TNF Inhibitors and TB Reactivation: Screening and Monitoring

When doctors prescribe TNF inhibitors for conditions like rheumatoid arthritis, psoriatic arthritis, or Crohn’s disease, they’re targeting a powerful driver of inflammation. These drugs - including infliximab, a monoclonal antibody that blocks tumor necrosis factor-alpha, adalimumab, another monoclonal antibody with similar action, and etanercept, a soluble TNF receptor - work by shutting down a key immune signal called TNF-alpha. But in doing so, they also weaken the body’s ability to contain hidden infections, especially latent tuberculosis (LTBI), a dormant form of TB that affects up to one-quarter of the global population. The result? A real and measurable spike in active TB cases among people taking these medications.

Why Some TNF Inhibitors Are Riskier Than Others

Not all TNF inhibitors carry the same risk. Data from the British Society for Rheumatology Biologics Register shows that patients on infliximab or adalimumab are more than three times as likely to develop TB as those on etanercept. Why? It comes down to how each drug interacts with the immune system at a cellular level.

Infliximab and adalimumab are monoclonal antibodies that bind tightly to both free-floating and membrane-bound TNF. This blocks the signal completely - but membrane-bound TNF is essential for keeping TB bacteria locked inside granulomas, the body’s natural containment structures. When that signal is wiped out, granulomas fall apart, and TB wakes up.

Etanercept works differently. It’s a fusion protein that acts like a decoy receptor. It soaks up excess TNF but leaves membrane-bound TNF mostly untouched. That’s why its TB risk is far lower - studies show it’s only about one-fifth as risky as the antibody-based drugs.

Screening Isn’t Optional - It’s Life-Saving

Before anyone starts a TNF inhibitor, screening for latent TB is non-negotiable. The American Thoracic Society, CDC, and Infectious Diseases Society of America all agree: you must test. Two tools are used: the tuberculin skin test (TST) and the interferon-gamma release assay (IGRA). Each has strengths and limits. TST is cheaper and widely available, but can give false positives if you’ve had the BCG vaccine. IGRA is more specific, especially in vaccinated people, but costs more and isn’t available everywhere.

A 2019-2024 study of 519 patients found that 87% received TST, 37% got a booster TST, and only 6% got IGRA. That’s not enough. Guidelines now recommend IGRA for high-risk patients - especially those from countries with high TB rates. In places like India, the Philippines, or Nigeria, where TB is common, even a negative test doesn’t guarantee safety. That’s why the European League Against Rheumatism (EULAR) says: if you’re from a high-burden country, treat for latent TB even if your test is negative.

Treatment Before Therapy

If you test positive for latent TB, you don’t start the TNF inhibitor right away. You treat the TB first. The gold standard used to be nine months of isoniazid. But adherence was terrible - nearly a third of patients quit because of liver concerns or just forgetting pills. That’s changing. In 2024, the FDA approved a new 4-month regimen combining rifampin and isoniazid. Clinical trials showed adherence jumped from 68% to 89%. That’s huge. It means more people complete treatment, and fewer develop active TB later.

Isoniazid, a first-line TB drug can cause liver damage, especially in older adults or those with alcohol use. That’s why liver enzymes are checked before and during treatment. But skipping treatment because of fear is riskier than the side effects. A single case of active TB on a TNF inhibitor can be deadly.

What Happens Even After Screening?

Here’s the uncomfortable truth: screening isn’t perfect. A review of 1,200 patients across five clinics found that 18% of those who developed TB had negative screening results. Why? Some people get infected right before starting the drug - their bodies haven’t had time to react yet. Others have false negatives because their immune systems are already suppressed by other medications. And some infections are so early, the test just can’t detect them.

That’s why monitoring doesn’t stop after the first dose. Patients need to be watched closely for the first year. Every three months, doctors should ask: Have you had fever? Night sweats? Unexplained weight loss? A cough that won’t go away? These aren’t just symptoms - they’re red flags. In patients on TNF inhibitors, TB often spreads beyond the lungs. Up to 78% of cases involve the spine, lymph nodes, or even the brain - making diagnosis harder and treatment more urgent.

When TB Strikes: TB-IRIS and Other Complications

Sometimes, when you start treating TB in someone who’s been on a TNF inhibitor, their immune system overreacts. This is called TB-IRIS - immune reconstitution inflammatory syndrome. It happens when the immune system wakes up, fights the TB bacteria too hard, and causes swelling, pain, and fever. It’s not the infection getting worse - it’s the body’s own response.

In one study, 12.7% of patients on anti-TNF therapy developed TB-IRIS after starting TB treatment. Most cases appeared about 110 days after their last TNF inhibitor dose. Treatment often requires high-dose steroids for months. It’s complicated, scary, and avoidable - if screening and timing are done right.

Global Disparities and Real-World Challenges

In the U.S., where TB is rare, the absolute risk is low - but it’s still there. In high-burden countries, the risk jumps dramatically. WHO reports that 80% of rheumatology clinics in low-resource settings can’t even access IGRA testing. Many patients never get screened at all. And when they do, follow-up care is patchy. One rheumatology nurse on Reddit shared a case: a patient from Bangladesh tested negative, started adalimumab, and developed miliary TB - a deadly, widespread form - within four months.

Cost is another barrier. Screening adds $150-$300 to initial treatment. But compared to the cost of treating active TB - which can run over $100,000 in hospital stays, antibiotics, and long-term care - screening is a bargain. And it saves lives.

The Future: Safer Drugs Are Coming

Researchers are already working on next-generation TNF inhibitors that don’t disrupt granulomas. Early animal studies show a new class of drugs - like those targeting CD271 - reduce TB reactivation risk by 80% compared to current drugs. These are still in Phase II trials, but they offer real hope. The goal isn’t just to treat inflammation - it’s to do it without leaving patients vulnerable to deadly infections.

What You Need to Do

If you’re considering a TNF inhibitor:

• Ask for a TB test - TST or IGRA - before your first dose.
• If you’re from a country with high TB rates, insist on treatment even if your test is negative.
• If you’re positive for latent TB, complete the full 4-month or 9-month regimen before starting the biologic.
• Report any fever, night sweats, weight loss, or cough immediately - even months after starting treatment.
• Don’t skip follow-ups. TB can strike even after a year.

If you’re a provider:

• Use IGRA for high-risk patients.
• Consider the 4-month rifampin/isoniazid regimen - it works better and sticks better.
• Don’t rely on one negative test. Repeat if symptoms appear.
• Remember: extrapulmonary TB is common in these patients. Think beyond the lungs.

Managing TB risk with TNF inhibitors isn’t about fear - it’s about smart, consistent care. Test before you start. Treat if needed. Watch for symptoms. The science is clear. The protocols exist. The tools are available. What matters now is making sure they’re used - every time, for every patient.