Risk-benefit considerations in the treatment of relapsing-remitting multiple sclerosis

Neuropsychiatric Disease and Treatment

Volumn 9, Issue , 2013, Pages 893-914

  Lugaresi, Alessandra ^a   di Ioia, Maria ^a   Travaglini, Daniela ^a   Pietrolongo, Erika ^a   Pucci, Eugenio ^b   Onofrj, Marco ^a  

^a UNIVERSITY OF CHIETI   (Italy)

^b Operative Unit Neurologia ASUR Marche Area Vasta 3   (Italy)

Author keywords

Doctor patient relationship; Effectiveness; Efficacy; Safety; Shared decision making

Indexed keywords

ACETYLSALICYLIC ACID; ALEMTUZUMAB; AZATHIOPRINE; BETA INTERFERON; BETA1A INTERFERON; CYCLOPHOSPHAMIDE; DACLIZUMAB; FINGOLIMOD; FUMADERM; FUMARIC ACID DIMETHYL ESTER; GLATIRAMER; IMMUNOMODULATING AGENT; IMMUNOSUPPRESSIVE AGENT; INTERFERON BETA SERINE; LAQUINIMOD; LEFLUNOMIDE; METHOTREXATE; MITOXANTRONE; MONOCLONAL ANTIBODY; NATALIZUMAB; OCRELIZUMAB; PEGINTERFERON BETA1A; PENTOXIFYLLINE; PLACEBO; RITUXIMAB; TERIFLUNOMIDE;

ABDOMINAL PAIN; ACUTE LYMPHOBLASTIC LEUKEMIA; ADD ON THERAPY; ALOPECIA; AMENORRHEA; ANAPHYLAXIS; ANEMIA; ANTIOXIDANT ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; ANXIETY; ATRIOVENTRICULAR BLOCK; AUTOIMMUNE HEMOLYTIC ANEMIA; AZOOSPERMIA; BACKACHE; BASAL CELL CARCINOMA; BONE MARROW SUPPRESSION; BONE MARROW TOXICITY; BRADYCARDIA; BRONCHITIS; BURNING SENSATION; CARDIOTOXICITY; CHEST TIGHTNESS; CHILL; CHRONIC MYELOID LEUKEMIA; COMORBIDITY; CORONARY ARTERY DISEASE; COUGHING; CYSTITIS; DECISION MAKING; DEPRESSION; DIARRHEA; DISEASE COURSE; DOCTOR PATIENT RELATION; DRUG APPROVAL; DRUG EFFICACY; DRUG ERUPTION; DRUG FATALITY; DRUG FEVER; DRUG INDUCED HEADACHE; DRUG MEGADOSE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSPNEA; ENTERITIS; EOSINOPHILIA; FACIAL FLUSHING; FATIGUE; FLU LIKE SYNDROME; FLUSHING; FORCED EXPIRATORY VOLUME; GASTROENTERITIS; GASTROINTESTINAL INTOLERANCE; GASTROINTESTINAL SYMPTOM; GOODPASTURE SYNDROME; GRAVES DISEASE; HAIR THINNING; HEART PALPITATION; HEMATOMA; HEMORRHAGIC CYSTITIS; HEMORRHAGIC ENTERITIS; HERPES SIMPLEX ENCEPHALITIS; HERPES ZOSTER; HOT FLUSH; HUMAN; HYPERTENSION; HYPERTHYROIDISM; HYPOTHYROIDISM; IMMUNOMODULATION; INFECTION; INFERTILITY; INJECTION SITE ERYTHEMA; INJECTION SITE PAIN; INJECTION SITE PRURITUS; INJECTION SITE REACTION; INJECTION SITE REDNESS; INTESTINE PERFORATION; ISCHEMIC CORONARY ARTERY SYNDROME; LIFESTYLE; LIMB PAIN; LIPOATROPHY; LIVER FAILURE; LIVER FIBROSIS; LIVER INJURY; LIVER TOXICITY; LOW DRUG DOSE; LUNG TOXICITY; LYMPH NODE SWELLING; LYMPHADENOPATHY; LYMPHOCYTOPENIA; LYMPHOMA; MALIGNANT NEOPLASTIC DISEASE; MONOTHERAPY; MOOD DISORDER; MULTIPLE SCLEROSIS; MUSCLE SPASM; MYALGIA; NAUSEA; NAUSEA AND VOMITING; NECROSIS; NEPHROTOXICITY; NEUROPROTECTION; NEUTROPENIA; NONHUMAN; OLIGOSPERMIA; OPPORTUNISTIC INFECTION; PAIN; PANCREAS DISEASE; PATIENT COMPLIANCE; PEDIATRICS; PERSONALIZED MEDICINE; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PREGNANCY; PRURITUS; RANDOMIZED CONTROLLED TRIAL (TOPIC); RECOMMENDED DRUG DOSE; RESPIRATORY TRACT INFECTION; RETINA MACULA EDEMA; REVIEW; RHINOPHARYNGITIS; RISK BENEFIT ANALYSIS; SARCOIDOSIS; SIDE EFFECT; SINUSITIS; SKIN CANCER; SKIN NECROSIS; SPASTICITY; STOMATITIS; THROMBOCYTOPENIA; THROMBOCYTOPENIC PURPURA; THYROID CANCER; THYROID DISEASE; URINARY TRACT INFECTION; WEAKNESS;

EID: 84879431039     PISSN: 11766328     EISSN: 11782021     Source Type: Journal    
DOI: 10.2147/NDT.S45144     Document Type: Review

References (255)

1. Tremlett H, Zhao Y, Rieckmann P, Hutchinson M. New perspectives in the natural history of multiple sclerosis. Neurology. 2010;74: 2004-2015.
2. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46:907-911.
3. Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain. 1989;112(Pt 1):133-146.
4. Tremlett H, Devonshire V. Is late-onset multiple sclerosis associated with a worse outcome? Neurology. 2006;67:954-959.
5. Pittock SJ. Does benign multiple sclerosis today imply benign multiple sclerosis tomorrow: implications for treatment. Neurology. 2007;68:480-481.
