Leray et al. Evidence for a two-stage disability progression in multiple sclerosis. Brain. 2010 Jul;133(Pt 7):1900-13.
Background: It is well documented that disability accumulation in MS is correlated with axonal injury and that the extent of axonal injury is correlated with the degree of inflammation. However, the interdependence between focal inflammation, diffuse inflammation and neurodegeneration, and their relative contribution to clinical deficits, remains ambiguous.
Hypothesis: A hypothesis might be that early focal inflammation could be the pivotal event from which all else follows, suggesting the consideration of MS as a two-stage disease.
Objective & Methods: This prompted these investigators to define two phases in the disease course of MS by using two scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: an early phase, 'Phase 1', from MS clinical onset to irreversible EDSS 3 and a late phase, 'Phase 2', from irreversible EDSS 3 to irreversible EDSS 6. Outcome was assessed through five parameters: Phase 1 duration, age at EDSS 3, time to EDSS 6 from MS onset, Phase 2 duration and age at EDSS 6. The first three were calculated among all MSers , while the last two were computed only among MSers who had reached Disability Status Scale 3. The possible influence of early clinical markers on these outcomes was studied using Kaplan-Meier estimates and Cox models. The analysis was performed in the Rennes multiple sclerosis database (2054 MSers , accounting for 26,273 MSer-years) as a whole, and according to phenotype at onset (1609 relapsing/445 progressive onset).
Results: The results indicated that the disability progression during Phase 2 was independent of that during Phase 1. Indeed, the median Phase 2 duration was nearly identical (from 6 to 9 years) irrespective of Phase 1 duration (<3, 3 to <6, 6 to <10, 10 to <15, >or=15 years) in the whole population, and in both phenotypes.
Conclusions: In relapsing onset MS, gender, age at onset, residual deficit after the first relapse and relapses during the first 2 years of MS were found to be independent predictive factors of disability progression, but only during Phase 1. These findings demonstrate that MS disability progression follows a two-stage process, with a first stage probably dependent on focal inflammation and a second stage probably independent of current focal inflammation. This concept has obvious implications for the future therapeutic strategy in MS.
"Another natural history study demonstrating a disconnect between the initial inflammatory or relapsing stage of MS and the later or second stage that is characterised by progression. Whether this latter stage is non-inflammatory is a moot point. Several pathological studies have demonstrated active inflammation in both SPMS and PPMS. This question will be answered by several clinical trials testing more effective anti-inflammatory agents in progressive MS, i.e. natalizumab and siponimod trials in SPMS and fingolimod and ocrelizumab trials in PPMS. The corollary about whether or not suppressing relapses in early MS will prevent or delay the onset of SPMS is also being tested in clinical trials at present; i.e. the natalizumab, fingolimod and alemtuzumab extensions studies. The 21-year and 15-year long-term follow-up of the original IFN-beta-1b (Betaseron/Betaferon) and IFN-beta-1a (Avonex) trials suggests these DMTs will have an impact on long-term disability and survival. However, we need more data, in particular more data from DMTs that are more effective, in suppressing inflammatory activity before being confident about this. I think an early surrogate for long-term effects will be brain atrophy, i.e. drugs that reduce the rate of brain atrophy are the ones that will most likely to have a long-term impact on disability. As several drugs impact on this metric MSers need to remain positive and hopeful about the future."