An holistic approach to MS

An holistic approach to MS

Gavin GiovannoniBarts and The London School of Medicine and Dentistry

PURCHASER

S

VALUE

QUALITY

TEACHING

RESEARCH

CLINICAL

CLINICAL SERVICE

“All those who work on the frontline should be thinking carefully, and imaginatively, about how we can do things differently. The QIPP process is a home for this in the NHS and the way that we can implement the best and brightest ideas across the service. As the Prime Minister said: ‘Don’t hold back – be innovative, be radical, challenge the way things are done.”

Andrew Lansley, Secretary of State for Health – 2 July 2010.

“We need to fashion a vibrant, creative NHS that really fizzes with ideas of how to improve quality and how to reduce costs........ So, instead of relying on ever more funds flowing from the Treasury, we must look to ourselves to make savings. This practical imperative is what QIPP is all about......... We have the resources, we have the knowledge and we have the ability to give the people of this country a truly first class NHS and to deliver it within our means.”

Earl Howe, Minister for QIPP - 2 July 2010

Dr Janet Williamson National Director, NHS Improvement

Gastrostomy

Primary Care Referral Diagnosis Minimal impairment

Moderateimpairment

Severeimpairment

End oflife care

Prevention

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

Pain

Swallowing

Spasticity

Falls

Balance problems

Insomnia

Restless legs

Studying

Employment

RelapsesDMTs

Fertility

Rehab

Suprapubiccatheter

Intrathecal baclofern

Palliative Care

Physiotherapy

Speech therapy

OccupationalTherapy

Nurse specialists Counselling

Neuroradiology

Neurophysiology

Clinical trials

Gait

Neuroimmunology

Pressure sores

Driving

Anxiety

DMTs

Functional neurosurgery

Oscillopsia

Sexual dysfunction

Pseudobulbar affect

Seizures

Advanced directive

Assisted suicide

Colostomy

Tendonotomy

Relationships

Travel vaccination

Socialservices Legal aid

1st line

2nd line

maintenanceescalation

induction

risks

adverse events

monitoring

disease-free

family counselling

vD

A ‘holistic’ approach to MS

www.ms-res.org

Who of you routinely measures blood vitamin D levels in people with MS?

Sustained-release oral fampridine in multiple sclerosis:a randomised, double-blind, controlled trial

Goodman et al. Lancet 2009; 373: 732–38.

Gastrostomy


Moderateimpairment

Severeimpairment

End oflife care

Prevention

Cognition

Depression

Fatigue

Bladder

Bowel


Pain

Swallowing

Spasticity

Falls

Balance problems

Insomnia

Restless legs

Studying

Employment

RelapsesDMTs

Fertility

Rehab

Suprapubiccatheter


Palliative Care

Physiotherapy

Speech therapy

OccupationalTherapy


Neuroradiology

Neurophysiology

Clinical trials

Gait

Neuroimmunology

Pressure sores

Driving

Anxiety

DMTs


Oscillopsia

Sexual dysfunction

Pseudobulbar affect

Seizures

Advanced directive

Assisted suicide

Colostomy

Tendonotomy

Relationships

Travel vaccination


1st line

2nd line


induction

risks

adverse events

monitoring

disease-free

family counselling

vD


Bone Health

Fracture risk in multiple sclerosis

Dobson et al. Submitted 2012.

Risk of fractures in patients with MS: record-linkage study

Ramagopalan et al. Unpublished data 2012

Osteoporosis in multiple sclerosis


What is the prevalence of falls in MS?

Sosnoff et al. PLoS One. 2011;6(11):e28021.

Sosnoff et al. PLoS One. 2011;6(11):e28021.

