Advances in Rheumatoid Arthritis (RA) treatment

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Advances in Rheumatoid Arthritis (RA) treatment

  1. 1. 魏正宗 James C. WEI, MD, PhD. 中山醫學大學附設醫院過敏免疫風濕科
  2. 2. Chief, Division of Allergy, Immunology and Rheumatology Director, Chinese Medicine Clinical Trial Center Associate professor, Institute of Medicine, Chung Shan Medical University. Clinical Trials Experience 2010.Oct. FDA GCP SITE INSPECTION PASSED 2012.Aug. TFDA (Taiwan) GCP SITE INSPECTION PASSED **World top one enroller in -Norvatis RHAK study in ankylosing spondylitis. -Pfizer Etanercept study in non-radiographic axial spondyloarthritis. * *Taiwan top one enroller in -BMS abatacept study in rheumatoid arthritis -UCB anti-IL6 in rheumatoid arthritis -MSD Etoricoxib in ankylosing spondylitis -TWi Biotechnology, Inc. IL-1 receptor antagonist in gouty arthritis
  3. 3. Pathogenesis of RA  Traditional therapies  Immune target therapies  Biological agents  Small molecules  Summary & Take home message 
  4. 4. Pathogenesis of RA  Traditional therapies  Immune target therapies  Biological agents  Small molecules  Summary & Take home message 
  5. 5. Prevalence: 0.4~1%  A prototype of autoimmune chronic inflammatory arthritis.  Lifelong, progressive damage to joints and bone.  Market of Humira & Enbrel are top 1 and 2 in the world. 
  6. 6. Courtesy of J. Cush, 2002.
  7. 7. Overview of Immunity -Cellular -Humoral -Innate Macrophage Monocyte Neutrophil Eosinophil… -Acquired B cell T cell Dendritic cell…
  8. 8. Pathogenesis of Rheumatoid Arthritis
  9. 9. Pathogenesis of RA  Traditional therapies  Immune target therapies  Biological agents  Small molecules  Summary & Take home message 
  10. 10. 新的消炎止痛藥 --COX-2抑制劑-- 如 meloxicam (Mobic骨敏捷), celecoxib (Celebrex希樂葆), etoricoxib (Arcoxia萬克適) 已證實效果與傳統的消炎藥相當且較不傷 胃。  消炎藥併用止痛劑(如acetamenophen, tramadol, ultracet及通安)及肌肉鬆弛劑, 有很好的加成效果。 
  11. 11. 1. 2. 3. 4. 5. Hydroxyclhoroquine (Plaquenil, Genuquine) 奎寧、必賴克廔 Methotrexate (MTX) 滅殺除癌 , 治善錠 Sulfasalazine (Salazopyrin) 斯樂, 撒樂 Leflunomide (Arava, Arheuma) 亞努麻 Cyclosporin (Neoral) 環孢靈,新體睦
  12. 12. 足夠劑量(一般每天400毫克)的奎寧 是治療紅斑狼瘡最基本的藥  最沒有副作用的免疫調節劑  還有降血脂、抗血栓、增加骨質、降 血糖等附帶好處。 
  13. 13. 適應症:風濕性關節炎、牛皮癬或其他自 體免疫相關疾病。亦可治療癌症。  每周4-6顆:使用方式為每周固定一日早餐後 服用2顆,晚餐後再服2顆,隔日早餐後再 服2顆。  副作用:口腔炎、白血球減少、血小板缺 少、噁心、肝炎  用藥期間須特別監測血液功能。 
  14. 14. 主治:潰瘍性結腸炎,僵直性脊椎 炎,類風濕性關節炎。  副作用:頭痛、食慾不振、腹痛、 皮膚紅疹、蕁痲疹。多於停藥後可 恢復。  早晚各兩顆 
  15. 15. 治療類風濕性關節炎、乾癬關節炎  用於Methotrexate治療無效,或無法忍 受Methotrexate副作用時使用。  可能副作用:腹痛、噁心、腹瀉、影 響肝功能、貧血、白血球減少、皮膚 疹、高血壓、感染、掉髮。 
  16. 16. Pathogenesis of RA  Traditional therapies  Immune target therapies  Biological agents  Small molecules  Summary & Take home message 
  17. 17.   Aiming molecular target Receptor / Ligand Signaling pathway Complex biotechnology Biological agent生物製劑 Small molecule小分子藥物
  18. 18. Normal Interaction Neutralization of Cytokines Inflammatory Cytokine Monoclonal Antibody Cytokine Receptor Soluble Receptor Inflammatory Signal No Signal Activation of Receptor Blockade Anti-inflammatory Pathways Monoclonal Antibody Receptor Antagonist Antiinflammatory Cytokine Block signaling No Signal Choy EHS, Panayi GS. N Engl J Med. 2001;344:907–916.
