Emily Sena, Gillian Currie, Hanna Vesterinen, Kieren Egan, Nicki Sherratt, Cristina Fonseca, Zsannet Bahor, Jing Liao,

Theo Hirst, Kim Wever, Hugo Pedder, Katerina Kyriacopoulou, Julija Baginskaite, Ye Ru, Stelios Serghiou, AaronMcLean, Catherine Dick, Tracey Woodruff, Patrice Sutton, Andrew Thomson, Aparna Polturu, Sarah MaCann, GillianMead, Joanna Wardlaw, Rustam Salman, Joseph Frantzias, Robin Grant, Paul Brennan, Ian Whittle, Andrew Rice,

Rosie Moreland, Nathalie Percie du Sert, Paul Garner, Lauralyn McIntyre, Gregers Wegener, Lindsay Thomson, DavidHowells, Ana Antonic, Tori O’Collins, Uli Dirnagl, H Bart van der Worp, Philip Bath, Mharie McRae, Stuart Allan, Ian

Marshall, Xenios Mildonis, Konstantinos Tsilidis, Orestis Panagiotou, John Ioannidis, Peter Batchelor, David Howells,Sanne Jansen of Lorkeers, Geoff Donnan, Peter Sandercock, Emily Sena, Gillian Currie, Hanna Vesterinen, KierenEgan, Nicki Sherratt, Cristina Fonseca, Zsannet Bahor, Jing Liao, Theo Hirst, Kim Wever, Hugo Pedder, Katerina

Kyriacopoulou, Julija Baginskaite, Ye Ru, Stelios Serghiou, Aaron McLean, Catherine Dick, Tracey Woodruff, PatriceSutton, Andrew Thomson, Aparna Polturu, Sarah MaCann, Gillian Mead, Joanna Wardlaw, Rustam Salman, Joseph

Frantzias, Robin Grant, Paul Brennan, Ian Whittle, Andrew Rice, Rosie Moreland, Nathalie Percie du Sert, Paul Garner,Lauralyn McIntyre, Gregers Wegener, Lindsay Thomson, David Howells, Ana Antonic, Tori O’Collins, Uli Dirnagl, H Bartvan der Worp, Philip Bath, Mharie McRae, Stuart Allan, Ian Marshall, Xenios Mildonis, Konstantinos Tsilidis, Orestis

Panagiotou, John Ioannidis, Peter Batchelor, David Howells, Sanne Jansen of Lorkeers, Geoff Donnan, PeterSandercock, Emily Sena, Gillian Currie, Hanna Vesterinen, Kieren Egan, Nicki Sherratt, Cristina Fonseca, Zsannet

Bahor, Jing Liao, Theo Hirst, Kim Wever, Hugo Pedder, Katerina Kyriacopoulou, Julija Baginskaite, Ye Ru, SteliosSerghiou, Aaron McLean, Catherine Dick, Tracey Woodruff, Patrice Sutton, Andrew Thomson, Aparna Polturu, SarahMaCann, Gillian Mead, Joanna Wardlaw, Rustam Salman, Joseph Frantzias, Robin Grant, Paul Brennan, Ian Whittle,

Andrew Rice, Rosie Moreland, Nathalie Percie du Sert, Paul Garner, Lauralyn McIntyre, Gregers Wegener, LindsayThomson, David Howells, Ana Antonic, Tori O’Collins, Uli Dirnagl, H Bart van der Worp, Philip Bath, Mharie McRae,

Stuart Allan, Ian Marshall, Xenios Mildonis, Konstantinos Tsilidis, Orestis Panagiotou, John Ioannidis, Peter Batchelor,David Howells, Sanne Jansen of Lorkeers, Geoff Donnan, Peter Sandercock, Emily Sena, Gillian Currie, HannaVesterinen, Kieren Egan, Nicki Sherratt, Cristina Fonseca, Zsannet Bahor, Jing Liao, Theo Hirst, Kim Wever, Hugo

Pedder, Katerina Kyriacopoulou, Julija Baginskaite, Ye Ru, Stelios Serghiou, Aaron McLean, Catherine Dick, TraceyWoodruff, Patrice Sutton, Andrew Thomson, Aparna Polturu, Sarah MaCann, Gillian Mead, Joanna Wardlaw, Rustam

Salman, Joseph Frantzias, Robin Grant, Paul Brennan, Ian Whittle, Andrew Rice, Rosie Moreland, Nathalie Percie duSert, Paul Garner, Lauralyn McIntyre, Gregers Wegener, Lindsay Thomson, David Howells, Ana Antonic, Tori O’Collins,Uli Dirnagl, H Bart van der Worp, Philip Bath, Mharie McRae, Stuart Allan, Ian Marshall, Xenios Mildonis, Konstantinos

Tsilidis, Orestis Panagiotou, John Ioannidis, Peter Batchelor, David Howells, Sanne Jansen of Lorkeers, Geoff Donnan,Peter Sandercock, Emily Sena, Gillian Currie, Hanna Vesterinen, Kieren Egan, Nicki Sherratt, Cristina Fonseca,

Zsannet Bahor, Jing Liao, Theo Hirst, Kim Wever, Hugo Pedder, Katerina Kyriacopoulou, Julija Baginskaite, Ye Ru,Stelios Serghiou, Aaron McLean, Catherine Dick, Tracey Woodruff, Patrice Sutton, Andrew Thomson, Aparna Polturu,Sarah MaCann, Gillian Mead, Joanna Wardlaw, Rustam Salman, Joseph Frantzias, Robin Grant, Paul Brennan, Ian

CAMARADES: Bringing evidence to translational medicine

Lessons for translation: SRMA in

understanding the pathogenesis of MS

Malcolm Macleod

Professor of Neurology and Translational Neurosciences

University of Edinburgh

and

Honorary Consultant Neurologist, NHS Forth Valley

Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies

CAMARADES: Bringing evidence to translational medicine

Multiple sclerosis

• Neuroinflammatory condition of 4 types:

– Clinically Isolated Syndrome

– Relapsing Remitting MS

– Secondary progressive MS

– Primary progressive MS

– Second leading cause of disability in young adults.

