As the treatment of multiple sclerosis continues to evolve and improve, the proposition of lifetime therapy has come under scrutiny.
Robert Bermel, MD
Treatment of multiple sclerosis (MS) has reached a new milestone, in which discontinuation of therapy for some patients may be possible. This is a unique therapeutic situation, a crossroads of the benefits of long-term treatment with disease-modifying therapies (DMTs) in preventing progression of disability and a point when the disease course naturally wanes. In theory, if patients with MS can maintain function long enough, they will outlive the active period of the disease and no longer need therapy.
Since their introduction in the 1990s, DMTs have demonstrated significant efficacy in reducing the incidence of relapses and the appearance of new T2 lesions indicative of disease activity in MS, as well as the capacity to slow progression of disability.1,2 Perhaps one of the most significant clinical realizations recently is that DMTs are most effective in slowing progression of MS when they are initiated in the disease’s earliest preclinical stages, at the first sign of clinically isolated syndrome.1,2 Results of research have shown that aggressive treatment at the time of the first attack with drugs such as interferon beta, glatiramer acetate, and terifluno-mide can delay conversion to clinically definite MS and lead to a milder course of disease that preserves patient function longer.1
The notion of being able to “retire” from a costly, long-term therapy associated with adverse effects and the risk of life-threatening infections holds great appeal to many patients who have for decades faced the effects of MS and its treatments. “It’s all rooted in the idea that the window of opportunity for most effectively treating MS is early on in the disease,” Robert Bermel, MD, director of the Mellen Center for Multiple Sclerosis at Cleveland Clinic in Ohio, told NeurologyLive®. “Additionally, there’s been some research showing that not only are the DMTs less effective the older people are, but the disease is less active the older people are.” Taken together, he said, these factors suggest that continued lifelong therapy may not be necessary or even bene-ficial, but determining which patients will remain disease free after discontinuation has been a major obstacle to implementing a general plan for stopping MS treatment.
As the efficacy of DMTs has allowed patients to achieve and main-tain very low levels of disease activity, the question of whether these benefits would continue even with cessation of drug therapy has become increasingly relevant. According to Tanuja Chitnis, MD, an MS neurologist at Brigham and Women’s Hospital and Massachusetts General Hospital, and professor of neurology at Harvard Medical School, both in Boston, Massachusetts, “We’re entering an era where we have more patients who have been on DMTs long term and have been doing well, so we have a unique situation now.” Unfortunately, previous studies of interruption of DMTs focused on patients with ongoing disease activity who were nonadherent or who could not tolerate their therapies at earlier disease stages. Data on the outcomes after deliberate, medically endorsed discontinuation of DMTs in patients with stable disease are still largely lacking.
Bermel and his colleagues at Cleveland Clinic have been increasingly introducing patients who have been on long-term therapy to the concept of discontinuation. “We do believe that at some point, it’s appropriate to consider discontinuing DMT. We usually require that the person [has] been stable for 5 years or more, with no relapses and no new MRI [magnetic resonance imaging] activity,” he said.
Chitnis, who is also the director of the Partners Pediatric MS Center at Massachusetts General Hospital for Children in Boston, takes a more conservative approach—at least for now. “There were some early studies, including ours,2 that suggested that there might be some patients for whom it might be safe to discontinue treatments,” she told NeurologyLive®, “but I think we are finding now in our further work, as we and others are looking into our cohorts of patients who have discontinued, that some patients continue to have disease activity. So I think we need to have better indicators, such as maybe biomarkers or biological mechanisms, to identify who might be safely discontinued.”
Early treatment with DMTs significantly modifies the natural course of MS. Tobin and Weinshenker2 noted “prolonged periods of disease quiescence during long term treatment of patients with clinically isolated syndrome,” suggesting the opportunity for discontinuing DMTs in these patients. However, the risks of relapse and accumulating disability associated with premature discontinuation of therapy were too high to ignore.2 This illuminated the second challenge, that if patients might indeed no longer need therapy for active MS, at what age could they safely discontinue treatment without reactivating disease?
