1. General information:
Forty-seven cases were enrolled, with a median age of 11.0 years (9.0, 12.0 years), including 18 males (38.3%) and 29 females (61.7%). In the traditional treatment group, there were 30 cases with a median age of 10.5 years (8.75, 12.0 years), including 13 males (43.3%) and 17 females (56.7%). The initial diagnosis was between December 2004 and April 2022. The belimumab group had 17 cases, with a median age of 11.0 years (9.0, 13.0 years), including five males (29.4%) and 12 females (70.6%). The initial diagnoses were made between September 2020 and February 2023.
2. Clinical manifestations and treatment:
1) Extrarenal manifestations: At disease onset, there were no statistically significant differences between the two groups regarding the extrarenal organs involved, including the skin, mucosa, musculoskeleton, blood, nervous system, and complement C3/C4 levels. The SLEDAI-2000 score in the belimumab group (23.59 ± 7.78) was higher than that in the traditional treatment group (19.13 ± 6.10), with statistical significance (t = 2.176, P = 0.035).
2) Renal changes: The two groups had no significant differences in pyuria, gross hematuria, 24-h urine protein content, or eGFR. Among all cases, acute nephritis (16/47, 34.0%) and nephrotic syndrome (23/47, 48.9%) were the most common, and there was no statistically significant difference in clinical subtype distribution between both groups (χ2 = 2.192, P = 0.533). Forty-two pediatric patients underwent renal tissue biopsy, of which 41 (97.6%) were type III (including type III + V) and type IV (including type IV + V), with type IV being the most common. There was no statistically significant difference in pathological subtype distribution between both groups (χ2 = 4.441, P = 0.35). The belimumab group’s average activity index (10.47 ± 2.72) was higher than that of the traditional treatment group (9.59 ± 2.78). However, there was no statistically significant difference (t = 0.935, P = 0.357), and the median chronic index between both groups was not statistically different (Z = 1.244, P = 0.322) (Table 1).
Table 1
Comparison of baseline clinical and laboratory data between the traditional treatment group and the belimumab group
|
Traditional treatment group
(n = 30)
|
Belimumab group
(n = 17)
|
t/Z/χ2值
|
P
|
Male (n %)
|
13 (43.3)
|
5 (29.4)
|
0.89
|
0.345
|
Age (year)
|
10.10 ± 3.11
|
11.00 ± 2.78
|
–0.989
|
0.328
|
Organ involvement
|
|
|
|
|
Mucocutaneous
|
14 (46.7)
|
9 (52.9)
|
0.171
|
0.679
|
musculoskeletal
|
6 (20.0)
|
4 (23.5)
|
0.008
|
0.931
|
Hematologic
|
24 (80.0)
|
17 (100.0)
|
2.309
|
0.129
|
Nervous system
|
6 (20.0)
|
3 (17.7)
|
0.036
|
0.85
|
Kidney
|
|
|
|
|
Gross hematuria
|
14 (46.7)
|
7 (41.2)
|
0.132
|
0.716
|
Pyuria
|
21 (70.0)
|
13 (76.5)
|
0.061
|
0.805
|
UTP (mg/kg.d)
|
63.3 (22.3,146.2)
|
75.9(34.5,117.0)
|
–0.133
|
0.894
|
Scr (umol/L)
|
62.54 (48.5,74.6)
|
65.50(49.5,102.4)
|
–0.831
|
0.406
|
eGFR (mL/min.1.73 m2)
|
94.72 ± 32.07
|
81.02 ± 37.88
|
1.298
|
0.201
|
Clinical typing (n %)
|
|
|
2.192
|
0.533
|
Hematuria proteinuria type
|
3 (10.0)
|
2 (11.8)
|
|
|
Nephrotic syndrome type
|
12 (40.0)
|
4 (23.5)
|
|
|
Acute nephritis type
|
14 (46.7)
|
9 (52.9)
|
|
|
Acute progressive nephritis type
|
1 (3.33)
|
2 (11.8)
|
|
|
Pathological classification (n %)
|
|
|
4.441
|
0.35
|
Ⅱ
|
1 (4.0)
|
0 (0.0)
|
|
|
Ⅲ
|
1 (4.0)
|
0 (0.0)
|
|
|
Ⅳ
|
19 (76.0)
|
15 (88.2)
|
|
|
Ⅲ+Ⅴ
|
1 (4.0)
|
2 (11.8)
|
|
|
Ⅳ+Ⅴ
|
3 (12.0)
|
0 (0.0)
|
|
|
AI
|
9.59 ± 2.78
|
10.47 ± 2.72
|
–0.935
|
0.357
|
CI
|
0.0 (0.0.1.5)
|
0.0 (0.0.0.0)
|
–1.244
|
0.322
|
C3 (g/L)
|
0.27 (0.2,0.5)
|
0.32 (0.2,0.4)
|
–0.444
|
0.657
|
C4 (g/L)
|
0.04 (0.0,0.1)
|
0.06 (0.0,0.1)
|
–0.692
|
0.489
|
SLEDAI-2000
|
19.13 ± 6.10
|
23.59 ± 7.78
|
–2.176
|
0.035
|
UTP, Uridine-5′-triphosphate; Scr, serum creatinine; eGFR, estimated glomerular filtration rate; SLEDAI-2000, Systemic Lupus Erythematosus Disease Activity Index-2000 |
Immune induction therapy: Among the two groups, CTX was the most commonly used immunosuppressive induction therapy, with 39 cases. Among them, the traditional treatment and belimumab groups had 27 (93.10%) and 12 cases (70.59%), respectively; joint calcineurin inhibitor class (χ2 = 1.951, P = 0.163) and hydroxychloroquine (χ2 = 0.171, P = 0.679) but there was no difference in treatment between the two groups. Four children were treated with blood purification, including two continuous bedside blood filtration, one peritoneal dialysis, and one plasma exchange (Table 2).
Table 2
Comparison of induction therapy between the traditional treatment and belimumab groups
|
Traditional treatment group
(n = 30)
|
Belimumab group
(n = 17)
|
χ2
|
P
|
Immune induction therapy n (%)
|
|
|
2.647
|
0.104
|
GC + CTX
|
27 (90.0)
|
12 (70.6)
|
|
|
GC + MMF
|
2 (6.7)
|
5 (29.4)
|
|
|
CNI n (%)
|
4 (13.33)
|
6 (35.29)
|
1.951
|
0.163
|
HCQ n (%)
|
16 (53.33)
|
8 (47.06)
|
0.171
|
0.679
|
Blood purification therapy n (%)
|
2 (6.67)
|
2 (11.76)
|
|
0.613
|
GC, glucorcorticoid; CTX, cyclophosphamide; MMF, mycophenolate mofetil; CNI, Calcineurin inhibitors; HCQ, hydroxychloroquine |
3. Belimumab treatment:
Seventeen enrolled cases of LN had a course of 2 weeks to 3 months of belimumab therapy, with an average of 1.9 ± 1.4 months. Fourteen patients completed 52 weeks of treatment, whereas the remaining three received belimumab for 12–20 weeks.
4. Validity
1)Activity: The SLEDAI-2000 score was comparable between the two groups at 6 months of treatment, whereas at 12 months, the belimumab group had a lower score; however, the difference between the groups was not statistically significant. Comparing the complement C3 and C4 levels, the belimumab group recovered faster than the traditional treatment group at 3, 6, and 12 months of treatment (P < 0.05). There were no differences in the titer changes of anti-double-stranded DNA antibodies between the two treatment groups (Fig. 1).
2) There were no significant differences in 24-h urine protein quantification and eGFR between the two groups after 3, 6, and 12 months of treatment (P > 0.05) (Fig. 2).
3) Renal response rate: At 6 months of treatment, the CR rate of all patients was 37/47 (78.7%), with that in the belimumab group (88.2%) being higher than that in the traditional treatment group (73.3%). The PR and NR rates were lower in the belimumab group than in the traditional treatment group; however, the difference was not statistically significant. At 12 months of treatment, the CR rate of all patients was 40/44 (90.9%), and there was no significant difference in the CR or PR rates between the two groups. There were no unrelieved cases in either group.
Recurrence and end-stage renal disease: median follow-up of 13.0 months (9.0, 28.0 months) in the belimumab group, with no clinical recurrence cases (χ 2 = 1.061, P = 0.303). At 12 months of treatment, there were four cases (13.3%) of recurrence in the traditional treatment group, all of whom were followed up on time and treated regularly. As of October 31, 2023, the median follow-up time for all children in the traditional treatment group was 49.5 months (16.5, 70.0 months), of which 13 cases (43.3%) had 21 relapses, all within 5 years. The median time from onset to the first recurrence was 2 years (1, 3.5 years). Ten patients (76.9%) had one recurrence, one (7.7%) had two relapses, one (7.7%) had three relapses, and one (7.7%) had six relapses. Thirteen of the 21 relapses (61.9%) occurred after infection, fatigue, and irregular medication use, whereas eight (38.1%) had no triggers. At the end of follow-up, 16 patients in the traditional treatment group had become adults, of which one patient had developed stage 2 of end-stage renal disease (followed up for 116 months, with six relapses), whereas the other patients showed continuous CR. Further details are presented in Table 3.
Table 3
Comparison of SLE activity and renal response rates between the traditional treatment and the belimumab groups at 6 and 12 months of treatment
|
6 month
|
12 month
|
|
Traditional treatment group
|
Belimumab group
|
t/Z/χ2
|
P
|
Traditional treatment group
|
Belimumab group
|
t/Z/χ2
|
P
|
SLEDAI-2000
|
4 (2,8)
|
4 (2,7)
|
–0.255
|
0.799
|
4 (1,6)
|
0(0,4)
|
–1.507
|
0.132
|
eGFR (mL/min.1.73 m2)
|
128.65 ± 26.33
|
121.72 ± 21.96
|
0.863
|
0.394
|
116.80 ± 20.90
|
115.36 ± 18.32
|
0.196
|
0.846
|
Renal remission rate n (%)
|
|
|
1.631
|
0.442
|
|
|
0.094
|
0.759
|
CR
|
22 (73.3)
|
15 (88.2)
|
|
|
27 (90.0)
|
13 (92.9)
|
|
|
PR
|
7 (23.3)
|
2 (11.8)
|
|
|
3 (10.0)
|
1 (7.1)
|
|
|
NR
|
1 (3.3)
|
0 (0.0)
|
|
|
0 (0.0)
|
0 (0.0)
|
|
|
Recurrence rate within 1 year n (%)
|
|
|
|
|
4 (13.3%)
|
0 (0.0%)
|
1.061
|
0.303
|
SLE, Systemic Lupus Erythematosus; SLEDAI-2000, Systemic Lupus Erythematosus Disease Activity Index-2000; eGFR, estimated glomerular filtration rate; CR, complete remission; NR, no renal remission; PR, partial remission |
Glucocorticoid dosage: Both groups were treated with sufficient glucocorticoids following the guidelines [6] to induce remission. After 6 months of treatment, the steroid dosage in the belimumab group (17.87 ± 6.96 mg/d) was significantly lower than that in the traditional treatment group (27.33 ± 8.40 mg/d) (P < 0.001). The hormone dose in the belimumab group (10.00 (5.3, 10.0) mg/d) after 12 months of treatment was significantly lower than that in the traditional treatment group (13.75 (10.0,22.5) mg/d) (P = 0.007), with significant statistical significance. See Fig. 3 for details
5) Safety: No infusion-related reactions occurred in any patient during belimumab administration. Nine children (52.9%) experienced acute upper respiratory tract infections two to four times, one (5.9%) had gastroenteritis, one (5.9%) had tinea versicolor, and one (5.9%) had a varicella zoster virus infection. Notably, all infections improved within 1 week, and no serious adverse reactions occurred. There was a downward trend in serum immunoglobulin M (IgM), IgG, and IgA levels compared with baseline at 6 and 12 months after administering belimumab; however, there was no statistically significant difference (Table 4).
Table 4
Comparison of immunoglobulin levels in the belimumab group
|
baseline
|
6 month
|
12 month
|
F
|
P
|
IgG (g/L)
|
8.65 ± 4.60
|
7.52 ± 3.21
|
7.16 ± 2.97
|
0.669
|
0.517
|
IgM (g/L)
|
1.26 ± 0.47
|
0.95 ± 0.40
|
0.93 ± 0.37
|
2.955
|
0.063
|
IgA (g/L)
|
0.83 ± 0.42
|
0.56 ± 0.30
|
0.64 ± 0.38
|
2.18
|
0.125
|
IG, immunoglobulin |