Advertisement

Systemic Juvenile Idiopathic Arthritis and Adult Onset Still Disease

  • Peter A. NigrovicEmail author
  • Rayfel Schneider
Chapter

Abstract

Systemic juvenile idiopathic arthritis (sJIA) and adult onset Still disease (AOSD) are characterized by the triad of fever, rash and arthritis, together with high-grade systemic inflammation and other manifestations such as serositis, lymphadenopathy and hepatosplenomegaly. Patients exhibit considerable heterogeneity in disease severity and course, with some experiencing episodes of life-threatening inflammation termed macrophage activation syndrome. Pathophysiologic investigation into sJIA/AOSD implicates dysregulated immune control, with potential roles for both innate and adaptive immune cells, and for cytokines including interleukin (IL)-1β, IL-6, IL-18 and interferon (IFN)-γ. Therapeutic intervention with antagonists of IL-1 and IL-6 provide important clinical benefit for many patients.

Keywords

Systemic juvenile idiopathic arthritis Adult-onset Still disease Fever Arthritis Interleukin Inflammasomes Macrophage activation syndrome Anakinra Rilonacept Canakinumab Tocilizumab 

Abbreviations

ACR

American College of Rheumatology

AOSD

Adult-onset Still disease

CRP

C-reactive protein

DAMP

Damage-associated molecular pattern

DIC

Disseminated intravascular coagulation

DMARD

Disease-modifying anti-rheumatic drug

ESR

Erythrocyte sedimentation rate

FAMIN

Fatty acid metabolism-immunity nexus

GWAS

Genome-wide association study

HLA

Human leukocyte antigen

HLH

Hemophagocytic lymphohistiocyosis

HSCT

Hematopoietic stem cell transplantation

IL

Interleukin

IL-(X)R

Interleukin (X) receptor

IL1ra

IL-1 receptor antagonist

ILAR

International League of Associations for Rheumatology

INF

Interferon

IVIG

Intravenous immunoglobulin

JAK

Janus kinase

JIA

Juvenile idiopathic arthritis

MAS

Macrophage activation syndrome

MHC

Major histocompatibility complex

MKD

Mevalonate kinase deficiency

NK

Natural killer

NSAIDs

Non-steroid anti-inflammatory drugs

sIL-(X)R

Soluble interleukin (X) receptor

sJIA

Systemic juvenile idiopathic arthritis

STAT

Signal transducer and activator of transcription

References

  1. 1.
    Still GF. On a form of chronic joint disease in children. Med Chir Trans. 1897;80:47–60.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Bywaters EG. Still’s disease in the adult. Ann Rheum Dis. 1971;30(2):121–33.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2):390–2.PubMedGoogle Scholar
  4. 4.
    Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still’s disease. J Rheumatol. 1992;19(3):424–30.PubMedGoogle Scholar
  5. 5.
    Masson C, Le Loet X, Liote F, et al. Comparative study of 6 types of criteria in adult Still’s disease. J Rheumatol. 1996;23(3):495–7.PubMedGoogle Scholar
  6. 6.
    Behrens EM, Beukelman T, Gallo L, 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(2):343–8.PubMedGoogle Scholar
  7. 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(2):545–55.PubMedCrossRefGoogle Scholar
  8. 8.
    Kumar S, Kunhiraman DS, Rajam L. Application of the Yamaguchi criteria for classification of “suspected” systemic juvenile idiopathic arthritis (sJIA). Pediatr Rheumatol Online J. 2012;10(1):40.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    DeWitt EM, Kimura Y, Beukelman T, et al. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2012;64(7):1001–10.Google Scholar
  10. 10.
    Nigrovic PA, Raychaudhuri S, Thompson SD. Genetics and the classification of arthritis in adults and children. Arthritis Rheumatol. 2018;70(1):7–17.PubMedCrossRefGoogle Scholar
  11. 11.
    Ogilvie EM, Fife MS, Thompson SD, et al. The -174G allele of the interleukin-6 gene confers susceptibility to systemic arthritis in children: a multicenter study using simplex and multiplex juvenile idiopathic arthritis families. Arthritis Rheum. 2003;48(11):3202–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Russo RA, Katsicas MM. Patients with very early-onset systemic juvenile idiopathic arthritis exhibit more inflammatory features and a worse outcome. J Rheumatol. 2013;40(3):329–34.PubMedCrossRefGoogle Scholar
  13. 13.
    Klotsche J, Raab A, Niewerth M, et al. Outcome and trends in treatment of systemic juvenile idiopathic arthritis in the German National Pediatric Rheumatologic Database, 2000-2013. Arthritis Rheumatol. 2016;68(12):3023–34.PubMedCrossRefGoogle Scholar
  14. 14.
    Saurenmann RK, Levin AV, Feldman BM, et al. Prevalence, risk factors, and outcome of uveitis in juvenile idiopathic arthritis: a long-term followup study. Arthritis Rheum. 2007;56(2):647–57.PubMedCrossRefGoogle Scholar
  15. 15.
    Feldman BM, Birdi N, Boone JE, et al. Seasonal onset of systemic-onset juvenile rheumatoid arthritis. J Pediatr. 1996;129(4):513–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Uziel Y, Pomeranz A, Brik R, et al. Seasonal variation in systemic onset juvenile rheumatoid arthritis in Israel. J Rheumatol. 1999;26(5):1187–9.PubMedGoogle Scholar
  17. 17.
    Berntson L, Andersson Gare B, Fasth A, et al. Incidence of juvenile idiopathic arthritis in the Nordic countries. A population based study with special reference to the validity of the ILAR and EULAR criteria. J Rheumatol. 2003;30(10):2275–82.PubMedGoogle Scholar
  18. 18.
    Huemer C, Huemer M, Dorner T, et al. Incidence of pediatric rheumatic diseases in a regional population in Austria. J Rheumatol. 2001;28(9):2116–9.PubMedGoogle Scholar
  19. 19.
    Danner S, Sordet C, Terzic J, et al. Epidemiology of juvenile idiopathic arthritis in alsace, france. J Rheumatol. 2006;33(7):1377–81.PubMedGoogle Scholar
