类风湿关节炎相关自身抗体及其意义

类风湿关节炎（RA）是一种以累及周围关节为主的系统性自身免疫性疾病,全世界患病率为0．5％-1．0％,可引起骨质破坏、关节功能障碍。早期诊断、早期治疗是改善类风湿关节炎患者预后的关键,深入了解类风湿关节炎相关自身抗体的意义对于临床诊治十分重要。     

类风湿关节炎自身抗体检测

类风湿关节炎(rheumatoid arthritis,RA)是一种病因不明的自身免疫性疾病,主要累及四肢关节,也常侵犯关节外器官。RA是一种致畸性关节炎,常导致患者关节畸形,关节功能丧失,严重影响患者的生存质量。早期诊断、治疗可以延缓和防止关节畸形,提高患者生存质量,延长患者生命,因此十     

自身抗体阴性类风湿关节炎的临床及实验室特点

目的 探讨自身抗体阴性类风湿关节炎（rheumatoid arthritis，RA）的临床及实验室特点。方法 分析247例RA患者，比较自身抗体阴性RA（30例）与抗体阳性RA的临床及实验室特点，以骨关节炎患者（34例）作为对照组。结果 自身抗体阴性的RA占12．1％（30／247），自身抗体阴性RA患者的晨僵时间较自身抗体阳性RA患者短（P〈0．05）；血清免疫球蛋白IgG、IgA及γ球蛋白比率水平显著低于自身抗体阳性RA患者（P〈0．01）。而自身抗体阴性RA患者的红细胞沉降率（ESR）、C反应蛋白（CRP）、免疫球蛋白IgM、γ球蛋白比率均明显高于骨关节炎患者（P〈0．05），同时与骨关节炎患者比较，其血红蛋白降低及血小板升高的幅度更明显（P〈0．05）。结论 RA患者中自身抗体阴性者占12．1％．提示自身抗体阴性RA并不少见。ESR、CRP、免疫球蛋白IgM及γ球蛋白的增高在自身抗体阴性RA的诊断中有参考意义。     

自身抗体阴性类风湿关节炎的临床及实验室特点

目的探讨自身抗体阴性类风湿关节炎(rheumatoid arthritis,RA)患者的临床及实验室特点。方法分析11例自身抗体阴性RA患者的临床和实验室特点并监测其自身抗体的变化。结果自身抗体阴性RA患者在全部RA中占6.1%,3个月后有27.3%的自身抗体阴性RA患者的自身抗体转为阳性,6个月后有45.5%的自身抗体阴性RA患者的自身抗体转为阳性。结论自身抗体阴性RA患者较为常见,短期内部分患者的自身抗体可转为阳性,临床上应密切监测RA患者的自身抗体变化。     

类风湿关节炎自身抗体的新认识

类风湿关节炎 (ｒｈｅｕｍａｔｏｉｄａｒｔｈｒｉｔｉｓ,ＲＡ)是一种致残性疾病 ,发病 2年即可出现不可逆的骨关节破坏。现行的美国风湿病学会 (ＡＣＲ)诊断标准主要依靠临床表现、Ｘ线以及类风湿因子 (ＲＦ)检测。符合此标准时病人常已出现骨关节破坏 ,加之ＲＦ缺乏特异性 ,不利于早期诊断、早期干预治疗 ,因此临床需要能用于ＲＡ早期诊断的实验室指标。自从196 4年证实抗核周因子 (ａｎｔｉｐｅｒｉｎｕｃｌｅａｒｆａｃｔｏｒ,ＡＰＦ) [1] 是ＲＡ的特异性抗体并可在疾病早期出现后 ,又陆续发现抗角蛋白抗体 (ＡＫＡ) [2 ] 、抗聚角蛋白…     

