multiple sclerosis gp update martin duddy consultant neurologist royal victoria infirmary newcastle...
TRANSCRIPT
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?