Baseline characteristics
In total, 281 patients were enrolled in this study. The patients’ mean age at the onset of symptoms was 42.64 ± 15.87 years. The majority were females (n = 196, 69.8%). The age and sex distribution of patients with AOSD is shown in Fig.1. The peak age of disease onset in the 25-35s, and the frequency of female AOSD patients was higher than male patients in all age groups. There are fewer patients in the ≥65 years group than in younger groups. From these results, we defined the elderly onset group as patients diagnosed with AOSD after the age of 65, as a result, 249 (88.6%, <65 years) patients and 32 (11.4%, ≥65 years) patients were classified into the younger onset and elderly onset groups.
Clinical features of elderly onset and younger onset AOSD patients
Comparisons of clinical features between elderly onset group and younger onset group are summarized in Table 1. The mean age at onset of AOSD was 39.08 ± 13.03 years and 70.41 ± 4.35 (p < 0.001) in the younger onset group and elderly onset group. The frequency of female AOSD patients was higher than male patients in both two groups, with no significance between them. Compared to the younger onset group, the percentage of patients with skin rash (85.5% vs 71.9%, respectively; p=0.047), sore throat (62.7% vs 31.3%, respectively; p=0.001), myalgia (52.2% vs 18.8%, respectively; p=0.001), splenomegaly (44.2% vs 25.0%, respectively; p=0.039), hepatosplenomegaly (63.1% vs 34.4%, respectively; p=0.002) and the Pouchot’s score (6 (5, 7) vs 5 (4, 6), respectively; p=0.002) were significantly lower in the elderly onset group. In contrast, percentage of patients with fever, arthralgia, lymphadenopathy, and splenomegaly were not significantly different in both groups.
Table 1. Clinical features of patients with adult-onset Still’s disease by age group.
|
Younger onset group (n=249)
|
Elderly onset group (n=32)
|
p
|
Demographic features
|
|
|
|
Age at onset (years)a
|
39 (28, 50)
|
69 (67, 75)
|
0.000***
|
Sex (female)
|
176 (70.7%)
|
20 (62.5%)
|
0.343
|
Clinical findings
|
|
|
|
Fever (>39℃, lasting 1 week or longer)
|
225 (90.4%)
|
26 (81.3%)
|
0.081
|
Skin rash
|
213 (85.5%)
|
23 (71.9%)
|
0.047*
|
Typical skin rash
|
128 (51.4%)
|
16 (50.0%)
|
0.881
|
Arthralgia (lasting 2 weeks or longer)
|
122 (50.0%)
|
19 (82.6%)
|
0.269
|
Sore throat
|
156 (62.7%)
|
10 (31.3%)
|
0.001**
|
Myalgia
|
130 (52.2%)
|
6 (18.8%)
|
0.001**
|
Lymphadenopathy
|
195 (78.3%)
|
23 (71.9%)
|
0.411
|
Hepatomegaly
|
62 (24.9%)
|
4 (12.5%)
|
0.182
|
Splenomegaly
|
110 (44.2%)
|
8 (25.0%)
|
0.039*
|
Hepatosplenomegaly
|
157 (63.1%)
|
11 (34.4%)
|
0.002**
|
Pleuritis
|
8 (3.2%)
|
1 (3.1%)
|
0.979
|
Pneumonia
|
13 (5.2%)
|
2 (6.3%)
|
0.807
|
Pericarditis
|
32 (12.9%)
|
8 (25.0%)
|
0.064
|
Pouchot’s score
|
6 (5, 7)
|
5 (4, 6)
|
0.002**
|
Complications
|
|
|
|
Macrophage activation syndrome
|
23 (9.2%)
|
3 (9.4%)
|
0.980
|
Disseminated intravascular coagulation
|
3 (1.2%)
|
0 (0.0%)
|
0.532
|
The number and percentages (%) of patients are shown.
a Median with 25th and 75th percentiles in parenthesis.
* p<0.05, ** p<0.01, *** p<0.001.
