Oligoarticular and polyarticular JIA: Epidemiology and pathogenesis

Nature Reviews Rheumatology

Volumn 5, Issue 11, 2009, Pages 616-626

  Macaubas, Claudia ^a   Nguyen, Khoa ^a   Milojevic, Diana ^b   Park, Jane L ^a   Mellins, Elizabeth D ^a  

^a STANFORD UNIVERSITY   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINUCLEAR ANTIBODY; CD45RO ANTIGEN; CHEMOKINE RECEPTOR CCR7; CHEMOKINE RECEPTOR CXCR3; CYCLIC CITRULLINATED PEPTIDE ANTIBODY; GAMMA INTERFERON; HLA A ANTIGEN; INTERLEUKIN 6; RECEPTOR ACTIVATOR OF NUCLEAR FACTOR KAPPA B; RHEUMATOID FACTOR; TUMOR NECROSIS FACTOR;

ADAPTIVE IMMUNITY; B LYMPHOCYTE; CD4 CD8 RATIO; CD4+ CD25+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; DENDRITIC CELL; ETHNIC GROUP; GENETIC ASSOCIATION; HUMAN; IMMUNOPHENOTYPING; INNATE IMMUNITY; JUVENILE RHEUMATOID ARTHRITIS; MONOCYTE; OLIGOARTICULAR JUVENILE IDIOPATHIC ARTHRITIS; PATHOGENESIS; POLYARTICULAR JUVENILE IDIOPATHIC ARTHRITIS; PREVALENCE; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; SYNOVITIS; T LYMPHOCYTE ACTIVATION;

ADAPTIVE IMMUNITY; ARTHRITIS, JUVENILE RHEUMATOID; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MAJOR HISTOCOMPATIBILITY COMPLEX; MORBIDITY; PHENOTYPE; RISK FACTORS; WORLD HEALTH;

EID: 70449522359     PISSN: 17594790     EISSN: 17594804     Source Type: Journal    
DOI: 10.1038/nrrheum.2009.209     Document Type: Review

References (148)

1. Petty, R. E. et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton, 2001. J. Rheumatol. 31, 390-392 (2004).
2. Manners, P., Lesslie, J., Speldewinde, D. & Tunbridge, D. Classification of juvenile idiopathic arthritis: Should family history be included in the criteria? J. Rheumatol. 30, 1857-1863 (2003).
3. Tsitsami, E. et al. Positive family history of psoriasis does not affect the clinical expression and course of juvenile idiopathic arthritis patients with oligoarthritis. Arthritis Rheum. 49, 488-493 (2003).
4. Berntson, L. et al. HLA-B27 predicts a more extended disease with increasing age at onset in boys with juvenile idiopathic arthritis. J. Rheumatol. 35, 2055-2061 (2008).
5. Stoll, M., Lio, P., Sundel, R. & Nigrovic, P. Comparison of vancouver and International League of Associations for rheumatology classification criteria for juvenile psoriatic arthritis. Arthritis Rheum. 59 51-58 (2008).
6. Hayem, F. Is Still's disease an autoinflammatory syndrome? Joint Bone Spine 76, 7-9 (2009).
7. Ravelli, A. & Martini, A. Juvenile idiopathic arthritis. Lancet 369, 767-778 (2007).
8. Manners, P. J. Delay in diagnosing juvenile arthritis. Med. J. Australia 171, 367-369 (1999).
9. Manners, P. J. & Diepeveen, D. A. Prevalence of juvenile chronic arthritis in a population of 12-year-old children in urban Australia. Pediatrics 98, 84-90 (1996).
10. Mielants, H. et al. Prevalence of inflammatory rheumatic diseases in an adolescent urban student population, age 12 to 18, in Belgium. Clin. Exp. Rheumatol. 11, 563-567 (1993).
11. Manners, P. J. & Bower, C. Worldwide prevalence of juvenile arthritis why does it vary so much? J. Rheumatol. 29, 1520-1530 (2002).
