抗环瓜氨酸肽抗体对类风湿性关节炎早期诊断的应用研究

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王玉俊, 陈洁, 万年红, 顾军, 顾国宝. 抗环瓜氨酸肽抗体对类风湿性关节炎早期诊断的应用研究. 26(7): 440-443
WANG Yujun, CHEN Jie, WAN Nianhong, GU Jun, GU Guobao. Application research of anti-cyclic citrullinated peptide antibody in the early diagnosis of rheumatoid arthritis. Labratory Medicine, 26(7): 440-443 复制到剪切板

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《检验医学》编辑部

抗环瓜氨酸肽抗体对类风湿性关节炎早期诊断的应用研究

王玉俊, 陈洁, 万年红, 顾军, 顾国宝

上海市闸北区中心医院检验科,上海 200070

作者简介：王玉俊,女,1965年生,学士,副教授,主要从事临床免疫学和临床微生物学检验工作。

基金:上海市闸北区科委、闸北区卫生局医学科研资助项目（2006一般02）;

摘要

目的

探讨抗环瓜氨酸肽(CCP)抗体对类风湿性关节炎(RA)早期诊断的临床意义。

方法

应用酶联免疫吸附试验(ELISA)对126例病程<2年的RA患者、135例非RA患者、112名健康体检者进行抗CCP抗体的定量检测,并与类风湿因子(RF)相比较。

结果

抗CCP抗体在RA组的阳性率为63.5%,明显高于非RA患者组(2.2%)和健康对照组(0.0%),抗CCP抗体的特异性(97.8%)显著高于RF(83.7%),假阳性率(2.2%)显著低于RF(16.3%)(P均<0.001);抗CCP抗体阳性RA患者的红细胞沉降率(ESR)和C反应蛋白(CRP)均显著高于抗CCP抗体阴性的RA患者。对抗CCP抗体阳性而RF阴性的RA患者追踪观察表明,半年后其中42.9%的患者RF转为阳性。

结论

抗CCP抗体对早期RA诊断有很高的特异性,具有反映RA病情是否活动和帮助判断预后的应用价值;由于血清抗CCP抗体可以较RF先出现,具有早期诊断价值。

关键词: 抗环瓜氨酸肽抗体; 类风湿性关节炎; 类风湿因子; 早期诊断; 评价

中图分类号:R446.62 文献标志码:A 文章编号:1673-8640(2011)07-0440-04

Application research of anti-cyclic citrullinated peptide antibody in the early diagnosis of rheumatoid arthritis

WANG Yujun, CHEN Jie, WAN Nianhong, GU Jun, GU Guobao

Department of Clinical Laboratory, Shanghai Zhabei District Centre Hospital, Shanghai 200070, China

Fund:

Abstract

Objective

To investigate the clinical significance of anti-cyclic citrullinated peptide (CCP) antibody in the early diagnosis of rheumatoid arthritis (RA).

Methods

Anti-CCP antibody expression levels were detected by enzyme-linked immunosorbent assay (ELISA) and compared with the rheumatoid factor (RF) expression in 126 cases of RA patients with the disease course <2 years,135 cases of non-RA patients and 112 cases of healthy subjects.

Results

The positive rate of anti-CCP antibody in RA group was 63.5%,and was significantly higher than those in the non-RA group (2.2%) and the healthy control group (0.0%). The specificity of anti-CCP antibody (97.8%) was higher than that of RF (83.7%), while the false positive rate (2.2%) was significantly lower than that of RF (16.3%,P<0.001). Erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) level in the anti-CCP antibody positive patients were significantly higher than those in the anti-CCP antibody negative RA patients. The follow-up results to the anti-CCP antibody positive and RF negative patients demonstrated that RF turned to be positive in 42.9% patients after a half year.

Conclusions

Anti-CCP antibody is highly specific in the early diagnosis of RA, and can reflect the disease progression and help the prognosis prediction. Because the anti-CCP antibody appears earlier than RF,anti-CCP antibody has an early diagnosis value.

