Mechanism of SLE

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Mechanism of SLE

  1. 1. MECHANISM OF DISEASE(SLE) นพ . สุรสฤษดิ์ ขาวละออ 11/11/2009
  2. 2. outlines <ul><li>GENETIC AND EPIDEMIOLOGIC FACTORS </li></ul><ul><li>AUTOANTIBODIES IN LUPUS </li></ul><ul><li>SOURCE OF AUTOANTIGENS IN LUPUS </li></ul><ul><li>TISSUE DAMAGE BY AUTOANTIBODY </li></ul><ul><li>ROLE OF T CELLS </li></ul><ul><li>CYTOKINES IN LUPUS </li></ul><ul><li>IMPLICATION FOR TREATMENT </li></ul>
  3. 3. Genetic & epidemiologic factors <ul><li>Female hormones </li></ul><ul><li>-90% are female </li></ul><ul><li>-unclear how sex hormone promote </li></ul><ul><li>Drug-induced lupus </li></ul><ul><li>-best known : procainamide, </li></ul><ul><li> hydralazine, quinidine </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  4. 4. Genetic & epidemiologic factors <ul><li>3. Antecedent viral-like illness : EBV </li></ul><ul><li>4. Ultraviolet radiation </li></ul><ul><li>5. Gene : 8 susceptibility loci </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  5. 5. GENETIC Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  6. 6. GENETIC Abul K. Abbas. Cellular and molecular immunology 6th edition 2007
  7. 7. GENETIC Mary K Crow.Developments in the clinical understading of lupus. Arthritis Research & Therapy 2009;11:245
  8. 8. GENETIC Mary K Crow.Developments in the clinical understading of lupus. Arthritis Research & Therapy 2009;11:245
  9. 9. Autoantibodies in lupus <ul><li>Anti-dsDNA : highly specific for lupus </li></ul><ul><li> 70% of pt. with lupus </li></ul><ul><li> < 0.5% of healthy/other </li></ul><ul><li>Mannik et al. detected IgG for </li></ul><ul><li>-Ro(ribonucleoprotein complex) -La(RNA-binding protein) </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  10. 10. Autoantibodies in lupus <ul><li>-C1q </li></ul><ul><li>-Sm(nuclear particle) </li></ul><ul><li>3. Anti-  -actinin : kidney disease </li></ul><ul><li>4. Anti-nucleosome : kidney, skin disease </li></ul><ul><li>5. Anti-N-methyl-D-aspartate(NMDA) Rc </li></ul><ul><li>6. Antiplatelet Ab </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  11. 11. Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  12. 12. Autoantibodies in lupus
  13. 13. Autoantibodies in lupus
  14. 14. Autoantibodies in lupus การติดสี fluorescein จากการตรวจ indirect immunofluorescent assay & specific autoantibodies ที่เกี่ยวข้อง
  15. 15. Autoantibodies in lupus การติดสี fluorescein จากการตรวจ indirect immunofluorescent assay & specific autoantibodies ที่เกี่ยวข้อง
  16. 16. Autoantibodies in lupus <ul><li>-not know why some anti-dsDNA Ab </li></ul><ul><li>deposit preferentially in kidney </li></ul><ul><li>-Is  -Actinin a target for Pathogenic </li></ul><ul><li>Anti-DNA Antibodies in Lupus Nephritis ? </li></ul><ul><li>-candidate Ag = 100-kd actin-binding & </li></ul><ul><li>crosslinking protein, human  -actinin </li></ul><ul><li>4 isoforms </li></ul>Lesley J et al.Arthritis & Rheumatism 2004;50(3):866-70
  17. 17. Autoantibodies in lupus <ul><li>-ACTN1 : non muscle forms </li></ul><ul><li>-ACTN2 : limit to skeleton & cardiac m </li></ul><ul><li>-ACTN3 : limit to skeleton & cardiac m </li></ul><ul><li>-ACTN4 : non muscle forms </li></ul><ul><li>-in kidney  -Actinin 4 localized in podocyte </li></ul><ul><li>foot processes & mesangial cells </li></ul>Lesley J et al.Arthritis & Rheumatism 2004;50(3):866-70
