Methods: We studied
patients with primary progressive MS (n = 322) and bout-onset
progressive MS (BOPMS) including single-attack progressive
MS (n = 112) and secondary progressive MS (n =
421). The effect of relapses on time to Expanded Disability Status Scale
score of 6 was studied using multivariate Cox
regression analysis (sex, age at progression, and immunomodulation
covariates). Kaplan-Meier analysis was performed
using EDSS 6 as endpoint.
Preprogression relapses (hazard ratio [HR]: 1.63; 95% confidence
interval [CI]: 1.34–1.98), post-progression relapses (HR:
1.37; 95% CI: 1.11–1.70), female sex (HR: 1.19;
95% CI: 1.00–1.43), and progression onset after age 50 years (HR: 1.47;
CI: 1.21–1.78) were associated with shorter time
to EDSS 6. Post-progression relapses occurred in 29.5% of secondary
MS, 10.7% of single-attack progressive MS, and
3.1% of primary progressive MS. Most occurred within 5 years (91.6%)
progressive disease onset and/or before age 55
(95.2%). Immunomodulation after onset of progressive disease course (HR:
95% CI: 0.52–0.78) seemingly lengthened time to
EDSS 6 (for BOPMS with ongoing relapses) when analyzed as a dichotomous
but not as a time-dependent variable.
and post-progression relapses accelerate time to severe disability in
progressive MS. Continuing immunomodulation for
5 years after the onset of progressive disease
or until 55 years of age may be reasonable to consider in patients with
who have ongoing relapses.
Everyone included in this study come from the Mayo Clinic (USA) who fulfilled the McDonald diagnostic criteria for MS, followed up from 1992. They defined progressive disease as insidious or worsening brain, brainstem-cerebellar (outflow from the brain and the balance center of the brain, respectively), and spinal cord syndromes most frequently characterized by weakness, ataxia or bladder dysfunction of >/= 1 year.
Like studies before them, they found that relapses before progressive MS onset accelerate post-progression disability accumulation, i.e. suppressing clinical relapses matters. But more importantly, they studied the effect of relapses after onset of progressive MS. This amounts to 3% of those with primary progressive MS, 11% of those with a single attack followed by progressive MS, and 30% with secondary progressive MS. This work will hopefully alleviate or in some cases introduce doubt into the randomness of clinical prescribing of immunomodulatory therapy during the onset of progressive symptoms - very pertinent to the US.
Survival curves (proportion of people at each point) from progressive onset to EDSS 6 (dependency on unilateral support, e.g. a stick). Post-progression relapses increase the pace of post-progression disability accrual (B), and progressive MS onset 50+ years old also mildly increases the pace of post-progression disability accrual (D).
The researchers found that, although most of the disability accrual in MS had occurred by the onset of the progressive disease course, superimposed relapses further sped up the post-progression disability accumulation (Figure B, above). These post-progressive relapses typically occurred within 5 years and in those younger than 55 years. Being in the 50+ age group also mildly increased the pace of post-progression disability accumulation (Figure D, above). Moreover, they observed a protective effect of post-progression immunomodulatory medication in delaying the accrual of disability after onset of progressive MS (Figure A, below).
The effect of immunomodulation in post-progression disability accrual
So, in answer to the question when does relapsing-remitting MS stop? It would be five years after the onset of progressive disease. A logical extension of this argument would be to recommend immunomodulatory therapy into this period,where it is most effective in preventing post-progression relapses, thereby slowing post-progression disability accumulation. Or is this a logical fallacy?!