12. Malleson, P. N., Fung, M. Y. & Rosenberg, A. M. The incidence of pediatric rheumatic diseases: Results from the Canadian Pediatric Rheumatology Association Disease Registry. J. Rheumatol. 23, 1981-1987 (1996).
13. Denardo, B. A., Tucker, L. B., Miller, L. C., Szer, I. S. & Schaller, J. G. Demography of a regional pediatric rheumatology patient population. Affiliated Children's Arthritis Centers of New England. J. Rheumatol. 21, 1553-1561 (1994).
14. Oen, K., Fast, M. & Postl, B. Epidemiology of juvenile rheumatoid arthritis in Manitoba, Canada, 1975-1992: Cycles in incidence. J. Rheumatol. 22, 745-750 (1995).
15. Sacks, J. J., Helmick, C. G., Luo, Y-H., Ilowite, N. T. & Bowyer, S. Prevalence of and annual ambulatory health care visits for pediatric arthritis and other rheumatologic conditions in the United States in 2001-2004. Arthritis Rheum. 57, 1439-1445 (2007).
16. Saurenmann, R. K. et al. Epidemiology of juvenile idiopathic arthritis in a multiethnic cohort: Ethnicity as a risk factor. Arthritis Rheum. 56, 1974-1984 (2007).
17. Ravelli, A. et al. Patients with antinuclear antibody-positive juvenile idiopathic arthritis constitute a homogeneous subgroup irrespective of the course of joint disease. Arthritis Rheum. 52, 826-832 (2005).
18. Schwartz, M. M., Simpson, P., Kerr, K. L. & Jarvis, J. N. Juvenile rheumatoid arthritis in African Americans. J. Rheumatol. 24, 1826-1829 (1997).
19. Rosenberg, A. M., Petty, R. E., Oen, K. G. & Schroeder, M. L. Rheumatic diseases in Western Canadian Indian children. J. Rheumatol. 9 589-592 (1982).
20. Wu, C. J. et al. Clinical characteristics of juvenile rheumatoid arthritis in Taiwan. J. Microbiol. Immun. Infect. 34, 211-214 (2001).
21. See, Y., Koh, E. T. & Boey, M. L. One hundred and seventy cases of childhood-onset rheumatological disease in Singapore. Ann. Acad. Med. Singapore 27, 496-502 (1998).
22. Fujikawa, S. & Okuni, M. A nationwide surveillance study of rheumatic diseases among Japanese children. Acta Paediatrica Japonica 39 242-244 (1997).
23. Sawhney, S. & Magalhaes, C. Paediatric rheumatology - a global perspective. Best Pract. Res. Clin. Rheumatol. 20, 201-221 (2006).
24. Carvounis, P. E., Herman, D. C., Cha, S. & Burke, J. P. Incidence and outcomes of uveitis in juvenile rheumatoid arthritis, a synthesis of the literature. Graefes Arch. Clin. Exp. Ophthalmol. 244, 281-290 (2006).
25. Haffejee, I. E., Raga, J. & Coovadia, H. M. Juvenile chronic arthritis in black and Indian South African children. S. Afr. Med. J. 65 510-514 (1984).
26. Kurahara, D. K. et al. visiting consultant clinics to study prevalence rates of juvenile rheumatoid arthritis and childhood systemic lupus erythematosus across dispersed geographic areas. J. Rheumatol. 34, 425-429 (2007).
27. Mauldin, J., Cameron, H. D., Jeanotte, D., Solomon, G. & Jarvis, J. N. Chronic arthritis in children and adolescents in two Indian health service user populations. BMC Musculoskelet. Disord. 5, 30 (2004).
28. Kaipiainen-Seppanen, O. & Savolainen, A. Incidence of chronic juvenile rheumatic diseases in Finland during 1980-1990. Clin. Exp. Rheumatol. 14, 441-444 (1996).
29. Towner, S. R., Michet, C. J., O'Fallon, W. M. & Nelson, A. M. The epidemiology of juvenile arthritis in Rochester, Minnesota 1960-1979. Arthritis Rheum. 26, 1208-1213 (1983).
