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Correlation between elevation of serum antinuclear antibody titer and decreased therapeutic efficacy in the treatment of Behçet’s disease with infliximab

  • Daiju Iwata
  • Kenichi NambaEmail author
  • Kazuomi Mizuuchi
  • Nobuyoshi Kitaichi
  • Satoru Kase
  • Yuko Takemoto
  • Shigeaki Ohno
  • Susumu Ishida
Inflammatory Disorders

Abstract

Background

Infliximab, an anti-TNF-α monoclonal antibody, administered to Behçet’s disease (BD) patients in Japan with refractory intraocular inflammation, has shown excellent clinical results. However, some patients demonstrate a decreased response to infliximab during the course of the treatment. In the present study, we investigated the correlation between this reduced therapeutic effect and elevation of the serum antinuclear antibody (ANA) titers in patients with BD who were undergoing infliximab therapy.

Methods

Seventeen patients (14 males and three females) with uveitis in BD who were undergoing treatment with infliximab for 2 years or longer were enrolled. Their blood test results and clinical histories were obtained from medical records.

Results

One patient (5.9%) was ANA-positive prior to the initiation of infliximab, and 11 patients (64.7%) developed positive ANA during the therapy. The appearance of ANA was observed 6 months after the initiation of the infliximab therapy, and its titers gradually increased. None of the patients showed lupus symptoms. Five patients (29.4%) have suffered from ocular inflammatory attacks since the sixth month from the initiation of infliximab treatment and all of them were ANA-positive. In contrast, four patients (23.5%) who were ANA-negative experienced no ocular attacks during the follow-up period.

Conclusions

Here we report the positive conversion and subsequent elevation of serum ANA titers in some patients with BD after the initiation of infliximab therapy. Since all recurrences of uveitis were shown only in the ANA-positive patients, serum ANA titer may be a helpful biomarker for predicting the recurrence of ocular attacks in BD patients treated with anti-TNF-α antibody therapies.

Keywords

Behçet’s disease Retinal vasculitis Uveitis Antinuclear antibody Infliximab Biomarker Anti-TNF-α monoclonal antibody 

Notes

Competing interests

None.

Funding

None.

Ethics approval

This study was approved by the institutional Ethics Committee of Hokkaido University

Patient consent

Obtained.

