Multiple Sclerosis Flashcards
What are some etiology factors of MS?
- MS susceptibility genes (HLA class II genes)
- Late onset/severe childhood infections (e.g., EBV)
- Viral infections may also be trigger for new exacerbations
- Increased vitamin D may be protective
What is the pathophysiology of MS?
- Auto-reactive T lymphocytes are activated, cross into the CNS, and attack myelin
- Damage to both myelin and underlying axon
- Damage to grey and white matter caused by inflammation involving activation of T cells
- T cells differentiate into T helper cells that induce pro-inflammatory response in which cytokines further activate B cells and macrophage
What are some primary clinical presentations of MS?
- Optic neuritis
- Gait problems
- Paresthesia
- Pain
- Spasticity
- Weakness
- Speech difficulty
- Bowel/bladder dysfunction
- Sexual dysfunction
- Tremor
- Cognitive changes
What are some secondary clinical presentations of MS?
- Recurrent UTI
- Urinary calculi
- Decubiti
- Muscle contractures
- Resp infections
- Poor nutrition
What are some tertiary clinical presentations of MS?
- Financial problems
- Personal/social problems
- Vocational problems
- Emotional problems
Relapsing-remitting MS (RRMS)
- Clearly defined relapses with full recovery or with residual deficit following recovery
- 85%
Secondary progressive MS (SPMS)
- Disease progression with or without occasional relapses, minor remissions and plateau
- 50% will progress to this form
Primary progressive MS (PPMS)
- Progressive from onset with occasional plateau and temporary improvements
- 10%
Progressive relapsing MS (PRMS)
- Progressive from onset with acute relapses, with or without full recovery, and continuous progression between relapses
What are some favorable prognostic factors of MS?
- < 40 years
- Female
- Optic neuritis or sensory sx
- Low attack frequency in early disease
- Relapsing/remitting course of dz
What are some unfavorable prognostic factors of MS?
- > 40 years
- Male
- Motor or cerebellar sx
- High attack frequency in early dz
- Progressive course of dz
What is the McDonald Criteria for MS indicative for a positive sign with no additional data needed?
> = 2 attacks (relapses) and objective clinical evidence >= 2 lesions
What do you look for is CSF evaluation for MS?
- CNS synthesis of IgG is increased, whereas serum IgG are normal
- Oligoclonal bands are present in electrophoretic studies
What are the 3 broad categories of the treatment of MS?
- Tx of acute attacks
- Disease-modifying therapies
- Symptomatic therapy
What is the treatment of acute exacerbations of MS?
- Mild with no functional decline may not require tx
- IV high dose corticosteroids (DOC methylprednisone) x 3-5 days
What is the disease-modifying treatment?
- The primary MOA for all DMTs is thought to be diminishing neuroinflammation
- All DMTs modulate the immune system through mechanisms that include sequestration of lymphocytes
What are some oral DMTs?
- Teriflunomide
- Dimethyl fumerate
- Monomethyl fumarate
- Diroxemil fumarate
- Fingolimod
- Siponimod
- Ozanimod
- Cladribine
Teriflunomide
Broad, general MOA
Pyrmidine synthesis inhibitor, anti-proliferative and anti-inflammatory
* first line
Dimethyl fumarate
More broad MOA
Fumaric acid derivative, anti-inflammatory and cytoprotective properties
* First line
* Biosimilar available
Fingolimod, Siponimod, Ozanimod
Sphingosine 1-phosphate receptor modulator
* First line
Cladribine
Purine nucleoside analog, cytotoxic to B- and T-cells
* Second line, due to adverse effects
What are some injectable DMTs?
- Interferon, beta-1a
- Interferon, beta-2a
- Peginferon beta-1a
- Glatiramer
- Ofatumumab
Interfernon, beta-1a; Interferon, beta-2a; Peginferon, beta-1a
Changes cytokine balance, favors anti-inflammatory cytokines
* First line
Glatiramer acetate MOA
Induces and activates T-cell suppressor cells specific for myelin antigen
* First line
Ofatumumab
Anti-CD20, B-cell depletion
* First line(?) FDA approved recently
What are some infusion DMTs?
- Alemtuzumab
- Mitoxantrone
- Natalizumab
- Ocriluzumab
- Rituximab (off-label)
Alemtuzumab
Anti-CD52, T-cell and B-cell depletion
* Second line due to adverse effects
Mitoxantrone
Topoisomerase II inhibitor; inhibits DNA and RNA synthesis; broad immunosuppression
* Third line reserved for rapidly-advancing disease due to adverse effects
* Biosimilar available
Natalizumab
Very broad general MOA
Selective adhesion-molecule inhibitor; blocks T cell migration into CNS
* First line
Ocrlizumab, Rituximab
Anti-CD20, B-cell depletion
* First line off-label use
* Ocrevus is the only FDA approved drug for PPMS
What are some common side effects of interferon-beta?
