Multiple Sclerosis (MS) Pathophysiology

Autoimmune disease Reduction in T-cell suppressor activity Role of cytokines and their contribution to the diseaseTNF-a: demyelination, direct cell injury or promote BBB breakdown TH1, Th2, Th17 & Treg --> either pro or anti-inflammatory INF-gamma(y): enhances MHC class II expression on macrophages, microglia, and astrocytes promoting inflammatory response + facilitate T-cell across the BBB T- cell differentiation & plasticity, APC initiates the process that forms T helper cell subtypesIL-2 also contributes to the disease Questions:Does where you live in the USA contribute towards a risk factor for MS?Yes, above or below the 37th parallelWhat part of the neuron is damaged by MS?Myelin sheetWhat diagnostic tool is used to identify persons w/ MS?MRI scan

The W's & H's

What: CNS inflammatory disease that affects
the brain and spinal cord

Who:
-15-45 yrs
-women

Why:
-geography
-age
-environment
-genetics

How:
1. T-cells (CD+4) attack of self myelin antigens
2. CD+4 cells activated --> recognize myelin basic protein (MBP) and other components
3. Antigents present on HLA class II molecules
4. Activated T-cells cross the BBB --> become effector macrophages --> bind to the HLA class II of the myelin that causes the destruction

What happens next?
-inflammatory processes --> demyelination --> lesions in the brain, spinal cord, optic nerves
-Lesions appear as holes on MRI --> correlate w/ physical disability
-damaged neurons --> disruption of nerve impulses

Presentation

Clinical Presentation:
A. Primary - direct result of neuronal damage
B. Secondary - occurs when primary are affected
C. Tertiary - daily life changes
D. Clinical course and prognosis

is divided into 4 categories by the patterns of exacerbations + remission at the onset of new attacks that last 24hrs, separated by other symptoms by 30 days followed by remission. -- called the relapsing-remitting type (RRMS)attacks are referred to as relapses or exacerbations1st attack: clinically isolated syndrome (CIS)during RRMS --> direct correlation w/ brain MRI lesion/attackRRMS most common (85%)10-20% of RRMS have benign course20% of RRMS --> progressive phase --> attacks + remission difficult to identify --> AKA secondary progressive type (SPMS)15% have primary progressive type (PPMS) --> slow onset w/o attacks + worsens over time fatality occurs due to complications, suicide rates 7x than normal

Primary signs+sxs:
-optic neuritis
-gait
-pain
-spasticity
-weakness
-ataxia
-speech problems
-fatigue
-sexual dysfunction
-bladder/bowel problem
-tremors

Diagnosis:
-MRI, CBC, U/A

Treatment

What class of agents were originally used to treat persons with MS?InterferonsWhat MS agent was the first oral product that can also be used in the pediatric population? FingolimodWhy does the effect of interferons decrease over time?Development of neutralizing antibodies (NABs)What warning is included for natalizumab usage and also mentioned for similar agents in this category?Progressive multifocal leukoencephalopathy (PML)What agent requires thyroid function tests for monitoring during treatment? AlemtuzumabWhat agent is FDA approved for CIS, RRMS, and SPMS?Siponimod Therapeutic Algorithm:Monitor w/ annual MRI or sooner with attacks.Failure --> consider conversion to SPMSChange to another interferon, newer oral agents or copaxane agent + adj therapy (methotrexate, azathiopurine, etc.)mitoxantrone as LAST LINE agentWhich agent to choose?Initial: based upon lifestyleIf severe depression, interferons are CI --> start anti-depressantsWomen who are preg/attempting/breastfeeding - Do Not UseIf pt decompensates and has NAB --> stop interferons, rechallenge when other agents don't work Cautions:Watch for progressive multifocal leukoencephalopathy (PML) Potentially fatal opportunistic infection caused by John Cunningham polyomavirus (JCV)Caused by weakened immune system --> demyelinating condition like MS but there's no mylin regeneration Risk: tx >24 mo; JCV, prior immunosuppression use

Acute Attack: optic nerve damage (visual loss,
blurred or hazy vision)

Treatment for RRMS:

-IV methylprednisone 500-1000mg daily for 3-10 days
-follow with oral prednisone 60-80mg
for 3-5 days then taper
-for severe/unresponsive attacks: plasma exchange QOD X7

Symptomatic therapy

-Common symptoms fall into 4 categories: spasticity, bladder sxs, sensory symptoms, fatigue
-Annual flu vaccine --> do NOT use nasal preparation (live)

Disease-modifying therapies (DMT): reduce relapse and maintain QOL

-Interferons (IFN) - naturally occurring proteins --> interfere w/ viral replication. IFN B marketed agents are this type
-Agents: 1b (betaseron), 1a (Rebif, Avonex, Plegridy)
-MOA: decrease lymph proliferation, IFN expression, reduce HLA II expression + antigen presentation, reduce T-cell movement BBB.