30. Peterson, L. S., Mason, T., Nelson, A. M., O'Fallon, W. M. & Gabriel, S. E. Juvenile rheumatoid arthritis in Rochester, Minnesota 1960-1993. Is the epidemiology changing? Arthritis Rheum. 39, 1385-1390 (1996).
31. Jarvis, J. N., Jiang, K., Petty, H. R. & Centola, M. Neutrophils: The forgotten cell in JIA disease pathogenesis. Pediatr. Rheumatol. Online J. 5, 13 (2007).
32. Prahalad, S. & Glass, D. N. A comprehensive review of the genetics of juvenile idiopathic arthritis. Pediatr. Rheumatol. Online J. 6 11 (2008).
33. Prahalad, S. et al. Familial aggregation of juvenile idiopathic arthritis. Arthritis Rheum. 50, 4022-4027 (2004).
34. Thompson, S. et al. A genome-wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage. Arthritis Rheum. 50, 2920-2930 (2004).
35. Hinks, A. et al. Identification of a novel susceptibility locus for juvenile idiopathic arthritis by genome-wide association analysis. Arthritis Rheum. 60, 258-263 (2009).
36. Murray, K. J. et al. Age-specific effects of juvenile rheumatoid arthritis-associated HLA alleles. Arthritis Rheum. 42, 1843-1853 (1999).
37. Zeggini, E., Donn, R., Ollier, W. E. R. & Thomson, W. Evidence for linkage of HLA loci in juvenile idiopathic oligoarthritis: Independent effects of HLA-A and HLA-DRB1. Arthritis Rheum. 46, 2716-2720 (2002).
38. Garavito, G. et al. HLA-DRB1 alleles and HLADRB1 shared epitopes are markers for juvenile rheumatoid arthritis subgroups in Colombian mestizos. Hum. Immun. 65, 359-365 (2004).
39. Huang, J. L. et al. HLA-DRB1 genotyping in patients with juvenile idiopathic arthritis in Taiwan. Eur. J. Immunogenet. 31, 185-188 (2004).
40. Alsaeid, K., Haider, M. Z., Sharma, P. N. & Ayoub, E. M. The prevalence of human leukocyte antigen (HLA) DR/DQ/DP alleles in Kuwaiti children with oligoarticular juvenile idiopathic arthritis. Rheumatol. Int. 26, 224-228 (2006).
41. Prahalad, S. et al. Juvenile rheumatoid arthritis: Linkage to HLA demonstrated by allele sharing in affected sibpairs. Arthritis Rheum. 43, 2335-2338 (2000).
42. Hinks, A. et al. Association of the IL2RA/CD25 gene with juvenile idiopathic arthritis. Arthritis Rheum. 60, 251-257 (2009).
43. Prahalad, S., Shear, E. S., Thompson, S. D., Giannini, E. H. & Glass, D. N. Increased prevalence of familial autoimmunity in simplex and multiplex families with juvenile rheumatoid arthritis. Arthritis Rheum. 46, 1851-1856 (2002).
44. Prahalad, S. et al. Variants in TNFAIP3, STAT4, and C12orf30 loci associated with multiple autoimmune diseases are also associated with juvenile idiopathic arthritis. Arthritis Rheum. 60, 2124-2130 (2009).
45. Marciano, R. et al. A polymorphic variant inside the osteopontin gene shows association with disease course in oligoarticular juvenile idiopathic arthritis. Ann. Rheum. Dis. 65, 662-665 (2006).
46. Prelog, M. et al. Premature aging of the immune system in children with juvenile idiopathic arthritis. Arthritis Rheum. 58, 2153-2162 (2008).
47. Lorenzi, A. R. et al. Thymic function in juvenile idiopathic arthritis. Ann. Rheum. Dis. 68, 983-990 (2009).
48. + T cell recent thymic emigrants are identified by protein tyrosine kinase 7 and have reduced immune function. J. Exp. Med. 206, 275-285 (2009).
