M Attur1, A Statnikov2, J Samuels3, Z Li4, A V Alekseyenko5, J D Greenberg6, S Krasnokutsky7, L Rybak8, Q A Lu9, J Todd10, H Zhou11, J M Jordan12, V B Kraus13, C F Aliferis14, S B Abramson15. 1. Division of Rheumatology, New York University School of Medicine, New York, NY 10016, USA; Department of Medicine, NYU School of Medicine, USA. Electronic address: Mukundan.Attur@nyumc.org. 2. Division of Translational Medicine, NYU School of Medicine, USA; Center for Health Informatics and Bioinformatics (CHIBI), NYU School of Medicine, USA. Electronic address: Alexander.Statnikov@nyumc.org. 3. Division of Rheumatology, New York University School of Medicine, New York, NY 10016, USA; Department of Medicine, NYU School of Medicine, USA. Electronic address: Jonathan.Samuels@nyumc.org. 4. Department of Medicine, NYU School of Medicine, USA. Electronic address: Zhiguo.Li@nyumc.org. 5. Division of Translational Medicine, NYU School of Medicine, USA; Center for Health Informatics and Bioinformatics (CHIBI), NYU School of Medicine, USA. Electronic address: Alexander.Alekseyenko@nyumc.org. 6. Division of Rheumatology, New York University School of Medicine, New York, NY 10016, USA; Department of Medicine, NYU School of Medicine, USA. Electronic address: JGreenberg@corrona.org. 7. Division of Rheumatology, New York University School of Medicine, New York, NY 10016, USA; Department of Medicine, NYU School of Medicine, USA. Electronic address: krasns01@nyumc.org. 8. Department of Radiology, NYU School of Medicine, New York, NY, USA. Electronic address: Leon.Rybak@nyumc.org. 9. Singulex, Inc., Alameda, CA 94502, USA. Electronic address: A.Lu@singulex.com. 10. Singulex, Inc., Alameda, CA 94502, USA. Electronic address: J.Todd@singulex.com. 11. Division of Translational Medicine, NYU School of Medicine, USA; Center for Health Informatics and Bioinformatics (CHIBI), NYU School of Medicine, USA. Electronic address: Hua.Zhou@nyumc.org. 12. Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: joanne_jordan@med.unc.edu. 13. Duke Molecular Physiology Institute and Division of Rheumatology, Duke University School of Medicine, Durham, NC 27701, USA. Electronic address: vbk@duke.edu. 14. Department of Medicine, NYU School of Medicine, USA; Center for Health Informatics and Bioinformatics (CHIBI), NYU School of Medicine, USA; Department of Pathology, NYU School of Medicine, New York, NY, USA. Electronic address: Constantin.Aliferis@nyumc.org. 15. Division of Rheumatology, New York University School of Medicine, New York, NY 10016, USA; Department of Medicine, NYU School of Medicine, USA; Department of Pathology, NYU School of Medicine, New York, NY, USA. Electronic address: StevenB.Abramson@nyumc.org.
Abstract
OBJECTIVE: Pro- and anti-inflammatory mediators, such as IL-1β and IL1Ra, are produced by joint tissues in osteoarthritis (OA), where they may contribute to pathogenesis. We examined whether inflammatory events occurring within joints are reflected in plasma of patients with symptomatic knee osteoarthritis (SKOA). DESIGN: 111 SKOA subjects with medial disease completed a 24-month prospective study of clinical and radiographic progression, with clinical assessment and specimen collection at 6-month intervals. The plasma biochemical marker IL1Ra was assessed at baseline and 18 months; other plasma biochemical markers were assessed only at 18 months, including IL-1β, TNFα, VEGF, IL-6, IL-6Rα, IL-17A, IL-17A/F, IL-17F, CRP, sTNF-RII, and MMP-2. RESULTS: In cross-sectional studies, WOMAC (total, pain, function) and plasma IL1Ra were modestly associated with radiographic severity after adjustment for age, gender and body mass index (BMI). In addition, elevation of plasma IL1Ra predicted joint space narrowing (JSN) at 24 months. BMI did associate with progression in some but not all analyses. Causal graph analysis indicated a positive association of IL1Ra with JSN; an interaction between IL1Ra and BMI suggested either that BMI influences IL1Ra or that a hidden confounder influences both BMI and IL1Ra. Other protein biomarkers examined in this study did not associate with radiographic progression or severity. CONCLUSIONS: Plasma levels of IL1Ra were modestly associated with the severity and progression of SKOA in a causal fashion, independent of other risk factors. The findings may be useful in the search for prognostic biomarkers and development of disease-modifying OA drugs.
OBJECTIVE: Pro- and anti-inflammatory mediators, such as IL-1β and IL1Ra, are produced by joint tissues in osteoarthritis (OA), where they may contribute to pathogenesis. We examined whether inflammatory events occurring within joints are reflected in plasma of patients with symptomatic knee osteoarthritis (SKOA). DESIGN: 111 SKOA subjects with medial disease completed a 24-month prospective study of clinical and radiographic progression, with clinical assessment and specimen collection at 6-month intervals. The plasma biochemical marker IL1Ra was assessed at baseline and 18 months; other plasma biochemical markers were assessed only at 18 months, including IL-1β, TNFα, VEGF, IL-6, IL-6Rα, IL-17A, IL-17A/F, IL-17F, CRP, sTNF-RII, and MMP-2. RESULTS: In cross-sectional studies, WOMAC (total, pain, function) and plasma IL1Ra were modestly associated with radiographic severity after adjustment for age, gender and body mass index (BMI). In addition, elevation of plasma IL1Ra predicted joint space narrowing (JSN) at 24 months. BMI did associate with progression in some but not all analyses. Causal graph analysis indicated a positive association of IL1Ra with JSN; an interaction between IL1Ra and BMI suggested either that BMI influences IL1Ra or that a hidden confounder influences both BMI and IL1Ra. Other protein biomarkers examined in this study did not associate with radiographic progression or severity. CONCLUSIONS: Plasma levels of IL1Ra were modestly associated with the severity and progression of SKOA in a causal fashion, independent of other risk factors. The findings may be useful in the search for prognostic biomarkers and development of disease-modifying OA drugs.
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