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Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)

John Varga, MD
Andrew M Tager, MD
Section Editors
Talmadge E King, Jr, MD
John S Axford, DSc, MD, FRCP, FRCPCH
Deputy Editor
Helen Hollingsworth, MD


Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc) that is often progressive and has a poor prognosis [1-4]. In a retrospective study of 619 patients with SSc, 40 percent of patients had a restrictive ventilatory defect (suggesting ILD) either alone or in combination with pulmonary arterial hypertension [5].

The treatment and prognosis of SSc-ILD will be reviewed here. The clinical presentation and diagnosis of SSc lung disease, the treatment of SSc in general, and the treatment of SSc-associated pulmonary arterial hypertension are discussed separately. (See "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)" and "Overview of pulmonary complications of systemic sclerosis (scleroderma)" and "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults" and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, classification, risk factors, screening, and prognosis".)


The term interstitial lung disease (ILD) is broadly used to describe a heterogeneous group of disorders that are classified together because of similar clinical, radiographic, physiologic, or pathologic manifestations. In this topic review, we refer broadly to systemic sclerosis (SSc)-ILD and do not distinguish among the histopathologic subtypes.

In the vast majority of patients with SSc-ILD, the lung injury is characterized by a pattern termed nonspecific interstitial pneumonia (NSIP) [6]. Histopathologically, NSIP is characterized by varying degrees of pulmonary inflammation and fibrosis, with some forms being primarily inflammatory (cellular NSIP) and others primarily fibrotic (fibrotic NSIP). Most investigators believe that cellular NSIP is the early stage of fibrotic NSIP. Although NSIP may have significant fibrosis, it is usually of uniform temporality. Fibroblastic foci and honeycombing, if present, are rare. (See "Idiopathic interstitial pneumonias: Clinical manifestations and pathology", section on 'Nonspecific interstitial pneumonia'.)

A minority of patients with SSc-ILD have the histopathologic pattern of usual interstitial pneumonia (UIP), the pattern that is also associated with idiopathic pulmonary fibrosis (IPF). This pattern is characterized by a non-uniform distribution of alternating zones of dense fibrosis, fibroblast foci, scant inflammation, normal lung, and honeycomb change.


