Zusammenfassung
Die systemische Sklerodermie ist eine generalisierte Erkrankung des kollagenen Bindegewebes unbekannter Ätiologie. Sie ist durch eine Dysregulation von Immunsystem sowie Endothelzellen charakterisiert, die schließlich zu Hautsklerose (akral limitiert oder diffus) mit unterschiedlicher Organbeteiligung führt. Die limitierte und diffuse systemische Sklerodermie unterscheiden sich signifikant in Verlauf und Prognose. Antinukleäre Antikörper gegen Topoisomerase (Scl-70), zentromere Proteine und nukleoläre Antigene sind für die Diagnostik, das Risiko für assoziierte Organmanifestationen und die Prognose wichtig (prognostische Autoantikörper). Für die meisten dieser Antikörper ist eine pathogenetische Bedeutung jedoch nicht gesichert. So sind anti-zentromere Antikörper typischerweise mit der limitierten (Akrosklerose-) Form der systemischen Sklerodermie und der Entwicklung einer pulmonalen arteriellen Hypertonie (PAH) assoziiert, während anti-Topoisomerase I Antikörper mit diffuser Sklerodermie und häufig schwerer Lungenfibrose assoziiert sind. Anti-Th/To Antikörper sind mit limitierter Hautsklerose aber dem Risiko schwerer Organbeteiligung (Niere, PAH, Lungenfibrose) und anti-RNA polymerase I/III Antikörper mit häufiger Nierenbeteiligung assoziiert. Anti-Fibrillarin (anti-U3-RNP) Antikörper wiederum sind ein Risiko für Lungenfibrose, aber auch PAH. Autoantikörper gegen den PDGF Rezeptor und Fibrillin-1 spielen vermutlich eine wichtige Rolle in der Pathogenese der systemischen Sklerodermie.
Summary
Systemic sclerosis is a generalized autoimmune connective tissue disease of unknown aetiology. Profound vascular and immunological dysregulations result in tissue fibrosis affecting the skin and internal organs. Currently, two main clinical subtypes are distinguished, i.e. limited and diffuse cutaneous systemic sclerosis, which differ significantly in the clinical course and prognosis. Autoantibodies against topoisomerase (Scl-70), centromere-associated proteins, and nucleolar antigens are important for the diagnosis of the disease and give clues for its clinical manifestations and prognosis (prognostic autoantibodies). For most of these antibodies, however, the role in pathogenesis is not established. Anti-centromere antibodies are associated with limited cutaneous involvement and risk for pulmonary hypertension, whereas anti-topoisomerase I is associated with diffuse progressive disease and severe interstitial lung disease. Anti-Th/To positivity is associated with limited skin involvement but a high risk for severe internal organ involvement (Kidneys, PAH, Lung fibrosis). Anti-RNA polymerase I/III antibodies are associated with a high risk for renal involvement. Autoantibodies against the PDGF receptor and fibrillin-1 seem to play important roles in the pathogenetic process of systemic sclerosis.