49. Wouters, C. H. P., Ceuppens, J. L. & Stevens, E. A. M. Different circulating lymphocyte profiles in patients with different subtypes of juvenile idiopathic arthritis. Clin. Exp. Rheumatol. 20, 239-248 (2002).
50. Murray, K. J. et al. Immunohistological characteristics of T cell infiltrates in different forms of childhood onset chronic arthritis. J. Rheumatol. 23, 2116-2124 (1996).
51. Thompson, S. D. et al. Comparative sequence analysis of the human T cell receptor beta chain in juvenile rheumatoid arthritis and juvenile spondylarthropathies: Evidence for antigenic selection of T cells in the synovium. Arthritis Rheum. 41, 482-497 (1998).
52. Wedderburn, L. R., Patel, A., varsani, H. & Woo, P. Divergence in the degree of clonal expansions in inflammatory T cell subpopulations mirrors HLA-associated risk alleles in genetically and clinically distinct subtypes of childhood arthritis. Int. Immunol. 13, 1541-1550 (2001).
53. Kamphuis, S. et al. Novel self-epitopes derived from aggrecan, fibrillin, and matrix metalloproteinase-3 drive distinct autoreactive T-cell responses in juvenile idiopathic arthritis and in health. Arthritis Res. Ther. 8, R178 (2006).
54. Sedlackova, L., Velek, J., Vavrincova, P. & Hromadnikova, I. Peripheral blood mononuclear cell responses to heat shock proteins and their derived synthetic peptides in juvenile idiopathic arthritis patients. Inflamm. Res. 55, 153-159 (2006).
55. De Graeff-Meeder, E. R. et al. Recognition of human 60 kD heat shock protein by mononuclear cells from patients with juvenile chronic arthritis. Lancet 337, 1368-1372 (1991).
56. Nguyen, T. T. H. et al. Heat shock protein 70 membrane expression on fibroblast-like synovial cells derived from synovial tissue of patients with rheumatoid and juvenile idiopathic arthritis. Scand. J. Rheumatol. 35, 447-453 (2006).
57. + T cells in juvenile idiopathic arthritis patients in remission. Clin. Rheumatol. 28, 385-389 (2009).
58. Massa, M. et al. Proinflammatory responses to self HLA epitopes are triggered by molecular mimicry to Epstein-Barr virus proteins in oligoarticular juvenile idiopathic arthritis. Arthritis Rheum. 46, 2721-2729 (2002).
59. Stechova, K. et al. In vitro autoreactivity against skin and synovial cells in patients with juvenile idiopathic and rheumatoid arthritis. Pathobiology 70, 76-82 (2002).
60. Wedderburn, L. R., Robinson, N., Patel, A., varsani, H. & Woo, P. Selective recruitment of polarized T cells expressing CCR5 and CXCR3 to the inflamed joints of children with juvenile idiopathic arthritis. Arthritis Rheum. 43, 765-774 (2000).
61. Saxena, N., Aggarwal, A. & Misra, R. Elevated concentrations of monocyte derived cytokines in synovial fluid of children with enthesitis related arthritis and polyarticular types of juvenile idiopathic arthritis. J. Rheumatol. 32, 1349-1353 (2005).
62. + memory T cells homing to the joints in juvenile idiopathic arthritis. Arthritis Res. Ther. 7, R256-R267 (2005).
63. Martini, G. et al. CXCR3/CXCL10 expression in the synovium of children with juvenile idiopathic arthritis. Arthritis Res. Ther. 7, R241-R249 (2005).
64. + T cells. Arthritis Res. Ther. 8, R50 (2006).
65. Appay, V. et al. RANTES activates antigen-specific cytotoxic T lymphocytes in a mitogen-like manner through cell surface aggregation. Int. Immunol. 12, 1173-1182 (2000).
66. Chiesa, S. et al. Cytokine flexibility of early and differentiated memory T helper cells in juvenile idiopathic arthritis. J. Rheumatol. 31, 2048-2054 (2004).
67. Murray, K. J. et al. Contrasting cytokine profiles in the synovium of different forms of juvenile rheumatoid arthritis and juvenile spondyloarthropathy: Prominence of interleukin 4 in restricted disease. J. Rheumatol. 25, 1388-1398 (1998).
