In adult breakthrough disease, treatment strategies include switching to another first-line agent, adding another agent to the on-going therapy, or switching to a second-line drug such as natalizumab or immunosuppression. Therapeutic strategies such as switch to a second-line agent are typically associated with the possibility of more severe adverse events than those seen with first-line agents, including life-threatening conditions such as progressive multifocal leukoencephalopathy (PML), leukemia, secondary cancers, or infections. The primary goal of breakthrough therapy in pediatric multiple sclerosis (MS) is to prevent disease activity and disability progression in patients who have continued disease activity despite appropriate first-line therapy. Methotrexate (MTX) is a dicarboxylic acid used in the treatment of various cancers and autoimmune diseases. Combination therapy of either first-line drugs or first-line drugs with a second-line agent is sometimes used as an approach to obtain better disease control in breakthrough MS.