Methotrexate has the potential of causing various adverse events with higher doses or may be ineffective if given at inappropriate doses. Here we present 11 important points to keep in mind when prescribing Methotrexate in order to ensure better efficacy and safety.

Methotrexate is a less toxic derivative of Aminopterin, an antifolate chemotherapeutic. It was discovered in 1950 by Sidney Farber; father of modern chemotherapy for the treatment of metastatic solid and haematological cancers.

Similar to various other chemotherapeutic agents; methotrexate was also found to be efficacious in various rheumatological conditions. In the 1980s Rex Hoffmeister demonstrated its role in rheumatoid arthritis which was later backed by a large clinical trial conducted by Lederle Labs; the originator of methotrexate. Since then methotrexate has become the backbone for the management of various rheumatological disorders.

Methotrexate prescription- 11 points to keep in mind

1. Anti-inflammatory effects: They are mainly mediated by inhibiting dihydrofolate reductase involved in de novo synthesis of purine and pyrimidine, and partly by inhibiting AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) transformylase and thereby adenosine mediated anti-inflammatory action.
2. Dosage: The dosage used in rheumatology is very low (maximum 25 mg per week) in contrast to the high dose used in the management of malignancies. It is given through oral, intravenous, intramuscular, subcutaneous and intrathecal routes. In rheumatology, oral as well as intramuscular or subcutaneous routes are preferred. Bioavailability is comparable to the parenteral route for low oral doses (<10-15 mg per week) but variable for higher doses (>15 mg per week) and absorption may decrease if taken along with food. Hence to increase bioavailability it is recommended to split the dose and not to be taken along with food.
3. Half-life: It is 6 hours. But inside the cell, it converts from methotrexate monoglutamate to polyglutamate which has a long-lasting half-life.
4. Metabolism: It takes place mainly in the liver and elimination is via the kidney. Along with regular monitoring of liver enzymes, blood counts are recommended. The risk of fibrosis increases with persistent transaminitis. Risk of toxicity increases in patients with chronic kidney disease; hence it is recommended to avoid eGFR less than 30 mmol/L or a reduced dose in eGFR less than 45 mmol/L.
5. Adverse events: The dosage used for the management of rheumatological conditions are low; hence chances of serious adverse events are quite rare. Common adverse events range from G.I toxicity (dyspepsia, diarrhoea, oral ulcers), hepatotoxicity (transaminitis, rarely fibrosis and cirrhosis), bone marrow suppression (cytopenias), nodulosis, and rarely it can cause pulmonary toxicity. Malignancies have not been proven secondary to low-dose methotrexate.
6. Dosage considerations: Methotrexate causes bone marrow suppression by interfering with folic acid metabolism; it should be avoided if TLC <4000/ cu.mm or platelet counts of less than 1 lakh/ cu.mm. If haemoglobin is less than 10 mg/dl; methotrexate should be given in a low dose or avoided in severe anaemia. Always other causes of anaemia, cytopenia should be sought and managed aggressively.
7. When to avoid: Methotrexate is a teratogenic agent, should be avoided in pregnant women or stopped three months before conception. It should be avoided in lactating mothers. Evidence states it doesn't affect fertility in males and females. There is no recommendation of stopping it in males planning for conception.
8. Toxicity: Methotrexate toxicity is uncommon with rheumatological doses. The reason might be a higher cumulative dose or incorrectly administered a higher dose. Toxicity can present with mucositis, transaminitis, bi or pancytopenia. Management of methotrexate toxicity is by folinic acid or leucovorin rescue along with a supportive measure of hydration, alkalinising urine, blood product transfusions, G-CSF, GM CSF or eltrombopag supplementation, broad-spectrum antibiotic coverage etc. Sometimes glucarpidase is also used; it inactivates extracellular methotrexate.
9. Serious side effects: Rarely, it can lead to progressive pneumonitis and can cause pulmonary fibrosis. Mostly seen acutely within a few days of starting methotrexate and not associated with dosage. Risk factors are pre-existing lung disease or kidney disease or male sex or age more than 60 years. Radiologically it presents mostly as NSIP ILD or organising pneumonia. Prognosis is better, management is stopping the medication and trial of glucocorticoids.
10. Recommendation for monitoring: Complete blood count, liver enzymes, serum creatinine initially 6 - 8 weekly followed by 3-monthly and later 6-monthly.
11. Biomarker for monitoring: There is no specific recommended biomarker for monitoring methotrexate.
    1. Indirect measure- Elevation of mean corpuscular volume by 5 from baseline in initial 3 months of starting methotrexate
    2. Serum level of methotrexate polyglutamate

Although Methotrexate was discovered as an anticancer agent, it also works very well and has become the cornerstone in the management of systemic autoimmune conditions. It is now the comparator molecule for new drug development. Over time, newer mechanisms have been discovered as we use and study Methotrexate and other drugs. It requires monitoring for long term use and secondary malignancy has not been associated with it in low doses.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author is a practising Rheumatologist from Bangalore.