Choroba śródmiąższowa płuc związana z reumatoidalnym zapaleniem stawów – niedoceniany, złożony i interdyscyplinarny problem w codziennej praktyce klinicznej Artykuł przeglądowy
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Opublikowane:
gru 31, 2020
Słowa kluczowe:
reumatoidalne zapalenie stawów, choroba śródmiąższowa płuc, diagnostyka, monitorowanie, leczenie
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Abstrakt
Reumatoidalne zapalenie stawów (RZS) jest przewlekłą, zapalną, układową chorobą tkanki łącznej dotykającą 0,5–1% populacji ogólnej. Choroba śródmiąższowa płuc (ChŚP) to poważne powikłanie RZS, które prowadzi do pogorszenia jakości życia, zwiększa ryzyko hospitalizacji i przedwczesnego zgonu. Przebieg kliniczny ChŚP związanej z RZS może być zróżnicowany: od zmian obejmujących niewielkie obszary płuc, niedających objawów klinicznych, po szybko postępujące zmiany śródmiąższowe mogące prowadzić do nagłego zaostrzenia objawów oddechowych, rozwoju niewydolności oddychania i zgonu. Do głównych czynników ryzyka rozwoju ChŚP w przebiegu RZS obok starszego wieku i płci męskiej należy wysoka aktywność choroby podstawowej. W związku z tym skuteczne leczenie RZS, ukierunkowane na remisję, może stanowić prewencję rozwoju ChŚP w jej przebiegu. Ponieważ objawy są nieswoiste, ChŚP związana z RZS bywa często nierozpoznana. Pomimo istotnej chorobowości i zwiększonego ryzyka zgonu z powodu ChŚP w przebiegu RZS obecnie nie dysponujemy wytycznymi postępowania w tej sytuacji klinicznej. Komplikuje to ponadto możliwa pneumotoksyczność wielu leków modyfikujących przebieg choroby oraz ich niejasna skuteczność wobec zmian w płucach w przebiegu RZS. W związku z powyższym w praktyce wyzwaniem pozostaje optymalne postępowanie u chorego na RZS ze współistniejącą ChŚP. Pilnego wyjaśnienia wymaga szereg aspektów klinicznych dotyczących wczesnego rozpoznania, monitorowania, ustalenia wskazań do leczenia i wyboru odpowiedniego postępowania terapeutycznego. W niniejszej pracy dokonano autorskiego przeglądu aktualnego stanu wiedzy na temat ChŚP związanej z RZS i wskazano kierunki niezbędnych przyszłych badań mających na celu poprawę opieki nad chorymi.
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Jak cytować
Majewski, S., & Makowska , J. (2020). Choroba śródmiąższowa płuc związana z reumatoidalnym zapaleniem stawów – niedoceniany, złożony i interdyscyplinarny problem w codziennej praktyce klinicznej. Medycyna Faktów , 13(4(49), 431-441. https://doi.org/10.24292/01.MF.0420.7
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Bibliografia
1. Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med. 2018; 378(19): 1811-23.
2. Wallace B, Vummidi D, Khanna D. Management of connective tissue diseases associated interstitial lung disease: a review of the published literature. Curr Opin Rheumatol. 2016; 28(3): 236-45.
3. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. The Lancet. 2016; 388(10055): 2023-38.
4. Nannini C, Ryu JH, Matteson EL. Lung disease in rheumatoid arthritis. Curr Opin Rheumatol. 2008; 20(3): 340-6.
5. Marigliano B, Soriano A, Margiotta D et al. Lung involvement in connective tissue diseases: a comprehensive review and a focus on rheumatoid arthritis. Autoimmun Rev. 2013; 12(11): 1076-84.
6. Bongartz T, Nannini C, Medina-Velasquez YF et al. Incidence and Mortality of Interstitial Lung Disease in Rheumatoid Arthritis: A Population Based Study. Arthritis Rheum. 2010; 62(6): 1583-91.
