MULTIPLE SCLEROSIS Flashcards
What is the treatment for MS flare - 1st and 2nd line?
1st - 1g methylprednisolone for 3-5 days
IVIG – 2nd tier
Plasmapheresis – 2nd tier
ACTH – expensive and not commonly available
What do you know about ocrelizumab?
Ocrelizumab (ocrevus) is widely used as only 6 monthly *compliance is ensured. And it is very effective.
It is a monoclonal antibody against CD20. This is a marker expressed on mature B cells. Ocrelizumab kills off the “middle aged” B cells. Plasma cells (and therefore immune memory) is unaffected, as are the precursor cells. As new cells mature they replace the mature B cells removed by ocrelizumab, and as such, the effect of this medication lasts for about 6 months. Infused 6 monthly. Highly effective for relapsing MS – almost all have cessation of radiological disease.
Also approved for primary progressive MS. 1/3 rate slowing of disease progression. Only medicine approved for primary progressive MS.
Side effects – infusion reactions very common, general infection advice.
With time people can get hypogammaglobulinemia with long term use of ocrelizumab – esp IgG and IgA. The health implications of this are not clear.
What do you know about natalizumab?
Natalizumab (Tysabri) is a monoclonal antibody against alpha 4 integrin. Effectively prevents leukocyte migration across blood brain barrier. Works by relocating cells – the lymphocytes are now no longer able to enter CNS where they would have attacked myelin.
Monthly infusions.
Associated with PML. We do additional screening for people taking natalizumab via a REMs programme. Run by the company that makes the drug. Only authorised people are able to prescribe this drug.
Natalizumab also requires CBC, LFTs and JC virus abs q 6 monthly
- can cause eosinophilia, leucocytosis, thrombocytopenia
Because natalizumab works by preventing cell relocation it is understandable that we see higher blood concentrations of eosinophils and leukocytosis.
How do you stratify risk of PML on natalizumab?
There are 3 strata to consider in working out PML risk.
JC virus antibody – if patients don’t have this antibody present – they have not been exposed to JC virus and are really not at risk. Natalizumab could be used freely in this group provided you monitor for ab conversion regularly. If positive for JC virus they go into higher risk group. If they become positive you would usually switch to another agent. The urgency of switch depends on JC virus titre.
Amount of time on natalizumab (more or less than 2 years). Very low risk of PML developing in the first 2 years, risk is higher after that – goes up quite steeply.
Previous chemotherapy use (for cancer or transplant) puts up PML risk.
What do you know about Alemtuzumab?
Alemtuzumab (lemtrada) is a monoclonal antibody against CD52 – expressed on a wide range of lymphocytes so will kill B cells and T cells pretty broadly. Can be conceptualised as causing a functional reset of the adaptive immune system. It is extremely effective at preventing relapses and new disease activity. Will become lymphopenic intially.
Dosed as 1 infusion daily for 5 days in year 1, then 1 infusion daily for 3 days in year 2 and the course is complete. Will not require other DMARDs unless have a relapse – it is supposed to put MS into long term remission.
Downside is that it increases risk of other autoimmune disease – esp thyroiditis in year 3, also autoimmune kidney disease and ITP. Must do monthly blood work for 4 years after last dose of alemtuzumab in REM programme.
What do you know about fingolimod?
Fingolimod (gilenya)
Taken daily orally. This is a functional antagonist of the s1P receptor – blocks receptors 1, 3, 4, 5. It does not block 2.
These receptors are widely expressed across the body including the lymph nodes. Works in MS by preventing lymphocyte egress from nodes. No longer freely circulating.
Also have these receptors on cardiac cells resulting in off target effects on cardiac tissue. This can cause bradycardia, esp with first dose. It can also exacerbate long QT. The first dose needs to be monitored in a medical setting. Need pre and post ECG as well as hourly obs. There are not usually long term.
As such it can be a bit logistically difficult to start.
Well tolerated, not a lot of day to day side effects but risk of infection (as with all MS meds). In particular JC virus, crypotcoccus and herpes virus.
Needs monitoring -
Macular oedema can occur – so need OCP at baseline and 3 months later
CBC and liver tests q 6 months.
Because lymphocytes removed from circulation you will see lymphopenia but there are not alot of functional consequences from this lymphopenia and it can be used as a marker for compliance.
