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New advances in juvenile spondyloarthritis

Abstract

Juvenile spondyloarthritis (SpA) is a distinct disease to adult SpA, and usually manifests as peripheral arthritis and enthesitis. Importantly, many patients with juvenile SpA continue to be at risk of developing ankylosing spondylitis during their disease course. In this Review, the classification and diagnostic criteria, clinical manifestations and treatment guidelines for juvenile SpA will be discussed. Advances in the diagnosis of and management strategies for juvenile SpA will lead to earlier recognition, appropriate treatment and improved rates of inactive disease, which should lead to improved patient outcomes and quality of life.

Key Points

  • Juvenile SpA commonly manifests as peripheral arthritis and enthesitis affecting the lower extremities

  • Spinal or sacroiliac joint involvement is infrequent at disease onset, but can develop during the disease course

  • A single diagnostic or classification system that is representative of the juvenile SpA population is still needed

  • MRI, whole-body MRI and power Doppler ultrasonography are useful imaging tools for the early detection and monitoring of disease activity in the joints and entheses

  • Establishment of treatment guidelines with early and appropriate use of anti-TNF agents will assist in improving the outcomes of patients with juvenile SpA

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Figure 1: Clinical manifestations of juvenile SpA.
Figure 2: MRI manifestations of juvenile SpA.
Figure 3: 2011 ACR treatment recommendations for JIA.

References

  1. Burgos-Vargas, R. The juvenile-onset spondyloarthritides. Rheum. Dis. Clin. North Am. 28, 531–560 (2002).

    PubMed  Article  Google Scholar 

  2. van Tubergen, A. & Weber, U. Diagnosis and classification in spondyloarthritis: identifying a chameleon. Nat. Rev. Rheumatol. http://dx.doi.org/10.1038/nrrheum.2012.33.

  3. Lin, Y. C., Liang, T. H., Chen, W. S. & Lin, H. Y. Differences between juvenile-onset ankylosing spondylitis and adult-onset ankylosing spondylitis. J. Chin. Med. Assoc. 72, 573–580 (2009).

    PubMed  Article  Google Scholar 

  4. 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).

    CAS  PubMed  Article  Google Scholar 

  5. Baek, H. J. et al. Juvenile onset ankylosing spondylitis (JAS) has less severe spinal disease course than adult onset ankylosing spondylitis (AAS): clinical comparison between JAS and AAS in Korea. J. Rheumatol. 29, 1780–1785 (2002).

    PubMed  Google Scholar 

  6. van der Linden, S., Valkenburg, H. A. & Cats, A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 27, 361–368 (1984).

    CAS  Article  PubMed  Google Scholar 

  7. 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).

    CAS  Article  PubMed  Google Scholar 

  8. Kleinman, P., Rivelis, M., Schneider, R. & Kaye, J. J. Juvenile ankylosing spondylitis. Radiology 125, 775–780 (1977).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  10. Amor, B. et al. Evaluation of the Amor criteria for spondylarthropathies and European Spondylarthropathy Study Group (ESSG). A cross-sectional analysis of 2,228 patients [French]. Ann. Med. Interne (Paris) 142, 85–89 (1991).

    CAS  Google Scholar 

  11. Amor, B. In 50 ans de Rhumatologie...et l'avenir 29–31 (Expanscience, Courbevoie, 2005).

    Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  13. Rudwaleit, M. et al. The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann. Rheum. Dis. 70, 25–31 (2011).

    CAS  Article  PubMed  Google Scholar 

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

  15. Hafner, R. Juvenile spondarthritis. Retrospective study of 71 patients [German]. Monatsschr. Kinderheilkd. 135, 41–46 (1987).

    CAS  PubMed  Google Scholar 

  16. Hussein, A., Abdul-Khaliq, H. & von der Hardt, H. Atypical spondyloarthritis in children: proposed diagnostic criteria. 148, 513–517 (1989).

  17. Petty, R. E. et al. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J. Rheumatol. 25, 1991–1994 (1998).

    CAS  PubMed  Google Scholar 

  18. 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).

