15 - Multiple Sclerosis Flashcards Preview

Year 3 - Clinical (Winter) > 15 - Multiple Sclerosis > Flashcards

Flashcards in 15 - Multiple Sclerosis Deck (27)
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1
Q

What is the classic description of MS?

A
  • 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
2
Q

Describe the relapsing-remitting category of MS

A
  • 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
3
Q

What is defined as a relapse in clinical trials?

A
  • 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
4
Q

Describe the secondary progressive category of MS

A
  • 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)
5
Q

Describe the primary progressive category of MS

A
  • 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
6
Q

Immunology of MS

A
  • 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
7
Q

Natural hx of MS

A
  • 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
8
Q

Genetics of MS

A
  • 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
9
Q

Clinical measurements in MS for inflammatory disease activity

A
  • Relapse rate (annualized)

- Accrual of new MRI lesions

10
Q

Clinical measurements in MS for disability progression

A
  • EDSS (complex nonlinear scale)

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

11
Q

Clinical presentation of MS

A
  • Sx of a relapse depend on location of the lesion
  • Common presentations include:
    • Optic neuritis
    • Transverse myelitis (sensory, motor, bladder)
    • Brainstem syndromes
    • Cerebellar syndrome
12
Q

Diagnosing MS – 2017 Mcdonald Criteria

A
  • 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
13
Q

Pharmacotherapy of MS relapses

A
  • 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
14
Q

Pharmacotherapy of MS – CIS (clinically isolated syndrome)

A
  • 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
15
Q

Pharmacotherapy of MS – RRMS

A
  • 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)
16
Q

Interferon-beta products for MS

A
  • 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
17
Q

Glatiramer acetate products for MS

A
  • 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
18
Q

Tecfidera for MS

A
  • 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
19
Q

Aubagio for MS

A
  • 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
20
Q

Ocrevus for MS

A
  • Ocrelizumab 600 mg IV q6months

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

21
Q

Tysabri for MS

A
  • 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
22
Q

Gilenya for MS

A
  • 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)
23
Q

Lemtrada for MS

A
  • 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
24
Q

Other drugs for RRMS

A
  • 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
25
Q

Pharmacotherapy for SPMS

A
  • 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
26
Q

Pharmacotherapy for PPMS

A
  • 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
27
Q

Symptomatic therapies for MS

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