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Ustekinumab

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Advances in Psoriasis

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Abstract

Ustekinumab is a fully human IgG antibody to the common p40 subunit of interleukin-12 (IL-12) and IL-23, which has shown considerable efficacy in the treatment of psoriasis and psoriatic arthritis. This review examines the efficacy and safety of ustekinumab for the treatment of psoriasis in clinical studies to date. Ustekinumab was shown to be highly effective in the treatment of moderate-to-severe psoriasis with sustained response for up to 5 years in the majority of patients. Adverse events in clinical studies to date have been for the most part, mild and similar to that in placebo-treated patients. Controversial meta-analyses, however, have generated concern regarding the cardiovascular safety of this class of drugs and some have advised caution when using ustekinumab in patients with cardiovascular risk factors until more robust, long-term safety data is available.

Conflicts of Interest

Caitriona Ryan, MD

CR has acted as a speaker for Janssen Pharmaceuticals, Inc and Pfizer, an advisory board member for Galderma, Pfizer and Abbvie, has received fellowship support from Abbvie and has received research support from Janssen Pharmaceuticals, Inc.

Craig L. Leonardi, MD

Consultant for Abbvie, Amgen, Janssen, Eli-Lilly, Leo, Pfizer and Sandoz.

Investigator for Abbott, Amgen, Anacor, Celgene, Janssen, Eli Lilly, Galderma, Glaxo Smith Kline, Incyte, Maruho, Merck, Pfizer, Schering-Plough, Sirtris, Stiefel, Leo, Novartis, Tolmar, Novo Nordisk, Vascular Biogenics, Warner Chilcott and Wyeth.

Speaker bureau for Abbvie.

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References

  1. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371(9625):1665–74.

    Article  CAS  PubMed  Google Scholar 

  2. Au SC, Goldminz AM, Kim N, et al. Investigator-initiated, open-label trial of ustekinumab for the treatment of moderate-to-severe palmoplantar psoriasis. J Dermatolog Treat 2013;24(3):179–87.

    Article  CAS  PubMed  Google Scholar 

  3. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003;3(2):133–46.

    Article  CAS  PubMed  Google Scholar 

  4. Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13(5):715–25.

    Article  CAS  PubMed  Google Scholar 

  5. Yao Z, Painter SL, Fanslow WC, et al. Human IL-17: a novel cytokine derived from T cells. J Immunol. 1995;155(12):5483–6.

    CAS  PubMed  Google Scholar 

  6. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361(5):496–509.

    Article  CAS  PubMed  Google Scholar 

  7. Lowes MA, Kikuchi T, Fuentes-Duculan J, et al. Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol. 2008;128(5):1207–11.

    Article  CAS  PubMed  Google Scholar 

  8. Murphy CA, Langrish CL, Chen Y, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med. 2003;198(12):1951–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744–8.

    Article  CAS  PubMed  Google Scholar 

  10. Ryan C, Leonardi CL, Krueger JG, et al. Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis of randomized controlled trials. JAMA. 2011;306(8):864–71.

    Article  CAS  PubMed  Google Scholar 

  11. Kauffman CL, Aria N, Toichi E, et al. A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis. J Invest Dermatol. 2004;123(6):1037–44.

    Article  CAS  PubMed  Google Scholar 

  12. Gottlieb AB, Cooper KD, McCormick TS, et al. A phase 1, double-blind, placebo-controlled study evaluating single subcutaneous administrations of a human interleukin-12/23 monoclonal antibody in subjects with plaque psoriasis. Curr Med Res Opin. 2007;23(5):1081–92.

    Article  CAS  PubMed  Google Scholar 

  13. FDA Center for Drug Evaluation and Research report 2008. See URL: http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4361b1-01-FDA.pdf. Last accessed 21 May 2014.

  14. Zhu Y, Hu C, Lu M, et al. Population pharmacokinetic modeling of ustekinumab, a human monoclonal antibody targeting IL-12/23p40, in patients with moderate to severe plaque psoriasis. J Clin Pharmacol. 2009;49(2):162–75.

    Article  CAS  PubMed  Google Scholar 

  15. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371(9625):1675–84.

    Article  CAS  PubMed  Google Scholar 

  16. Toichi E, Torres G, McCormick TS, et al. An anti-IL-12p40 antibody down-regulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis. J Immunol. 2006;177(7):4917–26.

    Article  CAS  PubMed  Google Scholar 

  17. Reddy M, Davis C, Wong J, Prabhakar U. Cutaneous lymphocyte antigen expression on activated lymphocytes and its association with IL-12R (beta1 and beta2), IL-2Ralpha, and CXCR3. Cell Immunol. 2005;236(1–2):131–9.

    Article  CAS  PubMed  Google Scholar 

  18. Kimball AB, Gordon KB, Fakharzadeh S, et al. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years. Br J Dermatol. 2012;166(4):861–72.

    Article  CAS  PubMed  Google Scholar 

  19. Griffiths CE, Strober BE, van de Kerkhof P, et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010;362(2):118–28.

    Article  CAS  PubMed  Google Scholar 

  20. Gottlieb A, Menter A, Mendelsohn A, et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet. 2009;373(9664):633–40.