68. Jarvis, J. N. et al. Novel approaches to gene expression analysis of active polyarticular juvenile rheumatoid arthritis. Arthritis Res. Ther. 6, R15-R32 (2004).
69. + effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123-1132 (2005).
70. Nistala, K. et al. Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers. Arthritis Rheum. 58 875-887 (2008).
71. Agarwal, S., Misra, R. & Aggarwal, A. Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to produce proinflammatory cytokines and matrix metalloproteinases. J. Rheumatol. 35, 515-519 (2008).
72. Milojevic, D., Nguyen, K. D., Wara, D. & Mellins, E. D. Regulatory T cells and their role in rheumatic diseases: A potential target for novel therapeutic development. Pediatr. Rheumatol. Online J. 6, 20 (2008).
73. Smolewska, E., Brozik, H., Smolewski, P., Darzynkiewicz, Z. & Stanczyk, J. Regulation of peripheral blood and synovial fluid lymphocyte apoptosis in juvenile idiopathic arthritis. Scand. J. Rheumatol. 33, 7-12 (2004).
74. + regulatory T cells in inflamed synovia. J. Exp. Med. 201, 1793-1803 (2005).
75. bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J. Immunol. 172, 6435-6443 (2004).
76. + regulatory T cells in children with juvenile idiopathic arthritis. J. Microbiol. Immunol. Infect. 41, 78-87 (2008).
77. Massa, M. et al. Differential recognition of heatshock protein dnaJ-derived epitopes by effector and Treg cells leads to modulation of inflammation in juvenile idiopathic arthritis. Arthritis Rheum. 56, 1648-1657 (2007).
78. + T cells directed to human heat-shock protein 60 capable of producing the regulatory cytokine interleukin-10. Arthritis Rheum. 48, 2001-2010 (2003).
79. Kamphuis, S. et al. Tolerogenic immune responses to novel T-cell epitopes from heatshock protein 60 in juvenile idiopathic arthritis. Lancet 366, 50-56 (2005).
80. Gattorno, M. et al. Distinct expression pattern of IFN-alpha and TNF-alpha in juvenile idiopathic arthritis synovial tissue. Rheumatology (Oxford) 46, 657-665 (2007).
81. Smolewska, E. et al. Distribution and clinical significance of blood dendritic cells in children with juvenile idiopathic arthritis. Ann. Rheum. Dis. 67, 762-768 (2008).
82. varsani, H., Patel, A., van Kooyk, Y., Woo, P. & Wedderburn, L. R. Synovial dendritic cells in juvenile idiopathic arthritis (JIA) express receptor activator of NF-κB (RANK). Rheumatology (Oxford) 42 583-590 (2003).
83. Anderson, D. M. et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390, 175-179 (1997).
84. van Rossum, M. et al. Anti-cyclic citrullinated peptide (anti-CCP) antibodies in children with juvenile idiopathic arthritis. J. Rheumatol. 30, 825-828 (2003).
85. Griffin, T. et al. Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets. Arthritis Rheum. 60, 2113-2123 (2009).
86. Taniguchi, O. et al. The Leu-1 B-cell subpopulation in patients with rheumatoid arthritis. J. Clin. Immunol. 7, 441-448 (1987).
87. Looney, R. J. B cell-targeted therapy for rheumatoid arthritis: An update on the evidence. Drugs 66, 625-639 (2006).
88. Mangge, H. et al. Serum cytokines in juvenile rheumatoid arthritis. Correlation with conventional inflammation parameters and clinical subtypes. Arthritis Rheum. 38, 211-220 (1995).
89. Yilmaz, M., Kendirli, S. G., Altintas, D., Bingol, G. & Antmen, B. Cytokine levels in serum of patients with juvenile rheumatoid arthritis. Clin. Rheumatol. 20, 30-35 (2001).
