Early effective treatments

Early and effective treatment

Gavin Giovannoni

Barts and The London

Disclosures

Professor 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 Biogen-Idec, Genzyme, Merck-Serono and Novartis for making available data slides on natalizumab, alemtuzumab, oral cladribine and fingolimod for this presentation.

Professor Giovannoni’s trip to Australia is being sponsored by Novartis.

http://www.ms-res.org/







.

Thomas Blizard Curling 1811 – 1888

• Assistant-surgeon to The Royal London Hospital in 1883 and full surgeon in 1849

• President of the Royal College of Surgeons

• Seminal work on tetanus, winning the Jacksonian prize for his work

• Famous for his skill in treating diseases of the testes and rectum

1. Early therapy 2. Highly-effective therapy 3. Induction therapy

Objectives

Why early?

Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN-1b trial

Goodin et al. Neurology 2012;78:1315-1322.

Natalizumab STRATA: stable EDSS scores for up to 5 years

*P<0.0001

Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520.

1 Year 2 Years 3 Years 4 Years 5 Years

Cessation/

Treatment Gap* Original Placebo

Original Natalizumab

Original Placebo – Now on Natalizumab

Mean

ED

SS

Sco

re

n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393

14

TOP: earlier natalizumab treatment favors annualized relapse rate outcomes

15

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.

Baseline EDSS Score

<3.0 ≥3.0

Prior DMTs Used

0 1 ≥2

P<0.0001 P<0.0001

Theoretical model: treat early and effectively

Natural course of disease

Later intervention

Later treatment

Treatment at diagnosis

Intervention at diagnosis

Time Disease Onset

Dis

abili

ty

Time is brain

Does the biology of MS change with time?

Coles et al. J Neurol. 2006 Jan;253(1):98-108..

Post-inflammatory neurodegeneration

May be MS is not autoimmune?

Can we learn anything from animal models?

Limp tail

Impaired righting reflex

hindlimb paralysis

Moribund

partial paralysis

Normal

Remission

Day 7 0

1

2

3

4

5

(1)

Clinical Score

Induction and assessment of chronic relapsing experimental allergic

encephalomyelitis

Day 0

Spinal cord homogenate in Freund’s complete adjuvant in ABH

Slide courtesy David Baker

Average disease course

ACUTE RELAPSE 1 RELAPSE 2

RELAPSE 3 CHRONIC

Slide courtesy Sam Jackson & Ian Duncan.

Prevention of relapsing CREAE after three paralytic episodes does not inhibit secondary progression and deterioration of mobility

Pryce et al. J Neuroimmunol 2005.

The current dogma

Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.

MRI Events

Time (Years)

Inflammation

Brain volume

Axonal loss

Dis

eas

e S

eve

rity

SPMS RRMS CIS RIS

The current paradigm

safe & slow

S&S treatment paradigm

A

B

C

D

E

N M

Y X Moderate

Efficacy

Intermediate

Efficacy

High

Efficacy

1st-line

2nd-line

3rd-line

100 MSers

Who are the

responders?

~20% responders

~40% sub-optimal responders

~40% non-responders

vs.

1

2

3

Clinical

MRI

NABs

S&S treatment paradigm

A

B

C

D

E

N M

Y X Moderate

Efficacy

Intermediate

Efficacy

High

Efficacy

1st-line

2nd-line

3rd-line

How bad is MS?

Untreated MS is a devastating disease

Cognitive Dysfunction

• Prevalence: 43% to 65%1,2

• Affects employment, activities of daily living, and social functioning2

Life Shortening

• 5- to 11-year decrease in life expectancy3-7

• 2- to 7-fold increase in suicide risk5,8

• 50% MS patients die of disease-related causes5,6,8

1. Rao SM et al. Neurology. 1991;41:685-691; 2. Rao SM et al. Neurology. 1991;41:692-696; 3. Sadovnick AD et al. Neurology. 1992;42:991-994;

4. Ebers GC. J Neurol Neurosurg Psychiatry. 2001;71:16-19; 5. Torkildsen G et al. Mult Scler. 2008;14:1191-1198; 6. Smestad C et al. Mult Scler.

