Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment

Hatcher, Stacy E.; Waubant, Emmanuelle; Nourbakhsh, Bardia; Crabtree-Hartman, Elizabeth; Graves, Jennifer

doi:10.1001/jamaneurol.2016.0826

Cited by 185 publications

(189 citation statements)

References 18 publications

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“…Depressed peripheral lymphocyte counts increase to the normal range within 4–8 weeks after cessation 16, 54. In accordance with this, several case reports have described rebound events approximately 2–4 months after stopping FTY 43, 44, 45, 47, 50, 51, 53, 55.…”

Section: Rebound After Withdrawal Of Fingolimodsupporting

confidence: 61%

“…An analysis of >1800 patients who stopped NTZ therapy showed that relapse of disease activity was particularly evident in patients who had had highly active disease before NTZ therapy 42. Similarly, there are some case reports of exacerbation after discontinuation of FTY 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56. Patients with highly active disease before the start of treatment with FTY51 or who showed a good therapeutic response to FTY53 might be predisposed to severe rebound after withdrawal.…”

Section: Rebound After Withdrawal Of Fingolimodmentioning

confidence: 99%

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Neurological safety of fingolimod: An updated review

Yoshii

Moriya

Ohnuki

et al. 2017

Clinical & Exp Neuroim

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Fingolimod (FTY) is the first oral medication approved for treatment of relapsing–remitting multiple sclerosis (RRMS). Its effectiveness and safety were confirmed in several phase III clinical trials, but proper evaluation of safety in the real patient population requires long‐term post‐marketing monitoring. Since the approval of FTY for RRMS in Japan in 2011, it has been administered to approximately 5000 MS patients, and there have been side‐effect reports from 1750 patients. Major events included infectious diseases, hepatobiliary disorders, nervous system disorders and cardiac disorders. In the present review, we focus especially on central nervous system adverse events. The topics covered are: (i) clinical utility of FTY; (ii) safety profile; (iii) post‐marketing adverse events in Japan; (iv) white matter (tumefactive) lesions; (v) rebound after FTY withdrawal; (vi) relationship between FTY and progressive multifocal leukoencephalopathy; (vii) FTY and progressive multifocal leukoencephalopathy‐related immune reconstitution inflammatory syndrome; and (viii) neuromyelitis optica and leukoencephalopathy.

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Section: Rebound After Withdrawal Of Fingolimodsupporting

confidence: 61%

Section: Rebound After Withdrawal Of Fingolimodmentioning

confidence: 99%

Neurological safety of fingolimod: An updated review

Yoshii

Moriya

Ohnuki

et al. 2017

Clinical & Exp Neuroim

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“…Irrespective of the disease course, withdrawal of DMT in MS poses the risk of resuming disease activity including rebound 3, 6, 7. Whilst progressive MS, particularly PPMS is often characterized by a relative quiescence in terms of lesion activity detected on MRI,8 there are many exceptions from this rule, and PPMS should therefore be considered as one end of the spectrum of MS presentations (the other being relapsing MS with a high relapse rate), rather than an altogether distinct subtype 8.…”

Section: Discussionmentioning

confidence: 99%

“…In the OLYMPUS trial of PPMS, Rituximab slowed disease deterioration in patients less than 51 years of age, and with Gd + lesions, suggesting a subgroup of pwPMS may well benefit from B cell depletion 18. Rituximab has also been offered recently as an off‐label rescue therapy in pwRRMS following rebound activity after cessation of fingolimod 3. Moreover, the humanised anti‐CD20 antibody Ocrelizumab has been successfully tested in a phase III trial of patients with PPMS 19.…”

Section: Discussionmentioning

confidence: 99%

“…When treatment is stopped lymphocyte levels usually return to normal within 4–8 weeks. The resulting release of lymphocytes back into the blood circulation may cause “rebound” disease, defined as a degree of disease activity significantly exceeding pre‐DMT activity 3, 4. We report a case of rebound disease after fingolimod cessation in a pwPMS, who was successfully treated with Cladribine as an off‐label “rescue” therapy.…”

Section: Introductionmentioning

confidence: 99%

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Cladribine to treat disease exacerbation after fingolimod discontinuation in progressive multiple sclerosis

Alvarez-Gonzalez

Adams

Mathews

et al. 2017

Ann Clin Transl Neurol

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Rebound disease following cessation of disease modifying treatment (DMT) has been reported in people with both relapsing and progressive multiple sclerosis (pwRMS, pwPMS) questioning strict separation between these two phenotypes. While licensed DMT is available for pwRMS to counter rebound disease, no such option exists for pwPMS. We report on a pwPMS who developed rebound disease, with 45 Gadolinium‐enhancing lesions on T1 weighted MRI brain, within 6 months after fingolimod 0.5 mg/day was stopped. Treatment with a short course of subcutaneous cladribine 60 mg led to effective suppression of inflammatory activity and partial recovery with no short‐term safety issues or adverse events.

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Rebound Syndrome in Multiple Sclerosis After Fingolimod Cessation

2016

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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.

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Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment

Cited by 185 publications

References 18 publications

Neurological safety of fingolimod: An updated review

Neurological safety of fingolimod: An updated review

Cladribine to treat disease exacerbation after fingolimod discontinuation in progressive multiple sclerosis

Rebound Syndrome in Multiple Sclerosis After Fingolimod Cessation

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