs used in rheumatoid arthritis management have anti-inflammatory effects that can hinder atherosclerosis development and progression. However, these drugs can also concurrently have different pro-atherogenic effects, complicating the relationship between these drugs and cardiovascular involvement in rheumatoid arthritis. Effective disease control with anti-rheumatic drugs in rheumatoid arthritis is expected to reduce cardiovascular risk in the same way that it reduces disease activity, by dampening inflammation. Treatment with DMARDs can promote adverse vascular outcomes and trigger paradoxical effects on traditional risk factors, thus functioning as a double-edged sword in terms of cardiovascular risk management. Overall, the use of conventional synthetic DMARDs, with the exception of methotrexate, is associated with some detrimental cardiovascular effects, depending on the dosages and length of usage. Biologic DMARDs can reduce the cardiovascular burden, but can also have paradoxical effects on traditional cardiovascular risk factors; to what extent these effects translate into cardiovascular risk is unclear. Targeted synthetic DMARDs might confer a slightly higher risk of thrombotic events than standard of care therapy in some patients, but evidence is limited and long-term clinical studies are needed. Further efforts should focus on improving knowledge on vascular repair mechanisms, running prospective long-term trials, handling confounding by indication bias and providing critical appraisal of treatment targets. Effective disease control with anti-rheumatic drugs in rheumatoid arthritis is expected to reduce cardiovascular risk in the same way that it reduces disease activity, by dampening inflammation. Treatment with DMARDs can promote adverse vascular outcomes and trigger paradoxical effects on traditional risk factors, thus functioning as a double-edged sword in terms of cardiovascular risk management. Overall, the use of conventional synthetic DMARDs, with the exception of methotrexate, is associated with some detrimental cardiovascular effects, depending on the dosages and length of usage. Biologic DMARDs can reduce the cardiovascular burden, but can also have paradoxical effects on traditional cardiovascular risk factors; to what extent these effects translate into cardiovascular risk is unclear. Targeted synthetic DMARDs might confer a slightly higher risk of thrombotic events than standard of care therapy in some patients, but evidence is limited and long-term clinical studies are needed. Further efforts should focus on improving knowledge on vascular repair mechanisms, running prospective long-term trials, handling confounding by indication bias and providing critical appraisal of treatment targets.