多种自身抗体在老年类风湿关节炎诊断中的临床应用价值

目的：探讨抗环瓜氨酸（CCP）抗体、抗角蛋白（AKA）抗体、抗核周因子（APF）和RA33抗体在老年起病类风湿关节炎（EORA）诊断和鉴别诊断中的临床意义。方法：对95例EORA（EORA组）、69例风湿性多肌痛（PMR）患者（PMR组）和47例健康者（对照组）进行抗CCP抗体、AKA、APF和RA33抗体检测,其中抗CCP抗体和RA33抗体采用酶联免疫吸附法（ELISA法）检测,AKA和APF采用间接免疫荧光法（ⅡF）法检测。结果：①抗CCP抗体、AKA、APF和RA33抗体在EORA组的敏感性和特异性分别为（58．9％、95．8％）、（33．7％、91．4％）、（31．6％、89．4％）和（36．8％、86．7％）,显著高于PMR组和对照组（P〈0．01）。②EORA组抗CCP抗体的敏感性显著高于AKA、APF和RA33抗体（P〈0．05）。联合检测4种抗体,敏感性有所降低,但使阳性率提高至98．9％,且有更高的阳性预测值。③69例PMR患者中有6例患者CCP抗体阳性,3例AKA阳性,且与CCP抗体相重叠,2例APF阳性,2例RA33阳性,1年后3例重叠阳性的PMR患者确诊为EORA。结论：PMR与EORA有相似的临床症状和特征,临床上有时难以鉴别,极少数病例,在早期不典型时易误诊,但抗CCP抗体、AKA、APF和RA33抗体仍主要出现在EORA患者中,尤其抗CCP抗体有较高的敏感性和特异性,4种抗体联合检测有更高的特异性和阳性预测值,同时结合临床症状、影像学改变等,4种抗体联合检测对EORA的诊断和鉴别诊断有很高的临床应用价值。     

抗突变型瓜氨酸波形蛋白抗体在类风湿关节炎中的诊断价值

目的 通过与类风湿因子(RF)、抗环瓜氨酸肽(CCP)抗体的比较,探讨抗突变型瓜氨酸波形蛋白(MCV)抗体对类风湿关节炎(RA)的诊断价值,方法采用酶联免疫吸附试验(ELISA)定量检测177例RA患者、46例其他风湿性疾病患者及48名健康对照者血清中抗MCV水平,并同时测定血清中抗CCP抗体、RF水平.采用t检验和χ2检验.结果 抗MCV抗体在RA组、疾病对照组及健康对照组的抗体平均滴度依次为(523±376)、(96±55)、(34±18)U/ml;此外,通过ROC曲线计算曲线下面积来确定最佳阳性阈值(分别以20、40、60、80、100、120、140 U/ml),结果为0.521、0.706、0.769、0.791、0.816、0.826、0.822.其中以抗MCV抗体≥120 U/ml为阳性阈值临床诊断效能最大.所以本研究以抗MCV抗体≥120U/ml为阳性阈值,对RA诊断的敏感性为78.0%,特异性为87.2%,阳件预测值及阴性预测值分别为92.0%和67.8%;抗MCV抗体对RA诊断的特异性与抗CCP抗体相当,但敏感性高于抗CCP抗体;与RF相比较,抗MCV抗体的敏感性和特异性均高于前者.抗MCV抗体联合抗CCP抗体或RF或三者联合检测对诊断RA的特异性提高到95.7%;此外,67例抗CCP抗体阴性的RA患者中有32例抗MCV抗体阳性,占55.2%,59例RF阴性的RA患者中有31例抗MCV抗体阳性,占52.5%.结论 抗MCV抗体可以作为RA的临床诊断血清学指标之一,与抗CCP抗体、RF联合柃测可提高对RA诊断的特异性.     

