What are the potential side effects of methotrexate, especially in patients with a history of liver disease, kidney disease, or bone marrow suppression?

Methotrexate Side Effects

Methotrexate causes a spectrum of adverse effects ranging from common gastrointestinal symptoms to potentially fatal bone marrow suppression, hepatotoxicity, and pulmonary fibrosis, with risk substantially increased in patients with liver disease, kidney disease, or bone marrow suppression who require dose reduction or complete avoidance of the drug. 1

Common Side Effects

Gastrointestinal toxicity is the most frequent adverse effect, occurring in approximately 30-32% of patients 2:

• Nausea, vomiting, anorexia, and abdominal distress typically manifest within 12-24 hours of dosing 2
• Ulcerative stomatitis and mouth ulcers are very common early toxicities 2
• Diarrhea may occur and requires immediate drug interruption to prevent hemorrhagic enteritis and intestinal perforation 1

Management strategies for GI symptoms include switching to parenteral administration (intramuscular or subcutaneous), taking medication with food or at bedtime, or splitting the weekly dose into three doses given 12 hours apart 3, 2

Transient liver enzyme elevations occur frequently within 3-4 days after dosing and are usually asymptomatic 1. These do not predict subsequent serious hepatic disease and often normalize without intervention 4.

Fatigue, malaise, and general constitutional symptoms are common but typically manageable 2.

Serious and Life-Threatening Toxicities

Bone Marrow Suppression

Myelosuppression accounts for the majority (67 out of 164 cases) of methotrexate-associated fatalities 4:

• Can occur after even a single dose in high-risk patients 5
• Typically manifests in the first 4-6 weeks but can occur at any time 2
• Presents as pancytopenia, leukopenia, neutropenia, thrombocytopenia, or aplastic anemia 1
• Early warning sign: elevated mean corpuscular volume (MCV >105 fL) indicating folate deficiency 5

Immediate action required if white blood cells <3.5×10⁹/L, neutrophils <2×10⁹/L, or platelets <100×10⁹/L: discontinue methotrexate immediately 4. For severe neutropenia (<1×10⁹/L), administer filgrastim (G-CSF) 5 µg/kg subcutaneously daily 4.

Hepatotoxicity

Chronic hepatotoxicity develops after prolonged use (generally ≥2 years) and cumulative doses ≥1.5 grams 1:

• Can progress to fibrosis and cirrhosis, which may be irreversible 1
• In psoriasis patients, risk is enhanced by alcoholism, obesity, diabetes, and advanced age 1
• Persistent liver function test abnormalities may precede fibrosis/cirrhosis in rheumatoid arthritis patients 1

In patients with preexisting liver disease: Methotrexate should be used with extreme caution or avoided entirely 1. If transaminases exceed twice the upper limit of normal on repeat testing, stop methotrexate immediately 4.

Pulmonary Toxicity

Methotrexate-induced lung disease is the second most common cause of methotrexate-related death after myelosuppression 2:

• Can occur acutely at any time during therapy, even at low doses 1
• Presents with dry, nonproductive cough, dyspnea, and fever 4, 1
• May not be fully reversible; fatalities have been reported 1
• Patients with preexisting pulmonary disease (asthma, chronic cough) may not be candidates for methotrexate 3

Baseline chest x-ray is mandatory for all patients starting methotrexate 4. Pulmonary symptoms require immediate drug interruption and investigation 1.

Nephrotoxicity

Methotrexate is 85% renally excreted, making renal function critical for safe elimination 3, 1:

• Renal insufficiency is the primary risk factor for methotrexate toxicity due to impaired drug clearance 4
• Patients with impaired renal function require marked dose reduction or discontinuation 1
• Abnormal renal function may lead to severe toxicity even after single doses 3

In patients with kidney disease: If creatinine clearance is 20-50 mL/min, dose reduction is required; if <20 mL/min, methotrexate should be avoided 2. For rheumatoid arthritis, methotrexate is contraindicated if eGFR <30 mL/min 6.

Special Populations at Increased Risk

Patients with Preexisting Bone Marrow Suppression

Methotrexate should be used with extreme caution, if at all, in patients with preexisting hematopoietic impairment 1:

• Risk of pancytopenia is substantially elevated 5
• More frequent monitoring (CBC at weeks 2,4,8, and 12, then every 3 months) is essential 4
• Any significant drop in blood counts requires immediate drug discontinuation 1

Patients with Liver Disease

Preexisting liver damage or impaired hepatic function requires special caution 1:

• Liver biopsy should be performed before or shortly after therapy initiation (2-4 months) 1
• Moderate fibrosis or any cirrhosis normally leads to discontinuation 1
• Chronic hepatitis B or C infection requires pretreatment liver biopsy 1

Patients with Kidney Disease

Renal impairment dramatically increases toxicity risk 4, 6:

• Methotrexate accumulation leads to prolonged exposure and enhanced toxicity 6
• Patients with ascites or pleural effusions also have reduced elimination and require careful monitoring 1
• More accurate renal function assessment (creatinine clearance rather than serum creatinine alone) should be used, especially in elderly patients 1

Critical Drug Interactions Increasing Toxicity

NSAIDs reduce renal elimination of methotrexate, leading to elevated drug levels and increased toxicity risk 3, 4, 1. This interaction is particularly dangerous with any dose of methotrexate 4.

Trimethoprim-sulfamethoxazole (Bactrim) is absolutely contraindicated with methotrexate due to severe bone marrow suppression risk from dual folic acid antagonism 4, 2.

Other high-risk interactions include salicylates, sulfonamides, penicillins, probenecid, and colchicine, which decrease methotrexate binding to albumin or reduce renal tubular excretion 3.

Hepatotoxic agents (alcohol, statins, leflunomide, retinoids, azathioprine, minocycline) should be used with caution as they compound liver toxicity risk 3.

Additional Serious Adverse Effects

Immunosuppression increases susceptibility to infections, including potentially fatal opportunistic infections such as Pneumocystis carinii pneumonia 1. Risk of reactivation of latent tuberculosis and hepatitis exists 2.

Lymphoproliferative disorders, including Epstein-Barr virus-associated B-cell lymphoma, may occur but can regress following methotrexate withdrawal 1.

Severe skin reactions (including toxic epidermal necrolysis) have been reported following single or multiple doses 1.

Tumor lysis syndrome may occur in patients with rapidly growing tumors 1.

Teratogenicity and reproductive toxicity: Methotrexate causes fetal death and congenital anomalies 1. It is contraindicated in pregnant women with psoriasis or rheumatoid arthritis 1. Women should avoid conception for 6 months after stopping methotrexate; men should wait 3 months 4.

Essential Prevention Strategies

Mandatory folic acid supplementation (1-5 mg daily except on methotrexate day, or 5 mg weekly) reduces gastrointestinal, hepatic, and hematologic toxicity without compromising efficacy 3, 4, 2, 5. Lack of folate supplementation is a common preventable risk factor for toxicity 4.

Regular laboratory monitoring is essential 4:

• Baseline: CBC with differential, creatinine, liver function tests (including albumin and bilirubin), hepatitis B and C screening 3
• First 3 months: CBC, liver function tests, creatinine at least monthly 4
• After stabilization: CBC and liver function tests every 3-6 months 4

Patient education about warning signs requiring immediate medical attention: unusual fatigue, fever, chills, sore throat, easy bruising/bleeding, persistent cough, shortness of breath, mouth sores, severe nausea/vomiting, or diarrhea 4.