Интерстициальные заболевания легких при системном прогрессирующем склерозе (системной склеродермии)

При системной склеродермии (ССД) интерстициальное поражение легких (ИПЛ) встречается часто (>80%) и ухудшает прогноз заболевания, но тяжелое прогрессирующее поражение развивается только в 8–10% случаев. Интерстициальные изменения в легких возникают рано (в первые 3–5 лет болезни). Гистологические проявления сходны с таковыми при идиопатических ИПЛ.

Основным инструментом для скрининга и диагностики ИПЛ, ассоциированного с ССД, является компьютерная томография легких высокого разрешения, данные которой влияют на выбор терапии. У большинства больных длительно регистрируется относительно сохранная и стабильная форсированная жизненная емкость легких, но рано и стойко снижается диффузионная способность легких. Показатели функциональных легочных тестов имеют прогностическое значение.

Выбор оптимальной терапии ССД с поражением легких осуществляется с учетом общей активности (выраженность воспаления и фиброзирования) и тяжести, темпов прогрессирования болезни в целом и ведущей патологии – интерстициальной пневмонии (ИП) – в частности. У пациентов с ССД и тяжелой или прогрессирующей ИП следует рассматривать лечение микофенолата мофетилом (ММФ), циклофосфамидом или нинтеданибом либо, при необходимости, нинтеданибом в комбинации с ММФ. При неэффективности этой терапии может быть применен ритуксимаб.

1. Manetti M, Matucci-Cerinic M. The new frontier in systemic sclerosis: from epigenetics to new treatments. Rheumatology (Oxford). 2015 Oct;54(10):1757-8. doi: 10.1093/rheumatology/kev264. Epub 2015 Jul 30.

2. Bossini-Castillo L, Lopez-Isac E, Mayes MD, Martin J. Genetics of systemic sclerosis. Semin Immunopathol. 2015 Sep;37(5):443-51. doi: 10.1007/s00281-015-0499-z. Epub 2015 Jun 2.

3. Насонов ЕЛ, редактор. Российские клинические рекомендации. Ревматология. Москва: ГЭОТАР-Медиа; 2017. 464 с.

4. Elhai M, Meune C, Avouac J, et al. Trends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). 2012 Jun;51(6):1017-26. doi: 10.1093/rheumatology/ker269. Epub 2011 Sep 7.

5. Mayes MD, Lacey JV Jr, Beebe-Dimmer J, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003 Aug;48(8):2246-55. doi: 10.1002/art.11073.

6. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis. 2007 Jul;66(7):940-4. doi: 10.1136/ard.2006.066068.

7. Nyhtyanova SI, Schreiber BE, Ong VN, et.al. Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheumatol. 2014 Jun;66(6):1625-35. doi: 10.1002/art.38390.

8. Volkmann ER, Tashkin DP, Sim M, et al. groups SIaSIs. Short-term progression of interstitial lung disease in systemic sclerosis predicts long-term survival in two independent clinical trial cohorts. Ann Rheum Dis. 2019 Jan;78(1):122-130. doi: 10.1136/annrheumdis-2018-213708. Epub 2018 Nov 8.

9. Nichtyanova SI, Tang EC, Coghlan JG, et al. Improved survival in systemic sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort study. QJM. 2010 Feb;103(2):109-15. doi: 10.1093/qjmed/hcp174. Epub 2009 Dec 4.

10. Sverzellati N, Lynch DA, Hansell DM, et al. American Thoracic Society-European Respiratory Society Classification of the Idiopathic Interstitial Pneumonias: Advances in Knowledge since 2002. Radiographics. Nov-Dec 2015;35(7):1849-71. doi: 10.1148/rg.2015140334.

11. Nathan N, Corvol H, Amselem S, Clement A. Biomarkers in Interstitial lung diseases. Paediatr Respir Rev. 2015 Sep;16(4):219-24. doi: 10.1016/j.prrv.2015.05.002. Epub 2015 May 12.

12. Hunzelmann N, Brinckmann J. What are the milestones in the pathogenesis of systemic sclerosis? Ann Rhеum Dis. 2010; 69 Suppl: i52–i56. doi: 10.1136/ard.2009.1171191-4.

13. Gasser SW, Hardie WD, Hagood JS. Pathogenesis of interstitial disease in children and adult. Pediatr Allergy Immunol Pulmonol. 2010 Mar;23(1):9-14. doi: 10.1089/ped.2010.0004.

14. Clement A, Eber E. Interstitial lung diseases in infants and children. Eur Respir J. 2008 Mar;31(3):658-66. doi: 10.1183/09031936.00004707.

