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Systemic juvenile idiopathic arthritis: Treatment

Author
Yukiko Kimura, MD
Section Editor
Marisa Klein-Gitelman, MD, MPH
Deputy Editor
Elizabeth TePas, MD, MS

INTRODUCTION

Systemic juvenile idiopathic arthritis (sJIA, formerly called Still's disease or systemic-onset juvenile rheumatoid arthritis) is a subset of JIA. Adult-onset Still's disease (AOSD) is probably the same or similar disease when it begins in patients ≥16 years of age. sJIA is classified as a subset of JIA, but the pathophysiology is most consistent with an autoinflammatory disorder. (See "Classification of juvenile arthritis", section on 'Systemic arthritis'.)

The treatment options for sJIA are discussed in this review. The clinical manifestations, diagnosis, complications, and prognosis of sJIA are discussed separately, as are other subtypes of JIA. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis" and "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications" and "Oligoarticular juvenile idiopathic arthritis" and "Polyarticular juvenile idiopathic arthritis: Clinical manifestations and diagnosis" and "Classification of juvenile arthritis".)

OVERVIEW

Nonsteroidal anti-inflammatory drugs (NSAIDs) alone are effective for some children with sJIA [1]. Glucocorticoids along with the disease-modifying antirheumatic drug (DMARD), methotrexate, were traditionally used in patients who failed NSAID therapy. However, glucocorticoids are a poor long-term therapeutic option because of associated toxicity, and methotrexate often does not change the aggressive and often permanently disabling consequences of unremitting disease. Biologic DMARDs, such as interleukin (IL)-1 or IL-6 inhibitors, were initially reserved for patients refractory to conventional therapy (NSAIDs followed by the addition of glucocorticoids with or without methotrexate). However, they are increasingly the agent of choice after failure of NSAID therapy in patients with a confirmed diagnosis of sJIA since they are highly effective.

Treatment guidelines, based upon presence or absence of active systemic features, clinician global assessment, active joint count, and presence or absence of features concerning for macrophage activation syndrome (MAS), are outlined by the American College of Rheumatology (ACR) [2]. These guidelines emphasize the earlier use of biologics in children with sJIA, although specific information on appropriate dose is lacking. Another set of standardized treatment plans was developed through a consensus process by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) based upon the most commonly used treatment approaches for systemic JIA [3].

OUR APPROACH

Our general approach is reviewed here, and the specific agents are discussed in greater detail below, including dosing and withdrawal of therapy.

                                     