  19. 19. -cept : fusion of a receptor  -mab : a monoclonal antibody (mAb)  -ximab: a chimeric mAb  -zumab : a humanized mAb  -tinib: tyrosine kinase inhibitors 
  20. 20. Biological agents T cell modulation CTLA4/CD28 anti-CD2 anti-CD11a B cell modulation anti-CD20 anti-BAFF Cytokines inhibition anti-TNF anti-IL6 anti-IL1 anti-IL12/23 anti-RANKL
  21. 21. Etanercept(商品名Enbrel恩博)是一種 由中國倉鼠卵巢細胞組織培養而來的對 抗腫瘤壞死因子的融合蛋白,需皮下注 射,每周兩次。  Adalimumab(商品名Humira復邁)是一 種全人的腫瘤壞死因子的單株抗體,皮 下注射,每兩周一次。  Golimumab(商品名Simponi辛普尼), 是一種全人的腫瘤壞死因子的單株抗體, 皮下注射每四週一次即可。 
  22. 22. 目前第一線生物製劑  目前健保給付於嚴重頑固型之類風溼 性關節炎、僵直性脊椎炎、乾癬、乾 癬關節炎、發炎性大腸疾病。  需事先報健保局審查。   70-90%的病患可以有明顯的進步。
  23. 23.   發燒、倦怠、頭痛、背痛,輕微上呼吸道感染, 打針處發生皮膚疹或細菌感染。 最需要注意是可能造成肺結核的復發或擴散。發 生率大約是每100,000的病人當中24個,相當於正 常人的3倍左右。    B肝復發機率15-60%。   Baseline screening for TB Monitor Quantiferon q6m Close monitor or Preemptive anti-viral agents 長期使用,人體會產生對抗該藥物之抗體。
  24. 24. Mode of Action of Tocilizumab [soluble IL-6 receptor (sIL-6R)] Tocilizumab IL-6 [membrane bound IL-6 receptor (IL-6R)] Outer cellular gp130 Cell membrane Intra cellular × Signal transduction
  25. 25. 個 疼痛關節數逐 漸減少 CRP, C反應蛋白 疼 痛 的 關 節 數 量 週
  26. 26. 是一種IL-6單株抗體  適應症為類風濕性關節炎  靜脈輸注,每月一次。  可以幫助60-80%的患者症狀進步及減少關 節破壞,30%以上的患者達成疾病緩解,也 能改善患者的貧血及疲倦症狀及生活品質。  是目前唯一單一療法與合併DMARD或MTX 治療臨床療效相當生物製劑 
  27. 27. IL-17為更專一性造成發炎的細胞 激素之ㄧ  為學術研究的熱門主題  每四週皮下注射一次  目前正進行類風濕性關節炎及僵直 性脊椎炎臨床試驗。 
  28. 28. Biological agents T cell modulation CTLA4/CD28 anti-CD2 anti-CD11a B cell modulation anti-CD20 anti-BAFF Cytokines inhibition anti-TNF anti-IL6 anti-IL1 anti-IL12/23 anti-RANKL
  29. 29. B cell development Antigen-independent phase Surrogate light chain Stem cell Pro-B cell Pre-B cell IgM Immature B cell Antigen-dependent phase IgM IgD Mature B cell IgM, IgD, IgA, or IgE Activated B cell CD19 CD20 Adapted from Sell et al. Immunology, Immunopathology, and Immunity. 6th ed. 2001; Roitt et al. Immunology. 6th ed. 2001; Tedder et al. J Immunol 1985;135:973. Secreted IgG, IgA, IgE, or IgM Plasma cell
  30. 30. Rituximab(anti-CD20) in RA Edwards et al. Engl J Med. 2004 Jun 17;350(25):2572-81. 80 70 60 50 ACR 20 ACR 50 ACR 70 40 30 20 10 0 MTX control Ritux only Ritux + Ritux + CTX MTX • 1000 mg at Day 1&15, q6m • Better response in RF+ or CCP+ pts • TNF-IR RA • Combine with MTX
