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Treatment of Multiple
Sclerosis
MNI grand rounds
Joshua Chalkley D.O. M.S.
Faculty Disclosures I have none
Objectives
Introduce concepts in treatment
Review established treatments
Introduce emerging therapeutic options
Treatment of Multiple Sclerosis
• MS is a complicated disease state
• Multiple Sclerosis is not a classic Autoimmune disease
• Multiple sclerosis is an inflammatory neurodegenerative disease which the immune systems plays an important role
A little History
• Debate over the initial case of MS
• First described in a detailed journal of Augustus d’Estes 1794-1845
• Some credit Linwana Holland 1380
MS Through the Ages
History Howard Weiner and Stephen Hauser treated MS
patients with systemic induction cyclophosphamide
First concept of disease modifying therapy
Immune regulation played key role in the treatment of
disease
Very controversial at the time they were highly criticized
given most experts in the field felt MS was likely related
to a latent virus
Weiner et al., 1983
Curing MS
• Three main goals in the treatment of MS
• Stop attacks and prevent disease progression
• Aid in repair and recovery of the CNS
• Prevent MS
• Weiner states we are doing a good job of one of these three goals and for all extensive purposes MS is now “curable” in some populations
Weiner et al., 2009
Treatment Approach
• Traditional approach choose first line therapy with minimal risk and if the patient progresses or has relapse switch to stronger treatment
• Pick the most effective treatment from the onset, in a hope of arresting the disease
Approach to MS Patient Bactericidal vs bacteriostatic?
Likely have the most impact if the disease is treated aggressively from the beginning
Most of our current agents modulate the immune system
Some of the newer drugs change in the immune system and likely have long lasting effects on immune function
Some of the newer drugs kill certain cell lines
No Evidence of Disease
Activity No new symptoms
No change in exam
No change in functional status
No change in MRI
Lofty goal we are not meeting this in the real world
Climb 7 year outcomes showed only 7.9% met this
criteria at 7 years
Rostein et al,.
2015
Interferon Multiple preperations of interferon beta
All are injections
All are beta interferons
All work by regulating T cell response although exact mechanism is unknown
They all work to reduce antigen presentation and T cell proliferation
All effective in reducing relapse rates in relapse remitting multiple sclerosis, both through clinical relapse and radiographically
Coyel et al., 2004
Pros Very good safety profile
Over 25 years of clinical data
Very effective
Multiple preparation choices
Cons Injectable
Neutralizing antibodies can render these drugs ineffective over time
Flu-like symptoms
Depression
Liver disease
Psychiatric disease
Limited role in current treatment
Glatiramer Acetate 1994
Works through unknown mechanism but is likely a mimics myelin, also likely regulates T cell response through an unknown mechanism
Made from a polymer of 4 amino acids found in myelin basic protein, which likely fools the immune system in mounting an attack against the drug
Once a day injection
Very effective in the treatment of MS
Johnson et al., 1995
Pros Very safe, no major side effects, no routine labs
Long safety record and effective
Cons Daily injections
Can cause pain
Panic attack like reaction
Lipodystrophy
Natalizumab First non injectable
Infusion every month
Works by cell adhesion on a alpha4- integrin receptor
inhibiting T-cell migration into the CNS
Very effective in the treatment of MS
This is considered one of the most potent of all the MS
drugs
Coleman et al 2005
Pros Extremely effective
Once monthly infusion
Overall good safety profile
Often effective in pt who were refractory to other drugs
Rapid effects in the CNS
Cons Serious side effects
PML- we will discuss this more
Increased risk of infections
Likely increased risk of melanoma
Cases of intraocular melanoma
PML
Natalizumab associated PML 731 cases of Natalizumab associated PML as of June
2017 (Biogen Idec)
JC virus titers are important for initiating treatment
Need to check these every 6 months
Natalizumab associated PML is about 30% fatal has much better outcome than with other diseases
If JC virus titer is negative risk of PML is minimal
Predilection for frontal lobes, often presents with subtle bhx changes
Berger et al., 2013
Risk Stratification The risk of developing PML under most circumstances is
fairly low
Risk of developing PML depends of JC virus status, duration
