title: Methotrexate and leflunomide: biochemical basis for combination therapy in the treatment of rheumatoid arthritis.
abstract: OBJECTIVE
  Methotrexate is currently one of the most widely prescribed disease-modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA). Combination therapy of methotrexate with other DMARDs increases the clinical success of low-dose methotrexate treatment. Leflunomide is a new DMARD that may have a high potential for success in combination therapy with methotrexate. This review compares the mode of action of methotrexate and leflunomide and speculates on how this contributes to therapeutic efficacy in RA when these agents are used singly or in combination.
  
  
  METHODS
  A literature review of the biochemical mechanisms considered to be the basis for the therapeutic efficacy of methotrexate and leflunomide in treating RA is presented.
  
  
  RESULTS
  Low-dose methotrexate inhibits cytokine production, purine biosynthesis, and, in an animal model, causes the release of adenosine, a potent antiinflammatory agent. Leflunomide, through inhibition of de novo pyrimidine biosynthesis, can regulate lymphocyte proliferation.
  
  
  CONCLUSIONS
  The biochemical mechanisms underlying the therapeutic efficacy of low-dose methotrexate and leflunomide in the treatment of RA are quite different. The potentially complementary mechanisms of action of these two effective DMARDs should provide a rationale for their use in combination therapy for patients whose condition no longer responds to methotrexate alone.
authors.affiliation: Department of Medicine, The Albany Medical College, NY 12208-3479, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Kremer
mesh_terms: D000241:Adenosine / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D007555:Isoxazoles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000077339:Leflunomide; D008214:Lymphocytes / Q000187:drug effects; D008727:Methotrexate / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D015394:Molecular Structure; D011687:Purines / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D011687:Purines; D011743:Pyrimidines; D000077339:Leflunomide; D000241:Adenosine; D008727:Methotrexate