Clinical Rheumatology

, Volume 28, Issue 10, pp 1127–1134 | Cite as

Autoantibodies and other serological markers in rheumatoid arthritis: predictors of disease activity?

  • Licia Maria Henrique da Mota
  • Leopoldo Luiz dos Santos Neto
  • Jozélio Freire de CarvalhoEmail author
Review Article


The description of potential serological markers of rheumatoid arthritis (RA) activity can be quite useful in optimizing RA treatment, since the laboratory markers currently used, namely erythrocyte sedimentation rate and C-reactive protein, are not specific for RA and are influenced by several other variables. The markers proposed for assessing RA activity include rheumatoid factor, anti-citrullinated protein/peptide antibodies, immunoglobulin M (IgM) anti-IgG advanced glycation end products, markers of bone/cartilage metabolism, mannose-binding lectin, E-selectin, interleukin-6, and leptin. Various studies have investigated the correlation between some of these markers and other variables that might indicate disease activity, e.g., inflammatory activity tests and disease activity scores. However, there is as yet insufficient evidence that any of these markers, in isolation or in combination, are useful in the assessment of RA activity.


Autoantibodies Disease activity Rheumatoid arthritis Serological markers 



L. M. H. da Mota: none

L. L. dos Santos Neto: none

J. F. de Carvalho: received a grant from Federico Foundation


  1. 1.
    Cabral D, Katz JN, Weinblatt ME, Ting G, Avorn J, Solomon DH (2005) Development and assessment of indicators of rheumatoid arthritis severity: results of a Delphi panel. Arthritis Rheum 53:61–66PubMedCrossRefGoogle Scholar
  2. 2.
    Khanna D, Oh M, Furst DE et al (2007) Evaluation of the preliminary definitions of minimal disease activity and remission in an early seropositive rheumatoid arthritis cohort. Arthritis Rheum 15(57):440–447CrossRefGoogle Scholar
  3. 3.
    Pincus T (2008) Limitations of a quantitative swollen and tender joint count to assess and monitor patients with rheumatoid arthritis. Bull NYU Hosp Jt Dis 66:216–223PubMedGoogle Scholar
  4. 4.
    Mallya RK, de Beer FC, Berry H, Hamilton ED, Mace BE, Pepys MB (1982) Correlation of clinical parameters of disease activity in rheumatoid arthritis with serum concentration of C-reactive protein and erythrocyte sedimentation rate. J Rheumatol 19:224–228Google Scholar
  5. 5.
    Ringold S, Singer NG (2008) Measures of disease activity in rheumatoid arthritis: a clinician’s guide. Curr Rheum Rev 4:259–265CrossRefGoogle Scholar
  6. 6.
    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 38:44–48PubMedCrossRefGoogle Scholar
  7. 7.
    Smolen JS, Breedveld FC, Schiff MH et al (2003) A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology 42:244–257PubMedCrossRefGoogle Scholar
  8. 8.
    Aletaha D, Nell VP, Stamm T et al (2005) Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res Ther 7:R796–R806PubMedCrossRefGoogle Scholar
  9. 9.
    Devlin J (1997) The acute phase and function in early rheumatoid arthritis. C-reactive protein levels correlate with functional outcome. J Rheumatol 24:9–13PubMedGoogle Scholar
  10. 10.
    Keenan RT, Swearingen CJ, Yazici Y (2008) Erythrocyte sedimentation rate and C-reactive protein levels are poorly correlated with clinical measures of disease activity in rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis patients. Clin Exp Rheumatol 26:814–819PubMedGoogle Scholar
  11. 11.
    Renaudineau Y, Jamin C, Saraux A, Youinou P (2005) Rheumatoid factor on a daily basis. Autoimmunity 38:11–16PubMedCrossRefGoogle Scholar
