今日の臨床サポート

間質性肺炎

著者: 高橋弘毅 札幌医科大学 内科学

監修: 長瀬隆英 東京大学 内科学専攻器官病態内科学講座

著者校正/監修レビュー済:2021/02/24
参考ガイドライン:
  1. 日本呼吸器学会:特発性間質性肺炎診断と治療の手引き(改訂第3版)(2016)
  1. 日本呼吸器学会:特発性肺線維症の治療ガイドライン2017
  1. [米国胸部学会(ATS)]:【翻訳版】ATS 特発性肺線維症の診断. 公式ATS/ERS/JRS/ALAT臨床実践ガイドライン(2018)
  1. [米国胸部学会(ATS)]:【翻訳版】ATS/ERS/JRS/ALAT公式ステートメント:特発性肺線維症:科学的根拠に基づく診断および管理ガイドライン(2011)
患者向け説明資料

概要・推奨   

抗線維化薬ニンテダニブ(オフェブ)は薬事法上これまで特発性肺線維症と全身性強皮症に伴う間質性肺疾患に限定され使用されてきたが、新たな大規模ランダム化比較試験によって、それ以外の進行性線維化を伴う間質性肺疾患においてもその有効性(努力性肺活量の経時的減少を有意に抑制)が示され[1]、2020年5月、「進行性線維化を伴う間質性肺疾患」が追加承認された。
 
  1. 特発性肺線維症(IPF)患者では「急性増悪」と呼ばれる急激な病状悪化を伴うことがある。発症すると致命率が高く、入院し早急に治療を開始する必要がある。IPF以外の間質性肺炎患者においても同様の現象が起きることがあり、安定している患者においても、急な変化があり得ることを認識し、日常から注意を払う必要がある(推奨度1)
  1. 添付文書にある使用上の注意事項に重篤な副作用(有害事象)として「間質性肺炎」が記載されている薬剤を投与する際には、使用前に検査1)2)を実施することが推奨されている(推奨度1)。また、間質性肺炎発症をいち早く気づくために投与期間にも適宜繰り返し施行する。
  1. 1)血清マーカー(KL−6、SP-A、SP−D)、2)胸部X線、胸部HRCT
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  1. 安静時の経皮酸素飽和度(SpO2)が正常であっても、労作時に90%未満まで低下する患者には積極的に在宅酸素療法(HOT)の導入を勧める(推奨度1)。
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要とな ります。閲覧 にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
高橋弘毅 : 原稿料(日本ベーリンガーインゲルハイム社)[2021年]
監修:長瀬隆英 : 講演料(アストラゼネカ),研究費・助成金など(中外製薬)[2021年]

  1. 改訂のポイント:
  1. 定期レビューを行い、ニンテダニブ(オフェブ)の追加承認について追記した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 間質性肺炎/肺線維症は炎症の場を間質主体とし、種々の程度の線維性変化を伴う疾患群の総称である。
  1. 画像で間質性肺炎/肺線維症を疑うことから診断がスタートする。
  1. 聴診所見(捻髪音)を契機に発見されることがあり、膠原病や放射線治療後など、発症リスクのある患者の診察では背部の聴診も怠らないようにする。
  1. 間質性肺炎に類似した画像所見を示す疾患(肺水腫、癌性リンパ管症など)が鑑別除外する。
  1. 間質性肺炎/肺線維症の原因・基礎疾患を検索することが適切な治療導入にとって重要である。
  1. 正確な鑑別診断と亜型診断を行うには、高い専門性が必要である。
  1. 呼吸機能検査はスパイロメトリーに加え、肺拡散能検査が重要である。
  1. 安静時の酸素化が正常であっても、労作によって低酸素血症が顕在化する患者がいるので、運動負荷時の酸素飽和度(6分間歩行試験)を調べる必要がある。
  1. 血清マーカー(KL-6、SP−D、SP−A)は高い特異度と鋭敏度を持ち、診断根拠の1つとして有用である。臨床経過を経時的にフォローする際にも有用である。
  1. 確定診断と治療方法の決定に、気管支肺胞洗浄(BAL)、経気管支肺生検(TBLB)、胸腔鏡下外科的肺生検(VATS肺生検)がある。一定のリスクを伴うので、重症度、合併症、全身状態などを考慮し施行の可否を決める。
  1. 特発性間質性肺炎は、指定難病であり、特に現行の特定疾患治療研究事業のものを用いて評価してⅢ度以上の重症度を認める場合などでは、申請し認定されると保険料の自己負担分の一部が公費負担として助成される。([平成27年1月施行])
  1. 難病法に基づく医療費助成制度
  1. また、軽症例(Ⅰ、Ⅱ度)であっても、高額な医療を継続することが必要な人は、医療費助成の対象となる(難病情報センター)。
  
間質性肺炎の初期変化(イメージ)

正常肺胞の内腔は細胞質が薄くシート状のI型肺胞上皮細胞で覆われ、隣り合う肺胞同士はきわめて薄い結合織で隔てられている。この結合織の中に毛細血管が豊富に分布している。結合織と毛細血管を合わせた部位は「間質」と呼ばれる。間質に炎症が生じると、浮腫・肥厚化し、リンパ球などの炎症細胞が浸潤してくる。上皮と毛細血管との距離が広がるため、ガス交換が妨げられ、低酸素血症を引き起こす。また、炎症細胞が産生するサイトカインや増殖因子(TGF−βなど)によって線維芽細胞(特に筋線維芽細胞が病態形成に重要な役割を持つ)が増殖し、過剰のコラーゲンを産生・沈着させる。コラーゲン沈着の場として、間質内が主体の病態と、気腔内に形成される“ナメクジ様”の線維化巣が主体の病態がある。

出典

img1:  著者提供
 
 
 
