The treatment of multiple sclerosis has changed over the last 20 years. The advent of disease-modifying drugs in the mid-1990s heralded a period of rapid progress in the understanding and management of multiple sclerosis. With the support of magnetic resonance imaging early diagnosis is possible, enabling treatment initiation at the time of the first clinical attack. As most of the disease-modifying drugs are associated with adverse events, patients and clinicians need to weigh the benefit and safety of the various early treatment options before taking informed decisions.

1. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for the treatment of a first clinical attack suggestive of MS compared either with placebo or no treatment;

2. to assess the relative efficacy and safety of disease-modifying drugs according to their benefit and safety;

3. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for treatment started after a first attack (‘early treatment’) compared with treatment started after a second attack or at another later time point (‘delayed treatment’).

We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register, MEDLINE, Embase, CINAHL, LILACS, clinicaltrials.gov, the WHO trials registry, and US Food and Drug Administration (FDA) reports, and searched for unpublished studies (until December 2016).

We included randomised and observational studies that evaluated one or more drugs as monotherapy in adult participants with a first clinical attack suggestive of MS. We considered evidence on alemtuzumab, azathioprine, cladribine, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, immunoglobulins, interferon beta-1b, interferon beta-1a (Rebif®, Avonex®), laquinimod, mitoxantrone, natalizumab, ocrelizumab, pegylated interferon beta-1a, rituximab and teriflunomide.

Two teams of three authors each independently selected studies and extracted data. The primary outcomes were disability-worsening, relapses, occurrence of at least one serious adverse event (AE) and withdrawing from the study or discontinuing the drug because of AEs. Time to conversion to clinically definite MS (CDMS) defined by Poser diagnostic criteria, and probability to discontinue the treatment or dropout for any reason were recorded as secondary outcomes. We synthesized study data using random-effects meta-analyses and performed indirect comparisons between drugs. We calculated odds ratios (OR) and hazard ratios (HR) along with relative 95% confidence intervals (CI) for all outcomes. We estimated the absolute effects only for primary outcomes. We evaluated the credibility of the evidence using the GRADE system.

We included 10 randomised trials, eight open-label extension studies (OLEs) and four cohort studies published between 2010 and 2016. The overall risk of bias was high and the reporting of AEs was scarce. The quality of the evidence associated with the results ranges from low to very low.

Early treatment versus placebo during the first 24 months’ follow-up

There was a small, non-significant advantage of early treatment compared with placebo in disability-worsening (6.4% fewer (13.9 fewer to 3 more) participants with disability-worsening with interferon beta-1a (Rebif®) or teriflunomide) and in relapses (10% fewer (20.3 fewer to 2.8 more) participants with relapses with teriflunomide). Early treatment was associated with 1.6% fewer participants with at least one serious AE (3 fewer to 0.2 more). Participants on early treatment were on average 4.6% times (0.3 fewer to 15.4 more) more likely to withdraw from the study due to AEs. This result was mostly driven by studies on interferon beta 1-b, glatiramer acetate and cladribine that were associated with significantly more withdrawals for AEs. Early treatment decreased the hazard of conversion to CDMS (HR 0.53, 95% CI 0.47 to 0.60).

Comparing active interventions during the first 24 months’ follow-up

Indirect comparison of interferon beta-1a (Rebif®) with teriflunomide did not show any difference on reducing disability-worsening (OR 0.84, 95% CI 0.43 to 1.66). We found no differences between the included drugs with respect to the hazard of conversion to CDMS. Interferon beta-1a (Rebif®) and teriflunomide were associated with fewer dropouts because of AEs compared with interferon beta-1b, cladribine and glatiramer acetate (ORs range between 0.03 and 0.29, with substantial uncertainty).

Early versus delayed treatment

We did not find evidence of differences between early and delayed treatments for disability-worsening at a maximum of five years’ follow-up (3% fewer participants with early treatment (15 fewer to 11.1 more)). There was important variability across interventions; early treatment with interferon beta-1b considerably reduced the odds of participants with disability-worsening during three and five years’ follow-up (OR 0.52, 95% CI 0.32 to 0.84 and OR 0.57, 95% CI 0.36 to 0.89). The early treatment group had 19.6% fewer participants with relapses (26.7 fewer to 12.7 fewer) compared to late treatment at a maximum of five years’ follow-up and early treatment decreased the hazard of conversion to CDMS at any follow-up up to 10 years (i.e. over five years’ follow-up HR 0.62, 95% CI 0.53 to 0.73). We did not draw any conclusions on long-term serious AEs or discontinuation due to AEs because of inadequacies in the available data both in the included OLEs and cohort studies.

