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Rituximab suppresses disease activity after natalizumab withdrawal: an exploratory study

Rituximab suppresses disease activity after natalizumab withdrawal: an exploratory study 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. Case Presentation: Ten relapsing-remitting multiple sclerosis patients treated with natalizumab stopped it for the high risk of progressive multifocal leukoencephalopathy and started rituximab after a wash out period of two months; Second cycle of rituximab was planned in case of CD19+ cells increase and/or disease reactivation; brain MRI 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 had exacerbation 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), Rituximab Background are controversial, but consensus exists about the need to Natalizumab has been confirmed as highly effective in short wash out period after natalizumab interruption [3, 4]. reducing multiple sclerosis (MS) disease activity. In this report we want to share our experience about However, it carries a risk of progressive multifocal the use of rituximab after natalizumab withdrawal with leukoencephalopathy (PML), an opportunistic disease the aim to evaluate its efficacy in controlling disease with high morbidity, that represents the major cause course. of natalizumab interruption. Upon withdrawing natalizumab, resumption of disease Case Presentation activity is soon observed [1, 2]. An unsolved problem is Ten RR-MS patients (8 women and 2 male) have been the lack of therapies able to abolish the risk of disease treated with natalizumab for a median number of 38 reactivation after natalizumab withdrawal. infusions (range 22–76); patients had a median number Many strategies aiming at reducing the risk of disease of 2 relapses in the year preceding natalizumab in spite reactivation have been tried; switching to first-line of disease modifying drugs (DMDs) and full response to therapies or high dose corticosteroids failed to control natalizumab (neither clinical nor radiological activity the disease; literature data about the use of fingolimod during treatment); demographic and clinical characteristics are presented in Table 1. All the patients had high risk of PML, due to the association of a stratify index >1.5 and the * Correspondence: simona.malucchi@gmail.com elevated number of infusions. After consultation between University Hospital San Luigi Gonzaga, SCDO Neurologia 2- Regional neurologist and patient, decision to stop natalizumab was Multiple Sclerosis Center, Regione Gonzole 10, 10043 Orbassano, Torino, Italy Full list of author information is available at the end of the article taken and patients have been proposed to switch to © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Malucchi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:11 Page 2 of 3 Table 1 Demographic and clinical characteristics Gender Age at Relapses in the year N° of natalizumab EDSS after last Brain MRI at 6 months Brain MRI at 12 months natalizumab start before natalizumab infusions natalizumab infusion after rituximab after rituximab F 29 2 35 1.5 unchanged unchanged F 44 2 76 3.5 unchanged unchanged F 32 1 27 2.0 unchanged unchanged F 38 2 69 2.0 unchanged unchanged M 25 1 37 4.5 unchanged unchanged F 33 2 39 3.5 unchanged unchanged F 40 1 22 2.0 unchanged unchanged F 30 2 67 3.5 unchanged n.a. F 35 2 71 2.0 unchanged n.a. M 32 2 30 7.0 unchanged unchanged n.a. not available (follow up <1 year) rituximab after a wash out period of 2 months; written in- increase in the number of T2 lesions compared to the formed consent was obtained from each patient; as the use brain MRI that had been performed after the last of rituximab was off label, approval was obtained from the natalizumab infusion. In patients with a follow up of one local ethics committee of the University Hospital San year (8 patients), brain MRI performed 12 months after Luigi. rituximab was unchanged. In our real-world clinical study median wash out No patient experienced clinical rebound; two out of ten period was 3.2 months (range 2–4.2 months). had a worsening of pre-existing sensitive symptoms: the The choice of rituximab was due to the impossibility first patient had an exacerbation of paresthesia in left of using fingolimod, because of cardiologic contraindica- limbs six months after rituximab, the second had exacer- tion (2 patients), or patients’ refusal (8 patients). bation of