Identification of progressors in osteoarthritis by combining biochemical and MRI-based markers

Abstract

Introduction: At present, no disease-modifying osteoarthritis drugs (DMOADS) are approved by the FDA (US Food and Drug Administration); possibly partly due to inadequate trial design since efficacy demonstration requires disease progression in the placebo group. We investigated whether combinations of biochemical and magnetic resonance imaging (MRI)-based markers provided effective diagnostic and prognostic tools for identifying subjects with high risk of progression. Specifically, we investigated aggregate cartilage longevity markers combining markers of breakdown, quantity, and quality.

Methods: The study included healthy individuals and subjects with radiographic osteoarthritis. In total, 159 subjects (48% female, age 56.0 +/- 15.9 years, body mass index 26.1 +/- 4.2 kg/m2) were recruited. At baseline and after 21 months, biochemical (urinary collagen type II C-telopeptide fragment, CTX-II) and MRI-based markers were quantified. MRI markers included cartilage volume, thickness, area, roughness, homogeneity, and curvature in the medial tibio-femoral compartment. Joint space width was measured from radiographs and at 21 months to assess progression of joint damage.

Results: Cartilage roughness had the highest diagnostic accuracy quantified as the area under the receiver-operator characteristics curve (AUC) of 0.80 (95% confidence interval: 0.69 to 0.91) among the individual markers (higher than all others, P < 0.05) to distinguish subjects with radiographic osteoarthritis from healthy controls. Diagnostically, cartilage longevity scored AUC 0.84 (0.77 to 0.92, higher than roughness: P = 0.03). For prediction of longitudinal radiographic progression based on baseline marker values, the individual prognostic marker with highest AUC was homogeneity at 0.71 (0.56 to 0.81). Prognostically, cartilage longevity scored AUC 0.77 (0.62 to 0.90, borderline higher than homogeneity: P = 0.12). When comparing patients in the highest quartile for the longevity score to lowest quartile, the odds ratio of progression was 20.0 (95% confidence interval: 6.4 to 62.1).

Conclusions: Combination of biochemical and MRI-based biomarkers improved diagnosis and prognosis of knee osteoarthritis and may be useful to select high-risk patients for inclusion in DMOAD clinical trials.

Figure 1

Marker types needed for clinical study. For a clinical study, diagnostic and prognostic markers are needed to select a population at the proper stage of osteoarthritis (OA) with a high risk of progression; and an efficacy marker is needed to evaluate the treatment effect. Supplementing the diagnostic marker, a burden of disease marker could be used to assess the total disease severity.

Figure 2

Magnetic resonance imaging-based biomarker quantification framework. Top left: a slice from a magnetic resonance imaging scan. Top right: segmentation of the medial tibial cartilage compartment shown in sagittal and coronal slice with a shape model fitted to the segmentation. Bottom left: thickness map. Bottom right: curvature map in the central region of interest used for the curvature marker. All computational steps are fully automatic.

Figure 3

Diagnostic ability for separating healthy individuals from osteoarthritis subjects. The diagnostic ability for separating healthy individuals from osteoarthritis (OA) subjects (defined by Kellgren and Lawrence index >1) of key markers, illustrated by a receiver-operator characteristics diagram. The areas under the curves are: joint space width (JSW), 0.73; urinary marker of collagen type II C-telopeptide fragment (uCTX-II), 0.70; volume, 0.52; roughness, 0.81; homogeneity, 0.65; and longevity-tib, 0.87. The aggregate longevity-tib marker provided superior ability to all the individual markers (P < 0.05).

Figure 4

Prognostic ability of key markers for separating healthy non-progressors from early progressors. Early progressors were defined by whether the KL score increased from a baseline score of 0. For each marker, the population was divided into quartiles and each quartile was compared with the lowest quartile in terms of the odds ratio (OR) for predicting the progressors. Each OR is given with the 95% confidence interval and with the significance level: *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. Cartilage longevity-tib proved superior to the individual markers (P < 0.05) except for roughness/homogeneity (P = 0.2/0.3) with OR of 20.0 for the highest quartile. JSW = joint space width; uCTX-II, urinary marker of collagen type II C-telopeptide fragment.