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Journal of Peking University(Health Sciences) ›› 2019, Vol. 51 ›› Issue (6): 996-1002. doi: 10.19723/j.issn.1671-167X.2019.06.003

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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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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

CLC Number: 

  • R593.2

Table 1

Demographic, clinical and laboratory characteristics of 67 MAS patients"

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

Table 2

Laboratory characteristics of MAS patients and comparison of SLE and AOSD"

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

Table 3

Treatment and outcomes of 67 MAS patients"

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

Table 4

Analysis of factors associated with complete remissiom at week 8"

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

Table 5

Analysis of factors associated with mortality"

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

Table 6

Factors associated with mortality of MAS patients as determined by Logistic regression"

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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