IL-23 inhibitors have emerged as one of the most effective and well-tolerated classes of biologic therapy for immune-mediated diseases, reshaping treatment across dermatology, gastroenterology, and rheumatology over the past decade. These drugs work by selectively blocking interleukin-23, a signaling molecule that drives a specific arm of the immune system responsible for chronic inflammation in conditions like psoriasis, Crohn’s disease, and ulcerative colitis. What makes the class genuinely noteworthy is the combination of high skin-clearance rates, a favorable safety record compared to older biologics, and dosing schedules that can stretch to once every two or three months. The story gets more interesting when you look at where these drugs succeed spectacularly and where, against expectations, they fail entirely.
Why IL-23 Matters in Immune-Driven Disease
IL-23 is a two-part protein made up of a p19 subunit and a p40 subunit. Its primary job is maintaining a population of immune cells called Th17 cells, which produce inflammatory molecules like IL-17, IL-22, and GM-CSF. Under normal circumstances, Th17 cells help defend against bacterial and fungal infections. But when IL-23 keeps these cells activated for too long or in the wrong context, the result is the kind of sustained, tissue-damaging inflammation seen in autoimmune and autoinflammatory diseases.
Research has shown that IL-23 does not create Th17 cells from scratch; other signals handle that initial step. Instead, IL-23 sustains their inflammatory behavior and pushes them toward a more aggressive, disease-causing state.
1PubMed Central. IL-23 promotes maintenance but not commitment to the Th17 lineage IL-23 regulates key effector molecules that drive inflammation in autoimmune disease, making it a linchpin in the inflammatory cascade rather than just one contributor among many.2Journal of Cellular Immunology. Persistence, Pathogenicity and Plasticity: The Role of IL-23 in Th17 Fate This upstream role is what makes IL-23 such an appealing drug target: blocking it interrupts the inflammatory process closer to its source rather than mopping up individual downstream messengers one at a time.3PubMed Central. The Role of IL-23 in the Development of Inflammatory Diseases
Selective p19 Blockers Versus the Older Approach
The first drug to target IL-23 was ustekinumab, approved in 2009. It binds the p40 subunit shared by both IL-12 and IL-23, so it blocks both cytokines at once.4PubMed. Structural basis for the dual recognition of IL-12 and IL-23 by ustekinumab That was a reasonable strategy at the time, but it came with a theoretical concern: IL-12 drives a different branch of immunity involved in tumor surveillance and defense against certain infections. Dermatologists and rheumatologists long suspected that the clinical benefit of ustekinumab was really coming from its anti-IL-23 activity rather than its anti-IL-12 activity, and early evidence from mouse models and human studies supported that idea.5PubMed. Specific targeting of interleukin-23p19 as effective treatment for psoriasis
This led to the development of a newer generation of drugs that bind only the p19 subunit of IL-23, leaving IL-12 intact. Three p19-specific inhibitors are now widely approved: guselkumab, risankizumab, and tildrakizumab. While all three target p19, they bind to different spots on the protein. Risankizumab and guselkumab grab onto larger surface areas of p19, while tildrakizumab binds a smaller patch. Guselkumab has the most overlap with the site where IL-23 normally docks with its receptor on immune cells, which may partly explain differences in how these drugs perform clinically.6JID Innovations. Structural Basis for p19 Targeting by Anti–IL-23 Biologics: Correlations with Short- and Long-Term Efficacy in Psoriasis
Psoriasis Clearance Rates
Psoriasis was the first disease to see the full impact of selective IL-23 blockade, and the results set a high bar. In clinical trials, these drugs consistently outperformed both placebo and older biologics. Guselkumab achieved a 90 percent improvement in the Psoriasis Area and Severity Index (PASI 90) in about three-quarters of patients by week 16. Risankizumab performed similarly, with PASI 90 rates of roughly 75 percent at week 16, compared to about 42 percent for ustekinumab and under 5 percent for placebo in the same trial. Tildrakizumab showed somewhat lower numbers, with PASI 75 responses in the low 60 percent range at week 12, though it still vastly outperformed placebo.7Journal of Inflammation Research. IL-23 Inhibitors in Psoriasis: What Have We Learnt so Far?
