Catastrophic outcome of patients with a rebound after Natalizumab treatment discontinuation

Abstract Introduction Natalizumab (NTZ) is an effective drug for the treatment of relapsing‐remitting multiple sclerosis. In some patients discontinuation is mandatory due to the risk of progressive multifocal leukoencephalopathy. However, severe clinical and radiological worsening has been described after drug cessation. Our aim was to describe the clinical and radiological features of the rebound phenomenon. Material and Methods Patients switched from NTZ to Fingolimod (FTY) who had presented a rebound after discontinuation were selected. Clinical and magnetic resonance imaging (MRI) data were collected. Results Four JC virus positive patients were included. The mean disease duration was 9.5 years (SD: 4.12) with a mean time of 3.1 years on NTZ. All patients started FTY within 3–4 months. Neurological deterioration started in a mean time of 3.5 months (SD: 2.08) with multifocal involvement: 75% motor disturbances, 50% cognitive impairment, 25% seizures. The average worsening in Expanded Disability Status Scale [EDSS] was of 3.25 points (SD: 2.33). The MRI showed a very large increase in T2 and gadolinium‐enhanced lesions (mean: 23.67, SD: 18.58). All patients received 5 days of IV methylprednisolone, one patient required plasma exchange. All the patients presented neurological deterioration with an EDSS worsening of 1.13 points (SD: 0.48). After the rebound three patients continued treatment with FTY, only one patient restarted NTZ. Conclusion Discontinuation of NTZ treatment may trigger a severe rebound with marked clinical and radiological worsening. A very careful evaluation of benefit‐risk should be considered before NTZ withdrawal, and a close monitoring and a short washout period is recommended after drug withdrawal.

with aggressive multiple sclerosis (MS) or poor response to the first-line therapy (Goodman et al., 2009;Miller et al., 2003;Polman et al., 2006). However, its use has been limited due to the risk of opportunistic infections, highlighting the progressive multifocal leukoencephalopathy (PML) secondary to JC virus reactivation. PML is a demyelinating disease of the CNS with frequent fatal consequences and with an incidence of approximately 1:1,000 in the treated patients (Yousry et al., 2006). The risk increases with longer treatment duration, the presence of anti-JCV antibodies and the prior use of immunosuppression (Fernandez et al., 2015;Yousry et al., 2006). 638 PML cases have been reported with an incidence of 4.15/1,000 in treated patients (Biogen Idec data, March 2016, website http://www.biogenidec-international.com/tysabri.aspx?).
Therefore, in some cases, the risk is not acceptable and the discontinuation of NTZ is mandatory; the European Medicines Agency and US Food and Drug Administration have established a risk management plan, and a re-consent of all patients treated for longer than 2 years is recommended (European Medicines Agency; Fernandez et al., 2015).

| PATIENTS AND METHODS
From a cohort of NTZ-treated patients from three hospitals in Madrid, Spain, between 2012-2013; those switched to Fingolimod (FTY) who had presented a rebound after discontinuation were reported. Clinical and magnetic resonance imaging (MRI) data were collected.

| Case report 1
A 29-year-old male was diagnosed with relapsing-remitting MS (RRMS) in 1999. He was treated with interferon beta until 2010. He started NTZ due to two relapses in previous year (no gadolinium [Gd] enhanced lesions in MRI). In February 2012 NTZ was discontinued due to the presence of 2 risk factors for PML (26 NTZ infusions and anti-JCV+). At this time, he had mild left hemiparesis and needed a cane for ambulation (Expanded Disability Status Scale [EDSS]: 6) but he was fully independent. In June 2012 FTY was started after a washout period of 3 months without adverse effects. One day later the patient was admitted to the emergency room due to drowsiness, disorientation, inattention, bradypsychia, and behavioral changes. 15 days' prior the patient had had a worsening in his left hemiparesis. On admission, neurological examination revealed a moderate encephalopathy with disorientation, severe inattention and bradyspsychia; Language was less fluent without dysphasia, he comprehended simple commands but not complex ones. He presented a worsening of his left hemiparesis with strength of 4/5 in left upper limb and 3/5 in left lower limb with generalized hyperreflexia and severe dysmetria, the patient was unable to stand up with aid (EDSS: 7). The MRI showed confluent bilateral white matter T2 hyperintensities with enhancement of multiple lesions ( Figure 1a,b), also a Vth and VIIth nerve enhancement bilaterally.
This enhancement was prolonged further. Spinal fluid examination was normal with absence of JCV by PCR. High-dose methylprednisolone (MTP) for 5 days was started with progressive improvement.
Fingolimod was restarted without new relapses but with a marked deterioration in comparison to his prior situation (EDSS:7).