    PubMed  Google Scholar 

  19. Prieur, A. M. Spondyloarthropathies in childhood. Baillieres Clin. Rheumatol. 12, 287–307 (1998).

    CAS  PubMed  Article  Google Scholar 

  20. Prieur, A. M. Spondylarthropathies in children. Ann. Med. Interne (Paris) 149, 156–158 (1998).

    CAS  Google Scholar 

  21. Kasapcopur, O. et al. Evaluation of classification criteria for juvenile-onset spondyloarthropathies. Rheumatol. Int. 25, 414–418 (2005).

    PubMed  Article  Google Scholar 

  22. Joos, R. et al. Sensitivity and specificity of criteria for spondyloarthritis in children with late onset pauciarticular juvenile chronic arthritis as well as their characteristics. Clin. Exp. Rheumatol. 27, 870–876 (2009).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  24. Alvarez-Madrid, C., Merino, R., De Inocencio, J. & Garcia-Consuegra, J. Tarsitis as an initial manifestation of juvenile spondyloarthropathy. Clin. Exp. Rheumatol. 27, 691–694 (2009).

    CAS  PubMed  Google Scholar 

  25. Petty, R., Cassidy, J. T. in Textbook of Pediatric Rheumatology (eds Cassidy, J. T., Petty, R, Laxer, R. & Lindsley, C.) 272–286 (Elsevier, Amsterdam, 2011).

    Book  Google Scholar 

  26. Burgos-Vargas, R. & Vazquez-Mellado, J. The early clinical recognition of juvenile-onset ankylosing spondylitis and its differentiation from juvenile rheumatoid arthritis. Arthritis Rheum. 38, 835–844 (1995).

    CAS  PubMed  Article  Google Scholar 

  27. Burgos-Vargas, R. & Clark, P. Axial involvement in the seronegative enthesopathy and arthropathy syndrome and its progression to ankylosing spondylitis. J. Rheumatol. 16, 192–197 (1989).

    CAS  PubMed  Google Scholar 

  28. 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  PubMed  Google Scholar 

  29. 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  PubMed  Google Scholar 

  30. Minden, K. et al. Long-term outcome in patients with juvenile idiopathic arthritis. Arthritis Rheum. 46, 2392–2401 (2002).

    Article  PubMed  Google Scholar 

  31. Burgos-Vargas, R. et al. Genuine ankylosing spondylitis in children: a case–control study of patients with early definite disease according to adult onset criteria. J. Rheumatol. 23, 2140–2147 (1996).

    CAS  PubMed  Google Scholar 

  32. Burgos-Vargas, R., Lardizabal-Sanabria, J. & Katona, G. Anterior spinal flexion in healthy Mexican children. J. Rheumatol. 12, 123–125 (1985).

    CAS  PubMed  Google Scholar 

  33. Weiss, P. F. et al. Enthesitis in an inception cohort of enthesitis-related arthritis. Arthritis Care Res. (Hoboken) 63, 1307–1312 (2011).

    Article  Google Scholar 

  34. Mielants, H. et al. The evolution of spondyloarthropathies in relation to gut histology. II. Histological aspects. J. Rheumatol. 22, 2273–2278 (1995).

    CAS  PubMed  Google Scholar 

  35. Mielants, H. et al. Gut inflammation in children with late onset pauciarticular juvenile chronic arthritis and evolution to adult spondyloarthropathy—a prospective study. J. Rheumatol. 20, 1567–1572 (1993).

    CAS  PubMed  Google Scholar 

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

    PubMed  Article  Google Scholar 

  37. Stamato, T. et al. Prevalence of cardiac manifestations of juvenile ankylosing spondylitis. Am. J. Cardiol. 75, 744–746 (1995).

    CAS  PubMed  Article  Google Scholar 

  38. Bollow, M. et al. Use of dynamic magnetic resonance imaging to detect sacroiliitis in HLA-B27 positive and negative children with juvenile arthritides. J. Rheumatol. 25, 556–564 (1998).

