Targeting IL-17 to treat psoriasis
Why treat psoriasis?
Psoriasis is a common, lifelong, painful, disfiguring and disabling disease (World Health Organization, 2016).
Psoriasis has a substantial negative impact on individuals and patients with moderate-to-severe psoriasis often have poor physical and mental health-related quality of life (Menter et al., 2008). Physically, affected body areas can cause sleep disturbances and restricted use of affected body areas (Menter et al., 2008) but there are also far-reaching mental consequences.
Unsurprisingly, psoriasis also has implications for patients in the workplace. Patients often face discrimination and have difficulties in workplace interactions (Narayanan et al., 2015). More than one-third of patients lose ≥3 days of work every three months due to psoriasis (Ayala et al., 2014) and moderate-to-severe psoriasis leads indirectly to early retirement, unemployment and lost work productivity (Mustonen et al., 2015).
Treatments for moderate-to-severe psoriasis should aim to reduce the general disease burden and improve the health-related quality of life for individual patients.
Why target IL-17?
A large number of inflammatory cytokines are elevated in psoriasis lesional skin and the serum concentrations of a subset of these correlate with disease severity (Baliwag et al., 2015). The combined effects of the cytokines found in psoriatic lesions may explain most of the clinical features of psoriasis, such as the hyperproliferation of keratinocytes, increased neovascularisation and skin inflammation (Baliwag et al., 2015). An understanding of which cytokines play a pivotal role in the disease process has revealed potential therapeutic targets, and a number of cytokines have been successfully targeted, revolutionising treatment of this disease (Baliwag et al., 2015). These include tumour necrosis factor-alpha (TNFα), IL-23 and IL-12/23 in addition to IL-17. Here, we explore how biologics target the IL-17 pathway in psoriasis, however, afterwards, why not visit the cytokines in psoriasis section of the Psoriasis Learning Zone for more information about the other implicated cytokines.
The development of psoriasis involves activated dendritic cells that produce IL-12 and IL-23 cytokines, which drive the differentiation of type I and type 17 T-helper cells (Figure 3).
T-helper 17 cells produce IL-17A and IL-17F which are both present at much higher levels in psoriatic plaques than in healthy skin (Johansen et al., 2009). While IL-17A and IL-17F play distinct but overlapping roles in host defence against bacterial and fungal infections, IL-17A has been implicated in many autoimmune diseases, including psoriasis and psoriatic arthritis (Goepfert et al., 2017). Indeed, IL-17 receptor A is expressed on both the keratinocyte cell surface and immune cells and so is an essential component of the IL-17 receptor complexes (Johansen et al., 2009; Martin et al., 2013).
The IL-17 pathway is crucial to the development and maintenance of psoriatic plaques and has therefore become a target for the treatment of plaque psoriasis (Johansen et al., 2009; Martin et al., 2013; Lowes et al., 2014).
MoA of IL-17 treatments
A number of cytokines from the IL-17 family must bind to IL-17 receptor A (IL-17RA) in order to complete their biological function (Kyntheum® Summary of Product Characteristics, 2017).
Increased expression of IL-17A, IL-17C and IL-17F cytokines, which activate IL-17RA complexes on keratinocytes and immune cells, leads to inflammation and the clinical manifestations of psoriasis (Toy et al., 2006; Wright et al., 2008; Ramirez-Carrozzi et al., 2011; Martin et al., 2013).
IL-17A can be produced by multiple cell types (Beringer et al., 2016); therefore, while upstream inhibition of TNF-α, IL-12 or IL-23 partly attenuates IL-17A production, other cytokines can synergise with residual levels of IL-17A (Russell et al., 2014).
Inhibition of the IL-17RA directly blocks the action of multiple IL-17 cytokines, including IL-17A, IL-17C, IL-17E, IL-17F and IL-17A/F (Ramirez-Carrozzi et al., 2011; Martin et al., 2013), helping to normalise the inflammatory response (Russel et al., 2014) (Figure 4).
