J Rheum Dis.  2016 Dec;23(6):373-381. 10.4078/jrd.2016.23.6.373.

Diagnostic Accuracies of Anti-carbamylated and Anti-citrullinated Fibrinogen Antibodies in Rheumatoid Arthritis: A Meta-analysis

• Lee YH

• KMID: 2364691
• DOI: http://doi.org/10.4078/jrd.2016.23.6.373

Abstract

OBJECTIVES
This study evaluated the diagnostic performance of anti-carbamylated protein (anti-CarP) and anti-citrullinated fibrinogen (ACF) antibodies in rheumatoid arthritis (RA).
METHODS
We searched the Pubmed, Embase, and Cochrane library databases, and performed two meta-analyses on the diagnostic accuracy of anti-CarP and ACF antibodies in patients with RA.
RESULTS
The meta-analysis included data from 12 studies. Of these, seven studies, which included 1,749 patients and 1,044 controls, examined anti-CarP antibody, and five studies, which included 733 patients and 1,178 controls, examined ACF antibody. The pooled sensitivities and specificities of anti-CarP antibody were 43.9% (95% confidence interval [CI], 41.6~46.3) and 94.5% (95% CI, 93.0~95.8), respectively, and those of ACF antibody were 68.3% (95% CI, 64.9~71.6) and 95.8% (95% CI, 94.5~96.9), respectively. The positive likelihood ratio (PLR) of anti-CarP antibody were 9.901 (95% CI, 5.005~19.58), negative likelihood ratio (NLR) was 0.597 (95% CI, 0.541~0.658), and diagnostic odds ratio (DOR) was 14.64 (95% CI, 8.004~34.45). For ACF antibody, PLR was 16.14 (95% CI, 10.23~25.42), NLR was 0.292 (95% CI, 0.192~0.444), and DOR was 58.61 (95% CI, 26.61~129.1). There were no significant difference in sensitivity, specificity, PLR, NLR, AUC, or Q* index between ACF and anti-cyclic citrullinated peptide (anti-CCP) in the diagnosis of RA.
CONCLUSION
Our meta-analysis demonstrates that both anti-CarP and ACF antibodies are highly specific for diagnosing RA. However, while ACF and anti-CCP showed comparably high diagnostic accuracy, anti-CarP antibody showed low sensitivity in diagnosing RA.

Keyword

Arthritis; Rheumatoid arthritis; Anti-carbamylated protein antibody; Anti-citrullinated fibrinogen antibody; Diagnostic accuracy

MeSH Terms

Antibodies*
Area Under Curve
Arthritis
Arthritis, Rheumatoid*
Diagnosis
Fibrinogen*
Humans
Odds Ratio
Sensitivity and Specificity
Antibodies
Fibrinogen

Figure

• 

  Figure 1. Estimates of the specificities of anti-carbamylated protein (A) and anti-citrullinated fibrinogen (B) antibodies in diagnosing rheumatoid arthritis. Circles and lines represent point estimates and 95% confidence intervals (CIs), respectively. Circled areas represent relative study sizes. df: degree of free-dom.

• 

  Figure 2. Estimates of the positive likelihood ratio (PLR)s of anti-carbamylated protein (A) and anti-citrullinated fibrinogen (B) antibodies in diagnosing rheumatoid arthritis. Circles and lines represent point estimates and 95% confidence intervals (CIs), respectively. Circled areas represent relative study sizes. df: degree of freedom.

• 

  Figure 3. Summary receiver operating characteristic (SROC) curves of anti-carbamylated protein (A) and anti-citrullinated fibrinogen (B) antibodies in diagnosing rheumatoid arthritis. Solid circles represent individual studies included in the meta-analysis. The curve shown is a regression line that summarizes overall diagnostic accuracy. SE: standard error, AUC: area under the curve. Q*, index defined by a point on the SROC curve where sensitivity is equal to specificity; SE (Q*), standard error of the Q* index.

Reference

1. Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001; 358:903–11.

2. Lard LR, Visser H, Speyer I, vander Horst-Bruinsma IE, Zwinderman AH, Breedveld FC, et al. Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies. Am J Med. 2001; 111:446–51.

3. Dörner T, Egerer K, Feist E, Burmester GR. Rheumatoid factor revisited. Curr Opin Rheumatol. 2004; 16:246–53.

4. 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; 101:273–81.

5. van Boekel MA, Vossenaar ER, van den Hoogen FH, van Venrooij WJ. Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value. Arthritis Res. 2002; 4:87–93.

6. Shi J, van Veelen PA, Mahler M, Janssen GM, Drijfhout JW, Huizinga TW, et al. Carbamylation and antibodies against carbamylated proteins in autoimmunity and other pathologies. Autoimmun Rev. 2014; 13:225–30.

7. Wang Z, Nicholls SJ, Rodriguez ER, Kummu O, Hörkkö S, Barnard J, et al. Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nat Med. 2007; 13:1176–84.

8. Shi J, van Steenbergen HW, van Nies JA, Levarht EW, Huizinga TW, van der Helm-van Mil AH, et al. The specificity of anti-carbamylated protein antibodies for rheumatoid arthritis in a setting of early arthritis. Arthritis Res Ther. 2015; 17:339.

