How multiple sclerosis treatments evolved: from interferons to BTK inhibitors

What treatment means here

Multiple sclerosis (MS) is not one uniform course. Relapses, inflammatory lesions and gradual disability progression can differ between people and over time. Disease-modifying therapies (DMTs) aim to reduce future disease activity or slow worsening; they do not reverse all established damage. A steroid course for a disabling relapse is a different intervention: it can shorten that episode but does not replace long-term disease modification. Rehabilitation, symptom management, mental-health support and practical adaptations also matter, even when a DMT is working. [18]

This guide follows the major treatment families and regulatory milestones, not every brand or national prescribing rule. Labels differ by jurisdiction, disease form, age and current product information. An EU authorisation does not establish availability or reimbursement in Greece. The treatment choice depends on activity, prior history, risks, pregnancy plans, monitoring capacity and a conversation with the treating MS team.

The main courses of MS

Relapsing-remitting MS (RRMS): distinct attacks of new or worsening symptoms are followed by periods of partial or full recovery. Between attacks, the course is described as remitting, although an attack can leave lasting symptoms and disability can accumulate. The word “remitting” does not promise complete recovery. [23]

Secondary progressive MS (SPMS): after an earlier relapsing-remitting course, disability gradually worsens over time. Relapses may still occur, or progression may continue without obvious attacks. There can also be periods of relative stability; the change in course is assessed from a pattern over time, not one difficult day. [23]

Primary progressive MS (PPMS): gradual worsening begins from the onset, rather than following years of relapses. The pace can vary and include plateaus or small temporary improvements. Some people with PPMS also have relapses or new inflammatory MRI lesions, so “progressive” does not automatically mean “never active.” [23]

Activity is a separate description: over a stated assessment period, a course is called active when there are clinical relapses and/or new inflammatory MRI findings. Worsening disability over time is assessed separately as progression. A person may therefore have progressive MS with activity, or progression without detected activity. If the necessary clinical or MRI assessments are missing, activity is unknown rather than established as absent. [23]

These terms describe observed patterns; they are not three inevitable stages through which everyone passes. They help frame evidence and licensed indications in the sections below, but a label alone cannot predict one person's future. [23]

The turning points

1. 1993, United States: the FDA approved interferon beta-1b (Betaseron) for ambulatory people with relapsing-remitting MS to reduce clinical exacerbations. Betaferon later received EU authorisation in 1995. This was a decisive shift from treating attacks alone toward trying to prevent them. [1] [2]
2. Late 1990s–2000s: glatiramer acetate expanded injectable options; natalizumab brought a targeted infusion approach, alongside a serious infection-monitoring problem. These treatments did not make relapsing MS curable. [6] [16]
3. 2010s–2020: tablets such as fingolimod, teriflunomide and dimethyl fumarate widened routes and mechanisms. Alemtuzumab, cladribine and then anti-CD20 treatment added different ways to suppress or reconstitute immune activity. In 2018, ocrelizumab gained EU authorisation including a defined early primary progressive MS population; in 2020, siponimod gained an EU indication for active secondary progressive MS. [3] [4] [5] [7] [9] [10] [21]
4. 2026, European Union: tolebrutinib (Cenrifki) became the first EU-authorised BTK inhibitor for adults with secondary progressive MS who had no relapses in the previous two years. Other BTK molecules still have distinct evidence and regulatory positions. [11] [12]

The first long-term options: interferons and glatiramer

Interferon beta changes messages between immune cells; glatiramer acetate is a mixture of synthetic peptides that alters immune responses. Their clinical place began in relapsing disease: trials showed fewer relapses, and interferon approval established that future attacks could be reduced. Both are injections, sometimes frequent, and require persistence over years. Interferons can cause flu-like effects and require liver and blood-count checks; injection reactions and mood concerns may also matter. Glatiramer commonly causes injection-site reactions and can rarely cause serious anaphylaxis, now highlighted in a US boxed warning. Neither reliably repairs lost myelin or solves non-active progression. [1] [2] [16] [22]

Oral medicines broadened choice, but do not share one mechanism

S1P receptor modulators such as fingolimod retain many lymphocytes in lymph nodes, reducing their passage into the central nervous system. They are used in specified relapsing forms. Starting or stopping treatment needs planning: heart-rate effects at initiation, infections, eye and liver monitoring, pregnancy restrictions and possible rebound activity after discontinuation are relevant to the product and person. [3]

