Review Article | Published:

Uveitis associated with juvenile idiopathic arthritis

Nature Reviews Rheumatology volume 11, pages 338348 (2015) | Download Citation

Abstract

Uveitis is a potentially sight-threatening complication of juvenile idiopathic arthritis (JIA). JIA-associated uveitis is recognized to have an autoimmune aetiology characterized by activation of CD4+ T cells, but the underlying mechanisms might overlap with those of autoinflammatory conditions involving activation of innate immunity. As no animal model recapitulates all the features of JIA-associated uveitis, questions remain regarding its pathogenesis. The most common form of JIA-associated uveitis is chronic anterior uveitis, which is usually asymptomatic initially. Effective screening is, therefore, essential to detect early disease and commence treatment before the development of visually disabling complications, such as cataracts, glaucoma, band keratopathy and cystoid macular oedema. Complications can result from uncontrolled intraocular inflammation as well as from its treatment, particularly prolonged use of high-dose topical corticosteroids. Accumulating evidence supports the early introduction of systemic immunosuppressive drugs, such as methotrexate, as steroid-sparing agents. Prospective randomized controlled trials of TNF inhibitors and other biologic therapies are underway or planned. Future research should aim to identify biomarkers to predict which children are at high risk of developing JIA-associated uveitis or have a poor prognosis. Such biomarkers could help to ensure that patients receive earlier interventions and more-potent therapy, with the ultimate aim of reducing loss of vision and ocular morbidity.

Key points

  • Uveitis affects 11–30% of children with juvenile idiopathic arthritis (JIA)

  • Chronic anterior uveitis is usually asymptomatic initially but can lead to visually disabling complications; therefore, screening is essential

  • Initial treatment is with topical corticosteroids but evidence supports the early introduction of systemic immunosuppressive drugs, such as methotrexate, as steroid-sparing agents

  • Prospective controlled studies of biologic therapies, including adalimumab and tocilizumab, are underway or planned

  • Future research to investigate the pathogenesis of JIA-associated uveitis and identify novel biomarkers could enable earlier diagnosis and more-effective treatment

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Pathogenesis of juvenile idiopathic arthritis associated uveitis: the known and unknown. Surv. Ophthalmol. 59, 517–531 (2014).

  2. 2.

    , , & Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am. J. Ophthalmol. 140, 509–516 (2005).

  3. 3.

    , , , & International Uveitis Study Group. International Uveitis Study Group (IUSG): clinical classification of uveitis. Ocul. Immunol. Inflamm. 16, 1–2 (2008).

  4. 4.

    , , & Incidence and outcomes of uveitis in juvenile rheumatoid arthritis, a synthesis of the literature. Graefes Arch. Clin. Exp. Ophthalmol. 244, 281–290 (2006).

  5. 5.

    et al. Risk markers of juvenile idiopathic arthritis-associated uveitis in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry. J. Rheumatol. 40, 2088–2096 (2013).

  6. 6.

    , & The role of gender in juvenile idiopathic arthritis-associated uveitis. J. Ophthalmol. 2014, 461078 (2014).

  7. 7.

    & Juvenile idiopathic arthritis-associated uveitis. Curr. Opin. Ophthalmol. 21, 468–472 (2010).

  8. 8.

    , , , & Review for disease of the year: epidemiology of juvenile idiopathic arthritis and its associated uveitis: the probable risk factors. Ocul. Immunol. Inflamm. 21, 180–191 (2013).

  9. 9.

    , , , & Extended oligoarthritis and other risk factors for developing JIA-associated uveitis under ILAR classification and its implication for current screening guideline. Ocul. Immunol. Inflamm. 14, 353–357 (2006).

  10. 10.

    , , & The evaluation of uveitis in juvenile idiopathic arthritis (JIA) patients: are current ophthalmologic screening guidelines adequate? Clin. Exp. Rheumatol. 26, 367–372 (2008).

  11. 11.

    et al. Female sex and oligoarthritis category are not risk factors for uveitis in Italian children with juvenile idiopathic arthritis. J. Rheumatol. 41, 1416–1425 (2014).

