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北京大学学报（医学版） ›› 2023, Vol. 55 ›› Issue (6): 966-974. doi: 10.19723/j.issn.1671-167X.2023.06.003

• 论著 • 上一篇    下一篇

系统性红斑狼疮及成人Still病合并巨噬细胞活化综合征的临床特点及诊断指标

姚海红1,杨帆1,2,唐素玫1,张霞1,何菁1,贾园1,*()   

  1. 1. 北京大学人民医院风湿免疫科, 北京 100044
    2. 首都医科大学附属北京友谊医院风湿内科, 北京 100050
  • 收稿日期:2023-09-01 出版日期:2023-12-18 发布日期:2023-12-11
  • 通讯作者: 贾园 E-mail:jiayuan1023@sina.com
  • 基金资助:
    国家自然科学基金(81801618)

Clinical characteristics and diagnostic indicators of macrophage activation syndrome in patients with systemic lupus erythematosus and adult-onset Still's disease

Hai-hong YAO1,Fan YANG1,2,Su-mei TANG1,Xia ZHANG1,Jing HE1,Yuan JIA1,*()   

  1. 1. Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing 100044, China
    2. Department of Rheumatology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
  • Received:2023-09-01 Online:2023-12-18 Published:2023-12-11
  • Contact: Yuan JIA E-mail:jiayuan1023@sina.com
  • Supported by:
    the National Natural Science Foundation of China(81801618)

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摘要：

目的: 分析和比较系统性红斑狼疮(systemic lupus erythematosus，SLE)和成人Still病(adult-onset Still’s disease，AOSD)合并巨噬细胞活化综合征(macrophage activation syndrome，MAS)患者的临床及实验室指标特点，评估已有的2016年欧洲抗风湿病联盟/美国风湿病学会/儿童风湿病国际试验组织发布的全身型幼年特发性关节炎(systemic juvenile idiopathic arthritis，sJIA)合并MAS(sJIA-MAS)分类标准在不同自身免疫病背景下的适用情况, 并提出新的诊断预测指标，为提高MAS早期诊断率、改善患者预后提供参考。方法: 回顾性分析2000—2018年在北京大学人民医院住院的24例SLE合并MAS患者和24例AOSD合并MAS患者的临床及实验室数据，分别与同期未发生MAS的50例SLE及50例AOSD患者进行比较，通过受试者工作特征(receiver operating characteristic，ROC)曲线确定预测MAS的实验室指标截断值。进一步使用实验室诊断预测值对2016年sJIA-MAS分类标准进行改进，探讨改进后的标准对于AOSD合并MAS的适用性。结果: 约60%的SLE合并MAS及40%的AOSD合并MAS患者发生在原发病确诊后的3个月内。发热是MAS最常见的临床表现。实验室指标除了2004年国际组织细胞学会修订的噬血细胞综合征诊断标准中的指标外，MAS患者的天冬氨酸转氨酶及乳酸脱氢酶也显著升高，白蛋白显著下降，噬血现象仅见于约50%的MAS患者。ROC曲线分析显示，当SLE患者铁蛋白≥1 010 μg/L、乳酸脱氢酶≥359 U/L，AOSD患者纤维蛋白原≤225.5 mg/dL、甘油三酯≥2.0 mmol/L时，对MAS诊断有最好的区分价值。将2016年sJIA-MAS分类标准应用于AOSD合并MAS，诊断的敏感性和特异性分别为100%和62%，对其中特异性低的铁蛋白和纤维蛋白原条目进行改进，诊断特异性可升高为86%。结论: SLE合并MAS及AOSD合并MAS最常发生于疾病确诊后的早期，不同疾病继发MAS因受自身免疫病特点的影响而在实验室指标方面存在明显差异，以同一标准进行MAS诊断可能导致误诊或漏诊。2016年sJIA-MAS分类标准在AOSD合并MAS诊断中敏感性高而特异性低，对之进行改进可提高特异性。

关键词: 巨噬细胞活化综合征, 噬血细胞性淋巴组织细胞增多症, 系统性红斑狼疮, 成人Still病, 诊断

Abstract:

