Using the MS Clinical Course Descriptions in Clinical Practice

Mark J. Tullman, MDDirector of Clinical Research

The MS Center for Innovations in CareMissouri Baptist Medical Center

Disclosures

Consultant/speaking fees: AcordaTherapeutics, Allergan, Bayer Healthcare, Biogen, Genzyme, Novartis, Questcor Teva, Research support: Acorda Therapeutics,

Genzyme, Novartis, Roche

Consensus Points: At least annual assessment of clinical and MRI

disease activity for relapsing MS At least annual clinical assessments for

progressive forms of MS No consensus on optimal imaging frequency that

would be beneficial for progressive MS

Lublin FD et al. Neurology 2014;83:278-86.

Case 1

A 32-year-old female awoke with mild blurred vision in her left eye accompanied by eye pain that was worse with eye movement She was evaluated by an ophthalmologist,

diagnosed with optic neuritis, and referred to a neurologist

Case 1

2 years prior - tingling traveling down her spine and into her legs with neck flexion and numbness and tingling in her hands and feet x 2 weeks No other significant past medical history Exam: VA 20/80 OS, APD, and mild decreased

vibratory sensation if her toes Blood work, including NMO IgG was negative

Case 1

Case 1 LP: 1 WBC, protein 40 mg/dL, elevated IgG index and

OCBs Diagnosed with RRMS. Treated with a 3-day course of

intravenous methylprednisolone and her symptoms resolved Treated with glatiramer acetate Doing well one year later with no new/worsening

symptoms. Exam normal with the exception of mild temporal pallor OS and decreased vibratory sensation in her feet Brain MRI - no new, enlarging, or enhancing lesions

Case 1

She was still doing well 1 year later Tolerating glatiramer acetate nicely and reported

rarely missing a dose No new/worsening symptoms Exam unchanged

Case 1

1996 MS Clinical Description Subtypes

2013 MS Disease Modifiers Phenotypes

Relapsing RemittingDisease (RRMS)

With full recoveryfrom relapses

With sequelae / residual deficit after incompleterecovery

Relapsing-RemittingDisease (RRMS)

Clinically Isolated Syndrome (CIS)

Not active*

Active*

Not active*

Active*

*Activity : clinical relapses and/or MRI (Gd-enhancing MRI lesions; new/enlarging T2 lesions

Lublin, et al. Neurology. 2014;83(3):278-86.

Baseline Brain MRI Lesion Number: 20-Year Clinical Status

0

10

20

30

40

50

EDSS ≥6 EDSS ≤3

≥10 lesions

Patie

nts,

%Fisniku LK et al. Brain. 2008;131:808-817.

0

10

20

30

40

50

60

70

0 1-3 4-9 10No. of Brain Lesions

Patie

nts,

%EDSS >3

EDSS 6

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

Change in Brain MRI T2 Lesion Volume Correlates with the Development of SPMS

Fisniku LK et al. Brain. 2008;131:808-817.

Clinically isolated syndromeRRMSSPMS

Time, years

Med

ian

T2 L

esio

n Vo

lum

e, c

m3

0 5 10 15 20 0

20

40

60

POST HOC ANALYSIS ARR BG-12 BID 0.22, GA 0.29, P=0.10 P=0.007 BG-12 BID vs. GA for T2 lesions P value BG-12 BID vs. GA for Gd+ lesions not published

Fox RJ et al. N Eng J Med 2012;367:1087-97.

MRI Outcomes in DEFINE and ENDOSRSE

Mean # of new/enlarging T2 lesions

3.5

2.6

3.7

1.6 1.6

0

1

2

3

4

5

1 2 3 4 5Year

GADMF

Mean # of gadolinium-enhancing lesions

0.6

0.40.5

0.6 0.6

0

0.2

0.4

0.6

0.8

1 2 3 4 5Year

GADMF

Arnold DL et al. Poster P059. Presented at the Joint ACTRIMS-ECTRIMS Meeting 2014, Boston, MA.

“At present, there are no evidence-based guidelines for using activity assessment for management decisions in clinical practice.”

Lublin FD et al. Neurology 2014;83:278-86.

Clinical and MRI Activity-Free: A Realistic Goal?

