Scalfari et al. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain. 2010 Jul;133(Pt 7):1914-29.
Background: The relationship of relapses to long-term disability in MS is uncertain. Relapse reduction is a common therapeutic target but clinical trials have shown dissociation between relapse suppression and disability accumulation.
Methods: They therefore investigated relationships between relapses and disability progression for outcomes of requiring assistance to walk, being bedridden and dying from MS [EDSS 6, 8, 10] by analysing 28 000 patient-years of evolution in 806-bout onset MSers from the London Ontario natural history cohort. Having previously shown no effect of relapse frequency among progressive multiple sclerosis subtypes, here they examined these measures in the pre-progressive or relapsing-remitting phase. Survival was compared among groups stratified by (i) early relapses–number of attacks during the first 2 years of MS; (ii) length of first inter-attack interval; (iii) interval between onset and EDSS 3 (moderate disability); (iv) number of attacks from the third year of disease up to onset of progression; and (v) during the entire relapsing-remitting phase.
Results: Early clinical features can predict hard disability outcomes. Frequent relapses in the first 2 years and shorter first inter-attack intervals predicted shorter times to reach hard disability endpoints. Attack frequencies, in the first 2 years, of 1 versus >or=3, gave differences of 7.6, 12.8 and 20.3 years in times from disease onset to EDSS 6, 8 and 10, respectively. Time to Disability Status Scale 3 highly and independently predicted time to EDSS 6, 8 and 10. In contrast, neither total number of relapsing-remitting phase attacks nor of relapses experienced during the relapsing-remitting phase after the second year up to onset of progression showed a deleterious effect on times from disease onset, from progression onset and from EDSS 3 to these hard endpoints.
Conclusion: The failure of a regulatory mechanism tied to neurodegeneration is suggested. Relapse frequency beyond Year 2 does not appear to predict the key outcome of secondary progression or times to EDSS 6, 8 or 10, highlighting two distinct disease phases related to late outcome. These appear to be separated by a watershed within the relapsing-remitting phase, just a few years after clinical onset. Higher early relapse frequencies and shorter first inter-attack intervals herald more rapid deterioration via interaction with the neurodegeneration characterizing secondary progression. They increase the probability of its occurrence, its latency and influence–to a lesser degree–its slope. The prevention or delay of the progressive phase of the disease is implicated as a key therapeutic target in relapsing-remitting MSers.
Figure legend; survival curves of time from disease onset to EDSS 6 in MSers grouped according to:
(A) total number of relapses in Year 1 and Year 2 (1 relapse; 2 relapses; ≥3 relapses). The estimated mean time from disease onset to EDSS 6 was significantly shorter in those MSer with a larger number of attacks in Years 1 and 2: 1 relapse group = 22.7 mean years, 2 relapses group = 18.7 mean years, ≥3 relapses group = 15.1 mean years.
(B) First inter-attack interval (0–2 years; 3–5 years; ≥6 years). The estimated mean time from disease onset to EDSS 6 was significantly shorter in those MSers with a shorter interval between the first and the second attack. 0–2 years interval group = 18.2 mean years, 3–5 years interval group = 21.0 mean years, ≥6 years interval group=25.9 mean years.
(C) Time from onset to moderate disability (EDSS 3) (0–2 years; 3–7 years; ≥8 years). The estimated mean time from EDSS 3 to EDSS 6 was significantly shorter in those MSers with a shorter interval between disease onset and moderate disability (EDSS 3). 0–2 years interval group = 5.4 mean years, 3–7 years interval group = 7.4 mean years, ≥8 years interval group = 8.7 mean years.
(D) total number of relapses before the onset of progression (1–2 relapses; 3–4 relapses; ≥6 relapses). The estimated mean times from disease onset to EDSS 6 were remarkably similar in all three groups. 1–2 relapses group = 15.6 mean years, 3–4 relapses group = 15.7 mean years, ≥5 relapses group = 15.9 mean years.
“The information in this abstract should be well know to readers of this blog. In summary relapses that occur after year 2 form the first attack, don’t predict or correlate with long-term disability outcomes. Therefore suppressing relapses beyond this point may not impact in long-term clinical outcome. This is why we need to focus on DMTs that appear to impact on disability progression and/or brain atrophy the marker that we think best correlates with disease progression. I hope the data presented in the posts over the last 3 days is clear. If not I will be posting a short web lecture to explain things using simple slides.”