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北京大学学报（医学版） ›› 2019, Vol. 51 ›› Issue (6): 996-1002. doi: 10.19723/j.issn.1671-167X.2019.06.003

• 论著 • 上一篇    下一篇

67例成人巨噬细胞活化综合征的临床特征及治疗转归

姚海红1,王旖旎2,张霞1,赵金霞3,贾园1,△(),王昭2,栗占国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血液科, 北京　100050
    3. 北京大学第三医院风湿免疫科, 北京　100191
  • 收稿日期:2019-09-09 出版日期:2019-12-18 发布日期:2019-12-19
  • 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 treatment outcomes of macrophage activation syndrome in adults: A case series of 67 patients

Hai-hong YAO1,Yi-ni WANG2,Xia ZHANG1,Jin-xia ZHAO3,Yuan JIA1,△(),Zhao WANG2,Zhan-guo LI1   

  1. 1. Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing 100044, China
    2. Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
    3. Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, China
  • Received:2019-09-09 Online:2019-12-18 Published:2019-12-19
  • Contact: Yuan JIA E-mail:jiayuan1023@sina.com
  • Supported by:
    Supported by the National Natural Science Foundation of China(81801618)

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摘要：

目的 探讨巨噬细胞活化综合征患者的特征及转归。方法 纳入3个中心自2007年1月至2017年12月住院诊断的巨噬细胞活化综合征患者67例,回顾其主要临床特征、实验室数据、治疗及转归情况,并分析与缓解及死亡的可能相关因素。结果 67例确诊巨噬细胞活化综合征的患者平均年龄为(36.1±16.3)岁,诊断巨噬细胞活化综合征时结缔组织病的中位病程为8个月。巨噬细胞活化综合征潜在的结缔组织病中56.7%为成人Still病,30.0%为系统性红斑狼疮。所有患者均有发热,82.1%有脾大。实验室指标异常以高铁蛋白血症最为常见(100.0%),其次为血清可溶性白细胞介素-2受体升高(93.2%)。成人Still病继发巨噬细胞活化综合征组谷丙转氨酶、D-二聚体、血清铁蛋白及C反应蛋白均显著高于系统性红斑狼疮继发巨噬细胞活化综合征组,而动态红细胞沉降率显著降低。所有患者均使用了糖皮质激素治疗,91.0%加用了丙种球蛋白, 64.2%加用环孢素A, 46.3%加用依托泊苷。治疗8周时完全缓解率为47.8%,治疗16周时死亡率为22.4%。与未达到完全缓解组的患者比较,达到完全缓解组的脾大发生率更低(71.9% vs.91.4%,P=0.037),血碱性磷酸酶、谷氨酰转肽酶、总胆红素、直接胆红素更低。死亡患者巨噬细胞活化综合征的诊断年龄(P=0.014)、结缔组织病诊断年龄(P=0.017)均显著高于存活组,血小板水平显著低于存活组(P=0.018)。Logistic回归分析显示,使用环孢素A显著降低巨噬细胞活化综合征的死亡风险(P=0.004)。结论 结缔组织病继发巨噬细胞活化综合征以成人Still病和系统性红斑狼疮最多见,二者实验室指标差异有统计学意义;年龄增长及血小板低是死亡相关危险因素,使用环孢素A治疗可能降低死亡风险。

关键词: 巨噬细胞活化综合征, 结缔组织病, 缓解

Abstract:

Objective: To described the clinical and laboratory features and outcome of 67 macrophage activation syndrome (MAS).Methods: A total of 67 MAS patients from three centers from January 2007 to December 2017 were enrolled. Clinical and laboratory features, and response to therapy were analyzed. Predictive factors for remission and survival were explored.Results: We identified a mean age of(36.1±16.3) years at diagnosis of MAS and a median connective tissue disease (CTD) duration of 8 months prior to MAS development. Among 67 MAS patients identified, underlying diseases included adult-onset Still’s disease (AOSD) in 56.7% and systemic lupus erythematosus (SLE) in 30.0%. Fever and splenomegaly were found in 100.0% and 82.1% of the patients, respectively. Ferritinemia and elevation of serum soluble interleukin-2 receptor was seen in 100.0% and 93.2% of the patients. Serum levels of alanine aminotransferase, D-dimer, ferritin and C reactive protein were significantly higher in MAS associated with the AOSD patients than in MAS associated with the SLE patients. A significant decrease of erythrocyte sedimentation rate was found in MAS associated with AOSD, as compared with MAS associated with SLE. The most commonly used therapy was corticosteroids, which were initially administered in 100.0% of the patients. Intravenous immunoglobulin (IVIG) was administered in 91.0%, cyclosporine A in 64.2%, and etoposide in 46.3% of the patients, respectively. The induction therapy yielded a complete remission (CR) at the end of week 8 in 47.8% of the MAS patients. The overall mortality rate at the end of week 16 was 22.4%. The median serum levels of gamma-glutamyltransferase, alkaline phosphatase, total bilirubin and direct bilirubin were significantly lower in the patients who achieved complete remission at the end of week 8 than in those who did not, and splenomegaly was significantly less frequent (71.9% vs.91.4%, P=0.037). Both the mean age at diagnosis of MAS and the mean age at diagnosis of underlying CTD of the deceased patients were elder than those of the survived population (P=0.014 and P=0.017, respectively). The platelet count was significantly less in the deceased population as compared with the living population (P=0.018). No addition of cyclosporine A (P=0.004) was identified as risk factors associated with death in Logistic regression analysis.Conclusion: MAS secondary to connective tissue disease is most common with AOSD and SLE. In terms of laboratory findings, there were considerable differences between the patients with underlying SLE and those with AOSD. Advanced age and low platelet counts are significant predictive factors for death, while treatment with cyclosporine may reduce the risk.

