Immunomudulators in multiple_sclerosis

immunomodulation in multiple
sclerosis
Presenter- Dr Santosh Dash
Chair person- Dr P.S Mathuranath

Introduction
• Multiple sclerosis (MS) is a chronic disease
characterized by inflammation, demyelination,
gliosis and neuronal loss.
• Although the earliest recorded description of
multiple sclerosis (MS) dates back to the 14th
century, it was not until the latter years of the
20th that treatments for this disabling
condition were found.

Jean-Martin Charcot (1825–1893)
who made the first definite links
between the symptoms of MS
and the pathological changes of
inflammations in autopsy
sample.
After his work, the era of
immunomodulatory therapy in MS
was started.

Brief treatment history
 In 1960s, corticosteroids were first
introduced to reduce the severity of relapses
but not effective at reducing the number of
relapses or the rate of disease progression.
 However it was not until the late 1980s that
the concept of immunomodulation was
extensively explored.

Why this topic ?
 Though in 1993 the first drug was approved (IFN-β)
but since last 5 yr there is emergence of a large
number of new disease modifying treatments for
MS.
 These should prompt a re-evaluation of our
approaches to the long-term management of these
patients.

Immunopathology of MS
 Type-1 -Involves activated T-cells, macrophage
and cytokine mediated multifocal damage of
myelin. Most common
 Type-2- B cells (antibody) and complement
mediated multifocal damage.
 Type-3- Diffuse low grade inflammation with loss
of myelin associated glycoprotein (MAG) and
apoptosis of oligodendrocytes.
 Type-4- Degeneration of oligodendroglia cells
Neurol Clin. 2011 May ; 29(2): 257–278

Goal of immunomodulators
1
• First and most important is higher standard
of treatment success.
2
• Freedom from disease defined by absence of
Relapse, Disability progression and no Radiological
evidence of disease.
3
• Practically we should reduce ARR(Annual relapsed
rate ) and Reduced EDSS(Expanded Disability Status
Scale) score.

Immunomodulators Classification
• Steroids or LVPP
For Acute
episodes
(Relapse)
•IFN, GA etc..
Disease
modifying
agents

Approved Drugs
INJECTABLE ORAL
1.IFN beta-1b(Betaseron)
(1993) SC
9.Fingolimod (2010)
2.IFN beta-1a(Avonex) IM
(1996)
10.Teriflunomide (2012)
3. Glatiramer acetate (1997) 11.Dimethyl fumarate
(BG-12) (2013)
4.Mitoxantrone (2000)
5.IFN beta-1a(Rebif) SC (2002)
6.Natalizumab (2005)
7.Alemtuzumab (2014)
8. Pegylated Beta 1-a (2014)

Others ..
Ocrelizumab Daclizumab Cladribine Laquinimod Rituximab
Phase 3- Trial

Questions to be asked ?
How these drug works ? Mechanism of action.
Where to use ? Indications.
How to use ? Dose and route.
Any adverse reactions ?
Any evidence ?
Which is better ? Any head to head trial.
What to do if one treatment failed ?Algorithm.

1.Interferons
• IFNs belong to the large class of proteins
known as cytokines.
• Used for communication between cells to
trigger the protective defenses of the immune
system that help eradicate pathogen.
• In MS interferon Beta (IFNβ) is used.

Mechanism of Action
• Down regulating expression of MHC molecule on
Antigen presenting cell.
 Reducing pro-inflammatory and increasing
regulatory cytokine level.
 Inhibiting T-cell proliferation.
 Limiting the trafficking of inflammatory cell in
CNS. Nature reviews.
Immunology 2005 (5): 375–386

Types of Interferon
Interferon β-1a
Interferon β-
1a
Interferon β-
1b

Indication of Use
1. Relapsing Remitting MS (RRMS).
2. SPMS with superimposed relapse.
3. Clinically isolated syndrome (CIS).
(In SPMS with out relapse efficacy not established)

Comparison of IFNs
IFN-β DOSE
Clinical outcome MRI Outcome
Attack rate Change in
Severity
New T2
lesions
Total
Burden
IFN-β-1a
(Avonex)
30µg x IM
weekly once
18% 37% 36% 4%
IFN-β-1a
(Rebif)
44µg x SC
Thrice weekly
32% 30% 78% 15%
IFN-β-1b
(Betaseron)
250µg x SC
EOD
34% 29% 83% 17%
Ther Adv Neurol Disord (2011) 4(5)
281-296

Side effect of IFN
 Flu like symptoms ( fever & chills )(40-60%)
 Injection side reactions like erythema or skin
necrosis, more after SC route. (F>M).
 Hepatitis , Hypertonia
 Neutropenia, lymphocytpenia
 Depression ,Cognitive changes.
Curr Med Res Opin 24: 2679-2690.

