Composite Inflammatory Index Linked to Elevated RA Risk

A new composite biomarker combining measures of inflammation and metabolic dysfunction demonstrates a strong, nonlinear association with rheumatoid arthritis (RA) risk, with body mass index accounting for nearly one-third of this relationship, according to research published in Mediators of Inflammation.1

Investigators evaluated 4292 US adults participating in the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2010 to examine whether the C-reactive protein-triglyceride-glucose index (CTI) was associated with RA risk in a cross-sectional population sample. Emerging evidence suggests that, in addition to genetic and autoimmune factors, systemic low-grade inflammation and metabolic disturbances may also contribute meaningfully to RA pathogenesis.2 This led researchers to examine CTI as a unified marker that captures both inflammatory and metabolic burden.

CTI was analyzed both continuously and across population-weighted quartiles, with RA prevalence progressively increasing across CTI categories. | Image credit: cacaroot - stock.adobe.com

They found that elevated CTI values independently correlated with higher odds of RA across multiple analytical models. After adjusting for demographic, socioeconomic, lifestyle, and clinical factors, including sex, age, race, education, smoking status, alcohol consumption, diabetes, and hypertension, each one-unit increase in CTI corresponded to a 45% increase in RA odds (OR, 1.45; 95% CI, 1.22-1.73; P < .001).

“Unlike earlier studies that assessed CRP or TyG in isolation, our analysis offers novel insights by evaluating CTI as a unified marker and examining its underlying mechanism of action. Importantly, our mediation analysis adds a new dimension to existing knowledge by identifying BMI as a significant mediator in the CTI-RA association,” the authors note.

CTI was analyzed both continuously and across population-weighted quartiles, with RA prevalence progressively increasing across CTI categories. The prevalence of RA increased steadily from 1.8% in the lowest quartile to 9.1% in the highest quartile (P < .001). In unadjusted analyses, participants in the highest quartile had more than a 5-fold increased likelihood of RA compared with those in the lowest (OR, 5.39; 95% CI, 3.13-9.29; P < .001). Even after comprehensive adjustment for confounding variables, participants in the highest quartile maintained a greater than 2-fold increased risk (OR, 2.66; 95% CI: 1.41-5.01; P = .004). Individuals in the upper CTI ranges also had substantially higher rates of obesity, diabetes, and hypertension, consistent with greater metabolic burden. Restricted cubic spline modeling demonstrated a nonlinear association, with RA risk rising more sharply once CTI exceeded approximately 7.0. This pattern persisted even after full adjustment (P = .048), suggesting that individuals with CTI values in the upper range face substantially elevated risk compared with those in lower ranges.

BMI demonstrated a strong positive correlation, with each unit increase in CTI corresponding to a 3.2 kg/m2 rise in BMI. BMI itself was associated with increased RA risk, with each unit increase linked to a 5% to 6% rise in odds (P < .001), and investigators found that BMI accounted for 32.31% of the total CTI-RA association (P < .001). The authors suggest, “The relationship between elevated CTI and increased RA risk—partially mediated by BMI—likely reflects the convergence of multiple interconnected biological pathways involving systemic inflammation, insulin resistance, and adiposity-driven immune dysregulation.”

Subgroup analyses demonstrated consistent CTI-RA associations across demographic and clinical strata. Associations remained significant in both men and women, and sex did not modify the association (interaction P = .760). Similarly, race, smoking status, alcohol use, and hypertension did not significantly alter the CTI-RA relationship (interaction P = .353, .710, .543, and .695, respectively). The only significant interaction emerged for diabetes status. Among non-diabetic individuals, CTI remained strongly associated with RA risk, whereas this association attenuated and lost statistical significance among participants with diabetes, yielding a significant interaction term (P = .036). The authors note that advanced metabolic dysregulation may obscure the relationship between CTI and RA among patients with existing diabetes.

TheiInvestigators noted limitations, including reliance on self-reported RA, potential residual confounding, and the inherently observational, cross-sectional nature of the dataset, which preclude definitive causal inferences. However, the authors concluded that CTI may prove useful in RA.

“This study highlights CTI as a promising biomarker reflecting the interplay between metabolic dysfunction and systemic inflammation in relation to RA risk,” the authors wrote, adding that the findings suggest CTI may help identify individuals with elevated metabolic-inflammatory burden who could face heightened RA risk.

References

1. Xie H, Liu Q, Xu X, et al. Nonlinear association between the C-reactive protein-triglyceride-glucose index and rheumatoid arthritis risk: the mediating role of body mass index. Mediators Inflamm. 2025;2025:8729780. doi:10.1155/mi/8729780
2. Jutley GS, Sahota K, Sahbudin I, et al. Relationship between inflammation and metabolism in patients with newly presenting rheumatoid arthritis. Front Immunol. 2021;12:676105. doi:10.3389/fimmu.2021.676105