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Abstract
Objectives
This study evaluated the diagnostic performance of anti-carbamylated protein (anti-CarP) and anti-citrullinated fibrinogen (ACF) antibodies in rheumatoid arthritis (RA).
Methods
We searched the Pubmed, Embase, and Cochrane library data-bases, and performed two meta-analyses on the diagnostic accuracy of anti-CarP and ACF antibodies in patients with RA.
Results
The meta-analysis included data from 12 studies. Of these, seven studies, which included 1,749 patients and 1,044 controls, examined anti-CarP antibody, and five studies, which included 733 patients and 1,178 controls, examined ACF antibody. The pooled sensitivities and specificities of anti-CarP antibody were 43.9% (95% confidence interval [CI], 41.6∼46.3) and 94.5% (95% CI, 93.0∼95.8), respectively, and those of ACF antibody were 68.3% (95% CI, 64.9∼71.6) and 95.8% (95% CI, 94.5∼96.9), respectively. The positive likelihood ratio (PLR) of anti-CarP antibody were 9.901 (95% CI, 5.005∼19.58), negative likelihood ratio (NLR) was 0.597 (95% CI, 0.541∼0.658), and diagnostic odds ratio (DOR) was 14.64 (95% CI, 8.004∼34.45). For ACF antibody, PLR was 16.14 (95% CI, 10.23∼25.42), NLR was 0.292 (95% CI, 0.192∼0.444), and DOR was 58.61 (95% CI, 26.61∼129.1). There were no significant difference in sensitivity, specificity, PLR, NLR, AUC, or Q* index between ACF and anticyclic citrullinated peptide (anti-CCP) in the diagnosis of RA.
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Figure 1.
Estimates of the specificities of anti-carbamylated protein (A) and anti-citrullinated fibrinogen (B) antibodies in diagnosing rheumatoid arthritis. Circles and lines represent point estimates and 95% confidence intervals (CIs), respectively. Circled areas represent relative study sizes. df: degree of free-dom.
Figure 2.
Estimates of the positive likelihood ratio (PLR)s of anti-carbamylated protein (A) and anti-citrullinated fibrinogen (B) antibodies in diagnosing rheumatoid arthritis. Circles and lines represent point estimates and 95% confidence intervals (CIs), respectively. Circled areas represent relative study sizes. df: degree of freedom.
Figure 3.
Summary receiver operating characteristic (SROC) curves of anti-carbamylated protein (A) and anti-citrullinated fibrinogen (B) antibodies in diagnosing rheumatoid arthritis. Solid circles represent individual studies included in the meta-analysis. The curve shown is a regression line that summarizes overall diagnostic accuracy. SE: standard error, AUC: area under the curve. Q*, index defined by a point on the SROC curve where sensitivity is equal to specificity; SE (Q*), standard error of the Q* index.
Table 1.
Characteristics of individual studies included in the meta-analysis
| Study | Country | Region | Number | Control type | Antibody | Antibody | Study quality† | ||
|---|---|---|---|---|---|---|---|---|---|
| RA | Control | Sensitivity* | Specificity* | ||||||
| Koppejan et al., 2016 [14] | Canada | Europe | 95 | 85 | HC | Ant-CarP | 0.452 | 0.953 | 11 |
| Shi et al., 2015 [8] | Netherlands | Europe | 969 | 305 | HC | Ant-CarP | 0.440 | 0.889 | 11 |
| Alessandri et al., 2015 [15] | Italy | Europe | 63 | 56 | NRA | Ant-CarP | 0.460 | 0.982 | 10 |
| Verheul et al., 2015 [16] | Japan | Asia | 268 | 324 | NRA | Ant-CarP | 0.451 | 0.919 | 9 |
| Janssen et al., 2015 [17] | Netherlands | Europe | 86 | 36 | NRA | Ant-CarP | 0.558 | 1.000 | 10 |
| Brink et al., 2015 [18] | Sweden | Europe | 192 | 197 | NRA | Ant-CarP | 0.422 | 0.970 | 10 |
| Gan et al., 2015 [19] | United States | America | 76 | 41 | NRA | Ant-CarP | 0.263 | 0.951 | 10 |
| Cornillet et al., 2014 [10] | France | Europe | 181 | 436 | NRA | ACF | 0.834 | 0.950 | 10 |
| Zhao et al., 2008 [20] | China | Asia | 183 | 108 | HC | ACF | 0.672 | 0.981 | 11 |
| Cruyssen et al., 2008 [11] | France | Europe | 86 | 450 | NRA | ACF | 0.663 | 0.971 | 10 |
| Hill et al., 2006 [12] | Canada | America | 65 | 63 | NRA | ACF | 0.815 | 0.952 | 10 |
| Nielen et al., 2005 [13] | Netherlands | Europe | 258 | 121 | NRA | ACF | 0.558 | 0.926 | 10 |
Table 2.
