M.

A Sahraian
MS Fellowship
Associate Professor of Neurology
Tehran University of Medical
Science

Treatment
Of Multiple Sclerosis
Treatment Strategy
I. Treatment of relapses
II. Treatment of disease course
III. Symptomatic management

Treatment of Exacerbations
1. Definition of relapse
2. Psuedoexacerbations (Fever, Infections,
Drugs)
3. Some infections may lead to a bona fide
exacerbation

Treatment of Relapse
IV Methyle prednisolone 3000-10000mg in 5
days with or without taper
Oral steroids are effective but the
investigators concluded that it may be
premature to declare equivalence of oral and
IV steroids in terms of their efficacy and
safety.


Adverse Effects of steroids
Susceptibility to steroid side effects varies
from patient to patient.
GI (Dysgeusia, Pyrosis, Peptic Ulcer, GI
bleeding).
Psychiatric (Insomnia, Elevated mood,
Anxiety, frank psychosis).
Hyperglycemia
Increase appetite, Wt gain, Fluid retention
Hypokalemia
Less-common side effects
Hiccups
Elevated levels of liver enzymes
Pancreatitis
Anaphylactoid reactions.

Long-term corticosteroid
Osteoporosis
Acne
Moon facies
Hypertrichosis
Short-term steroid treatment is not expected to
suppress the endogenous hypothalamic-pituitary-
adrenal axis, obviating oral taper, although some
investigators have found the oral taper helpful in
alleviating let-downafter steroid treatment.
A useful rule of thumb is that the first time steroid
infusions are best performed under supervision,
either in a clinic or in an inpatient setting.

TREATMENT OF STEROID-
UNRESPONSIVE EXACERBATIONS
Plasmapheresis
Male , brisk reflexes, early initiation
Anemia, Heparin induced thrombocthemia
Parenthesis
Rehabilitation
IV cyclophosphamide???
IV Ig???
Disease Modifying
Therapies
Currently there are 8 diseases modifying
therapies approved by FDA:
1. Betaferon
2. Avonex
3. Rebif
4. Copaxone
5. Mitoxantrone
6. Tysabri
7. Extavia
8. Gilenya


Interferon Beta
Mechanism of Action
Reduce the production of the TNFa (tumor necrosis
factor alpha) and T-cells, known to induce damage to
myelin
Reduce inflammation by:
Switching cytokine production from type 1 (pro-
inflammatory) to type 2 (anti-inflammatory) cells
Increasing levels of interleuken 10 (IL-10)
Decrease antigen presentation, to reduce the attack on
myelin
Reduce the ability of immune cells to cross the
blood-brain barrier, by affecting adhesion molecules,
chemokines, and proteases
INF beta 1b
Lyophilized
250 mic 8 MIU
May be in room Tempreture until get ready;
CBC, LFT 3 to 6 months
Aproved for RRMS, CIS, SPMS (Europe
not US).

IM INF beta
Approved for RRMS, CIS
30 mic
6 MIU Antiviral activity


INF beta 1a sub q
Premixed formulation
When refrigeration is not available, it can
remain at room temperature for up to 30
days
Approved for RRMS

Aproved Drugs

Generally safe drugs
Adverse effects have been studied in these trials and
postmarketing studies.
They have common and rare adverse events.
They may cause discontinuation of treatment


Discontinue the drugs

INFB1b in RRMS 6% in two years
INFB1b in SPMS 12.5%
INFB1a in RRMS 4.4% (Avonex)
INFB1a in RRMS (Rebif ) 4%
Common Adverse Events

Flue like syndrome
Injection site reaction
Laboratory abnormalities
Flu like Syndrome

Variable combination of fever, chills, sweating,
muscle ache in about 75% of patients
Usually begin 2-8h after injections
Usually resolves in 24 h
In temperature sensitive and low BMI patients
may worsen the symptoms
Occur most frequently with initiation of
treatment and usually resolves in the first 3
moths
Treatment Modification

