By Jai S. Perumal, MD

Assistant Professor of Neurology, Weill Cornell Medical College

Dr. Perumal reports she receives grant/research support from Genzyme Corp., and is on the speakers bureau for Biogen Idec, Genzyme Corp., Acorda Therapeutics, and Teva Pharmaceuticals.

SYNOPSIS: In a long-term study, the rate of disability progression in treated relapsing and progressive, multiple sclerosis patients was lower than that reported in earlier natural history studies.

SOURCE: Cree BA, Gourraud PA, Oksenberg JR, et al, for the University of California, San Francisco, MS-EPIC Team. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol 2016;80:499-510.

Five hundred and seventeen patients, including 366 relapsing-remitting (RMS), 48 secondary progressive (SPMS), 21 primary progressive (PPMS), and 82 clinically isolated syndrome (CIS) patients participated in a prospective, longitudinal study of disability in multiple sclerosis (MS) patients. The study was conducted at the MS center at the University of California, San Francisco. Patients were enrolled between July 2004 and September 2005. Ninety-one percent of patients were followed for the entire duration of the study. Median follow-up for the group was 9.8 years. The mean disease duration at enrollment was seven years, mean age was 42.7 ± 9.9 years, and mean Expanded Disability Status Scale (EDSS) at enrollment was 1.5.

For the analysis, CIS and RMS patients were grouped together as RMS, and SPMS and PPMS patients were grouped together as PMS, respectively. In terms of treatments, the patients were divided into two tiers. The first tier included patients on glatiramer acetate, one of the interferons, monthly pulsed steroids, azathioprine, and mycophenolate mofetil. The second tier were patients on natalizumab, rituximab, mitoxantrone, and cyclophosphamide. Clinical evaluations and MRIs were obtained at least annually for the duration of the study. Disability progression was assessed based on EDSS, timed 25-foot walk, nine-hole peg test, and paced serial auditory addition test. In the first two years of follow-up, patients were deemed to have met NEDA (No Evidence of Disease Activity) if they had no relapses, no clinically significant increase in EDSS, no new or enlarging T2 lesions, or gadolinium-enhancing lesions on MRI. Vitamin D levels also were measured annually in the first two years of follow-up.

Over the 10 years of follow-up, 225/471 (55.3%) patients experienced a clinically significant increase in EDSS. EDSS progression was defined as a 1.5 increase for patients with a baseline score of 0, a 1-point increase for scores between 1-5, and a 0.5-point increase for those with scores > 5 at baseline. In the RMS group, 4.7% of patients reached an EDSS of 6 at 10 years after disease onset and 16.2% after 20 years since disease onset.

Forty-six out of 407 (10.1%) RMS patients at baseline transitioned to SPMS in the 10 years. Female sex was modestly associated with a lower risk of SPMS, and a later age at onset was associated with an increased risk of SPMS. The risk of transition to SPMS was 6.4% at 10 years and 24.2% at 20 years from disease onset.

Seventy-three (17.9%) RMS patients met the criteria for NEDA in the first two years of the study. NEDA during this period did not show a statistically significant association with disability progression at year 10. When radiologic disease over the initial two-year period was examined, the development of new T2 lesions during this period was not associated with disability progression at year 10. Similarly, serum levels of vitamin D in the first two years did not show an association with disability at year 10.


The rates of transition to SPMS and disability worsening in this study are lower than the rates reported in prior natural history studies.1,2 The authors noted that after 16.8 years from disease onset, 10.7% of their patients reached an EDSS of 6, while in some natural history studies, rates as high as 50% were reported. This might point to a long-term, therapeutic benefit from disease-modifying treatment. However, one needs to keep in mind that there may be inaccuracies in the data from older natural history studies and changing inherent characteristics of the disease itself as possible explanations. The authors reported no correlation between the clinical and MRI activity during the initial two years of enrollment to disability progression at 10 years. This highlights the limitations of predicting long-term prognosis by examining a brief two-year window of the disease. Since most therapeutic clinical trials are of two-year duration, this finding exposes the drawbacks of judging long-term efficacy of therapies based on results from such short-term studies. However, the mean disease duration at baseline of patients in this study was seven years; thus, this was not a study of patients who were very early in their disease course. Hence, the lack of prognostic utility by examining a two-year window in this study does not necessarily refute studies that have tried to delineate clinical and radiologic prognostic factors early in the disease course. Lastly, 59% of the patients in this study showed clinically significant disability progression. This shows the shortcomings of our current treatment strategies in managing patients with MS.


  1. Confavreux C, Vukusic S, Moreau T, et al. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000;343:1430-1438.
  2. Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression of irreversible disability in multiple sclerosis: An amnesic process. Brain 2003;126:770-782.