7. Raimundo K, Solomon JJ, Olson AL et al. Rheumatoid Arthritis-Interstitial Lung Disease in the United States: Prevalence, Incidence, and Healthcare Costs and Mortality. J Rheumatol. 2019; 46(4): 360-9.
8. Shaw M, Collins BF, Ho LA et al. Rheumatoid arthritis-associated lung disease. Eur Respir Rev. 2015; 24(135): 1-16.
9. Olson AL, Swigris JJ, Sprunger DB et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med. 2011; 183(3): 372-8.
10. Myasoedova E, Crowson CS, Turesson C et al. Incidence of extraarticular rheumatoid arthritis in Olmsted County, Minnesota, in 1995-2007 versus 1985-1994: a population-based study. J Rheumatol. 2011; 38(6): 983-9.
11. Bartels CM, Bell CL, Shinki K et al. Changing trends in serious extra-articular manifestations of rheumatoid arthritis among United State veterans over 20 years. Rheumatol Oxf Engl. 2010; 49(9): 1670-5.
12. Cavagna L, Monti S, Grosso V et al. The multifaceted aspects of interstitial lung disease in rheumatoid arthritis. BioMed Res Int. 2013; 2013: 759760.
13. Assayag D, Lubin M, Lee JS et al. Predictors of mortality in rheumatoid arthritis-related interstitial lung disease. Respirol Carlton Vic. 2014; 19(4): 493-500.
14. Saag K, Cerhan J, Kolluri S et al. Cigarette smoking and rheumatoid arthritis severity. Ann Rheum Dis. 1997; 56(8): 463-9.
15. Kronzer VL, Huang W, Dellaripa PF et al. Lifestyle and clinical risk factors for incident rheumatoid arthritis-associated interstitial lung disease. J Rheumatol. 2020 [online ahead of print]. https://doi.org/10.3899/jrheum.200863.
16. Sparks JA, He X, Huang J et al. Rheumatoid Arthritis Disease Activity Predicting Incident Clinically Apparent Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Prospective Cohort Study. Arthritis Rheumatol Hoboken NJ. 2019; 71(9): 1472-82.
17. Turesson C. Extra-articular rheumatoid arthritis. Curr Opin Rheumatol. 2013; 25(3): 360-6.
18. Yang JA, Lee JS, Park JK et al. Clinical characteristics associated with occurrence and poor prognosis of interstitial lung disease in rheumatoid arthritis. Korean J Intern Med. 2019; 34(2): 434-41.
19. Hyldgaard C, Hilberg O, Pedersen AB et al. A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality. Ann Rheum Dis. 2017; 76(10): 1700-6.
20. Habib HM, Eisa AA, Arafat WR et al. Pulmonary involvement in early rheumatoid arthritis patients. Clin Rheumatol. 2011; 30(2): 217-21.
21. Koduri G, Norton S, Young A et al. Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort. Rheumatology. 2010; 49(8): 1483-9.
22. Assayag D, Elicker BM, Urbania TH et al. Rheumatoid arthritis-associated interstitial lung disease: radiologic identification of usual interstitial pneumonia pattern. Radiology. 2014; 270(2): 583-8.
23. Kim EJ, Elicker BM, Maldonado F et al. Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2010; 35(6): 1322-8.
24. Solomon JJ, Ryu JH, Tazelaar HD et al. Fibrosing interstitial pneumonia predicts survival in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Respir Med. 2013; 107(8): 1247-52.
25. Zamora-Legoff JA, Krause ML, Crowson CS et al. Progressive Decline of Lung Function in Rheumatoid Arthritis-Associated Interstitial Lung Disease. Arthritis Rheumatol Hoboken NJ. 2017; 69(3): 542-9.
26. Sperandeo M, Varriale A, Sperandeo G et al. Transthoracic ultrasound in the evaluation of pulmonary fibrosis: our experience. Ultrasound Med Biol. 2009; 35(5): 723-9.
