An holistic approach to MS
Gavin GiovannoniBarts and The London School of Medicine and Dentistry
PURCHASER
S
VALUE
QUALITY
TEACHING
RESEARCH
CLINICAL
CLINICAL SERVICE
“All those who work on the frontline should be thinking carefully, and imaginatively, about how we can do things differently. The QIPP process is a home for this in the NHS and the way that we can implement the best and brightest ideas across the service. As the Prime Minister said: ‘Don’t hold back – be innovative, be radical, challenge the way things are done.”
Andrew Lansley, Secretary of State for Health – 2 July 2010.
“We need to fashion a vibrant, creative NHS that really fizzes with ideas of how to improve quality and how to reduce costs........ So, instead of relying on ever more funds flowing from the Treasury, we must look to ourselves to make savings. This practical imperative is what QIPP is all about......... We have the resources, we have the knowledge and we have the ability to give the people of this country a truly first class NHS and to deliver it within our means.”
Earl Howe, Minister for QIPP - 2 July 2010
Dr Janet Williamson National Director, NHS Improvement
Gastrostomy
Primary Care Referral Diagnosis Minimal impairment
Moderateimpairment
Severeimpairment
End oflife care
Prevention
Cognition
Depression
Fatigue
Bladder
Bowel
Sexual dysfunction Tremor
Pain
Swallowing
Spasticity
Falls
Balance problems
Insomnia
Restless legs
Studying
Employment
RelapsesDMTs
Fertility
Rehab
Suprapubiccatheter
Intrathecal baclofern
Palliative Care
Physiotherapy
Speech therapy
OccupationalTherapy
Nurse specialists Counselling
Neuroradiology
Neurophysiology
Clinical trials
Gait
Neuroimmunology
Pressure sores
Driving
Anxiety
DMTs
Functional neurosurgery
Oscillopsia
Sexual dysfunction
Pseudobulbar affect
Seizures
Advanced directive
Assisted suicide
Colostomy
Tendonotomy
Relationships
Travel vaccination
Socialservices Legal aid
1st line
2nd line
maintenanceescalation
induction
risks
adverse events
monitoring
disease-free
family counselling
vD
A ‘holistic’ approach to MS
www.ms-res.org
Who of you routinely measures blood vitamin D levels in people with MS?
Sustained-release oral fampridine in multiple sclerosis:a randomised, double-blind, controlled trial
Goodman et al. Lancet 2009; 373: 732–38.
Gastrostomy
Primary Care Referral Diagnosis Minimal impairment
Moderateimpairment
Severeimpairment
End oflife care
Prevention
Cognition
Depression
Fatigue
Bladder
Bowel
Sexual dysfunction Tremor
Pain
Swallowing
Spasticity
Falls
Balance problems
Insomnia
Restless legs
Studying
Employment
RelapsesDMTs
Fertility
Rehab
Suprapubiccatheter
Intrathecal baclofern
Palliative Care
Physiotherapy
Speech therapy
OccupationalTherapy
Nurse specialists Counselling
Neuroradiology
Neurophysiology
Clinical trials
Gait
Neuroimmunology
Pressure sores
Driving
Anxiety
DMTs
Functional neurosurgery
Oscillopsia
Sexual dysfunction
Pseudobulbar affect
Seizures
Advanced directive
Assisted suicide
Colostomy
Tendonotomy
Relationships
Travel vaccination
Socialservices Legal aid
1st line
2nd line
maintenanceescalation
induction
risks
adverse events
monitoring
disease-free
family counselling
vD
A ‘holistic’ approach to MS
Bone Health
Fracture risk in multiple sclerosis
Dobson et al. Submitted 2012.
Risk of fractures in patients with MS: record-linkage study
Ramagopalan et al. Unpublished data 2012
Osteoporosis in multiple sclerosis
Dobson et al. Submitted 2012.
What is the prevalence of falls in MS?
Sosnoff et al. PLoS One. 2011;6(11):e28021.
Sosnoff et al. PLoS One. 2011;6(11):e28021.