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Literature review current through: Jun 2015. | This topic last updated: Jun 18, 2015.
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References
Top
  1. Beukelman T, Patkar NM, Saag KG, et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res (Hoboken) 2011; 63:465.
  2. Ringold S, Weiss PF, Beukelman T, et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Care Res (Hoboken) 2013; 65:1551.
  3. DeWitt EM, Kimura Y, Beukelman T, et al. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2012; 64:1001.
  4. Vastert SJ, de Jager W, Noordman BJ, et al. Effectiveness of first-line treatment with recombinant interleukin-1 receptor antagonist in steroid-naive patients with new-onset systemic juvenile idiopathic arthritis: results of a prospective cohort study. Arthritis Rheumatol 2014; 66:1034.
  5. Lomater C, Gerloni V, Gattinara M, et al. Systemic onset juvenile idiopathic arthritis: a retrospective study of 80 consecutive patients followed for 10 years. J Rheumatol 2000; 27:491.
  6. Singh-Grewal D, Schneider R, Bayer N, Feldman BM. Predictors of disease course and remission in systemic juvenile idiopathic arthritis: significance of early clinical and laboratory features. Arthritis Rheum 2006; 54:1595.
  7. Nigrovic PA, Mannion M, Prince FH, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum 2011; 63:545.
  8. Nigrovic PA. Review: is there a window of opportunity for treatment of systemic juvenile idiopathic arthritis? Arthritis Rheumatol 2014; 66:1405.
  9. Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012; 367:2396.
  10. De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012; 367:2385.
  11. Ringold S, Weiss PF, Beukelman T, et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum 2013; 65:2499.
  12. Ilowite NT. Current treatment of juvenile rheumatoid arthritis. Pediatrics 2002; 109:109.
  13. Celebrex gets committee nod for juvenile arthritis, but safety registry urged. "The Pink Sheet" 2006; 68(49):7.
  14. Sbarbaro JA, Bennett RM. Aspirin hepatotoxicity and disseminated intravascular coagulation. Ann Intern Med 1977; 86:183.
  15. Goldstein JL. Who needs prophylaxis of nonsteroidal anti-inflammatory drug-induced ulcers and what is optimal prophylaxis? Eur J Gastroenterol Hepatol 2000; 12 Suppl 1:S11.
  16. Muzaffer MA, Dayer JM, Feldman BM, et al. Differences in the profiles of circulating levels of soluble tumor necrosis factor receptors and interleukin 1 receptor antagonist reflect the heterogeneity of the subgroups of juvenile rheumatoid arthritis. J Rheumatol 2002; 29:1071.
  17. de Benedetti F, Massa M, Robbioni P, et al. Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis Rheum 1991; 34:1158.
  18. Elliott MJ, Woo P, Charles P, et al. Suppression of fever and the acute-phase response in a patient with juvenile chronic arthritis treated with monoclonal antibody to tumour necrosis factor-alpha (cA2). Br J Rheumatol 1997; 36:589.
  19. Irigoyen PI, Olson J, Horn C, et al. Treatment of systemic onset juvenile rheumatoid arthritis with anakinra. Arthritis Rheum 2004; 50:S437.
  20. Yokota S, Miyamae T, Imagawa T, 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.
  21. Henrickson M. Efficacy of anakinra in refractory systemic arthritis. Arthritis Rheum 2004; 50:S438.
  22. Müller K, Herner EB, Stagg A, et al. Inflammatory cytokines and cytokine antagonists in whole blood cultures of patients with systemic juvenile chronic arthritis. Br J Rheumatol 1998; 37:562.
  23. Mangge H, Schauenstein K. Cytokines in juvenile rheumatoid arthritis (JRA). Cytokine 1998; 10:471.
  24. Woo P, Wilkinson N, Prieur AM, et al. Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement. Arthritis Res Ther 2005; 7:R1281.
  25. Sfikakis PP. The first decade of biologic TNF antagonists in clinical practice: lessons learned, unresolved issues and future directions. Curr Dir Autoimmun 2010; 11:180.
  26. De Benedetti F, Ruperto N, Brunner H, et al. Tapering and withdrawal of tocilizumab in patients with systemic juvenile idiopathic arthritis in inactive disease: results from an alternative dosing regimen in the TENDER study. Pediatr Rheumatol Online J 2014; 12 (Suppl 1):O13.
  27. Ilowite NT, Prather K, Lokhnygina Y, et al. Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis. Arthritis Rheumatol 2014; 66:2570.
  28. Pascual V, Allantaz F, Arce E, et al. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med 2005; 201:1479.
  29. Verbsky JW, White AJ. Effective use of the recombinant interleukin 1 receptor antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid arthritis. J Rheumatol 2004; 31:2071.
  30. Lequerré T, Quartier P, Rosellini D, et al. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 2008; 67:302.
  31. Zeft A, Hollister R, LaFleur B, et al. Anakinra for systemic juvenile arthritis: the Rocky Mountain experience. J Clin Rheumatol 2009; 15:161.
  32. Quartier P, Allantaz F, Cimaz R, et al. 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 2011; 70:747.
  33. Urien S, Bardin C, Bader-Meunier B, et al. Anakinra pharmacokinetics in children and adolescents with systemic-onset juvenile idiopathic arthritis and autoinflammatory syndromes. BMC Pharmacol Toxicol 2013; 14:40.
  34. Ilowite N, Porras O, Reiff A, et al. Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study. Clin Rheumatol 2009; 28:129.
  35. Fisher CJ Jr, Dhainaut JF, Opal SM, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 1994; 271:1836.
  36. Dhimolea E. Canakinumab. MAbs 2010; 2:3.
  37. Ruperto N, Quartier P, Wulffraat N, et al. A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Arthritis Rheum 2012; 64:557.
  38. Breda L, Del Torto M, De Sanctis S, Chiarelli F. Biologics in children's autoimmune disorders: efficacy and safety. Eur J Pediatr 2011; 170:157.
  39. Moltó A, Olivé A. Anti-IL-1 molecules: new comers and new indications. Joint Bone Spine 2010; 77:102.
