IL-23/IL-17 axis in psoriatic disease: From pathogenesis to personalized treatment

Introduction

Psoriasis is a chronic, immune-mediated inflammatory disease in which dysregulation of the interleukin (IL)-23/IL-17 axis plays a pivotal role. Genetic and environmental factors trigger keratinocyte stress, initiating an inflammatory cascade that activates plasmacytoid dendritic cells (pDCs) and promotes the release of pro-inflammatory mediators.^1,2 This, in turn, leads to activation of myeloid dendritic cells (mDCs) and production of IL-12, IL-23, and tumor necrosis factor (TNF)-α. IL-23 is a key driver of T helper 17 (Th17) responses and induces secretion of IL-17, which stimulates keratinocytes to release antimicrobial peptides, cytokines, and chemokines, thereby driving keratinocyte proliferation and the formation of psoriatic plaques (Figure 1).^1,2

IL-23/IL-17 axis as a therapeutic target in psoriatic disease

Among the six identified IL-17 isoforms, IL-17A and IL-17F are considered the most pathogenic in psoriasis.⁴ The interaction between IL-17A/A, IL-17A/F, and IL-17F/F cytokines, and their receptors IL-17RA and IL-17RC, drives the immune response.² Figure 2 illustrates the therapeutic targets of biologic agents directed against the IL-17/IL-23 pathway. IL-17 pathway inhibition may be achieved through selective inhibition of IL-17A (secukinumab, ixekizumab), blockade of the IL-17RA (brodalumab), or dual inhibition of IL-17A and IL-17F (bimekizumab, sonelokimab, ORKA-002).^2,5,6 IL-23 inhibitors act by targeting the shared IL-12/23 p40 subunit (ustekinumab) or the IL-23 p19 subunit (risankizumab, guselkumab, tildrakizumab, icotrokinra).^2,7 

Several of these biologic agents are approved by the U.S. Food and Drug Administration (FDA) for the treatment of plaque psoriasis (PsO) and psoriatic arthritis (PsA), reflecting their established efficacy and safety profiles in phase III trials (Table 1).^16–38 IL-17A inhibitors such as secukinumab and ixekizumab, as well as the IL-17RA blocker brodalumab, are approved for moderate-to-severe PsO, with secukinumab and ixekizumab also indicated for PsA.^8–10 The dual IL-17A/IL-17F inhibitor bimekizumab has been more recently approved for both PsO and PsA,¹¹ while sonelokimab and ORKA-002 remain investigational.^5,6 Watch a discussion by the PsOPsA Hub Steering Committee to gain further insights into the clinical implications of IL-17A/F dual inhibitors in the treatment of psoriatic disease.

Among IL-23 inhibitors, ustekinumab was the first to gain FDA approval through its dual targeting of IL‑12/23 p40,¹² followed by the selective IL‑23p19 inhibitors guselkumab, risankizumab and tildrakizumab in moderate-to-severe PsO, with ustekinumab, guselkumab, and risankizumab also approved for the treatment of active PsA.^13–15 Emerging agents like icotrokinra are undergoing clinical development, underscoring the continued evolution of targeted therapy within the IL-23/IL-17 axis.

Table 1. Efficacy of FDA-approved IL-17, IL-12/23, and IL-23 inhibitors for psoriatic disease*

Comparative efficacy of IL-23/IL-17 inhibitors

Given the growing number of biologic treatment options for psoriasis, selecting the most appropriate therapy remains a key clinical challenge. Several comparative trials between these agents, as summarized in Table 2, provide valuable insights to guide clinicians in tailoring therapy to individual patient needs. Clinical evidence indicates that IL-17 inhibitors are associated with a more rapid onset of response compared with IL-23 inhibitors, whereas IL-23 blockade demonstrates durable responses.³ In addition, dual inhibition of IL-17A/F appears to offer superior efficacy than with IL-17A inhibition alone.³ In the BE RADIANT trial, bimekizumab administered over 16 weeks achieved greater skin clearance than secukinumab in patients with moderate-to-severe psoriasis (Table 2).³⁹ Although no direct head-to-head trial has evaluated bimekizumab vs secukinumab in PsA, a matching-adjusted indirect comparison suggested a higher likelihood of achieving ACR70 responses with bimekizumab in patients who were biologic-naïve (odds ratio [OR], 2.39; p = 0.008) or those with prior inadequate response to TNF inhibitors (OR, 2.95; p = 0.035).⁴⁰ However, as IL-17F also plays a role in mucosal immunity, dual IL-17A/F blockade carries an elevated risk of Candida infections than with IL-17A inhibition alone. Accordingly, selection of an appropriate agent should consider individual patient factors, including comorbidities, prior treatment history, and safety profiles.

Table 2. Key head-to-head trials between IL-17/23 inhibitors*

Future directions

Future research on IL-23/IL-17 inhibitors is focused on leveraging a multi-omics approach to investigate the pathway’s nuanced effects across different cell types and tissues. In addition, there is a need to identify optimal timing for therapy initiation, uncover biomarkers predictive of treatment response, and characterize epigenetic and post-translational modifications influencing disease progression and therapeutic outcomes. These insights may inform personalized treatment strategies, improve prediction of clinical outcomes, and optimize the long-term efficacy and safety of IL-17/IL-23-targeted therapies in psoriatic disease.⁴⁴

Conclusions

The IL-23/IL-17 axis is central to the pathogenesis of psoriatic disease, and targeting this pathway with biologics has transformed treatment for both PsO and PsA. IL-17 inhibitors offer rapid clinical responses, while IL-23 blockade provides durable outcomes, and dual IL-17A/F inhibition may further enhance efficacy over IL-17 inhibition alone. Future research leveraging multi-omics approaches and biomarker-driven strategies is needed to optimize therapy timing, personalize treatment, and improve long-term efficacy and safety, guiding more precise management of psoriatic disease.

This educational resource is independently supported by UCB. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.