What is the best course of action for an elderly patient with rheumatoid arthritis (RA) on methotrexate (MTX) for over 16 years, with a history of breast cancer, currently on nintedanib (Esbriet) for idiopathic pulmonary fibrosis (ILD)-usual interstitial pneumonia (UIP) pattern, recently started on mycophenolic acid (Cellcept) with elevated liver enzymes, including alanine transaminase (ALT), aspartate transaminase (AST), and gamma-glutamyl transferase (GGT)?

Management of Elevated Liver Enzymes in a Complex RA-ILD Patient

Immediate Action Required

Mycophenolic acid must be discontinued immediately given the significant transaminase elevations (ALT 175, AST 120, GGT 238), and methotrexate should also be stopped given the 16-year cumulative exposure and elevated liver enzymes. 1, 2, 3

The pattern of elevation (ALT/AST >3× ULN with markedly elevated GGT) indicates drug-induced hepatotoxicity requiring prompt intervention. 1

Identifying the Culprit Medication

Mycophenolic Acid as Primary Suspect

• Mycophenolic acid is the most likely culprit given it was "recently started" and the temporal relationship with liver enzyme elevation strongly suggests drug-induced liver injury. 1
• The ACR/CHEST guidelines note concerns about gastrointestinal adverse effects with mycophenolate, though hepatotoxicity is less commonly emphasized. 4

Methotrexate Contribution

• After 16 years of methotrexate therapy, this patient has exceeded the typical 1.5-2 gram cumulative dose threshold where chronic hepatotoxicity risk substantially increases. 3
• The FDA label explicitly states that chronic hepatotoxicity "generally has occurred after prolonged use (generally two years or more) and after a total dose of at least 1.5 grams." 3
• Methotrexate should be permanently discontinued given the prolonged exposure, elevated enzymes, and availability of alternative RA therapies. 2, 3

Nintedanib Consideration

• Nintedanib can cause transaminase elevations, but the patient has been stable on this medication for 4 years without prior liver issues. 4
• Continue nintedanib as it is critical for managing the UIP-pattern ILD and the temporal relationship does not implicate it as the primary cause. 4, 5

Monitoring Protocol

Intensive Short-Term Monitoring

• Check ALT, AST, total/direct bilirubin, GGT, and albumin every 3-7 days until enzymes show consistent downward trend. 1, 2
• If enzymes remain >3× ULN after 2 weeks, consider hepatology consultation and abdominal ultrasound to assess for structural liver disease. 1, 2

Expected Timeline

• Liver enzymes typically normalize within 1-4 months after discontinuation of the offending agent(s). 1, 6
• If enzymes remain elevated >2× ULN after 3 months despite drug discontinuation, liver biopsy should be considered to evaluate for alternative causes or established fibrosis. 1, 2

Alternative Treatment Strategy for RA-ILD

First-Line Immunosuppression Options

Given the need to discontinue both methotrexate and mycophenolate, rituximab is the preferred alternative for managing both RA and RA-ILD. 4, 7, 8

• The 2023 ACR/CHEST guideline conditionally recommends rituximab as a first-line option for RA-ILD treatment. 4
• Rituximab has demonstrated efficacy in retrospective studies for RA-ILD and does not carry the same hepatotoxicity concerns as methotrexate or mycophenolate. 7, 8
• Abatacept is an emerging alternative that may be particularly suitable given the patient's history of breast cancer (rituximab carries lymphoproliferative concerns, though remote cancer history may be acceptable). 8

Azathioprine as Alternative

• Azathioprine is conditionally recommended by ACR/CHEST for RA-ILD, but should be used with caution in UIP-pattern disease. 4, 7
• Avoid azathioprine in this patient given the UIP pattern, as data from IPF trials showed worse outcomes with azathioprine compared to placebo. 7

Role of Antifibrotic Therapy

• Continue nintedanib as the patient has established UIP-pattern RA-ILD and has been stable on this medication for 4 years. 4, 5
• The 2023 ACR/CHEST guideline notes that "some panelists consider nintedanib as a first-line ILD therapy option in patients with RA-ILD with a fibrotic/UIP pattern." 4
• Nintedanib has demonstrated efficacy in reducing FVC decline in progressive fibrosing ILD, including RA-UIP. 5, 9, 8

Critical Pitfalls to Avoid

Do Not Restart Methotrexate

• Methotrexate should never be restarted in this patient given the 16-year exposure, current transaminitis, and availability of safer alternatives. 2, 3
• The ACR guideline states that methotrexate use should be restricted to patients with "normal liver enzymes and liver function tests and without evidence of liver disease or liver fibrosis." 4

Do Not Add Glucocorticoids

• Long-term glucocorticoids are conditionally recommended against for RA-ILD progression. 4, 7
• Short-term glucocorticoids may be considered during transition to rituximab if RA disease activity flares, but should be minimized given infection risk in ILD patients. 4

Monitor for Hepatitis B Reactivation

• Before initiating rituximab, check hepatitis B core antibody and surface antigen status. 4
• If hepatitis B core antibody positive, prophylactic antiviral therapy is strongly recommended when initiating rituximab regardless of surface antigen status. 4

Specific Treatment Algorithm

1. Immediately discontinue mycophenolic acid and methotrexate 1, 2
2. Continue nintedanib for ILD management 4, 5
3. Check hepatitis B serologies (core antibody, surface antigen) 4
4. Monitor LFTs every 3-7 days until consistent downward trend 1, 2
5. Initiate rituximab once LFTs show improvement (ideally <2× ULN) with hepatitis B prophylaxis if indicated 4, 7
6. Consider abatacept as alternative if concerns about rituximab given cancer history 8
7. Obtain hepatology consultation if LFTs remain elevated after 2-4 weeks 1, 2
8. Transition to monthly LFT monitoring once normalized, given ongoing nintedanib therapy 4