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#146 Anti-CCP: A truly helpful Rheumatoid Arthritis lab test?

For Adult Rheumatoid Arthritis (RA), what is the diagnostic utility of Anti-Cyclic Citrullinated Protein antibodies (Anti-CCP)?

Anti-CCP, with ~96% specificity and ~14 positive likelihood ratio, is good for assisting with the diagnosis of RA. Anti-CCP is present in only ¼ to ½ of patients before or at diagnosis, so a negative test does NOT rule out RAIt can also predict more aggressive joint erosion.  

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  • Seven systematic reviews1-7 of Anti-CCP in adult RA, with 27-151 observational studies. Pooled results: 
    • Sensitivity and specificity2-4,7 were 53%-71% and 95-96%, respectively. 
    • Likelihood ratios:3,4 Positive likelihood ratio 12.5-15.9 and negative 0.36-0.42. 
    • Focusing on higher-level studies (diagnostic cohort) with an undifferentiated arthritis presentation: sensitivity generally lower (~54%) but specificity similar.4 
  • Interpretation: Positive Anti-CCP means RA likely but a negative does NOT rule out RA. 
  • Concerns (although study quality did not seem to impact findings7): 
    • Minority of studies well-designed: Cohorts of early, undifferentiated patients with prolonged follow-up by blinded study personnel.4   
    • Significant heterogeneity: Different control population,4 study designs,4 test cut-offs,2,6 and laboratory standardizations.2,6  
  • Positive Anti-CCP also predicts joint erosion in RA, Odds Ratio 4.4 (95% Confidence Interval 3.6-5.3).8 
  • How common is Anti-CCP: 
    • In RA patients?2 
      • 23% early in symptoms.   
      • ~50% at diagnosis. 
      • ~53-70% at two years after diagnosis.  
    • Other populations?2 
      • ≤1.5% in healthy populations. 
      • ≤10% in other rheumatic disease (from lupus to psoriatic arthritis), except palindromic which is similar to RA.   
        • Perhaps higher in some if erosive joint disease present.9  
  • Rheumatoid Factor has a similar sensitivity but worse specificity.3 
    • SpecificityAnti-CCP=95% and Rheumatoid Factor=85%. 
      • Positive likelihood ratios are 12.5 versus 4.9, respectively. 
    • Interpretation: Positive Anti-CCP > positive Rheumatoid Factor for making an RA diagnosis. 
  • In Juvenile RA, Anti-CCP has a similar specificity (99%) but considerably worse sensitivity (10%): Anti-CCP is commonly negative, which does not rule out RA.10   
  • RA diagnostic criteria: As well as joint involvement and acute phase reactants (ESR or C-Reactive Protein), Anti-CCP and Rheumatoid Factor are RA serology markers.11   
    • Note: Anti-CCP is sometimes called ACPA (Anti-Citrullinated Protein Antibody). 

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  • Emelie Braschi PhD MD
  • G. Michael Allan MD CCFP

1. Riedemann JP, Muñoz S, Kavanaugh A. Clin Exp Rheumatol. 2005; 23(5 Suppl 39):S69-76.

2. Avouac J, Gossec L, Dougados M. Ann Rheum Dis. 2006; 65:845-51.

3. Nishimura K, Sugiyama D, Kogata Y, et al. Ann Intern Med. 2007; 146:797-808.

4. Whiting PF, Smidt N, Sterne JA, et al. Ann Intern Med. 2010; 152:456-64; W155-66.

5. Schoels M, Bombardier C, Aletaha D. J Rheumatol Suppl. 2011; 87:20-5.

6. Taylor P, Gartemann J, Hsieh J, et al. Autoimmune Dis. 2011;2011:815038.

7. Zintzaras E, Papathanasiou AA, Ziogas DC, et al. BMC Musculoskelet Disord. 2012; 13:113.

8. Jilani AA, Mackworth-Young CG. Int J Rheumatol. 2015; 2015:728610.

9. Budhram A, Chu R, Rusta-Sallehy S, et al. Lupus. 2014; 23(11):1156-63.

10. Wang Y, Pei F, Wang X, et al. J Immunol Res. 2015; 2015:915276.

11. Aletaha D, Neogi T, Silman AJ, et al. Arthritis Rheum. 2010; 62:2569-81.

Authors do not have any conflicts to disclose