RESUMEN

La escleroderma tiene una prevalencia de 242 casos por millón en los Estados Unidos. Uno de los órganos más afectados es el pulmón, siendo las manifestaciones más frecuentes la enfermedad pulmonar intersticial y la hipertensión arterial pulmonar. La enfermedad intersticial progresa a ser severa en cerca del 15% y hoy en día es la primera causa de muerte en pacientes con escleroderma, con una sobrevida media de 6.5 años después del diagnóstico. Los pacientes en mayor riesgo de desarrollar enfermedad intersticial son aquéllos con el tipo escleroderma difusa y con anticuerpos anti-SCL-70 positivos. En esta revisión, se discuten las manifestaciones radiográficas y patológicas de la fibrosis pulmonar asociada a escleroderma, la utilidad de las pruebas de función pulmonar y del lavado bronquioloalveolar para identificar la presencia de fibrosis y la decisión de a quiénes tratar. Aunque no del todo efectivos, ciclofosfamida o micofenolato ofrecen buena alternativa de tratamiento.

PALABRAS CLAVE

Escleroderma, enfermedad pulmonar intersticial (EIP), hipertensión arterial pulmonar (HAP), anticuerpos anti-SCL-70, ciclofosfamida, micofenolato.

REFERENCIAS

1. 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. Aug 2003; 48(8): 2246-2255.

2. Ferri C, Valentini G, Cozzi F, et al. Systemic sclerosis: demographic, clinical, and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore). Mar 2002; 81(2): 139-153.

3. Denton CP, Black CM. Targeted therapy comes of age in scleroderma. Trends Immunol 2005; 26(11): 596-602.

4. Salerni R, Rodnan GP, Leon DF, et al. Pulmonary hypertension in the CREST syndrome variant of progressive systemic sclerosis (scleroderma). Ann Intern Med 1977; 86(4): 394-399.

5. Stupi AM, Steen VD, Owens GR, et al. Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis. Arthritis Rheum. 1986; 29(4): 515-524.

6. Trad S, Amoura Z, Beigelman C, et al. Pulmonary arterial hypertension is a major mortality factor in diffuse systemic sclerosis, independent of interstitial lung disease. Arthritis Rheum 2006; 54(1): 184-191.

7. Steen VD. The lung in systemic sclerosis. J Clin Rheumatol 2005; 11(1): 40-46.

8. Freemer M aTKJ. in Chapter 21. Connective Tissue Diseases. Interstitial Lung Diseases Fourth Edition. 2003; Schwarz & King (Eds). p. 535.

9. Sahhar J, Littlejohn G, Conron M. Fibrosing alveolitis in systemic sclerosis: the need for early screening and treatment. Intern Med J 2004; 34(11): 626-638.

10. 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(12): 947-954.

11. Steen VD, Costantino JP, Shapiro AP, et al. Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med 1990; 113(5): 352-357.

12. Altman RD, Medsger TA, Jr., Bloch DA, et al. Predictors of survival in systemic sclerosis (scleroderma). Arthritis Rheum 1991; 34(4): 403-413.

13. Morel PA, Chang HJ, Wilson JW, et al. HLA and ethnic associations among systemic sclerosis patients with anticentromere antibodies. Hum Immunol 1995; 42(1): 35-42.

14. Reveille JD, Owerbach D, Goldstein R, et al. Association of polar amino acids at position 26 of the HLA-DQB1 first domain with the anticentromere autoantibody response in systemic sclerosis (scleroderma). J Clin Invest 1992; 89(4): 1208-1213.

15. Kuwana M, Kaburaki J, Okano Y, et al. The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma). J Clin Invest 1993; 92(3): 1296-1301.

16. Morel PA, Chang HJ, Wilson JW, et al. Severe systemic sclerosis with anti-topoisomerase I antibodies is associated with an HLA-DRw11 allele. Hum Immunol 1994; 40(2): 101-110.

17. Briggs DC, Vaughan RW, Welsh KI, et al. Immunogenetic prediction of pulmonary fibrosis in systemic sclerosis. Lancet 1991; 338(8768): 661-662.

18. Avila JJ, Lympany PA, Pantelidis P, et al. Fibronectin gene polymorphisms associated with fibrosing alveolitis in systemic sclerosis. Am J Respir Cell Mol Biol 1999; 20(1): 106-112.

19. Abraham DJ, Varga J. Scleroderma: from cell and molecular mechanisms to disease models. Trends Immunol 2005; 26(11): 587-595.

20. Rottoli P, Magi B, Perari MG, et al. Cytokine profile and proteome analysis in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis. Proteomics 2005; 5(5): 1423-1430.

21. Henault J, Robitaille G, Senecal JL, et al. DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti-topoisomerase I autoantibodies from systemic sclerosis patients. Arthritis Rheum 2006; 54(3): 963-973.

22. Henault J, Tremblay M, Clement I, et al. Direct binding of anti-DNA topoisomerase I autoantibodies to the cell surface of fibroblasts in patients with systemic sclerosis. Arthritis Rheum 2004; 50(10): 3265-3274.

23. Okano Y. Antinuclear antibody in systemic sclerosis (scleroderma). Rheum Dis Clin North Am 1996; 22(4): 709-735.

24. Nishijima C, Hayakawa I, Matsushita T, et al. Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis. Clin Exp Immunol 2004; 138(2): 357-363.

25. Highland KB, Silver RM. New developments in scleroderma interstitial lung disease. Curr Opin Rheumatol 2005; 17(6): 737-745.

26. Hummers LK. Microvascular damage in systemic sclerosis: detection and monitoring with biomarkers. Curr Rheumatol Rep 2006; 8(2): 131-137.

27. Weaver AL, Divertie MB, Titus JL. The lung scleroderma. Mayo Clin Proc 1967; 42(11): 754-766.

28. Basu D, Reveille JD. Anti-scl-70. Autoimmunity 2005; 38(1): 65-72.

29. Senecal JL, Henault J, Raymond Y. The pathogenic role of autoantibodies to nuclear autoantigens in systemic sclerosis (scleroderma). J Rheumatol 2005; 32(9): 1643-1649.

30. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 2005; 35(1): 35-42.

31. Vano Sanchis D AGG, Yglesias PJ. Systemic sclerosis sine scleroderma presenting as pulmonary interstitial fibrosis. Clin Rheumatol 2006; 25: 382-383.

32. Wilson RJ, Rodnan GP, Robin ED. An Early Pulmonary Physiologic Abnormality in Progressive Systemic Sclerosis (Diffuse Scleroderma). Am J Med 1964; 36: 361-369.

33. Wells AU, Hansell DM, Rubens MB, et al. Functional impairment in lone cryptogenic fibrosing alveolitis and fibrosing alveolitis associated with systemic sclerosis: a comparison. Am J Respir Crit Care Med 1997; 155(5): 1657-1664.

34. Webb WR. in Chapter14. Collagen-vascular Diseases. “Thoracic Imaging” Webb&Higgins (eds). 2005: 429.

35. Franquet T. Cap 9. Enfermedad pulmonar infiltrativa difusa. Tórax, pulmón, pleura y mediastino (Cardoso&Criales&Moncada) eds. 1999: 12.

36. Wells AU, Cullinan P, Hansell DM, et al. Fibrosing alveolitis associated with systemic sclerosis has a better prognosis than lone cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 1994; 149(6): 1583-1590.

37. 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(12): 1581-1586.

38. Fujita J, Yoshinouchi T, Ohtsuki Y, et al. Non-specific interstitial pneumonia as pulmonary involvement of systemic sclerosis. Ann Rheum Dis 2001; 60(3): 281-283.

39. Kim DS, Yoo B, Lee JS, et al. The major histopathologic pattern of pulmonary fibrosis in scleroderma is nonspecific interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19(2): 121-127.

40. 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; 189(3): 693-698.

41. MacDonald SL, Rubens MB, Hansell DM, et al. Nonspecific interstitial pneumonia and usual interstitial pneumonia: comparative appearances at and diagnostic accuracy of thin-section CT. Radiology 2001; 221(3): 600-605.

42. Wells AU, Hansell DM, Corrin B, et al. High resolution computed tomography as a predictor of lung histology in systemic sclerosis. Thorax 1992; 47(9): 738-742.

43. Bronchoalveolar lavage constituents in healthy individuals, idiopathic pulmonary fibrosis, and selected comparison groups. The BAL Cooperative Group Steering Committee. Am Rev Respir Dis 1990; 141(5 Pt 2): S169-202.

44. Behr J, Vogelmeier C, Beinert T, et al. Bronchoalveolar lavage for evaluation and management of scleroderma disease of the lung. Am J Respir Crit Care Med 1996; 154(2 Pt 1): 400-406.

45. Silver RM, Miller KS, Kinsella MB, et al. Evaluation and management of scleroderma lung disease using bronchoalveolar lavage. Am J Med 1990; 88(5): 470-476.

46. Wells AU, Hansell DM, Haslam PL, et al. Bronchoalveolar lavage cellularity: lone cryptogenic fibrosing alveolitis compared with the fibrosing alveolitis of systemic sclerosis. Am J Respir Crit Care Med 1998; 157(5 Pt 1): 1474-1482.

47. Latsi PI, Wells AU. Evaluation and management of alveolitis and interstitial lung disease in scleroderma. Curr Opin Rheumatol 2003; 15(6): 748-755.

48. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 2002; 165(2): 277-304.

49. Valentini G. [Therapy of systemic sclerosis]. Reumatismo 2004; 56(1): 1-8.

50. Kohno K, Katayama T, Majima K, et al. A case of normotensive scleroderma renal crisis after high-dose methylprednisolone treatment. Clin Nephrol 2000; 53(6): 479-482.

51. Steen VD, Medsger TA, Jr. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum 1998; 41(9): 1613-1619.

52. 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(6): 455-461.

53. Giacomelli R, Valentini G, Salsano F, et al. Cyclophosphamide pulse regimen in the treatment of alveolitis in systemic sclerosis. J Rheumatol 2002; 29(4): 731-736.

54. Ostojic P, Damjanov N. Improvement of lung function in patients with systemic sclerosis after 6 months cyclophosphamide pulse therapy. Clin Rheumatol 2006: 1-3.

55. Valentini G, Paone C, La Montagna G, et al. Low-dose intravenous cyclophosphamide in systemic sclerosis: an open prospective efficacy study in patients with early diffuse disease. Scand J Rheumatol 2006; 35(1): 35-38.

56. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006; 354(25): 2655-2666.

57. Martinez FJ, McCune WJ. Cyclophosphamide for scleroderma lung disease. N Engl J Med 2006; 354(25): 2707-2709.

58. Dheda K, Lalloo UG, Cassim B, et al. Experience with azathioprine in systemic sclerosis associated with interstitial lung disease. Clin Rheumatol 2004; 23(4): 306-309.

59. Nadashkevich O, Davis P, Fritzler M, et al. A randomized unblinded trial of cyclophosphamide versus azathioprine in the treatment of systemic sclerosis. Clin Rheumatol 2006; 25(2): 205-212.

60. Liossis SN, Bounas A, Andonopoulos AP. Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease. Rheumatology (Oxford). 2006.

61. 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(1): 30-36.

62. AC Zamora PW, HR Collard, MK Konolly, BM Elicker, WR Webb, N Tchao, LL Koth, TE King, Jr., JA Golden. Mycophenolate Mofetil in Scleroderma-related Interstitial Lung Disease. Presented as Abstract in ATS. 2006.

63. Rosas V, Conte JV, Yang SC, et al. Lung transplantation and systemic sclerosis. Ann Transplant 2000; 5(3): 38-43.

64. Massad MG, Powell CR, Kpodonu J, et al. Outcomes of lung transplantation in patients with scleroderma. World J Surg 2005; 29(11): 1510-1515.