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Literature review current through: Oct 2015. | This topic last updated: Mar 10, 2015.
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  1. Herzog EL, Mathur A, Tager AM, et al. Review: interstitial lung disease associated with systemic sclerosis and idiopathic pulmonary fibrosis: how similar and distinct? Arthritis Rheumatol 2014; 66:1967.
  2. Highland KB, Silver RM. New developments in scleroderma interstitial lung disease. Curr Opin Rheumatol 2005; 17:737.
  3. Al-Dhaher FF, Pope JE, Ouimet JM. Determinants of morbidity and mortality of systemic sclerosis in Canada. Semin Arthritis Rheum 2010; 39:269.
  4. Mathai SC, Hummers LK, Champion HC, et al. Survival in pulmonary hypertension associated with the scleroderma spectrum of diseases: impact of interstitial lung disease. Arthritis Rheum 2009; 60:569.
  5. Chang B, Wigley FM, White B, Wise RA. Scleroderma patients with combined pulmonary hypertension and interstitial lung disease. J Rheumatol 2003; 30:2398.
  6. King TE Jr. Clinical advances in the diagnosis and therapy of the interstitial lung diseases. Am J Respir Crit Care Med 2005; 172:268.
  7. Wells AU, Denton CP. Interstitial lung disease in connective tissue disease--mechanisms and management. Nat Rev Rheumatol 2014; 10:728.
  8. Steen VD, Medsger TA Jr. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 2000; 43:2437.
  9. Iudici M, Moroncini G, Cipriani P, et al. Where are we going in the management of interstitial lung disease in patients with systemic sclerosis? Autoimmun Rev 2015; 14:575.
  10. 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; 52:155.
  11. Nihtyanova SI, Schreiber BE, Ong VH, et al. Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheumatol 2014; 66:1625.
  12. Steen VD, Lanz JK Jr, Conte C, et al. Therapy for severe interstitial lung disease in systemic sclerosis. A retrospective study. Arthritis Rheum 1994; 37:1290.
  13. 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; 63:3078.
  14. 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; 165:1581.
  15. Goh NS, Desai SR, Veeraraghavan S, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med 2008; 177:1248.
  16. Goh NS, Veeraraghavan S, Desai SR, et al. Bronchoalveolar lavage cellular profiles in patients with systemic sclerosis-associated interstitial lung disease are not predictive of disease progression. Arthritis Rheum 2007; 56:2005.
  17. Harrison NK, Glanville AR, Strickland B, et al. Pulmonary involvement in systemic sclerosis: the detection of early changes by thin section CT scan, bronchoalveolar lavage and 99mTc-DTPA clearance. Respir Med 1989; 83:403.
  18. Strange C, Bolster MB, Roth MD, et al. Bronchoalveolar lavage and response to cyclophosphamide in scleroderma interstitial lung disease. Am J Respir Crit Care Med 2008; 177:91.
  19. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006; 354:2655.
  20. Martinez FJ, McCune WJ. Cyclophosphamide for scleroderma lung disease. N Engl J Med 2006; 354:2707.
  21. Hoyles RK, Ellis RW, Wellsbury J, et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 2006; 54:3962.
  22. Roth MD, Tseng CH, Clements PJ, et al. Predicting treatment outcomes and responder subsets in scleroderma-related interstitial lung disease. Arthritis Rheum 2011; 63:2797.
  23. Nannini C, West CP, Erwin PJ, Matteson EL. Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial lung disease: a systematic review and meta-analysis of randomized controlled trials and observational prospective cohort studies. Arthritis Res Ther 2008; 10:R124.
  24. Silver RM, Warrick JH, Kinsella MB, et al. Cyclophosphamide and low-dose prednisone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease. J Rheumatol 1993; 20:838.
  25. White B, Moore WC, Wigley FM, et al. Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis. Ann Intern Med 2000; 132:947.
  26. Theodore AC, Tseng CH, Li N, et al. Correlation of cough with disease activity and treatment with cyclophosphamide in scleroderma interstitial lung disease: findings from the Scleroderma Lung Study. Chest 2012; 142:614.
  27. 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; 136:1333.
  28. Khanna D, Yan X, Tashkin DP, et al. Impact of oral cyclophosphamide on health-related quality of life in patients with active scleroderma lung disease: results from the scleroderma lung study. Arthritis Rheum 2007; 56:1676.
  29. Tashkin DP, Elashoff R, Clements PJ, et al. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med 2007; 176:1026.
  30. Várai G, Earle L, Jimenez SA, et al. A pilot study of intermittent intravenous cyclophosphamide for the treatment of systemic sclerosis associated lung disease. J Rheumatol 1998; 25:1325.