Gastrostomy


Moderateimpairment

Severeimpairment

End oflife care

Prevention

Cognition

Depression

Fatigue

Bladder

Bowel


Pain

Swallowing

Spasticity

Falls

Balance problems

Insomnia

Restless legs

Studying

Employment

RelapsesDMTs

Fertility

Rehab

Suprapubiccatheter


Palliative Care

Physiotherapy

Speech therapy

OccupationalTherapy


Neuroradiology

Neurophysiology

Clinical trials

Gait

Neuroimmunology

Pressure sores

Driving

Anxiety

DMTs


Oscillopsia

Sexual dysfunction

Pseudobulbar affect

Seizures

Advanced directive

Assisted suicide

Colostomy

Tendonotomy

Relationships

Travel vaccination


1st line

2nd line


induction

risks

adverse events

monitoring

disease-free

family counselling

vD


Who delegates bladder dysfunction to the continence advisor?

Gastrostomy


Moderateimpairment

Severeimpairment

End oflife care

Prevention

Cognition

Depression

Fatigue

Bladder

Bowel


Pain

Swallowing

Spasticity

Falls

Balance problems

Insomnia

Restless legs

Studying

Employment

RelapsesDMTs

Fertility

Rehab

Suprapubiccatheter


Palliative Care

Physiotherapy

Speech therapy

OccupationalTherapy


Neuroradiology

Neurophysiology

Clinical trials

Gait

Neuroimmunology

Pressure sores

Driving

Anxiety

DMTs


Oscillopsia

Sexual dysfunction

Pseudobulbar affect

Seizures

Advanced directive

Assisted suicide

Colostomy

Tendonotomy

Relationships

Travel vaccination


1st line

2nd line


induction

risks

adverse events

monitoring

disease-free

family counselling

vD


Preserving cognitive function for patients with overactive bladder: evidence for a differential effect with darifenacin

Kay et al. Int J Clin Pract. 2008 Nov;62(11):1792-800.

Systemic infections and inflammation affect chronic neurodegenerationPerry et al. Nat Rev Immunol. 2007 Feb;7(2):161-7.

Who agrees that after making a diagnosis of MS the main role of the neurologist is to prescribe DMTs?

Gastrostomy


Moderateimpairment

Severeimpairment

End oflife care

Prevention

Cognition

Depression

Fatigue

Bladder

Bowel


Pain

Swallowing

Spasticity

Falls

Balance problems

Insomnia

Restless legs

Studying

Employment

RelapsesDMTs

Fertility

Rehab

Suprapubiccatheter


Palliative Care

Physiotherapy

Speech therapy

OccupationalTherapy


Neuroradiology

Neurophysiology

Clinical trials

Gait

Neuroimmunology

Pressure sores

Driving

Anxiety

DMTs


Oscillopsia

Sexual dysfunction

Pseudobulbar affect

Seizures

Advanced directive

Assisted suicide

Colostomy

Tendonotomy

Relationships

Travel vaccination


1st line

2nd line


induction

risks

adverse events

monitoring

disease-free

family counselling

vD


Theoretical model: treat early and aggressively

Natural course of disease

Laterintervention

Latertreatment

Treatmentat diagnosis Intervention

at diagnosis

Time

Disease Onset

Dis

abili

ty

Who discusses mortality with their patients?

Survival in MSers is shortened by 8 to 12 yearsSurvival Probability of Norwegian Patients with RRMS

(Hordaland County, Western Norway, 1953–2003)

RRMS=relapsing-remitting MS.Adapted from Torkildsen NG et al. Mult Scler. 2008;14:1191-1198.

500 5 10 15 20 25 30 35 40 450

10

20

30

40

50

60

70

80

90

100

Surv

ival

(%)

Years After Onset

30 35 40 45 50 55 60 65 70 75 80Approximate Patient Age

General PopulationRRMS95% CI

The survival disadvantage in MS is greater than in other chronic diseases

Standardized Mortality Ratios in Chronic Diseases

Disease SMR (range)

Cardiovascular disease1* 1.34 (1.23–1.44)

Ischemic stroke2† 1.75(1.38–2.19)

Early breast cancer3 2.0 (1.6–2.7)

Crohn’s disease4 2.8

MS5 2.8 (2.6–3.1)

MS (2–9.9 years after diagnosis)5 2.4 (1.9–2.9)

MS (≥10 years after diagnosis)5 3.1 (2.8–3.4)

Parkinson’s disease6 3.66 (3.37–3.95)

Type 2 diabetes1 4.47 (3.91–5.10)

*In patients with type 2 diabetes; †in patients with valvular heart disease in Olmsted County, Minnesota.1. De Marco R et al. Diabetes Care. 1999;22:756-761; 2. Petty DW et al. Mayo Clin Proc. 2005;80:1001-1008; 3. Hooning MJ et al. Int J Radiat Oncol Biol Phys. 2006;64:1081-1091; 4. South East England Public Health Observatory, Mortality trends. 2006; 5. Sumelahti ML et al. Mult Scler. 2010;16:1437-1442; 6. Hristova DR. Folia Medica. 2009;51:40-45.

