Prevalence of anti cyclic citrullinated peptide antibodies in Malaysian rheumatoid arthritis patients and its correlation with disease activity

Aim: The objectives of this study are to provide data regarding the prevalence of anti‐cyclic citrullinated peptide (CCP) antibodies in Malaysian rheumatoid arthritis (RA) patients and to correlate the levels of anti‐CCP antibody with the Disease Activity Score (DAS). Method: We studied the prevalence of anti‐CCP antibodies in 51 RA patients attending our clinic and 29 controls. We also looked for correlation between anti‐CCP antibody levels with the DAS and parameters such as duration of disease, rheumatoid factor (RF) and disease‐modifying anti rheumatic drug (DMARD) usage. Results: None of the controls demonstrated anti‐CCP antibodies. Forty‐one out of 51 patients (80.4%) were positive for anti‐CCP antibodies. Sensitivity and specificity were 80.4% and 100% respectively in this study. Anti‐CCP levels correlated significantly with rheumatoid factor, but no correlation was observed with the other parameters. Conclusions: Anti‐CCP antibody is prevalent in Malaysian RA patients at 80.4% and more sensitive than RF in our cohort of established RA patients. Even though the anti‐CCP levels correlated with RF, it did not show correlation with DAS.     

Ethnic differences in the prognostic utility of rheumatoid factor isotypes and anticyclic citrullinated peptides in rheumatoid arthritis patients: a cross-sectional study

Abstract

Objectives The prognostic significance of rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (anti-CCP) in rheumatoid arthritis (RA) remains contentious due to the conflicting lines of evidence. This study aims to determine the association between RF isotypes and anti-CCP with disease severity in RA patients from three ethnic groups.

Methods A total of 147 RA patients from three different ethnic groups (Malays, Chinese, and Indians) who fulfilled the 1987 American College of Rheumatology (ACR) revised criteria for RA were recruited into this study. The seroprevalence of RF isotypes immunoglobulin (Ig)A, IgG, and IgM, as well as anti-CCP was determined using commercial enzyme-linked immunosorbent assay (ELISA) kits. Multinomial regression analysis was performed to assess the independent effects of autoantibody status on the development of deforming and erosive RA and the presence of extra-articular manifestations (EAM).

Results In Chinese patients, we found a significant association (p < 0.05) between IgG RF and anti-CCP and the presence of erosive disease, as well as IgM RF and IgG RF with the presence of joint deformities. In Indian patients, IgM RF was associated with deforming disease, whereas none of the antibodies were associated with disease severity in Malay patients. Multinomial regression analysis revealed that IgG RF was the most important predictor variable for erosive disease in Chinese patients, and IgM RF the only predictor variable associated with deforming disease in both Chinese and Indian RA patients.

Conclusions There is variability in the phenotypic association of RF isotypes and anti-CCP in relation to disease severity of RA in the three ethnic groups. RF, in particular, IgG and IgM, may be better prognosticators of severe disease in Chinese and Indian patients.     

Anti‐citrullinated protein antibodies and their clinical utility in rheumatoid arthritis

One of the most important serological discoveries in rheumatology in recent years has been the characterization of autoantigens in rheumatoid arthritis (RA) containing the amino acid citrulline. There are many citrullinated proteins in the inflamed RA synovium. Rheumatoid factor (RF), which is the immunologic hallmark of RA, is not specific for RA, as it is found in 5% of healthy individuals and in 10–20% of those over the age of 65 years. RFs are of low titer in early disease stages when a clear diagnosis is often not yet possible; But anti‐citrullinated protein antibodies (ACPAs) can be found early in the disease course of RA, even years before the onset of clinical symptoms. The identification of citrullinated epitopes led to the development of the first and later second generation anti‐cyclic citrullinated peptide (anti‐CCP) antibody assays. Anti‐CCP2 antibody has shown a specificity of 98% in sera from patients with established RA and 96% in sera from subjects with early RA. Anti‐CCP can predict erosive disease, therefore could be a good serological marker for RA diagnosis.     

