Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2016

Open Access 01-12-2016 | Research article

Identification of definitive serum biomarkers associated with disease activity in primary Sjögren’s syndrome

Authors: Ayumi Nishikawa, Katsuya Suzuki, Yoshiaki Kassai, Yuumi Gotou, Maiko Takiguchi, Takahiro Miyazaki, Keiko Yoshimoto, Hidekata Yasuoka, Kunihiro Yamaoka, Rimpei Morita, Akihiko Yoshimura, Tsutomu Takeuchi

Published in: Arthritis Research & Therapy | Issue 1/2016

Login to get access

Abstract

Background

In this study, we sought to identify definitive biomarkers associated with disease activity in primary Sjögren’s syndrome (pSS).

Methods

Serum protein concentrations in pSS patients and healthy controls (HCs) were comprehensively screened using high-throughput proteomic analysis, and differentially expressed proteins were extracted. Correlation between differentially expressed proteins and European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index (ESSDAI) scores was analyzed and disease activity-associated biomarkers were identified. These biomarkers were validated by enzyme-linked immunosorbent assay (ELISA) in a separate pSS cohort.

Results

The serum concentrations of 1100 proteins were compared between 30 pSS patients and 30 HCs, with 82 differentially expressed proteins identified as pSS-associated proteins. Of these 82 proteins, 9 were identified as disease activity-associated biomarkers. These nine biomarkers underwent validation by ELISA in a separate pSS validation cohort (n = 58), with five proteins (CXCL13, TNF-R2, CD48, B-cell activating factor (BAFF), and PD-L2) subsequently being confirmed as candidate biomarkers. Of these five candidate biomarkers, CXCL13 exhibited the most significant correlation with the lymphadenopathy, glandular, and pulmonary domains of the ESSDAI. CXCL13, TNF-R2 and CD48 exhibited a positive correlation with the biological domain of the ESSDAI. TNF-R2 exhibited the most negative correlation with uptake in the submandibular gland on technetium 99m-pertechnetate salivary gland scintigraphy.

