原发性干燥综合征合并自身免疫性肝病的临床特点及预后分析

doi:10.19723/j.issn.1671-167X.2020.05.015

摘要/Abstract

摘要：

目的:分析原发性干燥综合征(primary Sjögren’s syndrome,pSS)合并自身免疫性肝病(autoimmune liver disease,ALD)的临床特点和预后。方法:回顾性分析浙江大学医学院附属第一医院2014年2月至2017年12月住院的pSS患者,比较pSS伴或不伴ALD两组间的临床表现和预后的差异。结果:共纳入203例pSS患者,其中合并ALD者68例(自身免疫性肝炎31例,原发性胆汁性胆管炎37例),不合并ALD者135例。两组间年龄、性别比例、口干、眼干、疼痛、乏力、淋巴结肿大、涎腺肿大、皮疹、肺部病变、肾脏受累等临床表现,其他免疫性疾病(如自身免疫性甲状腺疾病、类风湿关节炎和血管炎)的发生率,抗核抗体(antinuclear antibody,ANA)滴度,抗干燥综合征A抗体(Sjögren’s syndrome A antibody,SSA)、SSA52、抗干燥综合征B抗体(Sjögren’s syndrome B antibody,SSB)阳性率,红细胞沉降率和C反应蛋白水平差异均无统计学意义。pSS合并ALD的患者病程较短、抗线粒体-M2抗体 (anti-mitochondrial M2 antibody, AMA-M2)和抗着丝点抗体阳性率高,IgG、IgM水平高,C3水平低,血细胞减少,肝脏相关血清学指标(如谷丙转氨酶、谷草转氨酶、谷氨酰转肽酶、碱性磷酸酶、总胆红素、直接胆红素、间接胆红素)水平升高,肝硬化的比例增加,死亡事件明显增多(死亡率13.24% vs. 2.96%, P=0.013),预后更差。二元Logistic回归分析发现,pSS合并ALD的患者出现死亡事件的不良因素为肝硬化、EULAR干燥综合征疾病活动性指数评分(the EULAR Sjögren’s syndrome disease activity index,ESSDAI)和总胆红素水平。Kaplan-Meier生存曲线提示合并ALD的患者生存率低于对照组。结论:pSS合并ALD的患者病情更重、死亡事件发生率高,需要临床重视并加强对症治疗。

关键词: 干燥综合征, 自身免疫性肝病, 自身免疫性肝炎, 预后

Abstract:

Objective: To analyze the clinical features and prognosis in patients with primary Sjögren’s syndrome (pSS) and autoimmune liver diseases (ALD). Methods: A retrospective analysis of clinical manifestation and prognosis was performed in patients with ALD or without ALD during the three years (February 2014 to December 2017). Results: Totally, 203 patients with pSS were included in this study, 68 patients had ALD (31 patients with autoimmune hepatitis, 37 patients with primary biliary cholangitis), while 135 patients did not have ALD. There were no differences between the two groups regarding age, gender, clinical manifestations, such as dry mouth, dry eyes, pain, fatigue, lymphadenopathy, glandular swelling, cutaneous involvement, lung involvement, and renal involvement, and the incidence rate of other autoimmune diseases, such as autoimmune thyroid disease, rheumatoid arthritis, and vasculitis. There were also no differences in the titer of antinuclear antibody (ANA), the positive rates of anti-Sjögren’s syndrome A antibody (SSA), SSA52, and anti-Sjögren’s syndrome B antibody (SSB), and at the levels of erythrocyte sedimentation rate and C-reactive protein between the two groups. Most importantly, the pSS patients with ALD had a shorter disease course, a higher positive rate of anti-mitochondrial M2 antibody (AMA-M2) and anti-centromere antibody, a higher level of IgG and IgM, a lower level of complement 3, and a decreased number of blood cells. They also had a higher level of liver related serum index, such as alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase and total bilirubin, direct bilirubin, indirect bilirubin, a higher incidence rate of liver cirrhosis, an increased death incident (the mortality was 13.24% in the pSS patients with ALD, while 2.96% in the controls, P=0.013), and a worse prognosis. Binary Logistic regression analysis revealed that liver cirrhosis, the EULAR Sjögren’s syndrome disease activity index (ESSDAI) scores and the level of total bilirubin were the prognostic factors of mortality in the pSS patients with ALD. The survival curve was estimated by the Kaplan-Meier method. It demonstrated that the pSS patients with ALD had a lower survival rate when compared with the controls. Conclusion: The patients with both pSS and ALD will suffer from a more severe disease and a higher death incident. We should pay more attention to these patients and provide a better symptomatic treatment for them during clinical practice.

Key words: Sjögren’s syndrome, Autoimmune liver disease, Autoimmune hepatitis, Prognosis

中图分类号:

R593.2

陈伟钱,戴小娜,余叶,王沁,梁钧昱,柯旖旎,易彩虹,林进. 原发性干燥综合征合并自身免疫性肝病的临床特点及预后分析[J]. 北京大学学报（医学版）, 2020, 52(5): 886-891.

