History of multiple sclerosis treatment: from Charcot to BTK inhibitors and CAR-T therapy
How understanding and treatment of MS has evolved over two centuries — from leeches and strychnine, through ACTH and corticosteroids, interferons and monoclonal antibodies, to BTK inhibitors, remyelination and CAR-T cell therapy.
Introduction: two centuries against an invisible enemy
When I first started looking for MS information, what I needed most was a clear explanation without grand promises. For most of history, multiple sclerosis was a disease without a name. Patients were described as "paralysed by an unknown cause", "hysterical" or "possessed", and physicians offered whatever they had — leeches, arsenic, electricity, hydrotherapy and prayer. It was only in 1868 that the French neurologist Jean-Martin Charcot gave the disease its name, shape and first clinical definition. Since then, MS treatment has travelled from symbolic interventions with no real effect, through the first immunomodulators of the 1990s, to today's high-efficacy monoclonal antibodies, BTK inhibitors and experimental CAR-T cell therapies. This article is a chronological overview of that evolution — who discovered what, when, and how each era reshaped what we now know about MS. For diagnostic milestones see [How to recognise MS and how it is diagnosed](post40); modern therapeutic options are covered in [All MS DMTs in 2026](post42) and [MS medications in Serbia 2026](post56).
Pre-Charcot era (1395–1868): a disease without a name
The earliest probable account of MS is the biography of Saint Lidwina of Schiedam (Netherlands, 1380–1433): from age 16 she had episodes of leg weakness, vision loss and numbness alternating over decades with periods of improvement — a clinical picture that today reads like classic relapsing-remitting MS. In the 19th century the British physician Robert Carswell (1838) and the Frenchman Jean Cruveilhier (1841) independently described and drew the pathological lesions in the spinal cord and brain — yellowish "patches" along the white matter, without realising they were observing demyelination. Sir Augustus d'Esté, grandson of King George III, kept a detailed diary of his symptoms between 1822 and 1846 — today the earliest autobiographical medical account of MS. Treatments of the era included bloodletting with leeches, enemas, cold baths, mercury rubs and horseback riding — none with any proven effect.
Charcot and the birth of neurology (1868–1900)
At the Salpêtrière hospital in Paris, Jean-Martin Charcot in 1868 united the clinical and pathological findings and named the disease "sclérose en plaques disséminées". He defined the famous Charcot triad (nystagmus, intention tremor, scanning speech), described optic neuritis, paresis and sphincter disturbance, and was the first to recognise it as a central nervous system disease with multiple foci. Charcot honestly admitted there was no cure: he tried strychnine, silver nitrate, zinc, arsenic, quinine, ergot, electrotherapy and hydrotherapy — and wrote that "for now, we must be content to relieve, since cure we cannot offer". His student Pierre Marie in 1884 first proposed an infectious hypothesis of MS — an idea that would only return 140 years later with the discovery of the role of Epstein-Barr virus.
The empirical era (1900–1950): from arsenic to malaria
The first half of the 20th century brought countless attempts, almost all without effect. Treatments included: arsenic compounds (Salvarsan), bismuth, antimony, intravenous typhoid vaccine (to deliberately induce fever and "burn out the disease"), malaria therapy (modelled on Wagner-Jauregg's neurosyphilis treatment), pneumothorax, X-ray irradiation of the spine, sheep spinal cord extracts and even ovarian transplants. Late-20th-century reviews of medical archives found no evidence that any of these worked. The most important advance of the era was diagnostic, not therapeutic: in 1916 James Dawson described "Dawson's fingers" — periventricular vein-oriented lesions which we still see on every MS patient's MRI today.
