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IL-6R: A logical target in RA

IL-6R: A logical target in RA. Dr Ernest Choy King’s College Hospital, London, UK. IL-6 is a key regulator of the inflammatory response. IFN . sTNFR, TNF-  IL-10, IL-1, IL-18, IL-IR. IL-17. T cell. Macrophage. Fibroblast. IL-15. IL-18. IL-8. FGF TGF . IL-6. IL-6. B cell.

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IL-6R: A logical target in RA

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  1. IL-6R: A logical target in RA Dr Ernest Choy King’s College Hospital, London, UK

  2. IL-6 is a key regulator of the inflammatory response IFN sTNFR, TNF-IL-10, IL-1, IL-18, IL-IR IL-17 T cell Macrophage Fibroblast IL-15 IL-18 IL-8 FGFTGF IL-6 IL-6 B cell RANKL Rheumatoid factor Liver Chondrocyte Cartilage Acute-phaseproteinsHepcidin Osteoclast Bone Firestein GS. Nature 2003; 423:356–361; Smolen JS and Steiner G. Nat Rev Drug Disc 2003; 2:473–488.

  3. IL-6 has both articular and systemic effects in RA Articular effects • Pannus formation • IL-6 induces VEGF production • Bone • IL-6 is known to promote osteoclast maturation and activation • IL-6 may be crucial in mediating the impact of chronic inflammation Systemic effects • Liver • IL-6 is the chief stimulator of acute phase proteins • IL-6 induces hepatocyte proliferation • Anaemia • Chronic inflammatory diseases are characterised by anaemia • A clear association between IL-6 and anaemia has been shown • Lipids and lipid metabolism • IL-6 can stimulate both hepatic fatty acid synthesis and adipose tissue lipolysis

  4. IL-6 and rheumatoid arthritis • IL-6 and cell signalling • IL-6 articular effects • IL-6 systemic effects • IL-6 immune effects • Summary and conclusions

  5. IL-6 and rheumatoid arthritis • IL-6 and cell signalling • IL-6 articular effects • IL-6 systemic effects • IL-6 immune effects • Summary and conclusions

  6. Brookhaven Databank accession number for IL-6 is 1IL6 Properties of IL-6 • Small polypeptide1 • Four -helix bundle1 • Structure stabilisationby intramolecular disulphide bridges2 1 Heinrich PC, et al. Biochem J 1998; 334:297–314.2 Somers W, et al. EMBO J 1997; 16:989–997.

  7. The IL-6 receptor (IL-6R) complex has multiple subunits • Membrane-anchoredIL-6 receptor1 • Glycoprotein (gp)130 signal-transducing subunit1 • Low expression levels of the cognate membrane-anchored IL-6R is restricted to a sub-population of cells in healthy tissue2 mIL-6R gp130 Membrane signalling 1. Heinrich PC, et al. Biochem J 2003; 374:1–20.2. Rose-John S, et al. J Leukoc Biol 2006; 80:227–236.

  8. IL-6 trans-signalling • A soluble IL-6R (sIL-6R) is formed by: • Proteolytic cleavage of the extracellular portion of the membrane-bound IL-6R (mIL-6R) • Alternative mRNA splicing • The IL-6/sIL-6R complex interacts with membrane-bound gp130 to induce signalling (trans-signalling) • IL-6 activates cells that do not express the mIL-6R sIL-6R gp130 Trans-signalling

  9. IL-6 IL-6 IL-6 signals through membrane-bound and soluble receptors sIL-6R mIL-6R gp130 gp130 Membrane signalling Trans-signalling

  10. P P P P JAK Y Y IL-6 IL-6R JAK gp130 STAT3 SHP2 P P gp130-mediated signal transduction • JAK1, an intracellular tyrosine kinase • SHP2, a tyrosine phosphatase recruitedto activated gp130 • STAT3, an SH2-domain-containing transcription factor • SOCS3, produced in response to IL-6R signalling; inhibits IL-6R signalling Cytoplasm Nucleus Target genes SOCS3 • JAK, Janus kinase • SHP2, SH2-domain-containing tyrosine phosphatase • STAT, signal transducer and activator of transcription • SOCS, suppressor of cytokine signalling Heinrich PC, et al. Biochem J 2003; 374:1–20; Heinrich PC, et al. Biochem J 1998; 334:297–314.

