soniza vieira alves-leon professora associada de ... · • identificar etapas da fisiopatologia da...

SONIZA VIEIRA ALVES-LEON Professora Associada de Neurologia da

Universidade Federal do Estado do Rio de Janeiro Docente Livre em Neurologia

[email protected]

14:00 às 14:30 h Local: Hotel Blue Tree

CONFLITO DE INTERESSES

• Pesquisadora CNPq: Bolsista de produtividade

• Suporte FAPERJ para pesquisa e apoio a instituição

universitária

• Membro de comitê Ad Hoc CNPq e FAPERJ

• Recebeu suporte educacional e de pesquisa: Biogen Idec,

Teva, Novartis, Genzyme

• Recebeu honorários de consultoria: Novartis, Biogem Idec,

Genzyme

• Membro de Advisory Board: Novartis, Biogen Idec, Genzyme

OBJETIVOS

• Identificar etapas da fisiopatologia da Esclerose Múltipla

e alvos terapêuticos em potencial

• Identificar o papel dos Fármacos Modificadores do curso

da Doença (FMCD) que têm no seu racional diferentes

alvos terapêuticos e vêm mudando os paradigmas de

tratamento da EM

• O SNC é dotado de um repertório de resposta elaborada denominado 'neuroinflamação', que lhe permite lidar com patógenos, toxinas, traumas e degeneração.

• Ações orquestradas por células do sistema imunológico, células vasculares e neurônios, que constituem a neuroinflamação, não são apenas provocados por condições patológicas, mas podem também ser induzidas pelo aumento da atividade neuronal.

• A neuroinflamação mantém a homeostase, para permitir que o SNC possa lidar com maiores demandas metabólicas e aumenta o poder computacional e plasticidade das redes neurais.

• Esclerose Múltipla é uma doença dual, neuroinflamatória e neurodegenerativa, com diferentes gatilhos agindo em indivíduos geneticamente susceptíveis.

NEUROINFLAMAÇÃO: QUAIS AS

IMPLICAÇÕES TERAPÊUTICAS?

Dimitris N. Xanthos and Jurgen Sandkuhler, Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. NATURE REVIEWS | NEUROSCIENCE Volume 14, January 2014

NOVOS ALVOS TERAPÊUTICOS

NEUROINFLAMAÇÃO NEUROGÊNICA

Dimitris N. Xanthos and Jurgen Sandkuhler, Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. NATURE REVIEWS | NEUROSCIENCE Volume 14, January 2014

MUDANÇA DA INCIDÊNCIA DE

DOENÇAS AUTOIMUNES EM 50 ANOS

In humans, more than 100 trillion

microorganisms, mostly bacteria, colonize the oral–gastrointestinal tract, and most of these microorganisms reside in the distal intestine.

The microbiota enhances innate immunity to

pathogens. The microbiota promotes adaptive immunity

Segmented filamentous bacteria (SFB) and

other commensal microorganisms activate lamina propria dendritic cells (DCs) and macrophages to induce T helper 17 (TH17) cells and TH1 cells through the production of interleukin-1β ?(IL-1β)?, IL-6 and IL-23 in the case of TH17 cells, and possibly IL-12 in the case of TH1 cells

Microbiota and extra-intestinal diseases

MULTIPLE SCLEROSIS

Increased intestinal TH17 cells enhance the expansion of pathogenic autoantigen-specific T cells in the intestine and cause inflammation in the CNS. By contrast, ‘beneficial’ commensal bacteria can attenuate CNS inflammation through the induction of forkhead box P3 (FOXP3)+ regulatory T (TReg) cells

Patients with multiple sclerosis who were infected with helminths showed higher levels of IL-10 production by B cells and a lower frequency of disease relapse than non-infected patients with this disease.

B

T

APC

IL-4

IL-6

B

MF TH1

TH 2

-

Periferia BBB CNS

FISIOPATOLOGIA DA EM E ALVOS TERAPÊUTICOS

Ativação

celular e

proliferação

Ligação células

endoteliais e migração

Cortesia do Prof. Volker Limnorth12

13

B

T

APC

IL-4

IL-6

B

MF

Reativação celular imune e proliferação

TH1

TH 2

IL-10

TGFb

-

Perifeia BBB CNS

Adapted from: Wiendl H, et al. Expert Opin Investig Drugs. 2003;12:689-712.

