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Advances In The Therapy Of Multiple Sclerosis

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Advances In The Therapy Of Multiple Sclerosis
Author: Ghassan Haddad
Publisher: Haddad Ghassan
17 pages
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 Advances in the Therapy of Multiple Sclerosis

 Edited by Dr Ghassan George Haddad

Introduction

 Multiple Sclerosis is characterized by a triad of inflammation, demyelination,
and gliosis .Lesions of MS typically occur at different times and in different central
nervous system (CNS) locations (i.e., disseminated in time and space) .

The course can be relapsing-remitting or progressive. Manifestations of MS vary
from a benign illness beginning in early to middle adulthood to a rapidly evolving
and incapacitating disease requiring profound lifestyle adjustments.

MS affects 2.5 million individuals worldwide . MS is approximately threefold more
common in women than men. The age of onset is between 20 and 40 years. Rarely
the disease’s onset maybe as early as 1–2 years of age or as late as the eighth decade

Epidemiology

The prevalence rates of MS increases with higher latitudes. The highest known
prevalence for MS is from northern Europe, the northern United States, and
Canada. By contrast, the prevalence is low in Japan and in other parts of Asia, in
equatorial Africa, and in the Middle East. There is a protective effect of sun
exposure. At high latitudes where sun exposure may be low, particularly during
winter months, low levels of vitamin D are common and several prospective studies
have confirmed that vitamin D deficiency is associated

Migration studies provide additional support for an environmental effect on MS
risk with the related exposure occurs in childhood and years before MS is clinically
evident. Very young children moving from a low risk to a high risk area was found
to increase MS risk

A higher risk of infectious mononucleosis is associated with high MS risk. At this
time, however, a causal role for EBV or for any specific infectious agent in MS
remains uncertain.


Genetic prints

Twin studies support an important genetic influence on MS. The highest lifetime
risk for MS ~30%, occurs in monozygotic twins of MS patients. Caucasians are
inherently at higher risk for MS than Africans or Asians. Although susceptibility to
MS is clearly inherited, these risk estimates do not follow a simple Mendelian
pattern, but are more consistent with the presence of multiple MS susceptibility
genes, each contributing a relatively small amount to the overall risk. The strongest
MS susceptibility region is the major histocompatibility complex (MHC) on
chromosome 6 .See picture 1

 

Picture 1 showing the chromosome 6:

 p designates the short arm of the chromosome 6 and q the long arm.

Magnification of p segment shows the major histocompatibility complex class I, II
and III

Mapping of Class II shows the DR locus (in blue)

 

 


Magnification of the DR locus shows the DRB1*1501 molecule, which is particularly
associated with increasing MS risk See picture 2

 

Picture 2 showing the DRB1 molecule in white with its P4 socket.

This DRB1 molecule has an abnormal structure in patients with MS in that the
major peptide-binding pocket, termed the P4 pocket, has a large hydrophobic
region into which aromatic amino acids are bound. An amino residue of the myelin
basic protein (MBP) is believed to be bound in this pocket in DR2 positive
individuals. It is believed that this binding promotes CD4 T cell responses against
the amino acids of the myelin basic protein (MBP).

Other recently identified MS susceptibility genes encode receptors for two
proinflammatory cytokines, the IL-7 receptor alpha chain (CD127) and the IL-2
receptor alpha chain (CD25)

 

 

 

 

 

 

 


Disease Course

 

Figure 3. Relapsing/remitting MS

Relapsing/remitting MS (RRMS) accounts for 85% of MS cases at onset and is
characterized by definite attacks (seen as red bar in the figure above) that generally
evolve over days to weeks. There is often total recovery over the ensuing weeks to
months (Fig. 3) In between attacks, the patients are neurologically intact at the
beginning of the disease and may eventually develop baseline deficit between the
attacks. For a patient with RRMS, the risk of developing SPMS is ~2.5% each year
this signifies that with time the great majority of RRMS ultimately evolves into
SPMS.

 

Figure 4. Secondary progressive MS

Secondary progressive MS begins as RRMS and then the clinical course changes so
that the patient experiences a progressive deterioration in status unassociated with
acute attacks .Once the progressive course starts there is a greater burden of fixed
neurological disability than that seen in RRMS. SPMS appears to represent a late
stage of the same underlying illness as RRMS


 

Figure 5. Primary progressive MS

Primary progressive MS (PPMS) accounts for ~15% of cases. These patients
presents from onset with steadily increasing functional decline with no attacks (Fig.
5). Compared to RRMS, the disease begins later in life (mean age ~40 years), and
disability develops faster.

