Advancements in therapeutic strategies and drug development for inflammatory bowel diseases

Abstract

Inflammatory bowel disease (IBD), consisting of Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gastrointestinal tract with significant clinical impact, leading to debilitating symptoms, impaired quality of life, and an increased risk of complications such as colorectal cancer. This review provides a comprehensive overview of current and emerging therapeutic strategies for IBD. We conducted a narrative review to explore therapeutic advances in IBD treatment, focusing on mechanisms of action, clinical development, and current therapeutic challenges. We analyzed existing knowledge on clinical drug development for IBD, up to July 2025. Our search encompassed databases including PubMed, ClinicalTrials.gov, and Google Scholar, using keywords such as “Inflammatory bowel disease”, “Crohn’s disease”, “Ulcerative colitis”, “therapeutics”, and relevant drug names. We delve into key progress in approved drugs in recent years, including biologic and targeted small molecule therapies, which have advanced the treatment paradigms by offering more precise targeting of inflammatory pathways. This review also covers investigational drugs in clinical development, including biologics and small molecules against novel molecular targets, cell and gene therapies, precision medicine approaches, and microbiome-based interventions. Those novel therapies could potentially address unmet medical needs by achieving deeper and more durable responses, inducing remission, preventing disease progression, and ultimately improving long-term patient outcomes. This review summarizes the latest progress in IBD treatment, outlines the advantages, pitfalls, and research prospects of various drugs and therapies, aiming to provide a foundational understanding for both clinical decision-making and future IBD research.

Keywords

inflammatory bowel disease / Crohn’s disease / ulcerative colitis / molecular target / clinical drug development

References

[1] Wilks S. Morbid appearances in the intestine of Miss Bankes. Med Times Gazette. 1859; 2: 264-5.

[2] Kirsner JB. Historical origins of current IBD concepts. World J Gastroenterol. 2001; 7: 175-84.

[3] Maaser C, Sturm A, Vavricka SR, Kucharzik T, Fiorino G, Annese V, et al. ; European Crohn’s and Colitis Organisation [ECCO] and the European Society of Gastrointestinal and Abdominal Radiology [ESGAR]. ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications. J Crohns Colitis. 2019; 13: 144-64.

[4] Colombel JF, Shin A, Gibson PR. AGA Clinical Practice Update on Functional Gastrointestinal Symptoms in Patients With Inflammatory Bowel Disease: Expert Review. Clin Gastroenterol Hepatol. 2019; 17: 380-90.e1.

[5] Le Berre C, Honap S, Peyrin-Biroulet L. Ulcerative colitis. Lancet. 2023; 402: 571-84.

[6] Hilas O. Trends in IBD Incidence, Prevalence, and Biological Therapy. US Pharm. 2024; 49: 10.

[7] Wang R, Li Z, Liu S, Zhang D. Global, regional and national burden of inflammatory bowel disease in 204 countries and territories from 1990 to 2019: a systematic analysis based on the Global Burden of Disease Study 2019. BMJ Open. 2023; 13: e065186.

[8] Cai Z, Wang S, Li J. Treatment of Inflammatory Bowel Disease: A Comprehensive Review. Front Med (Lausanne). 2021; 8: 765474.

[9] Garcia NM, Cohen NA, Rubin DT. Treat-to-target and sequencing therapies in Crohn’s disease. United European Gastroenterol J. 2022; 10: 1121-8.

[10] Melsheimer R, Geldhof A, Apaolaza I, Schaible T. Remicade^® (infliximab): 20 years of contributions to science and medicine . Biologics. 2019; 13: 139-78.

[11] Peek-Kuijt NMS, Aantjes MJ, Verwey M, Van Bodegom-Vos L, van der Meulen-de Jong AE, Maljaars JPW. Treatment goals in IBD: A perspective from patients and their partners. PEC Innov. 2022; 1: 100034.

[12] Kubas A, Malecka-Wojciesko E. COVID-19 Vaccination in Inflammatory Bowel Disease (IBD). J Clin Med. 2022; 11: 2676.

[13] Dmochowska N, Wardill HR, Hughes PA. Advances in Imaging Specific Mediators of Inflammatory Bowel Disease. Int J Mol Sci. 2018; 19: 2471.

[14] Greuter T, Piller A, Fournier N, Safroneeva E, Straumann A, Biedermann L, et al. ; Swiss IBD Cohort Study Group. Upper Gastrointestinal Tract Involvement in Crohn’s Disease: Frequency, Risk Factors, and Disease Course. J Crohns Colitis. 2018; 12: 1399-409.

[15] Gisbert JP, Chaparro M. Clinical Usefulness of Proteomics in Inflammatory Bowel Disease: A Comprehensive Review. J Crohns Colitis. 2019; 13: 374-84.

[16] Jackson B, De Cruz P. Algorithms to facilitate shared decision-making for the management of mild-to-moderate ulcerative colitis. Expert Rev Gastroenterol Hepatol. 2018; 12: 1079-100.

[17] Spiceland CM, Lodhia N. Endoscopy in inflammatory bowel disease: Role in diagnosis, management, and treatment. World J Gastroenterol. 2018; 24: 4014-20.

[18] Loddo I, Romano C. Inflammatory Bowel Disease: Genetics, Epigenetics, and Pathogenesis. Front Immunol. 2015; 6: 551.

[19] Gaya DR, Russell RK, Nimmo ER, Satsangi J. New genes in inflammatory bowel disease: lessons for complex diseases? Lancet. 2006; 367: 1271-84.

[20] El Hadad J, Schreiner P, Vavricka SR, Greuter T. The Genetics of Inflammatory Bowel Disease. Mol Diagn Ther. 2024; 28: 27-35.

[21] Mirkov MU, Verstockt B, Cleynen I. Genetics of inflammatory bowel disease: beyond NOD2 . Lancet Gastroenterol Hepatol. 2017; 2: 224-34.

[22] Ellinghaus D, Ellinghaus E, Nair RP, Stuart PE, Esko T, Metspalu A, et al. Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. Am J Hum Genet. 2012; 90: 636-47.

[23] Kayali S, Fantasia S, Gaiani F, Cavallaro LG, de’Angelis GL, Laghi L. NOD2 and Crohn’s Disease Clinical Practice: From Epidemiology to Diagnosis and Therapy, Rewired . Inflamm Bowel Dis. 2025; 31: 552-62.

[24] Sewell GW, Kaser A. Interleukin-23 in the Pathogenesis of Inflammatory Bowel Disease and Implications for Therapeutic Intervention. J Crohns Colitis. 2022; 16: ii3-19.

[25] Gordon H, Trier Moller F, Andersen V, Harbord M. Heritability in inflammatory bowel disease: from the first twin study to genome-wide association studies. Inflamm Bowel Dis. 2015; 21: 1428-34.

[26] Shan Y, Lee M, Chang EB. The Gut Microbiome and Inflammatory Bowel Diseases. Annu Rev Med. 2022; 73: 455-68.

[27] Saez A, Herrero-Fernandez B, Gomez-Bris R, Sánchez-Martinez H, Gonzalez-Granado JM. Pathophysiology of Inflammatory Bowel Disease: Innate Immune System. Int J Mol Sci. 2023; 24: 1526.

[28] Abegunde AT, Muhammad BH, Bhatti O, Ali T. Environmental risk factors for inflammatory bowel diseases: Evidence based literature review. World J Gastroenterol. 2016; 22: 6296-317.

[29] de Castro MM, Pascoal LB, Steigleder KM, Siqueira BP, Corona LP, Ayrizono MLS, et al. Role of diet and nutrition in inflammatory bowel disease. World J Exp Med. 2021; 11: 1-16.

[30] Gubatan J, Kulkarni CV, Talamantes SM, Temby M, Fardeen T, Sinha SR. Dietary Exposures and Interventions in Inflammatory Bowel Disease: Current Evidence and Emerging Concepts. Nutrients. 2023; 15: 579.

[31] Shafiee NH, Manaf ZA, Mokhtar NM, Raja Ali RA. Anti-inflammatory diet and inflammatory bowel disease: what clinicians and patients should know? Intest Res. 2021; 19: 171-85.

[32] Nielsen OH, Hansen TI, Gubatan JM, Jensen KB, Rejnmark L. Managing vitamin D deficiency in inflammatory bowel disease. Frontline Gastroenterol. 2019; 10: 394-400.

[33] Venkata KVR, Arora SS, Xie FL, Malik TA. Impact of vitamin D on the hospitalization rate of Crohn’s disease patients seen at a tertiary care center. World J Gastroenterol. 2017; 23: 2539-44.

[34] Kaplan GG, Pedersen BV, Andersson RE, Sands BE, Korzenik J, Frisch M. The risk of developing Crohn’s disease after an appendectomy: a population-based cohort study in Sweden and Denmark. Gut. 2007; 56: 1387-92.

[35] Agrawal M, Allin KH, Mehandru S, Faith J, Jess T, Colombel JF. The appendix and ulcerative colitis - an unsolved connection. Nat Rev Gastroenterol Hepatol. 2023; 20: 615-24.

[36] Lakatos PL, Szamosi T, Lakatos L. Smoking in inflammatory bowel diseases: good, bad or ugly? World J Gastroenterol. 2007; 13: 6134-9.

[37] Berkowitz L, Schultz BM, Salazar GA, Pardo-Roa C, Sebastián VP, Álvarez-Lobos MM, et al. Impact of Cigarette Smoking on the Gastrointestinal Tract Inflammation: Opposing Effects in Crohn’s Disease and Ulcerative Colitis. Front Immunol. 2018; 9: 74.

[38] Bilski J, Brzozowski B, Mazur-Bialy A, Sliwowski Z, Brzozowski T. The role of physical exercise in inflammatory bowel disease. Biomed Res Int. 2014; 2014: 429031.

[39] Chen J, Sun S. Unlocking the Power of Physical Activity in Inflammatory Bowel Disease: A Comprehensive Review. Gastroenterol Res Pract. 2024; 2024: 7138811.

[40] Sehgal P, Shen B, Li J, Freedberg DE. Obesity among those newly diagnosed with Crohn’s disease and ulcerative colitis compared with the general population. Frontline Gastroenterol. 2023; 14: 319-25.

[41] Alperen CC, Soydas B, Serin E, Erbayrak M, Savas NA, Unler GK, et al. Role of Environmental Risk Factors in the Etiology of Inflammatory Bowel Diseases: A Multicenter Study. Dig Dis Sci. 2024; 69: 2927-36.

[42] Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al.; International IBD Genetics Consortium (IIBDGC); Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012; 491: 119-24.

[43] Liu CY, Polk DB. Microbiomes through the Looking Glass: What Do UC? Cell Host Microbe. 2018; 24: 472-4.

[44] DeGruttola AK, Low D, Mizoguchi A, Mizoguchi E. Current Understanding of Dysbiosis in Disease in Human and Animal Models. Inflamm Bowel Dis. 2016; 22: 1137-50.

[45] Mostafavi Abdolmaleky H, Zhou JR. Gut Microbiota Dysbiosis, Oxidative Stress, Inflammation, and Epigenetic Alterations in Metabolic Diseases. Antioxidants (Basel). 2024; 13: 985.

[46] Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermúdez-Humarán LG, Gratadoux JJ, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients . Proc Natl Acad Sci U S A. 2008; 105: 16731-6.

[47] He Q, Niu M, Bi J, Du N, Liu S, Yang K, et al. Protective effects of a new generation of probiotic Bacteroides fragilis against colitis in vivo and in vitro . Sci Rep. 2023; 13: 15842.

[48] Zeng MY, Inohara N, Nuñez G. Mechanisms of inflammation-driven bacterial dysbiosis in the gut. Mucosal Immunol. 2017; 10: 18-26.

[49] Hrncir T. Gut Microbiota Dysbiosis: Triggers, Consequences, Diagnostic and Therapeutic Options. Microorganisms. 2022; 10: 578.

[50] Potrykus M, Czaja-Stolc S, Stankiewicz M, Kaska Ł, Małgorzewicz S. Intestinal Microbiota as a Contributor to Chronic Inflammation and Its Potential Modifications. Nutrients. 2021; 13: 3839.

[51] Xie H, Yu S, Tang M, Xun Y, Shen Q, Wu G. Gut microbiota dysbiosis in inflammatory bowel disease: interaction with intestinal barriers and microbiota-targeted treatment options. Front Cell Infect Microbiol. 2025; 15: 1608025.

[52] Qiu P, Ishimoto T, Fu L, Zhang J, Zhang Z, Liu Y. The Gut Microbiota in Inflammatory Bowel Disease. Front Cell Infect Microbiol. 2022; 12: 733992.

[53] Neurath MF, Artis D, Becker C. The intestinal barrier: a pivotal role in health, inflammation, and cancer. Lancet Gastroenterol Hepatol. 2025; 10: 573-92.

[54] Chelakkot C, Ghim J, Ryu SH. Mechanisms regulating intestinal barrier integrity and its pathological implications. Exp Mol Med. 2018; 50: 1-9.

[55] Vancamelbeke M, Vermeire S. The intestinal barrier: a fundamental role in health and disease. Expert Rev Gastroenterol Hepatol. 2017; 11: 821-34.

[56] Parikh K, Antanaviciute A, Fawkner-Corbett D, Jagielowicz M, Aulicino A, Lagerholm C, et al. Colonic epithelial cell diversity in health and inflammatory bowel disease. Nature. 2019; 567: 49-55.

[57] Liebing E, Krug SM, Neurath MF, Siegmund B, Becker C. Wall of Resilience: How the Intestinal Epithelium Prevents Inflammatory Onslaught in the Gut. Cell Mol Gastroenterol Hepatol. 2025; 19: 101423.

[58] Li J, Simmons AJ, Hawkins CV, Chiron S, Ramirez-Solano MA, Tasneem N, et al. Identification and multimodal characterization of a specialized epithelial cell type associated with Crohn’s disease. Nat Commun. 2024; 15: 7204.

[59] Lee C, Hong SN, Kim ER, Chang DK, Kim YH. Epithelial Regeneration Ability of Crohn’s Disease Assessed Using Patient-Derived Intestinal Organoids. Int J Mol Sci. 2021; 22: 6013.

[60] Prame Kumar K, Ooi JD, Goldberg R. The interplay between the microbiota, diet and T regulatory cells in the preservation of the gut barrier in inflammatory bowel disease. Front Microbiol. 2023; 14: 1291724.

[61] Antoni L, Nuding S, Wehkamp J, Stange EF. Intestinal barrier in inflammatory bowel disease. World J Gastroenterol. 2014; 20: 1165-79.

[62] Lopetuso LR, Felice C, Pugliese D, Scaldaferri F, Gasbarrini A, Armuzzi A. Innate Immune Response and Gut Microbiota in Inflammatory Bowel Disease. CellR4. 2014; 2: e1212.

[63] Yan JB, Luo MM, Chen ZY, He BH. The Function and Role of the Th17/Treg Cell Balance in Inflammatory Bowel Disease. J Immunol Res. 2020; 2020: 8813558.

[64] Gareb B, Otten AT, Frijlink HW, Dijkstra G, Kosterink JGW. Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease. Pharmaceutics. 2020; 12: 539.

[65] Cui G, Fan Q, Li Z, Goll R, Florholmen J. Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: Current and novel biomarkers. EBioMedicine. 2021; 66: 103329.

[66] Cosovanu C, Neumann C. The Many Functions of Foxp3⁺ Regulatory T Cells in the Intestine . Front Immunol. 2020; 11: 600973.

[67] Colonna M. Innate Lymphoid Cells: Diversity, Plasticity, and Unique Functions in Immunity. Immunity. 2018; 48: 1104-17.

[68] Ouyang W, O’Garra A. IL-10 Family Cytokines IL-10 and IL-22: from Basic Science to Clinical Translation. Immunity. 2019; 50: 871-91.

[69] Neurath MF. Strategies for targeting cytokines in inflammatory bowel disease. Nat Rev Immunol. 2024; 24: 559-76.

[70] Vebr M, Pomahačová R, Sýkora J, Schwarz J. A Narrative Review of Cytokine Networks: Pathophysiological and Therapeutic Implications for Inflammatory Bowel Disease Pathogenesis. Biomedicines. 2023; 11: 3229.

[71] Bhol NK, Bhanjadeo MM, Singh AK, Dash UC, Ojha RR, Majhi S, et al. The interplay between cytokines, inflammation, and antioxidants: mechanistic insights and therapeutic potentials of various antioxidants and anti-cytokine compounds. Biomed Pharmacother. 2024; 178: 117177.

[72] Liang Y, Li Y, Lee C, Yu Z, Chen C, Liang C. Ulcerative colitis: molecular insights and intervention therapy. Mol Biomed. 2024; 5: 42.

[73] Schmitt H, Neurath MF, Atreya R. Role of the IL23/IL17 Pathway in Crohn’s Disease. Front Immunol. 2021; 12: 622934.

[74] Mills KHG. IL-17 and IL-17-producing cells in protection versus pathology. Nat Rev Immunol. 2023; 23: 38-54.

[75] Li M, Jiang W, Wang Z, Lu Y, Zhang J. New insights on IL-36 in intestinal inflammation and colorectal cancer (Review). Exp Ther Med. 2023; 25: 275.

[76] Herrera-deGuise C, Serra-Ruiz X, Lastiri E, Borruel N. JAK inhibitors: A new dawn for oral therapies in inflammatory bowel diseases. Front Med (Lausanne). 2023; 10: 1089099.

[77] Zarrin AA, Bao K, Lupardus P, Vucic D. Kinase inhibition in autoimmunity and inflammation. Nat Rev Drug Discov. 2021; 20: 39-63.

[78] Morsy Y, Brillant N, Franc Y, Scharl M, Wawrzyniak M ; On Behalf Of The Swiss Ibd Cohort Study Group. Unravelling the Impact of the Genetic Variant rs1042058 within the TPL2 Risk Gene Locus on Molecular and Clinical Disease Course Patients with Inflammatory Bowel Disease. Cells. 2021; 10: 3589.

[79] Gong W, Yu J, Zheng T, Liu P, Zhao F, Liu J, et al. CCL4-mediated targeting of spleen tyrosine kinase (Syk) inhibitor using nanoparticles alleviates inflammatory bowel disease. Clin Transl Med. 2021; 11: e339.

[80] Arseneau KO, Cominelli F. Targeting leukocyte trafficking for the treatment of inflammatory bowel disease. Clin Pharmacol Ther. 2015; 97: 22-8.

[81] Nakamura K, Honda K, Mizutani T, Akiho H, Harada N. Novel strategies for the treatment of inflammatory bowel disease: Selective inhibition of cytokines and adhesion molecules. World J Gastroenterol. 2006; 12: 4628-35.

[82] Choon XY, Yeo JH, White C, Sharma E, Samaan MA. The Current Sphingosine 1 Phosphate Receptor Modulators in the Management of Ulcerative Colitis. J Clin Med. 2025; 14: 3475.

[83] Verstockt B, Vetrano S, Salas A, Nayeri S, Duijvestein M, Vande Casteele N ; Alimentiv Translational Research Consortium (ATRC). Sphingosine 1-phosphate modulation and immune cell trafficking in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2022; 19: 351-66.

[84] Imbrizi M, Magro F, Coy CSR. Pharmacological Therapy in Inflammatory Bowel Diseases: A Narrative Review of the Past 90 Years. Pharmaceuticals (Basel). 2023; 16: 1272.

[85] Di Rienzo A, Marinelli L, Dimmito MP, Toto EC, Di Stefano A, Cacciatore I. Advancements in Inflammatory Bowel Disease Management: From Traditional Treatments to Monoclonal Antibodies and Future Drug Delivery Systems. Pharmaceutics. 2024; 16: 1185.

[86] Ferretti F, Cannatelli R, Monico MC, Maconi G, Ardizzone S. An Update on Current Pharmacotherapeutic Options for the Treatment of Ulcerative Colitis. J Clin Med. 2022; 11: 2302.

[87] Williams C, Panaccione R, Ghosh S, Rioux K. Optimizing clinical use of mesalazine (5-aminosalicylic acid) in inflammatory bowel disease. Therap Adv Gastroenterol. 2011; 4: 237-48.

[88] Levesque BG, Kane SV. Searching for the delta: 5-aminosalicylic Acid therapy for Crohn’s disease. Gastroenterol Hepatol (N Y). 2011; 7: 295-301.

[89] Barrett K, Saxena S, Pollok R. Using corticosteroids appropriately in inflammatory bowel disease: a guide for primary care. Br J Gen Pract. 2018; 68: 497-8.

[90] Bruscoli S, Febo M, Riccardi C, Migliorati G. Glucocorticoid Therapy in Inflammatory Bowel Disease: Mechanisms and Clinical Practice. Front Immunol. 2021; 12: 691480.

[91] Feuerstein JD, Rubin DT, Aberra FN, Yarur AJ, Malter L. Appropriate Use and Complications of Corticosteroids in Inflammatory Bowel Disease: A Comprehensive Review. Clin Gastroenterol Hepatol. 2025; 23: 2068-82.

[92] Nguyen GC, Harris ML, Dassopoulos T. Insights in immunomodulatory therapies for ulcerative colitis and Crohn’s disease. Curr Gastroenterol Rep. 2006; 8: 499-505.

[93] Nielsen OH, Bjerrum JT, Herfarth H, Rogler G. Recent advances using immunomodulators for inflammatory bowel disease. J Clin Pharmacol. 2013; 53: 575-88.

[94] Axelrad JE, Roy A, Lawlor G, Korelitz B, Lichtiger S. Thiopurines and inflammatory bowel disease: Current evidence and a historical perspective. World J Gastroenterol. 2016; 22: 10103-17.

[95] Strigáč A, Caban M, Małecka-Wojciesko E, Talar-Wojnarowska R. Safety and Effectiveness of Thiopurines and Small Molecules in Elderly Patients with Inflammatory Bowel Diseases. J Clin Med. 2024; 13: 4678.

[96] Nitzan O, Elias M, Peretz A, Saliba W. Role of antibiotics for treatment of inflammatory bowel disease. World J Gastroenterol. 2016; 22: 1078-87.

[97] Gold SL, Cohen-Mekelburg S, Schneider Y, Steinlauf A. Perianal Fistulas in Patients With Crohn’s Disease, Part 1: Current Medical Management. Gastroenterol Hepatol (N Y). 2018; 14: 470-81.

[98] Ramirez J, Guarner F, Bustos Fernandez L, Maruy A, Sdepanian VL, Cohen H. Antibiotics as Major Disruptors of Gut Microbiota. Front Cell Infect Microbiol. 2020; 10: 572912.

[99] Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. ; ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002; 359: 1541-9.

[100] Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004; 350: 876-85.

[101] Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005; 353: 2462-76.

[102] Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology. 2006; 130: 323-33.

[103] Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh DG, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut. 2007; 56: 1232-9.

[104] Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007; 132: 52-65.

[105] Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007; 146: 829-38.

[106] Rutgeerts P, Van Assche G, Sandborn WJ, Wolf DC, Geboes K, Colombel JF, et al.; EXTEND Investigators; Kumar A, Lazar A, Camez A, Lomax KG, Pollack PF, D’Haens G. Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial. Gastroenterology. 2012; 142: 1102-11.e2.

[107] Dewint P, Hansen BE, Verhey E, Oldenburg B, Hommes DW, Pierik M, et al. Adalimumab combined with ciprofloxacin is superior to adalimumab monotherapy in perianal fistula closure in Crohn’s disease: a randomised, double-blind, placebo controlled trial (ADAFI). Gut. 2014; 63: 292-9.

[108] Reinisch W, Sandborn WJ, Hommes DW, D’Haens G, Hanauer S, Schreiber S, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 2011; 60: 780-7.

[109] Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D’Haens G, Wolf DC, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012; 142: 257-65.e3.

[110] Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, et al. ; PRECISE 1 Study Investigators. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med. 2007; 357: 228-38.

[111] Schreiber S, Khaliq-Kareemi M, Lawrance IC, Thomsen OØ, Hanauer SB, McColm J, et al. ; PRECISE 2 Study Investigators. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med. 2007; 357: 239-50.

[112] Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. ; PURSUIT-SC Study Group. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014; 146: 85-95.

[113] Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. ; PURSUIT-Maintenance Study Group. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014; 146: 96-109.e1.

[114] Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, et al. ; International Efficacy of Natalizumab as Active Crohn’s Therapy (ENACT-1) Trial Group; Evaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial Group. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005; 353: 1912-25.

[115] Targan SR, Feagan BG, Fedorak RN, Lashner BA, Panaccione R, Present DH, et al. ; International Efficacy of Natalizumab in Crohn’s Disease Response and Remission (ENCORE) Trial Group. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology. 2007; 132: 1672-83.

[116] Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. ; GEMINI 1 Study Group. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013; 369: 699-710.

[117] Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. ; GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013; 369: 711-21.

[118] Sands BE, Feagan BG, Rutgeerts P, Colombel JF, Sandborn WJ, Sy R, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology. 2014; 147: 618-27.e3.

[119] Vermeire S, D’Haens G, Baert F, Danese S, Kobayashi T, Loftus EV, et al. Efficacy and Safety of Subcutaneous Vedolizumab in Patients With Moderately to Severely Active Crohn’s Disease: Results From the VISIBLE 2 Randomised Trial. J Crohns Colitis. 2022; 16: 27-38.

[120] Sands BE, Peyrin-Biroulet L, Loftus EV Jr, Danese S, Colombel JF, Törüner M, et al. ; VARSITY Study Group. Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis. N Engl J Med. 2019; 381: 1215-26.

[121] Sandborn WJ, Baert F, Danese S, Krznarić Ž, Kobayashi T, Yao X, et al. Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis. Gastroenterology. 2020; 158: 562-72.e12.

[122] Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, et al. ; UNITI-IM-UNITI Study Group. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2016; 375: 1946-60.

