Comparative Risk of Cardiovascular Events With Biologic and Synthetic Disease‐Modifying Antirheumatic Drugs in Patients With Rheumatoid Arthritis: A Systematic Review and Meta‐Analysis

Abstract

Objective We performed a systematic review and meta‐analysis to evaluate the comparative effects of tumor necrosis factor inhibitors (TNFi), non‐TNFi biologics, and conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs) on cardiovascular risk in rheumatoid arthritis (RA). Methods Using a systematic search through May 8, 2018, we included 14 observational studies in adults with RA treated with TNFi, non‐TNFi biologics, tofacitinib, or csDMARDs, reporting the risk of major adverse cardiovascular events (MACE) or stroke. Only studies reporting active comparators were included. We performed random effects meta‐analysis and estimated odds ratios (ORs) and 95% confidence intervals (95% CIs). Results As compared to TNFi, tocilizumab was associated with a decreased risk of MACE (OR 0.59 [95% CI 0.34–1.00]), whereas csDMARDs were associated with an increased risk of MACE (csDMARDs including methotrexate OR 1.45 [95% CI 1.09–1.93]; without methotrexate OR 2.57 [95% CI 1.32–5.00]), without heterogeneity (I2 = 0%); there was no difference in risk of MACE between abatacept and TNFi (OR 0.89 [95% CI 0.71–1.11]), or between tocilizumab and abatacept (OR 0.81 [0.57–1.16]). Based on 11 cohorts (n = 135,053 patients), as compared to TNFi, csDMARDs were associated with an increased risk of stroke (OR 1.17 [95% CI 1.01–1.36]); there was no difference in risk of stroke between different biologics (tocilizumab versus TNFi OR 0.98 [95% CI 0.59–1.61]; abatacept versus TNFi OR 1.08 [0.86–1.34]; tocilizumab versus abatacept OR 0.73 [95% CI 0.39–1.38]), without heterogeneity (I2 = 0%). No comparative studies on cardiovascular risk with tofacitinib were identified. Conclusion Based on meta‐analysis, as compared to TNFi, tocilizumab may be associated with a reduced risk of MACE, whereas csDMARDs may be associated with an increased risk of MACE and stroke.

A Systematic Review Comparing Experimental Design of Animal and Human Methotrexate Efficacy Studies for Rheumatoid Arthritis: Lessons for the Translational Value of Animal Studies

“…The RA-field is no exception, as e.g., clearly shown by an SR of in vivo animal experiments published in the "Annals of the Rheumatic Diseases" and "Arthritis and Rheumatism" [41]. Recent SRs of human RA studies did not describe percentages of included studies reporting experimental details [42,43], restricting the interpretation of our data in relation to theirs.…”

Clinical Aspects of Janus Kinase (JAK) Inhibitors in the Cardiovascular System in Patients with Rheumatoid Arthritis

“…Followed observation on cholesterol increase in tocilizumab-treated RA patients, the interest on impact of various biologic and non-biologic DMARDs increased significantly. tocilizumab, an IL-6 receptor inhibitor, increases circulating LDL levels [ 77 ], but no increased risk of major cardiovascular events was observed [ 78 , 79 ]. It is established that tocilizumab reduces the LDL hypercatabolic state and diminishes the expression of LDL receptor on hepatocytes via a proprotein convertase subtilisin/kexin type-9-mediated mechanism [ 80 , 81 ].…”

Chronic inflammatory diseases, myocardial function and cardioprotection

“…Several of these cytokines have been associated with myocardial and vascular dysfunction including arterial stiffness (Pryshchep et al, 2006;Yong et al, 2013), coronary atherosclerosis (Zhang et al, 2006), left ventricular hypertrophy and cardiac remodelling (Madhur et al, 2010;Sheu et al, 2013) and myocardial ischaemia (Ikonomidis et al, 2005(Ikonomidis et al, , 2017. IL-17A, one of the main inflammatory mediators in psoriasis (Lockshin, Balagula, & Merola, 2018), has pro-atherogenic action (Karbach et al, 2014) and has been detected in patients with acute coronary syndromes (Cheng et al, 2008).…”

“…Anti‐IL‐1 regimens seem to have a more favourable profile on myocardial function when compared to anti‐IL‐6 regimens, whereas anti‐IL‐6 regimens mostly benefit vascular function (Ikonomidis, Pavlidis, et al, 2019). In addition, two recent meta‐analyses indicated that tocilizumab (an anti‐IL‐6 agent) is safe in terms of CV outcomes compared to disease‐modifying antirheumatic drugs (Castagné et al, 2019) and may also be associated with decreased risk of major adverse cardiovascular events in comparison to TNF‐α inhibitors (Singh et al, 2019).…”