Antinuclear Antibodies Associated with Pulmonary Involvement in Systemic Sclerosis
1989; Elsevier BV; Volume: 96; Issue: 4 Linguagem: Inglês
10.1378/chest.96.4.960-b
ISSN1931-3543
Autores Tópico(s)Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
ResumoTo the Editor: Previous studies on antinuclear antibodies in systemic sclerosis (SSc) have described a high frequency of anti-Scl-70 antibodies in patients with diffuse cutaneous subset of the disease.1Fritzler NJ Kinsella TD Garbutt E The CREST syndrome: a distinct serologic entity with anticentromere antibodies.Am J Med. 1980; 99: 520-526Abstract Full Text PDF Scopus (304) Google Scholar, 2Cattogio LJ Skinner RP Maddison PJ Frequency and clinical significance of anticentromere and anti-Scl-70 antibodies in an English connective tissue disease population.Rheumatol Int. 1983; 3: 19-21Crossref Scopus (33) Google Scholar, 3Giordano M Valentini G Migliaresi S Picillo U Vatti M Different antibody patterns and different prognoses in patients with scleroderma with various extent of skin sclerosis.J Rheumatol. 1986; 13: 911-916PubMed Google Scholar, 4Burgos-Vargas R Martínez-Cordero E Reyes PA Herrera-Esparza R Antibody pattern and other criteria for diagnosis and classification in PSS.J Rheumatol. 1988; 15: 153-154Google Scholar Further, some authors have recorded that serologic abnormalities (such as circulating immune complexes, rheumatoid factor, anti-Scl-70 and antinucleolar antibodies) may be associated with severe visceral involvement of SSc, including restrictive lung disease.5Pisko E Gallup K Turner R Parker M Nomeir AM Box J Davis J Box PJ Rothberg H Cardiopulmonary manifestations of progressive systemic sclerosis: Association with circulating immune complexes and fluorescent antinuclear antibodies.Arthritis Rheum. 1979; 22: 518-523Crossref PubMed Scopus (22) Google Scholar, 6Cattogio LJ Bernstein RM Black CM Hughes GRV Maddison PJ Serological markers in progressive systemic sclerosis.Arthritis Rheum. 1980; 23: 617-625Crossref Scopus (424) Google Scholar, 7Steen VD Powell DL Medsger TA Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis.Arthritis Rheum. 1988; 31: 196-203Crossref PubMed Scopus (552) Google Scholar, 8Manoussakis MN Constantopoulos SH Gharavi AE Moutsopoulos HM Pulmonary involvement in systemic sclerosis. Association with anti-Scl-70 antibody and digital pitting.Chest. 1987; 92: 509-513Crossref PubMed Google Scholar, 9Weiner ES Earnshaw WC Senécal JL Bordwell B Johnson P Rothfield NF Clinical association of anticentromere antibodies and antibodies to topoisomerase I. A study of 355 patients.Arthritis Rheum. 1988; 31: 196-203Crossref Scopus (195) Google Scholar, 10Seibold VR Medsger T Winkelstein A Kelly RH Rodnan GP Immune complexes in progressive systemic sclerosis (scleroderma).Arthritis Rheum. 1982; 25: 1167-1173Crossref PubMed Scopus (33) Google Scholar, 11Reimer G Steen VD Penning CA Medsger TA Tan EM Correlates between autoantibodies to nucleolar antigens and clinical features in patients with systemic sclerosis (scleroderma).Arthritis Rheum. 1988; 31: 525-532Crossref PubMed Scopus (177) Google Scholar In this study we report the association between serum autoantibodies with pulmonary abnormalities in SSc. We included 41 diffuse SSc patients (ARA criteria).4Burgos-Vargas R Martínez-Cordero E Reyes PA Herrera-Esparza R Antibody pattern and other criteria for diagnosis and classification in PSS.J Rheumatol. 1988; 15: 153-154Google Scholar, 12Martínez-Cordero E Burgos-Vargas R Herrera Esparza R Reyes PA Antinuclear antibodies profile in progressive systemic sclerosis: A multicentric study.Rev Invest Clín (Méx). 1983; 35: 273-277Google Scholar Respiratory function tests and serologic studies were performed as previously described.12Martínez-Cordero E Burgos-Vargas R Herrera Esparza R Reyes PA Antinuclear antibodies profile in progressive systemic sclerosis: A multicentric study.Rev Invest Clín (Méx). 