  12. 12.

    et al. Risk factors for development of uveitis differ between girls and boys with juvenile idiopathic arthritis. Arthritis Rheum. 62, 1824–1828 (2010).

  13. 13.

    , , & Course, complications, and outcome of juvenile arthritis-related uveitis. J. AAPOS 12, 539–545 (2008).

  14. 14.

    et al. The frequency and outcome of uveitis in patients with newly diagnosed juvenile idiopathic arthritis in two 4-year cohorts from 1990–1993 and 2000–2003. Clin. Exp. Rheumatol. 32, 143–147 (2014).

  15. 15.

    , , & Risk factors and longterm outcome of juvenile idiopathic arthritis-associated uveitis in Switzerland. J. Rheumatol. 35, 703–706 (2008).

  16. 16.

    , , & Factors related to severe uveitis at diagnosis in children with juvenile idiopathic arthritis in a screening programme. Am. J. Ophthalmol. 135, 757–762 (2003).

  17. 17.

    et al. The clinical course of juvenile idiopathic arthritis-associated uveitis in childhood and puberty. Br. J. Ophthalmol. 96, 852–856 (2012).

  18. 18.

    , , & Long-term follow-up of patients with uveitis associated with juvenile idiopathic arthritis: a cohort study. Ocul. Immunol. Inflamm. 17, 104–108 (2009).

  19. 19.

    , , & Uveitis in young adults with juvenile idiopathic arthritis: a clinical evaluation of 123 patients. Ann. Rheum. Dis. 64, 871–874 (2005).

  20. 20.

    , & Updates on the risk markers and outcomes of severe juvenile idiopathic arthritis-associated uveitis. Int. J. Clin. Rheumatol. 8 109–121 (2013).

  21. 21.

    , , , & An evaluation of baseline risk factors predicting severity in juvenile idiopathic arthritis associated uveitis and other chronic anterior uveitis in early childhood. Br. J. Ophthalmol. 86, 51–56 (2002).

  22. 22.

    , , , & Male gender and poor visual outcome in uveitis associated with juvenile idiopathic arthritis. Am. J. Ophthalmol. 149, 987–993 (2010).

  23. 23.

    et al. Timing of uveitis onset in oligoarticular juvenile idiopathic arthritis (JIA) is the main predictor of severe course uveitis. Acta Ophthalmol. 90, 91–95 (2012).

  24. 24.

    et al. Risk factors for loss of visual acuity among patients with uveitis associated with juvenile idiopathic arthritis: the Systemic Immunosuppressive Therapy for Eye Diseases study. Ophthalmology 120, 186–192 (2013).

  25. 25.

    British Society for Paediatric and Adolescent Rheumatology (BSPAR) & Royal College of Ophthalmology. Guidelines for screening for uveitis in juvenile idiopathic arthritis (JIA) , (2006).

  26. 26.

    et al. Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested modification of the current screening guidelines. Rheumatology (Oxford) 46, 1015–1019 (2007).

  27. 27.

    et al. Ophthalmologic examinations in children with juvenile rheumatoid arthritis. Paediatrics 117, 1843–1845 (2006).

  28. 28.

    et al. BSPAR Standards of Care for children and young people with juvenile idiopathic arthritis. Rheumatology (Oxford) 49, 1406–1408 (2010).

  29. 29.

    , , & Elevated laser flare values correlate with complicated course of anterior uveitis in patients with juvenile idiopathic arthritis. Acta Ophthalmol. 89, e521–e527 (2011).

  30. 30.

    A reconsideration of anterior chamber flare and its clinical relevance for children with chronic anterior uveitis (an American Ophthalmological Society thesis). Trans. Am. Ophthalmol. Soc. 105, 344–364 (2007).

  31. 31.

    et al. Maculopathy in uveitis of juvenile idiopathic arthritis: an optical coherence tomography study. Br. J. Ophthalmol. 92, 64–69 (2008).