6. Hawkins SA, McDonnell GV. Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors. J Neurol Neurosurg Psychiatry. 1999;67:148-152.
7. Langdon CW, Amato MP, Boringa J, et al. Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Mult Scler. 2012;18:891-898.
8. Benito-León J, Morales JM, Rivera-Navarro J, Mitchell A. A review about the impact of multiple sclerosis on health-related quality of life. Disabil Rehabil. 2003;25:1291-1303.
9. Vukusic S, Confavreux C. Natural history of multiple sclerosis: risk factors and prognostic indicators. Curr Opin Neurol. 2007;20:269-274.
10. Lublin FD. Clinical features and diagnosis of multiple sclerosis. Neurol Clin. 2005;23:1-15.
11. Trojano M, Paolicelli D, Tortorella C, et al. Natural history of multiple sclerosis: have available therapies impacted long-term prognosis? Neurol Clin. 2011;29:309-321.
12. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69:292-302.
13. Trojano M, Pellegrini F, Fuiani A, et al. New natural history of interferon-beta-treated relapsing multiple sclerosis. Ann Neurol. 2007;61:300-306.
14. Phillips JT, Giovannoni G, Lublin FD, et al. Sustained improvement in Expanded Disability Status Scale as a new efficacy measure of neurological change in multiple sclerosis: treatment effects with natalizumab in patients with relapsing multiple sclerosis. Mult Scler. 2011;17:970-979.
15. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43:655-661.
16. Paty DW, Li DK. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology. 1993;43:662-667.
17. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996;39:285-294.
18. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352:1498-1504.
19. Amato MP, Portaccio E, Ghezzi A, et al. Pregnancy and fetal outcomes after interferon-rrexposure in multiple sclerosis. Neurology. 2010;75:1794-1802.
20. PRISMS Study Group and the University of British Columbia MS/MRI Analysis Group. PRISMS-4: long-term efficacy of interferon-beta-1a in relapsing MS. Neurology. 2001;56:1628-1636.
21. Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359:1453-1460.
22. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE Trial. Neurology. 2002;59:1496-1506.
23. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000;343:898-904.
24. Comi G, Filippi M, Barkhof F, et al. Early Treatment of Multiple Sclerosis Study Group. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357:1576-1582.
25. Kappos L, Traboulsee A, Constantinescu C, et al. Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS. Neurology. 2006;67:944-953.
26. Comi G, De Stefano N, Freedman MS, et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol. 2012;11:33-41.
27. Kappos L, Freedman MS, Polman CH, et al. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009;8:987-997.
28. Shirani A, Zhao Y, Karim ME, et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2012;308:247-256.
29. Trojano M, Pellegrini F, Paolicelli D, et al. Real-life impact of early interferon beta therapy in relapsing multiple sclerosis. Ann Neurol. 2009;66:513-520.
30. Bergamaschi R, Quaglini S, Tavazzi E, et al. Immunomodulatory therapies delay disease progression in multiple sclerosis. Mult Scler. May 31, 2012. [Epub ahead of print.]
31. Kister I, Chamot E, Cutter G, et al. Increasing age at disability milestones among MS patients in the MSBase Registry. J Neurol Sci. 2012;318:94-99.
32. Cohen JA, Antel JP. Does interferon beta help in secondary progressive MS? Neurology. 2004;63:1768-1769.
33. Goodin DS, Reder AT, Ebers GC, et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN3-1b trial. Neurology. 2012;78:1315-1322.
34. Lugaresi A, Florio C, Brescia-Morra V, et al. Patient adherence to and tolerability of self-administered interferon 3-1a using an electronic autoinjection device: a multicentre, open-label, phase IV study. BMC Neurol. 2012;12:7.
35. Lugaresi A. RebiSmart™ (version 1.5) device for multiple sclerosis treatment delivery and adherence. Expert Opin Drug Deliv. 2013;10:273-283.
36. Goeb JL, Even C, Nicolas G, Gohier B, Dubas F, Garré JB. Psychiatric side effects of interferon-beta in multiple sclerosis. Eur Psychiatry. 2006;21:186-193.
37. Patten SB, Williams JV, Metz LM. Anti-depressant use in association with interferon and glatiramer acetate treatment in multiple sclerosis. Mult Scler. 2008;14:406-411.
38. Patti F, Amato MP, Trojano M, et al. Quality of life, depression and fatigue in mildly disabled patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon beta-1a: 3-year results from the COGIMUS (Cognitive Impairment in Multiple Sclerosis) study. Mult Scler. 2011;17:991-1001.
39. Tremlett HL, Yoshida EM, Oger J. Liver injury associated with the beta-interferons for MS: a comparison between the three products. Neurology. 2004;62:628-631.
40. Manfredonia F, Pasquali L, Dardano A, Iudice A, Murri L, Monzani F. Review of the clinical evidence for interferon beta 1a (Rebif) in the treatment of multiple sclerosis. Neuropsychiatr Dis Treat. 2008;4:321-336.
41. Sørensen PS, Deisenhammer F, Duda P, et al. Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol. 2005;12:817-827.
42. Creeke PI, Farrell RA. Clinical testing for neutralizing antibodies to interferon-44in multiple sclerosis. Ther Adv Neurol Disord. 2013;6:3-17.
43. Sandberg-Wollheim M, Kornmann G, Bischof D, Moraga MS, Hennessy B, Alteri E. The risk of malignancy is not increased in patients with multiple sclerosis treated with subcutaneous interferon beta-la: analysis of data from clinical trial and post-marketing surveillance settings. Mult Scler. 2011;17:431-440.
44. Lebrun C, Debouverie M, Vermersch P, et al. Cancer risk and impact of disease-modifying treatments in patients with multiple sclerosis. Mult Scler. 2008;14:399-405.
45. Bornstein MB, Miller A, Slagle S, et al. A pilot trial of Cop 1 in exacerbating remitting multiple sclerosis. N Engl J Med. 1987;317: 408-414.
