Multiple Sclerosis and Demyelinating Diseases 2

Question 1

Selecting initial DMT in MS

Answer 1

Higher effectiveness DMTs

*Intravenous natalizumab
*Intravenous ocrelizumab
*Subcutaneous ofatumumab

Intermediate effectiveness DMTs

*Oral fumarates (dimethyl fumarate)
*Oral sphingosine 1-phosphate receptor (S1PR) modulators (fingolimod, siponimod, ozanimod, or ponesimod)

Lower effectiveness DMTs

*Oral teriflunomide
*Intramuscular recombinant human interferon beta-1a
*Subcutaneous recombinant human interferon beta-1a
*Subcutaneous pegylated recombinant human interferon beta-1a
*Subcutaneous recombinant human interferon beta-1b
*Subcutaneous glatiramer acetate

Question 2

What is washout period?

Answer 2

Some DMTs decrease the pool of circulating lymphocytes, and the level of lymphocytes increases again within a few weeks or months after discontinuation.
Therefore, when the decision has been made to switch DMTs, a washout period is observed before the start of the second DMT to prevent the risk of adverse events due to cumulative effects.

Question 3

How to switch disease modifying treatment in MS

Answer 3

Question 4

Interferon beta -1b in the treament of MS: indications, dosage

Answer 4

• CIS, RRMS, active SPMS
• target dose of 0.25 mg every other day sc

Question 5

Interferon beta -1b in the treament of MS: mechanism of action, monitoring

Answer 5

inhibits proinflammatory cytokines, such as interferon gamma, tumor necrosis factor-α, and lymphotoxin; increases interleukin 10; reduced adhesion molecule and class II MHC expression

Monitor:
Before initiating:
- Latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden

Following initiation:
- complete metabolic panel, CBC with differential, liver function tests (1, 3, and 6 months following initiation of therapy; periodically thereafter)
- thyroid function tests (every 6 months in patients with history of thyroid dysfunction or as clinically necessary)
- assess patients who develop unexplained symptoms (eg, dyspnea, new or worsening fatigue) for pulmonary arterial hypertension
- symptoms of flu, allergic or anaphylactic reactions, injection-site reactions, worsening of cardiac symptoms (in heart failure patients)
- sign/symptoms of depression

Question 6

Interferon beta -1a in the treament of MS: indications, dosage

Answer 6

• CIS, RRMS, active SPMS
• Avonex 30 mcg once weekly IM
  Rebif Target dose 44 mcg 3 times weekly sc

Question 7

Interferon beta -1a in the treament of MS: mechanism of action, monitoring

Answer 7

• Inhibits proinflammatory cytokines, such as interferon gamma, tumor necrosis factor-α, and lymphotoxin; increases interleukin 10; reduced adhesion molecule and class II MHC expression

Monitoring
Before initiating:
- latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden

Following initiation:
- Thyroid function tests, CBC with differential, complete metabolic panel
- symptoms of autoimmune disorders
- signs/symptoms of psychiatric disorder (including depression and/or suicidal ideation)
- signs/symptoms of injection-site reactions
- signs/symptoms of new onset/worsening cardiovascular disease
- signs/symptoms of thrombotic microangiopathy (new-onset hypertension, thrombocytopenia, renal impairment)
- assess patients who develop unexplained symptoms (eg, dyspnea, new or worsening fatigue) for pulmonary arterial hypertension

Avonex: Frequency of monitoring for patients receiving Avonex has not been specifically defined; in clinical trials, monitoring was at 6-month intervals.

Rebif: CBC and liver function testing at 1-, 3-, and 6 months, then periodically thereafter. Thyroid function every 6 months (in patients with pre-existing abnormalities and/or clinical indications).

Question 8

Interferons side effects

Answer 8

• influenza-like symptoms,
• Local reactions at the injection site
• Elevated liver enzymes
• Leukopenia
• anemia
• Depression
• neutralizing antibodies against IFNs that may reduce the clinical efficacy of the drug.

