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E Choy King’s College Hospital, London, UK

Assembling the Orchestra Understanding the Dynamics: Pathways Which are Involved in the Pathophysiology of RA. E Choy King’s College Hospital, London, UK. What is the role of T cells in the pathogenesis of RA?. Abatacept. TNF- α , IL-12. T cell. T cell. Dendritic cell. Co-stimulatory

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E Choy King’s College Hospital, London, UK

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  1. Assembling the OrchestraUnderstanding the Dynamics: Pathways Which are Involved in the Pathophysiology of RA E ChoyKing’s College Hospital, London, UK

  2. What is the role of T cells in the pathogenesis of RA? Abatacept TNF-α, IL-12 T cell T cell Dendritic cell Co-stimulatory signal blocked X IFN- IL-2 T cell activation inhibited IFN- CD80 TH1 CD28 IL-17 TCR IL-15 MHC II Macrophage (Auto?) antigen IL-1, IL-6, IL-18 Adapted from: Smolen JS & Steiner G. Nat Rev Drug Disc 2003; 2:473–488. Smolen JS, et al. Lancet 2007; 370:1861–1874. TNF-α, IL-6, IL-1

  3. What is the role of B cells in the pathogenesis of RA? Rituximab Co-stimulation BCR cross linking B cell X TH1 B cell IL-6 Antigen presentation T cell activation Autoantibody activation Pro-inflammatory cytokine secretion T cell help IC formation CD40 CD40L Plasma cell TCR MHC II Macrophage Autoantibodies (RF and others) (Auto?) antigen CD20 TNF, IL-6, IL-1 Adapted from: Smolen JS & Steiner G. Nat Rev Drug Disc 2003; 2:473–488. Smolen JS, et al. Lancet 2007; 370:1861–1874. BCR=B cell receptor; IC=immune complex; RF=rheumatoid factor; TCR=T cell receptor

  4. Cytokines play a key role in the pathogenesis of RA Many of the effects of RA are mediated by small signalling molecules e.g. cytokines1 Pro-inflammatory and anti-inflammatory1 Rapidly synthesised and secreted after stimulation2 Unlike hormones, not stored in glands Cytokines act on target cells close to the site of secretionthrough specific surface receptors2 Cytokines can also act ondistant target cells via trans-signalling through ubiquitously expressed receptor molecules2 e.g. IL-6 1. Firestein GS. Nature 2003; 423:356–336. 2. Heinrich PC, et al. Biochem J 1998; 334:297–314.

  5. TNF inhibitors: Mode of action In synovial tissue, activated T cells stimulate macrophages and fibroblasts to secrete TNF- Adalimumab, infliximab and etanercept bind to and block the activity of TNF-, resulting in inhibition of TNF--induced joint damage Fibroblasts Macrophages TNF- Infliximab Adalimumab Etanercept X Joint damage inhibited Targetcells Adapted from: Scott DL & Kingsley GH. N Engl J Med 2006; 355:704–712.

  6. Synoviocytes and chondrocytes secrete MMPs in response to inflammatory cytokineswhich promote cartilage damage TNF-α, IL-1, IL-6 Synovial fibroblast MMPs Chondrocyte Cartilage Bone Adapted from: Smolen JS & Steiner G. Nat Rev Drug Disc 2003; 2:473–488. Smolen JS, et al. Lancet 2007; 370:1861–1874. MMPs=matrix metalloproteinases

  7. Osteoclasts have a central role in mediating bone destruction in RA IL-6, TNF-, IL-1 Synovial fibroblast RANKL expression IL-6 Activation RANKL RANK M-CSF Differentiation Osteoclast Macrophage Cathepsin K Bone M-CSF=macrophage colony-stimulating factorRANK=receptor activator of nuclear factor-κBRANKL=RANK ligand Schett G. Arthritis Res Ther 2007; 9:203. Teitelbaum SL, et al. Science 2000; 289:1504–1508. Kudo O, et al. Bone 2003; 32:1–7.