    CAS  PubMed  Google Scholar 

  39. Bollow, M. et al. Use of contrast-enhanced MR imaging to detect sacroiliitis in children. Skeletal Radiol. 27, 606–616 (1998).

    CAS  PubMed  Article  Google Scholar 

  40. Yilmaz, M. H., Ozbayrak, M., Kasapcopur, O., Kurugoglu, S. & Kanberoglu, K. Pelvic MRI findings of juvenile-onset ankylosing spondylitis. Clin. Rheumatol. 29, 1007–1013 (2010).

    PubMed  Article  Google Scholar 

  41. Rachlis, A. C. et al. Whole body MR imaging in juvenile spondyloarthritis: will it provide vital information compared to clinical exam alone? [abstract]. Arthritis Rheum. 63, S292 (2011).

    Google Scholar 

  42. Jousse-Joulin, S. et al. Ultrasonography for detecting enthesitis in juvenile idiopathic arthritis. Arthritis Care Res. (Hoboken) 63, 849–855 (2011).

    Article  Google Scholar 

  43. van der Linden, S. M., Valkenburg, H. A., de Jongh, B. M. & Cats, A. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients with the general population. Arthritis Rheum. 27, 241–249 (1984).

    CAS  PubMed  Article  Google Scholar 

  44. Reveille, J. D. Genetic basis of spondyloarthritis—beyond the MHC. Nat. Rev. Rheum. http://dx.doi.org/10.1038/nrrheum.2012.41.

  45. Stanevicha, V. et al. HLA B27 allele types in homogeneous groups of juvenile idiopathic arthritis patients in Latvia. Pediatr. Rheumatol. Online J. 8, 26 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  46. Hinks, A. et al. Subtype specific genetic associations for juvenile idiopathic arthritis: ERAP1 with the enthesitis related arthritis subtype and IL23R with juvenile psoriatic arthritis. Arthritis. Res. Ther. 13, R12 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 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).

    CAS  Article  PubMed  Google Scholar 

  48. Jarrett, S. J. et al. MRI and clinical findings in patients with ankylosing spondylitis eligible for anti-tumour necrosis factor therapy after a short course of etoricoxib. Ann. Rheum. Dis. 68, 1466–1469 (2009).

    CAS  PubMed  Article  Google Scholar 

  49. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. van Rossum, M. A. et al. Sulfasalazine in the treatment of juvenile chronic arthritis: a randomized, double-blind, placebo-controlled, multicenter study. Dutch Juvenile Chronic Arthritis Study Group. Arthritis Rheum. 41, 808–816 (1998).

    CAS  PubMed  Article  Google Scholar 

  51. Imundo, L. F. & Jacobs, J. C. Sulfasalazine therapy for juvenile rheumatoid arthritis. J. Rheumatol. 23, 360–366 (1996).

    CAS  PubMed  Google Scholar 

  52. Suschke, H. J. Treatment of juvenile spondylarthritis and reactive arthritis with sulfasalazine [German]. Monatsschr. Kinderheilkd. 140, 658–660 (1992).

    CAS  PubMed  Google Scholar 

  53. Job-Deslandre, C. & Menkes, C. J. Treatment of juvenile spondyloarthropathies with sulfasalazine [French]. Rev. Rhum. Ed. Fr. 60, 489–491 (1993).

    CAS  PubMed  Google Scholar 

  54. Huang, J. L. & Chen, L. C. Sulphasalazine in the treatment of children with chronic arthritis. Clin. Rheumatol. 17, 359–363 (1998).

    CAS  PubMed  Article  Google Scholar 

  55. Woo, P. et al. Randomized, placebo-controlled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Arthritis Rheum. 43, 1849–1857 (2000).

    CAS  PubMed  Article  Google Scholar 

  56. 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).

    CAS  Article  PubMed  Google Scholar 

  57. Giannini, E. H. et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the USA-USSR double-blind, placebo-controlled trial. The Pediatric Rheumatology Collaborative Study Group and The Cooperative Children's Study Group. N. Engl. J. Med. 326, 1043–1049 (1992).

