Interferon, azathioprine and corticosteroids in multiple sclerosis: 6-year follow-up of the ASA cohort

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Abstract

Objective

To evaluate long-term effects of 2-year treatment with interferon beta combined with low-dose azathioprine and prednisone in multiple sclerosis.

Methods

In the original 2-year ASA study, 181 patients with early relapsing–remitting multiple sclerosis were randomised into 3 treatment arms: those treated with interferon beta (n = 60), with interferon beta and low-dose azathioprine (n = 58), and interferon beta, azathioprine and low-dose prednisone (n = 63). Of these, 172 were included in this 4-year non-study extension. Three monthly clinical controls and annual MRI scans were carried out. The primary endpoint was annual relapse activity. The secondary endpoints were disability and quantitative MRI parameters.

Results

Nine patients were lost to follow-up and 172 were included in the analyses. None of relapse activity, disability accumulation or MRI parameters differed significantly between the groups over 6 years. Only 5.5% and 0.6% of patients were free from disease activity at year 2 and year 6 of the treatment initiation.

Conclusion

The tested combined therapeutic regimen does not improve long-term outcomes in patients with multiple sclerosis. Furthermore, interferon is not able to completely abolish disease activity.

Introduction

Interferon (IFN) β is the most common immunomodulatory substance used in multiple sclerosis (MS); yet, its efficacy is only limited (reported reduction in relapse rate ranges from 18% to 34% [1]). Combination of IFN with other agents might enhance its clinical effect (for review see [2]). Particularly those targeting pathophysiological mechanisms other than those altered by IFNβ are likely to show synergistic effect. For instance, corticosteroids are known to attenuate inflammation and tissue damage during relapses in MS [3], [4]. Moreover, it was suggested that corticosteroids in high-dose pulses may ameliorate brain atrophy and disability progression [5]. Clinical trials showed that combination of IFN and oral methylprednisolone decreases frequency of relapses, T2 lesion volume (T2LV), however with no effect on disability progression [6], [7]. Immunosuppressant agents are recognised as a second-line therapy for MS. In combination with IFN, they were reported to decrease T2LV and number of gadolinium-enhancing lesions [8], [9]. On the other hand, immunosuppressants are associated with a number of adverse effects, including bone marrow suppression, hepatotoxicity and malignancies. Their use in combination with disease modifying drugs may allow for decrease in dose, thus ameliorating their side effects.

Here we present results of 4-year extension of the original 2-year ASA (Avonex–Steroids–Azathioprine) study, a randomised, double-blind, placebo-controlled trial that evaluated combination of IFNβ with low-dose azathioprine and low-dose prednisone in relapsing–remitting MS. The 2-year outcomes have been previously published in Havrdova et al. [10] and have suggested only marginal effect of the combination treatment on the relapse rate (p = 0.06), with no effect on disability and MRI parameters (T2LV and percentage brain volume change). The aim of the current 4-year extension was to evaluate long-term efficacy of this combined treatment when administered for at least 2 years. We hypothesised that the combination of IFNβ with immunosuppressants and corticosteroids would allow to use lower doses of the latter two with improved clinical and MRI outcomes.

Section snippets

Subjects

This study was approved by the Medical Ethics Committee of the General University Hospital and the First Faculty of Medicine, Charles University in Prague and was performed in accordance with the 1964 Declaration of Helsinki. Written informed consent was obtained from all patients upon enrolment in the original ASA study as well as its 4-year extension.

The original ASA study was a 2-year randomised, double-blind, placebo-controlled trial investigating clinical and MRI outcomes of IFNβ-1a

Results

Out of 191 patients screened in the original ASA study, data from 172 patients with complete 6-year clinical and MRI follow-up were used in our current intention-to-treat analysis (see Fig. 1). The details of adherence to treatment are shown in Table 1. On average, the original treatment remained unchanged for 43 (27–72) months [median (interquartile range)], with 46 patients on the original treatment throughout the 6-year follow-up period. Demographic and basic clinical characteristics of the

Discussion

In this work we have presented results of 4-year non-study extension of the original ASA study. We have shown that the combination of interferon β with low-dose azathioprine and prednisone does not improve 6-year outcomes in patients with clinically active multiple sclerosis.

The original ASA study reported a statistically non-significant decrease in the proportion of patients with relapses after 2 years of combination treatment with IFN, azathioprine and prednisone [10]. In this extension of

Acknowledgements

The authors thank all patients who participated in the ASA study, the personnel at our MS Centre, and the contributors from the 2nd Faculty of Medicine, Charles University in Prague – Dr. Eva Houzvickova, Dr. Eva Meluzinova and Dr. Jana Pikova. This work was supported by the Czech Ministry of Education [MSM 0021620849 and MZOVFN2005]. MRI acquisition and analysis was supported by Schering Plough, Gedeon Richter and Biogen Idec.

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