Advertisement

Systemic Juvenile Idiopathic Arthritis

  • Ricardo A. G. RussoEmail author
  • María Martha Katsicas
Chapter

Abstract

Systemic-onset juvenile idiopathic arthritis is a complex, polygenic autoinflammatory disease affecting young individuals. It is an innate immunity-driven condition characterized by chronic, multiorganic inflammatory involvement. Typical clinical features including young age at presentation, fever, neutrophilic skin lesions, synovitis, serositis, organomegaly, as well as increased risk of amyloidosis are reminiscent of (and may mimic) certain monogenic autoinflammatory disorders. Strikingly high acute phase reactants, thrombocytosis, hyperferritinemia, and elevated serum levels of inflammatory-related proteins such as IL-1, IL-18, S100A8/9, and S100A12 characterize active phases. The disease may follow a relapsing or a continuous course into adulthood, frequently leading to joint damage, disability, and poorer quality of life. Major morbidity and mortality arise from the hypercytokinemic, hyperinflammatory stages called macrophage activation syndrome, a form of reactive hemophagocytic lymphohistiocytosis, which may occur in 50% of patients but become clinically overt only in a smaller proportion. Multidisciplinary teams are best fit to treat this complex disease. Decades after nonbiologic drugs and TNF inhibitors had consistently failed, the advent of biologic agents blocking IL-1 and IL-6 has proven dramatically efficacious for medical management.

Keywords

Juvenile systemic arthritis Anakinra Canakinumab Tocilizumab Innate immunity Genetics 

References

  1. 1.
    Woo P. Anakinra treatment for systemic juvenile idiopathic arthritis and adult onset Still disease. Ann Rheum Dis. 2008;67:281–2.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Masters SL, Simon A, Aksentijevich I, et al. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–68.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Mellins ED, Macaubas C, Grom AA. Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more questions. Nat Rev Rheumatol. 2011;7:416–26.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Hedrich CM, Tsokos GC. Bridging the gap between autoinflammation and autoimmunity. Clin Immunol. 2013;147:151–4.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Nigrovic PA. Autoinflammation and autoimmunity in systemic juvenile idiopathic arthritis. PNAS. 2015;112:15785–6.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Modesto C, Antón J, Rodriguez B, Bou R, Arnal C, Ros J, et al. Incidence and prevalence of juvenile idiopathic arthritis in Catalonia (Spain). Scand J Rheumatol. 2010;39:472–9.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Gurion R, Lehman TJ, Moorthy LN. Systemic arthritis in children: a review of clinical presentation and treatment. Int J Inflam. 2012;2012:271569.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Behrens EM, Beukelman T, Gallo L, Spangler J, Rosenkranz M, Arkachaisri T, et al. Evaluation of the presentation of systemic onset juvenile rheumatoid arthritis: data from the Pennsylvania Systemic Onset Juvenile Arthritis Registry. (PASOJAR). J Rheumatol. 2008;35:343–8.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Russo R, Katsicas MM. Patients with very early-onset systemic juvenile idiopathic arthritis exhibit more inflammatory features and a worse outcome. J Rheumatol. 2013;40:329–34.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Wallace CA, Levinson JE. Juvenile rheumatoid arthritis: outcome and treatment for the 1990s. Rheum Dis Clin North Am. 1991;17:891–905.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Woo P. Systemic juvenile idiopathic arthritis: diagnosis, management, and outcome. Nat Clin Pract Rheumatol. 2006;2:28–34.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31:390–2.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Kumar S, Kunhiraman DS, Rajam L. Application of the Yamaguchi criteria for classification of “suspected” systemic juvenile idiopathic arthritis (sJIA). Pediatr Rheumatol. 2012;10:40.CrossRefGoogle Scholar
  14. 14.
    Martini A. It is time to rethink juvenile idiopathic arthritis classification and nomenclature? Ann Rheum Dis. 2012;71:1437–9.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Deslandre C. Juvenile idiopathic arthritis: definition and classification. Arch Pediatr. 2016;23:437–41.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Fall N, Barnes M, Thornton S, et al. Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome. Arthritis Rheum. 2007;56:3793–804.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Cepika AM, Banchereau R, Segura E, et al. A multidimensional blood stimulation assay reveals immune alterations underlying systemic juvenile idiopathic arthritis. J Exp Med. 2017;214:3449–66.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Hinze CH, Fall N, Thornton S, et al. Immature cell populations and an erythropoiesis gene-expression signature in systemic juvenile idiopathic arthritis: implications for pathogenesis. Arthritis Res Ther. 2010;12:R123.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Omoyinmi E, Hamaoui R, Pesenacker A, et al. Th1 and Th17 cell subpopulations are enriched in the peripheral blood of patients with systemic juvenile idiopathic arthritis. Rheumatology. 2012;51:1881–6.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Nigrovic PA. Is there a window of opportunity for treatment of systemic juvenile idiopathic arthritis? Arthritis Rheum. 2014;66:1405–13.CrossRefGoogle Scholar
  21. 21.
