Patients with rheumatoid arthritis who have high brain pain activation on functional MRI before starting therapy were more likely to achieve low disease activity with TNF inhibitor treatment, according to a multi-center, randomized, double-blind, placebo-controlled phase 3 trial.
The study enrolled 139 adults with active rheumatoid arthritis (RA) who had not responded to at least one conventional synthetic disease-modifying antirheumatic drug (DMARD). Participants underwent baseline functional MRI scans to assess brain activation during painful joint compression and were categorized as high or low activation. They were then randomly assigned in a 2:1 ratio to receive the TNF inhibitor certolizumab pegol or placebo.
Treatment consisted of certolizumab pegol 400 mg subcutaneously at weeks 0, 2, and 4, followed by 200 mg every 2 weeks for up to 24 weeks. The primary outcome was the proportion of patients achieving low disease activity, defined as a Disease Activity Score in 28 joints–C-reactive protein (DAS28–CRP) of 3.2 or less at 12 weeks.
At week 12, 57% of patients in the high-activation group treated with certolizumab pegol reached low disease activity, compared with 44% in the low-activation group and 26% in the placebo group. The high-activation group had a significantly greater response than placebo, while the low-activation group did not.
Physician-assessed measures such as C-reactive protein levels and global disease activity improved similarly in both certolizumab pegol groups. However, patient-reported outcomes, including pain, global disease activity, and tender joint counts, improved more in the high-activation group.
Functional MRI results showed that certolizumab pegol treatment in high-activation patients reduced activation volumes in pain-related brain regions, including the primary somatosensory cortex, primary motor cortex, and frontal pole. In contrast, activation increased in the low-activation group and decreased slightly in the placebo group without specific regional changes.
Machine learning analysis found that pain-related brain activation data accurately distinguished high-activation from low-activation patients, while clinical and laboratory data were not predictive of treatment response.
"These data highlight the role of subjective patient-related parameters in the response to cytokine inhibition and suggest that a high-volume representation of the disease in the CNS—involving more frontal-associative brain circuits—increases the likelihood to respond to TNF inhibitor," noted Koray Tascilar, MD, of the Friedrich-Alexander-Universität Erlangen–Nürnberg and Universitätsklinikum Erlangen, Germany, and colleagues.
A total of 178 adverse events occurred across all groups, with 47% in the high-activation group, 22% in the low-activation group, and 30% in placebo. Twenty-five events were considered possibly related to treatment, and six serious adverse events were reported, including infections and cardiovascular events. No deaths or new safety concerns were identified.
The reseachers noted that the blood oxygen-level dependent signal used in functional MRI can be affected by factors such as circulatory or mental health status, though imaging protocols were standardized to minimize variability. The low disease activity threshold used was validated for DAS28–erythrocyte sedimentation rate, not DAS28–CRP, and sensitivity analyses using a lower cutoff reduced statistical significance. Differences between high-activation and low-activation groups were small, and the voxel-based measure of brain activity may not fully capture disease-related central nervous system patterns.
Full disclosures can be found in the published study.
Source: The Lancet Rheumatology