What Is Secondary Progressive MS and How Does It Progress?

Secondary progressive multiple sclerosis (SPMS) is the phase of MS in which disability accumulates steadily, no longer tied to the distinct relapses and remissions that mark the earlier stage of the disease. Most people with relapsing-remitting MS (RRMS) eventually transition to SPMS: roughly half within 20 years and over 90% within 30 years of their initial diagnosis.¹ The shift is gradual and often hard to pinpoint, which creates real challenges for diagnosis, treatment decisions, and planning ahead. Understanding what drives SPMS, how clinicians identify it, and what can actually be done about it matters for anyone living with MS or caring for someone who is.

How the Transition From Relapsing-Remitting MS Happens

In RRMS, the immune system launches periodic attacks on the myelin sheath protecting nerve fibers. Between those attacks, people often recover partially or fully. SPMS begins when that recovery stops keeping pace with the damage. Disability starts creeping upward between relapses, or relapses stop happening altogether while function still declines. In a large cohort study of over 1,900 people with RRMS, about 10% had converted to SPMS by the 10-year mark, half by 20 years, and 93% by 30 years.²

The transition is not a switch that flips on a particular date. It is usually recognized in hindsight, after a clinician notices a pattern of worsening over months or years that cannot be explained by individual relapses. This makes the boundary between RRMS and SPMS frustratingly blurry, both for the person experiencing it and for their medical team.

What Is Actually Happening in the Brain

The biology of SPMS looks different from the biology of early relapsing disease, and understanding that difference helps explain why treatments that work in RRMS often fall short once progression sets in. In RRMS, much of the damage comes from immune cells crossing from the bloodstream into the central nervous system and attacking myelin in discrete bursts. In SPMS, the problem shifts. Immune activity becomes trapped inside the brain and spinal cord, operating behind the blood-brain barrier where most conventional drugs cannot easily reach.

A central concept in recent research is the “smouldering lesion.” These are brain lesions that evolved from earlier acute inflammatory attacks but never fully resolved. Instead of healing, they settle into a state of ongoing, low-grade damage. Macrophages and microglia, the brain’s resident immune cells, remain chronically activated at the edges of these lesions, slowly expanding the zone of demyelination and neuronal loss over years.³ Some researchers have argued that this smouldering process, rather than acute relapses, represents the core of MS pathology throughout the disease course.⁴

Meningeal inflammation also plays a role. Clusters of immune cells can form in the meninges, the membranes surrounding the brain, and the inflammation they generate damages the cortex directly underneath. This process is strongly linked to the loss of neurons and myelin in the outer layers of the brain, contributing to the accumulating disability characteristic of SPMS.⁵

On top of all this, the energy supply of nerve cells starts to fail. Research has documented deficiencies in the mitochondrial respiratory chain within neurons in progressive MS. Mitochondria are the structures inside cells that generate energy, and when they malfunction, neurons cannot keep up with the increased energy demands created by demyelinated axons. Long nerve tracts, like those running from the brain down the spinal cord, are especially vulnerable because their axons are so long that even modest energy shortfalls can be devastating.⁶ The result is a vicious cycle: chronic inflammation damages mitochondria, energy-starved neurons degenerate, and the functional reserve that once masked the damage gradually runs out.

Why Diagnosing SPMS Is So Difficult

There is no single blood test or MRI scan that definitively says “this person has entered SPMS.” The diagnosis remains primarily clinical, meaning it depends on a doctor recognizing a pattern of gradual worsening that is not explained by relapses. Various expert groups have proposed diagnostic criteria using combinations of standardized tests, including timed walking tests, hand dexterity tests, cognitive processing speed assessments, and disability rating scales. A validation study found that the expanded disability status scale and timed physical tests were highly sensitive for identifying the transition to SPMS, though different expert panels disagreed on exactly which combination of tests performed best.⁷

One practical consequence of this diagnostic murkiness is that SPMS is often recognized years after it actually began. By the time the pattern is clear enough for a confident diagnosis, the person may have been gradually worsening for some time. Efforts to identify earlier biomarkers are an active area of research.

Biomarkers That May Help Track Progression

Two blood-based biomarkers have attracted particular interest. Neurofilament light chain (NfL) is a protein released into the blood when nerve fibers are damaged, and it tends to be elevated in people with active inflammatory disease, like new relapses or new MRI lesions. Glial fibrillary acidic protein (GFAP) tells a different story: it reflects activation of astrocytes, a type of brain cell involved in chronic neurodegeneration. In people with progressive MS, higher GFAP levels were associated with roughly 70% greater risk of confirmed disability progression, and this association was strongest in patients without signs of active inflammation.⁸ This distinction matters because it suggests GFAP may capture the slow, smouldering neurodegeneration that NfL misses.

On MRI, paramagnetic rim lesions (PRLs) have emerged as a promising marker of chronic active, smouldering disease. These are lesions with a visible rim of iron-laden immune cells on specialized MRI sequences. Having PRLs was associated with about 80% higher risk of disability progression independent of relapses, and the number of PRLs correlated with faster brain shrinkage over time.⁹ However, interpreting PRLs is not straightforward. Rim visibility can fade over time as lesions age and tissue degenerates, meaning a disappearing rim does not necessarily mean the inflammation has resolved. Persistent rims may be a more reliable marker of ongoing compartmentalized inflammation than rim disappearance is of its resolution.¹⁰

Active Versus Non-Active SPMS

Clinicians sometimes categorize SPMS as “active” (still showing relapses or new MRI lesions) or “non-active” (progressing without any signs of inflammatory flare-ups). You might assume that active SPMS would be worse, since inflammatory attacks are piled on top of steady progression. But a registry study of over 800 people with SPMS found that disability worsened at similar rates in both groups. About 27-30% of patients in each group reached confirmed disability progression within two years, and there was no significant difference in the time it took to reach major disability milestones like needing a cane or a wheelchair.¹¹ The takeaway is sobering: progression in SPMS is driven primarily by the slow, relapse-independent process rather than by acute inflammatory attacks. Relapses add some disability, but they account for a relatively small share of the worsening.

Available Treatments

Treatment options for SPMS are far more limited than for RRMS, and the honest reality is that none of the currently approved therapies can halt progression. Siponimod is the only drug specifically approved in many countries for active SPMS based on a dedicated phase 3 trial. In the EXPAND trial, siponimod reduced the risk of three-month confirmed disability progression by about 21% compared with placebo.¹² In people with active SPMS specifically, the benefit was somewhat larger, with a 31-37% reduction in confirmed disability progression depending on how long improvement had to be sustained. Siponimod also improved cognitive processing speed in this subgroup and dramatically reduced new inflammatory lesions on MRI.¹³ Imaging data from the same trial showed siponimod slowed brain shrinkage and improved measures of tissue integrity.¹⁴

Several other drugs approved for relapsing MS, including ocrelizumab, cladribine, ofatumumab, and ponesimod, carry broad labels that technically encompass active SPMS. But the evidence behind those approvals for SPMS is thin. The data come from post-hoc analyses of very small subgroups within trials that were designed and powered for RRMS, and whether these drugs reduce relapse-independent progression in SPMS remains unclear.¹⁵ This is an important gap: the drugs work on the inflammatory component, but for people whose progression is happening without relapses, the evidence for benefit is largely assumed rather than demonstrated.

A New Drug Class Targeting the Brain Directly

The most exciting development in SPMS treatment in years came from the trial of tolebrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor. Unlike most existing MS drugs, BTK inhibitors are small molecules that can cross the blood-brain barrier and act on microglia and B cells directly inside the central nervous system, exactly where the smouldering pathology of SPMS plays out. In a phase 3 trial of people with nonrelapsing SPMS, tolebrutinib reduced the risk of six-month confirmed disability progression by 31% compared with placebo.¹⁶ That result is significant because this is the population with the fewest treatment options: people who are worsening without any detectable relapses, where standard anti-inflammatory drugs have not clearly shown benefit.

Several other BTK inhibitors are in various stages of clinical testing for progressive MS, and the class as a whole has shown promising results in modulating disease through this novel mechanism.¹⁷ If these results hold up and the drugs gain approval, they could represent the first treatments to meaningfully address the non-relapsing component of MS progression.

