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Secondary progressive multiple sclerosis (SPMS) is a stage of multiple sclerosis that develops in some patients after an initial relapsing-remitting course and is characterized by a gradual, sustained worsening of neurological function that continues independently of relapses. In everyday life, this often feels like slowly increasing difficulty with walking, reduced endurance, increasing stiffness, worsening balance and coordination, weakness in the limbs, and sometimes cognitive or bladder symptoms.
It is important to understand that SPMS does not mean “treatment failure” or that a patient “did something wrong.” Rather, it reflects a shift in the underlying biology of the disease. Over time, neurodegeneration (loss of nerve fibers and reduced repair capacity) becomes more prominent, while inflammatory activity may become less “dramatic” clinically, but more chronic and compartmentalized within the central nervous system (CNS).
During the relapsing-remitting phase of multiple sclerosis (RRMS), clinical worsening is typically linked to relapses: new symptoms appear or existing symptoms worsen, followed by partial or complete recovery. Over time, in some patients, processes that are less reversible begin to dominate. In SPMS, progression is increasingly driven by a combination of chronic inflammatory activity within the CNS and neurodegenerative damage. Key contributors include:
This shift helps explain an important clinical reality: in SPMS, disability may continue to accumulate even if overt inflammatory activity seems quieter than before. Many standard disease-modifying therapies (DMTs) primarily target peripheral immune activation, while in SPMS a portion of the inflammatory drive can become “internal,” sustained within the CNS itself.
A major modern concept in progressive MS is the formation of tertiary lymphoid (follicle-like) structures, most commonly described in the meninges. These are localized immune aggregates that include B cells, T cells, and supporting stromal elements that can maintain immune activity within the CNS. Their presence is associated with:
For patients, this provides a biological explanation for why progression in SPMS may be sustained by “internal” inflammatory mechanisms even in the absence of frequent relapses.
SPMS is closely linked to the phenomenon of silent progression, often described as PIRA (Progression Independent of Relapse Activity). This means that neurological function worsens gradually without clinical relapses. Many patients describe this as: “I haven’t had relapses for a long time, but walking is slowly getting harder.”
This can occur even when MRI does not show new enhancing lesions. MRI lesions reflect focal inflammatory activity, but SPMS is often driven by additional mechanisms—diffuse neurodegeneration, axonal loss, microglial activation, and brain/spinal cord atrophy—features that may not appear as “new lesions.” Therefore, in progressive MS, clinical follow-up and functional assessment (walking, balance, endurance, daily activity) are especially important.
SPMS is typically diagnosed retrospectively, based on sustained progression of disability over time. In practice, clinicians look for a stable pattern of worsening lasting at least 6–12 months that cannot be explained solely by relapses.
Assessment commonly includes:
There are no universally accepted diagnostic criteria for SPMS. Diagnosis remains clinical and depends on longitudinal observation and careful interpretation of symptoms, function, and imaging.
From a practical standpoint, SPMS is classified as:
This distinction matters because anti-inflammatory DMTs tend to have greater impact when inflammatory activity is present. When SPMS is non-active, clinical strategy relies more heavily on rehabilitation, symptom control, and prevention of complications—while still reassessing the overall treatment plan individually.
Treatment goals in SPMS typically include: (1) controlling inflammatory activity when present; (2) slowing progression where possible; and (3) proactive symptom management to preserve independence and quality of life. Therapy selection depends on activity status, disability level, comorbidities, prior treatments, tolerability, and individual risk profile.
Siponimod is the most “SPMS-specific” therapy in terms of evidence base: it was studied in a large randomized trial (EXPAND) and demonstrated a reduction in confirmed disability progression compared with placebo. In many healthcare systems, siponimod is positioned primarily for active SPMS. However, labeling and practical eligibility differ by country.
In some countries, including Russia, regulatory wording permits siponimod use in SPMS without mandatory documentation of relapses. In practice, this can allow consideration of therapy even when progression is occurring without overt relapses, provided the clinician weighs potential benefit, safety, monitoring requirements, and overall clinical context. Real-world Russian clinical experience has been described by Ilves and Prakhova (see References).
Interferon beta-1b has historically been used in subsets of SPMS patients, particularly when inflammatory activity persists (such as relapses). In modern practice, its role is individualized and depends on disease activity, treatment history, and availability of higher-efficacy options.
Mitoxantrone has regulatory indications for aggressive MS courses, including SPMS, and may reduce disease activity and disability progression in selected patients. However, it is used sparingly due to potentially serious toxicity (including cardiotoxicity and long-term risks). It is considered only in specific clinical scenarios with strict selection and monitoring.
Cladribine is approved for relapsing forms of MS; in some regulatory frameworks, this includes active SPMS. Practically, this means that in SPMS with relapses and/or MRI activity, cladribine may be considered depending on clinical goals, prior therapies, safety profile, and infection/vaccination planning.
In progressive MS, treatment discussions should not focus only on relapse count. Equally important is functional trajectory: walking ability, fatigue, spasticity, tremor, fall risk, hand function, daily independence, and work capacity.
Relapses can occur in SPMS, especially in active disease. Standard relapse treatment usually involves high-dose corticosteroids; in refractory cases, therapeutic plasma exchange may be considered. It is also essential to recognize pseudo-relapse triggers—particularly infection, overheating, and sleep disruption—which can temporarily worsen symptoms and require targeted management.