  20. 20.
    Moe N, Rygg M. Epidemiology of juvenile chronic arthritis in northern Norway: a ten-year retrospective study. Clin Exp Rheumatol. 1998;16(1):99–101.PubMedGoogle Scholar
  21. 21.
    Gare BA, Fasth A. Epidemiology of juvenile chronic arthritis in southwestern Sweden: a 5-year prospective population study. Pediatrics. 1992;90(6):950–8.PubMedGoogle Scholar
  22. 22.
    Seth V, Kabra SK, Semwal OP, Jain Y. Clinico-immunological profile in juvenile rheumatoid arthritis—an Indian experience. Indian J Pediatr. 1996;63(3):293–300.PubMedCrossRefGoogle Scholar
  23. 23.
    Fujikawa S, Okuni M. A nationwide surveillance study of rheumatic diseases among Japanese children. Acta Paediatr Jpn. 1997;39(2):242–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Magadur-Joly G, Billaud E, Barrier JH, et al. Epidemiology of adult Still’s disease: estimate of the incidence by a retrospective study in west France. Ann Rheum Dis. 1995;54(7):587–90.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Wakai K, Ohta A, Tamakoshi A, et al. Estimated prevalence and incidence of adult Still’s disease: findings by a nationwide epidemiological survey in Japan. J Epidemiol. 1997;7(4):221–5.PubMedCrossRefGoogle Scholar
  26. 26.
    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. Proc Natl Acad Sci U S A. 2015;112(52):15970–5.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    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(4):765–72.PubMedCrossRefGoogle Scholar
  28. 28.
    Asano T, Furukawa H, Sato S, et al. Effects of HLA-DRB1 alleles on susceptibility and clinical manifestations in Japanese patients with adult onset Still’s disease. Arthritis Res Ther. 2017;19(1):199.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Nigrovic PA. Autoinflammation and autoimmunity in systemic juvenile idiopathic arthritis. Proc Natl Acad Sci U S A. 2015;112(52):15785–6.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Ombrello MJ, Arthur VL, Remmers EF, et al. Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications. Ann Rheum Dis. 2017;76(5):906–13.PubMedCrossRefGoogle Scholar
  31. 31.
    Wakil SM, Monies DM, Abouelhoda M, et al. Association of a mutation in LACC1 with a monogenic form of systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 2015;67(1):288–95.PubMedCrossRefGoogle Scholar
  32. 32.
    Kallinich T, Thorwarth 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 Online J. 2016;14(1):63.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Cader MZ, Boroviak K, Zhang Q, et al. C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nat Immunol. 2016;17(9):1046–56.PubMedCrossRefGoogle Scholar
  34. 34.
    Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119–24.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Liu H, Irwanto A, Fu X, et al. Discovery of six new susceptibility loci and analysis of pleiotropic effects in leprosy. Nat Genet. 2015;47(3):267–71.PubMedCrossRefGoogle Scholar
  36. 36.
    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(2):567–70.PubMedCrossRefGoogle Scholar
  37. 37.
    Vastert SJ, van Wijk R, D’Urbano LE, 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(3):441–9.CrossRefGoogle Scholar
  38. 38.
    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 Rheumatol. 2014;66(12):3486–95.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    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(7):1369–76.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Date Y, Seki N, Kamizono S, et al. Identification of a genetic risk factor for systemic juvenile rheumatoid arthritis in the 5’-flanking region of the TNFalpha gene and HLA genes. Arthritis Rheum. 1999;42(12):2577–82.PubMedCrossRefGoogle Scholar
  41. 41.
    Donn RP, Shelley E, Ollier WE, Thomson W. A novel 5’-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2001;44(8):1782–5.PubMedCrossRefGoogle Scholar
  42. 42.
    Lamb R, Thomson W, Ogilvie EM, Donn R. Positive association of SLC26A2 gene polymorphisms with susceptibility to systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2007;56(4):1286–91.PubMedCrossRefGoogle Scholar
  43. 43.
    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(4):349–57.PubMedCrossRefGoogle Scholar
  44. 44.
    Day TG, Ramanan AV, Hinks A, et al. Autoinflammatory genes and susceptibility to psoriatic juvenile idiopathic arthritis. Arthritis Rheum. 2008;58(7):2142–6.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Arthur V, Shuldiner E, Remmers E, et al. IL1RN variation influences both disease susceptibility and response to human recombinant IL-1RA therapy in systemic juvenile idiopathic arthritis. Arthritis Rheum. 2018;70(8):1319–30.CrossRefGoogle Scholar
  46. 46.
    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(10):2071–5.PubMedGoogle Scholar
  47. 47.
    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(9):1479–86.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    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(9):1158–63.PubMedCrossRefGoogle Scholar
  49. 49.
    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(5):589–98.PubMedCrossRefGoogle Scholar
  50. 50.
    Shimizu M, Nakagishi Y, Yachie A. Distinct subsets of patients with systemic juvenile idiopathic arthritis based on their cytokine profiles. Cytokine. 2013;61(2):345–8.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    De Benedetti F, Pignatti P, Gerloni V, et al. Differences in synovial fluid cytokine levels between juvenile and adult rheumatoid arthritis. J Rheumatol. 1997;24(7):1403–9.PubMedGoogle Scholar
  52. 52.
    Garlanda C, Riva F, Bonavita E, Mantovani A. Negative regulatory receptors of the IL-1 family. Semin Immunol. 2013;25(6):408–15.PubMedCrossRefGoogle Scholar
