NEW ORLEANS – There appear to be four clinical situations “when it might be reasonable to open up conversations with patients about discontinuation of DMTs,” Devyn Parsons said at the annual meeting of the Consortium of Multiple Sclerosis Centers.

While disease-modifying treatments (DMTs) are well established in their ability to decrease relapse rates and slow the progression of disability early in the course of relapsing-remitting MS, it remains unknown whether they maintain their efficacy late in the course of disease after many years of treatment or after progression to secondary progressive MS, said Ms. Parsons, a medical student at the University of British Columbia, Vancouver. Scientific evidence related to when disease-modifying treatments should be discontinued in patients with multiple sclerosis is generally poor, she said.

Ms Parsons and her associates set out to review the literature relevant to the discontinuation of DMTs and to provide some initial clinical recommendations on the circumstances in which discontinuation of DMTs may be a reasonable choice. The researchers assembled four clinical situations in which a discussion with patients about discontinuation of DMTs would be a reasonable option. “These are not meant to be firm guidelines, but rather more of a jumping-off point for discussion regarding this issue,” Ms. Parsons said. They include:

• Patients with secondary progressive MS who have ongoing progression and no new brain or spinal MRI lesions during the prior 12-24 months.

• Patients with stable relapsing-remitting MS aged 65 or older who have had no new brain or spinal MRI lesions during the prior 12-24 months.

• Patients with stable relapsing-remitting MS aged 55-65 years with no new brain or spinal MRI lesions within the prior 5 years.

• Patients who are pregnant or trying to conceive, or breastfeeding.

“Upon discontinuation of DMTs patients should continue to undergo annual assessments and an annual brain MRI for at least 2-5 years,” Ms. Parsons said. “Reuse of DMTs should be considered if there’s any evidence of relapse or new MRI lesion.”

The investigators conducted a systematic review of medical literature from MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews through June of 2016. They used the keywords “multiple sclerosis” and “disease-modifying treatments” and “treatment withdrawal” or “stopping medication” or “medication withdrawal.” Articles were reviewed in full and classified according to the American Academy of Neurology’s classification of evidence guidelines.

The review yielded what Ms. Parsons described as “a paucity of information” in the existing literature on MS course following discontinuation of DMTs. “There have been no randomized, controlled trials on the subject, and relatively few observational studies,” she said. “Of the observational studies that do exist, several have suggested a return to baseline disease activity following discontinuation of DMTs. In particular these studies examined natalizumab and interferon beta-1a discontinuation. At first glance these studies seem to suggest that discontinuation of DMTs is generally not appropriate, as there is likely to be a return to baseline disease activity. But it’s important to consider that many of these were retrospective, cross-sectional studies with small patient populations and aren’t the best quality data. Furthermore, these studies had relatively short follow-up periods, they didn’t include older patients, and they examined the discontinuation of DMTs after less than 2 years of continuous treatment. These results may not apply to older patients, and they might not apply to patients who have been continuously treated with DMTs for many years. At this point there is sufficient evidence in the literature to allow a randomized, controlled trial in a low-risk patient population of discontinuations of DMTs.”

Ms. Parsons discussed three observational studies from the review. One was a prospective study of 40 patients who discontinued DMTs after a minimum 5 years’ continuous use of a single DMT without new disease activity (Arquivos de Neuro-Psiquiatria 2013;71:516-20). At 46-month follow-up, the investigators found that 90% of patients remained free of clinical attack, and 85% had stable MRIs. “However, this was a really small trial, and the specific DMTs were not reported,” she said.

A larger, separate study evaluated 303 patients aged 40 and older who discontinued DMTs after a minimum of 3 years’ continuous use of a single DMT and who had no clinical relapse in the past 5 years (ECTRIMS Online Library. 2015 Oct 8. 116635). The majority of patients resumed DMT use because of an increase in disease activity following discontinuation. However, for every 10-year increase in patient age, there was a 25% decrease in the rate of resuming DMT. “This might suggest a greater feasibility of discontinuation of DMTs in older patients,” Ms. Parsons said.

The third observational study she discussed included 485 patients, mean age of 45 years, who discontinued DMTs after a minimum of 3 years of treatment with a single DMT and had no clinical relapses in the previous 5 years (J Neurol Neurosurg Psychiatry. 2016 Oct;87[10]:1133-7). These were compared with 854 propensity score–matched individuals who continued DMT. The mean annualized relapse rates and time to first relapse were similar for those who discontinued DMTs and those who continued DMTs. However, survival time to confirmed disability progression was shorter among those who discontinued DMTs (adjusted hazard ratio of 1.47; P = .001). Younger age was found to be a significant predictor of relapse risk among the DMT discontinuation group, with a 25% reduction in relapse risk ratio for every 10-year increase in age.

“DMTs cannot be said with certainty to be effective in older patients, given that patients over the age of 55 have rarely been included in clinical trials of these agents, Ms. Parsons said. Many patients with relapsing-remitting MS are continuously administered DMTs for many years. This long-term use of DMTs is not without cost. It is important to consider things like medication burden of the patient, the potential for adverse effects, as well as the possibility of unnecessary health care costs if these agents are no longer effective in some cases.”

Sanofi Genzyme supported the study. Ms. Parsons reported having no financial disclosures.

dbrunk@frontlinemedcom.com

What’s the evidence for stopping DMTs in MS patients?