Rebound Syndrome in Multiple Sclerosis After Fingolimod Cessation

Abstract

To the Editor In 5 of 46 patients (10.9%) at their center, Hatcher and colleagues 1 reported "unexpectedly severe clinical relapses" that they described as "clinical rebound syndrome confirmed on magnetic resonance imaging within 4 to 16 weeks after ceasing fingolimod treatment" for multiple sclerosis. The postulated frequency of "rebound" is intriguing, and we agree with the authors that it is clinically relevant to carefully evaluate and treat patients who discontinue a disease-modifying treatment. However, we wish to express our concerns about the conclusions drawn from this small uncontrolled sample, given that the data contrast strongly with those from a thorough evaluation in a large controlled data set on fingolimod. 2,3 Rebound syndrome has been described as "a return of disease activity exceeding predrug activity approximately 8 to 24 weeks after cessation." 4,5 In the context of the case series by Hatcher et al, 1 characterization of the observed clinical relapses as "unexpectedly severe" is subjective because the baseline disease activity at diagnosis was not reported. In fact, all 5 patients had a long history of multiple sclerosis and were treated prior to initiation of fingolimod with other, sometimes multiple, disease-modifying treatments (including off-label monoclonal antibodies), suggesting highly active disease. Notably, the incidence and severity of relapses remained low during fingolimod therapy. The return of considerable disease activity when discontinuing effective treatment in patients with highly active disease seems intuitive. Similar cases are reported in the literature, again without reference to baseline activity. The authors rightly mention the need for controlled data to explore the question at stake. Follow-up of patients post-study drug discontinuation (typically within 3 months) is part of all fingolimod study protocols. Results of 2 retrospective analyses investigating more than 2000 patients from 3 randomized clinical trials suggested no increased risk for rebound following fingolimod cessation. 2,3 In the most recent analysis, the incidence of severe/atypical relapses or possible disease rebound after study drug discontinuation was low and similarly distributed in the fingolimod and placebo groups (1.1% vs 1.4%), as were the proportion of patients with unexpected high magnetic resonance imaging activity (4.9% vs 3.6%). 2 We believe that the case reports, together with cases from the controlled data set, display the unpredictable and highly variable course of multiple sclerosis. Conversely, a systematic controlled approach applied on large populations, as per the referenced analyses, provides sound scien-tific evidence to conclude that there is no risk for rebound following fingolimod discontinuation.

Clinical exacerbation of SARS‐CoV2 infection after fingolimod withdrawal

“…[4][5][6] Fingolimod (FNG) is a drug used for immune therapy in patients with MS and has been associated with a rebound effect of the inflammatory activity of MS after withdrawal. [7][8][9] When the drug is withdrawn, patients may suffer an exacerbation because of the lack of therapeutic coverage, or due to clinical variability. 10 The effect of the withdrawal of this drug in patients infected with SARS-CoV2 is not known.…”

“…But on the other, some therapies that act on immune response could play a protective role by dampening the cytokine‐release syndrome 4‐6 . Fingolimod (FNG) is a drug used for immune therapy in patients with MS and has been associated with a rebound effect of the inflammatory activity of MS after withdrawal 7‐9 . When the drug is withdrawn, patients may suffer an exacerbation because of the lack of therapeutic coverage, or due to clinical variability 10 .…”