Keyword: Anti-cyclic citrullinated peptide antibody; Rheumatoid arthritis; Rheumatoid factor; Early diagnosis; Evaluation

Show Figures

类风湿性关节炎( rheumatoid arthritis, RA)是临床最常见的自身免疫性疾病之一,全世界约有1%的人患有此病^{[ 1]},其临床特征为对称性的大小关节滑膜的炎症,可导致关节强直、畸形和功能丧失。RA早期临床表现复杂多变,大多不典型,容易造成误诊或漏诊^{[ 2, 3]}。目前按照美国风湿病学会(ACR)1987年修订的诊断标准^{[ 4]},主要依据临床表现、X线改变和类风湿因子(rheumatoid factor,RF)检测进行诊断。因RF缺乏特异性^{[ 5]},不利于早期诊断,影响了早期干预治疗和降低致残率。抗环瓜氨酸肽(cyclic citrullinated peptide,CCP)抗体是目前所知最有希望广泛应用于RA早期诊断的一种自身抗体^{[ 6]},但目前国内对抗CCP抗体的临床应用尚缺乏较系统的试验研究。本研究通过其与RF的比较,探讨抗CCP抗体在RA早期诊断中的临床意义,为临床推广提出新的策略。

材料和方法

一、研究对象

上海市闸北区中心医院2006年2月至2009年12月间门诊的RA患者、非RA患者及健康体检者共373例,分为3组。(1)RA组:风湿科门诊早期RA患者126例,其中男40例,年龄(51.2±10.2)岁;女86例,年龄(48.3±9.3)岁,临床表现和辅助检查均符合1987年ACR修订的RA诊断标准,且病程均<24个月;(2)非RA患者组:135例,包括风湿性关节炎74例,骨性关节炎61例,均符合国内及国际相应疾病的诊断标准;(3)健康对照组:正常健康体检者112名,均无自身免疫性疾病及骨关节性疾病病史。

二、方法

所有受检者抽取静脉血3 mL,分离血清,存放在-20 ℃低温冰箱待检。抗CCP抗体定量检测应用酶联免疫吸附试验(ELISA),试剂购自上海富纯中南生物技术有限公司,是该公司自主研发的试剂盒,属于第2代抗CCP抗体检测试剂。RF定量检测采用DADE Behring BN ProSpec特定蛋白分析仪及配套试剂。检测结果以抗CCP抗体>25 RU/mL、RF>20 U/mL 作为阳性临界值。对抗CCP抗体阳性而RF阴性的RA患者进行0.5~1年的RF追踪测定。C反应蛋白(CRP)定量检测采用芬兰Orion公司生产的QuickRead CRP分析仪。红细胞沉降率(ESR)检测采用Dragon Medical ESR2010型分析仪。检测均按操作说明书进行。

三、统计学方法

采用SPSS 16.0统计软件,计量资料用 t检验,对率的比较进行 χ²检验,组内两指标阳性率的比较用配对 χ²检验, P<0.05表示差异有统计学意义。

结果

一、RA组、非RA患者组和健康对照组血清学检测阳性率的比较

RA组抗CCP抗体与RF检测的阳性率高,见表1。抗CCP抗体及RF检测RA的阳性率差异无统计学意义,二者也无相关性;但对非RA患者及健康人,抗CCP抗体的假阳性率显著低于RF,对非RA的检测结果,二者呈显著的正相关关系。见表2、3。

表1 各组抗CCP抗体和RF的检测结果

表2 抗CCP抗体和RF在RA组中阳性率的比较和相关性

表3 抗CCP抗体和RF在非RA患者组中阳性率的比较和相关性

二、抗CCP抗体与RF诊断RA的评价指标比较

抗CCP抗体、RF在126例RA患者中敏感性分别为63.5%、73.8%,特异性分别为97.8%、83.7%,抗CCP抗体的特异性和阳性预测值均显著高于RF,假阳性率低于RF,而2项指标的敏感性及阴性预测值差异无统计学意义。见表4。

表4 抗CCP抗体与RF诊断RA的评价指标比较(%)

三、RA患者抗CCP抗体检测结果与其他实验室指标变化的关系

抗CCP抗体阳性的患者,其ESR和CRP均显著高于抗CCP抗体阴性者。见表5。

表5 抗CCP抗体不同检测结果的RA患者ESR、CRP比较

四、RA患者血清抗CCP抗体含量与RF的关系

抗CCP抗体和RF 2项指标均为阳性的RA患者血清抗CCP抗体含量显著高于仅抗CCP抗体单项阳性的RA患者。见表6。

表6 RA患者抗CCP抗体含量与RF的关系

五、抗CCP抗体阳性而RF阴性的RA患者前瞻性血清学追踪观察

为进一步明确抗CCP抗体对RA的早期诊断价值,对21例抗CCP抗体阳性而RF检测阴性的患者于首次检测后每0.5~1年进行上述项目的追踪实验室检测,观察其抗CCP 抗体和RF的含量变化,其中9例(42.9%)抗CCP 抗体含量较高患者的RF由阴性转为阳性,且抗CCP抗体的含量较前次均有明显增高;4例患者的抗CCP抗体含量虽较前次明显增高,RF含量仍为正常;其余8例患者的抗CCP抗体和RF含量均未见明显变化。

