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  • 1. Approximately 5% to 10% of patients with asthma have severe disease that is refractory or poorly responsive to inhaled corticosteroid therapy
  • 2. Tumor necrosis factor › TNF-a – cachectin, cachexin › TNF-b - lyphotoxin Tumor necrosis factor and asthma Anti-tumor necrosis factor in asthma
  • 3. Pleiotropic pro-inflammatory cytokine initially produced as a 26 kDa membrane-anchored precursor protein TNF reppresent 2 homologus protein primarily derived from mononuclear phagocytes (TNF-α) and Lymphocyte (TNF-β) Larry Borish : Middleton 7th edition
  • 4. TNF-α is processed as a membrane- bound protein from which the soluble active factor (17 kDa free protein) is derived via cleavage using the enzyme TNF-α converting enzyme (TACE), known as ADAM 17 The active form is a homotrimer (51 kDa) Larry Borish : Middleton 7th edition
  • 5. Most potent inducer of TNF by monocytes is LPS acting through TLR4 and CD14γ TNF-α may be produced by neutrophils, activated lymphocytes, natural killer cells, endothelial cells, and mast cells Larry Borish : Middleton 7th edition
  • 6. Activation results in a remarkably diverse set of cellular responses, apoptosis, inflammation and inhibit tumor genesis and viral replication C. Russo and R. Polosa:Clinical Science (2005) 109, 135–142
  • 7. TNF-α and TNF-β bind to the same two distinct cell surface receptors – TNFR I (p55 or CD120a) and TNFR II (p75 or CD120b) 2 receptors are expressed on the surface of many cell types › TNFR I expressed on cells susceptible to the cytotoxic action of TNF-α › TNFR II expressed strongly on stimulated B- and T- cells Larry Borish : Middleton 7th edition
  • 8. Subsequent phosphorylation of NF-κB activates the p50–65 subunit, interact with DNA chromatin structure to increase the transcription of pro- inflammatory genes, such as IL-8, IL-6, and TNF-a Summary of TNF-a biology and signaling Christopher Brightling, Mike Berry : J Allergy Clin Immunol 2008;121:5-10
  • 9. TNF interacts with endothelial cells to induce intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, permitting the egress of granulocytes into inflammatory loci TNF is a potent activator of neutrophils, mediating adherence, chemotaxis, degranulation, and the respiratory burst Larry Borish : Middleton 7th edition
  • 10. TNF is responsible for the severe cachexia that occurs in chronic infections and cancer TNF induces vascular leakage, has negative inotropic effects, and is the primary endogenous mediator of toxic shock and sepsis Larry Borish : Middleton 7th edition
  • 11. Role of TNF-a in the pathogenesis of asthma. TNF-a plays a central role in many of the features of the asthma paradigm by exerting important effects on both inflammatory and structural cells Christopher Brightling, Mike Berry : J Allergy Clin Immunol 2008;121:5-10
  • 12. TNF-a contributes to the dysregulated inflammatory response seen in the asthmatic airway was raised by the findings of increased TNF-a mRNA and protein in the airways of patients with asthma Administration of inhaled recombinant TNF-a to normal subjects led to the development ofAHR and an airway neutrophilia Thomas PS, Barnes PJ: Tumor necrosis factor-alpha increases airway responsiveness and sputum neutrophilia in normal human subjects. Am J Respir Crit Care Med 1995, Mike Berry: Current Opinion in Pharmacology 2007
  • 13. Administration of TNF-a to patients with asthma also leads to an increase in AHR, as measured by a reduction in methacholine PC20 Thomas PS, Heywood G: Effects of inhaled tumour necrosis factor alpha in subjects with mild asthma. Thorax 2002 It could be caused by a direct effect of TNF-a on airway smooth muscle or by the release of the cysteinyl- leukotrienes LTC4 and LTD4 Mike Berry: Current Opinion in Pharmacology 2007
  • 14. TNF-a induces histamine release from human mast cells directly van Overveld FJ, Vermeire PA: Tumour necrosis factor stimulates human skin mast cells to release histamine and tryptase. Clin Exp Allergy 1991 Participates in a positive autocrine loop that potentiates human mast cell cytokine secretion Coward WR, Holgate ST: NF-kappa B and TNF- alpha: a positive autocrine loop in human lung mast cells? J Immunol 2002 Mike Berry: Current Opinion in Pharmacology 2007
