Multiple Sclerosis Treatment Flashcards
What is the MOA of fingolimod?
Fingolimod is a sphingosine-1 phosphate-receptor modulator approved for oral therapy for relapsing remitting multiple sclerosis. Activating the first subtype of the sphingosine-1 phosphate-receptor reduces lymphocyte recirculation from the lymph nodes resulting in functional immunosuppression.
Fingolimod is a sphingosine-1-phosphate (S1P) receptor modulator. S1P is a phospholipid that is primarily produced in the plasma by erythrocytes, but is ubiquitous in the body (14). One of the roles of S1P is chemoattraction and motility, particularly with regard to lymphocytes. The active form of fingolimod, binds non-specifically to 4 of the 5 S1P receptor types. The S1P1 receptor is highly expressed on unactivated lymphocytes. Binding of fingolimod to the S1P1 receptor causes abnormal phosphorylation, resulting in internalization and degradation of the receptor. The decrease in S1P1 receptor expression on plasma lymphocytes results in their sequestration in the lymph nodes, thus preventing lymphocyte activation and subsequent transit to sites of inflammation.
Fingolimod likely has other effects that may be responsible for its efficacy. The S1P1 and S1P3 receptors are expressed on astrocytes. In vitro studies of active and chronic MS lesions show an increase in S1P1 and S1P3 expression. In the experimental autoimmune encephalitis (EAE) model, injections of S1P into mice resulted in astrogliosis. Thus, a decrease in the expression of S1P may be protective to astrocytes in the CNS (14). In addition, treatment of cultured human astrocytes with fingolimod resulted in decreased production of pro-inflammatory cytokines.
MOA of Dalfampridine? Use in MS?
“Dalfampridine is a potassium-channel blocker that improves nerve conduction along centrally demyelinated axons, and has been demonstrated to improve ambulation speed in approximately one-third of patients with multiple sclerosis. The drug carries a 0.2% risk of seizures, which is usually associated with toxic blood levels. Fampridine is cleared unchanged by the kidneys and is
contraindicated in patients with creatinine clearance (GFR) of less than 50 cc/min because of the resultant risk of developing seizures. The risk of seizures in patients with GFR of 51-80 is uncertain.”
MOA of teriflunomide?
“Teriflunomide (TF) is a new oral immunomodulating agent approved for relapsing-remitting multiple sclerosis. TF reversibly inhibits dihydroorotate dehydrogenase, a key mitochondrial enzyme involved in new pyrimidine synthesis for DNA replication. Consequently, the drug reduces T- and B-cell activation, proliferation, and function in response to autoantigens. However, teriflunomide preserves the replication and function of slowly dividing cells that use exogenous supplies of pyrimidine
nucleotides through the so-called salvage pathway.”
Teriflunomide’s primary mechanism of action is inhibition of dihydro-orotate dehydrogenase (DHODH) (15). Dihydro-orotate dehydrogenase is necessary for the de novo synthesis of pyrimidines and, thus, DNA replication in rapidly proliferating cells such as lymphocytes. Because teriflunomide inhibits lymphocyte proliferation by interfering with DNA replication, its effect is cytostatic rather than cytotoxic. Other mechanisms of action for teriflunomide have been proposed based upon studies in the murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). These other mechanisms include decreased production of interferon gamma, decreased T cell chemotaxis, and increased secretion of the anti-inflammatory cytokine, interleukin-10
SE of Natalizumab?
Natalizumab can cause a second neurologic disease, progressive multifocal leukoencephalopathy (PML); like multiple sclerosis, it affects the oligodendrocytes and central nervous system myelin. There is an estimated risk of PML of 1 case per 1000 patients. All the patients in whom PML developed had tested positive for anti-JC virus antibodies before the onset of PML. For seropositive patients with prior immunosuppressant use and 25 to 48 months of natalizumab treatment, the estimated rate is 11 cases per 1000 patients.
In February 2005, 3 months after natalizumab (NTZ) first received FDA approval for treatment of relapsing-remitting multiple sclerosis (RRMS), the drug was withdrawn from the market when 3 cases of progressive multifocal leukoencephalopathy (PML) were reported in natalizumab-treated patients who participated clinical trials in MS and Crohn disease.
MOA of Natalizumab
“Natalizumab is a recombinant humanized monoclonal antibody that binds to the 4-subunit of 4β1-integrin that is expressed on activated T-lymphocytes.
