Ciclosporin A Proof of Concept Study in Patients with Active, Progressive HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis

IntroductionPatients 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. Materials and MethodsOpen label, proof of concept, pilot study of 48 weeks therapy with the calcineurin antagonist, ciclosporin A (CsA), in seven patients with ‘early’ (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. ResultsAll 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. ConclusionsThese 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.

引言
HTLV-1相关脊髓病/热带痉挛性截瘫（HTLV-1-associated myelopathy/tropical spastic paraparesis, HAM/TSP）患者会出现进行性神经功能损害，伴随慢性疼痛、肢体活动不能以及膀胱、肠道与性功能障碍。现有经测试的抗逆转录病毒疗法均未取得理想疗效，多数患者仅能接受短疗程糖皮质激素或α干扰素治疗、物理干预及对症管理。发病机制研究显示，活化T淋巴细胞与细胞因子参与了组织损伤过程。因此本研究验证了如下假说：采用环孢素A抑制T细胞活化，对于早期和/或临床进展的HAM/TSP患者安全且具有临床获益。

材料与方法
本研究为开放标签、概念验证性初步研究，纳入7例符合“早期”标准（前3个月内计时步行能力下降50%）的HAM/TSP患者，给予时长48周的钙调神经磷酸酶抑制剂环孢素A（ciclosporin A, CsA）治疗。主要结局指标为48周时的临床失败发生率及临床失败时间。

结果
所有患者均完成了72周的研究随访，其中5例在接受CsA治疗3个月后出现临床改善的客观证据。在截至第48周的6.4人-年随访期间，共有2例患者出现临床失败：1例患者在第8周和第12周时的IPEC（Evandro Chagas临床研究所，Insituto de Pesquisa Clinica Evandro Chagas）残疾评分恶化超过2分，随后停止治疗；另1例患者于第4周因头痛、震颤以及于第45周出现的计时步行能力下降停止治疗。至第48周随访结束时，患者的总体疼痛程度、活动能力、痉挛状态及膀胱功能均得到改善。另有2例患者因病情复发，在随访期间重新接受CsA治疗。

结论
本研究数据初步证实，CsA治疗安全且可部分逆转早期/进展性HAM/TSP患者的临床恶化进程。本试验支持开展更大规模的随机对照研究，对经过严格筛选的疾病进展患者进行该药物的安全性与有效性验证。