血清IgG4对IgG4相关性疾病诊断价值的Meta分析

doi:10.3969/j.issn.1004-583X.2021.07.002

摘要/Abstract

摘要：

目的系统评价血清IgG4对IgG4相关性疾病(IgG4-RD)的诊断价值。方法计算机检索PubMed、EMBASE、万方数据库、维普数据库和中国知网数据库,收集自2011年1月1日至2020年1月1日所有以探讨血清IgG4对IgG4相关性疾病诊断价值为目的的英文文献,制定严格的纳入及排除标准进行文献筛选及数据提取,采用质量评价工具(QUADAS-2)进行文献质量评估,采用Meta-Disc 1.4软件及STATA15.0软件中“midas”命令进行异质性分析及综合定量合成,计算合并的敏感度、特异度、诊断优势比、阳性似然比及阴性似然比,绘制相关森林图并拟合受试者工作特征曲线(SROC)。将纳入文献按地区、疾病类型以及样本量大小进行亚组分析。结果共有17篇文献, 17095名研究对象纳入本次Meta分析,IgG4的临界值为1.3~1.44 g/L,各研究合并的灵敏度0.88(95%CI:0.81-0.93),特异度为0.89(95%CI:0.83-0.93),阳性似然比为8.3( 95%CI:5.1-13.7),阴性似然比为0.13(95%CI:0.08-0.22),诊断优势比为62(95%CI:25-153)。11篇文献报道了血清IgG4>2×ULN(2.7-2.8 g/L)时的诊断价值,各研究合并的灵敏度0.59(95%CI:0.47-0.7),特异度为0.96(95%CI:0.94-0.97),阳性似然比为14.3( 95%CI:9.1-22.7),阴性似然比为0.42(95%CI:0.32-0.57),诊断优势比为34(95%CI:17-69)。亚组分析显示地域、是否仅纳入自身免疫性胰腺炎(AIP)患者以及IgG4-RD患者样本量大小均可能为异质性来源。Deeks漏斗图显示不存在发表偏倚,敏感性分析结果稳定可靠。结论血清IgG4在IgG4-RD的诊断中具有较高的参考价值,提高临界值至2×ULN并没有明显的诊断优势,这一结果仍需更多前瞻性高质量诊断试验进行验证。

关键词: 免疫球蛋白G, IgG4相关性疾病, 诊断, Meta分析

Abstract:

Objective To systematically evaluate the diagnostic value of serum IgG4 for IgG4-related diseases (IgG4-RD).Methods All related English studies to explore diagnostic value of serum IgG4 in IgG4-related diseases published in PubMed, EMBASE, Wangfang, Weipu and CNKI from January 1st, 2011 to January 1st, 2020 were searched by computer. Strict inclusion and exclusion criteria for literature screening and data extraction were established, the quality assessment was made by the quality evaluation tool (QUADAS-2), and meta-disc 1.4 software and the “Midas” command in STATA15.0 software were used for heterogeneity analysis and comprehensive quantitative synthesis. The pooled sensitivity, specificity, diagnostic advantage ratio, positive likelihood ratio and negative likelihood ratio were calculated respectively, and the relevant forest map was drawn, and the summary receiver operating curve (SROC) was fitted. The included literature were subgroup analyzed by region, disease type and sample size. Results A total of 17 articles and 17 095 patients were included in this meta-analysis. The cut-off value of IgG4 ranged from 1.3 to 1.44 g/L, the pooled sensitivity was 0.88(95%CI:0.81-0.93), the pooled specificity was 0.89(95%CI: 0.83-0.93), the pooled positive likelihood ratio was 8.3(95%CI: 5.1-13.7), the pooled negative likelihood ratio was 0.13(95%CI: 0.08-0.22) and the diagnostic advantage ratio was 62 (95%CI:25-153),respectively. The diagnostic value of serum IgG4>2×ULN (2.7-2.8 g/L) was reported in 11 studies, and the pooled sensitivity was 0.59(95%CI: 0.47-0.7), the pooled specificity was 0.96(95%CI: 0.94-0.97), the pooled positive likelihood ratio was 14.3(95%CI:9.1-22.7), the pooled negative likelihood ratio was 0.42(95%CI: 0.32-0.57), and the pooled diagnostic advantage ratio was 34(95%CI:17-69). Subgroup analysis showed that geography, whether only AIP patients were included, and sample size of IgG4-RD patients were all possible sources of heterogeneity. Deeks funnel plot showed no publication bias, and the sensitivity analysis revealed that the analysis result were stable and reliable. Conclusion Serum IgG4 has a high reference value in the diagnosis of IgG4-RD, and there is no significant diagnostic advantage in increasing the cut-off value to 2×ULN. This result still needs to be verified by more prospective and high-quality diagnostic tests.

