What is brain health?

Gavin GiovannoniBarts and The London

DisclosuresProfessor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni.

Professor Giovannoni would like to acknowledge and thank several companies for making available data slides on natalizumab and alemtuzumab for this presentation.

Reasoning by analogy

Images courtesy of Professor Gavin Giovannoni /

ESRFend-stage renal failure

Images courtesy of Professor Gavin Giovannoni /

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

DifferentialDiagnosis

At risk

RIS CIS

Minimal impairment

Moderate

impairment

Severeimpairment

Terminal

Phase

MRI

EvokedPotentials

Lumbar puncture

BloodTests

DiagnosticCriteria

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

PainSwallowing

SpasticityFalls

Balance problems Insomnia

Restless legsFertility

Clinical trials

Gait

Pressuresores

Oscillopsia

Emotionallability

Seizures

Gastrostomy

Rehab

Suprapubiccatheter Intrathecal

baclofen

Physio-therapy

Speech therapy

OccupationalTherapy

Functional neurosurgery

Colostomy

Tendonotomy

Studying

EmploymentRelationships

Travel

Vaccination

Anxiety

Driving

Nurse specialists

Family counselling

Relapses

1st line

2nd line

Maintenance Escalation Induction

Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet

AlternativeMedicine

PregnancyBreastFeeding

Research

Insurance

Visual loss

PalliativeCare

Assistedsuicide

Socialservices

Legalaid

Genetic counselling

PreventionDiagnosis

DMTSymptomatic

Therapist

Terminal

CounsellingAn holistic approach to MS

Intrathecalphenol

Fractures

Movement disorders

Osteopaenia

Brain atrophy

Hearing loss

Tinnitus

Photophobia

Hiccoughs

DVLA

Neuroprotection

Psychosis

Depersonaliation

BrainHealth

CognitiveReserve

Sudden death

SuicideOCD

Narcolepsy

ApnoeaCarers

Respite

Hospice

Respite

Dignitas

Advanced Directive

Rhiztomy

Rhiztomy

Wheelchair

Walking aids

Blood/Organdonation

Brain donation

Exercise therapy

NABs

Autoimmunity

Infections

Outcome measures

WebResources

Pathogenesis

Doublevision

What isMS?

NEDA

T2TOCT

Neurofilaments

JCV statusPharma

Anaesthesia

Early intervention and long-term prognosis

www.msbrainhealth.orgImage reproduced with permission from Giovannoni G, et al. Brain health: Time matters in multiple sclerosis. 2015 Available at www.msbrainhealth.org/report Accessed 26 May 2016.

Incr

easi

ng d

isab

ility

Time

Intervention at diagnosis

Intervention later

Potentialrange ofoutcomes

No treatment

Later intervention

Intervention at diagnosis

Responsibility

Who should take responsibility?

• The person with MS?

• The HCP or neurologist?

• The healthcare system?

• The regulators?

• Society?

HCP, healthcare practitioner; MS, multiple sclerosis.

Neuro-restoration

Remyelination

Neuroprotection

Anti-inflammatory

Therapeutic pyramid

Anti-ageing

Brain Health Initiative

• Smoking• Exercise• Diet• Alcohol• Sleep• Co-morbidities• Infections• Concomitant medications

• ? Menopause / HRT

MS-specific

MS non-specific

What is brain health?

Relapses

Unreported relapses

Clinical disease progression

Subclinical relapses: focal MRI activity

Focal gray and white matter lesions not detected by MRI

Brain atrophy

Spinal fluid neurofilament levels

Etc.

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

NEDA

END-

ORG

AN D

AMAG

E

MS Specific Targets: MS Iceberg

MRI, magnetic resonance imaging; NEDA, no evidence of disease activity. Images reproduced with permission from: http://multiple-sclerosis-research.blogspot.com/2015/07/cortical-lesions-and-cognitive-ability.html Accessed 27 May 2016.

