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Ann Rheum Dis. Aug 2005; 64(8): 1199–1204.
Published online Jan 7, 2005. doi:  10.1136/ard.2004.029389
PMCID: PMC1755615

Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis

Abstract

Background: The anti-cyclic citrullinated peptide (CCP) test has a high sensitivity and specificity for rheumatoid arthritis, although CCP is not the physiological target of the autoantibodies. Citrullinated fibrin is abundant in inflamed synovium

Objective: To assess the diagnostic and prognostic value of antibodies against citrullinated fibrinogen (ACF), a soluble precursor of fibrin, in comparison with IgM-rheumatoid factor (IgM-RF) and the second generation anti-CCP test.

Methods: In 379 patients with early arthritis (258 rheumatoid and 121 undifferentiated), the sensitivity, specificity, and positive predictive value of ACF, anti-CCP, and IgM-RF for diagnosing rheumatoid arthritis were calculated. Multivariate logistic regression analysis was used to assess the diagnostic and prognostic value (radiographic progression after two years) of the tests.

Results: The sensitivities of the ACF, anti-CCP, and IgM-RF tests were 55.8%, 57.8%, and 44.6%, with specificities of 92.6%, 94.2%, and 96.7%, respectively. Approximately 30% of the IgM-RF negative patients were positive for ACF or anti-CCP or both. The ACF and anti-CCP test had a high agreement in early arthritis (κ = 0.84). Of all baseline characteristics, the ACF test and the anti-CCP test were the best predictors for diagnosing rheumatoid arthritis at one year (odds ratio (OR) = 10.3 and 10.6, respectively) and for radiographic progression after two years (OR = 12.1 and 14.8).

Conclusions: ACF is as sensitive as anti-CCP and more sensitive than IgM-RF in diagnosing rheumatoid arthritis in early arthritis. The ACF test is also a good predictor of radiographic progression, with a performance similar to the anti-CCP test. The ACF test and the anti-CCP test are especially valuable in IgM-RF negative arthritis.