Lesão CNS (desmielinização, Transecção e Perda Neuronal)

FISIOPATOLOGIA DA EM E ALVOS TERAPÊUTICOS


FATORES GENÉTICOS E AMBIENTAIS CONTRIBUEM PARA O

DESENVOLVIMENTO DA EM

1. Sospedra. Ann Rev Immunol 2005;23:683-747; 2. Kleinewietfeld et al. Nature 2013; 496

Células T autoreativas

Ativação de células T

autoreativas

Desenvolvimento de EM

Fatores ambientais de

risco/Gatilhos1, 2

GENES RELACIONADOS

À SUSCEPTIBILIDADE

PARA EM TÊM FUNÇÕES

IMUNOLÓGICAS :1

HLA-DR, HLA-DQ

CCR5

IFN-γ

IL-10

IL-4 receptor α

IL-2 receptor β

Epstein-Barr Virus

HHV-6, HSV-1

Varicella zoster virus

Chlamydia pneumoniae

Vitamin D levels

Geographic factors


1950 2000 2010 2020

ACTH

1868

EVOLUÇÃO NO TRATAMENTO DA ESCLEROSE MÚLTIPLA

Jean M Charcot

Azatioprina

MP alta dose

Esteróides baixa dose

1950 2000 2010 2020

ACTH

Azatioprina

Avonex : 1996

Betaferon : 1993

Rebif 22 : 1998

Rebif 44 : 1999

1868

MP alta dose


Mitoxantrone 2002 Copaxone : 2001

W. Ian McDonald, MB, ChB, PhD


Charles Poser, MD, PhD

JM Charcot

PRIMEIROS CRITÉRIOS DIAGNÓSTICOS PARA TRATAMENTO USANDO RM

PRIMEIROS CRITÉRIOS DIAGNÓSTICOS APLICADOS PARA TRATAMENTO

21

B

T

APC

IL-4

IL-6

B

MF TH1

TH 2

-

Periferia BBB CNS

IFNβ pode diminuir a migração de

leucócitos na BBB

1Muraro PA, et al. J Neuroimmunol. 2000;111:186-194; 2Avolio C, et al. J Neurol Sci. 2001;186:65-73; 3Defazio G, et al. J Interferon Cytokine Res. 2001;21:267-272; 4Defazio G, et al.

J Neuroimmunol.1998; 88:13-20; 5Floris S, et al. J Neuroimmunol. 2002;127:69-79; 6Muraro PA, et al. J Neuroimmunol. 2004;150:123-131; 7Soilu-Hanninen M, et al. J Neuroimmunol.

2005;167:175-182; 8Gelati M, et al. J Neurol.1999;246:569-573; 9Avolio C, et al. Mult Scler. 2005;11:441-446; 10Waubant E, et al. J Interferon Cytokine Res. 2001 ;21:181-185; 11Boz

C, et al. Clin Neurol Neurosurg. 2006;108:124-128; figure adapted from: Wiendl H, et al. Expert Opin Investig Drugs. 2003;12:689-712.

• IFNβ diminui a expressão de moléculas de adesão na

superfície celular 1-8

• IFNβ inibe atividade de MMP 9-11

• Glatiramer in vitro atua provavelmente substituindo

MBP no complexo trimolecuar

IFNβ-1a


22

B

T

APC

IL-4

IL-6

B

MF TH1

TH 2

IL-10

TGF-b

-

Periferia BBB CNS

IFNb e GA podem reataurar o balanço do sistema imune em pacientes com EM

Adapted from Wiendl H, et al. Expert Opin Investig Drugs. 2003;12:689-712

• IFNb-1e GA aumentam ação de IL-10 1-4 e

suprimem IL-121,5,6 e atividade de IL-231

1Krakauer M, et al. Mult Scler. 2008;14:622-630; 2Kozovska ME, et al. Neurology. 1999;53:1692-1697; 3Liu Z, et al. J Neuroimmunol. 2001;112:153-162; 4Rudick RA, et al. Neurology. 1998;50:1294-1300; 5Huang Y-M, et al. Clin Exp Immunol. 2001;124:306-314; 6Byrnes AA, et al. Ann Neurol. 2002;51:165-174; figure adapted from: Wiendl H, et al. Expert Opin Investig Drugs. 2003;12:689-712.



