DISEASE MODIFYING THERAPY IN DISEASE MODIFYING THERAPY IN MULTIPLE SCLEROSIS -MULTIPLE SCLEROSIS -

INTERFERONSINTERFERONSProf. A.V. SRINIVASAN

EMERITUS PROFESSOR - THE TAMILNADU DR.M.G.R.

MEDICAL UNIVERSITY

Prof. A.V. SRINIVASANEMERITUS PROFESSOR - THE TAMILNADU DR.M.G.R.

MEDICAL UNIVERSITY

04-04-10

LAND MARKS IN MS:LAND MARKS IN MS:

Top Ten Events...Thus FarTop Ten Events...Thus Far 18681868: MS described by Jean-Martin Charcot.: MS described by Jean-Martin Charcot. 1878: Myelin discovered by Louis Ranvier.1878: Myelin discovered by Louis Ranvier. 1916: Detailed microscopic description made 1916: Detailed microscopic description made

by James Dawson revealed the basic damage by James Dawson revealed the basic damage done in MS.done in MS.

1935: An animal form of NIS (EAE) developed 1935: An animal form of NIS (EAE) developed by Thomas Rivers, ultimately suggesting an by Thomas Rivers, ultimately suggesting an autoimmune basis for the disease.autoimmune basis for the disease.

1946: National Multiple Sclerosis Society 1946: National Multiple Sclerosis Society founded by Sylvia Lawry.founded by Sylvia Lawry.

1948: Under an early NMSS grant, oligoclonal bands 1948: Under an early NMSS grant, oligoclonal bands discovered in the spinal fluid by Elvin Kabat and discovered in the spinal fluid by Elvin Kabat and others, provided a diagnostic test suggestive of MS others, provided a diagnostic test suggestive of MS and linking MS to immune system problems.and linking MS to immune system problems.

1965: Definite criteria for MS diagnosis developed by 1965: Definite criteria for MS diagnosis developed by NMSS expert committee.NMSS expert committee.

1969-1970: ACTH used to treat MS exacerbations. This 1969-1970: ACTH used to treat MS exacerbations. This was the first controlled trial of a successful treatment was the first controlled trial of a successful treatment for MS: it used newly standardized diagnostic criteria for MS: it used newly standardized diagnostic criteria and rating scales to evaluate the efficacy of treatment.and rating scales to evaluate the efficacy of treatment.

Success is a prize to be won. Action is the road to it.

Chance is what may lurk in the shadows at the road side.

- O. Henry

1981: MRI first used to examine a person 1981: MRI first used to examine a person with MS. MRI revolutionized diagnosis with MS. MRI revolutionized diagnosis and provided evidence that MS is a and provided evidence that MS is a constantly active disease even when constantly active disease even when symptoms abate.symptoms abate.

1993: Beta-interferon 1b (Betaseron) 1993: Beta-interferon 1b (Betaseron) approved as the first drug to alter the approved as the first drug to alter the course of MS.course of MS.

2001:Macdonald’s criteria.2001:Macdonald’s criteria.

Discipline Weighs Ounces Regret Weighs TonsDiscipline Weighs Ounces Regret Weighs Tons

MS IN INDIAMS IN INDIA::

1.33/100000 – Singhal etal.1.33/100000 – Singhal etal. 2.54% of total neurology admissions between 2.54% of total neurology admissions between

January'93 to March'98 -Syal,Khandelwal N, PGI January'93 to March'98 -Syal,Khandelwal N, PGI Chandigarh.Chandigarh.

In the Parsi - a prevalence of 26/100,000 – Wadia etal.

Optico spinal form more common than west -Pandit et al.

Class II HLA association in 23 MS - non Parsi origin DRB1*1501 (50%) similar to western studies.11

Resistance drains energyAcceptance saves it

Cheerfulness sustains it -- Anonymous

LUCCHINETTI CATEGORISATIONLUCCHINETTI CATEGORISATION::

Type 1- demyelination and macrophages Type 1- demyelination and macrophages relate products.relate products.

Type 2-presence of immunoglobulin and Type 2-presence of immunoglobulin and complement.complement.

Type 3-lacks immunoglobulin and Type 3-lacks immunoglobulin and complement,early loss of myelin associate complement,early loss of myelin associate glycoprotein-oligodendrocyte dysfunction.glycoprotein-oligodendrocyte dysfunction.

Type 4-apoptosis of oligodendrocytes-DNA Type 4-apoptosis of oligodendrocytes-DNA fragmentation.fragmentation.

