Summary

The intersection of ILD and CTD is complex and commonly includes a well-documented CTD complicated by the presence of ILD, ILD as the presenting manifestation of a CTD, or arising within the context of IPAF. A consensus on characteristic criteria and phenotyping will lead to further prospective studies that will improve our understanding of the natural history and appropriate management. An interdisciplinary dialogue that includes pulmonologists, rheumatologists, radiologists, and pathologists will continue to advance our understanding of IPAF [2, 6]. Finally, as there is potential for evolution to de ned forms of CTD, longitudinal assessment of these patients is required.

References

1.\ATS/ERS. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classi cation 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, June 2001. Am J Respir Crit Care Med. 2002;165(2):277–304. Epub 2002/01/16. https://doi.org/10.1164/ajrccm.165.2.ats01.

https://doi.org/10.1016/S0140-6736(12)61079-4.

3.\Mittoo S, Gelber AC, Christopher-Stine L, Horton MR, Lechtzin N, Danoff SK. Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease. Respir Med. 2009;103(8):1152–8. Epub 2009/03/24. https://doi.org/10.1016/j. rmed.2009.02.009.

4.\Strange C, Highland KB. Interstitial lung disease in the patient who has connective tissue disease. Clin Chest Med. 2004;25(3):549–59.

5.\Kinder BW, Collard HR, Koth L, Daikh DI, Wolters PJ, Elicker B, Jones KD, King TE Jr. Idiopathic nonspeci c interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med. 2007;176(7):691–7.

6.\Fischer A, West SG, Swigris JJ, Brown KK, du Bois RM. Connective tissue disease-associated interstitial lung disease: a call for clari-cation. Chest. 2010;138(2):251–6. Epub 2010/08/05. https://doi. org/10.1378/chest.10-0194.

7.\Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease: a distinct entity. Chest. 2011;140(5):1292–9. https://doi. org/10.1378/chest.10-2662.

8.\Fischer A, Antoniou KM, Brown KK, Cadranel J, Corte TJ, du Bois RM, Lee JS, Leslie KO, Lynch DA, Matteson EL, Mosca M, Noth I, Richeldi L, Strek ME, Swigris JJ, Wells AU, West SG, Collard HR, Cottin V, CTD-ILD EATFoUFo. An of cial European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J. 2015;46(4):976–87. Epub 2015/07/15. https://doi. org/10.1183/13993003.00150-2015.

9.\LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, Rowell N, Wollheim F. Scleroderma (systemic sclerosis): classi cation, subsets and pathogenesis. J Rheumatol. 1988;15(2):202–5.

10.\LeRoy EC, Medsger TA Jr. Criteria for the classi cation of early systemic sclerosis. J Rheumatol. 2001;28(7):1573–6. Epub 2001/07/27.

11.\Corte TJ, Copley SJ, Desai SR, Zappala CJ, Hansell DM, Nicholson AG, Colby TV, Renzoni E, Maher TM, Wells AU. Signi cance of connective tissue disease features in idiopathic interstitial pneumonia. Eur Respir J. 2012;39(3):661–8. Epub 2011/09/17. https://doi. org/10.1183/09031936.00174910.

12.\Fischer A, Swigris JJ, du Bois RM, Lynch DA, Downey GP, Cosgrove GP, Frankel SK, Fernandez-Perez ER, Gillis JZ, Brown KK. Anti-synthetase syndrome in ANA and anti-Jo-1 negative patients presenting with idiopathic interstitial pneumonia. Respir Med. 2009;103(11):1719–24. PubMed PMID: 19497723; PMCID: 2857337. https://doi.org/10.1016/j.rmed.2009.05.001.

13.\Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, Behr J, Cottin V, Danoff SK, Morell F, Flaherty KR, Wells A, Martinez FJ, Azuma A, Bice TJ, Bouros D, Brown KK, Collard HR, Duggal A, Galvin L, Inoue Y, Jenkins RG, Johkoh T, Kazerooni EA, Kitaichi M, Knight SL, Mansour G, Nicholson AG, SNJ P, Buendia-Roldan I, Selman M, Travis WD, Walsh S, Wilson KC, American Thoracic Society ERSJRS, Latin American Thoracic S. Diagnosis of idiopathic pulmonary brosis. An of - cial ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44–68. Epub 2018/09/01. https://doi. org/10.1164/rccm.201807-1255ST.