 

Figure 6. Progressive/relapsing MS

Progressive/relapsing MS (PRMS) is a combination of primary and secondary
progressive illness and accounts for ~5% of MS patients. Like patients with PPMS,
these patients experience a steady deterioration in their condition from disease onset
and they have occasional attacks superimposed upon their progressive course (Fig.
6)

Clinical Presentations

Symptoms of MS varies and depend on the location and severity of lesions within
the CNS .Weakness and sensory symptoms of the limbs may manifest as loss of
strength or dexterity, fatigue, or a disturbance of gait. Exercise-induced weakness is
a characteristic symptom of MS.

Gait, visual and cognitive impairment are commonly encountered .Patients may
manifest bladder and sexual dysfunction such as decreased libido, impaired genital


sensation, impotence in men, and diminished vaginal lubrication or adductor
spasms in women. The patient may also report paroxysmal symptoms with pain
such as in trigeminal neuralgia , and glossopharyngeal neuralgia, paroxysmal
dysarthria and ataxia; paroxysmal sensory disturbances with hemifacial spasm and
facial myokymia (persistent rapid flickering contractions of the facial musculature
especially under the eyes.)

Symptomatic Therapy

Ataxia/tremor: is difficult to treat, some positive result have been reported with:

Clonazepam 0.5 bid, Isoniazid 800-1200mg, Topamax 200-400mg, Gabapentin up to
3600 mg, Carbamazepine 800 mg, Ondansetron 4 mg bid

Carefully selected patients not responding to oral medication could benefit from
stereotactic thalamotomy, or deep brain stimulation,

Spasticity and spasms: An oromucosal spray (Sativex; GW Pharmaceuticals,
Wiltshire, UK) containing dronabinol (delta-9 tetrahydrocannibinol) and
cannabidiol (CBD), has become available for use as an add-on treatment for MS-
related spasticity that is not adequately controlled with current best treatments such
as:

 Baclofen (10-120mg), clonazepam (0.5-6mg), tizanidine (6-36mg), gabapentin (300-
3600mg) and/or, lamotrigine (200-400mg)

Botulinum toxin into specific muscles may also be effective

Fatigue and Ambulation

 Fatigue occurs commonly in MS patients and interferes with daily activities.
Studies have reported efficacy with the following drugs:

Amantadine (Symmetrel), 100 mg twice a day, Modafinil (Provigil) starts at 100 mg
- 400 mg/day ,methylphenidate (Ritalin) 10 to 60 mg/day in 2 to 3 divided doses,
Selective serotonin reuptake inhibitors : Fluoxetine (Prozac), 10 to 40 mg
,Bupropion XR 75-150 mg

 4-Aminopyridine and 3,4-diaminopyridine (3,4-DAP) are compounds that block
potassium channels in the axolemma, and a double-blind trial showed improvement
in motor strength and ambulation : Dalfampridine(Ampyra) 10 mg tab every 12
hours had shown positive results for this drug on walking ability.

 

 


Bladder dysfunction:

Symptomatic bladder dysfunction occurs at some time during the course of MS in
50% to 80% of patients. The severity of bladder symptoms is unrelated to the
duration of the disease but often parallels the severity of other myelopathic
symptoms. Differentiating between bladder spasticity and hypotonia is important
before initiating therapy, because different therapies are employed for each
condition. Initial steps in managing bladder dysfunction include timed voiding, fluid
management, , and the use of a bedside commode.

A- When the urinary symptoms are due to a hyperreflexic bladder (urgency,
frequency, and urge incontinence) without outlet obstruction.

Anticholinergic medications are often used for patients without outlet obstruction.
Oxybutynin (Ditropan) 2.5 to 5 mg 1 to 3 times daily. An extended-release
formulation is now available, tolterodine (Detrol or detrusitol)2mg bid or Detrol LA
4mg daily, fesoterodine,(Toviaz) 4-8mg daily,trospium (Sanctura XR), 60 mg
daily,darifenacin(Enablex)7.5-15 mg , solifenacin(VESIcare), 5-10mg daily,
Imipramine (Tofranil) 25 to 150 mg in divided daily doses (also helps enuresis),

DDAVP one to two nasal spray at bed time may also be tried.