    Kessel C, Lippitz A, Weinhage T, et al. Proinflammatory cytokine environments can drive Interleukin-17 overexpression by γ/δ T cells in systemic juvenile idiopathic arthritis. Arthritis Rheum. 2017;69:1480–94.CrossRefGoogle Scholar
  22. 22.
    Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J. 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;201:1479–86.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    de Jager W, Hoppenreijs EP, Wulffraat NM, Wedderburn LR, Kuis W, Prakken BJ. Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross-sectional study. Ann Rheum Dis. 2007;66:589–98.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Frosch M, Roth J. New insights in systemic juvenile idiopathic arthritis-from pathophysiology to treatment. Rheumatology. 2008;47:121–5.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Shimizu M, Nakagishi Y, Kasai K, Yamasaki Y, Miyoshi M, Takei S, et al. Tocilizumab masks the clinical symptoms of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: the diagnostic significance of interleukin-18 and interleukin-6. Cytokine. 2012;58:287–94.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Shimizu M, Nakagishi Y, Yachie A. Distinct subsets of patients with systemic juvenile idiopathic arthritis based on their cytokine profiles. Cytokine. 2013;61:345–8.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Muller K, Herner EB, Stagg A, Bendtzen K, Woo P. Inflammatory cytokines and cytokine antagonists in whole blood cultures of patients with systemic juvenile chronic arthritis. Br J Rheumatol. 1998;37:562–9.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Gattorno M, Piccini A, Lasiglie D, et al. The pattern of response to anti-interleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2008;58:1505–15.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Allantaz F, Chaussabel D, Stichweh D, et al. Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade. J Exp Med. 2007;204:2131–44.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    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;70:747–54.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of Canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367:2396–406.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Lotito AP, Campa A, Silva CA, Kiss MH, Mello SB. Interleukin 18 as a marker of disease activity and severity in patients with juvenile idiopathic arthritis. J Rheumatol. 2007;34:823–30.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Shimizu M, Yokoyama T, Yamada K, Kaneda H, Wada H, Wada T, et al. Distinct cytokine profiles of systemic-onset juvenile idiopathic arthritis-associated macrophage activation syndrome with particular emphasis on the role of interleukin-18 in its pathogenesis. Rheumatology (Oxford). 2010;49:1645–53.CrossRefGoogle Scholar
  34. 34.
    de Benedetti F, Massa M, Robbioni P, Ravelli A, Burgio GR, Martini A. Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis Rheum. 1991;34:1158–63.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Cazzola M, Ponchio L, de Benedetti F, Ravelli A, Rosti V, Beguin Y, et al. Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis. Blood. 1996;87:4824–30.PubMedPubMedCentralGoogle Scholar
  36. 36.
    de Benedetti F, Meazza C, Oliveri M, Pignatti P, Vivarelli M, Alonzi T, et al. Effect of IL-6 on IGF binding protein-3: a study in IL-6 transgenic mice and in patients with systemic juvenile idiopathic arthritis. Endocrinology. 2001;142:4818–26.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    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;371:998–1006.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Raziuddin S, Bahabri S, al-Dalaan A, Siraj AK, al-Sedairy S. A mixed Th1/Th2 cell cytokine response predominates in systemic onset juvenile rheumatoid arthritis: immunoregulatory IL-10 function. Clin Immunol Immunopathol. 1998;86:192–8.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Pignatti P, Vivarelli M, Meazza C, Rizzolo MG, Martini A, De BF. Abnormal regulation of interleukin 6 in systemic juvenile idiopathic arthritis. J Rheumatol. 2001;28:1670–6.PubMedPubMedCentralGoogle Scholar
  40. 40.
    de Benedetti F, Alonzi T, Moretta A, Lazzaro D, Costa P, Poli V, et al. Interleukin-6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I. A model for stunted growth in children with chronic inflammation. J Clin Invest. 1997;99:643–50.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Strippoli R, Carvello F, Scianaro R, Pasquale LD, Vivarelli M, Petrini S, et al. Amplification of the response to toll-like receptor ligands by prolonged exposure to interleukin-6 in mice: implications for the pathogenesis of macrophage activation syndrome. Arthritis Rheum. 2012;64:1680–8.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Canna SW, Wrobel J, Chu N, Kreiger PA, Paessler M, Behrens EM. Interferon-gamma mediates anemia but is dispensable for fulminant toll-like receptor 9- induced macrophage activation syndrome and hemophagocytosis in mice. Arthritis Rheum. 2013;65:1764–75.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Avau A, Mitera T, Put S, Put K, Brisse E, Filtjens J, et al. Systemic juvenile idiopathic arthritis-like syndrome in mice following stimulation of the immune system with Freund’s complete adjuvant: regulation by interferon- gamma. Arthritis Rheum. 2014;66:1340–51.CrossRefGoogle Scholar
  44. 44.
