The role of B cells in multiple sclerosis: rationale for B-cell-targeted therapies

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system with no clear etiology. Until recently, most studies have emphasized the role of T cells in the pathogenesis of multiple sclerosis. Data suggesting that B cells play a role in the pathogenesis of multiple sclerosis have been accumulating for the past five decades, demonstrating that the cerebrospinal fluid and central nervous system tissues of multiple sclerosis patients contain B cells, plasma cells, antibodies, and immunoglobulins. Data suggest that B cells are involved in antigen capture and presentation to T cells, cytokine production, antibody secretion, demyelination, tissue damage, and remyelination in multiple sclerosis. These advances in the understanding of B-cell and antibody roles in the pathophysiology of multiple sclerosis provide a strong rationale for B-cell-targeted therapies.     

Fumarates for the treatment of multiple sclerosis: potential mechanisms of action and clinical studies

All licensed disease-modifying drugs for the treatment of relapsing-remitting multiple sclerosis (MS) only display partial efficacy and hitherto require parenteral administration. Thus, there is a high demand for innovative and at the same time orally available MS therapeutics. Fumaric acids and their esters (FAE) may represent such a new class of compounds. FAE display immunomodulatory properties and may also exert neuroprotective effects, as shown in vitro as well as in experimental models of MS. A first Phase II study with the new, modified FAE BG00012/FAG-201 (BG-12) in relapsing-remitting MS revealed significant effects on MRI parameters such as gadolinium-enhancing lesions, T1 hypointense lesions and T2 lesion load after 24 weeks of treatment. The trial also underlined the safety and good tolerability of FAE that are already in clinical use for the systemic treatment of severe psoriasis. Presently, two Phase III studies are ongoing to investigate the clinical long-term efficacy of BG-12. In summary, FAE are potential candidates that may open a new therapeutic option for relapsing-remitting MS in the near future.     

The mechanism of action of methylprednisolone in the treatment of multiple sclerosis

Methylprednisolone plays an important role in the current treatment of multiple sclerosis (MS), particularly in the acute phase of relapse. It acts in various ways to decrease the inflammatory cycle including: dampening the inflammatory cytokine cascade, inhibiting the activation of T cells, decreasing the extravasation of immune cells into the central nervous system, facilitating the apoptosis of activated immune cells, and indirectly decreasing the cytotoxic effects of nitric oxide and tumor necrosis factor alpha. This paper reviews the most recent observations on these mechanisms both to understand the disease mechanism and its treatment. As more becomes known about these mechanisms, it may become possible to design treatment regimes that are more specific towards both the individual and the disease state.     

Cladribine: mode of action and implications for treatment of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system. The inflammation is driven significantly by autoreactive lymphocytes, which recruit cells of the innate immune system such as macrophages that contribute to subsequent tissue damage, ultimately resulting in demyelination and axonal damage that are characteristic in MS lesions. Cladribine (2-chlorodeoxyadenosine [2-CdA]) is a synthetic chlorinated deoxyadenosine analog that is biologically active in selected cell types and provides targeted and sustained reduction of circulating T and B lymphocytes implicated in the pathogenesis of MS. The biologic activity of cladribine depends on the preferential accumulation of cladribine phosphates in cell types with a high intracellular ratio of deoxycytidine kinase to 5'-nucleotidases. Cladribine-phosphates interfere with DNA synthesis and repair through incorporation into DNA and through inhibition of enzymes involved in DNA metabolism, including DNA polymerase and ribonucleotide reductase. This in turn leads to DNA strand breaks and ultimately cell death. This review explores the mechanism of action of cladribine further, in the context of recent clinical data, after completion of the phase III, 96-week, placebo-controlled CLARITY study. In this study, cladribine tablets demonstrated significant efficacy on clinical and neuroimaging outcomes in relapsing-remitting MS.     

Childhood-juvenile multiple sclerosis: clinical characteristics and treatment

The characteristics of multiple sclerosis with onset during childhood or adolescence are presented in this review. The clinical findings are similar to those of the adult form, but some aspects are peculiar: the high female to male ratio, occurrence of hyperacute forms, occurrence of encephalopatic symptoms and high relapse rate. The evolution is relapsing-progressive in most cases. Mild and severe disability are reached after a longer interval than in the adult form but, in spite of this, at a given age disability is higher. A high relapse rate, short interval between first and second attack and high disability after the first year are negative prognostic factors. Magnetic resonance imaging and cerebrospinal fluid data are discussed, with particular reference to differential diagnosis from acute disseminated encephalomyelitis. Currently, there are no controlled trials concerning subjects aged under 16 years. Some observations demonstrate that immunomodulatory drugs are well tolerated and have a beneficial effect, reducing the relapse rate and progression of the disease.     

Neurodegeneration and clinical relevance for early treatment in multiple sclerosis

The treatment of MS with immunomodulatory agents such as interferon beta and glatiramer acetate, early in the disease course, is increasingly recognized as benefiting patient outcome. MS is a chronic inflammatory disease of the central nervous system with morphological hallmarks of inflammation, demyelination, axonal loss and gliosis. While inflammation and demyelination induce neurological deficit, which is at least partly reversible, axonal loss beyond the threshold of compensation is always accompanied by irreversible clinical disease progression. These neuropathological findings suggest that, in addition to reducing the impact of inflammation, the ability to prevent axonal degeneration is a vital component of MS treatment. Approved immunomodulatory therapies shift immunological status from a pro-inflammatory response toward more beneficial anti-inflammatory conditions. Clinical studies also suggest that beta interferon helps to prevent, and may at least partially reverse, axonal injury. Future work in this area will be aided by using magnetic resonance imaging (MRI) to follow hypointense lesions and quantification of N-acetyl aspartate by MR spectroscopy, both of which are potential markers of structural damage. The urgent need to identify definitive markers of neuroprotection in humans remains. Such markers explain more about the underlying mechanisms of early MS pathophysiology.     

Symptomatic cranial neuralgias in multiple sclerosis: clinical features and treatment

In multiple sclerosis, neuropathic pain is a frequent condition, negatively influencing the overall quality of life. Cranial neuralgias, including trigeminal, glossopharyngeal neuralgias, as well as occipital neuralgia, are typical expression of neuropathic pain. Neuralgias are characterised by paroxysmal painful attacks of electric shock-like sensation, occurring spontaneously or evoked by innocuous stimuli in specific trigger areas. In multiple sclerosis, demyelination in the centrally myelinated part of the cranial nerve roots plays an important role in the origin of neuralgic pain. These painful syndromes arising in multiple sclerosis are therefore considered "symptomatic", in contrast to classic cranial neuralgias, in which no cause other than a neurovascular contact is identified. At this time, the evidence on the management of symptomatic cranial neuralgias in multiple sclerosis is fragmentary and a comprehensive review addressing this topic is still lacking. For that reason, treatment is often based on personal clinical experience as well as on anecdotal reports. The aim of this review is to critically summarise the latest findings regarding the pathogenesis, the diagnosis, the instrumental evaluation and the medical as well as neurosurgical treatment of symptomatic trigeminal, glossopharyngeal and occipital neuralgia in multiple sclerosis, providing useful insights for neurologists and neurosurgeons and a broad range of specialists potentially involved in the treatment of these painful syndromes.     

105例多发性硬化临床特点及治疗分析

目的 探讨多发性硬化的临床发病特点及临床治疗疗效.方法 从2005-01至2010-10月间收治的多发性硬化患者105例为研究对象.结果 105例患者中以20-40岁女性多见,以急性、亚急性起病,以肢体无力为首发症状最常见,病变部位多以脑和脊髓多见,脑脊液蛋白升高、IgG增高及寡克隆区带阳性常见,核磁共振较计算机断层扫...     

Oral treatment for multiple sclerosis

Background

The armamentarium for the treatment of relapsing-remitting multiple sclerosis (RRMS) is increasing rapidly. Several oral treatments have shown benefit and will generate much interest because of the convenience of such administration. However, availability of convenient oral drugs will not necessarily translate into clinical effectiveness and safety. Here, we provide an interim report about the mechanisms of action, and efficacy and safety results that have been reported since January, 2010, for five new oral drugs. Additionally, we draw attention to issues that neurologists and patients will encounter when considering the use of new oral drugs.

Recent developments

Positive results have been reported for five new oral drugs for RRMS—fingolimod, cladribine, teriflunomide, laquinimod, and dimethyl fumarate—in phase 3 studies; a few new oral drugs are likely to be approved for RRMS soon.

Where next?

Emerging oral treatments are ushering in a new era in the treatment of MS, providing not only new treatment options but also new challenges. Since data for some of the new drugs have not been reported in peer-reviewed journals yet and safety profiles are not yet fully developed, opinions about the use of these new oral drugs in practice are preliminary and tentative. Practice will evolve with time as information and experience accumulates. Of importance will be results from comparator trials, information about management of patients with breakthrough disease, results from long-term safety studies, and results of studies to assess the potential for neuroprotective effects of the new drugs.     

Mechanism of action of glatiramer acetate in treatment of multiple sclerosis

Glatiramer acetate (GA) (Copolymer-1, Copaxone, Teva, Israel, YEAK) is a polypeptide-based therapy approved for the treatment of relapsing-remitting multiple sclerosis. Most investigations have attributed the immunomodulatory effect of GAs to its capability to alter T-cell differentiation. Specifically, GA treatment is believed to promote development of Th2-polarized GA-reactive CD4⁺ T-cells, which may dampen neighboring inflammation within the central nervous system. Recent reports indicate that the deficiency in CD4⁺CD25⁺FoxP3⁺ regulatory T-cells in multiple sclerosis is restored by GA treatment. GA also exerts immunomodulatory activity on antigen presenting cells, which participate in innate immune responses. These new findings represent a plausible explanation for GA-mediated T-cell immune modulation and may provide useful insight for the development of new and more effective treatment options for multiple sclerosis.     

