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Eckstein F.,Paracelsus Medical University | Eckstein F.,Chondrometrics GmbH | Le Graverand M.-P.H.,Pfizer
Seminars in Arthritis and Rheumatism | Year: 2015

Osteoarthritis (OA) is the most common disease of synovial joints and currently lacks treatment options that modify structural pathology. Imaging is ideally suited for directly evaluating efficacy of disease-modifying OA drugs (DMOADs) in clinical trials, with plain radiography and MRI being most often applied. The current article is based on a debate held on April 26, 2014, at the World Congress of Osteoarthritis: The authors were invited to contrast strengths and limitations of both methods, highlighting scientific evidence on reliability, construct-validity, and correlations with clinical outcome, and comparing their sensitivity to change in knee OA and sensitivity to DMOAD treatment. The authors concluded that MRI provides more comprehensive information on articular tissues pathology, and that implementation of radiography in clinical trials remains a challenge. However, neither technique has thus far been demonstrated to be strongly superior over the other; for the time being it therefore appears advisable to use both in parallel in clinical trials, to provide more evidence on their relative performance. Radiographic JSW strongly depends on adequate positioning; it is not specific to cartilage loss but also to the meniscus. MRI provides somewhat superior sensitivity to change compared with the commonly used non-fluoroscopic radiographic acquisition protocols, and has recently provided non-location-dependent measures of cartilage thickness loss and gain, which are potentially more sensitive in detecting DMOAD effects than radiographic JSW or region-specific MRI. Non-location-dependent measures of cartilage thickness change should thus be explored further in context of anabolic and anti-catabolic DMOADs. © 2015 Elsevier Inc.


Crema M.D.,University of Massachusetts Boston | Crema M.D.,University of Sydney | Crema M.D.,Beth Israel Deaconess Medical Center | Crema M.D.,Chondrometrics GmbH
Annals of the rheumatic diseases | Year: 2014

OBJECTIVE: To determine the association between changes in the delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) index over 2 years as a measure of cartilage proteoglycan concentration, with changes in cartilage thickness in the medial tibiofemoral compartment of knees in middle-aged women.METHODS: One hundred and forty-eight women (one knee for each subject) aged ≥40 years were included. 3.0 T MR images of the knee were acquired at baseline, 1 year and 2 years. Three-dimensional (3D) spoiled gradient recalled echo (SPGR) sequences (for cartilage thickness) and 3D inversion recovery-prepared SPGR sequences after dGEMRIC were acquired. Segmentation was performed in the medial central (weight-bearing) femur and tibia to determine cartilage proteoglycan concentration and thickness. The association of change in the dGEMRIC indices between baseline and 1-year follow-up with (a) concomitant changes in cartilage thickness and (b) change in cartilage thickness between 1 and 2 years was assessed using linear regression.RESULTS: In the whole-sample model, a decrease in dGEMRIC indices over time at the central medial femur significantly predicted an increase in cartilage thickness at both the central medial femur (p=0.008) and the medial tibia (p=0.04).CONCLUSIONS: A decrease in dGEMRIC indices was associated with an increase in cartilage thickness in the medial compartment. Our results suggest that an increase in cartilage thickness may also be related to a decrease in proteoglycan concentration, which may represent swelling of cartilage in early stages of degeneration. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.


Eckstein F.,Paracelsus Medical University | Wirth W.,Chondrometrics GmbH | Nevitt M.C.,University of California at San Francisco
Nature Reviews Rheumatology | Year: 2012

Osteoarthritis (OA) is the most common joint disorder.The Osteoarthritis Initiative (OAI) is a multicentre, longitudinal, prospective observational cohort study of knee OA that aims to provide publicly accessible clinical datasets, images and biospecimens, to enable researchers to investigate factors that influence the onset and development of OA, and evaluate biomarkers that predict and track the course of the disease.In this Perspectives, we describe the rationale and design of the OAI and its cohort, discuss imaging protocols and summarize image analyses completed to date.We include descriptive analyses of publicly available longitudinal (2-year) data of changes in cartilage thickness in a core sample of 600 knees from 590 participants in the OAI progression subcohort.Furthermore, we describe published methodological and applied imaging research that has emerged from OAI pilot studies and OAI data releases, and how these studies might contribute to clinical development of biomarkers for assessing the efficacy of intervention trials.© 2012 Macmillan Publishers Limited.All rights reserved .