of treatment, and prior immunosuppressant use
If JC virus titer is negative, and there is no hx of previous
immunosuppression then overall risk is 0.01/1000 pts
If JC virus titer is positive, and there is hx of previous
immunosuppressant use and treatment duration is greater
than 25 months then risk is 11.1/1000
Chalkley et al., 2014
PML Risk Initial data likely underestimated the risk of PML
Berger and Fox reexamined current data in 2016
If all three risk factors were present, treatment over two
years, JCV positive, and prior exposure to
immunosuppressive therapy
The risk of developing PML is 1/44
Berger et al., 2016
CASE 1 44 year old male comes to clinic with new onset ataxia
and left leg weakness. His right disk is pale with right
RAPD. MRI of the brain shows several scattered white
matter lesions along with C4 enhancing lesion. 12 OCB
were seen in the CSF and he had hx of optic neuritis in
his early thirties with no clinical relapses. NMO is
negative infectious workup is clean what do you want
to do
CASE 1
Case Continued He was started on Glatiramer and did well for 7 months
when he had clinical relapse with enhancing lesions in
the spinal cord and brain. JC virus titer was negative at
this time. He was switched in interferon and a month
later had another serious relapse with enhancing
lesions in the brain and spinal cord. He is now wheel
chair bound and weak on his right side. Thoughts from
the crowd
Fingolimod First oral medication for MS
Sphingosine-1-phosphate receptor modulator
Traps developing T cells in peripheral lymph tissue
Very effective in the treatment of MS
Over a 50% reduction in total relapse rates
Cohen et al., 2010
Fingolimod Very effective, was far superior to IFN in initial clinical
trails (Cohen, NEJM 2010)
First oral drug approved for MS
Initial clinical trials had two deaths in the fingolimod
group secondary to infections, and an unexplained
death
May also have significant effect on brain atrophy
Cohen et al.,2010
Radue et al., 2015
Pros Once a day oral medication
Very effective
Good overall safety profile
Most experts believe this to be the most potent of the
oral drugs
Cons Difficult to get started
Associated with fatal bradycardia
Associated with two fatal infections
Systemic varicella
9 cases of PML
Lymphadenopathy
Macular Edema
Increase risk of skin cancer
Rare fungal infections, Kaposi sarcoma
Teriflunomide Second oral preparation
Inhibits pyrimidine de nova synthesis which
consequently inhibits rapidly dividing cells including T
cells
Also blocks transcription factors including NF-kB
Very effective
Once a day oral medication
O’Conner et al., 2011
Pros Oral med
Effective
To date no serious life threatening complications
Easy to start
Minimal monitoring
Improved disability progression
May work better late in the disease
O’Conner et al., 2011
Cons Its new and not used as much as the other medications
Alopecia
Nausea
Can cause liver damage
Category X for pregnancy
Also passed in significant levels in semen? (risk in
males)
Dimethyl fumarate Newest oral drug
Unknown how it protects in MS
Rapidly attacked by glutathione, then has multiple
possible immune reactions including up regulating anti-
inflammatory stress protein HO-1
Used for Psoriatic arthritis for 10 years in Europe
Gold et al., 2012
Pros 10 years of safety data
Safe
Well tolerated
Effective
Oral preparation
Cons Flushing
GI upset
Lymphopenia
Hepatic toxicity
PML risk
PML Cases in both formulations for MS and psoriasis
All cases were associated with absolute lymphocyte
counts less than 600 except one
Recommend stopping the drug in lymphocyte counts
less than 600
One case of PML with normal lymphocyte counts
Alemtuzumab
• Approved for refractory MS
• Humanized monoclonal Antibody with directed affect against CD52
• Binds to CD52, which is present on more than 95% of T cells, B cells, monocytes, eosinophils
• Actual CD52 function is unknown
• Initially designed for the treatment of leukemia
Cohen et al., 2012
Effects on the immune system
• Causes prolonged lymphocyte depletion (B cells, T cells, monocytes) for up to 5 years
• Within an hour after dose lymphocytes and monocytes are no longer detectable
• Median recovery time CD4 T cells 61 months, CD8 cells 30 months, monocytes 3 months, B cells 3 months
Cohen et al., 2012
Alemtuzumab
• Initial clinical trials were very impressive
• CAMMS223 trial, and CARE MS-I, CARE MS-II showed statistically significant reduction in relapse rate, Mean EDSS, contrasting lesions, and increase in disease free activity
• Outperformed IFNB-1a in all trials
Cohen et al.