• Glatiramer parece ter como alvo o

complexo trimolecular atuando no SNC

e na periferia 7-11

Miller A, et al. J Neuroimmunol. 1998;92:113-121.7

Duda PW, et al. J Immunol. 2000;165:7300-7307.8

Aharoni R, et al. Proc Natl Acad Sci. 1997;94:10821-10826.9 Bradl M, et al. J Neurol Neurosurg Psychiatry. 2003;74:1364-1370.10 Raivich G, et al. J Neurosci. 1998:18:5804-5816.11

IFNb e GA podem reataurar o balanço do sistema imune em pacientes com EM

MAS NEM TODOS OS PACIENTES RESPONDIAM AOS INTERFERONS E AO

GLATIRAMER…

1950 2000 2010 2020

ACTH

Avonex : 1996

Betaferon : 1993

Rebif 22 : 1998

Rebif 44 : 1999

1868

Mitoxantrone 2002 Copaxone : 2001


EVOLUÇÃO NO TRATAMENTO DA ESCLEROSE MÚLTIPLA E ALVOS TERAPÊUTICOS


JM Charcot

Jordi Rio, MD PhD

Azatioprina

MP alta dose




PRIMEIROS CRITÉRIOS NÃO RESPOSTA

1950 2000 2010 2020

ACTH

Avonex : 1996

Betaferon : 1993

Rebif 22 : 1998

Rebif 44 : 1999

1868

Mitoxantron 2002 Copaxone : 2001

Natalizumabe 2006 Cladribin 2011

Fumarate 2013

Fingolimod 2011

Teriflunomide 2013

Alemtuzumabe 2013


Chris Polman, MD PhD

EVOLUÇÃO NO TRATAMENTO DA ESCLEROSE MÚLTIPLA E ALVOS TERAPÊUTICOS


JM Charcot

Azatioprina

MP alta dose




PRIMEIROS CRITÉRIOS PARA DIAGNÓSTICO PRECOCE COM DIS E DIT RM

E O CONCEITO DE TRATAMENTO ALTAMENTE EFICAZ -

NEDA

NATALIZUMABE

• Natalizumab is a humanized recombinant monoclonal antibody against α4-integrin.

• It diminishes leukocyte migration from the peripheral blood into the CNS by preventing its binding via α4-integrin to the ligand vascular cell adhesion molecule (VCAM) found on endothelial surfaces.

• This blocks the adhesion and subsequent migration of lymphocytes lymphocytes across the blood–brain barrier (BBB), attenuating CNS inflammation

30

B

T

APC

IL-4

IL-6

B

MF TH1

TH 2

IL-10

TGFb

-

Periferia BBB CNS

NATALIZUMABE



Oral, uma vez ao dia (0,5 mg)1

Primeiro em uma nova classe de compostos

terapêuticos1

Liga-se as S1P-Rs expressos nos linfócitos e células

neurais do SNC1-8

Retenção seletiva e reversível de linfócitos circulantes

dos linfonodos1,3,9

linfócitos T de memória centrais e virgens retidas

linfócitos T de memória efetora de vigilância imune

poupadas

Age no interior do SNC2,10-13

atravessa a BHE para o SNC10

reduz astrogliose e ativação de astrócitos lesionais

(receptores S1P estão presentes nos astrócitos)11,12

Alvo / princípio: sistema imune e outros (SNC)

APC

Linfonodo

S1P-R

T

Gliose S1P-R

Fingolimode

Fingolimode

SNC / Sistema Imune e Neural

Sistema Periférico / Imune

OGD

1. Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol. 2010 Mar-Apr;33(2):91-101. 2. Brinkmann V. FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol. 2009 Nov;158(5):1173-82. 3. Matloubian M, Lo CG, Cinamon G et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature. 2004 Jan 22;427(6972):355-60. 4. Kimura A, Ohmori T, Ohkawa R et al. Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury. Stem Cells. 2007 Jan;25(1):115-24. 5. Mandala S, Hajdu R, Bergstrom J et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002 Apr 12;296(5566):346-9. 6. Brinkmann V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther. 2007 Jul;115(1):84-105. 7. Baumruker T, Billich A, Brinkmann V et al. FTY720, an immunomodulatory sphingolipid mimetic: translation of a novel mechanism into clinical benefit in multiple sclerosis. Expert Opin Investig Drugs. 2007 Mar;16(3):283-9. 8. Massberg S, von Andrian UH. Fingolimod and sphingosine-1-phosphate--modifiers of lymphocyte migration. N Engl J Med. 2006 Sep 14;355(11):1088-91. 9. Mehling M1, Brinkmann V, Antel J et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology. 2008 Oct 14;71(16):1261-7. 10. Tamagnan GD et al. Pôster P839 apresentado em ECTRIMS 2012. 11. Choi JW, Gardell SE, Herr DR et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):751-6. 12. Mehling M, Lindberg R, Raulf F et al. Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology. 2010 Aug 3;75(5):403-10. 13. Anthony DC, Sibson NR et al. Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model. Neuropharmacology. 2014 Apr;79:534-41. Imagens de mecanismo adaptadas de: Linker RA, Kieseier BC, Gold R. Identification and development of new therapeutics for multiple sclerosis. Trends Pharmacol Sci. 2008 Nov;29(11):558-65.

