FDA/Arthritis Foundation osteoarthritis drug development workshop recap: Assessment of long-term benefit.

OBJECTIVE: To summarize proceedings of a workshop convened to discuss the current state of science in the disease of osteoarthritis (OA), identify the knowledge gaps, and examine the developmental and regulatory challenges in bringing these products to market. DESIGN: Summary of the one-day workshop held virtually on June 22nd, 2021. RESULTS: Speakers selected by the Planning Committee presented data on the current approach to assessment of OA therapies, biomarkers in OA drug development, and the assessment of disease progression and long-term benefit. CONCLUSIONS: Demonstrated by numerous failed clinical trials, OA is a challenging disease for which to develop therapeutics. The challenge is magnified by the slow time of onset of disease and the need for clinical trials of long duration and/or large sample size to demonstrate the effect of an intervention. The OA science community, including academia, pharmaceutical companies, regulatory agencies, and patient communities, must continue to develop and test better clinical endpoints that meaningfully reflect disease modification related to long-term patient benefit.

Combined Inflammation and Metabolism Biomarker Indices of Robust and Impaired Physical Function in Older Adults.

OBJECTIVES: To determine whether combinations of inflammatory markers are related to physical function. DESIGN AND SUBJECTS: secondary analysis of baseline of three observational studies of community-dwelling older adults MEASUREMENTS: The baseline data from 3 cohorts of older adults with different health and disease status were employed. Twenty markers of inflammation and metabolism were individually assessed for correlation with usual gait speed and were separated into robust and impairment quartiles. For the robustness and impairment indices, individual markers were selected using step-wise regression over bootstrapping iterations, and regression coefficients were estimated for the markers individually and collectively as an additive score. RESULTS: We developed a robustness index involving 6 markers and an impairment index involving 8 markers corresponding positively and negatively with gait speed. Two markers, glycine and tumor necrosis factor receptor 1 (TNFR1), appeared only in the robustness index, and TNFR2; regulated on activation, normal T-cell expressed and secreted; the amino acid factor; and matrix metallopeptidase 3; appeared only in the impairment index. CONCLUSION: Indices of biomarkers were associated with robust and impaired physical performance but differ, in composition suggesting potential biological differences that may contribute to robustness and impairment.

Accuracy and precision of quantitative assessment of cartilage morphology by magnetic resonance imaging at 3.0T.

OBJECTIVE: Quantitative magnetic resonance imaging (MRI) of articular cartilage represents a powerful tool in osteoarthritis (OA) research, but has so far been confined to a field strength of 1.5T. The aim of this study was to evaluate the precision of quantitative MRI assessments of human cartilage morphology at 3.0T and to correlate the measurements at 3.0T with validated measurements at 1.5T. METHODS: MR images of the knee of 15 participants with OA and 15 healthy control subjects were acquired using Siemens 1.5T and 3.0T scanners. Double oblique coronal scans were obtained at 1.5T with a 1.5-mm partition thickness, at 3.0T with a 1.5-mm partition thickness, and at 3.0T with a 1.0-mm partition thickness. Cartilage volume, thickness, and surface area of the femorotibial cartilage plates were quantified using proprietary software. RESULTS: For 1.5-mm partition thickness at 1.5T, the precision error was 3.0% and 2.6% for cartilage volume and cartilage thickness, respectively. The error was smaller for a 1.5-mm partition thickness at 3.0T (2.6% and 2.5%) and still smaller for a 1.0-mm partition thickness at 3.0T (2.1% and 2.0%). Correlation coefficients between values obtained at 3.0T and 1.5T were high (r > or = 0.96), with no significant deviation between the two field strengths. CONCLUSION: Quantitative MRI measurement of cartilage morphology at 3.0T (partition thickness 1 mm) was found to be accurate and tended to be more reproducible than at 1.5T (partition thickness 1.5 mm). Imaging at 3.0T may therefore provide superior ability to detect changes in cartilage status over time and to determine responses to treatment with structure-modifying drugs.

A comparative assessment of alignment angle of the knee by radiographic and physical examination methods.

OBJECTIVE: To compare the knee-alignment angle from a full-limb radiograph (mechanical axis) with the anatomic-axis angle as measured by physical examination using a goniometer and by 2 other radiographic methods. METHODS: The knee-alignment angle was measured in 114 knees of 57 subjects who had radiographic osteoarthritis (OA), with a Kellgren/Lawrence grade of >/=1 in at least one knee. The mechanical axis was defined as the angle formed by the intersection of 2 lines, one from the center of the head of the femur to the center of the tibial spines, and a second from the center of the talus to the center of the tibial spines. The anatomic axis was defined as the angle formed by 2 lines, each originating from a point bisecting the femur and tibia and converging at the center of the tibial spine tips. The anatomic-axis angle was measured by 3 methods: 1) physical examination using a goniometer, 2) a posteroanterior (PA) fixed-flexion knee radiograph (anatomic(PA) axis), and 3) an anteroposterior (AP) full-limb radiograph (anatomic(AP) axis). RESULTS: Significant correlations were found between the mechanical-axis angle and the anatomic-axis angle measured by each of the 3 methods: by goniometer (r = 0.70, P < 0.0001), by anatomic(PA) axis (r = 0.75, P < 0.0001), and by anatomic(AP) axis (r = 0.65, P < 0.0001). The anatomic axis was offset a mean 4.21 degrees valgus from the mechanical axis (3.5 degrees in women, 6.4 degrees in men), which was consistent across all methods. CONCLUSION: Knee alignment assessed clinically by goniometer or measured on a knee radiograph is correlated with the angle measured on the more cumbersome and costly full-limb radiograph. These alternative measures have the potential to provide useful information regarding the risk of progression of knee OA when a full-limb radiograph is not available.