Conclusions

Our approach successfully identified serum biomarkers associated with disease activity in pSS patients. These markers might be potential therapeutic targets in pSS patients.
Appendix
Available only for authorised users
Literature
1.
Mariette X, Seror R, Quartuccio L, et al. Efficacy and safety of belimumab in primary Sjögren’s syndrome: results of the BELISS open-label phase II study. Ann Rheum Dis. 2015;74:526–31.CrossRefPubMed
2.
Brkic Z, Versnel MA. Type I IFN signature in primary Sjögren’s syndrome patients. Expert Rev Clin Immunol. 2014;10:457–67.CrossRefPubMed
3.
Mavragani CP, Moutsopoulos HM. Sjögren’s syndrome. Annu Rev Pathol Mech Dis. 2014;9:273–85.CrossRef
4.
Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, et al. Treatment of primary Sjögren syndrome with rituximab: a randomized trial. Ann Intern Med. 2014;160:233–42.CrossRefPubMed
5.
Guellec D, Cornec D, Jousse-Joulin S, et al. Diagnostic value of labial minor salivary gland biopsy for Sjögren’s syndrome: a systematic review. Autoimmunity Reviews. 2013;12:416–20.CrossRefPubMed
6.
Zhou D, McNamara NA. Macrophages: important players in primary Sjögren’s syndrome? Expert Rev Clin Immunol. 2014;10:513–20.CrossRefPubMed
7.
Al-Tarawneh SK, Border MB, Dibble CF, et al. Defining salivary biomarkers using mass spectrometry-based proteomics: a systematic review. OMICS. 2011;15:353–61.CrossRefPubMedPubMedCentral
8.
Deutsch O, Krief G, Konttinen YT, et al. Identification of Sjögren’s syndrome oral fluid biomarker candidates following high-abundance protein depletion. Rheumatology (Oxford). 2015;54:884–90.CrossRef
9.
Fleissig Y, Deutsch O, Reichenberg E, et al. Different proteomic protein patterns in saliva of Sjögren’s syndrome patients. Oral Dis. 2009;15:61–8.CrossRefPubMed
10.
Giusti L, Baldini C, Bazzichi L, et al. Proteomic diagnosis of Sjögren’s syndrome. Expert Rev Proteomics. 2007;4:757–67.CrossRefPubMed
11.
Hu S, Vissink A, Arellano M, et al. Identification of autoantibody biomarkers for primary Sjögren’s syndrome using protein microarrays. Proteomics. 2011;11:1499–507.CrossRefPubMedPubMedCentral
12.
Peluso G, De Santis M, Inzitari R, et al. Proteomic study of salivary peptides and proteins in patients with Sjögren’s syndrome before and after pilocarpine treatment. Arthritis Rheum. 2007;56:2216–22.CrossRefPubMed
13.
Ryu OH, Atkinson JC, Hoehn GT, et al. Identification of parotid salivary biomarkers in Sjögren’s syndrome by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry and two-dimensional difference gel electrophoresis. Rheumatology. 2006;45:1077–86.CrossRefPubMed
14.
Baldini C, Giusti L, Ciregia F, et al. Proteomic analysis of saliva: a unique tool to distinguish primary Sjögren's syndrome from secondary Sjögren’s syndrome and other sicca syndromes. Arthritis Res Ther. 2011;13(6):R194.CrossRefPubMedPubMedCentral
15.
Quartuccio L, Salvin S, Fabris M, et al. BLyS upregulation in Sjögren’s syndrome associated with lymphoproliferative disorders, higher ESSDAI score and B-cell clonal expansion in the salivary glands. Rheumatology (Oxford). 2013;52:276–81.CrossRef
16.
Gottenberg JE, Seror R, Miceli-Richardo C, et al. Serum levels of beta2-microglobulin and free light chains of immunoglobulins are associated with systemic disease acitivity in primary Sjögren’s syndrome. data at enrollment in the prospective ASSESS cohort. PLoS One. 2013;8(5):e59868.CrossRefPubMedPubMedCentral
17.
Maria NI, Brkic Z, Waris M, et al. MxA as a clinically applicable biomarker for identifying systemic interferon type I in primary Sjögren’s syndrome. Ann Rheum Dis. 2014;73:1052–9.CrossRefPubMedPubMedCentral
18.
Seror R, Ravaud P, Bowman S, et al. EULAR Sjögren’s syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjögren’s syndrome. Ann Rheum Dis. 2010;69:1103–9.CrossRefPubMedPubMedCentral
19.
Moerman RV, Arends S, Meiners PM, et al. EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) is sensitive to show efficacy of rituximab treatment in a randomized controlled trial. Ann Rheum Dis. 2014;73:472–4.CrossRefPubMed
20.
Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;6:554–8.CrossRef
21.
Shiboski SC, Shiboski CH, Criswell L, et al. American College of Rheumatology classification criteria for Sjögren’s syndrome: a data-driven, expert consensus approach in the Sjögren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res. 2012;64:475–87.CrossRef
22.
Tsuboi H, Hagiwara S, Asashima H, et al. Validation of different sets of criteria for the diagnosis of Sjögren’s syndrome in Japanese patients. Mod Rheumatol. 2013;23:219–25.CrossRefPubMed
23.
Brito-Zerón P, Kostov B, Solans R, et al. Systemic activity and mortality in primary Sjögren syndrome: predicting survival using the EULAR-SS Disease Activity Index (ESSDAI) in 1045 patients. Ann Rheum Dis. 2014;0:1–8. doi:10.​1136/​annrheumdis-2014-206418.
24.
Rohloff JC, Gelinas AD, Jarvis TC, et al. Nucleic acid ligands with protein-like side chains: modified aptamers and their use as diagnostic and therapeutic agents. Mol Ther Nucleic Acids. 2014;3:e201.CrossRefPubMedPubMedCentral
25.
26.
Webber J, Stone TC, Katilius E, et al. Proteomics analysis of cancer exosomes using a novel modified aptamer-based array (SOMAscanTM) platform. Mol Cell Proteomics. 2014;13:1050–64.CrossRefPubMedPubMedCentral
27.
Yoshimoto K, Tanaka M, Kojima M, et al. Regulatory mechanisms for the production of BAFF and IL-6 are impaired in monocytes of patients of primary Sjögren’s syndrome. Arthritis Res Ther. 2011;13(5):R170.CrossRefPubMedPubMedCentral
28.
Tomlins SA, Mehra R, Rhodes DR, et al. Integrative molecular concept modeling of prostate cancer progression. Nat Genet. 2007;39:41–51.CrossRefPubMed
29.
Markeljevic J, Sarac H, Bozina N, et al. Serotonin transporter gene polymorphisms: relation with platelet serotonin level in patients with primary Sjogren’s syndrome. J Neuroimmunol. 2015;282:104–9.CrossRefPubMed
30.
Sarac H, Markeljevic J, Erdeljic V, et al. Signal hyperintensities on brain magnetic resonance imaging in patients with primary Sjögren’s syndrome and frequent episodic tension-type headache; relation to platelet serotonin level and disease activity. J Rheumatol. 2013;40:1360–6.CrossRefPubMed
31.
Delaleu N, Mydel P, Kwee I, et al. High fidelity between saliva proteomics and the salivary glands’ biological state defines biomarker-signatures for primary Sjögren’s syndrome. Arthritis Rheumatol. 2015;67:1084–95.CrossRefPubMed
32.
Campar A, Isenberg DA. Primary Sjögren’s syndrome activity and damage indices comparison. Eur J Clin Invest. 2010;40:636–44.CrossRefPubMed
33.
Nocturne G, Seror R, Fogel O, et al. CXCL13 and CCL11 serum levels and lymphoma and disease activity in primary Sjögren Syndrome. Arthritis Rheumatol. 2015. doi:10. 1002/art.393915.
34.
Manzo A, Vitolo B, Humby F, et al. Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint. Arthritis Rheum. 2008;58:3377–87.CrossRefPubMed
35.
Gunn MD, Ngo VN, Ansel KM, et al. A B-cell-homing chemokine made in lymphoid follicles activates Burkitt’s lymphoma receptor-1. Nature. 1998;391:799–803.CrossRefPubMed
36.
Cyster JG, Ansel KM, Reif K, et al. Follicular stromal cells and lymphocyte homing to follicles. Immunol Rev. 2000;176:181–93.CrossRefPubMed
37.
Kramer JM, Klimatcheva E, Rothstein TL, et al. CXCL13 is elevated in Sjögren’s syndrome in mice and humans and is implicated in disease pathogenesis. J Leukoc Biol. 2013;94:1079–89.CrossRefPubMedPubMedCentral
38.
Barone F, Bombardieri M, Manzo A, et al. Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjögren’s syndrome. Arthritis Rheum. 2005;52:1773–84.CrossRefPubMed
39.
Barone F, Bombardieri M, Rosado MM, et al. CXCL13, CCL21, and CXCL12 expression in salivary glands of patients with Sjögren’s syndrome and MALT lymphoma: association with reactive and malignant areas of lymphoid organization. J Immunol. 2008;180:5130–40.CrossRefPubMed
40.
Fraustman DL, Davis M. TNF receptor 2 and disease: autoimmunity and regenerative medicine. Front Immunol. 2013;4:478.
41.
42.
Horiuchi T, Mitoma H, Harashima S, et al. Transmembrane TNF-a: structure, function and interaction with anti-TNF agents. Rheumatology. 2010;49:1215–28.CrossRefPubMedPubMedCentral