  53. 53.
    Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2396–406.PubMedCrossRefGoogle Scholar
  54. 54.
    Akitsu A, Ishigame H, Kakuta S, et al. IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2(+)Vgamma6(+)gammadelta T cells. Nat Commun. 2015;6:7464.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    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(5):1505–15.PubMedCrossRefGoogle Scholar
  56. 56.
    Ikeda S, Saijo S, Murayama MA, Shimizu K, Akitsu A, Iwakura Y. Excess IL-1 signaling enhances the development of Th17 cells by downregulating TGF-beta-induced Foxp3 expression. J Immunol. 2014;192(4):1449–58.PubMedCrossRefGoogle Scholar
  57. 57.
    Dinarello CA. The history of fever, leukocytic pyrogen and interleukin-1. Temperature (Austin). 2015;2(1):8–16.CrossRefGoogle Scholar
  58. 58.
    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(4):1034–43.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Calabrese LH, Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol. 2014;10(12):720–7.PubMedCrossRefGoogle Scholar
  60. 60.
    De Benedetti F, Massa M, Pignatti P, Albani S, Novick D, Martini A. Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J Clin Invest. 1994;93(5):2114–9.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    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(9617):998–1006.PubMedCrossRefGoogle Scholar
  62. 62.
    De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2385–95.PubMedCrossRefGoogle Scholar
  63. 63.
    De Benedetti F, Alonzi T, Moretta A, 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(4):643–50.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Cifaldi L, Prencipe G, Caiello I, et al. Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome. Arthritis Rheumatol. 2015;67(11):3037–46.PubMedCrossRefGoogle Scholar
  65. 65.
    Schulert GS, Minoia F, Bohnsack J, et al. Biologic therapy modifies clinical and laboratory features of macrophage activation syndrome associated with systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2018;70:409–19.CrossRefGoogle Scholar
  66. 66.
    McInnes IB, Gracie JA, Liew FY. Interleukin-18: a novel cytokine in inflammatory rheumatic disease. Arthritis Rheum. 2001;44(7):1481–3.PubMedCrossRefGoogle Scholar
  67. 67.
    Dinarello CA, Novick D, Kim S, Kaplanski G. Interleukin-18 and IL-18 binding protein. Front Immunol. 2013;4:289.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Girard C, Rech J, Brown M, et al. Elevated serum levels of free interleukin-18 in adult-onset Still’s disease. Rheumatology (Oxford). 2016;55(12):2237–47.CrossRefGoogle Scholar
  69. 69.
    Mazodier K, Marin V, Novick D, et al. Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Blood. 2005;106(10):3483–9.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Put K, Avau A, Brisse E, et al. Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-gamma. Rheumatology (Oxford). 2015;54(8):1507–17.CrossRefGoogle Scholar
  71. 71.
    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(4):823–30.PubMedGoogle Scholar
  72. 72.
    Put K, Vandenhaute J, Avau A, et al. Inflammatory gene expression profile and defective interferon-gamma and Granzyme K in natural killer cells from systemic juvenile idiopathic arthritis patients. Arthritis Rheumatol. 2017;69(1):213–24.PubMedCrossRefGoogle Scholar
  73. 73.
    Shimizu M, Yokoyama T, Yamada K, 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(9):1645–53.CrossRefGoogle Scholar
  74. 74.
    de Jager W, Vastert SJ, Beekman JM, et al. Defective phosphorylation of interleukin-18 receptor beta causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2009;60(9):2782–93.PubMedCrossRefGoogle Scholar
  75. 75.
    Behrens EM. Editorial: caught in the act: dissecting natural killer cell function in systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 2017;69(1):6–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Bracaglia C, de Graaf K, Pires Marafon D, et al. Elevated circulating levels of interferon-gamma and interferon-gamma-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2017;76(1):166–72.PubMedCrossRefGoogle Scholar
  77. 77.
    Konishi K, Tanabe F, Taniguchi M, et al. A simple and sensitive bioassay for the detection of human interleukin-18/interferon-gamma-inducing factor using human myelomonocytic KG-1 cells. J Immunol Methods. 1997;209(2):187–91.PubMedCrossRefGoogle Scholar
  78. 78.
    Wittkowski H, Frosch M, Wulffraat N, 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(12):3924–31.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Frosch M, Ahlmann M, Vogl T, et al. The myeloid-related proteins 8 and 14 complex, a novel ligand of toll-like receptor 4, and interleukin-1beta form a positive feedback mechanism in systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2009;60(3):883–91.PubMedCrossRefGoogle Scholar
  80. 80.
    Kessel C, Holzinger D, Foell D. Phagocyte-derived S100 proteins in autoinflammation: putative role in pathogenesis and usefulness as biomarkers. Clin Immunol. 2013;147(3):229–41.PubMedCrossRefGoogle Scholar
  81. 81.
    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(3):292–6.PubMedCrossRefGoogle Scholar
  82. 82.
    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(1):R30–7.PubMedCrossRefGoogle Scholar
  83. 83.
    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(2):375–9.CrossRefGoogle Scholar
  84. 84.
