Efficacy and Safety of Tocilizumab in Patients with Severe Systemic Juvenile Idiopathic Arthritis

CLINICAL RESEARCH
Ekaterina I. Alekseeva, PhD, ScD¹,²*, Rina V. Denisova, PhD¹, Saniya I. Valieva, PhD¹, Tatyana M. Bsarova, PhD¹, Kseniya B. Isaeva, PhD¹, Evgeniya G. Chistyakova, PhD¹, Tatyana V. Sleptsova, PhD¹, Elena V. Mitenko¹

¹Scientific Centre of Children Health of RAMS, Moscow, Russian Federation

²I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

*Corresponding author: Prof. Ekaterina I. Alekseeva, PhD, ScD, Scientific Centre of Children Health of RAMS, 2/62, Lomonosov avenue, 119991, Moscow, Russian Federation. Tel/Fax: 7-499-1340297 E-Mail: alekatya@yandex.ru

Abstract: 

It has been observed that 10-20% of children with juvenile idiopathic arthritis (JIA) have a characteristically wide range of extra-articular manifestations. The treatment of systemic JIA with glucocorticoids and immunosuppressants has not always been effective. Significantly, interleukin-6 has been found to play an important role in the development of extra-articular manifestations and complications of the disease. Inhibition of this cytokine appears to be a promising therapeutic approach. The article presents the results of research on the effectiveness and safety of tocilizumab treatment in 39 patients with severe systemic JIA, refractory to standard immunosuppressive therapy. Tocilizumab therapy is characterized by high efficacy and safety. After six months of treatment, 50% of patients were recorded as having inactive disease status, while 57% of patients had no symptoms of the disease after 12 months. Adverse events manifested included mild to moderately severe infections, leukopenia and neutropenia. 