15. Hoffmann-Vold AM, Weigt SS, Saggar R, et al. Endotype-phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease. EBioMedicine. 2019 Dec;50: 379-386. doi: 10.1016/j.ebiom.2019.10.050.

16. Richeldi L, Varone F, Bergna M, et al. Pharmacological management of progressive-fibrosing interstitial lung diseases: a review of the current evidence. Eur Respir Rev. 2018 Dec 21; 27(150):180074. doi: 10.1183/16000617.0074-2018. Print 2018 Dec 31.

17. Wells AU, Brown KK, Flaherty KR, et al. What’s in a name? That which we call IPF, by any other name would act the same. Eur Respir J. 2018 May 17;51(5):1800692. doi: 10.1183/13993003.00692-2018. Print 2018 May.

18. Cottin V, Wollin L, Fischer A, et al. Fibrosing interstitial lung diseases: knowns and unknowns. Eur Respir Rev. 2019 Feb 27;28(151):180100. doi: 10.1183/16000617.0100-2018. Print 2019 Mar 31.

19. Cottin V, Brown KK. Interstitial lung disease associated with systemic sclerosis (SSc-ILD). Respir Res. 2019 Jan 18;20(1):13. doi: 10.1186/s12931-019-0980-7.

20. Travis WD, Costabel U, Hansell DM, et al. An ofcial American Toracic Society/European Respiratory Society statement: Update of the international multidisciplinary classifcation of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013 Sep 15;188(6): 733-48. doi: 10.1164/rccm.201308-1483ST.

21. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2018 Sep 1;198(5):e44-e68. doi: 10.1164/rccm.201807-1255ST.

22. Travis WD, Hunninghake G, King TEJ, Lynch DA, et al. Idiopathic nonspecific interstitial pneumonia: Report of an American Thoracic Society project. Am J Respir Crit Care Med. 2008 Jun 15;177(12):1338-47. doi: 10.1164/rccm.200611-1685OC. Epub 2008 Apr 3.

23. Todd NW, Marciniak ET, Sachdeva A, et al. Organizing pneumonia/non-specific interstitial pneumonia overlap is associated with unfavorable lung disease progression. Respir Med. 2015 Nov;109(11):1460-8. doi: 10.1016/j.rmed.2015.09.015. Epub 2015 Oct 9.

24. Bouros D, Wells AU, Nicholson AG, et al. Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med. 2002 Jun 15;165(12):1581-6. doi: 10.1164/rccm.2106012.

25. Park JH, Kim DS, Park I, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007 Apr 1; 175(7):705-11. doi: 10.1164/rccm.200607-912OC. Epub 2007 Jan 11.

26. Baha A, Yildirim F, Kö ktü rk N, et al. Cryptogenic and Secondary Organizing Pneumonia: Clinical Presentation, Radiological and Laboratory Findings, Treatment, and Prognosis in 56 Cases. Turk Thorac J. 2018 Sep 13;19(4):201-208. doi: 10.5152/TurkThoracJ.2018.18008.

27. Adegunsoye A, Oldham JM, Bellam SK, et al. Computed Tomography Honeycombing Identifies a Progressive Fibrotic Phenotype with Increased Mortality across Diverse Interstitial Lung Diseases. Ann Am Thorac Soc. 2019 May;16(5):580-588. doi: 10.1513/AnnalsATS.201807-443OC.

28. Steen VD, Conte C, Owens GR, Medsgar TA Jr. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum. 1994 Sep;37(9):1283-9. doi: 10.1002/art.1780370903.

29. Hoffmann-Vold AM, Allanore Y, Alves M, et al. Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis. 2020 Sep 28;annrheumdis-2020-217455. doi: 10.1136/annrheumdis-2020- 217455. Online ahead of print.

30. Rubio-Rivas M, Royo C, Simeon CP, et al. Mortality and survival in systemic sclerosis: systematic review and meta-analysis. Semin Arthritis Rheum. 2014 Oct;44(2):208-19. doi: 10.1016/j.semarthrit.2014.05.010. Epub 2014 May 14.

31. Van den Hoogen F, Khanna D, Fransen J, et al. Classification criteria for systemic sclerosis: An ACR-EULAR collaborative initiative. Arthritis Rheum. 2013 Nov;65(11):2737-47. doi: 10.1002/art.38098. Epub 2013 Oct 3.

32. Ананьева ЛП, Александрова ЕН. Аутоантитела при системной склеродермии: спектр, клинические ассоциации и прогностическое значение. Научно-практическая ревматология. 2016;54(1):86-99.

33. Bankier AA, O’Donnell CR, Boiselle PM. Quality initiatives. Respiratory instructions for CT examinations of the lungs: a hands-on guide. Radiographics. Jul-Aug 2008;28(4): 919-31. doi: 10.1148/rg.284085035.

