Multiple Sclerosis Flashcards

Question

what is the alternative MS model?

Answer 1

a disease of oligodendrocyte apoptosis - Oligodendrocyte apoptosis precedes cellular infiltration – the defining event? - Changes in myelin sheath activate local microglia. These are principally involved in phagocytosis of apoptotic oligodendrocytes - This leads to a secondary recruitment of a systemically activated immune response. - “Inside out” rather than “outside in” pathology e.g. EBV causes damage - peripheral inflammatory infiltrate is a secondary phenomenon to deal with viral infection - So, an immunosuppressant is good to inhibit inflammatory T cells, but not good for viral infection resolution

Answer 2

- sampling MS CNS tissue is difficult compared to RA - have to take educated guesses - Therapeutics in MS are often taken from rheumatology and haematology - Not a MS-specific therapy available - not sure what to target in MS, don’t fully understand pathogenesis; many immune targets - No one target will work - Likely contribution from inflammatory processes. Possible primary event of oligodendroglial damage (?caused by unidentified virus)

Answer 3

Some indivuduals have a benign MS disease - A patient had 2 relapses in 20s, then third relapse when near 70 – unpredictable disease - Treatment here may not have had an effect MS impacts young women - In a life-long illness, with onset frequently in 20s, important to consider risk-benefit ratio - May impact jobs - Treatment may affect pregnancy - Treatment of a 20 year old may last many many years If early (inflammatory) damage leads to worse outcome over time, sensible to treat as early as possible with potent anti inflammatory agents If early (inflammatory) damage is a secondary event or is beneficial (clearing up or remodelling damage tissue), early anti-inflammatory treatment not recommended

Answer 4

DMT changes the natural pattern or progression of the disease over time (years) - MS (usually) has relapses, remissions and deterioration over time (years) Long duration of disease course makes clinical trials difficult – can't rely on EDSS score only - Surrogate markers (relapse rates, MRI) need to be used - additional info - Use MRI for monitoring: Very sensitive to disease activity, see enhanced breakdown of BBB, look at no. attacks/relapses/flares - new T2 lesions and gadolinium-enhancing lesions (active at time of scanning) - clinical outcomes: annualised relapse rate, 0-10 on EDSS, change from baseline

Answer 5

Inflammatory condition - use steroids - High-dose IV steroids given to someone with optic neuritis or other type of relapse, the patient will improve at 30 days consistently, but 6 months later there will be no benefit – no long-term change - not a DMT as in the long-term there's no benefit - Steroids aren’t disease modifying – just good for acute symptom treatment - not worth the side effects and risks - steroids can be used to speed up recovery from relapses

Answer 6

Give 2 doses of IFNb – risk of RRMS is reduced but not that effective - Placebo = 1.27 relapses - IFNb = 0.84 relapses - Difference of a third - significant - But side effects with IFNb Despite this, it was approved - because, no. new MRI lesions significantly reduced in IFNb (0.5) treatment compared to placebo (2.0) - Disease modifying whilst clinical data wasn't impressive, the MRI data led to first DMT for MS being approved: IFNb

Answer 7

First generation of DMT approved for use: Relapsing remitting MS (beta interferon or glatiramer acetate) Active disease defined as one or more of: - Two clinically significant relapses in the last two years - One disabling relapse in the last year - Active MRI scan containing new or gadolinium-enhancing lesions that have developed in the last year Secondary progressive MS - When relapses are the predominant cause of increasing disability

Answer 8

fully mouse: infusion reactions very frequent, only used as a one off - not in MS chimeric - rituximab, effective in MS - frequent infusion reactions but controllable The more human the mAb, the better tolerated humanised: alemtuzumab, natalizumab - occasional infusion reaction human: ofatumumab - rare infusion reaction, can do the treatment at home

Answer 9

inhibits immune cell trafficking/ transmigration across BBB - humanized anti-a4-Integrin antibody - first mAb used in MS mAb directed against a4 subunit of the cell adhesion molecule very late antigen 4 (VLA-4) - Expressed on lymphocyte and monocyte surface - VLA-4 binds to vascular cell adhesion molecule-1 (VCAM-1) on vascular endothelium - Required for transmigration of immune cells across BBB