  12. 12.
    Vittecoq O, Pouplin S, Krzanowska K et al (2003) Rheumatoid factor is the strongest predictor of radiological progression of rheumatoid arthritis in a three-year prospective study in community-recruited patients. Rheumatology (Oxford) 42:939–946CrossRefGoogle Scholar
  13. 13.
    Visser H (2005) Early diagnosis of rheumatoid arthritis. Best Pract & Res Clin Rheum 19:55–72CrossRefGoogle Scholar
  14. 14.
    Visser H, Gelinck LB, Kampfraath AH, Breedveld FC, Hazes JM (1996) Diagnostic and prognostic characteristics of the enzyme linked immunosorbent rheumatoid factor assays in rheumatoid arthritis. Ann Rheum Dis 55:157–161PubMedCrossRefGoogle Scholar
  15. 15.
    Wolfe F, Cathey MA, Roberts FK (1991) The latex test revised rheumatoid factor testing in 8287 rheumatic disease patients. Arthritis Rheum 34:951–960PubMedCrossRefGoogle Scholar
  16. 16.
    Swedler W, Wallman J, Froelich CJ, Teodorescu M (1997) Routine measurement of IgM, IgG, and IgA rheumatoid factors: high sensitivity, specificity, and predictive value for rheumatoid arthritis. J Rheumatol 24:1037–1044PubMedGoogle Scholar
  17. 17.
    Lemm G, Ruschen S, Warnatz H (1988) An ELISA for IgA-IgG and IgM-RF measurement II. RF in several disease and control groups and under gold therapy in RA. Scand J Rheumatol Suppl 75:256–260PubMedCrossRefGoogle Scholar
  18. 18.
    Bobbio-Pallavicini F, Alpini C, Caporali R, Avalle S, Bugatti S, Montecucco C (2004) Autoantibody profile in rheumatoid arthritis during long-term infliximab treatment. Arthritis Res Ther 6:R264–R272PubMedCrossRefGoogle Scholar
  19. 19.
    Bobbio-Pallavicini F, Caporali R, Alpini C et al (2007) High IgA rheumatoid factor levels are associated with poor clinical response to tumour necrosis factor alpha inhibitors in rheumatoid arthritis. Ann Rheum Dis 66:302–307PubMedCrossRefGoogle Scholar
  20. 20.
    Bos WH, Bartelds GM, Wolbink GJ et al (2008) Differential response of the rheumatoid factor and anticitrullinated protein antibodies during adalimumab treatment in patients with rheumatoid arthritis. J Rheumatol 35:1972–1977PubMedGoogle Scholar
  21. 21.
    Ates A, Kinikli G, Turgay M, Akay G, Tokgöz G (2007) Effects of rheumatoid factor isotypes on disease activity and severity in patients with rheumatoid arthritis: a comparative study. Clin Rheumatol 26:538–545PubMedCrossRefGoogle Scholar
  22. 22.
    Vallbracht I, Rieber J, Oppermann M, Förger F, Siebert U, Helmke K (2004) Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis. Ann Rheum Dis 63:1079–1084PubMedCrossRefGoogle Scholar
  23. 23.
    Greiner A, Plischke H, Kellner H, Gruber R (2005) Association of anti-cyclic citrullinated peptide antibodies, anti-citrullin antibodies, and IgM and IgA rheumatoid factors with serological parameters of disease activity in rheumatoid arthritis. Ann N Y Acad Sci 1050:295–303PubMedCrossRefGoogle Scholar
  24. 24.
    Raza K, Breese M, Nightingale P et al (2005) Predictive value of antibodies to cyclic citrullinated peptides in patients with very early inflammatory arthritis. J Rheumatol 32:231–238PubMedGoogle Scholar
  25. 25.
    Solbritt RD, Ben AWJ, Berglin E, Hallmans G et al (2003) Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 48:2741–2749CrossRefGoogle Scholar
  26. 26.
    Svärd A, Kastbom A, Reckner-Olsson A, Skogh T (2008) Presence and utility of IgA-class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis: the Swedish TIRA project. Arthritis Res Ther 10:R75PubMedCrossRefGoogle Scholar
  27. 27.
