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Anti-interferon alpha antibodies and autoantibodies in patients with Behçet’s disease uveitis treated with recombinant human interferon alpha-2a

  • Inflammatory Disorders
  • Published:
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Abstract

Background

Recombinant human (rh) interferon alpha2a (IFN-α2a) therapy is successfully used for the treatment of Behçet’s disease (BD) uveitis refractory to conventional immunosuppressive treatment.

Purpose

Our aim in this study was to investigate the frequency and clinical significance of anti-IFN-α antibodies and autoantibodies during recombinant human rhIFN-α2a therapy in patients with BD uveitis.

Methods

This comparative, cross-sectional, serological screening study included 30 BD patients treated with rhIFN-α2a (Group 1), 29 BD patients treated with conventional immunosuppressive agents (Group 2), 29 BD patients who received only colchicine (Group 3), and 30 healthy subjects (Group 4). Anti-IFN-α–binding antibodies and autoantibodies, including anti-nuclear antibody, anti-thyroid peroxidase antibody, and anti-cardiolipin antibody, were measured in serum samples. Antibody seropositivity was compared between study groups. Retrospective clinical data were compared between antibody-positive and antibody-negative patients.

Results

A significantly higher proportion of patients in Group 1 had anti-interferon-α (26.6 %) and autoantibody (30 %) seropositivity compared to the other groups. No correlation was found between seropositivity for anti-interferon-α and other autoantibodies. No significant difference was found in cumulative dose of IFN-α, duration of IFN-α therapy, time to first uveitis attack, or attack rate between anti-interferon-α antibody-positive and antibody-negative patients in Group 1. Uveitis attacks were observed in 22 % of autoantibody-positive and 71 % of autoantibody-negative patients in Group 1 (p = 0.018).

Conclusions

Patients with BD uveitis develop anti-IFN-α–binding antibodies and autoantibodies during treatment with rhIFN-α2a. While the clinical relevance of anti-IFN-α–binding antibodies remains unclear in this study, induction of autoimmunity was found to be associated with a tendency for better therapeutic response.

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References

  1. Gül A (2005) Behçet’s disease as an autoinflammatory disorder. Curr Drug Targets Inflamm Allergy 4(1):81–83

    Article  PubMed  Google Scholar 

  2. Kapsimali VD, Kanakis MA, Vaiopoulos GA, Kaklamanis PG (2010) Etiopathogenesis of Behçet’s disease with emphasis on the role of immunological aberrations. Clin Rheumatol 29(11):1211–1216

    Article  PubMed  Google Scholar 

  3. Direskeneli H (2006) Autoimmunity vs autoinflammation in Behcet’s disease: do we oversimplify a complex disorder? Rheumatology (Oxford) 45(12):1461–1465

    Article  CAS  Google Scholar 

  4. Yazıcı H (1997) The place of Behcet’s Syndrome among the autoimmune diseases. Intern Rev Immunol 14(1):1–10

    Article  Google Scholar 

  5. Crow MK (2010) Type I interferon in organ-targeted autoimmune and inflammatory diseases. Arthritis Res Ther 12(Suppl 1):S5

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Pascual V, Banchereau J (2012) Tracking interferon in autoimmunity. Immunity 36(27):7–9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Trinchieri G (2010) Type I interferon: friend or foe? J Exp Med 207(10):2053–2063

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Gutterman JU (1994) Cytokine therapeutics: lessons from interferon alpha. Proc Natl Acad Sci U S A 91(4):1198–1205

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Deuter CM, Zierhut M, Möhle A, Vonthein R, Stöbiger N, Kötter I (2010) Long-term remission after cessation of interferon-alpha treatment in patients with severe uveitis due to Behçet’s disease. Arthritis Rheum 62(9):2796–2805

    Article  CAS  PubMed  Google Scholar 

  10. Tugal-Tutkun I, Güney-Tefekli E, Urgancioglu M (2006) Results of interferon-alfa therapy in patients with Behçet uveitis. Graefes Arch Clin Exp Ophthalmol 244(12):1692–1695