Cont..
• So periodic monitoring of LFT and CBC is
required.
• Monitoring spasticity is also important as it
may increased during therapy .
These are contraindicated (relative) in
Pregnancy and breast feeding cat-C

Immunomudulators in multiple_sclerosis

Which is better interferon ?
CONS- More neutralizing antibody on higher doses which may having
neutralising effect on response.

Neutralizing Antibody (NAB)
• These appear during long term treatment
• These NABs are clinically relevant and reduce the
clinical efficacy of interferon beta.
• Subcutaneous interferon beta-1b (Betaseron,30-
40%) is the most immunogenic, followed by
subcutaneous interferon beta-1a (Rebif,15-25%),
with intramuscular interferon beta-1a (Avonex, 2-
10%) being the least immunogenic.
Ther Adv Neurol Disord (2013) 6(1) 3–17

When to check for NABs
Ther Adv Neurol Disord.
2013 Jan; 6(1): 3–17

What is new in
interferons ?
• Pegylated form of interferon
• More stability to its action.
• The recommended dosage
125µg X SC every 14 days.
• Available as prefilled syringe.
• Same contraindication as
plane interferons
US FDA Approved on
Aug-15 2014

2.Glatirmer Acetate
• Glatirmer Acetate is also known as
Co polymer-1 or copaxone.
• It is a synthetic random polypeptide of
four amino acid (glutamic acid, lysine,
alanine and tyrosine).
• Approved for RRMS in 1997.

Mechanism of Action
• Competitive binding to molecules of the major
histocompatibility complex (MHC) expressed on
antigen-presenting cells (APCs) in preference to
myelin protein antigens.
• Preferred binding of GA-MHC complexes over
MBP–MHC complexes to appropriate T-cell
receptors (TCR).
• A neuroprotective effect by expressing
neurotrophic factors such as brain-derived
neurotrophic factor (BDNF)
Neurology 45 (7): 1268–76

• The mean annualized relapse-rate was 0.59
per year for the GA treated patients and 0.84
per year for the placebo group, a 29%
reduction (P =0.007).
• New T2 lesion reduced by 38%.

Dose and side effect
 20 mg via subcutaneous injection (SC) once daily.
 Side effect
 Injection site reactions.
 Immediate post-injection reaction
 Transient flushing
 Chest pain with palpitations,
 Anxiety, or Dyspnea
 Pregnancy class B.

Which is better, IFN or GA ?
Lancet Neuro-Volume 7, N0-10,
p903–914, October 2008
Lancet neuro-Vol-8,no-10, p889–897, October 2009

Result
• There was no significant difference between
interferon beta-1a and Glatiramer acetate in
the primary outcome.
• No differences in relapse risk, EDSS progression, T1-
hypointense lesion volume between beta 1b and
Glatirmer acetate.
• Whereas injection-site reactions were more common
in patients treated with glatiramer acetate
(p=0·0005).

3.Mitoxantrone
• It is an Anthracenedione derivative with
antineoplastic, immunomodulatory effect.
• Exerts its action by
Intercalated with DNA and produces breaks in
it.
Inhibiting Topoisomerase inhibitor II involved
in DNA repair.
Interfering with RNA synthesis
• Approved in yr 2000

Dose and Indication of use
 Dose is 12mg/m2 IV infusion x every 3 monthly
 Maximum duration of use is 2-3 yrs.
 Used in SPMS(secondary progressive)
 In PRMS (progressive relapsing)
 In patients with worsening RRMS
 (Defined as pt whose neurologic status remains significantly
abnormal in between attacks)
 It should not be used as a 1st line agent in
RRMS or SPMS.
Clin Ther 28 (4): 461–74.

