MS management Flashcards
List drugs of MS: 2 first line and 2 second line
First line:
Interferon beta
Teriflunomide
Second line:
Natalizumab
Alemtuzumab
IFN beta MoA:
MoA: Interferon beta is a naturally occurring polypeptide predominantly produced by fibroblasts.
Its anti-inflammatory effects are largely believed to result from
- the inhibition of T-lymphocyte proliferation
- a shift of cytokine response to an anti-inflammatory profile
- reduced migration of inflammatory cells across the blood–brain barrier
Efficacy of IFN beta:
Phase III trials of all the interferon beta preparations have shown beneficial effects in reducing the annualized relapse rate (ARR) reducing the progression of disability in RRMS as well as magnetic resonance imaging (MRI) disease activity
Side effects of IFN beta:
Side effects:
1. Most patients experience flu-like symptoms, including muscle aches, fever, chills, headache and back pain, that usually appear 2–8 h after an injection and resolve within 24 h.
- Liver enzymes may be elevated and bone marrow function may be depressed, which warrants periodic surveillance of liver function and blood counts before starting therapy and every 6 months thereafter
- Interferon beta treatment may induce formation of specific neutralizing antibodies (NABs).
That usually appear within 6–18 months of treatment: evidence that the efficacy of treatment is reduced in the presence of NABs.
Test all patients for the presence of NABs every 6 months during the first 2 years of therapy, and treatment should be switched in patients who are confirmed to be NAB positive
MoA of Teriflunomide:
MoA: Teriflunomide is an immunomodulatory agent that selectively and reversibly inhibits the mitochondrial enzyme DHODH required for de novo pyrimidine synthesis.
The therapeutic effect in MS is not fully understood but it is probably mediated by reduced proliferation of dividing cells that need de novo synthesis of pyrimidine to expand therefore reduced number of circulating lymphocytes
Efficacy of teriflunomide:
Efficacy: Two phase III trials in RRMS showed that teriflunomide 14 mg once daily, compared to placebo, reduced the ARR, the rate of disability progression by and MRI gadolinium enhancing
Teriflunomide treatment was associated with significantly prolonged time to a second relapse and a reduction in new MRI lesions.
Side effects of Teriflunomide:
Side effects:
Common adverse events include upper respiratory tract infection, urinary tract infection, paraesthesia, diarrhoea, nausea, hair thinning, alanine aminotransferase (ALT) increase, reduction in blood leucocytes and increase in blood pressure.
Teriflunomide treatment should be stopped if liver transaminase levels increase 3x above upper normal levels.
MoA of Natalizumab:
MoA: Natalizumab is a monoclonal antibody against a4-integrin,
- blocking the interaction with its ligands
- preventing adherence of activated leucocytes to inflamed endothelium
- thus inhibiting the migration of inflammatory cells into the CNS.
Efficacy of Natalizumab
Efficacy: The pivotal phase III trial of RRMS showed that natalizumab monotherapy reduced the ARR, rate of disability progression and MRI gadolinium-enhancing lesions most effectively compared to placebo.
Another study found that treatment with natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in reducing ARR, new T2 lesions and disability progression.
Side effect of natalizumab:
Risk of developing Progressive multifocal leukoencephalopathy PML.
o This is a potentially life-threatening CNS infection of oligodendrocytes by the JCV. Therefore all patients receiving natalizumab should be screened for previous JCV infection.
o Amongst the JCV-positive patients the risk of developing PML is influenced by treatment duration and previous immunosuppressive treatment.
As a general rule, it is recommended that JCV-positive patients who have been treated with natalizumab for more than 2 years should be switched to another second-line therapy
o Natalizumab treatment may induce an immune response, with the formation of persistent NABs (~4%–6%) against the preparation.
reduce the efficacy of the treatment and are associated with higher rates of infusion-related adverse events therefore, should be tested for NABs at 6 and 12 months of therapy
MoA of Alemtuzumab
MoA: Alemtuzumab is a recombinant, humanized monoclonal antibody directed against CD52, a cell surface antigen present at high levels on especially T and B lymphocytes causing:
- antibody dependent cellular cytolysis and complement-mediated lysis following cell surface binding
- depletion and repopulation of lymphocytes that reduces the potential for relapses and thereby delays disease progression.
Efficacy of Alemtuzumab
Efficacy: Two phase III trials of RRMS have shown that alemtuzumab, compared to interferon beta-1a 44 lg administered subcutaneously three times weekly, reduced the ARR the rate of disability progression and MRI gadolinium enhancing lesions
Side effects of Alemtuzumab
Side effects:
Patients commonly experience infusion-associated reactions including flushing, nausea, headache, tachycardia, urticaria, rash, pruritus, pyrexia and fatigue
o Oral antiviral prophylaxis with aciclovir 200 mg twice daily (or equivalent) should be administered and continued for a minimum of 1 month after the last dose.
Because Alemtuzumab increases the risk of secondary autoimmunity, second-line preparations are recommended
Alemtuzumab treatment may also result in the formation of autoantibodies and increased risk of autoimmune-mediated conditions (occurring a median of 32 months after the first treatment), including thyroid disorders (41%), immune thrombocytopenic purpura (3.5%) or, rarely, nephropathies (e.g. anti-glomerular basement membrane disease) (<1%)