ACTH and corticosteroids (1950–1970): the first real relapse treatment
The breakthrough came in 1950 when the American endocrinologist Philip Hench (later Nobel laureate) showed that adrenocorticotropic hormone (ACTH) shortened acute rheumatic episodes. As early as 1951 Maurice Jolliffe and in 1961 Leo Alexander applied ACTH to acute MS relapses and reported faster symptom resolution. The multicentre ACTH vs placebo trial (Rose et al., Neurology 1970) [2] — the first major randomised study in MS — confirmed the effect. ACTH was soon replaced by synthetic corticosteroids: prednisone, dexamethasone, and from the late 1980s high-dose intravenous methylprednisolone (Solu-Medrol) 1 g/day for 3–5 days. This protocol — still used worldwide and in Serbia through RFZO — was the first MS treatment principle to survive the test of time. More detail in [How to recognise an MS relapse](post57) and [MS relapse — recognition and management](post28).
The immunology era (1960–1980): MS becomes an autoimmune disease
During the 1960s and 1970s, experimental autoimmune encephalomyelitis (EAE) in animals proved that T-lymphocytes can attack myelin in the CNS and cause demyelination. The discovery of oligoclonal bands in cerebrospinal fluid (1959, Lowenthal), the role of B-lymphocytes and complement, and HLA-DR2 genetic predisposition (1972), gradually reframed MS from a "mysterious neurological disease" into an "organ-specific autoimmune disease". This opened the door to the next era — immunomodulatory therapy.
The first DMTs era (1993–2000): interferons and Copaxone
1993 is a historic year — the FDA approves interferon beta-1b (Betaseron) [3] as the first disease-modifying treatment (DMT) for relapsing-remitting MS. The pivotal trial (IFNB Multiple Sclerosis Study Group, Neurology 1993) showed a 30% reduction in annualised relapse rate. Interferon beta-1a soon followed (Avonex 1996, Rebif 1998), as well as a completely different agent — glatiramer acetate (Copaxone, 1996) [4], a synthetic mixture of four amino acids mimicking myelin basic protein. For the first time patients had medications that not only relieved a relapse but actually altered the course of the disease. The roughly 30% relapse reduction with interferons and Copaxone was revolutionary at the time. In Serbia, interferons became available through RFZO in the late 1990s and early 2000s.
Oral DMTs and the first monoclonal antibodies (2004–2014)
The next decade brought an explosion of options. Natalizumab (Tysabri, 2004 [5]; withdrawn in 2005 due to PML risk, returned in 2006 with a controlled programme) — the first MS monoclonal antibody, blocks lymphocyte migration into the CNS, reducing relapses by about 70%. Fingolimod (Gilenya, 2010) [6] — the first oral DMT, a sphingosine-1-phosphate receptor modulator. Teriflunomide (Aubagio, 2012) and dimethyl fumarate (Tecfidera, 2013) — additional oral options with different mechanisms. Alemtuzumab (Lemtrada, 2014) — an anti-CD52 antibody that radically resets the immune system in two annual courses. For the first time neurologists could choose between "mild" and "high-efficacy" drugs — and the lifelong "step-up vs hit-hard early" debate began.
The B-cell therapy era (2017–2023): ocrelizumab changes the game
Ocrelizumab (Ocrevus, 2017) — a humanised anti-CD20 monoclonal antibody — became the first and still only drug approved for both relapsing-remitting and primary progressive MS (PPMS). The OPERA I/II and ORATORIO trials [7][8] (Hauser et al., Montalban et al., NEJM 2017) showed superiority over interferon and the first statistically significant effect in PPMS. This reframed our understanding of MS — B-lymphocytes, not just T-lymphocytes, are key drivers of the disease. A wave of related drugs followed: ofatumumab (Kesimpta, monthly subcutaneous injection, RFZO-covered since 2023) [9], ublituximab (Briumvi, 2022), as well as selective S1P modulators siponimod (Mayzent, for secondary progressive MS) and ozanimod (Zeposia). A detailed overview is in [All MS DMTs in 2026](post42) and [MS medications in Serbia 2026](post56).
