Progression independent of relapse activity (PIRA) in the Era of high-efficacy treatments

Abstract

Background: Progression independent of relapse activity (PIRA) is a key marker of chronic neurodegeneration in multiple sclerosis (MS), reflecting sustained disability progression unrelated to inflammatory relapses. While high-efficacy therapies (HETs) have significantly reduced relapse-associated worsening (RAW), the contribution of PIRA to disability progression has increased in recent diagnostic periods.

Objectives: This study aimed to evaluate the prevalence and predictors of PIRA in Argentine patients with relapsing-remitting MS (RRMS) receiving HETs and to explore the impact of early treatment initiation on disease progression.

Methods: A post hoc analysis of the Argentine MS registry (RelevarEM) was conducted, including RRMS patients treated with natalizumab, alemtuzumab, cladribine (Cladribine), rituximab, or ocrelizumab. Patients required ≥1 relapse in the preceding 12 months, biannual EDSS assessments, and annual MRI scans. PIRA was defined as EDSS progression (≥1.0 or ≥0.5 points, depending on baseline score) confirmed 24 weeks apart, outside the relapse period. Logistic regression identified predictors of PIRA.

Results: Among 287 patients (68.2 % female, mean age 37.33±11.10 years), 22 (7.7 %) developed PIRA. PIRA patients were older (42.58±13.46 vs. 36.85±10.79 years, p = 0.015) and had longer disease duration (6.87±6.18 vs. 4.41±4.96 years, p = 0.023). Treatment-naïve patients showed lower PIRA risk (OR=0.10, p = 0.0049), while absence of prior relapses increased risk (OR=8.17, p = 0.0087).

Conclusions: PIRA prevalence was lower in this cohort compared to prior studies, reflecting the effectiveness of HETs in RRMS. Early initiation of HETs is critical to mitigating PIRA and long-term disability. These findings underscore the need for timely diagnosis and treatment to alter MS progression.

Keywords: Disability; Disease progression; High-efficacy therapy; Multiple sclerosis.