4steffen gay(2) - Ankara Romatoloji Sempozyumu

4steffen gay(2) - Ankara Romatoloji Sempozyumu

Coxib’s have taught us a lesson to explore more
diligently the molecular and cellular pathways of
inflammation
Steffen Gay
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
Arthritis linked to cardiovascular disease
CV Death
Osteoarthritis
CHF
Rheumatoid Arthritis
CVA
MI
1.0
1.5
Odds Ratio
2.0
Wolfe J Rheumatol 2003
Haara Ann Rheum Dis 2003
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
Rheumatoid Arthritis and Atherosclerosis A tale of two diseases
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
Prognostic impact of endothelial function in
angiographically normal coronary arteries
Schächinger V et al, Circulation 2000
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
Baseline
Acetylcholine
Nitroglycerin
Follow-up (3.7 Years)
V. Schächinger et al, Circulation 101:1899-1906, 2000
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
TNFα-blockade and endothelial function in
patients with Rheumatoid Arthritis
Endothelial Function +
Blood Sampling
0
2
Endothelial Function +
Blood Sampling
6
12 weeks
Infliximab 3 mg/kg
Hürlimann Circ 2002
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
Assessment of endothelial function
flow-mediated vasodilation
HRUSTransducer
Brachial
Artery
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
GTN induced dilatation (%)
Flow mediated dilatation (%)
TNFα-blockade normalizes endothelial function
in Rheumatoid Arthritis
5
4
*
3
2
1
16
12
8
4
0
0
Control
RA
RA
TNF
Control
RA
RA
TNF
Hürlimann Circ 2002
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
Published online before print October 7, 2002
(Circulation 2002, 10.1161/01.CIR.0000037521.71373.44)
Anti-Tumor Necrosis Factor-α Treatment Improves Endothelial Function in
Patients With Rheumatoid Arthritis
David Hürlimann MD, Adrian Forster MD, Georg Noll MD, Frank Enseleit MD, Rémy Chenevard MD,
Oliver Distler MD, Markus Béchir MD, Lukas E. Spieker MD, Michel Neidhart PhD, Beat A. Michel MD,
Renate E. Gay MD, Thomas F. Lüscher MD, Steffen Gay MD, and Frank Ruschitzka MD*
From Cardiology (D.H., G.N., F.E., R.C., M.B., L.E.S., T.F.L.) and Department of Rheumatology and
Institute for Physical Medicine (A.F., O.D., M.N., B.A.M., R.E.G., S.G.), University Hospital, Zürich,
Switzerland.
Methods and Results—Eleven RA patients (mean age 46±5 years; disease duration 9±2 years) with high
disease activity despite treatment with stable doses of methotrexate (≤ 25 mg/wk) and prednisone (≤ 10
mg/d) were investigated. Clinical status and endothelium-dependent and -independent vasodilation of the
brachial artery as assessed by high-resolution ultrasound were measured before and after 12 weeks of
infliximab therapy. Flow-mediated vasodilation improved from 3.2±0.4% to 4.1±0.5% (P=0.018), whereas
endothelium-independent vasodilation with nitroglycerin and baseline diameter remained unchanged
(13.6±1.2% versus 12.8±1.4%, P=0.98, and 3.74±0.15 versus 3.66±0.11 mm, P=0.54, respectively).
Disease activity score (DAS28) was significantly reduced, from 5.6±0.3 to 3.5±0.6 (P=0.002). Erythrocyte
sedimentation rate and C-reactive protein were lowered from 34±7 to 19±5 mm/h (P=0.04) and from 38±11
to 15±10 mg/L (P=0.08), respectively.
Conclusions—This is the first study to show that anti-TNF-α treatment improves
endothelial function in RA. The data suggest that in RA, endothelial dysfunction is part
of the disease process and is mediated by TNF-α.
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
Local Plaque and Thrombus Recovery
Culprit lesion
•
Local sample
•
Maier et al, Circulation 22:111, 2005
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
CD 68
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
TNFa
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
TNFa and the cardiovascular system in RA
thrombus
TNFa
TF h
JNK h
Prothrombin
Thrombin
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
Conclusion
Based on the fact that inhibition of TNFalpha leads to
• improved endothelial dysfunction in cardiovascular
diseases
• that TNFalpha is present in early thrombus formation in
the acute myacardial syndrome (myocardial infarct)
Complete new indications for a TNFalpha targeted therapy
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
Celecoxib reduces tissue factor expression
through JNK-inhibition
Steffel et al, Circulation 2005
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
SP600125, a specific inhibitor of JNK, impairs
TNF-α-induced TF expression
Steffel et al, Circulation 2005
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
JNK and the cardiovascular system in RA
thrombus
TNFa
TF h
JNK h
Prothrombin
Thrombin
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
JNK and the cardiovascular system in RA
TNFa
TF h
Celecoxib
JNK i
Prothrombin
Thrombin
Celecoxib might inhibit JNK and JNK-mediated thrombin formation
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
drug
no drug
mRNA
RNA-Isolation
cDNA
Reverse
Transcription
Microarray
Subtractive Hybridization
down regulated
up regulated
ANKARA ROMATOLOJİ SEMPOZYUMU
“Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
Newsletter Nr. 4 · May 2005
www.rheumaportal.ch
Novel strategies for the development of safer drugs
Steffen Gay
Today we have the molecular tools to explore the mode of action for
drugs on a more comprehensive level than ever before.
Since it is not fully known what the effects of both ligand-receptor
signalling and potential effects on unknown signalling pathways is in the
exposure of a given drug with individual cells in treated patients, it is
imperative to search much more diligently for "early signals", indicating
potentially harmful side effects.
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
Strategies to characterize
differentially expressed genes
Profiling of gene expression
•Subtractive hybridization
Quantitative and qualitative
analysis of gene expression
Functional analysis by
in vitro and in vivo system
•Quantitative PCR
Amplification by PCR
• Gain of function
ectopic overexpression
Cloning
•In situ hybridization
•Immunohistochemistry
• Loss of function
antisense
ribozyme
dominant neg. mutants
siRNA
•DNA microarray
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara
ANKARA ROMATOLOJİ SEMPOZYUMU “Romatoid Artrit Patogenezi”
29 Mart 2006 Sheraton Otel, Ankara