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. 2003 Mar;88(3):186–191. doi: 10.1136/adc.88.3.186

Biologic therapies for juvenile arthritis

N Wilkinson 1, G Jackson 1, J Gardner-Medwin 1
PMCID: PMC1719495  PMID: 12598373

Abstract

A group of therapies with exciting potential has emerged for children and young people with severe juvenile idiopathic arthritis (JIA) uncontrolled by conventional disease modifying drugs. Theoretical understanding from molecular biologic research has identified specific targets within pathophysiological pathways that control rheumatoid arthritis (RA) and JIA. This review identifies the pathways of autoimmunity to begin to show how biologic agents have been produced to replicate, mimic, or block culpable molecules and so promote or inhibit cellular activity or proliferation. Of these agents, cytokine antagonists have shown greatest promise, and early clinical studies of tumour necrosis factor (TNF) blockade have identified dramatic clinical benefit in many children with JIA. However, as will also be discussed, overlap of pathways within a complex immune system makes clinical response unpredictable and raises additional ethical and administrative concerns.

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Figure 1 .

Figure 1

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TNFα activity. Macrophages and monocytes are a major source of TNFα, which in turn acts on these and other cells to stimulate the production of biochemical, enymatic, and cytokine mediators of inflammation. Further cellular activity ensues. Specifically TNFα acts on synoviocytes resulting in pannus formation and together with the activation of osteoclasts this results in articular erosions and reduced bone density.

Figure 2 .

Figure 2

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The three phases of the trial of etanercept in children with polyarticular JIA. In part 1 both groups received enbrel. In part 2 patients were blinded and randomised to receive enbrel or placebo. Part 3 was again open label with all patients receiving the active agent.32

