Antifolate Effectiveness in Arthritis

Study Overview
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Brief Summary
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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
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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.

Official Title
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Mechanisms of Antifolate Efficacy in Arthritis

Conditions
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Rheumatoid Arthritis, Adjuvant Arthritis

Intervention / Treatment
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* Drug: Methotrexate
* Dietary Supplement: Folinic acid
* Dietary Supplement: Folic acid


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - Folinic acid<br>Subjects receiving Methotrexate for 6 weeks and 5 mg of Folinic acid daily for 1 week. | Drug: Methotrexate<br> <br> Dietary Supplement: Folinic acid<br> <br> |
| Experimental: Group 2: Folic acid<br>Subjects receiving Methotrexate for 6 weeks and 5 mg of Folic acid daily for 1 week. | Drug: Methotrexate<br> <br> Dietary Supplement: Folic acid<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid arthritis, Lewis rat adjuvant arthritis, Antifolate efficacy, Autoimmunity, Adenosine metabolism, Methotrexate therapy, Skeletal disorder, Dietary supplement, Antiarthritic agent, Folic acid