Gonsette.qxp 18/7/07 15:43 Page 20
Multiple Sclerosis
to the discontinuation of clinical trials combining Fingolimod with lymphocytes. Monocytes and B cells return to normal within three months,
other immunosuppressants. Combination therapies with Fingolimod but T-cell depletion persists for up to five years. Administration of
should thus be considered cautiously. alemtuzumab early after disease onset (mean disease duration 2.7 years) not
only stopped relapses but also yielded a definite reduction in disability state
Rituximab
Rituximab is a monoclonal Ab binding to the CD20 surface molecule that
induces a selective, long-lasting depletion of B cells that is only partially
reconstituted after one year. B cells play an important role in humoral
The main side effect of alemtuzumab
immune mechanisms, which seem to predominate in certain MS
phenotypes such as Marburg’s and Devic’s diseases, in which rituximab is a cytokine-release syndrome requiring
provided a substantial improvement. Rituximab has been rarely
pre-treatment with corticosteroids.
administered to MS patients, but recent trials in a small number of patients
with the RR type suggest a positive effect on relapses and Gd+ lesions.
Unfortunately, like other immunosuppressants, rituximab exposes patients
to potential adverse reactions and the FDA has recently reported 21
patients with PML after rituximab therapy for haematological malignancies. over two years.
17
These observations suggest that a very early suppression
of the inflammatory environment likely reduces the production of microglial
BBR2778 (Pixantrone
®
) toxic factors and the early concomitant axonal loss. The main side effect of
Pixantrone
®
is an analogue of MX without severe cardiotoxicity. In alemtuzumab is a cytokine-release syndrome requiring pre-treatment with
addition, its weaker DNA-constant binding and its lower stimulation of corticosteroids. The development of autoimmunity after alemtuzumab
topoisomerase II-mediated DNA alterations suggest a lower risk of administration is another concern, leading to Graves’ disease in 27% of
TRAL. In animal experiments, pixantrone was found to be less treated patients and, less frequently, to Goodpasture’s syndrome.
cardiotoxic than MX, and its immunosuppressive activity on the cellular
and humoral components of the immune system is the same as that of Conclusions
MX. This new molecule might thus be an interesting substitute for MX The overall benefit of INFβ and GA is modest. Nevertheless, given their
in MS patients, and a phase I/II trial is in progress. acceptable tolerance there is ample evidence to recommend early and
continuous treatment with one of these immunomodulators in order to
Alemtuzumab (Campath-1H
®
) delay the conversion of patients from the clinical isolated syndrome to
Alemtuzumab, a monoclonal Ab targeting the surface CD52 molecule confirmed MS and the shift from the RR to the secondary-progressive (SP)
phase. Mitoxantrone can block disease evolution in most patients with
Rituximab has been rarely administered
breakthrough MS. Long-term tolerance appears acceptable when properly
administered. Adverse cardiac events can be avoided with careful
to multiple sclerosis patients, but recent
monitoring of myocardial functions. However, cardiotoxicity remains a
trials in a small number of patients with
strict dose-limiting factor and there is no clear therapeutic strategy so far
to maintain the benefit after an effective MX immunosuppression. After a
the relapsing-remitting type suggest a
temporary suspension of alemtuzumab (February 2005 to June 2006), the
positive effect on relapses and
FDA recommended its return to market. Given that the mechanisms
responsible for PML occurrence are unknown and that there is no cure for
gadolinium-enhancing lesions.
PML, careful patient selection and monitoring according to recent
recommendations are essential before starting treatment.
18
Several
mainly expressed on T lymphocytes and monocytes, is a potent and selective experimental therapies appear promising, but the follow-up is too short to
immunosuppressant of cellular immunity leading to a complete deletion of fully appreciate their long-term toxicity. ■
1. Goodin DS, Frohman EM, Hurwitz B, et al., Neutralizing A274, P06.077. promyelocytic leukemia following mitoxantrone treatment in
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20 EUROPEAN NEUROLOGICAL DISEASE 2007
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