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Advances from clinical trials in juvenile idiopathic arthritis

Nature Reviews Rheumatology volume 9, pages 557563 (2013) | Download Citation

Abstract

Treatments available to children with juvenile idiopathic arthritis (JIA) have improved dramatically in the past 15 years, largely because of the development of powerful new biologic treatments. However, the seeds of this development were sewed over 40 years ago with the formation of a group of paediatric rheumatologists who understood the necessity of performing clinical trials in children with JIA. From there, international paediatric rheumatology networks have grown, and are dedicated to and highly experienced in performing such clinical trials. Development of validated outcomes and methodologies has also been critical. The ability to perform these trials stems from legislation enabling the FDA and the European Medicines Agency to require studies to be performed in children before they can be licensed for use in children. Current efforts to enhance the understanding of treatment options for patients with JIA include the development of disease-specific rather than drug-specific consolidated registries, studies in personalized predictive medicine and the development of treatment protocols for regular clinical care of these patients.

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References

  1. 1.

    & Juvenile idiopathic arthritis. Pediatr. Rev. 33, 303–313 (2012).

  2. 2.

    et al. Comparison of tolmetin sodium and aspirin in the treatment of juvenile rheumatoid arthritis. J. Pediatr. 91, 799–804 (1977).

  3. 3.

    & Drug treatment in children with juvenile rheumatoid arthritis. Past, present, and future. Pediatr. Clin. North Am. 42, 1099–1125 (1995).

  4. 4.

    & Standard methodology for segment I, II, and III pediatric rheumatology collaborative study group studies. I. Design. J. Rheumatol. 9, 109–113 (1982).

  5. 5.

    & Standard methodology for segment I, II, and III pediatric rheumatology collaborative study group studies. II. Analysis and presentation of data. J. Rheumatol. 9, 114–122 (1982).

  6. 6.

    et al. Controlled trial of hydroxychloroquine and D-penicillamine singly and in combination in the treatment of rheumatoid arthritis. Arthritis Rheum. 27, 267–276 (1984).

  7. 7.

    , , & Penicillamine and hydroxychloroquine in the treatment of severe juvenile rheumatoid arthritis. Results of the U.S.A.–U.S.S.R. double-blind, placebo-controlled trial. N. Engl. J. Med. 314, 1269–1276 (1986).

  8. 8.

    , , , & Auranofin in the treatment of juvenile rheumatoid arthritis. Results of the U.S.A.–U.S.S.R. double-blind, placebo-controlled cooperative trial. The USA Pediatric Rheumatology Collaborative Study Group. The USSR Cooperative Children's Study Group. Arthritis Rheum. 33, 466–476 (1990).

  9. 9.

    et al. Comparison of auranofin, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum. 35, 1406–1407 (1992).

  10. 10.

    et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the U.S.A.–U.S.S.R. 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).

  11. 11.

    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).

  12. 12.

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

  13. 13.

    et al. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res. (Hoboken) 63, 929–936 (2011).

  14. 14.

    et al. Intravenous immunoglobulin in the treatment of polyarticular juvenile rheumatoid arthritis: a phase I/II study. Pediatric Rheumatology Collaborative Study Group. J. Rheumatol. 23, 919–924 (1996).

  15. 15.

    et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N. Engl. J. Med. 342, 763–769 (2000).

  16. 16.

    et al. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rheum. 64, 2012–2021 (2012).

  17. 17.

    A look at the future of pediatric therapeutics: an investigator's perspective of the new pediatric rule. Pediatrics 104, 610–613 (1999).

  18. 18.

    & Use of unlabeled and off license drugs in children. A European paediatric rule is needed to protect children. BMJ 320, 1210–1211 (2000).

  19. 19.

    European Parliament, Council. Regulation (EC) no 1901/2006 of the European parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. Official Journal of the European Union 378, 1–19 (2006).

  20. 20.

    et al. International league of associations for rheumatology classification of juvenile idiopathic arthritis: Second revision, Edmonton, 2001. J. Rheumatol. 31, 390–392 (2004).

  21. 21.

    et al. A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum. 56, 3096–3106 (2007).

  22. 22.

    et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. N. Engl. J. Med. 359, 810–820 (2008).

  23. 23.

    US National Library of Medicine. ClinicalTrials.gov , (2013).

  24. 24.

    US National Library of Medicine. ClinicalTrials.gov , (2013).

  25. 25.

    et al. Patterns of expression of tumor necrosis factor α, tumor necrosis factor β, and their receptors in synovia of patients with juvenile rheumatoid arthritis and juvenile spondylarthropathy. Arthritis Rheum. 39, 1703–1710 (1996).

  26. 26.

    et al. The German etanercept registry for treatment of juvenile idiopathic arthritis. Ann. Rheum. Dis. 63, 1638–1644 (2004).

  27. 27.

    et al. Long-term follow-up on effectiveness and safety of etanercept in juvenile idiopathic arthritis: the Dutch national register. Ann. Rheum. Dis. 68, 635–641 (2009).