  18. 18. Autoantibodies in lupus
  19. 19. Autoantibodies in lupus
  20. 20. Autoantibodies in lupus
  21. 21. Autoantibodies in lupus <ul><li>disruption of morphology of actin </li></ul><ul><li>cytoskeleton </li></ul><ul><li> </li></ul><ul><li>Foot process effacement and fusion </li></ul><ul><li> </li></ul><ul><li>proteinuria </li></ul>Lesley J et al.Arthritis & Rheumatism 2004;50(3):866-70
  22. 22. Autoantibodies in lupus <ul><li>-purified anti-dsDNA Ab from sera of </li></ul><ul><li>SLE pt. who had active renal dz & had </li></ul><ul><li>never had renal dz </li></ul><ul><li>-enzyme-linked immunosorbent assay to </li></ul><ul><li>measure Ig binding to  -Actinin </li></ul>Lesley J et al.Arthritis & Rheumatism 2004;50(3):866-70
  23. 23. Autoantibodies in lupus <ul><li>Result </li></ul><ul><li>-greater proportion of anti-dsDNA IgG </li></ul><ul><li> from pt. with renal dz bound to  -actinin </li></ul><ul><li> than did those purified from sera of pt. </li></ul><ul><li> without renal dz </li></ul><ul><li>-pathogenic anti-dsDNA Ab cross-react </li></ul><ul><li> with  -Actinin </li></ul>Lesley J et al.Arthritis & Rheumatism 2004;50(3):866-70
  24. 26. <ul><li>-Ag ที่กระตุ้น T cell จากผู้ป่วย lupus มักเป็น </li></ul><ul><li>histone-derived peptides ซึ่งได้จาก histone </li></ul><ul><li>(protein core of nucleosome) แต่ Ag เหล่านี้ </li></ul><ul><li>ไม่กระตุ้น T cell จากคนปกติ </li></ul><ul><li>- H2B 10-33 , H4 16-39 , H4 71-94 , H3 91-105 , </li></ul><ul><li> H2A 34-48 , H4 49-63 </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  25. 28. Autoantibodies in lupus <ul><li>NMDA (N-methyl-D-Aspartate) </li></ul><ul><li>-excitatory amino acid </li></ul><ul><li>-released by neurons </li></ul><ul><li>-lupus pt. who had serum Ab against </li></ul><ul><li> DNA & NMDA receptors caused </li></ul><ul><li> cognitive impairment & hippocampal </li></ul><ul><li> damage </li></ul>Kowal C et al.Proc Natl Acad Sci USA 2006;103:19854-9
  26. 29. Source of autoantigens in lupus <ul><li>cellular debris (as result of apoptosis) </li></ul><ul><li>-apoptotic bleb on surface of dying </li></ul><ul><li> cell </li></ul><ul><li> </li></ul><ul><li>Ag within cell expose on surface of blebs </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  27. 30. Source of autoantigens in lupus Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  28. 31. Source of autoantigens in lupus <ul><li>2. Removal of apoptotic debris </li></ul><ul><li>-C1q play role in phagocytosis </li></ul><ul><li>-phagocytes from lupus pt. engulf less </li></ul><ul><li> than phagocytes from healty people </li></ul><ul><li>3. Deficiency of complement  poor </li></ul><ul><li> “waste disposal” </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  29. 32. Tissue damage by autoantibody <ul><li>-Two main theories </li></ul><ul><li>extracellular dsDNA bind to autoAb </li></ul><ul><li> </li></ul><ul><li> enter bloodstream </li></ul><ul><li> </li></ul><ul><li>complexes settle in renal glomerular basement membrane </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  30. 33. Tissue damage by autoantibody <ul><li>2. Autoantibodies cross-react with proteins [Ag similar shape (shared epitopes) or similar charge] </li></ul><ul><li> </li></ul><ul><li>direct pathogenic effect on cells </li></ul><ul><li> (  -actinin) </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  31. 