27. Manfredi A, Cassone G, Cerri S et al. Diagnostic accuracy of a velcro sound detector (VECTOR) for interstitial lung disease in rheumatoid arthritis patients: the InSPIRAtE validation study (INterStitial pneumonia in rheumatoid ArThritis with an electronic device). BMC Pulm Med. 2019; 19(1): 111.
28. Avouac J, Cauvet A, Steelandt A et al. Improving risk-stratification of rheumatoid arthritis patients for interstitial lung disease. PLoS One. 2020; 15(5): e0232978.
29. Kawano-Dourado L, Doyle TJ, Bonfiglioli K et al. Baseline Characteristics and Progression of a Spectrum of Interstitial Lung Abnormalities and Disease in Rheumatoid Arthritis. Chest. 2020; 158(4): 1546-54.
30. Izuka S, Yamashita H, Iba A et al. Acute exacerbation of rheumatoid arthritis-associated interstitial lung disease: clinical features and prognosis. Rheumatol Oxf Engl. 2020 [online Ahead of print]. https://doi.org/10.1093/rheumatology/keaa608.
31. Fragoulis GE, Nikiphorou E, Larsen J et al. Methotrexate-Associated Pneumonitis and Rheumatoid Arthritis-Interstitial Lung Disease: Current Concepts for the Diagnosis and Treatment. Front Med. 2019; 6: 238.
32. Imokawa S, Colby TV, Leslie KO et al. Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients. Eur Respir J. 2000; 15(2): 373.
33. Conway R, Low C, Coughlan RJ et al. Methotrexate and Lung Disease in Rheumatoid Arthritis: A Meta-Analysis of Randomized Controlled Trials: Risk of Lung Disease in RA Patients Treated With MTX. Arthritis Rheumatol. 2014; 66(4): 803-12.
34. Kiely P, Busby AD, Nikiphorou E et al. Is incident rheumatoid arthritis interstitial lung disease associated with methotrexate treatment? Results from a multivariate analysis in the ERAS and ERAN inception cohorts. BMJ Open. 2019; 9(5): e028466.
35. Lake F, Proudman S. Rheumatoid Arthritis and Lung Disease: From Mechanisms to a Practical Approach. Semin Respir Crit Care Med. 2014; 35(02): 222-38.
36. Conway R, Low C, Coughlan RJ et al. Leflunomide Use and Risk of Lung Disease in Rheumatoid Arthritis: A Systematic Literature Review and Metaanalysis of Randomized Controlled Trials. J Rheumatol. 2016; 43(5): 855-60.
37. Curtis JR, Sarsour K, Napalkov P et al. Incidence and complications of interstitial lung disease in users of tocilizumab, rituximab, abatacept and anti-tumor necrosis factor α agents, a retrospective cohort study. Arthritis Res Ther. 2015; 17(1): 319.
38. Sparks JA, He X, Huang J et al. Rheumatoid Arthritis Disease Activity Predicting Incident Clinically Apparent Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Prospective Cohort Study. Arthritis Rheumatol. 2019; 71(9): 1472-82.
39. Herrinton LJ, Harrold LR, Liu L et al. Association between anti-TNF- α therapy and interstitial lung disease: ANTI-TNF-Α AND INTERSTITIAL LUNG DISEASE. Pharmacoepidemiol Drug Saf. 2013; 22(4): 394-402.
40. Vadillo C, Nieto MA, Romero-Bueno F et al. Efficacy of rituximab in slowing down progression of rheumatoid arthritis-related interstitial lung disease: data from the NEREA Registry. Rheumatology. 2020; 59(8): 2099-108.
41. Fui A, Bergantini L, Selvi E et al. Rituximab therapy in interstitial lung disease associated with rheumatoid arthritis. Intern Med J. 2020; 50(3): 330-6.
