Comparative Study

. 2014 Nov;41(11):2104-13.

doi: 10.3899/jrheum.131446. Epub 2014 Aug 15.

Serum 14-3-3η is a novel marker that complements current serological measurements to enhance detection of patients with rheumatoid arthritis

Walter P Maksymowych¹, Stanley J Naides², Vivian Bykerk², Katherine A Siminovitch², Dirkjan van Schaardenburg², Maarten Boers², Robert Landewé², Désirée van der Heijde², Paul-P Tak², Mark C Genovese², Michael E Weinblatt², Edward C Keystone², Olga S Zhukov², Rania W Abolhosn², Joanna M Popov², Karin Britsemmer², Arno W van Kuijk², Anthony Marotta²

Affiliations

¹ From the University of Alberta, Edmonton, Alberta; Augurex Life Sciences Corp., North Vancouver, British Columbia; Mount Sinai Hospital, Toronto, Ontario, Canada; Quest Diagnostics Nichols Institute, San Juan Capistrano; Stanford University Medical Center, Palo Alto, California; Hospital for Special Surgery, New York, New York; Brigham and Women's Hospital, Boston, Massachusetts, USA; Vrije Universiteit University Medical Center; Academic Medical Center/University of Amsterdam; Jan van Breemen Research Institute, Reade organization, Amsterdam; the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands; University of Cambridge, Cambridge; GlaxoSmithKline, Stevenage, UK.W.P. Maksymowych, MD, Professor of Medicine, University of Alberta; S.J. Naides, MD, Quest Diagnostics Nichols Institute; V. Bykerk, MD, Hospital for Special Surgery; K.A. Siminovitch, MD, Mount Sinai Hospital; D. van Schaardenburg, MD, Jan van Breemen Research Institute; M. Boers, MD, Vrije Universiteit University Medical Center; R. Landewé, MD, Academic Medical Center/University of Amsterdam; D. van der Heijde, MD, Department of Rheumatology, Leiden University Medical Center; P-P. Tak, MD, Academic Medical Center/University of Amsterdam, University of Cambridge, GlaxoSmithKline; M.C. Genovese, MD, Stanford University Medical Center; M.E. Weinblatt, MD, Brigham and Women's Hospital; E.C. Keystone, MD, Mount Sinai Hospital; O.S. Zhukov, MS; R.W. Abolhosn, BS; J.M. Popov, MD, PhD, Quest Diagnostics Nichols Institute; K. Britsemmer, MD, Jan van Breemen Research Institute; A.W. van Kuijk, MD, Academic Medical Center/University of Amsterdam; A. Marotta, PhD, Augurex Life Sciences Corp. walter.maksymowych@ualberta.ca.
² From the University of Alberta, Edmonton, Alberta; Augurex Life Sciences Corp., North Vancouver, British Columbia; Mount Sinai Hospital, Toronto, Ontario, Canada; Quest Diagnostics Nichols Institute, San Juan Capistrano; Stanford University Medical Center, Palo Alto, California; Hospital for Special Surgery, New York, New York; Brigham and Women's Hospital, Boston, Massachusetts, USA; Vrije Universiteit University Medical Center; Academic Medical Center/University of Amsterdam; Jan van Breemen Research Institute, Reade organization, Amsterdam; the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands; University of Cambridge, Cambridge; GlaxoSmithKline, Stevenage, UK.W.P. Maksymowych, MD, Professor of Medicine, University of Alberta; S.J. Naides, MD, Quest Diagnostics Nichols Institute; V. Bykerk, MD, Hospital for Special Surgery; K.A. Siminovitch, MD, Mount Sinai Hospital; D. van Schaardenburg, MD, Jan van Breemen Research Institute; M. Boers, MD, Vrije Universiteit University Medical Center; R. Landewé, MD, Academic Medical Center/University of Amsterdam; D. van der Heijde, MD, Department of Rheumatology, Leiden University Medical Center; P-P. Tak, MD, Academic Medical Center/University of Amsterdam, University of Cambridge, GlaxoSmithKline; M.C. Genovese, MD, Stanford University Medical Center; M.E. Weinblatt, MD, Brigham and Women's Hospital; E.C. Keystone, MD, Mount Sinai Hospital; O.S. Zhukov, MS; R.W. Abolhosn, BS; J.M. Popov, MD, PhD, Quest Diagnostics Nichols Institute; K. Britsemmer, MD, Jan van Breemen Research Institute; A.W. van Kuijk, MD, Academic Medical Center/University of Amsterdam; A. Marotta, PhD, Augurex Life Sciences Corp.

