Fig. 1.

In most patients, MS starts as a relapsing–remitting disease (RRMS), which is termed Clinically Isolated Syndrome (CIS) after a first bout of clinical symptoms. This is often preceded by a phase of subclinical disease activity that can be detected with magnetic resonance imaging (MRI; yellow stars denote MRI signs of active inflammation). In later stages of RRMS, patients accumulate persistent disabilities, where recent evidence suggests that a progressive component may start already soon after diagnosis (light grey). This underlying progressive disease component becomes more pronounced at later stages, when the disease converts to secondary progressive MS (SPMS). The fact that inflammatory disease activity, as reflected by frequency of bouts or MRI activity, diminishes over time suggests a shift from adaptive to innate or local disease mechanisms, which may explain the relative loss of efficacy of disease‐modulatory treatments (DMT).