E.H. Oei

Prediction model for knee osteoarthritis incidence, including clinical, genetic and biochemical risk factors

Objective To develop and validate a prognostic model for incident knee osteoarthritis (KOA) in a general population and determine the value of different risk factor groups to prediction. Methods The prognostic model was developed in 2628 individuals from the Rotterdam Study-I (RS-I). Univariate and multivariate analyses were performed for questionnaire/easily obtainable variables, imaging variables, genetic and biochemical markers. The extended multivariate model was tested on discrimination (receiver operating characteristic curve and area under the curve (AUC)) in two other population-based cohorts: Rotterdam Study-II and Chingford Study. Results In RS-I, there was moderate predictive value for incident KOA based on the genetic score alone in subjects aged <65u2005years (AUC 0.65), while it was only 0.55 for subjects aged ≥65u2005years. The AUC for gender, age and body mass index (BMI) in prediction for KOA was 0.66. Addition of the questionnaire variables, genetic score or biochemical marker urinary C-terminal cross-linked telopeptide of type II collagen to the model did not change the AUC. However, when adding the knee baseline KL score to the model the AUC increased to 0.79. Applying external validation, similar results were observed in the Rotterdam Study-II and the Chingford Study. Conclusions Easy obtainable ‘Questionnaire’ variables, genetic markers, OA at other joint sites and biochemical markers add only modestly to the prediction of KOA incidence using age, gender and BMI in an elderly population. Doubtful minor radiographic degenerative features in the knee, however, are a very strong predictor of future KOA. This is an important finding, as many radiologists do not report minor degenerative changes in the knee.

Crepitus is a first indication of patellofemoral osteoarthritis (and not of tibiofemoral osteoarthritis)

OBJECTIVEnThe patellofemoral joint (PFJ) is important in early detection of knee osteoarthritis (OA). Little is known about the relationship between specific clinical findings and PFJ Magnetic resonance Imaging (MRI) features. The objective was to examine the relationship between (early) clinical findings and PFJ MRI features in females (45-60 years) without knee OA (PFJ or tibiofemoral joint (TFJ) OA) based on a recently suggested MRI definition.nnnMETHODSnMRIs of knees of women of a sub-study of the Rotterdam Study were scored with semi-quantitative scoring. Specific patellar tests were performed on physical examination. Current knee pain and history of patellar knee pain were reported. Binomial logistic generalized estimated equations were used to determine the association between clinical findings of OA and PFJ MRI features. All associations were adjusted for age, body mass index (BMI) and TFJ MRI features.nnnRESULTSnIn 888 women (1776 knees, mean age: 55.1 years and mean BMI: 27.0xa0kg/m(2)) we found significant associations between crepitus and all PFJ MRI features (Odds ratios (OR) range: 2.61-5.49). A history of patellar pain was significantly associated with almost all PFJ MRI features (ORcartilage: 1.95; ORcysts: 1.86; ORbone marrow lesions: 1.83), except for osteophytes. No significant associations were found between the clinical findings and TFJ MRI features.nnnCONCLUSIONnCrepitus and history of patellar pain are clinical findings that indicate PFJ lesions seen on MRI. These tests could help to indicate signs of PFJOA. Follow-up data needs to confirm whether these tests have an additional diagnostic value for early knee OA in PFJ or TFJ.

Clinically applied CT arthrography to measure the sulphated glycosaminoglycan content of cartilage

OBJECTIVEnSimilar to delayed gadolinium enhanced MRI of cartilage, it might be possible to image cartilage quality using CT arthrography (CTa). This study assessed the potential of CTa as a clinically applicable tool to evaluate cartilage quality in terms of sulphated glycosaminoglycan content (sGAG) and structural composition of the extra-cellular matrix (ECM).nnnMETHODSnEleven human cadaveric knee joints were scanned on a clinical CT scanner. Of each knee joint, a regular non-contrast CT (ncCT) and an ioxaglate injected CTa scan were performed. Mean X-ray attenuation of both scans was compared to identify contrast influx in seven anatomical regions of interest (ROIs). All ROIs were rescanned with contrast-enhanced μCT, which served as the reference standard for sGAG content. Mean X-ray attenuation from both ncCT and CTa were correlated with μCT results and analyzed with linear regression. Additionally, residual values from the linear fit between ncCT and μCT were used as a covariate measure to identify the influence of structural composition of cartilage ECM on contrast diffusion into cartilage in CTa scans.nnnRESULTSnCTa resulted in higher X-ray attenuation in cartilage compared to ncCT scans for all anatomical regions. Furthermore, CTa correlated excellent with reference μCT values (sGAG) (R=0.86; R(2)=0.73; P<0.0001). When corrected for structural composition of cartilage ECM, this correlation improved substantially (R=0.95; R(2)=0.90; P<0.0001).nnnCONCLUSIONSnContrast diffusion into articular cartilage detected with CTa correlates with sGAG content and to a lesser extent with structural composition of cartilage ECM. CTa may be clinically applicable to quantitatively measure the quality of articular cartilage.