抗突变型瓜氨酸波形蛋白抗体在类风湿关节炎中的诊断价值

Objective To assess the diagnostic value of anti-mutated citrullinated vimentin antibodies (anti-MCV) for rheumatoid arthritis (RA), and compare it with anti-cyclic citrullinated peptide antibodies (anti-CCP), rheumatoid factors (RF). Methods Commercially available enzyme-linked immunosorbent assay (ELISA) kit was used to detect anti-MCV antibodies in a group of 177 RA patients, 46 patients with other rheumatic diseases, and 48 healthy blood donors. At the same time, anti-CCP, RF were detected. T test and χ2 test were selected. Results The average concentration of anti-MCV was (523±376) U/ml in RA, (96± 55) U/ml in patients with other rheumatic diseases, (34±18) U/ml in healthy controls. Different threshold levels (20, 40, 60, 80, 100, 120, 140 U/ml) for positive results were calculated bythe areas under the ROC curve (the areas were 0.521, 0.706, 0.769, 0.791, 0.816, 0.826, 0.822), then the best diagnosis efficacy for RA was determined as more than 120 U/ml. At this level, the sensitivity and the specificity for anti-MCV were 80.1% and 80.9% for RA diagnosis. The positive and negative predictive value were 92% and 67.8%. Comparing with anti-CCP, anti-MCV showed comparable specificity but higher sensitivity. And it's also better than RF apparently. If all 3 antibodies were detected at the same time, or anti-MCV combine with one of them, the sensitivity would increase to 95.7%. In addition, Anti-MCV showed positive in 32 of 67(55.2%) patients with RA whose anti-CCP was negative, meanwhile 31 of 59 (52.5%) patients with RA whose RF was negative. Conclusion RF and anti-CCP are complementary in diagnosing RA. The combination detection of RF and anti-CCP could significantly improve the specificity for the diagnosis of RA.     

抗突变型瓜氨酸波形蛋白抗体在类风湿关节炎中的诊断价值

Objective To assess the diagnostic value of anti-mutated citrullinated vimentin antibodies (anti-MCV) for rheumatoid arthritis (RA), and compare it with anti-cyclic citrullinated peptide antibodies (anti-CCP), rheumatoid factors (RF). Methods Commercially available enzyme-linked immunosorbent assay (ELISA) kit was used to detect anti-MCV antibodies in a group of 177 RA patients, 46 patients with other rheumatic diseases, and 48 healthy blood donors. At the same time, anti-CCP, RF were detected. T test and χ2 test were selected. Results The average concentration of anti-MCV was (523±376) U/ml in RA, (96± 55) U/ml in patients with other rheumatic diseases, (34±18) U/ml in healthy controls. Different threshold levels (20, 40, 60, 80, 100, 120, 140 U/ml) for positive results were calculated bythe areas under the ROC curve (the areas were 0.521, 0.706, 0.769, 0.791, 0.816, 0.826, 0.822), then the best diagnosis efficacy for RA was determined as more than 120 U/ml. At this level, the sensitivity and the specificity for anti-MCV were 80.1% and 80.9% for RA diagnosis. The positive and negative predictive value were 92% and 67.8%. Comparing with anti-CCP, anti-MCV showed comparable specificity but higher sensitivity. And it's also better than RF apparently. If all 3 antibodies were detected at the same time, or anti-MCV combine with one of them, the sensitivity would increase to 95.7%. In addition, Anti-MCV showed positive in 32 of 67(55.2%) patients with RA whose anti-CCP was negative, meanwhile 31 of 59 (52.5%) patients with RA whose RF was negative. Conclusion RF and anti-CCP are complementary in diagnosing RA. The combination detection of RF and anti-CCP could significantly improve the specificity for the diagnosis of RA.     

自身精氨酸肽的瓜氨酸化与类风湿关节炎

类风湿关节炎（rheumatoid arthritis，RA）患者血液中存在许多针对大量自身抗原的自身抗体，其中被广泛了解的是类风湿因子（RF），但RA中RF阳性率仅约75％，而且RF也可出现在其他风湿性疾病和感染性疾病中．甚至一部分正常人中，对RA的诊断价值受到限制。四十余年研究发现抗核周因子（APF）、抗角蛋白抗体（AKA）、抗丝聚蛋白抗体（anti-fi-laggrin antibody，AFA）、抗Sa抗体、抗环瓜氨酸肽（cyclic citrullinated peptide，CCP）抗体是RA的特异性抗体，这些抗体几乎不出现在其他风湿性疾病、炎症疾病以及正常人中．特别是抗CCP抗体对RA诊断的敏感性达80％，特异性达90％～100％。这些抗体所针对的抗原肽均包含非标准氨基酸一瓜氨酸，瓜氨酸肽是由肽酰基精氨酸脱亚氨酶（PADI）对包含精氨酸的肽脱亚氨基而来．因此这些抗体统称抗瓜氨酸肽抗体（ACPA）。     

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.     

白细胞介素-33的测定及其与早期类风湿关节炎相关性的研究

目的 通过检测早期类风湿关节炎(RA)患者血清中的白细胞介素(IL)-33水平,分析其与早期RA之间的相关性.方法 收集病程<1年的早期RA患者100例,骨关节炎(OA)患者40例以及健康对照者70名.采用双抗体夹心酶联免疫吸附试验(ELISA)测定血清中的IL-33水平,并分析血清IL-33水平与RA各临床和实验室指标的相关性.计量资料的比较采用Kruskal-Wallis检验和(或)Mann-Whitney U检验,计数资料比较采用X2检验,相关性分析采用Spearman相关分析.结果 RA患者血清IL-33水平为(282±871)pg/ml,显著高于健康对照组[(7±38)pg/ml,P(0.01)和OA患者[(8±35)pg/ml,P<0.01].血清IL-33水平与类风湿因子(RF)、隐性类风湿因子IgG(HRF-IgG)、抗环瓜氨酸肽(CCP)抗体、抗突变型瓜氨酸化波形蛋白(MCV)抗体呈正相关(r分别为:0.312,0.277,0.213,0.302,P<0.01或P<0.05). IL-33阳性组患者的RF阳性率、HRF-IgG阳性率、抗CCP抗体阳性率、抗MCV抗体阳性率(86%、31%、86%、94%)较IL-33阴性组患者(54%、11%、42%、72%)显著升高(P均<0.05). 结论 IL-33在RA患者血清中显著升高,并与多种自身抗体(包括RF、抗CCP抗体、抗MCV抗体和HRF-IgG)显著相关,可能是RA预后不良的因素之一.     

Diagnostic accuracy of a clinical prediction rule (CPR) for identifying patients with recent-onset undifferentiated arthritis who are at a high risk of developing rheumatoid arthritis: A systematic review and meta-analysis

Objectives

The Leiden clinical prediction rule (CPR) was developed in 2007 to predict disease progression in patients with recent-onset undifferentiated arthritis (UA). This systematic review and meta-analysis investigates the predictive ability of the rule at identifying patients who are at a high risk of developing rheumatoid arthritis (RA).

Methods

A systematic review of the literature search was conducted from 2007 to May 2013 to identify studies that validated the rule. This study adhered to the PRISMA guidelines. The methodological quality of studies was assessed using the QUADAS-2 tool. Pooled sensitivity and specificity values for each of the cut points were generated using a bivariate random-effects model. Heterogeneity was assessed using the variance of logit-transformed sensitivity and specificity. Bayes' theorem was used to calculate post-test probability of progression from UA to RA.

Results

The search identified four relevant studies, resulting in six data sets (n = 1084). A cut point of ≥9 was identified as the optimal cut point for determining progression to RA. It is associated with a greater pooled specificity (0.99, 95% CI 0.95–1.00) than sensitivity (0.31, 95% CI 0.24–0.37). Using Bayes' theorem, a score of ≥9 points increased the pre-test probability from 40.04% to 93.63%. A less stringent cut-off of ≥8 also identified a significant proportion of patients at risk of RA who have a high likelihood of progressing to RA (LR + 9.5, 95% CI 6.21–14.54).