Gastrostomy
Primary Care Referral Diagnosis Minimal impairment
Moderateimpairment
Severeimpairment
End oflife care
Prevention
Cognition
Depression
Fatigue
Bladder
Bowel
Sexual dysfunction Tremor
Pain
Swallowing
Spasticity
Falls
Balance problems
Insomnia
Restless legs
Studying
Employment
RelapsesDMTs
Fertility
Rehab
Suprapubiccatheter
Intrathecal baclofern
Palliative Care
Physiotherapy
Speech therapy
OccupationalTherapy
Nurse specialists Counselling
Neuroradiology
Neurophysiology
Clinical trials
Gait
Neuroimmunology
Pressure sores
Driving
Anxiety
DMTs
Functional neurosurgery
Oscillopsia
Sexual dysfunction
Pseudobulbar affect
Seizures
Advanced directive
Assisted suicide
Colostomy
Tendonotomy
Relationships
Travel vaccination
Socialservices Legal aid
1st line
2nd line
maintenanceescalation
induction
risks
adverse events
monitoring
disease-free
family counselling
vD
A ‘holistic’ approach to MS
Who delegates bladder dysfunction to the continence advisor?
Gastrostomy
Primary Care Referral Diagnosis Minimal impairment
Moderateimpairment
Severeimpairment
End oflife care
Prevention
Cognition
Depression
Fatigue
Bladder
Bowel
Sexual dysfunction Tremor
Pain
Swallowing
Spasticity
Falls
Balance problems
Insomnia
Restless legs
Studying
Employment
RelapsesDMTs
Fertility
Rehab
Suprapubiccatheter
Intrathecal baclofern
Palliative Care
Physiotherapy
Speech therapy
OccupationalTherapy
Nurse specialists Counselling
Neuroradiology
Neurophysiology
Clinical trials
Gait
Neuroimmunology
Pressure sores
Driving
Anxiety
DMTs
Functional neurosurgery
Oscillopsia
Sexual dysfunction
Pseudobulbar affect
Seizures
Advanced directive
Assisted suicide
Colostomy
Tendonotomy
Relationships
Travel vaccination
Socialservices Legal aid
1st line
2nd line
maintenanceescalation
induction
risks
adverse events
monitoring
disease-free
family counselling
vD
A ‘holistic’ approach to MS
Preserving cognitive function for patients with overactive bladder: evidence for a differential effect with darifenacin
Kay et al. Int J Clin Pract. 2008 Nov;62(11):1792-800.
Systemic infections and inflammation affect chronic neurodegenerationPerry et al. Nat Rev Immunol. 2007 Feb;7(2):161-7.
Who agrees that after making a diagnosis of MS the main role of the neurologist is to prescribe DMTs?
Gastrostomy
Primary Care Referral Diagnosis Minimal impairment
Moderateimpairment
Severeimpairment
End oflife care
Prevention
Cognition
Depression
Fatigue
Bladder
Bowel
Sexual dysfunction Tremor
Pain
Swallowing
Spasticity
Falls
Balance problems
Insomnia
Restless legs
Studying
Employment
RelapsesDMTs
Fertility
Rehab
Suprapubiccatheter
Intrathecal baclofern
Palliative Care
Physiotherapy
Speech therapy
OccupationalTherapy
Nurse specialists Counselling
Neuroradiology
Neurophysiology
Clinical trials
Gait
Neuroimmunology
Pressure sores
Driving
Anxiety
DMTs
Functional neurosurgery
Oscillopsia
Sexual dysfunction
Pseudobulbar affect
Seizures
Advanced directive
Assisted suicide
Colostomy
Tendonotomy
Relationships
Travel vaccination
Socialservices Legal aid
1st line
2nd line
maintenanceescalation
induction
risks
adverse events
monitoring
disease-free
family counselling
vD
A ‘holistic’ approach to MS
Theoretical model: treat early and aggressively
Natural course of disease
Laterintervention
Latertreatment
Treatmentat diagnosis Intervention
at diagnosis
Time
Disease Onset
Dis
abili
ty
Who discusses mortality with their patients?
Survival in MSers is shortened by 8 to 12 yearsSurvival Probability of Norwegian Patients with RRMS
(Hordaland County, Western Norway, 1953–2003)
RRMS=relapsing-remitting MS.Adapted from Torkildsen NG et al. Mult Scler. 2008;14:1191-1198.