Factors that predict a poor outcome 5–8 years after the diagnosis of patellofemoral pain: a multicentre observational analysis

Background Patellofemoral pain (PFP) has traditionally been viewed as self-limiting, but recent studies show that a large proportion of patients report chronic knee pain at long-term follow-up. We identified those patients with an unfavourable recovery (‘moderate improvement’ to ‘worse than ever’ measured on a Likert scale) and examined whether there is an association between PFP and osteoarthritis (OA) at 5–8-year follow-up. Methods Long-term follow-up data were derived from 2 randomised controlled trials (n=179, n=131). Patient-reported measures were obtained at baseline. Pain severity (100u2005mm visual analogue scale (VAS)), function (Anterior Knee Pain Scale (AKPS)) and self-reported recovery were measured 5–8u2005years later, along with knee radiographs. Multivariate backward stepwise linear regression analyses were used to evaluate the prognostic ability of baseline pain duration, pain VAS and AKPS on outcomes of pain VAS and AKPS at 5–8u2005years. Results 60 (19.3%) participants completed the questionnaires at 5–8-year follow-up (45 women, mean age at baseline 26u2005years) and 50 underwent knee radiographs. No differences were observed between responders and non-responders regarding baseline demographics, and 3-month and 12-month pain severity and recovery. 34 (57%) reported unfavourable recovery at 5–8u2005years. 48 out of 50 participants (98%) had no signs of radiographic knee OA. Multivariate models revealed that baseline PFP duration (>12u2005months; R2=0.22) and lower AKPS (R2=0.196) were significant predictors of poor prognosis at 5–8u2005years on measures of worst pain VAS and AKPS, respectively. Summary and conclusion More than half of participants with PFP reported an unfavourable recovery 5–8u2005years after recruitment, but did not have radiographic knee OA. Longer PFP duration and worse AKPS score at baseline predict poor PFP prognosis. Education of health practitioners and the general public will provide patients with more realistic expectations regarding prognosis.

CT arthrography of the human knee to measure cartilage quality with low radiation dose

OBJECTIVEnRecently, CT arthrography (CTa) was introduced as a non-destructive technique to quantitatively measure cartilage quality in human knees. This study investigated whether this is also possible using lower radiation dose CT protocols. Furthermore, we studied the ability of (lower radiation) CTa to distinguish between local sulphated glycosaminoglycan (sGAG) content differences.nnnDESIGNnOf ten human cadaveric knee joints, six CT scans using different radiation doses (81.33-8.13 mGy) were acquired after intra-articular ioxaglate injection. The capability of CTa to measure overall cartilage quality was determined in seven anatomical regions of interest (ROIs), using equilibrium partitioning of an ionic contrast agent using (EPIC)-microCT (μCT) as reference standard for sGAG content. To test the capability of CTa to spatially distinguish between local differences in sGAG content, we calculated the percentage of pixels incorrectly predicted as having high or low sGAG content by the different CTa protocols.nnnRESULTSnLow radiation dose CTa correlated well with EPIC-μCT in large ROIs (R = 0.78; R(2) = 0.61; P < 0.0001). CTa can also distinguish between high and low sGAG content within a single slice. However, the percentage of incorrectly predicted quality pixels increases (from 35% to 41%) when less radiation is used. This makes is hard or even impossible to differentiate between spatial differences in sGAG content in the lowest radiation scans.nnnCONCLUSIONSnCTa acquired using low radiation exposure, comparable to a regular knee CT, is able to measure overall cartilage quality. Spatial sGAG distribution can also be determined using CTa, however for this purpose a higher radiation dose is necessary. Nevertheless, radiation dose reduction makes CTa suitable for quantitative analysis of cartilage in clinical research.

