This study looks at how the arthritis drug methotrexate works in low doses to treat
rheumatoid arthritis. (High doses of methotrexate are used to treat some types of cancer.)
Methotrexate blocks the action of the B-vitamin known as folic acid. We are studying the
biochemical reactions affected by this vitamin because we think that blocking many of these
reactions may be necessary for methotrexate to work in treating rheumatoid arthritis.
Through these studies, we hope to gain a better understanding of how this drug and related
drugs work as treatments for arthritis.
Low-dose methotrexate therapy suppresses autoimmune arthritis in human and animal models. We
hypothesize that the effect of methotrexate in the treatment of rheumatoid arthritis 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 methotrexate therapy of rheumatoid arthritis.
Several studies indicate that supplemental folinic acid (5-formyltetrahydrofolate) used in
large doses during low-dose methotrexate therapy for rheumatoid arthritis causes a flare in
joint inflammation. However, supplemental folic acid (pteroylglutamic acid) does not lessen
the efficacy of the therapy. We further hypothesize that if methotrexate 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 the accumulation of these
We will test our hypotheses both in people with rheumatoid arthritis and in Lewis rat
adjuvant arthritis. Our objectives include: (1) determining if the dose level of
methotrexate that is clinically optimal in the treatment of Lewis rat adjuvant arthritis
interferes with normal adenosine metabolism; (2) determining the effectiveness of drugs that
interfere with adenosine metabolism (deoxycoformycin, aminoimidazole carboxamide, and
aminoimidazole carboxamide with a suboptimal dose of methotrexate) in Lewis rat adjuvant
arthritis; and (3) determining whether supplemental folic acid and folinic acid during
methotrexate therapy normalize adenosine metabolism in patients with rheumatoid arthritis.
The information we obtain will enhance the understanding of the biochemical action of
antifolates/antimetabolites that are effective in the treatment of human and animal
- Individuals starting methotrexate for rheumatoid arthritis.
- Study subjects should not currently be taking folic acid-containing vitamins.
- Cancer, renal, or liver disease.
- Previous use of methotrexate within the past 6 months or current use of folic
Sarah L. Morgan, M.D., R.D.
University of Alabama Department of Nutrition Sciences