Evidence
Involving 51 relapsing-remitting multiple sclerosis patients
A statistically significant difference in the mean number of
exacerbations was observed
 A trend towards a reduction in the number of new lesions on
T2-weighted images in the mitoxantrone group

Adverse drug reaction
• Myelosuppression (periodic Blood count)
• Congestive heart failure (irreversible)
(ECHO before therapy)
• Secondary Acute myeloid leukemia (AML)( 1%)
• Skin problems at injection site.
• Gonadal dysfunction, Amenorrhea and alopecia.
Not to used in pregnancy or planning for it.
Max cumulative dose is 140mg/m2.
CNS Drugs. 2004;18(6):379-96.

• In 2005, the FDA issued a “black box”
warning.
• The warning advises heart monitoring for
anyone taking mitoxantrone for MS.
• The doctor is encouraged to monitor the
patient before beginning the drug and before
each injection.
• Yearly heart monitoring after stopping the
drug is also urged.

4.Natalizumab
• Natalizumab is a Humanized monoclonal
antibody.(MABs)
• It is an α4β1 integrin antagonist, a new class
of selective adhesion molecule inhibitors.
These inhibits lymphocyte from binding to
endothelial cells of BBB, there by preventing
its entry into brain.

Indication and dose
• Approved in 2006
• To be used as Monotherapy. In pt age >18 and less than 65 yrs
• 300 mg IV infusion x monthly once
• On head to head trial it was found it was superior to IFN β-1a
(Acta Neurologica Scandinavica,2012 Issue 5, 306-314 )
 Indicated in RRMS when 1st line tretment failed, not tolerated
or pt relapse on 1st line therapy.
Prescribe Int 17 (93): 7–10. 2008

• It is a randomised, multi-centre, placebo-
controlled, double-blind study of 942 people.
• The proportion of people who remained relapse
free was 67% in the treatment group compared
to 41% in the placebo group.
• 29% of placebo-treated patients had progressed,
compared to 17% of natalizumab-treated
patients.
AFFIRM study

Adverse drug reaction
• Headache
• Fatigue
• Urinary tract infections
• Depression
• Respiratory tract infection
• Less common: allergic or hypersensitivity
reactions( within two hours of infusion ).
Most serious are PML(progressive multifocal leuko
encephalopathy), liver failure and Herpes infection)

Contraindications
• Patients who are hypersensitive to this drug
• Patients who have or had progressive
multifocal leukoencephalopathy (PML)
• Patients who are immunocompromised,
including (immunosuppressant or anti
neoplastic therapies, HIV, leukemias,
lymphomas, etc.)

Progressive multifocal
leukoencephalopathy (PML)
• It is a serious infection due to JC virus reactivation
• Found only in 0.3% of patients only on long term therapy
(2yrs).
• Risk increase if pt having positive antibody against JC virus
or prior immunosuppressant use.
 So in all patients we should check for antibody against JC
virus prior to start the treatment also every 6 monthly if
initial tests are negative.
 There are no interventions that are known to cure PML
once it occurs but LVPP can be offered to fast remove the
Drug.
N. Engl. J. Med. 353 (4): 362–8

5.Alemtuzumab
• Alemtuzumab, a humanised monoclonal
antibody targeting CD52 antigen on
lymphocyte.,
• It causes depletion and repopulation of B
lymphocytes and T lymphocytes, leading to
long lasting changes in adaptive immunity.
• Approved by FDA in Nov-2014

Dose and indication
• 12mg IV infusion x 5 days then repeat the
same dose after 1 yr for 3 days.
• Used in- RRMS(relapsing forms of MS).
 It should generally be reserved for people
who have had an inadequate response to two
or more disease-modifying therapies.
Neurotherapeutics. 2013 Jan;10(1):29-33

Adverse reactions
• Infusion-related events including hypotension, rigors, fever,
bronchospasm.
• Autoimmune diseases like Thyroiditis, Haemolytic anemia
and thrmbocytopenia.
• Cancers like thyroid, melanoma and breast.
• Serious infections.
 Post-marketing reports of respiratory arrest, cardiac
arrhythmias, myocardial infarction.
Expert Rev Neurother 12 (3): 335–41

6.Fingolimod (FTY-720)
• It is a Sphingosisne-1-phosphate receptor
(S1P) Inhibitor.
• It sequesters lymphocytes in lymph nodes and
spleen there by preventing them to enter into
CNS.
• Approved by FDA in 2010
Clin Neuropharmacol.
2010 Mar-Apr;33(2):91-101

Dose and indication
• 0.5mg Once Daily (OD)
• Used in RRMS
• Reduces mean attack rate by 55% and new T2
lesion by 74 %
• Used as a 1st line oral therapy.

Adverse reactions
• Bradycardia (After first dose, 3% )
• Infections
• Progressive multifocal leukoencephalopathy
(PML)
• Macular edema (0.5 %) and PRES .
• Liver injury.
.
First Dose Monitoring: Observe all patients for
bradycardia for at least 6 hours after first dose with
hourly pulse and blood pressure measurement
N Engl J Med 2012; 366:339-347

Contraindications
• Recent (within the last 6 months) myocardial
infarction, unstable angina, stroke.
• History of Mobitz Type II 2nd degree or 3rd
degree AV block or sick sinus syndrome.
• Baseline QTc interval ≥500 msec.

Teriflunomide
• It is an active metabolite of Leflunomide.
• It inhibits Pyrimidine synthesis by blocking the
enzyme Dihydroorotase dehydrogenase.
• Both antiproliferative and anti-inflammatory
activities.
• Approved by FDA in Sept-2012

Dose and indication
• Dose- Oral Tab 7mg or 14 mg daily.
(In trials 14mg found more effective) TEMSO trial
• Indicated in RRMS.
• It reduces mean attack rate by 31 % and new
T2 lesion 70 %.

Adverse reactions
Common ADRs
Hair thinning, Nasopharyngitis, diarrhea, flu,
nausea, abnormal liver tests and paresthesias.
Less common: lowered WBC, increase in BP
and severe liver damage and renal failure.
Contraindicated in Pregnancy.(category-X)
Check for TB before starting the drug.

Lancet Neurol 2014; 13: 247–56

Dimethyl fumarate (BG-12)
• It is an oral Fumaric acid ester.
• Related to a drug “FUNADERM” used in
Psoriasis for many years in Germany.
• Act by anti-inflammatory and neuroprotective
effect.
• Also having Antioxidant effect mediated by
(nuclear factor (erythroid-derived 2)-like 2
(Nrf2)
• Approved in March 2013

Dose and indication
• Dose- 120 mg BD for one week and 240 mg BD
• Indication- 1st line in RRMS
• Side effect
• Flushing,
• Gastrointestinal complaint
• Rash
• Elevated liver enzymes
•PML
•Reduction in
blood
lymphocyte
counts

Precaution required
• Anaphylaxis and angioedema: Discontinue and
do not restart if these occur.
• PML: With hold at the first sign or symptom
suggestive of PML.
• Lymphopenia: Obtain a CBC including
lymphocyte count before initiating, after 6
months, and every 6 to 12 months thereafter.

Comparison of New immunomodulators

Phase 3 Trial drugs.
Daclizumab
Ocrelizumab
Cladribine
Laquinimod
Rituximab

Daclizumab
• It is a Humanized MAB act against CD25.
• Used in- RRMS and SPMS.
• IV infusion or SC every 4wkly
• Currently in phase-3 Study.

DECIDE study
• Methods-The study randomly assigned 1841 patients
to 150 mg of subcutaneous daclizumab HYP every 4
weeks or interferon β-1a, 30 μg given by
intramuscular injection once weekly. ACTRIMS group
END POINT
Interferon
β-1a
Daclizumb
Risk
Reduction
(%)
P Value
Annualized
relapse rate
0.393 0.216 45 <.0001
New/enlarging
T2 lesions
9.4 4.3 54 <.0001
New
gadolinium-
enhancing
lesion
1.0 0.4 65 <.0001

Ocrelizumab
• Humanized MAB
• Act against CD20
• Phase 3 trials- OPERA 1 &2 is going in RRMS
patients.
• ORATORIO study is going in PPMS patients.

Laquinimod
• It is a derivative of Linomide, having potent
anti-inflammatoryproperty.
• Immunomodulatory effect by
Ability to decrease the infiltration of
inflammatory cells into brain.
Decreased the expression MHC class II required
for antigen presentation.
Down-regulates pro-inflammatory cytokines, up-
regulates anti-inflammatory

• Phase-3 trials- ALLEGRO(Placebo) and BRAVO
trial(IFN group) in RRMS patients is
undergoing.

Rituximab
• It is a Monoclonal antibody
• Act on CD20 positive B cell.
• 1st Trial
• B-Cell Depletion with Rituximab in Relapsing–
Remitting Multiple Sclerosis.(NEJM 2008) showed
• As compared to placebo patients who received
rituximab (1000mg IV )had reduced counts of
total gadolinium-enhancing lesions at weeks 12,
16, 20, and 24 (P<0.001).

Cladribine
Cladribine, a synthetic purine nucleoside
analoge.
Act as anti-inflammatory agent by reducing T
cell population.
Used as oral tablets .
Lymphocytopenia is a common side effect.

In Pipeline
Drug name Mechanism of
action
Trial
Ofatumumab- Anti CD20 MIRROR trial in
RRMS
Vatelizumab- Humanized MAB
target VLA-2
EMPAIRE study
New S1P receptor
modulators
- -

To Summarize all drugs(Available in India)

1st line Drugs and indications

2nd line drugs and indications

How to use these immunomodulators in a
given case of Multiple sclerosis ?
MS
Treatment
Chronic
RRMS
80%
Progressive
MS
SPMS PPMS
Acute
relapse
Clinically
isolated
syndrome (CIS)

1.Treatment of Relapse
Relapse
True relapse
Functional
Impairement
Methyl
Prednisolone
1gm X IV
5 Days
LVPP 5 to 7 cycles
No
functional
imapirement
Symptomatic
therapy
Pseudo
relapse
Treat fever or
infection

• Plasmapheresis should not be offered for chronic
progressive or secondary progressive MS (Level A)
• Plasmapheresis may be considered in the
treatment of fulminant CNS demyelinating diseases
that fail to respond to high-dose corticosteroid
treatment (Level C).

2. Treatment for RRMS
• Immunomodulators should be started early.
• Conditions where treatment can be delayed.
Normal neurological exam
Single attack or low attack frequency
Almost normal MRI or low disease burden.
But untreated pts should be closely followed with
periodic MRI.
Multiple sclerosis
international ,Vol-2011

Management Approach in RRMS
 Induction Therapy-It is an aggressive approach in
which powerful immunosuppressant drugs are used
right from the beginning to tackle the disease process
hard and early.
 The goal is to “re-set” the immune system to avoid
epitope spreading and prevent early structural damage
 Escalation therapy- Defined as a therapeutic strategy
in which drugs with the best risk/benefit ratio are first
preferred and, if needed, drugs with increasing power
or toxicity (but not necessarily more effective) are
successively adopted.
Journal of the Neurological Sciences
277 (2009) S42 S45

E
S
C
A
L
A
T
I
O
N
I
N
D
U
C
T
I
O
N

Treatment Algorithm for RRMS
RRMS
Mild
EDSS <2.5
IFN β /GA
1.DMF
2.Fingolimod
3.Teriflunomide
Natalizumab
(JC Negative)
Moderate
or
Severe(EDSS > 2.5)
1.DMF
2.Fingolimod
3.Teriflunomide
Natalizumab

Neurology India | Jul-Aug 2009 |

2. Treatment of CIS
(clinically isolated syndrome)
• Patients treated with IFNβ-1a (30 μg) IM once a
week had a 37% conversion to clinically definite
MS after 2 years compared with 50% of patients
who received placebo. Lancet 2001;357: 1576–82.
• Glatiramer acetate (30 mg) SC daily was
associated with a 35% conversion to clinically
definite MS compared with 50% in the placebo
group.
• Lancet 2009; 374: 1503–11.

3. Treatment algorithm for
Progressive MS
Progressive
MS
SPMS
With
relapse
1.IFN-β1a
or 1b
Intolerance or
No response
1. Mitoxantrone
2.Azathioprine
3.Methotrexate
4.Pulse cyclophosphamide
Without
relapse
No proven
treatment
PPMS
Symptomatic
therapy
Off label
use

Take home message
• Immunomodualtory treatment is cornerstone
of management in MS.
• Treatment should start early before the
permanent axon loss.
• IFN or GA can be tried as 1st line in mild MS
or start with DMF or Fingolimod.(less experience)
• Availability of new oral drugs offer a great
relief from painful injection.(Limitation is less
experience with new drug ).

Immunomudulators in multiple_sclerosis

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