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.

Terilunomide is being investigated in a comprehensive program of clinical trials in patients with multiple sclerosis (MS) with relapses and in patients with a clinically isolated syndrome (CIS). This program evaluates the efficacy and safety of terilunomide on a range of clinical and magnetic resonance imaging (MRI) end-points when administered either as monotherapy or as an adjunctive therapy to ongoing treatment with conventional disease-modifying therapies (DMTs). Clinical data indicates that terilunomide is generally well tolerated with an acceptable safety profile, with no significant safety concerns identified to date. Safety data from the open-label extension phase of the study are consistent with the safety profile of terilunomide observed in the double-blind treatment phase, without the emergence of any new safety concerns. Based on currently available data on monotherapy and adjunctive therapy, terilunomide appears to have a favorable benefit/risk ratio in relapsing MS, and as such, represents a promising new first-line treatment.