Skip to main content
Log in

Targeting the IL-23/IL-17 Pathway in Psoriasis: the Search for the Good, the Bad and the Ugly

  • Leading Article
  • Published:
American Journal of Clinical Dermatology Aims and scope Submit manuscript

Abstract

New promising treatments have been developed for psoriasis that target different parts of the interleukin (IL)-23/IL-17 pathway. This approach is believed to be more disease specific, and sparing the T helper 1 pathway might prevent serious long-term adverse events. Moreover, superior Psoriasis Area and Severity Index improvements are observed, which has redefined treatment goals in psoriasis. The new molecules can be divided into different categories, according to the target: blocking agents can target the upstream cytokine IL-23 or the downstream IL-17. In the latter, a variety of targets exist, such as the ligands IL-17A and IL-17F, or a combination thereof, or a subunit of the receptor, IL-17RA. Each target seems to have its own set of advantages and pitfalls, which will impact the treatment decision in clinical practice. In this review, we summarize the current knowledge on the different inhibitors of the IL-23/IL-17 pathway. Furthermore, we briefly discuss the role of IL-17 in other diseases and comorbidities. Finally, we discuss how comprehensive knowledge is needed for the prescribing physician in order to make the most appropriate therapeutic choice for each individual patient.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Cooper KD, Voorhees JJ, Fisher GJ, Chan LS, Gupta AK, Baadsgaard O. Effects of cyclosporine on immunologic mechanisms in psoriasis. J Am Acad Dermatol. 1990;23:1318–28.

    Article  PubMed  CAS  Google Scholar 

  2. Weinstein GD, Jeffes E, McCullough JL. Cytotoxic and immunologic effects of methotrexate in psoriasis. J Invest Dermatol. 1990;95:S49–52.

    Article  Google Scholar 

  3. Roenigk HH, Auerbach R, Maibach HI, Weinstein GD. Methotrexate in psoriasis: revised guidelines. J Am Acad Dermatol. 1988;19:145–56.

    Article  PubMed  Google Scholar 

  4. Gearing AJ, Fincham NJ, Bird CR, Wadhwa M, Meager A, Cartwright JE, et al. Cytokines in skin lesions of psoriasis. Cytokine. 1990;2:68–75.

    Article  PubMed  CAS  Google Scholar 

  5. Zaba LC, Suárez-Fariñas M, Fuentes-Duculan J, Nograles KE, Guttman-Yassky E, Cardinale I, et al. Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes. J Allergy Clin Immunol. 2009;124:1022–1010.e1-395.

  6. Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med. 2008;14:275–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Matsuzaki G, Umemura M. Interleukin-17 family cytokines in protective immunity against infections: role of hematopoietic cell-derived and non-hematopoietic cell-derived interleukin-17s. Microbiol Immunol. 2018;62:1–13.

    Article  PubMed  CAS  Google Scholar 

  8. Blauvelt A, Lebwohl MG, Bissonnette R. IL-23/IL-17A dysfunction phenotypes inform possible clinical effects from anti-IL-17A therapies. J Invest Dermatol. 2015;135:1946–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science. 2011;332:65–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Johansen C, Usher P a., Kjellerup R b., Lundsgaard D, Iversen L, Kragballe K. Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Br J Dermatol. 2009;160:319–24.

  11. Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, et al. Development, cytokine profile and function of human interleukin 17–producing helper T cells. Nat Immunol. 2007;8:950–7.

    Article  PubMed  CAS  Google Scholar 

  12. Zaba LC, Cardinale I, Gilleaudeau P, Sullivan-Whalen M, Suárez-Fariñas M, Fuentes-Duculan J, et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med. 2007;204:3183–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature. 2007;445:866–73.

    Article  PubMed  CAS  Google Scholar 

  14. Arican O, Aral M, Sasmaz S, Ciragil P. Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediat Inflamm. 2005;2005:273–9.

    Article  CAS  Google Scholar 

  15. Soderstrom C, Berstein G, Zhang W, Valdez H, Fitz L, Kuhn M, et al. Ultra-sensitive measurement of IL-17A and IL-17F in psoriasis patient serum and skin. AAPS J. 2017;19:1218–22.

    Article  PubMed  CAS  Google Scholar 

  16. Liblau RS, Singer SM, McDevitt HO. Th1 and Th2 CD4 + T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today. 1995;16:34–8.

    Article  PubMed  CAS  Google Scholar 

  17. Allen JE, Maizels RM. Th1-Th2: reliable paradigm or dangerous dogma? Immunology today. Elsevier. 1997;18:387–92.

    CAS  Google Scholar 

  18. Sonobe Y, Jin S, Wang J, Kawanokuchi J, Takeuchi H, Mizuno T, et al. Chronological changes of CD4(+) and CD8(+) T cell subsets in the experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Tohoku J Exp Med. 2007;213:329–39.

