Clinical Rheumatology

, Volume 37, Issue 8, pp 2055–2062 | Cite as

Serum calprotectin may reflect inflammatory activity in patients with active rheumatoid arthritis despite normal to low C-reactive protein

  • Jana Hurnakova
  • Hana Hulejova
  • Jakub Zavada
  • Martin Komarc
  • Lucie Andres Cerezo
  • Herman Mann
  • Jiri Vencovsky
  • Karel Pavelka
  • Ladislav Senolt
Original Article


Approximately half of patients with rheumatoid arthritis (RA) have normal C-reactive protein (CRP) levels. Calprotectin is a promising and likely more specific biomarker of disease activity than conventionally used acute phase reactants. We aimed to analyse the levels of serum calprotectin in RA patients with clinically active disease and with normal/low CRP. A total of 160 RA patients underwent clinical examination (DAS28-ESR and CDAI). The levels of calprotectin were analysed in patients with moderate to high disease activity with normal/low CRP levels and in 32 healthy subjects. The discriminatory capacity of calprotectin to identify clinically active patients in spite of normal/low CRP was assessed using ROC curves. Out of all RA patients, 74/160 (46.3%) were in remission or had low disease activity according to DAS28 and had normal/low CRP levels. However, 51/160 (32%) had normal/low CRP levels despite having moderate to high disease activity. In these patients, calprotectin levels were significantly higher than those in patients who had normal/low CRP and were in remission or showed low disease activity (2.7 ± 1.5 vs. 2.1 ± 1.2 μg/mL, p = 0.043), which differed from those in healthy subjects (2.7 ± 1.5 vs. 1.9 ± 1.2 μg/mL, p = 0.011). The discriminatory capacity for calprotectin to distinguish clinically active vs. inactive disease despite normal/low CRP using AUC of the DAS28 was 0.607 (95% CI 0.503 to 0.711, p = 0.043). The present study demonstrates that calprotectin may reflect inflammatory activity in RA patients where CRP fails to do so.


Calprotectin C-reactive protein Inflammation Rheumatoid arthritis 



anti-cyclic citrullinated peptide antibody


area under the curve


Clinical Disease Activity Index


C-reactive protein


Disease Activity Score for 28 joints with erythrocyte sedimentation rate


enzyme-linked immunosorbent assay


erythrocyte sedimentation rate


rheumatoid arthritis


rheumatoid factor


receiver operating curves


swollen joint count


tender joint count


visual analogue scale


Author contributions

JH was the principal investigator for the study, participated in the data analysis and interpretation and prepared the first draft of the manuscript. HH and LAC were responsible for the quantification of calprotectin and the manuscript revision. JZ and HM participated in the data analysis and interpretation and revised the manuscript. MK performed statistical analysis, participated in the data interpretation and helped draft the manuscript. JV revised the manuscript critically for important intellectual content. KP facilitated the performance of the study and revised the manuscript. LS participated in the study design, facilitated the performance of the study and revised the final draft of the paper. All authors have read and approved the final manuscript.

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication.


This work was supported by a project of the Ministry of Health of the Czech Republic for conceptual research development by organisation [023728] and Specific Academy Research Projects (SVV) [260373].

Compliance with ethical standards

The study was performed according to the Declaration of Helsinki and was approved by the local ethics committee of the Institute of Rheumatology in Prague (Reference number 3560/2010).