Population-based MS mortality studies

First Author Population

and Time Period Size

of Cohort SMR Additional Survival MeasuresGryttenTorkildsenMult Scler 2008

Western Norway 1953–2003

878 2.66(95% CI: 2.31–3.06)

• Median survival time from onset: 41 years MS vs 49 years general population

– 8 years of life lost in MS

SmestadMult Scler 2009

Oslo 1940–1980

368 2.47(95% CI: 2.09–2.90)

• Reduction of median life expectancyvs general population

– Female: 11.2 years– Male: 7.4 years

Bronnum-Hansen Brain 2004

Danish MS Registry

1949–1996

9881 2.89 (95% CI: 2.81±2.98)

• Median survival time (from disease onset)vs general population:

– ≈10 years of life lost in MS

HirstJNNP 2008

South Wales1985–2006

373 2.79(95% CI: 2.44–3.18)

• Median age of death: 63.1 years MSvs 70.6 years general population

– 7.5 years of life lost in MS

Sumelahti Mult Scler 2010

Finland1964–1993

1595 2.8 (95% CI: 2.6–3.1)

• Survival decreases with disease progression– SMR, 2–9.9 years after diagnosis: 2.4 – SMR, ≥10 years after diagnosis: 3.1

WallinBrain 2000

USA1956–1996

2489 2.18(not specified)

• Healthy soldier effect speculated to have a favorable effect on survival

Leray Mult Scler 2007

West France1976–2004

1879 1.3(95% CI: 1.01–1.7)

• Mean follow-up duration = 12.7 years from clinical onset; may be basing estimate on relatively immature dataset

MS=multiple sclerosis; SMR=standardized mortality ratio; CI=confidence interval.

21-year long-term follow-up of IFNb-1b studytime from study randomization to death

Early treatment (3 years) with IFNb-1b was associated with a 47% reduction in the risk of dying over 21 years compared with initial placebo treatment

Goodin et al. Neurology. 2012 Apr 24;78(17):1315-22..

At risk:IFNB-1b 250 µgPlacebo

124123

124120

121117

118109

10488

HR=0.532 (95% CI: 0.314–0.902)46.8% reduction in hazard ratio Log rank, P=0.0173

IFNB-1b 250 µg

Placebo

0 2 4 6 8 10 12 14 16 18 20 2265%

70%

75%

80%

85%

90%

95%

100%

Time (Years)

Pro

po

rtio

n o

f p

ati

en

ts w

ho

are

sti

ll a

live

Disability

Time

6 months 12 months 24 months

Active

Placebo

6 months

Relapsing MS

1. Delay attacks / onset of MS2. Reduce number of attacks3. Reduce severity of attacks4. Reduce disability5. Delay onset of SPMS

Any Negative EDSS=6 SPMS Wheelchair

% R

isk

Rel

ativ

e to

Lo

w E

xpo

sure

Long-term follow-up 16 yearsIFN-beta exposure 80% vs. 20%

Goodin et al. PLoS One. 2011;6(11):e22444. Epub 2011 Nov 30.

Treat early (and aggressively)


Laterintervention

Latertreatment


at diagnosis

Time

Disease Onset

Disability

Who likes doughnuts?

The relapsing MS doughnut

Inactive RRMS

CIS

RIS

Suboptimal responders ?

Active RRMSIFNb / GA

IFNb

Highly active RRMSFingolimod

Natalizumab Natalizumab

Who discusses employment with their patients?

Unemployment

Pfleger CC et al. Mult Scler. 2010;16:121-126.