42. Manfredi A, Cassone G, Furini F et al. Tocilizumab therapy in rheumatoid arthritis with interstitial lung disease: a multicenter retrospective study. Intern Med J. 2020; 50(9): 1085-90.
43. Fernández-Díaz C, Castañeda S, Melero-González RB et al. Abatacept in interstitial lung disease associated with rheumatoid arthritis: national multicenter study of 263 patients. Rheumatology. 2020; 59(12): 3906-16.
44. Md Yusof MY, Kabia A, Darby M et al. Effect of rituximab on the progression of rheumatoid arthritis-related interstitial lung disease: 10 years’ experience at a single centre. Rheumatology. 2017; 56(8): 1348-57.
45. England BR, Hershberger D. Management issues in rheumatoid arthritis-associated interstitial lung disease: Curr Opin Rheumatol. 2020; 32(3): 255-63.
46. Sendo S, Saegusa J, Yamada H et al. Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates interstitial lung disease in SKG mice. Arthritis Res Ther. 2019; 21(1): 184.
47. d’Alessandro M, Perillo F, Metella Refini R et al. Efficacy of baricitinib in treating rheumatoid arthritis: Modulatory effects on fibrotic and inflammatory biomarkers in a real-life setting. Int Immunopharmacol. 2020; 86: 106748.
48. 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(2): e3-19.
49. Flaherty KR, Wells AU, Cottin V et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med. 2019; 381(18): 1718-27.
50. Wells AU, Flaherty KR, Brown KK et al. Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Respir Med. 2020; 8(5): 453-60.
2. Wallace B, Vummidi D, Khanna D. Management of connective tissue diseases associated interstitial lung disease: a review of the published literature. Curr Opin Rheumatol. 2016; 28(3): 236-45.
3. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. The Lancet. 2016; 388(10055): 2023-38.
4. Nannini C, Ryu JH, Matteson EL. Lung disease in rheumatoid arthritis. Curr Opin Rheumatol. 2008; 20(3): 340-6.
5. Marigliano B, Soriano A, Margiotta D et al. Lung involvement in connective tissue diseases: a comprehensive review and a focus on rheumatoid arthritis. Autoimmun Rev. 2013; 12(11): 1076-84.
6. Bongartz T, Nannini C, Medina-Velasquez YF et al. Incidence and Mortality of Interstitial Lung Disease in Rheumatoid Arthritis: A Population Based Study. Arthritis Rheum. 2010; 62(6): 1583-91.
7. Raimundo K, Solomon JJ, Olson AL et al. Rheumatoid Arthritis-Interstitial Lung Disease in the United States: Prevalence, Incidence, and Healthcare Costs and Mortality. J Rheumatol. 2019; 46(4): 360-9.
8. Shaw M, Collins BF, Ho LA et al. Rheumatoid arthritis-associated lung disease. Eur Respir Rev. 2015; 24(135): 1-16.
9. Olson AL, Swigris JJ, Sprunger DB et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med. 2011; 183(3): 372-8.
10. Myasoedova E, Crowson CS, Turesson C et al. Incidence of extraarticular rheumatoid arthritis in Olmsted County, Minnesota, in 1995-2007 versus 1985-1994: a population-based study. J Rheumatol. 2011; 38(6): 983-9.
11. Bartels CM, Bell CL, Shinki K et al. Changing trends in serious extra-articular manifestations of rheumatoid arthritis among United State veterans over 20 years. Rheumatol Oxf Engl. 2010; 49(9): 1670-5.
12. Cavagna L, Monti S, Grosso V et al. The multifaceted aspects of interstitial lung disease in rheumatoid arthritis. BioMed Res Int. 2013; 2013: 759760.
13. Assayag D, Lubin M, Lee JS et al. Predictors of mortality in rheumatoid arthritis-related interstitial lung disease. Respirol Carlton Vic. 2014; 19(4): 493-500.