References

  1. 1.
    Kitamei H, Kitaichi N, Namba K, Kotake S, Goda C, Kitamura M, Miyazaki A, Ohno S (2009) Clinical features of intraocular inflammation in Hokkaido, Japan. Acta Ophthalmol 87:424–428PubMedCrossRefGoogle Scholar
  2. 2.
    Kitaichi N, Miyazaki A, Iwata D, Ohno S, Stanford MR, Chams H (2007) Ocular features of Behçet’s disease: an international collaborative study. Br J Ophthalmol 91:1579–1582PubMedCrossRefGoogle Scholar
  3. 3.
    Kitaichi N, Miyazaki A, Stanford MR, Iwata D, Chams H, Ohno S (2009) Low prevalence of juvenile-onset Behçet’s disease with uveitis in East/South Asian people. Br J Ophthalmol 93:1428–1430PubMedCrossRefGoogle Scholar
  4. 4.
    Kaklamani V, Vaiopoulos G, Kaklamanis P (1998) Behçet’s disease. Semin Arthritis Rheum 27:197–217PubMedCrossRefGoogle Scholar
  5. 5.
    Sakane T, Takeno M, Suzuki N, Inaba G (1999) Behçet’s disease. N Engl J Med 341:1284–1291PubMedCrossRefGoogle Scholar
  6. 6.
    Zouboulis C (1999) Epidemiology of Adamantiades-Behçet’s disease. Ann Med Interne (Paris) 150:488–498Google Scholar
  7. 7.
    Knight D, Trinh H, Le J, Siegel S, Shealy D, McDonough M, Scallon B, Moore M, Vilcek J, Daddona P (1993) Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol 30:1443–1453PubMedCrossRefGoogle Scholar
  8. 8.
    Elliott M, Maini R, Feldmann M, Long-Fox A, Charles P, Bijl H, Woody J (1994) Repeated therapy with monoclonal antibody to tumour necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet 344:1125–1127PubMedCrossRefGoogle Scholar
  9. 9.
    Maini R, St Clair E, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P (1999) Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 354:1932–1939PubMedCrossRefGoogle Scholar
  10. 10.
    Hanauer S, Feagan B, Lichtenstein G, Mayer L, Schreiber S, Colombel J, Rachmilewitz D, Wolf D, Olson A, Bao W, Rutgeerts P, Group AIS (2002) Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 359:1541–1549CrossRefGoogle Scholar
  11. 11.
    Zhang Z, Schmitt J, Wozel G, Kirch W (2009) Treatment of plaque psoriasis with biologics. A meta-analysis of randomized controlled trials. Med Klin (Munich) 104:125–136CrossRefGoogle Scholar
  12. 12.
    Nestle F, Kaplan D, Barker J (2009) Psoriasis. N Engl J Med 361:496–509PubMedCrossRefGoogle Scholar
  13. 13.
    Sfikakis P, Theodossiadis P, Katsiari C, Kaklamanis P, Markomichelakis N (2001) Effect of infliximab on sight-threatening panuveitis in Behçet’s disease. Lancet 358:295–296PubMedCrossRefGoogle Scholar
  14. 14.
    Muñoz-Fernández S, Hidalgo V, Fernández-Melón J, Schlincker A, Martín-Mola E (2001) Effect of infliximab on threatening panuveitis in Behçet’s disease. Lancet 358:1644PubMedCrossRefGoogle Scholar
  15. 15.
    Ohno S, Nakamura S, Hori S, Shimakawa M, Kawashima H, Mochizuki M, Sugita S, Ueno S, Yoshizaki K, Inaba G (2004) Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in Behçet’s disease with refractory uveoretinitis. J Rheumatol 31:1362–1368PubMedGoogle Scholar
  16. 16.
    Sfikakis P, Kaklamanis P, Elezoglou A, Katsilambros N, Theodossiadis P, Papaefthimiou S, Markomichelakis N (2004) Infliximab for recurrent, sight-threatening ocular inflammation in Adamantiades-Behçet disease. Ann Intern Med 140:404–406PubMedGoogle Scholar
  17. 17.
    Tugal-Tutkun I, Mudun A, Urgancioglu M, Kamali S, Kasapoglu E, Inanc M, Gül A (2005) Efficacy of infliximab in the treatment of uveitis that is resistant to treatment with the combination of azathioprine, cyclosporine, and corticosteroids in Behçet’s disease: an open-label trial. Arthritis Rheum 52:2478–2484PubMedCrossRefGoogle Scholar
  18. 18.
    Accorinti M, Pirraglia M, Paroli M, Priori R, Conti F, Pivetti-Pezzi P (2007) Infliximab treatment for ocular and extraocular manifestations of Behçet’s disease. Jpn J Ophthalmol 51:191–196PubMedCrossRefGoogle Scholar
  19. 19.
    Niccoli L, Nannini C, Benucci M, Chindamo D, Cassarà E, Salvarani C, Cimino L, Gini G, Lenzetti I, Cantini F (2007) Long-term efficacy of infliximab in refractory posterior uveitis of Behçet’s disease: a 24-month follow-up study. Rheumatology (Oxford) 46:1161–1164CrossRefGoogle Scholar