Across the class, IL-23 inhibitors have proven safe and effective for psoriasis, and head-to-head data suggest they outperform older treatments including TNF-alpha inhibitors.8PubMed Central. Use of IL-23 Inhibitors for the Treatment of Plaque Psoriasis and Psoriatic Arthritis: A Comprehensive Review The practical appeal is reinforced by dosing: after an initial loading period, patients on risankizumab or guselkumab typically inject once every eight to twelve weeks, a schedule far less burdensome than the every-two-week regimens common with TNF blockers.
Inflammatory Bowel Disease
The expansion into Crohn’s disease and ulcerative colitis has been one of the most significant recent developments for IL-23 inhibitors. Across phase II and III trials, risankizumab, mirikizumab, and guselkumab have demonstrated clinical remission rates approaching 40 to 50 percent in ulcerative colitis and exceeding 50 percent in Crohn’s disease during maintenance therapy, with improvements in both endoscopic healing and tissue-level outcomes.9PubMed Central. Interleukin-23 Inhibitors in Inflammatory Bowel Disease
Mirikizumab, the newest member of the class, was the first IL-23 inhibitor approved specifically for ulcerative colitis. In its pivotal phase III trial, patients receiving mirikizumab were significantly more likely to achieve clinical remission than those on placebo at both the end of induction (about 24 percent versus 13 percent at week 12) and through maintenance (roughly 50 percent versus 25 percent at week 40).10PubMed. Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis A network meta-analysis comparing agents for Crohn’s disease induction found mirikizumab with the strongest odds of inducing complete remission, followed by guselkumab, risankizumab, and then ustekinumab, though all performed better than placebo.11PubMed Central. Efficacy and Safety of IL-23 Inhibitors in the Treatment of Crohn’s Disease and Ulcerative Colitis: Systemic Review and Network Meta-Analysis
For gastroenterologists, this class fills a real gap. Many patients with IBD lose response to TNF inhibitors over time or never respond adequately in the first place. Having a mechanistically distinct option with strong remission data and a clean safety record changes treatment planning in a concrete way.
Psoriatic Arthritis and Joint Disease
Psoriatic arthritis involves both skin and joint inflammation, and the response to IL-23 inhibitors here tells a more nuanced story. For the skin component, these drugs work about as well as they do in pure plaque psoriasis. For joint inflammation, the picture is more mixed.
Guselkumab has shown meaningful improvement in enthesitis (inflammation where tendons attach to bone) and dactylitis (swollen “sausage” fingers or toes), two particularly troublesome features of psoriatic arthritis. In a phase II study, patients treated with guselkumab had significantly greater resolution of both enthesitis and dactylitis by week 24 compared to placebo.12RMD Open. Impact of guselkumab, an interleukin-23 p19 subunit inhibitor, on enthesitis and dactylitis in patients with moderate to severe psoriatic arthritis Risankizumab has also demonstrated improvements in patient-reported outcomes for psoriatic arthritis, including significant gains in physical function, fatigue, and pain scores compared to placebo at week 24.13RMD Open. Improved patient-reported outcomes in patients with psoriatic arthritis treated with risankizumab: analysis of the Phase 3 trial KEEPsAKE 2
That said, the joint response rates tend to be somewhat more modest than what is achieved by IL-17 inhibitors or TNF blockers in the same setting, particularly when measuring traditional composite joint scores. For patients whose disease burden is split heavily between skin and joints, the choice between drug classes often depends on which domain is causing more trouble.
How IL-23 Inhibitors Compare to IL-17 and TNF Blockers
The immune pathway from IL-23 to IL-17 to tissue inflammation means that drugs targeting IL-17 directly and drugs targeting IL-23 upstream are working on the same cascade, but at different points. This creates real differences in clinical performance that matter for treatment decisions.