34. The role of T cells <ul><li>1. Antigen-driven process </li></ul><ul><li>process which Ag bind Ig on surface of </li></ul><ul><li>B-cells </li></ul><ul><li>  </li></ul><ul><li>high affinity of surface Ig for Ag </li></ul><ul><li>more strongly stimulated & more </li></ul><ul><li>proliferate </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  32. 35. The role of T cells <ul><li>B-cells are stimulated by T-cells as </li></ul><ul><li>“ T-lymphocyte help” </li></ul><ul><li> </li></ul><ul><li>-B-cell division, switching Ab production </li></ul><ul><li>-promote change in molecular sequence </li></ul><ul><li>of secreted Ab </li></ul><ul><li>T-cell help  high affinity IgG autoAb </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  33. 37. The role of T cells <ul><li>-Autoantigen-specific B cells & T cells ที่ </li></ul><ul><li>ผลิต injurious autoAb ไม่พบในคนปกติ เนื่องจาก </li></ul><ul><li>1. removal(deletion) of autoreactive B </li></ul><ul><li>2.inactivation of cells( remain in body </li></ul><ul><li>but anergy ) </li></ul><ul><li>3.change in light chain of Ab(from </li></ul><ul><li>autoreactive B cell) : receptor editing </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  34. 38. The role of T cells <ul><li>Regular T cell </li></ul><ul><li>-suppress activation of helper T cell </li></ul><ul><li> & B cells reduction number or </li></ul><ul><li> function or both </li></ul><ul><li>- But Treg with active lupus reduce </li></ul><ul><li> ability this activity( เทียบกับ inactive or </li></ul><ul><li> control) </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  35. 39. The role of T cells Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  36. 40. The role of T cells Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  37. 41. Cytokines in lupus <ul><li>TNF-  : controversial </li></ul><ul><li>- ในหนูพบว่า ถ้าให้ TNF-  จะสามารถ delay development of lupus </li></ul><ul><li>Jacob CO, McDevitt HO.Nature 1988;331:356-8 </li></ul><ul><li>-in human with RA who treated with </li></ul><ul><li> anti- TNF-  Ab พบ anti-dsDNA Ab และ lupus </li></ul><ul><li> develop บ้างในบางราย </li></ul><ul><li>Charles Pj et al.Arthritis Rheum 2000;43:2383-90 </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  38. 42. Cytokines in lupus <ul><li>-low TNF-  activity associated with </li></ul><ul><li> increase dz. Activity </li></ul><ul><li>Gabay C et al.J rheumatology 1997:24;303-8 </li></ul><ul><li>-By contrast, level of TNF-  </li></ul><ul><li> messenger RNA was high in </li></ul><ul><li> kidney-biopsy specimens from pt. LN </li></ul><ul><li>Herrera-Esparza et al.Lupus 1998;7:154-8 </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  39. 43. Cytokines in lupus <ul><li>-Aringer et al. รักษาผู้ป่วย lupus 6 คน ด้วย </li></ul><ul><li> infiximab(monoclonal Ab of anti- TNF-  </li></ul><ul><li> Ab) พบว่า </li></ul><ul><li> - 3 คน ลดอาการปวด , บวมของข้อ </li></ul><ul><li> - 60 % ลด urinary protein loss ใน LN </li></ul><ul><li>Aringer M et al.Arthritis Rheum 2004;50:3161-90 </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  40. 44. Cytokines in lupus <ul><li>2. IL-10 </li></ul><ul><li>-high level in lupus pt. correlate with </li></ul><ul><li> activity of disease </li></ul><ul><li>-stimulate of polyclonal populations of </li></ul><ul><li> B cells </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  41. 