  20. 20.
    Al-Rayes H, Al-Swailem R, Al-Balawi M, Al-Dohayan N, Al-Zaidi S, Tariq M (2008) Safety and efficacy of infliximab therapy in active Behçet’s uveitis: an open-label trial. Rheumatol Int 29:53–57PubMedCrossRefGoogle Scholar
  21. 21.
    Yamada Y, Sugita S, Tanaka H, Kamoi K, Kawaguchi T, Mochizuki M (2010) Comparison of infliximab versus ciclosporin during the initial 6-month treatment period in Behçet disease. Br J Ophthalmol 94:284–288PubMedCrossRefGoogle Scholar
  22. 22.
    Elezoglou A, Kafasi N, Kaklamanis PH, Theodossiadis PG, Kapsimali V, Choremi E, Vaiopoulos G, Sfikakis PP (2007) Infliximab treatment-induced formation of autoantibodies is common in Behçet’s disease. Clin Exp Rheumatol 25:S65–S69PubMedGoogle Scholar
  23. 23.
    Mizushima Y (1988) Recent research into Behçet’s disease in Japan. Int J Tissue React 10:59–65PubMedGoogle Scholar
  24. 24.
    Jabs DA, Nussenblatt RB, Rosenbaum JT, Group SoUNSW (2005) Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 140:509–516CrossRefGoogle Scholar
  25. 25.
    Fritzler MJ, Pauls JD, Kinsella TD, Bowen TJ (1985) Antinuclear, anticytoplasmic, and anti-Sjögren’s syndrome antigen A (SS-A/Ro) antibodies in female blood donors. Clin Immunol Immunopathol 36:120–128PubMedCrossRefGoogle Scholar
  26. 26.
    de Vlam K, De Keyser F, Verbruggen G, Vandenbossche M, Vanneuville B, D’Haese D, Veys EM (1993) Detection and identification of antinuclear autoantibodies in the serum of normal blood donors. Clin Exp Rheumatol 11:393–397PubMedGoogle Scholar
  27. 27.
    Forslid J, Heigl Z, Jonsson J, Scheynius A (1994) The prevalence of antinuclear antibodies in healthy young persons and adults, comparing rat liver tissue sections with HEp-2 cells as antigen substrate. Clin Exp Rheumatol 12:137–141PubMedGoogle Scholar
  28. 28.
    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 40:1601–1611PubMedCrossRefGoogle Scholar
  29. 29.
    Fernandez SA, Lobo AZ, Oliveira ZN, Fukumori LM, AM Prigo, Rivitti EA (2003) Prevalence of antinuclear autoantibodies in the serum of normal blood donors. Rev Hosp Clin Fac Med Sao Paulo 58:315–319PubMedCrossRefGoogle Scholar
  30. 30.
    Watanabe A, Kodera M, Sugiura K, Usuda T, Tan EM, Takasaki Y, Tomita Y, Muro Y (2004) Anti-DFS70 antibodies in 597 healthy hospital workers. Arthritis Rheum 50:892–900PubMedCrossRefGoogle Scholar
  31. 31.
    Al Jabri AA, Al Buloshi MS (2004) Anticardiolipin and antinuclear antibodies in the adult healthy Omani individuals. Saudi Med J 25:313–317PubMedGoogle Scholar
  32. 32.
    De Rycke L, Kruithof E, Van Damme N, Hoffman IE, Van den Bossche N, Van den Bosch F, Veys EM, De Keyser F (2003) Antinuclear antibodies following infliximab treatment in patients with rheumatoid arthritis or spondylarthropathy. Arthritis Rheum 48:1015–1023PubMedCrossRefGoogle Scholar
  33. 33.
    Elkayam O, Burke M, Vardinon N, Zakut V, Yitzhak RB, Paran D, Levartovsky D, Litinsky I, Caspi D (2005) Autoantibodies profile of rheumatoid arthritis patients during treatment with infliximab. Autoimmunity 38:155–160PubMedCrossRefGoogle Scholar
  34. 34.
    Eriksson C, Engstrand S, Sundqvist KG, Rantapää-Dahlqvist S (2005) Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNF alpha. Ann Rheum Dis 64:403–407PubMedCrossRefGoogle Scholar
  35. 35.
    Pink AE, Fonia A, Allen MH, Smith CH, Barker JN (2010) Antinuclear antibodies associate with loss of response to antitumour necrosis factor-alpha therapy in psoriasis: a retrospective, observational study. Br J Dermatol 162:780–785PubMedCrossRefGoogle Scholar
  36. 36.
    Nancey S, Blanvillain E, Parmentier B, Flourié B, Bayet C, Bienvenu J, Fabien N (2005) Infliximab treatment does not induce organ-specific or nonorgan-specific autoantibodies other than antinuclear and anti-double-stranded DNA autoantibodies in Crohn’s disease. Inflamm Bowel Dis 11:986–991PubMedCrossRefGoogle Scholar
  37. 37.
