S.A. Mazzuca

Precision of 3.0 Tesla quantitative magnetic resonance imaging of cartilage morphology in a multicentre clinical trial

Objective: Quantitative MRI (qMRI) of cartilage morphology is a promising tool for disease-modifying osteoarthritis drug (DMOAD) development. Recent studies at single sites have indicated that measurements at 3.0 Tesla (T) are more reproducible (precise) than those at 1.5 T. Precision errors and stability in multicentre studies with imaging equipment from various vendors have, however, not yet been evaluated. Methods: A total of 158 female participants (97 Kellgren and Lawrence grade (KLG) 0, 31 KLG 2 and 30 KLG 3) were imaged at 7 clinical centres using Siemens Magnetom Trio and GE Signa Excite magnets. Double oblique coronal acquisitions were obtained at baseline and at 3 months, using water excitation spoiled gradient echo sequences (1.0×0.31×0.31 mm3 resolution). Segmentation of femorotibial cartilage morphology was performed using proprietary software (Chondrometrics GmbH, Ainring, Germany). Results: The precision error (root mean square coefficient of variation (RMS CV)%) for cartilage thickness/volume measurements ranged from 2.1%/2.4% (medial tibia) to 2.9%/3.3% (lateral weight-bearing femoral condyle) across all participants. No significant differences in precision errors were observed between KLGs, imaging sites, or scanner manufacturers/types. Mean differences between baseline and 3 months ranged from <0.1% (non-significant) in the medial to 0.94% (p<0.01) in the lateral femorotibial compartment, and were 0.33% (p<0.02) for the total femorotibial subchondral bone area. Conclusions: qMRI performed at 3.0 T provides highly reproducible measurements of cartilage morphology in multicentre clinical trials with equipment from different vendors. The technology thus appears sufficiently robust to be recommended for large-scale multicentre trials.

Head-to-head comparison of the Lyon Schuss and fixed flexion radiographic techniques. Long-term reproducibility in normal knees and sensitivity to change in osteoarthritic knees

OBJECTIVE The Lyon Schuss (LS) and fixed flexion (FF) views of the knee are superior to a conventional standing anteroposterior view in evaluating joint space narrowing (JSN) in osteoarthritis (OA). Both position the knee identically but only the LS aligns the medial tibial plateau (MTP) with the x-ray beam fluoroscopically. The present study provides the first head-to-head comparison of the LS and FF views. METHODS At baseline and 12 months, 62 OA and 99 control knees were imaged twice on the same day with LS and FF views. Minimum joint space width (mJSW) was measured by computer and MTP alignment was assessed from the distance between anterior and posterior margins of the MTP (intermargin distance, IMD). Reproducibility of measurements of mJSW and sensitivity to change were evaluated. RESULTS In normal knees, JSW did not vary over 12 months with either view. In OA knees, 12-month mJSN was 0.22 (0.43) mm with the LS view and -0.01 (0.46) mm with the FF view (p = 0.0002 and p = 0.92, respectively). Mean IMD was only half as large in LS as in FF views (0.9 (0.5) mm vs 1.9 (1.2) mm, p<0.0001). CONCLUSIONS LS and FF radiographs offer similar reproducibility in JSW measurement. However, presumably due to its superiority in aligning the MTP, the LS view is much more sensitive to JSN in OA knees.

Comparative evaluation of three semi-quantitative radiographic grading techniques for hip osteoarthritis in terms of validity and reproducibility in 1404 radiographs: report of the OARSI-OMERACT Task Force

OBJECTIVE The objective of this work was to compare the measurement properties of three categorical X-ray scoring methods of knee osteoarthritis (OA), both on semiflexed and extended views. METHODS In data obtained from trials and cohorts, X-rays were graded using Kellgren and Lawrence (KL), the OA Research Society International (OARSI) joint space narrowing score, and measurement of joint space width (JSW). JSW was analyzed as a categorical variable. Construct validity was assessed through logistic regression between X-ray stages and Western Ontario and McMaster Universities OA Index. Inter-observer reliability was assessed in 50 subjects for extended views by weighted kappa. Intra-observer reliability and sensitivity to change were assessed separately for extended and semiflexed views in 50 patients who had both views performed, over a 30-month interval, by weighted kappa and standardized response mean (SRM). RESULTS Extended views were available from three trials and two cohorts (1759 X-rays), including one trial in which both extended and semiflexed views (antero-posterior) were obtained. Correlation with clinical parameters was low for the three scoring methods, except for the single community-based cohort. Inter-rater reliability was higher for categorical JSW in extended views (kappa, 0.86 vs 0.56 and 0.48 for KL and OARSI, respectively). Intra-rater reliability was higher for categorical JSW, both in extended views (0.83 vs 0.61 and 0.71) and in semiflexed views (0.89 vs 0.50 and 0.67). Sensitivity to change was also higher for categorical JSW, particularly in semiflexed views (SRM, 0.49 vs 0.22 and 0.34). CONCLUSION These results indicate categorical JSW, in particular on semiflexed views, may be the preferred method to evaluate structural severity in knee OA clinical trials.