13

Rapid adoption of innovations has the potential to improve MS care

Reproduced and adapted from Rogers EM. Diffusion of innovation. New York: Simon and Schuster, 2003

100

80

60

40

20

0

Pro

porti

on o

f ado

pter

s (%

)

Innovators

Early adopters

Majority adopters

Late adopters

Laggards

30% tipping point

Time

14

Slow adoption of innovations results in healthcare inequity

Per

form

ance

Time1 2

1st line

2nd and 3rd line

Old

New

Newer3rd line

2nd line

1st line

15

0 20 40 60 80 100

Large disparities exist in access to disease-modifying therapies

DMT, disease-modifying therapy. 1. Hollingworth S et al. J Clin Neurosci 2014;21:2083–7; 2. World Bank, 2015. http://data.worldbank.org/indicator/SP.POP.TOTL; 3. MSIF, 2013. http://www.atlasofms.org; 4. Wilsdon T et al. 2013. http://crai.com/sites/default/files/publications/CRA-Biogen-Access-to-MS-Treatment-Final-Report.pdf. Figure reproduced from Giovannoni G et al. Brain health: time matters in multiple sclerosis. Available at: www.msbrainhealth.org

Newer DMTEstablished DMTNo DMT

All people with MS (%)

All data are from 2013

4

4

4

4

4

4

4

4

4

4

4

4

4

1–3

Established DMTsDMTs approved for relapsing forms of MS during the 1990s and reformulations or generic versions of these substances

Newer DMTsDMTs approved for relapsing forms of MS that have a different mechanism of action from established DMTs

16

Brain health: time matters in multiple sclerosis – a policy report

■ Brain health perspective■ Multidisciplinary international

author group■ Structured discussions

during 2015 ■ Evidence-based consensus

recommendations on:□ diagnosis□ therapeutic strategies□ access to treatment

www.msbrainhealth.org

International policy initiative

DMT, disease-modifying therapy. Images used with permission from Giovannoni G, et al. Brain health: Time matters in multiple sclerosis. 2015 www.msbrainhealth.org/report. Accessed 26 May 2016.

Stroke or brain attack: ‘time really is brain’

Passive Active

Defining the therapeutic target

Relapses

Unreported relapses

Clinical disease progression

Subclinical relapses: focal MRI activity

Focal gray and white matter lesions not detected by MRI

Brain atrophy

Spinal fluid neurofilament levels

Etc.

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

NEDA

END-

ORG

AN D

AMAG

E

MS Specific Targets: MS Iceberg

MRI, magnetic resonance imaging; NEDA, no evidence of disease activity. Images reproduced with permission from: http://multiple-sclerosis-research.blogspot.com/2015/07/cortical-lesions-and-cognitive-ability.html Accessed 27 May 2016.

Treatment effect on disability predicted by effect on T2-lesion load and brain atrophy

Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions and brain atrophy, individually or combined, in 13 placebo-controlled RRMS trials (13,500 patients)

Sormani MP et al. Ann Neurol. 2014;75:43-49.

BARTS-MS T2T-NEDA ALGORITHM T2T = treating-to-target; NEDA = no evident disease activity

Choose therapy

A B C

Define the individual’s MS

Treatment failure?

• Patient’s preferences?• Your choice?

Individual measures:• Evidence of disease activity?• Tolerability/safety?• Adherence?• Drug or inhibitory markers,

e.g. NABs?

Monitoring

• MS prognosis based on clinical and MRI indices

• Life style and goals • Shared goals for therapy

Rebaseline

Rebaselining:• IFNβ, natalizumab, fingolimod,

teriflunomide, Dimethyl-Fumarate=3-6 months

• Glatiramer acetate=9 months• Alemtuzumab=24 months

Choose a therapeutic strategy

Maintenance-escalation Induction

Choose therapy

X Z

Rebaseline

Monitoring

Initiate or Switch or Escalate Rx Complete course / Re-treat

Breakthrough disease

Y

• Patient’s preferences?• Your choice?

NoYes Yes

• Only one licensed induction therapy at present

Ifn-β = interferon-beta; NABs = neutralizing antibodies; Rx = treatment;Giovannoni G et al. Multiple Sclerosis and Related Disorders 2015;4;329-33

Rheumatoid arthritisEnd-stage joint disease

Baseline Month 6

Month 12 Month 18

Baseline Month 6

Month 12 Month 18

Patient 1 Patient 2

End-organ damage

www.ms-res.org

Does the biology of MS change with time?

