Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials

Abstract

in multiple sclerosis may occur as relapse-associated worsening (RAW) or steady progression independent of relapse activity (PIRA), with PIRA regarded as a feature of primary and secondary progressive multiple sclerosis. OBJECTIVE To investigate the contributions of relapse-associated worsening vs relapse-independent progression to overall confirmed disability accumulation (CDA) and assess respective baseline prognostic factors and outcomes of 2 treatments. DESIGN, SETTING, AND PARTICIPANTS Analyses occurred from July 2015 to February 2020 on pooled data from the intention-to-treat population of 2 identical, phase 3, multicenter, double-blind, double-dummy, parallel-group randomized clinical trials (OPERA I and II) conducted between August 2011 and April 2015. In the trials, patients with relapsing multiple sclerosis (RMS), diagnosed using the 2010 revised McDonald criteria, were randomized from 307 trial sites in 56 countries; resulting data were analyzed in the pooled data set. INTERVENTIONS Participants were randomized 1:1 to receive 600 mg of ocrelizumab by intravenous infusion every 24 weeks or subcutaneous interferon β-1a 3 times a week at a dose of 44 μg throughout a 96-week treatment period. MAIN OUTCOMES AND MEASURES Confirmed disability accumulation was defined by an increase in 1 or more of 3 measures (Expanded Disability Status Scale, timed 25-ft walk, or 9-hole peg test), confirmed after 3 or 6 months, and classified per temporal association with confirmed clinical relapses (PIRA or RAW). RESULTS In the pooled OPERA I and II population (1656 of 2096 eligible participants), baseline demographics and disease characteristics were similar for patients randomized to interferon β-1a vs ocrelizumab (mean [SD] age, 37.2 [9.2] vs 37.1 [9.2] years; 552 [66.6%] vs 541 women [65.4%]). After 96 weeks, 12-week composite CDA had occurred in 223 (29.6% by Kaplan-Meier estimate) randomized to interferon β-1a and 167 (21.1%) randomized to ocrelizumab; 24-week composite CDA had occurred in 170 (22.7%) taking interferon β-1a and 129 (16.2%) taking ocrelizumab. The PIRA events were the main contributors to 12-week and 24-week composite CDA after 96 weeks in patients treated with interferon β-1a (174 of 223 [78.0%] and 137 of 170 [80.6%], respectively) and ocrelizumab (147 of 167 [88.0%] and 115 of 129 [89.1%], respectively); a minority had CDA explained by RAW events (69 of 390 [17.7%] and 52 of 299 [17.4%], respectively). Very few patients with composite CDA experienced both RAW and PIRA events (17 of 390 [4.4%] for 12-week and 15 of 299 [5.0%] for 24-week composite CDA). Ocrelizumab (vs interferon β-1a) was associated with reduced risk of composite CDA (hazard ratio [HR], 0.67) and confirmed PIRA (HR, 0.78) and RAW (HR, 0.47) events. CONCLUSIONS AND RELEVANCE Most disability accumulation in RMS is not associated with overt relapses. This indicates an underlying progression in this typical RMS population and challenges the current clinical distinction of relapsing and progressive forms of multiple sclerosis. Ocrelizumab...

Retinal layer thinning is reflecting disability progression independent of relapse activity in multiple sclerosis

“…PIRA was defined as either an EDSS or SDMT worsening during the observation period confirmed after 24 weeks with no relapse in the 30 days before or after the EDSS/SDMT worsening. 3 , 5 …”

“… 3 PIRA can be variously defined as worsening disability (with EDSS or a composite) independent of relapses (within a defined period or in relapse-free patients) and occurs in 10–25% of RMS patients over 4–5 years representing about 50–80% of all disability worsening events. 3 – 6 Thus, PIRA is purported to quantify the proportion of disability worsening due to (non-inflammatory) neurodegenerative processes.…”

Ocrelizumab zur Behandlung der Multiplen Sklerose

“…In einer kürzlich veröffentlichen Analyse der Krankheitsprogression in den OPERA-Studien, zeigt sich, dass in der gesamten RMS-Population der größte Anteil der erworben Behinderung schubunabhängig erfolgt [28].…”

Machine Learning Use for Prognostic Purposes in Multiple Sclerosis

“…MS is also the autoimmune disease mostly addressed by ML [ 6 ]. MS typically starts with a relapsing-remitting (RR) phase that gradually turns into a secondary progressive (SP) form, during which relapse-independent progression becomes more evident [ 7 ], disability increases and the patient’s health irreversibly declines. Relapses occur randomly [ 8 ] and the duration of the RR phase is quite variable, with 50% of the patients converting to the SP form within about 30 years of disease onset [ 9 ].…”