15 - Multiple Sclerosis

Question 1

What is the classic description of MS?

Answer 1

• Immune-mediated demyelinating disease of the CNS
• 3:1 female:male incidence (up from 2:1)
• Leading cause of non-traumatic neurologic disability in young adults in North America
• Etiology is unknown (genetic + environmental)
• Disease course is variable
• Most commonly relapsing-remitting early on

Question 2

Describe the relapsing-remitting category of MS

Answer 2

• 85% of px present w/ relapsing-remitting MS (RRMS)
• 1st symptomatic demyelinating attack is “clinically isolated syndrome” (CIS)
• MS is defined by a second event representing dissemination in space and time
• New diagnostic criteria allow lab evidence (specifically MRI) to confirm MS

Question 3

What is defined as a relapse in clinical trials?

Answer 3

• Relapse is defined as a neurologic episode attributable to a lesion in the CNS associated w/ an objective change on exam lasting at least 24 h in the absence of fever or other potential triggering factor (pseudo-relapse)
• MRI studies demonstrate many more lesions than clinically apparent relapses

Question 4

Describe the secondary progressive category of MS

Answer 4

• Most px w/ RRMS develop progressive disability in the absence of ongoing relapses – secondary progressive MS (SPMS)
• About 50% have SPMS 10 years from diagnosis
• However, 10-20% have minimal physical disability after 20 years (“benign” MS)

Question 5

Describe the primary progressive category of MS

Answer 5

• 15% of px present w/ progression at onset w/ no relapses – primary progressive MS (PPMS)
• Usually have progressive myelopathy w/ less cerebral involvement than RRMS
• May not be a homogeneous group as some may be similar to SPMS but w/o recognized clinical relapses

Question 6

Immunology of MS

Answer 6

• Balance of evidence suggests MS is an autoimmune disease
• Autoimmunity as a breakdown of self-tolerance may be over-simplification
• Genetics may provide susceptibility
• Environmental factor(s) may provide “danger signal” to initiate immune attack
• Generally considered to be a T-cell mediated disease, specifically TH1-mediated
• Now recognizing role of newly described TH17 cells
• Increasing interest in the role of B cells
• Innate immune system probably helps regulate adaptive immunity as well

Question 7

Natural hx of MS

Answer 7

• Disease is highly variable, even within families
• Rare fulminant forms may lead to early death
• Generally, life expectancy is only a few years shorter than average (becoming bed-bound decreases life expectancy)
• About 50% of px require assistance for walking after 15 years
• Prognostic factors are highly unreliable

Question 8

Genetics of MS

Answer 8

• 25-30% concordance in monozygotic twins
• About 1/30 risk of MS in 1st degree relatives compared to about 1/1000 risk in population
• Most consistent genetic linkage is w/ the MHC region on chromosome 6 (HLA-DR2 and HLA-DQw6)
• More than 100 risk alleles have now been identified
• Each individual risk allele contributes a small amount of risk

Question 9

Clinical measurements in MS for inflammatory disease activity

Answer 9

• Relapse rate (annualized)

- Accrual of new MRI lesions

Question 10

Clinical measurements in MS for disability progression

Answer 10

• EDSS (complex nonlinear scale)

- MSFC (weighted score based on tests of ambulation, hand coordination, and cognition)

Question 11

Clinical presentation of MS

Answer 11

• Sx of a relapse depend on location of the lesion
• Common presentations include:
• • Optic neuritis
• • Transverse myelitis (sensory, motor, bladder)
• • Brainstem syndromes
• • Cerebellar syndrome

Question 12

Diagnosing MS – 2017 Mcdonald Criteria

Answer 12

• Hx must be consistent w/ demyelinating disease
• Exclude MS mimics
• MRI has improved diagnostic sensitivity
• CSF analysis can be helpful (added to 2017 criteria)
• Bloodwork aims to rule out other diagnoses

Question 13

Pharmacotherapy of MS relapses

Answer 13

• Goal is to shorten duration and severity of relapse
• No effect on long-term outcome
• High dose IV or oral corticosteroids
• • Methylprednisolone 1000 mg IV daily x 3 days
• • Methylprednisolone 500 mg PO daily x 5 days (rarely used in Canada)
• • Prednisone 1250 mg daily x 3 days

Question 14

Pharmacotherapy of MS – CIS (clinically isolated syndrome)

Answer 14

• CIS = first symptomatic presentation of an inflammatory demyelinating event consistent w/ MS
• Optic neuritis tx trial long-term follow-up shows that ~50% of CIS px had clinically definite MS after 15 years
• • 25% of px w/ no MRI lesions at baseline
• • 65% of px w/ 1-2 MRI lesions at baseline
• • 78% of px w/ >2 MRI lesions at baseline
• Clinical trials have shown benefit of tx of CIS for glatiramer acetate, interferon-beta, teriflunomide, and minocycline
• Actual benefit is probably minimal given sensitivity of MRI for disease activity allowing early diagnosis of clinically definite MS