    Serdaroglu M, Cakirbay H, Defer O, Cengiz S, Kul S (2008) The association of anti-CCP antibodies with disease activity in rheumatoid arthritis. Rheumatol Int 28:965–970PubMedCrossRefGoogle Scholar
  28. 28.
    Mathson L, Mullazei M, Wick MC et al (2008) Antibodies against citrullinated vimentin in rheumatoid arthritis: higher sensitivity and extended prognostic value concerning future radiographic progression as compared with antibodies against cyclic citrullinated peptides. Arthritis Rheum 58:36–45CrossRefGoogle Scholar
  29. 29.
    Ursum J, Nielen MMJ, van Schaardenburg D, van der Horst AR, van de Stadt RJ, Dijkmans BA (2008) Antibodies to mutated citrullinated vimentin and disease activity score in early arthritis: a cohort study. Arthritis Res Ther 10:R12PubMedCrossRefGoogle Scholar
  30. 30.
    Innala L, Kokkonen H, Ericsson C, Jidell E, Berglin E, Rantapää-Dahlqvist S (2008) Antibodies against mutated citrullinated vimentin are a better predictor of disease activity at 24 months in early rheumatoid arthritis than antibodies against cyclic citrullinated peptides. J Rheumatol 5:1002–1008Google Scholar
  31. 31.
    Ursum J, Nielen MMJ, Schaardenburg DV, van der Horst AR, van de Stadt RJ, Dijkmans BA (2008) Antibodies to mutated citrullinated vimentin and disease activity score in early arthritis: a cohort study. Arthritis Res Ther 10:1–6CrossRefGoogle Scholar
  32. 32.
    Cordonnier C, Meyer O, Palazzo E, De Bandt M, Elias A, Nicaise P et al (1996) Diagnostic value of anti-RA33 antibody, antikeratin antibody, antiperinuclear factor and antinuclear antibody in early rheumatoid arthritis: comparison with rheumatoid factor. Br J Rheumatol 35:620–624PubMedCrossRefGoogle Scholar
  33. 33.
    Vittecoq O, Incaurgarat B, Jouen-Beades F et al (2004) Autoantibodies recognizing citrullinated rat filaggrin in an ELISA using citrullinated and non-citrullinated recombinant proteins as antigens are highly diagnostic for rheumatoid arthritis. Clin Exp Rheumatol 135:173–180Google Scholar
  34. 34.
    Nielen MM, van der Horst AR, van Schaardenburg D et al (2005) Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis. Ann Rheum Dis 64:1199–1204PubMedCrossRefGoogle Scholar
  35. 35.
    Graudal N, Svenson M, Tarp U, Garred P, Jurik A, Bendtzen K (2002) Autoantibodies against interleukin-1 alfa in rheumatoid arthritis: association with long-term radiographic outcome. Ann Rheum Dis 61:598–602PubMedCrossRefGoogle Scholar
  36. 36.
    Saulot V, Vittecoq O, Charlionet R et al (2002) Presence of autoantibodies to the glycolytic enzyme alpha-enolase in sera from patients with early rheumatoid arthritis. Arthritis Rheum 46:1196–1201PubMedCrossRefGoogle Scholar
  37. 37.
    Newkirk MM, Goldbach-Mansky R, Lee J et al (2003) Advanced glycation end-product (AGE)-damaged IgG and IgM autoantibodies to IgG-AGE in patients with early synovitis. Arthritis Res Ther 5:R82–90PubMedCrossRefGoogle Scholar
  38. 38.
    Garnero P, Delmas PD (2004) Noninvasive techniques for assessing skeletal changes in inflammatory arthritis: bone biomarkers. Curr Opin Rheumatol 16:428–434PubMedCrossRefGoogle Scholar
  39. 39.
    Mohammed F, Smookler D, Khokha R (2003) Metalloproteinases, inflammation, and rheumatoid arthritis. Ann Rheum Dis 62:43–47CrossRefGoogle Scholar
  40. 40.
    Jensen T, Klarlund M, Hansen M (2004) Connective tissue metabolism in patients with unclassified polyarthritis and early rheumatoid arthritis. Relationship to disease activity, bone mineral density and radiographic outcomes. J Rheumatol 31:1698–1708PubMedGoogle Scholar
  41. 41.