TOP: earlier natalizumab treatment favours annualised relapse rate outcomes

P values from a negative binomial regression model adjusted for gender, baseline EDSS score (<3.0 vs ≥3.0l), relapse status in the prior year (≤1 vs >1), prior DMT use (<3 vs ≥3), disease duration (<8 vs ≥8 years), and treatment duration (≥3 vs <3 years), except for the factor of interest. Error bars represent 95% CIs.DMT=disease-modifying therapy; CI=confidence interval.Wiendl et al. Presented at ENS; June 8–11, 2013; Barcelona, Spain,. P372.

NEDA outcomes with alemtuzumab:3-year follow-up of the CARE-MS studies

MRI, magnetic resonance image; CI, confidence interval.Adapted from Havrdova E et al. Presented on ACTRIMS/ECTRIMS, 2014, FC1.4.

↑32.2%P=0.0062

↑45.8%P<0.0001

CARE-MS I: NEDA by year

SC IFNB-1aALEM 12 mg

174369

170 356

—349

SC IFNB-1aALEM 12 mg

187405

173434

— 393

↑61.2%P<0.0001

CARE-MS II: NEDA by year

↑84.3%P<0.0001

Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology

Magliozzi et al. Brain 2007; 130:1089-1104.

Cortical and white matter demyelination

Female

Age 47 years

MS for 30 years

Proportion of cortex demyelinated= 59%

Schmierer-Lab, Blizard Institute

Intrathecal Antibody Response

local OCBs

local & systemic OCBs

systemic OCBs

normal / polyclonal

CSFSerum

Intrathecal or central compartment

Systemic or peripheral compartment

C

S

C

S

C

S

C

S

Meningeal Perivascular

Time is brain!

Stroke or brain attack: ‘time really is brain’

Passive Active

www.msbrainhealth.org

www.msbrainhealth.org

Baseline Month 6

Month 12 Month 18

Baseline Month 6

Month 12 Month 18

www.msbrainhealth.org

Neuro-restoration

Remyelination

Neuroprotection

Anti-inflammatory

Therapeutic pyramid

Anti-ageing

Brain

Health

Initiative

• Smoking• Exercise• Diet• Alcohol• Sleep• Co-morbidities• Infections• Concomitant medications

• ? Menopause / HRT

MS-specific

MS non-specific

Brain Health

Walk the talk!

2016Brain Health

Challenge

Barts-MS☑ Treat-2-Target

☑ Lifestyle

☑ Co-morbidities

☑ Wellness

☑ Treat-2-Target

☑ Prognosis

☑ Active MS

☑ Treatment

☑ Re-baselining

☑ Monitoring

☑ NEDA

#ThinkHand 95%

clinicspeak.com

clinicspeak.com

☑ Lifestyle

☑ Diet & supplements

☑ Exercise

☑ Smoking

☑ Alcohol

☑ Sleep

☑ Stress

Lifestyle modification in MS

John Saxton Department of Sport, Exercise and Rehabilitation Northumbria UniversityNewcastle Upon Tyne, UK

Morphological(Body

composition)

Cardio-respiratory

Metabolic

Motor

Immunological

Molecular

Muscular

Depression

Anxiety

Stress

Self-esteem

Cognitive function

Mood states

Locus of control

Perceived fatigue

Perceived ability to cope

PerceivedPhysical

attractiveness

Social integration

Enjoyment of life

Physiological Psychosocial

Health is a state of complete physical, mental and social well-being and not merely the absence of disease or

infirmity (WHO)

Positive side effects

Rietberg MB et al. (2004). Exercise therapy for multiple sclerosis. Cochrane Database of Systematic Reviews.