  • 15. Chemoattractant for neutrophils and eosinophils it increases the cytotoxic effect of eosinophils on endothelial cells It is involved in the activation of cytokine release by T cells and it increases epithelial expression of adhesion molecules such as ICAM-1 and VCAM-1 Mike Berry: Current Opinion in Pharmacology 2007
  • 16. TNF-a has several properties that might be relevant to refractory asthma, including › recruitment of neutrophils › induction of glucocorticoid resistance › myocyte proliferation › stimulation of fibroblast growth and maturation into myofibroblasts by promoting TGF-a expression Mike Berry: Current Opinion in Pharmacology 2007
  • 17. Serpil C. Erzurum, N Engl J Med 2006;354:754-758
  • 18. Direct modulation of ASM contractile function by mast-cell derived TNF-a, mechanism in AHR Mast cell number correlated positively with the degree ofAHR Brightling CE, Holgate ST. Mastcell infiltration of airway smooth muscle in asthma. N Engl J Med 2002 Mast cells are the major source of TNF- a in the airways TNF-a induced AHR is mediated by direct effects on ASM Christopher Brightling, Mike Berry : J Allergy Clin Immunol 2008;121:5-10
  • 19. 1. enhanced receptor-associated calcium signals as a result of an increased expression, function, or both of the receptor G protein (Gaq or Gai) 2. altered signal transduction, such as increased phospholipase C (PLCb) expression, activity, or both Molecular mechanisms activated in ASM induced by TNF-a–activated molecular mechanisms in ASM possibly contributing to AHR in asthma Christopher Brightling, Mike Berry : J Allergy Clin Immunol 2008;121:5-10
  • 20. 3. abnormal calcium handling by exerting effects on key enzymes that regulate inositol-1,4,5- trisphosphate (IP3) metabolism, such as 5- phosphatase I and II, effects on function, and/or the expression of Ryanodine receptors (RyR), IP3 receptor (IP3R), or calcium ATPases called sarcoendoplasmic calcium ATPases (SERCA), which regulate calcium fluxes, or calmodulin (CaM) 4. changes in calcium sensitivity mediated by effects on RhoA expression or increases in both myosin light chain kinase (MLCK) or myosin light chain phosphatase (Pase) content, activity, or both Christopher Brightling, Mike Berry : J Allergy Clin Immunol 2008;121:5-10
  • 21. 3 TNFα antagonists licensed in USA › 2 monoclona lAb : adalimumab (ADA) and infliximab (INF) › soluble receptor : etanercept (ETA) Certolizumab pegol : Crohn ‘s disease Sandborn WJ, et al (2007). "Certolizumab pegol for the treatment of Crohn's disease". N. Engl. J. Med. 357 (3): 228–38 Golimumab : human monoclonal Ab, phase III clinical trial treatmeat RA
  • 22. prevention of the cleavage of the 26 kDa membrane-bound protein to the active 17 kDa molecule inhibition of TNFα protein translation acceleration of TNFα mRNA degradation inhibition of TNFα mRNA transcription Enrico Heffler, Mike Berry : Biodrugs 2007; 21
  • 23. a : Indications approved by the Food and Drug Administration (FDA) and European Union EMEA Jan Lin : Clin Immunol. 2008 January ; 126(1): 13–30
  • 24. Infliximab is a chimaeric mouse/human monoclonal anti-TNF-α antibody etanercept is a soluble fusion protein combining two p75 TNFRs with an Fc fragment of human IgG1 adalimumab is a fully human monoclonal anti-TNF-α antibody C. Russo and R. Polosa:Clinical Science (2005) 109, 135–142
  • 25. This was the first description of the use of anti-TNFa in asthma and, although an open study, it generated considerable excitement in the field Method › TNFa BAL fluid of 26 healthy controls, 42 subjects with mild asthma and 20 with severe asthma › TNFa gene expression was determined in endobronchial biopsy specimens from 14 patients with mild asthma and 14 with severe asthma › open label uncontrolled clinical study in 17 subjects with severe asthma to evaluate the effect of 12 weeks of treatment with the soluble TNFa receptor- IgG Fc fusion protein, etanercept 1 P H Howarth, S T Holgate : Thorax 2005;60:1012–1018
