Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Classification of juvenile spondyloarthritis: enthesitis-related arthritis and beyond

Abstract

Spondyloarthritis (SpA) refers to a spectrum of immune-mediated inflammatory diseases with overlapping features, which differ from other types of inflammatory arthritis in genetic predisposition, pathogenesis and outcome. SpA frequently involves the axial skeleton, and can result in abnormal bone formation with eventual ankylosis of the spine, resulting in substantial disability. SpA often begins as an 'undifferentiated' disease, the presentation of which differs in children and adults; most notably, spinal involvement is uncommon, while hip arthritis and enthesitis are frequently seen in juvenile-onset disease. Currently, the classification of SpA in adults and children is approached differently. Using the International League of Associations for Rheumatology (ILAR) system for juvenile idiopathic arthritis, most childhood SpA is classified as enthesitis-related arthritis. However, in contrast to adult SpA classification, the presence of, or a family history of, psoriasis dictates a separate category of juvenile idiopathic arthritis. More importantly, the ILAR system does not specifically recognize the presence of axial disease in juvenile SpA. Resolution of these issues will improve communication and the transitioning of patients from pediatric to adult clinics, will facilitate research in genetics and pathogenesis, and will be particularly important in the evaluation of tumor necrosis factor inhibitors and other biologic agents for early, axial SpA.

Key Points

  • Spondyloarthritis (SpA) in children is often undifferentiated at onset, and is less likely to involve the axial skeleton but more likely to affect hips and peripheral entheses in children than in adults

  • Historically, the classification of SpA has been handled differently in adults and children

  • Using the ILAR system, most juvenile SpA will be classified as enthesitis-related arthritis or undifferentiated arthritis, depending on whether psoriasis is present in the patient or their family

  • The ILAR system does not specifically address children who have SpA by fulfilling the criteria for ankylosing spondylitis, or who have coexisting conditions such as inflammatory bowel disease

  • The development and validation of criteria that recognize juvenile SpA with axial inflammation could be an important step in facilitating therapeutic trials in children

  • HLA-B27 is only one element of the complex genetics of ankylosing spondylitis, and additional susceptibility genes could be useful predictors of long-term outcome in children with early, undifferentiated SpA

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: ASAS classification criteria for axial spondyloarthritis.9,10
Figure 2: MRI demonstrating acute inflammation highly suggestive of sacroiliitis associated with spondyloarthropathy in a 12-year-old HLA-B27-positive male.
Figure 3: Hypothetical functional interactions between gene products associated with ankylosing spondylitis.

References

  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).

    Google Scholar 

  2. Krumrey-Langkammerer, M. & Häfner, R. Evaluation of the ILAR criteria for juvenile idiopathic arthritis. J. Rheumatol. 28, 2544–2547 (2001).

    CAS  PubMed  Google Scholar 

  3. Hofer, M. F., Mouy, R. & Prieur, A. M. Juvenile idiopathic arthritides evaluated prospectively in a single center according to the Durban criteria. J. Rheumatol. 28, 1083–1090 (2001).

    CAS  PubMed  Google Scholar 

  4. Macaubas, C., Nguyen, K., Milojevic, D., Park, J. L. & Mellins, E. D. Oligoarticular and polyarticular JIA: epidemiology and pathogenesis. Nat. Rev. Rheumatol. 5, 616–626 (2009).

    Article  Google Scholar 

  5. Burgos-Vargas, R., Rudwaleit, M. & Sieper, J. The place of juvenile onset spondyloarthropathies in the Durban 1997 ILAR classification criteria of juvenile idiopathic arthritis. International League of Associations for Rheumatology. J. Rheumatol. 29, 869–874 (2002).

    PubMed  Google Scholar 

  6. Fink, C. W. Proposal for the development of classification criteria for idiopathic arthritides of childhood. J. Rheumatol. 22, 1566–1569 (1995).

    CAS  PubMed  Google Scholar 

  7. Petty, R. E. et al. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J. Rheumatol. 25, 1869–1870 (1998).

    CAS  PubMed  Google Scholar 

  8. Duffy, C. M., Colbert, R. A., Laxer, R. M., Schanberg, L. E. & Bowyer, S. L. Nomenclature and classification in chronic childhood arthritis: time for a change? Arthritis Rheum. 52, 382–385 (2005).

    Article  Google Scholar 

  9. Rudwaleit, M. et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty appraisal. Ann. Rheum. Dis. 68, 770–776 (2009).

    Article  CAS  Google Scholar 

  10. Rudwaleit, M. et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann. Rheum. Dis. 68, 777–783 (2009).

    Article  CAS  Google Scholar 

  11. Feldtkeller, E., Khan, M. A., van der Heijde, D., van der Linden, S. & Braun, J. Age at disease onset and diagnosis delay in HLA-B27 negative vs positive patients with ankylosing spondylitis. Rheumatol. Int. 23, 61–66 (2003).

    Article  Google Scholar 

  12. van der Linden, S., Valkenburg, H. A. & Cats, A. Evaluation of diagnostic criteria for ankylosing spondylitis. Arthritis Rheum. 27, 361–368 (1984).

    Article  CAS  Google Scholar 

  13. Dougados, M. et al. The European Spondyloarthropathy Study Group preliminary criteria for the classification of spondyloarthropathy. Arthritis Rheum. 34, 1218–1227 (1991).

    Article  CAS  Google Scholar 

  14. Amor, B., Dougados, M. & Mijiyawa, M. Criteria of the classification of spondylarthropathies [French]. Rev. Rhum. Mal. Osteoartic. 57, 85–89 (1990).

    CAS  Google Scholar 

  15. Sieper, J., Braun, J., Rudwaleit, M., Boonen, A. & Zink, A. Ankylosing spondylitis: an overview. Ann. Rheum. Dis. 61 (Suppl. 3), iii8–iii18 (2002).

    Article  Google Scholar 

  16. LaSalle, S. P. & Deodhar, A. A. Appropriate management of axial spondyloarthritis. Curr. Rheumatol. Rep. 9, 375–382 (2007).

    Article  CAS  Google Scholar 

  17. van der Heijde, D. et al. Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum. 58, 3063–3070 (2008).

    Article  Google Scholar 

  18. van der Heijde, D. et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum. 58, 1324–1331 (2008).

    Article  CAS  Google Scholar 

  19. Maksymowych, W. P. What do biomarkers tell us about the pathogenesis of ankylosing spondylitis? Arthritis Res. Ther. 11, 101 (2009).

    Article  Google Scholar 

  20. Hofer, M. Spondylarthropathies in children—are they different from those in adults? Best Pract. Res. Clin. Rheumatol. 20, 315–328 (2006).

    Article  Google Scholar 

  21. Rosenberg, A. M. & Petty, R. E. A syndrome of seronegative enthesopathy and arthropathy in children. Arthritis Rheum. 25, 1041–1047 (1982).

    Article  CAS  Google Scholar 

  22. Fantini, F. Classification of chronic arthritides of childhood (juvenile idiopathic arthritis): criticisms and suggestions to improve the efficacy of the Santiago-Durban criteria. J. Rheumatol. 28, 456–459 (2001).

    CAS  PubMed  Google Scholar 

  23. 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).

    Google Scholar 

  24. Butbul, Y. A. et al. Comparison of patients with juvenile psoriatic arthritis and nonpsoriatic juvenile idiopathic arthritis: how different are they? J. Rheumatol. 36, 2033–2041 (2009).

    Article  Google Scholar 

  25. Flato, B., Lien, G., Smerdel-Ramoya, A. & Vinje, O. Juvenile psoriatic arthritis: longterm outcome and differentiation from other subtypes of juvenile idiopathic arthritis. J. Rheumatol. 36, 642–650 (2009).

    Article  Google Scholar 

  26. Southwood, T. R. et al. Psoriatic arthritis in children. Arthritis Rheum. 32, 1007–1013 (1989).

    Article  CAS  Google Scholar 

  27. Stoll, M. L. et al. Patients with juvenile psoriatic arthritis comprise two distinct populations. Arthritis Rheum. 54, 3564–3572 (2006).

    Article  Google Scholar 

  28. Stoll, M. L., Lio, P., Sundel, R. P. & Nigrovic, P. A. Comparison of Vancouver and International League of Associations for rheumatology classification criteria for juvenile psoriatic arthritis. Arthritis Rheum. 59, 51–58 (2008).

    Article  Google Scholar 

  29. Nigrovic, P. A. Juvenile psoriatic arthritis: bathwater or baby? J. Rheumatol. 36, 1861–1863 (2009).

    Article  Google Scholar 

  30. Tse, S. M. & Laxer, R. M. Juvenile spondyloarthropathy. Curr. Opin. Rheumatol. 15, 374–379 (2003).

    Article  Google Scholar 

  31. Gomez, K. S., Raza, K., Jones, S. D., Kennedy, L. G. & Calin, A. Juvenile onset ankylosing spondylitis—more girls than we thought? J. Rheumatol. 24, 735–737 (1997).

