Predicting treatment response to TNF inhibitors remains challenging because of the complex and heterogeneous nature of immune-mediated diseases. Not all inflammation in conditions like RA, PsA, AS, or IBD is TNF-driven, and patient-to-patient variability adds to the difficulty. Genetic differences, such as polymorphisms in TNF or its receptors, and disease-specific immune pathways influence outcomes, but findings have been inconsistent. Clinical factors, including age, sex, disease duration, activity levels, obesity, smoking, and comorbidities, further modify response, while drug-related issues such as immunogenicity, variable pharmacokinetics, and the impact of concomitant methotrexate use complicate prediction. Although markers like baseline CRP, ESR, or cytokine profiles have shown some associations, none are robust or universally applicable.
A recent study published in Lancet Rheumatology has provided a new perspective by looking beyond traditional markers. The PreCePra trial, a multicentre, randomised, double-blind, placebo-controlled phase 3 study, investigated whether brain activity associated with RA could predict clinical response to TNF inhibition. The trial enrolled 139 patients with active RA across six centres in Germany, Portugal, and Serbia between 2013 and 2020. All participants underwent baseline functional MRI scans to measure central nervous system (CNS) pain activation before being stratified into high-volume or low-volume brain activity groups. Patients were then randomised in a 2:1 ratio to receive either the TNF inhibitor certolizumab pegol or placebo for up to 24 weeks.
The results showed that 57% of patients in the high-volume brain activity group treated with certolizumab pegol achieved low disease activity, compared with 44% in the low-volume group and 26% in the placebo group. Only the high-volume group showed statistically significant improvement over placebo. Adverse events were consistent with known safety profiles, with 25 treatment-related events reported, 22 in the certolizumab pegol groups and three in placebo. Researchers highlighted that this is the first randomised controlled trial to demonstrate a link between RA-associated brain activity and TNF inhibitor response. Interestingly, improvements were most pronounced in patient-reported outcomes, while physician-assessed and laboratory outcomes showed similar responses across groups.
These findings suggest that the way RA is represented in the brain plays a key role in shaping response to treatment. By recognising the CNS as an important factor in disease perception and response, the study opens a pathway toward more personalised therapy. If validated in larger cohorts, functional MRI could become a tool for tailoring biologic therapy, helping identify patients most likely to benefit from TNF inhibition.
Reference
Hess A, Tascilar K, Schenker HM, Konerth L, Schönau V,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. 2025 Aug;7(8):e565-e575.