More closely analogous to the use of combination therapies in multiple sclerosis (MS) is the use of combination therapies in autoimmune diseases such as rheumatoid arthritis. In the case of MS, drugs could be directed at different therapeutic domains such as tissue destruction and tissue repair. Currently, natalizumab is approved only as a monotherapy. This is due to concern over combined toxicity because of the two cases of progressive multifocal leukoencephalopathy (PML) that occurred in patients enrolled in the combination arm of the SENTINEL trial. Perhaps the most frequently used combination therapy approach utilized in clinical practice for patients with relapsing-remitting MS and continued disease activity while on platform therapy is the ad hoc addition of periodic courses of corticosteroids, most often intravenous methylprednisolone. This chapter discusses cytotoxic therapies and combination trials with other immunomodulating agents such as daclizumab, terilunomide and statins.

In vitro, two different classes of antibodies are recognized according to the assay used to identify them: binding antibodies (BAbs) and neutralizing antibodies (NAbs). There is emerging agreement that NAbs are correlated with reduced therapeutic efficacy of IFNβ. None of the pivotal trials in relapsing-remitting multiple sclerosis (MS) showed an effect of NAbs on disease progression. Among the therapeutic monoclonal antibodies natalizumab, alemtuzumab, and daclizumab are humanized monoclonal antibodies, whereas rituximab is a mouse-human chimeric antibody. NAbs are associated with reduction of the therapeutic effect of IFNβ, and patients with persistent high titers of NAbs should be switched to an alternative therapy. Patients with low or intermediate titers should have their IFN bioactivity measured with an in vivo mRNA MxA induction test. Patients with repeated abrogation of the mRNA MxA response to IFN injections should be switched to another therapy.

Research into therapeutic applications of apheresis is limited by the rarity of many of the diseases for which plasma exchange (PLEX) is indicated. PLEX has now become a widely used treatment in select patients with acute relapses of inflammatory demyelinating disease in a variety of contexts including multiple sclerosis (MS). Natalizumab inhibits central nervous system (CNS) lymphocyte trafficking by blocking alpha4-integrin, and its serological clearance is enhanced by PLEX. Circulating pathologic antibodies directed against myelin oligodendrocyte glycoprotein and myelin basic protein have been implicated in subsets of MS patients. Complications occur in 4.75% to 36% of PLEX procedures. The majority are mild, easily treated, and self-limited and include paresthesias and muscle cramping due to hypocalcemia from citrate anticoagulant, bleeding and hematoma formation from vascular access, urticaria/pruritus and fever from blood products, hypotension, pallor, nausea, and vomiting.

The pharmacokinetics of a single I.V dose of natalizumab were studied in a phase 1, dose-escalation study in 28 multiple sclerosis (MS) patients. As part of the clinical trial program to establish the pharmacokinetic/pharmacodynamic and safety profiles of natalizumab, four Phase 1, dose-finding studies were conducted. An additional Phase 2 study was conducted to evaluate the safety and efficacy of natalizumab in combination with glatiramer acetate (GA). One of the recommendations of the therapeutics and technology assessment subcommittee of the AAN about the use of natalizumab was to carefully monitor patients receiving natalizumab to establish its long-term safety i.e. the true risk of progressive multifocal leukoencephalopathy (PML). Large Phase 3 trials of natalizumab alone or in combination with interferon (IFN)β-1a show that natalizumab reduces the progression of disability, and dramatically reduces the frequency of relapses and magnetic resonance imaging (MRI) lesion formation in patients with relapsing MS.

This chapter deals with epidemiology, pathology, clinical patterns and diagnosis of multiple sclerosis (MS). It also discusses the treatment options for MS and provides a brief account of other acquired demyelinating diseases. MS is characterized clinically by two major patterns: relapsing-remitting neurological deficits and a progressive neurological deficit. The key diagnostic investigation in MS is magnetic resonance imaging (MRI) scanning, which is abnormal in 95 % of patients. The relationship of seizures to MS activity has been explored and most studies report that about one-third of seizures occur in the context of an acute relapse of MS, sometimes taking the form of focal status epilepticus, usually focal motor status. The treatment of multiple sclerosis falls into three broad categories: symptomatic treatment of the neurological complications of MS, treatment of acute relapses with high-dose corticosteroids, and the use of disease- modifying therapies, including beta-interferon, glatarimer acetate, natalizumab, and mitoxantrone.