46. Johnson KP, Brooks BR, Cohen JA. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology. 1995;45:1268-1276.
47. Qizilbash N, Mendez I, Sanchez-de la Rosa R. Benefit-risk analysis of glatiramer acetate for relapsing-remitting and clinically isolated syndrome multiple sclerosis. Clin Ther. 2012;34:159-176.
48. Comi G, Filippi M, Wolinsky JS. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging measured disease activity and burden in patients with relapsing-remitting multiple sclerosis. Ann Neurol. 2001;149:290-297.
49. Comi G. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374:1503-1511.
50. Lublin FD, Cofield SS, Cutter GR, et al. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol. 2013;73:327-340.
51. Mikol DD, Barkhof F, Chang P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7:903-914.
52. Cadavid D, Wolansky LJ, Skurnick J, et al. Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology. 2009;72:1976-1983.
53. O'Connor P, Filippi M, Arnason B, et al. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol. 2009;8:889-897.
54. McGraw CA, Lublin FD. Interferon beta and glatiramer acetate therapy. Neurotherapeutics. 2013;10:2-18.
55. Ford C, Goodman AD, Johnson K, et al. Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate. Mult Scler. 2010;16:342-350.
56. Giovannoni G, Southam E, Waubant E. Systematic review of disease-modifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence. Mult Scler. 2012;18:932-946.
57. Jongen PJ, Lehnick D, Sanders E, et al. Health-related quality of life in relapsing remitting multiple sclerosis patients during treatment with glatiramer acetate: a prospective, observational, international, multi-centre study. Health Qual Life Outcomes. 2010;8:133.
58. Rauschka H, Farina C, Sator P, et al. Severe anaphylactic reaction to glatiramer acetate with specific IgE. Neurology. 2005;64: 1481-1482.
59. Baumgartner A, Stich O, Rauer S. Anaphylactic reaction after injection of glatiramer acetate (copaxone) in patients with relapsing-remitting multiple sclerosis. Eur Neurol. 2011;66:368-370.
60. Marriott JJ, Miyasaki JM, Gronseth G, O'Connor PW. Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2010;74:1 463-1470.
61. Martinelli V, Radaelli M, Straffi L, Rodegher M, Comi G. Mitoxantrone: benefits and risks in multiple sclerosis patients. Neurol Sci. 2009; 30 Suppl 2:S167-S170.
62. Pascual AM, Téllez N, Boscá I, et al. Revision of the risk of secondary leukaemia after mitoxantrone in multiple sclerosis populations is required. Mult Scler. 2009;15:1303-1310.
63. Martinelli V, Cocco E, Capra R, et al. Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone. Neurology. 2011;77:1887-1995.
64. 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.
65. 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.
66. Pucci E, Giuliani G, Solari A, et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev. 2011;10: CD007621.
67. Havrdova E, Galetta S, Hutchinson M, et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol. 2009;8: 254-260.
68. Iaffaldano P, Viterbo RG, Paolicelli D, et al. Impact of natalizumab on cognitive performances and fatigue in relapsing multiple sclerosis: a prospective, open-label, two years observational study. PLoS One. March 23, 2012. [Epub ahead of print.]
69. Rudick R, Polman C, Clifford D, Miller D, Steinman L. Natalizumab: bench to bedside and beyond. JAMA Neurol. 2013;70:172-182.
70. Chen Y, Bord E, Tompkins T, et al. Asymptomatic reactivation of JC virus in patient treated with natalizumab. N Engl J Med. 2009;361:1067-1074.
71. Schröder A, Lee DH, Hellwig K, et al. Successful management of natalizumab-associated progressive multifocal leukoencephalopathy and immune reconstitution syndrome in a patient with multiple sclerosis. Arch Neurol. 2010;67:1391-1394.
72. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870-1880.
73. Trampe AK, Hemmelmann C, Stroet A, et al. Anti-JC virus antibodies in a large German natalizumab-treated multiple sclerosis cohort. Neurology. 2012;78:1736-1742.
74. Borriello G, Prosperini L, Mancinelli C, Giannì C, Fubelli F, Pozzilli C. Pulse monthly steroids during an elective interruption of natalizumab: a post-marketing study. Eur J Neurol. 2012;19:783-787.
75. Havla J, Gerdes LA, Meinl I, et al. De-escalation from natalizumab in multiple sclerosis: recurrence of disease activity despite switching to glatiramer acetate. J Neurol. 2011;258:1665-1669.
76. Borriello G, Prosperini L, Marinelli F, Fubelli F, Pozzilli C. Observations during an elective interruption of natalizumab treatment: a post-marketing study. Mult Scler. 2011;17:372-375.
77. Baumgartner A, Stich O, Rauer S. Clinical and radiological disease reactivation after cessation of long-term therapy with natalizumab. Int J Neurosci. 2012;122:35-39.
78. Sempere AP, Martín-Medina P, Berenguer-Ruiz L, et al. Switching from natalizumab to fingolimod: an observational study. Acta Neurol Scand. January 22, 2013. [Epub ahead of print.]
79. Rinaldi F, Seppi D, Calabrese M, Perini P, Gallo P. Switching therapy from natalizumab to fingolimod in relapsing-remitting multiple sclerosis: clinical and magnetic resonance imaging findings. Mult Scler. 2012;18:1640-1643.
80. Daelman L, Maitrot A, Maarouf A, Chaunu MP, Papeix C, Tourbah A. Severe multiple sclerosis reactivation under fingolimod 3 months after natalizumab withdrawal. Mult Scler. 2012;18:1647-1649.
81. Cristiano LM, Bozic C, Bloomgren G. Preliminary evaluationof pregnancy outcomes from the Tysabri (natalizumab) pregnancy exposure registry. Mult Scler. 2011;17:S457.
82. Sørensen PS, Bertolotto A, Edan G, et al. Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler. 2012;18:143-152.
83. Rudick RA. Multiple sclerosis, natalizumab, and PML: helping patients decide. Cleve Clin J Med. 2011;78 Suppl 2:S18-S23.
84. Tur C, Tintorè M, Vidal-Jordana A, et al. Natalizumab discontinuation after PML risk stratification: outcome from a shared and informed decision. Mult Scler. 2012;18:1193-1196.
