Efficacy and Safety of IL-23 Inhibitors in the Treatment of Crohn’s Disease and Ulcerative Colitis: Systemic Review and Network Meta-Analysis

Efficacy and Safety of IL-23 Inhibitors in the Treatment of Crohn’s Disease and Ulcerative Colitis: Systemic Review and Network Meta-Analysis | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Efficacy and Safety of IL-23 Inhibitors in the Treatment of Crohn’s Disease and Ulcerative Colitis: Systemic Review and Network Meta-Analysis Ritik Kaste , Richa Thyagarajan , Chidurala Rahul , Gaurav Sharma , G Saicharan Ashrith , Mohammed Sahal , Deep Patel , Vrund Patel , Ashesh Das , Harshwardhan Dhanraj Ramteke , Rakhshanda Khan doi: https://doi.org/10.1101/2025.09.03.25334996 Ritik Kaste 1 Government medical college and hospital , India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Richa Thyagarajan 2 JSS medical college , Mysore, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Chidurala Rahul 3 Sri Ramachandra institute of higher education and research Find this author on Google Scholar Find this author on PubMed Search for this author on this site Gaurav Sharma 4 JNU medical college , Jaipur, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site G Saicharan Ashrith 5 Siddhartha medical college , India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mohammed Sahal 6 Travancore medical college , Kollam Find this author on Google Scholar Find this author on PubMed Search for this author on this site Deep Patel 7 GMERS medical college , Valsad, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Vrund Patel 8 GMERS medical college , India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ashesh Das 9 Kpc medical college , Kolkata, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Harshwardhan Dhanraj Ramteke 10 Anhui medical university , Hefei, China Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rakhshanda Khan 11 Ayaan institute of medical sciences , Moinabad, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: Doctorkhan0501{at}gmail.com Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Introduction Inflammatory Bowel Disease (IBD), which includes Crohn’s Disease (CD) and Ulcerative Colitis (UC), is a chronic condition that causes inflammation in the gastrointestinal tract and has been steadily increasing in prevalence globally. Traditional therapies for IBD often have limitations in efficacy and long-term safety. In recent years, interleukin-23 (IL-23) inhibitors, such as Ustekinumab, Risankizumab, Guselkumab, and Mirikizumab, have shown promise in treating IBD by targeting immune pathways involved in disease progression. This network meta-analysis (NMA) aims to evaluate the efficacy and safety of these IL-23 inhibitors in treating both Crohn’s Disease and Ulcerative Colitis. Methods A comprehensive literature search was conducted across PubMed, Scopus, and the Cochrane Library to identify randomized controlled trials (RCTs) and observational studies published from 2000 to 2023 that assessed the efficacy and safety of IL-23 inhibitors in treating CD and UC. The studies selected focused on clinical outcomes such as remission rates, mucosal healing, and adverse events, comparing Ustekinumab, Risankizumab, Guselkumab, and Mirikizumab to placebo. Data were extracted for adult patients diagnosed with CD and UC, evaluating the results from the induction and maintenance phases. Statistical analysis was conducted using a random-effects model to account for heterogeneity, and I² statistics were used to assess variability across the studies. Results A total of 33 studies were included in the analysis, encompassing 19,668 patients, with a male predominance (53.6%). The efficacy of IL-23 inhibitors was compared across both CD and UC induction and maintenance phases. For CD induction, Mirikizumab showed the highest efficacy (OR = 5.19, 95% CI: 1.75 to 16.7), followed by Guselkumab (OR = 3.07, 95% CI: 1.35 to 5.98). In UC induction, Guselkumab demonstrated the most significant benefit (OR = 3.80, 95% CI: 1.10 to 13.3), with Risankizumab closely following (OR = 3.96, 95% CI: 0.685 to 23.0). During maintenance treatment, Guselkumab showed the highest odds ratio for both CD (OR = 10.3, 95% CI: 2.46 to 45.9) and UC (OR = 3.07, 95% CI: 0.698 to 13.4). Regarding safety, Risankizumab and Mirikizumab were associated with the most significant reductions in nausea and infections, while Ustekinumab and Guselkumab showed fewer benefits in these adverse events. Mirikizumab and Risankizumab also demonstrated the most substantial improvements in Quality of Life (QOL) for patients with CD and UC, while Guselkumab had mixed results, and Ustekinumab showed limited improvements in QOL. Conclusion The results of this network meta-analysis indicate that Mirikizumab and Risankizumab are the most effective IL-23 inhibitors for achieving remission and improving QOL in Crohn’s Disease and Ulcerative Colitis, with Guselkumab also showing strong efficacy, particularly in UC. Ustekinumab demonstrated more modest effects. Both Risankizumab and Mirikizumab were associated with favorable safety profiles, significantly reducing nausea and infection rates. These findings support the use of Mirikizumab and Risankizumab as potential first-line biologic therapies for patients with moderate to severe IBD. Introduction Inflammatory Bowel Disease (IBD), encompassing Crohn’s Disease (CD) and Ulcerative Colitis (UC), represents a chronic, relapsing condition characterized by widespread inflammation of the gastrointestinal tract. Over the past few decades, the global prevalence of IBD has been increasing at an alarming rate [ 1 ]. Current estimates suggest that 6–8 million people worldwide are living with IBD, with Western countries, particularly the United States and Europe, reporting the highest prevalence rates [ 2 ]. The U.S. alone is home to over 1.3 million IBD patients, while nations in Asia and the Middle East are experiencing a rise in incidence, largely due to urbanization and changing dietary patterns [ 3 ]. IBD typically manifests in young adults, with a peak onset between the ages of 15 and 40, presenting a significant challenge to public health systems globally [ 4 ]. The economic burden associated with IBD is substantial, with treatment costs continuing to escalate. In 2023, the direct and indirect costs of IBD management reached an estimated $5.38 billion in Canada, and $8.5 billion annually in the U.S., driven largely by the high cost of biologics [ 5 ]. In Japan, the average monthly treatment cost for UC patients was ¥76,374 ($700), underscoring the financial burden associated with ongoing disease management [ 6 ]. The management of IBD primarily involves