讨论

RA是最常见的以慢性、对称性、侵袭性关节炎为主要表现的全身性自身免疫性疾病之一。男女患病率之比为1∶(2~4),患病率随年龄增长而增高,以40~60岁为发病高峰^{[ 7]}。90%患者发病2年内即出现不可逆的骨关节损伤^{[ 8]},并可引起心血管、神经等多系统损害,给患者带来极大痛苦,早期诊断及治疗是控制病情的关键。由于RA早期临床表现复杂多变,大多不典型,容易造成误诊或漏诊,2000年有学者首先将抗CCP抗体检测用于RA的检验诊断^{[ 9]},给RA的早期诊断带来了希望^{[ 10]}。

本研究应用ELISA定量检测抗CCP抗体在RA、非RA患者及健康人血清中的含量,抗CCP抗体在RA组的阳性率明显高于非RA患者组和健康对照组,与传统的RF检测相比较,抗CCP抗体在病程不足2年的早期RA患者中,特异性和阳性预测值显著高于RF,假阳性率显著低于RF。抗CCP抗体的特异性高、假阳性率低,反映其排除非RA的能力较RF强,对确诊RA更有把握。2种检测手段的敏感性和阴性预测值差异无统计学意义。

分析早期RA患者抗CCP抗体与其他实验室指标的关系,发现抗CCP抗体阳性的RA患者,其ESR和CRP均显著高于抗CCP抗体阴性RA患者,同时发现抗CCP抗体和RF 2项指标均为阳性的RA患者血清抗CCP抗体含量显著高于仅抗CCP抗体单项阳性的RA患者,且抗CCP抗体含量较高的患者,其RF含量也常较高,提示抗CCP抗体可反映患者的病情变化,可作为判断病情和预后的指标。Kroot等^{[ 11]}对数百例RA患者进行1~6年随访,通过影像学评分的连续观察指出,抗CCP抗体阳性患者较阴性患者更易发展成影像学可见的关节损害,抗CCP抗体的含量与疾病的预后和患者的治疗反应有关,高含量的抗CCP抗体预示了较严重的疾病过程^{[ 12]},并且应用肿瘤坏死因子α拮抗剂治疗RA患者,高含量抗CCP抗体患者对治疗无效,而低含量抗CCP抗体患者有较好的治疗效果^{[ 13]}。本研究发现抗CCP抗体与RF两者都呈阳性的RA患者,其抗CCP抗体含量明显高于仅单项抗CCP抗体阳性的患者,这可能与RA患者的病程及其自身免疫反应的程度有关^{[ 14]};HLA-DR4基因与抗CCP抗体阳性患者具有紧密的相关性^{[ 15, 16]},HLA-DR4分子上的特殊结构在诱导对瓜氨酸蛋白的自身免疫中起了重要作用;影响抗CCP抗体滴度最重要的基因区位于人类主要组织复合体(MHC)区^{[ 17]}。

通过对抗CCP抗体阳性而RF阴性RA患者的随访观察,0.5~1年后有42.9%抗CCP抗体含量较高的患者RF由阴性转为阳性,提示RA患者检出抗CCP抗体的时间较RF早,更具有早期诊断价值。

总之,抗CCP抗体对RA诊断有较好的敏感性和很高的特异性,抗CCP抗体的含量与RF阳性与否、ESR加快及CRP升高相一致,因此抗CCP抗体具有反映RA病情是否活动和帮助判断预后的应用价值。通过对抗CCP抗体阳性而RF阴性的RA患者的随访观察,早期RA患者的抗CCP抗体可以较RF先出现,具有早期诊断价值,对于疑似RA病例的早期诊断,抗CCP抗体是较理想的首选指标,值得推广。

The authors have declared that no competing interests exist.