用受试者工作曲线评价抗环瓜氨酸肽抗体对诊断类风湿关节炎的价值

目的评价抗环瓜氨酸肽抗体(抗CCP抗体)在类风湿关节炎(RA)诊断中的价值。方法收集110例RA患者,与38例其他疾病患者以及36名正常人作为对照,应用受试者工作曲线(re-ceiveroperativecharacteristiccurve,ROC)分析软件评价抗CCP抗体在RA诊断中的价值,在ROC曲线上制定抗CCP抗体与类风湿因子(RF)各亚型在诊断RA中的最佳临界点。用四格表计算系列试验的特异度,进行统计学检验。用SPSS软件比较抗CCP抗体与RF各亚型之间的相关性。结果在诊断RA中,抗CCP抗体的ROC曲线下的面积(AUCROC)明显大于RF(IgA、IgM、IgG)AUCROC(P<0.01),抗CCP抗体联合任何一个RF亚型的系列试验的特异度高达100%。抗CCP抗体和RF(IgA、IgM、IgG)经Spearman相关分析,呈正相关。结论抗CCP抗体对RA有较高的诊断价值;诊断RA的系列试验中,含抗CCP抗体的系列试验的特异度高。     

抗环瓜氨酸肽抗体检测在类风湿关节炎中的意义

目的 检测抗环瓜氨酸肽（CCP）抗体在类风湿关节炎（RA）中的阳性率,探讨抗CCP抗体检测在RA中的意义。方法 以根据已知cDNA序列人工合成的CCP为抗原建立ELISA方法检测294例RA,132例其他风湿性疾病,135例非风湿性疾病中的抗CCP抗体的分布。比较抗CCP抗体与抗核周因子（APF）、抗角蛋白抗体（AKA）、类风湿因子（RF）以及HLA－DR4的相关性。结果 294例RA病人中,抗CCP抗体的阳性率为46．6％,其他风湿性疾病的阳性率为5．3％,非风湿性疾病的阳性率为1．5％。抗CCP抗体对RA的敏感性和特异性分别为46．6％,96．6％。抗CCP抗体与APF、AKA以及HLA－DR4之间有相关性,与RF之间无相关性。结论 抗CCP抗体对RA具有良好的敏感性（46．6％）和特异性（96．6％）,能用于RA的诊断。抗CCP抗体与AFP、AKA有相关性,但不完全重叠。抗CCP抗体可视为RA新的血清学诊断指标。     

Low levels of anti-cyclic citrullinated peptide (CCP) 3.1 associated with diseases other than rheumatoid arthritis

Our aim was to investigate the newest generation anti-cyclic citrullinated peptide (CCP) antibody 3.1 assay in diagnosing rheumatoid arthritis (RA) compared with other autoimmune and non-autoimmune diseases. We performed a retrospective observational chart review of patients with a positive CCP level over a one-year period at a single academic institution and assessed the associated diagnoses after at least six-months of follow-up. Of the 281 CCP positive patients during that period, 48% had a diagnosis of RA. The positive predictive value of RA in patients with a high CCP 3.1 assay was 0.619 compared to 0.248 with a low positive CCP 3.1 assay (P < .0001). Overall, there was a lower than expected positive predictive value of CCP 3.1 level with an RA diagnosis, though the likelihood of having an RA diagnosis was higher with a higher CCP level.     

