From EyeWiki


Corticosteroids have been a mainstay of treatment for noninfectious uveitis; however, there are serious side effects associated with their long-term use, and this has led to the utilization of alternate systemic noncorticosteroid immunomodulatory agents.[1] Immunomodulatory agents include the categories of antimetabolites (azathioprine, methotrexate, mycophenolate mofetil), T-cell inhibitors (cyclosporine, tacrolimus), alkylating agents (cyclophosphamide, chlorambucil), and biologic agents (adalimumab, infliximab, rituximab).[2] Of these, methotrexate is one of the most commonly used in ocular inflammatory disease.


In the 1940s, folic acid antagonists were found to induce remission in children with acute leukemia.[3] This discovery paved the way to search for novel folate antagonists and the advent of modern chemotherapy.[4] Further research in the inhibition of folic acid metabolism led to the isolation and characterization of the enzyme dihydrofolate reductase (DHFR), which subsequently led to the development of methotrexate. Since then, methotrexate has been evaluated in the treatment of a variety of neoplastic as well as systemic inflammatory conditions. The use of methotrexate in ocular inflammatory disease has been reported since the 1960s.[5]

Mechanism of Action

Methotrexate inhibits dihydrofolate reductase, thus interfering with DNA synthesis, repair, and cellular replication.[6] Methotrexate reduces the rate of cell proliferation, increases the rate of T-cell apoptosis, increases endogenous concentrations of adenosine, and alters the production of cytokines and humoral responses. [7]    

Indications and Uses

FDA-Labeled Indications (per IBM Micromedex Drug Reference)

  • Acute lymphoid leukemia
  • Breast cancer
  • Leukemia
  • Gestational trophoblastic neoplasia
  • Head and neck cancer
  • Lung cancer
  • Mycosis fungoides
  • Non-Hodgkin's lymphoma
  • Osteosarcoma
  • Polyarticular juvenile idiopathic arthritis
  • Psoriasis
  • Rheumatoid arthritis

Non-FDA Labeled Indications (per IBM Micromedex Drug Reference)

  • Acute myeloid leukemia
  • Asthma
  • Bullous pemphigoid
  • Carcinoma of bladder
  • Carcinoma of penis
  • Crohn's disease
  • Cutaneous lupus erythematosus
  • Ectopic pregnancy
  • Felty's syndrome
  • Graft versus host disease
  • Granulomatosis with polyangiitis
  • Hodgkin's disease
  • Malignant epithelial tumor of ovary
  • Malignant lymphoma
  • Malignant lymphoma of the eye region
  • Polyarteritis nodosa
  • Primary central nervous system lymphoma
  • Psoriasis
  • Sarcoidosis
  • Soft tissue sarcoma
  • Systemic lupus erythematosus
  • Termination of pregnancy
  • Urothelial carcinoma
  • Uveitis

Dosing and Administration

MTX formulations can be oral, subcutaneous, intramuscular, intravenous, intrathecal, and intravitreal. High systemic doses should be accompanied by leucovorin (folinic acid) to reduce potential toxicity (known as leucovorin rescue). Methotrexate therapy is usually initiated as a 7.5 mg oral dose given once a week, and it can be increased up to 25 mg given weekly depending on the response. Parenteral dosing results in greater bioavailability.[2]

Safety and Adverse Effects (per IBM Micromedex Drug Reference)


  • Patients who are pregnant (methotrexate is teratogenic)
  • Patients who are breastfeeding
  • Patients with known hypersensitivity to methotrexate
  • Patients with alcoholism, alcoholic liver disease, or other chronic liver disease
  • Patients with preexisting blood dyscrasias
  • Patients with immunodeficiency syndromes

Common Adverse Effects

  • Dermatologic: Alopecia (0.5% to 10% ), Photosensitivity (3% to 10% ), Rash (0.2% to 10% )
  • Gastrointestinal: Diarrhea (1% to less than 3% ), Nausea and vomiting (10% )
  • Hematologic: Leukopenia (1% to less than 3% ), Thrombocytopenia (3% to 10% )
  • Neurologic: Dizziness (0.2% to less than 3% )
  • Other: Fatigue, Fever, Malaise, Shivering

