RA Linked to Increased Frailty Risk, Mediated by Inflammatory Cytokines

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A new study found an indirect effect of RA on frailty index through inflammatory cytokines.

A new study found genetically predicted rheumatoid arthritis (RA) was linked to an increased frailty risk, but genetically predicted frailty did not show any association with the risk of RA.1 The study also saw the association between RA and frailty risk was mediated by inflammatory cytokines.

Among people ≥ 65 years old, the US prevalence of frailty ranges from 7% to 12%. The frailty prevalence goes up with age. People aged 65 – 74 years have a frailty prevalence of 3.9% and people aged ≥ 85 years have a frailty prevalence of 25%.2

Previous studies have found a link between RA and frailty. In the first systematic review and meta-analysis to evaluate frailty in RA back in 2022, investigators found the pooled prevalence of frailty in the patients with RA was 33.5% and the pooled prevalence of prefrailty was 39.9%.3 The same study also found frailty in RA was linked to the female sex and disease activity.

Patients with RA are at a high risk for frailty due to the disease itself, adverse events of drug treatments, and susceptibility to comorbidities like chronic inflammation and sarcopenia. Frailty also poses a large hurdle to disease management.1

Despite research on the link, it was unknown whether RA and frailty had a casual association. Thus, investigators, led by Long Wen, from the department of epidemiology and biostatistics at Zhengzhou University in China, sought to investigate if a casual association existed between RA and frailty and the mediation effect of inflammatory cytokines.

The team leveraged data for RA (n = 58,285), frailty index (n = 175,226), Fried frailty score (n = 386,565), and 41 inflammatory cytokines (n = 8293) from recent genome-wide association studies. After they conducted univariable and multivariable analyses using a Mendelian randomization design. They examined the mediation effects of inflammatory cytokines using a 2-step Mendelian randomization design.

The univariable inverse variance weighted analysis revealed genetically determined RA was linked to an increased frailty index (95% confidence interval [CI], 0.012 to 0.03; P = 2.2 x 10-6) and Fried frailty score (95% CI, 0.007 to 0.015; P = 8.811 x 10-8). Furthermore, the multivariable analysis adjusted for asthma, smoking, body mass index, physical activity, telomere length, and depression demonstrated consistent results.

Additionally, a mediation analysis provided evidence of an indirect effect of RA on frailty index through inflammatory cytokines. Monokine induced by interferon-gamma had a mediated proportion of 9.8% (95% CI, 4.76% to 19.05%) on Fried frailty score and stromal cell-derived factor-I alpha with a mediated proportion of 9.6% (95% CI, 0% to 18.18%) and 8.44% (95% CI, 0% to 18.18%), respectively.

“Taken together, our [Mendelian randomization] study supports the evidence that genetically predicted RA was associated with an increased risk of frailty measured by both FI and FFS,” investigators concluded. “Moreover, the mediation effect of MIG and SDF1a in the relationship between RA and frailty revealed that inflammatory cytokines may be a part of the mechanism for RA-induced frailty. These findings might provide a potential strategy for the prevention of frailty.”


  1. Wen L, Fan J, Shi X, Zhou H, Yang Y, Jia X. Causal association of rheumatoid arthritis with frailty and the mediation role of inflammatory cytokines: A Mendelian randomization study. Arch Gerontol Geriatr. 2024;122:105348. doi:10.1016/j.archger.2024.105348
  2. Frailty: A New Predictor of Outcome as We Age. Musc Health Medical University of South Carolina. Accessed June 12, 2024.
  3. Gao RC, Wu ZG, Wu ZZ, Hao M, Wu GC. Frailty in rheumatoid arthritis: A systematic review and meta-analysis. Joint Bone Spine. 2022;89(4):105343. doi:10.1016/j.jbspin.2022.105343