Psoriasis and psoriatic arthritis (PsA) are pathophysiological enigmas among rheumatic diseases. Substantial clinical advances have been made with new therapy targeting different components of the IL-17 and IL-23 pathways. At the same time, an increase in research on the topic has provided new insights into the potential functional effects of treatments on cell types, pathways, and tissues of interest. Here we review our knowledge of all IL-17 family members, their relationships with the IL-23 pathway, and the outcomes of relevant clinical trials in which different strategies for targeting these molecules have been tested in the treatment of moderate to severe psoriasis and PsA.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price includes VAT (USA)
Tax calculation will be finalised during checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Rouvier E, Luciani MF, Mattéi MG, Denizot F, Golstein P. CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J Immunol (Baltimore, Md: 1950). 1993;150(12):5445–56.
Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol. 2007;25(1):821–52.
Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 2011;12(3):255–63. Describes the plasticity of IL-17A-producing cells. Uncovers IFNγ expression by T H 17 cells in chronic inflammation model.
Awasthi A, Riol-Blanco L, Jäger A, Korn T, Pot C, Galileos G, et al. Cutting edge: IL-23 receptor GFP reporter mice reveal distinct populations of IL-17-producing cells. J Immunol. 2009;182(10):5904–8.
Croxford AL, Kurschus FC, Waisman A. Cutting edge: an IL-17F-CreEYFP reporter mouse allows fate mapping of Th17 cells. J Immunol. 2009;182(3):1237–41.
Fossiez F, Banchereau J, Murray R, Van Kooten C, Garrone P, Lebecque S. Interleukin-17. Int Rev Immunol. 1998;16(5–6):541–51.
Johansen C, Usher PA, Kjellerup RB, Lundsgaard D, Iversen L, Kragballe K. Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Br J Dermatol. 2009;160(2):319–24.
Rickel EA, Siegel LA, Yoon B-RP, Rottman JB, Kugler DG, Swart DA, et al. Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J Immunol (Baltimore, Md: 1950). 2008;181(6):4299–310.
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 U S A. 2000;97(2):773–8.
Haines CJ, Cua DJ. Orphan cytokine reveals IL-17 family secret. Immunity. 2011;35(4):498–500.
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(12):1151–8.
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(12):1159–66. Reports the profound homeostatic role of IL-17C in gut mucosal defence.
Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature. 2007;445(7128):648–51.
Wu Q, Martin RJ, Rino JG, Breed R, Torres RM, Chu HW. IL-23-dependent IL-17 production is essential in neutrophil recruitment and activity in mouse lung defense against respiratory mycoplasma pneumoniae infection. Microbes Infect Inst Pasteur. 2007;9(1):78–86.
Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 2003;14(2):155–74.
Kouri VP, Olkkonen J, Ainola M, Li T-F, Björkman L, Konttinen YT, et al. Neutrophils produce interleukin-17B in rheumatoid synovial tissue. Rheumatology. 2013;ket309.
Starnes T, Broxmeyer HE, Robertson MJ, Hromas R. Cutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis. J Immunol. 2002;169(2):642–6.
Nograles KE, Brasington RD, Bowcock AM. New insights into the pathogenesis and genetics of psoriatic arthritis. Nat Rev Rheumatol. 2009;5(2):83–91.
Ritchlin C. Psoriatic disease—from skin to bone. Nat Rev Rheumatol. 2007;3(12):698–706.
Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296(14):1735–41.
Kurd SK, Troxel AB, Crits-Christoph P, Gelfand JM. The risk of depression, anxiety and suicidality in patients with psoriasis: a population-based cohort study. Arch Dermatol. 2010;146(8):891–5.
Haroon M, Kirby B, FitzGerald O. High prevalence of psoriatic arthritis in patients with severe psoriasis with suboptimal performance of screening questionnaires. Ann Rheum Dis. 2013;72(5):736–40.
Gladman DD, Antoni C, Mease P, Clegg DO, Nash P. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis. 2005;64 suppl 2:ii14–7.
Eder L, Chandran V, Pellet F, Shanmugarajah S, Rosen CF, Bull SB, et al. Human leucocyte antigen risk alleles for psoriatic arthritis among patients with psoriasis. Ann Rheum Dis. 2012;71(1):50–5.
Winchester R, Minevich G, Steshenko V, Kirby B, Kane D, Greenberg DA, et al. HLA associations reveal genetic heterogeneity in psoriatic arthritis and in the psoriasis phenotype. Arthritis Rheum. 2012;64(4):1134–44.
Liu Y, Helms C, Liao W, Zaba LC, Duan S, Gardner J, et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 2008;4(3):e1000041.
Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet. 2007;80(2):273–390.
Capon F, Di Meglio P, Szaub J, Prescott NJ, Dunster C, Baumber L, et al. Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. Hum Genet. 2007;122(2):201–6.
Weaver CT, Elson CO, Fouser LA, Kolls JK. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu Rev Pathol. 2013;8:477–512. Important review describing the complexity of the T H 17 pathway in the variety of pathologies and tissues.
Hirota K, Ahlfors H, Duarte JH, Stockinger B. Regulation and function of innate and adaptive interleukin-17-producing cells. EMBO Rep. 2012;13(2):113–20. Emphasises the crucial importance of resident γδT cells in chronic inflammation and as a major source of IL-17A.
Walker JA, Barlow JL, McKenzie ANJ. Innate lymphoid cells—how did we miss them? Nat Rev Immunol. 2013;13(2):75–87. Excellent review on types and features of different innate lymphoid cells, including IL-17-producing ILC3s.
Zheng J, Liu Y, Lau Y-L, Tu W. γδ-T cells: an unpolished sword in human anti-infection immunity. Cell Mol Immunol. 2013;10(1):50–7.
Doisne J-M, Becourt C, Amniai L, Duarte N, Le Luduec J-B, Eberl G, et al. Skin and peripheral lymph node invariant NKT cells are mainly retinoic acid receptor-related orphan receptor (gamma)t+ and respond preferentially under inflammatory conditions. J Immunol (Baltimore, Md: 1950). 2009;183(3):2142–9.
Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M. Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity. 2009;31(2):321–30.
Sieper J, Porter-Brown B, Thompson L, Harari O, Dougados M. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis. 2013.
Zaba LC, Cardinale I, Gilleaudeau P, Sullivan-Whalen M, Suarez-Farinas M, Fuentes-Duculan J, et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med. 2007;204(13):3183–94.
Yeremenko N, Noordenbos T, Cantaert T, van Tok M, van de Sande M, Cañete JD, et al. Disease-specific and inflammation-independent stromal alterations in spondylarthritis synovitis. Arthritis Rheum. 2013;65(1):174–85. Interesting publication, reporting the abundance of non-immune tissue changes that occur during chronic synovitis.
Sherlock JP, Joyce-Shaikh B, Turner SP, Chao C-C, Sathe M, Grein J, Gorman DM, et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4-CD8- entheseal resident T cells. Nat. Med. 2012;18(7):1069–76. Reports identification of resident T cells capable of initiating entheseal inflammation and subsequent arthritis in response to IL-23 in the animal model.
Lories RJ, McInnes IB. Primed for inflammation: enthesis-resident T cells. Nat Med. 2012;18(7):1018–9.
Andersen T, Rasmussen TK, Hvid M, Holm CK, Madsen KJ-NB, Jurik AG, et al. Increased plasma levels of IL-21 and IL-23 in spondyloarthritis are not associated with clinical and MRI findings. Rheumatol Int. 2010;32(2):387–93.
Boniface K, Guignouard E, Pedretti N, Garcia M, Delwail A, Bernard F-X, et al. A role for T cell-derived interleukin 22 in psoriatic skin inflammation. Clin Exp Immunol. 2007;150(3):407–15.
Shimauchi T, Hirakawa S, Suzuki T, Yasuma A, Majima Y, Tatsuno K, et al. Serum interleukin-22 and vascular endothelial growth factor serve as sensitive biomarkers but not as predictors of therapeutic response to biologics in patients with psoriasis. J Dermatol. 2013.
Tillack C, Ehmann LM, Friedrich M, Laubender RP, Papay P, Vogelsang H, et al. Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-γ-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment. Gut. 2013;gutjnl–2012–302853.
Wallis DEJ, Waldron NM, Korendowych E. Ustekinumab for resistant psoriatic arthritis. J Rheumatol. 2013;40(2):207.
Harrison MJ, Dixon WG, Watson KD, King Y, Groves R, Hyrich KL, et al. Rates of new-onset psoriasis in patients with rheumatoid arthritis receiving anti-tumour necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2009;68(2):209–15.
Wollenberg A, Wagner M, Günther S, Towarowski A, Tuma E, Moderer M, et al. Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases. J Investig Dermatol. 2002;119(5):1096–102.
