To assess: (i) relapse-associated worsening (RAW) of cognitive decline, measured by the Symbol Digit Modalities Test (SDMT), and SDMT progression independent of relapse activity (PIRA) in OPERA I (NCT01247324) and OPERA II (NCT01412333); (ii) the effect of ocrelizumab on these measures.

Cognitive impairment in relapsing multiple sclerosis (RMS) is common, disabling and may be measured by SDMT. Recent research shows that SDMT can decline in association with acute disease activity, i.e. relapses. The Phase III OPERA studies in RMS demonstrated consistent beneficial effect of ocrelizumab on SDMT improvement, and a reduction of SDMT decline versus interferon-beta-1a (IFNβ1a). Overall disability progression in OPERA was driven mainly by PIRA rather than RAW. The degree to which SDMT results are influenced by relapses in OPERA is unknown.

24-week confirmed SDMT decline (≥4-point reduction) and its association with relapses (RAW-SDMT) or SDMT progression independent of relapse activity (PIRA-SDMT) was assessed in the pooled OPERA population. RAW-SDMT events were defined as confirmed SDMT worsening occurring ≤90 days after onset of a protocol-defined relapse. SDMT scores were ‘re-baselined’ ≥30 days after each relapse, and PIRA-SDMT events were defined as confirmed SDMT worsening that occurred independently of relapse activity.

24-week confirmed SDMT decline was almost exclusively related to PIRA-SDMT, with events occurring in 11.3% of IFNβ1a-treated patients and 7.0% of ocrelizumab-treated patients, versus RAW-SDMT, experienced by 0.3% of all patients. Ocrelizumab significantly reduced the risk of 24-week confirmed SDMT worsening (hazard ratio [HR] 0.57; 95% CI 0.39–0.82; p=0.003) and 24-week confirmed PIRA-SDMT worsening (HR 0.58; 95% CI 0.39–0.86); p=0.006) versus IFNβ1a. No differences were seen in 24-week confirmed RAW-SDMT.

SDMT decline in OPERA primarily occurred independently of relapses, similar to gradual physical disability worsening, or PIRA. Ocrelizumab was superior to IFNβ1a in preventing the gradual cognitive decline that characterizes RMS.