Association of HLA-DR3 with anti-cyclic citrullinated peptide antibody-negative rheumatoid arthritis

OBJECTIVE: Recent data have shown that the most prominent and longest known genetic risk factors for rheumatoid arthritis (RA), HLA-DRB1 shared epitope alleles, are only associated with RA that is characterized by the presence of antibodies against cyclic citrullinated peptide (anti-CCP antibodies) and not with anti-CCP-negative RA. We undertook this study to investigate whether anti-CCP-negative RA is associated with other HLA-DRB1 alleles. METHODS: HLA typing was performed for 377 patients from the Leiden Early Arthritis Clinic who were diagnosed as having RA within the first year of followup (206 anti-CCP-positive patients and 171 anti-CCP-negative patients), 235 patients who, after 1 year, had undifferentiated arthritis (UA) (28 anti-CCP-positive patients and 207 anti-CCP-negative patients), and 423 healthy control subjects. Odds ratios (ORs) with 95% confidence intervals (95% CIs) for HLA-DRB1 allele frequencies were determined for all patient groups compared with the healthy control group. RESULTS: HLA-DR3 was more frequently present in the anti-CCP-negative RA group than in the control group (OR 1.84, 95% CI 1.26-2.67). This was not the case for anti-CCP-positive RA (OR 0.92, 95% CI 0.60-1.40). HLA-DR3 was also more frequently present in anti-CCP-negative UA patients (OR 1.59, 95% CI 1.10-2.28), but not in anti-CCP-positive UA patients (OR 0.68, 95% CI 0.17-1.92). CONCLUSION: HLA-DR3 is associated with anti-CCP-negative arthritis and not with anti-CCP-positive arthritis. These data show that distinct genetic risk factors are associated with the presence of anti-CCP antibodies in RA and indicate that different pathogenetic mechanisms underlie anti-CCP-positive and anti-CCP-negative RA.     

Diagnostic utility of anti-cyclic citrullinated peptide antibodies for very early rheumatoid arthritis

OBJECTIVE: To compare the diagnostic utility of anti-cyclic citrullinated peptide (anti-CCP) antibodies with other serological markers including rheumatoid factor (RF), anti-agalactosyl immunoglobulin G (IgG) antibody, and matrix metalloproteinase (MMP)-3 in very early rheumatoid arthritis (RA). METHODS: Serum concentrations of anti-CCP antibodies, RF, anti-agalactosyl IgG antibody, and MMP-3 were measured in 262 patients with RA ("total RA") including 55 patients with disease duration of less than 6 months who had not been treated before entry ("very early RA") and 116 patients with rheumatic diseases other than RA. RESULTS: The diagnostic sensitivity of anti-CCP antibodies was 82.4% in total RA and 67.3% in very early RA and was lower than that of RF (84.0% total RA, 83.6% very early RA) and anti-agalactosyl IgG antibody (90.5%, 90.9%), whereas specificity, positive predictive value, and diagnostic accuracy were the best among markers tested both in total RA and in very early RA. The presence of either anti-CCP antibodies or RF increased the sensitivity, but any combination of serological markers was not significantly better in diagnostic accuracy than anti-CCP antibodies alone. The rates of RF-positive subjects in anti-CCP antibody-negative patients both in total RA (43.5%) and in very early RA (61.1%) were higher than those of anti-CCP antibody-positive subjects in RF-negative patients (38.1% and 22.2%, for total RA and early RA, respectively). CONCLUSION: Measurement of anti-CCP antibodies, by itself, is useful for the diagnosis of RA; however, combined use of anti-CCP antibodies with RF may be more useful than either method alone for the diagnosis of very early RA.     