paresthesia in left face nine months after rituxi- Each patient underwent gadolinium-enhanced brain mab; both patients were treated with intravenous steroids MRI scan after the last infusion of natalizumab and two for 3 days; in both cases CD19 at the time of clinical re- months later, in order to exclude signs suggestive for lapse were detectable and II cycle of rituximab was admin- PML; than brain MRI was performed six and twelve istered; brain MRI in both cases showed disease stability. months after rituximab infusion; MRI was performed in Compared to EDSS after the last natalizumab infusion, the same 1.5 T scanner using the same protocol for each EDSS was unchanged at six months in all the patients patients; protocol included axial T2-weighted scans, and at 12 months in patients with one year follow up. coronal Flair-weighted scans, DWI sequences and post- contrast T1-weighted scans. Conclusions Rituximab was administered at the dosage of 375 mg/mq This is a preliminary study, conducted on a small number once/week for 4 weeks (I cycle); blood sample was taken of patients, aiming at the evaluation of rituximab efficacy monthly in order to count CD19+ cells; second cycle at the after natalizumab withdrawal. The choice of rituximab dosage of 1000 mg at day 0 and 15 was planned in case of was due to two main reasons: the evidence of efficacy in CD19+ increase and/or clinical or radiological disease aggressive RR-MS patients [5] and the minor risk of PML reactivation. compared to that of natalizumab [6, 7]. Patients started rituximab from October 2013 to May Furthermore, the use of rituximab was due to the 2014; median follow up after rituximab was 15.8 months impossibility of using fingolimod, because of bradycardia (range 11.5–18.5 months). in 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 characterized Results by young people with desire for parenthood; patients No patient had disease reactivation during the wash out would have to undergo fertility preservation procedures period; brain MRI performed two months after the last that would have extended the time of drug initiation. natalizumab infusion was unchanged compared to the Alemtuzumab was not yet available at the time the study one performed immediately after the last infusion. was conducted, so its use was not allowed. A brain MRI performed six months after rituximab This work shows rituximab is highly efficacious in con- infusions did not show contrast-enhancing lesions or an trolling disease course after natalizumab discontinuation, Malucchi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:11 Page 3 of 3 as no patient had disease rebound, nor radiological reacti- Disclosure Dr Simona Malucchi, Dr Marco Capobianco, Dr Antonio Bertolotto received vation at six months after rituximab infusion, that corres- consultation and speaking fees from Sanofi-Genzyme, Biogen-Idec, Merck-Serono, pond to at least 8 months after natalizumab withdrawal. Novartis and Teva; Dr Alessia di Sapio received consultation and speaking fees Eight patients reached a follow up of one year and in from Biogen-Idec, Merck Serono, Teva and Novartis. Dr Paola Cavalla. these patients MRI at 12 months showed persistence of Dr Marianna Lo Re has nothing to disclose. stability. We observed two very mild relapses in two patients at Author details University Hospital San Luigi Gonzaga, SCDO Neurologia 2- Regional six and nine months after rituximab, without brain MRI Multiple Sclerosis Center, Regione Gonzole 10, 10043 Orbassano, Torino, Italy. activity; in that circumstance the two patients showed an 2 Dipartimento di Biomedicina Sperimentale e di Neuroscienze Cliniche, increase of CD19+ cells that required the second cycle Università di Palermo, Via del Vespro 129, 90127 Palermo, Italy. Department of Neuroscience and Mental Health, Health and Science City, University of treatment. Hospital of Turin, MS Center, I Neurologic Clinic, Via Cherasco 15, 10126 A matter of concern in using Rituximab is the risk of Torino, Italy. PML; compared to natalizumabverylittledataare known Received: 2 July 2015 Accepted: 24 May 2016 about PML risk during rituximab treatment; data from rheumatologic experience suggest a PML risk of 1/25000 in rheumatoid arthritis affected patients treated with rituxi- References 1. O’Connor PW, Goodman A, Kappos L, Lublin FD, Miller DH, Polman C, et al. mab, including both JCV positive and negative patients (6), Disease activity return during natalizumab treatment interruption in patients whereas patients in our work had a risk of 1/120–1/145 [8]. with multiple sclerosis. Neurology. 