    Article  PubMed  CAS  Google Scholar 

  19. Gran B, Zhang G-X, Yu S, Li J, Chen X-H, Ventura ES, et al. IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J Immunol. 2002;169:7104–10.

    Article  PubMed  CAS  Google Scholar 

  20. Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med. 2003;198:1951–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Nakajima K, Sano S. Mouse models of psoriasis and their relevance. J Dermatol. 2018;45:252–63.

    Article  PubMed  Google Scholar 

  22. Chiricozzi A, Saraceno R, Chimenti MS, Guttman-Yassky E, Krueger JG. Role of IL-23 in the pathogenesis of psoriasis: a novel potential therapeutic target? Expert Opin Ther Targets. 2014;18:513–25.

    Article  PubMed  CAS  Google Scholar 

  23. Li H, Yao Q, Mariscal AG, Wu X, Hülse J, Pedersen E, et al. Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation. Nat Commun. 2018;9:1420.

  24. Piskin G, Tursen U, Sylva-Steenland RMR, Bos JD, Teunissen MBM. Clinical improvement in chronic plaque-type psoriasis lesions after narrow-band UVB therapy is accompanied by a decrease in the expression of IFN-gamma inducers—IL-12, IL-18 and IL-23. Exp Dermatol. 2004;13:764–72.

    Article  PubMed  CAS  Google Scholar 

  25. Gottlieb AB, Chamian F, Masud S, Cardinale I, Abello MV, Lowes MA, et al. TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol. 2005;175:2721–9.

    Article  PubMed  CAS  Google Scholar 

  26. Russell CB, K Kerkof, Bigler, J. Blockade of the IL-17R with AMG 827 leads to rapid reversal of gene expression and histopathologic abnormalities in psoriatic skin, including substantial pathway-specific effects within one week (abstract 065). J Investig Dermatol. 2011;131:S11.

  27. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte 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;13:715–25.

    Article  PubMed  CAS  Google Scholar 

  28. Chen X, Tan Z, Yue Q, Liu H, Liu Z, Li J. The expression of interleukin-23 (p19/p40) and interleukin-12 (p35/p40) in psoriasis skin. J Huazhong Univ Sci Technol Med Sci. 2006;26:750–2.

    Article  CAS  Google Scholar 

  29. Kulig P, Musiol S, Freiberger SN, Schreiner B, Gyülveszi G, Russo G, et al. IL-12 protects from psoriasiform skin inflammation. Nat Comm. 2016;7:13466.

    Article  CAS  Google Scholar 

  30. Harden JL, Johnson-Huang LM, Chamian MF, Lee E, Pearce T, Leonardi CL, et al. Humanized anti–IFN-γ (HuZAF) in the treatment of psoriasis. J Allergy Clin Immunol. 2015;135(553–556):e3.

    Google Scholar 

  31. Lo C-H, Lee S-C, Wu P-Y, Pan W-Y, Su J, Cheng C-W, et al. Antitumor and antimetastatic activity of IL-23. J Immunol. 2003;171:600–7.

    Article  PubMed  CAS  Google Scholar 

  32. Hymowitz SG, Filvaroff EH, Yin JP, Lee J, Cai L, Risser P, et al. IL-17 s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding. EMBO J. 2001;20:5332–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Pappu R, Ramirez-Carrozzi V, Ota N, Ouyang W, Hu Y. The IL-17 family cytokines in immunity and disease. J Clin Immunol. 2010;30:185–95.

    Article  PubMed  CAS  Google Scholar 

  34. Ishigame H, Kakuta S, Nagai T, Kadoki M, Nambu A, Komiyama Y, et al. Differential roles of interleukin-17a and -17f in host defense against mucoepithelial bacterial infection and allergic responses. Immunity. 2009;30:108–19.

    Article  PubMed  CAS  Google Scholar 

  35. Yang XO, Chang SH, Park H, Nurieva R, Shah B, Acero L, et al. Regulation of inflammatory responses by IL-17F. J Exp Med. 2008;205:1063–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Li H, Chen J, Huang A, Stinson J, Heldens S, Foster J, et al. Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family. Proc Natl Acad Sci USA. 2000;97:773–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Ramirez-Carrozzi V, Sambandam A, Luis E, Lin Z, Jeet S, Lesch J, et al. IL-17C regulates the innate immune function of epithelial cells in an autocrine manner. Nat Immunol. 2011;12:1159–66.