45. Cytokines in lupus <ul><li>3. Interferon </li></ul><ul><li>- พบว่าระดับของ IFN-  เพิ่มขึ้นในผู้ป่วย lupus </li></ul><ul><li>-Baechler EC et al ได้รายงานเมื่อปี 2003 ว่าพบมี 13 gene ที่ up-regulate in PBMC </li></ul><ul><li>โดย IFN จากผู้ป่วย lupus เมื่อเปรียบเทียบกัน cell </li></ul><ul><li>เดียวกันของ control </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  42. 46. Cytokines in lupus <ul><li>-Studies of lupus-prone NZB/W F1 mice </li></ul><ul><li>พบ nephritis ในหนูที่ได้ expose กับ IFN-  ตลอด </li></ul><ul><li>ตั้งแต่อายุน้อยๆจนอายุ 15-20 สัปดาห์ มากกว่ากลุ่ม control </li></ul><ul><li>Mathian A et al.journal of immunity 2005;174:2499-506 </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  43. 47. Cytokines in lupus <ul><li>4. B-lymphocyte stimulator </li></ul><ul><li>-member of TNF-ligand superfamily </li></ul><ul><li>-promote proliferation & survival of B </li></ul><ul><li>-detect overexpression of stimulator in </li></ul><ul><li> both lupus pt. & lupus-prone mice </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  44. 48. Cytokines in lupus <ul><li>-Stohl et al report </li></ul><ul><li>-elevated levels of soluble B-cell </li></ul><ul><li> stimulator in serum & on PBMC up </li></ul><ul><li> to 50 % of active lupus pt. </li></ul><ul><li>Stohl W.Arthritis Rheum 2003;48:3475-86 </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  45. 49. Cytokines in lupus <ul><li>-Level of B-lymphocyte stimulators </li></ul><ul><li>correlate with level of anti-dsDNA Ab in </li></ul><ul><li>serum & decreased in 9 pt. who were </li></ul><ul><li>treated with corticosteroids </li></ul><ul><li>Stohl W.Arthritis Rheum 2003;48:3475-86 </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  46. 50. Cytokines in lupus Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939 Treatment of patients who had elevated serum BLyS levels with intensive courses of high - dose corticosteroids resulted in marked reductions in serum BLyS levels
  47. 51. Implications for treatment <ul><li>Aim at reducing autoantibody levels </li></ul><ul><li>1.corticosteroids reduced level of </li></ul><ul><li> anti-dsDNA Ab & reduced frequency </li></ul><ul><li> of severe flares of disease </li></ul><ul><li>*side effect of corticosteroids* </li></ul><ul><li>Bootma H et al.Lancet 1995;345:1595-9 </li></ul><ul><li>Tseng CE et al.Arthritis Rheum 2009;54:3623-32 </li></ul>Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  48. 52. Implications for treatment <ul><li>2.Rituximab : monoclonal Ab of CD20 </li></ul><ul><li>- เป็น Chimeric mouse/human </li></ul><ul><li> monoclonal IgG antibody </li></ul><ul><li>- กลไกของ Rituximab ในการทำลาย B cells </li></ul><ul><li> ยังไม่ถูกค้นพบแน่นอนแต่จากการศึกษา in vitro </li></ul><ul><li> พบว่าการทำลาย B cells เกิดจาก 3 กลไกหลักคือ </li></ul>Eisenberg R et al. Clin Immunol 2005;117(3):207-13 Thatayatikom A et al. Autoimmun Rev 2006;5(1):18-24
  49. 53. Implications for treatment <ul><li>Antibody-dependent cell-mediated cytotoxicity (ADCC) และ apoptosis โดยเกิดการ engagement ของ FcγRIIIa (CD16) บน macrophages และ natural killer cells </li></ul><ul><li>Complement-dependent cytotoxicity </li></ul><ul><li>I ntracellular signa l ing ทำให้เกิด B cell </li></ul><ul><li> apoptosis </li></ul>Eisenberg R et al. Clin Immunol 2005;117(3):207-13 Thatayatikom A et al. Autoimmun Rev 2006;5(1):18-24