2011;76:1858–65. Finally, at present there is no agreement on what 2. Sorensen PS, Koch-Henriksen N, Petersen T, Ravnborg M, Oturai A, Sellebjerg F. Recurrence of rebound of clinical relapses after discontinuation of natalizumab would be the best posological scheme for rituximab in therapy in highly active MS patients. J Neurol. 2014;261(6):1170–7. MS, including its duration. Different protocols have been doi:10.1007/s00415-014-7325-8. Epub 2014 Apr 12. suggested and applied: 375 mg every week for 4 weeks 3. Laroni A, Brogi D, Milesi V, Abate L, Uccelli A, Mancardi G. Early switch to fingolimod may decrease the risk of disease recurrence after natalizumab [9] or 1000 mg i.v. at day 0 and 15 [10]. Whatever interruption. Mult Scler. 2013;19(9):1236–7. regimen is adopted and despite the lower risk of PML, 4. Cohen M, Maillart E, Tourbah A, De Seze J, Vukusic S, Brassat D, et al. we believe that the use of rituximab to prevent Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 2014;71(4):436–41. breakthrough disease after natalizumab should be 5. Naismith RT, Piccio L, Lyons JA, Lauber J, Tutlam NT, Parks BJ, et al. restricted to the first month after its discontinuation. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis. A Later on additional strategies have to be found. In 52-week phase II trial. Neurology. 2010;74:1860–7. 6. Palazzo E, Yahia SA. Progressive multifocal leukoencephalopaty in our Clinic we are planning to use a standard regimen autoimmune disease. Joint Bone Spine. 2012;79(4):351–5. with retreatment six month after the first cycle of 7. Carson KR, Focosi D, Major EO, Petrini M, Richey EA, West DP, et al. rituximab followed by a switch to another drug such Monoclonal antibody-associated progressive multifocal leukoencefalophaty in patients treated with rituximab, natalizumab, and efalizumab: a review as dimethyl fumarate. from the Research ion Adverse Drug Events and Reports (RADAR) project. Despite the small number of patients this study has Lancet Oncol. 2009;10(8):816–24. two strong points: 1) patients had similar disease 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 of features before natalizumab initiation with very active Natalizumab-Associated Progressive Multifocal Leukoencephalopathy. Ann course, and high risk of disease reactivation after its Neurol. 2014;76(6):802–12. interruption; brain MRI were performed at the same 9. Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E. Rituximab in Relapsing and Progressive Forms of Multiple Sclerosis: A Systematic Review. time points with the same scanner and same protocol; 2) Plos One. 2013;8(7), e66308. it shows rituximab appears an efficacious strategy to 10. Bar-Or A, Calabresi PAJ, Arnold D, Markowitz C, Shafer S, Kasper LH, et al. manage natalizumab discontinuation; therefore we think Rituximab in Relapsing-Remitting Multiple Sclerosis: A 72-Week, Open-Label, Phase I Trial. Ann Neurol. 2008;63:395–400. our experience needs to be shared. Authors’ contributions Submit your next manuscript to BioMed Central SM, MC, AdS, and MLR participated in the selection of patient, clinical evaluation of patients and coordination of the study; PC participated in and we will help you at every step: selection and clinical evaluation of patients; AB participated in the design of the study. All authors read and approved the final manuscript. • We accept pre-submission inquiries � Our selector tool helps you to find the most relevant journal � We provide round the clock customer support Competing interests � Convenient online submission The authors declare that they have no competing interests. � Thorough peer review � Inclusion in PubMed and all major indexing services Consent statement � Maximum visibility for your research Written informed consent was obtained from the patients for publication of these case reports. A copy of the written consent is available for review by Submit your manuscript at the Editor-in-Chief of this journal. www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Multiple Sclerosis and Demyelinating Disorders Springer Journals

Rituximab suppresses disease activity after natalizumab withdrawal: an exploratory study

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References (13)

Publisher
Springer Journals
Copyright
Copyright © 2016 by The Author(s).
