517281
article2014
MSJ0010.1177/1352458513517281Multiple Sclerosis Journal 0(0)Tur and Montalban
MULTIPLE SCLEROSIS MSJ JOURNAL
Clinical Commentary
Comment on ‘Fingolimod to treat severe MS after natalizumabassociated progressive multifocal leukoencephalopathy: a valid option?’ Maillart et al.
Multiple Sclerosis Journal 2014, Vol. 20(4) 510–511 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1352458513517281 msj.sagepub.com
Carmen Tur and Xavier Montalban After the approval of natalizumab for relapsing–remitting multiple sclerosis (MS),1–3 it has been extensively used, mainly as a second line therapy, with very good results.4 However, in 2005, it was voluntarily withdrawn from the market after the appearance of two cases of progressive multifocal leukoencephalopathy (PML), a rare infection of the central nervous system (CNS) caused by the John Cunningham virus (JCV), which may have fatal consequences in 20% of those affected, or lead to serious disability in 40% of survivors.5 Although natalizumab was reintroduced in 2006, its use has been limited due to the appearance of PML which has been associated with natalizumab treatment duration longer than two years, presence of antibodies against JCV, and a prior history of immunosuppression.5 Yet when natalizumab is discontinued, either due to the presence of PML signs or to a high PML risk, an immune reconstitution inflammatory syndrome (IRIS) may appear in a third of the patients, sometimes causing severe disability or even death.6 In this issue of the journal, Maillart et al. describe two cases of MS patients who withdrew from natalizumab after showing signs of PML and who, after being treated with plasmapheresis, developed IRIS. Afterwards, they started fingolimod, showing a favourable clinical and magnetic resonance imaging (MRI) evolution, from both the IRIS and the PML points of view. Three points arise with these two cases. First, despite all of the risk stratification algorithms published so far, it is not possible to predict which individual patients will develop PML. Furthermore, there is no treatment to prevent its appearance. Of note, at the last meeting of the European Neurological Societies, it was suggested that the titres of anti-JCV antibodies could be used as better markers of PML risk than just the presence of anti-JCV antibodies, especially if they had not received prior immunosuppression (IS).7 Thus, should the accuracy of the titres of antiJCV antibodies in predicting PML be confirmed, the current risk stratification algorithms –and therefore the decision making processes–surely need to be improved. Second, it is not possible to predict which patients will develop IRIS
after natalizumab withdrawal. More studies in this direction are urgently needed but some degree of IRIS seems to be desirable in order to effectively attack the virus. Finally, there are no clear guidelines as to which is the best diseasemodifying treatment after natalizumab withdrawal, especially if discontinuation occurs due to the presence of PML signs. Maillart et al. suggest that fingolimod may be a safe option. As regards the two cases described by them, both MS and PML remained stable. Along these lines, fingolimod has recently been evaluated as a post-natalizumab MS treatment within the TOFINGO trial.8 Interestingly, this showed that the earlier fingolimod started after natalizumab discontinuation, the lower the risk of IRIS was. Nonetheless, the relative immunosuppression within the CNS caused by fingolimod,9 which hypothetically could worsen a case of PML, should also make clinicians be cautious when prescribing fingolimod after natalizumab treatment. In sum, prediction and management of both natalizumab-associated PML and natalizumab withdrawalassociated IRIS are unresolved issues. In addition, treatment strategies after natalizumab withdrawal need to be investigated. Yet, as Maillart et al. suggest, fingolimod might well be an option for those patients who discontinue natalizumab in the context of PML. Conflicts of interest Carmen Tur has received honoraria and support for travel from Merk-Serono, Serono Foundation, Sanofi-Aventis, BayerSchering, Teva and Novartis. Xavier Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory
Multiple Sclerosis Centre of Catalonia, Neurology/Neuroimmunology Department, Vall d’Hebron University Hospital, Barcelona, Spain. Corresponding author: Carmen Tur, Multiple Sclerosis Centre of Catalonia. Neurology/ Neuroimmunology Department, Vall d’Hebron University Hospital, Pg. Vall d’Hebron 119-129, Barcelona, 08035, Spain. Email: [email protected]
Downloaded from msj.sagepub.com at UCSF LIBRARY & CKM on April 2, 2015
511
Tur and Montalban boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall.
Funding For this paper, the authors received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354: 911–923. 2. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354: 899–910. 3. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348: 15–23. 4. Horga A, Castillo J, Rio J, et al. [An observational study of the effectiveness and safety of natalizumab in the treatment of multiple sclerosis]. Rev Neurol 2011; 52: 321–330.
5. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012; 366: 1870–1880. 6. Vellinga MM, Castelijns JA, Barkhof F, et al. Postwithdrawal rebound increase in T2 lesional activity in natalizumabtreated MS patients. Neurology 2008; 70: 1150–1151. 7. Plavina T, Subramanyam M, Bloomgren G, et al. Use of JC virus antibody index to stratify risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis (oral communication). 23rd Meeting of the European Neurological Society. 8–11 June, 2013. Barcelona, Spain. 8. Kappos L, Comi G, Montalban X, et al. Disease control and safety in relapsing-remitting multiple sclerosis (RRMS) patients switching from natalizumab to fingolimod: A 32-week, rater- and patient-blind, randomized, parallelgroup study (TOFINGO). Oral communication at ECTRIMS meeting 2013. 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, 2–5 October, 2013. Copenhagen, Denmark. 9. Singer BA. Initiating oral fingolimod treatment in patients with multiple sclerosis. Ther Adv Neurol Disord 2013; 6: 269–275.