    Article  CAS  PubMed  Google Scholar 

  21. McInnes IB, Kavanaugh A, Gottlieb AB, et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013;382(9894):780–9.

    Article  CAS  PubMed  Google Scholar 

  22. Lebwohl M, Leonardi C, Griffiths CE, et al. Long-term safety experience of ustekinumab in patients with moderate-to-severe psoriasis (Part I of II): Results from analyses of general safety parameters from pooled Phase 2 and 3 clinical trials. J Am Acad Dermatol. 2012;66(5):731–41.

    Article  CAS  PubMed  Google Scholar 

  23. Gordon KB, Papp KA, Langley RG, et al. Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis (Part II of II): Results from analyses of infections and malignancy from pooled phase II and III clinical trials. J Am Acad Dermatol. 2012;66(5):742–51.

    Article  CAS  PubMed  Google Scholar 

  24. Reich K, Papp KA, Griffiths CE, et al. An update on the long-term safety experience of ustekinumab: results from the psoriasis clinical development program with up to four years of follow-up. J Drugs Dermatol. 2012;11(3):300–12.

    CAS  PubMed  Google Scholar 

  25. Livonesi MC, Souto JT, Campanelli AP, et al. Deficiency of IL-12p40 subunit determines severe paracoccidioidomycosis in mice. Med Mycol. 2008;46(7):637–46.

    Article  CAS  PubMed  Google Scholar 

  26. de Jong R, Altare F, Haagen IA, et al. Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science. 1998;280(5368):1435–8.

    Article  PubMed  Google Scholar 

  27. Fieschi C, Casanova JL. The role of interleukin-12 in human infectious diseases: only a faint signature. Eur J Immunol. 2003;33(6):1461–4.

    Article  CAS  PubMed  Google Scholar 

  28. Fieschi C, Dupuis S, Catherinot E, et al. Low penetrance, broad resistance, and favorable outcome of interleukin 12 receptor beta1 deficiency: medical and immunological implications. J Exp Med. 2003;197(4):527–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Sanal O, Turul T, De Boer T, et al. Presentation of interleukin-12/-23 receptor beta1 deficiency with various clinical symptoms of Salmonella infections. J Clin Immunol. 2006;26(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  30. Carr JA, Rogerson J, Mulqueen MJ, Roberts NA, Booth RF. Interleukin-12 exhibits potent antiviral activity in experimental herpesvirus infections. J Virol. 1997;71(10):7799–803.

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Gazzinelli RT, Giese NA, Morse HC. In vivo treatment with interleukin 12 protects mice from immune abnormalities observed during murine acquired immunodeficiency syndrome (MAIDS). J Exp Med. 1994;180(6):2199–208.

    Article  CAS  PubMed  Google Scholar 

  32. Ozmen L, Aguet M, Trinchieri G, Garotta G. The in vivo antiviral activity of interleukin-12 is mediated by gamma interferon. J Virol. 1995;69(12):8147–50.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Milich DR, Wolf SF, Hughes JL, Jones JE. Interleukin 12 suppresses autoantibody production by reversing helper T-cell phenotype in hepatitis B e antigen transgenic mice. Proc Natl Acad Sci U S A. 1995;92(15):6847–51.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Hoag KA, Lipscomb MF, Izzo AA, Street NE. IL-12 and IFN-gamma are required for initiating the protective Th1 response to pulmonary cryptococcosis in resistant C.B-17 mice. Am J Respir Cell Mol Biol. 1997;17(6):733–9.

    Article  CAS  PubMed  Google Scholar 

  35. Decken K, Köhler G, Palmer-Lehmann K, et al. Interleukin-12 is essential for a protective Th1 response in mice infected with Cryptococcus neoformans. Infect Immun. 1998;66(10):4994–5000.

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Lieberman LA, Cardillo F, Owyang AM, et al. IL-23 provides a limited mechanism of resistance to acute toxoplasmosis in the absence of IL-12. J Immunol. 2004;173(3):1887–93.

    Article  CAS  PubMed  Google Scholar 

  37. Orgun NN, Mathis MA, Wilson CB, Way SS. Deviation from a strong Th1-dominated to a modest Th17-dominated CD4 T cell response in the absence of IL-12p40 and type I IFNs sustains protective CD8 T cells. J Immunol. 2008;180(6):4109–15.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Henry CJ, Grayson JM, Brzoza-Lewis KL, et al. The roles of IL-12 and IL-23 in CD8+ T cell-mediated immunity against Listeria monocytogenes: Insights from a DC vaccination model. Cell Immunol. 2010;264(1):23–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Wozniak TM, Saunders BM, Ryan AA, Britton WJ. Mycobacterium bovis BCG-specific Th17 cells confer partial protection against Mycobacterium tuberculosis infection in the absence of gamma interferon. Infect Immun. 2010;78(10):4187–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Chackerian AA, Chen SJ, Brodie SJ, et al. Neutralization or absence of the interleukin-23 pathway does not compromise immunity to mycobacterial infection. Infect Immun. 2006;74(11):6092–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Lima HC, Kimball AB. Targeting IL-23: insights into the pathogenesis and the treatment of psoriasis. Indian J Dermatol. 2010;55(2):171–5.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Khader SA, Pearl JE, Sakamoto K, et al. IL-23 compensates for the absence of IL-12p70 and is essential for the IL-17 response during tuberculosis but is dispensable for protection and antigen-specific IFN-gamma responses if IL-12p70 is available. J Immunol. 2005;175(2):788–95.

