Differentiation of multiple sclerosis subtypes: implications for treatment.

There has been tremendous progress in the immunomodulatory treatment of multiple sclerosis (MS) during recent years. With the introduction of interferon-beta, glatiramer acetate and mitoxantrone (recently registered for MS in the US), there are at least three therapeutic strategies that have proven effective in large phase III studies. However, not all patients with MS respond well to treatment with these drugs. This may largely be a consequence of disease heterogeneity. From a clinical perspective, patients with different disease courses show different treatment responses. Patients with relapsing-remitting MS are more likely to respond to immunomodulatory therapy than those with a progressive disease course. Studies of patients with secondary progressive MS have yielded inconsistent results and, so far, there has been no positive phase III study of immunomodulatory therapy in patients with primary progressive MS. Pathological evidence indicates that subtyping based on clinical findings alone does not reflect actual disease heterogeneity. In a large series of biopsy and autopsy specimens, at least four subtypes could be identified with respect to oligodendrocyte/myelin pathology and immunopathology. As long as the only method of identifying subtypes of disease is histopathology, differential therapy will remain a future goal. Thus, there is an urgent need for in vivo markers of immunopathogenesis in an individual patient that would allow treatment to be specifically directed towards a given pathological focus. However, at least from a theoretical point of view, some therapeutic approaches appear very attractive. Plasmapheresis and/or intravenous immunoglobulins could most plausibly be the best approach for the immunopathological subtype of MS, which is characterised by antibody and complement deposition next to demyelinated axons, in order to remove antibodies. The subtype of MS that is associated with heavy macrophage activation, T cell infiltration and expression of inflammatory mediator molecules, including tumour necrosis factor-alpha, may be most likely to respond to immunomodulation with interferon-beta or glatiramer acetate. There are other subtypes of MS in which viral infection or oligodendrocyte degeneration, rather than autoimmunity, appear to play a role. It is possible that these could benefit from antiviral therapy, oligodendrocyte protection or oligodendrocyte transplantation, although therapies based on these latter approaches have yet to be developed.