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Meta-analysis: Diagnostic Accuracy of Anti–Cyclic Citrullinated Peptide Antibody and Rheumatoid Factor for Rheumatoid Arthritis

Kunihiro Nishimura, MD, MPH, MS; Daisuke Sugiyama, MD, MPH; Yoshinori Kogata, MD; Goh Tsuji, MD, PhD; Takashi Nakazawa, MD, PhD; Seiji Kawano, MD, PhD; Katsuyasu Saigo, MD, PhD; Akio Morinobu, MD, PhD; Masahiro Koshiba, MD, PhD; Karen M. Kuntz, ScD; Isao Kamae, MD, DrPH; and Shunichi Kumagai, MD, PhD
[+] Article and Author Information

From Harvard School of Public Health, Boston, Massachusetts, and Hyogo College of Medicine and Kobe University Graduate School of Medicine, Hyogo, Japan.


Acknowledgments: The authors thank their colleagues from Kobe University Graduate School of Medicine: Yumiko Nobuhara, MD, for language assistance and Yasuko Nakayama for logistic assistance. They also thank Yasushi Kaji, Dokkyo Medical University, Department of Radiology, for methods assistance and Dr. William F. Goldman (MST Editing Company, Baltimore, Maryland) for editorial assistance and preparation of the manuscript.

Grant Support: In part by a Grant-in-Aid for Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and a grant for Research on Allergic Disease and Immunology from the Ministry of Health, Labor and Welfare, Japan.

Potential Financial Conflicts of Interest: Grants received: S. Kumagai (Japanese Ministry of Health).

Requests for Single Reprints: Kunihiro Nishimura, MD, MPH, MS, Department of Health Policy Management, Harvard School of Public Health, 718 Huntington Avenue, Boston, MA 02215; e-mail, knishimu@hsph.harvard.edu.

Current Author Addresses: Drs. Nishimura and Kuntz: Department of Health Policy Management, Harvard School of Public Health, 718 Huntington Avenue, Boston, MA 02215.

Drs. Sugiyama, Kogata, Tsuji, Nakazawa, Kawano, Saigo, Morinobu, and Kumagai: Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, 7-5-2 Kusunokicho, Kobe, Hyogo, Japan 650-0017.

Dr. Koshiba: Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo, Japan 663-8501.

Dr. Kamae: Department of Applied Biostatistics, Kobe University Graduate School of Medicine, 7-5-2 Kusunokicho, Kobe, Hyogo, Japan 650-001.


Ann Intern Med. 2007;146(11):797-808. doi:10.7326/0003-4819-146-11-200706050-00008
Text Size: A A A

Background: Rheumatoid factor (RF) and autoantibodies against cyclic citrullinated peptide (CCP) are markers that might help physicians diagnose rheumatoid arthritis.

Purpose: To determine whether anti-CCP antibody more accurately identifies patients with rheumatoid arthritis and better predicts radiographic progression than does RF.

Data Sources: MEDLINE through September 2006 and reference lists of retrieved studies and review articles.

Study Selection: Studies in any language that enrolled at least 10 participants and that examined the role of anti-CCP antibody and RF in the diagnosis or prognosis of known or suspected rheumatoid arthritis.

Data Extraction: Two authors independently evaluated studies for inclusion, rated methodological quality, and abstracted relevant data.

Data Synthesis: The DerSimonian–Laird random-effects method was used to summarize sensitivities, specificities, and positive and negative likelihood ratios from 37 studies of anti-CCP antibody and 50 studies of RF. The pooled sensitivity, specificity, and positive and negative likelihood ratios for anti-CCP antibody were 67% (95% CI, 62% to 72%), 95% (CI, 94% to 97%), 12.46 (CI, 9.72 to 15.98), and 0.36 (CI, 0.31 to 0.42), respectively. For IgM RF, the values were 69% (CI, 65% to 73%), 85% (CI, 82% to 88%), 4.86 (CI, 3.95 to 5.97), and 0.38 (CI, 0.33 to 0.44). Likelihood ratios among IgM RF, IgG RF, and IgA RF seemed to be similar. Results from studies of patients with early rheumatoid arthritis were similar to those from all studies. Three of 4 studies found that risk for radiographic progression was greater with anti-CCP antibody positivity than with IgM RF positivity.

Limitations: Many studies had methodological limitations. Studies of RF were heterogeneous and had wide ranges of sensitivity and specificity.

Conclusions: Anti-CCP antibodies are more specific than RF for diagnosing rheumatoid arthritis and may better predict erosivedisease.

