Article In Brief
The distinct clinical course of disease progression for patients with pediatric-onset multiple sclerosis should be considered in pediatric treatment. Progression may be slower, a new study suggests, but early aggressive treatment could stave off disability.
Pediatric-onset multiple sclerosis (MS) has a course of progression that is distinct from that of adult-onset MS, according to an analysis of long-term data from a large Swedish registry.
“POMS [pediatric-onset multiple sclerosis] differed from adult-onset cases in several ways, including an increased diagnostic delay and relapse rate and a higher proportion of cases with relapsing-onset MS,” researchers reported in the May 15 online edition of Neurology. “While the POMS cohort took longer to reach disability milestones from their MS onset, they did so at a younger age than the AOMS [adult-onset MS] cohort.”
The findings, which align fairly closely with previous smaller studies on the clinical course of pediatric MS, provide a decades-long view of a disease that usually strikes later in life, often in early adulthood. Pediatric-onset MS accounts for anywhere from 2 to 10 percent of all MS cases, according to background in the study.
Most studies to date on pediatric MS have been small and limited to a short period of follow-up, leaving many unanswered questions about the ultimate prognosis of patients who get MS in childhood.
“Persons who develop MS early in life appear to be vulnerable to heightened inflammation and axonal loss,” the study authors said. “At the same time, their younger age may provide protection through the brain's enhanced compensatory abilities.”
Study Design, Findings
For the current study, researchers with the Karolinska Institutet in Stockholm used prospectively-collected data in the Swedish MS Registry to compare the course of pediatric-onset MS to adult-onset MS. The registry collects detailed clinical reports from all 64 neurology clinics in Sweden, capturing about 80 percent of MS cases nationwide.
The analysis included registered cases of definite MS with a disease onset between January 1, 1975 and December 31, 2014. The lengthy timeframe meant that considerable follow-up information on patients had accumulated in the registry before the study ended on April 15, 2018. Only persons with two or more Expanded Disability Status Scale (EDSS) measurements on record were included in the analysis.
“When it comes to the use of second-line therapies, I tend to be on the conservative side because these are young people with developing immune systems.”
—DR. LESLIE BENSON
In all, the study cohort totaled 12,482 patients, including 549 (4.4 percent) pediatric-onset cases and 11,933 (95.6 percent) adult-onset cases. Pediatric-onset cases were defined as those that occurred before the age of 18. For the pediatric cases, the age of onset ranged from 5 to 17 years, with most occurring in adolescence.
Most of the pediatric cases (98 percent) had a relapsing-onset disease course; only 2 percent were diagnosed with primary progressive MS, and most of the patients (94.7 percent) received a disease modifying therapy (DMT) at some point. Medications were classified as first-line (interferon-betas, glatiramer acetate, teriflunomide, and dimethyl fumarate) or second-line (daclizumab, rituximab, mitoxantrone and natalizumab).
The main goal of the analysis was to assess the risk of reaching EDSS 3-6, reflecting moderate disability though the ability to walk with unilateral support no more than 100 meters without rest. The EDSS scale ranges from 1 (no disability) to 10 (death due to MS).
The study found that pediatric-onset cases took longer to reach all three disability milestones but did so at a younger age than adult-onset patients. For instance, the median time from MS onset to EDSS 4 was 31 years for pediatric-onset patients as compared with 25 years for adult-onset patients. The median age at which pediatric- onset patients reached EDSS 4 was 47, comparted to 60 for adult-onset patients.
Pediatric-onset patients with a higher annualized relapse rate in the first five years of disease were more likely to reach all three disability milestones, while those who had a complete remission from the initial relapse were less likely to reach EDSS 3, 4, and 6. Having a progressive course of disease at onset was associated with an elevated risk of disability compared to relapsing disease.
While overall trends aligned fairly closely with previous research, the researchers noted that the median time of 31 years from pediatric onset to EDSS 4 was much better than previous reports of 10.8 to 23.8 years.
“Disease progression appears to be slower than we previously thought,” study coauthor Kyla McKay, PhD, a postdoctoral researcher at Karolinska Institutet told Neurology Today in an email.
She said the same trend has been observed in previous studies of adult-onset MS. For instance, another analysis conducted by Karolinska researchers using the Swedish registry data found that among MS patients diagnosed between 1995 and 2010 with relapsing disease at onset, the more recently diagnosed patients took longer to accrue disability. That finding, published in March in JAMA Neurology, and others suggest that new, more aggressive disease-modifying therapies may have significantly changed the course of MS for the better, but that has not been proven.
The new study hints that MS drugs may be making a difference. In a multivariate analysis of pediatric-onset cases, the researchers found that use of a second-line DMT was associated with a reduced risk of reaching EDSS 3 and 4, and they noted that “it's possible that DMT use has contributed to the extended period of time before reaching disability thresholds.”