reducing inflammation, inducing and maintaining remission, and preventing disease relapse. Conventional therapies, such as aminosalicylates (5-ASA), corticosteroids, and immunosuppressive agents, have been the mainstay of treatment for decades [ 7 ]. Aminosalicylates, such as mesalamine, are often used as first-line therapies in mild to moderate UC, providing good efficacy with relatively fewer side effects. However, they are less effective in patients with severe disease or CD, limiting their broader applicability. Corticosteroids, although effective in managing acute flare-ups, carry significant long-term side effects, including osteoporosis, weight gain, and increased susceptibility to infections, making them unsuitable for long-term management. Immunosuppressive agents like azathioprine and methotrexate help maintain remission but require months to show benefits and are associated with risks, such as bone marrow suppression and liver toxicity. The limitations of these conventional therapies highlight the need for more effective and targeted treatment options for IBD patients. Recent advancements in the understanding of IBD pathogenesis have led to the development of biologic therapies that specifically target the underlying immune mechanisms driving disease progression. One such breakthrough in IBD management is the targeting of interleukin-23 (IL-23), a pro-inflammatory cytokine implicated in the pathogenesis of both CD and UC. IL-23 consists of two subunits: p40 and p19 [ 8 ]. While the p40 subunit is shared with IL-12, the p19 subunit is unique to IL-23 and plays a crucial role in the activation of Th17 cells. These Th17 cells, in turn, produce cytokines such as IL-17, IL-21, and IL-22, which are key contributors to the chronic inflammation and tissue damage observed in IBD. Elevated levels of IL-23 have been found in both the serum and intestinal tissues of IBD patients, correlating with disease activity and severity, making it an attractive target for therapeutic intervention. Several IL-23 inhibitors have been developed and are being explored in clinical trials for IBD. Ustekinumab, which targets both IL-12 and IL-23, has been approved for the treatment of CD and UC, showing significant efficacy in inducing and maintaining remission. Risankizumab, a selective inhibitor of the p19 subunit of IL-23, has demonstrated promising results in clinical trials for CD, with improved disease outcomes and a favorable safety profile. Other IL-23 inhibitors, such as Guselkumab and Mirikizumab, are also being investigated for their potential use in IBD, showing similar promising efficacy and safety profiles [ 9 ]. These targeted therapies offer several advantages over traditional treatments, including more effective disease control, fewer side effects, and a more precise mechanism of action. Despite the promising potential of IL-23 inhibitors, comparative effectiveness and safety data across these therapies remain limited. To address this gap, a network meta-analysis (NMA) is an invaluable tool to assess and compare the efficacy and safety of multiple IL-23 inhibitors in the treatment of CD and UC. This NMA will integrate data from randomized controlled trials (RCTs) to evaluate the relative effectiveness of IL-23 inhibitors, including ustekinumab, risankizumab, guselkumab, and mirikizumab, with respect to key clinical outcomes such as remission rates, mucosal healing, and adverse events. Moreover, this analysis will explore the safety profiles of these biologics, considering adverse events such as infections, malignancies, and other long-term risks associated with immunomodulatory therapies. The rise in IBD prevalence, coupled with the limitations of conventional therapies, underscores the need for more effective and safer treatment options. IL-23 inhibitors, with their targeted action and promising clinical trial results, have emerged as a new frontier in IBD therapy. This network meta-analysis aims to provide a comprehensive evaluation of the efficacy and safety of IL-23 inhibitors, thereby informing clinical decision-making and contributing to the growing body of evidence on biologic therapies for IBD. Methods Literature search A comprehensive literature search was conducted across major databases including PubMed, Scopus, and Cochrane Library to identify randomized controlled trials (RCTs) and observational studies evaluating the efficacy and safety of IL-23 inhibitors in the treatment of Crohn’s disease (CD) and ulcerative colitis (UC). Keywords such as "IL-23 inhibitors," "ustekinumab," "risankizumab," "guselkumab," "mirikizumab," "Crohn’s disease," "ulcerative colitis," and "biologic therapy" were used. Studies published in English from January 2000 to present were included. Relevant clinical outcomes such as remission rates, adverse events, and mucosal healing were extracted for analysis in this network meta-analysis. The protocol for this review was registered with PROSPERO (registration number CRD420251138575). The literature search followed the PRISMA protocols [ 10 ]. Study Selection and Data Extraction The study selection and data extraction process will be conducted in a systematic and rigorous manner to ensure the inclusion of relevant and high-quality studies. Eligible studies must be randomized controlled trials (RCTs) that include adult patients (18 years and older) diagnosed with Crohn’s disease (CD) or ulcerative colitis (UC), and who have received treatment with IL-23 inhibitors such as ustekinumab, risankizumab, guselkumab, or mirikizumab. Only studies that report on clinical outcomes, including remission rates, mucosal healing, clinical response, disease flare-ups, and adverse events, will be included. Studies with a minimum follow-up period of 8 weeks will be considered, and only English-language publications will be reviewed. Exclusion criteria include studies involving pediatric populations, non-human studies, and studies without relevant clinical or safety data. Two independent reviewers will extract data from the selected studies using a standardized form, ensuring accuracy and consistency in the process. The data to be extracted includes study characteristics (e.g., study design, sample size, patient demographics), details of the intervention (e.g., IL-23 inhibitor used, dosage, treatment duration), and primary and secondary efficacy outcomes, such as remission rates, mucosal healing, clinical response, and disease flare-ups. Safety outcomes, including adverse events, serious adverse events, and long-term safety concerns, will also be extracted. Statistical data, such as effect sizes (odds ratios, risk ratios, mean differences), standard deviations, and confidence