  40. Lovell DJ, Giannini EH, Reiff AO, et al. Long-term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis. Arthritis Rheum 2013; 65:2486.
  41. Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 2008; 371:998.
  42. Yokota S, Miyamae T, Imagawa T, et al. Clinical study of tocilizumab in children with systemic-onset juvenile idiopathic arthritis. Clin Rev Allergy Immunol 2005; 28:231.
  43. Nishimoto N. Interleukin-6 as a therapeutic target in candidate inflammatory diseases. Clin Pharmacol Ther 2010; 87:483.
  44. Inaba Y, Ozawa R, Imagawa T, et al. Radiographic improvement of damaged large joints in children with systemic juvenile idiopathic arthritis following tocilizumab treatment. Ann Rheum Dis 2011; 70:1693.
  45. Prince FH, Twilt M, ten Cate R, et al. Long-term follow-up on effectiveness and safety of etanercept in juvenile idiopathic arthritis: the Dutch national register. Ann Rheum Dis 2009; 68:635.
  46. Russo RA, Katsicas MM. Clinical remission in patients with systemic juvenile idiopathic arthritis treated with anti-tumor necrosis factor agents. J Rheumatol 2009; 36:1078.
  47. Carrasco R, Smith JA, Lovell D. Biologic agents for the treatment of juvenile rheumatoid arthritis: current status. Paediatr Drugs 2004; 6:137.
  48. Horneff G, Schmeling H, Biedermann T, et al. The German etanercept registry for treatment of juvenile idiopathic arthritis. Ann Rheum Dis 2004; 63:1638.
  49. Kimura Y, Pinho P, Walco G, et al. Etanercept treatment in patients with refractory systemic onset juvenile rheumatoid arthritis. J Rheumatol 2005; 32:935.
  50. Eberhard BA, Ilowite NT. Response of systemic onset juvenile rheumatoid arthritis to etanercept: is the glass half full or half empty? J Rheumatol 2005; 32:763.
  51. Otten MH, Prince FH, Armbrust W, et al. Factors associated with treatment response to etanercept in juvenile idiopathic arthritis. JAMA 2011; 306:2340.
  52. Ramanan AV, Schneider R. Macrophage activation syndrome following initiation of etanercept in a child with systemic onset juvenile rheumatoid arthritis. J Rheumatol 2003; 30:401.
  53. Prahalad S, Bove KE, Dickens D, et al. Etanercept in the treatment of macrophage activation syndrome. J Rheumatol 2001; 28:2120.
  54. Food and Drug Administration MedWatch. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm175843.htm (Accessed on September 29, 2009).
  55. Beukelman T, Haynes K, Curtis JR, et al. Rates of malignancy associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum 2012; 64:1263.
  56. Lionetti G, Kimura Y, Schanberg LE, et al. Using registries to identify adverse events in rheumatic diseases. Pediatrics 2013; 132:e1384.
  57. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01879.html (Accessed on November 23, 2008).
  58. Feito JG, Pereda CA. Rituximab therapy produced rapid and sustained clinical improvement in a patient with systemic onset juvenile idiopathic arthritis refractory to TNF alpha antagonists. J Clin Rheumatol 2009; 15:363.
  59. Wallace CA. The use of methotrexate in childhood rheumatic diseases. Arthritis Rheum 1998; 41:381.
  60. Woo P, Southwood TR, Prieur AM, et al. Randomized, placebo-controlled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Arthritis Rheum 2000; 43:1849.
  61. Ravelli A, Martini A. Methotrexate in juvenile idiopathic arthritis: answers and questions. J Rheumatol 2000; 27:1830.
  62. Reiff A, Shaham B, Wood BP, et al. High dose methotrexate in the treatment of refractory juvenile rheumatoid arthritis. Clin Exp Rheumatol 1995; 13:113.
  63. Tamilarasan KP, Kolluru GK, Rajaram M, et al. Thalidomide attenuates nitric oxide mediated angiogenesis by blocking migration of endothelial cells. BMC Cell Biol 2006; 7:17.
  64. Lehman TJ, Striegel KH, Onel KB. Thalidomide therapy for recalcitrant systemic onset juvenile rheumatoid arthritis. J Pediatr 2002; 140:125.
  65. Lehman TJ, Schechter SJ, Sundel RP, et al. Thalidomide for severe systemic onset juvenile rheumatoid arthritis: A multicenter study. J Pediatr 2004; 145:856.
  66. Foeldvari I, Wierk A. Effectiveness of leflunomide in patients with juvenile idiopathic arthritis in clinical practice. J Rheumatol 2010; 37:1763.
  67. Jahan A, Dewan V, Yadav TP. Leflunomide in systemic onset Juvenile idiopathic arthritis. Indian Pediatr 2012; 49:750.
  68. Silverman E, Mouy R, Spiegel L, et al. Leflunomide or methotrexate for juvenile rheumatoid arthritis. N Engl J Med 2005; 352:1655.
  69. Mouy R, Stephan JL, Pillet P, et al. Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: report of five cases. J Pediatr 1996; 129:750.
  70. Ravelli A, De Benedetti F, Viola S, Martini A. Macrophage activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine. J Pediatr 1996; 128:275.
  71. Wallace CA, Sherry DD. Trial of intravenous pulse cyclophosphamide and methylprednisolone in the treatment of severe systemic-onset juvenile rheumatoid arthritis. Arthritis Rheum 1997; 40:1852.
  72. Savolainen HA. Chlorambucil in severe juvenile chronic arthritis: longterm followup with special reference to amyloidosis. J Rheumatol 1999; 26:898.
  73. Milanetti F, Abinun M, Voltarelli JC, Burt RK. Autologous hematopoietic stem cell transplantation for childhood autoimmune disease. Pediatr Clin North Am 2010; 57:239.
  74. Tyndall A. Application of autologous stem cell transplantation in various adult and pediatric rheumatic diseases. Pediatr Res 2012; 71:433.
  75. Daikeler T, Tichelli A, Passweg J. Complications of autologous hematopoietic stem cell transplantation for patients with autoimmune diseases. Pediatr Res 2012; 71:439.
  76. De Kleer IM, Brinkman DM, Ferster A, et al. Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical effects, mortality, and transplant related morbidity. Ann Rheum Dis 2004; 63:1318.
  77. Brinkman DM, de Kleer IM, ten Cate R, et al. Autologous stem cell transplantation in children with severe progressive systemic or polyarticular juvenile idiopathic arthritis: long-term follow-up of a prospective clinical trial. Arthritis Rheum 2007; 56:2410.