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Secondary progressive multiple sclerosis is a phase of MS in which, after a period of relapsing disease, gradual and persistent worsening of neurological function becomes increasingly prominent. This progression may occur even without new relapses and without new gadolinium-enhancing MRI lesions.
Today, transition to SPMS is viewed not as a sudden switch from one disease to another, but as a gradual change in the balance between inflammation, neuroaxonal injury and the nervous system’s capacity to compensate. Recognizing progression early is important because treatment strategies differ between active SPMS and progression without recent relapses.
The transition to SPMS is usually gradual. There is often no single date when one can say: “SPMS started on this day.”
PIRA — progression independent of relapse activity — describes disability accumulation that is not directly associated with a clinical relapse.
PIRA does not begin only after a formal diagnosis of SPMS. It may occur during relapsing MS and gradually become an increasingly important source of long-term disability accumulation.
There are no clear new inflammatory attacks, but neurological function gradually declines.
Conventional MRI is very useful for detecting new focal inflammatory activity, but it does not capture the full extent of chronic diffuse injury.
Walking, hand function, balance and daily activities become particularly important to follow over time.
There is no single blood test, MRI marker or other investigation that confirms SPMS. Diagnosis is primarily clinical and depends on objective change over time.
Two processes need to be assessed separately: inflammatory activity and disability progression.
There is evidence of ongoing inflammation: clinical relapses and/or new MRI activity.
In this situation, anti-inflammatory disease-modifying therapy remains particularly important.
New relapses may be absent, while disability continues to accumulate gradually.
This is the population studied in the HERCULES trial of tolebrutinib, which changed the therapeutic landscape in 2026.
Progressive MS cannot be reduced simply to “inflammation disappears and neurodegeneration begins.” Both processes may coexist, but the nature of inflammation changes over time.
Part of the inflammatory process becomes compartmentalized within the central nervous system and may be less visible through conventional relapse activity.
Microglia and other cells of innate immunity contribute to chronic neuroinflammation.
Damage to axons and neuronal networks gradually reduces the functional reserve of the nervous system.
Some lesions expand slowly over time and may show a paramagnetic rim, reflecting a chronically active lesion edge.
The ability to restore damaged myelin and compensate for previous injury becomes less effective over time.
With aging, the brain becomes less able to compensate for accumulated structural injury, making previously hidden damage clinically apparent.
In SPMS, it is not enough simply to continue the treatment used during relapsing disease. The neurologist needs to reassess whether inflammatory activity persists, how quickly function is worsening and whether the current treatment still matches the disease phenotype.
| Clinical situation | Main treatment goal | What may be considered |
|---|---|---|
| SPMS with relapses and/or MRI activity | Control ongoing inflammatory activity as effectively as possible. | Disease-modifying therapy selected according to previous treatment, disease activity, age and individual safety profile. |
| Active SPMS | Reduce inflammatory activity and the risk of further disability accumulation. | Depending on local indications, siponimod and other therapies approved for active or relapsing forms of MS may be considered. |
| SPMS without recent relapses | Target progression occurring outside clinical relapses. | In the European Union, tolebrutinib became an approved option for a defined group of patients in 2026. |
| Advanced disability | Preserve function, safety and independence as much as possible. | Disease-modifying strategy, rehabilitation, treatment of spasticity, pain, gait impairment, bladder symptoms and other functional problems. |
Siponimod was specifically studied in the large Phase III EXPAND trial in patients with SPMS. It reduced the risk of confirmed disability progression, and long-term follow-up supported sustained treatment benefit.
In many current regulatory systems, its use is primarily associated with active SPMS. Before treatment, individual contraindications and risk factors need to be assessed, including CYP2C9 genotype.
Dr. Lidiia Prakhova was a co-author of a 2022 publication describing the first Russian real-world experience with siponimod.
When relapses or new MRI activity persist, modern therapies approved for active or relapsing forms of MS may remain appropriate.
The most useful question is therefore usually not “Which drug is for SPMS?” but which disease mechanism is dominant in this individual patient now?
Tolebrutinib is an oral Bruton’s tyrosine kinase (BTK) inhibitor that penetrates the central nervous system. It affects both B cells and myeloid-lineage cells, including microglia, making it particularly relevant to chronic compartmentalized inflammation.
The HERCULES trial included 1,131 patients with non-relapsing SPMS. Tolebrutinib reduced the risk of 6-month confirmed disability progression compared with placebo.
On June 19, 2026, the European Commission granted marketing authorization for Cenrifki (tolebrutinib).
The European indication is for adults with secondary progressive multiple sclerosis who have not experienced relapses during the previous two years.
This is an important change, because historically most disease-modifying therapies were considerably more effective against focal inflammatory activity than against progression without relapses.
European authorization does not automatically mean that the treatment is available in Israel. Regulatory status, health-fund coverage and actual availability should be checked separately.
In progressive MS, treatment success is not defined only by MRI or disease-modifying therapy. Preserving walking, hand function, safety and independence is equally important.
Weakness, spasticity, foot drop, sensory impairment, poor balance and fatigue often contribute together.
Treatment may combine exercise, oral medication and focal botulinum toxin therapy depending on the pattern of spasticity.
Sleep problems, depression, infection, anemia, medication adverse effects and heat sensitivity should be considered.
Depending on the pattern of weakness, AFOs, dynamic orthoses or functional electrical stimulation may be considered.
Pain may be neuropathic, related to spasticity or altered gait, or caused by specific syndromes such as trigeminal neuralgia.
Bladder, bowel and sexual dysfunction may have a major effect on quality of life and deserve active assessment and treatment.
Monitoring SPMS needs to go beyond the question: “Are there new MRI lesions?”
Repeated assessment of EDSS, walking speed, hand function and other measures can reveal gradual change earlier.
MRI remains important for detecting new focal inflammatory activity, but stable conventional MRI does not exclude progression.
NfL may provide information about neuroaxonal injury, while GFAP is increasingly studied as a marker related to progressive disease biology.
Progression cannot be completely prevented, but modern evidence suggests that effective early control of inflammatory activity is important for long-term outcome.
Observational studies have shown that patients treated earlier with more effective therapies were, on average, less likely or took longer to transition to SPMS than patients with prolonged insufficient disease control.
This does not mean that every patient should receive the most intensive treatment available. Treatment intensity should be individualized according to disease risk, age, comorbidities and safety.
Compare functional changes, neurological findings, previous relapses and MRI over time.
Exclude infection, deconditioning, heat sensitivity, poor sleep, anemia and other reversible causes.
Determine whether relapses or new MRI lesions continue, or whether progression now dominates.
Assess whether the current therapy still matches the present disease phenotype and individual risk profile.
Review siponimod, therapies for active SPMS and new approaches to progression without recent relapses.
Prioritize treatment of walking, spasticity, fatigue, pain, bladder dysfunction and other symptoms affecting independence.
A consultation may be particularly useful when walking or another neurological function is gradually worsening despite the absence of relapses, when transition to SPMS is suspected, or when treatment needs to be reassessed in light of newer therapeutic options.
Regulatory information: European Medicines Agency. Cenrifki (tolebrutinib). Marketing authorization issued 19 June 2026. Indication: adults with SPMS without relapses during the previous two years.