間質性肺炎/肺線維症と通常の肺炎との病理所見の比較

細菌感染などで起きる通常の肺炎の場合、主な炎症の場は肺胞腔である。肺胞腔内は浸出液と好中球主体の炎症細胞浸潤で充満する。それに対して、間質性肺炎は、主な炎症の場が間質であり、浮腫・肥厚化した間質にはリンパ球主体の炎症細胞浸潤がみられる。さらに進行すると肺胞は虚脱し畳み込まれるように収縮する。同時に線維成分が沈着し組織が硬化する。肺胞より中枢の気道(肺胞道、呼吸細気管支)が代償的に拡張し気腔を形成する(「蜂巣肺」と呼ぶ)。

出典

img1:  著者提供
 
 
 
間質性肺炎の胸部単純X線所見

間質性肺炎(a)は淡い陰影(すりガラス影、粒状影、線状網状陰影)が特徴で、ときに両肺野に広く分布し、肺胞虚脱や線維化が広範囲に存在すると肺野が縮小し、横隔膜が挙上する。一方、細菌感染などが原因で発症する肺炎(b)の場合、濃い陰影(浸潤影)が一区域または一肺葉に現れる。その内部に枝状の透亮像(エアーブロンコグラム)を伴うことがある。

出典

img1:  著者提供
 
 
 
間質性肺炎・肺線維症にみられる特徴的CT画像所見

(a)すりガラス病変(ground glass attenuation、GGA);病変内部にある既存の血管構造が判別できる程度の淡い濃度上昇域のことであり、その背景にある病理変化として、肺胞間質の浮腫・肥厚と軽度の線維化がある。可逆性変化の可能性が高く、治療に反応性のことが多い。
(b)蜂巣肺 (honeycombing lung);胸膜面から直接連なる小嚢胞性変化のことであり、その背景にある病理変化は、肺胞の虚脱・線維化と肺胞道・呼吸細気管支の嚢胞性拡張である。肺胞間質の浮腫・肥厚と軽度の線維化がある。線維化の終末像で不可逆的変化である。
(c)牽引性気管支拡張(traction bronchiectasis、 TBE);気管支・細気管支周囲の肺胞が虚脱・線維化することによって気管支壁に外向きのテンションが加わり、気腔が拡張する現象のことである。肺胞虚脱が短期間の場合には治療に反応すれば拡張が改善する。しかし、線維化が進むと治療効果は得られないことが多い。
(d)浸潤影・コンソリデーション(consolidation);一般的には細菌性肺炎などでみられる所見であるが、複数の肺区域にまたがって病変が連続してみられること、また、陰影が縮小・消失しても別な区域に新たな病変が出現する、いわゆる遊走性陰影を特徴とすることが鑑別のポイントである。病理変化は多くが器質化肺炎パターンである。

出典

img1:  著者提供
 
 
 
微少な間質性変化を反映する血清マーカー

間質性肺炎の特異的血清マーカーとして、わが国ではKL-6, SP-A, SP-Dの3種類の測定が保険診療において可能である。鋭敏度はいずれのマーカーでも80%前後ときわめて高い。病変の広がりが僅かであっても、基準値を超え陽性を示す症例をしばしば経験する。この図は人間ドックにおいて胸部CT(背臥位)で間質性病変があるが胸部X線で異常のない受診者(n=21)を対象に血清マーカー値を検討した論文からの引用である。腹臥位でCTを再撮すると間質性病変が消失する “重力効果による陰影”(Control)群 n=14と消失しなかった“真の間質性肺炎”(True abnormalities)群n=7に分割し比較した。KL-6, SP-A, SP-Dはすべて、“真の間質性肺炎”群において有意に高値であった。

出典

img1:  Characteristics and disease activity of early interstitial lung disease in subjects with true parenchymal abnormalities in the posterior subpleural aspect of the lung.
 
 Chest. 2006 Feb;129(2):402-6. doi: 10.13・・・
 
強皮症肺における血清マーカー測定の有用性

強皮症患者をX線とCT所見の結果を基に、A)肺病変がX線だけでも検出可能な症例(進行例)、B) CTでのみで検出可能な症例(軽症/早期例)、C)肺病変がない症例(正常例)の三群(A、B、C)に分け、2種類の血清マーカー値を解析した。SP-DはSP-Aに比べ肺病変のある群(A、B群)での陽性率が高かった。X線では検出できない微少な病変をCTで認めた症例(B群)6例中5例(83%)がSP-D陽性であった。

出典

img1:  著者提供
 
 
 
間質性肺疾患(Progressive Fibrosing ILD:PF-ILD:
  1. 間質性肺疾患(interstitial lung diseases:ILD)は様々な間質性肺炎・肺線維症を包含する疾患群の総称である。最近、進行性線維化を伴う間質性肺疾患(Progressive Fibrosing ILD:PF-ILD)が注目されている。これは原因・基礎疾患の如何を問わない、疾患横断的概念である。
  1. ILDの中にはステロイドと免疫抑制薬を用いた抗炎症療法の治療効果が限定的で、線維化の進行を防止することが困難な症例が存在し、PF-ILDはこういった線維化が進行するILDの一群を意識した名称である。
  1. PF-ILDという用語は2017年当時進行中であったINBUILD試験[1]において使用された。この試験はPF-ILD患者を対象とした日本を含む国際共同第Ⅲ相試験であり、そこから得られた知見は間質性肺疾患の薬物治療の概念を大きく変化させた。
 
間質性肺疾患の病態スペクトラム

間質性肺疾患(ILD)は、「原因・基礎疾患」と「炎症・線維化」という2つの座標軸で分類される。特発性間質性肺炎(IIPs)では、炎症主体のDIPから線維化主体のIPFまで、幅広い病態スペクトラムをもつ。膠原病肺もまた、線維化が比較的少ないSLE、PM/DMから、線維化の目立つMCTD、SSc、RAまで、幅広い病態スペクトラムをもつ。
最近、PF-ILDという疾患概念が提唱された。これは原因・基礎疾患を問わず、進行性の線維化を示すILDを一括した疾患群の総称である。これまで、IPF以外でも進行性の線維化を来す症例はしばしば経験されてきたが、すべて抗線維化薬の保険適用外であった。しかし、2020年5月、IPFと強皮症肺のみに保険適用のあったニンテダニブ(オフェブ)の使用が様々な原因・基礎疾患に伴ったPF-ILDにも認可された。したがって、PF-ILDと診断された場合には積極的に抗線維化療法を検討することが推奨される。また、症例によっては、抗炎症治療を併用したほうがよい場合もある。
 
