What are the treatment options for progressive multiple sclerosis (primary‑progressive and secondary‑progressive)?

Treatment Options for Progressive Multiple Sclerosis

For secondary progressive MS with active disease (ongoing relapses or MRI activity), ocrelizumab is the only FDA-approved disease-modifying therapy and should be initiated immediately, while for primary progressive MS, ocrelizumab remains the sole approved option. 1, 2

Disease-Modifying Therapies by MS Subtype

Secondary Progressive MS (SPMS)

Active SPMS (with relapses or MRI activity):

• Ocrelizumab is FDA-approved for active secondary progressive disease and should be the first-line treatment 1, 2
• Administered as 920 mg subcutaneously every 6 months in the abdomen 1
• Interferon-beta-1b is licensed in Europe and the US specifically for SPMS patients who continue to have relapses 3
• Mitoxantrone is licensed in the US but only for patients with continuing relapses 3

Non-active SPMS (without relapses):

• No FDA-approved disease-modifying therapies currently exist for this population 2, 4
• Siponimod has shown promise in recent trials but approval status should be verified 5

Primary Progressive MS (PPMS)

• Ocrelizumab is the only FDA-approved disease-modifying therapy for primary progressive MS 1, 2
• Same dosing regimen: 920 mg subcutaneously every 6 months 1

Critical Pre-Treatment Requirements

Before initiating ocrelizumab, the following assessments are mandatory 1:

• Hepatitis B screening (HBsAg and anti-HBV tests) - treatment is contraindicated with active HBV
• Quantitative serum immunoglobulins - consult immunology if low
• Vaccination status - administer live vaccines at least 4 weeks prior, non-live vaccines at least 2 weeks prior
• Active infection screening - delay treatment until resolved

Emerging and Investigational Therapies

Several agents have shown promise in clinical trials for progressive MS 5:

• Simvastatin - investigated for neuroprotective effects
• Ibudilast - anti-inflammatory and neuroprotective properties
• Alpha-lipoic acid - antioxidant therapy
• High-dose biotin - metabolic support for demyelinated axons
• Cell-based therapies - under investigation

Autologous Hematopoietic Stem Cell Transplantation (AHSCT)

For active secondary progressive MS, AHSCT shows significant promise based on recent 2025 ECTRIMS/EBMT guidelines 6:

• Registry data demonstrates AHSCT significantly slows disability progression compared to standard immunotherapy in active SPMS 6
• Progression-free survival rates of 87% at 10 years have been reported 6
• Most commonly uses BEAM-ATG (carmustine, etoposide, cytosine arabinoside, melphalan with anti-thymocyte globulin) conditioning regimen 6
• AHSCT reduced brain atrophy rates in SPMS patients and normalized neurofilament light chain levels 6

Important caveat: AHSCT outcomes in progressive MS are highly variable (progression-free survival ranging from 36% at 3 years to 77% at 5 years), likely due to patient selection heterogeneity 6

Symptomatic Management: The Cornerstone of Progressive MS Care

Since disease-modifying therapies have largely failed in progressive MS, symptomatic management remains the primary treatment approach 7, 3:

Priority Symptoms to Address

Patients with progressive MS rate these as most important 7:

• Balance and mobility impairments
• Weakness and reduced cardiovascular fitness
• Ataxia
• Fatigue
• Bladder dysfunction
• Spasticity
• Pain
• Cognitive deficits
• Depression and pseudobulbar affect

Multidisciplinary Approach Required

Effective symptomatic therapy requires a multidisciplinary team approach targeting not just neurological impairments but also disability, handicap, emotional well-being, and quality of life 3

Critical Clinical Pitfalls

Distinguishing Active from Non-Active Disease

• Approximately 80% of new lesions show gadolinium enhancement in SPMS 6, 8
• Clinical assessments alone substantially underestimate disease activity - most inflammatory activity occurs asymptomatically 8
• Serial MRI monitoring with gadolinium is essential to identify patients with active disease who may benefit from disease-modifying therapy 8
• Disease activity varies dramatically between patients (range of 1-207 active lesions over 6 months in untreated patients) 8

Treatment Timing Matters

• Treatment at younger age and after fewer prior DMTs is associated with lower rates of long-term progression 9
• For patients with aggressive markers (frequent relapses, high MRI activity, rapid disability onset, age <45 years with disease duration <10 years), high-efficacy therapy should be considered immediately 9
• Poor recovery from relapses accounts for disability acquisition, so stopping relapses delays disability but does not prevent SPMS development 3

The Evidence Gap

There is a notable paucity of studies devoted to symptomatic management specifically in progressive MS, resulting in few proven therapeutic options despite these symptoms being rated as most important by patients 7. Most treatment decisions are extrapolated from relapsing-remitting MS data rather than progressive MS-specific evidence 7.

Why Treatments Fail in Progressive MS

• Immunosuppressive therapies that reduce relapses and MRI activity generally do not stop disease progression 3
• The pathogenesis of progressive MS is poorly understood, with neurodegenerative processes increasingly predominating over inflammatory processes 5
• Disease progression occurs regardless of superimposed relapses 3
• Of 34 randomized controlled trials involving 21 different molecules since 1988, only 38% reached their primary outcome 4