Early Treatment and the Transition From Clinically Isolated Syndrome to MS

The findings from the extension study support prior research that showed the benefits of early treatment.

Early treatment with interferon beta-1b (IFNß-1b) delayed progression to multiple sclerosis (MS) when given at the first signs of clinically isolated syndrome (CIS), according to the latest results from the 8-year extension of the Betaferon/Betaseron in Newly Emerging MS for Initial Treatment (BENEFIT) trial.  The 11-year follow-up findings to the double-blind, randomized, placebo-controlled BENEFIT CIS trial were reported in Neurology.

Up to 85% patients with CIS go on to be diagnosed with MS according to criteria of MRI evidence for dissemination of lesions in time and space.1,2 “Not much research has been done on how starting treatment this early affects the long-term course of the disease,” Ludwig Kappos, MD, who is chair of the department of neurology at the University Hospital Basel, in Basel, Switzerland, told Neurology Advisor.

All patients in the original BENEFIT trial were randomized to either IFNß-1b 250 µg or placebo given subcutaneously every other day. At the onset of a second CIS or 2 years at the latest, patients on placebo were given the option of switching to IFNß-1b, which constituted a delay of treatment. The BENEFIT CIS extension trial captured 11-year data on 278 (54%) of the original 468 patients from the BENEFIT trial: 167 (57.2%) of patients in the treatment arm given early treatment immediately after CIS and 111 (63.1%) in the placebo arm who had active treatment delayed for up to 2 years post CIS.

Risk of conversion to clinically definite MS (CDMS) was reduced by 33% in patients who received early treatment compared to those whose treatment was delayed (hazard ratio (HR) 0.670; 95% confidence interval (CI) 0.526-0.854, P= .0012). Risk of relapse was reduced in the early treatment group by 34.5% compared with the delayed treatment group. The annualized relapse rate (AAR) was not only reduced during the initial study period, but remained lower through all but 2 years of the follow-up.

In addition to a reduction in the percentage of patients converting to CDMS in the early treatment vs delayed treatment group (66.6% and 75%, respectively), time to first relapse was much longer (1888 days vs 931 days). The percentage of patients who converted to secondary progressive MS (5.9% overall) was also significantly lower in the early treatment group (4.5% vs 8.3% delayed).

Despite benefits to early initiation of treatment, it did not translate into improved clinical outcomes, as there was little difference in the number and volume of brain lesions seen on magnetic resonance imaging (MRI) or in Expanded Disability Status Scale (EDSS) scores between the 2 groups, which remained stable and consistent throughout the study period.

Ultimately, the BENEFIT CIS study offered Class IV evidence that early treatment after CIS was associated with prolonged time to conversion to CDMS.

The long-term follow up to the BENEFIT CIS study allowed the investigators to detect a general pattern of stability to both the early and delayed treatment groups, demonstrated by a high percentage of the patients remaining employed after 11 years, with EDSS scores that remained below 3.0. Dr Kappos and colleagues suggested this was attributable to the fact that all of the patients were on IFNß-1b therapy by the end of 2 years, and so technically, both groups had “relatively” early treatment of MS.

“Our study adds to the evidence supporting treatment at the earliest sign of the disease and indicates that early treatment has a long-lasting effect on disease activity,” Dr Kappos said.


  1. Kappos L, Edan G, Freedman MS, et al. The 11-year long-term follow-up study from the randomized BENEFIT CIS trial. Neurology. 2016;87:1-10.
  2. Miller DH, Chard DT, Ciccarelli O. Clinically isolated syndromes. Lancet Neurol. 2012;11:157–169.
  3. Miller DH, Barkhof F, Montalban X, et al. Clinically isolated syndromes suggestive of multiple sclerosis: part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol 2005;4:281–288.