Every discovery contains an irrational element or 4 creative intuition

Favorable indicators:Favorable indicators:

Early age of onset.Early age of onset. Female sex.Female sex. Optic neuritis as presenting episode.Optic neuritis as presenting episode. Sensory symptoms as presenting episode.Sensory symptoms as presenting episode. Acute onset.Acute onset. Little residual disabilty.Little residual disabilty. Long inter exacerbation period.Long inter exacerbation period. Small lesion load.Small lesion load.

Unfavorable indicators:Unfavorable indicators:

Later age of onset.Later age of onset. Progressive course.Progressive course. Male sex.Male sex. Frequent exacerbations.Frequent exacerbations. Poor recovery.Poor recovery. Involvement of cerebellar and or motor functions.Involvement of cerebellar and or motor functions. More disease load in MRI.More disease load in MRI. Positive oligoclonal bands.Positive oligoclonal bands.

New Queensquare’s criteriaNew Queensquare’s criteria

In 2007, new criteria were proposed in In 2007, new criteria were proposed in which DIS requires at least one T2 lesion in which DIS requires at least one T2 lesion in at least two of four locations (juxtacortical, at least two of four locations (juxtacortical, periventricular, infratentorial, and spinal-periventricular, infratentorial, and spinal-cord) and DIT requires a new T2 lesion on a cord) and DIT requires a new T2 lesion on a follow-up scan follow-up scan

““Back pain – prize human beings pay Back pain – prize human beings pay for their UPRIGHT POSTURE”for their UPRIGHT POSTURE”

Three Categories of Treatment

Treatment of disease activity.Treatment of disease activity. Treatment of exacerbations.Treatment of exacerbations. Treatment of symptoms.Treatment of symptoms.

A open foe may prove a curse ; but

a pretended friend is worse

Rationale for disease modifying Rationale for disease modifying treatments in MStreatments in MS

Relapsing remitting Relapsing remitting MSMS

Secondary & primary Secondary & primary progressive MSprogressive MS

Prevent new inflammatory Prevent new inflammatory lesions:lesions:

ββ--interferoninterferon

CopaxoneCopaxone

MitoxantroneMitoxantrone

Prevent loss of nerve fibres:Prevent loss of nerve fibres: (neuroprotection)(neuroprotection)

?lamotrigine?lamotrigine

?cannabinoids?cannabinoids

Prevent development of Prevent development of secondary progressive MS:secondary progressive MS:

?possible with existing ?possible with existing treatmentstreatments

Remyelination:Remyelination:

?stem cells?stem cells

Interferons :

Discovered in 1957

Significant antiviral agents

phenomenon where one infection with one virus interferes with a subsequent infection with another virus

The Truth is fear and immorality are two of the The Truth is fear and immorality are two of the greatest inhibitors of Performance too progressgreatest inhibitors of Performance too progress

What are they??

A protein substance naturally produced in the body and believed to function to modulate the immune system. Interferons interact with receptors on non-infected cells to promote the synthesis of antiviral proteins that prevent further infection. They belong to Cytokines, which are hormones of the immune system.

Beta Interferon

Beta interferon-1a

Avonex – administered weekly by an intramuscularly injection (2003)

Rebif – administered subcutaneously three times a week (2002)

Beta interferon-1b

Betaseron – administered subcutaneously every other day (1993)

Early and aggressive treatment with immune stimulating interferons can delay diseae progression.

Prevents crippling symptoms of MS

““Men of Genius Admired: Men of Wealth envied: Men of Genius Admired: Men of Wealth envied: women of power feared: But only women of character are women of power feared: But only women of character are

trusted”trusted”-A- Friedman-A- Friedman

Common Side Effects…

Typical Flu-like symptoms

headache, nausea, and fever

muscle aches

Chills

Irritation at the injection site

Alcohol and exposure to sunlight may irritate side effects

TRIALS:CHAMPIONS: Avonex altered long-term course MS in patients who began treatment immediately after initial attack

35% decrease in the rate of developing second attack

42% reduction in new or enlarging T2 hyper intense lesions

Avonex associated with fewer neutralizing antibodies. Binding antibodies decrease the medications efficacy. They hasten the drugs removal from the bloodstream.

