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24827 © 2009, American College of Rheumatology
Anti–Citrullinated Peptide Antibody Assays and Their Role in the Diagnosis of Rheumatoid Arthritis
ROHIT AGGARWAL,1 KATHERINE LIAO,2 RAJ NAIR,3 SARAH RINGOLD,4 KAREN H. COSTENBADER2
The diagnosis of early rheumatoid arthritis (RA) has relied on clinical criteria, including history and physical examination ﬁndings and laboratory and radiographic results. Irreversible damage frequently occurs early in RA (1–5). With mounting evidence supporting early diagnosis and aggressive treatment to prevent damage and disability, there is a need to improve identiﬁcation and diagnosis of early RA (6). Until recently, assays detecting rheumatoid factor (RF), antibodies directed against the Fc portion of the IgG molecule, have been the primary serologic tests for RA diagnosis. Anti– citrullinated peptide antibody (ACPA) assays, developed and commercialized in the past decade, are now being employed clinically. Since ACPAs are present before the onset of RA symptoms and are predictive of RA development, they are a valuable diagnostic test early in the course of the disease (4).
Dr. Aggarwal is recipient of the RUSH-CCH collaborative research grant 2008. Dr. Liao’s work was supported by an NIH grant (T32-AR-055885). Dr. Nair’s work was supported by an NIH grant (T32-AR-007416). Dr. Ringold’s work was supported by the Mentored Scholar Program through the Seattle Children’s Hospital Research Institute’s Center for Clinical and Translational Research. Dr. Costenbader’s work was supported by an Arthritis Foundation/American College of Rheumatology Arthritis Investigator Award and NIH grants (P60-AR-047782 and BIRCWH K12-HD051959, funded by the National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and Ofﬁce of the Director). 1 Rohit Aggarwal, MD, MS: Rush University Medical Center, Chicago, Illinois; 2Katherine Liao, MD, Karen H. Costenbader, MD, MPH: Brigham & Women’s Hospital, Boston, Massachusetts; 3Raj Nair, MD: University of North Carolina, Chapel Hill; 4Sarah Ringold, MD, MS: Seattle Children’s Hospital & Regional Medical Center, Seattle, Washington. Drs. Aggarwal, Liao, Nair, and Ringold contributed equally to this work. Address correspondence to Rohit Aggarwal, MD, MS, Rush University Medical Center, Division of Rheumatology, Chicago, IL 60612. E-mail: firstname.lastname@example.org. Submitted for publication February 12, 2009; accepted in revised form July 22, 2009.
This review synthesizes currently available data regarding the diagnostic properties of RF and ACPAs for the diagnosis of early RA. We focus on ACPAs, given their recent development and their potential role in the improved identiﬁcation of early, undifferentiated RA. Data included in this review were obtained from medical literature searches, Web sites of and contact with companies marketing the assays, and information and opinions obtained from experts in the ﬁeld. We have included information on the biologic basis and development of ACPA assays, the available assays, and data concerning assay performance characteristics, in particular those published in peer-reviewed journals, but also those publicized by manufacturers. Diagnostic properties of these tests are reviewed, including but not limited to sensitivity, speciﬁcity, and positive and negative predictive values.
