Article Figures & Data
Figures
- Fig 1.
Relapse onset multiple sclerosis leads to the progressive accumulation of disability with neurodegeneration after 10–15 years, with less focal inflammation as highlighted by fewer relapses and MRI T2 lesions or gadolinium-enhancing lesions. MRI = magnetic resonance imaging
- Fig 2.
The number of multiple sclerosis disease-modifying therapies (DMTs) that have European Medicines Agency (EMA) or US Food and Drug Administration (FDA) approval. DMTs approved in 2016: β-interferon-1α (Avonex), β-interferon-1b (betaferon), glatiramer acetate (Copaxone), mitoxantrone (Novantrone)*, β-interferon-1α (Rebif), natalizumab (Tysabri), teriflunomide (Aubagio), alemtuzumab (Lemtrada), fingolimod (Gilenya), dimethyl fumarate (Tecfidera), interferon beta 1b (Extavia), β-interferon-1α (Plegridy). *Mitoxantrone (Novantrone) has FDA approval only.
Tables
- Table 1.
UK-licensed disease-modifying treatments (DMTs) for relapsing remitting MS11,27–30
Treatment Mode and frequency Side effects Indication Notes Interferon beta 1a (Avonex) Intramuscular injection 30 μg once per week >1:100: flu-like, injection site reactions, headache, lymphopaenia, insomnia, diarrhoea, nausea and vomiting, depression, hair loss, liver function derangement, thyroid disease First-line: active RRMS with ≥2 relapses, or 1 relapse and new MRI lesions as per McDonald 2010 criteria in ≤2 years EDSS<6.5 (able to walk 20 m)
CIS and at high risk of developing MS with MRI T2 lesions
SPMS with ≥2 relapses in ≤2 years and EDSS progression ≤2 points over 2 yearsFridge storage
Caution if depression/suicidal ideationPegylated interferon beta 1a (Plegridy) Subcutaneous injection
Start with a dose of 63 μg on day 1, followed by 94 μg on day 15, then 125 μg on day 29 and once every 2 weeks thereafterCaution re: neutralising antibodies with interferon beta 1b in up to 46% of patients. Monitor antibody titres Fridge storage
Keep out of sunlightInterferon beta 1a (Rebif) Subcutaneous injection
Start at 22 μg three times weekly and escalate over 4 weeks to 44 μg three times weekly.Fridge storage Interferon beta 1b (Betaferon) Subcutaneous injection
Alternate days
Escalate to 250 μg over 3-6 weeksInterferon beta 1b (Extavia) Glatiramer acetate (Copaxone) Subcutaneous injection 20 mg once daily or 40 mg three times per week. >1:100: injection site reactions including lipoatrophy, headache, depression, anxiety and nausea. Also IPIR with flushing, palpitations, dyspnoea and chest pain lasting 15–30 minutes First-line: active RRMS with ≥2 relapses, or 1 relapse and new MRI lesions, as per McDonald 2010 criteria, in ≤2 years. Able to walk more than 100 m without aids
CIS and at high risk of developing MS with MRI T2 lesions
SPMS with ≥2 relapses in ≤2 years and EDSS progression ≤2 points over 2 yearsIf IPIR lasts longer than 30 minutes then patients should seek urgent medical attention Teriflunamide (Aubagio) Oral 7 or 14 mg once daily >1:100: liver function derangement, diarrhoea, nausea, hair thinning and loss First-line: active RRMS with ≥2 relapses, or 1 relapse and new MRI lesions in ≤2 years Dimethyl fumarate (Tecfidera) Oral
Initially 120 mg twice daily, then increase after 7 days to 240 mg twice daily>1:100: flushing, gastrointestinal upset, lymphopaenia, rash, ketonuria, proteinuria, liver function derangement
Very rare cases of PML reportedFirst-line: active RRMS with ≥2 relapses, or 1 relapse and new MRI lesions in ≤2 years Taking oral doses with food may reduce the incidence of flushing and gastrointestinal effects Fingolimod (Gilenya) Oral 0.5 mg once daily >1:100: cough, headache, back pain, diarrhoea, infections, liver function derangement, lymphopaenia.