FINGOLIMODE

Evidâncias sugerem alteração na biologia do S1P no SNC de pacientes com EM1

• Concentração de S1P está significantemente maior no LCR de pacientes com EM (n = 40)2

• Correlação positiva entre concentração de S1P e escore de EDSS 2

**p<0.01 vs control; CSF, cerebrospinal fluid; EDSS, Expanded Disability Status Scale; NAWM, normal appearing white matter 1. Wheeler et al. Brain 2008; 2. Kulakowska A et al. Neurosci Lett 2010; 3. Van Doorn R et al. Glia 2010; 4. Van Doorn R et al. Poster P662 presented at ECTRIMS 2010

15

10

5

0 Control MS

**

(S1

P)

nM

12

8

4

0

EDSS

(S1

P)

nM

2

6

10

5 4 3 2 1 0

R = 0.5867 p<0.001

• Receptores S1P (S1P1 e S1P3) estão up-regulados nos astrocitos das lesões de EM 3,4

Control brain tissue Active MS lesion NAWM

Immunohistochemical staining for S1P1

ALEMTUZUMABE

Alemtuzumab (Campath-1H) is a humanized monoclonal antibody targeting CD52 expressed on lymphocytes, natural killer (NK) cells, monocytes, and some granulocytes.

It produces antibody-dependent cellular cytotoxicity with rapid and profound lymphopenia lasting for years

Hartung et al.

ALEMTUZUMABE

Minagar et al. Expert Opin Biol Ther 2010;10:421-9.

Lymphocyte

CD52

Alemtuzumab Dead lymphocyte

Complement binding and

activation

Membrane attack complex

Fc Receptor

Immune cells (eg, NK cells or neutrophils)

Dead lymphocyte

Antibody-dependent Cellular Cytolysis (ADCC)

Complement-dependent Cytolysis (CDC)

Fc region

• Reconstituição subsequente do sistema imune com preservação relativa de células Treg e células B naive

• Linfócitos B – 6 meses • Linfócitos T – 12 meses

1. Fox. Expert Rev Neurother 2010;10:1789-97;

2. Coles et al. J Neurol 2006;253:98-108;

3. Rudick et al. Ann Neurol 2004;56:548–55;

4. Jones et al. Brain 2010:133;2232-47; 5. Cox et al. Eur J Immunol. 2005;35:3332-42.

Alemtuzumabe depleta rapidamente células B e T por meio de 2 principais mecanismos:

TERIFLUNOMIDA • Teriflunomide is the metabolite of leflunomide

• It inhibits dihydroorotate dehydrogenase (DHODH), the rate-limiting mitochondrial enzyme in de novo pyrimidine synthesis.

• A salvage pathway independent of DHODH suffices for resting lymphocytes, but fast-proliferating cells such as activated lymphocytes are dependent on de novo synthesis and are a selective target of teriflunomide.

TERIFLUNOMIDA

• Other actions include impairing the migratory capacity of T cells, biasing the differentiation of naive T cells toward a Th2 phenotype, decreasing T cell–dependent antibody production, and effects on B cells.

DIMETILFUMARATO (BG12)

• BG12 (dimethyl fumarate) is an ester of dimethyl fumaric acid, already licensed as a second-line agent in severe psoriasis.

• The exact mode of action of BG12 is not completely understood:

• It may polarize the immune system toward a Th2 phenotype, increase the production of the anti-inflammatory cytokines interleukin (IL)-10 and IL-1 receptor antagonist (IL-1RA), attenuate lipopolysaccharide-induced production of tumor necrosis factor-alpha (TNFα), IL-1β, IL-6, and nitric oxide (NO).