Wei-qian CHEN,Xiao-na DAI,Ye YU,Qin WANG,Jun-yu LIANG,Yi-ni KE,Cai-hong YI,Jin LIN. Analysis of clinical features and prognosis in patients with primary Sjögren’s syndrome and autoimmune liver disease[J]. Journal of Peking University (Health Sciences), 2020, 52(5): 886-891.

图/表 4

表1

表2

pSS合并ALD患者的临床特征"

Items	pSS (with ALD) (n=68)	pSS (without ALD) (n=135)	P value
Age/years	56.6±11.1	54.3±13.1	0.220
Male/Female	10/58	10/125	0.133
Course/months	12.0 (2.0, 48.0)	24.0 (6.0, 84.0)	0.002
Dry mouth score (0-10)	2.0 (0, 3.0)	2.0 (1.0, 3.8)	0.422
Dry eye score (0-10)	2.0 (0, 2.5)	2.0 (0, 3.0)	0.727
Pain score (0-10)	0 (0, 0.5)	0 (0, 2.0)	0.386
Fatigue score (0-10)	2.0 (0, 3.0)	2.0 (0, 4.0)	0.749
Lymphadenopathy (+/-)	16/52	20/115	0.248
Glandular swelling (+/-)	21/47	44/91	0.874
Arthritis (+/-)	3/65	32/103	0.001
Cutaneous involvement (+/-)	5/63	22/113	0.077
Lung involvement (+/-)	15/53	34/101	0.729
Renal involvement (+/-)	10/58	31/104	0.167
AMA-M2 (+/-)	33/35	12/113	<0.001
Anti-centromere antibody (+/-)	16/52	14/121	0.012
IgG/(g/dL)	2.11±0.96	1.81±0.88	0.039
IgM/(g/dL)	0.15 (0.1, 0.35)	0.10 (0.06, 0.17)	0.001
IgA/(g/dL)	0.33 (0.25, 0.43)	0.30 (0.19, 0.38)	0.118
IgG4/(g/dL)	0.45 (0.16, 0.98)	0.36 (0.18, 0.64)	0.521
C3/(mg/dL)	88.2±33.8	99.6±26.0	0.011
WBC/(×10⁹/L)	4.4±2.4	5.3±2.8	0.022
Hb/(g/L)	107.7±21.9	117.5±19.2	0.001
Lymphocytes/(×10⁹/L)	1.1 (0.8, 1.4)	1.3 (1.0, 1.7)	0.007
PLT/(×10⁹/L)	121.0±67.7	194.5±83.7	<0.001
ALT/(U/L)	77.0 (19.5, 218.3)	14.5 (10.0, 24.0)	<0.001
AST/(U/L)	88.0 (39.3, 217.5)	20.0 (16.0, 26.0)	<0.001
GGT/(U/L)	112.0 (51.8, 213.3)	19.0 (13.0, 32.3)	<0.001
ALP/(U/L)	165.2±133.3	77.7±47.1	<0.001
Total bilirubin/(μmol/L)	34.5 (13.5, 162.5)	8.0 (6.0, 11.0)	<0.001
Direct bilirubin/(μmol/L)	19.0 (5.0, 93.5)	3.0 (2.0, 3.3)	<0.001
Indirect bilirubin/(μmol/L)	15.5 (9.0, 44.6)	5.0 (3.8, 8.0)	<0.001
Liver cirrhosis (+/-)	27/41	0/135	<0.001
ESSDAI scores	3.4±2.1	3.4±1.9	0.903
UCDA (+/-)	31/35	3/132	<0.001
Hepatic protector (+/-)	32/34	5/130	<0.001
Steroid dose/(mg daily)^*	0 (0, 20.0)	5 (0, 25.0)	0.266
Immunosuppressive agent (+/-)	7/61	10/125	0.593
Steroid dose (last follow-up)/mg	2.5 (0, 5.0)	2.5 (0, 5.0)	0.864
Deaths during follow-up	9	4	0.011

表2

表3

图1

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Autoimmune diseases	pSS (with ALD) (n=68)	pSS (without ALD) (n=135)
AITD	25 (36.8%)	43 (31.9%)
RA	1 (1.5%)	2 (1.5%)
AS	0	3 (2.2%)
IM	0	2 (1.5%)
Scleroderma	0	1 (0.7%)
AOSD	0	1 (0.7%)
Vasculitis	1 (1.5%)	2 (1.5%)

Variables	P value	OR	95%CI for OR
Liver cirrhosis	0.010	6.39	1.57-26.09
ESSDAI scores	0.008	1.55	1.12-2.14
Total bilirubin	0.008	1.01	1.003-1.020
Constant	0.000	0.004