Signalling through the IL-17 receptor activates many common downstream signalling pathways, including Nuclear Factor-KappaB (NF-κB), c-Jun N-terminal Kinase (JNK), p38 and Extracellular signal-Related Kinase (ERK), CCAAT/Enhancer Binding Protein (C/EBP) beta/gamma, phosphatidylinositide 3-kinase (PI3-K) and Janus kinases/Signal Transducer and Activator of Transcription proteins (JAK/STATs). Activation of these signalling pathways results in the production of pro-inflammatory effects in a variety of cell types, including keratinocytes and endothelial cells, which leads to several of the pathological changes that characterise psoriatic skin (Martin et al., 2013; Coimbra et al., 2014).
Blocking IL-17 signalling can occur at the ligand or receptor level (Figure 5).
Treatments that block IL-17A signalling at the ligand level
Two anti-IL-17A treatments are currently available for the treatment of moderate-to-severe psoriasis.
Ixekizumab is a humanised IgG4 monoclonal anti body that binds interleukin 17A (both IL-17A and IL-17A/F) and is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. Ixekizumab, alone or in combination with methotrexate, is also indicated for the treatment of active psoratic arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying anti-rheumatic drug (DMARD) therapies (Taltz® Prescribing Information, 2016; Taltz® Summary of Product Characteristics, 2018). Ixekizumab was considered in a recent review of psoriasis guidelines as an approved treatment but it was felt at that time expert experience with ixekizumab was still too limited to be conclusive and it would be considered at the next update (Nast et al., 2017).
Secukinumab is a recombinant fully human IgG1/κ-class monoclonal antibody selective for interleukin-17A. Secukinumab is indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. Secukinumab, alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic arthritis in adult patients when the response to previous disease-modifying anti-rheumatic drug (DMARD) therapy has been inadequate. Secukinumab is also indicated for the treatment of active ankylosing spondylitis in adults who have responded inadequately to conventional therapy. (Cosentyx® Summary of Product Characteristics, 2018; CosentyxTM Prescribing Information, 2016). A recent guidelines update included secukinumab (along with the PDE4 inhibitor apremilast) as a new treatment option for psoriasis (Nast et al., 2017).
Treatments that block IL-17 signalling at the receptor level
While other IL-17 biologics for moderate-to-severe psoriasis bind to the IL-17A ligand, the fully human IgG2 monoclonal antibody brodalumab binds to the IL-17 receptor subunit A, which blocks the inflammatory signalling not only of IL-17A but also IL-17F, IL-17A/F and IL-25 (Figure 6) (Campa et al., 2016; Kyntheum® Summary of Product Characteristics, 2017).
Brodalumab is approved for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy in Europe (Kyntheum® Summary of Product Characteristics, 2017). In the US brodalumab is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies (Siliq™ Prescribing Information, 2017).
Armstrong AW, Schupp C, Wu J, Bebo B. Quality of life and work productivity impairment among psoriasis patients: findings from the National Psoriasis Foundation survey data 2003-2011. PLoS One. 2012;7(12):e52935.
Ayala F, Sampogna F, Romano GV, Merolla R, Guida G, Gualberti G et al. The impact of psoriasis on work-related problems: a multicenter cross-sectional survey. J Eur Acad Dermatol Venereol. 2014;28(12):1623–32.
Baliwag J, Barnes DH, Johnston A. Cytokines in psoriasis. Cytokine. 2015;73:342–50.
Baker & Isaacs KF, Issacs JD. Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, Crohn’s disease and ulcerative colitis? Ann Rheum Dis. 2017;0:1‒3.
Beringer A, Noack M, Miossec P. IL-17 in chronic inflammation. Trends Mol Med. 2016;22(3):230‒41.
Campa M, Mansouri B, Warren R, Menter A. A review of biologic therapies targeting IL-23 and IL-17 for use in moderate-to-severe plaque psoriasis. Dermatol Ther (Heidelb). 2016;6(1):1–12.
Coimbra S, Figueiredo A, Santos-Silva A. Brodalumab: an evidence-based review of its potential in the treatment of moderate-to-severe psoriasis. Core Evid. 2014;9:89–97.
Cosentyx® Summary of Product Characteristics, 2018. Available at: https://www.ema.europa.eu/documents/product-information/cosentyx-epar-product-information_en.pdf (accessed February 2019).
Cosentyx™ Prescribing Information, 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125504s001s002lbl.pdf (accessed September 2018).
Donigan JM, Pascoe VL, Kimball AB. Psoriasis and herpes simplex virus are highly stigmatizing compared with other common dermatologic conditions: A survey-based study. J Am Acad Dermatol. 2015;73(3):525–6.
