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

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

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

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The clinical evidence supporting PIRA as a legitimate concept in MS management is substantial and growing. Key landmark studies have validated PIRA’s role in disability progression, starting with the University of California, San Francisco’s 2019 EPIC data analysis following relapsing patients over 10 years. This study revealed that many relapsing patients showed gradual deterioration by 5 years, maintained at 10 years, initially termed “silent progression.” However, this progression wasn’t truly silent—it was simply subtle and slow, occurring in relapsing patients where clinicians weren’t actively monitoring for progressive disease development.

Subsequent validation came from the 2020 analysis of OPERA 1 and 2 phase 3 trials comparing ocrelizumab with interferon beta-1a in patients with relapsing MS. This analysis demonstrated that the majority of confirmed disability was due to PIRA rather than relapse-associated worsening, with approximately 5% of relapsing patients developing PIRA annually. The 2022 Novartis Oxford database study, encompassing over 27,000 patients, further confirmed PIRA as the primary driver of disability development in relapsing MS, particularly after 2 years of disease duration.

The most meaningful clinical metrics for assessing treatment impact on disability progression involve confirmed clinical parameters rather than surrogate markers. Confirmed disability progression, measured over 3, 6, or 12 months, provides increasingly solid evidence of neurological deterioration. Sustained disability progression, measured to study end, represents the most significant end point because some patients with PIRA may show improvement. These clinical measurements remain the gold standard for evaluating therapeutic interventions targeting disability progression in MS.