Boster A, Edan G, Frohman E, et al. Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician. Lancet Neurol. 2008;7:173–183. [PubMed]

Patients with treatment-refractory, clinically active multiple sclerosis (MS) present considerable management challenges. Recurrent relapses may rapidly result in irreversible neurologic disability despite immunomodulatory therapy and frequent pulsed courses of intravenous methylprednisolone. In view of these problems in this patient population, interest has turned to the potential advantages of intense immunosuppression. Of concern, however, is the difficulty of assessing interventions for such patients in the clinical trial setting. Not only does their worsening condition in the absence of treatment pose ethical concerns, but those who exhibit rapid decline during active therapy are deemed treatment failures.

Despite limitations of the available evidence, guidelines have now been proposed for the use of intense immunosuppression in patients with this type of MS who do not respond to immunomodulating agents such as interferon or glatiramer acetate. Data from several open-label studies have suggested, for example, that intravenous cyclophosphamide may be beneficial in patients with rapidly worsening, treatment-refractory relapsing-remitting MS. Similarly, mitoxantrone appears effective for stabilizing the course of disease in these patients, according to data from a phase III trial.

However, use of intensive mitoxantrone therapy is limited by the risk of dose-dependent cardiotoxicity. (Both mitoxantrone and cyclophosphamide are associated with development of leukemia.) Autologous hematopoietic stem cell transplantation may produce prolonged periods of stable disease, although questions remain with respect to appropriate patient selection as well as risks of toxicity and treatment-related brain atrophy. Natalizumab may have a role to play, but has not yet been evaluated (as monotherapy) in this type of MS. Other monoclonal antibodies (such as alemtuzumab, rituximab, and daclizumab) may be of interest as well, but further investigation is needed.

Han MH, Hwang S-I, Roy DB, et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature. 2008;451:1076–1083. [PubMed]

Proteomic profiling of lesions from patients with multiple sclerosis (MS) has identified potential new treatment targets, which may ultimately lead to more specific interventions.