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Advances in Treating Multiple Sclerosis
suppressor acting on intracellular ligands with an exceptionally long (RRR 42 versus ~20%). Unfortunately, two out of 1,216 patients treated
terminal half-life. In addition, it is sequestered for weeks in deep tissues with natalizumab experienced progressive multifocal leucoencephlopathy
and slowly released. Immunocompetent cells are thus exposed to MX for
long periods of time, which explains the efficacy of quite low doses
(12mg/m
2
) administered as infrequently as once every three months.
Importantly, MX exerts immunosuppressive effects on both cellular and
It has been observed in animal
humoral parts of the immune system. In addition to the inhibition of
experiments that Fingolimod
antigen- and non-antigen-specific proliferation of activated T cells,
B cells and dendritic cells, a selective and long-persisting decrease in
strongly reduces transmigration of
B lymphocytes and antibody production is consistently observed.
macrophages into brain parenchyma.
It has come to be accepted that MX provides an effective treatment in
most acutely worsening MS patients who do not respond to IFNβ or GA.
7
The best responders to MX therapy are patients with an RR course, more (PML) – a JC virus infection. Even though both of these patients were
than three relapses in the previous 24 months and at least one Gd+ participating in the trial combining IFNβ and natalizumab,
14
it seems
lesion.
8
Two important issues can be addressed: the most effective and unlikely that IFNβ contributed to the onset of PML.
least toxic treatment regimen, and the optimal maintenance therapy. The
eradication of Gd+ lesions within three months of monthly infusions There is no definite explanation concerning the emergence of PML in
versus six months after quarterly administration favours a treatment MS patients treated with natalizumab. However, neutralising VLA-4
regimen combining an induction phase of three monthly infusions may have unpredictable consequences, as this molecule has other
followed by administration every three months as a maintenance therapy. important functions. Notably, VLA-4 plays a role in the formation of the
The cardiotoxicity of MX is a major dose-limiting factor. Cumulative doses immune synapse and in the cell interaction between CD8 cytotoxic
over 140mg/m
2
can lead to severe and irreversible myocardial T cells and their target. Interestingly, natalizumab administration leads
dysfunction. However, there is a growing appreciation that cardiotoxicity to a net decrease of the CD4/CD8 ratio in the CSF
15
similar to that
can occur at lower cumulative doses. The FDA has thus recently updated observed in HIV-infected patients, of whom 5% develop PML. CD4 cells
its warnings and recommends a control of the left ventricular ejection play an important role in the control of JC virus and their reduction in
fraction (LVEF) before every dose. Another concern about MX toxicity is the CSF may put MS patients at an increased risk. On the other hand,
the delayed occurrence of therapeutic-related acute leukaemia (TRAL). It natalizumab favours the release of bone-marrow cells and possibly of
is difficult to correctly appreciate the risk of TRAL, as the exact number of those harbouring JC virus. Finally, the physiological trafficking of
MS patients exposed to MX is unknown and cases of TRAL can be subject lymphocytes from blood to CSF and brain parenchyma represents the
to under-reporting. According to the data from two prospective post- essential immunosurveillance that is possibly impaired by natalizumab.
marketing studies
9,10
on a total of 1,311 patients, the incidence is
between 0.20 and 0.25%. However, 19 sporadic cases have been Experimental Therapies
reported in the literature with a worrying incidence in two centres of
2.7% (3/111 patients)
11
and 0.8% (2/250 patients).
12
FTY720 (Fingolimod
®
)
Fingolimod
®
converts endogenous sphingosine into its phosphate form,
Natalizumab (Tysabri
®
) which is a high-affinity agonist of the sphingosine 1 (S1P1) receptor.
Natalizumab, an immunosuppressor acting on cell-surface ligands, is a Fingolimod first accelerates homing of lymphocytes to lymph nodes and
humanised monoclonal antibody targeting the α4 integrin chain of the then blocks egress of lymphocytes from lymphoid tissues. The
VLA-4 adhesion molecule involved in transendothelial cell migration of lymphocyte sequestration in lymphoid tissues leads to a major decrease
immunocompetent cells into brain parenchyma. Leukocyte and in T- and particularly B-cell count (25% of baseline values) in peripheral
lymphocyte counts in peripheral blood remain unaltered. In contrast, blood. Fingolimod also causes thymocyte apoptosis, inhibits vascular
all lymphocyte subtypes are significantly reduced in the cerebrospinal endothelial growth factor (VEGF)-induced brain capillary leakage,
impairs dendritic cell trafficking and induces a shift from Th1 (pro-
It has come to be accepted that
inflammatory) to Th2 (anti-inflammatory) cytokine production. It has
been observed in animal experiments that Fingolimod strongly reduces
mitoxantrone provides an effective
transmigration of macrophages into brain parenchyma.
treatment in most acutely worsening
In a preliminary phase II trial in RR MS patients,
16
a marked reduction
multiple sclerosis patients who do not
in the relapse rate and Gd+ lesions was demonstrated at months 12
respond to interferons-beta or
and 18. The most frequent side effects were infection and increased
blood pressure. Bradycardia is commonly observed within six hours of
glatiramer acetate.
the first administration, but disappears with continued treatment.
It is too early to fully appreciate the future interest of this
fluid (CSF), likely mirroring reduced brain infiltration. In RR MS patients, immunosuppressant in MS, given its potential long-term toxicity. One
natalizumab reduces Gd+ lesions by 92%.
13
The benefit seems better case of reversible posterior encephalopathy with a residual
than after administration of IFNβ or GA; this also applies to relapses homonymous hemianopsia was reported. It is of note that other safety
(relative risk reduction (RRR) 68 versus 33%) and disability progression issues – such as macular oedema and pulmonary complications – led
EUROPEAN NEUROLOGICAL DISEASE 2007 19