15 - Multiple Sclerosis Flashcards
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
