Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)

John Varga, 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 one of the major types of lung involvement in systemic sclerosis (SSc). SSc-associated ILD consists of various histopathologic subtypes, most commonly nonspecific interstitial pneumonitis and usual interstitial pneumonitis. Affected patients have a worse prognosis than patients with SSc who are free of pulmonary involvement.

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


Two major subsets of SSc are commonly recognized and are distinguished by the extent of skin sclerosis and pattern of organ involvement. The type of cutaneous involvement has some correlation with the risk for ILD, as described below. (See "Overview and classification of scleroderma disorders", section on 'Limited and diffuse cutaneous SSc' and "Overview of pulmonary complications of systemic sclerosis (scleroderma)", section on 'Influence of diffuse cutaneous and limited cutaneous disease'.)

Diffuse cutaneous SSc is characterized by extensive skin involvement with extension of skin sclerosis proximal to the wrists (particularly over the proximal limbs and trunk, but commonly sparing the upper back). Patients with diffuse cutaneous SSc are at an increased risk of developing ILD early in the course of their disease [1].

Limited cutaneous SSc is characterized by skin sclerosis restricted to the hands, distal extremities, and, to a lesser extent, the face and neck. Patients with limited cutaneous SSc are less likely to develop ILD early in the course of disease, but may develop ILD as a late manifestation [1,2].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Jul 12, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. 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; 35:112.
  2. Fischer A, Swigris JJ, Groshong SD, et al. Clinically significant interstitial lung disease in limited scleroderma: histopathology, clinical features, and survival. Chest 2008; 134:601.
  3. van Bon L, Affandi AJ, Broen J, et al. Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med 2014; 370:433.
  4. McNearney TA, Reveille JD, Fischbach M, et al. Pulmonary involvement in systemic sclerosis: associations with genetic, serologic, sociodemographic, and behavioral factors. Arthritis Rheum 2007; 57:318.
  5. 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; 90:223.
  6. King TE Jr, Kim EJ, Kinder BW. Connective tissue diseases. In: Interstitial Lung Disease, 5th, Schwartz MI, King TE Jr.. (Eds), People's Medical Publishing House, Shelton, CT 2011. p.689.
  7. Reveille JD, Solomon DH, American College of Rheumatology Ad Hoc Committee of Immunologic Testing Guidelines. Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum 2003; 49:399.
  8. Steen VD, Powell DL, Medsger TA Jr. Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum 1988; 31:196.
  9. Okano Y, Steen VD, Medsger TA Jr. Autoantibody reactive with RNA polymerase III in systemic sclerosis. Ann Intern Med 1993; 119:1005.
  10. Sacks DG, Okano Y, Steen VD, et al. Isolated pulmonary hypertension in systemic sclerosis with diffuse cutaneous involvement: association with serum anti-U3RNP antibody. J Rheumatol 1996; 23:639.
  11. Wallace DJ, Lin HC, Shen GQ, Peter JB. Antibodies to histone (H2A-H2B)-DNA complexes in the absence of antibodies to double-stranded DNA or to (H2A-H2B) complexes are more sensitive and specific for scleroderma-related disorders than for lupus. Arthritis Rheum 1994; 37:1795.
  12. Greidinger EL, Flaherty KT, White B, et al. African-American race and antibodies to topoisomerase I are associated with increased severity of scleroderma lung disease. Chest 1998; 114:801.
  13. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005; 35:35.
  14. Fertig N, Domsic RT, Rodriguez-Reyna T, et al. Anti-U11/U12 RNP antibodies in systemic sclerosis: a new serologic marker associated with pulmonary fibrosis. Arthritis Rheum 2009; 61:958.
  15. Plastiras SC, Karadimitrakis SP, Ziakas PD, et al. Scleroderma lung: initial forced vital capacity as predictor of pulmonary function decline. Arthritis Rheum 2006; 55:598.
  16. 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; 67:3256.
  17. Wells AU, Hansell DM, Rubens MB, et al. Fibrosing alveolitis in systemic sclerosis: indices of lung function in relation to extent of disease on computed tomography. Arthritis Rheum 1997; 40:1229.
  18. 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.
  19. Garin MC, Highland KB, Silver RM, Strange C. Limitations to the 6-minute walk test in interstitial lung disease and pulmonary hypertension in scleroderma. J Rheumatol 2009; 36:330.
