EARLY DIAGNOSIS AND DEVELOPMENT OF A NEW GENERATION OF DRUGS FOR PERSONALIZED TREATMENT OF RHEUMATOID ARHTRITIS

In a direct approach to connect molecular research to patient care, the principle goal of the present project is to develop a diagnostic method and highly specific metabolic drugs for the personalized early treatment of patients suffering from the autoimmune disease rheumatoid arthritis (RA). Autoimmunity is with cancer and cardiovascular disease ranked as the most common causes of morbidity in the world today. RA is a chronic, systemic inflammatory autoimmune disorder associated with harmful activity and proliferation of white blood cells (lymphocytes) that attacks and destroys flexible (synovial) joints. The etiology of RA is not known and there is no known cure. However, early detection and aggressive therapy have proven effective in dampening RA symptoms. At an early stage methotrexate (MTX), a potent an anti-cancer drug is prescribed. The use of MTX which inhibits all forms of cell proliferation is associated with severe side effects and markedly reduced life quality for many of the RA patients. We hypothesize that developing drugs which specifically target lymphocyte proliferation can be used to more precisely treat and dampen RA symptoms. The project is performed in collaboration with Professor Tore K. Kvien and Dr. Guro Løvik Goll at the Dept. of Rheumatology, Diakonhjemmet Hospital in Oslo, Professor Friedrich Herberg, Department of Biochemistry, University of Kassel, Germany, Professor Magnar Bjørås, the Core facility for Structural Biology at Centre for Molecular Biology and Neuroscience (CMBN) at Oslo University Hospital (OUS) and Dr. Katja B. P. Elgstøen Dept of Medical Biochemistry, OUS. We have made several key observations suggesting both cellular an molecular patterns of RA. Two key observations are from a pilot study on sero + RA patients (n = 15, both sexes) demonstrating 1) there is a marked increase in the Th17/Treg ratio in inflamed synovial tissues. Th17 cell proliferation and activity are associated with type 3 immune complex and complement-mediated hypersensitivity, and are associated with early onset of RA. 2) There is a marked increase in the lactate, glutamine, taurine and lipid concentration in synovium and synovial fluid of RA patients Lactate and lipid production as well as glutamine consumption are markers of proliferating cells and taurine is a marker of hypoxia (O2 < 5 %), a condition promoting Th17 cell differentiation.

Autoimmunity is with cancer and cardiovascular disease the most common causes of morbidity in the world and is a feature of many different diseases including rheumatoid arthritis (RA). RA affects about 1% of the world's population and is gender-biased tow ards the female. RA is a chronic and systemic inflammatory disorder associated with harmful proliferation of white blood cells (lymphocytes) that attack and destroy flexible joints. Early detection and aggressive therapy is crucial to successfully treat a nd dampen symptoms of RA. At an early stage RA patients normally receive the anti-cancer drug methotrexate (MTX), which inhibits all forms of cell proliferation. This together with the fact that some RA patients do not respond to MTX and that medication i s life-lasting may explain the severe side effects and the low life quality associated with RA-medication. A method to diagnose MTX-none-responders and to develop more specific drugs to treat RA patients are greatly needed. Proliferating lymphocytes requ ire large amounts of the carbohydrat glucose and the amino acid glutamine to support proliferation. Interestingly, proliferating but not quiescent lymphocytes over-produce lactate and alanine when combusting glucose and glutamine, respectively, demonstrat ing a major metabolic difference between the two cell populations. Lactate dehydrogenase (LDH) catalyse the formation of lactate and our preliminary results demonstrate a 30-40 forld induction of the A form of LDH (LDHA) in proliferating lymphocytes. This together with the fact that glutaminase (GLS) converts glutamine to glutamate, make LDHA and GLS promising therapeutic targets of RA patients responsive to MTX. Moreover, the fact that lactate and alanine are over-produced by proliferating lymphocytes ma ke these molecules promising biomarkers for RA which may provide early diagnosis of MTX responsive RA patients. Results from the present project will open for new and personalized treatment of RA patients.