Current and emerging disease-modulatory therapies and treatment targets for multiple sclerosis

The treatment of multiple sclerosis (MS), the most common chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS), continues to transform. In recent years, a number of novel and increasingly effective disease-modulatory therapies (DMTs) have been approved, including oral fumarates and selective sphingosine 1-phosphate modulators, as well as cell-depleting therapies such as cladribine, anti-CD20 and anti-CD52 monoclonals. Amongst DMTs in clinical development, inhibitors of Bruton's tyrosine kinase represent an entirely new emerging drug class in MS, with three different drugs entering phase III trials. However, important remaining fields of improvement comprise tracking of long-term benefit-risk with existing DMTs and exploration of novel treatment targets relating to brain inherent disease processes underlying the progressive neurodegenerative aspect of MS, which accumulating evidence suggests start already early in the disease process. The aim here is to review current therapeutic options in relation to an improved understanding of the immunopathogenesis of MS, also highlighting examples where controlled trials have not generated the desired results. An additional aim is to review emerging therapies undergoing clinical development, including agents that interfere with disease processes believed to be important for neurodegeneration or aiming to enhance reparative responses. Notably, early trials now have shown initial evidence of enhanced remyelination both with small molecule compounds and biologicals. Finally, accumulating evidence from clinical trials and post-marketing real-world patient populations, which underscore the importance of early high effective therapy whilst maintaining acceptable tolerability, is discussed.     

Late-onset multiple sclerosis

OBJECTIVE: The onset of multiple sclerosis (MS) after age 50 is infrequent and presents a diagnostic challenge. The purpose of the present study was to review the prevalence, presentation, and clinical characteristics of late-onset MS. DESIGN: A retrospective chart review. SETTING: The Multiple Sclerosis Center at Sheba Medical Center, Israel. PARTICIPANTS: 640 patients with a definite diagnosis of MS. MEASUREMENTS: Diagnosis of MS was established according to Poser criteria and confirmed by brain magnetic resonance imaging (MRI) using our unit's computerized database. Late-onset MS was defined as the first presentation of clinical symptoms after the age of 50 years. For each patient, age, gender, clinical presentation, disease course, neurological involvement, disease duration, neurological disability assessed, and Progression Index (PI) were analyzed. All patients were interviewed using the structured clinical interview for DSM-IV, SCID-lifetime Hebrew version. RESULTS: Of 640 MS patients, 30 (4.6%) were diagnosed as suffering from late-onset MS. Mean age at onset was 53.5 +/- 3.1, range 50 to 62 years. Female to male ratio was 1.73:1. Mean disease duration was 7.6 years, range 2 to 11 years. In 50% of patients the disease course was relapsing-remitting. Motor symptoms were the most common neurological presentation at onset (63.3%). Major depressive episode was diagnosed in 6 out of 30 patients (20%) in the two years prior to the diagnosis of MS. After a mean disease duration of 7.6 years there was a marked increase in sphincteric and cerebellar involvement. In addition 7 out of 30 patients had suffered a major depressive episode within 4 years of diagnosis. Mean PI was 0.81, suggesting rapid neurological deterioration. CONCLUSIONS: Late-onset MS is not rare and may present as major depression and, although neurological presentation at onset is similar to that of young adults, progression to disability is more rapid and a primary progressive course is more prevalent.     