Exercise, Rehabilitation, and Cognitive Training

Pharmacological treatment is only part of the picture for people living with SPMS. Exercise and rehabilitation can make a meaningful difference in fatigue, physical function, and quality of life, even when the disease itself continues to progress. A study of structured exercise training in people with advanced MS found significant reductions in physical and psychosocial fatigue, with both treadmill-based and body-weight-supported training producing large effects.¹⁸ Neuromuscular electrical stimulation, a physical therapy technique often used for muscle weakness and spasm, has also been associated with measurable improvements in walking ability in people with SPMS.¹⁹

Cognitive decline is common in SPMS and often overlooked. A randomized controlled trial of computer-based cognitive neurorehabilitation found that people with SPMS who completed the program showed large improvements in verbal learning, visual memory, and processing speed compared with a sham control group. They also reported less fatigue, less depression, and better quality of life.²⁰ A larger multi-arm trial, however, found that combining cognitive rehabilitation with exercise did not improve processing speed in progressive MS compared with sham interventions, though the researchers noted that their control interventions were not truly inactive, muddying the comparison.²¹ The evidence is mixed but promising enough that cognitive rehabilitation deserves more attention in SPMS care than it typically receives.

How Age of Onset Shapes the Course of Progression

Not everyone’s progression looks the same, and age at MS onset turns out to be a meaningful factor. A study comparing disability trajectories across pediatric-onset, adult-onset, and late-onset MS found that people with late-onset disease accumulated disability faster after their first episode of relapse-independent progression. Three years after that first progression event, disability scores increased by about 0.5 points in pediatric-onset MS, 0.8 in adult-onset MS, and 1.6 in late-onset MS.²² This suggests that the brain’s ability to compensate for ongoing damage declines with age, so progression that begins later tends to become disabling more quickly. For people diagnosed with MS later in life, this makes early attention to relapse-independent worsening especially important.

The Financial and Personal Toll

SPMS imposes a heavy economic burden that goes well beyond medication costs. A Spanish study estimated the total annual cost per person with SPMS at nearly €41,500. More than half of that came from indirect costs like lost productivity and early retirement, with over 90% of people with SPMS no longer working. Direct healthcare costs accounted for about 30%, and direct non-healthcare costs like home modifications and assistive devices made up the remaining 20%. Unpaid caregivers experienced high rates of work absenteeism and significant loss of leisure time.²³ These numbers from Spain will vary across countries, but the overall pattern is consistent: SPMS disrupts careers, reshapes family finances, and absorbs the time and energy of the people closest to the person with the disease.

The Gut Microbiome and Progressive MS

An emerging and somewhat unexpected line of research involves the gut microbiome. People with progressive MS show alterations in their gut bacteria, and these changes appear to have measurable links to disease outcomes. A study that combined stool samples, blood metabolite profiles, and clinical measures found that certain short-chain fatty acid-producing bacteria were associated with less disability worsening, better cognition, and higher quality of life. In contrast, other bacterial species showed detrimental associations. Most of the fecal metabolites linked to disease progression were decreased in progressive MS, suggesting a deficiency of protective factors rather than an excess of harmful ones.²⁴ Short-chain fatty acids specifically have been found to be lower in people with SPMS and long disease duration compared with healthy controls.²⁵

Whether manipulating the gut microbiome through diet, probiotics, or other interventions could slow progression is still unknown. The research is in its early stages, and correlation is a long way from causation. But the findings are intriguing because they suggest a modifiable factor that lies outside the central nervous system and is potentially accessible to intervention. For people with SPMS who feel they have few options, this is a space worth watching.

Stem Cells and Regenerative Approaches

Stem cell therapy for SPMS remains largely experimental, but early clinical work has been cautiously encouraging. A small open-label trial tested autologous mesenchymal stem cells, cells harvested from a person’s own bone marrow and then infused intravenously, in people with SPMS. The treatment was safe, and some participants showed improvements in visual function that the researchers interpreted as potentially neuroprotective.²⁶ A broader review of the field has noted that while several types of stem cells show promise in preclinical models, significant hurdles remain before any stem cell therapy could become a standard treatment for progressive MS.²⁷ The challenges include determining the best cell type, the best route of delivery, the right timing in the disease course, and how to measure meaningful outcomes in a disease that progresses slowly over years.