Relationship between serum calprotectin (S100A8/9) and clinical, laboratory and ultrasound parameters of disease activity in rheumatoid arthritis: A large cohort study

Jana Hurnakova, Hana Hulejova, Jakub Zavada, Petra Hanova, Martin Komarc, Herman Mann, Martin Klein, Olga Sleglova, Marta Olejarova, Sarka Forejtova, Olga Ruzickova, Jiri Vencovsky, Karel Pavelka, Ladislav Senolt, Jana Hurnakova, Hana Hulejova, Jakub Zavada, Petra Hanova, Martin Komarc, Herman Mann, Martin Klein, Olga Sleglova, Marta Olejarova, Sarka Forejtova, Olga Ruzickova, Jiri Vencovsky, Karel Pavelka, Ladislav Senolt

Abstract

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Box plots showing the associations…
Fig 1. Box plots showing the associations between Power Doppler synovitis score and disease activity according to A) DAS28-ESR, B) DAS28-CRP, C) SDAI, and D) CDAI.
Fig 2. Box plots showing the associations…
Fig 2. Box plots showing the associations between calprotectin serum levels and disease activity according to A) DAS28-ESR, B) DAS28-CRP, C) SDAI, and D) CDAI.

References

    1. Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res. 2002;4 Suppl 3:S265–72.
    1. Andersson AK, Li C, Brennan FM. Recent developments in the immunobiology of rheumatoid arthritis. Arthritis Res Ther. 2008;10(2):204 doi:
    1. 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.
    1. 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.
    1. 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:
    1. Foell D, Roth J. Proinflammatory S100 proteins in arthritis and autoimmune disease. Arthritis Rheum. 2004;50(12):3762–71. doi:
    1. 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.
    1. 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.
    1. 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.
    1. 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:
    1. 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.
    1. 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:
    1. 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:
    1. 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:
    1. 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:
    1. 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:
    1. 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:
    1. 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:
    1. 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:
    1. 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:
    1. 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:
    1. 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:
    1. 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.
    1. 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.
    1. 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.
    1. 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:
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. 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:
    1. 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:

Source: PubMed

3
S'abonner