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 the first of two studies reported by Rose and coworkers, patients with relapsing-remitting multiple sclerosis (RRMS) or secondary-progressive multiple sclerosis (SPMS) were initiated on daclizumab with the same dose. A positive effect on relapses was observed. Safety data coming from daclizumab's regulatory-approved indication in renal transplantation suggest that the drug is overall safe and well tolerated. However, safety data from other of-label indications, such as uveitis, seem to confirm safety concerns regarding a mild increase in infection rate as well as skin reactions. Daclizumab is a novel and promising therapy for MS patients now being tested as monotherapy in a large Phase 3 trial using an active comparator arm. Daclizumab's mechanism of action is not fully understood, but an increase in regulatory immune cells has been related to clinical response and is now thought to play a more important role than direct anti-inflammatory effects derived from IL-2 blockade.