Discipline MCP5777 In-depth Study of the Treatment of Interstitial Idiopathic Pulmonary Fibrosis. Duration Total

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1 Discipline MCP5777 In-depth Study of the Treatment of Interstitial Idiopathic Pulmonary Fibrosis Subject Area: 5150 Created: 27/11/2014 Active since: 27/11/2014 Number of credits: 1 Hours: Theoretical Practical Self-study Duration Total (per week) (per week) (per week) week 15 hours Faculty Members Responsible: Ronaldo Adib Kairalla Carlos Roberto Ribeiro de Carvalho Bruno Guedes Baldi Objectives: To critically discuss and analyze the therapeutic options available for the idiopathic pulmonary fibrosis (IPF), taking into account the pathophysiological aspects and the new pharmacological options based in recent studies, which brought more favorable perspectives to patients. Background: The better understanding of the mechanisms of the alveolar-capillary membrane injury and of the repair response in idiopathic pulmonary fibrosis (IPF), which has been acquired in recent years, in addition to the appearance of new perspectives in the treatment with blockers of the fibrosis, such as pirfenidone and tyrosine kinase inhibitors, has improved the perspective for IPF patients. The aim of this discipline is to present and discuss these new concepts and the results observed with the new treatments of IPF, besides discussing the optimized monitoring of the pharmaceutical response. Content: Theoretical lessons: 1. In-depth study of the pathophysiology of idiopathic pulmonary fibrosis (IPF). 2. Correlation between pathology and pulmonary function in the IPF. Seminars 1. In-depth study of the etiology and pathogenesis of the idiopathic pulmonary fibrosis, including analysis of experimental models used in IPF. 2. Analysis of the

2 established prognostic factors, including clinical, tomographic, functional and histopathological parameters. 3. Critical study of the pharmacological treatment with corticosteroids, immunosuppressants and n-acetyl-cysteine. 4. Critical study of the pharmacological treatment with medications that act in the fibrosis, such as the pirferidone and the tyrosine kinase inhibitors. 5. Pharmacological treatment: future perspectives. 6. Analysis of the parameters used for the evaluation of therapeutic response. 7. Critical analysis of pulmonary transplant as a therapeutic option. Assessment Method: 1. Seminar presentation 2. Participation in the discussion of the topics. Observation: Bibliography: 1. American Thoracic Society. (2000) Idiopathic pulmonary fibrosis: diagnosis and treatment: international consensus statement; American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 161(2 pt 1), Alton, EW, Johnson, M, Turner-Warwick, M. Advanced cryptogenic fibrosing alveolitis: preliminary report on treatment with cyclosporin A. Respir Med 1989; 83: Baughman, RP, Lower, EE. Use of intermittent, intravenous cyclophosphamide for idiopathic pulmonary fibrosis. Chest 1992; 102: Carrington, CB, Gaensler, EA, Coutu, RE, et al. Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 1978; 298: Cegla, UH. Treatment of idiopathic fibrosing alveolitis. Therapeutic experiences with azathioprine-prednisolone and D-penicillamine-prednisolone combination therapy. Schw Med Woch 1977; 107: Chapela, R, Zuniga, G, Selman, M. D-penicillamine in the therapy of fibrotic lung diseases. Int Jour Clin Pharm Ther Tox 1986; 24: Costabel, U, Matthys, H. Different therapies and factors influencing response to therapy in idiopathic diffuse fibrosing alveolitis. Respiration 1981; 42: Johnson, MA, Kwan, S, Snell, NJC, et al. Randomized controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis. Thorax 1989; 44: Keogh, BA, Bernardo, J, Hunninghake, GW, et al. Effect of intermittent high dose parenteral corticosteroids on the alveolitis of idiopathic pulmonary fibrosis. Am Rev Respir Dis 1983; 127: Panos, RJ, Mortenson, R, Niccoli, SA, King, TE Jr. Clinical deterioration in patients with idiopathic pulmonary fibrosis. Causes and assessment. Am J Med 1990; 88: Peters, SG, McDougall, JC, Douglas, WW, et al. Colchicine in the treatment of pulmonary fibrosis. Chest 1993; 103: Raghu, G, Depaso, WJ, Cain, K, et al. Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: A prospective, double-blind randomized, placebo-controlled clinical trial. Am Rev Respir Dis 1991; 144: Schwartz, DA, Helmers, RA, Galvin, JR, et al. Determinants of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1994; 149: Schwartz, DA, Van Fossen, DS, Davis, CS, et al. Determinants of progression in

