- Email: [email protected]
The ‘Field Hypothesis’: rebound activity after stopping disease-modifying therapies
Multiple Sclerosis and Related Disorders 15 (2017) A1–A2
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
The ‘Field Hypothesis’: rebound activity after stopping disease-modifying therapies
MARK
People with multiple sclerosis who stop treatment with natalizumab or fingolimod, drugs that can broadly be classified as lymphocyte antitrafficking therapies, are at risk of developing rebound disease activity. Rebound can be defined as disease activity that is well above the level of disease activity that one would expect based on pre-treatment, i.e. prior to starting on natalizumab or fingolimod. In this issue of the journal Forci and colleagues describe two cases with severe MS rebound activity with very high numbers of gadolinium-enhancing lesions on brain MRI, a few weeks after stopping fingolimod (Forci et al., 2017). In general, patients treated with natalizumab have more active MS pre-treatment and are at risk of a more ‘severe rebound’, typically occurring on MRI around 3-4 months after stopping the drug (Martinelli et al., 2013; O’Connor et al., 2011). Natalizumab rebound activity coincides with a drop in blood levels of natalizumab and consequent re-trafficking of lymphocyte across the blood brain barrier. In the two cases of fingolimod rebound reported in this journal, clinical activity occurred 3 and 6 weeks after discontinuing treatment (Forci et al., 2017), arguably a time course compatible with fingolimod’s elimination half-life of approximately 8 days (Kovarik et al., 2004a). Fingolimod works by trapping lymphocytes in lymph nodes and bone marrow (Chun and Hartung, 2010). When the drug is stopped, average lymphocyte counts exceeded the lower limit of normal range within 6-8 weeks and return to 80% of baseline values by three months (Francis et al., 2014; Kovarik et al., 2004b). This recovery explains why fingolimod-related clinical rebound occurs sooner than with natalizumab. The two cases reported in this journal are not the first to be described in relation to stopping fingolimod (De Masi et al., 2015; Gross et al., 2012; Sempere et al., 2013). To prevent rebound disease activity one should consider starting alternative disease modifying treatment (DMT) soon after the last dose of either natalizumab or fingolimod, unless pregnancy is an issue. In the case of natalizumab another therapy should be introduced preferably within 4 weeks of the last dose (Giovannoni and Naismith, 2014), because natalizumab wash-out periods of longer than 4 weeks have been associated with higher levels of recurrent, or rebound, disease activity. With fingolimod the follow-on DMT should probably be started as early as possible to give it the best chance of becoming active when lymphocytes start recirculating. There has been considerable debate about the sequencing of therapies post-natalizumab, particularly if the reason for stopping is to reduce the risk of developing progressive multifocal leukoencephalopathy (PML). One potential risk of switching patients to another DMT is ‘carry-over’ PML (Killestein et al., 2014; Putzki et al., 2014) a phenomenon that develops typically within a few months after starting the new medication. Problems, however, may arise if the follow-on treatments results in long-term lymphocyte depletion, for example alemtuzumab (anti-CD52 antibody) or potentially with other induction therapies (cladribine, mitoxantrone, haemopoietic stem cell transplant). These strategies induce long-term immunosuppressive effects with delayed immune reconstitution. As survival from PML is strongly linked to the cytotoxic CD8+ T-cell response against JCV (Tassie et al., 1999), these patients would be at high risk of succumbing to PML due to their compromised immune system. Although anti-CD20 therapies, rituximab and ocrelizumab, result in prolonged B-cell depletion (but not T-cell depletion) they should be ‘less risky’ than T-cell depleting agents mentioned above. However, B-cell responses may be important for immunity against JCV escape variants associated with PML (Lutterotti and Martin, 2008). Therefore, we will need to study the outcome of carry-over PML in patients who have received rituximab, or ocrelizumab, to determine whether the mortality is higher than expected for other reversible, and slowly reversible, DMTs. It also emphasises the need for imaging of natalizumab treated patients who are JCV antibody positive before they receive the first infusion of a T cell and/or B