Keywords: 
juvenile idiopathic arthritis; extra-articular manifestations; interleukin-6; tocilizumab therapy.
References: 
  1. Cassidy JT, Petty RE. Juvenile idiopathic arthritis. In: Cassidy JT, Petty RE, editors. Textbook of pediatric rheumatology, 5th ed. Philadelphia: WB Saunders, 2005.
  2. Alekseeva EI, Valieva SI, Bzarova TM. Efficacy and safety of repeat courses of rituximab treatment of severe refractory juvenile rheumatoid arthritis. Modern problem of Pediatrics 2009; 8(5):14-25.
  3. Alekseeva EI, Litvisky PF. Juvenile rheumatoid arthritis. Etiology. Pathogenesis. Clinic. Algorithms for diagnosis and treatment. Guidelines for physicians, teachers, researchers. Under the general editorship of Academician of RAMS, professor AA Baranov. Moscow, 2007.
  4. Veldhuis GJ, Willemse PHB., Sleijfer DT, van der Graaf WT, Groen HJ, Limburg PC et al. Toxicity and efficacy of escalating dosages of recombinant human interleukin-6 after chemotherapy in patients with breast cancer or non-small-cell lung cancer. J Clin Oncol 1995; 13:2585–2593.
  5. Rothwell NJ, Busbridge NJ, Lefeuvre RA, Hardwick AJ. Interleukin-6 is a centrally acting endogenous pyrogen in the rat. Can J Physiol Pharmacol 1991; 69:1465–1469.
  6. Castell JV, Gomez-Lechon MJ, David M, Hirano T, Kishimoto T, Heinrich PC. Recombinant human interleukin-6 (IL-6/BSF-2/HSF) regulates the synthesis of acute phase proteins in human hepatocytes. FEBS Lett 1988; 232:347–350.
  7. Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004; 113:1271–1276.
  8. Ikebuchi K, Wong GG, Clark SC, Ihle JN, Hirai Y, Ogawa M. Interleukin-6 enhancement of interleukin-3-dependent proliferation of multipotential hemopoietic progenitors. Proc Natl Acad Sci USA 1987; 84:9035–9039.
  9. Kimura H, Ishibashi T, Uchida T, Maruyama Y, Friese P, Burstein SA. Interleukin 6 is a differentiation factor for human megakaryocytes in vitro. Eur. J Immunol 1990; 20:1927–1931.
  10. Tsigos C, Papankolaou DA, Defensor R, Mitsiadis CS, Kyrou I, Chrousos G.P. Dose-effects of recombinant human interleukin-6 on pituitary hormone secretion and energy expenditure. Neuroendocrinology 1997; 66:54–62.
  11. Heliovaara MK, Teppo AM, Karonen SL, Tuominen JA, Ebeling P. Plasma IL-6 concentration is inversely related to insulin sensitivity, and acute phase proteins associate with glucose and lipid metabolism in healthy subjects. Diabetes Obes Metab 2005; 7:729–736.
  12. Cutolo M, Straub RH. Circadian rhythms in arthritis: hormonal effects on the immune/inflammatory reaction. Autoimmun Rev 2008; 7:223–228.
  13. Nishimoto N, Kishimoto T. Humanized antihuman IL-6 receptor antibody, tocilizumab. Handb Exp Pharmacol 2008; 181:151-160.
  14. European Medicines Agency. RoActemra (tocilizumab): summary of product characteristics [online]. Available from URL: http://www.emea.europa.eu/humandoes/PDFs/EPAR/RoActemra/H-955-PI-en.pdf [accessed 2009 Mar 23].
  15. Chugai Pharmactutical Co. Actemra, a humanized antihuman IL-6 receptor monoclonal antibody obtained approval for indications of rheumatoid arthritis, polyarticular-course juvenile idiopathic arthritis and systemic-onset juvenile idiopathic arthritis [media release]. Available from URL: http://www.chugai-pharm.co.jp [accessed 2008 Sep 24].
  16. Imagawa T, Ozawa R, Miyamae T, Mori M, Nerome Y, Imanaka H, et al. Efficacy and safety in 48-week treatment of tocilizumab in children with polyaticular course JIA with polyarticlar or olygoarticular onset. Ann Rheum Dis 2007; 66(Suppl. II): 550.
  17. Yokota S, Imagawa, Miyamae T. Safety and efficacy of up to three years of continuous tocilizumab therapy in children with systemic-onset juvenile idiopathic arthritis [SAT0536]. Ann Rheum Dis 2009; 68 (Suppl. 3):715.
  18. Inaba Y, Aoki C, Ozawa R. Radiologic evaluation of large joints during tocilizumab treatment in children with systemic juvenile idiopathic arthritis [SAT0555]. Ann Rheum Dis 2009; 68(Suppl. 3):720.
  19. Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei S et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomized, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 2008; 371:998-1006.
  20. Yokota S, Miyamae T, Imagawa T, Iwata N, Katakura S, Mori M, et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 2005; 52:818-825.
  21. Aoki C, Inaba Y, Ozawa R. Effects of tocilizumab on radiological findings in polyarticular juvenile idiopathic arthritis [OP-0145]. Ann Rheum Dis 2009; 68(Suppl. 3):118.
  22. Quartier P, Maire D, Souabni L. Efficacy and safety of tocilizumab in systemic onset juvenile idiopathic arthritis in french centers [FRI0462]. Ann Rheum Dis 2009; 68(Suppl.3):506.
  23. Kaneko U, Imagawa T, Kishi T. Discrepancy between progression of joint damage and improvement of systemic inflammation in patients with systemic-onset juvenile idiopathic arthritis treated with tocilizumab [SAT0548]. Ann Rheum Dis 2009; 68(Suppl.3):719.
  24. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997; 40:1202–1209.
  25. Yokota S, Imagawa T, Miyamae T. Safety and efficacy of up to three years of continuous tocilizumab therapy in children with systemic-onset juvenile idiopathic arthritis [SAT0536]. Ann Rheum Dis 2009; 68(Suppl.3):715.

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Int J Biomed. 2011; 1(4):190-198. © 2011 International Medical Research and Development Corporation. All rights reserved.