Intravesical injection of botulinum toxin A is an effective treatment for symptoms of
bladder overactivity. Sacral neuromodulation with electrical stimulation of the S3-
nerve root can be considered in detrusor overactivity unresponsive to botulinum
toxin

B-When the urinary symptoms are due to hyperreflexic bladder with outlet
obstruction (incomplete emptying, residual urine):

 Anticholinergic drugs in addition to an Alpha 1 blockers such as indoramin or
cardular 2-4 mg can be used.

Depression

The prevalence rates for depression in patients with MS are higher than one might
expect from having a chronic disease or taking multiple medications. SSRIs are the
medications of choice .Amitriptyline, 25 to 100 mg daily with its anticholinergic
properties may be helpful to patients with symptoms of bladder dysfunction.

Cognitive problems

Cognitive decline is reported in patient with MS .Switching the patient to an
interferon beta 1a may reduce the decline.L-Amphetamine and provigyl may
improve attention and dexterity.Donepezil 5-23mg may improve dysfunction in
advanced cases.


Paroxysmal symptoms

Paroxysmal symptoms in MS consist of brief, almost stereotypical events occurring
frequently and often triggered by movement or sensory stimuli. These symptoms
include trigeminal neuralgia, shooting pains, paresthesia, tonic seizures, hemifacial
spasm, and dystonia. Anticonvulsants, Benzodiazepines, Baclofen, acetazolamide
(Diamox), ibuprofen, and bromocriptine

 

Sexual dysfunction:

The main complaints in male patients with MS are premature ejaculation, reduced
libido and erectile impotence. Alprostadil; 1.25 micrograms of alprostadil. The dose
may be increased by 1.25 micrograms to a dose of 2.5 micrograms, followed by an
increment of 2.5 micrograms to a dose of 5 micrograms, and then in 5-microgram
increments until the dose that produces an erection suitable for intercourse and not
exceeding a duration of 1 hour is reached,sildenafil-viagra :50-100mg ,tadalafil -
cialis: 10-20mg or 5 mg daily,Vardenafil -levitra:10-20mg.

In female patients with MS, the main complaints are reduced libido, difficulties in
achieving orgasm, and decreased vaginal lubrication; in women, well designed study
assessing sildenafil showed improved vaginal lubrication.

Interferons:

Interferons were the first medicine approved by the FDA in 1993 for RRMS.

 Decreased Relapse at 2 years by

Betaseron Beta 1b 8 MIU SC every other day 34%

Avonex Beta 1a 30 Mcg IM every week 29%

Rebiff Beta 1a 44Mcg SC three times per week 32%

 

 Disease Progression

Betaseron No significant change in disease progression occurred over 5 years

Avonex Although, reports claimed 37% reduction in disease progression

 Over 2 years.


Rebiff And although reports claimed time to first progression of

 disability was 21.3 months

Recent work published in the July18 2012 edition of Jama showed that: Among
patients with relapsing-remitting MS, administration of interferon beta1b
(betaseron) or beta 1a (Avonex and Rebif) was not associated with a reduction in
progression of disability.

The Side-effect profile: is similar between all interferons and includes Influenza-like
symptoms, which usually diminish over weeks to months and can be well managed
by nonsteroidal anti-inflammatory drugs prior to the injections.

Leukopenia, anemia and elevation of liver enzymes can occur, and blood
monitoring is recommended every 3 to 6 months.Depression,reactions at the
injection site are also common .A number of patients develop neutralizing
antibodies against interferons that may reduce the clinical efficacy of the drug.

Glatiramer acetate

In the Cochrane Database Syst Rev 2010, glatiramer acetate produced by Teva (the
Israeli pharmaceutical company) did not show any beneficial effect on the main
outcome measures in MS, i.e. disease progression, and it does not substantially affect
the risk of clinical relapses as shown in the Cochrane Database Syst Rev 2004.

Local injection-site reactions were observed in up to a half of patients treated with
glatiramer acetate, thus making a blind assessment of outcomes questionable .A
wide spectrum of cutaneous adverse events, the most frequently reported being
lipoatrophy, Nicolau Syndrome (cutaneous necrosis and ulcers), and various
immune-mediated inflammatory skin diseases and even anaphylactic reaction have
been reported after injection of glatiramer acetate in patients with multiple
sclerosis.

