Understanding PIRA: will I get worse?

The most obvious feature of multiple sclerosis is a relapse – an inflammatory flare-up that affects nerve function and causes a host of symptoms. The damage caused by inflammation in the brain and spinal cord was assumed to be the main reason that people gradually developed disability during their course of MS. That is why MS treatments have targeted this process with increasingly potent anti-inflammatory medications.

However, about four years ago, researchers looked at disability worsening among people enrolled in a drug trial (Kappos and colleagues. JAMA Neurol 2020;77:1132-1140). They found that most of the accumulating disability was not attributable to relapses. Disability appeared to worsen in the periods between relapses – or after people no longer had relapses. This accumulation of disability was termed ‘progression independent of relapse activity’, or PIRA.

PIRA is the hidden face of MS. It is the slow process of irreversible nerve damage that occurs in parallel to the process of inflammatory flare-ups. Treating inflammation with a medication may slow the process down, but current medications cannot halt or reverse PIRA.

A new study has looked at PIRA over the long term to get a sense of how quickly disability worsens (Tur and colleagues. JAMA Neurol 2023;80:151-160). The database included 1128 people with clinically isolated syndrome (CIS), i.e. people with a clinical symptom (such as optic neuritis) who do not yet meet the diagnostic criteria for MS. Since many people with CIS never go on to develop MS, we must presume that this group ultimately did during the 27-year observation period.

The average age of people was 32 years at the start of the study. Overall, 25% of people had a  PIRA event over a 12-year period, and another 12% had some amount of disability worsening. This shows that most of the accumulating disability is attributable to PIRA. The group estimated that 50% would have a PIRA event by the time they reached their mid fifties.

While PIRA was associated with more rapid progression of disability, the actual rate of disability worsening in this study was relatively low. The average amount of disability worsening was less than 1 point on the EDSS scale after 10 years. This means that a person with an EDSS score of 3.0 at the beginning (mild disability, no problem walking) would have a score of 4.0 (moderate disability but still able to walk 500 metres without walking aids) a decade later. The proportion of people who reached EDSS 6.0 (can walk 100 metres with a cane) after 25 years was less than 5% in people without PIRA, and about 30% for those with PIRA.

PIRA is not the ideal way of assessing disease activity and the way it is calculated likely underestimates how frequently it occurs. This in turn may overestimate the amount of disability worsening attributable to relapses. A further limitation is that people in this study had CIS – not MS. So the rate of progression may be somewhat faster in people diagnosed with MS. However, what this analysis does show is that some people with early MS – perhaps 10% or so – are at risk of more rapid worsening of disability. Early PIRA may be a useful ‘red flag’ to identify the people who are at high risk of disability and who may benefit from a more aggressive treatment approach.

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