14. Saag K, Cerhan J, Kolluri S et al. Cigarette smoking and rheumatoid arthritis severity. Ann Rheum Dis. 1997; 56(8): 463-9.
15. Kronzer VL, Huang W, Dellaripa PF et al. Lifestyle and clinical risk factors for incident rheumatoid arthritis-associated interstitial lung disease. J Rheumatol. 2020 [online ahead of print]. https://doi.org/10.3899/jrheum.200863.
16. Sparks JA, He X, Huang J et al. Rheumatoid Arthritis Disease Activity Predicting Incident Clinically Apparent Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Prospective Cohort Study. Arthritis Rheumatol Hoboken NJ. 2019; 71(9): 1472-82.
17. Turesson C. Extra-articular rheumatoid arthritis. Curr Opin Rheumatol. 2013; 25(3): 360-6.
18. Yang JA, Lee JS, Park JK et al. Clinical characteristics associated with occurrence and poor prognosis of interstitial lung disease in rheumatoid arthritis. Korean J Intern Med. 2019; 34(2): 434-41.
19. Hyldgaard C, Hilberg O, Pedersen AB et al. A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality. Ann Rheum Dis. 2017; 76(10): 1700-6.
20. Habib HM, Eisa AA, Arafat WR et al. Pulmonary involvement in early rheumatoid arthritis patients. Clin Rheumatol. 2011; 30(2): 217-21.
21. Koduri G, Norton S, Young A et al. Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort. Rheumatology. 2010; 49(8): 1483-9.
22. Assayag D, Elicker BM, Urbania TH et al. Rheumatoid arthritis-associated interstitial lung disease: radiologic identification of usual interstitial pneumonia pattern. Radiology. 2014; 270(2): 583-8.
23. Kim EJ, Elicker BM, Maldonado F et al. Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J. 2010; 35(6): 1322-8.
24. Solomon JJ, Ryu JH, Tazelaar HD et al. Fibrosing interstitial pneumonia predicts survival in patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Respir Med. 2013; 107(8): 1247-52.
25. Zamora-Legoff JA, Krause ML, Crowson CS et al. Progressive Decline of Lung Function in Rheumatoid Arthritis-Associated Interstitial Lung Disease. Arthritis Rheumatol Hoboken NJ. 2017; 69(3): 542-9.
26. Sperandeo M, Varriale A, Sperandeo G et al. Transthoracic ultrasound in the evaluation of pulmonary fibrosis: our experience. Ultrasound Med Biol. 2009; 35(5): 723-9.
27. Manfredi A, Cassone G, Cerri S et al. Diagnostic accuracy of a velcro sound detector (VECTOR) for interstitial lung disease in rheumatoid arthritis patients: the InSPIRAtE validation study (INterStitial pneumonia in rheumatoid ArThritis with an electronic device). BMC Pulm Med. 2019; 19(1): 111.
28. Avouac J, Cauvet A, Steelandt A et al. Improving risk-stratification of rheumatoid arthritis patients for interstitial lung disease. PLoS One. 2020; 15(5): e0232978.
29. Kawano-Dourado L, Doyle TJ, Bonfiglioli K et al. Baseline Characteristics and Progression of a Spectrum of Interstitial Lung Abnormalities and Disease in Rheumatoid Arthritis. Chest. 2020; 158(4): 1546-54.
30. Izuka S, Yamashita H, Iba A et al. Acute exacerbation of rheumatoid arthritis-associated interstitial lung disease: clinical features and prognosis. Rheumatol Oxf Engl. 2020 [online Ahead of print]. https://doi.org/10.1093/rheumatology/keaa608.
31. Fragoulis GE, Nikiphorou E, Larsen J et al. Methotrexate-Associated Pneumonitis and Rheumatoid Arthritis-Interstitial Lung Disease: Current Concepts for the Diagnosis and Treatment. Front Med. 2019; 6: 238.
32. Imokawa S, Colby TV, Leslie KO et al. Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients. Eur Respir J. 2000; 15(2): 373.
