Comparative efficacy of pharmacological interventions in ulcerative colitis: A Network Meta Analysis

Comparative efficacy of pharmacological interventions in ulcerative colitis: A Network Meta Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (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],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Comparative efficacy of pharmacological interventions in ulcerative colitis: A Network Meta Analysis Atta Ullah Khan, Maria Ali, Muhammad Aamir Wahab This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6255469/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction Ulcerative colitis is chronic inflammatory condition affecting the colon, necessitating remission inducing therapeutic interventions. With the emergence of newer more advanced options, their relative effectiveness remains unclear. This network meta-analysis (NMA) will compare the effectiveness of presently available biologics and small molecules in achieving and maintaining remission amongst patients of moderate to severe ulcerative colitis as part of induction and maintenance therapy. Methods A systematic search was conducted up to 21st February 2025, including only phase 2b/3 or 3 randomized controlled trials. The primary outcome was induction and maintenance of clinical remission (Full Mayo Score (FMS) ≤ 2, with no individual subscore > 1). Secondary outcomes assessed were clinical response, endoscopic improvement (Mayo Endoscopic Score (MES) ≤ 1 either with or without friability) and steroid free remission. Results Across 22 studies (7,683 patients), upadacitinib had the highest likelihood of inducing clinical remission (99.08%), clinical response (97.44%) and endoscopic improvement (99.32%), followed by Infliximab and guselkumab following close by for specific outcomes. In maintenance of clinical remission and endoscopic improvement upadacitinib again ranked highest (95.60%) and (99.46%). Tofacitinib (92.43%) has the highest probability with upadacitinib (87.73%) following behind in achieving steroid free remission. Conclusion Upadacitinib displayed high efficacy across multiple outcomes in both induction and maintenance therapy with Infliximab, guselkumab, and filgotinib following closely behind. For achieving steroid free remission tofacitinib has the highest probability of doing so. Overall small molecules and selective IL-23 inhibitors seems promising alternative to older biologics though additional head-to-head trial are warranted along with more real-world data. Gastroenterology & Hepatology Clinical Pharmacology Ulcerative Colitis Biologics Small molecules Induction Maintenance Figures Figure 1 Figure 2 Figure 3 1. Introduction Ulcerative colitis (UC) is amongst the two well-known forms of inflammatory bowel disease (IBD), characterized by a continuously progressing inflammation that starts from rectum moving proximally affecting the mucosa. Ulcerative colitis (UC) follows a relapsing-remitting course and with the global prevalence on the rise UC poses a significant impact on patients' quality of life(Caron et al., 2024 ; Feuerstein & Cheifetz, 2014 ; Lewis et al., 2023 ). The exact cause of UC development is still far from being fully known but factors believed to be associated with its development or somehow play a part in its development includes genetic, environmental and at the forefront is a dysregulated immune response(Danese & Fiocchi, 2011 ; Kobayashi et al., 2020 ; Voelker, 2024 ). The fundamental goal of any UC treatment is the reduction in symptoms and maintenance of that state, preventions of complications usually associated with UC and finally improve patient quality of life(Raine et al., 2022 ; Rubin et al., 2019 ). The usual medications for UC includes 5-aminosalicylates (5-ASA), corticosteroids, and immunomodulators as first line therapy. These are vital in restricting disease progression, but a more specific approach is certainly needed considering the wide-ranging side effects associated with these medications. With that in mind, a new class of drugs called biologics which at molecular level comprises of monoclonal antibodies that target multiple pathway components involved in the inflammatory response has been developed. These include tumor necrosis factor (TNF-α) inhibitors, such as infliximab and adalimumab which were amongst the first biologics to gain approval and show efficacy in both inducing and maintaining remission(D’Amico et al., 2020 ; Danese et al., 2015 ; Fausel et al., 2015 ). Moving forward, the development of newer biologics, such as anti-integrins (e.g., vedolizumab) as well as interleukin antagonists (e.g., ustekinumab) have been achieved, thereby expanding the already extensive set of therapy choices for UC(Hanžel & D’Haens, 2020 ; Kashani & Schwartz, 2019 ; Lamb et al., 2018 ; Thomas & Baumgart, 2012 ). The latest class of medication available for UC therapy and that also have gained FDA approval includes Janus kinase (JAK) inhibitors and sphingosine 1-phosphate (S1P) modulators. These are known as small molecules drugs that also offer the convenience of oral administration. Janus kinase (JAK) inhibitors target numerous molecules belonging to the JAK-STAT signaling pathway while sphingosine 1-phosphate (S1P), a lipid-based mediator involved in immune trafficking and vascular health. They provide more robust immunosuppressive effect and have shown efficacy in both induction of and maintaining remission in UC patients(Ben Ghezala et al., 2021 ; Y. Jiang et al., 2022 ; Liang et al., 2024 ; Nakamura et al., 2024 ; Neri et al., 2024 ; Shivaji et al., 2020 ; Vieujean et al., 2025 ). With increasing diversity in therapeutic options becoming available, the need for comparative efficacy and safety evaluations is becoming more important today to specifically evaluate and synthesize the available evidence on clinically meaningful endpoints that reflect key therapeutic goals, including clinical remission, clinical response, and endoscopic improvement during induction therapy, as well as clinical remission, endoscopic improvement, and steroid-free remission during maintenance therapy to guide clinical judgment. Whilst standard meta-analyses do hold value the heterogeneity in patient populations, disease severity, and treatment protocols across studies highlights the importance of a network-based approach that can integrate diverse sources of evidence. Network meta-analysis (NMA) removes these limitations by allowing the indirect comparison of many therapies using a common comparator and establishing a treatment hierarchy based on their relative efficacy and safety. The aim of this network meta-analysis is to compare the efficacy of biologics and small molecules utilizing key outcomes as part of both induction and maintenance therapy. 2. Methods 2.1 Search strategy and Selection Criteria This Network Meta Analysis adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Network Meta-Analyses (PRISMA-NMA) guidelines(Hutton et al., 2015 ). The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420250655739. A wide-ranging retrieval strategy was developed to catch all relevant studies. From inception to 21 January 2025, two independent reviewers (MAW and MA) performed a very thorough search of search of PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL). Concomitantly, unpublished or advancing studies were also searched by reviewing multiple leading gastroenterology symposiums (e.g., ECCO) and clinical trial registers (e.g., ClinicalTrials.gov). Search terms included Medical Subject Headings (MeSH) and free-text keywords related to ulcerative colitis, biologics, small molecules, and efficacy outcomes. Specific search strings combined terms such as "ulcerative colitis," "biologics," "small molecules," "clinical remission," "endoscopic improvement," and drug-specific names (e.g., infliximab, vedolizumab, tofacitinib, upadacitinib). No language or geographic restrictions were applied. Detailed search strategy is available in Supplementary Table 1. Randomized control trials (RCTs) that are Phase 2b/3 or 3 evaluating biologics or small molecule drugs against placebo or other active comparator involving adults (≥ 18 years) with a confirmed diagnosis of moderate to severe ulcerative colitis (UC) defined by a Full Mayo Score (MCS) of 6–12(Dignass et al., 2012 ; Sicilia et al., 2020 ). Studies reporting efficacy outcomes, including clinical remission, clinical response, endoscopic improvement, and steroid-free remission were included. RCTs that are not phase 2b/3 or 3. Studies focusing on pediatric populations. Trials that do not report key efficacy outcomes according to defined criteria. Studies about non-human subjects or in vitro testing, non-randomized studies, observational studies, case reports, reviews, summaries, meta-analyses, letters to the editor along with irretrievable full text studies or with incomplete data were excluded. 2.1.2. Outcomes Induction therapy was considered for 6–14 weeks, outcomes assessed were Clinical Remission (defined as FMS ≤ 2, with no individual subscore > 1), Clinical Response (defined as Reduction in FMS by ≥ 3 points and ≥ 30% from baseline, including a decrease in rectal bleeding subscore) and Endoscopic Improvement (defined as MES ≤ 1 either with or without friability). The maintenance Phase was considered for ≥ 40 weeks and the assessed outcomes were Clinical Remission, Endoscopic Improvement and Steroid-Free Remission. To maintain uniformity across studies, outcomes for mucosal healing and endoscopic improvement were harmonized as much as possible based on their definitions even though studies reported these outcomes under different terminologies, they were included in the same analytical category if they shared identical definitions which is Mayo Endoscopic Subscore (MES) of ≤ 1. 2.1.3. Study selection Two independent reviewers (MAW and MA) extracted data from eligible studies using a standardized data extraction form. Extracted information included, study related information (author, year), Patient related information (age, sex, disease duration), Intervention related details (drug, dosage, administration route) and Outcome measures (time points, and results for each efficacy endpoint). Discrepancies in data extraction were resolved through consensus or consultation with a third reviewer. 2.1.4. Risk of Bias and Quality Assessment The Cochrane Risk of Bias 2.0 tool (RoB 2)(Sterne et al., 2019 ), was used to assess the methodological quality of included RCTs. This tool evaluates studies across five domains, Bias arising because of the randomization process, Bias arising as a result of deviation from intended interventions, Bias due to lack of outcome data, Bias due to measurement of the outcome and Bias because of selection of the reported result. Individual studies were classified as having a low, some concerns, or high risk of bias based on individual domain evaluation. For results of RoB assessment see Supplementary Figure S1. Discrepancies were resolved through discussion or by consultation involving a third reviewer. 2.1.5. Statistical Analysis A frequentist approach was utilized to conduct our network meta-analysis (NMA) using R software version 4.4.2 and netmeta package(Balduzzi et al., 2023 ). Effect measures comprising of odds ratios with 95% Confidence Intervals (95% CI) were calculated utilizing dichotomous data. I 2 statistic was utilized for calculating in between studies heterogeneity(Higgins et al., 2003 ; Higgins & Thompson, 2002 ), node splitting model used for inconsistency determination. Lastly P-Scores was used to rank treatments efficacy with higher scores denoting better efficacy. 3. Results A total of 22 randomized controlled trials (RCTs), comprising of 7,683 patients with moderate-to-severe ulcerative colitis Fig. 1 , were included in this network meta-analysis(Danese, Colombel, et al., 2022 ; Danese, Vermeire, et al., 2022 ; D’Haens et al., 2023 ; Feagan et al., 2013 , 2021 ; Hibi et al., 2017 ; X.-L. Jiang et al., 2015 ; Motoya et al., 2019 ; Panaccione et al., 2014 ; Peyrin-Biroulet et al., 2022 ; Reinisch et al., 2011 ; Rubin et al., 2024 ; Rutgeerts et al., 2005 ; Sandborn et al., 2012 , 2017 , 2020 , 2021 ; Sandborn, Feagan, Marano, Zhang, Strauss, Johanns, Adedokun, Guzzo, Colombel, Reinisch, Gibson, Collins, Järnerot, & Rutgeerts, 2014; Sandborn, Feagan, Marano, Zhang, Strauss, Johanns, Adedokun, Guzzo, Colombel, Reinisch, Gibson, Collins, Järnerot, Hibi, et al., 2014; Sands, Peyrin-Biroulet, et al., 2019 ; Sands, Sandborn, et al., 2019 ; Suzuki et al., 2014 ). The studies evaluated the efficacy of biologics and small molecules, including Upadacitinib, Infliximab, Ozanimod, Guselkumab, Ustekinumab, Tofacitinib, Golimumab, Etrolizumab, Vedolizumab, Filgotinib, Mirikizumab, and Adalimumab, compared to placebo. The interventions were assessed for their effectiveness in inducing remission, response, and endoscopic improvement and maintaining remission, endoscopic improvement and steroid free remission. Baseline characteristics of included studies are presented in Supplementary Table 2. Heterogeneity was low in all the analyzed outcomes for both induction and maintenance therapies, with I 2 < 30%, and there were no elements for inconsistency (p < 0.05) invalidating the model. The results are represented in the supplementary appendix. 3.1. Induction therapy 3.1.1. Clinical remission All treatments displayed statistical significance in inducing clinical remission as compared to placebo with upadacitinib (OR 9.43, 95% CI 5.36–16.61), infliximab 5 mg (OR 4.96, 95% CI 3.29–7.46) and infliximab 3.5 mg (OR 4.17, 95% CI 1.84–9.41) ranking 1st, 2nd and 3rd. In comparison to other treatments upadacitinb possessed statistically significant superiority over all except infliximab 5 mg (OR 1.90, 95% CI 0.95–3.82) and infliximab 3.5 mg (OR 2.26, 95% CI 0.84–6.11). Additionally, infliximab 5 mg showed statistically significant superiority over etrolizumab, vedolizumab, filgotinib, mirikizumab and adalimumab as is evident from Suplementary Table 3. Per the P-score ranking, upadacitinib ranked highest in inducing clinical remission (99.08%), followed by Infliximab 5 mg (84.6%). Infliximab 3.5 mg (70.93%) ranked third. P-score table is available as part of Supplementary Figure S2. Also, for network plot see Fig. 2 3.1.2. Clinical response All treatments displayed statistical significance in inducing clinical response as compared to placebo except for azathioprine (OR 1.78, 95% CI 0.79–4.01). Upadacitinib (OR 7.85, 95% CI 5.41–11.38), infliximab/azathioprine (OR 5.94, 95% CI 2.53–13.98) and guselkumab (OR 4.14, 95% CI 2.64–6.49) ranking 1st, 2nd and 3rd when compared to placebo. In comparison to other treatments upadacitinb statistically significant superiority over all except infliximab/azathioprine (OR 1.32, 95% CI 0.52–3.35) and infliximab 3.5 mg (OR 2.01, 95% CI 0.76–5.32) as is eveident from Suplementary Table 4. Per the P-score ranking, upadacitinib ranked highest in inducing clinical response (97.44%), followed by infliximab/azathioprine (87.79%) and guselkumab (76.08%) ranked third. P-score table is available as part of Supplementary Figure S3. 3.1.3. Endoscopic improvement All treatments displayed statistical significance in inducing endoscopic improvement as compared to placebo except for azathioprine (OR 1.55, 95% CI 0.76–3.17). Upadacitinib (OR 8.25, 95% CI 5.33–12.77), infliximab/azathioprine (OR 4.49, 95% CI 2.21–9.14) and infliximab 5 mg (OR 3.19, 95% CI 2.35–4.33) ranked 1st, 2nd and 3rd. In comparison to other treatments, upadacitinib showed statistical significance over all except infliximab/azathioprine as is evident from Suplementary Table 5. Per the P-score ranking, upadacitinib ranked highest in inducing endoscopic improvement (99.32%), followed by Infliximab/azathioprine (87.17%) while infliximab 5 mg (75.89%) ranked third. P-score table is available as part of Supplementary Figure S4. 3.2. Maintenance therapy 3.2.1. Clinical remission All treatments except for etrolizumab showed statistical significance in maintaining clinical remission in comparison to placebo. Upadacitinib (OR 7.87, 95% CI 3.90–15.88) displayed statistically significant superiority to all other treatments except filgotinib, guselkumab, tofacitinib and vedolizumab as is evident from Suplementary Table 6. According to P- Score, upadacitinib (95.60%) ranked highest in maintaining clinical remission with filgotinib (81.28%) and guselkumab (73.75%) following behind, P-score table is available as part of Supplementary Figure S5. As for network plot see Fig. 3 . 3.2.2. Endoscopic improvement All treatments were significantly superior in comparision to placebo for maintaining endoscopic improvement. Except for guselkumab, upadacitinib was significantly superior to all drugs in maintaining endoscopic improvement. Upadacitinib (OR 9.30, 95% CI 5.32–16.23), guselkumab (OR 4.56, 95% CI 2.87–7.23) and tofacitinib (OR 3.95, 95% CI 2.39–6.53) ranked 1st, 2nd and 3rd as seen through Supplementary Table 7. P-scores ranking also confirms upadacitinib (99.46%) ranked highest in maintaining endoscopic improvement with guselkumab (80.46%) and tofacitinib (70.67%) following behind. P-score table is available as part of Supplementary Figure S6. 3.2.3. Steroid Free Remission With the exception of golimumab all treatments were significantly superior in comparison to placebo in achieving steroid free remission. Tofacitinib (OR 10.22, 95% CI 2.88–36.32) has the best odds in achieving steroid free remission with upadacitinib (OR 7.18, 95% CI 3.09–16.71) and adalimumab (OR 4.51, 95% CI 2.31–8.79) coming 2nd and 3rd. Looking at p-scores we can see that tofacitinib (92.43%) has the highest probability with upadacitinib (87.73%) and adalimumab (71.59%) following behind as is evident from Suplementary Table 8. P-score table is available as part of Supplementary Figure S7. 4. Discussion A comprehensive comparative assessment of treatment options comprising of biologics and small molecules available for moderate to severe ulcerative colitis (UC) treatment through this network meta-analysis (NMA) was carried out revealing upadacitinib demonstrating superior efficacy in inducing clinical remission, clinical response, and endoscopic improvement, as well as maintaining remission and endoscopic improvement, this positions Janus kinase (JAK) inhibitors such as upadacitinib and tofacitinib in particular, as an effective option in both induction and maintenance therapies. Infliximab an anti-TNF agent also gave performed well in inducing remission and endoscopic improvement, following just behind upadacitinib. Likewise, guselkumab, an IL-23 inhibitor, also performed well in achieving clinical response and maintaining endoscopic improvement. Tofacitinib exhibited the highest probability of achieving steroid-free remission, reinforcing the relevance of JAK inhibitors in reducing corticosteroid dependence in UC management. Filgotinib, which is another member of the JAK inhibitor family of medications, was also quite impressive during maintenance therapy, particularly in sustaining clinical remission, which suggests that selective JAK1 inhibition might also be an effective and well-tolerated option for long-term UC management. The S1P receptor modulator ozanimod did perform well but its comparative effectiveness did not surpass those of JAK inhibitors and IL-23 antagonists, which indicates that newer biologics might be preferable in many cases. The results of this NMA emphasizes the importance of personalized treatment strategies integrating patient specific factors including previous medication history of patients. Keeping that in mind results from this NMA also reinforces the fact that IL-23 inhibitors could be a viable alternative therapeutic option with the strong performance of guselkumab in clinical response and maintenance of endoscopic improvement further supports the integration of IL-23 antagonists into treatment algorithms for UC. 5. Conclusion While the results from our NMA does provide a robust comparative efficacy ranking of currently available treatment options for UC management, several undeniable limitations still exists that need acknowledgment. First, real world performance may be different from trial setting. Secondly, data on safety outcomes were excluded from this NMA mainly because of too much variability precluding any meaningful harmonization. As a result, a definitive conclusion regarding which treatment is both effective and safe is not possible here. Future studies with standardized safety data is needed to carry out a comprehensive benefit-risk profile of treatments for UC According to this NMA upadacitinib came out to be the most effective therapy across multiple outcomes following close behind are infliximab, guselkumab and tofacitinib outranking upadacitinib in specific outcomes. JAK inhibitors and IL-23 inhibitors emerge as promising alternatives due to their strong efficacy. Future research should focus on identifying biomarkers for response prediction and optimizing treatment sequencing to improve patient outcomes in UC management. Declarations Competing interests: The authors have no relevant financial or non-financial interests to disclose. Funding : The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Data Availability: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethical Approval Statement: This study is a network meta-analysis of previously published data and does not involve any new studies with human participants or animals performed by the authors. Therefore, ethical approval and informed consent were not required. Consent to publish: Not Applicable Author Contributions: Atta Ullah Khan conceptualized the idea for the network meta-analysis, performed the data analysis, and drafted the manuscript. Maria Ali and Muhammad Aamir Wahab conducted the literature search. All authors critically revised the manuscript and approved the final version for submission. References Balduzzi, S., Rücker, G., Nikolakopoulou, A., Papakonstantinou, T., Salanti, G., Efthimiou, O., & Schwarzer, G. (2023). netmeta: An R Package for Network Meta-Analysis Using Frequentist Methods. Journal of Statistical Software , 106 (2), 1–40. https://doi.org/10.18637/JSS.V106.I02 Ben Ghezala, I., Charkaoui, M., Michiels, C., Bardou, M., & Luu, M. (2021). Small Molecule Drugs in Inflammatory Bowel Diseases. Pharmaceuticals 2021, Vol. 14, Page 637 , 14 (7), 637. https://doi.org/10.3390/PH14070637 Caron, B., Honap, S., & Peyrin-Biroulet, L. (2024). Epidemiology of Inflammatory Bowel Disease across the Ages in the Era of Advanced Therapies. Journal of Crohn’s and Colitis , 18 (Supplement_2), ii3–ii15. https://doi.org/10.1093/ECCO-JCC/JJAE082 D’Amico, F., Parigi, T. L., Bonovas, S., Peyrin-Biroulet, L., & Danese, S. (2020). Long-term safety of approved biologics for ulcerative colitis. Expert Opinion on Drug Safety , 19 (7), 807–816. https://doi.org/10.1080/14740338.2020.1773430 Danese, S., Colombel, J. F., Lukas, M., Gisbert, J. P., D’Haens, G., Hayee, B., Panaccione, R., Kim, H. S., Reinisch, W., Tyrrell, H., Oh, Y. S., Tole, S., Chai, A., Chamberlain-James, K., Tang, M. T., Schreiber, S., Aboo, N., Ahmad, T., Aldeguer Mante, X., … Ziady, C. (2022). Etrolizumab versus infliximab for the treatment of moderately to severely active ulcerative colitis (GARDENIA): a randomised, double-blind, double-dummy, phase 3 study. The Lancet Gastroenterology and Hepatology , 7 (2), 118–127. https://doi.org/10.1016/S2468-1253(21)00294-6 Danese, S., & Fiocchi, C. (2011). Ulcerative Colitis. New England Journal of Medicine , 365 (18), 1713–1725. https://doi.org/10.1056/NEJMRA1102942 Danese, S., Vermeire, S., Zhou, W., Pangan, A. L., Siffledeen, J., Greenbloom, S., Hébuterne, X., D’Haens, G., Nakase, H., Panés, J., Higgins, P. D. R., Juillerat, P., Lindsay, J. O., Loftus, E. V., Sandborn, W. J., Reinisch, W., Chen, M. H., Sanchez Gonzalez, Y., Huang, B., … Panaccione, R. (2022). Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. The Lancet , 399 (10341), 2113–2128. https://doi.org/10.1016/S0140-6736(22)00581-5 Danese, S., Vuitton, L., & Peyrin-Biroulet, L. (2015). Biologic agents for IBD: practical insights. Nature Reviews Gastroenterology & Hepatology 2015 12:9 , 12 (9), 537–545. https://doi.org/10.1038/nrgastro.2015.135 D’Haens, G., Dubinsky, M., Kobayashi, T., Irving, P. M., Howaldt, S., Pokrotnieks, J., Krueger, K., Laskowski, J., Li, X., Lissoos, T., Milata, J., Morris, N., Arora, V., Milch, C., Sandborn, W., & Sands, B. E. (2023). Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis. New England Journal of Medicine , 388 (26), 2444–2455. https://doi.org/10.1056/nejmoa2207940 Dignass, A., Eliakim, R., Magro, F., Maaser, C., Chowers, Y., Geboes, K., Mantzaris, G., Reinisch, W., Colombel, J. F., Vermeire, S., Travis, S., Lindsay, J. O., & Van Assche, G. (2012). Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 1: Definitions and diagnosis. Journal of Crohn’s and Colitis , 6 (10), 965–990. https://doi.org/10.1016/J.CROHNS.2012.09.003 Fausel, R., Afzali, A., & Afzali, A. (2015). Biologics in the management of ulcerative colitis – comparative safety and efficacy of TNF-α antagonists. Therapeutics and Clinical Risk Management , 11 , 63–72. https://doi.org/10.2147/TCRM.S55506 Feagan, B. G., Danese, S., Loftus, E. V., Vermeire, S., Schreiber, S., Ritter, T., Fogel, R., Mehta, R., Nijhawan, S., Kempiński, R., Filip, R., Hospodarskyy, I., Seidler, U., Seibold, F., Beales, I. L. P., Kim, H. J., McNally, J., Yun, C., Zhao, S., … Peyrin-Biroulet, L. (2021). Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. The Lancet , 397 (10292), 2372–2384. https://doi.org/10.1016/S0140-6736(21)00666-8 Feagan, B. G., Rutgeerts, P., Sands, B. E., Hanauer, S., Colombel, J.-F., Sandborn, W. J., Van Assche, G., Axler, J., Kim, H.-J., Danese, S., Fox, I., Milch, C., Sankoh, S., Wyant, T., Xu, J., & Parikh, A. (2013). Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis. New England Journal of Medicine , 369 (8), 699–710. https://doi.org/10.1056/nejmoa1215734 Feuerstein, J. D., & Cheifetz, A. S. (2014). Ulcerative Colitis: Epidemiology, Diagnosis, and Management. Mayo Clinic Proceedings , 89 (11), 1553–1563. https://doi.org/10.1016/J.MAYOCP.2014.07.002 Hanžel, J., & D’Haens, G. R. (2020). Anti-interleukin-23 agents for the treatment of ulcerative colitis. Expert Opinion on Biological Therapy , 20 (4), 399–406. https://doi.org/10.1080/14712598.2020.1697227 Hibi, T., Imai, Y., Senoo, A., Ohta, K., & Ukyo, Y. (2017). Efficacy and safety of golimumab 52-week maintenance therapy in Japanese patients with moderate to severely active ulcerative colitis: a phase 3, double-blind, randomized, placebo-controlled study-(PURSUIT-J study). Journal of Gastroenterology , 52 (10), 1101–1111. https://doi.org/10.1007/s00535-017-1326-1 Higgins, J. P. T., & Thompson, S. G. (2002). Quantifying heterogeneity in a meta-analysis. Statistics in Medicine , 21 (11), 1539–1558. https://doi.org/10.1002/SIM.1186 Higgins, J. P. T., Thompson, S. G., Deeks, J. J., & Altman, D. G. (2003). Measuring inconsistency in meta-analyses. BMJ : British Medical Journal , 327 (7414), 557. https://doi.org/10.1136/BMJ.327.7414.557 Hutton, B., Salanti, G., Caldwell, D. M., Chaimani, A., Schmid, C. H., Cameron, C., Ioannidis, J. P. A., Straus, S., Thorlund, K., Jansen, J. P., Mulrow, C., Catala-Lopez, F., Gotzsche, P. C., Dickersin, K., Boutron, I., Altman, D. G., & Moher, D. (2015). The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: Checklist and explanations. Annals of Internal Medicine , 162 (11), 777–784. https://doi.org/10.7326/M14-2385/ASSET/IMAGES/6FF14_APPENDIX_BOX_5_DIFFERENCES_IN_APPROACH_TO_FITTING_NETWORK_META-ANALYSES.JPG Jiang, X.-L., Cui, H.-F., Gao, J., & Fan, H. (2015). Low-dose Infliximab for Induction and Maintenance Treatment in Chinese Patients With Moderate to Severe Active Ulcerative Colitis . www.jcge.com Jiang, Y., Kong, D., Miao, X., Yu, X., Wu, Z., Liu, H., & Gong, W. (2022). Anti-cytokine therapy and small molecule agents for the treatment of inflammatory bowel disease. European Cytokine Network 2021 32:4 , 32 (4), 73–82. https://doi.org/10.1684/ECN.2021.0472 Kashani, A., & Schwartz, D. A. (2019). The Expanding Role of Anti–IL-12 and/or Anti–IL-23 Antibodies in the Treatment of Inflammatory Bowel Disease. Gastroenterology & Hepatology , 15 (5), 255. https://pmc.ncbi.nlm.nih.gov/articles/PMC6589846/ Kobayashi, T., Siegmund, B., Le Berre, C., Wei, S. C., Ferrante, M., Shen, B., Bernstein, C. N., Danese, S., Peyrin-Biroulet, L., & Hibi, T. (2020). Ulcerative colitis. Nature Reviews Disease Primers 2020 6:1 , 6 (1), 1–20. https://doi.org/10.1038/s41572-020-0205-x Lamb, C. A., O’Byrne, S., Keir, M. E., & Butcher, E. C. (2018). Gut-Selective Integrin-Targeted Therapies for Inflammatory Bowel Disease. Journal of Crohn’s and Colitis , 12 (suppl_2), S653–S668. https://doi.org/10.1093/ECCO-JCC/JJY060 Lewis, J. D., Parlett, L. E., Jonsson Funk, M. L., Brensinger, C., Pate, V., Wu, Q., Dawwas, G. K., Weiss, A., Constant, B. D., McCauley, M., Haynes, K., Yang, J. Y., Schaubel, D. E., Hurtado-Lorenzo, A., & Kappelman, M. D. (2023). Incidence, Prevalence, and Racial and Ethnic Distribution of Inflammatory Bowel Disease in the United States. Gastroenterology , 165 (5), 1197-1205.e2. https://doi.org/10.1053/j.gastro.2023.07.003 Liang, Y., Li, Y., Lee, C., Yu, Z., Chen, C., & Liang, C. (2024). Ulcerative colitis: molecular insights and intervention therapy. Molecular Biomedicine 2024 5:1 , 5 (1), 1–32. https://doi.org/10.1186/S43556-024-00207-W Motoya, S., Watanabe, K., Ogata, H., Kanai, T., Matsui, T., Suzuki, Y., Shikamura, M., Sugiura, K., Oda, K., Hori, T., Araki, T., Watanabe, M., & Hibi, T. (2019). Vedolizumab in Japanese patients with ulcerative colitis: A Phase 3, randomized, double-blind, placebo-controlled study. PLoS ONE , 14 (2). https://doi.org/10.1371/journal.pone.0212989 Nakamura, N., Honzawa, Y., Ohtsu, T., Sano, Y., Ito, Y., Fukata, N., Fukui, T., & Naganuma, M. (2024). Efficacy of upadacitinib in the achievement of clinical and endoscopic remission in hospitalized patients with ulcerative colitis. Clinical Journal of Gastroenterology , 17 (4), 654–657. https://doi.org/10.1007/S12328-024-01976-1/FIGURES/1 Neri, B., Mancone, R., Fiorillo, M., Schiavone, S. C., Migliozzi, S., & Biancone, L. (2024). Efficacy and Safety of Janus Kinase-Inhibitors in Ulcerative Colitis. Journal of Clinical Medicine 2024, Vol. 13, Page 7186 , 13 (23), 7186. https://doi.org/10.3390/JCM13237186 Panaccione, R., Ghosh, S., Middleton, S., Márquez, J. R., Scott, B. B., Flint, L., Van Hoogstraten, H. J. F., Chen, A. C., Zheng, H., Danese, S., & Rutgeerts, P. (2014). Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology , 146 (2). https://doi.org/10.1053/j.gastro.2013.10.052 Peyrin-Biroulet, L., Hart, A., Bossuyt, P., Long, M., Allez, M., Juillerat, P., Armuzzi, A., Loftus, E. V., Ostad-Saffari, E., Scalori, A., Oh, Y. S., Tole, S., Chai, A., Pulley, J., Lacey, S., & Sandborn, W. J. (2022). Etrolizumab as induction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY): a phase 3, randomised, controlled trial. The Lancet Gastroenterology and Hepatology , 7 (2), 128–140. https://doi.org/10.1016/S2468-1253(21)00298-3 Raine, T., Bonovas, S., Burisch, J., Kucharzik, T., Adamina, M., Annese, V., Bachmann, O., Bettenworth, D., Chaparro, M., Czuber-Dochan, W., Eder, P., Ellul, P., Fidalgo, C., Fiorino, G., Gionchetti, P., Gisbert, J. P., Gordon, H., Hedin, C., Holubar, S., … Doherty, G. (2022). ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. Journal of Crohn’s and Colitis , 16 (1), 2–17. https://doi.org/10.1093/ECCO-JCC/JJAB178 Reinisch, W., Sandborn, W. J., Hommes, D. W., D’Haens, G., Hanauer, S., Schreiber, S., Panaccione, R., Fedorak, R. N., Tighe, M. B., Huang, B., Kampman, W., Lazar, A., & Thakkar, R. (2011). Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: Results of a randomised controlled trial. Gut , 60 (6), 780–787. https://doi.org/10.1136/gut.2010.221127 Rubin, D. T., Allegretti, J. R., Panés, J., Shipitofsky, N., Yarandi, S. S., Huang, K.-H. G., Germinaro, M., Wilson, R., Zhang, H., Johanns, J., Feagan, B. G., Hisamatsu, T., Lichtenstein, G. R., Bressler, B., Peyrin-Biroulet, L., Sands, B. E., Dignass, A., & QUASAR Study Group. (2024). Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. Lancet (London, England) . https://doi.org/10.1016/S0140-6736(24)01927-5 Rubin, D. T., Ananthakrishnan, A. N., Siegel, C. A., Sauer, B. G., & Long, M. D. (2019). ACG Clinical Guideline: Ulcerative Colitis in Adults. American Journal of Gastroenterology , 114 (3), 384–413. https://doi.org/10.14309/AJG.0000000000000152 Rutgeerts, P., Sandborn, W. J., Feagan, B. G., Reinisch, W., Olson, A., Johanns, J., Travers, S., Rachmilewitz, D., Hanauer, S. B., Lichtenstein, G. R., De Villiers, W. J. S., Present, D., Sands, B. E., & Colombel, J. F. (2005). Infliximab for Induction and Maintenance Therapy for Ulcerative Colitis (Vol. 8). www.nejm.org Sandborn, W. J., Baert, F., Danese, S., Krznarić, Ž., Kobayashi, T., Yao, X., Chen, J., Rosario, M., Bhatia, S., Kisfalvi, K., D’Haens, G., & Vermeire, S. (2020). Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis. Gastroenterology , 158 (3), 562-572.e12. https://doi.org/10.1053/j.gastro.2019.08.027 Sandborn, W. J., Feagan, B. G., D’Haens, G., Wolf, D. C., Jovanovic, I., Hanauer, S. B., Ghosh, S., Petersen, A., Hua, S. Y., Lee, J. H., Charles, L., Chitkara, D., Usiskin, K., Colombel, J.-F., Laine, L., & Danese, S. (2021). Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. New England Journal of Medicine , 385 (14), 1280–1291. https://doi.org/10.1056/nejmoa2033617 Sandborn, W. J., Feagan, B. G., Marano, C., Zhang, H., Strauss, R., Johanns, J., Adedokun, O. J., Guzzo, C., Colombel, J. F., Reinisch, W., Gibson, P. R., Collins, J., Järnerot, G., Hibi, T., & Rutgeerts, P. (2014). Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology , 146 (1), 85–95. https://doi.org/10.1053/j.gastro.2013.05.048 Sandborn, W. J., Feagan, B. G., Marano, C., Zhang, H., Strauss, R., Johanns, J., Adedokun, O. J., Guzzo, C., Colombel, J. F., Reinisch, W., Gibson, P. R., Collins, J., Järnerot, G., & Rutgeerts, P. (2014). Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology , 146 (1). https://doi.org/10.1053/j.gastro.2013.06.010 Sandborn, W. J., Su, C., Sands, B. E., D’Haens, G. R., Vermeire, S., Schreiber, S., Danese, S., Feagan, B. G., Reinisch, W., Niezychowski, W., Friedman, G., Lawendy, N., Yu, D., Woodworth, D., Mukherjee, A., Zhang, H., Healey, P., & Panés, J. (2017). Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. New England Journal of Medicine , 376 (18), 1723–1736. https://doi.org/10.1056/nejmoa1606910 Sandborn, W. J., Van Assche, G., Reinisch, W., Colombel, J., D’Haens, G., Wolf, D. C., Kron, M., Tighe, M. B., Lazar, A., & Thakkar, R. B. (2012). Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology , 142 (2). https://doi.org/10.1053/j.gastro.2011.10.032 Sands, B. E., Peyrin-Biroulet, L., Loftus, E. V., Danese, S., Colombel, J.-F., Törüner, M., Jonaitis, L., Abhyankar, B., Chen, J., Rogers, R., Lirio, R. A., Bornstein, J. D., & Schreiber, S. (2019). Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis. New England Journal of Medicine , 381 (13), 1215–1226. https://doi.org/10.1056/nejmoa1905725 Sands, B. E., Sandborn, W. J., Panaccione, R., O’Brien, C. D., Zhang, H., Johanns, J., Adedokun, O. J., Li, K., Peyrin-Biroulet, L., Van Assche, G., Danese, S., Targan, S., Abreu, M. T., Hisamatsu, T., Szapary, P., & Marano, C. (2019). Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis. New England Journal of Medicine , 381 (13), 1201–1214. https://doi.org/10.1056/nejmoa1900750 Shivaji, U. N., Nardone, O. M., Cannatelli, R., Smith, S. C., Ghosh, S., & Iacucci, M. (2020). Small molecule oral targeted therapies in ulcerative colitis. The Lancet Gastroenterology and Hepatology , 5 (9), 850–861. https://doi.org/10.1016/S2468-1253(19)30414-5/ASSET/C35A8F20-91D5-47A3-B3D8-81F0189EBFBB/MAIN.ASSETS/GR2.SML Sicilia, B., García-López, S., González-Lama, Y., Zabana, Y., Hinojosa, J., & Gomollón, F. (2020). Guía GETECCU 2020 para el tratamiento de la colitis ulcerosa. Elaborada con metodología GRADE. Gastroenterología y Hepatología , 43 , 1–57. https://doi.org/10.1016/J.GASTROHEP.2020.07.001 Sterne, J. A. C., Savović, J., Page, M. J., Elbers, R. G., Blencowe, N. S., Boutron, I., Cates, C. J., Cheng, H. Y., Corbett, M. S., Eldridge, S. M., Emberson, J. R., Hernán, M. A., Hopewell, S., Hróbjartsson, A., Junqueira, D. R., Jüni, P., Kirkham, J. J., Lasserson, T., Li, T., … Higgins, J. P. T. (2019). RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ , 366 . https://doi.org/10.1136/BMJ.L4898 Suzuki, Y., Motoya, S., Hanai, H., Matsumoto, T., Hibi, T., Robinson, A. M., Mostafa, N. M., Chao, J., Arora, V., Camez, A., Thakkar, R. B., & Watanabe, M. (2014). Efficacy and safety of adalimumab in Japanese patients with moderately to severely active ulcerative colitis. Journal of Gastroenterology , 49 (2), 283–294. https://doi.org/10.1007/s00535-013-0922-y Thomas, S., & Baumgart, D. C. (2012). Targeting leukocyte migration and adhesion in Crohn’s disease and ulcerative colitis. Inflammopharmacology , 20 (1), 1–18. https://doi.org/10.1007/S10787-011-0104-6/FIGURES/2 Vieujean, S., Jairath, V., Peyrin-Biroulet, L., Dubinsky, M., Iacucci, M., Magro, F., & Danese, S. (2025). Understanding the therapeutic toolkit for inflammatory bowel disease. Nature Reviews Gastroenterology and Hepatology , 1–24. https://doi.org/10.1038/S41575-024-01035-7/METRICS Voelker, R. (2024). What Is Ulcerative Colitis? JAMA , 331 (8), 716–716. https://doi.org/10.1001/JAMA.2023.23814 Additional Declarations The authors declare no competing interests. Supplementary Files Supplementary.docx Supplemmentary Data Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6255469","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":430645050,"identity":"11138df6-47bb-4f6a-8cc1-cbaed58efc58","order_by":0,"name":"Atta Ullah Khan","email":"data:image/png;base64,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","orcid":"https://orcid.org/0009-0006-6016-9221","institution":"Vanvitelli University Napoli, Italy","correspondingAuthor":true,"prefix":"","firstName":"Atta","middleName":"Ullah","lastName":"Khan","suffix":""},{"id":430646186,"identity":"a66111db-2bdd-4e9e-a8b6-f3c04ccfc40b","order_by":1,"name":"Maria Ali","email":"","orcid":"","institution":"Vanvitelli University Napoli, Italy","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Ali","suffix":""},{"id":430646187,"identity":"75958f86-592f-4570-84cf-1919c7287f70","order_by":2,"name":"Muhammad Aamir Wahab","email":"","orcid":"","institution":"Vanvitelli University Napoli, Italy","correspondingAuthor":false,"prefix":"","firstName":"Muhammad","middleName":"Aamir","lastName":"Wahab","suffix":""}],"badges":[],"createdAt":"2025-03-18 17:38:56","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6255469/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6255469/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":78888319,"identity":"fb26cedf-0d15-4738-870e-d57c3eba00e5","added_by":"auto","created_at":"2025-03-20 09:59:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":128948,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow chart of search strategy\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6255469/v1/f70a231eaee71ec64dea9879.png"},{"id":78888709,"identity":"33491abc-39c7-447c-a12b-6bd35ddf1204","added_by":"auto","created_at":"2025-03-20 10:07:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":79674,"visible":true,"origin":"","legend":"\u003cp\u003eNetwork plot for clinical remission-Induction therapy\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6255469/v1/e5ede9fd40346d450c6adc0c.png"},{"id":78888322,"identity":"4c7c8b84-1b8c-4867-a7cb-02f02461cc4f","added_by":"auto","created_at":"2025-03-20 09:59:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":78034,"visible":true,"origin":"","legend":"\u003cp\u003eNetwork plot clinical remission-maintenance therapy\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6255469/v1/e4a1cd83d9f409261490facb.png"},{"id":78889415,"identity":"32a62263-5772-4b22-98ec-8ebe72538275","added_by":"auto","created_at":"2025-03-20 10:15:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":865344,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6255469/v1/31e09475-2a6b-486c-bb96-c9a22067787c.pdf"},{"id":78888710,"identity":"303a78d3-1c44-4846-8aab-252ae35c339f","added_by":"auto","created_at":"2025-03-20 10:07:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":422404,"visible":true,"origin":"","legend":"\u003cp\u003eSupplemmentary Data\u003c/p\u003e","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-6255469/v1/fb1e2022e7a565b1a560f336.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eComparative efficacy of pharmacological interventions in ulcerative colitis: A Network Meta Analysis\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eUlcerative colitis (UC) is amongst the two well-known forms of inflammatory bowel disease (IBD), characterized by a continuously progressing inflammation that starts from rectum moving proximally affecting the mucosa. Ulcerative colitis (UC) follows a relapsing-remitting course and with the global prevalence on the rise UC poses a significant impact on patients' quality of life(Caron et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Feuerstein \u0026amp; Cheifetz, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Lewis et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). The exact cause of UC development is still far from being fully known but factors believed to be associated with its development or somehow play a part in its development includes genetic, environmental and at the forefront is a dysregulated immune response(Danese \u0026amp; Fiocchi, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Kobayashi et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Voelker, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). The fundamental goal of any UC treatment is the reduction in symptoms and maintenance of that state, preventions of complications usually associated with UC and finally improve patient quality of life(Raine et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Rubin et al., \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). The usual medications for UC includes 5-aminosalicylates (5-ASA), corticosteroids, and immunomodulators as first line therapy. These are vital in restricting disease progression, but a more specific approach is certainly needed considering the wide-ranging side effects associated with these medications.\u003c/p\u003e \u003cp\u003eWith that in mind, a new class of drugs called biologics which at molecular level comprises of monoclonal antibodies that target multiple pathway components involved in the inflammatory response has been developed. These include tumor necrosis factor (TNF-α) inhibitors, such as infliximab and adalimumab which were amongst the first biologics to gain approval and show efficacy in both inducing and maintaining remission(D\u0026rsquo;Amico et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Danese et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Fausel et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Moving forward, the development of newer biologics, such as anti-integrins (e.g., vedolizumab) as well as interleukin antagonists (e.g., ustekinumab) have been achieved, thereby expanding the already extensive set of therapy choices for UC(Hanžel \u0026amp; D\u0026rsquo;Haens, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Kashani \u0026amp; Schwartz, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Lamb et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Thomas \u0026amp; Baumgart, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2012\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe latest class of medication available for UC therapy and that also have gained FDA approval includes Janus kinase (JAK) inhibitors and sphingosine 1-phosphate (S1P) modulators. These are known as small molecules drugs that also offer the convenience of oral administration. Janus kinase (JAK) inhibitors target numerous molecules belonging to the JAK-STAT signaling pathway while sphingosine 1-phosphate (S1P), a lipid-based mediator involved in immune trafficking and vascular health. They provide more robust immunosuppressive effect and have shown efficacy in both induction of and maintaining remission in UC patients(Ben Ghezala et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Y. Jiang et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Liang et al., \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Nakamura et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Neri et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Shivaji et al., \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Vieujean et al., \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2025\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWith increasing diversity in therapeutic options becoming available, the need for comparative efficacy and safety evaluations is becoming more important today to specifically evaluate and synthesize the available evidence on clinically meaningful endpoints that reflect key therapeutic goals, including clinical remission, clinical response, and endoscopic improvement during induction therapy, as well as clinical remission, endoscopic improvement, and steroid-free remission during maintenance therapy to guide clinical judgment. Whilst standard meta-analyses do hold value the heterogeneity in patient populations, disease severity, and treatment protocols across studies highlights the importance of a network-based approach that can integrate diverse sources of evidence. Network meta-analysis (NMA) removes these limitations by allowing the indirect comparison of many therapies using a common comparator and establishing a treatment hierarchy based on their relative efficacy and safety.\u003c/p\u003e \u003cp\u003eThe aim of this network meta-analysis is to compare the efficacy of biologics and small molecules utilizing key outcomes as part of both induction and maintenance therapy.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Search strategy and Selection Criteria\u003c/h2\u003e \u003cp\u003eThis Network Meta Analysis adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Network Meta-Analyses (PRISMA-NMA) guidelines(Hutton et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420250655739.\u003c/p\u003e \u003cp\u003eA wide-ranging retrieval strategy was developed to catch all relevant studies. From inception to 21 January 2025, two independent reviewers (MAW and MA) performed a very thorough search of search of PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL). Concomitantly, unpublished or advancing studies were also searched by reviewing multiple leading gastroenterology symposiums (e.g., ECCO) and clinical trial registers (e.g., ClinicalTrials.gov).\u003c/p\u003e \u003cp\u003eSearch terms included Medical Subject Headings (MeSH) and free-text keywords related to ulcerative colitis, biologics, small molecules, and efficacy outcomes. Specific search strings combined terms such as \"ulcerative colitis,\" \"biologics,\" \"small molecules,\" \"clinical remission,\" \"endoscopic improvement,\" and drug-specific names (e.g., infliximab, vedolizumab, tofacitinib, upadacitinib). No language or geographic restrictions were applied. Detailed search strategy is available in Supplementary Table\u0026nbsp;1.\u003c/p\u003e \u003cp\u003eRandomized control trials (RCTs) that are Phase 2b/3 or 3 evaluating biologics or small molecule drugs against placebo or other active comparator involving adults (\u0026ge;\u0026thinsp;18 years) with a confirmed diagnosis of moderate to severe ulcerative colitis (UC) defined by a Full Mayo Score (MCS) of 6\u0026ndash;12(Dignass et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Sicilia et al., \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Studies reporting efficacy outcomes, including clinical remission, clinical response, endoscopic improvement, and steroid-free remission were included.\u003c/p\u003e \u003cp\u003eRCTs that are not phase 2b/3 or 3. Studies focusing on pediatric populations. Trials that do not report key efficacy outcomes according to defined criteria. Studies about non-human subjects or in vitro testing, non-randomized studies, observational studies, case reports, reviews, summaries, meta-analyses, letters to the editor along with irretrievable full text studies or with incomplete data were excluded.\u003c/p\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003e2.1.2. Outcomes\u003c/h2\u003e \u003cp\u003eInduction therapy was considered for 6\u0026ndash;14 weeks, outcomes assessed were Clinical Remission (defined as FMS\u0026thinsp;\u0026le;\u0026thinsp;2, with no individual subscore\u0026thinsp;\u0026gt;\u0026thinsp;1), Clinical Response (defined as Reduction in FMS by \u0026ge;\u0026thinsp;3 points and \u0026ge;\u0026thinsp;30% from baseline, including a decrease in rectal bleeding subscore) and Endoscopic Improvement (defined as MES\u0026thinsp;\u0026le;\u0026thinsp;1 either with or without friability). The maintenance Phase was considered for \u0026ge;\u0026thinsp;40 weeks and the assessed outcomes were Clinical Remission, Endoscopic Improvement and Steroid-Free Remission.\u003c/p\u003e \u003cp\u003eTo maintain uniformity across studies, outcomes for mucosal healing and endoscopic improvement were harmonized as much as possible based on their definitions even though studies reported these outcomes under different terminologies, they were included in the same analytical category if they shared identical definitions which is Mayo Endoscopic Subscore (MES) of \u0026le;\u0026thinsp;1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003e2.1.3. Study selection\u003c/h2\u003e \u003cp\u003eTwo independent reviewers (MAW and MA) extracted data from eligible studies using a standardized data extraction form. Extracted information included, study related information (author, year), Patient related information (age, sex, disease duration), Intervention related details (drug, dosage, administration route) and Outcome measures (time points, and results for each efficacy endpoint).\u003c/p\u003e \u003cp\u003eDiscrepancies in data extraction were resolved through consensus or consultation with a third reviewer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003e2.1.4. Risk of Bias and Quality Assessment\u003c/h2\u003e \u003cp\u003eThe Cochrane Risk of Bias 2.0 tool (RoB 2)(Sterne et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), was used to assess the methodological quality of included RCTs. This tool evaluates studies across five domains, Bias arising because of the randomization process, Bias arising as a result of deviation from intended interventions, Bias due to lack of outcome data, Bias due to measurement of the outcome and Bias because of selection of the reported result. Individual studies were classified as having a low, some concerns, or high risk of bias based on individual domain evaluation. For results of RoB assessment see Supplementary Figure S1. Discrepancies were resolved through discussion or by consultation involving a third reviewer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e2.1.5. Statistical Analysis\u003c/h2\u003e \u003cp\u003eA frequentist approach was utilized to conduct our network meta-analysis (NMA) using R software version 4.4.2 and netmeta package(Balduzzi et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Effect measures comprising of odds ratios with 95% Confidence Intervals (95% CI) were calculated utilizing dichotomous data. I\u003csup\u003e2\u003c/sup\u003e statistic was utilized for calculating in between studies heterogeneity(Higgins et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Higgins \u0026amp; Thompson, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2002\u003c/span\u003e), node splitting model used for inconsistency determination. Lastly P-Scores was used to rank treatments efficacy with higher scores denoting better efficacy.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eA total of 22 randomized controlled trials (RCTs), comprising of 7,683 patients with moderate-to-severe ulcerative colitis Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, were included in this network meta-analysis(Danese, Colombel, et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Danese, Vermeire, et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; D\u0026rsquo;Haens et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Feagan et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2013\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Hibi et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; X.-L. Jiang et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Motoya et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Panaccione et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Peyrin-Biroulet et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Reinisch et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Rubin et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Rutgeerts et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2005\u003c/span\u003e; Sandborn et al., \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2012\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2017\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2020\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Sandborn, Feagan, Marano, Zhang, Strauss, Johanns, Adedokun, Guzzo, Colombel, Reinisch, Gibson, Collins, J\u0026auml;rnerot, \u0026amp; Rutgeerts, 2014; Sandborn, Feagan, Marano, Zhang, Strauss, Johanns, Adedokun, Guzzo, Colombel, Reinisch, Gibson, Collins, J\u0026auml;rnerot, Hibi, et al., 2014; Sands, Peyrin-Biroulet, et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Sands, Sandborn, et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Suzuki et al., \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). The studies evaluated the efficacy of biologics and small molecules, including Upadacitinib, Infliximab, Ozanimod, Guselkumab, Ustekinumab, Tofacitinib, Golimumab, Etrolizumab, Vedolizumab, Filgotinib, Mirikizumab, and Adalimumab, compared to placebo. The interventions were assessed for their effectiveness in inducing remission, response, and endoscopic improvement and maintaining remission, endoscopic improvement and steroid free remission. Baseline characteristics of included studies are presented in Supplementary Table\u0026nbsp;2. Heterogeneity was low in all the analyzed outcomes for both induction and maintenance therapies, with I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026lt;\u0026thinsp;30%, and there were no elements for inconsistency (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) invalidating the model. The results are represented in the supplementary appendix.