What labs are recommended prior to starting methotrexate (anti-folate medication)?

Pre-Treatment Laboratory Testing for Methotrexate

Before initiating methotrexate therapy, obtain a complete blood count with differential and platelet count, comprehensive liver function tests (ALT, AST, alkaline phosphatase, albumin, bilirubin), serum creatinine, hepatitis B and C serologies, and a chest X-ray. 1, 2, 3

Essential Baseline Laboratory Tests

Hematologic Assessment

• Complete blood count (CBC) with differential and platelet count is mandatory to establish baseline bone marrow function, as bone marrow suppression typically occurs early in treatment (first 4-6 weeks) and accounts for the majority of methotrexate-associated fatalities. 2, 3
• An initial test dose of 2.5-5 mg (or 1.25-5 mg in pediatric patients) should be considered, especially in patients with impaired kidney function, followed by a CBC 5-6 days later to detect acute idiosyncratic bone marrow toxicity. 4, 2

Hepatic Assessment

• Comprehensive liver function tests including ALT, AST, alkaline phosphatase, albumin, and bilirubin must be obtained before starting therapy to establish baseline hepatic function. 1, 2, 3
• Hepatitis B and C serologic studies are required for all patients prior to initiating methotrexate, regardless of apparent risk factors, as undiagnosed hepatitis significantly increases the risk of hepatotoxicity. 1, 2, 5
• Baseline liver biopsy is NOT recommended regardless of risk factors, as routine liver biopsies are no longer considered necessary. 1, 2
• Non-invasive baseline liver fibrosis assessment is recommended before starting methotrexate in psoriasis patients, particularly those with BMI >28 kg/m² or alcohol intake >14 drinks per week. 2

Renal Assessment

• Serum creatinine measurement is mandatory before initiation because methotrexate is eliminated almost entirely by the kidneys, and renal insufficiency is a primary risk factor for methotrexate toxicity due to impaired drug clearance. 1, 2, 3, 6
• In elderly patients or those with low muscle mass, calculate GFR rather than relying solely on serum creatinine to accurately assess renal function. 1

Pulmonary Assessment

• A chest X-ray (obtained within the previous year) is required to establish baseline pulmonary status, as pulmonary fibrosis accounts for a significant proportion of methotrexate-associated fatalities. 2

Additional Pre-Treatment Screening

Infectious Disease Screening

• HIV serology should be considered based on individual circumstances and local epidemiology. 4, 2
• Monitoring for latent tuberculosis should be considered before therapy based on individual circumstances and local epidemiology. 4

Pregnancy Testing

• Pregnancy testing must be performed in women of childbearing potential before initiating therapy, as methotrexate is pregnancy category X. 1, 2, 3
• Both male and female patients should be counseled about the need for effective contraception (two methods for women). 1, 2

Clinical History Requirements

Medication History

• Obtain comprehensive medication history to identify potential drug interactions, particularly NSAIDs, salicylates, sulfonamides, trimethoprim-sulfamethoxazole, penicillins, and probenecid, which can reduce tubular secretion of methotrexate and enhance toxicity. 1, 2, 3

Alcohol and Lifestyle Assessment

• Document alcohol intake, as patients should limit consumption to well below national guidelines; excessive alcohol consumption is a major risk factor for hepatotoxicity. 1, 2
• Family history of inheritable liver disease should be obtained. 1

Monitoring Schedule After Initiation

• The American College of Rheumatology strongly recommends monitoring CBC, liver function tests, and renal function tests within the first 1-2 months of starting methotrexate and every 3-4 months thereafter. 4, 2
• Laboratory tests should be performed at least 4-6 days after methotrexate dosing to avoid making dosage adjustments based on transient elevations of hepatic transaminases. 4
• Avoid liver function tests within 2 days after methotrexate dose as transient elevations may occur. 4, 7

Common Pitfalls to Avoid

• Do not skip hepatitis B and C screening even in patients without obvious risk factors, as undiagnosed hepatitis significantly increases hepatotoxicity risk. 1, 2, 5
• Do not perform routine baseline liver biopsies in psoriasis or rheumatoid arthritis patients, as they are no longer recommended. 1, 2
• Do not rely solely on serum creatinine in elderly patients or those with low muscle mass; calculate GFR for accurate renal function assessment. 1
• Do not obtain laboratory tests within 2-4 days after methotrexate administration, as transient elevations in liver enzymes are common during this window and may lead to inappropriate dose adjustments. 4

Folic Acid Supplementation

• Use of folic/folinic acid in conjunction with methotrexate is strongly recommended to mitigate adverse events and improve tolerability, typically 1 mg daily (or 6 days per week, sparing the day of methotrexate administration). 4, 7