0

20

40

60

80

100

Avonex

Rebif

Betaseron

EVIDENCE: Showed that patients on Avonex who converted to Rebif showed signs of relapse reduction

Patients taking Rebif had fewer active lesions per MRI scan for all studied activity

QUASIMS: Higher doses and frequencies of interferon beta are not necessarily better with comparable disease progression

Annual Relapse rates

Avonex - .52

Rebif - .69

June 18th 2003

July 21st 2003

Treatment of Underlying DiseaseInterferons vs. Glatiramer Acetate

Glatirmer acetate is a substitute antigen that mimics myelin basic protein. It inhibits the CNS immune reactions that are responsible for tissue damage.

Given subcutaneously daily injection

Reduces number of attacks and brain lesions seen on MRI patients

No flu-like side effects associated with interferons

Other trials:Other trials:

AFFIRM STUDY-AFFIRM STUDY- NATALIZUMAB MONOTHERAPY NATALIZUMAB MONOTHERAPY MORE EFFECTIVE THAN INTERFERONS IN TREATING MORE EFFECTIVE THAN INTERFERONS IN TREATING RRMS.RRMS.

BEYOND TRIALBEYOND TRIAL-DOUBLE DOSE INTERFERON -DOUBLE DOSE INTERFERON BETA1B – NO ADVANTAGE OVER CONEVENTIONAL BETA1B – NO ADVANTAGE OVER CONEVENTIONAL DOSAGE.DOSAGE.

REGARD TRIALREGARD TRIAL - THRICE WEEKLY INTERFERON - THRICE WEEKLY INTERFERON SHOWED NO ADVANTAGE OVER GLATIRMER SHOWED NO ADVANTAGE OVER GLATIRMER ACETATE.ACETATE.

ETOMS TRIAL-ETOMS TRIAL- EARLY TREATMENT WITH EARLY TREATMENT WITH INTERFERONS REDUCED SECOND ATTACK BY 24%INTERFERONS REDUCED SECOND ATTACK BY 24%

COMBINATION THERAPY:COMBINATION THERAPY:

NATALIZUMAB WITH IM BETA 1A OVER INTERFERON NATALIZUMAB WITH IM BETA 1A OVER INTERFERON AND PLACEBO – FORMER WAS BETTER – REDUCED AND PLACEBO – FORMER WAS BETTER – REDUCED MRI LOAD AND RELAPSES (RUDICK ETAL 2006)MRI LOAD AND RELAPSES (RUDICK ETAL 2006)

PML WAS A DREADED SIDE EFFECT IN TWO PML WAS A DREADED SIDE EFFECT IN TWO PATIENTS.PATIENTS.

COMBINATION OF MINOCYCLINE AND GLATIRMER COMBINATION OF MINOCYCLINE AND GLATIRMER ACETATE IS UNDER WAY NOW.ACETATE IS UNDER WAY NOW.

BETA1A COMBINATION WITH GA (TULLMAN AND BETA1A COMBINATION WITH GA (TULLMAN AND LUBLIN) WAS SUCCESSFUL AND NOW A PHASE 3 LUBLIN) WAS SUCCESSFUL AND NOW A PHASE 3 TRIAL IS ONGOING – RESULTS EXPECTED IN 2011TRIAL IS ONGOING – RESULTS EXPECTED IN 2011

“ “ Maintaining the right attitude is easier than Maintaining the right attitude is easier than regaining the right mental attitude”regaining the right mental attitude”

WHOM TO START AND WHEN TO WHOM TO START AND WHEN TO TREAT:TREAT:

When to start DMD- as When to start DMD- as early as possible.early as possible.

Interferons,glatirmer Interferons,glatirmer acetate- RRMS.acetate- RRMS.

IFN beta – relapsing form IFN beta – relapsing form of SPMS (goodin etal of SPMS (goodin etal 2002).2002).

MITOXONTRONE - MITOXONTRONE - Relaping MS Relaping MS (RR,SP,PROG.RELAPSIN(RR,SP,PROG.RELAPSING).G).

NO SUCCESFUL TRIALS NO SUCCESFUL TRIALS FOR PPMS.FOR PPMS.

UNANSWERED QUESTIONS:UNANSWERED QUESTIONS:

DOSE vs DOSING DOSE vs DOSING FREQUENCY.FREQUENCY.

DOES TIME ON DOES TIME ON THERAPY MATTER.THERAPY MATTER.

WHEN TO START WHEN TO START NATALIZUMAB.NATALIZUMAB.

HIGH DOSE IFN vs HIGH DOSE IFN vs NATALIZUMAB.NATALIZUMAB.