[123] Sandborn WJ, Rebuck R, Wang Y, Zou B, Adedokun OJ, Gasink C, et al. Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn’s Disease: The IM-UNITI Trial. Clin Gastroenterol Hepatol. 2022; 20: 578-90.e4.

[124] Sands BE, Sandborn WJ, Panaccione R, O’Brien CD, Zhang H, Johanns J, et al. ; UNIFI Study Group. Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2019; 381: 1201-14.

[125] D’Haens G, Panaccione R, Baert F, Bossuyt P, Colombel JF, Danese S, et al. Risankizumab as induction therapy for Crohn’s disease: results from the phase 3 ADVANCE and MOTIVATE induction trials. Lancet. 2022; 399: 2015-30.

[126] Ferrante M, Panaccione R, Baert F, Bossuyt P, Colombel JF, Danese S, et al. Risankizumab as maintenance therapy for moderately to severely active Crohn’s disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial. Lancet. 2022; 399: 2031-46.

[127] Louis E, Schreiber S, Panaccione R, Bossuyt P, Biedermann L, Colombel JF, et al. ; INSPIRE and COMMAND Study Group. Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials. JAMA. 2024; 332: 881-97.

[128] Peyrin-Biroulet L, Chapman JC, Colombel JF, Caprioli F, D’Haens G, Ferrante M, et al. ; SEQUENCE Study Group. Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn’s Disease. N Engl J Med. 2024; 391: 213-23.

[129] The phase 3, randomized, double-blind trial evaluated Omvoh in adult patients with moderately to severely active CD [Internet]. Lilly USA, LLC; c2025 [cited 2025 Aug 18]. Available from: https://omvoh.lilly.com/hcp/crohns-disease/clinical-studies#endoscopic-response-week-52

[130] Kobayashi T, Matsuoka K, Watanabe M, Hisamatsu T, Hirai F, Milata J, et al. Efficacy and safety of mirikizumab as induction and maintenance therapy for Japanese patients with moderately to severely active ulcerative colitis: a subgroup analysis of the global phase 3 LUCENT-1 and LUCENT-2 studies. Intest Res. 2024; 22: 172-85.

[131] TREMFYA^® SC induction study assessed clinical remission and endoscopic response at Week 12 and deep remission* at Week 48 [Internet] . Johnson & Johnson and its affiliates; c2025 [cited 2025 Jul 20]. Available from: https://www.tremfyahcp.com/crohns-disease/efficacy/sc-induction-study-graviti

[132] Panaccione R, Feagan BG, Afzali A, Rubin DT, Reinisch W, Panés J, et al. ; GALAXI 2 & 3 Study Group. Efficacy and safety of intravenous induction and subcutaneous maintenance therapy with guselkumab for patients with Crohn’s disease (GALAXI-2 and GALAXI-3): 48-week results from two phase 3, randomised, placebo and active comparator-controlled, double-blind, triple-dummy trials. Lancet. 2025; 406: 358-75.

[133] Peyrin-Biroulet L, Allegretti JR, Danese S, Germinaro M, Baker T, Alvarez Y, et al. OP10 Efficacy and safety of subcutaneous guselkumab induction therapy in patients with Ulcerative Colitis: Results through week 12 from the phase 3 ASTRO study. J Crohns Colitis. 2025; 19: i19-20.

[134] The Efficacy and Safety of Guselkumab Induction Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: Results From the Phase 3 QUASAR Induction Study. Gastroenterol Hepatol (N Y). 2023; 19: 9-10.

[135] Sandborn WJ, Su C, Sands BE, D’Haens GR, Vermeire S, Schreiber S, et al. ; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2017; 376: 1723-36.

[136] Sandborn WJ, Lawendy N, Danese S, Su C, Loftus EV Jr, Hart A, et al. Safety and efficacy of tofacitinib for treatment of ulcerative colitis: final analysis of OCTAVE Open, an open-label, long-term extension study with up to 7.0 years of treatment. Aliment Pharmacol Ther. 2022; 55: 464-78.

[137] Loftus EV Jr, Panés J, Lacerda AP, Peyrin-Biroulet L, D’Haens G, Panaccione R, et al. Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2023; 388: 1966-80.

[138] Jairath V, Dubinsky M, Biedermann L, Fujii T, Cunneen C, Dubcenco E, et al. P0561 Sustained Corticosteroid-Sparing Effects of Upadacitinib Maintenance Therapy in Patients With Moderate-to-Severe Crohn’s Disease: 2-Year Results From the U-ENDURE Long-Term Extension Study. J Crohns Colitis. 2025; 19: i1130-2.

[139] Danese S, Vermeire S, Zhou W, Pangan AL, Siffledeen J, Greenbloom S, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet. 2022; 399: 2113-28.

[140] Matsuoka K, Nakase H, Fujii T, Hisamatsu T, Suzuki Y, Watanabe M, et al. P687 Ozanimod as a once-daily oral therapy for Japanese patients with ulcerative colitis: results from the induction period of a Phase 2/3 study (J-True North). J Crohns Colitis. 2024; 18: i1295-6.

[141] Sandborn WJ, Feagan BG, D’Haens G, Wolf DC, Jovanovic I, Hanauer SB, et al. ; True North Study Group. Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2021; 385: 1280-91.

[142] Sandborn WJ, Vermeire S, Peyrin-Biroulet L, Dubinsky MC, Panes J, Yarur A, et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet. 2023; 401: 1159-71.

[143] Sinha A, Roy S. Prospective therapeutic targets and recent advancements in the treatment of inflammatory bowel disease. Immunopharmacol Immunotoxicol. 2024; 46: 550-63.

[144] Catalan-Serra I, Brenna Ø. Immunotherapy in inflammatory bowel disease: Novel and emerging treatments. Hum Vaccin Immunother. 2018; 14: 2597-611.

[145] Petronio L, Dal Buono A, Gabbiadini R, Migliorisi G, Privitera G, Ferraris M, et al. Drug Development in Inflammatory Bowel Diseases: What Is Next? Pharmaceuticals (Basel). 2025; 18: 190.

[146] Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature. 1997; 385: 729-33.

[147] Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, et al. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α. Nature. 1997; 385: 733-6.

[148] Wong E, Cohen T, Romi E, Levin M, Peleg Y, Arad U, et al. Harnessing the natural inhibitory domain to control TNFα Converting Enzyme (TACE) activity in vivo . Sci Rep. 2016; 6: 35598.

[149] Aggarwal BB. Tumour necrosis factors receptor associated signalling molecules and their role in activation of apoptosis, JNK and NF-κB. Ann Rheum Dis. 2000; 59: i6-16.