    CAS  PubMed  Article  Google Scholar 

  58. Burgos-Vargas, R. Efficacy, safety, and tolerability of Infliximab in Juvenile-onset Spondyloarthropathies (JO-SpA): results of the three-month, randomized, double-blind, placebo-controlled trial phase [abstract]. Arthritis Rheum. 56, S319 (2007).

    Google Scholar 

  59. Burgos-Vargas, R., Casasola-Vargas, J. & Gutierrez-Suarez, R. A 3-month, double-blind, placebo-controlled, randomized trial of infliximab in juvenile-onset spondyloarthritis (SpA) and a 52-week open extension. Clin. Exp. Rheumatol. 26, 745 (2008).

    Google Scholar 

  60. Henrickson, M. & Reiff, A. Prolonged efficacy of etanercept in refractory enthesitis-related arthritis. J. Rheumatol. 31, 2055–2061 (2004).

    CAS  PubMed  Google Scholar 

  61. 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).

    CAS  PubMed  Article  Google Scholar 

  62. Tse, S. M. L., Burgos-Vargas, R., O'Shea F, Inman, R. & Laxer, R. Long term outcome of anti-TNF therapy in juvenile spondyloarthropathy. Arthritis Rheum. 56, 898 (2007).

    Google Scholar 

  63. Tse, S. M., Laxer, R. M., Babyn, P. S. & Doria, A. S. Radiologic Improvement of juvenile idiopathic arthritis-enthesitis-related arthritis following anti-tumor necrosis factor-alpha blockade with etanercept. J. Rheumatol. 33, 1186–1188 (2006).

    PubMed  Google Scholar 

  64. Sulpice, M., Deslandre, C. J. & Quartier, P. Efficacy and safety of TNFalpha antagonist therapy in patients with juvenile spondyloarthropathies. Joint Bone Spine 76, 24–27 (2009).

    CAS  PubMed  Article  Google Scholar 

  65. Schmeling, H. & Horneff, G. Infliximab in two patients with juvenile ankylosing spondylitis. Rheumatol. Int. 24, 173–176 (2004).

    PubMed  Article  Google Scholar 

  66. Otten, M. H. et al. Tumor necrosis factor-blocking agents for children with enthesitis-related arthritis--data from the Dutch Arthritis and Biologicals in Children Register, 1999–2010. J. Rheumatol. 38, 2258–2263 (2011).

    CAS  PubMed  Article  Google Scholar 

  67. Beukelman, T. et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res. (Hoboken) 63, 465–482 (2011).

    Article  Google Scholar 

  68. Flato, B. et al. The influence of patient characteristics, disease variables, and HLA alleles on the development of radiographically evident sacroiliitis in juvenile idiopathic arthritis. Arthritis Rheum. 46, 986–994 (2002).

    Article  PubMed  Google Scholar 

  69. Bennett, A. N. et al. Severity of baseline magnetic resonance imaging-evident sacroiliitis and HLA-B27 status in early inflammatory back pain predict radiographically evident ankylosing spondylitis at eight years. Arthritis Rheum. 58, 3413–3418 (2008).

    CAS  PubMed  Article  Google Scholar 

  70. Braun, J. et al. 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann. Rheum. Dis. 70, 896–904 (2011).

    CAS  PubMed  Article  Google Scholar 

  71. van der Heijde, D. et al. 2010 Update of the international ASAS recommendations for the use of anti-TNF agents in patients with axial spondyloarthritis. Ann. Rheum. Dis. 70, 905–908 (2011).

    Article  PubMed  Google Scholar 

  72. Sieper, J. Developments in therapies for spondyloarthritis. Nat. Rev. Rheumatol. http://dx.doi.org/10.1038/nrrheum.2012.40.

  73. Batthish, M. R. A. et al. Intra-rater Reliability of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI) in Children with Spondyloarthritis [abstract]. Arthritis Rheum. 62, S95 (2010).

