Nancy Glickenhaus Pier Professor of Pediatric Neuropsychiatry, Department of Neurology, NYU Grossman School of Medicine

Lauren B. Krupp, MD

Some of the unmet needs for pediatric MS [multiple sclerosis] I think are the number of treatments available; we have 1 therapy approved by the FDA, which is great. However, it’s very important to have additional FDA-approved therapies so that we can have an armamentarium to choose from. If someone is either not able to take one therapy or is not doing well, then we can switch to another type of therapy. It’s very important to have these clinical trials, which will hopefully lead to FDA-approval of more treatments for pediatric MS. I also think another important paradigm in the treatment of pediatric MS is to start with a higher efficacy treatment. I tend to do that in my clinic rather than starting with an induction treatment or lower efficacy and seeing how things go, because we know that time is brain. If relapses do occur, that might be damage that’s long term and might have long-term effects.

Due to pediatric MS being associated with a higher relapse rate compared to adults, I believe the future is going to be geared toward getting control of relapses early and aggressively. That means using high-efficacy medications in the pediatric age group. What I’m not sure about, and what I think future research is going to need to address, is whether after disease control has been achieved, do we decrease the dose or lengthen the frequency of administration of those agents? Or, whether by starting with a high-efficacy therapy for a short period, 2 years say, good results and better safety could be achieved by de-escalating to potentially something that’s more in the moderate range with respect to efficacy. That’s one possibility. More needs to be done to improve the safety of these agents in terms of long-term use. I do believe we will get to a point where we have medications that are great at stopping the disease, halting the development of atrophy, and minimizing adverse effects, so that kids with MS, like kids without MS, can go ahead and live normal, healthy, and productive lives; they should be able to do that now. I tell parents and the kids themselves they should go out there and not be limited in terms of their interests, hobbies, activities; this is a condition that we can control very effectively now and even better in the future.

My advice for community neurologists who are treating pediatric MS is to think about the overall disease activity of that young person. Recognizing that it’s an active disease and that these patients have high relapse rates might push you toward a higher efficacy treatment. Really consider that strongly, because again, this is time that is lost if a relapse does occur; it is potentially disability down the road. If one is not fully comfortable with some of these questions or therapies, then consider working with or referring a patient to a pediatric MS center that might be able to do a consult or help with the management of this young person.

My advice for community neurologists in treating kids with MS is that if this is a patient group you’re not comfortable with, communicate with someone who sees a lot of kids. It absolutely does not mean that you need to give up the care of that patient. However, there are a lot of neurologists who specialize in pediatric MS who are eager to provide a helping hand and guidance. You don’t want to undertreat these patients. The accumulation of lesions is not a good thing in the brain of individuals with MS. Relapses are to be avoided; effective therapy is important. There’s a lot of opportunity to get help in management. There also, through the National MS Society, are programs where difficult cases can be presented. 

The National MS Society has a difficult case conference where community neurologists, pediatric neurologists and adult neurologists can present challenging MS cases or cases for which they’re not sure what the diagnosis is. They’re discussed by a group in a HIPAA privacy rule-compliant manner. So resources are out there. There are also resources for families, and it’s important to recognize that we’re all in this together with the goal of making it easier for these families.

Videos

Tanuja Chitnis, MD and Lauren B. Krupp, MD give insight into the future of pediatric multiple sclerosis by discussing unmet needs and advice for community neurologists.  

The Future of Pediatric Multiple Sclerosis 

The medications used in adults with MS [multiple sclerosis] are being examined for pediatric MS in clinical trials. There have been clinical trials done with teriflunomide and dimethyl fumarate; there have been clinical trials done with the infusions or being planned with the infusions, specifically with ocrelizumab. There are studies that are planned with other oral S1P [sphingosine-1-phosphate] modulators, such as siponimod or ozanimod. There are pediatric MS studies being planned for almost all of the therapies that are used in adults with MS.

It’s a very exciting time for pediatric MS. There are a number of therapies in development or in clinical trials for this disease. There has been a recent clinical trial of Aubagio [teriflunomide], which has just been completed. There are several clinical trials of dimethyl fumarate that are ongoing, and we should get some results from those soon. There’s also a new category of therapy that has been used extensively in adult MS, which is now being trialed in pediatric MS. These include studies for ocrelizumab as well as for ofatumumab, that will be launched. There has been a fair bit of off-label use of a cousin of those 2 drugs called rituximab, and there have been open-label studies and case series evaluating rituximab as a treatment for pediatric MS.

As I mentioned earlier, it’s very important to monitor patients regularly and to ensure that they are not having either new clinical relapses or new MRI lesions. There’s now an evolving role for biomarkers to monitor disease course both in adults and potentially in children with MS; this includes a biomarker called neurofilament light chain, which can be measured in the serum and is very accessible. We might see this or other biomarkers come to the foreground as a way to monitor treatment response and to monitor for new relapses or disease activity. That’s very exciting because then we’ll be able to really track how individual patients are doing, and ensure they are on the right therapy and be able to switch as early as possible.