Natalizumab is a recombinant humanized monoclonal antibody which antagonizes the α4β1 integrin (also known as very late activation antigen or VLA-4) expressed on the surface of activated lymphocytes and monocytes. It is a selective adhesion molecule inhibitor which binds specifically to the α4 subunit (13). This prevents activated leukocytes from adhering to and migrating across the endothelial blood brain barrier yielding its therapeutic effect in MS.
By blocking the interaction of 4β1-integrin with the vascular cell adhesion molecule 1 (VCAM-1) ligand on endothelial cells, natalizumab blocks adhesion and transmigration of activated Tlymphocytes across the blood-brain barrier, reducing the inflammatory component in the MS plaque.
What is PML? PML risk factors? PML treatment?
PML is a typically fatal opportunistic infection of central nervous system oligodendrocytes caused by reactivation of latent JC polyomavirus infection. It is primarily seen in disorders associated with severely impaired cell-mediated immunity, including acquired immunodeficiency syndrome (AIDS) leukemia, and organ transplantation. After infection in immunocompetent hosts, the JC virus remains quiescent in kidney tissue and is often detected in urine. CNS infection is likely established via hematogenous dissemination of virus across the blood-brain barrier. It is plausible that inhibition of leukocyte trafficking into the CNS by natalizumab was responsible in part or whole for development
of PML.
There is no treatment established for PML. Current recommendations for NTZ-associated PML include stopping the medication and then initiating plasma exchange to remove the drug from the circulation. Restoration of immune function may result in immune reconstitution inflammatory syndrome (IRIS), with worsening neurologic symptoms. Most experts recommend treating IRIS with high-dose intravenous steroids, followed by oral steroids. Duration of treatment is not established and is determined on a case-by-case basis.”
Which treatments are associated with neutralising ABx?
Glatiramer acetate therapy is not associated with the development of clinically significant neutralizing antibodies. All formulations of beta-interferon and natalizumab can result in the formation of neutralizing antibodies, which abrogate their clinical and MRI efficacy against disease activity.
Interferon beta
- MOA, route, frequency, efficacy, impact on relapses vs active treatment, side effects?
Interferon-beta-1b (Betaseron, Betaferon) is a nonglycosylated recombinant human interferon-beta.
MOA: not completely known, may involve modulation of the autoimmune pathogenic processes of MS
Route: SC, Daily administration
Efficacy: 34% reduction in ARR at 2 years
and increased the proportion of relapse-free patients compared with placebo. It also reduced relapse severity, hospitalizations, and disease activity assessed by MRI and increased the time to first relapse.
Impact on relapses vs other active treatment: comparable to glatiramer
Adverse effects: flu like sx, transaminase elevation, skin site reactions, frequent NABs (neutralising antibodies)
What is the pathological finding in PML?
This is a case of progressive multifocal leukoencephalopathy which is caused by JC virus; glassy plumb-colored intranuclear inclusions are found in oligodendrocytes in these cases, along with enlarged bizarre appearing astrocytes and areas of demyelination.
What is the role of steroids in MS?
Methylprednisolone will speed recovery of neurologic deficit after an acute
exacerbation but would have no effect on the risk of future episodes.
What is the role of Vitamin D in MS treatment?
Vitamin D intake has been shown to have a protective effect in the development of MS, and low vitamin D levels have been implicated as a causative factor in the
development of the disease. There is no strong evidence for VIt D supplementation once diagnosed with MS
What are the relative risk reductions for MS treatments in relapse prevention?
Relative risk reduction of relapse Approx 30% o Inteferon, glatiramer, teriflunomide, o Inteferon and glatiramer have longer established safety profiles Approx 50% o Fingolimod, dimethylfumarate Approx 70% o Natalizumab, alemtuzumab
What are the SE of interferon? How is it administered?
b-interferon
o Injections
o Side effects – flu like symptoms are common
Glatiramer? Route, efficacy, comparison to others, adverse events?
Copaxone / glatiramer SC daily or three times weekly 29% reduction in ARR at 2 years Comparable with interferons, SE: Safety record > 20 years Favourable side effect profile, skin site reactions, post injection systemic reactions
Teriflunomide - administration, efficacy, side effects, comparitors?
Aubagio / Teriflunomide
Once oral daily tablet
Efficacy 30-36% reduced relapse and reduced progression at 2 years
Comparitor: similar to interferon beta-1a SC
SE profile
nausea diarrhoea,
hair thinning,
Transaminase elevation
Teratogenicity
liver derangement
o Good medium to long term safety profile given in RA
Rare SE - toxic epidermal necrolysis, Stevens Johnson Syndrome
Requires cholestyramine washout or activated charcoal for rapid elimination