1. Administer at evening
2. Escalate the dose (If sever side effect reduce or
kept at the same level for a longer time)
3. In INFB1b (more common in young)
4. Inverse relationship with body surface area and
weight
5. NSAIDS, paracetamole, pentoxifyline,
corticoestroids
Analgesics

Antipyeretic analgesics 4 hours before , at injection
and 4 hours therafter
6 weeks prohylactically then therapitically
Corticosteroids

Corticosteroid may be coadmistered with
paracetamole
INF may be started at tapering schedule
Second line
30mg for two weeks followed by tapering in two other
weeks




Injection Site Reaction

50 -85% of the patients in the early phase of sub q
Mild erythema to sever necrosis
Injection site necrosis
Abscess formation rare with IM INF
Technical support
The solution should be warmed up gently
Different needles
Change injection site
Local icing of the injection site
Injection Site Reaction

Gently massage the site after injection
Topical hydrocortisone
Ibuprofen
Avoiding UV (solarium)
Topical steroid is contraindicated in skin necrosis
Anti bacterial /surgery
Discontinue drug
In some cases they have been continued
J Neurol Neurosurg Psychiatry.
1997 Apr;62(4):418
INF Beta Sub-Q
Neurol Neurosurg Psychiatry 1999;67:115 ( July )
INF Beta-1a Sub-Q
Neurol Neurosurg Psychiatry 1999;67:115 ( July )


Lipodystrophy with INF beta 1a
Laboratory Abnormalities

lymphopenia, neutropenia, Leukopenia
Anemia
Elevation of AST, ALT
Granulocytopenia

Liver Function Abnormalities
Liver function alterations occur in 8-38% of RRMS
Mostly asymptomatic



Hepatic Toxicity Grading


Grade 1: >1 to 2.5 Times of ULN
Grade 2: >2.5 to 5 Times of ULN
Grade3: >5 to 20 Times of ULN
Grade 4: 20 Times of ULN





What to do in elevated LFT?
Grade 4 or Jaundice: STOP INF permanently!
Grade 3: Reduce the dose or interrupt
and
Restate when enzymes return
to normal or to grade 1
Recurrent Grade 3: Reduce the dose permanently
or
discontinue the drug
permanently
Grade 2: CloselyMonitor
or
Managed similar to Grade 3
Educated patients for the symptoms
Percentage of Patients With At Least One
Abnormal LFT in The First 6 Months
Francis GS
2003
Drug Safty
Some Points Regarding Elevated LFT
Mostly occur in the first 3 months (50%) up to 1 year
Rarely need to discontinue the Drug
Potential Risk Factors:
Gender: Males are more susceptible to elevated ALT
Age: Ages older than 40 are more prone to elevated ALT
Concomitant Medication
Long use of Paracetamole with INF might damage the liver?
The drugs below seems safe in petients receiving INF-Beta:
Acetaminophen, Ibuprofen, SSRI, Opioids, Baclofen,
Anticonvulsives, Amantadine, Tizaninde, Dantrolen, COX
Inhibitors
Weight: Lower BMI does not necessarily predispose to
elevarted LFT



Limits of Acceptable Lab Values

Hb>9.4
WBC >3000
ANC> 1500
Lymphocyte >1000
Platelet> 75000
Bilirubin <2.5 times baseline
AST,ALT <5 times baseline
Alk.Phosphatase < 5 baseline
Regular Laboratory Checklist

CBC
LFT
Before starting therapy, 4 weeks months 3, then
every 3 months
If > accepted reduce 50-25%
Therapy should be interrupted if abnormalities are
sever
Recurrence of liver abnormalities are rare
Caution

There should be no reintroduction of therapy if liver
enzyme levels remain abnormal, with AST/ALT >10
folds or bili > 5
Accepted value on individual basis
T3 T4 TSH, 6 month
Menstural Abnormalities

Reported in 28% of patients in comparison to placebo
(13%)
Intermenstural bleeding
Spotting
Early or delayed
Gynecological evaluation
Decrease of fertility was not observed


Ross AP. International Journal of MS Care
Side effects
IFN beta 1a(
Avonex) / Placebo
(MSCRG, Ann Neurol 1996)

