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New Therapeutics in Rheumatoid Arthritis

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  1. New Therapeutics in Rheumatoid Arthritis Eulji University Eulji University Hospital Seung-cheol Shim M.D., Ph.D. Division of Rheumatology Eulji University Hospital

  2. How to take care of these ? Eulji University Hospital

  3. Eulji University Hospital

  4. Eulji University Hospital

  5. 보건의료 환경의 변화 의료소비자의 서비스 질에 대한 기대 증대 • 의료소비자의 의식수준, 생활수준향상 • 건강정보의 대중화로 매스컴, 인터넷을 통해 의료정보 습득용이 건강, 질병에 대한 관심고조 양질의 서비스요구 의료기관에서 환자 건의 사례 및 의료분쟁증가 의료소비자 욕구의 다양화 의료수혜자로써의 의식변화 Eulji University Hospital

  6. Eulji University Hospital

  7. Treat what? Eulji University Hospital

  8. Rheumatoid arthritis (RA) is a systemic disorder characterized predominately by a chronic inflammatory polyarthritis, with frequent progression to joint destruction and disability. Eulji University Hospital

  9. Eicosonoid pathway Eulji University Hospital

  10. 류마티스 질환의 치료제 Pyramid therapy Radiographic joint damage develops in 75% of patients within the first 2 years of disease Eulji University Hospital Dimaryp therapy

  11. 류마티스관절염의 진행 Severity (arbitrary units) Eulji University 0 5 10 15 20 25 30 RA Duration of Disease (years) Kirwan et al, J rheumatol, 2001

  12. Needs for developing novel therapy Methotrexate (MTX) remains the first-choice DMARD for the treatment of moderate to severe RA, and is often the anchor drug for combination regimens. Eulji University Hospital Combined use of MTX and a TNF-a inhibitor is among the most potent of treatment regimens, Yet clinical trials of early RA show that this combination produces ACR70 responses of only 35% to 45%

  13. Cell types and cytokines involved in RA pathogenesis as potential targets for treatment with biologic drugs. Eulji University Hospital

  14. Eulji University Hospital

  15. Cytokine targeting Eulji University Hospital

  16. 류마티스관절염에서 싸이토카인의 불균형 Eulji University Hospital

  17. TNF란? Eulji University Hospital

  18. 생물학적제제 • TNF-α • Inflixmab(Remicade) • Etanercept(Enbrel) • Adalimumab(Humira) APC T B Eulji University Hospital

  19. Apoptotic Pathways within the Cell Eulji University Hospital

  20. Eulji University Hospital

  21. Eulji University Hospital Should be balanced

  22. Comparison of ACR20, ACR50, ACR70, and ACR90 responses. Eulji University Hospital

  23. Change in radiographic scores* Eulji University Hospital

  24. Serious infections observed in 0.5% of patients who received at least 1 dose of study drug* Eulji University Hospital

  25. Pharmaceutical companies are developing other TNF-a inhibitors pegylated form of an antibody fragment (certolizumab pegol [CDP-870]) and human anti–TNF-a monoclonal antibody (CNTO 148). Eulji University Hospital

  26. IL- Eulji University Hospital

  27. Anakinra Although the results of randomized, placebo-controlled trials have shown anakinra (recombinant human IL-1 receptor antagonist) to be effective in treating RA, the reduction in signs and symptoms is modest compared with TNF-a blockade. Moreover, IL-1 blockade may not be a useful strategy for treating patients who fail therapy with a TNF-a antagonist. Eulji University Hospital

  28. IL-1-TRAP developed to create a more potent IL-1 blocker. high-affinity inhibitor of IL-1 consisting of the Fc portion of human IgG1 and the extracellular domains of both IL-1 receptor components. However, the results from a phase 2 trial involving 201 patients who had RA show that weekly subcutaneous administration of IL-1 TRAP produces only modest clinical improvements compared with placebo. Eulji University Hospital

  29. Efficacy of combined biologic agents Eulji University Hospital

  30. Serious adverse events that occurred during the study* Eulji University Hospital

  31. Anakinra in AOSD Anakinra in adult-onset Still’s disease who are refractory to corticosteroids, methotrexate, and TNF-a blockade Eulji University Hospital

  32. Proposed cytokine cascades in AOSD. Eulji University Hospital

  33. IL- Eulji University Hospital

  34. Pleiotropic action of IL-6 Eulji University Hospital

  35. Role of interleukin-6 (IL-6) in murine models of arthritis* Eulji University Hospital

  36. Eulji University Hospital

  37. recombinant,humanized, monoclonal antibody against the IL-6 receptor (MRA, tocilizumab). Eulji University Hospital

  38. Adverse events observed in at least 3% of patients* Eulji University Hospital

  39. Increase level of cholesterol in the patients on tocilizumab Eulji University Hospital

  40. IL- Eulji University Hospital

  41. IL-15 is a proinflammatory cytokine produced in rheumatoid synovium by macrophages, fibroblasts, and endothelial cells. essential for the development of natural killer (NK) cells, NK T cells, and intraepithelial lymphocytes, and the proliferation and maintenance of CD8+ memory T cells Eulji University Hospital

  42. Clinical responses to anti–IL-15 antibody in RA patients* human IgG1 anti–IL-15 monoclonal antibody (HuMax-IL-15, AMG714) Eulji University Hospital

  43. IL-15 binds to the heterotrimeric, high-affinity IL-15 receptor (IL-15R), which consists of the α-subunit (IL-15R α), IL-2/IL-15β-subunit, and common γ-chain (γc). IL-15 alone binds with high affinity to IL-15R α; it shares the common γc-subunit with IL-2, IL-4, IL-7, IL-9, and IL-21 Eulji University Hospital

  44. IL- Eulji University Hospital

  45. IL-12 A heterodimer consisting of a p40 and p35 subunit, critically involved in the development of Th1 immune responses. RA is often assumed to be a Th1-mediated disease process. Eulji University Hospital

  46. Signals that Influence Th Cell Differentiation Eulji University Hospital

  47. Currently, a monoclonal antibody to human IL-12 p40 subunit is in early clinical development. Results are available from a phase 1 study using this antibody in patients who had psoriasis, but not yet for studies of RA. Eulji University Hospital

  48. IL- Eulji University Hospital

  49. IL-18 a member of the IL-1 family of cytokines, was initially discovered based on its interferon-γ–inducing activity, and is produced by macrophages and dendritic cells. IL-18 is a Th1 cytokine, and can induce the synthesis of proinflammatory cytokines and chemokines Eulji University Hospital

  50. Phylogenetic tree of IL-1 family amino acid sequences. Eulji University Hospital