Aims of talk

1. Aims of talk RA is a serious disease Convince you that it is driven by T-cells Cyclosporin first �proof of concept� of the T-cell hypothesis Developments since Cyclosporin

2. Synopsis of talk What is rheumatoid arthritis Pathogenesis of the synovitis Mechanism of bone damage CsA as model of T-cell directed therapy Era of biologicals

3. Rheumatoid arthritis Chronic inflammatory symmetrical polyarthritis Damages joints irreversibly 3F:1M Prevalence 0.5-1% Rheumatoid factor positive

4. RA �aetiology & pathogenesis Environment Proven: Smoking Unproven Infection Dietary Stress Autoimmunity: RF, anti-CCP Genetics HLA-DR4 PTPN22

5. Consequences of RA Premature mortality Increased morbidity Significant impact on quality of life Pain with associated functional disability Fatigue, 81% of patients; 41% with severe fatigue Depression Work disability 25% within 7 years of onset, 50% within 21 years 33% reduction in income vs non work-disabled Consequences of RA RA has severe consequences including premature mortality and increased morbidity.2 RA has a high negative impact on quality of life with disease-associated pain resulting in significant functional disability.1 In addition, 81% of patients with RA report fatigue and 41% experience extreme fatigue.1 RA is also associated with depression and changes in family structure. 1 Work disability is the highest indirect cost of RA. Early treatment can prevent or delay work disability. Self-reporting questionnaires can be used to identify those at high risk for work disability.1 1. Wolfe F, Hawley DJ. Work disability in Rheumatoid Arthritis. Journal of Rheumatology. 1998; 25:2108-2117. 2. Wolfe F, Mitchell DM, Sibley ST, et al. The mortality of rheumatoid arthritis. Arthritis Rheum. 1994; 37:481-494.Consequences of RA RA has severe consequences including premature mortality and increased morbidity.2 RA has a high negative impact on quality of life with disease-associated pain resulting in significant functional disability.1 In addition, 81% of patients with RA report fatigue and 41% experience extreme fatigue.1 RA is also associated with depression and changes in family structure. 1 Work disability is the highest indirect cost of RA. Early treatment can prevent or delay work disability. Self-reporting questionnaires can be used to identify those at high risk for work disability.1 1. Wolfe F, Hawley DJ. Work disability in Rheumatoid Arthritis. Journal of Rheumatology. 1998; 25:2108-2117. 2. Wolfe F, Mitchell DM, Sibley ST, et al. The mortality of rheumatoid arthritis. Arthritis Rheum. 1994; 37:481-494.

6. Economic Burden in Europe In West Germany, RA costs were >DM 40 billion (US $17.6 billion) in 1994 for treatment alone In the UK, average RA outpatient cost per case per year was �798 (US $1,126) and �1,253 (US $1,769) per inpatient in 1997 Rheumatoid arthritis per capita costs average: 49% of cost of cancer 68% of cost of stroke 82% of cost of coronary heart disease 5 times the cost of motor vehicle accidents RA has a negative impact on society and imposes a significant economic burden. It accounts for 1% to 2.5% of Germany�s gross national product (GNP). In West Germany alone, more than 40 billion DM (US $17.6 billion) were spent on the care and treatment of those suffering with RA in 1994. Costs for inpatient care (per admission) and rehabilitation are higher than those for comparable care provided on an outpatient basis. In the UK, the average outpatient cost per case of RA per year was �798 (US $1,126) in 1997, compared with the inpatient cost per case per year of �1,253 (US $1,769). The demand for total joint replacement increases as surgical techniques are perfected and the population ages. When a total knee or hip replacement is needed, the cost per case of RA increases by $24,083. The costs of RA are comparable to those of other chronic diseases. Overall, RA per capita costs average 49% of the cost of cancer, 68% of the cost of stroke, 82% of the cost of coronary heart disease, and 5 times the cost of motor vehicle accidents.RA has a negative impact on society and imposes a significant economic burden. It accounts for 1% to 2.5% of Germany�s gross national product (GNP). In West Germany alone, more than 40 billion DM (US $17.6 billion) were spent on the care and treatment of those suffering with RA in 1994. Costs for inpatient care (per admission) and rehabilitation are higher than those for comparable care provided on an outpatient basis. In the UK, the average outpatient cost per case of RA per year was �798 (US $1,126) in 1997, compared with the inpatient cost per case per year of �1,253 (US $1,769). The demand for total joint replacement increases as surgical techniques are perfected and the population ages. When a total knee or hip replacement is needed, the cost per case of RA increases by $24,083. The costs of RA are comparable to those of other chronic diseases. Overall, RA per capita costs average 49% of the cost of cancer, 68% of the cost of stroke, 82% of the cost of coronary heart disease, and 5 times the cost of motor vehicle accidents.