剝離性間質性肺:DIP、呼吸細気管支炎を伴うILD:RB-ILD、特発性器質化肺炎:COP、
細胞浸潤性非特異性間質性肺炎:cNSIP、線維化性非特異性間質性肺炎:fNSIP、特発性肺線維症:IPF、
全身性エリテマトーデス:SLE、多発性筋炎/皮膚筋炎:PM/DM、シェーグレン症候群:SjS、
混合性結合組織病:MCTD、全身性強皮症:SSc、関節リウマチ:RA

出典

img1:  著者提供
 
 
 
  1. それまで特発性肺線維症と全身性強皮症に伴う間質性肺疾患にのみ使用が認可されていた抗線維化薬ニンテダニブ(オフェブ)が、2019年5月にPF-ILDに対しても国内での製造販売が承認され、多くのタイプのPF-ILDに使用可能となった。なお、臨床試験では以下の(1)~(4)のいずれかを満たした場合をPF-ILDとして対象患者を登録した。
  1. %FVCの10%以上の減少(相対変化量)がみられる。
  1. %FVCの5%以上、10%未満の減少(相対変化量)がみられ、かつ、呼吸器症状の悪化がみられる。
  1. %FVCの5%以上、10%未満の減少(相対変化量)がみられ、かつ、胸部画像上での線維化変化の増加がみられる。
  1. 呼吸器症状の悪化及び胸部画像上での線維化変化の増加がみられる。
  1. INBUILD試験において、とくに臨床的意義の大きな結果は以下の2つである。
  1. プラセボ群に比し実薬群では観察期間(52週)におけるFVCの変化量を有意に減少させた。
  1. プラセボ群に比し実薬群では全期間におけるILDの急性増悪または死亡例の割合を有意に減少させた。
  1. FVCの低下は慢性呼吸不全の進行に関係する。また、ILDの急性増悪は軽症であっても発症する重要な死因である。この2つの事象を抑制することによって、PF-ILD患者のADLの低下と死亡リスクを軽減することができる。
病歴・診察のポイント  
  1. 発症と増悪のリスク因子を確認する。

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文献 

著者: Kevin R Flaherty, Athol U Wells, Vincent Cottin, Anand Devaraj, Simon L F Walsh, Yoshikazu Inoue, Luca Richeldi, Martin Kolb, Kay Tetzlaff, Susanne Stowasser, Carl Coeck, Emmanuelle Clerisme-Beaty, Bernd Rosenstock, Manuel Quaresma, Thomas Haeufel, Rainer-Georg Goeldner, Rozsa Schlenker-Herceg, Kevin K Brown, INBUILD Trial Investigators
雑誌名: N Engl J Med. 2019 Oct 31;381(18):1718-1727. doi: 10.1056/NEJMoa1908681. Epub 2019 Sep 29.
Abstract/Text BACKGROUND: Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown.
METHODS: In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern.
RESULTS: A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was -80.8 ml per year with nintedanib and -187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was -82.9 ml per year with nintedanib and -211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group.
CONCLUSIONS: In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.).

Copyright © 2019 Massachusetts Medical Society.
PMID 31566307  N Engl J Med. 2019 Oct 31;381(18):1718-1727. doi: 10.10・・・
著者: Aryeh Fischer, Katerina M Antoniou, Kevin K Brown, Jacques Cadranel, Tamera J Corte, Roland M du Bois, Joyce S Lee, Kevin O Leslie, David A Lynch, Eric L Matteson, Marta Mosca, Imre Noth, Luca Richeldi, Mary E Strek, Jeffrey J Swigris, Athol U Wells, Sterling G West, Harold R Collard, Vincent Cottin, “ERS/ATS Task Force on Undifferentiated Forms of CTD-ILD”
雑誌名: Eur Respir J. 2015 Oct;46(4):976-87. doi: 10.1183/13993003.00150-2015. Epub 2015 Jul 9.
Abstract/Text Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus over nomenclature and classification limits the ability to conduct prospective studies of a uniform cohort.The "European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease" was formed to create consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity.The task force proposes the term "interstitial pneumonia with autoimmune features" (IPAF) and offers classification criteria organised around the presence of a combination of features from three domains: a clinical domain consisting of specific extra-thoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic or pulmonary physiologic features.A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD. With IPAF, a sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort.

Copyright ©ERS 2015.
PMID 26160873  Eur Respir J. 2015 Oct;46(4):976-87. doi: 10.1183/13993・・・
著者: Ganesh Raghu, Martine Remy-Jardin, Jeffrey L Myers, Luca Richeldi, Christopher J Ryerson, David J Lederer, Juergen Behr, Vincent Cottin, Sonye K Danoff, Ferran Morell, Kevin R Flaherty, Athol Wells, Fernando J Martinez, Arata Azuma, Thomas J Bice, Demosthenes Bouros, Kevin K Brown, Harold R Collard, Abhijit Duggal, Liam Galvin, Yoshikazu Inoue, R Gisli Jenkins, Takeshi Johkoh, Ella A Kazerooni, Masanori Kitaichi, Shandra L Knight, George Mansour, Andrew G Nicholson, Sudhakar N J Pipavath, Ivette Buendía-Roldán, Moisés Selman, William D Travis, Simon Walsh, Kevin C Wilson, American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society
雑誌名: Am J Respir Crit Care Med. 2018 Sep 1;198(5):e44-e68. doi: 10.1164/rccm.201807-1255ST.
Abstract/Text BACKGROUND: This document provides clinical recommendations for the diagnosis of idiopathic pulmonary fibrosis (IPF). It represents a collaborative effort between the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society.
METHODS: The evidence syntheses were discussed and recommendations formulated by a multidisciplinary committee of IPF experts. The evidence was appraised and recommendations were formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach.
RESULTS: The guideline panel updated the diagnostic criteria for IPF. Previously defined patterns of usual interstitial pneumonia (UIP) were refined to patterns of UIP, probable UIP, indeterminate, and alternate diagnosis. For patients with newly detected interstitial lung disease (ILD) who have a high-resolution computed tomography scan pattern of probable UIP, indeterminate, or an alternative diagnosis, conditional recommendations were made for performing BAL and surgical lung biopsy; because of lack of evidence, no recommendation was made for or against performing transbronchial lung biopsy or lung cryobiopsy. In contrast, for patients with newly detected ILD who have a high-resolution computed tomography scan pattern of UIP, strong recommendations were made against performing surgical lung biopsy, transbronchial lung biopsy, and lung cryobiopsy, and a conditional recommendation was made against performing BAL. Additional recommendations included a conditional recommendation for multidisciplinary discussion and a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other ILDs.
CONCLUSIONS: The guideline panel provided recommendations related to the diagnosis of IPF.