  50. 54. Implications for treatment Leandro MJ et al.Arthritis Rheum.2002 Oct;46(10):2673-7
  51. 55. Implications for treatment Thatayatikom A et al. Autoimmun Rev 2006;5(1):18-24
  52. 56. Implications for treatment <ul><ul><li>CD20 </li></ul></ul><ul><ul><li>-35 Kd , non-glycosylated tetraspannin cell </li></ul></ul><ul><ul><li>membrane-embedded phosphoprotein </li></ul></ul><ul><ul><li>- พบเฉพาะใน B –lineage ตั้งแต่ระยะ pre-B cells, </li></ul></ul><ul><ul><li>immature B cells, mature naive B cells, </li></ul></ul><ul><ul><li>pre-germinal center mature B cells, GC </li></ul></ul><ul><ul><li>mature B cells จนถึง memory (GC) B cells </li></ul></ul><ul><ul><li>- ไม่พบใน plasma cells </li></ul></ul>Eisenberg R et al. Clin Immunol 2005;117(3):207-13 Thatayatikom A et al. Autoimmun Rev 2006;5(1):18-24
  53. 57. Implications for treatment
  54. 58. Implications for treatment <ul><li>- not known natural ligand </li></ul><ul><li>- CD20 functions as a Ca ( 2+ )- permeable </li></ul><ul><li>cation channel and is involved in cell </li></ul><ul><li>activation and growth regulation of B cells </li></ul><ul><li>Bubien et al, 1993; Tedder et al, 1985; Tedder and Engel, 1994 </li></ul>Leandro MJ et al.Arthritis Rheum.2002 Oct;46(10):2673-7
  55. 59. Implications for treatment <ul><li>3.Abtimus sodium (LJP 394) </li></ul><ul><li>-four DNA epitopes conjugated </li></ul><ul><li> to pharmacologically inert </li></ul><ul><li> triethylene glycol platform </li></ul><ul><li>-can crosslinking of membrane </li></ul><ul><li> Ig on surface of naïve B cell in </li></ul><ul><li> absence of T cell help  anergy or </li></ul><ul><li> apoptosis </li></ul>Alarcon-Segovia D et al.Arthritis Rheum.2003 Feb;48(2):442-54
  56. 60. Implications for treatment <ul><li> 3.Abtimus sodium (cont.) </li></ul><ul><li>- 2 mechanism to reduce circulating </li></ul><ul><li> anti-dsDNA Ab </li></ul><ul><li> 2.1.form small soluble complex </li></ul><ul><li> 2.2.induce B cell tolerance by crosslinking </li></ul><ul><li> anti-dsDNA surface Ig Rc on B cell  trigger </li></ul><ul><li> B cell anergy / apoptosis </li></ul>Alarcon-Segovia D et al.Arthritis Rheum.2003 Feb;48(2):442-54
  57. 61. Implications for treatment <ul><li>4.Anti-CD22(Epratuzumab) </li></ul><ul><li>-monoclonal antibodies that prevent CD22 binding </li></ul><ul><li> to its natural ligands </li></ul><ul><li>- มี การศึกษาแบบ open-label, single-center study </li></ul><ul><li> ในผู้ป่วย SLE 14 คนที่มีความรุนแรงแบบ moderate </li></ul><ul><li> degrees ( BILAG >2) โดยไม่มี concomitant </li></ul><ul><li> immunosuppressants หรือ steroid พบว่าร้อยละ 93 </li></ul><ul><li> ของผู้ป่วยมีอาการดีขึ้น , level B cell มีจำนวนลดลง </li></ul><ul><li> ประมาณร้อยละ 35 ที่ 18 สัปดาห์และความรุนแรงของ </li></ul><ul><li> โรคคงที่ระดับต่ำๆ จนถึง 6 เดือน </li></ul>Dorner T et al.Arthritis Research & therapy 2006;84:R74
  58. 62. Implications for treatment <ul><li>CD22 </li></ul><ul><li>-135kDa glycoprotein </li></ul><ul><li>-B-lymphocyte-restricted membrane of </li></ul><ul><li> immonoglobulin superfamily </li></ul><ul><li>-first expressed in cytoplasm of pro-B </li></ul><ul><li> & pre-B cells, then on surface as mature </li></ul><ul><li> , expression ceasing when diff. to plasma </li></ul>Dorner T et al.Arthritis Research & therapy 2006;84:R74