Summary data from the meta-analysis
| Antibody | Number of study | Number | Sensitivity* (95% CI) | Heterogeneity | Specificity* (95% CI) | Heterogeneity | PLR (95% CI) | NLR (95% CI) | DOR (95% CI) | AUC (SE) | Q* (SE) | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| RA | Control | I2 | p-value | I2 | p-value | |||||||||
| Anti-CarP | 7 | 1,749 | 1,044 | 0.439 (0.416-0.463) | 61.4 | 0.014 | 0.945 (0.930-0.958) | 78.6 | < 0.001 | 9.901 (5.005-19.58) | 0.597 (0.541-0.658) | 14.64 (8.004-34.45) | 0.460 (0.104) | 0.470 (0.070) |
| ACF | 5 | 773 | 1,178 | 0.683 | 91.1 | <0.001 | 0.958 | 45.7 | 0.118 | 16.14 | 0.292 | 58.61 | 0.954 | 0.896 |
| (0.649-0.716) | (0.945-0.969) | (10.23-25.42) | (0.192-0.444) | (26.61-129.1) | (0.046) | (0.064) | ||||||||
| Anti-CCP | 4 | 590 | 1,070 | 0.668 | 85.5 | <0.001 | 0.960 | 44.5 | 0.145 | 16.34 | 0.310 | 51.80 | 0.951 | 0.892 |
| (0.628-0.706) | (0.946-0.971) | (10.63-25.1 1) | (0.213-0.452) | (28.46-94.27) | (0.059) | (0.080) | ||||||||
RA: rheumatoid arthritis, CI: error, Anti-CarP: anti-carbam confidence interval, PLR: positive likelihood ratio, NLR: negative likelihood ratio, DOR: diagnostic odds ratio, AUC: area under the curve, SE: standard error, Anti-CarP: anti-carbamylated protein, ACF: anti-citrullinated fibrinogen, Anti-CCP: anticyclic citrullinated peptide.
Table 3.
Paired comparison (ACF vs. anti-CCP) of accuracy in diagnosing rheumatoid arthritis
| Diagnostic accuracy | Number of study | Number | ACF* (95% CI) | Anti-CCP* (95% CI) | Difference for ACF vs. anti-CCP | p-value | |
|---|---|---|---|---|---|---|---|
| RA | Control | ||||||
| Sensitivity | 4 | 590 | 1,070 | 0.686 (0.647∼0.724) | 0.668 (0.628∼0.706) | 0.018 | 0.517 |
| Specificity | 4 | 590 | 1,070 | 0.956 (0.942∼0.968) | 0.960 (0.946∼0.971) | −0.004 | 0.658 |
| PLR | 4 | 590 | 1,070 | 14.93 (9.161∼24.33) | 16.34 (10.63∼25.11) | −1.410 | 0.792 |
| NLR | 4 | 590 | 1,070 | 0.278 (0.150∼0.516) | 0.310 (0.213∼0.452) | −0.032 | 0.774 |
| AUC | 4 | 590 | 1,070 | 0.973 (0.034) | 0.951 (0.059) | 0.022 | 0.747 |
| Q* index | 4 | 590 | 1,070 | 0.925 (0.057) | 0.892 (0.080) | 0.033 | 0.730 |
Supplementary Table 1
QUADAS quality evaluation of studies
QUADAS: Quality Assessment of Diagnostic Accuracy Studies, Y: Yes, N: No, U: Unclear. Item 1. Was the spectrum of patients representative of the patients who will receive the test in practice? 2. Were selection criteria clearly described? 3. Is the reference standard likely to correctly classify the target condition? 4. Is the time period between reference standard and index test short enough to be reasonably sure that the target condition did not change between the two tests? 5. Did the whole study population or a random selection of the sample, receive verification using a reference standard for diagnosis? 6. Did patients receive the same reference standard regardless of the index test result? 7. Was the reference standard independent of the index test? 8. Was the execution of the index test described in sufficient detail to permit replication of the test? 9. Was the execution of the reference standard described in sufficient detail to permit its replication? 10. Were the index test results interpreted without the knowledge of the results of the reference standard? 11. Were the reference standard results interpreted without knowledge of the index test results? 12. Were the same clinical data available when test results were interpreted as would be available when the test is used in practice? 13. Were uninterpretable / intermediate test results reported? 14. Were withdrawals from the study explained?
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