- Injection site redness and swelling
- Flu-like symptoms (fever, chills, myalgias) - 24 hours after inj
What are some less common side effects of interferon-beta?
- SOB
- Tachycardia
- Depression
What are some counseling points of interferon-beta?
- CONTRAINDICATED in patients who have severe depression
- Counsel women to use appropriate contraception
Glatiramer acetate
- 20 mg SQ daily
- ADE: 10% transient chest tightness, flushing, and dyspnea, if no hx CAD (self-limiting and benign)
- Store in refrigerator, room temp for up to 1 week
- Pregnancy category B
What is the MOA of natalizumab (Tysabri)?
Very specific MOA
Attaches to VLA-1 and blocks the interaction with CNS endothelium vascular cell adhesion (VCAM)-1. Thus, activated lymphocytes are denied entry past the BBB
What is natalizumab?
Partially humanized monoclonal antibody against alpha4 integrins
What is the counseling point for natalizumab?
Black box warning: Increases the risk of Progressive multifocal leukoencephalopathy (PML)
* was put off the market for awhile bc of this
* A potentially lethal CNS viral infection caused by infection with the John Cunningham polyomavirus (JCV)
What is the place of therapy of natalizumab?
- Monotheray for RRMS to reduce the exacerbations and reduce deficits
- In patients who have not responded adequately to, or who cannot tolerate the other DMDs
What are the common AEs of natalizumab?
- Infusion reaction
- HA
- Fatigue
- UTI
- Depression
- Joint pain
- Abdominal pain
What are some monitoring parameters of natalizumab?
JCV antibody monitoring every 3-6 months
What is Fingolimod (Gilenya)?
- First ORAL DMD for use in relapsing MS
- A sphingosine analogue that modulates sphingosine-1-phosphate receptor
- Alters lymphocyte migration
What are some common side effects of Fingolimod?
- HA
- Diarrhea
- Back pain
- Elevated liver enzymes
- Cough
What are some less common but serious AEs for Fingolimod?
- Bradyarrhythmias
- AV block
- Macular edema
- Diminished respiratory function and tumor development
What are some counseling points of Fingolimod?
- CONTRAINDICATION to recent hx of MI, stroke, TIA, heart failure, second or third degree heart block, QTc > 500 ms, use of class 1a or III antiarrhythmics (amio or sotalol)
- Avoid live attenuated vaccines
- Eye exams should be repeated 3-4 months after tx started
Before starting Fingolimod, patients should have the following?
- CBC, LFTs
- ECG
- Ophthalmologic exams
- Varicella serology and zoster vaccination if antibody negative
- Pregnancy cat C: inform woman of potential fetal outcomes
What is Teriflunomide?
Second ORAL agent for relapsing MS
What is the MOA of Teriflunomide?
Specific
- Is an active metabolite of leflunomide
- Reduces B and T cell proliferation by reversibly inhibiting the mitochondrial enzyme dihydro-orotate dehydrogenase
What are some counseling points for Teriflunomide?
- Hepatoxicity
- Risk of teratogenicity (Pregnancy cat X)
What are some monitoring parameters of Teriflunomide?
- Check LFTs, before start of med, q month for 6 months
- Check CBC before start of med, monitor for infection
- Monitor renal function, electrolytes (K+) and blood pressure
What are some drug interactions of Teriflunomide?
- Drugs metabolized by CYP2C8 (repaglinide, pioglitazone)
- Teriflunomide increases their exposure
- Drugs metabolized by CYP1A2 (fluoxetine, tizanidine)
- Teriflunomide decreases their exposure
- Warfarin – unknown mechanism
- Teriflunomide may decrease INR
What is the MOA of Dimethyl fumarate?
More specific MOA
DMF has been shown to activate the Nuclear factor-like 2 (Nrf2) pathway which is involved in cellular response
What are the monitoring parameters of Dimethyl fumarate?
- Baseline CBC with lymphocyte count at baseline, 6 months later, then every 6-12 months
- May cause lymphophenia, interrupt therapy if lymphocyte count is less than 0.5x10^9 cells/L for more than 6 months
- Consider holding therapy in patients with serious infections
What is Alemtuzumab?
Humanized monoclonal antibody directed at CD52 on the surface of lymphocytes and monocytes, resulting in rapid and marked lymphopenia
What is the place of therapy of Alemtuzumab?
Due to safety profile the FDA recommends this be reserved for patients with inadequate response to two or more MS therapies (at least second line)
What is the counseling points of Alemtuzumab?