  28. 28.

    et al. Effects of long-term etanercept treatment on growth in children with selected categories of juvenile idiopathic arthritis. Arthritis Rheum. 62, 3259–3264 (2010).

  29. 29.

    et al. Abatacept in children with juvenile idiopathic arthritis: a randomized, double-blind, placebo-controlled withdrawal trial. Lancet 372, 383–391 (2008).

  30. 30.

    et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group. N. Engl. J. Med. 343, 1594–1602 (2000).

  31. 31.

    European Medicines Agency. EPAR summary for the public: Humira , (2013).

  32. 32.

    , & Juvenile idiopathic arthritis. Lancet 377, 2138–2149 (2011).

  33. 33.

    & Is systemic juvenile rheumatoid arthritis an interleukin 6 mediated disease? J. Rheumatol. 25, 203–207 (1998).

  34. 34.

    , , , & Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J. Exp. Med. 201, 1479–1486 (2005).

  35. 35.

    & Tocilizumab: molecular intervention therapy in children with systemic juvenile idiopathic arthritis. Expert Rev. Clin. Immunol. 6, 735–743 (2010).

  36. 36.

    et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367, 2385–2395 (2012).

  37. 37.

    et al. A multicenter, randomized, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann. Rheum. Dis. 70, 747–754 (2011).

  38. 38.

    et al. A phase II study to evaluate dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Arthritis Rheum. 64, 557–567 (2012).

  39. 39.

    et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367, 2396–2407 (2012).

  40. 40.

    & A new era in the treatment of systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367, 2439–2440 (2012).

  41. 41.

    et al. Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTE-JIA): a multicenter randomized open-label clinical trial. Ann. Rheum. Dis. 70, 1605–1612 (2011).

  42. 42.

    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).

  43. 43.

    et al. Predictive markers of therapeutical outcome and their role in the ethiopathology of juvenile idiopathic arthritis [abstract]. Arthritis Rheum. 64 (Suppl. 10), S1097–S1098 (2012).

  44. 44.

    et al. Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial. JAMA 303, 1266–1273 (2010).

  45. 45.

    et al. Phagocyte-specific S100 proteins and high-sensitivity C reactive protein as biomarkers for a risk-adapted treatment to maintain remission in juvenile idiopathic arthritis: a comparative study. Ann. Rheum. Dis. 71, 1991–1997 (2012).

  46. 46.

    , & Summary of AHRQ's comparative effectiveness review of disease-modifying antirheumatic drugs for children with juvenile idiopathic arthritis. J. Manag. Care Pharm. 18 (Suppl. B), 1–16 (2012).

  47. 47.

    et al. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res. (Hoboken) 64, 1001–1010 (2012).

  48. 48.

    et al. A European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA). Arch. Dis. Child. 97, 185–188 (2012).

  49. 49.

    et al. Preliminary evidence that etanercept may reduce radiographic progression in juvenile idiopathic arthritis. Clin. Exp. Rheumatol. 26, 688–692 (2008).

  50. 50.

    & The safety profile of biologic therapies for juvenile idiopathic arthritis. Nat. Rev. Rheumatol. 6, 561–571 (2010).

  51. 51.

    et al. Tumor necrosis factor α blockers and malignancy in children: forty-eight cases reported to the Food and Drug Administration. Arthritis Rheum. 62, 2517–2524 (2010).

  52. 52.

    et al. Rates of malignancy associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum. 64, 1263–1271 (2012).

  53. 53.

    , , & Juvenile idiopathic arthritis and risk of cancer: A nationwide cohort study. Arthritis Rheum. 62, 3776–3782 (2010).

  54. 54.

    & Pediatric rheumatology: JIA, treatment and possible risk of malignancies. Nat. Rev. Rheumatol. 7, 6–7 (2011).

  55. 55.

    , , , & Report on malignancies in the German juvenile idiopathic arthritis registry. Rheumatology (Oxford) 50, 230–236 (2011).

  56. 56.

    et al. Malignancies in juvenile idiopathic arthritis: a preliminary report. J. Rheumatol. 38, 760–763 (2011).

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Acknowledgements

The authors would like to thank the patients, families and all the members of the PRCSG and PRINTO networks who have participated in the trials. Without their contributions none of these remarkable advances in treatments for children with JIA worldwide would have been possible.

Author information

Affiliations

  1. Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, ML 4010, Cincinnati, OH 45229, USA

    • Daniel J. Lovell
    •  & Edward H. Giannini
  2.  IRCCS G. Gaslini, Pediatria II, Pediatric Rheumatology Clinical Trials Organization, Universita di Genova, Genoa, Italy

    • Nicola Ruperto
    •  & Alberto Martini

Authors

  1. Search for Daniel J. Lovell in:

  2. Search for Nicola Ruperto in:

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Contributions

All authors contributed to researching data for the article, discussing its content, writing, editing, and revising the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Daniel J. Lovell.

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DOI

https://doi.org/10.1038/nrrheum.2013.105

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