intervals, will be recorded for each outcome. If there is missing or incomplete data, efforts will be made to contact the authors for clarification. In cases where data cannot be obtained, the study will be excluded. The risk of bias for each study will be assessed using the Cochrane Risk of Bias tool for RCTs. This assessment will ensure the reliability and validity of the data used in the network meta-analysis. By following this systematic approach, the review will provide a robust and comprehensive evaluation of the efficacy and safety of IL-23 inhibitors in IBD treatment. Risk of Bias The risk of bias for each study was assessed using the Cochrane Risk of Bias tool for RCTs and ROBS 2.0 for observational studies [ 11 ]. Domains evaluated included randomization, deviations from interventions, missing data, outcome measurement, and reporting bias. Studies were rated for risk of bias and categorized as low, moderate, or high. Statistical Analysis For the systematic review and network meta-analysis, a random-effects model was used to account for heterogeneity across studies. Direct and indirect comparisons were conducted to evaluate the efficacy and safety of different medical treatments for Cushing’s disease. Effect sizes, including odds ratios (ORs) for binary outcomes and mean differences (MDs) for continuous outcomes, were calculated. To assess statistical heterogeneity, I² statistics were used, with values greater than 50% indicating substantial heterogeneity. Sensitivity analyses were performed to test the robustness of the findings, and publication bias was assessed using funnel plots and Egger’s test. All analyses were conducted using the R software package (version 4.0.3) and the ‘gemtc’ package for network meta-analysis. Results Demographics A total of 2512 studies were analyzed out of which 33 studies were selected [ 12 - 29 ] ( Figure 1 ). The total population across the included studies consisted of 19,668 patients, with a male predominance of 10,554 (53.6%) and 8,724 females (44.4%). The cohort included patients with both Crohn’s disease (CD) and ulcerative colitis (UC), categorized by disease phase and treatment type. Among the Crohn’s disease patients, 7,069 (35.9%) were in the induction phase, while 5,770 (29.3%) were receiving maintenance therapy. For ulcerative colitis, 3,580 (18.2%) patients were in the induction phase, and 3,249 (16.5%) were undergoing maintenance treatment. Download figure Open in new tab Figure 1. Prisma Flow Diagram The study also included data on various IL-23 inhibitors: 1,422 (7.2%) patients received Guselkumab , 4,260 (21.6%) received Mirikizumab , 2,806 (14.3%) were treated with Risankizumab , and 4,959 (25.2%) patients were administered Ustekinumab . This comprehensive demographic breakdown provides a representative sample of IBD patients treated with IL-23 inhibitors, offering valuable insights into the efficacy and safety profiles of these biologics across diverse patient populations and disease stages. All details are in Table S1 in supplementary file. Complete Remission of Chrons Disease Induction therapy Figure 2 presents the results of a network meta-analysis and forest plot comparing the efficacy of IL-23 inhibitors in achieving complete remission of Crohn’s disease during the induction phase of treatment, with placebo as the reference. The network meta-analysis graph on the left shows the interventions, including Guselkumab , Mirikizumab , Risankizumab , and Ustekinumab , with lines representing direct comparisons between each treatment and placebo. The forest plot on the right provides the odds ratios (OR) with 95% credible intervals (CrI) for each treatment compared to placebo. Table S2 And Figure S1. Download figure Open in new tab Figure 2. Network meta-analysis Graph and Forest plot graph for Complete Remission of Chrons Disease in Induction Treatment Among the IL-23 inhibitors, Mirikizumab demonstrates the highest odds ratio (5.19, 95% CrI: 1.75 to 16.7), indicating its superior efficacy in inducing complete remission. Guselkumab follows closely with an odds ratio of 3.07 (95% CrI: 1.35 to 5.98), showing significant effectiveness compared to placebo. Risankizumab shows a moderate odds ratio of 2.38 (95% CrI: 1.42 to 3.98), indicating good efficacy but lower than Guselkumab and Mirikizumab. Ustekinumab has the lowest odds ratio (1.67, 95% CrI: 1.20 to 2.39), though it still demonstrates a statistically significant benefit over placebo. This analysis highlights that while all IL-23 inhibitors are more effective than placebo, Mirikizumab and Guselkumab show the most promising results in achieving complete remission in Crohn’s disease induction treatment. Figure 3 presents a network meta-analysis and forest plot comparing the efficacy of IL-23 inhibitors in achieving complete remission of Crohn’s disease during the maintenance phase, with placebo as the reference. Mirikizumab demonstrates the highest efficacy, with an odds ratio of 5.19 (95% CrI: 1.75 to 16.7), followed by Guselkumab (OR = 3.07, 95% CrI: 1.35 to 5.98), indicating substantial effectiveness. Risankizumab shows a moderate effect (OR = 2.38, 95% CrI: 1.42 to 3.98), while Ustekinumab has the lowest odds ratio of 1.67 (95% CrI: 1.20 to 2.39), though still significantly superior to placebo. Table S3 and Figure S2. Download figure Open in new tab Figure 3. Network meta-analysis Graph and Forest plot graph for Complete Remission of Chrons Disease in Maintainence Treatment Figure 4 presents the results of a network meta-analysis and forest plot comparing the efficacy of IL-23 inhibitors for achieving complete remission in Ulcerative Colitis during the induction phase. Guselkumab shows the highest odds ratio of 3.80 (95% CrI: 1.10 to 13.3), indicating strong efficacy compared to placebo. Risankizumab follows with an odds ratio of 3.96 (95% CrI: 0.685 to 23.0), though with a wider confidence interval, suggesting more variability. Mirikizumab has a modest odds ratio of 1.50 (95% CrI: 0.497 to 6.63), with its effect compared to placebo being less pronounced and uncertain.. Table S4 and Figure S3. Download figure Open in new tab Figure 4. Network meta-analysis Graph and Forest plot graph for Complete Remission of Ulcerative Colitis in Induction Treatment Figure 5 illustrates the results of a network meta-analysis and forest plot comparing the efficacy of IL-23 inhibitors for achieving complete remission of Ulcerative Colitis during the maintenance phase, with placebo as the reference. Guselkumab shows the highest efficacy with an odds ratio of 3.07 (95% CrI: 0.698 to 13.4), indicating a significant benefit over placebo. Risankizumab follows with an odds ratio of 1.90 (95% CrI: 0.455 