Established and novel disease‐modifying treatments in multiple sclerosis

Multiple sclerosis (MS) is a presumed autoimmune disorder of the central nervous system, resulting in inflammatory demyelination and axonal and neuronal injury. New diagnostic criteria that incorporate magnetic resonance imaging have resulted in earlier and more accurate diagnosis of MS. Several immunomodulatory and immunosuppressive therapeutic agents are available for relapsing forms of MS, which allow individualized treatment based upon the benefits and risks. Disease‐modifying therapies introduced in the 1990s, the beta‐interferons and glatiramer acetate, have an established track record of efficacy and safety, although they require administration via injection. More recently, monoclonal antibodies have been engineered to act through specific mechanisms such as blocking alpha‐4 integrin interactions (natalizumab) or lysing cells bearing specific markers, for example CD52 (alemtuzumab) or CD20 (ocrelizumab and ofatumumab). These agents can be highly efficacious, but sometimes have serious potential complications (natalizumab is associated with progressive multifocal leukoencephalopathy; alemtuzumab is associated with the development of new autoimmune disorders). Three new oral therapies (fingolimod, teriflunomide and dimethyl fumarate, approved for MS treatment from 2010 onwards) provide efficacy, tolerability and convenience; however, as yet, there are no long‐term postmarketing efficacy and safety data in a general MS population. Because of this lack of long‐term data, in some cases, therapy is currently initiated with the older, safer injectable medications, but patients are monitored closely with the plan to switch therapies if there is any indication of a suboptimal response or intolerance or lack of adherence to the initial therapy. For patients with MS who present with highly inflammatory and potentially aggressive disease, the benefit‐to‐risk ratio may support initiating therapy using a drug with greater potential efficacy despite greater risks (e.g. fingolimod or natalizumab if JC virus antibody‐negative). The aim of this review is to discuss the clinical benefits, mechanisms of action, safety profiles and monitoring strategies of current MS disease‐modifying therapies in clinical practice and of those expected to enter the market in the near future.     

传统型和视神经脊髓型多发性硬化临床特征的比较

目的:分析和比较视神经脊髓型多发性硬化(OS-MS)与传统型多发性硬化(C-MS)患者的临床特征。方法:在苏州地区收集99例按照McDonald诊断标准(2001)确诊为MS患者(其中C-MS73例,OS-MS26例)的临床资料,并结合实验室及相关检查的结果进行分析比较。结果:与C-MS相比,OS-MS患者中女性更多见,首发症状以视力减退和运动障碍最常见,整个病程中运动障碍、感觉障碍及视力减退的发生率较高,预后较差。2组患者在首次发病年龄、病程等方面未见显著差异。结论:C-MS与OS-MS患者在临床特征方面存在一定的差异。     

Melatonin treatment improves primary progressive multiple sclerosis: a case report

We describe the case of a female patient who, at the age of 28, was diagnosed with symptoms of primary progressive multiple sclerosis (PPMS). Glucocorticoid treatment was immediately initiated. The disease and the demyelinating lesions progressed during the following 9 years reaching Expanded Disability Status Scale (EDSS) 8.0 (patient essentially restricted to bed, a chair or perambulated in a wheelchair). At this point, the patient began taking melatonin at doses ranging from 50 to 300 mg per day. Melatonin was her only treatment for the next 4 years; during this interval, her EDSS progressively recovered to 6.0 (the person needs intermittent or unilateral constant assistance such as cane, crutch, or brace to walk 100 meters with or without resting). This long‐lasting improvement is likely due to melatonin usage since it is related in time and because of its exceptionally long duration.     

Serum sex hormone and gonadotropin concentrations in premenopausal women with multiple sclerosis

Dysfunctions within the hypothalamic-pituitary-gonadal axis occur frequently among women with multiple sclerosis (MS) and may induce menstrual disturbances and subsequent infertility. We have measured serum concentrations of prolactin. gonadotropins and sex hormone binding globulin (SHBG) as well as free and bound oestrogen and androgen levels in 14 women of fertile age with MS. These women all displayed regular cycles without having experienced fertility problems. As controls 14 normal women with regular periods and ideal body weight of 91% (range 80-101) were included. Serum from both groups was sampled during the early follicular phase. The MS-patients had significantly (P less than 0.05) higher concentrations of prolactin, LH, FSH, total and free testosterone (P less than 0.01) and a significantly lower serum concentration of oestrone sulphate (P less than 0.01). The abnormal hormone concentrations were not related to clinical status of the disease. We propose that the increased androgen levels are of ovarian origin as adrenal androgens were normal. The reason for the slight increase of prolactin and the marked increase of gonadotropins in women with MS is speculative. As oestradiol levels, however, were within normal range, we assume that a peripheral resistance to gonadotropins combined with an abnormal central regulation causes the increased pituitary secretion.     

