Effect of Early Treatment Intensity on Progression Independent of Relapse Activity and Disability Accumulation in Multiple Sclerosis

Background and ObjectivesTreatment initiation strategies for disease modifying therapy in multiple sclerosis (MS) are debated, with recent trends favoring induction over escalation approaches. Whether this impacts risk of progressive disease and long-term accumulation of disability is unclear. MethodsAn observational study of a real-world cohort of patients diagnosed with MS registered in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Womens Hospital study and the Massachusetts General Hospital Pediatric Multiple Sclerosis Database was performed. Patients 12-50 years old at diagnosis were grouped by treatment initiated within 6 months of diagnosis into low-efficacy early therapy (LEET) and high-efficacy early therapy (HEET) groups. Risks of progression independent of relapse activity (PIRA), relapse associated worsening (RAW), and sustaining an Expanded Disability Status Scale (EDSS) score [≥] 5.0 were calculated. Results750 patients were analyzed (n = 583 LEET, 112 HEET). HEET vs LEET groups had a similar risk of PIRA (adjusted hazard ratio = 0.99, P-adjusted = 0.95) but a significantly lower risk of RAW (adjusted hazard ratio = 0.48, P-adjusted = 0.015). Sub-stratification of the HEET group into high- and very high-efficacy early therapy groups (i.e. ocrelizumab, natalizumab) showed similar risk of PIRA. Cox proportional hazards analysis revealed older age at diagnosis as a significant contributor to risk of PIRA. Nonetheless young patients still had substantial risk of PIRA, which was similar regardless of treatment efficacy group. In a subset of patients with MRI data, lower brain parenchymal also significantly increased risk of PIRA. LEET, HEET, and VHEET groups also had a similar risk of sustaining an EDSS score [≥] 5.0. HEET and VHEET patients, however, had a slightly lower change in EDSS over time. DiscussionWhile HEET reduces risk of RAW, it does not significantly affect the risk of PIRA, even in patients diagnosed before age 30. It also does not significantly affect the risk of sustaining an EDSS score [≥] 5.0, though may minimally decrease change in EDSS/year. This suggests inductive versus escalation strategies primarily influence patient outcomes by decreasing RAW, and underscores the need for emerging therapeutics to target PIRA, which continues to cause significant disability in patients on treatment.