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Treatment of relapsing progressive MS may reduce disability progression

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Results begin to answer questions about inflammation in progressive MS

This study is important because it addresses an area of controversy in management of patients with a progressive multiple sclerosis (MS) phenotype. The role of superimposed relapses in patients with progressive MS has long been debated, with some studies reporting no impact on long-term disability accrual and other reporting a negative impact of relapses. Treatment of progressive MS remains controversial as well, with only one therapy approved by the Food and Drug Administration for any form of progressive MS. There is considerable ongoing debate about whether MS disease-modifying therapies (MSDMT) are effective in progressive forms of MS, and whether clinical or MRI evidence of active inflammation predicts a better chance of response.

Dr. Jonathan L. Carter

Dr. Jonathan L. Carter

The article by Hughes et al. attempted to answer some of these questions through the use of the MSBase database, which is a multicenter, multinational, observational cohort study that provides a large patient population for study using standardized methodologies. The study included almost 1,500 patients with either primary progressive MS (PPMS) or progressive relapsing MS (PRMS) who had at least three visits with disability status (EDSS) recorded, with at least 3 months between the second and last visit. Median prospective follow-up in this cohort was 5 years, which is important given the generally slow rate of progression in this patient population. Patients with PRMS were younger and less disabled at baseline than were those with PPMS, and the cumulative hazard of confirmed disability progression was slightly lower (hazard ratio, 0.86; 95% CI, 0.78-0.96; P = .005). Multivariate analysis showed a slightly lower disability progression risk in patients with PRMS who were on MSDMT for longer periods of time, but this was not seen in PPMS patients. Male sex and higher EDSS score at baseline were poorer prognostic factors in both groups.

This study has several important strengths and limitations. The large sample size allowed statistical power to detect relatively small differences in disability progression risk between progressive MS subtypes. The better prognosis in progressive patients with superimposed relapses contradicts some earlier studies that suggested a worse prognosis or no difference in prognosis between progressive patients with and without relapses. This study also supports a role for MSDMT in progressive MS patients, at least those with clinical evidence of relapses, and possibly MRI evidence of inflammatory disease activity (although this was not specifically addressed in the current study). Limitations of the study include the observational nature of the database, variable periods of follow-up, lack of objective verification of recorded relapses either with EDSS scores or MRI confirmation, and lack of an untreated control group. Therefore, no conclusions can be drawn as to whether MSDMT exposure had a favorable impact on the whole cohort of progressive patients versus no treatment.

Jonathan L. Carter, MD , is an MS specialist at the Mayo Clinic in Scottsdale, Ariz. He had no relevant disclosures to report.



Superimposed relapses were associated with a significantly reduced risk of disability progression in a longitudinal, prospective cohort study of 1,419 multiple sclerosis patients (MS) of the progressive-onset type.

Multiple sclerosis is written on the screen of a tablet. HUNG KUO CHUN/Thinkstock
“Progressive-onset MS with and without superimposed relapse is associated with a reduced time to irreversible disability milestones; however, there is limited research to date identifying factors that contribute to this disability accrual,” wrote Jordana Hughes, MD, of the University of Melbourne, and her colleagues.

To determine the role of inflammatory relapses on disability in the progressive-relapsing phenotype of progressive-onset MS, the researchers collected data from MSBase, an international, observational cohort of MS patients, from January 1995 to February 2017. The study population included 1,419 adults with MS (553 in the relapse subgroup, 866 in a nonrelapse subgroup) from 83 centers in 28 countries; the median prospective follow-up period was 5 years. The patients included in the analysis had adult-onset disease, at least three clinic visits with Expanded Disability Status Scale (EDSS) score recorded, and a time frame of more than 3 months between the second and last visit.

Overall, patients with relapses had significantly less risk of disability progression after adjusting for confounding variables (adjusted hazard ratio, 0.83; 95% confidence interval, 0.74-0.94; P = .003). Disease progression was defined as worsening of the EDSS score.

In addition, the researchers examined the data in a stratified model and found a 4% relative decrease in the hazard of confirmed disability progression events for each 10% increment of follow-up time for receiving disease-modifying therapy (DMT). However, DMT did not reduce disease progression risk in progressive-onset MS patients without relapse.

“This suggests that relapses in progressive-onset MS, as a clinical correlate of episodic inflammatory activity, represent a positive prognostic marker and provide an opportunity to improve disease outcomes through prevention of relapse-related disability accrual,” the researchers wrote.

Interferon-beta was the most common DMT, given to 73% of the relapse patients and 56% of the nonrelapse patients, followed by glatiramer acetate (20% and 13%, respectively), and fingolimod (12% and 16%, respectively).

The study’s main limitation was the use of the EDSS as a measure of disability, as well as the absence of quantifiable disability change to confirm relapse, the researchers noted. However, “these findings provide further evidence for a progressive-onset MS phenotype with acute episodic inflammatory changes, thereby identifying patients who may respond to existing immunotherapies.”

The study was supported by grants from the National Health and Medical Research Council of Australia and the MSBase Foundation, a nonprofit organization that itself receives support from multiple companies, including Merck, Novartis, and Sanofi. Dr. Hughes had no financial conflicts to disclose, but most coauthors disclosed relationships with multiple companies including Merck, Novartis, Sanofi. Genzyme, and Biogen.

SOURCE: Hughes J et al. JAMA Neurol. 2018 Aug 6. doi: 10.1001/jamaneurol.2018.2109.

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