Skip to main content
Top
Published in: Arthritis Research & Therapy 4/2011

Open Access 01-08-2011 | Research article

Decreases in serum levels of S100A8/9 (calprotectin) correlate with improvements in total swollen joint count in patients with recent-onset rheumatoid arthritis

Authors: Lucie Andrés Cerezo, Heřman Mann, Ondřej Pecha, Lenka Pleštilová, Karel Pavelka, Jiří Vencovský, Ladislav Šenolt

Published in: Arthritis Research & Therapy | Issue 4/2011

Login to get access

Abstract

Introduction

The aim of this study was to examine the serum levels of S100 proteins and to evaluate their role in patients with recent-onset rheumatoid arthritis (RA).

Methods

Serum levels of S100A8/9 and S100A12 were analysed in 43 patients with recent-onset RA, both before and three months after the initiation of conventional treatment, as well as in 32 healthy individuals. Disease activity was assessed based on serum levels of C-reactive protein (CRP), the Disease Activity Score for 28 joints (DAS28) and the total number of swollen joints count for 66 joints (SJC).

Results

The levels of serum S100A8/9 and S100A12 were significantly higher in patients with recent-onset RA compared to the levels in healthy individuals (P < 0.0001) and normalised after three months of treatment. Using age- and sex-adjusted analysis, S100A8/9 levels were correlated with CRP (r = 0.439, P < 0.01), DAS28 (r = 0.501, P = 0.002) and SJC (r = 0.443, P = 0.007), while S100A12 was less significantly correlated with these parameters. Higher levels of S100A8/9 at baseline predicted improvement in the levels of CRP and SJC over time. Moreover, decreases in serum S100A8/9 were associated with decreased serum levels of CRP (r = 0.459, P = 0.005) and improvements in SJC (r = 0.459, P = 0.005). In multiple linear regression analyses, decreases in S100A8/9 but not CRP were significant predictors for improvements in SJC (P = 0.001).

