Clinical Rheumatology

, Volume 34, Issue 7, pp 1293–1301 | Cite as

Anakinra treatment in drug-resistant Behcet’s disease: a case series

  • Luca Cantarini
  • Antonio Vitale
  • Perla Scalini
  • Charles A. Dinarello
  • Donato Rigante
  • Rossella Franceschini
  • Gabriele Simonini
  • Giulia Borsari
  • Francesco Caso
  • Orso Maria Lucherini
  • Bruno Frediani
  • Ilaria Bertoldi
  • Leonardo Punzi
  • Mauro Galeazzi
  • Rolando Cimaz
Case Based Review


The study objective was to report treatment with an interleukin (IL)-1 receptor antagonist, anakinra, in patients with multiorgan Behcet's disease (BD). Comparison of clinical manifestations, previous treatments, markers of inflammation, concomitant medications, treatment regimen modifications, relapses, and adverse events before and during anakinra administration among patients with BD were evaluated. Nine BD patients (mean age 34.55 ± 16.30 years) refractory to tumor necrosis factor blockers and standardized therapies are reported in our survey. Their mean age at disease onset was 25 ± 13.88 years and their overall disease duration was 9.55 ± 5.33 years. All patients were positive for the HLA-B51 allele. Within 1 or 2 weeks following the initiation of anakinra, eight out of nine patients promptly responded, and most of them were maintained on 100 mg of daily anakinra with low doses of prednisone. However, most patients experienced a relapse in one or more clinical manifestations over time (mean time to relapse 29 ± 21.65 weeks), and only one patient remained completely under control on anakinra monotherapy. Despite a relapse in one or more disease manifestations, treatment was continued in most patients for a mean period of 13.75 ± 6.49 months. No serious adverse events occurred. Eight out of nine refractory BD patients showed a prompt improvement after starting anakinra, supporting the concept that IL-1 plays a pathological role in this disease. Nevertheless, after several months, most patients experienced a relapse. It remains unclear whether increasing the dose of anakinra would have prevented the reoccurrence of disease activity.


