IPF IPF 7 IPF 5-7 IPF 20 IPF 8 ( / ) (Epstein-Barr virus, influenza virus, cytomegalovirus, hepatitis C virus) 9 IPF IPF (a

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附雍幸
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1 DOI /JIMT _29(5) 摘要 (usual interstitial pneumonia, UIP) 0.9 nintedanib pirfenidone (Lung fibrosis) (Interstitial lung disease) (idiopathic pulmonary fibrosis, IPF) (idiopathic interstitial pneumonia, IIP) IPF (usual interstitial pneumonia, UIP) / IPF IPF IPF 4 IPF 2~10 14~43 5 IPF

2 IPF IPF 7 IPF 5-7 IPF 20 IPF 8 ( / ) (Epstein-Barr virus, influenza virus, cytomegalovirus, hepatitis C virus) 9 IPF IPF (autosomaldominant) ELMOD2 (ELMO Domain Containing 2) (htert, human telomerase reverse transcriptase) RNA (htr, human telomerase RNA) 10 IPF surfactant protein A, surfactant protein C (htert, htr) (DSP, DPP9) IPF IPF 11,12 IPF (fibrogenic growth factor) (macrophages, T-cells, NK cells, etc.) (cytokines) transforming growth factor β(tgf β), plateletderived growth factor (PDGF), vascular endothelial growth factor receptors (VEGFR), Alpha-v-beta-6 integrin (αvβ6), Sonic Hedgehog (SHh) (fibroblasts) (myofibroblasts) IPF (Velcro crackles) (clubbing finger) IPF (interstitial lung disease) (UIP) / 1 IPF IPF C-reactive Protein (CRP) erythrocyte sedimentation rate (ESR) lactic dehydrogenase (LDH) antinuclear antibody (ANA) rheumatoid factor(rf) IPF

285 (bronchoalveolar lavage, BAL) IPF IPF (restrictive lung disease) total lung capacity (TLC) functional residual capacity (FRC) residual volume(rv) forced vital capacity (FVC) forced expiratory

3 285 (bronchoalveolar lavage, BAL) IPF IPF (restrictive lung disease) total lung capacity (TLC) functional residual capacity (FRC) residual volume(rv) forced vital capacity (FVC) forced expiratory volume-one second(fev1) diffusing capacity of lung for carbon monoxide(dlco) IPF (HRCT, high-resolution computed tomography) UIP IPF UIP 4 ( 1) UIP UIP UIP UIP IPF HRCT UIP UIP IPF 4 high-resolution computed tomography, HRCT 2015 Usual interstitial pneumonia (UIP, ) UIP ( ) UIP ( ) UIP ( ) UIP ( ) UIP ( ) (mosaic attenuation) air-trapping 7. /

286 IPF IPF UIP 4 (geographic heterogeneity) (temporal heterogeneity) 4 / / (subpleural/paraseptal) (honeycombing) (patchy involvement) (fibroblast foci) UIP 1. (geographic heterogeneity) 2.

4 286 IPF IPF UIP 4 (geographic heterogeneity) (temporal heterogeneity) 4 / / (subpleural/paraseptal) (honeycombing) (patchy involvement) (fibroblast foci) UIP 1. (geographic heterogeneity) 2. (temporal heterogeneity) 2015 probable UIP possible UIP ( ) UIP (multidisciplinary discussion, MDD) IPF ( ) 4 IPF IPF (acute exacerbation) IPF 5,7 IPF (DLco FVC TLC) (Body Mass Index, BMI) 23 (>320 ) IPF Krebs von den Lungen-6 (KL-6) matrix metalloproteinase-7 (MMP-7) surfactant proteins A D (SP-A SP-D) 16 Usual interstitial pneumonia (UIP, ) UIP ( ) UIP (Probable UIP) UIP (Possible UIP) ( ) UIP ( ) 1. / / UIP ( ) 1. / UIP ( ) ( ) 2. UIP ( ) 3. UIP ( )

