Antifolate Effectiveness in Arthritis
Condition: Rheumatoid Arthritis; Adjuvant Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid; Arthritis, Experimental
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Methotrexate; Folinic acid; Folic acid
Intervention type(s): Drug; Dietary Supplement; Dietary Supplement
Intervention MeSH terms: Folic Acid; Leucovorin; Methotrexate; Levoleucovorin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Diagnostic
Keywords: Rheumatoid arthritis; Lewis rat adjuvant arthritis; Antifolate efficacy; Autoimmunity; Adenosine metabolism; Methotrexate therapy; Skeletal disorder; Dietary supplement; Antiarthritic agent; Folic acid