Clinical Rheumatology

, Volume 38, Issue 4, pp 1075–1081 | Cite as

Evaluation of cytokine profiles in rheumatoid arthritis patients with clinically active disease and normal inflammatory indices

  • Asha M. Alex
  • Harlan Sayles
  • Ted R. Mikuls
  • Gail S. KerrEmail author
Original Article



To assess the potential utility of a cytokine measurement in rheumatoid arthritis (RA) patients with active joint disease but normal acute phase reactants (APR).


RA patients in a longitudinal observational registry with available cytokine array data were included. Patients were categorized based on agreement/disagreement of physical examination and APR measurements: concordant high (CH) [high tender and/or swollen joint counts (TJC + SJC > 3) and APR (ESR ≥ 28 mm/h + CRP ≥ 1.5 mg/L)]; concordant low (CL) [TJC + SJC ≤ 3 and normal APR]. Discordant (D) [TJC + SJC > 3 and normal APR] patients were stratified into low, medium, and high-disease activity (DL, DM, DH). Weighted-average and log-transformed cytokine scores were calculated based on results of a cytokine array. Chi-square tests compared categorical variables by concordance status; t tests, Wilcoxon rank-sum tests, ANOVA models, and ordinary least squares (OLS) regressions were used to compare continuous measures.


RA patients (n = 1467) were predominantly male (91%). Compared to CH patients (n = 174), D (n = 434) were younger, less frequently seropositive, with lower TJC, SJC, and DAS28-3v scores (p < 0.001). Cytokine scores for DL, DM, and DH groups were lower than CH patients (p < 0.001) and did not differ between DL, DM, and DH subgroups and were similar to CL (n = 356) patients. In multivariable analyses including CH and D patients, log-cytokine score was associated with higher DAS28-3v scores (p = 0.029). In multivariable analyses including CL patients, concordance status (p = 0.011) and ACPA (p = 0.013) were predictors of higher log cytokine score.


In this study, cytokine scores did not identify active joint disease in RA patients with normal APR.


Biomarkers Cytokine profiles Disease activity Rheumatoid arthritis 



This work was supported by the following sources that fund the Veterans Affairs Rheumatoid Arthritis Registry (VARA): Nebraska Arthritis Outcomes Research Center at the University of Nebraska Medical Center; Veterans Affairs Health Services Research and Development Program of the Veterans Health Administration (HSR&D), Veterans Health Administration (Veterans Affairs Merit award); HSR&D Career Development Award, Grant Number: CDA 07-221.