In 1940, Waaler observed that mixing serum from an RA patient with IgG-sensitized sheep erythrocytes inhibited hemolysis, but caused cell agglutination (7). Rose later reported that RA sera agglutinated sheep erythrocytes coated with rabbit anti-sheep erythrocyte antibodies more than sera from healthy individuals (8). These ﬁndings formed the basis of the earliest RA assay, the Rose-Waaler test. RF assays most commonly detect IgM antibodies directed against the Fc portion of the IgG molecule. The agglutination test measures IgM-RF only and remains the most widely used assay. Agglutination assays are reported as either titers or units. Cutoffs for positivity are determined by manufacturers and based on results from RA patients compared with healthy controls (4,9). Agglutination assays have sensitivities for RA ranging from 70% to 85% and speciﬁcities ranging from 40% to 90%, as agglutination in individuals without RA may occur (10 –12). Other assays for RF have been developed, including enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays, and laser or rate nephelometry techniques (13). Assays for the detection of IgA-RF and IgG-RF are also available (14 –19). The sensitivity of RF for RA diagnosis by these techniques is 50 –90% and the speciﬁcity is 50 –
1 assay marketed by Inova Diagnostics (San Diego.42 (0. 100. 114–144 17.25–0.27). False-positive RF results commonly occur in the setting of chronic infections. relatively inexpensive. and understood by both primary care physicians and arthritis specialists (21). This ELISA-based test employed a single CCP derived from ﬁlaggrin (38).17) 0. malignancy. Peptide libraries were then screened for better epitopes. and reinterpretation.69) 0. 93.96–5. Antibodies to citrullinated peptides In 1964. an epithelial cell protein (33). 27. 136–138. 44. Citrullination is a posttranslational modiﬁca- tion of arginine to citrulline by the enzyme peptidyl arginine deiminase. Euro-Diagnostica has developed a point-of-care assay. several citrullinated proteins. and for using a higher versus lower RF titer for positivity (26) (Table 1). The anti-CCP3. controls. In 1998. the pooled likelihood ratios (dependent on both sensitivities and speciﬁcities) were quantitatively similar for IgM-RF. and other rheumatic diseases (21). Positive and negative LRs for IgM-RF in the diagnosis of rheumatoid arthritis* Positive LR (95% CI) Pooled LR RF assay type Nephelometry Latex agglutination ELISA RF value. antiperinuclear factor recognized antigens present in keratohyalin granules surrounding the nucleus (30).95–5. AxSYM Anti-CCP (Abbott. The ﬁrst commercially available ACPA assay (ﬁrst-generation CCP [CCP-1]) was developed by Euro-Diagnostica (Arnhem. 25.38 (0. Most studies. with permission. This process occurs naturally during inﬂammation. To improve antigen composition and antibody recognition. a cyclic citrullinated peptide (CCP) was developed (38).50) 6.97) Negative LR (95% CI) 0.05 (3. 121.51) 4. from ref. Antiperinuclear factor was present in up to 90% of established RA patients.29). 119. In 1995. 139. ELISA 4. healthy controls. apoptosis. 146 26 26 26 95% conﬁdence interval. 142. 