Clinical Features and Treatment

Outcomes in MS An Update from Contemporary Cohorts

PVA Summit –August 2013 Orlando, FL

Mitchell T. Wallin, MD, MPH Clinical Associate Director

VA MS Center of Excellence East-Baltimore

Associate Professor of Neurology

Georgetown University School of Medicine

University of Maryland School of Medicine

Disclosures

This continuing education activity is managed and accredited

by Professional Education Services Group in cooperation

with the Paralyzed Veterans of America. Neither PESG

nor PVA nor any accrediting organization supports or

endorses any product or service mentioned in this activity.

PESG Staff and the Program Planning Committee have no

financial interest to disclose.

Commercial Support was not received for this activity.

Disclosures (cont.)

M. Wallin, MD, MPH has the following disclosures:

Biogen-Idec, Inc. Investigator Initiated Grant Support

Learning Objectives:

Understand the clinical course of MS in recent

population-based cohort studies

Discuss optimal models to study MS therapy

outcomes in representative patient populations

Provide an overview of current MS disease

modifying therapy use and the associated clinical

impact in large patient populations

Topical Outline

MS morbidity overview Relapses

Progressive disability

Gulf War Era MS Cohort

Clinical & research tools for MS outcomes

MS Disease Morbidity Timeline (Lublin F, Neurol in Clin Pract, 2008)

Relapses

EDSS, PDDS

MSFC

Imaging outcomes

Study population issues

Representative

Adequate size

Disease status

Controls

Follow-up time

*In 224 placebo patients from the NMSS task force on clinical outcome assessment.

Relapses Can Result in

Residual Long-Term Disability Lublin FD, et al. Neurology. 2003;61:1528-1532

Net Change in EDSS Score from before a Relapse to after a Relapse*

42% of patients had a residual deficit ≥0.5 point

28% had a residual deficit ≥1.0 point

42.4% increase 0.5 or more

28.1% increase 1 or more

Nu

mb

er

of

Subje

cts

1 3 7 4

8

20

86

32 33

14 8 5

1 2

0

20

40

60

80

100

-3.5 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.5 4.0

Low (0-1 attacks in 2 years)

Intermediate (2-4 attacks in 2 years)

High (> 5 in 2 years)

Long-Term Disability Effect of Early Relapses

(Weinshenker, Brain 1989)

50 40 30 20 10

20

0

0

40

60

80

100

Time from onset of MS (years)

Per

cent

Pts

DS

S =

6

p < 0.0001

Risk of Permanent Disability from an

MS Relapse (Bejaoui K, Neurology 2010)

1,078 patients with RR MS

mean EDSS 3.4

mean of 2.4 relapses/patient (range: 1-11)

mean follow-up time 7.4 yrs

7 patients with relapse resulting in EDSS > 6

2 on INF beta at time of relapse

Initial sx onset in 2

156 reached EDSS > 6 by secondary progression

Relapses and Progression in MS (Kremenchutzky, 2006)

Three subgroups defined:

PP MS (N=219)

SP MS (N=146)

Single attack before onset of progression (SAP; N=140)

PP had the worse outcome vs. SP and SAP based on time from onset of MS

No difference in time to reach DSS 6, 8 and 10 from onset of progression

Progressive course independent of relapses

Initial Course of MS and Time to EDSS 4 and

EDSS 6 (Confavreux, 2000)

Median time to EDSS 4

RR Onset: 11.4 yrs

Progressive Onset: 0 yrs

Median time EDSS 4 to 6

RR Onset: 5.7 yrs

Progressive Onset: 5.4 yrs

EDSS 4 Threshold: once EDSS

4 is reached, progression in MS

is not affected by relapses

Influence of Initial Course on Age to

Reach EDSS End-Points (Confavreux, 2006 )

RR MS were older than PP MS to reach EDSS 4 (Graph A) & EDSS 6 (Graph B); 95% CI overlap

Age to reach EDSS 7 between groups similar (Graph C)

Age and Disability Progression (Confavreux, Brain 2006)

Clinical & Demographic Predictors

of Progressive Disability in MS (Langer-Gould, 2007)

Favorable Risk Factors Unfavorable Risk Factors

Young age at onset Older age at onset

Female Sex Male sex

Race: White Race: African American

Onset sx: optic neuritis, sensory Onset sxs: motor, cerebellar, sphincter

RR disease onset Severe disability after first attack

Short interval between first-second

attack

High frequency of attacks in first 5 yrs

Progressive disease from onset

African Americans and MS Progression (Cree, et al 2004)

Large retrospective cohort

of AA (N=375) vs. CA

(N=427)

Median time to EDSS 6

(16 yrs vs. 22 yrs

p=0.0001)

