Trial Information

Mechanisms of Antifolate Efficacy in 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
compounds.

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
arthritis.