In SPMS, quality of life is often determined by how effectively symptoms are managed and how well function is maintained. Rehabilitation is therefore not “optional”—it is central to comprehensive care.
Rehabilitation strategies in SPMS may include gait training and balance work, fall prevention, strength and endurance programs adapted to fatigue, and individualized energy management strategies. The goals differ between patients: for some, safety and stability of walking are the priority; for others, controlling fatigue and maintaining daily activity without overexertion is more important.
Detailed materials on key symptoms that commonly shape quality of life in SPMS:
Spasticity deserves special attention, as it can significantly impair walking, sleep, self-care, and cause pain. In addition to medication and rehabilitation strategies, botulinum toxin therapy for spasticity may be used as part of a comprehensive plan in selected patients.
Because SPMS is driven not only by relapses but also by chronic intrathecal inflammation, microglial activation, and neurodegeneration, research is increasingly focused on approaches that target these mechanisms. The therapies below remain investigational or highly specialized; they do not replace standard care and are not suitable for every patient. However, they reflect the direction of modern MS research.
Bruton’s tyrosine kinase (BTK) inhibitors are widely considered one of the most promising emerging therapy classes for progressive MS. Conceptually, they act on B-cell signaling and also modulate innate immune pathways, including microglia—key players in chronic neuroinflammation. This matters in SPMS because inflammation often becomes compartmentalized inside the CNS and can be less responsive to therapies that mainly suppress peripheral immune activation.
BTK inhibitors can cross the blood-brain barrier, which may increase their potential relevance for progressive MS. Several BTK inhibitor molecules have been studied in clinical trials across relapsing and progressive MS populations. Outcomes are evaluated not only by relapse control but also by disability progression and functional decline. A dedicated review (Russian language): BTK inhibitors in multiple sclerosis.
Masitinib is a tyrosine kinase inhibitor studied in progressive forms of MS. Interest in masitinib arises from its influence on innate immune mechanisms and neuroinflammatory pathways that may contribute to progression even without relapses. In clinical trials, signals of disability slowing have been reported in certain patient groups, but the approach remains investigational and is not standard therapy.
Statins are best known for cardiovascular prevention, but they have been explored in SPMS as potential neuroprotective agents. The MS-STAT trial (high-dose simvastatin) demonstrated a reduction in brain atrophy rate and suggested potential clinical benefit without a strong effect on relapses. This has been important conceptually, supporting the idea that progression may be influenced through mechanisms beyond classical relapse suppression. At present, statins are not a standard SPMS therapy and remain an area of research interest.
Alpha-lipoic acid has been evaluated as an antioxidant and metabolic approach. In a randomized trial in SPMS, alpha-lipoic acid was associated with a reduction in brain atrophy rate and showed good overall tolerability during follow-up. As with many neuroprotective candidates, larger confirmation studies and clinically meaningful endpoints are needed before broad recommendations are possible.
Autologous hematopoietic stem cell transplantation (AHSCT) is an intensive immune “reset” strategy. Its strongest evidence is in highly active inflammatory MS, where it can dramatically suppress disease activity. In SPMS, its role is much more limited: when progression is predominantly neurodegenerative and non-active, the expected benefit is lower. However, in carefully selected cases—particularly when inflammatory activity persists—AHSCT may be discussed in specialized centers. Detailed review (Russian language): AHSCT in multiple sclerosis.
CAR-T therapy is a developing form of cellular therapy in which immune cells are engineered to target specific pathological immune mechanisms. In neurology and autoimmunity, CAR-T remains at an early stage, but interest is growing because of the possibility of more precise immune correction where conventional therapies are insufficient. In MS, CAR-T is currently best viewed as a future-oriented experimental direction rather than a routine treatment. Overview: CAR-T therapy in neurology.
One of the most important practical insights of recent years is that treatment strategy early in MS can influence long-term outcomes. Modern understanding suggests that a meaningful portion of irreversible CNS injury accumulates early—sometimes before major disability is obvious. If inflammatory activity is not adequately controlled in the first years of disease, the risk of long-term disability accumulation and transition into a progressive phase may be higher.
Large observational real-world studies have reported that patients who start with higher-efficacy disease-modifying therapies tend to have a lower risk of later conversion to SPMS compared with those who begin with lower-efficacy options. These results require careful interpretation because observational studies cannot fully eliminate selection bias, but findings have been reproduced across cohorts and align with the biological logic of MS: sustained inflammatory activity accelerates neuroaxonal loss, and earlier disease control may preserve “neurological reserve” over time.
This does not mean that every patient should begin with the most intensive therapy. Treatment decisions must consider prognosis, age, comorbidities, safety profile, and personal priorities. However, the overarching principle is important for patients: MS treatment aims not only to prevent near-term relapses, but also to reduce the risk of long-term progression and preserve function years into the future.
In clinical practice, disease activity is assessed through symptoms, neurological examination, and MRI. In some situations, additional biomarkers may be used as supportive tools. A separate explanation is available here: MSDA test in multiple sclerosis.
This page is for educational purposes and does not replace an in-person consultation and individualized treatment planning.