Answer 10

- Natalizumab leads to mild overall leukocyte elevation in blood - More significant for pre-B and B cells - Difficult to distinguish - ?reduced egress from blood - ?increased release from bone marrow - reduces in leukocytes in the CSF and brain, including T (CD4, CD8) and B (CD19) cells CSF changes are maintained at 6 months after stopping natalizumab

Answer 11

68% Reduction in Annualized Relapse Rate vs. Placebo - very effective Also significantly reduces disability in highly active patients - Only 10% had disability with natalizumab compared to placebo (26%) - 64% reduction - 81% reduction in ARR in active patients

Answer 12

can cause progressive multifocal leukoencephalopathy (PML) - reactivation of dormant JC virus in brain - due to reduced immunosurvelliance of viruses in the brain because of leukocyte trafficking across BBB being inhibited - PML can develop over weeks and cause disability/death - Lesions look similar to MS lesions - very difficult to monitor - If it wasn’t for PML, most MS patients would be on natalizumab

Answer 13

Natalizumab is recommended as an option for treatment only of rapidly evolving severe relapsing-remitting multiple sclerosis (RES) - Nata restricted to aggressive severe relapsing remitting MS e.g. 2 or more diabling relapses in a year and high MRI activity

Answer 14

S1P1 is required for T and B cell egress from lymphoid tissues (thymus, spleen, lymph nodes, tonsil) - Activated lymphocytes transiently down-regulate S1PR1 and are retained in the responding lymphoid tissue until they become effectors - Fingolimod is a sphingosine-1-phosphate (S1P) agonist - Binds to 4 of 5 members of S1P receptor family (S1P1, S1P2, S1P3 and S1P5) Once bound, fingolimod acts as functional antagonist - inhibits S10 intracellular signalling and causes receptor internalisation - Prevents C-C chemokine receptor type 7 (CCR7) positive lymphocytes (includes naive and central memory T cells) from exiting lymph nodes - Lymphopaenia occurs within hours of administration, as T cells can't egress from lymph nodes - fingolimod inhibits immune cell trafficking into the brain - Fingolimod penetrates the CNS and S1P receptors are present on both neurons and glia ?direct CNS effects - oral tablet - commonly used, more effective than IFNb

Answer 15

fingolimod reduced annual relapse rate to 0.18 compared to 0.4 with placebo - improves MRI scans, disability

Answer 16

promotes immune cell depletion - T and B cells - humanised mAb - Originally developed as treatment for B cell lymphoma (known as CAMPATH-1H - Targets CD52, present on several mature leukocyte subpopulations – T, B and NK cells - Leads to complement and antibody dependent cytotoxic elimination - B cells recover in 6 months, T cells over 1Y - not used much in MS, as its not effective in later disease, EDSS worsens over 3 years

Answer 17

Rituximab: Selective CD20+ B cell depletion - Chimeric Ocrelizumab: Selective CD20+ B cell depletion - Humanised - approved in UK 5 years ago Ofatumumab: Human CD20+ B cell depletion - Fully human, patients can do it at home each month all of these deplete B cells via complement activation - very effective

Answer 18

inhibits B and T cell replication - form of chemotherapy - stabilises relapses, used in those with treatment-resistance - cheap tablet - But dose-dependent in cardiotoxic effects - 20% individuals treated with mito developed cardiac problem/failure - Should be given as short-course only – ineffective for chronic MS - discontinued

Answer 19

- DMT used in RA - Inhibits mitochondrial dihydroorate dehydrogenase (enzyme used in synthesis of pyrimidine nucleotides in proliferating cells). Does not inhibit salvage pathway in resting cells - Reduces no. proliferating cells - Well tolerated – 1 tablet per day - Few side effects side effects only seen in 5%: lymphopenia, liver function disturbance Teratogenic – can't be used in pregnancy - Long-half life – detectable in blood a year after stopping

Answer 20

Not sure, speculated: - DMF preserves neurons and glial cells in EAE - MMF protects murine neurons and human astrocytes from oxidative insult in vitro - Induce anti-inflammatory type II dendritic cells, driving anti- inflammatory T cell polarization - DMF has anti-proliferative effects - Patients can be on DMF for many years and no relapse not many side effects: flushing, nausea, lymphopenia in 5%

