Disability Accumulation in Multiple Sclerosis Is Independent of Relapses

June 22, 2020

The study authors tested the risk-reducing effects of ocrelizumab compared with interferon β-1a for treatment of multiple sclerosis disability accumulation, with ocrelizumab showing better results in lowering disability accumulation scores.

Ocrelizumab was better at reducing the risk for disability accumulation in patients with multiple sclerosis (MS) compared with treatment with interferon B-1a, according to a paper published in JAMA Neurology. Additionally, a majority of all disability accumulation occurred outside of relapses.

The results clearly show progression in patients with relapsing multiple sclerosis (RMS) and throw into question the current thought that there are 2 distinct forms of MS: relapsing and progressive. The authors wrote that their finding "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."

Disability progression is measured on an increasing scale and be confirmed at 12 weeks, 24 weeks, or later points, they noted. Increasing disability in MS can occur as relapse-associated worsening (RAW) or steady progression independent of relapse activity (PIRA). They added that PIRA is a feature typical of primary and secondary progressive MS (SPMS).

The researchers examined 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. Analyses occurred from July 2015 to February 2020.

In the trials, patients with RMS, which was diagnosed using the 2010 revised McDonald criteria, came from 307 trial sites in 56 countries. They were randomized 1:1 to receive 600 mg of ocrelizumab by intravenous infusion every 24 weeks or 44-μg subcutaneous interferon β-1a 3 times a week throughout a 96-week treatment period.

In the pooled population from the 2 trials (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 confirmed disability accumulation (CDA) had occurred in 223 (29.6% by Kaplan-Meier estimate) randomized to interferon β-1a and 167 (21.1%) randomized to ocrelizumab. In addition, 24-week composite CDA had occurred in 170 (22.7%) taking interferon β-1a and 129 (16.2%) taking ocrelizumab.

PIRA factored heavily in the 12-week and 24-week composite CDA after 96 weeks in patients treated with interferon β-1a (78.0% [174 of 223] and 80.6% [137 of 170], respectively) and ocrelizumab (88.0% [147 of 167] and 89.1% 115 of 129]). A minority of patients had CDA-explained RAW events (17.7% [69 of 390] and 17.4% [52 of 299]).

Very few patients with composite CDA experienced both RAW and PIRA events (4.4% [17 of 390] for 12-week and 5.0% [15 of 299] for 24-week composite CDA.

Ocrelizumab, compared with interferon β-1a, was associated with reduced risk of composite CDA (HR, 0.67) and confirmed PIRA (HR, 0.78) and RAW (HR, 0.47) events.

The investigators determined that most first events of composite CDA corresponded to composite PIRA events in patients treated with either interferon β-1a or ocrelizumab. Only a small number of patients experienced composite RAW and composite PIRA events in either of the groups. The few patients who did experience 12- or 24-week composite CDA without composite PIRA or composite RAW more frequently came from the interferon β-1a treatment group compared with the ocrelizumab group, they noted.

The baseline factors associated with 12-week composite CDA and 12-week composite PIRA were nearly identical among both groups, the authors said. Ocrelizumab was associated with a 33% lower risk of 12-week overall composite CDA compared with interferon β-1a , they found. In addition, the risk for 24-week overall composite CDA was 30% lower for the ocrelizumab-treated group compared with interferon β-1a.

The researchers also did a subgroup analysis for patients at higher risk of SPMS and learned that the risk of 12-week and 24-week composite PIRA was lower with treatment of ocrelizumab compared with interferon β-1a by 39% and 36%, respectively. The risk reductions for composite RAW at corresponding 12-and 24-week intervals were 54% and 33%, respectively, for this group, the investigators determined. They also said that there were consistent reductions for composite PIRA and RAW defined by Expanded Disability Status Scale in this subgroup.

The researchers noted that the detection of progressive disease in patients who experience MS relapses is extremely subjective and based on clinical judgement. There still may be cases of progressive MS that are not clinically obvious, they said.

“The prominent role of PIRA vs RAW events with respect to overall CDA indicates that optimal prevention or delay of long-term accrual of irreversible disability in patients with RMS will depend on the control of the underlying progressive disease course, as measured by PIRA events.”


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