Background and purpose The prevention of disability over the long term is the main
treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate
only short-term treatment effects on disability. This study aimed to define criteria
for 6-month confirmed disability progression events of MS with a high probability
of resulting in sustained long-term disability worsening. Methods In total, 14,802
6-month confirmed disability progression events were identified in 8741 patients from
the global MSBase registry. For each 6-month confirmed progression event (13,321 in
the development and 1481 in the validation cohort), a sustained progression score
was calculated based on the demographic and clinical characteristics at the time of
progression that were predictive of long-term disability worsening. The score was
externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally
(CLARITY) trial. Results The score was based on age, sex, MS phenotype, relapse activity,
disability score and its change from baseline, number of affected functional system
domains and worsening in six of the domains. In the internal validation cohort, a
61% lower chance of improvement was estimated with each unit increase in the score
(hazard ratio 0.39, 95% confidence interval 0.29-0.52; discriminatory index 0.89).
The proportions of progression events sustained at 5 years stratified by the score
were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed
for reduction of disability progression that was >88% likely to be sustained (events
with score >1.5). Conclusions Clinicodemographic characteristics of 6-month confirmed
disability progression events identify those at high risk of sustained long-term disability.
This knowledge will allow future trials to better assess the effect of therapy on
long-term disability accrual.
