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Primary progressive multiple sclerosis is a form of MS in which neurological function gradually worsens from the beginning of the disease, without a preceding period of typical relapses and remissions.
The first noticeable changes most often involve walking, weakness or stiffness in the legs, reduced endurance and impaired balance. The rate of progression varies considerably between individuals, and inflammatory disease activity may still be present even when there are no clinical relapses.
Gradual worsening begins from the onset of the disease. There is no preceding typical period of relapses and remissions.
The disease initially follows a relapsing course, after which persistent disability progression gradually becomes the dominant feature.
PPMS rarely begins dramatically. Changes generally develop slowly and may initially be subtle.
The 2024 McDonald criteria introduced a more unified modern approach to relapsing and progressive-onset MS. In PPMS, however, it remains essential to establish sustained progression and demonstrate findings characteristic of multiple sclerosis.
Cervical or thoracic spinal canal stenosis can produce gradually progressive spastic paraparesis.
Metabolic myelopathies can clinically resemble chronic progressive spinal cord disease.
This diagnosis is particularly relevant with slowly progressive leg spasticity and a suggestive family history.
An atypical myelitis pattern should prompt consideration of other inflammatory CNS disorders.
These become especially relevant with later age at onset and vascular risk factors.
Depending on the clinical picture, investigation may include infectious, autoimmune, metabolic and rare hereditary causes.
Part of the inflammatory process becomes compartmentalized within the central nervous system and is less likely to produce typical relapses.
The efficacy of anti-CD20 therapy supports an important role for B-cell biology even in primary progressive disease.
Cells of the innate immune system contribute to persistent chronic neuroinflammation.
Some MS lesions continue to expand slowly despite little or no obvious new focal inflammatory activity.
Progressive injury to nerve fibers gradually reduces the functional reserve of the nervous system.
The nervous system becomes less able to repair and compensate for accumulated structural damage.
The central challenge in treating PPMS is that disability progression is not driven only by peripheral inflammatory activity. Treatments that strongly suppress relapses do not necessarily have the same effect on progression.
Ocrelizumab is an anti-CD20 monoclonal antibody and the principal disease-modifying treatment with established evidence for slowing disability progression in PPMS.
In the pivotal ORATORIO trial, ocrelizumab reduced the risk of confirmed disability progression compared with placebo.
Historically, treatment benefit was considered more likely in younger patients and in those with evidence of inflammatory activity. The 2026 ORATORIO-HAND results, however, broadened the evidence base to include older patients and people with more advanced disability.
| What should be assessed before treatment? | Why does it matter? |
|---|---|
| Age, disease duration and rate of progression | These factors help estimate expected treatment benefit and overall prognosis. |
| New or enhancing MRI lesions | They indicate a persisting inflammatory component. |
| Infection risk | Anti-CD20 therapy affects humoral immunity and requires appropriate monitoring. |
| Immunoglobulins and blood count | These are important for safe long-term treatment. |
| Vaccination status | Vaccination should preferably be planned with B-cell-depleting therapy in mind. |
| Comorbidities | With increasing age, the balance between expected benefit and immunotherapy risk changes. |
ORATORIO-HAND included 1,013 people with PPMS. It studied a broader population than the original ORATORIO trial, including older patients and people with more advanced disability.
Ocrelizumab reduced the risk of 12-week composite confirmed disability progression compared with placebo.
An important aspect of ORATORIO-HAND was the demonstration of benefit in preserving upper-limb function, which is especially relevant for patients who already have substantial walking impairment.
The GAVOTTE study evaluated a higher bodyweight-adjusted dose of ocrelizumab.
The higher dose did not provide additional reduction in disability progression compared with the standard 600 mg regimen.
This is clinically useful: increasing the ocrelizumab dose above the standard regimen does not appear to improve PPMS control.
Fenebrutinib is an oral, CNS-penetrant, highly selective BTK inhibitor.
In the Phase III FENtrepid study, fenebrutinib met the primary endpoint of non-inferiority to ocrelizumab for composite confirmed disability progression.
The hazard ratio was 0.88, corresponding to a numerical 12% reduction in the risk of disability progression compared with ocrelizumab. The trial was designed primarily to demonstrate non-inferiority, not superiority.
A particularly interesting signal was observed for upper-limb function. Fenebrutinib remains investigational and should not yet be regarded as an established standard treatment for PPMS.
Positive results with one BTK inhibitor cannot automatically be extrapolated to the entire drug class.
The Phase III PERSEUS study of tolebrutinib in PPMS did not meet its primary endpoint of delaying 6-month composite confirmed disability progression.
Based on these results, regulatory submission of tolebrutinib for PPMS is not being pursued.
Even when disease-modifying therapy slows biological progression, everyday function depends on the combined effects of weakness, spasticity, foot drop, balance impairment, fatigue and other symptoms.
It is important to determine what actually limits walking: weakness, spasticity, foot drop, sensory loss, ataxia or fatigue.
Depending on the pattern of weakness, AFOs, dynamic orthoses and functional electrical stimulation may be useful.
Management may include exercise, medication, orthoses and botulinum toxin therapy for focal spasticity.
Sleep, mood, anemia, infection, medication effects and heat sensitivity should all be considered.
In selected patients, FES, robotic gait training, exoskeletons and other assistive technologies may support function.
Neuropathic pain, bladder and bowel dysfunction and sexual dysfunction should be assessed and treated rather than accepted as inevitable consequences of PPMS.
EDSS is useful for standardized disability assessment, but it does not capture every aspect of progression.
Timed 25-Foot Walk, 9-Hole Peg Test and other quantitative measures can objectively document change.
MRI helps detect ongoing focal inflammatory activity, but stable MRI does not mean that progression has stopped.
Walking distance, falls, stairs, hand use and the ability to remain independent are clinically meaningful outcomes.
Neurofilament light chain may provide additional information about neuroaxonal injury, but it is not a PPMS-specific test.
GFAP is increasingly being studied as a potential complementary biomarker associated with progressive MS biology.
There is progressive walking impairment and MRI abnormalities, but it is unclear whether the diagnosis is truly PPMS.
It may be important to evaluate not only the radiology report, but also the actual location and characteristics of the lesions.
The expected benefit of ocrelizumab, inflammatory activity and individual safety risks can be assessed.
It is important to determine whether the rate of change is consistent with the disease course and whether reversible factors can be corrected.
The relative contribution of weakness, spasticity, foot drop and balance impairment can be assessed and a rehabilitation strategy developed.
This can be especially valuable when the diagnosis was made primarily from MRI or when the clinical picture is atypical for PPMS.
When primary progressive MS is suspected, the clinical history, neurological examination, brain and spinal cord MRI, cerebrospinal fluid findings and other investigations can be reviewed together to determine an appropriate strategy for treatment, monitoring and rehabilitation.
Fenebrutinib remains investigational. Regulatory status and availability of individual therapies may vary between countries and healthcare systems.