cell depleting agents in order to identify the few patients who may have asymptomatic PML. When patients require induction therapy post-natalizumab, some clinicians promote a 6-12 month bridge, with a reversible oral DMT, from which patients are switched to rapidly effective reversible maintenance therapy to offset the risk of carry-over PML (Giovannoni et al., 2016; Lutterotti and Martin, 2008). It should be noted that the risk of PML after natalizumab withdrawal is unlikely to disappear completely, despite a bridge with another DMT. The pathogenesis of PML is complex, and if JCV has acquired pathogenic mutations these are unlikely to be reversed by simply stopping natalizumab. Data from animal studies suggest that intravenous alemtuzumab targets circulating lymphocytes and therefore less effective at depleting lymphocytes in lymph nodes (Hu et al., 2009) that are trapped by fingolimod. Accordingly, some recommend stopping fingolimod, waiting 2-4 weeks, checking peripheral lymphocyte counts to ensure they are returning towards normal before giving the first course of alemtuzumab. A prolonged wash-out after fingolimod discontinuation to try and prevent rebound is not recommended (Sempere et al., 2013)(Gross et al., 2012). Another reason for administering a brief fingolimod washout period is to exclude the remote possibility of persistent post-fingolimod lymphopenia. A few cases of persistent lymphopenia lasting several years have been reported with fingolimod (Johnson et al., 2010). Whether persistent lymphopenia can occur after a 6-12-month bridge is unknown, but some have recommended that the lymphocyte count should have recovered towards normal (at least 0.8 x 109/L) after stopping fingolimod before administering alemtuzumab (Giovannoni et al., 2016). Rebound may be telling us something about the pathogenesis of MS. When autoreactive cells are allowed to recirculate and/or enter the central nervous system (CNS), they might be detect something pathogenic that triggers the development of a new lesion or the reactivation of an old lesion. http://dx.doi.org/10.1016/j.msard.2017.06.005
2211-0348/ © 2017 Elsevier B.V. All rights reserved.
Multiple Sclerosis and Related Disorders 15 (2017) A1–A2
According to the field hypothesis, there is something in the field, or CNS tissue, that triggers focal inflammation, for example a virus. Rebound is not too dissimilar to IRIS (immune reconstitution inflammatory syndrome) in patients with PML when natalizumab clears from the blood, allowing anti-JCV cytotoxic T-lymphocytes to traffic into the brain and to find and kill their target. Could rebound following natalizumab and fingolimod simply represent IRIS in response to a yet to be identified viral aetiology of MS? Interestingly, when patients with MS were treated with interferon-gamma, a potent antiviral cytokine that stimulates immune responses, they all had relapses (Panitch et al., 1987a, 1987b) that occurred in sites previously affected by MS (personal communication, Hillel Panitch). Another observation supporting the field hypothesis comes from serial MRI studies that demonstrate subtle changes in the white matter many weeks, or months, before a focal gadolinium-enhancing lesion appears (Filippi et al., 1998). This suggests that the primary pathology is a neuropathogen that takes weeks or months to activate a focal inflammatory lesion. The challenge is to find out what the field abnormality is. One way to resolve this would be to study post-mortem brains from MS subjects who die while receiving natalizumab or fingolimod. Recently, Serafini and colleagues described numerous EBV infected B cells and plasma cells, and marked CD8+ T cell infiltration of white matter lesions in postmortem brain tissue from a patient who died from fulminating MS due to post-natalizumab rebound (Serafini et al., 2017). Importantly, the highest frequency of EBV infected cells, with lytic infection, and granzyme B+ CD8+ T cells was observed in actively demyelinating lesions (Serafini et al., 2017). These results need to be reproduced but highlight a potential causal role of EBV in relapse of MS. As the number of DMTs increases, the challenges for safe management escalates. Observations and insights surrounding the mechanisms of rebound provide a unique opportunity to study the pathobiology of MS. References Chun, J., Hartung, H.-P., 2010. Mechanism of Action of Oral Fingolimod (FTY720) in Multiple Sclerosis. Clin. Neuropharmacol. 