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.

Project Start
1996-09-30
Project End
2001-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Nutrition
Type
Schools of Allied Health Profes
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Baggott, Joseph E; Morgan, Sarah L (2009) Methotrexate catabolism to 7-hydroxymethotrexate in rheumatoid arthritis alters drug efficacy and retention and is reduced by folic acid supplementation. Arthritis Rheum 60:2257-61
Baggott, Joseph E; Morgan, Sarah L (2007) Methotrexate and erythro-9-(2-hydroxynon-3-yl) adenine therapy for rat adjuvant arthritis and the effect of methotrexate on in vivo purine metabolism. Eur J Pharm Sci 31:95-101
Morgan, Sarah L; Oster, Robert A; Lee, Jeannette Y et al. (2004) The effect of folic acid and folinic acid supplements on purine metabolism in methotrexate-treated rheumatoid arthritis. Arthritis Rheum 50:3104-11
Morgan, Sarah L; Chen, Dung-Tsa; Carlee, Jodelle et al. (2004) Effect of methotrexate therapy on bone mineral density and body composition in rat adjuvant arthritis. J Rheumatol 31:1693-7
Morgan, Sarah L; Abercrombie, William; Lee, Jeannette Y (2003) Need for precision studies at individual institutions and assessment of size of regions of interest on serial DXA scans. J Clin Densitom 6:97-101
Goodson, Tara; Morgan, Sarah L; Carlee, Jodelle R et al. (2003) The energy cost of adjuvant-induced arthritis in rats. Arthritis Rheum 48:2979-82
Fox, R I; Morgan, S L; Smith, H T et al. (2003) Combined oral cyclosporin and methotrexate therapy in patients with rheumatoid arthritis elevates methotrexate levels and reduces 7-hydroxymethotrexate levels when compared with methotrexate alone. Rheumatology (Oxford) 42:989-94
Morgan, S L; Baggott, J E; Bernreuter, W K et al. (2001) MTX affects inflammation and tissue destruction differently in the rat AA model. J Rheumatol 28:1476-81
Morgan, S L (2001) Calcium and vitamin D in osteoporosis. Rheum Dis Clin North Am 27:101-30
Baggott, J E; Morgan, S L; Sams, W M et al. (1999) Urinary adenosine and aminoimidazolecarboxamide excretion in methotrexate-treated patients with psoriasis. Arch Dermatol 135:813-7

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