34. Remy-Jardin M, Campistron P, Amara A, et al. Usefulness of coronal reformations in the diagnostic evaluation of infiltrative lung disease. J Comput Assist Tomogr. Mar 2003;27(2): 266-73. doi: 10.1097/00004728-200303000-00028.

35. Johkoh T, Sakai F, Noma S, et al. Honeycombing on CT; its definition, pathologic correlation, and future direction of its diagnosis. Eur J Radiol. 2014 Jan;83(1):27-31. doi: 10.1016/j.ejrad.2013.05.012. Epub 2013 Jun 24.

36. Bankier AA, Tack D. Dose reduction strategies for thoracic multidetector computed tomography: background, current issues, and recommendations. J Thorac Imaging. 2010 Nov;25(4):278-88. doi: 10.1097/RTI.0b013e3181eebc49.

37. Pontana F, Billard AS, Duhamel A, et al. Effect of iterative reconstruction on the detection of systemic sclerosis-related interstitial lung disease: clinical experience in 55 patients. Radiology. 2016 Apr;279(1):297-305. doi: 10.1148/radiol.2015150849. Epub 2015 Nov 18.

38. Hansell DM. Thin-section CT of the lungs: the Hinterland of normal. Radiology. 2010 Sep;256(3):695-711. doi: 10.1148/radiol.10092307.

39. Kim M, Lee SM, Song JW, et al. Added value of prone CT in the assessment of honeycombing and classification of usual interstitial pneumonia pattern. Eur J Radiol. 2017 Jun; 91:66-70. doi: 10.1016/j.ejrad.2017.03.018. Epub 2017 Mar 30.

40. Tokura S, Okuma T, Akira M, et al. Utility of expiratory thin-section CT for fibrotic interstitial pneumonia. Acta Radiol. 2014 Nov;55(9):1050-5. doi: 10.1177/0284185113512300. Epub 2013 Nov 19.

41. Gotway MB, Lee ES, Reddy GP, et al. Low-dose, dynamic, expiratory thin-section CT of the lungs using a spiral CT scanner. J Thorac Imaging. 2000 Jul;15(3):168-72. doi: 10.1097/00005382-200007000-00003.

42. Wells AU, Hansell DM, Rubens MB, et al. The predictive value of appearances on thinsection computed tomography in fibrosing alveolitis. Am Rev Respir Dis. 1993 Oct; 148(4 Pt 1):1076-82. doi: 10.1164/ajrccm/148.4_Pt_1.1076.

43. Lynch DA, Godwin JD, Safrin S, et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med. 2005 Aug 15;172(4): 488-93. doi: 10.1164/rccm.200412-1756OC. Epub 2005 May 13.

44. Shin KM, Lee KS, Chung MP, et al. Prognostic determinants among clinical, thin-section CT, and histopathologic findings for fibrotic idiopathic interstitial pneumonias: tertiary hospital study. Radiology. 2008 Oct;249(1):328-37. doi: 10.1148/radiol.2483071378. Epub 2008 Aug 5.

45. Hansell DM, Bankier AA, MacMahon H, et al. Fleischner Society: glossary of terms for thoracic imaging. Radiology. 2008 Mar;246(3):697-722. doi: 10.1148/radiol.2462070712. Epub 2008 Jan 14.

46. Watadani T, Sakai F, Johkoh T, et al. Interobserver variability in the CT assessment of honeycombing in the lungs. Radiology. 2013 Mar;266(3):936-44. doi: 10.1148/radiol.12112516. Epub 2012 Dec 6.

47. Jacob J, Hansell DM. HRCT of fibrosing lung disease. Respirology. 2015 Aug;20(6):859-72. doi: 10.1111/resp.12531. Epub 2015 Apr 21.

48. Staats P, Kligerman S, Todd N, et al. A comparative study of honeycombing on high resolution computed tomography with histologic lung remodeling in explants with usual interstitial pneumonia. Pathol Res Pract. 2015 Jan;211(1):55-61. doi: 10.1016/j.prp.2014.08.013. Epub 2014 Oct 22.

49. Edey AJ, Devaraj AA, Barker RP, et al. Fibrotic idiopathic interstitial pneumonias: HRCT findings that predict mortality. Eur Radiol. 2011 Aug;21(8):1586-93. doi: 10.1007/s00330-011-2098-2. Epub 2011 Mar 6.

50. Piciucchi S, Tomassetti S, Ravaglia C, et al. From «traction bronchiectasis» to honeycombing in idiopathic pulmonary fibrosis: a spectrum of bronchiolar remodeling also in radiology? BMC Pulm Med. 2016 May 23;16(1):87. doi: 10.1186/s12890-016-0245-x.