SC IFN beta 1a(
Rebif 44) /
Placebo
(PRISMS Lancet 1998)
IFN beta 1b( Betaferon)
/ Placebo
Neurology (1993)

Hepatic
abnormalities
No hepatic
abnormalities
5.4%/ 1% 14 patients/5 patients
Blood abnormalities Anemia 3%/1% in 2-9%/ 1-3.7% Lymphopenia 80%/65%
Neuropenia 17%/ 4%
Mood alteration
(Depression)
10-15% in both arms
(MSCRG)
24%/ 28% Not reported
Injection site
reaction
10-15% in both arms
(MSCRG)
40%/ 21%

69%/6%
Menstrual
Abnormalities
10-15% in both arms
(MSCRG)
Not reported Not reported
Side effects in Pivotal studies (MSCRG, PRISMS, IFN beta 1b study
group)
Thyroid Dysfunction

Autoimmune hyperthyroidism and hypothyroidism
Clinical thyroid disease and development of
autoantibodies most commonly in the first year after
treatment
Females are more affected but more persistent in
males

Rare Potential Side Effects

Fatal capillary leak syndrome (in a patient with
monoclonal gammapathy)
Intracerebral hemmorhhage
Anaphylaxis
TTP like syndrome
Demyelinating Neuropathy

Rare side effects of beta interferons
Occurrence of concomitant autoimmune
diseases
Hyper- and hypothyroidism
Myasthenia gravis(IFN beta 1b)
Raynaud's phenomenon (IFN beta 1b) (Cruz BA et al. Arq Neuropsiquiatr
2000) (SC IFN beta 1a ) (De Broucker T 2000)
Autoimmune hepatitis
Arthritis (INF beta 1b) (Altintas A. et al Mult Scler 2002)
lupus erythematosus
Aplastic anemia (SC IFN beta 1a) (Aslam AK Am J Ther. 2002)
Polyneuropathy (IM IFN beta 1a , SC beta 1a) (Eckstein D, et al. Neurology
2005)
Capillary leak syndrome
Anaphylaxis

The possibility of transient worsening of MS
symptoms in the early treatment phase
This may be due to upregulation of INF gama

Copaxone (glatiramer acetate)
Indication: Reduction of frequency of relapses in
patients with RRMS, CIS
Dose: 20 mcg SC once daily
Reduces the frequency of exacerbations
Moderately reduces the
development of new lesions


Copaxone Mechanism of
Action
Synthetic chain of four amino acids
Structurally resembles the myelin basic
protein molecule
Believed to block the immune system from
attacking myelin
Switches the immune response from TH-1 cells
(pro-inflammatory) to TH-2 cells (anti-
inflammatory) which could reduce myelin
damage

Copaxone:
Side Effects
Common
Injection site
reactions
Chest pain,
Anxiety (transient
20 to 30 minutes
not life threatening
but very scary)

Uncommon
Nausea
Vomiting
Dizziness
Lipodystrophy
Injection site skin
necrosis

Antineoplastics:
Novantrone (mitoxantrone)
Indication: Reduction
of relapse rate and
clinical disability in
patients with SPMS,
PRMS or worsening
RRMS
Dose: 12 mg/m
2
as
short IV
infusion (five minutes
to 15 minutes every
three months)

Antineoplastics:
Novantrone (cont.)
Reduces exacerbation rate
Prolongs time to first treated relapse
Improves EDSS scores versus baseline
Novantrone
Mechanism of Action
Inhibits or prevents the development of any
uncontrolled new or abnormal growth, such as a
neoplasm or tumor
Suppresses B-cell and T-cell immunity

Novantrone
Side Effects
Moderate to severe
Bone marrow suppression
Neutropenia (decreased WBC and ANC)
Thrombocytopenia (decreased platelets)
Acute myelogenous leukemia
Cardiac toxicity
Congestive heart failure (CHF)
Decreased left ventricular ejection fraction (LVEF)
Maximum cumulative dose 140 mg/m
2