Conclusions

This study is the first to show normalisation of elevated S100 proteins in patients with recent-onset RA after the initiation of conventional treatment. Therefore, S100A8/9 might potentially be a predictive marker for improvement in the total number of swollen joints in patients in the early phase of RA.
Appendix
Available only for authorised users
Literature
1.
2.
go back to reference Huber LC, Distler O, Tarner I, Gay RE, Gay S, Pap T: Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology (Oxford). 2006, 45: 669-675. 10.1093/rheumatology/kel065.CrossRef Huber LC, Distler O, Tarner I, Gay RE, Gay S, Pap T: Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology (Oxford). 2006, 45: 669-675. 10.1093/rheumatology/kel065.CrossRef
3.
go back to reference Nell VP, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS: Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology (Oxford). 2004, 43: 906-914. 10.1093/rheumatology/keh199.CrossRef Nell VP, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS: Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology (Oxford). 2004, 43: 906-914. 10.1093/rheumatology/keh199.CrossRef
4.
go back to reference Raza K, Breese M, Nightingale P, Kumar K, Potter T, Carruthers DM, Situnayake D, Gordon C, Buckley CD, Salmon M, Kitas GD: Predictive value of antibodies to cyclic citrullinated peptide in patients with very early inflammatory arthritis. J Rheumatol. 2005, 32: 231-238.PubMedCentralPubMed Raza K, Breese M, Nightingale P, Kumar K, Potter T, Carruthers DM, Situnayake D, Gordon C, Buckley CD, Salmon M, Kitas GD: Predictive value of antibodies to cyclic citrullinated peptide in patients with very early inflammatory arthritis. J Rheumatol. 2005, 32: 231-238.PubMedCentralPubMed
5.
go back to reference Nell VP, Machold KP, Stamm TA, Eberl G, Heinzl H, Uffmann M, Smolen JS, Steiner G: Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis. 2005, 64: 1731-1736. 10.1136/ard.2005.035691.PubMedCentralCrossRefPubMed Nell VP, Machold KP, Stamm TA, Eberl G, Heinzl H, Uffmann M, Smolen JS, Steiner G: Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis. 2005, 64: 1731-1736. 10.1136/ard.2005.035691.PubMedCentralCrossRefPubMed
6.
go back to reference Smolen JS, Aletaha D, Grisar J, Redlich K, Steiner G, Wagner O: The need for prognosticators in rheumatoid arthritis: biological and clinical markers: where are we now?. Arthritis Res Ther. 2008, 10: 208-10.1186/ar2418.PubMedCentralCrossRefPubMed Smolen JS, Aletaha D, Grisar J, Redlich K, Steiner G, Wagner O: The need for prognosticators in rheumatoid arthritis: biological and clinical markers: where are we now?. Arthritis Res Ther. 2008, 10: 208-10.1186/ar2418.PubMedCentralCrossRefPubMed
7.
go back to reference Donato R: Intracellular and extracellular roles of S100 proteins. Microsc Res Tech. 2003, 60: 540-551. 10.1002/jemt.10296.CrossRefPubMed Donato R: Intracellular and extracellular roles of S100 proteins. Microsc Res Tech. 2003, 60: 540-551. 10.1002/jemt.10296.CrossRefPubMed
8.
go back to reference Bianchi ME: DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007, 81: 1-5.CrossRefPubMed Bianchi ME: DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007, 81: 1-5.CrossRefPubMed
9.
go back to reference Foell D, Wittkowski H, Vogl T, Roth J: S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol. 2007, 81: 28-37.CrossRefPubMed Foell D, Wittkowski H, Vogl T, Roth J: S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol. 2007, 81: 28-37.CrossRefPubMed
10.
go back to reference Brun JG, Haga HJ, Bøe E, Kallay I, Lekven C, Berntzen HB, Fagerhol MK: Calprotectin in patients with rheumatoid arthritis: relation to clinical and laboratory variables of disease activity. J Rheumatol. 1992, 19: 859-862.PubMed Brun JG, Haga HJ, Bøe E, Kallay I, Lekven C, Berntzen HB, Fagerhol MK: Calprotectin in patients with rheumatoid arthritis: relation to clinical and laboratory variables of disease activity. J Rheumatol. 1992, 19: 859-862.PubMed