Subject
Medicine & Public Health; Neurology; Rehabilitation Medicine
eISSN
2056-6115
DOI
10.1186/s40893-016-0013-z
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Abstract

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. Case Presentation: Ten relapsing-remitting multiple sclerosis patients treated with natalizumab stopped it for the high risk of progressive multifocal leukoencephalopathy and started rituximab after a wash out period of two months; Second cycle of rituximab was planned in case of CD19+ cells increase and/or disease reactivation; brain MRI 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 had exacerbation 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), Rituximab Background are controversial, but consensus exists about the need to Natalizumab has been confirmed as highly effective in short wash out period after natalizumab interruption [3, 4]. reducing multiple sclerosis (MS) disease activity. In this report we want to share our experience about However, it carries a risk of progressive multifocal the use of rituximab after natalizumab withdrawal with leukoencephalopathy (PML), an opportunistic disease the aim to evaluate its efficacy in controlling disease with high morbidity, that represents the major cause course. of natalizumab interruption. Upon withdrawing natalizumab, resumption of disease Case Presentation activity is soon observed [1, 2]. An unsolved problem is Ten RR-MS patients (8 women and 2 male) have been the lack of therapies able to abolish the risk of disease treated with natalizumab for a median number of 38 reactivation after natalizumab withdrawal. infusions (range 22–76); patients had a median number Many strategies aiming at reducing the risk of disease of 2 relapses in the year preceding natalizumab in spite reactivation have been tried; switching to first-line of disease modifying drugs (DMDs) and full response to therapies or high dose corticosteroids failed to control natalizumab (neither clinical nor radiological activity the disease; literature data about the use of fingolimod during treatment); demographic and clinical characteristics are presented in Table 1. All the patients had high risk of PML, due to the association of a stratify index >1.5 and the * Correspondence: simona.malucchi@gmail.com elevated number of infusions. After consultation between University Hospital San Luigi Gonzaga, SCDO Neurologia 2- Regional neurologist and patient, decision to stop natalizumab was Multiple Sclerosis Center, Regione Gonzole 10, 10043 Orbassano, Torino, Italy Full list of author information is available at the end of the article taken and patients have been proposed to switch to © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Malucchi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:11 Page 2 of 3 Table 1 Demographic and clinical characteristics Gender Age at Relapses in the year N° of natalizumab EDSS after last Brain MRI at 6 months Brain MRI at 12 months natalizumab start before natalizumab infusions natalizumab infusion after rituximab after rituximab F 29 2 35 1.5 unchanged unchanged F 44 2 76 3.5 unchanged unchanged F 32 1 27 2.0 unchanged unchanged F 38 2 69 2.0 unchanged unchanged M 25 1 37 4.5 unchanged unchanged F 33 2 39 3.5 unchanged unchanged F 40 1 22 2.0 unchanged unchanged F 30 2 67 3.5 unchanged n.a. F 35 2 71 2.0 unchanged n.a. M 32 2 30 7.0 unchanged unchanged n.a. not available (follow up <1 year) rituximab after a wash out period of 2 months; written in- increase in the number of T2 lesions compared to the formed consent was obtained from each patient; as the use brain MRI that had been performed after the last of rituximab was off label, approval was obtained from the natalizumab infusion. In patients with a follow up of one local ethics committee of the University Hospital San year (8 patients), brain MRI performed 12 months after Luigi. rituximab was unchanged. In our real-world clinical study median wash out No patient experienced clinical rebound; two out of ten period was 3.2 months (range 2–4.2 months). had a worsening of pre-existing sensitive symptoms: the The choice of rituximab was due to the impossibility first patient had an exacerbation of paresthesia in left of using fingolimod, because of cardiologic contraindica- limbs six months after rituximab, the second had exacer- tion (2 patients), or patients’ refusal (8 patients). bation of paresthesia in left face nine months after rituxi- Each patient underwent gadolinium-enhanced brain mab; both patients were treated with intravenous steroids MRI scan after the last infusion of natalizumab and two for 3 days; in both cases CD19 at the time of clinical re- months later, in order to exclude signs suggestive for lapse were detectable and II cycle of rituximab was admin- PML; than brain MRI was performed six and twelve istered; brain MRI in both cases showed disease stability. months after rituximab infusion; MRI was performed in Compared to EDSS after the last natalizumab infusion, the same 1.5 T scanner using the same protocol for each EDSS was unchanged at six months in all the patients patients; protocol included axial T2-weighted scans, and at 12 months in patients with one year follow up. coronal Flair-weighted scans, DWI sequences and post- contrast T1-weighted scans. Conclusions Rituximab was administered at the dosage of 375 mg/mq This is a preliminary study, conducted on a small number once/week for 4 weeks (I cycle); blood sample was taken of patients, aiming at the evaluation of rituximab efficacy monthly in order to count CD19+ cells; second cycle at the after natalizumab withdrawal. The choice of rituximab dosage of 1000 mg at day 0 and 15 was planned in case of was due to two main reasons: the evidence of efficacy in CD19+ increase and/or clinical or radiological disease aggressive RR-MS patients [5] and the minor risk of PML reactivation. compared to that of natalizumab [6, 7]. Patients started rituximab from October 2013 to May Furthermore, the use of rituximab was due to the 2014; median follow up after rituximab was 15.8 months impossibility of using fingolimod, because of bradycardia (range 11.5–18.5 months). in 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 characterized Results by young people with desire for parenthood; patients No patient had disease reactivation during the wash out would have to undergo fertility preservation procedures period; brain MRI performed two months after the last that would have extended the time of drug initiation. natalizumab infusion was unchanged compared to the Alemtuzumab was not yet available at the time the study one performed immediately after the last infusion. was conducted, so its use was not allowed. A brain MRI performed six months after rituximab This work shows rituximab is highly efficacious in con- infusions did not show contrast-enhancing lesions or an trolling disease course after natalizumab discontinuation, Malucchi et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:11 Page 3 of 3 as no patient had disease rebound, nor radiological reacti- Disclosure Dr Simona Malucchi, Dr Marco Capobianco, Dr Antonio Bertolotto received vation at six months after rituximab infusion, that corres- consultation and speaking fees from Sanofi-Genzyme, Biogen-Idec, Merck-Serono, pond to at least 8 months after natalizumab withdrawal. Novartis and Teva; Dr Alessia di Sapio received consultation and speaking fees Eight patients reached a follow up of one year and in from Biogen-Idec, Merck Serono, Teva and Novartis. Dr Paola Cavalla. these patients MRI at 12 months showed persistence of Dr Marianna Lo Re has nothing to disclose. stability. We observed two very mild relapses in two patients at Author details University Hospital San Luigi Gonzaga, SCDO Neurologia 2- Regional six and nine months after rituximab, without brain MRI Multiple Sclerosis Center, Regione Gonzole 10, 10043 Orbassano, Torino, Italy. activity; in that circumstance the two patients showed an 2 Dipartimento di Biomedicina Sperimentale e di Neuroscienze Cliniche, increase of CD19+ cells that required the second cycle Università di Palermo, Via del Vespro 129, 90127 Palermo, Italy. Department of Neuroscience and Mental Health, Health and Science City, University of treatment. Hospital of Turin, MS Center, I Neurologic Clinic, Via Cherasco 15, 10126 A matter of concern in using Rituximab is the risk of Torino, Italy. PML; compared to natalizumabverylittledataare known Received: 2 July 2015 Accepted: 24 May 2016 about PML risk during rituximab treatment; data from rheumatologic experience suggest a PML risk of 1/25000 in rheumatoid arthritis affected patients treated with rituxi- References 1. O’Connor PW, Goodman A, Kappos L, Lublin FD, Miller DH, Polman C, et al. mab, including both JCV positive and negative patients (6), Disease activity return during natalizumab treatment interruption in patients whereas patients in our work had a risk of 1/120–1/145 [8]. with multiple sclerosis. Neurology. 