NON-CHONDRAL MULTI-TISSUE PATHOLOGY AS ASSESSED BY MRI INCREASES RATES OF QUANTITATIVE MRI-DEFINED CARTILAGE THICKNESS LOSS OVER 24 MONTHS: THE APPROACH STUDY

Abstract

The Innovative Medicines Initiative - Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) consortium is a longitudinal cohort study to combine conventional and new disease markers and to identify different OA phenotypes. Historical data were used to train machine learning models to provide a structural and pain progression score for each individual, which was used as basis for inclusion. Study parameters used to assess structural progression include quantitative MRI of cartilage including thickness and semi-quantitative MRI scoring of cartilaginous and non-cartilaginous features of OA. To assess whether baseline presence of non-cartilaginous OA features, i.e. bone marrow lesions (BMLs), meniscal damage, meniscal extrusion, and MRI-defined signs of inflammation (effusion-synovitis and Hoffa-synovitis) is associated with increased rates of ipsicompartmental cartilage loss over 24 months when compared to those compartments without presence of these features. In addition, we wished to explore whether lesion load, i.e. number of features present in a given compartment at baseline further increases rates of ipsicompartmental progression. 297 people with knee OA were included in the APPROACH cohort study (age: 66.5±7.1 years, BMI: 28.1±5.3 kg/m², 77.5% women). The MRI protocols included triplanar proton density-weighted fat-suppressed, a coronal T1-weighted sequence and a high-resolution fat-suppressed gradient echo sequence for cartilage quantification. MRI assessment was performed using the semi-quantitative MOAKS instrument for BMLs, meniscal damage, meniscal extrusion, and effusion-synovitis and Hoffa-synovitis. Quantitative cartilage thickness measurements were performed by experienced readers. BMLs are evaluated on a three-dimensional scale. For this study only the size portion was considered. Presence of BML was defined as either at least one grade 3 BML (size) in any of 5 medial or lateral compartmental subregions or presence in 3 out of 5 medial or lateral subregions. Meniscal damage was collapsed to either normal, or any damage including any tear and any maceration. Meniscal extrusion is scored from 0 to 3 in the coronal plane. Inflammation was assessed as effusion-synovitis and Hoffa-synovitis and scored each from 0-3 each. Lesion load was defined as number of features present (i.e. max. number 4: BML, meniscus damage, meniscus extrusion, inflammation) compared to those without any ipsicompartmental OA features present. Only the medial and lateral tibio-femoral compartments (MFTC and LFTC) were considered. Between-group comparisons regarding cartilage loss in the medial and lateral compartment were performed using ANCOVA with adjustment for age, sex, and BMI. Results were presented as adjusted mean difference (MAD) and 95% confidence intervals (CI). Knees with presence of BMLs in the MFTC at baseline (n=34) showed more MFTC cartilage loss than knees without BMLs (mean adjusted difference (MAD) -0.19 mm, 95% CI [-0.23, -0.14] mm). Presence of meniscal damage (n=113) resulted in a MAD of cartilage loss of -0.08 mm, 95% CI: [-0.12, -0.04] mm, while presence of meniscal extrusion (n=70) resulted in an adjusted MAD of -0.09 mm, 95% CI: [-0.13, -0.04] mm). Baseline presence of either effusion- and/or Hoffa-synovitis resulted in an adjusted MAD of -0.06 mm, 95% CI: [-0.10, -0.01] mm. Regarding number of features present at baseline, increasing number of features was associated with increasing rates of cartilage thickness loss suggesting a cumulative effect of each baseline MRI feature (1 feature: -0.02 mm [-0.07,0.03], 2 features: -0.06 mm [-0.12,-0.01], 3 features: -0.10 mm [-0.16,-0.04], 4 features: -0.22 mm [-0.30,-0.15]). Baseline presence of non-cartilaginous MRI OA features increased ipsicompartmental rate of cartilage loss at 24 months. This effect was strongest for ipsicompartmental presence of BMLs. The number of features present at baseline increases rates of cartilage loss in a linear fashion. This work was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115770, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution. See www.imi.europa.eu and www.approachproject.eu . FWR is shareholder of Boston Imaging Core Lab. (BICL), LLC. And is consultant to Calibr and Grünenthal. CL reports other from Merck KGaA, during the conduct of the study; MK reports grants from IMI-APPROACH, grants from Dutch Arthritis Association, during the conduct of the study; other from GlaxoSmithKline, Pfizer, Merck-Serono, Kiniksa, Abbvie, outside the submitted work; FJB reports grants from Gebro Pharma, grants from BIOIBERICA, grants from AB Science, grants from Abbvie, grants from Ablynx N.V., grants from Amgen, grants from Archigen Biotech Limited, grants from Boehringer, grants from Bristol-Myers, grants from Celgene Int., grants from Eli Lilly and Company, grants from F. Hoffmann-La Roche, grants from Galapagos, grants from Gedeon, grants from Genentech, grants from Gideal Sciences, NC, grants from Glaxosmithkline, grants from Hospira, grants from INC Research UK, grants from Inventiv Health Clinical, grants from Janssen, grants from Lilly, grants from Nichi-IKO Pharmaceutical, grants from Novartis, grants from ONO Pharma, grants from Pfizer, grants from Pharmaceutical Research, grants from Regeneron, grants from Roche, grants from SA UCB Pharma, grants from Sanofi, grants from TRB Chemedica, grants from UCB Biosciences GMBH, outside the submitted work; IKH reports personal fees from AbbVie, grants from Pfizer, outside the submitted work; FB reports personal fees from Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, TRB Chemedica, 4P Pharma CORRESPONDENCE ADDRESS: frank.roemer@uk-erlangen.de