11.
go back to reference Youssef P, Roth J, Frosch M, Costello P, Fitzgerald O, Sorg C, Bresnihan B: Expression of myeloid related proteins (MRP) 8 and 14 and the MRP8/14 heterodimer in rheumatoid arthritis synovial membrane. J Rheumatol. 1999, 26: 2523-2528.PubMed Youssef P, Roth J, Frosch M, Costello P, Fitzgerald O, Sorg C, Bresnihan B: Expression of myeloid related proteins (MRP) 8 and 14 and the MRP8/14 heterodimer in rheumatoid arthritis synovial membrane. J Rheumatol. 1999, 26: 2523-2528.PubMed
12.
go back to reference Sunahori K, Yamamura M, Yamana J, Takasugi K, Kawashima M, Yamamoto H, Chazin WJ, Nakatani Y, Yui S, Makino H: The S100A8/9 heterodimer amplifies proinflammatory cytokine production by macrophages via activation of nuclear factor κB and p38 mitogen-activated protein kinase in rheumatoid arthritis. Arthritis Res Ther. 2006, 8: R69-10.1186/ar1939.PubMedCentralCrossRefPubMed Sunahori K, Yamamura M, Yamana J, Takasugi K, Kawashima M, Yamamoto H, Chazin WJ, Nakatani Y, Yui S, Makino H: The S100A8/9 heterodimer amplifies proinflammatory cytokine production by macrophages via activation of nuclear factor κB and p38 mitogen-activated protein kinase in rheumatoid arthritis. Arthritis Res Ther. 2006, 8: R69-10.1186/ar1939.PubMedCentralCrossRefPubMed
13.
go back to reference Foell D, Kane D, Bresnihan B, Vogl T, Nacken W, Sorg C, Fitzgerald O, Roth J: Expression of the pro-inflammatory protein S100A12 (EN-RAGE) in rheumatoid and psoriatic arthritis. Rheumatology (Oxford). 2003, 42: 1383-1389. 10.1093/rheumatology/keg385.CrossRef Foell D, Kane D, Bresnihan B, Vogl T, Nacken W, Sorg C, Fitzgerald O, Roth J: Expression of the pro-inflammatory protein S100A12 (EN-RAGE) in rheumatoid and psoriatic arthritis. Rheumatology (Oxford). 2003, 42: 1383-1389. 10.1093/rheumatology/keg385.CrossRef
14.
go back to reference Wulffraat NM, Haas PJ, Frosch M, De Kleer IM, Vogl T, Brinkman DM, Quartier P, Roth J, Kuis W: Myeloid related protein 8 and 14 secretion reflects phagocyte activation and correlates with disease activity in juvenile idiopathic arthritis treated with autologous stem cell transplantation. Ann Rheum Dis. 2003, 62: 236-241. 10.1136/ard.62.3.236.PubMedCentralCrossRefPubMed Wulffraat NM, Haas PJ, Frosch M, De Kleer IM, Vogl T, Brinkman DM, Quartier P, Roth J, Kuis W: Myeloid related protein 8 and 14 secretion reflects phagocyte activation and correlates with disease activity in juvenile idiopathic arthritis treated with autologous stem cell transplantation. Ann Rheum Dis. 2003, 62: 236-241. 10.1136/ard.62.3.236.PubMedCentralCrossRefPubMed
15.
go back to reference Hammer HB, Haavardsholm EA, Kvien TK: Calprotectin (a major leucocyte protein) is associated with the levels of anti-CCP and rheumatoid factor in a longitudinal study of patients with very early rheumatoid arthritis. Scand J Rheumatol. 2008, 37: 179-182. 10.1080/03009740701874451.CrossRefPubMed Hammer HB, Haavardsholm EA, Kvien TK: Calprotectin (a major leucocyte protein) is associated with the levels of anti-CCP and rheumatoid factor in a longitudinal study of patients with very early rheumatoid arthritis. Scand J Rheumatol. 2008, 37: 179-182. 10.1080/03009740701874451.CrossRefPubMed
16.
go back to reference Foell D, Wittkowski H, Hammerschmidt I, Wulffraat N, Schmeling H, Frosch M, Horneff G, Kuis W, Sorg C, Roth J: Monitoring neutrophil activation in juvenile rheumatoid arthritis by S100A12 serum concentrations. Arthritis Rheum. 2004, 50: 1286-1295. 10.1002/art.20125.CrossRefPubMed Foell D, Wittkowski H, Hammerschmidt I, Wulffraat N, Schmeling H, Frosch M, Horneff G, Kuis W, Sorg C, Roth J: Monitoring neutrophil activation in juvenile rheumatoid arthritis by S100A12 serum concentrations. Arthritis Rheum. 2004, 50: 1286-1295. 10.1002/art.20125.CrossRefPubMed
