Clinical Rheumatology

, Volume 32, Issue 1, pp 141–147

Tocilizumab in the treatment of the adult-onset Still's disease: current clinical evidence

  • Hubert de Boysson
  • Jérome Février
  • Amélie Nicolle
  • Christophe Auzary
  • Loïk Geffray
Case Based Review

Abstract

This study aimed to review and analyze the effectiveness and safety of tocilizumab in the treatment of patients with adult-onset Still's disease (AOSD). We report on two patients with AOSD who were successfully treated with tocilizumab. All published information on the use of tocilizumab in this disease was also retrieved through a systematic review of the English-language literature. Including our cases, 35 patients were given tocilizumab for AOSD (8 mg/kg/month in 22 patients). The main clinical manifestations were arthritis in all 35 patients and systemic symptoms such as fever or skin rash in 28 (80 %). Thirty-three (94 %) patients had unsuccessfully tried other immunosuppressive agents such as methotrexate, tumor necrosis factor-α blockers, or anakinra. Most of the patients achieved a response with tocilizumab, such as a prompt articular improvement in 30/35 (86 %) patients and a disappearance of systemic symptoms in 27/28 (96 %). Twenty-eight (80 %) patients tapered their steroid intakes, including seven (20 %) who were able to discontinue them. Four (11 %) patients relapsed, and two were successfully retreated with tocilizumab. Regarding safety, tocilizumab is a well-tolerated treatment, but severe side effects such as macrophage activation syndrome or cytomegalovirus reactivation are possible and require ongoing vigilance. Our findings suggest that tocilizumab should probably be proposed in refractory AOSD, as it allows for remission to be induced and the dose of steroid intakes to be reduced. It is a well-tolerated treatment that can be administered according to the therapeutic sequence of rheumatoid arthritis. Further prospective studies are required to assess the better use of this treatment (dosage and duration) and its place among other conventional treatments.

