Antirheumatic drugs confer cardioprotection, too

Treatments used in rheumatoid arthritis (RA), called disease-modifying antirheumatic drugs (DMARDs), can also lower the risk of heart disease among patients, as shown in a recent study.

“[W]e conducted a randomized active comparator trial to compare the effects of two different accepted RA treatment strategies on vascular inflammation among patients with active RA despite weekly methotrexate,” according to investigators co-led by Dr Joan Bathon, a professor of medicine and director of the division of rheumatology at Columbia University Vagelos College of Physicians and Surgeons in New York City, New York, US.

Bathon and colleagues looked at the change in arterial target-to-background ratio (TBR) in the carotid arteries and aorta—a biomarker for atherosclerotic vascular inflammation, which is in turn a proxy for heart disease. They measured TBR over 24 weeks of treatment with methotrexate plus a tumour necrosis factor inhibitor (TNFi) or sulfasalazine and hydroxychloroquine (triple therapy).

Results showed that TBR decreased by 0.24 with methotrexate plus TNFi (n=58) and by 0.19 with triple therapy (n=57). The between-group difference of –0.02 (95 percent confidence interval, −0.19 to 0.15) was not significant (p=0.79).  [Ann Rheum Dis 2022;doi:10.1136/ard-2022-223302]

These data suggest that vascular inflammation, as measured by FDG-PET/CT*, was considerably reduced within both treatment strategies, without differences between them, the investigators noted.

Patients in both treatment groups also showed marked reductions in disease activity, although such improvements were not correlated with the changes in TBR.

“The reassuring message is that as your joints are improving with RA treatments, so too is your risk for cardiovascular disease,” Bathon said.

The study included 115 RA patients (median age 58 years, 71 percent women), of whom 57 percent were seropositive. Their baseline disease activity score in 28 joints was 4.8, and baseline TBR did not differ in the two treatment groups.

Inflammation and immunomodulation

The present work builds on previous studies that demonstrated the critical role of inflammation and immunomodulation in cardiovascular (CV) risk. [N Engl J Med 2017;377:1119-1131; Circulation 2002;105:1135-1143]

“Inflammation drives atherosclerosis and contributes to CV disease. Based on human and animal data, elevated cytokine levels in coronary arteries … appear to lead to plaque formation and rupture, and C-reactive protein elevations predict future CV events,” according to the investigators. [N Engl J Med 2013;368:2004-2013; Nat Rev Drug Discov 2012;11:633-652; Nat Rev Cardiol 2021;18:58-68; Lancet 2010;375:132-140]

The observed link of inflammation to plaque rupture and atherosclerotic disease events may explain the elevated risk of heart disease in RA, they pointed out. RA patients have an approximately 50-percent increased risk of CV events, with epidemiologic studies reporting a strong, independent correlation between RA disease activity and CV events. More importantly, this CV risk can be modified through several treatment strategies that slow disease activity in RA. [Ann Rheum Dis 2012;71:1524-1529; Arthritis Rheumatol 2015;67:1995-2003; Arthritis Rheumatol 2015;67:1449-1455; Ann Rheum Dis 2018;77:48-54; N Engl J Med 2017;377:1119-1131; N Engl J Med 2019;381:2497-2505]

“We were surprised to see that both of these powerful anti-inflammatory treatment strategies reduced heart disease risk in patients with RA,” Bathon said in a statement.

“Doctors still need to pay attention to the usual heart disease risk factors, such as high cholesterol, high blood pressure, and obesity. But since inflammation—a key feature of RA—elevates CV risk even further, reducing inflammation by treating the arthritis is a novel mechanism to reduce heart disease risk in these patients,” she added.

As for whether different RA treatments impact arterial inflammation differentially, this issue remains to be addressed. The investigators called for additional studies to explore the mechanisms by which RA therapies attenuate vascular inflammation independent of their effect on articular disease activity.

* ¹⁸F-fluorodeoxyglucose-positron emission tomography/CT scans