Median time to EDSS 7

(30 yrs vs. 38 yrs)

Adjusted Cox Hazard

Ratio: 1.67 for walking

with cane (p < 0.001)

Longitudinal Follow-up of Benign MS at 10

years (Sayao, 2007)

200 MS pts with EDSS

< 3 at 10 yrs from onset from British Columbia Database

Conversion to SP MS in 23%

10 -year EDSS score was only significant predictor of

progression

Time to EDSS 6 from first onset

symptoms of MS

Study Location (n) Mean Disease

Duration

(yrs)

Median Time to

EDSS 6

(yrs)

Weinshenker, 1989 Ontario (1,099) 12 15

Confavreux, 2000 Europe (1,844) 11 20

Pittock, 2004 Rochester, MN (166) 19 29

Tremlett, 2006 British Columbia (2,319) 20 28

Gulf War-Era MS Cohort (n=2,691)

3,499 veterans with MS/CIS SC dx and active duty

service between1990-2007

2,478 with diagnosis of MS/Possible

116 with diagnosis of optic

neuritis

97 with diagnosis of transverse

myelitis/other/CIS NMO

561 Not MS/CIS

247 with dx < 1990

Risk of MS by Sex and Race Groups (Kurtzke, 1979; Wallin, 2004 & 2012)

Group WWII & KC Adjusted CC Ratios

Vietnam & Later Adjusted CC Ratios

Gulf War Era Relative Risk (95%CI)

White-Male 1.00 1.00 1.00

Black-Male 0.44 0.67 1.16 (1.03-1.30)

Other-Male 0.22 0.30 0.77 (0.65-0.92)

White Female 1.79 2.99 3.54 (3.20-3.91)

Black Female 1.28 2.86 3.62 (3.18-4.11)

Other Female --- 3.51 1.98 (1.52-2.58)

2000 - 2007

Total Black White Other Hisp AsPac NatAm

AN

NU

AL

RA

TE

PE

R 1

00,0

00

0

2

4

6

8

10

12

14

1990 - 2007TOTAL BLACK WHITE OTHER HISPANIC

AN

NU

AL

RA

TE

PE

R 1

00

,00

0

0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

30

32

Male

Female

GW MS Cohort: Average Annual

MS Incidence Rates (Wallin, Brain 2012)

TOTAL ARMY NAVY MARINES AF CG

AN

NU

AL

RA

TE

PE

R 1

00

,00

0

0

2

4

6

8

10

12

14

GW MS Cohort: Average Annual

MS Incidence Rates (Wallin, Brain 2012)

TOTAL ARMY NAVY MARINES AF CG

AN

NU

AL

RA

TE

PE

R 1

00,0

00

0

5

10

15

20

25

30

35Male

Female

MS Incidence in Active

Component, US Armed Forces

2000-2009 (Duessing, et al 2011 & 2012)

MS Incidence

Southern California HMO Population

Clinical Features of the GW-Era

MS Cohort (n=2,478)

Onset subtype: relapsing (94%),

progressive (6%) with no single

presenting DSS functional system

being significantly different between

groups

Significantly more males and AA had

progressive onset MS

Optico-spinal MS presentation:

Asian > NA/Alaska native >

Hispanic > AA>Whites

NMO confirmed cases: n=6 (AA:

66%, White: 33%)

Visual

Brainstem

Pyramidal

Cerebellar

Sensory

Bladder/Bowel

Mental

Spinal CordMultip

le OTH

Perc

en

tag

e o

f P

ati

en

ts

0

10

20

30

40

50

White (n=1,833)

Black (n=656)

Hispanic (n=153)

Asian/Hawaiin/Pacific Islander (n=26)

Am In/Alk Nat (n = 7)

Unknown (n = 14)

Clinical Features of the GW-Era

MS Cohort

DSS Score

0-2 3-4 5-6 7-9

Pe

rce

nta

ge

of

Pa

tie

nts

0

10

20

30

40

50

60

Male (n = 1,603)

Female (n = 845)

Total (N = 2,448)

DSS Score

0-2 3-4 5-6 7-9

Pe

rce

nta

ge

of

Pa

tie

nts

0

10

20

30

40

50

60

White (n = 1,684)

Black (n = 600)

Hispanic (n = 135)

Asian/Hawaiin/Pac Isl (n = 20)

Am In / Alk Nat (n = 5)

Unknown (n = 4)

GW Era MS Cohort:

Risk Factors for MS Progression

Included all MS cases (N = 2,841)

Followed strategy of Tremlett et al. 2006

Cox Proportional Hazard Endpoint

Time to reach DSS of 6

Risk Factors Age at onset

• < 20 years

• 20 to <30 years

• 30 to < 40 years

• 40 to < 50 years

• 50+ years

Gender

Type of symptom at onset

Initial disease course (relapsing vs. progressive)

Race (Black vs. White and Other)

DMT use

GWEMSC - Morbidity Risk Factor N Hazard Ratio 95%CI

Gender

Female

Male

943

1,898

1

1.36

1.18 – 1.58

Age @ Onset

< 20

20 to <30

30 to <40

40 to <50

50+

72

1,361

1,046

321

33

1

1.76

2.04

2.17

3.55

1.09 – 2.83

1.23 – 3.28

1.31 – 3.59

1.78 – 7.08

Type of Symptom at onset

Motor

Sensory

Visual/ON

Cerebellar/Brain Stem

762

1,226

800

962

1.21

0.96

1.05

1.23

1.05 – 1.39

0.84 – 1.10

0.89 – 1.23

1.08 – 1.39

Initial Disease Course (progressive) 172 4.54 3.77 – 5.48

Race (Black) 660 1.54 1.33 – 1.77

DMT use (ever used) 2,265 0.69 0.58 – 0.83

28

GWEMSC - Morbidity Figure 1. Cumulative probability of reaching DSS 6 from birth in years by Age at Onset. Control variables were: gender,race, disease course at onset, type of symptom at onset, and DMT use (see Table 6 for results).

Years from Birth to DSS 6

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85

Cu

mu

lati

ve S

urv

ival

0.0

0.2

0.4

0.6

0.8

1.0

< 20

20 -< 30

30 -< 40

40 -< 50

50+

p < 0.001

MS Assessment Tool & Database

CPRS-based annual assessment

of all VA-users with MS (MS

Policy Handbook-2009)

Core demographic & clinical

information captured/stored

Pilot in VISN 5 & 20 (n=200)

Goals:

Improved real-time surveillance of

MS population

Efficient monitoring of DMT use

& untoward effects

Optimize management of patients

Data for epidemiology and policy

decisions

CPRS Template: Baseline Assessment

MS Assmt Tool: EDMUS Scale

MS Assmt Tool: Relapse History

MSCoE MS Registry Main Page

• Data updated daily

• Main page allows for filtered cohort selection based on individual search preferences

Expanded Diagnosis & DMT Medication

Filter Options

Clinician Dashboard Display

• Current meds pulled from the Corporate Data Warehouse – updated daily

MS Risk Assessment Through the Lifespan

MS Disease Course

fewer relapses with full recovery (RRMS)

shorter disease history

DMT

Vitamin-D supplements (UVB exposure) ??

frequent relapses without full recovery (SPMS)

primary progressive disease course

longer disease history

comorbidities

smoking ??

OUTCOMESClinical

QOL

Disability

ADLs

MSSymptoms

Survival

Infections - Decubiti - UTI - Pneumonia

DVT / PE

Pro

tecti

ve

Exacerb

ati

ng

Ris

k F

acto

rs

Environmental

EBV, HHV-6

other viruses &toxin(s)

smoking ??vaccines ??

Equitorial Latitude

Vitamin-D (diet)

UVB exposure

Prognosticators@ onset of MS

Female

younger age

sensory symptoms

relapsing MS

Male

older age

motor symptoms

progressive MS

family HX of MS

NOTE: Items displayed in BLUE are EFFECT MODIFIERS that can varry naturally (e.g., living at a southern latitude) or are modifiable (e.g., smoking, DMT use). A '??" is placed next to those items that have been suggested, but not conclusively demonstrated, to impact MS risk or outcomes.

Birth ~10 ~20 ~40 Death

+

-

Clinical Features and Treatment

Outcomes in MS Conclusions

Relapses rarely associated with significant sustained disability progression in population-based studies

MS disease morbidity progression is more benign in recent population-based cohorts

MS clinical phenotype and course are age dependent and relatively uniform

US DoD/VA MS population-based cohort studies offer opportunity to evaluate: Incident MS (service-connection)

Real time disability & DMT outcomes: MS Assmt Tool & Databases

MSCoE Epidemiology Research Group

VA MSCoE

Joel Culpepper, PhD

Parisa Coffman, MPH

Heidi Maloni, PhD

Jodie Haselkorn, MD, MPH

John Kurtzke, MD

NW Innovation Center Staff

VA Environmental Epidemiology

Han Kang, PhD

Clare Mahan, PhD

NIH-NINDS

Steve Jacobson, PhD

DoD Serum Repository &

WRAMC/DoD Neurology

Mark Rubertone, MD

Angie Eick, PhD

Johns Hopkins University/Welch Ct

Joseph Finkelstein, MD, PhD

Funding: VA Merit Review, VA MSCoE, NMSS