No disrespect to the authours here, but when I read the title of the paper I asked what the flip does this mean? What is the Era of PIRA-A. This is an MDPI journal and so is a pay to publish site so you can have a read if interested. It concerns progression and PIRA. You know me and PIRA is a term that I don’t like because of the way it is defined. Progression is a composite of mechansisms that are either targeted or not targeted by currently available disease modifying drugs. The companies split MS into relapsing and secondary and primary progressive MS as it helped them to get drugs approved for relapsing MS.

Now it bites them as they have to do separate studies on relapsing and primary progressive MS and the regulators now aid the diffences when they talk about active (i.e. detectable MRI lesions) and non-active (where lesions cant be seen) and so make the trial process even more costly and therefore more restrictive to the development of new treatments.

PIRA in my mind measures worsening due to the influence of lesions associated with active immunity and it measures worsening as a consequence of these lesions. Now pharma may like to be lumpers rather than splitters as it may make it easier to get agents approved for the non-active progression that occurs in progressive and relapsing MS.

I look through the paper and there is no mention of PIRA-A and now realise it is “in the era of PIRA, a framework integrating PIRA, smouldering worsening and neurological reserve. ProfK is a big fan of the hyphen and should have realised this was about a new sentence. Duh

However smouldering worsening is glial activation and innate inflammation that is distinct from but related to the lymphocytic inflammation and surely is part of the driver of what PIRA is. However smouldering worsening probably has lymphocytic inflammation at its core.

As you age and as disease progresses you lose your reserve of nerves that can compensate for nerve loss. In my mind it simply tells us that a single drug approach to MS is not based on a logical biology and combinations are needed. However, until pharma are not making enough on single treatments it will be interesting if things change.

As you can see from the diagram in the paper acute focal (lymphocytic) inflammation is there from the beginning to the end of MS and progression related mechanisms (glial inflammation) is present from the begining to the end of MS

Vasilev GV, Ivanova S, Milanov I. From Phenotypes to Spectrum: Rethinking RRMS, SPMS and PPMS in the Era of PIRA-A Framework Integrating PIRA, Smouldering-Associated Worsening, and Neurologic Reserve to Facilitate Earlier Recognition of Progression. Neurol Int. 2026;18:86. 

The conventional classification of multiple sclerosis (MS) into relapsing-remitting, secondary progressive, and primary progressive phenotypes has long guided diagnosis, prognosis, and therapeutic decision-making. However, accumulating evidence indicates that disability accumulation frequently occurs independently of clinical relapses, challenging relapse-centric and phenotype-based models of disease evolution. The concept of progression independent of relapse activity (PIRA) has emerged as a clinically relevant framework capturing this phenomenon across MS phenotypes. In this state-of-the-art narrative review, we propose a spectrum-based reinterpretation of MS, integrating PIRA with concepts of smouldering-associated worsening and neurologic reserve. We highlight the heterogeneity of relapse-independent worsening, distinguishing transient from persistent PIRA, and discuss how ageing-related decline in compensatory capacity contributes to the clinical unmasking of progression over time. Within this framework, secondary progressive MS is redefined as the clinically recognizable accumulation of persistent relapse-independent worsening, while primary progressive MS is conceptualized as early predominance of clinically manifest progression due to limited reserve rather than a distinct disease entity. Finally, we examine diagnostic and therapeutic implications of a spectrum-based model in the contemporary era, emphasizing the limitations of relapse-centric treatment strategies and unmet needs in addressing progression-related biology. By reframing MS as a dynamic continuum shaped by the interaction between ongoing pathology and evolving neurologic reserve, this review aims to support earlier recognition of clinically meaningful progression and to inform more biology-aware approaches to disease monitoring and therapy.

PIRA-A

Source: multiple-sclerosis-research.org