    Nakae S, Saijo S, Horai R, Sudo K, Mori S, Iwakura Y. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci U S A. 2003;100(10):5986–90.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Horai R, Nakajima A, Habiro K, et al. TNF-alpha is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist-deficient mice. J Clin Invest. 2004;114(11):1603–11.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Nigrovic PA. Review: is there a window of opportunity for treatment of systemic juvenile idiopathic arthritis? Arthritis Rheumatol. 2014;66(6):1405–13.PubMedCrossRefGoogle Scholar
  87. 87.
    Kessel C, Lippitz K, Weinhage T, et al. Proinflammatory Cytokine Environments Can Drive Interleukin-17 Overexpression by gamma/delta T Cells in Systemic Juvenile Idiopathic Arthritis. Arthritis Rheumatol. 2017;69(7):1480–94.PubMedCrossRefGoogle Scholar
  88. 88.
    Macaubas C, Nguyen KD, Peck A, et al. Alternative activation in systemic juvenile idiopathic arthritis monocytes. Clin Immunol. 2012;142(3):362–72.PubMedCrossRefGoogle Scholar
  89. 89.
    Macaubas C, Wong E, Zhang Y, et al. Altered signaling in systemic juvenile idiopathic arthritis monocytes. Clin Immunol. 2016;163:66–74.PubMedCrossRefGoogle Scholar
  90. 90.
    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(11):3449–66.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    ter Haar N, Tak T, Mokry M, et al. Neutrophils in systemic onset juvenile idiopathic arthritis display sepsis-like features which can be reverted by IL-1 blockade. Arthritis Rheumatol. 2018;70(6):943–56.PubMedCrossRefGoogle Scholar
  92. 92.
    Vogl T, Propper C, Hartmann M, et al. S100A12 is expressed exclusively by granulocytes and acts independently from MRP8 and MRP14. J Biol Chem. 1999;274(36):25291–6.PubMedCrossRefGoogle Scholar
  93. 93.
    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(9):2622–6.PubMedCrossRefGoogle Scholar
  94. 94.
    Chou RC, Kim ND, Sadik CD, et al. Lipid-cytokine-chemokine cascade drives neutrophil recruitment in a murine model of inflammatory arthritis. Immunity. 2010;33(2):266–78.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Wipke BT, Allen PM. Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. J Immunol. 2001;167(3):1601–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Kawashima M, Yamamura M, Taniai M, et al. Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still’s disease. Arthritis Rheum. 2001;44(3):550–60.PubMedCrossRefGoogle Scholar
  97. 97.
    Priori R, Colafrancesco S, Alessandri C, et al. Interleukin 18: a biomarker for differential diagnosis between adult-onset Still’s disease and sepsis. J Rheumatol. 2014;41(6):1118–23.PubMedCrossRefGoogle Scholar
  98. 98.
    Inoue N, Shimizu M, Tsunoda S, Kawano M, Matsumura M, Yachie A. Cytokine profile in adult-onset Still’s disease: comparison with systemic juvenile idiopathic arthritis. Clin Immunol. 2016;169:8–13.PubMedCrossRefGoogle Scholar
  99. 99.
    Kim HA, An JM, Nam JY, Jeon JY, Suh CH. Serum S100A8/A9, but not follistatin-like protein 1 and interleukin 18, may be a useful biomarker of disease activity in adult-onset Still’s disease. J Rheumatol. 2012;39(7):1399–406.PubMedCrossRefGoogle Scholar
  100. 100.
    Park JH, Kim HS, Lee JS, et al. Natural killer cell cytolytic function in Korean patients with adult-onset Still’s disease. J Rheumatol. 2012;39(10):2000–7.PubMedCrossRefGoogle Scholar
  101. 101.
    Lee SJ, Cho YN, Kim TJ, et al. Natural killer T cell deficiency in active adult-onset Still’s disease: correlation of deficiency of natural killer T cells with dysfunction of natural killer cells. Arthritis Rheum. 2012;64(9):2868–77.PubMedCrossRefGoogle Scholar
  102. 102.
    McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLoS Med. 2006;3(8):e297.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Bywaters EG, Isdale IC. The rash of rheumatoid arthritis and Still’s disease. Q J Med. 1956;25(99):377–87.PubMedGoogle Scholar
  104. 104.
    Pouchot J, Sampalis JS, Beaudet F, et al. Adult Still’s disease: manifestations, disease course, and outcome in 62 patients. Medicine (Baltimore). 1991;70(2):118–36.CrossRefGoogle Scholar
  105. 105.
    Frosch M, Metze D, Foell D, et al. Early activation of cutaneous vessels and epithelial cells is characteristic of acute systemic onset juvenile idiopathic arthritis. Exp Dermatol. 2005;14(4):259–65.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Larson AR, Laga AC, Granter SR. The spectrum of histopathologic findings in cutaneous lesions in patients with Still disease. Am J Clin Pathol. 2015;144(6):945–51.PubMedCrossRefGoogle Scholar
  107. 107.
    Fortna RR, Gudjonsson JE, Seidel G, et al. Persistent pruritic papules and plaques: a characteristic histopathologic presentation seen in a subset of patients with adult-onset and juvenile Still’s disease. J Cutan Pathol. 2010;37(9):932–7.PubMedCrossRefGoogle Scholar
  108. 108.
    Kim HA, Kwon JE, Yim H, Suh CH, Jung JY, Han JH. The pathologic findings of skin, lymph node, liver, and bone marrow in patients with adult-onset still disease: a comprehensive analysis of 40 cases. Medicine (Baltimore). 2015;94(17):e787.CrossRefGoogle Scholar
  109. 109.
    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(4):596–8.CrossRefGoogle Scholar
  110. 110.
    Pay S, Turkcapar N, Kalyoncu M, et al. A multicenter study of patients with adult-onset Still’s disease compared with systemic juvenile idiopathic arthritis. Clin Rheumatol. 2006;25(5):639–44.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Minoia F, Davi S, Horne A, et al. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheumatol. 2014;66(11):3160–9.PubMedCrossRefGoogle Scholar
  112. 112.
    Behrens EM, Beukelman T, Paessler M, Cron RQ. Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. J Rheumatol. 2007;34(5):1133–8.PubMedGoogle Scholar