Objective: To analyze and compare the clinical and laboratory characteristics of macrophage activation syndrome (MAS) in patients with systemic lupus erythematosus (SLE) and adult-onset Still's disease (AOSD), and to evaluate the applicability of the 2016 European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organization classification criteria for MAS complicating systemic juvenile idiopathic arthritis (sJIA) in different auto-immune diseases contexts and to propose new diagnostic predictive indicators. Methods: A retrospective analysis was conducted on the clinical and laboratory data of 24 SLE patients with MAS (SLE-MAS) and 24 AOSD patients with MAS (AOSD-MAS) who were hospitalized at Peking University People's Hospital between 2000 and 2018. Age- and sex-matched SLE (50 patients) and AOSD (50 patients) diagnosed in the same period without MAS episodes were selected as controls. The cutoff values for laboratory indicators predicting SLE-MAS and AOSD-MAS were determined using receiver operating characteristic (ROC) curves. Furthermore, the laboratory diagnostic predictive values for AOSD-MAS were used to improve the classification criteria for systemic juvenile idiopathic arthritis-associated MAS (sJIA-MAS), and the applicability of the revised criteria for AOSD-MAS was explored. Results: Approximately 60% of SLE-MAS and 40% of AOSD-MAS occurred within three months after the diagnosis of the underlying diseases. The most frequent clinical feature was fever. In addition to the indicators mentioned in the diagnosis criteria for hemophagocytic syndrome revised by the International Society for Stem Cell Research, the MAS patients also exhibited significantly elevated levels of aspartate aminotransferase and lactate dehydrogenase, along with a significant decrease in albumin. Hemophagocytosis was observed in only about half of the MAS patients. ROC curve analysis demonstrated that the optimal discriminative values for diagnosing MAS was achieved when SLE patients had ferritin level≥1 010 μg/L and lactate dehydroge-nase levels≥359 U/L, while AOSD patients had fibrinogen levels≤225.5 mg/dL and triglyceride levels≥2.0 mmol/L. Applying the 2016 sJIA-MAS classification criteria to AOSD-MAS yielded a diagnostic sensitivity of 100% and specificity of 62%. By replacing the less specific markers ferritin and fibrinogen in the 2016 sJIA-MAS classification criteria with new cutoff values, the revised criteria for classifying AOSD-MAS had a notable increased specificity of 86%. Conclusion: Secondary MAS commonly occurs in the early stages following the diagnosis of SLE and AOSD. There are notable variations in laboratory indicators among different underlying diseases, which may lead to misdiagnosis or missed diagnosis when using uniform classification criteria for MAS. The 2016 sJIA-MAS classification criteria exhibit high sensitivity but low specificity in diagnosing AOSD-MAS. Modification of the criteria can enhance its specificity.

Key words: Macrophage activation syndrome, Hemophagocytic lymphohistiocytosis, Systemic lupus erythematosus, Adult-onset Still's disease, Diagnosis

中图分类号: 

  • R593.2

表1

HLH患者人口学特征及主要临床和实验室特征"

Items AOSD-MAS (n=24) SLE-MAS (n=24) LYM-HLH (n=20)
Epidemiological features
  Female 21/24 (87.5) 20/24 (83.3) 9/20 (45.0)*#
  Age at diagnosis of HLH/years 34.7±15.2 40.0±15.2 49.1±20.0*
  Age at diagnosis of AD or LYM/years 33.0±16.9 38.5±16.5 48.3±20.2*
  Disease duration before HLH/months 22.7±66.9 21.4±43.0 11.3±26.9
Clinical and laboratory characteristics
  Fever (>38.5 ℃) 24/24 (100.0) 23/24 (95.8) 20/20 (100.0)
  Splenomegaly 18/24 (75.0) 13/24 (54.2) 15/20 (75.0)
  Hepatomegaly 1/24 (4.2) 4/24 (16.7) 5/20 (25.0)
  Lymphadenopathy 9/24 (37.5) 10/24 (41.7) 13/20 (65.0)
  Neurological involvement 4/24 (16.7) 3/24 (12.5) 7/20 (35.0)
  Disseminated intravascular coagulation 7/24 (29.2) 1/24 (4.2) 1/20 (5.0)
Cytopenia
  HB < 90 g/L 17/24 (70.8) 20/24 (83.3) 16/20 (80.0)
  PLT < 100×109/L 16/24 (66.7) 22/24 (91.7) 20/20 (100.0)*
  NE < 1×109/L 10/23 (43.5) 15/22 (68.2) 13/19 (68.4)
Hyperferritinemia (SF>500 μg/L) 24/24 (100.0) 23/24 (95.8) 18/19 (94.7)
Hypofibrinogenemia (FIBC < 1.5 g/L) 15/24 (62.5) 12/23 (52.2) 16/20 (80.0)
Hypertriglyceridemia (TG≥3 mmol/L) 14/24 (58.3) 13/23 (56.5) 10/10 (100.0)*#
LDH>250 U/L 23/24 (95.8) 24/24 (100.0) 18/20 (90.0)
Elevated aminotransferases
  ALT>40 U/L 23/24 (95.8) 15/23 (65.2)* 15/20 (75.0)
  AST>40 U/L 23/24 (95.8) 19/23 (82.6) 16/20 (80.0)
Hypoalbuminemia (ALB < 40 g/L) 23/24 (95.8) 24/24 (100.0) 19/20 (95.0)
Elevated ESR (>20 mm/h) 14/23 (60.7) 22/24 (91.7)* 19/20 (95.0)*
Elevated CRP(>8 mg/dL) 23/24 (95.8) 20/24 (83.3) 18/20 (90.0)
Hemophagocytosis in bone marrow 12/23 (52.2) 13/24 (54.2) 8/18 (44.4)
Low NK cell activity 8/21 (38.1) 9/17 (52.9) 6/10 (60.0)
Serum soluble CD25 receptor≥2 400 U/mL 16/17 (94.1) 14/17 (82.4) 9/10 (90.0)

