Disease-modifying agents in the Sonya Slifka Longitudinal Multiple Sclerosis Study

BACKGROUND: Although experts recommend that people with multiple sclerosis (MS) should begin treatment with disease-modifying agents (DMAs) as soon as possible after diagnosis and continue indefinitely, many do not use these agents or discontinue them prematurely. Since DMAs reduce relapse rates and slow disease progression, and since even benign relapses and course can lead to axonal damage and permanent neurologic impairment, it is important that all appropriate candidates have access to treatment. We used a population-based sample of people with MS to determine rates, predictors, and reasons for use, non-use, and discontinuation of DMAs. METHODS: We collected data from 2156 people with MS on their use of and experience with DMAs. We used chi-squared tests to compare current, past, and never users of any DMA and ever users of individual DMAs, and logistic regression to identify predictors of use. RESULTS: One-half of the participants were using a DMA at the time of the interview; 12.2% had used previously, but stopped. Reasons for never using and reasons for stopping were at odds with expert recommendations. Characterization of users, and of their experiences by type of DMA, was consistent with current knowledge of these agents. Seeing a neurologist for usual MS care was an important factor in starting and persisting with DMA therapy. CONCLUSIONS: Dissemination of expert opinion about, and management strategies for, use of DMAs to non-neurologic professionals and patients and their families might help more people who are appropriate candidates for DMA therapy to start and continue treatment.     

Disease-modifying agents in multiple sclerosis

Since 1993, six disease-modifying therapies for multiple sclerosis (MS) have been proven to be of benefit in rigorous phase III clinical trials. Other agents are also available and are used to treat MS, but definitive data on their efficacy is lacking. Currently, disease-modifying therapy is used for relapsing forms of MS. This includes clinically isolated syndrome/first-attack high-risk patients, relapsing patients, secondary progressive patients who are still experiencing relapses, and progressive relapsing patients. The choice of agent depends upon drug factors (including affordability, availability, convenience, efficacy, and side effects), disease factors (including clinical and neuroimaging prognostic indicators), and patient factors (including comorbidities, lifestyle, and personal preference). This review will discuss the disease-modifying agents used currently in MS, as well as available alternative agents.     

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Multiple sclerosis (MS) is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, many disease-modifying therapies that primarily target adaptive immunity have been shown to prevent exacerbations and new lesions in patients with relapsing-remitting MS. However, these therapies only have limited efficacy on the progression of disability. Increasing evidence has pointed to innate immunity, axonal damage and neuronal loss as important contributors to disease progression. Remyelination of denuded axons is considered an effective way to protect neurons from damage and to restore neuronal function. The identification of several key molecules and pathways controlling the differentiation of oligodendrocyte progenitor cells and myelination has yielded clues for the development of drug candidates that directly target remyelination and neuroprotection. The long-term efficacy of this strategy remains to be evaluated in clinical trials. Here, we provide an overview of current and emerging therapeutic concepts, with a focus on the opportunities and challenges for the remyelination approach to the treatment of MS.     

Characterizing the mechanisms of progression in multiple sclerosis: evidence and new hypotheses for future directions

Major advancements have been achieved in our ability to diagnose multiple sclerosis (MS) and to commence treatment intervention with agents that can favorably affect the disease course. Although MS exacerbations and the emergence of disability constitute the more conspicuous aspects of the disease process, evidence has confirmed that most of the disease occurs on a constitutive and occult basis. Disease-modifying therapies appear to be modest in the magnitude of their treatment effects, particularly in the progressive stage of the disease. Therapeutic strategies currently used for MS primarily target the inflammatory cascade. Several potential mechanisms appear to be involved in the progression of MS. Characterizing these mechanisms will result in a better understanding of the various forms of the disorder and how to effectively treat its clinical manifestations. It is our objective within this 2-part series on progression in MS to offer both evidence-based observations and hypothesis-driven expert perspectives on what constitutes the cause of progression in MS. We have chosen areas of inquiry that appear to have been most productive in helping us to better conceptualize the landscape of what MS looks like pathologically, immunologically, neuroscientifically, radiographically, and genetically. We have attempted to advance hypotheses focused on a deeper understanding of what contributes to the progression of this illness and to illustrate new technical capabilities that are catalyzing novel research initiatives targeted at achieving a more complete understanding of progression in MS.     

