This study provides a complete account of mean/median ages at all milestone disability levels in a large well-ascertained population with a long-term follow-up. Our study redefines age as an independent and important factor contributing to disease evolution.
Age at onset of the RR phase and advancing years (current age) affect disability accumulation, independent of disease duration, largely by increasing the probability of experiencing a progressive course and by shortening the latency to progression. This is further confirmed by the lack of effect of current age on disability accumulation during the PP phase, indicating that the effect of growing older on long-term outcome in RR patients is secondary to the increased probability of converting to SPMS, while having relatively little if any effect on the evolution of the progressive phase. Similarly, older age at onset of the RR phase, independently of the number of early relapses, associated with an increased probability and a shorter latency to the progressive course and therefore significantly affected the long-term disease evolution.
The evolution of the SP phase was confirmed to be largely independent of factors preceding its onset.5,7,8
Times to DSS levels from onset of SP were similar among patients grouped according to age at disease onset, indicating that the slope of the secondary progressive phase was not much affected by age at which the RR phase started. However, the anamnestic nature of SP does not extend to the age at its onset. Patients with a worse outcome had a shorter RR phase7
and therefore entered the SP phase at younger age. Groups younger when converting to SPMS were at higher risk of developing severe disability and took significantly shorter times to attain endpoints from disease onset () but the size of this effect is seen in the small difference in ORs for DSS 6 (OR 0.96; p
= 0.03) and DSS 8 (OR 0.97; p
= 0.003). These results emphasize the key role played by the onset of the progressive phase on long-term evolution and confirm that outcome is mainly determined before becoming progressive.
However, the rate of disability accumulation during progression not only was unaffected by age at onset of RR phase but was also not influenced by age at onset of progression or by aging. PP and SP started at similar ages and their similar evolution led all patients to accumulate disability at similar ages (). Accordingly, though in mild contrast with a previous report20
(which, it must be said, had a frequency of right-censored patients exceeding 50%), Kaplan-Meier estimated times from birth to disability landmarks were not affected by type of initial disease course ().
These findings imply that the progressive phase may be the core phenotype of MS, and its probability, latency, and slope should be the essential targets of treatment and investigation. Prognosis is confirmed to be largely determined before the onset of progression and age appears to have a strong effect on the evolution of the RR phase. Elucidation of mechanisms is beyond the capacity and scope of the present study, but there are immediate implications for prognosis in all types of MS and for clinical trials design and treatment strategy. Broad age ranges (e.g., 18–55 years) being commonly recruited in clinical trials may add unanticipated variation that may weaken randomization schemes. Stratification by age, heretofore underutilized, may be advantageous, especially if the primary outcome is onset of SP. Early disease stages, especially during young ages, represent a window of opportunity for future treatments that should be focused on preventing or delaying the onset of the secondary progression, the major determinant of permanent disability development.