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Anti-RNP/Sm antibodies in patients with systemic lupus erythematosus and its role in thrombosis: a case-control study

  • María del Carmen Zamora-Medina
  • Andrea Hinojosa-Azaola
  • Carlos A. Nuñez-Alvarez
  • Angel Gabriel Vargas-Ruiz
  • Juanita Romero-Diaz
Original Article
  • 16 Downloads

Abstract

Objective

To validate the association of thrombotic events with positive lupus anticoagulant (LA) and co-presence of anti-RNP/Sm, as well as the diagnostic accuracy of this combination of antibodies for thrombosis.

Methods

Case-control study of patients with systemic lupus erythematosus (SLE) who presented thrombosis after SLE diagnosis and controls with SLE without thrombosis. Comorbidities, traditional risk factors, clinical variables, and treatment were evaluated. Antiphospholipid (aPL) and anti-RNP/Sm antibodies were determined.

Results

Sixty-three cases and 63 controls were studied, 88% women, median age of 40 years, and disease duration of 135 months at study inclusion. No differences were found between groups regarding age, comorbidities, or clinical characteristics at SLE diagnosis. Patients with thrombosis were more frequently positive for anti-RNP/Sm (p = 0.001), IgG aCL (p = 0.02), IgG anti-B2GPI (p = 0.02), IgM anti-B2GPI (p = 0.02), LA (p < 0.001), the combination of anti-RNP/Sm + LA (p < 0.001), and aPL triple marker (p = 0.002), compared to controls. The combination of anti-RNP/Sm + LA, SLEDAI-2 K, and prednisone dose was associated with thrombosis (p < 0.05). The combination of anti-RNP/Sm + LA showed 56% sensitivity, 79% specificity, 73% positive predictive value, 64% negative predictive value, positive likelihood ratio (LR) 2.69, and negative LR 0.56 for predicting thrombosis. No difference was found in the comparison of area under the curve between LA alone and the combination of anti-RNP/Sm + LA (p = 0.73).

Conclusion

Thrombosis was associated with disease activity, dose of prednisone, and the combination of anti-RNP/Sm antibodies and LA. This combination of antibodies could be useful in the identification of SLE patients at risk of thrombosis.

Keywords

Diagnostic accuracy Lupus anticoagulant Anti-RNP/Sm Systemic lupus erythematosus Thrombosis 

Notes

Acknowledgements

We thank Darinel Hernández Hernández, Andrés Valencia Martínez, Ariadna Jiménez González, and Luis Ángel Mendoza Vargas for their assistance in the blood sample collection and lupus anticoagulant detection.

Authors’ contributions

MCZM, AHA, and JRD designed the study; MCZM, CANA, and AGVR participated in acquisition of data; AHA and JRD analyzed and interpreted data; MCZM, AHA, and JRD drafted the manuscript; MCZM, AHA, JRD, CANA, and AGVR revised the manuscript.

Funding

This work was supported by the National Institute of Medical Science and Nutrition S.Z. Grants [INCMNSZ-AI-024 (JRD)], the National Council of Science and Technology [CONACYT SALUD-214395 (JRD)].

Compliance with ethical standards

Research was conducted in compliance with the Helsinki Declaration. Informed consent and approval by the local ethical committee was obtained.

Disclosures

None.

Ethical standards statement

The manuscript does not contain clinical studies or patient data.

