Mechanisms of action for treatments in multiple sclerosis: Does a heterogeneous disease demand a multi-targeted therapeutic approach?

The etiology of multiple sclerosis (MS) is incompletely understood, and evidence suggests there may be more than one underlying cause in this disorder. Furthermore, this complex and heterogeneous autoimmune disease shows a high degree of clinical variability between patients. Therefore, in the absence of a single therapeutic target for MS, it is difficult to apply conventional drug design strategies in the search for new treatments. We review the potential mechanisms of action of several effective therapies for MS that are currently available or in development. The effects of each treatment are described in terms of their actions on key processes in a five-step model of MS pathogenesis. Conventional immunosuppressants targeting intracellular ligands (e.g. mitoxantrone) have broad cytotoxic effects on B cells, T cells, and macrophages. This suppresses the pathogenic immune response in MS with high efficacy but is also associated with high toxicity, limiting the long-term use of these agents. Monoclonal antibodies (e.g. natalizumab and alemtuzumab) are a new generation of immunosuppressants that act on immune-cell surface ligands. These agents have narrower immunosuppressive actions and different safety profiles compared with conventional immunosuppressants. Immunomodulators (interferon-beta and glatiramer acetate), which shift the immune balance toward an anti-inflammatory response, are at the frontline of treatments for MS. Immunomodulators have targeted actions on the immune system, but affect a greater number of immunopathogenic processes than monoclonal antibodies. Given the inherent heterogeneity of MS, such treatments, which act at many levels of the disease, may achieve the best clinical results. Using our understanding of the interplay between mechanism of action and clinical effects in MS therapies may help us to better design and select new treatments for the future.