Division of Clinical Neuroscience, University of Nottingham, Nottingham, England.
Department of Neurology, Nottingham University Hospitals National Health Service Trust, Nottingham, England.
JAMA Neurol. 2020 Sep 1;77(9):1089-1098. doi: 10.1001/jamaneurol.2020.1118.
Studies suggest gut worms induce immune responses that can protect against multiple sclerosis (MS). To our knowledge, there are no controlled treatment trials with helminth in MS.
To determine whether hookworm treatment has effects on magnetic resonance imaging (MRI) activity and T regulatory cells in relapsing MS.
DESIGN, SETTING, AND PARTICIPANTS: This 9-month double-blind, randomized, placebo-controlled trial was conducted between September 2012 and March 2016 in a modified intention-to-treat population (the data were analyzed June 2018) at the University of Nottingham, Queen's Medical Centre, a single tertiary referral center. Patients aged 18 to 61 years with relapsing MS without disease-modifying treatment were recruited from the MS clinic. Seventy-three patients were screened; of these, 71 were recruited (2 ineligible/declined).
Patients were randomized (1:1) to receive either 25 Necator americanus larvae transcutaneously or placebo. The MRI scans were performed monthly during months 3 to 9 and 3 months posttreatment.
The primary end point was the cumulative number of new/enlarging T2/new enhancing T1 lesions at month 9. The secondary end point was the percentage of cluster of differentiation (CD) 4+CD25highCD127negT regulatory cells in peripheral blood.
Patients (mean [SD] age, 45 [9.5] years; 50 women [71%]) were randomized to receive hookworm (35 [49.3%]) or placebo (36 [50.7%]). Sixty-six patients (93.0%) completed the trial. The median cumulative numbers of new/enlarging/enhancing lesions were not significantly different between the groups by preplanned Mann-Whitney U tests, which lose power with tied data (high number of zeroactivity MRIs in the hookworm group, 18/35 [51.4%] vs 10/36 [27.8%] in the placebo group). The percentage of CD4+CD25highCD127negT cells increased at month 9 in the hookworm group (hookworm, 32 [4.4%]; placebo, 34 [3.9%]; P = .01). No patients withdrew because of adverse effects. There were no differences in adverse events between groups except more application-site skin discomfort in the hookworm group (82% vs 28%). There were 5 relapses (14.3%) in the hookworm group vs 11 (30.6%) receiving placebo.
Treatment with hookworm was safe and well tolerated. The primary outcome did not reach significance, likely because of a low level of disease activity. Hookworm infection increased T regulatory cells, suggesting an immunobiological effect of hookworm. It appears that a living organism can precipitate immunoregulatory changes that may affect MS disease activity.
ClinicalTrials.gov Identifier: NCT01470521.
研究表明肠道蠕虫可诱导免疫反应，从而预防多发性硬化症（MS）。据我们所知，目前尚无针对 MS 患者的蠕虫治疗对照试验。
确定钩虫治疗是否对复发型 MS 的磁共振成像（MRI）活动和 T 调节细胞有影响。
设计、地点和参与者：这是一项为期 9 个月的双盲、随机、安慰剂对照试验，于 2012 年 9 月至 2016 年 3 月在诺丁汉大学（University of Nottingham）、皇后医学中心（Queen's Medical Centre）进行，该研究采用修改后的意向治疗人群（数据于 2018 年 6 月进行分析），为单中心三级转诊中心。招募年龄在 18 至 61 岁之间、未经疾病修饰治疗的复发型 MS 患者，从 MS 诊所招募。共筛选了 73 名患者，其中 71 名符合条件（2 名不符合条件/拒绝）。
患者以 1:1 的比例随机接受 25 条美洲钩虫幼虫或安慰剂经皮接种。MRI 扫描在第 3 至 9 个月和治疗后 3 个月每月进行一次。
第 9 个月时新/扩大 T2/新强化 T1 病变的累积数量。次要终点是外周血中 CD4+CD25highCD127negT 调节细胞的百分比。
患者（平均[标准差]年龄 45[9.5]岁；50 名女性[71%]）被随机分为钩虫（35[49.3%]）或安慰剂（36[50.7%]）组。66 名患者（93.0%）完成了试验。预先计划的曼-惠特尼 U 检验未显示两组间累积新/扩大/强化病变的中位数有显著差异，而这些检验在数据存在关联时会失去效力（钩虫组有大量零活动 MRI，18/35[51.4%]比安慰剂组 10/36[27.8%]）。钩虫组的 CD4+CD25highCD127negT 细胞百分比在第 9 个月时增加（钩虫组 32[4.4%]；安慰剂组 34[3.9%]；P=0.01）。没有患者因不良反应而退出。除钩虫组更多出现应用部位皮肤不适（82%比 28%）外，两组间不良反应无差异。钩虫组有 5 例（14.3%）复发，安慰剂组有 11 例（30.6%）。
钩虫治疗安全且耐受性良好。主要结局未达到显著性，可能是由于疾病活动水平较低。钩虫感染增加了 T 调节细胞，提示钩虫具有免疫生物学作用。似乎生物体可以引发免疫调节变化，从而可能影响 MS 的疾病活动。
ClinicalTrials.gov 标识符：NCT01470521。
