Prof Jeannette Lechner-Scott - MS

MS Symposium – Rydges Newcastle 30 May 2019

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Prof Jeannette Lechner-ScottHunter New England Local Health District

MS Symposium – World MS Day 30 May 2019

MS SymposiumCurrent Understanding of MS

Jeannette Lechner-Scott

John Hunter Hospital

May 2019


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Topics

• Etiology

• Genetics

• Immunology

• New diagnostic criteria

• Risk factors for disease activity

• Novel therapies

• Differential diagnosis

Increasing prevalence and incidence of MS in young women

Ribbons K. et al. Mult Scler. 2017 Jul;23(8):1063-1071


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Etiology

Genetics


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Genetics

• HLA-DRB1*1501 main susceptibility factor (OR 3)

• HLA-A *02 decreases risk (OR -0.6)

• Presence of HLA-DRB1*1501 and absence of HLA-A*02 has an OR of 5

Genes affected by autoimmune disease

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K K-H Farh et al. Nature 518, 337-347 2015


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Nat Rev Neurol. 2017 Jan;13(1):25-36

Environmental risk factors


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Interaction between smoking and genetic risk

factors

Hedstroem, Mult Scler 2019;25:180-

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How does MS work

Jelcic et al., 2018, Cell 175, 85–100


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Clinical symptoms

Subclinical degeneration

Time (years)

+

-

THERAPYAxonal dam

age

Disease course

2017 MS diagnostic criteria

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Thompson, Lancet Neurol 2018


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2017 MS diagnostic

criteria

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Thompson, Lancet Neurol 2018

Lublin criteria

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Neurology. 2014 Jul 15;83(3):278-86


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Prognosishighly variable

Brain reserve

Stephen C. Krieger et al. Neurol Neuroimmunol Neuroinflamm 2016;3:e279


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What can be done?

EARLY DIAGNOSIS

EARLY ACCESS TO EFFECTIVE

THERAPY


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Effect of DMT on disability pension in Swedish registry

Brown W et al.JAMA. 2019 Jan 15;321(2):175-187


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Predictors of progressionUher, Mult Scl January 2017Min M, Mult Scler. 2018 Oct;24(12):1569-1577Marrie RA, Mult Scler. 2015 Mar; 21(3): 263–281Tettey P Neuroepidemiology 2016;46:106-113

o Disability at baseline

o Brain atrophy

o Number of new lesion

o Age at onset

o Pyramidal or cerebellar symptoms at onset

o Obesity

o Co-morbidities

o Hypercholesterolemia

o Anxiety/depression

o smoking

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AlemtuzumabTeriflunomide

Ocrelizumab Cladribine Tablets

sc IFN β-1b

im IFN β-1a

sc IFN β-1a

Natalizumab

Glatiramer acetate Fingolimod Daclizumab

Immunomodulation/immunostimulation

Chronic drug administration resulting in modulation of immune

function without immunosuppression

Clinical efficacy onlyduring active treatment

Selective, continuousimmunosuppression

Chronic drug administration resulting in ongoing suppression of

immune function

Clinical efficacy onlyduring active treatment

DMF

Broad spectrum immunosuppression

Prior to 1990s MS treatment options limited to

broad-spectrum immunosuppressants

Therapeutic evolution over the last 30y

DMF, dimethyl fumarate; IFN, interferon; im, intramuscular; sc, subcutaneous

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Cyclophosphamide

Azathioprine

Therapies with potential for remission?

Short-course administration

Clinical efficacy extends well beyond period of active treatment


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Disease modifying treatment

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Relapses80%

relapse free

6-monthconfirmed EDSS

91% progression

free

NEDA44%

Active T262%

lesion free

T1 Gd+87%

lesion free

NEDA was defined as no relapses, no 6-month confirmed EDSS progression and no new T1 Gd+ lesions and no active T2 lesions on cranial MRI. Post hoc analysis EDSS, Expanded Disability Status Scale; Gd+, gadolinium-enhancing; NEDA, no evidence of disease activityGiovannoni G et al. Lancet Neurol 2011;10:329–37


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Comparison of NEDA outcome over 2 years

0 5 10 15 20 25 30 35 40 45 50

Opera

CLARITY

Care MS I

AFFIRM

FREEDOMS

CARE MSII

beta IFN 1a in CARE

DEFINE/CONFIRM

TEMSO

% NEDA

% NEDA33%

37%

39%

27%

47%

32%

23%

23%

44%

Hauser ectrims 2015Giovannoni, Lancet Neurology 2011Nixon, Adv Therap 2014;31:1134Havdrova, Lancet Neurol 2009Havdrova, Therp Adv Neurol Dis 2014

