Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter February 13, 2006

Diagnosis and prognosis of early rheumatoid arthritis, with special emphasis on laboratory analysis

Rudolf Mierau and Ekkehard Genth


Diagnosis of rheumatoid arthritis (RA) is mainly based on clinical criteria of symmetric polyarthritis of the hands and feet, with morning stiffness lasting usually more than 1h. Autoantibodies typical for RA, i.e., rheumatoid factors and anti-cyclic citrullinated peptide, and measurements of inflammation add more specific information, especially for early diagnosis, where clinical presentation may be oligosymptomatic involving only a few joints. These laboratory parameters are also relevant for prognosis of disease persistence, functional impairment and radiological progression.

Corresponding author: Dr. rer. nat. Rudolf Mierau, Labor an der Rheumaklinik Aachen, Burtscheider Markt 24, 52066 Aachen, Germany Phone: +49-241-6096-4077/4060, Fax: +49-241-6096-1964, ,


1. Emery P, Breedveld FC, Dougados M, Kalden JR, Schiff MH, Smolen JS. Early referral recommendation for newly diagnosed rheumatoid arthritis: evidence based development of a clinical guide. Ann Rheum Dis 2002; 61:290–7.10.1136/ard.61.4.290Search in Google Scholar

2. Scott DL. Prognostic factors in early rheumatoid arthritis. Rheumatology 2000; 39(Suppl 1):24–9.10.1093/oxfordjournals.rheumatology.a031490Search in Google Scholar

3. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31:315–24.10.1002/art.1780310302Search in Google Scholar

4. Caruso I, Santandrea S, Sarzi-Puttini P, Boccassini L, Montrone F, Cazzola M, et al. Clinical, laboratory and radiographic features in early rheumatoid arthritis. J Rheumatol 1990; 17:1263–7.Search in Google Scholar

5. Plant MJ, Jones PW, Saklatvala J, Ollier WE, Dawes PT. Patterns of radiological progression in early rheumatoid arthritis: results of an 8year prospective study. J Rheumatol 1998; 25:417–26.Search in Google Scholar

6. Bukhari M, Harrison B, Lunt M, Scott DG, Symmons DP, Silman AJ. Time to first occurrence of erosions in inflammatory polyarthritis: results from a prospective community-based study. Arthritis Rheum 2001; 44:1248–53.10.1002/1529-0131(200106)44:6<1248::AID-ART215>3.0.CO;2-8Search in Google Scholar

7. Visser H, le Cessie S, Vos K, Breedveld FC, Hazes JM. How to diagnose rheumatoid arthritis early – a prediction model for persistent (erosive) arthritis. Arthritis Rheum 2002; 46:357–65.10.1002/art.10117Search in Google Scholar

8. Kim JM, Weisman MH. When does rheumatoid arthritis begin and why do we need to know? Arthritis Rheum 2000; 43:473–84.10.1002/1529-0131(200003)43:3<473::AID-ANR1>3.0.CO;2-ASearch in Google Scholar

9. Paget SA. The no man's land of undifferentiated inflammatory polyarthritis. J Rheumatol 2004; 31:1673–5.Search in Google Scholar

10. van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, de Jong BA, Breedveld FC, Verweij CL, et al. Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis – a prospective cohort study. Arthritis Rheum 2004; 50:709–15.10.1002/art.20044Search in Google Scholar

11. Raza K, Breese M, Nightingale P, Kumar K, Potter T, Carruthers DM, et al. Predictive value of antibodies to cyclic citrullinated peptide in patients with very early inflammatory arthritis. J Rheumatol 2005; 32:231–8.Search in Google Scholar

12. Keitel W, Genth E, Gromnica-Ihle E, Häntzschel H, Kalden JR, Mathies H, et al. Leitlinie für das Symptom Gelenkschwellung – Primärärztliches Problemmanagement und Überweisungsindikationen. Z Rheumatol 2000; 59:151–61.10.1007/s003930070075Search in Google Scholar