参考文献

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2007

2.037

0.0

. 2007, 26(4):499-504 DOI:10.1007/s10067-006-0309-z

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

1.Numune Training and Research Hospital Department of Rheumatology Ankara Turkey 2.Numune Training and Research Hospital Department of Microbiology Ankara Turkey 3.Refik Belendir sokak 57/5, Y. Ayranc? 06550 Ankara Turkey

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.

... 类风湿性关节炎( rheumatoid arthritis, RA)是临床最常见的自身免疫性疾病之一,全世界约有1%的人患有此病^[1],其临床特征为对称性的大小关节滑膜的炎症,可导致关节强直、畸形和功能丧失 ...

2007

13.976

0.0

... RA早期临床表现复杂多变,大多不典型,容易造成误诊或漏诊^[2,3] ...

2007

2.037

0.0

. 2007, 26(1):17-23 DOI:10.1007/s10067-006-0214-5

Anti-CCP antibodies in rheumatoid arthritis and psoriatic arthritis

1.University of Marmara Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine Istanbul Turkey Istanbul Turkey 2.University of Marmara Division of Hematology–Immunology, Department of Internal Medicine, Faculty of Medicine Istanbul Turkey Istanbul Turkey 3.Uluda? University Medical School Department of Internal Medicine Bursa Turkey Bursa Turkey 4.Istanbul University Division of Rheumatology, Department of Internal Medicine, Istanbul Medical Faculty Istanbul Turkey Istanbul Turkey 5.Fahrettin Kerim G?kay Cad. Gül AP. No: 168/13, 34730 G?ztepe Istanbul Turkey Istanbul Turkey

Our aim is to assess the prevalence and associated clinical features of anti-CCP (cyclic citrullinated peptide) antibodies for RF (rheumatoid factor)-positive and RF-negative rheumatoid arthritis (RA) and psoriatic arthritis (PsA). In a prospective, cross-sectional, multi-centre study, we determined the titres of anti-CCP antibodies in 208 RA patients (129 RF-positive, 79 RF-negative), 56 PsA patients and 39 healthy controls (HC). Clinical parameters including disease activity (disease activity score 28—DAS28), physical disability (health assessment questionnaire—HAQ), functional capacity (functional class) and radiological erosions were investigated in patients with RA. In PsA patients, clinical and radiological features were determined. Anti-CCP2 antibodies were measured using a second-generation anti-CCP enzyme-linked immunosorbent assay (Euro-Diagnostica, Netherlands). One-hundred four of 129 RF-positive RA (81%), 16 of 79 RF-negative RA (20%), seven of 56 PsA patients (12.5%) and none of the HC had anti-CCP antibodies. RA patients with anti-CCP antibodies had significantly higher disease activity, greater loss of function and more frequent erosive disease than anti-CCP antibody-negative group. In subgroup analysis, anti-CCP antibodies in RF-negative patients were also associated with erosive disease. All PsA patients with anti-CCP antibodies had symmetric arthritis with higher number of swollen joints. The prevalence of anti-CCP antibodies in RF-positive RA patients was significantly higher than in RF-negative RA and PsA patients. Anti-CCP antibodies were also associated with erosive disease in RF-negative RA patients. Both anti-CCP and RF tests were negative in 30% of the patients. Anti-CCP positivity was a frequent finding in PsA and associated with symmetrical polyarthritis.

... RA早期临床表现复杂多变,大多不典型,容易造成误诊或漏诊^[2,3] ...

1988

7.477

0.0

. 1988, 31(3):315-324

The american rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis

Frank C. Arnett MD 1,19,* ,Steven M. Edworthy MD 2,19 ,Daniel A. Bloch PhD 3,19 ,Dennis J. Mcshane MD 4,19 ,James F. Fries MD 5,19 ,Norman S. Cooper MD 6,19 ,Louis A. Healey MD 7,19 ,Stephen R. Kaplan MD 8,19 ,Matthew H. Liang MD MPH 9,19 ,Harvinder S. Luthra MD 10,19 ,Thomas A. Medsger Jr MD 11,19 ,Donald M. Mitchell MD 12,19 ,David H. Neustadt MD 13,19 ,Robert S. Pinals MD 14,19 ,Jane G. Schaller MD 15,19 ,John T. Sharp MD 16,19 ,Ronald L. Wilder MD PhD 17,19 andGene G. Hunder MD 18,19