Prevalence survey of multiple sclerosis in the Australian Capital Territory

Abstract
Aim : This study sought to obtain an estimate of the prevalence of multiple sclerosis (MS) in the Australian Capital Territory (ACT), a largely urban region that differs climatically and socioeconomically from other Australian cities examined in previous MS surveys.
Methods : Prevalence day was chosen to coincide with the 1996 National Census. All ACT neurologists' records for the previous 5 years were examined and cases of MS were classified according to the published diagnostic criteria of Rose et al. and Poser et al.
Results : By the criteria of Rose et al. , as used in previous Australian surveys of MS, prevalence was 79.9/100 000 (95% confidence interval (CI) = 63.4–99.2) for females, 32.8 (22.7–46.2) for males and 56.7 (43.1–74.1) for all people, standardized to the 1996 population. Standardized to the 1981 population for direct comparison with 1981 surveys in New South Wales, the prevalence of MS in the ACT was still unexpectedly high, particularly for females. Using the criteria of Poser et al. , the prevalence of MS standardized to the 1996 population was 70.6/ 100 000 (95% CI = 58.4–85.3) for females, 28.0 (20.3–37.8) for males and 49.5 (42.2–58.2) for all people. There was evidence from a relatively short duration of disease in the ACT sample that some persons with long-standing MS had been missed in the survey and therefore that the prevalence of MS observed in the ACT was an underestimate.
Conclusions : The survey found an unexpectedly high prevalence of MS in the ACT. Possible reasons for this are discussed. There was no evidence that the advent of magnetic resonance imaging had increased the numbers of persons diagnosed with MS in the present survey. (Intern Med J 2001; 31: 161–167)     

Immunoglobulin G in multiple sclerosis brain

We extracted free and bound IgG from plaques and normal-appearing white matter of multiple sclerosis (MS) brains. By isoelectric focusing (IEF), three patterns of IgG distribution were seen: (A) a restricted high-pI distribution with a specific band at low pH, (B) a restricted high-pI pattern, and (C) a broad pI pattern similar to that of the unbound IgG extracted at neutral pH. In one MS brain, we compared the IEF pattern of plaque material with that of normal-appearing white matter (NAWM); the low-pH extract of plaque material (PM) had a restricted pattern at high pI. In another MS brain, a specific band of bound IgG was found. These data suggest that MS lesions expose an antigen(s) unique to MS. B cells consequently might be stimulated by a disease-related antigen(s) in the MS lesion.     

Intestinal pseudo-obstruction complicating multiple sclerosis

Three patients with intestinal pseudo-obstruction secondary to multiple sclerosis are reported. This is a serious complication with significant morbidity and mortality, which is infrequently recognized in clinical practice and rarely reported in the medical literature.     

Use of low-dose mitozantrone to treat aggressive multiple sclerosis: a single-centre open-label study using patient self-assessment and clinical measures of multiple sclerosis status

BACKGROUND: There is significant evidence supporting the use of mitozantrone in the treatment of multiple sclerosis (MS) but few data on the subtypes of MS that respond or which measures of disease status are most useful. AIMS: To assess the efficacy of low-dose (5 mg/m2 3 monthly) mitozantrone using patient self-assessment questionnaire (SAQ), expanded disability status score (EDSS), multiple sclerosis functional composite score (MSFC), and the fatigue severity scale (FSS). Then, to compare the responses of a subgroup of relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) patients to treatment, and to assess which measures of MS disease status are the most useful in a study of this type. METHOD: Thirty-one patients with definite (McDonald criteria) active MS were commenced on mitozantrone 5 mg/m2 every 3 months. EDSS, MSFC and FSS data collected before treatment and after 12 months were analysed. The SAQ was administered after at least 12 months of therapy. RESULTS: RRMS patients showed significantly more response to mitozantrone than SPMS patients in terms of MSFC (P = 0.02) and SAQ (P = 0.01). CONCLUSIONS: Low-dose mitozantrone was well tolerated and useful in active RRMS in the short term; however, mitozantrone did not display any useful activity in SPMS patients over this time interval or at the mitozantrone dose used. Patient perception of treatment is a worthwhile outcome measure and the MSFC is the most useful objective measure of MS status change in this type of study.     