7. Indirect Productivity Costs of RA Sweden: 37% retired early after the first 2 years of RA Finland: 64% retired after 8 years The Netherlands: 60% were not employed 73% full disability from RA 21% partial disability from RA Dr. Wong: source(s)Dr. Wong: source(s)

8. Synopsis of talk What is rheumatoid arthritis Pathogenesis synovitis Mechanism of bone damage CsA as model of T-cell directed therapy Era of biologicals

9. The pathogenesis of rheumatoid arthritis

10. Pathogenesis

11. These 4 photo-micrographs show the presence of tumour necrosis factor alpha, granulocyte macrophage-colony stimulating factor, interleukin-1 and interleukin 17 in biopsies of rheumatoid synovial membrane. It is these observations that have led to the use of biologics for treatment by inhibiting some of these inflammatory cytokines. No doubt in the future therapies directed against all of them will be attempted.These 4 photo-micrographs show the presence of tumour necrosis factor alpha, granulocyte macrophage-colony stimulating factor, interleukin-1 and interleukin 17 in biopsies of rheumatoid synovial membrane. It is these observations that have led to the use of biologics for treatment by inhibiting some of these inflammatory cytokines. No doubt in the future therapies directed against all of them will be attempted.

12. RA- pathogenesis: the players Macrophages T cells Synovial fibroblasts B cells

15. T cells and target cells Interferon g Cell-to-cell interction RANK-L: activates osteoclasts IL-17: activates osteoclasts activates other target cells

16. RA Pathogenesis: mediators Macrophages: TNFa, IL-1, IL-6, GM-CSF, reactive oxygen species, prostaglandins B cells: RF, anti-citrulline antibodies, other auto-antibodies Synovial fibroblasts: enzymes (collagenases, stromelysin)

17. Synopsis of talk What is rheumatoid arthritis Pathogenesis synovitis Mechanism of bone damage CsA as model of T-cell directed therapy Era of biologicals

18. Pathogenesis: bone damage

20. Synopsis of talk What is rheumatoid arthritis Pathogenesis synovitis Mechanism of bone damage CsA as model of T-cell directed therapy Era of biologicals

21. CsA: Mode of action

22. CsA: Immunological Effects

23. Clinical efficacy of cyclosporin in severe RA

24. Cyclosporin slows joint damage

25. Developments from success CsA Leflunomide (arava) Inhibition T-cell co-stimulation (biologics)

26. Leflunomide Blocks T Cell Clonal Expansion

27. Synopsis of talk What is rheumatoid arthritis Pathogenesis synovitis Mechanism of bone damage CsA as model of T-cell directed therapy Era of biologicals

28. RA pathogenesis: the outcome of clinical trials Anti-Cytokines: Tumour necrosis factor a: in the clinic Interleukin 1: very weak effect, in the clinic Interleukin 6: on trial Anti-B cells: Rituximab: in the clinic Anti-T cells Leflunomide, cyclosporin A Abatacept (CTLA4.Ig): in the clinic Anti-CD4: under trial

29. STRUCTURE OF ETANERCEPT This cartoon is a schematic representation of recombinant human TNF receptor (p75) Fc fusion protein (TNFR:Fc). It consists of two molecules of the extracellular domain of p75 TNFR linked to the Fc region of human IgG1. Because of its bivalent nature, TNFR:Fc is an effective competitive inhibitor of TNF binding to cell surface receptors. The monomeric form has a half life of 4hours and the same binding affinity as soluble TNF receptors. Dimerisation increases the half life to 19 hours and the relative binding affinity to 1000. This cartoon is a schematic representation of recombinant human TNF receptor (p75) Fc fusion protein (TNFR:Fc). It consists of two molecules of the extracellular domain of p75 TNFR linked to the Fc region of human IgG1. Because of its bivalent nature, TNFR:Fc is an effective competitive inhibitor of TNF binding to cell surface receptors. The monomeric form has a half life of 4hours and the same binding affinity as soluble TNF receptors. Dimerisation increases the half life to 19 hours and the relative binding affinity to 1000.