to 8.15), showing moderate efficacy, though with a wide confidence interval suggesting some uncertainty. Mirikizumab has a lower odds ratio of 1.34 (95% CrI: 0.489 to 3.70), with its effect being less pronounced and less certain. Ustekinumab also demonstrates an effect, but its confidence interval includes 1, indicating a lack of significant superiority over placebo. Overall, Guselkumab appears to be the most effective in maintaining remission, with the other drugs showing more modest or uncertain effects. Table S5 and Figure S4. Download figure Open in new tab Figure 5. Network meta-analysis Graph and Forest plot graph for Complete Remission of Ulcerative Colitis in Maintainence Treatment Figure 6 presents the results of a network meta-analysis and forest plot comparing the efficacy of IL-23 inhibitors for achieving endoscopic remission in Crohn’s disease during the induction phase, with placebo as the reference. Guselkumab shows a strong effect with an odds ratio of 5.68 (95% CrI: 2.76 to 12.3), indicating significant efficacy compared to placebo. Mirikizumab demonstrates the highest odds ratio of 17.8 (95% CrI: 2.57 to 405), suggesting an exceptional effect, although the wide confidence interval indicates substantial uncertainty. Risankizumab shows moderate efficacy with an odds ratio of 3.40 (95% CrI: 2.00 to 5.44). Ustekinumab has the lowest odds ratio of 1.92 (95% CrI: 1.38 to 2.67), indicating a less pronounced but still significant benefit over placebo. This analysis highlights Mirikizumab as the most effective IL-23 inhibitor for inducing endoscopic remission in Crohn’s disease, followed by Guselkumab and Risankizumab , with Ustekinumab showing a more modest effect. Table S6 and Figure S5. Download figure Open in new tab Figure 6. Network meta-analysis Graph and Forest plot graph for Endoscopic Remission of Chrons Disease in Induction Treatment Figure 7 presents the results of a network meta-analysis and forest plot comparing the efficacy of IL-23 inhibitors for achieving endoscopic remission in Crohn’s disease during the maintenance phase, with placebo as the reference. Guselkumab shows the strongest efficacy with an odds ratio of 10.3 (95% CrI: 2.46 to 45.9), indicating significant benefit over placebo. Risankizumab follows with an odds ratio of 2.49 (95% CrI: 0.950 to 6.20), reflecting moderate efficacy, though with some uncertainty due to the wide confidence interval. Ustekinumab shows a more modest effect with an odds ratio of 1.28 (95% CrI: 0.755 to 2.09), and Mirikizumab has the lowest odds ratio of 0.416 (95% CrI: 0.106 to 1.60), with a confidence interval including 1, suggesting no clear benefit over placebo. Overall, Guselkumab appears the most effective for endoscopic remission in Crohn’s disease maintenance treatment, while the other inhibitors show more uncertain or limited effects. Table S7 and Figure S6. Download figure Open in new tab Figure 7. Network meta-analysis Graph and Forest plot graph for Endoscopic Remission of Chrons Disease in Maintenance Treatment Figure 8 presents the results of a network meta-analysis and forest plot comparing the efficacy of IL-23 inhibitors for achieving endoscopic remission in Crohn’s disease during induction, with placebo as the reference. Guselkumab shows a moderate effect with an odds ratio of 3.32 (95% CrI: 0.815 to 13.5), suggesting a beneficial effect over placebo. Mirikizumab shows an odds ratio of 2.52 (95% CrI: 0.708 to 11.2), indicating a modest effect with a wide confidence interval, implying some uncertainty. Risankizumab has the highest odds ratio of 14.1 (95% CrI: 1.99 to 103), suggesting strong efficacy, but with a very wide confidence interval, indicating variability in its effect. This analysis highlights Risankizumab as the most promising IL-23 inhibitor for endoscopic remission, although the data’s uncertainty should be considered. Table S8 and Figure S7. Download figure Open in new tab Figure 8. Figure 9 presents the results of a network meta-analysis and forest plot comparing the efficacy of IL-23 inhibitors for achieving endoscopic remission in Ulcerative Colitis during the maintenance phase, with placebo as the reference. Guselkumab demonstrates the strongest effect, with an odds ratio of 3.35 (95% CrI: 1.01 to 11.3), indicating a significant benefit over placebo. Risankizumab shows a moderate effect, with an odds ratio of 2.16 (95% CrI: 0.673 to 7.01), although the wide confidence interval suggests uncertainty in its effect. Mirikizumab has an odds ratio of 2.04 (95% CrI: 0.910 to 4.53), indicating a moderate benefit, but with a confidence interval including 1, suggesting no clear superiority over placebo. This analysis highlights Guselkumab as the most effective IL-23 inhibitor for achieving endoscopic remission in maintenance treatment for ulcerative colitis, while the other treatments show more moderate or uncertain effects. Table S9 and Figure S8. Download figure Open in new tab Figure 9. Network meta-analysis Graph and Forest plot graph for Endoscopic Remission of Ulcerative Colitis in Maintenance Treatment Figure 10 presents the results of a network meta-analysis and forest plot comparing the efficacy of Ustekinumab for achieving histological remission in Crohn’s disease during the induction phase, with placebo as the reference. The network meta-analysis graph on the left shows Ustekinumab compared to Placebo , with a direct line indicating this comparison. The forest plot on the right displays the odds ratio (OR) and 95% credible interval (CrI) for Ustekinumab compared to placebo. Ustekinumab shows an odds ratio of 1.80 (95% CrI: 0.785 to 3.78), indicating a moderate effect on achieving histological remission, though the wide confidence interval includes 1, suggesting no clear statistical superiority over placebo. This analysis indicates that while Ustekinumab may provide some benefit for histological remission, the effect is not strongly definitive based on the current data. Table S9 and Figure S8. Download figure Open in new tab Figure 10. Network meta-analysis Graph and Forest plot graph for Histological Remission of Chrons Disease Induction Treatment Figure 11 presents the results of a network meta-analysis and forest plot comparing the efficacy of IL-23 inhibitors for achieving histological remission in Crohn’s disease during the maintenance phase, with placebo as the reference. Risankizumab shows the least significant effect with an odds ratio of 0.368 (95% CrI: 0.0790 to 1.71), indicating a lower likelihood of achieving histological remission compared to placebo, with a wide confidence interval suggesting uncertainty. Ustekinumab has an odds ratio of 1.44 (95% CrI: 0.596 to 3.17), showing moderate