Design of oral agents for the management of multiple sclerosis: benefit and risk assessment for dimethyl fumarate.

Dimethyl fumarate (DMF) is the most recent oral disease-modifying therapy approved by the US Food and Drug Administration and is indicated for the treatment of relapsing forms of multiple sclerosis (MS). Prior to approval for use in MS, DMF and its active metabolite, monomethyl fumarate, had been used for decades as two of the fumaric acid esters in Fumaderm, a medication used in Europe for the treatment of psoriasis. The unique mechanism of action of DMF remains under evaluation; however, it has been shown to act through multiple pathways leading to shifts away from the Th1 proinflammatory response to the less inflammatory Th2 response. Preliminary data suggest that DMF may induce neuroprotective effects in central nervous system white matter, although further studies are needed to demonstrate these effects on inflammatory demyelination. The DMF Phase III clinical trials demonstrated its efficacy with regard to a reduction in the annualized relapse rate and reductions in new or enlarging T2 lesions and numbers of gadolinium-enhancing lesions on magnetic resonance imaging. DMF has a well-defined safety profile, given the experience with its use in the treatment of psoriasis, and more recently from the DMF clinical trials program and post-marketing era for treatment of MS. The safety profile and oral mode of administration of DMF place it as an attractive first-line therapy option for the treatment of relapsing forms of MS. Long-term observational studies will be needed to determine the effects of DMF on progression of disability in MS.

First-line natalizumab in multiple sclerosis: rationale, patient selection, benefits and risks.

Natalizumab (NTZ) is a highly effective disease modifying therapy for the treatment of relapsing forms of multiple sclerosis (MS). Despite evidence to support its use as first-line therapy, risk of NTZ-associated progressive multifocal leukoencephalopathy (PML) has largely contributed to it being relegated to a second-line position. Recent preliminary data may allow for a more accurate analysis of JC virus (JCV) risk stratification of a given patient's PML risk. Herein we propose an algorithm to help guide clinicians through this decision-making process. We recommend that NTZ be considered for first-line use in JCV antibody negative MS patients, JCV 'low positive' MS patients without prior exposure to immunosuppression and for a limited period (12-24 months) in JCV 'high positive' MS patients with an aggressive disease course . We caution against first-line use in JCV antibody 'high positive' patients beyond 12-24 months and any JCV antibody positive patient with a history of prior immunosuppression.