利妥昔单抗对肾小球疾病患者血淋巴细胞及免疫球蛋白的影响

Effects of rituximab on lymphocytes and immunoglobulin in the treatment of glomerular disease

目的探讨利妥昔单抗治疗局灶节段性肾小球硬化(focal segmental glomerulosclerosis,FSGS)和肾小球微小病变(minimal change disease,MCD)对体液免疫和细胞免疫的影响。方法研究对象来自2014年7月1日至2019年7月1日上海交通大学医学院附属瑞金医院收治的FSGS和MCD患者,所有入选者均经临床和肾活组织病理检查确诊并接受了利妥昔单抗治疗(用药剂量为375 mg/m2体表面积,共治疗4次,每次治疗间隔时间7~14 d)。比较基线和利妥昔单抗治疗后3、6、9、12个月患者免疫球蛋白IgA、IgG、IgM,淋巴细胞CD19^(+)、CD20^(+)、CD3^(+)、CD3^(+)CD4^(+)、CD3^(+)CD8^(+)、自然杀伤细胞(CD56^(+)CD16^(+))水平的差异。结果96例FSGS和MCD患者入选本研究,中位年龄28岁(14~77岁),男女比为1.8∶1,MCD 65例,FSGS 31例。利妥昔单抗治疗后患者尿蛋白量较治疗前显著下降,血白蛋白水平上升(均P<0.01)。利妥昔单抗治疗后外周血CD19^(+)和CD20^(+)淋巴细胞计数均<5个/μl,治疗后3、6、9、12个月CD19^(+)和CD20^(+)淋巴细胞计数较基线值显著下降(均P<0.05),6个月后逐渐恢复。与基线值比较,利妥昔单抗治疗后3、6、9、12个月血IgG水平显著上升(P值分别为0.004、<0.001、<0.001、<0.001),血IgM水平显著下降(P值分别为<0.001、0.008、0.005、<0.001)但中位数水平仍在正常范围(400~3450 mg/L),而血IgA水平无明显变化(均P>0.05)。T淋巴细胞(CD3^(+)、CD3^(+)CD4^(+)、CD3^(+)CD8^(+))和自然杀伤细胞(CD56^(+)CD16^(+))计数与基线值比较差异无统计学意义(均P>0.05)。结论利妥昔单抗可有效清除CD19^(+)和CD20^(+)淋巴细胞,对除外CD19^(+)、CD20^(+)的外周血淋巴细胞计数及免疫球蛋白的影响较小。规范的利妥昔单抗用药可安全用于FSGS和MCD患者的治疗。

Objective To investigate the effects of rituximab on lymphocytes and immunoglobulin in the treatment of focal segmental glomerulosclerosis(FSGS)and minimal change disease(MCD).Methods The subjects were FSGS and MCD patients admitted to Ruijin Hospital affiliated to Shanghai Jiaotong University on July 1,2014 and July 1,2019.All the enrolled patients were confirmed by clinical examination and renal biopsy,and received rituximab treatment(4 infusions of 375 mg/m2 with the interval of 7-14 d).The levels of immunoglobulin IgA,IgG,IgM,and lymphocytes of CD19^(+),CD20^(+),CD3^(+),CD3^(+)CD4^(+),CD3^(+)CD8^(+)and natural killer cells(CD56^(+)CD16^(+))were compared between baseline and the third month,the sixth month,the ninth month and the twelfth month after treatment.Results Ninety-six patients with FSGS or MCD were enrolled in this study.The midian age was 28 years old(14-77 years old).The ratio of men to woman was 1.8∶1.There were 65 cases of MCD and 31 cases of FSGS.After rituximab treatment,the 24 h-proteinuria was significantly lower than that before treatment,and the serum albumin level was increased(both P<0.05).After rituximab treatment of 3 months,6 months,9 months and 12 months,CD19^(+)and CD20^(+)lymphocyte counts were significantly decreased(all P<0.01),and gradually recovered after 6 months.Compared with baseline,at 3,6,9,12 months after rituximab treatment,the level of blood IgG was significantly increased(P=0.004,<0.001,<0.001,<0.001,respectively),and the level of blood IgM was significantly decreased(P<0.001,=0.008,=0.005,<0.001,respectively)but the median level still within the normal range(400-3450 mg/L).The level of blood IgA was not significantly changed(all P<0.05).T lymphocytes(CD3^(+),CD3^(+)CD4^(+)and CD3^(+)CD8^(+))and natural killer cells(CD56^(+)CD16^(+))showed no significant difference from baseline(all P>0.05).Conclusions Rituximab can effectively eliminate CD19^(+)and CD20^(+)lymphocytes,and has little influence on peripheral blood lymphocyte count and immunoglobulin level except CD19^(+)and CD20^(+)lymphocytes.The standard administration of rituximab is safe for patients with FSGS and MCD.