Baseline fMRI May Predict TNF Inhibitor Response in Rheumatoid Arthritis, Trial Finds

A phase 3 randomized trial has found that functional MRI (fMRI) measures of central nervous system (CNS) pain activation at baseline may help predict clinical response to tumor necrosis factor (TNF) inhibitor therapy in rheumatoid arthritis (RA). These findings suggest a potential neurobiological marker for treatment stratification in RA, where current predictors of therapeutic response remain limited.

The study enrolled 139 adults with active RA who had inadequate response to at least one conventional synthetic disease-modifying antirheumatic drug. All participants underwent baseline fMRI to measure CNS pain activation and were stratified into high- or low-volume activation groups. Participants were then randomly assigned in a 2:1 ratio to receive certolizumab pegol or placebo, with all treatment administered double-blind for 24 weeks.

The primary endpoint was the proportion of patients who achieved low disease activity, defined as a Disease Activity Score in 28 joints (DAS28) ≤3.2, at week 12. This outcome integrates both objective and subjective domains, including joint counts, acute-phase reactants, and patient-reported symptoms.

By week 12, 57% of participants in the high-volume certolizumab pegol group achieved low disease activity, compared with 44% in the low-volume certolizumab pegol group and 26% in the placebo group. The difference in response between the high-volume certolizumab pegol and placebo groups was statistically significant (p=0.0017), while the difference between the low-volume and placebo groups did not reach statistical significance (p=0.063).

“High disease-associated fMRI CNS pain activation might predict clinical response of patients with rheumatoid arthritis to TNF inhibitor treatment,” the authors concluded.

These results support the hypothesis that greater disease representation in the CNS, as captured through fMRI imaging, may enhance the likelihood of response to TNF inhibition. The finding is especially relevant because subjective components such as pain and global assessment carry substantial weight in composite disease activity scores used to define therapeutic success in RA.

The trial involved six rheumatology centers across Germany, Portugal, and Serbia. Of the 139 patients randomized, 99 were women (71%) and 40 were men (29%). Patients in the certolizumab pegol arm received 400 mg subcutaneously at weeks 0, 2, and 4, followed by 200 mg every 2 weeks through 24 weeks.

Treatment-related adverse events were reported in 25 participants—22 in the certolizumab pegol arms and 3 in the placebo arm.

For practicing rheumatologists, the key takeaway is the potential utility of baseline CNS pain processing patterns in predicting treatment response to TNF inhibitors. While further validation is needed, these findings highlight the role of central pain mechanisms in RA disease expression and treatment outcomes.

As the field moves toward more personalized therapeutic strategies, neuroimaging-based biomarkers may offer an additional layer of precision in guiding biologic therapy decisions in RA.

Reference
Hess A, Tascilar K, Schenker HM, et al. Disease-associated brain activation predicts clinical response to TNF inhibition in rheumatoid arthritis (PreCePra): a randomised, multicentre, double-blind, placebo-controlled phase 3 study. Lancet Rheumatol. Published online June 23, 2025. doi:10.1016/S2665-9913(25)00032-3