Key words: immunoglobulin G, IgG4-related diseases, diagnosis, meta-analysis

中图分类号:

R392.11

丁航, 刘源, 张连峰, 周琳. 血清IgG4对IgG4相关性疾病诊断价值的Meta分析[J]. 临床荟萃, 2021, 36(7): 587-594.

Ding Hang, Liu Yuan, Zhang Lianfeng, Zhou Lin. Diagnostic value of serum IgG4 for IgG4-related diseases: A meta-analysis[J]. Clinical Focus, 2021, 36(7): 587-594.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2021.07.002

https://huicui.hebmu.edu.cn/CN/Y2021/V36/I7/587

图/表 13

参考文献 30

[1]	Takahashi H, Yamamoto M, Suzuki C, et al. The birthday of a new syndrome: IgG4-related diseases constitute a clinical entity[J]. Autoimmun Rev, 2010,9(9):591-594. doi: 10.1016/j.autrev.2010.05.003 pmid: 20457280
[2]	Umehara H, Okazaki K, Nakamura T, et al. Current approach to the diagnosis of IgG4-related disease-Combination of comprehensive diagnostic and organ-specific criteria[J]. Mod Rheumatol, 2017,27(3):381-391. doi: 10.1080/14397595.2017.1290911 URL
[3]	Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis[J]. N Engl J Med, 2001,344(10):732-738. doi: 10.1056/NEJM200103083441005 URL
[4]	Wallace ZS, Deshpande V, Mattoo H, et al. IgG4-related disease: Clinical and laboratory features in one hundred twenty-five patients[J]. Arthritis Rheumatol, 2015,67(9):2466-2475. doi: 10.1002/art.39205 URL
[5]	Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies[J]. Ann Intern Med, 2011,155(8):529-536. doi: 10.7326/0003-4819-155-8-201110180-00009 pmid: 22007046
[6]	Naitoh I, Nakazawa T, Hayashi K, et al. Clinical differences between mass-forming autoimmune pancreatitis and pancreatic cancer[J]. Scand J Gastroenterol, 2012,47(5):607-613. doi: 10.3109/00365521.2012.667147 URL
[7]	Wang L, Chu X, Ma Y, et al. A Comparative analysis of serum IgG4 levels in patients with IgG4-related disease and other disorders[J]. Am J Med Sci, 2017,354(3):252-256. doi: S0002-9629(17)30278-1 pmid: 28918831
[8]	Su Y, Sun W, Wang C, et al. Detection of serum IgG4 levels in patients with IgG4-related disease and other disorders[J]. PLoS One, 2015,10(4):e0124233. doi: 10.1371/journal.pone.0124233 URL
[9]	Yu KH, Chan TM, Tsai PH, et al. Diagnostic performance of serum IgG4 levels in patients with IgG4-related disease[J]. Medicine (Baltimore), 2015,94(41):e1707. doi: 10.1097/MD.0000000000001707 URL
[10]	Carruthers MN, Khosroshahi A, Augustin T, et al. The diagnostic utility of serum IgG4 concentrations in IgG4-related disease[J]. Ann Rheum Dis, 2015,74(1):14-18. doi: 10.1136/annrheumdis-2013-204907 pmid: 24651618
[11]	Sanchez-Castanon M, de Las Heras-Castano G, Gomez C, et al. Differentiation of autoimmune pancreatitis from pancreas cancer: Utility of anti-amylase and anti-carbonic anhydrase II autoantibodies[J]. Auto Immun Highlights, 2012,3(1):11-17.
[12]	Yang H, Li J, Wang Y, et al. Distribution characteristics of elevated serum immunoglobulin G₄(IgG₄) and its relationship with IgG4-related disease[J]. Scand J Rheumatol, 2019,48(6):497-504. doi: 10.1080/03009742.2019.1602882 pmid: 31354076
[13]	Culver EL, Sadler R, Simpson D, et al. Elevated serum IgG4 levels in diagnosis, treatment response, organ involvement, and relapse in a prospective IgG4-related disease UK cohort[J]. Am J Gastroenterol, 2016,111(5):733-743. doi: 10.1038/ajg.2016.40 pmid: 27091321
[14]	Li P, Chen H, Deng C, et al. Establishment of a serum IgG4 cut-off value for the differential diagnosis of IgG4-related disease in Chinese population[J]. Mod Rheumatol, 2016,26(4):583-587. doi: 10.3109/14397595.2015.1117171 URL
