The participant will receive weekly intramuscular treatment with AVONEX® (interferon beta 1-a) and bi-monthly high dose intravenous methotrexate with Leucovorin rescue.

The participant will receive weekly intramuscular treatment with AVONEX® (interferon beta 1-a) and bi-monthly high dose intravenous methotrexate with Leucovorin rescue. Entrance into the study will be based on Multiple Sclerosis Functional Composite Score (MSFC) evaluations at –4 months, and - 1 month prior to study, where a decrease in score is noted. The composite score consists of the Timed 25-Foot Walk, Nine-Hole Peg Test (9HPT), and Paced Auditory Serial Addition Test 3 (PASAT 3). The patient must have been on AVONEX® for at least 6 months.

At study entrance, baseline lab work (complete blood count, platelet count, routine electrolytes, blood urea nitrogen, creatinine, liver function tests, 24 hour urine collection for creatinine clearance, and urine pH), an electrocardiogram (measurement of heart activity) and serum pregnancy test will be done. A complete physical examination will be performed, including measurements of vital signs (heart rate and blood pressure), as well as magnetic resonance imaging (MRI) to document status of disease. A self-administered questionnaire, the MSQLI (Multiple Sclerosis Quality of Life Instrument), will be completed at baseline and at the end of the study. MSFC and safety evaluations (previously mentioned blood and urine tests and electrocardiograms (EKG), will be conducted throughout the study at months 2, 4, 6, 8, 10, and 12. Blood tests of immune cells will also be drawn at these visits. The patient can continue this regimen of treatment at their own discretion and cost, and outside the parameters of this study, if there is apparent efficacy without serious adverse events. This treatment would be under the supervision of Dr. Rowe.

The patients will continue their AVONEX® intramuscular injections of 30 micrograms (administered by patient or caregiver) on a weekly basis with scheduled intravenous high dose methotrexate at 2 Gm/m2 followed by intravenous and oral leucovorin rescue once every 2 months. The methotrexate infusions will be performed in our outpatient infusion center. The patient will be required to complete a patient diary during the course of the trial, participate in and keep all scheduled appointments, and to inform the research staff and physician of any change in concomitant medications or adverse events that they may experience.

To be eligible for entry into this study, candidates must meet the following eligibility criteria at the time of enrollment:

• Between the ages of 18 and 60 years, inclusive.
• Diagnosis of clinically definite relapsing MS.
• Must have been on AVONEX® therapy for at least six months.
• Brain MRI scans demonstrating lesions consistent with MS.
• Subject must have had at least one clinical exacerbation in the last year, and this must have occurred after having been on AVONEX® therapy for at least six to twelve (6-12) months. A clinical exacerbation is defined as a decrease of 0.1 in the MSFC composite or any of the subset domains scores administered 3 months apart.
• Give written informed consent prior to any testing under this protocol, including screening tests and evaluation that are not considered part of the subject's routine care.

To be eligible for treatment with methotrexate, subjects must have evidence for MS disease activity on their baseline screening MRI.