Methotrexate and Quantiferon Testing for Latent Tuberculosis
Baseline tuberculosis screening with Quantiferon (or other IGRA tests) should be considered before starting methotrexate, particularly in patients with TB risk factors, though this is not an absolute requirement like it is for TNF-α inhibitors.
Risk-Based Screening Approach
The relationship between methotrexate and TB reactivation is less clearly defined compared to biologic agents 1. The decision to screen should be based on individual patient risk factors rather than universal testing 1.
When to Screen for Latent TB Before Methotrexate:
High-priority screening indications 1:
- Personal history of tuberculosis
- Known TB exposure or contact with active TB cases
- Immigration from or residence in TB-endemic countries
- Healthcare workers or prison populations
- Homelessness or injection drug use
- HIV infection
- Diabetes mellitus
- Chronic alcohol use or smoking
Additional considerations for screening 1:
- Patients receiving concomitant glucocorticoids ≥15 mg prednisone daily for >4 weeks
- Plans for future combination therapy with biologics
Preferred Testing Method
IGRA tests (Quantiferon-TB Gold or T-SPOT) are preferred over tuberculin skin test (TST) when screening patients who will receive methotrexate 1.
Key advantages of IGRA over TST:
- IGRAs are less affected by methotrexate and other immunosuppressants 1, 2
- Better specificity in BCG-vaccinated populations 1
- No need for return visit for reading 1
- Methotrexate therapy is associated with false-positive TST results (two-fold increased risk) in a dose-dependent manner 3
Important Testing Caveats:
- Prednisolone (but not long-acting corticosteroids) severely impairs both IGRA and TST performance, with doses ≥10 mg prednisolone associated with 27% indeterminate IGRA results 2
- Methotrexate alone does not significantly impair IGRA test performance 2, 4
- Both tests can be performed if high suspicion exists, though concordance is only moderate (kappa = 0.584) 4
- Chest X-ray should be included in screening protocols, as negative IGRA/TST cannot exclude active TB 1
Management of Positive Results
Any suspicion of latent TB based on history or positive screening should result in treatment prior to commencing methotrexate 1.
Treatment considerations:
- Isoniazid prophylaxis combined with methotrexate is well-tolerated, with only 11% experiencing transient LFT elevations (none >2× upper limit of normal) that resolved spontaneously 5
- Follow national/regional guidelines for latent TB treatment regimens 1
- Common regimens include: isoniazid 9 months, rifampin 4 months, or combination therapy 3-4 months 1
- Monitor liver function tests closely when combining isoniazid with methotrexate, though additive hepatotoxicity risk is low 5
Contrast with Biologic Therapy
The evidence clearly distinguishes methotrexate from TNF-α inhibitors 1:
- TNF-α inhibitors have a well-established association with TB reactivation and require mandatory screening 1
- Methotrexate has a less clearly defined link to TB reactivation, with no specific guidance from major health authorities mandating universal screening 1
- Yearly TB rescreening is recommended for high-risk patients on TNF-α inhibitors but not routinely for methotrexate monotherapy 1
Practical Algorithm
- Assess TB risk factors (history, exposure, endemic country origin, comorbidities) 1
- If risk factors present: Perform IGRA (preferred) and chest X-ray 1
- If no risk factors: Screening at clinician's discretion based on local TB prevalence 1
- If positive screening: Treat latent TB before or concurrent with methotrexate initiation 1, 5
- Avoid screening during high-dose prednisolone therapy (≥10 mg daily) due to test unreliability 2