Should methotrexate be stopped in a patient with latent tuberculosis (TB)?

Management of Methotrexate in Patients with Latent Tuberculosis

Methotrexate does not need to be stopped in patients with latent tuberculosis infection (LTBI) as it does not significantly increase the risk of TB reactivation compared to placebo. 1

Risk Assessment of Methotrexate in LTBI

Methotrexate alone has not been shown to significantly increase the risk of tuberculosis reactivation:

• According to the 2021 ECCO guidelines, "In patients treated with methotrexate or azathioprine, a short course of corticosteroids, or ciclosporin, several studies showed that the risk of TB is not higher when compared with placebo alone, and thus no treatment of LTBI is recommended in these patients." 1

• The 2014 ECCO consensus similarly indicates that the primary concern for TB reactivation is with biologic therapies, particularly anti-TNF agents, rather than with conventional immunosuppressants like methotrexate 1

Important Distinctions in Medication Risk

Low-Risk Medications:

• Methotrexate monotherapy
• Azathioprine
• Short courses of corticosteroids
• Ciclosporin

High-Risk Medications (requiring LTBI treatment):

• Anti-TNF agents (4.7-fold increased risk of TB reactivation) 1
• JAK inhibitors 1
• Combination therapy of anti-TNF with methotrexate (13-fold increased risk compared to anti-TNF monotherapy) 1

Management Algorithm for Patients with LTBI on Methotrexate

1. For patients on methotrexate monotherapy:

   • Continue methotrexate
   • No LTBI treatment required based on methotrexate use alone 1
   • Monitor for symptoms of active TB as part of routine care

2. For patients planning to start anti-TNF or JAK inhibitors:

   • Complete LTBI treatment before starting these medications
   • Methotrexate can be continued during LTBI treatment 2
   • Studies show that combined methotrexate and isoniazid treatment is generally well-tolerated with only 11% of patients experiencing transient liver function test elevations 2

3. For patients on combination therapy (methotrexate + anti-TNF):

   • Higher risk of TB reactivation (13-fold increased compared to anti-TNF alone) 1
   • LTBI treatment is mandatory before starting this combination

Monitoring Recommendations

• Regular clinical monitoring for TB symptoms
• Liver function tests should be monitored when methotrexate is used, especially if combined with isoniazid for LTBI treatment 2
• No need for annual TB re-screening in patients on methotrexate monotherapy 1

Cautions and Pitfalls

1. Diagnostic confusion: Be aware that methotrexate therapy may be associated with false-positive tuberculin skin test results. If TB testing is needed in patients on methotrexate, IGRAs (Interferon-Gamma Release Assays) are preferred over tuberculin skin tests 3

2. Combination risk: The greatest risk occurs when methotrexate is combined with biologics, not when used alone. The combination of anti-TNF agents with methotrexate results in a 13-fold increased risk of TB reactivation compared with anti-TNF monotherapy 1

3. Active infection management: While methotrexate can be continued in LTBI, it should be temporarily discontinued during active infections until they resolve 4

In conclusion, methotrexate monotherapy does not significantly increase the risk of tuberculosis reactivation in patients with LTBI and does not need to be stopped. However, careful monitoring and appropriate LTBI treatment should be implemented if adding higher-risk medications like anti-TNF agents or JAK inhibitors to the treatment regimen.