2009;15:1263-1270; 7. Kingwell E et al. J Neurol Neurosurg Psychiatry. 2012;83:61-66; 8. Sadovnick AD et al. Neurology. 1991;41:1193-1196;

9. Orme M et al. Value Heath. 2007;10:54-60; 10. De Marco R et al. Diabetes Care. 1999;22:756-761; 11. Petty DW et al. Mayo Clin Proc.

2005;80:1001-1008; 12. Hooning MJ et al. Int J Radiat Oncol Biol Phys. 2006;64:1081-1091; 13. Pfleger CC et al. Mult Scler. 2010;16:121-126;

14. Beg J et al. Eur J Health Econ. 2006;7(suppl 2):S75-S85.

*In this study, utility measures were derived from EQ-5D using the EuroQoL instrument; †in patients with type 2 diabetes; ‡in patients with valvular heart disease in Olmsted County,

Minnesota; §MS patients with EDSS ≥6.

EDSS=Expanded Disability Status Scale; QOL=quality of life; CV=cardiovascular;

EQ-5D=European Quality of Life-5 Dimensions.

QOL EDSS and utility* have shown a

significant inverse relationship9

Mortality Mortality ratio of patients with MS

exceeds CV disease,†,10 stroke,‡,11 and

early breast cancer12

Employment 50% of patients with MS are

unemployed as of EDSS 3.0 and/or

after 10 years from diagnosis13

Healthcare costs Bulk of cost attributed to services

(28.5%) and long-term sick leave and

early retirement (30%)§,14

Relationships Compared with general population, patients

with MS have a higher probability of

separating/divorcing and doing so sooner13

MS has a negative

impact on…

Consequences of increasing EDSS scores: loss of employment1

0

10

20

30

40

50

60

70

80

90

Work Capacity by Disability Level

0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0

EDSS Score

Pro

po

rtio

n o

f P

ati

en

ts ≤

65 Y

ears

Old

Wo

rkin

g (

%)

The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger.

1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926;

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

Spain

Sweden

Switzerland

United Kingdom

Netherlands

Italy

Germany

Belgium

Austria

~10 yrs2

Uti

lity

EDSS Status

EDSS and utilitya show a significant inverse relationship

1,b

aUtility measures are derived from EQ-5D using the EuroQoL instrument. bError bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis, except at EDSS 6.5.

• 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, and 30 years to reach the

irreversible disability levels of

EDSS 4, 6, and 7, respectively3

1. Adapted from Orme M et al. Value In Health. 2007;10:54-60. 2. WHO and MSIF. http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1 &codcol=15&codcch=747. Accessed October 6, 2010. 3. Confavreaux, Compston. 2005. 4. Compston A, Coles A. Lancet 2008

The effect of MS on quality of life

34

What about benign MS?

163 patients with “benign” MS

(disease duration >15 years and EDSS <3.5):

45% cognitive impairment

49% fatigue

54% depression

What is benign MS?

Impact of MS: cognitive functioning in the CIS stage

Feuillet et al. MSJ 2007

CIS Patients n = 40

57%

7%

-20%

0%

20%

40%

60%

Healthy Controls n = 30

p < 0.0001

Deficits were found mainly in memory, speed of information

processing, attention and executive functioning Patients failing

≥ 2 cognitive tests

Relapses don’t count!

Weinshenker et al. Brain. 1989 Dec;112 ( Pt 6):1419-28.

Predictors of long-term outcome in MSers treated with interferon beta-1a

Bermel et al. Ann Neuol 2012.


Predictors of long-term outcome in

MSers treated with interferon beta-1a

Treatment vs. Natural History

Relapse on IFNβ Therapy Increases Risk of

Sustained Disability Progression

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 Relapses One Relapse Two or More Relapses

1.00

EDSS

Pro

gre

ssio

n

Surv

ival

Pro

bab

ility

HR=hazard ratio; SE=standard error

Relapses and residual deficits

Lublin FD et al. Neurology. 2003;61:1528-1532.

MRI activity doesn’t count!


Predictors of long-term outcome in

MSers treated with interferon beta-1a

MRI to monitor treatment response to IFNβ: a meta-analysis

Dobson et al. Neurology 2013.

Study or Subgroup Odds Ratio

IV, Random, 95% CI

Kinkel 2008

Prosperini 2009

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


IV, Random, 95% CI

Kinkel 2008

Pozzilli 2005

Prosperini 2009

Sormani 2011

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

0.01 0.1 1 10 100 Disease Less Likely Disease More Likely

One New T2 Lesion

Favors Experimental Favors Control

100 10 1 0.1 0.01

Two or More New T2 Lesions


IV, Random, 95% CI

Kinkel 2008

Rio 2008

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

MRI to monitor treatment response to IFNβ: a meta-analysis


IV, Random, 95% CI

Kinkel 2008

Pozzilli 2005

Tomassini 2006

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

0.01 0.1 1 10 100 Disease 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

Dobson et al. Neurology 2013.

Disease progression doesn’t count!

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

Group Sensitivity (%)

(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.

Relationship between early clinical characteristics and long term disability

outcomes: 16 year cohort study (follow-up) of the pivotal interferon-beta-1b trial

Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.

Why highly-effective treatments?

Control Multiple sclerosis

Can we prevent end-organ damage?

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

Treatment-effect on atrophy correlates with treatment-effect on disability

Sormani et al. Ann Neurol 2013, In Press.

Treatment Effect on Disability Strongly Predicted by Effect on T2 Lesion Volume and Brain Atrophy, Combined

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.

-1.0%

-0.8%

-0.6%

-0.4%

-0.2%

0.0% Years 0-2

-0.82%

-0.80%

P=0.822†

Placebo (N=315) Natalizumab (N=627)

Year 0-1* Year 1-2

-0.40%

-0.56%

-0.43%

-0.24%

P=0.004†

P=0.002†

†Difference between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401.

AFFIRM Study: natalizumab and brain atrophy

Mea

n (

SE

) p

erc

en

tag

e c

ha

ng

e i

n B

PF

Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM

FREEDOMS, 2 years

Fingolimod 0.5 mg (n = 356)

Placebo (n = 329)

***

* **

6 0 12 24

Time (months)

0

-0.4

-0.8

-1.2

-1.6

-2.0

−38%

vs placebo p<0.001

Ch

ange

in m

ean

BV

fro

m

bas

elin

e (%

)

TRANSFORMS, 1 year

0 12

Time (months)

0.0

-0.4

-0.6

-1.0

IFNb-1a IM (n = 359)

Fingolimod 0.5 mg (n = 368)

−40%

vs IFNb-1a IM p<0.001

*** -0.2

-0.8

Ch

ange

in m

ean

BV

fro

m

bas

elin

e (%

)

ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved

Laquinimod: Percent of brain volume

change from baseline to month 24

% C

ha

ng

e F

rom

Ba

se

line

-1.2

-0.4

-1.6

-0.8

Placebo (n = 1006)

Laquinimod 0.6 mg (n = 984)

0

-1.188

-0.834

POOLED

30% P<0.0001

Vollmer T et al. Presented at 64th American Academy of Neurology Annual meeting, New Orleans 2012 Session S01.007

BRAVO: reduced rate of brain volume loss

*Adjusted for baseline characteristics.

Reference: 1. Vollmer T et al. Presented at: 5th Joint Triennial Congress of the European and Americas Committee for Treatment and Research in Multiple Sclerosis; October 19-22, 2011; Amsterdam, Netherlands. Abstract 148. Mult Scler. 2011;17:S507.

62

27.5% Reduction P<0.0001

-27.4% Improvement P<0.0001

LAQUINIMOD 0.6mg

PLACEBO

-1.14% -0.83% Percent Brain Volume

Change* (Months 0-24)

-1.25%

AVONEX® 30mcg

+9% Deterioration P=0.14

750

800

850

900

950

1000

1050

1100

1150

1200

1250

1300

1350

1400

1450

1500

30 35 40 45 50 55 60 65 70 75 80

Bra

in V

olu

me

(m

L)

Age (years)

