What are we actually measuring in MS?

“Preventing end-organ damage: Saving Brain”

Gavin Giovannoni

Disclosure

Gavin Giovannoni: has provided consultation to Bayer Schering Healthcare, Biogen Idec, Genzyme, GlaxoSmithKline, Merck Serono, Novartis, Protein Discovery Laboratories, Teva Aventis, UCB Pharma, Ironwood, Eisai, Vertex, Roche, Synthon, Canbex. He has received grant support from Bayer Schering Healthcare, Biogen Idec, Merck Serono, Merz, Novartis, Teva Aventis, GW Pharma.

Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling A clinical perspective of multiple sclerosis

Epstein–Barr virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

Differential diagnosis

MRI

Evoked potentials

Lumbar puncture

Blood tests

Diagnostic criteria

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

Pain Swallowing

Spasticity Falls

Balance problems Insomnia

Restless legs Fertility

Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter

Intrathecal baclofen

Physio- therapy

Speech therapy

Occupational Therapy

Functional neurosurgery

Colostomy

Tendonotomy

Studying

Employment Relationships

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

Alternative medicine

Pregnancy Breast- feeding

Research

Insurance

Visual loss

Palliative care

Assisted suicide

Social services

Legal aid

Genetic counselling

Intrathecal phenol

Fractures

Movement disorders

Osteopaenia

Brain atrophy

Hearing loss

Tinnitus

Photophobia

Hiccoughs

DVLA

Neuroprotection

Psychosis

Depersonalisation

Brain health

Cognitive reserve

Sudden death

Suicide

OCD

Narcolepsy

Apnoea Carers

Respite

Hospice

Respite

Dignitas

Advanced directive

Rhiztomy

Wheelchair

Walking aids

Blood/Organ donation

Brain donation

Exercise therapy

NABs

Autoimmunity

Infections

Outcome measures

Web Resources

Pathogenesis

Double vision

What is MS?

NEDA

T2T OCT

Neurofilaments

JCV status Pharma

Anaesthesia

Natural history

Delayed intervention

Later treatment

Treatment at diagnosis

Early intervention

Time Disease onset

Dis

abili

ty

Time is brain

Theoretical model: treat early and effectively

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

Survival from pivotal randomized controlled trial randomization over 21 years is shown for interferon β-1b (IFNβ-1b) 250 μg vs. placebo (A) and IFNβ-1b 50 μg vs. placebo (B). Time from onset of clinical symptoms to death is shown for IFNβ-1b 250 μg vs. placebo (C) and IFNβ-1b 50 μg vs. placebo (D). Hazard ratios (HRs) and 95% confidence intervals (CIs) are estimated using Cox proportional hazard models without stratification. Goodin DS, et al. Neurology 2012; 78:1315–1322

Pro

po

rtio

n o

f p

atie

nts

w

ho

are

sti

ll al

ive

(%)

Time (y) At risk (n): IFNβ-1b 50 µg Placebo

125 125 123 73 48 125 116 32 13 31 69 118 123 123 121 107 24 12

IFNβ-1b 50 µg Placebo

HR = 0.545 (95% CI 0.321–0.924) 45.5% reduction in hazard rate Log-rank, P = 0.0223

100 95

85

75 70

60 55

45

90

80

65

50

0 5 15 20 25 10 30 35 40

Pro

po

rtio

n o

f p

atie

nts

w

ho

are

sti

ll al

ive

(%)

Time (y) At risk (n): IFNβ-1b 250 µg Placebo

124 124 122 93 52 122 120 35 9 31 69 118 123 123 121 107 24 12

IFNβ-1b 250 µg Placebo

HR = 0.495 (95% CI 0.289–0.847) 50.5% reduction in hazard rate Log-rank, P = 0.0089

100 95

85

75 70

60 55

45

90

80

65

50

0 5 15 20 25 10 30 35 40

Pro

po

rtio

n o

f p

atie

nts

w

ho

are

sti

ll al

ive

(%)

Time (y) At risk (n): IFNβ-1b 250 µg Placebo

124 124 121 118 104 88 109 117 120 123

IFNβ-1b 250 µg Placebo

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

100

95

90

85

80

75

70

65

0 5 10 15 20

Pro

po

rtio

n o

f p

atie

nts

w

ho

are

sti

ll al

ive

(%)

Time (y) At risk (n): IFNβ-1b 50 µg Placebo

125 122 120 113 109 88 109 117 120 123

IFNβ-1b 50 µg Placebo

HR = 0.540 (95% CI 0.318–0.915) 46.0% reduction in hazard rate Log-rank, P = 0.0202

100

95

90

85

80

75

70

65

0 5 10 15 20

A B

C D

38-year-old teacher with relapsing–remitting MS under the care of a hospital in central London

• Glatiramer acetate treatment for 3 years (good adherence and tolerance)

• Relapse with a mild left sensory loss

• Referred to me for a second opinion

• Switched to interferon β (intramuscular interferon β-1a; www.msdecisions.org.uk)

• Mild persistent flu-like side effects and lymphopenia

• 12/12’s neutralizing antibodies screen negative

• Volunteered for new research programme, which included a gadolinium-enhanced MRI protocol

Teacher

Teacher

38-year-old teacher with relapsing–remitting MS

• As a result of fatigue and cognitive problems she is forced to take early retirement

• Although fully functional she develops depression and anxiety

• In her spare time she spends a lot of time on the web and becomes an expert patient

X

How bad is MS?

Consequences of increasing EDSS scores: loss of employment1

The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger. * In a Danish cohort study, the median time to early pension was 10 years for patients and 24 years for controls 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

Work capacity by disability level

~10 yrs*,2

0

10

20

30

40

50

60

70

80

90

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

atie

nts

≤6

5 y

ear

s o

ld

wo

rkin

g (%

)

Gambler’s Dilemma

Benign MS

What is benign MS?

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

163 patients with “benign” MS

(disease duration ≥15 years and EDSS ≤3.5):

45% cognitive impairment

49% fatigue

54% depression

Maria Pia Amato

Valentina Zipoli

Benedetta Goretti

Emilio Portaccio

Maria Fara De Caro

Laura Ricchiuti

Gianfranco Siracusa

Medena Masini

Sandro Sorbi

Maria Trojano

Impact of MS: cognitive functioning in the CIS stage

Feuillet L, et al. Mult Scler 2007; 13:124–127

Pat

ien

ts f

ailin

g

≥ 2

co

gnit

ive

te

sts

57%

7%

0%

10%

20%

30%

40%

50%

60%

CIS patientsn = 40

Healthy controlsn = 30

P < 0.0001

Deficits were found mainly in memory, speed of

information processing, attention and executive

functioning

Relapses

Weinshenker BG, et al. Brain 1989; 112:1419–1428

Pe

rce

nta

ge o

f p

atie

nts

*

Time from onset of MS (yrs)

0 10 20 30 40 50

100

80

60

40

20

0

0–1 attacks in first 2 years

2–4 attacks in first 2 years

≥5 attacks in first 2 years

* The percentage of patients not having reached DSS 6 is shown after stratification according to the number of attacks in the first 2 years from onset of MS. The difference between the groups is significant (P < 0.0001). Patients with chronically progressive MS were excluded.

Predictors of long-term outcomes in MSers treated with IFNβ-1a

Bermel RA, et al. Ann Neurol 2013; 73:95–103

15 years 2 years

Treatment chosen by the treating physician

ASSURANCE study: long-term clinical follow-up

MSCRG study: MRI at baseline, Year 1 and Year 2

Placebo

IM IFNβ-1a 30 μg qwk

Predictors of long-term outcomes in MSers treated with IFNβ-1a

Bermel RA, et al. Ann Neurol 2013; 73:95–103

IM IF

Nβ

-1a

P

lace

bo

OR of advancing into the worst quartile of EDSS change after 15 years

40 30 20 10 1

Early disease activity*

New T2

Relapse

Gd+

New T2

Relapse

Gd+

OR (confidence interval)

2.62 (0.93, 7.43)

1.53 (0.56, 4.19)

1.79 (0.62, 5.16)

2.89 (0.88, 9.54)

4.44 (1.43, 13.85)

8.96 (2.53, 31.65)

P value

0.069

0.408

0.284

0.080

0.010

< 0.001

Gd+, gadolinium-enhancing; IM, intramuscular; OR, odds ratio. * ≥2 gadolinium-enhancing lesions (cumulative) on year 1 and/or year 2 MRI; ≥3 new T2 lesions on Year 2 MRI compared with baseline; and ≥2 relapses over 2 years.

27 29 30

42 44

41

0

5

10

15

20

25

30

35

40

45

50

30–59 60–89 ≥90

≥1.0 EDSS point

≥0.5 EDSS point

Relapses and residual deficits

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

Patients with a change in EDSS score of ≥1.0 or ≥0.5 after relapse

Pat

ien

ts (

%)

Days after exacerbation

(n = 62) (n = 85) (n = 77)

Disease progression

Relationship between early clinical characteristics and long-term disability outcomes: 16-year cohort study (follow-up) of the

pivotal IFNβ-1b trial

Physical outcome = either SPMS or EDSS = 6; † Cognitive outcome = cognitive performance index; BOD, burden of disease; EDSS, Expanded Disability Status Scale score; LTF, long-term follow-up; RCT, randomized controlled trial; SPMS, secondary progressive multiple sclerosis Goodin DS, et al. J Neurol Neurosurg Psychiatry 2012; 83:282–287

Multiple regression model for outcome at long-term follow-up derived with stepwise model selection procedure: fitted regression model including predictors with P ≤ 0.5 to enter; P < 0.1 to stay in the model.