Expert neurologists discuss drugs in development for pediatric multiple sclerosis and consider the potential for biomarkers to monitor treatment response or new disease activity in the future.  

Drugs and Biomarkers in Development for Pediatric MS 

One of the questions is, how do we define treatment failure? That can be defined in a variety of ways. There is certainly the way the neurologist looks at it, which is a relapse for sure is a treatment failure; new lesions may be a treatment failure, enlarging lesions may be a treatment failure. Also, an inability to either tolerate the medication or take the medication is another problem. We want to try to avoid treatment failure. The best way to do that is to closely monitor patients. When I begin a disease-modifying therapy, I make sure there’s a baseline MRI near the time the treatment is started. I like to get a follow-up MRI, generally 6 months later. After that, I tend to do brain MRIs annually. Depending on the other problems the patient may have, I will include spinal cord imaging sometimes every other year, sometimes annually depending on the circumstances. All of that is of course modulated by the financial realities of insurance, and MRI availability, and so forth. Monitoring is important in terms of making sure the disease is well controlled. One new lesion over 3 or 4 years to me is not necessarily an example of breakthrough disease. However, 3 or 4 lesions over 6 to 12 months, in my view, is a suboptimal treatment response. Some of that is controversial. What I think is clearer is that when a child has a relapse despite compliance with disease-modifying therapy, that’s something we want to avoid.

In my experience, the initial therapies to control MS [multiple sclerosis]—the injectables and the platform therapies—were suboptimal. I saw a lot of children with MS in the period between 2000 and 2010; these kids would relapse frequently on 1 interferon. We would switch them to glatiramer acetate, and they would get new lesions. Then we would switch them to another interferon, and they would relapse again; it was common for that to happen. In the paradigms study, we have numbers to show us that those on interferon beta-1a relapse at a rate of over 0.66; that means you’re having a relapse almost more than every other year while on treatment. It was not an uncommon situation. In contrast, the newer therapies are not associated with that kind of relapse rate. What was in the paradigms study, a relapse rate of 0.12, or a relapse less than once every 8 years, is much more consistent with what I consider to be the modern era and what my clinical practice would be consistent with.

Lauren B. Krupp, MD considers how treatment failure in pediatric multiple sclerosis may be defined as disease relapse, new or enlarging legions, inability to tolerate treatment, or lack of adherence. 

Defining Treatment Failure in Pediatric MS 

 The most common clinical subtype in pediatric MS [multiple sclerosis] is relapsing-remitting MS. About 95% of all pediatric patients are relapsing-remitting at onset. If I saw a patient with progressive pediatric MS, I would be very suspicious for a metabolic disorder; that’s an important differential diagnosis. Another important factor is that patients with pediatric MS have a high relapse rate; this can be 2 to 3 times as many relapses as a typical adult patient has. I take that into account when I am choosing treatments. I really look for a high efficacy treatment to reduce this high relapse rate.

 The availability of disease-modifying therapy revolutionized the treatment of MS. The first disease-modifying therapy that became available in the United States was in 1993; before that there was nothing. Children have been treated with almost all of what we would call the first-line therapies. This consists of glatiramer acetate, interferon beta-1a subq [subcutaneous] 3 times a week, interferon beta-1a IM [intramuscular] weekly, and interferon beta-1b, which is subq every other day. The interferons and glatiramer acetate have benefit in relapsing-remitting MS; all cases through observational studies to small pilot studies have been shown to lower the relapse rate in pediatric MS. Although these therapies are very safe, they do require injections, which many kids are very reluctant to do; compliance can be a challenge. What I observed when these were the only therapies we had, was that a substantial proportion of patients clearly broke through. Despite being compliant with the medication, they would have new MS relapses, and they would develop new lesions while on therapy. It’s with a great welcoming that more potent disease-modifying therapies have become available.

 In terms of acute attacks, I use glucocorticoids. They come in different forms; I tend to use methylprednisolone dosed at 20 to 30 mg/kg, up to 1 g a day. I usually administer that for 3 to 5 days in a young person who’s having an acute attack. In some patients, I give them a prednisone taper if I feel they’ve not fully resolved their attack and/or if am suspicious of another disorder. Sometimes it’s hard to tell at the first attack, therefor I will do a prednisone taper for about 4 weeks. If a patient is not responding to glucocorticoids at the time of their attack, maybe if after 3 or 4 days there’s been little to no improvement, I will consider a second-line treatment for attacks, which includes plasmapheresis.

Leaders in neurology provide insight into first-line disease-modifying therapies for relapsing-remitting multiple sclerosis, such as interferon or glatiramer acetate, and glucocorticoids for acute events.

Lauren B. Krupp, MD

Articles

The Future of Pediatric Multiple Sclerosis

Drugs and Biomarkers in Development for Pediatric MS

Defining Treatment Failure in Pediatric MS

Disease-Modifying Therapy in Relapsing-Remitting MS