Biologic use regulates the impact of inflammation on ischemic cardiovascular risk in rheumatoid arthritis.

Abstract

Chronic inflammation contributes to enhanced cardiovascular risk in patients with rheumatoid arthritis (RA). Biologic disease modifying antirheumatic drugs (bDMARDs) have been shown to effectively control inflammation in many conventional synthetic DMARD non-responders and improve cardiovascular outcomes. We here explored whether baseline bDMARD use may influence the impact of disease activity and systemic inflammation on long-term cardiovascular risk in patients with RA. We studied 4370 patients with RA who were free of cardiovascular disease upon registration to�Annternational�Cardiovascular�Consortium for people with�RA�(ATACC-RA) and followed prospectively. Prespecified outcomes included (a) major adverse cardiovascular events (MACE) defined as non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death and (b) any ischemic cardiovascular events (CVE) comprising MACE, coronary revascularization, stable angina pectoris, transient ischemic attack and peripheral arterial disease with or without revascularization. Missing covariate data were imputed using multiple imputation with 10 repetitions. Multivariable Cox models stratified by center evaluated the impact of disease activity [based on 28 joint counts and C-reactive protein (DAS28-CRP)], systemic inflammation (CRP), bDMARD use and their respective interactions on CVE risk after adjusting for age, gender, hypertension, diabetes, family history of CAD, smoking and total cholesterol to high-density lipoprotein ratio. Two corroborating sensitivity analyses were performed; the first included patients enrolled in the cohort on or after January 1, 2000, when bDMARD use became more prevalent among enrollees. The second used inverse probability of treatment weights (IPTW) to balance differences in bDMARD treated and untreated patients. Throughout 26534 patient years of follow-up, 239 first MACE and 362 total ischemic CVE were recorded. Among bDMARD nonusers, incidence of MACE and any ischemic CVE was [9.3 (95% CI 8.2-10.6) and 14.2 (12.8-15.8) events/1000PY respectively. Corresponding rates for bDMARD users were [5.4 (95% CI 2.9-10.1) and 8.2 (5.0-13.6) events/1000PY respectively. In the entire cohort, DAS-28 CRP and CRP(ln) associated with greater risk of MACE [(adjusted hazards ratio [HR] 1.19 (95%CI 1.06-1.34), p=0.004 and HR 1.15 (1.02-1.28), p=0.017 respectively], while for all ischemic CVE the association was significant for DAS-28 CRP [adjusted HR 1.1 (95%CI 1.07 to 1.30)], but not CRP(ln) [HR 1.06 (0.97 to 1.16)]. In bDMARD nonusers at baseline, higher DAS28-CRP and CRP(ln) associated with greater risk of MACE [adjusted HR 1.21 (95%CI 1.07-1.37), p=0.002 and HR 1.16 (1.04-1.30), p=0.009 respectively]. However, this was not the case in bDMARD users [p-for-interaction= 0.017 and 0.011 correspondingly, Figure 1]. In contrast, no significant interaction between DAS28-CRP or CRP and bDMARD use on any ischemic CVE risk was observed (p-for-interaction= 0.167 and 0.237 respectively). Both sensitivity analyses yielded similar results. Higher disease activity and systemic inflammation at baseline associated with greater risk of MACE in bDMARD nonusers but not in patients receiving bDMARDs. This may suggest the presence of additional bDMARD-specific benefits directly on atherosclerotic plaque �such as plaque stabilization[1]� above and beyond their effects on systemic inflammation.