贝利尤单抗联合传统方案治疗儿童活动性狼疮性肾炎疗效分析

doi:10.12372/jcp.2024.23e0911

摘要/Abstract

摘要：

目的探讨贝利尤单抗靶向药物与传统方案相结合在早期诱导期治疗活动性儿童狼疮性肾炎的疗效，为儿童狼疮性肾炎（LN）治疗提供新的诊疗理念及依据。方法收集2018年1月至2021年8月58例初发的儿童活动性LN，根据诱导早期有无加用贝利尤单抗联合治疗分为观察组（传统方案联合BLM治疗）32例及对照组（传统方案治疗）26例，观察两组患儿基线及第4、12、24周血清生化指标（ALB、BUN、Cr、eGRF）、免疫指标（C3、C4、IgG、CD19⁺B计数、抗ds-DNA抗体）、尿微量白蛋白、24 h尿蛋白定量及SLEDAI-2K评分。随访2年后两组患儿达标率、复发率及糖皮质激素的使用剂量。结果两组患儿肾脏病理类型及传统治疗方案比较差异无统计学意义（P>0.05）。两组患儿基线、4周、12周、24周血ALB、BUN、CR、C3、C4组间比较无统计学差异（P>0.05）；组内比较差异均有统计学意义（P<0.05）；治疗4周、12周观察组eGRF明显高于对照组，差异有统计学意义（P<0.05），两组组内比较无统计学差异（P>0.05）；治疗12周、24周尿微量白蛋白及24 h尿蛋白定量较对照组明显下降，组间差异有统计学意义（P<0.05）；组内比较差异有统计学差异（P<0.05）。治疗24周观察组CD19⁺B细胞计数由基线653.00（438.00~933.25）cells/μL降至45（30.50~66.50）cells/μL，IgG由14.84（12.03~17.64）g/L降至5.45（5.11~5.79）g/L，抗ds-DNA抗体阳性率由100%降至46.87%，SLEDAI-2K评分达无疾病活动状态完全缓解率（87.50%）及总效率（93.75%），明显高于对照组(65.38%、84.62%)，差异均有统计学意义（P<0.05）。治疗24周观察组中87.50%患儿糖皮质激素减至5 mg/d，高于对照组（76.92%，P<0.05）。2年后随访中观察组达标率（93.75%）高于对照组（61.54%），复发率（6.25%）低于对照组（30.77%），差异有统计学意义（P<0.05）。结论贝利尤单抗联合传统治疗诱导期治疗儿童活动性LN可减轻蛋白尿、降低SLE疾病活动度，助减激素，尽快达标，且可降低患儿复发率，改善预后，疗效优于单纯传统治疗方案。

关键词: 活动性狼疮性肾炎, 贝利尤单抗, 传统治疗, 儿童

Abstract:

Objective To investigate the efficacy of combining Belimumab with traditional therapy in treating active lupus nephritis (LN) in children during the early induction period, and to provide a novel diagnostic and therapeutic framework for the future treatment of LN in children. Method Clinical data were collected from 58 children with active LN newly diagnosed from January 2018 to August 2021. Participants were divided into observation group (32 cases) and control group (26 cases) based on the use of Belimumab in the induction stage. Serum biochemical markers(ALB, BUN, Cr, eGRF), immune markers (IgG, C3, C4, CD19⁺B count, anti-nuclear antibody), along with urinary microalbumin, urinary protein quantity at at 24h and SLEDAI-2K score were were assessed at baseline and after 4, 12, and 24 weeks of treatment. The compliance rate, recurrence rate and glucocorticoid dosage of the two groups were also followed up. Results No significant differences were found in renal pathological type and traditional treatment between the two groups (P>0.05), there were no significant differences in blood ALB, BUN, CR, C3 and C4 between the two groups(P>0.05). However, statistically significant differences were observed among all groups (P<0.05).The eGFR was higher in the observation group at 4 and 12 weeks, but no statistically significant difference was noted between the two groups (P>0.05). After 12 and 24 weeks of treatment,urinary microalbumin and urinary protein quantity at 24h were significantly reduced compared to the control group, with statistical significance (P<0.05); intergroup comparisons also showed significant differences (P<0.05). In the observation group at 24 weeks, the CD19⁺B cell count decreased from 653 (438-933.25) cells/μL to 45 (30.50-66.50) cells/μL, IgG decreased from 14.84 (12.03-17.64) g/L to 5.45 (5.11-5.79) g/L. The positive rate of anti-nuclear antibodies decreased from 100% to 46.87%, SLEDAI-2K score reached disease-free activity status. The complete remission rate (87.50%) and total efficiency (93.75%) in the observation group were significantly higher than those in the control group (65.38% and 84.62%, respectively), with statistical significance (P<0.05). The glucocorticoid dosage was reduced to 5 mg/d in 87.50% of children in the observation group after 24 weeks, compared to 76.92% in the control group, with statistically significant differences (P<0.05). After 2 years follow-up, the compliance rate in the observation group (93.75%) was significantly higher than that in the control group (61.54%), while the recurrence rate (6.25%) was lower than that of the control group (30.77%), with statistical significance (P<0.05). Conclusion The combination of Belimumab and traditional therapy is effective in treating active LN in children during the induction period. This approach alleviates proteinuria, improves disease activity in systemic lupus erythematosus (SLE), facilitates early glucocorticoid reduction, and enhances overall outcomes, demonstrating superior efficacy compared to traditional therapy alone.

Key words: active lupus nephritis, belimumb, standard treatment, child

彭倩倩, 杨焕丹, 袁婷婷, 邱闪, 李艳, 周苏芹, 陆倩. 贝利尤单抗联合传统方案治疗儿童活动性狼疮性肾炎疗效分析[J]. 临床儿科杂志, 2024, 42(11): 975-982.

PENG Qianqian, YANG Huandan, YUAN Tingting, QIU Shan, LI Yan, ZHOU Suqin, LU Qian. Efficacy of Belimumab combined with traditional regimen in the treatment of active lupus nephritis in children[J]. Journal of Clinical Pediatrics, 2024, 42(11): 975-982.

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参考文献 34

[1]	Harry O, Yasin S, Brunner H. Childhood-onset systemic lupus erythematosus: a review and update[J]. J Pediatr, 2018, 196: 22-30.
[2]	Smith EMD, Lythgoe H, Midgley A, et al. Juvenile-onset systemic lupus erythematosus: update on clinical presentation, pathophysiology and treatment options[J]. Clin Immunol, 2019, 209: 108274.
[3]	Mok CC, Teng YKO, Saxena R, et al. Treatment of lupus nephritis: consensus, evidence and perspectives[J]. Nat Rev Rheumatol, 2023, 19(4): 227-238. doi: 10.1038/s41584-023-00925-5 pmid: 36864291
[4]	Tunnicliffe DJ, Palmer SC, Henderson L, et al. Immuno-suppressive treatment for proliferative lupus nephritis[J]. Cochrane Database Syst Rev, 2018, 6(6): CD002922.
[5]	曾萍, 曾华松, 唐雪梅, 等. 贝利尤单抗治疗中国儿童系统性红斑狼疮28周有效性和安全性分析: 一项回顾性多中心真实世界的初步研究[J]. 中国实用儿科杂志, 2021, 36(11): 858-868.
[6]	Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis[J]. N Engl J Med, 2020, 383(12): 1117-1128.
[7]	Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythe-matosus[J]. Arthritis Rheum, 2012, 64(8): 2677-2686.
[8]	中华医学会儿科学分会肾脏学组. 狼疮性肾炎诊治循证指南(2016)[J]. 中华儿科杂志, 2018, 56(2): 88-94.
[9]	Bajema IM, Wilhelmus S, Alpers CE, et al. Revision of the international society of nephrology/renal pathology society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices[J]. Kidney Int, 2018, 93(4): 789-796. doi: S0085-2538(17)30859-1 pmid: 29459092
[10]	Rovin BH, Adler SG, Barratt J, et al. Executive summary of the KDIGO 2021 guideline for the management of glomerular diseases[J]. Kidney Int, 2021, 100(4): 753-779. doi: 10.1016/j.kint.2021.05.015 pmid: 34556300
[11]	中华医学会儿科学分会免疫学组, 中华儿科杂志编辑委员会. 中国儿童系统性红斑狼疮诊断与治疗指南[J]. 中华儿科杂志, 2021, 59(12): 1009-1024.
[12]	Morales E, Galindo M, Trujillo H, et al. Update on lupus nephritis: looking for a new vision[J]. Nephron, 2021, 145(1): 1-13.
[13]	Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000[J]. J Rheumatol, 2002, 29(2): 288-291. pmid: 11838846
[14]	Schwartz GJ, Haycock GB, Edelmann CM Jr, et al. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine[J]. Pediatrics, 1976, 58(2): 259-263. pmid: 951142
[15]	中华医学会儿科学分会肾脏学组, 中华儿科杂志编辑委员会. 中国儿童慢性肾脏病早期筛查临床实践指南(2021版)[J]. 中华儿科杂志, 2022, 60(9): 858-868.
[16]	范晖, 闫银坤, 米杰. 中国3-17岁儿童性别、年龄别和身高别血压参照标准[J]. 中华高血压杂志, 2017, 25(5): 428-435.
[17]	钟旭辉, 丁洁, 周建华, 等. 中国儿童15项常用临床检验指标的生物参考区间研究[J]. 中华儿科杂志, 2018, 56(11): 835-845.
[18]	程程, 文思佳, 林知朗, 等. 儿童狼疮性肾炎的疗效及预后分析[J]. 中华儿科杂志, 2021, 59(9): 730-736.
[19]	Pinheiro SVB, Dias RF, Fabiano RCG, et al. Pediatric lupus nephritis[J]. J Bras Nefrol, 2019, 41(2): 252-265. doi: S0101-28002019000200252 pmid: 30465590
[20]	Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 clinical practice guideline for the management of glomerular diseases[J]. Kidney Int, 2021, 100(4S): S1-S276.
[21]	Anders HJ, Appel GB. Lupus nephritis: Implications of the new ACR lupus nephritis guidelines[J]. Nat Rev Nephrol, 2012, 8(9): 500-501.
[22]	Fanouriakis A, Kostopoulou M, Cheema K, et al. 2019 update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis[J]. Ann Rheum Dis, 2020, 79(6): 713-723.
[23]	中国狼疮肾炎诊断和治疗指南编写组. 中国狼疮肾炎诊断和治疗指南[J]. 中华医学杂志, 2019, 99(44): 3441-3455.
[24]	Kostopoulou M, Adamichou C, Bertsias G. An update on the diagnosis and management of lupus nephritis[J]. Curr Rheumatol Rep, 2020, 22(7): 30.
[25]	Kostopoulou M, Fanouriakis A, Cheema K, et al. Management of lupus nephritis: a systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations[J]. RMD Open, 2020, 6(2): e001263.
[26]	Porta S, Danza A, Arias Saavedra M, et al. Glucocorticoids in systemic lupus erythematosus. Ten questions and some issues[J]. J Clin Med, 2020, 21; 9(9): 2709.
[27]	Obrișcă B, Sorohan B, Tuță L, et al. Advances in lupus nephritis pathogenesis: from bench to bedside[J]. Int J Mol Sci, 2021, 22(7): 3766.
[28]	徐男男, 付文轶, 张宁. 贝利尤单抗治疗系统性红斑狼疮的效果分析[J]. 中国免疫学杂志, 2022, 38(18): 2264-2268.
[29]	Sciascia S, Radin M, Yazdany J, et al. Efficacy of belimumab on renal outcomes in patients with systemic lupus erythematosus: a systematic review[J]. Autoimmun Rev, 2017, 16(3): 287-293. doi: S1568-9972(17)30022-8 pmid: 28147262
[30]	张晓枫, 陈琳, 马秋玲, 等. 贝利尤单抗治疗重型Ⅳ、Ⅳ+Ⅴ及Ⅴ型狼疮性肾炎的有效性及安全性分析[J]. 实用药物与临床, 2023, 26(10): 893-898.
[31]	王倩涵, 苗永红, 安乐美. 小样本应用贝利尤单抗治疗儿童系统性红斑狼疮的临床疗效观察[J]. 中国中西医结合儿科学, 2023, 15(2): 137-141.
[32]	高雨彤, 何孝亮, 陈登环, 等. 贝利尤单抗治疗儿童系统性红斑狼疮17例临床疗效分析[J]. 临床儿科杂志, 2022, 40(10): 745-749.
[33]	Tucker LB, Uribe AG, Fernández M, et al. Adolescent onset of lupus results in more aggressive disease and worse outcomes: results of a nested matched case-control study within LUMINA, a multiethnic US cohort (LUMINA LVII)[J]. Lupus, 2008, 17(4): 314-322. doi: 10.1177/0961203307087875 pmid: 18413413
[34]	卢小平, 周涛, 曾惠琼. 贝利尤单抗联合糖皮质激素治疗系统性红斑狼疮的临床疗效观察[J]. 吉林医学, 2022, 43(9): 2412-2415.

治疗方案	观察组（n=32）	对照组（n=26）	统计量	P
GC+HCQ+ACEI+MMF	9	7	2.14	0.677
Ⅲ型	3	4
Ⅲ+Ⅴ型	2	0
Ⅳ型	2	1
Ⅳ+Ⅴ型	0	0
Ⅴ型	2	2
GC+HCQ+ACEI+CTX	13	13	2.55	0.329
Ⅲ型	0	0
Ⅲ+Ⅴ型	2	4
Ⅳ型	10	6
Ⅳ+Ⅴ型	1	3
Ⅴ型	0	0
GC+HCQ+ACEI+FK506	8	3	1.94	0.709
Ⅲ型	0	0
Ⅲ+Ⅴ型	0	0
Ⅳ型	3	0
Ⅳ+Ⅴ型	3	1
Ⅴ型	2	2
GC+HCQ+ACEI+MMF +FK506	2	3	-	0.400^1）
Ⅲ型	0	0
Ⅲ+Ⅴ型	0	0
Ⅳ型	0	2
Ⅳ+Ⅴ型	2	1
Ⅴ型	0	0

指标	组别	基线	4周	12周	24周	F值	P
ALB/g·L^-1	观察组	27.17±6.28	33.54±4.94	40.42±3.97	43.72±3.49	6.11	<0.001
ALB/g·L^-1	对照组	29.25±5.77	34.68±5.13	40.74±3.87	43.42±2.98	2.82	0.004
t值		1.30	0.86	0.30	0.34
P		0.199	0.395	0.762	0.734
BUN/mmol/L^-1	观察组	8.38±3.83	6.52±1.61	4.96±0.78	4.24±0.77	3.46	<0.001
BUN/mmol/L^-1	对照组	7.95±3.15	6.18±1.24	4.99±0.66	4.32±0.60	3.55	<0.001
t值		0.46	0.88	0.18	0.44
P		0.647	0.384	0.861	0.661
Cr/μmol·L^-1	观察组	73.09±25.13	51.56±10.68	43.38±4.94	41.16±5.12	3.54	<0.001
Cr/μmol·L^-1	对照组	76.31±25.97	57.57±12.53	45.91±5.85	41.27±5.36	2.73	<0.001
t值		-0.48	1.97	1.79	0.08
P		0.635	0.054	0.079	0.9351
eGRF/mL·min^-1·1.73m^-2	观察组	109.51±39.18	143.07±29.60	164.23±17.38	173.70±18.26	1.02	0.533
eGRF/mL·min^-1·1.73m^-2	对照组	99.46±31.03	124.59±25.81	152.14±20.11	168.77±18.49	1.20	0.422
t值		1.07	2.50	2.46	1.02
P		0.292	0.015	0.017	0.313

指标	组别	基线	4周	12周	24周	统计量	P
C3[M(P₂₅~P₇₅)]/g·L^-1	观察组	0.39 （0.29~0.50）	0.75 （0.68~0.85）	1.03 （0.97~1.13）	1.23 （1.14~1.35）	H=105.79	<0.001
C3[M(P₂₅~P₇₅)]/g·L^-1	对照组	0.32 （0.25~0.46）	0.75 （0.71~0.80）	0.98 （0.91~1.21）	1.32 （1.23~1.34）	H=12.75	<0.001
Z值		1.16	0.19	0.44	0.98
P		0.247	0.851	0.661	0.328
C4[M(P₂₅~P₇₅)]/g·L^-1	观察组	0.05 （0.03~0.07）	0.13 （0.10~0.15）	0.20 （0.16~0.23）	0.25 （0.24~0.30）	H=100.89	<0.001
C4[M(P₂₅~P₇₅)]/g·L^-1	对照组	0.04 （0.03~0.05）	0.14 （0.24~0.30）	0.20 （0.16~0.23）	0.26 （0.24~0.30）	H=9.98	<0.001
Z值		1.93	0.47	-0.02	0.28
P		0.054	0.637	0.987	0.781
IgG[M(P₂₅~P₇₅)]/g·L^-1	观察组	14.84 （12.03~17.64）	8.81 （7.38~10.25）	6.53 （5.77~7.29）	5.45 （5.11~5.79）	H=60.13	<0.001
IgG[M(P₂₅~P₇₅)]/g·L^-1	对照组	14.92 （11.41~17.21）	8.46 （7.35~9.50）	6.36 （6.06~6.95）	5.25 （5.21~6.02）	H=12.84	<0.001
Z值		0.60	1.08	0.74	0.34
P		0.547	0.280	0.457	0.731
CD19⁺B[M(P₂₅~P₇₅)]/ 个·μL^-1	观察组	653 （438~933.25）	342 （295.25~439.50）	105 （99~122.25）	45 （30.50~66.50）	H=102.64	<0.001
CD19⁺B[M(P₂₅~P₇₅)]/ 个·μL^-1	对照组	543 （279.25~695.75）	345 （315~481.75）	181 （113.50~217.50）	156 （98.50~191.25）	H=4.70	<0.001
Z值		2.18	0.32	3.32	5.24
P		0.029	0.748	0.001	<0.001
抗ds-DNA抗体[n（%）]	观察组	32（100）	32（100）	25（78.13）¹⁾	15（46.87）²⁾	χ²=14.94	0.001
抗ds-DNA抗体[n（%）]	对照组	26（100）	26（100）	23（88.46）	20（76.92）	χ²=6.160	0.046
χ²值		7.55	7.55	4.31	3.66
P		<0.001	<0.001	<0.001	<0.001

指标	组别	基线	4周	12周	24周	H值	P
尿微量白蛋白/mg·d^-1	观察组	257 （84.01~402.75）	73.40 （35.31~103.52）	5.93 （2.42~15.66）	1.24 （0.98~2.65）	93.22	<0.001
尿微量白蛋白/mg·d^-1	对照组	191.60 （30.36~136.45）	66.03 30.36~136.46）	15.36 （3.98~45.64）	6.91 （1.36~20.83）	51.98	<0.001
Z值		-0.625	-0.023	-2.205	-3.120
P		0.532	0.981	0.027	0.002
24 h尿蛋白定量	观察组	2.39 （0.90~4.75）	0.86 （0.53~1.26）	0.21 （0.14~0.45）	0.12 （0.08~0.25）	90.55	<0.001
24 h尿蛋白定量	对照组	1.86 （0.67~3.50）	0.21 （0.14~0.45）	0.42 （0.17~0.74）	0.30 （0.13~0.36）	2.42	0.002
Z值		1.00	0.16	2.30	3.18
P		0.317	0.870	0.021	0.001

	基线	12周	24周	χ²值	P
观察组	32（100）	20（62.50）	28（87.50）	16.63	<0.001
对照组	26（100）	13（50.00）	20（76.92）	17.45	<0.001
χ²值	7.55	5.68	6.86
P	<0.001	<0.001	<0.001