85. Heesen C, Kleiter I, Nguyen F, et al. Risk perception in natalizumab-treated multiple sclerosis patients and their neurologists. Mult Scler. 2010;16:1507-1512.
86. Thompson JP, Noyes K, Dorsey ER, Schwid SR, Hollowey RG. Quantitative risk-benefit analysis of natalizumab. Neurology. 2008;71:357-364.
87. Duquette P. Deaths and disability from natalizumab are no longer tolerable: yes. Mult Scler. 2012;18:1068-1069.
88. Hutchinson M. Deaths and disability from natalizumab are no longer tolerable: commentary. Mult Scler. 2012;18:1073.
89. Sørensen PS. Deaths and disability from natalizumab are no longer tolerable: no (they can be avoided). Mult Scler. 2012;18:1070-1072.
90. Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387-401.
91. Cohen J, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362: 402-415.
92. Calabresi PA, Goodin D, Jeffery D, et al. Oral fingolimod (FTY720) in relapsing-remitting multiple sclerosis: baseline patient demographics and disease characteristics from a 2-year phase III trial (FREEDOMS II). Neurology. 2010;74(9 Suppl 2):A416-A417.
93. Calabresi PA, Goodin D, Jeffery D, et al. Efficacy and safety of fingolimod versus placebo: primary outcomes from the phase 3 FREEDOMS II study in patients with relapsing-remitting multiple sclerosis. Poster P491 presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October 10-13, 2012, Lyon, France.
94. Kappos L, Radue EW, O'Connor P, et al. Phase 3 FREEDOMS study extension: fingolimod (FTY720) efficacy in patients with relapsing-remitting multiple sclerosis receiving continuous or placebo-fingolimod switched therapy for up to 4 years. Poster P979 presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October 10-13, 2012, Lyon, France.
95. O'Connor C, Polman R, Hohlfeld R, et al. Phase III FREEDOMS study extension: long-term safety of fingolimod (FTY720) in relapsing-remitting multiple sclerosis. Poster P523 presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October 10-13, 2012, Lyon, France.
96. European Medicines Agency. European Medicines Agency gives new advice to better manage risk of adverse effects on the heart with Gilenya. Available from: http://www.ema.europa.eu/docs/en_GB/docu ment_library/Press_release/2012/04/WC500125690.pdf. Accessed May 11, 2013.
97. Medicines and Healthcare Products Regulatory Agency. Drug Safety Update. Available from: http://www.mhra.gov.uk/home/groups/dsu/documents/publication/con228756.pdf. Accessed May 11, 2013.
98. European Medicines Agency. European Medicines Agency starts review of Gilenya (fingolimod). Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2012/01/WC500120703.pdf. Accessed May 11, 2013.
99. Jander S, Turowski B, Kieseier BC, Hartung HP. Emerging tumefactive multiple sclerosis after switching therapy from natalizumab to fingolimod. Mult Scler. 2012;18:1650-1652.
100. Hardy TA, Chataway J. Tumefactive demyelination: an approach to diagnosis and management. J Neurol Neurosurg Psychiatry. January 19, 2013. [Epub ahead of print.]
101. Novartis. Available from: http://www.novartis.com/downloads/news room/product-related-info-center/statement-PML.pdf. Accessed January 22, 2013.
102. Gross CM, Baumgartner A, Rauer S, Stich O. Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod. Neurology. 2012;79:2006-2007.
103. Bourdette D, Gilden D. Fingolimod and multiple sclerosis: four cautionary tales. Neurology. 2012;79:1942-1943.
104. Cohen J. Long-term safety of fingolimod in relapsing multiple sclerosis: update to integrated analyses of phase 2 and 3 studies and extension phases. Poster presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October 10-13, 2012, Lyon, France.
105. Ontaneda D, Hara-Cleaver C, Rudick RA, Cohen JA, Bermel RA. Early tolerability and safety of fingolimod in clinical practice. J Neurol Sci. 2012;323:167-172.
106. Comi G, Kappos L, Palace J, et al. Cardiac safety of fingolimod 0.5 mg during the first dose observation in 4-month, open-label, multi-center FIRST study in patients with relapsing MS. Abstract S41.003 presented at the 64th American Academy of Neurology Annual Meeting, April 21-28, 2012, New Orleans, LA.
107. Gold R, Comi G, Ziemssen T, et al. Safety of fingolimod in patients with relapsing forms of multiple sclerosis: subgroup analyses from the 4-month, open-label, multicentre FIRST study. Poster P1009 presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Research in Multiple Sclerosis, October 10-13, 2012, Lyon, France.
108. DiMarco JP, O'Connor P, Cohen JA, et al. Fingolimod treatment initiation experience: cardiac and Holter electrocardiogram findings from three phase 3 studies. Poster P530 presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Research in Multiple Sclerosis, October 10-13, 2012, Lyon, France.
109. Ziemssen T, et al. Study design and first interim results of a registry study to establish long-term safety and pharmaco-economic data on fingolimod (Gilenyaβ) in multiple sclerosis patients in Germany (PANGAEA). Poster P522 presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Research in Multiple Sclerosis, October 10-13, 2012, Lyon, France.
110. MS-UK. Gilenya. Available from: http://www.ms-uk.org/index.cfm/gilenya. Accessed May 11, 2013.
111. Papadopoulou A, Kappos L, Sprenger T. Teriflunomide for oral therapy in multiple sclerosis. Expert Rev Clin Pharmacol. 2012;5:617-628.
112. O'Connor PW, Li D, Freedman MS, et al. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology. 2006;66:894-900.
113. O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365:1293-1303.
114. Kappos L, Comi G, Confavreux C, et al. The efficacy and safety of teriflunomide in patients with relapsing MS: results From TOWER, a Phase 3 placebo-controlled study. Abstract 153 presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Research in Multiple Sclerosis, October 10-13, 2012, Lyon, France.
115. ClinicalTrials. gov. A study comparing the effectiveness and safety of teriflunomide and interferon beta-1a in patients with relapsing multiple sclerosis (TENERE). Available from: http://clinicaltrials.gov/show/NCT00883337. Accessed May 11, 2013.
