Part 1 · The disease
The immune attack
How immune cells switched on in a lymph node leave it, cross the blood-brain barrier and strip myelin, then smoulder behind a closed barrier. Step through the attack, or turn on where each drug class acts.
Teal numbered badges mark the step each drug class targets. Mechanism only; trial results are in How the drugs work.
Schematic, not to scale. Cells are drawn large; the order of events follows the working model of relapsing MS.
Why removing B cells works before antibodies fall
Anti-CD20 antibodies empty the blood of B cells within two weeks, yet antibody levels and the plasma cells that make them barely change. Scrub through the first year after a first infusion to see the order of events.
Schematic curves through the published anchor points (B cells low by day 14; response as early as 8–12 weeks; IgG generally unchanged with initial courses). Heights are not measured values.
Where each drug class acts in this sequence
| Step | Drug class | Published mechanism | |
|---|---|---|---|
| 1 · Activation | Teriflunomide | Reversibly inhibits DHODH, an enzyme of new pyrimidine synthesis that rapidly dividing activated T and B cells depend on; resting cells use a salvage pathway, so proliferation slows without cell death. 22 | 4.1 → |
| 1 · Activation | Glatiramer acetate | Binds MHC molecules and competes with myelin antigens for presentation; induces Th2 suppressor cells that release IL-10, TGF-β and BDNF in the brain ("bystander suppression"). 10 | 4.1 → |
| 1 · Activation | Cladribine | A purine analogue that lymphocytes cannot inactivate; it accumulates in them, breaks DNA and kills them. Counts are lowest 2–3 months after each cycle. 278,302,340 | 4.1 → |
| 1 · Activation | Alemtuzumab | Binds CD52 on T and B cells, NK cells and monocytes and depletes them; B cells usually recover within 6 months, T cells more slowly. 279 | 4.1 → |
| 2 · Exit | S1P receptor modulators | Fingolimod-phosphate first activates S1P1, then causes its down-regulation (functional antagonism), so lymphocytes cannot leave the nodes. Siponimod binds S1P1 and S1P5. 81,304 | 4.1 → |
| 3 · Entry | Natalizumab | Binds the α4 subunit of α4β1 (VLA-4) and α4β7 integrins, blocking adhesion to VCAM-1 on activated endothelium and so blocking entry into inflamed tissue. 473,502 | 4.1 → |
| 3–4 · Entry, attack | Interferon-β | Raises anti-inflammatory and lowers proinflammatory cytokines, may reduce trafficking across the barrier; mechanism "multifactorial and incompletely understood". 243 | 4.1 → |
| 4 · Attack | Fumarates | Dimethyl fumarate and its metabolite monomethyl fumarate stabilise the antioxidant transcription factor Nrf2; monomethyl fumarate also activates the receptor HCAR2 (both shown in mouse EAE). 78,283 | 4.1 → |
| 5 · B cells | Anti-CD20 antibodies | Kill CD20+ pre-B and mature B cells; stem cells, many plasmablasts and long-lived plasma cells lack CD20 and are spared. 175,363 | 4.1 → |
| 6 · Smouldering | BTK inhibitors Mostly in trials | Target B cells and microglia; CNS-penetrant ones could reach both sides of the barrier, which anti-CD20 antibodies penetrate poorly. 257 Tolebrutinib was authorised in the EU in June 2026 for SPMS without relapses in the last 2 years; the FDA issued a complete response letter. 124,419 | 4.4 → |