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Immunological biomarkers and intervention with immunoglogbulin in the post
Kristian Borg MD, PhD professor
Div of Rehabilitation Medicine, Dept of Clinical Sciences, Karolinska Institutet and Danderyd University Hospital Stockholm Sweden
Immunological biomarkers and intervention with polio syndrome
Karolinska Institutet and Danderyd University
• Ongoing denervation compensated by reinnervation
• Failing capacity to maintain large motor units ie failing capacity to compensate denervation by reinnervation
• Uncompensated denervation leads to decrease of muscle strength
Postpolio syndrome – background
going denervation compensated
Failing capacity to maintain large motor failing capacity to compensate
denervation by reinnervation
Uncompensated denervation leads to decrease
background
ØOverstress of remaining motor units.
ØOveruse of remaining motor units.
ØAge.
ØAmyotrophic lateral sclerosis (ALS).
ØPersistent polio virus infection.
ØImmunological factors.
Pathophysiology denervationreinnervation
Overstress of remaining motor units.
Overuse of remaining motor units.
Amyotrophic lateral sclerosis (ALS).
Persistent polio virus infection.
PPSInflammation
CNS Dalakas et al 1984, Sharief et al 1984,1991
PPSInflammation
Spinal cord Pezeshkpour and Dalakas 1987 Miller DC 1995 Pezeshkpour and Dalakas 1987
PPSInflammation
Muscle Dalakas et al 1984 Dalakas 1988, 1995 SeminoMora and Dalakas 1998 Mora and Dalakas 1998
PPSinflammation
Peripheral blood Ginsberg et al 1989
PPSinflammation
Peripheral nerve Brown and Patten 1987
PPSinflammation
Cytokines
Gonzalez et al 2002
Farbu et al 2007
Fordyce et al 2008
Immunemodulatory drugs used in PPS
§ Cortison § Interferon § Immunosuppressants § Immunotherapy
modulatory drugs used in PPS
In order to downregulate the inflammatory reaction in CNS, 16 post treated with intravenous immunoglobulin (Xepol)
regulate the inflammatory reaction in CNS, 16 postpolio patients were treated with intravenous immunoglobulin
TNF TNF α α
0,00
0,50
1,00
1,50
2,00
2,50
3,00
P=0.016
Poliopatients Poliopatients before and after before and after Xepol Xepol treatment treatment
TNF-alfa CSF
Before After
Serie1
Serie2
Serie3
Serie4
Serie5
Serie6
Serie7
Serie8
Serie9
Serie1 0 Serie1 1 Serie1 2 Serie1 3 Serie1
INFgamma
P=0.00003
0 ,00
0 ,20
0 ,40
0 ,60
0 ,80
1 ,00
1 ,20
0,00
0,20
0,40
0,60
0,80
1,00
1,20
IFN-gamma c sf
B efo re A fte r
Ser ie1
S er ie2
S er ie3
S er ie4
S er ie5
S er ie6
S er ie7
S er ie8
S er ie9
S er ie10
S er ie11
S er ie12
S er ie13
S er ie14
S er ie15
S er ie16
0
20
40
60
80
100
120
Phys. funct.
Role Phys.
Bodily Pain
Gen. Health
95% CI Swedish norm age 5564 n=1093
SF36 Scales:
Healthrelated quality of life
95 % CI
Scores
p 0.007 0.007 0.001 0.003
Health Vitality Soc.
Func. Role Emot.
Mental Health
95% CI Swedish norm age 5564 n=1093
Before treatment 2 months after treatment 6 months after treatment
0.003 0.001 0.001 0.047 >0.001
Multicenter, placebocontrolled, double blinded study including 142 post patients
controlled, double blinded study including 142 postpolio
Increase of muscle strength
Treated + 4.3%
Placebo 5.7%
Increase of muscle strength
4.3% P < 0.05
5.7%
0
20
40
60
80
100
Role Phys.
Bodily Pain
Gen. Health
SF36 Scales:
Healthrelated quality of life
mean, ± 95%
CI
Xepol before after
Scores
Placebo before after
*
* **
*
Phys. Funct.
Gen. Health
Vitality Soc. Func.
Role Emot.