14.\Steen VD. Auto antibodies in systemic sclerosis. Semin Arthritis Rheum. 2005;35(1):35–42. Epub 2005/08/09. https://doi. org/10.1016/j.semarthrit.2005.03.005.

15.\Reveille JD, Solomon DH, American College of Rheumatology ad hoc Committee of immunologic testing G. Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum. 2003;49(3):399–412. Epub 2003/06/10. https://doi.org/10.1002/art.11113.

16.\Lynch DA. Quantitative CT of brotic interstitial lung disease. Chest. 2007;131(3):643–4. Epub 2007/03/16. https://doi. org/10.1378/chest.06-2955.

17.\Lynch DA, Travis WD, Muller NL, Galvin JR, Hansell DM, Grenier PA, King TE Jr. Idiopathic interstitial pneumonias: CT features. Radiology. 2005;236(1):10–21. Epub 2005/07/01. https://doi. org/10.1148/radiol.2361031674.

18.\Hwang JH, Misumi S, Sahin H, Brown KK, Newell JD, Lynch DA. Computed tomographic features of idiopathic brosing interstitial pneumonia: comparison with pulmonary brosis related to collagen vascular disease. J Comput Assist Tomogr. 2009;33(3):410–5. Epub 2009/05/30. https://doi.org/10.1097/ RCT.0b013e318181d551.

19.\Tansey D,WellsAU, Colby TV, Ip S, NikolakoupolouA, du Bois RM, Hansell DM, Nicholson AG. Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis. Histopathology. 2004;44(6):585–96. Epub 2004/06/10. https://doi.org/10.1111/j.1365-2559.2004.01896.x.

20.\Leslie KO, Trahan S, Gruden J. Pulmonary pathology of the rheumatic diseases. Semin Respir Crit Care Med. 2007;28(4):369–78.

21.\Graney BA, Fischer A. Interstitial pneumonia with autoimmune features. Ann Am Thorac Soc. 2019;16(5):525–33. Epub 2019/01/30. https://doi.org/10.1513/AnnalsATS.201808-565CME.

22.\Lega JC, Reynaud Q, Belot A, Fabien N, Durieu I, Cottin V. Idiopathic infammatory myopathies and the lung. Eur Respir Rev. 2015;24(136):216–38. Epub 2015/06/02. https://doi. org/10.1183/16000617.00002015.

23.\Connors GR, Christopher-Stine L, Oddis CV, Danoff SK. Interstitial lung disease associated with the idiopathic infammatory myopathies: what progress has been made in the past 35 years? Chest. 2010;138(6):1464–74. Epub 2010/12/09. https://doi.org/10.1378/ chest.10-0180.

24.\Jee AS, Bleasel JF, Adelstein S, Keir GJ, Corte TJ. A call for uniformity in implementing the IPAF (interstitial pneumonia with autoimmune features) criteria. Eur Respir J. 2016;48(6):1811–3. Epub 2016/12/03. https://doi.org/10.1183/13993003.01259-2016.

25.\Jee AS, Adelstein S, Bleasel J, Keir GJ, Nguyen M, Sahhar J, Youssef P, Corte TJ. Role of autoantibodies in the diagnosis of connective-tissue disease ILD (CTD-ILD) and interstitial pneumonia with autoimmune features (IPAF). J Clin Med. 2017;6(5):51. PubMed PMID: 28471413; PMCID: PMC5447942. Epub 2017/05/05. https://doi.org/10.3390/jcm6050051.

26.\Scire CA, Gonzalez-Gay MA, Selva-O'Callaghan A, Cavagna L. Clinical spectrum time course of interstitial pneumonia with autoimmune features in patients positive for antisynthetase antibodies. Respir Med. 2017;(132):265–6. Epub 2017/04/08. https://doi. org/10.1016/j.rmed.2017.03.028.

