DMARDs for Early Rheumatoid Arthritis Have Cardiovascular Benefits Save

Patients with RA have up to a three-fold increased risk of mortality versus the general population, largely due to an increased incidence of premature CVD, such as atherosclerosis and heart failure. This excess risk is as high as that of patients with major CVD risk factors such as type 2 diabetes and is considered independent of traditional cardiovascular risk factors.

Recent studies have identified shared immune pathways and mediators between RA and CVD, suggesting that immunomodulating therapies for RA might help alter the pathogenesis of cardiovascular disease in these patients and lower the risk of subsequent events. It is also conceivable that disturbances in lipid and glucose metabolism might play a role.

In recent substudy results published in the Annals of the Rheumatic Diseases, researchers found that abnormal vascular stiffness, which can predict major cardiovascular events independently of traditional clinical risk scoring models in patients without known CVD, was already present in patients with early RA.

First-line treatment with etanercept plus methotrexate or methotrexate alone improved these abnormalities, reported Maya H. Buch, MBChB, PhD, of the University of Manchester in England, and colleagues.

Buch and team analyzed data from the VEDERA trial to determine whether DMARDs for RA might reduce the risk of CVD in these patients. Participants were randomized to receive either etanercept plus methotrexate or a methotrexate treat-to-target strategy. While neither strategy outperformed the other in VEDERA, improvements were observed in the presence of vascular and myocardial abnormalities.

Vascular abnormalities were already present at the time of diagnosis of rheumatoid arthritis (RA) in patients with no known cardiovascular disease (CVD), but improved over time with treatment with disease-modifying antirheumatic drugs (DMARDs), according to data from the VEDERA trial.

Note that there were no differences at year 1 between patients receiving methotrexate alone or in combination with etanercept in aortic distensibility, left ventricular mass, or other secondary outcomes, or between patients considered responders or nonresponders.

A subset of 81 patients in the trial underwent cardiovascular MRI, a sensitive technique for assessing cardiac anatomic and functional characteristics, as did 30 matched controls. Two-thirds of the patients were women, and median age was 51. The majority of patients were seropositive, and baseline disease activity score was 5.3. Only 7% had hypertension, 2% had high cholesterol, and 5% had a family history of ischemic heart disease at baseline, while none had diabetes. Of the patients, 55% were current or former smokers, and the median pack-years of smoking was 0.1. None had a history of cardiovascular symptoms or disease.

The primary endpoint was aortic distensibility, which was chosen because of its ability to reliably predict cardiovascular outcomes independent of conventional risk models, the team noted.

Compared with healthy controls, patients with early RA showed 50% lower aortic distensibility, with a geometric mean of 3.0×10-3 mm Hg-1 versus 4.4×10-3 mm Hg-1, for an unadjusted geometric mean ratio of 1.5 (95% CI 1.2-1.8, P<0.01).

After the patients received 1 year of treatment with methotrexate alone or in combination with etanercept, aortic distensibility improved by 20%, with a geometric mean ratio versus baseline of 1.2 (95% CI 1.1-1.3, P<0.01).

The significant difference between cases and controls in aortic distensibility persisted after adjustment for age, sex, blood pressure, and history of smoking, with a geometric mean ratio of 1.5 (95% CI 1.3-1.7, P<0.01).

Differences were also seen between cases and controls on other endpoints. Left ventricular mass was 20% less in the early RA patients compared with controls (78.2 vs 92.9 g, P<0.01) and myocardial extracellular volume, suggesting diffuse myocardial fibrosis, was 10% higher (27.2% vs 24.9%, P<0.01).

At 1 year, there were modest but significant increases in left ventricular mass, with a geometric mean ratio compared with baseline of 1 (95% CI 1-1.1, P=0.01), but no differences in other secondary outcomes such as left ventricular ejection fraction or left ventricular longitudinal strain.

After year 1, patients who had been randomized to receive etanercept plus methotrexate stopped the tumor necrosis factor inhibitor, and follow-up continued through year 2.

There were no differences at year 1 between patients receiving methotrexate alone or in combination with etanercept in aortic distensibility, left ventricular mass, or other secondary outcomes, or between patients considered responders or nonresponders.

At 2 years, the geometric mean ratio for aortic distensibility had improved by 10% from baseline (1.1, 95% CI 1-1.4, P=0.05), and the increase in left ventricular mass also remained significant, with a ratio of 1.1 (95% CI 1-1.2, P=0.02).

A limitation of the study, Buch and team said, was its reliance on surrogate markers for the estimation of cardiovascular risk.

Source Reference: Plein S, et al "Cardiovascular effects of biological versus conventional synthetic disease-modifying antirheumatic drug therapy in treatment-naive, early rheumatoid arthritis" Ann Rheum Dis 2020; DOI: 10.1136/annrheumdis-2020-217653.