Eckstein F.,Paracelsus Medical University | Eckstein F.,Chondrometrics GmbH | Kwoh C.K.,University of Arizona | Link T.M.,University of California at San Francisco
Annals of the Rheumatic Diseases | Year: 2014

The Osteoarthritis Initiative (OAI) is a multicentre, prospective, observational, cohort study of knee osteoarthritis (OA) that began recruitment in 2004. The OAI provides public access to clinical and image data, enabling researchers to examine risk factors/predictors and the natural history of knee OA incidence and progression, and the qualification of imaging and other biomarkers. In this narrative review, we report imaging findings and lessons learned 10 years after enrolment has started. A literature search for full text articles published from the OAI was performed up to 31 December 2013 using Pubmed and the OAI web page. We summarise the rationale, design and imaging protocol of the OAI, and the history of OAI publications. We review studies from early partial, and later full OAI public data releases. The latter are structured by imaging method and tissue, reviewing radiography and then MRI findings on cartilage morphology, cartilage lesions and composition (T2), bone, meniscus, muscle and adipose tissue. Finally, analyses directly comparing findings from MRI and radiography are summarised. Ten years after the first participants were enrolled and first papers published, the OAI has become an invaluable resource to the OA research community. It has fuelled novel methodological approaches of analysing images, and has provided a wealth of information on OA pathophysiology. Continued collection and public release of long-term observations will help imaging measures to gain scientific and regulatory acceptance as 'prognostic' or 'efficacy of intervention' biomarkers, potentially enabling shorter and more efficient clinical trials that can test structure-modifying therapeutic interventions (NCT00080171).


Lohmander L.S.,Lund University | Lohmander L.S.,University of Southern Denmark | Hellot S.,Merck Serono | Dreher D.,Totzke and Dreher Scientific | And 5 more authors.
Arthritis and Rheumatology | Year: 2014

Objective To evaluate the efficacy and safety of intraarticular sprifermin (recombinant human fibroblast growth factor 18) in the treatment of symptomatic knee osteoarthritis (OA). Methods The study was a randomized, double-blind, placebo-controlled, proof-of-concept trial. Intraarticular sprifermin was evaluated at doses of 10 μg, 30 μg, and 100 μg. The primary efficacy end point was change in central medial femorotibial compartment cartilage thickness at 6 months and 12 months as determined using quantitative magnetic resonance imaging (qMRI). The primary safety end points were nature, incidence, and severity of local and systemic treatment-emergent adverse events (AEs) and acute inflammatory reactions, as well as results of laboratory assessments. Secondary end points included changes in total and compartment femorotibial cartilage thickness and volume as assessed by qMRI, changes in joint space width (JSW) seen on radiographs, and pain scores on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Results One hundred ninety-two patients were randomized and evaluated for safety, 180 completed the trial, and 168 were evaluated for the primary efficacy end point. We found no statistically significant dose response in change in central medial femorotibial compartment cartilage thickness. Sprifermin was associated with statistically significant, dose-dependent reductions in loss of total and lateral femorotibial cartilage thickness and volume and in JSW narrowing in the lateral femorotibial compartment. All groups had improved WOMAC pain scores, with statistically significantly less improvement at 12 months in patients receiving the 100-μg dose of sprifermin as compared with those receiving placebo. There was no significant difference in serious AEs, treatment-emergent AEs, or acute inflammatory reactions between sprifermin and placebo groups. Conclusion No statistically significant relationship between treatment group and reduction in central medial femorotibial compartment cartilage thickness was observed; however, prespecified structural secondary end points showed statistically significant dose-dependent reductions after sprifermin treatment. Sprifermin was not associated with any local or systemic safety concerns. Copyright © 2014 by the American College of Rheumatology.

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