    Smith CH, Jackson K, Bashir SJ, Perez A, Chew AL, Powell AM, Wain M, Barker JN (2006) Infliximab for severe, treatment-resistant psoriasis: a prospective, open-label study. Br J Dermatol 155:160–169PubMedCrossRefGoogle Scholar
  38. 38.
    Charles PJ, Smeenk RJ, De Jong J, Feldmann M, Maini RN (2000) Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open-label and randomized placebo-controlled trials. Arthritis Rheum 43:2383–2390PubMedCrossRefGoogle Scholar
  39. 39.
    Cairns AP, Duncan MK, Hinder AE, Taggart AJ (2002) New onset systemic lupus erythematosus in a patient receiving etanercept for rheumatoid arthritis. Ann Rheum Dis 61:1031–1032PubMedCrossRefGoogle Scholar
  40. 40.
    Debandt M, Vittecoq O, Descamps V, Le Loët X, Meyer O (2003) Anti-TNF-alpha-induced systemic lupus syndrome. Clin Rheumatol 22:56–61PubMedCrossRefGoogle Scholar
  41. 41.
    Favalli EG, Sinigaglia L, Varenna M, Arnoldi C (2002) Drug-induced lupus following treatment with infliximab in rheumatoid arthritis. Lupus 11:753–755PubMedCrossRefGoogle Scholar
  42. 42.
    Suhler EB, Smith JR, Wertheim MS, Lauer AK, Kurz DE, Pickard TD, Rosenbaum JT (2005) A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes. Arch Ophthalmol 123:903–912PubMedCrossRefGoogle Scholar
  43. 43.
    Osada A, Nakashima H, Furue M, Tamaki K (1995) Up-regulation of CD44 expression by tumor necrosis factor-alpha is neutralized by interleukin-10 in Langerhans cells. J Invest Dermatol 105:124–127PubMedCrossRefGoogle Scholar
  44. 44.
    Hart SP, Dougherty GJ, Haslett C, Dransfield I (1997) CD44 regulates phagocytosis of apoptotic neutrophil granulocytes, but not apoptotic lymphocytes, by human macrophages. J Immunol 159:919–925PubMedGoogle Scholar
  45. 45.
    Herrmann M, Voll RE, Zoller OM, Hagenhofer M, Ponner BB, Kalden JR (1998) Impaired phagocytosis of apoptotic cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum 41:1241–1250PubMedCrossRefGoogle Scholar
  46. 46.
    Cairns AP, Crockard AD, McConnell JR, Courtney PA, Bell AL (2001) Reduced expression of CD44 on monocytes and neutrophils in systemic lupus erythematosus: relations with apoptotic neutrophils and disease activity. Ann Rheum Dis 60:950–955PubMedCrossRefGoogle Scholar
  47. 47.
    Finckh A, Dudler J, Wermelinger F, Ciurea A, Kyburz D, Gabay C, Bas S, SCQM PO (2010) Influence of anti-infliximab antibodies and residual infliximab concentrations on the occurrence of acquired drug resistance to infliximab in rheumatoid arthritis patients. Joint Bone Spine 77: 313–318Google Scholar
  48. 48.
    Yamada A, Sono K, Hosoe N, Takada N, Suzuki Y (2010) Monitoring functional serum antitumor necrosis factor antibody level in Crohn’s disease patients who maintained and those who lost response to anti-TNF. Inflamm Bowel Dis 16:1898–1904PubMedCrossRefGoogle Scholar
  49. 49.
    Reich K, Nestle FO, Papp K, Ortonne JP, Evans R, Guzzo C, Li S, Dooley LT, Griffiths CE, investigators Es (2005) Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet 366: 1367–1374Google Scholar
  50. 50.
    Adişen E, Aral A, Aybay C, Gürer MA (2010) Anti-infliximab antibody status and its relation to clinical response in psoriatic patients: a pilot study. J Dermatol 37:708–713PubMedCrossRefGoogle Scholar
  51. 51.
    Sugita S, Yamada Y, Mochizuki M (2010) Relationship between serum infliximab levels and acute uveitis attacks in patients with Behçet disease. Br J Ophthalmol 95:549–552PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Daiju Iwata
    • 1
  • Kenichi Namba
    • 1
    Email author
  • Kazuomi Mizuuchi
    • 1
  • Nobuyoshi Kitaichi
    • 2
    • 3
  • Satoru Kase
    • 1
  • Yuko Takemoto
    • 1
  • Shigeaki Ohno
    • 3
  • Susumu Ishida
    • 1
  1. 1.Department of OphthalmologyHokkaido University Graduate School of MedicineSapporoJapan
  2. 2.Department of OphthalmologyHealth Sciences University of HokkaidoSapporoJapan
  3. 3.Department of Ocular Inflammation and ImmunologyHokkaido University Graduate School of MedicineSapporoJapan

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