Supplementary Material for: The Association Between Tumor Necrosis Factor-Alpha Inhibitor Use and Dementia Risk in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-analysis

Introduction: Tumor necrosis factor-alpha inhibitors (TNFi), commonly prescribed for rheumatoid arthritis (RA), have been studied for their potential association with dementia risk. However, previous findings are inconclusive. This study aims to evaluate the impact of TNFi use on dementia in patients with RA.
Methods: Systematical search of MEDLINE, Embase, and CENTRAL databases from inception to October 1, 2023, was conducted. Longitudinal comparative studies investigating the association between TNFi use and risk of dementia in patients with RA were included. Pooled adjusted risks of dementia, and meta-analysis conducted to synthesize relative estimates with 95% confidence intervals (CIs).
Results: Seven observational studies involving 633,089 patients with RA were included, of which six were included in the meta-analysis. The pooled meta-analysis comparing the risk of dementia (hazard ratio [HR] = 0.77, 95% CI 0.64–0.93) and Alzheimer's disease (AD) (odds ratio = 0.31, 95% CI 0.23–0.43) between TNFi users and non-users showed a significant association. However, the pooled HR for AD risk was inconsistent. Also, the subgroup analyses indicated that TNFi use was associated with a decreased dementia risk in older adult patients with a mean age of ≥65 years at enrollment (HR = 0.86, 95% CI 0.80-0.92) and in TNFi new users (HR = 0.86, 95% CI 0.80-0.92).
Conclusions: Systematic review and meta-analysis suggest that lowering the level of systemic TNF-alpha by using TNFi could lower the risk of dementia. However, given the retrospective nature of the included studies, further prospective studies are needed to evaluate the role of TNFi in dementia onset.