The International Federation of Psoriasis Associations, 2017. Available at: https://ifpa-pso.com/wp-content/uploads/2016/12/Infographic-2.png (accessed May 2018).
Feldman SR, Zhao Y, Shi L, Tran MH. Economic and comorbidity burden among patients with moderate-to-severe psoriasis. J Manag Care Spec Pharm. 2015;21(10):874–88.
Goepfert A, Lehmann S, Wirth E, Rondeau JM. The human IL-17A/F heterodimer: a two-faced cytokine with unique receptor recognition properties. Sci Rep. 2017;7(1):8906.
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.
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.
Kyntheum® Summary of Product Characteristics, 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003959/WC500232913.pdf (accessed September 2018).
Lowes MA, Suárez-Fariñas M, Krueger JG. Immunology of psoriasis. Annu Rev Immunol. 2014;32:227–55.
Martin DA, Towne JE, Kricorian G, Klekotka P, Gudjonsson JE, Krueger JG et al. The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings. J Invest Dermatol. 2013;133(1):17–26.
Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58(5):826–50.
Molina-Leyva A, Jiménez-Moleón JJ, Naranjo-Sintes R, Ruiz-Carrascosa JC. Sexual dysfunction in psoriasis: a systematic review. J Eur Acad Dermatol Venereol. 2015;29(4):649–55.
Mustonen A, Mattila K, Leino M, Koulu L, Tuominen R. How much of the productivity losses among psoriasis patients are due to psoriasis. BMC Health Serv Res. 2015;15:87.
Narayanan S, Guyatt V, Franceschetti A, Hautamaki EL. Disease burden and patient reported outcomes among patients with moderate to severe psoriasis: an ethnography study. Psoriasis (Auckl). 2014;5:1–7.
Nast A, Spuls PI, van der Kraaij G, Gisondi P, Paul C, Ormerod AD et al. European S3‐Guideline on the systemic treatment of psoriasis vulgaris – Update Apremilast and Secukinumab – EDF in cooperation with EADV and IPC. J Eur Acad Dermatol Venereol. 2017;31:1951–63.
Ortonne J, Prinz JC. Alefacept: a novel and selective biologic agent for the treatment of chronic plaque psoriasis. Eur J Dermatol 2004;14:41–45.
Papp KA, Leonardi C, Menter A, Ortonne JP, Krueger JG, Kricorian G et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012;366(13):1181–9.
Ramirez-Carrozzi V, Sambandam A, Luis E, Lin Z, Jeet S, Lesch J, et al. IL-17C regulates the immune function of epithelial cells in an autocrine manner. Nat Immunol. 2011;12(12):1159‒66.
Russell CB, Rand H, Bigler J, Kerkof K, Timour M, Bautista E et al. Gene expression profiles normalized in psoriatic skin by treatment with brodalumab, a human anti-IL-17 receptor monoclonal antibody. J Immunol. 2014;192(8):3828–36.
Sharma J, Balakrishnan L, Datta KK, Sahasrabuddhe NA, Khan AA, Sahu AJ et al. A knowledge base resource for interleukin-17 family mediated signaling. Cell Commun Signal. 2015;9(3):291–6.
SiliqTM Prescribing information, 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761032lbl.pdf (accessed September 2018).
Taltz® Summary of Product Characteristics, 2018. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/taltz#authorisation-details-section (accessed February 2019).
TaltzTM Prescribing Information, 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125521s000lbl.pdf (accessed September 2018).
Toy D, Kugler D, Wolfson M, Vanden Bos T, Gurgel J, Derry Jet al. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J Immunol. 2006;177(1):36‒9.
Weiss SC, Kimball AB, Liewehr DJ, Blauvelt A, Turner ML, Emanuel EJ. Quantifying the harmful effect of psoriasis on health-related quality of life. J Am Acad Dermatol. 2002;47(4):512–8.
World Health Organization, 2016. Global report on psoriasis. Available at: http://apps.who.int/iris/handle/10665/204417 (accessed September 2018).
Wright JF, Bennett F, Li B, Brooks J, Luxenberg DP, Whitters MJ et al. The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. J Immunol. 2008;15(4):2799‒805.
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