2012
Adverse Events
• Infusion reactions, 3% serious
• Increased risk of infection- mostly simple infections nasopharyngitis, UTI, herpes, (acyclovir is given 1 month post therapy)
• Autoimmune disorders- thyroid disease most common 18%, thrombocytopenia, renal disease, pancytopenia with one death in trials
Pros
• Overall great efficacy
• Induction therapy with no ongoing injections
• One of the strongest treatments for MS
• Long lasting effects on the immune system
Cons Long acting effects on the immune system
Serious risk of autoimmune disorders
May have long term unknown consequences
Difficult infusion
Unclear dosing
Unclear what to do in case of relapse
Daclizumab
• Humanized IgG1 MAD against IL-R chain (CD25)
• IL-2R is expressed on active T and B cells
• Approved for treatment of renal transplant rejection
• Approved this year for MS
Milo et al., 2014
Daclizumab
• Approved in 2016
• Select trial showed significant decrease in Relapses, along with decrease in new lesion burden
• One death in this trial due to autoimmune hepatitis
• Injection every 6 weeks
Gold et al., 2013
Pros Novel mechanism of action
Well tolerated
Very effective in trials
Outperformed interferon beta-1a
cons Very new
Rash
Autoimmune reactions
Hepatic injury
As with all monoclonals side effects may be long term
and far reaching
Laquinimod
• Oral quinoline-3 carboxamide • Three phase III clinical trials show efficacy in
terms of disability progression(Allegro, Bravo, Concerta)
• Phase III trials showed decreased disability but no not decreased MRI activity, or relapse rates when compared to interferon
• Given unique model of action may be a favorable combination drug
• Continued debate
Comi et al., 2012
Anti-CD20 Most effective therapies to date have targeted T cells,
however increasing clinical data for the role of B cells in
treatment
CD20 is a transmembrane protein which functions as a
CA+ permeable cation channel
CD20 is present on greater than 95% of B cells
It is also found on a small subset of normal/neoplastic T
cells
Rituximab Chimeric anti-CD20 monocloncal antibody
Approved for non-Hodgkin lymphoma and refractory
RA, used off label in MS
Causes rapid depletion of B cells
Initial studies show significant decrease in contrasting
lesions, and relapse rates
Also being studied in progressive MS
Castillo et al., 2013
Rituximab In trials sub group analysis effective in progressive patients
less than 55
Rituximab success spawned other B cell therapies in MS
Salzer and colleagues looked at large retrospective group
which showed decreased relapse rates, decreased disability
with very little in terms of side effects
Apling and colleagues looked at aggressive MS patients
who stopped natalizumab due to JCV status and compared
fingolimod to Rituximab, Rituximab pts were more stable
with fewer side effects
Slazer et al., 2016
Apling et al., 2016
Pros Very effective
Safe
Long term data available from other disease states
Well tolerated with few side effects
Cons Small risk of increased infection
Small risk of PML although this difficult to ascertain,
never seen in pure MS populations
Allergic reaction
Headache
Ocrelizumab Approved this year for MS
Humanized form of Rituxan
Very effective in MS, outperformed interferon in trials
Was effective in both RRMS and PPMS in trials
Some debate over its true effectiveness in progressive
MS
Novel Anti-CD20
Ofatumumab
Ocaratuzumab
Veltuzumab
Obinutuzumab
SMIP-small, modular immuno-pharmaceutical
All are being studied in the treatment of RRMS
Ocrelizumab Opera I, II, phase two clinical trials showed clinically
significant, and showed treatment effect
ORATORIO- phase three clinical trial on primary
progressive MS
Appears to slow disease progression in primary
progressive MS
Chateway et al., 2011
Ocrelizumab Pros
Very Effective
Possibly new avenue for progressive MS
No daily injection or pill
Anti-CD20 Cons
Unknown side effects
Single doses cause long term effects on the immune
system which can not be easily reversed
Cyclophosphamide First drug to show promise in the treatment of MS
Still used off label in MS
Alkylating chemotherapeutic agent binds to DNA and
interferes with mitosis, and cell replication
Decreases pro-inflammatory T helper cell, and
cytokines, causes the secretion of anti-inflammatory
Th2 cytokines IL-4 and IL-10 in both CSF blood
Weiner et al., 1983
Cyclophosphamide Good induction therapy
Very effective
Lots of toxic side effects
Nausea, hair loss
Infertility
Hemorrhagic cystitis, bladder cancer
Increased risk of lymphomas, leukemia, transitional cell carcinoma
Infections
Biotin High dose biotin
Several small phase II studies showing it improves EDSS in progressive MS
Activates Acytel Coenzyme Decarboxolase a rate limiting step in Myelin synthesis
All had EDSS 4.5-7
13 participants improved,
Studies were small
Larger studies are underway Tourbah et al., 2016
More than just inflammation So far all the drugs we use for MS down regulate the
immunes response
There are still a role for neuroprotection inflammation
Although MS was initially thought to be primarily a white matter disease there is growing evidence MS effects grey matter as well and there is non-inflammatory aspects that contribute to disease progression as well as disability