References
Röcken M, Biedermann T (2001) Pathogenesis of autoimmune disease. In: Hertl M (ed) Autoimmune diseases of the skin. Pathogenesis, Diagnosis, Management. Springer Wien, New York, pp 1–20
Kromminga A (2000) The pathogenetic role of autoantibodies in the genesis of autoimmune diseases. In: Conrad K, Humbel RL, Meurer M, Shoenfeld Y, Tan EM (eds) Autoantigens and Autoantibodies: diagnostic tools and clues to understanding autoimmunity. Pabst Science Publishers, pp 260–274
LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, Rowell N, Wollheim F (1988) Scleroderma (systemic sclerosis): classification, subsets, and pathogenesis. J Rheumatol 15: 202–205
Barnett AJ, Miller M, Littlejohn GO (1988) The diagnosis and classification of scleroderma (systemic sclerosis). Postgrad Med J 64: 121–125
Medsger TA (2004) Classification, Prognosis. In: Clements PJ, Furst DE (eds) Systemic Sclerosis. Lippincott Williams & Wilkins, pp 17–28
Wolheim FA (2005) Classification of systemic sclerosis. Visions and reality. Rheumatology 44: 1212–1216
Clements PJ, Furst DE (eds) (2004) Systemic Sclerosis. Lippincott Williams & Wilkins
Mayes MD, Reveille JD (2004) Epidemiology, demographics, and genetics. In: Clements PJ, Furst DE (eds) Systemic Sclerosis. Lippincott Williams & Wilkins, pp 1–15
Jimenez SA, Derk CT (2004) Following the molecular pathways toward understanding of the pathogenesis of systemic sclerosis. Ann Int Med 140: 37–50
Varga J (2002) Scleroderma and Smads. Arthritis Rheum 46: 1703–1713
Abraham DJ, Varga J (2005) Scleroderma:from cell and molecular mechanisms to disease models. Trends Immunol 26: 587–595
Steen VD (2003) Scleroderma renal crisis. Rheum Dis Clin North Am 29(2): 315–333
Allanore Y, Avouac J, Wipff J, Kahan A (2007) New therapeutic strategies in the management of systemic sclerosis. Expert Opin Pharmacother 8(5): 607–615
Denton CP, Black CM (2005) Targeted therapy comes of age in scleroderma. Trends Immunol 26: 596–602
Connolly MK (2001) Scleroderma. Dermatol Therapy 14: 81–94
Walker UA, Tyndall A, Czirják L, Denton CP, Farge-Bancel D, Kowal-Bielecka O, Müller-Ladner U, Bocelli-Tyndall C, Matucci-Cerinic M, EUSTAR Co-authors (2007) Clinical assessment of organ manifestations in systemic sclerosis – a report from the EULAR Scleroderma Trials And Research (EUSTAR) group data base. Ann Rheum Dis 66(6): 754–763
Steen VD (2005) Autoantibodies in systemic sclerosis. Sem Arthritis Rheum 35: 35–42
Conrad K, Schößler W, Hiepe F (2006) Autoantikörper bei systemischen Autoimmunerkrankungen. Ein diagnostischer Leitfaden. Pabst Science Publishers, Lengerich
Reveille JD, Solomon DH (2003) American College of Rheumatology, ad hoc Committee on Immunologic Testing Guidelines.: Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and antinucleolar antibodies. Arthritis Rheum 49: 399–412
Humbel RL (2000) New developments in autoantibody detection. In: Conrad K, Humbel RL, Meurer M, Shoenfeld Y, Tan EM (eds) Autoantigens and Autoantibodies: diagnostic tools and clues to understanding autoimmunity. Pabst Science Publishers, pp 652–668
Tan EM, Rodnan GP, Garcia I, Moroi Y, Fritzler MJ, Peebles C (1980) Diversity of antinuclear antibodies in progressive systemic sclerosis: anti-centromere antibody and its relationship to CREST syndrome. Arthritis Rheum 23: 617–625
Earnshaw WC, Machlin PS, Bordwell BJ, Rothfield NF, Ceveland DW (1987) Analysis of anticentromere autoantibodies using cloned autoantigen CENP-B. Proc Natl Acad Sci USA 84: 4979–4983
Douvas A (1996) Pathogenesis: Serologic correlates. In: Clements PJ, Furst DE (eds) Systemic Sclerosis. Lippincott Williams & Wilkins, pp 175–202
