Medications that are biological and targeted for rheumatoid arthritis (RA) are recognized for elevating the likelihood of serious infection, which may be life-threatening and necessitate hospitalization or the use of intravenous antibiotics. Recently, emerging medications like upadacitinib, peficitinib, and filgotinib have become accessible. Evaluating whether these new targeted therapies contribute to an elevated risk of serious infection is crucial. Additionally, it is essential to determine if the risk distinctions between biological and targeted medications. 

Previous meta-analysis had evaluated the likelihood of developing serious infection connected to targeted therapies. Nevertheless, several novel targeted agents, such as peficitinib, filgotinib, and upadacitinib, have become available. Only one NMA by Carlos et al. suggested that the risk of serious infection is comparable among presently authorized tsDMARDs (including tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib). However, this study was limited to tsDMARDs but did not include bDMARDs. It is unclear whether novel tsDMARDs of different types and doses are safer than other bDMARDs. Therefore, this systematic review and NMA were designed to evaluate the safety of various targeted therapies in individuals with active RA who have inadequately responded to csDMARDs.

We queried PubMed, Embase, and the Cochrane Library until April 2025 to acquire applicable English-language studies. Subsequently, we evaluated the disparity in serious infection risk among treatments employing both direct pairwise comparison and network meta-analysis.

The research analyzed 73 studies, encompassing 20 treatment arms involving 35345 patients. The findings revealed upadacitinib 30mg, tofacitinib10mg, tofacitinib 5mg, tocilizumab, and adalimumab were linked to a notably elevated risk of serious infection when compared to the control group, which mainly receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) [OR (95%CI): 5.64 (1.81-17.52), 3.41 (1.19 - 9.77), 2.58 (1.10 - 6.07), 1.67 (1.10 - 2.55), 1.60 (1.09 - 2.36)]. According to the surface under the cumulative ranking curve, etanercept presented the lowest risk for serious infection.

Peficitinib and filgotinib showed risks similar to the control group without notable differences. However, upadacitinib, tofacitinib, adalimumab, and tocilizumab carried a higher serious infection risk, while etanercept might offer a lower one. Thus, it is essential to consider changes in the risk of serious infection when determining optimal treatments among RA patients.