Unbiased analysis of knee cartilage thickness change over three years after sprifermin vs. placebo treatment - A post-hoc analysis from the phase 2B FORWARD study.

Objective: Post-treatment cartilage morphometry in the FORWARD study was performed without blinding to MRI acquisition order, involving potential reader bias. Here we obtained unbiased estimates of cartilage change post-treatment, reading year (Y)2 and Y5 MRIs with blinding to time point. We studied whether post-treatment cartilage thickness change differed between sprifermin- and placebo-treated knees. Methods: FORWARD was a 5-year randomized control trial in 549 knee osteoarthritis patients. Here, Y2/Y5 images were analyzed with blinding to relative temporal order and treatment group. Cartilage change during Y2→Y5 was obtained in 337 participants: n â€‹= â€‹57 treated with placebo intra-articular injections every 6 months (q6M); n â€‹= â€‹69 with 30 â€‹µg sprifermin every 12 months (q12 â€‹M), n â€‹= â€‹67 with 30 â€‹µg q6M, n â€‹= â€‹73 with 100 â€‹µg q12 â€‹M, and n â€‹= â€‹71 with 100 â€‹µg q6M between baseline (BL) and 18 â€‹M. Total femorotibial joint (TFTJ) cartilage thickness was the primary analytic focus. Results: TFTJ cartilage thickness change during Y2→Y5 was -26µm (SD64; 95%CI -32,-19) across the cohort; no statistically significant difference (p â€‹= â€‹0.80) was observed between Sprifermin treated or placebo arms (one-way ANOVA). All groups lost cartilage, but the treatment-related difference in cartilage thickness in Sprifermin arms relative to placebo at Y2 was maintained until Y5. Annualized cartilage change in placebo participants was -8.2 â€‹µm (SD21; 95%CI -14,-2.5) during Y2→Y5 vs. -5.4 â€‹µm (SD27; 95%CI -13,1.8) during BL→Y2; no significant difference was identified (t-test). Conclusion: FORWARD is the first study evaluating post-treatment benefits of a potential disease modifying osteoarthritis drug. Cartilage thickness gained with 100 â€‹µg sprifermin at Y2 is maintained to Y5 and thus appears viable and sustainable.This is a post-hoc analysis of the FORWARD trial: ClinicalTrials.gov Identifier: NCT01919164.

Is detection of disease-modifying osteoarthritis drug treatment more effective when performing cartilage morphometry without blinding to MR image acquisition order?

OBJECTIVE: We here explore whether observed treatment effects of a putative disease-modifying osteoarthritis drug (DMOAD) are greater when cartilage morphometry is performed with rather than without knowledge of magnetic resonance imaging (MRI) acquisition order (unblinded/blinded to time point). METHODS: In the FORWARD (FGF-18 Osteoarthritis Randomized Controlled Trial with Administration of Repeated Doses) randomized controlled trial, 549 knee osteoarthritis patients were randomized 1:1:1:1:1 to three once-weekly intra-articular injections of placebo, 30 µg sprifermin every 6 or 12 months (M), or 100 µg every 6/12 M. After year 2, cartilage segmentation of BL through 24 M MRIs was performed, with blinding to acquisition order. After year 5, 24 and 60 M MRIs were analyzed together, with unknown relative order, but with segmented BL images as reference (24 M unblinded vs. BL), by the same operators. Total femorotibial joint cartilage thickness (TFTJ_ThC) change was obtained for 352 participants analyzed under both conditions. RESULTS: Twenty-four-month data read unblinded to order revealed a -35 ± 44 µm lower TFTJ_ThC than blinded analysis (all groups: lower/upper bounds -120/+51 µm; correlation r2 = 97%). With unblinded analysis, the placebo group lost -46 ± 57 µm TFTJ_ThC over 24 M, whereas 100 µg/every 6 M lost -2.2 ± 73 µm (difference =44 µm [95% CI: 22, 66]). With blinded analysis, placebo lost -11 ± 53 µm, whereas 100 µg/every 6 M gained 30 ± 62 µm (difference = 40 µm [95% CI: 21, 60]). 100 µg sprifermin injected every 6 M showed statistically significant (p < 0.001) treatment effects on TFTJ_ThC, with Cohen D = -0.66 for unblinded and D = -0.69 for blinded analysis. CONCLUSIONS: These results do not reveal that detection of proposed DMOAD treatment is enhanced with MRIs read unblinded to order; rather, the sensitivity is similar to blinded analysis. Choices on blinded vs. unblinded analysis may thus be based on other criteria.

