Whether or not one should eventually stop a disease modifying therapy (DMT) at some point in their journey with Multiple Sclerosis (MS) is a complex and, at times, emotional decision. Often people face this decision after placing their hopes on DMTs  for well over a decade.  There is some data to help with these decisions and several larger studies underway to provide even better data. Here is what the data suggests so far:

1. People  over the age of 55 (some say 60) with secondary progressive MS (SPMS) on DMTs but no relapses or MRI activity for over 2 years may consider discontinuing DMTs, even if they have experienced continued progression 
2. One retrospective observational study of people over the age of 60 with any type of MS who were on DMTs for more than 2 years reported no increase in relapses or progression after stopping DMTs
3. One retrospective, matched case control study from a single center in Boston (CLIMB study cohort) suggested that there was no increase in relapses, progression or MRI activity in people with stable MS over age 45 who stop DMTs compared to a paired group of  patients who continued their DMTs
4. A large observation study of people with MS (MSbase cohort) over the age of 18 with no relapses for more than 5 years at the time of treatment discontinuation  showed no increased risk of relapses overall in those who stayed on DMTs compared to those who stopped DMTs after more than 3 years of follow-up. There was a higher rate of disease progression in those who stopped DMTs, which requires further controlled studies to understand better; For instance, did those patients who progressed after stopping DMTs do so because they or their doctors already knew they were progressing at the time they stopped their DMT (i.e. this was the reason they stopped) or did they progress because they were no longer taking a DMT. It should be noted that the average age of this cohort of patients was 45, and few MS specialists recommend stopping DMTs under the age of 45, which was half of their cohort.

To summarize:

1. There is little evidence that current DMTs are effective in people with progressive MS over the age of 55, if they have experienced no relapses or MRI activity for more than 2 years. There is also little evidence that stopping DMTs in this situation increases the risk of relapses or the rate of disease progression.
2. Few MS specialists would recommend discontinuing DMTs in people under the age of 45
3. There is some evidence that people with MS over the age of 60, regardless of disease type, may stop DMTs without experiencing an increase in relapses or disease progression
4. The need for DMTs (starting or stopping) should be assessed on a case by case basis in people between the ages of 45 and 60, depending on disease type, risk factors for relapses and progression and co-morbid conditions
5. There is a great need for controlled studies (i.e. where patients are randomly assigned to discontinuation or continuation of DMTs) assessing the risk and benefits of discontinuing disease modifying therapy in different groups of people with MS
   

​Revere (Rip) Kinkel MD
Professor of Clinical Neurosciences
Director of the Multiple Sclerosis Program
Clinical Neurosciences Director
University of California San Diego

“Kids are not young adults”. Perhaps you’ve heard this quote before in another context. It seems obvious to most of us from everyday experience. In medicine there are special hospitals and separate medical specialties just for kids. You would not send your child to a cardiologist, who by lack of the appropriate modifier is assumed to be an adult cardiologist; instead, we have pediatric cardiologists and other kid specialists in fields like gastroenterology, pulmonology and neurology to name just a few. 

The field of Multiple Sclerosis (MS) specialists is no exception. In 2006 the Network of Pediatric MS Centers was established through a National MS Society initiative and has subsequently expanded with further support from the NIH and the Guthrie Jackson Foundation.  The initial focus of the pediatric MS network was to facilitate the appropriate diagnosis and comprehensive care of people under the age of 18 with MS and related diseases.  This focus was justified since fewer than 5 % of people with MS experience an onset of the disease before the age of 18, misdiagnosis was commonplace and the consequences of misdiagnosis with a treatable condition like MS were large. The Pediatric MS network established separate diagnostic criteria for kids with MS allowing for earlier diagnosis and treatment, and an enhanced understanding of the age dependent clinical features of MS.  We learned that children with MS often experience a very aggressive onset, sometimes with altered mental state and seizures, followed by a high rate of relapses, but we also learned that children can recover more completely than adults in the early stages of the disease with a longer interval between symptom onset and the development of progressive disease. In fact, unlike adults, it is extremely uncommon for kids with MS to experience progressive disease from the onset of the disease.
 
The Pediatric MS Network also made it possible to organize clinical trials to determine the safety and effectiveness of disease modifying therapies (DMTs) in kids with MS.  This was important since all clinical trials undertaken to obtain regulatory approval of MS DMTs in the US specifically excluded, and still exclude, children under the age of 18.  Because of this age dependent exclusion the most effective DMTs, beginning with the approval of Tysabri in November 2004, were avoided in kids because of the lack of a specific FDA approval and the unknown risks in this vulnerable population. Without the evidence to support the safety of highly active disease modifying therapies, most kids with MS were relegated to treatment with potentially less effective and less tolerated injectable DMTs.  There were, of course, exceptions mostly in academic centers, but injectable therapies remained the mainstay of management despite evidence of poor adherence to these DMTs, particularly in kids.
 
Novartis altered this landscape with the FDA approval of Gilenya on May 11, 2018 for children with MS 10 years of age and older.  In many ways Gilenya is a natural treatment choice for kids with MS.  First and foremost, it is a once a day pill with few immediate side effects to negatively impact adherence to the treatment schedule. Most of the concerns in adults treated with Gilenya, notably the cardiac risks and the reactivation of herpetic infections like shingles, are less of a concern in kids. Yet we also knew that Gilenya and other medications in this class of drugs could potentially have adverse effects in kids that could not be anticipated based on the experience in adults. Importantly, the study was designed to compare Gilenya to Avonex, one of the more popular DMTs used as initial treatment in kids with MS. We already knew based on many years of experience that Avonex and the other injectable DMTs were relatively safe and effective in kids with MS. What we really needed to know was whether Gilenya offered greater benefits than a popular injectable DMT with an acceptable risk profile and acceptance by kids. 
 
It turns out that Gilenya is a lot more effective than Avonex in kids; 86 % of kids treated with Gilenya in the study were relapse free compared to only 46 % of kids treated with Avonex. Overall, there was an 82 % reduction in relapse rates. For kids, who tend to experience multiple relapses a year that take them away from school for prolonged periods of time, this is a very meaningful outcome. We also learned there is at least one unique risk when prescribing Gilenya in kids that can be potentially mitigated through preventative strategies.  Six of the kids (5.6 %) treated with Gilenya experienced seizures compared to only 1 of the kids (0.9 %) treated with Avonex.  This tells us that Gilenya may not be the best DMT in kids with a history of seizures or a susceptibility to seizures, particularly those not taking effective anti-seizure medications.
 
Now that Novartis has led the way with clinical trials of MS DMTs in kids with MS, other companies are following their lead with numerous clinical trials for kids with MS now in various stages of planning or recruitment. This will help us better understand the relative effectiveness and sequencing of MS DMTs in kids in the near future. But what about other vulnerable populations excluded from MS clinical trials, notably those over the age of 55?  As many of you know, all MS clinical trials exclude people over the age of 55 from participation and the average participant in MS clinical trials is approximately 37 years old. This leaves MS specialists with virtually no information on the effectiveness and safety of DMTs in older, more vulnerable population. This is a huge problem since unlike pediatric MS, which is a rare condition, people between the ages of 55 and 64 now represent the peak prevalence age group for MS. 
 
In the next blog we will begin to address the issue of MS management in older MS patients, starting with the need for specific clinical trials for people over the age of 55. Stay tuned.
 
Revere (Rip) Kinkel MD
Professor of Clinical Neurosciences
Director of the Multiple Sclerosis Program
Clinical Neurosciences Director
University of California San Diego