Consenso Brasileiro para o Tratamento da Esclerose Múltipla: Academia Brasileira de Neurologia e Comitê Brasileiro de Tratamento e Pesquisa em Esclerose Múltipla

Marques, Vanessa Daccach; Passos, Giordani Rodrigues dos; Mendes, Maria Fernanda; Callegaro, Dagoberto; Lana-Peixoto, Marco Aurélio; Comini-Frota, Elizabeth Regina; Vasconcelos, Cláudia Cristina Ferreira; Sato, Douglas Kazutoshi; Ferreira, Maria Lúcia Brito; Parolin, Mônica Koncke Fiuza; Damasceno, Alfredo; Grzesiuk, Anderson Kuntz; Muniz, André; Matta, André Palma da Cunha; Oliveira, Bianca Etelvina Santos de; Tauil, Carlos Bernardo; Maciel, Damacio Ramón Kaimen; Diniz, Denise Sisteroli; Corrêa, Eber Castro; Coronetti, Fernando; Jorge, Frederico M. H.; Sato, Henry Koiti; Gonçalves, Marcus Vinícius Magno; Sousa, Nise Alessandra de C.; Nascimento, Osvaldo J. M.; Gama, Paulo Diniz da; Domingues, Renan; Simm, Renata Faria; Thomaz, Rodrigo Barbosa; Morales, Rogério de Rizo; Dias, Ronaldo Maciel; Apóstolos-Pereira, Samira dos; Machado, Suzana Costa Nunes; Junqueira, Thiago de Faria; Becker, Jefferson

doi:10.1590/0004-282X20180078

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Consensus • Arq. Neuro-Psiquiatr. 76 (8) • Ago 2018 • https://doi.org/10.1590/0004-282X20180078 copiar

Consenso Brasileiro para o Tratamento da Esclerose Múltipla: Academia Brasileira de Neurologia e Comitê Brasileiro de Tratamento e Pesquisa em Esclerose Múltipla

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO

O crescent arsenal terapêutico na esclerose múltipla (EM) tem permitido tratamentos mais efetivos e personalizados, mas a escolha e o manejo das terapias modificadoras da doença (TMDs) tem se tornado cada vez mais complexos. Neste contexto, especialistas do Comitê Brasileiro de Tratamento e Pesquisa em Esclerose Múltipla e do Departamento Científico de Neuroimunologia da Academia Brasileira de Neurologia reuniram-se para estabelecer este Consenso Brasileiro para o Tratamento da EM, baseados no entendimento de que neurologistas devem ter a possibilidade de prescrever TMDs para EM de acordo com o que é melhor para cada paciente, com base em evidências e práticas atualizadas. Por meio deste documento, propomos recomendações práticas para o tratamento da EM, com foco principal na escolha e no manejo das TMDs, e revisamos os argumentos que embasam as estratégias de tratamento na EM.

