Multiple Sclerosis (not finished)

What is multiple sclerosis (MS)?

A chronic, progressive autoimmune disease in which the immune system attacks the myelin sheath surrounding nerve fibers in the brain and spinal cord which leads to impaired motor and autonomic function

How does demyelination in MS affect nerve function?

Nerves can no longer properly conduct electrical impulses → impaired motor and autonomic function

What are common early symptoms of MS?

Fatigue, weakness, tingling, numbness, and blurred vision

What symptoms can occur as MS progresses?

Cognitive decline, muscle spasms, pain, bladder spasticity, depression, heat sensitivity, sexual dysfunction, gait instability, and visual disturbances

What will 30% of patients with MS develop if left untreated?

significant physical disability

Which type of MS generally has the worst prognosis?

Primary progressive MS

How are primary, secondary, and tertiary MS symptoms characterized?

Primary = muscle weakness;

secondary = consequences of primary symptoms

tertiary = psychological and social concerns

What sex and age groups are most commonly affected by MS?

Females more than males (2:1), typically ages 20–40

How does MS tend to differ between males and females?

MS is more common in females, but males are more likely to have progressive disease

What tests are used to help diagnose MS?

Symptoms plus MRI of brain/spinal lesions, spinal fluid analysis, and evoked potentials

What is a primary goal of MS therapy?

Prevent disease progression because lost neuronal function cannot be regained

What non-drug approaches are used in MS management?

Functional rehabilitation, anti-inflammatory diet, emotional support, vocational/cognitive rehabilitation, and physical/occupational therapy

How are acute MS relapses typically treated?

3–7 days of IV methylprednisolone with or without an oral steroid taper

What is the purpose of disease-modifying therapies (DMTs) in MS?

Reduce the frequency and severity of relapses

Which parenteral DMTs were historically the mainstay for relapsing MS and remain preferred when considering pregnancy?

Interferon beta formulations and glatiramer acetate

Pegylated interferon beta allows for SC dosing every ____

14 days

Which oral DMTs are often used as initial treatment for relapsing-remitting MS?

Fingolimod, diroximel fumarate, and ozanimod

What higher-risk MS therapies are generally second- or third-line but may be first-line for aggressive disease?

Monoclonal antibodies and chemotherapy drugs

What is the mechanism of action of glatiramer acetate?

Immune modulator thought to activate T-lymphocyte suppressor cells in relapsing MS

What is the brand name and dosing of glatiramer acetate

Copaxone; SC daily or 3 times per week at least 48 hours apart

How should the 3-times-weekly glatiramer acetate regimen be administered?

On the same 3 days each week with doses ≥48 hours apart

Are the 20 mg/mL and 40 mg/mL glatiramer acetate concentrations interchangeable?

No

What is the boxed warning for glatiramer acetate?

Anaphylaxis, which can occur at any time

What major warnings are associated with glatiramer acetate?

Chest pain, immediate post-injection reaction, and lipoatrophy

What are common adverse effects of glatiramer acetate?

Injection-site reactions, flushing, diaphoresis, dyspnea, infection, pain, weakness, rash, anxiety, nausea, nasopharyngitis, and vasodilation

What is the preferred medication for MS in a pregnant person?

glatiramer acetate

What should be checked before administering glatiramer acetate?

Check the solution for discoloration and discard if present

How should glatiramer acetate be stored?

Refrigeration preferred; may be kept at room temperature for up to 1 month

What should be done before injecting refrigerated glatiramer acetate?

Allow it to stand at room temperature for 20 minutes

What is the general mechanism of action of interferon beta products in MS?

Alter expression and response to surface antigens → enhance immune cell function

What are the routes of administration for interferon beta products?

SC except Avonex, which is IM

What is the dosing of interferon beta-1a (Avonex)?

IM once weekly

What is the dosing of interferon beta-1a (Rebif)?

SC 3 times per week at least 48 hours apart

What is the dosing of interferon beta-1b (Betaseron, Extavia)?

SC every other day

What is the dosing of peginterferon beta-1a (Plegridy)?

SC every 14 days

What major warnings are associated with interferon beta products?

Psychiatric disorders including depression/suicide, injection-site necrosis, myelosuppression, increased LFTs, thyroid dysfunction, infections, anaphylaxis, worsening cardiovascular disease, and seizures

What is a characteristic adverse effect of interferon beta products?

Flu-like symptoms following administration that can last minutes to hours

How can flu-like symptoms from interferon beta products be managed?

Acetaminophen or NSAIDs before injection and/or start at a lower dose and titrate weekly

What are other common adverse effects of interferon beta products?

Visual disturbances, fatigue, depression, pain, UTI, and headache

What should be monitored with interferon beta products?

LFTs, CBC, and thyroid function

How should LFTs and CBC be monitored with interferon beta products?

At 1, 3, and 6 months, then periodically

How should thyroid function be monitored with interferon beta products?

Every 6 months if thyroid dysfunction is present or as clinically necessary

Which interferon beta products can be stored at room temperature?

Betaseron and Extavia

What administration precaution applies to prefilled interferon beta syringes?

Do not expel the air bubble because this can cause loss of dose

Which interferon beta products should NOT be shaken?

Avonex, Betaseron, and Extavia

Why may some interferon beta formulations be inappropriate for patients with albumin sensitivity?

Some contain albumin

What is the mechanism of action of S1P receptor modulators in MS?

Block lymphocytes from exiting lymph nodes → reduce peripheral lymphocytes and may limit lymphocyte migration into the CNS

Which drugs are S1P receptor modulators?

Fingolimod, ozanimod, ponesimod, and siponimod

What cardiovascular conditions contraindicate S1P receptor modulators?

