Editorial Opinion
monitored compared with patients receiving injectable immunomodulator therapies. In spite of these considerations, however, a consistent bulk of data are now available to indicate that escalating to the more effective medications ARTICLE INFORMATION Author Affiliations: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas (Stüve); Neurology Section, VA North Texas Health Care System, Medical Service, Dallas (Stüve); Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (Stüve); Associate Editor, JAMA Neurology (Stüve); Department of Systems Medicine, Multiple Sclerosis Clinical and Research Center, Tor Vergata University and Hospital, Rome, Italy (Centonze); Istituto Di Ricovero e Cura a Carattere Scientifico, Fondazione Santa Lucia, Centro Europeo di Ricerca sul Cervello, Rome, Italy (Centonze). Corresponding Author: Diego Centonze, MD, PhD, Department of Systems Medicine, Multiple Sclerosis Clinical and Research Center, Tor Vergata University and Hospital, Via Montpellier 1, 00133 Rome, Italy ([email protected]). Published Online: February 9, 2015. doi:10.1001/jamaneurol.2014.4494. Conflict of Interest Disclosures: Dr Stüve serves on the editorial boards of JAMA Neurology, the Multiple Sclerosis Journal, and Therapeutic Advances in Neurological Disorders. He has received grant support from Teva Pharmaceuticals and Opexa Therapeutics. Dr Centonze acted as an
natalizumab or fingolimod should be an early consideration for most patients with breakthrough disease. Switching to another injectable immunomodulator may still be considered in certain cases only.
advisory board member of, and received funding for traveling and honoraria for speaking or consultation fees from, Merck Serono, Teva Pharmaceuticals, Genzyme, Bayer Schering, Biogen Idec, Novartis, Almirall, and GW Pharmaceuticals. He is the principal investigator in clinical trials for Novartis, Merck Serono, Teva Pharmaceuticals, Biogen Idec, Roche, and Mitsubishi. He has received research support from Teva Pharmaceuticals, Novartis, Merck Serono, Biogen Idec, and Bayer Schering.
exposure to natalizumab [published online September 25, 2014]. Mult Scler. doi:10.1177 /1352458514549404.
REFERENCES
7. Bergvall N, Makin C, Lahoz R, et al. Relapse rates in patients with multiple sclerosis switching from interferon to fingolimod or glatiramer acetate: a US claims database study. PLoS One. 2014;9(2):e88472.
1. Río J, Tintoré M, Sastre-Garriga J, et al. Change in the clinical activity of multiple sclerosis after treatment switch for suboptimal response. Eur J Neurol. 2012;19(6):899-904. 2. Prosperini L, Giannì C, Leonardi L, et al. Escalation to natalizumab or switching among immunomodulators in relapsing multiple sclerosis. Mult Scler. 2012;18(1):64-71. 3. Cohen M, Maillart E, Tourbah A, et al; Club Francophone de la Sclérose en Plaques Investigators. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 2014;71(4):436-441.
5. Stangel M, Stüve O. Multiple sclerosis: natalizumab to fingolimod—the washout whitewash. Nat Rev Neurol. 2014;10(6):311-313. 6. Roskell NS, Zimovetz EA, Rycroft CE, Eckert BJ, Tyas DA. Annualized relapse rate of first-line treatments for multiple sclerosis: a meta-analysis, including indirect comparisons versus fingolimod. Curr Med Res Opin. 2012;28(5):767-780.
8. He A, Spelman T, Jokubaitis V, et al; MSBase Study Group. Comparison of switch to fingolimod or interferon beta/glatiramer acetate in active multiple sclerosis [published online February 9, 2015]. JAMA Neurol. doi:10.1001/jamaneurol.2014 .4147. 9. Cohen JA, Barkhof F, Comi G, et al. Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS. J Neurol. 2013;260 (8):2023-2032.