| Case report 2
A 28-year-old female was diagnosed with RRMS in 2006. She was treated with interferon, Glatiramer Acetate and since September 2009 (a severe motor relapse the previous year) with NTZ. She presented no evidence of clinical and radiological activity in 2 years. In September 2012 NTZ was stopped due to a positive serology for VJC (EDSS: 1). Within the first month after the discontinuation the patient showed progressive worsening with paresthesia, instability, dizziness, and occasional diplopia. She was treated with several IV steroid pulses (MTP 13gr in total); in January 2013 FTY was started without response (EDSS: 6.5). An MRI revealed multiple T2 hyperintensities, of which at least 11 showed enhancement after Gd administration ( Figure 1c,d). Due to the progressive worsening despite the treatment, the patient was admitted for plasma exchange (PLEX) with progressive clinical and radiological improvement. She was discharged and FTY was continued with a partial recovery (EDSS: 2.5).

| Case report 4
A 32-year-old female was diagnosed of MS in 2007 after myelitis. She started treatment with AG but she was switched to NTZ in July 2008 due to persistence of clinical activity (severe relapse with myelitis) and disability progression. In November 2011 NTZ was stopped because of the presence of two risk factors for PML (>2 years and JCV+) she was included in a clinical trial. During the first 4 months, she received placebo, starting FTY in March 2012, no bridging therapy was initiated (EDSS: 3.5). In March, she complained of cognitive worsening and weakness in lower limbs, she was unable to read, presented a severe inattention and behavioral changes (EDSS: 5); a neuropsychological study was conducted, with normal processing speed, verbal fluency and abstract reasoning. A moderate impairment of visuospatial processing information and visual-constructional execution with dysgraphia was present. Also, Difficulty encoding and retrieval in ver-

| RESULTS
Four patients with a mean disease duration of 9.5 years (SD: 4.12) were switched from NTZ to FTY due to PML risk (mean time on NTZ of 3.1 years, all patients anti-JCV+, at that time the JCV-index status was not available). The patients presented a mean of 1.5 relapses prior to NTZ therapy. FTY was started in the 3-4 following months after discontinuation. Despite the treatment, the patients presented neurological deterioration (mean: 3.5 months, SD: 2.08) with multifo-

| DISCUSSION
The existence of a rebound phenomenon after NTZ withdrawal is   (Fox et al., 2014). The TY-STOP, an observational study, revealed that in the first year after NTZ cessation, up to 35% of patients had a relapse (Clerico et al., 2014). None of these studies described a rebound phenomenon.
There are controversial data on factors predisposing to recurrence, however some studies suggest that pretreatment activity, longer MS duration (Havla, Tackenberg, et al., 2013;Lenhard et al., 2010;Miravalle et al., 2011), increased activity in the prior months to cessation (Jokubaitis et al., 2014) and longer washout periods are the main predisposing factors. Classically, a 3-to 6-month washout period has been recommended for FTY switching (Fazekas et al., 2013;Jeffery et al., 2011 (Kappos et al., 2013). Moreover, other series supports that initiating FTY within the first 3 months is associated with a significantly lower risk of relapse (Cohen et al., 2014;Havla et al., 2011;O'Connor et al., 2011). In our series, all the patients started FTY after 3 months, classically recommended as washout period.
There are no randomized controlled trials or established guidelines about the correct treatment in a rebound. The most frequent treatment is pulsed IV MTP for 5 days. The usefulness of PLEX is controversial with some reports of worsening maybe due to a rapid NTZ clearance in peripheral blood and an increased flux of lymphocytes into the brain (Lenhard et al., 2010). Our patients had severe deterioration during the rebound; however, despite a mild improvement after the rebound treatment, significant disabilities (exceeding pre-NTZ treatment) were maintained over time.

| CONCLUSION
After stopping NTZ, disease activity may return to pretreatment levels or a severe rebound with a marked clinical and radiological worsening could be seen. Prior to NTZ withdraw, a risk benefit balance should be evaluated and, if cessation is mandatory, a close monitoring and an early initiation of alternative treatment are recommended after drug withdrawal.