Letter/Replies
Interestingly, natalizumab was withdrawn in the majority of patients (59%) in our case series after they tested positive for serum anti-JC virus antibodies, which was likely interpreted in conjunction with other PML risk factors (76% of patients had 2 risk factors). PML risk factors, although well documented in our case series, did not lead to preemptive MRI screening(s) to identify PML, but instead prompted clinicians to stop natalizumab. Our case assessments were sometimes limited by missing and incomplete data, which made it challenging to ascertain PML and/or immune reconstitution inflammatory syndrome symptoms, and to interpret reported MRI results. However, it was evident that many patients experienced neurologic decline following natalizumab withdrawal and were treated, on clinical grounds, for suspected multiple sclerosis (MS) relapse with immunomodulating agents or high-dose steroids; PML was considered only in the context of failure to respond to such treatments, thus impacting timely PML diagnosis. Also, we could not ascertain whether the MS therapies adversely affected the PML risk. Finally, and in agreement with Wattjes and Killstein, our case series supports the concept that the risk for PML extends for several months beyond the time of natalizumab withdrawal. Clinicians need to be vigilant for PML at the time of natalizumab discontinuation and during the post-treatment period, especially in patients with PML risk factors.
increase on the Expanded Disability Status Scale of 0.5 or 1 point from baseline sustained for at least 3 months, but with a different design. Trial definitions of disability progression identify mainly transient progression that is no more obvious at the end of the study, raising concerns about the efficacy of diseasemodifying drugs on disability progression. Few studies give the information based on sustained disability progression,2,3 that is, disability progression persisting for at least 3 months and sustained until the end of the trial. In the BENEFIT study, disability progression decreased from 24% (during the trial) to 15% (sustained up to 36 months), and in the PRISMS study from 29% to 9%. Unfortunately, this important information is not available for the trials that were used in the statistical analysis of Sormani and colleagues. This strongly questions the relevance of their findings.
Potential Conflicts of Interest Nothing to report regarding this letter. 1
Department of Neurology, Adolphe de Rothschild Foundation, Paris, and 2Department of Neurology, University Hospital Center of Reims, University of Reims Champagne-Ardenne, Reims, France
References
Potential Conflicts of Interest
1.
Sormani MP, Arnold DL, De Stefano N. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol 2014;75:43–49.
2.
Kappos L, Freedman MS, Polman CH, et al. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 2007;370:389–397.
3.
Medical officer’s clinical review of Rebif. February 9, 1999. Available at: http://www.fda.gov/downloads/Drugs/DevelopmentApproval Process/HowDrugsareDevelopedandApproved/ApprovalApplications/ TherapeuticBiologicApplications/ucm094516.pdf. Accessed March 7, 2002.
Nothing to report.
US Food and Drug Administration Center for Drug Evaluation and Research, Silver Spring, MD The views expressed are those of the authors and do not necessarily represent those of, nor imply endorsement from, the US Food and Drug Administration or the US government.
References 1.
Fine AJ, Sorbello A, Kortepeter C, Scarazzini L. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann Neurol 2013 Nov 16. [Epub ahead of print].