Autoantibodies to cyclic citrullinated peptide 2 (CCP2) are superior to other potential diagnostic biomarkers for predicting rheumatoid arthritis in early undifferentiated arthritis

We evaluated the diagnostic value of anti-cyclic citrullinated peptide 2 (anti-CCP2) antibodies and other potential diagnostic biomarkers (IgM rheumatoid factor, anti-agalactosyl IgG antibodies, matrix metalloproteinase 3, C-reactive protein) for predicting early development of rheumatoid arthritis (RA). Patients were defined as having recent-onset undifferentiated arthritis (UA) if they had developed arthritis in two or more joints within the previous 2 years and could not be classified with a well-defined arthropathy. Baseline levels of biomarkers were measured in blood samples collected at the entry of the study and the patients were followed for 1 year to monitor development of RA. Diagnoses of RA and non-RA arthropathies were made according to individual standard diagnostic criteria. A total of 146 patients were enrolled in the study. In the follow-up year, 18 patients developed RA, 54 developed non-RA arthropathies, and 60 remained in the UA category. The sensitivity and specificity of the presence of anti-CCP2 antibodies for the diagnosis of RA were 83.3 and 93.0%, respectively. The positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of anti-CCP2 antibodies for RA (65.2, 97.2, and 91.7%, respectively) were higher than for any other biomarker. Combination of anti-CCP2 with any other biomarker only slightly improved each diagnostic value compared to the presence of anti-CCP2 alone. Among the anti-CCP2-positive patients, the average titer was significantly higher in those with RA than in non-RA or UA patients (163.7 +/- 138.4 vs 55.2 +/- 72.0 U/ml, p = 0.017). Anti-CCP2 antibodies are superior to any other single biomarker for predicting early development of RA in patients with recent-onset UA and the diagnostic value of anti-CCP2 alone is similar to that for biomarker combinations. Moreover, the anti-CCP2 antibody titer is useful to discriminate between patients at high risk for early developing RA from those at risk of developing non-RA arthropathies.     

自身抗体阳性的未分化关节炎向类风湿关节炎转化的预测价值

目的 探讨类风湿因子(RF)、抗角蛋白抗体(AKA)、抗环瓜氨酸肽(CCP)抗体、抗核周因子(APF)4种自身抗体对未分化关节炎(UA)转化为类风湿关节炎(RA)的临床预测价值,并分析其临床相关因素.方法 对271例UA患者随访1年,采用免疫比浊法检测RF,酶联免疫吸附试验(ELISA)检测抗CCP抗体,间接免疫荧光法(IIF)检测APF与AKA,魏氏法测定红细胞沉降率(ESR),记录患者的晨僵时间、关节肿胀数、关节压痛数、不同关节受累及DAS28评分.结果 4种抗体均阳性的UA患者转化为RA的阳性率为99%;任2种及2种以上抗体阳件的UA患者转化为RA的敏感性83.0%,特异性65.9%;RF/抗CCP抗体阳性的UA患者转化为RA的敏感性77.8%,特异性80.5%;抗体均阴性和任1、2、3种抗体阳性及4种抗体全阳性患者的多关节肿胀及多个小关节受累的比率分别为48%、57%、59%、70%、70%和71%、71%、72%、76%、82%;抗体阴性的UA患者中肘关节受累所占比例最大,为72%;多关节肿胀及多个小关节受累在UA转化为RA与无多关节肿胀及多个小关节受累的转化率最大.结论 4种抗体联合检测可提高RA早期诊断的特异性,阳性抗体越多.UA越容易发展为RA;RF/抗CCP抗体阳性的UA患者转化为RA的敏感性和特异性均较高.多关节肿胀和多个小关节受累对评估RA病情有重大意义.     

Prevalence and predictive value of anti-cyclic citrullinated protein antibodies for future development of rheumatoid arthritis in early undifferentiated arthritis

The aim of this study is to evaluate the prevalence and predictive value of anti-cyclic citrullinated protein (CCP) antibodies as a diagnostic marker for future development of rheumatoid arthritis (RA) in a cohort of patients presenting with undifferentiated arthritis (UA). The study comprised 69 patients (22 males and 47 females) presenting with UA, and 66 healthy subjects as control group. For all patients the following parameters were assessed: swollen joint count (SJC), tender joint count (TJC), and duration of morning stiffness in minutes. Baseline laboratory investigations included erythrocyte sedimentation rate (ESR) first hour, C-reactive protein (CRP), complete blood count, complete liver and kidney function tests, urine analysis, anti-nuclear antibodies, rheumatoid factor (RF), and anti-CCP antibodies. Positive correlations were observed between anti-CCP versus SJC, TJC (p = 0.001), duration of morning stiffness (p = 0.04), ESR first hour, and bone erosive changes (p = 0.001). Anti-CCP showed sensitivity of 57%, specificity of 37.9%, positive predictive value of 65.1%, and negative predictive value of 39.3%. Sensitivity and positive predictive values of anti-CCP are close to those observed for RF. In patients presenting with UA, anti-CCP antibodies may allow prediction of RA, thereby allowing early individualized therapeutic decisions.     

