Background Natalizumab is highly effective in reducing multiple sclerosis disease activity; however it carries a risk of progressive multifocal leukoencephalopathy, that represents the main reason of drug discontinuation. After natalizumab withdrawal, reactivation of disease is soon observed and, until now, it is not known which treatment strategy should be followed after natalizumab discontinuation. Aim of this study is to evaluate rituximab efficacy in controlling disease activity after natalizumab withdrawal

A Bar-Or

A Laroni

E Palazzo

KR Carson

M Cohen

PS Sorensen

PW O’Connor

RT Naismith

T Castillo-Trivino

T Plavina

Simona Malucchi

Marco Capobianco

Alessia di Sapio

Marianna Lo Re

Paola Cavalla

Antonio Bertolotto

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Multiple Sclerosis and Demyelinating Disorders

Rituximab suppresses disease activity after natalizumab withdrawal: an exploratory study

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Multiple Sclerosis andDemyelinating DisordersMalucchi et al. Multiple Sclerosis and Demyelinating Disorders  (2016) 1:11 DOI 10.1186/s40893-016-0013-zCASE REPORT Open AccessRituximab suppresses disease activity afternatalizumab withdrawal: an exploratorystudySimona Malucchi1*, Marco Capobianco1, Alessia di Sapio1, Marianna Lo Re2, Paola Cavalla3 and Antonio Bertolotto1AbstractBackground: Natalizumab is highly effective in reducing multiple sclerosis disease activity; however it carries a riskof progressive multifocal leukoencephalopathy, that represents the main reason of drug discontinuation. Afternatalizumab withdrawal, reactivation of disease is soon observed and, until now, it is not known which treatmentstrategy should be followed after natalizumab discontinuation. Aim of this study is to evaluate rituximab efficacy incontrolling disease activity after natalizumab withdrawal.Case Presentation: Ten relapsing-remitting multiple sclerosis patients treated with natalizumab stopped it for thehigh risk of progressive multifocal leukoencephalopathy and started rituximab after a wash out period of twomonths; Second cycle of rituximab was planned in case of CD19+ cells increase and/or disease reactivation; brainMRI was performed before starting rituximab and then at six and twelve months after it.Conclusions: All the patients showed disease stability during the wash out period.Radiological stability was observed at 6 and at 12 months in all the patients; during the follow up two patients hadexacerbation of sensitive symptoms without evidence of brain MRI activity.This study gives evidence of rituximab efficacy in abolishing disease reactivation after natalizumab withdrawal.Keywords: Multiple sclerosis, Natalizumab, Progressive multifocal leukoencephalopathy (PML), RituximabBackgroundNatalizumab has been confirmed as highly effective inreducing multiple sclerosis (MS) disease activity.However, it carries a risk of progressive multifocalleukoencephalopathy (PML), an opportunistic diseasewith high morbidity, that represents the major causeof natalizumab interruption.Upon withdrawing natalizumab, resumption of diseaseactivity is soon observed [1, 2]. An unsolved problem isthe lack of therapies able to abolish the risk of diseasereactivation after natalizumab withdrawal.Many strategies aiming at reducing the risk of diseasereactivation have been tried; switching to first-linetherapies or high dose corticosteroids failed to controlthe disease; literature data about the use of fingolimod* Correspondence: simona.malucchi@gmail.com1University Hospital San Luigi Gonzaga, SCDO Neurologia 2- RegionalMultiple Sclerosis Center, Regione Gonzole 10, 10043 Orbassano, Torino, ItalyFull list of author information is available at the end of the article© 2016 The Author(s). Open Access This articInternational License (http://creativecommonsreproduction in any medium, provided you gthe Creative Commons license, and indicate if(http://creativecommons.org/publicdomain/zeare controversial, but consensus exists about the need toshort wash out period after natalizumab interruption [3, 4].In this report we want to share our experience aboutthe use of rituximab after natalizumab withdrawal withthe aim to evaluate its efficacy in controlling diseasecourse.Case PresentationTen RR-MS patients (8 women and 2 male) have beentreated with natalizumab for a median number of 38infusions (range 22–76); patients had a median numberof 2 relapses in the year preceding natalizumab in spiteof disease modifying drugs (DMDs) and full response tonatalizumab (neither clinical nor radiological activityduring treatment); demographic and clinical characteristicsare presented in Table 1. All the patients had high risk ofPML, due to the association of a stratify index >1.5 and theelevated number of infusions. After consultation betweenneurologist and patient, decision to stop natalizumab wastaken and patients have been proposed to switch tole is distributed under the terms of the Creative Commons Attribution 4.0.org/licenses/by/4.0/), which permits unrestricted use, distribution, andive appropriate credit to the original author(s) and the source, provide a link tochanges