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. 11 treatment of paediatric rheumatic diseases. Ann Rheum Dis. 2000 Sep;59(9):740–746. doi: 10.1136/ard.59.9.740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Almawi W. Y., Beyhum H. N., Rahme A. A., Rieder M. J. Regulation of cytokine and cytokine receptor expression by glucocorticoids. J Leukoc Biol. 1996 Nov;60(5):563–572. doi: 10.1002/jlb.60.5.563. [DOI] [PubMed] [Google Scholar]
  3. Attur M. G., Dave M. N., Stuchin S., Kowalski A. J., Steiner G., Abramson S. B., Denhardt D. T., Amin A. R. Osteopontin: an intrinsic inhibitor of inflammation in cartilage. Arthritis Rheum. 2001 Mar;44(3):578–584. doi: 10.1002/1529-0131(200103)44:3<578::AID-ANR106>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  4. Attur M. G., Dave M. N., Stuchin S., Kowalski A. J., Steiner G., Abramson S. B., Denhardt D. T., Amin A. R. Osteopontin: an intrinsic inhibitor of inflammation in cartilage. Arthritis Rheum. 2001 Mar;44(3):578–584. doi: 10.1002/1529-0131(200103)44:3<578::AID-ANR106>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  5. Auphan N., DiDonato J. A., Rosette C., Helmberg A., Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science. 1995 Oct 13;270(5234):286–290. doi: 10.1126/science.270.5234.286. [DOI] [PubMed] [Google Scholar]
  6. Breedveld F. C. Monoclonal antibodies to CD4. Rheum Dis Clin North Am. 1998 Aug;24(3):567–578. doi: 10.1016/s0889-857x(05)70026-0. [DOI] [PubMed] [Google Scholar]
  7. Bresnihan B., Alvaro-Gracia J. M., Cobby M., Doherty M., Domljan Z., Emery P., Nuki G., Pavelka K., Rau R., Rozman B. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 1998 Dec;41(12):2196–2204. doi: 10.1002/1529-0131(199812)41:12<2196::AID-ART15>3.0.CO;2-2. [DOI] [PubMed] [Google Scholar]
  8. Buchs N., di Giovine F. S., Silvestri T., Vannier E., Duff G. W., Miossec P. IL-1B and IL-1Ra gene polymorphisms and disease severity in rheumatoid arthritis: interaction with their plasma levels. Genes Immun. 2001 Jun;2(4):222–228. doi: 10.1038/sj.gene.6363766. [DOI] [PubMed] [Google Scholar]
  9. Campion G. V., Lebsack M. E., Lookabaugh J., Gordon G., Catalano M. Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. The IL-1Ra Arthritis Study Group. Arthritis Rheum. 1996 Jul;39(7):1092–1101. doi: 10.1002/art.1780390704. [DOI] [PubMed] [Google Scholar]
  10. Chernajovsky Y., Dreja H., Daly G., Annenkov A., Gould D., Adams G., Croxford J. L., Baker D., Podhajcer O. L., Mageed R. A. Immuno- and genetic therapy in autoimmune diseases. Genes Immun. 2000 Jun;1(5):295–307. doi: 10.1038/sj.gene.6363683. [DOI] [PubMed] [Google Scholar]
  11. Corral L. G., Muller G. W., Moreira A. L., Chen Y., Wu M., Stirling D., Kaplan G. Selection of novel analogs of thalidomide with enhanced tumor necrosis factor alpha inhibitory activity. Mol Med. 1996 Jul;2(4):506–515. [PMC free article] [PubMed] [Google Scholar]
  12. Date Y., Seki N., Kamizono S., Higuchi T., Hirata T., Miyata K., Ohkuni M., Tatsuzawa O., Yokota S., Joo K. Identification of a genetic risk factor for systemic juvenile rheumatoid arthritis in the 5'-flanking region of the TNFalpha gene and HLA genes. Arthritis Rheum. 1999 Dec;42(12):2577–2582. doi: 10.1002/1529-0131(199912)42:12<2577::AID-ANR10>3.0.CO;2-O. [DOI] [PubMed] [Google Scholar]
  13. De Benedetti F., Massa M., Pignatti P., Albani S., Novick D., Martini A. Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J Clin Invest. 1994 May;93(5):2114–2119. doi: 10.1172/JCI117206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dighiero G., Rose N. R. Critical self-epitopes are key to the understanding of self-tolerance and autoimmunity. Immunol Today. 1999 Sep;20(9):423–428. doi: 10.1016/s0167-5699(99)01509-1. [DOI] [PubMed] [Google Scholar]
  15. Dinarello C. A., Thompson R. C. Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro. Immunol Today. 1991 Nov;12(11):404–410. doi: 10.1016/0167-5699(91)90142-G. [DOI] [PubMed] [Google Scholar]
  16. Edwards J. C., Cambridge G., Abrahams V. M. Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology. 1999 Jun;97(2):188–196. doi: 10.1046/j.1365-2567.1999.00772.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fellowes R., Etheridge C. J., Coade S., Cooper R. G., Stewart L., Miller A. D., Woo P. Amelioration of established collagen induced arthritis by systemic IL-10 gene delivery. Gene Ther. 2000 Jun;7(11):967–977. doi: 10.1038/sj.gt.3301165. [DOI] [PubMed] [Google Scholar]
  18. Fishman D., Faulds G., Jeffery R., Mohamed-Ali V., Yudkin J. S., Humphries S., Woo P. 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. 1998 Oct 1;102(7):1369–1376. doi: 10.1172/JCI2629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Giannini E. H., Brewer E. J., Kuzmina N., Shaikov A., Maximov A., Vorontsov I., Fink C. W., Newman A. J., Cassidy J. T., Zemel L. S. 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. 1992 Apr 16;326(16):1043–1049. doi: 10.1056/NEJM199204163261602. [DOI] [PubMed] [Google Scholar]