  113. 113.
    Ravelli A, Minoia F, Davi S, et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Arthritis Rheumatol. 2016;68(3):566–76.PubMedCrossRefGoogle Scholar
  114. 114.
    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(1):e000161.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Minoia F, Bovis F, Davi S, et al. Development and initial validation of the macrophage activation syndrome/primary hemophagocytic lymphohistiocytosis score, a diagnostic tool that differentiates primary hemophagocytic lymphohistiocytosis from macrophage activation syndrome. J Pediatr. 2017;189:72–78 e73.PubMedCrossRefGoogle Scholar
  116. 116.
    Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31.PubMedCrossRefGoogle Scholar
  117. 117.
    Gerfaud-Valentin M, Hot A, Huissoud C, Durieu I, Broussolle C, Seve P. Adult-onset Still’s disease and pregnancy: about ten cases and review of the literature. Rheumatol Int. 2014;34(6):867–71.PubMedCrossRefGoogle Scholar
  118. 118.
    Bloom BJ, Tucker LB, Miller LC, McCauley RG, Schaller JG. Bicipital synovial cysts in juvenile rheumatoid arthritis: clinical description and sonographic correlation. J Rheumatol. 1995;22(10):1953–5.PubMedGoogle Scholar
  119. 119.
    Miller ML, Levinson L, Pachman LM, Poznanski A. Abnormal muscle MRI in a patient with systemic juvenile arthritis. Pediatr Radiol. 1995;25(Suppl 1):S107–8.PubMedGoogle Scholar
  120. 120.
    Kimura Y, Weiss JE, Haroldson KL, et al. Pulmonary hypertension and other potentially fatal pulmonary complications in systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2013;65(5):745–52.CrossRefGoogle Scholar
  121. 121.
    Cangemi G, Pistorio A, Miano M, et al. Diagnostic potential of hepcidin testing in pediatrics. Eur J Haematol. 2013;90(4):323–30.PubMedCrossRefGoogle Scholar
  122. 122.
    Kaser A, Brandacher G, Steurer W, et al. Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis. Blood. 2001;98(9):2720–5.PubMedCrossRefGoogle Scholar
  123. 123.
    Sibille JC, Kondo H, Aisen P. Interactions between isolated hepatocytes and Kupffer cells in iron metabolism: a possible role for ferritin as an iron carrier protein. Hepatology. 1988;8(2):296–301.PubMedCrossRefGoogle Scholar
  124. 124.
    Ghosh S, Hevi S, Chuck SL. Regulated secretion of glycosylated human ferritin from hepatocytes. Blood. 2004;103(6):2369–76.PubMedCrossRefGoogle Scholar
  125. 125.
    Cohen LA, Gutierrez L, Weiss A, et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood. 2010;116(9):1574–84.PubMedCrossRefGoogle Scholar
  126. 126.
    Gozzelino R, Soares MP. Coupling heme and iron metabolism via ferritin H chain. Antioxid Redox Signal. 2014;20(11):1754–69.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Rogers JT, Andriotakis JL, Lacroix L, Durmowicz GP, Kasschau KD, Bridges KR. Translational enhancement of H-ferritin mRNA by interleukin-1 beta acts through 5’ leader sequences distinct from the iron responsive element. Nucleic Acids Res. 1994;22(13):2678–86.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood. 2002;99(10):3505–16.PubMedCrossRefGoogle Scholar
  129. 129.
    Slaats J, Ten Oever J, van de Veerdonk FL, Netea MG. IL-1beta/IL-6/CRP and IL-18/ferritin: distinct inflammatory programs in infections. PLoS Pathog. 2016;12(12):e1005973.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Pelkonen P, Swanljung K, Siimes MA. Ferritinemia as an indicator of systemic disease activity in children with systemic juvenile rheumatoid arthritis. Acta Paediatr Scand. 1986;75(1):64–8.PubMedCrossRefGoogle Scholar
  131. 131.
    Van Reeth C, Le Moel G, Lasne Y, et al. Serum ferritin and isoferritins are tools for diagnosis of active adult Still’s disease. J Rheumatol. 1994;21(5):890–5.PubMedGoogle Scholar
  132. 132.
    Cragg SJ, Wagstaff M, Worwood M. Detection of a glycosylated subunit in human serum ferritin. Biochem J. 1981;199(3):565–71.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Vignes S, Le Moel G, Fautrel B, Wechsler B, Godeau P, Piette JC. Percentage of glycosylated serum ferritin remains low throughout the course of adult onset Still’s disease. Ann Rheum Dis. 2000;59(5):347–50.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Fautrel B, Le Moel G, Saint-Marcoux B, et al. Diagnostic value of ferritin and glycosylated ferritin in adult onset Still’s disease. J Rheumatol. 2001;28(2):322–9.PubMedGoogle Scholar
  135. 135.
    Bloom BJ, Tucker LB, Miller LC, Schaller JG. Fibrin D-dimer as a marker of disease activity in systemic onset juvenile rheumatoid arthritis. J Rheumatol. 1998;25(8):1620–5.PubMedGoogle Scholar
  136. 136.
    Kawaguchi Y, Terajima H, Harigai M, Hara M, Kamatani N. Interleukin-18 as a novel diagnostic marker and indicator of disease severity in adult-onset Still’s disease. Arthritis Rheum. 2001;44(7):1716–7.PubMedCrossRefGoogle Scholar
  137. 137.
    Lachmann HJ, Lowe P, Felix SD, et al. In vivo regulation of interleukin 1beta in patients with cryopyrin-associated periodic syndromes. J Exp Med. 2009;206(5):1029–36.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Scire CA, Cavagna L, Perotti C, Bruschi E, Caporali R, Montecucco C. Diagnostic value of procalcitonin measurement in febrile patients with systemic autoimmune diseases. Clin Exp Rheumatol. 2006;24(2):123–8.PubMedGoogle Scholar
  139. 139.
    Rau M, Schiller M, Krienke S, Heyder P, Lorenz H, Blank N. Clinical manifestations but not cytokine profiles differentiate adult-onset Still’s disease and sepsis. J Rheumatol. 2010;37(11):2369–76.PubMedCrossRefGoogle Scholar
  140. 140.
    Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503–16.PubMedCrossRefGoogle Scholar
  141. 141.
