Do Methotrexate (methotrexate) and Cimzia (certolizumab pegol) affect liver enzymes in an adult patient with a chronic inflammatory condition, such as rheumatoid arthritis or Crohn's disease?

Hepatotoxicity of Methotrexate and Cimzia

Yes, both methotrexate and Cimzia (certolizumab pegol) affect liver enzymes, with methotrexate causing transaminase elevations in approximately 48.9% of patients and Cimzia requiring liver enzyme monitoring every 3-6 months due to potential hepatotoxicity. 1, 2

Methotrexate and Liver Enzymes

Frequency and Spectrum of Hepatotoxicity

Methotrexate causes a spectrum of liver enzyme abnormalities ranging from transient, asymptomatic elevations to more serious hepatotoxicity. 1 The data shows:

• Elevated liver enzymes occur in approximately 48.9% of patients on methotrexate at some point during therapy 1
• 16.8% of patients will experience elevations exceeding 2× the upper limit of normal 1
• In IBD patients specifically, 24% developed liver enzyme abnormalities, though many normalized without stopping methotrexate and only 5% required drug discontinuation 2

The risk of serious liver injury, including cirrhosis, is substantially lower than historically believed when modern dosing regimens and monitoring protocols are followed. 1 Methotrexate-induced cirrhosis is rare (0.5%) in rheumatoid arthritis patients. 1

Baseline Testing Requirements

Before initiating methotrexate, obtain: 1, 3

• Complete blood count with differential
• Liver function tests (ALT, AST, alkaline phosphatase, albumin, bilirubin)
• Renal function tests
• Hepatitis B and C screening (especially in patients with risk factors)
• Non-invasive fibrosis assessment (FIB-4 Index, FibroSure, Fibrometer, or Hepascore) for patients with risk factors 1

Monitoring Schedule

The monitoring protocol varies by treatment phase: 2, 3

• Initial phase: Check liver enzymes at weeks 2,4,8, and 12 after starting methotrexate 2, 3
• After dose increases: Repeat measurements 1-2 months after any dose increase 2
• Stable therapy: Monitor every 3-4 months for patients on stable doses with no recent abnormalities 2, 3

Critical timing consideration: Avoid checking liver enzymes within 1-2 days after the weekly methotrexate dose, as transient elevations may occur. 2, 3

Response to Elevated Liver Enzymes

The management algorithm is based on the degree of elevation: 2, 1, 4

• <2× upper limit of normal: Continue methotrexate at current dose with close monitoring; repeat tests in 2-4 weeks 4
• 2-3× upper limit of normal: Either recheck at shorter intervals or decrease the methotrexate dose; repeat tests in 2-4 weeks 2, 1, 4
• >3× upper limit of normal (confirmed on repeat): Stop methotrexate immediately 2, 1, 4

If liver enzymes remain >3× upper limit of normal following dose reduction, discontinue methotrexate permanently. 2

Risk Factors for Methotrexate Hepatotoxicity

Patients with the following conditions require enhanced monitoring: 2, 1, 3

• Obesity (BMI >28 kg/m²) 2
• Metabolic syndrome 1
• Diabetes mellitus 1, 3
• Hyperlipidemia 1
• Alcohol consumption (>14 drinks per week) 2
• Pre-existing liver disease 3
• Lack of folic acid supplementation 3

Risk Mitigation

Folic acid supplementation is mandatory to reduce hepatotoxicity, gastrointestinal toxicity, and hematologic toxicity. 2, 1, 3 Administer either:

• 1 mg daily, or
• 5 mg weekly (taken 1-2 days after the methotrexate dose) 2

Advanced Fibrosis Assessment

For patients with risk factors or on long-term therapy, vibration-controlled transient elastography (FibroScan) is the preferred non-invasive method for assessing liver fibrosis. 1 Standard liver function tests are only 38% sensitive and 83% specific for detecting hepatic fibrosis, making them inadequate in isolation for monitoring chronic liver damage. 1

Patients with BMI >28 kg/m² and alcohol intake >14 drinks per week should be screened using transient elastography. 2 Routine liver biopsy after prolonged use is not necessary, as the risk of cirrhosis is much lower than previously thought. 2

Cimzia (Certolizumab Pegol) and Liver Enzymes

Monitoring Requirements for TNF-α Inhibitors

Cimzia, as a TNF-α inhibitor, requires liver enzyme monitoring: 2

• Baseline: Measure complete blood count, liver enzymes, and serum creatinine prior to initiation 2
• Ongoing: Monitor approximately every 3-6 months for patients who continue to receive TNF-α inhibitors 2

The guidelines do not specify the exact frequency or severity of liver enzyme elevations with Cimzia, but the monitoring requirement indicates recognized hepatotoxic potential.

Combined Therapy Considerations

When methotrexate and Cimzia are used together (a common combination in rheumatoid arthritis and inflammatory bowel disease), maintain the more frequent monitoring schedule dictated by methotrexate (every 3-4 months for stable patients). 2

Critical Pitfalls to Avoid

• Do not rely solely on standard liver function tests to detect fibrosis in patients on long-term methotrexate, as they have poor sensitivity (38%) for chronic liver damage 1
• Do not check liver enzymes within 1-2 days after methotrexate administration, as transient elevations may lead to unnecessary interventions 2, 3
• Do not continue methotrexate if confirmed ALT/AST >3× upper limit of normal—this requires immediate discontinuation 2, 1, 4
• Do not forget folic acid supplementation, as this significantly reduces hepatotoxicity risk 2, 1, 3
• Do not overlook underlying risk factors such as obesity, diabetes, and alcohol use, which substantially increase hepatotoxicity risk 2, 1