  20. Goldin JG, Lynch DA, Strollo DC, et al. High-resolution CT scan findings in patients with symptomatic scleroderma-related interstitial lung disease. Chest 2008; 134:358.
  21. de Souza RB, Borges CT, Capelozzi VL, et al. Centrilobular fibrosis: an underrecognized pattern in systemic sclerosis. Respiration 2009; 77:389.
  22. 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.
  23. Kim EA, Lee KS, Johkoh T, et al. Interstitial lung diseases associated with collagen vascular diseases: radiologic and histopathologic findings. Radiographics 2002; 22 Spec No:S151.
  24. 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.
  25. Hoffmann-Vold AM, Aaløkken 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; 67:2205.
  26. 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.
  27. Kowal-Bielecka O, Kowal K, Highland KB, Silver RM. Bronchoalveolar lavage fluid in scleroderma interstitial lung disease: technical aspects and clinical correlations: review of the literature. Semin Arthritis Rheum 2010; 40:73.
  28. Wells AU, Hansell DM, Rubens MB, et al. Fibrosing alveolitis in systemic sclerosis. Bronchoalveolar lavage findings in relation to computed tomographic appearance. Am J Respir Crit Care Med 1994; 150:462.
  29. 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.
  30. 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.
  31. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006; 354:2655.
  32. Fujita J, Yoshinouchi T, Ohtsuki Y, et al. Non-specific interstitial pneumonia as pulmonary involvement of systemic sclerosis. Ann Rheum Dis 2001; 60:281.
  33. 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; 20:235.
  34. Tansey D, Wells AU, Colby TV, et al. Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis. Histopathology 2004; 44:585.
  35. Nicholson AG, Colby TV, Wells AU. Histopathological approach to patterns of interstitial pneumonia in patient with connective tissue disorders. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19:10.
  36. Harrison NK, Myers AR, Corrin B, et al. Structural features of interstitial lung disease in systemic sclerosis. Am Rev Respir Dis 1991; 144:706.
  37. al-Sabbagh MR, Steen VD, Zee BC, et al. Pulmonary arterial histology and morphometry in systemic sclerosis: a case-control autopsy study. J Rheumatol 1989; 16:1038.
  38. Song JW, Do KH, Kim MY, et al. Pathologic and radiologic differences between idiopathic and collagen vascular disease-related usual interstitial pneumonia. Chest 2009; 136:23.
  39. Kobayashi J, Kitamura S. KL-6: a serum marker for interstitial pneumonia. Chest 1995; 108:311.
  40. Hant FN, Ludwicka-Bradley A, Wang HJ, et al. Surfactant protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma. J Rheumatol 2009; 36:773.
  41. Nakajima H, Harigai M, Hara M, et al. KL-6 as a novel serum marker for interstitial pneumonia associated with collagen diseases. J Rheumatol 2000; 27:1164.
  42. Takahashi H, Kuroki Y, Tanaka H, et al. Serum levels of surfactant proteins A and D are useful biomarkers for interstitial lung disease in patients with progressive systemic sclerosis. Am J Respir Crit Care Med 2000; 162:258.
  43. Yanaba K, Hasegawa M, Takehara K, Sato S. Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis. J Rheumatol 2004; 31:1112.
  44. Kodera M, Hasegawa M, Komura K, et al. Serum pulmonary and activation-regulated chemokine/CCL18 levels in patients with systemic sclerosis: a sensitive indicator of active pulmonary fibrosis. Arthritis Rheum 2005; 52:2889.
  45. Gladman DD, Kung TN, Siannis F, et al. HLA markers for susceptibility and expression in scleroderma. J Rheumatol 2005; 32:1481.
  46. Carmona FD, Martin JE, Beretta L, et al. The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis. PLoS One 2013; 8:e54419.
  47. Peljto AL, Steele MP, Fingerlin TE, et al. The pulmonary fibrosis-associated MUC5B promoter polymorphism does not influence the development of interstitial pneumonia in systemic sclerosis. Chest 2012; 142:1584.
  48. McGuire F, Kennelly T, Tillack T, Robbins M. Pulmonary capillary hemangiomatosis associated with CREST syndrome: a case report and review of the literature. Respiration 2010; 80:435.
  49. Humbert M, Maître S, Capron F, et al. Pulmonary edema complicating continuous intravenous prostacyclin in pulmonary capillary hemangiomatosis. Am J Respir Crit Care Med 1998; 157:1681.
  50. Günther S, Jaïs X, Maitre S, et al. Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension. Arthritis Rheum 2012; 64:2995.