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Induction therapy\u003c/h2\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e3.1.1. Clinical remission\u003c/h2\u003e \u003cp\u003eAll treatments displayed statistical significance in inducing clinical remission as compared to placebo with upadacitinib (OR 9.43, 95% CI 5.36\u0026ndash;16.61), infliximab 5 mg (OR 4.96, 95% CI 3.29\u0026ndash;7.46) and infliximab 3.5 mg (OR 4.17, 95% CI 1.84\u0026ndash;9.41) ranking 1st, 2nd and 3rd. In comparison to other treatments upadacitinb possessed statistically significant superiority over all except infliximab 5 mg (OR 1.90, 95% CI 0.95\u0026ndash;3.82) and infliximab 3.5 mg (OR 2.26, 95% CI 0.84\u0026ndash;6.11). Additionally, infliximab 5 mg showed statistically significant superiority over etrolizumab, vedolizumab, filgotinib, mirikizumab and adalimumab as is evident from Suplementary Table\u0026nbsp;3. Per the P-score ranking, upadacitinib ranked highest in inducing clinical remission (99.08%), followed by Infliximab 5 mg (84.6%). Infliximab 3.5 mg (70.93%) ranked third. P-score table is available as part of Supplementary Figure S2. Also, for network plot see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003e3.1.2. Clinical response\u003c/h2\u003e \u003cp\u003eAll treatments displayed statistical significance in inducing clinical response as compared to placebo except for azathioprine (OR 1.78, 95% CI 0.79\u0026ndash;4.01). Upadacitinib (OR 7.85, 95% CI 5.41\u0026ndash;11.38), infliximab/azathioprine (OR 5.94, 95% CI 2.53\u0026ndash;13.98) and guselkumab (OR 4.14, 95% CI 2.64\u0026ndash;6.49) ranking 1st, 2nd and 3rd when compared to placebo. In comparison to other treatments upadacitinb statistically significant superiority over all except infliximab/azathioprine (OR 1.32, 95% CI 0.52\u0026ndash;3.35) and infliximab 3.5 mg (OR 2.01, 95% CI 0.76\u0026ndash;5.32) as is eveident from Suplementary Table\u0026nbsp;4. Per the P-score ranking, upadacitinib ranked highest in inducing clinical response (97.44%), followed by infliximab/azathioprine (87.79%) and guselkumab (76.08%) ranked third. P-score table is available as part of Supplementary Figure S3.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e3.1.3. Endoscopic improvement\u003c/h2\u003e \u003cp\u003eAll treatments displayed statistical significance in inducing endoscopic improvement as compared to placebo except for azathioprine (OR 1.55, 95% CI 0.76\u0026ndash;3.17). Upadacitinib (OR 8.25, 95% CI 5.33\u0026ndash;12.77), infliximab/azathioprine (OR 4.49, 95% CI 2.21\u0026ndash;9.14) and infliximab 5 mg (OR 3.19, 95% CI 2.35\u0026ndash;4.33) ranked 1st, 2nd and 3rd. In comparison to other treatments, upadacitinib showed statistical significance over all except infliximab/azathioprine as is evident from Suplementary Table\u0026nbsp;5. Per the P-score ranking, upadacitinib ranked highest in inducing endoscopic improvement (99.32%), followed by Infliximab/azathioprine (87.17%) while infliximab 5 mg (75.89%) ranked third. P-score table is available as part of Supplementary Figure S4.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Maintenance therapy\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e3.2.1. Clinical remission\u003c/h2\u003e \u003cp\u003eAll treatments except for etrolizumab showed statistical significance in maintaining clinical remission in comparison to placebo. Upadacitinib (OR 7.87, 95% CI 3.90\u0026ndash;15.88) displayed statistically significant superiority to all other treatments except filgotinib, guselkumab, tofacitinib and vedolizumab as is evident from Suplementary Table\u0026nbsp;6. According to P- Score, upadacitinib (95.60%) ranked highest in maintaining clinical remission with filgotinib (81.28%) and guselkumab (73.75%) following behind, P-score table is available as part of Supplementary Figure S5. As for network plot see Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003e3.2.2. Endoscopic improvement\u003c/h2\u003e \u003cp\u003eAll treatments were significantly superior in comparision to placebo for maintaining endoscopic improvement. Except for guselkumab, upadacitinib was significantly superior to all drugs in maintaining endoscopic improvement. Upadacitinib (OR 9.30, 95% CI 5.32\u0026ndash;16.23), guselkumab (OR 4.56, 95% CI 2.87\u0026ndash;7.23) and tofacitinib (OR 3.95, 95% CI 2.39\u0026ndash;6.53) ranked 1st, 2nd and 3rd as seen through Supplementary Table\u0026nbsp;7. P-scores ranking also confirms upadacitinib (99.46%) ranked highest in maintaining endoscopic improvement with guselkumab (80.46%) and tofacitinib (70.67%) following behind. P-score table is available as part of Supplementary Figure S6.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e3.2.3. Steroid Free Remission\u003c/h2\u003e \u003cp\u003eWith the exception of golimumab all treatments were significantly superior in comparison to placebo in achieving steroid free remission. Tofacitinib (OR 10.22, 95% CI 2.88\u0026ndash;36.32) has the best odds in achieving steroid free remission with upadacitinib (OR 7.18, 95% CI 3.09\u0026ndash;16.71) and adalimumab (OR 4.51, 95% CI 2.31\u0026ndash;8.79) coming 2nd and 3rd. Looking at p-scores we can see that tofacitinib (92.43%) has the highest probability with upadacitinib (87.73%) and adalimumab (71.59%) following behind as is evident from Suplementary Table\u0026nbsp;8. P-score table is available as part of Supplementary Figure S7.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eA comprehensive comparative assessment of treatment options comprising of biologics and small molecules available for moderate to severe ulcerative colitis (UC) treatment through this network meta-analysis (NMA) was carried out revealing upadacitinib demonstrating superior efficacy in inducing clinical remission, clinical response, and endoscopic improvement, as well as maintaining remission and endoscopic improvement, this positions Janus kinase (JAK) inhibitors such as upadacitinib and tofacitinib in particular, as an effective option in both induction and maintenance therapies. Infliximab an anti-TNF agent also gave performed well in inducing remission and endoscopic improvement, following just behind upadacitinib. Likewise, guselkumab, an IL-23 inhibitor, also performed well in achieving clinical response and maintaining endoscopic improvement. Tofacitinib exhibited the highest probability of achieving steroid-free remission, reinforcing the relevance of JAK inhibitors in reducing corticosteroid dependence in UC management. Filgotinib, which is another member of the JAK inhibitor family of medications, was also quite impressive during maintenance therapy, particularly in sustaining clinical remission, which suggests that selective JAK1 inhibition might also be an effective and well-tolerated option for long-term UC management. The S1P receptor modulator ozanimod did perform well but its comparative effectiveness did not surpass those of JAK inhibitors and IL-23 antagonists, which indicates that newer biologics might be preferable in many cases.\u003c/p\u003e \u003cp\u003eThe results of this NMA emphasizes the importance of personalized treatment strategies integrating patient specific factors including previous medication history of patients. Keeping that in mind results from this NMA also reinforces the fact that IL-23 inhibitors could be a viable alternative therapeutic option with the strong performance of guselkumab in clinical response and maintenance of endoscopic improvement further supports the integration of IL-23 antagonists into treatment algorithms for UC.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eWhile the results from our NMA does provide a robust comparative efficacy ranking of currently available treatment options for UC management, several undeniable limitations still exists that need acknowledgment. First, real world performance may be different from trial setting. Secondly, data on safety outcomes were excluded from this NMA mainly because of too much variability precluding any meaningful harmonization. As a result, a definitive conclusion regarding which treatment is both effective and safe is not possible here. Future studies with standardized safety data is needed to carry out a comprehensive benefit-risk profile of treatments for UC\u003c/p\u003e \u003cp\u003eAccording to this NMA upadacitinib came out to be the most effective therapy across multiple outcomes following close behind are infliximab, guselkumab and tofacitinib outranking upadacitinib in specific outcomes. JAK inhibitors and IL-23 inhibitors emerge as promising alternatives due to their strong efficacy. Future research should focus on identifying biomarkers for response prediction and optimizing treatment sequencing to improve patient outcomes in UC management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability:\u0026nbsp;\u003c/strong\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval Statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a network meta-analysis of previously published data and does not involve any new studies with human participants or animals performed by the authors. Therefore, ethical approval and informed consent were not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish:\u0026nbsp;\u003c/strong\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAtta Ullah Khan conceptualized the idea for the network meta-analysis, performed the data analysis, and drafted the manuscript. Maria Ali and Muhammad Aamir Wahab conducted the literature search. All authors critically revised the manuscript and approved the final version for submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBalduzzi, S., R\u0026uuml;cker, G., Nikolakopoulou, A., Papakonstantinou, T., Salanti, G., Efthimiou, O., \u0026amp; Schwarzer, G. (2023). netmeta: An R Package for Network Meta-Analysis Using Frequentist Methods. \u003cem\u003eJournal of Statistical Software\u003c/em\u003e, \u003cem\u003e106\u003c/em\u003e(2), 1\u0026ndash;40. https://doi.org/10.18637/JSS.V106.I02\u003c/li\u003e\n\u003cli\u003eBen Ghezala, I., Charkaoui, M., Michiels, C., Bardou, M., \u0026amp; Luu, M. (2021). Small Molecule Drugs in Inflammatory Bowel Diseases. \u003cem\u003ePharmaceuticals 2021, Vol. 14, Page 637\u003c/em\u003e, \u003cem\u003e14\u003c/em\u003e(7), 637. https://doi.org/10.3390/PH14070637\u003c/li\u003e\n\u003cli\u003eCaron, B., Honap, S., \u0026amp; Peyrin-Biroulet, L. (2024). Epidemiology of Inflammatory Bowel Disease across the Ages in the Era of Advanced Therapies. \u003cem\u003eJournal of Crohn\u0026rsquo;s and Colitis\u003c/em\u003e, \u003cem\u003e18\u003c/em\u003e(Supplement_2), ii3\u0026ndash;ii15. https://doi.org/10.1093/ECCO-JCC/JJAE082\u003c/li\u003e\n\u003cli\u003eD\u0026rsquo;Amico, F., Parigi, T. L., Bonovas, S., Peyrin-Biroulet, L., \u0026amp; Danese, S. (2020). Long-term safety of approved biologics for ulcerative colitis. \u003cem\u003eExpert Opinion on Drug Safety\u003c/em\u003e, \u003cem\u003e19\u003c/em\u003e(7), 807\u0026ndash;816. https://doi.org/10.1080/14740338.2020.1773430\u003c/li\u003e\n\u003cli\u003eDanese, S., Colombel, J. F., Lukas, M., Gisbert, J. P., D\u0026rsquo;Haens, G., Hayee, B., Panaccione, R., Kim, H. S., Reinisch, W., Tyrrell, H., Oh, Y. S., Tole, S., Chai, A., Chamberlain-James, K., Tang, M. T., Schreiber, S., Aboo, N., Ahmad, T., Aldeguer Mante, X., \u0026hellip; Ziady, C. (2022). Etrolizumab versus infliximab for the treatment of moderately to severely active ulcerative colitis (GARDENIA): a randomised, double-blind, double-dummy, phase 3 study. \u003cem\u003eThe Lancet Gastroenterology and Hepatology\u003c/em\u003e, \u003cem\u003e7\u003c/em\u003e(2), 118\u0026ndash;127. https://doi.org/10.1016/S2468-1253(21)00294-6\u003c/li\u003e\n\u003cli\u003eDanese, S., \u0026amp; Fiocchi, C. (2011). Ulcerative Colitis. \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e, \u003cem\u003e365\u003c/em\u003e(18), 1713\u0026ndash;1725. https://doi.org/10.1056/NEJMRA1102942\u003c/li\u003e\n\u003cli\u003eDanese, S., Vermeire, S., Zhou, W., Pangan, A. L., Siffledeen, J., Greenbloom, S., H\u0026eacute;buterne, X., D\u0026rsquo;Haens, G., Nakase, H., Pan\u0026eacute;s, J., Higgins, P. D. R., Juillerat, P., Lindsay, J. O., Loftus, E. V., Sandborn, W. J., Reinisch, W., Chen, M. H., Sanchez Gonzalez, Y., Huang, B., \u0026hellip; Panaccione, R. (2022). Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. \u003cem\u003eThe Lancet\u003c/em\u003e, \u003cem\u003e399\u003c/em\u003e(10341), 2113\u0026ndash;2128. https://doi.org/10.1016/S0140-6736(22)00581-5\u003c/li\u003e\n\u003cli\u003eDanese, S., Vuitton, L., \u0026amp; Peyrin-Biroulet, L. (2015). Biologic agents for IBD: practical insights. \u003cem\u003eNature Reviews Gastroenterology \u0026amp; Hepatology 2015 12:9\u003c/em\u003e, \u003cem\u003e12\u003c/em\u003e(9), 537\u0026ndash;545. https://doi.org/10.1038/nrgastro.2015.135\u003c/li\u003e\n\u003cli\u003eD\u0026rsquo;Haens, G., Dubinsky, M., Kobayashi, T., Irving, P. M., Howaldt, S., Pokrotnieks, J., Krueger, K., Laskowski, J., Li, X., Lissoos, T., Milata, J., Morris, N., Arora, V., Milch, C., Sandborn, W., \u0026amp; Sands, B. E. (2023). Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis. \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e, \u003cem\u003e388\u003c/em\u003e(26), 2444\u0026ndash;2455. https://doi.org/10.1056/nejmoa2207940\u003c/li\u003e\n\u003cli\u003eDignass, A., Eliakim, R., Magro, F., Maaser, C., Chowers, Y., Geboes, K., Mantzaris, G., Reinisch, W., Colombel, J. F., Vermeire, S., Travis, S., Lindsay, J. O., \u0026amp; Van Assche, G. (2012). Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 1: Definitions and diagnosis. \u003cem\u003eJournal of Crohn\u0026rsquo;s and Colitis\u003c/em\u003e, \u003cem\u003e6\u003c/em\u003e(10), 965\u0026ndash;990. https://doi.org/10.1016/J.CROHNS.2012.09.003\u003c/li\u003e\n\u003cli\u003eFausel, R., Afzali, A., \u0026amp; Afzali, A. (2015). Biologics in the management of ulcerative colitis \u0026ndash; comparative safety and efficacy of TNF-\u0026alpha; antagonists. \u003cem\u003eTherapeutics and Clinical Risk Management\u003c/em\u003e, \u003cem\u003e11\u003c/em\u003e, 63\u0026ndash;72. https://doi.org/10.2147/TCRM.S55506\u003c/li\u003e\n\u003cli\u003eFeagan, B. G., Danese, S., Loftus, E. V., Vermeire, S., Schreiber, S., Ritter, T., Fogel, R., Mehta, R., Nijhawan, S., Kempiński, R., Filip, R., Hospodarskyy, I., Seidler, U., Seibold, F., Beales, I. L. P., Kim, H. J., McNally, J., Yun, C., Zhao, S., \u0026hellip; Peyrin-Biroulet, L. (2021). Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. \u003cem\u003eThe Lancet\u003c/em\u003e, \u003cem\u003e397\u003c/em\u003e(10292), 2372\u0026ndash;2384. https://doi.org/10.1016/S0140-6736(21)00666-8\u003c/li\u003e\n\u003cli\u003eFeagan, B. G., Rutgeerts, P., Sands, B. E., Hanauer, S., Colombel, J.-F., Sandborn, W. J., Van Assche, G., Axler, J., Kim, H.-J., Danese, S., Fox, I., Milch, C., Sankoh, S., Wyant, T., Xu, J., \u0026amp; Parikh, A. (2013). Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis. \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e, \u003cem\u003e369\u003c/em\u003e(8), 699\u0026ndash;710. https://doi.org/10.1056/nejmoa1215734\u003c/li\u003e\n\u003cli\u003eFeuerstein, J. D., \u0026amp; Cheifetz, A. S. (2014). Ulcerative Colitis: Epidemiology, Diagnosis, and Management. \u003cem\u003eMayo Clinic Proceedings\u003c/em\u003e, \u003cem\u003e89\u003c/em\u003e(11), 1553\u0026ndash;1563. https://doi.org/10.1016/J.MAYOCP.2014.07.002\u003c/li\u003e\n\u003cli\u003eHanžel, J., \u0026amp; D\u0026rsquo;Haens, G. R. (2020). Anti-interleukin-23 agents for the treatment of ulcerative colitis. \u003cem\u003eExpert Opinion on Biological Therapy\u003c/em\u003e, \u003cem\u003e20\u003c/em\u003e(4), 399\u0026ndash;406. https://doi.org/10.1080/14712598.2020.1697227\u003c/li\u003e\n\u003cli\u003eHibi, T., Imai, Y., Senoo, A., Ohta, K., \u0026amp; Ukyo, Y. (2017). Efficacy and safety of golimumab 52-week maintenance therapy in Japanese patients with moderate to severely active ulcerative colitis: a phase 3, double-blind, randomized, placebo-controlled study-(PURSUIT-J study). \u003cem\u003eJournal of Gastroenterology\u003c/em\u003e, \u003cem\u003e52\u003c/em\u003e(10), 1101\u0026ndash;1111. https://doi.org/10.1007/s00535-017-1326-1\u003c/li\u003e\n\u003cli\u003eHiggins, J. P. T., \u0026amp; Thompson, S. G. (2002). Quantifying heterogeneity in a meta-analysis. \u003cem\u003eStatistics in Medicine\u003c/em\u003e, \u003cem\u003e21\u003c/em\u003e(11), 1539\u0026ndash;1558. https://doi.org/10.1002/SIM.1186\u003c/li\u003e\n\u003cli\u003eHiggins, J. P. T., Thompson, S. G., Deeks, J. J., \u0026amp; Altman, D. G. (2003). Measuring inconsistency in meta-analyses. \u003cem\u003eBMJ : British Medical Journal\u003c/em\u003e, \u003cem\u003e327\u003c/em\u003e(7414), 557. https://doi.org/10.1136/BMJ.327.7414.557\u003c/li\u003e\n\u003cli\u003eHutton, B., Salanti, G., Caldwell, D. M., Chaimani, A., Schmid, C. H., Cameron, C., Ioannidis, J. P. A., Straus, S., Thorlund, K., Jansen, J. P., Mulrow, C., Catala-Lopez, F., Gotzsche, P. C., Dickersin, K., Boutron, I., Altman, D. G., \u0026amp; Moher, D. (2015). The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: Checklist and explanations. \u003cem\u003eAnnals of Internal Medicine\u003c/em\u003e, \u003cem\u003e162\u003c/em\u003e(11), 777\u0026ndash;784. https://doi.org/10.7326/M14-2385/ASSET/IMAGES/6FF14_APPENDIX_BOX_5_DIFFERENCES_IN_APPROACH_TO_FITTING_NETWORK_META-ANALYSES.JPG\u003c/li\u003e\n\u003cli\u003eJiang, X.-L., Cui, H.-F., Gao, J., \u0026amp; Fan, H. (2015). \u003cem\u003eLow-dose Infliximab for Induction and Maintenance Treatment in Chinese Patients With Moderate to Severe Active Ulcerative Colitis\u003c/em\u003e. www.jcge.com\u003c/li\u003e\n\u003cli\u003eJiang, Y., Kong, D., Miao, X., Yu, X., Wu, Z., Liu, H., \u0026amp; Gong, W. (2022). Anti-cytokine therapy and small molecule agents for the treatment of inflammatory bowel disease. \u003cem\u003eEuropean Cytokine Network 2021 32:4\u003c/em\u003e, \u003cem\u003e32\u003c/em\u003e(4), 73\u0026ndash;82. https://doi.org/10.1684/ECN.2021.0472\u003c/li\u003e\n\u003cli\u003eKashani, A., \u0026amp; Schwartz, D. A. (2019). The Expanding Role of Anti\u0026ndash;IL-12 and/or Anti\u0026ndash;IL-23 Antibodies in the Treatment of Inflammatory Bowel Disease. \u003cem\u003eGastroenterology \u0026amp; Hepatology\u003c/em\u003e, \u003cem\u003e15\u003c/em\u003e(5), 255. https://pmc.ncbi.nlm.nih.gov/articles/PMC6589846/\u003c/li\u003e\n\u003cli\u003eKobayashi, T., Siegmund, B., Le Berre, C., Wei, S. C., Ferrante, M., Shen, B., Bernstein, C. N., Danese, S., Peyrin-Biroulet, L., \u0026amp; Hibi, T. (2020). Ulcerative colitis. \u003cem\u003eNature Reviews Disease Primers 2020 6:1\u003c/em\u003e, \u003cem\u003e6\u003c/em\u003e(1), 1\u0026ndash;20. https://doi.org/10.1038/s41572-020-0205-x\u003c/li\u003e\n\u003cli\u003eLamb, C. A., O\u0026rsquo;Byrne, S., Keir, M. E., \u0026amp; Butcher, E. C. (2018). Gut-Selective Integrin-Targeted Therapies for Inflammatory Bowel Disease. \u003cem\u003eJournal of Crohn\u0026rsquo;s and Colitis\u003c/em\u003e, \u003cem\u003e12\u003c/em\u003e(suppl_2), S653\u0026ndash;S668. https://doi.org/10.1093/ECCO-JCC/JJY060\u003c/li\u003e\n\u003cli\u003eLewis, J. D., Parlett, L. E., Jonsson Funk, M. L., Brensinger, C., Pate, V., Wu, Q., Dawwas, G. K., Weiss, A., Constant, B. D., McCauley, M., Haynes, K., Yang, J. Y., Schaubel, D. E., Hurtado-Lorenzo, A., \u0026amp; Kappelman, M. D. (2023). Incidence, Prevalence, and Racial and Ethnic Distribution of Inflammatory Bowel Disease in the United States. \u003cem\u003eGastroenterology\u003c/em\u003e, \u003cem\u003e165\u003c/em\u003e(5), 1197-1205.e2. https://doi.org/10.1053/j.gastro.2023.07.003\u003c/li\u003e\n\u003cli\u003eLiang, Y., Li, Y., Lee, C., Yu, Z., Chen, C., \u0026amp; Liang, C. (2024). Ulcerative colitis: molecular insights and intervention therapy. \u003cem\u003eMolecular Biomedicine 2024 5:1\u003c/em\u003e, \u003cem\u003e5\u003c/em\u003e(1), 1\u0026ndash;32. https://doi.org/10.1186/S43556-024-00207-W\u003c/li\u003e\n\u003cli\u003eMotoya, S., Watanabe, K., Ogata, H., Kanai, T., Matsui, T., Suzuki, Y., Shikamura, M., Sugiura, K., Oda, K., Hori, T., Araki, T., Watanabe, M., \u0026amp; Hibi, T. (2019). Vedolizumab in Japanese patients with ulcerative colitis: A Phase 3, randomized, double-blind, placebo-controlled study. \u003cem\u003ePLoS ONE\u003c/em\u003e, \u003cem\u003e14\u003c/em\u003e(2). https://doi.org/10.1371/journal.pone.0212989\u003c/li\u003e\n\u003cli\u003eNakamura, N., Honzawa, Y., Ohtsu, T., Sano, Y., Ito, Y., Fukata, N., Fukui, T., \u0026amp; Naganuma, M. (2024). Efficacy of upadacitinib in the achievement of clinical and endoscopic remission in hospitalized patients with ulcerative colitis. \u003cem\u003eClinical Journal of Gastroenterology\u003c/em\u003e, \u003cem\u003e17\u003c/em\u003e(4), 654\u0026ndash;657. https://doi.org/10.1007/S12328-024-01976-1/FIGURES/1\u003c/li\u003e\n\u003cli\u003eNeri, B., Mancone, R., Fiorillo, M., Schiavone, S. C., Migliozzi, S., \u0026amp; Biancone, L. (2024). Efficacy and Safety of Janus Kinase-Inhibitors in Ulcerative Colitis. \u003cem\u003eJournal of Clinical Medicine 2024, Vol. 13, Page 7186\u003c/em\u003e, \u003cem\u003e13\u003c/em\u003e(23), 7186. https://doi.org/10.3390/JCM13237186\u003c/li\u003e\n\u003cli\u003ePanaccione, R., Ghosh, S., Middleton, S., M\u0026aacute;rquez, J. R., Scott, B. B., Flint, L., Van Hoogstraten, H. J. F., Chen, A. C., Zheng, H., Danese, S., \u0026amp; Rutgeerts, P. (2014). Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. \u003cem\u003eGastroenterology\u003c/em\u003e, \u003cem\u003e146\u003c/em\u003e(2). https://doi.org/10.1053/j.gastro.2013.10.052\u003c/li\u003e\n\u003cli\u003ePeyrin-Biroulet, L., Hart, A., Bossuyt, P., Long, M., Allez, M., Juillerat, P., Armuzzi, A., Loftus, E. V., Ostad-Saffari, E., Scalori, A., Oh, Y. S., Tole, S., Chai, A., Pulley, J., Lacey, S., \u0026amp; Sandborn, W. J. (2022). Etrolizumab as induction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY): a phase 3, randomised, controlled trial. \u003cem\u003eThe Lancet Gastroenterology and Hepatology\u003c/em\u003e, \u003cem\u003e7\u003c/em\u003e(2), 128\u0026ndash;140. https://doi.org/10.1016/S2468-1253(21)00298-3\u003c/li\u003e\n\u003cli\u003eRaine, T., Bonovas, S., Burisch, J., Kucharzik, T., Adamina, M., Annese, V., Bachmann, O., Bettenworth, D., Chaparro, M., Czuber-Dochan, W., Eder, P., Ellul, P., Fidalgo, C., Fiorino, G., Gionchetti, P., Gisbert, J. P., Gordon, H., Hedin, C., Holubar, S., \u0026hellip; Doherty, G. (2022). ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. \u003cem\u003eJournal of Crohn\u0026rsquo;s and Colitis\u003c/em\u003e, \u003cem\u003e16\u003c/em\u003e(1), 2\u0026ndash;17. https://doi.org/10.1093/ECCO-JCC/JJAB178\u003c/li\u003e\n\u003cli\u003eReinisch, W., Sandborn, W. J., Hommes, D. W., D\u0026rsquo;Haens, G., Hanauer, S., Schreiber, S., Panaccione, R., Fedorak, R. N., Tighe, M. B., Huang, B., Kampman, W., Lazar, A., \u0026amp; Thakkar, R. (2011). Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: Results of a randomised controlled trial. \u003cem\u003eGut\u003c/em\u003e, \u003cem\u003e60\u003c/em\u003e(6), 780\u0026ndash;787. https://doi.org/10.1136/gut.2010.221127\u003c/li\u003e\n\u003cli\u003eRubin, D. T., Allegretti, J. R., Pan\u0026eacute;s, J., Shipitofsky, N., Yarandi, S. S., Huang, K.-H. G., Germinaro, M., Wilson, R., Zhang, H., Johanns, J., Feagan, B. G., Hisamatsu, T., Lichtenstein, G. R., Bressler, B., Peyrin-Biroulet, L., Sands, B. E., Dignass, A., \u0026amp; QUASAR Study Group. (2024). Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. \u003cem\u003eLancet (London, England)\u003c/em\u003e. https://doi.org/10.1016/S0140-6736(24)01927-5\u003c/li\u003e\n\u003cli\u003eRubin, D. T., Ananthakrishnan, A. N., Siegel, C. A., Sauer, B. G., \u0026amp; Long, M. D. (2019). ACG Clinical Guideline: Ulcerative Colitis in Adults. \u003cem\u003eAmerican Journal of Gastroenterology\u003c/em\u003e, \u003cem\u003e114\u003c/em\u003e(3), 384\u0026ndash;413. https://doi.org/10.14309/AJG.0000000000000152\u003c/li\u003e\n\u003cli\u003eRutgeerts, P., Sandborn, W. J., Feagan, B. G., Reinisch, W., Olson, A., Johanns, J., Travers, S., Rachmilewitz, D., Hanauer, S. B., Lichtenstein, G. R., De Villiers, W. J. S., Present, D., Sands, B. E., \u0026amp; Colombel, J. F. (2005). \u003cem\u003eInfliximab for Induction and Maintenance Therapy for Ulcerative Colitis\u003c/em\u003e (Vol. 8). www.nejm.org\u003c/li\u003e\n\u003cli\u003eSandborn, W. J., Baert, F., Danese, S., Krznarić, Ž., Kobayashi, T., Yao, X., Chen, J., Rosario, M., Bhatia, S., Kisfalvi, K., D\u0026rsquo;Haens, G., \u0026amp; Vermeire, S. (2020). Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis. \u003cem\u003eGastroenterology\u003c/em\u003e, \u003cem\u003e158\u003c/em\u003e(3), 562-572.e12. https://doi.org/10.1053/j.gastro.2019.08.027\u003c/li\u003e\n\u003cli\u003eSandborn, W. J., Feagan, B. G., D\u0026rsquo;Haens, G., Wolf, D. C., Jovanovic, I., Hanauer, S. B., Ghosh, S., Petersen, A., Hua, S. Y., Lee, J. H., Charles, L., Chitkara, D., Usiskin, K., Colombel, J.-F., Laine, L., \u0026amp; Danese, S. (2021). Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e, \u003cem\u003e385\u003c/em\u003e(14), 1280\u0026ndash;1291. https://doi.org/10.1056/nejmoa2033617\u003c/li\u003e\n\u003cli\u003eSandborn, W. J., Feagan, B. G., Marano, C., Zhang, H., Strauss, R., Johanns, J., Adedokun, O. J., Guzzo, C., Colombel, J. F., Reinisch, W., Gibson, P. R., Collins, J., J\u0026auml;rnerot, G., Hibi, T., \u0026amp; Rutgeerts, P. (2014). Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. \u003cem\u003eGastroenterology\u003c/em\u003e, \u003cem\u003e146\u003c/em\u003e(1), 85\u0026ndash;95. https://doi.org/10.1053/j.gastro.2013.05.048\u003c/li\u003e\n\u003cli\u003eSandborn, W. J., Feagan, B. G., Marano, C., Zhang, H., Strauss, R., Johanns, J., Adedokun, O. J., Guzzo, C., Colombel, J. F., Reinisch, W., Gibson, P. R., Collins, J., J\u0026auml;rnerot, G., \u0026amp; Rutgeerts, P. (2014). Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. \u003cem\u003eGastroenterology\u003c/em\u003e, \u003cem\u003e146\u003c/em\u003e(1). https://doi.org/10.1053/j.gastro.2013.06.010\u003c/li\u003e\n\u003cli\u003eSandborn, W. J., Su, C., Sands, B. E., D\u0026rsquo;Haens, G. R., Vermeire, S., Schreiber, S., Danese, S., Feagan, B. G., Reinisch, W., Niezychowski, W., Friedman, G., Lawendy, N., Yu, D., Woodworth, D., Mukherjee, A., Zhang, H., Healey, P., \u0026amp; Pan\u0026eacute;s, J. (2017). Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e, \u003cem\u003e376\u003c/em\u003e(18), 1723\u0026ndash;1736. https://doi.org/10.1056/nejmoa1606910\u003c/li\u003e\n\u003cli\u003eSandborn, W. J., Van Assche, G., Reinisch, W., Colombel, J., D\u0026rsquo;Haens, G., Wolf, D. C., Kron, M., Tighe, M. B., Lazar, A., \u0026amp; Thakkar, R. B. (2012). Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. \u003cem\u003eGastroenterology\u003c/em\u003e, \u003cem\u003e142\u003c/em\u003e(2). https://doi.org/10.1053/j.gastro.2011.10.032\u003c/li\u003e\n\u003cli\u003eSands, B. E., Peyrin-Biroulet, L., Loftus, E. V., Danese, S., Colombel, J.-F., T\u0026ouml;r\u0026uuml;ner, M., Jonaitis, L., Abhyankar, B., Chen, J., Rogers, R., Lirio, R. A., Bornstein, J. D., \u0026amp; Schreiber, S. (2019). Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis. \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e, \u003cem\u003e381\u003c/em\u003e(13), 1215\u0026ndash;1226. https://doi.org/10.1056/nejmoa1905725\u003c/li\u003e\n\u003cli\u003eSands, B. E., Sandborn, W. J., Panaccione, R., O\u0026rsquo;Brien, C. D., Zhang, H., Johanns, J., Adedokun, O. J., Li, K., Peyrin-Biroulet, L., Van Assche, G., Danese, S., Targan, S., Abreu, M. T., Hisamatsu, T., Szapary, P., \u0026amp; Marano, C. (2019). Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis. \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e, \u003cem\u003e381\u003c/em\u003e(13), 1201\u0026ndash;1214. https://doi.org/10.1056/nejmoa1900750\u003c/li\u003e\n\u003cli\u003eShivaji, U. N., Nardone, O. M., Cannatelli, R., Smith, S. C., Ghosh, S., \u0026amp; Iacucci, M. (2020). Small molecule oral targeted therapies in ulcerative colitis. \u003cem\u003eThe Lancet Gastroenterology and Hepatology\u003c/em\u003e, \u003cem\u003e5\u003c/em\u003e(9), 850\u0026ndash;861. https://doi.org/10.1016/S2468-1253(19)30414-5/ASSET/C35A8F20-91D5-47A3-B3D8-81F0189EBFBB/MAIN.ASSETS/GR2.SML\u003c/li\u003e\n\u003cli\u003eSicilia, B., Garc\u0026iacute;a-L\u0026oacute;pez, S., Gonz\u0026aacute;lez-Lama, Y., Zabana, Y., Hinojosa, J., \u0026amp; Gomoll\u0026oacute;n, F. (2020). Gu\u0026iacute;a GETECCU 2020 para el tratamiento de la colitis ulcerosa. Elaborada con metodolog\u0026iacute;a GRADE. \u003cem\u003eGastroenterolog\u0026iacute;a y Hepatolog\u0026iacute;a\u003c/em\u003e, \u003cem\u003e43\u003c/em\u003e, 1\u0026ndash;57. https://doi.org/10.1016/J.GASTROHEP.2020.07.001\u003c/li\u003e\n\u003cli\u003eSterne, J. A. C., Savović, J., Page, M. J., Elbers, R. G., Blencowe, N. S., Boutron, I., Cates, C. J., Cheng, H. Y., Corbett, M. S., Eldridge, S. M., Emberson, J. R., Hern\u0026aacute;n, M. A., Hopewell, S., Hr\u0026oacute;bjartsson, A., Junqueira, D. R., J\u0026uuml;ni, P., Kirkham, J. J., Lasserson, T., Li, T., \u0026hellip; Higgins, J. P. T. (2019). RoB 2: a revised tool for assessing risk of bias in randomised trials. \u003cem\u003eBMJ\u003c/em\u003e, \u003cem\u003e366\u003c/em\u003e. https://doi.org/10.1136/BMJ.L4898\u003c/li\u003e\n\u003cli\u003eSuzuki, Y., Motoya, S., Hanai, H., Matsumoto, T., Hibi, T., Robinson, A. M., Mostafa, N. M., Chao, J., Arora, V., Camez, A., Thakkar, R. B., \u0026amp; Watanabe, M. (2014). Efficacy and safety of adalimumab in Japanese patients with moderately to severely active ulcerative colitis. \u003cem\u003eJournal of Gastroenterology\u003c/em\u003e, \u003cem\u003e49\u003c/em\u003e(2), 283\u0026ndash;294. https://doi.org/10.1007/s00535-013-0922-y\u003c/li\u003e\n\u003cli\u003eThomas, S., \u0026amp; Baumgart, D. C. (2012). Targeting leukocyte migration and adhesion in Crohn\u0026rsquo;s disease and ulcerative colitis. \u003cem\u003eInflammopharmacology\u003c/em\u003e, \u003cem\u003e20\u003c/em\u003e(1), 1\u0026ndash;18. https://doi.org/10.1007/S10787-011-0104-6/FIGURES/2\u003c/li\u003e\n\u003cli\u003eVieujean, S., Jairath, V., Peyrin-Biroulet, L., Dubinsky, M., Iacucci, M., Magro, F., \u0026amp; Danese, S. (2025). Understanding the therapeutic toolkit for inflammatory bowel disease. \u003cem\u003eNature Reviews Gastroenterology and Hepatology\u003c/em\u003e, 1\u0026ndash;24. https://doi.org/10.1038/S41575-024-01035-7/METRICS\u003c/li\u003e\n\u003cli\u003eVoelker, R. (2024). What Is Ulcerative Colitis? \u003cem\u003eJAMA\u003c/em\u003e, \u003cem\u003e331\u003c/em\u003e(8), 716\u0026ndash;716. https://doi.org/10.1001/JAMA.2023.23814\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Campania \"Luigi Vanvitelli\"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Ulcerative Colitis, Biologics, Small molecules, Induction, Maintenance","lastPublishedDoi":"10.21203/rs.3.rs-6255469/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6255469/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction\u003c/h2\u003e \u003cp\u003eUlcerative colitis is chronic inflammatory condition affecting the colon, necessitating remission inducing therapeutic interventions. With the emergence of newer more advanced options, their relative effectiveness remains unclear. This network meta-analysis (NMA) will compare the effectiveness of presently available biologics and small molecules in achieving and maintaining remission amongst patients of moderate to severe ulcerative colitis as part of induction and maintenance therapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA systematic search was conducted up to 21st February 2025, including only phase 2b/3 or 3 randomized controlled trials. The primary outcome was induction and maintenance of clinical remission (Full Mayo Score (FMS)\u0026thinsp;\u0026le;\u0026thinsp;2, with no individual subscore\u0026thinsp;\u0026gt;\u0026thinsp;1). Secondary outcomes assessed were clinical response, endoscopic improvement (Mayo Endoscopic Score (MES)\u0026thinsp;\u0026le;\u0026thinsp;1 either with or without friability) and steroid free remission.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAcross 22 studies (7,683 patients), upadacitinib had the highest likelihood of inducing clinical remission (99.08%), clinical response (97.44%) and endoscopic improvement (99.32%), followed by Infliximab and guselkumab following close by for specific outcomes. In maintenance of clinical remission and endoscopic improvement upadacitinib again ranked highest (95.60%) and (99.46%). Tofacitinib (92.43%) has the highest probability with upadacitinib (87.73%) following behind in achieving steroid free remission.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eUpadacitinib displayed high efficacy across multiple outcomes in both induction and maintenance therapy with Infliximab, guselkumab, and filgotinib following closely behind. For achieving steroid free remission tofacitinib has the highest probability of doing so. Overall small molecules and selective IL-23 inhibitors seems promising alternative to older biologics though additional head-to-head trial are warranted along with more real-world data.\u003c/p\u003e","manuscriptTitle":"Comparative efficacy of pharmacological interventions in ulcerative colitis: A Network Meta Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-20 09:59:43","doi":"10.21203/rs.3.rs-6255469/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ab49da32-6bcf-4b39-8438-8269c14731ac","owner":[],"postedDate":"March 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":45867497,"name":"Gastroenterology \u0026 Hepatology"},{"id":45867498,"name":"Clinical Pharmacology"}],"tags":[],"updatedAt":"2025-03-20T09:59:43+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-20 09:59:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6255469","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6255469","identity":"rs-6255469","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}