Corticosteroids for multiple sclerosis: I. Application for treating exacerbations

Multiple sclerosis (MS) is an inflammatory demyelinating disorder characterized by a multiphasic course of neurological exacerbations, periods of clinical remission, and, in most patients, ultimately progressive deterioration of functional capabilities. The relapsing-remitting phase of the disease involves acute interruption in neurological functioning relating to areas of inflammation in discrete central-tract systems. The treatment of MS exacerbations with anti-inflammatory agents such as corticosteroids and adrenocorticotropic hormone has represented an established practice throughout the neurology community. Although there is scientific rationale supporting application of these agents for this purpose, the broad diversity of approaches to using these drugs in clinical practice is a derivative of expert opinion and anecdotal experience. Ultimately, the treatment of MS-related exacerbations is part science, but mostly art. This review discusses the pharmacology of these agents, to better understand how they may act to mitigate attacks and to provide some practical formulations for how to use them in the clinic for the benefit of patients.     

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.     

Current disease-modifying therapies in multiple sclerosis

In recent years, the usefulness of interferon beta and glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis (RRMS) has been established. Interferon beta has also been shown to be efficacious in secondary-progressive multiple sclerosis (SPMS) as well as in patients with isolated syndromes at risk to develop clinically definite multiple sclerosis (MS). Mitoxantrone is another disease-modifying drug that is available for SPMS and severe cases of RRMS. The clinical utility of disease-modifying agents in MS will be reviewed with respect to the anti-inflammatory, immunomodulatory, and immunosuppressive treatments that are currently available. Symptomatic therapies will not be considered.     

Estimating long-term effects of disease-modifying drug therapy in multiple sclerosis patients

Two methods were used to estimate the long-term impact of disease-modifying drug therapy (DMDT) in patients with relapsing multiple sclerosis (MS) who completed a placebo-controlled, randomized clinical trial of interferon beta-1a (IFNbeta-1a). The study cohort consisted of patients with ambulatory relapsing MS who had previously participated in a placebo-controlled clinical trial for two years. At its end, patients were managed in an unstructured fashion by their neurologists and re-evaluated at an average of 6.1 years after the end of the trial. Follow-up evaluation was obtained for 93% of the 172 eligible patients. Because study inclusion criteria required that all patients have an Expanded Disability Status Scale (EDSS) score of < or = 3.5 at entry, disability progression at follow-up was defined as EDSS > or = 6.0. Two methods were used to estimate the expected proportions that reached EDSS > or = 6.0 at follow-up. Estimates were compared with observed proportions. Method 1 used progression rates observed during the two-year phase III clinical trial and the percentage of time that patients were on DMDT during the follow-up period. Method 2 used progression rates from a natural history comparison group of relapsing-remitting MS patients. At the eight-year follow-up, 42.0% of the original placebo patients and 29.1% of the original IFNbeta-1a patients reached an EDSS > or = 6.0, an observed treatment effect of approximately 30%. Using method 1, it was estimated that 36.3% of the original placebo patients and 27.6% of the original IFNbeta-1a patients should have reached an EDSS > or = 6.0. Use of the natural history control group (method 2) predicted less plausible outcomes. Estimated proportions of patients reaching the endpoint were 63.3% for the original placebo group and 55.8% for the original IFNbeta-1a group. Treatment effect sizes of 75-90% would be required to match estimates from method 2 with the observed outcome. The paucity of data on the long-term treatment of patients with MS may be aided by applying these or similar methods to vigorously followed cohorts of patients.     

Postmarketing evidence of disease-modifying drugs in multiple sclerosis

There is growing interest in the use of observational data to estimate treatment effects in chronic diseases such as multiple sclerosis (MS). The main results derived from postmarketing evaluations, in the last 2 years, of short-and long-term disease modifying drugs (DMDs) effectiveness will be reported in this Review. Moreover, some of the methodological improvements that may be useful to enhance the quality of observational studies will also be discussed.     

Corticosteroids and plasma exchange in multiple sclerosis

Journal of Neurology - Corticosteroids (CS) remain a mainstay of treatment for relapses in multiple sclerosis (MS) and optic neuritis. Currently, there is not enough evidence that long-term...     

Long-term experience with current disease-modifying drugs in multiple sclerosis

Journal of Neurology - Five different immunomodulatory treatments have been developed and approved for the treatment of multiple sclerosis. These have been shown to be efficacious over the...     

Persistence to oral disease-modifying therapies in multiple sclerosis patients

Dimethyl fumarate (DMF), fingolimod (FTY) and teriflunomide (TFN) are oral disease-modifying therapies (DMTs) approved for relapsing–remitting multiple sclerosis (RRMS) whose efficacy and tolerability have been separately assessed in phase III trials. Conversely, little evidence exists about their head-to-head comparison. The aim of the study was to evaluate the 1-year persistence to DMF, FTY and TFN in patients with RRMS. Patients affected by RRMS who started treatment with DMF, FTY or TFN were identified. The study end-point was 12-month drug persistence as time to discontinuation and proportion of patients who discontinued medication within 1-year. A total of 307 patients were included (DMF = 114, FTY = 129, TFN = 64). The mean times to discontinuation were 144 (84), 189 (72) and 138 (120) days in the DMF, FTY and TFN cohorts (p = 0.036). At 12-month, the proportion of patients discontinuing medication was lower for subjects taking FTY (9.8%) compared with those starting DMF (21.9%) and TFN (23.6%) (p = 0.020). Compared to FTY cohort, DMF [_adjOR = 3.26 (1.38–7.70); p = 0.007] and TFN [_adjOR = 2.89 (1.10–7.63); p = 0.032] treated patients were more likely to have discontinued their drug at 1-year since initiation. In patients with RRMS, FTY was associated with a better persistence profile as compared to DMF and TFN.     

Sequencing of high-efficacy disease-modifying therapies in multiple sclerosis: perspectives and approaches

Multiple sclerosis(MS) is characterized by chronic inflammation in conjunction with neurodegeneration within the central nervous system. Most individuals with MS begin with a relapsing remitting course that later transitions to secondary progressive MS. Currently available disease-modifying therapies(DMTs) for relapsing MS have been demonstrated to reduce disease activity, however most patients require a change in therapy over the course of their disease. Treatment goals include the prevention of relapses and disability accumulation and to achieve this objective requires careful planning. Sequencing of DMTs for individual patients should be designed in such a way to maximize disease control and minimize risk based on the mechanism of action, pharmacokinetic and pharmacodynamic properties of each therapy. This includes the DMT patients are being switched from to those they are being switched to. The reversibility of immune system effects should be a key consideration for DMT sequence selection. This feature varies across DMTs and should factor more prominently in decision making as newer treatments become available for the prevention of disability accumulation in patients with progressive MS. In this short review, we discuss the landscape of existing therapies with an eye to the future when planning for optimal DMT sequencing. While no cure exists for MS, efforts are being directed toward research in neuroregeneration with the hope for positive outcomes.