30. Overall responses (25mg twice weekly)

31. Monoclonal Anti-TNF-? Antibodies

32. Infliximab + MTX (ATTRACT):ACR Responses at 30 and 54 Weeks Slide 21. Infliximab + Methotrexate (ATTRACT): ACR Responses at 30 and 54 Weeks International, double-blind, placebo-controlled Phase III clinical trial of infliximab in 428 patients with RA who had received continuous methotrexate (MTX) for at least 3 months and then had infliximab (3 or 10 mg/kg injected every 4 or 8 weeks). At 30 weeks, ACR 20% response was achieved in 50%, 53%, 52%, and 58% of patients receiving 3 mg/kg every 8 or 4 weeks or 10 mg/kg every 8 or 4 weeks, respectively, compared with 20% of patients receiving placebo plus MTX. The ACR 20% response rates at 54 weeks were 42%, 48%, 59%, and 59%, respectively, for patients administered infliximab vs 17% of patients on placebo. ACR 50% response was achieved in 29%, 27%, 26%, and 31% of those in the same infliximab plus MTX treatment groups, compared with 5% of patients on placebo plus MTX. Corresponding ACR 50% response rates at 54 weeks were 21%, 34%, 39%, and 38%, respectively, vs 8% for placebo. Corresponding ACR 70% response rates at 54 weeks were 10%, 17%, 25%, and 19% vs 2% for placebo. References: 1. Maini R, St. Clair EW, Breedveld F, et al. Lancet. 1999;354:1932-9; 2. Lipsky PE, van der Heijde DM, St. Clair EW, et al. N Engl J Med. 2000;343:1594-1602.Slide 21. Infliximab + Methotrexate (ATTRACT): ACR Responses at 30 and 54 Weeks International, double-blind, placebo-controlled Phase III clinical trial of infliximab in 428 patients with RA who had received continuous methotrexate (MTX) for at least 3 months and then had infliximab (3 or 10 mg/kg injected every 4 or 8 weeks). At 30 weeks, ACR 20% response was achieved in 50%, 53%, 52%, and 58% of patients receiving 3 mg/kg every 8 or 4 weeks or 10 mg/kg every 8 or 4 weeks, respectively, compared with 20% of patients receiving placebo plus MTX. The ACR 20% response rates at 54 weeks were 42%, 48%, 59%, and 59%, respectively, for patients administered infliximab vs 17% of patients on placebo. ACR 50% response was achieved in 29%, 27%, 26%, and 31% of those in the same infliximab plus MTX treatment groups, compared with 5% of patients on placebo plus MTX. Corresponding ACR 50% response rates at 54 weeks were 21%, 34%, 39%, and 38%, respectively, vs 8% for placebo. Corresponding ACR 70% response rates at 54 weeks were 10%, 17%, 25%, and 19% vs 2% for placebo. References: 1. Maini R, St. Clair EW, Breedveld F, et al. Lancet. 1999;354:1932-9; 2. Lipsky PE, van der Heijde DM, St. Clair EW, et al. N Engl J Med. 2000;343:1594-1602.

33. Adalimumab gives sustained improvements in signs & symptoms of RA at 1 year and 3 years

34. Adalimumab inhibits radiographic progression at 1 year & 3 years Here�s where we talk about how big and robust a program we hadHere�s where we talk about how big and robust a program we had

35. RA pathogenesis: the outcome of clinical trials Anti-Cytokines: Tumour necrosis factor a: in the clinic Interleukin 1: very weak effect, in the clinic Interleukin 6: on trial Anti-B cells: Rituximab: in the clinic Anti-T cells Leflunomide, cyclosporin A Abatacept (CTLA4.Ig): in the clinic Anti-CD4: under trial

36. Rituximab: Disease Activity Scores

37. Median CD19 (Up to Week 24)

38. Mean Total Immunoglobulins (IgG/A/M)

39. Median Changes in RF (Total)

40. What are predictors of rituximab response? Not related to fall in Ig�s Not related to fall in RF Not related to duration of B-cell depletion ? Indirect effect on T-cells?

42. RA pathogenesis: the outcome of clinical trials Cytokines: Tumour necrosis factor a: in the clinic Interleukin 1: very weak effect Interleukin 6: on trial B cells: Rituximab: in the clinic T cells Leflunomide, cyclosporin A Abatacept (CTLA4.Ig): in the clinic Anti-CD4: under trial

43. 2-signals required for T-cell activation

44. CTLA4 and regulation of T-cell activation

45. Structure of Abatecept

46. Mechanism abatacept therapy

47. Clinical efficacy inhibition of T-cell activation with abatacept

48. RA pathogenesis: the outcome of clinical trials Cytokines: Tumour necrosis factor a: in the clinic Interleukin 1: very weak effect Interleukin 6: on trial B cells: Rituximab: in the clinic T cells Leflunomide, cyclosporin A Abatacept (CTLA4.Ig): in the clinic Anti-CD4: under trial

49. Role of CD4 in costimulation

50. Lymphokines/chemokines produced by RA synovial membrane T cells interleukin 2 interferon g interleukin 6 IL-8: chemotactic for PMN MCP-1: chemotactic for macrophages