Downloaded from msj.sagepub.com at UCSF LIBRARY & CKM on April 2, 2015
article2014
MSJ0010.1177/1352458513517281Multiple Sclerosis Journal 0(0)Tur and Montalban
MULTIPLE SCLEROSIS MSJ JOURNAL
Clinical Commentary
Comment on ‘Fingolimod to treat severe MS after natalizumabassociated progressive multifocal leukoencephalopathy: a valid option?’ Maillart et al.
Multiple Sclerosis Journal 2014, Vol. 20(4) 510–511 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1352458513517281 msj.sagepub.com
Carmen Tur and Xavier Montalban After the approval of natalizumab for relapsing–remitting multiple sclerosis (MS),1–3 it has been extensively used, mainly as a second line therapy, with very good results.4 However, in 2005, it was voluntarily withdrawn from the market after the appearance of two cases of progressive multifocal leukoencephalopathy (PML), a rare infection of the central nervous system (CNS) caused by the John Cunningham virus (JCV), which may have fatal consequences in 20% of those affected, or lead to serious disability in 40% of survivors.5 Although natalizumab was reintroduced in 2006, its use has been limited due to the appearance of PML which has been associated with natalizumab treatment duration longer than two years, presence of antibodies against JCV, and a prior history of immunosuppression.5 Yet when natalizumab is discontinued, either due to the presence of PML signs or to a high PML risk, an immune reconstitution inflammatory syndrome (IRIS) may appear in a third of the patients, sometimes causing severe disability or even death.6 In this issue of the journal, Maillart et al. describe two cases of MS patients who withdrew from natalizumab after showing signs of PML and who, after being treated with plasmapheresis, developed IRIS. Afterwards, they started fingolimod, showing a favourable clinical and magnetic resonance imaging (MRI) evolution, from both the IRIS and the PML points of view. Three points arise with these two cases. First, despite all of the risk stratification algorithms published so far, it is not possible to predict which individual patients will develop PML. Furthermore, there is no treatment to prevent its appearance. Of note, at the last meeting of the European Neurological Societies, it was suggested that the titres of anti-JCV antibodies could be used as better markers of PML risk than just the presence of anti-JCV antibodies, especially if they had not received prior immunosuppression (IS).7 Thus, should the accuracy of the titres of antiJCV antibodies in predicting PML be confirmed, the current risk stratification algorithms –and therefore the decision making processes–surely need to be improved. Second, it is not possible to predict which patients will develop IRIS
after natalizumab withdrawal. More studies in this direction are urgently needed but some degree of IRIS seems to be desirable in order to effectively attack the virus. Finally, there are no clear guidelines as to which is the best diseasemodifying treatment after natalizumab withdrawal, especially if discontinuation occurs due to the presence of PML signs. Maillart et al. suggest that fingolimod may be a safe option. As regards the two cases described by them, both MS and PML remained stable. Along these lines, fingolimod has recently been evaluated as a post-natalizumab MS treatment within the TOFINGO trial.8 Interestingly, this showed that the earlier fingolimod started after natalizumab discontinuation, the lower the risk of IRIS was. Nonetheless, the relative immunosuppression within the CNS caused by fingolimod,9 which hypothetically could worsen a case of PML, should also make clinicians be cautious when prescribing fingolimod after natalizumab treatment. In sum, prediction and management of both natalizumab-associated PML and natalizumab withdrawalassociated IRIS are unresolved issues. In addition, treatment strategies after natalizumab withdrawal need to be investigated. Yet, as Maillart et al. suggest, fingolimod might well be an option for those patients who discontinue natalizumab in the context of PML. Conflicts of interest Carmen Tur has received honoraria and support for travel from Merk-Serono, Serono Foundation, Sanofi-Aventis, BayerSchering, Teva and Novartis. Xavier Montalban has received speaking honoraria and travel expenses for scientific meetings, has been a steering committee member of clinical trials or participated in advisory
Multiple Sclerosis Centre of Catalonia, Neurology/Neuroimmunology Department, Vall d’Hebron University Hospital, Barcelona, Spain. Corresponding author: Carmen Tur, Multiple Sclerosis Centre of Catalonia. Neurology/ Neuroimmunology Department, Vall d’Hebron University Hospital, Pg. Vall d’Hebron 119-129, Barcelona, 08035, Spain. Email: [email protected]
Downloaded from msj.sagepub.com at UCSF LIBRARY & CKM on April 2, 2015
511
Tur and Montalban boards of clinical trials in the past years with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals and Almirall.
Funding For this paper, the authors received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354: 911–923. 2. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354: 899–910. 3. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348: 15–23. 4. Horga A, Castillo J, Rio J, et al. [An observational study of the effectiveness and safety of natalizumab in the treatment of multiple sclerosis]. Rev Neurol 2011; 52: 321–330.
5. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012; 366: 1870–1880. 6. Vellinga MM, Castelijns JA, Barkhof F, et al. Postwithdrawal rebound increase in T2 lesional activity in natalizumabtreated MS patients. Neurology 2008; 70: 1150–1151. 7. Plavina T, Subramanyam M, Bloomgren G, et al. Use of JC virus antibody index to stratify risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis (oral communication). 23rd Meeting of the European Neurological Society. 8–11 June, 2013. Barcelona, Spain. 8. Kappos L, Comi G, Montalban X, et al. Disease control and safety in relapsing-remitting multiple sclerosis (RRMS) patients switching from natalizumab to fingolimod: A 32-week, rater- and patient-blind, randomized, parallelgroup study (TOFINGO). Oral communication at ECTRIMS meeting 2013. 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, 2–5 October, 2013. Copenhagen, Denmark. 9. Singer BA. Initiating oral fingolimod treatment in patients with multiple sclerosis. Ther Adv Neurol Disord 2013; 6: 269–275.
Downloaded from msj.sagepub.com at UCSF LIBRARY & CKM on April 2, 2015
