Management of Cardiovascular Disease Risk in Rheumatoid Arthritis

Methotrexate

Methotrexate (MTX), a mainstay in the treatment of RA, is a conventional DMARD observed to improve overall survival and mitigate CVD risk in multiple RA cohorts.^75,87,88 In a recent meta-analysis comprised of 236,525 RA patients and 5410 CVD events, MTX use was associated with a 28% reduction in overall CVD events across 8 studies (RR, 0.72; 95% CI, 0.57-0.91), substantiating similar findings in a prior meta-analysis.^75,88 MTX use was specifically associated with a decreased risk of MI (RR, 0.81; 95% CI, 0.68-0.96). Case-control and cohort studies have cited a 20% to 50% reduced risk of CHF with MTX use.^89,90 The potential cardioprotective effect of MTX appears to be both multifactorial and complex, likely mediated through both direct and indirect mechanisms. MTX directly promotes anti-atherogenic lipoprotein function, improves endothelial function, and scavenges free radicals.^91,92 Indirectly, MTX likely reduces CVD risk by effectively reducing RA disease activity. Based on these and other data, MTX remains the cornerstone of DMARD therapy in RA patients when targeting CVD risk reduction.

Hydroxychloroquine

Emerging evidence suggests that hydroxychloroquine (HCQ), an antimalarial most often utilized in combination with alternative DMARDs in RA, prevents DM and has beneficial effects on lipid profiles. A recent meta-analysis compiled 3 homogenous observational studies that investigated the effect of HCQ on incident DM. RA patients ever exposed to HCQ had a 40% lower incidence of DM (HR, 0.59; 95% CI, 0.49-0.70).⁹³ Increased duration of HCQ use was shown to further reduce risk of incident DM.⁹⁴ The aforementioned meta-analysis also pooled 5 studies investigating the effect of HCQ on lipid profiles, with favorable mean differences in TC (–9.82 mg/dL), LDL (–10.61 mg/dL), HDL (4.13 mg/dL), and triglycerides (–19.15 mg/dL) in HCQ users compared to non-users.⁹³ Given these favorable changes to traditional CVD risk factors, it is not surprising that in a retrospective study of 1266 RA patients without prior CVD, HCQ was associated with significantly lower risk of incident CVD. While external validation of these findings is needed, HCQ is an attractive conventional DMARD to be used in RA for CVD risk reduction. Moreover, its combination with MTX and sulfasalazine also shows promise for CVD risk reduction.^95,96

TNF Inhibitors

Tumor necrosis factor (TNF) inhibitors are often the initial biologic DMARD therapy used in RA patients not responding to conventional DMARDs. In the previously described meta-analysis, TNF inhibitors were associated with similar reductions in CVD events as MTX (RR, 0.70; 95% CI, 0.54-0.90).⁷⁵ Of note, there was a trend toward reduced risk of CHF (RR, 0.75; 95% CI, 0.49-1.15) in this same meta-analysis, an area of concern with TNF inhibitor use due to a prior randomized controlled trial demonstrating worsening clinical status in patients with existing moderate-to-severe CHF treated with high-dose infliximab.⁹⁷ Current RA treatment guidelines recommend avoiding TNF inhibitor use in individuals with CHF.⁹⁸

Aside from the risk of CHF exacerbation, TNF inhibitors appear to be cardioprotective. Similar to MTX, the mechanism by which TNF inhibition reduces cardiovascular risk is complex and likely due to both direct and indirect mechanisms. Substantial research has been conducted on the effect of TNF inhibition on lipids, with a recent meta-analysis demonstrating increases in HDL and TC, with stable LDL and atherogenic index over treatment follow-up.⁹⁹ A subsequent meta-analysis not limited to RA patients yielded similar results.¹⁰⁰ In addition to quantitative lipid changes, alteration of lipoprotein function, improvement in myocardial function, reduced aortic stiffness, improved blood pressure, and reduced RA disease activity may also be responsible for cardioprotective benefits of these agents.^101,102

Non-TNF Biologic and Traditional Synthetic DMARDs

Tocilizumab, an IL-6 inhibitor, can potently increase LDL levels, but it does not appear to increase the risk of CVD events and may actually promote more favorable anti-atherogenic lipoprotein function.^103-106 Although these quantitative lipid changes received significant attention in the wake of early reports detailing this effect, similar lipid changes appear to accompany other DMARDs including TNF inhibitors and tofacitinib.¹⁰⁷ There have been few studies evaluating the risk of CVD with other non-TNF inhibitor biologic DMARDs and traditional synthetic DMARDs, warranting future study.