27.\Cavagna L, Nuno L, Scire CA, Govoni M, Longo FJ, Franceschini F, Neri R, Castaneda S, Sifuentes Giraldo WA, Caporali R, Iannone F, Fusaro E, Paolazzi G, Pellerito R, Schwarting A, Saketkoo LA, Ortego-Centeno N, Quartuccio L, Bartoloni E, Specker C, Murcia TP, La Corte R, Furini F, Foschi V, Corral JB, Airo P, Cavazzana I, Martinez-Barrio J, Hinojosa M, Giannini M, Barsotti S, Menke J, Triantafyllias K, Vitetta R, Russo A, Bajocchi G, Bravi E, Barausse G, Bortolotti R, Selmi C, Parisi S, Montecucco C, Gonzalez-Gay MA, Group Ac. Clinical spectrum time course in anti Jo-1 positive antisynthetase syndrome: results from an international retrospective multicenter study. Medicine (Baltimore). 2015;94(32):e1144. Epub 2015/08/13. PubMed PMID: 26266346; PMCID: PMC4616698. https://doi.org/10.1097/MD.0000000000001144.

28.\Graham J, BauerVentura I, Newton CA, Lee C, Boctor N, Pugashetti JV, Cutting C, Joerns E, Sandhu H, Chung JH, Garcia CK, Kadoch M, Noth I, Adegunsoye A, Strek ME, Oldham JM. Myositis-­ speci c antibodies identify a distinct interstitial pneumonia with autoimmune features phenotype. Eur Respir J. 2020:2001205. Epub 2020/07/18. https://doi.org/10.1183/13993003.01205-2020.

29.\Yamada H. ANCA: associated lung brosis. Semin Respir Crit Care Med. 2011;32(3):322–7. Epub 2011/06/16. https://doi. org/10.1055/s-0031-1279828.

30.\Hervier B, Pagnoux C, Agard C, Haroche J, Amoura Z, Guillevin L, Hamidou MA, French Vasculitis study G. Pulmonary brosis associated with ANCA-positive vasculitides. Retrospective study of 12 cases and review of the literature. Ann Rheum Dis. 2009;68(3):404– 7. Epub 2008/10/30. https://doi.org/10.1136/ard.2008.096131.

31.\Comarmond C, Crestani B, Tazi A, Hervier B, Adam-Marchand S, Nunes H, Cohen-Aubart F, Wislez M, Cadranel J, Housset B, Lloret-Linares C, Seve P, Pagnoux C, Abad S, Camuset J, Bienvenu B, Duruisseaux M, Hachulla E, Arlet JB, Hamidou M, Mahr A, Resche-Rigon M, Brun AL, Grenier P, Cacoub P, Saadoun D. Pulmonary brosis in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis: a series of 49 patients and review of the literature. Medicine (Baltimore). 2014;93(24):340–9. Epub 2014/12/17. https://doi.org/10.1097/MD.0000000000000217.

32.\Moiseev S, Cohen Tervaert JW, Arimura Y, Bogdanos DP, Csernok E, Damoiseaux J, Ferrante M, Flores-Suarez LF, Fritzler MJ, Invernizzi P, Jayne D, Jennette JC, Little MA, SP MA, Novikov P, Pusey CD, Radice A, Salama AD, Savige JA, Segelmark M, Shoenfeld Y, Sinico RA, Sousa MJ, Specks U, Terrier B, Tzioufas AG, Vermeire S, Zhao MH, Bossuyt X. 2020 international consensus on ANCA testing beyond systemic vasculitis. Autoimmun Rev. 2020;19(9):102618. Epub 2020/07/15. https://doi.org/10.1016/j. autrev.2020.102618.

33.\Hozumi H, Oyama Y, Yasui H, Suzuki Y, Kono M, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Inui N, Nakamura Y, Suda T. Clinical signi cance of myeloperoxidase-anti-neutrophil cytoplasmic antibody in idiopathic interstitial pneumonias. PLoS One. 2018;13(6):e0199659. Epub 2018/06/22. PubMed PMID: 29928060; PMCID: PMC6013167. https://doi.org/10.1371/journal. pone.0199659.

