What is the use of Methotrexate (MTX)?

From the Guidelines

Methotrexate should be started at a dose of 15 mg/week orally, escalating with 5 mg/month to 25–30 mg/week, or the highest tolerable dose, with a subsequent switch to subcutaneous administration in the case of an insufficient response, as this approach has been shown to be effective in treating rheumatoid arthritis 1. When using methotrexate, it is essential to consider the following key points:

• Methotrexate is a disease-modifying antirheumatic drug (DMARD) of first choice in the treatment of rheumatoid arthritis (RA) and is also used in other systemic rheumatic disorders 1.
• For autoimmune conditions, methotrexate is usually started at a lower dose and gradually increased as needed, with folic acid supplementation recommended to reduce side effects.
• The medication can be administered orally or by injection, with the injectable form sometimes better tolerated.
• Regular monitoring is essential, including baseline and periodic blood tests to check liver function, complete blood count, and kidney function.
• Common side effects include nausea, fatigue, mouth sores, and hair thinning, while serious concerns include liver toxicity, lung inflammation, and bone marrow suppression.
• Patients should avoid alcohol, limit sun exposure, and use reliable contraception as methotrexate can cause birth defects.
• Methotrexate may also be used in the treatment of psoriatic arthritis, although the evidence is limited to small controlled trials 1.
• In the management of inflammatory bowel disease, methotrexate should not be used as monotherapy for induction of remission, but may be used in patients failing to respond to corticosteroids, with subcutaneous administration preferred over oral due to better bioavailability 1.

From the FDA Drug Label

Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. Methotrexate is also indicated in the treatment of meningeal leukemia. Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas Methotrexate in high doses followed by leucovorin rescue in combination with other chemotherapeutic agents is effective in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who have undergone surgical resection or amputation for the primary tumor Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy Methotrexate is indicated in the management of selected adults with severe, active rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis

Methotrexate is used to treat various neoplastic diseases, including:

• Gestational choriocarcinoma
• Chorioadenoma destruens
• Hydatidiform mole
• Meningeal leukemia
• Breast cancer
• Epidermoid cancers of the head and neck
• Advanced mycosis fungoides (cutaneous T cell lymphoma)
• Lung cancer
• Non-Hodgkin’s lymphomas
• Non-metastatic osteosarcoma It is also used to treat severe psoriasis and rheumatoid arthritis 2.

From the Research

Methotrexate Overview

• Methotrexate (MTX) is a first-line antirheumatic drug used to treat severe and persistent rheumatoid arthritis (RA) and various malignant disorders 3.
• MTX is eliminated via the kidneys and can produce toxicity and side effects such as bone marrow suppression, pulmonary toxicity, nephrotoxicity, hematologic toxicity, and an increased risk of infections 3.

Methotrexate Toxicity and Side Effects

• Higher doses of MTX (high-dose MTX, defined as doses of 500 mg/m2 or greater) can produce toxicity and side effects 3.
• Leucovorin is highly beneficial in preventing myelosuppression, gastric toxicity, and neurotoxic effects after high-dose MTX therapy 3.
• Folinic acid is the preferred antidote for MTX poisoning, and glucarpidase has been licensed for the treatment of high plasma MTX levels in patients with compromised renal function 3.

Monitoring Liver Toxicity

• The American College of Rheumatology recommends obtaining liver blood tests, hepatitis B and C serologic studies, and other standard tests prior to starting treatment with MTX 4.
• Routine surveillance liver biopsies are not recommended for RA patients receiving traditional doses of MTX, but a biopsy should be performed if a patient develops persistent abnormalities on liver blood tests 4.
• Methotrexate can worsen the course of non-alcoholic fatty liver disease (NAFLD), and patients with NAFLD are at increased risk for methotrexate hepatotoxicity 5.

Methotrexate Use in Rheumatoid Arthritis

• Methotrexate use in rheumatoid arthritis is associated with few clinically significant liver function test abnormalities 6.
• Consideration may be given to revising the current MTX monitoring guidelines in the direction of less frequent monitoring, especially in patients with no risk factors for liver disease 6.
• Methotrexate is a key component of the treatment of inflammatory rheumatic diseases and the mainstay of therapy in rheumatoid arthritis 5.

Mechanism of Action

• The anti-inflammatory mechanism-of-action of low-dose MTX is not fully understood, but it is suggested that MTX acts as an inhibitor of JAK/STAT pathway activity 7.
• The JAK/STAT pathway is central to both the inflammatory and immune systems and is a pathway already targeted by other RA treatments 7.