ATORVASTATIN THERAPY IN EARLY MULTIPLE SCLEROSIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 多发性硬化症(MS)是人类最常见的中枢神经系统慢性炎症性脱髓鞘疾病。发病年龄通常在20岁至40岁之间，因此多发性硬化症成为年轻人非创伤性神经功能障碍的主要原因。在美国，大约有30万人(0.1%)被诊断出患有多发性硬化。 多发性硬化症的炎性脱髓鞘病变可以发生在整个中枢神经系统，这是个体患者可能出现的各种神经体征和症状的原因。通常，患有临床孤立综合征(CIS)的MS患者只有一组神经学表现提示MS，CIS患者中MRI病变的存在对MS的未来诊断具有很高的预测性。 超过85%的MS患者最初经历了复发-缓解(RR)过程，伴随着神经系统症状的临床恶化，随后可能会或可能不会完全恢复。虽然10%至20%的多发性硬化症患者的形态为“良性”，但50%的患者在经过10至15年的多发性硬化症演变后，行动能力明显受限，需要协助。 他汀类药物已成功用于治疗因血脂异常引起的心血管疾病。据信，他汀类药物发挥其有益作用，至少部分是通过抗炎过程。多发性硬化症通常被认为是一种由抗髓鞘自身反应性抗体引起的中枢神经系统炎症性疾病。在实验性自身免疫性脑炎(EAE)的小鼠模型中，阿托伐他汀显示出可能有益于MS治疗的免疫调节活性。此外，他汀类药物中的另一种药物辛伐他汀在人类MS复发缓解型(RRMS)的开放标签研究中显示出良好的效果。最近的一项研究表明，复发缓解型多发性硬化症患者接受辛伐他汀治疗后，与治疗前相比，在治疗4、5和6个月时，MRI上Gd增强病变的平均数量减少。 所有已批准的治疗多发性硬化症的方法都具有深刻的免疫学效应，并采用免疫调节策略。由于高毒性和非肠道使用，这些药物被保留用于已确定的疾病。Avonex(干扰素-1a)最近已被批准用于出现CIS和磁共振成像(MRI)结果提示干扰素-1a女士的患者，需要每周肌肉注射，具有高毒性。由于中枢神经系统脱髓鞘过程的不可逆性和MS的高发病率，开发既易于给药又毒性最小的早期干预措施是非常有意义的。这项研究还将检查对CIS患者的早期干预是否会导致免疫耐受状态，以及阿托伐他汀在停药后是否有任何残留效应。这可能使患者在接受治疗一段时间后退出治疗。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system (CNS) in humans. Onset typically occurs between ages 20 and 40, thus making MS the leading cause of atraumatic neurological disability in young adults. Approximately 300,000 (0.1%) individuals in the United States have been diagnosed with MS. Inflammatory demyelinating lesions in MS can occur throughout the CNS, accounting for the variety of neurological signs and symptoms that may develop in individual patients. Frequently, MS patients present with a clinically isolated syndrome (CIS) with only one set of neurological presentation suggestive of MS. The presence of MRI lesions in patients with CIS has been highly predictive of a future diagnosis of MS. More than 85% of patients with MS initially experience a relapsing-remitting (RR) course with clinical exacerbations of neurological symptoms, followed by recovery that may or may not be complete. Although 10% to 20% of patients with MS have a "benign" form, 50% of the patients develop a significant limitation to ambulate and require assistance after 10 to 15 years of MS evolution. Statins have been successfully used to treat cardiovascular diseases due to abnormal lipid profile. It is believed that statins exert their beneficial effects, at least partly, through an anti-inflammatory process. Multiple sclerosis is generally viewed as an inflammatory disease of the CNS caused by autoreactive antibodies against myelin. In a murine model of experimental autoimmune encephalitis (EAE), an experimental model for MS, atorvastatin has shown immunomodulatory activity that may be beneficial in MS treatment.Furthermore, simvastatin, another agent in the statin family, has shown promising effect in an open label study of the relapsing remitting form of MS (RRMS) in humans. A more recent study showed that Simvastatin treatment in patients with relapsing remitting MS was associated with a decrease the mean number of gadolinium enhancing lesions on MRI at months 4,5 and 6 of treatment compared to pre treatment MRI scans. All approved therapies for MS have profound immunological effects and employ immunomodulatory strategies. Due to a high toxicity profile and parenteral use, these agents are reserved for established disease. Avonex (interferon ¿-1a) has been recently approved for patients presenting with CIS and magnetic resonance imaging (MRI) findings suggestive of MS. Interferon ¿-1a requires weekly intramuscular injections and has a high toxicity profile. Due to the irreversiblity of the demyelinating process in CNS and high morbidity of MS, it is of great interest to develop early interventional measures that possess both ease of administration and a minimal toxicity profile. This study will also examine whether early intervention in patients with CIS may result in a state of immunological tolerance and whether atorvastatin has any residual effect after discontinuation. This may enable the patient to be withdrawn from therapy after a certain period of receiving treatment.