  31. Giacomelli R, Valentini G, Salsano F, et al. Cyclophosphamide pulse regimen in the treatment of alveolitis in systemic sclerosis. J Rheumatol 2002; 29:731.
  32. Airò P, Danieli E, Parrinello G, et al. Intravenous cyclophosphamide therapy for systemic sclerosis. A single-center experience and review of the literature with pooled analysis of lung function test results. Clin Exp Rheumatol 2004; 22:573.
  33. Tzelepis GE, Plastiras SC, Karadimitrakis SP, Vlachoyiannopoulos PG. Determinants of pulmonary function improvement in patients with scleroderma and interstitial lung disease. Clin Exp Rheumatol 2007; 25:734.
  34. Bérezné A, Ranque B, Valeyre D, et al. Therapeutic strategy combining intravenous cyclophosphamide followed by oral azathioprine to treat worsening interstitial lung disease associated with systemic sclerosis: a retrospective multicenter open-label study. J Rheumatol 2008; 35:1064.
  35. Furst DE, Tseng CH, Clements PJ, et al. Adverse events during the Scleroderma Lung Study. Am J Med 2011; 124:459.
  36. Pakas I, Ioannidis JP, Malagari K, et al. Cyclophosphamide with low or high dose prednisolone for systemic sclerosis lung disease. J Rheumatol 2002; 29:298.
  37. Stratton RJ, Wilson H, Black CM. Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma. Rheumatology (Oxford) 2001; 40:84.
  38. Liossis SN, Bounas A, Andonopoulos AP. Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease. Rheumatology (Oxford) 2006; 45:1005.
  39. Swigris JJ, Olson AL, Fischer A, et al. Mycophenolate mofetil is safe, well tolerated, and preserves lung function in patients with connective tissue disease-related interstitial lung disease. Chest 2006; 130:30.
  40. Simeón-Aznar CP, Fonollosa-Plá V, Tolosa-Vilella C, et al. Effect of mycophenolate sodium in scleroderma-related interstitial lung disease. Clin Rheumatol 2011; 30:1393.
  41. Saketkoo LA, Espinoza LR. Experience of mycophenolate mofetil in 10 patients with autoimmune-related interstitial lung disease demonstrates promising effects. Am J Med Sci 2009; 337:329.
  42. Koutroumpas A, Ziogas A, Alexiou I, et al. Mycophenolate mofetil in systemic sclerosis-associated interstitial lung disease. Clin Rheumatol 2010; 29:1167.
  43. Mendoza FA, Nagle SJ, Lee JB, Jimenez SA. A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset. J Rheumatol 2012; 39:1241.
  44. Zamora AC, Wolters PJ, Collard HR, et al. Use of mycophenolate mofetil to treat scleroderma-associated interstitial lung disease. Respir Med 2008; 102:150.
  45. Gerbino AJ, Goss CH, Molitor JA. Effect of mycophenolate mofetil on pulmonary function in scleroderma-associated interstitial lung disease. Chest 2008; 133:455.
  46. Nadashkevich O, Davis P, Fritzler M, Kovalenko W. A randomized unblinded trial of cyclophosphamide versus azathioprine in the treatment of systemic sclerosis. Clin Rheumatol 2006; 25:205.
  47. Dheda K, Lalloo UG, Cassim B, Mody GM. Experience with azathioprine in systemic sclerosis associated with interstitial lung disease. Clin Rheumatol 2004; 23:306.
  48. Daoussis D, Liossis SN, Tsamandas AC, et al. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford) 2010; 49:271.
  49. 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:S17.
  50. Lafyatis R, Kissin E, York M, et al. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum 2009; 60:578.
  51. Keir GJ, Maher TM, Hansell DM, et al. Severe interstitial lung disease in connective tissue disease: rituximab as rescue therapy. Eur Respir J 2012; 40:641.
  52. Bosello SL, De Luca G, Rucco M, et al. Long-term efficacy of B cell depletion therapy on lung and skin involvement in diffuse systemic sclerosis. Semin Arthritis Rheum 2015; 44:428.
  53. Jordan S, Distler JH, 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; 74:1188.
  54. Giuggioli D, Lumetti F, Colaci M, et al. Rituximab in the treatment of patients with systemic sclerosis. Our experience and review of the literature. Autoimmun Rev 2015; 14:1072.
  55. Bernstein EJ, Peterson ER, Sell JL, et al. Survival of adults with systemic sclerosis following lung transplantation: a nationwide cohort study. Arthritis Rheumatol 2015; 67:1314.
  56. Launay D, Savale L, Berezne A, et al. Lung and heart-lung transplantation for systemic sclerosis patients. A monocentric experience of 13 patients, review of the literature and position paper of a multidisciplinary Working Group. Presse Med 2014; 43:e345.
  57. Rosas V, Conte JV, Yang SC, et al. Lung transplantation and systemic sclerosis. Ann Transplant 2000; 5:38.
