Relapses add to permanent disability in relapsing multiple sclerosis patients

OBJECTIVE: Whether relapses have direct effects on permanent disability in multiple sclerosis is still an unsettled issue. We aimed at investigating the cumulative effect of breakthrough relapses on the Expanded Disability Status Scale (EDSS) in relapsing-onset MS patients under disease modifying therapy (DMT).

METHODS: From the Danish Multiple Sclerosis Registry we identified all patients in Denmark with relapsing-onset MS who had started DMT and followed them from the first day of treatment. We included patients aged 18-59 with Kurtzke's EDSS score < 6.0 at entry, and we compared patients with and without relapses during follow-up. Endpoints were 1) annualized increase in EDSS; 2) time to 6-month sustained EDSS-worsening; 3) time to EDSS 6.0; and 4) time to increase in pyramidal- and cerebellar functional systems. Patients with and without relapses after entry were 1:1 matched by sex, EDSS, and age at entry. We analysed EDSS-worsening with adjusted Generalized Linear Models and time to the endpoints with adjusted Cox regression.

RESULTS: We included 1,428 patients with breakthrough relapses and 1,428 without. The adjusted annualized increase in EDSS was 0.179 in patients with relapses (95% CI 0.164 - 9.194) and 0.086 in patients without relapses (95% CI 0.074 - 0.097), but in patients with EDSS ≥ 4.0 at entry there was no difference. The hazard ratio for irreversible worsening of EDSS was 1.83 (95% CI 1.58 - 2.12) and for irreversible increase to EDSS 6.0 or more 1.62 (95% CI 1.25 - 2.10). Irreversible increase in pyramidal and cerebellar functional system scores also happened significantly earlier in patients with breakthrough relapses.

CONCLUSIONS: Our results indicate that breakthrough relapses under DMT is associated with increasing permanent disability in patients with EDSS < 4.0 at treatment start which calls for effective prevention of relapses.