    Bracaglia C, de Graaf K, Marafon DP, et al. Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterize patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2017;76:166–72.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Wouters CH, Ceuppens JL, Stevens EA. Different circulating lymphocyte profiles in patients with different subtypes of juvenile idiopathic arthritis. Clin Exp Rheumatol. 2002;20:239–48.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Zhou J, Tang X, Ding Y, An Y, Zhao X. Natural killer cell activity and frequency of killer cell immunoglobulin-like receptors in children with different forms of juvenile idiopathic arthritis. Pediatr Allergy Immunol. 2013;24:691–6.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Grom AA, Villanueva J, Lee S, Goldmuntz EA, Passo MH, Filipovich A. Natural killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome. J Pediatr. 2003;142:292–6.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Villanueva J, Lee S, Giannini EH, et al. Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res Ther. 2005;7:R30–7.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Wulffraat NM, Rijkers GT, Elst E, Brooimans R, Kuis W. Reduced perforin expression in systemic juvenile idiopathic arthritis is restored by autologous stem-cell transplantation. Rheumatology (Oxford). 2003;42:375–9.CrossRefGoogle Scholar
  50. 50.
    Put K, Vandenhaute J, Avau A, et al. Inflammatory gene expression profile and defective interferon-γ and Granzyme K in natural killer cells from systemic juvenile idiopathic arthritis patients. Arthritis Rheum. 2017;69:213–24.CrossRefGoogle Scholar
  51. 51.
    Brady J, Carotta S, Thong RP, Chan CJ, Hayakawa Y, Smyth MJ, et al. The interactions of multiple cytokines control NK cell maturation. J Immunol. 2010;185:6679–88.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Cifaldi L, Prencipe G, Caiello I, Bracaglia C, Locatelli F, de Benedetti F, et al. Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome. Arthritis Rheum. 2015;67:3037–46.CrossRefGoogle Scholar
  53. 53.
    de Jager W, Vastert SJ, Beekman JM, Wulffraat NM, Kuis W, Coffer PJ, et al. Defective phosphorylation of interleukin-18 receptor b causes impaired natural killer cell function in systemic onset juvenile idiopathic arthritis. Arthritis Rheum. 2009;60:2782–93.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Macaubas C, Nguyen K, Deshpande C, et al. Distribution of circulating cells in systemic juvenile idiopathic arthritis across disease activity states. Clin Immunol. 2010;134:206–16.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Macaubas C, Nguyen KD, Peck A, Buckingham J, Deshpande C, Wong E, et al. Alternative activation in systemic juvenile idiopathic arthritis monocytes. Clin Immunol. 2012;142:362–72.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Schulert GS, Fall N, Harley JB, et al. Monocyte MicroRNA expression in active systemic juvenile idiopathic arthritis implicates MicroRNA-125a-5p in polarized monocyte phenotypes. Arthritis Rheum. 2016;68:2300–13.CrossRefGoogle Scholar
  57. 57.
    Frosch M, Vogl T, Seeliger S, et al. Expression of myeloid-related proteins 8 and 14 in systemic-onset juvenile rheumatoid arthritis. Arthritis Rheum. 2003;48:2622–6.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Foell D, Wittkowski H, Hammerschmidt I, et al. Monitoring neutrophil activation in juvenile rheumatoid arthritis by S100A12 serum concentrations. Arthritis Rheum. 2004;50:1286–95.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Foell D, Roth J. Proinflammatory S100 proteins in arthritis and autoimmune disease. Arthritis Rheum. 2004;50:3762–71.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Ombrello MJ, Remmers EF, Tachmazidou I, et al. HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. PNAS. 2015;112:15970–5.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Hinks A, Bowes J, Cobb J, et al. Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases. Ann Rheum Dis. 2017;76:765–72.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Stock CJ, Ogilvie EM, Samuel JM, Fife M, Lewis CM, Woo P. Comprehensive association study of genetic variants in the IL-1 gene family in systemic juvenile idiopathic arthritis. Genes Immun. 2008;9:349–57.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    de Benedetti F, Meazza C, Vivarelli M, et al. Functional and prognostic relevance of the −173 polymorphism of the macrophage migration inhibitory factor gene in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2003;48:1398–407.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest. 1998;102:1369–76.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Ogilvie EM, Fife MS, Thompson SD, et al. The -174G allele of the Interleukin-6 gene confers susceptibility to systemic arthritis in children. Arthritis Rheum. 2003;48:3202–6.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Donn RP, Barrett JH, Farhan A, et al. Cytokine gene polymorphisms and susceptibility to juvenile idiopathic arthritis. British Paediatric rheumatology study group. Arthritis Rheum. 2001;44:802–10.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Donn RP, Shelley E, Ollier WE, et al. A novel 5′-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2001;44:1782–5.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Fife MS, Gutierrez A, Ogilvie EM, Stock CJ, Samuel JM, Thomson W, et al. Novel IL10 gene family associations with systemic juvenile idiopathic arthritis. Arthritis Res Ther. 2006;8:R148.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Moller JC, Paul D, Ganser G, Range U, Gahr M, Kelsch R, et al. IL10 promoter polymorphisms are associated with systemic onset juvenile idiopathic arthritis (SoJIA). Clin Exp Rheumatol. 2010;28:912–8.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Yanagimachi M, Goto H, Miyamae T, et al. Association of IRF5 polymorphisms with susceptibility to Hemophagocytic Lymphohistiocytosis in children. J Clin Immunol. 2011;31:946–51.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Ayaz NA, Ozen S, Bilginer Y, et al. MEFV mutations in systemic onset juvenile idiopathic arthritis. Rheumatology. 2009;48:23–5.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Cantarini L, Lucherini OM, Simonini G, Galeazzi M, Baldari CT, Cimaz R. Systemic-onset juvenile idiopathic arthritis complicated by early onset amyloidosis in a patient carrying a mutation in the MEFV gene. Rheumatol Int. 2012;32:465–7.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Tadaki H, Saitsu H, Nishimura-Tadaki A, et al. De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis. J Human Gen. 2011;56:343–7.CrossRefGoogle Scholar
  74. 74.