[150] Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E, et al. Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell. 2009; 36: 831-44.

[151] Rothe M, Pan MG, Henzel WJ, Ayres TM, Goeddel DV. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell. 1995; 83: 1243-52.

[152] Chan FK. The pre-ligand binding assembly domain: a potential target of inhibition of tumour necrosis factor receptor function. Ann Rheum Dis. 2000; 59: i50-3.

[153] Mandel MD, Miheller P, Müllner K, Golovics PA, Lakatos PL. Have biologics changed the natural history of Crohn’s disease? Dig Dis. 2014; 32: 351-9.

[154] Adegbola SO, Sahnan K, Warusavitarne J, Hart A, Tozer P. Anti-TNF Therapy in Crohn’s Disease. Int J Mol Sci. 2018; 19: 2244.

[155] Ward D, Nyboe Andersen N, Gørtz S, Thorn Iversen A, Højgaard Allin K, Beaugerie L, et al. Tumor Necrosis Factor Inhibitors in Inflammatory Bowel Disease and Risk of Immune Mediated Inflammatory Diseases. Clin Gastroenterol Hepatol. 2024; 22: 135-43.e8.

[156] Peyrin-Biroulet L, Sandborn WJ, Panaccione R, Domènech E, Pouillon L, Siegmund B, et al. Tumour necrosis factor inhibitors in inflammatory bowel disease: the story continues. Therap Adv Gastroenterol. 2021; 14: 17562848211059954.

[157] Lu RM, Hwang YC, Liu IJ, Lee CC, Tsai HZ, Li HJ, et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci. 2020; 27: 1.

[158] Harding FA, Stickler MM, Razo J, DuBridge RB. The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. MAbs. 2010; 2: 256-65.

[159] Croft M, Salek-Ardakani S, Ware CF. Targeting the TNF and TNFR superfamilies in autoimmune disease and cancer. Nat Rev Drug Discov. 2024; 23: 939-61.

[160] Lim H, Lee SH, Lee HT, Lee JU, Son JY, Shin W, et al. Structural Biology of the TNFα Antagonists Used in the Treatment of Rheumatoid Arthritis. Int J Mol Sci. 2018; 19: 768.

[161] Osterman MT, Haynes K, Delzell E, Zhang J, Bewtra M, Brensinger C, et al. Comparative effectiveness of infliximab and adalimumab for Crohn’s disease. Clin Gastroenterol Hepatol. 2014; 12: 811-7.e3.

[162] Archer R, Tappenden P, Ren S, Martyn-St James M, Harvey R, Basarir H, et al. Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including a review of TA140 and TA262): clinical effectiveness systematic review and economic model. Southampton (UK): NIHR Journals Library; 2016.

[163] Stidham RW, Lee TC, Higgins PD, Deshpande AR, Sussman DA, Singal AG, et al. Systematic review with network meta-analysis: the efficacy of anti-TNF agents for the treatment of Crohn’s disease. Aliment Pharmacol Ther. 2014; 39: 1349-62.

[164] Singh S, Heien HC, Sangaralingham LR, Schilz SR, Kappelman MD, Shah ND, et al. Comparative Effectiveness and Safety of Anti-Tumor Necrosis Factor Agents in Biologic-Naive Patients With Crohn’s Disease. Clin Gastroenterol Hepatol. 2016; 14: 1120-9.e6.

[165] Mei WQ, Hu HZ, Liu Y, Li ZC, Wang WG. Infliximab is superior to other biological agents for treatment of active ulcerative colitis: A meta-analysis. World J Gastroenterol. 2015; 21: 6044-51.

[166] Petryszyn P, Ekk-Cierniakowski P, Zurakowski G. Infliximab, adalimumab, golimumab, vedolizumab and tofacitinib in moderate to severe ulcerative colitis: comparative cost-effectiveness study in Poland. Therap Adv Gastroenterol. 2020; 13: 1756284820941179.

[167] Mitoma H, Horiuchi T, Tsukamoto H, Tamimoto Y, Kimoto Y, Uchino A, et al. Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor α-expressing cells: comparison among infliximab, etanercept, and adalimumab. Arthritis Rheum. 2008; 58: 1248-57.

[168] Ueda N, Tsukamoto H, Mitoma H, Ayano M, Tanaka A, Ohta S, et al. The cytotoxic effects of certolizumab pegol and golimumab mediated by transmembrane tumor necrosis factor α. Inflamm Bowel Dis. 2013; 19: 1224-31.

[169] Roda G, Jharap B, Neeraj N, Colombel JF. Loss of Response to Anti-TNFs: Definition, Epidemiology, and Management. Clin Transl Gastroenterol. 2016; 7: e135.

[170] Fine S, Papamichael K, Cheifetz AS. Etiology and Management of Lack or Loss of Response to Anti-Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y). 2019; 15: 656-65.

[171] Marsal J, Barreiro-de Acosta M, Blumenstein I, Cappello M, Bazin T, Sebastian S. Management of Non-response and Loss of Response to Anti-tumor Necrosis Factor Therapy in Inflammatory Bowel Disease. Front Med (Lausanne). 2022; 9: 897936.

[172] Mitrev N, Leong RW. Therapeutic drug monitoring of anti-tumour necrosis factor-α agents in inflammatory bowel disease. Expert Opin Drug Saf. 2017; 16: 303-17.

[173] Hendy P, Hart A, Irving P. Anti-TNF drug and antidrug antibody level monitoring in IBD: a practical guide. Frontline Gastroenterol. 2016; 7: 122-8.

[174] Solovic I, Sester M, Gomez-Reino JJ, Rieder HL, Ehlers S, Milburn HJ, et al. The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement. Eur Respir J. 2010; 36: 1185-206.

[175] Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001; 345: 1098-104.

[176] Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infect Dis. 2017; 64: 111-5.

[177] D’Arcy ME, Beachler DC, Pfeiffer RM, Curtis JR, Mariette X, Seror R, et al. Tumor Necrosis Factor Inhibitors and the Risk of Cancer among Older Americans with Rheumatoid Arthritis. Cancer Epidemiol Biomarkers Prev. 2021; 30: 2059-67.

[178] Long MD, Kappelman MD, Pipkin CA. Nonmelanoma skin cancer in inflammatory bowel disease: a review. Inflamm Bowel Dis. 2011; 17: 1423-7.

[179] Jani M, Dixon WG, Chinoy H. Drug safety and immunogenicity of tumour necrosis factor inhibitors: the story so far. Rheumatology (Oxford). 2018; 57: 1896-907.

[180] Dai C, Huang YH, Jiang M. Combination therapy in inflammatory bowel disease: Current evidence and perspectives. Int Immunopharmacol. 2023; 114: 109545.