Keywords

Adult-onset Still's disease Macrophage activation syndrome Tocilizumab 

References

  1. 1.
    Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H (1992) Preliminary criteria for classification of adult Still's disease. J Rheumatol 19:424–430PubMedGoogle Scholar
  2. 2.
    Fautrel B (2008) Adult-onset Still disease. Best Pract Res Clin Rheumatol 22(5):773–792. doi:10.1016/j.berh.2008.08.006 PubMedCrossRefGoogle Scholar
  3. 3.
    Cunha ML, Wagner J, Osawa A, Scheinberg M (2010) The effect of tocilizumab on the uptake of 18FDG-PET imaging in patients with adult-onset Still's disease. Rheumatology (Oxford) 49(5):1014–1016CrossRefGoogle Scholar
  4. 4.
    De Bandt M, Saint-Marcoux B (2009) Tocilizumab for multi-refractory adult-onset Still's disease. Ann Rheum Dis 68:153–154PubMedCrossRefGoogle Scholar
  5. 5.
    Iwamoto M, Nara H, Hirata D, Minota S, Nishimoto N, Yoshizaki K (2002) Humanized monoclonal anti-interleukin-6 receptor antibody for treatment of intractable adult-onset Still's disease. Arthritis Rheum 46:3388–3389PubMedCrossRefGoogle Scholar
  6. 6.
    Kishida D, Okuda Y, Onishi M, Takebayashi M, Matoba K, Jouyama K, Yamada A, Sawada N, Mokuda S, Takasugi K (2011) Successful tocilizumab treatment in a patient with adult-onset Still's disease complicated by chronic active hepatitis B and amyloid A amyloidosis. Mod Rheumatol Jpn Rheum Assoc 21(2):215–218. doi:10.1007/s10165-010-0365-8 CrossRefGoogle Scholar
  7. 7.
    Kobayashi M, Takahashi Y, Yamashita H, Kaneko H, Mimori A (2011) Benefit and a possible risk of tocilizumab therapy for adult-onset Still's disease accompanied by macrophage-activation syndrome. Mod Rheumatol Jpn Rheum Assoc 21(1):92–96. doi:10.1007/s10165-010-0348-9 CrossRefGoogle Scholar
  8. 8.
    Lopez Buitrago R, Estrada Dorronsoro S, Cervera Segura R, Espinosa Garriga G (2012) Tocilizumab effectiveness in adult Still's disease. Med Clin (Barc) 138(1):42–43CrossRefGoogle Scholar
  9. 9.
    Matsumoto K, Nagashima T, Takatori S, Kawahara Y, Yagi M, Iwamoto M, Okazaki H, Minota S (2009) Glucocorticoid and cyclosporine refractory adult onset Still's disease successfully treated with tocilizumab. Clin Rheumatol 28(4):485–487. doi:10.1007/s10067-009-1097-z PubMedCrossRefGoogle Scholar
  10. 10.
    Nakahara H, Mima T, Yoshio-Hoshino N, Matsushita M, Hashimoto J, Nishimoto N (2009) A case report of a patient with refractory adult-onset Still's disease who was successfully treated with tocilizumab over 6 years. Mod Rheumatol Jpn Rheum Assoc 19:69–72CrossRefGoogle Scholar
  11. 11.
    Naniwa T, Ito R, Watanabe M, Hayami Y, Maeda S, Sasaki K, Iwagaitsu S (2010) Case report: successful use of short-term add-on tocilizumab for multirefractory systemic flare of adult-onset Still's disease. Clin Rheumatol. doi:10.1007/s10067-010-1562-8
  12. 12.
    Perdan-Pirkmajer K, Praprotnik S, Tomsic M (2010) A case of refractory adult-onset Still's disease successfully controlled with tocilizumab and a review of the literature. Clin Rheumatol 29:1465–1467PubMedCrossRefGoogle Scholar
  13. 13.
    Puechal X, DeBandt M, Berthelot JM, Breban M, Dubost JJ, Fain O, Kahn JE, Lequen L, Longy-Boursier M, Perdriger A, Schaeverbeke T, Toussirot E, Sibilia J (2011) Tocilizumab in refractory adult Still's disease. Arthritis Care Res (Hoboken) 63(1):155–159. doi:10.1002/acr.20319 CrossRefGoogle Scholar
  14. 14.
    Rech J, Ronneberger M, Englbrecht M, Finzel S, Katzenbeisser J, Manger K, Manger B, Schett G (2011) Successful treatment of adult-onset Still's disease refractory to TNF and IL-1 blockade by IL-6 receptor blockade. Ann Rheum Dis 70(2):390–392. doi:10.1136/ard.2010.129403 PubMedCrossRefGoogle Scholar
  15. 15.
    Rkiouak A, Ennibi K, Zinebi A, Akhouad Y, Reggad A, Rabhi M, Chaari J (2012) Adult refractory Still disease with atypical articular manifestations: efficacity of interleukin-6 antagonists (tocilizumab). Ann Pharm Fr 70(3):163–168. doi:10.1016/j.pharma.2012.03.001 PubMedCrossRefGoogle Scholar
  16. 16.
    Sabnis GR, Gokhale YA, Kulkarni UP (2011) Tocilizumab in refractory adult-onset Still's disease with aseptic meningitis–efficacy of interleukin-6 blockade and review of the literature. Semin Arthritis Rheum 40(4):365–368. doi:10.1016/j.semarthrit.2010.05.003 PubMedCrossRefGoogle Scholar
  17. 17.
    Sakai R, Nagasawa H, Nishi E, Okuyama A, Takei H, Kurasawa T, Kondo T, Nishimura K, Shirai Y, Ito T, Kameda H, Takeuchi T, Amano K (2012) Successful treatment of adult-onset Still's disease with tocilizumab monotherapy: two case reports and literature review. Clin Rheumatol 31(3):569–574. doi:10.1007/s10067-011-1917-9 PubMedCrossRefGoogle Scholar
  18. 18.
