Value of new-type serum fibrosis-related biomarkers level in diagnosing IgG4-related disease

Abstract

Abstract:

Objective:To explore serological biomarkers which can be used for diagnosing IgG4-related diseases (IgG4-RD) and to analyze its correlation with involvement of IgG4-RD and patients' response to corticosteroid therapy.Methods:Seventy-two patients with untreated IgG4-RD from January 2015 to January 2019 were enrolled. The serum concentrations of growth differentiation factor 15 (GDF-15), CC chemokine ligand 2 (CCL2), hyaluronic acid (HA), amino-terminal propeptide of type Ⅲ procollagen (PⅢNP), and tissue inhibitor of metalloproteinases 1 (TIMP-1) were measured by enzyme-linked immunosorbent assay. The enhanced liver fibrosis (ELF) score was calculated from the TIMP-1, PⅢNP and HA values. The value of these biomarkers in reflecting the degree of tissue fibrosis and extent of organ involvement was assessed.Results:Compared with healthy controls, patients with IgG4-RD had significantly elevated serum concentrati-ons of GDF-15, HA, PⅢNP, and TIMP-1; the average concentrations of CCL2, HA, PⅢNP and TIMP-1 were 1 121 pg/mL, 398 pg/mL, 87.2 ng/mL and 211 ng/mL, respectively. The ELF score of IgG4-RD patients was also significantly elevated (11.2). Among them, serum GDF-15 of 666 pg/mL distinguished most efficiently patients with IgG4-RD from healthy controls (area under ROC 0.92, sensitivity 77.8%, specificity 100%).Conclusions:New-type serological biomarker GDF-15 and CCL2 have substantial clinical value in diagnosis of IgG4-RD but can not reflect the severity of organ involvement and degree of fibrosis, or cannot be served as criteria of outcome of corticosteroid treatment.

Key words:IgG4-related disease,Fibrosis,Growth differentiation factor 15,CC chemokine ligand 2

CLC Number:

R539.3

ZHOU Xinyun, CHEN Hui, SHEN Lisong. Value of new-type serum fibrosis-related biomarkers level in diagnosing IgG4-related disease[J]. Journal of Diagnostics Concepts & Practice, 2019, 18(03): 329-333.

Figures/Tables4

项目	中位数（四分位数间距）
年龄（岁）	64（57~74）
性别（男/女）	51（70.8%）/21（29.2%）
病程持续时间（月）	10（4~33）
实验室数据
总IgG（mg/dL）	1 885（1 380~2 460）
IgG4（mg/dL）	457（260~705）
IgG4≥135 mg/dL的比例	68/72（94.4%）
IgE（U/mL）	408（125~774）
C₃（mg/dL）	78.9（69.6~101.9）
C₄（mg/dL）	20.8（13.3~29.2）
sIL-2R（U/mL）	788（485~1 123）

指标	IgG4-RD（n=72）	健康对照组（n=50）	P值
GDF-15（pg/mL）	1 121（645~2033）	286（133~325）	<0.000 1
CCL2（pg/mL）	398（231~475）	309（207~350）	0.014 0
TIMP-1（ng/mL）	211（138~279）	135（103~159）	<0.000 1
HA（ng/mL）	87.2（46.3~132）	20.9（10.8~41.7）	<0.000 1
PⅢNP（ng/mL）	26.1（13.6~50.1）	5.2（0.7~19.9）	<0.000 1
ELF评分（分）	11.2（8.8~13.9）	6.6（4.1~8.9）	<0.000 1

项目	Spearman相关系数	P值
GDF-15	0.08	0.490 0
CCL2	0.04	0.770 0
TIMP-1	0.09	0.450 0
HA	0.16	0.160 0
PⅢNP	-0.16	0.190 0
ELF评分	-0.05	0.850 0
总IgG	0.50	0.000 3
IgG4	0.68	<0.000 1
C₃	-0.31	0.016 0
C₄	-0.47	0.003 7
sIL-2R	0.55	<0.000 1

参数	治疗前	治疗后	P值
IgG4（mg/dL）	248（191~504）	91（59~163）	0.000 5
GDF-15（pg/mL）	989（571~1537）	1 158（872~1743）	0.034 0
CCL2（pg/mL）	310（248~392）	359（297~434）	0.033 0
TIMP-1（ng/mL）	220（172~245）	246（207~280）	0.019 0
HA（ng/mL）	70.6（51.4~86.6）	70.8（55.4~91.0）	0.970 0
PⅢNP（ng/mL）	20.4（5.7~76.8）	35.6（28.2~57.4）	0.860 0
ELF评分	10.3（9.4~10.9）	10.8（10.5~11.4）	0.250 0