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Selected References

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  • Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. [PubMed]
  • Saraux A, Berthelot JM, Chalès G, Le Henaff C, Thorel JB, Hoang S, Valls I, Devauchelle V, Martin A, Baron D, et al. Ability of the American College of Rheumatology 1987 criteria to predict rheumatoid arthritis in patients with early arthritis and classification of these patients two years later. Arthritis Rheum. 2001 Nov;44(11):2485–2491. [PubMed]
  • Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1998 Jan 1;101(1):273–281. [PMC free article] [PubMed]
  • Schellekens GA, Visser H, de Jong BA, van den Hoogen FH, Hazes JM, Breedveld FC, van Venrooij WJ. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 2000 Jan;43(1):155–163. [PubMed]
  • Zendman Albert J W, Vossenaar Erik R, van Venrooij Walther J. Autoantibodies to citrullinated (poly)peptides: a key diagnostic and prognostic marker for rheumatoid arthritis. Autoimmunity. 2004 Jun;37(4):295–299. [PubMed]
  • van Venrooij WJ, Hazes JM, Visser H. Anticitrullinated protein/peptide antibody and its role in the diagnosis and prognosis of early rheumatoid arthritis. Neth J Med. 2002 Nov;60(10):383–388. [PubMed]
  • Goldbach-Mansky R, Lee J, McCoy A, Hoxworth J, Yarboro C, Smolen JS, Steiner G, Rosen A, Zhang C, Ménard HA, et al. Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset. Arthritis Res. 2000;2(3):236–243. [PMC free article] [PubMed]
  • Kroot EJ, de Jong BA, van Leeuwen MA, Swinkels H, van den Hoogen FH, van't Hof M, van de Putte LB, van Rijswijk MH, van Venrooij WJ, van Riel PL. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 2000 Aug;43(8):1831–1835. [PubMed]
  • Visser Henk, le Cessie Saskia, Vos Koen, Breedveld Ferdinand C, Hazes Johanna M W. How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive) arthritis. Arthritis Rheum. 2002 Feb;46(2):357–365. [PubMed]
  • Jansen Annemarie L M A, van der Horst-Bruinsma Irene, van Schaardenburg Dirkjan, van de Stadt Rob J, de Koning Margret H M T, Dijkmans Ben A C. Rheumatoid factor and antibodies to cyclic citrullinated Peptide differentiate rheumatoid arthritis from undifferentiated polyarthritis in patients with early arthritis. J Rheumatol. 2002 Oct;29(10):2074–2076. [PubMed]
  • Vencovský J, Machácek S, Sedová L, Kafková J, Gatterová J, Pesáková V, Růzicková S. Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis. Ann Rheum Dis. 2003 May;62(5):427–430. [PMC free article] [PubMed]
  • Baeten D, Peene I, Union A, Meheus L, Sebbag M, Serre G, Veys EM, De Keyser F. Specific presence of intracellular citrullinated proteins in rheumatoid arthritis synovium: relevance to antifilaggrin autoantibodies. Arthritis Rheum. 2001 Oct;44(10):2255–2262. [PubMed]
  • Reparon-Schuijt CC, van Esch WJ, van Kooten C, Schellekens GA, de Jong BA, van Venrooij WJ, Breedveld FC, Verweij CL. Secretion of anti-citrulline-containing peptide antibody by B lymphocytes in rheumatoid arthritis. Arthritis Rheum. 2001 Jan;44(1):41–47. [PubMed]
  • Masson-Bessière C, Sebbag M, Durieux JJ, Nogueira L, Vincent C, Girbal-Neuhauser E, Durroux R, Cantagrel A, Serre G. In the rheumatoid pannus, anti-filaggrin autoantibodies are produced by local plasma cells and constitute a higher proportion of IgG than in synovial fluid and serum. Clin Exp Immunol. 2000 Mar;119(3):544–552. [PMC free article] [PubMed]
  • Masson-Bessière C, Sebbag M, Girbal-Neuhauser E, Nogueira L, Vincent C, Senshu T, Serre G. The major synovial targets of the rheumatoid arthritis-specific antifilaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. J Immunol. 2001 Mar 15;166(6):4177–4184. [PubMed]
  • Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum. 1980 Feb;23(2):137–145. [PubMed]
  • Nogueira L, Sebbag M, Vincent C, Arnaud M, Fournié B, Cantagrel A, Jolivet M, Serre G. Performance of two ELISAs for antifilaggrin autoantibodies, using either affinity purified or deiminated recombinant human filaggrin, in the diagnosis of rheumatoid arthritis. Ann Rheum Dis. 2001 Sep;60(9):882–887. [PMC free article] [PubMed]
  • Nissinen R, Paimela L, Julkunen H, Tienari PJ, Leirisalo-Repo M, Palosuo T, Vaarala O. Peptidylarginine deiminase, the arginine to citrulline converting enzyme, is frequently recognized by sera of patients with rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren syndrome. Scand J Rheumatol. 2003;32(6):337–342. [PubMed]
  • Bruynesteyn Karin, van der Heijde Désirée, Boers Maarten, Saudan Ariane, Peloso Paul, Paulus Harold, Houben Harry, Griffiths Bridget, Edmonds John, Bresnihan Barry, et al. Determination of the minimal clinically important difference in rheumatoid arthritis joint damage of the Sharp/van der Heijde and Larsen/Scott scoring methods by clinical experts and comparison with the smallest detectable difference. Arthritis Rheum. 2002 Apr;46(4):913–920. [PubMed]
  • van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, de Jong BA, Breedveld FC, Verweij CL, Toes REM, Huizinga TWJ. Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study. Arthritis Rheum. 2004 Mar;50(3):709–715. [PubMed]
  • Meyer O, Labarre C, Dougados M, Goupille Ph, Cantagrel A, Dubois A, Nicaise-Roland P, Sibilia J, Combe B. Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage. Ann Rheum Dis. 2003 Feb;62(2):120–126. [PMC free article] [PubMed]
  • Jansen Louise M A, van Schaardenburg Dirkjan, van der Horst-Bruinsma Irene, van der Stadt Rob J, de Koning Margret H M T, Dijkmans Ben A C. The predictive value of anti-cyclic citrullinated peptide antibodies in early arthritis. J Rheumatol. 2003 Aug;30(8):1691–1695. [PubMed]
  • Forslind K, Ahlmén M, Eberhardt K, Hafström I, Svensson B. Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: role of antibodies to citrullinated peptides (anti-CCP). Ann Rheum Dis. 2004 Sep;63(9):1090–1095. [PMC free article] [PubMed]
  • Doyle HA, Mamula MJ. Post-translational protein modifications in antigen recognition and autoimmunity. Trends Immunol. 2001 Aug;22(8):443–449. [PubMed]
  • Monneaux Fanny, Muller Sylviane. Epitope spreading in systemic lupus erythematosus: identification of triggering peptide sequences. Arthritis Rheum. 2002 Jun;46(6):1430–1438. [PubMed]
  • Aho K, Heliövaara M, Maatela J, Tuomi T, Palosuo T. Rheumatoid factors antedating clinical rheumatoid arthritis. J Rheumatol. 1991 Sep;18(9):1282–1284. [PubMed]
  • Rantapä-Dahlqvist Solbritt, de Jong Ben A W, Berglin Ewa, Hallmans Göran, Wadell Göran, Stenlund Hans, Sundin Ulf, van Venrooij Walther J. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003 Oct;48(10):2741–2749. [PubMed]
  • Nielen Markus M J, van Schaardenburg Dirkjan, Reesink Henk W, van de Stadt Rob J, van der Horst-Bruinsma Irene E, de Koning Margret H M T, Habibuw Moud R, Vandenbroucke Jan P, Dijkmans Ben A C. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004 Feb;50(2):380–386. [PubMed]
  • Hill Jonathan A, Southwood Scott, Sette Alessandro, Jevnikar Anthony M, Bell David A, Cairns Ewa. 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. 2003 Jul 15;171(2):538–541. [PubMed]

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