Figures

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Appendix Figure. CCP = cyclic citrullinated peptide; RF = rheumatoid factor.
Study flow diagram.
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Figure 1.
Likelihood ratio (LR) for autoantibodies against cyclic citrullinated peptides (anti-CCP).
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Figure 2.
Likelihood ratio (LR) for autoantibodies against IgM rheumatoid factor (RF).
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Figure 3.
Likelihood ratio (LR) for IgA rheumatoid factor (RF) and IgG RF.
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Figure 4.
Pooled likelihood ratio (LR) for first-generation assays for autoantibodies against cyclic citrullinated peptide (CCP1), second-generation assays (CCP2), anti-CCP antibody and rheumatoid factor (RF), and anti-CCP antibody or RF.
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Tables

References

Letters

NOTE:
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Comments

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CCP or RF Which Should It Be
Posted on June 5, 2007
Daniel G. Arkfeld
USC Keck School of Medicine
Conflict of Interest: None Declared

It is with great interest that I read the article entitled "Meta- analysis: Diagnostic Accuracy of Anti"“Cyclic Citrullinated Peptide Antibody and Rheumatoid Factor for Rheumatoid Arthritis" by Nishimura et al. Certainly the use of anti-CCP testing has invigorated the importance of diagnosing rheumatoid arthritis. However, there are 3 potential pitfalls in the study. First, up to 20% of new RA patients are seronegative in the first year, a time where early diagnosis is essential to prevent erosive joint disease. This is the time of utmost important and it would have been nice to see the anti-CCP data during the first year of disease. Other modalities including MRI and ultrasound are pursuing their role in the early detection of RA. Second, false positives do occur with the anti-CCP test due to cross reactivity to citrullinated proteins found in inflammed joints. Personally, I have several gout and lupus patients who have tested false positive for anti-CCP which in some cases has delayed a correct diagnosis. Third, most physicians including rheumatologist don't differentiate first and second generation CCP assays and use whatever is clinically available to them. As mentioned, this is an important area with false positive results. It appears that many of the studies excluded in the metaanalysis used such assays. Thus, in conclusion don't give fully up on the use of RF in diagnosing RA. Often the use of both a RF and a CCP test can be clues that lead to accurate assessment of RA. Additionally, the importance of rheumatology consultation to make an early diagnosis and initiate aggressive treatment is encouraged.

Conflict of Interest:

None declared

Prevalence of autoimmune diseases
Posted on June 11, 2007
Edgard Gonzalez Feldman M.D.
St. John River District Hospital
Conflict of Interest: None Declared

In their meta-analysis Nishimura et al. estate that rheumatoid arthritis is the most common autoimmune disease with a prevalence of 1% in the world's population. But many studies have prooven that autoimmune hypothyroidism is by far more common. In the Wickham Survey (1,2) clinical autoimmune thyroid disease had a prevalence of 2% in women and 0.2% in men. The prevalence of subclinical disease is known to be much higher . In the NHANES-III survey, the prevalence of autoimmune hypothyroidism was 4% and the prevalence of thyroid peroxidase antibodies was close to 15%(3).

1.Turnbridge, WM, Evered, DC, Hall, R, et al. The spectrum of thyroid disease in a community: the Wickham survey. Clin Endocrinol (Oxf) 1977; 7: 481.

2. Vanderpump, MPJ, Turnbridge, WMG, French, JM, ET AL. The incidence of thyroid disorders in the community: a twenty year follow up of the Wickham study. Clin Endocrinol 1995; 43:55.

3. Hollowell, JG, Staehling, NW, Flanders, WD, et al. Serum TSH, T4 and thyroid antibodies in the United States Population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J lin Endocrinol Metab 2002; 87: 489

Conflict of Interest:

None declared

Re: Prevalence of autoimmune diseases
Posted on June 13, 2007
Prasanta Padhan
Department of Clinical Immunology and Rheumatology,Christian Medical College,Vellore
Conflict of Interest: None Declared

There are two group of autoimmune diseases-organ specific and systemic.Nishimura et al in their meta-analysis consider rheumatoid arthritis as the most common systemic autoimmune disease(1).However,hypothyroidism remains the most common organ specific autoimmune disease.Hence it should not create cofusion amongst the physicians. Reference: (1)Nishimura K 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.

Conflict of Interest:

None declared

Biological significance of anti-CCP antibody in rheumatoid arthritis
Posted on June 22, 2007
Ronenn Roubenoff
Biogen Idec and Tufts University
Conflict of Interest: None Declared

To the Editor:

We read with great interest the through meta-analysis and review of the diagnostic accuracy of anti-cyclic citrullinated peptide (CCP) antibody in rheumatoid arthritis (RA) by Nishimura et al.1 The authors conclude that while anti-CCP antibodies are more specific than rheumatoid factor, their sensitivity is only 67%. However, we believe that anti-CCP may in fact define a biologically distinct subset of RA, and as such a simple assessment of their sensitivity for RA in toto may be misleading. Emerging data show that the presence of anti-CCP antibodies interacts with genetic risk factors such as the shared epitope in the HLA locus2; environmental risk factors such as smoking3, 4; and response to treatment5. Thus CCP positivity may not be important so much for diagnosing RA as for being the first of a new generation of biomarkers that allow us to redefine RA according to biological and genetic categories rather than purely phenotypic ones. Such a transition has already begun in oncology, where lymphomas have been reclassified according to biomarker status rather than histology, leading to better definition of prognosis and treatment responses6. Thus, in the future we should be thinking not about the sensitivity and specificity of CCP for RA, but rather about CCP-positive RA vs. CCP-negative RA.

