Disease Modifying Agents in the Treatment of Multiple Sclerosis

Numerous agents have been tested in multiple sclerosis and the vast majority of these have either failed to show a beneficial effect or produced undesirable side effects. In some cases, there was worsening of disease activity. Treatment strategies for multiple sclerosis over the last 16 years have undergone a profound change. Several treatment options are now available primarily targeting the inflammatory phase of the disease [clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), and secondary progressive multiple sclerosis (SPMS) with relapses]. All currently approved disease-modifying agents (DMA) are moderately effective in reducing relapses and MRI activity. The treatment effect appears to be greater when these drugs are used soon after onset of symptoms. The effect on long-term disability seems to be modest if any. This post reviews both currently used agents (both FDA approved and off-label) and also discusses several promising agents in various phases of development. Disease Modifying Agents in the Treatment of Multiple Sclerosis: Currently Approved Agents Treatment of Radiologically Isolated Syndrome Several recent studies have raised awareness of patients with incidentally discovered Read more [...]

Disease Modifying Agents in the Treatment of Multiple Sclerosis: Currently Approved Agents

Interferons Interferons (IFN) act through cell receptors producing a variety of immu-nological and antiviral effects. Although the exact mechanism of action in multiple sclerosis is unknown, an anti-inflammatory effect may be the result of inhibition of interferon gamma, inhibition of T-cell activation, production of anti-inflammatory cytokines, reduced T-cell migration, decrease blood brain barrier permeability, or possibly other unknown mechanisms. IFN β-1b subcutaneous (S/Q) every other day (Betaseron/Betaferon) was the first disease modifying agent approved for the treatment of RRMS. In the pivotal trial of IFN β-1b involving 372 relapsing remitting multiple sclerosis patients, two different doses were compared with placebo. Both doses were found to be significantly better than placebo with about one-third greater reduction in relapse rate (8 MIU vs. placebo p = 0.0001, 1.6 MIU vs. placebo p = 0.0101, and 8 MIU vs. 1.6 MIU p = 0.0086). IFN β-1b had a profound beneficial effect on MRI parameters. The pivotal trial for IFN β-1a intramuscular (I/M) once weekly (Avonex) involved 301 relapsing remitting multiple sclerosis patients and also showed a relapse rate reduction of about one-third and a positive effect Read more [...]

Other Off-Label Agents Used in the Treatment of RRMS

Corticosteroids Corticosteroids are considered as standard treatment for acute relapses. Corticosteroids decrease inflammation and stabilize the blood brain barrier, resulting in more rapid recovery from relapses. The standard dose is 1 g of methylprednisolone (MP) daily for 3-5 days through I/V infusion, although other regimens also have been used. Some studies have suggested that oral forms are also equally effective. One randomized study noted decrease brain atrophy, decreased T1 lesion volume, and decreased progression in patients treated with pulse steroids for 5 years. Pulse steroids may also have a beneficial effect on disease activity when used in combination with interferons. Corticosteroids are also safe to use during pregnancy and may have a role in the postpartum period. Treatment with steroids may reduce the development of neutralizing antibodies to IFN. Corticosteroids when used as short-term or long-term pulse therapy seem to be well tolerated. Unusual but serious side effects may include steroid-induced psychosis, mood disorders, reversible memory disturbance, and aseptic vascular necrosis. Cyclophosphamide Cyclophosphamide is an alkylating agent that binds to DNA and suppresses both B and T Read more [...]

Disease Modifying Oral Agents in the Treatment of Multiple Sclerosis

Cladribine Cladribine reduces lymphocyte counts selectively by getting incorporated into dividing cells leading to DNA damage and cell death. It has long-lasting effects and is currently approved for the treatment of hairy cell leukemia. When tested in the intravenous and subcutaneous forms, treatment of a mixed population of multiple sclerosis patients produced a clear beneficial effect on MRI parameters of inflammation, but its effects on clinical measures and MRI measures of degeneration were less pronounced. The recently completed CLARITY study was a randomized, double-blinded, placebo-controlled trial involving 1,326 patients with relapsing-remitting MS. Patients were randomized in a 1:1:1 ratio to receive placebo or one of two dosing regimens of oral cladribine. The trial met its primary end point, with a 58% reduction in annualized relapse rates with the low dose and a 55% reduction with the high dose at 2 years There was a statistically significant reduction in MRI activity as well as disability progression. A greater percentage of patients remained disease activity free over 96 weeks (placebo = 16%, low dose=43%, and high dose=44.3%). The drug was well tolerated and only 2.6% of patients discontinued treatment Read more [...]

Combination Therapy in Multiple Sclerosis

The treatment of multiple sclerosis (MS) has been revolutionalized over the past decade. Just 12 years ago, multiple sclerosis was not considered a treatable neurologic illness and our therapeutic armamentarium consisted largely of symptomatic therapies and corticosteroids to treat acute exacerbations. Currently, there are five drugs [the three beta interferons (IFNs) (Avonex®, Betaseron®, and Rebif®), Glatiramer Acetate (Copaxone®), and mitoxantrone (Novantrone®)] representing three different classes of agents, approved by the Food and Drug Administration (FDA) and available in the United States, that alter the course of multiple sclerosis. However, these therapies provide a rather modest benefit and none results in complete disease control. Consequently, many patients continue to have exacerbations and accumulate disability and demyelinating lesions in the central nervous system (CNS). To improve upon the existing multiple sclerosis therapies, the efficacy and safety of novel treatment approaches need to be established. However, with the advent of partially effective therapies, we are now confronted with new challenges in developing better disease-modifying agents and treatment strategies. Because roughly Read more [...]

