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Systematic Review: Accuracy of Anti–Citrullinated Peptide Antibodies for Diagnosing Rheumatoid Arthritis

Penny F. Whiting, PhD; Nynke Smidt, PhD; Jonathan A.C. Sterne, PhD; Roger Harbord, MSc; Anya Burton, BSc; Margaret Burke, MSc; Rebecca Beynon, MA; Yoav Ben-Shlomo, PhD, MD; John Axford, DSc, MD; and Paul Dieppe, MD
[+] Article and Author Information

From University of Bristol, Bristol, The Sir Joseph Hotung Centre, St. George's Healthcare Trust and St. George's University of London, London, and University of Exeter, Exeter, United Kingdom, and Leiden University Medical Center, Leiden, the Netherlands.


Acknowledgment: The authors thank Nicola Bizzaro, MD, Laboratory of Clinical Pathology, Hospital of Tolmezzo, Tolmezzo, Italy, and Dr. Richard Haigh, Consultant Rheumatologist, Royal Devon & Exeter Foundation Trust, Exeter, United Kingdom, for their help with the classification of anti-CCP antibodies. They also thank the people who assisted with translating foreign-language studies and the authors who provided additional information on their papers.

Grant Support: By the United Kingdom Medical Research Council.

Potential Conflicts of Interest: Dr. Whiting: Grants received/pending (money to institution): United Kingdom Medical Research Council. Dr. Sterne: Grants received/pending (money to institution): United Kingdom Medical Research Council. Mr. Harbord: Grants received/pending (money to institution): United Kingdom Medical Research Council. Ms. Burton: Grants received/pending: United Kingdom Medical Research Council. Ms. Burke: Grants received/pending (money to institution): United Kingdom Medical Research Council. Ms. Beynon: Grants received/pending (money to institution): United Kingdom Medical Research Council. Dr. Ben-Shlomo: Grants received/pending (money to institution): United Kingdom Medical Research Council. Dr. Dieppe: Grants received/pending (money to institution): United Kingdom Medical Research Council; Support for travel to meetings for the study or otherwise (money to institution): United Kingdom Medical Research Council. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M09-1631.

Requests for Single Reprints: Penny F. Whiting, PhD, Department of Social Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol BS8 2PS, United Kingdom; e-mail, penny.whiting@bristol.ac.uk.

Current Author Addresses: Drs. Whiting, Sterne, and Ben-Shlomo; Mr. Harbord; Ms. Burton; Ms. Burke; and Ms. Beynon: Department of Social Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol BS8 2PS, United Kingdom.

Dr. Smidt: Public Health and Primary Care, Leiden University Medical Center, Box 9600, 2300 RC Leiden, the Netherlands.

Dr. Axford: The Sir Joseph Hotung Centre, St. George's Healthcare Trust and St. George's University of London, Blackshaw Road, London SW17 0QT, United Kingdom.

Dr. Dieppe: Peninsula Medical School, University of Exeter, Heavitree Road, Exeter EX1 2LU, United Kingdom.

Author Contributions: Conception and design: P.F. Whiting, N. Smidt, J.A.C. Sterne, R. Harbord, Y. Ben-Shlomo, J. Axford, P. Dieppe.

Analysis and interpretation of the data: P.F. Whiting, N. Smidt, J.A.C. Sterne, R. Harbord, Y. Ben-Shlomo.

Drafting of the article: P.F. Whiting, N. Smidt, J.A.C. Sterne, R. Harbord, A. Burton, J. Axford, P. Dieppe.

Critical revision of the article for important intellectual content: P.F. Whiting, N. Smidt, J.A.C. Sterne, R. Harbord, Y. Ben-Shlomo, J. Axford, P. Dieppe.

Final approval of the article: P.F. Whiting, N. Smidt, J.A.C. Sterne, R. Harbord, A. Burton, M. Burke, Y. Ben-Shlomo, P. Dieppe.

Statistical expertise: J.A.C. Sterne, R. Harbord.

Obtaining of funding: P.F. Whiting, J.A.C. Sterne, P. Dieppe.

Administrative, technical, or logistic support: J.A.C. Sterne, A. Burton, M. Burke, J. Axford.

Collection and assembly of data: P.F. Whiting, N. Smidt, J.A.C. Sterne, A. Burton, M. Burke, R. Beynon.


Ann Intern Med. 2010;152(7):456-464. doi:10.7326/0003-4819-152-7-201004060-00010
Text Size: A A A

Background: Early recognition and treatment of rheumatoid arthritis is important to prevent irreversible joint damage. Anti–citrullinated peptide antibodies (ACPA) have been suggested for early diagnosis.

Purpose: To compare the accuracy of ACPA and rheumatoid factor in diagnosing rheumatoid arthritis in patients with early symptoms of the disease.

Data Sources: 10 medical databases from inception to September 2009, with no language or publication restrictions, and references of included studies.

Study Selection: Two independent reviewers screened searches. Full articles were assessed by one reviewer and checked by a second reviewer to identify studies that reported 2 × 2 data on ACPA for the diagnosis of rheumatoid arthritis (by 1987 American College of Rheumatology criteria).

Data Extraction: One reviewer abstracted data on patient characteristics, ACPA details, and 2 × 2 data and assessed study quality by using the QUADAS tool. A second reviewer checked extractions.

Data Synthesis: 151 studies were included, with considerable heterogeneity in sensitivity (range, 12% to 93%) and specificity (range, 63% to 100%). In cohort studies that investigated second-generation anti–cyclic citrullinated peptide antibodies (anti-CCP2) in patients with early rheumatoid arthritis (<2 years), summary sensitivity and specificity were 57% (95% CI, 51% to 63%) and 96% (CI, 93% to 97%), respectively. Case–control and cross-sectional studies and studies of patients with established rheumatoid arthritis all overestimated sensitivity. Anti-CCP2 had greater specificity than rheumatoid factor (96% vs. 86%), with similar sensitivity. Evidence was insufficient to ascertain whether the combination of anti-CCP2 and rheumatoid factor provides additional benefit over anti-CCP2 alone.

Limitations: Most studies used a diagnostic case–control design, which overestimated sensitivity. Items relating to study quality were rarely reported. Publication bias could not be assessed.

Conclusion: Anti-CCP2 should be included in the work-up of patients with early symptoms of rheumatoid arthritis.

Primary Funding Source: United Kingdom Medical Research Council.

Figures

Grahic Jump Location
Appendix Figure.
Literature search and selection.

ACPA = anti–citrullinated peptide antibodies.

Grahic Jump Location
Grahic Jump Location
Figure 2.
HSROC plots.

HSROC = hierarchical summary receiver-operating characteristic. Top. HSROC curve for all studies. Bottom. HSROC curve for cohort studies of CCP2 in early rheumatoid arthritis.

Grahic Jump Location

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