33, 91–101. De Masi, R., Accoto, S., Orlando, S., De Blasi, V., Pasca, S., Scarpello, R., Spagnolo, L., Idolo, A., De Donno, A., 2015. Dramatic recovery of steroid-refractory relapsed multiple sclerosis following Fingolimod discontinuation using selective immune adsorption. BMC Neurol. 15, 125. Filippi, M., Rocca, M.A., Martino, G., Horsfield, M.A., Comi, G., 1998. Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis. Ann. Neurol. 43, 809–814. Forci, B., Mariottini, A., Mechi, C., Massacesi, L., Repice, A., 2017. Disease reactivation following fingolimod withdrawal in multiple sclerosis: Two case reports. Mult. Scler. Relat. Disord. 15, 24–26. Francis, G., Kappos, L., O’Connor, P., Collins, W., Tang, D., Mercier, F., Cohen, J.A., 2014. Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy. Mult. Scler. 20, 471–480. Giovannoni, G., Marta, M., Davis, A., Turner, B., Gnanapavan, S., Schmierer, K., 2016. Switching patients at high risk of PML from natalizumab to another disease-modifying therapy. Pract. Neurol. 16, 389–393. Giovannoni, G., Naismith, R.T., 2014. Natalizumab to fingolimod washout in patients at risk of PML: when good intentions yield bad outcomes. Neurology 82, 1196–1197. Gross, C.M., Baumgartner, A., Rauer, S., Stich, O., 2012. Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod. Neurology 79, 2006–2007. Hu, Y., Turner, M.J., Shields, J., Gale, M.S., Hutto, E., Roberts, B.L., Siders, W.M., Kaplan, J.M., 2009. Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 128, 260–270. Johnson, T.A., Shames, I., Keezer, M., Lapierre, Y., Haegert, D.G., Bar-Or, A., Antel, J., 2010. Reconstitution of circulating lymphocyte counts in FTY720-treated MS patients. Clin. Immunol. 137, 15–20. Killestein, J., Vennegoor, A., van Golde, A.E.L., Bourez, R.L.J.H., Wijlens, M.L.B., Wattjes, M.P., 2014. PML-IRIS during Fingolimod Diagnosed after Natalizumab Discontinuation. Case Rep. Neurol. Med. 2014, 307872. Kovarik, J.M., Schmouder, R., Barilla, D., Riviere, G.-J., Wang, Y., Hunt, T., 2004a. Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects. J. Clin. Pharmacol. 44, 532–537. Kovarik, J.M., Schmouder, R., Barilla, D., Wang, Y., Kraus, G., 2004b. Single-dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects. Br. J. Clin. Pharmacol. 57, 586–591. Lutterotti, A., Martin, R., 2008. Getting specific: monoclonal antibodies in multiple sclerosis. Lancet Neurol. 7, 538–547. Martinelli, V., Colombo, B., Dalla Costa, G., Dalla Libera, D., Moiola, L., Falini, A., Comi, G., Filippi, M., 2013. Recurrent disease-activity rebound in a patient with multiple sclerosis after natalizumab discontinuations for pregnancy planning. Mult. Scler. http://dx.doi.org/10.1177/1352458513492246. O’Connor, P.W., Goodman, A., Kappos, L., Lublin, F.D., Miller, D.H., Polman, C., Rudick, R.A., Aschenbach, W., Lucas, N., 2011. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 76, 1858–1865. Panitch, H.S., Hirsch, R.L., Haley, A.S., Johnson, K.P., 1987a. Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet 1, 893–895. Panitch, H.S., Hirsch, R.L., Schindler, J., Johnson, K.P., 1987b. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 37, 1097–1102. Putzki, N., Clifford, D.B., Bischof, D., Moore, A., Weinshenker, B.G., Freedman, M.S., 2014. Characteristics of PML cases in multiple sclerosis patients switching to fingolimod from natalizumab. Presentation at ECTRIMS. Sempere, A.P., Berenguer-Ruiz, L., Feliu-Rey, E., 2013. Rebound of disease activity during pregnancy after withdrawal of fingolimod. Eur. J. Neurol. 20, e109–10. Serafini, B., Scorsi, E., Rosicarelli, B., Rigau, V., Thouvenot, E., Aloisi, F., 2017. Massive intracerebral Epstein-Barr virus reactivation in lethal multiple sclerosis relapse after natalizumab withdrawal. J. Neuroimmunol. 307, 14–17. Tassie, J.-M., Gasnault, J., Bentata, M., Deloumeaux, J., Boué, F., Billaud, E., Costagliola, D., 1881. the Clinical Epidemiology Group from the French Hospital Database on HIV, 1999. Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. AIDS 13.
⁎
Gavin Giovannoni Blizard Institute, Queen Mary University London, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK E-mail address: [email protected]
Chris Hawkes Blizard Institute, Queen Mary University London, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK E-mail address: [email protected] Emmanuelle Waubant Department of Neurology, UCSF School of Medicine, 675 Nelson Rising Lane, San Francisco CA 94158, USA E-mail address: [email protected] Fred Lublin Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai School of Medicine, New York, NY, USA E-mail address: [email protected]
⁎
Corresponding author.