Question 9

Interferons: pregnancy, breastfeeding and effect on immunization

Answer 9

As of 2020, interferons beta are considered nonteratogenic based on cumulative real-world pregnancy data.
++ Based on animal data, there is a possibly increased risk for spontaneous abortion (SPC)
It is considered safe to breastfeed while using interferon beta.
Numerous studies have reported adequate immune responses to a variety of vaccine types in patients with MS treated with interferons beta

Question 10

Glatiramer acetate: indications, dosage

Answer 10

• CIS, RRMS, active SPMS
• SUBQ: 20 mg once daily or 40 mg 3 times per week

Question 11

Glatiramer acetate: mechanism of action, monitoring

Answer 11

• Alters T cell cytokine profile toward that of Th2 immunomodulatory cells (less inflammatory subtype); induces regulatory T cells
• No laboratory monitoring

Question 12

Glatiramer acetate: side effects

Answer 12

Local reactions and lipoatrophy
Transient postinjection reactions (chest pain, flushing, dyspnea, palpitations, anxiety)

Question 13

Glatiramer acetate: pregnancy, breastfeeding and effect on immunization

Answer 13

Glatiramer acetate is considered safe for women to take at the time of conception and throughout pregnancy with no increased risk of teratogenicity or fetal loss, and it is safe to use while breastfeeding.

response to vaccinations: reduced responses compared with controls and with patients treated with interferons beta but still at levels considered to be protective

Question 14

Teriflunomide: indications, dosage

Answer 14

• CIS, RRMS, active SPMS
• Oral: 7 mg or 14 mg once daily

Question 15

Teriflunomide: mechanism of action, monitoring, pregnancy

Answer 15

Η τεριφλουνομίδη είναι ένας ανοσοτροποποιητικός παράγοντας με αντιφλεγμονώδεις ιδιότητες που εκλεκτικά και αναστρέψιμα αναστέλλει το μιτοχονδριακό ένζυμο διϋδροοροτική αφυδρογονάση, που απαιτείται για τη de novo σύνθεση της πυριμιδίνης.
Ως συνέπεια, η τεριφλουνομίδη μειώνει τον πολλαπλασιασμό των διαιρούμενων κυττάρων που χρειάζονται τη de novo σύνθεση της πυριμιδίνης για να επεκταθούν.
Ο ακριβής μηχανισμός με τον οποίο η τεριφλουνομίδη ασκεί τη θεραπευτική της δράση στην ΠΣ δεν είναι πλήρως κατανοητός, αλλά διαμεσολαβείται από ένα μειωμένο αριθμό λεμφοκυττάρων

Monitor
Before initiating:
* Screen for tuberculosis
* Screen for other latent infections (eg, hepatitis) in high-risk populations.
* Evaluate pregnancy status in females of reproductive potential
* Monitor for signs/symptoms of severe infection, abnormalities in hepatic function tests, symptoms of hepatotoxicity, hypophosphatemia, and blood pressure (baseline and periodically thereafter)

Following initiation:
* CBC within 6 months of initiation and periodically thereafter based on signs/symptoms of infection
* serum creatinine
* serum transaminase and bilirubin within 6 months of initiation of therapy and monthly during the initial 6 months of treatment
* Monitor hepatic function tests weekly until normalized in patients with suspected teriflunomide-induced hepatotoxicity

Pregnancy not recommended

Question 16

Teriflunomide: side effects , contraindications

Answer 16

1)
- Alopecia
- Hypophosphatemia
- Diarrhea, nausea
- Lymphocytopenia
- Increased serum alanine aminotransferase
- Headache
- Hypertension
- Paresthesia, peripheral neuropathy (including carpal tunnel syndrome)

2)
Contraindications: patients with severe hepatic impairment, pregnancy, hypersensitivity to teriflunomide, or current leflunomide treatment.

