Antifolate Effectiveness in Arthritis

Phase 2

Completed

• Conditions: Adjuvant Arthritis; Rheumatoid Arthritis
• Interventions: Drug: Methotrexate; Dietary Supplement: Folinic acid; Dietary Supplement: Folic acid

• Registration Number: NCT00000395
• Lead Sponsor: University of Alabama at Birmingham

Brief 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.

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.

Study Timeline

• Study Start: 1996-09
• Study First Submitted: 1999-11-03
• Study First Submitted QC: 1999-11-03
• Study First Posted: 1999-11-04
• Primary Completion: 2002-08
• Study Completion: 2002-08
• Status Verified: 2013-06
• Last Update Submitted: 2016-12-14
• Last Update Posted: 2016-12-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 40

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

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Group 1 - Folinic acid	Folinic acid	Subjects receiving Methotrexate for 6 weeks and 5 mg of Folinic acid daily for 1 week.
Group 2: Folic acid	Folic acid	Subjects receiving Methotrexate for 6 weeks and 5 mg of Folic acid daily for 1 week.
Group 1 - Folinic acid	Methotrexate	Subjects receiving Methotrexate for 6 weeks and 5 mg of Folinic acid daily for 1 week.
Group 2: Folic acid	Methotrexate	Subjects receiving Methotrexate for 6 weeks and 5 mg of Folic acid daily for 1 week.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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

Trial Locations

Locations (1)

The University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States