0 5 10 15 20 25

Time (years)

0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty

Control PersonsMS Patients

Probability of Remaining in Active Employment After Onset of MS

Who discusses relationships with their patients?

Divorce and separation

*Life table method.Pfleger CC et al. Mult Scler. 2010; 16:121-126.

0 5 10 15 20 25

Time to Event or End of Observation (years)

0

0.2

0.4

0.6

0.8

1.0

Prob

abili

ty

Population ControlsMSers

Crude probability of remaining in a relationship after onset of MS*

Who discusses QoL with their patients?

The effect of MS on Quality of Life

• MS is one of the most common causes of neurological disability in young adults2

• Natural history studies indicate that it takes a median time of 8, 20, and30 years to reach the irreversible disability levels of EDSS scores 4.0, 6.0, and 7.0, respectively3

*Utility measures are derived from EQ-5D using the EuroQoL instrument; †error bars depict 95% CIs. Half points on EDSSare not shown on graph axis, except at EDSS score 6.5.EDSS=Expanded Disability Status Scale; EQ-5D=European Quality of Life-5 Dimensions; QoL=quality of life.1. Adapted from Orme M et al. Value In Health. 2007;10:54-60; 2. WHO and MS International Foundation (MSIF). http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1 &codcol=15&codcch=747. Accessed March 6, 2012;3. Confavreaux C et al. Brain 2003; 176:770-782. 4. Compston A, Coles A. Lancet. 2008;372:1502-1517.

Util

ity

EDSS and Utility* Show a Significant Inverse Relationship1†

Util

ity

EDSS Status

0.0 1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0 9.0–0.4–0.3–0.2–0.1

00.10.20.30.40.50.60.70.80.9

Who monitors prognostic factors of treatmentresponse to DMTs?

Breakthrough disease after treatment initiation

Patients with breakthrough disease can be identified with• Clinical measures

– Relapses– EDSS progression

• MRI measures– T2 and Gd+ lesions

• Biological markers– IFNβ NAbs/lack of MxA gene induction– Natalizumab antibodies

Gd+=gadolinium-enhancing; IFNβ=interferon beta; NAbs=neutralizing antibodies; Abs=antibodies; MxA= myxovirus protein A.

Relapse on IFNβ therapy increases risk of sustained disability progression

• Risk is not much greater for 2 relapses or more• Sensitivity is only 50%

HR=hazard ratio; SE=standard error.Bosca et al. Mult Scler. 2008;14:636-639.

HR SE P Value 95% CI

No relapses (reference=1) 1

One relapse 3.41 1.47 0.005 1.46–7.98

Two or more relapses 4.37 1.74 0.000 1.90–9.57

HR of EDSS Increase in Patients with No Relapses, 1 Relapse, and 2 or More Relapses During the First 2 Years of IFN Treatment

0 20 40 60 80

0

0.25

0.50

0.75

Analysis Time (Months)

No RelapsesOne RelapseTwo or More Relapses

1.00

EDSS

Pro

gres

sion

Surv

ival

Pro

babi

lity

Study or SubgroupOdds Ratio

IV, Random, 95% CIKinkel 2008

Prosperini 2009Total (95% CI) 9.86 (2.33, 41.70)


MRI to monitor treatment response toIFNβ: a systematic review



Pozzilli 2005Prosperini 2009

Sormani 2011Total (95% CI) 2.69 (0.72, 10.04)

0.01 0.1 1 10 100Disease Less Likely Disease More Likely

One New T2 Lesion

Favors Experimental Favors Control1001010.10.01

Two or More New T2 Lesions



Rio 2008

Total (95% CI) 5.46 (2.48, 12.04)

MRI to monitor treatment response toIFNβ: a systematic review




Pozzilli 2005Tomassini 2006

Total (95% CI) 3.34 (1.36, 8.22)

0.01 0.1 1 10 100Disease Less Likely Disease More Likely

One New Gd+ Lesion

0.01 0.1 1 10 100

Disease Less Likely Disease More Likely

Two or More New Gd+ Lesions

Strongest predictor of disability progression on IFNβ therapy is progression itself

