Leflunomide and Anesthesia: Perioperative Management
Primary Recommendation
Continue leflunomide through the perioperative period for patients undergoing elective orthopedic surgery, as discontinuation increases infection risk and disease flare without providing safety benefit. 1
Evidence-Based Management Algorithm
Preoperative Management
- Do not discontinue leflunomide before elective total hip or knee arthroplasty (THA/TKA) 1
- Continue the current dose through surgery without interruption 1, 2
- RCT evidence demonstrates that continuing DMARDs (including leflunomide) actually reduces infection risk by 61% (RR 0.39,95% CI 0.17-0.91) compared to discontinuation 1
- Continuing therapy also dramatically reduces postoperative disease flares (RR 0.06,95% CI 0.0-1.10) 1
Rationale for Continuation
The 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons guideline specifically recommends continuing leflunomide based on moderate-quality evidence showing improved outcomes when DMARDs are maintained perioperatively 1. This applies to patients with rheumatoid arthritis, spondyloarthropathies (including ankylosing spondylitis and psoriatic arthritis), juvenile idiopathic arthritis, and systemic lupus erythematosus 1.
Postoperative Management
- Continue leflunomide at the same dose immediately postoperatively 1
- No washout period or dose adjustment is required 1
- Monitor for standard postoperative complications (wound healing, infection) but do not attribute these to leflunomide continuation 1
Important Nuances and Contradictory Evidence
Conflicting Older Data
One 2006 observational study suggested leflunomide increased wound-healing complications (40.6% vs 13.6% with methotrexate, P=0.01) and recommended preoperative discontinuation 3. However, this conflicts with:
- A 2003 study showing no increased infection risk with continuous leflunomide (6.1% infection rate vs 6.3% without leflunomide) 4
- The definitive 2017 ACR/AAHKS guideline based on RCT evidence showing benefit from continuation 1
The highest-quality evidence (2017 guideline based on RCTs) supersedes older observational studies and supports continuation. 1
Why Not Discontinue Despite Long Half-Life?
Leflunomide's active metabolite (A77 1726) has a half-life of approximately 2 weeks 5. Despite this, the guideline recommends continuation because:
- The immunosuppressive effect when continued at therapeutic doses is protective against infection in the surgical setting 1
- Discontinuation would require weeks to months for complete elimination, making brief perioperative cessation ineffective 5
- Drug elimination procedures (cholestyramine or activated charcoal) can reduce plasma levels by 40-65% in 24-48 hours if rapid elimination is needed, but this is not indicated for routine surgery 6
Contrast with Biologic DMARDs
Unlike leflunomide, biologic agents should be withheld before surgery and the procedure scheduled at the end of the dosing cycle 1, 7. This distinction is critical:
- Nonbiologic DMARDs (methotrexate, leflunomide, hydroxychloroquine, sulfasalazine): Continue 1, 2
- Biologic agents (TNF inhibitors, rituximab, etc.): Withhold one dosing cycle 1, 7
- Targeted synthetic DMARDs (tofacitinib, JAK inhibitors): Withhold 7 days preoperatively 8
Critical Safety Monitoring
Baseline and Perioperative Monitoring
The FDA label requires specific monitoring that continues through the perioperative period 6:
- Liver enzymes (ALT): Monthly for first 6 months, then every 6-8 weeks 6
- Complete blood count: Monthly for first 6 months, then every 6-8 weeks 6
- Blood pressure: Check before surgery and monitor postoperatively 6
Infection Risk Considerations
Leflunomide carries FDA black box warnings for immunosuppression and potential for serious infections including sepsis, Pneumocystis jiroveci pneumonia, and aspergillosis 6. However, in the surgical context, continuing the medication reduces rather than increases infection risk 1.
When to Consider Drug Elimination
Rapid elimination with cholestyramine (8g three times daily) or activated charcoal (50g every 6 hours) is indicated only for 6:
- Serious infection requiring leflunomide interruption 6
- Severe liver injury (ALT >3-fold upper limit of normal) 6
- Bone marrow suppression or pancytopenia 6
- Interstitial lung disease 6
Routine elective surgery is NOT an indication for drug elimination procedures. 1
Common Pitfalls to Avoid
Pitfall 1: Discontinuing Leflunomide "To Be Safe"
This actually increases infection risk and causes disease flares without providing benefit 1. The evidence clearly shows continuation is safer 1.
Pitfall 2: Confusing Leflunomide with Biologic DMARDs
Leflunomide is a nonbiologic DMARD and follows different perioperative management than biologics 1, 2. Do not withhold leflunomide based on recommendations for TNF inhibitors 1, 7.
Pitfall 3: Assuming Long Half-Life Requires Extended Discontinuation
While leflunomide has a 2-week half-life, this is irrelevant for perioperative management—the drug should be continued 1, 5. Brief discontinuation provides no benefit and causes harm 1.
Pitfall 4: Applying Non-Orthopedic Surgery Data
The strongest evidence is for THA/TKA, but indirect evidence suggests low infection risk with leflunomide in other surgical settings 1. The recommendation to continue can reasonably be extrapolated to other elective procedures 9.
Special Populations
Systemic Lupus Erythematosus
Continue leflunomide perioperatively in SLE patients, particularly those with severe disease where discontinuation risks life-threatening flares 1, 2.
Concomitant Methotrexate
When leflunomide and methotrexate are used together, both should be continued perioperatively, with monthly liver enzyme monitoring 6. The combination does not require discontinuation despite theoretical additive immunosuppression 1, 9.
Glucocorticoid Co-therapy
Continue baseline glucocorticoid doses perioperatively; consider stress-dose supplementation based on standard protocols for HPA axis suppression 9, 10. Leflunomide continuation does not alter glucocorticoid management 9.