Imaging the effects of tumour necrosis factor inhibition on pain processing in severe rheumatoid arthritis

Background Monoclonal antibodies against tumour necrosis factor (TNF) markedly reduce inflammation and disease activity in rheumatoid arthritis; however, the mechanisms through which they affect pain are not fully understood. Aims The aim of this study was to investigate how monoclonal antibodies against TNF alter pain processing and to determine whether neuroimaging can be used as a marker of treatment efficacy and a predictor of treatment response. Methods Functional magnetic resonance imaging was used to study the neural correlates of clinically-relevant pain evoked by pressing the most painful joint of the right hand and experimental pain evoked by a thermal stimulus applied to the right forearm. A flashing checkerboard was used as a control stimulus. Patients with severe rheumatoid arthritis, qualifying for the anti-TNF treatment, were scanned before the beginning of the therapy and then approximately one and six months after the first injection. Results TNF inhibition was associated with a marked reduction in pain ratings, inflammation, disease activity as well as depression and catastrophising scores. Effective treatment was linked with less pressure-evoked brain activation in the regions involved in the processing of the sensory aspect of pain and in the limbic structures. Baseline pressure-evoked activation in the thalamus predicted future response to treatment. There was no reduction in heat-evoked brain activation; on the contrary, there was an increase in the activation in the precuneus, which is involved in interoception. There were no differences in response to the visual stimulus. Conclusions TNF inhibition strongly reduces brain activation in response to clinically relevant pressure pain but not experimental heat pain and these changes reflect the decrease of nociceptive input from the periphery due to the reduction of inflammation as well as central changes in pain modulation. Neuroimaging methods have the potential to explain and predict treatment effects in inflammatory pain conditions. ### Competing Interest Statement This research project was supported by unrestricted grants from GlaxoSmithKline (KW), the Wellcome Trust (IT), the Biotechnology and Biological Sciences Research Council - David Phillips Fellowship (MJ) and the Medical Research Council of Great Britain and Northern Ireland (FMRIB Centre). There was no conflict of interest. The funding bodies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Funding Statement This research project was supported by unrestricted grants from GlaxoSmithKline (KW), the Wellcome Trust (IT), the Biotechnology and Biological Sciences Research Council - David Phillips Fellowship (MJ) and the Medical Research Council of Great Britain and Northern Ireland (FMRIB Centre). There was no conflict of interest. The funding bodies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Oxfordshire Research Ethics Committee and conducted in accordance with the principles of the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.