Therapeutic options in multiple sclerosis

CHRONIC CEREBROSPINAL VENOUS INSUFFICIENCY

Although MS is viewed by many to be an autoimmune disease, the evidence supporting this concept is elusive.¹⁰ There remains no evidence, for example, that Igs identified within the CSF of patients with MS are directed against any myelin proteins.¹¹
Into this breach comes the theory that MS is fundamentally a disorder

of venous backflow in any of several combinations of

veins draining the brain and spinal cord. In a

series of articles using transcranial color-coded sonography (TCCS),

Zamboni

et al.¹²

in Italy first reported in 2007 that, compared to 60 normal control

patients, 89 patients with MS had significantly increased

risk of bidirectional flow and/or reflux in deep

middle cerebral veins and the transverse sinus. The term CCSVI was

coined.

They subsequently expanded this approach using TCCS

and imaged extracranial veins with echo color Doppler (ECD).¹³

Examining 5 sets of potential venous abnormalities, they reported that

having at least 2 of 5 abnormalities correctly distinguished

between 65 patients with MS (at least 2

abnormalities in all patients) and 235 controls (0 patients with 2 of 5

abnormalities)

with 100% specificity and 100% sensitivity. Venous

catheterization of the azygous and internal jugular venous systems

appeared

to confirm the results in all 65 patients with MS

compared to 48 controls. A subsequent 18-month open-label treatment

study

of balloon angioplasty in these 65 patients

reported that, compared to baseline measurements, there was no

significant decrease

in annual relapse rate, but there was a higher

number of patients free of relapses and of gadolinium-enhancing lesions,

and

quality of life was improved in relapsing-remitting

multiple sclerosis (RRMS) on both physical and mental subscales at 6

and

18 months, but only minimally for progressive

patients at 6 but not 18 months.¹⁴

Notably, all patients stayed on their DMT, and in nearly 50% of cases,

internal jugular veins restenosed after angioplasty.

In a podium presentation at the annual Academy of

Neurology meeting in Toronto in the spring of 2010, Dr. Zamboni also

claimed

a significant number of these venous abnormalities

appear to be caused by congenital valvular problems in the veins,

although

the number of inspected cases was not clear.

Although MS is viewed by many to be an autoimmune disease, the evidence supporting this concept is elusive

Even if accurate, it is unclear if venous abnormalities represent a cause or an effect of MS. In addition, there
were a number

of methodologic issues raised by these studies,

including lack of blinding, use of a single sonographer, lack of

verification

at other clinic sites, and others.¹⁵

In a press release dated February 9, 2010, after training with Dr.

Zamboni, researchers at the University of Buffalo reported

62.5% of 280 patients with MS and 25.9% of 220

controls had at least 1 of the same 5 criteria abnormal (somewhat lower

percentages

for both groups when using 2 criteria as the

cutoff). Thus, they could not reproduce the remarkable 100% sensitivity

and specificity

of the Italian group. In addition, a collaboration

between the Italian and the Buffalo groups reported significantly lower

venous volumes in the intracranial veins of

patients with MS compared to controls.¹⁶ It is not immediately apparent, however, how venous backflow would result in lower intracranial venous volumes. In addition,

2 very recent controlled and blinded studies using either MRI (phase contrast and contrast-enhanced)¹⁷ or TCCS¹⁸

failed to confirm either the Italian or Buffalo reports. Finally, the

National Multiple Sclerosis Society and Multiple Sclerosis

Society of Canada have funded 7 2-year grants to

independently assess, using multiple different techniques and control

groups,

whether the general concept of CCSVI is relevant in

MS or not.

BIOMARKERS IN MS

A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic
processes, pathologic

processes, or pharmacologic responses to a

therapeutic intervention. An ideal biomarker should provide accuracy,

reproducibility,

high sensitivity to detect changes and disease

progression, and good correlation with other, validated disease

measurements.

Identification of markers that could make an

accurate MS diagnosis early in the disease process, predict the

development of

MS in high-risk populations, or predict response to

therapy would be extremely helpful.