  59. 63. Implications for treatment <ul><li>CD22(cont.) </li></ul><ul><li>-cytoplamic tail contain ITIM </li></ul><ul><li>-inhibition of BCR signal </li></ul><ul><li>-key role in B cell development & </li></ul><ul><li> survival(def. enhanced apoptosis) </li></ul><ul><li> แต่หน้าที่ที่แน่นอนยังไม่ชัดเจน </li></ul>Dorner T et al.Arthritis Research & therapy 2006;84:R74
  60. 64. Implications for treatment
  61. 65. Implications for treatment <ul><li>5. Anti-IL-10 </li></ul><ul><li>-SLE pt. produce abnormally large </li></ul><ul><li> amounts of IL-10 </li></ul><ul><li>-serum levels correlate with dz activity </li></ul><ul><li>-IL-10 inhibits Ag presentation & Th1 </li></ul><ul><li> lymphocyte activation </li></ul>Llorente L et al.Arthritis Rheumatism 2000;43:1790-1800
  62. 66. Implications for treatment <ul><li>-In vivo function of IL-10 poorly </li></ul><ul><li> understood </li></ul><ul><li>-Chernoff AE et al และ Huhn RD et al ได้ </li></ul><ul><li> ทำการศึกษาไว้ ตั้งแต่ปี 1995-6 พบว่า IL-10 </li></ul><ul><li> สามารถยับยั้งการผลิตของ proinflammatory cytokine </li></ul><ul><li> จาก mononuclear cell และยับยั้ง T cell </li></ul><ul><li> proliferation ได้อีกด้วย </li></ul>Llorente L et al.Arthritis Rheumatism 2000;43:1790-1800
  63. 67. Implications for treatment <ul><li>-Luis LLorente et al ได้ทดลองประเมินความปลอดภัย และประสิทธิผลของ anti-IL-10 monoclonal Ab </li></ul><ul><li>เป็นครั้งแรกที่ใช้ในมนุษย์ โดยให้สารนี้ในผู้ป่วย active </li></ul><ul><li>SLE & steroid dependent dz . ในขนาด 20 </li></ul><ul><li>mg/d IV เป็นเวลาต่อเนื่องกัน 21 วัน และติดตามต่ออีก 6 </li></ul><ul><li>เดือน พบว่าผู้ป่วยทุกคนสามารถทนยาได้ดี และไม่พบอาการ </li></ul><ul><li>ข้างเคียงใดๆ โดยอาการทางข้อ และผิวหนังดีขึ้นอย่างเห็นได้ชัด </li></ul>Llorente L et al.Arthritis Rheumatism 2000;43:1790-1800
  64. 68. Implications for treatment <ul><li>- นอกจากนี้ผู้ป่วยทุกคนยังสามารถลดขนาดของ </li></ul><ul><li> prednisolone ลงได้ </li></ul><ul><li>- หลังจากติดตามต่ออีก 6 เดือน ยังสามารถควบคุมอาการของ </li></ul><ul><li> โรคได้ </li></ul>Llorente L et al.Arthritis Rheumatism 2000;43:1790-1800
  65. 69. Implications for treatment Llorente L et al.Arthritis Rheumatism 2000;43:1790-1800
  66. 70. Implications for treatment Llorente L et al.Arthritis Rheumatism 2000;43:1790-1800
  67. 71. Implications for treatment <ul><li>5.Anti-TNF-  </li></ul><ul><li>-TNF-  is important proinflammatory </li></ul><ul><li> cytokine with pleiotropic properties </li></ul><ul><li>-activation of cascade of inflammatory </li></ul><ul><li> events lead to tissue destruction </li></ul><ul><li>-markeddly increased & appear to be </li></ul><ul><li> bioactive in active SLE pt. </li></ul>Aringer M et al.Arthritis & Rheumatism 2004;50(10):3161-69
  68. 72. Implications for treatment <ul><li>-find TNF-  in renal tissue in all types </li></ul><ul><li> of lupus glomerulonephritis and ass. </li></ul><ul><li> with renal disease activity </li></ul><ul><li>-NZB/NZW mice application high dose </li></ul><ul><li> TNF-  shown to delay dz onset in this </li></ul><ul><li> lupus-prone mouse </li></ul>Aringer M et al.Arthritis & Rheumatism 2004;50(10):3161-69
  69. 73. Implications for treatment <ul><li>-but in kidney MRL/ lpr Lupus-prone </li></ul><ul><li> mice contain high levels of TNF and </li></ul><ul><li> serum levels of TNF in these mice </li></ul><ul><li> correlate with disease activity, similar </li></ul><ul><li> to finding in human </li></ul>Aringer M et al.Arthritis & Rheumatism 2004;50(10):3161-69