were made. The Creative Commons Public Domain Dedication waiverro/1.0/) applies to the data made available in this article, unless otherwise stated.Table 1 Demographic and clinical characteristicsGender Age atnatalizumab startRelapses in the yearbefore natalizumabN° of natalizumabinfusionsEDSS after lastnatalizumab infusionBrain MRI at 6 monthsafter rituximabBrain MRI at 12 monthsafter rituximabF 29 2 35 1.5 unchanged unchangedF 44 2 76 3.5 unchanged unchangedF 32 1 27 2.0 unchanged unchangedF 38 2 69 2.0 unchanged unchangedM 25 1 37 4.5 unchanged unchangedF 33 2 39 3.5 unchanged unchangedF 40 1 22 2.0 unchanged unchangedF 30 2 67 3.5 unchanged n.a.F 35 2 71 2.0 unchanged n.a.M 32 2 30 7.0 unchanged unchangedn.a. not available (follow up <1 year)Malucchi et al. Multiple Sclerosis and Demyelinating Disorders  (2016) 1:11 Page 2 of 3rituximab after a wash out period of 2 months; written in-formed consent was obtained from each patient; as the useof rituximab was off label, approval was obtained from thelocal ethics committee of the University Hospital SanLuigi.In our real-world clinical study median wash outperiod was 3.2 months (range 2–4.2 months).The choice of rituximab was due to the impossibilityof using fingolimod, because of cardiologic contraindica-tion (2 patients), or patients’ refusal (8 patients).Each patient underwent gadolinium-enhanced brainMRI scan after the last infusion of natalizumab and twomonths later, in order to exclude signs suggestive forPML; than brain MRI was performed six and twelvemonths after rituximab infusion; MRI was performed inthe same 1.5 T scanner using the same protocol for eachpatients; protocol included axial T2-weighted scans,coronal Flair-weighted scans, DWI sequences and post-contrast T1-weighted scans.Rituximab was administered at the dosage of 375 mg/mqonce/week for 4 weeks (I cycle); blood sample was takenmonthly in order to count CD19+ cells; second cycle at thedosage of 1000 mg at day 0 and 15 was planned in case ofCD19+ increase and/or clinical or radiological diseasereactivation.Patients started rituximab from October 2013 to May2014; median follow up after rituximab was 15.8 months(range 11.5–18.5 months).ResultsNo patient had disease reactivation during the wash outperiod; brain MRI performed two months after the lastnatalizumab infusion was unchanged compared to theone performed immediately after the last infusion.A brain MRI performed six months after rituximabinfusions did not show contrast-enhancing lesions or anincrease in the number of T2 lesions compared to thebrain MRI that had been performed after the lastnatalizumab infusion. In patients with a follow up of oneyear (8 patients), brain MRI performed 12 months afterrituximab was unchanged.No patient experienced clinical rebound; two out of tenhad a worsening of pre-existing sensitive symptoms: thefirst patient had an exacerbation of paresthesia in leftlimbs six months after rituximab, the second had exacer-bation of paresthesia in left face nine months after rituxi-mab; both patients were treated with intravenous steroidsfor 3 days; in both cases CD19 at the time of clinical re-lapse were detectable and II cycle of rituximab was admin-istered; brain MRI in both cases showed disease stability.Compared to EDSS after the last natalizumab infusion,EDSS was unchanged at six months in all the patientsand at 12 months in patients with one year follow up.ConclusionsThis is a preliminary study, conducted on a small numberof patients, aiming at the evaluation of rituximab efficacyafter natalizumab withdrawal. The choice of rituximabwas due to two main reasons: the evidence of efficacy inaggressive RR-MS patients [5] and the minor risk of PMLcompared to that of natalizumab [6, 7].Furthermore, the use of rituximab was due to theimpossibility of using fingolimod, because of bradycardiain 2 patients and patients’ refusal in the other 8 patients;the use of ciclophosphamide was not taken into consid-eration because our study population was characterizedby young people with desire for parenthood; patientswould have to undergo fertility preservation proceduresthat would have extended the time of drug initiation.Alemtuzumab was not yet available at the time the studywas conducted, so its use was not allowed.This work shows rituximab is highly efficacious in con-trolling disease course after natalizumab discontinuation,Malucchi et al. Multiple Sclerosis and Demyelinating Disorders  (2016) 1:11 Page 3 of 3as no patient had disease rebound, nor radiological reacti-vation at six months after rituximab infusion, that corres-pond to at least 8 months after natalizumab withdrawal.Eight patients reached a follow up of one year and inthese patients MRI at 12 months showed persistence ofstability.We observed two very mild relapses in two patients atsix and nine months after rituximab, without brain MRIactivity; in that circumstance the two patients showed anincrease of CD19+ cells that required the second cycleof treatment.A matter of concern in using Rituximab is the risk ofPML; compared to natalizumab very little data are knownabout PML risk during rituximab treatment; data fromrheumatologic experience