4. Comi G, Gold R, Dahlke F, et al. Relapses in patients treated with fingolimod after previous
Probing the Exome in Alzheimer Disease and Other Neurodegenerative Disorders Lars Bertram, MD; Christine Klein, MD
Alzheimer disease (AD) is a heterogeneous disorder with a substantial genetic component. A small number of cases (ie, early-onset familial AD) are caused by exceedingly rare but pathogenic and highly penetrant mutations, while most cases (ie, late-onset AD) are caused by an intricate—and still only Related article page 414 partially understood—interplay of genetic and nongenetic risk factors.1 The past decade has seen unprecedented progress in deciphering the genetic underpinnings of lateonset AD. This advancement was achieved mostly by the application of high-throughput microarray genotyping in the context of genome-wide association studies (GWASs) comparing the allele status at millions of different base pairs on increasingly large samples of affected and unaffected individuals.2 Most AD GWAS findings to date were made with common (ie, frequency of the minor allele typically >5%) single-nucleotide polymorphisms (SNPs) typically exerting small genetic effect sizes (ie, odds ratios
monitored compared with patients receiving injectable immunomodulator therapies. In spite of these considerations, however, a consistent bulk of data are now available to indicate that escalating to the more effective medications ARTICLE INFORMATION Author Affiliations: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas (Stüve); Neurology Section, VA North Texas Health Care System, Medical Service, Dallas (Stüve); Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (Stüve); Associate Editor, JAMA Neurology (Stüve); Department of Systems Medicine, Multiple Sclerosis Clinical and Research Center, Tor Vergata University and Hospital, Rome, Italy (Centonze); Istituto Di Ricovero e Cura a Carattere Scientifico, Fondazione Santa Lucia, Centro Europeo di Ricerca sul Cervello, Rome, Italy (Centonze). Corresponding Author: Diego Centonze, MD, PhD, Department of Systems Medicine, Multiple Sclerosis Clinical and Research Center, Tor Vergata University and Hospital, Via Montpellier 1, 00133 Rome, Italy ([email protected]). Published Online: February 9, 2015. doi:10.1001/jamaneurol.2014.4494. Conflict of Interest Disclosures: Dr Stüve serves on the editorial boards of JAMA Neurology, the Multiple Sclerosis Journal, and Therapeutic Advances in Neurological Disorders. He has received grant support from Teva Pharmaceuticals and Opexa Therapeutics. Dr Centonze acted as an
natalizumab or fingolimod should be an early consideration for most patients with breakthrough disease. Switching to another injectable immunomodulator may still be considered in certain cases only.
advisory board member of, and received funding for traveling and honoraria for speaking or consultation fees from, Merck Serono, Teva Pharmaceuticals, Genzyme, Bayer Schering, Biogen Idec, Novartis, Almirall, and GW Pharmaceuticals. He is the principal investigator in clinical trials for Novartis, Merck Serono, Teva Pharmaceuticals, Biogen Idec, Roche, and Mitsubishi. He has received research support from Teva Pharmaceuticals, Novartis, Merck Serono, Biogen Idec, and Bayer Schering.
exposure to natalizumab [published online September 25, 2014]. Mult Scler. doi:10.1177 /1352458514549404.
REFERENCES
7. Bergvall N, Makin C, Lahoz R, et al. Relapse rates in patients with multiple sclerosis switching from interferon to fingolimod or glatiramer acetate: a US claims database study. PLoS One. 2014;9(2):e88472.
1. Río J, Tintoré M, Sastre-Garriga J, et al. Change in the clinical activity of multiple sclerosis after treatment switch for suboptimal response. Eur J Neurol. 2012;19(6):899-904. 2. Prosperini L, Giannì C, Leonardi L, et al. Escalation to natalizumab or switching among immunomodulators in relapsing multiple sclerosis. Mult Scler. 2012;18(1):64-71. 3. Cohen M, Maillart E, Tourbah A, et al; Club Francophone de la Sclérose en Plaques Investigators. Switching from natalizumab to fingolimod in multiple sclerosis: a French prospective study. JAMA Neurol. 2014;71(4):436-441.
5. Stangel M, Stüve O. Multiple sclerosis: natalizumab to fingolimod—the washout whitewash. Nat Rev Neurol. 2014;10(6):311-313. 6. Roskell NS, Zimovetz EA, Rycroft CE, Eckert BJ, Tyas DA. Annualized relapse rate of first-line treatments for multiple sclerosis: a meta-analysis, including indirect comparisons versus fingolimod. Curr Med Res Opin. 2012;28(5):767-780.
8. He A, Spelman T, Jokubaitis V, et al; MSBase Study Group. Comparison of switch to fingolimod or interferon beta/glatiramer acetate in active multiple sclerosis [published online February 9, 2015]. JAMA Neurol. doi:10.1001/jamaneurol.2014 .4147. 9. Cohen JA, Barkhof F, Comi G, et al. Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS. J Neurol. 2013;260 (8):2023-2032.
4. Comi G, Gold R, Dahlke F, et al. Relapses in patients treated with fingolimod after previous
Probing the Exome in Alzheimer Disease and Other Neurodegenerative Disorders Lars Bertram, MD; Christine Klein, MD
Alzheimer disease (AD) is a heterogeneous disorder with a substantial genetic component. A small number of cases (ie, early-onset familial AD) are caused by exceedingly rare but pathogenic and highly penetrant mutations, while most cases (ie, late-onset AD) are caused by an intricate—and still only Related article page 414 partially understood—interplay of genetic and nongenetic risk factors.1 The past decade has seen unprecedented progress in deciphering the genetic underpinnings of lateonset AD. This advancement was achieved mostly by the application of high-throughput microarray genotyping in the context of genome-wide association studies (GWASs) comparing the allele status at millions of different base pairs on increasingly large samples of affected and unaffected individuals.2 Most AD GWAS findings to date were made with common (ie, frequency of the minor allele typically >5%) single-nucleotide polymorphisms (SNPs) typically exerting small genetic effect sizes (ie, odds ratios