Betaseron

-reduces annual relapse rate/MRI burden of disease
-ADEs: inj site redness, flu-like, SOB, tachycardia, depression
-lower starting doses 1/4 to 1/2 for 1-2 mo. with increase to full dose @ 2 mo. to lessen flu-like.

Rebif (SQ), Avonex (IM), Pelgridy (SQ)

-disability reduction: 30-40% (higher than glatiramer)
-development of neutralizing antibodies (NAB)
-time-dependent for INFs as NAB inc at 6 mo. + develop as early as 3 mo. Happens w/ all agents.

Glatiramer (Copaxone)

-Copolymer 1
-MOA: MBP binding or mimics antigen actions of MBP, suppress T-cell activation and possibly migration
-ADEs: 10% chest tightness, flushing and dyspnea a few minutes after injection (<20mins). Flu-like/depression noted.

Fingolimod

-1st oral agent
-acts on S1P: responsible for lymphocyte release
-depletes CD4/8 lymphocytes in the blood
-does NOT inhibit T or B cells in organs or lymphocyte recruits
which means no immunosuppression or inc infection risk!
- approved for adults/peds

ADEs:
-CI w/ class I/II anti arrhythmic drugs; 2nd/3rd AV block
-1st dose observ req
-metabolized by CYP3A4, avoid inhibitors!!

Teriflunomide

-equal efficacy to IFNs and glatiramer
-prevents proliferation of peripheral lymphocytes
-inhibits CYP2C8, OATP1B1, OAT3. Induces CYP1A2
-warfarin use dec 25% INR

BLACK BOX WARNING:
-hepatotoxicity
-teratogenicity

Dimethyl fumarate

-Unknown MOA, NKDI
-preg C

Natalizumab

-MS/Crohn's disease
-Blocks leukocyte from crossing BBB
-Mono or given + IFNs

Alemtuzumab

-reserved for refractory pts > 2DMTs-watch before and after 2hrs
-monitor thyroid func q3m and then for 48mo after
last dose

Ocrelizumab

-first agent for primary progressive and relapsing MS
-give methylpred before

Ofatumumab

-RRMS + active secondary progressive disease in adults
-MOA: anti-CD 20 antibody
-CI: persons w/ active HBV infection

Siponimod:

-FDA for CIS, RRMS, and SPMS
-CYP2C9

Ozanimod:

-RRMS
-S1P receptor modulator
-DI w/ CYP2C8 inhibitors and inducers
-CI: Cardiac MI or class III/IV HF; 2/3rd AV block

Cladribine

-RRMS + SPMS

Mitoxantrone

-SPMS, PRMS, RRMS
-lifetime cumulative dose is 140mg/mm due to CHF
-cyclophosphamide + cyclosporine can be used
-depression major issue -> starts antidepressants w/ IFN tx

Grouping:

Progressive Multifocal Leukoencephalopathy (PML)

Natalizumab

RRMS

-Avonex, Rebif
-Betaseron
-Glatiramer
-Teriflunomide
-Dimethyl fumarate
-Fingolimod
-Alemtuzumab
-Ocrelizumab
-Natalizumab
-Siponimod
-Cladribine

CIS (clinically isolated syndrome)

-Avonex, Rebif (Interferon Beta-1a)
-Betaseron (Interferon Beta-1b)
-Glatiramer acetate (Copaxone)
-Teriflunomide
-Dimethyl Fumarate
-Ocrelizumab
-Cladribine

PPMS/SPMS (Primary/Secondary progressive type MS)

-Ocrelizumab (only one approved for both RRMS/PPMS)

When + a corticosteroid is needed:

Alemtuzumab

Start methylprednisone for 3 days and just prior to infusion

RRMS acute attack leading to optic nerve damage

IV methylprednisone QD for 3-10D followed by oral prednisone for 3-5D then taper

Agents by class:

Interferons:

Beta-1a

Avonex, Rebif

Beta-1b

Betaseron

Glatiramer Acetate

Copaxone

Oral Immunomodulators

-Dimethyl fumarate
-Teriflunomide
-Cladribine

Sphingosine-1-Phosphate (S1P) receptor modulators:

Fingolimod (1st oral agent)
Siponimod

Monoclonal Antibodies:

Ocrelizumab
Natalizumab
Alemtuzumab

CD20-Directed cytolytic antibodies

Ocrelizumab

Pyrimidine Synthesis inhibitor

Cladribine