    Article  CAS  PubMed  Google Scholar 

  11. Kötter I, Zierhut M, Eckstein AK et al (2003) Human recombinant interferon alfa-2a for the treatment of Behçet’s disease with sight threatening posterior or panuveitis. Br J Ophthalmol 87(4):423–431

    Article  PubMed Central  PubMed  Google Scholar 

  12. Kötter I, Vonthein R, Zierhut M et al (2004) Differential efficacy of human recombinant interferon- 2a on ocular and extraocular manifestations of behcet disease: results of an open 4-center trial. Semin Arthritis Rheum 33(5):311–319

    Article  PubMed  Google Scholar 

  13. Kötter I, Günaydin I, Zierhut M, Stübiger N (2004) The use of interferon alpha in Behçet disease: review of the literature. Semin Arthritis Rheum 33(5):320–335

    Article  PubMed  Google Scholar 

  14. Wechsler B, Bodaghi B (2000) Efficacy of interferon alfa-2a in severe and refractory uveitis associated with Behçet’s disease. Ocul Immunol Inflamm 8(4):293–301

    Article  CAS  PubMed  Google Scholar 

  15. Hamuryudan V, Ozyazgan Y, Fresko I (2002) Interferon alfa combined with azathioprine for the uveitis of Behçet’s disease: an open study. Isr Med Assoc J 4(11):928–930

    CAS  PubMed  Google Scholar 

  16. Gueudry J, Wechsler B, Terrada C et al (2008) Long-term efficacy and safety of low-dose interferon alpha2a therapy in severe uveitis associated with Behçet disease. Am J Ophthalmol 146(6):837–844

    Article  CAS  PubMed  Google Scholar 

  17. Krause L, Altenburg A, Pleyer U, Köhler AK, Zouboulis CC, Foerster MH (2008) Longterm visual prognosis of patients with ocular adamantiades-Behçet’s disease treated with interferon-alpha-2a. J Rheumatol 35(5):896–903

    CAS  PubMed  Google Scholar 

  18. Sobaci G, Erdem U, Durukan AH et al (2010) Safety and effectiveness of interferon alpha-2a in treatment of patients with Behçet’s uveitis refractory to conventional treatments. Ophthalmology 117(7):1430–1435

    Article  PubMed  Google Scholar 

  19. Onal S, Kazokoglu H (2009) Low-dose interferon alfa-2a therapy in severe uveitis associated with Behçet disease. Am J Ophthalmol 147(6):1109–1110

    Article  PubMed  Google Scholar 

  20. Onal S, Kazokoglu H (2011) Long-term efficacy and safety of low-dose and dose-escalating interferon alfa-2a therapy in refractory Behçet uveitis. Arch Ophthalmol 129(3):288–294

    Article  CAS  PubMed  Google Scholar 

  21. Yalçindağ FN, Uzun A (2012) Results of interferon alpha-2a therapy in patients with Behcet’s disease. J Ocul Pharmacol Ther 28(4):439–443

    Article  PubMed  Google Scholar 

  22. Deuter CM, Kötter I, Günaydin I, Stübiger N, Doycheva DG, Zierhut M (2009) Efficacy and tolerability of interferon alpha treatment in patients with chronic cystoid macular oedema due to non-infectious uveitis. Br J Ophthalmol 93(7):906–913

    Article  CAS  PubMed  Google Scholar 

  23. Mackensen F, Max R, Becker MD (2006) Interferon therapy for ocular disease. Curr Opin Ophthalmol 17(6):567–573

    Article  PubMed  Google Scholar 

  24. Bodaghi B, Gendron G, Wechsler B et al (2007) Efficacy of interferon alpha in the treatment of refractory and sight threatening uveitis: a retrospective monocentric study of 45 patients. Br J Ophthalmol 91(3):335–339

    Article  PubMed Central  PubMed  Google Scholar 

  25. Plskova J, Greiner K, Forrester JV (2007) Interferon-alpha as an effective treatment for noninfectious posterior uveitis and panuveitis. Am J Ophthalmol 144(1):55–61