Rothfield N, Whitaker D, Bordwell B, Weiner E, Senecal JL, Earnshaw W (1987) Detection of anticentromere antibodies using the cloned autoantigen CENP-B. Arthritis Rheum 30: 1416–1419
Tan EM, Smolen JS, McDougal JS et al (1999) A critical evaluation of enzyme immuno-assays for detection of antinuclear autoantibodies of defined specificities. I. Precision, sensitivity, and specificity. Arthritis Rheum 42: 455–464
Makinen D, Fritzler MJ, Davis P, Sherlock S (1983) Anticentromere antibodies in primary biliary cirrhosis. Arthritis Rheum 26: 914–917
Lee S-L, Tsay GJ Tsai R-T (1993) Anticentromere antibodies in subjects with no apparent connective tissue disease. Ann Rheum Dis 52: 586–589
Hesselstrand R, Scheja A, Shen GQ, Wiik A, Akesson A (2003) The association of antinuclear antibodies with organ involvement and survival in systemic sclerosis. Rheumatology 42: 534–540
Duncan SC, Winkelmann RK (1979) Cancer and scleroderma. Arch Dermatol 115: 950–955
Roumm AD, Medsger TA (1985) Cancer and systemic sclerosis: an epidemiologic study. Arthritis Rheum 28: 1336–1340
Rosenthal AK, McLaughlin JK, Gridely G, Nyren O (1995) Incidence of cancer among patients with systemic sclerosis. Cancer 76: 910–914
Higuchi M, Horiuchi T, Ishibashi N et al (2000) Anticentromere antibody as a risk factor for cancer in patients with systemic sclerosis. Clin Rheumatol 19: 123–126
Derk CT, Sakkas LI, Rasheed M, Artlett C, Jimenez SA (2003) Autoantibodies in patients with systemic sclerosis and cancer: a case-control study. J Rheumatol 30: 1994–1996
Reveille JD, Fischbach M, McNearney T, Friedman AW, Agvilar MB, Lisse J, Fritzler MJ, Ahn C, Arnett FC; GENISOS study group (2001) Systemic sclerosis in 3 US ethnic groups: a comparison of clinical, sociodemographic, serologic, and immunogenetic determinants. Semin Arthritis Rheum 30: 332–346
Sato H, Lagan AL, Alexopoulou C, Vassilakis DA, Ahmad T, Pantelidis P, Veeraraghavan S (2004) The TNF-863A allele strongly associates with anticentromere autoantibody positivity in scleroderma. Arthritis Rheum 50: 558–564
Douvas AS, Achten M, Tan EM (1979) Identification of a nuclear protein (Scl-70) as a unique target of human antinuclear antibodies in scleroderma. J Biol Chem 254: 10514–10522
Shero JH, Bordwell B, Earnshaw WC (1986) High titers of autoantibodies to topoisomerase I (Scl-70) in sera from scleroderma patients. Science 14: 737–740
Kuwana M, Kaburaki J, Okano Y, Tojo T, Medsger TA Jr (1994) Clinical and prognostic associations based on serum antinuclear antibodies in Japanese patients with systemic sclerosis. Arthritis Rheum 37: 75–83
Dick T, Mierau R, Bartz-Bazzanella P, Alavi M, Stoyanova-Scholz M, Kindler J, Genth E (2002) Coexistence of antitopoisomerase I and anticentromere antibodies in patients with systemic sclerosis. Ann Rheum Dis 61: 121–127
RuffattiA, Calligaro A, Ferri C, Bombardieri S, Gambari PF, Todesco S (1988) Association of anticentromere and anti-Scl-70 antibodies in scleroderma: report of two cases. J Clin Lab Immunol 16: 227–229
Gussin HA, Ignat P, Varga J, Teodorescu M (2001) Anti-topoisomerase I (anti-Scl-70) antibodies in patients with systemic lupus erythematosus. Arthritis Rheum 44: 376–383
Cepeda EJ, Reveille JD (2004) Autoantibodies in systemic sclerosis and fibrosing syndromes: clinical indications and relevance. Curr Opin Rheumatol 16: 723–732
Clements PJ, Medsger TA Jr, Feghali CA (2004) Cutaneous involvement in systemic sclerosis. In Clements PJ, Furst DE (eds) Systemic Sclerosis. Lippincott Williams & Wilkins, pp 129–150
Ho KT, Reveille JD (2003) The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 5: 80–93
