What are IL-23 Inhibitors and how do they work?
IL-23 inhibitors represent a class of biologic medications that have transformed the treatment of chronic inflammatory diseases. They work by targeting interleukin-23 (IL-23), a key inflammatory cytokine that plays a central role in driving immune system dysfunction.
IL-23 is a pro-inflammatory cytokine composed of two subunits called p19 and p40. When this cytokine becomes overactive, it triggers a cascade of inflammatory responses that can lead to painful, debilitating conditions affecting the skin, joints, and digestive system. By blocking IL-23's action, these inhibitors help limit the inflammation that causes symptoms in conditions like psoriasis, psoriatic arthritis, and inflammatory bowel diseases.
This cytokine is essential for maintaining and expanding T helper type 17 cells (Th17 cells), which release inflammatory substances including IL-17, IL-21, IL-22, and GM-CSF. When this system becomes dysregulated, it contributes to the chronic inflammation seen in autoimmune diseases.
Which Drugs Are IL-23 Inhibitors?
Currently, there are four FDA-approved IL-23 inhibitors available for treating various inflammatory conditions:
These medications differ in their specific targeting mechanisms. Older medications like Stelara (ustekinumab) block the p40 subunit shared by both IL-12 and IL-23, while newer agents like Tremfya (guselkumab) and Skyrizi (risankizumab) specifically target the p19 subunit unique to IL-23.
What Conditions Are Treated by IL-23 Inhibitors?
IL-23 inhibitors have proven effective across multiple inflammatory conditions:
Plaque Psoriasis
Skyrizi, Tremfya, and Ilumya are approved for treating moderate to severe plaque psoriasis. Clinical trials have shown impressive results, with around 75% of patients achieving at least 90% improvement in their psoriasis symptoms after 12-16 weeks of treatment.
Psoriatic Arthritis
Both Skyrizi and Tremfya are approved for psoriatic arthritis, effectively improving joint disease activity while also addressing skin symptoms. Meta-analyses confirm that IL-23 inhibitors significantly improve joint function scores and quality of life measures.
Inflammatory Bowel Diseases
- Ulcerative Colitis (UC): Omvoh became the first IL-23 inhibitor approved specifically for this condition. Skyrizi and Trefyma are also approved for adults with UC.
- Crohn's Disease (CD): Omvoh, Tremfya, and Skyrizi have received approval for treating Crohn's disease.
How Do IL-23 Inhibitors Work? (Mechanism of Action)
IL-23 is a chemical that helps maintain immune cells called Th17 cells, which normally protect against infections. In autoimmune disease, IL-23 becomes overactive and causes Th17 cells to produce excessive amounts of inflammatory substances. IL-23 inhibitors attach to IL-23 and prevent it from activating Th17 cells, thereby reducing inflammation.
This mechanism differs from other biologics. While TNF inhibitors block a downstream inflammatory protein and IL-17 inhibitors directly target the end product of inflammation, IL-23 inhibitors work upstream, potentially providing more comprehensive inflammatory control.
The specificity of newer IL-23 inhibitors offers advantages over older drugs like Stelara (ustekinumab). By targeting only IL-23 (not IL-12), these newer medications preserve important immune functions while effectively reducing pathogenic inflammation.
IL-23 vs. IL-17 Inhibitors: What’s the Difference?
Both IL-23 and IL-17 inhibitors are highly effective, but they have distinct characteristics that influence treatment decisions.
IL-23 Inhibitors
- Block inflammation upstream in the immune cascade
- Provide longer-lasting effects with less frequent dosing (every 8-12 weeks)
- Show sustained efficacy even after discontinuation, with median time to symptom return ranging from 23-42 weeks
- Associated with strong safety profiles
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IL-17 Inhibitors
- Block inflammation directly at the tissue level
- Offer faster symptom relief, particularly for skin clearance
- Require more frequent dosing
- Have demonstrated radiographic benefits in preventing joint damage in psoriatic arthritis
Network meta-analyses show that the most effective IL-17 inhibitors (ixekizumab and brodalumab) and IL-23 inhibitors (guselkumab and risankizumab) achieve similar efficacy rates. However, IL-17 inhibitors provide more rapid initial responses, while IL-23 inhibitors excel in sustained, long-term control. Healthcare providers choose based on factors like disease type, severity, and comorbidities.
Are IL-23 Inhibitors Safe for Long-Term Use?
Long-term safety data for IL-23 inhibitors is reassuring, with studies following patients for up to 6 years. Key safety findings include:
Common Side Effects
The most frequently reported adverse events are mild and include:
- Upper respiratory tract infections
- Nasopharyngitis (common cold symptoms)
- Injection site reactions
- Mild, transient liver enzyme elevations
Serious Risks
IL-23 inhibitors have a robust safety profile with low rates of serious adverse events. The incidence of serious infections and malignancies appears comparable to rates seen in the general psoriasis population. Importantly, IL-23 inhibitors show lower infection risks compared to IL-17 inhibitors, likely because they preserve some protective immune functions.