Palavras-chave:
esclerose múltipla; tratamento farmacológico; consenso

Category	Disease-modifying treatment	Maintenance dose, route and schedule^* * Some drugs have been tested in more than one dose or administration scheme; in such cases, only the dose(s) and scheme(s) that have been approved by health authorities or are most commonly used for MS in clinical practice are shown. Some drugs may require dose titration upon start of treatment; we refer the reader to the locally-approved label or to the specific trial publication for detailed prescribing information.	Phenotype	Pivotal or reference trial (and phase of development)	Selected comparator	Relative reduction in endpoints versus the selected comparator^ The effect of each drug on these outcomes is shown for reference purposes only. Significant inter-study variability in terms of eligibility criteria, primary and secondary endpoints, comparator group (placebo or active treatment) and duration of follow-up prevents a direct comparison of treatment effects across different studies.			Currently approved for MS?
Category	Disease-modifying treatment		Phenotype	Pivotal or reference trial (and phase of development)	Selected comparator	Conversion from CIS to MS	Relapse rate	Disability progression	ANVISA	FDA	EMA
Injectable drugs		20 mg s.c. once daily	CIS	PreCISe (phase 3)⁶⁸68. Comi G, Martinelli V, Rodegher M, Moiola L, Bajenaru O, Carra A et al. 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 Oct;374(9700):1503-11. https://doi.org/10.1016/S0140-6736(09)61259-9 https://doi.org/10.1016/S0140-6736(09)61...	Placebo	45%	–	–
	Glatiramer acetate	20 mg s.c. once daily	RRMS	Copolymer 1 MS Study (phase 3)⁸⁷87. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP et al; The Copolymer 1 Multiple Sclerosis Study Group. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology. 1995 Jul;45(7):1268-76. https://doi.org/10.1212/WNL.45.7.1268 https://doi.org/10.1212/WNL.45.7.1268...	Placebo	–	29%	28%	Yes	Yes	Yes
		40 mg s.c. three times a week	RRMS	GALA (phase 3)⁸⁸88. Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadinov R. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol. 2013 Jun;73(6):705-13. https://doi.org/10.1002/ana.23938 https://doi.org/10.1002/ana.23938...	Placebo	–	34%	N.S.	Yes	Yes	Yes
	Interferon beta-1 a i.m.	30 mcg i.m. once a week	CIS	CHAMPS (phase 3)⁶⁵65. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000 Sep;343(13):898-904. https://doi.org/10.1056/NEJM200009283431301 https://doi.org/10.1056/NEJM200009283431...	Placebo	30%	–	–
	Interferon beta-1 a i.m.	30 mcg i.m. once a week	RRMS	The MSCRG study (phase 3)⁸⁴84. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al.; The Multiple Sclerosis Collaborative Research Group (MSCRG). Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. 1996 Mar;39(3):285-94. https://doi.org/10.1002/ana.410390304 https://doi.org/10.1002/ana.410390304...	Placebo	–	18%	37%	Yes	Yes	Yes
	Interferon beta-1 a s.c.	22 mcg s.c. three times a week	CIS	ETOMS (phase 3)⁶⁶66. Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernández O, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001 May;357(9268):1576-82. https://doi.org/10.1016/S0140-6736(00)04725-5 https://doi.org/10.1016/S0140-6736(00)04...	Placebo	24%	23%	N.S.	Yes	Yes	Yes
		22 mcg s.c. three times a week	RRMS	PRISMS (phase 3)⁸⁵85. PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet. 1998 Nov;352(9139):1498-504. https://doi.org/10.1016/S0140-6736(98)03334-0 https://doi.org/10.1016/S0140-6736(98)03...	Placebo	–	29%	32%	Yes	Yes	Yes
		44 mcg s.c. three times a week	CIS	REFLEX (phase 3)⁶⁹69. Comi G, De Stefano N, Freedman MS, Barkhof F, Polman CH, Uitdehaag BM 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 Jan;11(1):33-41. https://doi.org/10.1016/S1474-4422(11)70262-9 https://doi.org/10.1016/S1474-4422(11)70...	Placebo	51%	–	–	Yes	Yes	Yes
		44 mcg s.c. three times a week	RRMS	PRISMS (phase 3)⁸⁵85. PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet. 1998 Nov;352(9139):1498-504. https://doi.org/10.1016/S0140-6736(98)03334-0 https://doi.org/10.1016/S0140-6736(98)03...	Placebo	–	32%	38%	Yes	Yes	Yes
			CIS	BENEFIT (phase 3)⁶⁷67. Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006 Oct;67(7):1242-9. https://doi.org/10.1212/01.wnl.0000237641.33768.8d https://doi.org/10.1212/01.wnl.000023764...	Placebo	46%	–	–
	Interferon beta-1 b	250 mcg s.c. every other day	RRMS	The IFNB MS Study (phase 3)⁸⁶86. 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 Apr;43(4):655-61. https://doi.org/10.1212/WNL.43.4.655 https://doi.org/10.1212/WNL.43.4.655...	Placebo	–	34%	N.S.	Yes	Yes	Yes