Henault J, Robitaille G, Senecal JL, Raymond Y (2006) DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of antitopoisomerase I autoantibodies from systemic sclerosis patients. Arthritis Rheum 54: 963–973
Henault J, Tremblay M, Clement I, Raymond Y, Senecal JL (2004) Direct binding of anti-DNA topoisomerase I autoantibodies to the cell surface of fibroblasts in patients with systemic sclerosis. Arthritis Rheum 50: 3265–3274
Jacobsen S, Ullman S, Shen GQ, Wiik A, Halberg P (2001) Influence of clinical features, serum antinuclear antibodies, and lung function on survival of patients with systemic sclerosis. J Rheumatol 28: 2454–2459
Peters-Golden M, Wise RA, Hochberg M, Stevens MB, Wigley FM (1985) Incidence of lung cancer in systemic sclerosis. J Rheumatol 12: 1136–1139
Weiner ES, Earnshaw WC, Senecal JL, Bordwell B, Johnson P, Rothfield NF (1988) Clinical associations of anticentromere antibodies and antibodies to topoisomerase I: a study of 355 patients. Arthritis Rheum 31: 378–385
Rothfield N, Kurtzman S, Vasques-Abad D, Charron C, Daniels L, Greenberg B (1992) Association of anti-topoisomerase I with cancer. Arthr Rheum 35: 724
Hu PQ, Fertig N, Medsger TA Jr, Wright TM (2003) Correlation of serum anti-DNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis. Arthritis Rheum 48: 1363–1373
Ritchie RF (1970) Antinucleolar antibodies: their frequency and diagnostic association. N Engl J Med 282: 1174–1178
Lischwe MA, Ochs RL, Reddy R, Cook RG, Yeoman LC, Tan EM, Reichlin M, Busch H (1985) Purification and partial characterization of a nucleolar scleroderma antigen (Mr = 34,000; pI = 8.5) rich in Ng,Ng-dimethylarginine. J Biol Chem 260: 14304–14310
Harvey G, Black C, Maddison P, McHugh N (1997) Characterization of antinucleolar antibody reactivity in patients with systemic sclerosis and their relatives. J Rheumatol 24: 477–484
Reichlin M, Maddison PJ, Targoff IN, Bunch T, Arnett F, Sharp G, Treadwell E, Tan EM (1984) Antibodies to a nuclear/nucleolar antigen in patients with polymyositis overlap syndromes. J Clin Immunol 4: 40–44
Satoh M, Kuwana M, Ogasawara T, Ajmani AK, Langdon JJ, Kimpel D, Wang J, Reeves WH (1994) Association of autoantibodies to topoisomerase I and the phosphorylated (IIO) form of RNA polymerase II in Japanese scleroderma patients. J Immunol 153: 5838–5848
Solomon DH, Kavanaugh AJ, Schur PH (2002) The American College of Rheumatology Ad Hoc Committee on Immunologic Testing Guidelines. Evidence-based guidelines for the use of immunologic tests: antinuclear antibody testing. Arthritis Rheum 47: 434–444
Reimer G, Steen VD, Penning CA, Medsger TA Jr, Tan EM (1988) Correlates between autoantibodies to nucleolar antigens and clinical features in patients with systemic sclerosis (scleroderma). Arthritis Rheum 31: 525–532
Van Eenenaam H, Vogelzangs JHP, Lugtenberg D, Van Den Hoogen FH, Van Venrooij WJ, Pruijn GJ (2002) Identity of the RNase MRP and RNase P-associated Th/To autoantigen. Arthritis Rheum 46: 3266–3272
Van Eenennaam H, Vogelzangs JH, Bisschops H, Te Boome LC, Seelig HP et al (2002) Autoantibodies against small nucleolar ribonucleoprotein complexes and their clinical associations. Clin Exp Immunol 130: 532–540
Gündüz OH, Fertig N, Lucas M, Medsger TA Jr (2001) Systemic sclerosis with renal crisis and pulmonary hypertension: report of eleven cases. Arthritis Rheum 44: 1663–1666
Yamane K, Ihn H, Kubo M, Kuwana M, Asano Y, Yazawa N, Tamaki K (2001) Antibodies to Th/To ribonucleoprotein in patients with localized scleroderma. Rheumatology (Oxford) 40: 683–686
