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Antinuclear Antibodies in Systemic Sclerosis: an Update

  • Anna Stochmal
  • Joanna Czuwara
  • Maria Trojanowska
  • Lidia RudnickaEmail author
Article

Abstract

Systemic sclerosis is an autoimmune disease characterized by fibrosis of skin and internal organs, vasculopathy, and dysregulation of immune system. A diagnostically important feature of immunological abnormalities in systemic sclerosis is the presence of circulating antinuclear antibodies, which may be detected in 90–95% of patients with either of the four main laboratory methods: immunofluorescence, enzyme-linked immunosorbent assay, immunodiffusion, and immunoblotting. There are several antinuclear antibodies specific for systemic sclerosis. These include antibodies against topoisomerase (anti-TOPO I), kinetochore proteins (ACA), RNA polymerase enzyme (anti-RNAP III), ribonuclear proteins (anti-U11/U12 RNP, anti-U1 RNP, anti-U3 RNP) and nucleolar antigens (anti-Th/To, anti-NOR 90, anti-Ku, antiRuvBL1/2, and anti-PM/Scl). Autoantibodies specific for systemic sclerosis have been linked to distinct clinical features. Therefore, detecting a particular antibody type is important in predicting a possible organ involvement and prognosis and may have an impact on monitoring and treatment.

Keywords

Antinuclear antibodies Connective tissue diseases Diagnosis Immunology Malignancy Prognosis Scleroderma Systemic sclerosis 

Notes

Acknowledgements

The authors thank Mr. Michał Zaremba for taking photographs of the immunofluorescence patterns.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Denton CP, Khanna D (2017) Systemic sclerosis. Lancet 390(10103):1685–1699.  https://doi.org/10.1016/S0140-6736(17)30933-9 CrossRefPubMedGoogle Scholar
  2. 2.
    Steen VD (2005) Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 35(1):35–42.  https://doi.org/10.1016/j.semarthrit.2005.03.005 CrossRefPubMedGoogle Scholar
  3. 3.
    Mierau R, Moinzadeh P, Riemekasten G, Melchers I, Meurer M, Reichenberger F, Buslau M, Worm M, Blank N, Hein R, Muller-Ladner U, Kuhn A, Sunderkotter C, Juche A, Pfeiffer C, Fiehn C, Sticherling M, Lehmann P, Stadler R, Schulze-Lohoff E, Seitz C, Foeldvari I, Krieg T, Genth E, Hunzelmann N (2011) Frequency of disease-associated and other nuclear autoantibodies in patients of the German Network for Systemic Scleroderma: correlation with characteristic clinical features. Arthritis Res Ther 13(5):R172.  https://doi.org/10.1186/ar3495 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Mehra S, Walker J, Patterson K, Fritzler MJ (2013) Autoantibodies in systemic sclerosis. Autoimmun Rev 12(3):340–354.  https://doi.org/10.1016/j.autrev.2012.05.011 CrossRefPubMedGoogle Scholar
  5. 5.
    van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger TA Jr, Carreira PE, Riemekasten G, Clements PJ, Denton CP, Distler O, Allanore Y, Furst DE, Gabrielli A, Mayes MD, van Laar JM, Seibold JR, Czirjak L, Steen VD, Inanc M, Kowal-Bielecka O, Muller-Ladner U, Valentini G, Veale DJ, Vonk MC, Walker UA, Chung L, Collier DH, Csuka ME, Fessler BJ, Guiducci S, Herrick A, Hsu VM, Jimenez S, Kahaleh B, Merkel PA, Sierakowski S, Silver RM, Simms RW, Varga J, Pope JE (2013) 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis Rheum 65(11):2737–2747.  https://doi.org/10.1002/art.38098 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Jordan S, Maurer B, Toniolo M, Michel B, Distler O (2015) Performance of the new ACR/EULAR classification criteria for systemic sclerosis in clinical practice. Rheumatology 54(8):1454–1458.  https://doi.org/10.1093/rheumatology/keu530 CrossRefPubMedGoogle Scholar
  7. 7.
    Knobler R, Moinzadeh P, Hunzelmann N, Kreuter A, Cozzio A, Mouthon L, Cutolo M, Rongioletti F, Denton CP, Rudnicka L, Frasin LA, Smith V, Gabrielli A, Aberer E, Bagot M, Bali G, Bouaziz J, Braae Olesen A, Foeldvari I, Frances C, Jalili A, Just U, Kahari V, Karpati S, Kofoed K, Krasowska D, Olszewska M, Orteu C, Panelius J, Parodi A, Petit A, Quaglino P, Ranki A, Sanchez Schmidt JM, Seneschal J, Skrok A, Sticherling M, Sunderkotter C, Taieb A, Tanew A, Wolf P, Worm M, Wutte NJ, Krieg T (2017) European Dermatology Forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin. Part 1: localized scleroderma, systemic sclerosis and overlap syndromes. J Eur Acad Dermatol Venereol 31(9):1401–1424.  https://doi.org/10.1111/jdv.14458 CrossRefPubMedGoogle Scholar
  8. 8.
