Elsevier

The Lancet

Volume 349, Issue 9052, 1 March 1997, Pages 589-593
The Lancet

Articles
Randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis*

https://doi.org/10.1016/S0140-6736(96)09377-4Get rights and content

Summary

Background

Multiple sclerosis is an autoimmune disorder characterised by the repeated occurrence of demyelinating lesions within the central nervous system. Uncontrolled studies and experimental evidence suggest beneficial effects of repeated administration of intravenous immunoglobulin (IVIg) by immunomodulating mechanisms and induction or remyelination. We aimed to investigate the efficacy of IVIg in a randomised double-blind multicentre study.

Methods

Patients with relapsing-remitting multiple sclerosis were randomly assigned a monthly dose of IVIg (0·15–0·2 g/kg bodyweight) or placebo. Duration of treatment was 2 years. The primary outcome measures were the effect of treatment on clinical disability—measured by the absolute change in Kurtzke's expanded disability status scale (EDSS) score—and the proportion of patients with improved, stable, or worse clinical disability (⩾ 1·0 grade on EDSS score).

Findings

Of the 243 patients screened, 150 met our eligibility criteria and were randomly assigned to IVIg or placebo. Before the start of treatment two patients in the placebo group dropped out, so there were 75 patients in the IVIg group and 73 in the placebo group. Intention-to-treat analysis showed that IVIg treatment had a beneficial effect on the course of clinical disability. The EDSS score decreased in the IVIg-treated patients and increased in the placebo group (−0·23 [95% CI −0·43 to −0·03] vs 0·12 [−0·13 to 0·37], p=0·008). In the IVIg group, the numbers of patients with improved, stable, or worse clinical disability were 23 (31%), 40 (53%), and 12 (16%) compared with ten (14%), 46 (63%), and 17 (23%) in the placebo group. Side-effects were reported in three (4%) IVIg-treated patients and in four (5%) placebo-group patients, but were not directly linked to study medication.

Introduction

Multiple sclerosis is the most common demyelinating disorder of the central nervous system, and is characterised by repeated episodes of neurological dysfunction with variable remission. Previous studies have suggested that autoimmune mechanisms have an important role in the pathogenesis of multiple sclerosis.1, 2 Intravenous immunoglobulin (IVIg) has been successful in other autoimmune neurological disorders, such as acute and chronic inflammatory demyelinating radiculoneuropathies,3, 4 myasthenia gravis,5 and dermatomyositis.6 Yan and colleagues7 recommended IVIg treatment for acute exacerbations of multiple sclerosis and three uncontrolled or open-label studies reported a beneficial effect of long-term IVIg treatment on the course of the disease.8, 9, 10, 11 Several immunological mechanisms may be involved in multiple sclerosis.12, 13 IVIg produced from pooled blood from healthy donors may contain antiidiotypic antibodies, which have regulatory effects on antibody production and lymphocyte activity.14 IVIg may also reduce the autoaggressive effect of macrophages by blocking their Fc-receptors,15 or it may act as a receptor for activated complement components preventing their binding to the oligodendrocyte surface and myelin proteins.16 In addition, IVIg can down-regulate cytokine production and neutralise inflammatory cytokines.17 All these mechanisms are involved in the pathogenesis of multiple sclerosis lesions.

Experiments in mice have shown that IVIg may promote remyelination within demyelinative lesions induced by Theiler's virus.18 The clinical significance of this mechanism was supported by van Engelen and colleagues' study19 of five multiple sclerosis patients with optic neuritis: after a period of stable visual impairment for between 7 months and 4 years, IVIg treatment led to an increase in visual acuity and colour vision 1–2 months after the start of treatment which continued thereafter.19 This finding suggests that repeated IVIg therapy may not only delay or prevent the progression of multiple sclerosis but can even induce clinical improvement.20

Our randomised, double-blind, placebo-controlled, multicentre study was designed to assess the effect of monthly IVIg treatment on the clinical course of relapsingremitting multiple sclerosis.

Section snippets

Methods

Between December, 1992, and January, 1996, 243 patients from 13 neurological centres throughout Austria were considered for enrolment in our study.

Our definition of relapsing-remitting multiple sclerosis included individuals with complete and incomplete remissions.21 Inclusion criteria were a clinically definite diagnosis of relapsingremitting multiple sclerosis,22 a baseline Kurtzke's expanded disability status scale (EDSS)21 score of between 1·0 (minor neurological signs but no disability)

Results

Of the 243 patients screened for eligibility, 93 did not meet the inclusion criteria: 17 had an EDSS score of less than 1·0 or more than 6·0; 16 had too low progression rates; seven had had fewer than two relapses within the previous 2 years; 12 did not have relapsing-remitting multiple sclerosis; 14 were taking immunomodulatory drugs, four were not available to take part in the study; 12 did not give their consent; and 11 were excluded for other reasons. Two patients withdrew their consent to

Discussion

Our study is the first large-scale placebo-controlled trial of the efficacy of long-term IVIg treatment in relapsingremitting multiple sclerosis. Our findings show that a monthly dose of IVIg (0·15–0·20 g/kg bodyweight) improved the course of clinical disability and reduced the frequency of relapses. At the end of 2 years, the magnitude of the absolute change in EDSS score and, thus, in clinical disability was small in both groups. However, the between-group difference in absolute change in

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