1Professor of Internal Medicine, The University of Texas Health Science Center at Houston 2Fellow of Immunology, Stanford University School of Medicine, Stanford, CA 3Senior Research Associate of Biostatistics in Immunology, Stanford University School of Medicine 4Assistant Professor of Immunology, Stanford University School of Medicine 5James F. Fries, MD: Associate Professor of Medicine, Stanford University School of Medicine 6Professor of Pathology, New York University School of Medicine, New York, NY 7Virginia Mason Clinic, Seattle, WA 8Professor of Medicine, Brown University Program in Medicine, Providence, RI 9Associate Professor of Medicine, Harvard Medical School, Boston, MA 10Associate Professor of Medicine, Mayo Medical School and Clinic, Rochester, MN 11Professor of Medicine, University of Pittsburgh, Pittsburgh, PA 12Professor of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada 13Clinical Professor of Medicine, University of Louisville School of Medicine, Louisville, KY 14Professor of Medicine, UMDNJ-Robert Wood Johnson Medical School, Newark, NJ, and The Medical Center at Princeton, Princeton, NJ 15Professor of Pediatrics, Tufts-New England Medical Center, Boston, MA 16Staff Physician, Tifton Medical Clinic, Tifton, GA 17Senior Investigator, National Institute of Arthritis and Musculoskeletal and Skin Diseases 18Professor of Medicine, Mayo Medical School and Clinic. 19From the Rheumatoid Arthritis Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. *requests to the American Rheumatism Association, 17 Executive Park Drive, NE, Suite 480, Atlanta, GA 30329

The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a “classification tree” schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91–94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.

... 目前按照美国风湿病学会(ACR)1987年修订的诊断标准^[4],主要依据临床表现、X线改变和类风湿因子(rheumatoid factor,RF)检测进行诊断 ...

2008

3.258

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... 因RF缺乏特异性^[5],不利于早期诊断,影响了早期干预治疗和降低致残率 ...

2002

2.383

0.0

... 抗环瓜氨酸肽(cyclic citrullinated peptide,CCP)抗体是目前所知最有希望广泛应用于RA早期诊断的一种自身抗体^[6],但目前国内对抗CCP抗体的临床应用尚缺乏较系统的试验研究 ...

2005

0.0

... (2~4),患病率随年龄增长而增高,以40~60岁为发病高峰^[7] ...

2005

0.0

... 90%患者发病2年内即出现不可逆的骨关节损伤^[8],并可引起心血管、神经等多系统损害,给患者带来极大痛苦,早期诊断及治疗是控制病情的关键 ...

2007

0.0

... 由于RA早期临床表现复杂多变,大多不典型,容易造成误诊或漏诊,2000年有学者首先将抗CCP抗体检测用于RA的检验诊断^[9],给RA的早期诊断带来了希望^[10] ...

2008

9.111

0.0

2000

7.477

0.0

. 2000, 43(8):null-null

The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis

... Kroot等^[11]对数百例RA患者进行1~6年随访,通过影像学评分的连续观察指出,抗CCP抗体阳性患者较阴性患者更易发展成影像学可见的关节损害,抗CCP抗体的含量与疾病的预后和患者的治疗反应有关,高含量的抗CCP抗体预示了较严重的疾病过程^[12],并且应用肿瘤坏死因子#cod#x003b1 ...

2005

3.258

0.0

2006

3.258

0.0

... 拮抗剂治疗RA患者,高含量抗CCP抗体患者对治疗无效,而低含量抗CCP抗体患者有较好的治疗效果^[13] ...

2005

4.302

0.0

... 本研究发现抗CCP抗体与RF两者都呈阳性的RA患者,其抗CCP抗体含量明显高于仅单项抗CCP抗体阳性的患者,这可能与RA患者的病程及其自身免疫反应的程度有关^[14] ...

2000

0.0

... HLA-DR4基因与抗CCP抗体阳性患者具有紧密的相关性^[15,16],HLA-DR4分子上的特殊结构在诱导对瓜氨酸蛋白的自身免疫中起了重要作用 ...

2003

5.52

0.0

... HLA-DR4基因与抗CCP抗体阳性患者具有紧密的相关性^[15,16],HLA-DR4分子上的特殊结构在诱导对瓜氨酸蛋白的自身免疫中起了重要作用 ...

2009

4.469

0.0

... 影响抗CCP抗体滴度最重要的基因区位于人类主要组织复合体(MHC)区^[17] ...