OBJECTIVE: Clinical remission in some patients with rheumatoid arthritis (RA) may be associated with ongoing synovial inflammation that is not always detectable on clinical examination or reflected by laboratory tests but can be visualized by musculoskeletal ultrasound. The goal of our study was to determine the levels of serum calprotectin, a major leukocyte protein, in patients with RA in clinical remission and to investigate the ability of serum calprotectin levels to distinguish patients in ultrasound-defined remission from those with residual ultrasound subclinical inflammation. METHODS: Seventy RA patients in clinical remission underwent clinical and ultrasound examination. Ultrasound examination was performed according to the German US7 score. Ultrasound remission was defined as grey scale (GS) range 0-1 and power Doppler (PD) range 0. The levels of serum calprotectin and C-reactive protein (CRP) were determined. The discriminatory capacity of calprotectin and CRP in detecting residual ultrasound inflammation was assessed using ROC curves. RESULTS: The total number of patients fulfilling the DAS28-ESR, DAS28-CRP, SDAI and CDAI remission criteria was 58, 67, 32 and 31, respectively. Residual synovial inflammation was found in 58-67% of the patients who fulfilled at least one set of clinical remission criteria. Calprotectin levels were significantly higher in patients with residual synovial inflammation than in those with ultrasound-defined remission (mean 2.5±1.3 vs. 1.7±0.8 μg/mL, p<0.005). Using ultrasound-defined remission criteria, calprotectin had an AUC of 0.692, p<0.05 using DAS28-ESR remission criteria and an AUC of 0.712, p<0.005 using DAS28-CRP remission criteria. Calprotectin correctly distinguished ultrasound remission from subclinical activity in 70% of patients. CRP (AUC DAS28-ESR = 0.494, p = NS; AUC DAS28-CRP = 0.498, p = NS) had lower and insignificant discriminatory capacity. CONCLUSION: The present study demonstrates the potential of calprotectin to distinguish RA patients in both clinical and ultrasound-defined remission from patients in clinical remission but with residual subclinical disease activity.

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

Institute of Rheumatology Prague Czech Republic

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

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Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004;363(9410):675–81. 10.1016/S0140-6736(04)15640-7 . PubMed DOI

Korpela M, Laasonen L, Hannonen P, Kautiainen H, Leirisalo-Repo M, Hakala M, et al. Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: five-year experience from the FIN-RACo study. Arthritis Rheum. 2004;50(7):2072–81. 10.1002/art.20351 . PubMed DOI

Emery P, Salmon M. Early rheumatoid arthritis: time to aim for remission? Ann Rheum Dis. 1995;54(12):944–7. PubMed Central PMCID: PMCPMC1010056. PubMed PMC

Molenaar ET, Voskuyl AE, Dinant HJ, Bezemer PD, Boers M, Dijkmans BA. Progression of radiologic damage in patients with rheumatoid arthritis in clinical remission. Arthritis Rheum. 2004;50(1):36–42. 10.1002/art.11481 . PubMed DOI

Mulherin D, Fitzgerald O, Bresnihan B. Clinical improvement and radiological deterioration in rheumatoid arthritis: evidence that the pathogenesis of synovial inflammation and articular erosion may differ. Br J Rheumatol. 1996;35(12):1263–8. . PubMed

Cohen G, Gossec L, Dougados M, Cantagrel A, Goupille P, Daures JP, et al. Radiological damage in patients with rheumatoid arthritis on sustained remission. Ann Rheum Dis. 2007;66(3):358–63. PubMed Central PMCID: PMCPMC1856000. 10.1136/ard.2006.057497 PubMed DOI PMC

Brown AK, Quinn MA, Karim Z, Conaghan PG, Peterfy CG, Hensor E, et al. Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: evidence from an imaging study may explain structural progression. Arthritis Rheum. 2006;54(12):3761–73. 10.1002/art.22190 . PubMed DOI

Brown AK, Conaghan PG, Karim Z, Quinn MA, Ikeda K, Peterfy CG, et al. An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum. 2008;58(10):2958–67. 10.1002/art.23945 . PubMed DOI

Balsa A, de Miguel E, Castillo C, Peiteado D, Martin-Mola E. Superiority of SDAI over DAS-28 in assessment of remission in rheumatoid arthritis patients using power Doppler ultrasonography as a gold standard. Rheumatology (Oxford). 2010;49(4):683–90. 10.1093/rheumatology/kep442 . 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. PubMed Central PMCID: PMCPMC1755396. 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. 10.1002/art.10877 . PubMed DOI

Szkudlarek M, Wakefield RJ, Backhaus M, Terslev L. The discriminatory capacity of ultrasound in rheumatoid arthritis: active vs inactive, early vs advanced, and more. Rheumatology (Oxford). 2012;51 Suppl 7:vii6–9. 10.1093/rheumatology/kes334 . PubMed DOI

Backhaus M, Kamradt T, Sandrock D, Loreck D, Fritz J, Wolf KJ, et al. Arthritis of the finger joints: a comprehensive approach comparing conventional radiography, scintigraphy, ultrasound, and contrast-enhanced magnetic resonance imaging. Arthritis Rheum. 1999;42(6):1232–45. 10.1002/1529-0131(199906)42:6<1232::AID-ANR21>3.0.CO;2-3 . PubMed DOI

