From the Guidelines
Interleukin-17 (IL-17) and Interleukin-23 (IL-23) inhibitors are highly effective in treating psoriasis due to their targeted mechanism of disrupting the IL-23/IL-17 axis, a key inflammatory pathway in the disease's pathogenesis. The IL-23/IL-17 axis plays a central role in the development of psoriatic lesions, with IL-23 stimulating the differentiation and activation of Th17 cells, which then produce IL-17 1. IL-17 promotes keratinocyte proliferation, neutrophil recruitment, and production of antimicrobial peptides and other pro-inflammatory cytokines, creating the characteristic psoriatic plaques.
Mechanism of Action
IL-23 inhibitors, such as guselkumab, risankizumab, and tildrakizumab, prevent IL-23 from binding to its receptor, thereby inhibiting Th17 cell activation upstream 1. On the other hand, IL-17 inhibitors, including secukinumab, ixekizumab, and brodalumab, directly block IL-17 or its receptor, preventing downstream inflammatory effects 1.
Clinical Efficacy
These medications have demonstrated superior efficacy compared to older biologics, with PASI 90 (90% improvement) achieved in 50-70% of patients within 12-16 weeks 1. Their targeted mechanism minimizes systemic immunosuppression while effectively resolving the specific inflammatory cascade responsible for psoriatic lesions, explaining their remarkable clinical success in clearing skin and maintaining long-term remission.
Key Considerations
It is essential to note that while IL-17 inhibitors are effective in treating psoriasis, they may exacerbate inflammatory bowel disease (IBD) in some patients 1. In contrast, IL-23 inhibitors have shown promise in treating IBD, including Crohn's disease 1. Therefore, careful consideration of a patient's medical history and comorbidities is necessary when selecting a biologic therapy for psoriasis.
Treatment Recommendations
The use of IL-17 and IL-23 inhibitors is recommended as a first-line treatment option for patients with moderate-to-severe plaque psoriasis, given their high efficacy and favorable safety profile 1. The choice between IL-17 and IL-23 inhibitors should be individualized based on patient-specific factors, including comorbidities and potential risks of adverse effects.
From the FDA Drug Label
Secukinumab is a human IgG1 monoclonal antibody that selectively binds to the interleukin-17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Secukinumab inhibits the release of proinflammatory cytokines and chemokines. Elevated levels of IL-17A are found in psoriatic plaques and in HS lesions. Treatment with COSENTYX may reduce epidermal neutrophils and IL-17A levels in psoriatic plaques.
The molecular mechanism behind the high efficacy of IL-17 inhibitors, such as secukinumab, in treating psoriasis is the inhibition of IL-17A interaction with the IL-17 receptor, which leads to a decrease in the release of proinflammatory cytokines and chemokines. This results in a reduction of epidermal neutrophils and IL-17A levels in psoriatic plaques. Although the provided label does not directly discuss IL-23, the mechanism of IL-17 inhibition provides insight into the potential efficacy of IL-17 and IL-23 inhibitors in treating psoriasis 2.
From the Research
Molecular Mechanism of IL-17 and IL-23 Inhibitors in Psoriasis Treatment
The molecular mechanism behind the high efficacy of Interleukin-17 (IL-17) and Interleukin-23 (IL-23) inhibitors in treating psoriasis involves the inhibition of the IL-23/IL-17 axis, which plays a central role in the immunopathogenesis of psoriasis 3. This axis stimulates keratinocyte hyperproliferation and feeds forward circuits of perpetual T cell-mediated inflammation.
Key Players in the IL-23/IL-17 Axis
- IL-23: plays a pivotal role in stimulating the production of IL-17 by activating the Th17 cells 4
- IL-17: an essential proinflammatory cytokine, mainly secreted by the CD4+ helper T cells (Th17 cells) and subsets of innate lymphoid cells, associated with the pathogenesis of inflammatory diseases, including psoriasis 4
- Th17 cells: activated by IL-23, produce IL-17, which drives the inflammatory cascade in psoriasis 5
Mechanism of Action of IL-17 Inhibitors
- Secukinumab, a fully human mAb that selectively inhibits IL-17A, improves the complete spectrum of psoriasis manifestations, with durable clinical responses beyond 5 years of treatment 5
- IL-17A inhibition by secukinumab induces early clinical, histopathologic, and molecular resolution of psoriasis, reversing plaque histopathology and modulating thousands of transcripts 5
- Suppression of the IL-23/IL-17 axis by secukinumab is evident at week 1 and continues through week 12, including reductions in levels of the upstream cytokine IL-23, the drug target IL-17A, and downstream targets 5
Efficacy of IL-17 and IL-23 Inhibitors
- IL-17 inhibitors have the shortest time to achieve PASI75 and PASI90, followed by IL-23 inhibitors 6
- Biologic therapies targeting the IL-23/IL-17 immune axis have high efficacy in the treatment of moderate-to-severe plaque psoriasis, with IL-17 inhibitors showing higher efficacy than IL-23 inhibitors during induction therapy 7
- However, IL-17 inhibitors have an increased risk of adverse events compared to IL-23 inhibitors 7