5 287 疑似 IPF 可否找到其他間質性肺炎的成因是肺部高解像度的電腦斷層 (HRCT) UIP 可能為 UIP 不符合 UIP 外科手術肺切片非 UIP IPF MDD* 決定是否為 IPF 非 IPF *MDD: (Multidisciplinary discussion) (idiopathic pulmonary fibrosis, IPF) 2015 IPF 17 cyclosporine cyclophosphamide everolimus 2012 PANTHER trial FVC 50% DLCO 30% IPF prednisone azathioprine N-acetylcysteine prednisone azathioprine N-acetylcysteine IPF ,18,19 IPF 18 warfarin acetylcysteine (endothelin receptor antagonist) IPF 2013 IPF 20,21 IPF 50% 2

6 288 IPF IPF pirfenidone nintedanib Pirfenidone (phenyl pyridone) TGF-β 22 Pirfenidone Shionogi phase II trial Shionogi phase III trial Shionogi phase II 107 (primary endpoint) (SpO2) pirfenidone pirfenidone (SpO2) (pirfenidone versus. placebo 0.46% versus -1.59%, p=0.03) (secondary endpoint) pirfenidone 23 Shionogi phase III trial pirfenidone 1800mg/day (p=0.03) pirfenidone (progression-free survival) 24 pirfenidone 2008 pirfenidone CAPACITY trial ASCEND trial IPF (FVC >50% of predicted DLco > 30% of predicted 6 minute walking test >150 meters) CAPACITY 004 CAPACITY 006 trial primary endpoint 72 (Δforced vital capacity, ΔFVC) pirfenidone 2403mg/day CAPACITY (-8.0% versus -12.0%, p=0.001) CAPACITY 006 (-9.0% versus -9.5%, p=0.5)capacity trial pirfenidone (University of California San Diego Shortness of Breath Questionnaire, SOBQ) CAPACITY (All-cause mortality) (HR 0.77, 95% CI , p=0.3) 25 CAPACITY trial ASCEND trial ASCEND trial 555 primary endpoint 52 pirfenidone 2403mg/day 52 (-258mL versus -423mL, p<0.001) All-cause mortality ASCEND trial (4.0% versus 7.2%, p=0.1) CAPACITY 004/006 ASCEND All-cause mortality pirfenidone (3.5% versus 6.7%, p=0.01) pirfenidone 2014 IPF 26 pirfenidone (28%) (8%) (photosensitivity, 14%) (3%) (1%) / / / pirfenidone 3 nintedanib (tyrosine kinase inhibitor)

7 289 (platelet derived growth factor receptor PDGFR) (fibroblast growth factor receptor FGFR) (vascular endothelial growth factor receptor VEGFR) 28 Nintedanib TOMORROW trial INPULSIS trial IPF (FVC >50% of predicted DLco 30-80% of predicted) TOMORROW trial 432 (nintedanib 50mg/day 100mg/day 200mg/day 300mg/day placebo) 52 nintedanib 300mg/day ( forced vital capacity -60mL versus -190mL, p=0.01) (2.4 versus 15.7 per 100 patient year, p=0.02) (St. George s Respiratory Questionnaire SGRQ versus 5.46 points, p=0.007) allcause mortality 29 TOMORROW trial nintedanib 300mg INPULSIS-1 INPULSIS-2 trial nintedanib 300 mg/day 52 (INPULSIS-1 trial -115mL versus -239mL, p<0.001 INPULSIS-2 trial -114mL versus -207mL, p<0.001) INPULSIS-2 trial (SGRQ) INPULSIS-1 INPULSIS-2 trial nintedanib 300mg/day all-cause mortality (Hazard ratio % confidence interval , p=0.14) 30 TOMORROW trial INPULSIS trial nintedanib 2014 nintedanib 5% / / / nintedanib 3 IPF UIP IPF nintedanib pirfenidone 1. American Thoracic Society. 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 2000; 161: 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: Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med 2015; 192: e Hutchinson J, Fogarty A, Hubbard R, McKeever T. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J 2015; 46: Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006; 174: Lai CC, Wang CY, Lu HM, et al. Idiopathic pulmonary fibrosis in Taiwan - a population-based study. Am J Respir Crit Care Med 2012; 106:

8 Ekstrom M, Gustafson T, Boman K, et al. Effects of smoking, gender and occupational exposure on the risk of severe pulmonary fibrosis: a population-based case-control study. BMJ Open 2014; 4: e Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet (London, England) 2017; 389: Pulkkinen V, Bruce S, Rintahaka J, et al. ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses. FASEB J 2010; 24: Selman M, Pardo A, Barrera L, et al. Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis. Am J Respir Crit Care Med 2006; 173: Peljto AL, Zhang Y, Fingerlin TE, et al. Association between the muc5b promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA 2013; 309: Rockey DC, Bell PD, Hill JA. Fibrosis--a common pathway to organ injury and failure. N Engl J Med 2015; 372: Rock JR, Barkauskas CE, Cronce MJ, et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proceedings of the National Academy of Sciences of the United States of America 2011; 108: E Horowitz JC, Thannickal VJ. Epithelial-mesenchymal interactions in pulmonary fibrosis. Seminars in respiratory and critical care medicine 2006; 27: Ley B, Collard HR, King TE, Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 183: Richeldi L, Davies HR, Ferrara G, Franco F. Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2003: CD Rafii R, Juarez MM, Albertson TE, Chan AL. A review of current and novel therapies for idiopathic pulmonary fibrosis. J Thorac Dis 2013; 5: Idiopathic Pulmonary Fibrosis Clinical Research N, Raghu G, Anstrom KJ, et al. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012; 366: Johannson KA, Strambu I, Ravaglia C, et al. Antacid therapy in idiopathic pulmonary fibrosis: more questions than answers? Lancet Respir Med 2017; 5: Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006; 27: Schaefer CJ, Ruhrmund DW, Pan L, Seiwert SD, Kossen K. Antifibrotic activities of pirfenidone in animal models. Eur Respir Rev 2011; 20: Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebocontrolled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005; 171: Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010; 35: Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377: King TE, Jr., Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: Ogura T, Azuma A, Inoue Y, et al. All-case post-marketing surveillance of 1371 patients treated with pirfenidone for idiopathic pulmonary fibrosis. Respir Investig 2015; 53: Fukihara J, Kondoh Y. Nintedanib (OFEV) in the treatment of idiopathic pulmonary fibrosis. Expert Rev Respir Med 2016; 10: Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011; 365: Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: Richeldi L, Cottin V, du Bois RM, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS((R)) trials. Respir Med 2016; 113: 74-9.

9 291 Idiopathic Pulmonary Fibrosis Chang-Wei Wu, Hao-Chun Chang, Tien-Hua Chen, Hsin-Tuan Huang, Chia-Jung Liu, and Hao-Chien Wang Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic, and idiopathic interstitial pneumonia. It s prone to elderlies, and the disease involvement is confined to the lungs. There has a unique pathological findings called usual interstitial pneumonia (UIP) that can be found in both histology and images on computer tomography (CT). To make the diagnosis of IPF, all known-cause of interstitial lung diseases such as environmental factors, medications, connective tissue diseases should be excluded first. In the past, IPF is considered as a poorly prognostic disease, while the median survival time was 0.9 year in Taiwan. However, as the pathogenesis is being studied, anti-fibrotic drugs (nintedanib and pirfenidone) have been developed. They were proved to be effective to decrease lung function decline in some large-scale studies. Moreover, there are more ongoing studies among IPF trying to improve prognosis of IPF patients. (J Intern Med Taiwan 2018; 29: )

Williams-Campbell 2-3 Marfan's syndrome / % ~ 48% common variable immunodeficiency CVID X- X-linked agammaglobulinemia XLA lga - IgA Ig

Williams-Campbell 2-3 Marfan's syndrome / % ~ 48% common variable immunodeficiency CVID X- X-linked agammaglobulinemia XLA lga - IgA Ig 315 2012 COPD 2005 2011 [1-2] 2010 [3-4] [5] 3.7 / 10 [6] 52 / 10 [5] 100 / 10 18 ~ 34 4.2 / 10 70 272 / 10 [7] CT 50 CT - COPD 15% ~ 30% COPD 50% [11] DOI: 10. 3877/ cma. j. issn. 1674-6880. 2012. 05.