Estimate SE P value

Physical outcome* model fit (logistic regression): R2 = 0.51

Baseline variables

Intercept –5.3 0.91 < 0.0001

EDSS at baseline 1.2 0.22 < 0.0001

MRI T2 BOD at baseline (cm2) 0.05 0.02 0.001

Gender 0.93 0.47 0.045

On-RCT variables

Actual EDSS change from baseline 0.86 0.21 < 0.0001

Annualized relapse rate 0.52 0.23 0.025

Cognitive outcome† model fit (linear regression): R2 = 0.49

Baseline variables

Intercept –11.2 3.98 0.006

EDSS at baseline –0.99 0.25 < 0.0001

Pre-morbid IQ 0.12 0.035 0.0007

MRI T2 BOD at baseline (cm2) –0.05 0.02 0.018

Third ventricular width at baseline (mm) –0.41 0.16 0.014

On-RCT variables

Actual EDSS change from baseline –0.67 0.24 0.007

Change, third ventricular width (mm) –0.87 0.33 0.009

Strongest predictor of disability progression on IFNβ therapy is progression itself

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

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 (22–61) 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)

What to measure?

Normal neurological examination

No disability

Minimal disability

Moderate disability

Relatively severe disability

Disability precludes full daily activities

Assistance required to walk Restricted

to a wheelchair

Restricted to bed or chair Confined

to bed

Death

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0

Adapted from http://www.msdecisions.org.uk/. Accessed 15 April 2014. Previously adapted from Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983; 33: 1444-52.

Yes – I do an EDSS whenever I see a patient 14 25%

Yes – I do an EDSS annually 10 18%

Yes – I occasionally do an EDSS 20 36%

No – I never do an EDSS 3 5%

Other 9 16% Yes – I do an EDSS whenever I see a

patient [14] Yes – I do an EDSS

annually [10]

Yes – I occasionally do an EDSS [20]

No – I never do an EDSS [3]

Other [9]

Survey of UK MSologists

Schmierer K, et al. ABN 2014; unpublished.

Clinical – In your routine MS clinical practice, do you use the EDSS?

Clinical – If you do an EDSS in your routine clinical practice, do you walk the patients to assess their walking distance?

Yes [9]

No [20]

Sometimes [22]

Other [5] Yes 9 16%

No 20 36%

Sometimes 22 39%

Other 5 9%

Validating a novel web-based method to capture disease progression outcomes in multiple sclerosis

The midpoint of the diamonds is the mean difference between the two EDSS scores, the upper and lower lines within the diamonds are the 95 % confidence interval. The width of the diamond indicates the sample size, the dots the actual values. The horizontal line at 0.46 indicates the mean difference between the two scores. The graph indicates the greater variation at lower EDSS scores, with greater agreement at scores >5. Leddy S, et al. J Neurol 2013; 260:2505–2510

ORIGINAL COMMUNICATION

we

b-

EDSS

– P

-ED

SS

P-EDSS

–4

–3

–2

–1

0

1

2

3

4

0 1 1.5 2 2.5 3 3.5 4 4.5 5.5 6 6.5 7 8

Monitoring your own disease

http://www.patientslikeme.com/

Teacher

38-year-old teacher with relapsing–remitting MS

• As a result of fatigue and cognitive problems she is forced to take early retirement

• Although fully functional she develops depression and anxiety

• In her spare time she spends a lot of time on the web and becomes an expert patient

• Possible undocumented relapses

– Several episodes of pins and needles and numbness in her feet – An episode of urinary frequency and urgency – Cognitive impairment waxed and waned

X

Teacher X

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 a patient-related outcome measure be included in our definition for ‘no evidence of disease activity’?

‘No evidence of disease activity’ defined as:1,2

No relapses

No focal MRI activity – sub clinical relapses

No new or enlarging T2 lesions

No Gd-enhancing lesions

No sustained disability progression

Control Multiple sclerosis

End-organ damage: saving brain

Conclusions

• Treat early and effectively

• The gambler’s dilemma

– What is benign MS?

• Relapses and disease progression count

– Relapses are often missed

– Poor recovery from relapses is a cause of disease progression

– EDSS is not routinely done, and if done it is not reliable

– Need sensitive and objective measures such as MRI and PROMS

• Need to target both inflammation and neurodegeneration

– Treat-2-target NEDA

– Do we need to expand our current definition of NEDA?

– Do we need to focus on end-organ damage and saving brain?