  1. 1.
    Sokka T, Kautiainen H, Pincus T, Verstappen SM, Aggarwal A, Alten R, Andersone D, Badsha H, Baecklund E, Belmonte M, Craig-Muller J, da Mota LM, Dimic A, Fathi NA, Ferraccioli G, Fukuda W, Geher P, Gogus F, Hajjaj-Hassouni N, Hamoud H, Haugeberg G, Henrohn D, Horslev-Petersen K, Ionescu R, Karateew D, Kuuse R, Laurindo IM, Lazovskis J, Luukkainen R, Mofti A, Murphy E, Nakajima A, Oyoo O, Pandya SC, Pohl C, Predeteanu D, Rexhepi M, Rexhepi S, Sharma B, Shono E, Sibilia J, Sierakowski S, Skopouli FN, Stropuviene S, Toloza S, Valter I, Woolf A, Yamanaka H, Quest RA (2010) Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA study. Arthritis Res Ther 12(2):R42. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F (2002) Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 359(9313):1173–1177. CrossRefPubMedGoogle Scholar
  3. 3.
    Smolen JS, Aletaha D, Bijlsma JW, Breedveld FC, Boumpas D, Burmester G, Combe B, Cutolo M, de Wit M, Dougados M, Emery P, Gibofsky A, Gomez-Reino JJ, Haraoui B, Kalden J, Keystone EC, Kvien TK, McInnes I, Martin-Mola E, Montecucco C, Schoels M, van der Heijde D, Committee TTE (2010) Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 69(4):631–637. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Pincus T, Castrejon I, Bergman MJ, Yazici Y (2012) Treat-to-target: not as simple as it appears. Clin Exp Rheumatol 30(4 Suppl 73):S10–S20PubMedGoogle Scholar
  5. 5.
    Wolfe F, Michaud K (1994) The clinical and research significance of the erythrocyte sedimentation rate. J Rheumatol 21(7):1227–1237PubMedGoogle Scholar
  6. 6.
    Pincus T, Sokka T (2009) Laboratory tests to assess patients with rheumatoid arthritis: advantages and limitations. Rheum Dis Clin N Am 35(4):731–734, vi-vii. CrossRefGoogle Scholar
  7. 7.
    Sokka T, Pincus T (2009) Erythrocyte sedimentation rate, C-reactive protein, or rheumatoid factor are normal at presentation in 35%-45% of patients with rheumatoid arthritis seen between 1980 and 2004: analyses from Finland and the United States. J Rheumatol 36(7):1387–1390. CrossRefPubMedGoogle Scholar
  8. 8.
    Pincus T, Gibson KA, Shmerling RH (2014) An evidence-based approach to laboratory tests in usual care of patients with rheumatoid arthritis. Clin Exp Rheumatol 32(5 Suppl 85):S-23-28Google Scholar
  9. 9.
    Odink K, Cerletti N, Bruggen J, Clerc RG, Tarcsay L, Zwadlo G, Gerhards G, Schlegel R, Sorg C (1987) Two calcium-binding proteins in infiltrate macrophages of rheumatoid arthritis. Nature 330(6143):80–82. CrossRefPubMedGoogle Scholar
  10. 10.
    Foell D, Roth J (2004) Proinflammatory S100 proteins in arthritis and autoimmune disease. Arthritis Rheum 50(12):3762–3771. CrossRefPubMedGoogle Scholar
  11. 11.
    Johne B, Fagerhol MK, Lyberg T, Prydz H, Brandtzaeg P, Naess-Andresen CF, Dale I (1997) Functional and clinical aspects of the myelomonocyte protein calprotectin. Mol Pathol 50(3):113–123CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81(1):1–5. CrossRefPubMedGoogle Scholar
  13. 13.
    Sunahori K, Yamamura M, Yamana J, Takasugi K, Kawashima M, Yamamoto H, Chazin WJ, Nakatani Y, Yui S, Makino H (2006) The S100A8/A9 heterodimer amplifies proinflammatory cytokine production by macrophages via activation of nuclear factor kappa B and p38 mitogen-activated protein kinase in rheumatoid arthritis. Arthritis Res Ther 8(3):R69. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Berntzen HB, Olmez U, Fagerhol MK, Munthe E (1991) The leukocyte protein L1 in plasma and synovial fluid from patients with rheumatoid arthritis and osteoarthritis. Scand J Rheumatol 20(2):74–82CrossRefPubMedGoogle Scholar
  15. 15.
    Andres Cerezo L, Mann H, Pecha O, Plestilova L, Pavelka K, Vencovsky J, Senolt L (2011) 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 13(4):R122. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Brun JG, Haga HJ, Boe E, Kallay I, Lekven C, Berntzen HB, Fagerhol MK (1992) Calprotectin in patients with rheumatoid arthritis: relation to clinical and laboratory variables of disease activity. J Rheumatol 19(6):859–862PubMedGoogle Scholar
  17. 17.
    Brun JG, Jonsson R, Haga HJ (1994) Measurement of plasma calprotectin as an indicator of arthritis and disease activity in patients with inflammatory rheumatic diseases. J Rheumatol 21(4):733–738PubMedGoogle Scholar