  11. IL-6 IL-6 IL-6 signals through membrane-bound and soluble receptors sIL-6R mIL-6R gp130 gp130 Membrane signalling Trans-signalling

  12. IL-6 and rheumatoid arthritis • IL-6 and cell signalling • IL-6 articular effects • IL-6 systemic effects • IL-6 immune effects • Summary and conclusions

  13. Elevated levels of IL-6 and sIL-R correlate with disease activity in RA • IL-6 is associated with increases in rheumatoid factor1 • IL-6 and sIL-6R correlate with severity of joint destruction1 • sIL-6R correlates with leukocyte infiltration1 • Elevated serum IL-6 and sIL-6R correlate with RA disease stage2 IL-6 sIL-6R 90 60 Serum sIL-6R concentration (ng/mL) Serum IL-6 concentration (pg/mL) 80 55 70 60 50 50 45 40 30 40 20 35 10 0 30 Stage 4 Healthy controls Stage 1/2 Stage 3 1. Jones SA, et al. J Interferon Cytokine Res2005; 25:241–253.2. Robak T, et al. Mediators Inflamm1998; 7:347–353.

  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 R2=0.774 4000 p<0.01 IL-6 (pg/ml) 2000 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. Anti-IL-6R mAb inhibits leukocyte accumulation in a murine inflammatory model 10 8 6 * ** Total leukocytes (x106/mL) 4 2 0 Mice mAb IL-6 +/+ – IL-6 -/- – IL-6 +/+ Irrelevant IL-6 +/+ Anti-IL-6R *p≤0.05, **p≤0.01 Romano M, et al. Immunity 1997; 6:315–325.

  16. * * * Joint destruction induced by excessive IL-6 200 • 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 fluid2,3 150 * 100 Osteoclast-like cells/well 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. *p≤0.05

  17. IL-6 may contribute to pannus formation by stimulating 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 102pg/mL) 8 4 0 IL-6/sIL-6R — — + + + + IL-1 — + + + + + TNF- — + + + + + Inhibitors — — — IL-6R IL-1R TNF- Nakahara H, et al. Arthritis Rheum 2003; 8:1521–1529.

  18. IL-6 and rheumatoid arthritis • IL-6 and cell signalling • IL-6 articular effects • IL-6 systemic effects • IL-6 immune effects • Summary and conclusions

  19. Acute inflammation is generally accompanied by a systemic reaction known as the acute-phase response, which is characterised by a rapid alteration in the levels of several plasma proteins IL-6 is the chief stimulator of the production of most acute-phase proteins IL-6 is the chief stimulator of the acute-phase response 30,100 30,000 700 600 C-reactive protein 500 Serum amyloid A Change in plasma concentration (%) 400 Haptoglobin 300 Fibrinogen 200 100 C3 0 Transferrin Albumin 0 7 14 21 Time after inflammatory stimulus (days) Gabay C and Kushner K. N Engl J Med 1999; 340:448–454.

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

  21. IL-6 induces hepcidin production by hepatocytes • Hepcidin inhibits: • Release of iron from macrophages (reticuloendothelial block) • Absorption of dietary iron (iron deficiency) Inflammation Macrophage iron release Hepcidin IL-6 Macrophage Hepatocytes Intestinal iron absorption Andrews NC, J Clin Invest 2004; 113:1251–1253; Nemeth E, J Clin Invest 2004; 113:1271–1276.

  22. Strong association between systemic inflammation and coronary artery disease • Levels of inflammatory mediators (acute-phase reactants) are higher in patients with coronary artery disease1 • Patients with RA experience a markedly increased frequency of CVD and have increased CV mortality1,2 • In active RA, the majority of CV deaths result from accelerated atherosclerosis3 1. Dessein PH, et al. Arthritis Res 2002; 4:R5. 2. Del Rincon I, et al. Arthritis Rheum 2001; 44:2737–2745. 3. Georgiadis AN, et al. Arthritis Res Ther 2006; 8:R82.