    Schram AM, Comstock P, Campo M, et al. Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years. Br J Haematol. 2016;172(3):412–9.PubMedCrossRefGoogle Scholar
  142. 142.
    Lehmberg K, Sprekels B, Nichols KE, et al. Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents. Br J Haematol. 2015;170(4):539–49.PubMedCrossRefGoogle Scholar
  143. 143.
    Lipsker D. The Schnitzler syndrome. Orphanet J Rare Dis. 2010;5:38.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Gusdorf L, Asli B, Barbarot S, et al. Schnitzler syndrome: validation and applicability of diagnostic criteria in real-life patients. Allergy. 2017;72(2):177–82.PubMedCrossRefGoogle Scholar
  145. 145.
    Oen K, Duffy CM, Tse SM, et al. Early outcomes and improvement of patients with juvenile idiopathic arthritis enrolled in a Canadian multicenter inception cohort. Arthritis Care Res (Hoboken). 2010;62(4):527–36.CrossRefGoogle Scholar
  146. 146.
    Kimura Y, Fieldston E, Devries-Vandervlugt B, Li S, Imundo L. High dose, alternate day corticosteroids for systemic onset juvenile rheumatoid arthritis. J Rheumatol. 2000;27(8):2018–24.PubMedGoogle Scholar
  147. 147.
    Ilowite NT, Sandborg CI, Feldman BM, et al. Algorithm development for corticosteroid management in systemic juvenile idiopathic arthritis trial using consensus methodology. Pediatr Rheumatol Online J. 2012;10(1):31.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    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(5):747–54.PubMedCrossRefGoogle Scholar
  149. 149.
    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(9):2570–9.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Tarp S, Amarilyo G, Foeldvari I, et al. Efficacy and safety of biological agents for systemic juvenile idiopathic arthritis: a systematic review and meta-analysis of randomized trials. Rheumatology. 2016;55(4):669–79.PubMedCrossRefGoogle Scholar
  151. 151.
    Colafrancesco S, Priori R, Valesini G, et al. Response to interleukin-1 inhibitors in 140 Italian patients with adult-onset Still’s disease: a multicentre retrospective observational study. Front Pharmacol. 2017;8:369.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Laskari K, Tzioufas AG, Moutsopoulos HM. Efficacy and long-term follow-up of IL-1R inhibitor anakinra in adults with Still’s disease: a case-series study. Arthritis Res Ther. 2011;13(3):R91.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Nordstrom D, Knight A, Luukkainen R, et al. Beneficial effect of interleukin 1 inhibition with anakinra in adult-onset Still’s disease. an open, randomized, multicenter study. J Rheumatol. 2012;39(10):2008–11.PubMedCrossRefGoogle Scholar
  154. 154.
    Giampietro C, Ridene M, Lequerre T, et al. Anakinra in adult-onset Still’s disease: long-term treatment in patients resistant to conventional therapy. Arthritis Care Res (Hoboken). 2013;65(5):822–6.CrossRefGoogle Scholar
  155. 155.
    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(1):180–1.PubMedCrossRefGoogle Scholar
  156. 156.
    Miettunen PM, Narendran A, Jayanthan A, Behrens EM, Cron RQ. 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(2):417–9.CrossRefGoogle Scholar
  157. 157.
    Pardeo M, Pires Marafon D, Insalaco A, et al. Anakinra in systemic juvenile idiopathic arthritis: a single-center experience. J Rheumatol. 2015;42(8):1523–7.PubMedCrossRefGoogle Scholar
  158. 158.
    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(1):40.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    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(3):302–8.PubMedCrossRefGoogle Scholar
  160. 160.
    Zeft A, Hollister R, LaFleur B, et al. Anakinra for systemic juvenile arthritis: the Rocky Mountain experience. J Clin Rheumatol. 2009;15(4):161–4.PubMedCrossRefGoogle Scholar
  161. 161.
    Nigrovic PA, Beukelman T, Tomlinson G, Feldman BM, Schanberg LE, Kimura Y. Bayesian comparative effectiveness study of four consensus treatment plans for initial management of systemic juvenile idiopathic arthritis: FiRst Line Options for Systemic JIA Treatment (FROST). Clin Trials. 2018;15(3):268–77.PubMedCrossRefGoogle Scholar
  162. 162.
    Yokota S, Imagawa T, Mori M, et al. Long-term treatment of systemic juvenile idiopathic arthritis with tocilizumab: results of an open-label extension study in Japan. Ann Rheum Dis. 2013;72(4):627–8.PubMedCrossRefGoogle Scholar
  163. 163.
    Aoki C, Inaba Y, Choe H, et al. Discrepancy between clinical and radiological responses to tocilizumab treatment in patients with systemic-onset juvenile idiopathic arthritis. J Rheumatol. 2014;41(6):1171–7.PubMedCrossRefGoogle Scholar
  164. 164.
    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 Rheumatol. 2015;67(3):840–8.PubMedCrossRefGoogle Scholar
  165. 165.
    Ortiz-Sanjuan F, Blanco R, Calvo-Rio V, et al. Efficacy of tocilizumab in conventional treatment-refractory adult-onset Still’s disease: multicenter retrospective open-label study of thirty-four patients. Arthritis Rheumatol. 2014;66(6):1659–65.PubMedCrossRefGoogle Scholar
  166. 166.
    Song ST, Kim JJ, Lee S, et al. Efficacy of tocilizumab therapy in Korean patients with adult-onset Still’s disease: a multicentre retrospective study of 22 cases. Clin Exp Rheumatol. 2016;34(6. Suppl 102):S64–71.PubMedGoogle Scholar
  167. 167.
    Li T, Gu L, Wang X, et al. A pilot study on Tocilizumab for treating refractory adult-onset Still’s disease. Sci Rep. 2017;7(1):13477.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Ravelli A, Ramenghi B, Di Fuccia G, Ruperto N, Zonta L, Martini A. Factors associated with response to methotrexate in systemic-onset juvenile chronic arthritis. Acta Paediatr. 1994;83(4):428–32.PubMedCrossRefGoogle Scholar
  169. 169.
    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(8):1849–57.PubMedCrossRefGoogle Scholar
  170. 170.
    Fautrel B, Borget C, Rozenberg S, et al. Corticosteroid sparing effect of low dose methotrexate treatment in adult Still’s disease. J Rheumatol. 1999;26(2):373–8.PubMedGoogle Scholar
  171. 171.
    Gerloni V, Cimaz R, Gattinara M, Arnoldi C, Pontikaki I, Fantini F. Efficacy and safety profile of cyclosporin A in the treatment of juvenile chronic (idiopathic) arthritis. Results of a 10-year prospective study. Rheumatology (Oxford). 2001;40(8):907–13.CrossRefGoogle Scholar
  172. 172.
    Ruperto N, Ravelli A, Castell E, et al. Cyclosporine A in juvenile idiopathic arthritis. Results of the PRCSG/PRINTO phase IV post marketing surveillance study. Clin Exp Rheumatol. 2006;24(5):599–605.PubMedGoogle Scholar
  173. 173.
    Tanaka H, Tsugawa K, Suzuki K, et al. Treatment of difficult cases of systemic-onset juvenile idiopathic arthritis with tacrolimus. Eur J Pediatr. 2007;166(10):1053–5.PubMedCrossRefGoogle Scholar
  174. 174.
    Horneff G, Schmeling H, Biedermann T, et al. The German etanercept registry for treatment of juvenile idiopathic arthritis. Ann Rheum Dis. 2004;63(12):1638–44.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    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(5):635–41.PubMedCrossRefGoogle Scholar
  176. 176.
    Quartier P, Taupin P, Bourdeaut F, et al. Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to the onset type. Arthritis Rheum. 2003;48(4):1093–101.PubMedCrossRefGoogle Scholar
  177. 177.
    Russo RA, Katsicas MM. Clinical remission in patients with systemic juvenile idiopathic arthritis treated with anti-tumor necrosis factor agents. J Rheumatol. 2009;36(5):1078–82.PubMedCrossRefGoogle Scholar
  178. 178.
    Husni ME, Maier AL, Mease PJ, et al. Etanercept in the treatment of adult patients with Still’s disease. Arthritis Rheum. 2002;46(5):1171–6.PubMedCrossRefGoogle Scholar
  179. 179.
    Kraetsch HG, Antoni C, Kalden JR, Manger B. Successful treatment of a small cohort of patients with adult onset of Still’s disease with infliximab: first experiences. Ann Rheum Dis. 2001;60(Suppl 3):iii55–7.PubMedPubMedCentralGoogle Scholar
  180. 180.
    Cavagna L, Caporali R, Epis O, Bobbio-Pallavicini F, Montecucco C. Infliximab in the treatment of adult Still’s disease refractory to conventional therapy. Clin Exp Rheumatol. 2001;19(3):329–32.PubMedGoogle Scholar
  181. 181.
    Fautrel B, Sibilia J, Mariette X, Combe B. Tumour necrosis factor alpha blocking agents in refractory adult Still’s disease: an observational study of 20 cases. Ann Rheum Dis. 2005;64(2):262–6.PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Lehman TJ, Schechter SJ, Sundel RP, Oliveira SK, Huttenlocher A, Onel KB. Thalidomide for severe systemic onset juvenile rheumatoid arthritis: a multicenter study. J Pediatr. 2004;145(6):856–7.PubMedCrossRefGoogle Scholar
  183. 183.
    Garcia-Carrasco M, Fuentes-Alexandro S, Escarcega RO, Rojas-Rodriguez J, Escobar LE. Efficacy of thalidomide in systemic onset juvenile rheumatoid arthritis. Joint Bone Spine. 2007;74(5):500–3.PubMedCrossRefGoogle Scholar
  184. 184.
    Stambe C, Wicks IP. TNFalpha and response of treatment-resistant adult-onset Still’s disease to thalidomide. Lancet. 1998;352(9127):544–5.PubMedCrossRefGoogle Scholar
  185. 185.
    Uziel Y, Laxer RM, Schneider R, Silverman ED. Intravenous immunoglobulin therapy in systemic onset juvenile rheumatoid arthritis: a followup study. J Rheumatol. 1996;23(5):910–8.PubMedGoogle Scholar
  186. 186.
    Silverman ED, Cawkwell GD, Lovell DJ, et al. Intravenous immunoglobulin in the treatment of systemic juvenile rheumatoid arthritis: a randomized placebo controlled trial. Pediatric Rheumatology Collaborative Study Group. J Rheumatol. 1994;21(12):2353–8.PubMedGoogle Scholar
  187. 187.
    Shaikov AV, Maximov AA, Speransky AI, Lovell DJ, Giannini EH, Solovyev SK. Repetitive use of pulse therapy with methylprednisolone and cyclophosphamide in addition to oral methotrexate in children with systemic juvenile rheumatoid arthritis—preliminary results of a longterm study. J Rheumatol. 1992;19(4):612–6.PubMedGoogle Scholar
  188. 188.
    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(10):1852–5.PubMedCrossRefGoogle Scholar
  189. 189.
    Alexeeva EI, Valieva SI, Bzarova TM, et al. Efficacy and safety of repeat courses of rituximab treatment in patients with severe refractory juvenile idiopathic arthritis. Clin Rheumatol. 2011;30(9):1163–72.PubMedCrossRefGoogle Scholar
  190. 190.
    Wulffraat NM, Brinkman D, Ferster A, et al. Long-term follow-up of autologous stem cell transplantation for refractory juvenile idiopathic arthritis. Bone Marrow Transplant. 2003;32(Suppl 1):S61–4.PubMedCrossRefGoogle Scholar
  191. 191.
    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(7):2410–21.PubMedCrossRefGoogle Scholar
  192. 192.
    Abinun M, Flood TJ, Cant AJ, et al. Autologous T cell depleted haematopoietic stem cell transplantation in children with severe juvenile idiopathic arthritis in the UK (2000-2007). Mol Immunol. 2009;47(1):46–51.PubMedCrossRefGoogle Scholar
  193. 193.
    Delemarre EM, van den Broek T, Mijnheer G, et al. Autologous stem cell transplantation aids autoimmune patients by functional renewal and TCR diversification of regulatory T cells. Blood. 2016;127(1):91–101.PubMedCrossRefGoogle Scholar
  194. 194.
    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(10):1551–63.CrossRefGoogle Scholar
  195. 195.
