Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Elevated Expression of Inflammatory Mediators Cyclooxygenase-2, Its Product Prostaglandin E2 and Interleukin-1 Beta by Peripheral Blood Leukocytes in Symptomatic Knee Osteoarthritis.
Attur1, Mukundan, Statnikov2, Alexander, Aliferis2, Constantin F., Li2, Zhiguo, Krasnokutsky3, Svetlana, Samuels1, Jonathan, Greenberg4, Jeffrey D.
NYU Hospital for Joint Diseases, New York, NY
NYU Langone, New York, NY
NYU Hospital for Joint Disease, New York, NY
New York University School of Medicine, New York, NY
New York University, New York, NY
OA is considered a local joint disease, with increasing recognition of the involvement of cartilage, bone and synovium. We and others have reported that inflammatory mediators, such as PGE2 and IL-1b, are produced by OA joint tissues, where they may contribute to disease pathogenesis. In the current studies we examined whether inflammatory events occurring within joint tissues could be reflected in the plasma and PBLs of patients with OA.
Two independent cohorts of patients with OA, and a cohort of healthy control subjects, were studied: 44 patients with tibiofemoral OA and 26 healthy control volunteers comprised the NYUHJD Learning Cohort, and 150 patients with knee OA and 21 health controls were enrolled in the NYUHJD Validation Cohort.
Using support vector machine (SVM) methodology we constructed a combinatorial biomarker of OA based on microarray data of the Learning Cohort. Among these probe sets representing PGE2 synthase and cyclooxygenase could classify the case vs. control with 0.83 mean AUC (95% CI 0.72 0.95) (AUC: area under ROC curve), as estimated by 10-fold cross-validation procedure. Further cluster analysis also revealed two distinct subclasses among these OA patients: those (OA1) with increased expression (>4-fold) of inflammatory genes (e.g., IL-1b, COX-2) compared to non-OA controls and those OA patients (OA2) with expression comparable to controls. Overexpression of inflammatory genes were validated using QPCR (p<0.0001). In association studies, patients in the OA1 group exhibited: a) greater JSW at baseline; b) higher WOMAC pain, stiffness and decreased physical function (p<0.0001), c) higher VAS pain (p<0.001) than OA2 group. Longitudinal studies indicated that OA1 patients with increased PBL IL-1b gene expression, were at higher risk for disease progression, as measured by change in JSW at 24 months (Table 1), Similarly COX-2 overexpressors had greater JSW 3.57 ± 1.91 mm Vs 3.13 ± 1.69 compared to OA patients with less than 2 fold COX-2 expression and higher WOMAC (p<0.033) and VAS (p<0.041) pain. To determine whether OA PBLs were "primed", we measured PGE2 production by whole blood PBL cultured (24h) ex vivo. PGE2 in controls did not change, while levels in OA patients increased 300% over baseline (p<0.01). In these validation cohort, the mean plasma PGE2 levels in OA patients was two-fold higher than in healthy controls (72 ± 33 vs. 163 ± 64 pg/ml, p=0.001).
|Mean (standard deviation)|
|NYUHJD Validation Cohort||OAIL-1 (n=74)||OAnl (n=100)||p-value|
|Joint space width (JSW) in mm at baseline||3.01 (2.1)||2.5 (1.94)||0.055|
|JSW (mm) at 24 months||2.53 (1.96)||2.4 (1.96)||0.614|
|Change (JSN)||0.48 (0.88)||0.097 (0.91)||0.0079|
There is increased inflammatory mediator gene expression (COX-2, IL-1b) in a subset of patients with SKOA, which identifies a cohort of patients with increased pain who are at increased risk for disease progression. The data indicate that inflammatory events within joint tissues of patients with SKOA are reported in peripheral blood. These transcriptome and lipidomic signals of local joint inflammation merit further study as potential biomarkers for OA disease activity and progression.
To cite this abstract, please use the following information:
Attur, Mukundan, Statnikov, Alexander, Aliferis, Constantin F., Li, Zhiguo, Krasnokutsky, Svetlana, Samuels, Jonathan, et al; Elevated Expression of Inflammatory Mediators Cyclooxygenase-2, Its Product Prostaglandin E2 and Interleukin-1 Beta by Peripheral Blood Leukocytes in Symptomatic Knee Osteoarthritis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :169