Assessment of definitions of sustained disease progression in relapsing-remitting multiple sclerosis

Abstract

Sustained progression on the expanded disability status scale (EDSS) is a common outcome measure of disease progression in clinical studies of MS. Unfortunately, this outcome may not accurately measure long-term and irreversible disease progression. To assess the performance of definitions of sustained progression, patients with relapsing-remitting MS (RRMS) or a clinically isolated syndrome with evidence of lesions on a brain MRI were included in our study. Fifteen definitions of sustained progression using both the EDSS and the functional system (FS) scales were investigated. The impact of both relapses and changes in provider on the probability of maintaining progression was also evaluated. Although the provider scoring the EDSS sometimes changed during followup, the provider had access to previous EDSS scores. Between 15.8% and 42.2% of patients experienced sustained progression based on the definitions using EDSS as the outcome, but nearly 50% of these patients failed to maintain sustained progression for the duration of followup. When FS scales were used, progression was most common on the pyramidal and sensory scales. Unfortunately, progression on specific FS scales failed to be more sensitive to irreversible disability. Relapses or changes in provider did not explain the poor performance of the measures. Short-term changes in the EDSS or FS scores may not be an accurate marker of irreversible change in RRMS.

Figure 1

Flow chart for selection of patients included in study.

Figure 2

Time to sustained progression for EDSS definitions. EDSS: expanded disability status scale. Each Kaplan-Meier plot presents the time to sustained progression using a specific definition: (a) top left: increase of 0.5 on the EDSS sustained for two visits (D1); (b) top right: increase of 1 on the EDSS sustained for two visits (D2); (c) bottom left: increase of 1.5 on the EDSS sustained for two visits (D3); (d) bottom right: increase of 1.5 for baseline EDSS  =  0 and increase of 1 for baseline EDSS ≥ 1 sustained for two visits (D4).

Figure 3

Time to sustained progression for functional system score definitions. Each graph represents a different definition of sustained progression: top row (from left to right)—increase on pyramidal subscale (D5), increase on cerebellar subscale (D6), increase on brainstem subscale (D7), increase on sensory subscale (D8); middle row (from left to right)—increase on bowel-bladder subscale (D9), increase on mental subscale (D10), increase on visual subscale (D11), increase on any subscale (D12); bottom row (from left to right)—increase in first subscale (D13), increase of 2 in the sum of the subscales (D14), increase of 3 in the sum of the subscales (D15).

Figure 4

Time to sustained progression stratified by baseline EDSS value. Colors of Kaplan-Meier curve are based on baseline EDSS value: EDSS  =  0: red, EDSS  =  1/1.5: orange, EDSS   =  2/2.5: green, EDSS  =  3/3.5: blue, EDSS  =  4–5.5: black. Progression definition for each plot: (a) D1, (b) D2, (c) D3, and (d) D4.

Figure 5

Time to sustained progression stratified by baseline functional system score value. Colors indicate baseline functional system score: score  =  0: red, score  =   1: orange, score =  2: green, score  =  3: blue, score ≥  4: purple. Progression definition for each plot: top row: D5 to D8; bottom row: D9 to D11.