[181] Savelkoul EHJ, Hoentjen F. Editorial: anti-TNF combination therapy for inflammatory bowel disease-one size does not fit all. Aliment Pharmacol Ther. 2022; 55: 750-1.

[182] Liu J, Cao S, Kim S, Chung EY, Homma Y, Guan X, et al. Interleukin-12: an update on its immunological activities, signaling and regulation of gene expression. Curr Immunol Rev. 2005; 1: 119-37.

[183] Ma C, Panaccione R, Khanna R, Feagan BG, Jairath V. IL12/23 or selective IL23 inhibition for the management of moderate-to-severe Crohn’s disease? Best Pract Res Clin Gastroenterol. 2019; 38-39: 101604.

[184] Jefremow A, Neurath MF. All are Equal, Some are More Equal: Targeting IL 12 and 23 in IBD - A Clinical Perspective. Immunotargets Ther. 2020; 9: 289-97.

[185] Iliopoulou L, Lianopoulou E, Kollias G. IL-23 exerts dominant pathogenic functions in Crohn’s disease-ileitis. Mucosal Immunol. 2024; 17: 769-76.

[186] Vuyyuru SK, Solitano V, Hogan M, MacDonald JK, Zayadi A, Parker CE, et al. Efficacy and Safety of IL-12/23 and IL-23 Inhibitors for Crohn’s Disease: Systematic Review and Meta-Analysis. Dig Dis Sci. 2023; 68: 3702-13.

[187] Benson JM, Peritt D, Scallon BJ, Heavner GA, Shealy DJ, Giles-Komar JM, et al. Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders. MAbs. 2011; 3: 535-45.

[188] Deepak P, Loftus EV Jr. Ustekinumab in treatment of Crohn’s disease: design, development, and potential place in therapy. Drug Des Devel Ther. 2016; 10: 3685-98.

[189] Ghosh S, Feagan BG, Ott E, Gasink C, Godwin B, Marano C, et al. Safety of Ustekinumab in Inflammatory Bowel Disease: Pooled Safety Analysis Through 5 Years in Crohn’s Disease and 4 Years in Ulcerative Colitis. J Crohns Colitis. 2024; 18: 1091-101.

[190] Pang Y, D’Cunha R, Winzenborg I, Veldman G, Pivorunas V, Wallace K. Risankizumab: Mechanism of action, clinical and translational science. Clin Transl Sci. 2024; 17: e13706.

[191] ~9 YEARS OF CONSISTENT SAFETY DATA IN Ps [Internet]. AbbVie; c2025 [cited 2025 Jul 20]. Available from: https://www.skyrizihcp.com/dermatology/pso-psa-safety-profile#overview

[192] Long-Term Efficacy and Safety of Mirikizumab Following 104 Weeks of Continuous Treatment for CD: Results From the VIVID-2 Open-Label Extension Study. Gastroenterol Hepatol (N Y). 2025; 21: 17-8.

[193] TREMFYA^® (guselkumab) receives U.S. FDA approval for adults with moderately to severely active ulcerative colitis, strengthening Johnson & Johnson’s leadership in inflammatory bowel disease [Internet]. Johnson & Johnson and its affiliates; c2025 [cited 2025 Sep 26]. Available from: https://www.jnj.com/media-center/press-releases/tremfya-guselkumab-receives-u-s-fda-approval-for-adults-with-moderately-to-severely-active-ulcerative-colitis-strengthening-johnson-johnsons-leadership-in-inflammatory-bowel-disease

[194] Villablanca EJ, Cassani B, von Andrian UH, Mora JR. Blocking lymphocyte localization to the gastrointestinal mucosa as a therapeutic strategy for inflammatory bowel diseases. Gastroenterology. 2011; 140: 1776-84.e5.

[195] Mehandru S, Colombel JF, Juarez J, Bugni J, Lindsay JO. Understanding the molecular mechanisms of anti-trafficking therapies and their clinical relevance in inflammatory bowel disease. Mucosal Immunol. 2023; 16: 859-70.

[196] Gubatan J, Keyashian K, Rubin SJS, Wang J, Buckman CA, Sinha S. Anti-Integrins for the Treatment of Inflammatory Bowel Disease: Current Evidence and Perspectives. Clin Exp Gastroenterol. 2021; 14: 333-42.

[197] Fayyaz M, Jaffery SS. Natalizumab-associated Progressive Multifocal Leukoencephalopathy in Patients with Multiple Sclerosis: A Mini Review. Cureus. 2018; 10: e3093.

[198] Shirani A, Stüve O. Natalizumab: Perspectives from the Bench to Bedside. Cold Spring Harb Perspect Med. 2018; 8: a029066.

[199] Loftus EV Jr, Feagan BG, Panaccione R, Colombel JF, Sandborn WJ, Sands BE, et al. Long-term safety of vedolizumab for inflammatory bowel disease. Aliment Pharmacol Ther. 2020; 52: 1353-65.

[200] Singh S, Heien HC, Herrin J, Dulai PS, Sangaralingham L, Shah ND, et al. Comparative Risk of Serious Infections With Tumor Necrosis Factor α Antagonists vs Vedolizumab in Patients With Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol. 2022; 20: e74-88.

[201] McLean LP, Cross RK. Integrin antagonists as potential therapeutic options for the treatment of Crohn’s disease. Expert Opin Investig Drugs. 2016; 25: 263-73.

[202] Bravatà I, Allocca M, Fiorino G, Danese S. Integrins and adhesion molecules as targets to treat inflammatory bowel disease. Curr Opin Pharmacol. 2015; 25: 67-71.

[203] Rubin DT, Dotan I, DuVall A, Bouhnik Y, Radford-Smith G, Higgins PDR, et al. ; HIBISCUS Study Group. Etrolizumab versus adalimumab or placebo as induction therapy for moderately to severely active ulcerative colitis (HIBISCUS): two phase 3 randomised, controlled trials. Lancet Gastroenterol Hepatol. 2022; 7: 17-27.

[204] Sandborn WJ, Panés J, Danese S, Sharafali Z, Hassanali A, Jacob-Moffatt R, et al. ; BERGAMOT Study Group. Etrolizumab as induction and maintenance therapy in patients with moderately to severely active Crohn’s disease (BERGAMOT): a randomised, placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2023; 8: 43-55.

[205] Peyrin-Biroulet L, Hart A, Bossuyt P, Long M, Allez M, Juillerat P, et al. ; HICKORY Study Group. 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. Lancet Gastroenterol Hepatol. 2022; 7: 128-40.