The answer is not yet apparent. Chitnis was coauthor of a 2019 study by Yano et al3 that found a similar clinical course after 2 years among patients with relapsing-remitting MS who discontinued treatment compared with those who remained on therapy. This pattern was consistent across measures of clinical relapse, MRI event, disability progression, and disease activity, although the results varied by age at the time of discontinuation. “Older subjects (age >45) had a better disease course after discontinuation in terms of risk of MRI event and disease activity, while younger subjects (age ≤45) were more likely to experience disease activity after treat-ment cessation,”3 the authors reported. Likewise, Kister et al4 found that although relapse rates were equivalent between patients with MS (age >18) who discontinued first-line DMTs and with those who continued, time to disability progression was shorter following discontinuation.3,4
Although these studies did not look specifically at outcomes in older patients who discontinued treatment, they did suggest that cessation at a late stage of MS was less likely to result in relapse or renewed activity on MRI. Supporting this, a 2019 investigation by Hua et al5 found that stopping DMTs in patients with MS over age 60 had only a minimal effect on outcomes, yet quality of life (QoL) was reduced. Studies suggest that older patients make better candidates for cessation because they have a more stable course of disease, whereas younger patients are more likely to discontinue therapy on their own.6 Bermel observed that as a result, the strategy of discontinuing DMTs after a certain age is becoming more common.
"We do believe that at some point, it's appropriate to consider discontinuing DMT. We usually require that the person [has] been stable for 5 years or more, with no relapses and no new MRI activity," Bermel said.
Bermel and Chitnis both observe similar guidelines for discon-tinuation as those outlined by Tobin and Weinshenker,2 who determined, “It may be reasonable to stop immunomodulatory medications in patients who have experienced a progressive disease course for 5 years or longer, particularly those who are over the age of 60 years, if there are no accumulating T2 lesions or gadolinium enhancing lesions on MRI brain or spinal cord after a period of observation of several years. Earlier discontinuation, particularly in patients with active disease, may lead to increased disease activity, especially in patients treated with natalizumab. Clinical and MRI monitoring for recurrent disease activity is warranted in those discontinuing treatment.”
Continuation of immunomodulating therapy in older patients is associated with increased risk of infection and a higher susceptibility to malignancy, as well as a greater potential for drug inter-actions.1,7,8 Because it is now common for patients to have been on DMTs for decades, concerns are growing over the adverse effects of these powerful drugs. Adverse events range from non—life-threatening events such as flulike symptoms and local injection site reactions to dangerous infections like progressive multifocal leuko-encephalopathy associated with several DMTs.3
"The primary risk to discontinuing is that the patient would have a relapse that would otherwise have been prevented, but we think we can minimize that risk by selecting patients who have been stable for 5 or more years and also who are above age 60, when the immune system becomes more senescent and they are less prone to disease activity,” Bermel said. “The other reason to consider stopping DMTs is [adverse] effects. Interferon is one of the medica-tions that may be worsening spasticity or depression that can make the patient’s quality of life worse, and in that setting, we definitely want to think about at least switching, if not stopping, DMTs.”
Chitnis agreed with the idea of switching therapies. Deciding not to discontinue does not necessarily mean that patients continue on the same therapy, she said. “I think there’s also the concept with older age of immunosenescence, and patients may not need to be on a stronger DMT, as there’s a lesser likelihood of relapse or developing new lesions, which presents an opportunity to either discontinue or step down to a milder therapy,” she said. “That is something I am increasingly considering doing. As patients who are on very high-efficacy treatments are nearing 50 or 60, I start to have the conversation about paring down to something that is milder. Although there are fewer relapses in older age, we know that patients do progress, and there might be benefits to a different profile of DMTs.”
As their base of patients with MS on aggressive drug therapies grows older, clinicians have been weighing the idea of discontinuing DMTs without reaching any definitive conclusions. Chitnis reserved judgment on whether DMT discontinuation is warranted. “I rarely discontinue patients,” she said, noting that they some-times bring up the idea of discontinuing because they might have seen an article on the topic. She will also discuss it with patients over 60, by letting them know this is something being studied and considered. “There are some I will discontinue, if I think based on the literature that they might be a good candidate, especially if they are having difficulty with their disease-modifying treatment, but usually at an older age above 60, at about 70,” she added.
Currently, no protocol exists for how or when to discontinue DMTs. The decision comes down to patient preference and clinical judgment. And although most patients are likely to look forward to not having to take medication (especially by injection) for the rest of their lives, Bermel has had some patients who prefer to remain on treatment, even in the absence of disease activity on MRI. “People who are stable on medication sometimes attribute that to being on the medication, and they’re not comfortable making a change. They feel protected and choose to stay on to avoid risk of relapse,” he said. “The only time we truly object to that is if the patient is having infectious complications or [adverse] effects of the drug, where I feel they would benefit by going off. But if the patient is tolerating it well, it’s perfectly fine for them to continue.”
Bermel reported that Cleveland Clinic has been successfully discontinuing DMTs in older patients in routine clinical practice for at least the past 5 years. “Discontinuation is not for everyone,” he said, “and it’s not across the board but in patients who have been very stable for 5 years or more, and where we consider the risk of the disease activity returning is low, we certainly consider it and may suggest that people discontinue after the age of 60.”