Combination therapy for the treatment of multiple sclerosis: Challenges and opportunities

Objective: Multiple sclerosis (MS) is a complex, heterogeneous disease. Standard treatment of relapsing MS includes interferon beta (IFN beta) and glatiramer acetate. These agents reduce relapse rates, and IFN beta-1a is associated with a slowing of disease progression. Despite treatment, many patients experience disease progression, prompting neurologists to use combination therapies to delay this progression. Agents that may be considered for combination therapy are those with unique mechanisms of action that exert additive or synergistic efficacy. This article reviews combination treatment with immunosuppressive therapies and new agents for the management of MS. Methods: The Medline and EMBASE databases were searched for clinical trials using the following search terms: multiple sclerosis, interferon, Avonex, Betaseron, Rebif, glatiramer, copolymer 1, Copaxone, immunosuppressant, cytotoxic, corticosteroid, azathioprine, cyclophosphamide, methotrexate, mitoxantrone, natalizumab, combination therapy. The National MS Society website was searched for clinical trials of combination therapies. Results: Several small studies have analyzed the effects of immunosuppressive therapy added to IFN beta treatment, and some encouraging results have been obtained. Few data are available on combination therapy with new drug classes; however, current data suggest that combination therapy with new agents is effective. Although the available data on combination regimens are promising, interpretation is limited by lack of controlled study design, small patient population, and short study duration. Conclusions: Combination of standard therapies with immunosuppressive agents or with new therapies may provide synergistic effects that will likely benefit patients with MS. Larger, well-controlled trials need to be conducted.