  20. Giannini E. H., Ruperto N., Ravelli A., Lovell D. J., Felson D. T., Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum. 1997 Jul;40(7):1202–1209. doi: 10.1002/1529-0131(199707)40:7<1202::AID-ART3>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
  21. Goldrath A. W., Bevan M. J. Selecting and maintaining a diverse T-cell repertoire. Nature. 1999 Nov 18;402(6759):255–262. doi: 10.1038/46218. [DOI] [PubMed] [Google Scholar]
  22. Grom A. A., Murray K. J., Luyrink L., Emery H., Passo M. H., Glass D. N., Bowlin T., Edwards C., 3rd Patterns of expression of tumor necrosis factor alpha, tumor necrosis factor beta, and their receptors in synovia of patients with juvenile rheumatoid arthritis and juvenile spondylarthropathy. Arthritis Rheum. 1996 Oct;39(10):1703–1710. doi: 10.1002/art.1780391013. [DOI] [PubMed] [Google Scholar]
  23. Gu H., Tarlinton D., Müller W., Rajewsky K., Förster I. Most peripheral B cells in mice are ligand selected. J Exp Med. 1991 Jun 1;173(6):1357–1371. doi: 10.1084/jem.173.6.1357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Gäre B. A. Epidemiology. Baillieres Clin Rheumatol. 1998 May;12(2):191–208. doi: 10.1016/s0950-3579(98)80014-9. [DOI] [PubMed] [Google Scholar]
  25. Hanauer S. B. Review article: safety of infliximab in clinical trials. Aliment Pharmacol Ther. 1999 Sep;13 (Suppl 4):16–38. doi: 10.1046/j.1365-2036.1999.00027.x. [DOI] [PubMed] [Google Scholar]
  26. Hirano T., Akira S., Taga T., Kishimoto T. Biological and clinical aspects of interleukin 6. Immunol Today. 1990 Dec;11(12):443–449. doi: 10.1016/0167-5699(90)90173-7. [DOI] [PubMed] [Google Scholar]
  27. Isaacs J. D., Burrows N., Wing M., Keogan M. T., Rebello P. R., Watts R. A., Pye R. J., Norris P., Hazelman B. L., Hale G. Humanized anti-CD4 monoclonal antibody therapy of autoimmune and inflammatory disease. Clin Exp Immunol. 1997 Nov;110(2):158–166. doi: 10.1111/j.1365-2249.1997.tb08312.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Jones R. E., Moreland L. W. Tumor necrosis factor inhibitors for rheumatoid arthritis. Bull Rheum Dis. 1999;48(3):1–4. [PubMed] [Google Scholar]
  29. Keul R., Heinrich P. C., Müller-newen G., Muller K., Woo P. A possible role for soluble IL-6 receptor in the pathogenesis of systemic onset juvenile chronic arthritis. Cytokine. 1998 Sep;10(9):729–734. doi: 10.1006/cyto.1997.0343. [DOI] [PubMed] [Google Scholar]
  30. Kietz D. A., Pepmueller P. H., Moore T. L. Clinical response to etanercept in polyarticular course juvenile rheumatoid arthritis. J Rheumatol. 2001 Feb;28(2):360–362. [PubMed] [Google Scholar]
  31. Lechman E. R., Jaffurs D., Ghivizzani S. C., Gambotto A., Kovesdi I., Mi Z., Evans C. H., Robbins P. D. Direct adenoviral gene transfer of viral IL-10 to rabbit knees with experimental arthritis ameliorates disease in both injected and contralateral control knees. J Immunol. 1999 Aug 15;163(4):2202–2208. [PubMed] [Google Scholar]
  32. Leonard B. J. Siblings of chronically ill children: a question of vulnerability versus resilience. Pediatr Ann. 1991 Sep;20(9):501-2, 505-6. doi: 10.3928/0090-4481-19910901-09. [DOI] [PubMed] [Google Scholar]
  33. Lovell D. J., Giannini E. H., Reiff A., Cawkwell G. D., Silverman E. D., Nocton J. J., Stein L. D., Gedalia A., Ilowite N. T., Wallace C. A. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med. 2000 Mar 16;342(11):763–769. doi: 10.1056/NEJM200003163421103. [DOI] [PubMed] [Google Scholar]
  34. Marinova-Mutafchieva L., Williams R. O., Mauri C., Mason L. J., Walmsley M. J., Taylor P. C., Feldmann M., Maini R. N. A comparative study into the mechanisms of action of anti-tumor necrosis factor alpha, anti-CD4, and combined anti-tumor necrosis factor alpha/anti-CD4 treatment in early collagen-induced arthritis. Arthritis Rheum. 2000 Mar;43(3):638–644. doi: 10.1002/1529-0131(200003)43:3<638::AID-ANR21>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
  35. Markham A., Lamb H. M. Infliximab: a review of its use in the management of rheumatoid arthritis. Drugs. 2000 Jun;59(6):1341–1359. doi: 10.2165/00003495-200059060-00010. [DOI] [PubMed] [Google Scholar]
  36. Minter R. M., Ferry M. A., Murday M. E., Tannahill C. L., Bahjat F. R., Oberholzer C., Oberholzer A., LaFace D., Hutchins B., Wen S. Adenoviral delivery of human and viral IL-10 in murine sepsis. J Immunol. 2001 Jul 15;167(2):1053–1059. doi: 10.4049/jimmunol.167.2.1053. [DOI] [PubMed] [Google Scholar]
