Unpacking MS Progression - Part 1

When "Progression" Means Many Things: Decoding the Language of Worsening in MS.

Few words in multiple sclerosis carry as much weight or ambiguity as “progression.”

Progression is defined as “the process of developing or moving gradually toward a more advanced state.” It sounds straightforward enough. Yet in multiple sclerosis, the concept has proven anything but simple. Over the years, clinicians and researchers have proposed a succession of definitions and catchy acromyms to capture a process that is difficult to grasp, harder to measure, and sometimes impossible to pinpoint with certainty.

In this first part of our series on MS progression, I want to walk you through the evolving history of how the MS community has perceived and defined this elusive but crucial concept.

The Initial Clinical Course Descriptors

In 1996, Fred Lublin and colleagues published the first formal clinical course descriptors of multiple sclerosis. [1] They divided the disease into four categories: relapsing-remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS), and progressive-relapsing (PRMS). Progressive forms of MS were described as nearly continuous worsening though minor remissions and plateaus were allowed.

At the dawn of the MS therapeutic era, a common language had become essential. Multicenter clinical trials depend on enrolling relatively homogeneous patient populations with a predictable enough course to reveal whether a treatment makes a difference. The new clinical course descriptors accomplished exactly that. They were rapidly adopted into trial eligibility criteria and provided the structure needed to propel MS therapeutic research forward, a framework that arguably helped fuel the breakthroughs that followed.

Incorporating these terms into clinical practice, however, proved far messier. On one hand, the new vocabulary gave patients and clinicians shared words to describe lived experiences that had previously felt inarticulate or invalidated. For some, it was empowering to have a name for what they were feeling. For others, it brought confusion and fear. Progression in MS is rarely linear; it can be subtle, fluctuate over time, and resist neat categorization. Labeling someone as having “progressive MS” often felt premature or even cruel, a declaration of inevitability rather than a description of the present. “Progressive” became a heavy word in the clinic room, carrying with it an air of finality.

Clinicians, too, were uneasy. The classification system was rooted in clinical observation rather than biology. At the time, we lacked the imaging and biomarker data to meaningfully correlate clinical courses with underlying pathology.

By 2014, the need for refinement was clear. Lublin and colleagues updated the descriptors, [2] adding modifiers and integrating MRI findings to capture disease activity more precisely. The update acknowledged that people with relapsing disease can still experience disability worsening, and that those with progressive disease may have long periods of stability. These nuances introduced complexity and, at times, confusion but also a necessary recognition: progression is not confined to a single MS subtype. It can emerge across the spectrum, challenging our efforts to define the disease in simple, binary terms

Understanding Disability Progression Across the Spectrum of MS

While the 2014 clinical course descriptors have not yet been updated, the MS research community has turned its attention toward understanding how people with MS accumulate disability, regardless of which diagnostic “box” they fall into. Over the past decade, a growing body of evidence has confirmed that progression is not confined to the progressive forms of MS.

Starting in 2018, several pivotal studies analyzed large clinical trial datasets and real-world cohorts, revealing two distinct pathways to disability accumulation:

• Relapse-Associated Worsening (RAW): Disability that follows a clinical relapse, typically due to incomplete recovery.

• Progression Independent of Relapse Activity (PIRA): Disability accumulation that occurs without a preceding relapse.

A landmark study involving more than 27,000 patients followed for up to 15 years [3] demonstrated that PIRA often begins early in the disease course, even in those with relapsing-remitting MS, and gradually becomes the dominant driver of disability accumulation over time.

More recently, the acronym PIRMA (progression independent of relapse and MRI activity) has emerged and further refines the concept. PIRMA describes disability progression that occurs even if there are no overt relapses and MRI scans also appear stable, as disease activity can happen beneath the surface in MS.

This distinction between RAW and PIRA/PIRMA is not just semantic; it reflects fundamentally different biology and has profound therapeutic implications.

RAW is driven by peripheral inflammatory processes: immune cells activated outside the central nervous system that cross the blood–brain barrier to form new lesions and cause relapses. When the damage from these focal attacks is severe enough that axons are damaged and repair mechanisms fall short, residual disability remains. Because RAW is inflammation-driven, it can often be mitigated, even prevented, by today’s high efficacy disease-modifying therapies, which suppress focal inflammatory activity.

PIRA/PIRMA, on the other hand, stems from chronic, compartmentalized inflammation within the central nervous system itself, slow neurodegeneration, mitochondrial dysfunction, and the gradual failure of repair and plasticity mechanisms, processes that accelerate with aging. Unlike RAW, these changes persist despite effective control of relapses and MRI activity and can be manifest even in people optimally treated with high-efficacy DMTs.

In short, RAW is what our current therapies can prevent; PIRA is what remains.

Capturing subtle worsening

Although PIRA has been increasingly recognized as the key driver of disability accumulation across the MS spectrum, clinicians have criticized its current definition for relying too heavily on motor-based measures such as the EDSS, the disability scale most commonly used in clinical trials. More recent efforts have aimed to broaden this definition, incorporating additional assessments to make it more meaningful in clinical practice. Some have even proposed a new term altogether: smouldering-associated worsening (SAW).

The concept, introduced by Scalfari and colleagues in 2024, sought to expand beyond the EDSS-driven definition of PIRA to include more delicate shifts, motor or cognitive, that unfold even when inflammation appears to be under control. [4] It was also an attempt to tie these clinical observations to the biology we increasingly recognize: that progression can arise from slow, persistent processes within the brain itself, not just from new inflammatory storms.

It’s an appealing idea, and the name, SAW, has a certain poetry to it. Yet I can’t help but wonder whether we truly need another acronym. Perhaps, instead of multiplying definitions, we might do better to broaden PIRA itself, to let it breathe and stretch enough to encompass the nuances we see in our patients.

“Smouldering disease,” as the authors describe it, captures something vast, an umbrella of chronic neuroinflammation, neurodegeneration, failing repair mechanisms and impaired plasticity. It’s a compelling image, but perhaps too sweeping to serve as a compass in clinical trials, especially now that therapies are emerging to target these biological fires more individually.

And so we return to a familiar tension: the one between clinical simplicity and biological complexity. Every new term promises precision but risks losing practicality. The art, perhaps, lies in finding definitions and frameworks that illuminate without obscuring, and that serve both science and the people who live with the disease we are trying to understand.

I, for one, look forward to the next revision of the MS Clinical Course Descriptors by the International Advisory Committee on Clinical Trials in Multiple Sclerosis; [5] an update that will, I believe, bring together the lessons of the past decade and set the stage for the next wave of discoveries in how we understand and treat progression.

Next on the Unpacking MS Progression Series…

In part 2, I’ll take you inside my clinic to show how these definitions meet real patients, and how I make sense of it all in daily practice. Stay tuned.

References:

[1] Lublin, F. D., Reingold, S. C. & Sclerosis*, N. M. S. S. (USA) A. C. on C. T. of N. A. in M. Defining the clinical course of multiple sclerosis. Neurology 46, 907-911. (1996).

[2] Lublin, F. D. et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 83, 278–286 (2014).

[3] Lublin, F. D. et al. How patients with multiple sclerosis acquire disability. Brain 145, awac016- (2022).

[4] Scalfari, A. et al. Smouldering‐Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions. Ann. Neurol. 96, 826–845 (2024).

[5] NMSS website (accessed October 2025) https://www.nationalmssociety.org/news-and-magazine/momentum-magazine/from-the-community/updating-how-we-classify-ms