Clinical features and independent predictors in the further development of rheumatoid arthritis in undifferentiated arthritis

This study aims to investigate the prognosis of undifferentiated arthritis (UA) and to estimate the putative predictors contributing to predict the development of UA into rheumatoid arthritis (RA); thus, it could improve appropriate medical intervention. A retrospective cohort study of 218 patients with an initial diagnosis of UA and 2-year follow-up monitoring was carried out. The baseline information including demographic variables, clinical features, and laboratory data was collected. A logistic regression model was used for the statistical analysis. After 2 years of follow-up, 20.18 % of UA patients evolved into RA, but 33.03 % remained undifferentiated. Meanwhile, 25.23 % went into remission, and 21.56 % developed into other connective tissue diseases. Univariate and multivariate analysis showed that the titer of antibodies to cyclic citrullinated peptide (anti-CCP), tender joint count and duration of morning stiffness were independent predictors for the development of RA. The area under the curve (AUC) of duration of morning stiffness (0.81) was largest, followed by tender joint count (0.74). The AUC of anti-CCP antibodies (0.68) was higher than that of rheumatoid factor of IgM type (IgM-RF) (0.60), and the combination of these two antibodies was significantly higher than each alone (P < 0.001). In conclusion, UA patients had variable clinical outcomes and prognosis. Only the titer of anti-CCP antibodies, tender joint count, and duration of morning stiffness, instead of IgM-RF, could predict the development of RA. Although the anti-CCP antibody was better than the IgM-RF in predicting RA, a combined detection of them still improved the diagnostic performance.     

Anti-MCV antibodies predict radiographic progression in Greek patients with very early (&lt;3 months duration) rheumatoid arthritis

This study aimed to assess the diagnostic and prognostic value of anti-mutated citrullinated vimentin (MCV) antibodies in very early rheumatoid arthritis (VERA) and in established rheumatoid arthritis (RA). Seventy-one patients with undifferentiated arthritis (UA) of <3 months duration, 141 with established RA, 53 with other rheumatic diseases, and 40 healthy individuals were included in the study. Anti-MCV, anti-cyclic citrullinated peptide (CCP) antibodies, and rheumatoid factor (RF) were determined and hand radiographs were recorded. Patients were assessed prospectively for 2 years, and hand radiographs were repeated. Diagnostic performance of anti-MCV was studied with receiver operating characteristic (ROC) curves and evaluation of sensitivity, specificity, and likelihood ratios. Forty-six percent of UA patients progressed to RA at 2 years. In VERA patients, sensitivity of anti-MCV was 52 %, compared to 44 % of anti-CCP and 37 % of RF, while specificity was 91 %, compared to 91 % of RF and 84 % of anti-CCP. Anti-MCV were detected in 25 % of VERA patients negative for both anti-CCP and RF. In established RA, anti-MCV did not sustain its diagnostic performance. By multivariable analysis, anti-MCV, but not anti-CCP or RF, showed significant correlation with radiographic progression in VERA patients. In established RA, anti-MCV, anti-CCP, and RF were associated with active disease (p ≤ 0.03) and joint damage (p ≤ 0.004). By multivariate analysis, the strongest factors for radiographic damage were disease duration (p = 0.000), HAQ score (p = 0.000), and RF (p = 0.002). In conclusion, in patients with very early UA, anti-MCV predict both progression to RA and radiological damage, and therefore, anti-MCV antibody testing may be useful in every day practice.     