	Interferon beta-1 b	250 mcg s.c. every other day	SPMS	European Study on IFN β-1 b In SPMS (phase 3)¹¹⁰110. European Study Group on Interferon β-1b in Secondary Progressive MS. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. Lancet. 1998;352(9139):1491-7. https://doi.org/10.1016/S0140-6736(98)10039-9 https://doi.org/10.1016/S0140-6736(98)10...	Placebo	–	31%	22%	Yes	Yes	Yes
	Pegylated Interferon beta-1 a	125 mcg s.c. once every two weeks	RRMS	ADVANCE (phase 3)⁸⁹89. Calabresi PA, Kieseier BC, Arnold DL, Balcer LJ, Boyko A, Pelletier J et al. Pegylated interferon β-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 2014 Jul;13(7):657-65. https://doi.org/10.1016/S1474-4422(14)70068-7 https://doi.org/10.1016/S1474-4422(14)70...	Placebo	–	36%	38%	Yes	Yes	Yes
Oral drugs	Cladribine	3.5 mg/kg body weight p.o. (cumulative over two years) - see the study or label for detailed schedule	CIS	ORACLE MS (phase 3)⁸²82. Leist TP, Comi G, Cree BA, Coyle PK, Freedman MS, Hartung HP et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014 Mar;13(3):257-67. https://doi.org/10.1016/S1474-4422(14)70005-5 https://doi.org/10.1016/S1474-4422(14)70...	Placebo	67%	–	–
	Cladribine		RRMS	CLARITY (phase 3)⁹⁶96. Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010 Feb;362(5):416-26. https://doi.org/10.1056/NEJMoa0902533 https://doi.org/10.1056/NEJMoa0902533...	Placebo	–	58%	33%	No	No	Yes
	Dimethyl fumarate	240 mg p.o. twice daily	RRMS	DEFINE (phase 3)⁹⁰90. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012 Sep;367(12):1098-107. https://doi.org/10.1056/NEJMoa1114287 https://doi.org/10.1056/NEJMoa1114287...	Placebo	–	53%	38%	Yes	Yes	Yes
	Dimethyl fumarate	240 mg p.o. twice daily	RRMS	CONFIRM (phase 3)⁹¹91. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012 Sep;367(12):1087-97. https://doi.org/10.1056/NEJMoa1206328 https://doi.org/10.1056/NEJMoa1206328...	Placebo	–	44%	21%	Yes	Yes	Yes
	Fingolimod	0.5 mg p.o. once daily	RRMS	FREEDOMS (phase 3)⁹⁷97. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010 Feb;362(5):387-401. https://doi.org/10.1056/NEJMoa0909494 https://doi.org/10.1056/NEJMoa0909494...	Placebo	–	55%	27%	Yes	Yes	Yes
	Fingolimod	0.5 mg p.o. once daily	RRMS	FREEDOMS 2 (phase 3)⁹⁸98. Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Jun;13(6):545-56. https://doi.org/10.1016/S1474-4422(14)70049-3 https://doi.org/10.1016/S1474-4422(14)70...	Placebo	–	48%	N.S.	Yes	Yes	Yes
			CIS	TOPIC (phase 3)⁷⁰70. Miller AE, Wolinsky JS, Kappos L, Comi G, Freedman MS, Olsson TP. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Oct;13(10):977-86. https://doi.org/10.1016/S1474-4422(14)70191-7 https://doi.org/10.1016/S1474-4422(14)70...	Placebo	43%	32%	30%
	Teriflunomide	14 mg p.o. once daily	RRMS	TEMSO (phase 3)⁹²92. O’Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011 Oct;365(14):1293-303. https://doi.org/10.1056/NEJMoa1014656 https://doi.org/10.1056/NEJMoa1014656...	Placebo	–	32%	30%	Yes	Yes	Yes
			RRMS	TOWER (phase 3)⁹³93. Confavreux C, O’Connor P, Comi G, Freedman MS, Miller AE, Olsson T, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Mar;13(3):247-56. https://doi.org/10.1016/S1474-4422(13)70308-9 https://doi.org/10.1016/S1474-4422(13)70...	Placebo	–	36%	32%
	Alemtuzumab	12 mg i.v. once a day for 5 days at baseline + 12 mg i.v. once a day for three days after 12 months	RRMS	CARE-MS I (phase 3)⁹⁴94. Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP 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 Nov;380(9856):1819-28. https://doi.org/10.1016/S0140-6736(12)61769-3 https://doi.org/10.1016/S0140-6736(12)61...	Interferon beta-1 a 44 meg s.c.	–	55%	30%	Yes	Yes	Yes
	Alemtuzumab		RRMS	CARE-MS 2 (phase 3)⁹⁵95. Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012 Nov;380(9856):1829-39. https://doi.org/10.1016/S0140-6736(12)61768-1 https://doi.org/10.1016/S0140-6736(12)61...	Interferon beta-1 a 44 mcg s.c.	–	49%	42%	Yes	Yes	Yes
	Cyclophosphamide	750 mg/m² body surface area i.v. every four weeks In the first year; variable Intervals thereafter, according to each study protocol	RRMS	Controlled Pilot Trial of Monthly Cyclophosphamide In MS (phase 2)¹⁰⁵105. Killian JM, Bressler RB, Armstrong RM, Huston DP. Controlled pilot trial of monthly intravenous cyclophosphamide in multiple sclerosis. Arch Neurol. 1988 Jan;45(1):27-30. https://doi.org/10.1001/archneur.1988.00520250033014 https://doi.org/10.1001/archneur.1988.00...	Placebo	–	N.S.^* ***** Due to recruitment difficulties, these studies were terminated prematurely, which impaired their ability to carry out the planned statistical analysis. However, despite the insufficient sample size, some of their findings do suggest a possible benefit of cyclophosphamide. ANVISA: Agência Nacional de Vigilância Sanitária, (Brazilian Health Regulatory Agency), Brazil; CIS: clinically isolated syndrome; EMA; European Medicines Agency; FDA: Food and Drug Administration, United States of America; i.v.: intravenously; MS: multiple sclerosis; N/A: not applicable; N.S.: not statistically significant; p.o.: orally; PPMS: primary progressive MS; RRMS: relapsing-remitting MS; s.c.: subcutaneously; SPMS: secondary progressive MS.	–	No	No	No
