What are the adverse reactions associated with methotrexate?

Adverse Reactions to Methotrexate

Methotrexate causes a spectrum of adverse reactions ranging from common, minor gastrointestinal effects to life-threatening myelosuppression, hepatotoxicity, and pulmonary fibrosis, with the three major causes of methotrexate-related fatalities being myelosuppression (67/164 deaths), pulmonary fibrosis (30/164 deaths), and hepatotoxicity (8/164 deaths). 1

Common Adverse Reactions (Occur Frequently)

The most frequently reported adverse reactions include 2:

• Gastrointestinal effects: Nausea, vomiting, anorexia, abdominal distress, ulcerative stomatitis, diarrhea (occur in >10% of patients)
• Constitutional symptoms: Malaise, undue fatigue, chills and fever, dizziness
• Hematologic: Leukopenia
• Decreased resistance to infection

These common effects can often be minimized by administering methotrexate via intramuscular or subcutaneous injection, splitting the dose, using folate supplementation (1-5 mg daily except on methotrexate day), or taking the medication with food or at bedtime 1.

Major Life-Threatening Toxicities

Myelosuppression (Most Common Cause of Death)

Myelosuppression represents the leading cause of methotrexate-related mortality and can occur even after single doses. 1

Key risk factors for hematologic toxicity 1:

• Advanced age
• Renal impairment
• Lack of folate supplementation
• Methotrexate dosing errors
• Drug interactions (especially sulfonamides, NSAIDs, penicillins)
• Hypoalbuminemia
• Greater than moderate alcohol intake

Manifestations include anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, and agranulocytosis 2. Pancytopenia can occur 4-6 weeks after dose increases, necessitating more frequent monitoring during dose escalation 1.

Hepatotoxicity

Hepatotoxicity ranges from transient liver enzyme elevations (occurring in ~15% of patients) to chronic fibrosis, cirrhosis, and hepatic failure. 3

Risk factors for hepatotoxicity 1:

• History of or current greater than moderate alcohol consumption (>1 drink/day for women, >2 drinks/day for men)
• Persistent abnormal liver chemistry findings
• History of liver disease including chronic hepatitis B or C
• Family history of inheritable liver disease
• Diabetes mellitus
• Obesity
• History of significant exposure to hepatotoxic drugs or chemicals
• Hyperlipidemia

The 2020 AAD-NPF guidelines recommend liver function test monitoring every 3-6 months, with abnormal elevations prompting repeat testing in 2-4 weeks and GI referral for persistent elevations 3. Noninvasive liver fibrosis assessment is recommended before starting treatment, with baseline liver biopsy no longer recommended regardless of risk factors 3.

Pulmonary Toxicity

Pulmonary fibrosis is one of the most severe manifestations of methotrexate toxicity and must be ruled out in patients presenting with new pulmonary symptoms such as cough. 1

Pulmonary manifestations include 2:

• Respiratory fibrosis
• Respiratory failure
• Alveolitis
• Interstitial pneumonitis (incidence ~1% in RA patients on 7.5-15 mg/week)
• Chronic interstitial obstructive pulmonary disease

Notably, this complication is much less common in psoriasis patients than in rheumatoid arthritis patients 1.

Organ System-Specific Adverse Reactions

Cardiovascular

Pericarditis, pericardial effusion, hypotension, and thromboembolic events (arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolus) 2

Central Nervous System

• Headaches, drowsiness, blurred vision, transient blindness
• Speech impairment (dysarthria, aphasia)
• Hemiparesis, paresis, convulsions
• Following low doses: transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations
• Leukoencephalopathy or encephalopathy 2
• Neuropsychiatric adverse reactions occur in approximately 6.8% of patients, with headache, dizziness, and depression most frequently reported 4

Infections

Fatal opportunistic infections have been reported, with Pneumocystis carinii pneumonia being the most common. 2

Other infections include: Cytomegalovirus infection (including pneumonia), sepsis (including fatal sepsis), nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, H. simplex hepatitis, and disseminated H. simplex 2.

Dermatologic

• Erythematous rashes, pruritus, urticaria
• Photosensitivity (rare) 3
• Pigmentary changes
• Alopecia (rare, seen in 3-10% of psoriasis patients) 3
• Ecchymosis, telangiectasia, acne, furunculosis
• Severe reactions: erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration, exfoliative dermatitis 2

Renal/Urogenital

• Severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria
• Defective oogenesis or spermatogenesis, transient oligospermia
• Menstrual dysfunction, vaginal discharge, gynecomastia
• Infertility, abortion, fetal death, fetal defects 2

Pregnancy and Reproductive Toxicity

Methotrexate is absolutely contraindicated during pregnancy (FDA Category X) and is both an abortifacient and teratogen. 3, 1, 3

Fetal abnormalities include cardiac, skeletal, and central nervous system defects 1. The critical period for teratogenic effects is within the first 6-8 weeks of pregnancy, though abnormalities have been reported at all gestational ages 3.

Women must wait at least 3 months after discontinuation before attempting to conceive to ensure methotrexate is fully cleared from tissues 3, 5. The Toronto Consensus strongly recommends stopping methotrexate at least 3 months before attempting conception 5.

For male patients, one cycle of spermatogenesis requires 74 days, so it is appropriate to wait 3 months after discontinuing methotrexate before attempting to conceive 1.

Drug Interactions Increasing Toxicity Risk

Concomitant use of NSAIDs with methotrexate significantly increases the risk of serious adverse events (weighted hazard ratio 1.40; 95% CI 1.07-1.82), particularly acute renal failure and cytopenia. 6

Other medications that may increase methotrexate toxicity 1:

• Antibiotics: Trimethoprim/sulfamethoxazole, sulfonamides, penicillins, minocycline, ciprofloxacin
• NSAIDs: Salicylates, naproxen, ibuprofen, indomethacin, phenylbutazone
• Others: Barbiturates, colchicine, dipyridamole, ethanol, phenytoin, sulfonylureas, furosemide, thiazide diuretics

Mitigation Strategies

Folic acid supplementation (1-5 mg daily except on methotrexate day) is strongly recommended (Grade A) to reduce the incidence of gastrointestinal and hepatic adverse effects. 3

Recent evidence demonstrates that combining folic acid with methotrexate reduces dose-dependent adverse events including hepatotoxicity and myelosuppression, without reducing efficacy 7. Large doses of folic acid may reduce methotrexate efficacy, so dosing should be balanced 3.

Monitoring Requirements

Critical monitoring parameters 3, 1:

• CBC and platelet counts: Initially every 2-4 weeks for first few months, then every 1-3 months
• Liver function tests: Every 3-6 months (monthly intervals initially)
• BUN and creatinine: Every 2-3 months
• Noninvasive liver fibrosis assessment at baseline and annually for high-risk patients

Absolute Contraindications

Methotrexate is contraindicated in 3, 1, 3:

• Pregnancy and nursing mothers
• Cirrhosis or chronic liver disease
• Significant thrombocytopenia, leukopenia, or anemia
• Bone marrow hypoplasia
• Immunodeficiency syndromes
• Hypersensitivity to methotrexate