    Grom AA, Ilowite NT, Pascual V, et al. Rate and clinical presentation of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis treated with canakinumab. Arthritis Rheumatol. 2016;68(1):218–28.PubMedCrossRefGoogle Scholar
  196. 196.
    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(5):1595–601.PubMedCrossRefGoogle Scholar
  197. 197.
    Oen K, Malleson PN, Cabral DA, Rosenberg AM, Petty RE, Cheang M. Disease course and outcome of juvenile rheumatoid arthritis in a multicenter cohort. J Rheumatol. 2002;29(9):1989–99.PubMedGoogle Scholar
  198. 198.
    Nigrovic PA, White PH. Care of the adult with juvenile rheumatoid arthritis. Arthritis Rheum. 2006;55(2):208–16.PubMedCrossRefGoogle Scholar
  199. 199.
    Selvaag AM, Aulie HA, Lilleby V, Flato B. Disease progression into adulthood and predictors of long-term active disease in juvenile idiopathic arthritis. Ann Rheum Dis. 2016;75(1):190–5.PubMedCrossRefGoogle Scholar
  200. 200.
    Hashkes PJ, Wright BM, Lauer MS, et al. Mortality outcomes in pediatric rheumatology in the US. Arthritis Rheum. 2010;62(2):599–608.PubMedGoogle Scholar
  201. 201.
    Stoeber E. Prognosis in juvenile chronic arthritis. Follow-up of 433 chronic rheumatic children. Eur J Pediatr. 1981;135(3):225–8.PubMedCrossRefGoogle Scholar
  202. 202.
    Svantesson H, Akesson A, Eberhardt K, Elborgh R. Prognosis in juvenile rheumatoid arthritis with systemic onset. A follow-up study. Scand J Rheumatol. 1983;12(2):139–44.PubMedCrossRefGoogle Scholar
  203. 203.
    Cabane J, Michon A, Ziza JM, et al. Comparison of long term evolution of adult onset and juvenile onset Still’s disease, both followed up for more than 10 years. Ann Rheum Dis. 1990;49(5):283–5.PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Polito C, Strano CG, Olivieri AN, et al. Growth retardation in non-steroid treated juvenile rheumatoid arthritis. Scand J Rheumatol. 1997;26(2):99–103.PubMedCrossRefGoogle Scholar
  205. 205.
    Simon D, Fernando C, Czernichow P, Prieur AM. Linear growth and final height in patients with systemic juvenile idiopathic arthritis treated with longterm glucocorticoids. J Rheumatol. 2002;29(6):1296–300.PubMedGoogle Scholar
  206. 206.
    Brik R, Keidar Z, Schapira D, Israel O. Bone mineral density and turnover in children with systemic juvenile chronic arthritis. J Rheumatol. 1998;25(5):990–2.PubMedGoogle Scholar
  207. 207.
    Bechtold S, Ripperger P, Dalla Pozza R, et al. Growth hormone increases final height in patients with juvenile idiopathic arthritis: data from a randomized controlled study. J Clin Endocrinol Metab. 2007;92(8):3013–8.PubMedCrossRefGoogle Scholar
  208. 208.
    David H, Aupiais C, Louveau B, et al. Growth outcomes after GH therapy of patients given long-term corticosteroids for juvenile idiopathic arthritis. J Clin Endocrinol Metab. 2017;102(12):4578–87.PubMedCrossRefGoogle Scholar
  209. 209.
    Mozziconacci P, Prieur AM, Hayem F, Oury C. Articular prognosis of the systemic form of chronic juvenile arthritis (100 cases). Ann Pediatr. 1983;30(8):553–6.Google Scholar
  210. 210.
    Prieur AM, Bremard-Oury C, Griscelli C, Mozziconacci P. Prognosis of the systemic forms of juvenile chronic arthritis. Apropos of 100 cases. Arch Fr Pediatr. 1984;41(2):91–7.PubMedGoogle Scholar
  211. 211.
    Schneider R, Lang BA, Reilly BJ, et al. Prognostic indicators of joint destruction in systemic-onset juvenile rheumatoid arthritis. J Pediatr. 1992;120(2. Pt 1):200–5.PubMedCrossRefGoogle Scholar
  212. 212.
    Gerfaud-Valentin M, Maucort-Boulch D, Hot A, et al. Adult-onset still disease: manifestations, treatment, outcome, and prognostic factors in 57 patients. Medicine (Baltimore). 2014;93(2):91–9.CrossRefGoogle Scholar
  213. 213.
    Ichida H, Kawaguchi Y, Sugiura T, et al. Clinical manifestations of Adult-onset Still’s disease presenting with erosive arthritis: association with low levels of ferritin and interleukin-18. Arthritis Care Res (Hoboken). 2014;66(4):642–6.CrossRefGoogle Scholar
  214. 214.
    Ruscitti P, Cipriani P, Masedu F, et al. Adult-onset Still’s disease: evaluation of prognostic tools and validation of the systemic score by analysis of 100 cases from three centers. BMC Med. 2016;14(1):194.PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Russo RA, Katsicas MM. Global damage in systemic juvenile idiopathic arthritis: preliminary early predictors. J Rheumatol. 2008;35(6):1151–6.PubMedGoogle Scholar
  216. 216.
    Masson C, Le Loet X, Liote F, et al. Adult Still’s disease: part I. Manifestations and complications in sixty-five cases in France. Rev Rhum Engl Ed. 1995;62(11):748–57.PubMedGoogle Scholar
  217. 217.
    Schaller J, Wedgwood RJ. Juvenile rheumatoid arthritis: a review. Pediatrics. 1972;50(6):940–53.PubMedGoogle Scholar
  218. 218.
    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(2):491–6.PubMedGoogle Scholar
  219. 219.
    Fantini F, Gerloni V, Gattinara M, Cimaz R, Arnoldi C, Lupi E. Remission in juvenile chronic arthritis: a cohort study of 683 consecutive cases with a mean 10 year followup. J Rheumatol. 2003;30(3):579–84.PubMedGoogle Scholar
  220. 220.
    Bloom BJ, Alario AJ, Miller LC. Persistent elevation of fibrin D-dimer predicts longterm outcome in systemic juvenile idiopathic arthritis. J Rheumatol. 2009;36(2):422–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of ImmunologyBoston Children’s Hospital, Harvard Medical SchoolBostonUSA
  2. 2.Division of Rheumatology, Allergy and ImmunologyCenter for Adults with Pediatric Rheumatic Illness, Brigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  3. 3.Department of PaediatricsThe Hospital for Sick Children, University of TorontoTorontoCanada

Personalised recommendations