Andreas Hess, Juergen Rechb, Raja Atreyac, Arnd Doerflerd, Markus Friedrich Neurathc and Georg Schettb
Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Internal Medicine 3, Department of Internal Medicine 1, Division of Neuroradiology, all University of Erlangen-Nuremberg, 91054 Erlangen, Germany
Medical Imaging in general is rated to be the number one technological development with the highest impact on modern health care. Due to its unique properties like low invasiveness, high spatial and temporal resolution, and high sensitivity, medical imaging paved the way for dramatically improved diagnostics. Besides high resolution anatomical data, medical imaging becomes more and more important for gaining inside in functional properties of the human body. Lately also validation of treatment success by medical imaging became feasible. Here we exemplify this for brain function. Pain is the key symptom in patients with inflammatory diseases like rheumatoid arthritis (RA) or Morbus Crohn (MC). It is well known, that TNF-alpha is the primary molecule in these pathological processes. However the role of TNF-alpha for the concomitant pain perception remains unclear. Therefore, we hypothesized that a hyper-nociception due to chronic TNF overexpression leads to an altered pain processing in the brain which should be true for different inflammatory diseases which depend on TNF-alpha. Consequently we investigated patients suffering RA  as well as from MC  using standard BOLD fMRI and disease specific painful stimuli. For both diseases after treatment with an anti-TNF drug (Infliximab) a reduction of the hyper-nociception, i.e. reduced activated brain volume, in brain areas activated by the painful stimulation was found. For RA and MC this happened as fast as 24 h after the first drug application which is weeks before any established clinical score indicates an improvement. Most interestingly was the finding that by our fMRI approach we were able to retrospectively differentiate between therapy responders and non-responders, again for both diseases. In order to further validate, if this predictive value of fMRI for indicating treatment success was limited to the anti-TNF tested so far (Infliximab) we investigated the anti-TNF Certolizumab pegol in RA patients . Likewise for Certolizumab fMRI was able to demonstrate a fast but long lasting reduction of pain induced activity in the brain of the patients. Further graph theoretical connectivity analysis data showed rewiring within the pain matrix under chronic pain conditions i.e. tight clustering of brain activity in thalamus and periaqueductal grey. Neutralization TNF by antibodies rapidly reversed this hyper-nociception. This was reflected by an overall decrease of the functional activity in the brain pain matrix and by dissociation of the tight clustering. These dynamic changes in the brain happened long before anti-inflammatory effects were evident. Our results suggest profound functional changes of nociceptive brain activity in inflammatory diseases like RA or MC, which normalizes upon hTNF blockade very fast and strongly contributes to the well-being of the patients.
 Hess, A. et al. Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci U S A. (2011); 108, 3731-3736.
 Hess, A. et al. Functional Brain Imaging Reveals Rapid Blockade of Abdominal Pain Response Upon Anti-TNF Therapy in Crohn's Disease. Gastroenterology. 2015;149(4):864-6.
 Rech, J. et al. Association of brain functional magnetic resonance activity with response to tumor necrosis factor inhibition in rheumatoid arthritis. Arthritis Rheum. (2013); 65, 325-333.