Mitoxantrone treatment in multiple sclerosis: a 5-year clinical and MRI follow-up

Mitoxantrone (MTX) is an antineoplastic agent approved for treatment of secondary progressive and rapidly worsening relapsing-remitting multiple sclerosis (MS). We designed a longitudinal open-label prospective study to evaluate the efficacy and toxicity of MTX over a 2-year treatment period with a further 3-year follow-up. Fifty consecutive MS patients were included and received MTX intravenously (8 mg/m² every 2 months for a total of 12 infusions). Efficacy was assessed clinically and by brain MRI performed before MTX therapy, at the end of treatment and at the end of each year of follow-up. Forty-nine patients completed the 5-year study, 44 (89.8%) completed the MTX course, five (10.2%) interrupted the treatment because of side effects. Fifteen (30.6%) patients showed Expanded Disability Status Scale (EDSS) progression on treatment and nine (18.4%) during follow-up. Seventeen (34.7%) patients had enhancing lesions at baseline, nine (18.4%) at the end of treatment, but none at the end of follow-up. In conclusion, we observed EDSS progression in about 1/3 of the patients during the treatment period and in 1/5 during the further 3-year follow-up period. This evidence suggests a delayed beneficial effect after MTX treatment is completed with only a minority of patients showing disability progression once the drug was suspended.     

Targeting remyelination treatment for multiple sclerosis

Since disability in multiple sclerosis (MS) is a product of neurodegeneration and deficient remyelination, the ability to enhance neuroregeneration and myelin regeneration in MS is an enticing goal for MS drug development. In particular, remyelination treatments could promote return of neurological function and also prevent further axonal loss and neurodegeneration in MS due to trophic effects of myelin. The study of remyelination has advanced dramatically in the last several years such that a number of pathways inhibiting remyelination have been discovered, including those involving LINGO-1, Notch-1, hyaluronan, retinoid X receptor, and wnt/ß-catenin. Other approaches such as high throughput drug screening for remyelination drugs have caught fire, with identification of dozens of known drugs with oligodendrocyte maturation stimulatory effects. Several drugs identified through screens and other mechanisms are in the process of being further evaluated for remyelination in MS and MS models. We discuss the potential molecular targets and the variety of mechanisms towards drug identification and development in remyelination for MS.     

Interferon-β treatment for multiple sclerosis

Multiple sclerosis (MS) is the leading nontraumatic cause of neurologic disability in young adults. Interferon-β, approved for use in 1993, was the first treatment to modify the course and prognosis of the disease and remains a mainstay of MS treatment. Numerous large-scale clinical trials in early, active patient populations have established the clinical efficacy of interferon-β in reducing relapses and delaying disability progression. Although its mechanism of action remains incompletely understood, a reduction in active lesions seen on magnetic resonance imaging implies primary anti-inflammatory properties, a mechanism supported by basic immunologic research. Variation in individual patient responsiveness to interferon-β may be due to disease variability or differential induction of interferon-stimulated genes. The magnitude of the therapeutic effect appears to be similar among products, but the optimal dose, route, and frequency of administration of the drug remain uncertain.     

A new treatment era in multiple sclerosis: clinical applications of new concepts

Several clinical courses have been defined in multiple sclerosis (MS), but uncertainty remains as to whether they reflect different neuropathological mechanisms. Two recent concepts have emerged which could influence the treatment strategy adopted in MS: inflammation drives axonal damage; disability progression in MS follows a two-stage process.     

Teriflunomide for the treatment of multiple sclerosis

Teriflunomide is a new active drug which has recently been approved as a first-line treatment of relapsing forms of MS in the US, Australia, Argentina, and the European Union. It is characterized by a once-daily oral application and a well-established long-term safety profile. The main therapeutic effect is considered to be mediated via the inhibition of the de novo synthesis of pyrimidine in proliferating immune cells. Two phase III clinical trials (TEMSO, TOWER) tested teriflunomide in patients with relapsing forms of MS: efficacy was shown, with positive effects on relapse rates and disease progression for 14 mg/day. Overall, the safety profile in these studies was favorable. In patients treated with teriflunomide, the regular monitoring of blood cell counts and liver enzymes is required. Teriflunomide must not be used during pregnancy. In this article, we review recent phase II and phase III clinical trial data, and discuss the potential of teriflunomide for the treatment of relapsing forms of MS.