126. CCP-3 assays rely on additional epitopes not present in the CCP-2 antigen sequence (39.50 (0.34–0. The assay detected autoantibodies in 53% of established RA patients.38) 4. 101. 26. 27.ACPA Assays in RA 1473 Table 1. Nienhuis and Mandema described an autoantibody they called antiperinuclear factor.57 (4.41) 0. with 73–99% speciﬁcity (31).42 (0.33–0. Studies directly comparing RF detection techniques in cohorts of established RA patients.44) References 9.6–8.32 (0. 124. The compositions of many new CCP-3 peptides are not yet publicly available because patents are pending. 116. CA) detects both IgG and IgA CCP-3 antibodies in an effort to increase sensitivity (41). The Netherlands) and was used in early studies (2000 to 2001). easily detected by ELISA with enhanced sensitivity and no loss of speciﬁcity (35). 101. and IgG-RF assays. Detected by indirect immunoﬂuorescence test on human buccal mucosa cells.15 (2. diluents. Although ﬁlaggrin is not present in the synovium (34). 128. 14–17. both CCP-2 and CCP-3 use ELISA methods and similar dilutions (1:101). however.42 (3. 25. 19.17) likelihood ratio. 144. 129–132 9. Since 2000. second-generation CCP (CCP-2) and third-generation CCP (CCP-3) assays have been developed.51) * Adapted. 118. including ﬁbrinogen and ﬁbronectin. are present in RA synovium. 115. conjugates.01–8. In a meta-analysis of 50 studies of RF assays from 1998 to 2005.84) 5. These wide ranges reﬂect the differences in the populations tested (20 –26). IgA-RF. LR enzyme-linked immunosorbent assay. 95% CI 95%.50) 0. 93. 135. Dundee. Several companies market these assays for RA diagnosis. 140. Despite the high speciﬁcity for RA. and other citrullinated epitopes have been identiﬁed as targets of highly RAspeciﬁc autoantibodies (35–37).34–0. 46. 44. The RF assay. RF is detected in the sera of 1– 4% of healthy young persons and in a higher percentage of elderly persons without RA (28. 39. Sebbag and colleagues demonstrated that both of these antibodies belonged to a family of autoantibodies directed against citrullinated ﬁlaggrin. these tests were not widely used because of difﬁculty in standardization of natural substrates and arbitrary interpretation of the indirect immunoﬂuorescence pattern. 134. Schellekens and colleagues produced synthetic linear citrullinated peptides derived from human ﬁlaggrin. however.40). Apart from the main difference in substrate. show no evident improvement of CCP-3 compared with CCP-2 assays (41– 43). . with 96% speciﬁcity (38). Young and colleagues later detected antikeratin antibodies using indirect immunoﬂuorescence on cryosections of rat esophagus (32). 40.02–6. 123. 117. 38–40. and patients with noninﬂammatory joint disease have reported latex agglutination test performance to be similar to that of nephelometry and radioimmunoassays (12. is widely available. The reported sensitivity of the antikeratin assay in RA patients was 36 –59% and the speciﬁcity was 88 – 99% (31). UK) uses microparticle enzyme immunoassay for the semiquantitative determination of the IgG class of autoantibodies speciﬁc to CCP-2. 114. 19. 143. 120.86 (3. 56.27–0. 125.25–13.60–8.39 (0.39 (0. IgM-RF 0. 133.56) 0. and keratinization (9).31–0.37–0. 122.49 (2.47) 5. IgM rheumatoid factor. 145 14–16. 127.13 (4. units/ml 20 40 80 4.
