Experience with TNF Antagonists in Rheumatology Practice

Mechanisms of actionEfficacy and safety

Ahmet GülI. U. Istanbul Faculty of MedicineDepartment of Internal MedicineDivision of Rheumatology

Outline Inflammation and TNF TNF antagonists Efficacy in different inflammatory disorders Safety

Disclosure:Honoraria for Scientific Talks and Scientific Meeting Support:

Schering-Plough, Wyeth, AbbottResearch Grants: Schering-PloughAdvisory Board: Abbott, UCB

Inflammatory Disorders

Disease specific Genetic susceptibility Different pathogenetic

mechanisms

Inflammation Local (e.g. joint) Systemic

McInness & Schett. Nature Rev Immunol 2007; 7: 429-42

Rheumatoid Arthritis

Chronic symmetrical polyarthritis

Joint inflammation Pain, swelling, loss of

function, .. Cartilage and bone

destruction

Rheumatoid Arthritis Joint deformities and severe disability

Rheumatoid ArthritisExtra-articular involvement

Rheumatoid Arthritis and Cytokines

McInnes IB, Liew FY. Nature Clin Prac Rheum 2005

Role of TNF in Inflammation Cascade

Monocyte /Macrophage TNF IL-1

ProinflammatoryCytokines

IL-6, IL-8, GM-CSF

Brennan et al. Lancet 1989; 2: 244-7

TNF and Inflammation TNF signaling

Bradley JR. J Pathol 2008; 214: 149-60.

Nat Rev Immunol 2003; 3: 745-56

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

TNF Neutralisation with Monoclonal Antibodies

Makrofaj veya uyarılmış T-hücresi

Hedef hücre

TNFreseptörü

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

TNF Antagonists

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

Anti-TNF Treatment

Rheumatic Disorders

Rheumatoid arthritis Ankylosing spondylitis Psoriasis - Psoriatic arthritis Juvenile idiopathic arthritis Inflamatory bowel disorders

Crohn disease and ulcerative colitis

Anti-TNF Treatments Ankylosing Spondylitis – Efficacy in both spinal and peripheral

disease

Sieper & Rutwaleit. Ann Rheum Dis 2005; 64: iv61-4

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, ...

TNF Antagonists

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

TNF Antagonists

Farmacokinetic features

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

TNF and Inflamation

Blockade of TNF and LT action

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

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

TNF and Inflammation

Wong et al. Clin Immunol 2008; 126: 121-36

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

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 ....

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

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

Anti-TNF and infections

Anti-TNF and infections – BSR Series

Dixon et al. A&R 2006; 54: 2368-76

Anti-TNF and infections

Schneeweiss et al. A&R 2007; 56: 1754-64

Anti-TNF and TB Risk

Jacobs et al. Microbes Infect 2007; 9: 623-8

Anti-TNF and TB Risk

Wallis RS. Arthritis Rheum 2008; 58: 947-52

Anti-TNF and Malignancy

Anti-TNF and Malignancy

Wolfe and Michaud. A&R 2007; 56: 1433-9

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

Anti-TNF and Malignancy

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 ?

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)