How should I monitor a patient on methotrexate, including baseline labs, frequency of CBC (complete blood count), LFT (liver function tests) and renal function tests, pregnancy testing, folic acid supplementation, and pulmonary toxicity surveillance?

Monitoring Methotrexate Therapy

All patients on methotrexate require baseline testing followed by monitoring of CBC, liver function tests, and renal function at weeks 2,4,8, and 12, then every 3 months thereafter, with mandatory folic acid supplementation and pregnancy prevention in women of childbearing potential. 1, 2

Baseline Testing Before Initiation

Before starting methotrexate, obtain the following tests:

• Complete blood count with differential and platelet count to assess baseline bone marrow function, as myelosuppression accounts for the majority of methotrexate-associated fatalities 2, 3
• Liver function tests (ALT, AST, alkaline phosphatase, albumin, bilirubin) to establish baseline hepatic function 1, 2, 3
• Hepatitis B and C serologies for all patients regardless of apparent risk factors, as undiagnosed hepatitis significantly increases hepatotoxicity risk 3, 4
• Serum creatinine and renal function tests (eGFR) because methotrexate is eliminated almost entirely by the kidneys 2, 3, 5
• Chest X-ray to establish baseline pulmonary status, as pulmonary fibrosis accounts for a significant proportion of methotrexate-associated fatalities 1, 2, 3
• Pregnancy test in women of childbearing potential, as methotrexate is pregnancy category X and teratogenic 1, 2, 3

Do not perform baseline liver biopsy, regardless of risk factors, as routine liver biopsies are no longer recommended 1, 2, 6

For high-risk patients (BMI >28 kg/m² or alcohol intake >14 drinks per week), consider non-invasive liver fibrosis assessment using FIB-4 Index or transient elastography 1, 2

Regular Monitoring Schedule

Initial Phase (First 3 Months)

• Monitor CBC, liver function tests, and renal function at weeks 2,4,8, and 12 after starting methotrexate 1, 2, 6
• More frequent monitoring (every 2-4 weeks) is required during dose increases or in patients with risk factors 1, 2, 6

Maintenance Phase

• Monitor CBC, liver function tests, and renal function every 3 months for stable patients 1, 2, 6
• Avoid checking liver function tests within 2 days after methotrexate dose, as transient elevations are common and may lead to unnecessary dose adjustments 2, 6, 5

Critical timing consideration: 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 3, 5

Specific Monitoring Parameters

Hematologic Toxicity

• Stop methotrexate immediately if:
  • White blood cell count <3.0 × 10⁹/L 2
  • Absolute neutrophil count <1.0 × 10⁹/L 2
  • Platelet count <100 × 10⁹/L 2
  • Hemoglobin decreased by >2 g/L from previous level 7

Maximal myelosuppression typically occurs 7-10 days after dosing 5

Hepatotoxicity

• Stop methotrexate if transaminases exceed 2 times the upper limit of normal on repeat testing 1
• For psoriasis patients only, monitor serum PIIINP (procollagen III N-terminal peptide) at least every 3 months 1
• Refer for specialist assessment if:
  • PIIINP >8 mg/L on two occasions 1
  • Three PIIINP measurements >4.2 mg/L in 12 months 1
  • PIIINP >10 mg/L on one occasion 1

The negative predictive value of normal serial PIIINP measurements is 97%, making it a cost-effective method for monitoring hepatic fibrosis in psoriasis patients 1

Renal Toxicity

• Monitor serum creatinine and eGFR every 2-3 months 1
• Methotrexate is contraindicated if eGFR <30 mL/minute 8
• Consider lower initial doses and more frequent monitoring if eGFR is 30-59 mL/minute 8

Worsening renal function is associated with increasing toxicity, particularly myelosuppression, which is the most important cause of methotrexate-associated death 1

Pulmonary Toxicity

• Inquire about respiratory symptoms at every visit (dyspnea, dry cough, fever) 1
• Obtain chest X-ray, further investigations, and/or respiratory referral if:
  • Symptoms are present 1
  • Patient is >40 years old and a cigarette smoker 1
  • Patient has background disease putting them at risk (e.g., sarcoidosis) 1

Pulmonary toxicity is not related to cumulative dose and presents as acute interstitial pneumonitis; most cases are reversible on withdrawal 1

Mandatory Folic Acid Supplementation

Prescribe folic acid 1-5 mg daily, taken 6 days per week (omitting the day of methotrexate administration) to reduce gastrointestinal, hepatic, and hematologic toxicity 2, 3, 6

This supplementation is strongly recommended to mitigate adverse events and improve tolerability 3, 6

Pregnancy Prevention and Testing

• Women of childbearing potential must use assured contraception during therapy and for 6 months after stopping methotrexate 1
• If concerns exist about reliability of adherence to effective contraception, use alternative therapy 1
• Perform pregnancy testing before initiation and as indicated during therapy 1, 2
• Men should discontinue methotrexate for 3 months before attempting conception, though evidence suggests this may not be necessary based on reassuring cohort studies 1

Management of Abnormal Results

Elevated Liver Enzymes

• Withhold methotrexate for 1-2 weeks if significant persistent abnormality develops, then repeat liver chemistry tests 1
• Liver chemistry values likely return to normal in 1-2 weeks 1
• If significantly abnormal values persist for 2-3 months, consider liver biopsy if continuation of methotrexate is desired 1

Decreased Blood Counts

• Decrease or hold methotrexate dose if clinically relevant elevation in liver function tests or decreased neutrophil/platelet count is found 2
• Administer leucovorin (folinic acid) as the antidote for hematologic toxicity 2, 8

Common Pitfalls to Avoid

• Do not check liver function tests within 2 days of methotrexate dose, as this leads to unnecessary dose adjustments based on transient elevations 2, 6
• Do not perform routine surveillance liver biopsies, as they are no longer recommended and carry significant morbidity risk 1, 2, 6
• Do not prescribe methotrexate on a PRN basis; prescriptions should specify weekly dosing to prevent fatal toxicity from mistaken daily use 5
• Do not administer NSAIDs prior to or concomitantly with high-dose methotrexate, as this can elevate and prolong serum methotrexate levels, resulting in severe toxicity 5

Patient Education Requirements

Patients must understand and be counseled about:

• Weekly dosing schedule (not daily) to prevent fatal toxicity 6, 5
• Seek urgent medical attention for: fever/flu-like illness, mouth ulceration, unexplained bruising or bleeding, severe sore throat, nausea/vomiting/abdominal pain, or breathlessness 6
• Limit alcohol intake to well below national guidelines 3, 6
• Use effective contraception during therapy and for 6 months after stopping 1, 6
• Omit methotrexate dose during intercurrent illness causing dehydration 6

Special Populations

Elderly Patients

• Use relatively low initial doses due to diminished hepatic and renal function and decreased folate stores 5
• Monitor closely for early signs of toxicity 5

Patients with Renal Impairment

• Consider an initial test dose of 2.5-5 mg, followed by CBC 5-6 days later to detect acute idiosyncratic bone marrow toxicity 3, 5
• More frequent monitoring is indicated during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration) 5