““Peace Rules the day where reason Rules the Peace Rules the day where reason Rules the mind”mind”

- - CollingColling

CONCLUSIONS:CONCLUSIONS: SIGNIFICANT ADVANCES HAVE BEEN MADE,IN SIGNIFICANT ADVANCES HAVE BEEN MADE,IN

IMMUNOPATHOLOGY,CATEGORISATION OF IMMUNOPATHOLOGY,CATEGORISATION OF SEVERITY,DISEASE MODIFYING DRUGS AND THEIR SEVERITY,DISEASE MODIFYING DRUGS AND THEIR USAGE.USAGE.

CRIPPLING DISABLTY CAN BE LIMITED,EARLIER CRIPPLING DISABLTY CAN BE LIMITED,EARLIER DIAGNOSIS AND BETTER SYMPTOMATIC THERAPY ARE DIAGNOSIS AND BETTER SYMPTOMATIC THERAPY ARE AVAILABLE NOW.AVAILABLE NOW.

RESEARCH IS STILL ON IN FINDING THE ELUSIVE GENE RESEARCH IS STILL ON IN FINDING THE ELUSIVE GENE OR AN ENVIRONMENTAL AGENT OR BOTH.OR AN ENVIRONMENTAL AGENT OR BOTH.

DESPITE ALL THESE ADVANCES TWO THINGS ARE STILL DESPITE ALL THESE ADVANCES TWO THINGS ARE STILL UNANSWERED – CURATIVE THERAPY & THE EXACT UNANSWERED – CURATIVE THERAPY & THE EXACT CAUSE FOR MS.CAUSE FOR MS.

OVER 140 YEARS MS REMAINS AN UNSOLVED PUZZLE OVER 140 YEARS MS REMAINS AN UNSOLVED PUZZLE AND AN ENIGMA.AND AN ENIGMA.

Take home advances in MS:Take home advances in MS:

Queen square criteria – Earlier diagnosis of Queen square criteria – Earlier diagnosis of MS.MS.

DIS & DIT – Predicts conversion rate to DIS & DIT – Predicts conversion rate to Definite MS even in CIS.Definite MS even in CIS.

NMO & NMO spectrum disorder – distinct NMO & NMO spectrum disorder – distinct disorder from MS?disorder from MS?

In terms of Biological difference thin line In terms of Biological difference thin line separates PPMS & SPMS.separates PPMS & SPMS.

TH 17 a Subset of CD4 and Treg TH 17 a Subset of CD4 and Treg cells(expressing CD25 & transcription factor cells(expressing CD25 & transcription factor Fox p 3) – pro inflammatory – a significant Fox p 3) – pro inflammatory – a significant advance in immunopathogenesis.advance in immunopathogenesis.

Two new gene loci IL2 and IL 7 - Two new gene loci IL2 and IL 7 - IDENTIFIED – needs substantiation.IDENTIFIED – needs substantiation.

EBV, SMOKING – INCREASES RISK OF EBV, SMOKING – INCREASES RISK OF MS WHILE Vitamin D – Decreases risk of MS WHILE Vitamin D – Decreases risk of MS.MS.

Negative prognosticators are, bladder Negative prognosticators are, bladder symtoms as presentation, incomplete symtoms as presentation, incomplete recovery from an attack, shorter interval recovery from an attack, shorter interval between first and second attack and early between first and second attack and early accumulation of disability.accumulation of disability.

Benign MS – percentage of cases less – Benign MS – percentage of cases less – they eventually progress – not ACTUALLY they eventually progress – not ACTUALLY BENIGN.BENIGN.

A MAGIC PILL – BASED ON A MAGIC PILL – BASED ON PHRMACOGENETICS(DNA LEVEL) AND PHRMACOGENETICS(DNA LEVEL) AND PHRAMACOGENOMICS(RNA LEVEL)OF PHRAMACOGENOMICS(RNA LEVEL)OF AN INDIVIDUAL.AN INDIVIDUAL.

PROTEOMICS INFACT RESEARCH PROTEOMICS INFACT RESEARCH BEYOND RNA LEVEL – FUTURE HOLDS BEYOND RNA LEVEL – FUTURE HOLDS PROMISE .PROMISE .

Dedicated to my family Dedicated to my family for making everything worthwhilefor making everything worthwhile

READ not to contradict or confute

Nor to Believe and Take for Granted

but TO WEIGH AND CONSIDER

THANK YOU