Disease reactivation after fingolimod discontinuation in two multiple sclerosis patients

Fingolimod (FTY) is the first oral drug approved for relapsing-remitting (RR) multiple sclerosis (MS). Little is known about MS evolution after its suspension and three reports of high disease activity after FTY withdrawal have recently been published [1–3]. Here we describe two MS patients with massive disease reactivation after FTY discontinuation. Patient 1: This 47-year-old lady presented the first neurological episode in 1995. She was initially treated with interferon-beta in 2000, and thereafter with glatiramer acetate. As she continued to experience many relapses, in February 2004 she entered a phase 2 trial comparing FTY against placebo, followed by an extension study in which all subjects were treated with FTY [4]. She remained free from relapses and disease progression until October 2009, but since then she entered a progressive phase of the disease. In February 2011, she reached EDSS 6.0; brain magnetic resonance imaging (MRI) showed a gadolinium (Gd)enhancing lesion. In July 2011, she reached EDSS 7, but brain and spinal cord MRI showed no disease activity. Intravenous methylprednisolone pulses did not lead to clinical amelioration and FTY was withdrawn because the disease continued to progress. In November 2011 she presented a rapid deterioration of her mental status and generalized seizures. Brain MRI showed multiple Gd-enhancing lesions ([20) and the presence of a severe atrophy. She was again treated with intravenous methylprednisolone pulses for five consecutive days and levetiracetam 1,000 mg daily with benefit. To date, the patient is free from seizures, EDSS is unchanged, but brain MRI, performed in March 2012, showed 15 Gd-enhancing lesions (Fig. 1). Patient 2: This 30-year-old lady presented the initial symptoms of MS in 2002, at the age of 20 years. She was initially treated with glatiramer acetate, and then with interferon-beta without significant effects on relapse rate or brain MRI activity. In March 2007 she was included in the TRANSORMS study [5]; during the blind phase (about 13 months), in which the patient could be treated with FTY or Avonex, she developed two clinical relapses. In April 2008 she entered the extension phase of the study (in which all patients received FTY), and remained clinically stable until June 2008 when FTY was suspended because of genital human papilloma virus infection. From August to December 2008 the patient had three severe relapses which led to a deterioration of her EDSS score from 1.5 to 4.0. Brain MRI showed 20 Gd-enhancing lesions. Intravenous methylprednisolone pulses led to a partial clinical recovery (EDSS = 2.5) and, in January 2009, she started natalizumab, which resulted in a complete suppression of clinical and MRI activity. In April 2011 she decided to A. Ghezzi D. Baroncini P. Annovazzi M. Zaffaroni Multiple Sclerosis Study Center, Hospital of Gallarate, Gallarate, Italy