A2
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
The ‘Field Hypothesis’: rebound activity after stopping disease-modifying therapies
MARK
People with multiple sclerosis who stop treatment with natalizumab or fingolimod, drugs that can broadly be classified as lymphocyte antitrafficking therapies, are at risk of developing rebound disease activity. Rebound can be defined as disease activity that is well above the level of disease activity that one would expect based on pre-treatment, i.e. prior to starting on natalizumab or fingolimod. In this issue of the journal Forci and colleagues describe two cases with severe MS rebound activity with very high numbers of gadolinium-enhancing lesions on brain MRI, a few weeks after stopping fingolimod (Forci et al., 2017). In general, patients treated with natalizumab have more active MS pre-treatment and are at risk of a more ‘severe rebound’, typically occurring on MRI around 3-4 months after stopping the drug (Martinelli et al., 2013; O’Connor et al., 2011). Natalizumab rebound activity coincides with a drop in blood levels of natalizumab and consequent re-trafficking of lymphocyte across the blood brain barrier. In the two cases of fingolimod rebound reported in this journal, clinical activity occurred 3 and 6 weeks after discontinuing treatment (Forci et al., 2017), arguably a time course compatible with fingolimod’s elimination half-life of approximately 8 days (Kovarik et al., 2004a). Fingolimod works by trapping lymphocytes in lymph nodes and bone marrow (Chun and Hartung, 2010). When the drug is stopped, average lymphocyte counts exceeded the lower limit of normal range within 6-8 weeks and return to 80% of baseline values by three months (Francis et al., 2014; Kovarik et al., 2004b). This recovery explains why fingolimod-related clinical rebound occurs sooner than with natalizumab. The two cases reported in this journal are not the first to be described in relation to stopping fingolimod (De Masi et al., 2015; Gross et al., 2012; Sempere et al., 2013). To prevent rebound disease activity one should consider starting alternative disease modifying treatment (DMT) soon after the last dose of either natalizumab or fingolimod, unless pregnancy is an issue. In the case of natalizumab another therapy should be introduced preferably within 4 weeks of the last dose (Giovannoni and Naismith, 2014), because natalizumab wash-out periods of longer than 4 weeks have been associated with higher levels of recurrent, or rebound, disease activity. With fingolimod the follow-on DMT should probably be started as early as possible to give it the best chance of becoming active when lymphocytes start recirculating. There has been considerable debate about the sequencing of therapies post-natalizumab, particularly if the reason for stopping is to reduce the risk of developing progressive multifocal leukoencephalopathy (PML). One potential risk of switching patients to another DMT is ‘carry-over’ PML (Killestein et al., 2014; Putzki et al., 2014) a phenomenon that develops typically within a few months after starting the new medication. Problems, however, may arise if the follow-on treatments results in long-term lymphocyte depletion, for example alemtuzumab (anti-CD52 antibody) or potentially with other induction therapies (cladribine, mitoxantrone, haemopoietic stem cell transplant). These strategies induce long-term immunosuppressive effects with delayed immune reconstitution. As survival from PML is strongly linked to the cytotoxic CD8+ T-cell response against JCV (Tassie et al., 1999), these patients would be at high risk of succumbing to PML due to their compromised immune system. Although anti-CD20 therapies, rituximab and ocrelizumab, result in prolonged B-cell depletion (but not T-cell depletion) they should be ‘less risky’ than T-cell depleting agents mentioned above. However, B-cell responses may be important for immunity against JCV escape variants associated with PML (Lutterotti and Martin, 2008). Therefore, we will need to study the outcome of carry-over PML in patients who have received rituximab, or ocrelizumab, to determine whether the mortality is higher than expected for other reversible, and slowly reversible, DMTs. It also emphasises the need for imaging of natalizumab treated patients who are JCV antibody positive before they receive the first infusion of a T cell and/or B cell depleting agents in order to identify the few patients who may have asymptomatic PML. When patients require