Novantrone
Side Effects
Moderate to severe
Teratogenic effects
Fetal growth retardation in rats
Shortened gestation period
Excreted in breast milk
Mild to moderate
Increased liver enzymes
Nausea
Alopecia (hair loss - transient)

Novantrone
Contraindications
LVEF < 50%
CHF
Baseline neutrophil count < 1500 cells/mm
3
Pre-existing myelosuppression
Abnormal LFT
Pregnancy, breastfeeding
Cumulative lifetime dose 140 mg/m
2

Mitoxantrone Updates
Case-series including 5472 patients were identified; mean dose
of Mitoxantrone was 74.2 mg/m2 (range:12120 mg/m2).
Therapy related leukemia was diagnosed in 0.30% (1 in 333).
Onset was a median of 18.5 months following Mitoxantrone
treatment (range:460).
Over 80% of cases occurred in patients exposed to >60 mg/m2
with a relative risk of 1.44.


The accumulated Class III and IV evidence
suggests an increased incidence of systolic
dysfunction and acute leukemia
Systolic dysfunction occurs in 12% of patients
Congestive heart failure occurs in 0.4%.
leukemia occurs in 0.8%.
The number needed to harm is 8 for systolic
dysfunction and 123 for leukemia
Assess signs and symptoms of cardiac disesase with
history, PE, and ECG before initiation of therapy
Baseline quantitative evaluation of LVEF
Assess with history, PE, ECG and Echo before each
dose (with the same methods)
Patients should undergo yearly quantitative LVEF
evaluation after stopping Mitoxantrone.
Gilenya
72
T cell FTY720-
P
S1P
receptor
FTY720 results in internalisation
of the receptor S1P1


This blocks lymphocyte egress
from lymph nodes while sparing
immune surveillance by circulating
memory T cells
LN
Prevents T
cell invasion
of CNS
FTY720
traps
circulating
lymphocyt
es in
peripheral
lymph
nodes
Fingolimod :Sphingosine 1-phosphate (S1P)
receptor modulator
The most common side effects of
GILENYA include
Headache
Flu
Diarrhea
Back pain
Abnormal liver tests
Cough
Serious side effects
Slow Heart Rate
Infections
Macular edema (Diabetes, Uveitis)
Breathing Problems
Liver problems

Considerations prior to initiating
treatment
Recent (i.e. within 6 months) CBC should be available
Recent (i.e. within 6 months) liver transaminase and
bilirubin levels should be available
Patients using antiarrhythmics (including beta-
blockers, calcium channel blockers, Class Ia and Class
III antiarrhythmics), or with history of 2nd degree or
higher AV block, sick sinus syndrome, prolonged QT
interval, ischemic cardiac disease, congestive heart
failure, heart rate below 55 bpm, or irregular heart beat:
Obtain ECG if no recent ECG available (i.e. within 6
months)
Considerations prior to initiating
treatment
Baseline ophthalmologic examination
Patients without a history of chicken pox or without
vaccination against varicella zoster virus (VZV):
Consider serology. If patient is antibody negative, VZV
vaccine should be considered
Patients who get VZV vaccination should not begin
GILENYA treatment for one month

Treatment initiation (first dose)
Measure baseline pulse and blood pressure just before
first dose
Observe all patients for 6 hours after the first dose
If patient becomes symptomatic, repeat pulse and
blood pressure measurement, assess need for
additional monitoring procedures or clinical
intervention, and continue observation until the
symptoms have resolved

