Real risk of rebound syndrome following fingolimod cessation for MS

By Lucy Piper

Rebound syndrome following cessation of fingolimod for multiple sclerosis (MS) occurs at a clinically relevant rate, shows research, prompting the need for further study on how best to sequence and discontinue such drugs.

Stacy Ellen Hatcher and team, from the University of California, San Francisco, USA, found that rebound occurred in five (10.9%) of 46 patients discontinuing fingolimod at their Multiple Sclerosis Center between January 2014 and December 2015.

The most common reasons for cessation included to attempt pregnancy, adverse effects and breakthrough disease activity.

Rebound syndrome, defined as new severe neurological symptoms with the development of multiple new or enhancing lesions exceeding baseline activity, occurred after a short washout period of 4 weeks in two patients and after 6 weeks and 12 weeks in one patient and two patients, respectively.

All five patients were female and the course of relapse-remitting MS prior to stopping fingolimod varied in severity.

Magnetic resonance imaging showed that there was a median increase of nine new gadolinium-enhancing lesions and nine new T2 lesions, ranging from nine to more than 30 for both types.

And despite steroid treatment or acute treatment with a fast-acting immune therapy, such as rituximab, new lesion development persisted for 3 to 6 months.

"Thus, the most effective treatment of rebound syndrome is not clear. Most of our cases did not immediately respond to steroids and new lesions continued to form despite B-cell depletion in some cases", the team reports in JAMA Neurology.

Their findings were also corroborated in a literature search, which identified 11 similar cases of rebound syndrome following fingolimod cessation occurring at between 4 weeks and 4 months.

Fingolimod is a sphingosine-1-phosphate receptor modulator that sequesters lymphocytes in lymph nodes, preventing them from entering the central nervous system, Hatcher and colleagues explain. But their re-entry into the central nervous system following treatment discontinuation may prompt the rebound syndrome.

Lymphocyte subset testing may be useful to identify which patients are at risk, the team speculates. Although not all patients had subsets measured, the team found that in the two most severe cases, CD8 cells were the first to recover during rebound, while CD4 and CD19 remained persistently low.

In a related editorial, Rhonda Voskuhl (University of California, Los Angeles, USA) says that rebound relapses after stopping fingolimod "must now be considered in its risk-benefit ratio when treating patients with early RRMS [relapse-remitting multiple sclerosis]."

And noting that two of the affected patients in the current case series were stopping fingolimod to get pregnant, she points out that "consideration of which treatment to start in young women with early RRMS should include total risks related to the patient's future life plans and not only those suggested by adverse events observed in trials while receiving treatment."

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JAMA Neurol 2016; Advance online publication


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