  8. Angiogenesis is a key process in the formation and maintenance of the pannus as invasion of cartilage and bone requires an increased blood supply1 VEGF has been identified as a key element in the development of new blood vessels1,2 VEGF contributes to the formation of destructive pannus tissue in the rheumatoid joint IL-6 Synovial fibroblasts VEGF Endothelial cells Pannusformation 1. Paleolog EM. Arthritis Res 2002; 4 (suppl 3):S81–S90. 2. Koch AE. Ann Rheum Dis 2003; 62 (suppl 2):ii60–ii67. VEGF=vascular endothelial growth factor

  9. The cytokine network in RA sTNFR, TNF-IL-10, IL-1, IL-18, IL-IR IFN IL-17 T cell Fibroblast Macrophage IL-15 FGFTGF- IL-18 IL-8 B cell IL-6 RANKL Rheumatoid factor Liver Chondrocyte Cartilage Acute-phase proteinsHepcidin Osteoclast Bone Adapted from: Firestein GS. Nature 2003; 423:356–361. Smolen JS, et al. Lancet 2007; 370:1861–1874. Smolen JS & Steiner G. Nat Rev Drug Disc 2003; 2:473–488. Nemeth E, et al.J Clin Invest2004; 113:1271–1276. sTNFR=soluble TNF receptor TGF-=transforming growth factor- FGF=fibroblast growth factor

  10. The role of cytokines in B cell proliferation and differentiation Range of cytokinesincluding IL-6, IFN-, IL-12 Dendritic cells Cytokine production IL-6 Immunoglobulin production TH1 Plasma cell B cell ActivatedB cell differentiation/proliferation Jego G, et al.Curr Dir Autoimmun 2005; 8:124–139.

  11. The role of cytokines in T-helper cell differentiation IFN-γ IL-12 TH1 IL-4 TH0 TH2 TGF-β Treg TGF-β IL-6 TH17 Autoimmune disease Smolen JS and Steiner G. Nat Rev Drug Disc 2003; 2:473–488. Mangan PR, et al. Nature 2006; 441:231–234. Bettelli E, et al. Nature 2006; 441:235–238.

  12. Reduction in IL-6 levels correlates with improvement of disease activity Decrease in the duration of morning stiffness after 3 years (hr) Decrease in active jointsafter 3 years (n) 5 25 4 20 3 15 2 10 1 RRank=0.6561 p<0.005 5 0 RRank=0.7608 p<0.005 0 –1 –5 –2 –20 –10 0 10 20 30 40 50 60 –20 –10 0 10 20 30 40 50 60 Decrease in IL-6 afterfirst year (pg/ml) Decrease in IL-6 after first year (pg/ml) Straub RH, et al. Br J Rheumatol 1997; 36:1298–1303.

  13. Joint destruction is induced by excessive IL-6 Local bone destruction in RA is mediated by osteoclasts within the synovial tissue1 Formation of osteoclast-like cells in vitro is induced by addition of IL-6 and sIL-6R, or by addition of RA synovial fluid2,3 200 * 150 * Osteoclast-like cells/well 100 * * 50 0 0 5 10 20 40 hIL-6 (ng/ml) 1. Schett G. Arthritis Res Ther 2007; 9 (suppl 1):S2.2. Kotake S, et al. J Bone Miner Res 1996; 11:88–95. 3. Kudo O, et al. Bone 2003; 32:1–7. hIL-6=human IL-6*p<0.05 vs. culture without hIL-6

  14. IL-6/sIL-6R contribute to leukocyte recruitment at inflammatory sites IL-6 in conjunction with sIL-6R1: Activates production of a subset of chemokines by endothelial cells Upregulates expression of adhesion molecules IL-6 supports neutrophil recruitment2 4,000 r2=0.774 p<0.01 2,000 IL-6 (pg/ml) 0 0 20 40 60 80 Adherent neutrophils 1. Romano M, et al. Immunity 1997; 6:315–325. 2. Lally F, et al. Arthritis Rheum 2005; 52:3460–3469.