9. Masson-Bessière C, Sebbag M, Girbal-Neuhauser E, Nogueira L, Vincent C, Senshu T, et al. 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; 166:4177–84.

10. Cornillet M, Sebbag M, Verrouil E, Magyar A, Babos F, Ruyssen-Witrand A, et al. The fibrin-derived citrullinated peptide β 60-74Cit60,72,74 bears the major ACPA epitope recognised by the rheumatoid arthritis-specific anticitrullinated fibrinogen autoantibodies and anti-CCP2 antibodies. Ann Rheum Dis. 2014; 73:1246–52.

11. Vander Cruyssen B, Nogueira L, Van Praet J, Deforce D, Elewaut D, Serre G, et al. Do all anti-citrullinated protein/peptide antibody tests measure the same? Evaluation of discrepancy between anti-citrullinated protein/peptide antibody tests in patients with and without rheumatoid arthritis. Ann Rheum Dis. 2008; 67:542–6.

12. Hill JA, Al-Bishri J, Gladman DD, Cairns E, Bell DA. Serum autoantibodies that bind citrullinated fibrinogen are frequently found in patients with rheumatoid arthritis. J Rheumatol. 2006; 33:2115–9.

13. Nielen MM, van der Horst AR, van Schaardenburg D, van der Horst-Bruinsma IE, van de Stadt RJ, Aarden L, et al. Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis. Ann Rheum Dis. 2005; 64:1199–204.

14. Koppejan H, Trouw LA, Sokolove J, Lahey LJ, Huizinga TJ, Smolik IA, et al. Role of anti-carbamylated protein antibodies compared to anti-citrullinated protein antibodies in indigenous North Americans with rheumatoid arthritis, their first-degree relatives, and healthy controls. Arthritis Rheumatol. 2016; 68:2090–8.

15. Alessandri C, Bartosiewicz I, Pendolino M, Mancini R, Colasanti T, Pecani A, et al. Anti-carbamylated protein antibodies in unaffected first-degree relatives of rheumatoid arthritis patients: lack of correlation with anticyclic citrullinated protein antibodies and rheumatoid factor. Clin Exp Rheumatol. 2015; 33:824–30.

16. Verheul MK, Shiozawa K, Levarht EW, Huizinga TW, Toes RE, Trouw LA, et al. Anti-carbamylated protein antibodies in rheumatoid arthritis patients of Asian descent. Rheumatology (Oxford). 2015; 54:1930–2.

17. Janssen KM, de Smit MJ, Brouwer E, de Kok FA, Kraan J, Altenburg J, et al. Rheumatoid arthritis-associated autoantibodies in non-rheumatoid arthritis patients with mucosal inflammation: a case-control study. Arthritis Res Ther. 2015; 17:174.

18. Brink M, Verheul MK, Rönnelid J, Berglin E, Holmdahl R, Toes RE, et al. Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage. Arthritis Res Ther. 2015; 17:25.

19. Gan RW, Trouw LA, Shi J, Toes RE, Huizinga TW, Demoruelle MK, et al. Anti-carbamylated protein antibodies are present prior to rheumatoid arthritis and are associated with its future diagnosis. J Rheumatol. 2015; 42:572–9.

20. Zhao X, Okeke NL, Sharpe O, Batliwalla FM, Lee AT, Ho PP, et al. Circulating immune complexes contain citrullinated fibrinogen in rheumatoid arthritis. Arthritis Res Ther. 2008; 10:R94.

21. Lee YH, Rho YH, Choi SJ, Ji JD, Song GG. PADI4 polymorphisms and rheumatoid arthritis susceptibility: a meta-analysis. Rheumatol Int. 2007; 27:827–33.

22. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Associations between osteoprotegerin polymorphisms and bone mineral density: a meta-analysis. Mol Biol Rep. 2010; 37:227–34.

23. Lee YH, Choi SJ, Ji JD, Song GG. Candidate gene studies of fibromyalgia: a systematic review and meta-analysis. Rheumatol Int. 2012; 32:417–26.

24. Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009; 6:e1000097.

25. Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol. 2003; 3:25.

26. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21:1539–58.

27. Egger M, Smith GD, Phillips AN. Meta-analysis: principles and procedures. BMJ. 1997; 315:1533–7.

28. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177–88.

29. Lijmer JG, Bossuyt PM, Heisterkamp SH. Exploring sources of heterogeneity in systematic reviews of diagnostic tests. Stat Med. 2002; 21:1525–37.

30. Walter SD. Properties of the summary receiver operating characteristic (SROC) curve for diagnostic test data. Stat Med. 2002; 21:1237–56.

31. Zamora J, Abraira V, Muriel A, Khan K, Coomarasamy A. Meta-DiSc: a software for meta-analysis of test accuracy data. BMC Med Res Methodol. 2006; 6:31.

32. Nielen MM, van Schaardenburg D, Reesink HW, van de 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.

33. Liu X, Piela-Smith TH. Fibrin(ogen)-induced expression of ICAM-1 and chemokines in human synovial fibroblasts. J Immunol. 2000; 165:5255–61.

34. Marty I, Péclat V, Kirdaite G, Salvi R, So A, Busso N. Amelioration of collagen-induced arthritis by thrombin inhibition. J Clin Invest. 2001; 107:631–40.