When does releapsing-remitting MS stop?

Relapses and disability accumulation in progressive multiple sclerosis

M. Mateo Paz Soldán, MD, PhD, Martina Novotna, MD,Nuhad Abou Zeid, MD, Nilufer Kale, MD, Melih Tutuncu, MD, Daniel J. Crusan, Elizabeth J. Atkinson, Aksel Siva, MD, B. Mark Keegan, MD, Istvan Pirko, MD, Sean J. Pittock, MD, Claudia F. Lucchinetti, MD,Brian G. Weinshenker, MD, Moses Rodriguez, MD and Orhun H. Kantarci, MD Neurology vol. 84 no. 1 81-88 

Objective: We examined the effect of relapses—before and after progression onset—on the rate of post-progression disability accrual in a progressive multiple sclerosis (MS) cohort. 

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 (EDSS) score of 6 was studied using multivariate Cox regression analysis (sex, age at progression, and immunomodulation modeled as covariates). Kaplan-Meier analysis was performed using EDSS 6 as endpoint. 

Results: 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; 95% CI: 1.21–1.78) were associated with shorter time to EDSS 6. Post-progression relapses occurred in 29.5% of secondary progressive MS, 10.7% of single-attack progressive MS, and 3.1% of primary progressive MS. Most occurred within 5 years (91.6%) after progressive disease onset and/or before age 55 (95.2%). Immunomodulation after onset of progressive disease course (HR: 0.64; 95% CI: 0.52–0.78) seemingly lengthened time to EDSS 6 (for BOPMS with ongoing relapses) when analyzed as a dichotomous variable, but not as a time-dependent variable. 

Conclusions: Pre- 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 BOPMS 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?!

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