13. Genth E, Gromnica-Ihle E, Häntzschel H, Kalden JR, Keitel W, Mathies H, et al. Qualitätssicherung in der Rheumatologie. Darmstadt: Steinkopf, 2000.Search in Google Scholar

14. Schellekens GA, deJong 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; 101:273–81.10.1172/JCI1316Search in Google Scholar

15. Schellekens GA, Visser H, deJong BA, van den Hoogen FH, Hazes JM, Breedveld FC, et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 2000; 43:155–63.10.1002/1529-0131(200001)43:1<155::AID-ANR20>3.0.CO;2-3Search in Google Scholar

16. Vincent C, Nogueira L, Sebbag M, Chapuy-Regaud S, Arnaud M, Letourneur O, et al. Detection of antibodies to deiminated recombinant rat filaggrin by enzyme-linked immunosorbent assay: a highly effective test for the diagnosis of rheumatoid arthritis. Arthritis Rheum 2002; 46:2051–8.10.1002/art.10436Search in Google Scholar

17. Vittecoq O, Incaurgarat B, Jouen-Beades F, Legoedec J, Letourneur O, Rolland D, et al. 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 Immunol 2004; 135:173–80.10.1111/j.1365-2249.2004.02341.xSearch in Google Scholar

18. Bizzaro N, Mazzanti G, Tonutti E, Villalta D, Tozzoli R. Diagnostic accuracy of the anti-citrulline antibody assay for rheumatoid arthritis. Clin Chem 2001; 47:1089–93.10.1093/clinchem/47.6.1089Search in Google Scholar

19. Avcin T, Cimaz R, Falcini F, Zulian F, Martini G, Simonini G, et al. Prevalence and clinical significance of anti-cyclic citrullinated peptide antibodies in juvenile idiopathic arthritis. Ann Rheum Dis 2002; 61:608–11.10.1136/ard.61.7.608Search in Google Scholar

20. Hromadnikova I, Stechova K, Vavrincova P, Hridelova D, Houbova B, Voslarova S, et al. Anti-cyclic citrullinated peptide antibodies in patients with juvenile idiopathic arthritis. Autoimmunity 2002; 35:397–401.10.1080/0891693021000014970Search in Google Scholar

21. Lee DM, Schur PH. Clinical utility of the anti-CCP assay in patients with rheumatic diseases. Ann Rheum Dis 2003; 62:870–4.10.1136/ard.62.9.870Search in Google Scholar

22. van Rossum M, van Soesbergen R, de Kort S, ten Cate R, Zwinderman AH, de Jong B, et al. Anti-cyclic citrullinated peptide (anti-CCP) antibodies in children with juvenile idiopathic arthritis. J Rheumatol 2003; 30:825–8.Search in Google Scholar

23. Kasapcopur O, Altun S, Aslan M, Karaarslan S, Kamburoglu-Goksel A, Saribas S, et al. Diagnostic accuracy of anti-cyclic citrullinated peptide antibodies in juvenile idiopathic arthritis. Ann Rheum Dis 2004; 63:1687–9.10.1136/ard.2003.019331Search in Google Scholar

24. Ferucci ED, Majka DS, Parrish LA, Moroldo MB, Ryan M, Passo M, et al. Antibodies against cyclic citrullinated peptide are associated with HLA-DR4 in simplex and multiplex polyarticular-onset juvenile rheumatoid arthritis. Arthritis Rheum 2005; 52:239–46.10.1002/art.20773Search in Google Scholar

25. Lopez-Hoyos M, Ruiz de Alegria C, Blanco R, Crespo J, Pena M, Rodriguez-Valverde V, et al. Clinical utility of anti-CCP antibodies in the differential diagnosis of elderly-onset rheumatoid arthritis and polymyalgia rheumatica. Rheumatology 2004; 43:655–7.10.1093/rheumatology/keh143Search in Google Scholar

26. Salvador G, Gomez A, Vinas O, Ercilla G, Canete JD, Munoz-Gomez J, et al. Prevalence and clinical significance of anti-cyclic citrullinated peptide and antikeratin antibodies in palindromic rheumatism. An abortive form of rheumatoid arthritis? Rheumatology 2003; 42:972–5.Search in Google Scholar

27. Jansen LM, van Schaardenburg D, van der Horst-Bruinsma IE, van der Stadt RJ, de Koning MH, Dijkmans BA. The predictive value of anti-cyclic citrullinatedpeptide antibodies in early arthritis. J Rheumatol 2003; 30:1691–5.Search in Google Scholar

28. Rantapää Dahlqvist S, deJong BA, Berglin E, Hallmans G, Wadell G, Stenlund H, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 2003; 48:2741–9.10.1002/art.11223Search in Google Scholar

29. Nielen MM, van Schaardenburg D, Reesink HW, van der Stadt RJ, van der Horst-Bruinsma IE, de Koning MH, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis – a study of serial measurements in blood donors. Arthritis Rheum 2004; 50:380–6.10.1002/art.20018Search in Google Scholar

30. Scott DL. The diagnosis and prognosis of early arthritis: rationale for new prognostic criteria. Arthritis Rheum 2002; 46:286–90.10.1002/art.10134Search in Google Scholar

31. Voskuyl AE, Boers M. Can progression of radiographic joint damage be predicted early in rheumatoid arthritis? J Rheumatol 2003; 30:905–7.Search in Google Scholar

32. Gorman JD, Lum RF, Chen JJ, Suarez-Almazor ME, Thomson G, Criswell LA. Impact of shared epitope genotype and ethnicity on erosive disease – a meta-analysis of 3240 rheumatoid arthritis patients. Arthritis Rheum 2004; 50:400–12.10.1002/art.20006Search in Google Scholar

33. American College of Rheumatology Guidelines Subcommittee. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum 2002;46:328–46.10.1002/art.10148Search in Google Scholar

34. Goldbach-Mansky R, Lee J, McCoy A, Hoxworth J, Yarboro C, Smolen JS, et al. Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset. Arthritis Res 2000; 2:236–43.10.1186/ar93Search in Google Scholar

35. Vasishta A. Diagnosing early-onset rheumatoid arthritis: the role of anti-CCP antibodies. Am Clin Lab 2002; 21:34–6.Search in Google Scholar

36. Zeng XF, Ai MX, Tian XP, Gan XD, Shi YP, Song QF, et al. Diagnostic value of anti-cyclic citrullinated peptide antibody in patients with rheumatoid arthritis. J Rheumatol 2003; 30:1451–5.Search in Google Scholar

37. Vencovsky J, Machacek S, Sedova L, Kafkova J, Gatterova J, Pesakova V, et al. Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis. Ann Rheum Dis 2003; 62:427–30.10.1136/ard.62.5.427Search in Google Scholar

38. Suzuki K, Sawada T, Murakami A, Matsui T, Tohma S, Nakazono K, et al. High diagnostic performance of ELISA detection of antibodies to citrullinated antigens in rheumatoid arthritis. Scand J Rheumatol 2003; 32:197–204.10.1080/03009740310003677Search in Google Scholar

39. Pinheiro GC, Scheinberg MA, Aparecida da Silva M, Maciel S. Anti-cyclic citrullinated peptide antibodies in advanced rheumatoid arthritis. Ann Intern Med 2003; 139:234–5.10.7326/0003-4819-139-3-200308050-00021Search in Google Scholar

40. Dubucquoi S, Solau-Gervais E, Lefranc D, Marguerie L, Sibilia J, Goetz J, et al. Evaluation of anti-citrullinated filaggrin antibodies as hallmarks for the diagnosis of rheumatic diseases. Ann Rheum Dis 2004; 63:415–9.10.1136/ard.2003.008623Search in Google Scholar

41. Vallbracht I, Rieber J, Oppermann M, Forger F, Siebert U, Helmke K. Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis. Ann Rheum Dis 2004; 63:1079–84.10.1136/ard.2003.019877Search in Google Scholar

42. Grootenboer-Mignot S, Nicaise-Roland P, Delaunay C, Meyer O, Chollet-Martin S, Labarre C. Second generation anti-cyclic citrullinated peptide (Anti-CCP2) anti-bodies can replace other anti-filaggrin antibodies and improve rheumatoid arthritis diagnosis. Scand J Rheumatol 2004; 33:218–20.10.1080/03009740410005403Search in Google Scholar

43. Bombardieri M, Alessandri C, Labbadia G, Iannuccelli C, Carlucci F, Riccieri V, et al. Role of anti-cyclic citrullinated peptide antibodies in discriminating patients with chronic hepatitis C infection associated polyarticular involvement. Arthritis Res 2004; 6:R137–41.10.1186/ar1041Search in Google Scholar

44. Bongi SM, Manetti R, Melchiorre D, Turchini S, Boccaccini P, Vanni L, et al. Anti-cyclic citrullinated peptide antibodies are highly associated with severe bone lesions in rheumatoid arthritis. Autoimmunity 2004; 37:495–501.10.1080/08916930400011965Search in Google Scholar

45. Tobon GJ, Correa PA, Anaya JM. Anti-cyclic citrullinated peptide antibodies in patients with primary Sjogern's syndrome. Ann Rheum Dis 2005; 64:791–2.10.1136/ard.2004.029603Search in Google Scholar

46. Tampoia M, Bresica V, Fontana A, Maggiolini P, Lapadula G, Pansini N. Anti-cyclic citrullinated peptide autoantibodies measured by an automated enzyme immuno-assay: analytical performance and clinical correlations. Clin Chim Acta 2005; 355:137–44.10.1016/j.cccn.2004.12.017Search in Google Scholar

47. Parodi A, Drosera M, Seriolo B, Barbieri L, Rebora A. Anti-citrulline antibodies in psoriatic patients with and without arthritis. Acta Dermato Venereol 2005; 85:253–4.10.1080/00015550410024490Search in Google Scholar

48. Aotsuka S, Okawa-Takatsuji M, Nagatani K, Nagashio C, Kano T, Nakajima K, et al. A retrospective study of the fluctuation in serum levels of anti-cyclic citrullinated peptide antibody in patients with rheumatoid arthritis. Clin Exp Rheumatol 2005; 23:475–81.Search in Google Scholar

49. Kroot EJ, dejong BA, van Leeuwen MA, Swinkels H, van den Hoogen FH, van't Hof M, et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 2000; 43:1831–5.10.1002/1529-0131(200008)43:8<1831::AID-ANR19>3.0.CO;2-6Search in Google Scholar

50. Jansen AL, van der Horst Bruinsma IE, van Schaardenburg D, van de Stadt RJ, de Koning MH, Dijkmans BA. Rheumatoid factor and antibodies to cyclic citrullinated peptide differentiate rheumatoid arthritis from undifferentiated polyarthritis in patients with early arthritis. J Rheumatol 2002; 29:2074–6.Search in Google Scholar

51. Meyer O, Labarre C, Dougados M, Goupille P, Cantagrel A, Dubois A, et al. Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage. Ann Rheum Dis 2003; 62:120–6.10.1136/ard.62.2.120Search in Google Scholar

52. Saraux A, Berthelot JM, Devauchelle V, Bendaoud B, Chales G, LeHenaff C, et al. Value of antibodies to citrulline-containing peptides for diagnosing early rheumatoid arthritis. J Rheumatol 2003; 30:2535–9.Search in Google Scholar

53. Söderlin MK, Kastbom A, Kautiainen H, Leirisalo-Repo M, Strandberg G, Skogh T. 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 2004; 33:185–8.10.1080/03009740310004856Search in Google Scholar

