What are the potential side effects of Methotrexate (Disease-Modifying Antirheumatic Drug)?

Methotrexate Side Effects

Methotrexate causes a wide spectrum of adverse effects ranging from common gastrointestinal symptoms to potentially fatal complications including bone marrow suppression, hepatotoxicity, and pulmonary fibrosis. 1

Most Common Side Effects

The most frequently reported adverse reactions include:

• Gastrointestinal toxicity: Ulcerative stomatitis, nausea, vomiting, abdominal distress, diarrhea, anorexia, and GI ulceration are the most common side effects 2, 1
• Constitutional symptoms: Malaise, undue fatigue, chills, fever, and dizziness occur frequently 1
• Mucocutaneous effects: Stomatitis and mouth ulcers are very common early toxicities 2, 1

These common toxicities typically occur shortly after medication initiation and can often be mitigated by altering the dose, route (switching from oral to subcutaneous), or frequency of administration, or by taking the medication with food 2

Serious and Potentially Fatal Side Effects

Bone Marrow Suppression

• Myelosuppression is the leading cause of methotrexate-related death and includes leukopenia, neutropenia, thrombocytopenia, pancytopenia, and aplastic anemia 3, 1
• Bone marrow suppression generally occurs early in treatment (first 4-6 weeks) and is reversible with cessation 2
• Risk is increased by medications that interfere with folic acid metabolism (trimethoprim-sulfamethoxazole) and NSAIDs that decrease renal clearance 2

Hepatotoxicity

• Liver enzyme elevations are common, especially transient increases within 3-4 days after dosing 2
• Long-term use can induce liver fibrosis or cirrhosis, though this is dose- and duration-dependent 2
• Persistent liver function test abnormalities and decreased serum albumin may indicate serious liver toxicity requiring evaluation 1
• Risk factors include alcohol consumption, chronic hepatitis B or C infection, and persistently abnormal baseline liver function 1

Pulmonary Toxicity

• Pulmonary fibrosis is the second most common cause of methotrexate-related death after myelosuppression, with 30 of 164 reported fatalities attributed to this complication 4
• Presents with dry, nonproductive cough, dyspnea, fever, hypoxemia, and infiltrates on chest X-ray 4, 3, 1
• Risk factors include advanced age, pre-existing pulmonary disease, renal impairment, and rheumatoid arthritis (more common than in psoriasis) 4, 3
• Can occur at any dose and requires immediate interruption of treatment 1

Renal Toxicity

• Methotrexate can cause nephrotoxicity leading to acute renal failure, primarily due to precipitation of methotrexate and its metabolites in renal tubules 1
• Severe nephropathy, azotemia, proteinuria, and hematuria have been reported 1

Infectious Complications

• Increased risk of serious and potentially fatal opportunistic infections including Pneumocystis carinii pneumonia (most common), cytomegalovirus, herpes zoster, cryptococcosis, histoplasmosis, and sepsis 1
• Immunosuppression increases susceptibility to infections and reactivation of latent tuberculosis and hepatitis 2

Dermatologic Reactions

• Severe, occasionally fatal reactions including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, and skin necrosis have been reported 1
• These can occur after single or multiple doses at any dosage level 1

Neurologic Toxicity

• Leukoencephalopathy can occur, particularly following craniospinal irradiation 1
• Acute neurologic syndrome with stroke-like encephalopathy including confusion, hemiparesis, transient blindness, seizures, and coma 1
• Transient cognitive dysfunction, mood alteration, headaches, and speech impairment have been reported 1

Less Common but Important Side Effects

• Cardiovascular: Pericarditis, pericardial effusion, and thromboembolic events including deep vein thrombosis and pulmonary embolus 1
• Reproductive: Defective oogenesis/spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, fetal death, and fetal defects (absolutely contraindicated in pregnancy) 2, 1
• Hematologic: Lymphoproliferative disorders including Epstein-Barr virus-associated B-cell lymphoma 2
• Ocular: Conjunctivitis and serious visual changes 1

Critical Risk Factors for Increased Toxicity

• Renal impairment significantly increases toxicity risk due to reduced drug clearance 3, 1
• Advanced age due to diminished hepatic/renal function and decreased folate stores 1
• Drug interactions: NSAIDs, salicylates, penicillin, sulfonamides, trimethoprim, proton pump inhibitors, and ciclosporin can increase methotrexate levels 2, 3
• Hypoalbuminemia increases free drug levels 5
• Accidental daily dosing instead of weekly dosing has led to fatal toxicity 1, 5

Monitoring and Prevention Strategies

• Baseline assessment: Complete blood count with differential, hepatic enzymes, renal function, chest X-ray, and screening for hepatitis B/C and tuberculosis based on risk factors 4, 1
• During therapy: CBC monthly, renal and liver function every 1-2 months 1
• Timing of labs: Perform at least 4-6 days after dosing to avoid misinterpreting transient elevations 2
• Folic acid supplementation (1 mg daily or 5 mg weekly) reduces hepatic abnormalities and GI adverse effects without compromising efficacy 2
• Patient education: Emphasize weekly (not daily) dosing to prevent fatal overdose 1

Management of Toxicity

• Most adverse reactions are reversible if detected early; reduce dose or discontinue drug when reactions occur 1
• For overdose or severe toxicity, use leucovorin (folinic acid) rescue, maintain hydration, and consider urine alkalinization 2
• Filgrastim can be used for toxic bone marrow suppression 2
• Switching from oral to subcutaneous administration may reduce GI adverse effects 6