1. Treatment of Multiple Sclerosis
2/13/18

3. Key Things That Haven’t Changed:
MS is best diagnosed by a clinician with MS-related expertise with support of imaging and other tests.
Dissemination of lesions in the nervous system in space and time are required, but the revisions provide additional avenues for obtaining supporting evidence of dissemination.
The need to ensure there is no better explanation for the individual’s symptoms remains an essential consideration.
The McDonald Diagnostic Criteria apply to individuals experiencing a typical clinically isolated syndrome -- CIS. (CIS is a first episode of neurologic symptoms typical of an MS relapse in a person not known to have MS.)

4. What Are the Key Changes? In individuals with typical CIS:
CSF oligoclonal bands -- Positive findings of oligoclonal bands in the spinal fluid can substitute for demonstration of dissemination of lesions in time in some settings.
Types of lesions – Both asymptomatic and now symptomatic MRI lesions can be considered in determining dissemination in space or time. (This does NOT include MRI lesions in the optic nerve in a person presenting with optic neuritis.)
Site of lesions – Cortical lesions have been added to juxtacortical lesions for use in determining MRI criteria for dissemination of lesions in space.

6. Why do we need to treat MS?
Progressive disease
Patients acquire significant disability over time
50% of all individuals diagnosed with MS will need at least a unilateral aid to walk 15 years after the onset of illness

7. Which patients need treatment?
Clinically Isolated Syndrome with MRI findings
Relapsing-Remitting MS
Secondary Progressive MS with activity
Primary Progressive MS with activity

9. “Predicting the course” of MS
Clinical features at onset
Motor worse than sensory
Polyregional worse than monosymptomatic
Early bladder involvement, poor prognosis
Incomplete recovery from initial attack
Short interval between attacks

11. Strategies for use of DMT
Step Therapy
Start with more potent therapy
Induction therapy

13. DMT
Self-injected
Oral
Intravenous

14. Self-injected Interferon beta-1b (Betaseron)
Interferon beta-1a (Avonex)
Glatiramer acetate (Copaxone)
Interferon beta-1a (Rebif)
Peginterferon beta-1a (Plegridy)
Daclizumab (Zinbryta)
Avonex is IM weekly
Rebif is SC three times weekly
Glatiramer acetate (Copaxone)

15. Interferons PROS CONS Moderate Effectiveness Long safety record
Fewer injections than GA (sometimes)
CONS
Moderate effectiveness
Tolerability (Flu-like symptoms, mood changes, blood monitoring)
Neutralizing antibodies

16. Glatiramer acetate (Copaxone)
PROS
Long safety record
Better tolerated than interferons
Moderate efficacy
No neutralizing antibodies (**on RITE)
CONS
Daily injection or three times weekly
Injection site reactions
Less reduction of MRI lesions

18. Daclizumab (Zinbryta) MOA
IL-2 receptor blocking antibody
IL-2 is a cytokine signaling molecule in the immune system. IL-2 discriminates b/t “foreign” and “self.”
Il-2 mediates its affects by binding to IL-2 receptors on lymphocytes
Therefore by blocking this receptor, there is reduced inflammatory lymphocyte proliferation

19. Daclizumab (Zinbryta)
PROS
Once monthly SC injection
CONS
Hepatic injury
Immune-mediated disorders
Increased risk of infections
Generally need to have failed to other MS medications

20. Oral Fingolimod (Gilenya) Terifulnomide (Aubagio)
Dimethyl fumarate (Tecfidera)

21. Fingolimod (Gilenya)
RITE!!- Fingolimod is a sphingosine-1 phosphate-receptor modulator approved for oral therapy for relapsing remitting multiple sclerosis. Activating the first subtype of the sphingosine-1 phosphate-receptor reduces lymphocyte recirculation from the lymph nodes resulting in functional immunosuppression. Activating the third subtype of the sphingosine-1 phosphate-receptor reduces heart rate and prolongs the PR interval. The cardiac effects of fingolimod are maximal after the first dose but persist for about 14 days

22. Fingolimod (Gilenya) PROS CONS Moderate to high efficacy
50% better than weekly IFNB-1a
Daily oral capsule
CONS
Infections (PML, Crypto, Herpes)
Cardiovasular
Macular edema
Monitoring requirements

25. Terifulnomide (Aubagio)
Metabolite of leflunomide (used in RA)
inhibit dihydroorotate dehydrogenase (DHODH), a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway required by rapidly dividing cells.
Has a cytostatic effect on rapidly dividing T and B lymphocytes in the periphery (so therefore can’t get into CNS)

26. Aubagio moa

27. Terifulnomide (Aubagio)
PROS
Moderate effectiveness
Once daily oral medication
Statistically significant reduction in disability progression in 2 trials
Lefllunomide has an extensive good safety record
CONS
Pregnancy category X
Hair loss
Liver monitoring monthly x 6

29. Dimethyl fumarate (Tecfidera) MOA
Unknown
thought to constrain immune cells and prevent them from attacking the body’s nervous system
Promotes anti-inflammatory and cytoprotective activities mediated by Nrf2 pathway

30. Dimethyl fumarate (Tecfidera)
PROS
Moderate to high effectiveness
Oral medication
CONS
Twice daily doing
Side effects (flushing, GI symptoms)
Risk of PML

32. Intravenous Mitoxantrone (Novantrone) Natalizumab (Tysabri)
Alemtuzumab (Lemtrada)
Ocrelizumab (Ocrevus)

33. Mitoxantrone (Novantrone)
Disrupts DNA synthesis and repair
Inhibits B cell, T cell, and macrophage proliferation
Impairs antigen presentation

34. Mitoxantrone (Novantrone)
PROS
Effective
CONS
Cardiotoxicity
Blood cancer
Pregnancy Category D

35. Natalizumab (Tysabri) MOA
Monoclonal antibody
Binds to α4 integrin(common on all white blood cells, except neutrophils), thus reducing trafficking of lymphocytes into the CNS
This prevents autoreactive leukocytes from exiting blood vessels and entering target organs to cause inflammation.

36. Natalizumab (Tysabri)
PROS
Highly effective
Well tolerated
Intravenous infusion every 4 weeks
CONS
Progressive multifocal leukoencephalopathy (PML)
Infusion is 3 hours every 4 weeks
Rebound activity 3-4 months after stopping

40. Alemtuzumab (Lemtrada)

41. Alemtuzumab (Lemtrada)
PROS
Once per year infusion x 2 (hopefully)
Showed RRR for disability at 2 years compared with Rebif
Significant percentage remaining relapse free at year 2 compared with Rebif
CONS
Infusion reactions (common: skin rash, fever, headache, muscle aches)
Usually reserved for patients that have failed 2 or more DMT
Risk of autoimmunity (thyroid, ITP, glomerular nephropathies
Risk of malignancy (thyroid, melanoma, lymphoproliferative)
Annual skin exams
Monthly labs until 48 months after last treatment
Available only through REMS

44. Ocrelizumab
precise mechanism of action is not known but is presumed to involve binding to CD20, a cell surface antigen on pre-B and mature B lymphocytes, causing antibodydependent and complementmediated cytolysis

45. Ocrevus Side Effects
infusion reactions (potentially life-threatening) -infections -possible increased risk of malignancies (including breast cancer, which occurred in 6 of 781 treated patients and no placebo patients)

46. Disability in PPMS
mean change [improved performance] in 25ft walk performance baseline to week 120: 55.1% placebo; 38.9% treated: relative reduction 29.3% (p=0.04)