1474 Aggarwal et al Table 2. Immunoscan-CCP Plus. Quanta Lite. ACPAs are strongly associated with an increased risk of developing RA in healthy individuals and are detectable in the blood of healthy persons prior to clinical RA (14.4 (41) 96. Among those with RA. Nielen and colleagues detected the presence of ACPA antibodies up to 14 years prior to RA onset. autoantibody-positive. In a 3-year study of 97 individuals with RA. The Netherlands Euroimmun.2–9. An ELISA for the detection of autoantibodies against mutated citrullinated vimentin (anti-MCV) has better sensitivity than anti-Sa antibodies. Geneticists and epidemiologists hold ACPA-positive RA to be a homogeneous phenotype of severe RA. ultimately.3 (77) 95.64). and smoking (65.3 (41) Within-assay CV. US Phadia. Germany. Inova.51). anti-MCV anti–mutated citrullinated vimentin.). UK.9–7. % (ref. ELiA CCP. Newer assays detect non-CCPs (41).5–4.73–75). Phadia. Friedberg.3 (41) Name Diastat CCPoint CCPlus EDIA RA anti-CCP ELISA Euroimmun Quanta Lite ELiA CCP Quanta Lite CCP3 Quanta Lite CCP3.6–34.4–12. Germany Type of assay (generation) ELISA (2nd) Colloidal gold immunoassay (2nd) ELISA (2nd) ELISA (2nd) ELISA (2nd) ELISA (2nd) ELISA (2nd) Immunocap method (2nd) ELISA (3rd) ELISA (3rd) ELISA MCV Sensitivity for RA.) 76. RA rheumatoid arthritis.8 (41) 89. N/A not available. ACPA is strongly associated with the HLA–DRB1 shared epitope (62) and PTPN22 (63. ACPA status was relatively stable: 3 ACPA-positive subjects became negative. % (ref. US Orgentec.4 (41) 91. Axis-Shield Diagnostics. The sensitivity of anti-MCV is comparable (or even higher in some studies) to that of ACPA (82% versus 72%) (47).48). the anti-MCV levels may correlate with disease activity (47.5 (41) Speciﬁcity for RA.4–12.3 (41) 6. Most of the currently available assays are kits employing a substrate derived from the synthetic cy- . anti-CCP anti– cyclic citrullinated peptide.69.5 (41) 70 (77) 77.1 (41) 0. strong genetic risk factors for RA. Decreases in ACPAs may be observed with some RA therapies.5 (41) 72. Germany Inova. The ACPA assays employed by European and Canadian early arthritis cohorts are mainly CCP-2 assays (Diastat.1 (41) 6 (147) 7.1 (150) 1. Anti-Sa antibodies have reported a sensitivity of 20 –25% and a speciﬁcity of 95% in early RA (46). while 2 ACPAnegative subjects became positive (67). % (ref.8 (148) 97.9 (41) 87. UK Euro-Diagnostica. employing a ﬁnger lancet to obtain a drop of blood for rapid ofﬁce-based results. the strongest known environmental risk factor for RA. actions to citrullinated peptides. and poorer response to therapy (26.1 (77) 98.0 (148) 70 (149) 66. Citrullinated vimentin is present in synovial ﬂuid and anti-Sa antibodies directed against it are detectable in RA synovium (44.5 (41) 77.50. US Inova. symptom-free period prior to RA may increase with increasing age (60).66).6 (147) N/A 0. Euro-Diagnostica.49).) 13. Pathogenetic role of ACPA in RA The roles of citrullinated peptides and autoantibodies to them in RA pathogenesis remain unclear.8 (41) 3. while speciﬁcity of anti-MCV is slightly lower than ACPA in several studies (90 –92% versus 96 –98%) (41.38.6 (132) 90. with gradually increasing prevalence and increased sensitivity and speciﬁcity for RA compared with RF (51). Smoking by individuals with inherited HLA–DRB1 shared epitope genes may trigger RA-speciﬁc immune re- Currently available ACPA assay performance characteristics Several ACPA assays are currently approved by the US Food and Drug Administration (Table 2).8 (132) 8. Dundee. the term ACPA has therefore replaced anti-CCP antibody.7 (78) 76. The Netherlands Euro-Diagnostica. Examples of available ACPA assays on the market* Manufacturer.52– 61). but generally patients do not lose their positive results (68 – 72). CV coefﬁcient of variation. ELISA enzyme-linked immunosorbent assay. radiographic progression. ACPA reproducibility and stability over time In stored blood bank samples.7–5. The Netherlands Euro-Diagnostica.4–5.45). Sweden/ Germany Inova. Although in some small studies ACPA levels paralleled RA disease activity (68. this has not been corroborated in subsequent studies and ACPA assay results are not clinically employed to monitor disease activity (70 –72).5 (149) 97 (78) 95. Unlike ACPA assays. ACPA anti– citrullinated peptide antibody. disease (65). country Axis-Shield Diagnostics.5 (41) 74 (132) 74. etc. The duration of the preclinical.5 (77) 56. the generation of ACPAs and.9 (150) 12. The Netherlands Euro-Diagnostica.1 Org 548 anti-MCV * The 1987 American College of Rheumatology (formerly the American Rheumatism Association) criteria for RA (79) was used for calculating the sensitivity and speciﬁcity in most studies. their presence is associated with more severe structural damage.) 86.
