Rebound Relapses After Ceasing Another Disease Modifying Treatment in Patients With Multiple Sclerosis: Are There Lessons to Be Learned?
"Do no harm" is the timeless tenet of the Hippocratic Oath. It applies not only to how patients tolerate prescribed treatments but also to how they tolerate treatments after discontinuation. The sum of both events must be considered in the overall risk benefit ratio before starting any given treatment. The article by Hatcher et al1 published in this issue of JAMA Neurology describes a rebound in multiple sclerosis (MS) relapses after ceasing fingolimod treatment. Rebound occurred in 5 of 46 patients (10.9% at their center, with additional reports identified by the authors' literature search. Rebounds in relapses were clinically severe and accompanied by magnetic resonance imaging lesion activity that surpassed the level of activity before starting treatment. The first step during postmarketing experience is to report adverse events to increase awareness and provide a rationale for a registry to be created to establish frequency. This is addressed by Hatcher et al.1 The next step is to understand why rebound is occurring in order to prevent it from happening to other patients in the future. Finally, a discussion of the altered riskbenefit ratio of fingolimod within the context of currently evolving schools of thought regarding disease modifying treatments in relapsing remitting MS (RRMS) is warranted. The present article1 documenting rebound relapse activity after stopping fingolimod treatment is particularly important because a similar rebound of disease activity after stopping natalizumab treatment has been well documented.2 4 Why would fingolimod and natalizumab be associated with a rebound in disease activity after ceasing treatment compared with other MS disease modifying therapies that have not been associated with a rebound? It may have to do with targeting immune cell trafficking. Fingolimod acts on sphingosine1 phosphate receptors, which results in sequestration of lymphocytes in secondary lymphoid tissues and leads to less infiltration of these cells into the brain during MS. In turn, this reduces inflammatory lesions in white matter and reduces MS relapses. Natalizumab acts on a 4 integrin receptors on lymphocytes to block their passage across the blood brain barrier and reduce their infiltration into the brain. Perhaps treatments that are designed to block immune cells from entering the brain, either at the level of the blood brain barrier with natalizumab or at the level of lymphoid tissues with fingolimod, can be associated with rebound relapses after ceasing treatment. In contrast, rebound disease activity over and above pretreatment levels is not an issue for first line diseasemodifying treatments for MS (eg, glatiramer acetate and interferon b) despite extensive use for decades. These relatively safe, long standing disease modifying injectable treatments do not directly target immune cell trafficking but instead act indirectly through a variety of immunomodulatory mechanisms to reduce the proinflammatory profile of immune cells in peripheral blood, with a downstream effect of less inflammation in the brain. In many biological systems, chronic receptor blocking and/or receptor stimulation can eventually affect not only the expression of target receptors but also the expression of transcription factors involved in receptor stimulation. Accordingly, chronic targeting of the receptor interactions related to trafficking immune cells from lymphoid organs could lead to compensatory changes in other molecules redundant in such trafficking. It is tempting to speculate that chronic sphingosine1 phosphate receptor blocking with fingolimod could have unexpected effects on receptor physiology in secondary lymphoid tissues. Therefore, sudden cessation of fingolimod treatment could result in even more efflux of lymphocytes from lymph nodes than during pretreatment as a consequence of these upregulated compensatory pathways. This efflux would involve immune cells that are not otherwise immunomodulated, paving the way for rebounds of disease activity even higher than pretreatment. Future studies are needed to discern the mechanism of rebound relapses with cessation of fingolimod treatment, as Hatcher et al1 acknowledge. However, these future studies will require much more than quantification of immune cell types in the blood during rebound; they will likely entail assessment of receptor physiology within secondary lymphoid tissues. Such mechanistic studies are important because there may be implications for treatments beyond fingolimod, both currently and in the future. Given the new finding of the potential for rebound relapses after ceasing fingolimod treatment, a discussion of the altered risk benefit ratio is salient and should be considered in the context of larger treatment related issues in MS. Indeed, this is timely in light of evolving opinions regarding the selection of the best disease modifying treatment approach for early RRMS. There are 2 schools of thought regarding how aggressive treatments should be in patients with early RRMS. In the past, most physicians started patients with the safest MS treatments. If they "failed" such treatments, as evidenced by relapse frequency at or near pretreatment levels, then escalaRelated article Opinion
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