AT THE AAN 2016 ANNUAL MEETING
VANCOUVER (FRONTLINE MEDICAL NEWS) – Certain patient and disease characteristics may help guide decisions about starting and stopping therapy in progressive multiple sclerosis, according to a pair of longitudinal cohort studies reported at the annual meeting of the American Academy of Neurology.
In a cohort of patients transitioning from relapsing-remitting to progressive multiple sclerosis (MS), the age at onset of progression predicted the likelihood of subsequent relapses. The absolute lifetime risk ranged from 18% for patients younger than 35 years at the time to just 5% for those aged 55 years or older at the time.
And in a cohort of patients with secondary progressive MS, the annual rate of clinical relapse fell in the third year after immunomodulator discontinuation. Overall, 35% had a clinical relapse or radiologic disease activity. Patients had a lower risk of this outcome if they had greater disability at the time of discontinuation or if they had not had any radiologic disease activity in the antecedent years.
“These studies address a very important question, because not many people talk about stopping drugs,” commented session comoderator Helen Tremlett, Ph.D., of the division of neurology at the University of British Columbia, Vancouver, and the Canada Research Chair in Neuroepidemiology and Multiple Sclerosis. “I would like to see some of these findings validated in other cohorts. But I did like the questions they are asking.”
Age, risk of postprogression relapse
The first study focused on ongoing relapses in patients transitioning to progressive MS. “We have recently shown that these relapses indeed matter. People who continue to relapse after progressive MS onset develop a need for a cane 2 years earlier than those who don’t” continue to have relapses, explained senior author Dr. Orhun H. Kantarci of the department of neurology at the Mayo Clinic in Rochester, Minn. Therefore, continuation or initiation of disease-modifying drugs (DMDs) during this period of overlap may be beneficial.
He and his colleagues followed 946 patients with MS from a clinic- and population-based cohort, assessing the age at various disease landmarks.
Results showed the mean age at first relapse was 33 years, the mean age at the onset of progressive MS was 45 years, and the mean age at last relapse (whether it occurred before or after the onset of progressive disease) was 43 years.
The 95% overlap age range for age at first relapse and age at onset of progressive MS was 27-46 years, Dr. Kantarci reported. Therefore, DMDs would be expected to have a some impact during those years.
Further analyses showed that if the age of progressive MS onset was before 35 years, 35-44 years, 45-54 years, and 55 years or older, the absolute lifetime risk of relapse after progressive MS onset was 18%, 17%, 13%, and 5%, respectively. The corresponding last predicted relapse for these groups was before age 50, age 60, age 70, and age 70.
Taken together, the data suggest that in patients transitioning to progressive MS, initiation or continuation of a DMD is most likely to be beneficial if the patient is younger than 35, with some benefit, albeit less, up to the age of 54, according to Dr. Kantarci.
“But above 55, if a person has never been on a DMD, it is unlikely to be recommended, because I don’t expect it to do anything from the data we have,” he said. Furthermore, “DMD stopping can be offered to these patients. If a person is on a DMD and they are asking, ‘Can I stop it? I have been stable,’ and they are above age 55, it can be considered.”
The investigators are performing additional analyses of the data to assess the impact of DMDs on disease course, including the influence of initial and maintenance treatment choices, and factors that prompt physicians to switch treatments.
“What we haven’t done and will not be possible with this data … the most interesting question is the impact of subclinical MRI disease, which is a different question,” Dr. Kantarci concluded. “And ultimately, we will have to have an actual stopping experiment and [assess] outcomes, which is an ongoing major planned effort.”
Outcomes after stopping immunomodulators
The second study assessed clinical and radiologic outcomes after discontinuation of immunomodulatory therapy in patients with secondary progressive MS.
“We have more and more patients [with secondary progressive disease] treated for several years, yet the natural history of the disease is less and less relapse, and progression of disability,” commented first author Dr. Julien Bonenfant, a neurologist at the Rennes University Hospital in France. Thus, the benefit of continuing treatment is unclear, especially given its cost and side effects.
He and his colleagues studied 106 consecutive patients with secondary progressive MS who had been on immunomodulators for at least 6 months, were taken off the immunomodulators, and were followed for a mean of 5 years.
Results showed that 16% of the patients had a clinical relapse after discontinuation, nearly all within the first 3 years. The annualized rate of clinical relapse actually fell from 0.13 in the 3 years before discontinuation to 0.07 in the 3 years afterward.
Overall, 35% of patients had either a clinical relapse and/or new contrast enhancement on MRI. Again, most of these events occurred within the first 3 years of discontinuation.
Patients had a lower risk of this outcome after treatment discontinuation if they had an Expanded Disability Status Scale ( EDSS ) score of 6 or greater at the time of discontinuation (hazard ratio, 0.4) and if they had not had any gadolinium enhancement on MRI in the 3 years before treatment discontinuation (HR, 0.4).
“Disease activity remained low after treatment withdrawal. We found no rebound of relapse rate in our population,” Dr. Bonenfant summarized. “There was no consequence on the slope of disability progression,” nor on the finding of enhancement on MRI alone.
Thirty patients were restarted on immunomodulators, about half of them solely because of MRI findings, he noted. This raises “the controversial question, is it relevant or not to resume treatment in these patients?”
“This study suggests that immunomodulatory treatment withdrawal seems reasonable for patients with advanced secondary progressive MS, especially with an EDSS of 6 or greater and no focal inflammatory disease [clinical or radiologic] at least in the past 3 years,” Dr. Bonenfant maintained. “It shows the importance of MRI monitoring to define the patients who are still in a focal immunoreactive state.”
“The results are far from being definitive, and further prospective studies are needed to provide evidence-based recommendations for clinical practice,” he concluded.
Dr. Kantarci disclosed that he has given scientific presentations at meetings supported by Novartis Pharmaceuticals and has presented as an invited speaker for Biogen but has received no personal compensation from either company. Dr. Bonenfant disclosed that he had no relevant conflicts of interest.
