Ahmet Gül I. U. Istanbul Faculty of Medicine Department of Internal Medicine

1. Experience with TNF Antagonists in Rheumatology PracticeMechanisms of action Efficacy and safety Ahmet Gül I. U. Istanbul Faculty of Medicine Department of Internal Medicine Division of Rheumatology

2. Outline • Inflammation and TNF • TNF antagonists • Efficacy in different inflammatory disorders • Safety Disclosure: Honoraria for Scientific Talks and Scientific Meeting Support: Schering-Plough, Wyeth, Abbott Research Grants: Schering-Plough Advisory Board: Abbott, UCB

3. Inflammatory Disorders • Disease specific • Genetic susceptibility • Different pathogenetic mechanisms • Inflammation • Local (e.g. joint) • Systemic McInness & Schett. Nature Rev Immunol 2007; 7: 429-42

4. Rheumatoid Arthritis • Chronic symmetrical polyarthritis • Joint inflammation • Pain, swelling, loss of function, .. • Cartilage and bone destruction

5. Rheumatoid Arthritis • Joint deformities and severe disability

6. Rheumatoid ArthritisExtra-articular involvement

7. Rheumatoid Arthritis and Cytokines McInnes IB, Liew FY. Nature Clin Prac Rheum 2005

8. Role of TNF in Inflammation Cascade Monocyte / Macrophage IL-1 TNF Proinflammatory Cytokines IL-6, IL-8, GM-CSF Brennan et al. Lancet 1989; 2: 244-7

9. TNF and Inflammation • TNF signaling Bradley JR. J Pathol 2008; 214: 149-60.

10. Nat Rev Immunol 2003; 3: 745-56

11. Tracey et al. Pharmacol Ther 2008; 117: 244-79

12. TNF Neutralisation with Monoclonal Antibodies Makrofajveyauyarılmış T-hücresi TNF reseptörü Hedef hücre

13. Rheumatoid Arthritis - Efficacy • Improvement of clinical and laboratory findings of RA with anti -TNF treatments • Fast acting and sustained efficacy of anti-TNF drugs in RA patients resistant to standard treatments • Prevention of radiologic progression (erosion / structural damage) • Prevention of functional loss and improvement in quality of life

14. TNF Antagonists Tracey et al. Pharmacol Ther 2008; 117: 244-79

15. Anti-TNF Treatment • Rheumatic Disorders • Rheumatoid arthritis • Ankylosing spondylitis • Psoriasis - Psoriatic arthritis • Juvenile idiopathic arthritis • Inflamatory bowel disorders • Crohn disease and ulcerative colitis

16. Anti-TNF Treatments • Ankylosing Spondylitis – Efficacy in both spinal and peripheral disease Sieper & Rutwaleit. Ann Rheum Dis 2005; 64: iv61-4

17. Anti-TNF Treatment • Off-label experience • Behçet disease (resistant uveitis) • Sarcoidosis • Pyoderma gangrenosum • TRAPS (autoinflammatory disorders) • Adult Still disease, dermatomyositis, SAPHO, chronic HCV hepatitis, amyloidosis, ...

18. TNF Antagonists Tracey et al. Pharmacol Ther 2008; 117: 244-79

19. TNF Antagonists • Farmacokinetic features Tracey et al. Pharmacol Ther 2008; 117: 244-79

20. TNF and Inflamation • Blockade of TNF and LT action Tracey et al. Pharmacol Ther 2008; 117: 244-79

21. TNF and Inflammation • Transmembrane TNF • Apoptosis • Reverse signaling • Suppression of proinflammatory cytokines • Complement dependent cytotoxicity • Antibody dependent cytotoxicity Tracey et al. Pharmacol Ther 2008; 117: 244-79

22. TNF and Inflammation Wong et al. Clin Immunol 2008; 126: 121-36

23. Treatment with TNF Antagonists • Differences in Efficacy • Monoclonal antibody x Receptor fusion protein • Blockade of transmembrane or soluble TNF • Blockade of TNF or LT • Farmacokinetics • Monoclonal antibodies • Chimeric, humanized or fully human • Farmacokinetics • Crohn disease – No efficacy with etanercept

24. Treatment with TNF Antagonists • Overall efficacy • 50-70% response • Heterogenous patient groups, different patogenetic mechanisms, etc. • Other treatment targets • CD20 • IL-1 • IL-6 • CTLA-4 • ....

25. TNF Antagonists and Safety • Adverse events resulting from antigenic structure of drugs • Development of antibodies, infüsion reactions, delayed type hypersensitivity, injection site reactions • Adverse events due to immune suppression • Infections • Demyelinating CNS disease • Lupus-like disorder • Hematologic adverse events • Malignancy

26. Anti-TNF and infections • Infectious disease • Not serious • Serious infections (hospitalization) • Tuberculosis • Viral infections (HBV, HCV) • Opportunistic infections • Increased risk for non-serious infections (~2) • Controversial data for serious infections

27. Anti-TNF and infections – BSR Series Dixon et al. A&R 2006; 54: 2368-76

28. Anti-TNF and infections Schneeweiss et al. A&R 2007; 56: 1754-64

29. Anti-TNF and TB Risk Jacobs et al. Microbes Infect 2007; 9: 623-8

30. Anti-TNF and TB Risk Wallis RS. Arthritis Rheum 2008; 58: 947-52

31. Anti-TNF and Malignancy

32. Anti-TNF and Malignancy Wolfe and Michaud. A&R 2007; 56: 1433-9

33. Anti-TNF and Malignancy • There may be a small increase in the risk of malignancy. However, this risk is associated with various factors: • Underlying disorder • Disease activity, severity and duration • Other drugs used for the treatment • Dosage and duration of anti-TNF treatment • Response to anti-TNF drugs

34. Other Adverse Events • Congestive heart failure (NYHA stage III-IV) • Aplastic anemia and pancytopenia • Vasculitis, type III hypersensitivity • Demyelinating disorders • Injection site and infusion reactions • Development of autoantibodies • ANA, anti-DNA, aCL, anti-histon • Cutaneous lesions ? • Deterioration of ILD ?

35. Anti-TNF Treatments • Postmarketing observations supports the efficacy and safety of anti-TNF drugs in many immune mediated inflammatory disorders • We need more data on the risk of infections and malignancy for better management plans • Methodological problems with the current data • National databases • Education of patients and doctors • Other risk factors (corticosteroids, other immunosuppressive drugs)