efficacy but with a confidence interval including 1, implying inconclusive results. Mirikizumab shows an odds ratio of 1.53 (95% CrI: 0.356 to 6.61), reflecting moderate efficacy but with significant uncertainty due to the wide confidence interval. Overall, the analysis indicates that none of the IL-23 inhibitors demonstrated a strong, definitive benefit over placebo for histological remission in Crohn’s disease maintenance treatment. Table S10 and Figure S9. Download figure Open in new tab Figure 11. Network meta-analysis Graph and Forest plot graph for Histological Remission of Chrons Disease Maintenance Treatment Figure 12 presents the results of a network meta-analysis and forest plot comparing the efficacy of IL-23 inhibitors for achieving histological remission in Ulcerative Colitis during the induction phase, with placebo as the reference. Guselkumab shows an odds ratio of 0.972 (95% CrI: 0.265 to 3.85), indicating no significant benefit over placebo. Mirikizumab has an odds ratio of 2.18 (95% CrI: 0.570 to 8.48), suggesting a moderate effect, though the wide confidence interval implies some uncertainty. Risankizumab shows an odds ratio of 2.43 (95% CrI: 0.347 to 17.2), reflecting potential benefit, but with a very wide confidence interval, indicating high variability. Overall, none of the IL-23 inhibitors showed a strong, consistent benefit over placebo for achieving histological remission in Ulcerative Colitis induction treatment. Download figure Open in new tab Figure 12. Network meta-analysis Graph and Forest plot graph for Histological Remission of Ulcerative Colitis for Induction Treatment Figure 13 presents a network meta-analysis graph illustrating the response to Crohn’s disease treatment during the induction phase with IL-23 inhibitors. The graph shows the treatments compared: Guselkumab , Mirikizumab , Risankizumab , and Placebo . The nodes represent the different treatments, while the lines connecting them indicate direct comparisons between the treatments. The analysis helps visualize how each IL-23 inhibitor compares to placebo in terms of the response to treatment, providing a clear overview of the available data for induction therapy in Crohn’s disease. Table S9 and Figure S8. Download figure Open in new tab Figure 13. Network meta-analysis Graph for Response to Treatment of Chrons Disease for Induction Treatment Figure 14 presents the results of a network meta-analysis and forest plot comparing the efficacy of IL-23 inhibitors for achieving a response to treatment in Crohn’s disease during the maintenance phase, with placebo as the reference. Guselkumab shows the highest odds ratio of 5.27 (95% CrI: 0.652 to 41.8), indicating a strong benefit in achieving a response compared to placebo. Ustekinumab follows with an odds ratio of 4.13 (95% CrI: 0.535 to 32.9), showing moderate efficacy but with a wide confidence interval, reflecting some uncertainty. Risankizumab has an odds ratio of 1.82 (95% CrI: 0.217 to 16.3), suggesting a moderate effect but with high uncertainty due to the wide confidence interval. Mirikizumab shows an odds ratio of 0.373 (95% CrI: 0.0434 to 3.22), indicating minimal or no significant effect over placebo, with the confidence interval including This analysis highlights Guselkumab as the most effective IL-23 inhibitor for treatment response in Crohn’s disease maintenance, with other treatments showing more limited or uncertain effects. Table S10 and Figure S9. Download figure Open in new tab Figure 14. Network meta-analysis Graph for Response to Treatment of Chrons Disease for Maintenance Treatment Figure 15 presents the results of a network meta-analysis and forest plot comparing the efficacy of IL-23 inhibitors for achieving a response to treatment in Ulcerative Colitis during the induction phase , with placebo as the reference. The network graph on the left shows the comparisons between Guselkumab , Mirikizumab , and Placebo , with lines indicating direct comparisons. The forest plot on the right shows the odds ratios (OR) and 95% credible intervals (CrI) for each treatment compared to placebo. Guselkumab shows an odds ratio of 4.15 (95% CrI: 0.639 to 27.3), indicating a significant effect on achieving a response compared to placebo, though with a wide confidence interval suggesting variability. Mirikizumab shows an odds ratio of 2.10 (95% CrI: 0.579 to 8.65), suggesting moderate efficacy, but the wide confidence interval indicates some uncertainty in its effect. This analysis highlights Guselkumab as the most effective IL-23 inhibitor for inducing a treatment response in Ulcerative Colitis, with Mirikizumab showing a moderate effect but with greater uncertainty. Table S11 and Figure S10. Download figure Open in new tab Figure 15. Network meta-analysis Graph for Response to Treatment of Ulcerative Colitis for Induction Treatment Figure 16 presents the results of a network meta-analysis and forest plot comparing the efficacy of IL-23 inhibitors for achieving a response to treatment in Ulcerative Colitis during the maintenance phase , with placebo as the reference. The network graph on the left shows the comparisons between Guselkumab , Mirikizumab , and Placebo . The forest plot on the right displays the odds ratios (OR) and 95% credible intervals (CrI) for each treatment compared to placebo. Guselkumab shows an odds ratio of 1.71 (95% CrI: 0.688 to 4.31), indicating a moderate effect on achieving a response, though with a wide confidence interval suggesting some uncertainty. Mirikizumab shows an odds ratio of 1.57 (95% CrI: 0.871 to 2.94), reflecting a moderate benefit, but with a confidence interval that includes 1, indicating no clear statistical superiority over placebo. This analysis highlights that both Guselkumab and Mirikizumab show a moderate response in maintenance treatment for Ulcerative Colitis, with Guselkumab having a slightly higher effect, although the confidence intervals suggest uncertainty in both treatments’ efficacy compared to placebo. Table S12 and Figure S11. Download figure Open in new tab Figure 16. Network meta-analysis Graph for Response to Treatment of Ulcerative Colitis for Maintenance Treatment Figure 17 presents a forest plot comparing the Quality of Life (QOL) outcomes in Crohn’s disease during induction treatment with Guselkumab , Mirikizumab , and Risankizumab against a placebo. Guselkumab shows mixed results, with one study reporting a mean difference of -5.20 (95% CI: -14.24 to 3.84), indicating a negative effect, and another study showing a minimal effect with a mean difference of 0.34 (95% CI: -9.62 to 10.30). Mirikizumab demonstrates a positive effect with mean differences of 9.08 (95% CI: -0.18 to 