Specific heart blocks or MI, unstable angina, stroke, TIA, or decompensated heart failure within the past 6 months

What additional contraindications apply to ozanimod and siponimod?

Ozanimod: severe untreated sleep apnea or concomitant MAOI use; siponimod: CYP2C9*3/*3 genotype

What important cardiac adverse effects occur with S1P receptor modulators?

Bradycardia and other bradyarrhythmias

What first-dose monitoring is required with fingolimod?

Monitor for at least 6 hours with ECG at baseline and at the end of observation

What infection precautions apply to S1P receptor modulators?

Increased infection risk; monitor CBC, screen for VZV antibodies, and vaccinate if nonimmune

What other major adverse effects occur with S1P receptor modulators?

Increased LFTs, hypertension, decreased lung function, macular edema, and fetal risk

What monitoring is required for macular edema with S1P receptor modulators?

Eye exams

What pregnancy counseling applies to S1P receptor modulators?

Use contraception during treatment and for 7–90 days after stopping depending on the drug

What important counseling applies when stopping an S1P receptor modulator?

MS can become much worse after discontinuation

What is the mechanism of action of fumarates used for MS?

Nrf2 activators with anti-inflammatory and cytoprotective effects

Which fumarates are used for MS?

Dimethyl fumarate, diroximel fumarate, and monomethyl fumarate

What major warnings are associated with fumarates?

Hepatotoxicity, reversible neutropenia, and PML

What common adverse effects occur with fumarates?

Flushing and GI effects such as N/V/D, abdominal pain, and dyspepsia

How can flushing from fumarates be reduced?

Aspirin 30 minutes before the dose and administration with food

Which fumarate causes fewer GI adverse effects?

Diroximel fumarate (Vumerity)

How should fumarate capsules be administered?

Do not crush, chew, or sprinkle capsule contents on food

What is the relationship among dimethyl fumarate, diroximel fumarate, and monomethyl fumarate?

Monomethyl fumarate is the active metabolite of dimethyl fumarate and diroximel fumarate

What is the mechanism of action of teriflunomide?

Inhibits pyrimidine synthesis → anti-inflammatory effects and may reduce activated lymphocytes in the CNS

What are the major contraindications to teriflunomide?

Pregnancy due to teratogenicity and severe hepatic impairment due to hepatotoxicity

What is the relationship between teriflunomide and leflunomide?

Teriflunomide is the active metabolite of leflunomide

How can teriflunomide be rapidly removed from the body?

Accelerated elimination procedure

Which CD20-directed monoclonal antibodies are used for MS?

Ofatumumab, ublituximab, and ocrelizumab

What must be screened for before starting a CD20-directed monoclonal antibody?

Active hepatitis B infection

What major warnings are associated with CD20-directed monoclonal antibodies?

Serious infections including PML, fetal risk, infusion reactions, and decreased immunoglobulin levels

What vaccine precaution applies to CD20-directed monoclonal antibodies?

Avoid live vaccines during treatment

Which CD20-directed monoclonal antibody can cause immune-mediated colitis?

Ocrelizumab

Which CD20-directed monoclonal antibodies are indicated for relapsing forms of MS?

Ublituximab and ocrelizumab

How should patients be premedicated for ublituximab or ocrelizumab?

Steroid plus an antihistamine and/or acetaminophen

What special administration requirement applies to ocrelizumab?

Requires a 0.22-micron in-line filter

What is the mechanism of action of alemtuzumab?

CD52-directed cytolytic monoclonal antibody

What are the boxed warnings for alemtuzumab?

Serious/fatal autoimmune conditions, infusion reactions, malignancies, and stroke

What is a contraindication to alemtuzumab?

HIV because it causes prolonged decreases in CD4 count

When is alemtuzumab generally used for MS?

After an inadequate response to ≥2 MS drugs

What vaccine counseling applies before alemtuzumab?

Complete all vaccinations at least 6 weeks before treatment

How should patients be premedicated before alemtuzumab?

Steroid plus an antihistamine and/or acetaminophen

What is the mechanism of action of natalizumab?

Monoclonal antibody that binds the alpha-4 subunit of integrin molecules

What is the boxed warning for natalizumab?

Progressive multifocal leukoencephalopathy (PML)

What special prescribing program is required for natalizumab?

TOUCH Prescribing Program REMS

What major warnings are associated with natalizumab?

Herpes encephalitis/meningitis, hepatotoxicity, hypersensitivity, and immunosuppression/infections

What are common adverse effects of natalizumab?

Infusion reactions, headache, fatigue, arthralgia, nausea, rash, depression, gastroenteritis, and abdominal/back pain

How often is natalizumab administered?

Every 4 weeks

What medications should not be used with natalizumab?

Other immunosuppressants

What administration precautions apply to natalizumab?

Stable in normal saline only and do not shake

What are the boxed warnings for cladribine (Mavenclad)?

Malignancies and teratogenicity

What are the contraindications to cladribine?

Current malignancy, HIV, or active chronic infections

What contraception counseling applies to cladribine?

Males and females of reproductive potential should use contraception during treatment and for 6 months after the last dose

What is the mechanism of action of dalfampridine (Ampyra)?

Potassium channel blocker that may increase nerve signal conduction

What is the role of dalfampridine in MS?

Symptom treatment that increases walking speed; it is not disease-modifying

What major contraindication applies to dalfampridine?

History of seizures

How long may dalfampridine take to show efficacy?

Up to 6 weeks, and most patients do not respond

Which medications can be used for MS-related incontinence?

Anticholinergics

Which medications can be used for constipation and diarrhea in MS?

Laxatives for constipation and loperamide for diarrhea