Automatic Detection of Medial and Lateral Compartments from Histological Sections of Mouse Knee Joints Using the Single-Shot Multibox Detector Algorithm.

OBJECTIVE: Although mouse osteoarthritis (OA) models are widely used, their histological analysis may be susceptible to arbitrariness and inter-examiner variability in conventional methods. Therefore, a method for the unbiased scoring of OA histology is needed. In this study, as the first step for establishing this system, we developed a computer-vision algorithm that automatically detects the medial and lateral compartments of mouse knee sections in a rigorous and unbiased manner. DESIGN: A total of 706 images of coronal sections of mouse knee joints stained by hematoxylin and eosin, safranin O, or toluidine blue were randomly divided into training and validation images at a ratio of 80:20. A model to detect both compartments automatically was built by machine learning using a single-shot multibox detector (SSD) algorithm with training images. The model was tested to determine whether it could accurately detect both compartments by analyzing the validation images and 52 images of sections stained with Picrosirius red, a method not used for the training images. RESULTS: The trained model accurately detected both medial and lateral compartments of all 140 validation images regardless of the staining method employed, severity of articular cartilage defects, and the anatomical positions and conditions of the sections. Our model also correctly detected both compartments of 50 of 52 Picrosirius red-stained images. CONCLUSIONS: By applying deep learning based on the SSD algorithm, we successfully developed a model that detects the locations of the medial and lateral compartments of tissue sections of mouse knee joints with high accuracy.

Contribution of regional 3D meniscus and cartilage morphometry by MRI to joint space width in fixed flexion knee radiography--a between-knee comparison in subjects with unilateral joint space narrowing.

BACKGROUND: Radiographic joint space width (JSW) is considered the reference standard for demonstrating structural therapeutic benefits in knee osteoarthritis. Our objective was to determine the proportion by which 3D (regional) meniscus and cartilage measures explain between-knee differences of JSW in the fixed flexion radiographs. METHODS: Segmentation of the medial meniscus and tibial and femoral cartilage was performed in double echo steady state (DESS) images. Quantitative measures of meniscus size and position, femorotibial cartilage thickness, and radiographic JSW (minimum, and fixed locations) were compared between both knees of 60 participants of the Osteoarthritis Initiative, with strictly unilateral medial joint space narrowing (JSN). Statistical analyses (between-knee, within-person comparison) were performed using regression analysis. RESULTS: A strong relationship with side-differences in minimum and a central fixed location JSW was observed for percent tibial plateau coverage by the meniscus (r = .59 and .47; p<.01) and central femoral cartilage thickness (r = .69 and .75; p<.01); other meniscus and cartilage measures displayed lower coefficients. The correlation of central femoral cartilage thickness with JSW (but not that of meniscus measures) was greater (r = .78 and .85; p<.01) when excluding knees with non-optimal alignment between the tibia and X-ray beam. CONCLUSION: 3D measures of meniscus and cartilage provide significant, independent information in explaining side-differences in radiographic JSW in fixed flexion radiographs. Tibial coverage by the meniscus and central femoral cartilage explained two thirds of the variability in minimum and fixed location JSW. JSW provides a better representation of (central) femorotibial cartilage thickness, when optimal positioning of the fixed flexion radiographs is achieved.