Question 15

Pharmacotherapy of MS – RRMS

Answer 15

• 1st line therapies include interferon-beta, glatiramer acetate, dimethyl fumarate, and teriflunomide
• Ocrelizumab may be approved first-line for highly active RRMS
• 2nd line agents include mitoxantrone, natalizumab, fingolimod, and alemtizumab
• Excellent long-term data regarding safety of interferon-beta and glatiramer acetate products
• • Evidence suggests minimal long-term benefit for reducing incidence of progression
• Newer first-line agents include 2 oral agents and possibly, one biologic agent (Tecfidera, Aubagio, Ocrevus)
• The rise of 2nd (or 3rd) line agents – higher efficacy w/ higher risk and/or higher cost (Tysabri, Gilenya, Lemtrada)

Question 16

Interferon-beta products for MS

Answer 16

• Interferon-beta-1b SC 3 times/week (betaseron and extavia)
• Interferon-beta-1a SC 3 times/week (rebif-22 and rebif-44)
• Interferon beta-1a IM weekly (Avonex)
• Pegylated interferon-beta-1a SC q2weeks (plegridy)
• Pivotal clinical trials generally showed 33% reduction in relapses vs. placebo
• Px may develop neutralizing Abs which abrogate the clinical effect
• SE = flu-like phenomena, injection-site reactions, elevation of liver transaminases, thyroid dysfunction, headaches, depression

Question 17

Glatiramer acetate products for MS

Answer 17

• GA 20 mg SC daily (copaxone and glatect)
• GA 40 mg SC 3 times/week (copaxone forte)
• Initial clinical trial data showed 33% reduction in relapses vs. placebo
• SE = injection-site reactions, lipoatrophy, idiopathic post-injection reactions, allergy

Question 18

Tecfidera for MS

Answer 18

• Dimethyl fumarate 240 mg po BID
• Higher efficacy and oral, but high rate of SE and risk of PML in px w/ sustained lymphopenia
• SE = flushing & GI sx

Question 19

Aubagio for MS

Answer 19

• Teriflunomide 14 mg po daily
• Likely no better efficacy than injectables (possibly worse?)
• Only 1st line agent to meet prevention of sustained disability outcome in 2 RCTs
• Teratogenic
• SE = alopecia, hepatic dysfunction, GI sx

Question 20

Ocrevus for MS

Answer 20

• Ocrelizumab 600 mg IV q6months

- Will likely only be approved 1st line for highly active px

Question 21

Tysabri for MS

Answer 21

• Natalizumab 300 mg IV monthly
• Excellent efficacy (67% reduction in relapses) and tolerability
• Neutralizing Abs abrogate clinical effect
• Risk for progressive multifocal leukoencephalopathy secondary to JC virus infection

Question 22

Gilenya for MS

Answer 22

• Fingolimod 0.5 mg po daily
• High efficacy (>50% reduction in relapses)
• Generally, well tolerated
• Risk of symptomatic bradycardia; highest in first 6 h but present for up to 4 weeks
• Risk of macular edema and respiratory dysfunction (reduced FEV1 & DLCO)

Question 23

Lemtrada for MS

Answer 23

• Alemtuzumab 12 mg IV daily x 5 days in year one, then 12 mg IV daily x 3 days in year two
• Exceptional efficacy w/ an active comparator (Rebif 44 mcg)
• Induction therapy w/ sustained efficacy over years w/ no further tx
• Risk of other autoimmune conditions w/ immune reconstitution (autoimmune thrombocytopenia, autoimmune thyroiditis/Graves)
• Increased risk of infections
• High rate of infusion reactions which can be severe
• Px must commit to monthly bloodwork for 5 years to allow early identification of serious SE

Question 24

Other drugs for RRMS

Answer 24

• Zinbryta -> daclizumab 150 mg SC monthly; unlikely to ever be used due to high risk of hepatic failure
• Cladribine 3.5 mg/kg po divided over 2 years (10 or 20 mg daily x 4-5 days in each of 2 weeks in years 1 & 2)
• Mitoxantrone 12 mg/m2 IV q3months up to maximum cumulative lifetime dose of 140 mg/m2; high risk of cardiac toxicity that can manifest years after d/c, so not used much
• Cyclophosphamide and rituximab can be used off-label in selected cases

Question 25

Pharmacotherapy for SPMS

Answer 25

- Betaseron (Ifn beta-1b) was approved for tx of SPMS in px who have ongoing relapses in addition to progression - 2 clinical trials of betaseron for SPMS had conflicting results - - European trial showed benefit in reducing progression; North American trial showed no benefit - - Major difference between the trials was the inflammatory activity of the px enrolled (European trial enrolled a large % of px w/ ongoing disease activity as shown by relapses and MRI) - Mitoxantrone is also approved for tx of SPMS but is rarely used due to safety issues

Question 26

Pharmacotherapy for PPMS

Answer 26

- Ocrelizumab 600 mg IV q6months (Ocrevus) - First approved therapy for PPMS (mitoxantrone and Ifn beta-1b had been approved for SPMS only) - Absolute effect on slowing progression is modest - Clearly most beneficial in px w/ inflammatory disease activity on MRI

Question 27

Symptomatic therapies for MS

Answer 27

- Multiple sx present in MS which can be treated pharmacologically or non-pharmacologically - Fatigue, depression, pain, spasticity, sphincter dysfunction, sexual dysfunction