Laboratory findings of elderly onset and younger onset AOSD patients
Comparisons of laboratory findings between elderly onset group and younger onset group are summarized in Table 2. Although not significant, the median with 25th and 75th percentiles of white blood cell (11.6 (6.6, 14.9) vs 13.25 (9.7, 17.6), respectively) and erythrocyte sedimentation rate (58 (38, 77) vs 72 (44, 88), respectively) were lower in the elderly onset group compared to the younger onset group, in contrast, the ferritin levels (6550.7 (2000.0, 33511.2) vs 4834.1 (1979.9, 12989.2), respectively) and interleukin (IL)-6 (201.1 (14.8, 1044.5) vs 45.0 (17.5, 128.5), respectively) levels were higher in the elderly onset group compared to the younger onset group. The Other laboratory findings and inflammatory cytokines including tumor necrosis factor (TNF)-α and interferon (IFN)-γ were not different between the two groups.
Table 2. Laboratory findings of patients with adult-onset Still’s disease by age group.
|
Younger onset group (n=249)
|
Elderly onset group (n=32)
|
p
|
White blood cell (109/L)
|
13.25 (9.7, 17.6)
|
11.6 (6.6, 14.9)
|
0.468
|
Neutrophils (%)
|
84.65 (78.6, 89.5)
|
84.4 (73.3, 88.2)
|
0.479
|
Hemoglobin (g/L) a
|
109.51 ± 18.48
|
104.75 ± 14.53
|
0.162
|
Red blood cell (1012/L)
|
3.9 (3.5, 4.2)
|
3.7 (3.3, 4.1)
|
0.051
|
Platelet (109/L)
|
266.5 (207.3, 345.5)
|
214 (154.0, 355.0)
|
0.382
|
C-reactive protein (mg/dl)
|
90.5 (54.1, 145.7)
|
90.3 (50.7, 147.2)
|
0.577
|
Erythrocyte sedimentation rate (mm/h)
|
72 (44, 88)
|
58 (38, 77)
|
0.279
|
Ferritin (ng/ml)
|
4834.1 (1979.9, 12989.2)
|
6550.7 (2000.0, 33511.2)
|
0.585
|
Alanine aminotransferase (U/L)
|
41 (22, 90)
|
45 (26, 54)
|
0.457
|
Aspartate aminotransferase (U/L)
|
43 (27, 70)
|
54 (40, 69)
|
0.467
|
Creatinine (μmol/L)
|
55 (48, 66)
|
58 (53, 74)
|
0.116
|
Lactic dehydrogenase (U/L)
|
404 (307, 567)
|
418 (249, 705)
|
0.822
|
Interleukin -6
|
45.0 (17.5, 128.5)
|
201.1 (14.8, 1044.5)
|
0.512
|
Tumor necrosis factor-α
|
1.0 (0.1, 2.6)
|
0.1 (0.1, 2.1)
|
0.223
|
Interferon-γ
|
3.8 (0.1, 10.2)
|
0.1 (0.1, 3.5)
|
0.318
|
Median with 25th and 75th percentiles in parenthesis are shown.
a Mean and SD.
Correlations of age with clinical features of AOSD patients
Correlations of age with clinical features of AOSD patients are summarized in Table 3. The results showed that negative correlations were found between age and sore throat (coefficient=-0.242, p=0.000), myalgia (coefficient=-0.303, p=0.000), hepatomegaly (coefficient=-0.129, p=0.031), splenomegaly (coefficient=-0.119, p=0.046) and Pouchot’s score (coefficient=-0.180, p=0.002). In addition, the pneumonia (coefficient=0.224, p=0.000) and pericarditis (coefficient=0.160, p=0.000) were positively correlated with age. Other clinical features including sex, laboratory findings, MAS and disease patterns were not related to age.
Table 3. Correlations of age with clinical features of adult-onset Still’s disease patients.
Clinical features
|
Coefficient/p
|
Clinical features
|
Coefficient/p
|
Sex (female)
|
-0.013/0.822
|
Hemoglobin
|
-0.074/0.217
|
Fever
|
-0.043/0.476
|
Red blood cell
|
-0.107/0.074
|
Skin rash
|
-0.052/0.387
|
Platelet
|
-0.027/0.658
|
Arthralgia
|
0.077/0.197
|
C-reactive protein
|
-0.053/0.379
|
Sore throat
|
-0.242/0.000***
|
Erythrocyte sedimentation rate
|
-0.087/0.150
|
Myalgia
|
-0.303/0.000***
|
Ferritin
|
-0.094/0.121
|
Lymphadenopathy
|
-0.006/0.922
|
Alanine aminotransferase
|
-0.019/0.755
|
Hepatomegaly
|
-0.129/0.031*
|
Creatinine
|
-0.077/0.200
|
Splenomegaly
|
-0.119/0.046*
|
Lactic dehydrogenase
|
-0.012/0.849
|
Pleuritis
|
0.043/0.468
|
Interleukin -6
|
-0.127/0.192
|
Pneumonia
|
0.224/0.000***
|
Interleukin -10
|
0.277/0.007
|
Pericarditis
|
0.160/0.007**
|
Macrophage activation syndrome
|
0.027/0.656
|
Pouchot’s score
|
-0.180/0.002**
|
Relapse
|
-0.062/0.300
|
White blood cell
|
-0.103/0.083
|
Death
|
0.112/0.062
|
Neutrophils
|
-0.005/0.939
|
Glucocorticoids
|
0.038/0.521
|
The number and percentages (%) of patients are shown.
a Median with 25th and 75th percentiles in parenthesis.
* p<0.05, ** p<0.01, *** p<0.001.
Outcome and treatment of elderly onset and younger onset AOSD patients
Overall, the median follow-up interval of our patients was 47 months, with a range of 11–115 months. During the follow-up, 72 (25.6%) of the 281 patients had experienced at least one relapse of AOSD, as determined by either their rehospitalization records or clinical judgments by experienced doctors. Comparisons of outcome and treatment between elderly onset group and younger onset group are summarized in Table 4. The death rate (6.3% vs 0.8%, respectively; p=0.014) of elderly onset group is higher than younger onset group, with no significance in relapse and other disease features including monocyclic, polycyclic and chronic patterns. Two of elderly onset patients and one of younger onset patient died because of MAS, and the other one of younger onset patient died because of cerebral infarction. Survival was significantly reduced in the elderly onset group compared with the younger onset group (p=0.013, Fig2(a)), although the relapse was not significantly different in the elderly onset group compared with the younger onset group (p=0.263, Fig2(b)). Interestingly, the probability of relapse was significantly increased in the patients with MAS compared with the patients without MAS (p<0.001, Fig2(c)), though the different age groups of AOSD patients with MAS showed no difference in the probability of relapse (p=0.737, Fig2(d)).
Table 4. Relapse and treatment of patients with adult-onset Still’s disease by age group.
|
Younger onset group (n=249)
|
Elderly onset group (n=32)
|
p
|
Relapse
|
67 (26.9%)
|
5 (15.6%)
|
0.169
|
Follow up (months) a
|
46 (30, 74)
|
51 (29, 64)
|
0.772
|
Time to relapse (after disease onset, months) a
|
6 (3, 12)
|
6 (4, 9)
|
0.911
|
Deaths
|
2 (0.8%)
|
2 (6.3%)
|
0.014*
|
Disease pattern
|
|
|
|
Monocyclic
|
182 (73.1%)
|
27 (84.4%)
|
0.169
|
Polycyclic
|
43 (17.3%)
|
3 (9.4%)
|
0.256
|
Chronic
|
28 (11.2%)
|
2 (6.3%)
|
0.577
|
Treatment
|
|
|
0.585
|
Glucocorticoids (GCs)
|
227 (91.2%)
|
30 (93.8%)
|
0.622
|
Methotrexate (MTX)
|
10 (4.0%)
|
0 (0%)
|
0.610
|
Non-steroid anti-inflammatory drugs
|
62 (24.9%)
|
10 (31.3%)
|
0.439
|
Hydroxychloroquine
|
18 (7.2%)
|
1 (3.1%)
|
0.620
|
Cyclosporine
|
1 (0.4%)
|
0 (0%)
|
1.000
|
GCs only
|
165 (66.3%)
|
21 (65.6%)
|
0.943
|
GCs + MTX
|
9 (3.6%)
|
0 (0%)
|
0.604
|
The number and percentages (%) of patients are shown.
a Median with 25th and 75th percentiles in parenthesis.
