BACKGROUND: Calprotectin may be a sensitive biomarker of rheumatoid arthritis (RA) disease activity. OBJECTIVES: In the current study, we investigated whether calprotectin is a better biomarker than CRP for predicting clinical activity and ultrasound parameters in patients with RA. METHODS: A total of 160 patients with RA underwent clinical (swollen joint count-SJC, tender joint count-TJC, Disease Activity Score-DAS28, Clinical Disease Activity Index-CDAI, and simplified Disease Activity Index-SDAI) and ultrasound (German US7) examination. Clinical and laboratory measures were correlated with ultrasound findings using Spearman´s correlation coefficient. Differences in serum calprotectin levels in patients with variable disease activity according to the DAS28-ESR and CDAI scores were assessed using ANOVA. Multivariate regression analysis was used to determine the predictive values of calprotectin, CRP and SJC for CDAI and PD US synovitis scores. RESULTS: Serum calprotectin was significantly associated with DAS28-ESR (r = 0.321, p<0.001), DAS28-CRP (r = 0.346, p<0.001), SDAI (r = 0.305, p<0.001), CDAI (r = 0.279, p<0.001) scores and CRP levels (r = 0.556, p<0.001). Moreover, calprotectin was significantly correlated with GS (r = 0.379, p<0.001) and PD synovitis scores (r = 0.419, p<0.001). The multivariate regression analysis showed that calprotectin is a better predictor of the CDAI score and PD US synovitis than CRP. CONCLUSIONS: The results of this study support an additional role of calprotectin in assessing inflammatory activity in patients with RA.

Department of Methodology Faculty of Physical Education and Sport Charles University Prague Czech Republic

Department of Rheumatology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Rheumatology Prague Czech Republic

See more in PubMed

Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res. 2002;4 Suppl 3:S265–72. PubMed PMC

Andersson AK, Li C, Brennan FM. Recent developments in the immunobiology of rheumatoid arthritis. Arthritis Res Ther. 2008;10(2):204 doi: 10.1186/ar2370 PubMed DOI PMC

Huber LC, Distler O, Tarner I, Gay RE, Gay S, Pap T. Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology (Oxford). 2006;45(6):669–75. PubMed

Odink K, Cerletti N, Bruggen J, Clerc RG, Tarcsay L, Zwadlo G, et al. Two calcium-binding proteins in infiltrate macrophages of rheumatoid arthritis. Nature. 1987;330(6143):80–2. PubMed

Garcia-Arias M, Pascual-Salcedo D, Ramiro S, Ueberschlag ME, Jermann TM, Cara C, et al. Calprotectin in rheumatoid arthritis: association with disease activity in a cross-sectional and a longitudinal cohort. Mol Diagn Ther. 2013;17(1):49–56. doi: 10.1007/s40291-013-0016-9 PubMed DOI

Foell D, Roth J. Proinflammatory S100 proteins in arthritis and autoimmune disease. Arthritis Rheum. 2004;50(12):3762–71. doi: 10.1002/art.20631 PubMed DOI

Wilkinson MM, Busuttil A, Hayward C, Brock DJ, Dorin JR, Van Heyningen V. Expression pattern of two related cystic fibrosis-associated calcium-binding proteins in normal and abnormal tissues. J Cell Sci. 1988;91 (Pt 2):221–30. PubMed

Dale I, Fagerhol MK, Frigard M. Quantitation of a highly immunogenic leukocyte antigen (L1) by radioimmunoassay: methodological evaluation. J Immunol Methods. 1983;65(1–2):245–55. PubMed

Johne B, Fagerhol MK, Lyberg T, Prydz H, Brandtzaeg P, Naess-Andresen CF, et al. Functional and clinical aspects of the myelomonocyte protein calprotectin. Mol Pathol. 1997;50(3):113–23. PubMed PMC

Ehrchen JM, Sunderkotter C, Foell D, Vogl T, Roth J. The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol. 2009;86(3):557–66. doi: 10.1189/jlb.1008647 PubMed DOI

Berntzen HB, Olmez U, Fagerhol MK, Munthe E. The leukocyte protein L1 in plasma and synovial fluid from patients with rheumatoid arthritis and osteoarthritis. Scand J Rheumatol. 1991;20(2):74–82. PubMed

Hammer HB, Odegard S, Fagerhol MK, Landewe R, van der Heijde D, Uhlig T, et al. Calprotectin (a major leucocyte protein) is strongly and independently correlated with joint inflammation and damage in rheumatoid arthritis. Ann Rheum Dis. 2007;66(8):1093–7. doi: 10.1136/ard.2006.064741 PubMed DOI PMC

Andres Cerezo L, Mann H, Pecha O, Plestilova L, Pavelka K, Vencovsky J, et al. Decreases in serum levels of S100A8/9 (calprotectin) correlate with improvements in total swollen joint count in patients with recent-onset rheumatoid arthritis. Arthritis Res Ther. 2011;13(4):R122 doi: 10.1186/ar3426 PubMed DOI PMC

Choi IY, Gerlag DM, Herenius MJ, Thurlings RM, Wijbrandts CA, Foell D, et al. MRP8/14 serum levels as a strong predictor of response to biological treatments in patients with rheumatoid arthritis. Ann Rheum Dis. 2015;74(3):499–505. doi: 10.1136/annrheumdis-2013-203923 PubMed DOI

Nair SC, Welsing PM, Choi IY, Roth J, Holzinger D, Bijlsma JW, et al. A Personalized Approach to Biological Therapy Using Prediction of Clinical Response Based on MRP8/14 Serum Complex Levels in Rheumatoid Arthritis Patients. PLoS One. 2016;11(3):e0152362 doi: 10.1371/journal.pone.0152362 PubMed DOI PMC