38

147

6458

37

0

10

20

30

40

50

60

70

Placebo

Natalizumab

% without disease activity in CARE-MS II

Hardova E et al. Lancet Neurol 2009;8:254-60.Hartung HP et al. P07.093. Presented at the AAN Annual Meeting 2013, San Diego, CA.

4132

14

6053

32

0

10

20

30

40

50

60

70

IFN beta-1a

Alemtuzumab

% without disease activity in AFFIRM

Case 2

61-year-old male diagnosed with MS in 1991 was referred by his sister 1st symptoms: diplopia and impaired balance x 3

weeks in 1985 Right hemiparesis in 1991. MRI and LP. Diagnosed

with MS Relapsing-remitting course with incomplete

recovery over the next 7 years. Symptoms included blurred vision, vertigo, and weakness

Case 2

Late 1990s, developed gradually progressive paraparesis and gait imbalance. Started using a walker in 2002. Treated with IFN beta-1b from 1995-2003. Last relapse 1990s Hasn’t had an MRI or seen a neurologist in > 10

years Stable for ≥ 5 years

Case 2

Medications include baclofen, gabapentin, dalfampridine, and oxybutynin Examination findings include an INO on right

lateral gaze, appendicular ataxia, and a spastic paraparesis Impression: SPMS. Clinically stable for ≥ 5 years.

MRI activity indeterminate

Case 2

1996 MS Clinical Description Subtypes

2013 MS Disease Modifiers Phenotypes

ProgressiveDisease

ProgressiveDisease

Progressive accumulationof disability from onsetwith or without temporaryplateaus, minor remissions and improvements

PP

SP

Progressive accumulationof disability after initialrelapsing course, with orwithout occasional relapsesand minor remissions

Progressive accumulationof disability from onsetbut clear acute clinical attacks with or without full recovery

PR

(PP)

(SP)

Active* and with progression#

Active but without progression

Not active but with progression

Not active and without progression (stable disease)

Progressiveaccumulation of disability from onset

Progressive accumulation of disability after initial relapsing course

*Activity : clinical relapses and/or MRI (Gd-enhancing MRI lesions; new/enlarging T2 lesions)# progression measured by clinical evaluation at least annually

Lublin, et al. Neurology. 2014;83(3):278-86.

Case 3 42-year-old male with PPMS referred for a 2nd opinion

regarding possible treatment with disease-modifying therapy 7-year history of gradually progressive weakness in his

extremities, gait imbalance, and slurred speech• More difficulty using a paint brush over the past year• Started using a cane 2 years ago• Walker for the past 10 months

He has never had an exacerbation Treated with glatiramer acetate for 2 years followed

by IFN beta-1a 44 mcg for about 2 years. IFN beta-1a was discontinued 18 months ago due to apparent lack of efficacy

Case 3

“Afraid” to discontinue LDN in case it might be helping No prior response to dalfampridine several years

ago Recently complete PT/OT Exam findings include cerebellar speech,

quadriparesis, ataxic, spastic, and paretic gait MRIs 2 years ago revealed multiple non-enhancing

brain and spinal cord lesions. MRIs of the brain & cervical spine were obtained

Case 3

1996 MS Clinical Description Subtypes

2013 MS Disease Modifiers Phenotypes

ProgressiveDisease

ProgressiveDisease

Progressive accumulationof disability from onsetwith or without temporaryplateaus, minor remissions and improvements

PP

SP

Progressive accumulationof disability after initialrelapsing course, with orwithout occasional relapsesand minor remissions

Progressive accumulationof disability from onsetbut clear acute clinical attacks with or without full recovery

PR

(PP)

(SP)

Active* and with progression#

Active but without progression

Not active but with progression

Not active and without progression (stable disease)

Progressiveaccumulation of disability from onset

Progressive accumulation of disability after initial relapsing course

*Activity : clinical relapses and/or MRI (Gd-enhancing MRI lesions; new/enlarging T2 lesions)# progression measured by clinical evaluation at least annually

Lublin, et al. Neurology. 2014;83(3):278-86.

Rituximab in Primary Progressive MS

Hawker K et al. Ann Neurol 2009;66:460-71.

Conclusions

The 2013 revisions: Provide guidance for routine clinical and MRI

assessments Help to better characterize the disease course Might influence treatment decisions

Properly designed studies are needed to help determine the adequacy of treatment and when therapy should be changed or discontinued