Answer 21

dimethyl fumarate - BG-12 only contains DMF, converted to monomethyl fumarate (MMF) and methanol - DMF and MMF activate antioxidant transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) pathway Not sure how it works - Originally used in psoriasis - MS activity improved as off-target effect - safe, not immunosuppressive

Answer 22

- Difficult to do clinical trials - Not fully aware of underlying pathology - patients often convert from RRMS, which is easier to treat, to degenerative SPMS which is harder to treat - Large drop out rate in MS trials - Rate of success of small molecules from trial to approval is low - Success rate from Phase 1 to approval ~10-15% - Biologicals better (22%) than small molecules (5%), but expensive and struggle to cross BBB - new therapies now look to SPMS, funding for RRMS is reduced because there are many DMTs now Treatments for advanced/progressive MS lag behind RRMS

Answer 23

Relapsing remitting MS trials Typically requires 2x phase III trials of ~400 patients vs comparator (eg IFN) - Primary outcome measure usually effect on relapse rates Progressive MS different - Who to recruit - primary vs secondary progressive - Different outcome measures - Progression slower - need to be larger and longer - surrogate markers are more difficult compared to RRMS - Use of biomarkers (usually imaging) Atrophy MRI, OCT, markers of axon degeneration products in CSF ?relevance Phase III requires primary clinical outcome measure

Answer 24

For advanced MS, monitoring for 3 years, need 1000 patients in trial - High disability so difficult to get to trial centre – high drop out rate - Very expensive to monitor and treat all - need 700 patients per arm to detect 30% difference in disability - disability measures are not as sensitive as relapse rates e.g. gadolinium enhancing lesions - in a 2 year trial, only 6% would worsen to EDSS 6, only 25% in 5 years - patients tend to be stable - Challenging trial RRMS is less challenging

Answer 25

Secondary progressive MS – EXPAND trial with siponimod (similar to fingolimod) - >1000 individuals with advanced MS – EDSS 5.4 - Primary endopoint 1 point EDSS change within trial time frame - 21% reduction risk of decline of EDSS by more than 0.5 points vs placebo (p=0.013) Recently approved by NICE for use in secondary progressive MS (Nov 2020) - Siponimod now somewhat widely used

Answer 26

Use of biologics approved in PPMS - Ocrelizumab in PPMS patients with disability - approved for PPMS (10% of MS patients) - Placebo arm: Looking at accumulating disability over time – 50% increase over 4 years - With ocrelizumab, 24% reduction in disability progression - not major reduction, but still approved

Answer 27

focus on oligodendrocyte precursor (OPC) cell promotion to repair damage rather than stopping damage accumulation

Answer 28

Opicinumab - anti-LINGO1 mAb - peripherally infused mAb - blocks lingo1 which reduces OPCs differentiation and remyelination - Promotes oligodendrocytes to repair myelin

Answer 29

To work, anti LINGO1 has to penetrate into brain - Most antibody remains in the periphery, only 0.1% mAb cross BBB Rest of mAb in blood can go to kidneys and other organs – side effects - 0.1% entering brain may not be enough Dose is 100mg per kg – in 70kg patient, 7g mAb – major infusion - High risk of side effects - Exprensive They did the trial but it didn’t work in reducing disability measures significantly

Answer 30

Autologous HSC transplantation (HSCT) – for progressive MS with relapses and no therapy response - Used as bone marrow rescue following intense immunosuppression to reset immune system - available for patients, used in treatment-resistant MS to stabilise disease - Aggressive unresponsive MS patients can be stabilised for 5-6 years with HSCT, EDSS improves slightly Mesenchymal Stem Cell (MSC) transplantation - Mechanism undecided ? anti-inflammatory or tissue repair infusion of MSC Human Oligodendrocyte Progenitor Cell transplantation - Surgical implantation of CD140a+ cell populations into brain to promote repair

Answer 31

MS is a chronic demyelinating disorder of the CNS The patterns of disease are well established The cause(s) are unknown The relevance of animal models is in dispute Underlying pathogenesis is contested The past 15 years have seen a huge increase in the (disease modifying) therapies available for the disease The key unmet need remains therapy for progressive MS – through remyelination and tissue repair