Emerging disease-modifying oral therapies for multiple sclerosis

Although therapy for multiple sclerosis (MS) has changed substantially over the past few decades, introducing immunomodulatory drugs into everyday clinical practice, it is still not satisfactory enough in halting the disease progression and increasing disability. Moreover, its injection-based administration leads to suboptimal adherence, even further reducing the potential treatment benefits. Emerging disease-modifying oral agents for MS are therefore warranted. In this paper advances in the novel oral therapeutic approaches to MS treatment are reviewed.     

Early use of high-efficacy disease‑modifying therapies makes the difference in people with multiple sclerosis: an expert opinion

Multiple sclerosis (MS) is a chronic and progressive neurological disease that is characterized by neuroinflammation, demyelination and neurodegeneration occurring from the earliest phases of the disease and that may be underestimated. MS patients accumulate disability through relapse-associated worsening or progression independent of relapse activity. Early intervention with high-efficacy disease-modifying therapies (HE-DMTs) may represent the best window of opportunity to delay irreversible central nervous system damage and MS-related disability progression by hindering underlying heterogeneous pathophysiological processes contributing to disability progression. In line with this, growing evidence suggests that early use of HE-DMTs is associated with a significant greater reduction not only of inflammatory activity (clinical relapses and new lesion formation at magnetic resonance imaging) but also of disease progression, in terms of accumulation of irreversible clinical disability and neurodegeneration compared to delayed HE-DMT use or escalation strategy. These beneficial effects seem to be associated with acceptable long-term safety risks, thus configuring this treatment approach as that with the most positive benefit/risk profile. Accordingly, it should be mandatory to treat people with MS early with HE-DMTs in case of prognostic factors suggestive of aggressive disease, and it may be advisable to offer an HE-DMT to MS patients early after diagnosis, taking into account drug safety profile, disease severity, clinical and/or radiological activity, and patient-related factors, including possible comorbidities, family planning, and patients’ preference in agreement with the EAN/ECTRIMS and AAN guidelines. Barriers for an early use of HE-DMTs include concerns for long-term safety, challenges in the management of treatment initiation and monitoring, negative MS patients’ preferences, restricted access to HE-DMTs according to guidelines and regulatory rules, and sustainability. However, these barriers do not apply to each HE-DMT and none of these appear insuperable.

     

Progression of motor symptoms in Parkinson’s disease

Parkinson’s disease(PD)is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms-rigidity,bradykinesia and tremor-due to loss of dopaminergic neurons.The motor symptoms of PD become progressively worse as the disease advances.PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others.In recent years,many studies have investigated the progression of the hallmark symptoms over time,and the cardinal motor symptoms have different rates of progression,with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor.The current treatment regime of dopamine-replacement therapy improves motor symptoms and alleviates disability.Increasing the dosage of dopaminergic medication is commonly used to combat the worsening symptoms.However,the drug-induced involuntary body movements and motor complications can significantly contribute to overall disability.Further,none of the currently-available therapies can slow or halt the disease progression.Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression.In this article,the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed.     

Multiple sclerosis disease-modifying therapies: adverse effect surveillance and management

There are five approved, partially effective, parenteral disease-modifying therapies for multiple sclerosis (MS), including three interferon-beta preparations, glatiramer acetate and the antineoplastic agent mitoxantrone. A sixth drug, natalizumab, was withdrawn from the market in 2005 but could return with increased safety measures. Careful surveillance for, and management of, the minor and serious adverse effects associated with these therapies in routine practice provides the best opportunity for maintaining compliance and achieving maximal therapeutic efficacy. This review outlines the strategies for the prevention, identification and management of the complications associated with administration and ongoing use of current MS therapies. These skills will become increasingly important to those caring for MS patients as contemporary treatment regimens become increasingly complex.     

