Flashcards in Multiple Sclerosis Treatment Deck (35):
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
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.
- 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
o Inteferon, glatiramer, teriflunomide,
o Inteferon and glatiramer have longer established safety profiles
o Fingolimod, dimethylfumarate
o Natalizumab, alemtuzumab
What are the SE of interferon? How is it administered?
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,
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
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
Fingolimod: Administration, efficacy, SE,
Oral daily dosing
Efficacy: 55% reduction in ARR at 2 years
Comparitavely: superior to interferon
SE: Less long term data on se profile
Bradycardia - Activating the third subtype of the sphingosine-1 phosphate-receptor reduces heart rate and prolongs the PR interval. The cardiac effects of fingolimod are maximal after the first dose but persist for about 14 days.(First dose given in hospital due to bradycardia then given as outpatient),
RARE: PRESS, PML, cryptococcosis, kaposi sarcoma, primary CNS lymphoma, 1:10,000 risk of overall opportunistic infetion
Administration, efficacy, comparisons, SE profile
BD oral dosing
53% reduction in ARR compared to placebo, 70% reduction in MRI lesions, 40% decrease in progression
Flushing and GI side effects common.
There have been cases of PML with dimethyl fumarate. Seems to be associated with level of lymphopenia
Natalizumab: administration, efficacy, SE
Administation: IV infusion once every 4 weeks
Efficacy: 67% reduction in ARR at 2 years
PML – progressive multifocal leukoencephalopathy – rare but serious
JC virus status and implementation
(think of it with - subacute onset hemiparesis, dysphasia, cognitive decline, seizures), HSV encephalitis, hepatotoxicity
Alemtuzumab: MOA, administration, Comparison, SE?
Monoclonal antibody: humanized monoclonal antibody which targets CD52, an epitope expressed on T and B lymphocytes, natural killer cells and most monocytes, but it is not expressed on hematopoietic precursors. (1,2) Treatment with alemtuzumab results in rapid depletion of CD52 containing cells by antibody dependent cellular toxicity. (3) Following treatment, reconstitution of these cell populations is staggered with return to baseline for monocytes and B cells at 3 months, CD8+ T cells around 30 months and CD4+ T cells at approximately 61 months
IV, Initial course, then shorter course 1 yr later
Effective. Significant reduction in relapse rate and disease progression (70%)
Comparison: superior to interferon beta 1a SC in reducing relapses
Need: Monthly blood test monitoring
De novo autoimmunity (primarily thyroid), herpes reactivation, Burkitt's Lymphoma, listeria meningitis, lymphoproliferative disorders
20% autoimmune thyroid disease,
1% idiopathic thrombocytopenic purpura, >1%: anti-glomerular basement membrane antibody (glomerular nephritis),
Daclizumab - MOA, route, efficacy, SE
Daclizumab is a humanized monoclonal antibody against the α subunit, CD25, of the IL-2 receptor on T cells, B cells, macrophages and natural killer cells (5). Interleukin-2 plays a key role in T cell activation and proliferation. Cluster of differentiation-25 (CD-25) blockade selectively inhibits activated T cells which play an important role in the pathogenesis of auto-immune disease and therefore, this drug is of interest in the treatment of MS. In addition, daclizumab has been shown to increase the quantity of CD56bright natural killer (NK) cells (a regulatory subset of NK cells) which down regulate adaptive T cell responses. (6) Administration of 1mg/kg of daclizumab every 4 weeks results in blockade of 95% of CD25 on T cells.
Self - injected once monthly
Superior to interferon beta-1a IM in reducing relapses
SE - hepatotoxicity and cutaneous rashes
Need monthly LFT monitoring
Ocrelizumab - MOA, route, efficacy, SE
Ocrelizumab is a humanized, recombinant monoclonal antibody against CD20 on B cells. (7) It has been shown to enhance antibody dependent cell mediated cytotoxicity and leads to a reduction in complement dependent cytotoxicity similar to rituximab (8). Clinical trials were recently completed studying ocrelizumab in both relapsing remitting and primary progressive multiple sclerosis. Positive results of these studies have been presented and were recently published (41, 42).
IV administered - 6 monthly
Therapeutic effect similar to alemtuzumab or natalizumab - superior to interferon beta 1a SC in reducing relapses -
Has been shown to reduce disability accumulation in primary progressive MS
SE - were more than expected malignancies in trial (including breast ca, but small study), herpes reactivation.
Mitoxantrone - route, efficacy, SE
Mitoxantrone: IV 3 monthly injections
Efficacy: 38% reduction in ARR at 2 years
Dose related cardiomyopathy, promyelocytic leukemia, elevated transaminases
What is lipid specific IgM and its significance?
Recently lipid specific IgM bands in CSF were found to be a protective factor for the development of PML
Interferon Beta - 1a:
Route, frequency, MOA, efficacy (vs placebo, vs other), adverse events
Weekly subcut injections, or three times weekly subcut injections
Efficacy: 18% reduction in ARR at 2 years if used weekly, 30% reduction in ARR if used 3 x weekly
Inferior if used weekly, comparable to glatiramer if used 3x weekly, and superior to beta 1 IM
Side effects: flue like symptoms, transaminase elevation, skin site reactions, frequent NABs
Interferon Beta 1a (pegylated)
Frequency, route, efficacy, side effects
39% reduction in ARR at 1 year
Flu like sx, transaminase elevation, skin site reactions,
Ofatumumab - MOA?
Ofatumumab is a type I, humanized monoclonal (IgG1ĸ) antibody against a novel epitope of CD20 on B lymphocytes. It is believed to mediate B cell lysis by complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity (9, 10). It targets a CD20 epitope which is distinct from that targeted by rituximab, by binding both small and large extracellular loops of the CD20 surface antigen (11, 12).
Stem cell transplant summary?
Stem cell transplantation has been used almost as long as the interferons to treat multiple sclerosis. Initially, patients with secondary progressive MS were treated with various stem cell regimens, but good treatment outcomes were not obtained. Some felt that even for stem cell transplantation to be effective, it had to be initiated earlier in the disease course. The HALT-MS clinical trial was initiated in patients with relapsing-remitting (RR) MS with active CNS inflammation relatively early in the course of their disease. We hypothesized that high dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT) would remove disease-causing cells and induce a re-set of the immune system, and thereby control disease. Patients were selected based on significant loss of neurological function (Expanded Disability Status Scale (EDSS) 3.0-5.5) and failure of MS disease modifying therapy (DMT) to control disease activity. At 5 years after HDIT / HCT and, importantly, with no post-transplant immunosuppressive therapy administered, event-free survival (EFS) was 69%, defined as absence of progression, relapse activity, or new MRI lesions (43).
Treatment options in pregnancy?
Of all MS medications, glatiramer is the only one with Category B status (no risk in animal studies, insufficient data in humans). The rest carry pregnancy risks
Teriflunomide has category X as there are fetal developmental risks demonstrated in studies
Drug options to treat fatigue?
Drug options to treat spasticity?
Baclofen and tizanidine
Drug options to treat gait impairment
Drug options to treat neurogenic bladder and erectile dysfunction?
Neurogenic bladder - anticholinesterase inhibitor, alpha 1a antagonists
Erectile dysfunction? sildenafil and tadalafil
Drugs to treat depression
Drugs to treat cognitive impairment?