General information
A total of 74 patients with autoimmune disease related hemophagocytic syndrome were involved in this study, female patients representing 78.4% of the total number (58/74), male representing 21.6% (16/74). The male to female ratio was 1:3.6. The median age of the patients was 31 years (16~72 years). Among these cases, underlying diseases included AOSD, SLE, undifferentiated connective tissue disease(UCTD), rheumatoid arthritis(RA) and other variety of autoimmune diseases(Fig 1).
Clinic Features
All patients(74/74) had fever at diagnosis, 60.8%(45/74) of patients had skin rashes, 55.4%(41/74) of patients had joint pain. Splenomegaly was found in 85.1%(63/74) patients, and hepatomegaly had a lower rate at 9.4%(7/74). Leukocytopenia, anemia and thrombocytopenia were found in 41.9%(31/74), 51.4%(38/74), 59.5%(44/74) of patients, respectively. Hepatic transaminases elevation was shown in 63.5%(47/74) patients, the incidence of hyperlipidemia, hyperbilirubinemia and hypofibrinogenemia was 43.2%(32/74), 50.0%(37/74) and 40.5%(30/74). The incidence of elevated serum ferritin was 97.3%(72/74), which is extremely high. Only part of patients were able to accomplish the tests of soluble CD25(sCD25) or NK cell activity by the time of HLH diagnosis, 67.3%(33/49) of them showed sCD25 elevation, and 75.0%(30/40) showed low NK cell activity(Fig 2).
Treatment
Patients were defined into two groups based on the initial regimens. Group 1(n=53): the initial treatment plan didn’t contain VP-16, the specific treatment includes corticosteroids, corticosteroids plus cyclosporine A, corticosteroids plus methotrexate and corticosteroids plus hydroxychloroquine. Group 2(n=21): the initial treatment included VP-16, the specific treatment options includes HLH-94, HLH-2004 and DEP regimen. Group 2 patients had lower ALT and T-BIL than group 1 patients, other baseline data showed no significant difference(Table 1).
Table 1. Initial clinical characteristics of the patients according to group
|
|
Group 1
|
Group 2
|
P value
|
Gender
|
|
|
|
Male
|
12
|
4
|
0.980
|
Female
|
41
|
17
|
Age
|
33(18-62)
|
27(18-72)
|
0.118
|
Fever(>38.5℃,n)
|
53
|
21
|
|
Splenomegaly (n)
|
44
|
19
|
0.652
|
Hepatomegaly (n)
|
6
|
1
|
0.668
|
Skin rashes (n)
|
33
|
12
|
0.886
|
Joint pain (n)
|
30
|
11
|
0.944
|
Haemophagocytosis (n)
|
32
|
13
|
1.000
|
WBC (x109/L)
|
5.94±5.28
|
6.78(0.50~29.30)
|
0.300
|
NEU (x109/L)
|
3.10(0.02~25.68)
|
5.24(0.25~27.10)
|
0.260
|
HGB (g/L)
|
91(48~145)
|
96.76±26.30
|
0.820
|
PLT (x109/L)
|
95.81±65.59
|
135.00(25.00~471.00)
|
0.170
|
ALT (U/L)
|
67.00(2.10~2252.00)
|
23.00(5.00~926.00)
|
0.022
|
AST (U/L)
|
75.50(7.65~2057.00)
|
23.6(12.00~1579.00)
|
0.164
|
T-BIL (µmol/L)
|
16.87(5.82~554.80)
|
11.89(4.05~28.41)
|
0.003
|
TG (mmol/L)
|
2.80±1.07
|
2.72±0.83
|
0.679
|
Fbg (g/L)
|
1.76(0.56~4.49)
|
2.20±1.50
|
0.838
|
Fer (ng/mL)
|
2000.00(466.00~67830.00)
|
3343.00(109.60~100000.00)
|
0.527
|
sCD25 (pg/mL)
|
11934.00(639.00~40435.00)
|
9790.00 (2337.00~26732.00)
|
0.401
|
NK cell activity (%)
|
12.05±5.18
|
12.55±3.92
|
0.727
|
WBC, white blood cell count; NEU, neutrophil count; HGB, haemoglobin concentration; PLT, platelet count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; T-BIL, serum Total Bilirubin; TG, triglycerides; Fbg, fibrinogen; Fer, serum ferritin; sCD25, soluble CD25.
After initial therapy, of 53 patients in group 1, 2 achieved CR(2/53,3.8%), 11 achieved PR(11/53,20.8%), the overall response rate was 24.5%(13/53), 40 patients with no response were confirmed as refractory MAS. Among patients in group 2, the overall response rate was 90.5%(19/21), with a CR rate of 33.3%(7/21) and a PR rate of 57.1%(12/21). There were significant differences in ORR(P<10-6) and CRR(P=0.002) between two groups. 37 refractory MAS patients received salvage treatment contains VP-16, 24.3%(9/37) of them achieved CR and 67.6%(25/37) achieved PR, the ORR was 91.9%(34/37).
A total of 65 patients reached at least PR eventually, according to whether VP-16 was used or not, we divided this part of patients into two groups, group A: VP-16 was not included during the whole treatment, and group B: VP-16 was administrated in the treatment. We compared laboratory indicators of two groups at the remission stage of HLH, the data suggested patients in group B had lower sCD25 and higher NK cell activity than group A, while blood cell counts had no significant differences between two groups(Table 2).
Table 2. Clinical characteristics of the patients at remission stage according to group.
|
|
Group A
|
Group B
|
P value
|
WBC (x109/L)
|
6.79(0.60~16.94)
|
7.71±4.74
|
0.768
|
NEU (x109/L)
|
4.29(0.13~14.91)
|
6.01±4.32
|
0.491
|
HGB (g/L)
|
96(58~132)
|
101.94±13.40
|
0.987
|
PLT (x109/L)
|
197(42~395)
|
194.50(60.00~426.00)
|
0.993
|
ALT (U/L)
|
43.00(6.00~283.00)
|
24.00(6.00~189.00)
|
0.053
|
AST (U/L)
|
41.11±28.71
|
24.77±16.23
|
0.008
|
T-BIL (µmol/L)
|
12.31(6.78~171.80)
|
13.16±8.82
|
0.286
|
TG (mmol/L)
|
2.05±1.88
|
2.23±1.36
|
0.754
|
Fbg (g/L)
|
2.03(0.77~3.68)
|
2.43±1.14
|
0.394
|
Fer (ng/mL)
|
1198.00(62.40~8234.90)
|
374.60(6.40~17300.00)
|
0.071
|
sCD25 (pg/mL)
|
4442.00(742.00~22826.00)
|
1441.00 (139.00~9177.00)
|
0.014
|
NK cell activity (%)
|
13.54(9.89~16.44)
|
16.25(6.38~18.7)
|
0.010
|
Survival
The survival time was calculated from the time patients were diagnosed HLH until death or January 2020. A total of 9 deaths occurred in 74 patients with a mortality of 12.16%. The mortality rate of group 1 was 13.2%(7/53), and that of group 2 was 9.5%(2/21). Of patients who achieved PR, 1 patient died(1/48,2.1%), nonresponsive patients were all died within 6 weeks after diagnosis with a median survival of 29 days, the HLH states influenced the prognosis significantly(Fig 3, P<0.01).