Mental Health
**
***
* *
1year followup study
§ Still significant decrease of cytokines § Still significantly better quality of life for physical domains
Still significant decrease of
Still significantly better quality of
VAS
33,2 28,5
34,8 30,2
0
10
20
30
40
Placebo
28,5 25,2
18,3
Xepol
baseline
6 months
12 months
2.5 year followup study
§ Cytokine levels ? § Clinical parameters back to base line Clinical parameters back to base
Werhagen and Borg 2008
§ 64 PPS patient treated § 90 gram IVIG 64 PPS patient treated
Werhagen and Borg 2008
§ Significant effect of IVIG
§ 2/3 of patients had a decrease of pain and fatigue 2/3 of patients had a decrease of
Werhagen and Borg 2008
§ Effect correlated to age and paresis
§ Better effect if the patients was < 10 years of age at the acute polio
Effect correlated to age and
Better effect if the patients was < 10 years of age at the acute
Gonzales et al 2009 a proteomic study of CSF
§ Disease specific differential expression of 3 proteins
§ Involved in neuroinflammation and/or apoptosis
a proteomic study of CSF
Disease specific differential
Involved in neuroinflammation
GELSOLIN fragments
KALLIKREIN 6
HEMOPEXIN
28
6.3
54
5.1
77
5.7
Hemopexin
Identification of predictive proteins Identification of predictive proteins Contribution to prediction
HEMOPEXIN
Rank
5.9
Hemopexin: glycoprotein, induced during inflammation.
OND/HC PPS
HEMOPEXIN fragments
6.0 6.4 28
34
OND/HC PPS
Identification of predictive proteins Identification of predictive proteins
Inflammatory cascade Inflammatory cascade Gelsolin Gelsolin cell death cell death
Kothakota S. et al. Science, 278, 294298, 1997
TNF TNF α α
Inflammatory cascade Inflammatory cascade cell death cell death
298, 1997
Other studies
§ Farbu et al 2007. TNFalfa increase, effect on pain after 3 months.
§ Open study, Stockholm end 2009.
§ Fordyce et al 2008 TNFalfa increase correlated to pain, no intervention
alfa increase, effect on pain after 3 months.
Open study, Stockholm end 2009.
alfa increase correlated to pain, no intervention
Summary
§ Postpolio patients have an increase of cytokines in the CSF indicating an inflammation in the CNS
§ The inflammation is down treatment with intravenous gammaglobulin
§ Clinically, the downmodulated inflammation leads to an increased muscle strength and a better quality of life, mainly for the general health and vitality domains, as well as for pain and fatigue
§ Recent studies suggest that there are specific biomarkers for PPS in CSF and blood
polio patients have an increase of cytokines in the CSF indicating an inflammation in the CNS The inflammation is downmodulated by means of treatment with intravenous gammaglobulin
modulated inflammation leads to an increased muscle strength and a better quality of life, mainly for the general health and vitality domains, as well as for pain and fatigue Recent studies suggest that there are specific biomarkers for PPS in CSF and blood
IS IT NECESSARY TO DOWN MODULATE THE INFLAMMATION ?
IS IT NECESSARY TO DOWN MODULATE THE INFLAMMATION ?
Cytokines have a harmful effect on motoneurones
Cytokines have a harmful effect on motoneurones
YES !
§ Improvement of motor function
§ Increased vitality and general health
§ Decrease of pain and fatigue
§ Avoiding the natural course
§ Avoiding neurodegeneration
Improvement of motor function
Increased vitality and general health
Decrease of pain and fatigue
Avoiding the natural course
Avoiding neurodegeneration
GRIFOLS
PHARMALINK
ASTRAZENECA
GRIFOLS
PHARMALINK
ZENECA
Karolinska Institutet
Div of Rehabilitation Medicine Kristian Borg Lisbet Broman Henrik Gonzalez Giorgios Kaponides Gunilla Östlund
Div of Molecular Medicine Tomas Olsson Mohsen Khademi Magnus Andersson Erik Wallström Fredrik Piehl
Karolinska Institutet
Div of Rehabilitation Medicine
Div of Molecular Medicine
Dept of Psychology, Stockholm University, Stockholm Sweden Åke Wahlin
Dept of Rehabilitation Medicine, Sahlgrenska University Hospital Göteborg, Sweden Katarina StibrandtSunnerhagen
Dept of Rehabilitation Medicine, Uppsala University Hospital, Uppsala, Sweden Inger Sjöberg
AstraZeneca Lund and Södertälje, Sweden Jan Otterwald, Bo Franzén
Dept of Psychology, Stockholm University, Stockholm Sweden
Sahlgrenska University Hospital Göteborg, Sweden
Dept of Rehabilitation Medicine, Uppsala University Hospital, Uppsala, Sweden
AstraZeneca Lund and Södertälje, Sweden
