Rebound after Fingolimod suspension in a pediatric-onset multiple sclerosis patient

Abstract

Fingolimod is an oral agent approved for the treatment of relapsing-remitting Multiple Sclerosis (RRMS). Data about a possible reactivation of disease activity after Fingolimod withdrawal are limited [1–3]. We report a case of clinical and magnetic resonance (MR) rebound after Fingolimod discontinuation in a 19-year-old woman with pediatriconset MS (POMS). Case-report: A 19-year-old woman was diagnosed as RRMS in February 2004, when she was 11. Two relapses occurred before initiation of interferon beta in 2009. She experienced two new episodes of optic neuritis until 2011. In June 2011, brain MR showed ten new T2 lesions, five with Gadolinium (Gd) enhancement, in comparison with a scan of September 2010 which already showed a high lesion load ([9 T2-lesions). After a steroid course the EDSS score was 3.0. The patient was shifted to fingolimod treatment in December 2011. After 10 days from fingolimod initiation, she presented a severe relapse; the brain MR showed 10 new T2 lesions. She recovered after intravenous methyl-prednisolone (IVMP) therapy. Two new relapses occurred in March and May 2012, the latter treated with steroids. Brain MR, compared with the scan performed in June 2011, showed ten new T2 lesions with eight Gdenhancing lesions. After IVMP therapy the EDSS was 3.5. Fingolimod was discontinued due to lack of efficacy. The patient started laboratory, cardiologic and radiologic examinations preliminary to intravenous cyclophosphamide therapy. In June, she experienced a new relapse; brain and spinal cord MR, performed 50 days after Fingolimod discontinuation, showed a drastic increase of the brain lesion burden ([35 T2 lesions) with 25 Gd-enhancing lesions, suggesting a rebound phenomenon (Fig. 1). At that time the peripheral lymphocyte count had returned within the normal limits. Moreover, in August, the MR showed enlargement of some pre-existing brain lesions and the presence of a new lesion in the spinal cord. She underwent five plasmaexchange courses, followed by good recovery (EDSS 3.0). She then started intravenous cyclophosphamide therapy (800 mg/m of body surface every month). Over the sevenmonth follow-up no new relapse occurred, EDSS remained unchanged and no new MR lesion was documented. In conclusion, in our POMS patient, Fingolimod was not effective to contain the inflammatory process and the drug discontinuation resulted in a rebound phenomenon, although this was observed during a phase of continuing disease activity rather than in the context of quiescent disease. A systematic review of the patients coming off from the TRANSFORMS and the FREEDOMS studies did not demonstrate similar rebound [4]; however, other examples of rebound after Fingolimod suspension are reported in the literature suggesting that the phenomenon could be linked to immunological recovery [1–3]. Rebound can also occur after discontinuation of Natalizumab, a monoclonal antibody used in very active MS patients [5, 6]. There is no standardized management of rebound periods. We did not use natalizumab due to JC virus positivity and the associated risk of rebound in case of discontinuation. Mitoxantrone treatment was ruled out due to the risk of leukemia [7]. Using intensive immunosuppression with cyclophosphamide [8], we obtained clinical and MR remission over a 7-months follow-up, although this period is relatively short E. Piscolla B. Hakiki L. Pasto L. Razzolini E. Portaccio M. P. Amato (&) Department of Neurology, University of Florence, Largo Brambilla 3, 50134 Florence, Italy e-mail: mariapia.amato@unifi.it