	Cyclophosphamide		SPMS	PROMESS (phase 3)¹²⁵125. Brochet B, Deloire MSA, Perez P, Loock T, Baschet L, Debouverie M et al; PROMESS study investigators. Double-Blind Controlled Randomized Trial of Cyclophosphamide versus Methylprednisolone in Secondary Progressive Multiple Sclerosis. PLOS One. 2017 Jan; 12(1):e0168834. https://doi.org/10.1371/journal.pone.0168834 https://doi.org/10.1371/journal.pone.016...	Methylprednisolone i.v. every four weeks	–	N.S.^* ***** Due to recruitment difficulties, these studies were terminated prematurely, which impaired their ability to carry out the planned statistical analysis. However, despite the insufficient sample size, some of their findings do suggest a possible benefit of cyclophosphamide. ANVISA: Agência Nacional de Vigilância Sanitária, (Brazilian Health Regulatory Agency), Brazil; CIS: clinically isolated syndrome; EMA; European Medicines Agency; FDA: Food and Drug Administration, United States of America; i.v.: intravenously; MS: multiple sclerosis; N/A: not applicable; N.S.: not statistically significant; p.o.: orally; PPMS: primary progressive MS; RRMS: relapsing-remitting MS; s.c.: subcutaneously; SPMS: secondary progressive MS.	N.S.^* ***** Due to recruitment difficulties, these studies were terminated prematurely, which impaired their ability to carry out the planned statistical analysis. However, despite the insufficient sample size, some of their findings do suggest a possible benefit of cyclophosphamide. ANVISA: Agência Nacional de Vigilância Sanitária, (Brazilian Health Regulatory Agency), Brazil; CIS: clinically isolated syndrome; EMA; European Medicines Agency; FDA: Food and Drug Administration, United States of America; i.v.: intravenously; MS: multiple sclerosis; N/A: not applicable; N.S.: not statistically significant; p.o.: orally; PPMS: primary progressive MS; RRMS: relapsing-remitting MS; s.c.: subcutaneously; SPMS: secondary progressive MS.
	Intravenous Immunoglobulin	0.15-0.20 g/kg body weight i.v. once a month	RRMS	AIMSS (phase 2)¹⁰⁶106. Fazekas F, Deisenhammer F, Strasser-Fuchs S, Nahler G, Mamoli B. Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet. 1997 Mar;349(9052):589-93. https://doi.org/10.1016/S0140-6736(96)09377-4 https://doi.org/10.1016/S0140-6736(96)09...	Placebo	–	59%	N.S.	No	No	No
Infusion drugs	Mitoxantrone	12 mg/m² i.v. every three months	Worsening RRMS and SPMS	MIMS (phase 3)¹⁰⁷107. Hartung HP, Gonsette R, König N, Kwiecinski H, Guseo A, Morrissey SP et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002 Dec;360(9350):2018-25. https://doi.org/10.1016/S0140-6736(02)12023-X https://doi.org/10.1016/S0140-6736(02)12...	Placebo	–	66%	64%	No	Yes	Yes
	Natalizumab	300 mg i.v. every four weeks	RRMS	AFFIRM (phase 3)⁹⁹99. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006 Mar;354(9):899-910. https://doi.org/10.1056/NEJMoa044397 https://doi.org/10.1056/NEJMoa044397...	Placebo	–	68%	42%	Yes	Yes	Yes
			RRMS	OPERA I (phase 3)¹⁰⁰100. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B et al. Ocrelizumab versus Interferon Beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017 Jan;376(3):221-34. https://doi.org/10.1056/NEJMoa1601277 https://doi.org/10.1056/NEJMoa1601277...	Interferon beta-1 a 44 mcg s.c.	–	46%	43%
	Ocrelizumab	600 mg i.v. every 24 weeks	RRMS	OPERA II (phase 3)¹⁰⁰100. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B et al. Ocrelizumab versus Interferon Beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017 Jan;376(3):221-34. https://doi.org/10.1056/NEJMoa1601277 https://doi.org/10.1056/NEJMoa1601277...	Interferon beta-1 a 44 mcg s.c.	–	47%	37%	Yes	Yes	Yes
			PPMS	ORATORIO (phase 3)¹¹²112. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan;376(3):209-20. https://doi.org/10.1056/NEJMoa1606468 https://doi.org/10.1056/NEJMoa1606468...	Placebo	–	–	24%
	Rituximab	1000 mg i.v. on days 1 and 15; repeated every 6 months, or at variable Intervals according to CD19+ lymphocyte counts	RRMS	HERMES (phase 2)¹⁰⁸108. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008 Feb;358(7):676-88. https://doi.org/10.1056/NEJMoa0706383 https://doi.org/10.1056/NEJMoa0706383...	Placebo	–	50%	–	No	No	No
Other	Autologous hematopoietic stem cell transplantation	N/A	Severe RRMS and SPMS	ASTIMS (phase 2)¹⁰⁹109. Mancardi GL, Sormani MP, Gualandi F, Saiz A, Carreras E, Merelli E et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a phase II trial. Neurology. 2015 Mar;84(10):981-8. https://doi.org/10.1212/WNL.0000000000001329 https://doi.org/10.1212/WNL.000000000000...	Mitoxantrone	–	64%	N.S.	–	–	–

