Should methotrexate (Disease-Modifying Antirheumatic Drug (DMARD)) be discontinued in patients who develop a significant infection?

Management of Methotrexate During Active Infection

Methotrexate should be temporarily discontinued during severe infection or when infection is not responding to standard treatment, and can be restarted once the infection has cleared. 1

Immediate Management During Active Infection

When to Stop Methotrexate

• Discontinue immediately in patients with severe infection or infection not responding to standard antimicrobial therapy 1
• The FDA label indicates 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 2
• Permanently discontinue methotrexate if opportunistic infections develop (such as Pneumocystis jirovecii pneumonia) 1

Clinical Assessment During Infection

• Obtain complete blood count with differential to assess for neutropenia or other cytopenias that may complicate infection management 1
• Monitor renal function closely, as decreased renal function can lead to increased methotrexate levels and toxicity, particularly problematic during acute illness 1
• Monitor patients carefully for signs of sepsis and treat accordingly 1

Evidence Supporting Temporary Discontinuation

Infection Risk Profile

• Methotrexate increases infection risk, particularly for pneumonia, skin/soft tissue infections, and urinary tract infections, with most infections occurring within the first 18 months of treatment 1
• Research demonstrates that methotrexate-treated RA patients have a relative risk of 1.52 for infections and 2.19 specifically for skin infections compared to non-methotrexate treated patients 3
• A greater than expected number of deaths from infections has been observed in methotrexate-treated RA cohorts, suggesting methotrexate may be implicated as an associated factor 4

Immunosuppressive Effects

• Potentially fatal opportunistic infections may occur with methotrexate therapy 2
• Hypogammaglobulinemia has been reported, further compromising immune function 2
• Disseminated vaccinia infections after smallpox immunization have been reported in patients on methotrexate 2

Restarting Methotrexate After Infection Resolution

Criteria for Restarting

• Restart methotrexate when the infection has completely cleared 1
• Resume regular monitoring schedule after restarting therapy 1
• Ensure renal function has normalized before restarting, as impaired renal function increases toxicity risk 1

Post-Infection Monitoring

• Return to standard monitoring intervals: complete blood count every 2-3 months once therapy is stabilized 1
• Continue vigilance for recurrent infection, particularly in the first 18 months of treatment 1

Special Considerations During Infection Management

Drug Interactions to Avoid

• Avoid co-trimoxazole, trimethoprim, and other antifolate drugs during methotrexate therapy due to risk of severe bone marrow suppression 1
• This is particularly critical during infection when these antibiotics might otherwise be considered
• Other antibiotics can increase methotrexate toxicity through reduced protein binding or decreased renal elimination 1

High-Risk Patient Populations

• Use extreme caution in patients with comorbidities that increase infection risk, such as diabetes 1
• Patients with HIV or hepatitis require particularly careful consideration 1
• Chronic infections are a relative contraindication to methotrexate due to likely worsening from immunosuppressive effects 1

Contrast with ACR Guidelines on Previous Serious Infection

The 2021 ACR guidelines address previous serious infection (within 12 months) rather than active infection, conditionally recommending addition of conventional synthetic DMARDs over biologics or targeted synthetic DMARDs for patients with moderate-to-high disease activity 5. However, this guidance applies to patients with resolved infections, not active ongoing infections where immediate discontinuation is warranted 1.

Common Pitfalls to Avoid

• Do not continue methotrexate through severe infection hoping the antimicrobial therapy alone will suffice—the immunosuppression may prevent adequate immune response 1, 2
• Do not use trimethoprim-containing antibiotics (including co-trimoxazole) in patients on methotrexate due to synergistic antifolate effects causing potentially fatal bone marrow suppression 1
• Do not restart methotrexate prematurely before infection has completely resolved and renal function normalized 1
• Do not assume all infections require discontinuation—mild, responding infections may not require stopping the drug, but severe or non-responding infections mandate immediate discontinuation 1