73 0. clic peptide described by Schellekens and colleagues (38.86 0.67 Inova 3 CCP Euroimmun CCP EuroDiagnostica CCP AxisShield CCP EDIA CCP Pharmacia CCP Triturus CCP 0.78) (Table 3). For example. CCP-2 assays have slightly higher sensitivity than CCP-1 assays.78). Although changes in antibody concentration are reﬂected in a corresponding rise or fall in results.6 – 34.3% intraassay CV) (41. In a study by Coenen and colleagues comparing 6 ACPA assays. the greatest precision was found with the Genesis (4. IgM-RF IgM rheumatoid factor. and the lowest with the Euro-Diagnostica assay (12. 78.9% intraassay CV) and Inova assays (3.41). Development of an international reference range for standardized ACPA reporting Given the variety of ACPA assays. 7%). To determine the diagnostic performance.64 0. with within-assay (intraassay) coefﬁcients of variation (CVs) for most available assays ranging from 4% to 19% (41. including the Inova CCP-3 assay. are highly correlated among . In a head-to-head comparison of the technical performance of 6 different commercially available ACPA assays. expressed as positive or negative values. but differ in incubation time.ACPA Assays in RA 1475 Table 3.80.7 0. (83).59 0. manufacturers have tested established RA patients and healthy individuals meeting the 1987 American College of Rheumatology (ACR.e. a doubling of the antibody concentration will not double the reactivity) (41). followed by Sjogren’s syndrome (6%) and vasculitis ¨ (5%) (Table 4). If one false-positive ACPA was found in an individual without RA. there was a high probability that ACPAs would be negative in a different ACPA assay (82). Because many patients in these studies do not have long-term followup. and juvenile idiopathic arthritis (8%). Inova. Germany).8 0. Euro-Diagnostica. Work is underway to develop standardized ACPA units. The lowest intertest discrepancy is observed between tests using the same substrate (82). they may have ultimately been diagnosed with ACPA-positive RA or an overlap syndrome.8 0.74 0.48 to 0.87 0. the potential for lower speciﬁcity in the setting of other inﬂammatory disorders such as psoriatic arthritis.75 0. CCP cyclic citrullinated peptide. SLE (8%). the newest non-cyclic ACPA assays report similar performance compared with CCP-2 (42. formerly the American Rheumatism Association) criteria (79).8 –5. but require additional conﬁrmation in large numbers of samples and acceptance by assay manufacturers (Bizzaro N: personal communication). esophageal dysmotility. type of conjugate and enzymatic substrate. They found that the discrepancy between the ACPA assays was due to borderline results.83 0.1% intraassay CV).8 0.62 0. The presence of immune complexes or other immunoglobulin aggregates can cause increased nonspeciﬁc binding and false-positive results. reactivity is related to the quantity of antibodies present in a nonlinear fashion.67 0. quantitative results are not currently comparable between studies.59 0.42.58 0.76 –78). Results were promising. UK) (41) demonstrated signiﬁcant deviation from linearity. Raynaud’s phenomenon. scleroderma. ACPA assays in other diseases While the speciﬁcity of ACPA assays for RA compared with healthy individuals is good. systemic lupus erythematosus (SLE). and seronegative spondylarthritides is of concern (84). as well as scleroderma and CREST syndrome (calcinosis. telangiectasias.76 –78. with permission.7–5. from ref.71 0. with correlation coefﬁcients ranging from 0. the best linearity was achieved by Euroimmun (Luebeck.48 * Reproduced. volume and dilution of serum.82 0.. the change is not proportional in most assays (i.71 0.86 0. and intertest variability. We identiﬁed and reviewed 63 studies that examined the cross-reactivity rate of ACPA in non-RA rheumatic diseases and common infections. the results.93 0. and Genesis (Cambridgeshire.66 0. interassay variability. sclerodactyly. ACPA assay correlation Although different antigens and methods are employed to quantitate and report ACPAs.93 0.82 0.76 0.96 0.81).71 0.65 0.81 0. Vander Cruyssen and colleagues studied 4 ACPA assays. Sensitivities range from 60% to 80% and speciﬁcities range from 85% to 99%. 7 of 126 psoriatic arthritis pa- ACPA assay precision Studies comparing different ACPA assays have concluded that the majority of assays are precise.77 0. and range of units reported and thresholds for positive results (41. Because ACPA assays are based on the detection of autoantibodies by ELISA or microparticle enzyme immunoassay or immunoenzymoﬂuorometry.84 0.63 0.96 (41. commercially available ACPA assays.79 0.78). Spearman’s rho correlations comparing quantitative anti– citrullinated peptide antibody assays* Inova CCP Inova 3 CCP Euroimmun CCP Euro-Diagnostica CCP Axis-Shield CCP EDIA CCP Pharmacia CCP Triturus CCP IgM-RF nephelometry 0. The highest frequency of ACPA positivity in non-RA autoimmune conditions is found in psoriatic arthritis (9%).83 0.