  32. 32.

    , , & Analysis of paediatric uveitis cases at a tertiary referral centre. Ophthalmology 112, 1287–1292 (2005).

  33. 33.

    , , & Elevated intraocular pressure in uveitis associated with juvenile idiopathic arthritis-associated uveitis, often detected after achieving inactivity. Br. J. Ophthalmol. 96, 140–141 (2012).

  34. 34.

    et al. Proposed outcome measures for prospective clinical trials in juvenile idiopathic arthritis-associated uveitis: a consensus effort from the multinational interdisciplinary working group for uveitis in childhood. Arthritis Care Res. (Hoboken) 64, 1365–1372 (2012).

  35. 35.

    Improving the reporting of clinical case series. Am. J. Ophthalmol. 139, 900–905 (2005).

  36. 36.

    et al. The importance of visual function in the quality of life of children with uveitis. J. AAPOS 14, 163–168 (2010).

  37. 37.

    et al. Development of a vision-related quality of life instrument for children ages 8–18 years for use in juvenile idiopathic arthritis-associated uveitis. Arthritis Care Res. (Hoboken) 63, 1254–1261 (2011).

  38. 38.

    A look at autoimmunity and inflammation in the eye. J. Clin. Invest. 120, 3073–3083 (2010).

  39. 39.

    , & Cutting-edge issues in autoimmune uveitis. Clin. Rev. Allergy Immunol. 41, 214–223 (2011).

  40. 40.

    & Experimental autoimmune uveitis and its relationship to clinical ocular inflammatory disease. J. Autoimmun. 9, 575–585 (1996).

  41. 41.

    et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat. Med. 13, 711–718 (2007).

  42. 42.

    , , & TREG lymphocytes in autoimmune uveitis. Ocul. Immunol. Inflamm. 20, 255–261 (2012).

  43. 43.

    , & Immunohistochemical study of chronic nongranulomatous anterior uveitis in juvenile idiopathic arthritis. Ophthalmology 115, 1833–1836 (2008).

  44. 44.

    et al. Cytokines, chemokines and soluble adhesion molecules in aqueous humour of children with uveitis. Exp. Eye Res. 85, 443–449 (2007).

  45. 45.

    et al. Interplay between innate and adaptive immunity in the development of non-infectious uveitis. Prog. Retin. Eye Res. 31, 182–194 (2012).

  46. 46.

    , , , & Uveitis related to juvenile idiopathic arthritis: familial cases and possible genetic implication in the pathogenesis. Ocul. Immunol. Inflamm. 18, 172–177 (2010).

  47. 47.

    et al. Uveitis in sibling pairs with juvenile idiopathic arthritis. Rheumatology (Oxford) 40, 221–224 (2001).

  48. 48.

    , & Pathophysiology of JIA-associated uveitis. Ocul. Immunol. Inflamm. 22, 414–423 (2014).

  49. 49.

    et al. Longitudinal analysis of HLA associated risks for iridocyclitis in juvenile rheumatoid arthritis. J. Rheumatol. 18, 1394–1397 (1991).

  50. 50.

    et al. Human leucocyte antigen-DRB1*1104 in the chronic iridocyclitis of pauciarticular juvenile rheumatoid arthritis. J. Paediatr. 121, 56–60 (1992).

  51. 51.

    , & Immune response genes in uveitis. Ocul. Immunol. Inflamm. 17, 249–256 (2009).

  52. 52.

    & Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation. Eye (Lond.) 26, 17–28 (2012).

  53. 53.

    et al. Autoimmune and autoinflammatory mechanisms in uveitis. Semin. Immunopathol. 36, 581–594 (2014).

  54. 54.

    Experimental autoimmune uveoretinitis in the rat and mouse. Curr. Protoc. Immunol. Ch. 15, Unit 15.6 (2003).

  55. 55.

    , & Recent advances in Toll-like receptors and anterior uveitis. Clin. Experiment. Ophthalmol. 40, 821–828 (2012).

  56. 56.

