Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: The Chingford Study

Gregory Livshits, Guangju Zhai, Deborah J Hart, Bernet S Kato, Huizhong Wang, Frances M K Williams, Tim D Spector, Gregory Livshits, Guangju Zhai, Deborah J Hart, Bernet S Kato, Huizhong Wang, Frances M K Williams, Tim D Spector

Abstract

Objective: There is a great need for identification of biomarkers that could improve the prediction of early osteoarthritis (OA). We undertook this study to determine whether circulating levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and C-reactive protein (CRP) can serve as useful markers of radiographic knee OA (RKOA) in a normal human population.

Methods: RKOA data were obtained from the cohort of the Chingford Study, a prospective population-based study of healthy, middle-aged British women. The RKOA-affected status of the subjects was assessed using the Kellgren/Lawrence (K/L) grade as determined on radiographs obtained at baseline (n = 908) and at 10 years and 15 years thereafter. Serum levels of CRP, IL-6, and TNFalpha were assayed at 5, 8, and 15 years, using high-sensitivity commercial assays. A K/L grade of >or=2 in either knee was used as the outcome measure. Statistical analyses included analysis of variance for repeated measurements and logistic regression models, together with longitudinal modeling of dichotomous responses.

Results: During 15 years of followup, the prevalence of RKOA (K/L grade >or=2) increased from 14.7% to 48.7% (P < 0.00001 versus baseline). The body mass index (BMI) and circulating levels of CRP and IL-6 were consistently and significantly higher in subjects diagnosed as having RKOA. When multiple logistic regression was applied to the data, the variables of older age (P = 3.93 x 10(-5)), higher BMI at baseline (P = 0.0003), and increased levels of IL-6 at year 5 (P = 0.0129) were determined to be independent predictors of the appearance of RKOA at year 10. The results were fully confirmed using longitudinal modeling of repeated measurements of the data obtained at 3 visits. The odds ratio for RKOA in subjects whose IL-6 levels were in the fourth quartile of increasing levels (versus the first quartile) was 2.74 (95% confidence interval 1.94-3.87).

Conclusion: This followup study showed that individuals were more likely to be diagnosed as having RKOA if they had a higher BMI and increased circulating levels of IL-6. These results should stimulate more work on IL-6 as a potential therapeutic target.

Figures

Figure 1
Figure 1
Mean interleukin-6 (IL-6) levels standardized for visit-specific mean and variance (IL6 STD) in 3 radiographic knee osteoarthritis (RKOA) categories: 1 = unaffected (Kellgren/Lawrence [K/L] grade 2). Bars show the 95% confidence intervals. The unadjusted sample sizes were 931, 174, and 101 individuals in RKOA categories 1, 2, and 3, respectively.
Figure 2
Figure 2
Risk probability for radiographic knee osteoarthritis (Kellgren/Lawrence grade ≥2) in the Chingford Study at ages 50 years (A), 60 years (B), and 70 years (C) as a function of body mass index (BMI) and circulating levels of interleukin-6 (IL-6). Values are the mixed-effects logistic model parameter estimates (see Table 4) for 3 categories of BMI (1 = 21–30 kg/m2, 2 = 31–40 kg/m2, and 3 = 41–50 kg/m2) and for quartiles of IL-6 distribution (S1– S4). The values of the boundary at the 25th, 50th (median), and 75th percentiles of IL-6 levels were 0.767 pg/ml, 1.235 pg/ml, and 2.310 pg/ml, respectively, with corresponding minimum and maximum values of 0.162 pg/ml and 30.228 pg/ml, respectively, at the tails of the distribution. All IL-6 data were logarithm-transformed.

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