From the University of Münster (H.W.), Münster, Germany; Novant Health (M.C.), Charlotte, NC; University Vita-Salute San Raffaele (G.C.), Milan, Italy; Virgen Macarena University Hospital (G.I.), Seville, Spain; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals, University of Sheffield (B.S.), Sheffield, United Kingdom; Georgetown University Medical Center (C.T.), Washington, DC; Sanofi (N.D., L.C., A.K.J.), Cambridge, MA; Eloquent Scientific Solutions (R.J.H.), Sydney, NSW, Australia; Eloquent Scientific Solutions (L.V.W.), Philadelphia, PA; and Rehabilitation & MS-Centre Overpelt (B.V.W.), BIOMED, Hasselt University, Hasselt, Belgium.
Neurol Neuroimmunol Neuroinflamm. 2019 Oct 29;7(1). doi: 10.1212/NXI.0000000000000635. Print 2020 Jan.
To examine the association between peripheral blood lymphocyte pharmacodynamics and autoimmune adverse events (AEs) or return of disease activity in alemtuzumab-treated patients with relapsing-remitting MS.
Patients received 2 alemtuzumab courses (12 mg/d IV; 5 days at baseline, 3 days 12 months later) in the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis studies (NCT00530348 and NCT00548405) and could then receive as-needed alemtuzumab or other disease-modifying therapy in a 4-year extension (NCT00930553). Lymphocytes were phenotyped quarterly over 2 years using fluorescence-activated cell sorting. Pharmacodynamic assessments included counts of total lymphocytes, CD3 T cells, CD4/CD8 T cells (total/naive/memory/regulatory [T]), and CD19 B cells (total/immature/mature/memory) and ratios of CD19 (total/immature/mature/memory) to T (CD4/CD8) counts. Assessed autoimmune AEs included immune thrombocytopenia, nephropathies, and thyroid events. Efficacy assessments included relapses, 6-month confirmed disability worsening (CDW), and MRI disease activity.
Lymphocyte repopulation patterns, including ratios between distinct lymphocyte subsets (e.g., CD19 to T cell count ratios), showed no significant differences over 2 years in patients developing/not developing autoimmune AEs, relapses, CDW, or MRI activity through 6 years following alemtuzumab. Lymphocyte kinetics were also unrelated to multiple autoimmune AEs or extreme clinical phenotypes.
Repopulation kinetics of the evaluated peripheral lymphocyte subsets did not predict autoimmune AE occurrence or disease activity, including return of disease activity after 2 alemtuzumab courses. Further study is needed to investigate potential antigen-level markers of treatment response.
研究在接受来氟米特治疗的复发缓解型多发性硬化症患者中，外周血淋巴细胞药效学与自身免疫不良事件（AE）或疾病活动度恢复之间的关系。
在为期 2 年的来氟米特与干扰素β-1a 疗效比较多发性硬化症研究（NCT00530348 和 NCT00548405）中，患者接受了 2 个来氟米特疗程（静脉注射 12mg/d；基线时连续 5 天，12 个月后连续 3 天），然后在 4 年的扩展期内按需接受来氟米特或其他疾病修正治疗（NCT00930553）。在 2 年内，每季度使用荧光激活细胞分选术对淋巴细胞进行表型分析。药效学评估包括总淋巴细胞计数、CD3 T 细胞计数、CD4/CD8 T 细胞（总/幼稚/记忆/调节性[T]）计数和 CD19 B 细胞计数（总/未成熟/成熟/记忆）以及 CD19（总/未成熟/成熟/记忆）与 T（CD4/CD8）计数的比值。评估的自身免疫性 AE 包括免疫性血小板减少症、肾病和甲状腺事件。疗效评估包括复发、6 个月确认的残疾加重（CDW）和 MRI 疾病活动度。
在接受来氟米特治疗后 2 年内，发生/未发生自身免疫性 AE、复发、CDW 或 MRI 活动的患者，其淋巴细胞再增殖模式（包括不同淋巴细胞亚群之间的比值，如 CD19 与 T 细胞计数的比值）无显著差异。淋巴细胞动力学与多种自身免疫性 AE 或极端临床表型也无关。
评估的外周淋巴细胞亚群的再增殖动力学不能预测自身免疫性 AE 的发生或疾病活动度，包括接受 2 个来氟米特疗程后疾病活动度的恢复。需要进一步研究以探讨潜在的治疗反应抗原水平标志物。
