Researchers pin 50%-70% drop in risk to therapeutic, management improvements over time for pediatric-onset MS

The risk of persistent disability in patients with pediatric-onset multiple sclerosis (POMS) dropped by more than half in recent decades, likely due to improvements in disease-modifying therapies (DMTs) and disease management, according to results from a retrospective study from Italy.

The increased availability of new DMTs, enhanced MS diagnostic criteria, and changes in therapeutic paradigms—such as early DMT initiation, a new definition of treatment failure, and an early shift to more powerful DMTs in patients who don’t respond to treatment—have led to improvements in the disease course for patients with MS, Damiano Baroncini, MD, of the Multiple Sclerosis Center at Gallarate Hospital in Gallarate, Italy, and colleagues explained in JAMA Neurology. However, while the risk of persistent disability is decreasing over time among adults with MS, the same trend has not previously been verified for POMS. In order to evaluate how the disease course of POMS has changed over time, Baroncini and colleagues conducted a study to assess changes in time to persistent disability among POMS patients across four consecutive diagnostic epochs.

“In POMS, the risk of persistent disability has been reduced by 50% to 70% within the past few decades, probably owing to improvement in therapeutic and managing standards,” they found. “In the coming years, an increase of approved DMTs before age 18 years and upgrades in drug safety may lead to a further improvement of prognosis in this population.”

For their retrospective, multicenter, observational study, Baroncini and colleagues extracted data from the Italian MS Registry—inclusion criteria were MS onset prior to age 18 years, confirmed MS diagnosis before January 2014, and disease duration of at least three years at last observation. Patients were excluded if they had “primary progressive or undefined MS course, crucial errors in data entry (e.g., date of onset before date of birth), Expanded Disability Status Scale (EDSS) score of at least 8 one year after the onset of disease (outliers), missing diagnosis date, and less than 2 EDSS score evaluations,” they wrote.

The primary analysis compared time to disability milestones from MS clinical onset by consecutive epochs of diagnosis, which were divided into four time periods: before 1993, 1993-1999, 2000-2006, and 2007-2013. These epochs were chosen to correspond with the approval of pivotal DMTs in Italy—interferons beta in 1996-1998; glatiramer acetate in 2002; and natalizumab in 2007. Disability milestones were EDSS score of 4.0 (impairment to walk) and 6.0 (need of a walking aid). The analysis was adjusted for eight possible confounders, three of which were linked to EDSS score detection (EDSS score evaluations per year, period of EDSS assessment, and disease duration at first EDSS evaluation) and five of which were linked to disease activity (age at onset, sex, [annualized relapse rate] ARR in the first three years, type of clinical onset, and time from onset to diagnosis).

The final study cohort consisted of 3,198 patients with POMS (mean age at onset, 15.2 years; median age at diagnosis, 22.1 years; 69% female; median time to diagnosis, 3.2 years; annualized relapse rate in first 1 and 3 years, 1.3 and 0.6, respectively), mean (SD) follow-up was 21.8 (11.7) years, and median survival times to reach EDSS scores of 4.0 and 6.0 were 31.7 and 40.5 years, respectively.

“The cumulative risk of reaching disability milestones gradually decreased over time, both for EDSS score of 4.0 (hazard ratio [HR], 0.70; 95% CI, 0.58-0.83 in 1993-1999; HR, 0.48; 95% CI, 0.38-0.60 in 2000-2006; and HR, 0.44; 95% CI, 0.32-0.59 in 2007-2013) and 6.0 (HR, 0.72; 95% CI, 0.57-0.90; HR, 0.44; 95% CI, 0.33-0.60; and HR, 0.30; 0.20-0.46),” Baroncini and colleagues found. “In later diagnosis epochs, a greater number of patients with POMS were treated with DMTs, especially high-potency drugs, that were given earlier and for a longer period. Demographic characteristics and clinical disease activity at onset did not change significantly over time.”

Due to the finding that the gradual decrease in disability risk corresponded to increased use of DMTs, as well as the fact that patients with POMS in recent diagnosis epochs started earlier and continued taking DMTs longer compared to past patients, Baroncini and colleagues concluded that the improvement of POMS prognosis “probably depends on changing therapeutic standards in MS.”

The study authors pointed out that most patients (59%) were not officially diagnosed with POMS until adult age, which they attributed to international diagnostic criteria for POMS only becoming available in 2007.

“Similarly to what has been observed in adult patients with MS, we found a gradual reduction of the risk of reaching a moderate/severe disability over time in POMS,” they wrote. “This was more evident for reaching an EDSS of at least 6, while we found a sort of slowdown for reaching EDSS of at least 4 after the year 2000. The reason for the latter result is not clear, but it has to be considered that the EDSS is not a linear measure of disability, and while step 4.0 is more influenced by functional system scores, step 6.0 is totally dependent on motor impairment, thus representing a different type of disability.”

Study limitations included lack of MRI data, lack of cognitive assessment, recall bias owing to the retrospective design, and right-censoring—and, the study authors added, “the particular design of this study cannot definitively exclude other possible causes for the reduction of disability risk, such as a general improvement in health care, clinical assessment, and other therapeutic interventions (e.g., physiotherapy).”

  1. The risk of persistent disability in patients with pediatric-onset multiple sclerosis (POMS) dropped by 50%-70% in recent decades, most likely due to improvements in disease-modifying therapies (DMTs) and disease management.

  2. Researchers hypothesized that, in the coming years, an increase of approved DMTs before age 18 years and upgrades in drug safety may lead to a further improvement of prognosis in patients with POMS.

John McKenna, Associate Editor, BreakingMED™

Baroncini received travel grants for participation at national/international congresses and compensations for consulting/speaking/scientific publications activities from Sanofi Genzyme, Teva, Merck, Biogen, Roche, Almirall, and Novartis. Coauthor Filippi is editor-in-chief of the Journal of Neurology, received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries; and still receives research support from Biogen Idec, Merck Serono, Novartis, Roche, Teva Pharmaceutical Industries, and others. Other coauthors reported relationships with Biogen, Novartis, Roche, Merck, Teva, and others.

Cat ID: 138

Topic ID: 85,138,730,36,138,192,925