Interleukin-6 Targeted Therapies in Pediatric Rheumatology

cocukromatolojisi-5-1-2024

Nergis AKAYa , Ümit GÜLa , Sezgin ŞAHİNa

aİstanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Department of Pediatric Rheumatology, İstanbul, Türkiye

ABSTRACT
The usage and preference of selectively targeting biological agents in pediatric rheumatology setting are steadily increasing with the elucidation of the pathophysiology of rheumatological diseases. Uncontrolled inflammation in joints and/or many organ systems is responsible from the manifestations of rheumatological diseases. Upon stimulation of the innate and/or adaptive immune system, release of various cytokines leads to the development of clinical and laboratory findings. One of these cytokines is interleukin-6 (IL-6), which was first stated as a soluble factor released from T-cells in 1973. With the understanding the crucial role of IL-6 in chronic inflammation, researchers focused on IL-6 pathway to develop targeted treatments. Especially in the last two decades, many studies showed that humanized monoclonal antibody targeting IL-6R, namely tocilizumab, is effective in the treatment of systemic and polyarticular juvenile idiopathic arthritis, systemic large-vessel vasculitis (specifically Takayasu arteritis), juvenile scleroderma as well as in many other rare rheumatic diseases. In this article we tried to recap IL-6 targeted therapies in pediatric rheumatology.
Keywords: Arthritis; pediatric rheumatology; cytokine; inflammation; interleukin-6; tocilizumab

