Transcript Slide 1

Multiple Sclerosis
GP 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
shifting the definition
normal
clinically
isolated McDonald
syndrome criteria 2005
radiologically McDonald
isolated
criteria
syndrome
2010
active RRMS
clinically
definite MS
secondary
progressive
MS
diagnostic criteria (McDonald 2010)
Polman et al. Ann Neurol 2011;69:292–302
PPMS
patterns of MS (1996)
85%
13%
primary progressive
relapsing/ remitting
5%
(benign)
secondary progressive
2%
PRMS
defining phenotypes
“The Group recommended at
least annual assessment of
disease activity by clinical and
brain imaging criteria for
relapsing MS”
Lublin et al. Neurology 2014;83:278
referral for diagnosis
progression of MS
Relapsing forms
Increasing disability/deterioration
Subclinical
Monosymptomatic
Time
Gd = gadolinium;
MRI = magnetic resonance
imaging.
Relapsing-Remitting
Secondary Progressive
Cognitive dysfunction
Level of disability
Accumulated MRI lesion burden
Brain volume
Acute (new and Gd+) MRI activity
T1 lesion load
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
teriflunomide
(Betaferon/Extavia
Avonex
Rebif)
(Aubagio)
glatiramer acetate
dimethyl fumarate
(BG12, Tecfidera)
(Copaxone)
natalizumab
(Tysabri)
fingolimod
(Gilenya)
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
reducing relapse rates
drug
reduction in annualised relapse rate
against placebo
ARR on drug in
RCT
interferon-b/
glatiramer
acetate1
sc
im
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
49% (vs interferon-b)
0.26
alemtuzumab7,8 iv
1.
2.
3.
4.
Galetta et al. Arch Intern Med 2002;19:2161
Kappos et al. P618 ECTRIMS 2013
Fox et al. P07.097 AAN 2013
Kappos et al. N Engl J Med 2010;362:387
5.
6.
7.
8.
9.
Calabresi et al. Lancet Neurol 2014;13:545
Polman et al. N Engl J Med 2006;354: 899
Coles et al. Lancet 2012;380:1829
Cohen et al. Lancet 2012;380:1819
Kieseier et al. Mult Scler 2014 Nov 28. pii:
1352458514557986
reducing short term disability
refs as slide 18 unless stated
drug
reduction in sustained progression in
disability
rate of
progression in
placebo
12-37%
c.30%
interferon-b/
glatiramer
acetate
sc
im
pegylated
interferon
sc
38% (1 yr)
Q2W
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)
10.5% (1 yr)
Calabresi et al. Lancet Neurol 2014;13:657
reducing MRI measures of inflammation
refs as slide 18 unless stated
drug
reduction in number of
new/enlarging T2 lesions
reduction in number of Gd+ve
lesions
interferon-b/
glatiramer
acetate
sc
im
-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
reducing brain atrophy
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)
NEDA 4
NEDA 3
relapses
EDSS
progression
relapses
MRI activity
EDSS
progression
MRI activity
brain
volume loss
definable?
achievable?
useful?
quoted rates for NEDA3
25
23%
x 1.6
23%
OR 2.56
vs placebo
vs placebo
TEMSO
combined
analysis
20
15
10
crude
5
logistic regression
0
placebo
teriflunomide
Freedman et al. Neurology PD5.007 AAN 2012
Hardova et al P521 ECTRIMS 2013
45
30
25
20
15
10
5
0
placebo
natalizumab
Havrdova et al Lancet Neurol 2009;8:254
27%
x 13.5
vs placebo
AFFIRM
RES subgroup
40
39%
x 1.75
35
30
25
20
vs Rebif
15
CARE-MS1
10
5
0
Rebif
alemtuzumab
Giovannoni et al. 2012 ENS
all 2year
quoted rates for NEDA3
30
45
25
40
24%
OR 4.0
20
15
vs placebo
10
combined
analysis
5
0
placebo
fingolimod
logistic model
39.8%
1 year
OR 3.06
35
30
25
20
15
10
vs placebo
5
0
placebo
pegylated interferon
Arnold et al BMC Neurol 2014; doi:10.1186/s12883-014-0240-x
Bergvall et al P112 ECTRIMS Boston 2014
NEDA 4
OR 4.41
p<0.0001
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)
NEDA 4 at 2 years
25
20
15
10
5
0
placebo fingolimod
4. atrophy:
>0.4%
Kappos 2014 platform ECTRIMS Boston
tolerability and safety
interferons
(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
thyroid
disorders
infections:
LRTI
HZV 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 (95% CI) per 1000 patients (no prior IS use)
Index threshold
≤0.9
≤1.1
≤1.3
≤1.5
>1.5
1−24 months
25−48 months
49−72 months
0.1
0.3
0.4
(0–0.41)
(0.04–1.13)
(0.01–2.15)
0.1
0.7
0.7
(0–0.34)
(0.21–1.53)
(0.08–2.34)
0.1
1.0
1.2
(0.01–0.39)
(0.48–1.98)
(0.31–2.94)
0.1
1.2
1.3
(0.03–0.42)
(0.64–2.15)
(0.41–2.96)
1.0
8.1
8.5
(0.64–1.41)
(6.64–9.8)
(6.22–11.38)
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.
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 disability
Tuohy 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
teriflunomide
(Betaferon/Extavia
Avonex
Rebif)
(Aubagio)
glatiramer acetate
dimethyl fumarate
(BG12, Tecfidera)
(Copaxone)
natalizumab
(Tysabri)
fingolimod
(Gilenya)
alemtuzumab
(Campath, Lemtrada)
pegylated interferon
(Plegridy)
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]
UK risk-sharing scheme: modelled
natural history of cohort
4,5
4
3,5
EDSS
3
2,5
nat Hx
modelled on treatment
2
1,5
1
0,5
0
0
1
2
3
time (years)
4
5
6
UK risk-sharing scheme:
EDSS results against -38% target
4,5
4
3,5
EDSS
3
2,5
nat Hx
actual RSS
2
modelled to HR 0.62
1,5
1
0,5
0
0
1
2
3
time (years)
4
5
6
UK risk-sharing scheme:
utility results against -38% target
0,74
0.12
change in utility
0,72
0.10
0,7
0.08
0,68
0.06
nat Hx
0,66
0.04
actual RSS
modelled to HR 0.62
0,64
0.02
0,62
0
1
2
3
time (years)
4
5
6
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?
DMF
IFN/GA
teriflunomide
alemtuzumab
fingolimod
alemtuzumab
natalizumab
alemtuzumab
after second line
• fingolimod
– concordance?
– tolerability
– efficacy
• natalizumab
– efficacy (Nabs)
– hypersensitivity
– JC concerns
• alemtuzumab
– efficacy
– adverse event
switch: ?DMF
alemtuzumab
escalation: natalizumab/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
systematic enquiry of impairment/symptoms
fatigue
mood
memory & concentration
vision
swallow & speech
arms ADL
sexual dysfunction
bowels
bladder
numbness/tingling/pain
spasticity
ambulation
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
5. 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?