PMID 30168753  Am J Respir Crit Care Med. 2018 Sep 1;198(5):e44-e68. d・・・
著者: Jin Woo Song, Kyung-Hyun Do, Mi-Young Kim, Se Jin Jang, Thomas V Colby, Dong Soon Kim
雑誌名: Chest. 2009 Jul;136(1):23-30. doi: 10.1378/chest.08-2572. Epub 2009 Mar 2.
Abstract/Text BACKGROUND: Patients with usual interstitial pneumonia (UIP) associated with collagen vascular disease (CVD) have been reported to have a better prognosis than those with idiopathic pulmonary fibrosis with a UIP pattern (IPF/UIP) seen on histology. The aim of this study was to evaluate the pathologic and radiologic differences between the two conditions and their relationship with clinical outcome.
METHODS: A retrospective review of 100 patients (CVD-UIP, 39 patients; IPF/UIP, 61 patients) with UIP pattern diagnosed by surgical lung biopsy at one tertiary referral center.
RESULTS: The median follow-up period was 34.4 months. The CVD-UIP group was younger, included more women and nonsmokers, and showed better survival than the IPF/UIP group. Pathologically, CVD-UIP patients had fewer fibroblastic foci and smaller honeycombing (HC) spaces with higher germinal centers and total inflammation scores than IPF/UIP patients. Radiologically, CVD-UIP patients had a lower emphysema score and more likely a nontypical UIP pattern without HC. The germinal centers score was the best distinguishing feature between CVD-UIP and IPF/UIP patients (odds ratio, 2.948; p = 0.001) and was marginally related to survival (p = 0.076). The HC score (hazard ratio [HR], 1.134; p < 0.001), total lung capacity (TLC) [HR, 0.932; p = 0.004], and age (HR, 1.052; p = 0.017) were significant predictors of survival in all patients with UIP histology, regardless of the presence of CVD. Among IPF/UIP patients, those with positive autoantibodies were pathologically more similar to CVD-UIP than to IPF/UIP without autoantibodies, despite no difference in survival between them.
CONCLUSIONS: The germinal centers score was the best discriminative between CVD-UIP and IPF/UIP patients; it was of marginal prognostic significance. Age, TLC, and HC score were independent prognostic factors in all patients with UIP histology.

PMID 19255290  Chest. 2009 Jul;136(1):23-30. doi: 10.1378/chest.08-257・・・
著者: Yasuhiro Kondoh, Hiroyuki Taniguchi, Kensuke Kataoka, Taiki Furukawa, Masahiko Ando, Kenta Murotani, Michiaki Mishima, Yoshikazu Inoue, Takashi Ogura, Masashi Bando, Koichi Hagiwara, Takafumi Suda, Hirofumi Chiba, Hiroki Takahashi, Yukihiko Sugiyama, Sakae Homma
雑誌名: Respirology. 2017 Nov;22(8):1609-1614. doi: 10.1111/resp.13138. Epub 2017 Aug 8.
Abstract/Text BACKGROUND AND OBJECTIVE: In Japan, the classification of disease severity of idiopathic pulmonary fibrosis (IPF) (J-system) has been used in making decisions on medical care subsidies. The present J-system consists of arterial partial pressure of oxygen (PaO2 ) and exercise desaturation in stages of I-IV. It provides a good prognostic classification in stages III and IV, but not in stages I and II. Therefore, we propose a revised system to improve discriminative ability in stages I and II.
METHODS: We compared the revised J-system with the present J-system using Cox proportional hazards model to predict mortality rate. We also evaluated the recently proposed GAP (Gender, Age and Physiology) system in comparison to both J-systems.
RESULTS: Two-hundred and fifteen IPF patients were studied retrospectively. A univariate model showed that the present and revised J-systems and a modified GAP system were all significant prognostic factors. The C-statistic for discriminating prognosis was higher in the revised J-system than the modified GAP system and the present J-system (0.677, 0.652 and 0.659, respectively). The C-statistics of these models produced from the 10 000 bootstrap samples were similar to those of the original models, suggesting good internal validation (0.665 (95% CI: 0.621-0.705), 0.645 (0.600-0.686) and 0.659 (0.616-0.700), respectively). Multivariate analysis revealed that the revised J-system (P = 0.0038) and the modified GAP system (P = 0.0029) were independent prognostic factors.
CONCLUSION: The revised J-system can provide a better mortality prediction than the present one. Both the revised J-system and the modified GAP system are independent and valuable tools for prognostication and clinical management for IPF.