  70. 74. Implications for treatment <ul><li>-In human </li></ul><ul><li> RA & Crohn’s disease : TNF </li></ul><ul><li> blockage lead to formation of ANA </li></ul><ul><li> 30-40%, anti-dsDNA 15% of pt., </li></ul><ul><li> which occasionally ass. with transient </li></ul><ul><li> drug-induced lupus-like syndrome </li></ul><ul><li>-because of controversy data, blockage of </li></ul><ul><li> TNF not be considered to be option ; trial </li></ul>Aringer M et al.Arthritis & Rheumatism 2004;50(10):3161-69
  71. 75. Implications for treatment <ul><li>-Aringer M et al ได้รายงานการให้ยา TNF-  </li></ul><ul><li> 4300 mg infliximab (chimeric anti- </li></ul><ul><li> TNF-  Ab) ในผู้ป่วย 6 คน ที่เป็น active SLE(4 </li></ul><ul><li> with nephritis, 3 with arthritis </li></ul><ul><li> ที่ดื้อต่อการรักษาด้วยวิธีอื่นๆ ) เพิ่มเข้าไปจากการรักษาเดิมที่ </li></ul><ul><li> มีอยู่แล้ว เช่น ร่วมกับ azathioprine or MTX </li></ul>Aringer M et al.Arthritis & Rheumatism 2004;50(10):3161-69
  72. 76. Implications for treatment <ul><li>-Aringer M et al. ได้สรุปว่า infliximab ไม่ทำ </li></ul><ul><li> ให้เพิ่ม adverse event ที่สัมพันธ์กับ SLE </li></ul><ul><li> activity แม้ว่าจะพบระดับของ anti-dsDNA และ </li></ul><ul><li> ระดับของ anti-cardiolipin จะเพิ่มขึ้นก็ตาม ทั้งนี้ยัง </li></ul><ul><li> ได้เสนอแนะให้มีการศึกษาเพิ่มเติมในระดับ large </li></ul><ul><li> controlled trials ต่อไป </li></ul>Aringer M et al.Arthritis & Rheumatism 2004;50(10):3161-69
  73. 77. Implications for treatment <ul><li>6.Anti-CD40 ligand </li></ul><ul><li>-phase I/II studies in humans with LN </li></ul><ul><li> demonstrated reduction of anti- </li></ul><ul><li> dsDNA Ab but not of protective Ab </li></ul><ul><li>Sidiropoulos PI.Lupus 2004;13(5):391-7 </li></ul>
  74. 78. Implications for treatment <ul><li>-reduction of anti-DNA associated </li></ul><ul><li> with increase serum complement </li></ul><ul><li> levels & reduce glomerular inflammation </li></ul><ul><li> </li></ul><ul><li>Sidiropoulos PI.Lupus 2004;13(5):391-7 </li></ul><ul><li>7.CTLA-4-Ig </li></ul>
  75. 79. Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939
  76. 80. CONCLUSION <ul><li>Genetic & many factors link to lupus </li></ul><ul><li>Lupus-associated genes contribute to </li></ul><ul><li>one or more mechanisms of lupus </li></ul><ul><li>pathogenesis </li></ul><ul><li>3. At the present we find many </li></ul><ul><li>autoantibodies which have different </li></ul><ul><li>prevalence in SLE </li></ul>
  77. 81. CONCLUSION <ul><li>Most studies of autoantibody-mediated </li></ul><ul><li> tissue damage have focused on </li></ul><ul><li> role of anti-dsDNA Ab in pt. with LN </li></ul><ul><li>5. Antigen-driven is process which Ag </li></ul><ul><li> binds Ig on surface o B cells and can </li></ul><ul><li>occur only in B lymphocytes that are </li></ul><ul><li> being stimulated by T cells(T lymph.help) </li></ul>
  78. 82. CONCLUSION <ul><li>6. Apoptotic blebs are source of </li></ul><ul><li> autoantigen </li></ul><ul><li>7. Many cytokines that found in SLE </li></ul><ul><li>and new treatment which correlate </li></ul><ul><li> with these cytokines may use for </li></ul><ul><li> treatment SLE pt. in future </li></ul>
  79. 83. TNANK YOU

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