抗GP2和抗CUZD1抗体对克罗恩病的诊断价值评估
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摘要
目的 :评估抗酶原颗粒膜糖蛋白2(zymogen granule membrane glycoprotein 2,GP2)抗体和抗带状疱疹透明带样结构域蛋白1(CUB and zonapellucida-like domains-containing protein 1,CUZD1)抗体检测对克罗恩病(Crohn's disease,CD)的诊断效能,并分析2个抗体与CD患者临床特征及临床表型间的相关性。方法 :采用间接免疫荧光法,检测128例CD患者、82例溃疡性结肠炎(ulcerative colitis,UC)患者和60名健康体检者血清中的抗GP2和抗CUZD1抗体。采用χ~2检验比较各组间的抗体表达情况,根据抗GP2和抗CUZD1抗体在各组中的阳性表达情况绘制受试者工作特征曲线,计算曲线下面积(area under the cure,AUC),以评价其单项及联合检测时对CD的辅助诊断效能。通过Logistic回归分析,探讨抗GP2抗体、抗CUZD1抗体表达情况与CD患者的临床特征及临床表型间的关系。结果:(1)抗GP2抗体在CD组、UC组和健康对照组中的阳性率分别为45.3%、11.0%和0,CD组与UC组比较,差异具有统计学意义(χ~2=27.12,P<0.01),CD组与健康对照组比较,差异也有统计学意义(χ~2=39.32,P<0.01)。抗CUZD1抗体在CD组、UC组和健康对照组中的阳性率分别为19.5%、14.6%和0,CD组与对照组间比较,差异有统计学意义(χ~2=13.52,P<0.01);但CD组与UC组比较,差异无统计学意义(χ~2=0.83,P=0.36)。(2)抗GP2抗体、抗CUZD1抗体单项检测时,诊断CD的灵敏度分别为45.3%、19.5%,特异度分别为93.7%、91.5%,AUC分别为0.695、0.555。抗GP2抗体与抗CUZD1抗体联合检测时,其诊断灵敏度为58.6%,特异度为90.1%,AUC为0.744,显著高于抗GP2、抗CUZD1单项检测的AUC值(Z=4.44,2.57,P<0.01)。(3)抗GP2抗体阳性与合并肛周及肠外病变、穿透型疾病行为及病变部位为回结肠呈正相关(P<0.05);抗CUZD1抗体阳性与男性、狭窄型疾病行为及回肠末端病变呈正相关(P<0.05)。结论 :抗GP2抗体和抗CUZD1抗体是CD的特异性血清学标志物,两者联合检测可以提高对CD的诊断效能。抗GP2抗体及抗CUZD1抗体与CD患者的临床特征、表型间具有一定的相关性,有助于预测复杂的疾病表型,可能为临床治疗决策的制定及生物制剂使用时机的把握提供参考依据。
Objective: To investigate the diagnostic value and clinical significance of anti-zymogen granule membrane glycoprotein 2 antibody(GP2) and anti-CUB and zonapellucida-like domains-containing protein 1 antibody(CUZD1) in patients with Crohn's disease(CD). Methods: A total of 128 CD patients, 82 ulcerative colitis(UC) patients and 60 healthy controls were enrolled. Serum anti-GP2 and anti-CUZD1 antibodies were detected by indirect immunofluorescence assay(IIF). Receiver operator characteristic curve(ROC) was used to evaluate the diagnostic efficiency of anti-GP2 and anti-CUZD1 antibodies in single and combining form. The correlation between the two antibodies and clinical characteristics were analyzed by Logistic regression. Results:(1) The positive rates of serum antiGP2 antibodies in CD, UC and health control groups were 45.3%, 11.0%, 0%, respectively. There was significant difference between CD and UC groups( χ~2=27.12, P<0.01)and between CD and health control groups( χ~2=39.32, P<0.01).Positive rates of serum anti-CUZD1 antibodies in CD, UC and health control groups were 19.5%, 14.6%, 0%, respectively.There was significant difference between CD and health control groups( χ~2=13.52, P<0.01), but no significant differences was found between CD and UC groups( χ~2=0.83, P =0.36).(2) The sensitivity of anti-GP2 antibodies was 45.3%, the specificity was 93.7% and the area under ROC curve(AUC)was 0.695; the sensitivity of anti-CUZD1 antibodies was19.5%, the specificity was 91.5% and AUC was 0.555. The diagnostic value of combined anti-GP2 and anti-CUZD1 antibodies was significantly higher than one of them only(Z =4.44, 2.57, respectively, all P <0.01).(3) Multiple linear regression analysis indicated a positive correlation between anti-GP2 antibody and the perianal, penetrated and ileocolon form of CD(P<0.05); and anti-CUZD1 antibody was associated with stenosis and terminal ileum form of CD(P<0.05).Conclusions: Anti-GP2 and anti-CUZD1 antibodies are potential biomarker for the diagnosis of CD. The combination of anti-GP2 and anti-CUZD1 antibodies have higher diagnostic value than one of them only, and could be used to stratify CD patients phenotypically for providing references to establish specific therapeutic strategies.
