In-service presentation for pharmacists regarding the etiology, presentation, and treatment of multiple sclerosis.

1. MULTIPLE SCLEROSIS (MS)
PRESENTED BY: Sandeepkumar Balabbigari
CYCLE 7: Qualitas Pharmacy Services
February 2nd, 2016

2. OBJECTIVES
•Review the etiology and epidemiology of
the multiple sclerosis (MS)
•Identify the different types of MS and their
associated symptoms
•Understand the pharmacology of the
different MS treatments

3. DISEASE STATE OVERVIEW

4. BACKGROUND
•Most common inflammatory demyelinating
disease of the CNS
•Characterized by inflammation, demyelination, and
axon degeneration leading to chronic
neurodegeneration
•Myelin sheath is damaged
resulting in a breakdown of
communication
between the
CNS and periphery

5. EPIDEMIOLOGY
•More than 400,000 people in the United States
and more than 2 million people globally are
affected
•Mean age of onset ranges from 28 to 31 years
•Incidence varies geographically and genetically
•Smoking, Epstein-Barr Virus seropositivity, and other
immunologic conditions are other risk factors
•Total lifetime cost: >$4million

6. ETIOLOGY
•Exact cause remains unknown
•Widely accepted theory:
autoimmune disorder
•Autoimmunity is thought to be due to
molecular mimicry
•Some evidence indicates MS is an immune-mediated
disorder
•Inflammation with blood-brain-barrier disruption
•MS lesions and cerebrospinal fluid (CSF) may show
inflammatory T cells, B cells, and macrophages

7. DIAGNOSIS
•Clinical diagnosis based on
exclusion and history of symptoms
•Magnetic resonance imaging (MRI)
•Examine active areas of inflammation and scar tissue
•Cerebrospinal fluid (CSF)
•Identify certain antibodies and inflammatory cells
•McDonald Criteria
•Evaluate patients symptoms to determine if they are
suggestive of MS

8. SIGNS AND SYMPTOMS
•Highly variable between patients
•Most common initial symptom:
optic neuritis
•As MS progresses, common
signs and symptoms include:
•Extreme fatigue
•Heat intolerance
•Depression
•Memory impairment
•Muscle spasticity
•Chronic pain

9. TYPES OF MS
• Relapsing-remitting MS (RRMS)
• Most common (affects 80-85%
patients)
• Symptoms flare for 1-3 months, then
condition is stable in between
attacks
• Secondary Progressive MS (SPMS)
• Initially presents like RRMS, but
there is a progressive worsening of
symptoms
• Primary Progressive MS (PPMS)
• Steady, gradual neurological
decline
• Symptoms are constantly flared
with no period of stability
• Progressive Relapsing MS (PRMS)
• Progressive decline in neurological
function but with some relapse

10. TREATMENTS
•Managing acute exacerbations
•Corticosteroids
•Disease-modifying therapy
•Interferons
•Monoclonal Antibodies
•Other immunosuppressants

11. ACUTE EXACERBATIONS

12. MANAGING ACUTE EXACERBATIONS
•Indications for treatment include functionally
disabling symptoms with evidence of neurologic
impairment
•Treatment: methylprednisolone 500-1000 mg IV
daily for 3 - 10 days with or without an oral
taper (usually prednisone)
•High dose is essential to ensure T-cell death and
prevent destruction of myelin sheath
•Plasma exchange (PE) may benefit patients who
do not respond to corticosteroid therapy

13. CORTICOSTEROIDS: MECHANISM OF
ACTION
•Decreases formation, release, and activity of
inflammatory mediators and ultimately inhibits
migration to the area of injury
•Used for anti-inflammatory activity,
immunosuppressive properties, and
antiproliferative actions
•Also reverse the dilation and increased vessel
permeability in areas of inflammation

14. CORTICOSTEROIDS: SIDE EFFECTS
Short Term Side Effects
•Abdominal discomfort
•Weight gain
•Rounded face, upper back,
and belly
•Hyperglycemia, hypertension
•Behavioral changes
•Increased risk for infection
Long Term Side Effects
•Worsening short term
side effects
•Osteoporosis
•Adrenal insufficiency
•Glaucoma, cataracts
•Cardiovascular disease
•Slow wound healing
Side effects are managed by using the lowest dose for the shortest
time to achieve goals, treating preexisting conditions,
and monitoring