Discriminative and diagnostic value of anti-cyclic citrullinated peptide antibodies in Iranian patients with rheumatoid arthritis

Most studies on the diagnostic utility of the anti-cyclic citrullinated peptide antibody (anti-CCP) test in rheumatoid arthritis (RA) have been performed in developed countries, with only a few done in the developing world. We undertook a cross-sectional study to determine the diagnostic utility of the rheumatoid factor (RF) and anti-CCP tests in urbanized Iranians with early RA. One hundred and ninety-three serum samples were obtained from consecutive patients who were diagnosed with RA. Serum samples of 254 ones without RA, consisting of other inflammatory polyarthritis disorders, were also collected as controls. RF was measured for IgM by latex agglutination test, and titers higher than 1/80 were considered positive. Anti-CCP was also assayed using an ELISA with 6.25 RU/ml as the threshold for a positive result. The anti-CCP had sensitivity, specificity, positive predictive value, and negative predictive value for a diagnosis of RA of 47.2, 92.9, 83.5, and 69.8 %, respectively. Those for RF were 57.0, 83.9, 72.8, and 72.0 %, respectively. For anti-CCP antibodies in combination with RF, they were 38.9, 96.5, 89.3, and 67.5 %, respectively. Anti-CCP has higher specificity and predictive values compared with the RF parameter in diagnosing RA in Iranian patients, but their discriminative values were similar. Anti-CCP and RF in combination further increases the diagnostic value for RA.     

Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review

OBJECTIVE: To evaluate the two generations of anti-cyclic citrullinated protein (CCP) antibodies as a diagnostic marker of rheumatoid arthritis (RA) and as a predictor of future development of RA in healthy subjects and in patients with early undifferentiated arthritis. METHODS: A systematic analysis of the literature published between 1999 and February 2006 was conducted. Data were collected on the sensitivity and specificity of the two generations of anti-CCP antibodies for diagnosing RA and predicting future development of the disease. RESULTS: Among 107 studies initially identified, 68 had interpretable data and were analysed. Diagnostic properties were assessed in 58 studies: mean (SD) sensitivity was 53 (10)% (range 41-68) and 68 (15)% (range 39-94) for anti-CCP1 and anti-CCP2, respectively; mean (SD) specificity was 96 (3)% (range 90-99) and 95 (5)% (range 81-100) for anti-CCP1 and anti-CCP2, respectively. Predictive properties were assessed in 14 studies; odds ratio (95% confidence interval) of anti-CCP1 and anti-CCP2 for the future development of RA were 20 (14 to 31) and 25 (18 to 35), respectively, among patients with early undifferentiated arthritis and 64.5 (8.5 to 489) and 28 (8 to 95), respectively, among healthy subjects. CONCLUSION: Sensitivity of the second generation of anti-CCP is close to that of rheumatoid factor, with a higher specificity, for distinguishing RA from other rheumatic diseases. Moreover, anti-CCP antibodies appear to be highly predictive of the future development of RA in both healthy subjects and patients with undifferentiated arthritis.     

Rheumatoid factor and antibodies to cyclic citrullinated Peptide differentiate rheumatoid arthritis from undifferentiated polyarthritis in patients with early arthritis

OBJECTIVE: To study the diagnostic value of IgM rheumatoid factor (RF), IgA-RF, antibodies to cyclic citrullinated peptide (anti-CCP), and combinations of these antibodies, measured at baseline, to discriminate rheumatoid arthritis (RA) from undifferentiated polyarthritis (uPA) in patients with recent onset arthritis. METHODS: Patients with early arthritis with peripheral arthritis of 2 or more joints and symptom duration less than 3 years were clinically diagnosed as having RA or uPA by an experienced rheumatologist during the first year. Patients with bacterial, psoriatic, or crystal induced arthritis or spondyloarthropathy were excluded. Optimal cutoff values for serum IgM RF, IgA RF, and anti-CCP were deduced from receiver operating characteristics curves in order to predict the diagnosis of RA in early arthritis. RESULTS: A total of 379 patients (69% female, median age 57 yrs, range 17-86 yrs) were studied; 258 patients were clinically diagnosed as RA and 121 as uPA. Both IgM-RF > 40 IU/ml and anti-CCP > 50 AU/ml showed high specificity, but the sensitivity of these tests was low. In many RA patients the occurrence of IgM-RF and anti-CCP antibodies was independent. Thus the optimal criterion proved to be the combination of IgM-RF > 40 or anti-CCP > 50, which yielded sensitivity of 55.4% and specificity of 96.7%. CONCLUSION: The criterion IgM-RF > 40 or anti-CCP > 50 is able to predict the diagnosis of RA in early arthritis patients with high specificity and acceptable sensitivity. Anti-CCP testing combined with IgM-RF testing has additional value over IgM-RF testing alone in patients with early undifferentiated oligo and polyarthritis.     