Strong evidence in favour of exercise therapy vs no exercise therapy in terms of:• Muscle power function• Exercise tolerance• Mobility-related activities

Exercise therapy is well tolerated

No evidence for a positive impact of exercise therapy on symptoms of fatigue

Cognitive dysfunction • Cognitive dysfunction is observed in up to 65% of PwMS and impacts

employability, activities of daily living, social and family functions and overall quality of life (Feinstein et al., Mult Scler Relat Dis 2013, 2: 4-12)

Systematic review: Sandroff et al., Neuropsychol Rev: Epub 22 July 2016

• Collectively, there is insufficient well-designed research to definitively conclude that exercise, physical activity, and physical fitness are effective for improving cognition in MS.

• Promising evidence from non-randomised trials may be useful for informing the development of better intervention research.

• Very common amongst PwMS: Annual prevalence rate of 20% and lifetime prevalence rate of 50% (Sadnovick et al., Neurology 1996, 46:628-632)

Cross-sectional study of 2459 PwMS: Taylor et al. BMC Psychiatry 2014, 14:327:

• Poor diet, low levels of exercise, obesity, smoking, marked social isolation and taking interferon were associated with greater depression risk in PwMS, whereas use of omega-3 FA and vitamin D supplements, frequent fish consumption, moderate alcohol consumption and meditation reduced depression risk.

Depression

Exercise prescription

F-I-T-TPRINCIPLE

TYPE

FREQUENCY

TIME

INTENSITY

Challenges for exercise studies in MS• Fatigue• Relapse• Heterogeneous range of symptoms, disabilities• Heat sensitivity• Flexible approach needed• Control of exercise stimulus

“Exercise training programs have traditionally been discouraged in the MS population because of the belief that they might exacerbate fatigue and other MS symptoms. To the contrary, recent studies have demonstrated positive effects of physical therapy and increased physical activity in reducing pain and improving mobility in MS patients.”

Filipi et al. (2010); Int J MS Care 12, 6–12.

Aerobic exercise studies

Resistance exercise studies

Combined studiesOther exercise studies

Study design 8 x RCTs2 x Non-controlled1 x Controlled

2 x Non-controlled trials1 x RCT

3 x RCTs2 x Non-controlled

2 x Non-controlled

N 8 – 112 8 – 38 10 – 95 4 – 31

Exercise modality Arm/leg ergometryTreadmill/home walking

Machine exercises1 x upper & lower extremities2 x lower extremities only

Circuit training; combinations of aerobic, resistance, stretching and/or balance exercises

2 x Acquatic therapy

Total duration/ frequency

4-26 weeks / 1-5 x per week

8-10 weeks / 2 x per week

8-26 weeks / 2-5 x per week 8-12 weeks / 2-3 x per week

Intensity/volume Typically 30 min @ 55-80% VO

2 max or

predicted HRmax

1-4 sets of 8-15 reps (progressive based on Rep Max / MVC)

30 – 90 min per session No details given

Main results FSS: x x x x x √ MFIS: √MFI: √

Qualitative interviews: √MFIS: √FSS & MFI: √

FSS: xChalder: √MFI: xQualitative interviews: √ + xMFIS: √

Chalder physical: √MFIS: √

Notes Of the 5 largest controlled trials (N=39-112), 3 reported improvements in fatigue.

Key points

• Heterogeneous findings between studies• Studies have not targeted patients who are

experiencing significant levels of fatigue• Only a few studies have evaluated fatigue as

the primary outcome measure• Only 12/21 studies were RCTs• Choice of fatigue scale may have some

bearing on the results

☑ Co-morbidities

☑ Obesity☑ Hypertension☑ Glucose☑ Cholesterol☑ Smoking☑ Sleep disorders☑ Infections☑ Falls☑ Depression & anxiety☑ Con-medications

Comorbidities in Multiple Sclerosis

Ruth Ann Marrie, MD, PhDProfessor of Medicine & Community

Health SciencesUniversity of Manitoba

Winnipeg, Canada

Psychiatric Comorbidity is Common• Depression

– Up to 50% lifetime prev. (3X higher than gen pop’n)

– 12-month prev. 14% (vs. 5.9-7.3% in gen pop’n)