    Article  PubMed  CAS  Google Scholar 

  38. Song X, Zhu S, Shi P, Liu Y, Shi Y, Levin SD, et al. IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens. Nat Immunol. 2011;12:1151.

    Article  PubMed  CAS  Google Scholar 

  39. Chang SH, Reynolds JM, Pappu BP, Chen G, Martinez GJ, Dong C. Interleukin-17C promotes Th17 cell responses and autoimmune disease via interleukin-17 receptor E. Immunity. 2011;35:611–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Johnston A, Fritz Y, Dawes SM, Diaconu D, Al-Attar PM, Guzman AM, et al. Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation. J Immunol. 2013;190:2252–62.

    Article  PubMed  CAS  Google Scholar 

  41. Morizane S, Nomura H, Tachibana K, Nakagawa Y, Iwatsuki K. The synergistic activities of the combination of TNF-α, IL-17A, and IFN-γ in epidermal keratinocytes. Br J Dermatol. 2018. https://doi.org/10.1111/bjd.16443.

    Article  PubMed  Google Scholar 

  42. Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity. 2004;21:467–76.

    Article  PubMed  CAS  Google Scholar 

  43. Senra L, Stalder R, Alvarez Martinez D, Chizzolini C, Boehncke W-H, Brembilla NC. Keratinocyte-derived IL-17E contributes to inflammation in psoriasis. J Investig Dermatol. 2016;136:1970–80.

    Article  PubMed  CAS  Google Scholar 

  44. Xu M, Dong C. IL-25 in allergic inflammation. Immunol Rev. 2017;278:185–91.

    Article  PubMed  CAS  Google Scholar 

  45. Reynolds JM, Lee Y-H, Shi Y, Wang X, Angkasekwinai P, Nallaparaju KC, et al. Interleukin-17B antagonizes interleukin-25-mediated mucosal inflammation. Immunity. 2015;42:692–703.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. von Moltke J, Ji M, Liang H-E, Locksley RM. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature. 2016;529:221–5.

    Article  CAS  Google Scholar 

  47. Wang A-J, Yang Z, Grinchuk V, Smith A, Qin B, Lu N, et al. IL-25 or IL-17E protects against high-fat diet–induced hepatic steatosis in mice dependent upon IL-13 activation of STAT6. J Immunol. 2015;195:4771–80.

    Article  PubMed  CAS  Google Scholar 

  48. Zhang Y, Zhang Y, Wang Y, Wang Y, Li M-Q, Li M-Q, et al. IL-25 promotes Th2 bias by upregulating IL-4 and IL-10 expression of decidual γδT cells in early pregnancy. Exp Ther Med. 2018;15:1855–62.

    PubMed  Google Scholar 

  49. Ziolkowska M, Koc A, Luszczykiewicz G, Ksiezopolska-Pietrzak K, Klimczak E, Chwalinska-Sadowska H, et al. High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin a-sensitive mechanism. J Immunol. 2000;164:2832–8.

    Article  PubMed  CAS  Google Scholar 

  50. Albanesi C, Scarponi C, Cavani A, Federici M, Nasorri F, Girolomoni G. Interleukin-17 is produced by both Th1 and Th2 lymphocytes, and modulates interferon-gamma- and interleukin-4-induced activation of human keratinocytes. J Invest Dermatol. 2000;115:81–7.

    Article  PubMed  CAS  Google Scholar 

  51. Chan JR, Blumenschein W, Murphy E, Diveu C, Wiekowski M, Abbondanzo S, et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2–dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med. 2006;203:2577–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Krueger JG, Fretzin S, Suárez-Fariñas M, Haslett PA, Phipps KM, Cameron GS, et al. IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis. J Allergy Clin Immunol. 2012;130(145–154):e9.

    Google Scholar 

  53. Liao W, Hei TK, Cheng SK. Radiation-induced dermatitis is mediated by IL17-expressing γδ T cells. Radiat Res. 2017;187:464–74.

    Article  Google Scholar 

  54. Speeckaert R, Lambert J, Grine L, Van Gele M, De Schepper S, van Geel N. The many faces of interleukin-17 in inflammatory skin diseases. Br J Dermatol. 2016;175:892–901.

    Article  PubMed  CAS  Google Scholar 

  55. Bissonnette R, Fuentes-Duculan J, Mashiko S, Li X, Bonifacio KM, Cueto I, et al. Palmoplantar pustular psoriasis (PPPP) is characterized by activation of the IL-17A pathway. J Dermatol Sci. 2017;85:20–6.

    Article  PubMed  CAS  Google Scholar 

  56. Conrad C, Gilliet M. Psoriasis: from pathogenesis to targeted therapies. Clin Rev Allerg Immunol. 2018. https://doi.org/10.1007/s12016-018-8668-1.

