Article In Brief
Advances in disease-modifying therapies (DMTs) have resulted in more children with pediatric-onset multiple sclerosis living for extended periods of time and without persistent disability. Experts share how they manage their younger patients considering the new developments in DMTs.
Patients with pediatric-onset multiple sclerosis (POMS) who take the newer disease-modifying therapies (DMTs) are living longer without developing persistent disability, according to a 30-year analysis of Italian MS patient records published in the May 3 online edition of JAMA Neurology.
In the study, a retrospective review of more than 3,000 patients over two decades, starting in 1993 and including 1,300 pediatric-onset cases, researchers found the risk of persistent disability fell by an estimated 50 percent to 70 percent since 2007, when POMS diagnostic criteria were introduced.
The new data reflect a steady increase in the use of DMTs—notably natalizumab and fingolimod—from 6 percent before 1993 to 11 percent between 1993 and 1999, and from 26 percent between 2000 and 2006 to 39 percent between 2007 and 2013.
While only 22 percent of the entire cohort started DMTs as children, the percentage increased to 53 percent in the latter time periods, noted lead author Damiano Baroncini, MD, a researcher at Gallarate Hospital's Multiple Sclerosis Center in Gallarate, Italy. The median survival times to reach an Expanded Disability Status Scale (EDSS) score of 4, indicating moderate disability, was 31.7 years; it took 40.5 years to reach an EDSS score of 6, reflecting more severe disability.
“New drugs permit an energetic approach, without too much risk for our young patients. New DMTs and changes in therapeutic approaches have led to a general improvement of MS prognosis in adults, but [until now] it was unknown whether this improvement also involves POMS, whose early management is more challenging,” Dr. Baroncini told Neurology Today.
First-line injectables were the most-used DMTs at any time, while low-potency immunosuppressor use decreased after 2000. Treatment with high-efficacy drugs gradually increased: High-potency immunosuppressors were used mainly before 1993, while second-line treatments, such as natalizumab and fingolimod, became the first choice in the later diagnosis periods. High-efficacy induction treatments such as bone marrow transplants and alemtuzumab were rarely used, the researchers found.
First-line DMTs included interferons, glatiramer acetate, dimethyl fumarate, and teriflunomide; second-line treatments included natalizumab, fingolimod, ocrelizumab, rituximab, alemtuzumab, and cladribine, and immunosuppressors. Azathioprine and methotrexate were characterized as low-potency agents, while high potency drugs included mitoxantrone and cyclophosphamide. Bone marrow transplants, alemtuzumab, and cladribine were classified as induction therapies. Adherence data were not available.
“To our knowledge, this is the largest POMS cohort that has ever been analyzed,” said Dr. Baroncini. “I think that early and prolonged use of drugs with a high anti-inflammatory potential really makes the difference. All recent research about MS treatment has demonstrated that the right way to manage MS is to treat early, and treat it hard,” he said.
Neurology Today asked several of MS experts in the US who participated, and continue to be involved in developing POMS diagnostic criteria, for their views on the study's findings, and how they treat their younger patients given the evolving DMT landscape.
“The paper directly corresponds to my 23 years of experience treating pediatric MS,” commented Lauren B. Krupp, MD, FAAN, director of the multiple sclerosis division at NYU Langone Medical Center. “Better outcomes in the current era are due to earlier and better therapy. Infusion therapies made a huge difference and, after that, fingolimod.”
MS specialist Brenda Banwell, MD, FAAN, professor and chief of neurology at Children's Hospital of Philadelphia, said that not only has treatment improved, but so has diagnosis. The oral DMTs—fingolimod, teriflunomide, and dimethyl fumarate— are approved for relapsing and remitting MS in adults in the US, she noted, but only fingolimod has been approved for children aged 10 years or older with relapsing MS. Because of this, only fingolimod is currently widely used in children, she said, although many adult treatments are being used off-label or by special FDA exception.
She told Neurology Today that many of these drugs have been safely used for some years in treating other diseases, including cancer, and appear to be just as safe and effective in POMS. Yet convincing health insurers to cover treatment remains a major barrier.
“It's unbelievable how much of my time is spent dealing with health insurers trying to obtain coverage,” Dr. Banwell said.
Still, treatment is helping younger patients live relatively normal lives without relapse and minimal need for clinical visits, she said. “When you see my pediatric patients, you wouldn't have a clue that they are any different from their peers—they're playing basketball and engaging in other normal school activities.”