    Posthumus MD, Limburg PC, Westra J, van Leeuwen MA, van Rijswijk MH (2000) Serum matrix metalloproteinase 3 in with early rheumatoid arthritis is correlated with disease activity and radiological progression. J Rheumatol 27:2761–2768PubMedGoogle Scholar
  42. 42.
    Posthumus MD, Limburg PC, Westra J, van Leeuwen MA, van Rijswijk MH (2003) Serum matrix metalloproteinase 3 levels in comparison to C-reactive protein in periods of radiological damage in patients with early rheumatoid arthritis. Clin Exp Rheumatol 21:465–472PubMedGoogle Scholar
  43. 43.
    Green MJ, Gough AKS, Devlin J, Smith J, Astin P, Taylor D (2003) Serum MMP-3 and MMP-1 and progression of joint damage in early rheumatoid arthritis. Rheumatology (Oxford) 42:83–88CrossRefGoogle Scholar
  44. 44.
    Majeed M, McQueen F, Yeoman S, McLean L (2004) Relationship between serum hyaluronic acid level and disease activity in early rheumatoid arthritis. Ann Rheum Dis 63:1166–1168PubMedCrossRefGoogle Scholar
  45. 45.
    Garnero P, Landewé R, Boers M et al (2002) Association of baseline levels of markers of bone and cartilage degradation with long-term progression of joint damage in patients with early rheumatoid arthritis: the COBRA study. Arthritis Rheum 46:2847–2856PubMedCrossRefGoogle Scholar
  46. 46.
    Landewé R, Geusens P, Boers M, van der Heijde D, Lems W, te Koppele J (2004) Markers for type II collagen breakdown predict the effect of disease modifying treatment on long-term radiographic progression in patients with rheumatoid arthritis. Arthritis Rheum 50:1390–1399PubMedCrossRefGoogle Scholar
  47. 47.
    Landewé RB, Geusens P, van der Heijde DM, Boers M, van der Linden SJ, Garnero P (2006) Arthritis instantaneously causes collagen type I and type II degradation in patients with early rheumatoid arthritis: a longitudinal analysis. Ann Rheum Dis 65:40–44PubMedCrossRefGoogle Scholar
  48. 48.
    Charni N, Juillet F, Garnero P (2005) Urinary type II collagen helical peptide (HELIX-II) as a new biochemical marker of cartilage degradation in patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum 52:1081–1090PubMedCrossRefGoogle Scholar
  49. 49.
    Jansen LMA, van der Horst-Bruinsma IE, Lems WF (2004) Serological bone markers and joint damage in early polyarthritis. J Rheumatol 31:1491–1496PubMedGoogle Scholar
  50. 50.
    Forslind K, Eberhardt K, Jonsson A, Saxne T (1992) Increased serum concentrations of cartilage oligomeric matrix protein. A prognostic marker in early rheumatoid arthritis. Br J Rheumatol 31:593–598PubMedCrossRefGoogle Scholar
  51. 51.
    Soderlin MK, Kastbom A, Kautiainen H, Leirisalo-Repo M, Strandberg G, Skogh T (2004) Antibodies against cyclic citrullinated peptide (CCP) and levels of cartilage oligomeric matrix protein (COMP) in very early arthritis: relation to diagnosis and disease activity. Scand J Rheumatol 33:185–188PubMedCrossRefGoogle Scholar
  52. 52.
    Crnkic M, Månsson B, Larsson L, Geborek P, Heinegård D, Saxne T (2003) Serum cartilage oligomeric matrix protein (COMP) decreases in rheumatoid arthritis patients treated with infliximab or etanercept. Arthritis Res Ther 5:R181–R185PubMedCrossRefGoogle Scholar
  53. 53.
    György B, Tóthfalusi L, Nagy G et al (2008) Natural autoantibodies reactive with glycosaminoglycans in rheumatoid arthritis. Arthritis Res Ther 10:R110PubMedCrossRefGoogle Scholar
  54. 54.
    Morgante M, Di Munno O, Morgante D (1999) YKL 40: marker of disease activity in rheumatoid arthritis? Minerva Med 90:437–441PubMedGoogle Scholar
  55. 55.
    Johansen JS, Stoltenberg M, Hansen M et al (1999) Serum YKL-40 concentrations in patients with rheumatoid arthritis: relation to disease activity. Rheumatology (Oxford) 38:618–626CrossRefGoogle Scholar