References

  1. 1.
    Kaiser R, Cleveland CM, Criswell LA (2009) Risk and predictive factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort. Ann Rheum Dis 68:238–241CrossRefGoogle Scholar
  2. 2.
    Sarabi ZS, Chang E, Bobba R, Ibanez D, Gladman D, Urowitz M, Fortin PR (2005) Incidence rates of arterial and venous thrombosis after diagnosis of systemic lupus erythematosus. Arthritis Rheum 53:609–612CrossRefGoogle Scholar
  3. 3.
    Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, Mejía JC, Aydintug AO, Chwalinska-Sadowska H, de Ramón E, Fernández-Nebro A, Galeazzi M, Valen M, Mathieu A, Houssiau F, Caro N, Alba P, Ramos-Casals M, Ingelmo M, Hughes GR, European Working Party on Systemic Lupus Erythematosus (2003) Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine 82:299–308CrossRefGoogle Scholar
  4. 4.
    Mok C, Ho L, Yu K, To C (2010) Venous thromboembolism in southern Chinese patients with systemic lupus erythematosus. Clin Rheumatol 29:599–604CrossRefGoogle Scholar
  5. 5.
    Calvo-Alen J, Toloza SMA, Fernández M, Bastian HM, Fessler BJ, Roseman JM et al (2005) Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid use as risk factors for the occurrence of venous thrombosis in lupus patients. Arthritis Rheum 52:2060–2068CrossRefGoogle Scholar
  6. 6.
    Mok CC, Tang SS, To CH, Petri M (2005) Incidence and risk factors of thromboembolism in systemic lupus erythematosus. A comparison of three ethnic groups. Arthritis Rheum 52:2774–2782CrossRefGoogle Scholar
  7. 7.
    Esmon CT (2005) The interaction between inflammation and coagulation. Br J Haematol 131:417–430CrossRefGoogle Scholar
  8. 8.
    Romero-Díaz J, García-Sosa I, Sánchez-Guerrero J (2009) Thrombosis in systemic lupus erythematosus and other autoimmune diseases of recent onset. J Rheumatol 36:68–75CrossRefGoogle Scholar
  9. 9.
    Tektonidou M, Laskari K, Panagiotakos D, Moutsopoulos H (2009) Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Care Res 61:29–36CrossRefGoogle Scholar
  10. 10.
    Petri M (1996) Thrombosis and systemic lupus erythematosus: the Hopkins lupus cohort perspective. Scand J Rheumatol 25:191–193CrossRefGoogle Scholar
  11. 11.
    Hinojosa-Azaola A, Romero-Díaz J, Vargas-Ruiz A, Nuñez-Alvarez CA, Cicero-Casarrubias A, Ocampo-Torres MC et al (2016) Venous and arterial thrombotic events in systemic lupus erythematosus. J Rheumatol 43:576–586CrossRefGoogle Scholar
  12. 12.
    Vlachoyiannopoulos PG, Routsias JG (2010) A novel mechanism of thrombosis in antiphospholipid antibody syndrome. J Autoimmun 35:248–255CrossRefGoogle Scholar
  13. 13.
    Tarr T, Lakos G, Bhattoa HP, Shoenfeld Y, Szegedi G, Kiss E et al (2007) Analysis of risk factors for the development of thrombotic complications in antiphospholipid antibody positive lupus patients. Lupus 16:39–45CrossRefGoogle Scholar
  14. 14.
    Pengo V, Ruffatti A, Legnani C, Testa S, Fierro T, Marongiu F, de Micheli V, Gresele P, Tonello M, Ghirarduzzi A, Bison E, Denas G, Banzato A, Padayattil Jose S, Iliceto S (2011) Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood 118:4714–4718CrossRefGoogle Scholar
  15. 15.
    Mustonen P, Lehtonen KV, Javela K, Puurunen M (2014) Persistent antiphospholipid antibody (aPL) in asymptomatic carriers as a risk for future thrombotic events: a nationwide prospective study. Lupus 23:1468–1476CrossRefGoogle Scholar
  16. 16.
    Danowski A, Kickler TS, Petri M (2006) Anti-β2-glycoprotein I: prevalence, clinical correlations, and importance of persistent positivity in patients with antiphospholipid syndrome and systemic lupus erythematosus. J Rheumatol 33:1775–1779Google Scholar
  17. 17.
    Pengo V, Ruffati A, Legnani C, Gresele P, Barcellona D, Erba N et al (2009) Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 8:237–242CrossRefGoogle Scholar
  18. 18.
    Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF et al (1982) The 1982 American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271–1277CrossRefGoogle Scholar
  19. 19.
    Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725CrossRefGoogle Scholar
  20. 20.
    Ibañez D, Urowitz MB, Gladman DD (2003) Summarizing disease features over time: I. Adjusted mean SLEDAI derivation and application to an index of disease activity in lupus. J Rheumatol 30:1977–1982Google Scholar
  21. 21.
    Gladman DD, Urowitz MB, Goldsmith CH, Fortin P, Ginzler E, Gordon C, Hanly JG, Isenberg DA, Kalunian K, Nived O, Petri M, Sanchez-Guerrero J, Snaith M, Sturfelt G (1997) The reliability of the systemic lupus international collaborating clinics/American College of Rheumatology Damage Index in patients with systemic lupus erythematosus. Arthritis Rheum 40:809–813CrossRefGoogle Scholar
  22. 22.
    García D, Erkan D (2018) Diagnosis and management of antiphospholipid syndrome. N Engl J Med 378:2010–2021CrossRefGoogle Scholar
  23. 23.