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[1] Correspondence: Jefferson Becker; Pontifícia Universidade Católica do Rio Grande do Sul, Hospital São Lucas, Serviço de Neurologia; Avenida Ipiranga, 6690, sala 220; 90610-000 Porto Alegre RS, Brasil. E-mail: jefferson.becker@pucrs.br.

Demographic features
	Male sex
	Age > 40 years at onset
	African American or African Latin-American ethnicity
Clinical features
	Severe relapse(s) (i.e., associated with ≥ 1-point change on EDSS, ≥2-point change on any individual functional system, or ≥ 1-point change on any two functional systems during the acute phase; or requiring steroids or other acute-phase treatments; or requiring hospitalization)
	Multifocal relapse(s), especially if affecting motor, cerebellar, sphincteric, or cognitive functions
	Disabling relapses (i.e., with partial or incomplete recovery)
	Frequent relapses in the first 2-5 years after disease onset, or short inter-relapse interval
	Rapid accumulation of disability related to relapses, e.g., reaching EDSS score ≥3.0 within five years after disease onset
Radiologic features (MRI)
	High disease burden at onset (i.e., high T2 lesion volume, ≥ 2 gadolinium-enhancing lesions; T1 lesions suggestive of “black holes”; early signs of brain atrophy; infratentorial and spinal cord lesions)
	Evidence of disease activity on follow-up (i.e. new/enlarging T2 lesions and/or gadolinium-enhancing lesions)