1. DISEASE MODIFYING THERAPY IN
MULTIPLE SCLEROSIS -
INTERFERONS
Prof. A.V. SRINIVASAN
EMERITUS PROFESSOR - THE TAMILNADU DR.M.G.R.
MEDICAL UNIVERSITY
04-04-10

2. LAND MARKS IN MS:
 Top Ten Events...Thus Far
 1868: MS described by Jean-Martin Charcot.
 1878: Myelin discovered by Louis Ranvier.
 1916: Detailed microscopic description made
by James Dawson revealed the basic damage
done in MS.
 1935: An animal form of NIS (EAE) developed
by Thomas Rivers, ultimately suggesting an
autoimmune basis for the disease.
 1946: National Multiple Sclerosis Society
founded by Sylvia Lawry.

3.  1948: Under an early NMSS grant, oligoclonal bands
discovered in the spinal fluid by Elvin Kabat and
others, provided a diagnostic test suggestive of MS
and linking MS to immune system problems.
 1965: Definite criteria for MS diagnosis developed by
NMSS expert committee.
 1969-1970: ACTH used to treat MS exacerbations. This
was the first controlled trial of a successful treatment
for MS: it used newly standardized diagnostic criteria
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

4.  1981: MRI first used to examine a person
with MS. MRI revolutionized diagnosis
and provided evidence that MS is a
constantly active disease even when
symptoms abate.
 1993: Beta-interferon 1b (Betaseron)
approved as the first drug to alter the
course of MS.
 2001:Macdonald’s criteria.
Discipline Weighs Ounces Regret Weighs Tons

5. MS IN INDIA:
 1.33/100000 – Singhal etal.
 2.54% of total neurology admissions between
January'93 to March'98 -Syal,Khandelwal N, PGI
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 energy
Acceptance saves it
Cheerfulness sustains it -- Anonymous

6. LUCCHINETTI CATEGORISATION:
 Type 1- demyelination and macrophages
relate products.
 Type 2-presence of immunoglobulin and
complement.
 Type 3-lacks immunoglobulin and
complement,early loss of myelin associate
glycoprotein-oligodendrocyte dysfunction.
 Type 4-apoptosis of oligodendrocytes-DNA
fragmentation.
Every discovery contains an irrational element or 4 creative intuition

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

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

9. New Queensquare’s criteria
 In 2007, new criteria were proposed in
which DIS requires at least one T2 lesion in
at least two of four locations (juxtacortical,
periventricular, infratentorial, and spinal-
cord) and DIT requires a new T2 lesion on a
follow-up scan
“ Back pain – prize human beings pay
for their UPRIGHT POSTURE”

10. Three Categories of Treatment
 Treatment of disease activity.
 Treatment of exacerbations.
 Treatment of symptoms.
A open foe may prove a curse ; but
a pretended friend is worse

11. Rationale for disease modifying
treatments in MS
Relapsing remitting Secondary & primary
MS progressive MS
Prevent new inflammatory Prevent loss of nerve fibres:
lesions: (neuroprotection)
β-interferon ?lamotrigine
Copaxone ?cannabinoids
Mitoxantrone
Prevent development of Remyelination:
secondary progressive MS: ?stem cells
?possible with existing
treatments

12. 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 greatest inhibitors
of Performance too progress

13. 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.

14. 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)

15.  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:
women of power feared: But only women of character are trusted”
-A- Friedman

16. 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

17. 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.
10 0
80
Avonex
60
40
Rebif
20 Betaseron
0

18. June 18th 2003
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
July 21st 2003
QUASIMS: Higher doses and frequencies of interferon beta are
not necessarily better with comparable disease progression
 Annual Relapse rates
Avonex - .52
Rebif - .69

19. Treatment of Underlying
Disease
Interferons 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

20. Other trials:
 AFFIRM STUDY- NATALIZUMAB MONOTHERAPY
MORE EFFECTIVE THAN INTERFERONS IN TREATING
RRMS.
 BEYOND TRIAL-DOUBLE DOSE INTERFERON
BETA1B – NO ADVANTAGE OVER CONEVENTIONAL
DOSAGE.
 REGARD TRIAL - THRICE WEEKLY INTERFERON
SHOWED NO ADVANTAGE OVER GLATIRMER
ACETATE.
 ETOMS TRIAL- EARLY TREATMENT WITH
INTERFERONS REDUCED SECOND ATTACK BY 24%