Teriflunomide inhibits an enzyme needed by proliferating immune cells; dimethyl fumarate acts through different immune and cellular stress pathways. Both are oral options for relapsing disease, but their safety checks are different. Teriflunomide has major pregnancy restrictions, liver monitoring and a long elimination time unless an accelerated removal procedure is used. Dimethyl fumarate commonly causes flushing or gastrointestinal effects and can lower lymphocyte counts; prolonged severe lymphopenia raises concern about rare serious infection. Convenient dosing does not mean freedom from monitoring. [4] [5]

Targeted antibodies and the balance of stronger control

Natalizumab limits immune-cell entry across the blood–brain barrier and can strongly suppress inflammatory activity in relapsing MS. Its central limitation is progressive multifocal leukoencephalopathy (PML), a rare but potentially devastating brain infection. Prior JC-virus exposure, treatment duration and previous immunosuppression inform risk assessment; surveillance and switching plans matter. [6]

Anti-CD20 antibodies remove many B lymphocytes, immune cells involved in MS inflammation. Ocrelizumab is authorised in the EU for active relapsing MS and for early primary progressive MS with specified inflammatory imaging features; ofatumumab is another EU-authorised relapsing-MS option. These are different products with different schedules. Infusion or injection reactions, infections, hepatitis-B screening, immunoglobulin levels and vaccine timing shape monitoring. A strong reduction in inflammatory activity does not guarantee that gradual progression stops. [7] [8]

Immune reconstitution: courses with long consequences

Cladribine tablets and alemtuzumab are given in defined treatment courses rather than indefinitely every day. They aim to reset parts of the immune-cell population and are reserved under their EU labels for forms of highly active relapsing MS. The appeal of fewer dosing days comes with screening, contraception rules and prolonged observation. Cladribine can cause lymphopenia and infections; alemtuzumab can trigger serious autoimmune disease, infections and cardiovascular reactions, with long-term laboratory follow-up. Neither approach is a simple one-time cure. [9] [10]

Autologous haematopoietic stem-cell transplantation is considered in some centres for carefully selected people with very active relapsing disease despite treatment. It uses intensive immune suppression and has substantial short- and long-term risks; it is not a routine answer for all MS or established non-inflammatory disability. [17]

Paid “stem-cell” clinics: how to tell them apart

The autologous haematopoietic stem-cell transplantation (aHSCT) described above is a specific procedure, not a general “stem-cell therapy”. The 2025 ECTRIMS and EBMT recommendations place it mainly as an escalation option for highly active relapsing MS after a high-efficacy treatment has failed. The profile they describe is indicative, not a strict cut-off: roughly under 45 years of age, MS for under about 10 years and an EDSS disability score below 6. They recommend accredited transplant units (FACT–JACIE or equivalent), a joint neurology and haematology team, long follow-up, reporting to a registry and offering clinical trials to eligible people. In the analyses they cite, deaths within the first 100 days ranged from 0.3% in people treated after 2005 to 2.8–4.0% in older or mainly progressive-MS analyses. The aim is to stop inflammatory activity; these cells do not regenerate damaged nerves. [17] [32]

Some private clinics advertise “stem-cell therapy” for MS online and on social media, sometimes abroad and for a high fee paid by the patient. Such offers are not approved MS treatments. The US FDA states that no stem-cell product has been approved to treat any neurological disorder, including MS. The largest randomised trial of bone-marrow mesenchymal cells in active MS, MESEMS with 144 participants, did not meet its main goal, and its authors concluded that it does not support this use. In the EU, cell-based advanced therapy medicinal products may be given only with an EU authorisation, within an authorised clinical trial or, under strict conditions, through a national exemption for use in a specific hospital. The EOF stresses for Greece that this also covers products made from the patient's own cells. [25] [28] [30] [26] [27]

Warning signs named by the International Society for Stem Cell Research (ISSCR), the European medicines regulators and the MS Society UK include: patient testimonials instead of published trial results; the same cells offered for many unrelated diseases; claims that there is no risk; high or hidden costs; claims that regulatory approval is not needed; an “experimental” treatment you pay for outside an authorised trial; promised benefits greater than those of approved treatments without support in the scientific literature; and advertising online and on social media. [24] [25] [26] [31] Promises that lesions will disappear or symptoms will reverse, and pressure to decide quickly because places are “limited”, are not evidence; they are reasons to pause and check.

