Imaging atlas for eligibility and on-study safety of potential knee adverse events in anti-NGF studies (Part 1)

SummaryMonoclonal antibodies that bind and inhibit nerve growth factor (NGF) have demonstrated both, good analgesic efficacy and improvement in function in patients with osteoarthritis (OA). Despite initial promising data, trials in OA had been suspended by the Federal Food and Drug Administration (FDA) due to concerns over accelerated rates of OA progression. Imaging will play a crucial role in future clinical trials to define eligibility of potential participants and to monitor safety during the course of these studies. This will require baseline and frequent follow-up radiographs of both, the index joints and other large weight bearing joints to identify subjects at risk prior inclusion and on study so treatment can be discontinued.This imaging overview in the form of an atlas describes and illustrates potential exclusionary joint imaging findings at eligibility and potential adverse joint events on radiography and magnetic resonance imaging (MRI) in studies investigating a-NGF compounds. The overarching goal of this atlas is to facilitate trial design and to promote a common language and understanding between potential expert readers. This first section of the atlas will focus on knee joint specific findings that are relevant to a-NGF studies

Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI Osteoarthritis Knee Score)

SummaryObjectiveIn an effort to evolve semi-quantitative scoring methods based upon limitations identified in existing tools, integrating expert readers’ experience with all available scoring tools and the published data comparing the different scoring systems, we iteratively developed the magnetic resonance imaging (MRI) Osteoarthritis Knee Score (MOAKS). The purpose of this report is to describe the instrument and its reliability.MethodsThe MOAKS instrument refines the scoring of bone marrow lesions (BMLs) (providing regional delineation and scoring across regions), cartilage (sub-regional assessment), and refines the elements of meniscal morphology (adding meniscal hypertrophy, partial maceration and progressive partial maceration) scoring. After a training and calibration session two expert readers read MRIs of 20 knees separately. In addition, one reader re-read the same 20 MRIs 4 weeks later presented in random order to assess intra-rater reliability. The analyses presented here are for both intra- and inter-rater reliability (calculated using the linear weighted kappa and overall percent agreement).ResultsWith the exception of inter-rater reliability for tibial cartilage area (kappa=0.36) and tibial osteophytes (kappa=0.49); and intra-rater reliability for tibial BML number of lesions (kappa=0.54), Hoffa-synovitis (kappa=0.42) all measures of reliability using kappa statistics were very good (0.61–0.8) or reached near-perfect agreement (0.81–1.0). Only intra-rater reliability for Hoffa-synovitis, and inter-rater reliability for tibial and patellar osteophytes showed overall percent agreement <75%.ConclusionMOAKS scoring shows very good to excellent reliability for the large majority of features assessed. Further iterative development and research will include assessment of its validation and responsiveness

Three-dimensional turbo spin-echo magnetic resonance imaging (MRI) and semiquantitative assessment of knee osteoarthritis: comparison with two-dimensional routine MRI

SummaryPurposeThe aim of this study was to evaluate three-dimensional (3D) turbo spin-echo (TSE) magnetic resonance imaging (MRI) for semiquantitative assessment of knee OA.Materials and methodTwenty subjects fulfilling the American College of Rheumatology clinical criteria of knee OA underwent both two-dimensional (2D) and 3D MRIs on the same day. The 2D MRI protocol included triplanar fat-suppressed (FS) intermediate-weighted (Iw) TSE. For the 3D TSE technique, a sagittal FS Iw sequence was acquired and triplanar reformations were constructed. 2D and 3D MRIs were read separately by two radiologists using the Whole-Organ Magnetic Resonance Imaging Score (WORMS) system. Agreement was determined using weighted kappa statistics and percentage of overall agreement. The diagnostic performance of WORMS readings using 3D TSE MRI to detect the presence or absence of features was assessed using readings from 2D TSE images as a reference.ResultsAgreement for the scored features ranged between 0.62 (osteophytes (OS)) and 0.94 (meniscal extrusion). The sensitivity of WORMS readings using the 3D TSE technique ranged between 80% (periarticular cysts) and 100% (several features), the specificity ranged between 62.3% (OS) and 100% (several features), and accuracy ranged between 77.2% (OS) and 99.3% (subchondral cysts).ConclusionsSemiquantitative assessment of knee OA can be reliably performed using 3D TSE MRI, showing substantial to almost perfect agreement and high accuracy when compared to routine 2D TSE MRI. 3D TSE MRI also takes less time, which is important for large OA studies