Skip to main content

Is rheumatoid factor still a superior test for the diagnosis of rheumatoid arthritis?

Abstract

The diagnosis of rheumatoid arthritis (RA) is based primarily on the 1987 revised American College of Rheumatology criteria for RA, which considers mainly the clinical symptoms. But typical clinical symptoms of RA are not manifested completely in early disease course. On the other hand, appreciable advantages have been made in the therapeutic strategy of RA in the last decade and highly effective disease-modifying anti-rheumatic drugs are available now for the control of RA. The treatment strategy for the control of early RA is aggressive. Thus, a highly specific and early diagnostic marker is needed for the detection of RA. Our study is an attempt to see the role of anti-CCP2 antibody (claimed to be highly specific and early diagnostic tool) in the diagnosis of RA. We studied 119 cases of RA in terms of clinical symptoms, disease duration and various autoantibody [including rheumatoid factor (RF), anti-CCP2 antibody, antinuclear antibody, anti-dsDNA] and C-reactive protein status. All the tests were also performed in 26 age and sex-matched healthy controls. Estimation of antibodies was done by quantitative ELISA. IgM RF was positive in 47.89% cases (p value = 0.000), followed by IgG RF (42.01%, p = 0.000) and IgA RF (36.97%, p = 0.000). RF was positive in 64.7% RA cases (p value = 0.000) when all three isotypes were tested together. RF was also detected in one healthy control. In 92 cases, anti-CCP2 Ab was done, hence other data were analyzed further in 92 cases only. Anti-CCP2 Ab was positive (cut-off = 15.0 U/ml) in only 50% RA patients but none of the healthy controls was positive for it. Swelling of joints was seen in 82.6% anti-CCP2 Ab positive cases (p value = 0.092) when compared with anti-CCP2 Ab negative cases (67.4%) while among RF positive cases, only 65.4% ((p value = 0.010) cases had swelling of joints. Out of 39 RA cases presenting with disease duration less than 1 year, only 48.71% patients were anti-CCP2 Ab positive while RF was positive in 61.53% patients. Utility of various combined autoantibody tests revealed that if one does all isotypes of RF (IgG, IgA and IgM) only, then 64.7% RA cases can be diagnosed and if anti-CCP2 Ab is added to it, the sensitivity increases to 75.56%. Thus, our study concludes that anti-CCP2 Ab is not a sensitive test for the diagnosis of RA neither it is useful in early diagnosis of RA, but it increases the sensitivity if added with all RF isotypes.

This is a preview of subscription content, access via your institution.

References

  1. Vasishta A (2002) Diagnosing early-onset rheumatoid arthritis: the role of anti-CCP antibodies. Am Clin Lab 21(7):34–36

    CAS  PubMed  Google Scholar 

  2. Kvien TK (2002) Epidemiology of disability in rheumatoid arthritis. Rheumatology (Oxford) 41:121–123

    Article  CAS  Google Scholar 

  3. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31(3):315–324

    Article  CAS  PubMed  Google Scholar 

  4. Visser H, Cessie Le, Vos K, Breedveld FC, Hazes JM (2002) How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive) arthritis. Arthritis Rheum 46:357–365

    Article  PubMed  Google Scholar 

  5. Machold KP, Stamm TA, Eberl GJ, Nell VK, Dunky A, Uffmann M, Smolen JS (2002) Very recent onset arthritis- clinical, laboratory and radiological findings during the first year of disease. J Rheumatol 29:2278–2287

    PubMed  Google Scholar 

  6. Emery P, Breedveld FC, Dougados M, Kalden JR, Schiff MH, Smolen JS (2002) Early referral recommendation for newly diagnosed rheumatoid arthritis: evidence based development of a clinical guide. Ann Rheum Dis 61:290–297

    Article  CAS  PubMed  Google Scholar 

  7. Bukhari MA, Wiles NJ, Lunt M, Harrison BJ, Scott DG, Symmons DP, Silman AJ (2003) Influence of disease modifying therapy on radiographic outcome in inflammatory polyarthritis at five years: results from a large observational inception study. Arthritis Rheum 48:46–53

    Article  CAS  PubMed  Google Scholar 

  8. Landewe RB (2003) The benefits of early treatment in rheumatoid arthritis: confounding by indication, and the issue of timing. Arthritis Rheum 48:1–5

    Article  PubMed  Google Scholar 

  9. Lard LR, Visser H, Speyer I, van der Horst-Bruinsma IE, Zwinderman AH, Breedveld FC, Hazes JM (2001) Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies. Am J Med 111:446–451

    Article  CAS  PubMed  Google Scholar 

  10. Lisse JR (1993) Does rheumatoid factor always mean arthritis? Postgrad Med 94(6):133–134, 139

    CAS  PubMed  Google Scholar 

  11. Hoet RM, van Venrooij WJ (1992) The antiperinuclear factor (APF) and antikeratin antibodies (AKA) in rheumatoid arthritis. In: Smolen JS, Kalden JR, Maini RN (eds) Rheumatoid arthritis. Springer, Berlin, pp 299–318

    Google Scholar 

  12. Schellekens GA, Visser H, de Jong BAW, van den Hoogen FH, Hazes JM, Breedveld FC, van Venrooij WJ (2000) The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 43:155–163

    Article  CAS  PubMed  Google Scholar 

  13. Bizzaro N, Mazzanti G, Tonutti E, Vellalta D, Tozzoli R (2001) Diagnostic accuracy of the anti-citrulline antibody assay for rheumatoid arthritis. Clin Chem 47:1089–1093