17.
go back to reference Wittkowski H, Foell D, af Klint E, De Rycke L, De Keyser F, Frosch M, Ulfgren AK, Roth J: Effects of intra-articular corticosteroids and anti-TNF therapy on neutrophil activation in rheumatoid arthritis. Ann Rheum Dis. 2007, 66: 1020-1025. 10.1136/ard.2006.061507.PubMedCentralCrossRefPubMed Wittkowski H, Foell D, af Klint E, De Rycke L, De Keyser F, Frosch M, Ulfgren AK, Roth J: Effects of intra-articular corticosteroids and anti-TNF therapy on neutrophil activation in rheumatoid arthritis. Ann Rheum Dis. 2007, 66: 1020-1025. 10.1136/ard.2006.061507.PubMedCentralCrossRefPubMed
18.
go back to reference De Rycke L, Baeten D, Foell D, Kruithof E, Veys EM, Roth J, De Keyser F: Differential expression and response to anti-TNFα treatment of infiltrating versus resident tissue macrophage subsets in autoimmune arthritis. J Pathol. 2005, 206: 17-27. 10.1002/path.1758.CrossRefPubMed De Rycke L, Baeten D, Foell D, Kruithof E, Veys EM, Roth J, De Keyser F: Differential expression and response to anti-TNFα treatment of infiltrating versus resident tissue macrophage subsets in autoimmune arthritis. J Pathol. 2005, 206: 17-27. 10.1002/path.1758.CrossRefPubMed
19.
go back to reference Foell D, Wulffraat N, Wedderburn LR, Wittkowski H, Frosch M, Gerss J, Stanevicha V, Mihaylova D, Ferriani V, Tsakalidou FK, Foeldvari I, Cuttica R, Gonzalez B, Ravelli A, Khubchandani R, Oliveira S, Armbrust W, Garay S, Vojinovic J, Norambuena X, Gamir ML, García-Consuegra J, Lepore L, Susic G, Corona F, Dolezalova P, Pistorio A, Martini A, Ruperto N, Roth J, Paediatric Rheumatology International Trials Organization (PRINTO): Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial. JAMA. 2010, 303: 1266-1273. 10.1001/jama.2010.375.CrossRefPubMed Foell D, Wulffraat N, Wedderburn LR, Wittkowski H, Frosch M, Gerss J, Stanevicha V, Mihaylova D, Ferriani V, Tsakalidou FK, Foeldvari I, Cuttica R, Gonzalez B, Ravelli A, Khubchandani R, Oliveira S, Armbrust W, Garay S, Vojinovic J, Norambuena X, Gamir ML, García-Consuegra J, Lepore L, Susic G, Corona F, Dolezalova P, Pistorio A, Martini A, Ruperto N, Roth J, Paediatric Rheumatology International Trials Organization (PRINTO): Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial. JAMA. 2010, 303: 1266-1273. 10.1001/jama.2010.375.CrossRefPubMed
20.
go back to reference Hammer HB, Odegard S, Fagerhol MK, Landewé R, van der Heijde D, Uhlig T, Mowinckel P, Kvien TK: Calprotectin (a major leucocyte protein) is strongly and independently correlated with joint inflammation and damage in rheumatoid arthritis. Ann Rheum Dis. 2007, 66: 1093-1097. 10.1136/ard.2006.064741.PubMedCentralCrossRefPubMed Hammer HB, Odegard S, Fagerhol MK, Landewé R, van der Heijde D, Uhlig T, Mowinckel P, Kvien TK: Calprotectin (a major leucocyte protein) is strongly and independently correlated with joint inflammation and damage in rheumatoid arthritis. Ann Rheum Dis. 2007, 66: 1093-1097. 10.1136/ard.2006.064741.PubMedCentralCrossRefPubMed
21.
go back to reference Hammer HB, Ødegård S, Syversen SW, Landewé R, van der Heijde D, Uhlig T, Mowinckel P, Kvien TK: Calprotectin (a major S100 leucocyte protein) predicts 10-year radiographic progression in patients with rheumatoid arthritis. Ann Rheum Dis. 2010, 69: 150-154. 10.1136/ard.2008.103739.CrossRefPubMed Hammer HB, Ødegård S, Syversen SW, Landewé R, van der Heijde D, Uhlig T, Mowinckel P, Kvien TK: Calprotectin (a major S100 leucocyte protein) predicts 10-year radiographic progression in patients with rheumatoid arthritis. Ann Rheum Dis. 2010, 69: 150-154. 10.1136/ard.2008.103739.CrossRefPubMed
22.
