Systemic sclerosis-associated interstitial lung disease: review of the literature


interstitial lung disease, systemic sclerosis, pulmonary fibrosis, antibodies

How to Cite

Dacheva, R. and Monov, S. 2020. Systemic sclerosis-associated interstitial lung disease: review of the literature. Revmatologiia (Bulgaria). 28, ONLINE (Dec. 2020).


Systemic sclerosis (SSc) is a connective tissue disease characterized by progressive sclerosis, affecting the skin and the internal organs, vasculopathy, and immune dysregulation. Interstitial pneumonias are a group of diffuse parenchymal lung diseases (DPLDs), or also called interstitial lung diseases (ILDs). ILD is a leading complication of SSc and is a leading cause of mortality in patients with SSc. The pathogenesis of lung injury involves three major processes - persistent endothelial cell damage, immune system activation, and fibroblast activation leading to the accumulation of extracellular matrix and tissue damage. A comprehensive approach is required to properly diagnose and to select appropriate therapy.


    1. Abraham DJ, Varga J. 2005. Scleroderma: from cell and molecular mechanism to disease model. Trends Immunol. 26:587-595
    2. Jogannes WJ Bijlsma, Jose Antinio P da Silva, Eric Hachulla et al., Textbook on rheumatic diseases, 2012, 546-567
    3.Abraham, DJ, T. Krieg, J. Distler et al. Overview of pathogenesis of systemic sclerosis, Rheumatology Oxford, 2009; 48, Suppl. 3: iii3-7
    4. Katsumoto TR, Whitfield ML, Connolly MK, The pathogenesis of systemic sclerosis, Annu Rev Pathol, 2011, 6:509-37
    5. Eric Hachulla, Laszlo Czirjak, Textbook on Systemic Sclerosis, EULAR 2013, 53-59
    6/ Bordon A., M.Dueymes, Y. Levy, The binding of some human antiendothelial cell antibodies induces endothelial cell apoptosis, J.Clin Invest, 1998 May 15, 101(10): 2029-2035
    7. American Thoracic Society/European Respiratory Society. International multidisciplinary consensus classification of idiopathic interstitial pneumonias, Am J Respir Crit Care Med 2002; 165 (2) 277-304
    8. An official American Thoracic Society/European Respiratory Society Statement: Update of the International multidisciplinary consensus classification of the idiopathic interstial pneumonias. Am J Respir Crit Care Med 2013; 188 (6): 733-748.
    9. Katerina M. Antoniou, George A. Margaritopoulos, Sara Tomassetti et al. Interstitial lung disease, European Respiratory Review 2014 23:40-54
    10. Daniel Simoes Oliveira, Jose de Arimatela Araujo Filho, Antonio Fernando Lins Paica et al. Idiopathic interstitial pneumonias: review of the latest American Thoracic Society/European Respiratory Society classification, Radiol Bras 2018, Sep-Oct; 51(5): 321-327
    11. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis. 2007; 66(7):940-944.
    12. Honda, N., M. Jinnin, I. Kajihara et al., TGF-beta-mediated downregulation ot microRNA-196a contributes to the constitutive upregulated type I collagen expression in scleroderma dermal fibroblasts. J Immunol 2012; 188:3323-3331
    13. Susanna Cappelli, Silvia Bellando Randone, Gianna Camiciottoli et al. Interstitial Lung Disease in Systemiv Sclerosis: where do we stand, European Respiratory Review, 2015, 24:411-419
    14. John Varga, David Abraham, Systemic sclerosis: a prototypic multisystem fibrotic disorder, The Journal of Clinical Investigation, 117, 557-567
    15. Mehdi Mirsaeidi, Pamela Barletta, Marilyn K. Glassberg, Systemic Sclerosis Associated Interstitial Lung Disease: New Direction in Disease Management, Frontiers in Medicine (Lausanne), 2019:6:248
    16. Park JH, Kim DS, Park IN 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
    17. Ganesh Raghu, Harold R. Collard, Jim J Egan et al. An official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management, Am J Respir Crit Care Med, 2011 Mar 15; 186(6): 788-824
    18. Solomon JJ, Chartrand S, Fischer A., Current approach to connective tissue disease-associated interstitial lung disease, Curr Opin Pulm Med, 2014 Sep 20(5): 449-56
    19. Apostolos Perelas, Richard M Silver, Andrea V Arrossi, et al. Systemic sclerosis-associated interstitial lung dissease, Lancet Respir Med 2020, Volume 8, Issue 3, 304-320,
    20.Steen VD, Owens GR, Fino GJ et al. Pulmonary Involvement in systemic sclerosis (scleroderma). Arthritis Rheum, 1985 Jul;28(7):759-67
    21. Assassi S, Sharif R, Lasky RE et al. Predictors of interstitial lung disease in early systemic sclerosis: a prospective longitudinal study of the GENISOS cohort. Arthritis Res Ther 12, R166 (2010)
    22. Ysamat Marfa R, Benito YsamatA., Espejo Perez S., et al. Lung disease associated with connective tissue disease. Radiology 2013;55:107-117
    23. Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR scleroderma trials and research (EUSTAR) database. Ann Rheum Dis. 2010; 69:1809-15
    24. Goh NS, Desai SR, Veeraraghavan S, et al. Interstitial lung disease in systemic sclerosis: a simple staging system, American Journal of Respiratory and Critical Care Medicine, 2008; 177(11); 1248-54
