Risk of Infections of Biological and Targeted Drugs in Patients with Spondyloarthritis: Meta-Analysis of Randomized Clinical Trials
Spondyloarthritis (SpA) is a group of chronic inflammatory conditions that primarily affect the axial skeleton (axial SpA) or peripheral joints (peripheral SpA). These conditions include radiographic axial SpA (axSpA), non-radiographic axial SpA, enteropathic arthritis, reactive arthritis, and psoriatic arthritis. While non-steroidal anti-inflammatory drugs (NSAIDs) and conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) are often effective in managing symptoms, a significant proportion of patients do not respond adequately to these treatments. In such cases, biologics and small molecular targeted drugs are used to target specific inflammatory mediators, providing better control of symptoms and structural damage. However, concerns have been raised about the safety of these therapies, particularly their immunosuppressive effects, which may increase the risk of infections in patients with SpA.
This meta-analysis aimed to evaluate the risk of infections associated with biological and targeted drugs in patients with SpA by systematically reviewing randomized controlled trials (RCTs). The study included 62 RCTs involving 19,411 patients, published between 2002 and 2021. The analysis focused on various types of infections, including serious infections, upper respiratory tract infections (URTI), nasopharyngitis, Candida infections, and herpes zoster, comparing the risk in patients treated with biologics or targeted drugs versus placebo.
The findings revealed that patients with SpA treated with biologics or targeted drugs had a significantly increased risk of infections compared to those receiving placebo. Specifically, the risk of serious infections was higher in patients treated with interleukin-17 (IL-17) inhibitors, both in axial and peripheral SpA. Additionally, IL-17 inhibitors were associated with an elevated risk of Candida infections in peripheral SpA. Tumor necrosis factor-alpha (TNF-α) inhibitors were linked to a higher risk of common infections, URTI, and nasopharyngitis in axial SpA. Janus kinase (JAK) inhibitors were associated with an increased risk of herpes zoster in peripheral SpA.
The study also highlighted the biological mechanisms underlying these risks. IL-17, a pro-inflammatory cytokine, plays a crucial role in defending against extracellular pathogens, including bacteria and fungi. Inhibition of IL-17 can impair the host’s ability to fight infections, particularly those caused by Candida and Klebsiella pneumoniae. Similarly, TNF-α inhibitors, which modulate the immune response, can increase susceptibility to common infections such as URTI and nasopharyngitis. JAK inhibitors, which interfere with the JAK-STAT signaling pathway, are associated with a higher risk of herpes zoster due to their impact on natural killer cell function and the immune response to varicella-zoster virus.
The meta-analysis also addressed the limitations of the included RCTs. Many studies had short follow-up periods, limiting the ability to assess long-term risks of infections. Additionally, definitions of infections varied across studies, and some trials did not strictly adhere to standardized criteria, potentially introducing heterogeneity. The use of concomitant medications such as csDMARDs and corticosteroids, which can further increase infection risk, was another confounding factor that could not be fully accounted for in the analysis.
Despite these limitations, the study provides robust evidence that biologics and targeted drugs increase the risk of infections in patients with SpA. The findings underscore the importance of weighing the benefits and risks of these therapies in clinical practice. Physicians should remain vigilant for signs of infection, particularly in patients treated with IL-17 inhibitors, TNF-α inhibitors, and JAK inhibitors. Preventive measures, such as vaccination against herpes zoster and close monitoring for fungal infections, may be warranted in high-risk patients.
In conclusion, this meta-analysis highlights the increased risk of infections associated with biological and targeted therapies in patients with SpA. The study emphasizes the need for careful consideration of the risks and benefits of these treatments, particularly in patients with severe or refractory disease. Further research, including long-term studies and real-world data, is needed to fully understand the safety profile of these therapies and to develop strategies for minimizing infection risk in patients with SpA.
doi.org/10.1097/CM9.0000000000001928
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