Should I discontinue methotrexate while I have an active herpes infection?

Should You Stop Methotrexate During Active Herpes Infection?

Yes, you should temporarily discontinue methotrexate during active herpes infection, whether herpes simplex or herpes zoster, and restart only after the infection has completely resolved with appropriate antiviral therapy. 1, 2

Immediate Management Algorithm

Step 1: Discontinue Methotrexate Immediately

• Stop methotrexate as soon as active herpes infection is diagnosed 1, 2
• This applies to both herpes simplex virus (HSV) and varicella zoster virus (VZV/herpes zoster) infections 3
• The rationale is that continuing immunosuppression prevents adequate immune response and increases risk of severe complications 1

Step 2: Initiate Antiviral Therapy

• Start appropriate antiviral treatment promptly (acyclovir, valacyclovir, or famciclovir depending on severity) 3, 4
• For severe HSV disease, intravenous aciclovir may be required 3, 5
• For disseminated herpes zoster, intravenous acyclovir for 48 hours followed by oral therapy is recommended 4

Step 3: Monitor for Complications

• Obtain complete blood count with differential to assess for neutropenia or cytopenias that may complicate infection management 1, 2
• Monitor renal function closely, as decreased renal function can lead to increased methotrexate levels and toxicity 1, 2
• Watch for signs of disseminated infection, particularly in herpes zoster (involvement of multiple dermatomes, visceral involvement) 4, 6

Evidence Supporting Discontinuation

Guideline Recommendations

The most recent and authoritative guidance comes from multiple sources:

• British Association of Dermatologists explicitly states methotrexate should be stopped during severe infection or infection not responding to standard treatment 1, 2
• European Crohn's and Colitis Organisation recommends immunomodulators should not be commenced during active chickenpox or herpes zoster, and should be discontinued in severe cases 3
• American College of Rheumatology COVID-19 guidance (while focused on COVID-19) establishes the principle of temporarily withholding methotrexate during active infection 3

Clinical Evidence of Risk

Methotrexate-treated patients face specific herpes-related risks:

• Increased incidence: Herpes zoster occurs at 14.5 cases per 1,000 patient-years in methotrexate-treated rheumatoid arthritis patients versus 1.3-4.8 per 1,000 in the general population 7
• Disseminated infection risk: Case reports document disseminated herpes zoster with multiple organ involvement (hepatitis, pancreatitis, encephalitis) in methotrexate-treated patients 4, 6
• Severe HSV complications: Herpes simplex hepatitis with 81% mortality has been reported in immunocompromised hosts on methotrexate 5
• Atypical presentations: Isolated HSV laryngitis and other unusual manifestations occur with methotrexate-induced immunosuppression 8

When to Restart Methotrexate

Criteria for Restarting

• Complete resolution of infection: All vesicles must be crusted over and fever resolved 3
• Completion of antiviral course: Restart only after the full antibiotic/antiviral course is complete 1, 2
• Normalized renal function: Ensure renal function has returned to baseline before restarting 1, 2

Post-Restart Monitoring

• Resume regular monitoring schedule including complete blood count every 2-3 months once therapy is stabilized 1, 2
• Consider whether prophylactic antiviral therapy is warranted for future prevention, especially in patients with recurrent herpes 9

Critical Pitfalls to Avoid

Do Not Continue Through Active Infection

• Never continue methotrexate through severe herpes infection, as this prevents adequate immune response and dramatically increases risk of dissemination and mortality 1, 2, 5
• Even "mild" appearing herpes can progress to life-threatening disseminated disease in immunosuppressed patients 4, 6

Avoid Drug Interactions During Treatment

• Do not use trimethoprim or co-trimoxazole if bacterial superinfection occurs, as synergistic antifolate effects can cause fatal bone marrow suppression 1, 2
• Be cautious with penicillins and other antibiotics that may increase methotrexate toxicity through reduced renal elimination 1, 2

Do Not Restart Prematurely

• Restarting before complete infection resolution risks relapse and severe complications 1, 2
• Ensure adequate time for immune reconstitution after stopping methotrexate 3

Special Considerations

Risk Factors for Severe Disease

The risk of complicated herpes infection depends on multiple factors beyond methotrexate alone:

• Advanced age (particularly >80 years) 4
• Concurrent corticosteroid use 5, 6
• Longer duration of underlying rheumatic disease 7
• High rheumatoid factor titers 7
• Comorbidities including diabetes 1, 2

Long-term Context

While methotrexate does increase herpes zoster risk, the 2009 multinational evidence-based recommendations note that long-term methotrexate use was not associated with increased risk of herpes zoster overall (HR 1.0; 95% CI 0.8 to 1.3) 3. However, this population-level data does not negate the need to stop during active infection, as individual cases can be severe and life-threatening 4, 5, 6.