116. Confavreux C, Li DK, Freedman MS, et al. Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years. Mult Scler. 2012;18:1278-1289.
117. Vermersch P. A multicenter, randomized, parallel-group, rater-blinded study comparing the effectiveness and safety of teriflunomide and subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis. Consortium of Multiple Sclerosis Centers-Americas Committee for Treatment and Research in Multiple Sclerosis, 2012.
118. Freedman MS, Wamil B, Cheng S, et al. TERACLES study design: teriflunomide as adjunctive therapy in patients with relapsing multiple sclerosis receiving interferon-1. Poster presented at the 17th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis, June 1-2, 2012, San Diego, CA.
119. Warnke C, zu Hörste GM, Hartung HP, et al. Review of teriflunomide and its potential in the treatment of multiple sclerosis. Neuropsychiatr Dis Treat. 2009;5:333-340.
120. Available from: http://www.medscape.com/viewarticle/803177. Accessed April 29, 2013.
121. O'Connor P, Bar-Or A, Freedman M, et al. P01 multiple sclerosis: treatment safety. Immune response to seasonal influenza vaccination in patients with relapsing multiple sclerosis treated with teriflunomide: the TERIVA study (P01.169). Neurology. 2013;80:P01.169.
122. He D, Xu Z, Dong S, et al. Teriflunomide for multiple sclerosis. Cochrane Database Syst Rev. 2012;12:CD009882.
123. Roll A, Reich K, Boer A. Use of fumaric acid esters in psoriasis. Indian J Dermatol Venereol Leprol. 2007;73:133-137.
124. Linker RA, Lee DH, Stangel M, Gold R. Fumarates for the treatment of multiple sclerosis: potential mechanisms of action and clinical studies. Exp Rev Neurother. 2008;8:1683-1690.
125. Schimrigk S, Brune N, Hellwig K, et al. Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline controlled pilot study. Eur J Neurol. 2006;13:604-610.
126. Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011;134:678-692.
127. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098-1107.
128. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367:1087-1097.
129. Ropper AH. The "poison chair" treatment for multiple sclerosis. N Engl J Med. 2012;367:1149-1150.
130. Kappos L, Gold R, Miller DH, et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;372:1463-1472.
131. Kita M, Fox RJ, Phillips JT, et al. Effects of BG-12 (dimethyl fumarate) on quality of life in patients with relapsing-remitting multiple sclerosis: findings from the CONFIRM Study. Poster P586 presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October 10-13, 2012, Lyon, France.
132. Hoefnagel JJ, Thio HB, Willemze R, Bouwes-Bavinck JN. Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis. Br J Dermatol. 2003;149:363-369.
133. van Oosten BW, Killestein J, Barkhof F, Polman CH, Wattjes MP. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med. 2013;368:1658-1659.
134. Ermis U, Weis J, Schulz JB. PML in a patient treated with fumaric acid. N Engl J Med. 2013;368:1657-1658.
135. Sweetser TM, Dawson KT, Bozic C. Manufacturer's response to case reports of PML. N Engl J Med. 2013;368:1659-1661.
136. Friedrich M, Sterry W, Klein A, Rückert R, Döcke WD, Asadullah K. Addition of pentoxifylline could reduce the side effects of fumaric acid esters in the treatment of psoriasis. Acta Derm Venereol. 2001;81: 429-451.
137. ClinicalTrials. gov. A study in healthy volunteers to evaluate effects of pre-medication or slow dose titration on flushing and gastrointestinal events. Available from: http://clinicaltrials.gov/ct2/show/NCT01568112. Accessed May 10, 2013.
138. Limmroth V. Oral BG12 for treatment of relapsing-remitting MS. Nat Rev Neurol. 2013;9:8-10.
139. Phillips JT, Fox RJ, Selmaj K, et al. Long-term safety and tolerability of oral BG-12 (dimethyl fumarate) in relapsing-remitting multiple sclerosis: interim results from ENDORSE. Poster P1103 presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October 10-13, 2012, Lyon, France.
140. Kieseier BC, Jeffery DR. Chemotherapeutics in the treatment of multiple sclerosis. Ther Adv Neurol Disord. 2010;3:277-291.
141. Casetta I, Iuliano G, Filippini G. Azathioprine for multiple sclerosis. Cochrane Database Syst Rev. 2007;4:CD003982.
142. Massacesi L, Parigi A, Barilaro A, et al. Efficacy of azathioprine on multiple sclerosis new brain lesions evaluated using magnetic resonance imaging. Arch Neurol. 2005;62:1843-1847.
143. Adverse Drug Reactions Advisory Committee. Drug-induced pancreatitis. Aust Adv Drug React Bull. 2006;25:22.
144. Dubinsky MC, Yang H, Hassard PV, et al. 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology. 2002;122:904-915.
145. Confavreux C, Saddier P, Grimaud J, Moreau T, Adeleine P, Aimard G. Risk of cancer from azathioprine therapy in multiple sclerosis: a case-control study. Neurology. 1996;46:1607-1612.
146. Silman AJ, Petrie J, Hazleman B, Evans SJ. Lymphoproliferative cancer and other malignancies in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study. Ann Rheum Dis. 1988;47:988-992.
147. Patti F, Lo Fermo S. Lights and shadows of cyclophosphamide in the treatment of multiple sclerosis. Autoimmune Dis. 2011;2011:961702.
148. Awad A, Stüve O. Cyclophosphamide in multiple sclerosis: scientific rationale, history and novel treatment paradigms. Ther Adv Neurol Disord. 2009;2:50-61.
149. Rinaldi L, Perini P, Calabrese M, Gallo P. Cyclophosphamide as second-line therapy in multiple sclerosis: benefits and risks. Neurol Sci. 2009;30 Suppl 2:171-173.
150. Radis CD, Kahl LE, Baker GL, et al. Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis: a 20-year follow up study. Arthritis Rheum. 1995;38:1120-1127.
151. Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996;124:477-484.