Very low-quality evidence suggests a small and uncertain benefit with early treatment compared with placebo in reducing disability-worsening and relapses. The advantage of early treatment compared with delayed on disability-worsening was heterogeneous depending on the actual drug used and based on very low-quality evidence. Low-quality evidence suggests that the chances of relapse are less with early treatment compared with delayed. Early treatment reduced the hazard of conversion to CDMS compared either with placebo, no treatment or delayed treatment, both in short- and long-term follow-up. Low-quality evidence suggests that early treatment is associated with fewer participants with at least one serious AE compared with placebo. Very low-quality evidence suggests that, compared with placebo, early treatment leads to more withdrawals or treatment discontinuation due to AEs. Difference between drugs on short-term benefit and safety was uncertain because few studies and only indirect comparisons were available. Long-term safety of early treatment is uncertain because of inadequately reported or unavailable data.

This summary presents data about the benefit and side effects of some disease-modifying drugs used at the time when multiple sclerosis is diagnosed after a first clinical attack. We reviewed the available evidence to answer three questions: 1) is early treatment beneficial and safe? 2) which drug is best for early treatment? 3) is early treatment better than later treatment?

Sufficient data were available from 22 studies on the following drugs: cladribine (Movectro), glatiramer acetate (Copaxone), interferon beta-1b (Betaferon), interferon beta-1a (Rebif; Avonex), and teriflunomide (Aubagio).

First question: is early treatment beneficial and safe?

Disability-worsening
Among people who took Aubagio or Rebif, 28 people out of 100 experienced disability-worsening over two years’ treatment compared to 34 people out of 100 who took placebo (6% absolute benefit). The overall quality of the included studies is very low, so our confidence in this result is low.

Relapse
Early treatment was associated with lower proportions of people who had a second attack – ie who received a diagnosis of MS – during the first two years’ treatment, compared to people who took placebo. Among people who took Aubagio, 32 people out of 100 experienced recurrent relapses over two years’ treatment compared to 42 people out of 100 who took placebo (10% absolute benefit). Again, the overall quality of evidence is very low.

Serious side effects
Among people who took Aubagio, Avonex, Betaferon, Copaxone, Movectro, or Rebif, there is probably little or no difference in serious side effects over two years’ treatment compared with people who took placebo.

Side effects
Among people who took Betaferon, 11 people out of 100 experienced side effects compared to one person out of 100 people who took placebo (10% absolute harm). Among people who took Movectro, seven people out of 100 experienced side effects compared to two out of 100 people who took placebo (5% absolute harm). Among people who took Copaxone, six people out of 100 experienced a side effect compared to two out of 100 people who took placebo (4% absolute harm).

Second question: which drug is best for early treatment?

Disability-worsening
Indirect comparison of Rebif with Aubagio did not show any difference on reducing disability-worsening over two years’ treatment. However, there were few studies and the overall quality of evidence is very low.

Relapse

Only one study on Aubagio was available, so we cannot compare the effects of each drug compared with one other.

Side effects
Rebif and Aubagio were associated with fewer dropouts because of side effects compared with Betaferon, Copaxone, or Movectro.

Third question: is early treatment better than later treatment?

Disability-worsening
Among people who received early treatment with Avonex, Betaferon, Copaxone, or Rebif, 37 people out of 100 experienced disability-worsening at a maximum of five years’ follow-up compared with 40 people out of 100 who received later treatment (3% absolute benefit). However, the great variability between the studies and the low quality of the evidence make our confidence in this result low.

Relapse
Early treatment was associated with lower proportions of people who had a second attack at any follow-up up to 10 years, compared to people who received later treatment. Among people who received early treatment with Betaferon, Copaxone, or Rebif, 64 people out of 100 experienced recurrent relapses at a maximum of five years’ follow-up compared to 83 people out of 100 who received these drugs later (19% absolute benefit).

Side Effects
We did not draw any conclusions on long-term serious side effects or treatment discontinuation due to side effects because of inadequacies in the available data in the included studies.

Conclusion

The low-quality evidence of the included studies suggests a small and uncertain benefit with early treatment compared with placebo or later treatment in reducing disability-worsening and relapses.

We cannot draw conclusions on the long-term safety of these drugs when administered as early treatment because of inadequately reported or unavailable data.

Until convincing evidence of any difference on benefit between disease-modifying drugs becomes available, the drugs that have been in use in clinical practice for many years and whose safety profile is better understood are probably the most sensible choice for early treatment.