Background/Purpose: Osteoarthritis is multi-factorial complex degenerative joint disease that leads to permanent joint damage. We and others have shown elevated levels of inflammatory and anti-inflammatory mediators in OA. Furthermore, polymorphism in IL-1RN gene has been shown to predict radiographic severity and progression in OA. There is currently great interest in the field of OA to identify biomarkers that identify patients at higher risk for disease progression and to identify biomarkers that can lead to new drug targets. This study was designed to test the hypothesis that plasma levels of IL-1Ra predict radiographic knee OA severity and progression and to examine IL-1Ra interactions with other biomarkers and confounding covariates.

Methods: 178 SKOA patients (mean age 62.5 + 10.5, mean BMI 26.7 ± 3.5) fulfilling ACR criteria for knee OA were recruited as part of an NIH-funded prospective study. Patients were followed longitudionally for 24 months with standard semi-flexed radiographs taken at 0 and 24 months, scored for overall KL grade and joint space width (JSW) by the same radiologist. SKOA patients (n=111) with medial OA and baseline JSW >0 completed the two year study. The blood samples collected at baseline were assayed for IL-1Ra by ELISA. For radiographic severity, biomarkers were evaluated between KL scores of 1, 2 with those with scores of 3, 4. Progression was defined as a change in medial JSW between baseline and 24 month radiographs of the signal knee, defined as the more symptomatic knee by the WOMAC pain scale.

Results: The mean plasma IL-1Ra level in SKOA subjects was 318.6 ± 205.8 pg/ml. Our data indicate that plasma IL-1Ra levels predicted higher risk for disease severity (KL grade), with an area under the curve (AUC) under receiver operating characteristic curve of 0.699 (p=0.0006). We found no significant association of IL-1Ra with WOMAC or VAS pain scores. In the 24-month longitudinal study we examined IL-1Ra in patients with JSN < 0 mm (non-progressors, 35% of cohort) and those with JSN > 0.6mm (fast-progressors,38% of cohort). Baseline IL-1Ra was significantly elevated in fast-progressors (p= 0.0142) relative to non-progressors. After adjustment for BMI, age and gender, plasma IL-1Ra approached significance as a predictor of fast progression (p=0.0586). In order to determine the dependence of IL-1Ra on covariates (BMI, age, gender) we performed causal graph analysis [FCI algorithm, Spirtes et al 2000)] of continuous JSN. FCI allows discovering causality from observational data and identifying hidden confounding covariates. This method has been proven to be correct (i.e., to identify underlying causal structures that are consistent with the data) under broad distributional assumptions. Based on this analysis, plasma IL-1Ra plays a causal role and positively influences JSN independent of BMI, age and gender.

Conclusion: These findings suggest that plasma IL-1Ra is a candidate biomarker of radiographic progressive JSN. The analysis also suggests that IL-1Ra elevations are associated with causal events in OA disease progression.  These observations will be further validated in a larger cohort of SKOA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interleukin-1-receptor-antagonist-il-1ra-plasma-levels-predict-radiographic-progression-of-symptomatic-knee-osteoarthritis-over-24-months/