But Dr. McKay reiterated a point made in the paper, that “this study was not designed to measure treatment effectiveness, nor the impact of interventions on disease outcomes.” Because of that, she said she could not comment “on disease management based on findings from this study.”
“At the moment we are not that great at figuring out who is going to do well and who is not. I can't say who is going to remyelinate, who can compensate, who can rewire.”
—DR. LAUREN B. KRUPP
Dr. McKay said there is still much to be learned including “the longer-term socioeconomic consequences of pediatric-onset MS, the long-term effects of disease-modifying therapy exposure in terms of safety and effectiveness, as well as risk factors for the development of MS in childhood.”
Independent MS experts interviewed by Neurology Today said the new analysis of the Swedish registry data, which was collected during a time of changes in MS care, should help enhance the understanding of the expected course of pediatric-onset MS and perhaps provide some comfort to patients and families. And for the most part, they said it supports treating these children with early, aggressive therapy.
“I think the optimistic message is that the time from the first attack to measurable disability is long,” said Brenda Banwell, MD, FAAN, chief of child neurology at The Children's Hospital of Philadelphia. At the same time, “the data show that patients with early relapses have an increased risk of disability, which emphasizes the importance of early treatment.”
Dr. Banwell, who is also professor of neurology and pediatrics at University of Pennsylvania's Perelman School of Medicine, said today's younger MS patients stand to benefit from the start from newer, more effective disease-modifying therapies and she generally favors using them as soon as a diagnosis of MS is made.
“The relapse rate in children is higher than in adults so it is even more pivotal to treat early,” she said. But she does not make light of safety considerations associated with the newer MS medications.
“I think we all use medications humbly, knowing we have to follow patients carefully,” Dr. Banwell said.
Leslie Benson, MD, assistant director of pediatric neuro-immunology at Boston Children's Hospital, said the findings from the Swedish registry raise some interesting questions that MS researchers like herself are interested in, including “why do kids recover better (from relapses) and take longer to hit EDSS landmarks.” She said kids may heal differently than adults from attacks, with their brains perhaps better able to rewire or develop work-around solutions.
When it comes to the use of second-line therapies, she said she tends “to be on the conservative side because these are young people with developing immune systems.” Dr. Benson, an instructor in neurology at Harvard Medical School, said that while the Swedish analysis suggested that second-line DMTs offered an advantage, it didn't take into consideration potential downsides of the drugs, such as infectious risks.
Emmanuelle Waubant, MD, PhD, FAAN, professor of neurology and pediatrics at University of California, San Francisco, said pediatric-onset MS “takes place during a very demanding time of life,” with challenging demands such as multitasking, and learning new material and skills in school.
She said that “cognitive problems related to MS with childhood onset can impair the ability to be successful in school and later become young adults with productive jobs.”
Dr. Waubant, director of the pediatric MS program at UCSF, said she is among the physicians who tend to treat pediatric MS aggressively early on, hoping to slow or prevent long-term impairment, and said evidence is starting to emerge from clinical trials on both the efficacy and tolerability of higher efficacy therapies in children.
She is the lead author of the International Pediatric Multiple Sclerosis Study Group's recently published consensus statement in Neurology on clinical trials for pediatric MS. While it is difficult to do phase 3 clinical trials of all new adult-approved MS drugs in pediatric patients due to the relatively small patient population and ethical concerns in case of control arms using placebo or low efficacy agents, “more needs to be done such as open-label PK/PD [pharmacodynamics] studies and registries to examine safety issues,” Dr. Waubant said.
Lauren B. Krupp, MD, FAAN, who is director of the MS Comprehensive Care Center and the Pediatric MS program at NYU Langone, said the Swedish study confirms previous research that while pediatric-onset MS patients reach significant levels of disability as their disease advances, “they will do it more gradually, they will get there more slowly than adults.”
She said what caught her eye the most in the new report was that “when they (researchers) did the regression analysis, going on a high-efficacy medicine was associated with a better outcome in the long run.” She said that suggestion supports her own tendency to favor aggressive treatment for pediatric patients.
Dr. Krupp said a conundrum that all doctors who treat MS face is that “at the moment we are not that great at figuring out who is going to do well and who is not. I can't say who is going to remyelinate, who can compensate, who can rewire.”
She said that her clinical experience has led her to believe that she'd rather over treat and assume the risk of possible a medication side effects, than leave a child at heightened risk of the life-long consequences of neurologic damage.
Dr. Benson has received funding for research unrelated to this study for a Biogen-sponsored clinical trial. Dr. Banwell has received compensation from Novartis for work as a consultant and as a central MRI reviewer, and speaker honoraria from Medscape and Novartis.