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Targeting IL-17 to treat psoriasis

Targeting IL-17 to treat psoriasis

Read time: 20 mins
This section of the Learning Zone describes the burden of disease for psoriasis and summarises the role of IL-17 in the development of psoriatic skin as well as the mechanism of action of the different anti-IL-17 biologics that are currently approved for treating moderate-to-severe psoriasis. Choose one of the subsections below, or scroll down the page, to learn more.

Why treat psoriasis?

Psoriasis is a common, lifelong, painful, disfiguring and disabling disease (World Health Organization, 2016).

The impact of psoriasis

Figure 1. The impact of psoriasis (Ortonne & Prinz, 2004; Menter et al., 2008; World Health Organisation, 2016; The International Federation of Psoriasis Associations, 2017).

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.

Impact of psoriasis on mental health

Figure 2. Impact of psoriasis on mental health (Weiss et al., 2002; Kurd et al., 2010; Armstrong et al., 2012; Donigan et al., 2015; Feldman et al., 2015; Molina-Leyva- et al., 2015; Narayanan et al., 2015)

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.

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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).

IL-17A in the pathogenesis of psoriasis

Figure 3. IL-17A in the pathogenesis of psoriasis, and targets for brodalumab, ixekizumab and secukinumab. The cells possibly contributing to the majority of IL-17A in psoratic skin are shown. Bold arrows indicate higher IL-17A production. The schematic also represents the increasingly accurate selection of therapeutic targets in psoriasis (adapted from Lonnberg et al., 2014).
IFN-γ, interferon-gamma; IL-17RA/RC, Interleukin receptor A/C complex; IL-17RA/RB, Interleukin receptor A/B complex; ; IL-17RA/RE, Interleukin receptor A/E complex; NK, natural killer; Tc, cytotoxic T cell; TGF-β, transforming growth factor-beta; Th, T helper cell; TNFα, tumour necrosis factor-alpha.

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).

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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).

IL-17 receptor signalling

Figure 4. IL-17 receptor signalling. (a) IL-17 receptor components and ligands, (b) IL-17R receptor activation (adapted from Martin et al., 2013; Sharma et al., 2015).

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).

An overview of brodalumab targeting against IL-17 in the pathogenesis of psoriasis compared to other biologics

Figure 5. An overview of brodalumab targeting against IL-17 in the pathogenesis of psoriasis compared to other biologics.
CD8+ T cells, cytotoxic T lymphocytes; γδ T cells, gamma delta T cells; ILC3, type 3 innate lymphoid cells; NK, natural killer cells; Th, T helper cell; TNFα, tumour necrosis factor-alpha (adapted from Baker & Isaacs. 2018).

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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

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

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). 

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Treatments that block IL-17 signalling at the receptor level

Brodalumab

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).

IL-17A in the pathogenesis of psoriasis

Figure 6. IL-17A in the pathogenesis of psoriasis. (A) targets for brodalumab, secukinumab, and ixekizumab (B) blocking IL-17A alone rather than targeting the IL-17 receptor subunit A will lead to continuation of inflammation (adapted from Lønnberg et al., 2014).

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). 

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This content has been developed in collaboration with LEO Pharma A/S who provided some of the content. Medthority received educational funding from the sponsor in order to help provide its healthcare professional members with access to the highest quality medical and scientific information, education and associated relevant content.