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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