  15. IL-6 increases neutrophil survival rate in vitro IL-6 (100 ng/ml) Control 70 100 60 75 2x107 PMN/ml 50 40 1x107 PMN/ml Survival (%) Survival (%) 50 30 5x106 PMN/ml 20 25 10 1x106 PMN/ml 0 0 0 6 12 18 24 30 0 10 100 1 Time (hr) IL-6 (ng/ml) PMNs=polymorphonuclear leukocytes Biffl WL. J Leukoc Biol 1995; 58:582–584.

  16. Contribution of cytokines to pannus formation via VEGF production Anti-IL-6R mAb but not IL-1R antagonist or anti-TNF mAb inhibited VEGF production from synovial cells 16 12 VEGF (x 102 pg/ml) 8 4 0 – – – – – + + – + + + – + + + IL-6R + + + IL-1R + + + TNF-α IL-6/sIL-6R IL-1 TNF- Inhibitors Nakahara H, et al. Arthritis Rheum 2003; 8:1521–1529. Values are mean ± SD

  17. IL-6 is a major hepatocyte growth/stimulating factor Acute-phase response (CRP, SAA) Haptoglobin, fibrinogen IL-6 Ceruloplasmin (C3, C4) Liver Fibroblast Hepcidin Albumin, transferrin C3=serum complement 3 C4=serum complement 4 CRP=C-reactive protein SAA=serum amyloid A Adapted from: Panichi V, et al. Kidney Int Suppl 2000; 76:S96–S103.Nemeth E, et al.J Clin Invest2004; 113:1271–1276.

  18. Innate body defence which involves the increased production of acute-phase proteins Proteins include CRP and SAA Production stimulated by pro-inflammatory cytokines such as TNF-, IL-1 and IL-6 Acute-phase changes reflect the presence and intensity of inflammation, and are used as a clinical guide to diagnosis and management The acute-phase response 30,100 30,000 700 600 CRP 500 SAA 400 Change in plasma concentration (%) Haptoglobin 300 Fibrinogen 200 100 C3 0 Transferrin Albumin 0 7 14 21 Timeafter inflammatory stimulus (days) Gabay C & Kushner I. N Engl J Med 1999; 340:448–454.

  19. High CRP levels can independently predict long-term X-ray progression OR=odds ratio; CI=confidence interval Combe B, et al.Arthritis Rheum 2001; 44:1736–1743.

  20. Anaemia of chronic inflammation is commonlyobserved in RA Hepcidin inhibits: Release of iron from macrophages (reticuloendothelial block) Absorption of dietary iron (iron deficiency) Inflammation Macrophage iron release IL-6 Hepcidin Macrophage Hepatocytes Intestinal iron absorption Adapted from: Andrews NC. J Clin Invest 2004; 113:1251–1253. Nemeth E, et al.J Clin Invest2004; 113:1271–1276.

  21. Overproduction of IL-6 correlates with anaemia Increased serum IL-6 concentrations correlate with anaemia in RA patients1 IL-6 infusions induced anaemia in a rat model2 p=0.0001 Control 8 10.5 IL-6 6.8 7 10.0 6 9.5 5 9.0 Serum IL-6 (pg/ml) 3.9 Haemoglobin level (mmol/l) 4 8.5 3 * * 8.0 2 * * 7.5 Treatment 1 7.0 0 0 5 10 15 20 25 Anaemic Non-anaemic Days 1. Voulgari P, et al. Clin Immunol 1999; 92:153–160. 2. Jongen-Lavrencic M, et al. Clin Exp Immunol 1996; 103:328–334. *p<0.01 vs. control

  22. Inhibition of IL-6 function can prevent bone loss in mice Systemic osteoporosis is a common feature of RA1 Osteoclast activation by excessive levels of IL-6 leads to bone resorption2 IL-6-deficient mice are protected from bone loss caused by oestrogen depletion3 Wild-type IL-6 deficient 0 –10 –20 Change in bone volume (%) –30 –40 –50 p<0.05 –60 1. Lipsky P. Arthritis ResTher 2006; 8 (suppl 2):S4. 2.Kotake S, et al. J Bone Miner Res 1996; 11:88–95. 3. Poli V, et al. EMBO J 1994; 13:1189–1196.