    Hazen MM, Woodward AL, Hofmann I, et al. Mutations of the Hemophagocytic Lymphohistiocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis. Arthritis Rheum. 2008;58:567–70.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Vastert SJ, van Wijk R, D’Urbano LE, de Vooght KM, de Jager W, Ravelli A, et al. Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis. Rheumatology (Oxford). 2010;49:441–9.CrossRefGoogle Scholar
  76. 76.
    Zhang K, Biroschak J, Glass DN, et al. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms. Arthritis Rheum. 2008;58:2892–6.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Kaufman KM, Linghu B, Szustakowski JD, et al. Whole-exome sequencing reveals overlap between macrophage activation syndrome in systemic juvenile idiopathic arthritis and familial hemophagocytic lymphohistiocytosis. Arthritis Rheum. 2014;66:3486–95.CrossRefGoogle Scholar
  78. 78.
    Wakil SM, Monies DM, Abouelhoda M, et al. Association of a mutation in LACC1 with a monogenic form of systemic juvenile idiopathic arthritis. Arthritis Rheum. 2015;67:288–95.CrossRefGoogle Scholar
  79. 79.
    Kallinich T, Thorworth A, von Stuckrad SL, et al. Juvenile arthritis caused by a novel FAMIN (LACC1) mutation in two children with systemic and extended oligoarticular course. Pediatr Rheumatol. 2016;14:63.CrossRefGoogle Scholar
  80. 80.
    Calabro JJ. Other extraarticular manifestations of juvenile rheumatoid arthritis. Arthritis Rheum. 1977;20:237–40.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Shimizu M, Yokoyama T, Wada T, Yachie A. Bicipital synovial cyst in systemic-onset juvenile idiopathic arthritis. J Pediatr. 2010;157:168.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Schneider R, Laxer RM. Systemic onset juvenile rheumatoid arthritis. Baillieres Clin Rheumatol. 1998;12:245–71.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Frosch M, Metze D, Foell D, Vogl T, Sorg C, Sunderkötter C, et al. Early activation of cutaneous vessels and epithelial cells is characteristic of acute systemic onset juvenile idiopathic arthritis. Exp Dermatol. 2005;14:259–65.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Ramanan AV, Wynn RF, Kelsey A, Baildam EM. Systemic juvenile idiopathic arthritis, Kikuchi’s disease and haemophagocytic lymphohistiocytosis - is there a link? Case report and literature review. Rheumatology (Oxford). 2003;42:596–8.CrossRefGoogle Scholar
  85. 85.
    Tabak F, Tanverdi M, Ozaras R, Mert A, Tartan Z, Ozturk R, et al. Neutrophilic pleocytosis in cerebrospinal fluid: adult-onset Still’s disease. Intern Med. 2003;42:1039–41.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Heyd J, Glaser J. Early occurrence of aortic valve regurgitation in a youth with systemic-onset juvenile rheumatoid arthritis. Am J Med. 1990;89:123–4.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Kimura Y, Weiss JE, Haroldson KL, Lee T, Punaro M, Oliveira S, et al. Pulmonary hypertension and other potentially fatal pulmonary complications in systemic juvenile idiopathic arthritis. Arthritis Care Res. 2013;65(5):745–52.CrossRefGoogle Scholar
  88. 88.