Referanslar

  1. Hirano T, Taga T, Yasukawa K, Nakajima K, Nakano N, Takatsuki F, et al. Human B-cell differentiation factor defined by an anti-peptide antibody and its possible role in autoantibody production. Proc Natl Acad Sci U S A. 1987;84(1):228-31. [Crossref]  [PubMed]  [PMC]
  2. Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B, et al. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 1988;18(11):1797-801. [Crossref]  [PubMed]
  3. Yoshizaki K, Matsuda T, Nishimoto N, Kuritani T, Taeho L, Aozasa K, et al. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease. Blood. 1989;74(4):1360-7. [Crossref]  [PubMed]
  4. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature. 1988;332(6159):83-5. [Crossref]  [PubMed]
  5. Nishimoto N, Yoshizaki K, Tagoh H, Monden M, Kishimoto S, Hirano T, et al. Elevation of serum interleukin 6 prior to acute phase proteins on the inflammation by surgical operation. Clin Immunol Immunopathol. 1989;50(3):399-401. [Crossref]  [PubMed]
  6. Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S, et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 2005;106(8):2627-32. [Crossref]  [PubMed]
  7. Sato K, Tsuchiya M, Saldanha J, Koishihara Y, Ohsugi Y, Kishimoto T, et al. Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth. Cancer Res. 1993;53(4):851-6.
  8. Kishimoto T. Interleukin-6: from basic science to medicine-40 years in immunology. Annu. Rev. Immunol. 2005;23:1-21. [Crossref]  [PubMed]
  9. Choy EH, De Benedetti F, Takeuchi T, Hashizume M, John MR, Kishimoto T. Translating IL-6 biology into effective treatments. Nature Reviews Rheumatology. 2020;16(6):335-45. [Crossref]  [PubMed]  [PMC]
  10. Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harbor perspectives in biology. 2014;6(10):a016295. [Crossref]  [PubMed]  [PMC]
  11. Kastrati K, Aletaha D, Burmester GR, et al. A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases. RMD open. 2022;8(2):e002359. [Crossref]  [PubMed]  [PMC]
  12. Ebata S, Yoshizaki-Ogawa A, Sato S, Yoshizaki A. New era in systemic sclerosis treatment: recently approved therapeutics. Journal of Clinical Medicine. 2022;11(15):4631. [Crossref]  [PubMed]  [PMC]
  13. Boyce EG, Rogan EL, Vyas D, Prasad N, Mai Y. Sarilumab: review of a second IL-6 receptor antagonist indicated for the treatment of rheumatoid arthritis. Annals of Pharmacotherapy. 2018;52(8):780-91. [Crossref]  [PubMed]
  14. Clinicaltrials. U.S Department of Health and Human Services, National Library of Medicine. Available from: [Link]
  15. de Benedetti F, Massa M, Robbioni P, Ravelli A, Burgio GR, Martini A. Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis Rheum. 1991; 34(9):1158-63. [Crossref]  [PubMed]
  16. De Benedetti F, Robbioni P, Massa M, Viola S, Albani S, Martini A. Serum interleukin-6 levels and joint involvement in polyarticular and pauciarticular juvenile chronic arthritis. Clinical and experimental rheumatology. 1992;10(5):493-8.
  17. De Benedetti F, Pignatti P, Gerloni V, et al. Differences in synovial fluid cytokine levels between juvenile and adult rheumatoid arthritis. The Journal of rheumatology. 1997;24(7):1403-9.
  18. Mangge H, Kenzian H, Gallistl S, et al. Serum cytokines in juvenile rheumatoid arthritis: correlation with conventional inflammation parameters and clinical subtypes. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 1995;38(2):211-20. [Crossref]  [PubMed]
  19. Rooney M, David J, Symons J, Giovine Fd, Varsani H, Woo P. Inflammatory cytokine responses in juvenile chronic arthritis. Rheumatology. 1995;34(5):454-60. [Crossref]  [PubMed]
  20. Keul R, Heinrich P, 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;10(9):729-34. [Crossref]  [PubMed]
  21. Yokota S, Miyamae T, Imagawa T, et al. Therapeutic efficacy of humanized recombinant anti-interleukin‐6 receptor antibody in children with systemic‐onset juvenile idiopathic arthritis. Arthritis & Rheumatism. 2005;52(3):818-25. [Crossref]  [PubMed]
  22. Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. The Lancet. 2008;371(9617):998-1006. [Crossref]  [PubMed]
  23. Imagawa T, Yokota S, Mori M, et al. Safety and efficacy of tocilizumab, an anti-IL-6-receptor monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis. Modern rheumatology. 2012;22(1):109-15. [Crossref]  [PubMed]
  24. De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. New England Journal of Medicine. 2012;367(25):2385-95. [Crossref]  [PubMed]
  25. Brunner H, Ruperto N, Zuber Z, et al. Efficacy and Safety of Tocilizumab in Patients with Polyarticular Juvenile Idiopathic Arthritis: Data From a Phase 3 Trial. Paper presented at: Arthritis and Rheumatism. 2012.
  26. Frampton JE. Tocilizumab: a review of its use in the treatment of juvenile idiopathic arthritis. Pediatric Drugs. 2013;15:515-31. [Crossref]  [PubMed]
