Cardiovascular safety of anti-TNF-alpha therapies: facts and unsettled issues.

Tumor necrosis factor alpha (TNFa) plays a central role in the pathogenesis of both rheumatoid arthritis (RA) and heart failure (HF). Over the last years RA could benefit from TNFa inhibitors that mitigated disease activity, decreased structural damage, and prevented cardiovascular events. Contraindications to clinical use of TNFa inhibitors may include infections, autoimmune disorders, demyelinating disease, cancer, and heart failure. Overall, these pathological conditions do not appear to increase significantly during treatment with TNFa antagonists compared to placebo. Clinical trials probed these drugs in non RA HF patients produced disappointing results and formed the basis to contraindicate TNFa inhibitors in patients with moderate-severe HF. Although National Registries provide apparently encouraging data about HF safety of anti-TNFa therapies, they cannot adequately assess the actual risk, as these drugs are administered to patients with no cardiac dysfunction. These findings introduced a "rheumatological dilemma" in the clinical management of RA with anti-TNFa. Probably, in RA patients anti-TNFa agents would intercept TNFa and prevent its toxic effects on heart function, while in patients with advanced heart damage (NYHA class III-IV HF), anti-TNFa agents would interfere with the beneficial preconditioning effects of TNFa.