  18. 18.
    Hammer HB, Fagerhol MK, Wien TN, Kvien TK (2011) 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 13(5):R178. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hurnakova J, Zavada J, Hanova P, Hulejova H, Klein M, Mann H, Sleglova O, Olejarova M, Forejtova S, Ruzickova O, Komarc M, Vencovsky J, Pavelka K, Senolt L (2015) Serum calprotectin (S100A8/9): an independent predictor of ultrasound synovitis in patients with rheumatoid arthritis. Arthritis Res Ther 17:252. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, 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, Menard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62(9):2569–2581. CrossRefPubMedGoogle Scholar
  21. 21.
    Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, Aletaha D, Allaart CF, Bathon J, Bombardieri S, Brooks P, Brown A, Matucci-Cerinic M, Choi H, Combe B, de Wit M, Dougados M, Emery P, Furst D, Gomez-Reino J, Hawker G, Keystone E, Khanna D, Kirwan J, Kvien TK, Landewe R, Listing J, Michaud K, Martin-Mola E, Montie P, Pincus T, Richards P, Siegel JN, Simon LS, Sokka T, Strand V, Tugwell P, Tyndall A, van der Heijde D, Verstappen S, White B, Wolfe F, Zink A, Boers M (2011) American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis 70(3):404–413. CrossRefPubMedGoogle Scholar
  22. 22.
    Sokka T, Pincus T (2003) Most patients receiving routine care for rheumatoid arthritis in 2001 did not meet inclusion criteria for most recent clinical trials or American College of Rheumatology criteria for remission. J Rheumatol 30(6):1138–1146PubMedGoogle Scholar
  23. 23.
    Wolfe F, Pincus T (2001) The level of inflammation in rheumatoid arthritis is determined early and remains stable over the longterm course of the illness. J Rheumatol 28(8):1817–1824PubMedGoogle Scholar
  24. 24.
    Garcia-Arias M, Pascual-Salcedo D, Ramiro S, Ueberschlag ME, Jermann TM, Cara C, Martin-Mola E, Balsa A (2013) Calprotectin in rheumatoid arthritis: association with disease activity in a cross-sectional and a longitudinal cohort. Mol Diagn Ther 17(1):49–56. CrossRefPubMedGoogle Scholar
  25. 25.
    Abildtrup M, Kingsley GH, Scott DL (2015) Calprotectin as a biomarker for rheumatoid arthritis: a systematic review. J Rheumatol 42(5):760–770. CrossRefPubMedGoogle Scholar
  26. 26.
    Hammer HB, Odegard S, Fagerhol MK, Landewe R, van der Heijde D, Uhlig T, Mowinckel P, Kvien TK (2007) Calprotectin (a major leucocyte protein) is strongly and independently correlated with joint inflammation and damage in rheumatoid arthritis. Ann Rheum Dis 66(8):1093–1097. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hammer HB, Odegard S, Syversen SW, Landewe R, van der Heijde D, Uhlig T, Mowinckel P, Kvien TK (2010) Calprotectin (a major S100 leucocyte protein) predicts 10-year radiographic progression in patients with rheumatoid arthritis. Ann Rheum Dis 69(1):150–154. CrossRefPubMedGoogle Scholar
  28. 28.
    Inciarte-Mundo J, Ruiz-Esquide V, Hernandez MV, Canete JD, Cabrera-Villalba SR, Ramirez J, Yague J, Sanmarti R (2015) Calprotectin more accurately discriminates the disease status of rheumatoid arthritis patients receiving tocilizumab than acute phase reactants. Rheumatology (Oxford) 54(12):2239–2243. Google Scholar
  29. 29.
    Inciarte-Mundo J, Ramirez J, Hernandez MV, Ruiz-Esquide V, Cuervo A, Cabrera-Villalba SR, Pascal M, Yague J, Canete JD, Sanmarti R (2016) 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 18(1):160. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Hurnakova J, Hulejova H, Zavada J, Komarc M, Hanova P, Klein M, Mann H, Sleglova O, Olejarova M, Forejtova S, Ruzickova O, Vencovsky J, Pavelka K, Senolt L (2016) Serum calprotectin discriminates subclinical disease activity from ultrasound-defined remission in patients with rheumatoid arthritis in clinical remission. PLoS One 11(11):e0165498. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  1. 1.Institute of Rheumatology, Prague, Czech RepublicPrague 2Czech Republic
  2. 2.Department of Rheumatology, First Faculty of MedicineCharles University in Prague, Czech RepublicPrague 2Czech Republic
  3. 3.Department of Methodology, Faculty of Physical Education and SportCharles University in Prague, Czech RepublicPrague 6Czech Republic

Personalised recommendations