自体外周血纯化CD34+细胞移植治疗进展型多发性硬化

目的 评价自体外周血纯化CD34+细胞移植治疗进展型多发性硬化(PMS)的安全性和疗效.方法 2002-09―2006-03期间15例PMS患者在首都医科大学宣武医院接受了自体外周血纯化CD34+细胞移植.单独使用粒细胞集落刺激因子(G-CSF)动员造血干细胞,全部回输采集物进行CD34+细胞纯化.预处理采用BEAM(卡氮芥、依托泊甙、阿糖胞苷、马法兰)方案.中位随访期为21(3～45)个月,移植前后应用扩充神经功能残疾量表(EDSS)、年平均发病次数进行疗效评价. 结果分选后中位CD34+细胞纯度为93.2 (78.6～97.7)%,中位回收率为67.0(22.4～79.8)%,相当于减少了4个对数级的T细胞.无移植相关死亡,造血重建时间与其自体外周造血干细胞移植(APBSCT)相当,未出现严重的毒性反应及并发症.患者移植后12个月EDSS评分(3.95±2.55)较移植前(5.64±0.71)降低(P＜0.05),年平均发病次数移植后(0.45±0.82)较移植前(1.31±0.71)减少(P＜0.05).移植后45个月疾病无活动者生存率为(47.01±17.87)%,EDSS评分无进展者(包括稳定和改善)生存率为(57.69±20.24)%. 结论自体外周血纯化CD34+细胞移植治疗PMS安全有效.     

Immune Mechanisms Underlying the Beneficial Effects of Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

A recent phase I/II clinical trial drew serious attention to the therapeutic potential of autologous hematopoietic stem cell transplantation (AHSCT) in multiple sclerosis. However, questions were raised as to whether these beneficial effects should be attributed to the newly reconstituted immune system per se, or to the lymphoablative conditioning regimen-induced immunosuppression, given that T-cell depleting combinational drug therapies were used in the study. We discuss here the possibility that both AHSCT and T-cell depleting therapies may re-program alternatively the immune system, and why transplantation of CD34⁺ hematopoietic stem cells may offer AHSCT a possible advantage regarding long-term remission.     

自体外周造血干细胞移植治疗进展型多发性硬化的临床观察(附一例报告)

目的观察自体外周造血干细胞移植(auto-PBSCT)治疗进展型多发性硬化(PMS)的疗效及安全性。方法PMS 1例,以重组人粒细胞集落刺激因子(G-CSF)动员造血干细胞(HSC),血细胞分离仪分离外周血干细胞50 mL,按患者体重拟回输的CD34 细胞2.85×106个/kg于-80℃液氮冻存。在马利兰/环磷酰胺方案预处理后,经锁骨下静脉回输HSC,G-CSF协助造血恢复。移植后2、4、8、12周观察患者临床、体征、实验室及影像学指标。结果移植后患者临床症状及体征基本恢复,MRI显示病灶有所缩小。结论auto-PBSCT治疗PMS较为安全、有效。     

多发性硬化的治疗进展

多发性硬化（MS）是一种常见的中枢神经系统自身免疫性炎性脱髓鞘疾病,自身抗原激活T细胞和B细胞介导的免疫机制异常在MS的致病过程中起重要作用。MS改良治疗（DMTs）可特异性作用于某个与致病机制相关的靶细胞或分子而发挥治疗作用,本文就近年口服药物和单克隆抗体治疗MS的新进展做一综述。     

Role of Immunosuppressive Therapy for the Treatment of Multiple Sclerosis

Immunosuppressives have been used in multiple sclerosis (MS) since 1966. Today, we have many treatments for the relapsing forms of the disease, including 8 US Food and Drug Administration-approved therapies, with more soon to be introduced. Given the current treatment landscape what place do immunosuppressants have in combating MS? Trial work and our experience suggest that immunosuppressives still have an important role in treating MS. Cyclophosphamide finds use in treating patients with severe, inflammatory relapsing remitting MS or those suffering from a fulminant attack. We tend to employ mycophenolate mofetil as an add-on to injectable therapy for patients experiencing breakthrough activity. Some progressive (primary progressive multiple sclerosis or secondary progressive multiple sclerosis) patients may stabilize after treatment with either cyclophosphamide or mycophenolate. We rarely employ mitoxantrone because of potential cardiac or carcinogenic effects. We prefer to use cyclophosphamide or mycophenolate mofetil in preference to methotrexate because evidence of efficacy is limited for this drug. We have less experience with azathioprine, but it may be an alternative for patients with limited options who are unable to tolerate conventional therapies.     

多发性硬化的治疗进展

传统观点认为多发性硬化（MS）是一种中枢神经系统的自身免疫性炎性脱髓鞘疾病,常采用免疫抑制和抗炎治疗。随着对MS发病机制研究的深入,许多新的治疗策略被用于MS的治疗。MS疾病修正治疗已尝试进行MS发病的特异性靶点治疗,而对进展性MS则采用神经保护和神经修复治疗。与当前的治疗措施相比,新的治疗方案对控制MS复发更有效,但也带来一定的风险。目前仍在积极寻找进展性MS的有效治疗手段。     

High-Dose Cyclophosphamide in the Treatment of Multiple Sclerosis

High dose cyclophosphamide (HDC) has been successfully used for the treatment of a variety of autoimmune diseases. In this study, we sought to determine whether the use of high dose cyclophosphamide provided stabilization of relapsing remitting MS (RRMS), secondary progressive MS (SPMS), or primary progressive MS (PPMS). The parameters evaluated were EDSS scores, lesion load and brain volumes by MRI and frequency of relapses. Twenty-three patients underwent immunoablative therapy with HDC and were followed for 3.5 years. Nine were relapsing remitting (RRMS), 11 secondary progressive (SPMS), and 3 primary progressive (PPMS). Four of 9 RRMS have had no clinical progression up to 3.5 years following treatment. Three of 9 patients maintained a normal neurologic examination with improved EDSS scores. Seven of the nine RRMS patients had reduction in flare frequency which was maintained for 3.5 years following treatment or no immunomodulating agents. Subgroup analysis in the RRMS patients of lesion load and brain parenchymal volume revealed a favorable trend in these parameters which did not reach statistical significance. The treatment was generally ineffective for SPMS and failed in the 2 PPMS patients. HDC was well tolerated, demonstrated a good safety profile and had minimal adverse effects. These results along with previous reports suggest that early use of HDC therapy in RRMS is promising.     

