Natural history: early relapses and progression

#MSBlog: Why do relapse on and off a DMT mean something different? We need a serious discussion on this topic!

Scalfari et al. Early relapses, onset of progression, and late outcome in multiple sclerosis. JAMA Neurol. 2013;70:214-22. doi: 10.1001/jamaneurol.2013.599.

OBJECTIVES: To investigate the relationship among attacks in the first 2 years (early relapses), secondary progression (SP), and late disability in multiple sclerosis (MS).

DESIGN: Cohort study with follow-up of 28 years.

MSers: MSers (N = 730) with relapsing-remitting MS diagnosed according to Poser criteria, from the database of the London Multiple Sclerosis Clinic, London, Ontario, Canada.

MAIN OUTCOME MEASURE: Long-term evolution of MSers with high (≥3 attacks) and early (within the first 2 years of the disease) frequency of relapses. In the total SP population and in MSers grouped by numbers of early relapses, they assessed the predictive effect of latency to progression (time to SP) on times to attain cane requirement (Disability Status Scale score of 6 [DSS 6]) and bedridden status (DSS 8).

RESULTS: Among the group with frequent early relapses (n = 158), outcomes were variable. Although 103 (65.2%) experienced rapid conversion to SPMS (median duration, 5 years) and rapidly attained DSS 6 and DSS 8 scores (7 and 17 years, respectively), the remainder (n = 55) did not enter the SP phase, despite adverse early relapse features. Among the total SP population, longer latency to progression was associated with lower probability of attaining DSS 6 (odds ratio, 0.76 [95% CI, 0.69-0.84] and 0.44 [95% CI, 0.37-0.52] for 5- and 15-year latency, respectively) and longer times to severe disability. The same association between time to onset of SP and late outcomes was observed even in MSers matched by number of early attacks. However, duration of the relapsing-remitting phase did not influence the times from SP onset to DSS levels.

CONCLUSIONS: These results indicate dissociation between early inflammatory attacks and onset of the SP phase and further question the validity of relapse frequency as a surrogate marker for late disability. Among the group with frequent early relapses, we observed a large variability of outcomes, ranging from one extreme to the opposite.

"An important study that needs confirmation. It is becoming increasingly clear that there is a dissociation between the natural history of MS off DMTs and that which occurs on a DMT. Relapses and disease activity on a DMT appear to much more sinister and predict a poor outcome compared to what occurs when MSers are not on a DMTs. Maybe the relapses and MRI activity on a DMT imply that the DMT is having no effect on the underlying cause of the disease; relapses and MRI activity are  the immune systems way of highlighting this. In comparison in MSers not on a DMT relapses, may or may not occur in response to the underlying cause, and hence have a poor predictive value in that the underlying cause continues unabated."

"This is clearly a topic for further discussion and debate."

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