Long-term Monitoring
Real-world studies support the safety of long-term IL-23 inhibitor use across diverse patient populations, including older patients and those with multiple comorbidities. Safety profiles remain consistent or even improve with prolonged treatment duration.
IL-23 vs. TNF Inhibitors: When Are They Used?
TNF inhibitors like Humira and Enbrel were the first-generation biologics for treating inflammatory diseases. While still effective, IL-23 inhibitors offer several potential advantages.
When IL-23 Inhibitors May Be Preferred
- Patients seeking less frequent dosing schedules
- Those who have failed or developed intolerance to TNF inhibitors
- Patients preferring newer agents with more targeted mechanisms of action
- Cases where sustained, long-term remission is prioritized
Treatment Persistence Considerations
Interestingly, real-world data suggests that patients may have higher medication adherence with TNF inhibitors during the first year of treatment, though overall treatment persistence rates are similar between drug classes. This may reflect dosing frequency differences and patient preferences.
The choice between IL-23 and TNF inhibitors often depends on individual patient factors, including disease severity, comorbidities, previous treatment responses, and dosing preferences.
Summary
IL-23 inhibitors represent a major advance in treating chronic inflammatory diseases, offering several compelling benefits:
- Targeted effectiveness: These medications provide highly effective treatment for psoriasis, psoriatic arthritis, and inflammatory bowel diseases
- Convenient dosing: Most require injections only every 8-12 weeks, improving quality of life
- Strong safety profile: Long-term studies support their safety across diverse patient populations
- Sustained benefits: Patients often maintain improvement for months even after discontinuation
The choice between different biologic options should involve thorough discussion between patients and healthcare providers, considering individual disease characteristics, lifestyle preferences, and treatment goals.
References
- Huang, X., Shentu, H., He, Y., Lai, H., Xu, C., Chen, M., & Zhu, H. 2023. Efficacy and safety of IL-23 inhibitors in the treatment of psoriatic arthritis: a meta-analysis based on randomized controlled trials. Immunologic research, 71(4), 505–515. https://doi.org/10.1007/s12026-023-09366-4
- Ilumya [package insert]. Updated 2025. Sun Pharmaceutical Industries, Inc. Accessed on July 29, 2025 at https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c6a322bb-51b9-4f0e-8642-62a9682ffcde
- Jairath, V., Acosta Felquer, M. L., & Cho, R. J. 2024. IL-23 inhibition for chronic inflammatory disease. Lancet (London, England), 404(10463), 1679–1692. https://doi.org/10.1016/S0140-6736(24)01750-1
- Jin, Y., et. al. 2021. Patient characteristics associated with use of TNF vs interleukin inhibitors as first-line biologic treatment for psoriatic arthritis. Journal of managed care & specialty pharmacy, 27(8), 1106–1117. https://doi.org/10.18553/jmcp.2021.27.8.1106
- Omvoh [package insert]. Updated 2025. Eli Lilly and Company. Accessed July 29, 2025 at https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=472cbe04-263e-433d-9a0f-58c1b50b715a
- Parigi, T. L., et. al. 2022. Blockade of IL-23: What is in the Pipeline?, Journal of Crohn's and Colitis, Volume 16, Issue Supplement_2, April 2022, Pages ii64–ii72, https://doi.org/10.1093/ecco-jcc/jjab185
- Sawyer, L. M., Malottki, K., Sabry-Grant, C., Yasmeen, N., Wright, E., Sohrt, A., Borg, E., & Warren, R. B. (2019). Assessing the relative efficacy of interleukin-17 and interleukin-23 targeted treatments for moderate-to-severe plaque psoriasis: A systematic review and network meta-analysis of PASI response. PloS one, 14(8), e0220868. https://doi.org/10.1371/journal.pone.0220868
- Skyrizi [package insert]. Updated 2025. AbbVie Inc. Accessed July 29, 2025 at https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7148c8eb-b39e-e20a-6494-a6df82392858
- Tremfya [package insert]. Updated 2025. Janssen Biotech, Inc. Accessed on July 29, 2025 at https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1e6dc9ae-1c4c-42d9-87aa-c315ecc51b56
- Wu, S., Xu,et. al. 2023. Short-term risk and long-term incidence rate of infection and malignancy with IL-17 and IL-23 inhibitors in adult patients with psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Frontiers in immunology, 14, 1294416. https://doi.org/10.3389/fimmu.2023.1294416
- Yang, K., Oak, A. S. W., & Elewski, B. E. (2021). Use of IL-23 Inhibitors for the Treatment of Plaque Psoriasis and Psoriatic Arthritis: A Comprehensive Review. American journal of clinical dermatology, 22(2), 173–192. https://doi.org/10.1007/s40257-020-00578-0
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