During treatment
Instruct patients to report symptoms of infection
Avoid live attenuated vaccines
Perform ophthalmologic examination 3-4 months after
starting GILENYA, and at any time if patient reports visual
disturbances. Perform regular follow-up ophthalmologic
evaluations in patients with diabetes mellitus or a history of
uveitis
Obtain spirometric evaluation of respiratory function and
diffusion lung capacity for carbon monoxide (DLCO) if
clinically indicated
Monitor liver enzymes in patients who develop symptoms
suggestive of hepatic dysfunction
After treatment discontinuation
Instruct patients to report symptoms of infection for
up to 2 months
If GILENYA is discontinued for more than 14 days, the
effects on heart rate and AV conduction may recur on
therapy re-initiation
Counsel women of childbearing potential on need for
continuing contraception for 2 months
Infections
The use of live attenuated vaccines should be
avoided during and for 2 months after treatment
with GILENYA because of the risk of infection.
VZV vaccination of antibody negative patients should
be considered prior to commencing treatment with
GILENYA, following which initiation of treatment with
GILENYA should be postponed for one month to allow
for full effect of vaccination to occur.
Consider suspending treatment with GILENYA if a
patient develops a serious infection
Macular Edema
0.4% of patients who received GILENYA
Predominantly within the first 3-4 months
Asymptomatic or blurred vision or decreases visual
acuity
Generally improved or resolved with or without
treatment after drug discontinuation
Increased risk of macular edema in patients who have
a history of uveitis or diabetes.

Respiratory Effects
Small dose-dependent reductions in (FEV1) and
Diffusion Capacity of the Lung for Carbon Monoxide
(DLCO) were observed in patients treated with
GILENYA, as early as 1 month after treatment
initiation.
The changes in FEV1 appear to be reversible after
treatment discontinuation.
Spirometric evaluation of respiratory function and
evaluation of diffusion lung capacity for carbon
monoxide (DLCO) should be performed during
therapy with GILENYA if clinically indicated.
Hepatic Effects
Recent (i.e. within last 6 months) transaminase
and bilirubin levels should be available before
initiation of GILENYA therapy.
Patients with pre-existing liver disease may be at
increased risk of developing elevated liver function
tests when taking GILENYA.

Natalizumab
(Tysabri)
Inflammatory Trafficking into the CNS
in Multiple Sclerosis
In the Inflammatory Process,
Natalizumab Could Intervene at Multiple Points
1. Leukocyte migration
from blood to tissue
3. Modulation of
leukocyte
apoptosis
2. Leukocyte priming
and activation
Natalizumab
Natalizumab
Natalizumab:
the only
targeted
therapy
86
Tysabri Indication in EU
Natalizumab is indicated as single disease modifying
therapy in RRMS to prevent relapses and delay
progression of disability
Indicated patients:

Patients who have failed to respond to IFN-

1 relapse in previous year on therapy
and 9 T2-lesions or 1 Gd-lesion
Patients with rapidly evolving, severe MS

2 disabling relapses in previous year
and 1 Gd-lesion or increased T2 burden
Prior to Treatment
Candidates to NA therapy should be carefully
evaluated in order to rule out active urinary or
pulmonary infections, viral chronic infections, active
infections induced by herpes simplex, herpes zoster,
fungal infections, or malignancies, with special
reference to retinal and skin melanoma
Wash out period


Monitoring of subjects receiving
natalizumab treatment
During NA treatment, the clinical course should be carefully
monitored, with at least quarterly and, preferably, monthly
evaluations
Brain MRI should be performed at the beginning of therapy or
within the previous 3 months
Brain MRI be repeated at least once a year
Blood tests, including a complete blood count, bilirubinemia
and ALT/AST, should be repeated on a monthly basis or at
least every 3 months (Italian)
There are no studies supporting the clinical usefulness of JC
viral load monitoring at the blood-urinary level; at the moment,
this is justified only at a scientific level
Natalizumab
Monotherapy
Steroid courses are allowed
Neutralizing Antibody
Subjects with allergic reactions;
Subjects with a clinical relapse;
Subjects with MRI evidence of disease activity.




PML Suspect conditions include

behavioral and cognitive disorders
Hemianoptic field defect
language disorders
Seizure
Key Learnings: PML Risk
Mean duration of natalizumab dosing at time of PML
diagnosis was approximately 2 years
Overall risk: 0.91 per 1000 patients (95% CI; range: 0.71 to 1.15
per 1000 patients)
The overall worldwide incidence of PML associated with
natalizumab therapy remains generally consistent with the
rate previously observed in clinical trials
Risk of PML increases with longer treatment duration and in
patients who had been treated with an immunosuppressant
prior to receiving TYSABRI; these risks appear to be
independent of each other
Patients with positive JCV serology

Biogen Idec Data on file.