    Krasowska D, Rudnicka L, Dańczak-Pazdrowska A, Chodorowska G, Woźniacka A, Lis-Święty A, Czuwara J, Maj J, Majewski S, Sysa-Jędrzejowska A, Wojas-Pelc A (2017) Systemic sclerosis—diagnostic and therapeutic recommendations of the Polish Dermatological Society. Part 1: diagnosis and monitoring. Dermatol Rev 104(5):483–498.  https://doi.org/10.5114/dr.2017.71214 CrossRefGoogle Scholar
  9. 9.
    Kranenburg P, van den Hombergh WM, Knaapen-Hans HK, van den Hoogen FH, Fransen J, Vonk MC (2016) Survival and organ involvement in patients with limited cutaneous systemic sclerosis and anti-topoisomerase-I antibodies: determined by skin subtype or auto-antibody subtype? A long-term follow-up study. Rheumatology (Oxford) 55(11):2001–2008.  https://doi.org/10.1093/rheumatology/kew298 CrossRefGoogle Scholar
  10. 10.
    Moinzadeh P, Nihtyanova SI, Howell K, Ong VH, Denton CP (2012) Impact of hallmark autoantibody reactivity on early diagnosis in scleroderma. Clin Rev Allergy Immunol 43(3):249–255.  https://doi.org/10.1007/s12016-012-8331-1 CrossRefPubMedGoogle Scholar
  11. 11.
    Srivastava N, Hudson M, Tatibouet S, Wang M, Baron M, Fritzler MJ, (CSRG) CSRG (2015) Thinking outside the box—the associations with cutaneous involvement and autoantibody status in systemic sclerosis are not always what we expect. Semin Arthritis Rheum 45(2):184–189.  https://doi.org/10.1016/j.semarthrit.2015.04.009 CrossRefPubMedGoogle Scholar
  12. 12.
    Claessens J, Belmondo T, De Langhe E, Westhovens R, Poesen K, Hue S, Blockmans D, Mahler M, Fritzler MJ, Bossuyt X (2018) Solid phase assays versus automated indirect immunofluorescence for detection of antinuclear antibodies. Autoimmun Rev 17:533–540.  https://doi.org/10.1016/j.autrev.2018.03.002 CrossRefPubMedGoogle Scholar
  13. 13.
    Agmon-Levin N, Damoiseaux J, Kallenberg C, Sack U, Witte T, Herold M, Bossuyt X, Musset L, Cervera R, Plaza-Lopez A, Dias C, Sousa MJ, Radice A, Eriksson C, Hultgren O, Viander M, Khamashta M, Regenass S, Andrade LE, Wiik A, Tincani A, Ronnelid J, Bloch DB, Fritzler MJ, Chan EK, Garcia-De La Torre I, Konstantinov KN, Lahita R, Wilson M, Vainio O, Fabien N, Sinico RA, Meroni P, Shoenfeld Y (2014) International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann Rheum Dis 73(1):17–23.  https://doi.org/10.1136/annrheumdis-2013-203863 CrossRefPubMedGoogle Scholar
  14. 14.
    Meroni PL, Schur PH (2010) ANA screening: an old test with new recommendations. Ann Rheum Dis 69(8):1420–1422.  https://doi.org/10.1136/ard.2009.127100 CrossRefPubMedGoogle Scholar
  15. 15.
    Agmon-Levin N, Damoiseaux J, Shoenfeld Y (2014) Response to: ‘detection of antinuclear antibodies: added-value of solid phase assay?’ by Bossuyt and Fieuws. Ann Rheum Dis 73(3):e11.  https://doi.org/10.1136/annrheumdis-2013-204797 CrossRefPubMedGoogle Scholar
  16. 16.
    Hamaguchi Y (2010) Autoantibody profiles in systemic sclerosis: predictive value for clinical evaluation and prognosis. J Dermatol 37(1):42–53.  https://doi.org/10.1111/j.1346-8138.2009.00762.x CrossRefPubMedGoogle Scholar
  17. 17.
    Mariz HA, Sato EI, Barbosa SH, Rodrigues SH, Dellavance A, Andrade LE (2011) Pattern on the antinuclear antibody-HEp-2 test is a critical parameter for discriminating antinuclear antibody-positive healthy individuals and patients with autoimmune rheumatic diseases. Arthritis Rheum 63(1):191–200.  https://doi.org/10.1002/art.30084 CrossRefPubMedGoogle Scholar
  18. 18.
    Stearns NA, Zhou S, Petri M, Binder SR, Pisetsky DS (2016) The use of poly-L-lysine as a capture agent to enhance the detection of antinuclear antibodies by ELISA. PLoS One 11(9):e0161818.  https://doi.org/10.1371/journal.pone.0161818 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Fritzler MJ (2012) Toward a new autoantibody diagnostic orthodoxy: understanding the bad, good and indifferent. Auto Immun Highlights 3(2):51–58.  https://doi.org/10.1007/s13317-012-0030-7 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Tan EM, Feltkamp TE, Smolen JS, Butcher B, Dawkins R, Fritzler MJ, Gordon T, Hardin JA, Kalden JR, Lahita RG, Maini RN, McDougal JS, Rothfield NF, Smeenk RJ, Takasaki Y, Wiik A, Wilson MR, Koziol JA (1997) Range of antinuclear antibodies in “healthy” individuals. Arthritis Rheum 40(9):1601–1611.  https://doi.org/10.1002/1529-0131(199709)40:9<1601::AID-ART9>3.0.CO;2-T CrossRefPubMedGoogle Scholar
  21. 21.
    Blaszczyk M, Beutner EH, Rogozinski T, Rzesa G, Jarzabek-Chorzelska M, Jablonska S, Chorzelski TP (1977) Substrate specificity of antinuclear antibodies in scleroderma. J Invest Dermatol 68(4):191–193CrossRefGoogle Scholar
  22. 22.
    Murdjeva MA, Ryasheva NP, Draganov MM, Paunov LD (2011) A comparative study of immunological methods for determination of serum antinuclear antibodies. Folia Med (Plovdiv) 53(4):21–27CrossRefGoogle Scholar
  23. 23.
    Fritzler MJ, Wiik A (2006) CHAPTER 72—autoantibody assays, testing, and standardization A2—Rose, Noel R. In: Mackay IR (ed) The autoimmune diseases, Fourth edn. Academic Press, St. Louis, pp 1011–1022.  https://doi.org/10.1016/B978-012595961-2/50075-5 CrossRefGoogle Scholar
  24. 24.
    de Almeida BF, Maria Eloi Santos S, Aparecida Ferreira G, Pedrosa W, Gradisse J, Cristina Costa L, Pretti Figueiredo Neves S (2016) Diagnostic evaluation of ELISA and chemiluminescent assays as alternative screening tests to indirect immunofluorescence for the detection of antibodies to cellular antigens. Am J Clin Pathol 145(3):323–331.  https://doi.org/10.1093/ajcp/aqv083 CrossRefGoogle Scholar
  25. 25.
    Op De Beeck K, Vermeersch P, Verschueren P, Westhovens R, Marien G, Blockmans D, Bossuyt X (2011) Detection of antinuclear antibodies by indirect immunofluorescence and by solid phase assay. Autoimmun Rev 10(12):801–808.  https://doi.org/10.1016/j.autrev.2011.06.005 CrossRefGoogle Scholar
  26. 26.
    Mahler M, You D, Baron M, Taillefer SS, Hudson M, Fritzler MJ (2011) Anti-centromere antibodies in a large cohort of systemic sclerosis patients: comparison between immunofluorescence, CENP-A and CENP-B ELISA. Clin Chim Acta 412(21):1937–1943.  https://doi.org/10.1016/j.cca.2011.06.041 CrossRefPubMedGoogle Scholar
  27. 27.
    Conrad K, Rober N, Andrade LE, Mahler M (2017) The clinical relevance of anti-DFS70 autoantibodies. Clin Rev Allergy Immunol 52(2):202–216.  https://doi.org/10.1007/s12016-016-8564-5 CrossRefPubMedGoogle Scholar
  28. 28.
    Hornbeck P (2001) Double-immunodiffusion assay for detecting specific antibodies. Curr Protoc Immunol Chapter 2:Unit 2.3. doi: https://doi.org/10.1002/0471142735.im0203s00
  29. 29.
    Peterson LK, Jaskowski TD, Mayes MD, Tebo AE (2016) Detection of anti-U3-RNP/fibrillarin IgG antibodies by line immunoblot assay has comparable clinical significance to immunoprecipitation testing in systemic sclerosis. Immunol Res 64(2):483–488.  https://doi.org/10.1007/s12026-015-8710-9 CrossRefPubMedGoogle Scholar
  30. 30.
    Aksu G, Gulez N, Azarsiz E, Karaca N, Kutukculer N (2010) Determination of cut-off titers and agreement between immunofluorescence and immunoblotting methods for detecting antinuclear antibodies in children. J Clin Lab Anal 24(4):230–236.  https://doi.org/10.1002/jcla.20391 CrossRefPubMedGoogle Scholar
  31. 31.
    Gonzalez C, Martin T, Arroyo T, Garcia-Isidoro M, Navajo JA, Gonzalez-Buitrago JM (1997) Comparison and variation of different methodologies for the detection of autoantibodies to nuclear antigens (ANA). J Clin Lab Anal 11(6):388–392CrossRefGoogle Scholar
  32. 32.
    Nihtyanova SI, Denton CP (2010) Autoantibodies as predictive tools in systemic sclerosis. Nat Rev Rheumatol 6(2):112–116.  https://doi.org/10.1038/nrrheum.2009.238 CrossRefPubMedGoogle Scholar
  33. 33.