Diagnostic utility of anti-cyclic citrullinated peptide antibodies for rheumatoid arthritis in patients with active lung tuberculosis

This study was intended to evaluate the utility of anti-cyclic citrullinated peptide antibodies (second generation, anti-CCP2) as a diagnostic marker for rheumatoid arthritis (RA) in patients with active tuberculosis. Among 89 patients with active tuberculosis, anti-CCP2 was detected in six (6.7%), and three of these (3.4%) were strongly positive for anti-CCP2. The positive rate of anti-CCP2 in patients with newly diagnosed RA was 82.1% (87 of 106 cases), while the rate in healthy control subjects was 0.4% (one of 237 individuals). The mean level of anti-CCP2 among the RA group was 159.3 U/ml, which was significantly higher than both that among the tuberculosis group (15.4 U/ml) and that among the healthy controls (0.7 U/ml). IgM rheumatoid factor (RF) was detected in 16 patients from the tuberculosis group (18.0%) with a mean serum level of 18.6 IU/ml and in 77 patients of the RA group (72.6%) with a mean level of 164.0 IU/ml. Only two cases in the tuberculosis group were positive for both anti-CCP2 and IgM RF. These observations show that measurement of anti-CCP2 seems to be a reliable serological tool for identifying early RA in patients with active tuberculosis.     

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。     

抗环瓜氨酸肽抗体与系统性红斑狼疮关节炎的相关性研究

目的 研究抗环瓜氨酸肽(CCP)抗体在系统性红斑狼疮(SLE)患者中的临床意义,探讨抗CCP抗体与SLE患者关节炎及骨侵蚀的关系.方法 采用酶联免疫吸附试验(ELISA)方法检测138例SLE患者血清中抗CCP抗体水平,并与SLE患者关节表现及其他临床指标进行相关性分析.结果 抗CCP抗体在SLE患者中的阳性率为13.8%(19/138).SLE患者关节炎的发生率为50.7%,关节炎组抗CCP抗体阳性率(20%)高于非关节炎组(7.4%)(P＜0.05).在SLE关节炎患者中,抗CCP抗体阳性者类风湿因子(RF)阳性率显著高于抗CCP抗体阴性者(71.4%与14.3%)(P＜0.01).而且,抗CCP抗体与RF之间显著相关(r=0.36,P=0.002).抗CCP抗体阳性的SLE患者关节炎的发生率明显高于抗CCP抗体阴性者(73.7%与47.1%,P＜0.05).138例SLE患者中有8例出现受累关节的影像学改变,与抗CCP抗体阴性患者相比,抗CCP抗体阳性患者表现出侵蚀性关节炎的比例显著为高(35.7%与5.4%,P＜0.01).在8例表现为侵蚀性关节炎的患者中有2例患者抗CCP抗体和RF均阴性,而抗RA33抗体阳性.此8例患者均满足美国风湿病学学会(ACR)1987年类风湿关节炎(RA)的分类标准.SLE相关其他临床指标分析显示,关节炎组.与非关节炎组、抗CCP抗体阳性组与阴性组之间差异均无统计学意义.结论 13.8%的SLE患者体内存在抗CCP抗体.抗CCP抗体的出现与SLE患者关节炎和骨侵蚀密切相关,并对判断SLE关节炎的预后具有重要的临床价值.     