图1

发生MAS时SLE及AOSD病程分布情况"

表2

不同疾病继发HLH患者的实验室指标的比较"

Items SLE (n=50) AOSD (n=50) SLE-MAS (n=24) AOSD-MAS (n=24) LYM-HLH (n=20)
WBC/(×109/L) 5.2
(1.0, 12.8)		 15.1
(4.9, 38.0)*#		 2.1
(0.2, 13.4)*		 3.8
(0.3, 27.0)		 1.7
(0.1, 6.4)
NE/(×109/L) 3.4
(0.7, 8.6)		 12.6
(3.3, 35.1)*#		 1.2
(0, 7.4)*		 2.6
(0, 24.2)		 1.1
(0, 5.5)
HB/(g/L) 107.8
(46.0, 180.0)		 107.3
(84.0, 129.0)#		 70.5
(40.0, 104.2)*#		 82.5
(49.0, 122.0)△		 70.4
(47.0, 136.0)
PLT/(×109/L) 155.8
(5.0, 381.0)		 305.0
(84.0, 576.0)*#		 42.8
(2.0, 134.0)*#△		 88.4
(7.0, 296.0)△		 23.6
(2.0, 90.0)
ESR/(mm/h) 31.8
(3.0, 92.0)		 72.3
(1.0, 133.0)*#		 66.6
(7.0, 120.0)*#		 32.0
(2.0, 78.0)		 44.6
(3.0, 129.0)
CRP/(mg/dL) 9.6
(0.3, 50.2)		 89.9
(4.0, 339.0)*		 60.4
(2.3, 364.0)*		 67.8
(7.5, 272.0)		 77.9
(3.0, 211.0)
ALT/(U/L) 33.0
(5.0, 215.0)		 19.8
(5.0, 73.0)*#		 109.4
(5.0, 619.0)*#		 715.8
(28.0, 3 550.0)△		 132.2
(11.0, 286.0)
AST/(U/L) 36.4
(9.0, 477.0)		 58.1
(11.0, 873.0)#		 308.5
(8.0, 1 424.0)*		 682.0
(14.0, 2 174.0)△		 203.5
(13.0, 665.0)
LDH/(U/L) 233.8
(120.0, 867.0)		 421.8
(140.0, 1 269.0)*#		 930.3
(360.0, 2 185.0)*#		 1 814.1
(244.0, 5 099.0)		 1 934.7
(170.0, 8 517.0)
TG/(mmol/L) 1.9
(0.4, 6.9)		 1.4
(0.7, 2.6)*#		 4.0
(1.4, 10.7)*		 3.2
(1.3, 5.8)△		 4.3
(1.0, 9.6)
ALB/(g/L) 34.9
(17.2, 46.8)		 33.1
(20.4, 41.0)*#		 24.6
(16.3, 34.2)*#		 29.3
(20.0, 40.0)△		 26.0
(19.0, 41.0)
FIBC/(mg/dL) 292.2
(123.0, 465.0)		 348.8
(178.0, 737.0)*#		 165.1
(26.0, 436.0)*		 139.0
(55.0, 307.0)		 129.6
(55.0, 349.0)
SF/(μg/L) 308.0
(11.0, 1 665.0)		 5 214.6
(522.0, 21 133.0)*#		 10 968.8
(455.0, 83 039.0)*#		 37 098.8
(2 000.0, 100 000.0)△		 18 364.7
(101.0, 63 917.0)