    , & Basic pathogenic mechanisms operating in experimental models of acute anterior uveitis. Immunol. Cell Biol. 76, 497–512 (1998).

  57. 57.

    , , & Neutralization of IL-17 ameliorates uveitis but damages photoreceptors in a murine model of spondyloarthritis. Arthritis Res. Ther. 14, R18 (2012).

  58. 58.

    et al. Prevalence, risk factors, and outcome of uveitis in juvenile idiopathic arthritis: a long-term followup study. Arthritis Rheum. 56, 647–657 (2007).

  59. 59.

    et al. Autoinflammation and autoimmunity: bridging the divide. Autoimmun. Rev. 12, 22–30 (2012).

  60. 60.

    , & Antibodies to iris and retina detected in sera from patients with juvenile rheumatoid arthritis with iridocyclitis by indirect immunofluorescence studies on human eye tissue. J. Rheumatol. 16, 1074–1078 (1989).

  61. 61.

    et al. Correlation between disease severity and presence of ocular autoantibodies in juvenile idiopathic arthritis-associated uveitis. Invest. Ophthalmol. Vis. Sci. 55, 3447–3453 (2014).

  62. 62.

    et al. Evidence-based, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis. Rheumatol. Int. 32, 1121–1133 (2012).

  63. 63.

    , & Treatment of uveitis associated with juvenile idiopathic arthritis. Curr. Rheumatol. Rep. 16, 437 (2014).

  64. 64.

    et al. Current therapeutic approaches to autoimmune chronic uveitis in children. Autoimmun. Rev. 9, 674–683 (2010).

  65. 65.

    et al. Efficacy and safety of rimexolone 1% ophthalmic suspension vs 1% prednisolone acetate in the treatment of uveitis. Am. J. Ophthalmol. 122, 171–182 (1996).

  66. 66.

    , , & Risk of cataract development among children with juvenile idiopathic arthritis-related uveitis treated with topical corticosteroids. Ophthalmology 117, 1436–1441 (2010).

  67. 67.

    & Blinded by lack of evidence. Rheumatology (Oxford) 52, 765–766 (2013).

  68. 68.

    , & Intravenous pulse methylprednisolone therapy in severe inflammatory eye disease. Arch. Ophthalmol. 104, 847–851 (1986).

  69. 69.

    et al. High-dose intravenous corticosteroids for ocular inflammatory diseases. Ocul. Immunol. Inflamm. 20, 91–99 (2012).

  70. 70.

    , , , & Current evidence of methotrexate efficacy in childhood chronic uveitis: a systematic review and meta-analysis approach. Rheumatology (Oxford) 52, 825–831 (2013).

  71. 71.

    & Methotrexate is an effective treatment for chronic uveitis associated with juvenile idiopathic arthritis. J. Rheumatol. 32, 362–365 (2005).

  72. 72.

    , , , & Risk factors for the development of cataract requiring surgery in uveitis associated with juvenile idiopathic arthritis. Am. J. Ophthalmol. 144, 574–579 (2007).

  73. 73.

    , , & Relapse rate of uveitis post-methotrexate treatment in juvenile idiopathic arthritis. Am. J. Ophthalmol. 151, 217–222 (2011).

  74. 74.

    , & Non-infectious paediatric uveitis: an update on immunomodulatory management. Paediatr. Drugs 11, 229–241 (2009).

  75. 75.

    & New age of biological therapies in paediatric rheumatology. Arch. Dis. Child. 99, 679–685 (2014).

  76. 76.

    et al. A randomized, placebo-controlled, double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis Rheum. 53, 18–23 (2005).

  77. 77.

    , , , & Infliximab and etanercept in the treatment of chronic uveitis associated with refractory juvenile idiopathic arthritis. Ann. Rheum. Dis. 66, 548–550 (2007).

  78. 78.

    & Etanercept and uveitis in patients with juvenile idiopathic arthritis. Rheumatology (Oxford) 44, 1008–1011 (2005).

