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