Relapsing Multiple Sclerosis Disability Not Linked to Overt Relapses


An overwhelming number of patients with relapsing multiple sclerosis may accumulate disability due to underlying progressive disease course independent of relapse activity.

Ludwig Kappos, MD

Ludwig Kappos, MD

Pooled data from 2 phase 3, double-blind, double-dummy, parallel-group, randomized trials—OPERA I (NCT01247324) and OPERA II (NCT01412333)—revealed most disability accumulation in relapsing multiple sclerosis (RMS) is not associated with overt relapses.1

Research conducted by Ludwig Kappos, MD, professor of neurology, University Hospital Basel, Switzerland, and colleagues aimed to investigate the contributions of relapse-associated worsening (RAW) vs. relapse-independent progression (PIRA) to overall confirmed disability accumulation (CDA). They found that very few patients with composite CDA experienced both RAW and PIRA events (12- week composite CDA: 17 of 390 [4.4%]; 24-week composite CDA: 15 of 299 [5.0%]).

After 96 weeks, 12-week composite CDA had occurred in 223 patients (29.6%% by Kaplan-Meier estimate) randomized to interferon β-1a and 167 (21.1%) randomized to ocrelizumab among a pooled population of 1656 eligible participants. Additionally, 24-week composite CDA had occurred in 170 (22.7%) participants taking interferon β-1a and 129 (16.2%) taking ocrelizumab.

Investigators noted that 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%] and 137 of 170 [80.6%], respectively). They found similar results in those treated with ocrelizumab (147 of 167 [88%] and 115 of 129 [89.1%], respectively).

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When assessing respective baseline prognostic factors and outcomes of ocrelizumab and interferon β-1a, those who received ocrelizumab were associated with a reduced risk of composite CDA (hazard ratio [HR], 0.67), confirmed PIRA (HR, 0.78) and RAW (HR, 0.47) events compared with interferon β-1a.

Analyses of the relative proportion of composite PIRA and composite RAW events driven by Expanded Disability Status Score (EDSS), timed 25-foot walk (T25FW) and 9-hole peg test (9HPT) revealed that an increase in EDSS accounted for most of the 12-week (41 of 69 [59.4%]) and 24-week (36 of 52 [69.2%]) composite RAW events. In contrast, most of the 12-week composite PIRA events (148 of 321 [46.1%]) and 24-week composite PIRA events (122 of 251 [48.6%]) were driven by T25FW, with EDSS contributing 29.3% (94 of 321) and 29.5% (74 of 251), respectively.

“Together with findings previously obtained in less well-controlled observational settings, our study strongly supports that MS may be a single disease continuum with an underlying progressive disease course and a highly variable superimposed accumulation of disability resulting from relapses with incomplete recovery,” Kappos and colleagues concluded.

Patients included in the study were randomized 1:1 to 600-mg 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. That included a per-label incremental titration scheme in the first 4 weeks.

If confirmed after 12 or more or 24 or more weeks, increases of ≥1.0 point if baseline EDSS was ≤5.5 points or a ≥0.5-point increase if baseline EDSS was >5.5 points, or an increase of 20% of more in T25FW or increases of 20% or more in 9-hole peg test were defined as composite CDA.

The 2 studies were conducted between August 2011 and April 2015 and included patients with RMS diagnosed using the 2010 revised McDonald criteria, randomized from 307 total sites across 56 countries. Overall, the baseline demographics and disease characteristics were similar for patients randomized to interferon β-1a vs ocrelizumab (mean age, 37.2 [standard deviation (SD), 9.2] vs 37.1 [SD, 9.2] years; 552 [66.6%] vs 541 women [65.4%]).

After completion of the 96-week controlled treatment period, most patients participated in the open-label extension phase of the OPERA studies and had their EDDS scores used to confirm potential initial increase of disability (IID) events that occurred at the end of the controlled period. Researchers also performed analysis on a post-hoc subgroup in addition to the analysis of the overall IIT population.

The few patients in each treatment group who experienced 12-week or 24-week composite CDA without fulfilling either definition of composite PIRA or composite RAW were more frequent with interferon β-1a treatment (14 of 829 [1.7%] and 8 of 829 [1.0%], respectively) compared with ocrelizumab treatment (3 of 827 [0.4%] and 2 of 827 [0.2%], respectively).

Ocrelizumab has been FDA approved for the treatment of primary progressive MS and relapsing MS since 2017, but recently had its supplemental applications review accepted by both the FDA and EMA in late April for those with relapsing or primary progressive MS. As for interferon β-1a, the FDA approved updated prescribing information for the treatment in early April that included the removal of contraindications for pregnancy.2


1. Kappos L, Wolinsky JS, Giovannoni G, et al. 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. JAMA Neurol. Published online June 8, 2020. doi: 10.1001/jamaneurol.2020.1568.

2. US FDA and EMA accept applications for Roche’s OCREVUS (ocrelizumab) shorter 2-hour infusion time [press release]. Basel, Switzerland: Genentech; Published April 20, 2020. Accessed April 20, 2020.

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