  37. Panayi G. S., Corrigall V. M., Pitzalis C. Pathogenesis of rheumatoid arthritis. The role of T cells and other beasts. Rheum Dis Clin North Am. 2001 May;27(2):317–334. doi: 10.1016/s0889-857x(05)70204-0. [DOI] [PubMed] [Google Scholar]
  38. Protheroe A., Edwards J. C., Simmons A., Maclennan K., Selby P. Remission of inflammatory arthropathy in association with anti-CD20 therapy for non-Hodgkin's lymphoma. Rheumatology (Oxford) 1999 Nov;38(11):1150–1152. doi: 10.1093/rheumatology/38.11.1150. [DOI] [PubMed] [Google Scholar]
  39. Rooney M., David J., Symons J., Di Giovine F., Varsani H., Woo P. Inflammatory cytokine responses in juvenile chronic arthritis. Br J Rheumatol. 1995 May;34(5):454–460. doi: 10.1093/rheumatology/34.5.454. [DOI] [PubMed] [Google Scholar]
  40. Rooney M., Varsani H., Martin K., Lombard P. R., Dayer J. M., Woo P. Tumour necrosis factor alpha and its soluble receptors in juvenile chronic arthritis. Rheumatology (Oxford) 2000 Apr;39(4):432–438. doi: 10.1093/rheumatology/39.4.432. [DOI] [PubMed] [Google Scholar]
  41. Sampaio E. P., Sarno E. N., Galilly R., Cohn Z. A., Kaplan G. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med. 1991 Mar 1;173(3):699–703. doi: 10.1084/jem.173.3.699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Shakoor Najia, Michalska Margaret, Harris Charlotte A., Block Joel A. Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet. 2002 Feb 16;359(9306):579–580. doi: 10.1016/S0140-6736(02)07714-0. [DOI] [PubMed] [Google Scholar]
  43. Silverstein A. M., Rose N. R. There is only one immune system! The view from immunopathology. Semin Immunol. 2000 Jun;12(3):173–344. doi: 10.1006/smim.2000.0228. [DOI] [PubMed] [Google Scholar]
  44. Thomas R., Lipsky P. E. Could endogenous self-peptides presented by dendritic cells initiate rheumatoid arthritis? Immunol Today. 1996 Dec;17(12):559–564. doi: 10.1016/s0167-5699(96)20030-1. [DOI] [PubMed] [Google Scholar]
  45. Wallace C. A. On beyond methotrexate treatment of severe juvenile rheumatoid arthritis. Clin Exp Rheumatol. 1999 Jul-Aug;17(4):499–504. [PubMed] [Google Scholar]
  46. Wallace C. A. The use of methotrexate in childhood rheumatic diseases. Arthritis Rheum. 1998 Mar;41(3):381–391. doi: 10.1002/1529-0131(199803)41:3<381::AID-ART2>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  47. Wendling D., Racadot E., Wijdenes J., Sibilia J., Flipo R. M., Cantagrel A., Miossec P., Eschard J. P., Macro M., Bertin P. A randomized, double blind, placebo controlled multicenter trial of murine anti-CD4 monoclonal antibody therapy in rheumatoid arthritis. J Rheumatol. 1998 Aug;25(8):1457–1461. [PubMed] [Google Scholar]
  48. Xu X., Williams J. W., Bremer E. G., Finnegan A., Chong A. S. Inhibition of protein tyrosine phosphorylation in T cells by a novel immunosuppressive agent, leflunomide. J Biol Chem. 1995 May 26;270(21):12398–12403. doi: 10.1074/jbc.270.21.12398. [DOI] [PubMed] [Google Scholar]
  49. Yetgin S., Ozen S., Saatci U., Bakkaloglu A., Topaloglu R., Yenicesu I., Olcay L., Okur H., Karaagaoglu E., Tuncer M. Evaluation of tumour necrosis factor alpha, interferon gamma and granulocyte-macrophage colony stimulating factor levels in juvenile chronic arthritis. Rheumatology (Oxford) 1999 May;38(5):468–471. doi: 10.1093/rheumatology/38.5.468. [DOI] [PubMed] [Google Scholar]
  50. Yocum D. E., Solinger A. M., Tesser J., Gluck O., Cornett M., O'Sullivan F., Nordensson K., Dallaire B., Shen C. D., Lipani J. Clinical and immunologic effects of a PRIMATIZED anti-CD4 monoclonal antibody in active rheumatoid arthritis: results of a phase I, single dose, dose escalating trial. J Rheumatol. 1998 Jul;25(7):1257–1262. [PubMed] [Google Scholar]
  51. de Benedetti F., Massa M., Robbioni P., Ravelli A., Burgio G. R., Martini A. Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis Rheum. 1991 Sep;34(9):1158–1163. doi: 10.1002/art.1780340912. [DOI] [PubMed] [Google Scholar]
  52. ten Hove T., van Montfrans C., Peppelenbosch M. P., van Deventer S. J. H. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease. Gut. 2002 Feb;50(2):206–211. doi: 10.1136/gut.50.2.206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. van Roon J. A., Lafeber F. P., Bijlsma J. W. Synergistic activity of interleukin-4 and interleukin-10 in suppression of inflammation and joint destruction in rheumatoid arthritis. Arthritis Rheum. 2001 Jan;44(1):3–12. doi: 10.1002/1529-0131(200101)44:1<3::AID-ANR2>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
  54. van den Berg W. B., Joosten L. A., Kollias G., van De Loo F. A. Role of tumour necrosis factor alpha in experimental arthritis: separate activity of interleukin 1beta in chronicity and cartilage destruction. Ann Rheum Dis. 1999 Nov;58 (Suppl 1):I40–I48. doi: 10.1136/ard.58.2008.i40. [DOI] [PMC free article] [PubMed] [Google Scholar]

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