Ocrelizumab touches a RAW spot, It also stops progression related disability


Before you read this paper you have to grasp the new concepts of RAW and PIRA. RAW is worsening in disability due to relapses and PIRA is progression independent of relapse activity. Therefore in PPMS, the progressive worsening would largely be a production of PIRA.


a) Composite RAW and b) composite PIRA are the two non-mutually exclusive components/drivers of overall accumulation of disability (as measured by composite CDA) in relapsing and progressive forms of MS.
CDA=confirmed disability accumulation; IID, initial increase of disability; MS=multiple sclerosis. PIRA=progression independent of relapse activity. RAW=relapse-associated worsening.

In this study they try and work out what the disability in relapsing and remitting MS is due to. RAW or PIRA or RAW & PIRA

Preprint site Kappos et al study put online and may be published in the Lancet.

Progression Independent of Relapse Activity (PIRA) in Patients with Relapsing Multiple Sclerosis

Background: Accumulation of disability in multiple sclerosis (MS) may occur as relapse-associated worsening (RAW) or as steady progression independent of relapse activity (PIRA), regarded as a feature of primary and secondary progressive MS. Using two Phase III trials comparing ocrelizumab and interferon (IFN) β-1a in a typical relapsing MS (RMS) population, we investigated the relative contribution of RAW and PIRA to overall confirmed disability accumulation (CDA), assessed baseline prognostic factors of PIRA and RAW, and respective effects of the two treatments.

Methods: CDA, PIRA, and RAW events were assessed in the pooled intent-to-treat population of the OPERA I and II trials. CDA was defined using a composite measure that included a defined increase in Expanded Disability Status Scale, Timed 25-Foot Walk, or 9-Hole Peg Test confirmed after ≥12 or ≥24 weeks. RAW events were defined as a confirmed worsening occurring ≤90 days after onset of a protocol-defined relapse.

Findings: PIRA events were the main contributors to 12/24-week composite CDA after 96 weeks. Of this overall risk, 78·7% to 88·9% corresponded to PIRA while 13·0% to 21·1% was explained by RAW events. Acute baseline lesional MRI activity only predicted RAW, whereas PIRA was predicted by baseline T1 and T2 lesion burden, whole brain and cortical grey matter atrophy, disease duration, male sex, baseline disability, and perceived quality of life. Very few patients experienced both RAW and PIRA. Compared with IFN β-1a, ocrelizumab reduced the risk of composite CDA, composite PIRA, and composite RAW events confirmed at 12/24 weeks.

Interpretation: A considerable proportion of overall accumulation of disability in RMS is not related to overt relapses. This indicates an underlying progressive course in this typical RMS population and challenges the current clinical distinction of relapsing and progressive forms of MS. Ocrelizumab was superior to IFN β-1a in preventing both RAW and PIRA

CoI None relevant but ProfG is a co author of this

About the author



  • ”Accumulation of disability in multiple sclerosis (MS) may occur as relapse-associated worsening (RAW) or as steady progression independent of relapse activity (PIRA), regarded as a feature of primary and secondary progressive MS.”

    Ok, change terminology of MS from relapsing and progressive to RAW and PIRA. Everyone knows that ocrelizumab is much more effective than interferons in relapsing MS but how do the numbers of disability progression compare to: https://www.nejm.org/doi/full/10.1056/NEJMoa1606468
    What is the main conclusion?

  • There is two classical form of MS, RRMS and PPMS. But both have progression and we can classify RRMS in to two group at follow up Rapidly Evolving(REMS) and Slowly evolving(SEMS) forms. We have to find an evaluation method to measure the evolution speed so we can make decisions on treatment. This is how I look MS evolution in time.

  • It seems that once you’ve reached the PPMS or SPMS stage the only way to know if a noticeable bout of worsening is RAW or PIRA is after the event ie if you recover or part recover. Eg your foot drops and you start tripping. One day it was ok then it wasn’t. RAW or PIRA? Easy to say RAW if foot recovers somewhat but if not? RAW with flat line after? Or PIRA that became annoying one day?

    It’s a tough call for pwPPMS or SPMS to notice relapses against the background of existing weakness, numbness, visual disturbances and neuropathy. And very few have the luxury of regular MRIs.

    And I know we’re all desperate for treatments to stop progression etc but don’t forget there are tens of thousands of pwMS in the UK alone ineligible for existing DMTs.

  • Thanks MD for this explanation of RAW and PIRA and the Lancet publication by Dr. Kappos.

    This study exposes a huge unmet need for treatment of PIRA from the beginning of the MS, in which there is an underwhelming effectiveness by the current immunosuppressant DMDs only model, which is treating a downstream reaction/adaptive peripheral immunity likely related to RAW, not PIRA.

    Also, thanks for the NEJM publication by Anonymous 1:57. It confirms the underwhelming ocrezulimab’s effectiveness, in terms of treating PIRA, just barely above placebo only relevant to the statistician, not the patient.

    • Opera extension data is more favorable as presented at ECTRIMS this past Sept in 2019 with a 42% reduction of ending in a wheelchair after 6 years if on Ocrevus before the switch over from IFN rather than after the switchover. Suggestive that the reduction in the slope of the line continues, and patients must overcome all initial “fuses” as previously described.

      People crap way too much on Ocrevus on this blog.

  • Predictors of long-term disability accrual in relapse-onset multiple sclerosis.

    Relapses are not good for you

    So if you have relapses it is a predictor of your disability in the future. Don’t have relapses and then maybe disability will not develop but if you are relapsing on therapy then it is worse news if you are not on therapy so maybe we need to change therapy if they are not working propertly.


    Worsening of MS Associated With Relapse
    Contributes to Disability Over the First 15

    Worsening of treated MS was associated with relapses in many RMS patients throughout the first 15 years after
    onset, suggesting an opportunity for long term benefit through relapse reduction. Worsening due to slow
    progression played an increasing role over time.



  • Thanks for this post MD.

    Provides additional evidence of smouldering MS and the need for further treatments is what I’m taking from this.

    Seems to me it also further undermines the escalation model and the use of CRABS.

    Sorry Dr T but this increases my sense of inverting the pyramid needing to become the norm.

    I watched the Bill Turnbull documentary, in which Nick Robinson spoke about his cancer treatment. He describes feeling that loss of his voice after surgery was worse than the cancer, referencing your voice is your identity/sense of self. This is so often the reality of MS: and treating it somewhat gently seems to imply a loss of self is acceptable. It isn’t!

    Btw – Can’t help but hate the use of the word Progression. Word used should be deterioration as everyone with MS sees worsening of their symptoms, generally interlinked with worsening of their quality of life.
    Whenever I see the use of the word progression I envisage the MS giving itself a high five, but in terms of human reality it’s a misnomer!

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