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.
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References
Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H (1992) Preliminary criteria for classification of adult Still's disease. J Rheumatol 19:424–430
Fautrel B (2008) Adult-onset Still disease. Best Pract Res Clin Rheumatol 22(5):773–792. doi:10.1016/j.berh.2008.08.006
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):1014–1016
De Bandt M, Saint-Marcoux B (2009) Tocilizumab for multi-refractory adult-onset Still's disease. Ann Rheum Dis 68:153–154
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 46:3388–3389
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
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
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):42–43
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
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 19:69–72
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
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 29:1465–1467
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
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
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
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
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
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
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
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
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):1757–1760
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):141–142
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
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):2189–2198
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):653–655
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
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
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
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
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
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
Mima T, Nishimoto N (2009) Clinical value of blocking IL-6 receptor. Curr Opin Rheumatol 21(3):224–230. doi:10.1097/BOR.0b013e3283295fec
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
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The authors thank Laura O’Leary for her help.
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de Boysson, H., Février, J., Nicolle, A. et al. Tocilizumab in the treatment of the adult-onset Still's disease: current clinical evidence. Clin Rheumatol 32, 141–147 (2013). https://doi.org/10.1007/s10067-012-2105-2
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DOI: https://doi.org/10.1007/s10067-012-2105-2