Baseline characteristics
Ten infants qualified for the study - two boys and eight girls. The ages of onset of their TA ranged from 1 month, 17 days to 5 months, 7 days. At the time of diagnosis, durations of illness were less than 1 month in seven cases and 1-3 months in the other three cases.
Clinical manifestation and Medication before IFX
The most common clinical manifestation was fever in 9 cases (90%). Six (60%) infants had hypertension; three (30%) had weak or no detectable pulse; two (20%) had vomiting, and one had transient low-grade fever twice during the illness; no infants had rashes or vascular bruits (Table 1).
The most commonly-involved vessels were carotid arteries, abdominal aortas, and coronary arteries (9 cases, 90%); Thoracic aortas and subclavian aortas (8 cases, 80%), renal arteries (7 cases, 70%), axillary arteries, pulmonary arteries and descending aortas (6 cases, 60%), and superior mesenteric arteries (4 cases, 40%) (Table 2).
Five of the infants were treated with IFX alone. Five infants had been treated with GC (1-1.5mg/kg/day) prior to receiving IFX, which was started because their inflammation indexes did not decrease and/or vascular imaging showed extensive involvement or no improvement. Cases 6, 7, and 8 had been treated with GC (1mg/kg/day) prior to receiving IFX; their inflammation indexes decreased slightly. After combination therapy with IFX, the GC doses were decreased - quickly at first, then gradually, discontinuing at 12 weeks into therapy in 2 cases and 16 weeks in the other case. The Case 9 infant had been treated with prednisone (1.5mg/kg/day). Temperature and inflammatory indexes quickly returned to normal. After oral administration of prednisone for 4 months, the dose was reduced to 5mg/day for 3 months and was combined with methotrexate (MTX) for 4 more months. However, CTA showed that the celiac trunk artery and the left iliac artery were thinner than before, suggesting that the vascular lesion was worsening. The infant had slow growth and development. IFX therapy was added, and the prednisone was reduced and then discontinued in 2 weeks. For the Case 10 infant, oral GC (1mg/kg/day) was used in combination with anti-interleukin 6 receptor antibody (tocilizumab) (12mg/kg, every two weeks) for 3 months. The coronary arteries showed significant improvement, but CTA showed no more improvement than as seen at the beginning of the disease; therapy was changed to IFX (Table 2).
Table 1 Clinical characteristics of 10 infants with Takayasu arteritis
Case
|
Fever
|
Hypertension
|
Vomiting
|
Rash
|
Pulselessness
|
Vascular bruit
|
1
|
Y
|
Y
|
Y
|
N
|
Y
|
N
|
2
|
Y
|
N
|
N
|
N
|
N
|
N
|
3
|
Y
|
Y
|
N
|
N
|
N
|
N
|
4
|
Y
|
Y
|
N
|
N
|
N
|
N
|
5
|
Y
|
Y
|
N
|
N
|
Y
|
N
|
6
|
Y
|
Y
|
N
|
N
|
N
|
N
|
7
|
Y
|
N
|
N
|
N
|
N
|
N
|
8
|
Y
|
Y
|
N
|
N
|
N
|
N
|
9
|
Y
|
N
|
N
|
N
|
N
|
N
|
10
|
N
|
N
|
Y
|
N
|
Y
|
N
|
Note:Y represents positive, N represents negative.
Table 2 Involved arteries before and after treatment, and treatment regimens in 10 infants with Takayasu arteritis
Case
|
Time
|
Carotid artery
L/R
|
Subclavian artery
L/R
|
Coronary artery L/R
|
Coronary artery aneurysm L/R
|
Brachial artery
L/R
|
Axillary artery
L/R
|
Pulmonary artery
|
Descending aorta
|
Thoracic aorta
|
Abdominalaorta
|
Renalartery
L/R
|
Superior mesenteric
artery
|
Treatment
|
1
|
Before
|
+/+
|
+/+
|
+/+
|
+/+
|
+/+
|
+/+
|
+
|
+
|
+
|
+
|
+/+
|
+
|
IFX
|
|
4 months
|
+/+
|
+/+
|
+/+
|
+/+
|
+/+
|
+/+
|
+
|
+
|
+
|
+
|
+/+
|
+
|
|
|
8 months
|
+/+
|
+/+
|
+/+
|
+/+
|
−/−
|
+/+
|
+
|
+
|
+
|
+
|
+/+
|
+
|
|
|
14 months
|
+/+
|
+/+
|
+/+
|
+/+
|
−/−
|
−/−
|
+
|
+
|
+
|
+
|
+/−
|
+
|
|
|
20 months
|
+/+
|
−/−
|
+/+
|
−/+
|
−/−
|
−/−
|
−
|
+
|
+
|
+
|
+/−
|
−
|
|
|
26 months
|
−/−
|
−/−
|
+/+
|
−/+
|
−/−
|
−/−
|
−
|
−
|
+
|
+
|
+/−
|
−
|
|
|
38 months
|
−/−
|
−/−
|
+/+
|
−/+
|
−/−
|
−/−
|
−
|
−
|
+
|
+
|
−/−
|
−
|
|
|
44 months
|
−/−
|
−/−
|
+/+
|
−/+
|
−/−
|
−/−
|
−
|
−
|
+
|
+
|
−/−
|
−
|
|
|
20 months after stopping IFX
|
−/−
|
−/−
|
+/+
|
−/+
|
−/−
|
−/−
|
−
|
−
|
+
|
+
|
−/−
|
−
|
|
2
|
Before
|
+/+
|
+/+
|
+/+
|
−/−
|
−/−
|
+/+
|
+
|
−
|
−
|
−
|
−/−
|
−
|
IFX
|
|
4 months
|
+/+
|
+/−
|
+/+
|
−/−
|
−/−
|
+/+
|
+
|
−
|
−
|
−
|
−/−
|
−
|
|
|
8 months
|
+/+
|
−/−
|
+/−
|
−/−
|
−/−
|
−/−
|
−
|
−
|
−
|
−
|
−/−
|
−
|
|
|
14 months
|
+/−
|
−/−
|
−/−
|
−/−
|
−/−
|
−/−
|
−
|
−
|
−
|
−
|
−/−
|
−
|
|
|
20 months
|
−/−
|
−/−
|
−/−
|
−/−
|
−/−
|
−/−
|
−
|
−
|
−
|
−
|
−/−
|
−
|
|
3
|
Before
|
+/+
|
+/+
|
+/+
|
+/+
|
−/−
|
−/−
|
−
|
−
|
−
|
+
|
+/−
|
−
|
IFX
|
|
4 months
|
−/−
|
+/+
|
+/+
|
−/+
|
−/−
|
−/−
|
−
|
−
|
−
|
+
|
+/−
|
−
|
|
|
8 months
|
−/−
|
−/−
|
+/−
|
−/−
|
−/−
|
−/−
|
−
|
−
|
−
|
−
|
−/−
|
−
|
|
|
25 months after stopping IFX
|
−/−
|
−/−
|
+/−
|
−/−
|
−/−
|
−/−
|
−
|
−
|
−
|
−
|
−/−
|
−
|
|
4
|
Before
|
−/−
|
−/−
|
+/+
|
+/+
|
−/−
|
−/−
|
+
|
−
|
+
|
+
|
+/−
|
−
|
IFX
|
|
4 months
|
−/−
|
−/−
|
+/+
|
−/−
|
−/−
|
−/−
|
+
|
−
|
+
|
+
|
+/−
|
−
|
|
|
8 months
|
−/−
|
−/−
|
+/+
|
−/−
|
−/−
|
−/−
|
−
|
−
|
+
|
+
|
−/−
|
−
|
|
|
10 months
|
−/−
|
−/−
|
−/−
|
−/−
|
−/−
|
−/−
|
−
|
−
|
−
|
+
|
−/−
|
−
|
|
5
|
Before
|
+/+
|
+/+
|
+/+
|
−
|
−/−
|
+/+
|
+
|
+
|
+
|
+
|
−/−
|
+
|
IFX
|
|
4 months
|
+/+
|
+/+
|
+/+
|
−
|
−/−
|
+/+
|
+
|
+
|
+
|
+
|
−/−
|
+
|
|
|
8 months
|
+/−
|
−/−
|
+/+
|
−
|
−/−
|
−/−
|
−
|
−
|
+
|
+
|
−/−
|
−
|
|
|
14 months
|
−/−
|
−/−
|
−/−
|
−
|
−/−
|
−/−
|
−
|
−
|
+
|
−
|
−/−
|
−
|
|
|
20months
|
−/−
|
−/−
|
−/−
|
−
|
−/−
|
−/−
|
−
|
−
|
−
|
−
|
−/−
|
−
|
|
|
22months
|
−/−
|
−/−
|
−/−
|
−
|
−/−
|
−/−
|
−
|
−
|
−
|
−
|
−/−
|
−
|
|
6
|
Before
|
+/+
|
+/+
|
+/+
|
−
|
+/+
|
+/+
|
+
|
+
|
+
|
+
|
−/+
|
−
|
GC+IFX
|
|
4 months
|
+/+
|
+/+
|
+/+
|
−
|
+/+
|
+/+
|
+
|
+
|
+
|
+
|
−/+
|
−
|
|
|
8 months
|
+/+
|
+/+
|
−/−
|
−
|
−/−
|
+/+
|
−
|
+
|
+
|
+
|
−/−
|
−
|
|
|
14 months
|
−/−
|
+/+
|
−/−
|
−
|
−/−
|
+/+
|
−
|
+
|
+
|
−
|
−/−
|
−
|
|
|
20 months
|
−/−
|
−/−
|
−/−
|
−
|
−/−
|
+/+
|
−
|
+
|
+
|
−
|
−/−
|
−
|
|
|
22 months
|
−/−
|
−/−
|
−/−
|
−
|
−/−
|
+/+
|
−
|
+
|
+
|
−
|
−/−
|
−
|
|
7
|
Before
|
+/+
|
+/+
|
+/+
|
+/+
|
−/−
|
+/+
|
−
|
−
|
+
|
+
|
+/+
|
−
|
GC+ IFX
|
|
4 months
|
+/+
|
+/+
|
+/+
|
+/+
|
−/−
|
+/+
|
−
|
−
|
+
|
+
|
+/+
|
−
|
|
|
8 months
|
−/−
|
−/−
|
+/+
|
−/−
|
−/−
|
+/+
|
−
|
−
|
+
|
+
|
−/−
|
−
|
|
|
14 months
|
−/−
|
−/−
|
+/+
|
−/−
|
−/−
|
−/−
|
−
|
−
|
+
|
+
|
−/−
|
−
|
|
|
20 months
|
−/−
|
−/−
|
+/+
|
−/−
|
−/−
|
−/−
|
−
|
−
|
+
|
+
|
−/−
|
−
|
|
8
|
Before
|
+/+
|
+/+
|
+/+
|
−/−
|
−/−
|
+/+
|
−
|
+
|
+
|
+
|
+/+
|
+
|
GC+ IFX
|
|
4 months
|
+/+
|
+/+
|
+/+
|
−/−
|
−/−
|
+/+
|
−
|
+
|
+
|
+
|
−/−
|
+
|
|
|
8 months
|
+/−
|
+/+
|
+/+
|
−/−
|
−/−
|
−/−
|
−
|
+
|
−
|
+
|
−/−
|
−
|
|
|
12 months
|
−/−
|
−/+
|
−/−
|
−/−
|
−/−
|
−/−
|
−
|
−
|
−
|
−
|
−/−
|
−
|
|
|
14 months after stopping IFX
|
−/−
|
−/+
|
−/−
|
−/−
|
−/−
|
−/−
|
−
|
−
|
−
|
−
|
−/−
|
−
|
|
9
|
Before
|
+/+
|
−/−
|
−/−
|
−
|
−/−
|
−/−
|
+
|
+
|
+
|
+
|
−/−
|
+
|
GC+MTX, IFX
|
|
4 months
|
+/+
|
−/−
|
−/−
|
−
|
−/−
|
−/−
|
+
|
+
|
+
|
+
|
−/−
|
+
|
|
|
8 months
|
+/−
|
−/−
|
−/−
|
−
|
−/−
|
−/−
|
−
|
+
|
+
|
+
|
−/−
|
−
|
|
10
|
Before
|
+/−
|
+/−
|
+/+
|
+/+
|
−/−
|
−/−
|
−
|
+
|
+
|
+
|
+/−
|
−
|
|
|
3 months of GC +TCZ
|
+/−
|
+/−
|
+/+
|
−/−
|
−/−
|
−/−
|
−
|
+
|
+
|
−
|
−/−
|
−
|
GC+TCZ
|
|
4 months
|
+/−
|
+/−
|
+/+
|
−/−
|
−/−
|
−/−
|
−
|
+
|
+
|
−
|
−/−
|
−
|
GC+IFX
|
|
8 months
|
−/−
|
−/−
|
+/−
|
−/−
|
−/−
|
−/−
|
−
|
+
|
+
|
−
|
−/−
|
−
|
|
|
12 months
|
−/−
|
−/−
|
+/−
|
−/−
|
−/−
|
−/−
|
−
|
+
|
−
|
−
|
−/−
|
−
|
|
|
4 months after stopping IFX
|
−/−
|
−/−
|
−/−
|
−/−
|
−/−
|
−/−
|
−
|
+
|
−
|
−
|
−/−
|
−
|
|
Note: + means involved, − means not involved or recovered; IFX=infliximab, GC=glucocorticoids, MTX=methotrexate, TCZ=tocilizumab, L=Left, R=Right.
Clinical manifestations and outcomes after IFX treatment
In the five patients treated with IFX alone, fever was controlled in 1-2 days. Blood pressures decreased to normal ranges after 3-8 months of IFX, without use of antihypertensives. Three infants continued to have weak pulses that did not improve with IFX.
Coronary arteries were reexamined one and a half months after initiation of IFX; coronary artery examinations and vascular imaging were performed at 4, 8, 14, 20, 26 and 32 months. After one and a half months of treatment, coronary ultrasound showed that the diameters of affected coronary arteries decreased. After four months, vascular ultrasound showed that the average thickness of affected arterial walls decreased, the number of diseased vessels decreased, and vessel wall thickening decreased. After 8 months, the affected vessels improved to a great extent and in some cases returned to normal. With continuation of treatment, vascular wall lesions ultimately improved, but some complications remained. Affected artery lumens were uneven; there was some vascular dilatation and stenosis, especially of the thoracic and abdominal aorta. Subjects did not worsen, and vascular narrowing showed some improvement (Table 2).
Growth and development of nine infants with TA was similar to age-matched healthy infants after 8-64 months of follow-up. In one infant treated with GC combined with MTX, height was less than the 3rd percentile for same-age healthy infants. At eight months, height was at the 5th percentile.
Laboratory tests
At onset of TA, leukocyte and platelet counts were high, hemoglobin was low, and inflammatory indexes were high, suggesting that all ten cases were in the active, acute stage. Leukocytes and platelet counts decreased, and hemoglobin increased after two weeks of IFX treatment. At six weeks, these laboratory values improved compared with values before treatment (p<0.05); Two weeks after IFX treatment started, the inflammatory indexes of C-reactive protein and erythrocyte sedimentation rate decreased significantly compared with before treatment (p<0.05) (Table 3).
Table 3 Changes in laboratory values
Treatment
|
Period
|
Laboratory tests
|
WBC
|
HGB
|
PLT
|
CRP
|
ESR
|
IFX
|
Before
|
19.31±3.22
|
95.8±11.26
|
828.6±192.94
|
66.8±39.32
|
79±40.51
|
After 2 weeks
|
14.53±1.82
|
111.8±7.53*
|
441.6±151.15
|
3.66±2.36
|
17.6±13.15
|
t value
|
2.89
|
2.64
|
3.53
|
3.58
|
3.22
|
p
|
0.02
|
0.03
|
0.01
|
0.01
|
0.01
|
IFX+GC
|
Before
|
16.07±5.52
|
93.4±6.62
|
664.4±193.16
|
101.96±33.71
|
67.8±40.88
|
After 2 weeks
|
10.77±4.49
|
119.2±13.95*
|
386±91.59
|
14.88±11.33
|
21.2±13.97
|
t value
|
1.67
|
3.74
|
7.5
|
5.48
|
2.41
|
p
|
0.13
|
0.01
|
0.01
|
0.01
|
0.04
|
Note: *-after 6 weeks, WBC-leukocyte, HGB- hemoglobin, PLT-platelet, CRP-C-reactive protein, ESR-erythrocyte sedimentation rate, IFX=infliximab, GC=glucocorticoids.
Safety evaluation and follow-up
The Case10 infant had a red rash on her face and chest during the 4th and 7th infusion of IFX. The rash gradually subsided when the infusion was stopped, and no adverse events occurred when the infusion was resumed. During the first 15 minutes of her 8th infusion, she had vomiting and was pale, although with normal blood pressure. Vomiting stopped when the infusion was stopped. In addition, she had a red rash that subsided 30 minutes after oral antiallergic drugs were given. It was considered to be an allergic reaction, and the infusion was not restarted. No other infants had adverse reactions. No cases of severe infection or pneumonia were seen during treatment or follow-up. In Case 1, IFX was used for 44 months (24 infusions total) and then MTX was added. In Cases 2 and 7, IFX was used for 20 months (12 infusions total for each infant), and MTX was added in case 7 during IFX treatment. In Cases 3, IFX was used for 8 months (6 infusions total). In Case 4, IFX was used for 10 months (7 infusions total). In Case 5 and 6, IFX was used for 22 months (13 infusions total for each infant), and MTX was added in case 6. In Cases 8 and 10, IFX was used for 12 months (8 infusions total for each infant), and MTX was added in case 10. In Case 9, IFX was used for 8 months (6 infusions). One to three months after starting IFX treatment, inflammatory indexes and hematological tests of all cases returned to normal. Routine hematologic tests and inflammatory indexes remained normal during follow-up.