Hammer HB, Fagerhol MK, Wien TN, Kvien TK. The soluble biomarker calprotectin (an S100 protein) is associated to ultrasonographic synovitis scores and is sensitive to change in patients with rheumatoid arthritis treated with adalimumab. Arthritis Res Ther. 2011;13(5):R178 doi: 10.1186/ar3503 PubMed DOI PMC

Colebatch AN, Edwards CJ, Ostergaard M, van der Heijde D, Balint PV, D'Agostino MA, et al. EULAR recommendations for the use of imaging of the joints in the clinical management of rheumatoid arthritis. Ann Rheum Dis. 2013;72(6):804–14. doi: 10.1136/annrheumdis-2012-203158 PubMed DOI

Naredo E, Bonilla G, Gamero F, Uson J, Carmona L, Laffon A. Assessment of inflammatory activity in rheumatoid arthritis: a comparative study of clinical evaluation with grey scale and power Doppler ultrasonography. Ann Rheum Dis. 2005;64(3):375–81. doi: 10.1136/ard.2004.023929 PubMed DOI PMC

Szkudlarek M, Court-Payen M, Jacobsen S, Klarlund M, Thomsen HS, Ostergaard M. Interobserver agreement in ultrasonography of the finger and toe joints in rheumatoid arthritis. Arthritis Rheum. 2003;48(4):955–62. doi: 10.1002/art.10877 PubMed DOI

Hurnakova J, Hulejova H, Zavada J, Komarc M, Hanova P, Klein M, et al. Serum Calprotectin Discriminates Subclinical Disease Activity from Ultrasound-Defined Remission in Patients with Rheumatoid Arthritis in Clinical Remission. PLoS One. 2016;11(11):e0165498 doi: 10.1371/journal.pone.0165498 PubMed DOI PMC

Hurnakova J, Zavada J, Hanova P, Hulejova H, Klein M, Mann H, et al. Serum calprotectin (S100A8/9): an independent predictor of ultrasound synovitis in patients with rheumatoid arthritis. Arthritis Res Ther. 2015;17:252 doi: 10.1186/s13075-015-0764-5 PubMed DOI PMC

Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69(9):1580–8. doi: 10.1136/ard.2010.138461 PubMed DOI

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(1):44–8. PubMed

Smolen JS, Breedveld FC, Schiff MH, Kalden JR, Emery P, Eberl G, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford). 2003;42(2):244–57. PubMed

Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol. 2005;23(5 Suppl 39):S100–8. PubMed

Backhaus M, Ohrndorf S, Kellner H, Strunk J, Backhaus TM, Hartung W, et al. Evaluation of a novel 7-joint ultrasound score in daily rheumatologic practice: a pilot project. Arthritis Rheum. 2009;61(9):1194–201. doi: 10.1002/art.24646 PubMed DOI

Roth J, Vogl T, Sorg C, Sunderkotter C. Phagocyte-specific S100 proteins: a novel group of proinflammatory molecules. Trends Immunol. 2003;24(4):155–8. PubMed

Rammes A, Roth J, Goebeler M, Klempt M, Hartmann M, Sorg C. Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, are secreted by activated monocytes via a novel, tubulin-dependent pathway. J Biol Chem. 1997;272(14):9496–502. PubMed

Dale I, Fagerhol MK, Naesgaard I. Purification and partial characterization of a highly immunogenic human leukocyte protein, the L1 antigen. Eur J Biochem. 1983;134(1):1–6. PubMed

Brun JG, Haga HJ, Boe E, Kallay I, Lekven C, Berntzen HB, et al. Calprotectin in patients with rheumatoid arthritis: relation to clinical and laboratory variables of disease activity. J Rheumatol. 1992;19(6):859–62. PubMed

Brun JG, Jonsson R, Haga HJ. Measurement of plasma calprotectin as an indicator of arthritis and disease activity in patients with inflammatory rheumatic diseases. J Rheumatol. 1994;21(4):733–8. PubMed

Inciarte-Mundo J, Victoria Hernandez M, Ruiz-Esquide V, Raquel Cabrera-Villalba S, Ramirez J, Cuervo A, et al. Serum Calprotectin Versus Acute-Phase Reactants in the Discrimination of Inflammatory Disease Activity in Rheumatoid Arthritis Patients Receiving Tumor Necrosis Factor Inhibitors. Arthritis Care Res (Hoboken). 2016;68(7):899–906. PubMed

Inciarte-Mundo J, Ruiz-Esquide V, Hernandez MV, Canete JD, Cabrera-Villalba SR, Ramirez J, et al. Calprotectin more accurately discriminates the disease status of rheumatoid arthritis patients receiving tocilizumab than acute phase reactants. Rheumatology (Oxford). 2015;54(12):2239–43. PubMed

Nordal HH, Brokstad KA, Solheim M, Halse AK, Kvien TK, Hammer HB. Calprotectin (S100A8/A9) has the strongest association with ultrasound-detected synovitis and predicts response to biologic treatment: results from a longitudinal study of patients with established rheumatoid arthritis. Arthritis Res Ther. 2017;19(1):3 doi: 10.1186/s13075-016-1201-0 PubMed DOI PMC

Inciarte-Mundo J, Ramirez J, Hernandez MV, Ruiz-Esquide V, Cuervo A, Cabrera-Villalba SR, et al. Calprotectin and TNF trough serum levels identify power Doppler ultrasound synovitis in rheumatoid arthritis and psoriatic arthritis patients in remission or with low disease activity. Arthritis Res Ther. 2016;18(1):160 doi: 10.1186/s13075-016-1032-z PubMed DOI PMC

Chemokine and Cytokine Profiles in Patients with Hand Osteoarthritis