    Article  Google Scholar 

  57. Atwa Mona A., Youssef Nahed, Bayoumy Nervana M. T-helper 17 cytokines (interleukins 17, 21, 22, and 6, and tumor necrosis factor-α) in patients with alopecia areata: association with clinical type and severity. Int J Dermatol. 2016;55:666–72.

  58. Arakawa M, Dainichi T, Ishii N, Hamada T, Karashima T, Nakama T, et al. Lesional Th17 cells and regulatory T cells in bullous pemphigoid. Exp Dermatol. 2011;20:1022–4.

    Article  PubMed  CAS  Google Scholar 

  59. Tauber M, Beneton N, Reygagne P, Bachelez H, Viguier M. Alopecia areata developing during ustekinumab therapy: report of two cases. Eur J Dermatol. 2013;23:912–3.

    PubMed  Google Scholar 

  60. Grine L, Dejager L, Libert C, Vandenbroucke RE. Dual inhibition of TNFR1 and IFNAR1 in imiquimod-induced psoriasiform skin inflammation in mice. J Immunol. 2015;194:5094–102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012;61:1693–700.

    Article  PubMed  CAS  Google Scholar 

  62. Leppkes M, Becker C, Ivanov II, Hirth S, Wirtz S, Neufert C, et al. RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology. 2009;136:257–67.

    Article  PubMed  CAS  Google Scholar 

  63. Debnath M, Nagappa M, Murari G, Taly AB. IL-23/IL-17 immune axis in Guillain Barré syndrome: exploring newer vistas for understanding pathobiology and therapeutic implications. Cytokine. 2018;103:77–82.

    Article  PubMed  CAS  Google Scholar 

  64. Waisman A, Hauptmann J, Regen T. The role of IL-17 in CNS diseases. Acta Neuropathol. 2015;129:625–37.

    Article  PubMed  CAS  Google Scholar 

  65. Wong H, Hoeffer C. Maternal IL-17A in autism. Exp Neurol. 2018;299:228–40.

    Article  PubMed  CAS  Google Scholar 

  66. Wu L, Ong S, Talor MV, Barin JG, Baldeviano GC, Kass DA, et al. Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy. J Exp Med. 2014;211:1449–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Zhao X, Qi X, Wang C, Zhou Z, Cao H, Wu P, et al. Idiopathic thrombocytopenic purpura: pathogenesis and potential therapeutic approach. Minerva Med. 2017;108:502–6.

    PubMed  Google Scholar 

  68. Luo Z, Wang H, Wu Y, Sun Z, Wu Y. Clinical significance of IL-23 regulating IL-17A and/or IL-17F positive Th17 cells in chronic periodontitis. Mediat Inflamm. 2014;2014:627959.

    Article  CAS  Google Scholar 

  69. Frieder J, Kivelevitch D, Menter A. Secukinumab: a review of the anti-IL-17A biologic for the treatment of psoriasis. Ther Adv Chron Dis. 2018;9:5–21.

    Article  CAS  Google Scholar 

  70. Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CEM, Papp K, et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N Engl J Med. 2014;371:326–38.

    Article  PubMed  CAS  Google Scholar 

  71. Thaçi D, Blauvelt A, Reich K, Tsai T-F, Vanaclocha F, Kingo K, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol. 2015;73:400–9.

    Article  PubMed  CAS  Google Scholar 

  72. Blauvelt A, Prinz JC, Gottlieb AB, Kingo K, Sofen H, Ruer-Mulard M, et al. Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE). Br J Dermatol. 2015;172:484–93.

    Article  PubMed  CAS  Google Scholar 

  73. Mrowietz U, Leonardi CL, Girolomoni G, Toth D, Morita A, Balki SA, et al. Secukinumab retreatment-as-needed versus fixed-interval maintenance regimen for moderate to severe plaque psoriasis: a randomized, double-blind, noninferiority trial (SCULPTURE). J Am Acad Dermatol. 2015;73(27–36):e1.

    Google Scholar 

  74. Paul C, Lacour J-P, Tedremets L, Kreutzer K, Jazayeri S, Adams S, et al. Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE). J Eur Acad Dermatol Venereol. 2015;29:1082–90.

    Article  PubMed  CAS  Google Scholar 

  75. Blauvelt A, Reich K, Tsai T-F, Tyring S, Vanaclocha F, Kingo K, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate-to-severe plaque psoriasis up to 1 year: results from the CLEAR study. J Am Acad Dermatol. 2017;76(60–69):e9.