Ocrelizumab

• Approved since October 2018

• Monoclonal antibody against B cells

• 6 monthly infusions of 600 mg

• Most common side effect infusion reaction

• First drug to show benefit in PPMS

• 3mCDP HR 0.76

• OBOE presented at AAN 2019

• LP in 99 patients

• Reduced B cells in CSF

• Reduced CXCL13


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Cladribine

• Approved since January 2019

• Month one

• Oral tbl weight adjusted for 5d

• Month two

• Oral tbl weight adjusted

• Long lasting effect

• 75% stable for up to 4 y

• Well tolerated

• Crosses BBB


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Malignancy risk

• Fingolimod

• Skin cancer BCC 272

• Breast cancer 168

• Multiple myeloma 132

• Cladribine

• Withdrawn from the market in 2012

• Meta-analysis of 11 studies showed no increased risk compared to other IS

• Alemtuzumab

• Lymphoma

• Thyroid carcinoma

• Natalizumab

• Incidence of melanoma 5/100 000 MS person years

• Breast cancers 375

• Melanoma 150

• CNS lymphoma

• Ocrelizumab

• Breast cancer

• Lymphoproliferative disorders

• ECTRIMS guidelines recommend regular FU while on IS

• annual dermatological screen recommended

• 3 annual pap smear independent of HPV

• Increased risk with high efficacy DMT HR of 4 (40/100,000)

• Vaccination recommended

• Annual breast screen

Lebrun-Rocher, CNS Drugs 2018; 32:939

Forest plot end malignancy RDs using Mantel-Haenszel pooling. CI, confidence interval; IFN, interferon; RD, risk difference 1. Dendrou CA et al. Nat Rev Immunol 2015;15:545–58; 2. Pakpoor J et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e158. Figure adapted from reference 2

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Malignancy risk in studies

Year Trial Drug Malignancy risk differences RD (95% CI) Weight (%)

2010 FREEDOMS Fingolimod −0.01 (−0.03, 0.00) 5.16

2012 CONFIRM Dimethyl fumarate −0.01 (−0.02, 0.00) 7.43

2006 SENTINEL Natalizumab −0.01 (−0.02, 0.00) 6.09

2011 TEMSO Teriflunomide −0.01 (−0.02, 0.00) 9.04

2012 CONFIRM Dimethyl fumarate −0.00 (−0.01, 0.00) 11.67

2012 CARE-MS II Alemtuzumab −0.00 (−0.02, 0.01) 5.39

2012 DEFINE Dimethyl fumarate −0.00 (−0.01, 0.01) 10.35

2013 TENERE Teriflunomide 0.00 (−0.01, 0.02) 4.61

2006 AFFIRM Natalizumab 0.00 (−0.00, 0.01) 9.37

2012 CARE-MS I Alemtuzumab 0.01 (−0.01, 0.02) 8.06

2010 TRANSFORMS Fingolimod 0.01 (0.00, 0.02) 9.56

Overall (I-squared=56.3%; p=0.009) −0.00 (−0.01, 0.00) 100.00

Note: Weights are from random effects analysis

Lower risk in treatment group

–0.02 –0.01 0 0.01 0.02

Lower risk in control group


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Life style recommendations

Diet

• Roy Swank 1948• Low polysaturated fats

• OMS diet

• Terry Wahl• Raw foods, berry, fruits Paleo diet

• Rich in nutrients for mitochondria

• animal-based omega-3 fats, creatine, and coenzymeQ10, while your myelin needs vitamins B1, B9, B12, omega-3, and iodine

• Vitamin D

Cochrane Database Syst Rev. 2012 Dec 12http://www.msra.org.au/prevanzJagannath VA, Filippini G, Di Pietrantonj C, Asokan GV, Robak EW, Whamond L, Robinson SA. Vitamin D for the management of multiple sclerosis. Cochrane Database of Systematic Reviews. 2018(9).

Benefit of Vitamin D

• Jagannath VA, Filippini G, Di Pietrantonj C, Asokan GV, Robak EW, Whamond L, Robinson SA. Vitamin D for the management of multiple sclerosis. Cochrane Database of Systematic Reviews. 2018(9).


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Differential diagnosis

• Neuromyelitis spectrum disorder

• 1804 Antoine Portal

• 1894 Devic

• 2004 Aquaporin 4 antibody

• astrocytopathy

• 2014 anti-MOG antibody

• Oligodendropathy

• 2019 3 controlled trials in NMOSD

• Eculizumab

• Complement C5 inhibitor

• Inebilizumab

• Monoclonal Ab CD 19

• Satralizumab

• Monoclonal antibody against IL6

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Prof Jeannette Lechner-Scott - MS