500 5 10 15 20 25 30 35 40 450
10
20
30
40
50
60
70
80
90
100
Surv
ival
(%)
Years After Onset
30 35 40 45 50 55 60 65 70 75 80Approximate Patient Age
General PopulationRRMS95% CI
The survival disadvantage in MS is greater than in other chronic diseases
Standardized Mortality Ratios in Chronic Diseases
Disease SMR (range)
Cardiovascular disease1* 1.34 (1.23–1.44)
Ischemic stroke2† 1.75(1.38–2.19)
Early breast cancer3 2.0 (1.6–2.7)
Crohn’s disease4 2.8
MS5 2.8 (2.6–3.1)
MS (2–9.9 years after diagnosis)5 2.4 (1.9–2.9)
MS (≥10 years after diagnosis)5 3.1 (2.8–3.4)
Parkinson’s disease6 3.66 (3.37–3.95)
Type 2 diabetes1 4.47 (3.91–5.10)
*In patients with type 2 diabetes; †in patients with valvular heart disease in Olmsted County, Minnesota.1. De Marco R et al. Diabetes Care. 1999;22:756-761; 2. Petty DW et al. Mayo Clin Proc. 2005;80:1001-1008; 3. Hooning MJ et al. Int J Radiat Oncol Biol Phys. 2006;64:1081-1091; 4. South East England Public Health Observatory, Mortality trends. 2006; 5. Sumelahti ML et al. Mult Scler. 2010;16:1437-1442; 6. Hristova DR. Folia Medica. 2009;51:40-45.
Population-based MS mortality studies
First Author Population
and Time Period Size
of Cohort SMR Additional Survival MeasuresGryttenTorkildsenMult Scler 2008
Western Norway 1953–2003
878 2.66(95% CI: 2.31–3.06)
• Median survival time from onset: 41 years MS vs 49 years general population
– 8 years of life lost in MS
SmestadMult Scler 2009
Oslo 1940–1980
368 2.47(95% CI: 2.09–2.90)
• Reduction of median life expectancyvs general population
– Female: 11.2 years– Male: 7.4 years
Bronnum-Hansen Brain 2004
Danish MS Registry
1949–1996
9881 2.89 (95% CI: 2.81±2.98)
• Median survival time (from disease onset)vs general population:
– ≈10 years of life lost in MS
HirstJNNP 2008
South Wales1985–2006
373 2.79(95% CI: 2.44–3.18)
• Median age of death: 63.1 years MSvs 70.6 years general population
– 7.5 years of life lost in MS
Sumelahti Mult Scler 2010
Finland1964–1993
1595 2.8 (95% CI: 2.6–3.1)
• Survival decreases with disease progression– SMR, 2–9.9 years after diagnosis: 2.4 – SMR, ≥10 years after diagnosis: 3.1
WallinBrain 2000
USA1956–1996
2489 2.18(not specified)
• Healthy soldier effect speculated to have a favorable effect on survival
Leray Mult Scler 2007
West France1976–2004
1879 1.3(95% CI: 1.01–1.7)
• Mean follow-up duration = 12.7 years from clinical onset; may be basing estimate on relatively immature dataset
MS=multiple sclerosis; SMR=standardized mortality ratio; CI=confidence interval.
21-year long-term follow-up of IFNb-1b studytime from study randomization to death
Early treatment (3 years) with IFNb-1b was associated with a 47% reduction in the risk of dying over 21 years compared with initial placebo treatment
Goodin et al. Neurology. 2012 Apr 24;78(17):1315-22..
At risk:IFNB-1b 250 µgPlacebo
124123
124120
121117
118109
10488
HR=0.532 (95% CI: 0.314–0.902)46.8% reduction in hazard ratio Log rank, P=0.0173
IFNB-1b 250 µg
Placebo
0 2 4 6 8 10 12 14 16 18 20 2265%
70%
75%
80%
85%
90%
95%
100%
Time (Years)
Pro
po
rtio
n o
f p
ati
en
ts w
ho
are
sti
ll a
live
Disability
Time
6 months 12 months 24 months
Active
Placebo
6 months
Relapsing MS
1. Delay attacks / onset of MS2. Reduce number of attacks3. Reduce severity of attacks4. Reduce disability5. Delay onset of SPMS
Any Negative EDSS=6 SPMS Wheelchair
% R
isk
Rel
ativ
e to
Lo
w E
xpo
sure
Long-term follow-up 16 yearsIFN-beta exposure 80% vs. 20%
Goodin et al. PLoS One. 2011;6(11):e22444. Epub 2011 Nov 30.
Treat early (and aggressively)
Natural course of disease
Laterintervention
Latertreatment
Treatmentat diagnosis Intervention
at diagnosis
Time
Disease Onset
Disability
Who likes doughnuts?
The relapsing MS doughnut
Inactive RRMS
CIS
RIS
Suboptimal responders ?
