Multiple Sclerosis and Demyelinating Diseases 2 Flashcards
Selecting initial DMT in MS
Higher effectiveness DMTs
*Intravenous natalizumab
*Intravenous ocrelizumab
*Subcutaneous ocrelizumab-hyaluronidase
*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
What is washout period?
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.
How to switch disease modifying treatment in MS
Interferon beta -1b in the treament of MS: indications, dosage
- CIS, RRMS, active SPMS
- target dose of 0.25 mg every other day sc
Interferon beta -1b in the treament of MS: mechanism of action, monitoring
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
Interferon beta -1a in the treament of MS: indications, dosage
- CIS, RRMS, active SPMS
- Avonex 30 mcg once weekly IM
Rebif Target dose 44 mcg 3 times weekly sc
Interferon beta -1a in the treament of MS: mechanism of action, monitoring
- 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).
Interferons side effects
- 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.
Interferons: pregnancy, breastfeeding and effect on immunization
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
Glatiramer acetate: indications, dosage
- CIS, RRMS, active SPMS
- SUBQ: 20 mg once daily or 40 mg 3 times per week
Glatiramer acetate: mechanism of action, monitoring
- Alters T cell cytokine profile toward that of Th2 immunomodulatory cells (less inflammatory subtype); induces regulatory T cells
- No laboratory monitoring
Glatiramer acetate: side effects
Local reactions and lipoatrophy
Transient postinjection reactions (chest pain, flushing, dyspnea, palpitations, anxiety)
Glatiramer acetate: pregnancy, breastfeeding and effect on immunization
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
Teriflunomide: indications, dosage
- CIS, RRMS, active SPMS
- Oral: 7 mg or 14 mg once daily
Teriflunomide: mechanism of action, monitoring, pregnancy
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
Teriflunomide: side effects , contraindications
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.
How is accelerated removal of teriflunomide achieved in case of pregnancy or serious adverse effects
accelerated removal of the drug can be achieved with cholestyramine or activated charcoal given for 11 days
Dimethyl fumarate: indications, dosage
- CIS, RRMS, active SPMS
- Oral: Initial: 120 mg twice daily; after 7 days, increase to the maintenance dose: 240 mg twice daily
Dimethyl fumarate: monitoring
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)
Dimethyl fumarate: side effects
- 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
Dimethyl fumarate: mechanism of action, pregnancy, breastfeeding
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
Fingolimod: mechanism of action, pregnancy
- 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
Fingolimod monitoring
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.
Fingolimod: 1) side effects 2) contraindications
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