21. COMBINATION THERAPY:
 NATALIZUMAB WITH IM BETA 1A OVER INTERFERON
AND PLACEBO – FORMER WAS BETTER – REDUCED
MRI LOAD AND RELAPSES (RUDICK ETAL 2006)
 PML WAS A DREADED SIDE EFFECT IN TWO
PATIENTS.
 COMBINATION OF MINOCYCLINE AND GLATIRMER
ACETATE IS UNDER WAY NOW.
 BETA1A COMBINATION WITH GA (TULLMAN AND
LUBLIN) WAS SUCCESSFUL AND NOW A PHASE 3
TRIAL IS ONGOING – RESULTS EXPECTED IN 2011
“ Maintaining the right attitude is easier than regaining the
right mental attitude”

22. WHOM TO START AND WHEN TO
TREAT:
 When to start DMD- as
early as possible.
 Interferons,glatirmer
acetate- RRMS.
 IFN beta – relapsing form
of SPMS (goodin etal
2002).
 MITOXONTRONE -
Relaping MS
(RR,SP,PROG.RELAPSIN
G).
 NO SUCCESFUL TRIALS
FOR PPMS.

23. UNANSWERED QUESTIONS:
 DOSE vs DOSING
FREQUENCY.
 DOES TIME ON
THERAPY MATTER.
 WHEN TO START
NATALIZUMAB.
 HIGH DOSE IFN vs
NATALIZUMAB.
“ Peace Rules the day where reason Rules the mind”
- Colling

24. CONCLUSIONS:
 SIGNIFICANT ADVANCES HAVE BEEN MADE,IN
IMMUNOPATHOLOGY,CATEGORISATION OF
SEVERITY,DISEASE MODIFYING DRUGS AND THEIR
USAGE.
 CRIPPLING DISABLTY CAN BE LIMITED,EARLIER
DIAGNOSIS AND BETTER SYMPTOMATIC THERAPY
ARE AVAILABLE NOW.
 RESEARCH IS STILL ON IN FINDING THE ELUSIVE
GENE OR AN ENVIRONMENTAL AGENT OR BOTH.
 DESPITE ALL THESE ADVANCES TWO THINGS ARE
STILL UNANSWERED – CURATIVE THERAPY & THE
EXACT CAUSE FOR MS.
 OVER 140 YEARS MS REMAINS AN UNSOLVED
PUZZLE AND AN ENIGMA.

25. Take home advances in MS:
 Queen square criteria – Earlier diagnosis of
MS.
 DIS & DIT – Predicts conversion rate to
Definite MS even in CIS.
 NMO & NMO spectrum disorder – distinct
disorder from MS?
 In terms of Biological difference thin line
separates PPMS & SPMS.

26.  TH 17 a Subset of CD4 and Treg
cells(expressing CD25 & transcription factor
Fox p 3) – pro inflammatory – a significant
advance in immunopathogenesis.
 Two new gene loci IL2 and IL 7 -
IDENTIFIED – needs substantiation.
 EBV, SMOKING – INCREASES RISK OF
MS WHILE Vitamin D – Decreases risk of
MS.

27.  Negative prognosticators are, bladder
symtoms as presentation, incomplete
recovery from an attack, shorter interval
between first and second attack and early
accumulation of disability.
 Benign MS – percentage of cases less –
they eventually progress – not ACTUALLY
BENIGN.

28.  A MAGIC PILL – BASED ON
PHRMACOGENETICS(DNA LEVEL) AND
PHRAMACOGENOMICS(RNA LEVEL)OF
AN INDIVIDUAL.
 PROTEOMICS INFACT RESEARCH
BEYOND RNA LEVEL – FUTURE HOLDS
PROMISE .

29. Dedicated to my family
for making everything worthwhile

30. READ not to contradict or confute
Nor to Believe and Take for Granted
but TO WEIGH AND CONSIDER
THANK YOU