Conclusion

A cut point of ≥9 offers an optimal estimate for identifying patients with UA who are at a high risk of developing RA and warrant intervention. However, a number of methodological limitations identified across studies suggest that the results should be interpreted cautiously and that further validation of the Leiden CPR is necessary.     

抗PADI4抗体检测方法的建立及其在类风湿关节炎中的临床意义

目的检测类风湿关节炎（RA）患者血清中抗肽酰基精氨酸脱亚胺酶4（PADI4）抗体水平，并探讨其在RA中的临床意义。方法选取RA患者109例，系统性红斑狼疮（SEE）患者67例，干燥综合征（pSS）患者48例、系统性硬化症（SSc）患者41例、骨关节炎（OA）患者34例、皮肌炎／多发性肌炎（DM／PM）患者23例、强直性脊柱炎（AS）患者19例，健康对照106名。以重组的人PADI4蛋白为抗原，用酶联免疫吸附法（ELISA）检测患者血清中抗PADI4抗体水平。并研究其与RA患者发病年龄、病程、疾病活动指数DAS28评分、抗环瓜氨酸肽（CCP）抗体、C反应蛋白（CRP）、红细胞沉降率（ESR）、类风湿因子（RF）、免疫球蛋白（IgG、IgM、IgA）、关节x线分期等指标的关系。结果①RA患者血清中抗PADI4抗体的阳性率为45．0％，明显高于其他风湿性疾病患者和健康对照组（P值均〈0．01）。抗PADI4抗体对RA诊断的敏感性为45．0％，特异性为93．5％。②RA患者血清中抗PADI4抗体滴度明显高于其他风湿性疾病患者以及健康对照组（P均〈0．01）。③抗PADI4抗体阳性患者的DAS28评分、抗CCP抗体、ESR、RF、IgG、IgM水平均高于抗PADI4抗体阴性患者（P值均〈0．05）。相关性分析显示抗PADI4抗体水平与DAS28评分（r=0．333，P〈0．01）和抗CCP抗体（r=0．248，P〈0．05）具有相关性。并且阳性组患者出现皮下结节及关节X线Ⅲ期以上改变的比率也明显高于阴性组患者。结论RA患者血清中可以检测到抗PADI4抗体，该抗体在RA中具有很高的特异性，并且与疾病活动及病情严重程度相关，提示PADI4蛋白可能作为自身抗原在RA的发病和病理过程中起重要作用。     

老年类风湿关节炎患者43例临床分析

目的 探讨老年期发病的类风湿关节炎的临床特点。方法 对43例60岁以后发病的老年患者的临床特点进行分析，并与59例年青发病患者进行比较。结果 老年组男性发病多，急性起病较多；肩和膝等大关节作为首发关节者在老年组(37．2％)高于青中年组(11．8％)；老年组患者关节症状及关节功能障碍均重于青中年组患者，且并发心、肺疾患和骨关节炎者明显增多。结论 老年组在发病形式、首发受累关节均与青中年患者不同，且关节症状严重程度与青中年组患者显著不同，老年人并发症多于青中年人。     

抗Sa抗体的检测及其临床意义

目的　了解抗Sa抗体的临床意义。方法　从新鲜人胎盘中提取Sa抗原 ,应用免疫印迹法检测类风湿关节炎 (RA)及其他风湿病患者血清的抗Sa抗体 ,结合临床资料进行分析。结果　 192例RA中抗Sa抗体阳性 6 5例 ,对RA诊断的敏感性为 33 9% ,特异性为 96 9%。其中同时出现相对分子量为 5 0 0 0 0、5 5 0 0 0两条带的 15例 (2 3 1% ) ,其医师和患者对病情活动性的评价、患者对关节痛的评价及C反应蛋白 (CRP)增高与单独出现 5 0 0 0 0条带者相比 ,均显著增高。 31例早期RA抗Sa抗体阳性率为 32 3% ,9例经随访确诊RA者 4例抗Sa抗体阳性 ;6 3例RF阴性RA中抗Sa抗体阳性率为 2 7%。抗Sa抗体阳性组以小关节起病为主 ,且RF滴度明显较阴性组高。结论　抗Sa抗体有助于早期RA和RF阴性RA诊断 ,同时出现 5 0 0 0 0、5 5 0 0 0两条带可能与病情活动有关。     