Determinants of interferon β efficacy in patients with multiple sclerosis

Many patients with multiple sclerosis (MS) experience clinical relapses or progression of disability, or exhibit evidence of disease activity on MRI, despite the use of disease-modifying therapy. Although evidence clearly supports the efficacy of interferon β (IFN-β) in treating MS, the factors that determine the response to this drug in individual patients have not been fully elucidated. As more treatment options become available, the early identification of factors that can affect or predict the efficacy of agents in individual patients is important, because such knowledge facilitates early switching of treatment. Despite years of research and numerous reports of promising therapy markers for MS, few markers have emerged as clinically useful. Several studies suggest, however, that development of MRI lesions within 6-24 months after the initiation of IFN-β treatment predicts an unfavorable response. In addition, persistently high titers of neutralizing antibodies diminish or abrogate the therapeutic effects of IFN-β, and help to identify patients who do not respond. This Review highlights advances in research on the response to IFN-β in patients with MS and aims to provide a practical approach for incorporating clinical data, biological markers and MRI measures of disease activity into their therapeutic management.     

Recent developments in drug therapy for multiple sclerosis.

Symptomatic treatment of multiple sclerosis (MS) includes a diverse range of drugs intended to relieve the specific symptoms with which a patient may present at a particular point in the progression of the disease. These drugs, not specifically designed for the treatment of MS, may include antispastic agents (e.g. baclofen), drugs to reduce tremor (e.g. clonazepam), anticholinergics (e.g. oxybutynin) which relieve urinary symptoms, anti-epileptics (e.g. carbamazepine) to control neuralgia, stimulants to reduce fatigue (e.g. amantadine), and antidepressants (e.g. fluoxetine) to treat depression. The treatment of acute relapses or exacerbations is dominated by corticosteroids such as methylprednisolone. The most active area of current investigation is the development of drugs which will inhibit the progression of the disease process itself, and in this category the beta- and alpha-interferons are the most effective drugs currently available, although many new treatments are currently in trials, including immunoglobulin, copolymer-1. bovine myelin, T-cell receptor (TCR) peptide vaccines, platelet activating factor (PAF) antagonists, matrix metallo-proteinase inhibitors, campath-1, and insulin-like growth factor (IGF).     

The peculiar difficulties of therapeutic trials for multiple sclerosis.

Because the immune response appears important in the pathogenesis of MS, anti-inflammatory and immunomodulatory drugs and agents are used as a palliative treatment. Azathioprine alone is minimally efficacious and probably not worth the bother and risk. Cyclophosphamide alone is too toxic. Although cyclosporine A may slow the rate of deterioration in chronic progressive MS, adverse effects may limit its use outside major centers. Gamma interferon provokes exacerbations and should not be used. We do not recommend copolymer-1, alpha or beta interferon, monoclonal antibodies, plasmapheresis, and total lymphoid irradiation except in well-designed experimental protocols. Combination therapy of adrenal cortical steroids (ACS) with other immunosuppressants (cyclophosphamide or cyclosporine) merits further study. We think "pulse" synthetic ACS therapy has advantages over corticotropin and will become the "standard of care" for exacerbations. We also would try it for chronic progression. Even then, with the pulse treatment we still must determine the optimum dose, route, duration, and need for "taper."     

The Radiologically Isolated Syndrome: Look (Again) Before You Treat

The advent and wide use of magnetic resonance brain imaging has led to in the unexpected detection of lesions that appear typical of multiple sclerosis (MS) in otherwise asymptomatic patients. Several cohorts of patients with the “radiologically isolated syndrome (RIS)” have been studied mainly retrospectively, and a proportion of them do go on to have clinical symptoms of MS. This has led to the not infrequent clinical conundrum of whether or not to treat patients with MRI lesions suggestive of MS, given the knowledge that MS disease-modifying therapies work best when given early in the disease course. However, the decision to proactively treat patients with RIS is countered by the increasing risks associated with MS disease-modifying therapies as well as the uncertain prognostic outcome of RIS. This review will highlight what is and is not known about the long-term outcomes of RIS and present recommendations for clinicians when faced with this challenging situation.     

ACTH protects mature oligodendroglia from excitotoxic and inflammation‐related damage in vitro

Corticosteroids (CS) are widely employed to treat relapses in multiple sclerosis (MS). Endogenous ACTH is a 39‐amino acid peptide that, among other functions, stimulates CS production. Exogenous ACTH 1‐39 is used to treat MS relapses, presumably by stimulating endogenous CS production. However, unlike CS, ACTH binds to melanocortin receptors, found in the central nervous system (CNS) as well as on inflammatory cells. Since glia are implicated in MS and other neurodegenerative diseases, and oligodendroglia (OL) are more sensitive to injury than other glia, we characterized the protective effects of ACTH on OL in vitro without the confounding effects of CS. Rat brain cultures containing OL, astrocytes (AS), and microglia (MG) were incubated for 1 day with potentially cytotoxic agents with or without preincubation with ACTH 1‐39. The cytotoxic agents killed 55–70% of mature OL, but caused little or no death of AS or MG at the concentrations used. ACTH protected OL from death induced by staurosporine, AMPA, NMDA, kainate, quinolinic acid, or reactive oxygen species, but did not protect against kynurenic acid or nitric oxide. The protective effects of ACTH were dose dependent, and decreased OL death induced by the different agents by 30–60% at 200 nM ACTH. We show for the first time that melanocortin 4 receptor is expressed on OL in addition to MG and AS. In summary, ACTH 1‐39 protects OL in vitro from several excitotoxic and inflammation‐related insults. ACTH may be activating melanocortin receptors on OL or alternately on AS or MG to prevent OL death. GLIA 2013;61:1206–1217     

International consensus statement on the use of disease-modifying agents in multiple sclerosis

OBJECTIVE: To provide recommendations on the use of disease-modifying agents in the management of multiple sclerosis (MS) and to ensure that treatment will be available to those patients who may benefit. METHODS: An initial draft of the consensus statement was prepared by the Steering Committee and amended in the light of written comments from a group of MS specialists. At a subsequent workshop, the wording of the consensus statement was discussed, modified if necessary, and the participants indicated their level of support using an electronic voting system. A new draft of the statement was then sent to a much larger group of international opinion leaders in MS for further comment. RESULTS: A number of statements were agreed, which outline the criteria for consideration of disease-modifying therapy for MS and recommendations for treatment. Each statement was accepted completely, or with only minor reservations by 95% or more of those present at the workshop. CONCLUSIONS: Periodic reviews and modifications to the statement will be required, as new approaches to the treatment of MS and other therapeutic agents become available.     

Immunological treatment of multiple sclerosis

Immunosuppressive treatment of multiple sclerosis (MS) is based on the autoimmune hypothesis for which the main evidence is the close histological similarity between the human disease and chronic relapsing EAE. Although controlled trials indicate that ACTH is effective in accelerating recovery from relapses, long term ACTH or oral steroids are ineffective. Two controlled trials have suggested a beneficial effect of azathioprine, but neither was conducted "blind" and neither was sufficiently convincing to cause the widespread adoption of azathioprine by neurologists. One controlled trial, also not blind, reported a beneficial effect of an intensive course of cyclophosphamide, but this hazardous treatment will not be widely adopted unless other trials confirm this result. The converse hypothesis that MS is due to a deficient immune response to a virus has led to trials of immunostimulation. Interferon and levamisole have proven ineffective so far, but transfer factor slowed disease progression in one well conducted trial.     

