TNF Inhibitors and TB Reactivation: Screening and Monitoring Guidelines

When you start a TNF inhibitor for rheumatoid arthritis, psoriasis, or Crohn’s disease, you’re getting powerful relief from inflammation. But behind that relief is a quiet danger: TNF inhibitors can wake up dormant tuberculosis (TB) in your body. This isn’t theoretical. In real-world clinics, patients on these drugs are developing active TB-sometimes within months of their first dose. And not all TNF inhibitors carry the same risk.

Why TNF Inhibitors Reactivate TB

Your body keeps TB bacteria in check by building tiny walls of immune cells around them, called granulomas. These walls hold the infection in place, keeping you symptom-free. That’s latent TB infection (LTBI)-you’re infected, but not sick. TNF-alpha is the glue that holds those granulomas together. When you block TNF-alpha with a drug, those walls start to crumble.

Not all TNF blockers are the same. There are two main types: etanercept (a soluble receptor) and monoclonal antibodies like infliximab and adalimumab. The antibody types bind tightly to both free-floating and cell-bound TNF-alpha. That’s the problem. Cell-bound TNF-alpha is what keeps granulomas intact. Etanercept doesn’t bind as strongly to the cell-bound version, so it’s less likely to break down those walls. That’s why studies show patients on infliximab or adalimumab are more than three times as likely to develop TB as those on etanercept.

Who’s at Risk?

Anyone on a TNF inhibitor is at risk, but some faces higher danger. If you were born in or lived for a long time in a country with high TB rates-India, the Philippines, Nigeria, Vietnam, or parts of Eastern Europe-you’re at much greater risk. Even if you’ve lived in the UK or US for years, your past exposure matters. TB can lie dormant for decades.

Age also plays a role. Older adults are more likely to have had past exposure. People with diabetes, kidney disease, or who’ve had organ transplants are also more vulnerable. And if you’ve had TB before-even if you were treated-you’re still at risk. The bacteria can hide in scar tissue, waiting for the right moment to return.

Screening Before You Start

Before you get your first TNF inhibitor shot or infusion, you must be screened for latent TB. There are two main tests: the tuberculin skin test (TST) and the interferon-gamma release assay (IGRA). Both look for your immune system’s memory of TB bacteria.

In practice, TST is still more common because it’s cheaper and easier to do. But IGRA is more accurate, especially if you’ve had the BCG vaccine (given in many countries to prevent TB). The BCG vaccine can cause false positives on TST. IGRA doesn’t get fooled by that.

Guidelines say: do one or the other. Some clinics do both, especially for high-risk patients. A 2024 study from a major UK hospital found that 87% of patients got a TST, but only 6% got IGRA. That’s not enough. For people from high-TB-burden countries, IGRA should be the first choice.

What If You Test Positive?

If your test comes back positive, you don’t start the TNF inhibitor right away. You treat the latent TB first. The old standard was nine months of isoniazid. That’s effective-but hard to stick with. Side effects like liver damage, nausea, and fatigue make many people quit. A 2023 FDA-approved option is a four-month course of rifampin and isoniazid. It’s just as effective, and patients are nearly 90% more likely to finish it.

Some doctors now use a three-month course of rifampin alone, especially if liver concerns are high. The key is to complete the treatment. Studies show that even if you get screened and treated, you’re still at risk if you don’t finish the full course. One hospital study found that 32% of patients stopped their TB meds because they were scared of side effects. That’s dangerous.

Monitoring After You Start

Screening isn’t a one-time thing. TB can strike even if your test was negative. Why? Because you might have been recently infected and your immune system hasn’t reacted yet. Or the test missed it. About 18% of TB cases in TNF inhibitor patients had negative screening results before treatment.

That’s why you need ongoing monitoring. Every three months for the first year, your doctor should ask: Have you had a fever? Night sweats? Unexplained weight loss? A cough that won’t go away? These are red flags. Don’t wait. If you feel any of these, get checked immediately.

TB on TNF inhibitors often isn’t in the lungs. It’s in the spine, brain, liver, or lymph nodes-extrapulmonary TB. That makes it harder to diagnose. A chest X-ray might look normal. Blood tests might not show anything. You need a high index of suspicion.

The Hidden Risk: TB-IRIS

There’s another twist. If you develop TB while on a TNF inhibitor and then start TB treatment, your immune system can overreact. This is called TB-IRIS-immune reconstitution inflammatory syndrome. Your body, suddenly freed from TNF suppression, goes into overdrive trying to kill the TB. But it ends up attacking your own tissues. You get fever, swelling, pain-all signs of inflammation, even though you’re treating the infection.

TB-IRIS happens in about 13% of patients who start TB treatment while still on TNF inhibitors. It often appears 45 days after starting TB drugs and 110 days after the last TNF dose. Treatment usually requires steroids-sometimes for months. It’s not common, but it’s serious. And it’s preventable: if you delay starting TNF inhibitors until after you’ve completed TB treatment, you lower the risk.

Different Drugs, Different Risks

Here’s what the data says about the three most common TNF inhibitors:

Comparison of TB Reactivation Risk Among TNF Inhibitors

Drug	Class	TB Reactivation Risk	Key Reason
Infliximab (Remicade)	Monoclonal antibody	High	Binds strongly to membrane-bound TNF, disrupts granulomas
Adalimumab (Humira)	Monoclonal antibody	High	Same mechanism as infliximab; similar risk profile
Etanercept (Enbrel)	Soluble receptor	Low	Does not strongly bind membrane-bound TNF; preserves granuloma integrity

If you’re choosing between these drugs and you’re from a high-TB-burden country, etanercept is the safer option. But if your disease is severe and other drugs aren’t working, your doctor might still choose infliximab or adalimumab-just with extra caution.

What About Biosimilars?

Biosimilars of adalimumab and infliximab are now widely used. They’re cheaper-around $4,500 a month instead of $6,700. But do they carry the same TB risk? Yes. They’re designed to work exactly like the originals. The same screening and monitoring rules apply. Don’t assume a biosimilar is safer. It’s not.

Global Disparities

In the UK, TB rates are low-about 7 cases per 100,000 people. But in places like India or South Africa, it’s over 200 per 100,000. In those countries, many rheumatology clinics don’t even have access to IGRA tests. That’s a huge gap. The World Health Organization says 80% of clinics in low-resource settings lack reliable TB screening tools.

Even in the UK, patients from high-burden countries often face delays. Some doctors are afraid of giving TB treatment to people who might not return for follow-up. Others worry about liver toxicity. But skipping screening or treatment isn’t an option. The consequences-disseminated TB, meningitis, death-are too high.

What’s Next?

Scientists are working on new drugs that block TNF without breaking granulomas. Early animal studies show a new class of selective TNF inhibitors reduces TB reactivation by 80% compared to current drugs. These are still in trials, but they offer real hope.

Until then, the rules are clear: screen before you start. Treat latent TB. Monitor every three months. Don’t ignore symptoms. And choose your drug wisely.

TNF inhibitors save lives. But they also carry a silent threat. The difference between safety and disaster often comes down to one question: Did you get tested?