Ronenn Roubenoff, MD, MHS, FACP, FACR Evan Beckman, MD Biogen Idec Immunology Research & Development Cambridge, MA

Michael Weinblatt, MD Nancy Shadick, MD, MPH Brigham & Women's Hospital Boston, MA

Peter K. Gregersen, MD Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY

1. Nishimura K, Sugiyama D, Kogata Y, 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.

2. Irigoyen P, Lee A, Wener M, et al. Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis. Arthritis & Rheumatism 2005;52(12):3813-8.

3. Pedersen M, Jacobsen S, Garred P, et al. Strong combined gene- environment effects in anti-cyclic citrullinated peptide-positive rheumatoid arthritis. Arthritis & Rheumatism 2007;56(5):1446-53.

4. Lee H-S, Irigoyen P, Kern M, et al. Interaction between smoking, the shared epitope, and anti-cyclic citrullinated peptide. Arthritis & Rheumatism 2007;56(6):1745-53.

5. Mikuls T, O'Dell J, Stoner J, et al. Association of rheumatoid arthritis treatment response and disease duration with declines in serum levels of IgM rheumatoid factor and anti-cyclic citrullinated peptide antibody. Arthritis & Rheumatism 2004;50(12):3776-82.

6. Rosenwald A, Wright G, Chan W, et al. Molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. New England Journal of Medicine 2002;346(25):1937-47.

Conflict of Interest:

Drs. Roubenoff and Beckman are employees of Biogen Idec, Inc.

Response
Posted on July 17, 2007
Kunihiro Nishimura
Harvard School of Public Health
Conflict of Interest: None Declared

Each letter in response to our article raises interesting points. We admit that early diagnosis of RA need the combination of anti-CCP and other new biological markers or diagnostic imaging. However, currently available studies for these are limited to conduct meta-analysis quantitatively. The aim of this study is to clarify the diagnostic value of anti-CCP from studies conducted so far.

We appreciate the opinion expressed by Dr. Roubenoff and colleagues and agree that anti-CCP positive and negative RA is potentially different subset RA and other biological markers such as shared epitopes (SE) play important roles. However, from the currently available evidences, we believe arguing the sensitivity and specificity of anti-CCP for diagnosing RA is still crucial. First, although anti-CCP is widely used for diagnosing RA, new genetic markers such as shared epitopes are still not used routinely in daily practice. Second, the number of studies evaluating the SE and anti-CCP is still scarce and its clinical importance needs further evaluation. As far as we know, only one paper by Berglin et al reported the sensitivity and specificity for the combination of SE and anti-CCP 1). They reported the sensitivity of combination of anti-CCP with SE was only 28% and the specificity of SE is only 64%. We admit that the presence of anti-CCP antibodies interacts with genetic risk factors such as SE in the HLA locus 2). However, the data in the same study showed that anti-CCP was 50.9% positive for SE-negative NARAC cohort patients and this study has no information for specificity. To conduct systemic review for the diagnostic value of anti-CCP and other new biological markers, we need further studies.

We appreciate Dr. Arkfield's indication for 3 potential murky points. First, for the early diagnosis of RA, we already evaluated and reported the sensitivity 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 RF is 83% due to low specificity of RF for other rheumatic diseases. Therefore, if we include positive result of either RF or anti-CCP as the positive criteria for RA, we would observe potentially seventeen positive out of hundred among no RA population and have more false positive results. Therefore, we discussed to measure both anti-CCP and RF in case of patients with high prior probability of RA or patients in rheumatology clinics to avoid missing potentially treatable patient. Interpretation of these tests needs the prudent judgment with other clinical information. Third, although the currently commercially available anti-CCP is second generation in most of the time, old studies used first generation anti-CCP but its sensitivities are lower than RF. The second generation CCP was developed to improve the sensitivities 4). We excluded the studies not by the generation of anti-CCP but the availability of the information to calculate LRs, the sensitivity, and specificity. Studies that did not report the specificity give us no information for the false positives that Dr. Arkfield cared.

To evaluate the points indicated by these two letters need the accumulation of more concrete evidences and we will try to address these problems in the future study.

Kunihiro Nishimura, M.D., M.P.H., Ph.D.

Akio Morinobu, M.D., Ph.D.