Developing therapeutics for the treatment of multiple sclerosis

Multiple sclerosis (MS) is both a complex and chronic neurological disease of the CNS. This poses unique challenges for drug discovery in terms of delineating specific targets related to disease mechanisms and developing safe and effective molecules for clinical application. Preclinical animal models of MS provide the necessary test bed for evaluating the effects of novel therapeutic strategies. Because the clinical manifestations and pathological consequences of disease vary dramatically from individual to individual, as well as treatment response to existing therapies, this creates a significant research endeavor in terms of translating preclinical methodologies to the clinical domain. Potentially exciting treatments have emerged in the form of natalizumab (Tysabri), an α4 integrin antagonist, and more recently FTY720, a sphinogosine-1 phosphate receptor modulator, providing a compelling proof-of-principle from bench to bedside. However, further research is required to discharge safety concerns associated with these therapeutic avenues. Future prospects in the guise of disease-modifying therapies that target the inflammatory and neurodegenerative components of disease have come to the forefront of preclinical research with the sole aim of reducing the underlying irreversible progressive disability of MS. Significant progress with novel therapies will be made by implementing biomarker strategies that extrapolate robustly from animal models to the divergent patient populations of MS. The future therapeutic options for MS will depend on improvements in understanding the precise factors involved in disease onset and progression and subsequently the development of oral therapeutics that translate sustained benefit from the preclinical context into clinical reality.     

Natural history of multiple sclerosis: have available therapies impacted long-term prognosis?

Since the mid-1990s several disease-modifying drugs (DMDs), such as β-interferons and glatiramer acetate, have become available to treat patients with relapse-remitting multiple sclerosis (MS). These therapies have known short- and medium-term benefit in reducing relapses, disability progression, and accrual of new inflammatory lesions. However, the short duration of the randomized pivotal MS trials have provided little to no information about benefit from such treatment over periods of extended (>5 years) use. Whether DMDs may significantly alter the development of long-term disability remains uncertain, thus it remains challenging how to best approach the issue of long-term benefits from these treatments.     

A recommended treatment algorithm in relapsing multiple sclerosis: report of an international consensus meeting

An International Working Group for Treatment Optimization in MS met to recommend evidence-based therapeutic options for the management of suboptimal responses or intolerable side-effects in patients treated with disease-modifying drugs (DMDs) for multiple sclerosis (MS). Several DMDs are now available for the treatment of MS that have been shown to alter the clinical course of the disease by decreasing disease activity and delaying the progression of disability. Nevertheless, many patients continue to experience disease activity whilst on treatment, and recommendations have been made on how the success of therapy in an individual patient can be assessed. However, even after having identified criteria for a suboptimal response to current treatments, clinicians require guidance on how to improve the outcomes. This report summarizes the conclusions from a workshop at which this issue was addressed. We suggest treatment pathways for optimizing therapy for those patients with suboptimal responses to DMDs, and therapeutic options for patients with unacceptable side-effects on their current therapy.     

sICAM-1 is not a marker for disease activity in the relapse-free interval of multiple sclerosis - a cross-sectional pilot study

In multiple sclerosis (MS), serum levels of ICAM-1 were elevated during acute exacerbations and were therefore proposed as a marker of disease activity, but the potential of this molecule as an indicator of long-term activity, i. e. the progression of the disease outside acute exacerbations, is not known. We therefore measured sICAM-1 levels by an enzyme-linked immunosorbent assay in 26 patients with active relapsing-remitting (RR) MS (at least two relapses in the preceding 2 years, but not within the last 30 days), in 10 patients with active secondary-progressive MS (progression of at least one point on the EDSS and/or two relapses in the preceding 2 years, but not within the last 30 days), in 8 patients with stable RR MS (no relapse and no progression during the last two years), and in 16 healthy controls. There was no significant difference between the different MS subtypes and healthy controls, nor within the different MS subtypes. Thus, while sICAM-1 may be useful to indicate short-term activity of MS in terms of relapses and MRI activity, this does not hold true for the long-term activity of MS outside acute exacerbations.     

Transient movement disorders and multiple sclerosis

Movement disorders associated with multiple sclerosis (MS) are uncommon, except for tremor. We report two patients with relapsing-remitting MS, who developed either dystonia or chorea during clinical exacerbation of their MS. The movement disorders resolved during treatment with adrenocorticotropin hormone (ACTH). Acute exacerbations of MS may be associated with transient movement disorders, which are responsive to ACTH.