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Since the mid-1990s several disease-modifying drugs (DMDs), such as β-interferons and glatiramer acetate, have become available to treat patients with relapse-remitting multiple sclerosis (MS). These therapies have known short- and medium-term benefit in reducing relapses, disability progression, and accrual of new inflammatory lesions. However, the short duration of the randomized pivotal MS trials have provided little to no information about benefit from such treatment over periods of extended (>5 years) use. Whether DMDs may significantly alter the development of long-term disability remains uncertain, thus it remains challenging how to best approach the issue of long-term benefits from these treatments.