Anti-citrullinated protein antibodies in the diagnosis of rheumatoid arthritis <Emphasis Type="Bold">(</Emphasis>RA): diagnostic performance of automated anti-CCP-2 and anti-CCP-3 antibodies assays

This study compares the diagnostic performance of a second generation anti-cyclic citrullinated peptide antibody (CCP2) with a third generation anti-CCP antibodies assay (CCP3), as well as the combination of both tests. Serum samples of 127 patients were analyzed. IgG anti-CCP 2 and IgM rheumatoid factor were determined by EliA? technique on a Phadia 250 instrument (Thermo Fisher Scientific), anti-CCP3 by the Quanta Flash? anti-CCP3 IgG kit, BIO-FLASH Rapid Response Chemiluminscence Analyzer (INOVA Diagnostics). Diagnostic performance was compared using ROC-curves, sensitivity, specificity, likelihood ratios, and predictive values. Logistic regressions were used to investigate whether using both tests (anti-CCP2 and anti-CCP3) gives a better prediction of rheumatoid arthritis. At the manufacturer’s cut-offs sensitivity and specificity were 79.4 and 61.0% for CCP3 and 80.9 and 69.5% for CCP2. No significant differences could be observed regarding the areas under the curve (AUC) of both ROC-curves. The optimal cut-off point for CCP2 was 10.5 U/ml (sensitivity of 75.0% and specificity of 80.0%) and 5.6 U/ml for CCP3 (sensitivity of 86.9% and specificity of 61.0%). Binary logistic regressions indicated that the likelihood of having rheumatoid arthritis (RA) is significantly higher when testing positive on both CCP2 and CCP3 compared to CCP2 or CCP3 alone. In our cohort, comparable performance was found between the two CCP assays. Positivity for both CCP2 and CCP3 resulted in the most specific identification of RA patients. In patients with joint complaints suspected of having RA and with a weakly positive CCP 2 (≥7 and ≤16 U/ml) CCP3 testing could be of additive value for diagnosing RA.     

Predictive value of antibodies to cyclic citrullinated peptide in patients with very early inflammatory arthritis

OBJECTIVE: To study the prognostic value of antibodies to cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF), alone and in combination, in patients with very early synovitis. METHODS: A cross-sectional study was performed in patients with established inflammatory and noninflammatory disease to validate the assay in our unit and confirm previously reported sensitivities and specificities of anti-CCP antibodies. Subsequently, patients with synovitis of 3 months' duration were followed for 72 weeks and the ability of anti-CCP antibodies and RF to predict the development of rheumatoid arthritis (RA) and persistent inflammatory arthritis was assessed. RESULTS: One hundred twenty-four patients were assessed in the initial cross-sectional study. Anti-CCP antibodies and RF were detected by ELISA in only 4% of patients with non-RA inflammatory disease and in no patient with noninflammatory disease. Ninety-six patients with very early synovitis were assessed longitudinally. In these patients with early arthritis, the combination of anti-CCP antibodies and RF had a specificity, positive predictive value (PPV), sensitivity, and negative predictive value (NPV) for a diagnosis of RA of 100%, 100%, 58%, and 88%, respectively. The specificity, PPV, sensitivity, and NPV of this antibody combination for the development of persistent disease-fulfilling classification criteria for RA were 97%, 86%, 63%, and 91%, respectively. CONCLUSION: In patients with synovitis of 3 months' duration, a combination of anti-CCP antibodies and RF has a high specificity and PPV for the development of persistent RA. This autoantibody combination can be used to identify patients with disease destined to develop RA who may be appropriate for very early intervention.     

Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study

OBJECTIVE: Rheumatoid arthritis (RA) is a common, severe, chronic inflammatory joint disease. Since the disease may initially be indistinguishable from other forms of arthritis, early diagnosis can be difficult. Autoantibodies seen in RA can be detected years before clinical symptoms develop. In an inception cohort of patients with recent-onset arthritis, we undertook this study to assess the predictive value of RA-specific autoantibodies to cyclic citrullinated peptides (CCPs) in patients with undifferentiated arthritis (UA). METHODS: Anti-CCP2 antibody tests were performed at baseline in 936 consecutive, newly referred patients with recent-onset arthritis. Patients who could not be properly classified 2 weeks after inclusion were categorized as having UA. Patients with UA were followed up for 3 years and evaluated for progression of their disease to RA as defined by the American College of Rheumatology (ACR) 1987 revised criteria. RESULTS: Three hundred eighteen of 936 patients with recent-onset arthritis were classified as having UA and were available for analysis. After 3 years of followup, 127 of 318 UA patients (40%) had been classified as having RA. RA had developed in 63 of 249 patients (25%) with a negative anti-CCP test and in 64 of 69 patients (93%) with a positive anti-CCP test (odds ratio 37.8 [95% confidence interval 13.8-111.9]). Multivariate analysis of the presence of anti-CCP antibodies and parameters from the ACR criteria identified polyarthritis, symmetric arthritis, erosions on radiographs, and anti-CCP antibodies as significant predictors of RA. CONCLUSION: Testing for anti-CCP antibodies in UA allows accurate prediction of a substantial number of patients who will fulfill the ACR criteria for RA.     

The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis

OBJECTIVE: The shared epitope (SE)-containing HLA-DRB1 alleles represent the most significant genetic risk factor for rheumatoid arthritis (RA). Recent studies indicate that the SE alleles are associated with only RA that is characterized by the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies, and not with anti-CCP-negative disease. In this study we investigated whether the SE alleles contribute to the development of anti-CCP-positive RA, or whether they are associated solely with the presence of anti-CCP antibodies. We therefore determined the influence of the SE alleles and anti-CCP antibodies on the progression from recent-onset undifferentiated arthritis (UA) to RA. METHODS: Patients with recent-onset UA at the 2-week visit (n=570) were selected from the Leiden Early Arthritis Cohort. SE alleles, rheumatoid factor (RF) status, and anti-CCP antibody levels were determined. Progression to RA or other diagnoses was monitored. RESULTS: One hundred seventy-seven patients with UA developed RA during the 1-year followup, whereas the disease in 393 patients remained unclassified or was given other diagnoses. The SE alleles correlated with the presence of anti-CCP antibodies, but not with the presence of RF. Both in SE-positive and in SE-negative patients with UA, the presence of anti-CCP antibodies was significantly associated with the development of RA. More intriguingly, however, no apparent contribution of the SE alleles to the progression to RA was found when analyses were stratified according to the presence of anti-CCP antibodies. In patients with anti-CCP-positive disease, the presence of SE alleles was associated with significantly higher levels of anti-CCP antibodies, suggesting that the SE alleles act as classic immune response genes. CONCLUSION: The SE alleles do not independently contribute to the progression to RA from UA, but rather contribute to the development of anti-CCP antibodies.     

Predictive value of antibodies to cyclic citrullinated peptide in patients with early arthritis

The objective of this study was to determine the diagnostic value for rheumatoid arthritis (RA) of antibodies to cyclic citrullinated peptides (anti-CCP) in patients with early arthritis and vasculitis. Sixty-four adult patients with early arthritis and disease duration of less than 4 months were clinically diagnosed by an experienced rheumatologist as having RA (n=27), spondyloarthropathy (n=11), and undifferentiated arthritis (n=26). Eighteen patients with vasculitis were also included in the study. The patients with early arthritis were followed up for 9 months. After the follow-up period, five of 26 patients with undifferentiated arthritis were diagnosed as having RA. All serum samples were tested for anti-CCP and IgM rheumatoid factor (IgM-RF). The anti-CCP positivity in RA patients (44.4%) was significantly more frequent than in patients with undifferentiated arthritis (3.8%), spondyloarthropathy (0%), and vasculitis (5.6%) (p=0.001, p<0.01, and p<0.01, respectively). The frequency of IgM-RF positivity was 40.7% in RA, 7.7% in undifferentiated arthritis, 0% in spondyloarthropathy, and 22.2% in vasculitis groups. The respective specificity of anti-CCP and IgM-RF tests for early RA were 97.3 and 94.6%, and the respective sensitivity of them were 44.4 and 40.7%, respectively. The combination of anti-CCP and IgM-RF positivity had a very high specificity and positive predictive value (100%) but a rather low sensitivity (33.3%). When either anti-CCP or IgM-RF positivity combined into one criterion, the sensitivity became high (51.9%) but the specificity decreased to 91.9%. Overall performance of anti-CCP test alone for the early RA was higher than IgM-RF and the combination of anti-CCP and IgM-RF (p<0.05), and was similar to the combination of anti-CCP or IgM-RF. The specificity of positive anti-CCP test for diagnosis of established RA reached up to 100%. In conclusion, the anti-CCP test is a new diagnostic test with extremely high specificity for RA. Anti-CCP antibody testing combined with IgM-RF testing has additional value over IgM-RF testing alone in patients with early arthritis.     

