Rebound of disease activity during pregnancy after withdrawal of fingolimod

Sir Fingolimod is an oral sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing remitting multiple sclerosis (MS) [1]. There is little information on the evolution of MS after fingolimod withdrawal, and several reports have raised the possibility of a rebound of disease activity [2,3]. Pregnancy is an especially delicate situation for women with MS because the discontinuation of therapy may increase the risk of relapses, which may be potentially compensated for by the reduction of disease activity during pregnancy [4]. We describe a patient who had a rebound of disease activity during pregnancy shortly after discontinuation of fingolimod treatment. A 31-year-old woman was diagnosed with relapsing remitting MS according to the McDonald criteria. Treatment with interferon-b1a 44 lg was initiated in October 2005 and discontinued in October 2009 after a brainstem relapse. During the 4 years of treatment with interferon-b1a, she experienced two relapses. She started natalizumab in November 2009 without further relapses. In May 2011, the patient tested positive for anti-JC virus antibodies, and natalizumab was discontinued. Fingolimod was initiated in August 2011 and discontinued in October 2012 because the patient was trying to become pregnant. After switching to fingolimod, the patient experienced no clinical relapses and her Expanded Disability Status Scale (EDSS) score was 0. She became pregnant 6 weeks after stopping fingolimod without assisted reproduction techniques. The patient was not taking any medication. At week 5 of pregnancy, she suffered a relapse with paresis and severe hypesthesia of the left arm that was not treated. At week 11 of pregnancy, she suffered a new relapse. Examination showed an incomplete left hemianopsia and hypesthesia of the left arm; her EDSS score was 3.5. Brain MRI without gadolinium showed 14 new T2 lesions (Fig. 1). She was treated with daily 1000 mg intravenous methylprednisolone for 3 days with partial improvement. At the last followup, week 20 of pregnancy, the patient is stable and has not suffered further relapses. Our patient presented with severe disease recurrence beginning 11 weeks after the discontinuation of fingolimod. Compared with the clinical and MRI activity before the withdrawal of fingolimod, the recurrence of disease activity might be considered a rebound effect, similar to the immune reconstitution inflammatory syndrome that has been described after cessation of natalizumab therapy [5]. Women with MS are advised to discontinue disease-modifying drugs before conceiving to minimize the risk of foetal harm [6]. Fingolimod is labelled FDA pregnancy category C and a 2 month wash-out period is recommended prior to conception [4]. There is limited experience with fingolimod exposure during pregnancy; 34 exposed pregnancies resulted in one case of tibial malformation, one case of tetralogy of Fallot and five spontaneous abortions [6]. The evolution of MS during pregnancy after fingolimod withdrawal is largely unknown. Clinicians should be alert to the possibility of increased disease activity and a rebound-like response after cessation of therapy with fingolimod [7]. This situation is problematic for women who are planning to conceive and pose additional therapeutic problems.