    Google Scholar 

  76. van de Kerkhof PCM, Griffiths CEM, Reich K, Leonardi CL, Blauvelt A, Tsai T-F, et al. Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol. 2016;75(83–98):e4.

    Google Scholar 

  77. Mease PJ, McInnes IB, Reich K, Nash P, Andersson M, Abrams K, et al. FRI0511 Secukinumab demonstrates consistent safety over long-term exposure in patients with psoriatic arthritis and moderate-to-severe plaque psoriasis: updated pooled safety analyses. Ann Rheum Dis. 2017;76:683.

    Google Scholar 

  78. Gordon KB, Blauvelt A, Papp KA, Langley RG, Luger T, Ohtsuki M, et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375:345–56.

    Article  PubMed  CAS  Google Scholar 

  79. Blauvelt A, Gooderham M, Iversen L, Ball S, Zhang L, Agada NO, et al. Efficacy and safety of ixekizumab for the treatment of moderate-to-severe plaque psoriasis: results through 108 weeks of a randomized, controlled phase 3 clinical trial (UNCOVER-3). J Am Acad Dermatol. 2017;77:855–62.

    Article  PubMed  CAS  Google Scholar 

  80. Li J, Casanova J-L, Puel A. Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation. Mucosal Immunology [Internet]. 2017. https://www.nature.com/articles/mi201797. Accessed 3 May 2018.

  81. Silva-Fernández L, Lunt M, Kearsley-Fleet L, Watson KD, Dixon WG, Symmons DPM, et al. The incidence of cancer in patients with rheumatoid arthritis and a prior malignancy who receive TNF inhibitors or rituximab: results from the British Society for Rheumatology Biologics Register-Rheumatoid Arthritis. Rheumatology. 2016;55:2033–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  82. Mercer LK, Galloway JB, Lunt M, Davies R, Low ALS, Dixon WG, et al. Risk of lymphoma in patients exposed to antitumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann Rheum Dis. 2016: 0;1–7.

  83. Costa L, Caso F, Puente AD, Minno MNDD, Peluso R, Scarpa R. Incidence of malignancies in a cohort of psoriatic arthritis patients taking traditional disease modifying antirheumatic drug and tumor necrosis factor inhibitor therapy: an observational study. J Rheumatol. 2016;43:2149–54.

    Article  PubMed  Google Scholar 

  84. Nocturne G, Boudaoud S, Ly B, Pascaud J, Paoletti A, Mariette X. Impact of anti-TNF therapy on NK cells function and on immunosurveillance against B-cell lymphomas. J Autoimmun. 2017;80:56–64.

    Article  PubMed  CAS  Google Scholar 

  85. Song Y, Yang JM. Role of interleukin (IL)-17 and T-helper (Th)17 cells in cancer. Biochem Biophys Res Commun. 2017;493:1–8.

    Article  PubMed  CAS  Google Scholar 

  86. Iwakura Y, Nakae S, Saijo S, Ishigame H. The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev. 2008;226:57–79.

    Article  PubMed  CAS  Google Scholar 

  87. Watanabe H, Kawaguchi M, Fujishima S, Ogura M, Matsukura S, Takeuchi H, et al. Functional characterization of IL-17F as a selective neutrophil attractant in psoriasis. J Investig Dermatol. 2009;129:650–6.

    Article  PubMed  CAS  Google Scholar 

  88. Duan H, Koga T, Kohda F, Hara H, Urabe K, Furue M. Interleukin-8-positive neutrophils in psoriasis. J Dermatol Sci. 2001;26:119–24.

    Article  PubMed  CAS  Google Scholar 

  89. Papp KA, Merola JF, Gottlieb AB, Griffiths CEM, Cross N, Peterson L, et al. Dual neutralization of both IL-17A and IL-17F with bimekizumab in patients with psoriasis: results from BE ABLE 1, a 12-week randomized, double-blinded placebo-controlled phase 2b trial. J Am Acad Dermatol. 2018.

  90. Pre-clinical proof-of concept of ALX-0761, a nanobody neutralising both IL-17A and IL- 17F in a cynomolgus monkey collagen induced arthritis model [Internet]. [cited 2018 Feb 7]. http://ablynx.com/uploads/data/files/poster-acr-2013-c076.pdf.

  91. Wang Y, Atkins A, Vachhani K, Whyne C, Nam D. The absence of IL-17F impairs fracture healing in mice femira. J Orthop Res. 2017;35.

  92. Liu H, Luo T, Tan J, Li M, Guo J. Osteoimmunology’ offers new perspectives for the treatment of pathological bone loss. Curr Pharm Des. 2017;23(41):6272–78. https://doi.org/10.2174/1381612823666170511124459.

