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Progression Independent of Relapses (PIRA): Existing Knowledge and Avenues for Research

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Highlighting new research and increasing knowledge around multiple sclerosis is central to our mission at ECTRIMS. That’s why our annual congresses now include 10 Hot Topic sessions exploring some of today’s most pressing issues facing the MS research and neurological community.

At the 9th Joint ECTRIMS-ACTRIMS Meeting, #MSMilan2023, in October, one of those hot topics will be progression independent of relapse activity (PIRA) and silent progression in MS. The importance of this topic was underlined last month in our recent ECTRIMS webinar, where experts dove deep into increasing our understanding around PIRA in MS. Building upon recent work in the area, this ECTRIMS Insight continues the conversation by examining the learnings that could improve the delivery of quality, personalised care for everyone living with MS.

Importance and incidence of PIRA

PIRA describes an accumulation of disability in individuals with MS which is independent of relapse-associated worsening (RAW). Occurring from the early stages of MS, PIRA is seen relatively frequently, and is associated with underlying accelerated brain and spinal cord atrophy and inflammatory activity.

A study by Carmen Tur and colleagues [1], for example, noted that presenting with PIRA after a first demyelinating event was not uncommon, and suggestive of an unfavourable long-term prognosis. This was particularly true if PIRA occurred early in the MS disease course. This single-centre study, conducted in Barcelona between January 1994 and July 2021, included 1128 patients with a first demyelinating attack due to MS, approximately a quarter of whom developed one or more PIRA events at a median follow-up time of 7.2 years (for first PIRA). The investigators noted that individuals with MS and PIRA were older, had more brain lesions and steeper Expanded Disability Status Scale (EDSS) yearly increase rates.

These findings were similar to those of another European MS cohort where, over a period of 10 years, the incidence of PIRA was shown to be approximately 27%. In addition, this study noted that individuals with PIRA exhibited accelerated brain atrophy [2], particularly in the cerebral cortex – findings which align with those of the observational US MS-EPIC (Expression, Proteomics, Imaging, Clinical) team [3].

Factors associated with the risk of PIRA include age at the first demyelinating attack, brain and cervical spine volume and cortical volume. These important insights into the underlying pathology of MS could help clinicians more accurately diagnose the condition and deliver more personalised care.

PIRA, disease-modifying treatments and long-term outcomes

During the 31 May ECTRIMS webinar on understanding PIRA in MS, it was noted that PIRA is currently a clinical concept that is not fully understood pathologically at the present time. There are no published studies demonstrating any association between expansion of central nervous system lesions and PIRA, and further investigations are required before we can fully understand PIRA.

The potential role for disease-modifying treatments (DMTs) in preventing PIRA is another area requiring further research. Although studies suggest that ocrelizumab [4] and ofatumumab [5] may prevent PIRA, other studies have not shown any significant effects. Therefore, at the present time, there is a lack of evidence of any particular DMT having a strong treatment effect on the prevention of PIRA.

Promoting continued advances in research

These are just a few examples of the volume of research carried out by the MS scientific community every year.

Such research continually deepens our understanding of the disease and its treatments to improve diagnosis and permit earlier treatment, thereby halting disease progression and, ultimately, optimising patient care.

Be part of the charge by attending the 9th Joint ECTRIMS/ACTRIMS Congress in Milan, Italy, which will take place on 11–13 October 2023. Full details here:


ECTRIMS Insights articles are produced with the intent of being a neutral source of information sharing and objective analysis for the MS and neuroscience community. Unless otherwise stated, cited information in our articles does equivocate official endorsement from ECTRIMS.



[1] Tur C, et al. JAMA Neurol. 2023;80(2):151–160.

[2] Cagol A, et al. JAMA Neurol. 2022;79(7):682–692.

[3] University of California, San Francisco MS-EPIC Team, et al. Ann Neurol. 2019;85(5):653–666.

[4] Kappos L, et al. JAMA Neurol. 2020;77(9):1132–1140.

[5] Kappos L, et al. Annual Academy of Neurology Virtual Meeting; April 17-22, 2021.