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SPECIAL REPORT
Effect of HE DMTs on PIRA
Anti-CD20 therapy and PIRA
Future use of PIRA
Progression independent of relapse activity (PIRA) has emerged as a means of identifying neurodegenerative processes that can occur at the earliest stages of the MS disease process and which contribute to disability accrual even when there is no evidence of disease activity. PIRA is generally defined as confirmed disability progression (CDP) during a relapse-free period (e.g. >30 days before and >90 days after relapse). Unfortunately, over 300 permutations of this definition have been described (Muller et al. JAMA Neurol 2025;82:614-625), which has made it difficult to compare the prevalence of PIRA and the impact of treatments across studies.
The underlying assumption of PIRA is that relapsing biology (relapses [and MRI with PIRMA]), and progressive biology (EDSS change) are mutually exclusive (Ciccarelli et al. Neurology 2024;103:e209444). This contributes to the notion that DMTs that function primarily by reducing immune activation in the periphery will be ineffective against PIRA.
A further issue is that PIRA is often equated with smouldering inflammation, which conflates a clinical observation of disability worsening with a variety of pathological changes such as slowly-expanding lesions (SEL) or the development of paramagnetic rim lesions (PRL) (Bsteh et al. Int J Mol Sci 2025;26:4704). This implies that PIRA represents irreversible neurological damage that is untreatable.
A more likely scenario is that PIRA may occur with the onset of one or more neurodegenerative processes (SELs, microglial activation, diffuse white-matter inflammation), some of which may respond to conventional treatment. For example, the MSBase group recently differentiated persistent PIRA from PIRA events that showed disability improvement over a 9-year follow-up period (Zhu et al. Brain Commun 2025;7:fcaf306). About one-third of PIRA events were non-persistent, and patients were 80% less likely to reach disability milestones than those with persistent PIRA. This suggests that some processes contributing to PIRA may respond to treatment.
Moreover, high-efficacy DMTs have been shown to regress or stabilize PIRA, which may indicate that some components of neurodegeneration are the result of peripheral immune activation and/or are directly responsive to current treatments. In contrast, persistent PIRA may represent the onset of SPMS (Portaccio et al. J Neurol 2024;271:5074-5082), which has been shown to be less responsive to DMTs.
Effect of HE DMTs on PIRA
An analysis of the Italian MS register (N=908 matched pairs) compared patients started on a high-efficacy DMT to those for whom an escalation strategy was used (Iaffaldano et al. Ann Clin Transl Neurol 2025;12:2012-2019). At 10 years, the high-efficacy DMT group had a significantly lower risk of PIRA (odds ratio 1.22) and a lower EDSS score (mean difference 0.63 points). A separate analysis identified four patterns of disability accrual: minimal, early, late and rapid (De Meo et al. Neurology 2025;105:e214408). Regardless of the pattern, PIRA was the predominant mechanism of disability accrual. DMT exposure significantly reduced disability progression in all subtypes, with high-efficacy therapy being especially beneficial for rapidly-worsening disability. In addition, a newly-published retrospective study reported that the risk of PIRA and MRI activity (PIRMA) was significantly higher (hazard ratio 7.05) in patients treated with a lower-efficacy versus higher-efficacy DMT (Guarnaschelli et al. Mult Scler 2026; epublished April 29, 2026).
Anti-CD20 therapy and PIRA
Several recent studies have reported on the effectiveness of anti-CD20 agents in reducing the risk of PIRA. A subgroup analysis of newly-diagnosed and treatment-naïve patients in the ASCLEPIOS trial reported a six-month confirmed PIRA rate of 3.6% with ofatumumab versus 7.7% with teriflunomide (Gartner et al. Mult Scler 2022;28:1562-1575). A longer-term study reported a 6M-PIRA rate of 7.9% with ofatumumab after three years (Ziccardi et al. Ther Adv Neurol Disord 2026:19:17562864261434351). This was similar to the overall 6M-PIRA rate of 7.7% for patients in the Argentine MS database on higher-efficacy DMTs (anti-CD20s, natalizumab, alemtuzumab, cladribine) (Alonso et al. Mult Scler Relat Disord 2025:104:106775). Interestingly, in a real-world study of patients with pre-existing PIRA, 12 of 18 patients (66.7%) showed stabilization of PIRA in the 18 months after starting ofatumumab (Montague et al. Mult Scler J Exp Transl Clin 2026;12:20552173251414528).
In the RENEGADE observational study, PIRA and PIRMA were significantly reduced two years after switching to rituximab from a higher-efficacy DMT (fingolimod, cladribine or alemtuzumab) (Chisari et al. J Neurol 2025;273:47). Similarly, in the OPERA I/II trials, ocrelizumab was associated with a 22% reduction in composite PIRA risk compared to interferon-beta (Kappos et al. JAMA Neurol 2020;77:1132-1140). This reduction may underestimate the true effect of treatment on PIRA. An analysis of OPERA I/II data found that the treatment effect varied from a nonsignificant 17% reduction to a significant 27% reduction in the risk of composite PIRA depending on the definition used (Montobbio et al. EBioMedicine 2025:117:105802).
The risk of PIRA is 2-3-fold higher in patients with late-onset (50-59 years) or very-late-onset MS (>60 years) compared to the adult-onset MS population (Souissi et al. J Neurol 2026;273:114). A retrospective study of older MS patients found that ofatumumab and ocrelizumab stabilized EDSS worsening and reduced PIRA by 15% (Montague et al. Front Immunol 2026:16:1699550). The results suggested that aggressive treatment can continue to benefit older patients although closer safety monitoring may be required.
Future use of PIRA
A standardized definition of PIRA is needed so that the effects of treatment are more easily compared across studies. One group recently proposed a stratified definition that could include PIRA-1 (EDSS only), PIRA-5 (MRI) or PIRA-6 (advanced imaging), and PIRA-7 (biomarkers) (Hamdy et al. Clin Neurol Neurosurg 2026:267:109430). An accompanying survey found strong support for a stratified definition but little agreement on how PIRA measures would be obtained in clinical practice. Thus, while additional measures may more precisely characterize disability progression, they may be as likely as NEDA-5 to be adopted in practice. Additional work is needed to identify the underlying neuropathological processes that may contribute to worsening disability during relapse-free periods.