How to define subregional osteoarthritis progression using semi-quantitative MRI Osteoarthritis Knee Score (MOAKS)

OBJECTIVEnRecently, the MRI Osteoarthritis Knee Score (MOAKS), a new semi-quantitative magnetic resonance imaging (MRI) scoring tool, was introduced by a panel of experienced researchers in osteoarthritis (OA). The MOAKS is primarily applicable to quantify OA status, since the interpretation of change in the MOAKS features was not described. In order to enable longitudinal evaluation, we propose definitions for progression and improvement of the main MOAKS features.nnnMETHODnClear definitions for progression and improvement of the main MOAKS features are given in this brief report. 687 baseline and 30 months follow-up MRIs of the knees of 348 overweight and obese middle-aged women, free of OA at baseline, were scored using the MOAKS. Baseline prevalence and the change of MOAKS features after 30 months follow-up, based on our definitions for progression and improvement, are presented.nnnRESULTSnThe proposed definitions showed 3% to 23% progression and 0% to 11% improvement in the MOAKS features during the 30 months follow-up. Overall, progression rates were higher in the medial than in the lateral tibiofemoral (TF) joint. Progression of bone marrow lesions (BMLs) and cartilage defects was highest in the patellofemoral (PF) joint. Inter-rater reliability of the MOAKS scores was moderate to nearly perfect (PABAK 0.77-0.88), with high percentage of agreement overall (89-94%).nnnCONCLUSIONnThis brief report presents definitions for progression and improvement of the main MOAKS features for the longitudinal evaluation of knee OA features on MRI. We advocate uniform usage of the proposed definitions across studies, but welcome suggestions for optimization.

Dissecting the relationship between high-sensitivity serum C-reactive protein and increased fracture risk: the Rotterdam Study

SummarySerum high-sensitivity C-reactive protein (CRP) is an inflammatory biomarker. We investigated the relationship between CRP and bone health in the Rotterdam Study. Serum high-sensitivity CRP was associated with fracture risk and lower femoral neck bending strength. Mendelian randomization analyses did not yield evidence for this relationship being causal.IntroductionInflammatory diseases are associated with bone pathology, reflected in a higher fracture risk. Serum high-sensitivity CRP is an inflammatory biomarker. We investigated the relationship between CRP and bone mineral density (BMD), hip bone geometry, and incident fractures in the Rotterdam Study, a prospective population-based cohort.MethodsAt baseline, serum high-sensitivity CRP was measured. A weighted genetic risk score was compiled for CRP based on published studies (29 polymorphisms; Illumina HumanHap550 Beadchip genotyping and HapMap imputation). Regression models were reported per standard deviation increase in CRP adjusted for sex, age, and BMI. Complete data was available for 6,386 participants, of whom 1,561 persons sustained a fracture (mean follow-up, 11.6xa0years).ResultsCRP was associated with a risk for any type of fracture [hazard ratio (HR)u2009=u20091.06; 95xa0% confidence interval (CI), 1.02–1.11], hip fractures (HRu2009=u20091.09; 1.02–1.17) and vertebral fractures [odds ratio (OR)u2009=u20091.34; 1.14–1.58]. An inverse relationship between CRP levels and section modulus (−0.011xa0cm3; −0.020 to −0.003xa0cm3) was observed. The combined genetic risk score of CRP single nucleotide polymorphisms (SNPs) was associated with serum CRP levels (pu2009=u20099u2009×u200910−56), but not with fracture risk (HRu2009=u20091.00; 0.99–1.00; pu2009=u20090.23).ConclusionsSerum high-sensitivity CRP is associated with fracture risk and lower bending strength. Mendelian randomization analyses did not yield evidence for this relationship being causal. Future studies might reveal what factors truly underlie the relationship between CRP and fracture risk.

Incidence, prevalence, natural course and prognosis of patellofemoral osteoarthritis: the Cohort Hip and Cohort Knee study