Brain atrophy curves

Lower limit of normal

Average

Upper limit of normal

Hypothetical treatment effects

750

800

850

900

950

1000

1050

1100

1150

1200

1250

1300

1350

1400

1450

1500

30 35 40 45 50 55 60 65 70 75 80

Bra

in V

olu

me

(m

L)

Age (years)


MS lower limit

MS Average

MS Upper limit

-5%

-30%


-5%

-30%

750

800

850

900

950

1000

1050

1100

1150

1200

1250

1300

1350

1400

1450

1500

30 35 40 45 50 55 60 65 70 75 80

Bra

in V

olu

me

(m

L)

Age (years)


MS Average


-5%

-20%

750

800

850

900

950

1000

1050

1100

1150

1200

1250

1300

1350

1400

1450

1500

30 35 40 45 50 55 60 65 70 75 80

Bra

in V

olu

me

(m

L)

Age (years)


late treatment


750

800

850

900

950

1000

1050

1100

1150

1200

1250

1300

1350

1400

1450

1500

30 35 40 45 50 55 60 65 70 75 80

Bra

in V

olu

me

(m

L)

Age (years)


-5%

-18%

early treatment

late treatment


750

800

850

900

950

1000

1050

1100

1150

1200

1250

1300

1350

1400

1450

1500

30 35 40 45 50 55 60 65 70 75 80

Bra

in V

olu

me

(m

L)

Age (years)


-5% -11%

early very

highly-effective

treatment

late very

highly-effective

treatment

-15%


What is your treatment philosophy?

survival analysis

“hard and early ”

What is your treatment philosophy? maintenance-escalation vs. induction

survival analysis

“hard and early ”

MS is an autoimmune disease hypothesis

15-20 year experiment

What is your treatment philosophy? maintenance-escalation vs. induction

No evidence of disease activity: NEDA

Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.

Treat-2-target

Should brain volume loss and CSF neurofilament levels be

included in our definition for ‘no evidence of disease activity’?

No evidence of disease activity defined as:1,2

× No relapses

× No sustained disability progression

× No MRI activity

× No new or enlarging T2 lesions

× No Gd-enhancing lesions

T2T - NEDA

Zero Tolerance

Treatment objectives in relapsing MS

Freedom from

disease activity

Reduced ongoing

damage

Treat Early

73

T2T - NEDA

Zero Tolerance

Functional

Improvement

Maintain reserve

capacity


Freedom from

disease activity

Reduced ongoing

damage

Treat Early

74

T2T - NEDA

Zero Tolerance

Functional

Improvement

Maintain reserve

capacity


Freedom from

disease activity

Reduced ongoing

damage

CNS Repair

Healthy

ageing

Treat Early

75

T2T - NEDA

Zero Tolerance

Functional

Improvement

Maintain reserve

capacity


Freedom from

disease activity

Reduced ongoing

damage

CNS Repair

Healthy

ageing

Improved Quality of Life

Treat Early

76

Pros and cons of maintenance vs. induction therapies

Maintenance therapies

• Continuous treatment

• Low to very high efficacy

• Reversible

• Perceived to be lower risk

• Examples • Laquinimod, GA, IFN-beta, teriflunomide, BG12,

fingolimod, natalizumab, daclizumab

• Breakthrough disease • Suboptimal or failure to respond

• NEDA reliable metric for efficacy

• Rebound activity • Highly likely

• Can be life threatening

• Pregnancy • Contra-indicated

• No potential for a cure • Rebound

• SPMS & progressive brain atrophy

Induction therapies

• Short-courses or pulsed therapy

• Very high efficacy

• Irreversible

• Perceived to be higher risk

• Examples • Mitoxantrone, cladribine, alemtuzumab, anti-

CD20 (?), BMT

• Breakthrough disease • Marker for retreatment

• NEDA unreliable to assess efficacy

• Rebound activity • Less likely

• Unlikely to be life-threatening

• Pregnancy • Strategy of choice

• Potentially curative • 15-20 year experiment

• BMT, alemtuzumab, cladribine

Conclusions • MS is a bad disease

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

• Early highly-effective induction therapy is the only realistic option of offering a cure (autoimmune paradigm)

• Now an established treatment option

• NEDA (DAF) and T2T are entering the neurology lexicon

• Zero tolerance or ZeTo

• We need an acceptable working definition of an MS cure

• NEDA x 15 years?

• Induction therapies (alemtuzumab, cladribine)

• Improved risk mitigation tools

• JCV testing

• Autoimmune prediction for alemtuzumab

• Is it fair to make people with MS wait 20 years for the outcome of an ongoing experiment?

• Alemtuzumab, BMT, natalizumab, cladribine extension studies

early + highly effective + induction

Cladribine an example of treat early and effectively

Questions?

Emerging concepts in MS

Hagan M, et al. Int J Radiat Oncol Biol Phys 2004; 59:329−340.

NEDD – no evidence of detectable disease (oncology)

NEDA - no evidence of disease activity (msologoy)

DAF – disease activity free

T2T; treat-2-target (rheumatology)

10 9 7 6 5 4 3 2 1 0 8

0.8

0.6

0.4

0.2

0.0

1.0

Adjuvant (n = 50)

Salvage (n = 118)

p = 0.002

Surv

ival

Time since radiotherapy (years)

Biochemical relapse-free survival

ZeTo; zero tolerance

17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300m, unable to run &

exercise. Intermittent sensory symptoms

in L arm. Mild urinary frequency

Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

Early or late?

82

Mo

nito

ring

T

rea

tme

nt

Clin

ica

l O

ccu

p &

so

cia

l

What does the future hold?

83

17yr female, diagnosed with CIS

after presenting

with myelitis

18yr, 1st year university diagnosed

with MS after having

L optic neuritis

Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord

lesion at C5

2000 2001

clumsy left hand

pins & needles in

legs

IFN-beta

2001 2003

R optic neuritis

2004

Bladder dysfunction

Graduate trainee

marketing

Full time employment

Off work ~3 months of the

year

Dec 2007

Brainstem syndrome;

diplopia and

ataxia

? glatiramer acetate

Cervical cord relapse weak L arm with pain

High lesion load with brain

atrophy Gd-enhancing lesion

of upper cervical

cord

Splits from her partner

depression , anxiety and fatigue

Reduced mobility

Occupational health assessment

natalizumab

New partner

New job junior management

position

Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent

sensory symptoms in L arm. Mild urinary frequency

Jan 2008

JCV positive

3-monthly MRI monitoring

? fingolimod

Oct 2013

Annual MRI monitoring

mo

nit

ori

ng

trea

tmen

t cl

inic

al

Occ

up

. & s

oci

al

JCV high positive

Final year of

school

University

Pregnancy Old

Age

17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300m, unable to run &

exercise. Intermittent sensory symptoms

in L arm. Mild urinary frequency

Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

Early or late?

Mo

nito

ring

T

rea

tme

nt

Clin

ica

l O

ccu

p &

so

cia

l

Dec 2007 Jul 2010 Jul 2013

Case studies

Ian Rogers. ACNR 2007: 7(3);14.

The data presented for years 5, 10, 14, and 20 were obtained from different publications based on the same longitudinal study. The exact relationship between MRI findings and the clinical status of the patient is unknown.

Fisniku LK et al. Brain. 2008;131:808-817; Morrissey SP et al. Brain. 1993;116:135-146; O’Riordan JI et al. Brain. 1998;121:495-503;

Brex PA et al. N Engl J Med. 2002;346:158-164.

Baseline number of brain lesions predicts progression to EDSS Score ≥3.0

Queen Square Study

The 2-stage model of disability progression

PHASE 1 PHASE 2

• From MS clinical onset to Disability Status Scale 3

• From Disability Status Scale 3 to 6

• Multiple factors may influence disability progression (including gender, age, deficit after first relapse, number of relapses in first 2 years of disease)

• Factors shown to be predictive of disability progression in phase 1 have no influence at this stage

• Likely influenced by focal inflammation • Likely independent of focal inflammation

Leray E et al. Brain 2010;133:1900-13.

0 5 10 15 25 20 30

Years from Clinical Onset of Multiple Sclerosis

DSS

Sco

re

7

6

5

4

3

2

1

0

Phase 2

Phase 1

Including brain atrophy!

Health & Medicine

Early effective treatments