    Wang FM, Wertenbaker C, Behrens MM, Jacobs JC. Acquired Brown’s syndrome in children with juvenile rheumatoid arthritis. Ophthalmology. 1984;91:23–6.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Avcin T, Silverman ED, Forte V, Schneider R. Nasal septal perforation: a novel clinical manifestation of systemic juvenile idiopathic arthritis/adult onset Still’s disease. J Rheumatol. 2005;32:2429–31.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Dong S, Bout-Tabaku S, Texter K, Jaggi P. Diagnosis of systemic-onset juvenile idiopathic arthritis after treatment for presumed Kawasaki disease. J Pediatr. 2015;166:1283–8.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Solari N, Viola S, Pistorio A, Magni-Manzoni S, Vitale R, Ruperto N, et al. Assessing current outcomes of juvenile idiopathic arthritis: a cross-sectional study in a tertiary center sample. Arthritis Rheum. 2008;15(59):1571–9.CrossRefGoogle Scholar
  92. 92.
    Russo RAG, Katsicas MM. Global damage in systemic juvenile idiopathic arthritis: preliminary early predictors. J Rheumatol. 2008;35:1151–6.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Oen K, Reed M, Malleson PN, Cabral DA, Petty RE, Rosenberg AM, et al. Radiologic outcome and its relationship to functional disability in juvenile rheumatoid arthritis. J Rheumatol. 2003;30:832–40.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Bowyer SL, Roettcher PA, Higgins GC, Adams B, Myers LK, Wallace C, et al. Health status of patients with juvenile rheumatoid arthritis at 1 and 5 years after diagnosis. J Rheumatol. 2003;30:394–400.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Sudoł-Szopińska I, Matuszewska G, Gietka P, Płaza M, Walentowska-Janowicz M. Imaging of juvenile idiopathic arthritis. Part I: clinical classifications and radiographs. J Ultrason. 2016;16:225–36.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Behrens EM, Beukelman T, Paessler M, Cron RQ. Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. J Rheumatol. 2007;34:1133–8.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Minoia F, Davì S, Horne A, Demirkaya E, Bovis F, Li C, Lehmberg K, et al. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheum. 2014;66:3160–9.CrossRefGoogle Scholar
  98. 98.
    Stéphan JL, Koné-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur AM. Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology (Oxford). 2001;40:1285–92.CrossRefGoogle Scholar
  99. 99.
    Russo RAG, Rosenzweig S, Katsicas MM. Hepatitis A-associated macrophage activation syndrome in children with systemic juvenile idiopathic arthritis: report of 2 cases. J Rheumatol. 2008;35:166–8.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Schulert GS, Grom AA. Pathogenesis of macrophage activation syndrome and potential for cytokine-directed therapies. Annu Rev Med. 2015;66:18.1–18.15.CrossRefGoogle Scholar
  101. 101.
    Ravelli A, Minoia F, Davi S, et al. Expert consensus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. RMD Open. 2016;2:e000161.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2016;75:481–9.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Ravelli A, Magni-Manzoni S, Pistorio A, et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr. 2005;146:598–604.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Simon D. Management of growth retardation in juvenile idiopathic arthritis. Horm Res. 2007;68(Suppl 5):122–5.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Packham JC, Hall MA. Long-term follow-up of 246 adults with juvenile idiopathic arthritis: functional outcome. Rheumatology (Oxford). 2002;41:1428–35.CrossRefGoogle Scholar
  106. 106.
    Saha A, Chopra Y, Theis JD, Vrana JA, Sethi S. AA amyloidosis associated with systemic -onset juvenile idiopathic arthritis. Am J Kidney Dis. 2013;62:834–8.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Murray KJ, Boyle RJ, Woo P. Pathological fractures and osteoporosis in a cohort of 103 systemic onset juvenile idiopathic arthritis patients. Arthritis Rheum. 2000;43:S119.Google Scholar
  108. 108.
    Stagi S, Masi L, Capannini S, Cimaz R, Tonini G, Matucci-Cerinic M, et al. Cross- sectional and longitudinal evaluation of bone mass in children and young adults with juvenile idiopathic arthritis: the role of bone mass determinants in a large cohort of patients. J Rheumatol. 2010;37:1935–43.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Rodd C, Lang B, Ramsay T, Alos N, Huber AM, Cabral DA, et al. Incident vertebral fractures among children with rheumatic disorders 12 months after glucocorticoid initiation: a national observational study. Arthritis Care Res (Hoboken). 2012;64:122–31.CrossRefGoogle Scholar
  110. 110.