51. Remy-Jardin M, Giraud F, Remy J, et al. Importance of ground-glass attenuation in chronic diffuse infiltrative lung disease: pathologic-CT correlation. Radiology. 1993 Dec;189(3):693-8. doi: 10.1148/radiology.189.3.8234692.

52. Souza CA, Mü ller NL, Lee KS, et al. Idiopathic interstitial pneumonias: prevalence of mediastinal lymph node enlargement in 206 patients. AJR Am J Roentgenol. 2006 Apr; 186(4):995-9. doi: 10.2214/AJR.04.1663.

53. Kim TS, Han J, Chung MP, et al. Disseminated dendriform pulmonary ossification associated with usual interstitial pneumonia: incidence and thin-section CT-pathologic correlation. Eur Radiol. 2005 Aug;15(8):1581-5. doi: 10.1007/s00330-005-2671-7. Epub 2005 Apr 23.

54. Egashira R, Jacob J, Kokosi MA, et al. Diffuse pulmonary ossification in fibrosing interstitial lung diseases: prevalence and associations. Radiology. 2017 Jul;284(1):255-263. doi: 10.1148/radiol.2017152419. Epub 2017 Feb 9.

55. Reddy TL, Tominaga M, Hansell DM, et al. Pleuroparenchymal fibroelastosis: a spectrum of histopathological and imaging phenotypes. Eur Respir J. 2012 Aug;40(2):377-85. doi: 10.1183/09031936.00165111. Epub 2012 Mar 22.

56. Sumikawa H, Johkoh T, Colby TV, et al. Computed tomography findings in pathological usual interstitial pneumonia: relationship to survival. Am J Respir Crit Care Med. 2008 Feb 15;177(4):433-9. doi: 10.1164/rccm.200611-1696OC. Epub 2007 Nov 1.

57. Capobianco J, Grimberg A, Thompson BM, et al. Thoracic manifestations of collagen vascular diseases. Radiographics. Jan-Feb 2012;32(1):33-50. doi: 10.1148/rg.321105058.

58. Nagai S, Handa T, Tabuena R, et al. Nonspecific interstitial pneumonia: a real clinical entity? Clin Chest Med. 2004 Dec;25(4):705-15, vi. doi: 10.1016/j.ccm.2004.04.009.

59. Egashira R, Kondo T, Hirai T, et al. CT findings of thoracic manifestations of primary Sjogren syndrome: radiologicpathologic conrelation. Radiographics. Nov-Dec 2013;33(7): 1933-49. doi: 10.1148/rg.337125107.

60. 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 Jul 15;192(2):e3-19. doi: 10.1164/rccm.201506-1063ST.

61. Wells AU, Margaritopoulos GA, Antoniou KM, Denton C. Interstitial lung disease in systemic sclerosis. Semin Respir Crit Care Med. 2014 Apr;35(2):213-21. doi: 10.1055/s-0034-1371541. Epub 2014 Mar 25.

62. Гриппи МА, редактор. Патофизиология легких. Москва: БИНОМ; 2005. С. 58-78.

63. Schoenfeld SR, Castelino FV. Interstitial lung disease in scleroderma. Rheum Dis Clin North Am. 2015 May;41(2):237-48. doi: 10.1016/j.rdc.2014.12.005.

64. Showalter K, Hoffmann A, Rouleau G, et al. Performance of Forced Vital Capacity and Lung Diffusion Cutpoints for Associated Radiographic Interstitial Lung Disease in Systemic Sclerosis. J Rheumatol. 2018 Nov;45(11):1572-1576. doi: 10.3899/jrheum.171362. Epub 2018 Oct 1.

65. Теплова ЛВ, Ананьева ЛП, Лесняк ВН и др. Системная склеродермия с интерстициальным поражением легких: сравнительная клиническая характеристика с больными без поражения легких. Научно-практическая ревматология. 2010;48(3):41-47.

66. Steen VD, Medsger TA. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 2000 Nov;43(11):2437-44. doi: 10.1002/1529-0131(200011)43:113.0.CO;2-U.

67. Goldin J, Elashoff R, Kim HJ, et al. Treatment of scleroderma-interstitial lung disease with cyclophosphamide is associated with less progressive fibrosis on serial thoracic high-resolution CT scan than placebo: findings from the scleroderma lung study. Chest. 2009 Nov;136(5): 1333-1340. doi: 10.1378/chest.09-0108.

68. Nakamura Y, Chida K, Suda T, et al. Nonspecific interstitial pneumonia in collagen vascular diseases: comparison of the clinical characteristics and prognostic significance with usual interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis. 2003 Oct;20(3):235-41.

