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Special Report

We know how to prescribe natalizumab for multiple sclerosis, but do we know how to withdraw it? Expert Rev. Neurother. 14(2), 127–130 (2014)

Yara D Fragoso*, Niedja M Arruda, Walter O Arruda, Joseph BB Brooks, Eber C Correa, Alfredo Damasceno, Carlos A Damasceno, Maria LB Ferreira, Maria CB Giacomo, Sidney Gomes, Marcus VM Gonc¸alves, Anderson K Grzesiuk, Damacio R Kaimen-Maciel, Josiane Lopes, Suzana CN Machado, Celso LS Oliveira and Carla RAV Stella *Author for correspondence: Tel.: +55 133 226 3400 Fax: +55 133 226 3400 [email protected] For a full list of author affiliations, please see page 130.

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Natalizumab is a potent immunosuppressive monoclonal antibody used for the treatment of multiple sclerosis (MS). While definite guidelines for the safety of natalizumab prescriptions are available in all countries, there are no specific recommendations on how to withdraw the drug if the need arises. There are reports describing MS complications after natalizumab infusions were stopped. Most neurologists seem to stop natalizumab treatment according to their idea on how to best carry out the withdrawal. The present study shows the very different manners in which expert neurologists from 14 MS units in Brazil stopped natalizumab in their patients. The authors concluded that pharmacovigilance on natalizumab must persist after the drug is withdrawn in order to have enough data for adequate recommendations. KEYWORDS: fingolimod . JC virus . multiple sclerosis . natalizumab . relapses

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS characterized by multifocal localized inflammation leading to demyelination and axonal damage [1]. MS typically occurs in young adults (aged 20–40 years), is more prevalent in women and most commonly manifests in the form of relapsingremitting multiple sclerosis (RRMS). At present, RRMS is the only form of MS that responds to treatment with immunomodulatory and/or immunosuppressive drugs. Over recent years, new therapeutic options for MS management have become available [2]. One of these new drugs is natalizumab, a humanized monoclonal antibody against the a-4 chain of integrins. Natalizumab was the first targeted therapy to be approved for the treatment of RRMS. The drug acts as a selective adhesion molecule antagonist that binds very late antigen (VLA)-4 and inhibits the translocation of activated VLA-4-expressing leukocytes across the blood–brain barrier into the CNS [3]. Antagonism of VLA-4 is thought to interfere with leukocyte adhesion to the vascular wall, thus interfering with leukocyte trafficking across the blood–brain barrier and ultimately reducing the inflammation within the CNS [4]. 10.1586/14737175.2014.874947

While very effective for treatment of MS, natalizumab is not more widely used because of the risk of serious adverse events in patients, particularly occurrences of progressive multifocal leukoencephalopathy (PML), a potentially fatal condition caused by JC virus activation in the CNS. The risks are high if the patient is JC virus + in serum, has previously been treated with immunosuppressive drugs and/or has used natalizumab for over 2 years [5]. Use of natalizumab in Brazil is a relatively new alternative for patients with MS. Cases with many years of use of natalizumab are still rare, and most of these cases started as ‘compassionate use’ of the drug when it was not fully available in Brazil yet. However, as more and more patients reach longer periods of use of natalizumab and require drug withdrawal, new complications arise. Many studies and guidelines are clear on how to start natalizumab therapy. They state the type of patient who might benefit the most, the risks, the benefits and the therapeutic scheme to be followed [6]. The degree of efficacy with this drug is high, and although adverse events are not common, they are potentially very serious when present [7]. The

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Fragoso, Arruda, Arruda et al.

general recommendation is that natalizumab should be used only by skilled neurologists in MS centers under surveillance programs [6]. On the other hand, very few papers mention withdrawal of natalizumab. In fact, there is no standard recommendation for withdrawal of this drug and every specialist is left wondering what to do and how to do it. Both the risk of serious reactivation of MS and the acute immune reconstitution inflammatory syndrome caused by abrupt removal of a potent immunosuppressive monoclonal antibody worry neurologists faced with making a decision to withdraw it. The present study reports on the experience of this problem among a group of Brazilian neurologists, with particular expertise in diagnosing and treating MS. Methods

This study was approved by the Ethics Committee of Universidade Metropolitana de Santos, Brazil, under the number CAAE 05669912.3.0000.5509. Data were collected prospectively from patients who stopped using natalizumab at all the MS units participating in this project. No cases that were lost to follow-up were included. All the patients who had started treatment with natalizumab had presented suboptimal response to IFN-b and/or glatiramer acetate. This was an observational and open study, and every participating physician took his/her own decision on how to proceed with treatment according to his/her best judgment, considering that there were no guidelines to follow. Results

Thirty patients stopped natalizumab treatment at 14 MS units in 7 Brazilian states. There were 7 males and 23 females aged, on average, 38.2 years (median = 38.5; range: 20–62 years). They had received monthly infusions of natalizumab for an average period of 22.0 months (median: 19; range: 5–68 infusions). Three patients were lost to follow-up and, therefore, have not been included. The main reason for stopping natalizumab was the risk of PML (20 cases), inefficacy of the drug (4 cases), patient and family desires to withdraw from natalizumab (3 cases), pregnancy (1 case), herpes zoster (1 case, associated with a progressive course of MS) and occurrence of PML (1 case, which now presents a progressive course of MS) [8]. Except for the case of PML, in which plasma exchange was immediately performed, all the other 29 cases did not start any other therapy for at least 4 weeks. Ten patients were prescribed monthly pulses of corticosteroids, nine patients started fingolimod (one of them in association with monthly pulses of corticosteroids for 3 months), four patients started glatiramer acetate (one of them in association with monthly pulses of corticosteroids), two cases had the natalizumab monthly doses progressively reduced over 3 months and four cases were left without MS medications (two of whom had started a secondary progressive course of the disease). At the time of this report, the elapsed time between natalizumab withdrawal and the most recent consultation was an 128

average of 15.6 months (median: 10.5; range: 3–72 months). After stopping natalizumab, one patient had MS reactivation after a miscarriage and another patient had a severe relapse 4 months after stopping the drug. This latter patient developed significant lymphopenia while using fingolimod but is now recovering. Another patient also developed significant lymphopenia after 1 month of fingolimod use and withdrawal of this drug is under consideration. Discussion

The present study shows the need for precise guidelines for withdrawal of natalizumab. Even with a small number of cases, it is clear that, with the lack of specific recommendation for natalizumab withdrawal, every specialist is doing what he/she sees fit and is running the risks related to their decisions. Many patients may not have any complications with abrupt or gradual natalizumab withdrawal, but is there a recommended way to stop the treatment as there is one to start it? There is no doubt that neurologists are well aware of the guidelines on how to prescribe natalizumab. Many patients will thrive on the medication and the need for withdrawal may not arise. However, in cases of lack of efficacy, intolerance of the drug or safety risks, there is no recommendation. Simple withdrawal of natalizumab may induce disease reactivation with serious and even lethal relapses [4,9–14], and a single report on plasma exchange after natalizumab stated that a drastic worsening of MS activity was observed [15]. In fact, although plasma exchange clears natalizumab more rapidly from the circulation, there are no papers showing the benefits of this procedure to patients. Monthly pulses of corticosteroids were shown to be ineffective in reducing disease activity in a progressive study of 23 patients [16]. A prospective study on 18 patients showed that pulses of corticosteroids followed by glatiramer acetate decreased the risk of immune reconstitution inflammatory syndrome, but did not alter the course of MS after 6 months [17]. While one study [18] reported that glatiramer acetate prescribed soon after natalizumab withdrawal was able to keep the patients stable, another similar study showed that glatiramer acetate did not have any influence on the course of the disease [19]. A very recent report on a prospective assessment of 19 patients with IFN-b following natalizumab treatment showed little efficacy and no major adverse events in this therapeutic option [20]. Two poster presentations were identified with reports on natalizumab withdrawal, but these data are not yet published and do not particularly deal with the question raised by the present paper. In the RESTORE study [21], the main outcome was related to post-natalizumab return of MS activity. In the FIRST overall safety assessment [22], the switch from natalizumab to fingolimod was described as a safe and efficient option. The outcome of this study was clinical activity measured as disease relapses, and this parameter was described as fully successful with the drug switch. The most recommended course of action now, according to the literature on the subject, seems to be prescription of fingolimod for patients who stopped using Expert Rev. Neurother. 14(2), (2014)

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We know how to prescribe natalizumab for MS

natalizumab. Time delay between prescriptions is not usually discussed by the authors. While some groups have reported successful experience with this therapeutic approach [18,23], others have reported lack of disease control [24,25] or even severe MS reactivation [26] and tumefactive lesions [27], following fingolimod use after natalizumab. The present study included a relatively small number of patients, but this was typical of all of the abovementioned studies as well, where few or anecdotal cases were reported. Many of the Brazilian patients have not been followed-up for long periods, but the therapeutic approach to suspension of natalizumab was completely heterogeneous among the specialists involved, who have many years of experience with MS treatments. Expert commentary

The authors conclude that an independent, specific and large database on withdrawal of natalizumab is urgently needed in order to establish guidelines based on medical practice and evidence. Pharmacovigilance on natalizumab should be extended

Special Report

and reports should be mandatory after drug withdrawal. At the moment, there is not enough literature on the subject to allow conclusions to be drawn and learning from one’s attempts and errors is not an option. Five-year view

With the continuous arrival of new drugs for the treatment of MS, specific and medium to long-term pharmacovigilance programs will be necessary even for drugs that have been withdrawn. Newer drugs come with new adverse events and risks and must be well understood. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues .

Natalizumab is a potent and efficient drug for the treatment of multiple sclerosis.

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There are clear guidelines regarding the prescription of natalizumab.

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Patients usually do well on natalizumab and withdrawal may mainly be because of possible infections than for insufficient response.

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Progressive multifocal leukoencephalopathy caused by JC virus is the most important risk for patients on natalizumab.

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Natalizumab withdrawal may cause severe worsening of multiple sclerosis activity.

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Natalizumab withdrawal requires pharmacovigilance.

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The switch from natalizumab to another drug or procedure does not follow guidelines.

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It is imperative that we learn from data and experience in order to provide recommendations on natalizumab withdrawal.

References

5.

Papers of special note have been highlighted as: . of interest .. of considerable interest 1.

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2.

McCoyd M. Update on therapeutic options for multiple sclerosis. Neurol Clin 2013;31: 827-45

Sørensen PS, Bertolotto A, Edan G, et al. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler 2012;18:143-52

6.

Pucci E, Giuliani G, Solari A, et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev 2011;10:CD007621

.

Provides evidence of efficacy and safety issues of natalizumab. Concludes that only those with proven expertise in the field should use this drug.

.

Provides an interesting and updated review on MS treatment.

3.

McCormack PL. Natalizumab: a review of its use in the management of relapsing-remitting multiple sclerosis. Drugs 2013;73(13):1463-81

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Important and clear review on natalizumab. Efficient drug for the treatment of MS needs to be used with care by those with expertise in the field.

Fragoso YD, Alves-Leon SV, Arruda WO, et al. Natalizumab adverse events are rare in patients with multiple sclerosis. Arq Neuropsiquiatr 2013;71:137-41

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Damasceno A, von Glehn F, Martinez AR, et al. Early onset of natalizumab-related progressive multifocal leukoencephalopathy. Mult Scler 2011;17:1397-8

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..

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cessation of long-term therapy with natalizumab. Int J Neurosci 2012;122:35-9 .

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Affiliations Yara D Fragoso

Maria CB Giacomo

MS Reference Center, Medical School, Universidade Metropolitana de Santos, Santos, SP, Brazil and Department of Neurology, Medical School, Universidade Metropolitana de Santos, Rua da Constituicao 374, CEP 11015-470, Santos, SP, Brazil

MS Unit, Holus Medical Services, Sa˜o Paulo, SP, Brazil MS Unit, Hospital Beneficeˆncia Portuguesa and Hospital Paulistano, Sa˜o Paulo, SP, Brazil

Niedja M Arruda

Marcus VM Gonc¸alves

Demyelinating Diseases Reference Center, Hospital da Restaurac¸a˜o, Recife, PE, Brazil

MS Unit, Centro Hospitalar Unimed, Joinville, SC, Brazil

Walter O Arruda MS Unit, Medical School, Universidade Federal do Parana´, Curitiba, PR, Brazil

MS Reference Center, Centro de Reabilitac¸a˜o Dom Aquino Correa, Cuiaba, MT, Brazil

Joseph BB Brooks

Damacio R Kaimen-Maciel

MS Reference Center, Medical School, Universidade Metropolitana de Santos, Santos, SP, Brazil

MS Reference Center, Medical School, Universidade Estadual de Londrina, Londrina, PR, Brazil

Eber C Correa

Josiane Lopes

MS Unit, CLINEN – Neurologia e Endocrinologia, Brası´lia, DF, Brazil

MS Reference Center, Medical School, Universidade Estadual de Londrina, Londrina, PR, Brazil

Alfredo Damasceno MS Reference Center, Medical School, Universidade Estadual de Campinas, Campinas, SP, Brazil

Carlos A Damasceno MS Unit, Medical School, Universidade Federal de Juiz de Fora, Juiz de Fora, MG, Brazil

Maria LB Ferreira Demyelinating Diseases Reference Center, Hospital da Restaurac¸a˜o, Recife, PE, Brazil

130

Sidney Gomes

Anderson K Grzesiuk

Suzana CN Machado MS Reference Center, Imperial Hospital de Caridade, Hospital Governador Celso Ramos, Florianopolis, SC, Brazil

Celso LS Oliveira MS Reference Center, Medical School, Universidade Metropolitana de Santos, Santos, SP, Brazil

Carla RAV Stella MS Unit, Neurology, Campinas, SP, Brazil

Expert Rev. Neurother. 14(2), (2014)

We know how to prescribe natalizumab for multiple sclerosis, but do we know how to withdraw it?

Natalizumab is a potent immunosuppressive monoclonal antibody used for the treatment of multiple sclerosis (MS). While definite guidelines for the saf...
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