抗环瓜氨酸肽抗体检测在类风湿关节炎中的诊断及预后意义探讨

目的 评价抗环瓜氨酸肽(CCP)抗体和类风湿因子(RF)在鉴别类风湿关节炎(RA)和其他风湿性疾病中的意义．探讨RA骨侵蚀与上述两种抗体之间的相关性。方法采用横断面研究，在125例RA．56例其他风湿性疾病，55例非风湿性疾病中检测上述两种抗体，其中抗CCP抗体采用酶联免疫吸附试验(ELISA)法．IgM-RF采用速率比浊法。分析RA骨侵蚀与上述两种抗体之间的相关性。结果IgM-RF诊断RA的敏感性较抗CCP抗体高(RF58．4％，抗CCP抗体54．4％)(P=0．57)；但抗CCP抗体有更高的诊断特异性(抗CCP抗体94．6％，IgM-RF84．7％)(P=0．015)，且两种检测方法之间无相关性。联合检测抗CCP抗体和IgM-RF有很高的特异性98．2％．较单独检测IgM-RF有更高的阳性预测值(PPV)95．7％(P=0.019)．阴性预测值(NPV)有下降57.7％(P=-0.213)。抗CCP抗体阳性、IgM-RF阳性与RA骨侵蚀相关。结论抗CCP抗体与IgM-RF比较对RA有良好的诊断敏感性与特异性．可视为RA新的血清学诊断指标。抗CCP抗体与RA骨侵蚀的关系值得进一步研究。     

Antibodies to citrullinated peptides in tuberculosis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetric polyarthritis, rheumatoid factor (RF) positivity, and bone erosions. Recently, research has been conducted on anti-citrullinated peptide antibodies (ACPAs) to which there are greater sensitivity and specificity than RF. However, these antibodies have also been described in infectious diseases, particularly tuberculosis (TB), placing the high specificity of the test in doubt. The aim of this research was to study the prevalence of ACPAs in TB, RA, and healthy controls. Patients with bacteriologically confirmed pulmonary tuberculosis, RA (ACR criteria), in addition to healthy controls were included. ACPAs were researched by: anti-cyclic citrullinated peptide (CCP), anti-modified citrullinated vimentin (MCV), and RF by ELISA. The study was conducted in 50 TB patients, 50 with RA, and 20 controls. Anti-CCP antibodies were found in 39 (78 %) of the RA patients (median titer, 128 U), whereas anti-MCV antibodies were found in 25 (50 %). Of the patients with TB, two (4 %) had positivity for anti-CCP and anti-MCV and no patient in the control group tested positive for these antibodies. Sensitivity of anti-CCP for RA was 78 % (confidence interval (CI), 63 to 88 %) and specificity was 97 % (CI, 89 to 99 %) while the sensitivity of anti-MCV was 50 % (CI, 35–64 %) and specificity was 97 % (CI, 89 to 99 %). RF was positive in 40 samples (80 %) of RA, in 30 (60 %) of TB, and in 1 (5 %) of the controls. Our findings showed high sensitivity of anti-CCP and high specificity of both anti-CCP and anti-MCV antibodies for RA, even in a population with high incidence of tuberculosis. The higher frequency of positivity of ACPA in TB observed in previous studies may be attributed to methodological factors.     