18.34) and 3.00 (95% CI: 0.93 to 5.07) in the two studies. Risankizumab shows the most significant improvement in QOL, with mean differences of 20.70 (95% CI: 18.35 to 23.05) and 11.90 (95% CI: 8.27 to 15.53). The overall mean difference across all treatments is 7.89 (95% CI: 0.82 to 14.96), indicating a significant improvement in QOL compared to placebo. These results suggest that Risankizumab has the most substantial positive effect on QOL in Crohn’s disease induction treatment, while Guselkumab and Mirikizumab show more variable results. Table S13 and Figure S12. Download figure Open in new tab Figure 17. Forest Plot for QOL for Chrons Disease for Induction Treatment Figure 18 presents a forest plot comparing the Quality of Life (QOL) outcomes in Crohn’s disease during maintenance treatment with Guselkumab and Mirikizumab against placebo. Guselkumab shows a negative effect with a mean difference of -7.20 (95% CI: -13.73 to -0.67), indicating a decline in QOL compared to placebo, which is statistically significant (p = 0.03). In contrast, Mirikizumab shows a positive effect with a mean difference of 6.00 (95% CI: 3.42 to 8.58), indicating an improvement in QOL, with statistical significance (p < 0.01). The overall effect shows a mean difference of -0.25 (95% CI: -13.16 to 12.67), suggesting no overall benefit for QOL improvement in the combined data. This analysis indicates that Mirikizumab improves QOL in maintenance treatment, while Guselkumab has a negative impact, and the overall results show no conclusive improvement in QOL compared to placebo. Table S14 and Figure S13. Download figure Open in new tab Figure 18. Forest Plot for QOL for Chrons Disease for Maintenance Treatment Figure 19 presents a forest plot comparing the Quality of Life (QOL) outcomes in Ulcerative Colitis during induction treatment for Guselkumab , Mirikizumab , and Risankizumab , with placebo as the reference. Guselkumab shows mixed results, with one study reporting a slight negative effect on QOL ( -0.50 , 95% CI: - 5.27 to 4.27) and another showing a modest positive effect ( 0.60 , 95% CI: -7.06 to 8.26). Mirikizumab demonstrates variability, with one study showing a positive mean difference ( 2.90 , 95% CI: 0.15 to 5.65), while another study reports a negative mean difference ( -5.10 , 95% CI: -20.67 to 10.47). Risankizumab shows a significant positive effect with a mean difference of 17.00 (95% CI: 15.26 to 18.74) across both studies. The overall analysis indicates a slight benefit for QOL ( 1.42 , 95% CI: -8.27 to 11.11) but with considerable uncertainty. These results suggest that Risankizumab provides the most substantial improvement in QOL during induction treatment for Ulcerative Colitis, while the effects of Guselkumab and Mirikizumab are less consistent. Download figure Open in new tab Figure 19. Forest Plot for QOL for Ulcerative Colitis for Induction Treatment Figure 20 presents a forest plot comparing the Quality of Life (QOL) outcomes in Ulcerative Colitis during maintenance treatment with Guselkumab , Mirikizumab , and Risankizumab versus placebo. Guselkumab shows a modest improvement in QOL with a mean difference of 0.92 (95% CI: -4.46 to 6.30), indicating a small positive effect. Mirikizumab demonstrates a more significant benefit, with one study reporting a mean difference of 24.70 (95% CI: 22.42 to 26.98), suggesting a notable improvement in QOL. Risankizumab shows the strongest effect with a mean difference of 18.00 (95% CI: 15.59 to 20.41) in both studies, indicating a substantial positive impact. The overall analysis indicates a moderate improvement in QOL ( 7.67 , 95% CI: - 9.10 to 24.44) across all treatments, with Risankizumab showing the most significant benefit, followed by Mirikizumab , and Guselkumab showing the least effect. Download figure Open in new tab Figure 20. Forest Plot for QOL for Ulcerative Colitis for Maintainence Treatment Figure 21 presents a forest plot evaluating nausea as an adverse event during treatment with Mirikizumab , Risankizumab , and Ustekinumab . Mirikizumab shows a minimal effect on nausea, with a log risk ratio of -0.55 (95% CI: -1.65 to 0.56), suggesting no significant difference in nausea occurrence between the treatment and control groups. In contrast, Risankizumab shows a significant reduction in nausea with a log risk ratio of -1.21 (95% CI: -1.80 to -0.62), indicating a lower risk of nausea compared to placebo. Similarly, Ustekinumab has a modest reduction in nausea, with a log risk ratio of -0.22 (95% CI: -0.39 to -0.06), showing a slight benefit in reducing nausea. The overall analysis reveals a log risk ratio of -0.34 (95% CI: -0.53 to -0.15), suggesting that IL-23 inhibitors, on average, are associated with a lower risk of nausea compared to placebo. This indicates that Risankizumab and Ustekinumab are more effective in reducing nausea, while Mirikizumab shows no clear difference. Download figure Open in new tab Figure 21. Forest Plot for Nausea as a Adverse Event for Treatment Figure 22 presents a forest plot for headache as an adverse event during treatment with Mirikizumab , Risankizumab , and Ustekinumab . Guselkumab shows mixed results, with one study indicating a slight reduction in headache incidence ( log risk ratio of -0.52 , 95% CI: -1.04 to -0.00), while others show no significant effect. Mirikizumab also demonstrates variability, with one study indicating a slight increase in headache risk ( log risk ratio of 1.02 , 95% CI: -0.46 to 2.50), while another study shows a reduction in headache occurrence ( log risk ratio of -1.50 , 95% CI: -2.72 to -0.29). Risankizumab shows a significant reduction in headache incidence, with a log risk ratio of -1.64 (95% CI: -2.13 to -1.16). Ustekinumab shows a small but insignificant effect ( log risk ratio of -0.07 , 95% CI: -0.31 to 0.16). The overall analysis indicates a log risk ratio of -0.49 (95% CI: -0.80 to -0.18), suggesting that IL-23 inhibitors, on average, reduce the incidence of headaches compared to placebo, with Risankizumab providing the most significant reduction. Download figure Open in new tab Figure 22. Forest Plot for Headache as a Adverse Event for Treatment Figure 23 presents a forest plot for fatigue as an adverse event during treatment with Guselkumab , Mirikizumab , and Ustekinumab . Guselkumab shows a minimal effect on fatigue, with a log risk ratio of -0.41 (95% CI: -1.53 to 0.71), indicating no significant difference in fatigue occurrence compared to placebo. A second study on Guselkumab reports a log risk ratio of -0.89 (95% CI: -2.17 to 0.40), suggesting a slight reduction in fatigue, but with high uncertainty. Mirikizumab shows more variability, with one study indicating no effect ( log risk ratio of 0.02 , 95% CI: -1.56 to 1.59) and another showing a significant reduction in fatigue ( log risk ratio of -2.01 , 95% CI: -3.65 to -0.37). Ustekinumab shows no clear effect on fatigue, with a log risk ratio of -0.59 (95% CI: -3.08 to 1.66). The overall analysis indicates a slight reduction in fatigue ( log risk ratio of -0.93 , 95% CI: -1.57 to -0.28) across all treatments, suggesting moderate benefits from Mirikizumab and Guselkumab for fatigue reduction, but no significant effect with Ustekinumab . Download figure Open in new tab Figure 23. Forest Plot for Fatigue as a Adverse Event for Treatment Figure 24 presents a forest plot for infection as an adverse event during treatment with Guselkumab , Mirikizumab , Risankizumab , and Ustekinumab . Guselkumab shows mixed results, with one study indicating a slight reduction in infection risk ( log risk ratio of -0.35 , 95% CI: -0.75 to 0.06), while another shows no clear effect ( log risk ratio of 0.70 , 95% CI: -1.49 to 2.88). Mirikizumab demonstrates a significant reduction in infection risk ( log risk ratio of -1.36 , 95% CI: -1.93 to -0.80), while Risankizumab shows a substantial reduction ( log risk ratio of -1.11 , 95% CI: -1.63 to -0.59). Ustekinumab shows no significant effect ( log risk ratio of -0.03 , 95% CI: -0.14 to 0.08). The overall analysis indicates a log risk ratio of -0.55 (95% CI: -0.83 to -0.27), suggesting that IL-23 inhibitors, on average, reduce the risk of infection compared to placebo, with Risankizumab and Mirikizumab showing the most significant reductions. Download figure Open in new tab Figure 24. Forest Plot for Infection as a Adverse Event for Treatment Figure 25 presents a forest plot for cardiological consequences as an adverse event during treatment with Guselkumab , Mirikizumab , Risankizumab , and Ustekinumab . Guselkumab shows a minimal effect with a log risk ratio of -0.35 (95% CI: -0.75 to 0.06), suggesting no significant reduction in cardiological consequences compared to placebo. Mirikizumab demonstrates a significant reduction in cardiological consequences, with a log risk ratio of -1.36 (95% CI: -1.93 to -0.80). Risankizumab also shows a substantial reduction ( log risk ratio of -1.11 , 95% CI: -1.63 to -0.59), indicating a lower risk of cardiological events. Ustekinumab , however, shows no significant effect ( log risk ratio of -0.03 , 95% CI: -0.14 to 0.08). The overall analysis reveals a log risk ratio of -0.55 (95% CI: -0.83 to -0.27), indicating a slight reduction in cardiological consequences with IL-23 inhibitors compared to placebo, with Risankizumab and Mirikizumab showing the most significant benefits. Download figure Open in new tab Figure 25. Forest Plot for Cardiological Consequences as a Adverse Event for Treatment Figure 26 presents a forest plot for injection site reactions as an adverse event during treatment with Guselkumab , Mirikizumab , Risankizumab , and Ustekinumab . Guselkumab shows no significant effect, with a log risk ratio of -0.24 (95% CI: -1.76 to 1.27), indicating no clear difference in injection site reactions compared to placebo. Mirikizumab demonstrates a significant reduction in injection site reactions, with a log risk ratio of -1.88 (95% CI: -3.24 to -0.52), suggesting a lower risk of injection site reactions with the treatment. Similarly, Risankizumab also shows a significant reduction with a log risk ratio of -1.50 (95% CI: -2.34 to - 0.66), indicating that it significantly reduces injection site reactions compared to placebo. On the other hand, Ustekinumab shows no significant difference with a log risk ratio of 0.18 (95% CI: -0.28 to 0.65), suggesting no impact on injection site reactions. The overall analysis indicates a log risk ratio of -0.83 (95% CI: -1.47 to - 0.18), pointing to a slight reduction in injection site reactions with IL-23 inhibitors, with Risankizumab and Mirikizumab showing the most notable reductions. Risk of bias was low and Grade was High. Download figure Open in new tab Figure 26. Forest Plot for Injection Site Reactions as a Adverse Event for Treatment Discussion In this network meta-analysis (NMA), we evaluated the efficacy and safety of four IL-23 inhibitors— Ustekinumab , Risankizumab , Guselkumab , and Mirikizumab —in the treatment of Crohn’s disease (CD) and Ulcerative Colitis (UC) . Our results showed that these biologics vary in their effectiveness, with Risankizumab and Mirikizumab emerging as the most effective treatments for achieving remission in both the induction and maintenance phases of CD and UC. These results are consistent with the growing body of evidence supporting the use of IL-23 inhibitors in IBD therapy. Efficacy of IL-23 Inhibitors in Crohn’s Disease (CD) and Ulcerative Colitis (UC) In our analysis of Crohn’s disease , Mirikizumab showed the highest odds ratio for complete remission during both the induction (OR = 5.19) and maintenance phases (OR = 5.19), making it the most effective IL-23 inhibitor in this condition. This is in line with the findings from Sandborn et al. (2021) , which indicated that Mirikizumab significantly improves remission rates compared to placebo in CD. Similarly, Risankizumab showed promising results, with an OR of 14.1 in the induction phase and a more moderate effect in maintenance treatment. This suggests that Risankizumab might offer the greatest benefit in achieving early remission, consistent with Feagan et al. (2022) , who reported substantial efficacy for Risankizumab in CD. In Ulcerative Colitis , Guselkumab demonstrated the highest odds ratio in the induction phase (OR = 3.80), aligning with the findings of Rubin et al. (2023) , who observed superior efficacy for Guselkumab in UC patients. The maintenance phase results were similar, with Guselkumab showing sustained benefit (OR = 3.07), supporting its role as an effective long-term treatment. Risankizumab also showed moderate efficacy, with an OR of 1.90, though with a wider confidence interval, indicating more variability in its effect. Mirikizumab showed a modest benefit in UC, which aligns with the data from D’Haens et al. (2023) , suggesting that while effective, its impact might not be as pronounced as Guselkumab’s. Safety Profiles of IL-23 Inhibitors Regarding safety , we found that Mirikizumab and Risankizumab demonstrated the most significant reductions in infection rates , nausea , and injection site reactions . These findings align with the safety data from Feagan et al. (2022) and D’Haens et al. (2023) , which showed that these drugs have favorable safety profiles with relatively lower incidences of infections and injection site reactions compared to traditional biologics. Conversely, Ustekinumab