IL-17 inhibitors tend to clear psoriasis faster. Comparative analyses have found that IL-17 blockers generally achieve skin clearance more quickly than IL-23 inhibitors, though risankizumab at its standard dose comes close to matching some IL-17 agents in speed.14Journal of the American Academy of Dermatology. Extrapolating the speed of psoriasis clearance: a comparative analysis of biologic agents in clinical trials However, IL-23 inhibitors tend to win on durability and safety. Responses remain stable over long treatment periods, and the drugs lack the increased risks of mucocutaneous candidiasis and inflammatory bowel disease flares that have been associated with IL-17 blockade.15Biomolecules & Therapeutics. Current and Emerging Therapies Targeting the IL-23/IL-17 Axis in Psoriasis
When compared to TNF inhibitors, both IL-23 and IL-17 blockers are generally more effective for skin disease. The IL-17 signature is more pronounced in skin than in joint tissue, which helps explain why agents targeting the IL-23/IL-17 axis perform especially well on the dermatology side.16PubMed. Differential efficacy of biologic treatments targeting the TNF-α/IL-23/IL-17 axis in psoriasis and psoriatic arthritis Inhibitors specifically targeting IL-23 or IL-17 have been found to be more clinically beneficial than those blocking IL-12/IL-23 together (ustekinumab) or TNF alone.17PubMed. The TNF/IL-23/IL-17 axis-Head-to-head trials comparing different biologics in psoriasis treatment
Safety and Tolerability
The safety profile of selective IL-23 p19 inhibitors is one of the class’s strongest selling points. Across clinical trials with years of follow-up, serious adverse events have not been elevated with long-term use. Rates of serious infections, skin cancers, other malignancies, major cardiovascular events, and severe allergic reactions have remained low and comparable to placebo in controlled periods.18PubMed Central. Safety of IL-23 p19 Inhibitors for the Treatment of Patients With Moderate-to-Severe Plaque Psoriasis: A Narrative Review
The most commonly reported side effects are upper respiratory infections, which is a finding so common across biologic classes that it is almost unremarkable. Crucially, selective IL-23 blockade has not been linked to the safety signals that complicate other biologics: no increased risk of tuberculosis reactivation, opportunistic infections, oral candidiasis, inflammatory bowel disease flares, demyelinating disorders, or suicidal ideation.19PubMed Central. Safety of selective IL-23p19 inhibitors for the treatment of psoriasis The absence of the candidiasis risk seen with IL-17 inhibitors and the absence of IBD exacerbation risk are particularly meaningful, since these concerns sometimes force clinicians away from otherwise effective treatments.
Immunogenicity and the Antibody Question
Because IL-23 inhibitors are monoclonal antibodies, the body can sometimes develop anti-drug antibodies in response to treatment. A systematic review found that the incidence of these antibodies varied across agents: roughly 4 to 15 percent with guselkumab, 14 to 31 percent with risankizumab, and 7 to 18 percent with tildrakizumab. The rates of neutralizing antibodies, which are the ones most likely to interfere with the drug, were much lower: under 1 percent for guselkumab, 2 to 16 percent for risankizumab, and around 2.5 to 3 percent for tildrakizumab.20PubMed. Anti-drug antibodies of IL-23 inhibitors for psoriasis: a systematic review
The reassuring finding is that simply having detectable anti-drug antibodies did not predict a loss of clinical response in most cases. Some studies found that very high antibody levels or the presence of neutralizing antibodies specifically could be linked to reduced effectiveness, but routine testing for anti-drug antibodies does not appear useful as a clinical tool for managing these patients.21PubMed Central. The Phenomenon of Anti-Drug Antibodies in Psoriasis: Mechanisms, Clinical Impact, and Therapeutic Strategies In practice, this means most patients maintain their response over time, though a small subset will lose efficacy and need to switch agents.
Where IL-23 Inhibitors Fail
One of the more puzzling findings in the field is the complete failure of IL-23 inhibitors in axial spondyloarthritis, the form of inflammatory arthritis that primarily affects the spine and sacroiliac joints. On paper, this disease should respond: IL-23 is an upstream driver of Th17 cells, and IL-17 inhibitors do work in axial spondyloarthritis. Yet multiple trials of IL-23 blockade in this condition showed no clinical benefit whatsoever.22PubMed Central. IL-23 Inhibition in Ankylosing Spondylitis: Where Did It Go Wrong?