* p<0.05.
Treatments for AOSD patients were compared between the elderly onset and younger onset groups in Table 4. Almost all patients received glucocorticoids as the initial treatment in both groups (93.8% vs 91.2%, the elderly onset and younger onset groups respectively). The frequency of use of methotrexate, non-steroid anti-inflammatory drugs, hydroxychloroquine, and cyclosporine were not different between the two groups. None of our AOSD patients used biological agents as their treatments.
Both univariate and multivariate Cox regression models were built to predict the relapse and mortality of AOSD patients from their clinical and laboratory characteristics, reported in Table 5. The independent risk factor for relapse was MAS both in univariate Cox regression model (HR: 5.054, 95%CI: 2.692-9.488, p=0.000) and multivariate Cox regression model (HR: 4.388, 95%CI: 2.296-8.386, p=0.000). Lymphadenopathy was the independent risk factor for relapse only in univariate Cox regression model (HR: 3.214, 95%CI: 1.152-8.964, p=0.026) but had no significant result in multivariate Cox regression model (HR: 2.426, 95%CI: 0.830-7.093, p=0.106). In the univariate Cox regression model of mortality, the independent risk factors were DIC (HR: 35.185, 95%CI: 3.643-339.810, p=0.002) and pleuritis (HR: 9.675, 95%CI: 1.006-93.043, p=0.049). As for the multivariate Cox regression model of mortality, the independent risk factors were age at onset (HR: 1.115, 95%CI: 1.003-1.239, p=0.044), DIC (HR: 391.576, 95%CI: 10.085-15203.318, p=0.001) and pleuritis (HR: 23.162, 95%CI: 1.293-414.839, p=0.033).
Table 5. Cox regression analyze the correlation between clinical features and the survival/relapse of adult-onset Still’s disease patients.
Clinical features
|
Univariate analysis
|
Multivariate analysis
|
Hazard ratio (95% CI)
|
p
|
Hazard ratio (95% CI)
|
p
|
Relapse
|
Age at onset
|
0.989 (0.971-1.008)
|
0.247
|
0.987 (0.967-1.007)
|
0.207
|
Sex (female)
|
0.897 (0.472-1.705)
|
0.740
|
0.924 (0.483-1.768)
|
0.812
|
MAS
|
5.054 (2.692-9.488)
|
0.000***
|
4.388 (2.296-8.386)
|
0.000***
|
DIC
|
2.468 (0.339-17.946)
|
0.372
|
1.590 (0.212-11.942)
|
0.652
|
Lymphadenopathy
|
3.214 (1.152-8.964)
|
0.026*
|
2.426 (0.830-7.093)
|
0.106
|
Pouchot’s score
|
1.191 (0.987-1.436)
|
0.068
|
1.045 (0.838-1.303)
|
0.696
|
Mortality
|
Age at onset
|
1.065 (0.996-1.139)
|
0.067
|
1.115 (1.003-1.239)
|
0.044*
|
Sex (female)
|
2.346 (0.330-16.656)
|
0.394
|
6.280 (0.481-81.999)
|
0.161
|
MAS
|
-
|
0.674
|
-
|
0.989
|
DIC
|
35.185 (3.643-339.810)
|
0.002**
|
391.576 (10.085-15203.318)
|
0.001**
|
Pleuritis
|
9.675 (1.006-93.043)
|
0.049*
|
23.162 (1.293-414.839)
|
0.033*
|
Pouchot’s score
|
1.285 (0.689-2.397)
|
0.430
|
1.915 (0.876-4.186)
|
0.103
|
MAS Macrophage activation syndrome, DIC Disseminated intravascular coagulation.
* p<0.05, ** p<0.01, *** p<0.001.