suggest a PML risk of 1/25000 inrheumatoid arthritis affected patients treated with rituxi-mab, including both JCV positive and negative patients (6),whereas patients in our work had a risk of 1/120–1/145 [8].Finally, at present there is no agreement on whatwould be the best posological scheme for rituximab inMS, including its duration. Different protocols have beensuggested and applied: 375 mg every week for 4 weeks[9] or 1000 mg i.v. at day 0 and 15 [10]. Whateverregimen is adopted and despite the lower risk of PML,we believe that the use of rituximab to preventbreakthrough disease after natalizumab should berestricted to the first month after its discontinuation.Later on additional strategies have to be found. Inour Clinic we are planning to use a standard regimenwith retreatment six month after the first cycle ofrituximab followed by a switch to another drug suchas dimethyl fumarate.Despite the small number of patients this study hastwo strong points: 1) patients had similar diseasefeatures before natalizumab initiation with very activecourse, and high risk of disease reactivation after itsinterruption; brain MRI were performed at the sametime points with the same scanner and same protocol; 2)it shows rituximab appears an efficacious strategy tomanage natalizumab discontinuation; therefore we thinkour experience needs to be shared.Authors’ contributionsSM, MC, AdS, and MLR participated in the selection of patient, clinicalevaluation of patients and coordination of the study; PC participated inselection and clinical evaluation of patients; AB participated in the designof the study. All authors read and approved the final manuscript.Competing interestsThe authors declare that they have no competing interests.Consent statementWritten informed consent was obtained from the patients for publication ofthese case reports. A copy of the written consent is available for review bythe Editor-in-Chief of this journal.DisclosureDr Simona Malucchi, Dr Marco Capobianco, Dr Antonio Bertolotto receivedconsultation and speaking fees from Sanofi-Genzyme, Biogen-Idec, Merck-Serono,Novartis and Teva; Dr Alessia di Sapio received consultation and speaking feesfrom Biogen-Idec, Merck Serono, Teva and Novartis.Dr Paola Cavalla.Dr Marianna Lo Re has nothing to disclose.Author details1University Hospital San Luigi Gonzaga, SCDO Neurologia 2- RegionalMultiple Sclerosis Center, Regione Gonzole 10, 10043 Orbassano, Torino, Italy.2Dipartimento di Biomedicina Sperimentale e di Neuroscienze Cliniche,Università di Palermo, Via del Vespro 129, 90127 Palermo, Italy. 3Departmentof Neuroscience and Mental Health, Health and Science City, UniversityHospital of Turin, MS Center, I Neurologic Clinic, Via Cherasco 15, 10126Torino, Italy.Received: 2 July 2015 Accepted: 24 May 2016References1. O’Connor PW, Goodman A, Kappos L, Lublin FD, Miller DH, Polman C, et al.Disease activity return during natalizumab treatment interruption in patientswith multiple sclerosis. Neurology. 2011;76:1858–65.2. Sorensen PS, Koch-Henriksen N, Petersen T, Ravnborg M, Oturai A, Sellebjerg F.Recurrence of rebound of clinical relapses after discontinuation of natalizumabtherapy in highly active MS patients. J Neurol. 2014;261(6):1170–7.doi:10.1007/s00415-014-7325-8. Epub 2014 Apr 12.3. Laroni A, Brogi D, Milesi V, Abate L, Uccelli A, Mancardi G. Early switch tofingolimod may decrease the risk of disease recurrence after natalizumabinterruption. Mult Scler. 2013;19(9):1236–7.4. Cohen M, Maillart E, Tourbah A, De Seze J, Vukusic S, Brassat D, et al.Switching from natalizumab to fingolimod in multiple sclerosis: a Frenchprospective study. JAMA Neurol. 2014;71(4):436–41.5. Naismith RT, Piccio L, Lyons JA, Lauber J, Tutlam NT, Parks BJ, et al.Rituximab add-on therapy for breakthrough relapsing multiple sclerosis. A52-week phase II trial. Neurology. 2010;74:1860–7.6. Palazzo E, Yahia SA. Progressive multifocal leukoencephalopaty inautoimmune disease. Joint Bone Spine. 2012;79(4):351–5.7. Carson KR, Focosi D, Major EO, Petrini M, Richey EA, West DP, et al.Monoclonal antibody-associated progressive multifocal leukoencefalophatyin patients treated with rituximab, natalizumab, and efalizumab: a reviewfrom the Research ion Adverse Drug Events and Reports (RADAR) project.Lancet Oncol. 2009;10(8):816–24.8. Plavina T, Subramanyam M, Bloomgren G, Richman S, Pace A, Lee S, et al.Anti–JC Virus Antibody Levels in Serum or Plasma Further Define Risk ofNatalizumab-Associated Progressive Multifocal Leukoencephalopathy. AnnNeurol. 2014;76(6):802–12.9. Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E. Rituximab inRelapsing and Progressive Forms of Multiple Sclerosis: A Systematic Review.Plos One. 2013;8(7), e66308.10. Bar-Or A, Calabresi PAJ, Arnold D, Markowitz C, Shafer S, Kasper LH, et al.Rituximab in Relapsing-Remitting Multiple Sclerosis: A 72-Week, Open-Label,Phase I Trial. Ann Neurol. 2008;63:395–400.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:

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Rituximab suppresses disease activity after natalizumab withdrawal: an exploratory study

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