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, systemic autoimmune disease characterized by synovial joint inflammation and damage, leading to disability and impaired quality of life. Over the past two decades, significant advancements have been made in the treatment of RA, particularly with the introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs). These therapies have revolutionized the management of RA by targeting specific immune pathways, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), to achieve better control of symptoms and structural damage. However, the use of these agents has raised concerns about their safety, particularly regarding the risk of infections, including tuberculosis (TB). This meta-analysis systematically evaluates the risk of TB in patients with RA treated with biological and targeted drugs, providing a comprehensive overview of the evidence from randomized controlled trials (RCTs).
Background and Rationale
RA is a debilitating condition that affects millions of people worldwide. The introduction of bDMARDs and tsDMARDs has significantly improved outcomes for many patients who do not respond adequately to conventional synthetic DMARDs (csDMARDs) or non-steroidal anti-inflammatory drugs (NSAIDs). However, these therapies, which modulate the immune system, have been associated with an increased risk of infections, including TB. TB is a major global health concern, particularly in developing countries, and the use of biologics in RA treatment has been linked to an elevated risk of TB reactivation or new infections.
The relationship between biological therapies and TB risk is particularly concerning in regions with a high prevalence of TB. For example, data from China indicate that RA patients receiving anti-TNF therapy have a 10.1-fold to 34.9-fold increased risk of developing TB compared to the general population. Given the widespread use of biologics in RA management, it is crucial to understand the magnitude of this risk and to identify strategies to mitigate it.
Objectives and Methods
The primary objective of this meta-analysis was to assess and compare the risk of TB in patients with RA treated with biological and targeted drugs. The study focused on RCTs to provide high-quality evidence on the safety of these therapies. A systematic literature search was conducted in PubMed, Embase, the Cochrane Library, and the China Biology Medicine database from inception through August 2021. The search strategy included terms related to RA, biological and targeted drugs, and TB, and was restricted to human studies published in English and Chinese.
The eligibility criteria for inclusion in the meta-analysis required that studies be RCTs reporting data on TB in RA patients aged 18 years or older. The studies had to compare biologics (e.g., adalimumab, etanercept, infliximab, tocilizumab, tofacitinib) or targeted drugs (e.g., baricitinib, upadacitinib) against non-biologics (placebo or csDMARDs) or against each other. Two independent researchers screened the titles and abstracts of the retrieved studies, and any discrepancies were resolved through consensus or consultation with a third researcher.
The primary outcome measure was the Peto odds ratio (Peto OR) with 95% confidence intervals (CIs) for the risk of TB in patients treated with biologics compared to non-biologics. Traditional meta-analysis was used to compare biologics to non-biologics, while network meta-analysis was employed to compare different classes of biologics. The statistical analysis was performed using R 4.0.2 software for traditional meta-analysis and Stata/MP 16.0 for network meta-analysis.
Results
A total of 39 RCTs involving 20,354 RA patients were included in the meta-analysis. Among these patients, 82 developed TB during the study follow-up periods. The risk of TB was significantly higher in patients treated with biologics compared to non-biologics (Peto OR: 3.86, 95% CI: 2.36–6.32, P < 0.001). Stratification by biologics class revealed that TNF-α inhibitors were associated with a significantly higher risk of TB compared to placebo (Peto OR: 3.98, 95% CI: 2.30–6.88, P 0.05) and Janus kinase (JAK) inhibitors (Peto OR: 2.66, 95% CI: 0.69–10.18, P > 0.05) did not show a statistically significant increase in TB risk compared to non-biologics.
Subgroup analysis of JAK inhibitors revealed a dose-dependent risk of TB with tofacitinib. Patients treated with a high dose of tofacitinib (10 mg twice daily) had a significantly higher risk of TB compared to those receiving a low dose (5 mg twice daily) (Peto OR: 7.39, 95% CI: 2.00–27.31, P = 0.003).
Network meta-analysis, which compared different classes of biologics, found no significant differences in TB risk between TNF-α inhibitors, IL-6 inhibitors, and JAK inhibitors. However, the results suggested that IL-6 inhibitors and JAK inhibitors might have a higher risk of TB compared to TNF-α inhibitors, though the differences were not statistically significant.
Discussion
The findings of this meta-analysis highlight the increased risk of TB in RA patients treated with biologics, particularly TNF-α inhibitors. This is consistent with previous studies that have reported an elevated risk of TB in patients receiving anti-TNF therapy. TNF-α plays a critical role in the immune response to Mycobacterium tuberculosis, the causative agent of TB. By inhibiting TNF-α, biologics can impair the formation and maintenance of granulomas, which are essential for containing TB infection. This mechanism likely explains the increased risk of TB reactivation or new infections in patients treated with TNF-α inhibitors.
The study also identified a dose-dependent risk of TB with tofacitinib, a JAK inhibitor. This finding is particularly relevant given the increasing use of JAK inhibitors in RA management. The higher risk associated with the 10 mg dose of tofacitinib underscores the importance of careful dosing and monitoring in patients receiving this therapy. It also highlights the need for further research to better understand the mechanisms underlying the increased TB risk with JAK inhibitors and to develop strategies to mitigate this risk.
The geographic distribution of TB cases in the included studies reflects the global burden of TB, with the highest incidence observed in Asia, Eastern Europe, and South America. This emphasizes the importance of considering regional TB prevalence when assessing the risk of TB in RA patients treated with biologics. In regions with a high prevalence of TB, rigorous screening and monitoring for TB are essential to minimize the risk of infection in patients receiving biological therapies.
Clinical Implications
The results of this meta-analysis have important implications for the management of RA patients treated with biologics. Given the elevated risk of TB, particularly with TNF-α inhibitors and high-dose tofacitinib, clinicians should carefully weigh the benefits and risks of these therapies in individual patients. In regions with a high prevalence of TB, pre-treatment screening for latent TB infection (LTBI) and appropriate prophylactic treatment should be standard practice.
Screening for LTBI typically involves a combination of tuberculin skin tests (TST) and interferon-gamma release assays (IGRAs), along with chest X-rays. Patients with evidence of LTBI should receive prophylactic treatment with isoniazid (INH) or other anti-TB medications before initiating biological therapy. Ongoing monitoring for signs and symptoms of TB is also crucial during treatment, particularly in the first few years of therapy when the risk of TB reactivation is highest.
Limitations
While this meta-analysis provides valuable insights into the risk of TB in RA patients treated with biologics, several limitations should be acknowledged. First, the relatively short follow-up periods in many of the included RCTs may underestimate the long-term risk of TB. Long-term observational studies are needed to provide a more comprehensive assessment of the safety of biologics in RA patients. Second, the meta-analysis was limited to published studies, and the exclusion of unpublished data may have introduced bias. Finally, the geographic distribution of the included studies may not fully represent the global burden of TB, particularly in low-income countries where TB prevalence is highest.
Conclusion
This meta-analysis demonstrates that the use of biologics, particularly TNF-α inhibitors, is associated with an increased risk of TB in patients with RA. The risk is dose-dependent with tofacitinib, highlighting the importance of careful dosing and monitoring in patients receiving this therapy. Clinicians should be aware of the increased risk of TB in RA patients treated with biologics, particularly in regions with a high prevalence of TB. Rigorous screening and monitoring for TB, along with appropriate prophylactic treatment, are essential to minimize the risk of infection in these patients.
doi.org/10.1097/CM9.0000000000001948
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