Risk of tuberculosis in patients with rheumatoid arthritis treated with biological and targeted drugs: meta-analysis of randomized clinical trials

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Risk of tuberculosis in patients with rheumatoid arthritis treated with biological and targeted drugs: meta-analysis of randomized clinical trials

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint inflammation, pain, and long-term damage. Over the past 20 years, biological disease-modifying anti-rheumatic drugs (bDMARDs) and targeted small-molecule therapies like Janus kinase (JAK) inhibitors have transformed RA treatment, offering relief to patients who didn’t respond to older medications like methotrexate or non-steroidal anti-inflammatory drugs (NSAIDs). But these drugs work by suppressing parts of the immune system—and that has raised serious concerns about infections, including tuberculosis (TB). A 2022 meta-analysis published in the Chinese Medical Journal set out to answer a critical question: Do biologics or targeted drugs increase the risk of TB in RA patients?

What Did the Study Examine?

Researchers from the Chinese PLA General Hospital and Xiamen University analyzed 39 randomized controlled trials (RCTs)—the most reliable type of medical study—published between 1999 and 2021. They included data from 20,354 RA patients and compared three types of therapies:

  1. TNF-a inhibitors: bDMARDs like infliximab or adalimumab that block tumor necrosis factor-alpha, a protein driving RA inflammation.
  2. IL-6 inhibitors: bDMARDs like tocilizumab that target interleukin-6, another pro-inflammatory protein.
  3. JAK inhibitors: Targeted oral drugs like tofacitinib that block signaling pathways in immune cells.

The team used two meta-analysis methods to measure TB risk:

  • Traditional meta-analysis: Directly compared biologics/targeted drugs to non-biologics (placebo or traditional synthetic DMARDs).
  • Network meta-analysis: Indirectly compared different biologic/targeted drug classes to each other (since few RCTs directly compare them).

For rare events like TB (which is uncommon in short-term trials), the study used the Peto odds ratio (OR)—a statistical tool designed to handle small numbers of cases accurately.

What Did the Study Find?

The analysis uncovered three key results about TB risk in RA patients:

1. Biologics/Targeted Drugs Double TB Risk vs. Non-Biologics

Overall, patients taking biologics or targeted drugs had a 3.86 times higher risk of TB than those on non-biologics (95% confidence interval [CI]: 2.36–6.32, P < 0.001). This means for every 1,000 RA patients on non-biologics, about 4 might develop TB—but for those on biologics, that number rises to ~15.

2. TNF-a Inhibitors Are Linked to the Highest TB Risk

TNF-a inhibitors (the most widely used bDMARDs) had a 3.98 times higher risk of TB compared to placebo (95% CI: 2.30–6.88, P < 0.001). This aligns with global safety warnings: the World Health Organization (WHO) already labels TNF-a inhibitors with a “black box” warning for TB risk.

3. Tofacitinib Has a Dose-Dependent TB Risk

For the JAK inhibitor tofacitinib, the study found a clear dose effect: patients taking the 10mg twice-daily dose had a 7.39 times higher risk of TB than those on the 5mg dose (95% CI: 2.00–27.31, P = 0.003). Higher doses likely suppress the immune system more strongly, increasing infection risk.

Other Key Details

  • Types of TB: 29.3% of cases were pulmonary TB (affecting the lungs), followed by lymph node TB (12.2%) and disseminated TB (8.5%—a severe form that spreads throughout the body).
  • Mortality: Three patients died from TB-related causes: two from disseminated TB after infliximab treatment, and one from septic shock following peritoneal TB.
  • Regional Risk: TB was most common in patients from Asia (32%), Eastern Europe (22%), and South America (18)—regions with high TB rates in the general population.

What About Other Biologic Classes?

Network meta-analysis didn’t find significant differences in TB risk between TNF-a inhibitors, IL-6 inhibitors, and JAK inhibitors. However, the confidence intervals were wide—meaning the study couldn’t rule out small differences. This is likely because TB is rare in RCTs, making indirect comparisons less reliable.

Why Do Biologics Increase TB Risk?

The link between TNF-a inhibitors and TB boils down to how TNF-a works in the immune system:

  • TNF-a boosts the function of macrophages (cells that “eat” bacteria like Mycobacterium tuberculosis).
  • It helps form granulomas—clusters of immune cells that trap TB bacteria and prevent them from spreading.

Blocking TNF-a weakens these defenses, making it easier for TB to reactivate (if latent) or cause new infection. For JAK inhibitors, the dose-dependent risk with tofacitinib reflects how strongly higher doses suppress immune signaling pathways.

What Does This Mean for RA Patients?

The study’s findings have critical implications for doctors and patients:

1. Screen for Latent TB Before Treatment

All RA patients considering biologics or JAK inhibitors should get tested for latent TB (hidden infection without symptoms). Tests like the tuberculin skin test (TST) or interferon-gamma release assay (IGRA) can detect latent TB, which can be treated with preventive drugs (like isoniazid) before starting biologic therapy.

2. Choose Tofacitinib Doses Carefully

For patients on tofacitinib, the 5mg dose is safer than 10mg. The study’s results support EULAR recommendations to use the lowest effective dose of JAK inhibitors.

3. Monitor for TB During Treatment

Patients on biologics/JAK inhibitors should be checked for TB symptoms (cough, fever, weight loss) at least annually, especially if they live in high-TB regions. Early diagnosis saves lives—delayed treatment can lead to severe, fatal forms of TB.

Limitations to Consider

The study isn’t perfect:

  • Short Follow-Up: Most RCTs had an average follow-up of 54 weeks (just over a year). TB can take years to reactivate, so long-term risk isn’t fully captured.
  • Published Studies Only: The analysis only includes published trials—unpublished studies (which might have negative results) could change the findings.

Conclusion

This meta-analysis provides strong evidence that:

  • TNF-a inhibitors increase TB risk in RA patients.
  • Tofacitinib has a dose-dependent TB risk (10mg is riskier than 5mg).

While biologics and targeted drugs are life-changing for many RA patients, their benefits must be weighed against infection risks. Rigorous screening for latent TB, careful dose selection (especially for tofacitinib), and ongoing monitoring are essential to keep patients safe.

Xiaojian Ji1, Lidong Hu2, Yiwen Wang1, Siliang Man1, Xingkang Liu1, Chuan Song1, Jiaxin Zhang1, Jian Zhu1, Jianglin Zhang1, Feng Huang1
1Department of Rheumatology and Immunology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China;
2Xiamen Key Laboratory of Translational Medicine for Nucleic Acid Metabolism and Regulation, Xiang’an Hospital of Xiamen University, Xiamen, Fujian 361102, China

doi.org/10.1097/CM9.0000000000001948

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