What is the management approach for a patient taking leflunomide (generic name) who develops an acute infection?

Management of Leflunomide in Acute Infection

Leflunomide should be temporarily discontinued immediately when acute infection develops, and cholestyramine washout should be strongly considered to rapidly eliminate the drug, particularly in severe infections. 1, 2

Immediate Actions Upon Infection Diagnosis

Discontinue Leflunomide

• Stop leflunomide therapy immediately when active infection is diagnosed 1
• The American College of Rheumatology explicitly recommends temporarily withholding leflunomide in the setting of active infection 1
• This recommendation applies across all infection types, not just COVID-19 1

Consider Cholestyramine Washout

• Cholestyramine or activated charcoal should be administered to accelerate drug elimination in serious infections 2
• The FDA label specifically states that in the event of serious infection, it may be necessary to interrupt therapy and administer cholestyramine or charcoal 2
• Standard washout protocol: cholestyramine 8 grams three times daily 2
• This is particularly critical because leflunomide has a prolonged half-life due to enterohepatic recirculation, and therapeutic levels can persist for weeks after discontinuation 3

Rationale for Drug Elimination

Immunosuppression Risk

• Leflunomide has immunosuppression potential that increases susceptibility to infections, including opportunistic infections such as Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary), and aspergillosis 2
• Severe infections including sepsis, which may be fatal, have been reported in patients receiving leflunomide 2
• The risk is particularly elevated in patients with severe septic shock, where rapid drug elimination may correspond with resolution of sepsis 3

Pharmacokinetic Considerations

• Without washout, leflunomide's active metabolite can remain at therapeutic levels for extended periods even after discontinuation 3
• Case reports demonstrate that patients can have therapeutic leflunomide levels weeks after stopping the medication, potentially prolonging immunosuppression during critical illness 3

Infection-Specific Monitoring

Signs Requiring Immediate Attention

• Fever, chills, malaise 2
• Respiratory symptoms: cough, dyspnea, chest pain (pneumonia risk) 4
• Urinary symptoms: dysuria, frequency (pyelonephritis risk) 4
• Skin changes: cellulitis, disseminated herpes zoster 4
• Any signs of sepsis or severe systemic infection 2, 3

High-Risk Patient Populations

• Older age is a significant risk factor for severe leflunomide-associated infections 4
• Patients with diabetes mellitus have increased infection risk 4
• Concomitant corticosteroid use, particularly higher daily doses, substantially increases infection risk 4
• Patients receiving concurrent methotrexate or other immunosuppressive agents 2

Laboratory Monitoring During Infection

Hematologic Surveillance

• Monitor CBC with differential, platelet count, hemoglobin, and hematocrit closely during acute infection 2
• Rare reports of pancytopenia, agranulocytosis, and thrombocytopenia can occur, particularly in patients with concurrent immunosuppression 2
• If bone marrow suppression is evident, cholestyramine or charcoal should be used immediately to reduce plasma concentrations 2

Hepatic Function

• Continue monitoring ALT/AST during infection, as hepatotoxicity can complicate infectious presentations 2
• Severe liver injury has been reported, most commonly within 6 months of therapy 2

Common Pitfalls and Caveats

Do Not Delay Washout in Severe Infections

• A critical pitfall is failing to recognize that simply stopping leflunomide is insufficient in severe infections 3
• Active washout with cholestyramine accelerates drug elimination and may be lifesaving in septic patients 3

Distinguish Drug Toxicity from Infection

• Leflunomide can cause interstitial pneumonia, which may be confused with infectious pneumonia 5
• Approximately 1.1% of patients develop interstitial pneumonia in post-market surveillance, which can be fatal 5
• If new pulmonary symptoms develop, consider both infectious and drug-induced etiologies 1

Avoid Premature Reinitiation

• Do not restart leflunomide until infection has completely resolved 1
• When switching to another antirheumatic agent after infection, monitor for hematologic toxicity due to overlapping systemic exposure 2
• Consider that disease flare may occur during prolonged drug elimination, but infection control takes priority 2

Resumption of Therapy

After Infection Resolution

• Leflunomide may be resumed once the acute infection has completely resolved and clinical stability is achieved 1
• Ensure adequate time has passed for immune reconstitution 2
• Resume baseline monitoring schedule: monthly CBC and liver function tests for first 6 months, then every 6-8 weeks 1