and when indirect costs were incorporated. Germany) and Inova Quanta Lite (CCP-3) assays (41). which could be partially attributed to borderline results and interassay . and the Japanese Ministry of Health and Welfare. 78. Fully automated and point-of-care assays are beginning to be marketed by several companies. New anti-MCV assays also have similar performance. 148 86. for example.78. 86.7) 10 (2.82.000 per quality-adjusted life year.8) 10 (3. 90. 148 calcinosis. 157 78. 88. when ACPA assays were ﬁrst introduced. or £250 –300 in the UK. One study has shown 18% discrepancy between two different ACPA assays tested on RA patients (82). 86.1476 Aggarwal et al Table 4. 43. A high frequency of ACPA positivity has been observed in patients with erosive arthritis and overlap syndromes with features of scleroderma and SLE (41. 163 41.93). 148. Cost and availability of RF and ACPA assays RF assays have been widely used for years and are familiar to general practitioners. this study does provide evidence for changing the current approach to early inﬂammatory arthritis.43. 86.3) 26 (6.78. 86. 90 86. 78. They reported that reactivity to non-citrullinated arginine-containing residues was common in tuberculosis. 151. ACPA levels decreased somewhat. 151–155 41. 86 78.7) 0 (0) 5 (4.7) 0 (0) References 41. The surprisingly high prevalence of ACPA in active tuberculosis has been studied by Kakamanu and colleagues (92).48. They are now marketed almost worldwide by a variety of companies. 88. is sold globally. Higher false-positive rates have been reported with Orgentec Diagnostika (anti-MCV.43. rather than waiting and testing after a few years of symptoms. 156. 103 92. 90. establishing the comparative sensitivity and speciﬁcity of the 3 generations of assays is crucial if they are to be used interchangeably. and third-generation and newer ACPA assays Given the rapid evolution of ACPA assays. 148. no.96). 148 158 86.3) 0 (0) 2 (2. and estimated the effects of ACPA testing on incremental costs and quality-adjusted life years. The price per kit varies from market to market. It has the approval of the US Food and Drug Administration. esophageal tients with detectable ACPA had more severe.078 Sjogren’s syndrome ¨ 609 Spondylarthropathy 431 Scleroderma/CREST syndrome 380 Hepatitis C/cryoglobulinemia 285 Osteoarthritis 182 Hepatitis B 176 Juvenile idiopathic arthritis 169 Polymyalgia rheumatica 146 Vasculitis/Wegener’s granulomatosis 107 Tuberculosis 96 Polymyositis/dermatomyositis 75 Fibromyalgia 74 Gout and pseudogout 58 * ACPA anti– citrullinated peptide antibody. 154 41. The Diastat CCP-2 assay from Axis-Shield. with sensitivities of 70 – 82% and speciﬁcities of 90 –98% (47. including the impact of late diagnosis and treatment.75. was cost effective. 78.95. 159–161 88.6) 84 (7.343 Systemic lupus erythematosus 1. but not rapidly. 78. 82. 87. variability.8) 35 (5. telangiectasias syndrome. Their analysis revealed that the upfront use of ACPA testing. Raynaud’s phenomenon. Since 2000. $500 – 600 US dollars.5) 4 (2. Mainz. 90. ACPA positive. 90. 90 78. 85.2) 1 (0. (%) 115 (8. CCP-2 and CCP-3 assays offer slightly improved sensitivity over that of CCP-1 assays (84. ACPA in juvenile idiopathic arthritis has been associated with RF-positive disease similar to RA in adults (91).97). but not in RA. 82. 82. 103. Immunoscan second-generation ACPA assay 96 well kits from Euro-Diagnostica are currently marketed for €350 – 400.86 –90). Although based on multiple assumptions. The mechanism of induction of ACPA in active pulmonary tuberculosis is known. after treatment for tuberculosis (92). second-. Comparison of ﬁrst-. the availability of these tests has drastically increased and costs have decreased. although they have similar speciﬁcity for RA (86 –96%).81.7) 33 (34. 88–90 41. 86.6) 13 (7. There is some lack of agreement between the results obtained from different ACPA assays on the same subjects. sclerodactyly. with sensitivities of 68 –79% and speciﬁcities of 86 –96% (26. Konnopka and colleagues performed a cost-effectiveness analysis to address the incremental beneﬁt of testing for ACPAs in addition to the current ACR (formerly the American Rheumatism Association) criteria for RA classiﬁcation (79. 88. 162 78. 88. CREST dysmotility. erosive disease and a high prevalence of the RA-associated HLA– DRB1 shared epitope (85). saved in the range of €1.94). 88. but it is approximately $250 –300 US dollars per 96 well kits. the European Medicines Agency. They are relatively inexpensive and easy to obtain. 78. They developed a Markov model of the 10-year progression of RA in patients presenting with undifferentiated arthritis. CCP-2 and CCP-3 assays in most (41– 43) but not all studies (90) have had similar performance characteristics. Detection of ACPAs in other diseases* N Psoriatic arthritis 1.
