What infection should be ruled out by pre-treatment screening before initiating treatment with a Tumor Necrosis Factor-alpha (TNF-α) inhibitor?

Pre-Treatment Screening for Tuberculosis Before TNF-α Inhibitor Therapy

All patients must be screened for tuberculosis (TB)—both active and latent infection—before initiating TNF-α inhibitor therapy, as this represents the most critical infection to rule out given the substantially elevated risk of TB reactivation. 1

Primary Infection to Screen: Tuberculosis

Why TB Screening is Essential

• TNF-α inhibitors increase TB risk up to 25-fold, with the highest relative risks seen with adalimumab (29.3) and infliximab (18.6) 2, 3
• The incidence of TB in patients on anti-TNF therapy reaches 449 cases per 100,000 population annually, far exceeding background rates 4
• TB occurring during TNF-α treatment is more likely to be disseminated and extrapulmonary compared to typical TB cases 3

Mandatory Screening Components

Clinical Assessment

• Obtain complete medical history including prior TB exposure, household contacts with TB, prolonged stay or origin from TB-endemic areas 1
• Document any history of prior TB treatment and assess adequacy of that treatment 1
• Perform clinical examination for signs of active TB disease 1

Radiographic Evaluation

• Chest radiograph is mandatory for all patients before starting TNF-α inhibitors 1
• Any abnormal chest radiograph requires referral to a thoracic or infectious disease physician before proceeding 1

Immunologic Testing

• Interferon-gamma release assays (IGRAs) are the preferred test for latent TB infection screening 1, 2, 5
• Tuberculin skin test (TST) has unacceptably high false-negative rates in immunosuppressed patients, with 83% of patients on steroids or immunomodulators showing anergy 1, 6
• IGRAs maintain better sensitivity in immunosuppressed patients and higher specificity in BCG-vaccinated individuals 7, 5, 3

Interpretation of Testing

For patients without BCG vaccination:

• TST ≥5 mm is considered positive and warrants treatment for latent TB 1

For patients with BCG vaccination:

• IGRA is essential as TST has poor specificity 7, 5
• TST >15 mm (Heaf grades 3-4) may represent latent infection versus BCG effect and requires risk assessment 1

For patients already on immunosuppression:

• IGRA should be used rather than TST due to high anergy rates 1, 5
• Consider using both tests in combination to maximize sensitivity, though this increases cost 2, 3

Additional Infections to Screen (Secondary Priority)

While TB is the primary concern, manufacturers contraindicate TNF-α inhibitor use with HIV, hepatitis B, or hepatitis C co-infection 1

Viral Screening Panel

• Hepatitis B virus (HBV) serology 1
• Hepatitis C virus (HCV) serology 1
• HIV serology 1
• Varicella zoster virus (VZV) serology in patients without clear history of prior infection or vaccination 1

Parasitic Infections

• Strongyloides serology and eosinophil count should be checked in patients who have traveled for long periods or lived in endemic areas 1

Management of Positive TB Screening

Active TB Detected

• Do not start TNF-α inhibitor therapy 1
• Refer immediately to TB specialist for full evaluation and treatment 1

Latent TB Infection Detected

Treatment regimen:

• Isoniazid 5 mg/kg (maximum 300 mg) daily for 9 months is the cornerstone treatment 6
• Alternative: 6 months of isoniazid provides 60-80% effectiveness versus 90% with 9 months 6
• Alternative: Rifampicin for 4 months or 3 months rifampicin/isoniazid if shorter duration needed 1

Timing of TNF-α inhibitor initiation:

• Delay biologic therapy for at least 3-4 weeks after starting latent TB treatment 6
• Ideally, complete chemoprophylaxis before starting TNF-α inhibitor, though this causes 6-9 month delay 1
• In severe disease requiring urgent treatment, biologics may be started earlier with infectious disease consultation 6

Monitoring during latent TB treatment:

• Baseline liver function tests are essential before starting isoniazid 6
• Stop therapy if ALT/AST exceeds 3-fold normal with symptoms or 5-fold without symptoms 6

Previous Adequate TB Treatment

• Patients with adequately treated prior TB can start TNF-α inhibitors but require clinical monitoring every 3 months 1
• New respiratory symptoms within 3 months of starting TNF-α therapy require prompt investigation 1

Critical Pitfalls to Avoid

• Do not rely solely on TST in immunosuppressed patients—the false-negative rate is unacceptably high 1, 6
• Do not skip screening even in low TB prevalence areas—the risk with TNF-α inhibitors justifies screening universally 7, 2
• Chemoprophylaxis provides only partial protection—8 of 36 patients who received appropriate chemoprophylaxis still developed active TB in one study 4
• Consider annual re-screening for patients with ongoing TB risk factors during TNF-α inhibitor therapy 6
• Combination therapy with thiopurines increases TB risk 13-fold compared to anti-TNF monotherapy 6