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Antifolate Effectiveness in Arthritis

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00000395
First Posted: November 4, 1999
Last Update Posted: December 16, 2016
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Office of Dietary Supplements (ODS)
Information provided by (Responsible Party):
University of Alabama at Birmingham
  Purpose
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
Intervention Model: Crossover Assignment
Masking: Double (Participant, 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.

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
  • Correlate disease activity with urinary AICA and adenosine levels

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.

  Eligibility

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00000395


Locations
United States, Alabama
The University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
Sponsors and Collaborators
University of Alabama at Birmingham
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Office of Dietary Supplements (ODS)
Investigators
Principal Investigator: Sarah L. Morgan, M.D., R.D. University of Alabama Department of Nutrition Sciences
  More Information

Publications:
Morgan SL, Oster RA, Lee JY, Alarcón GS, Baggott JE. The effect of folic acid and folinic acid supplements on purine metabolism in methotrexate-treated rheumatoid arthritis. Arthritis Rheum. 2004 Oct;50(10):3104-11.
Morgan SL, Baggott JE, Vaughn WH, Young PK, Austin JV, Krumdieck CL, Alarcón GS. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 1990 Jan;33(1):9-18.
Morgan SL, Baggott JE, Refsum H, Ueland PM. Homocysteine levels in patients with rheumatoid arthritis treated with low-dose methotrexate. Clin Pharmacol Ther. 1991 Nov;50(5 Pt 1):547-56.
Morgan SL, Hine RJ, Vaughn WH, Brown A. Dietary intake and circulating vitamin levels of rheumatoid arthritis patients treated with methotrexate. Arthritis Care Res. 1993 Mar;6(1):4-10.
Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, Koopman WJ, Krumdieck CL, Alarcón GS. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med. 1994 Dec 1;121(11):833-41.
Morgan SL, Anderson AM, Hood SM, Matthews PA, Lee JY, Alarcón GS. Nutrient intake patterns, body mass index, and vitamin levels in patients with rheumatoid arthritis. Arthritis Care Res. 1997 Feb;10(1):9-17.
Morgan SL, Baggott JE, Alarcón GS. Methotrexate in rheumatoid arthritis: folate supplementation should always be given. BioDrugs. 1997 Sep;8(3):164-75.
Morgan SL, Baggott JE, Lee JY, Alarcón GS. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. J Rheumatol. 1998 Mar;25(3):441-6.
Baggott JE, Morgan SL, Koopman WJ. The effect of methotrexate and 7-hydroxymethotrexate on rat adjuvant arthritis and on urinary aminoimidazole carboxamide excretion. Arthritis Rheum. 1998 Aug;41(8):1407-10.
Strand V, Morgan SL, Baggott JE, Alarcón GS. Folic acid supplementation and methotrexate efficacy: comment on articles by Schiff, Emery et al, and others. Arthritis Rheum. 2000 Nov;43(11):2615-6.
Alarcón GS, Morgan SL. Guidelines for folate supplementation in rheumatoid arthritis patients treated with methotrexate: comment on the guidelines for monitoring drug therapy. Arthritis Rheum. 1997 Feb;40(2):391; author reply 391-2.
Morgan SL, Alarcón GS, Moreland L. Improved methotrexate patient information. Arthritis Rheum. 1995 Jun;38(6):874-5.
Morgan Sl, Alarcón GS, Krumdieck CL. Folic acid supplementation during methotrexate therapy: it makes sense. J Rheumatol. 1993 Jun;20(6):929-30.

Responsible Party: University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT00000395     History of Changes
Other Study ID Numbers: R29AR042674 ( U.S. NIH Grant/Contract )
NIAMS-035
First Submitted: November 3, 1999
First Posted: November 4, 1999
Last Update Posted: December 16, 2016
Last Verified: June 2013

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

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Arthritis, Experimental
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Methotrexate
Folic Acid Antagonists
Folic Acid
Vitamin B Complex
Leucovorin
Levoleucovorin
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Hematinics


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