A silent threat lurks in nearly a third of humanity, waiting for a moment of weakness to strike.
For millions living with autoimmune conditions like rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis, tumor necrosis factor-alpha (TNF-α) blockers have been revolutionary. These biologic drugs suppress the overactive immune responses that cause painful, debilitating symptoms. However, this very mechanism that brings relief also creates vulnerability: by tamping down immune activity, these medications can reactivate a dormant tuberculosis infection.
In Turkey, a country with intermediate TB prevalence, this risk became a critical public health concern as TNF-α blockers grew more common.
This article explores how medical researchers uncovered this danger and developed strategies to protect patients, focusing on a pivotal eight-year study at Ankara Numune Training and Research Hospital that demonstrated the effectiveness of preventive treatment.
TNF-α is a crucial immune signaling molecule—a cytokine—that plays a key role in defending against infections. It's particularly important in containing tuberculosis bacteria within specialized immune structures called granulomas1 .
Think of these granulomas as microscopic prisons that keep TB bacteria confined and dormant.
When doctors administer TNF-α blockers to treat autoimmune conditions, they inadvertently weaken these prisons. The drugs impair the granuloma-forming function of TNF-α, potentially allowing dormant TB bacteria to escape and cause active, contagious disease1 .
The connection between TNF-α inhibitors and tuberculosis is now well-established worldwide. A 2017 meta-analysis of 29 clinical trials found that patients receiving TNF-α antagonists had nearly double the risk of developing TB compared to those in control groups2 .
The World Health Organization has issued a "black box warning"—the strongest safety alert—regarding this danger2 .
Between 2006 and 2013, researchers at Ankara Numune Training and Research Hospital conducted a critical investigation to determine whether systematic screening and preventive treatment could protect patients from TB reactivation3 .
The most striking finding from the eight-year study was that none of the 134 patients developed active tuberculosis during the observation period3 .
This success demonstrated that with proper protocols, the increased TB risk associated with TNF-α blockers could be effectively managed.
Patients receiving preventive treatment
Active tuberculosis cases
| Characteristic | Details |
|---|---|
| Study Period | 2006-2013 (8 years) |
| Number of Patients | 134 |
| Age Range | 18-80 years |
| Primary Conditions | Rheumatologic and dermatologic diseases |
| TB Prophylaxis Rate | 73.9% |
| TB Cases During Study | 0 |
Detecting latent TB requires specialized approaches since these infections cause no symptoms and don't show up on standard tests. Doctors primarily use two methods:
This traditional test involves injecting a small amount of purified protein derivative (PPD) under the skin. If a person has been exposed to TB bacteria, their immune system will produce a raised, firm area (induration) at the injection site within 48-72 hours4 .
In Turkey, an induration of ≥5 mm is considered positive for patients scheduled for TNF-α blocker therapy1 .
These blood tests measure the immune system's response to TB-specific antigens. IGRAs are more specific than TST because they don't cross-react with BCG vaccination, which is common in many countries including Turkey4 .
Screening patients who are already immunocompromised presents unique challenges. Both TST and IGRA can produce false-negative results in people with weakened immune systems4 .
To address this, Turkish guidelines recommend a booster strategy—if the initial TST is negative, it's repeated within 1-3 weeks1 . This approach helps reveal hidden immune recognition of TB that might not show up on a single test.
| Method | Procedure | Interpretation | Advantages |
|---|---|---|---|
| Tuberculin Skin Test (TST) | Injection of PPD under skin; measurement of induration after 48-72 hours | ≥5 mm considered positive in Turkey for immunocompromised | Inexpensive; widely available |
| Interferon-Gamma Release Assay (IGRA) | Blood test measuring immune response to TB-specific antigens | IFN-ɣ response ≥0.35 IU/mL considered positive | High specificity; not affected by BCG vaccination |
| Chest X-ray | Radiographic imaging of lungs | Looks for evidence of old TB infection | Can detect inactive TB lesions |
When latent TB is detected, preventive treatment is essential before starting TNF-α blockers. The Ankara Numune Hospital study and other research support two main regimens:
The traditional standard for TB prevention
An alternative when isoniazid can't be used3
Preventive TB treatments aren't without risks, particularly potential liver toxicity. The Ankara researchers emphasized monthly monitoring of liver enzymes and bilirubin levels, along with regular physical examinations and chest X-rays every three months3 .
The success observed at Ankara Numune Hospital has been echoed in larger, more recent studies. A 2025 investigation tracking 519 patients on TNF-α blockers found that comprehensive LTBI screening and treatment kept TB cases low, though the risk remained higher than in the general population1 .
Interestingly, research from South Korea demonstrated that active TB can still develop in patients with negative baseline LTBI screening6 .
Some experts now recommend ongoing vigilance and possibly even repeat testing during long-term TNF-α blocker therapy, especially in regions with higher TB prevalence6 .
TB development rate in larger study1
The story of TNF-α blockers and tuberculosis risk demonstrates both the sophistication of modern medicine and its challenges. As we develop powerful treatments that target specific components of our biology, we must remain alert to unintended consequences.
The pioneering work at Ankara Numune Hospital and subsequent studies worldwide have established a crucial safety protocol: comprehensive TB screening and preventive treatment for all patients before starting TNF-α blockers.
This approach has transformed a significant treatment danger into a manageable risk. As research continues, scientists are working to improve screening tests, develop safer preventive regimens, and understand why some patients still develop TB despite negative screening.
In our pursuit of medical advancement, vigilance and prevention remain our strongest allies.