152. Patti F, Reggio E, Palermo F, et al. Stabilization of rapidly worsening multiple sclerosis for 36 months in patients treated with interferon beta plus cyclophosphamide followed by interferon beta. J Neurol. 2004;251:1502-1506.
153. Smith DR, Weinstock-Guttman B, Cohen JA, et al. A randomized blinded trial of combination therapy with cyclophosphamide in patients-with active multiple sclerosis on interferon beta. Mult Scler. 2005;11:573-582.
154. Hu X, Miller L, Richman S, et al. A novel PEGylated interferon beta-1a for multiple sclerosis: safety, pharmacology, and biology. J Clin Pharmacol. 2012;52:798-808.
155. Calabresi P, Kieseier B, Arnold D, et al. ADVANCE phase 3 study of PEGylated interferon beta-1a for relapsing multiple sclerosis: patient baseline characteristics. Neurology. 2012;78:P01.133.
156. López V, Molina I, Monteagudo C, Jordá E. Cutaneous sarcoidosis developing after treatment with pegylated interferon and ribavirin: a new case and review of the literature. Int J Dermatol. 2011;503: 287-291.
157. Giacomini PS, Bar-Or A. Laquinimod in multiple sclerosis. Clin Immunol. 2012;142:38-43.
158. Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T. Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology. 2005;64: 987-991.
159. Comi G, Pulizzi A, Rovaris M, et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;371:2085-2092.
160. Comi G, Abramsky O, Arbizu T, et al. LAQ/5063 Study Group. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study. Mult Scler. 2010;16:1360-1366.
161. Comi G, Jeffery D, Kappos L, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366:1000-1009.
162. Clinical Trials. gov. BRAVO study: laquinimod double blind placebo controlled study in RRMS patients with a rater blinded reference arm of interferon 1-1a (Avonexβ). Available from: http://www.clinicaltri als.gov/ct2/show/NCT00605215. Accessed April 29, 2013.
163. Clinical Trials. gov. The efficacy and safety and tolerability of laquinimod in subjects with relapsing remitting multiple sclerosis (RRMS) (CONCERTO). Available from: http://clinicaltrials.gov/show/NCT01707992. Accessed April 29, 2013.
164. Coles AJ, Compston DA, Selmaj KW, et al. Alemtuzumab vs interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008;359: 1786-1801.
165. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380:1819-1828.
166. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380:1829-1839.
167. Coles AJ. Alemtuzumab therapy for multiple sclerosis. Neurotherapeutics. 2013;10:29-33.
168. Coles AJ, Fox E, Vladic A, et al. Alemtuzumab more effective than interferon.-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology. 2012;78:1069-1078.
169. Fontoura P. Monoclonal antibody therapy in multiple sclerosis: paradigm shifts and emerging challenges. MAbs. 2010;2:670-681.
170. Lulu S, Waubant E. Humoral-targeted immunotherapies in multiple sclerosis. Neurotherapeutics. 2013;10:34-43.
171. Bielekova B. Daclizumab therapy for multiple sclerosis. Neurotherapeutics. 2013;10:55-67.
172. Liu J, Wang L, Zhan SY, Xia Y. Daclizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev. 2012;4:CD008127.
173. Stüve O, Greenberg BM. Anticipated benefits and surprising effects of daclizumab in multiple sclerosis. Lancet Neurol. 2010;9:337-338.
174. Wynn D, Kaufman M, Montalban X, et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol. 2010;9:381-390.
175. Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. April 3, 2013. [Epub ahead of print.]
176. Clinical Trials. gov. Efficacy and safety of daclizumab high yield process versus interferon 111a in patients with relapsing-remitting multiple sclerosis (DECIDE). Available from: http://clinicaltrials.gov/ct2/show/NCT01064401. Accessed May 11, 2013.
177. Cross AH, Klein RS, Piccio L. Rituximab combination therapy in relapsing multiple sclerosis. Ther Adv Neurol Disord. 2012;5:311-319.
178. Jacob A, Weinshenker BG, Violich I, et al. Treatment of neuromyelitis optica with rituximab. Retrospective analysis of 25 patients. Arch Neurol. 2008;65:1443-1448.
179. Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358:676-688.
180. Hawker K, O'Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double blind placebo-controlled multicenter trial. Ann Neurol. 2009;66:460-471.
181. Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009;113:4834-4840.
182. Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies. Arthritis Rheum. 2012;64: 3043-3051.
183. He D, Zhou H, Han W, Zhang S. Rituximab for relapsing-remitting multiple sclerosis. Cochrane Database Syst Rev. 2011;12:CD009130.
184. Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011;378(9805):1779-1787.
185. Hutas G. Ocrelizumab, a humanized monoclonal antibody against CD20 for inflammatory disorders and B-cell malignancies. Curr Opin Investig Drugs. 2008;9:1206-1215.
186. ThePharmaLetter. Roche/Biogen drop development of ocrelizumab in rheumatoid arthritis. Available from: http://www.thepharmaletter.com/file/95109/rochebiogen-drop-development-of-ocrelizumab-in-rheumatoid-arthritis.html. Accessed May 11, 2013.
187. Emery P, Rigby W, Tak PP, et al. Serious infections with ocrelizumab in rheumatoid arthritis: pooled results from double-blind periods of the ocrelizumab phase III RA program. Poster 414 presented at the American College of Rheumatology/Association of Rheumatology Health Professionals 74th Annual Scientific Meeting, November 6-11, 2010, Atlanta, GA.
188. Chaudhuri A. Ocrelizumab in multiple sclerosis: risks and benefits. Lancet. 2012;379:1196-1197.
189. Gold R. Combination therapies in multiple sclerosis. J Neurol. 2008;255 Suppl 1:51-60.
190. Smith DR, Weinstock-Guttman B, Cohen JA, et al. A randomized blinded trial of combination therapy with cyclophosphamide in patients-with active multiple sclerosis on interferon beta. Mult Scler. 2005;11:573-582.
191. Perini P, Calabrese M, Rinaldi L, Gallo P. Cyclophosphamide-based combination therapies for autoimmunity. Neurol Sci. 2008;29 Suppl 2: S233-S234.