<1:100: macular oedema
Very rare cases of PML reportedSecond-line:
highly active RRMS only with relapses despite treatment with beta interferon for at least 1 year or relapses on glatiramer acetate or tecfidera
RRMS on natalizumab at high risk of PML (2014 post-NICE approval)
First-line: across UK, ABN guidance suggests fingolimod can be used if highly active RRMS with 2 or more disabling relapses in 1 year and new MRI lesionsNote: bradycardia and atrioventricular conduction slowing can occur while taking the first dose of fingolimod, therefore the first dose is taken under medical supervision and cardiac monitoring for 6 hours Natalizumab (Tysabri) Intravenous infusion 300 mg once every 4 weeks >1:100: headache, dizziness, pruritic rash, infections
Clear risk gradient of PML.First-line: RES RRMS with ≥2 relapses ≤1 year and no previous DMT and either ≥1 gadolinium-enhancing MRI lesion(s) or ≥9 T2-hyperintense MRI brain lesions, if MRI available
Second-line: RES RRMS with ≥1 relapses ≤1 year and previous beta interferon not meeting stopping criteria and either ≥1 gadolinium-enhancing MRI lesion or ≥9 T2-hyperintense MRI brain lesions, if MRI availableAlemtuzumab (Lemtrada) Intravenous infusion Initially, 12 mg daily for 5 consecutive days to a total dose of 60 mg
Second course: 12 months post initial dose, 12 mg daily for 3 consecutive days to a total dose of 36 mg>1:100: acute cytokine release syndrome (headaches, rash, fever, nausea, diarrhoea, hypotension), infections including herpes virus, endocrinopathy (especially thryoid) First-line: active RRMS with ≥2 relapses in ≤2 years, or 1 relapse and new MRI lesions
Second-line: highly active RRMS on DMT and relapse within the last year and new MRI lesionsPre-medications: oral or intravenous corticosteroid, oral antihistamine and analgesic to prevent cytokine release syndrome
Oral prophylaxis with aciclovir for herpes infection and continued for 1 monthNHS England has taken on the commissioning of drugs since 2013 and advises that patients must be under the care of a designated MS centre that is registered to take part in the national risk sharing scheme involving the three beta interferon products and glatiramer acetate. The Association of British Neurologists (ABN) advises an annual review while on DMTs that will need to be conducted by the MS specialist neurologist who is also best placed to determine whether MRI scanning is required.
CIS = clinically isolated syndrome; DMT = disease-modifying treatment; EDSS = Expanded Disability Status Scale; IPIR = immediate post-injection reaction; MRI = magnetic resonance imaging; MS = multiple sclerosis; NICE = National Institute for Health and Care Excellence; PML = progressive multifocal leucoencephalopathy; RES = rapidly evolving severe; SPMS = secondary progressive multiple sclerosis; RRMS = relapsing remitting multiple sclerosis.
Drug* Interventional Multi-disciplinary input Fatigue Amantadine Occupational therapy and physiotherapy: fatigue management assessment and exercise programme Cognition/low mood Depression: eg citalopram duloxetine Neuropsychology service, cognitive behavioural therapy, occupational therapy Spasticity Baclofen, gabapentin, tizanidine, clonazepam, dantrolene Intrathecal baclofen, botulinum toxin Physiotherapy Bladder Frequency/urgency: oxybutynin, solifenacin, tolterodine, mirabegron
Nocturia: desmopressin/DDAVP sprayResidual bladder volume >100 ml: intermittent self-catheterisation or permanent catheter; intravesicular botulinum toxin, Uro-neurology Sexual dysfunction Sildenafil, tadalafil, alprostadil, yohimbine Uro-neurology Constipation Fibre/fluid, bulking agents, osmotic stimulant laxatives, suppositories, transanal irrigation Faecal incontinence Codeine, loperamide Biofeedback, neuro-gastroenterology Pain Amitriptyline, pregabalin, gabapentin, lamotrigine Ataxia/tremor Propranolol, clonazepam, levetiracetam, isoniazid (with pyridoxine), carbamazepine, ondansetron Botulinum toxin, thalamotomy Physiotherapy, occupational therapy, audiovestibular therapy Oscillopsia Gabapentin, memantine, levetiracetam, clonazepam, baclofen Neuro-ophthalmology *These may be unlicensed indications
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