69. Wells AU, Rubens MB, du Bois RM, Hansell DM. Serial CT in fibrosing alveolitis: prognostic significance of the initial pattern. AJR Am J Roentgenol. 1993 Dec;161(6):1159-65. doi: 10.2214/ajr.161.6.8249719.

70. Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D42-50. doi: 10.1016/j.jacc.2013.10.032.

71. Asano Y, Sato S. Vasculopathy in scleroderma. Semin Immunopathol. 2015 Sep;37(5): 489-500. doi: 10.1007/s00281-015-0505-5. Epub 2015 Jul 8.

72. Steen V, Medsger TA Jr. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum. 2003 Feb;48(2):516-22. doi: 10.1002/art.10775.

73. Man A, Davidyock T, Ferguson LT, et al. Changes in forced vital capacity over time in systemic sclerosis: application of group-based trajectory modelling. Rheumatology (Oxford). 2015 Aug;54(8):1464-71. doi: 10.1093/rheumatology/kev016. Epub 2015 Mar 17.

74. Khanna D, Tseng CH, Farmani N, et al. Clinical course of lung physiology in patients with scleroderma and interstitial lung disease: Analysis of the Scleroderma Lung Study Placebo Group. Arthritis Rheum. 2011 Oct;63(10):3078-85. doi: 10.1002/art.30467.

75. Tyndall A, Gratwohl AD. Adult stem cell transplantation in autoimmune disease. Curr Opin Hematol. 2009 Jul;16(4):285-91. doi: 10.1097/MOH.0b013e32832aacb3.

76. Goh NS, Hoyles RK, Denton CP, et al. Short-term pulmonary function trends are predictive of mortality in interstitial lung disease associated with systemic sclerosis. Arthritis Rheumatol. 2017 Aug;69(8):1670-1678. doi: 10.1002/art.40130.

77. Khanna D, Tseng CH, Farmani N, et al. Predictors of lung function decline in scleroderma-related interstitial lung disease based on high-resolution computed tomography: implications for cohort enrichment in systemic sclerosis-associated interstitial lung disease trials. Arthritis Res Ther. 2015 Dec 23;17:372. doi: 10.1186/s13075-015-0872-2.

78. Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019 Oct 31;381(18):1718-1727. doi: 10.1056/NEJMoa1908681. Epub 2019 Sep 29.

79. Gilson M, Zerkak D, Wipff J, et al. Prognostic factors for lung function in systemic sclerosis: prospective study of 105 cases. Eur Respir J. 2010 Jan;35(1):112-7. doi: 10.1183/09031936.00060209. Epub 2009 Jun 18.

80. Suliman YA, Dobrota R, Huscher D, et al. Brief Report: Pulmonary Function Tests: High Rate of False-Negative Results in the Early Detection and Screening of Scleroderma-Related Interstitial Lung Disease. Arthritis Rheumatol. 2015 Dec;67(12):3256-61. doi: 10.1002/art.39405.

81. Hoffmann-Vold AM, Aal∅kken TM, Lund MB, et al. Predictive value of serial high-resolution computed tomography analyses and concurrent lung function tests in systemic sclerosis. Arthritis Rheumatol. 2015 May;67(8):2205-12. doi: 10.1002/art.39166.

82. Cappelli S, Bellando Randone S, Camiciottoli G, et al. Interstitial lung disease in systemic sclerosis: where do we stand? Eur Respir Rev. 2015 Sep;24(137):411-9. doi: 10.1183/16000617.00002915.

83. Hoffmann-Vold AM, Maher TM, Philpot EE, et al. The identification and management of interstitial lung disease in systemic sclerosis: evidence-based European consensus statements. Lancet Rheumatol. 2020;9913(2): E71-E83. doi: 10.1016/S2665-9913(19)30144-4

84. Hoffmann-Vold AM, Allanore Y, Bendstrup E, et al. The need for a holistic approach for SScILD – achievements and ambiguity in a devastating disease. Respir Res. 2020 Jul 23;21(1):197. doi: 10.1186/s12931-020-01459-0.

85. Moore OA, Goh N, Corte T, et al. Extent of disease on high-resolution computed tomography lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease. Rheumatology (Oxford). 2013 Jan;52(1):155-60. doi: 10.1093/rheumatology/kes289

86. Goh N, Desai SR, Veeraraghavan S, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. 2008 Jun 1;177(11):1248-54. doi: 10.1164/rccm.200706-877OC

87. Jaeger VK, Wirz EG, Allanore Y, et al. Incidences and risk factors of organ manifestations in the early course of systemic sclerosis: a longitudinal EUSTAR study. PLoS One. 2016 Oct 5;11(10):e0163894. doi: 10.1371/journal.pone.0163894. eCollection 2016.

