Why It’s Time to Rethink Multiple Sclerosis

MS involves dynamic crosstalk between adaptive and innate immunity.¹ This dysregulation operates through both a peripheral immune response and a central nervous system (CNS)-compartmentalized immune response, and CNS border tissues play a key role in regulating chronic compartmentalized neuroinflammation.¹ 

Immune network dysregulation in MS is involved in two rather distinct disease biologies. The first is relapse-associated inflammation, which is acute inflammatory activity visible through symptom flare-ups and new lesions on MRI scans.¹ 

The second is Progression Independent of Relapse Activity (PIRA), which is a process of gradual disability accumulation that occurs even without relapses or new lesions, driven by chronic, or "smoldering", neuroinflammation within the CNS.³ Unlike relapse-associated inflammation, which resolves after a temporary flare, this chronic, compartmentalized activity behaves more like a smoldering fire: present from early in the disease and building gradually over time.¹ 

Microglia, the resident immune cells of the CNS, are key cellular drivers of this chronic neuroinflammatory process and contribute to PIRA.⁴ While microglia are central to this process, the field is increasingly viewing smoldering neuroinflammation as the product of a broader immune network, dysregulated crosstalk between adaptive and innate immune cells, rather than a single cell type acting in isolation.⁵ 

The impact of progression-related biology is felt by people with MS every day. Fatigue affects 94% of patients, while 75% report cognitive impairment, changes that routine clinical assessments frequently miss.^*6 The broader impact is substantial: more than 1 in 3 patients are unemployed, a figure that underscores how profoundly disability affects work capacity and independence.⁷ 

Most currently approved MS treatments have been developed with a primary focus on reducing relapse activity through depleting or suppression mechanisms.¹ But relapse reduction alone does not reduce or prevent disability accumulation: up to 70% of patients on existing treatments still experience PIRA, including gradual disability accumulation, persistent fatigue, and cognitive decline.⁸ Relapses are also found to poor predictors of long-term disability accumulation. 

Leading MS organizations have responded to this evolving understanding with updated treatment recommendations. The National Multiple Sclerosis Society (NMSS), Multiple Sclerosis International Federation (MSIF) and European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) have endorsed international consensus recommendations stating that MS treatments must go beyond relapse and MRI lesion control to prevent disability accumulation, protect against fatigue and cognitive impairment and preserve daily function and work capacity.^9,10 

Meeting the consensus recommendations requires multidimensional MS treatment framework, one that addresses relapses, PIRA, long-term safety considerations, tolerability and functional preservation, rather than optimizing one aspect of MS biology. Achieving this requires therapeutic approaches that regulate immune network dynamics involving both adaptive and innate immunity, addressing both relapse-associated and progression-related biology without depleting or broadly suppressing immune cells.^1,11 

Intervening as early as possible is essential to preventing irreversible disability accumulation.^1,12 

Dr. Daniel Ontaneda, MD, PhD, speaks about next steps for the MS field to take. 

Sanofi is pioneering new measurement strategies through the Smoldering-Associated Worsening (SAW) Index, which is grounded in the first international consensus framework for defining and measuring smoldering-associated disability progression. The SAW Index is being developed in collaboration with leading MS experts, people living with MS, and advocacy organizations to assess disability accumulation beyond traditional clinical metrics and capture the full multidimensional impact of the disease. 

Advancing MS care means addressing every signal the disease generates, from peripheral-driven relapse activity to CNS-driven progression, as early as possible, and measuring success across all the dimensions that matter to people living with MS. 

*Any person diagnosed with MS in the countries participating was able to take part in this survey after consenting.