    25. Jeong-Hwa Hwang, Shigeki Misumi, Hakan Sahin, et al. Computed Tomographic Features of Idiopatic Fibrosing Interstitial Pneumonia: Comparison With Pulmonary Fibrosis Related to Collagen Vascular Disease; Journal of Computer Asisted Tomography. 33(3):410-415
    26. Joo Hun Park, Dong Soon Kim, I-Nae Park, et al. Prognosis of Fibrotic Interstitial Pneumonia, American Journal of Respiratory and Critical Care Medicinie, Vol 175, No 7
    27. Kim EA, Lee KS, Johkoh T., et al. Interstitial lung diseases associated with collagen vascular diseases: radiologic and histopathologic findings, Radiographics, 2003 Sep-Oct; 23(5):1340
    28. J Fujita, T Yoshinouchi, Y Ohtsuki, Non-specific interstitial pneumonia as pulmonary involvement of systemic sclerosis, Ann Rheum Dis 2001; 60:281–28
    29. Katznestein AL., Fiorelli RF., Nonspecific interstitial pneumonia/fibrosis: histologic features and clinical significance, Am J Surg Pathol, 1994;18:136-147
    30. Seth J Kligerman, Steve Groshong, Kevin K. Brown, et al. Nonspecific Interstitial Pneumonia: Radiologic, Clinical, and Parhologic Consideration, Jan 1 2009, vol 29, no 1
    31. Solomon JJ, Olson AL, Fischer A. et al. Scleroderma lung disease, Eur Respir Rev, 2013 Mar 1;22(127):6-19
    32. Steen, V.D., Autoantibodies in Systemic Sclerosis, Seminars in Arthritis and Rhematism, 2005, 35(1), 35-42
    33. Vasquez-Abad D, Wallace S, Senecal JL et al. Anticentromere autoantibodies. Evaluation of an ELISA using recombinant fusion protein CENT-B as antigen, Arhtritis Rheum., 1994;37:248-252
    34. Sato S., Fujimoto M, Inh H, et al. Antibodies to centromere and centriole in scleroderma spectrum disorders, Dermatology, 1994; 189:23-26
    35. Clegg DO, Williams HJ, Singer JZ et al. Early undifferentiated connective tissue disease. II. The frequency of circulation antinuclear antibodies in patients with early rheumatic disease, J Rheumatol., 1991;18:1340-26
    36. Kane GC, Varga J, Conant EF, et al. Lung involvement in systemic sclerosis (scleroderma): relation to classification based on extent of skin involvement or autoantibody status, Respir Med, 1996 Apr; 90(4): 223-30
    37. Steen VD., Powell DL, Medsger TA., Jr Clinical correlations and prognosis based on serum autoantibodies in patients with progressive systemic sclerosis. Arthritis Rheum. 1988; 31:196-203
    38. Arnett FC, Reveille JD, Goldstein R et al. Autoantibodies to fibrillarin in systemic sclerosis (scleroderma): an immunogenetic, serologic and clinical analysis. Arthritis Rheum. 1996;39:1151-1160
    39. Kuwana M, Kaburaki J, Okano Y, et al. Clinical and prognostic associations based on serum antinuclear antibodies in Japanese patients with systemic sclerosis, Arhtritis Rheum. 1994;37:75-83
    40. Reveille JD, Solomon DH, American College of Rheumatology, Ad Hoc Committee on Immunological Testing Guidelines Evidence-based guidelines for the use of fimmunologic laboratory tests: anti-centromere, Scl-70 and nucleolar antibodies. Arthritis Rheum. 2003 Jun 15;49(3):399-412
    41. Spencet-Green G, Alter D, Welch HG. Test performance in systemic sclerosis: anti-centromere and anti-Scl-70 antibodies. Am J Med. 1998;103:242-248
    42. Ferri C, Valentini G, Cozzi F, et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine. 2002; 81:139-153.
    43. Riboldi P, Asero R, Origgi L et al. Antinuclear antibodies in progressive systemic sclerosis. Clin Exp Rheum. 1985;3:205-211
    44. Silver KC, Silver RM, Management of systemic-sclerosis-associated interstitial lung disease. Rheum Dis Clin N Am. 2015; 41:439-57
    45. Denton CP, Khanna D., Systemic sclerosis. Lancet 2017 Oct 7; 390(10103): 1685-1699  
    46. Vincent-Cottin, Kevin K., Brown, Interstitial lung disease associated with systemic sclerosis (SSc-ILD), Respir Res 20, 13(2019).
    47. Tashin DP, Roth MD, Clements PJ et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med 2016; 4:708-19
    48.Daoussis D, Liossis SN, Tsamandas AC et al. Effect of long-term treatment with rituximab on pulmonary function and skin fibrosis in patients with diffuse systemic sclerosis. Clin Exp Rheumatol. (2012) 30 (2 suppl.71): S17-22.
    49. Roth M. Scleroderma Lung Study III – Combining Pirfenidone With Mycophenolate (SLSIII). 
    50.Huang J. Beyer, Palumbo-Zerr K, Zhang Y. et al. Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis. 2016; 75:883-90
    51. 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;76:1941-8
    52. Wollin L, Maillet I, Quesniaux V et al. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther. 2014; 349:209-20
    53. Distler O., Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med 2019; 380:2518-28
    54.Burt RK, Shah SJ, Dill K et al. Autologous non-myeloablative haemopoetic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet. 2011; 378:498-506
    55. Kowal Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis 2017; 76: 1327-39.
Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.