title: Plasma levels of interleukin-1 receptor antagonist (IL1Ra) predict radiographic progression of symptomatic knee osteoarthritis.
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).
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Attur
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Statnikov
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Samuels
authors.affiliation: Department of Medicine, NYU School of Medicine, USA. Electronic address: Zhiguo.Li@nyumc.org.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: 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.
authors.forename: A V
authors.initials: AV
authors.lastname: Alekseyenko
authors.affiliation: 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.
authors.forename: J D
authors.initials: JD
authors.lastname: Greenberg
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Krasnokutsky
authors.affiliation: Department of Radiology, NYU School of Medicine, New York, NY, USA. Electronic address: Leon.Rybak@nyumc.org.
authors.forename: L
authors.initials: L
authors.lastname: Rybak
authors.affiliation: Singulex, Inc., Alameda, CA 94502, USA. Electronic address: A.Lu@singulex.com.
authors.forename: Q A
authors.initials: QA
authors.lastname: Lu
authors.affiliation: Singulex, Inc., Alameda, CA 94502, USA. Electronic address: J.Todd@singulex.com.
authors.forename: J
authors.initials: J
authors.lastname: Todd
authors.affiliation: 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.
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: joanne_jordan@med.unc.edu.
authors.forename: J M
authors.initials: JM
authors.lastname: Jordan
authors.affiliation: Duke Molecular Physiology Institute and Division of Rheumatology, Duke University School of Medicine, Durham, NC 27701, USA. Electronic address: vbk@duke.edu.
authors.forename: V B
authors.initials: VB
authors.lastname: Kraus
authors.affiliation: 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.
authors.forename: C F
authors.initials: CF
authors.lastname: Aliferis
authors.affiliation: 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.
authors.forename: S B
authors.initials: SB
authors.lastname: Abramson
mesh_terms: D015415:Biomarkers / Q000097:blood; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020370:Osteoarthritis, Knee / Q000097:blood* / Q000000981:diagnostic imaging; D011237:Predictive Value of Tests; D011446:Prospective Studies; D011859:Radiography; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000097:blood; D013997:Time Factors
chemical_list: D015415:Biomarkers; D017472:Receptors, Interleukin-1
keywords: Causal analysis; Interleukin-1 receptor antagonist (IL1Ra); Osteoarthritis; Radiographic progression