Work

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

Year: 2026

Type: article

Abstract: 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.

Source: Neurology International

DOI: 10.3390/neurolint18050086

Authors: Georgi V. Vasilev, Sonya Ivanova, Ivan Milanov

Institutions: Medical University of Sofia, Multiprofile Hospital for Active Treatment in Neurology and Psychiatry St. Naum

Language: English

Topic: Multiple Sclerosis Research Studies

Subfield: Pathology and Forensic Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $1,930