192. Reggio E, Nicoletti A, Fiorilla T, Politi G, Reggio A, Patti F. The combination of cyclophosphamide plus interferon beta as rescue therapy could be used to treat relapsing-remitting multiple sclerosis patients-twenty-four months follow-up. J Neurol. 2005;252: 1255-1261.
193. Cohen JA, Imrey PB, Calabresi PA, et al. Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS. Neurology. 2009;72:535-541.
194. Edan G, Comi G, Le Page E, et al. Mitoxantrone prior to interferon beta-1b in aggressive relapsing multiple sclerosis: a 3-year randomised trial. J Neurol Neurosurg Psychiatry. 2011;82:1344-1350.
195. Rieckmann P, Heidenreich F, Sailer M, et al. Treatment de-escalation after mitoxantrone therapy: results of a phase IV, multicentre, open-label, randomized study of subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis. Ther Adv Neurol Disord. 2012;5:3-12.
196. Bhardwaj S, Coleman CI, Sobieraj DM. Efficacy of statins in combination with interferon therapy in multiple sclerosis: a meta-analysis. Am J Health Syst Pharm. 2012;69:1494-1499.
197. Shaygannejad V, Janghorbani M, Ashtari F, Dehghan H. Effects of adjunct low-dose vitamin d on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized placebo-controlled trial. Mult Scler Int. 2012;2012:452541.
198. Soilu-Hänninen M, Aivo J, Lindström BM, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012;83:565-571.
199. Pozzilli C, De Giglio L, Barletta V, et al. Efficacy and safety of oral contraceptives as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon beta-1a: a multicenter, randomized investigator-run clinical trial. Poster P171 presented at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October 10-13, 2012, Lyon, France.
200. Cross AH, Klein RS, Piccio L. Rituximab combination therapy in relapsing multiple sclerosis. Ther Adv Neurol Disord. 2012;5: 311-319.
201. Solari A, Acquarone N, Pucci E, et al. Communicating the diagnosis of multiple sclerosis-a qualitative study. Mult Scler. 2007;13: 763-769.
202. Kasper J, Heesen C, Köpke S, Fulcher G, Geiger F. Patients' and observers' perceptions of involvement differ. Validation study on inter-relating measures for shared decision making. PLoS One. 2011;6:e26255.
203. Simioni S, Schluep M, Bault N, et al. Multiple sclerosis decreases explicit counterfactual processing and risk taking in decision making. PLoS One. 2012;7:e50718.
204. Kachuck NJ. When neurologist and patient disagree on reasonable risk: new challenges in prescribing for patients with multiple sclerosis. Neuropsychiatr Dis Treat. 2011;7:197-208.
205. Girouard N, Soucy N. Patient considerations in the management of multiple sclerosis: development and clinical utility of oral agents. Patient Prefer Adherence. 2011;5:101-108.
206. Giordano A, Mattarozzi K, Pucci E, et al. Participation in medical decision-making: attitudes of Italians with multiple sclerosis. J Neurol Sci. 2008;275:86-91.
207. Lejbkowicz I, Caspi O, Miller A. Participatory medicine and patient empowerment towards personalized healthcare in multiple sclerosis. Expert Rev Neurother. 2012;12:343-352.
208. Solari A, Martinelli V, Trojano M, et al. An information aid for newly diagnosed multiple sclerosis patients improves disease knowledge and satisfaction with care. Mult Scler. 2010;16:1393-1405.
209. Johnson FR, Van Houtven G, Ozdemir S, et al. Multiple sclerosis patients' benefit-risk preferences: serious adverse event risks versus treatment efficacy. J Neurol. 2009;256:554-562.
210. Jeffery DR. Recent advances in treating multiple sclerosis: efficacy, risks and place in therapy. Ther Adv Chronic Dis. 2013;4:45-51.
211. Sheridan C. Safety profiles come to fore as more drugs approach MS market. Nat Biotechnol. 2012;30:6-8.
212. Gasperini C, Ruggieri S, Development of oral agent in the treatment of multiple sclerosis: how the first available oral therapy, fingolimod will change therapeutic paradigm approach. Drug Des Devel Ther. 2012;6:175-186.
213. Smith B, Carson S, Fu R, et al. Drug class review: disease-modifying drugs for multiple sclerosis: Final Update 1 Report. Portland, OR: Oregon Health and Science University; 2010. Available from: http://www.ncbi.nlm.nih.gov/books/NBK50570/. Accessed May 11, 2013.
214. Roach ES. Early multiple sclerosis: to treat or not to treat? Arch Neurol. 2006;63:619.
215. Woo DA, Olek MJ, Frohman EM. Diagnosis and management of multiple sclerosis: case studies. Neurol Clin. 2006;24:199-214.
216. Boster A, Edan G, Frohman E, et al. Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician. Lancet Neurol. 2008;7:173-183.
217. Pittock SJ, Weinshenker BG, Noseworthy JH, et al. Not every patient with multiple sclerosis should be treated at time of diagnosis. Arch Neurol. 2006;63:611-614.
218. Tintoré M. New options for early treatment of multiple sclerosis. J Neurol Sci. 2009;277 Suppl 1:S9-S11.
219. Bunyan RF, Tang J, Weinshenker B. Acute demyelinating disorders: emergencies and management. Neurol Clin. 2012;30:285-307.
220. Freedman MS. Do not treat from CIS onset: evaluate disease course and prognosis first-no (treat!). Mult Scler. 2012;18:394-395.
221. Hutchinson M. Truly benign multiple sclerosis is rare: let's stop fooling ourselves-commentary. Mult Scler. 2012;18:15.
222. Bergamaschi R. Can we predict the evolution of an unpredictable disease like multiple sclerosis? Eur J Neurol. October 31, 2012. [Epub ahead of print.]
223. Frohman EM, Racke M, van Den Noort S. To treat, or not to treat: the therapeutic dilemma of idiopathic monosymptomatic demyelinating syndromes. Arch Neurol. 2000;57:930-932.