Although intrathecal IgG synthesis is both a relatively sensitive and specific indicator of demyelination, the
presence of

oligoclonal bands (OCBs) and IgG synthesis in CSF

of patients is not pathognomonic of the disease, and can be found in

other

inflammatory neurologic diseases.¹⁹ Some studies suggest the presence of IgM oligoclonal bands could be a more specific indicator for the diagnosis of MS and

predict a worse clinical course and high relapse rate.²⁰ Intrathecal production of soluble vascular adhesion molecule (sVCAM-1) is elevated in patients with MS and might play a role

in predicting the progression from clinically isolated syndrome (CIS) to clinically definite MS.²¹ It has been recently suggested that patients with RRMS have significantly higher CSF levels of a-1 antichymotrypsin (A1AC),

a-1 macroglobulin (A2MG), and fibulin 1 as compared to control subjects.²²

Another study notes serum IgG antibodies against Epstein-Barr virus

nuclear antigen-1 are present during active immune responses

in MS, with good correlation with

gadolinium-enhancing lesions on MRI.²³

MRI has become an important method for early diagnosis of MS.²⁴ Baseline MRI pattern might also be a strong predictor for accumulation
of disability as suggested by the presence of spinal

cord, infratentorial, and gadolinium-enhancing

lesions seen on early scans and accumulation of disability 6 years

later.²⁵²⁶ Lower levels of N-acetylaspartate

and increased levels of myoinositol and creatine in normal-appearing

white matter have been seen in patients

with CIS, suggesting widespread axonal damage, and

correlated with early conversion to clinically definite MS, and poor

executive

function performance 3 years later.²⁴ Nonconventional MRI techniques also show promising results as demonstrated by significantly lower regional magnetization

transfer ratio values in patients with CIS and MSFC scores.

Interferon-ß (IFNß) is one of the first-line DMTs in MS and significantly reduces clinical and MRI disease
activity. However,

only half of patients respond well. In a cohort of

26 subjects with RRMS, including 14 IFNß nonresponders, analysis of

serum

cytokines showed that 6 of the nonresponders had

significantly elevated interleukin-17 compared with responders (p

< 0.001). Nonresponders were defined by the presence of clinical

relapses and use of steroids. Other markers including endogenous

IFNß production could help predict responsiveness

to IFNß.²⁷ Another potential marker of biologic response to interferon therapy is the presence of myxovirus-resistance protein A (MxA),

an antiviral protein exclusively induced by type 1 interferons.²⁸ Quantification of MxA expression might be a sensitive measure of IFNß activity.

EFFICACY AND SAFETY OF EMERGING ORAL THERAPIES

In the last decade, a new armamentarium of novel and promising neurotherapeutic strategies have been developed
and tested

in patients with MS. Of those, 2 oral therapies are

showing a high level of efficacy, with acceptable safety and

tolerability

profile, and are under FDA review.

Fingolimod (FTY720), an oral sphingosine-1-phosphate (S1P) analog, is a partial agonist on S1P receptors, thereby blocking the mechanism that allows lymphocytes to migrate out of secondary lymphoid structures.²⁹ Multiple treatment studies in patients with MS have been performed and reported in the last several years.^29,30 In comparison to weekly IM IFNß1a, oral fingolimod (0.5 mg daily dose) demonstrated a 52% relative reduction on annualized
relapse rate (p < 0.001; 95% confidence interval [CI] 0.12–0.21).²⁹ A second study comparing 2 doses of fingolimod (1.25 mg and 0.5 mg) showed similar efficacy with a relative reduction in

annualized relapse rate of 60% and 54%, respectively, compared to placebo (p < 0.001; 95% CI 0.13–0.19 and 0.15–0.22, respectively).³⁰

In addition, fingolimod also reduced the probability of disability

progression at 3 and 6 months over a 24-month period compared

to placebo (hazard ratios, 0.68 for the 1.25-mg

dose and 0.70 for the 0.5-mg dose). Adverse reactions included

bradycardia,

nasopharyngitis, dyspnea, headaches, diarrhea, and

nausea. Initial bradycardia was seen more frequently in the high-dose

group.

Three cases of basal cell carcinoma, 3 cases of

squamous cell carcinoma, and 1 case of melanoma have been reported. Two

fatalities

occurred during the trial associated with

intracerebral varicella zoster and herpes simplex virus infections. In

addition,

a single case of hemorrhagic encephalitis was also

reported with unclear causal relationship, as was 1 case of fatal, and

1 nonfatal, lymphoma.

