ArticlesEffect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study*
Introduction
Multiple sclerosis is a severe disorder of the central nervous system. In about 85% of patients, the disease begins with a relapsing stage; the relapses are associated with perivenular foci of inflammation in the white matter. In the initial phase, relapses are generally followed by complete or almost complete clinical recovery. After this relapsing-remitting phase, most patients enter a secondary progressive phase and accumulate irreversible neurological deficits.1, 2
Treatment of patients in the early phases of the disease may be advisable for two reasons. First, studies by pathology and magnetic resonance imaging (MRI) suggest that axonal damage is an early event in multiple-sclerosis lesions and normal-appearing white matter.3, 4, 5, 6 Second, a large proportion of patients presenting with clinically isolated syndromes suggestive of demyelinating events develop new neurological symptoms leading to a diagnosis of clinically definite multiple sclerosis. In these cases, the burden of brain lesions visible on T2-weighted MRI scans is a strong predictor of conversion.7, 8, 9, 10 Interferon beta is known to reduce greatly the extent of active MRI lesions and, as a consequence, the accumulation of the MRI-measured lesion burden.11, 12, 13, 14 This treatment given early in the course of multiple sclerosis might therefore affect the subsequent course of the disease, by decreasing the amount of inflammation.15
Phase III clinical trials have shown that various formulations of interferon beta can significantly reduce clinically assessed and MRI-measured disease activity in patients with relapsing-remitting multiple sclerosis.11, 12, 13, 14 In two of these trials, the progression of disability was also decreased, albeit to a lesser extent. These studies also suggested that the beneficial effect of interferon beta in multiple sclerosis increases with drug dose and varies according to disease duration.
In a 2-year follow-up study of patients with isolated optic neuritis, treatment with high-dose intravenous methylprednisolone reduced the early risk of conversion to clinically definite multiple sclerosis.16 Although this beneficial effect seemed to be lost after 4 years,17 the findings suggest that early initiation of treatment might be important among patients presenting with clinically isolated syndromes suggestive of multiple sclerosis.
This double-blind placebo-controlled randomised study aimed to assess the effects of low-dose interferon beta-1a (Rebif, Serono, Geneva, Switzerland) on the risk of conversion to clinically definite multiple sclerosis.
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Patients
Eligible patients had clinical syndromes indicating unifocal or multifocal involvement of the central nervous system, were aged 18–40 years, had presented with a first neurological episode suggesting multiple sclerosis in the previous 3 months, had one or more abnormalities evident during the neurological examination, and had a positive brain MRI scan. An MRI scan was judged positive when one of the following criteria was met: presence of at least four white-matter lesions on the T2-weighted
Results
375 patients were screened for the study (figure 1). 73 patients were found not to be eligible: MRI criteria were not satisfied in 21, inclusion or exclusion criteria were not satisfied in 41, eight withdrew consent, treatment could not be started in time for two, and one patient withdrew between recruitment and randomisation.
Of the 309 patients randomised, 278 (90%) completed the study. One patient in the placebo group did not receive study medication and is not included in outcome analyses.
Discussion
Pathology3, 4 and MRI studies5, 6, 26 suggest that axonal damage is an early event in the evolution of multiple sclerosis. Evidence is accumulating that, in the early phases of the disease, axonal damage depends primarily on inflammatory processes.27, 28 The mechanism of action of interferon beta in multiple sclerosis is predominantly anti-inflammatory.14 Therefore, better results would be expected with early than with later treatment of multiple sclerosis, consistent with the observed greater
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