  31. 31.       是一種抗CD20單株抗体之抗B細胞療法 用來治療淋巴瘤;類風溼性關節炎,也對紅斑狼 瘡、乾燥症、血管炎等有效。 使用方法為靜脈輸注,劑量為每次 500-1000毫 克,間隔 14 天再次輸注 , 共 2 次為一個療程。 通常治療效果於靜脈注射後二個月出現,療效可 以持續6到9個月。 健保給付:限TNF抑制劑無效之類風濕性關節炎。 費用約需每年16-32萬元。
  32. 32. Potential use of Rituximab • Systemic lupus erythematosus • Idiopathic thrombocytopenic purpura • Multiple sclerosis • Cold agglutinin disease • Autoimmune hemolytic anemia • Antineutrophil cytoplasmic antibody— associated vasculitis • Cryoglobulinemia • Thrombotic thrombocytopenic purpura • Sjögren's syndrome • IgM mediated neuropathy • Pemphigus vulgaris • Grave's disease • Dermatomyositis • Neuromyelitis optica • Idiopathic membranous nephropathy
  33. 33. Infusion-related reactions  Anaphylaxis/angioedema  More severe  Lymphopenia (40%)  Neutropenia (6%)  Leukopenia (4%)  Hepatitis B!  Sepsis (2%) 
  34. 34. Belimumab, Benlysta Human genomic science, GSK First biologics for SLE MoAb of soluble BLyS
  35. 35.  是一種『B淋巴球刺激因子單株抗體』 (anti-BLyS) 已經在歐美上市,適應症是紅斑狼瘡 (SLE)  50年來第一個核可治療紅斑狼瘡的新藥。  另兩個類似機轉的藥正進行紅斑狼瘡臨 床試驗中。 
  36. 36. Biological agents T cell modulation CTLA4/CD28 anti-CD2 anti-CD11a B cell modulation anti-CD20 anti-BAFF Cytokines inhibition anti-TNF anti-IL6 anti-IL1 anti-IL12/23 anti-RANKL
  37. 37. Co-stimulatory Pathways APC There are several co-stimulatory and co-inhibitory pathways; signals through these pathways can either upregulate or downregulate T-cell activation + – + T cell –
  38. 38. CTLA4Ig (Abatacept, Orencia) Reduction of joint inflammation
  39. 39. Sustained ACR Responses Through 5 Years Double-blind Open-label LTE 100 % of Patients Achieving ACR Response 90 82% 84% 80 70 54% 61% 32% 60 40% 50 40 30 20 ACR 20 10 ACR 50 ACR 70 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Year 0.5 (n) Year 1 (n) Year 1.5 (n) Year 2 (n) Year 2.5 (n) Year 3 (n) Year 3.5 (n) Year 4 (n) Year 4.5 (n) Year 5 (n) ACR 20 371 373 353 337 311 303 289 288 273 268 ACR 50 373 372 348 338 314 306 289 288 274 270 ACR 70 374 374 350 340 314 309 289 288 278 270 As-observed analysis for patients initiated on ORENCIA® (abatacept) during the double-blind period. Kremer JM, et al. EULAR 2009. Poster #FRI0263.
