Addition of TNFi, Triple Therapy Improved Vascular Inflammation in Patients with RA

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Although previous studies have indicated differential effects on cardiovascular risk between immunomodulators, results showed similar reductions across both treatment groups.

The addition of a tumor necrosis factor inhibitor (TNFi) did not reduce arterial inflammation more than triple therapy in patients with rheumatoid arthritis (RA). However, adding either TNFi or triple therapy, defined as the addition of sulfasalazine and hydroxychloroquine, clinically improved vascular inflammation, according to a study published in Annals of the Rheumatic Diseases.

“Recent large-scale randomized trials demonstrate that immunomodulators reduce cardiovascular (CV) events among the general population,” investigators noted. “However, it is uncertain whether these effects apply to RA and if certain treatment strategies in RA reduce CV risk to a greater extent.”

Patients with active RA who had inadequate response to methotrexate were randomly assigned to either a TNFi (adalimumab 40 mg every other week or etanercept 50 mg every week) or triple therapy (sulfasalazine 1 g 2 times per day and hydroxychloroquine 200 mg 2 times per day), in addition to methotrexate, for 24 weeks. Those who did not achieve low disease activity by week 18 could switch to the alternative TNFi or to leflunomide 20 mg/day from methotrexate for those in the triple therapy group.

18F-fluorodeoxyglucose-positron emission tomography/CT scans (FDG-PET/CT), a predictor of atherosclerotic disease events, were taken at baseline and follow-up visits at week 6, 18, and 24, and evaluated arterial inflammation by measuring an arterial target-to-background ratio (TBR) in the aorta and carotid arteries. The secondary outcome was changes in the disease activity score in 28 joints (DAS28-CRP).

Ultimately, 115 patients completed the study. The mean age of patients was 58 years, approximately half (57%) were seropositive, 71% were women, the median disease duration was 1.4 years, median baseline disease activity was classified as moderate, baseline DAS28-CRP was 4.8, and baseline TBR was comparable among treatment arms.

Clinically significant TBR reductions were reported in both cohorts (TNFi: −0.24 [SD=0.51], triple therapy: −0.19 [SD=0.51]) and there was no observable difference between groups (baseline adjusted difference in changes: −0.02, 95% CI −0.19 to 0.15, p=0.79). Although disease activity was significantly reduced among patients treated with TNFi or triple therapy, changes were not associated with improvements in TBR (β=0.04, 95% CI −0.03 to 0.10). Further, TBR changes evaluated by RA disease activity were not significant and there were no differences between baseline and follow-up values for CV risk factors.

Balanced treatment groups and randomization of participants strengthened the study. However, the patient’s global assessments may have been impacted by a lack of patient and clinician masking; although, all other assessments were masked. The small sample size and short follow-up period hindered the statistical power for additional exploratory analyses. Additionally, follow-ups were modified due to the COVID-19 pandemic and caused delays in several follow-up scans. Future research should explore which RA therapies improve vascular inflammation independent of their effect on articular disease activity.

“Our results highlight the importance of conducting clinical trials specifically among patients with RA rather than the general population,” corresponding author Daniel H. Solomon of the Division of Rheumatology, Inflammation, and Immunology concluded. “Prior trials in the general population have shown differential effects on CV risk between different immunomodulators, but in our trial, 2 different immunomodulator treatment strategies produced similar reductions in CV risk.”


Solomon DH, Giles JT, Liao KP, et al. Reducing cardiovascular risk with immunomodulators: a randomised active comparator trial among patients with rheumatoid arthritis [published online ahead of print, 2022 Nov 30]. Ann Rheum Dis. 2022;ard-2022-223302. doi:10.1136/ard-2022-223302