The prevailing explanation is that the IL-17-producing cells driving spinal inflammation may not depend on IL-23 to the same extent as those in the skin or gut. In the spine, other cell populations that make IL-17 independently of IL-23 signaling could be dominant. This disconnect serves as a useful reminder that even when a pathway looks like a clean line from one cytokine to the next, the biology in different tissues can diverge in ways that defeat tidy predictions. For clinicians, it means that if a patient has psoriasis along with spinal disease, an IL-23 inhibitor may clear the skin beautifully while doing nothing for the back pain.
Quality of Life Beyond Skin Clearance
Psoriasis trials tend to be reported in PASI scores and clinical photographs, but what patients care about is whether they feel better in their daily lives. Quality-of-life data for IL-23 inhibitors has been consistently strong. In a real-world phase IV study of tildrakizumab, quality-of-life scores improved significantly over a year, with over 60 percent of patients achieving a Dermatology Life Quality Index score of 0 or 1 by week 64, meaning the disease had essentially no impact on their day-to-day experience.23PubMed. Long-term quality of life outcomes from a phase 4 study of tildrakizumab in patients with moderate-to-severe plaque psoriasis in a real-world setting
For psoriatic arthritis, risankizumab showed significant improvements in physical function, fatigue, and overall health-related quality of life in its phase III program.13RMD Open. Improved patient-reported outcomes in patients with psoriatic arthritis treated with risankizumab: analysis of the Phase 3 trial KEEPsAKE 2 These gains in how people feel and function, not just how their lab values or skin scores look, strengthen the case that IL-23 blockade is doing something real and durable for patients.
Biomarkers and the Push Toward Precision
Not everyone responds equally to IL-23 inhibitors, and researchers are working to figure out who will benefit most before treatment starts. Early biomarker research in Crohn’s disease found that non-responders to risankizumab had higher levels of certain activated immune cells in their blood before treatment began, particularly NKT cells and Th17 cells producing elevated TNF-alpha.24Journal of Crohn’s and Colitis. IL-23-activated cells as response biomarkers for risankizumab in Crohn’s disease patients In hidradenitis suppurativa, a different pattern emerged: patients who responded to IL-23 blockade were more likely to be male, have elevated testosterone levels, and show markers of Th17-polarized inflammation in their skin lesions.25PubMed. Baseline clinical, hormonal and molecular markers associated with clinical response to IL-23 antagonism in hidradenitis suppurativa
These findings are still preliminary and need validation in larger groups. But they point toward a future where a blood test or tissue biopsy before starting treatment could help predict whether a given patient is likely to respond to an IL-23 inhibitor or should start on a different class instead. Given how many biologic options now exist, and how long it takes to know whether one is working, even a rough predictive tool would be valuable.
An Oral IL-23 Inhibitor on the Horizon
Every currently approved IL-23 inhibitor is given by injection, either subcutaneously by the patient at home or intravenously during an induction phase for IBD. A development that could change the treatment landscape significantly is icotrokinra, an orally administered peptide that targets the IL-23 receptor. Early reports describe it as combining the immunological precision and high efficacy of injectable biologics with the convenience of a pill.26The Lancet. The management of moderate-to-severe psoriasis has been revolutionised by biological therapies targeting cytokines
If the ongoing trials confirm those early results, an oral option could broaden the reach of IL-23-targeted therapy considerably. Many patients with moderate psoriasis who might benefit from a biologic never start one, partly because of reluctance around injections and partly because of the monitoring infrastructure biologics require. An oral agent that avoids immunogenicity concerns entirely, since it is a small peptide rather than a monoclonal antibody, would lower those barriers. It would also create new questions about adherence, since the infrequent dosing of injectable IL-23 inhibitors is itself a compliance advantage that a daily pill does not share.