    Kuwana M (2017) Circulating anti-nuclear antibodies in systemic sclerosis: utility in diagnosis and disease subsetting. J Nippon Med Sch 84(2):56–63.  https://doi.org/10.1272/jnms.84.56 CrossRefPubMedGoogle Scholar
  34. 34.
    Ma WT, Chang C, Gershwin ME, Lian ZX (2017) Development of autoantibodies precedes clinical manifestations of autoimmune diseases: a comprehensive review. J Autoimmun 83:95–112.  https://doi.org/10.1016/j.jaut.2017.07.003 CrossRefPubMedGoogle Scholar
  35. 35.
    Gunther J, Rademacher J, van Laar JM, Siegert E, Riemekasten G (2015) Functional autoantibodies in systemic sclerosis. Semin Immunopathol 37(5):529–542.  https://doi.org/10.1007/s00281-015-0513-5 CrossRefPubMedGoogle Scholar
  36. 36.
    Salazar GA, Assassi S, Wigley F, Hummers L, Varga J, Hinchcliff M, Khanna D, Schiopu E, Phillips K, Furst DE, Steen V, Baron M, Hudson M, Taillefer SS, Pope J, Jones N, Docherty P, Khalidi NA, Robinson D, Simms RW, Silver RM, Frech TM, Fessler BJ, Molitor JA, Fritzler MJ, Segal BM, Al-Kassab F, Perry M, Yang J, Zamanian S, Reveille JD, Arnett FC, Pedroza C, Mayes MD (2015) Antinuclear antibody-negative systemic sclerosis. Semin Arthritis Rheum 44(6):680–686.  https://doi.org/10.1016/j.semarthrit.2014.11.006 CrossRefPubMedGoogle Scholar
  37. 37.
    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(20):10514–10522PubMedGoogle Scholar
  38. 38.
    Poormoghim H, Moghadam AS, Moradi-Lakeh M, Jafarzadeh M, Asadifar B, Ghelman M, Andalib E (2013) Systemic sclerosis: demographic, clinical and serological features in 100 Iranian patients. Rheumatol Int 33(8):1943–1950.  https://doi.org/10.1007/s00296-013-2668-5 CrossRefPubMedGoogle Scholar
  39. 39.
    Reveille JD, Solomon DH (2003) Evidence-based guidelines for the use of immunologic tests: anticentromere, Scl-70, and nucleolar antibodies. Arthritis Rheum 49(3):399–412.  https://doi.org/10.1002/art.11113 CrossRefPubMedGoogle Scholar
  40. 40.
    Hamaguchi Y, Kodera M, Matsushita T, Hasegawa M, Inaba Y, Usuda T, Kuwana M, Takehara K, Fujimoto M (2015) Clinical and immunologic predictors of scleroderma renal crisis in Japanese systemic sclerosis patients with anti-RNA polymerase III autoantibodies. Arthritis Rheumatol 67(4):1045–1052.  https://doi.org/10.1002/art.38994 CrossRefPubMedGoogle Scholar
  41. 41.
    Cappelli S, Bellando Randone S, Camiciottoli G, De Paulis A, Guiducci S, Matucci-Cerinic M (2015) Interstitial lung disease in systemic sclerosis: where do we stand? Eur Respir Rev 24(137):411–419.  https://doi.org/10.1183/16000617.00002915 CrossRefPubMedGoogle Scholar
  42. 42.
    Hasegawa M (2016) Biomarker. In: Takehara K, Fujimoto M, Kuwana M (eds) Systemic sclerosis. Springer Japan, Tokyo, pp 211–229.  https://doi.org/10.1007/978-4-431-55708-1_13 CrossRefGoogle Scholar
  43. 43.
    Ho KT, Reveille JD (2003) The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther 5(2):80–93CrossRefGoogle Scholar
  44. 44.
    Radic M, Martinovic Kaliterna D, Ljutic D (2006) The level of anti-topoisomerase I antibodies highly correlates with metacarpophalangeal and proximal interphalangeal joints flexion contractures in patients with systemic sclerosis. Clin Exp Rheumatol 24(4):407–412PubMedGoogle Scholar
  45. 45.
    Bohelay G, Blaise S, Levy P, Claeys A, Baudot N, Cuny JF, Maillard H, Granel-Brocard F, Boye T, Lok C, Beneton N, Frances C, Senet P (2018) Lower-limb ulcers in systemic sclerosis: a multicentre retrospective case-control study. Acta Derm Venereol 98:677–682.  https://doi.org/10.2340/00015555-2939 CrossRefPubMedGoogle Scholar
  46. 46.