Schunichi Kumagai, M.D., Ph.D.

Reference.

1) Berglin E, Padyukov L, Sundin U, Hallmans G, Stenlund H, Van Venrooij WJ, Klareskog L, Dahlqvist SR. 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(4):R303-8.

2)Lee H-S, Irigoyen P, Kern M, et al. Interaction between smoking, the shared epitope, and anti-cyclic citrullinated peptide. Arthritis & Rheumatism 2007;56(6):1745-53.

3) Nishimura K, Sugiyama D, Kogata Y, 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.

4) Van Gaalen FA, Visser H, Huizinga TWJ (2005) 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 64, 1510¨C2.

Role of anti-CCP in RA diagnosis
Posted on April 26, 2008
Theodore Pincus
NYU Hospital for Joint Diseases
Conflict of Interest: None Declared

A recent meta-analysis (1), editorial (2) and correspondence (3, 4) concerning anti-CCP in rheumatoid arthritis suggest that anti-CCP may identify a possible unique subset of patients with RA. This intriguing hypothesis requires further research. Anti-CCP provides higher hazard ratios than rheumatoid factor to identify people with progressive inflammatory joint disease. However, anti-CCP hardly provides a definitive clinical test.

Appendix Table 1 (1) indicates median sensitivity of 63.4% (mean 64%) and median specificity of 96.1% (mean 93.9%) of anti-CCP for progressive inflammatory arthritis in 37 studies. Therefore, more than one-third of people with progressive inflammatory arthritis are negative for anti-CCP, while 3.9% of people with anti-CCP do not have progressive inflammatory arthritis.

Appendix Table 2 indicates a median sensitivity of 67% (mean 65.3%) and median specificity 89.7% (mean 83.7%) of rheumatoid factor test for rheumatoid arthritis in 50 studies. The sensitivity is similar anti-CCP. The primary basis for improved hazard ratios for anti-CCP is greater specificity.

The prevalence of rheumatoid arthritis is 0.5%. If 63% are anti-CCP- positive, 0.3% of the population has anti-CCP and rheumatoid arthritis. However, 3.9% of individuals who do not have progressive inflammatory arthritis have positive anti-CCP tests, and 15% of the population has musculoskeletal complaints. These simple calculations indicate that if an anti-CCP test were used to identify all individuals with musculoskeletal pain who might have progressive inflammatory arthritis, 1 in 3 individuals would be missed, and 1 in 2 individuals with a positive test would be misclassified. We suggest that is not satisfactory for a clinical test.

These comments in no way deny the possible research value of anti-CCP to better understand pathogenesis of and develop new treatments for inflammatory arthritis. However, the "gold standard" for a diagnosis of progressive inflammatory arthritis remains careful assessment and observation over 3"“6 months by a knowledgeable physician. Spontaneous remission has been recognized in 75% of people who met criteria for rheumatoid arthritis in population-based studies (5, 6), but people who have persistent arthritis over 6 months are unlikely to enjoy spontaneous remission.

A 30"“60 day "n of 1" trial of low-dose methotrexate and/or prednisone is far less expensive and more likely medically effective than an anti-CCP test for people with suspected progressive inflammatory arthritis (7). Anti-CCP testing in routine care to guide for diagnosis and clinical decisions appears a poor use of limited resources available for people with rheumatic diseases and physicians who provide their care.

Reference List

1. 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.

2. Finckh A, Liang MH. Anti-cyclic citrullinated peptide antibodies in the diagnosis of rheumatoid arthritis: Bayes clears the haze. Ann Intern Med 2007;146:816-817.

3. Roubenoff R, Beckman E, Weinblatt M, Shadick N, Gregersen PK. Biological significance of anti-cyclic citrullinated peptide antibody in rheumatoid arthritis. [Comment on Ann Intern Med 2007;146:797-808.] Ann Intern Med 2008;148:403.

4. Arkfeld DG. Biological significance of anti-cyclic citrullinated peptide antibody in rheumatoid arthritis. [Comment on Ann Intern Med 2007;146:797-808.] Ann Intern Med 2008;148:403.

5. Mikkelsen WM, Dodge H. A four year follow-up of suspected rheumatoid arthritis: the Tecumseh, Michigan, community health study. Arthritis Rheum 1969; 12:87-91.

6. O'Sullivan JB, Cathcart ES. The prevalence of rheumatoid arthritis: follow-up evaluation of the effect of criteria on rates in Sudbury, Massachusetts. Ann Intern Med 1972; 76:573-577

7. Pincus T, Huizinga TWJ, Yazici Y. N-of-1 trial of low-dose methotrexate and/or prednisolone in lieu of anti-CCP, MRI, or ultrasound, as first option in suspected rheumatoid arthritis? J Rheumatol. 2007;34:250-252.

Conflict of Interest:

None declared

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