If lymphocytes drop very low (below 200), most doctors would switch to q 2 day dosing, but this is off label. Few cases of melanoma so should have skin checks regularly.
What do you know about siponimod and ozanimod?
The most recently approved medications for MS are “me too” meds – essentially newer versions of fingolimod
Siponimod (mayzent) - relapsing MS or active MS (this means that it includes some forms of secondary progressive MS)
Ozanimod (zeposia)
Approved in 2019 and 2020. Also S1p receptor functional antagonists
Impact receptors 1 and 5 only – so are more selective
Less off target effects
Risk profile very simialar to fingolimod, however not all patient require cardiac moniotoring for first doses.
What do you know about Dimethyl fumarate and diroximel fumarate?
Dimethylfumarate (tecvidera) was approved in 2013.
Thought at the time to be the easiest MS drug to take
Dosed twice daily. Multimodality immune system downregulation
Tolerated well – side effects to look out for are hot flushes at random times throughout the day – can try daily aspirin to try and reduce.
GI upset – stomach pain or diarrhoea – will improve aftter 1 month to 6 weeks
Diroximel fumarate (vumerity)
This is also a me too med -
Has slightly less GI side effects but basically the same as Dimethylfumarate.
Safety side effects with both types of DMF – came out after clinic trials
Lymphopenia is a potential problem. Most people lose about 1/3 of lymphocytes – the mechanism is not known. Some people however get a significant drop in lymphocytes and should be switched to a different med. This seems to be a functional lymphopenia and there have been cases of PML associated with it.
What do you know about Teriflunamide?
Teriflunamide
Once daily med given for relapsing forms of MS
Least effective oral medication.
Side effects of GI symptoms, hair thinning (improves after 3 months) , liver dysfunction – need to have monthly LFTs for first 6 months then to twice yearly after that if no problems.
Rarely associated with hypertension and peripheral neuropathy
Not recommended in pregnancy or in men who are trying to conceive
Stays in the body for a long time as highly bound. If a patient wants to get pregnant or is found to be pregnant the medication should be “washed out” using cholestyramine or activated charcoal. There is an 11 day elimination programme to follow.
What do you know about cladribine?
Cladribine
This is like an oral form of alemtuzumab in that it is an induction therapy. Generates a functional reset of the immune system.
Year 1 – 5 days of pills month 1, 5 days of pills month 2
Year 2 – repeat
No more after that.
Good for patients who are interested in a single definitive treatment for MS, who may not be well suited to infusion medications and who are not planning a pregnancy for 2 years.
Are there any MS medications somewhat safe in pregnancy?
Natalizumab sometimes used in pregnancy
Glatiramer acetate is safe
Ocrelizumab can be worked out so that infusions fall either side of pregnancy.
Why would we choose injectables in MS?
These are more old fashioned - they are dependable and perceived as safe. People are comfortable prescribing them and patients may have been on them for a long time and not want to change. If a patient is responding to the medications – ie not had any new relapses or disease activity, and they are stable then shouldn’t really be changed.
What do you know about glatiramer acetate?
Glatiramer Acetate (copaxone) - also comes in several generic forms
Safest MS med. Does not require blood monitoring.
20 years experience with this medication
SC injection either daily or q3 weeks
Lowest risk infection risk
Injection site reactions possible as injected.
Lipoatrophy from injections possible.
“modestly effective” against MS
Good option if planning a pregnancy as safe during pregnancy.
IPIR – “immediate post injection reaction” – idiopathic and not medically dangerous reaction that happens sometimes after administration of glatiramer acetate. Patient feels like they are going to die, short of breath, horrible. Lasts 20 minutes. Can happen at any point. May not recur. Good to counsel patients that this can happen. If they have them often you should change medication as it is so unpleasant.
What do you know about interferons for MS?
Interferons - Interferon (Avonex, Betaferon, Extavia, Plegridy, Rebif)
These immunomodulate and downregulate immune system. There are multiple different types of interferon which work in a similar way and have similar efficacy. They differ in their frequency of administration from daily to weekly and in between.
All come with risk of injection site reaction – lumps and bumps.
Also cause flu like symptoms – myalgias, feeling unwell – give with NSAIDS
Check bloods twice yearly -
Side effect of worsening depression on interferon
People can also develop neutralising antibodies as a reason for relapse on these medications. Would usually happen after some years on them.
