Saara Rawn MD/PhD, Raj Carmona MBBS FRCPC

INDICATIONS  (including off-label uses)

Rheumatoid Arthritis, Psoriasis, polyarticular Juvenile Onset Idiopathic Arthritis

Off-Label Uses: Psoriatic Arthritis and other seronegative spondyloarthropathies with peripheral arthritis, SLE, Uveitis, Polymyositis / Dermatomyositis, Vasculitis, Crohn’s Disease


Usually 15 mg PO/SC weekly for 2 weeks, then increase to 20 mg PO/SC weekly.  Consider lower starting/maintenance dose and slower titration in elderly patients or those with significant comorbidities.  Maximum dose: 25 mg PO/SC weekly.  Onset of action is relatively slow and can take 6-8 weeks to see benefit.

Folic Acid 5 mg PO weekly (on day after methotrexate): to reduce hematologic, gastrointestinal, and hepatic adverse events related to methotrexate.


Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; avoid or use with caution in patients with impaired hepatic function or pre-existing hepatic damage.

Renal Impairment  
CrCl 10 to 50 mL/minute: administer 50% of dose
CrCl <10 mL/minute: avoid use
Intermittent hemodialysis: Administer 50% of dose (post dialysis)


Baseline: CBC, Cr, LFTS (AST, ALT, ALP, GGT, Bilirubin, Albumin), Hepatitis B/C serology.  Consider CXR.

Every 1-2 months: CBC, Cr, AST, ALT, Albumin


Pregnant or at risk of becoming pregnant (counsel female patients!), hypersensitivity to methotrexate, alcoholism, alcoholic liver disease or other chronic liver disease, immunodeficiency syndromes (overt or laboratory evidence); pre-existing blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)


GI side-effects most common (10%): anorexia, nausea, vomiting, diarrhea, weight loss, oral ulcers

General: malaise, fatigue, dizziness

Hepatoxicity: elevated transaminases (up to 15%), cirrhosis (generally only after prolonged use)

Hematologic (1-3%): anemia, leucopenia, thrombocytopenia, pancytopenia

Respiratory: rarely, methotrexate can cause interstitial pneumonitis (fever, cough, SOB)

Dermatology: rarely, can cause severe skin reactions  

Methotrexate can cause an elevation of liver enzymes, so patient should be advised to abstain from alcohol.  It is a teratogen and effective birth control should be discussed in women of child-bearing age.  Methotrexate should be held in the case of serious infections.


Methotrexate has been reported to cause fetal death and/or congenital abnormalities. If used in women of childbearing potential, effective contraception is necessary.  Pregnant women should not receive methotrexate. Studies in animals and pregnant women have shown evidence of fetal abnormalities.  The manufacturer classifies methotrexate as pregnancy category X (for psoriasis or RA).


Methotrexate is a folate antimetabolite that inhibits DNA synthesis, repair, and cellular replication. It acts intra-cellular by irreversibly binding to and inhibiting dihydrofolate reductase, inhibiting the formation of reduced folates, and thymidylate synthetase, resulting in inhibition of purine and thymidylic acid synthesis.  Methotrexate is cell cycle specific for the S phase of the cycle. Actively proliferative tissues are more susceptible to the effects of methotrexate.

Low amounts of methotrexate are excreted into breast milk. Due to the potential risk of harm to the breast-feeding infant, use is contraindicated in nursing mothers.

SUMMARY OF EVIDENCE (in development)

Rheumatoid Arthritis

Psoriatic Arthritis