The systemic adverse events were flushing, chest tightness, palpitations and
maculopapular exanthema. Cases of alopecia, thyroid dysfunction and Guillain-
Barré syndrome have also been reported that improved dramatically after stopping
the glatiramer acetate.

Physicians should be aware that glatiramer acetate can be associated with
uncommon but yet significantly severe liver toxicity as reported in the Current Drug
Safety April 2012. Liver biopsy performed in Australia approximately 6 weeks after
commencement of glatiramer acetate showed predominantly centrilobular
hepatocyte necrosis with portal-venous bridging, along with mild portal and
interface hepatitis compatible with drug toxicity. Neuroscientists from Spain
reported similar findings.


Therefore its routine use in clinical practice is not currently supported despite
enormous promotion in many MS literature by its pharmaceutical company.
Moreover, independent medical journals not sponsored by pharmaceutical
companies showed that: With longer follow up –still no benefit in MS patients
(Prescrire Int. 2009)

In fact, most experienced international MS experts have abandoned using this drug
when the new effective disease-modifying therapies in multiple sclerosis surfaced.

Monoclonal Antibody

Natalizumab (Tysabri)

 A monoclonal antibody directed against the adhesion molecule, 4-integrin. Blocking
this molecule inhibits trafficking of lymphocytes from the blood into the CNS.

Two well-designed trials AFFIRM and SENTINEL led to FDA approval of this
agent. Natalizumab reduced relapse rate by 68% and progression of disability by
42% over 2 years. During the extension phase of the studies, two cases of
progressive multifocal leukoencephalopathy (PML) occurred in subjects receiving
both natalizumab and interferon beta 1a .This led biogen to withdrawal of
natalizumab from the market until July 2006, when it was reintroduced and
patients were enrolled in a TOUCH prescribing program (Tysabri Outreach:
Unified Commitment to Health) to monitor monthly for new neurological symptoms
that may be concerning for PML

Fingolimod (Gilenya)

It primarily acts to sequester circulating lymphocytes into secondary lymphoid
organs. 2 major studies confirmed efficacy. The first study FREEDOMS was a 24-
month, randomized, double-blind, placebo-controlled, multicenter study to
investigate fingolimod 1.25 mg versus 0.5 mg versus placebo on the annualized
relapse rate and EDSS and MRI progression over 24 months. There was 54%
reduction in annualized relapse rate and a 30 %s decrease in disability progression
and MRI lesions. No additional benefit was reported from the higher dose of
fingolimod

The second study called TRANSFORMS compared daily fingolimod 0.5 mg against
weekly IM interferon 30 µg. Superior efficacy was seen in the fingolimod group.

Adverse events

 Bradycardia (8-12bpm), herpesvirus infections, basal cell skin cancer, breast
macular edema, and pulmonary function test abnormalities. As noted by the EMA,
11 deaths have been reported due to any cause .It is not clear if these 11 deaths were
caused by Gilenya or not and the exact cause of death: 3 cases complications of


advanced MS, 3 cases of myocardial infarction, 2 cases of drowning, 2 cases of
unexplained death during sleep (including the November 2011 case),,1 case of
hypertensive cardiovascular disease, one patient who died within 24 hours of taking
Gilenya is still unexplained.

 

 

Promising Therapies

Alemtuzumab (Campath) is a humanized monoclonal antibody against CD52
antigen, which is expressed by all lymphocytes. It is administered as an IV over 3 to
5 days and depletes T cells and B cells for up to 1 year. In a Phase II study
randomized between high- and low-dose Campath (24 mg/day or 12 mg/day) against
high-dose interferon beta1a (Rebif), it showed efficacy in 75% relapse risk reduction
and 65% reduction in risk of sustained disability progression over 3 years . It
destroys multiple types of immune cells (T-cells, B-cells, Monocytes), thus reducing
autoimmunity.