    CAS  PubMed  Google Scholar 

  32. Manners, P. J. & Bower, C. Worldwide prevalence of juvenile arthritis why does it vary so much? J. Rheumatol. 29, 1520–1530 (2002).

    Google Scholar 

  33. Hofer, M. & Southwood, T. R. Classification of childhood arthritis. Best Pract. Res. Clin. Rheumatol. 16, 379–396 (2002).

    Article  Google Scholar 

  34. Hashkes, P. J. & Laxer, R. M. Medical treatment of juvenile idiopathic arthritis. JAMA 294, 1671–1684 (2005).

    Article  CAS  Google Scholar 

  35. Burgos-Vargas, R., Vazquez-Mellado, J., Pacheco-Tena, C., Hernandez-Garduno, A. & Goycochea-Robles, M. V. A 26 week randomised, double blind, placebo controlled exploratory study of sulfasalazine in juvenile onset spondyloarthropathies. Ann. Rheum. Dis. 61, 941–942 (2002).

    Article  CAS  Google Scholar 

  36. Tse, S. M., Burgos-Vargas, R. & Laxer, R. M. Anti-tumor necrosis factor alpha blockade in the treatment of juvenile spondylarthropathy. Arthritis Rheum. 52, 2103–2108 (2005).

    Article  CAS  Google Scholar 

  37. Wanders, A. et al. Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum. 52, 1756–1765 (2005).

    Article  CAS  Google Scholar 

  38. Dagfinrud, H., Kvien, T. K. & Hagen, K. B. The Cochrane review of physiotherapy interventions for ankylosing spondylitis. J. Rheumatol. 32, 1899–1906 (2005).

    PubMed  Google Scholar 

  39. Brown, M. A., Laval, S. H., Brophy, S. & Calin, A. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann. Rheum. Dis. 59, 883–886 (2000).

    Article  CAS  Google Scholar 

  40. Reveille, J. D. Recent studies on the genetic basis of ankylosing spondylitis. Curr. Rheumatol. Rep. 11, 340–348 (2009).

    Article  CAS  Google Scholar 

  41. Wellcome Trust Case Control Consortium et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329–1337 (2007).

  42. Brown, M. A. Genetics and the pathogenesis of ankylosing spondylitis. Curr. Opin. Rheumatol. 21, 318–323 (2009).

    Article  CAS  Google Scholar 

  43. Australo-Anglo-American Spondyloarthritis Consortium (TASC) et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat. Genet. 42, 123–127 (2010).

  44. Cargill, M. et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 (2007).

    Article  CAS  Google Scholar 

  45. Duerr, R. H. Genome-wide association studies herald a new era of rapid discoveries in inflammatory bowel disease research. Gastroenterology 132, 2045–2049 (2007).

    Article  CAS  Google Scholar 

  46. Schaller, J. G. et al. Histocompatibility antigens in childhood-onset arthritis. J. Pediatr. 88, 926–930 (1976).

    Article  CAS  Google Scholar 

  47. Jacobs, J. C., Berdon, W. E. & Johnston, A. D. HLA-B27-associated spondyloarthritis and enthesopathy in childhood: clinical, pathologic, and radiographic observations in 58 patients. J. Pediatr. 100, 521–528 (1982).

    Article  CAS  Google Scholar 

  48. Burgos-Vargas, R., Pacheco-Tena, C. & Vazquez-Mellado, J. Juvenile-onset spondyloarthropathies. Rheum. Dis. Clin. North Am. 23, 569–598 (1997).

    Article  CAS  Google Scholar 

  49. Tam, L.-S., Gu, J. & Yu, D. Pathogenesis of ankylosing spondylitis. Nat. Rev. Rheumatol. 6, 339–405 (2010).

    Article  Google Scholar 

  50. Colbert, R. A. From HLA-B27 to spondyloarthritis: a journey through the ER. Immunol. Rev. 233, 181–202 (2010).

    Article  CAS  Google Scholar 

  51. May, E. et al. CD8αβ T cells are not essential to the pathogenesis of arthritis or colitis in HLA-B27 transgenic rats. J. Immunol. 170, 1099–1105 (2003).