43.
Svenungsson E, Gunnarsson I, Fei GZ, et al. Elevated triglycerides and low levels of high-density lipoprotein as markers of disease activity in association with up-regulation of the tumor necrosis factor alpha/tumor necrosis factor receptor system in systemic lupus erythematosus. Arthritis Rheum. 2003;48:2533–40.CrossRefPubMed
44.
Ferreira GA, Teixeira A, Calderano DC, et al. Atorvastatin reduced soluble receptors of TNF-alpha in systemic lupus erythematosus. Clin Exp Rheumatol. 2016;34:42–8.PubMed
45.
Turan B, Pfister K, Diener PA, et al. Soluble tumour necrosis factor receptors sTNFR1 and sTNFR2 are produced at sites of inflammation and are markers of arthritis activity in Behçet’s disease. Scand J Rheumatol. 2008;37:135–41.CrossRefPubMed
46.
Koski H, Janin A, Humphreys-Beher MG, et al. Tumor necrosis factor-alpha and receptor for it in labial salivary glands in Sjögren’s syndrome. Clin Exp Rheumatol. 2001;19:131–7.PubMed
47.
Elishmereni M, Levi-Schaffer F. CD48: a co-stimulatory receptor of immunity. Int J Biochem Cell Biol. 2011;43:25–8.CrossRefPubMed
48.
49.
Ariel M et al. CD48 is an allergen and IL-3-induced activation molecule on eosinophils. J Immunol. 2006;177:77–83.CrossRef
50.
Smith GM et al. Detection of a soluble form of the leukocyte surface antigen CD48 in plasma and its elevation in patients with lymphoid leukemias and arthritis. J Clinical Immunol. 1997;17:502–9.CrossRef
51.
Boles KS et al. 2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes. Immunol Rev. 2001;181:234–49.CrossRefPubMed
52.
Candon S, Gottenberg JE, Bengoufa D, et al. Quantitative assessment of antibodies to ribonucleoproteins in primary Sjögren’s syndrome: correlation with B-cell biomarkers and disease activity. Ann Rheum Dis. 2009;68:1208–12.CrossRefPubMed
53.
Mariette X, Roux S, Zhang J, et al. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjögren’s syndrome. Ann Rheum Dis. 2003;62:168–71.CrossRefPubMedPubMedCentral
54.
Zhang J, Roschke V, Baker KP, et al. Cutting edge: a role for B lymphocytestimulator in systemic lupus erythematosus. J Immunol. 2001;166:6–10.
55.
Cheema GS, Roschke V, Hilbert DM, et al. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum. 2001;44:1313–9.CrossRefPubMed
56.
Dai S, Jia R, Zhang X, et al. The PD-1/PD-Ls pathway and autoimmune diseases. Cell Immunol. 2014;290:72–9.CrossRefPubMed
57.
Messal N, Serriari NE, Pastor S, et al. PD-L2 is expressed on activated human T cells and regulates their function. Mol Immunol. 2011;48:2214–9.CrossRefPubMed
Metadata
Title
Identification of definitive serum biomarkers associated with disease activity in primary Sjögren’s syndrome
Authors
Ayumi Nishikawa
Katsuya Suzuki
Yoshiaki Kassai
Yuumi Gotou
Maiko Takiguchi
Takahiro Miyazaki
Keiko Yoshimoto
Hidekata Yasuoka
Kunihiro Yamaoka
Rimpei Morita
Akihiko Yoshimura
Tsutomu Takeuchi
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2016
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-016-1006-1

Other articles of this Issue 1/2016

Arthritis Research & Therapy 1/2016 Go to the issue

Research article

Bone marrow contribution to synovial hyperplasia following joint surface injury

Research article

Nuclear factor erythroid 2-related factor 2 is a critical target for the treatment of glucocorticoid-resistant lupus nephritis

Research article

Human embryonic stem cell-derived mesenchymal stromal cells ameliorate collagen-induced arthritis by inducing host-derived indoleamine 2,3 dioxygenase

Research article

Effects on muscle tissue remodeling and lipid metabolism in muscle tissue from adult patients with polymyositis or dermatomyositis treated with immunosuppressive agents

Research article

Myocardial infarction and mortality following joint surgery in patients with rheumatoid arthritis: a retrospective cohort study

Research article

Differential response of serum amyloid A to different therapies in early rheumatoid arthritis and its potential value as a disease activity biomarker
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits