Skip to main content

Advertisement

Log in

Evaluation and management of pulmonary fibrosis in scleroderma

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Pulmonary fibrosis causes significant morbidity and mortality in patients with scleroderma. Lung inflammation identifies patients at greater risk for decline in forced vital capacity and diffusing capacity for carbon monoxide. Factors that are increased in patients with scleroderma with lung fibrosis include connective tissue growth factor, KL-6, pulmonary surfactant-D, tissue inhibitor of metalloproteinase 2, monocyte chemotactic protein-1, macrophage inhibitory protein-1α, soluble interleukin-6 receptors, antiendothelial cell antibodies, and anti-DNA topoisomerase I antibodies. Potential mechanisms of lung damage in scleroderma include increased production of profibrotic type 2 cytokines and abnormal signaling by thrombin of tenascin-C production by lung fibroblasts, with protein kinase Cε as an intermediate in the signaling pathway. Treatment of scleroderma lung disease with cyclophosphamide may have a beneficial effect on pulmonary function and survival. Lung transplantation provides a therapeutic option for patients with scleroderma with end-stage lung disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Steen VD, Conte C, Owens GR, Medsger TA Jr: Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum 1994, 37:1283–1289.

    Article  PubMed  CAS  Google Scholar 

  2. Black CM, du Bois RM: Organ involvement: pulmonary. In Systemic Sclerosis. Edited by Clements PJ and Furst DE. Baltimore: Williams & Wilkins; 1996:299–332.

    Google Scholar 

  3. Griedinger EL, Flaherty KT, White B, et al.: African American race and antibodies to topisomerase I are associated with increased severity of scleroderma lung disease. Chest 1998, 114:801–807.

    Google Scholar 

  4. Silver RM, Miller KS, Kinsella MB, Smith EA, Schabel SI: Evaluation and management of scleroderma lung disease using bronchoalveolar lavage. Am J Med 1990, 88:470–476.

    Article  PubMed  CAS  Google Scholar 

  5. White B, Moore WC, Wigley FM, Xiao HQ, Wise RA: Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis. Ann Intern Med 2000, 132:947–954. A retrospective cohort study of 103 patients with scleroderma shows that lung inflammation is associated with subsequent decline in lung function and worse survival. Treatment of patients with lung inflammation with cyclophosphamide is associated with stability or improvement in lung function and improvement in survival.

    PubMed  CAS  Google Scholar 

  6. Witt C, Borges AC, John M, et al.: Pulmonary involvement in diffuse cutaneous systemic sclerosis: bronchoalveolar fluid granulocytosis predicts progression of fibrosing alveolitis. Ann Rheum Dis 1999, 58:635–640. This study reports that increased granulocytes, but not lymphocytes, are associated with progressive lung disease in patients with scleroderma.

    Article  PubMed  CAS  Google Scholar 

  7. Renzoni E, Lympany P, Sestini P, et al.: Distribution of novel polymorphisms of the interleukin-8 and CXC receptor 1 and 2 genes in systemic sclerosis and cryptogenic fibrosing alveolitis. Arthritis Rheum 2000, 43:1633–1640.

    Article  PubMed  CAS  Google Scholar 

  8. Bolster MB, Ludwicka A, Sutherland SE, Strange C, Silver RM: Cytokine concentrations in bronchoalveolar lavage fluid of patients with systemic sclerosis. Arthritis Rheum 1997, 40:743–751.

    Article  PubMed  CAS  Google Scholar 

  9. Flavahan NA, Flavahan S, Liu Q, et al.: Increased alpha2-adrenergic constriction of isolated arterioles in diffuse scleroderma. Arthritis Rheum 2000, 43:1886–1890.

    Article  PubMed  CAS  Google Scholar 

  10. Yamane K, Ihn H, Kubo M, et al.: Serum levels of KL-6 as a useful marker for evaluating pulmonary fibrosis in patients with systemic sclerosis. J Rheumatol 2000, 27:930–934.

    PubMed  CAS  Google Scholar 

  11. Asano Y, Ihn H, Yamane K, et al.: Clinical significance of surfactant protein D as a serum marker for evaluating pulmonary fibrosis in patients with systemic sclerosis. Arthritis Rheum 2001, 44:1363–1369.

    Article  PubMed  CAS  Google Scholar 

  12. Yazawa N, Kikuchi K, Ihn H, et al.: Serum levels of tissue inhibitor of metalloproteinase 2 in patients with systemic sclerosis. J Am Acad Dermatol 2000, 42:70–75.

    Article  PubMed  CAS  Google Scholar 

  13. Hasegawa M, Sato S, Takehara K: Augmented production of chemokines (monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta) in patients with systemic sclerosis: MCP-1 and MIP-1alpha may be involved in the development of pulmonary fibrosis. Clin Exp Immunol 1999, 117:159–165. This report shows that production of certain chemokines in scleroderma patients and that increased production of MCP-1 and MIP-1_ occur more often in patients with lung fibrosis.

    Article  PubMed  CAS  Google Scholar 

  14. Gharaee-Kermani M, Denholm EM, Phan SH: Costimulation of fibroblast collagen and transforming growth factor beta1 gene expression by monocyte chemoattractant protein-1 via specific receptors. J Biol Chem 1996, 271:17779–17784.

    Article  PubMed  CAS  Google Scholar 

  15. Yamamoto T, Hartmann K, Eckes B, Krieg T: Role of stem cell factor and monocyte chemoattractant protein-1 in the interaction between fibroblasts and mast cells in fibrosis. J Dermatol Sci 2001, 26:106–111. This paper reports that the chemokine MCP-1 directly stimulates collagen production in human dermal fibroblasts.

    Article  PubMed  CAS  Google Scholar 

  16. Hasegawa M, Sato S, Ihn H, Takehara K: Enhanced production of interleukin-6 (IL-6), oncostatin M and soluble IL-6 receptor by cultured peripheral blood mononuclear cells from patients with systemic sclerosis. Rheumatology 1999, 38:612–617.

    Article  PubMed  CAS  Google Scholar 

  17. Ihn H, Sato S, Fujimoto M, et al.: Characterization of autoantibodies to endothelial cells in systemic sclerosis (SSc): association with pulmonary fibrosis. Clin Exp Immunol 2000, 119:203–209.

    Article  PubMed  CAS  Google Scholar 

  18. Briggs DC, Vaughan RW, Welsh KI, et al.: Immunogenetic prediction of pulmonary fibrosis in systemic sclerosis. Lancet 1991, 338:661–662.

    Article  PubMed  CAS  Google Scholar 

  19. Rizou C, Ioannidis JP, Panou-Pomonis E, et al.: B-cell epitope mapping of DNA topoisomerase I defines epitopes strongly associated with pulmonary fibrosis in systemic sclerosis. Am J Respir Cell Mol Biol 2000, 22:344–351. This study extends previous reports that anti-Scl-70 antibodies are associated with pulmonary fibrosis in scleroderma by showing that patients who have antibodies that recognize at least three of four Bcell epitopes are more likely to have pulmonary fibrosis than patients with reactivity to fewer epitopes.

    PubMed  CAS  Google Scholar 

  20. Henry PA, Atamas SP, Yurovsky VV, et al.: Diversity and plasticity of the anti-DNA topoisomerase I autoantibody response in scleroderma. Arthritis Rheum 2000, 43:2733–2742.

    Article  PubMed  CAS  Google Scholar 

  21. Atamas SP, Yurovsky VV, Wise R, et al.: Production of type 2 cytokines by CD8+ lung cells is associated with greater decline in pulmonary function in patients with systemic sclerosis. Arthritis Rheum 1999, 42:1168–1178. This report suggests that patients with scleroderma have increased production of a type 2 pattern of cytokine mRNAs by BAL cells, that CD8+ T cells are the source of this cytokine mRNA, and that production of type 2 cytokine mRNAs is associated with decline in lung function over time.

    Article  PubMed  CAS  Google Scholar 

  22. Yurovsky VV, Wigley FM, Wise RA, White B: Skewing of the CD8+ T-cell repertoire in the lungs of patients with systemic sclerosis. Hum Immunol 1996, 48:84–97.

    Article  PubMed  CAS  Google Scholar 

  23. Majumdar S, Li D, Ansari T, et al.: Different cytokine profiles in cryptogenic fibrosing alveolitis and fibrosing alveolitis associated with systemic sclerosis: a quantitative study of open lung biopsies. Eur Respir J 1999, 14:251–257. This report suggests that patients with scleroderma have increased production of type 2 and type 1 cytokines by airway cells.

    Article  PubMed  CAS  Google Scholar 

  24. Postlethwaite AE, Seyer JM: Fibroblast chemotaxis induction by human recombinant interleukin-4. Identification by synthetic peptide analysis of two chemotactic domains residing in amino acid sequences 70–88 and 89–122. J Clin Invest 1991, 87:2147–2152.

    PubMed  CAS  Google Scholar 

  25. Feghali CA, Bost KL, Boulware DW, Levy LS: Human recombinant interleukin-4 induces proliferation and interleukin-6 production by cultured human skin fibroblasts. Clin Immunol Immunopathol 1992, 63:182–187.

    Article  PubMed  CAS  Google Scholar 

  26. Postlethwaite AE, Holness MA, Katai H, Raghow R: Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4. J Clin Invest 1992, 90:1479–1485.

    Article  PubMed  CAS  Google Scholar 

  27. Ando M, Miyazaki E, Fukami T, Kumamoto T, Tsuda T: Interleukin-4-producing cells in idiopathic pulmonary fibrosis: an immunohistochemical study. Respirology 1999, 4:383–391.

    Article  PubMed  CAS  Google Scholar 

  28. Arras M, Huaux F, Vink A, et al.: Interleukin-9 reduces lung fibrosis and type 2 immune polarization induced by silica particles in a murine model. Am J Respir Cell Mol Biol 2001, 24:368–375.

    PubMed  CAS  Google Scholar 

  29. Westermann W, Schobl R, Rieber EP, Frank KH: Th2 cells as effectors in postirradiation pulmonary damage preceding fibrosis in the rat. Int J Radiat Biol 1999, 75:629–638.

    Article  PubMed  CAS  Google Scholar 

  30. McCormick LL, Zhang Y, Tootell E, Gilliam AC: Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: a model for human scleroderma. J Immunol 1999, 163:5693–5699. This report shows that the development of lung and skin fibrosis can be aborted in an animal model of fibrosis, using anti-TGFβ antibodies.

    PubMed  CAS  Google Scholar 

  31. Sato S, Nagaoka T, Hasegawa M, et al.: Serum levels of connective tissue growth factor are elevated in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. J Rheumatol 2000, 27:149–154.

    PubMed  CAS  Google Scholar 

  32. Tourkina E, Hoffman S, Fenton JW II, et al.: Depletion of protein kinase C_ in normal and scleroderma lung fibroblasts has opposite effects on tenascin expression. Arthritis Rheum 2001, 44:1370–1381. This report shows that thrombin signaling is abnormal in scleroderma fibroblasts and that it may induce increased production of the extracellular matrix protein teneascin through reduction in protein kinase Cε. This is of interest because thrombin levels are increased in scleroderma BAL fluids.

    Article  PubMed  CAS  Google Scholar 

  33. Ohba T, McDonald JK, Silver RM, et al.: Scleroderma bronchoalveolar lavage fluid contains thrombin, a mediator of human lung fibroblast proliferation via induction of platelet-derived growth factor alpha-receptor. Am J Respir Cell Mol Biol 1994, 10:405–412.

    PubMed  CAS  Google Scholar 

  34. Davas EM, Peppas C, Maragou M, et al.: Intravenous cyclophosphamide pulse therapy for the treatment of lung disease associated with scleroderma. Clin Rheumatol 1999, 18:455–461.

    Article  PubMed  CAS  Google Scholar 

  35. Varai G, Earle L, Jimenez SA, Steiner RM, Varga J: A pilot study of intermittent intravenous cyclophosphamide for the treatment of systemic sclerosis associated lung disease. J Rheumatol 1998, 25:1325–1329.

    PubMed  CAS  Google Scholar 

  36. Rosas V, Conte JV, Yang SC, et al.: Lung transplantation and systemic sclerosis. Ann Transplant 2000, 5:38–43. Results in patients with scleroderma undergoing lung transplantation for interstitial fibrosis or pulmonary hypertension suggest that transplantation can be successful in carefully screened patients with scleroderma.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

White, B. Evaluation and management of pulmonary fibrosis in scleroderma. Curr Rheumatol Rep 4, 108–112 (2002). https://doi.org/10.1007/s11926-002-0005-1

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-002-0005-1

Keywords

Navigation