单次小剂量利妥昔单抗治疗特发性膜性肾病的临床疗效分析

    Clinical efficacy of single low-dose rituximab for idiopathic membranous nephropathy

    • 摘要:
      目的  探讨单次小剂量利妥昔单抗(rituximab,RTX)治疗特发性膜性肾病(idiopathic membranous nephropathy,IMN)的有效性与安全性及与常规剂量治疗的差异。
      方法  回顾性分析2019年12月至2022年11月湖北省中医院光谷院区肾病科通过肾穿刺病理和检测抗磷脂酶A2受体抗体阳性诊断为IMN且使用RTX治疗的患者25例,在基础支持治疗方案基础上,单次小剂量组15例,使用RTX 200 mg/次;常规剂量组10例,使用RTX 500 mg/次,两组均为1次/周,总剂量2000 mg,对比两组治疗前与治疗3个月、治疗6个月的相关实验室检测指标。
      结果  治疗3个月,单次小剂量组总缓解率33%,常规剂量组总缓解率60%,两组总缓解率差异无统计学意义(P>0.05);治疗6个月,单次小剂量组总缓解率40%,常规剂量组总缓解率70%,两组总缓解率差异无统计学意义(P>0.05)。单次小剂量组治疗3个月、治疗6个月24 h尿蛋白定量分别为(3.42 ± 2.59)g、(1.96 ± 3.25)g,血白蛋白水平分别为(26.40 ± 9.90)g/L、(40.35 ± 5.06)g/L,血红蛋白含量分别为(120.00 ± 13.30)g/L、(130.60 ± 19.10)g/L,CD19+B淋巴细胞水平分别为(6.33 ± 5.50)个/μL、(2.67 ± 9.25)个/μL,CD19+B淋巴细胞计数<5个/μL分别为7例、13例,抗磷脂酶A2受体抗体阴性率分别为12例、14例,红细胞沉降率分别为(48.93 ± 25.89)mm/h、(38.13 ± 31.03)mm/h,总胆固醇分别为(5.27 ± 1.59)mmol/L、(4.67 ± 1.49)mmol/L,低密度脂蛋白分别为(2.80 ± 1.22)mmol/L、(2.58 ± 0.63)mmol/L,D-2聚体分别为(0.36 ± 0.29)mg/L、(0.11 ± 0.15)mg/L,与治疗前相比,组内差异均有统计学意义(P<0.05)。常规剂量组治疗3个月、治疗6个月24 h尿蛋白定量分别为(3.20 ± 3.56)g、(1.06 ± 1.14)g,血白蛋白水平分别为(32.10 ± 8.00)g/L、(36.26 ± 4.34)g/L,血红蛋白含量分别为(129.60 ± 15.70)g/L、(134.70 ± 10.99)g/L,CD19+B淋巴细胞水平分别为(5.50 ± 4.74)个/μL、(2.30 ± 6.25)个/μL,CD19+B淋巴细胞计数<5个/μL分别为9例、9例,抗磷脂酶A2受体抗体阴性率分别为7例、10例,与治疗前相比,组内差异均有统计学意义(P<0.05);治疗3个月,血清免疫球蛋白G为(3.13 ± 0.68)g/L、高密度脂蛋白为(0.58 ± 0.64)mmol/L,与治疗前相比,组内差异有统计学意义(P<0.05)。单次小剂量组患者治疗3个月后,血清免疫球蛋白G为(5.59 ± 2.48)g/L,常规剂量组为(3.13 ± 0.68)g/L;单次小剂量组患者治疗3个月后,白细胞介素6为(2.02 ± 1.65)ng/L,常规剂量组为(5.85 ± 5.09)ng/L;单次小剂量组治疗3个月后,高密度脂蛋白为(1.15 ± 0.42)mmol/L,常规剂量组为(0.58 ± 0.64)ng/L,组间差异有统计学意义(P<0.05)。两组治疗前、后,辅助性T细胞与抑制性T细胞比值、超敏C反应蛋白组内、组间比较,差异均无统计学意义(P>0.05)。治疗期间,单次小剂量组不良事件发生率13.33%,常规剂量组不良事件发生率50.00%,两组不良事件发生率比较,差异有统计学意义(P<0.05)。
      结论  单次小剂量RTX用药对清除IMN患者CD19+B淋巴细胞、提高抗磷脂酶A2受体抗体阴性率、促进病情缓解具有明显疗效,其疗效与常规剂量RTX相比无明显差异,但其不良事件发生率低于常规剂量用药,安全性较好。