88. Wijsenbeek M, Kreuter M, Olson A, et al. Progressive fibrosing interstitial lung diseases: current practice in diagnosis and management. Curr Med Res Opin. 2019 Nov;35(11): 2015-24. doi: 10.1080/03007995.2019.1647040. Epub 2019 Aug 2.

89. Iudici M, Fasano S, Iacono D, et al. Prevalence and factors associated with glucocorticoids (GC) use in systemic sclerosis (SSc): a systematic review and meta-analysis of cohort studies and registries. Clin Rheumatol. 2014 Feb;33(2):153-64. doi: 10.1007/s10067-013-2422-0. Epub 2013 Nov 19.

90. Kowal-Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017 Aug;76(8):1327-1339. doi: 10.1136/annrheumdis-2016-209909. Epub 2016 Nov 9.

91. Fernandez-Codina A, Walker KM, Pope JE, Scleroderma Algorithm Group. Treatment algorithms for systemic sclerosis according to experts. Arthritis Rheumatol. 2018 Nov;70(11): 1820-28. doi: 10.1002/art.40560. Epub 2018 Sep 17.

92. Adler S, Huscher D, Siegert E, et al. Systemic sclerosis associated interstitial lung diseaseindividualized immunosuppressive therapy and course of lung function: results of the EUSTAR group. Arthritis Res Ther. 2018 Jan 30;20(1):17. doi: 10.1186/s13075-018-1517-z.

93. Нoyles RK, Ellis RW, Wellsbury J, et al. A multicenter, prospective, randomized, doubleblind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006 Dec;54(12):3962-70. doi: 10.1002/art.22204.

94. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006 Jun 22;354(25):2655-66. doi: 10.1056/NEJMoa055120.

95. Roth MD, Tseng CH, Clements PJ, et al. Predicting treatment outcomes and responder subsets in scleroderma-related interstitial lung disease. Arthritis Rheum. 2011 Sep;63(9): 2797-808. doi: 10.1002/art.30438.

96. Goldin J, Elashoff R, Kim HJ, et al. Treatment of scleroderma-interstitial lung disease with cyclophosphamide is associated with less progressive fibrosis on serial thoracic high-resolution CT scan than placebo: findings from the scleroderma lung study. Chest. 2009 Nov; 136(5):1333-1340. doi: 10.1378/chest.09-0108.

97. Van den Hombergh WMT, Simons SO, Teesselink E, et al. Intravenous cyclophosphamide pulse therapy in interstitial lung disease associated with systemic sclerosis in a retrospective open-label study: influence of the extent of inflammation on pulmonary function. Clin Rheumatol. 2018 Oct;37(10):2715-22. doi: 10.1007/s10067-018-4171-6. Epub 2018 Jul 10.

98. Volkmann ER, Tashkin DP, Sim M, et al. Cyclophosphamide for Systemic Sclerosisrelated Interstitial Lung Disease: A Comparison of Scleroderma Lung Study I and II. J Rheumatol. 2019 Oct;46(10):1316-25. doi: 10.3899/jrheum.180441. Epub 2019 Feb 15.

99. Dan D, Fischer R, Adler S, et al. Cyclophosphamide: as bad as its reputation? Long-term single centre experience of cyclophosphamide side effects in the treatment of systemic autoimmune diseases. Swiss Med Wkly. 2014 Oct 23;144:w14030. doi: 10.4414/smw.2014.14030. eCollection 2014.

100. Omair MA, Alahmadi A, Johnson SR. Safety and effectiveness of mycophenolate in systemic sclerosis. A systematic review. PLoS One. 2015 May 1;10(5):e0124205. doi: 10.1371/journal.pone.0124205. eCollection 2015.

101. Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate mofetil versus oral cyclophosphamide in sclerodermarelated interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016 Sep;4(9):708-719. doi: 10.1016/S2213-2600(16)30152-7. Epub 2016 Jul 25.

102. Pavlov-Dolijanovic S, Vujasinovic Stupar N, Zugic V, et al. Long-term effects of immunosuppressive therapy on lung function in scleroderma patients. Clin Rheumatol. 2018 Nov; 37(11):3043-3050. doi: 10.1007/s10067-018-4266-0. Epub 2018 Aug 24.

103. Burt RK, Milanetti F. Hematopoietic stem cell transplantation for systemic sclerosis:history and current status. Curr Opin Rheumatol. 2011 Nov;23(6):519-29. doi: 10.1097/BOR.0b013e32834aa45f.

104. Van Laar JM, Farge D, Sont JK, et al. Autologous haemopoetic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014 Jun 25;311(24):2490-8. doi: 10.1001/jama.2014.6368.

