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吕超昌, 冯少杰, 张续德, 刘凤霞. 血清软骨寡聚基质蛋白对类风湿关节炎的诊断价值[J]. 武警医学, 2018,29(4): 378-380
LV Chaochang, FENG Shaojie, ZHANG Xude, LIU Fengxia. Role of serum cartilage oligomeric matrix protein in diagnosis of rheumatoid arthritis[J]. Medical Journal of the Chinese People's Armed Police Forces, 2018,29(4): 378-380  
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血清软骨寡聚基质蛋白对类风湿关节炎的诊断价值
吕超昌1, 冯少杰1, 张续德2, 刘凤霞2
1.261000,潍坊医学院
2.261000,潍坊市人民医院变态反应科
通讯作者：刘凤霞,E-mail:wf_lfx@163.com

作者简介:吕超昌,在读研究生。

收稿日期: 2017-11-15
摘要

目的 探讨血清软骨寡聚基质蛋白(Cartilage oligomeric matrix protein,COMP)对类风湿关节炎(Rheumatoid arthritis,RA)的诊断价值。方法 选取82例RA患者和34例健康对照人群,分为RA组和健康组。对类风湿关节炎患者,根据临床表现、实验室检查分为活动期组和缓解期组;根据放射学改变分为骨质破坏组和骨质未破坏组,并与抗环瓜氨酸抗体(抗CCP抗体)水平进行比较,评价COMP和抗CCP抗体在RA中的诊断作用,绘制ROC曲线,计算其各自的曲线下面积(AUC)、灵敏度、特异度。健康对照组检测指标同RA患者。结果 RA患者血清COMP水平显著高于健康对照人群( P<0.05),活动期组COMP水平显著高于缓解期组( P<0.05),骨质破坏组COMP水平高于骨质未破坏组( P=0.0156);当COMP和抗CCP抗体各自以21.51 ng/ml和34.76 RU/ml为最佳截断值来区分RA患者和健康人群时,COMP的AUC(0.864)、灵敏度(0.817)、特异度(0.882)均高于抗CCP抗体的AUC(0.764)、灵敏度(0.610)、特异度(0.824)。结论 COMP 作为软骨破坏的一种生物标记物,可以用来鉴别RA患者和健康人。

关键词: 血清软骨寡聚基质蛋白; 类风湿关节炎; 抗环瓜氨酸抗体
中图分类号:R593.22
Role of serum cartilage oligomeric matrix protein in diagnosis of rheumatoid arthritis
LV Chaochang1, FENG Shaojie1, ZHANG Xude2, LIU Fengxia2
1.Weifang Medical University, Weifang 261000,China
2.Allergy Department, Weifang People’s Hospital,Weifang 261000,China;
Abstract

Objective To analyze the role of serum cartilage oligomeric matrix protein (COMP) levels in differential diagnosis of rheumatoid arthritis (RA).Methods Eighty-two patients with RA and another thirty-four healthy control subjects were enrolled and divided into RA patients and healthy controls.According to clinical manifestations and results of laboratory examination, the patients were divided into active patients and patients in remission.According to the radiological changes,these patients were again divided into patients with joint bony damages and those without joint bony damage.The diagnostic ability of COMP for RA was evaluated by comparing it with anti-cyclic citrullinated peptide (anti-CCP) antibody levels.Receiver operating characteristic(ROC) curves were plotted before the areas under the ROC curves(AUC),while sensitivity and specificity were calculated.Results The serum COMP level was significantly higher in patients with RA than in control subjects( P<0.05), in active patients than in those in remission( P<0.05),and in patients with joint bony damages than in those without joint bony damage( P<0.05).When COMP and anti-CCP were used to distinguish between RA patients and healthy controls at the optimal cut-off value of 21.51 ng/ml and 34.76 RU/ml respectively, COMP’s AUC was (0.864), sensitivity (0.817) and specificity was (0.882), higher than those of anti CCP’s AUC (0.764), sensitivity (0.610) and specificity (0.824).Conclusions The serum COMP level can be used as a biological marker for cartilage destruction and for differentiating between patients with RA and healthy individuals.

Keyword: cartilage oligomeric matrix protein; rheumatoid arthritis; anti-cyclic citrullinated peptide antibody

软骨寡聚基质蛋白(cartilage oligomeric matrix protein, COMP)是近年来研究较多的一种软骨代谢标记物[1], 主要由软骨细胞和滑膜细胞分泌, 表达于所有关节结构中, 包括韧带、肌腱和滑膜等。关节软骨一旦损伤, COMP首先释放入滑液, 随后进入血液。因此, 血清和关节液中的COMP 水平可以反映软骨的降解破坏程度和滑膜炎的严重程度[2]。已有研究发现, 血清COMP水平可以作为风湿性疾病关节软骨破坏的新型标记物, 并且能作为观察关节炎患者疗效的指标[3]。本研究采用ELISA方法, 定量检测RA患者和健康人群中的COMP及抗环瓜氨酸肽抗体(anti-cyclic citrullinated peptide antibody, 抗CCP抗体)水平, 评价COMP对RA的诊断价值。

1 对象与方法
1.1 对象

选取2011-01至2013-02在山东潍坊市人民医院就诊的RA患者82例, 均符合2010年修订后的ACR推荐的RA诊断标准[4], 其中男21例, 女61例, 平均(49.93± 11.15)岁, 且符合下列要求:年龄> 18岁, 未经任何治疗, 无其他风湿性疾病或严重疾病, 自愿参加本次实验, 在潍坊居住时间≥ 1年。健康对照人群选取同一时间内在山东潍坊市人民医院查体中心进行体检的健康人34例, 其中男10例, 女24例, 平均(47.60± 15.49)岁, 且符合下列要求:无免疫风湿疾病、肿瘤、慢性感染等病史, 与患者无亲属关系, 与患者平均年龄差距在2岁以内。本研究经医院伦理委员会审核批准, 所有对象均签署了知情同意书。

1.2 方法

1.2.1 分组 根据体格、实验室检查将患者分为活动期组和缓解期组。活动期组患者满足下列标准中的4或5条:(1)晨僵时间≥ 1 h; (2)有中度静息痛; (3)肿胀关节≥ 3个; (4)压痛关节≥ 8个; (5)红细胞沉降率(ESR)> 30 mm/h。缓解期患者满足下列要求且时间超过2个月:(1)晨僵时间≤ 15 min; (2)无静息痛; (3)无关节肿胀和压痛; (4)ESR< 30 mm/h(男)或20 mm/h(女)。

根据患者手部X线表现和参考文献[5, 6]将患者分为两组:骨关节异常组和骨关节无异常组。

1.2.2 血样采集及试剂来源 所有患者(治疗前)及健康人群采集静脉血5 ml入含有分离胶的真空黄头管, 室温自然凝固20 min, 3800 r/min离心20 min后将血清移至EP管-80 ℃保存至待检。COMP试剂盒由美国神谷生物公司提供, 抗CCP抗体试剂盒和标准品均由上海富药科芯生物技术有限公司提供。两种试剂均采用酶联免疫吸附(ELISA)方法测定, 酶标仪判读结果。所有操作步骤均严格按照试剂盒说明书。COMP和抗CCP抗体最低检测浓度分别为0.4 ng/ml和0.1 U/L。

1.3 统计学处理

采用SPSS17.0软件进行统计学分析, 组间比较采用t检验或Mann-Whitney U-test。绘制ROC曲线, 选取最佳截断值并计算AUC、灵敏度和特异度, 分析COMP和抗CCP抗体的最佳截断值和诊断效果。P< 0.05为差异有统计学意义。

2 结 果
2.1 COMP、抗CCP抗体、ESR、CRP、RF水平的比较

RA患者COMP、抗CCP抗体水平高于健康组, 差异有统计学意义(P< 0.05); ESR、CRP、RF差异无统计学意义(表1)。

表1 类风湿关节炎患者和健康人血清COMP、抗CCP抗体、ESR、CRP、RF的比较( x̅± s)
2.2 RA患者活动期和缓解期COMP水平的比较

46例RA患者活动期COMP水平(33.08± 8.80) ng/ml和36例缓解期COMP水平(24.94± 8.80) ng/ml的比较得出两组COMP水平差异有统计学意义(t=4.4, P< 0.05), RA患者COMP水平活动期组高于缓解期组。

2.3 RA患者骨质破坏组和骨质未破坏组COMP水平的比较

44例RA患者骨关节异常组COMP水平(31.77± 8.21) ng/ml高于38例骨关节无异常组COMP水平(26.88± 9.71) ng/ml, 差异有统计学意义(t=2.471, P=0.0156)。

2.4 ROC曲线分析

COMP检测的ROC曲线下面积为0.864(95%CI为0.790, 0.937), 最佳截断值为21.51 ng/ml, 其对RA患者诊断的灵敏度为0.817, 特异度为0.882; 抗CCP抗体ROC曲线下面积为0.746(95%CI为0.674, 0.854), 最佳截断值为34.76 RU/ml, 其对RA患者诊断的敏感性为0.610, 特异性为0.824(表2)。

表2 类风湿关节炎COMP和抗CCP抗体检测的ROC曲线分析
3 讨 论

RA是以侵蚀性、对称性多关节炎为主要临床表现的慢性、系统性自身免疫性病, 影响世界0.5%~1.0%的人口[7], 最显著的特点是外周关节出现炎性滑膜炎[8], 常伴随有关节软骨和骨关节的进展性和不可逆性损伤, 可引起关节畸形和致残, 因此早期诊断对RA治疗和预后具有重要影响[9]。COMP由二巯键相连的五聚蛋白, 属于凝血栓蛋白家族, 是一类软骨基质破坏降解过程中释放到血液和滑膜的大分子物质[10], 成为研究骨与关节损伤的热点。本研究发现:(1)RA患者COMP水平高于健康组, 且活动期组高于缓解期组、骨关节异常组高于骨关节无异常组, 表明COMP不仅可以区分RA患者和健康人群, 还可判断疾病的严重性, 与国内外研究报道一致[11, 12, 13, 14]。虽然有研究表明RA患者的COMP水平显著高于健康对照人群, 在早期骨关节损害患者中也有意义, 但其实验结果受年龄、病程、体质指数等影响较大[15]。(2)RA患者和正常人ESR、CRP、RF差异无统计学意义, 与沈荣春等[16]研究结果一致。虽然ESR和CRP可以反映RA的疾病活动度, 但以此为实验室检查指标来诊断RA时其灵敏度和特异度较差[17]。(3)经ROC曲线分析得出:当COMP以21.51 ng/ml为最佳截断值来诊断和排除RA患者时, 其AUC(0.864)、灵敏度(0.817)、特异度(0.882)均高于抗CCP抗体以34.76 RU/ml为最佳截断值来诊断和排除RA患者时的AUC(0.764)、灵敏度(0.610)、特异度(0.824)。但也有研究结果显示COMP为指标来诊断RA时只有15%~48%的灵敏度和66%~69%的特异度[18], 因此COMP作为诊断指标的实用性仍需研究[19]。

综上所述, 本研究首次证明用COMP的最佳截断值为21.51 ng/ml来鉴别RA患者和健康人群, 推测COMP可以作为RA患者实验室诊断的最新指标, 但需要注意COMP水平受肌肉含量、年龄、性别、饮食等因素的影响[20]。

The authors have declared that no competing interests exist.

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