The pros and cons of discontinuing disease-modifying therapies in multiple sclerosis.
Neurology Times spoke with Dr John Corboy, Professor and Vice Chair of Faculty and Clinical Affairs; Co-Director, Rocky Mountain MS Center at the University of Colorado, Department of Neurology, University of Colorado School of Medicine, Aurora, CO.
Neurology Times (NT): What makes a patient who has multiple sclerosis (MS) a good candidate for medication discontinuation?
Dr Corboy: The real answer is we do yet not know. Data that do exist that suggest several things.
Clinically and on MRI scans we’ve seen that as people age they have less risk of new inflammatory disease activity. Moreover, patients with MS who die at an older age have very few, if any, active inflammatory lesions. All of these findings suggest that there is a general reduction in new inflammatory activity with aging.
When subgroup analyses of major clinical trials have been done, they nearly all show that the greatest benefit is seen in younger patients, or, in reverse, little if any effect is seen in older patients. This may account for the mostly negative progressive MS studies, which are made up of patients who are on average about 10 to 15 years older than those in relapsing MS studies. Indeed, all the relapsing MS studies, and many of the progressive MS studies, have used an age cutoff of 55. Thus, one could argue there are no data that support the use of any of the presently approved disease modifying therapies (DMTs) in people over 55.
The small number of discontinuation studies suffer from a variety of methodological flaws, but I think it is fair to conclude from them that many older patients with no recent inflammatory disease activity may safely stop their DMT.
Based on these findings, it is logical to consider whether discontinuation of DMTs is reasonable in older patients who have not displayed recent inflammatory disease activity as manifested by relapses and new changes seen on MRI. It is clearly a bad idea to discontinue DMTs in younger patients and those with significant recent new inflammatory disease activity.
Thus the hypothesis of our ongoing study, DISCOMS [Discontinuation of Disease Modifying Therapies in Multiple Sclerosis], is that patients who have MS are 55 and older and who have not had a new acute relapse or brain MRI change for at least five years will do no worse if they discontinue or if they stay on their DMT. This is a randomized controlled blinded study, funded by the Patient Centered Outcomes Research Institute and the National MS Society, and patients will be followed for two years. The primary outcome measure is percentage of patients with an acute MS relapse or any new brain lesion seen on MRI, with data hopefully available in 2020.
NT: What is the process of medication discontinuation?
Dr Corboy: If, after discussion with their physician, and including presently available knowledge, a patient decides to go off their medication, in most cases patients simply stop their DMT immediately.
NT: What sort of monitoring is needed during and after discontinuation? What should clinicians look for as signs that the discontinuation is no longer feasible?
Dr Corboy: It is best to get a brain MRI at the time of discontinuation to be certain there is no new activity, and annually for 1 to 2 years thereafter. We would use the patient’s history, exam and brain MRIs to determine if they remain stable, or, for those with progressive MS, the rate of progression is no greater than it was before stopping the DMT.
NT: What is the prognosis for patients who have successfully stopped medication?
Dr Corboy: My experience is that the vast majority of MS patients with quiescent-relapsing symptoms do well if they discontinue the DMT. We have had a few patients out of more than 100 who have had modest relapses or scan changes, and some have returned to taking a DMT. The vast majority of progressive MS patients have continued to progress at the same rate as before discontinuing DMT. Indeed, many patients, especially those still taking an interferon, feel demonstrably better after stopping the DMT, because the adverse effects that have tormented them for years have disappeared. Other potential benefits of DMT discontinuation include fewer visits to the doctor, fewer blood draws and other monitoring, fewer reminders that the patient has MS, and cost savings. All of these potential benefits should be weighed against the risks of indefinite continuation of DMTs for MS.
NT: Any other advice for clinicians?
Dr Corboy: Every patient is unique. I am not advocating that we simply discontinue MS DMT in every patient 55 or older, rather I’m suggesting that decisions about stopping or continuing DMTs should be re-evaluated on a routine basis as people age, especially in those with no new relapses or scan changes. We are hopeful that our study will be the first in a series of studies that allow us to gather the best possible data to help clinicians and patients address these issues over time. Finally, the apparent diminished benefit of presently available DMTs as people age, especially for those with progressive MS, is an important reminder that much work remains to develop neuroprotective and regenerative therapies for our MS patients.
1. Tortorella C, Bellacosa A, Paolicelli D, et al. Age-related gadolinium-enhancement of MRI brain lesions in multiple sclerosis. J Neurol Sci. 2005;239:95-99.
2. Tremlett H, Zhao Y, Joseph J, et al. Relapses in multiple sclerosis are age- and time-dependent. J Neurol Neurosurg Psychiatry. 2008;79:1368-1374.
3. Signori A1, Schiavetti I, Gallo F, Sormani MP. Subgroups of multiple sclerosis patients with larger treatment benefits: a meta-analysis of randomized trials. Eur J Neurol. 2015;22:960-966.
4. Fagius J, Feresiadou A, Larsson EM, Burman J. Discontinuation of disease modifying treatments in middle aged multiple sclerosis patients: first line drugs vs natalizumab. Mult Scler Relat Disord. 2017;12:82-87.
5. Bonenfant J, Bajeux E, Deburghgraeve V, et al. Can we stop immunomodulatory treatments in secondary progressive multiple sclerosis? Eur J Neurol. 2017;24:237-244.
6. Birnbaum G. Stopping Disease-Modifying Therapy in Nonrelapsing Multiple Sclerosis: Experience from a Clinical Practice. Int J MS Care. 2017;19:11-14.
7. Bsteh G, Feige J, Ehling R, et al. Discontinuation of disease-modifying therapies in multiple sclerosis: clinical outcome and prognostic factors. Mult Scler. 2016; Epub ahead of print. https://www.ncbi.nlm.nih.gov/labs/articles/27765877/.
8. Kister I, Spelman T, Alroughani R, et al. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016;87:1133-1137.
9. Tobin WO, Weinshenker BG. Stopping immunomodulatory medications in MS: Frequency, reasons and consequences. Mult Scler Relat Disord. 2015;4:437-443.