Raijmakers R, Renz M, Wiemann C, Egberts WV, Seelig HP, van Venrooij WH, Pruijn GJ (2004) PM-Scl-75 is the main autoantigen in patients with the polymyositis/scleroderma overlap syndrome. Arthritis Rheum 50: 565–569
Arnett FC, Reveille JD, Goldstein R, Pollard KM, Leaird K, Smith EA, LeRoy EC, Fritzler MJ (1996) Autoantibodies to fibrillarin in systemic sclerosis (scleroderma): an immunogenetic, serologic, and clinical analysis. Arthritis Rheum 39: 1151–1156
Ulanet DB, Wigley FM, Gelber AC, Rosen A (2003) Autoantibodies against B23, a nucleolar phosphoprotein, occur in scleroderma and are associated with pulmonary hypertension. Arthritis Rheum 49: 85–92
Harris ML, Rosen A (2003) Autoimmunity in scleroderma: the origin, pathogenetic role, and clinical significance of autoantibodies. Curr Opin Rheumatol 15: 778–784
Black C, Isenberg DA (1992) Mixed connective tissue disease – goodbye to all that. Br J Rheumatol 31: 695–700
Sharp GC, Irvin WS, May CM (1976) Association of antibodies to ribonucleoprotein and Sm antigens with mixed connective-tissue disease, systemic lupus erythematosus and other rheumatic diseases. N Engl J Med 295: 1149–1154
Jablonska S, Blaszczyk M (1999) Scleroderma overlap syndromes. Adv Exp Med Biol 455: 85–92
Asano Y, Ihn H, Yamane K, Kubo M, Tamaki K (2003) The prevalence and clinical significance of anti-U1 RNA antibodies in patients with systemic sclerosis. J Invest Dermatol 120: 204–210
Picillo U, Migliaresi S, Marcialis MR, Ferruzzi AM, Tirri G (1995) Clinical significance of anticardiolipin antibodies in patients with systemic sclerosis. Autoimmunity 20: 1–7
Black CM, Stevens WM (1989) Pregnancy in patients with rheumatic diseases: scleroderma. Rheum Dis Clin North Am 15: 193–212
Antonioli CM, Danieli E, Airo P, Cattaneo R, Tincani A (2003) More on cardiolipin and anti-beta2 glycoprotein I in systemic sclerosis. Ann Rheum Dis 62: 589–590
Malia RG, Greaves M, Rowlands LM, Lawrence AC, Hume A, Rowell NR, Moult J, Holt CM, Lindsey N, Hughes P (1988) Anticardiolipin antibodies in systemic sclerosis: immunological and clinical associations. Clin Exp Immunol 73: 456–460
Katayama I, Otoyama K, Kondo S, Nishioka K, Nishiyama S (1990) Clinical manifestations in anticardiolipin antibody-positive patients with progressive systemic sclerosis. J Am Acad Dermatol 23: 198–201
Sato S, Fujimoto M, Hasegawa M, Takehara K (2003) Antiphospholipid antibody in localized scleroderma. Ann Rheum Dis 62: 771–774
Goldblatt F, Gordon TP, Waterman SA (2002) Antibody-mediated gastrointestinal dysmotility in scleroderma. Gastroenterology 123: 1144–1150
Salojin KV, LeTonqueze M, Saraux A, Nassonor EL, Dueymes M, Piette JC, Youinov PY (1997) Antiendothelial cell antibodies: useful markers of systemic sclerosis. Am J Med 102: 178–185
Negi VS, Tripathy NK, Misra R, Nityanand S (1998) Antiendothelial cell antibodies in scleroderma correlate with severe digital ischemia and pulmonary arterial hypertension. J Rheumatol 25: 462–466
Wusirika R, Ferri C, Marin M, Knight DA, Waldman WH, Ross P Jr, Magro CM (2003) The assessment of antiendothelial cell antibodies in scleroderma-associated pulmonary fibrosis: a study of indirect immunofluorescent and western blot analysis in 49 patients with scleroderma. Am J Clin Pathol 120: 596–606
Ahmed SS, Tan FK, Arnett FC, Jin L, Geng YJ (2006) Induction of apoptosis and fibrillin-1 expression in human dermal endothelial cells by scleroderma sera containing anti-endothelial cell antibodies. Arthr Rheum 54: 2250–2262
Arnett FC (2006) Is scleroderma an autoantibody mediated disease? Curr Opin Rheumatol 18: 579–581
Brenntnall TJ, Kenneally D, Barnett AJ, De Aizpurua HJ, Lolait SJ, Ashcroft R, Toh BH (1982) Autoantibodies to fibroblasts in scleroderma. J Clin Lab Immunol 8: 9–12