OBJECTIVEnTo examine the proportion of isolated patellofemoral osteoarthritis (PFOA) compared to tibiofemoral osteoarthritis (TFOA) in middle-aged participants with early osteoarthritis (OA) symptoms of the knee; to describe the natural course of PFOA compared with that of TFOA and to identify whether patients with PFOA have a different phenotype compared to patients with TFOA, or with combined PFOA and TFOA (combined osteoarthritis (COA)).nnnDESIGNnParticipants with early OA symptoms of the knee were selected, completed questionnaires, underwent physical examination, and had knee radiographs at baseline, and at 2 and 5 years follow-up. Based on radiographs, participants were classified as having isolated TFOA, isolated PFOA, COA, or no radiographic OA. Multivariate logistic regression was used to identify participant characteristics associated with a specific group of OA at 2 years follow-up.nnnRESULTSnThe cohort comprised 845 participants (mean age 55.9 years). At baseline, 116 had PFOA, none had TFOA or COA. Of these 116 participants, 66.3% had developed COA at 5 years follow-up. At 2 years follow-up, PFOA, TFOA and COA were present in 77 (10.8%), 39 (5.5%) and 83 (11.6%) participants, respectively. Multivariate regression analyses at 2 years follow-up showed that participants with radiographic PFOA or TFOA were not significantly different from each other with respect to signs and symptoms.nnnCONCLUSIONSnThese results suggest that OA is more likely to start in the patellofemoral joint and then progress to COA in individuals with symptoms of early knee OA. No differences in TFOA and PFOA phenotypes were determined with respect to signs and symptoms.

Baseline meniscal extrusion associated with incident knee osteoarthritis after 30 months in overweight and obese women

OBJECTIVEnTo investigate the association between baseline meniscal extrusion and the incidence of knee osteoarthritis (KOA) after 30 months in a high-risk population of overweight and obese women, free of clinical and radiological KOA at baseline.nnnMETHODSn407 middle-aged overweight women (body mass index - BMIxa0≥xa027xa0kg/m2) were evaluated at baseline and after 30 months of follow-up. Meniscal extrusion was defined as grade ≥2 on MRI according to MRI Osteoarthritis Knee Score (MOAKS). The primary outcome measure was KOA after 30 months follow-up, defined using the following criteria: either incidence of radiographic KOA (Kellgren & Lawrence grade 2 or higher), or clinical osteoarthritis (OA) according to the American College of Radiology (ACR) criteria, or medial or lateral joint space narrowing (JSN) of ≥1.0xa0mm. Using generalized estimating equations (GEE), we determined the association between knees with and without meniscal extrusion and both outcomes, corrected for the baseline differences.nnnRESULTSn640 knees were available at baseline of which 24% (153) had meniscal extrusion. There was a significantly higher incidence of KOA according to the primary outcome measure in women with meniscal extrusion compared to those without extrusion (28.8%, odds ratio - OR 2.39, 95% CI 1.53, 3.73). A significantly higher incidence was found for the development of radiographic KOA (12.4%, OR 2.61, 95% CI 1.11, 6.13) and medial JSN (11.8%, OR 3.19, 95% CI 1.59, 6.41). Meniscal extrusion was not significantly associated with clinical KOA and lateral JSN.nnnCONCLUSIONnMeniscal extrusion was associated with a significantly higher incidence of KOA, providing an interesting target for early detection of individuals at risk for developing KOA.

Reducing progression of knee OA features assessed by MRI in overweight and obese women: secondary outcomes of a preventive RCT.

OBJECTIVEnTo evaluate the preventive effects of a randomized controlled trial on progression of Magnetic Resonance Imaging (MRI) features of knee osteoarthritis (OA) in overweight and obese women.nnnDESIGNnIn a 2xa0×xa02 factorial design, 2.5 years effects of a diet and exercise program and of glucosamine sulphate (double-blind, placebo-controlled) were evaluated in 407 middle-aged women with body mass index (BMI)xa0≥xa027xa0kg/m(2) without clinical signs of knee OA at baseline (ISRCTN 42823086). MRIs were scored with the MRI Osteoarthritis Knee Score (MOAKS). Progression was defined for bone marrow lesions (BMLs), cartilage defects, osteophytes, meniscal abnormalities and meniscal extrusion. Analyses on knee level were performed over the four intervention groups using adjusted Generalized Estimating Equations (GEE).nnnRESULTSn687 knees of 347 women with mean age 55.7 years (±3.2 SD) and mean BMI 32.3xa0kg/m(2) (±4.2 SD) were analyzed. Baseline prevalence was 64% for BMLs, 70% for cartilage defects, 24% for osteophytes, 66% for meniscal abnormalities and 52% for meniscal extrusions. The diet and exercise programxa0+xa0placebo intervention showed significantly less progression of meniscal extrusion compared to placebo only (12% vs 22%, OR 0.50, 95% CI [0.27-0.92]). The interventions did not result in significant differences on other OA MRI features.nnnCONCLUSIONSnIn subjects at high risk for future knee OA development, a diet and exercise program, glucosamine sulphate and their combination showed small and mainly non-significant effects on the progression of OA MRI features. Only progression of meniscal extrusion was significantly diminished by the diet and exercise program.