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Mechanisms of Antifolate Efficacy in Arthritis

Phase 2
18 Years
85 Years
Not Enrolling
Rheumatoid Arthritis, Adjuvant Arthritis

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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

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

Inclusion Criteria:

- Individuals starting methotrexate for rheumatoid arthritis.

- Study subjects should not currently be taking folic acid-containing vitamins.

Exclusion Criteria:

- Cancer, renal, or liver disease.

- Previous use of methotrexate within the past 6 months or current use of folic
acid-containing supplements.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Diagnostic

Outcome Measure:

Determine the effect of Folic acid and Folinic acid on urinary 5-amino=imidazole-4-carboxaminde (AICA in individuals with rheumatoid arthritis treated with low dose methotrexate.

Safety Issue:


Principal Investigator

Sarah L. Morgan, M.D., R.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Alabama Department of Nutrition Sciences


United States: Federal Government

Study ID:

R29 AR42674



Start Date:

September 1996

Completion Date:

August 2002

Related Keywords:

  • Rheumatoid Arthritis
  • Adjuvant Arthritis
  • Rheumatoid arthritis
  • Lewis rat adjuvant arthritis
  • Antifolate efficacy
  • Autoimmunity
  • Adenosine metabolism
  • Methotrexate therapy
  • Skeletal disorder
  • Dietary supplement
  • Antiarthritic agent
  • Folic acid
  • Arthritis
  • Arthritis, Experimental
  • Arthritis, Rheumatoid



The University of Alabama at Birmingham Birmingham, Alabama  35294