A consensus-based framework for conducting and reporting osteoarthritis phenotype research.

BACKGROUND: The concept of osteoarthritis (OA) heterogeneity is evolving and gaining renewed interest. According to this concept, distinct subtypes of OA need to be defined that will likely require recognition in research design and different approaches to clinical management. Although seemingly plausible, a wide range of views exist on how best to operationalize this concept. The current project aimed to provide consensus-based definitions and recommendations that together create a framework for conducting and reporting OA phenotype research. METHODS: A panel of 25 members with expertise in OA phenotype research was composed. First, panel members participated in an online Delphi exercise to provide a number of basic definitions and statements relating to OA phenotypes and OA phenotype research. Second, panel members provided input on a set of recommendations for reporting on OA phenotype studies. RESULTS: Four Delphi rounds were required to achieve sufficient agreement on 11 definitions and statements. OA phenotypes were defined as subtypes of OA that share distinct underlying pathobiological and pain mechanisms and their structural and functional consequences. Reporting recommendations pertaining to the study characteristics, study population, data collection, statistical analysis, and appraisal of OA phenotype studies were provided. CONCLUSIONS: This study provides a number of consensus-based definitions and recommendations relating to OA phenotypes. The resulting framework is intended to facilitate research on OA phenotypes and increase combined efforts to develop effective OA phenotype classification. Success in this endeavor will hopefully translate into more effective, differentiated OA management that will benefit a multitude of OA patients.

Change in regional cartilage morphology and joint space width in osteoarthritis participants versus healthy controls: a multicentre study using 3.0 Tesla MRI and Lyon-Schuss radiography.

OBJECTIVE: Cartilage morphology displays sensitivity to change in osteoarthritis (OA) with quantitative MRI (qMRI). However, (sub)regional cartilage thickness change at 3.0 Tesla (T) has not been directly compared with radiographic progression of joint space narrowing in OA participants and non-arthritic controls. METHODS: A total of 145 women were imaged at 7 clinical centres: 86 were non-obese and asymptomatic without radiographic OA and 55 were obese with symptomatic and radiographic OA (27 Kellgren-Lawrence grade (KLG)2 and 28 KLG3). Lyon-Schuss (LS) and fixed flexion (FF) radiographs were obtained at baseline, 12 and 24 months, and coronal spoiled gradient echo MRI sequences at 3.0 T at baseline, 6, 12 and 24 months. (Sub)regional, femorotibial cartilage thickness and minimum joint space width (mJSW) in the medial femorotibial compartment were measured and the standardised response means (SRMs) determined. RESULTS: At 6 months, qMRI demonstrated a -3.7% "annualised" change in cartilage thickness (SRM -0.33) in the central medial femorotibial compartment (cMFTC) of KLG3 subjects, but no change in KLG2 subjects. The SRM for mJSW in 12-month LS/FF radiographs of KLG3 participants was -0.68/-0.13 and at 24 months was -0.62/-0.20. The SRM for cMFTC changes measured with qMRI was -0.32 (12 months; -2.0%) and -0.48 (24 months; -2.2%), respectively. CONCLUSIONS: qMRI and LS radiography detected significant change in KLG3 participants at high risk of progression, but not in KLG2 participants, and only small changes in controls. At 12 and 24 months, LS displayed greater, and FF less, sensitivity to change in KLG3 participants than qMRI.

Novel synovial fluid recovery method allows for quantification of a marker of arthritis in mice.

OBJECTIVE: We evaluated three methodologies--a calcium sodium alginate compound (CSAC), polyacrylate beads (PABs), and Whatman paper recovery (WPR)--for the ability to recover synovial fluid (SF) from mouse knees in a manner that facilitated biochemical marker analysis. METHODS: Pilot testing of each of these recovery vehicles was conducted using small volumes of waste human SF. CSAC emerged as the method of choice, and was used to recover and quantify SF from the knees of C57BL/6 mice (n=12), six of which were given left knee articular fractures. SF concentrations of cartilage oligomeric matrix protein (COMP) were measured by enzyme-linked immunosorbent assay. RESULTS: The mean concentration ratio [(COMP(left knee))/(COMP(right knee))] was higher in the mice subjected to articular fracture when compared to the non-fracture mice (P=0.026). The mean total COMP ratio (taking into account the quantitative recovery of SF) best discriminated between fracture and non-fracture knees (P=0.004). CONCLUSIONS: Our results provide the first direct evidence of accelerated joint tissue turnover in a mouse model responding to acute joint injury. These data strongly suggest that mouse SF recovery is feasible and that biomarker analysis of collected SF samples can augment traditional histological analyses in mouse models of arthritis.

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.

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 (1.0x0.31x0.31 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.