血清白细胞介素-17检测在类风湿关节炎中的临床意义

目的 研究白细胞介素(IL)-17在活动期类风湿关节炎(RA)患者血清中水平变化及意义,探讨IL-17在RA的临床意义.方法 ①用酶联免疫吸附法(ELISA)检测51例活动期RA患者(RA组)血清IL-17水平,分析其IL-17水平与临床指标的关系.②检测30例活动期RA患者(治疗组)经来氟米特(LEF)治疗前后IL-17水平变化,分析其与lI缶床指标的关系.采用成组t检验,重复测量的方差分析,单因素方差分析及Spearman相关分析进行统计学处理.结果 ①RA组血清IL-17浓度为(365±63)pg/ml,高于健康对照组(86±13)pg/ml;治疗后较治疗前下降,差异有统计学意义(P<0.01);②RA组血清IL-17水平与晨僵时间、肿胀指数、压痛指数、C反应蛋白(CRP)、红细胞沉降率(ESR)、类风湿因子(RF)、X线分期评分、疾病活动度积分(DAS28)呈正相关(r值分别为:0.423,0.213,0.252,0.276,0.346,0.251,0.412,0.398;P均<0.05);③RA组不同x线分期:I期[(296±79)ps/L]与Ⅱ期[(360±89)pg/L]、Ⅱ期与Ⅲ期[(464±74)ps/L]、Ⅲ期与Ⅳ期[(369±83)pg/L]IL-17水平比较差异均有统计学意义(P<0.05).结论 活动期RA患者血清IL-17的水平比健康人升高,血清IL-17水平可作为RA活动性参考指标之一;血清IL-17水平变化可为RA疗效提供参考;IL-17参与RA的发病和骨侵蚀,可能是治疗RA的重要靶标.     

How to investigate: Pre-clinical rheumatoid arthritis

Multiple studies have shown that there is a pre-clinical period preceding the development of rheumatoid arthritis (RA). During this period, complex interactions between the environmental and genetic causes occur, and the expression “preclinical RA” has been proposed to define it. Early treatment intervention is associated with less joint damage and has an increased possibility of achieving remission. In this review, we provide an overview of the preclinical phases of RA, new immunological and imaging biomarkers, and the clinical features, and the management of individuals at-risk of developing RA.     

趋化素样因子1在类风湿关节炎滑膜中的表达研究

目的研究趋化素样因子1(CKLF1)在类风湿关节炎(RA)滑膜中的表达,探讨CKLF1在RA发病过程中的可能的病理作用。方法取35例RA,20例骨关节炎(OA)及20例半月板损伤患者手术切除的膝关节滑膜标本。采用反转录-聚合酶链反应(RT-PCR)方法检测CKLF1在上述3种病变滑膜中的mRNA水平表达水平。采用免疫组织化学方法检测CKLF1在滑膜组织中的蛋白水平表达特征。结果RA滑膜组织中CKLF1在mRNA水平的表达(0．41±0．17)明显高于OA(0．07±0．06)和半月板损伤患者(0．16±0．10)(P<0．05)。免疫组织化学结果显示,OA病例中仅有2例显示少量滑膜衬里层细胞着色,半月板损伤病例仅有5例显示少量滑膜衬里层细胞着色。在RA滑膜中20例染色强阳性,10例染色阳性,5例染色阴性。阳性染色颗粒位于细胞胞质内,阳性细胞定位在滑膜衬里层的成纤维细胞、滑膜下层大量的浆细胞以及增生的血管上皮细胞。结论CKLF1基因在RA滑膜中有高水平的表达特征,为进一步深入研究RA的发病机制提供新的研究思路。