Obesity and brain inflammation: a focus on multiple sclerosis

The increase in prevalence of obesity in industrialized societies is an indisputable fact. However, the apparent passive role played by adipocytes, in pathophysiological terms, has been gradually substituted by a metabolically active performance, relevant to many biochemical mechanisms that may contribute to a chronic low‐grade inflammatory status, which increasingly imposes itself as a key feature of obesity. This chronic inflammatory status will have to be integrated into the complex equation of many diseases in which inflammation plays a crucial role. Multiple sclerosis (MS) is a chronic inflammatory condition typically confined to the central nervous system, and many work has been produced to find possible points of contact between the biology of this immune‐mediated disease and obesity. So far, clinical data are not conclusive, but many biochemical features have been recently disclosed. Brain inflammation has been implicated in some of the mechanisms that lead to obesity, which has also been recognized as an important player in inducing some degree of immune dysfunction. In this review, we collected evidence that allows establishing bridges between obesity and MS. After considering epidemiological controversies, we will focus on possible shared mechanisms, as well as on the potential contributions that disease‐modifying drugs may have on this apparent relationship of mutual interference.     

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多发性硬化(MS)的诊断标准是根据病灶在空间上的弥散(DIS)和时间上的弥散(DIT)并除外其他原因。核磁共振检查(MRI)DIS的标准:≥1个无症状T2病灶,而且是在以前MS MRI标准认为具备特征性的4个部位(紧贴皮质,脑室周围,幕下和脊髓)中至少≥2个部位出现;MRI 2个DIT标准:(1)不论何时做的扫描能见到至少1个或多个无症状-钆增强和不增强病灶;(2)与以前的扫描相比出现新T2和(或)钆-增强病灶,不管扫描的时间。     

Association between ulcerative colitis and multiple sclerosis

An association between inflammatory bowel disease (IBD) and multiple sclerosis (MS) has been described. The current study was undertaken to explore this association further. Personal records of patients with IBD and MS were reviewed. In addition, a search of medical records at a large tertiary teaching hospital in Sydney was carried out for the years 1996–2006. Four patients (three women and one man) with both ulcerative colitis and MS were identified. MS did not occur in any of our patients with Crohn's disease. The association between ulcerative colitis and MS appears to be real and may help identify common factors involved in the cause of these two diseases. No association was found in this study between MS and Crohn's disease, sparking consideration why such difference should occur. With the increasing use of biological therapies in IBD and their reported propensity to cause demyelination, recognition of an association is all the more important.     

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依据新的证据,一致同意对McDonald多发性硬化诊断标准进行修改。简化中枢神经系统病灶空间和时间弥散影像的规定,可在某些情况下一次扫描确定空间和时间弥散。修改简化了标准并保持诊断的敏感性和特异性,适用于所有人群,可早期诊断并加强一致性,使之广泛应用。     

Cladribine followed by autologous stem-cell transplantation in progressive multiple sclerosis

Abstract
We studied the safety of autologous peripheral blood stem-cell transplantation (PBSCT) in four patients with progressive multiple sclerosis. Clinical and magnetic resonance imaging outcomes were secondary end-points. Cladribine administration preceded filgrastim-primed PBSC collection, aiming for lymphocyte depletion. Conditioning was with antithymocyte globulin and cyclophosphamide. The procedure was well tolerated, but without obvious clinical benefit. The study was ­terminated when other therapeutic options with lower morbidity became available. (Intern Med J 2004; 34: 66−69)     

Maternal obesity and offspring health: Adapting metabolic changes through autophagy and mitophagy

