利妥昔单抗在儿科视神经脊髓炎谱系疾病中的监测和再给药。
Rituximab monitoring and redosing in pediatric neuromyelitis optica spectrum disorder.
机构信息
Neuroimmunology Group (M. Nosadini, S.S.M., S.R., F.B., R.C.D.), Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, University of Sydney, Australia; Paediatric Neurology Unit (M. Nosadini), Department of Paediatrics, University of Padua, Italy; Clinical Neuroimmunology Program (G.A.), Division of Child Neurology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, PA; Neurology Department (C.J.R.), Lady Cilento Children's Hospital, University of Queensland, Australia; Pediatric Multiple Sclerosis and Related Diseases Program (L.A.B., M.P.G.), Boston Children's Hospital, Boston, MA; Department of Neurology (S.R.), Westmead Hospital, Sydney, Australia; Neurology Department (M. Nolan), Starship Children's Health, Auckland, New Zealand; The Roald Dahl EEG Unit (R.A.), Pediatric Neurosciences Foundation, Alder Hey Children's Hospital, Liverpool, UK; Department of Neurology (R.J.L.), Murdoch Childrens Research Institute and University of Melbourne Department of Paediatrics (R.J.L.), Royal Children's Hospital, Melbourne, Victoria, Australia; Assistance Publique-Hopitaux de Paris (K.D.), Hôpitaux Universitaires Paris-Sud, National Referral Center for Neuro-Inflammatory Diseases in Children (K.D.), Pediatric Neurology Department, and Université Paris-Sud (K.D.), Inserm U1012, Le Kremlin-Bicêtre, France; and Children's Hospital of Philadelphia (A.T.W., B.B.), University of Pennsylvania, Philadelphia.
出版信息
Neurol Neuroimmunol Neuroinflamm. 2016 Jan 21;3(1):e188. doi: 10.1212/NXI.0000000000000188. eCollection 2016 Feb.
OBJECTIVE
To study rituximab in pediatric neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD) and the relationship between rituximab, B cell repopulation, and relapses in order to improve rituximab monitoring and redosing.
METHODS
Multicenter retrospective study of 16 children with NMO/NMOSD receiving ≥2 rituximab courses. According to CD19 counts, events during rituximab were categorized as "repopulation," "depletion," or "depletion failure" relapses (repopulation threshold CD19 ≥10 × 10(6) cells/L).
RESULTS
The 16 patients (14 girls; mean age 9.6 years, range 1.8-15.3) had a mean of 6.1 events (range 1-11) during a mean follow-up of 6.1 years (range 1.6-13.6) and received a total of 76 rituximab courses (mean 4.7, range 2-9) in 42.6-year cohort treatment. Before rituximab, 62.5% had received azathioprine, mycophenolate mofetil, or cyclophosphamide. Mean time from rituximab to last documented B cell depletion and first repopulation was 4.5 and 6.8 months, respectively, with large interpatient variability. Earliest repopulations occurred with the lowest doses. Significant reduction between pre- and post-rituximab annualized relapse rate (ARR) was observed (p = 0.003). During rituximab, 6 patients were relapse-free, although 21 relapses occurred in 10 patients, including 13 "repopulation," 3 "depletion," and 4 "depletion failure" relapses. Of the 13 "repopulation" relapses, 4 had CD19 10-50 × 10(6) cells/L, 10 had inadequate monitoring (≤1 CD19 in the 4 months before relapses), and 5 had delayed redosing after repopulation detection.
CONCLUSION
Rituximab is effective in relapse prevention, but B cell repopulation creates a risk of relapse. Redosing before B cell repopulation could reduce the relapse risk further.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that rituximab significantly reduces ARR in pediatric NMO/NMOSD. This study also demonstrates a relationship between B cell repopulation and relapses.
目的
研究利妥昔单抗在儿科视神经脊髓炎（NMO）/NMO 谱系障碍（NMOSD）中的作用，以及利妥昔单抗、B 细胞再增殖与复发之间的关系，以期改进利妥昔单抗的监测和再给药方案。
方法
对 16 例接受了≥2 个利妥昔单抗疗程的 NMO/NMOSD 患儿进行多中心回顾性研究。根据 CD19 计数，将利妥昔单抗治疗期间的事件分为“再增殖”、“耗竭”或“耗竭失败”复发（再增殖阈值 CD19≥10×10(6)个细胞/L）。
结果
16 例患儿（14 例女性；平均年龄 9.6 岁，范围 1.8-15.3 岁）平均随访 6.1 年（范围 1.6-13.6 年），平均发生 6.1 次事件（范围 1-11 次），共接受了 76 个利妥昔单抗疗程（平均 4.7 个，范围 2-9 个）。在利妥昔单抗治疗前，62.5%的患儿曾接受过硫唑嘌呤、霉酚酸酯或环磷酰胺治疗。从利妥昔单抗到最后一次有记录的 B 细胞耗竭和首次再增殖的中位时间分别为 4.5 个月和 6.8 个月，个体间差异较大。最早的再增殖发生在最低剂量时。与利妥昔单抗治疗前相比，患儿的年化复发率（ARR）显著降低（p=0.003）。在利妥昔单抗治疗期间，有 6 例患儿无复发，但 10 例患儿中有 21 例复发，包括 13 例“再增殖”、3 例“耗竭”和 4 例“耗竭失败”复发。在 13 例“再增殖”复发中，4 例 CD19 为 10-50×10(6)个细胞/L，10 例患儿监测不足（复发前 4 个月内≤1 次 CD19 检测），5 例在检测到再增殖后延迟了再次给药。
结论
利妥昔单抗可有效预防复发，但 B 细胞再增殖会增加复发风险。在 B 细胞再增殖前再次给药可能会进一步降低复发风险。
证据分类
本研究提供了 IV 级证据，表明利妥昔单抗可显著降低儿科 NMO/NMOSD 的 ARR。本研究还证实了 B 细胞再增殖与复发之间存在关联。
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