Behcet's disease Biologic agents Interleukin-1 inhibition Uveitis 





  1. 1.
    International Study Group for Behcet disease (1990) Criteria for diagnosis of Behcet's disease. Lancet 335:1078–1080Google Scholar
  2. 2.
    Kural-Seyahi E, Fresko I, Seyahi N, Ozyazgan Y, Mat C, Hamuryudan V, Yurdakul S, Yazici H (2003) The long-term mortality and morbidity of Behçet syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated center. Medicine (Baltimore) 82:60–76CrossRefGoogle Scholar
  3. 3.
    Alexoudi I, Kapsimali V, Vaiopoulos A, Kanakis M, Vaiopoulos G (2011) Evaluation of current therapeutic strategies in Behçet's disease. Clin Rheumatol 30:157–163PubMedCrossRefGoogle Scholar
  4. 4.
    Pipitone N, Olivieri I, Padula A, D'angelo S, Nigro A, Zuccoli G, Boiardi L, Salvarani C (2008) Infliximab for the treatment of neuro-Behcet's disease: a case series and review of the literature. Arthritis Rheum 59:285–290PubMedCrossRefGoogle Scholar
  5. 5.
    Botsios C, Sfriso P, Furlan A, Punzi L, Dinarello CA (2008) Resistant Behçet disease responsive to anakinra. Ann Intern Med 149:284–286PubMedCrossRefGoogle Scholar
  6. 6.
    Gül A, Tugal-Tutkun I, Dinarello CA, Reznikov L, Esen BA, Mirza A, Scannon P, Solinger A (2012) Interleukin-1β-regulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behcet's disease: an open-label pilot study. Ann Rheum Dis 71:563–566PubMedCrossRefGoogle Scholar
  7. 7.
    Touitou I, Magne X, Molinari N, Navarro A, Quellec AL, Picco P, Seri M, Ozen S, Bakkaloglu A, Karaduman A, Garnier JM, Demaille J, Koné-Paut I (2000) MEFV mutations in Behçet's disease. Hum Mutat 16:271–272PubMedCrossRefGoogle Scholar
  8. 8.
    Amoura Z, Dodé C, Hue S, Caillat-Zucman S, Bahram S, Delpech M, Grateau G, Wechsler B, Piette JC (2005) Association of the R92Q TNFRSF1A mutation and extracranial deep vein thrombosis in patients with Behçet's disease. Arthritis Rheum 52:608–611PubMedCrossRefGoogle Scholar
  9. 9.
    Rigante D (2012) The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev 11:348–356PubMedCrossRefGoogle Scholar
  10. 10.
    Kotter I, Hamuryudan V, Ozturk ZE, Yazici H (2010) Interferon therapy in rheumatic diseases: state-of-the-art 2010. Curr Opin Rheumatol 22:278–283PubMedCrossRefGoogle Scholar
  11. 11.
    Cantarini L, Vitale A, Borri M, Galeazzi M, Franceschini R (2012) Successful use of canakinumab in a patient with resistant Behçet's disease. Clin Exp Rheumatol 30:S115PubMedGoogle Scholar
  12. 12.
    Ugurlu S, Ucar D, Seyahi E, Hatemi G, Yurdakul S (2012) Canakinumab in a patient with juvenile Behcet's syndrome with refractory eye disease. Ann Rheum Dis 71:1589–1591PubMedCrossRefGoogle Scholar
  13. 13.
    Direskeneli H (2006) Autoimmunity vs autoinflammation in Behcet's disease: do we oversimplify a complex disorder? Rheumatology (Oxford) 45:1461–1465CrossRefGoogle Scholar
  14. 14.
    Hatemi G, Silman A, Bang D, Bodaghi B, Chamberlain AM, Gul A, Houman MH, Kötter I, Olivieri I, Salvarani C, Sfikakis PP, Siva A, Stanford MR, Stübiger N, Yurdakul S, Yazici H, Expert Committee EULAR (2008) EULAR recommendations for the management of Behcet disease. Ann Rheum Dis 67:1656–1662PubMedCrossRefGoogle Scholar
  15. 15.
    Evereklioglu C, Er H, Turkoz Y, Cekmen M (2002) Serum levels of TNF-alpha, sIL-2R, IL-6, and IL-8 are increased and associated with elevated lipid peroxidation in patients with Behcet's disease. Mediators Inflamm 11:8793Google Scholar
  16. 16.
    Turan B, Gallati H, Erdi H, Gürler A, Michel BA, Villiger PM (1997) Systemic levels of the T cell regulatory cytokines IL-10 and IL-12 in Behcet's disease; soluble TNFR-75 as a biological marker of disease activity. J Rheumatol 24:12832Google Scholar
  17. 17.
    Arida A, Fragiadaki K, Giavri E, Sfikakis PP (2011) Anti-TNF agents for Behcet's disease: analysis of published data on 369 patients. Semin Arthritis Rheum 41:61–70PubMedCrossRefGoogle Scholar
  18. 18.
    Cantarini L, Tinazzi I, Caramaschi P, Bellisai F, Brogna A, Galeazzi M (2009) Safety and efficacy of etanercept in children with juvenile-onset Behcet's disease. Int J Immunopathol Pharmacol 22:551–555PubMedGoogle Scholar
  19. 19.
    Atzeni F, Leccese P, D’Angelo S, Sarzi-Puttini P, Olivieri I (2010) Successful treatment of leg ulcers in Behcet's disease using adalimumab plus methotrexate after the failure of infliximab. Clin Exp Rheumatol 28:S94PubMedGoogle Scholar
  20. 20.
    Belzunegui J, Lopez L, Paniagua I, Intxausti JJ, Maiz O (2008) Efficacy of infliximab and adalimumab in the treatment of a patient with severe neuro-Behcet's disease. Clin Exp Rheumatol 26:S1334Google Scholar
  21. 21.
    Leccese P, D’Angelo S, Angela P, Coniglio G, Olivieri I (2010) Switching to adalimumab is effective in a case of neuro-Behcet's disease refractory to infliximab. Clin Exp Rheumatol 28:S102PubMedGoogle Scholar
  22. 22.
    Lee SW, Lee SY, Kim KN, Jung JK, Chung WT (2010) Adalimumab treatment for life threatening pulmonary artery aneurysm in Behcet disease: a case report. Clin Rheumatol 29:91–93PubMedCrossRefGoogle Scholar
  23. 23.
    Mushtaq B, Saeed T, Situnayake RD, Murray PI (2007) Adalimumab for sight-threatening uveitis in Behcet’s disease. Eye 21:824–825PubMedCrossRefGoogle Scholar
  24. 24.
    Takase K, Ohno S, Ideguchi H, Uchio E, Takeno M, Ishigatsubo Y (2011) Successful switching to adalimumab in an infliximab-allergic patient with severe Behcet disease-related uveitis. Rheumatol Int 31:243–245PubMedCrossRefGoogle Scholar