[15]	Ohara H, Nakazawa T, Kawa S, et al. Establishment of a serum IgG4 cut-off value for the differential diagnosis of IgG4-related sclerosing cholangitis: A Japanese cohort[J]. J Gastroenterol Hepatol, 2013,28(7):1247-1251. doi: 10.1111/jgh.12248 URL
[16]	Chang MC, Liang PC, Jan S, et al. Increase diagnostic accuracy in differentiating focal type autoimmune pancreatitis from pancreatic cancer with combined serum IgG4 and CA19-9 levels[J]. Pancreatology, 2014,14(5):366-372. doi: 10.1016/j.pan.2014.07.010 URL
[17]	Boonstra K, Culver EL, de Buy Wenniger LM, et al. Serum immunoglobulin G4 and immunoglobulin G1 for distinguishing immunoglobulin G4-associated cholangitis from primary sclerosing cholangitis[J]. Hepatology, 2014,59(5):1954-1963. doi: 10.1002/hep.26977 pmid: 24375491
[18]	Kaji R, Takedatsu H, Okabe Y, et al. Serum immunoglobulin G4 associated with number and distribution of extrapancreatic lesions in type 1 autoimmune pancreatitis patients[J]. J Gastroenterol Hepatol, 2012,27(2):268-272. doi: 10.1111/jgh.2012.27.issue-2 URL
[19]	van Heerde MJ, Buijs J, Hansen BE, et al. Serum level of Ca 19-9 increases ability of IgG4 test to distinguish patients with autoimmune pancreatitis from those with pancreatic carcinoma[J]. Dig Dis Sci, 2014,59(6):1322-1329.
[20]	Oseini AM, Chaiteerakij R, Shire AM, et al. Utility of serum immunoglobulin G4 in distinguishing immunoglobulin G4-associated cholangitis from cholangiocarcinoma[J]. Hepatology, 2011 54(3):940-948. doi: 10.1002/hep.24487 pmid: 21674559
[21]	Detlefsen S, de Vos JD, Tanassi JT, et al. Value of anti-plasminogen binding peptide, anti-carbonic anhydrase II, immunoglobulin G4, and other serological markers for the differentiation of autoimmune pancreatitis and pancreatic cancer[J]. Medicine (Baltimore), 2018,97(31):e11641. doi: 10.1097/MD.0000000000011641 URL
[22]	Yamamoto M, Tabeya T, Naishiro Y, et al. Value of serum IgG4 in the diagnosis of IgG4-related disease and in differentiation from rheumatic diseases and other diseases[J]. Mod Rheumatol, 2012,22(3):419-425. doi: 10.3109/s10165-011-0532-6 URL
[23]	Bledsoe JR, Della-Torre E, Rovati L, et al. IgG4-related disease: review of the histopathologic features, differential diagnosis, and therapeutic approach[J]. APMIS, 2018,126(6):459-476. doi: 10.1111/apm.12845 pmid: 29924455
[24]	Varghese JL, Fung AWS, Mattman A, et al. Clinical utility of serum IgG4 measurement[J]. Clin Chim Acta, 2020,506:228-235. doi: S0009-8981(20)30147-9 pmid: 32272158
[25]	蒋晓涵, 胡乃中, 陈丽红. 免疫球蛋白G4鉴别诊断自身免疫性胰腺炎与胰腺癌价值的荟萃分析[J]. 中华胰腺病杂志, 2016,16(2):119-123.
[26]	乔敏, 董丽娜, 王俊平. 血清IgG4在鉴别自身免疫性胰腺炎与胰腺癌中应用价值的Meta分析[J]. 中国临床实用医学, 2017,11(5):30-34, 39.
[27]	Wallace ZS, Naden RP, Chari S, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease[J]. Ann Rheum Dis, 2020,79(1):77-87.
[28]	Shimosegawa T, Chari ST, Frulloni L, et al. International consensus diagnostic criteria for autoimmune pancreatitis: Guidelines of the International Association of Pancreatology[J]. Pancreas, 2011,40(3):352-358. doi: 10.1097/MPA.0b013e3182142fd2 URL
[29]	Yamada K, Yamamoto M, Saeki T, et al. New clues to the nature of immunoglobulin G4-related disease: A retrospective Japanese multicenter study of baseline clinical features of 334 cases[J]. Arthritis Res Ther, 2017,19(1):262. doi: 10.1186/s13075-017-1467-x URL
[30]	Harkness T, Fu X, Zhang Y, et al. Immunoglobulin G and immunoglobulin G subclass concentrations differ according to sex and race[J]. Ann Allergy Asthma Immunol, 2020,125(2):190-195. doi: 10.1016/j.anai.2020.03.018 URL

作者	年份	国家	疾病类型	IgG4-RD (例)	对照组主要疾病	对照组 (例)	诊断标准	IgGA 临界值 (g/L)	纳入及排除(例)
									TP	FP	FN	TN
									Natioh^[6]	2012	日本	AIP	30	PC	19	JPS2006标准或HISORt 标准	1.35 2.8	26 23	4 1	4 7	15 59
Wang^[7]	2017	中国	IgG4-RD	25	AID;PC;AP;CCA;胆道结石;胆道狭窄;十二指肠乳头癌	298	IgG4-RD病理诊断共识	1.35	25	0	0	298
Su^[8]	2015	中国	IgG4-RD	12	AID;消化系统疾病;肾脏疾病;感染性疾病;肾脏疾病;心血管及呼吸系统疾病	945	IgG4-RD综合诊断标准	1.35	12	32	0	913
Yu^[9]	2015	中国	IgG4-RD	161	AID;恶性肿瘤;胰腺炎;过敏性疾病等	2 740	IgG4-RD综合诊断标准	1.35 2.7	138 121	635 161	23 40	2 105 2 579
Carruthers^[10]	2015	美国	IgG4-RD	72	AID;免疫缺陷病;感染性疾病;肺炎;胰胆管疾病;白血病	308	IgG4-RD病理诊断共识	1.35 2.7	65 25	125 28	7 47	183 280
Sánchez Castañón^[11]	2012	西班牙	AIP	12	PC	175	HISORt标准	1.3	7	10	5	165
Yang^[12]	2019	中国	IgG4-RD	68	风湿性疾病;肾脏疾病;肝胆管及胰腺、胃肠道疾病;造血系统疾病;呼吸系统及心血管疾病;恶性肿瘤	8 097	IgG4-RD综合诊断标准;IgG4-RD病理诊断共识	1.4 2.8	67 58	846 219	1 10	7 251 7 878
Culver^[13]	2016	英国	IgG4-RD	58	恶性肿瘤;PSC;PBC;胰腺炎;肝炎;AIH;AID;IBD	1 082	IgG4-RD综合诊断标准;HISORt标准;ICDC	1.4 2.8	48 33	166 41	10 25	916 1041
Li^[14]	2016	中国	IgG4-RD	242	AID;肾脏疾病;恶性肿瘤;胰腺炎以及健康人群	255	IgG4-RD综合诊断标准	1.35 2.7	196 150	39 16	46 92	216 239
Ohara^[15]	2013	日本	IgG4-SC	344	PSC;CCA;PC	504	2012日本IgG4-SC诊断标准;ICDC	1.35 2.7	309 235	41 8	35 109	463 496
Chang^[16]	2014	中国	AIP	162	PC	90	亚洲标准或ICDC或 HISORt标准	1.4 2.8	105 49	18 5	57 113	72 85
Boonstra^[17]	2014	荷兰	IgG4-SC	73	PSC	310	HISORt标准	1.4 2.8	66 51	45 7	7 22	265 303
Kaji^[18]	2012	日本	AIP	35	PC	71	ICDC;亚洲标准	1.35	32	2	3	69
Van Heerde^[19]	2014	荷兰	AIP	33	PC	53	ICDC或亚洲标准或 HISORt标准	1.4	28	10	5	43
Oseini^[20]	2011	美国	IgG4-SC	97	CCA	287	HISORt标准	1.4 2.8	69 41	37 11	28 56	250 276
Detlefsen^[21]	2018	丹麦	AIP	19	PC	17	ICDC	1.4 2.8	11 7	2 1	8 12	15 16
Yamamoto^[22]	2012	日本	IgG4-RD	102	风湿性疾病;支气管哮喘;IPF;肝硬化;慢性肝炎;恶性肿瘤;MCD以及健康组	299	HISORt标准	1.44	97	28	5	271

作者	年份	国家	疾病类型	IgG4-RD (例)	对照组主要疾病	对照组 (例)	诊断标准	IgGA 临界值 (g/L)	纳入及排除(例)
									TP	FP	FN	TN
									Natioh^[6]	2012	日本	AIP	30	PC	19	JPS2006标准或HISORt 标准	1.35 2.8	26 23	4 1	4 7	15 59
Wang^[7]	2017	中国	IgG4-RD	25	AID;PC;AP;CCA;胆道结石;胆道狭窄;十二指肠乳头癌	298	IgG4-RD病理诊断共识	1.35	25	0	0	298
Su^[8]	2015	中国	IgG4-RD	12	AID;消化系统疾病;肾脏疾病;感染性疾病;肾脏疾病;心血管及呼吸系统疾病	945	IgG4-RD综合诊断标准	1.35	12	32	0	913
Yu^[9]	2015	中国	IgG4-RD	161	AID;恶性肿瘤;胰腺炎;过敏性疾病等	2 740	IgG4-RD综合诊断标准	1.35 2.7	138 121	635 161	23 40	2 105 2 579
Carruthers^[10]	2015	美国	IgG4-RD	72	AID;免疫缺陷病;感染性疾病;肺炎;胰胆管疾病;白血病	308	IgG4-RD病理诊断共识	1.35 2.7	65 25	125 28	7 47	183 280
Sánchez Castañón^[11]	2012	西班牙	AIP	12	PC	175	HISORt标准	1.3	7	10	5	165
Yang^[12]	2019	中国	IgG4-RD	68	风湿性疾病;肾脏疾病;肝胆管及胰腺、胃肠道疾病;造血系统疾病;呼吸系统及心血管疾病;恶性肿瘤	8 097	IgG4-RD综合诊断标准;IgG4-RD病理诊断共识	1.4 2.8	67 58	846 219	1 10	7 251 7 878
Culver^[13]	2016	英国	IgG4-RD	58	恶性肿瘤;PSC;PBC;胰腺炎;肝炎;AIH;AID;IBD	1 082	IgG4-RD综合诊断标准;HISORt标准;ICDC	1.4 2.8	48 33	166 41	10 25	916 1041
Li^[14]	2016	中国	IgG4-RD	242	AID;肾脏疾病;恶性肿瘤;胰腺炎以及健康人群	255	IgG4-RD综合诊断标准	1.35 2.7	196 150	39 16	46 92	216 239
Ohara^[15]	2013	日本	IgG4-SC	344	PSC;CCA;PC	504	2012日本IgG4-SC诊断标准;ICDC	1.35 2.7	309 235	41 8	35 109	463 496
Chang^[16]	2014	中国	AIP	162	PC	90	亚洲标准或ICDC或 HISORt标准	1.4 2.8	105 49	18 5	57 113	72 85
Boonstra^[17]	2014	荷兰	IgG4-SC	73	PSC	310	HISORt标准	1.4 2.8	66 51	45 7	7 22	265 303
Kaji^[18]	2012	日本	AIP	35	PC	71	ICDC;亚洲标准	1.35	32	2	3	69
Van Heerde^[19]	2014	荷兰	AIP	33	PC	53	ICDC或亚洲标准或 HISORt标准	1.4	28	10	5	43
Oseini^[20]	2011	美国	IgG4-SC	97	CCA	287	HISORt标准	1.4 2.8	69 41	37 11	28 56	250 276
Detlefsen^[21]	2018	丹麦	AIP	19	PC	17	ICDC	1.4 2.8	11 7	2 1	8 12	15 16
Yamamoto^[22]	2012	日本	IgG4-RD	102	风湿性疾病;支气管哮喘;IPF;肝硬化;慢性肝炎;恶性肿瘤;MCD以及健康组	299	HISORt标准	1.44	97	28	5	271

分组	篇数	敏感度(95%CI)	P值	特异度(95%CI)	P值	DOR(95%CI)	AUC(95%CI)
总体	17	0.88(0.81-0.93)		0.89(0.83-0.93)		62(25-153)	0.95(0.92-0.96)
地区
亚洲欧美	10 7	0.93(0.83-0.97) 0.8(0.69-0.87)	<0.05	0.92(0.84-0.96) 0.85(0.77-0.91)	<0.05	156(30-816) 23(15-34)	0.97(0.96-0.98) 0.89(0.86-0.92)
疾病谱
IgG4-RD AIP	11 6	0.92(0.84-0.96) 0.77(0.64-0.86)	<0.05	0.90(0.81-0.95) 0.89(0.81-0.94)	0.09	101(26-388) 27(10-75)	0.96(0.94-0.98) 0.91(0.88-0.93)
样本量(例)
<100 >100	5 12	0.89(0.79-0.95) 0.85(0.75-0.92)	0.05	0.91(0.83-0.96) 0.86(0.79-0.9)	<0.05	85(24-304) 34(12-95)	0.96(0.94-0.97) 0.92(0.89-0.94)

分组	篇数	敏感度(95%CI)	P值	特异度(95%CI)	P值	DOR(95%CI)	AUC(95%CI)
总体	17	0.88(0.81-0.93)		0.89(0.83-0.93)		62(25-153)	0.95(0.92-0.96)
地区
亚洲欧美	10 7	0.93(0.83-0.97) 0.8(0.69-0.87)	<0.05	0.92(0.84-0.96) 0.85(0.77-0.91)	<0.05	156(30-816) 23(15-34)	0.97(0.96-0.98) 0.89(0.86-0.92)
疾病谱
IgG4-RD AIP	11 6	0.92(0.84-0.96) 0.77(0.64-0.86)	<0.05	0.90(0.81-0.95) 0.89(0.81-0.94)	0.09	101(26-388) 27(10-75)	0.96(0.94-0.98) 0.91(0.88-0.93)
样本量(例)
<100 >100	5 12	0.89(0.79-0.95) 0.85(0.75-0.92)	0.05	0.91(0.83-0.96) 0.86(0.79-0.9)	<0.05	85(24-304) 34(12-95)	0.96(0.94-0.97) 0.92(0.89-0.94)

分组	篇数	敏感度(95%CI)	P值	特异度(95%CI)	P值	DOR(95%CI)	AUC(95%CI)
总体	11	0.59(0.47-0.7)		0.96(0.94-0.97)		34(17-69)	0.95(0.92-0.96)
地区
亚洲欧美	6 5	0.67(0.52-0.80) 0.49(0.36-0.61)	0.1	0.96(0.94-0.98) 0.95(0.93-0.97)	<0.05	53(21-135) 20(8-51)	0.96(0.94-0.97) 0.89(0.86-0.92)
样本量(例)
<100 >100	7 4	0.59(0.43-0.73) 0.6(0.42-0.75)	0.72	0.96(0.94-0.97) 0.96(0.92-0.98)	<0.05	33(13-83) 32(12-87)	0.95(0.93-0.97) 0.94(0.91-0.96)