54. Kastbom A, Strandberg G, Lindroos A, Skogh T. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (The Swedish TIRA project). Ann Rheum Dis 2004; 63:1085–9.10.1136/ard.2003.016808Search in Google Scholar

55. Hitchon CA, Alex P, Erdile LB, Frank MB, Dozmorov I, Tang YH, et al. A distinct multicytokine profile is associated with anti-cyclical citrullinated peptide antibodies in patients with early untreated inflammatory arthritis. J Rheumatol 2004; 31:2336–46.Search in Google Scholar

56. Mediwake R, Isenberg DA, Schellekens GA, van Venrooij WJ. Use of anti-citrullinated peptide and anti-RA33 antibodies in distinguishing erosive arthritis in patients with systemic lupus erythematosus and rheumatoid arthritis. Ann Rheum Dis 2001; 60:67–8.10.1136/ard.60.1.67Search in Google Scholar

57. Hoffman IE, Peene I, Cebecauer L, Isenberg D, Huizinga TW, Union A, et al. Presence of rheumatoid factor and antibodies to citrullinated peptides in systemic lupus erythematosus. Ann Rheum Dis 2005; 64:330–2.10.1136/ard.2004.022111Search in Google Scholar

58. van Noord C, Hooijkaas H, Dufour-van den Goorbergh BC, van Hagen PM, van Daele PLA, van de Merwe JP. Diagnostic value of anti-cyclic citrullinated peptide antibodies to detect rheumatoid arthritis in patients with Sjogren's syndrome. Ann Rheum Dis 2005; 64:160–2.10.1136/ard.2004.021477Search in Google Scholar

59. Gottenberg JE, Mignot S, Nicaise-Roland P, Cohen-Solal J, Aucouturier F, Goetz J, et al. Prevalence of anti-cyclic citrullinated peptide and anti-keratin antibodies in patients with primary Sjogren's syndrome. Ann Rheum Dis 2005; 64:114–7.10.1136/ard.2003.019794Search in Google Scholar

60. Bogliolo L, Alpini C, Caporali R, Scire CA, Moratti R, Montecucco C. Antibodies to cyclic citrullinated peptides in psoriatic arthritis. J Rheumatol 2005; 32:511–5.Search in Google Scholar

61. Korendowych E, Owen P, Ravindran J, Carmichael C, McHugh N. The clinical and genetic associations of anti-cyclic citrullinated peptide antibodies in psoriatic arthritis. Rheumatology (Oxford) 2005; 44:1056–60.10.1093/rheumatology/keh686Search in Google Scholar

62. Alessandri C, Bombardieri M, Papa N, Cinquini M, Magrini L, Tincani A, et al. Decrease of anti-cyclic citrullinated peptide antibodies and rheumatoid factor following anti-TNF alpha therapy (infliximab) in rheumatoid arthritis is associated with clinical improvement. Ann Rheum Dis 2004; 63:1218–21.10.1136/ard.2003.014647Search in Google Scholar

63. Wener MH, Hutchinson K, Morishima C, Gretch DR. Absence of antibodies to cyclic citrullinated peptide in sera of patients and with hepatitis C virus infection cryoglobulinemia. Arthritis Rheum 2004; 50:2305–8.10.1002/art.20355Search in Google Scholar

64. Lienesch D, Morris R, Metzger A, Debuys P, Sherman K. Absence of cyclic citrullinated peptide antibody in non-arthritic patients with chronic hepatitis C infection. J Rheumatol 2005; 32:489–93.Search in Google Scholar

65. Bas S, Genevay S, Meyer O, Gabay C. Anti-cyclic citrullinated peptide antibodies, IgM and IgA rheumatoid factors in the diagnosis and prognosis of rheumatoid arthritis. Rheumatology 2003; 42:677–80.10.1093/rheumatology/keg184Search in Google Scholar

Published Online: 2006-2-13
Published in Print: 2006-2-1

©2006 by Walter de Gruyter Berlin New York