© 2017 Asian Pacific Society of Respirology.
PMID 28787101  Respirology. 2017 Nov;22(8):1609-1614. doi: 10.1111/res・・・
著者: Brett Ley, Christopher J Ryerson, Eric Vittinghoff, Jay H Ryu, Sara Tomassetti, Joyce S Lee, Venerino Poletti, Matteo Buccioli, Brett M Elicker, Kirk D Jones, Talmadge E King, Harold R Collard
雑誌名: Ann Intern Med. 2012 May 15;156(10):684-91. doi: 10.7326/0003-4819-156-10-201205150-00004.
Abstract/Text BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an overall poor prognosis. A simple-to-use staging system for IPF may improve prognostication, help guide management, and facilitate research.
OBJECTIVE: To develop a multidimensional prognostic staging system for IPF by using commonly measured clinical and physiologic variables.
DESIGN: A clinical prediction model was developed and validated by using retrospective data from 3 large, geographically distinct cohorts.
SETTING: Interstitial lung disease referral centers in California, Minnesota, and Italy.
PATIENTS: 228 patients with IPF at the University of California, San Francisco (derivation cohort), and 330 patients at the Mayo Clinic and Morgagni-Pierantoni Hospital (validation cohort).
MEASUREMENTS: The primary outcome was mortality, treating transplantation as a competing risk. Model discrimination was assessed by the c-index, and calibration was assessed by comparing predicted and observed cumulative mortality at 1, 2, and 3 years.
RESULTS: Four variables were included in the final model: gender (G), age (A), and 2 lung physiology variables (P) (FVC and Dlco). A model using continuous predictors (GAP calculator) and a simple point-scoring system (GAP index) performed similarly in derivation (c-index of 70.8 and 69.3, respectively) and validation (c-index of 69.1 and 68.7, respectively). Three stages (stages I, II, and III) were identified based on the GAP index with 1-year mortality of 6%, 16%, and 39%, respectively. The GAP models performed similarly in pooled follow-up visits (c-index ≥71.9).
LIMITATION: Patients were drawn from academic centers and analyzed retrospectively.
CONCLUSION: The GAP models use commonly measured clinical and physiologic variables to predict mortality in patients with IPF.

PMID 22586007  Ann Intern Med. 2012 May 15;156(10):684-91. doi: 10.732・・・
著者: Shun Kondoh, Hirofumi Chiba, Hirotaka Nishikiori, Yasuaki Umeda, Koji Kuronuma, Mitsuo Otsuka, Gen Yamada, Hirofumi Ohnishi, Mitsuru Mori, Yasuhiro Kondoh, Hiroyuki Taniguchi, Sakae Homma, Hiroki Takahashi
雑誌名: Respir Investig. 2016 Sep;54(5):327-33. doi: 10.1016/j.resinv.2016.02.009. Epub 2016 Mar 30.
Abstract/Text BACKGROUND: The clinical course of idiopathic pulmonary fibrosis (IPF) shows great inter-individual differences. It is important to standardize the severity classification to accurately evaluate each patient׳s prognosis. In Japan, an original severity classification (the Japanese disease severity classification, JSC) is used. In the United States, the new multidimensional index and staging system (the GAP model) has been proposed. The objective of this study was to evaluate the model performance for the prediction of mortality risk of the JSC and GAP models using a large cohort of Japanese patients with IPF.
METHODS: This is a retrospective cohort study including 326 patients with IPF in the Hokkaido prefecture from 2003 to 2007. We obtained the survival curves of each stage of the GAP and JSC models to perform a comparison. In the GAP model, the prognostic value for mortality risk of Japanese patients was also evaluated.
RESULTS: In the JSC, patient prognoses were roughly divided into two groups, mild cases (Stages I and II) and severe cases (Stages III and IV). In the GAP model, there was no significant difference in survival between Stages II and III, and the mortality rates in the patients classified into the GAP Stages I and II were underestimated.
CONCLUSIONS: It is difficult to predict accurate prognosis of IPF using the JSC and the GAP models. A re-examination of the variables from the two models is required, as well as an evaluation of the prognostic value to revise the severity classification for Japanese patients with IPF.

Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
PMID 27566380  Respir Investig. 2016 Sep;54(5):327-33. doi: 10.1016/j.・・・
著者: Hirotaka Nishikiori, Hirofumi Chiba, Sang Hoon Lee, Shun Kondoh, Ken-Ichi Kamo, Koshi Nakamura, Kimiyuki Ikeda, Koji Kuronuma, Man Pyo Chung, Yasuhiro Kondoh, Sakae Homma, Naohiko Inase, Moo Suk Park, Hiroki Takahashi
雑誌名: Respir Investig. 2020 Sep;58(5):395-402. doi: 10.1016/j.resinv.2020.04.001. Epub 2020 Jul 24.
Abstract/Text BACKGROUND: The easy-to-calculate gender, age, and lung physiology (GAP) model shows good predictive and discriminative performance in the prognosis of idiopathic pulmonary fibrosis (IPF). However, the GAP model was not effective in predicting the prognosis accurately in previous Japanese and Korean IPF cohort studies. Therefore, we developed a modified GAP model for the East-Asian populations by weighing the GAP variables. The validity of the modified GAP model was subsequently evaluated in East-Asian IPF patients.
METHODS: The derivation cohort comprised 326 patients with IPF. Weights of the variables were adjusted on the basis of coefficients derived from Cox regression models. The total points were distributed to the three stages of the disease so that the number of patients included in each stage was appropriate. The validity of the modified model was analyzed in another Japanese cohort of 117 patients with IPF and a nationwide cohort of Korean patients with IPF.
RESULTS: Predicted survival rates differed significantly in the derivation cohort using the modified GAP model for each stage of IPF (log-rank test: stage I vs. stage II, p < 0.001; stage II vs. stage III, p < 0.001). Model performance improved according to Harrell's C-index (at three years: 0.696 in the original GAP model to 0.738 in the modified model). The performance of the modified model was validated in the Japanese validation and Korean national cohorts.
CONCLUSIONS: Our modification of the original GAP model showed improved performance in East-Asian IPF patient populations.

Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
PMID 32718834  Respir Investig. 2020 Sep;58(5):395-402. doi: 10.1016/j・・・
著者: Y Kondoh, H Taniguchi, Y Kawabata, T Yokoi, K Suzuki, K Takagi
雑誌名: Chest. 1993 Jun;103(6):1808-12.
Abstract/Text We treated three patients with idiopathic pulmonary fibrosis who had an acute clinical exacerbation. We analyzed their clinical, radiographic, therapeutic, and pathologic findings. Their initial symptoms were influenza-like illness or cough with fever, and all had leukocytosis and elevation of C-reactive protein. Infectious events were ruled out by extensive bacteriologic and serologic examination. The patients' lung injury scores progressed rapidly to severe lung injury compatible with adult respiratory distress syndrome. Findings from bronchoalveolar lavage fluid showed marked neutrophilia and elevation of albumin concentrations. All patients showed various degrees of improvement following corticosteroid therapy. Histologic findings from open lung biopsy specimens showed both usual interstitial pneumonia (UIP) and organizing acute lung injury pattern. Whether these two forms of interstitial pneumonia (UIP and acute lung injury pattern) are variants of one disease or are unrelated and also the effectiveness of corticosteroid therapy on such conditions remain to be determined by further studies.

PMID 8404104  Chest. 1993 Jun;103(6):1808-12.
著者: Harold R Collard, Bethany B Moore, Kevin R Flaherty, Kevin K Brown, Robert J Kaner, Talmadge E King, Joseph A Lasky, James E Loyd, Imre Noth, Mitchell A Olman, Ganesh Raghu, Jesse Roman, Jay H Ryu, David A Zisman, Gary W Hunninghake, Thomas V Colby, Jim J Egan, David M Hansell, Takeshi Johkoh, Naftali Kaminski, Dong Soon Kim, Yasuhiro Kondoh, David A Lynch, Joachim Müller-Quernheim, Jeffrey L Myers, Andrew G Nicholson, Moisés Selman, Galen B Toews, Athol U Wells, Fernando J Martinez, Idiopathic Pulmonary Fibrosis Clinical Research Network Investigators
雑誌名: Am J Respir Crit Care Med. 2007 Oct 1;176(7):636-43. doi: 10.1164/rccm.200703-463PP. Epub 2007 Jun 21.
Abstract/Text The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.

PMID 17585107  Am J Respir Crit Care Med. 2007 Oct 1;176(7):636-43. do・・・
著者: Ganesh Raghu, Harold R Collard, Jim J Egan, Fernando J Martinez, Juergen Behr, Kevin K Brown, Thomas V Colby, Jean-François Cordier, Kevin R Flaherty, Joseph A Lasky, David A Lynch, Jay H Ryu, Jeffrey J Swigris, Athol U Wells, Julio Ancochea, Demosthenes Bouros, Carlos Carvalho, Ulrich Costabel, Masahito Ebina, David M Hansell, Takeshi Johkoh, Dong Soon Kim, Talmadge E King, Yasuhiro Kondoh, Jeffrey Myers, Nestor L Müller, Andrew G Nicholson, Luca Richeldi, Moisés Selman, Rosalind F Dudden, Barbara S Griss, Shandra L Protzko, Holger J Schünemann, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis
雑誌名: Am J Respir Crit Care Med. 2011 Mar 15;183(6):788-824. doi: 10.1164/rccm.2009-040GL.
Abstract/Text This document is an international evidence-based guideline on the diagnosis and management of idiopathic pulmonary fibrosis, and is a collaborative effort of the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association. It represents the current state of knowledge regarding idiopathic pulmonary fibrosis (IPF), and contains sections on definition and epidemiology, risk factors, diagnosis, natural history, staging and prognosis, treatment, and monitoring disease course. For the diagnosis and treatment sections, pragmatic GRADE evidence-based methodology was applied in a question-based format. For each diagnosis and treatment question, the committee graded the quality of the evidence available (high, moderate, low, or very low), and made a recommendation (yes or no, strong or weak). Recommendations were based on majority vote. It is emphasized that clinicians must spend adequate time with patients to discuss patients' values and preferences and decide on the appropriate course of action.

PMID 21471066  Am J Respir Crit Care Med. 2011 Mar 15;183(6):788-824. ・・・
著者: Osamu Nishiyama, Hiroyuki Taniguchi, Yasuhiro Kondoh, Tomoki Kimura, Keisuke Kato, Tomoya Ogawa, Fumiko Watanabe, Shinichi Arizono
雑誌名: Respir Med. 2007 Apr;101(4):833-8. doi: 10.1016/j.rmed.2006.06.030. Epub 2006 Sep 8.
Abstract/Text The characteristics of dyspnoea in idiopathic pulmonary fibrosis (IPF) during a 6-min walk test are not clear. This study was designed to evaluate dyspnoea and desaturation during the 6-min walk test in IPF in comparison with that in chronic obstructive pulmonary disease (COPD), which is one of the most studied chronic lung diseases. The 41 consecutive patients with IPF included in this study were assessed by a 6-min walk test and concurrent measures of disease severity. Forty-one age-matched and resting PaO(2) value-matched COPD patients who had undertaken the test during the same period were selected as the control. Only O(2) saturation at the end of the test was an independent predictor of dyspnoea in IPF (r(2)=0.27, P=0.0005), whereas forced expiratory volume in 1s (FEV(1)) was the only predictor in COPD (r(2)=0.16, P=0.0096). Desaturation was significantly more severe in IPF (83.6+/-9.1% in IPF versus 88.0+/-5.9% in COPD, P<0.001). In contrast, dyspnoea assessed with the Borg scale was significantly more severe in COPD (3.6+/-2.1 in IPF versus 4.6+/-1.9 in COPD, P<0.05). O(2) saturation is an independent predictor of dyspnoea at the end of a 6-min walk test in IPF. In comparison with COPD, desaturation is more severe, although dyspnoea is milder.

