TNF Inhibitors Not Superior to Triple Therapy in Reducing Vascular Inflammation in Rheumatoid Arthritis

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Research in the general population has linked inflammation to plaque rupture and increased risk of atherosclerotic disease events. Those observations may help explain the approximately 50% elevated risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA).

Randomized controlled trials have found interleukin-1β blockade and low-dose colchicine reduce CVD event risk in the general population. Still, there’s been no high-quality data on the benefit of immunomodulators in RA.

Daniel H. Solomon, MD, MPH, a rheumatologist in the Division of Rheumatology, Inflammation and Immunity at Brigham and Women’s Hospital, and colleagues conducted The Treatments Against RA and Effect on FDG-PET/CT (TARGET) trial, the first randomized, active comparator trial to explore the effect of disease-modifying anti-rheumatic drugs on vascular inflammation in RA. In the Annals of the Rheumatic Diseases, the team reports significant reductions in arterial inflammation with either tumor necrosis factor-α (TNF) inhibitors or triple therapy, but no significant between-group differences.


TARGET was conducted at 41 U.S. centers. All participants had DAS28-CRP (DAS28 disease activity scores in 28 joints based on C-reactive protein) that were at least moderate (>3.2) despite the use of methotrexate.

159 patients remained on their baseline dosage of weekly methotrexate and were randomly assigned between March 16, 2016, and November 20, 2021, to 24 weeks of treatment with either:

  • A TNF inhibitor: adalimumab 40 mg every other week or etanercept 50 mg every week
  • Triple therapy: sulfasalazine 1 g two times daily and hydroxychloroquine 200 mg two times per day up to 6.5 mg/kg of body weight (plus methotrexate)

Subjects in the TNF inhibitor arm who did not reach DAS28-CRP ≤3.2 by week 18 could switch to the opposite agent. Those in the triple therapy arm could switch to leflunomide 20 mg/day from methotrexate.

The protocol called for patients to undergo 18F-fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT), a noninvasive measure of atherosclerotic plaque inflammation, at baseline and week 24.

Patient Characteristics

115 patients had paired FDG-PET/CT scans that could be analyzed for the primary outcome: change from baseline to week 24 in arterial inflammation, measured as arterial target-to-background ratio (TBR) in the most diseased segment of either the carotid artery or aorta.

71% of the 115 patients were women, the median age was 58, the median RA duration was 1.4 years, and the median DAS28-CRP at baseline was 4.8 (moderate).


Both treatment strategies resulted in significant within-group reductions in arterial inflammation as expressed by the TBR:

  • TNF inhibitors: −0.24 (P=0.001)
  • Triple therapy: −0.19 (P=0.001)

However, the difference between the two treatment groups in improvement was not statistically significant (baseline-adjusted difference in changes, −0.02, P=0.79).

There were no between-group differences in the:

  • Analyses limited to individual vessels
  • Subgroup analyses (age, sex, glucocorticoids yes/no, statins yes/no, serologic status +/−, CV risk factors yes/no, and RA duration <5 vs. ≥5 years)
  • An analysis restricted to patients deemed to adhere to >80% of study drug doses

Next Steps

Different classes of immunomodulators may influence arterial inflammation differently. The TARGET Trial Consortium plans additional studies to explore the effects of other RA therapies, such as interleukin-6 inhibitors, B cell–depleting antibodies, and Janus kinase inhibitors.

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