Question 17

How is accelerated removal of teriflunomide achieved in case of pregnancy or serious adverse effects

Answer 17

accelerated removal of the drug can be achieved with cholestyramine or activated charcoal given for 11 days

Question 18

Dimethyl fumarate: indications, dosage

Answer 18

• CIS, RRMS, active SPMS
• Oral: Initial: 120 mg twice daily; after 7 days, increase to the maintenance dose: 240 mg twice daily

Question 19

Dimethyl fumarate: monitoring

Answer 19

Monitoring
Before initiating:

• CBC including lymphocyte counts (obtained prior to initiation of therapy, then every 3 months thereafter and as clinically necessary)
• LFTs (transaminases, alkaline phosphatase, total bilirubin prior to treatment initiation and during treatment as clinically indicated)
• MRI (baseline and as clinically indicated) to monitor for early signs of progressive multifocal leukoencephalopathy
• latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline)

Following initiation:
- signs of infection (especially in patients with lower lymphocyte counts at baseline and mild to moderate lymphopenia)
- for patients with lymphopenia; monitor until resolution;
- grade 3 lymphopenia should be monitored more frequently at intervals <3 months);
- urinalysis (if proteinuria suspected and/or clinically indicated)

Question 20

Dimethyl fumarate: side effects

Answer 20

• Flushing
• Abdominal pain, diarrhea, nausea
  ** Because of the partially transient nature of these adverse effects, patient education and close monitoring is important, particularly during the first weeks of treatment, to ensure treatment tolerability and adherence.
• Lymphocytopenia
• Infection (60%; similar to placebo; including aspergillosis, candidiasis, cytomegalovirus disease, herpes meningoencephalitis, herpes simplex infection, herpes zoster infection [including disseminated, meningomyelitis, or ophthalmicus], listeriosis, nocardiosis, opportunistic infection [including West Nile], tuberculosis)

<1%: Nervous system: Progressive multifocal leukoencephalopathy

Question 21

Dimethyl fumarate: mechanism of action, pregnancy, breastfeeding

Answer 21

Activates nuclear factor erythroid 2 related factor 2 pathway, which enhances response to oxidative stress.
The mechanism of action in MS is still under investigation; however, it seems that at least some of the drug’s activity is related to monomethylfumarate’s release of the transcription factor Nrf-2, which ultimately leads to a decrease in several inflammatory cytokines, chemokines, and adhesion molecules

Pregnancy and breastfeeding not recommended

Question 22

Fingolimod: mechanism of action, pregnancy

Answer 22

• Modulates sphingosine-1-phosphate receptors 1,3,4,5;
  Fingolimod causes reduction of CD3+, CD4+, CD8+, CD45RA+ (naive T cells), CD45RO+ (memory T cells), and CD19+ cells;
  lymphocytes unable to migrate out of lymphoid tissue
• Not recommended

Question 23

Fingolimod monitoring

Answer 23

First dose: cardiac monitoring

Before initiating:
- Hepatic monitoring: Bilirubin and transaminase levels (baseline [within 6 months] and periodically thereafter [eg, 1, 3, 6, 9, and 12 months after initiation, and at regular intervals thereafter, including for 2 months after therapy is discontinued]; immediately in patients who develop symptoms of hepatic dysfunction).
- CBC, including lymphocyte counts (baseline, then every 3 months thereafter and as clinically necessary);
- latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline);
- VZV antibodies (prior to starting treatment; in patients with no health care professional–confirmed history of chickenpox or without documented previous full series VZV vaccination);
if no antibodies vaccination for VZV
- MRI to monitor for early signs of PML (baseline and as clinically indicated);
- ophthalmologic exam of the fundus, including macula, at baseline and 3 to 4 months after initiation of treatment (continue periodic examinations for duration of therapy in patients with diabetes, history of uveitis, or visual complaints);
- Evaluate pregnancy status prior to use in females of reproductive potential.

