Antifolate Effectiveness in Arthritis

Rheumatoid Arthritis Clinical Trial

Official title:

Mechanisms of Antifolate Efficacy in Arthritis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00000395
• Other study ID #: R29AR042674
• Secondary ID: R29AR042674NIAMS
• Status: Completed
• Phase: Phase 2
• First received: November 3, 1999
• Last updated: December 14, 2016
• Start date: September 1996
• Est. completion date: August 2002

Study information

• Verified date: June 2013
• Source: University of Alabama at Birmingham
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: August 2002
• Est. primary completion date: August 2002
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 85 Years

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Adjuvant Arthritis
• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Methotrexate

Dietary Supplement:
• Folinic acid

• Folic acid

Locations

Country	Name	City	State
United States	The University of Alabama at Birmingham	Birmingham	Alabama

Sponsors (3)

Lead Sponsor	Collaborator
University of Alabama at Birmingham	National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Office of Dietary Supplements (ODS)

Country where clinical trial is conducted

United States, 

References & Publications (13)

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. — View Citation

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. — View Citation

Morgan Sl, Alarcón GS, Krumdieck CL. Folic acid supplementation during methotrexate therapy: it makes sense. J Rheumatol. 1993 Jun;20(6):929-30. — View Citation

Morgan SL, Alarcón GS, Moreland L. Improved methotrexate patient information. Arthritis Rheum. 1995 Jun;38(6):874-5. — View Citation

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. — View Citation

Morgan SL, Baggott JE, Alarcón GS. Methotrexate in rheumatoid arthritis: folate supplementation should always be given. BioDrugs. 1997 Sep;8(3):164-75. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.			No
Secondary	Determine the effect of folic acid and folinic acid on urinary adenosine excretion in individuals with rheumatoid arthritis treated with low dose methotrexate			No
Secondary	Correlate disease activity with urinary AICA and adenosine levels			No