Ohrndorf S, Backhaus M. Advances in sonographic scoring of rheumatoid arthritis. Ann Rheum Dis. 2013;72 Suppl 2:ii69–75. 10.1136/annrheumdis-2012-202197 . PubMed DOI

Ozgocmen S, Ozdemir H, Kiris A, Bozgeyik Z, Ardicoglu O. Clinical evaluation and power Doppler sonography in rheumatoid arthritis: evidence for ongoing synovial inflammation in clinical remission. South Med J. 2008;101(3):240–5. 10.1097/SMJ.0b013e318164e16a . PubMed DOI

Saleem B, Brown AK, Keen H, Nizam S, Freeston J, Wakefield R, et al. Should imaging be a component of rheumatoid arthritis remission criteria? A comparison between traditional and modified composite remission scores and imaging assessments. Ann Rheum Dis. 2011;70(5):792–8. 10.1136/ard.2010.134445 . PubMed DOI

Scire CA, Montecucco C, Codullo V, Epis O, Todoerti M, Caporali R. Ultrasonographic evaluation of joint involvement in early rheumatoid arthritis in clinical remission: power Doppler signal predicts short-term relapse. Rheumatology (Oxford). 2009;48(9):1092–7. 10.1093/rheumatology/kep171 . PubMed DOI

Foltz V, Gandjbakhch F, Etchepare F, Rosenberg C, Tanguy ML, Rozenberg S, et al. Power Doppler ultrasound, but not low-field magnetic resonance imaging, predicts relapse and radiographic disease progression in rheumatoid arthritis patients with low levels of disease activity. Arthritis Rheum. 2012;64(1):67–76. 10.1002/art.33312 . PubMed DOI

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

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. 10.1038/330080a0 . PubMed DOI

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 Central PMCID: PMCPMC379605. PubMed PMC

Youssef P, Roth J, Frosch M, Costello P, Fitzgerald O, Sorg C, et al. Expression of myeloid related proteins (MRP) 8 and 14 and the MRP8/14 heterodimer in rheumatoid arthritis synovial membrane. J Rheumatol. 1999;26(12):2523–8. . PubMed

Berntzen HB, Munthe E, Fagerhol MK. A longitudinal study of the leukocyte protein L1 as an indicator of disease activity in patients with rheumatoid arthritis. J Rheumatol. 1989;16(11):1416–20. . 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. PubMed Central PMCID: PMCPMC1954700. 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 PubMed Central PMCID: PMCPMC3239361. 10.1186/ar3426 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 PubMed Central PMCID: PMCPMC3308113. 10.1186/ar3503 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 PubMed Central PMCID: PMCPMC4572609. 10.1186/s13075-015-0764-5 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 PubMed Central PMCID: PMCPMC4938924. 10.1186/s13075-016-1032-z 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. 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, Nell VP, Stamm T, Uffmann M, Pflugbeil S, Machold K, et al. Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res Ther. 2005;7(4):R796–806. PubMed Central PMCID: PMCPMC1175030. 10.1186/ar1740 PubMed DOI PMC

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. 10.1002/art.24646 . PubMed DOI

Backhaus M, Ohrndorf S, Alraqi S, Crowther S, Dhillon S, Dhindsa N. Can satisfactory reliability of the 7-joint ultrasound score be attained by inexperienced Readers In a single calibration exercise? results from the biodam program. [abstract]. Arthritis Rheum. 2013;(65):1946.

Smolen JS, Aletaha D, Bijlsma JW, Breedveld FC, Boumpas D, Burmester G, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010;69(4):631–7. PubMed Central PMCID: PMCPMC3015099. 10.1136/ard.2009.123919 PubMed DOI PMC

Padovano I, Costantino F, Breban M, D'Agostino MA. Prevalence of ultrasound synovial inflammatory findings in healthy subjects. Ann Rheum Dis. 2015. 10.1136/annrheumdis-2015-208103 . PubMed DOI

Witt M, Mueller F, Nigg A, Reindl C, Leipe J, Proft F, et al. Relevance of grade 1 gray-scale ultrasound findings in wrists and small joints to the assessment of subclinical synovitis in rheumatoid arthritis. Arthritis Rheum. 2013;65(7):1694–701. 10.1002/art.37954 . PubMed DOI

Saleem B, Brown AK, Keen H, Nizam S, Freeston J, Karim Z, et al. Disease remission state in patients treated with the combination of tumor necrosis factor blockade and methotrexate or with disease-modifying antirheumatic drugs: A clinical and imaging comparative study. Arthritis Rheum. 2009;60(7):1915–22. 10.1002/art.24596 . PubMed DOI

Ramirez J, Celis R, Usategui A, Ruiz-Esquide V, Fare R, Cuervo A, et al. Immunopathologic characterization of ultrasound-defined synovitis in rheumatoid arthritis patients in clinical remission. Arthritis Res Ther. 2015;18(1):74 PubMed Central PMCID: PMCPMC4818452. 10.1186/s13075-016-0970-9 PubMed DOI PMC

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

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