    Wirz EG, Jaeger VK, Allanore Y, Riemekasten G, Hachulla E, Distler O, Airo P, Carreira PE, Tikly M, Vettori S, Balbir Gurman A, Damjanov N, Muller-Ladner U, Distler J, Li M, Hausermann P, Walker UA (2016) Incidence and predictors of cutaneous manifestations during the early course of systemic sclerosis: a 10-year longitudinal study from the EUSTAR database. Ann Rheum Dis 75(7):1285–1292.  https://doi.org/10.1136/annrheumdis-2015-207271 CrossRefPubMedGoogle Scholar
  47. 47.
    Rudnicka L, Czuwara J, Barusinska A, Nowicka U, Makiela B, Jablonska S (1996) Implications for the use of topoisomerase I inhibitors in treatment of patients with systemic sclerosis. Ann N Y Acad Sci 803:318–320CrossRefGoogle Scholar
  48. 48.
    Saito A, Muro Y, Sugiura K, Akiyama M (2013) Low prevalence of autoantibodies to CENP-H, -I, -K, -L, -M, -N, -T and -U in a Japanese cohort of anti-centromere positive samples. Immunopharmacol Immunotoxicol 35(1):57–63.  https://doi.org/10.3109/08923973.2012.733707 CrossRefPubMedGoogle Scholar
  49. 49.
    Gelber AC, Pillemer SR, Baum BJ, Wigley FM, Hummers LK, Morris S, Rosen A, Casciola-Rosen L (2006) Distinct recognition of antibodies to centromere proteins in primary Sjogren’s syndrome compared with limited scleroderma. Ann Rheum Dis 65(8):1028–1032.  https://doi.org/10.1136/ard.2005.046003 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Lleo A, Marzorati S, Anaya JM, Gershwin ME (2017) Primary biliary cholangitis: a comprehensive overview. Hepatol Int 11(6):485–499.  https://doi.org/10.1007/s12072-017-9830-1 CrossRefPubMedGoogle Scholar
  51. 51.
    Walker UA, Tyndall A, Czirjak L, Denton C, Farge-Bancel D, Kowal-Bielecka O, Muller-Ladner U, Bocelli-Tyndall C, Matucci-Cerinic M (2007) Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials and Research Group Database. Ann Rheum Dis 66(6):754–763.  https://doi.org/10.1136/ard.2006.062901 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Heijnen IA, Foocharoen C, Bannert B, Carreira PE, Caporali R, Smith V, Kumanovics G, Becker MO, Vanthuyne M, Simsek I, Bocelli-Tyndall C, Walker UA (2013) Clinical significance of coexisting antitopoisomerase I and anticentromere antibodies in patients with systemic sclerosis: a EUSTAR group-based study. Clin Exp Rheumatol 31(2 Suppl 76):96–102PubMedGoogle Scholar
  53. 53.
    Sobanski V, Dauchet L, Lefevre G, Lambert M, Morell-Dubois S, Sy T, Hachulla E, Hatron PY, Launay D, Dubucquoi S (2014) Prevalence of anti-RNA polymerase III antibodies in systemic sclerosis: new data from a French cohort and a systematic review and meta-analysis. Arthritis Rheumatol 66(2):407–417.  https://doi.org/10.1002/art.38219 CrossRefPubMedGoogle Scholar
  54. 54.
    Denton CP, Steen V (2012) Scleroderma renal crisis. In: Varga J, Denton CP, Wigley FM (eds) Scleroderma: from pathogenesis to comprehensive management. Springer US, Boston, pp 361–371.  https://doi.org/10.1007/978-1-4419-5774-0_29 CrossRefGoogle Scholar
  55. 55.
    Ghrenassia E, Avouac J, Khanna D, Derk CT, Distler O, Suliman YA, Airo P, Carreira PE, Foti R, Granel B, Berezne A, Cabane J, Ingegnoli F, Rosato E, Caramaschi P, Hesselstrand R, Walker UA, Alegre-Sancho JJ, Zarrouk V, Agard C, Riccieri V, Schiopu E, Gladue H, Steen VD, Allanore Y (2014) Prevalence, correlates and outcomes of gastric antral vascular ectasia in systemic sclerosis: a EUSTAR case-control study. J Rheumatol 41(1):99–105.  https://doi.org/10.3899/jrheum.130386 CrossRefPubMedGoogle Scholar
  56. 56.
    Lazzaroni MG, Cavazzana I, Colombo E, Dobrota R, Hernandez J, Hesselstrand R, Varju C, Nagy G, Smith V, Caramaschi P, Riccieri V, Hachulla E, Balbir-Gurman A, Chatelus E, Romanowska-Prochnicka K, Araujo AC, Distler O, Allanore Y, Airo P (2017) Malignancies in patients with anti-RNA polymerase III antibodies and systemic sclerosis: analysis of the EULAR scleroderma trials and research cohort and possible recommendations for screening. J Rheumatol 44(5):639–647.  https://doi.org/10.3899/jrheum.160817 CrossRefPubMedGoogle Scholar
  57. 57.