Following initiation:
- signs and symptoms of infection (during treatment and at least 2 months after discontinuation), progressive multifocal leukoencephalopathy (PML), immune reconstitution inflammatory syndrome (IRIS), and/or posterior reversible encephalopathy syndrome;
- BP and heart rate;
- respiratory function (FEV1, diffusion lung capacity for carbon monoxide [DLCO]) if clinically indicated;
- skin examination and monitoring for suspicious skin lesions (periodically);
- severe increase in disability following discontinuation of therapy.

Question 24

Fingolimod: 1) side effects 2) contraindications

Answer 24

1)

• bradycardia during first-day dosing
• Abdominal pain, diarrhea, nausea
• Increased liver function tests
• Leukopenia, lymphocytopenia
• Actinic keratosis, alopecia, basal cell carcinoma of skin, cutaneous papilloma, tinea versicolor
• Influenza
• Headache
• Cough, sinusitis
• Macular edema (οίδημα ωχράς κηλίδας)

** Additional risks and side effects for this class of drug include risk of rebound of MS activity after discontinuation, PRES, PML, and the potential for increased malignancies including several types of lymphoma

2)
- Γνωστό σύνδρομο ανοσοανεπάρκειας.
- Ασθενείς που διατρέχουν αυξημένο κίνδυνο εμφάνισης ευκαιριακών λοιμώξεων, συμπεριλαμβανομένων των ανοσοκατεσταλμένων ασθενών (συμπεριλαμβανομένων εκείνων που λαμβάνουν ανοσοκατασταλτικές θεραπείες ή εκείνων που είναι ανοσοκατεσταλμένοι από προηγηθείσες θεραπείες).
- Σοβαρές ενεργές λοιμώξεις, ενεργές χρόνιες λοιμώξεις (ηπατίτιδα, φυματίωση).
- Γνωστές ενεργές κακοήθειες.
- Σοβαρή ηπατική δυσλειτουργία (Kατηγορίας Child-Pugh C).

+ contraindicated in any patient who within the prior 6 months had myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization and in those with class III/IV heart failure, Mobitz type II second-degree or third-degree atrioventricular block, or sick sinus syndrome without a functioning pacemaker

Question 25

Fingolimod: indications, dosage

Answer 25

• CIS, RRMS, active SPMS in adults and children aged 10 years and older
• Oral: 0.5 mg once daily

Question 26

Vaccination in S1P receptor modulators

Answer 26

Live-attenuated vaccines are contraindicated during treatment with any of the S1P receptor modulators

Question 27

Fingolimod: risk of infections, macular edema and malignancy

Answer 27

• Infections
  Obtain a CBC, including lymphocyte count, prior to initiation of therapy, then every 3 months thereafter or as clinically indicated
  (In patients who develop lymphopenia during fingolimod treatment, using an alternate dosing schedule (eg, every other day dosing or dosing 5 days out of 7 days) may raise circulating lymphocyte counts without increasing disease activity) monitor lymphocyte counts for at least 2 months after stopping therapy
• Macular edema: Macular edema may occur, typically within the first 6 months of treatment. Patients may present with blurred vision, decreased visual acuity, or without symptoms.
  Ophthalmologic exams (including the fundus and macula) should be performed prior to therapy, 3 to 4 months after treatment initiation, and anytime visual disturbances are reported; more frequent examination is warranted in patients with diabetes or a history of uveitis.
• Malignancy: Cases of lymphoma (eg, non-Hodgkin, CNS, mycosis fungoides) and skin cancers (eg, melanoma, squamous cell carcinoma, Merkel cell carcinoma) have been reported. Basal cell carcinoma and melanoma risk is increased with fingolimod use; monitor for suspicious skin lesions periodically (especially in patients with risk factors for skin cancer) and promptly evaluate. Patients should minimize exposure to sunlight and ultraviolet light by wearing protective clothing and sunscreen with high protection factor.