  58. Massad MG, Powell CR, Kpodonu J, et al. Outcomes of lung transplantation in patients with scleroderma. World J Surg 2005; 29:1510.
  59. Schachna L, Medsger TA Jr, Dauber JH, et al. Lung transplantation in scleroderma compared with idiopathic pulmonary fibrosis and idiopathic pulmonary arterial hypertension. Arthritis Rheum 2006; 54:3954.
  60. Saggar R, Khanna D, Furst DE, et al. Systemic sclerosis and bilateral lung transplantation: a single centre experience. Eur Respir J 2010; 36:893.
  61. Khan IY, Singer LG, de Perrot M, et al. Survival after lung transplantation in systemic sclerosis. A systematic review. Respir Med 2013; 107:2081.
  62. Rizzi M, Sarzi-Puttini P, Airoldi A, et al. Performance capacity evaluated using the 6-minute walk test: 5-year results in patients with diffuse systemic sclerosis and initial interstitial lung disease. Clin Exp Rheumatol 2015; 33:S142.
  63. Katzen JB, Raparia K, Agrawal R, et al. Early stage lung cancer detection in systemic sclerosis does not portend survival benefit: a cross sectional study. PLoS One 2015; 10:e0117829.
  64. Burt RK, Shah SJ, Dill K, et al. Autologous non-myeloablative haemopoietic 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.
  65. van Laar JM, Farge D, Sont JK, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 2014; 311:2490.
  66. Miura Y, Saito T, Fujita K, et al. Clinical experience with pirfenidone in five patients with scleroderma-related interstitial lung disease. Sarcoidosis Vasc Diffuse Lung Dis 2014; 31:235.
  67. Khanna D, Albera C, Fischer A, et al. Safety and tolerability of pirfenidone in patients with systemic sclerosis-associated interstitial lung disease – the Lotuss study. Ann Rheum Dis 2015; 74:816.
  68. Safety And Tolerability Of Pirfenidone In Patients With Systemic Sclerosis-Associated Interstitial Lung Disease - The LOTUSS Study. Am J Respir Crit Care Med 2015; 191:A1175.
  69. De Lauretis A, Sestini P, Pantelidis P, et al. Serum interleukin 6 is predictive of early functional decline and mortality in interstitial lung disease associated with systemic sclerosis. J Rheumatol 2013; 40:435.
  70. Denton C, Khanna D, van Laar JM, et al. Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis: Week 24 Data from a Phase 2/3 Trial. Rheumatology (Oxford) 2015; 54:i32.
  71. de Paoli FV, Nielsen BD, Rasmussen F, et al. Abatacept induces clinical improvement in patients with severe systemic sclerosis. Scand J Rheumatol 2014; 43:342.
  73. Guttadauria M, Diamond H, Kaplan D. Colchicine in the treatment of scleroderma. J Rheumatol 1977; 4:272.
  74. Sackner MA. Scleroderma. In: Modern Medical Monographs, Grune and Stratton, New York 1966. Vol 26, p.76.
  75. CONNER PK, BASHOUR FA. Cardiopulmonary changes in scleroderma. A physiologic study. Am Heart J 1961; 61:494.
  76. Steen VD, Owens GR, Redmond C, et al. The effect of D-penicillamine on pulmonary findings in systemic sclerosis. Arthritis Rheum 1985; 28:882.
  77. Böni A, Pavelka K, Kludas M. [Treatment of progressive scleroderma with D-penicillamine (Metalcaptase)]. Munch Med Wochenschr 1969; 111:1580.
  78. de Clerck LS, Dequeker J, Francx L, Demedts M. D-penicillamine therapy and interstitial lung disease in scleroderma. A long-term followup study. Arthritis Rheum 1987; 30:643.
  79. Clements PJ, Furst DE, Wong WK, et al. High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis: analysis of a two-year, double-blind, randomized, controlled clinical trial. Arthritis Rheum 1999; 42:1194.
  80. HUGHES DT, LEE FI. Lung function in patients with systemic sclerosis. Thorax 1963; 18:16.
  81. Kallenberg CG, Jansen HM, Elema JD, The TH. Steroid-responsive interstitial pulmonary disease in systemic sclerosis. Monitoring by bronchoalveolar lavage. Chest 1984; 86:489.
  82. NICE CM Jr, MENON AN, RIGLER LG. Pulmonary manifestations in collagen diseases. Am J Roentgenol Radium Ther Nucl Med 1959; 81:264.
  83. Wells AU, Hansell DM, Rubens MB, et al. The predictive value of appearances on thin-section computed tomography in fibrosing alveolitis. Am Rev Respir Dis 1993; 148:1076.
  84. Rossi GA, Bitterman PB, Rennard SI, et al. Evidence for chronic inflammation as a component of the interstitial lung disease associated with progressive systemic sclerosis. Am Rev Respir Dis 1985; 131:612.
  85. SULLIVAN MA, MILLER DK. Pulmonary manifestations in collagen disease. Arch Intern Med 1962; 110:769.
  86. Dines DE. Pulmonary disease of vascular origin. Dis Chest 1968; 54:3.
  87. Winstone TA, Assayag D, Wilcox PG, et al. Predictors of mortality and progression in scleroderma-associated interstitial lung disease: a systematic review. Chest 2014; 146:422.