Decision support only — MS is diagnosed and treated by neurology, and DMT selection, safety screening and monitoring sit with the treating team. Modern care runs on three moves: diagnose early (McDonald 2024 makes this possible), suppress relapse activity hard and early, and remember disability can accrue without relapses. Exclude the mimics first. Australian access is PBS-governed per agent. Verify all doses.
1 Classification & natural history
Disease course
- RRMS~85% at onset — discrete relapses with recovery, MRI activity between.
- SPMSGradual progression after an initial relapsing phase; described as active/non-active.
- PPMSProgression from onset without early relapses (~10–15%).
- CIS / RISFirst clinical episode / incidental MRI lesions — some now meet MS criteria (§2).
The two engines of disability
- RelapseFocal inflammation → relapse-associated worsening; the target of current DMTs.
- PIRAProgression independent of relapse activity — "smouldering" disease from chronic compartmentalised inflammation and neurodegeneration; drives long-term disability and current DMTs address it poorly.
- DescriptorModern framing classifies by activity (relapses/MRI) and progression, not the old rigid phenotypes alone.
2 Diagnosis — McDonald 2024
First major revision since 2017, from the ECTRIMS/NMSS international committee (Lancet Neurology, 2025). It broadens the criteria biologically and enables earlier diagnosis, with a matching overdiagnosis risk if applied without clinical context.
Dissemination in space (DIS)
- ≥2 of 5Characteristic lesions in ≥2 CNS regions: periventricular, cortical/juxtacortical, infratentorial, spinal cord, optic nerve (new 5th region).
- ≥4 of 5Lesions in ≥4 of the 5 regions can support diagnosis without separate DIT.
- ProgressiveIn ≥12 months' progression, ≥2 spinal-cord lesions count as DIS.
Dissemination in time (DIT) & biomarkers
- DITA new lesion on follow-up, simultaneous enhancing + non-enhancing lesions, or CSF positivity. No longer mandatory in some scenarios.
- CSFOligoclonal bands or the kappa free light chain index (new, equivalent) demonstrate DIT.
- SpecificityCentral vein sign and paramagnetic rim lesions (susceptibility MRI) support the diagnosis in ambiguous cases.
- Earlier dxA "biological" diagnosis is now possible before a first attack or progression in selected RIS — apply cautiously.
Exclude the mimics — this changes treatment
- NMOSDTest AQP4-IgG. Longitudinally extensive myelitis, area postrema syndrome, severe optic neuritis. Several MS DMTs (interferon, natalizumab, S1P modulators) worsen NMOSD — treatment diverges entirely.
- MOGADTest MOG-IgG. ADEM-like, bilateral optic neuritis; often monophasic; managed with steroids ± immunotherapy, not MS DMTs.
- OthersSusac, sarcoid/neurosarcoid, B12 deficiency, vasculitis, small-vessel ischaemia, infection (HIV, syphilis) — a T2 white-matter MRI is not, by itself, MS.
3 Disease-modifying therapy — tiers & the detail
DMTs sort into broad efficacy tiers. Anti-CD20 agents have become the pragmatic first-line high-efficacy choice for many neurologists, and in Australia PBS access is permissive enough to start there — you don't have to fail a platform agent first (§10).
Moderate efficacy"platform" agents
Lower disease activity, or patient preference/safety constraints.
Interferon-beta, glatiramer acetate, teriflunomide, dimethyl/diroximel fumarate. Safe, modest relapse reduction.
High efficacy
Active relapsing disease.
S1P modulators (fingolimod, ozanimod, ponesimod), natalizumab, cladribine.
Highest efficacyfirst-line HET of choice for many
Highly active disease, or an early high-efficacy strategy.
Anti-CD20 (ocrelizumab, ofatumumab, ublituximab, rituximab); alemtuzumab. PBS-accessible first-line for relapsing MS in Australia.
Progressive diseasefewer options
PPMS, or active SPMS.
Ocrelizumab for PPMS; siponimod for active SPMS; BTK inhibitors emerging (tolebrutinib in non-relapsing SPMS).
The table below carries the mechanism, route, pivotal trial and monitoring for each agent.
