May 15, 2026 | News |

The New MS – the MS disease process

Part 1 of 3

Multiple sclerosis was once conceived to be an autoimmune disorder in which the immune cells become abnormally activated, enter the central nervous system (CNS), and cause inflammation and nerve damage. The damage gradually accumulated, leading to varying levels of physical disability. This meant that MS was a two-stage disease: a relapsing-remitting phase (RRMS) marked by inflammation, followed by a secondary-progressive phase (SPMS) characterized by increasing nerve damage (neurodegeneration). People with worsening disability from the outset were labelled as having primary-progressive MS (PPMS), which was thought of SPMS that skipped the RRMS phase, or as another disease altogether.

However, over the past decade, many of these ideas have been revised or discarded. MS is now viewed through a different lens – which has affected how researchers study MS and how neurologists now treat it. In this article we will look at some of the observations that led researchers to a different set of conclusions about the nature of MS.

The types of MS – RRMS, SPMS and PPMS – were always an artificial construct. They were developed in 1996 based on the results of a survey of neurologists rather than on research data (Lublin and Reingold. Neurology 1996;46:907-911). The stated intent was to make it easier to recruit similar-appearing people into clinical trials. The description of MS subtypes became increasingly elaborate over the next two decades until this approach was largely replaced over the past decade. MS is now recognized as being one disease: the underlying disease processes are the same in everyone diagnosed with MS. The symptoms and the long-term outcomes may differ between individuals, but this may be because of environmental factors or genetic differences.

There was also a shift in how we think about immune dysfunction in MS. Animal studies used T cells to trigger CNS inflammation as a way to study MS, which made it seem as if MS were a ‘T cell disease’. This led to the development of Gilenya, which specifically targets T cells. Unfortunately, this focus on one type of immune cell overlooked the importance of B cells, which activate T cells and produce antibodies against the body’s own tissues. Once the B cell’s role in MS was recognized, it led to the development of B cell-targeted therapies, such as Ocrevus, Kesimpta, Rituxan and Briumvi, which are arguably the most effective MS medications we have to date.

T and B cells are two of the main players in the adaptive immune response so targeting them will reduce the abnormal inflammatory response that is seen in MS. However, this narrow focus overlooks the second of the body’s defences – the innate immune system – with its own stable of actors. Some of these likely play an important role in the development of disability. This will be discussed in Part 3 of this series.

Relapses and disability progression

Relapses are the hallmark of MS and were once considered to be the main driver of disability in MS. The development of potent immunosuppressive therapies unmasked what doctors may have already suspected: MS disability continues to get worse even when people have no relapses. For example, in the OPERA studies, 1 in 7 people taking Ocrevus had worsening disability during relapse-free periods (Kappos and colleagues. JAMA Neurol 2020;77:1132-1140). This worsening was called progression independent of relapse activity, or PIRA, which was distinct from relapse-associated worsening (RAW). RAW was once seen as the cause of disability. PIRA is now recognized as a far more important driver of disability throughout the course of MS.

PIRA demonstrated that the two-stage model was incorrect: inflammatory activity (relapses and MRI lesions) is not followed in turn by worsening nerve damage. Both of these processes can occur at the same time and from the earliest stages of the disease. In fact, early nerve damage can be detected fully six years before a person is diagnosed with MS (Bjornevik and colleagues. JAMA Neurol 2020;77:58-64).

What PIRA means in daily life is that even during periods when MS appears to be in remission, there are processes at work that are slowly worsening nerve function. PIRA is often equated with ‘smouldering inflammation,’ but this is incorrect (Bsteh and colleagues. Int J Mol Sci 2025;26:4704). There are many disease processes that contribute to neurodegeneration of which smouldering inflammation is but one. PIRA likely represents one or more of these processes, and some aspects may improve with treatment. MS medications cannot stop PIRA. But high-efficacy medications such as Ocrevus and Kesimpta can lower the risk that PIRA events will occur, and they may slow the rate of PIRA (Portaccio and colleagues. J Neurol 2024;271:5074-5082. Guarnaschelli and colleagues. Mult Scler 2026; epublished April 29, 2026).

RAW was considered to be treatable and, in some cases, reversible. The same is likely true of PIRA. Recent studies have started to distinguish ‘sustained PIRA’ (worsening disability that never gets better) from PIRA events that eventually show improvements in function (Zhu and colleagues. Brain Commun 2025;7:fcaf306). This may be because PIRA is a nonspecific finding (worsening disability) that may be caused by a range of underlying disease processes. Some of these processes may respond to current treatments, others may require new approaches to shut down and/or repair the damage.

In Part 2 we will look at the idea that ‘time is brain’.

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