Subregional femorotibial cartilage morphology in women – comparison between healthy controls and participants with different grades of radiographic knee osteoarthritis

OBJECTIVE To identify subregional differences in femorotibial cartilage morphology between healthy controls and women with different grades of radiographic knee osteoarthritis (OA). DESIGN 158 women aged > or =40 years were studied. Weight-bearing extended anterior-posterior (AP) and Lyon schuss radiographs were obtained and the Kellgren Lawrence grade (KLG) determined. 97 women had a body mass index (BMI)< or =28, no symptoms, and were AP KLG0. 61 women had a BMI> or =30, symptoms in the target knee, and mild (KLG2=31) to moderate (KLG3=30) medial femorotibial radiographic OA in the AP views. Coronal spoiled gradient echo water excitation sequences were acquired at 3.0 Tesla. Total plate and regional measures of cartilage morphology of the weight-bearing femorotibial joint were quantified. RESULTS KLG2 participants displayed, on average, thicker cartilage than healthy controls in the medial femorotibial compartment (particularly anterior subregion of the medial tibia (MT) and peripheral [external, internal] subregions of the medial femur), and in the lateral femur. KLG3 participants displayed significantly thinner cartilage than KLG0 participants in the medial weight-bearing femur (central subregion), in the external subregion of the MT, and in the internal subregion of the lateral tibia. These differences were generally unaffected when possible effects of demographic covariates were considered. CONCLUSIONS The results indicate that in femorotibial OA regional cartilage thickening and thinning may occur, dependent on the (radiographic) disease status of the joint. These changes appear to display a heterogeneous spatial pattern, where certain subregions are more strongly affected than others.

Relation of regional articular cartilage morphometry and meniscal position by MRI to joint space width in knee radiographs

OBJECTIVE To ascertain the contribution of articular cartilage morphometry and meniscal position on MRI to joint space width (JSW) measured in the Lyon schuss radiograph of the knee. DESIGN 62 obese women with knee OA and 99 non-obese female controls (mean age 56.6 years) were imaged using 3T MRI and coronal water excitation spoiled gradient echo sequences. Segmentation of femorotibial cartilage morphology and regional morphometric analysis was performed using custom software. Meniscal position was measured quantitatively in sagittal and coronal planes. Minimum space width (mJSW) was measured in the Lyon Schuss knee radiograph; Kellgren and Lawrence grades (KLG) were assigned on standing anteroposterior knee films. The relative contribution of regional cartilage thickness and meniscal position to mJSW was assessed initially in univariate models and subsequently with multivariable modelling. RESULTS 65% of the variation in mJSW was explained by regional cartilage thickness measures, different KLG and meniscal coverage. Of these measures the medial tibia cartilage thickness measures and central region of the central medial femur (ccMF) play a consistent role in variations in mJSW observed across all KLG. Further ccMF and the addition of percent meniscal coverage to this model explains the remaining differences in mean mJSW found between those subjects with definite joint space narrowing (KLG3) and those without OA. CONCLUSION The variation in radiographic mJSW is best described by five regional cartilage thickness measures and percent meniscal coverage. The magnitude of each measures contribution differs according to radiographic severity with more variability explained by cartilage thickness of ccMF cartilage thickness and percent meniscal coverage with more severe disease.

Alignment of the medial tibial plateau affects the rate of joint space narrowing in the osteoarthritic knee