induction therapy post-natalizumab, some clinicians promote a 6-12 month bridge, with a reversible oral DMT, from which patients are switched to rapidly effective reversible maintenance therapy to offset the risk of carry-over PML (Giovannoni et al., 2016; Lutterotti and Martin, 2008). It should be noted that the risk of PML after natalizumab withdrawal is unlikely to disappear completely, despite a bridge with another DMT. The pathogenesis of PML is complex, and if JCV has acquired pathogenic mutations these are unlikely to be reversed by simply stopping natalizumab. Data from animal studies suggest that intravenous alemtuzumab targets circulating lymphocytes and therefore less effective at depleting lymphocytes in lymph nodes (Hu et al., 2009) that are trapped by fingolimod. Accordingly, some recommend stopping fingolimod, waiting 2-4 weeks, checking peripheral lymphocyte counts to ensure they are returning towards normal before giving the first course of alemtuzumab. A prolonged wash-out after fingolimod discontinuation to try and prevent rebound is not recommended (Sempere et al., 2013)(Gross et al., 2012). Another reason for administering a brief fingolimod washout period is to exclude the remote possibility of persistent post-fingolimod lymphopenia. A few cases of persistent lymphopenia lasting several years have been reported with fingolimod (Johnson et al., 2010). Whether persistent lymphopenia can occur after a 6-12-month bridge is unknown, but some have recommended that the lymphocyte count should have recovered towards normal (at least 0.8 x 109/L) after stopping fingolimod before administering alemtuzumab (Giovannoni et al., 2016). Rebound may be telling us something about the pathogenesis of MS. When autoreactive cells are allowed to recirculate and/or enter the central nervous system (CNS), they might be detect something pathogenic that triggers the development of a new lesion or the reactivation of an old lesion. http://dx.doi.org/10.1016/j.msard.2017.06.005
2211-0348/ © 2017 Elsevier B.V. All rights reserved.
Multiple Sclerosis and Related Disorders 15 (2017) A1–A2
According to the field hypothesis, there is something in the field, or CNS tissue, that triggers focal inflammation, for example a virus. Rebound is not too dissimilar to IRIS (immune reconstitution inflammatory syndrome) in patients with PML when natalizumab clears from the blood, allowing anti-JCV cytotoxic T-lymphocytes to traffic into the brain and to find and kill their target. Could rebound following natalizumab and fingolimod simply represent IRIS in response to a yet to be identified viral aetiology of MS? Interestingly, when patients with MS were treated with interferon-gamma, a potent antiviral cytokine that stimulates immune responses, they all had relapses (Panitch et al., 1987a, 1987b) that occurred in sites previously affected by MS (personal communication, Hillel Panitch). Another observation supporting the field hypothesis comes from serial MRI studies that demonstrate subtle changes in the white matter many weeks, or months, before a focal gadolinium-enhancing lesion appears (Filippi et al., 1998). This suggests that the primary pathology is a neuropathogen that takes weeks or months to activate a focal inflammatory lesion. The challenge is to find out what the field abnormality is. One way to resolve this would be to study post-mortem brains from MS subjects who die while receiving natalizumab or fingolimod. Recently, Serafini and colleagues described numerous EBV infected B cells and plasma cells, and marked CD8+ T cell infiltration of white matter lesions in postmortem brain tissue from a patient who died from fulminating MS due to post-natalizumab rebound (Serafini et al., 2017). Importantly, the highest frequency of EBV infected cells, with lytic infection, and granzyme B+ CD8+ T cells was observed in actively demyelinating lesions (Serafini et al., 2017). These results need to be reproduced but highlight a potential causal role of EBV in relapse of MS. As the number of DMTs increases, the challenges for safe management escalates. Observations and insights surrounding the mechanisms of rebound provide a unique opportunity to study the pathobiology of MS. References Chun, J., Hartung, H.-P., 2010. Mechanism of Action of Oral Fingolimod (FTY720) in Multiple Sclerosis. Clin. Neuropharmacol. 33, 91–101. De Masi, R., Accoto, S., Orlando, S., De Blasi, V., Pasca, S., Scarpello, R., Spagnolo, L., Idolo, A., De Donno, A., 2015. Dramatic recovery of steroid-refractory relapsed multiple sclerosis following Fingolimod discontinuation using selective immune adsorption. BMC Neurol. 