treatment of multiple sclerosis https://www.youtube.com/watch?v=vEjQszROZZY&t=1256s

1. NATALIZUMAB
By
Dr Mohammud Ibraheem

2. Monoclonal Antibodies for MS
1) Natalizumab
2) Alemtuzumab
3) Ofatumumab
4) Orelizumab
5) Rituximab
6) Opicinumab (phase II study)
7) Elezanumab (withdrown 2018)
8) Ublituximab (phase III study)

3. What is natalizumab ?
Natalizumab is a humanized monoclonal antibody.
It was approved to treat MS in 2004, but after reported
cases of death due to PML during treatment, the FDA
removed the drug from the market.
In 2006, the FDA reintroduced the drug

4. Mechanism of action
Natalizumab binds to α4β1-integrin and blocks its interaction
with VCAM-1.
Alpha-4 beta-1 integrins are adhesion molecules aid in
the chemotaxis of leukocytes to sites of inflammation
throughout the body.
It decreases inflammation by blocking leukocytes from
crossing the blood vessel.

6. Indications
Natalizumab is FDA-approved for the treatment of:
1. MS
I. RRMS
II. SPMS
III. Clinical isolated syndrome
2. Crohn's disease.

7. Administration
Natalizumab is administered through IV every 28 days at a
TOUCH Prescribing Program approved site.
The recommended dose is 300 mg/15 mL; this dose can be
modified according to the response.
The infusion takes 1 hour, and the patient is then monitored
closely for an hour for any significant side effects.

8. Efficacy of natalizumab
In RRMS; 68% reduction in relapses, an 80%
reduction in new or enlarging T2 cerebral lesions
and a 96% reduction in gadolinium-enhancing
lesions on MRI after a year.
This represents a 2 folds improvement in
efficacy compared to what has been reported
with interferon and glatiramer acetate.
(Polman et al, 2006; the AFFIRM study)

9. Contraindications of natalizumab
i. Hypersensitivity
ii. Impaired immunity as in hematological diseases or
rheumatological disease
iii. Active/history of progressive multifocal
leukoencephalopathy

10. Side effects of
natalizumab

11. Side effects of natalizumab
A. Common side effects
B. CNS infection; herpes zoster, herpes simplex
encephalitis, tuberculosis
C. Hepatotoxicity
D. Thrombocytopenia
E. Progressive multifocal leukoencephalopathy

12. Common side effects
1) GIT adverse effects
A. Dyspepsia and Diarrhea
B. Abdominal pain and Flatulence
C. Constipation
2) Infections
A. Sinusitis
B. Vaginal infections
C. LRTI and UTI
D. Skin laceration
3) General
A. Fatigue
B. Arthralgia
C. Peripheral edema
D. Vertigo
4) Urinary adverse effects
A. Incontinence
B. Urgency
C. Frequency
5) Infusion related reactions
A. Headache
B. Flushing, Erythema
C. Nausea
D. Acute hypersensitivity reaction
6) Other side effects
A. Pruritus, Dermatitis
B. Amenorrhea, Irregular
menstruation
C. Tremor

13. progressive multifocal
leukoencephalopathy (PML)
PML is a rare brain disease caused by infection by, or re-
activation of the John Cunningham virus (JC virus).
PML can cause severe disability or death.
PML is an opportunistic infection.
Till March 2022

14. Risk factors for development of PML
1) Weakened immune systems
2) Autoimmune diseases such as multiple sclerosis, lupus
and rheumatoid arthritis who are treated with disease-
modifying therapies

15. PML with natalizumab
Factors that increase the risk of PML in patients treated
with NATALIZUMAB:
1) The presence of anti-JCV antibodies.
2) Longer treatment duration (24 months or more)
3) Prior treatment with an immunosuppressant

16. clinical presentation of PML
The clinical presentation of PML is heterogeneous and
include focal and nonfocal neurologic deficits affecting
neurobehavioral, motor, language, and visual functions :
1. Loss of coordination
2. Loss of language ability (aphasia)
3. Memory loss
4. Visual manifestations
5. Weakness of the legs and arms or gets worse

17. Imaging of PML
PML in MRI presents as one
or more peripheral and
bilateral areas of T2/FLAIR
hyperintensity in the WM
but asymmetric distribution.
The parietal, occipital, and
frontal lobes are the most
frequently involved.

18. Imaging of PML
Lesions vary in shape and
size, growing larger and
becoming confluent as the
disease progresses.
Lesions involve the subcortical
U-fibers in nearly all cases.
This subcortical involvement
leads to a sharp border
between the superficial aspect
of the lesion and the overlying
cortex, while the deeper border
remains ill defined.

19. Imaging of PML
PML can infiltrate the corpus
callosum but isolated corpus
callosal involvement is rare.
Deep gray matter involvement
has been reported in
conjunction with white matter
lesions in up to 5–31% of
patients.
The thalami are more
commonly involved than the
basal ganglia.
Cortical involvement is
reported in some cases.

20. Diagnosis of PML
I. The clinical manifestations
II. Brian MRI
III. CSF PCR for JCV
Negative CSF PCR for JCV does not exclude PML as viral
loads can be very low (<100 copies/mL)
In difficult cases where the clinical, radiologic, or laboratory
findings are inconclusive, brain biopsy can also be
performed

21. Treatment of PML
Immediate termination of causative medication. This is
achieved with plasma exchange or immunoadsorption,
which clears natalizumab from the alpa 4 bet1 receptors. 3
to 5 PLEX sessions over 2 weeks are recommended;
however, more or fewer sessions may be needed.
In some cases treatment may include treatment with
antiretroviral medication.

22. Prognosis of PML
The mortality rate in natalizumab associated PML is
approximately 22% .
This is considerably lower than the more common HIV-
AIDS associated form, which has been reported in up to
40–50% in the HAART era

23. PML-IRIS
In PML patients treated with PLEX, once clearance of
natalizumab has been achieved, many patients will
experience rapid worsening of neurologic symptoms.
This is due to an exuberant immune response to viral
antigens resulting in inflammatory mediated damage to
infected and noninfected neuronal and glial tissue.
PML-IRIS may occur following discontinuation of
natalizumab in the absence of PLEX, it occur later, usually
about 90 days after last dose, reflecting the longer time
necessary to clear the drug

24. Imaging of PML-IRIS
The existing PML lesions
increase in size and coalesce as
more white matter becomes
involved. This is accompanied
by increasing edema, cerebral
swelling, and mass effect, which
are not typical of PML.
Contrast enhancement develops
or increases and exhibits
variable patterns, including
patchy, punctate, irregular and
hazy, ill-defined enhancement
patterns

25. Treatment of PML-IRIS
The most common therapy for PML-IRIS is high dose
corticosteroids in an attempt to control the deleterious
effects of the exuberant inflammatory cascade.

26. Prognosis
PML-IRIS phenomenon is associated with worsened EDSS
scores and up to 30% mortality.

27. Thank you