  25. 25.
    van Laar JA, Missotten T, van Daele PL, Jamnitski A, Baarsma GS, van Hagen PM (2007) Adalimumab: a new modality for Behcet's disease? Ann Rheum Dis 66:565–566PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Bodar EJ, Kuijk LM, Drenth JP, van der Meer JW, Simon A, Frenkel J (2011) On-demand anakinra treatment is effective in mevalonate kinase deficiency. Ann Rheum Dis 70:2155–2158PubMedCrossRefGoogle Scholar
  27. 27.
    Neven B, Marvillet I, Terrada C, Ferster A, Boddaert N, Couloignier V, Pinto G, Pagnier A, Bodemer C, Bodaghi B, Tardieu M, Prieur AM, Quartier P (2010) Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum 62:258–267PubMedCrossRefGoogle Scholar
  28. 28.
    Quartier P, Allantaz F, Cimaz R, Pillet P, Messiaen C, Bardin C, Bossuyt X, Boutten A, Bienvenu J, Duquesne A, Richer O, Chaussabel D, Mogenet A, Banchereau J, Treluyer JM, Landais P, Pascual V (2011) A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis 70:747–754PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Obici L, Meini A, Cattalini M, Chicca S, Galliani M, Donadei S, Plebani A, Merlini G (2011) Favourable and sustained response to anakinra in tumour necrosis factor receptor-associated periodic syndrome (TRAPS) with or without AA amyloidosis. Ann Rheum Dis 70:1511–1512PubMedCrossRefGoogle Scholar
  30. 30.
    Zhou ZY, Chen SL, Shen N, Lu Y (2012) Cytokines and Behcet's disease. Autoimmun Rev 11:699–704PubMedCrossRefGoogle Scholar
  31. 31.
    Akman-Demir G, Tüzün E, Içöz S, Yeşilot N, Yentür SP, Kürtüncü M, Mutlu M, Saruhan-Direskeneli G (2008) Interleukin-6 in neuro-Behçet's disease: association with disease subsets and long-term outcome. Cytokine 44:373–376PubMedCrossRefGoogle Scholar
  32. 32.
    Akdeniz N, Esrefoglu M, Keleş MS, Karakuzu A, Atasoy M (2004) Serum interleukin-2, interleukin-6, tumour necrosis factor-alpha and nitric oxide levels in patients with Behcet's disease. Ann Acad Med Singapore 33:596–599PubMedGoogle Scholar
  33. 33.
    Borhani Haghighi A, Ittehadi H, Nikseresht AR, Rahmati J, Poorjahromi SG, Pourabbas B, Nazarinia MA, Habibagahi Z, Fattahi MJ, Ghaderi A (2009) CSF levels of cytokines in neuro-Behçet's disease. Clin Neurol Neurosurg 111:507–510PubMedCrossRefGoogle Scholar
  34. 34.
    Dinarello CA, Simon A, van der Meer JW (2012) Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 11:633–652PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Düzgün N, Ayaşlioğlu E, Tutkak H, Aydintuğ OT (2005) Cytokine inhibitors: soluble tumor necrosis factor receptor 1 and interleukin-1 receptor antagonist in Behçet's disease. Rheumatol Int 25:1–5PubMedCrossRefGoogle Scholar
  36. 36.
    Mege JL, Dilsen N, Sanguedolce V, Gul A, Bongrand P, Roux H, Ocal L, Inanç M, Capo C (1993) Overproduction of monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behçet's disease. A comparative study with familial Mediterranean fever and healthy subjects. J Rheumatol 20:1544–1549PubMedGoogle Scholar
  37. 37.
    Biasucci LM, Liuzzo G, Fantuzzi G, Caligiuri G, Rebuzzi AG, Ginnetti F, Dinarello CA, Maseri A (1999) Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation 99:2079–2084PubMedCrossRefGoogle Scholar
  38. 38.
    Yosipovitch G, Shohat B, Bshara J, Wysenbeek A, Weinberger A (1995) Elevated serum interleukin 1 receptors and interleukin 1B in patients with Behçet's disease: correlations with disease activity and severity. Isr J Med Sci 31:345–348PubMedGoogle Scholar
  39. 39.
    Ottenhoff TH, Verreck FA, Lichtenauer-Kaligis EG, Hoeve MA, Sanal O, van Dissel JT (2002) Genetics, cytokines and human infectious disease: lessons from weakly pathogenic mycobacteria and salmonellae. Nat Genet 32:97–105PubMedCrossRefGoogle Scholar
  40. 40.
    Song X, Krelin Y, Dvorkin T, Bjorkdahl O, Segal S, Dinarello CA, Voronov E, Apte RN (2005) CD11b+/Gr-1+ immature myeloid cells mediate suppression of T cells in mice bearing tumors of IL-1beta-secreting cells. J Immunol 175:8200–8208PubMedCrossRefGoogle Scholar
  41. 41.
    Okada AA, Goto H, Ohno S, Mochizuki M, Ocular Behçet's Disease Research Group Of Japan (2012) Multicenter study of infliximab for refractory uveoretinitis in Behçet disease. Arch Ophthalmol 130:592–598PubMedCrossRefGoogle Scholar
  42. 42.
    Accorinti M, Pirraglia MP, Paroli MP, 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
  43. 43.
    Perra D, Alba MA, Callejas JL, Mesquida M, Ríos-Fernández R, Adán A, Ortego N, Cervera R, Espinosa G (2012) Adalimumab for the treatment of Behçet's disease: experience in 19 patients. Rheumatology (Oxford) 51:1825–1831CrossRefGoogle Scholar
  44. 44.
    Iwata S, Saito K, Yamaoka K, Tsujimura S, Nawata M, Hanami K, Tanaka Y (2011) Efficacy of combination therapy of anti-TNF-α antibody infliximab and methotrexate in refractory entero-Behçet's disease. Mod Rheumatol 21:184–1891PubMedCrossRefGoogle Scholar
  45. 45.
    Joseph A, Raj D, Dua HS, Powell PT, Lanyon PC, Powell RJ (2003) Infliximab in the treatment of refractory posterior uveitis. Ophthalmology 110:1449–1453PubMedCrossRefGoogle Scholar
  46. 46.
    Borhani Haghighi A, Safari A, Nazarinia MA, Habibagahi Z, Shenavandeh S (2011) Infliximab for patients with neuro-Behcet's disease: case series and literature review. Clin Rheumatol 30:1007–1012PubMedCrossRefGoogle Scholar

