Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study

Summary

Background

High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4–6 years after disease onset.

Methods

In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0–2 years (early) or 4–6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0–10, with higher scores indicating increased disability), at 6–10 years after disease onset, assessed with a linear mixed-effects model.

Findings

We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7–8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of −0·98 (95% CI −1·51 to −0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6–10 year follow-up period.

Interpretation

High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6–10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy.

Funding

National Health and Medical Research Council Australia and MS Society UK.

Introduction

Multiple sclerosis is the leading non-traumatic cause of neurological disability in young adults.¹ The most common paradigm for treatment of relapsing-remitting multiple sclerosis, endorsed by many regulatory bodies, is treatment escalation. According to this paradigm, patients first start a low-risk, moderate-efficacy immunotherapy, switching to more efficacious therapies, with more serious side-effect profiles, if breakthrough disease activity is encountered.²

Rituximab,³ ocrelizumab,⁴ mitoxantrone,⁵ alemtuzumab,6, 7 and natalizumab⁶ (hereafter collectively called high-efficacy therapies) confer a greater reduction in relapse rates than do the traditional first-line drugs interferon-beta and glatiramer acetate. Whether early initiation of high-efficacy therapies also reduces accrual of long-term disability compared with later initiation is unclear.

No randomised trials have specifically addressed this question because of the cost and logistical aspects of recording long-term outcomes and ethical considerations, among other factors.⁸ High quality longitudinal observational data are valuable to address such questions by taking advantage of the heterogeneity in treatment protocols due to differences in drug licencing and availability across different geographical and historical patient cohorts.9, 10, 11

Research in context

Evidence before this study

We previously did a literature search using Ovid MEDLINE (for publications between Jan 1, 1950, and May 31, 2016), EMBASE (for publications between Jan 1, 1947, and May 31, 2016), and Cochrane Database of Systematic Reviews (for publications between Jan 1, 1998, and May 31, 2016) to identify reports of clinical studies, clinical trials, comparative studies, multicentre studies, observational studies, or randomised controlled trials. The search terms were “fingolimod” OR “natalizumab” OR “alemtuzumab” and both “multiple sclerosis” AND “relapsing-remitting multiple sclerosis”. This systematic review identified 12 relevant publications and its result was published in April, 2017. We have updated this literature search with a new search of PubMed, for publications between June 1, 2016, and June 10, 2019, which identified two additional relevant reports. The literature, consisting mostly of open-label extensions of randomised placebo-controlled trials, suggests that treatment of patients with relapsing-remitting multiple sclerosis with high-efficacy immunotherapies (natalizumab or alemtuzumab) is more potent in suppressing relapse activity when initiated early than when initiated with a delay after the diagnosis. An observational study showed that patients who commenced natalizumab or alemtuzumab as their first immunotherapy had a slower increase in disability over 5 years than did those who started other therapies. Escalation to natalizumab, alemtuzumab, or fingolimod within 5 years from disease onset is associated with a reduced risk of conversion to a secondary progressive disease course. To our knowledge, no information about the importance of timing of high-efficacy therapy on long-term disability outcomes in multiple sclerosis has been published to date.

Added value of this study

This study provides novel evidence about the long-term effectiveness of high-efficacy therapies (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, natalizumab) when commenced early (within 2 years) versus with a delay (within 4–6 years) from first clinical presentation of relapsing-remitting multiple sclerosis. Earlier initiation of high-efficacy therapies among patients who qualified for these therapies was associated with lower disability (close to 1 step on the Expanded Disability Status Scale) sustained at least 6–10 years from disease onset.

Implications of all the available evidence

Our findings suggest that high-efficacy immunotherapies provide the most benefit to patients with active relapsing-remitting multiple sclerosis when started without delay, early after first clinical presentation of multiple sclerosis. We propose that highly potent therapies should be considered as a first-line choice in these patients. Accurate and timely identification of patients in the greatest need of an aggressive therapeutic approach is a subject of our future research.

Here we compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with outcomes of patients who started 4–6 years after disease onset.