Compliance with ethical standards




  1. 1.
    Emery P, Gabay C, Kraan M, Gomez-Reino J (2007) Evidence-based review of biologic markers as indicators of disease progression and remission in rheumatoid arthritis. Rheumatol Int Springer-Verlag 27:793–806CrossRefGoogle Scholar
  2. 2.
    Wells G, Becker J-C, Teng J, Dougados M, Schiff M, Smolen J et al (2009) Validation of the 28-joint disease activity score (DAS28) and European league against rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis 68:954–960CrossRefGoogle Scholar
  3. 3.
    Brown AK, Conaghan PG, Karim Z, Quinn MA, Ikeda K, Peterfy CG, Hensor E, Wakefield RJ, O'Connor PJ, Emery P (2008) An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum 58:2958–2967CrossRefGoogle Scholar
  4. 4.
    Hirata S, Dirven L, Shen Y, Centola M, Cavet G, Lems WF, Tanaka Y, Huizinga TWJ, Allaart CF (2013) A multi-biomarker score measures rheumatoid arthritis disease activity in the BeSt study. Rheumatology (Oxford) 52:1202–1207CrossRefGoogle Scholar
  5. 5.
    Hambardzumyan K, Bolce R, Saevarsdottir S, Cruickshank SE, Sasso EH, Chernoff D, Forslind K, Petersson IF, Geborek P, van Vollenhoven RF (2015) Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial. Ann Rheum Dis 74:1102–1109CrossRefGoogle Scholar
  6. 6.
    Kay J, Morgacheva O, Messing SP, Kremer JM, Greenberg JD, Reed GW, Gravallese EM, Furst DE (2014) Clinical disease activity and acute phase reactant levels are discordant among patients with active rheumatoid arthritis: acute phase reactant levels contribute separately to predicting outcome at one year. Arthritis Res Ther 16:R40CrossRefGoogle Scholar
  7. 7.
    Hughes-Austin JM, Deane KD, Derber LA, Kolfenbach JR, Zerbe GO, Sokolove J, Lahey LJ, Weisman MH, Buckner JH, Mikuls TR, O'Dell JR, Keating RM, Gregersen PK, Robinson WH, Holers VM, Norris JM (2013) Multiple cytokines and chemokines are associated with rheumatoid arthritis-related autoimmunity in first-degree relatives without rheumatoid arthritis: studies of the Aetiology of rheumatoid arthritis (SERA). Ann Rheum Dis 72:901–907CrossRefGoogle Scholar
  8. 8.
    Prevoo MLL, Van’T Hof MA, Kuper HH, Van Leeuwen MA, Van De Putte LBA, Van Riel PLCM (1995) 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 38:44–48CrossRefGoogle Scholar
  9. 9.
    Pincus T, Yazici Y, Bergman M Development of a multi-dimensional health assessment questionnaire (MDHAQ) for the infrastructure of standard clinical care. Clin Exp Rheumatol 23:S19–S28Google Scholar
  10. 10.
    Bykerk VP, Massarotti EM. The new ACR/EULAR remission criteria: rationale for developing new criteria for remission. Rheumatology Oxford University Press; 2012;51:vi16-vi20Google Scholar
  11. 11.
    Khan NA, Spencer HJ, Abda E, Aggarwal A, Alten R, Ancuta C, Andersone D, Bergman M, Craig-Muller J, Detert J, Georgescu L, Gossec L, Hamoud H, Jacobs JWG, Laurindo IMM, Majdan M, Naranjo A, Pandya S, Pohl C, Schett G, Selim ZI, Toloza S, Yamanaka H, Sokka T (2012) Determinants of discordance in patients’ and physicians’ rating of rheumatoid arthritis disease activity. Arthritis Care Res (Hoboken) 64:206–214CrossRefGoogle Scholar
  12. 12.
    O’Dell JR, Mikuls TR (2011) To improve outcomes we must define and measure them: toward defining remission in rheumatoid arthritis. Arthritis Rheum 63:587–589CrossRefGoogle Scholar
  13. 13.
    Centola M, Cavet G, Shen Y, Ramanujan S, Knowlton N, Swan KA, Turner M, Sutton C, Smith DR, Haney DJ, Chernoff D, Hesterberg LK, Carulli JP, Taylor PC, Shadick NA, Weinblatt ME, Curtis JR Development of a multi-biomarker disease activity test for rheumatoid arthritis. Frey O, editor PLoS One 2013;8:e60635Google Scholar
  14. 14.
    Segurado OG, Sasso EH. Vectra DA for the objective measurement of disease activity in patients with rheumatoid arthritis Clin Exp Rheumatol 32:S-29-S-34Google Scholar
  15. 15.
    Bakker MF, Cavet G, Jacobs JW, Bijlsma JWJ, Haney DJ, Shen Y et al (2012) Performance of a multi-biomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study. Ann Rheum Dis 71:1692–1697CrossRefGoogle Scholar
  16. 16.
    Fleischmann R, Connolly SE, Maldonado MA, Schiff M (2016) Brief report: estimating disease activity using multi-biomarker disease activity scores in rheumatoid arthritis patients treated with abatacept or adalimumab. Arthritis Rheumatol 68:2083–2089CrossRefGoogle Scholar
  17. 17.
    Krabbe S, Bolce R, Brahe CH, Døhn UM, Ejbjerg BJ, Hetland ML, Sasso EH, Chernoff D, Hansen MS, Knudsen LS, Hansen A, Madsen OR, Hasselquist M, Møller J, Østergaard M (2017) Investigation of a multi-biomarker disease activity score in rheumatoid arthritis by comparison with magnetic resonance imaging, computed tomography, ultrasonography, and radiography parameters of inflammation and damage. Scand J Rheumatol 46:353–358CrossRefGoogle Scholar
  18. 18.
    Stenken JA, Poschenrieder AJ (2015) Bioanalytical chemistry of cytokines--a review. Anal Chim Acta 853:95–115CrossRefGoogle Scholar
  19. 19.
    England BR, Sokolove J, Robinson WH, Thiele GM, Ganti AK, Sayles H, Michaud K, Caplan L, Davis LA, Cannon GW, Sauer B, Singh N, Blair Solow E, Reimold AM, Kerr GS, Schwab P, Baker JF, Mikuls TR (2016) Associations of circulating cytokines and chemokines with cancer mortality in men with rheumatoid arthritis. Arthritis Rheumatol 68:2394–2402CrossRefGoogle Scholar
  20. 20.
    Sokolove J, Wagner CA, Lahey LJ, Sayles H, Duryee MJ, Reimold AM, Kerr G, Robinson WH, Cannon GW, Thiele GM, Mikuls TR (2016) Increased inflammation and disease activity among current cigarette smokers with rheumatoid arthritis: a cross-sectional analysis of US veterans. Rheumatology 55:1969–1977CrossRefGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  • Asha M. Alex
    • 1
    • 2
  • Harlan Sayles
    • 3
  • Ted R. Mikuls
    • 3
  • Gail S. Kerr
    • 1
    • 2
    • 4
    • 5
    Email author
  1. 1.Medstar Georgetown University HospitalWashingtonUSA
  2. 2.Washington DC Veteran Affairs Medical CenterWashingtonUSA
  3. 3.University of Nebraska Medical Center & VA Nebraska-Western Iowa Health Care SystemOmahaUSA
  4. 4.Howard UniversityWashingtonUSA
  5. 5.Rheumatology Section, 151K, Veterans Affairs Medical CenterWashingtonUSA

Personalised recommendations