    Article  CAS  PubMed  Google Scholar 

  26. Leroy V, Baud M, Traversay C, Maynard-Muet M, Lebon P, Zarski JP (1998) Role of anti-interferon antibodies in breakthrough occurrence during alpha 2a and 2b therapy in patients with chronic hepatitis C. J Hepatol 28(3):375–381

    Article  CAS  PubMed  Google Scholar 

  27. Rönnblom LE, Janson ET, Perers A, Oberg KE, Alm GV (1992) Characterization of anti-interferon-a antibodies appearing during recombinant interferon-alfa 2a treatment. Clin Exp Immunol 89(3):330–335

    Article  PubMed Central  PubMed  Google Scholar 

  28. Matsuda F, Torii Y, Enomoto H et al (2012) Anti-interferon-α neutralizing antibody is associated with nonresponse to pegylated interferon-α plus ribavirin in chronic hepatitis C. J Viral Hepat 19(10):694–703

    Article  CAS  PubMed  Google Scholar 

  29. Gogas H, Ioannovich J, Dafni U et al (2006) Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 354(7):709–718

    Article  CAS  PubMed  Google Scholar 

  30. Plskova J, Greiner K, Muckersie E, Duncan L, Forrester JV (2006) Interferon-alpha: A key factor in autoimmune disease? Invest Ophthalmol Vis Sci 47(9):3946–3950

    Article  PubMed  Google Scholar 

  31. Meager A, Wadhwa M, Dilger P et al (2003) Anti-cytokine autoantibodies in autoimmunity: preponderance of neutralizing autoantibodies against interferon-alpha, interferon-omega and interleukin-12 in patients with thymoma and/or myasthenia gravis. Clin Exp Immunol 132(1):128–136

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Wandl UB, Nagel-Hiemke M, May D et al (1992) Lupus-like autoimmune disease induced by interferon therapy for myeloproliferative disorders. Clin Immunol Immunopathol 65(1):70–4

    Article  CAS  PubMed  Google Scholar 

  33. Kötter I, Hamuryudan V, Ozturk ZE, Yazici H (2010) Interferon therapy in rheumatic diseases: state-of-the-art 2010. Curr Opin Rheumatol 22(3):278–283

    Article  PubMed  Google Scholar 

  34. Nussenblatt RB (2003) Behçet’s disease. In: Nussenblatt RB, Whitcup SM (eds) Uveitis: fundamentals and clinical practice, 3rd edn. Mosby, Philadelphia, pp 350–371

    Google Scholar 

  35. International Study Group for Behçet’s Disease (1990) Criteria for diagnosis of Behçet’s disease. Lancet 335(8697):1078–1080

    Google Scholar 

  36. Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature (SUN) Working Group (2005) Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 140(3):509–516

  37. Jabs DA (2005) Improving the reporting of clinical case series. Am J Ophthalmol 139(5):900–905

    Article  PubMed  Google Scholar 

  38. Pachner RA (2008) Measurement of binding anti-IFNbeta antibodies in IFNbeta-treated MS patients: lessons for the clinician and basic scientist. J Neuroimmunol 194(1–2):5–6

    Article  CAS  PubMed  Google Scholar 

  39. Sørensen PS, Deisenhammer F, Duda P et al (2005) Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS task force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 12(11):817–827

    Article  PubMed  Google Scholar 

  40. Jensen PE, Sellebjerg F, Søndergaard HB, Sørensen PS (2012) Correlation between anti-interferon-β binding and neutralizing antibodies in interferon-β-treated multiple sclerosis patients. Eur J Neurol 19(10):1311–1317

    Article  CAS  PubMed  Google Scholar 

  41. Ibrahim EH (2011) Anti-IFN autoantibodies are present in healthy Egyptian blood donors at low titer. Cell Immunol 271(2):365–370

    Article  CAS  PubMed  Google Scholar 

  42. Sorensen PS, Ross C, Clemmesen KM et al (2003) Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis. Lancet 362(9391):1184–1191

    Article  CAS  PubMed  Google Scholar 

  43. Lapé Nixon M, Matud J, Yeh C, Prince HE (2009) Evaluation of a multiplex bead-based screening assay for detection of binding antibodies to interferon-beta. J Neuroimmunol 210(1–2):104–107

