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St. Joseph's Hospital Site, L301-10
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HAMILTON, Ontario, CANADA L8N 4A6
PHONE: (905) 521-6141
FAX: (905) 521-6142
http://www.fhs.mcmaster.ca/hrlmp/
Issue No. 85
QUARTERLY NEWSLETTER
February 2006
Anti-Cyclic Citrullinated Peptide ( Anti-CCP )
Rheumatoid arthritis ( RA ) is a chronic systemic autoimmune disease that causes inflammation, stiffness,
pain and destructive changes in the hands, feet and other joints in the body. It is the most frequent
autoimmune rheumatic disease affecting approximately 1 - 2 % of the population in North America. While
the etiology of the disease remains unknown, several risk factors have been identified. The disease
occurs more frequently in females than in males( 3:1 ratio). Genetic studies have demonstrated that a
genetic predisposition resides in the HLA-DR Locus. There are studies which demonstrate that
environmental factors, such as smoking, oral contraceptives and infectious agents may play a role.
Although RA is diagnosed primarily according to clinical manifestations, it has been demonstrated that the
serum of patients with RA contains a spectrum of autoantibodies. However these autoantibodies are not
specific for RA and may be detected in other autoimmune conditions. These antibodies include
Rheumatoid factor (RF), Anti - RA33 antibodies, Anticalpastin, Sa Protein, heavy Chain Binding Protein
(p68), Glucose-6-phosphate Isomerase, Antifilaggrin antibody and Anti Cyclic Citrullinated Peptide, (AntiCCP).
Rheumatoid factor has been the serological test used to aid in the diagnosis of rheumatoid arthritis and to
distinguish it from other arthritic and inflammatory conditions for over 75 years. The sensitivity of RF for
Rheumatoid Arthritis has historically been very good, > 98%, but it has always had low specificity,
approximately 60% and has been demonstrated in healthy elderly individuals, immunized subjects and in
patients with other auto immune diseases and chronic infections.
A new serological test, the Anti-Citrullinated Cyclic peptide (Anti-CCP), was developed in 1998. It has
been reported to have equivalent sensitivity to RF, but demonstrates greater specificity for the diagnosis
of RA, particularly in patients with early disease.
Citrulline is an amino acid formed by post-translational modification of arginine residues. The arginine
residues are converted into citrulline by the enzyme peptidylarginine deiminase.
Anti-CCP for Diagnosis
Antibodies directed against Citrullinated proteins appear to provide a useful serological marker for the
diagnosis of RA during the early stages of the disease when not all clinical symptoms are present. The
most sensitive assay to detect these antibodies is the Anti-CCP ( IgG)Elisa assays.
The current literature indicates that the Anti-CCP antibodies have essentially the same Sensitivity as the
Rheumatoid Factor for RA, (77% vs. 74% in one study), while Anti-CCP demonstrates greater Specificity,
(97% vs. 78%). Results from a review by Vossenaar et al1 are summarized below.
2x2 Tables of Diagnostic Performance of Anti-CCP and RF1
Rheumatoid
Arthritis
Pos
Neg
Pos
865
79
Neg
252
2218
Anti-CCP
Rheumatoid
Arthritis
Rheumatoid
Factor
Pos
Neg
Pos
827
374
Neg
292
1294
Overview of CCP and RF sensitivity (%), specificity (%) and likelihood ratios (95% CI)1
Sensitivity Specificity
LR Pos
LR Neg
Anti-CCP 77 (74 - 79) 96 (95 - 97) 22.5 (18 - 28) 0.23 (0.21 - 0.26)
RF
73 (71 -76) 77 (75 - 79) 3.2 (2.9 - 3.6) 0.34 (0.30 - 0.37)
Anti-CCP is Present in Early Disease
Recent studies (summarized in review by Vossenaar1) provide evidence that Anti-CCP may be present in
the plasma of Rheumatoid Arthritis patients before the onset of clinical symptoms and before the
appearance of IgM-RF. Anti-CCP detects more positive subjects, longer before the onset of clinical
symptoms and with greater specificity than IgM-RF.
Anti-CCP Predicts Erosive Disease
Anti-CCP antibodies are able to predict erosive and progressive disease. A prospective study by
Vencovsky et al4 measured baseline levels of several autoantibodies. They report that differences in
disease progression were detected by, amongst others, the presence of Anti-CCP antibodies. The best
prediction was obtained by combined analysis of Anti-CCP and IgM-RF.
Anti-CCP (IgG) ELISA Assay
Sample: 0.5 mL Serum (only). <8 h room temperature, 8 - 48 h 2º - 8º C, > 48 h freeze -20º C
Reference Interval:
Negative: < 20 U/L
Weak Positive: 20 - 39 U/L
Positive: 40 - 59 U/L
Strong Positive: >= 60 U/L
Anti-CCP values obtained with different manufacturers' assay methods may not be used interchangeably.
The magnitude of the reported IgG levels cannot be correlated to an end point titre.
The Hamilton Regional Laboratory Medicine Program began offering this test in 2005.
References:
1. Vossenaar ER, Van Venrooij WJ. Anti -CCP antibodies, a highly specific marker for (early) rheumatoid
arthritis. Clinical and Applied Immunological Reviews 4, 239 - 262, 2004.
2. Nijenhuis S, Zendman AJW, Vossenaar ER et al. Autoantibodies to Citrullinated proteins in rheumatoid
arthritis: clinical performance and biochemical aspects of an RA specific marker. Clinica Chimica Acta
350, 17-34, 2004.
3. Van Boekel MMA, Vossenaar ER, Van den Hoogen, FHJ. Auto antibody systems in rheumatoid
arthritis: specificity, sensitivity and diagnostic value.
4. Vencovsky J., Machá ek S, edová L, Kafková J, Gatterová J, Pe áková V and R i ková . Autoantibodies
can be prognostic markers of erosive disease in early rheumatoid arthritis. Ann Rheum Dis. 2003:62 427430
Mark Donahoe, BSc, ART, Manager
Stephen Hill, PhD, FCACB, Clinical Biochemist
Discipline of Special Chemistry/Immunology