Key words: Macrophage activation syndrome, Connective tissue disease, Remission

中图分类号: 

  • R593.2

表1

67例MAS患者人口学特征及主要临床实验室特征"

Items All MAS(n=67) AOSD with MAS(n=38) SLE with MAS(n=20) P value
Epidemiological features
Woman, n(%) 53 (79.1) 27(71.1) 18(90.0) 0.100
Age at diagnosis of MAS/years, x?±s 36.1±16.3 34.4±15.2 36±17.1 0.726
Age at diagnosis of CTD/years, x?±s 34.5±17.2 34.1±15.5 33.7±19.3 0.915
CTD duration before MAS/months, M (Min,Max) 8 (0.5, 348) 3(0.5, 96) 18 (61,118) 0.131
Clinical and laboratory characteristics
Fever 67/67(100.0%) 38/38(100.0%) 20/20(100.0%)
Splenomegaly 55/67 (82.1%) 29/38(76.3%) 17/20(85.0%) 0.438
Hepatomegaly 15/67 (22.4%) 5/38(13.2%) 5/20(35.0%) 0.256
Cytopenias (at least two lienges) 55/67 (82.1%) 25/38(65.8%) 18/20(90.0%) 0.045
Hyperferritinemia (ferritin>500 μg/L) 67/67 (100.0%) 38/38(100.0%) 20/20(100.0%)
Hypofibrinogenemia (fibrinogen<1.5 g/L) 30/67 (44.8%) 18/38(47.4%) 7/20(35.0%) 0.810
Hypertriglyceridemia (triglycerides≥3 mmol/L) 32/67 (47.8%) 18/38(47.4%) 6/20(30.0%) 0.202
Hemophagocytosis in bone marrow 48/67 (71.6%) 29/38(76.3%) 17/20(85.0%) 0.438
Low NK cell activity 29/48 (60.4%) 15/31(48.4%) 8/12(66.7%) 0.281
Serum soluble CD25 receptor≥2 400 U/mL 41/44 (93.2%) 25/25(100.0%) 10/10(100.0%)
Neurological involvement 16/67 (23.9%) 8/38(21.1%) 7/20(35.0%) 0.249
Disseminated intravascular coagulation 13/67(19.4%) 8/38(21.1%) 2/20(10.0%) 0.289
Hepatic failure 9/67(13.4%) 6/38(15.8%) 2/20(10.0%) 0.544

表2

AOSD继发MAS与SLE继发MAS的实验室数据比较"

Items All MAS(n=67) AOSD with MAS(n=38) SLE with MAS(n=20) P value
WBC/(×109/L) 2.7(0.3, 28.6) 7.5(0.3, 28.6) 5.0 (0.4, 22.1) 0.248
HB/(g/L) 83(48, 137) 88.6 (48, 137) 78.4(45, 101) 0.064
PLT/(×109/L) 67.5(3, 481) 74.5(7, 481) 67.5 (3, 267) 0.280
ALT/(U/L) 118(5, 3 550) 248.5(16, 3 550) 81.5(5, 1 504) 0.030
AST/(U/L) 112(8, 2 174) 158(10, 2 174) 97.5 (8, 2 087) 0.187
LDH/ (U/L) 672(165, 15 038) 671(165, 15 038) 585(203, 2 066) 0.053
GGT/(U/L) 105(15, 512) 100.5(15, 420) 108(18, 357) 0.540
ALP/(U/L) 101(34, 495) 99.5(54, 403) 108 (18, 357) 0.320
TBIL/(mmol/L) 14.7(3, 647) 17.5(4.3, 647) 12(3, 189) 0.218
TG/(mmol/L) 2.8 (0.6, 10) 2.9(1, 10) 2.3 (0.6, 7) 0.137
ALB/(g/L) 30(10.4, 43.1) 30.4 (10.4, 40) 27.9 (23, 43.1) 0.153
Fibrinogen/ (g/L) 1.6(0, 7.7) 1.6(0, 7.7) 1.7(0.3, 4.8) 0.366
FDP/(mg/L) 10.7 (0.4, 339) 8.3(0.4, 339) 10.2(0.9, 80) 0.240
D-dimer/(μg/L) 2 935 (88, 86 600) 3 600(88, 86 600) 1 600(372, 13 900) 0.023
ESR/(mm/h) 28 (2, 101) 21(2, 101) 48(16, 101) 0.008
CRP/(mg/L) 33.5(0.3, 272) 43.7(0.3, 272) 16.8(4, 117) 0.007
Ferritin /(μg/L) 4 033(365, 100 000) 6 164 (640, 10 000) 2 600(365, 72 934) 0.043
Na/ (mmol/L) 132.2(122, 142) 132.1(122, 142) 134(125, 142) 0.544

