Coxib s have taught us a lesson to explore more diligently the molecular and cellular pathways of inflammation

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1 Coxib s have taught us a lesson to explore more diligently the molecular and cellular pathways of inflammation Steffen Gay

2 Arthritis linked to cardiovascular disease CV Death Osteoarthritis CHF Rheumatoid Arthritis CVA MI Odds Ratio Wolfe J Rheumatol 2003 Haara Ann Rheum Dis 2003

3 Rheumatoid Arthritis and Atherosclerosis - A tale of two diseases

4 Prognostic impact of endothelial function in angiographically normal coronary arteries Schächinger V et al, Circulation 2000

5 Baseline Acetylcholine Nitroglycerin Follow-up (3.7 Years) V. Schächinger et al, Circulation 101: , 2000

6 TNFα-blockade and endothelial function in patients with Rheumatoid Arthritis Endothelial Function + Blood Sampling Endothelial Function + Blood Sampling weeks Infliximab 3 mg/kg Hürlimann Circ 2002

Blood Sampling Endothelial Function + Blood

7 HRUS- Transducer Brachial Artery Assessment of endothelial function flow-mediated vasodilation

8 TNFα-blockade normalizes endothelial function in Rheumatoid Arthritis Flow mediated dilatation (%) * GTN induced dilatation (%)16 0 Control RA RA TNF 0 Control RA RA TNF Hürlimann Circ 2002

4 3 2 1 * 12 8 4 GTN induced dilatation (%)16 0

9 Published online before print October 7, 2002 (Circulation 2002, /01.CIR ) Anti-Tumor Necrosis Factor-a 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-a 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-a.

MD, Oliver Distler MD, Markus Béchir MD, Lukas E. Spieker MD, Michel Neidhart PhD, Beat A. Michel MD, Renate E. Gay MD, Thomas F.

10 Local Plaque and Thrombus Recovery Culprit lesion Local sample Maier et al, Circulation 22:111, 2005

11 CD 68

12 TNFa

13 TNFa and the cardiovascular system in RA thrombus TNFa TF h JNK h Prothrombin Thrombin

14 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

TNFalpha is present in early thrombus formation in the acute myacardial

15 Celecoxib reduces tissue factor expression through JNK-inhibition Steffel et al, Circulation 2005

16 SP600125, a specific inhibitor of JNK, impairs TNF-α-induced TF expression Steffel et al, Circulation 2005

17 JNK and the cardiovascular system in RA thrombus TNFa TF h JNK h Prothrombin Thrombin

18 JNK and the cardiovascular system in RA TNFa TF h JNK i Celecoxib Prothrombin Thrombin Celecoxib might inhibit JNK and JNK-mediated thrombin formation

19 no drug drug mrna RNA-Isolation Reverse Transcription cdna Microarray Subtractive Hybridization down regulated up regulated ANKARA ROMATOLOJİ SEMPOZYUMU Romatoid Artrit Patogenezi

20 Newsletter Nr. 4 May 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.

drugs on a more comprehensive level than ever before.

21 Strategies to characterize differentially expressed genes Profiling of gene expression Subtractive hybridization Amplification by PCR Quantitative and qualitative analysis of gene expression Quantitative PCR Functional analysis by in vitro and in vivo system Gain of function ectopic overexpression Cloning In situ hybridization Immunohistochemistry Loss of function antisense ribozyme dominant neg. mutants sirna DNA microarray

New Evidence reports on presentations given at EULAR 2012. Rituximab for the Treatment of Rheumatoid Arthritis

New Evidence reports on presentations given at EULAR 2012 Rituximab for the Treatment of Rheumatoid Arthritis Report on EULAR 2012 presentations Long-term safety of rituximab: 10-year follow-up in the