Impact of multiple sclerosis relapses on progression diminishes with time

Abstract

Objective: The relationship between relapses and long-term disability in multiple sclerosis (MS) remains to be fully elucidated. Current literature is conflicting and focused on early relapses. We investigated the effects of relapses at different stages on disability progression.

Methods: We conducted a retrospective review of 2,477 patients with definite relapsing-onset MS followed until July 2003 in British Columbia, Canada. Time-dependent Cox proportional hazards models examined the effect of relapses at different time periods (0-5; >5-10; >10 years postonset) on time to cane (Expanded Disability Status Scale [EDSS]) and secondary progressive MS (SPMS). Findings were derived from hazard ratios with 95% confidence intervals (CIs), adjusted for sex, onset age, and symptoms.

Results: Mean follow-up was 20.6 years; 11,722 postonset relapses were recorded. An early relapse (within 5 years postonset) was associated with an increased hazard in disease progression over the short term, by 48%; 95% CI 37%-60% for EDSS 6 and 29%; 95% CI 20%-38% for SPMS. However, this substantially lessened to 10%; 95% CI 4%-16% (EDSS 6) and 2%; 95% CI -2%-7% (SPMS) after 10 years postonset. The impact of later relapses (>5-10 years postonset) also lessened over time. Effects were modulated by age, impact being greatest in younger (<25 years at onset) and least in older (>or=35 years) patients where relapses beyond 5-years postonset typically failed to reach significance. Relapses during SPMS had no measurable impact on time to EDSS 6 from SPMS.

Conclusion: Relapses within the first 5 years of disease impacted on disease progression over the short term. However, the long-term impact was minimal, either for early or later relapses. Long-term disease progression was least affected by relapses in patients with an extended disease duration (>10 years) or already in the secondary progressive phase.

Figure 1 Effect of early relapses on disease progression Kaplan-Meier curves: annualized relapse rate in the first 5 years and time to Expanded Disability Status Scale (EDSS) 6 (A); Kaplan-Meier curves: annualized relapse rate in the first 5 years and time to secondary progressive multiple sclerosis (SPMS) (B).

Figure 2 Impact of a relapse on the hazard of reaching EDSS 6 at different time points Hazard ratios were calculated from Cox regression analysis, controlling for sex, age at onset, and onset symptoms. The percentage change in hazard is relative to the risk of reaching EDSS 6 under the same conditions, but under the scenario of no relapse. *Censored patients = those who did not reach sustained EDSS 6 by the study end. MS = multiple sclerosis; EDSS = Expanded Disability Status Scale; CI = confidence interval.

Figure 3 Impact of a relapse on the hazard of reaching SPMS at different time points Hazard ratios were calculated from Cox regression analysis, controlling for sex, age at onset, and onset symptoms. *Censored patients = those who did not reach SPMS by the study end. MS = multiple sclerosis; SPMS = secondary progressive multiple sclerosis; CI = confidence interval.