A listing in a trial registry is not an approval. The FDA notes that a registry entry does not mean a product is legally marketed, and that being charged for an experimental treatment outside a trial is a sign that the product is likely being offered illegally. Before travelling or paying, ask which authority approved the treatment or the trial, discuss it with your treating MS team and ask what aftercare you would have at home; the MS Society UK warns that follow-up after treatment abroad may be missing. In Greece, the EOF asks people to report suspected unauthorised cell therapies to [email protected]. [29] [31] [27]

Why treatment strategy changed

One historical approach began with a lower-risk drug and escalated after relapses or new MRI lesions. Another starts with a higher-efficacy option when evidence suggests a high risk of early damage. Earlier inflammatory control may avoid injury that cannot later be undone, but a more intensive treatment can bring greater infection, immune or reproductive risks and more complex monitoring. Trials of individual drugs and observational comparisons inform this discussion; percentages from separate trials cannot fairly rank the whole catalogue because populations, comparators and endpoints differ. [19]

The useful questions are concrete: Is the current course relapsing or progressive? Is there recent inflammatory activity? What is the treatment's exact licensed indication here? What benefit was demonstrated in the relevant population, and what uncertainty remains? Which monitoring and switching plan is feasible? No chronology implies that every newer medicine is better for every person.

Progressive MS: an important but narrower gain

Progression can occur with or without overt relapses. Evidence for reducing relapses in relapsing MS must not be transferred automatically to progressive disease. EU-authorised ocrelizumab addresses a defined early primary progressive group with inflammatory imaging features; it does not establish benefit for every stage of PPMS. Siponimod has an EU indication for secondary progressive MS with active disease shown by relapses or imaging; the EMA notes that benefit was not demonstrated in patients without active disease. Tolebrutinib's 2026 EU indication is specifically adults with secondary progressive MS without relapses during the preceding two years. The EMA reports a delay in confirmed disability progression in the studied population, while liver injury and other safety concerns require structured monitoring. These labels do not amount to a cure or a claim of restored function. [7] [11] [12] [21]

BTK inhibitors: one target, different answers

Why do they matter? BTK helps B cells receive activation signals and also acts in microglia, immune cells in the brain and spinal cord. Persistent inflammation there may contribute to disability worsening even without apparent relapses. Some BTK inhibitors are designed to enter the central nervous system, so researchers are testing whether they can affect this inflammation as well as immune activity elsewhere in the body. This is a treatment rationale, not proof that every BTK inhibitor slows progression. None is an established way to restore lost myelin or cure MS. Brain exposure, studied populations, results and safety differ by molecule. [11] [15]

Tolebrutinib: Cenrifki received EU marketing authorisation on 19 June 2026 for adults with secondary progressive MS who had no relapses in the past two years. The HERCULES study is the key clinical record. The EMA requires liver monitoring and patient warnings about liver injury. EU authorisation alone says nothing about Greek supply or reimbursement, and this indication must not be stretched to all MS forms. [11] [12]

Evobrutinib: the sponsor reported in December 2023 that both Phase III EVOLUTION trials in relapsing MS missed their primary annualised-relapse-rate endpoints against teriflunomide. A plausible mechanism did not translate into the hoped-for comparative result in those trials. [13]

Fenebrutinib: Roche reported that FENtrepid met non-inferiority against ocrelizumab for a composite disability endpoint in primary progressive MS; that is not proof of superiority. It also reported positive relapse endpoints versus teriflunomide in two relapsing-MS trials, while safety, including liver-enzyme changes and reported death imbalances, warrants full regulatory assessment. On 30 September 2026 Roche announced that the US FDA accepted its application for priority review for relapsing and primary progressive MS. Filing acceptance and priority review are not approval; fenebrutinib remains investigational as of this review. [14] [15]

The next frontier: protection and repair

Controlling immune inflammation does not automatically rebuild myelin or neurons already lost. Trials are exploring remyelination, neuroprotection and combinations with disease control. A laboratory effect, an MRI signal or a physiological measure can justify more research without demonstrating improved walking, vision or daily function. There is currently no established approved treatment in clinical practice proven to reliably restore myelin in MS. The research catalogue tracks these programmes alongside their evidence stage and limits; this guide describes the established treatment history rather than treating a candidate as available care. [20]