Risk of New-Onset Inflammatory Central Nervous System Diseases After Tumor Necrosis Factor Inhibitors Treatment for Autoimmune Diseases: A Systematic Review and Meta-Analysis

Abstract

Background: Tumor necrosis factor (TNF) inhibitors have been extensively utilized to treat various autoimmune diseases. However, there are ongoing debates about the risk of inflammatory central nervous system (CNS) diseases events following TNF inhibitors therapy, as well as uncertainty about how this risk varies across different autoimmune diseases or TNF blocking agents. We aimed to evaluate the risk of inflammatory CNS diseases after anti-TNF initiation and assess the difference in risk among different types of underlying autoimmune diseases, or TNF inhibitors. Method: Separate searches were conducted across PubMed, EMBASE, and the Cochrane Library from inception until March 1, 2024. Observational studies assessing the association between anti-TNF therapy and inflammatory CNS diseases relative to a comparator group. Study eligibility assessment and data extraction were independently conducted by two investigators following PRISMA guidelines. The risk ratio (RR) was used as the effect measure of the pooled analysis. The primary outcome was the risk of incident inflammatory CNS events after anti-TNF therapy for autoimmune diseases. Secondary analyses were performed based on different types of underlying autoimmune diseases and TNF inhibitors. Results: Eighteen studies involving 1,118,428 patients with autoimmune diseases contributing over 5,698,532 person-years of follow-up were analyzed. The incidence rates of new-onset inflammatory CNS events after initiating TNF inhibitors ranged from 2.0 to 13.4 per 10,000 person-years. Overall, exposure to TNF inhibitors was associated with a 33% increased risk of any inflammatory CNS diseases compared to conventional therapies (RR = 1.36, 95%CI 1.01-1.84; I2 = 49%), mainly attributed to demyelinating diseases (RR = 1.38, 95% CI 1.04-1.81; I2 = 31%). Secondary analyses revealed a similar risk of inflammatory CNS diseases across different types of underlying autoimmune diseases (rheumatic diseases: RR 1.36, 95%CI 0.84-2.21; inflammatory bowel disease 1.49, 95%CI 0.93-2.40; P for subgroup = 0.74) and TNF inhibitors (anti-TNF monoclonal antibodies versus etanercept: RR 1.04, 95%CI 0.93-1.15, I2 = 0%). Conclusions: Compared to conventional therapies, exposure to TNF inhibitors exposure was associated with a 36% increased risk of inflammatory CNS diseases, irrespective of background autoimmune diseases or TNF inhibitor types.