90. Lotito, A. P. N., Campa, A., Silva, C. A. A., Kiss, M. H. B. & Mello, S. B. v. Interleukin 18 as a marker of disease activity and severity in patients with juvenile idiopathic arthritis. J. Rheumatol. 34 823-830 (2007).
91. de Jager, W. et al. Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: A cross-sectional study. Ann. Rheum. Dis. 66, 589-598 (2007).
92. Peake, N. J. et al. Interleukin-6 signalling in juvenile idiopathic arthritis is limited by proteolytically cleaved soluble interleukin-6 receptor. Rheumatology (Oxford) 45, 1485-1489 (2006).
93. Prince, F. H. et al. Long-term follow-up on effectiveness and safety of etanercept in JIA: The Dutch national register. Ann. Rheum. Dis. 68, 635-641 (2009).
94. Rooney, M. et al. Tumour necrosis factor alpha and its soluble receptors in juvenile chronic arthritis. Rheumatology (Oxford) 39, 432-438 (2000).
95. Foell, D., Wittkowski, H. & Roth, J. Mechanisms of disease: A 'DAMP' view of inflammatory arthritis. Nat. Clin. Pract. Rheumatol. 3 382-390 (2007).
96. Foell, D., Wittkowski, H., vogl, T. & Roth, J. S100 proteins expressed in phagocytes: A novel group of damage-associated molecular pattern molecules. J. Leukoc. Biol. 81, 28-37 (2007).
97. Schulze zur Wiesch, A. et al. Myeloid related proteins MRP8/MRP14 may predict disease flares in juvenile idiopathic arthritis. Clin. Exp. Rheumatol. 22, 368-373 (2004).
98. Foell, D. et al. Monitoring neutrophil activation in juvenile rheumatoid arthritis by S100A12 serum concentrations. Arthritis Rheum. 50, 1286-1295 (2004).
99. Jarvis, J. N. et al. Evidence for chronic, peripheral activation of neutrophils in polyarticular juvenile rheumatoid arthritis. Arthritis Res. Ther. 8, R154 (2006).
100. Jarvis, J. et al. Gene expression profiling in neutrophils from children with polyarticular juvenile idiopathic arthritis. Arthritis Rheum. 60, 1488-1495 (2009).
101. Sandborg, C. et al. Candidate early predictors for progression to joint damage in systemic juvenile idiopathic arthritis. J. Rheumatol. 33, 2322-2329 (2006).
102. Singh-Grewal, D., Schneider, R., Bayer, N. & Feldman, B. M. Predictors of disease course and remission in systemic juvenile idiopathic arthritis: Significance of early clinical and laboratory features. Arthritis Rheum. 54, 1595-1601 (2006).
103. Sarma, P. K., Misra, R. & Aggarwal, A. Elevated serum receptor activator of NFκB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinase (MMP)3, and ProMMP1 in patients with juvenile idiopathic arthritis. Clin. Rheumatol. 27, 289-294 (2008).
104. Peake, N. J. et al. Levels of matrix metalloproteinase (MMP)-1 in paired sera and synovial fluids of juvenile idiopathic arthritis patients: Relationship to inflammatory activity, MMP-3 and tissue inhibitor of metalloproteinases-1 in a longitudinal study. Rheumatology (Oxford) 44, 1383-1389 (2005).
105. Spelling, P., Bonfa, E., Caparbo, V. F. & Pereira, R. M. R. Osteoprotegerin/RANKL system imbalance in active polyarticular-onset juvenile idiopathic arthritis: A bone damage biomarker? Scand. J. Rheumatol. 37, 439-444 (2008).
106. Caparbo, V. F., Prada, F., Silva, C. A. A., Regio, P. L. & Pereira, R. M. R. Serum from children with polyarticular juvenile idiopathic arthritis (pJIA) inhibits differentiation, mineralization and may increase apoptosis of human osteoblasts "in vitro". Clin. Rheumatol. 28, 71-77 (2009).
107. Hashkes, P. & Laxer, R. Medical treatment of juvenile idiopathic arthritis. JAMA 294, 1671-1684 (2005).
108. Saurenmann, R. K. et al. Prevalence, risk factors, and outcome of uveitis in juvenile idiopathic arthritis: A long-term followup study. Arthritis Rheum. 56, 647-657 (2007).