| Agent | Class / mechanism | Route | Tier | Pivotal trial (result) | Key safety / monitoring |
|---|
| Interferon-β |
Immunomodulator |
SC/IM |
MOD |
Historical (relapse ↓ ~30%) |
Flu-like symptoms, LFTs, cytopenias; safe in pregnancy. |
| Glatiramer acetate |
Immunomodulator |
SC |
MOD |
Relapse ↓ ~30% |
Injection reactions; most reassuring pregnancy data. |
| Teriflunomide |
DHODH inhibitor (pyrimidine synthesis) |
Oral |
MOD |
TEMSO |
LFTs, hair thinning; teratogenic — washout needed. |
| Dimethyl / diroximel fumarate |
Nrf2 pathway |
Oral |
MOD |
DEFINE CONFIRM |
Flushing, GI; lymphopenia → FBC; rare PML. |
| Fingolimod / ozanimod / ponesimod |
S1P-receptor modulator |
Oral |
HIGH |
FREEDOMS TRANSFORMS |
First-dose bradycardia (fingolimod), macular oedema, lymphopenia, VZV, ↑BP; rebound on cessation. |
| Siponimod |
S1P modulator (active SPMS) |
Oral |
HIGH |
EXPAND |
As S1P class; CYP2C9 genotyping before dosing. |
| Natalizumab |
Anti-α4-integrin (blocks CNS entry) |
IV/SC 4-weekly |
HIGHEST |
AFFIRM |
PML if JCV-positive — stratify by JCV index, duration, prior immunosuppression; severe rebound on cessation. |
| Cladribine |
Purine analogue (selective lymphocyte depletion) |
Oral, short annual courses |
HIGH |
CLARITY |
Lymphopenia, herpes; contraception (both sexes); durable effect after 2 courses. |
| Ocrelizumab |
Anti-CD20 (B-cell depletion) |
IV 6-monthly |
HIGHEST |
OPERA I/II · ORATORIO (PPMS) |
Infusion reactions, hep B reactivation, hypogammaglobulinaemia/infections; PML rare (mostly carryover); monitor IgG. |
| Ofatumumab |
Anti-CD20 |
SC monthly (self-inject) |
HIGHEST |
ASCLEPIOS I/II |
As anti-CD20; injection reactions; home-administered. |
| Ublituximab |
Anti-CD20 (glycoengineered) |
IV (short infusions) |
HIGHEST |
ULTIMATE I/II |
As anti-CD20; infusion reactions. |
| Rituximab |
Anti-CD20 (off-label) |
IV |
HIGHEST |
RCT/observational support |
As anti-CD20; widely used off-label (cost); access varies. |
| Alemtuzumab |
Anti-CD52 (immune reconstitution) |
IV, 2 annual courses |
HIGHEST |
CARE-MS I/II |
Secondary autoimmunity (thyroid, ITP, anti-GBM), infusion reactions, listeria — 48-month monitoring; now reserved. |
| Tolebrutinib |
BTK inhibitor (CNS-penetrant) |
Oral |
EMERGING |
GEMINI (RMS: not superior to teriflunomide) · HERCULES (nrSPMS: delayed progression) |
Liver enzyme elevations; role likely in progression, not relapse. |
4 Treatment strategy — the real debate
Early high-efficacy vs escalation
- EscalationStart moderate, step up on breakthrough activity — lower up-front risk, but allows early damage to accrue.
- Early HETStart high-efficacy up front — mechanism and observational data favour it; inflammation is most aggressive early. PBS access in Australia makes this practical.
- The RCTsDELIVER-MS and TREAT-MS were built to answer this. Genuine equipoise remains — a risk-stratified, shared decision, not a rule; "anti-CD20 first-line" is a strong trend, not a proven long-term disability win.
- SafetyHead-to-head, HET safety looked broadly comparable to platform agents in trials (bar infusion/injection reactions) — the trade-off is real but smaller than once assumed.
Targets, switching, de-escalation
- NEDATreat-to-target: no relapses, no new/enhancing MRI lesions, no confirmed progression. Useful, but blind to smouldering disease.
- SwitchBreakthrough activity → escalate efficacy tier (not a lateral swap); MRI is the main activity monitor. PBS permits switching for efficacy or tolerability.
- De-escalateIncreasingly considered in older patients with long-stable disease (immunosenescence lowers relapse risk, raises infection risk) — trials ongoing.
5 Progressive MS & emerging therapy
What's approved
- PPMSOcrelizumab — the only clearly effective agent ORATORIO; benefit greatest with active inflammation / younger age.
- Active SPMSSiponimod EXPAND; benefit concentrated in those with ongoing relapse activity.
- RealityOnce progression is established and inflammation quiet, current DMTs do little — the central unmet need.
The frontier
- BTK inhibitorsEvobrutinib and tolebrutinib failed to beat teriflunomide on relapse; tolebrutinib delayed progression in non-relapsing SPMS HERCULES — a possible first crack at smouldering disease. Fenebrutinib/remibrutinib ongoing.
- AHSCTAutologous haematopoietic stem-cell transplant — highly effective in aggressive, refractory relapsing MS at specialist centres; morbidity limits use.
- RemyelinationRepair-focused agents remain investigational.
6 Relapse management
Acute treatment
- SteroidsMethylprednisolone 1 g IV or PO daily × 3–5 days — hastens recovery, no effect on long-term disability; oral and IV are equivalent.
- RefractoryPlasma exchange for severe, steroid-unresponsive relapse (esp. with disabling deficits).
- Not every changeTreat disabling relapses; mild sensory relapses often need no steroids.
Pseudo-relapse — check first
- UhthoffHeat (fever, exercise, weather) transiently worsens old deficits — not a relapse, no steroids.
- InfectionScreen for UTI/other infection before calling a relapse; treating the infection resolves it.