    Article  PubMed  CAS  Google Scholar 

  93. Kathuria P, Gordon KB, Silverberg JI. Association of psoriasis and psoriatic arthritis with osteoporosis and pathological fractures. J Am Acad Dermatol. 2017;76:1045–53.

    Article  PubMed  Google Scholar 

  94. Glatt S, Baeten D, Baker T, Griffiths M, Ionescu L, Lawson ADG, et al. Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation. Ann Rheum Dis. 2017. https://doi.org/10.1136/annrheumdis-2017-212127.

    Article  PubMed  Google Scholar 

  95. Maroof A, Okoye R, Smallie T, Baeten D, Archer S, Simpson C, et al. THU0038 Bimekizumab dual inhibition of IL-17A and IL-17F provides evidence of IL-17F contribution to chronic inflammation in disease-relevant cells. Ann Rheum Dis. 2017;76:213.

    Google Scholar 

  96. Papp KA, Leonardi C, Menter A, Ortonne J-P, Krueger JG, Kricorian G, et al. Brodalumab, an anti–interleukin-17–receptor antibody for psoriasis. N Engl J Med. 2012;366:1181–9.

    Article  PubMed  CAS  Google Scholar 

  97. Lebwohl M, Strober B, Menter A, Gordon K, Weglowska J, Puig L, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373:1318–28.

    Article  PubMed  Google Scholar 

  98. Lebwohl MG, Papp KA, Marangell LB, Koo J, Blauvelt A, Gooderham M, et al. Psychiatric adverse events during treatment with brodalumab: analysis of psoriasis clinical trials. J Am Acad Dermatol. 2018;78(81–89):e5.

    Google Scholar 

  99. Rusta-Sallehy S, Gooderham M, Papp K. Brodalumab: a review of safety. Skin Ther Lett. 2018;23:1–3.

    CAS  Google Scholar 

  100. Regnault MM, Konstantinou M-P, Khemis A, Poulin Y, Bourcier M, Amelot F, et al. Early relapse of psoriasis after stopping brodalumab: a retrospective cohort study in 77 patients. J Eur Acad Dermatol Venereol. 2017;31:1491–6.

    Article  CAS  Google Scholar 

  101. El Malki K, Karbach SH, Huppert J, Zayoud M, Reißig S, Schüler R, et al. An alternative pathway of imiquimod-induced psoriasis-like skin inflammation in the absence of interleukin-17 receptor a signaling. J Invest Dermatol. 2013;133:441–51.

    Article  PubMed  CAS  Google Scholar 

  102. Sofen H, Smith S, Matheson RT, Leonardi CL, Calderon C, Brodmerkel C, et al. Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis. J Allergy Clin Immunol. 2014;133:1032–40.

    Article  PubMed  CAS  Google Scholar 

  103. Gooderham MJ, Papp KA, Lynde CW. Shifting the focus—the primary role of IL-23 in psoriasis and other inflammatory disorders. J Eur Acad Dermatol Venereol. 2018. https://doi.org/10.1111/jdv.14868.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Cua DJ, Tato CM. Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol. 2010;10:479–89.

    Article  PubMed  CAS  Google Scholar 

  105. Fasching P, Stradner M, Graninger W, Dejaco C, Fessler J. Therapeutic potential of targeting the Th17/Treg axis in autoimmune disorders. Molecules. 2017;22:134.

    Article  CAS  PubMed Central  Google Scholar 

  106. Langley RG, Lebwohl M, Krueger GG, Szapary PO, Wasfi Y, Chan D, et al. Long-term efficacy and safety of ustekinumab, with and without dosing adjustment, in patients with moderate-to-severe psoriasis: results from the PHOENIX 2 study through 5 years of follow-up. Br J Dermatol. 2015;172:1371–83.

    Article  PubMed  CAS  Google Scholar 

  107. Griffiths CEM, Strober BE, van de Kerkhof P, Ho V, Fidelus-Gort R, Yeilding N, et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. New Eng J Med. 2010;362:118–28.

    Article  PubMed  CAS  Google Scholar 

  108. Ikonomidis I, Papadavid E, Makavos G, Andreadou I, Varoudi M, Gravanis K, et al. Lowering interleukin-12 activity improves myocardial and vascular function compared with tumor necrosis factor-a antagonism or cyclosporine in psoriasis. Circ Cardiovasc Imaging. 2017;10:e006283.

    Article  PubMed  Google Scholar 

  109. Egeberg A, Ottosen MB, Gniadecki R, Broesby-Olsen S, Dam TN, Bryld LE, et al. Safety, efficacy and drug survival of biologics and biosimilars for moderate-to-severe plaque psoriasis. Br J Dermatol. 2018;178:509–19.