    Lien G, Flatø B, Haugen M, Vinje O, Sørskaar D, Dale K. Frequency of osteopenia in adolescents with early-onset juvenile idiopathic arthritis: a long-term outcome study of one hundred five patients. Arthritis Rheum. 2003;48:2214–23.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Foell D, Wittkowski H, Hammerschmidt I, Wulffraat N, et al. Monitoring neutrophil activation in juvenile rheumatoid arthritis by S100A12 serum concentrations. Arthritis Rheum. 2004;50:1286–95.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Wittkowski H, Frosch M, Wulffraat N, Goldbach-Mansky R, et al. S100A12 is a novel molecular marker differentiating systemic-onset juvenile idiopathic arthritis from other causes of fever of unknown origin. Arthritis Rheum. 2008;58:3924–31.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Gerss J, Roth J, Holzinger D, et al. Phagocyte-specific S100 proteins and high-sensitivity C reactive protein as biomarkers for a risk-adapted treatment to maintain remission in juvenile idiopathic arthritis: a comparative study. Ann Rheum Dis. 2012;71:1991–7.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Holzinger D, Frosch M, Kastrup A, et al. The toll-like receptor 4 agonist MRP8/14 protein complex is a sensitive indicator for disease activity and predicts relapses in systemic-onset juvenile idiopathic arthritis. Ann Rheum Dis. 2012;71:974–80.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Shenoi S, Ou JN, Ni C, et al. Comparison of biomarkers for systemic juvenile idiopathic arthritis. Pediatr Res. 2015;78:554–9.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Bleesing J, Prada A, Siegel DM, et al. The diagnostic significance of soluble CD163 and soluble Interleukin-2 receptor α-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheum. 2007;56:965–71.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Wilson DC, Marinov AD, Blair HC, et al. Follistatin-like protein 1 is a mesenchyme-derived inflammatory protein and may represent a biomarker for systemic-onset juvenile rheumatoid arthritis. Arthritis Rheum. 2010;62:2510–6.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    de Jager W, Hoppenreijs EP, Wulffraat NM, Wedderburn LR, et al. Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross-sectional study. Ann Rheum Dis. 2007;66:589–98.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Jelusic M, Lukic IK, Tambic-Bukovac L, Dubravcic K, et al. Interleukin-18 as a mediator of systemic juvenile idiopathic arthritis. Clin Rheumatol. 2007;26:1332–4.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Nguyen KD, Macaubas C, Nadeau KC, et al. Serum amyloid a overrides Treg anergy via monocyte-dependent and Treg-intrinsic, SOCS3-associated pathways. Blood. 2011;117:3793–8.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Ling XB, Park JL, Carroll T, et al. Plasma profiles in active systemic juvenile idiopathic arthritis: biomarkers and biological implications. Proteomics. 2010;10:4415–30.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Miyamae T, Malehorn DE, Lemster B, et al. Serum protein profile in systemic-onset juvenile idiopathic arthritis differentiates response versus nonresponse to therapy. Arthritis Res Ther. 2005;7:R746–55.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Ling XB, Lau K, Deshpande C, et al. Urine Peptidomic and targeted plasma protein analyses in the diagnosis and monitoring of systemic juvenile idiopathic arthritis. Clin Proteomics. 2010;6:175–93.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Gohar F, Kessel C, Lavric M, Holzinger D, Foell D. Review of biomarkers in systemic juvenile idiopathic arthritis: helpful tools or just playing tricks? Arthritis Res Ther. 2016;18:163.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Kimura Y, Fieldston E, Devries-Vandervlugt B, et al. High dose, alternate day corticosteroids for systemic onset juvenile rheumatoid arthritis. J Rheumatol. 2000;27:2018–24.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Nigrovic P, Mannion M, Prince FHM, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis. Arthritis Rheum. 2011;63:545–55.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Hedrich CM, Bruck N, Fiebig B, Gahr M. Anakinra: a safe and effective first-line treatment in systemic onset juvenile idiopathic arthritis (SoJIA). Rheumatol Int. 2012;32:3525–30.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    DeWitt EM, Kimura Y, Beukelman T, et al. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res. 2012;64:1001–10.Google Scholar
  129. 129.
    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. Arthritis Rheum. 2014;66:1034–43.CrossRefGoogle Scholar
  130. 130.
    Ilowite NT, Sandborg CI, Feldman BM, et al. Algorithm development for corticosteroid management in systemic juvenile idiopathic arthritis trial using consensus methodology. Pediatr Rheumatol. 2012;10:31.CrossRefGoogle Scholar
  131. 131.
    Woo P, Southwood TR, Prieur A-M, et al. Randomized, placebo-controlled crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Arthritis Rheum. 2000;43:1849–57.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Lehman TJ, Schechter SJ, Sundel RP, et al. Thalidomide for severe systemic onset juvenile rheumatoid arthritis: a multicenter study. J Pediatr. 2004;145:856–7.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    ten Cate R, Nibbering PH, Bredius RG. Therapy-refractory systemic juvenile idiopathic arthritis successfully treated with statins. Rheumatology (Oxford). 2004;43:934–5.CrossRefGoogle Scholar
  134. 134.
    Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med. 2000;342:763–9.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Ruperto N, Lovell DJ, Quartier P, et al. Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet. 2008;372:383–91.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Lovell DJ, Ruperto N, Goodman S, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N Engl J Med. 2008;359:810–20.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Russo RAG, Katsicas MM, Zelazko M. Etanercept in systemic juvenile idiopathic arthritis. Clin Exp Rheumatol. 2002;20:723–6.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Quartier P, Taupin P, Bordeaut F, et al. Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to the onset type. Arthritis Rheum. 2003;48:1093–101.PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Horneff G, Schmeling H, Biederman T, et al. The German etanercept registry for treatment of juvenile idiopathic arthritis. Ann Rheum dis 2004;63:1638-44.Katsicas MM and Russo R. Use of infliximab in patients with systemic juvenile idiopathic arthritis refractory to etanercept. Clin Exp Rheumatol. 2005;23:545–8.Google Scholar
  140. 140.
    Kimura Y, Pinho P, Walco G, et al. Etanercept treatment in patients with refractory systemic onset juvenile rheumatoid arthritis. J Rheumatol. 2005;32:935–42.PubMedPubMedCentralGoogle Scholar
  141. 141.
    Katsicas MM, Russo RAG. Use of adalimumab in patients with juvenile idiopathic arthritis refractory to etanercept and/or infliximab. Clin Rheumatol. 2009;28:985–8.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Russo RA, Katsicas MM. Clinical remission in patients with systemic juvenile idiopathic arthritis treated with anti-tumor necrosis factor agents. J Rheumatol. 2009;38:1078–82.CrossRefGoogle Scholar
  143. 143.
    Lovell DJ, Reiff A, Ilowite NT, et al. Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis. Arthritis Rheum. 2008;58:1496–504.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    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;31:2071–5.PubMedPubMedCentralGoogle Scholar
  145. 145.
    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;201:1479–86.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Ohlsson V, Balldam E, Foster H, et al. Anakinra treatment for systemic onset juvenile idiopathic arthritis (SOJIA). Rheumatology (Oxford). 2008;47:555–6.CrossRefGoogle Scholar
  147. 147.
    Lequerre 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;67:302–8.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Zeft A, Hollister R, LaFleur B, et al. Anakinra for systemic juvenile arthritis: the Rocky Mountain experience. J Clin Rheumatol. 2009;15:161–4.PubMedCrossRefPubMedCentralGoogle Scholar
  149. 149.
    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;70:747–54.PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Pardeo M, Marafon DP, Insalaco A, et al. Anakinra in systemic juvenile idiopathic arthritis: a single-center experience. J Rheumatol. 2015;42:1523–7.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Giannini EH, Ruperto N, Ravelli A, et al. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum. 1997;40:1202–9.PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Miettunen PM, Narendran A, Javanthan A, et al. Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients. Rheumatology (Oxford). 2011;50:417–9.CrossRefGoogle Scholar
  153. 153.
    Canna S, Frankovich J, Higgins G, et al. Acute hepatitis in three patients with systemic juvenile idiopathic arthritis taking interleukin-1 receptor antagonist. Pediatr Rheum. 2009;7:21.CrossRefGoogle Scholar
  154. 154.
    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;64:557–67.PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    Brachat AH, Grom AA, Wulffraat N, et al. Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy. Arthritis Res Ther. 2017;19:13.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    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;65:2486–96.PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Ilowite NT, Prather K, Lokhnuyina 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 Rheum. 2014;66:2570–9.CrossRefGoogle Scholar
  158. 158.
    De Benedetti F, Brunner H, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;67:2385–95.CrossRefGoogle Scholar
  159. 159.
    De Benedetti F, Brunner H, Ruperto N, et al. Catch-up growth during tocilizumab therapy for systemic juvenile idiopathic arthritis. Results from a phase III trial. Arthritis Rheum. 2015;67:840–8.CrossRefGoogle Scholar
  160. 160.
    Yokota S, Itoh Y, Morio T, et al. Tocilizumab in systemic juvenile idiopathic arthritis in a real-world clinical setting: results from 1 year of postmarketing surveillance follow-up of 417 patients in Japan. Ann Rheum Dis. 2016;75:1654–60.PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    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. 2013;65:1551–63.CrossRefGoogle Scholar
  162. 162.
    Kimura Y, DeWitt EM, Beukelman T, et al. Adding Canakinumab to the childhood arthritis and rheumatology research alliance consensus treatment plans for systemic juvenile idiopathic arthritis [letter]. Arthritis Care Res. 2014;66:1430–1.CrossRefGoogle Scholar
  163. 163.
    Woerner A, Uettwiller F, Melki I, et al. Biological treatment in systemic juvenile idiopathic arthritis: achievement of inactive disease or clinical remission on a first, second or third biological agent. RMD Open. 2015;1:e000036.  https://doi.org/10.1136/rmdopen-2014-000036.CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Record JL, Beukelman T, Cron RQ. Combination therapy of abatacept and anakinra in children with refractory systemic juvenile idiopathic arthritis: a retrospective case series. J Rheumatol. 2011;38:180–1.PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Lee M, Isaacs J. The novel use of combined IL-1 and IL-6 inhibition in a patient with severe, aggressive, erosive, systemic-onset juvenile idiopathic arthritis. Eur J Rheumatol. 2017;4:68–9.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Brinkman BMC, de Kleer M, ten Cate R, et al. Autologous stem cell transplantation in children with severe progressive systemic or polyarticular juvenile idiopathic arthritis. Arthritis Rheum. 2007;56:2410–21.PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Ravelli A, De Benedetti F, Viola S, et al. Macrophage activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine. J Pediatr. 1996;128:275–8.PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Ravelli A, Grom AA, Behrens EM, Cron RQ. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun. 2012;13:289–98.PubMedCrossRefPubMedCentralGoogle Scholar
  169. 169.
    Lomater C, Gerloni V, Gattinara M, Mazzotti J, Cimaz R, Fantini F. Systemic onset juvenile idiopathic arthritis: a retrospective study of 80 consecutive patients followed for 10 years. J Rheumatol. 2000;27:491–6.PubMedPubMedCentralGoogle Scholar
  170. 170.
    Nigrovic PA, White PH. Care of the adult with juvenile rheumatoid arthritis. Arthritis Rheum. 2006;15(55):208–16.CrossRefGoogle Scholar
  171. 171.
    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;54:1595–601.PubMedCrossRefPubMedCentralGoogle Scholar
  172. 172.
    Magni-Manzoni S, Pistorio A, Labo E, et al. A longitudinal analysis of physical functional disability over the course of juvenile idiopathic arthritis. Ann Rheum Dis. 2008;67:1159–64.PubMedCrossRefPubMedCentralGoogle Scholar
  173. 173.
    Schneider R, Lang BA, Reilly BJ, et al. Prognostic indicators of joint destruction in systemic onset juvenile rheumatoid arthritis. J Pediatr. 1992;120:200–5.PubMedCrossRefPubMedCentralGoogle Scholar
  174. 174.
    Spiegel LR, Schneider R, Lang BA, et al. Early predictors of poor functional outcome in systemic-onset juvenile rheumatoid arthritis. A multicenter cohort study. Arthritis Rheum. 2000;43:2402–9.PubMedCrossRefPubMedCentralGoogle Scholar
  175. 175.
    Modesto C, Woo P, García-Consuegra J, et al. Systemic onset juvenile chronic arthritis: polyarticular pattern and hip involvement as markers for a bad prognosis. Clin Exp Rheumatol. 2001;19:211–7.PubMedPubMedCentralGoogle Scholar
  176. 176.
    Magni-Manzoni S, Rossi F, Pistorio A, et al. Prognostic factors for radiographic progression, radiographic damage, and disability in juvenile idiopathic arthritis. Arthritis Rheum. 2003;48:3509–17.PubMedCrossRefPubMedCentralGoogle Scholar
  177. 177.
    Oen K, Malleson PN, Cabral DA, et al. Early predictors of longterm outcome in patients with juvenile rheumatoid arthritis: subset-specific correlations. J Rheumatol. 2003;30:585–93.PubMedPubMedCentralGoogle Scholar
  178. 178.
    Viola S, Felici E, Magni-Manzoni S, et al. Development and validation of a clinical index for assessment of long-term damage in juvenile idiopathic arthritis. Arthritis Rheum. 2005;52:2092–102.PubMedCrossRefPubMedCentralGoogle Scholar
  179. 179.
    Sandborg C, Holmes TH, Lee T, et al. Candidate early predictors for progression to joint damage in systemic juvenile idiopathic arthritis. J Rheumatol. 2006;33:2322–9.PubMedPubMedCentralGoogle Scholar
  180. 180.
    Wallace CA, Huang B, Bandeira M, et al. Patterns of clinical remission in select categories of juvenile idiopathic arthritis. Arthritis Rheum. 2005;52:3554–62.PubMedCrossRefPubMedCentralGoogle Scholar
  181. 181.
    Guzman J, Oen K, Tucker LB, et al. The outcomes of juvenile idiopathic arthritis in children managed with contemporary cohort treatments: results from the ReACCh-Out. Ann Rheum Dis. 2015;74:1854–60.PubMedCrossRefPubMedCentralGoogle Scholar
  182. 182.
    Simonini G, Ferrara G, Pontikaki I, et al. Flares after withdrawal of biologic therapies in juvenile idiopathic arthritis: clinical and laboratory correlates of remission duration. Arthritis Care Res (Hoboken). 2018;70:1046–51.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Ricardo A. G. Russo
    • 1
    Email author
  • María Martha Katsicas
    • 1
  1. 1.Service of Immunology & RheumatologyHospital de Pediatría Prof. Dr. Juan P. GarrahanBuenos AiresArgentina

Personalised recommendations