TNF inhibitor efficacy may depend on brain activity

Dec 24 2012

By Lynda Williams, Senior medwireNews Reporter

How well a patient responds to tumor necrosis factor (TNF) inhibitor therapy may depend on brain activity reflecting the individual's perception of their rheumatoid arthritis (RA), scientists believe.

As reported in Arthritis and Rheumatism, patients who responded to TNF inhibition showed significantly greater baseline brain volume activity in the thalamic, limbic, and associative areas of the brain than nonresponders.

Moreover, while responders showed a consistent decrease from baseline in blood oxygen level-dependent signals - indicating increased neuron activity - over follow up, nonresponders showed only a small and transient suppression at 3 days.

"The observation that brain activity in the fMRI [functional magnetic resonance imaging] is linked to responsiveness to TNF [inhibition] is interesting, given that standard clinical measures fail to predict clinical responses to TNF [inhibition]," say Georg Schett (University of Erlangen-Nuremberg, Germany) and co-authors.

"It implies that these drugs are effective if the peripheral inflammatory process is adequately reflected in the central nervous system. This central nervous 'mirror image' of disease, visualized by fMRI, likely reflects the perceived burden of RA, such as pain, fatigue and mood changes, rather than the activity of the inflammatory disease process itself."

The researchers used fMRI of the brain in 10 patients with highly active RA before and 3, 7, and 28 days after beginning treatment with subcutaneous certolizumab pegol 200 mg.

Five patients responded to anti-TNF treatment, with an average Disease Activity Score (DAS)28 for swollen and tender joints decrease of 1.8 points after 28 days, compared with a fall of 0.2 points in nonresponders.

Of note, patients who did and did not respond to anti-TNF therapy did not significantly differ with regard to baseline demographic factors, such as age or disease duration, DAS28, erythrocyte sedimentation rate, or global disease visual analog score.

Nor did anatomic hand MRI demonstrate any significant change in inflammatory infiltrates between baseline and 28 days after treatment.

This result is "clearly indicating that central nervous system activity in RA decreases before any known peripheral anti-inflammatory effects become measurable," say the researchers.

The researchers also found that connectivity of thalamic pain perception centers in the brain and the periaquaeductal grey, which elicits efferent anti-nociceptive signals, were both significantly higher in nonresponders than responders at baseline and throughout follow up. Preferential use of these signals may explain why nonresponders have lower overall cortical neuron activity and why TNF inhibition does not alter this process, the team hypothesizes.

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