    Article  PubMed  CAS  Google Scholar 

  110. Langley R g., Tsai T-F, Flavin S, Song M, Randazzo B, Wasfi Y, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial. Br J Dermatol. 2018;178:114–23.

  111. Blauvelt A, Papp KA, Griffiths CEM, Randazzo B, Wasfi Y, Shen Y-K, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo- and active comparator–controlled VOYAGE 1 trial. J Am Acad Dermatol. 2017;76:405–17.

    Article  PubMed  CAS  Google Scholar 

  112. Reich K, Armstrong AW, Foley P, Song M, Wasfi Y, Randazzo B, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator–controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017;76:418–31.

    Article  PubMed  CAS  Google Scholar 

  113. Reich K, Papp KA, Blauvelt A, Tyring SK, Sinclair Rodney, Thaçi D, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. Lancet. 2017;390:276–88.

    Article  PubMed  CAS  Google Scholar 

  114. Risankizumab meets all primary endpoints reporting positive results in fourth pivotal phase 3 psoriasis study | AbbVie Newsroom [Internet]. Abbvie news. 2018. https://news.abbvie.com/news/risankizumab-meets-all-primary-endpoints-reporting-positive-results-in-fourth-pivotal-phase-3-psoriasis-study.htm. Accessed 11 Apr 2018.

  115. Sullivan M. Risankizumab outpaced ustekinumab for complete clearance of plaque psoriasis [internet]. Dermatology News. 2018. https://www.mdedge.com/edermatologynews/article/158909/psoriasis/risankizumab-outpaced-ustekinumab-complete-clearance. Accessed 11 Apr 2018.

  116. Reich K., Bissonnette, Menter, A, Klekotka P., Patel D., Tuttle J., et al. Efficacy and safety of mirikizumab (LY3074828) in the treatment of moderate-to-severe plaque psoriasis: results from a phase II study. Br J Dermatol. 2017;177:177.

  117. Caughron B, Yang Y, Young MRI. Role of IL-23 signaling in the progression of premalignant oral lesions to cancer. PLoS One. 2018;13:e0196034.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Hoeve MA, Savage NDL, Boer T de, Langenberg DML, de Waal Malefyt R, Ottenhoff THM, et al. Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells. Eur J Immunol. 2006;36:661–70.

  119. Xie C, Ciric B, Yu S, Zhang G-X, Rostami A. IL-12Rβ2 has a protective role in relapsing-remitting experimental autoimmune encephalomyelitis. J Neuroimmunol. 2016;291:59–69.

    Article  PubMed  CAS  Google Scholar 

  120. Torti DC, Feldman SR. Interleukin-12, interleukin-23, and psoriasis: current prospects. J Am Acad Dermatol. 2007;57:1059–68.

    Article  PubMed  Google Scholar 

  121. Teng MWL, Vesely MD, Duret H, McLaughlin N, Towne JE, Schreiber RD, et al. Opposing roles for IL-23 and IL-12 in maintaining occult cancer in an equilibrium state. Cancer Res. 2012;72:3987–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Meeran SM, Mantena SK, Meleth S, Elmets CA, Katiyar SK. Interleukin-12-deficient mice are at greater risk of UV radiation-induced skin tumors and malignant transformation of papillomas to carcinomas. Mol Cancer Ther. 2006;5:825–32.

    Article  PubMed  CAS  Google Scholar 

  123. Yuzhalin AE, Kutikhin AG. Interleukin-12: clinical usage and molecular markers of cancer susceptibility. Growth Factors. 2012;30:176–91.

    Article  PubMed  CAS  Google Scholar 

  124. Grine L, Dejager L, Libert C, Vandenbroucke RE. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine Growth Factor Rev. 2015;26:25–33.

    Article  PubMed  CAS  Google Scholar 

  125. Silacci M, Lembke W, Woods R, Attinger-Toller I, Baenziger-Tobler N, Batey S, et al. Discovery and characterization of COVA322, a clinical-stage bispecific TNF/IL-17A inhibitor for the treatment of inflammatory diseases. MAbs. 2016;8:141–9.

    Article  PubMed  CAS  Google Scholar 

  126. Fleischmann RM, Wagner F, Kivitz AJ, Mansikka HT, Khan N, Othman AA, et al. Safety, tolerability, and pharmacodynamics of ABT-122, a tumor necrosis factor- and interleukin-17-targeted dual variable domain immunoglobulin, in patients with rheumatoid arthritis. Arthritis Rheumatol. 2017;69:2283–91.

    Article  PubMed  CAS  Google Scholar 

  127. Sedyh S, V Prinz V, N Buneva V, A Nevinsky G. Bispecific antibodies: design, therapy, perspectives. Drug Des Devel Ther. 2018;12:195–208.