109. Bolt, I., Cannizzaro, E., Seger, R. & Saurenmann, R. Risk factors and longterm outcome of juvenile idiopathic arthritis-associated uveitis in Switzerland. J. Rheumatol. 35, 703-706 (2008).
110. Low, J. et al. Determination of anti-cyclic citrullinated peptide antibodies in the sera of patients with juvenile idiopathic arthritis. J. Rheumatol. 31, 1829-1833 (2004).
111. Lovell, D. et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N. Engl. J. Med. 342, 763-769 (2000).
112. Lovell, D. et al. Long-term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis: interim results from an ongoing multicenter, open-label, extended-treatment trial. Arthritis Rheum. 48, 218-226 (2003).
113. Ravelli, A. et al. The extended oligoarticular subtype is the best predictor of methotrexate efficacy in juvenile idiopathic arthritis. J. Pediatr. 135, 316-320 (1999).
114. Ruperto, N. et al. A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Arthritis Rheum. 50, 2191-2201 (2004).
115. Fernandez-Via, M., Fink, C. W. & Stastny, P. HLA associations in juvenile arthritis. Clin. Exp. Rheumatol. 12, 205-214 (1994).
116. Thomson, W. et al. Juvenile idiopathic arthritis classified by the ILAR criteria: HLA associations in UK patients. Rheumatology (Oxford) 41, 1183-1189 (2002).
117. Zeggini, E. et al. Association of HLA-DRB1*13 with susceptibility to uveitis in juvenile idiopathic arthritis in two independent data sets. Rheumatology (Oxford) 45, 972-974 (2006).
118. Grassi, A., Corona, F., Casellato, A., Carnelli, V. & Bardare, M. Prevalence and outcome of juvenile idiopathic arthritis-associated uveitis and relation to articular disease. J. Rheumatol. 34, 1139-1145 (2007).
119. Zulian, F. et al. Early predictors of severe course of uveitis in oligoarticular juvenile idiopathic arthritis. J. Rheumatol. 29 2446-2453 (2002).
120. Donn, R. P., Shelley, E., Ollier, W. E. & Thomson, W. A novel 5′-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 44, 1782-1785 (2001).
121. Donn, R. et al. Mutation screening of the macrophage migration inhibitory factor gene: Positive association of a functional polymorphism of macrophage migration inhibitory factor with juvenile idiopathic arthritis. Arthritis Rheum. 46, 2402-2409 (2002).
122. Donn, R. et al. A functional promoter haplotype of macrophage migration inhibitory factor is linked and associated with juvenile idiopathic arthritis. Arthritis Rheum. 50, 1604-1610 (2004).
123. Viken, M. K. et al. Association analysis of the 1858C>T polymorphism in the PTPN22 gene in juvenile idiopathic arthritis and other autoimmune diseases. Genes Immun. 6, 1271-1273 (2005).
124. Hinks, A. et al. Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: Further support that PTPN22 is an autoimmunity gene. Arthritis Rheum. 52, 1694-1699 (2005).
125. Cinek, O. et al. No independent role of the -1123 G>C and A>G variants in the association of PTPN22 with type 1 diabetes and juvenile idiopathic arthritis in two Caucasian populations. Diabetes Res. Clin. Pract. 76, 297-303 (2007).
126. Sanjeevi, C. B. et al. Polymorphism at NRAMP1 and D2S1471 loci associated with juvenile rheumatoid arthritis. Arthritis Rheum. 43, 1397-1404 (2000).
127. Runstadler, J. A. et al. Association of SLC11A1 (NRAMP1) with persistent oligoarticular and polyarticular rheumatoid factor-negative juvenile idiopathic arthritis in Finnish patients: haplotype analysis in Finnish families. Arthritis Rheum. 52, 247-256 (2005).
128. Epplen, C. et al. Immunoprinting excludes many potential susceptibility genes as predisposing to early onset pauciarticular juvenile chronic arthritis except HLA class II and TNF. Eur. J. Immunogenet. 22, 311-322 (1995).
