How should I perform and interpret a tuberculin skin test (TST) for a patient who will be started on tofacitinib, including management of positive or negative results?

Tuberculin Skin Test for Tofacitinib Initiation

Perform a Mantoux tuberculin skin test (TST) using 0.1 ml of 5 TU PPD intradermally, read at 48-72 hours, and consider ≥5 mm induration as positive in patients starting tofacitinib due to their immunosuppressed status. 1

Test Administration

Administer the TST using the Mantoux method by injecting 0.1 ml of 5 tuberculin units (TU) PPD intradermally into the dorsal or volar surface of the forearm. Read the test between 48-72 hours after administration and measure the transverse diameter of induration in millimeters. 1 Multiple puncture tests (Tine, Heaf) and alternative PPD strengths should not be used as they lack sufficient accuracy.

Interpretation Criteria

For patients receiving immunosuppressive therapy like tofacitinib, use the ≥5 mm induration cutoff for positivity. 1 This lower threshold is appropriate because:

• Immunosuppressed patients have high likelihood of developing active TB if infected with M. tuberculosis
• Patients on systemic immunosuppression (including JAK inhibitors like tofacitinib) fall into the highest-risk category 1
• The increased sensitivity of the 5 mm cutoff ensures high-risk patients are appropriately identified and treated

Note that steroid use can suppress TST reactions and cause false-negative results 2, though this appears less problematic with DMARDs like methotrexate.

Management of Negative TST

If the initial TST shows <5 mm induration:

1. Repeat the TST within 1-2 weeks on the opposite forearm 3, 4, 5
2. Consider the test truly negative only if the repeat also shows <5 mm induration
3. Even with a negative TST, consider LTBI treatment in immunosuppressed patients before starting tofacitinib after risk/benefit assessment 4, 5, particularly if:
   • Patient is from or has lived in TB-endemic regions
   • Patient has history of TB exposure
   • Patient has poor socioeconomic circumstances or HIV positivity

The rationale for repeat testing addresses the "booster phenomenon" and ensures valid results in immunosuppressed patients who may have diminished initial responses. 3

Management of Positive TST (≥5 mm)

When TST is positive:

1. Obtain chest radiograph to assess for active TB 3, 1

   • Ghon complex indicates latent TB requiring treatment
   • Ghon complex with enlarged mediastinal lymph nodes suggests active primary TB
   • Scarring requires clinical correlation and exclusion of active disease

2. Evaluate for active disease if:

   • Patient has suspicious signs/symptoms (cough, fever, night sweats, weight loss)
   • Patient lives in or previously lived in endemic regions
   • Chest radiograph shows abnormalities

3. Obtain sputum examinations if suspicious signs/symptoms present or abnormal chest radiograph 3

4. Initiate LTBI treatment (if active TB excluded):

   • Isoniazid (INH) for 9 months OR rifampin for 4 months 3
   • Use 2-4 drug regimen for 2-3 months if resistance suspected (>10% background resistance in patient's region of origin) 3
   • Monitor liver function tests every 2-4 weeks during treatment 3

Timing of Tofacitinib Initiation

Complete LTBI or active TB treatment before starting tofacitinib whenever possible. 4, 5 However, if disease activity requires urgent treatment:

• For active TB: Start tofacitinib after 2 months of antituberculous therapy 4, 5
• For LTBI: Start tofacitinib after 1 month of LTBI treatment 4, 5

This approach balances TB risk mitigation with the need to control inflammatory disease activity.

Clinical Context

Recent data shows no cases of active TB occurred in tofacitinib users in a Korean cohort, compared to 32 cases in TNF inhibitor users 6, suggesting tofacitinib may carry lower TB reactivation risk than TNF inhibitors. However, this does not eliminate the need for proper TB screening, as tofacitinib remains an immunosuppressive agent.

Critical pitfall: Do not rely on anergy testing, as it has methodological problems and unclear benefits. 3 The risk of TB remains low even in anergic patients with negative PPD, and standardization issues make interpretation unreliable.