    Article  CAS  PubMed  Google Scholar 

  43. Happel KI, Dubin PJ, Zheng M, et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J Exp Med. 2005;202(6):761–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Rudner XL, Happel KI, Young EA, Shellito JE. Interleukin-23 (IL-23)-IL-17 cytokine axis in murine Pneumocystis carinii infection. Infect Immun. 2007;75(6):3055–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Tsai TF, Ho JC, Song M, et al. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci. 2011;63(3):154–63.

    Article  CAS  PubMed  Google Scholar 

  46. Brunda MJ, Luistro L, Warrier RR, et al. Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med. 1993;178(4):1223–30.

    Article  CAS  PubMed  Google Scholar 

  47. Cifaldi L, Quaglino E, Di Carlo E, et al. A light, nontoxic interleukin 12 protocol inhibits HER-2/neu mammary carcinogenesis in BALB/c transgenic mice with established hyperplasia. Cancer Res. 2001;61(7):2809–12.

    CAS  PubMed  Google Scholar 

  48. Cavallo F, Quaglino E, Cifaldi L, et al. Interleukin 12-activated lymphocytes influence tumor genetic programs. Cancer Res. 2001;61(8):3518–23.

    CAS  PubMed  Google Scholar 

  49. Langowski JL, Zhang X, Wu L, et al. IL-23 promotes tumour incidence and growth. Nature. 2006;442(7101):461–5.

    Article  CAS  PubMed  Google Scholar 

  50. Tzellos T, Kyrgidis A, Zouboulis CC. Re-evaluation of the risk for major adverse cardiovascular events in patients treated with anti-IL-12/23 biological agents for chronic plaque psoriasis: a meta-analysis of randomized controlled trials. J Eur Acad Dermatol Venereol. 2013;27(5):622–7.

    Article  CAS  PubMed  Google Scholar 

  51. Dommasch ED, Troxel AB, Gelfand JM. Major cardiovascular events associated with anti-IL 12/23 agents: a tale of two meta-analyses. J Am Acad Dermatol. 2013;68(5):863–5.

    Article  CAS  PubMed  Google Scholar 

  52. Bigby M. The use of anti-interleukin-12/23 agents and major adverse cardiovascular events. Arch Dermatol. 2012;148(6):753–4.

    PubMed  Google Scholar 

  53. Greenland S, Salvan A. Bias in the one-step method for pooling study results. Stat Med. 1990;9(3):247–52.

    Article  CAS  PubMed  Google Scholar 

  54. Papp KA, Griffiths CE, Gordon K, et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br J Dermatol. 2013;168(4):844–54.

    Article  CAS  PubMed  Google Scholar 

  55. Reich K, Langley RG, Lebwohl M, et al. Cardiovascular safety of ustekinumab in patients with moderate to severe psoriasis: results of integrated analyses of data from phase II and III clinical studies. Br J Dermatol. 2011;164(4):862–72.

    Article  CAS  PubMed  Google Scholar 

  56. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology. 2008;135(4):1130–41.

    Article  CAS  PubMed  Google Scholar 

  57. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007;356(6):580–92.

    Article  CAS  PubMed  Google Scholar 

  58. Stelara prescribing information. See URL: http://www.stelarainfo.com/pdf/PrescribingInformation.pdf.%C2%A0. Last accessed 21 June 2012.

  59. Gordon KB, Langley RG, Gottlieb AB, et al. A phase III, randomized, controlled trial of the fully human IL-12/23 mAb briakinumab in moderate-to-severe psoriasis. J Invest Dermatol. 2012;132(2):304–14.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Dermatology, Baylor University Medical Center, 3900 Junius St. Suite 125, Dallas, TX, 75245, USA

    Caitriona Ryan MD, MRCPI

  2. Department of Dermatology, Saint Louis University School of Medicine, 1034 S. Brentwood Blvd., Suite 600, St. Louis, MO, 63117, USA

    Craig L. Leonardi MD

Authors
  1. Caitriona Ryan MD, MRCPI
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  2. Craig L. Leonardi MD
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Correspondence to Caitriona Ryan MD, MRCPI .

Editor information

Editors and Affiliations

  1. St. Luke's -Roosevelt Hospital Center, New York, New York, USA

    Jeffrey M. Weinberg

  2. Department of Dermatology, Icahn School of Medicine, New York, New York, USA

    Mark Lebwohl

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Ryan, C., Leonardi, C.L. (2014). Ustekinumab. In: Weinberg, J., Lebwohl, M. (eds) Advances in Psoriasis. Springer, London. https://doi.org/10.1007/978-1-4471-4432-8_15

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  • DOI: https://doi.org/10.1007/978-1-4471-4432-8_15

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