Black box warnings:
* Causes serious and sometimes fatal autoimmune conditions such as immune thrombocytopenia
* Causes serious and life-threatening infusion reactions
* May cause increased risk of malignancies including thyroid cancer, melonoma, and lymphoproliferative disorders
What is the place of therapy of Ocrelizumab?
First treatment approved for RMS and PPMS
What is Ocrelizumab?
Humanized monoclonal antibody designed to target CD20-positive B cells
What do you premedicate before giving Ocrelizumab infusion?
Methylprednisone and antihistamine
What are some AEs of Ocrelizumab?
- Infusion reactions and infections (upper and lower respiratory tract infections, skin infections)
What is required before giving Ocrelizumab?
Hepatitis B virus screening required before first dose
What is the place of therapy of Siponimod?
Approved for RRMS and active SPMS
What are some counseling points of Siponimod?
- CONTRAINDICATED for patients with CYP2C9 3/3 genotype
- CONTRAINDICATED in recent MI, unstable angina, advanced HF, AV block
- Should not be started after alemtuzumab
What are some monitoring parameters of Siponimod?
- Liver function and BP during treatment
- First dose monitored for bradycardia and arrhythmias
What are some dose-dependent AE of Siponimod?
- Decreased lymphocyte counts
- Infections
- Macular edema
- Bradyarrhythmia
- Liver toxicity
What is the place of therapy of Cladribine?
- Approved for RRMS and SPMS
- Reserved for patients who do not tolerate or have inadequate response to other drugs for MS
What are the monitoring parameters of Cladribine?
- Lymphocyte counts should monitored before, during, and after treatment
What is the treatment course of Cladribine?
Each treatment course is divided into two treatment cycles of 4-5 days separated by 4 weeks
What are some counseling points of Cladribine?
- CONTRAINDICATED in pregnancy, breastfeeding, and for women and men of reproductive potential (unless effective contraception for 6 months after last dose)
- CONTRAINDICATED in patients with malignancy or active chronic infections
Diroximel fumarate (Vumerity)
- Rapidly converts to mono-methyl fumarate, the same active metabolite as dimethyl fumarate
- Lower rates of GI ADEs
- Should NOT be taken concurrently with dimethyl fumarate
What is the place of therapy of Ofatumumab?
Approved for RRMS and active SPMS
What do you give before Ofatumumab?
- Hepatitis B virus (HBV)
- Quantitative serum immunoglobulins screening is required
What is the dosing of Ofatumumab?
20 mg SQ at weeks 0,1, and 2
* Subsequent dosing: 20 mg administered monthly starting at week 4
What are some counseling points of Ofatumumab?
- CONTRAINDICATED: in active HBV infections
- Advise females to use an effective form of contraception during treatment and for 6 months after stopping Kesimpta
- Live, or live-attenuated vaccines are not recommended during treatment
What is the place of therapy of Mitoxantrone?
SPMS and PRMS or worsening RRMS
What is the monitoring of Mitoxantrone?
EF (req before each dose), sx of CHF
What are some counseling points of Mitoxantrone?
- May impart blue-green color to urine, bluish color to sclera
- Should NOT be used with natalizumab due to increased risk of PML
Stem Cell Transplantation
Goal of autologous hematopoietic stem cell transplantation (HSCT) is eliminating and replacing the patient’s pathogenic immune system to achieve long-term remission of MS
What is the MOA of Ergocalciferol (D2) and cholecalciferol (D3)?
Increasing vitamin D levels may decrease severity of MS symptoms
What is the place of therapy of * Ergocalciferol (D2) or Cholecalciferol (D3)?
Consider obtaining vitamin D level and/or providing supplementation to every patient with MS
Dalfampridine (Ampyra)
CNS potassium channel blocker indicated to improve walking in patients with MS
What is the administration of Dalfampridine?
- Tablets should only be taken whole
- Do not divide, crush, chew, or dissolve
What are some contraindications of Dalfampridine?
- History of seizures
- Moderate or seizures renal impairment (CrCl <= 50 mL/min)
What are some drug interaction of Dalfampridine?
W/ metformin
What is the DOC of spasticity?
- Baclofen
Baclofen
GABA analog
* Must NOT be discontinued abruptly
Tizanidine
- 2nd line for spasticity
- Short acting, centrally acting alpha-adrenergic agonist, increases presynaptic inhibition of motor neurons
What is the AEs of Tizanidine?
- Sedation
- Dizziness
- Dry mouth
- Hypotension
- RARE but SEVERE hepatoxicity
What is the treatment options of MS Fatigue?
- Amantadine 100 mg BID
- Modafinil 100-400 mg daily
