Before we understood the importance of the TH17 pathway, the TH1 pathway was thought to be the canonical pathway for psoriasis. We now appreciate that the TH17 pathway is the dominant pathogenic pathway in psoriasis and that this pathway interacts synergistically with the TH1 pathway.21–27 For example, inhibition of IL-17A has been shown to be highly effective in psoriasis.26–28 Evidence also suggests that the benefits of TNF-α inhibition may be primarily mediated through indirect downregulation of the TH17 pathway rather than direct inhibition of the TH1 pathway.26–28 To explain this TH17 pathway downregulation, TNF-α blockade is thought to suppress TNF-α activation of dendritic cells and, as a consequence, decreases IL-23 production.18 TNF-α inhibition also reduces the full effect of IL-17 on its targets.28
IL-23 in Psoriasis Pathogenesis and Therapies That Target IL-23
In psoriasis, IL-23 acts as a key regulator of the TH17 pathway. IL-23 promotes TH17 cell phenotype maintenance and survival and, therefore, the production of proinflammatory cytokines secreted by TH17 cells such as IL-17A and IL-17F.2,9,29–35 Furthermore, IL-23 promotes T-regulatory (Treg) cell differentiation into TH17 cells.36
IL-23 consists of a p19 subunit and a p40 subunit; the p40 subunit is also common to IL-12. IL-23 is secreted by innate immune cells (Langerhans cells, dendritic cells, and monocytes/macrophages) following an inflammatory or biochemical insult to the skin.37–39
Three FDA-approved biologic therapies target IL-23 in psoriasis. Ustekinumab inhibits both IL-12 and IL-23 by inhibiting the common p40 subunit. Guselkumab and tildrakizumab both target IL-23 specifically by inhibiting the p19 subunit. Two IL-23 inhibitors in late phase development, risankizumab and mirikizumab, also target the p19 subunit.
Interestingly, the pharmacodynamic properties of therapeutic IL-23 antibodies appear to exceed their pharmacokinetics. In other words, the clinical effect of IL-23 inhibition is much longer than the functional half-life of IL-23 antagonists; therefore, reduced dosing frequencies up to every 12 weeks are possible. 40–42 It is postulated that these effects may be secondary to the reversal of IL-23 effector functions in psoriasis. That is, IL-23 inhibition may bring about prolonged efficacy through improved Treg cell functioning, decreased production and survival of TH17 cells, and/or a phenotypic change of TH17 cells, resulting in reduced proinflammatory cytokines.20,43–46 Impaired survival of TH17 cells has important implications in psoriasis as TH17 cells are usually long-lasting and active as resident effector T-memory cells even after skin repair.44,45 A survey of psoriasis patients showed that, when considering treatment options, the medication’s ability to achieve clear or almost clear skin was more important than dosing frequency.47
Furthermore, IL-23 inhibition incompletely blocks IL-17. That is, when IL-23 is blocked, only TH17 cell derived IL-17 subtypes are at risk of being inhibited. However, IL-17 subtypes produced by cells independent of TH17 cells can still be expressed (Table 1).48–50 In the treatment of psoriasis, inhibiting only the pathogenically elevated amounts of IL-17 is important because appropriate amounts of IL-17 are necessary for protection against fungal infections including mucocutaneous infections such as candida albicans.51,52 The challenge lies in inhibiting just the appropriate amount. That is, while inhibiting too much IL-17 may be associated with emergence of fungal infections, inhibiting too little can be associated with residual psoriatic disease.
The IL-17 Family
The IL-17 family comprises five IL-17 isoforms based on subunits A, F, C, and E: AA homodimer, AF heterodimer, FF homodimer, CC homodimer, and EE homodimer.16,53 The most important IL-17 family members or subtypes in psoriasis pathology are IL-17A, IL-17F, IL-17C, and IL-17E.54–57
There are four relevant IL-17 receptor (R) isoforms in psoriasis: IL-17RA, IL-17RB, IL-17RC, and IL-17RE. All IL-17 family isoforms share the IL-17RA subunit.58
IL-23 in Psoriasis Pathogenesis and Therapies That Target IL-23
In psoriasis, IL-23 acts as a key regulator of the TH17 pathway. IL-23 promotes TH17 cell phenotype maintenance and survival and, therefore, the production of proinflammatory cytokines secreted by TH17 cells such as IL-17A and IL-17F.2,9,29–35 Furthermore, IL-23 promotes T-regulatory (Treg) cell differentiation into TH17 cells.36
IL-23 consists of a p19 subunit and a p40 subunit; the p40 subunit is also common to IL-12. IL-23 is secreted by innate immune cells (Langerhans cells, dendritic cells, and monocytes/macrophages) following an inflammatory or biochemical insult to the skin.37–39
Three FDA-approved biologic therapies target IL-23 in psoriasis. Ustekinumab inhibits both IL-12 and IL-23 by inhibiting the common p40 subunit. Guselkumab and tildrakizumab both target IL-23 specifically by inhibiting the p19 subunit. Two IL-23 inhibitors in late phase development, risankizumab and mirikizumab, also target the p19 subunit.
Interestingly, the pharmacodynamic properties of therapeutic IL-23 antibodies appear to exceed their pharmacokinetics. In other words, the clinical effect of IL-23 inhibition is much longer than the functional half-life of IL-23 antagonists; therefore, reduced dosing frequencies up to every 12 weeks are possible. 40–42 It is postulated that these effects may be secondary to the reversal of IL-23 effector functions in psoriasis. That is, IL-23 inhibition may bring about prolonged efficacy through improved Treg cell functioning, decreased production and survival of TH17 cells, and/or a phenotypic change of TH17 cells, resulting in reduced proinflammatory cytokines.20,43–46 Impaired survival of TH17 cells has important implications in psoriasis as TH17 cells are usually long-lasting and active as resident effector T-memory cells even after skin repair.44,45 A survey of psoriasis patients showed that, when considering treatment options, the medication’s ability to achieve clear or almost clear skin was more important than dosing frequency.47
Furthermore, IL-23 inhibition incompletely blocks IL-17. That is, when IL-23 is blocked, only TH17 cell derived IL-17 subtypes are at risk of being inhibited. However, IL-17 subtypes produced by cells independent of TH17 cells can still be expressed (Table 1).48–50 In the treatment of psoriasis, inhibiting only the pathogenically elevated amounts of IL-17 is important because appropriate amounts of IL-17 are necessary for protection against fungal infections including mucocutaneous infections such as candida albicans.51,52 The challenge lies in inhibiting just the appropriate amount. That is, while inhibiting too much IL-17 may be associated with emergence of fungal infections, inhibiting too little can be associated with residual psoriatic disease.
The IL-17 Family
The IL-17 family comprises five IL-17 isoforms based on subunits A, F, C, and E: AA homodimer, AF heterodimer, FF homodimer, CC homodimer, and EE homodimer.16,53 The most important IL-17 family members or subtypes in psoriasis pathology are IL-17A, IL-17F, IL-17C, and IL-17E.54–57
There are four relevant IL-17 receptor (R) isoforms in psoriasis: IL-17RA, IL-17RB, IL-17RC, and IL-17RE. All IL-17 family isoforms share the IL-17RA subunit.58