15, 125. Filippi, M., Rocca, M.A., Martino, G., Horsfield, M.A., Comi, G., 1998. Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis. Ann. Neurol. 43, 809–814. Forci, B., Mariottini, A., Mechi, C., Massacesi, L., Repice, A., 2017. Disease reactivation following fingolimod withdrawal in multiple sclerosis: Two case reports. Mult. Scler. Relat. Disord. 15, 24–26. Francis, G., Kappos, L., O’Connor, P., Collins, W., Tang, D., Mercier, F., Cohen, J.A., 2014. Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy. Mult. Scler. 20, 471–480. Giovannoni, G., Marta, M., Davis, A., Turner, B., Gnanapavan, S., Schmierer, K., 2016. Switching patients at high risk of PML from natalizumab to another disease-modifying therapy. Pract. Neurol. 16, 389–393. Giovannoni, G., Naismith, R.T., 2014. Natalizumab to fingolimod washout in patients at risk of PML: when good intentions yield bad outcomes. Neurology 82, 1196–1197. Gross, C.M., Baumgartner, A., Rauer, S., Stich, O., 2012. Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod. Neurology 79, 2006–2007. Hu, Y., Turner, M.J., Shields, J., Gale, M.S., Hutto, E., Roberts, B.L., Siders, W.M., Kaplan, J.M., 2009. Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 128, 260–270. Johnson, T.A., Shames, I., Keezer, M., Lapierre, Y., Haegert, D.G., Bar-Or, A., Antel, J., 2010. Reconstitution of circulating lymphocyte counts in FTY720-treated MS patients. Clin. Immunol. 137, 15–20. Killestein, J., Vennegoor, A., van Golde, A.E.L., Bourez, R.L.J.H., Wijlens, M.L.B., Wattjes, M.P., 2014. PML-IRIS during Fingolimod Diagnosed after Natalizumab Discontinuation. Case Rep. Neurol. Med. 2014, 307872. Kovarik, J.M., Schmouder, R., Barilla, D., Riviere, G.-J., Wang, Y., Hunt, T., 2004a. Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects. J. Clin. Pharmacol. 44, 532–537. Kovarik, J.M., Schmouder, R., Barilla, D., Wang, Y., Kraus, G., 2004b. Single-dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects. Br. J. Clin. Pharmacol. 57, 586–591. Lutterotti, A., Martin, R., 2008. Getting specific: monoclonal antibodies in multiple sclerosis. Lancet Neurol. 7, 538–547. Martinelli, V., Colombo, B., Dalla Costa, G., Dalla Libera, D., Moiola, L., Falini, A., Comi, G., Filippi, M., 2013. Recurrent disease-activity rebound in a patient with multiple sclerosis after natalizumab discontinuations for pregnancy planning. Mult. Scler. http://dx.doi.org/10.1177/1352458513492246. O’Connor, P.W., Goodman, A., Kappos, L., Lublin, F.D., Miller, D.H., Polman, C., Rudick, R.A., Aschenbach, W., Lucas, N., 2011. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 76, 1858–1865. Panitch, H.S., Hirsch, R.L., Haley, A.S., Johnson, K.P., 1987a. Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet 1, 893–895. Panitch, H.S., Hirsch, R.L., Schindler, J., Johnson, K.P., 1987b. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 37, 1097–1102. Putzki, N., Clifford, D.B., Bischof, D., Moore, A., Weinshenker, B.G., Freedman, M.S., 2014. Characteristics of PML cases in multiple sclerosis patients switching to fingolimod from natalizumab. Presentation at ECTRIMS. Sempere, A.P., Berenguer-Ruiz, L., Feliu-Rey, E., 2013. Rebound of disease activity during pregnancy after withdrawal of fingolimod. Eur. J. Neurol. 20, e109–10. Serafini, B., Scorsi, E., Rosicarelli, B., Rigau, V., Thouvenot, E., Aloisi, F., 2017. Massive intracerebral Epstein-Barr virus reactivation in lethal multiple sclerosis relapse after natalizumab withdrawal. J. Neuroimmunol. 307, 14–17. Tassie, J.-M., Gasnault, J., Bentata, M., Deloumeaux, J., Boué, F., Billaud, E., Costagliola, D., 1881. the Clinical Epidemiology Group from the French Hospital Database on HIV, 1999. Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. AIDS 13.
⁎
Gavin Giovannoni Blizard Institute, Queen Mary University London, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK E-mail address: [email protected]
Chris Hawkes Blizard Institute, Queen Mary University London, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK E-mail address: [email protected] Emmanuelle Waubant Department of Neurology, UCSF School of Medicine, 675 Nelson Rising Lane, San Francisco CA 94158, USA E-mail address: [email protected] Fred Lublin Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai School of Medicine, New York, NY, USA E-mail address: [email protected]
⁎
Corresponding author.
A2