PMID 16962758  Respir Med. 2007 Apr;101(4):833-8. doi: 10.1016/j.rmed.・・・
著者: Vibha N Lama, Kevin R Flaherty, Galen B Toews, Thomas V Colby, William D Travis, Qi Long, Susan Murray, Ella A Kazerooni, Barry H Gross, Joseph P Lynch, Fernando J Martinez
雑誌名: Am J Respir Crit Care Med. 2003 Nov 1;168(9):1084-90. doi: 10.1164/rccm.200302-219OC. Epub 2003 Aug 13.
Abstract/Text Exercise-induced hypoxia is an index of the severity of interstitial lung disease. We hypothesized that desaturation during a 6-minute walk test would predict mortality for patients with usual interstitial pneumonia (n = 83) and nonspecific interstitial pneumonia (n = 22). Consecutive patients with biopsy-proven disease performed a 6-minute walk test between January 1996 and December 2001. Desaturation was defined as a fall in oxygen saturation to 88% or less during the 6-minute walk test. Desaturation was common (44 of 83 usual interstitial pneumonia and 8 of 22 nonspecific interstitial pneumonia; chi square, p = 0.39). Patients with usual interstitial pneumonia or nonspecific interstitial pneumonia who desaturated had a significantly higher mortality than patients who did not desaturate (respective log-rank tests, p = 0.0018, p = 0.0089). In patients with usual interstitial pneumonia, the presence of desaturation was associated with an increased hazard of death (hazard ratio, 4.2; 95% confidence interval, 1.40, 12.56; p = 0.01) after adjusting for age, sex, smoking, baseline diffusion capacity for carbon monoxide, FVC, and resting saturation. We conclude that knowledge of desaturation during a 6-minute walk test adds prognostic information for patients with usual interstitial pneumonia and nonspecific interstitial pneumonia.

PMID 12917227  Am J Respir Crit Care Med. 2003 Nov 1;168(9):1084-90. d・・・
著者:
雑誌名: Am J Respir Crit Care Med. 2000 Feb;161(2 Pt 1):646-64. doi: 10.1164/ajrccm.161.2.ats3-00.
Abstract/Text
PMID 10673212  Am J Respir Crit Care Med. 2000 Feb;161(2 Pt 1):646-64.・・・
著者: H Taniguchi, M Ebina, Y Kondoh, T Ogura, A Azuma, M Suga, Y Taguchi, H Takahashi, K Nakata, A Sato, M Takeuchi, G Raghu, S Kudoh, T Nukiwa, Pirfenidone Clinical Study Group in Japan
雑誌名: Eur Respir J. 2010 Apr;35(4):821-9. doi: 10.1183/09031936.00005209. Epub 2009 Dec 8.
Abstract/Text Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease without proven effective therapy. A multicentre, double-blind, placebo-controlled, randomised phase III clinical trial was conducted in Japanese patients with well-defined IPF to determine the efficacy and safety of pirfenidone, a novel antifibrotic oral agent, over 52 weeks. Of 275 patients randomised (high-dose, 1,800 mg x day(-1); low-dose, 1,200 mg x day(-1); or placebo groups in the ratio 2:1:2), 267 patients were evaluated for the efficacy of pirfenidone. Prior to unblinding, the primary end-point was revised; the change in vital capacity (VC) was assessed at week 52. Secondary end-points included the progression-free survival (PFS) time. Significant differences were observed in VC decline (primary end-point) between the placebo group (-0.16 L) and the high-dose group (-0.09 L) (p = 0.0416); differences between the two groups (p = 0.0280) were also observed in the PFS (the secondary end-point). Although photosensitivity, a well-established side-effect of pirfenidone, was the major adverse event in this study, it was mild in severity in most of the patients. Pirfenidone was relatively well tolerated in patients with IPF. Treatment with pirfenidone may decrease the rate of decline in VC and may increase the PFS time over 52 weeks. Additional studies are needed to confirm these findings.

PMID 19996196  Eur Respir J. 2010 Apr;35(4):821-9. doi: 10.1183/090319・・・
著者: Arata Azuma, Yoshio Taguchi, Takashi Ogura, Masahito Ebina, Hiroyuki Taniguchi, Yasuhiro Kondoh, Moritaka Suga, Hiroki Takahashi, Koichiro Nakata, Atsuhiko Sato, Shoji Kudoh, Toshihiro Nukiwa, Pirfenidone Clinical Study Group in Japan
雑誌名: Respir Res. 2011 Oct 28;12:143. doi: 10.1186/1465-9921-12-143. Epub 2011 Oct 28.
Abstract/Text BACKGROUND: A phase III trial in Japan showed that pirfenidone is effective for idiopathic pulmonary fibrosis (IPF). To find out which patients specifically benefit from pirfenidone, we analyzed in an exploratory manner the data from the phase III trial.
METHODS: The patients in the phase III trial were stratified by baseline percentage predicted vital capacity (%VC), arterial oxygen partial pressure (PaO(2)), and the lowest oxygen saturation by pulse oximetry (SpO(2)) during the 6-minute steady-state exercise test (6MET). In the subpopulations, changes in VC and subjective symptoms (cough and dyspnea on the Fletcher, Hugh-Jones [F, H-J] Classification scale) were evaluated in patients treated with high-dose (1800 mg/day) pirfenidone, low-dose (1200 mg/day) pirfenidone, and placebo at week 52.
RESULTS: Significant efficacy of pirfenidone in reducing the decline in VC could be seen in a subpopulation having %VC ≥ 70% and SpO(2) < 90% at baseline. This favorable effect was accompanied by categorical change in VC and progression-free survival time. In the subpopulation, pirfenidone significantly suppressed cough and dyspnea.
CONCLUSIONS: IPF patients having %VC ≥ 70% and SpO(2) < 90% at baseline will most likely benefit from pirfenidone when evaluated using changes in VC (and %VC), and cough and dyspnea symptoms. This subpopulation could expect to benefit most from pirfenidone treatment.
TRIAL REGISTRATION: This clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13th, 2005 (REGISTRATION NUMBER: JAPICCTI-050121).

