multiple sclerosis-basic-principles-and-new-developments596 (1)

Multiple Sclerosis

DMW Dharmakeerthi (MD)

Senior Registrar in clinical Neurophysiology

Epidemiology

Compston A, et al. McAlpine’s Multiple Sclerosis, 4th ed. Churchill Livingston, London. 2006.

Prevalence 5–200/100,000 population

Sex distribution 70%–75% female

Age at onset 20–40 years

Ethnic origin Predominantly Caucasian

The Basics - Revision

The most common autoimmune inflammatory demyelinating disease of the CNS.

Episodes affecting different parts of the central nervous system at different times.

Inflammation, leading to demyelination and temporary conduction block, symptomatic only if it occurs in an eloquent area.

Pathogenesis

Pathogenesis of MS involves complex interactions between genetic and environmental factors

Multiple genes are involved

Timing of environmental factors is important– The 1st event: in utero or early postnatal period– The 2nd event: after birth to age 15– The 3rd event: in adulthood (may be several)

Vitamin D deficiency is a plausible candidate for the 1st factor; EBV infection is a plausible candidate for the 2nd factor

MS incidence has increased over the past 30 years due to a change in environmental exposure

Characterized pathologically by multifocal areas of demyelination with loss of oligodendrocytes and astroglial scarring.

Axonal injury is increasingly recognized as a prominent pathologic feature of MS.

Extravasation

astrocytes BRAIN TISSUE

M Y E L I Noligodendrocyte

B cell

Rolling Adhesion

a4 IntegrinVCAM

B L O O D F L O W

LUMEN OF VENULE

B A S A L L A M I N A

Circulation

Activated T cellProteases

Antigen presenting cell(Astrocyte or Microglial cell)Activated

microglia/macrophages

T CELL REACTIVA

TION

Activated Macrophage

Autoantibodies

Complement

IL-1, IL-12,chemokines

Cytokines andchemokines

ProteasesTNF-a

O2•-

NO•

AXONAL DAMAGE

Courtesy of Sergio Baranzini, PhD.

MS Disease Pathology

Oligodendrocyte Damage

Apoptotic Myelin Membranes

Macrophages phagocytoseMyelin sheaths

Denuded Axons

Chronic Demyelinated Axons

Accumulatingaxon loss

Progressive Disability

AcuteInflammation

?

Conduction BlockRemyelination

Slow, InsecureConduction

Transient Symptoms

AcuteRelapse

AxonProtected

Chronic Inflammationwithin BBB

Pathogenesis of Multiple SclerosisMicroscopic Pathology

Courtesy of D.P. Agamanolis, MD. http://neuropathology.neoucom.edu.

Some Definitions

A Relapse:- Onset of new neurological symptoms, or a substantial deterioration of previous symptoms, lasting more than 24 hours, not explicable on the basis of infection or other process

Clinically Isolated Syndrome:-Single neurological episode without clinical evidence of previous episodes, with a normal MRI scan has a ~20% chance of progressing to MS, with and abnormal scan fulfilling certain criteria has an 85% chance of developing MS

Some more definitions

Relapsing Remitting :- disease characterised by relapses with substantial regression of symptoms afterwards – 70% start like this

Primary Progressive :- gradual progressive disease from onset without relapses. ~15% of MS cases

Secondary Progressive :- progressive disease following period or relapsing remitting disease

2005 McDonald criteria revisions diagnostic criteria for multiple sclerosis

Clinical presentation Additional data needed for MS diagnosis

Two or more attacks*; objective clinical evidence of two or more lesions

None•

Two or more attacks*; objective clinical evidence of one lesion

Dissemination in space, demonstrated by: - MRIΔ or- Two or more MRI-detected lesions consistent with MS plus positive CSF or- Await further clinical attack* implicating a different site

One attack*; objective clinical evidence of two or more lesions

Dissemination in time, demonstrated by: - MRI§ or- Second clinical attack*

One attack*; objective clinical evidence of one lesion (monosymptomatic presentation; clinically isolated syndrome)

Dissemination in space, demonstrated by:- MRIΔ or- Two or more MRI-detected lesions consistent with MS plus positive CSF and Dissemination in time, demonstrated by:- MRI§ or Second clinical attack*

Insidious neurological progression suggestive of MS

One year of disease progression (retrospectively or prospectively determined) and Two of the following: - Positive brain MRI (nine T2 lesions or four or more T2 lesions with positive VEP)¥- Positive spinal cord MRI (two focal T2 lesions) - Positive CSF◊

Diagnosis

MRI

CSF

CSF total leukocyte count is normal in two-thirds of patients

CSF protein (or albumin) level is usually normal

Oligoclonal bands 

 Antimyelin antibodies - myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP)  

Time

Preclinical

MRI Activity

Relapses/Disability

MRI T2 Burden of Disease

Axonal Loss

Dis

abili

ty

CIS

*

Reprinted from Trapp BD, et al. Neuroscientist. 1999;5:48-57, with permission from Sage Publications.

Relapsing-Remitting MS

Secondary Progressive MS

Natural History of MSClinical and MRI Measures

Acute relapses

Indications for treatment of a relapse include functionally disabling symptoms with objective evidence of neurologic impairment.

Steroids in Acute Relapses

Speed recovery from an acute relapseDo not alter the outcome at 6 monthsIf relapse severe + not improving in a few days– Exclude infection – Need adequate doses (>60mg)

IV methyl pred 1g 3/7 or 500mg po for 5/7Gastric protection if a risk factorsAvoid oral tail-off unless prev. bad withdrawal

– Avoid long term steroids– Counsel about long term side effects (inc weakness,

avascular necrosis)– PE for those not responding to steroids

Treatment of RRMS

Immunomodulatory agents A decreased relapse rateA reduced progression of disabilityA slower accumulation of lesions on MRIInterferon beta-1a Interferon beta-1bGlatiramer acetate

Current First-Line MS Therapies

Interferon beta-1b

30 mcg Interferon beta-1a once weekly

Glatiramer acetate

Generally very safe and well tolerated

All require self-injection

When to treat?

Potent immune modulation (alemtuzumab) given early in the disease appears not just to stop relapses but to halt progression in the medium term (~5 years)

Coles et al NEJM ‘08 359(17)

The same treatment in patients with established secondary progression stops relapses but fails to halt progression

Coles et al Annals Neurol. ‘99 46

Interferon beta-1b & 1a 

First medication approved by the US FDA

Administered EOD subcutaneously by self injection

Injection site necrosis and Flu-like symptoms

Neutralizing antibodies reduce the bioavailability of interferon

Glatiramer acetate

Polymers of four amino acids compete with APC to T cell

Inducer of specific T helper 2 type suppressor cells

Injection site reactions, chest pain, flushing, dyspnea, palpitations

No laboratory monitoring is necessary

BEYOND, BECOME and REGARD trials

Fingolimod

Sphingosine-1-phosphate receptor modulatorInduces rapid and reversible sequestration of lymphocytes in lymph nodes– Prevents activated and autoreactive cells from

migrating to target organs

Lymphocytes remain functional and may still be activated as part of an immune responseCrosses blood brain barrier and may have neuroprotective properties

Brinkmann V, et al. J Biol Chem. 2002;277:21453-21457; Pinschewer DD, et al. J Immunol. 2000;164:5761-5770; Chiba K, et al. J Immunol. 1998;160:5037-5044.

Fingolimod

OH

NH2

HO

Fingolimod

Daily oral tablet, first dose given in hospital due to potential for bradycardia and AV block

Relapse reduction 55% (0.18 cf 0.4 relapse/yr)

Macular oedema (?high dose only)

Hypertension

2 deaths from HSV/ZVZ encephalitis

stopped two months prior to conception

FREEDOMS TRANSFORMS

Placebo 0.40 /yr

0.5 mg Fingolimod 0.18 /yr 0.16 /yr

1.25 mg Fingolimod

0.16 /yr 0.20 /yr

IFN-β1a (Avonex) 0.33 /yr

16

12

8

4

0

Cum

ulat

ive

Gad

+ L

esio

n (N

o. p

er p

atie

nt)

14.8 8.4 5.7

Placebo(n = 81)

Fingolimod 1.25 mg(n = 83)

Fingolimod 5 mg(n = 77)

43% P <0.001

61% P <0.006

Adapted from Kappos L, et al. N Engl J Med. 2006;355:1124-1140. Copyright ©2006. Massachusetts Medical Society. All rights reserved.

Fingolimod Primary Endpoint

Fumarate

O

O

OO

O

O

OO

Fumaric Acid EstersDerived from common fumitory (Fumaria officinalis), a plant rich in fumaric acidUsed to treat skin disorders since the 17th centuryFumaric acid esters used in severe psoriasis– First reported by Schweckendiek in 1959

Inhibits T-cell activity– Induction of activated lymphocyte apoptosis– Shift in cytokine profile from Th1 to Th2

Effective in chronic experimental autoimmune encephalomyelitisMay have neuroprotective properties by activating antioxidant response genes

Schilling S, et al. Clin Exp Immunol. 2006;145:101-107.

FumarateConclusions

Fumarate reduced the cumulative number of Gad+ lesions, with a trend toward reduced relapsesAdverse effects profile favorable with discontinuations due to nausea, flushing, headache, nasopharingitis (known effects in psoriasis)Phase III trials are actively recruiting, completion expected in 2011, launch in 2012

Teriflunomide

O

NH

N

FF

F

OH

H3C

Teriflunomide

Leflunomide parent compound used in treatment of rheumatoid arthritis

Inhibits pyrimidine synthesis– Binds dihydroorotate dehydrogenase, the fourth

enzyme in de novo pyrimidine synthesis

Inhibits T-cell division

Inhibits murine experimental autoimmune encephalomyelitis

Zeyda M, et al. Arthritis Rheum. 2005;52:2730-2739.

Teriflunomide Phase IIPrimary Outcome

13.4

5.2 5.3

0

2

4

6

8

10

12

14

16

Placebo 7 mg/day 14 mg/dayCu

mu

lati

ve

No

. o

f U

niq

ue

Ac

tiv

e L

es

ion

s

61%, P <0.03

O’Connor PW, et al. Neurology. 2006;66:894-900.

Teriflunomide ConclusionsReduced cumulative number of Gad + lesions with favorable trends for relapse rate reduction and disabilityOverall well tolerated with acceptable adverse effect profileTeriflunomide is teratogenic in animalsReproductive toxicity in humans is not fully understood– Women are advised not to become pregnant and men

cautioned not to parent children while on therapyWomen who wish to become pregnant– Washout with cholestyramine or activated charcoal and

confirmation of acceptable plasma levels of teriflunomide

– Without washout up to 2 years before plasma levels decrease sufficiently

O’Connor PW, et al. Neurology. 2006;66:894-900.

Cladribine

Purine analogue, preferentially depleting lymphocytes,

Leads to prolonged immune modulation

Short oral course at yearly intervals

Relapse reduction 58% (CLARITY trial )

Infections – zoster

Tumours – uterine fibroids, ?cancers

Rejected by European Medicines Agency– “Risks outweigh benefits”

CLARITY

Placebo 0.33 /yr

Cladribine 3.5 mg/kg 0.14 /yr

Cladribine 5.25 mg/kg 0.15 /yr

SummaryCumulative Number of

Gad+ lesionsAnnualized

Relapse Rate

Fingolimod (1.25 mg)(3-arm study, N = 277) -43%, P <0.001 -55%, P =0.009

Teriflunomide (7 mg)(3-arm study, N = 178) -61%, P <0.03 -32%, NS

Laquinimod (0.6 mg)(3-arm study, N = 306) -38%, P =0.005 -32%, NS

Fumarate (720 mg)(4-arm study, N = 256) -69%, P <0.001 -32%, NS

Cladribine (2.1 mg) (2-arm study, N = 52) -94%, P <0.001 -32%, P =0.01

1. Kappos L, et al. N Engl J Med. 2006;355:1124-1140. 2. O’Connor PW, et al. Neurology. 2006;66:894-900. 3. Comi G, et al. 59th AAN Meeting; April 28-May 5, 2007. Abstract S02.002. 4. Kappos L, et al. 22nd ECTRIMS 2006; September 27-30, 2006. Poster P325. 5. Romine JS, et al. Proc Assoc Am Physicians. 1999;111:35-44. 6. Sipe J, et al. 60th Annual Meeting AAN 2008; April 12-19, 2008. Abstract S02.004.

Natalizumab Tysabri

Integrin α4 blockade

Stops circulating lymphocytes entering the CNS

Well tolerated monthly infusions

Effective relapse suppression (68% cf placebo)

Risk of PML appears to increase with time on treatment:-

Very low in first year

By 2 years around 1 in 1000 per year of treatment

Risk of rebound disease activity when stopped

Mitoxantrone

Originally suggested for highly active RRMS and possibly early progression

50% reduction in relapse rate

Cardiotoxicity, less common with newer regimes

Risk of Leukaemia – particularly Promyelocytic leukaemia ?0.3%++

Alemtuzumab Campath

Anti CD52 monoclonal depletes all lymphocytes,

Prolonged immunomodulation

Highly effective relapse reduction (78% cf IFNβ1a)

Stops progressive disability when given early

30% risk of AutoimmunityITP

Thyroid

Campath (Alemtuzumab)

– Unlicensed, and cheap! (at present)

No effect on established progressionMarked reduction in relapse rate for those with highly active disease – 74% cf IFNMost convincing effect on progression of any drug, when started early enough25% occurrence of other autoimmune disease (Graves, ITP etc)

Azathioprine

One small, open-label study found that azathioprine up to 3 mg/kg per day was well tolerated and reduced the rate of new gadolinium-enhancing brain lesions in patients with RRMS

Cyclophosphamide

 Limited observational evidence supports the use of pulse (eg, monthly) IV cyclophosphamide for RRMS

Conclusions

To date, treatment has been successful in suppressing relapses and enhancing MRI lesions

Early treatment with effective immune therapy may alter the course of disease, preventing/ delaying later disability