  128. Klunder B, Khatri A, Minocha M, Peloso P, Othman AA. ABT-122, an immunoglobulin targeting both TNF-α and IL-17A, does not provide significantly greater efficacy compared with adalimumab in subjects with psoriatic arthritis: results from exposure-response analyses [abstract]. Arthritis Reumatol [Internet]. 2016. http://acrabstracts.org/abstract/abt-122-an-immunoglobulin-targeting-both-tnf-%ce%b1-and-il-17a-does-not-provide-significantly-greater-efficacy-compared-with-adalimumab-in-subjects-with-psoriatic-arthritis-results-from-exposure-re/. Accessed 9 Apr 2018.

  129. Desmyter A, Spinelli S, Boutton C, Saunders M, Blachetot C, de Haard H, et al. Neutralization of human interleukin 23 by multivalent nanobodies explained by the structure of cytokine-nanobody complex. Front Immunol. 2017;8:884.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Svecova D, Krueger J, Sverdlov O, Mackenzie H, Grenningloh R, Lubell M. Safety and efficacy of multiple ascending doses of subcutaneous M1095, an anti-interleukin-17a/f bispecific nanobody, in patients with moderate-to-severe psoriasis: 5511. J Am Acad Dermatol [Internet]. 2017;76. https://www.aad.org/eposters/view/Abstract.aspx?id=5511. Accessed 30 Apr 2018.

  131. Gege C. RORγt inhibitors as potential back-ups for the phase II candidate VTP-43742 from Vitae Pharmaceuticals: patent evaluation of WO2016061160 and US20160122345. Expert Opin Ther Pat. 2017;27:1–8.

    Article  PubMed  CAS  Google Scholar 

  132. Biswas PS, Gupta S, Chang E, Song L, Stirzaker RA, Liao JK, et al. Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Invest. 2010;120:3280–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Zanin-Zhorov A, Weiss JM, Trzeciak A, Chen W, Zhang J, Nyuydzefe M, et al. Selective oral ROCK2 inhibitor reduces clinical scores in patients with psoriasis vulgaris and normalizes skin pathology via concurrent regulation of IL-17 and IL-10 levels. J Immunol. 2017;198:197.3–197.3.

  134. Seale L, Cardwell LA, Feldman SR. Adherence to biologics in patients with psoriasis. Expert Rev Clin Immunol. 2018;14:155–61.

    Article  PubMed  CAS  Google Scholar 

  135. Martinez-Escala ME, Posligua AL, Wickless H, Rutherford A, Sable KA, Rubio-Gonzalez B, et al. Progression of undiagnosed cutaneous lymphoma after anti–tumor necrosis factor-alpha therapy. J Am Acad Dermatol. 2018. https://doi.org/10.1016/jaad.2017.12.068.

  136. Lacour J-P, Paul C, Jazayeri S, Papanastasiou P, Xu C, Nyirady J, et al. Secukinumab administration by autoinjector maintains reduction of plaque psoriasis severity over 52 weeks: results of the randomized controlled JUNCTURE trial. J Eur Acad Dermatol Venereol. 2017;31:847–56.

    Article  PubMed  CAS  Google Scholar 

  137. Papp K, Leonardi C, Menter A, Thompson EHZ, Milmont CE, Kricorian G, et al. Safety and efficacy of brodalumab for psoriasis after 120 weeks of treatment. J Am Acad Dermatol. 2014;71(1183–1190):e3.

    Google Scholar 

  138. Papp KA, Blauvelt A, Bukhalo M, Gooderham M, Krueger JG, Lacour J-P, et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med. 2017;376:1551–60.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This research is funded by a research grant to Nanja van Geel from the Scientific Research Foundation-Flanders (FWO Senior Clinical Investigator; grant number: 1831512 N).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Reinhart Speeckaert.

Ethics declarations

Funding

The work presented was performed without funding.

Conflict of interest

Sofie Mylle, Reinhart Speeckaert and Nanja van Geel declare no conflict of interest. Jo Lambert has received unrestricted educational grants, board and speaker’s fees from AbbVie, Celgene, Eli Lilly, Janssen Cilag, Leo Pharma, Novartis, Pfizer, and UCB. Lynda Grine has received a speaker’s fee from AbbVie.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mylle, S., Grine, L., Speeckaert, R. et al. Targeting the IL-23/IL-17 Pathway in Psoriasis: the Search for the Good, the Bad and the Ugly. Am J Clin Dermatol 19, 625–637 (2018). https://doi.org/10.1007/s40257-018-0366-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40257-018-0366-5

Navigation