  56. 56.
    Matsumoto T, Tsurumoto T (2001) Serum YKL-40 levels in rheumatoid arthritis: correlations between clinical and laboratory parameters. Clin Exp Rheumatol 19:655–660PubMedGoogle Scholar
  57. 57.
    Jäälinoja J, Nissilä M, Kauppi MJ et al (2008) Serum antibodies against intact human collagen IX are elevated at onset of rheumatoid arthritis but are not related to development of erosions. J Rheumatol 35:745–751PubMedGoogle Scholar
  58. 58.
    Saevarsdottir S, Vikingsdottir T, Vikingsson A, Manfredsdottir V, Geirsson AJ, Hl V (2001) Low mannose binding lectin predicts poor prognosis in patients with early rheumatoid arthritis. A prospective study. J Rheum 28:728–734PubMedGoogle Scholar
  59. 59.
    Grauldal N (2004) The natural history and prognosis of rheumatoid arthritis: association of radiographic outcome with process variables, joint motion and immune proteins. Scand J Rheumatol Suppl 118:1–38CrossRefGoogle Scholar
  60. 60.
    Kuuliala A, Eberhardt K, Takala A, Kautiainen H, Repo H, Leirisalo-Repo M (2002) Circulating soluble E-selectin in early rheumatoid arthritis: a prospective five year study. Ann Rheum Dis 61:242–246PubMedCrossRefGoogle Scholar
  61. 61.
    Corona-Sanchez EG, Gonzalez-Lopez L, Muñoz-Valle JF et al (2009) Circulating E-selectin and tumor necrosis factor-alpha in extraarticular involvement and joint disease activity in rheumatoid arthritis. Rheumatol Int 29:281–286PubMedCrossRefGoogle Scholar
  62. 62.
    Klimiuk PA, Sierakowski S, Domysławska I, Fiedorczyk M, Chwiećko J (2004) Reduction of soluble adhesion molecules (sICAM-1, sVCAM-1, and sE-selectin) and vascular endothelial growth factor levels in serum of rheumatoid arthritis patients following multiple intravenous infusions of infliximab. Arch Immunol Ther Exp (Warsz) 52:36–42Google Scholar
  63. 63.
    Sugiyama E, Kuroda A, Hori F, Hori T, Taki H, Arai N (1995) Serum Interleukin-6 level is a sensitive parameter of disease activity in rheumatoid arthritis. J Clin Rheumatol 1:93–98PubMedCrossRefGoogle Scholar
  64. 64.
    Madhok R, Crilly A, Watson J, Capell HA (1993) Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis 52:232–234PubMedCrossRefGoogle Scholar
  65. 65.
    Targońska-Stepniak B, Majdan M, Dryglewska M (2008) Leptin serum levels in rheumatoid arthritis patients: relation to disease duration and activity. Rheumatol Int 28:585–591PubMedCrossRefGoogle Scholar
  66. 66.
    Seven A, Güzel S, Aslan M, Hamuryudan V (2009) Serum and synovial fluid leptin levels and markers of inflammation in rheumatoid arthritis. Rheumatol Int 29(7):743–747PubMedCrossRefGoogle Scholar
  67. 67.
    Gunaydin R, Kaya T, Atay A, Olmez N, Hur A, Koseoglu M (2006) Serum leptin levels in rheumatoid arthritis and relationship with disease activity. South Med J 99:1078–1083PubMedGoogle Scholar
  68. 68.
    Hizmetli S, Kisa M, Gokalp N, Bakici MZ (2007) Are plasma and synovial fluid leptin levels correlated with disease activity in rheumatoid arthritis? Rheumatol Int 27:335–338PubMedCrossRefGoogle Scholar

Copyright information

© Clinical Rheumatology 2009

Authors and Affiliations

  • Licia Maria Henrique da Mota
    • 1
  • Leopoldo Luiz dos Santos Neto
    • 1
  • Jozélio Freire de Carvalho
    • 2
    • 3
    Email author
  1. 1.Department of RheumatologyBrasília University HospitalBrasíliaBrazil
  2. 2.Department of RheumatologyUniversity of São Paulo School of MedicineSão PauloBrazil
  3. 3.Disciplina de Reumatologia da FMUSPCerqueira CésarBrazil

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