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Abstract and Introduction
Abstract
Alemtuzumab is a humanized monoclonal antibody against CD52, an antigen found on lymphocytes and monocytes. Pulsed administration causes prolonged T-cell depletion and has been shown to be effective in early relapsing–remitting multiple sclerosis, reducing relapse rate and risk of acquiring disability in comparison with the standard therapy IFN-β. Alemtuzumab is currently approved for the treatment of B-cell chronic lymphocytic leukemia but not for multiple sclerosis. The most significant complication of treatment is the late development of autoimmunity, which occurs in 30% of patients. Serious infections are rare. Phase III trials are ongoing and it is possible that alemtuzumab will have a place among the range of emerging disease-modifying therapies for multiple sclerosis.
Introduction
Multiple sclerosis (MS) is the most common potentially disabling disease of the CNS of young adults in the western world (UK prevalence of 120 per 100,000 and UK annual incidence of seven per 100,000). It is an unpredictable illness; patients experience a fluctuating course and uncertain prognosis. This frightening nature is reflected in threefold-increased rates of depression and twofold-increased rates of suicide.
In most patients (85%), the illness starts as relapsing–remitting multiple sclerosis (RRMS), characterized by episodes of neurological symptoms separated by months to years of remission. Recovery from relapse is at first usually complete but later in the disease often leaves residual disability. Most patients eventually reach a phase in which remissions no longer occur and experience an inexorable worsening of their disease (secondary-progressive MS). A minority (15%) of patients have steadily worsening disease from the outset, termed primary-progressive MS (PPMS).
An MS relapse can affect any part of the CNS, causing an array of different symptoms (Figure 1). The associated pathology is focal areas of demyelination and axonal damage associated with infiltration of T cells and activation of macrophages. Epidemiological studies suggest that this is triggered by an as yet unknown environmental agent in individuals with a complex genetic susceptibility.
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Figure 1.
Symptoms and signs of multiple sclerosis by site.
Adapted from .
The diagnosis of MS requires the demonstration of two episodes of demyelination within the CNS, in separate anatomical locations and at different times. This has been formalized recently in the McDonald criteria, which allow for demonstration of lesions on MRI scans to replace clinical evidence of relapses in some situations (Table 1). The criteria are strictly applied in research; in routine practice they provide a framework rather than rigid definition.
The treatment of MS can be divided into symptomatic therapy, treatment of a relapse and disease-modifying treatment. There are treatments for many of the symptoms caused by MS. Particularly when used in the context of a specialist multidisciplinary team, these can give significant relief and improve quality of life. Pulsed high-dose corticosteroids shorten the duration of a relapse, but do not alter the residual disability acquired from the relapse and have not been demonstrated to have any clinical impact on the disease in the long term. A meta-analysis has shown no difference in outcome between intravenous or oral, and between inpatient or outpatient, treatment with high-dose methyl-prednisolone. Plasma exchange has shown benefit in the treatment of steroid-resistant relapses in a very small randomized study.
The consensus is that conventional immunosuppressant therapies are either ineffective or excessively toxic in comparison with current first-line disease-modifying therapies of MS; this certainly applies to ciclosporin, cyclophosphamide, sulfasazine and methotrexate. More recently, trials have been undertaken with combination therapy of such drugs, in low dose, combined with IFN-β. Azathioprine is currently being reassessed as a possible cheap alternative to the interferons, although its risk of malignancy long-term remains an uncertainty.
This review summarizes the current licensed disease-modifying agents for MS and tabulates the key agents currently undergoing trials. This describes the context in which alemtuzumab (Campath® or MabCampath®, Genzyme) may find a role in routine practice.
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