OBJECTIVE To determine, in serial fixed-flexion (FF) radiographs of subjects with knee osteoarthritis (KOA), the importance of, and basis for, the effect of alignment of the medial tibial plateau (MTP), as determined by the inter-margin distance (IMD), on joint space narrowing (JSN). METHODS Baseline and 12-month X-rays of 590 knees with Kellgren and Lawrence grade (KLG) 2/3 OA from the public-release dataset of the Osteoarthritis Initiative (OAI) were assigned to subgroups based upon IMD at baseline (IMD(BL)) and the difference between IMD(BL) and IMD(12 mos). Relationships of JSN to IMD(BL) and to the difference between IMD(BL and) IMD(12 mos) were evaluated. RESULTS In all 590 knees, mean JSN was 0.13 ± 0.51 mm (P<0.0001) and MTP alignment and replication of IMD(BL) in the 12-month film were, in general, poor. JSN was significantly (P=0.012) more rapid in Subgroup A (IMD≤1.70 mm at both time points) than in Subgroup B (both IMDs>1.70 mm): 0.15 ± 0.43; 0.08 ± 0.47. Within Subgroup B we identified a subset, Subgroup B1, in which, although alignment was poor at both time points, the large IMD(BL) was, by chance, highly reproduced by IMD(12 mos) (difference between the two IMDs=0.01 ± 0.27 mm, NS). JSN in Subgroup B1 was 0.06 ± 0.41 mm and did not differ from that in other knees of Subgroup B (P=0.87). The standardized response mean (SRM) in all 590 knees and Subgroups A, B and B1 was 0.25, 0.34, 0.17 and 0.06, respectively. Independent of IMD(BL), JSN correlated significantly with the difference between the IMDs in the two radiographs (r=0.17, P=0.0001). CONCLUSION Skewed MTP alignment in serial films and poor replication of IMD(BL) in the follow-up exam affect JSN measurement. The magnitude of change in joint space width (JSW) related to the poor quality of alignment that is common with the FF view jeopardizes accurate evaluation of JSN.

Radiographic grading and measurement of joint space width in osteoarthritis.

The progression of osteoarthritis is traditionally measured using radiographic joint space width (JSW). Numerous knee radiograph protocols have been developed with various levels of complexity and performance as it relates to detecting JSW loss (ie, joint space narrowing). Sensitivity to joint space narrowing is improved when radioanatomic alignment of the medial tibial plateau is achieved. Semiautomated software has been developed to improve the accuracy of JSW measurement over manual methods. JSW measurements include minimum JSW, mean JSW or joint space area, and JSW at fixed locations.

Progressive increase in body mass index is not associated with a progressive increase in joint space narrowing in obese women with osteoarthritis of the knee

Objective: Given that obesity is a risk factor for osteoarthritis (OA) of the knee, a study was undertaken to determine whether progressively higher body mass index (BMI) among obese women is associated with progressive increases in joint space narrowing (JSN). Methods: Medial compartment JSN over 12 months in Lyon Schuss radiographs of 60 obese women (BMI 30.0–50.5 kg/m2) with radiographic and symptomatic OA was compared with that in 81 non-obese women (BMI <28 kg/m2) with normal radiographs and minimal or no symptoms of knee OA. Results: Among the patients with OA, higher BMI tended to be associated with a higher Kellgren and Lawrence (KL) grade of OA severity. JSN in the non-obese controls was negligible, but in the 30 patients with KL grade 2 and KL grade 3 knees, mean (SD) JSN was 0.12 (0.31) mm and 0.32 (0.50) mm, respectively (p<0.005 and p<0.001). No association was seen between baseline BMI and 12-month JSN in patients with OA; indeed, the regression plot suggested a slight inverse relationship between the two. Conclusions: In obese patients with OA, progressively higher BMI values were not accompanied by a progressively increasing rate of JSN. Joint loading was not evaluated, but it is possible that marked obesity limited the functional capacity of some subjects with OA, protecting their knees from loading. For investigators considering eligibility criteria for a trial of a structure-modifying OA drug, these data suggest that recruitment of patients with a BMI much higher than 30 kg/m2 will not enrich the sample of subjects who will have more rapid JSN than those with a BMI of only 30 kg/m2.

117 TIINE MEASUREMENT OF TYPE II COLLAGEN BREAKDOWN AND JOINT SPACE NARROWING (JSN) IN THE RANDOMIZED CLINICAL TRIAL (RCT) OF DOXYCYCLINE (DOXY) IN OSTEOARTHRITIS (OA)

* p<0.01 vs corresponding fluids from patients with OA; # p<0.01 vs paired joint fluid As shown on the table, both in joint fluid and plasma, IIINys levels were significantly higher in patients with RA than in OA individuals. Plasma IIINys levels were significantly higher than paired joint fluid values in both OA and RA patients, as shown by a ratio (joint fluid/serum) <1. There was a significant correlation between knee joint fluid and paired plasma IIINys levels (r = 0.64, p=0.0034). Compared to healthy sex and age-matched controls, circulating IIINys levels were increased by a median of 43% in 89 patients with knee OA (p <0.0001) and by 216% (p<0001) in 55 patients with active RA. Conclusions: Type III collagen of synovial tissue from patients with OA and RA is characterized by increased N-telopeptide nitrosylation which can be detected by joint fluid and circulating IIINys levels. IIINys may be a useful biochemical marker of NO-induced joint damage in OA and RA.