抗环瓜氨酸肽抗体与类风湿关节炎的相关性研究

目的 研究类风湿关节炎（RA）患者抗环瓜氨酸肽抗体（CCP抗体）与肿瘤坏死因子（TNF）-α、类风湿因子（RF）、红细胞沉降率（ESR）、血小板计数（PLT）及临床的相关性，以及未分类关节炎（痛）患者6个月后随访转归情况，探讨其在RA早期诊断及发病机制中的意义。方法 对91例RA患者，46例未分类关节炎（痛）患者，45例其他风湿病患者，应用酶联免疫吸附试验（ELISA）法检测血清抗CCP抗体、TNF—α，速率散射免疫比浊法检测RF。结果 RA组及未分类关节炎（痛）组患者外周血抗CCP抗体水平与TNF—α水平、PLT、关节肿胀度呈显著正相关（r=0．854，P=0．000；r=0．882，P=0．000；r=0．318，P=0．002；r=0．486，P=0．001；r=0．291，P=0．005；r=0．731，P=0．000），RA组及未分类关节炎（痛）组患者外周血抗CCP抗体水平分别与握力呈弱负相关（r=-0．228，P=0．030）、与ESR呈弱正相关（r=0．365，P=0．013）；RA组及未分类关节炎（痛）组患者外周血抗CCP抗体水平明显高于其他风湿病组患者（P=0．000）；其他风湿病组患者外周血抗CCP抗体水平高于正常组对照组（P=0.011）。46例未分类关节炎（痛）组患者有24例抗CCP抗体阳性，6个月后随访，有32例为早期RA，抗CCP抗体在早期RA的阳性率为72％（23／32），96％（23／24）的未分类关节炎（痛）组抗CCP抗体阳性患者为早期RA.结论 抗CCP抗体反映了RA一定的病情活动性；可用于RA早期诊断及利于早期RA的鉴别诊断；抗CCP抗体水平升高，伴有TNF—α、ESR、PLT升高及关节肿胀时，有助于RA早期诊断。     

Citrullinated peptide and its relevance to rheumatoid arthritis: an update

Citrullinated peptides in autoimmune diseases have been extensively studied in the last two decades. It is suggested that citrullination and the anti-citrullinated peptide antibodies (ACPA) plays a critical role in initiating inflammatory responses in autoimmune diseases, such as rheumatoid arthritis (RA). The most commonly accepted molecular mechanism for citrullinated peptides/proteins in RA is that the modified antigen resulting from cell damage or uncontrolled apoptosis could evoke an immune response leading to autoantibodies against these peptide or the whole protein. Citrullination of arginine is catalyzed by the enzyme peptidylarginine-deiminase (PAD) in the presence of calcium, changing the positively charged arginine to a polar but neutral citrulline. These citrullinated peptides/proteins and the relevant antibodies (ACPA) are important, not only in initiation of RA, but also in the diagnosis of the disease. In this evidence-based clinical review, we summarize recently published data on peptide citrullination and ACPA gauging the ability of anti-cyclic citrullinated peptide (anti-CCP) antibodies for diagnosis of RA. We also recapitulate results of studies elucidating the mechanism underlying the disease.     

Antibodies against cyclic citrullinated peptides in patients affected by rheumatoid arthritis before and after infliximab treatment

To evaluate antibodies against cyclic citrullinated peptides (anti-CCP) together with rheumatoid factor (RF), antinuclear antibodies (ANA) and C-reactive protein (CRP), in patients affected by rheumatoid arthritis (RA), before and after infliximab treatment. Twenty-seven patients (five men and 22 women, mean age of 51.9 years, mean duration of disease 12.6 years) affected by RA, refractory to conventional DMARDs, were treated with infliximab, at the conventional dosage. Before starting infliximab and after 22 weeks, on the occasion of the fifth infusion, anti-CCP antibodies were tested by ELISA method. At the same time IgM RF, ANA and CRP level were measured. Before infliximab therapy, anti-CCP antibodies resulted positive in 23 patients (85.1%); the serum level did not change after infliximab treatment; only one case negative at baseline became slightly positive after treatment. Before and after therapy RF resulted positive in 22 cases (81.4%) and 21 cases (77.7%) respectively; comparing values at baseline with those after 22 weeks of treatment with infliximab, RF levels significantly decreased, as well as CRP values. In contrast to both anti-CCP antibodies, which remained stable, and to RF, which fell after infliximab, ANA were positive 1: 160 in four cases at baseline and in 12 after treatment. The titre of anti-CCP antibodies did not significantly change after anti-TNF blocker administration; instead the positivity of RF significantly decreased. As opposed to antinuclear and anti-dsDNA antibodies, which may appear or increase in titre during infliximab treatment, the typical autoantibodies detectable in RA show a different trend; in fact, anti-CCP antibodies remained stable and RF decreased.     

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。