Cladribine is a purine nucleoside analog that causes lymphotoxic effects by incorporation into DNA of resting and
dividing

cells with high deoxycytidine kinase activity

(lymphocytes and monocytes), and subsequent interruption on DNA

replication,

DNA damage, and cell death. In addition to its

lymphotoxic effects, cladribine possesses epigenetic properties, by

inhibiting

S-adenosyl homocysteine hydrolase and DNA

methylation. A recent placebo-controlled phase III trial using oral

cladribine in

patients with RRMS showed a 58% reduction in

annualized relapse rates (3.5 mg/kg daily for 4 to 5 days, with 2

courses in

the first year) at 2 years compared to placebo. In

addition, 80% of the patients remained relapse-free, compared with 61%

of the patients in the placebo group (p < 0.001 for both dose regimens). Patients in the active drug group experienced a 30% reduction in the risk of disability

progression relative to patients in the control group.³¹

Adverse events included headaches, nasopharyngitis, upper respiratory

tract infections, and nausea. Lymphopenia occurred

more frequently in the active drug group (22%). Of

the patients treated with cladribine tablets, 2.3% reported herpes

zoster

infections, although these were localized to the

skin and were responsive to preventative treatment.

Fingolimod is in the final stages of FDA approval process, with expected approval sometime in late summer or
early fall 2010,

and cladribine is on fast track as of August 2010.

These reports highlight the promising efficacy and potential significant

risks that accompany these new oral therapies. What

role they eventually play in the treatment of newly diagnosed and other

patients with MS remains to be seen.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY RISK WITH NATALIZUMAB THERAPY

Natalizumab, a humanized monoclonal antibody that binds to a-4 integrin molecule at the ß1 and ß7 epitopes,
prevents extravasation

of T and B cells into the CNS, and consequently

reduces inflammatory immune reactions in lesions of MS. Therapy with

natalizumab

has been shown to be highly effective in relapsing

forms of MS. However, natalizumab was associated with progressive

multifocal

leukoencephalopathy (PML), a rare opportunistic,

demyelinating viral infection of the CNS caused by JC virus (JCV),

shortly

after its approval in 2004, prompting temporary

cessation of all use in 2005. Between 50% and 86% of adults have

antibodies

against JCV, likely due to exposure to the virus

during early childhood.³²

It has been traditionally thought that JCV remains latent in the bone

marrow and kidneys of healthy individuals, and only

causes CNS infections under periods of

immunosuppression. Recent studies, however, suggest the infection is

active during

persistence at a basal level, and might be

activated by immune dysfunction. In addition, it is possible JCV is

already present

in the brain of healthy individuals and can undergo

reactivation after treatment with immunosuppressants.³³

During treatment with natalizumab, hematopoietic stem cells and pre-B

cells are forced to migrate from the bone marrow. Patients

with MS who receive natalizumab treatment have an

increase in CD34+ cells in their circulation, as well as an upregulation

of genes involved in B-cell maturation. This

dynamic creates a favorable environment for JCV, which can reside in a

latent

state in the bone marrow for long periods before

the development of PML and which can use B cells and their DNA-binding

proteins

to initiate viral multiplication.³³ These findings, however, were not supported by recent cross-sectional and longitudinal studies in this large cohort of patients

with MS, suggesting no substantial change in the presence of JCV DNA with natalizumab treatment.³⁴

Natalizumab was reintroduced in 2006. As of July 2010, 63 confirmed PML cases have been reported among more than
71,400 patients

exposed to natalizumab therapy. Based on those

numbers, the overall risk of PML is estimated to be 0.85 per 1,000

patients

(95% CI 0.65–1.09 per 1,000 patients). The duration

of therapy appears to impact the risk of developing PML, with higher

incidence

of PML with prolonged duration of treatment. As of

August 2010, among patients who had received 25 or more infusions, the

incidence of PML increased to 1.39 per 1,000

patients (95% CI 0.98–1.92). In addition, prior use of immunosuppressant

drugs

is associated with 4-fold higher risk of developing

PML. There are 2 clinical trials currently evaluating the presence of

anti-JCV antibodies in patients receiving

natalizumab therapy, both looking at patients independent of the

duration of treatment.

Although the ultimate significance of JCV antibody

titer as an indicator of PML risk is still unclear, it will be

advantageous,

if the test performs well, to know the antibody

status of patients before initiation and/or during natalizumab therapy.