A story beyond relapses and acute lesions has been ignited within the science of MS. It’s time to look inside

Current approaches to MS management are effective at controlling relapses and acute lesions, but may fail to address an important mechanism of disease progression that results in disability accumulation.1

Controlling relapse activity and acute lesions are important goals in relapsing MS, but there remains an unmet need: preventing disability accumulation that can occur despite relapse control.1

Activated peripheral B and T cells cross a leaky blood-brain barrier, causing acute neuroinflammation
  • Historically, MS has been considered a disease mediated by adaptive immune cells from the periphery, such as B cells and T cells4
  • Research is showing that innate immune cells originating in the CNS, including microglia, may play a pivotal role in disease progression4

Disease progression despite relapse control

Although current approaches may be addressing relapses and acute lesions, many will experience progression independent of relapse activity (PIRA) and accumulate significant disability, thought to be driven by smoldering neuroinflammation.1,5

Underlying smoldering neuroinflammation drives PIRA and resulting disability accumulation in MS

More about PIRA

  • The schematic represents 2 concurrent neuroinflammatory pathways that drive PIRA and resulting disability accumulation1
  • PIRA is a clinical manifestation of smoldering neuroinflammation1
  • PIRA is most apparent when patients exhibit disability progression despite being relapse-free1

EDSS=Expanded Disability Status Scale; IID=initially assessed increase of disability; MS=multiple sclerosis; RAW=relapse-associated worsening.


See the connection between smoldering neuroinflammation and disability accumulation


  1. Giovannoni G, Popescu V, Wuerfel J, et al. Smouldering multiple sclerosis: the ‘real MS’. Ther Adv Neurol Disord. 2022;15:17562864211066751. doi:10.1177/17562864211066751
  2. Gandhi R, Laroni A, Weiner HL. Role of the innate immune system in the pathogenesis of multiple sclerosis. J Neuroimmunol. 2010;221(1-2):7-14.
  3. Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. N Engl J Med. 2018;378(2):169-180.
  4. Hernández-Pedro NY, Espinosa-Ramirez G, de la Cruz VP, Pineda B, Sotelo J. Initial immunopathogenesis of multiple sclerosis: innate immune response. Clin Dev Immunol. 2013;2013:413465. doi:10.1155/2013/413465
  5. Tavazzi E, Rovaris M, La Mantia L. Drug therapy for multiple sclerosis. CMAJ. 2014;186(11):833-840.