• Anxiety– up to 35% lifetime prevalence

– Generalized anxiety disorder, social phobias

• Other disorders → less studied– Bipolar disorder: 5%

– Psychosis: 0.9-1%

• Under-diagnosed & undertreatedMarrie RA et al. MSJ 2015;21:305-317

Most Common Physical Comorbidities in MS

• Hypertension* 18.6% (13.9-23.2%)• Hyperlipidemia 10.9% (5.6-16.1%)• Chronic lung disease 10.0% (0-20.9%)• Irritable bowel syndrome 12.2%

• Thyroid disease 6.4% (0.19-12.7%)• Psoriasis 7.7%

*leading causes of disability in gen. pop’n are hypertension, arthritis, back/ spine problems, lung disease, and heart disease

Marrie RA et al. MSJ 2015;21:263-281

Comorbidity is common at diagnosis• 4 Canadian provinces: 23,382 incident MS cases & 116,638

matched controls

Marrie RA et al. Neurology 2016;86:1279-1286

Vascular Comorbidity Accelerates Disability Progression!

Neurology 2010;74:1041–1047

HR 1.68; 1.51-1.87 (accounting for disability at dx, SES, race, tx…)

Median difference 6 years

Hospitalization rates & comorbidity status

No. MS pop’n

0 1.01 1.32 (0.96-1.83)

2 1.80 (1.35-2.40)

3 2.11 (1.58-2.83)

≥4 3.65 (2.78-4.78)

Implications I• Comorbidity common in MS & affects outcomes• Consider when developing plans of care

• MS Team needs to be involved in: – diagnosis & management of comorbidity → depression,

anxiety, vascular in particular– educate patients & families

• Health promotion (next talk)– Address health behaviors: smoking, diet, weight,

physical activity– Preventive care

Conclusion• Comorbidity is common in MS

• Associated with broad range of adverse outcomes: disability, QOL, hospitalizations, mortality

• Affects treatment choices & responses

• Requires team approach, and possibly changes in models of care to achieve optimal outcomes

☑ Wellness

☑ Intellectual

☑ Emotional

☑ Physical

☑ Social

☑ Spiritual

☑ Occupational

☑ Environmental

Rheumatoid arthritisEnd-stage joint disease

Images courtesy of Professor Gavin Giovannoni and http://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-symptoms/

What next?

Example intervention

Specificintervention

Specificintervention

Specificintervention

Specificintervention

Improve accessto DMTs by…

Contributing factor

Early diagnosis

Aim: maximize lifelong brain health in people with MS and improve

outcomes

Contributing factor

MRI monitoring

Contributing factor

Optimize treatment for each individual

Action effect methodology is iterative; the diagram develops as different stakeholders are engaged

Engage with a wide range of stakeholders to gain buy-in and to agree on an overall aim, desired outcomes and

measure concepts

DMT treatment rates

The diagram acts as a ‘road map’ – a starting point for pilot projects in specific

healthcare systems

Local application

A quality improvement approach to measure local adoption of the recommendations

Agree on the overall aim, aspirations and scope

Agree on factors that contribute to the aim

Interventions are changes made to achieve the aim

Measure concept, are we seeing

improvement in a process/outcome?

Cause/effect arrow

Local application

M M M

M

M

M

M

MS Brain Health – a potential ‘tripadvisor’ for MS …

msAdvisor

msAdvisor Barts-MS, Royal London HospitalWhitechapel, London E1 1BB

Overall

Diagnosis

Monitoring

DMTs

Co-morbidities

Education

Relapses

62 reviews

38.6 days

868 MSers

54%

8.3 days

1211 MSers

187 reviews

Contact Staff Services For you search

Conclusions• MS is a bad disease

• Mortality, disability, unemployment, divorce, cognitive impairment, etc.

• On average early effective therapy is the only realistic option of preventing end-organ damage

• NEDA and T2T are current treatment target (zero tolerance)• Beyond NEDA we need to target end-organ damage (brain atrophy,

CSF NF levels, etc.)• Brain Health initiative

• Are you prepared to join the challenge?• Pledge your support?• Be an early adopter?• Walk the talk?

www.ms-res.org

www.clinicspeak.com

www.msbrainhealth.org

@GavinGiovannoni

Thank You!