PMID 22035508  Respir Res. 2011 Oct 28;12:143. doi: 10.1186/1465-9921-・・・
著者: Talmadge E King, Williamson Z Bradford, Socorro Castro-Bernardini, Elizabeth A Fagan, Ian Glaspole, Marilyn K Glassberg, Eduard Gorina, Peter M Hopkins, David Kardatzke, Lisa Lancaster, David J Lederer, Steven D Nathan, Carlos A Pereira, Steven A Sahn, Robert Sussman, Jeffrey J Swigris, Paul W Noble, ASCEND Study Group
雑誌名: N Engl J Med. 2014 May 29;370(22):2083-92. doi: 10.1056/NEJMoa1402582. Epub 2014 May 18.
Abstract/Text BACKGROUND: In two of three phase 3 trials, pirfenidone, an oral antifibrotic therapy, reduced disease progression, as measured by the decline in forced vital capacity (FVC) or vital capacity, in patients with idiopathic pulmonary fibrosis; in the third trial, this end point was not achieved. We sought to confirm the beneficial effect of pirfenidone on disease progression in such patients.
METHODS: In this phase 3 study, we randomly assigned 555 patients with idiopathic pulmonary fibrosis to receive either oral pirfenidone (2403 mg per day) or placebo for 52 weeks. The primary end point was the change in FVC or death at week 52. Secondary end points were the 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from idiopathic pulmonary fibrosis.
RESULTS: In the pirfenidone group, as compared with the placebo group, there was a relative reduction of 47.9% in the proportion of patients who had an absolute decline of 10 percentage points or more in the percentage of the predicted FVC or who died; there was also a relative increase of 132.5% in the proportion of patients with no decline in FVC (P<0.001). Pirfenidone reduced the decline in the 6-minute walk distance (P=0.04) and improved progression-free survival (P<0.001). There was no significant between-group difference in dyspnea scores (P=0.16) or in rates of death from any cause (P=0.10) or from idiopathic pulmonary fibrosis (P=0.23). However, in a prespecified pooled analysis incorporating results from two previous phase 3 trials, the between-group difference favoring pirfenidone was significant for death from any cause (P=0.01) and from idiopathic pulmonary fibrosis (P=0.006). Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group but rarely led to treatment discontinuation.
CONCLUSIONS: Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths. (Funded by InterMune; ASCEND ClinicalTrials.gov number, NCT01366209.).

PMID 24836312  N Engl J Med. 2014 May 29;370(22):2083-92. doi: 10.1056・・・
著者: Andreas Guenther, Ekaterina Krauss, Silke Tello, Jasmin Wagner, Bettina Paul, Stefan Kuhn, Olga Maurer, Sabine Heinemann, Ulrich Costabel, María Asunción Nieto Barbero, Veronika Müller, Philippe Bonniaud, Carlo Vancheri, Athol Wells, Martina Vasakova, Alberto Pesci, Matteo Sofia, Walter Klepetko, Werner Seeger, Fotios Drakopanagiotakis, Bruno Crestani
雑誌名: Respir Res. 2018 Jul 28;19(1):141. doi: 10.1186/s12931-018-0845-5. Epub 2018 Jul 28.
Abstract/Text BACKGROUND: Since 2009, IPF patients across Europe are recruited into the eurIPFreg, providing epidemiological data and biomaterials for translational research.
METHODS: The registry data are based on patient and physician baseline and follow-up questionnaires, comprising 1700 parameters. The mid- to long-term objectives of the registry are to provide clues for a better understanding of IPF phenotype sub-clusters, triggering factors and aggravating conditions, regional and environmental characteristics, and of disease behavior and management.
RESULTS: This paper describes baseline data of 525 IPF subjects recruited from 11/2009 until 10/2016. IPF patients had a mean age of 68.1 years, and seeked medical advice due to insidious dyspnea (90.1%), fatigue (69.2%), and dry coughing (53.2%). A surgical lung biopsy was performed in 32% in 2009, but in only 8% of the cases in 2016, possibly due to increased numbers of cryobiopsy. At the time of inclusion in the eurIPFreg, FVC was 68.4% ± 22.6% of predicted value, DLco ranged at 42.1% ± 17.8% of predicted value (mean value ± SD). Signs of pulmonary hypertension were found in 16.8%. Steroids, immunosuppressants and N-Acetylcysteine declined since 2009, and were replaced by antifibrotics, under which patients showed improved survival (p = 0.001).
CONCLUSIONS: Our data provide important insights into baseline characteristics, diagnostic and management changes as well as outcome data in European IPF patients over time.
TRIAL REGISTRATION: The eurIPFreg and eurIPFbank are listed in ClinicalTrials.gov( NCT02951416 ).

PMID 30055613  Respir Res. 2018 Jul 28;19(1):141. doi: 10.1186/s12931-・・・
著者: Luca Richeldi, Ulrich Costabel, Moises Selman, Dong Soon Kim, David M Hansell, Andrew G Nicholson, Kevin K Brown, Kevin R Flaherty, Paul W Noble, Ganesh Raghu, Michèle Brun, Abhya Gupta, Nolwenn Juhel, Matthias Klüglich, Roland M du Bois
雑誌名: N Engl J Med. 2011 Sep 22;365(12):1079-87. doi: 10.1056/NEJMoa1103690.
Abstract/Text BACKGROUND: Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis.
METHODS: In a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Secondary end points included acute exacerbations, quality of life (measured with the St. George's Respiratory Questionnaire [SGRQ]), and total lung capacity.
RESULTS: A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group.
CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683 .).

PMID 21992121  N Engl J Med. 2011 Sep 22;365(12):1079-87. doi: 10.1056・・・
著者: Luca Richeldi, Roland M du Bois, Ganesh Raghu, Arata Azuma, Kevin K Brown, Ulrich Costabel, Vincent Cottin, Kevin R Flaherty, David M Hansell, Yoshikazu Inoue, Dong Soon Kim, Martin Kolb, Andrew G Nicholson, Paul W Noble, Moisés Selman, Hiroyuki Taniguchi, Michèle Brun, Florence Le Maulf, Mannaïg Girard, Susanne Stowasser, Rozsa Schlenker-Herceg, Bernd Disse, Harold R Collard, INPULSIS Trial Investigators
雑誌名: N Engl J Med. 2014 May 29;370(22):2071-82. doi: 10.1056/NEJMoa1402584. Epub 2014 May 18.
Abstract/Text BACKGROUND: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis.
METHODS: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period.
RESULTS: A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2.
CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.).

PMID 24836310  N Engl J Med. 2014 May 29;370(22):2071-82. doi: 10.1056・・・

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