  • 26. A : TNFa concentrations in bronchoalveolar lavage B : TNFa gene expression in endobronchial biopsy C : Immunoreactive TNFa positive cell counts in endobronchial biopsy specimen D : Immunohistochemical staining and localisation of TNFa in submucosal cells P H Howarth, S T Holgate : Thorax 2005;60:1012–1018
  • 27. P H Howarth, S T Holgate : Thorax 2005;60:1012–1018
  • 28. P H Howarth, S T Holgate : Thorax 2005;60:1012–1018
  • 29. TNFa levels in BAL fluid, TNFa gene expression and TNFa immunoreative cells were increased in subjects with severe corticosteroid dependent asthma Etanercept treatment was associated with improvement in asthma symptoms, lung function, and bronchial hyperresponsiveness P H Howarth, S T Holgate : Thorax 2005;60:1012–1018
  • 30. This was the first double-blind placebo- controlled study of anti-TNFa in asthma Method › measured markers of TNF-α activity on peripheral-blood monocytes (CD14) › 10 refractory asthma, 10 mild-moderate asthma and 10 placebo › Investigated the effects of treatment with the soluble TNF-α receptor etanercept (25 mg twice weekly), refractory asthma Mike A. Berry, N Engl J Med 2006;354:697-708
  • 31. Treatment periods lasted 10 weeks and were separated by a 4-week washout period. The washout phase was chosen because the half-life of etanercept is 70 hours and, according to information provided by the manufacturer, clinical experience in patients with rheumatoid arthritis suggested that symptoms return within one month after treatment is stopped. Mike A. Berry, N Engl J Med 2006;354:697-708
  • 32. Mike A. Berry, N Engl J Med 2006;354:697-708
  • 33. Mike A. Berry, N Engl J Med 2006;354:697-708
  • 34. Open symbols in Panels A and B represent patients who received etanercept first in the crossover trial, and closed symbols those who received placebo first Mike A. Berry, N Engl J Med 2006;354:697-708
  • 35. Mike A. Berry, N Engl J Med 2006;354:697-708
  • 36. Compare patients with mild-to- moderate asthma and controls, patients with refractory asthma had increased expression of membrane-bound TNF-α, TNF-α receptor 1, and TNF-α–converting enzyme by peripheral-blood monocytes Mike A. Berry, N Engl J Med 2006;354:697-708
  • 37. Clinical trial, as compared with placebo, 10 weeks of treatment with etanercept was associated with a significant increase in the concentration PC20, improvement in the asthma-related quality-of-life score and 0.32-liter increase in postbronchodilator FEV1 Mike A. Berry, N Engl J Med 2006;354:697-708
  • 38. Method › Double-blind, placebo controlled, 38 moderate asthma with ICS but symptomatic during a run-in phase › Infliximab (5 mg/kg) or placebo by IV infusion at Weeks 0, 2, and 6 › clinical response by monitoring lung function, symptoms, and inhaled β2 agonist usage using hand held electronic device Edward M, Peter J. Barnes : Am J Respir Crit Care Med Vol 174. pp 753–762, 2006
  • 39. ITT intention to treat; PEP primary endpoint group with sufficient PEF rate in the last 7 d before the penultimate clinic visit (approximately 8 wk); PP per protocol (patients meet inclusion criteria and complete clinic visits). Edward M, Peter J. Barnes : Am J Respir Crit Care Med Vol 174. pp 753–762, 2006
  • 40. Electronic diary lung function, symptoms, and β2-agonist usage Edward M, Peter J. Barnes : Am J Respir Crit Care Med Vol 174. pp 753–762, 2006
  • 41. Edward M, Peter J. Barnes : Am J Respir Crit Care Med Vol 174. pp 753–762, 2006
  • 42. Edward M, Peter J. Barnes : Am J Respir Crit Care Med Vol 174. pp 753–762, 2006
  • 43. A : Incidence of exacerbations over Weeks 0–8 B : freedom from exacerbation over time. Infliximab (n = 14) and placebo (n = 18) Edward M, Peter J. Barnes : Am J Respir Crit Care Med Vol 174. pp 753–762, 2006
  • 44. Infliximab (n 15) and placebo (n 18). *p < 0.05 or **p < 0.01 for comparison of infliximab versus placebo at given time points, Edward M, Peter J. Barnes : Am J Respir Crit Care Med Vol 174. pp 753–762, 2006