33. Conway R, Low C, Coughlan RJ et al. Methotrexate and Lung Disease in Rheumatoid Arthritis: A Meta-Analysis of Randomized Controlled Trials: Risk of Lung Disease in RA Patients Treated With MTX. Arthritis Rheumatol. 2014; 66(4): 803-12.
34. Kiely P, Busby AD, Nikiphorou E et al. Is incident rheumatoid arthritis interstitial lung disease associated with methotrexate treatment? Results from a multivariate analysis in the ERAS and ERAN inception cohorts. BMJ Open. 2019; 9(5): e028466.
35. Lake F, Proudman S. Rheumatoid Arthritis and Lung Disease: From Mechanisms to a Practical Approach. Semin Respir Crit Care Med. 2014; 35(02): 222-38.
36. Conway R, Low C, Coughlan RJ et al. Leflunomide Use and Risk of Lung Disease in Rheumatoid Arthritis: A Systematic Literature Review and Metaanalysis of Randomized Controlled Trials. J Rheumatol. 2016; 43(5): 855-60.
37. Curtis JR, Sarsour K, Napalkov P et al. Incidence and complications of interstitial lung disease in users of tocilizumab, rituximab, abatacept and anti-tumor necrosis factor α agents, a retrospective cohort study. Arthritis Res Ther. 2015; 17(1): 319.
38. Sparks JA, He X, Huang J et al. Rheumatoid Arthritis Disease Activity Predicting Incident Clinically Apparent Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Prospective Cohort Study. Arthritis Rheumatol. 2019; 71(9): 1472-82.
39. Herrinton LJ, Harrold LR, Liu L et al. Association between anti-TNF- α therapy and interstitial lung disease: ANTI-TNF-Α AND INTERSTITIAL LUNG DISEASE. Pharmacoepidemiol Drug Saf. 2013; 22(4): 394-402.
40. Vadillo C, Nieto MA, Romero-Bueno F et al. Efficacy of rituximab in slowing down progression of rheumatoid arthritis-related interstitial lung disease: data from the NEREA Registry. Rheumatology. 2020; 59(8): 2099-108.
41. Fui A, Bergantini L, Selvi E et al. Rituximab therapy in interstitial lung disease associated with rheumatoid arthritis. Intern Med J. 2020; 50(3): 330-6.
42. Manfredi A, Cassone G, Furini F et al. Tocilizumab therapy in rheumatoid arthritis with interstitial lung disease: a multicenter retrospective study. Intern Med J. 2020; 50(9): 1085-90.
43. Fernández-Díaz C, Castañeda S, Melero-González RB et al. Abatacept in interstitial lung disease associated with rheumatoid arthritis: national multicenter study of 263 patients. Rheumatology. 2020; 59(12): 3906-16.
44. Md Yusof MY, Kabia A, Darby M et al. Effect of rituximab on the progression of rheumatoid arthritis-related interstitial lung disease: 10 years’ experience at a single centre. Rheumatology. 2017; 56(8): 1348-57.
45. England BR, Hershberger D. Management issues in rheumatoid arthritis-associated interstitial lung disease: Curr Opin Rheumatol. 2020; 32(3): 255-63.
46. Sendo S, Saegusa J, Yamada H et al. Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates interstitial lung disease in SKG mice. Arthritis Res Ther. 2019; 21(1): 184.
47. d’Alessandro M, Perillo F, Metella Refini R et al. Efficacy of baricitinib in treating rheumatoid arthritis: Modulatory effects on fibrotic and inflammatory biomarkers in a real-life setting. Int Immunopharmacol. 2020; 86: 106748.
48. 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(2): e3-19.
49. Flaherty KR, Wells AU, Cottin V et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med. 2019; 381(18): 1718-27.
50. Wells AU, Flaherty KR, Brown KK et al. Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Respir Med. 2020; 8(5): 453-60.