The EBV hypothesis confirmed (2022): a return to Marie's idea
In January 2022, the Bjornevik et al. study in Science [10] (analysis of 10 million US military personnel over 20 years) showed that Epstein-Barr virus (EBV) infection increases MS risk 32-fold — and is almost necessary, though not sufficient. The study revived Pierre Marie's 1884 infectious hypothesis and launched a new era of EBV-targeted therapies: vaccines in development (Moderna, Atara), anti-EBV CAR-T cells (ATA188), and preventive strategies for adolescents. More on this in [Epstein-Barr virus and multiple sclerosis](post20) and [EBV vaccine — horizon of MS prevention](post6).
BTK inhibitors and the assault on progressive MS (2024–2026)
The current frontier is the pharmacological assault on the progressive phase of the disease — where B-cell therapies have limited effect. BTK (Bruton's tyrosine kinase) inhibitors are small molecules that cross the blood-brain barrier and act on both B-lymphocytes and microglia inside the CNS. Tolebrutinib (Sanofi, FDA approval 2025) [11] is the first BTK inhibitor approved for non-relapsing secondary progressive MS. Fenebrutinib (Roche), remibrutinib (Novartis) and evobrutinib (Merck) are following. More detail in [Tolebrutinib FDA approved](post2), [Frexalimab phase 3](post1), [Remibrutinib REMASTER Novartis](post4) and [Fenebrutinib BTK relapsing/progressive MS](post21).
CAR-T cell therapy and remyelination (2024–2026)
The newest frontier is personalised cell therapy. CAR-T cells (chimeric antigen receptor T cells) [12] — engineered patient lymphocytes that selectively destroy pathogenic B-cells — showed in early small studies (2024–2025) complete disease activity quiescence in previously refractory patients. Details in [CAR-T cell therapy for MS](post24). In parallel, remyelination drugs (repairing damaged myelin) — clemastine, opicinumab, PIPE-307, K102/K110 — are being tested in clinical trials; see [K102 and K110 — nerve repair in MS](post23). If they succeed, for the first time there will be a therapy that not only halts but reverses damage. An overview of the major 2026 breakthroughs is in [MS breakthroughs 2026 — remyelination, BTK, EBV](post37).
What is coming next: prevention, prediction, personalisation
The next jump is expected in three directions: (1) prevention — an EBV vaccine for adolescents that could reduce MS incidence by 60–80%; (2) predictive biomarkers — serum neurofilament light chain (NfL) and serum GFAP, MRI brain volume loss, AI-driven analysis predicting relapse and progression up to 5 years ahead; (3) personalised treatment selection based on the patient's genetic and immunological profile rather than today's "step-up vs hit-hard" debate. Stem cell therapies are also in parallel development ([Stem cells and MS 2026](post12)) and autologous hematopoietic transplantation ([Stem cell transplantation — guide](post15)).
In the 158 years since Charcot named the disease, MS has travelled from a completely misunderstood condition with symbolic treatment, through the first corticosteroids and interferons, to today's 15+ approved DMTs that biologically alter the course of the disease. A patient diagnosed in 2026 has options [13][14] that did not exist even 30 years ago, and average life expectancy has approached that of the general population. The fight is not over — progressive MS, nerve regeneration and prevention remain great challenges — but the pace of progress over the last 30 years suggests that the coming decade may bring both a treatment that halts progression and prevention before the disease appears. KEY SOURCES: Compston A, McAlpine's Multiple Sclerosis (4th edition, Churchill Livingstone 2005); Murray TJ, Multiple Sclerosis: The History of a Disease (Demos Medical 2005); Charcot JM, Histologie de la sclérose en plaques (Gazette des hôpitaux 1868); IFNB MS Study Group, Neurology 1993 (https://pubmed.ncbi.nlm.nih.gov/8456292/); Hauser SL et al., NEJM 2017 — Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis (https://www.nejm.org/doi/full/10.1056/NEJMoa1601277); Bjornevik K et al., Science 2022 — Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis (https://www.science.org/doi/10.1126/science.abj8222); National MS Society — History of MS (https://www.nationalmssociety.org/What-is-MS/History-of-MS); MS Trust — History of MS (https://mstrust.org.uk/a-z/history-ms). [15][16] This article is informational and does not replace personalised medical advice.