    Kershaw G, Suresh S, Orellana D, Nguy YM (2012) Laboratory identification of lupus anticoagulants. Semin Thromb Hemost 38:375–384CrossRefGoogle Scholar
  24. 24.
    Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, de Groot PG, Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis (2009) Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 7:1737–1740CrossRefGoogle Scholar
  25. 25.
    Keith M, Moratz C, Tsokos G (2007) Anti-RNP immunity: implications for tissue injury and the pathogenesis of connective tissue disease. Autoimmunity Rev 6:232–236CrossRefGoogle Scholar
  26. 26.
    Okawa-Takatsuji M, Aotsuka S, Fujinami M, Uwatoko S, Kinoshita M, Sumiya M (1999) Up-regulation of intercellular adhesion molecules-1 (ICAM-1), endothelial leucocyte adhesion molecule-1 (ELAM-1) and class II MHC molecules on pulmonary artery endothelial cells by antibodies against U1-ribonucleoprotein. Clin Exp Immunol 116:174–180CrossRefGoogle Scholar
  27. 27.
    Carpintero MF, Martinez L, Fernandez I, Romero AC, Mejia C, Zang YJ (2015) Diagnosis and risk stratification in patients with anti-RNP autoimmunity. Lupus 24:1057–1066CrossRefGoogle Scholar
  28. 28.
    Paradowska-Gorycka A (2015) U1-RNP and TLR receptors in the pathogenesis of mixed connective tissue disease. Part I. the U1-RNP complex and its biological significance in the pathogenesis of mixed connective tissue disease. Reumatologia 53:94–100CrossRefGoogle Scholar
  29. 29.
    Morais SA, Isenberg DA (2017) A study of the influence of ethnicity on serology and clinical features in lupus. Lupus 26:17–26CrossRefGoogle Scholar
  30. 30.
    Okawa-Takatsuji M, Aotsuka S, Uwatoko M, Takaono M, Iwasaki K, Kinoshita M et al (2001) Endothelial cell-binding activity of anti-U1-ribonucleoprotein antibodies in patients with connective tissue diseases. Clin Exp Immunol 126:345–354CrossRefGoogle Scholar
  31. 31.
    Belizna C, Diujvestijn A, Hamidou M, Tervaert JW (2006) Antiendothelial cell antibodies in vasculitis and connective tissue disease. Ann Rheum Dis 65:1545–1550CrossRefGoogle Scholar
  32. 32.
    Meroni PL, D’Cruz D, Khamashta M, Youinou P, Hughes GR (1996) Anti-endothelial cell antibodies: only for scientists or for clinicians too? Clin Exp Immunol 104:199–202CrossRefGoogle Scholar
  33. 33.
    Yalavarthi S, Gould TJ, Rao AN, Mazza LF, Morris AE, Núñez-Álvarez C, Hernández-Ramírez D, Bockenstedt PL, Liaw PC, Cabral AR, Knight JS (2015) Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the amtiphospholipid syndrome. Arthritis Rheumatol 67:2990–3003CrossRefGoogle Scholar
  34. 34.
    Rao A, Kazzaz N, Knight JS (2015) Do neutrophil extracellular traps contribute to the heightened risk of thrombosis in inflammatory diseases? World J Cardiol 7:829–842CrossRefGoogle Scholar
  35. 35.
    Darrah E, Andrade F (2013) NETs: the missing link between cell death and systemic autoimmune disease? Front Immunol 3:428CrossRefGoogle Scholar
  36. 36.
    Yipp BG, Kubes P (2013) NETosis: how vital is it? Blood 122:2784–2794CrossRefGoogle Scholar
  37. 37.
    García-Romo G, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z et al (2011) Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med 3:73ra20CrossRefGoogle Scholar
  38. 38.
    Meng H, Yalavarthi S, Kanthi Y, Mazza LF, Elfline MA, Luke CE, Pinsky DJ, Henke PK, Knight JS (2017) In vivo role of neutrophil extracelular traps in antiphospholipid antibody-mediated venous thrombosis. Arthritis Rheumatol 69:655–667CrossRefGoogle Scholar
  39. 39.
    To CH, Petri M (2005) Is antibody clustering predictive of clinical subset and damage in systemic lupus erythematosus? Arthritis Rheum 52:4003–4010CrossRefGoogle Scholar
  40. 40.
    Neville C, Rauch J, Kassis J, Solymoss S, Joseph L, Belisle P, Subang R, Chang ER, Fortin PR (2006) The persistence of anticardiolipin antibodies is associated with an increased risk of the presence of lupus anticoagulant and anti-beta2-glycoprotein I antibodies. Rheumatology (Oxford) 45:1116–1120CrossRefGoogle Scholar
  41. 41.
    Sciascia S, Radin M, Sanna G, Cecchi I, Roccatello D, Bertolaccini ML (2018) Clinical utility of the global antiphospholipid syndrome score for risk stratification: a pooled analysis. Rheumatology (Oxford) 57:661–665CrossRefGoogle Scholar
  42. 42.
    Sciascia S, Bertolaccini ML (2014) Antibodies to phosphatidylserine/prothrombin complex and the antiphospholipid syndrome. Lupus 23:1309–1312CrossRefGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  • María del Carmen Zamora-Medina
    • 1
  • Andrea Hinojosa-Azaola
    • 1
  • Carlos A. Nuñez-Alvarez
    • 1
  • Angel Gabriel Vargas-Ruiz
    • 2
  • Juanita Romero-Diaz
    • 1
  1. 1.Department of Immunology and RheumatologyInstituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránMexico CityMexico
  2. 2.Department of Hematology and OncologyInstituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránMexico CityMexico

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