Adverse events

Increased risk for immune thrombocytopenia, with one fatality, autoimmune
thyroiditis, renal failure and a high rate of infections and infusion hypersensitivity
reactions

 

 

BG-12(oral dimethyl fumarate) is approved for treatment of severe refractory
psoriasis in several European countries. It induces apoptosis of activated T cells and
it down-regulates intracellular adhesion molecules and VCAM expression and
induces anti-inflammatory cytokines. Phase II studies in RRMS have been
completed and show 69% reduction in new Gd-enhancing and T2 lesions in the
high-dose group. It showed efficacy in 32% relapse risk reduction and 15%
reduction in risk of sustained disability progression over 2 years. It has an excellent
safety profile

Safety concerns:

 GI upset in 2/3 of patients, flushing in 1/3 of patients, Upper respiratory infections

 

 

 

 

 


Cladribine

 

Cladribine is an oral purine nucleoside with lymphocyte depleting properties

 It disrupts cellular metabolism, induces DNA damage and subsequent cell death.

It was shown to suppress Gad-enhancing lesions in patients which received IV
Cladribine for 12 months. It showed efficacy in 58% relapse risk reduction and 20%
reduction in risk of sustained disability progression over 2 years

 

 

 Side effect

Headaches, lymphocytopenia, infection and neoplasia (skin, uterine, pancreatic, and
ovarian)

Rituximab

 Rituxan is a chimeric murine-human monoclonal antibody directed against CD20
antigen on B lymphocytes. It is approved for treatment of non-Hodgkin B-cell
lymphoma and rheumatoid arthritis. It is also used in lupus. Phase II trials of
rituximab in RRMS showed a significant 91% decline in Gd-enhancing lesions and
a 57% reduction in relapse rate over 48 weeks. Phase III study is ongoing.

Laquinimod

 An orally active synthetic experimental immunomodulator developed by Active
Biotech and Teva (the israeli pharmaceutical company).Like glatiramer acetate, the
exact mechanism of action is not known. On August 1, 2011, results from the Phase
III BRAVO study, which was designed to evaluate the efficacy, safety and
tolerability of oral 0.6 mg laquinimod compared to placebo and to provide a
benefit-risk assessment comparing oral laquinimod and a reference arm of
injectable Interferon ß-1a (Avonex®). The BRAVO study demonstrated a trend of
reducing the annualized relapse rate in laquinimod treated patients compared to
placebo, the primary end point of the study, but did not reach statistical significance
(p=0.075). The reduction of disability progression measured by EDSS also showed a
trend in favor of laquinimod without reaching statistical significance.

 

 

 

 

 

 


 Decreased Relapse at 2 years by

Campath 75%

Tysabri 68%

Cladribine 58 %

Gilenya 54 %

Teriflunomide 35 %

BG-12 32 %

Laquinimod similar to placebo

 Reduction in disability progression at 2 years

Campath 65 %

Tysabri 42 %

Gilenya 30 %

Cladribine 20 %

Teriflunomide 20 %

BG-12 15 %

Laquinimod similar to placebo

 

In Summary

There is a significant increase in the number and potency of new MS medications

With oral medications gaining increasing popularity and more convenient dosage
frequency.

Caution still advised with new agents. Adverse events are what we have learned
from initial trials, plus some additional ones that come up with time.

 

 

 

 


Treatment of Progressive Disease

The most successful trial for progressing patients was performed in Europe using
the chemotherapeutic agent, mitoxantrone (Novantrone), which produced a
reduction in the progression of disability and a considerable decrease in relapse rate
in patients with worsening RRMS and SPMS over a 2-year period. Improvement in
MRI measures of disease was also demonstrated.

Side Effect and toxicity profile

 1-The agent has dose-related cardiac toxicity that limits lifetime dosing to 140
mg/m2.

2-include nausea, alopecia, and neutropenia and secondary leukemias.

Corticosteroid

 Chronic monthly administration of corticosteroids in MS has not been
demonstrated to be effective

Stem Cell

A multinational effort is now underway to establish protocols and procedures for
use of bone marrow/ stem cell transplantation in selected MS patients

Interferon beta-1b

 Patients treated with interferon beta-1b (8 MIU every other day) had significant
reduction in relapse rate reduction, MRI analyses, hospitalizations, and steroid use
and delays in progression of disability. On average, this delay amounted to 9 to 12
months.

In Conclusion

 There are two reasonably successful treatments of SPMS: mitoxantrone and
interferon beta 1b. There are no available treatments for PPMS.

 

 

Written by Dr Ghassan George Haddad

American Board of Psychiatry and Neurology

 


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 

 

 

 

 

 

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