Cavazzana I, Tincani A, Riboldi P, Meroni PL (2006) Autoantibodies and skin involvement in systemic autoimmune diseases. In Asherson RA (series-ed) Handbook of systemic autoimmune diseases. Volume 5: Sarzi-Puttini, Doria A, Girolomoni G, Kuhn A (eds) The skin in systemic autoimmune diseases. Elsevier BV, Amsterdam, pp 29–36
Chizzolini C, Raschi E, Rezzonico R, Testoni C, Mallone R, Gabrielli A, Facchini A, Del Papa N, Borghi MO, Dayer JM, Meroni PL (2002) Autoantibodies to fibroblasts induce a proadhesive and proinflammatory fibroblast phenotype in patients with systemic sclerosis. Arthritis Rheum 46: 1602–1613
Ronda N, Gatti R, Giacosa R, Raschi E, Testoni C, Meroni PL, Buzio C, Orlandini G (2002) Antifibroblast antibodies from systemic sclerosis patients are internalized by fibroblasts via a caveolin-linked pathway. Arthritis Rheum 46: 1595–1601
Sato S, Hayakawa I, Hasegawa M, Fujimoto M, Takehara K (2003) Function blocking autoantibodies against matrix metalloproteinase-1 in patients with systemic sclerosis. J Invest Dermatol 120: 542–547
Nishijima C, Hayakawa I, Matsushita T, Komura K, Hasegawa M, Takehara K, Sato S (2004) Autoantibody against metalloproteinase-3 in patients with systemic sclerosis. Clin Exp Immunol 138: 357–363
Lemaire R, Bayle J, Lafyatis R (2006) Fibrillin in Marfan syndrome and tight skin mice provides new insights into transforming growth factor-beta regulation and systemic sclerosis. Curr Opin Rheumatol 18: 582–587
Tan FK, Arnett FC, Antohi S, Saito S, Mirarchi A, et al (1999) Autoantibodies to the extracellular matrix microfibrillar protein, fibrillin-1, in patients with scleroderma and other connective tissue diseases. J Immunol 163: 1066–1072
Lundberg I, Antohi S, Takeuki K, Arnett F, Steiner G, Brumeanu TD, Klareskog L, Bona C (2000) Kinetics of anti-fibrillin-1 autoantibodies in MCTD and CREST syndrome. J Autoimmun 14: 267–274
Tan FK, Arnett FC, Reveille JD, Ahn C, Antohi S, Sasaki T, Nishioka K, Bona CA (2000) Autoantibodies to fibrillin 1 in systemic sclerosis: ethnic differences in antigen recognition and lack of correlation with specific clinical features or HLA alleles. Arthr Rheum 43: 2464–2471
Svegliati Baroni S, Santillo M, Bevilacqua F, Luchetti M, Spadoni T, Mancini M, Fraticelli P, Sambo P, Funaro A, Kazlauskas A, Avvedimento EV, Gabrielli A (2006) Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 354: 2667–2676
Svegliati S, Cancello R, Sambo P, Luchetti M, Paroncini P, Orlandini G, Discepoli G, Paterno R, Santillo M, Cuozzo C, Cassano S, Avvedimento EV, Gabrielli A (2005) Platelet-derived growth factor and reactive oxygen species (ROS) regulate Ras protein levels in primary human fibroblasts via ERK1/2: amplification of ROS and Ras in systemic sclerosis. J Biol Chem 280: 36474–36482
Tan FK (2006) Autoantibodies against PDGF receptor in scleroderma. N Engl J Med 354: 2709–2711
Hayakawa I, Hasegawa M, Takehara K, Sato S (2004) Anti-DNA topoisomerase II alpha autoantibodies in localized scleroderma. Arthritis Rheum 50: 227–232
Nagai M, Hasegawa M, Takehara, Sato S (2004) Novel autoantibody to Cu/Zn superoxide dismutase in patients with localized scleroderma. J Invest Dermatol 122: 594–601
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Grassegger, A., Pohla-Gubo, G., Frauscher, M. et al. Autoantibodies in systemic sclerosis (scleroderma): clues for clinical evaluation, prognosis and pathogenesis. Wien Med Wochenschr 158, 19–28 (2008). https://doi.org/10.1007/s10354-007-0451-5
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DOI: https://doi.org/10.1007/s10354-007-0451-5