Question 28

What should be considered in a patient with MS on fingolimod who presents with blurred vision?

Answer 28

• MS relapse
• Macular edema as an adverse effect of fingolimod

Question 29

Which is currently the only FDA approved oral DMT for pediatric patients with RRMS

Answer 29

Fingolimod

Question 30

Siponimod: indications, dosage

Answer 30

• CIS, RRMS, active SPMS
• Oral:

CYP2C9 Genotype 1/1, 1/2, or 2/2:

Initial: 0.25 mg once daily on Days 1 and 2, then 0.5 mg once daily on Day 3, then 0.75 mg once daily on Day 4, then 1.25 mg once daily on Day 5.

Maintenance: 2 mg once daily, beginning on Day 6.

CYP2C9 Genotype 1/3 or 2/3:

Initial: 0.25 mg once daily on Days 1 and 2, then 0.5 mg once daily on Day 3, then 0.75 mg once daily on Day 4.

Maintenance: 1 mg once daily, beginning on Day 5.

Question 31

Siponimod: mechanism of action

Answer 31

• Modulates sphingosine-1-phosphate receptors 1 and 5
  Lymphocytes are unable to migrate out of lymphoid tissue

Question 32

Siponimod: side effects (>10%), contraindications

Answer 32

• Hypertension
• Increased serum transaminases
• Falling, headache

Contraindications: CYP2C93/3 genotype; recent (in the past 6 months) myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure; Mobitz type II second-degree, third-degree atrioventricular block, or sick sinus syndrome, unless patient has a functioning pacemaker.

Question 33

Ozanimod: mechanism of action, dosing, contraindications

Answer 33

Modulated sphingosine 1 phosphate receptors 1 and 5, lymphocytes are unable to migrate out of lymphoid tissue

Dose 0.92mg daily

Contraindications:
* Immunodeficient state
* Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalisation or NYHA Class III/IV heart failure.
* Patients with history or presence of second-degree atrioventricular block Type II or thirddegree AV block or sick sinus syndrome unless the patient has a functioning pacemaker.
* Severe active infections, active chronic infections such as hepatitis and tuberculosis
* Active malignancies
* Severe hepatic impairment (Child Pugh class C).
* During pregnancy and in women of childbearing potential not using effective contraception

Question 34

Ozanimod indications

Answer 34

Multiple sclerosis, relapsing: Treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Ulcerative colitis: Treatment of moderately to severely active ulcerative colitis in adults.

Question 35

Ponesimod: mechanism of action

Answer 35

Modulates sphingosine1-phosphate receptor 1, lymphocytes are unable to migrate out of lymphoid tissue

Question 36

Ponesimod dosage and contraindications

Answer 36

Maintenance: 20 mg once daily

• Immunodeficient state
• Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalisation, or NYHA Class III or IV heart failure.
• Patients who have presence of Mobitz type II second-degree, third-degree atrioventricular block, or sick sinus syndrome, unless patient has a functioning pacemaker
• Severe active infections, active chronic infections.
• Active malignancies.
• Moderate or severe hepatic impairment (Child-Pugh class B and C, respectively).
• During pregnancy and in women of childbearing potential not using effective contraception

Question 37

Natalizumab: indications, dosage

Answer 37

• CIS, RRMS, active SPMS
• IV: 300 mg infused over 1 hour every 4 weeks; guidelines suggest limiting duration of therapy to 24 months unless benefits outweigh risks of PML
  sc 300mg every 4 weeks

Question 38

Natalizumab: mechanism of action, pregnancy

Answer 38

• Monoclonal antibody targeting the alpha 4 integrins.
  Blocking this molecule inhibits trafficking of lymphocytes from the blood into the CNS. Part of the VLA - 4 molecule.
• Pregnancy not recommended