  27. Barut K, Adrovic A, Sahin S, et al. Prognosis, complications and treatment response in systemic juvenile idiopathic arthritis patients: a single‐center experience. International Journal of Rheumatic Diseases. 2019;22(9):1661-9. [Crossref]  [PubMed]
  28. Sözeri B, Demir F, Barut K, et al. Evaluation of clinical outcomes in systemic juvenile idiopathic arthritis patients treated with biological agents in Turkey: the TURSIS study. Clinical and Experimental Rheumatology. 2023. [Crossref]
  29. Yazılıtaş F, Özdel S, Şimşek D, et al. Tocilizumab for juvenile idiopathic arthritis: a single-center case series. Sao Paulo Medical Journal. 2020;137:517-22. [Crossref]  [PubMed]  [PMC]
  30. Brunner HI, Ruperto N, Zuber Z, et al. Efficacy and safety of tocilizumab for polyarticular‐course juvenile idiopathic arthritis in the open‐label two‐year extension of a phase III trial. Arthritis & Rheumatology. 2021;73(3):530-41. [Crossref]  [PubMed]  [PMC]
  31. Grönlund MM, Remes-Pakarinen T, Kröger L, et al. Efficacy and safety of tocilizumab in a real-life observational cohort of patients with polyarticular juvenile idiopathic arthritis. Rheumatology. 2020;59(4):732-41. [Crossref]  [PubMed]
  32. Opoka-Winiarska V, Żuber Z, Alexeeva E, et al. Long-term, interventional, open-label extension study evaluating the safety of tocilizumab treatment in patients with polyarticular-course juvenile idiopathic arthritis from Poland and Russia who completed the global, international CHERISH trial. Clinical Rheumatology. 2018;37:1807-16. [Crossref]  [PubMed]  [PMC]
  33. Kasapçopur Ö, Barut K. Treatment in juvenile rheumatoid arthritis and new treatment options. Turkish Archives of Pediatrics/Türk Pediatri Arşivi. 2015;50(1):1. [Crossref]  [PubMed]  [PMC]
  34. Brunner HI, Ruperto N, Zuber Z, et al. Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial. Annals of the rheumatic diseases. 2015;74(6):1110-7. [Crossref]  [PubMed]  [PMC]
  35. Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11. [Crossref]  [PubMed]
  36. Arnaud L, Haroche J, Mathian A, Gorochov G, Amoura Z. Pathogenesis of Takayasu's arteritis: a 2011 update. Autoimmunity reviews. 2011;11(1):61-7. [Crossref]  [PubMed]
  37. Park M, Lee S, Park Y, Lee S. Serum cytokine profiles and their correlations with disease activity in Takayasu's arteritis. Rheumatology. 2006;45(5):545-8. [Crossref]  [PubMed]
  38. Clifford A, Hoffman GS. Recent advances in the medical management of Takayasu arteritis: an update on use of biologic therapies. Current opinion in rheumatology. 2014;26(1):7-15. [Crossref]  [PubMed]
  39. Mathew AJ, Goel R, Kumar S, Danda D. Childhood‐onset Takayasu arteritis: an update. International journal of rheumatic diseases. 2016;19(2):116-26. [Crossref]  [PubMed]
  40. Abisror N, Mekinian A, Lavigne C, Vandenhende MA, Soussan M, Fain O. Tocilizumab in refractory Takayasu arteritis: a case series and updated literature review. Autoimmunity reviews. 2013;12(12):1143-9. [Crossref]  [PubMed]
  41. Goel R, Danda D, Kumar S, Joseph G. Rapid control of disease activity by tocilizumab in 10 'difficult‐to‐treat'cases of Takayasu arteritis. International journal of rheumatic diseases. 2013;16(6):754-61. [Crossref]  [PubMed]
  42. Batu ED, Sönmez HE, Hazırolan T, Özaltın F, Bilginer Y, Özen S. Tocilizumab treatment in childhood Takayasu arteritis: Case series of four patients and systematic review of the literature. Semin Arthritis Rheum. 2017;46(4):529-35. [Crossref]  [PubMed]
  43. Adrovic A, Yildiz M, Haslak F, et al. Tocilizumab therapy in juvenile systemic sclerosis: A retrospective single centre pilot study. Rheumatology International. 2021;41(1):121-8. [Crossref]  [PubMed]
  44. Ventéjou S, Schwieger-Briel A, Nicolai R, et al. Case report: pansclerotic morphea-clinical features, differential diagnoses and modern treatment concepts. Frontiers in Immunology. 2021;12:656407. [Crossref]  [PubMed]  [PMC]
  45. Jung JY, Kim MY, Suh CH, Kim HA. Off-label use of tocilizumab to treat non-juvenile idiopathic arthritis in pediatric rheumatic patients: a literature review. Pediatric Rheumatology. 2018;16:1-9. [Crossref]  [PubMed]  [PMC]
  46. Lythgoe H, Baildam E, Beresford MW, Cleary G, McCann LJ, Pain CE. Tocilizumab as a potential therapeutic option for children with severe, refractory juvenile localized scleroderma. Rheumatology. 2018;57(2):398-401. [Crossref]  [PubMed]
  47. Koga T, Sato S, Miyamoto J, et al. Comparison of the efficacy and safety of tocilizumab for colchicine-resistant or colchicine-intolerant familial Mediterranean fever: study protocol for an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial. Trials. 2018;19:1-9. [Crossref]  [PubMed]  [PMC]
  48. Raj R, Uppuluri R, Venkateswaran VS. Tocilizumab Use in Children with Cytokine Release Syndrome. Indian Pediatr. 2021;58(2):186-7. [Crossref]  [PubMed]
  49. Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, et al. FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome. Oncologist. 2018;23(8):943-7. [Crossref]  [PubMed]  [PMC]