Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China.
J Neurol. 2022 Aug;269(8):4229-4240. doi: 10.1007/s00415-022-11048-4. Epub 2022 Mar 3.
Generalized AChR-MG is an archetype of B cell-mediated autoimmune disorders, and use of biologic agent rituximab (RTX) for B cell depletion is generally limited to immunosuppressive therapy-refractory cases. However, benefit of RTX monotherapy and individualized regimen with optimal dosage in early stage of new-onset generalized AChR-MG still remains to be elucidated. In this retrospective study, we explore the efficacy and safety of personalized regimen of 100 mg low-dose rituximab monotherapy in treating new-onset generalized AChR-MG.
Thirteen new-onset generalized AChR-MG patients were enrolled for the study, initiating RTX treatment from November 2017 to August 2020. The individualized low-dose RTX monotherapy protocol consisted of 100 mg induction treatment weekly with no more than three circles, followed by reinfusion (100 mg once) sequentially according to whether achieving primary endpoint and peripheral CD19 + B-cell repopulation ≥ 1% of total lymphocytes at each visit (every 3 months). Outcome measures included MGFA-PIS Minimal Manifestation (MM) or better status (primary endpoint), changes in QMG, MMT, MG-ADL and MGQOL-15 scores (secondary endpoint), as well as cholinesterase inhibitors dosage.
All 13 patients achieved the primary endpoint in parallel with significant improvement of QMG, MMT, MG-ADL MGQOL-15 scores, and reduction of cholinesterase inhibitors dose. A total of 52 visits were performed during follow-up, and only 10 assessments presenting peripheral CD19 + B-cell repopulation (≥ 1%) without "MM or better status" were followed by RTX reinfusions (100 mg once) for clinical remission. The total dosage of RTX was only 346.15 ± 96.74 mg (including 269.23 ± 63.04 mg for induction and 76.92 ± 59.91 mg for reinfusion), which seemed to be much lower than those dosages used in new-onset generalized AChR-MG as described previously. Moreover, compared with patients without thymoma, thymectomy markedly delayed initiation of RTX for patients with thymoma (log-rank test, p = 0.0002), but the delaying treatments showed no influence on the time for achieving primary outcome (log-rank test, p = 0.2517).
Our study firstly showed that individualized regimen of low-dose RTX monotherapy is effective and safe for early treatment of new-onset generalized AChR-MG, and practicable for directing RTX reinfusion and withdrawal. Moreover, the monotherapy protocol was also indicated to be extensively applicable in both new-onset AChR-MG with thymoma (thymectomy) and without thymoma.
广义乙酰胆碱受体肌病（generalized acetylcholine receptor myasthenia gravis，AChR-MG）是 B 细胞介导的自身免疫性疾病的典型范例，通常仅将生物制剂利妥昔单抗（rituximab，RTX）用于 B 细胞耗竭治疗免疫抑制治疗难治性病例。然而，在新诊断的广义 AChR-MG 早期阶段，RTX 单药治疗和个体化最佳剂量方案的获益仍有待阐明。在本回顾性研究中，我们探讨了个性化低剂量 100mg RTX 单药治疗新诊断的广义 AChR-MG 的疗效和安全性。
从 2017 年 11 月至 2020 年 8 月，纳入了 13 例新诊断的广义 AChR-MG 患者进行本研究，起始 RTX 治疗。个体化低剂量 RTX 单药治疗方案包括每周 100mg 诱导治疗，不超过 3 个周期，然后根据是否达到主要终点和每次就诊时外周血 CD19+B 细胞再增殖≥总淋巴细胞的 1%（每 3 个月一次）进行序贯再输注（每次 100mg）。主要终点为改良重症肌无力基金会日常生活活动量表（Myasthenia Gravis Foundation of America—Post-intervention Scale，MGFA-PIS）最小表现（minimal manifestation，MM）或更好状态，次要终点包括 QMG、MMT、MG-ADL 和 MGQOL-15 评分的变化，以及胆碱酯酶抑制剂的剂量。
所有 13 例患者均达到主要终点，QMG、MMT、MG-ADL 和 MGQOL-15 评分均显著改善，胆碱酯酶抑制剂的剂量减少。在随访期间共进行了 52 次评估，仅在 10 次评估中出现外周血 CD19+B 细胞再增殖（≥1%）但无“MM 或更好状态”时，给予 RTX 再输注（100mg 一次）以实现临床缓解。RTX 的总剂量仅为 346.15±96.74mg（包括诱导治疗的 269.23±63.04mg 和再输注的 76.92±59.91mg），似乎明显低于以前描述的新诊断的广义 AChR-MG 中的剂量。此外，与无胸腺瘤患者相比，胸腺瘤患者的 RTX 起始治疗明显延迟（对数秩检验，p=0.0002），但延迟治疗对达到主要结局的时间无影响（对数秩检验，p=0.2517）。
本研究首次表明，低剂量 RTX 单药个体化方案对新诊断的广义 AChR-MG 的早期治疗有效且安全，可指导 RTX 再输注和停药。此外，该单药方案在伴胸腺瘤（胸腺切除术）和不伴胸腺瘤的新诊断 AChR-MG 中也具有广泛的适用性。
