Understanding PIRA and Its Clinical Significance in MS

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EP: 1.Understanding PIRA and Its Clinical Significance in MS

EP: 2.Measuring What Matters: Evidence and End Points That Define Disability in MS

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MS is understood as a single disease with 2 distinct central nervous system (CNS) inflammatory processes. The first involves relapsing MS, characterized by focal inflammation where blood immune cells enter the CNS, creating contrast-enhancing lesions and potential clinical attacks. This relapsing component peaks in early years and gradually diminishes. The second process involves smoldering inflammation within the CNS, engaging innate immunity through monocytes, macrophages, and glial cells, particularly microglia, leading to neurodegeneration that affects synapses, axons, and neurons.

PIRA represents the gradual deterioration component that underlies progressive MS. Although present from the earliest stages in virtually every patient with MS, PIRA typically manifests clinically at midlife, in patients aged 45 to 55 years. This progression occurs independently of relapses and represents smoldering inflammation and neurodegeneration that becomes the major driver of disability in most MS patient groups, except pediatric cases. Understanding PIRA is crucial because it represents a distinct pathological process that requires different therapeutic approaches than traditional relapse-focused treatments.

The clinical significance of PIRA extends beyond simple disease progression, as it represents a fundamental shift in how MS affects patients. Unlike relapse-associated disability that may show some recovery, PIRA-driven disability tends to be permanent and progressive. This makes early identification and intervention critical for preserving long-term neurological function and quality of life in patients with MS.