表3

67例MAS治疗及转归情况"

Items AOSD(n=38) SLE(n=20) Total(n=67) P value
Treatment, n(%)
Glucocorticoid 38(100.0) 20(100.0) 67(100.0) -
Methylprednisolone pulse 14(36.8) 7(35.0) 26(38.8) -
Cyclosporine A 27(71.1) 1(5.0) 43(64.2) -
Etoposide 22(57.9) 6(30.0) 31(46.3) -
Fludarabine 2(5.3) 5(25.0) 7(14.9.0) -
Intravenous immunoglobulin, n(%) 37(97.4) 17(85.0) 61(91.0) -
Plasma exchange, n(%) 0(0) 0(0) 1(1.5) -
Splenectomy, n(%) 0(0) 0(0) 2(3.0) -
Allogeneic HSCT, n(%) 0(0) 0(0) 0(0) -
Response at week 8, n(%)
Complete remission 18(47.4) 11(55.0) 32(47.8) 0.581
Partial remission 17(44.7) 8(40.0) 26(38.8) 0.729
No response 3(7.9) 1(5.0) 9(13.4) >0.999
Alive at week 16, n(%) 29(76.3) 14(70.0) 47(70.1) 0.601
Deceased at week 16, n(%) 6(15.8) 4(20.0) 15(22.4) 0.654
Loss to follow up at week 16, n(%) 3(7.9) 2(10.0) 5 (7.5) 0.074
Infection complications, n(%)
CMV infection 8(21.1) 4(20.0) 17(25.4) >0.999
Bacterial infection 1(2.6) 6(30.0) 8(11.9) 0.005
Fungal infection 2(5.3) 3(15.0) 5 (7.5) 0.328

表4

67例MAS 8周时完全缓解相关因素比较"

Variables CR(n=32) No CR(n=35) P value
Splenomegaly, n(%) 23 (71.9) 32 (91.4) 0.037
ALP /(U/L), M(Min, Max) 94.5(36, 495) 139.0 (34, 403) 0.015
LDH/(U/L), M(Min, Max) 540.0 (201, 4312) 783.0 (165, 15 038) 0.135
GGT/(U/L), M(Min, Max) 87.5(15, 323) 124.0 (22, 512) 0.008
TBIL/(mmol/L), M(Min, Max) 14.5 (3, 136) 15.6(5.9, 647) 0.022
DBIL/(mmol/L), M(Min, Max) 7.5 (1.9, 79) 21.1(2, 302) 0.044
ALT/(U/L), M(Min, Max) 99.0 (5, 1 348) 122.0(23, 3 550) 0.071
AST/(U/L), M(Min, Max) 93.5 (8, 1 107) 137.0(10, 2 174) 0.191
CRP/(mg/L), M(Min, Max) 23.2 (2.6, 272) 44.0(0.3, 160) 0.353
IVIG, n(%) 27 (84.4) 34 (97.1) 0.068
Cyclosporine A, n(%) 22 (68.8) 20 (57.1) 0.326
Etoposide, n(%) 14 (43.8) 17 (48.3) 0.693
Methylprednisolone pulse, n(%) 12 (37.5) 13 (37.1) 0.770
Ferritin/(μg/L), M(Min, Max) 2 393 (365, 100 000) 7 326 (755, 100 000) 0.981

表5

67例MAS 16周死亡相关因素比较"

Variables Deceased(n=15) Survived(n=47) P value
Age at diagnosis of MAS/years, x?±s 44.3±16.7 32.8±15.1 0.014
Age at diagnosis of CTD/years, x?±s 43.6±16.4 31.1±16.5 0.017
PLT/(×109/L), x?±s 60.1±80.6 112.9±105.4 0.018
ALB/(g/L), x?±s 28.1±4.0 31.1±6.0 0.073
HB/(g/L), x?±s 77.3±12.6 86.8±19.8 0.084
Ferritin/(μg/L), M (Min, Max) 2 161(1 486, 10 000) 4 135(455, 10 000) 0.981
Addition of cyclosporine A, n(%) 5 (33.3) 36 (76.6) 0.002
Addition of etoposide, n(%) 5 (33.3) 26 (55.3) 0.138

表6

MAS死亡相关因素Logistic回归分析"

Risk factors OR 95%CI P value
All MAS Addition of cyclosporine 0.153 0.043-0.153 0.004
Age 1.043 1.002-1.085 0.038
AOSD with MAS Addition of cyclosporine A 0.164 0.025-1.084 0.061
Alb 0.850 0.727-0.994 0.042
SLE with MAS Addition of cyclosporine A 0.050 0.004-0.597 0.018
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CN 11-4691/R
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