Biological Significance of Anti–Cyclic Citrullinated Peptide Antibody in Rheumatoid Arthritis
Authors: Kunihiro Nishimura, Akio Morinobu, Shunichi Kumagai
Journal: Annals of Internal Medicine (2008)

Letters4 March 2008Biological Significance of Anti–Cyclic Citrullinated Peptide Antibody in Rheumatoid ArthritisKunihiro Nishimura, MD, MPH, PhD, Akio Morinobu, MD, PhD, and Shunichi Kumagai, MD, PhDKunihiro Nishimura, MD, MPH, PhDFrom Harvard School of Public Health, Boston, MA 02215, and Kobe University Graduate School of Medicine, Hyogo, Japan 650-0017.Search for more papers by this author, Akio Morinobu, MD, PhDFrom Harvard School of Public Health, Boston, MA 02215, and Kobe University Graduate School of Medicine, Hyogo, Japan 650-0017.Search for more papers by this author, and Shunichi Kumagai, MD, PhDFrom Harvard School of Public Health, Boston, MA 02215, and Kobe University Graduate School of Medicine, Hyogo, Japan 650-0017.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-148-5-200803040-00015 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:Dr. Roubenoff and colleagues and Dr. Arkfeld raise interesting points in their letters. We admit that early diagnosis of RA requires a combination of anti-CCP testing and other new biological markers or diagnostic imaging tests. However, currently available studies for these are too limited to conduct meta-analysis quantitatively. The aim of our study was to clarify the diagnostic value of anti-CCP testing from studies conducted so far.We appreciate the opinion expressed by Dr. Roubenoff and colleagues and agree that anti-CCP–positive and –negative RA may be different subsets of RA and that levels of other biological markers, such as shared epitopes, play important roles in diagnosis. However, from the currently available evidence, we believe that the sensitivity and specificity of anti-CCP testing is still crucial for diagnosing RA. First, whereas anti-CCP is widely used for diagnosing RA, tests for new genetic markers, such as shared epitopes, are still not used routinely in daily practice. Second, the number of studies evaluating shared epitopes and anti-CCP is still low, and the clinical importance of this combination needs further evaluation. As far as we know, only Berglin and colleagues (1) have reported the sensitivity and specificity for the combination of shared epitope and anti-CCP testing. They reported that the sensitivity of the combination of anti-CCP and shared epitope testing was only 28% and the specificity was only 64%. We admit that the presence of anti-CCP antibodies interacts with genetic risk factors, such as shared epitopes in the human leukocyte antigen locus (2). However, data in the same study showed that anti-CCP was 50.9% positive for shared epitope–negative patients in the North American Rheumatoid Arthritis Consortium cohort, and that study has no information for specificity. To conduct a systemic review for the diagnostic value of anti-CCP and other new biological marker levels, we need more studies.We thank Dr. Arkfeld for identifying 3 points that need clarification. First, for the early diagnosis of RA, we already evaluated and reported that the sensitivities and specificities showed the same tendencies (3). Second, we reported that, although the specificity of anti-CCP is 95%, the specificity of anti-CCP or rheumatoid factor is actually 83% because of the low specificity of rheumatoid factor for other rheumatic diseases. Therefore, if we include positive results of either rheumatoid factor or anti-CCP as the positive criteria for RA, we would observe potentially 17 positive results out of 100 in the population without RA and have more false-positive results. Therefore, we discussed measuring both anti-CCP and rheumatoid factor, in case there are any patients with high previous probability of RA or patients in rheumatology clinics, to avoid missing potentially treatable patient. Interpretation of these tests requires the prudent judgment of other clinical information. Third, although the current commercially available anti-CCP is usually a second-generation test, old studies used first-generation anti-CCP, which has lower sensitivity than rheumatoid factor.The second-generation anti-CCP was developed to improve these sensitivities (4). We excluded the studies not by the generation of anti-CCP but by the availability of information needed to calculate likelihood ratios, sensitivity, and specificity. Studies that did not report the specificity provide no information about the false-positive results that Dr. Arkfeld asked about.To further evaluate the points indicated in these 2 letters, we need more evidence.Kunihiro Nishimura, MD, MPH, PhDAkio Morinobu, MD, PhDHarvard School of Public HealthBoston, MA 02215Shunichi Kumagai, MD, PhDKobe University Graduate School of MedicineHyogo, Japan 650-0017References1. Berglin E, Padyukov L, Sundin U, Hallmans G, Stenlund H, Van Venrooij WJ, et al. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res Ther. 2004;6:R303-8. [PMID: 15225365] CrossrefMedlineGoogle Scholar2. Lee HS, Irigoyen P, Kern M, Lee A, Batliwalla F, Khalili H, et al. Interaction between smoking, the shared epitope, and anti-cyclic citrullinated peptide: a mixed picture in three large North American rheumatoid arthritis cohorts. Arthritis Rheum. 2007;56:1745-53. [PMID: 17530703] CrossrefMedlineGoogle Scholar3. Nishimura K, Sugiyama D, Kogata Y, Tsuji G, Nakazawa T, Kawano S, et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007;146:797-808. [PMID: 17548411] LinkGoogle Scholar4. van Gaalen FA, Visser H, Huizinga TW. A comparison of the diagnostic accuracy and prognostic value of the first and second anti-cyclic citrullinated peptides (CCP1 and CCP2) autoantibody tests for rheumatoid arthritis. Ann Rheum Dis. 2005;64:1510-2. [PMID: 15800005] CrossrefMedlineGoogle Scholar Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: From Harvard School of Public Health, Boston, MA 02215, and Kobe University Graduate School of Medicine, Hyogo, Japan 650-0017.Disclosures: None disclosed. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoMeta-analysis: Diagnostic Accuracy of Anti–Cyclic Citrullinated Peptide Antibody and Rheumatoid Factor for Rheumatoid Arthritis Kunihiro Nishimura , Daisuke Sugiyama , Yoshinori Kogata , Goh Tsuji , Takashi Nakazawa , Seiji Kawano , Katsuyasu Saigo , Akio Morinobu , Masahiro Koshiba , Karen M. Kuntz , Isao Kamae , and Shunichi Kumagai Biological Significance of Anti–Cyclic Citrullinated Peptide Antibody in Rheumatoid Arthritis Ronenn Roubenoff , Evan Beckman , Michael Weinblatt , Nancy Shadick , and Peter K. Gregersen Biological Significance of Anti–Cyclic Citrullinated Peptide Antibody in Rheumatoid Arthritis Daniel G. Arkfeld Metrics 4 March 2008Volume 148, Issue 5Page: 403-404KeywordsBiomarkersCohort studiesGenetic testingGeneticsMedical risk factorsRheumatoid arthritisRheumatologySpecificity ePublished: 4 March 2008 Issue Published: 4 March 2008 CopyrightCopyright © 2008 by American College of Physicians. All Rights Reserved.PDF DownloadLoading ...