Progression independent of relapse activity (PIRA) was a term coined a decade ago to describe the insidious disability worsening that occurs in multiple sclerosis during relapse-free periods due to neurodegenerative processes such as smouldering inflammation. A new study reports that 2.5% of patients with neuromyelitis optica spectrum disorder (NMOSD) also have PIRA events during long-term follow-up (Kang et al. Neurol Neuroimmunol Neuroinflamm 2026;13:e200533).

The retrospective study analysed data for 281 patients with NMOSD according to 2015 diagnostic criteria. Mean age at onset was 36.9 years. The mean duration of follow-up was 11.3 years. PIRA was defined as EDSS worsening from the previous EDSS during a relapse-free period and confirmed >6 months later.

Overall, 7 of 281 patients (2.5%) met PIRA criteria; the median time to a PIRA event was 6.2 years. PIRA events involved decreased visual acuity (3 cases), decreased walking distance (2 cases) and gait instability (2 cases). No new lesions were observed in the four cases for which MRIs were obtained. Treatment was not escalated in any of the PIRA cases, patients subsequently remained relapse-free and the median EDSS score was unchanged over the next 8.9 years. The proportion of these PIRA events that might be attributed to comorbidities or aging during the follow-up period was not reported. The authors noted that potential confounders to differentiating true progression from PIRA-like events are not always apparent in real-world evaluations.

In NMOSD, neurodegeneration has been reported in the visual system after optic neuritis and in the cervical spine and sensory cerebral pathways after transverse myelitis (Jakuszyk et al. Brain Commun 2025;7:fcaf417). However, it is unclear if these neurodegenerative changes, distinct from those occurring in MS, are best described as PIRA. The more conventional view is that disability worsening in NMOSD is largely attributable to relapses. Indeed, in the study by Kang and colleagues, relapse-associated worsening (RAW) events were 10-fold more common than PIRA events. Of the 76 RAW events, 50% occurred in patients receiving immunosuppressive therapies, 22% in patients receiving rituximab, 18% in untreated patients, and 8% in patients on interferon-beta. Only one patient receiving a newer biologic therapy (inebilizumab) had a RAW event.

The authors concluded that the true incidence of pathologic PIRA may be lower. While disability worsening events technically met PIRA criteria, it is possible that they were due to other causes, such as spasticity, physical inactivity, depression or fatigue.