34.\Hozumi H, Enomoto N, Oyama Y, Kono M, Fujisawa T, Inui N, Nakamura Y, Suda T. Clinical implication of proteinase- 3-­antineutrophil cytoplasmic antibody in patients with idio-

pathic interstitial pneumonias. Lung. 2016;194(2):235–42. Epub 2016/02/14. https://doi.org/10.1007/s00408-016-9851-x.

35.\Oldham JM, Adegunsoye A, Valenzi E, Lee C, Witt L, Chen L, Husain AN, Montner S, Chung JH, Cottin V, Fischer A, Noth I, Vij R, Strek ME. Characterisation of patients with interstitial pneumonia with autoimmune features. Eur Respir J. 2016;47(6):1767–75. Epub 2016/04/23. https://doi.org/10.1183/13993003.01565-2015.

36.\Oldham JM, Danoff SK. COUNTERPOINT: does interstitial pneumonia with autoimmune features represent a distinct class of patients with idiopathic interstitial pneumonia? No. Chest. 2019;155(2):260–3. Epub 2019/02/09. https://doi.org/10.1016/j. chest.2018.08.1073.

37.\Kim HC, Lee JH, Chae EJ, Song JS, Song JW. Long-term clinical course and outcome of interstitial pneumonia with autoimmune features. Respirology. 2019;25(6):636–43. Epub 2019/08/07. https://doi.org/10.1111/resp.13665.

38.\Newton CA, Oldham JM, Ley B, Anand V, Adegunsoye A, Liu G, Batra K, Torrealba J, Kozlitina J, Glazer C, Strek ME, Wolters PJ, Noth I, Garcia CK. Telomere length and genetic variant associations with interstitial lung disease progression and survival. Eur Respir J. 2019;53(4):1801641. Epub 2019/01/13. PubMed PMID: 30635297; PMCID: PMC6612265. https://doi. org/10.1183/13993003.01641-2018.

39.\Chartrand S, Swigris JJ, Stanchev L, Lee JS, Brown KK, Fischer A. Clinical features and natural history of interstitial pneumonia with autoimmune features: a single center experience. Respir Med. 2016;119:150–4. Epub 2016/10/04. https://doi.org/10.1016/j. rmed.2016.09.002.

40.\Ito Y, Arita M, Kumagai S, Takei R, Noyama M, Tokioka F, Nishimura K, Koyama T, Notohara K, Ishida T. Serological and morphological prognostic factors in patients with interstitial pneumonia with autoimmune features. BMC Pulm Med. 2017;17(1):111. Epub 2017/08/16. PubMed PMID: 28807021; PMCID: 5554971. https://doi.org/10.1186/s12890-017-0453-z.

41.\Dai J, Wang L, Yan X, Li H, Zhou K, He J, Meng F, Xu S, Liang G, Cai H. Clinical features, risk factors, and outcomes of patients with interstitial pneumonia with autoimmune features: a population-­based study. Clin Rheumatol. 2018;37(8):2125–32. Epub 2018/04/19. https://doi.org/10.1007/s10067-018-4111-5.

42.\Ferri C, Manfredi A, Sebastiani M, Colaci M, Giuggioli D, Vacchi C, Della Casa G, Cerri S, Torricelli P, Luppi F. Interstitial pneumonia with autoimmune features and undifferentiated connective tissue disease: our interdisciplinary rheumatology-pneumology experience, and review of the literature. Autoimmun Rev. 2016;15(1):61– 70. Epub 2015/09/20. https://doi.org/10.1016/j.autrev.2015.09.003.

43.\Bif A, Dei G, De Giacomi F, Stainer A, Parma LO, Pozzi MR, Faverio P, Pesci A. Non-speci c interstitial pneumonia and features of connective tissue disease: what are the consequences of a different point of view? Monaldi Arch Chest Dis. 2018;88(3):970. Epub 2018/09/06. https://doi.org/10.4081/monaldi.2018.970.