PMID: 25128504
DOI: 10.3899/jrheum.131446

Free article

Comparative Study

Serum 14-3-3η is a novel marker that complements current serological measurements to enhance detection of patients with rheumatoid arthritis

Walter P Maksymowych et al. J Rheumatol. 2014 Nov.

Free article

. 2014 Nov;41(11):2104-13.

doi: 10.3899/jrheum.131446. Epub 2014 Aug 15.

Authors

Affiliations

¹ From the University of Alberta, Edmonton, Alberta; Augurex Life Sciences Corp., North Vancouver, British Columbia; Mount Sinai Hospital, Toronto, Ontario, Canada; Quest Diagnostics Nichols Institute, San Juan Capistrano; Stanford University Medical Center, Palo Alto, California; Hospital for Special Surgery, New York, New York; Brigham and Women's Hospital, Boston, Massachusetts, USA; Vrije Universiteit University Medical Center; Academic Medical Center/University of Amsterdam; Jan van Breemen Research Institute, Reade organization, Amsterdam; the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands; University of Cambridge, Cambridge; GlaxoSmithKline, Stevenage, UK.W.P. Maksymowych, MD, Professor of Medicine, University of Alberta; S.J. Naides, MD, Quest Diagnostics Nichols Institute; V. Bykerk, MD, Hospital for Special Surgery; K.A. Siminovitch, MD, Mount Sinai Hospital; D. van Schaardenburg, MD, Jan van Breemen Research Institute; M. Boers, MD, Vrije Universiteit University Medical Center; R. Landewé, MD, Academic Medical Center/University of Amsterdam; D. van der Heijde, MD, Department of Rheumatology, Leiden University Medical Center; P-P. Tak, MD, Academic Medical Center/University of Amsterdam, University of Cambridge, GlaxoSmithKline; M.C. Genovese, MD, Stanford University Medical Center; M.E. Weinblatt, MD, Brigham and Women's Hospital; E.C. Keystone, MD, Mount Sinai Hospital; O.S. Zhukov, MS; R.W. Abolhosn, BS; J.M. Popov, MD, PhD, Quest Diagnostics Nichols Institute; K. Britsemmer, MD, Jan van Breemen Research Institute; A.W. van Kuijk, MD, Academic Medical Center/University of Amsterdam; A. Marotta, PhD, Augurex Life Sciences Corp. walter.maksymowych@ualberta.ca.
² From the University of Alberta, Edmonton, Alberta; Augurex Life Sciences Corp., North Vancouver, British Columbia; Mount Sinai Hospital, Toronto, Ontario, Canada; Quest Diagnostics Nichols Institute, San Juan Capistrano; Stanford University Medical Center, Palo Alto, California; Hospital for Special Surgery, New York, New York; Brigham and Women's Hospital, Boston, Massachusetts, USA; Vrije Universiteit University Medical Center; Academic Medical Center/University of Amsterdam; Jan van Breemen Research Institute, Reade organization, Amsterdam; the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands; University of Cambridge, Cambridge; GlaxoSmithKline, Stevenage, UK.W.P. Maksymowych, MD, Professor of Medicine, University of Alberta; S.J. Naides, MD, Quest Diagnostics Nichols Institute; V. Bykerk, MD, Hospital for Special Surgery; K.A. Siminovitch, MD, Mount Sinai Hospital; D. van Schaardenburg, MD, Jan van Breemen Research Institute; M. Boers, MD, Vrije Universiteit University Medical Center; R. Landewé, MD, Academic Medical Center/University of Amsterdam; D. van der Heijde, MD, Department of Rheumatology, Leiden University Medical Center; P-P. Tak, MD, Academic Medical Center/University of Amsterdam, University of Cambridge, GlaxoSmithKline; M.C. Genovese, MD, Stanford University Medical Center; M.E. Weinblatt, MD, Brigham and Women's Hospital; E.C. Keystone, MD, Mount Sinai Hospital; O.S. Zhukov, MS; R.W. Abolhosn, BS; J.M. Popov, MD, PhD, Quest Diagnostics Nichols Institute; K. Britsemmer, MD, Jan van Breemen Research Institute; A.W. van Kuijk, MD, Academic Medical Center/University of Amsterdam; A. Marotta, PhD, Augurex Life Sciences Corp.

PMID: 25128504
DOI: 10.3899/jrheum.131446

Abstract

Objective: Serum 14-3-3η is a novel joint-derived proinflammatory mediator implicated in the pathogenesis of rheumatoid arthritis (RA). In our study, we assessed the diagnostic utility of 14-3-3η and its association with standard clinical and serological measures.

Methods: A quantitative ELISA was used to assess 14-3-3η levels. Early (n=99) and established patients with RA (n=135) were compared to all controls (n=385), including healthy subjects (n=189). The sensitivity, specificity, positive and negative predictive values of 14-3-3η, and the likelihood ratios (LR) for RA were determined through receiver-operator curve analysis. The incremental value of adding 14-3-3η to anticitrullinated protein antibody (ACPA) and rheumatoid factor (RF) in diagnosing early and established RA was assessed.

Results: Serum 14-3-3η differentiated established patients with RA from healthy individuals and all controls (p<0.0001). A serum 14-3-3η cutoff of ≥0.19 ng/ml delivered a sensitivity and specificity of 77% and 93%, respectively, with corresponding LR positivity of 10.4. At this cutoff in early RA, 64% of patients with early RA were positive for 14-3-3η, with a corresponding specificity of 93% (LR+ of 8.6), while 59% and 57% were positive for ACPA or RF, respectively. When ACPA, RF, and 14-3-3η positivity were used in combination, 77 of the 99 patients (78%) with early RA were positive for any 1 of the 3 markers. Serum 14-3-3η did not correlate with C-reactive protein, erythrocyte sedimentation rate, or Disease Activity Score, but patients who were 14-3-3η-positive had significantly worse disease.

Conclusion: Serum 14-3-3η is a novel RA mechanistic marker that is highly specific, associated with worse disease, and complements current markers, enabling a more accurate diagnosis of RA.

Keywords: ANTICITRULLINATED PROTEIN ANTIBODIES; BIOMARKER; C-REACTIVE PROTEIN; RHEUMATOID ARTHRITIS; RHEUMATOID FACTOR; SERUM 14-3-3η.

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Comment in

Something old, something new: biomarkers in rheumatoid arthritis.
Pratesi F, Migliorini P. Pratesi F, et al. J Rheumatol. 2014 Nov;41(11):2091-3. doi: 10.3899/jrheum.141069. J Rheumatol. 2014. PMID: 25362703 No abstract available.
14-3-3η in "Seronegative" Rheumatoid Arthritis.
Naides SJ, Marotta A. Naides SJ, et al. J Rheumatol. 2015 Oct;42(10):1995. doi: 10.3899/jrheum.150330. J Rheumatol. 2015. PMID: 26429210 No abstract available.

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Serum 14-3-3η is a novel marker that complements current serological measurements to enhance detection of patients with rheumatoid arthritis

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Serum 14-3-3η is a novel marker that complements current serological measurements to enhance detection of patients with rheumatoid arthritis

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