Centre for Immunology and Infection, Department of Biology, Hull and York Medical School, University of York, York, United Kingdom.
PLoS Negl Trop Dis. 2012;6(6):e1675. doi: 10.1371/journal.pntd.0001675. Epub 2012 Jun 12.
Patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) become progressively impaired, with chronic pain, immobility and bladder, bowel and sexual dysfunction. Tested antiretroviral therapies have not been effective and most patients are offered a short course of corticosteroids or interferon-α, physiotherapy and symptomatic management. Pathogenesis studies implicate activated T-lymphocytes and cytokines in tissue damage. We therefore tested the hypothesis that inhibition of T-cell activation with ciclosporin A would be safe and clinically beneficial in patients with early and/or clinically progressing HAM/TSP.
Open label, proof of concept, pilot study of 48 weeks therapy with the calcineurin antagonist, ciclosporin A (CsA), in seven patients with 'early' (<two years) or 'progressive' (>50% deterioration in timed walk during the preceding three months) HAM/TSP. Primary outcomes were incidence of clinical failure at 48 weeks and time to clinical failure.
All patients completed 72 weeks study participation and five showed objective evidence of clinical improvement after 3 months treatment with CsA. Two patients exhibited clinical failure over 6.4 person-years of follow-up to week 48. One patient had a >2 point deterioration in IPEC (Insituto de Pesquisa Clinica Evandro Chagas) disability score at weeks 8 and 12, and then stopped treatment. The other stopped treatment at week 4 because of headache and tremor and deterioration in timed walk, which occurred at week 45. Overall pain, mobility, spasticity and bladder function improved by 48 weeks. Two patients recommenced CsA during follow-up due to relapse.
These data provide initial evidence that treatment with CsA is safe and may partially reverse the clinical deterioration seen in patients with early/progressive HAM/TSP. This trial supports further investigation of this agent's safety and effectiveness in larger, randomised controlled studies in carefully selected patients with disease progression.
人类嗜 T 淋巴细胞病毒 1 相关性脊髓病/热带痉挛性截瘫（HAM/TSP）患者逐渐出现进行性功能障碍，伴有慢性疼痛、活动障碍、膀胱、肠道和性功能障碍。已测试的抗逆转录病毒疗法均无效，大多数患者接受短期皮质类固醇或干扰素-α、物理治疗和对症治疗。发病机制研究提示活化的 T 淋巴细胞和细胞因子参与组织损伤。因此，我们假设使用环孢素 A 抑制 T 细胞活化可能对早期和/或临床进展性 HAM/TSP 患者安全且具有临床益处。
在 7 例“早期”（<2 年）或“进展性”（在过去 3 个月内定时行走恶化>50%）HAM/TSP 患者中进行为期 48 周的环孢素 A（CsA）治疗的开放性、概念验证性、试验性研究。主要终点为 48 周时临床失败的发生率和临床失败的时间。
所有患者均完成了 72 周的研究参与，5 例患者在接受 CsA 治疗 3 个月后出现了客观的临床改善证据。2 例患者在随访至第 48 周时出现了 6.4 年以上的临床失败。1 例患者在第 8 周和第 12 周时 IPEC（巴西埃维拉尔多·查加斯研究所）残疾评分恶化>2 分，随后停止治疗。另一位患者因头痛和震颤以及定时行走恶化（发生在第 45 周）在第 4 周停止治疗。总体而言，疼痛、活动能力、痉挛和膀胱功能在第 48 周时得到改善。2 例患者因复发在随访期间重新开始使用 CsA。
这些数据初步证明，CsA 治疗是安全的，可能部分逆转早期/进展性 HAM/TSP 患者的临床恶化。这项试验支持在精心选择的疾病进展患者中进行更大规模、随机对照研究，进一步评估该药物的安全性和有效性。