Serious Adverse Effects

  • Cardiovascular: Pericardial effusion, Thromboembolic disorder
  • Dermatologic: Toxic epidermal necrolysis
  • Gastrointestinal: Stomatitis (Polyarticular juvenile idiopathic arthritis; 2%; rheumatoid arthritis, 3% to less than 10% )
  • Hematologic: Malignant lymphoma, Myelosuppression, Pancytopenia (1% to less than 3% )
  • Hepatic: Cirrhosis of liver, Hepatic fibrosis, Hepatitis, Hepatotoxicity, Liver failure
  • Neurologic: Encephalopathy, Neurotoxicity, Seizure
  • Renal: Nephrotoxicity
  • Respiratory: Interstitial pneumonia (0.1% to 1.2% .), Pneumonitis, Interstitial (1% )
  • Other: Tumor lysis syndrome

Use of Methotrexate in Ocular Inflammatory Diseases

Several studies have shown that methotrexate is effective in the treatment of ocular inflammatory disease in general, as well as in ocular inflammation associated with juvenile idiopathic arthritis, sarcoidosis, ocular cicatricial pemphigoid, rheumatoid arthritis, and sympathetic ophthalmia.[8][9][10][11][12] Corticosteroid-sparing success after six months of methotrexate therapy was achieved in 46.1%, 41.3%, and 20.7% of patients with anterior, intermediate, and posterior or panuveitis, respectively.[8] This increased after 12 months of methotrexate therapy to 62.6%, 68.8%, and 39.1% for these anatomic locations, respectively. Gangaputra et. al. summarized that methotrexate is moderately effective in achieving corticosteroid-sparing success (i.e. prednisone dosages of ≤10 mg/day) with sustained control of ocular inflammation.[8] Other studies have also demonstrated improvement in anterior chamber cells, vitreous cells, and vitreous haze with the use of antimetabolites such as methotrexate to achieve corticosteroid-sparing control of ocular inflammation.[13]

Patient Assistance and Education


  1. Dick AD, Rosenbaum JT, Al-Dhibi HA, Belfort R Jr, Brézin AP, Chee SP, Davis JL, Ramanan AV, Sonoda KH, Carreño E, Nascimento H, Salah S, Salek S, Siak J, Steeples L; Fundamentals of Care for Uveitis International Consensus Group. Guidance on Noncorticosteroid Systemic Immunomodulatory Therapy in Noninfectious Uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative. Ophthalmology. 2018 May;125(5):757-773.
  2. 2.0 2.1 American Academy of Ophthalmology. Basic and Clinical Science Course Uveitis and Ocular Inflammation. American Academy of Ophthalmology; 2021-2022.
  3. Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med. 1948 Jun 3;238(23):787-93.
  4. Bertino, J.R. (2000). Methotrexate: historical aspects. In: Cronstein, B.N., Bertino, J.R. (eds) Methotrexate. Milestones in Drug Therapy. Birkhäuser, Basel.
  5. Wong VG, Hersh EM. Methotrexate in the therapy of cyclitis. Trans Am Acad Ophthalmol Otolaryngol. 1965;69:279–93.
  6. IBM Micromedex Drug Reference, Methotrexate, Accessed from 1/21/23.
  7. Wessels JA, Huizinga TW, Guchelaar HJ. Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2008;47:249–55.
  8. 8.0 8.1 8.2 Gangaputra S, Newcomb CW, Liesegang TL, Kaçmaz RO, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Suhler EB, Thorne JE, Foster CS, Kempen JH; Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Methotrexate for ocular inflammatory diseases. Ophthalmology. 2009 Nov;116(11):2188-98.
  9. Samson CM, Waheed N, Baltatzis S, Foster CS. Methotrexate therapy for chronic noninfectious uveitis: analysis of a case series of 160 patients. Ophthalmology. 2001 Jun;108(6):1134-9.
  10. Shetty AK, Zganjar BE, Ellis GS, Jr, et al. Low-dose methotrexate in the treatment of severe juvenile rheumatoid arthritis and sarcoid iritis. J Pediatr Ophthalmol Strabismus. 1999;36:125–8.
  11. McCluskey P, Chang JH, Singh R, Wakefield D. Methotrexate therapy for ocular cicatricial pemphigoid. Ophthalmology. 2004;111:796–801.
  12. Weinblatt ME, Coblyn JS, Fox DA, et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med. 1985;312:818–22.
  13. Rathinam SR, Babu M, Thundikandy R et al. A randomized clinical trial comparing methotrexate and mycophenolate mofetil for noninfectious uveitis. Ophthalmology, 121(10), 1863–1870 (2014).
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