    Google Scholar 

  74. Maksymowych, W. P. et al. The Canadian Rheumatology Association/ Spondyloarthritis Research Consortium of Canada treatment recommendations for the management of spondyloarthritis: a national multidisciplinary stakeholder project. J. Rheumatol. 34, 2273–2284 (2007).

    PubMed  Google Scholar 

  75. Minden, K. et al. Prognosis of patients with juvenile chronic arthritis and juvenile spondyloarthropathy. J. Rheumatol. 27, 2256–2263 (2000).

    CAS  PubMed  Google Scholar 

  76. Flato, B., Aasland, A., Vinje, O. & Forre, O. Outcome and predictive factors in juvenile rheumatoid arthritis and juvenile spondyloarthropathy. J. Rheumatol. 25, 366–375 (1998).

    CAS  PubMed  Google Scholar 

  77. 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).

    PubMed  Google Scholar 

  78. Sarma, P. K., Misra, R. & Aggarwal, A. Outcome in patients with enthesitis related arthritis (ERA): juvenile arthritis damage index (JADI) and functional status. Pediatr. Rheumatol. Online J. 6, 18 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  79. Oen, K. et al. Early outcomes and improvement of patients with juvenile idiopathic arthritis enrolled in a Canadian multicenter inception cohort. Arthritis Care Res (Hoboken) 62, 527–536 (2010).

    Article  Google Scholar 

  80. Oen, K. et al. Predictors of early inactive disease in a juvenile idiopathic arthritis cohort: results of a Canadian multicenter, prospective inception cohort study. Arthritis Rheum. 61, 1077–1086 (2009).

    PubMed  Article  Google Scholar 

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

    PubMed  PubMed Central  Article  Google Scholar 

  82. Calin, A. & Elswood, J. The natural history of juvenile-onset ankylosing spondylitis: a 24-year retrospective case-control study. Br. J. Rheumatol. 27, 91–93 (1988).

    CAS  PubMed  Article  Google Scholar 

  83. Stone, M. et al. Juvenile-onset ankylosing spondylitis is associated with worse functional outcomes than adult-onset ankylosing spondylitis. Arthritis Rheum. 53, 445–451 (2005).

    PubMed  Article  Google Scholar 

  84. Giannini, E. H. et al. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum. 40, 1202–1209 (1997).

    CAS  PubMed  Article  Google Scholar 

  85. Wallace, C. A., Ruperto, N. & Giannini, E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J. Rheumatol. 31, 2290–2294 (2004).

    PubMed  Google Scholar 

  86. Sieper, J. et al. The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann. Rheum. Dis. 68 (Suppl. 2), ii1–ii44 (2009).

    PubMed  Google Scholar 

  87. Thornton, J. et al. Costing juvenile idiopathic arthritis: examining patient-based costs during the first year after diagnosis. Rheumatology (Oxford) 47, 985–990 (2008).

    CAS  Article  Google Scholar 

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Authors and Affiliations

Authors

Contributions

Both authors contributed equally to researching data for the article. S. M. L. Tse wrote the article and R. M. Laxer reviewed and edited the manuscript before submission.

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Correspondence to Shirley M. L. Tse.

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Competing interests

S. M. L. Tse has acted as a consultant for Abbott, Schering–Plough (now merged with Merck) and Wyeth–Pfizer. R. M. Laxer declares no competing interests.

Supplementary information

Supplementary Table 1

Comparison of the criteria sets used for juvenile SpA (DOC 52 kb)

Supplementary Table 2

Disease activity measures for pediatric and adult SpA* (DOC 53 kb)

Supplementary Figure 1

Classication of SpA in adults. (PDF 72 kb)

Supplementary Figure 2

Treatment recommendations for anti-TNF agents in adult SpA and AS. (PDF 425 kb)

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Tse, S., Laxer, R. New advances in juvenile spondyloarthritis. Nat Rev Rheumatol 8, 269–279 (2012). https://doi.org/10.1038/nrrheum.2012.37

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