| Multiple Sclerosis  

Relapse-independent disability worsening plays a relevant role in every disease phase of MS

Insidious disability accrual starts already in the earliest phases of multiple sclerosis and becomes dominant over the disease course, suggesting an ongoing process of inflammation and/or degeneration secondary to disease burden.

Increasing evidence suggests that insidious disability accrual is more frequent than classically thought in every phase of multiple sclerosis (MS). In fact, other than relapse-associated worsening (RAW) following incomplete recovery from abrupt inflammatory activity, global impairment exacerbation can be the result of a progression independent of relapse activity (PIRA). In 2020, Kappos et al. (1) showed the high frequency of PIRA occurring in MS using a composite endpoint including Expanded Disability Status Scale (EDSS), timed 25-ft walk and 9-hole peg test.

Recently, Lublin et al. (2) used a large clinical trial dataset of more than 27,000 patients with MS with a follow up reaching 15 years and investigated how disability accumulated, defining PIRA as an irreversible worsening in EDSS separated by at least 90 days from a relapse. In this study, the Authors showed that in adult relapsing MS patients PIRA already occurred with similar or higher frequency to RAW (47.3% vs 26.9%), whereas it was the main driver of worsening in progressive MS patients. RAW was dominant only in pediatric MS. Disease modifying therapies (DMTs) treated patients showed a reduced frequency of disability worsening, though with a higher proportion of PIRA, suggesting the presence of an ongoing process of central or diffuse inflammation and/or degeneration secondary to accumulating subclinical disease burden.

Nonetheless, DMTs significantly delay the time to milestones disability by 3.5 years between EDSS 1 and 4 and by 1.4 years between EDSS 4 and 6, showing that treatment benefit is higher in the earliest disease phases.


Key Points:

  • Progression independent of relapse activity (PIRA) starts early in multiple sclerosis (MS), occurs in all phenotypes and becomes the principal driver of disability accumulation in the progressive phase of the disease.
  • Only pediatric MS showed relapse-associated worsening (RAW) as dominant driver of worsening.
  • Disease modifying treatments (DMTs) delay disability accrual reducing mostly RAW, while weakly prevent PIRA, suggesting an underlying ongoing process of inflammation and/or degeneration secondary to disease burden.
  • DMTs delay the time to milestones disability, showing that treatment is most effective in the earliest phases of the disease.



  1. Kappos L et al. Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials.  JAMA Neurol. 2020; 77(9):1132-1140. doi: 10.1001/jamaneurol.2020.1568. https://pubmed.ncbi.nlm.nih.gov/32511687/
  2. Lublin FD et al. How patients with multiple sclerosis acquire disability. Brain. 2022; awac016. doi: 10.1093/brain/awac016. https://pubmed.ncbi.nlm.nih.gov/35104840/