DOI: 10.1002/ana.24112
DOI: 10.1002/ana.24108
Reply Maria Pia Sormani, PhD,1 Douglas L. Arnold, MD,2 and Nicola De Stefano, MD3
Treatment Effect on Brain Atrophy Correlates with Treatment Effect on Disability in Multiple Sclerosis Olivier Gout, MD,1 and Ayman Tourbah, MD, PhD2 Sormani and colleagues1 reported that in relapsing–remitting multiple sclerosis, the treatment effect on brain atrophy is correlated with an effect on disability progression over 2 years. All the included studies consider disability progression as an March 2014
We thank Dr Gout and Dr Tourbah for their comment. We agree that an event of disability progression as defined by an Expanded Disability Status Scale (EDSS) increase can be transient, and therefore that the total event rate can depend on the time used to confirm the EDSS change. However, this correct reasoning does not apply to our analysis. We did not correlate the rate of brain atrophy accumulation with the probability of having a disability progression, but rather the treatment effect on brain atrophy with the treatment effect on disability 463
Interestingly, natalizumab was withdrawn in the majority of patients (59%) in our case series after they tested positive for serum anti-JC virus antibodies, which was likely interpreted in conjunction with other PML risk factors (76% of patients had 2 risk factors). PML risk factors, although well documented in our case series, did not lead to preemptive MRI screening(s) to identify PML, but instead prompted clinicians to stop natalizumab. Our case assessments were sometimes limited by missing and incomplete data, which made it challenging to ascertain PML and/or immune reconstitution inflammatory syndrome symptoms, and to interpret reported MRI results. However, it was evident that many patients experienced neurologic decline following natalizumab withdrawal and were treated, on clinical grounds, for suspected multiple sclerosis (MS) relapse with immunomodulating agents or high-dose steroids; PML was considered only in the context of failure to respond to such treatments, thus impacting timely PML diagnosis. Also, we could not ascertain whether the MS therapies adversely affected the PML risk. Finally, and in agreement with Wattjes and Killstein, our case series supports the concept that the risk for PML extends for several months beyond the time of natalizumab withdrawal. Clinicians need to be vigilant for PML at the time of natalizumab discontinuation and during the post-treatment period, especially in patients with PML risk factors.
increase on the Expanded Disability Status Scale of 0.5 or 1 point from baseline sustained for at least 3 months, but with a different design. Trial definitions of disability progression identify mainly transient progression that is no more obvious at the end of the study, raising concerns about the efficacy of diseasemodifying drugs on disability progression. Few studies give the information based on sustained disability progression,2,3 that is, disability progression persisting for at least 3 months and sustained until the end of the trial. In the BENEFIT study, disability progression decreased from 24% (during the trial) to 15% (sustained up to 36 months), and in the PRISMS study from 29% to 9%. Unfortunately, this important information is not available for the trials that were used in the statistical analysis of Sormani and colleagues. This strongly questions the relevance of their findings.
Potential Conflicts of Interest Nothing to report regarding this letter. 1
Department of Neurology, Adolphe de Rothschild Foundation, Paris, and 2Department of Neurology, University Hospital Center of Reims, University of Reims Champagne-Ardenne, Reims, France
References
Potential Conflicts of Interest
1.
Sormani MP, Arnold DL, De Stefano N. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol 2014;75:43–49.
2.
Kappos L, Freedman MS, Polman CH, et al. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet 2007;370:389–397.
3.
Medical officer’s clinical review of Rebif. February 9, 1999. Available at: http://www.fda.gov/downloads/Drugs/DevelopmentApproval Process/HowDrugsareDevelopedandApproved/ApprovalApplications/ TherapeuticBiologicApplications/ucm094516.pdf. Accessed March 7, 2002.
Nothing to report.
US Food and Drug Administration Center for Drug Evaluation and Research, Silver Spring, MD The views expressed are those of the authors and do not necessarily represent those of, nor imply endorsement from, the US Food and Drug Administration or the US government.
References 1.
Fine AJ, Sorbello A, Kortepeter C, Scarazzini L. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann Neurol 2013 Nov 16. [Epub ahead of print].
DOI: 10.1002/ana.24112
DOI: 10.1002/ana.24108
Reply Maria Pia Sormani, PhD,1 Douglas L. Arnold, MD,2 and Nicola De Stefano, MD3
Treatment Effect on Brain Atrophy Correlates with Treatment Effect on Disability in Multiple Sclerosis Olivier Gout, MD,1 and Ayman Tourbah, MD, PhD2 Sormani and colleagues1 reported that in relapsing–remitting multiple sclerosis, the treatment effect on brain atrophy is correlated with an effect on disability progression over 2 years. All the included studies consider disability progression as an March 2014
We thank Dr Gout and Dr Tourbah for their comment. We agree that an event of disability progression as defined by an Expanded Disability Status Scale (EDSS) increase can be transient, and therefore that the total event rate can depend on the time used to confirm the EDSS change. However, this correct reasoning does not apply to our analysis. We did not correlate the rate of brain atrophy accumulation with the probability of having a disability progression, but rather the treatment effect on brain atrophy with the treatment effect on disability 463
