Low-dose methotrexate therapy suppresses autoimmune arthritis in humans and animal models. The hypothesis of the proposed research is that the effect of MTX in the treatment of rheumatoid arthritis (RA) is due to the inhibition of aminoimidazole-carboxamide ribotide transformylase, a folate-dependent enzyme that catalyzes the last step in the de novo biosynthesis of inosine monophosphate. The resulting accumulation of aminoimidazole carboxamide riboside inhibits adenosine deaminase, therefore interfering with normal adenosine metabolism. It is well known that children with adenosine deaminase deficiency have severe-combined-immunodeficiency syndrome. This suggests that adenosine deaminase activity is key to immune competence and is associated with the mechanism of efficacy in MTX therapy of RA. Several studies indicate that supplemental folinic acid (5-formyl-tetrahydrofolate) used in large doses during low-dose MTX therapy for RA causes a flare in joint inflammation. However, supplemental folic acid (pteroylglutamic acid) does not lessen the efficacy of the therapy. It is further hypothesized that if MTX efficacy is driven by aminoimidazole-carboxamide ribotide transformylase inhibition, folic acid supplementation should not alter urinary levels of aminoimidazole carboxamide, adenosine, and deoxyadenosine, while folinic acid supplementation should prevent accumulation of these compounds. These hypotheses will be tested both in patients with RA and in Lewis rat adjuvant arthritis. Objectives include: A) to determine if the dose of MTX which is clinically optimal in the treatment of Lewis rats interferes with normal adenosine metabolism; B) to determine the effectiveness of drugs which interfere with adenosine metabolism in Lewis rat adjuvant arthritis; and C) to determine whether supplemental folic acid and folinic acid during MTX therapy normalize adenosine metabolism in patients with RA. The information obtained from the proposed research will enhance the understanding of the biochemical action of antifolates/antimetabolites that are effective in the treatment of human and animal arthritis.
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