- DefinitionA true relapse: new/worsening neuro symptoms >24 h, >30 days from the last, without fever/infection.
7 Symptomatic & modifiable-risk management
Neuro symptoms
- SpasticityBaclofen, gabapentinoids; botulinum toxin; physio.
- WalkingFampridine (dalfampridine) improves walking speed in responders.
- PainNeuropathic pain, trigeminal neuralgia (carbamazepine).
Hidden burden
- FatigueVery common, under-treated; exercise, sleep, screen for depression/OSA.
- Bladder/bowelUrgency, retention — continence assessment.
- Mood/cognitionDepression and cognitive change are common; screen actively.
Modifiable risk
- SmokingCessation — smoking accelerates progression.
- Vitamin DCorrect deficiency; low levels associate with activity.
- ExerciseImproves fatigue, mood, function; obesity & comorbidity worsen outcomes.
8 Safety & monitoring in depth
Before starting any DMT
- ScreenJCV antibody, hepatitis B/C, TB (IGRA), VZV serology, FBC, LFT, renal, immunoglobulins.
- VaccinateGive vaccines — especially live vaccines — before immunosuppression; live vaccines are contraindicated once immunosuppressed.
- Hep BReactivation risk with anti-CD20 — check surface antigen/core antibody; prophylaxis if needed.
On treatment
- PMLHighest with natalizumab in JCV-positive patients (rising with index, >2 years, prior immunosuppression); rare with fumarates, fingolimod, anti-CD20. New/subacute deficits → MRI + CSF JCV PCR.
- ReboundStopping natalizumab or an S1P modulator can trigger severe rebound — plan the bridge before stopping.
- Infection/IgAnti-CD20: monitor immunoglobulins and infections with repeated dosing; alemtuzumab needs 48 months of monthly monitoring for secondary autoimmunity.
9 Special situations
Pregnancy & postpartum
- CourseRelapse rate falls through pregnancy, rebounds post-partum.
- DMTsGlatiramer has the most reassuring data; interferon acceptable; time anti-CD20 before conception (long B-cell effect); avoid teriflunomide/S1P/fumarate/cladribine around conception.
- PlanPre-conception counselling is standard given the relapse timing.
Cause & prevention
- EBVEpstein–Barr virus is now regarded as a necessary cause (Bjornevik, Science 2022) — near-universal prior infection; vaccine/antiviral approaches are in research.
- Risk factorsLow vitamin D, smoking, adolescent obesity, latitude, genetics (HLA-DRB1*15:01).
Age extremes
- PaediatricHigher relapse frequency; the 2024 criteria explicitly extend to children with caveats.
- OlderRelapse risk falls, infection/malignancy risk rises — the setting for de-escalation discussions.
10 Australian access — aligning treatment to the PBS
What PBS access actually allows
- First-line HETDMTs are PBS-subsidised for relapsing MS diagnosed by a neurologist. Access is relatively permissive — high-efficacy agents (anti-CD20, natalizumab) can generally be started first-line without failing a platform agent first, which is what makes the early-HET principle deliverable here.
- PPMSOcrelizumab is PBS-listed for primary progressive MS; siponimod for active SPMS.
- SwitchingPBS permits switching between listed DMTs for efficacy or tolerability, documented against the criteria.
- CaveatAuthority criteria are agent-specific and change — confirm the current PBS listing per drug. Rituximab is used off-label (cost), outside PBS MS listings.
- ModelNeurologist-led with MS-nurse support; MS Australia is the peak body.
Guidelines. Montalban et al, "Diagnosis of multiple sclerosis: 2024 revisions of the McDonald criteria," Lancet Neurology 2025 (ECTRIMS/NMSS committee). ECTRIMS/EAN treatment guideline; ABN DMT prescribing guidance; MS Australia; eTG; PBS.
Pivotal trials. Relapsing: OPERA I/II, ASCLEPIOS I/II, ULTIMATE I/II (anti-CD20 vs interferon/teriflunomide); AFFIRM (natalizumab); CLARITY (cladribine); CARE-MS I/II (alemtuzumab); FREEDOMS/TRANSFORMS (fingolimod); DEFINE/CONFIRM (fumarate); TEMSO (teriflunomide). Progressive: ORATORIO (ocrelizumab, PPMS); EXPAND (siponimod, SPMS); HERCULES (tolebrutinib, non-relapsing SPMS); GEMINI (tolebrutinib, RMS — negative vs teriflunomide). Strategy: DELIVER-MS, TREAT-MS. Cause: Bjornevik, Science 2022 (EBV).
Caveats. Efficacy tiers are trial-derived, not head-to-head for disability. Early-vs-escalation is unsettled — treat it as a risk-stratified, shared decision. NMOSD/MOGAD must be excluded before MS DMTs (some worsen NMOSD). Screening, monitoring and prescribing are neurologist-led and PBS-governed; confirm current PBS criteria per agent. Verify all doses. Supersedes the separate MS overview and detailed pages.