– Aetiology unknown, but thought to be related to genetic and

environmental factors

• Twin studies

• Season of birth

• Latitude

• Evidence of CMV infection

CAMARADES: Bringing evidence to translational medicine

Onset/ relapses

• Antecedent immune priming events not recognised (c.f. Guillain

Barre syndrome)

• Onset, and relapses, characterised by rapidly evolving symptoms

due to focal neurological dysfunction

• Caused by an acute, focal episode of demyelination affecting the

white matter tracts

• Resolution of symptoms as the acute inflammation fades and

remyelination occurs.

• Recovery from initial events often complete

• In time, recovery becomes only partial and disability accumulates

• Later, disability may progress in the absence of relapses

CAMARADES: Bringing evidence to translational medicine

Pathophysiology

CAMARADES: Bringing evidence to translational medicine

Pathophysiology

CAMARADES: Bringing evidence to translational medicine

Which T cell populations are

involved?

IL-

17

CAMARADES: Bringing evidence to translational medicine

Systematic review of in vivo data

• Experiments

– Testing interventions in animal models of EAE

– Reporting

• Neurobehavioural outcome

• Change in population of Th1 cells, or Th17 cells, or both

• Meta-analysis by “vote counting”

– For each outcome, was it

• significantly worse/ higher;

• significantly better/ lower

• no significant difference

• Coded red to green on 6 study quality indicators

Hammar, Unpublished

CAMARADES: Bringing evidence to translational medicine

• Th1 / behaviour – 16 experiments

• Th17/ behaviour – 17 experiments

CAMARADES: Bringing evidence to translational medicine

Immunisation EAETh17

Th1

CD4+

- = +

- 6

= 3

+ 6 1

EAE

Th

1

- = +

- 11 1

= 1

+ 2 2

EAE

Th

17

kappa = 9% (95% CI 0-29%) kappa = 38% (95% CI 0-84%)

CAMARADES: Bringing evidence to translational medicine

interpretation

• The severity of EAE is driven more by

Th17 T lymphocytes than by Th1 T

lymphocytes

CAMARADES: Bringing evidence to translational medicine

Developing treatments for MS

• There are now many

immunomodulatory treatments which

reduce relapse rate

• Some of these also appear to

influence surrogate markers which

may imply an effect on disability

progression

– Reduced MRI plaque burden

– Reduced rate of loss of gray matter

volume

• No established treatments for primary

or secondary progressive disease

CAMARADES: Bringing evidence to translational medicine

Can in vivo data tell us anything

about how drugs work?

inflammation

demyelination axon loss

CAMARADES: Bringing evidence to translational medicine

Can in vivo data tell us anything

about how drugs work?

• Publications identified in Vesterinen et al 2010

• 1152 publications describing efficacy of 1717

interventions

• From these, we selected 287 experiments which

had reported at least 2 different categories of

outcome

– Inflammation, demyelination, axon loss,

neurobehaviour

CAMARADES: Bringing evidence to translational medicine

Mediation analysis

R2 = 0.70

R2 = 0.70

R2 = 0.60

R2 = 0.70

R2 = 0.70

dR2 =

0.60-(0.70*0.70)

=0.11

CAMARADES: Bringing evidence to translational medicine

Inflammation

Axon LossDemyelination

Neurobehaviour

Drug efficacy

in MS

CAMARADES: Bringing evidence to translational medicine

Inflammation

Axon LossDemyelination

Neurobehaviour

Pre induction

1.000 1.000

CAMARADES: Bringing evidence to translational medicine

Post induction

Pre disease

Inflammation

Axon LossDemyelination

Neurobehaviour

0.625

0.077 0.088

0.206

0.232

0.140

0.004 0.562

CAMARADES: Bringing evidence to translational medicine

Inflammation

Axon LossDemyelination

Neurobehaviour

Disease

0.464

0.066

0.470

0.530

0.464

CAMARADES: Bringing evidence to translational medicine

interpretation

• In the early stages of EAE, before a behavioural deficit is

established, immunomodulatory drugs are highly effective

• This is concordant with their effects in relapsing remitting MS

• In later stages of EAE, immunomodulatory effects must also reduce

axon loss for there to be any behavioural benefit

• About half of the observed effects on behaviour in later stages

appears to be independent of drug effects on inflammation,

demyelination or axon loss

• Defining the characteristics of interventions which improve

behavioural outcome without improvements in inflammation,

demyelination (and perhaps axon loss) may define new targets for

drug treatment of primary and secondary progressive MS

CAMARADES: Bringing evidence to translational medicine

Thanks

!!!!!!!!!!!!!!!!!! !

!!!!!!!!!

!

!

in vivo

Systematic Review

and Meta Analysis

Facility

CAMARADES: Bringing evidence to translational medicine

If you are planning a systematic review or meta-

analysis of animal data, CAMARADES are here to

help: malcolm.macleod@ed.ac.uk