  79. 79.

    et al. Risk of new-onset uveitis in patients with juvenile idiopathic arthritis treated with anti-TNFα agents. J. Paediatr. 149, 833–836 (2006).

  80. 80.

    , & Do tumour necrosis factor inhibitors cause uveitis? A registry-based study. Arthritis Rheum. 56, 3248–3252 (2007).

  81. 81.

    , , , & Current evidence of anti-tumour necrosis factor α treatment efficacy in childhood chronic uveitis: a systematic review and meta-analysis approach of individual drugs. Arthritis Care Res. (Hoboken) 66, 1073–1084 (2014).

  82. 82.

    et al. Prevention of flare recurrences in childhood-refractory chronic uveitis: an open-label comparative study of adalimumab versus infliximab. Arthritis Care Res. (Hoboken) 63, 612–618 (2011).

  83. 83.

    , & Switching biologic agents for uveitis. Eye (Lond.) 23, 1868–1870 (2009).

  84. 84.

    et al. A randomised controlled trial of the clinical effectiveness, safety and cost-effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis (SYCAMORE Trial). Trials 15, 14 (2014).

  85. 85.

    US National Library of Medicine. ClinicalTrials.gov , (2014).

  86. 86.

    US National Library of Medicine. ClinicalTrials.gov , (2014).

  87. 87.

    US National Library of Medicine. ClinicalTrials.gov , (2014).

  88. 88.

    & Prevention and management of cataracts in children with juvenile idiopathic arthritis-associated uveitis. Curr. Rheumatol Rep. 14, 142–149 (2012).

  89. 89.

    , , , & Outcomes of cataract surgery in children with chronic uveitis. J. Cataract Refract. Surg. 35, 725–731 (2009).

  90. 90.

    , , , & Favourable outcome after cataract surgery with IOL implantation in uveitis associated with juvenile idiopathic arthritis. Acta Ophthalmol. 90, 657–662 (2012).

  91. 91.

    , , & Goniotomy for glaucoma secondary to chronic childhood uveitis. Am. J. Ophthalmol. 133, 617–621 (2002).

  92. 92.

    , , , & Ahmed valve implantation for uncontrolled paediatric uveitic glaucoma. J. AAPOS 9, 336–340 (2005).

  93. 93.

    & Surgical outcomes in childhood uveitic glaucoma. Am. J. Ophthalmol. 155, 134–142 (2013).

  94. 94.

    et al. Biomarkers of chronic uveitis in juvenile idiopathic arthritis: predictive value of antihistone antibodies and antinuclear antibodies. J. Rheumatol. 36, 1737–1743 (2009).

  95. 95.

    et al. Predictive value of selected biomarkers, polymorphisms, and clinical features for oligoarticular juvenile idiopathic arthritis-associated uveitis. Ocul. Immunol. Inflamm. 22, 208–212 (2014).

  96. 96.

    et al. Intraocular biomarker identification in uveitis associated with juvenile idiopathic arthritis. Invest. Ophthalmol. Vis. Sci. 54, 3709–3720 (2013).

  97. 97.

    et al. A128: hierarchical clustering methodology for exploration of proteomic profile in tears: seeking for markers of uveitis associated with juvenile idiopathic arthritis. Arthritis Rheum. 66 (Suppl. S3), S168 (2014).

  98. 98.

    & The pathology and pathogenesis of retinal vasculitis. Neuropathol. Appl. Neurobiol. 29, 325–340 (2003).

  99. 99.

    Ocular autoimmunity: the price of privilege? Immunol. Rev. 213, 23–35 (2006).

  100. 100.

    & Methotrexate—how does it really work? Nat. Rev. Rheumatol. 6, 175–178 (2010).

  101. 101.

    et al. Azathioprine as a treatment option for uveitis in patients with juvenile idiopathic arthritis. Br. J. Ophthalmol. 95, 209–213 (2011).

  102. 102.

    , , , & Mycophenolate mofetil in the treatment of uveitis in children. Br. J. Ophthalmol. 91, 180–184 (2007).