    CAS  PubMed  Google Scholar 

  14. Girbal NE, Durieux JJ, Arnaud M, Dalbon P, Sebbag M et al (1999) The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J Immunol 162(1):585–594

    Google Scholar 

  15. Van Venrooij WJ, Van Beers JJBC, Pruijn GJM (2008) Anti-CCP antibody, a marker for the early detection of rheumatoid arthritis. Ann N Y Acad Sci 1143:268–285

    Article  PubMed  Google Scholar 

  16. Hill JA, Southwood S, Sette A, Jevinkar AM, Bell DA, Cairns E (2003) Cutting edge: the conversion of arginine to citrulline allows for a high affinity peptide interaction with the rheumatoid arthritis associated HLA-DRB1*0401 MHC class II molecule. J Immunol 171:538–541

    CAS  PubMed  Google Scholar 

  17. Vallbracht I, Rieber J, Oppermann M et al (2004) Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis. Ann Rheum Dis 63:1079–1084

    Article  CAS  PubMed  Google Scholar 

  18. Lee DM, Schur PH (2003) Clinical utility of the anti-CCP assay in patients with rheumatic diseases. Ann Rheum Dis 62:870–874

    Article  CAS  PubMed  Google Scholar 

  19. Pinheiro GC, Scheinberg MA, Aparecida DS, Maciel S (2003) Anti-cyclic citrullinated peptide antibodies in advanced rheumatoid arthritis. Ann Intern Med 139:234–235

    PubMed  Google Scholar 

  20. van Boekel MA, Vossenaar ER, van Den Hoogen FH, van Venrooij WJ (2001) Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value. Arthritis Res 4:87–93

    Article  PubMed  Google Scholar 

  21. Meyer O (2003) Evaluating inflammatory joint disease: how and when can autoantibodies help? Joint Bone Spine 70:433–447

    Article  PubMed  Google Scholar 

  22. Goldbach-Mansky R, Lee J, McCoy A, Hoxworth J, Yarboro C et al (2000) Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset. Arthritis Res 2:236–243

    Article  CAS  PubMed  Google Scholar 

  23. Bas S, Perneger TV, Seitz M, Tiercy JM, Roux-Lombard P, Guerne PA (2002) Diagnostic tests for rheumatoid arthritis: comparison of anti-cyclic citrullinated peptide antibodies, anti-keratin antibodies and IgM rheumatoid factors. Rheumatology (oxford) 41:809–814

    Article  CAS  Google Scholar 

  24. de Rycke L, Peene I, Hoffman IEA, Kruithof E, Union A, Meheus L et al (2004) Rheumatoid factor and anti-citrullinated protein antibodies in rheumatoid arthritis: diagnostic value, associations with radiological progression rate, and extra-articular manifestations. Ann Rheum Dis 63:1587–1593

    Article  PubMed  Google Scholar 

  25. Dubucquoi S, Solau-Gervais E, Lefranc D, Marquerie L, Sibilia J et al (2004) Evaluation of anti-citrullinated fillagrin antibodies as hallmarks for the diagnosis of rheumatic diseases. Ann Rheum Dis 63:415–419

    Article  CAS  PubMed  Google Scholar 

  26. Lindqvist E, Eberhardt K, Bendtzen K, Heinegard D, Saxne T (2005) Prognostic laboratory markers of joint damage in rheumatoid arthritis. Ann Rheum Dis 64:196–201

    Article  CAS  PubMed  Google Scholar 

  27. Kastbom A, Strandberg G, Lindroos A, Skogh T (2004) Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project). Ann Rheum Dis 63:1085–1089

    Article  CAS  PubMed  Google Scholar 

  28. van Venrooij WJ, Zendman AJ, Pruijn GJ (2006) Autoantibodies to citrullinated antigens in (early) rheumatoid arthritis. Autoimmun Rev 6:37–41

    Article  PubMed  Google Scholar 

  29. Vallbracht I, Helmke K (2005) Additional diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis. Autoimmun Rev 4(6):389–394

    Article  CAS  PubMed  Google Scholar 

  30. Ranatapaa-Dahlqvist S, de Jong BAW, Berglin E, Hallmans G, Wadell G (2003) Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 48:2741–2749

    Article  Google Scholar 

  31. Nielen MM, van Schaardenberg D, Reesink HW, van de Stadt RJ, van der Horst-Bruinsma IE, de Koning MH et al (2004) Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 50:380–386

    Article  PubMed  Google Scholar 

  32. Kroot EJ, de Jong BA, Van Leeuwen MA, van den Hoogen FH, van’t Hof M et al (2000) The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent onset rheumatoid arthritis. Arthritis Rheum 43:1831–1835

    Article  CAS  PubMed  Google Scholar 

  33. Meyer O, Labarre C, Dougados M, Goupille P, Cantagrel A et al (2003) Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage. Ann Rheum Dis 62:120–126

    Article  CAS  PubMed  Google Scholar 

  34. Ronnelid J, Wick MC, Lampa J, Lindblad S, Nordmark B et al (2005) Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 years follow-up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression. Ann Rheum Dis 64:1744–1749

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Anjali Vishwanath.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Singh, U., Vishwanath, A., Verma, P.K. et al. Is rheumatoid factor still a superior test for the diagnosis of rheumatoid arthritis?. Rheumatol Int 30, 1115–1119 (2010). https://doi.org/10.1007/s00296-009-1338-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-009-1338-0

Keywords

  • Anti-CCP2 Ab
  • Rheumatoid arthritis
  • RF