title: Serum levels of 14-3-3η protein supplement C-reactive protein and rheumatoid arthritis-associated antibodies to predict clinical and radiographic outcomes in a prospective cohort of patients with recent-onset inflammatory polyarthritis.
abstract: BACKGROUND
  Age, C-Reactive Protein (CRP) and autoantibodies (Abs) are associated with worse prognosis in patients with recent-onset inflammatory polyarthritis (EPA). Serum 14-3-3η protein is a joint-derived biomarker that up-regulates cytokines and enzymes that perpetuate local and systemic inflammation and may contribute to joint damage. Our objective was to evaluate, over a 5-year prospective period of observation, the additional prognostic potential of serum 14-3-3η protein in EPA patients.
  
  
  METHODS
  Clinical variables, serum and radiographs (scored according to the Sharp/van der Heijde (SvH) method) were collected serially. Relationships between serum 14-3-3η protein and other biomarkers were computed with Spearman correlations. Outcomes were Simple Disease Activity Index (SDAI) scores and joint damage progression: ΔSvH for SvH score and ΔErosion for its Erosive component. The additional predictive contribution of 14-3-3η was defined using generalized estimating equations (GEE) and generalized linear mixed models (GLMM).
  
  
  RESULTS
  Among 331 patients, baseline 14-3-3η was ≥0.19 and ≥0.50 ng/ml in 153 (46.2 %) and 119 (36.0 %), respectively; CRP was >8.0 mg/L in 207 (62.5 %), and at least one Ab (Rheumatoid Factor, anti-CCP2 or anti-Sa/citrullinated vimentin) was positive in 170 (51.5 %). Elevated 14-3-3η levels moderately correlated with positive Abs, but not with elevated CRP. Baseline 14-3-3η ≥0.19 ng/ml was associated with more radiographic progression over 5 years. The optimal levels of baseline 14-3-3η to predict radiographic progression was defined by ROC curves at 0.50 ng/ml. Levels of 14-3-3η ≥0.50 ng/ml at baseline were associated with lower likelihoods of ever reaching SDAI remission (RR 0.79 (95 % CI 0.64-0.98), p = 0.03) and higher subsequent progression of Total and Erosion SvH scores. Elevated levels of 14-3-3η during follow-up also predicted higher subsequent progression, even in patients in SDAI remission. Decreases of 14-3-3η levels by at least 0.76 ng/ml and reversion to negative during follow-up associated with less subsequent radiographic progression. In multivariate models, elevated 14-3-3η interacted with positive Abs, elevated CRP and older age to predict subsequent radiographic progression.
  
  
  CONCLUSIONS
  Levels of 14-3-3η protein ≥0.50 ng/ml predict poorer clinical and radiographic outcomes in EPA, both at baseline and after initiation of treatment, even in SDAI remitters. 14-3-3η, CRP, age and Abs represent independent predictors of subsequent joint damage.
  
  
  BACKGROUND
  ClinicalTrials.gov ID: NCT00512239 . Registered August 6, 2007.
authors.affiliation: Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada. nathalie.carrier2@usherbrooke.ca.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Carrier
authors.affiliation: Augurex Life Sciences Corp, Vancouver, BC, Canada. amarotta@augurex.com.
authors.forename: Anthony
authors.initials: A
authors.lastname: Marotta
authors.affiliation: Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada. artur.fernandes@usherbrooke.ca.|Université de Sherbrooke, Sherbrooke, QC, Canada. artur.fernandes@usherbrooke.ca.
authors.forename: Artur J
authors.initials: AJ
authors.lastname: de Brum-Fernandes
authors.affiliation: Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada. patrick.liang@usherbrooke.ca.|Université de Sherbrooke, Sherbrooke, QC, Canada. patrick.liang@usherbrooke.ca.
authors.forename: Patrick
authors.initials: P
authors.lastname: Liang
authors.affiliation: Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada. ariel.masetto@usherbrooke.ca.|Université de Sherbrooke, Sherbrooke, QC, Canada. ariel.masetto@usherbrooke.ca.
authors.forename: Ariel
authors.initials: A
authors.lastname: Masetto
authors.affiliation: Research Institute of the McGill University Health Center, Montreal, QC, Canada. henri.menard@sympatico.ca.
authors.forename: Henri A
authors.initials: HA
authors.lastname: Ménard
authors.affiliation: University of Alberta, Edmonton, AB, Canada. walter.maksymowych@ualberta.ca.
authors.forename: Walter P
authors.initials: WP
authors.lastname: Maksymowych
authors.affiliation: Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada. gilles.boire@usherbrooke.ca.|Université de Sherbrooke, Sherbrooke, QC, Canada. gilles.boire@usherbrooke.ca.|Division of Rheumatology, CHUS-Fleurimont, 3001, 12th Avenue North, Room 3853, Sherbrooke, QC, J1H 5N4, Canada. gilles.boire@usherbrooke.ca.
authors.forename: Gilles
authors.initials: G
authors.lastname: Boire
mesh_terms: D048948:14-3-3 Proteins / Q000097:blood*; D000368:Aged; D001168:Arthritis / Q000097:blood / Q000000981:diagnostic imaging; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000000981:diagnostic imaging*; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D011859:Radiography; D016896:Treatment Outcome
chemical_list: D048948:14-3-3 Proteins; D001323:Autoantibodies; D015415:Biomarkers; D002097:C-Reactive Protein
references.citation: J Rheumatol. 2000 Jan;27(1):261-3
references.pmid: 10648051
references.citation: J Rheumatol. 2002 Nov;29(11):2306-12
references.pmid: 12415585
references.citation: N Engl J Med. 2004 Jun 17;350(25):2591-602
references.pmid: 15201416
references.citation: Arthritis Rheum. 1990 Aug;33(8):1135-6
references.pmid: 2202312
references.citation: Arthritis Res Ther. 2005;7(3):R592-603
references.pmid: 15899046
references.citation: Clin Exp Rheumatol. 2005 Sep-Oct;23(5 Suppl 39):S100-8
references.pmid: 16273793
references.citation: J Rheumatol. 2007 Aug;34(8):1650-7
references.pmid: 17611984
references.citation: Arthritis Rheum. 2009 Mar;60(3):698-707
references.pmid: 19248090
references.citation: Rheum Dis Clin North Am. 2009 Nov;35(4):735-43, vii
references.pmid: 19962618
references.citation: Arthritis Rheum. 2010 Sep;62(9):2569-81
references.pmid: 20872595
references.citation: Arthritis Care Res (Hoboken). 2010 Nov;62(11):1624-32
references.pmid: 20617532
references.citation: Rheumatology (Oxford). 2011 Jan;50(1):93-100
references.pmid: 20639266
references.citation: J Rheumatol. 2012 Aug;39(8):1559-82
references.pmid: 21921096
references.citation: J Rheumatol. 2012 Nov;39(11):2088-97
references.pmid: 22896027
references.citation: Arthritis Care Res (Hoboken). 2013 Jun;65(6):992-9
references.pmid: 23281243
references.citation: Arthritis Res Ther. 2014;16(2):R99
references.pmid: 24751211
references.citation: J Rheumatol. 2014 Nov;41(11):2104-13
references.pmid: 25128504
references.citation: Clin Exp Rheumatol. 2014 Sep-Oct;32(5 Suppl 85):S-35-9
references.pmid: 25365087
references.citation: Arthritis Res Ther. 2015;17:280
references.pmid: 26449724