** Continuing treatment until pregnancy is confirmed and through the first trimester and then restarting soon after delivery may prevent relapse in high-risk patients.
When disease-modifying therapy is needed in patients at high risk for relapse, natalizumab may be continued during pregnancy following a full discussion of potential risks.
The last dose should be given ~34 to 40 weeks’ gestation to minimize fetal exposure.
The postpartum dose should be restarted within 8 to 12 weeks to prevent disease relapse (Uptodate)

Question 39

Natalizumab monitoring

Answer 39

Before initiating
* Symptoms of hepatotoxicity (eg, elevated serum transaminases, bilirubin) consider baseline and periodic monitoring
* latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline)
* anti-John Cunningham Virus (JCV) antibody testing is recommended prior to and periodically during therapy (patients who test positive for anti-JCV antibody at any time should be considered positive regardless of subsequent testing
* Baseline brain MRI scan; in patients with multiple sclerosis, additional MRI are generally recommended at 3 to 6 months, at 12 months, then annually; consider more frequent MRI (eg, every 3 to 4 months) in patients at high risk of developing PML

Following initiation:
* hypersensitivity reactions during, and for 1 hour after, infusion
* symptoms of persistent anti-natalizumab antibody-positivity (eg, anxiety, dizziness, dyspnea, feeling cold, flushing, headache, hypertension, myalgia, nausea, pruritus, pyrexia, rigors, tachycardia, tremor, urticaria or, vomiting)
* signs/symptoms of meningitis and encephalitis
* signs/symptoms of acute retinal necrosis
* Progressive multifocal leukoencephalopathy (PML):
Monitor for signs and symptoms of PML (eg, weakness in one side of the body, vision disturbance, changes in memory or thinking) during treatment and for 6 months after discontinuation; also monitor for radiographic signs of PML periodically; periodically test patients who are anti-JCV antibody negative to ensure they remain negative).
* Antibodies to natalizumab: Testing is recommended if persistent antibodies are suspected (if positive, repeat/confirm test in 3 months); consider antibody testing in patients that resume therapy following a period of dosage interruption.

Question 40

False-negative test for anti-JCV antibodies

Answer 40

False-negative test for anti-JCV antibodies can occur in the setting of plasma exchange; wait at least 2 weeks after plasma exchange to test for anti-JCV antibodies.

Intravenous immune globulin (IVIG) can produce a false positive for the presence of anti-JCV antibodies; wait at least 6 months after IVIG to verify anti-JCV antibody status.

Question 41

Vaccination and natalizumab

Answer 41

Vaccination with live or live-attenuated vaccines during natalizumab treatment is not recommended.

Question 42

Natalizumab: side effects (>10%), contraindications

Answer 42

• Herpes virus infection
  Rarely, risk for encephalitis and meningitis
• Abrupt discontinuation can result in rebound activity
• Skin rash
• Abdominal distress, gastroenteritis, nausea
• Urinary tract infection
• Influenza
• Depression, fatigue, headache
• Arthralgia , back pain , limb pain
• Flu-like symptoms , lower respiratory tract infection, upper respiratory tract infection
• Infusion related reaction

Contraindications: patients who have or have had PML, and in patients with a previous hypersensitivity reaction to natalizumab.
Because of the risk of PML, natalizumab should not be used for patients who may have impaired immunity

Question 43

Risk factors for PML in patients recieving Natalizumab

Answer 43

1) JC virus antibodies

2) Prior use of immunosuppresants

3) Increased duration of Natalizumab treatment

Question 44

1) Risk for PML in JC virus Ab negative patients
2) Risk for annual seroconversion
3) How often must JC virus status re-tested
4) Risk for PML in JC virus Ab positive patients

Answer 44

1) less than 1:10,000

2) 2-3% per year

3) every 6 months

4) 1:2,000 after 2 years / 1:150 after 4 years

** In patients with anti-JCV antibodies, consider switching to a disease-modifying therapy with lower risk of PML, especially if anti-JCV antibody index >0.9