Circulating TNF-α levels in rheumatoid arthritis: a systematic review and meta-analysis and comparison to TNF-α levels in sepsis.

Background: Tumor necrosis factor-alpha (TNF-α) is implicated in the pathogenesis of autoimmune conditions and sepsis. Although anti-TNF-α therapies have demonstrated clinical efficacy in rheumatoid arthritis (RA), there is no established evidence for benefit in patients with sepsis.

Objectives: We sought to quantify circulating TNF-α in patients with RA and compare results to TNF-α levels in sepsis.

Design: We performed a systematic review and meta-analysis of circulating TNF-α in patients with RA. We searched Cochrane Library, Google Scholar, Ovid Embase, Ovid MEDLINE, Scopus, and Web of Science Core Collection databases from inception until May 30, 2023. We included randomized controlled studies and observational reports containing more than ten subjects that reported mean serum or plasma TNF-α levels. We used the Newcastle-Ottawa Scale to assess methodological quality of studies.

Data Sources And Methods: Summary data were extracted and analyzed using a random-effects model to estimate the pooled mean circulating TNF-α. Circulating TNF-α in RA was compared to TNF-α levels reported in our systematic review and meta-analysis characterizing cytokine levels in sepsis.

Results: We identified and screened 8764 studies, and 104 studies satisfied the inclusion criteria (5399 total participants, including 4419 females). Pooled estimated mean RA TNF-α was 23.1 pg/mL (95% CI 17.8-30.1) in the random-effects model. There was significantly lower TNF-α in RA patients using disease-modifying antirheumatic drugs (DMARDs,  = 0.04) and patients using corticosteroids ( = 0.01). After adjustment for age and sex, there was no significant difference between TNF-α in RA compared to sepsis.

Conclusion: No significant difference between adjusted TNF-α levels in patients with RA versus sepsis was determined. Since TNF-α antagonists show benefit in RA but not sepsis despite comparable circulating concentrations, we conclude TNF-α does not contribute to sepsis pathogenesis. TNF-α concentration may be slightly higher due to study heterogeneity.

Trial Registration: This investigation was registered in PROSPERO (CRD42023425361).