Disease Activity During 2 Years of Treatment and Prediction of Disability Progression* at 6 Years

GroupSensitivity (%)

(CI)Specificity (%)

(CI)

A. An increase of at least one EDSS step confirmed at 6 months 85 (64–95) 93 (86–97)

B. Occurrence of any relapse 80 (58–92) 51 (41–61)

C. Occurrence of two or more relapses 45 (26–66) 81 (72–82)

D. A decrease in relapse rate less than 30% compared with 2 years before therapy 40 (22–61) 86 (77–91)

E. A decrease in relapse rate less than 50% compared with 2 years before therapy 40 (–61) 81 (72–88)

F. No decrease or identical relapse rate compared with 2 years before therapy 35 (18–57) 88 (79–93)

G. Definition A or B 90 (70–97) 48 (38–58)

H. Definition A or E 85 (64–95) 76 (66–83)

I. Definition A and B 75 (53–89) 97 (91–99)

J. Definition A and E 40 (22–61) 99 (94–99)

*EDSS score ≥6.0 or increase in at least 3 EDSS steps.Río J et al. Ann Neurol. 2006;59:344-352.

Clinical importance of neutralising antibodies against interferonbeta in patients with relapsing-remitting multiple sclerosis

Sorensen et al. Lancet 2003; 362: 1184–91.

Mean change in EDSS

Malluci et al. Neurology 2004.

Predictors of long-term clinical response to interferon beta therapy in relapsing multiple sclerosis

Tomassini et al. J Neurol (2006) 253 : 287–293.

The incidence and significance of anti-natalizumab antibodiesResults from AFFIRM and SENTINEL

Calebresi & Giovannoni, et al. Neurology 2007;69:1391–1403.

The incidence and significance of anti-natalizumab antibodiesResults from AFFIRM and SENTINEL

Calebresi & Giovannoni, et al. Neurology 2007;69:1391–1403.

Metrics for DMTs• What proportion of your patients are on a

DMT?– 1st line vs. escalation?– What proportion of your patient have NABs?

• What proportion of your patients have failed a first line DMT?

• What proportion of your patients are in a clinical trial?

• Etc.

Treatment Strategy

Theoretical model: treat early and aggressively


Laterintervention

Latertreatment


at diagnosis

Time

Disease Onset

Dis

abili

ty

Impact of MS: cognitive functioning in the CIS stage

CIS=clinically isolated syndrome.Feuillet L et al. Mult Scler. 2007;13:124-127.

Deficits were found mainly in memory, speed of information processing,

attention and executive functioning

CIS Patients (n=40)

Healthy Controls (n=30)

0

20

40

60Cognitive Test Performance in an Exploratory Study

57%

7%

Patie

nts

Faili

ng ≥

2 Co

gniti

ve T

ests

P<0.0001

What is benign MS?

• 163 patients with “benign” MS (disease duration >15 years and EDSS score <3.5)– 45% cognitive impairment – 49% fatigue– 54% depression

Amato MP et al. J Neurol. 2006;253:1054-1059.

Rx=prescription drugs; OTC=over-the-counter.Berg J et al. Eur J Health Econ. 2006;7(suppl 2):S75-S85.

Total mean annual cost per patient €53,601

Healthcare costs are linked to disability

Informal Care(Disposable Income)

(9.2%)

Ambulatory Care (5.6%)

Disease-Modifying Drugs (10.6%)

Other RX & OTC Drugs (1.6%)

Tests (0.4%)

Investments (2.0%)

Long-Term Sick Leave andEarly Retirement (30.0%)

Short-Term Absence(2.0%)

Services(28.5%)

Inpatient Care (10.2%)

Conclusion

• Equity and excellence: Liberating the NHS – patients will be at the heart of everything we do

• choice and control• easy access to the information they need about the best GPs

and hospitals• patients will be in charge of making decisions about their care

– a relentless focus on clinical outcomes• Success will be measured, not through bureaucratic process

targets, but against results that really matter to patients – such as improving …… survival rates

– we will empower health professionals

Health & Medicine

An holistic approach to MS