Therapy in Multiple Sclerosis: IFNβ and Glatiramer Acetate

IFNβ and Glatiramer Acetate are well suited for testing their combinatorial potential, as their mechanisms of action differ and could be complimentary. Furthermore, when used alone, they are partially effective, safe, and generally well tolerated. The therapeutic effects of IFN may be due to its antiproliferative action; down-regulation of costimulatory molecules; decrease of proinflammatory cytokines; and / or through its effects on matrix metalloproteinases and adhesion molecules, which reduce the permeability of the blood-brain barrier and limit trafficking of T-lymphocytes into CNS. The beneficial effects of Glatiramer Acetate may result from reactive Th2 cells that cross the blood-brain barrier and increase the secretion of suppressor type cytokines and downregulate inflammatory activity within the CNS — a process known as bystander suppression. Another interesting aspect of using Glatiramer Acetate in combination with IFN relates to the growing body of evidence suggesting that in addition to its immunomodulatory actions, Glatiramer Acetate may also have a neuroprotective effect. A recent study found that Glatiramer Acetate may favorably affect the development of Tl-hypointense lesions on brain magnetic Read more [...]

Therapy in Multiple Sclerosis: IFN, Methylprednisolone, and Methotrexate

Corticosteroids have anti-inflammatory and immunosuppressive properties and have been used to treat acute multiple sclerosis exacerbations for more than 30 years. While periodic pulses of intravenous (IV) methylprednisolone are not effective in preventing disability in patients with progressive MS, a phase II trial concluded that they do have an effect on disability, brain atrophy, and T1-hypointense lesions in patients with relapsing-remitting multiple sclerosis. Methotrexate impairs DNA and RNA synthesis by inhibiting dihydrofolate reductase and has potent immunosuppressive and anti-inflammatory activity. It was studied in patients with progressive multiple sclerosis in a randomized, double-blind, placebo-controlled trial. In this trial, 60 patients with progressive forms of multiple sclerosis with expanded disability status scale scores of 3.0 to 6.5 were randomized to receive methotrexate 7.5 mg or placebo orally every week for two years. The primary endpoint was the rate of sustained disability progression as determined by a composite of four clinical outcome measures. After two years, there was a significant treatment effect: 83% of patients in the placebo-treated group had sustained disability progression Read more [...]

Mitoxantrone in Multiple Sclerosis

Mitoxantrone () was developed in the 1970s and is an antineoplastic agent. It is an anthracenedione derivative related to the anthracyclins doxorubicine and daunorubicine. It interacts with topoisomerase-2, stabilizes its cleavable complex with DNA, thus prevents the ligation of DNA strands, and consecutively delays the cell-cycle progression. Mitoxantrone is used to effectively treat malignancies such as breast and advanced prostate cancer, lymphoma, and leukemia. Furthermore, in common with other antineoplastic agents, strong immunosuppressive properties of mitoxantrone have been observed providing a rationale for its use in autoimmune disorders. Evidence Leading To The Approval Of Mitoxantrone For Use In Multiple Sclerosis Mitoxantrone in Experimental Autoimmune Encephalomyelitis In the 1980s, mitoxantrone was proven effective in both actively and passively induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Ridge et al. observed a dose-dependent inhibitory effect as determined by clinical evaluation and histopathology in rat EAE. Interestingly, mitoxantrone was 10 to 20 times more effective than cyclophosphamide in suppressing the development of EAE. Moreover, Read more [...]

Epilepsy in the Elderly

Epilepsy can begin at any age, and the rate of newly diagnosed epilepsy is higher in elderly people than in middle-aged adults. As in younger people, the cause of epilepsy often cannot be determined when it begins in the elderly. Approximately half of the cases are caused by stroke (often a small one that did not cause other symptoms), head injury, or tumor (either benign or malignant). Recurrent seizures may also be caused by metabolic disorders or drugs (prescribed, over-the-counter, alcohol). Degenerative disorders such as Alzheimer's disease are a rare cause of seizures in the elderly. Effects of Seizures on Older People There are special concerns about the effects of seizures on older people. The body becomes less resilient with age, so the effects of tonic-clonic seizures can cause more serious damage. They can stress the heart and lungs and cause potential problems for people with cardiac or pulmonary disorders. Similarly, breathing is affected during a tonic-clonic seizure, which can aggravate lung disorders. Bones also are more fragile, increasing the risk of fracture during a tonic-clonic seizure or seizure-related fall. Despite these and other potential problems, most older people who suffer tonic-clonic Read more [...]

Outgrowing Epilepsy in Children

Slightly more than half of the children who have epilepsy outgrow it. This simple and positive fact raises important questions: Which children should be treated? How much medication should they receive? How long should antiepileptic drugs be used? Doctors' views on antiepileptic drugs have changed. Several decades ago, many doctors believed that seizures must be stopped at all costs and that, once stopped, medications should be continued for prolonged periods or indefinitely. This outdated approach reflected an overly pessimistic outlook on life with epilepsy. The risks of seizures were overestimated, and medications' side effects were underestimated. Issues such as the quality of life, or how patients felt about seizures and side effects, were rarely considered, and the natural course of epilepsy was poorly understood. Greater understanding has led to a better balance of seizure control and antiepileptic drug use. Stopping Antiepileptic Drugs Most children who remain seizure-free while taking medications for 1 or 2 years can safely have their medications slowly tapered by their doctors and eventually discontinued. Most of these children will not have another seizure. The current trend is toward discontinuing antiepileptic Read more [...]