Induction Versus Escalation in Multiple Sclerosis: A 10-Year Real World Study

Abstract

In this independent, multicenter, post-marketing study, we directly compare induction immunosuppression versus escalation strategies on the risk of reaching the disability milestone of Expanded Disability Status Scale (EDSS) ≥ 6.0 over 10 years in previously untreated patients with relapsing-remitting multiple sclerosis. We collected data of patients who started interferon beta (escalation) versus mitoxantrone or cyclophosphamide (induction) as initial treatment. Main eligibility criteria included an EDSS score ≤ 4.0 at treatment start and either ≥ 2 relapses or 1 disabling relapse with evidence of ≥ 1 gadolinium-enhancing lesion at magnetic resonance imaging scan in the pre-treatment year. Since patients were not randomized to treatment group, we performed a propensity score (PS)-based matching procedure to select individuals with homogeneous baseline characteristics. Comparisons were then conducted using Cox models stratified by matched pairs. Overall, 75 and 738 patients started with induction and escalation, respectively. Patients in the induction group were older and more disabled than those in the escalation group (p < 0.05). The PS-matching procedure retained 75 patients per group. In the re-sampled population, a lower proportion of patients reached the outcome after induction (21/75, 28.0%) than escalation (29/75, 38.7%) (hazard ratio = 0.48; p = 0.024). Considering the whole sample, serious adverse events occurred more frequently after induction (8/75, 10.7%) than escalation (18/738, 2.4%) (odds ratio = 3.36, p = 0.015). These findings suggest that, in patients with poor prognostic factors, induction was more effective than escalation in reducing the risk of reaching the disability milestone, albeit with a worse safety profile. Future studies are warranted to explore if newer induction agents may provide a more advantageous long-lasting risk:benefit profile.

Keywords: Multiple sclerosis; escalation; induction; therapeutic algorithm.

Fig. 1

Study flowchart of patients’ disposition

Fig. 2

Treatment sequencing after escalation and induction at 10-year follow-up (note that one patient in either group was submitted to autologous hematopoietic stem cell transplantation after high-efficacy treatments)

Fig. 3

Time since treatment start (A) and since symptom onset (B) to EDSS score ≥ 6.0 by initial treatment strategy. The gray area overlaid in part B indicates the estimated median time since symptom onset to EDSS score ≥ 6.0 in natural history studies ranging from 14 to 20 years (adapted from Confavreux and Vukusic [27])