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The combination of an inflammatory peripheral blood gene expression and imaging biomarkers enhance prediction of radiographic progression in knee osteoarthritis

Authors
  • Attur, Mukundan1, 2
  • Krasnokutsky, Svetlana1
  • Zhou, Hua3
  • Samuels, Jonathan1
  • Chang, Gregory4
  • Bencardino, Jenny4, 5
  • Rosenthal, Pamela1
  • Rybak, Leon3
  • Huebner, Janet L.6
  • Kraus, Virginia B.6
  • Abramson, Steven B.1
  • 1 Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA , New York (United States)
  • 2 NYU Langone Orthopedic Hospital, 301 East 17th Street, Suite 1612, New York, NY, 10003, USA , New York (United States)
  • 3 Applied Bioinformatics Laboratories, NYU Grossman School of Medicine, New York, NY, USA , New York (United States)
  • 4 Department of Radiology, NYU Grossman School of Medicine, New York, NY, USA , New York (United States)
  • 5 Division of Musculoskeletal Imaging, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104, USA , Philadelphia (United States)
  • 6 Duke University School of Medicine, Durham, NC, USA , Durham (United States)
Type
Published Article
Journal
Arthritis Research & Therapy
Publisher
Springer Science and Business Media LLC
Publication Date
Sep 10, 2020
Volume
22
Issue
1
Identifiers
DOI: 10.1186/s13075-020-02298-6
Source
Springer Nature
Keywords
License
Green

Abstract

ObjectivePredictive biomarkers of progression in knee osteoarthritis are sought to enable clinical trials of structure-modifying drugs. A peripheral blood leukocyte (PBL) inflammatory gene signature, MRI-based bone marrow lesions (BML) and meniscus extrusion scores, meniscal lesions, and osteophytes on X-ray each have been shown separately to predict radiographic joint space narrowing (JSN) in subjects with symptomatic knee osteoarthritis (SKOA). In these studies, we determined whether the combination of the PBL inflammatory gene expression and these imaging findings at baseline enhanced the prognostic value of either alone.MethodsPBL inflammatory gene expression (increased mRNA for IL-1β, TNFα, and COX-2), routine radiographs, and 3T knee MRI were assessed in two independent populations with SKOA: an NYU cohort and the Osteoarthritis Initiative (OAI). At baseline and 24 months, subjects underwent standardized fixed-flexion knee radiographs and knee MRI. Medial JSN (mJSN) was determined as the change in medial JSW. Progressors were defined by an mJSN cut-point (≥ 0.5 mm/24 months). Models were evaluated by odds ratios (OR) and area under the receiver operating characteristic curve (AUC).ResultsWe validated our prior finding in these two independent (NYU and OAI) cohorts, individually and combined, that an inflammatory PBL inflammatory gene expression predicted radiographic progression of SKOA after adjustment for age, sex, and BMI. Similarly, the presence of baseline BML and meniscal lesions by MRI or semiquantitative osteophyte score on X-ray each predicted radiographic medial JSN at 24 months. The combination of the PBL inflammatory gene expression and medial BML increased the AUC from 0.66 (p = 0.004) to 0.75 (p < 0.0001) and the odds ratio from 6.31 to 19.10 (p < 0.0001) in the combined cohort of 473 subjects. The addition of osteophyte score to BML and PBL inflammatory gene expression further increased the predictive value of any single biomarker. A causal analysis demonstrated that the PBL inflammatory gene expression and BML independently influenced mJSN.ConclusionThe use of the PBL inflammatory gene expression together with imaging biomarkers as combinatorial predictive biomarkers, markedly enhances the identification of radiographic progressors. The identification of the SKOA population at risk for progression will help in the future design of disease-modifying OA drug trials and personalized medicine strategies.

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