    Shah AA, Rosen A, Hummers L, Wigley F, Casciola-Rosen L (2010) Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies. Arthritis Rheum 62(9):2787–2795.  https://doi.org/10.1002/art.27549 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Joseph CG, Darrah E, Shah AA, Skora AD, Casciola-Rosen LA, Wigley FM, Boin F, Fava A, Thoburn C, Kinde I, Jiao Y, Papadopoulos N, Kinzler KW, Vogelstein B, Rosen A (2014) Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 343(6167):152–157.  https://doi.org/10.1126/science.1246886 CrossRefPubMedGoogle Scholar
  59. 59.
    Aggarwal R, Lucas M, Fertig N, Oddis CV, Medsger TA Jr (2009) Anti-U3 RNP autoantibodies in systemic sclerosis. Arthritis Rheum 60(4):1112–1118.  https://doi.org/10.1002/art.24409 CrossRefPubMedGoogle Scholar
  60. 60.
    Steen V (2003) Predictors of end stage lung disease in systemic sclerosis. Ann Rheum Dis 62(2):97–99CrossRefGoogle Scholar
  61. 61.
    Nishimagi E, Tochimoto A, Kawaguchi Y, Satoh T, Kuwana M, Takagi K, Ichida H, Kanno T, Soejima M, Baba S, Kamatani N, Hara M (2007) Characteristics of patients with early systemic sclerosis and severe gastrointestinal tract involvement. J Rheumatol 34(10):2050–2055PubMedGoogle Scholar
  62. 62.
    Maddison PJ (2000) Mixed connective tissue disease: overlap syndromes. Baillieres Best Pract Res Clin Rheumatol 14(1):111–124.  https://doi.org/10.1053/berh.1999.0080 CrossRefPubMedGoogle Scholar
  63. 63.
    Moinzadeh P, Aberer E, Ahmadi-Simab K, Blank N, Distler JH, Fierlbeck G, Genth E, Guenther C, Hein R, Henes J, Herich L, Herrgott I, Koetter I, Kreuter A, Krieg T, Kuhr K, Lorenz HM, Meier F, Melchers I, Mensing H, Mueller-Ladner U, Pfeiffer C, Riemekasten G, Sardy M, Schmalzing M, Sunderkoetter C, Susok L, Tarner IH, Vaith P, Worm M, Wozel G, Zeidler G, Hunzelmann N (2015) Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis 74(4):730–737.  https://doi.org/10.1136/annrheumdis-2013-204487 CrossRefPubMedGoogle Scholar
  64. 64.
    Steen V, Domsic RT, Lucas M, Fertig N, Medsger TA Jr (2012) A clinical and serologic comparison of African American and Caucasian patients with systemic sclerosis. Arthritis Rheum 64(9):2986–2994.  https://doi.org/10.1002/art.34482 CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Ihn H, Yamane K, Yazawa N, Kubo M, Fujimoto M, Sato S, Kikuchi K, Tamaki K (1999) Distribution and antigen specificity of anti-U1RNP antibodies in patients with systemic sclerosis. Clin Exp Immunol 117(2):383–387CrossRefGoogle Scholar
  66. 66.
    Sobanski V, Giovannelli J, Lynch BM, Schreiber BE, Nihtyanova SI, Harvey J, Handler CE, Denton CP, Coghlan JG (2016) Characteristics and survival of anti-U1 RNP antibody-positive patients with connective tissue disease-associated pulmonary arterial hypertension. Arthritis Rheumatol 68(2):484–493.  https://doi.org/10.1002/art.39432 CrossRefPubMedGoogle Scholar
  67. 67.
    Van Eenennaam H, Vogelzangs JH, 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(12):3266–3272.  https://doi.org/10.1002/art.10673 CrossRefPubMedGoogle Scholar
  68. 68.
    Okano Y, Medsger TA Jr (1990) Autoantibody to Th ribonucleoprotein (nucleolar 7-2 RNA protein particle) in patients with systemic sclerosis. Arthritis Rheum 33(12):1822–1828CrossRefGoogle Scholar
  69. 69.
    Mahler M, Satoh M, Hudson M, Baron M, Chan JY, Chan EK, Wick J, Fritzler MJ (2014) Autoantibodies to the Rpp25 component of the Th/To complex are the most common antibodies in patients with systemic sclerosis without antibodies detectable by widely available commercial tests. J Rheumatol 41(7):1334–1343.  https://doi.org/10.3899/jrheum.131450 CrossRefPubMedGoogle Scholar
  70. 70.
    Mitri GM, Lucas M, Fertig N, Steen VD, Medsger TA Jr (2003) A comparison between anti-Th/To- and anticentromere antibody-positive systemic sclerosis patients with limited cutaneous involvement. Arthritis Rheum 48(1):203–209.  https://doi.org/10.1002/art.10760 CrossRefPubMedGoogle Scholar
  71. 71.