Tanuja Chitnis, MD, FAAN, professor of neurology at Harvard Medical School, and director of the Pediatric Multiple Sclerosis Center at Massachusetts General Hospital, agreed that higher-efficacy DMTs are increasingly being used compared to 10 years ago. As shown in the current study, she said, higher-efficacy treatments including natalizumab, fingolimod, and rituximab are being used much more often compared with 10 to 20 years ago, when beta-interferons and glatiramer acetate were most commonly used.
“It is also important to remember that POMS is a highly inflammatory disease, so children experience two to three times as many relapses as adult patients, owing in part to the fact that they have younger, more active immune systems,” she said. “Therefore, children and adolescents with MS generally require higher-efficacy DMT.”
“Of course, this should be balanced with safety, as is suggested by recent pediatric MS clinical trials, such as PARADIGMS and TERIKIDS,” Dr. Chitnis added. [The PARADIGMS trial found fingolimod was associated with a lower relapse rate, but concluded that “longer studies are required to determine the durability and safety of fingolimod in pediatric multiple sclerosis.” TERIKIDS found teriflunomide lowered clinical relapses and the risk of 24-week sustained disability progression compared with delayed initiation of the therapy after placebo.]
She added that large observational studies are now providing well-controlled safety and efficacy data in children.
Dr. Chitnis pointed out that MS is rare in a child younger than 11 years of age, so it is important to rule out other differential diagnoses. Among these are MOG antibody associated disorder and neuromyelitis optica spectrum disorder.
“If an MS diagnosis is confirmed, then I would consider use of fingolimod, rituximab or possibly natalizumab, however at a reduced dose depending on the child's weight. Close monitoring for safety and efficacy of DMTs is important in all age groups,” Dr. Chitnis said.
Jonathan Santoro, MD, director of neuroimmunology and demyelinating disorders at Children's Hospital Los Angeles, Keck School of Medicine of the University of Southern California, said he makes treatment decisions based on each individual patient and their characteristics because hard data from quality clinical trials, while underway, have not yet been completed.
“Aside from fingolimod, there is only relatively poor, non-randomized data on the multitude of other DMTs in children,” Dr. Santoro said. “This yields an unfortunate void, where physicians often lack any algorithm for the best treatment options for patients. Choosing an appropriate treatment requires risk stratification of the disease, appropriate evaluation of medical comorbidities, and likelihood of adherence to the therapy.”
Dr. Santoro said he finds the most important factor when choosing a treatment is what is realistic for the patient. “For instance, if a patient doesn't feel confident that they will remember to take pills, then choosing options like fingolimod or dimethyl fumarate are probably not great options.
“Similarly, if a patient lives in a remote or rural area, distance is a consideration and for monthly infusions of natalizumab likely will be problematic. Ultimately, the choice of treatment is a joint one between patient, family, and physician, with the goal of finding a high efficacy treatment that will be easy for the family to use.
“Also, as my patients are younger, the risk for more accumulation of injury due to years with the disease is higher and for that reason I am much more aggressive in the treatment of disease.”
In most cases, treatment has transitioned away from the interferon class of therapies because nearly every clinical trial has shown them to be inferior from an efficacy standpoint, he continued. At the same time, earlier utilization of the newer, FDA-approved treatments has improved long-term disability outcomes in adults, highlighting the need for early and aggressive care.
“I would say that I am much more likely to use one of these [newer] treatment options as a first line therapy now than ten years ago, when the “step therapy” paradigm was still firmly in place.” [Step therapy is the so-called “fail-first” protocol in which managed care payment required clinicians try treatments that failed prior to authorizing newer medications.]
Because relapse rates in POMS are higher than in adult MS, the POMS treatment community, in general, usually opts for more aggressive treatment in children, noting that, in his view, 18 years of age is an arbitrary cutoff for differentiating pediatric disease from adult disease.
“Rather than classifying it as such, I think it is more prudent to view MS on a spectrum, with younger onset cases having a higher likelihood of more aggressive disease. As a pediatric neurologist, I think that many cases of MS likely start in the teen years, but it takes time to accumulate an inflammatory lesion in the right location to cause a clinical attack. This is why when we get our first MRI for adult-onset multiple sclerosis cases, there are multiple lesions, many of which are inactive and likely have been there for long periods of time.”