Abstract
Objective Predictive biomarkers of progression in knee osteoarthritis are sought to enable clinical trials of structure modifying drugs. A peripheral blood leukocyte (PBL) inflammatory gene signature, MRI-based bone marrow lesions (BML) and meniscus extrusion scores), meniscal lesions, and osteophytes on x-ray each have been shown separately to predict radiographic joint space narrowing (JSN) in subjects with symptomatic knee osteoarthritis (SKOA). In these studies, we determined whether the combination of the PBL transcriptome and these imaging findings at baseline enhanced the prognostic value of either alone. Methods An inflammatory PBL transcriptome (increased mRNA for IL-1β, TNFα, and COX-2), routine radiographs, and 3T knee MRI were assessed in two independent populations with SKOA: an NYU cohort, and the Osteoarthritis Initiative (OAI). At baseline and 24 months, subjects underwent standardized fixed-flexion knee radiographs and knee MRI. Medial JSN (mJSN) was determined as the change in medial JSW. Progressors were defined by a mJSN cut-point (≥0.5 mm/24 months). Models were evaluated by odds ratios (OR) and area under the receiver operating characteristic curve (AUC). Results We validated our prior finding in these two independent (NYU and OAI) cohorts, individually and combined, that an inflammatory PBL transcriptome predicted radiographic progression of SKOA after adjustment for age, gender, and BMI. Similarly, the presence of baseline BML and meniscal lesions by MRI or semi-quantitative osteophyte score on x-ray each predicted radiographic medial JSN at 24 months. The combination of the PBL transcriptome and medial BML increased the AUC from 0.66 (p=0.004) to 0.75 (p<0.0001) and the odds ratio from 6.31 to 19.10 (p<0.0001) in the combined cohort of 473 subjects. The addition of osteophyte score to BML and PBL transcriptome further increased the predictive value of any single biomarker. A causal analysis demonstrated that the PBL transcriptome and BML independently influenced mJSN. Conclusion The use of the PBL transcriptome together with imaging biomarkers as combinatorial predictive biomarkers, markedly enhances the identification of radiographic progressors. The identification of the SKOA population at risk for progression will help in the future design of disease-modifying OA drug trials and personalized medicine strategies.
Plasma levels of interleukin-1 receptor antagonist (IL1Ra) predict radiographic progression of symptomatic knee osteoarthritis