Copyright information

© Clinical Rheumatology 2013

Authors and Affiliations

  • Luca Cantarini
    • 1
    • 2
  • Antonio Vitale
    • 1
  • Perla Scalini
    • 3
  • Charles A. Dinarello
    • 4
    • 5
  • Donato Rigante
    • 6
  • Rossella Franceschini
    • 7
  • Gabriele Simonini
    • 3
  • Giulia Borsari
    • 7
  • Francesco Caso
    • 8
  • Orso Maria Lucherini
    • 1
  • Bruno Frediani
    • 1
  • Ilaria Bertoldi
    • 1
  • Leonardo Punzi
    • 8
  • Mauro Galeazzi
    • 1
  • Rolando Cimaz
    • 3
  1. 1.Research Center of Systemic Autoimmune and Autoinflammatory Diseases, Rheumatology Unit, Policlinico Le ScotteUniversity of SienaSienaItaly
  2. 2.Department of Medical Sciences, Surgery and Neurosciences, Rheumatology Unit, Policlinico Le ScotteUniversity of SienaSienaItaly
  3. 3.Department of Pediatrics, Rheumatology Unit, Anna Meyer Children’s HospitalUniversity of FlorenceFlorenceItaly
  4. 4.Department of MedicineUniversity of Colorado DenverAuroraUSA
  5. 5.Department of MedicineUniversity Medical Center NijmegenNijmegenThe Netherlands
  6. 6.Institute of PediatricsUniversità Cattolica Sacro CuoreRomeItaly
  7. 7.Ophthalmology and Neurosurgery DepartmentUniversity of SienaSienaItaly
  8. 8.Rheumatology Unit, Department of MedicineUniversity of PadovaPaduaItaly

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