Advances in and Algorithms for the Treatment of Relapsing-Remitting Multiple Sclerosis

Treatment options in relapsing-remitting multiple sclerosis have increased considerably in recent years; currently, a dozen different preparations of disease-modifying therapies are available and some more are expected to be marketed soon. For the treating neurologist this broad therapeutic repertoire not only greatly improves individualized management of the disease, but also makes choices more complex and difficult. A number of factors must be considered, including disease activity and severity, safety profile, and patient preference. We here discuss the currently existing options and suggest treatment algorithms for managing relapsing-remitting multiple sclerosis.     

Autologous and allogeneic hematopoietic stem cell transplantation for Multiple Sclerosis: perspective on mechanisms of action

Multiple Sclerosis (MS) is a frequent demyelinating immune-mediated disease of the central nervous system (CNS) that affects principally young adults and leads to severe physical and cognitive impairment. The current standard treatment makes use of the immune modulators beta-interferon, glatiramer acetate and natalizumab, or immunosuppressants such as mitoxantrone. However, these agents are only partially effective and in a number of patients fail to achieve satisfactory disease control. Autologous hematopoietic stem cell transplantation (HSCT) is being explored in the treatment of severe MS as a means of delivering high-dose immunosuppression followed by 'rescue' of the immuno-hematopoietic system with autologous HSC. The potential therapeutic benefit is based on the concept of so-called 'resetting' the immune system. The use of allogeneic HSCT as a possible therapeutic approach for severe MS is inspired by case reports of MS patients that underwent allogeneic HSCT for a concomitant hematological malignancy, and subsequently is supported by data from rodent models of MS. Allogeneic HSCT may offer specific therapeutic effects, such as the replacement of the autoreactive immune compartment by healthy allogeneic cells and the development of a graft-versus-autoimmunity (GVA) effect. Here, we review the currently available experimental and clinical evidence to support the role of autologous and allogeneic HSCT in MS.     

Treatment of Marburg Variant Multiple Sclerosis with Mitoxantrone

Marburg variant multiple sclerosis (MS) is a severe, sometimes monophasic, form of MS leading to advanced disability or death within a period of weeks to months. No consistently successful treatment for Marburg variant MS has been described. The case reported here is that of a 34-year-old woman with Marburg variant MS whose magnetic resonance imaging scan showed extensive brainstem, periventricular white matter, subcortical, and cortical involvement, giving the appearance of an "MS cerebritis." The patient had no response to treatment with methylprednisolone but improved and recovered after treatment with mitoxantrone (MITX). Because MITX has potent anti-inflammatory effects and demonstrated efficacy in worsening MS, it may be an appropriate agent for the treatment of Marburg variant MS.     

Alemtuzumab for Multiple Sclerosis

Alemtuzumab is a humanised anti-CD52 monoclonal antibody approved for use in active, relapsing multiple sclerosis (MS). Administration results in a rapid depletion of circulating lymphocytes with a subsequent beneficial immune reconstitution. Early open-label experience and recent clinical trials have demonstrated a dramatic effect on relapse rates as well as a positive effect on radiological disease outcomes and disability measures. Despite a mechanism of action that results in profound lymphopaenia, opportunistic infections are rarely seen and no excess association with malignancy has been identified. However, acquired autoimmune disease (AID) is a common adverse event following treatment, necessitating rigorous monitoring in order to facilitate prompt detection and management. Despite this issue, a unique dosing schedule and durability of effect make alemtuzumab a welcome addition to currently available treatment options for MS.     

Quetiapine Fumarate for the Treatment of Multiple Sclerosis: Focus on Myelin Repair

Multiple sclerosis (MS) is a central nervous system disorder that is associated with progressive oligodendrocyte and neuronal loss, axonal degeneration, and demyelination. Several medications that mitigate immune abnormalities reduce both the frequency of relapses and inflammation on magnetic resonance imaging, leading to improved outcomes for people with the relapsing–remitting form of MS. However, there are no treatments for the progressive forms of MS where neurons and axons continue to degenerate; here, neuroprotective therapies, or medications that rebuild myelin to confer axonal well‐being, may be useful. Quetiapine fumarate is an atypical antipsychotic with reported remyelinating and neuroprotective properties in inflammatory and noninflammatory models of demyelination, including experimental autoimmune encephalomyelitis, and both cuprizone‐ and global cerebral ischemia‐induced demyelination. Preclinical studies suggest that quetiapine may exert these effects by stimulating proliferation and maturation of oligodendrocytes, releasing neurotrophic factors, increasing antioxidant defences, scavenging for free radicals, and inhibiting activated microglia, astrocytes, and T lymphocytes. Additionally, quetiapine may be beneficial for psychiatric and nonpsychiatric symptoms of MS including depression, anxiety, insomnia, and possibly even pain. These data indicate that clinical trials are justified to determine the safety, tolerability, and efficacy of quetiapine fumarate in MS.