15. CORTICOSTEROIDS: INTERACTIONS
•Strong CYP3A4 Inducers: may decrease serum
concentration of corticosteroids
•Strong CYP3A4 Inhibitors: may increase serum
concentration of corticosteroids
•Immunosuppressants may enhance the risk for
hematologic toxicities and risk of infections

16. DISEASE-MODIFYING THERAPIES

17. DISEASE-MODIFYING THERAPIES
•Goal is to slow the progression of the disease
and reduce frequency and severity of relapses
•Not curative
•Treatment options
•Self-administered injections
•IV infusions
•Oral agents
•All agents are indicated to treat relapsing forms
of MS

18. SELF-ADMINISTERED INJECTIONS
•Interferon-β-1a
•Avonex® (IM)
 Rebif® (SubQ)
•Peginterferon-β-1a
•Plegridy® (SubQ)
•Interferon-β-1b
 Betaseron® (SubQ)
 Extavia® (SubQ)
•Glatriamer
•Copaxone® (SubQ)

19. INTERFERONS
Mechanism of Action
•Unknown
•Immunomodulator
•Suppresses immune
cell function and
proliferation
Adverse Drug Reactions
•Flu-like symptoms
•Injection site and
allergic reactions
•Depression and
suicidal ideation
•Hematologic abnormalities
•Congestive heart failure
•Hepatic injury

20. INTERFERONS
•Monitoring & ADR Management
•Alleviate flu-like symptoms with analgesics and/or
antipyretics
•Monitor baseline and changes in CBC, LFT, mental
status
•Assess for signs and symptoms of cardiac disease
progression
•Be aware of neutralizing antibodies
•No major drug interactions

21. GLATIRAMER (COPAXONE®)
Mechanism of Action
•Unknown
•Suppresses immune cell
function and proliferation
•Interfere with antigen
presenting cells (APCs)
Adverse Drug Reactions
•Immediate transient post-
injection reaction
•Lipoatrophy and skin
necrosis at injection site
•Increased risk for infection

22. GLATIRAMER
•Monitoring & ADR Management
•Avoid lipoatrophy and necrosis by following proper
injection technique and rotating injection sites
•Does not require as rigorous monitoring as interferon
products
•Interactions
•Other immunosuppressants may enhance the
immunosuppressive effect
•Toxic effects of vaccines are enhanced
•Therapeutic effects of vaccines are diminished

23. IV INFUSIONS
•Alemtezumab
•Lemtrada® (IV solution)
•Natalizumab
•Tysabri® (IV solution)
•Mitoxantrone
•Novantrone® (IV solution)

24. IV INFUSIONS: MECHANISMS OF ACTION
•Alemtezumab (Lemtrada®)
• Binds to CD52 antigens on immune cells’ surfaces,
which leads to the activation of cell death processes
•Natalizumab (Tysabri®)
• Binds to the α-4 subunit of integrin molecules to
block adhesion and migration of immune cells
•Mitoxantrone (Novantrone®)
• Inserts into and divides DNA and RNA strands and
prevents repair

25. IV INFUSIONS: ADVERSE DRUG REACTIONS
•Alemtezumab (Lemtrada®)
• >90% of patients in clinical trials experienced
infusion reactions
• Increased risk of Herpes Simplex Virus infections
•Natalizumab (Tysabri®)
• Box Warning: increased risk of developing
progressive multifocal leukoencephalopathy (PML)
• Hepatotoxicity and potential acute liver failure

26. IV INFUSIONS: ADVERSE DRUG REACTIONS
•Mitoxantrone (Novantrone®)
•Box Warning: myocardial toxicity and potentially-fatal
heart failure (HF)
• Maximum lifetime dose: 140 mg/m2 and must discontinue
if left ventricular ejection fraction (LVEF) is <50% or
significantly reduced
•Temporary blue discoloration of sclera and urine
•Menstrual disorders