       

      Abstract:
      Objective  To explore the efficacy and safety of single small-dose rituximab for idiopathic membranous nephropathy (IMN) and examine the difference with conventional-dose therapy.
      Methods  From December 2019 to November 2022, retrospective analysis was conducted for 25 IMN patients at Department of Nephrology, Guanggu Hospital, Hubei Provincial Hospital of Traditional Chinese Medicine. A definite diagnosis of IMN was made by renal puncture pathology and detection of positive anti-phospholipase A2 receptor antibody and using rituximab (RTX). An overall dose of 2,000 mg RTX was offered on the basis of basic supportive treatment. The once weekly dose was 200 mg in single small-dose group (n=15) versus 500 mg in conventional-dose group (n=10). The relevant laboratory parameters of two groups were compared at pre-treatment with those at Month 3/6 post-treatment.
      Results  At Month 3, overall remission rate was 33% in single small-dose group versus 60% in conventional-dose group and the inter-group difference was not statistically significant (P>0.05); at Month 6, overall remission rate was 40% in single small-dose group versus 70% in conventional-dose group and the inter-group difference was not statistically significant (P>0.05). At Months 3 and 6, quantitative 24 h urine protein was (3.42 ± 2.59)g vs (1.96 ± 3.25) g, blood albumin (26.40 ± 9.90) g/L vs (40.35 ± 5.06) g/L, hemoglobin (120.00 ± 13.30) g/L vs (130.60 ± 19.10) g/L, CD19+B lymphocyte (6.33 ± 5.50) cells/μL vs (2.67 ± 9.25) cells/μL, proportion of CD19+B lymphocyte count <5/μL (n=7 vs n=13), negativity rate of anti-phospholipase A2 receptor antibody (n=12 vs n=14), erythrocyte sedimentation rate (48.93 ± 25.89) mm/h vs (38.13 ± 31.03) mm/h, total cholesterol (5.27 ± 1.59) mmol/L vs (4.67 ± 1.49) mmol/L, low-density lipoprotein (2.80 ± 1.59) mmol/Lvs (4.67 ± 1.49) mmol/L and D-2 dimer (0.36 ± 0.29) mg/L vs (0.11 ± 0.15) mg/L were statistically different from those pre-treatment (P<0.05). In conventional-dose group, 24 h urine protein quantification was (3.20 ± 3.5)g vs (1.06 ± 1.14) g, blood albumin (32.10 ± 8.00) g/L vs (36.26 ± 4.34) g/L, hemoglobin (129.60 ± 15.70) g/L vs (134.70 ± 10.99) g/L, CD19+B lymphocyte (5.50 ± 4.74) cells/μL vs (2.30 ± 6.25) cells/μL, proportion of CD19+B lymphocyte count <5/μL (n=9 vs n=9) and negativity rate of anti-phospholipase A2 receptor antibody (n=7 vs n=10) were statistically significant from those pre-treatment (P<0.05); At Month 3, serum immunoglobulin G was (3.13 ± 0.68) g/L and high-density lipoprotein (0.58 ± 0.64) mmol/L. Both were statistically significant from those pre-treatment (P>0.05). When comparing single small-dose and conventional-dose groups at Month 3, serum immunoglobulin G was (5.59 ± 2.48) g/L vs (3.13 ± 0.68) g/L, interleukin 6 (2.02 ± 1.65) ng/L vs (5.85 ± 5.09) ng/L and high-density lipoprotein (1.15 ± 0.42) mmol/L vs (0.58 ± 0.64) mmol/L were statistically significant between two groups (P<0.05). No statistically significant inter-group differences existed in the ratio of helper T-cells to suppressor T-cells or ultrasensitive C-reactive protein (CRP) at pre/post-treatment (P>0.05). During treatment, the incidence of adverse events was lower in single small-dose group than that in conventional-dose group (13.33% vs 50%). And the inter-group difference was statistically significant (P<0.05).
      Conclusion  A single small-dose RTX has significant clearance of CD19+B lymphocytes, improvement of negativity rate of anti-phospholipase A2 receptor antibody (anti-phospholipase A2 receptor antibody) and promotion of remission in IMN patients. Its efficacy is not significantly different from that of conventional-dose RTX. However, the incidence of adverse events is lower and the safety is better.

       

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