    Jimenez-Garcia LF, Rothblum LI, Busch H, Ochs RL (1989) Nucleologenesis: use of non-isotopic in situ hybridization and immunocytochemistry to compare the localization of rDNA and nucleolar proteins during mitosis. Biol Cell 65(3):239–246CrossRefGoogle Scholar
  72. 72.
    Chan EK, Imai H, Hamel JC, Tan EM (1991) Human autoantibody to RNA polymerase I transcription factor hUBF. Molecular identity of nucleolus organizer region autoantigen NOR-90 and ribosomal RNA transcription upstream binding factor. J Exp Med 174(5):1239–1244CrossRefGoogle Scholar
  73. 73.
    Imai H, Fritzler MJ, Neri R, Bombardieri S, Tan EM, Chan EK (1994) Immunocytochemical characterization of human NOR-90 (upstream binding factor) and associated antigens reactive with autoimmune sera. Two MR forms of NOR-90/hUBF autoantigens. Mol Biol Rep 19(2):115–124CrossRefGoogle Scholar
  74. 74.
    Villalta D, Imbastaro T, Di Giovanni S, Lauriti C, Gabini M, Turi MC, Bizzaro N (2012) Diagnostic accuracy and predictive value of extended autoantibody profile in systemic sclerosis. Autoimmun Rev 12(2):114–120.  https://doi.org/10.1016/j.autrev.2012.07.005 CrossRefPubMedGoogle Scholar
  75. 75.
    Fujii T, Mimori T, Akizuki M (1996) Detection of autoantibodies to nucleolar transcription factor NOR 90/hUBF in sera of patients with rheumatic diseases, by recombinant autoantigen-based assays. Arthritis Rheum 39(8):1313–1318CrossRefGoogle Scholar
  76. 76.
    Imai H, Ochs RL, Kiyosawa K, Furuta S, Nakamura RM, Tan EM (1992) Nucleolar antigens and autoantibodies in hepatocellular carcinoma and other malignancies. Am J Pathol 140(4):859–870PubMedPubMedCentralGoogle Scholar
  77. 77.
    Dagher JH, Scheer U, Voit R, Grummt I, Lonzetti L, Raymond Y, Senecal JL (2002) Autoantibodies to NOR 90/hUBF: longterm clinical and serological followup in a patient with limited systemic sclerosis suggests an antigen driven immune response. J Rheumatol 29(7):1543–1547PubMedGoogle Scholar
  78. 78.
    Tarn WY, Steitz JA (1996) A novel spliceosome containing U11, U12, and U5 snRNPs excises a minor class (AT-AC) intron in vitro. Cell 84(5):801–811CrossRefGoogle Scholar
  79. 79.
    Fertig N, Domsic RT, Rodriguez-Reyna T, Kuwana M, Lucas M, Medsger TA Jr, Feghali-Bostwick CA (2009) Anti-U11/U12 RNP antibodies in systemic sclerosis: a new serologic marker associated with pulmonary fibrosis. Arthritis Rheum 61(7):958–965.  https://doi.org/10.1002/art.24586 CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Brouwer R, Vree Egberts WT, Hengstman GJ, Raijmakers R, van Engelen BG, Seelig HP, Renz M, Mierau R, Genth E, Pruijn GJ, van Venrooij WJ (2002) Autoantibodies directed to novel components of the PM/Scl complex, the human exosome. Arthritis Res 4(2):134–138.  https://doi.org/10.1186/ar389 CrossRefPubMedGoogle Scholar
  81. 81.
    Brouwer R, Hengstman GJ, Vree Egberts W, Ehrfeld H, Bozic B, Ghirardello A, Grondal G, Hietarinta M, Isenberg D, Kalden JR, Lundberg I, Moutsopoulos H, Roux-Lombard P, Vencovsky J, Wikman A, Seelig HP, van Engelen BG, van Venrooij WJ (2001) Autoantibody profiles in the sera of European patients with myositis. Ann Rheum Dis 60(2):116–123CrossRefGoogle Scholar
  82. 82.
    Gunawardena H (2017) The clinical features of myositis-associated autoantibodies: a review. Clin Rev Allergy Immunol 52(1):45–57.  https://doi.org/10.1007/s12016-015-8513-8 CrossRefPubMedGoogle Scholar
  83. 83.
    D'Aoust J, Hudson M, Tatibouet S, Wick J, Mahler M, Baron M, Fritzler MJ (2014) Clinical and serologic correlates of anti-PM/Scl antibodies in systemic sclerosis: a multicenter study of 763 patients. Arthritis Rheumatol 66(6):1608–1615.  https://doi.org/10.1002/art.38428 CrossRefPubMedGoogle Scholar
  84. 84.
    Mimori T (2002) Clinical significance of anti-Ku autoantibodies—a serologic marker of overlap syndrome? Intern Med 41(12):1096–1098CrossRefGoogle Scholar
  85. 85.