154. and IgG-RF (26). early arthritis has been deﬁned as a symptom duration of less than 2 years (median of approximately 2 months) and initial serologies of patients who developed RA have been compared with those who did not (14. The studies are heterogeneous in their comparison of ACPA assay utility with other tests. but the speciﬁcity is similar to that of RF alone (72– 82%) (101. % Early and established RA cohorts Sensitivity range. Positive ACPA results may be particularly helpful in the setting of a negative RF. 119. and the negative predictive value is 62–96% (38. with most values ranging from 70% to 80%. the performance characteristics of RF and ACPA are comparable and the sensitivity of both RF and ACPA is improved (although the ranges of performance characteristics are large and the data are mixed). The positive predictive value of a positive ACPA test was 91. In one study. ACPA also played an important role in a rule developed by van der Helm-van Mil and colleagues to predict which patients with undifferentiated arthritis would progress to RA (112). IgA-RF. ACPA cyclic citrullinated peptide 2.100.111). 82.76. 132.76. Although correlated.ACPA Assays in RA 1477 Table 5. Early RA cohorts Sensitivity range. In particular. from 36% to 97%. The positive predictive value for ACPA in the setting of early undifferentiated arthritis is 78 –96% in early RA cohorts. and Austria. 123. % Speciﬁcity range. the marginal diagnostic value of adding one test to the other and the added value of performing both must be addressed.103). and thus agreement between assay results is not static.38 – 40. with a good speciﬁcity of 91% (9).7% among 260 IgM-RF–negative early arthritis patients followed for one year (76). 105. IgM rheumatoid factor.103. the sensitivity is somewhat increased (52– 67%). 76. Adding ACPA results to the 1987 ACR (formerly the American Rheumatism Association) criteria increased the sensitivity for early RA (disease duration of 6 months) from 25% to 44% and did not change the speciﬁcity of 86%. 95. A strategy requiring either ACPA or RF may improve sensitivity for both early and established RA. 103. % Speciﬁcity range. the challenge is to decide on the assay or combination of assays that offers superior performance for the identiﬁcation of RA among patients presenting with early. In cohorts containing both established and early RA. undifferentiated inﬂammatory arthritis.46. ACPA testing is generally more speciﬁc than and equally sensitive to RF (Table 5). the performance characteristics of the two tests are comparable (Table 4). RF and ACPA assays detect different underlying biologic phenomena in RA. but likely ﬂuctuates during the disease course (102). RF and ACPA: one. 101. 41.101. The addition of ACPA testing improved the sensitivity of the 1987 ACR (formerly the American Rheumatism Association) criteria (which rely on the presence of RF as one of the 11 possible criteria. or both in early. The Netherlands. 58. Five hundred seventy patients with undifferentiated arthritis in the Leiden Early Arthritis Center were selected and reassessed at one year for RA development. and the negative predictive value is 69 –95%. 110. In the majority of studies. The deﬁnition of early arthritis or early RA has varied in these studies.58. Comparison of performance characteristics of IgM-RF and ACPA (CCP-2) assays in early RA cohorts and cohorts containing both early and established RA* Refs. while others have compared the diagnostic accuracy in different populations of individuals (early or established RA. 164 41–77 88–98 anti– citrullinated peptide antibody. 118 41–63 91–100 9. The prediction rule consisted of 9 variables: . CCP-2 41–66 87–97 52–67 72–82 33–58 98–100 62–87 43–96 70–81 80–91 33–57 91–99 rheumatoid arthritis. In cohorts containing both established and early RA. inﬂammatory arthritis? Given the substantial overlap between the diagnostic performance and utility of RF and ACPA for the diagnosis of RA. with most values ranging from 90% to 95%.26. 4 of which must be present) for the correct classiﬁcation of subjects with early RA (79.46. The positive predictive value for RF is broader. ACPA was slightly more speciﬁc than RF. In studies of early or undifferentiated RA. These studies vary substantially in focus: some have addressed technical aspects.98 –110). and their use of a gold standard for RA diagnosis (most often the existing 1987 ACR [formerly the American Rheumatism Association] criteria for the classiﬁcation of RA ). Employing both ACPA and RF positivity further increases speciﬁcity and positive predictive value to more than 95%. but substantially decreases sensitivity.51. RA Diagnostic accuracy of ACPA assays More than 300 studies have been published concerning the diagnostic accuracy of ACPA assays in RA diagnosis (26). In our review of data from early RA cohorts. including IgM-RF. but the two assays have equivalent sensitivity (Table 5). Most of these data are from the prospective followup of early arthritis cohorts in Japan.59.110). When either ACPA or RF positivity is required. % * IgM-RF ACPA (CCP-2) IgM-RF ACPA (CCP-2) or IgM-RF ACPA (CCP-2) and IgM-RF 38. 105. 100.56. the presence of either ACPA or RF increased testing sensitivity for RA from 66% (ACPA) and 72% (RF) to 81%. 46. 101. The speciﬁcity of requiring both to be present is comparable to that of ACPA alone. either. patients with other diseases or healthy controls).