Krueger GG, Langley RG, Leonardi C, Yeilding N, Guzzo C, Wang Y, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med. 2007;356(6):580–92.
Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, 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.
Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, 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.
Kumar N, Narang K, Cressey BD, Gottlieb AB. Long-term safety of ustekinumab for psoriasis. Expert Opin Drug Saf. 2013;12(5):757–65.
A Study to Assess the Effect of Ustekinumab (Stelara®) and Etanercept (Enbrel®) in Participants With Moderate to Severe Psoriasis (MK-0000-206). NCT01276847.
Gottlieb A, Menter A, Mendelsohn A, Shen Y-K, Li S, Guzzo C, 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.
McInnes IB, Kavanaugh A, Gottlieb AB, Puig L, Rahman P, Ritchlin C, 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.
Ritchlin CT, Gottlieb A, McInnes IB, Puig L, Rahman P, Li S, et al. Ustekinumab in active psoriatic arthritis including patients previously treated with anti-TNF agents: Results of a phase 3, multicentre, double-blind, placebo-controlled study [abstract]. Presented at the ACR 2012, vol. 2012;64 Suppl:S1080.
Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med. 2010;2(52):52ra72.
Baeten D, Baraliakos X, Braun J, Sieper J, Emery P, van der Heijde D, et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet. 2013.
Papp KA, Langley RG, Sigurgeirsson B, Abe M, Baker DR, Konno P, et al. Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study. Br J Dermatol. 2013;168(2):412–21.
McInnes IB, Sieper J, Braun J, Emery P, van der Heijde D, Isaacs JD, et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. Ann Rheum Dis. 2013. Report of the efficacy and safety of the new anti-IL-17A treatment.
A Three-year Extension Study to Evaluate the Long Term Efficacy, Safety and Tolerability of Secukinumab in Patients With Active Psoriatic Arthritis. NCT01892436.
Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012;366(13):1190–9.
A Study of Ixekizumab in Participants With Active Psoriatic Arthritis (SPIRIT-P1). NCT01695239.
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(13):1181–89. First report of the efficacy of targeting the IL-17A receptor in psoriasis.
Study of Efficacy and Safety of Brodalumab Compared With Placebo and Ustekinumab in Moderate to Severe Plaque Psoriasis Subjects (AMAGINE-2). NCT01708603.
A Randomized, Double-blinded, Placebo-controlled, Multiple-dose Study With an Open Label Extension to Evaluate the Safety and Efficacy of AMG 827 (Brodalumab) in Subjects With Psoriatic Arthritis. NCT01516957.
Moll JM, Wright V. The pattern of chest and spinal mobility in ankylosing spondylitis. An objective clinical study of 106 patients. Rheumatol Rehabil. 1973;12(3):115–34.
Mease PJ, Antoni CE, Gladman DD, Taylor WJ. Psoriatic arthritis assessment tools in clinical trials. Ann Rheum Dis. 2005;64 suppl 2:ii49–54.
Coates LC, Mumtaz A, Helliwell PS, Mease PJ, Callis-Duffin K, Krueger GG, et al. Development of a disease severity and responder index for psoriatic arthritis (PsA)—report of the OMERACT 10 PsA special interest group. J Rheumatol. 2011;38(7):1496–501.
Compliance with Ethics Guidelines
Conflict of Interest
Stefan Siebert has served as a consultant for UCB and Abbvie, has received grant support from Pfizer, has received payment for development of educational presentations (including service on speakers bureaus) from Novartis and Pfizer, and has had travel and accommodation expenses covered and reimbursed by Janssen Pharmaceutica, Pfizer, and Abbvie.
Iain B. McInnes has served as a consultant for, has received payment for development of educational presentations (including service on speakers bureaus) from, and had travel and accommodation expenses covered and reimbursed by Amgen, Novartis, and Janssen Pharmaceutica. He has also received grant support from Pfizer.
Marina Frleta declares that she has no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
This article is part of the Topical Collection on Psoriatic Arthritis
About this article
Cite this article
Frleta, M., Siebert, S. & McInnes, I.B. The Interleukin-17 Pathway in Psoriasis and Psoriatic Arthritis: Disease Pathogenesis and Possibilities of Treatment. Curr Rheumatol Rep 16, 414 (2014). https://doi.org/10.1007/s11926-014-0414-y
- Psoriatic arthritis
- Biologic agents