Medicine & Research

In 1993, the first disease-modifying therapies gained U.S. Food and Drug Administration approval for the treatment of multiple sclerosis. Since then, DMTs have revolutionized the treatment of MS and improved outcomes for people with the condition. DMTs have shown to decrease severity and frequency of relapses, and, in some instances, slow the progression of the disease.

But there is an open question about when it’s appropriate to stop treatment. At what age and under what conditions should treatment be discontinued? There are several subtypes of MS – including relapsing remitting multiple sclerosis, progressive MS, and clinically isolated syndromes – and people with these different subtypes need different approaches to treatment. This article will address available evidence regarding when to stop DMTs in these subtypes.

Relapsing-remitting

According to the 2018 American Academy of Neurology guidelines, no randomized clinical trials directly addressed discontinuing DMTs in patients with RRMS who showed no evidence of relapse or disability progression, or had a stable MRI findings. According to the guidelines, when discontinuing DMTs in patients with stable relapsing-remitting MS, monitoring from a MS specialist neurologist is still necessary since subclinical disease activity and relapses of disease can occur.

In a randomized control trial of 175 patients with RRMS receiving natalizumab who had not experienced a relapse in the past year and had no new lesions present on MRI, relapses occurred in 4 percent of patients that remained on therapy. Relapses occurred in 15-29 percent of patients that stopped or switched therapy. One observational study examined patients who did and did not stop DMT therapy after being relapse-free for at least five years.

The study found similar risk of relapse between both groups but saw an increased risk of disease progression in patients who stopped DMTs. In this observational study, younger age (younger than 55 years old) and lower Expanded Disability Status Score scores were significant predictors of relapse following the discontinuation of DMTs. It must be noted that there are no current biomarkers for medication efficacy that can guide the patient and physician in determining how and when to discontinue therapy. Patients and physicians should collaborate when discussing if, and when, to discontinue therapy.

Progressive MS

For patients with progressive disease, a search of the published biomedical literature revealed no randomized control trials addressing how and when to discontinue therapy. In patients younger than 55 years old, there was a higher chance of relapses when DMTs were discontinued. In many instances, relapses were linked to more rapid disease progression.

Researchers found that patients with progressive disease who discontinued DMTs for two years and had an EDSS score of six or greater had a 50 percent lower risk of relapse following therapy discontinuation. AAN guidelines suggest clinicians may consider discontinuing DMTs in non-ambulatory patients (EDSS scores, greater than seven) who have had no active relapses for the past two years.

Clinically Isolated Syndrome

In patients with CIS, DMTs may delay the progression of MS onset. However, not all patients with CIS will develop MS. Younger patients with CIS have been shown to have a higher risk of relapse. Therefore, caution should be exercised when deciding to discontinue therapy. AAN Guidelines from 2018 advise for more research to be done regarding highly active DMTs in the use of CIS.

According to Dr. Ben Thrower, director of the MS Institute at Shepherd Center, “Ultimately, the decision to stop DMTs should be a shared conversation between patients and physicians.” Dr. Thrower went on to explain that no two patients with MS are alike and because patients with RRMS, progressive MS, and CIS have different rates of disease progression, close monitoring before and after discontinuation is recommended.

Additionally, RRMS, progressive MS, and CIS have different responses to immunomodulating agents, and it is necessary to ensure there is no risk when deciding to stop DMTs. The link between age and relapses has been studied in numerous trials. Some data suggests relapses decrease with age; whereas other data suggests age does not affect relapse rates.

• A study conducted by the Cleveland Clinic examined the need for DMTs in patients older than 60. This age group is of particular significance because of the likelihood of patients having comorbidities and a declining immune system. Their finding suggested that discontinuation of DMTs were more successful when age was considered and not just stability of disease state. Researchers found the discontinuation of DMTs was primarily initiated by the physician due to a lack of benefits and side effects.

• A study in Current Opinions in Neurology found relapse rates decreased by 17 percent every five years of age. Patients with disease onset of greater than 40 years experienced more decreases in relapse rates as they aged. According to the authors, this is especially true for the immunomodulating DMTs (e.g., interferons, Copaxone).

• A 2022 article published by the Journal of Multiple Sclerosis and Related Disorders suggested that discontinuation of DMTs was linked to disease progression, regardless of age and prior stability of disease. A retrospective study of patients from the New York State MS Consortium saw that patients who experienced disability worsening or progression prior to the discontinuation of DMT experienced less disability worsening or progression after discontinuation when compared to stable patients with no disability worsening or progression prior to discontinuation. Researchers found that RRMS and SPMS patients who were previously stable experienced new disability worsening or progression following the discontinuation of DMTs.