表3

对SLE-MAS诊断有提示意义的实验室指标及其截断值"

Items AUC Cutoff value Sensitivity Specificity
SF 0.983 ≥1 010 μg/L 0.95 0.96
LDH 0.973 ≥359 U/L 0.90 1.00
AST 0.898 ≥33.5 U/L 0.82 0.96
PLT 0.887 ≤93.5×109/L 0.86 0.92
WBC 0.869 ≤2.5×109/L 0.86 0.79
NE 0.864 ≤1.6×109/L 0.84 0.83
HB 0.859 ≤85 g/L 0.82 0.83
FIBC 0.857 ≤183.5 mg/dL 0.94 0.71
CRP 0.836 ≥23.5 mg/dL 0.90 0.63
ALB 0.830 ≤29.7 g/L 0.82 0.79
TG 0.823 ≥1.9 mmol/L 0.58 0.96
ALT 0.807 ≥30.5 U/L 0.72 0.83
ESR 0.804 ≥57.0 mm/h 0.86 0.63

表4

对AOSD-MAS诊断有提示意义的实验室指标及其截断值"

Items AUC Cutoff value Sensitivity Specificity
FIBC 0.988 ≤225.5 mg/dL 0.98 0.92
TG 0.953 ≥2.0 mmol/L 0.84 0.92
WBC 0.948 ≤6.3×109/L 0.96 0.92
NE 0.946 ≤4.3×109/L 0.98 0.92
AST 0.943 ≥110.0 U/L 0.97 0.96
PLT 0.941 ≤164.5×109/L 0.94 0.88
ALT 0.938 ≥74.5 U/L 0.86 0.92
LDH 0.915 ≥667.5 U/L 0.90 0.83
HB 0.900 ≤97.5 g/L 0.76 0.92
ESR 0.862 ≥59.5 mm/h 0.64 0.92
SF 0.833 ≥13 283.5 μg/L 0.88 0.63
ALB 0.758 ≤31.7 g/L 0.70 0.79
CRP 0.636 ≥54.9 mg/dL 0.72 0.58

表5

2016 sJIA-MAS分类标准在AOSD-MAS患者中的应用"

Items AOSD-MAS, n(%) AOSD, n(%) Sensitivity/% Specificity/% PPV/% NPV/%
Fulfilling criteria 24 (100.0) 19 (38.0) 100.0 62.0 56.0 100.0
SF>684 μg/L 24 (100.0) 46 (92.0) 100.0 8.0 34.0 100.0
PLT≤181×109/L 21 (87.5) 9 (18.0) 87.5 82.0 70.0 93.0
AST>48 U/L 23 (95.8) 15 (30.0) 95.8 70.0 61.0 97.0
TG>156 mg/dL 22 (91.7) 9 (18.0) 91.7 82.0 71.0 95.0
FIBC≤360 mg/dL 24 (100.0) 32 (64.0) 100.0 36.0 43.0 100.0

表6

改进2016 sJIA-MAS分类标准在AOSD-MAS患者中的应用"

Items AOSD-MAS, n(%) AOSD, n(%) Sensitivity/% Specificity/% PPV/% NPV/%
Fulfilling criteria 24 (100.0) 7 (14.0) 100.0 86.0 77.1 100.0
SF>2 000 μg/L 24 (100.0) 32 (64.0) 100.0 36.0 42.9 100.0
PLT≤181×109/L 21 (87.5) 9 (18.0) 87.5 82.0 70.0 93.0
AST>48 U/L 23 (95.8) 15 (30.0) 95.8 70.0 61.0 97.0
TG>156 mg/dL 22 (91.7) 9 (18.0) 91.7 82.0 71.0 95.0
FIBC≤225.5 mg/dL 23 (95.8) 1 (2.0) 95.8 98.0 95.8 98.0
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ISSN 1671-167X
CN 11-4691/R
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