105. Burt RK, Shah SJ, Dill K, et al. Autologous non-myeloablative hemotopoetic stem-cell transplantation compared with pulse cyclophosphamide once per months for systemic sclerosis (ASSIST): an open label. Randomized phase 2 trial. Lancet. 2011 Aug 6; 378(9790):498-506. doi: 10.1016/S0140-6736(11)60982-3. Epub 2011 Jul 21.

106. Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018 Jan 4;378(1):35-47. doi: 10.1056/nejmoa1703327.

107. Farge D, Burt RK, Oliveire MC, et al. Cardiopulmonary assessment of patients with systemic sclerosis for hematopoietic stem cell transplantation: recommendations from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party and collaborating partners. Bone Marrow Transplant. 2017 Nov;52(11):1495-503. doi: 10.1038/bmt.2017.56. Epub 2017 May 22.

108. Del Papa N, Pignataro F, Zaccara E, et al. Autologous hematopoietic stem cell transplantation for treatment of systemic sclerosis. Front Immunol. 2018 Oct 16;9:2390. doi: 10.3389/fimmu.2018.02390. eCollection 2018.

109. Snowden JA, Badoglio M, Labopin M, et al. Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases. Blood Adv. 2017 Dec 20;1(27):2742-2755. doi: 10.1182/bloodadvances.2017010041. eCollection 2017 Dec 26.

110. Khanna D, Tashkin DP, Denton CP, et al. Ongoing clinical trials and treatment options for patients with systemic sclerosis-associated interstitial lung disease. Rheumatology (Oxford). 2019 Apr 1;58(4):567-579. doi: 10.1093/rheumatology/key151.

111. Giuggioli D, Lumetti F, Colaci Met al. Rituximab in the treatment of patients with systemic sclerosis. Our experience and review of the literature. Autoimmun Rev. 2015 Nov; 14(11):1072-8. doi: 10.1016/j.autrev.2015.07.008. Epub 2015 Jul 22.

112. Daoussis D, Melissaropoulos K, Sakellaropoulos G, et al. A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease. Semin Arthritis Rheum. 2017 Apr;46(5):625-631. doi: 10.1016/j.semarthrit.2016.10.003. Epub 2016 Oct 13.

113. Jordan S, Distler JHW, Maurer B, et al. Effects and safety of rituximab in systemic sclerosis: an analysis from the European Scleroderma Trial and Research (EUSTAR) group. Ann Rheum Dis. 2015 Jun;74(6):1188-94. doi: 10.1136/annrheumdis-2013-204522. Epub 2014 Jan 17.

114. Sircar G, Goswami RP, Sircar D, et al. Intravenous Cyclophosphamide vs Rituximab for the Treatment of Early Diffuse Scleroderma Lung Disease: Open Label, Randomized, Controlled Trial. Rheumatology (Oxford). 2018 Dec 1;57(12):2106-13. doi: 10.1093/rheumatology/key213.

115. Ананьева ЛП, Конева ОА, Десинова ОВ и др. Влияние ритуксимаба на проявления активности и легочную функцию у больных системной склеродермией: оценка после года наблюдения. Научно-практическая ревматология. 2019;57(3):265-73.

116. Saunders P, Tsipouri V, Keir GJ, et al. Rituximab versus cyclophosphamide for the treatment of connective tissue disease-associated interstitial lung disease (RECITAL): study protocol for a randomised controlled trial. Trials. 2017 Jun 15;18(1):275. doi: 10.1186/s13063-017-2016-2.

117. O’Reilly S, Cant R, Ciechomska M, van Laar JM. Interleukin-6: a newtherapeutic target in systemic sclerosis? Clin Transl Immunology. 2013 Apr 12;2(4):e4. doi: 10.1038/cti.2013. 2. eCollection 2013 Apr.

118. Shima Y,Kuwahara Y, Murota H, et al. The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology (Oxford). 2010 Dec;49(12):2408-12. doi: 10.1093/rheumatology/keq275. Epub 2010 Sep 5.

119. Elhai M, Meunier M, Matucci-Cerinic M, et al. Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study. Ann Rheum Dis. 2013 Jul;72(7):1217-20. doi: 10.1136/annrheumdis2012-202657. Epub 2012 Dec 19.

120. Khanna D, Denton CP, Jahreis A, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016 Jun 25;387(10038):2630-40. doi: 10.1016/S0140-6736(16)00232-4. Epub 2016 May 5.

121. Khanna D, Lin CJF, Kuwana M, et al. Efficacy and Safety of Tocilizumab for the treatment of systemic sclerosis: results from a phase 3 randomized controlled trial. Arthritis Rheumatol. 2018;70 (suppl 10):898.

122. Khanna D, Denton CP, Lin CJF, et al. Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis. 2018 Feb;77(2):212-20. doi: 10.1136/annrheumdis2017-211682. Epub 2017 Oct 24.