  23. Selective overexpression of IL-6 inhibits osteoblast function Reduction in enzymatic activity and lower osteoblast surface per bone surface (Ob.S/BS) ALP staining Transgenic (TG) Wild-type (WT) Osteoblast number Bone surface Trabecular Cortical p<0.01 p<0.005 40 60 30 40 Ob.S/BS (%) 20 20 10 0 0 WT TG WT TG ALP=alkaline phosphatase De Benedetti F, et al. Arthritis Rheum 2006; 54:3551–3563.

  24. Cytokines affect fatigue and mood in RA by influencing the hypothalamic pituitary adrenal axis Locus caeruleus (noradrenergic system) CRH AVP Stress system Corticotropin Fatigue and mood Catecholamines Cortisol ∆5-Adrenal androgens CRH=corticotropin releasing hormoneAVP=arginine vasopressin Adapted from: Chrousos GP. N Engl J Med 1995; 332:1351–1362.

  25. Increased incidence of cardiovascular events in RA patients Consecutive patients with RA assessed for 1-year occurrence of CV-related hospitalisation (N=236) Del Rincón I, et al.Arthritis Rheum 2001; 44:2737–2745.

  26. CRP is an independent predictor of cardiovascular risk Apparently healthy women (N=27,939) 8 7 6 5 Relative risk of future CV events 4 3 2 1 0 hsCRP (mg/l) <0.5 0.5–1 1–2 2–3 3–4 4–5 5–10 10–20 >20 ‘Low risk’ ‘Moderate risk’ ‘High risk’ hsCRP=high-sensitivity C-reactive protein Ridker PM, et al.Circulation 2004; 109:1955–1959.

  27. Increasing risk of future myocardial infarction with increasing IL-6 levels Apparently healthy men (non-smokers) 3 p=0.01* p=0.003* 2 p=0.3* Relative risk of MI 1 0 1 2 3 4 <1.04 1.04–1.46 1.47–2.28 >2.28 Quartile of IL-6 (pg/ml) * vs. lowest quartile Ridker PM, et al.Circulation 2000; 101:1767–1772.

  28. Mechanisms linking RA and increased vascular risk Synovitis IL-6, IL-1 TNF-α Adipose tissue Platelets Liver FFAs IR skeletal muscle HDL TCLDL CRP Fibrinogen Endothelial activation NO ICAM-1 VCAM-1 Accelerated atherogenesis Foam cell Macrophage FFA=free fatty acids; HDL=high-density lipoprotein; LDL=low-density lipoprotein; TC=total cholesterol; IR=insulin-resistant; ICAM-1=intercellular adhesion molecule 1; VCAM-1=vascular cell adhesion molecule 1; NO=nitric oxide Adapted from: Sattar N, et al.Circulation 2003; 108:2957–2963.

  29. Key cytokine effects in RA IL-6 has a broad and distinct range of highly relevant effects IL-6 TNF IL-1 + + ++++ Levels in blood and synovial fluid + ++ ++ Endothelium activation Joint inflammation ++ + + PMN (neutrophil migration) + ++ +++ Proteases, matrix metalloproteinase secretion ++ + + Osteoclast activation Bone destruction ++ + + Osteoblast inhibition ++ – (+) B cell function and survival Autoimmunity – ++ + TH17 promotion +++ + + Acute-phase proteins production Systemiceffects ++ + + Bone marrow (anaemia) Central nervous system +++ ++ ++ Choy E. Manuscript in preparation.

  30. Immune system • B cell • T cell • Systemic effects • Acute-phase protein production • Increased CV risk • Anaemia via hepcidin production • Osteoporosis • HPA axis – fatigue and mood • Local effects • Osteoclast activation • Neutrophil recruitment and survival • Pannus formation Understanding the dynamics: Pathways which are involved in the pathophysiology of RASummary of IL-6 effects in RA IL-6

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