3 idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1994; 149: Turner-Warwick, M, Burrows, B, Johnson, A. Cryptogenic fibrosing alveolitis: Response to corticosteroid treatment and its effect on survival. Thorax 1980; 35: Winterbauer, RH, Hammar, SP, Hallman, KO, et al. Diffuse interstitial pneumonitis: Clinicopathologic correlations in 20 patients treated with prednisone/azathioprine. Am J Med 1978; 65: Behr J, Maier K, Degenkolb B, Krombach F, Vogelmeier C. Antioxidative and clinical effects of high-dose N-acetylcysteine in fibrosing alveolitis. Adjunctive therapy to maintenance immunosuppression. Am J Respir Crit Care Med 156: , American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This Joint Statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS Board of Directors, June 2001 and by The ERS Executive Committee, Am. J. Respir. Crit. Care Med. 165: , Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 134:136-51, Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH.A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med 341:1264-9, Douglas WW, Ryu JH, Schroeder DR.Idiopathic pulmonary fibrosis: Impact of oxygen and colchicine, prednisone, or no therapy on survival. Am J Respir Crit Care Med 161:1172-8, Raghu, G Idiopathic pulmonary fibrosis: treatment options in pursuit of evidencebased approaches. Eur Respir J 2006;28, Ask, K, Martin, GE, Kolb, M, et al Targeting genes for treatment in idiopathic pulmonary fibrosis: challenges and opportunities, promises and pitfalls. Proc Am Thorac Soc 2006;3, Cool, CD, Groshong, SD, Rai, PR, et al Fibroblast foci are not discrete sites of lung injury or repair: the fibroblast reticulum. Am J Respir Crit Care Med 2006;174, Lama, VN, Phan, SH The extrapulmonary origin of fibroblasts: stem/progenitor cells and beyond. Proc Am Thorac Soc 2006;3, Azuma, A, Nukiwa, T, Tsuboi, E, et al Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005;171, Martinez, FJ, Safrin, S, Weycker, D, et al The clinical course of patients with idiopathic pulmonary fibrosis. Ann Int Med 2005;142, Lynch, DA, Travis, WA, Muller, NL, et al Idiopathic interstitial pneumonias: CT features. Radiology 2005;236, Aziz, AZ, Wells, AU, Bateman, ED, et al Interstitial lung disease: effects of thinsection CT on clinical decision making. Radiology 2006;238,

4 30. Souza, CA, Muller, NL, Flint, J, et al Idiopathic pulmonary fibrosis: spectrum of high-resolution CT findings. AJR Am J Roentgenol 2005;185, Orens, JB, Estenne, M, Arcasoy, S, et al International guidelines for the selection of lung transplant candidates: 2006 update; a consensus report from the pulmonary scientific council of the international society for heart and lung transplantation. J Heart Lung Transplant 2006;25, Azuma, A, Nukiwa, T, Tsuboi, E, et al Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005;171, Raghu G, Yang ST, Spada C, Hayes J, Pellegrini CA. Sole treatment of acid gastroesophageal reflux in idiopathic pulmonary fibrosis: a case series. Chest 2006;129: Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a 35. randomised controlled trial. Lancet 2002;360: Kubo, H, Nakayama, K, Yanai, M, et al Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005;128, Demedts, M, Behr, J, Buhl, R, et al High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353, Parambil, JG, Myers, JL, Ryu, JH Histopathologic features and outcome of patients with acute exacerbation of idiopathic pulmonary fibrosis undergoing surgical lung biopsy. Chest 2005;128, Hyzy, Robert, Huang, Steven, Myers, Jeffrey, Flaherty, Kevin, Martinez, Fernando Acute Exacerbation of Idiopathic Pulmonary Fibrosis. Chest : Thabut, G, Mal, H, Castier, Y, et al Survival benefit of lung transplantation for patients with idiopathic pulmonary fibrosis. J Thorac Cardiovasc Surg 2003;126, Kondoh, Y, Taniguchi, H, Kitaichi, M, et al Acute exacerbation of interstitial pneumonia following surgical lung biopsy. Respir Med 2006;100, Yuksel, M, Ozyurtkan, MO, Bostanci, K, et al Acute exacerbation of interstitial fibrosis after pulmonary resection. Ann Thorac Surg 2006;82, Ueda, T, Ohta, K, Suzuki, N, et al Idiopathic pulmonary fibrosis and high prevalence of serum antibodies to hepatitis C virus. Am Rev Respir Dis 1992;146, King Jr TE, Behr J, Brown KK, et al. A Randomized Placebo-Controlled Trial of Bosentan in Patients with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med

5 2008;177: King Jr TE, Brown KK, Raghu G, et al. A Randomized, Controlled Trial of Bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;184: Olschewski, H, Ghofrani, HA, Walmrath, D, et al Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med 1999;160: Ghofrani, HA, Wiedemann, R, Rose, F, et al Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002;360: Homma, S, Sakamoto, S, Kawabata, M, et al Cyclosporin treatment in steroidresistant and acutely exacerbated interstitial pneumonia. Intern Med 2005;44: Shulgina L, Cahn AP, Chilvers ER, et al. Treating idiopathic pulmonary fibrosis with the addition of co-trimoxazole: a randomized controlled trial. Thorax 2013;68: du Bois RM, Nathan SD, Richeldi L, et al. Idiopathic pulmonary fibrosis: lung function is a clinically meaningful endpoint for Phase III Trials. Am J Respir Crit Care Med 2010;186: King Jr TE, Albera C, Bradford WZ, et al. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomized, placebo-controlled trial. Lancet 2009;374: King Jr TE, Bradford WZ, Castro-Bernardini S, et al. A phase III trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014;370: Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011;377: Noth I, Anstrom KJ, Calvert SB, et al. A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2012;1: Raghu G, Collard HR, Anstrom KJ, et al. Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. Am J Respir Crit Care Med 2012;185: Idiopathic pulmonary fibrosis clinical research network, Martinez FJ, de Andrade JA, Anstrom KJ, et al. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2014;370: Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370: King Jr TE, Albera C, Bradford WZ, et al. All-cause mortality rate in patients with idiopathic pulmonary fibrosis.: implications for the design and execution of clinical

6 trials. Am J Respir Crit Care Med 2014;189: Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT Statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183: