Methotrexate is a member of the antimetabolite drug class. Drugs in this classification, including methotrexate, azathioprine, mycophenolate mofetil, and leflunomide, exert anti-inflammatory activity via their effect on DNA synthesis, which suppresses proliferation of rapidly dividing cells, including leukocytes, as well as by other mechanisms which are incompletely understood. Methotrexate has the longest track record for safety and efficacy of all the antimetabolites both in children and in adults, and this, combined with its relatively low cost and the convenience of once-weekly administration, makes it the first-line steroid-sparing immunosuppressive for many ocular and systemic inflammatory diseases. Its use was first described in the 1940s for treatment of malignant diseases, but it was found shortly thereafter to be useful for inflammatory diseases, including rheumatoid arthritis, for which it gained FDA approval in 1988. Although methotrexate, like all other commercially available immunosuppressives as of this writing, is not FDA approved for the treatment of uveitis, it is FDA approved for two diseases associated with uveitis, psoriatic arthritis and juvenile idiopathic arthritis. The off-label use of methotrexate for uveitis was first reported in 1965 and has been commonly reported since, both as monotherapy and in combination with other immunosuppressives. A recent survey of practice patterns among uveitis specialists cited methotrexate as the most commonly prescribed initial corticosteroid-sparing agent for all anatomic locations of uveitis and the most preferred agent for anterior uveitis.
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