MOLECULAR SIGNATURES AND NOVEL DRUGS FOR THE 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 aetiology 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, may be associated with severe side effects and markedly reduced life quality for many of the RA patients. We have developed a computer-base machine learning method that will predict sensitivity to MTX. The method will with precision, predict the outcome of MTX use in RA patients. Over time the method will contribute to prevent overuse of MTX in RA patients over time. The project is performed in collaboration with the Dept. of Rheumatology, Diakonhjemmet Hospital in Oslo, Department of Biochemistry, University of Kassel, Germany, University, and Cambridge, England, University of Dundee, England, NTNU and Rheumatech AS

Langvarig bruk av MTX kan gi alvorlige bivirkninger. Vi har i samarbeid med våre partnere brukt kliniske og demografiske pasientopplysninger sammen med virkningen av MTX over tid sammen med datamaskin-basert maskinlæring laget en metode som kan forutse hvilke leddgiktpasienter som vil ha god effekt av MTX behandling uten bivirkninger over tid. Resultatene vil ha store konsekvenser for livskvaliteten for pasienter med leddgikt da en vil med mer treffsikkerhet kunne medisinere denne pasientgruppen for å unngå overmedisinering og bivirkninger. Dette vil ha stor samfunnsøkonomisk nyttig da pasienter med tilpasset medisinering vil kunne fungere mer optimalt, også i arbeidslivet. I tillegg vil dette medføre reduserte kostnader i forbindelse med behandling av denne pasientgruppen.

Autoimmunity is ranked as one of the most common causes of morbidity in the world. Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting 1% of the worlds population and is associated with white blood cells attacking flexible joints. Hallmarks of RA are B lymphocytes producing antibodies to self-proteins and uncontrolled growth and activity of harmful T lymphocytes. Because, early detection and aggressive therapy is crucial, most RA patients receive the broad specter anti-cancer drug methotrexate (MTX), which can cause side effects and severely reduced life quality. Methods to stratify RA patients and specific drugs to avoid adverse effects are greatly needed. Dividing lymphocytes require glucose and glutamine to support synthesis of new biomass. The enzymes lactate dehydrogenase A (LDHA) is induced in proliferating cells and produce lactate from glucose even in the presence of ample amounts of oxygen in a process known as the Warburg effect. Proliferating cells also become "glutamine addicted" and metabolize glutamine by the enzyme glutaminase (GLS) to produce glutamate and alanine. The expression of LDHA and GLS and production of lactate and alanine are considered signatures of proliferating lymphocytes. Glucose metabolism also regulates transcription of genes involved in glutamine metabolism. The enzyme O-GlcNAc transferase (OGT) regulates the level of c-Myc which again regulates the levels of GLS. Inhibition of glucose and glutamine metabolism by targeting OGT and GLS activity is promising in cancer therapy. We hypothesize this applies to inflammatory cells and aim to stratify RA patients through molecular signatures and dampen and treat symptoms of RA with highly specific inhibitors to GLS and OGT. If successful, we see that patients will benefit from this research by receiving personal diagnosis followed by precise targeting of aggressive white blood cells. This will secure correct medication and reduction of adverse effects.