Should azathioprine (Aza) or methotrexate (MTX) be temporarily stopped in a patient with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) who develops an active infection like community-acquired pneumonia (CAP) or pyelonephritis, while starting antibiotics?

Management of Azathioprine and Methotrexate During Active Infection in RA/SLE Patients

Temporarily discontinue both azathioprine and methotrexate when a patient with RA or SLE develops an active serious infection like community-acquired pneumonia or pyelonephritis, and restart only after the infection has completely cleared. 1, 2

Evidence-Based Rationale

Methotrexate Management During Active Infection

The British Association of Dermatologists explicitly recommends that methotrexate should be immediately discontinued during severe infection or when infection is not responding to standard treatment. 1, 2 This recommendation is based on:

• MTX increases infection risk, particularly for pneumonia, skin/soft tissue infections, and urinary tract infections 1, 2
• The FDA label states that methotrexate should be used with extreme caution in the presence of active infection and is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency 3
• Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with methotrexate therapy 3

Azathioprine Management During Active Infection

While direct guidelines for azathioprine during active infection are less explicit, the ACR COVID-19 guidance provides relevant direction:

• Immunosuppressants including azathioprine should be stopped temporarily following known infection exposure, pending negative test results or after symptom-free observation 4
• In documented or presumptive infection, immunosuppressants including azathioprine should be stopped or withheld regardless of infection severity 4

Key Distinction: This is NOT Perioperative Management

The perioperative guidelines recommend continuing methotrexate through elective surgery 4, but this applies to planned procedures in infection-free patients, not active infections. The perioperative context involves:

• Controlled timing and sterile conditions 4
• Evidence showing decreased infection risk when DMARDs continued through surgery (RR 0.39) 4
• Elective procedures where infection risk can be minimized 4

Active infection represents a fundamentally different clinical scenario requiring immediate drug discontinuation. 1, 2

Clinical Algorithm for Management

Step 1: Immediate Actions Upon Diagnosis of Serious Infection

• Stop methotrexate immediately 1, 2
• Stop azathioprine immediately 4
• Initiate appropriate antibiotic therapy for CAP or pyelonephritis
• Obtain complete blood count with differential to assess for neutropenia or cytopenias 2
• Monitor renal function closely, as decreased renal function increases methotrexate toxicity risk 2

Step 2: Monitoring During Infection Treatment

• Monitor carefully for signs of sepsis 1
• Avoid trimethoprim, co-trimoxazole, or other antifolate antibiotics in patients who were on methotrexate due to risk of severe bone marrow suppression 2
• Be cautious with penicillins (including amoxicillin-clavulanate) as they can increase methotrexate toxicity through reduced renal elimination 2
• Consider cephalosporins or fosfomycin as safer antibiotic options for UTI in patients recently on methotrexate 2

Step 3: Criteria for Restarting Immunosuppression

Restart methotrexate and azathioprine only when ALL of the following criteria are met: 1, 2

• Infection has completely cleared clinically
• Antibiotic course is complete 2
• Renal function has normalized (particularly important for methotrexate) 2
• No ongoing signs of infection (fever, elevated inflammatory markers)
• Patient is clinically stable

For uncomplicated infections treated in the ambulatory setting, consider restarting 7-14 days after symptom resolution 4

Step 4: Post-Restart Monitoring

• Resume regular monitoring schedule including CBC every 2-3 months 2
• Monitor for disease flare, which may occur after temporary discontinuation
• Adjust corticosteroid dose if needed to prevent flare during the drug holiday

Critical Pitfalls to Avoid

Do not continue methotrexate or azathioprine through severe infection, as this prevents adequate immune response and increases risk of severe complications including opportunistic infections 1, 2, 3

Do not use trimethoprim-containing antibiotics in patients on or recently on methotrexate, as this combination can cause fatal bone marrow suppression through synergistic antifolate effects 2

Do not restart immunosuppression prematurely before infection has completely resolved and renal function normalized, as this increases toxicity and complication risk 2

Do not confuse perioperative management with active infection management - the evidence supporting continuation through elective surgery does not apply to active infections 4, 1, 2

Special Considerations

For SLE Patients with Severe Disease

Even in patients with severe SLE requiring immunosuppression, active serious infection takes priority over disease control 4. Temporarily increase corticosteroids if needed to bridge the period off immunosuppressants, but discontinue azathioprine and methotrexate during active infection 4.

Risk Factors Requiring Extra Vigilance

Patients at highest risk during infection include those with 1, 2, 3:

• Advanced age
• Renal impairment
• Diabetes mellitus
• Chronic lung disease
• Treatment duration >18 months (highest infection risk in first 18 months) 5