Purpose: Experts in the field of OA suggested that a shift in research focus towards the early disease stage is needed; here joint damage might still be reversible, pain is not chronic, and physical functioning is not heavily impaired. Studying incident knee OA among patients with early-stage disease requires very long follow-up when established measures of knee OA, e.g. Kellgren & Lawrence (KL) grade ≥2 or the ACR-criteria), are used. Validated surrogate outcomes of established knee OA, can boost the research on new disease- and symptom-modifying treatments within the ‘window of opportunity’ of early-stage knee OA. The current study aimed to evaluate the performance of the short-term change (2.5 years) of several clinical and imaging markers as surrogate outcomes for long-term (6.5 years) clinical knee OA development, among high-risk women with overweight and obesity.
Methods: Data of the PROOF study were used. In PROOF, 407 women (aged 50 - 60 years, BMI ≥27 kg/m2, and free of clinical knee OA) were recruited and followed for 6.5 years. At baseline, 2.5 years, and 6,5 years, questionnaires (demographics, knee symptoms, WOMAC scores), and standardized semi-flexed PA radiography (osteophytes, joint space width, and medial alignment angle) and multi-sequential MRIs (semi-quantitative scores using MOAKS) were obtained. For all pre-specified potential surrogate outcome, first the 2.5 years progression (i.e. worsening) was determined and compared to the 2.5 years incidence of clinical knee OA, using the combined ACR-criteria (i.e. pain on most days of the last month, definite osteophyte on radiography, and ≥1 out of age >50, morning stiffness <30 minutes, crepitus). Published measures of the Minimal Clinically Important Difference (MCID) were used to determine the number of knees with progression based on knee pain severity (NRS), WOMAC pain, WOMAC stiffness, WOMAC function, and medial and lateral joint space narrowing. For osteophytes scored on radiographs, progression ≥1 grade on the 0-4 scale, excluding progression from 0 to 1, was used to determine short-term progression. For MOAKS features (bone marrow lesions, cartilage defects, osteophytes, meniscal pathologies, and meniscal extrusion), published definitions by Runhaar et al (2014) were used to define progression. MOAKS features were stratified for medial/lateral and tibiofemoral/patellofemoral compartments, where appropriate. Potential surrogate outcomes showing progression ≥10% of the knees after 2.5 years were further analyzed for their association with the incidence of clinical knee OA after 6.5 years, using Generalized Estimating Equations to account for repeated measures within persons. Only for WOMAC pain, stiffness and function scores, a simple logistic regression was used, as these measures were obtained at a person-level. For all potential surrogate markers showing a significant association with incident clinical knee OA, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated.
Results: 470 knees from 238 women were free of clinical knee OA at baseline and had long-term OA incidence measures available (mean age 55.8 ±3.1 years and mean BMI 31.8 ± 3.8 kg/m2). After 2.5 and 6.5 years, incidence of clinical knee OA was 7% and 11% respectively. Table 1 presents the progression of the selected potential surrogate outcomes at 2.5 years and their association to incident clinical knee OA after 6.5 years. Ten potential surrogate outcomes had short-term progression in ≥10% of the knees. Of these, only the progression of medial tibiofemoral osteophytes on MRI (OR 2.2 [95% CI 1.1-4.6]) and pain severity (2.9 [95% CI 1.5-5.5]) were significantly associated to incident clinical knee OA. Both measures had low sensitivity and PPV (22%-28%), and high specificity and NPV (90%-91%).
Conclusions: Among a high-risk population of overweight/obese women free of clinical knee OA, both the progression of medial tibiofemoral osteophytes on MRI and of knee pain severity fulfill the basic requirements of a surrogate outcome; their short-term change was significantly associated to long-term OA development. The next step to validate these potential surrogate outcomes would be to show in an RCT that the long-term preventive effects of a treatment (i.e. less OA incidence) are captured by the short-term change in these surrogate outcomes. If so, future trials can evaluate their preventive effect more efficiently by evaluating the short-term change in these surrogate outcomes only.
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