Objective: To investigate the diagnostic value and clinical significance of anti-zymogen granule membrane glycoprotein 2 antibody(GP2) and anti-CUB and zonapellucida-like domains-containing protein 1 antibody(CUZD1) in patients with Crohn's disease(CD). Methods: A total of 128 CD patients, 82 ulcerative colitis(UC) patients and 60 healthy controls were enrolled. Serum anti-GP2 and anti-CUZD1 antibodies were detected by indirect immunofluorescence assay(IIF). Receiver operator characteristic curve(ROC) was used to evaluate the diagnostic efficiency of anti-GP2 and anti-CUZD1 antibodies in single and combining form. The correlation between the two antibodies and clinical characteristics were analyzed by Logistic regression. Results:(1) The positive rates of serum antiGP2 antibodies in CD, UC and health control groups were 45.3%, 11.0%, 0%, respectively. There was significant difference between CD and UC groups( χ~2=27.12, P<0.01)and between CD and health control groups( χ~2=39.32, P<0.01).Positive rates of serum anti-CUZD1 antibodies in CD, UC and health control groups were 19.5%, 14.6%, 0%, respectively.There was significant difference between CD and health control groups( χ~2=13.52, P<0.01), but no significant differences was found between CD and UC groups( χ~2=0.83, P =0.36).(2) The sensitivity of anti-GP2 antibodies was 45.3%, the specificity was 93.7% and the area under ROC curve(AUC)was 0.695; the sensitivity of anti-CUZD1 antibodies was19.5%, the specificity was 91.5% and AUC was 0.555. The diagnostic value of combined anti-GP2 and anti-CUZD1 antibodies was significantly higher than one of them only(Z =4.44, 2.57, respectively, all P <0.01).(3) Multiple linear regression analysis indicated a positive correlation between anti-GP2 antibody and the perianal, penetrated and ileocolon form of CD(P<0.05); and anti-CUZD1 antibody was associated with stenosis and terminal ileum form of CD(P<0.05).Conclusions: Anti-GP2 and anti-CUZD1 antibodies are potential biomarker for the diagnosis of CD. The combination of anti-GP2 and anti-CUZD1 antibodies have higher diagnostic value than one of them only, and could be used to stratify CD patients phenotypically for providing references to establish specific therapeutic strategies.
引文
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[3]中华医学会消化病学分会炎症性肠病学组.炎症性肠病诊断与治疗的共识意见(2012年·广州)[J].中华内科杂志,2012,51(10):818-831.
[4]Pavlidis P,Komorowski L,Teegen B,et al.Diagnostic and clinical significance of Crohn's disease-specific pancreatic anti-GP2 and anti-CUZD1 antibodies[J].Clin Chem Lab Med,2016,54(2):249-256.
[5]De Long ER,De Long DM,Clarke-Pearson DL.Comparing the areas under two or more correlated receiver operating characteristic curves:a nonparametric approach[J].Biometrics,1988,44(3):837-845.
[6]Geboes K,De Hertogh G.Indeterminate colitis[J].Inflamm Bowel Dis,2003,9(5):324-331.
[7]曾俊祥,潘秀军,沈立松.炎症性肠病血清学标志物的研究进展[J].检验医学,2018,33(2):170-176.
[8]Ooi CJ,Fock KM,Makharia GK,et al.The Asia-Pacific consensus on ulcerative colitis[J].J Gastroenterol Hepatol,2010,25(3):453-468.
[9]高翔,胡品津,郑瑶,等.炎症性肠病患者血清中自身抗体检测的临床意义[J].中华内科杂志,2005,44(6):428-430.
[10]Deng C,Li W,Li J,et al.Diagnostic value of the antiglycoprotein-2 antibody for Crohn's disease:a PRISMAcompliant systematic review and meta-analysis[J].BMJ Open,2017,7(6):e014843.
[11]Farkona S,Soosaipillai A,Filippou P,et al.Novel immunoassays for detection of CUZD1 autoantibodies in serum of patients with inflammatory bowel diseases[J].Clin Chem Lab Med,2017,55(10):1574-1581.