We did review published studies and presented sensitivity and speciﬁcity ranges of assays. Scott DG. the patient has a high likelihood of having or developing RA. a subject received 2 points (112). ACKNOWLEDGMENTS This publication was made possible in part by the ACREuropean League Against Rheumatism RA Classiﬁcation Criteria Committee. and the issue of timing [editorial]. de Vries-Bouwstra JK. We thank Gillian Hawker. Dr. Waaler E.34:83–96. 6. tender joint count. The assays have good predictive validity because ACPAs are associated with known genetic and epidemiologic risk factors for RA. in a high-risk population (rather than screening the entire population).111:446 –51. Study conception and design. Arthritis Rheum 2000. MD. accepting either ACPA. Aggarwal had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Wiles NJ. and good reproducibility for the diagnosis of early RA. Scand J Rheumatol 2005. Ringold. in a high-risk population with a high prevalence of disease (rather than screening the general population). Harrison BJ. Cost-effectiveness analyses suggest that upfront testing of ACPA in patients presenting with undifferentiated arthritis is cost effective.78.or RF-positive assay results for the diagnosis of RA did not improve on testing for RF alone. high predictive validity. Goekoop-Ruiterman YP. Hazes JM. Diagnostic and prognostic signiﬁcance of autoantibodies in early rheumatoid arthritis. RF and ACPA are two different autoantibody systems and do not measure or reﬂect the . van Zeben D. Aggarwal et al same underlying biology. for their expert opinions and input. Analysis and interpretation of data. Our results suggest that ACPA assays offer a slight advantage over RF (including hightiter RF and combined IgM-RF. ACPA offers similar sensitivity but higher speciﬁcity for RA than RF in early RA. depending on the level of clinical suspicion.1478 sex.94). from past comparisons of RF and ACPA assay performance or perform a formal meta-analysis. Ann Intern Med 2007. et al. Ringold. Discussion ACPA assays have good predictive validity in that they are associated with the known genetic and epidemiologic risk factors for RA and identify a population of RA patients with more severe. Aggarwal. When used in the identiﬁcation of patients potentially developing RA among those presenting with early undifferentiated symptoms. A modiﬁed form of this prediction rule was validated in 3 cohorts of patients with recent-onset undifferentiated arthritis and was found to have excellent discriminative ability to assess progression to RA (113). When does rheumatoid arthritis begin and why do we need to know? [review]. the positive predictive value of the ACPA assay is 95% (76).81. Liao. Speyer I. Although there is substantial correlation between ACPA and RF seropositivity within patients.146:406 –15. the indications for the testing. Landewe RB. On the occurrence of a factor in human serum activating the speciﬁc agglutination of sheep red blood corpuscles: 1939. Ultimately. and the inherent tradeoff between sensitivity and speciﬁcity. Zwinderman AH. Acta Pathol Microbiol Scand 1940. Visser H. ACPA assays have high speciﬁcity. and all authors approved the ﬁnal version to be published.48:46 –53. IgA-RF. the decision to use one or both tests depends on the population tested. in both early and established RA cohorts. high sensitivity. International standardization of reporting units is underway and will facilitate interassay comparisons. ACPA assays are increasingly available and affordable. RF and ACPA are two different autoantibody systems that do not measure or reﬂect the same underlying biology (102). Lard LR. MSc. alone and in combination. Both CCP-2 and CCP-3 assays have improved on CCP-1 assays and have comparable diagnostic utility. C-reactive protein level. Aggarwal. Allaart CF. MD. In the setting of relatively high clinical suspicion (pretest probability) and a positive ACPA result. and IgG-RF levels) due to higher speciﬁcity. Nair.17:172– 88. ACPA assays are becoming increasingly available and less expensive.75. Bukhari MA. apparent cost-effectiveness. age. In prior studies. et al. and requiring both assays to be positive for diagnosis is a very speciﬁc. van der Horst-Bruinsma IE. Weisman MH. Nair.48:1–5. Breedveld FC. and RF and ACPA positivity. morning stiffness. 2. further testing may be indicated. erosive joint disease at high risk for more rapid joint destruction. Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies. 5. If ACPA is negative. et al.43:473– 84. approach. 7. and Josef Smolen. Symmons DP. swollen joint count. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. published and unpublished. Arthritis Rheum 2003. Aggarwal. and therefore identify a population of RA patients with more severe. the prevalence of disease will be high and the positive predictive value of the ACPA assay is on the order of 95% (76). in particular in terms of the saved indirect costs of delayed diagnosis. If the role of the assay is to aid in the identiﬁcation of patients developing RA among those presenting with early undifferentiated symptoms. with sensitivities of 68 – 79% and speciﬁcities of 86 –96% for RA (26. We did not obtain all data. Arthritis Rheum 2003. Costenbader. Liao. 3. ACPA was one of the strongest predictors. MD. 4. Costenbader. REFERENCES 1. Rantapaa-Dahlqvist S. Inﬂuence of disease-modifying therapy on radiographic outcome in inﬂammatory polyarthritis at ﬁve years: results from a large observational inception study. Kerstens PJ. 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