References19

[1]	Kamisawa T, Zen Y, Pillai S, et al. IgG4-related disease[J]. Lancet, 2015, 385(9976):1460-1471. doi:10.1016/S0140-6736(14)60720-0pmid:25481618
[2]	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
[3]	Ohta N, Kurakami K, Ishida A, et al. Roles of TGF-beta and periostin in fibrosclerosis in patients with IgG4-rela-ted diseases[J]. Acta Otolaryngol, 2013, 133(12):1322-1327. doi:10.3109/00016489.2013.831187 URL
[4]	Tanaka A, Moriyama M, Nakashima H, et al. Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease[J]. Arthritis Rheum, 2012, 64(1):254-263. doi:10.1002/art.33320 URL
[5]	Akiyama M, Yasuoka H, Yoshimoto K, et al. CC-chemokine ligand 18 is a useful biomarker associated with disease activity in IgG4-related disease[J]. Ann Rheum Dis, 2018, 77(9):1386-1387. doi:10.1136/annrheumdis-2017-212110
[6]	Parkes J, Roderick P, Harris S, et al. Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease[J]. Gut, 2010, 59(9):1245-1251. doi:10.1136/gut.2009.203166pmid:20675693
[7]	Della-Torre E, Feeney E, Deshpande V, et al. B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease[J]. Ann Rheum Dis, 2015, 74(12):2236-2243. doi:10.1136/annrheumdis-2014-205799pmid:25143523
[8]	Abignano G, Cuomo G, Buch MH, et al. The enhanced liver fibrosis test: a clinical grade, validated serum test, biomarker of overall fibrosis in systemic sclerosis[J]. Ann Rheum Dis, 2014, 73(2):420-427. doi:10.1136/annrheumdis-2012-202843 URL
[9]	Wu M, Baron M, Pedroza C, et al. CCL2 in the Circulation Predicts Long-Term Progression of Interstitial Lung Disease in Patients With Early Systemic Sclerosis: Data From Two Independent Cohorts[J]. Arthritis Rheumatol, 2017, 69(9):1871-1878. doi:10.1002/art.40171 URL
[10]	Yalçinkaya Y, Çinar S, Artim-Esen B, et al. The relationship between vascular biomarkers and disease characteristics in systemic sclerosis: elevated MCP-1 is predomi-nantly associated with fibrotic manifestations[J]. Clin Exp Rheumatol, 2016, 34 Suppl 100(5):110-114.
[11]	Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011[J]. Mod Rheumatol, 2012, 22(1):21-30. doi:10.3109/s10165-011-0571-z URL
[12]	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
[13]	Ohara H, Okazaki K, Tsubouchi H, et al. Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012[J]. J Hepatobiliary Pancreat Sci, 2012, 19(5):536-542. doi:10.1007/s00534-012-0521-y URL
[14]	Goto H, Takahira M, Azumi A, et al. Diagnostic criteria for IgG4-related ophthalmic disease[J]. Jpn J Ophthalmol, 2015, 59(1):1-7. doi:10.1007/s10384-014-0352-2 URL
[15]	Matsui S, Yamamoto H, Minamoto S, et al. Proposed diagnostic criteria for IgG4-related respiratory disease[J]. Respir Investig, 2016, 54(2):130-132. doi:10.1016/j.resinv.2015.09.002pmid:26879484
[16]	Lichtinghagen R, Pietsch D, Bantel H, et al. The Enhanced Liver Fibrosis (ELF) score: normal values, influe-nce factors and proposed cut-off values[J]. J Hepatol, 2013, 59(2):236-242. doi:10.1016/j.jhep.2013.03.016pmid:23523583
[17]	de Jager SC, Bermúdez B, Bot I, et al. Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis[J]. J Exp Med, 2011, 208(2):217-225. doi:10.1084/jem.20100370 URL
[18]	Sierra-Filardi E, Nieto C, Domínguez-Soto A, et al. CCL2 shapes macrophage polarization by GM-CSF and M-CSF: identification of CCL2/CCR2-dependent gene expression profile[J]. J Immunol, 2014, 192(8):3858-3867. doi:10.4049/jimmunol.1302821pmid:24639350
[19]	Furukawa S, Moriyama M, Tanaka A, et al. Preferential M2 macrophages contribute to fibrosis in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's di-sease[J]. Clin Immunol, 2015, 156(1):9-18. doi:10.1016/j.clim.2014.10.008pmid:25450336