    Sekkach Y, Elqatni M, Khattabi AE, Fatihi J, Hammi S, Badaoui M, Elomri N, Mekouar F, Amezyane T, Abouzahir A, Ghafir D (2011) Antagonists of interleukin-6 (tocilizumab), in adult refractory still disease. Press Med 40(7–8):333–337. doi:10.1016/j.lpm.2011.03.012 CrossRefGoogle Scholar
  19. 19.
    Sumida K, Ubara Y, Hoshino J, Suwabe T, Hiramatsu R, Hasegawa E, Hayami N, Yamanouchi M, Sawa N, Takemoto F, Takaichi K (2010) Etanercept-refractory adult-onset Still's disease with thrombotic thrombocytopenic purpura successfully treated with tocilizumab. Clin Rheumatol 29(10):1191–1194. doi:10.1007/s10067-010-1418-2 PubMedCrossRefGoogle Scholar
  20. 20.
    Thonhofer R, Hiller M, Just H, Trummer M, Siegel C, Dejaco C (2011) Treatment of refractory adult-onset Still's disease with tocilizumab: report of two cases and review of the literature. Rheumatol Int 31(12):1653–1656. doi:10.1007/s00296-010-1631-y PubMedCrossRefGoogle Scholar
  21. 21.
    Yoshida Y, Sakamoto M, Yokota K, Sato K, Mimura T (2011) Tocilizumab improved both clinical and laboratory manifestations except for interleukin-18 in a case of multiple drug-resistant adult-onset Still's disease. Intern Med 50(16):1757–1760PubMedCrossRefGoogle Scholar
  22. 22.
    Yoshimura M, Makiyama J, Koga T, Miyashita T, Izumi Y, Torigoshi T, Motokawa S, Eguchi K, Migita K (2010) Successful treatment with tocilizumab in a patient with refractory adult-onset Still's disease (AOSD). Clin Exp Rheumatol 28(1):141–142PubMedGoogle Scholar
  23. 23.
    Fitzgerald AA, Leclercq SA, Yan A, Homik JE, Dinarello CA (2005) Rapid responses to anakinra in patients with refractory adult-onset Still's disease. Arthritis Rheum 52(6):1794–1803. doi:10.1002/art.21061 PubMedCrossRefGoogle Scholar
  24. 24.
    Chen DY, Lan JL, Lin FJ, Hsieh TY (2004) Proinflammatory cytokine profiles in sera and pathological tissues of patients with active untreated adult onset Still's disease. J Rheumatol 31(11):2189–2198PubMedGoogle Scholar
  25. 25.
    Scheinberg MA, Chapira E, Fernandes ML, Hubscher O (1996) Interleukin 6: a possible marker of disease activity in adult onset Still's disease. Clin Exp Rheumatol 14(6):653–655PubMedGoogle Scholar
  26. 26.
    Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T (2008) Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood 112(10):3959–3964. doi:10.1182/blood-2008-05-155846 PubMedCrossRefGoogle Scholar
  27. 27.
    Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei S, Iwata N, Umebayashi H, Murata T, Miyoshi M, Tomiita M, Nishimoto N, Kishimoto T (2008) Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 371(9617):998–1006. doi:10.1016/S0140-6736(08)60454-7 PubMedCrossRefGoogle Scholar
  28. 28.
    Nishimoto N, Hashimoto J, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Murata N, van der Heijde D, Kishimoto T (2007) Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis 66(9):1162–1167. doi:10.1136/ard.2006.068064 PubMedCrossRefGoogle Scholar
  29. 29.
    Arlet JB, Le TH, Marinho A, Amoura Z, Wechsler B, Papo T, Piette JC (2006) Reactive haemophagocytic syndrome in adult-onset Still's disease: a report of six patients and a review of the literature. Ann Rheum Dis 65(12):1596–1601. doi:10.1136/ard.2005.046904 PubMedCrossRefGoogle Scholar
  30. 30.
    Shimizu M, Nakagishi Y, Kasai K, Yamasaki Y, Miyoshi M, Takei S, Yachie A (2012) Tocilizumab masks the clinical symptoms of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: the diagnostic significance of interleukin-18 and interleukin-6. Cytokine 58(2):287–294. doi:10.1016/j.cyto.2012.02.006 PubMedCrossRefGoogle Scholar
  31. 31.
    Saiki O, Uda H, Nishimoto N, Miwa T, Mima T, Ogawara T, Azuma N, Katada Y, Sawaki J, Tsutsui H, Matsui K, Maeda A, Nakanishi K (2004) Adult Still's disease reflects a Th2 rather than a Th1 cytokine profile. Clin Immunol 112(1):120–125. doi:10.1016/j.clim.2004.03.023 PubMedCrossRefGoogle Scholar
  32. 32.
    Mima T, Nishimoto N (2009) Clinical value of blocking IL-6 receptor. Curr Opin Rheumatol 21(3):224–230. doi:10.1097/BOR.0b013e3283295fec PubMedCrossRefGoogle Scholar
  33. 33.
    Ostrowski RA, Tehrani R, Kadanoff R (2011) Refractory adult-onset still disease successfully treated with abatacept. J Clin Rheumatol: Pract Rep Rheum Musculoskelet Dis 17(6):315–317. doi:10.1097/RHU.0b013e31822c53ad Google Scholar

Copyright information

© Clinical Rheumatology 2012

Authors and Affiliations

  • Hubert de Boysson
    • 1
    • 2
  • Jérome Février
    • 1
  • Amélie Nicolle
    • 1
  • Christophe Auzary
    • 1
  • Loïk Geffray
    • 1
  1. 1.Service de médecine interneCentre Hospitalier Robert BissonLisieuxFrance
  2. 2.Department of Internal MedicineCentre Hospitalier et Universitaire Côte de NacreCaen Cedex 9France

Personalised recommendations