  23. IL-6 is implicated in the development of coronary artery disease • IL-6 is the chief inducer of CRP which stimulates macrophages to produce Tissue Factor – a pro-coagulant found in atherosclerotic plaques1 • IL-6 levels predict outcome following hospitalisation for unstable angina2 Outcomes according to IL-6 levels 48 hours following hospitalisation for unstable angina 80 60 IL-6 (pg/mL) 40 20 0 Good outcome Refractory angina AMI and death 1. Georgiadis AN, et al. Arthritis Res Ther 2006; 8:R82. 2. Biasucci LM, et al. Circulation 1999; 99:2079–2084. AMI = acute myocardial infarction

  24. IL-6 and lipid metabolism • Patients with RA have abnormal lipid levels (low total cholesterol, low LDL) • IL-6 can stimulate both hepatic fatty acid synthesis and adipose tissue lipolysis • The overall effect of IL-6 is to increase cholesterol synthesis but to decrease cholesterol secretion KhovidhunkitW, et al. J Lipid Res 2004; 45:1169–1196.

  25. Adverse lipid profile prior to the development of RA • Complete lipid profiles were determined from blood bank samples of which 79 patients later developed RA • Lipid profiles were assessed up to 10 years prior to the development of RA • These samples were compared with control samples of blood donors, matched for age, sex and storage time • Results: Samples from patients who later developed RA showed, 4% higher total cholesterol, 9% lower HDLc, 17% higher triglyceride and 6% higher apoB levels than matched controls (p<0.05) before the onset of RA • Conclusion: Patients with RA had a considerably higher atherogenic lipid profile prior to the onset of RA Van Helm VP et al. Ann Rheum Dis. 2007;66:184-8

  26. Serum cholesterol and triglycerides in active and inactive RA Situnayake RD and Kitas G. Ann Rheum Dis 1997;56:341-342.

  27. Excessive IL-6 contributes to osteoporosis in RA • Systemic osteoporosis is a common feature of RA and sJIA1 • 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 p<0.05 –40 –50 1. Lipsky P, Arthritis ResTher 2006; 8(Suppl 2):S4. 2.Kotake S, et al. J Bone Min Res 1996; 11:88–95. 3. Poli V, et al. EMBO 1994; 13:1189–1196. –60

  28. Summary • IL-6 is a key regulator of the inflammatory response • High levels of IL-6 are found in sera and synovial fluid • IL-6 concentrations correlate with disease activity and joint damage in RA • Elevated levels of IL-6 are responsible for many of the systemic manifestations of RA

  29. IL-6 and rheumatoid arthritis • IL-6 and cell signalling • IL-6 articular effects • IL-6 systemic effects • IL-6 immune effects • Summary and conclusions

  30. IL-6 and Th17 cells Weaver CT, et al. Immunology 2006; 24:677–688.

  31. Prevention of murine collagen-induced arthritis with a murine anti-IL-6R mAb 15 1500 Control IgG 8 mg MR16-1 0.5 mg MR16-1 2 mg MR16-1 8 mg 10 1000 IgG anti-collagen antibody (units/mL) Arthritis score 5 500 0 0 10 20 30 40 50 ControlIgG 0.5 mg 2 mg 8 mg Days after first immunisation MR16-1 • In mice with collagen-induced arthritis (CIA), serum IL-6increased in conjunction with the onset of arthritis • Anti-IL-6R antibody inhibited the development of arthritis in adose-dependent manner Takagi N, et al. Arthritis Rheum 1998; 41:2117–2121. Yoshizaki K, et al. Springer Semin Immunopathol 1998; 20:247–259. Data on file.

  32. Successful treatment of Cynomolgus monkey CIA with a human anti-IL-6R mAb Vehicle TCZ 10 mg/kg 2.0 2.0 1.8 1.8 1.6 1.6 1.4 1.4 Swelling Rate Rate 1.2 1.2 1.0 1.0 0.8 0.8 0.6 0.6 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 Weeks after collagen immunisation Weeks after collagen immunisation 50 50 Vehicle TCZ 10 mg/kg 40 40 Stiffness 30 30 Score Score 20 20 10 10 0 0 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 Weeks after collagen immunisation Weeks after collagen immunisation Each symbol indicates individual data from five monkeys (except for Weeks 12 and 14 of the vehicle group, where data from four monkeys were used). Mihara M, et al. Clinical Immunology 2001; 98:319–326.

  33. Conclusions • IL-6 is an important cytokine which has a major pathogenic role in RA • The role of IL-6 in the pathogenesis of RA suggests therapies that target IL-6 signalling by blocking the IL-6R will improve articular and systemic manifestations of RA

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