• BG12 may have neuroprotective effects via activation of the NF-E2-related factor 2 (Nrf-2) antioxidant pathway

ARE

Nukleus

Zytoplasma

DMF or MMF

Nrf2

Nrf2

Oxidative

Stress

Nrf2

Nrf2

Nrf2

Nrf2

Nrf2

Nuclear factor (erythroid-derived 2)-like 2 =NFE2L2 or Nrf2, van Horssen J et al. Biochim Biophys Acta. 2011; 1812:141-150 | Linker RA et al. Brain. 2011; 134:678-692

DIMETILFUMARATO (BG12)

DIMETILFUMARATO e seu metabólito ativo (monometil fumarato) agem ativando o Nrf2 (simulando o excesso de Ros). Nrf2 age no DNA ativando genes que levam a produção de Enzimas AntioxidanteS

1950 2000 2010 2020

ACTH

Azathioprin

Avonex : 1996

Betaseron : 1993

Rebif 22 : 1998

Rebif 44 : 1999

1868

steroids, low dose MP - high dose

Mitoxantron 2002 Copaxone : 2001

Natalizumab 2006 Cladribin 2011

Fumarate 2013

Fingolimod 2011

Teriflunomide 2013

Laquinimod 2014

Alemtuzumab 2013

Siponimod / ONO 2015

Daclizumab 2015

Ocrelizumab 2016

PegInterferon 2014


Chris Polman, MD PhD



JM Charcot

ESTUDOS EM ANDAMENTO E OUTROS FMCD EM FASE DE APROVAÇÃO

OCRELIZUMABE

• Ocrelizumab is a recombinant humanized antibody that binds to CD20 at a different epitope but partly overlapping with rituximab.

• Ocrelizumab has a half-life of 23-28 days and induces a rapid B cell depletion after infusion, with a recovery of B cell numbers at 3 months

DACLIZUMABE • Daclizumab is a humanized mouse monoclonal antibody. It

antagonizes CD25 which is otherwise up-regulated on activated T cells and allows them to receive the IL-2 signal.

• Daclizumab has a high specificity for IL-2R, with a capacity of saturating IL-2R for 43 days after a single dose of 2 mg/kg.

Hypothesized Immunomodulatory

Effect of Daclizumab Treatment

47

• DAC treatment reduces activated T-cells and increases CD56bright NK cell proliferation via intermediate affinity IL-2 signaling1

1. Martin J, et al. J Immunol 2010;185:1311–1320.

Giovannoni G et al. Presented at ECTRIMS-ACTRIMS; October 19 – 22, 2011, Amsterdam, The Netherlands. Oral presentation 149.

MAIS ALVOS TERAPÊUTICOS…

Sodium concentration is increased Within lesions, normal appearing white

Matter and cortical and deep grey matter

Sodium concentration is

higher in secondary

progressive MS and in

patients with greater

disability

Ocrelizumab Ofatunumab

FARMACOTERAPIA

(aguda e imunomoduladora)

EDUCAÇÃO

Fatores de risco

TRATAMENTO

SINTOMÁTICO

Fisioterapia, suporte

ALVOS TERAPÊUTICOS NA ESCLEROSE MÚLTIPLA

N=895 (270 males and 625

females), mean disease 17 years

Risk of reaching EDSS 4 and6

Regular smoking is associated with

more severe disease and faster

disability progression

Smoking cessation, whether before

or after onset of the disease is

associated with a slower

progression of disability

EDSS 4

EDSS 6

Adaptado de: Ingwersen J, Aktas O, Hartung HP. Advances in and Algorithms for the Treatment of Relapsing-Remitting Multiple Sclerosis. Neurotherapeutics. 2016 Jan;13(1):47-57.

CONCLUSÕES

• OS NOVOS ALVOS TERAPÊUTICOS MOSTRAM A NECESSIDADE DE UM MANEJO CADA VEZ MAIS INDIVIDUALIZADO DE DOENÇAS

• O RECONHECIMENTO DE NOVOS ASPECTOS FISIOPATOLÓGICOS É SEGUIDO DE NOVOS ALVOS TERAPÊUTICOS

• A ESCOLHA DOS FMCD DEVE CONSIDERAR A ATIVIDADE DA EM E ABOLIR O CONCEITO DE 1a, 2a., 3a. LINHA SOB PENA DE SE PERDER A MELHOR JANELA TERAPÊUTICA PARA IMPACTAR A MORBIDADE DA DOENÇA

RISCO BENEFÍCIO É INDIVIDUALIZADO!!!

soniza vieira alves-leon professora associada de ... · • identificar etapas da fisiopatologia da...

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