[12]Komorowski L,Teegen B,Probst C,et al.Autoantibodies against exocrine pancreas in Crohn's disease are directed against two antigens:the glycoproteins CUZD1 and GP2[J].J Crohns Colitis,2013,7(10):780-790.
[13]Michaels MA,Jendrek ST,Korf T,et al.Pancreatic Autoantibodies Against CUZD1 and GP2 Are Associated with Distinct Clinical Phenotypes of Crohn's Disease[J].Inflamm Bowel Dis,2015,21(12):2864-2872.
[14]张鑫,胡佳,徐婷,等.抗酶原颗粒膜糖蛋白2抗体在炎症性肠病中的临床意义[J].中华内科杂志,2014,53(3):214-215.
[15]Papp M,Sipeki N,Tornai T,et al.Rediscovery of the Anti-Pancreatic Antibodies and Evaluation of their Prognostic Value in a Prospective Clinical Cohort of Crohn's Patients:The Importance of Specific Target Antigens[GP2 and CUZD1][J].J Crohns Colitis,2015,9(8):659-668.
[16]van Assche G,Lewis JD,Lichtenstein GR,et al.The London position statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organisation:safety[J].Am J Gastroenterol,2011,106(9):1594-1602.
[2]Bernstein CN,Eliakim A,Fedail S,et al.World Gastroenterology Organisation Global Guidelines Inflammatory Bowel Disease:Update August 2015[J].J Clin Gastroenterol,2016,50(10):803-818.
[3]中华医学会消化病学分会炎症性肠病学组.炎症性肠病诊断与治疗的共识意见(2012年·广州)[J].中华内科杂志,2012,51(10):818-831.
[4]Pavlidis P,Komorowski L,Teegen B,et al.Diagnostic and clinical significance of Crohn's disease-specific pancreatic anti-GP2 and anti-CUZD1 antibodies[J].Clin Chem Lab Med,2016,54(2):249-256.
[5]De Long ER,De Long DM,Clarke-Pearson DL.Comparing the areas under two or more correlated receiver operating characteristic curves:a nonparametric approach[J].Biometrics,1988,44(3):837-845.
[6]Geboes K,De Hertogh G.Indeterminate colitis[J].Inflamm Bowel Dis,2003,9(5):324-331.
[7]曾俊祥,潘秀军,沈立松.炎症性肠病血清学标志物的研究进展[J].检验医学,2018,33(2):170-176.
[8]Ooi CJ,Fock KM,Makharia GK,et al.The Asia-Pacific consensus on ulcerative colitis[J].J Gastroenterol Hepatol,2010,25(3):453-468.
[9]高翔,胡品津,郑瑶,等.炎症性肠病患者血清中自身抗体检测的临床意义[J].中华内科杂志,2005,44(6):428-430.
[10]Deng C,Li W,Li J,et al.Diagnostic value of the antiglycoprotein-2 antibody for Crohn's disease:a PRISMAcompliant systematic review and meta-analysis[J].BMJ Open,2017,7(6):e014843.
[11]Farkona S,Soosaipillai A,Filippou P,et al.Novel immunoassays for detection of CUZD1 autoantibodies in serum of patients with inflammatory bowel diseases[J].Clin Chem Lab Med,2017,55(10):1574-1581.
[12]Komorowski L,Teegen B,Probst C,et al.Autoantibodies against exocrine pancreas in Crohn's disease are directed against two antigens:the glycoproteins CUZD1 and GP2[J].J Crohns Colitis,2013,7(10):780-790.
[13]Michaels MA,Jendrek ST,Korf T,et al.Pancreatic Autoantibodies Against CUZD1 and GP2 Are Associated with Distinct Clinical Phenotypes of Crohn's Disease[J].Inflamm Bowel Dis,2015,21(12):2864-2872.
[14]张鑫,胡佳,徐婷,等.抗酶原颗粒膜糖蛋白2抗体在炎症性肠病中的临床意义[J].中华内科杂志,2014,53(3):214-215.
[15]Papp M,Sipeki N,Tornai T,et al.Rediscovery of the Anti-Pancreatic Antibodies and Evaluation of their Prognostic Value in a Prospective Clinical Cohort of Crohn's Patients:The Importance of Specific Target Antigens[GP2 and CUZD1][J].J Crohns Colitis,2015,9(8):659-668.
[16]van Assche G,Lewis JD,Lichtenstein GR,et al.The London position statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organisation:safety[J].Am J Gastroenterol,2011,106(9):1594-1602.