  • 45. Infliximab was associated with a decrease in mean diurnal variation of PEF at Week 8 Decrease in the number of patients with exacerbations of asthma Increased probability of freedom from exacerbation with time Infliximab decreased levels of TNF-a in sputum No serious adverse events Edward M, Peter J. Barnes : Am J Respir Crit Care Med Vol 174. pp 753–762, 2006
  • 46. Method › RDBCT, Etanacept once weekly for 12 weeks 39 severe corticosteroid refractory asthma › Efficacy was measured by change from the pretreatment baseline in Asthma Related Quality of Life (AQLQ) and Asthma Control (ACQ) Questionnaire scores (the primary endpoints), › Lung function, PEF and BHR › Sputum and serum inflammatory cells and cytokines, serum albumin and C reactive protein as biomarkers of inflammation J B Morjaria, S T Holgate : Thorax 2008;63:584–591
  • 47. screening, baseline enrolment, during 12 weeks of etanercept treatment or placebo and subsequent follow-up J B Morjaria, S T Holgate : Thorax 2008;63:584–591
  • 48. J B Morjaria, S T Holgate : Thorax 2008;63:584–591
  • 49. J B Morjaria, S T Holgate : Thorax 2008;63:584–591
  • 50. Reduction of ACQ scores between treatment and placebo Improvement in systemic inflammation, as measured by serum albumin and CRP Minor adverse events, including injection site pain and skin rashes, were more frequent with etanercept J B Morjaria, S T Holgate : Thorax 2008;63:584–591
  • 51. Method › 309 severe and uncontrolled asthma, despite high-dose ICS and long-acting β2 agonists, were randomized 1:1:1:1 to monthly SC injections of placebo or golimumab (50, 100, or 200 mg) throughWeek 52 › prebronchodilator percent-predicted FEV1and the number of severe asthma exacerbations through Week 24 Sally E. Wenzel, Peter J. Barnes, Stephen T. Holgate : Am J Respir Crit Care Med Vol 179. pp 549–558, 2009
  • 52. Sally E. Wenzel, Peter J. Barnes, Stephen T. Holgate : Am J Respir Crit Care Med Vol 179. pp 549–558, 2009
  • 53. Change from baseline in prebronchodilator percent-predicted FEV1 through Week 24 Sally E. Wenzel, Peter J. Barnes, Stephen T. Holgate : Am J Respir Crit Care Med Vol 179. pp 549–558, 2009
  • 54. patients who completed Additional exacerbations study participation through calculated for patients who Week 24 withdrew early Number of severe asthma exacerbations from baseline through Week 24 Sally E. Wenzel, Peter J. Barnes, Stephen T. Holgate : Am J Respir Crit Care Med Vol 179. pp 549–558, 2009
  • 55. All patients all group Sally E. Wenzel, Peter J. Barnes, Stephen T. Holgate : Am J Respir Crit Care Med Vol 179. pp 549–558, 2009
  • 56. Unfavorable risk–benefit profile led to early discontinuation of study-agent administration after the Week-24 ThroughWeek 76, 20.5%of patients treated with placebo and 30.3% of patients treated with golimumab experienced serious adverse events, with serious infections One death and all eight malignancies occurred in the active groups Sally E. Wenzel, Peter J. Barnes, Stephen T. Holgate : Am J Respir Crit Care Med Vol 179. pp 549–558, 2009
  • 57. Study N Severity Design Outcome Result Howarth 15 GINA V Open label, 1: AQLQ Improvement in AQLQ, Etanercept uncontrolled 2:FEV1, AHR FEV1,AHR Berry 10 7 GINA V RCT, cross over 1: AHR and Improvement in AQLQ, Etanercept 3 GINA IV AQLQ FEV1,AHR 2: FEV1, eNO, Increase sputum sputum cell histamine counts Edward 38 Moderate RCT 1: morning PEF No change morning PEF Infliximab asthma, ICS 2: FEV1, Decrease exacerbate of onlly exacerbations, asthma sputum markers Improved PEF variability Morjaria 39 21 GINA V RCT 1: AQLQ No benefit compare Etanercept 18 GINA IV 2: ACQ, FEV1, with placebo PEF, AHR, Reduction ACQ exacerbation Sally 309 GINA V RCT 1: FEV1 Serious adverse effect Golimumab 2: exacerbation AHR, airway hyperresponsiveness; AQLQ, Asthma Quality of Life Questionnaire; ENO, exhaled nitric oxide; FEV1, forced expiratory volume in one second; ICS: inhaled corticosteroids; PEF, peak expiratory flow
  • 58. TNF-a elevate in severe asthma TNF-a and asthma › Direct histamine release from mast cell › Chemoattactant › Increase adhesion molecule › AHR, ASM contraction Anti-TNFa, etanercept improvement AQLQ in severe athma