  40. 40. 機轉是透過T細胞活化的抑制因子CTLA4  適應症為類風濕性關節炎  第一線生物製劑  即使對TNF抑制劑無效的RA病人,此藥仍 有50%的有效率  靜脈輸注,每月一次  10 mg/kg 
  41. 41. 英文藥名 台灣商品名 作用機轉 適應症 Etanercept (Enbrel) 恩博 抗腫瘤壞 死因子 類風溼性關節炎,僵直性脊椎炎, 有 乾癬,乾癬關節炎,幼年型關節炎 Adalimumab (Humira) 復邁 抗腫瘤壞 死因子 類風溼性關節炎,僵直性脊椎炎, 有 乾癬,乾癬關節炎,潰瘍性大腸炎 Golimumab (Simponi) 辛普尼 抗腫瘤壞 死因子 類風溼性關節炎,僵直性脊椎炎, 有 乾癬,乾癬關節炎, Rituxtimab (Mabthera) Denosumab (Prolia) Abatacept (Orencia) Tocilizumab (Actemra) 莫須瘤 類風溼性關節炎 B細胞 CD20抗原 抗RANKL 骨質疏鬆症 有 類風溼性關節炎 有 類風溼性關節炎 有 保骼麗 恩瑞舒 安挺樂 T細胞因 子CTLA4 細胞激素 IL-6 健保給付 有
  42. 42. Pathogenesis of immune system  Immune target therapies  Biological agents  Small molecules  Take home message 
  43. 43. The MAPK, Syk kinase, NF-κB and JAK/STAT intracellular signalling pathways Bonilla-Hernán M G et al. Rheumatology 2011;50:15421550
  44. 44. The majority of cytokine receptors use three JAK combinations Shown are well-studied cases where JAK usage by each cytokine receptor has been established by genetic and biochemical studies. Exceptions shown are the G-CSFR (*) where it is currently unclear whether both JAK1 and JAK2 are required together. Additionally, the IL-12R (†) and IL-23R (†) require TYK2 but the requirement for JAK2 has not been definitively determined. Receptors that use JAK2 and JAK3, JAK3 alone, TYK2 alone, or JAK3 and TYK2 have not been described.
  45. 45. ORAL Standard – MTX-IR RA
  46. 46. ORAL Standard – MTX-IR RA ACR 50 response rates over time
  47. 47. Xeljanz (tofacitinib) FDA approved on Nov. 6, 2012 5 mg twice daily adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to, or who are intolerant of, methotrexate. Cost: 90% of TNFi biologics
  48. 48.  Tofacitinib 機轉是抑制細胞內訊息傳遞分子JAK-3  用於治療類風濕性關節炎; 目前也針對中重度 乾癬及僵直性脊椎炎進行臨床試驗中   Apremilast 機轉是抑制細胞內訊息傳遞分子PDE-4  目前正針對中重度乾癬及僵直性脊椎炎進行 臨床試驗   Fostamatinib  Syk inhibitors, phase II clinical trial
  49. 49. Pathogenesis of immune system  Immune target therapies  Biological agents  Small molecules  Summary & Take home message 
  50. 50. 107 ongoing Phase 2 & 3 trial in RA @ clinicaltrial.gov, 2013-Oct-12
  51. 51. IL6 MoAb: Sirukumab  IL17 MoAb: Secukinumab  B cell: BAFF, CD22  JAKi: JNJ, VX-509 (Vertex).  Masitinib ,a tyrosine-kinase inhibitor  Mesenchymal Stem Cells 
  52. 52.  Small Molecules Target therapy JAK  SYK  PGE4  Tyrosine kinase inhibitor, TKI  Histamin-4 
  53. 53. Chronic inflammation and immune-related diseases markets arising.  Immune-target therapies is the trend!  Questions to be answered  What is the most important target?  Personalized medicine   Key to success: Sustained efficacy  Long-term safety  Availability 

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