2011;76:1858–65. Finally, at present there is no agreement on what 2. Sorensen PS, Koch-Henriksen N, Petersen T, Ravnborg M, Oturai A, Sellebjerg F. Recurrence of rebound of clinical relapses after discontinuation of natalizumab would be the best posological scheme for rituximab in therapy in highly active MS patients. J Neurol. 2014;261(6):1170–7. MS, including its duration. Different protocols have been doi:10.1007/s00415-014-7325-8. Epub 2014 Apr 12. suggested and applied: 375 mg every week for 4 weeks 3. Laroni A, Brogi D, Milesi V, Abate L, Uccelli A, Mancardi G. Early switch to fingolimod may decrease the risk of disease recurrence after natalizumab [9] or 1000 mg i.v. at day 0 and 15 [10]. Whatever interruption. Mult Scler. 2013;19(9):1236–7. regimen is adopted and despite the lower risk of PML, 4. Cohen M, Maillart E, Tourbah A, De Seze J, Vukusic S, Brassat D, et al. we believe that the use of rituximab to prevent Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 2014;71(4):436–41. breakthrough disease after natalizumab should be 5. Naismith RT, Piccio L, Lyons JA, Lauber J, Tutlam NT, Parks BJ, et al. restricted to the first month after its discontinuation. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis. A Later on additional strategies have to be found. In 52-week phase II trial. Neurology. 2010;74:1860–7. 6. Palazzo E, Yahia SA. Progressive multifocal leukoencephalopaty in our Clinic we are planning to use a standard regimen autoimmune disease. Joint Bone Spine. 2012;79(4):351–5. with retreatment six month after the first cycle of 7. Carson KR, Focosi D, Major EO, Petrini M, Richey EA, West DP, et al. rituximab followed by a switch to another drug such Monoclonal antibody-associated progressive multifocal leukoencefalophaty in patients treated with rituximab, natalizumab, and efalizumab: a review as dimethyl fumarate. from the Research ion Adverse Drug Events and Reports (RADAR) project. Despite the small number of patients this study has Lancet Oncol. 2009;10(8):816–24. two strong points: 1) patients had similar disease 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 of features before natalizumab initiation with very active Natalizumab-Associated Progressive Multifocal Leukoencephalopathy. Ann course, and high risk of disease reactivation after its Neurol. 2014;76(6):802–12. interruption; brain MRI were performed at the same 9. Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E. Rituximab in Relapsing and Progressive Forms of Multiple Sclerosis: A Systematic Review. time points with the same scanner and same protocol; 2) Plos One. 2013;8(7), e66308. it shows rituximab appears an efficacious strategy to 10. Bar-Or A, Calabresi PAJ, Arnold D, Markowitz C, Shafer S, Kasper LH, et al. manage natalizumab discontinuation; therefore we think Rituximab in Relapsing-Remitting Multiple Sclerosis: A 72-Week, Open-Label, Phase I Trial. Ann Neurol. 2008;63:395–400. our experience needs to be shared. Authors’ contributions Submit your next manuscript to BioMed Central SM, MC, AdS, and MLR participated in the selection of patient, clinical evaluation of patients and coordination of the study; PC participated in and we will help you at every step: selection and clinical evaluation of patients; AB participated in the design of the study. All authors read and approved the final manuscript. • We accept pre-submission inquiries � Our selector tool helps you to find the most relevant journal � We provide round the clock customer support Competing interests � Convenient online submission The authors declare that they have no competing interests. � Thorough peer review � Inclusion in PubMed and all major indexing services Consent statement � Maximum visibility for your research Written informed consent was obtained from the patients for publication of these case reports. A copy of the written consent is available for review by Submit your manuscript at the Editor-in-Chief of this journal. www.biomedcentral.com/submit

Journal

Multiple Sclerosis and Demyelinating DisordersSpringer Journals

Published: Jul 7, 2016

There are no references for this article.