Active RRMSIFNb / GA
IFNb
Highly active RRMSFingolimod
Natalizumab Natalizumab
Who discusses employment with their patients?
Unemployment
Pfleger CC et al. Mult Scler. 2010;16:121-126.
0 5 10 15 20 25
Time (years)
0
0.2
0.4
0.6
0.8
1.0
Prob
abili
ty
Control PersonsMS Patients
Probability of Remaining in Active Employment After Onset of MS
Who discusses relationships with their patients?
Divorce and separation
*Life table method.Pfleger CC et al. Mult Scler. 2010; 16:121-126.
0 5 10 15 20 25
Time to Event or End of Observation (years)
0
0.2
0.4
0.6
0.8
1.0
Prob
abili
ty
Population ControlsMSers
Crude probability of remaining in a relationship after onset of MS*
Who discusses QoL with their patients?
The effect of MS on Quality of Life
• MS is one of the most common causes of neurological disability in young adults2
• Natural history studies indicate that it takes a median time of 8, 20, and30 years to reach the irreversible disability levels of EDSS scores 4.0, 6.0, and 7.0, respectively3
*Utility measures are derived from EQ-5D using the EuroQoL instrument; †error bars depict 95% CIs. Half points on EDSSare not shown on graph axis, except at EDSS score 6.5.EDSS=Expanded Disability Status Scale; EQ-5D=European Quality of Life-5 Dimensions; QoL=quality of life.1. Adapted from Orme M et al. Value In Health. 2007;10:54-60; 2. WHO and MS International Foundation (MSIF). http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1 &codcol=15&codcch=747. Accessed March 6, 2012;3. Confavreaux C et al. Brain 2003; 176:770-782. 4. Compston A, Coles A. Lancet. 2008;372:1502-1517.
Util
ity
EDSS and Utility* Show a Significant Inverse Relationship1†
Util
ity
EDSS Status
0.0 1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0 9.0–0.4–0.3–0.2–0.1
00.10.20.30.40.50.60.70.80.9
Who monitors prognostic factors of treatmentresponse to DMTs?
Breakthrough disease after treatment initiation
Patients with breakthrough disease can be identified with• Clinical measures
– Relapses– EDSS progression
• MRI measures– T2 and Gd+ lesions
• Biological markers– IFNβ NAbs/lack of MxA gene induction– Natalizumab antibodies
Gd+=gadolinium-enhancing; IFNβ=interferon beta; NAbs=neutralizing antibodies; Abs=antibodies; MxA= myxovirus protein A.
Relapse on IFNβ therapy increases risk of sustained disability progression
• Risk is not much greater for 2 relapses or more• Sensitivity is only 50%
HR=hazard ratio; SE=standard error.Bosca et al. Mult Scler. 2008;14:636-639.
HR SE P Value 95% CI
No relapses (reference=1) 1
One relapse 3.41 1.47 0.005 1.46–7.98
Two or more relapses 4.37 1.74 0.000 1.90–9.57
HR of EDSS Increase in Patients with No Relapses, 1 Relapse, and 2 or More Relapses During the First 2 Years of IFN Treatment
0 20 40 60 80
0
0.25
0.50
0.75
Analysis Time (Months)
No RelapsesOne RelapseTwo or More Relapses
1.00
EDSS
Pro
gres
sion
Surv
ival
Pro
babi
lity
Study or SubgroupOdds Ratio
IV, Random, 95% CIKinkel 2008
Prosperini 2009Total (95% CI) 9.86 (2.33, 41.70)
Dobson et al. Submitted 2012.
MRI to monitor treatment response toIFNβ: a systematic review
Study or SubgroupOdds Ratio
IV, Random, 95% CIKinkel 2008
Pozzilli 2005Prosperini 2009
Sormani 2011Total (95% CI) 2.69 (0.72, 10.04)
0.01 0.1 1 10 100Disease Less Likely Disease More Likely
One New T2 Lesion
Favors Experimental Favors Control1001010.10.01
Two or More New T2 Lesions
Study or SubgroupOdds Ratio
IV, Random, 95% CIKinkel 2008
Rio 2008
Total (95% CI) 5.46 (2.48, 12.04)
MRI to monitor treatment response toIFNβ: a systematic review
Dobson et al. Submitted 2012.
Study or SubgroupOdds Ratio
IV, Random, 95% CIKinkel 2008
Pozzilli 2005Tomassini 2006
Total (95% CI) 3.34 (1.36, 8.22)
0.01 0.1 1 10 100Disease Less Likely Disease More Likely
One New Gd+ Lesion
0.01 0.1 1 10 100
Disease Less Likely Disease More Likely
Two or More New Gd+ Lesions
Strongest predictor of disability progression on IFNβ therapy is progression itself
Disease Activity During 2 Years of Treatment and Prediction of Disability Progression* at 6 Years
GroupSensitivity (%)
(CI)Specificity (%)
(CI)
A. An increase of at least one EDSS step confirmed at 6 months 85 (64–95) 93 (86–97)
B. Occurrence of any relapse 80 (58–92) 51 (41–61)
C. Occurrence of two or more relapses 45 (26–66) 81 (72–82)
D. A decrease in relapse rate less than 30% compared with 2 years before therapy 40 (22–61) 86 (77–91)
E. A decrease in relapse rate less than 50% compared with 2 years before therapy 40 (–61) 81 (72–88)
F. No decrease or identical relapse rate compared with 2 years before therapy 35 (18–57) 88 (79–93)
G. Definition A or B 90 (70–97) 48 (38–58)
H. Definition A or E 85 (64–95) 76 (66–83)
I. Definition A and B 75 (53–89) 97 (91–99)
J. Definition A and E 40 (22–61) 99 (94–99)
*EDSS score ≥6.0 or increase in at least 3 EDSS steps.Río J et al. Ann Neurol. 2006;59:344-352.
Clinical importance of neutralising antibodies against interferonbeta in patients with relapsing-remitting multiple sclerosis
Sorensen et al. Lancet 2003; 362: 1184–91.
Mean change in EDSS
Malluci et al. Neurology 2004.
Predictors of long-term clinical response to interferon beta therapy in relapsing multiple sclerosis
Tomassini et al. J Neurol (2006) 253 : 287–293.
The incidence and significance of anti-natalizumab antibodiesResults from AFFIRM and SENTINEL
Calebresi & Giovannoni, et al. Neurology 2007;69:1391–1403.
The incidence and significance of anti-natalizumab antibodiesResults from AFFIRM and SENTINEL
Calebresi & Giovannoni, et al. Neurology 2007;69:1391–1403.
Metrics for DMTs• What proportion of your patients are on a
DMT?– 1st line vs. escalation?– What proportion of your patient have NABs?
• What proportion of your patients have failed a first line DMT?
• What proportion of your patients are in a clinical trial?
• Etc.
Treatment Strategy
Theoretical model: treat early and aggressively
Natural course of disease
Laterintervention
Latertreatment
Treatmentat diagnosis Intervention
at diagnosis
Time
Disease Onset
Dis
abili
ty
Impact of MS: cognitive functioning in the CIS stage
CIS=clinically isolated syndrome.Feuillet L et al. Mult Scler. 2007;13:124-127.
Deficits were found mainly in memory, speed of information processing,
attention and executive functioning
CIS Patients (n=40)
Healthy Controls (n=30)
0
20
40
60Cognitive Test Performance in an Exploratory Study
57%
7%
Patie
nts
Faili
ng ≥
2 Co
gniti
ve T
ests
P<0.0001
What is benign MS?
• 163 patients with “benign” MS (disease duration >15 years and EDSS score <3.5)– 45% cognitive impairment – 49% fatigue– 54% depression
Amato MP et al. J Neurol. 2006;253:1054-1059.
Rx=prescription drugs; OTC=over-the-counter.Berg J et al. Eur J Health Econ. 2006;7(suppl 2):S75-S85.
Total mean annual cost per patient €53,601
Healthcare costs are linked to disability
Informal Care(Disposable Income)
(9.2%)
Ambulatory Care (5.6%)
Disease-Modifying Drugs (10.6%)
Other RX & OTC Drugs (1.6%)
Tests (0.4%)
Investments (2.0%)
Long-Term Sick Leave andEarly Retirement (30.0%)
Short-Term Absence(2.0%)
Services(28.5%)
Inpatient Care (10.2%)
Conclusion
• Equity and excellence: Liberating the NHS – patients will be at the heart of everything we do
• choice and control• easy access to the information they need about the best GPs
and hospitals• patients will be in charge of making decisions about their care
– a relentless focus on clinical outcomes• Success will be measured, not through bureaucratic process
targets, but against results that really matter to patients – such as improving …… survival rates
– we will empower health professionals