Maternal obesity leads to obstetric complications and a high prevalence of metabolic anomalies in the offspring. Among various contributing factors for maternal obesity-evoked health sequelae, developmental programming is considered as one of the leading culprit factors for maternal obesity-associated chronic comorbidities. Although a unified theory is still lacking to systematically address multiple unfavorable postnatal health sequelae, a cadre of etiological machineries have been put forward, including lipotoxicity, inflammation, oxidative stress, autophagy/mitophagy defect, and cell death. Hereinto, autophagy and mitophagy play an essential housekeeping role in the clearance of long-lived, damaged, and unnecessary cell components to maintain and restore cellular homeostasis. Defective autophagy/mitophagy has been reported in maternal obesity and negatively impacts fetal development and postnatal health. This review will provide an update on metabolic disorders in fetal development and postnatal health issues evoked by maternal obesity and/or intrauterine overnutrition and discuss the possible contribution of autophagy/mitophagy in metabolic diseases. Moreover, relevant mechanisms and potential therapeutic strategies will be discussed in an effort to target autophagy/mitophagy and metabolic disturbances in maternal obesity.     

Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes

Demyelination is a key pathogenic feature of multiple sclerosis (MS). Here, we evaluated the astrocyte contribution to myelin loss and focused on the neurotrophin receptor TrkB, whose up-regulation on the astrocyte finely demarcated chronic demyelinated areas in MS and was paralleled by neurotrophin loss. Mice lacking astrocyte TrkB were resistant to demyelination induced by autoimmune or toxic insults, demonstrating that TrkB signaling in astrocytes fostered oligodendrocyte damage. In vitro and ex vivo approaches highlighted that astrocyte TrkB supported scar formation and glia proliferation even in the absence of neurotrophin binding, indicating TrkB transactivation in response to inflammatory or toxic mediators. Notably, our neuropathological studies demonstrated copper dysregulation in MS and model lesions and TrkB-dependent expression of copper transporter (CTR1) on glia cells during neuroinflammation. In vitro experiments evidenced that TrkB was critical for the generation of glial intracellular calcium flux and CTR1 up-regulation induced by stimuli distinct from neurotrophins. These events led to copper uptake and release by the astrocyte, and in turn resulted in oligodendrocyte loss. Collectively, these data demonstrate a pathogenic demyelination mechanism via the astrocyte release of copper and open up the possibility of restoring copper homeostasis in the white matter as a therapeutic target in MS.

Astrocytes are the largest population of glial cells in the central nervous system (CNS) and are essential for brain homeostasis as they provide metabolites and growth factors to neurons, support synapse formation and plasticity, contribute to the blood brain barrier (BBB) structure and function, and support myelination (1, 2). Following CNS injury they undergo molecular and functional changes, which foster acquisition of an inflammatory phenotype, migration toward damaged areas, and proliferation and organization into the scar (1). These events are fundamental for tissue repair but bear the potential of hindering damage resolution if dysregulated under pathologic conditions (3). Multiple sclerosis (MS) is a chronic inflammatory disorder of the CNS characterized by demyelination, inflammation, and neuroaxonal damage (4). While active MS plaques are rich in infiltrating immune cells, activated microglia and macrophages throughout the partially demyelinated astrogliotic lesion, chronic inactive MS plaques lack T cell infiltration and are fully demyelinated sites with sharply demarcated borders, very low myeloid cell numbers, severe axonal injury, and dense astrocytic scars (5, 6). In vivo studies with transgenic animals have highlighted detrimental vs. protective signaling perturbations in astrocytes during CNS neuroinflammation (3), but the precise causal mechanisms linking the target to distinct neuropathological outcomes (e.g., immune cell infiltration, neurodegeneration, or demyelination) remain mostly ill-defined. For example, the neurotrophin receptor TrkB is up-regulated on astrocytes in chronic inactive MS lesions, where it promotes neurodegeneration via glial production of nitric oxide (NO) (7); however no information is available about the impact of TrkB signaling in astrocytes during demyelination. Further, astrocytes are concomitantly exposed to diverse stimuli within the scar (3, 8) and can activate an intricate network of intracellular events, with a net result remaining difficult to predict until relevant molecular and functional checkpoints are identified.Here, we describe a demyelination mechanism resulting from astrocyte-dependent copper redistribution in the white matter of MS patients and experimental models of MS. The relevant molecular checkpoint in astrocytes is TrkB, which can operate downstream of inflammatory or toxic insults, even in the absence of neurotrophin binding, and trigger astrocytosis and copper uptake and release following injury.