Progression Independent of Relapse Activity in Multiple Sclerosis: Closer to Solving the Pathologic Puzzle.

Progression independent of relapse activity (PIRA) is one of the main mechanisms of disability accrual in multiple sclerosis (MS) even in people with relapsing-remitting MS (RRMS). PIRA can occur at any stage of the disease and is associated with unfavorable long-term outcomes, especially if PIRA occurs early in the disease course. The pathologic substrates of PIRA are not yet well understood, although there is growing evidence suggesting that PIRA may occur mainly in a predominant neurodegenerative context, sometimes in combination with an acute inflammatory activity. A deeper understanding of the pathologic processes underlying PIRA represents a vital initial stride toward averting the accumulation of irreversible disability in MS.