    Cavazzana I, Ceribelli A, Quinzanini M, Scarsi M, Airo P, Cattaneo R, Franceschini F (2008) Prevalence and clinical associations of anti-Ku antibodies in systemic autoimmune diseases. Lupus 17(8):727–732.  https://doi.org/10.1177/0961203308089442 CrossRefPubMedGoogle Scholar
  86. 86.
    Rozman B, Cucnik S, Sodin-Semrl S, Czirjak L, Varju C, Distler O, Huscher D, Aringer M, Steiner G, Matucci-Cerinic M, Guiducci S, Stamenkovic B, Stankovic A, Kveder T (2008) Prevalence and clinical associations of anti-Ku antibodies in patients with systemic sclerosis: a European EUSTAR-initiated multi-centre case-control study. Ann Rheum Dis 67(9):1282–1286.  https://doi.org/10.1136/ard.2007.073981 CrossRefPubMedGoogle Scholar
  87. 87.
    Hoa S, Hudson M, Troyanov Y, Proudman S, Walker J, Stevens W, Nikpour M, Assassi S, Mayes MD, Wang M, Baron M, Fritzler MJ (2016) Single-specificity anti-Ku antibodies in an international cohort of 2140 systemic sclerosis subjects: clinical associations. Medicine (Baltimore) 95(35):e4713.  https://doi.org/10.1097/md.0000000000004713 CrossRefGoogle Scholar
  88. 88.
    Cavazzana I, Fredi M, Taraborelli M, Quinzanini M, Tincani A, Franceschini F (2013) A subset of systemic sclerosis but not of systemic lupus erythematosus is defined by isolated anti-Ku autoantibodies. Clin Exp Rheumatol 31(2 Suppl 76):118–121PubMedGoogle Scholar
  89. 89.
    Shah AA, Casciola-Rosen L, Rosen A (2015) Review: cancer-induced autoimmunity in the rheumatic diseases. Arthritis Rheumatol 67(2):317–326.  https://doi.org/10.1002/art.38928 CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Zaarur N, Xu X, Lestienne P, Meriin AB, McComb M, Costello CE, Newnam GP, Ganti R, Romanova NV, Shanmugasundaram M, Silva ST, Bandeiras TM, Matias PM, Lobachev KS, Lednev IK, Chernoff YO, Sherman MY (2015) RuvbL1 and RuvbL2 enhance aggresome formation and disaggregate amyloid fibrils. EMBO J 34(18):2363–2382.  https://doi.org/10.15252/embj.201591245 CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Pauling JD, Salazar G, Lu H, Betteridge ZE, Assassi S, Mayes MD, McHugh NJ (2018) Presence of anti-eukaryotic initiation factor-2B, anti-RuvBL1/2 and anti-synthetase antibodies in patients with anti-nuclear antibody negative systemic sclerosis. Rheumatology (Oxford) 57(4):712–717.  https://doi.org/10.1093/rheumatology/kex458 CrossRefGoogle Scholar
  92. 92.
    Kaji K, Fertig N, Medsger TA Jr, Satoh T, Hoshino K, Hamaguchi Y, Hasegawa M, Lucas M, Schnure A, Ogawa F, Sato S, Takehara K, Fujimoto M, Kuwana M (2014) Autoantibodies to RuvBL1 and RuvBL2: a novel systemic sclerosis-related antibody associated with diffuse cutaneous and skeletal muscle involvement. Arthritis Care Res (Hoboken) 66(4):575–584.  https://doi.org/10.1002/acr.22163 CrossRefGoogle Scholar
  93. 93.
    Betteridge ZE, Woodhead F, Lu H, Shaddick G, Bunn CC, Denton CP, Abraham DJ, du Bois RM, Lewis M, Wells AU, McHugh NJ (2016) Brief report: anti-eukaryotic initiation factor 2B autoantibodies are associated with interstitial lung disease in patients with systemic sclerosis. Arthritis Rheumatol 68(11):2778–2783.  https://doi.org/10.1002/art.39755 CrossRefPubMedGoogle Scholar
  94. 94.
    Pavitt GD (2005) eIF2B, a mediator of general and gene-specific translational control. Biochem Soc Trans 33(Pt 6):1487–1492.  https://doi.org/10.1042/bst20051487 CrossRefPubMedGoogle Scholar
  95. 95.
    Fattal I, Shental N, Molad Y, Gabrielli A, Pokroy-Shapira E, Oren S, Livneh A, Langevitz P, Pauzner R, Sarig O, Gafter U, Domany E, Cohen IR (2014) Epstein-Barr virus antibodies mark systemic lupus erythematosus and scleroderma patients negative for anti-DNA. Immunology 141(2):276–285.  https://doi.org/10.1111/imm.12200 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Anna Stochmal
    • 1
  • Joanna Czuwara
    • 1
  • Maria Trojanowska
    • 2
  • Lidia Rudnicka
    • 1
    Email author
  1. 1.Department of DermatologyMedical University of WarsawWarsawPoland
  2. 2.Arthritis CenterBoston University School of MedicineBostonUSA

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