    Article  PubMed  Google Scholar 

  44. Becker MD, Heiligenhaus A, Hudde T et al (2005) Interferon as a treatment for uveitis associated with multiple sclerosis. Br J Ophthalmol 89(10):1254–7

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Prince HE, Lapé-Nixon M, Audette C, Van Horn K (2007) Identification of interferon-beta antibodies in a reference laboratory setting: findings for 1144 consecutive sera. J Neuroimmunol 190(1–2):165–169

    Article  CAS  PubMed  Google Scholar 

  46. Qureshi H, Arif A, Ahmed W et al (2007) Role of interferon anti body in predicting the response to interferon therapy in HCV patients. J Pak Med Assoc 57(12):581–583

    PubMed  Google Scholar 

  47. Wejstål R, Norkrans G, Lenkei R, Weiland O, Schvarcz R, Frydén A (1992) Peripheral blood lymphocyte subsets in patients with chronic hepatitis C–effects of interferon treatment. Liver 12(4-1):161–167

    PubMed  Google Scholar 

  48. Treusch M, Vonthein R, Baur M et al (2004) Influence of human recombinant interferon-alpha2a (rhIFN-alpha2a) on altered lymphocyte subpopulations and monocytes in Behcet’s disease. Rheumatology 43(10):1275–1282

    Article  CAS  PubMed  Google Scholar 

  49. Wada M, Kang KB, Kinugasa A et al (1997) Does the presence of serum autoantibodies influence the responsiveness to interferon-alpha 2a treatment in chronic hepatitis C? Intern Med 36(4):248–254

    Article  CAS  PubMed  Google Scholar 

  50. Franzke A, Peest D, Probst-Kepper M et al (1999) Autoimmunity resulting from cytokine treatment predicts long-term survival in patients with metastatic renal cell cancer. J Clin Oncol 17(2):529–533

    CAS  PubMed  Google Scholar 

  51. Galeone M, Colucci R, D’Erme AM, Moretti S, Lotti T. Potential infectious etiology of Behçet’s disease. Patholog Res Int 2012;2012:595380

  52. Wahren-Herlenius M, Dörner T (2013) Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 382:819–31

    Article  CAS  PubMed  Google Scholar 

  53. Gül A (2014) Genetics of Behçet’s disease: lessons learned from genomewide association studies. Curr Opin Rheumatol 26(1):56–63

    Article  PubMed  Google Scholar 

  54. Ahn JK, Yu G, Chung H, Park YG (2006) Intraocular cytokine environment in active Behçet uveitis. Am J Ophthalmol 142(3):429–434

    Article  CAS  PubMed  Google Scholar 

  55. El-Asrar AM, Struyf S, Kangave D et al (2011) Cytokine profiles in aqueous humor of patients with different clinical entities of endogenous uveitis. Clin Immunol 139(2):177–184

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Dr Nuray Gürel-Polat for her help in the conduction of laboratory tests and interpretation of test results.

Funding

This study was supported by the Istanbul University Research Funds (Project number: 17149).

Financial disclosures

Ilknur Tugal-Tutkun has received financial support outside the submitted work, including honorarium from IRIS (Institut de Recherches Internationales Servier) and travel grants from Novartis Turkey and Allergan Turkey.

Contributions of Authors

Design of the study (ITT, ÖAC); Conduct of the study (ITT,ÖAC, SB); Analysis (ÖAC,BAE); Interpretation of the data (ITT,ÖAC,BAE,AG,SB); preparation of the manuscript (ÖAC,BAE); Review of the manuscript (ITT,AG,SB).

Conflict of interest

The authors have no commercial associations that might be perceived as a conflict of interest with the manuscript.

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Correspondence to Ilknur Tugal-Tutkun.

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Aydinoglu-Candan, Ö., Araz-Erşan, B., Gul, A. et al. Anti-interferon alpha antibodies and autoantibodies in patients with Behçet’s disease uveitis treated with recombinant human interferon alpha-2a. Graefes Arch Clin Exp Ophthalmol 253, 457–465 (2015). https://doi.org/10.1007/s00417-014-2856-3

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