  103. 103.

    et al. Mycophenolate mofetil monotherapy in the management of paediatric uveitis. Eye (Lond.) 25, 427–435 (2011).

  104. 104.

    , & Mycophenolate mofetil after methotrexate failure or intolerance in the treatment of scleritis and uveitis. Ophthalmology 115, 1416–1421, 1421.e1 (2008).

  105. 105.

    et al. Limited value of cyclosporine A for the treatment of patients with uveitis associated with juvenile idiopathic arthritis. Eye (Lond.) 23, 1192–1198 (2009).

  106. 106.

    , & Cyclosporin A therapy in refractory non-infectious childhood uveitis. Br. J. Ophthalmol. 82, 737–742 (1998).

  107. 107.

    , , & Long-term efficacy and tolerance of tacrolimus for the treatment of uveitis. Ophthalmology 114, 1000–1006 (2007).

  108. 108.

    , , & Golimumab for the treatment of refractory juvenile idiopathic arthritis-associated uveitis. J. Ophthalmic Inflamm. Infect. 2, 231–233 (2012).

  109. 109.

    , , & Is tocilizumab an effective option for treatment of refractory uveitis associated with juvenile idiopathic arthritis? J. Rheumatol. 39, 1294–1295 (2012).

  110. 110.

    , & Tocilizumab for severe chronic anterior uveitis associated with juvenile idiopathic arthritis in a paediatric patient. Ocul. Immunol. Inflamm. 22, 155–157 (2014).

  111. 111.

    et al. Abatacept for severe anti-tumour necrosis factor α refractory juvenile idiopathic arthritis-related uveitis. Arthritis Care Res. (Hoboken) 62, 821–825 (2010).

  112. 112.

    et al. Abatacept: a potential therapy in refractory cases of juvenile idiopathic arthritis-associated uveitis. Graefes Arch. Clin. Exp. Ophthalmol. 249, 297–300 (2011).

  113. 113.

    , , , & Treatment of severe uveitis associated with juvenile idiopathic arthritis with anti-CD20 monoclonal antibody (rituximab). Rheumatology (Oxford) 50, 1390–1394 (2011).

  114. 114.

    et al. Rituximab for uveitis. Ophthalmology 118, 223–224 (2011).

  115. 115.

    , , & Standardization of vitreal inflammatory activity in intermediate and posterior uveitis. Ophthalmology 92, 467–471 (1985).

Download references

Acknowledgements

A.D.D.'s research work was partly supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital National Health Service (NHS) Foundation Trust and the University College of London Institute of Ophthalmology. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Author information

Affiliations

  1. Department of Paediatric Rheumatology, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol BS2 8BJ, UK.

    • Ethan S. Sen
    •  & Athimalaipet V. Ramanan
  2. School of Clinical Sciences, University of Bristol, Retinal Treatment and Research Unit, Bristol Eye Hospital, Lower Maudlin Street, Bristol BS1 2LX, UK.

    • Andrew D. Dick

Authors

  1. Search for Ethan S. Sen in:

  2. Search for Andrew D. Dick in:

  3. Search for Athimalaipet V. Ramanan in:

Contributions

E.S.S. researched data for and wrote the article. A.D.D. and A.V.R. contributed substantially to discussions of the article content and review or editing of the manuscript before submission.

Competing interests

A.D.D. declares that he has served as a consultant for Abbvie, Genentech and Novartis, has received grants from Novartis, and is a co-investigator for the SYCAMORE trial of adalimumab in patients with JIA-associated uveitis, which is funded by Health Technology Assessment and Arthritis Research UK. A.V.R. declares that he has received honoraria or speaker's fees from Abbvie, Novartis, Pfizer, Roche, and Swedish Orphan Biovitrum Pharmaceuticals, and that he is co-chief investigator of the SYCAMORE trial. E.S.S. declares no competing interests.

Corresponding author

Correspondence to Athimalaipet V. Ramanan.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrrheum.2015.20

Further reading

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing