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Antifolate Effectiveness in Arthritis

This study has been completed.
Information provided by (Responsible Party):
Sarah Morgan, MD, University of Alabama at Birmingham Identifier:
First received: November 3, 1999
Last updated: June 7, 2013
Last verified: June 2013

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.

Condition Intervention Phase
Rheumatoid Arthritis
Adjuvant Arthritis
Drug: Methotrexate
Dietary Supplement: Folinic acid
Dietary Supplement: Folic acid
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Diagnostic
Official Title: Mechanisms of Antifolate Efficacy in Arthritis

Resource links provided by NLM:

Further study details as provided by University of Alabama at Birmingham:

Primary Outcome Measures:
  • 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. [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Determine the effect of folic acid and folinic acid on urinary adenosine excretion in individuals with rheumatoid arthritis treated with low dose methotrexate [ Designated as safety issue: No ]
  • Correlate disease activity with urinary AICA and adenosine levels [ Designated as safety issue: No ]

Enrollment: 40
Study Start Date: September 1996
Study Completion Date: August 2002
Primary Completion Date: August 2002 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1 - Folinic acid
Subjects receiving Methotrexate for 6 weeks and 5 mg of Folinic acid daily for 1 week.
Drug: Methotrexate Dietary Supplement: Folinic acid
Experimental: Group 2: Folic acid
Subjects receiving Methotrexate for 6 weeks and 5 mg of Folic acid daily for 1 week.
Drug: Methotrexate Dietary Supplement: Folic acid

Detailed Description:

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.


Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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.
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Please refer to this study by its identifier: NCT00000395

United States, Alabama
The University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
Sponsors and Collaborators
University of Alabama at Birmingham
Principal Investigator: Sarah L. Morgan, M.D., R.D. University of Alabama Department of Nutrition Sciences
  More Information

Morgan SL, Baggott JE, Alarcon GS. Methotrexate in rheumatoid arthritis. Folate supplementation should always be given. BioDrugs. 8: 164-175, 1997.

Responsible Party: Sarah Morgan, MD, Principal Investigator, University of Alabama at Birmingham Identifier: NCT00000395     History of Changes
Other Study ID Numbers: R29 AR42674, R29AR042674, NIAMS-035
Study First Received: November 3, 1999
Last Updated: June 7, 2013
Health Authority: United States: Federal Government

Keywords provided by University of Alabama at Birmingham:
Rheumatoid arthritis
Lewis rat adjuvant arthritis
Antifolate efficacy
Adenosine metabolism
Methotrexate therapy
Skeletal disorder
Dietary supplement
Antiarthritic agent
Folic acid

Additional relevant MeSH terms:
Arthritis, Experimental
Arthritis, Rheumatoid
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Folic Acid
Folic Acid Antagonists
Vitamin B Complex
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Growth Substances
Hematologic Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action processed this record on February 25, 2015