Methotrexate

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Article initiated by:

Jorge Meira

All contributors:

Andrew G. Meador, Brian T. Fowler, MD, Stephen C. Dryden, M.D., Luís Figueira, Fernando Falcao-Reis, Barbara Smith, Ghazala D. O'Keefe, MD, Stephen C. Dryden, M.D., Jorge Meira, Homaira Ayesha Hossain, MD

Assigned editor:

Homaira Ayesha Hossain, MD

Review:

Assigned status Up to Date

 by Homaira Ayesha Hossain, MD on June 30, 2024.

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Contributing Editors:	add

Methotrexate for the Treatment of Uveitis

Overview

The goal of treatment of noninfectious uveitis is to control inflammation and to prevent the devastating sequelae of chronic inflammation, such as loss of vision. Initial treatment of noninfectious uveitis is typically with topical, periocular, intraocular, or systemic corticosteroids. While corticosteroids have been a mainstay of treatment for noninfectious uveitis, there are serious side effects associated with their long-term use, and this has led to the utilization of alternate systemic noncorticosteroid immunomodulatory agents. Immunomodulatory agents include the categories of antimetabolites (azathioprine, methotrexate, mycophenolate mofetil), T-cell inhibitors (cyclosporine, tacrolimus), biologic agents (adalimumab, infliximab, rituximab), and alkylating agents (cyclophosphamide, chlorambucil). Of these, methotrexate is one of the most commonly used in ocular inflammatory disease.

History

In the 1940s, folic acid antagonists were found to induce remission in children with acute leukemia. This discovery paved the way to search for novel folate antagonists and the advent of modern chemotherapy. 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.

Mechanism of Action

Methotrexate inhibits dihydrofolate reductase, thus interfering with DNA synthesis, repair, and cellular replication. 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.     

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

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. 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. 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. 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.

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.

Safety and Adverse Effects (per IBM Micromedex Drug Reference)

Contraindications

• 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

Patient Assistance and Education

http://www.rasuvo.com/patient-resources/prescription-savings-2/

http://www.rasuvo.com/patient-resources/methotrexate-disposal/

https://www.otrexup.com/patients-caregivers/otrexup-totalcare-patient/co-pay-card/

https://www.otrexup.com/patients-caregivers/otrexup-totalcare-patient/

https://www.astrazeneca-us.com/medicines/Affordability.html

http://xatmep.com/co-pay-and-reimbursement/