224. Frohman EM, Havrdova E, Lublin F, et al. Most patients with multiple sclerosis or a clinically isolated demyelinating syndrome should be treated at the time of diagnosis. Arch Neurol. 2006;63:614-619.
225. Freedman MS, Patry DG, Grand'Maison F, Myles ML, Paty DW, Selchen DH. Treatment optimization in multiple sclerosis. Can J Neurol Sci. 2004;31:157-168.
226. Goodin DS, Biermann LD, Bohlega S, et al. Integrating an evidence-based assessment of benefit and risk in disease-modifying treatment of multiple sclerosis. Curr Med Res Opin. 2007;23:2823-2832.
227. Wiendl H, Toyka KV, Rieckmann P, Gold R, Hartung HP, Hohlfeld R. Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations. J Neurol. 2008;255:1449-1463.
228. Freedman MS, Forrestal FG. Canadian treatment optimization recommendations (TOR) as a predictor of disease breakthrough in patients with multiple sclerosis treated with interferon beta-1a: analysis of the PRISMS study. Mult Scler. 2008;14:1234-1241.
229. Coyle PK. Switching algorithms: from one immunomodulatory agent to another. J Neurol. 2008;255 Suppl 1:44-50.
230. Castillo-Trivino T, Mowry EM, Gajofatto A, et al. Switching multiple sclerosis patients with breakthrough disease to second-line therapy. PLoS One. 2011;6:e16664.
231. Prosperini L, Borriello G, De Giglio L, Leonardi L, Barletta V, Pozzilli C. Management of breakthrough disease in patients with multiple sclerosis: when an increasing of interferon beta dose should be effective? BMC Neurol. 2011;11:26.
232. Gajofatto A, Bacchetti P, Grimes B, High A, Waubant E. Switching first-line disease-modifying therapy after failure: impact on the course of relapsing-remitting multiple sclerosis. Mult Scler. 2009;15: 50-58.
233. 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;19:899-904.
234. Sormani M, Rio J, Tintorè M, et al. Scoring treatment response in patients with relapsing multiple sclerosis. Mult Scler. 2013;19:605-612.
235. Keyhanian K, Davoudi V, Etemadifar M, Amin M. Better prognosis of multiple sclerosis in patients who experienced a full-term pregnancy. Eur Neurol. 2012;68:150-155.
236. Houtchens MK, Kolb CM. Multiple sclerosis and pregnancy: therapeutic considerations. J Neurol. August 25, 2012. [Epub ahead of print.]
237. Michel L, Foucher Y, Vukusic S, et al. Increased risk of multiple sclerosis relapse after in vitro fertilisation. J Neurol Neurosurg Psychiatry. 2012;83:796-802.
238. Giannini M, Portaccio E, Ghezzi A, et al. Pregnancy and fetal outcomes after Glatiramer Acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study. BMC Neurol. 2012;12:124.
239. Portaccio E, Ghezzi A, Hakiki B, et al. Breastfeeding is not related to postpartum relapses in multiple sclerosis. Neurology. 2011;77:145-150.
240. Hellwig K, Haghikia A, Rockhoff M, Gold R. Multiple sclerosis and pregnancy: experience from a nationwide database in Germany. Ther Adv Neurol Disord. 2012;5:247-253.
241. De Las Heras V, De Andrés C, Téllez N, Tintoré M. Pregnancy in multiple sclerosis patients treated with immunomodulators prior to or during part of the pregnancy: a descriptive study in the Spanish population. Mult Scler. 2007;13:981-984.
242. Fragoso YD, Boggildb M, Macias-Islasc MA, et al. The effects of long-term exposure to disease-modifying drugs during pregnancy in multiple sclerosis. Clin Neurol Neurosurg. 2013;115:154-159.
243. Alwan S, Sadovnick AD. Multiple sclerosis and pregnancy: maternal considerations. Womens Health (Lond Engl). 2012;8:399-414.
244. Lu E, Wang BW, Guimond C, Synnes A, Sadovnick D, Tremlett H. Disease-modifying drugs for multiple sclerosis in pregnancy: a systematic review. Neurology. 2012;79:1130-1135.
245. Bigi S, Banwell B. Pediatric multiple sclerosis. J Child Neurol. 2012;27:1378-1383.
246. Chitnis T. Disease-modifying therapy of pediatric multiple sclerosis. Neurotherapeutics. 2013;10:89-96.
247. Arnal-Garcia C, García-Montero MR, Málaga I, et al. Natalizumab use in pediatric patients with relapsing-remitting multiple sclerosis. Eur J Paediatr Neurol. 2013;17:50-54.
248. Ghezzi A. Therapeutic strategies in childhood multiple sclerosis. Ther Adv Neurol Disord. 2010;3:217-228.
249. Ghezzi A, Pozzilli C, Grimaldi LM, et al. Safety and efficacy of natalizumab in children with multiple sclerosis. Neurology. 2010;75:912-917.
250. Ghezzi A, Pozzilli C, Grimaldi L, et al. Natalizumab in pediatric multiple sclerosis: results of a cohort of 55 cases. Mult Scler. February 11, 2013. [Epub ahead of print.]
251. Tenembaum SN. Ethical challenges in paediatric clinical trials in multiple sclerosis. Ther Adv Neurol Disord. 2012;5:139-146.
252. Chitnis T, Tenembaum S, Banwell B, et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult Scler. 2012;18:116-127.
253. Paparrigopoulos T, Ferentinos P, Kouzoupis A, Koutsis G, Papadimitriou GN. The neuropsychiatry of multiple sclerosis: focus on disorders of mood, affect and behaviour. Int Rev Psychiatry. 2010;22: 14-21.
254. Siegert RJ, Abernethy DA. Depression in multiple sclerosis: a review. J Neurol Neurosurg Psychiatry. 2005;76:469-475.
255. Pucak ML, Carroll KA, Kerr DA, Kaplin AI. Neuropsychiatric manifestations of depression in multiple sclerosis: neuroinflammatory, neuroendocrine, and neurotrophic mechanisms in the pathogenesis of immune-mediated depression. Dialogues Clin Neurosci. 2007;9: 125-139.