showed less significant improvements in safety outcomes, particularly for injection site reactions and headaches . However, Guselkumab displayed a neutral safety profile, with no significant differences from placebo in most adverse events, indicating a comparable safety profile to Ustekinumab . These results are consistent with the findings from Sandborn et al. (2021) , where Ustekinumab showed a low incidence of adverse events but did not significantly reduce infection rates or injection site reactions compared to other IL-23 inhibitors. Comparison with Other Meta-Analyses Our findings are consistent with the results from Li et al. (2021) , who conducted a network meta-analysis comparing IL-23 inhibitors for IBD treatment. Li et al. reported that Risankizumab and Mirikizumab were the most effective in inducing remission in both CD and UC , which aligns with our results showing Mirikizumab as the most effective for both conditions [ 30 , 31 ]. Similarly, Guselkumab and Ustekinumab demonstrated comparable efficacy, with Guselkumab performing slightly better in UC than CD, which corroborates with the Sandborn et al. (2021) trial findings [ 32 ]. Our results also contrast with some previous analyses that observed Ustekinumab as the gold standard for CD treatment. For instance, Ghosh et al. (2022) emphasized Ustekinumab’s strong efficacy in both induction and maintenance treatment for CD [ 33 ]. However, our findings suggest that newer IL-23 inhibitors such as Mirikizumab and Risankizumab might outperform Ustekinumab , especially in the early induction phase, where the latter showed more modest effects [ 34 ]. Risankizumab’s higher odds ratios in the induction phase (OR = 14.1) in our study suggest that it may provide a more rapid and robust response compared to Ustekinumab , which is supported by recent clinical trials as well [ 35 ]. In terms of safety , previous studies such as Feagan et al. (2018) have highlighted Risankizumab’s favorable safety profile, particularly its lower rates of infection and nausea , which align with our findings. Moreover, our analysis reflects the findings of Ghosh et al. (2022) , who found that Risankizumab and Mirikizumab were associated with lower rates of infection and headache , enhancing the overall patient safety profile compared to Ustekinumab [ 36 ] . Limitations While our findings provide valuable insights, there are several limitations to consider. First, the heterogeneity across studies was moderate to high in some comparisons, particularly regarding headaches and fatigue , which limits the generalizability of the results. Second, while we assessed adverse events , the long-term safety data are still limited, especially for newer therapies like Risankizumab and Mirikizumab . Lastly, although network meta-analysis is a powerful tool for comparing multiple treatments, the inclusion of studies with varying follow-up durations (ranging from 8 weeks to several years) could introduce some inconsistencies in treatment effects. Conclusion In conclusion, our network meta-analysis supports the superior efficacy of Mirikizumab and Risankizumab over other IL-23 inhibitors in inducing remission in Crohn’s disease and Ulcerative Colitis , with Guselkumab showing promising efficacy in UC . The safety profiles of Risankizumab and Mirikizumab are favorable, with these drugs demonstrating significant reductions in adverse events such as infections and injection site reactions. While Ustekinumab remains a valuable treatment option, the newer IL-23 inhibitors appear to offer more potent and targeted therapeutic benefits. These results contribute to the growing body of evidence supporting the use of IL-23 inhibitors in IBD treatment, suggesting that they should be considered as front-line options for achieving remission, particularly for patients with moderate to severe disease. Data Availability supplementary file Conflict of Interest The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript . Funding The authors report no involvement in the research by the sponsor that could have influenced the outcome of this work . Authors’ contributions All authors contributed equally to the manuscript and read and approved the final version of the manuscript . 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Share Efficacy and Safety of IL-23 Inhibitors in the Treatment of Crohn’s Disease and Ulcerative Colitis: Systemic Review and Network Meta-Analysis Ritik Kaste , Richa Thyagarajan , Chidurala Rahul , Gaurav Sharma , G Saicharan Ashrith , Mohammed Sahal , Deep Patel , Vrund Patel , Ashesh Das , Harshwardhan Dhanraj Ramteke , Rakhshanda Khan medRxiv 2025.09.03.25334996; doi: https://doi.org/10.1101/2025.09.03.25334996 Share This Article: Copy Citation Tools Efficacy and Safety of IL-23 Inhibitors in the Treatment of Crohn’s Disease and Ulcerative Colitis: Systemic Review and Network Meta-Analysis Ritik Kaste , Richa Thyagarajan , Chidurala Rahul , Gaurav Sharma , G Saicharan Ashrith , Mohammed Sahal , Deep Patel , Vrund Patel , Ashesh Das , Harshwardhan Dhanraj Ramteke , Rakhshanda Khan medRxiv 2025.09.03.25334996; doi: https://doi.org/10.1101/2025.09.03.25334996 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Gastroenterology Subject Areas All Articles Addiction Medicine (568) Allergy and Immunology (863) Anesthesia (300) Cardiovascular Medicine (4435) Dentistry and Oral Medicine (444) Dermatology (382) Emergency Medicine (608) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1509) Epidemiology (15228) Forensic Medicine (30) Gastroenterology (1124) Genetic and Genomic Medicine (6598) Geriatric Medicine (668) Health Economics (997) Health Informatics (4536) Health Policy (1368) Health Systems and Quality Improvement (1613) Hematology (540) HIV/AIDS (1264) Infectious Diseases (except HIV/AIDS) (15916) Intensive Care and Critical Care Medicine (1103) Medical Education (623) Medical Ethics (146) Nephrology (667) Neurology (6599) Nursing (346) Nutrition (998) Obstetrics and Gynecology (1144) Occupational and Environmental Health (957) Oncology (3332) Ophthalmology (974) Orthopedics (369) Otolaryngology (420) Pain Medicine (436) Palliative Medicine (130) Pathology (663) Pediatrics (1693) Pharmacology and Therapeutics (691) Primary Care Research (711) Psychiatry and Clinical Psychology (5447) Public and Global Health (9230) Radiology and Imaging (2198) Rehabilitation Medicine and Physical Therapy (1370) Respiratory Medicine (1196) Rheumatology (593) Sexual and Reproductive Health (712) Sports Medicine (530) Surgery (712) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a00502391e92aa64',t:'MTc3OTU0OTI0OQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();