Long-term evolution of multiple sclerosis disability in the treatment era

Abstract

Objective: To characterize the accrual of long-term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (MRI) data used in clinical trials have long-term prognostic value.

Methods: This is a prospective study of 517 actively managed MS patients enrolled at a single center.

Results: More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit. At this last assessment, neurologic disability as measured by the Expanded Disability Status Scale (EDSS) was stable or improved compared to baseline in 41% of patients. Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first 2 years had long-term outcomes that were no different from those of the cohort as a whole. 25-OH vitamin D serum levels were inversely associated with short-term MS disease activity; however, these levels had no association with long-term disability. At a median time of 16.8 years after disease onset, 10.7% (95% confidence interval [CI] = 7.2-14%) of patients reached an EDSS ≥ 6, and 18.1% (95% CI = 13.5-22.5%) evolved from relapsing MS to secondary progressive MS (SPMS).

Interpretation: Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies. Notably, the NEDA 2-year endpoint was not a predictor of long-term stability. Finally, the data call into question the utility of annual MRI assessments as a treat-to-target approach for MS care. Ann Neurol 2016;80:499-510.

Figure 1

Increase in Expanded Disability Status Scale (EDSS) at last visit by baseline EDSS score. For the subjects who died of multiple sclerosis (MS), an EDSS score of 10 was assigned. For subjects who became disabled due to non‐MS causes, the last EDSS score was carried forward. There is 1 patient with a visit at year 10 for whom an EDSS score is missing. For the 8 subjects who died due to non‐MS causes, year 10 EDSS scores were not available. The width of the bar represents the proportion of subjects in the cohort with each baseline EDSS score. The height of the black and gray bars represents the relative proportion of subjects with worse scores (black) versus stable or improved scores (gray). PMS = progressive MS; RMS = clinically isolated syndrome and relapsing–remitting multiple sclerosis as a single group.

Figure 2

Kaplan–Meier curves for time to Expanded Disability Status Scale (EDSS) = 6 and time to transition to secondary progressive multiple sclerosis (SPMS) for clinically isolated syndrome (CIS), relapsing–remitting, and secondary progressive subjects with long‐term follow‐up who met criteria for clinically definite MS either at baseline or during the study (n = 406). Kaplan–Meier survival curves for time to EDSS = 6 (ambulatory impairment requiring a cane to walk 100m) and time to onset of secondary progressive MS (insidious deterioration of neurological function that is not relapse related) are shown. Disease duration in years is graphed on the x‐axis and the percentage of the cohort at each time point that has not met the failure events is depicted on the y‐axis. For this analysis, subjects in our cohort were limited to those meeting criteria for clinically definite MS.34 Subjects who had 1 relapse and who met International Panel criteria for dissemination over time by magnetic resonance imaging criteria at baseline (n = 19) but did not experience further clinical events over the course of follow‐up were excluded (n = 10). Similarly, CIS subjects who did not experience further clinical relapses or disease progression (n = 48) were excluded. If subjects had already met the endpoint at the time of entry into the study (ie, subjects with EDSS = 6 or subjects with SPMS at baseline), time to EDSS = 6 or time to SPMS was obtained through systematic review of medical records and a standardized questionnaire administered to all subjects at study entry. CI = confidence interval.