Brazilian Consensus for the Treatment of Multiple Sclerosis: Brazilian Academy of Neurology and Brazilian Committee on Treatment and Research in Multiple Sclerosis

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) • Aug 2018 • https://doi.org/10.1590/0004-282X20180078 linkcopy

Brazilian Consensus for the Treatment of Multiple Sclerosis: Brazilian Academy of Neurology and Brazilian Committee on Treatment and Research in Multiple Sclerosis

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

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

The expanding therapeutic arsenal in multiple sclerosis (MS) has allowed for more effective and personalized treatment, but the choice and management of disease-modifying therapies (DMTs) is becoming increasingly complex. In this context, experts from the Brazilian Committee on Treatment and Research in Multiple Sclerosis and the Neuroimmunology Scientific Department of the Brazilian Academy of Neurology have convened to establish this Brazilian Consensus for the Treatment of MS, based on their understanding that neurologists should be able to prescribe MS DMTs according to what is better for each patient, based on up-to-date evidence and practice. We herein propose practical recommendations for the treatment of MS, with the main focus on the choice and management of DMTs, as well as present a review of the scientific rationale supporting therapeutic strategies in MS.

Keywords:
multiple sclerosis; drug therapy; consensus

Category	Disease-modifying treatment	Maintenance dose, route and schedule*	Phenotype	Pivotal or reference trial (and phase of development)	Selected comparator	Relative reduction in endpoints versus the selected comparator**			Currently approved for MS?
Category	Disease-modifying treatment	Maintenance dose, route and schedule*	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)⁶⁸	Placebo	45%	–	–
	Glatiramer acetate	20 mg s.c. once daily	RRMS	Copolymer 1 MS Study (phase 3)⁸⁷	Placebo	–	29%	28%	Yes	Yes	Yes
		40 mg s.c. three times a week	RRMS	GALA (phase 3)⁸⁸	Placebo	–	34%	N.S.	Yes	Yes	Yes
	Interferon beta-1 a i.m.	30 mcg i.m. once a week	CIS	CHAMPS (phase 3)⁶⁵	Placebo	30%	–	–
	Interferon beta-1 a i.m.	30 mcg i.m. once a week	RRMS	The MSCRG study (phase 3)⁸⁴	Placebo	–	18%	37%	Yes	Yes	Yes
	Interferon beta-1 a s.c.	22 mcg s.c. three times a week	CIS	ETOMS (phase 3)⁶⁶	Placebo	24%	23%	N.S.	Yes	Yes	Yes
		22 mcg s.c. three times a week	RRMS	PRISMS (phase 3)⁸⁵	Placebo	–	29%	32%	Yes	Yes	Yes
		44 mcg s.c. three times a week	CIS	REFLEX (phase 3)⁶⁹	Placebo	51%	–	–	Yes	Yes	Yes
		44 mcg s.c. three times a week	RRMS	PRISMS (phase 3)⁸⁵	Placebo	–	32%	38%	Yes	Yes	Yes
			CIS	BENEFIT (phase 3)⁶⁷	Placebo	46%	–	–
	Interferon beta-1 b	250 mcg s.c. every other day	RRMS	The IFNB MS Study (phase 3)⁸⁶	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)¹¹⁰	Placebo	–	31%	22%	Yes	Yes	Yes
	Pegylated Interferon beta-1 a	125 mcg s.c. once every two weeks	RRMS	ADVANCE (phase 3)⁸⁹	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)⁸²	Placebo	67%	–	–
	Cladribine		RRMS	CLARITY (phase 3)⁹⁶	Placebo	–	58%	33%	No	No	Yes
	Dimethyl fumarate	240 mg p.o. twice daily	RRMS	DEFINE (phase 3)⁹⁰	Placebo	–	53%	38%	Yes	Yes	Yes
	Dimethyl fumarate	240 mg p.o. twice daily	RRMS	CONFIRM (phase 3)⁹¹	Placebo	–	44%	21%	Yes	Yes	Yes
	Fingolimod	0.5 mg p.o. once daily	RRMS	FREEDOMS (phase 3)⁹⁷	Placebo	–	55%	27%	Yes	Yes	Yes
	Fingolimod	0.5 mg p.o. once daily	RRMS	FREEDOMS 2 (phase 3)⁹⁸	Placebo	–	48%	N.S.	Yes	Yes	Yes
			CIS	TOPIC (phase 3)⁷⁰	Placebo	43%	32%	30%
	Teriflunomide	14 mg p.o. once daily	RRMS	TEMSO (phase 3)⁹²	Placebo	–	32%	30%	Yes	Yes	Yes
			RRMS	TOWER (phase 3)⁹³	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)⁹⁴	Interferon beta-1 a 44 meg s.c.	–	55%	30%	Yes	Yes	Yes
	Alemtuzumab		RRMS	CARE-MS 2 (phase 3)⁹⁵	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)¹⁰⁵	Placebo	–	N.S.***	–	No	No	No
	Cyclophosphamide		SPMS	PROMESS (phase 3)¹²⁵	Methylprednisolone i.v. every four weeks	–	N.S.***	N.S.***
	Intravenous Immunoglobulin	0.15-0.20 g/kg body weight i.v. once a month	RRMS	AIMSS (phase 2)¹⁰⁶	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)¹⁰⁷	Placebo	–	66%	64%	No	Yes	Yes
	Natalizumab	300 mg i.v. every four weeks	RRMS	AFFIRM (phase 3)⁹⁹	Placebo	–	68%	42%	Yes	Yes	Yes
			RRMS	OPERA I (phase 3)¹⁰⁰	Interferon beta-1 a 44 mcg s.c.	–	46%	43%
	Ocrelizumab	600 mg i.v. every 24 weeks	RRMS	OPERA II (phase 3)¹⁰⁰	Interferon beta-1 a 44 mcg s.c.	–	47%	37%	Yes	Yes	Yes
			PPMS	ORATORIO (phase 3)¹¹²	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)¹⁰⁸	Placebo	–	50%	–	No	No	No
Other	Autologous hematopoietic stem cell transplantation	N/A	Severe RRMS and SPMS	ASTIMS (phase 2)¹⁰⁹	Mitoxantrone	–	64%	N.S.	–	–	–

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[TFN1] Adapted from Rush et al. (2015)¹⁸. EDSS: Expanded Disability Status Scale; MRI: magnetic resonance imaging.

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)