123. Zacay G, Levy Y. Outcomes of patients with systemic sclerosis treated with tocilizumab: Case series and review of the literature. Best Pract Res Clin Rheumatol. 2018 Aug;32(4): 563-71. doi: 10.1016/j.berh.2019.01.011. Epub 2019 Feb 21.

124. Sierra-Sepulveda A, Esquinca-Gonzalez A, Benavides-Suarez SA, et al. Systemic Sclerosis Pathogenesis and Emerging Therapies,beyond the Fibroblast. Biomed Res Int. 2019 Jan 23;2019:4569826. doi: 10.1155/2019/4569826. eCollection 2019.

125. Wollin L, Maillet I, Quesniaux V, et al. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitornintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther. 2014 May;349(2):209-20. doi: 10.1124/jpet.113.208223. Epub 2014 Feb 20.

126. Wollin L, Wex E, Pautsch A, et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur Respir J. 2015 May;45(5):1434-45. doi: 10.1183/09031936.00174914. Epub 2015 Mar 5.

127. Tandon K, Herrmann FE, Ayaub E, et al. Nintedanib attenuates the polarization of profibrotic macrophages through the inhibition of tyrosine phosphorylation on CSF1 receptor. Am J Respir Crit Care Med. 2017;195:A2397.

128. Huang J, Beyer C, Palumbo-Zerr K, et al. Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis. 2016 May;75(5):883-90. doi: 10.1136/annrheumdis-2014-207109. Epub 2015 Apr 9.

129. Huang J, Maier C, Zhang Y, et al. Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis. Ann Rheum Dis. 2017 Nov;76(11):1941-48. doi: 10.1136/annrheumdis-2016-210823. Epub 2017 Aug 16.

130. Wollin L, Ostermann A, Williams C. Nintedanib inhibits pro-fibrotic mediators from T cells with relevance to connective tissue disease-associated interstitial lung disease. Eur Respir J. 2017;50:Suppl. 61:PA903.

131. Distler O, Highland KB, Gahlemann M, et al. Nintedanib in systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019 Jun 27;380(26):2518-2528. doi: 10.1056/NEJMoa1903076. Epub 2019 May 20.

132. Авдеев СН, Ананьева ЛП, Жиляев ЕВ и др. Резолюция Совета экспертов, посвященная теме «Интерстициальные заболевания легких при системной скелродермии» (14 октября 2019 г.). Современная ревматология. 2020;14(1):125-8.

133. https://clinicaltrials.gov/ct2/show/NCT02745145

134. https://clinicaltrials.gov/ct2/show/NCT00574613

135. Rice LM, Padilla CM, McLaughlin SR, et al. Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. J Clin Invest. 2015 Jul 1;125(7):2795-807. doi: 10.1172/JCI77958. Epub 2015 Jun 22.

136. Khanna D. An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial. J Rheumatol. 2016 Sep;43(9):1672-9. doi: 10.3899/jrheum.151322. Epub 2016 Jul 1.

137. Weill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant candidates: 2014-an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2015 Jan;34(1):1-15. doi: 10.1016/j.healun.2014.06.014. Epub 2014 Jun 26.

138. Bernstein EJ, Peterson ER, Sell JL, et al. Survival of adults with systemic sclerosis following lung transplantation: a nationwide cohort study. Arthritis Rheumatol. 2015 May;67(5): 1314-22. doi: 10.1002/art.39021.

139. Khan IY, Singer LG, de Perrot M, et al. Survival after lung transplantation in systemic sclerosis. A systematic review. Respir Med. 2013 Dec;107(12):2081-7. doi: 10.1016/j.rmed.2013.09.015. Epub 2013 Sep 26.

140. Crespo MM, Bermudez CA, Dew MA, et al. Lung Transplant in Patients with Scleroderma Compared with Pulmonary Fibrosis. Short- and Long-Term Outcomes. Ann Am Thorac Soc. 2016 Jun;13(6):784-92. doi: 10.1513/AnnalsATS.201503-177OC.

141. Miele CH, Schwab K, Saggar R, et al. Lung Transplant Outcomes in Systemic Sclerosis with Significant Esophageal Dysfunction. A Comprehensive Single-Center Experience. Ann Am Thorac Soc. 2016 Jun;13(6):793-802. doi: 10.1513/AnnalsATS.201512-806OC.

142. Fernandez-Codina A, Berastegui C, Pinal-Fernandez I, et al. Lung transplantation in systemic sclerosis: A single center cohort study. Joint Bone Spine. 2018 Jan;85(1):79-84. doi: 10.1016/j.jbspin.2017.03.012. Epub 2017 Apr 11