1983; 35: 273-277Google Scholar, 13Perez-Neria J Selman M Rubio MH Ocaña H Chapela R Mendoza A Relationship between lung inflammation or fibrosis and frequency dependence of compliance in interstitial pulmonary disease.Respiration. 1987; 52: 254-262Crossref PubMed Scopus (6) Google Scholar Values of FVC and TLC less than 80 percent of predicted, FEV1/FVC less than 70 percent and MEF25 less than 60 percent of predicted were considered abnormal and indicative of restrictive, obstructiveventilatory defects and disease of the small airways, respectively. Antinuclear antibodies were carried out by the standard indirect immunofluorescent test using mouse kidney monolayers, HEp-2 and Crithidia luciliae targets. Antibodies to Scl-70, nRNP, Sm, SS-A(Ro) and SS-B(La) nuclear antigens were determined by the Ouchterlony test using rabbit thymus and human spleen preparations.4Burgos-Vargas R Martínez-Cordero E Reyes PA Herrera-Esparza R Antibody pattern and other criteria for diagnosis and classification in PSS.J Rheumatol. 1988; 15: 153-154Google Scholar, 12Martínez-Cordero E Burgos-Vargas R Herrera Esparza R Reyes PA Antinuclear antibodies profile in progressive systemic sclerosis: A multicentric study.Rev Invest Clín (Méx). 1983; 35: 273-277Google Scholar A summary of the results is shown in Table 1. The relation between the abnormal restrictive pulmonary function tests with positive fluorescent antinuclear antibodies, as well as the anti-Scl-70 antibodies reached significant values (p<0.001 and p<0.005 by χ2Cattogio LJ Skinner RP Maddison PJ Frequency and clinical significance of anticentromere and anti-Scl-70 antibodies in an English connective tissue disease population.Rheumatol Int. 1983; 3: 19-21Crossref Scopus (33) Google Scholar analysis). In contrast, no association with anti-ssDNA or anti-nRNP antibodies was noted. Antibodies to dsDNA, Sm, SS-A(Ro) and SS-B(La) antigens and anticentromere antibodies were negative. Secondary Sjögren syndrome and pulmonary alterations were more frequent in the SSc group with a positive rheumatoid factor test,10Seibold VR Medsger T Winkelstein A Kelly RH Rodnan GP Immune complexes in progressive systemic sclerosis (scleroderma).Arthritis Rheum. 1982; 25: 1167-1173Crossref PubMed Scopus (33) Google Scholar although the differences were not statistically significant. There was no relation with other SSc manifestations.Table 1Association of Autoantibodies with Pulmonary Functional Abnormalities in Systemic SclerosisFunctional abnormalityAntinuclear antibodies (IIF test)Anti-Scl-70 antibody (Ouchterlony)Anti-nRNP antibody (Ouchterlony)Anti-ssDNA antibody (Hemagglutination)Rheumatoid factor (Latex test)←% positive→TLC (< 80% of predicted)*All patients but one have both low FVC and TLC values69.2†p<0.001 and p<0.005 by χ2 test75†p<0.001 and p<0.005 by χ2 test33.337.555.5FVC (< 80% of predicted)*All patients but one have both low FVC and TLC values76.9†p<0.001 and p<0.005 by χ2 test83.3†p<0.001 and p<0.005 by χ2 test33.32544.4FEV1/FVC (< 70% of predicted)7.68.3012.511.1MEF23 (< 60% of predicted)15.316.68.312.511.1SSc cases with and without31.729.329.319.521.9functional abnormalities (n = 41)IIF = indirect immunofluorescence test* All patients but one have both low FVC and TLC values† p<0.001 and p<0.005 by χ2Cattogio LJ Skinner RP Maddison PJ Frequency and clinical significance of anticentromere and anti-Scl-70 antibodies in an English connective tissue disease population.Rheumatol Int. 1983; 3: 19-21Crossref Scopus (33) Google Scholar test Open table in a new tab IIF = indirect immunofluorescence test Antibodies to topoisomerase I (Scl-70) have been reported to be present in over 30 percent of SSc patients, and recently this figure appears to be more frequent in cases with severe disease, including a subgroup of limited scleroderma patients with prominent visceral manifestations.19Alcocer-Varela J Martínez-Cordero E Alarcón-Segovia D Spontaneous production of, and response to, interleukin-1 by peripheral blood mononuclear cells from patients with scleroderma.Clin Exp Immunol. 1985; 59: 666-672PubMed Google Scholar We have previously described that positive anti-Scl-70 antibodies occurred more frequently in SSc patients with slow progressive skin stiffness proximal to MCP joints sparing the trunk and in those cases with extensive skin changes all over the body4Burgos-Vargas R Martínez-Cordero E Reyes PA Herrera-Esparza R Antibody pattern and other criteria for diagnosis and classification in PSS.J Rheumatol. 1988; 15: 153-154Google Scholar, 12Martínez-Cordero E Burgos-Vargas R Herrera Esparza R Reyes PA Antinuclear antibodies profile in progressive systemic sclerosis: A multicentric study.Rev Invest Clín (Méx). 1983; 35: 273-277Google Scholar also known as diffuse cutaneous SSc.3Giordano M Valentini G Migliaresi S Picillo U Vatti M Different antibody patterns and different prognoses in patients with scleroderma with various extent of skin sclerosis.J Rheumatol. 1986; 13: 911-916PubMed Google Scholar, 14Barnett AJ Miller MH Littlejohn GO A survival study of patients with scleroderma diagnosed over 30 years (1953-1983): The value of a simple cutaneous classification in the early stages of the disease.J Rheumatol. 1988; 15: 276-283PubMed Google Scholar, 15LeRoy EC Black C Fleischmajer R Jablonska S Krieg T Medsger T Rowel N Wollhlin F Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis.J Rheumatol. 1988; 15: 202-205PubMed Google Scholar Such analysis, like other reports,1Fritzler NJ Kinsella TD Garbutt E The CREST syndrome: a distinct serologic entity with anticentromere antibodies.Am J Med. 1980; 99: 520-526Abstract Full Text PDF Scopus (304) Google Scholar, 2Cattogio LJ Skinner RP Maddison PJ Frequency and clinical significance of anticentromere and anti-Scl-70 antibodies in an English connective tissue disease population.Rheumatol Int. 1983; 3: 19-21Crossref Scopus (33) Google Scholar, 3Giordano M Valentini G Migliaresi S Picillo U Vatti M Different antibody patterns and different prognoses in patients with scleroderma with various extent of skin sclerosis.J Rheumatol. 1986; 13: 911-916PubMed Google Scholar, 4Burgos-Vargas R Martínez-Cordero E Reyes PA Herrera-Esparza R Antibody pattern and other criteria for diagnosis and classification in PSS.J Rheumatol. 1988; 15: 153-154Google Scholar have focused primarily on the extent of cutaneous abnormalities as the major criterion of the disease severity. However, the search for factors that may lead to recognition of the population at risk of developing visceral manifestations in SSc is relevant, and some authors have emphasized that chromosomal instability, nail fold capillaroscopy changes,15LeRoy EC Black C Fleischmajer R Jablonska S Krieg T Medsger T Rowel N Wollhlin F Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis.J Rheumatol. 1988; 15: 202-205PubMed Google Scholar, 16Martínez-Cordero E Reyes PA Vergara MD Morán-Ramón L Benavides de Larraza G Kofman de Alfaro S Katona G Progressive systemic sclerosis. Chromosome instability and its correlation with the presence of autoantibodies.Rev Invest Clin (Méx). 1985; 37: 329-335Google Scholar as well as serologic alterations including elevated levels of circulating immune complexes and rheumatoid factor are related to internal organ involvement.5Pisko E Gallup K Turner R Parker M Nomeir AM Box J Davis J Box PJ Rothberg H Cardiopulmonary manifestations of progressive systemic sclerosis: Association with circulating immune complexes and fluorescent antinuclear antibodies.Arthritis Rheum. 1979; 22: 518-523Crossref PubMed Scopus (22) Google Scholar, 10Seibold VR Medsger T Winkelstein A Kelly RH Rodnan GP Immune complexes in progressive systemic sclerosis (scleroderma).Arthritis Rheum. 1982; 25: 1167-1173Crossref PubMed Scopus (33) Google Scholar We report the association of anti-Scl-70 antibodies with restrictive lung disease, an organ involvement that may lower the survival rate and contribute to a poorer quality of life in SSc.3Giordano M Valentini G Migliaresi S Picillo U Vatti M Different antibody patterns and different prognoses in patients with scleroderma with various extent of skin sclerosis.J Rheumatol. 1986; 13: 911-916PubMed Google Scholar, 14Barnett AJ Miller MH Littlejohn GO A survival study of patients with scleroderma diagnosed over 30 years (1953-1983): The value of a simple cutaneous classification in the early stages of the disease.J Rheumatol. 1988; 15: 276-283PubMed Google Scholar, 15LeRoy EC Black C Fleischmajer R Jablonska S Krieg T Medsger T Rowel N Wollhlin F Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis.J Rheumatol. 1988; 15: 202-205PubMed Google Scholar Our findings showed a correlation between abnormal respiratory function and positive antinuclear antibodies similar to those reported previously.5Pisko E Gallup K Turner R Parker M Nomeir AM Box J Davis J Box PJ Rothberg H Cardiopulmonary manifestations of progressive systemic sclerosis: Association with circulating immune complexes and fluorescent antinuclear antibodies.Arthritis Rheum. 1979; 22: 518-523Crossref PubMed Scopus (22) Google Scholar, 6Cattogio LJ Bernstein RM Black CM Hughes GRV Maddison PJ Serological markers in progressive systemic sclerosis.Arthritis Rheum. 1980; 23: 617-625Crossref Scopus (424) Google Scholar, 7Steen VD Powell DL Medsger TA Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis.Arthritis Rheum. 1988; 31: 196-203Crossref PubMed Scopus (552) Google Scholar, 8Manoussakis MN Constantopoulos SH Gharavi AE Moutsopoulos HM Pulmonary involvement in systemic sclerosis. Association with anti-Scl-70 antibody and digital pitting.Chest. 1987; 92: 509-513Crossref PubMed Google Scholar Further, SSc patients who had positive antinucleolar anti-U3-RNP antibodies have also been related to more lung and heart involvement.11Reimer G Steen VD Penning CA Medsger TA Tan EM Correlates between autoantibodies to nucleolar antigens and clinical features in patients with systemic sclerosis (scleroderma).Arthritis Rheum. 1988; 31: 525-532Crossref PubMed Scopus (177) Google Scholar Like these authors, we were unable to support a direct role of the autoantibodies in pathogenesis of pulmonary disease. However, experimental studies in SSc avian models may give an insight about the value of antinuclear or antinucleolar antibodies in visceral damage. These studies have revealed that fluorescent antibodies' pattern changes from a cytoplasmic spider web or nucleolar staining to diffuse and finely-speckled, as well as to peripheral and homogeneous nuclear staining with sera from avians, in which the disease turns to chronic multiorgan involvement.17Haynes DC Gershwin ME Diversity of autoantibodies in avian scleroderma: An inherited fibrotic disease of white leghorn chickens.J Clin Invest. 1984; 73: 1557-1568Crossref PubMed Scopus (27) Google Scholar Autoantibodies production may also be increased by the high production of interleukin-2 that has been described in SSc patients with pulmonary fibrosis18Umehara H Kumagai S Ishida H Suginoshita T Maeda M Imura H Enhanced production of interleukin-2 in patients with progressive systemic sclerosis. Hyperactivity of CD4 positive T cells.Arthritis Rheum. 1988; 31: 401-407Crossref PubMed Scopus (50) Google Scholar or by spontaneous release of interleukin-1 since these alterations may enhance T helper cell function in antibody synthesis.19Alcocer-Varela J Martínez-Cordero E Alarcón-Segovia D Spontaneous production of, and response to, interleukin-1 by peripheral blood mononuclear cells from patients with scleroderma.Clin Exp Immunol. 1985; 59: 666-672PubMed Google Scholar This report emphasizes that antinuclear anti-Scl-70 antibodies may distinguish not only the diffuse cutaneous subset of SSc, but also patients at risk of developing severe lung disease.
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