44.\Ahmad K, Barba T, Gamondes D, Ginoux M, Khouatra C, Spagnolo P, Strek M, Thivolet-Bejui F, Traclet J, Cottin V. Interstitial pneumonia with autoimmune features: clinical, radiologic, and histological characteristics and outcome in a series of 57 patients. Respir Med. 2017;123:56–62. Epub 2017/02/01. https://doi.org/10.1016/j. rmed.2016.10.017.

45.\Yoshimura K, Kono M, Enomoto Y, Nishimoto K, Oyama Y, Yasui H, Hozumi H, Karayama M, Suzuki Y, Furuhashi K, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Sumikawa H, Johkoh T, Colby TV, Sugimura H, Suda T. Distinctive characteristics and prognostic signi cance of interstitial pneumonia with autoimmune features in patients with chronic brosing interstitial pneumonia. Respir Med. 2018;137:167–75. Epub 2018/04/02. https://doi.org/10.1016/j. rmed.2018.02.024.

46.\Collins BF, Spiekerman CF, Shaw MA, Ho LA, Hayes J, Spada CA, Stamato CM, Raghu G. Idiopathic interstitial pneumonia associated

with autoantibodies: a large case series followed over 1 year. Chest. 2017;152(1):103–12. Epub 2017/03/17. https://doi.org/10.1016/j. chest.2017.03.004.

47.\Kelly BT, Moua T. Overlap of interstitial pneumonia with autoimmune features with undifferentiated connective tissue disease and contribution of UIP to mortality. Respirology. 2018;23(6):600–5. Epub 2018/01/11. https://doi.org/10.1111/resp.13254.

48.\Sebastiani M, Cassone G, De Pasquale L, Cerri S, Della Casa G, Vacchi C, Luppi F, Salvarani C, Manfredi A. Interstitial pneumonia with autoimmune features: a single center prospective follow- ­up study. Autoimmun Rev. 2020;19(2):102451. Epub 2019/12/16. https://doi.org/10.1016/j.autrev.2019.102451.

49.\Tsukamoto T, Yamakawa Y. Effects of the cytosol fraction and ATP on the kinetics of cAMP binding to human erythrocyte membranes. Biochem Int. 1988;16(2):253–7. Epub 1988/02/01.

50.\Lim JU, Gil BM, Kang HS, Oh J, Kim YH, Kwon SS. Interstitial pneumonia with autoimmune features show better survival and less exacerbations compared to idiopathic pulmonary brosis. BMC Pulm Med. 2019;19(1):120. Epub 2019/07/06. PubMed PMID: 31272428; PMCID: PMC6610995. https://doi.org/10.1186/ s12890-019-0868-9.

51.\Sambataro G, Sambataro D, Torrisi SE, Vancheri A, Colaci M, Pavone M, Pignataro F, Del Papa N, Palmucci S, Vancheri C. Clinical, serological and radiological features of a prospective cohort of interstitial pneumonia with autoimmune features (IPAF) patients. Respir Med. 2019;150:154–60. Epub 2019/04/10. https:// doi.org/10.1016/j.rmed.2019.03.011.

52.\Yamakawa H, Kitamura H, Takemura T, Ikeda S, Sekine A, Baba T, Iwasawa T, Hagiwara E, Sato S, Ogura T. Prognostic factors and disease behaviour of pathologically proven brotic non-speci c interstitial pneumonia. Respirology. 2018;23(11):1032–40. Epub 2018/04/26. https://doi.org/10.1111/resp.13313.

53.\Hernandez-Gonzalez F, Prieto-Gonzalez S, Brito-Zeron P, Cuerpo S, Sanchez M, Ramirez J, Agusti C, Lucena CM, Paradela M, Gra a I, Espinosa G, Sellares J. Impact of a systematic evaluation of connective tissue disease on diagnosis approach in patients with interstitial lung diseases. Medicine (Baltimore). 2020;99(4):e18589. Epub 2020/01/25. PubMed PMID: 31977850; PMCID: PMC7004576. https://doi.org/10.1097/MD.0000000000018589.

54.\McCoy SS, Mukadam Z, Meyer KC, Kanne JP, Meyer CA, Martin MD, Sampene E, Aesif SW, Rice LN, Bartels CM. Mycophenolate therapy in interstitial pneumonia with autoimmune features: a cohort study. Ther Clin Risk Manag. 2018;14:2171–81. Epub 2018/11/23. PubMed PMID: 30464490; PMCID: PMC6219314. https://doi.org/10.2147/TCRM.S173154.

55.\Chung JH, Montner SM, Adegunsoye A, Lee C, Oldham JM, Husain AN, MacMahon H, Noth I, Vij R, Strek ME. CT ndings, radiologic-pathologic correlation, and imaging predictors of survival for patients with interstitial pneumonia with autoimmune features. AJR Am J Roentgenol. 2017;208(6):1229–36. Epub 2017/03/30. PubMed PMID: 28350485; PMCID: PMC6536259. https://doi.org/10.2214/AJR.16.17121.

56.\Wiertz IA, van Moorsel CHM, Vorselaars ADM, Quanjel MJR, Grutters JC. Cyclophosphamide in steroid refractory unclassi able idiopathic interstitial pneumonia and interstitial pneumonia with autoimmune features (IPAF). Eur Respir J. 2018;51(4):1702519. Epub 2018/03/03. https://doi.org/10.1183/13993003.02519-2017.

57.\Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR, Investigators IT. Ef cacy and safety of nintedanib in idiopathic pulmonary brosis. N Engl J Med. 2014;370(22):2071– 82. Epub 2014/05/20. https://doi.org/10.1056/NEJMoa1402584.

58.\Crestani B, Huggins JT, Kaye M, Costabel U, Glaspole I, Ogura T, Song JW, Stansen W, Quaresma M, Stowasser S, Kreuter M. Long-­

term safety and tolerability of nintedanib in patients with idiopathic pulmonary brosis: results from the open-label extension study, INPULSIS-ON. Lancet Respir Med. 2019;7(1):60–8. Epub 2018/09/19. https://doi.org/10.1016/S2213-2600(18)30339-4.

59.\Richeldi L, Cottin V, du Bois RM, Selman M, Kimura T, Bailes Z, Schlenker-Herceg R, Stowasser S, Brown KK. Nintedanib in patients with idiopathic pulmonary brosis: combined evidence from the TOMORROW and INPULSIS((R)) trials. Respir Med. 2016;113:74–9. Epub 2016/02/27. https://doi.org/10.1016/j. rmed.2016.02.001.

60.\Costabel U, InoueY, Richeldi L, Collard HR, Tschoepe I, Stowasser S, Azuma A. Ef cacy of Nintedanib in idiopathic pulmonary brosis across prespeci ed subgroups in INPULSIS. Am J Respir Crit Care Med. 2016;193(2):178–85. Epub 2015/09/24. https://doi. org/10.1164/rccm.201503-0562OC.

61.\Distler O, Highland KB, Gahlemann M,AzumaA, FischerA, Mayes MD, Raghu G, Sauter W, Girard M, Alves M, Clerisme-Beaty E, Stowasser S, Tetzlaff K, Kuwana M, Maher TM, Investigators ST. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019;380(26):2518–28. Epub 2019/05/22. https://doi.org/10.1056/NEJMoa1903076.

62.\Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, Richeldi L, Kolb M, Tetzlaff K, Stowasser S, Coeck C, Clerisme-­ Beaty E, Rosenstock B, Quaresma M, Haeufel T, Goeldner RG, Schlenker-Herceg R, Brown KK, Investigators IT. Nintedanib in progressive brosing interstitial lung diseases. N Engl J Med. 2019;381(18):1718–27. Epub 2019/10/01. https://doi.org/10.1056/ NEJMoa1908681.

63.\Flaherty KR, Brown KK, Wells AU, Clerisme-Beaty E, Collard HR, Cottin V, Devaraj A, Inoue Y, Le Maulf F, Richeldi L, Schmidt H, Walsh S, Mezzanotte W, Schlenker-Herceg R. Design of the PF-ILD trial: a double-blind, randomised, placebo-controlled phase III trial of nintedanib in patients with progressive brosing interstitial lung disease. BMJ Open Respir Res. 2017;4(1):e000212. Epub 2017/10/12. PubMed PMID: 29018526; PMCID: 5604725. https:// doi.org/10.1136/bmjresp-2017-000212.

64.\Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, King TE Jr, Lancaster L, Sahn SA, Szwarcberg J, Valeyre D, du Bois RM, Group CS. Pirfenidone in patients with idiopathic pulmonary brosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760–9. Epub 2011/05/17. https://doi. org/10.1016/S0140-6736(11)60405-4.

65.\King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW, Group AS. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary brosis. N Engl J Med. 2014;370(22):2083–92. Epub 2014/05/20. https://doi.org/10.1056/ NEJMoa1402582.

66.\Nathan SD, Albera C, Bradford WZ, Costabel U, Glaspole I, Glassberg MK, Kardatzke DR, Daigl M, Kirchgaessler KU, Lancaster LH, Lederer DJ, Pereira CA, Swigris JJ, Valeyre D, Noble PW. Effect of pirfenidone on mortality: pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary brosis. Lancet Respir Med. 2017;5(1):33–41. Epub 2016/11/24. https:// doi.org/10.1016/S2213-2600(16)30326-5.

67.\Noble PW, Albera C, Bradford WZ, Costabel U, du Bois RM, Fagan EA, Fishman RS, Glaspole I, Glassberg MK, Lancaster L, Lederer DJ, Leff JA, Nathan SD, Pereira CA, Swigris JJ, Valeyre D, King TE Jr. Pirfenidone for idiopathic pulmonarybrosis: analysis of pooled data from three multinational phase 3 trials. Eur Respir J. 2016;47(1):243–53. Epub 2015/12/10. PubMed PMID: 26647432; PMCID: PMC4697914. https://doi. org/10.1183/13993003.00026-2015.

68.\Maher TM, Corte TJ, Fischer A, Kreuter M, Lederer DJ, Molina-­ Molina M, Axmann J, Kirchgaessler KU, Samara K, Gilberg

F, Cottin V. Pirfenidone in patients with unclassi able progressive brosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med. 2020;8(2):147–57. Epub 2019/10/04. https://doi.org/10.1016/ S2213-2600(19)30341-8.

69.\Cantin AM, Hubbard RC, Crystal RG. Glutathione de ciency in the epithelial lining fuid of the lower respiratory tract in idiopathic pulmonary brosis. Am Rev Respir Dis. 1989;139(2):370–2.

70.\Behr J, Maier K, Degenkolb B, Krombach F, Vogelmeier C. Antioxidative and clinical effects of high-dose N-acetylcysteine in brosing alveolitis. Adjunctive therapy to maintenance immunosuppression. Am J Respir Crit Care Med. 1997;156(6):1897–901.

71.\Behr J, Neuser P, Prasse A, Kreuter M, Rabe K, Schade-Brittinger C, Wagner J, Gunther A. Exploring ef cacy and safety of oral pirfenidone for progressive, non-IPF lung brosis (RELIEF) - a

randomized, double-blind, placebo-controlled, parallel group, multi-center, phase II trial. BMC Pulm Med. 2017;17(1):122. Epub 2017/09/08. PubMed PMID: 28877715; PMCID: 5588600. https:// doi.org/10.1186/s12890-017-0462-y.

72.\Maher TM, Corte TJ, Fischer A, Kreuter M, Lederer DJ, Molina-­ Molina M, Axmann J, Kirchgaessler KU, Cottin V. Pirfenidone in patients with unclassi able progressive brosing interstitial lung disease: design of a double-blind, randomised, placebo-controlled phase II trial. BMJ Open Respir Res. 2018;5(1):e000289. Epub 2018/09/21. PubMed PMID: 30233802; PMCID: PMC6135451. https://doi.org/10.1136/bmjresp-2018-000289.

73.\A Study of pirfenidone in patients with unclassi able progressivebrosing interstitial lung disease. https://ClinicalTrials.gov/show/ NCT03099187.