27. IV INFUSIONS:
MONITORING & ADR MANAGEMENT
•Monitor CBC, signs of infection, dermatologic
changes
•Alemtezumab (Lemtrada®)
• Premedicate with high-dose corticosteroids
• Administer herpes viral prophylaxis
•Natalizumab (Tysabri®)
• Monitor for symptoms of PML
• Monitor for signs of liver injury
•Mitoxantrone (Novantrone®)
• Evaluate for cardiac-related signs/symptoms

28. IV INFUSIONS: INTERACTIONS
•Other immunosuppressants may enhance the
immunosuppressive effect
•Toxic effects of vaccines are enhanced
•Therapeutic effects of vaccines are diminished

29. ORAL AGENTS
•Dimethyl Fumarate
•Tecfidera® (capsule)
•Fingolimod
•Gilenya® (capsule)
•Teriflunomide
•Aubagio® (tablet)

30. ORAL AGENTS: MECHANISMS OF ACTION
•Dimethyl Fumarate (Tecfidera®)
•Activates the nuclear factor-like 2 (Nrf2) pathway
and increases interleukin-10, which have anti-
inflammatory and cytoprotective properties
•Fingolimod (Gilenya®)
•Sequesters lymphocytes within lymph nodes by
modulating the sphingosine 1-receptor
•Teriflunomide (Aubagio®)
•Inhibits de novo pyrimidine synthesis by inhibiting
dihydroorotate dehydrogenase, thus having a
ctoytostatic effect on lymphocytes

31. ORAL AGENTS: ADVERSE DRUG
REACTIONS
•Dimethyl Fumarate (Tecfidera®)
• Flushing
• GI events
• Increased risk of developing progressive multifocal
leukoencephalopathy (PML)
•Fingolimod (Gilenya®)
• Contraindicated in patients with cardiac abnormalities
• Bradycardia
• Hepatic dysfunction
•Teriflunomide (Aubagio®)
• Contraindicated in patients with severe hepatic impairment and in
pregnant women
• Box Warning: hepatic failure

32. ORAL AGENTS: MONITORING &
ADR MANAGEMENT
•Monitor CBC and signs of infection
•Dimethyl Fumarate (Tecfidera®)
• Take with aspirin (up to 325 mg PO) and food 30 minutes prior
to administration to decrease flushing and GI effects
• Withhold therapy if symptoms of PML appear
•Fingolimod (Gilenya®)
• First dose must be given in a healthcare setting due to the risk of
bradycardia
• Monitor cardiac function
• Monitor liver function and enzymes
•Teriflunomide (Aubagio®)
• Monitor liver function and enzymes

33. SUMMARY
•MS is an inflammatory disease that causes axonal
demyelination leading to chronic neurodegeneration
•Treatment of MS involves managing acute
exacerbations and slowing disease progression with
Disease-Modifying Therapy
•For most patients, the first-line treatment will be the
self-administered injectable interferons or glatiramer
•IV infusions and oral agents are options for patients
who cannot tolerate or whose condition does not
respond well to the self-administered medications

34. REFERENCES
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Neurol.2014;122:231–266.
4. Libbey JE, McCoy LL, Fujinami RS. Molecular mimicry in multiple sclerosis. Int. Rev. Neurobiol.2007;79:127–147.
5. Roach E.S. Is multiple sclerosis an autoimmune disorder? Arch. Neurol. 2004;61:1615–1616.
6. Buchman AL. Side effects of corticosteroid therapy. J Clin Gastroenterol. 2001;33:289–294. doi:
10.1097/00004836-200110000-00006.
7. Costello, K., J. Halper, and R. Kalb. "The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and
Current Evidence." (n.d.): n. pag. National MS Society. Multiple Sclerosis Coalition, Mar. 2015. Web. 19 Jan. 2016.
8. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: http://online.lexi.com. 19 Jan.
2016.
9. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at:
http://www.micromedexsolutions.com. 19 Jan. 2016.
10. Burnetti, Luigi. " Musculoskeletal Disorders: Multiple Sclerosis & Amyotrophic Lateral Sclerosis." Rutgers University.
Mar. 2015. Lecture.

35. THANK YOU!
QUESTIONS?

36. QUIZ TIME!