Diagnostic value of anti-cyclic citrullinated peptide antibodies in northern Chinese Han patients with rheumatoid arthritis and its correlation with disease activity

This study was to evaluate the diagnostic value of anti-cyclic citrullinated peptide (CCP) antibodies in northern Chinese Han patients with rheumatoid arthritis (RA) and its correlation with disease activity. Clinical data and serum samples were collected from 112 RA patients and 55 non-RA patients. Statistical analyses of the correlations among anti-CCP antibodies, other serological markers, and the RA patients’ clinical characteristics were performed using SPSS 11.5 software. Anti-CCP antibodies were detected in 77.7% of all RA patients and 80.4% of the RA patients with a disease duration of 3 years or less. The combined diagnosis using high titer anti-CCP antibodies (≥100 RU/ml) with a concomitant positive rheumatoid factor (RF) test exhibited the greatest diagnostic specificity; it achieved 87.9% for all RA patients and 90.1% for the patients with disease duration of three years or less. Moreover, anti-CCP antibodies showed medium correlations to the RA patient’s serum RF titer (r?=?0.560, P?<?0.001) and disease activity (DAS28 score; r?=?0.404, P?<?0.001). Compared with the patients with low anti-CCP antibody titers (<100 RU/ml), patients with high anti-CCP antibody titers showed higher RF titers, worse DAS28 scores, and severe morning stiffness (P?<?0.01). This study suggests that anti-CCP antibodies can be used for RA diagnosis and disease activity evaluation for northern Han Chinese patients. A combined diagnosis using both high titers of anti-CCP antibodies (≥100 RU/ml) and a positive RF test markedly improves RA diagnostic specificity. Patients’ DAS28 scores rise and morning stiffness intensifies with increasing anti-CCP antibody titers.     

Anti-cyclic citrullinated peptide versus anti-Sa antibodies in diagnosis of rheumatoid arthritis in an outpatient clinic for connective tissue disease and spondyloarthritis

OBJECTIVE: . To compare the diagnostic value of anti-cyclic citrullinated peptide (anti-CCP) and anti-Sa antibodies in serum for prediction of rheumatoid arthritis (RA) in an outpatient clinic for connective tissue diseases and spondyloarthritides. METHODS: A cross-sectional study was carried out to analyze the presence or absence of anti-CCP and anti-Sa antibodies in the sera of 250 randomly selected patients. The disease distribution in the study was as follows: 87 patients had RA (34.8%); 90 (36%) had other connective tissue diseases (CTD); 50 (20%) spondyloarthritis; 19 (7.6%) polymyalgia rheumatica; and 4 (1.6%) juvenile idiopathic arthritis. RESULTS: Anti-CCP antibodies were detected in 63 patients with RA and in 9 patients with other illnesses [sensitivity 72.4%, specificity 94.4%, positive predictive value (PPV) 87.5%]. Anti-Sa antibodies were detected in 38 patients with RA and in 6 patients with other illnesses (sensitivity 43.6%, specificity 96.3%, PPV 86.3%). Anti-CCP and anti-Sa results were discordant in up to 47 of 87 RA patients. No relation between the presence of anti-Sa and higher or lower titers of anti-CCP antibodies was observed. CONCLUSION: The diagnostic value in RA is similar for both antibodies. However, the sensitivity of anti-CCP detection is higher than that of anti-Sa. Our results suggest that presence of anti-Sa antibodies in serum may be useful as a complementary assay when anti-CCP antibodies are negative and RA is suspected.     

抗环瓜氨酸多肽抗体检测早期诊断类风湿关节炎研究

目的探讨抗环瓜氨酸多肽(CCP)抗体检测对类风湿关节炎(RA)早期诊断的意义。方法应用ELISA法检测2004—2005年中国医科大学附属盛京医院150份人血清的抗CCP抗体,包括54例RA患者,80例其它风湿病患者,16名正常人;并分析抗CCP抗体与类风湿因子(RF)、C反应蛋白(CRP)、血沉(ESR)的相关性。结果抗CCP抗体对RA的敏感性和特异性分别为70·4%和93·8%。发病2年内与2年以上的抗CCP抗体阳性率差异无显著性。抗CCP抗体阴性组与阳性组的关节畸形率差异无显著性。抗CCP抗体与RF、CRP、ESR无相关性。结论抗CCP抗体对RA具有较好的敏感性和很高的特异性,联合抗CCP抗体和RF可以提高诊断的准确性,对RA的早期诊断具有重要意义。