go back to reference Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, et al: 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010, 69: 1580-1588. 10.1136/ard.2010.138461.CrossRefPubMed Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, et al: 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010, 69: 1580-1588. 10.1136/ard.2010.138461.CrossRefPubMed
23.
go back to reference Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL: Modified disease activity scores that include twenty-eight-joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995, 38: 44-48. 10.1002/art.1780380107.CrossRefPubMed Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL: Modified disease activity scores that include twenty-eight-joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995, 38: 44-48. 10.1002/art.1780380107.CrossRefPubMed
24.
go back to reference van Gestel AM, Haagsma CJ, van Riel PL: Validation of rheumatoid arthritis improvement criteria that include simplified joint counts. Arthritis Rheum. 1998, 41: 1845-1850. 10.1002/1529-0131(199810)41:10<1845::AID-ART17>3.0.CO;2-K.CrossRefPubMed van Gestel AM, Haagsma CJ, van Riel PL: Validation of rheumatoid arthritis improvement criteria that include simplified joint counts. Arthritis Rheum. 1998, 41: 1845-1850. 10.1002/1529-0131(199810)41:10<1845::AID-ART17>3.0.CO;2-K.CrossRefPubMed
25.
go back to reference Chen YS, Yan W, Geczy CL, Brown MA, Thomas R: Serum levels of soluble receptor for advanced glycation end products and of S100 proteins are associated with inflammatory, autoantibody, and classical risk markers of joint and vascular damage in rheumatoid arthritis. Arthritis Res Ther. 2009, 11: R39-10.1186/ar2645.PubMedCentralCrossRefPubMed Chen YS, Yan W, Geczy CL, Brown MA, Thomas R: Serum levels of soluble receptor for advanced glycation end products and of S100 proteins are associated with inflammatory, autoantibody, and classical risk markers of joint and vascular damage in rheumatoid arthritis. Arthritis Res Ther. 2009, 11: R39-10.1186/ar2645.PubMedCentralCrossRefPubMed
26.
go back to reference de Seny D, Fillet M, Ribbens C, Marée R, Meuwis MA, Lutteri L, Chapelle JP, Wehenkel L, Louis E, Merville MP, Malaise M: Monomeric calgranulins measured by SELDI-TOF mass spectrometry and calprotectin measured by ELISA as biomarkers in arthritis. Clin Chem. 2008, 54: 1066-1075. 10.1373/clinchem.2007.099549.CrossRefPubMed de Seny D, Fillet M, Ribbens C, Marée R, Meuwis MA, Lutteri L, Chapelle JP, Wehenkel L, Louis E, Merville MP, Malaise M: Monomeric calgranulins measured by SELDI-TOF mass spectrometry and calprotectin measured by ELISA as biomarkers in arthritis. Clin Chem. 2008, 54: 1066-1075. 10.1373/clinchem.2007.099549.CrossRefPubMed
27.
go back to reference Bovin LF, Rieneck K, Workman C, Nielsen H, Sørensen SF, Skjødt H, Florescu A, Brunak S, Bendtzen K: Blood cell gene expression profiling in rheumatoid arthritis: discriminative genes and effect of rheumatoid factor. Immunol Lett. 2004, 93: 217-226. 10.1016/j.imlet.2004.03.018.CrossRefPubMed Bovin LF, Rieneck K, Workman C, Nielsen H, Sørensen SF, Skjødt H, Florescu A, Brunak S, Bendtzen K: Blood cell gene expression profiling in rheumatoid arthritis: discriminative genes and effect of rheumatoid factor. Immunol Lett. 2004, 93: 217-226. 10.1016/j.imlet.2004.03.018.CrossRefPubMed
Metadata
Title
Decreases in serum levels of S100A8/9 (calprotectin) correlate with improvements in total swollen joint count in patients with recent-onset rheumatoid arthritis
Authors
Lucie Andrés Cerezo
Heřman Mann
Ondřej Pecha
Lenka Pleštilová
Karel Pavelka
Jiří Vencovský
Ladislav Šenolt
Publication date
01-08-2011
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 4/2011
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar3426

Other articles of this Issue 4/2011

Arthritis Research & Therapy 4/2011 Go to the issue