    Article  CAS  Google Scholar 

  52. Taurog, J. D. et al. Spondylarthritis in HLA-B27/human β2-microglobulin-transgenic rats is not prevented by lack of CD8. Arthritis Rheum. 60, 1977–1984 (2009).

    Article  CAS  Google Scholar 

  53. DeLay, M. L. et al. HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis Rheum. 60, 2633–2643 (2009).

    Article  CAS  Google Scholar 

  54. Layh-Schmitt, G. & Colbert, R. A. The interleukin-23/interleukin-17 axis in spondyloarthritis. Curr. Opin. Rheumatol. 20, 392–397 (2008).

    Article  CAS  Google Scholar 

  55. Bettelli, E., Oukka, M. & Kuchroo, V. K. TH17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 8, 345–350 (2007).

    Article  CAS  Google Scholar 

  56. Jandus, C. et al. Increased numbers of circulating polyfunctional Th17 memory cells in patients with seronegative spondylarthritides. Arthritis Rheum. 58, 2307–2317 (2008).

    Article  Google Scholar 

  57. Shen, H., Goodall, J. C. & Hill Gaston, J. S. Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum. 60, 1647–1656 (2009).

    Article  CAS  Google Scholar 

  58. Singh, R., Aggarwal, A. & Misra, R. Th1/Th17 cytokine profiles in patients with reactive arthritis/undifferentiated spondyloarthropathy. J. Rheumatol. 34, 2285–2290 (2007).

    CAS  Google Scholar 

  59. Wendling, D., Cedoz, J. P., Racadot, E. & Dumoulin, G. Serum IL-17, BMP-7, and bone turnover markers in patients with ankylosing spondylitis. Joint Bone Spine 74, 304–305 (2007).

    Article  CAS  Google Scholar 

  60. Saric, T. et al. An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nat. Immunol. 3, 1169–1176 (2002).

    Article  CAS  Google Scholar 

  61. Serwold, T., Gonzalez, F., Kim, J., Jacob, R. & Shastri, N. ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum. Nature 419, 480–483 (2002).

    Article  CAS  Google Scholar 

  62. York, I. A. et al. The ER aminopeptidase ERAP1 enhances or limits antigen presentation by trimming epitopes to 8–9 residues. Nat. Immunol. 3, 1177–1184 (2002).

    Article  CAS  Google Scholar 

  63. Cabral, D. A., Oen, K. G. & Petty, R. E. SEA syndrome revisited: a longterm followup of children with a syndrome of seronegative enthesopathy and arthropathy. J. Rheumatol. 19, 1282–1285 (1992).

    CAS  Google Scholar 

  64. Selvaag, A. M. et al. Early disease course and predictors of disability in juvenile rheumatoid arthritis and juvenile spondyloarthropathy: a 3 year prospective study. J. Rheumatol. 32, 1122–1130 (2005).

    Google Scholar 

  65. Flato, B. et al. Long-term outcome and prognostic factors in enthesitis-related arthritis: a case-control study. Arthritis Rheum. 54, 3573–3582 (2006).

    Article  Google Scholar 

  66. 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).

    CAS  Google Scholar 

  67. Gensler, L. S. et al. Clinical, radiographic and functional differences between juvenile-onset and adult-onset ankylosing spondylitis: results from the PSOAS cohort. Ann. Rheum. Dis. 67, 233–237 (2008).

    Article  CAS  Google Scholar 

  68. O'Shea, F. D. et al. Comparison of clinical and radiographic severity of juvenile-onset versus adult-onset ankylosing spondylitis. Ann. Rheum. Dis. 68, 1407–1412 (2009).

    Article  CAS  Google Scholar 

  69. Chandran, V., Schentag, C. T. & Gladman, D. D. Sensitivity of the classification of psoriatic arthritis criteria in early psoriatic arthritis. Arthritis Rheum. 57, 1560–1563 (2007).

    Article  Google Scholar 

  70. Sieper, J. et al. New criteria for inflammatory back pain in patients with chronic back pain: a real patient exercise by experts from the Assessment of SpondyloArthritis International Society (ASAS). Ann. Rheum. Dis. 68, 784–788 (2009).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Colbert, R. Classification of juvenile spondyloarthritis: enthesitis-related arthritis and beyond. Nat Rev Rheumatol 6, 477–485 (2010). https://doi.org/10.1038/nrrheum.2010.103

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2010.103

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

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