Multiple SclerosisGP update

Martin Duddy

Consultant Neurologist

Royal Victoria Infirmary

Newcastle upon Tyne

epidemiology and nomenclature

risk factors for MS

• smoking (HR 1.48)– duration and intensity– also risk factor for progression

• vitamin D status– >100nmol/L HR 0.5 vs <75nmol/L

• EBV– 100% MS seropositivity vs 95% controls– IM HR 2.17

normal

clinically isolated syndrome

radiologically isolated syndrome

McDonald criteria 2005

McDonald criteria2010

secondary progressiveMS

clinically definite MS

active RRMS

shifting the definition

diagnostic criteria (McDonald 2010)

Polman et al. Ann Neurol 2011;69:292–302

PPMS

relapsing/ remitting

patterns of MS (1996)

primary progressive

(benign)

secondary progressive

85% 13%

5%

2%PRMS

Lublin et al. Neurology 2014;83:278

defining phenotypes

“The Group recommended at least annual assessment of disease activity by clinical and brain imaging criteria for relapsing MS”

referral for diagnosis

progression of MS

treating MS

• treatment of acute relapse

• disease modification– disease modifying treatments (DMTs)

• management of symptoms and disability

• treatment of acute relapse

• disease modification– disease modifying treatments (DMTs)

• management of symptoms and disability

case

• a 34-year-old woman with MS• 2d history of worsening intense pain in a band, right side,

roughly T7 distribution. • generally fatigued and her right leg feels heavier • worsening hesitancy• feels similar to a previous relapse successfully treated

with oral steroids in primary care• on oral fingolimod for 6 months• fully ambulant with no new signs on examination

would you?

1. prescribe oral steroids

2. prescribe oral steroids only after checking for a UTI

3. acknowledge episode as relapse but withhold treatment awaiting natural history

4. ask her to contact her MS team if symptoms don’t settle

5. refer as emergency to MS team

management of acute relapse

• increasingly rare: usually in consultation with local MS team

• methylprednisolone– oral 500mg x 5d (PPI cover if symptomatic)– IV 1000mg x 3d

• always specialist centre if on natalizumab, fingolimod or alemtuzumab

• treatment of acute relapse

• disease modification– disease modifying treatments (DMTs)

• management of symptoms and disability

where are we leaving?

• NI population study 19961, n=281

– fully independent for all ADLs

29%– unable to manage flight of stairs

23% – in full time employment

25%– institutionalised

5%– unable to use public transport or drive

a car 33%• half leave work force within 3 years of

diagnosis2

• employment at 10yr 25%

1.McDonnell & Hawkins Mult Scler 2001;7:111 2. Doogan & Playford. Mult Scler 2014;14:646

RRMS

interferon-b(Betaferon/Extavia

Avonex

Rebif)

glatiramer acetate(Copaxone)

natalizumab(Tysabri)

fingolimod(Gilenya)

teriflunomide(Aubagio)

dimethyl fumarate(BG12, Tecfidera)

alemtuzumab(Campath, Lemtrada)

pegylated interferon(Plegridy)

how good are current treatments?

reducing relapses

• transient disability• can leave persistent disability

– (> 1point EDSS in >15%)• impact on patients

– work– finances

• marker of disease activity• predictor of later disability

drug reduction in annualised relapse rate against placebo

ARR on drug in RCT

interferon-b/ glatiramer acetate1

scim

30-35% 0.3-0.7

pegylated IFN9 sc Q2W

36% 0.29

teriflunomide2 po 33.7% 0.35

dimethyl fumarate3

po 49% 0.19

fingolimod4,5 po 48-54% 0.18-0.21

natalizumab6 iv 68% (81% active disease) 0.26

alemtuzumab7,8 iv 49% (vs interferon-b) 0.26

reducing relapse rates

1. Galetta et al. Arch Intern Med 2002;19:21612. Kappos et al. P618 ECTRIMS 2013 3. Fox et al. P07.097 AAN 2013 4. Kappos et al. N Engl J Med 2010;362:387

5. Calabresi et al. Lancet Neurol 2014;13:5456. Polman et al. N Engl J Med 2006;354: 8997. Coles et al. Lancet 2012;380:18298. Cohen et al. Lancet 2012;380:18199. Kieseier et al. Mult Scler 2014 Nov 28. pii:

1352458514557986

drug reduction in sustained progression in disability

rate of progression in placebo

interferon-b/ glatiramer acetate

scim

12-37% c.30%

pegylated interferon

scQ2W

38% (1 yr) 10.5% (1 yr)

teriflunomide po 30.5% 24%

dimethyl fumarate

po 29% (combined analysis: NS CONFIRM) 15%

finglimod po 37% (F1) NS (F2) 19% (F1)

natalizumab iv 54% (-64% active disease) 28%

alemtuzumab iv NS (CARE-MS 1) -42% (CARE MS2) 20% (IFN-b)

reducing short term disability

Calabresi et al. Lancet Neurol 2014;13:657

refs as slide 18 unless stated

reducing MRI measures of inflammation

drug reduction in number of new/enlarging T2 lesions

reduction in number of Gd+ve lesions

interferon-b/ glatiramer acetate

scim

-78% -

pegylated interferon

sc Q2W

-67% -86%

teriflunomide po -69.4% (T2 and Gd combined)

dimethyl fumarate

po -78% -82%

finglimod po -74% (F1) -70% (F1)

natalizumab iv -83% -84% (active disease)

alemtuzumab iv -32% (no. pts vs IFN C-MS2)

-60% (no. pts vs IFN C-MS2)

Arnold et al BMC Neurol 2014; doi:10.1186/s12883-014-0240-x

refs as slide 18 unless stated

Therapy Reduction in PBVC

IFN β/glatiramer acetate Avonex: positive effect Year 2

pegylated interferon not presented

teriflunomide not significant

dimethyl fumarate no peer reviewed data presented

fingolimod –35% (FREEDOMS); –33% (FREEDOMS II); –32% (TRANSFORMS)

natalizumab -55% yr 2

alemtuzumab –42% (naive vs. IFN); –24% (previously treated vs. IFN)

reducing brain atrophyrefs as slide 18 unless stated

NEDA 3

relapses

EDSS progression

MRI activity

NEDA 4

relapses

EDSS progression

MRI activity

brain volume loss

definable?achievable?

useful?

0

5

10

15

20

25

quoted rates for NEDA3

23%OR 2.56vs placebocombined analysis

logistic regression

placebo teriflunomide

23%x 1.6

vs placeboTEMSO

crude

0

5

10

15

20

25

30

placebo natalizumab

27%x 13.5

vs placeboAFFIRM

RES subgroup0

5

10

15

20

25

30

35

40

45

Rebif alemtuzumab

39%x 1.75vs RebifCARE-MS1

all 2year

Havrdova et al Lancet Neurol 2009;8:254

Hardova et al P521 ECTRIMS 2013Freedman et al. Neurology PD5.007 AAN 2012

Giovannoni et al. 2012 ENS

0

5

10

15

20

25

30

quoted rates for NEDA3

39.8%1 yearOR 3.06vs placebo

placebo fingolimod

24%OR 4.0

vs placebocombined analysis

logistic model

Arnold et al BMC Neurol 2014; doi:10.1186/s12883-014-0240-xBergvall et al P112 ECTRIMS Boston 2014

0

5

10

15

20

25

30

35

40

45

placebo pegylated interferon

NEDA 4

Freedoms 1 and 2

1. relapse

protocol defined

2. EDSS confirmed at 3 months

1.5 from 0; 0.5 over 5; otherwise 1

3. MR:

NET2 only: m6, 12, 24

(Gd did not add anything)

4. atrophy:

>0.4% 

Kappos 2014 platform ECTRIMS Boston

0

5

10

15

20

25

NE

DA

4 a

t 2 y

ears

placebo fingolimod

OR 4.41 p<0.0001

tolerability and safetyinterferons(injectables)

fingolimod(tablet)

natalizumab(infusion)

teriflunomide(tablet)

DMF(tablet)

alemtuzumab(infusion)

flu-like symptoms

first dose bradycardia (1%)10AVB(0.5%)

PML 0.5% JC+ve >2yr

hair thinning (8%)

flushing (34%) thyroid disease (30%)

LFTs LFTs(can be late)

LFTs LFTs GI upset TTP (1.3%)

site reactions macular oedema (0.4%)

infections (HZV) hypertension leucopenia nephropathy

thyroiddisorders

infections:LRTIHZV 1/100 pt yr

accelerated washout

infusion reactions

capillary leak syndrome

hypertension cytotoxic infections HZV

microangiopathic haemolytic anaemia

potentially teratogenic

teratogenic in animals

bloods 0, 1, 3, 6, 9, 12

bloods 0, 1, 3, 6, 9, 12

bloods 0, 3, 6, 9, 12

2wkly testing x 6m

bloods 0, 1, 3, 6, 9, 12

monthly blood/urine 48m

Sept 27th 2011

risk management with natalizumab

PML risk estimates by index threshold in anti-JCV Ab+ patients with no prior IS use

PML risk estimates for anti-JCV antibody index thresholds were calculated based on the current PML risk stratification algorithm (from September 2012) and predicted probabilities shown in the previous slide (8) for the population at or below that particular index (0.9−1.5) and for the population above an index of 1.5. For index thresholds below 0.9, patient numbers were insufficient to allow for calculation of risk estimates.

Index threshold

PML risk estimates (95% CI) per 1000 patients (no prior IS use)

1−24 months 25−48 months 49−72 months

≤0.90.1

(0–0.41)0.3

(0.04–1.13)0.4

(0.01–2.15)

≤1.10.1

(0–0.34)0.7

(0.21–1.53)0.7

(0.08–2.34)

≤1.30.1

(0.01–0.39)1.0

(0.48–1.98)1.2

(0.31–2.94)

≤1.50.1

(0.03–0.42)1.2

(0.64–2.15)1.3

(0.41–2.96)

>1.51.0

(0.64–1.41)8.1

(6.64–9.8)8.5

(6.22–11.38)

Plavina et al. Ann Neurol; 76:802

presentation of PML

• asymptomatic (MR screening)• cognitive/behavioural• ataxia• hemiplegia

alemtuzumab

• NICE approval for “relapsing MS”

• dosing schedule: – year 1: 5d 12mg infusion – year 2: 3d 12mg infusion– subsequent years: 3d infusions if indicated

risk management strategy

• predose: VZV, cervical screening, HIV, HBV, HCV, TB

• aciclovir for first month• monthly for 4 years after last infusion

– CBC (platelets)– U&E and urine for microscopy– TFTs 3 monthly

• annual MRI (for efficacy)

long term study

• 87 patients 1999-2007• median 7 year follow up (33-144 months)• 48% (41 patients) had secondary autoimmunity

– 3 ITP– 1 neutropenia– 1 haemolytic anaemia– 1 Goodpasture’s (transplant required)– 35 thyroid (22 Graves, 1 transient thyroiditis, 12 1o

hypothyroidism)• relapses triggered reinfusion 45%

– (38% 3; 4% 4; 1% 5)

• 60% stabilisation of improvement in disabilityTuohy et al 2014 JNNP 10.1136/jnnp-2014-307721

DMT cases in primary care

case

• 34-year-old woman • presented for advice following a positive home

pregnancy test, 7 weeks after her last menstrual period

• teriflunomide 14mg daily for 9 months for relapsing remitting multiple sclerosis

• relapse free for 5 years. • relying on condoms for contraception• conception was unplanned but wishes to

continue with the pregnancy

options (nurses all on study day)

1. teriflunomide should be cleared by cholestyramine

2. teriflunomide should be cleared rapidly by plasmaphoresis

3. teriflunomide should be continued throughout the pregnancy

4. teriflunomide should be discontinued and allowed to clear gradually

5. termination is advisable due to an unacceptable risk of teratogenicity

pregnancy & conception

interferon-b(Betaferon/Extavia

Avonex

Rebif)

glatiramer acetate(Copaxone)

natalizumab(Tysabri)

fingolimod(Gilenya)

teriflunomide(Aubagio)

dimethyl fumarate(BG12, Tecfidera)

alemtuzumab(Campath, Lemtrada)

pegylated interferon(Plegridy)

case

• 42-year-old man • 18 month review on fingolimod 0.5mg• no attacks on the drug which was well tolerated

• felt well, had no history of infection and remained at work

• routine bloods

would you (neurology team on team bonding away day)?

1. admit immediately to unit equipped to manage severely immunocompromised patients

2. check JC antibody status to stratify risk of progressive multifocal leucoencephalopathy

3. continue at current dose while lymphocytes remain >0.2 x 109/l

4. discontinue drug and monitor lymphocyte count to ensure recovery

5. reduce dose to alternate days and monitor lymphocyte count to ensure recovery

case

• 42-year-old man • 18 month review on dimethyl fumarate 240mg

bd • no attacks on the drug which was well tolerated

 • felt well, had no history of infection and

remained at work• routine bloods

would you (neurology team all abroad at conference)?

1. admit immediately to unit equipped to manage severely immunocompromised patients

2. check JC antibody status to stratify risk of progressive multifocal leucoencephalopathy

3. continue at current dose while lymphocytes remain >0.2 x 109/l

4. discontinue drug and monitor lymphocyte count to ensure recovery

5. reduce dose to 120mg bd and monitor lymphocyte count to ensure recovery

case

• 36-year-old man with multiple sclerosis • 15 months after his completing his second year

of alemtuzumab (3 x 12mg infusions)• clinically well with no relapses or progression.•  no evidence of infection, rash or bruising.

plan?

1. monitor

2. admit as emergency

3. refer back to centre

case

• 37-year-old woman MS • presents late afternoon following an episode of

transient loss of consciousness lasting about one minute.

• returned from two weeks abroad that morning and recommenced her medication which she had omitted while on holiday.

• HR 38 beats • BP90/64

what’s going on?

cost effectiveness of disease modification?

UK risk-sharing scheme 6 year cohort

RSS n=4137

age at eligibility (mean)

38.4

age at onset (mean) 30.5

female (%) 75.5

disease duration (baseline)

7.7

relapses last 2 years (median [quartiles])

3 [2-3]

time (years)

ED

SS

UK risk-sharing scheme: modelled natural history of cohort

0 1 2 3 4 5 60

0.5

1

1.5

2

2.5

3

3.5

4

4.5

nat Hxmodelled on treatment

time (years)

ED

SS

UK risk-sharing scheme: EDSS results against -38% target

0 1 2 3 4 5 60

0.5

1

1.5

2

2.5

3

3.5

4

4.5

nat Hxactual RSSmodelled to HR 0.62

0 1 2 3 4 5 60.62

0.64

0.66

0.68

0.7

0.72

0.74

nat Hx

actual RSS

modelled to HR 0.62

UK risk-sharing scheme: utility results against -38% target

time (years)

change in

uti

lity

0.02

0.04

0.06

0.08

0.10

0.12

who is eligible?

interferons fingolimod natalizumab teriflunomide DMF alemtuzumab

first line(ABN guidelines 2009)

failed interferon or copaxone

2 relapses in 1 year and active MRI(rapidly evolving severe)

first line(unless rapidly evolving severe)

first line(unless rapidly evolving severe)

any relapsing MS

step down from natalizumab (if JC +ve plus prior IS plus 2 years natalizumab treatment)

either newly diagnosed or failed first line

phase III clinical trials in SPMS

– cladribine

– cyclophosphamide

– dirucotide

– dronabinol

– interferon-beta1a i.m.

– interferon-beta1a s/c

– interferon-beta-1b s/c

– intravenous immunoglobulin

– lamotrigine

– mitoxantrone

– alemtuzumab (phase 2 only)

first choices?

• standard newly diagnosed– DMF– IFN/GA– teriflunomide– alemtuzumab

• RES newly diagnosed– natalizumab– alemtuzumab

failing first line

• tolerability– determine issue– switch within licensed

drugs• efficacy

– consider concordance– escalate

• suboptimal response?• rapidly evolving severe?

DMFIFN/GAteriflunomidealemtuzumab

fingolimodalemtuzumab

natalizumabalemtuzumab

after second line

• fingolimod– concordance?– tolerability– efficacy

• natalizumab– efficacy (Nabs)– hypersensitivity– JC concerns

• alemtuzumab– efficacy– adverse event

escalation: natalizumab/alemtuzumab

switch: ?DMF alemtuzumab

alemtuzumab

fingolimod

repeat course; consider ASCT

? natalizumab

• treatment of acute relapse

• disease modification– disease modifying treatments (DMTs)

• management of symptoms and disability

NICE: 2014• comprehensive review

and symptom check– site not specified

• general health

• social activity and participation

• targeted systems review

arms ADL

swallow & speech

bowels

memory & concentration

bladder

ambulation

spasticity

sexual dysfunction

mood

fatigue

vision

numbness/tingling/pain

systematic enquiry of impairment/symptoms

continence in MS

1. assessment• urinary tract symptoms• bowel symptoms• sexual function• comorbidities• use of prescription and other medication

and therapies

2. if the dipstick test result and person's symptoms suggest an infection, • arrange a urine bacterial culture and

antibiotic sensitivity test before starting antibiotic treatment

• treatment need not be delayed but may be adapted when results are available

continence in MS

3. be aware that bacterial colonisation will be present in people using a catheter and so urine dipstick testing and bacterial culture may be unreliable for diagnosing active infection

4. red flags for referral• haematuria• recurrent UTI (≥3 in 6m)• loin pain• recurrent catheter blockages (<6 wk of

change)• hydronephrosis or kidney stones on

imaging (rare in MS)• biochemical evidence of renal

deterioration.

continence in MS

4. if catheters, appliances or pads:• training• access to suitable products• review of products, at least every 2 years

5. offer botulinum toxin to improve bladder storage if OAB and anti-muscarinics failed or not tolerated

6. do not routinely offer antibiotic prophylaxis but consider if recent history of frequent or severe UTI

intractable constipation: what’s new

• prucalopride (women only, specialist centre)

• Peristeen (continence service)

last one: vitamin D and MS

• role in susceptibility secure

• role in disease modification unsure

• advice on high dose replacement

thank you

reflections or questions?