129. Nikitina Zake, L., Cimdina, I., Rumba, I., Dabadghao, P. & Sanjeevi, C. B. Major histocompatibility complex class I chain related (MIC) A gene, TNFα microsatellite alleles and TNFβ alleles in juvenile idiopathic arthritis patients from Latvia. Hum. Immunol. 63, 418-423 (2002).
130. Schmeling, H., Wagner, U., Peterson, A. & Horneff, G. Tumor necrosis factor alpha promoter polymorphisms in patients with juvenile idiopathic arthritis. Clin. Exp. Rheumatol. 24, 103-108 (2006).
131. Lamb, R., Thomson, W., Ogilvie, E. & Donn, R. Wnt-1-inducible signaling pathway protein 3 and susceptibility to juvenile idiopathic arthritis. Arthritis Rheum. 52, 3548-3553 (2005).
132. De Benedetti, F. 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. 48, 1398-1407 (2003).
133. Berdeli, A. et al. Association of macrophage migration inhibitory factor gene -173 G/C polymorphism with prognosis in Turkish children with juvenile rheumatoid arthritis. Rheumatol. Int. 26, 726-731 (2006).
134. Ozen, S. et al. Tumour necrosis factor alpha G.A -238 and G→A -308 polymorphisms in juvenile idiopathic arthritis. Rheumatology (Oxford) 41, 223-227 (2002).
135. Schmeling, H. & Horneff, G. Tumour necrosis factor alpha promoter polymorphisms and etanercept therapy in juvenile idiopathic arthritis. Rheumatol. Int. 27, 383-386 (2007).
136. Mourão, A. F. et al. Tumor necrosis factor-α - 308 genotypes influence inflammatory activity and TNF-α serum concentrations in children with juvenile idiopathic arthritis. J. Rheumatol. 36 837-842 (2009).
137. McDowell, T. L., Symons, J. A., Ploski, R., Forre, O. & Duff, G. W. A genetic association between juvenile rheumatoid arthritis and a novel interleukin-1 alpha polymorphism. Arthritis Rheum. 38, 221-228 (1995).
138. Vencovsky, J. et al. Higher frequency of allele 2 of the interleukin-1 receptor antagonist gene in patients with juvenile idiopathic arthritis. Arthritis Rheum. 44, 2387-2391 (2001).
139. Cimaz, R. et al. IL1 and TNF gene polymorphisms in patients with juvenile idiopathic arthritis treated with TNF inhibitors. Ann. Rheum. Dis. 66, 900-904 (2007).
140. Stock, C. J. W. et al. Comprehensive association study of genetic variants in the IL-1 gene family in systemic juvenile idiopathic arthritis. Genes Immun. 9, 349-357 (2008).
141. Fishman, D. 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. 102, 1369-1376 (1998).
142. Ogilvie, E. M. 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. 48, 3202-3206 (2003).
143. Crawley, E. et al. Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum. 42, 1101-1108 (1999).
144. Fife, M. S. et al. Novel IL10 gene family associations with systemic juvenile idiopathic arthritis. Arthritis Res. Ther. 8 R148 (2006).
145. Bierbaum, S., Sengler, C., Gerhold, K., Berner, R. & Heinzmann, A. Polymorphisms within interleukin 15 are associated with juvenile idiopathic arthritis. Clin. Exp. Rheumatol. 24, 219 (2006).
146. Sugiura, T. et al. A promoter haplotype of the interleukin-18 gene is associated with juvenile idiopathic arthritis in the Japanese population. Arthritis Res. Ther. 8, R60 (2006).
147. Crawley, E., Kon, S. & Woo, P. Hereditary predisposition to low interleukin-10 production in children with extended oligoarticular juvenile idiopathic arthritis. Rheumatology (Oxford) 40, 574-578 (2001).
148. Petty, R. E. Classification of childhood arthritis: A work in progress. Baillieres Clin. Rheumatol. 12, 181-190 (1998).