In an adult with rheumatoid arthritis on low‑dose weekly methotrexate, should the medication be withheld before a moderate‑to‑major surgery requiring general anesthesia, and when can it be safely resumed?

Methotrexate Should Be Continued Through Surgery in Rheumatoid Arthritis Patients

For adults with rheumatoid arthritis on low-dose weekly methotrexate undergoing moderate-to-major surgery with general anesthesia, continue methotrexate at the current dose through the perioperative period without interruption. This approach decreases infection risk and prevents disease flares while maintaining optimal disease control 1, 2.

Evidence-Based Rationale

The 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons guideline provides the strongest evidence for this recommendation:

• Continuing methotrexate significantly reduces infection risk (RR 0.39,95% CI 0.17-0.91) compared to withholding it 1
• Disease flares are dramatically reduced when methotrexate is continued (RR 0.06,95% CI 0.0-1.10) 1
• This recommendation applies to elective orthopedic surgery and extends to other major surgical procedures including spine surgery 1, 2

Perioperative Management Algorithm

Preoperative Phase

• Continue methotrexate at the usual weekly dose without any interruption leading up to surgery 1, 2
• Verify adequate renal function (creatinine clearance >60 mL/min) before proceeding, as impaired renal function significantly increases methotrexate toxicity risk 1
• For patients with creatinine clearance 20-50 mL/min, reduce methotrexate dose by half; avoid entirely if <20 mL/min 3

Day of Surgery

• Administer methotrexate on the scheduled day if it falls on the day of surgery 1
• Continue glucocorticoids at the current daily dose rather than stress-dosing, as supraphysiologic doses lack evidence and may increase complications 4, 3

Postoperative Phase

• Resume methotrexate immediately when oral intake recommences after surgery 3, 2
• If methotrexate was inadvertently held, restart once the wound shows healing (typically ~14 days), all sutures/staples are removed, and there is no evidence of infection 4, 3

Critical Exceptions Requiring Temporary Discontinuation

While continuation is the standard approach, methotrexate should be temporarily withheld in these specific scenarios:

• Active infection requiring antibiotics: Stop methotrexate until infection resolves and antibiotic course is completed 3
• Severe acute illness during hospitalization: Temporarily discontinue during acute medical decompensation 3
• Abnormal liver function: Hold if transaminases exceed twice the upper limit of normal 3
• Bone marrow suppression: Withhold if WBC <3.5×10⁹/L or neutrophils <2×10⁹/L until counts normalize 3

Supporting Research Evidence

Multiple prospective studies confirm the safety of continuing methotrexate:

• A landmark 2001 randomized controlled trial of 388 RA patients showed that continuing methotrexate resulted in only 2% complications versus 15% in those who discontinued it (p<0.003) 5
• A 2011 ten-year follow-up study found no incidences of deep bone infection in patients who continued methotrexate perioperatively 6
• A 2006 study of 201 surgical procedures demonstrated no significant difference in infection rates between patients continuing versus discontinuing methotrexate 7

Common Pitfalls to Avoid

Do not reflexively stop methotrexate "to be safe" – this outdated practice actually increases both infection risk and disease flare risk based on current evidence 1, 5. The historical concern from the 1990s about methotrexate increasing surgical complications has been definitively refuted by subsequent high-quality studies 8, 6, 5.

Do not confuse methotrexate management with biologic therapy management – while biologics should be withheld prior to surgery (planned at the end of the dosing cycle), methotrexate follows different principles due to its short half-life and different mechanism of action 2.

Monitor for drug interactions postoperatively – if antibiotics are required for severe postoperative infection, temporarily stop methotrexate as many antibiotics (penicillins, tetracyclines) can increase methotrexate toxicity 3.

Disease-Specific Considerations

For patients with severe systemic lupus erythematosus, the recommendation is to continue methotrexate through surgery based on indirect evidence from organ transplant patients who maintain immunosuppression perioperatively 4.

For patients with inflammatory bowel disease on methotrexate, continuation during the perioperative period does not adversely affect postoperative outcomes given the 1-2 hour elimination half-life 3.