This growing data may provide newer avenues for treatment
Cortical Disease Cortical lesions
Hormonal Therapy PRIMS study followed several women with MS
throughout pregnancy and found significant decrease
in relapse rates in the third trimester. This was thought
to be closely related to estrogen levels
Estrogen treatment has been shown to affect cytokines,
chemokines, matrix metalloproteinase-9 (MMP-9),
antigen presentation and dendritic cell function
One phase I study showed promise, and there are
several phase II/III ongoing studies using estradiol
Vukusic et al., 2004
Vitamin D Multiple studies have shown MS in correlation with low
levels of vitamin D
Vitamin D levels are also inversely linked with disease activity, although these studies are mixed
It’s hard to say which came first the chicken or the egg
Studies with aggressive vitamin D supplementation show a mixed results
Vitamin D is easy to replace and safe, but evidence is mixed on its overall effectiveness
Thouvenot et al., 2014
Vitamin D
Vitamin D Vitamin D may be a downstream consequence of
multiple sclerosis on the genetic level
Ramasamy purposed link between MS and rs2248359-
C increases CYP24A1 which is also linked to Vitamin D
metabolism
Ramasamy et al., 2014
Antivirals There has always been speculation MS is secondary to a
viral cause
Some speculation this may be due to ongoing viral infection and not just the initiating event
Multiple case reports of MS remission following antiviral therapy (most were associated with HIV infection but not all)
human endogenous retroviruses
Two separate studies failed to show statistical significance with raltegravir
Fumaric Acid?
Chalkley et al., 2014
Combination therapy Intriguing concept
One three year study combining interferon and
glatiramer which showed no statistical significance
These studies have been difficult to start after the initial
PML cases with natalizumab
Benefits vs side effect profile
Lublin et al., 2013
Selection of Agents No perfect drug
All come with side effects and benefits
How confident are you of the diagnosis
You have to match the patient to the medication
These have not been studied head to head
There is meta-analysis data supporting Natalizumab, Rituximab, Fingolimod, Alemtuzumab, as superior
Problems when comparing across trials
All are considered first line except (Natalizumab, alemtuzumab, and daclizumab)
Weiner et al., 2009
Berger et al., 2014
My personal approach Take this slide with a grain of salt given it is more
expert opinion vs hard data
I tend to be more aggressive in the beginning given this
is when we can make the biggest impact on disease.
I do not think the step wise approach is as effective
This is being studied and I will let you know in 10 years
Treatment approach Its clear from the data all patient should be on treatment with
relapsing disease
If you have clear progression of disease or relapse need to switch to a strong agent
Silent MRI change is more difficult
I would not switch from similar strength agents
If patient is showing ongoing activity need to be aggressive
I tend to be more aggressive in high risk populations
Pt with brain stem or spinal cord disease, presentation with primary motor symptoms, male sex, minority race, short time between attacks
Case 1 44 year old male comes to clinic with new onset ataxia
and left leg weakness. MRI of the brain shows several
scattered white matter lesions along with C4 enhancing
lesion. 12 OCB were seen in the CSF and he had hx of
optic neuritis in his early thirties with no clinical
relapses. NMO is negative infectious workup is clean
what do you want to do
Case continued He was stared on glatiramer and did well for 7 months
when he had clinical relapse with enhancing lesions in
the spinal cord and brain. JC virus titer was negative at
this time. Switched in inferon and a month later had
another serious relapse with enhancing lesions in the
brain and spinal cord. He is now wheel chair bound and
weak on his right side. Thoughts from the crowd
Case continued Pt was stared on natalizumab and did very well. He
had stabilization of disease clinically and by MR. After
12 months of therapy JC titer was highly positive. What
now?
CASE 2 19 year old female presents to clinic after having three
week hx of painful vision loss in her right eye. Her right
eye visual acuity is 20/200, with right RAPD, and right
upgoing toe with brisk reflexes throughout. MRI of the
brain shows scattered white matter lesions, along with
11 OCB in the CSF. She has a hx of multiple sexual
partners with high risk sexual bhx and was recently
hospitalized for a suicide attempt two months ago,
along with heavy drug and alcohol abuse. Any thoughts
Case three 23 year of female presents to clinic with a PMH of
RRMS on glatiramer for two years. She is doing well in
college with no relapses since starting treatment. She
is tolerating the medication well but states she would
like to try “one of those pills for MS.” Thoughts
THANK YOU Questions
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