[206] Neurath MF. Targeting immune cell circuits and trafficking in inflammatory bowel disease. Nat Immunol. 2019; 20: 970-9.

[207] Greuter T, Biedermann L, Rogler G, Sauter B, Seibold F. Alicaforsen, an antisense inhibitor of ICAM-1, as treatment for chronic refractory pouchitis after proctocolectomy: A case series. United European Gastroenterol J. 2016; 4: 97-104.

[208] Wendt E, Keshav S. CCR9 antagonism: potential in the treatment of Inflammatory Bowel Disease. Clin Exp Gastroenterol. 2015; 8: 119-30.

[209] Oswald C, Rappas M, Kean J, Doré AS, Errey JC, Bennett K, et al. Intracellular allosteric antagonism of the CCR9 receptor. Nature. 2016; 540: 462-5.

[210] Veny M, Fernández-Clotet A, Panés J. Controlling leukocyte trafficking in IBD. Pharmacol Res. 2020; 159: 105050.

[211] Boyles JS, Beidler CB, Strifler BA, Girard DS, Druzina Z, Durbin JD, et al. Discovery and characterization of a neutralizing pan-ELR+CXC chemokine monoclonal antibody. MAbs. 2020; 12: 1831880.

[212] Xu WD, Li R, Huang AF. Role of TL1A in Inflammatory Autoimmune Diseases: A Comprehensive Review. Front Immunol. 2022; 13: 891328.

[213] Tettoni E, Gabbiadini R, Dal Buono A, Privitera G, Vadalà V, Migliorisi G, et al. TL1A as a Target in Inflammatory Bowel Disease: Exploring Mechanisms and Therapeutic Potential. Int J Mol Sci. 2025; 26: 5017.

[214] Danese S, Klopocka M, Scherl EJ, Romatowski J, Allegretti JR, Peeva E, et al. Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: A Phase 2a Single-Arm Study. Clin Gastroenterol Hepatol. 2021; 19: 2324-32.e6.

[215] Danese S, Allegretti JR, Schreiber S, Peyrin-Biroulet L, Jairath V, D’Haens G, et al. Anti-TL1A antibody, afimkibart, in moderately-to-severely active ulcerative colitis (TUSCANY-2): a multicentre, double-blind, treat-through, multi-dose, randomised, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol. 2025; 10: 882-95.

[216] Sands BE, Feagan BG, Peyrin-Biroulet L, Danese S, Rubin DT, Laurent O, et al. ; ARTEMIS-UC Study Group. Phase 2 Trial of Anti-TL1A Monoclonal Antibody Tulisokibart for Ulcerative Colitis. N Engl J Med. 2024; 391: 1119-29.

[217] Feagan BG, Sands BE, Siegel CA, Dubinsky MC, Longman RS, Sabino J, et al. Safety and efficacy of the anti-TL1A monoclonal antibody tulisokibart for Crohn’s disease: a phase 2a induction trial. Lancet Gastroenterol Hepatol. 2025; 10: 715-25.

[218] Duvakitug positive phase 2b results demonstrate best-in-class potential in ulcerative colitis and Crohn’s disease [Internet]. [cited 2025 Jul 20]. Available from: https://www.sanofi.com/assets/dotcom/pressreleases/2024/2024-12-17-12-30-00-2998154-en.pdf

[219] Press Release: ECCO 2025: new duvakitug data reinforce best-in-class potential in ulcerative colitis and Crohn’s disease [Internet]. Sanofi; c2004- 2025 [cited 2025 Jul 20]. Available from: https://www.sanofi.com/en/media-room/press-releases/2025/2025-02-22-07-30-00-3030764

[220] Ngo VL, Kuczma M, Maxim E, Denning TL. IL-36 cytokines and gut immunity. Immunology. 2021; 163: 145-54.

[221] Xie L, Huang Z, Li H, Liu X, Zheng S, Su W. IL-38: A New Player in Inflammatory Autoimmune Disorders. Biomolecules. 2019; 9: 345.

[222] Blair HA. Spesolimab: First Approval. Drugs. 2022; 82: 1681-6.

[223] Ferrante M, Irving PM, Selinger CP, D’Haens G, Kuehbacher T, Seidler U, et al. Safety and tolerability of spesolimab in patients with ulcerative colitis. Expert Opin Drug Saf. 2023; 22: 141-52.

[224] Dosh RH, Jordan-Mahy N, Sammon C, Le Maitre C. Interleukin 1 is a key driver of inflammatory bowel disease-demonstration in a murine IL-1Ra knockout model. Oncotarget. 2019; 10: 3559-75.

[225] Ludwiczek O, Vannier E, Borggraefe I, Kaser A, Siegmund B, Dinarello CA, et al. Imbalance between interleukin-1 agonists and antagonists: relationship to severity of inflammatory bowel disease. Clin Exp Immunol. 2004; 138: 323-9.

[226] Lacy SE, Wu C, Ambrosi DJ, Hsieh CM, Bose S, Miller R, et al. Generation and characterization of ABT-981, a dual variable domain immunoglobulin (DVD-Ig^TM) molecule that specifically and potently neutralizes both IL-1α and IL-1β . MAbs. 2015; 7: 605-19.

[227] Moran A, Pavord ID. Anti-IL-4/IL-13 for the treatment of asthma: the story so far. Expert Opin Biol Ther. 2020; 20: 283-94.

[228] Hoving JC. Targeting IL-13 as a Host-Directed Therapy Against Ulcerative Colitis. Front Cell Infect Microbiol. 2018; 8: 395.

[229] Bamias G, Cominelli F. Role of type 2 immunity in intestinal inflammation. Curr Opin Gastroenterol. 2015; 31: 471-6.

[230] Katsanos KH, Papadakis KA. Inflammatory Bowel Disease: Updates on Molecular Targets for Biologics. Gut Liver. 2017; 11: 455-63.

[231] Brown JB, Cheresh P, Zhang Z, Ryu H, Managlia E, Barrett TA. P-selectin glycoprotein ligand-1 is needed for sequential recruitment of T-helper 1 (Th1) and local generation of Th17 T cells in dextran sodium sulfate (DSS) colitis. Inflamm Bowel Dis. 2012; 18: 323-32.

[232] Aebisher D, Bartusik-Aebisher D, Przygórzewska A, Oleś P, Woźnicki P, Kawczyk-Krupka A. Key Interleukins in Inflammatory Bowel Disease-A Review of Recent Studies. Int J Mol Sci. 2025; 26: 121.

[233] Ben Ghezala I, Charkaoui M, Michiels C, Bardou M, Luu M. Small Molecule Drugs in Inflammatory Bowel Diseases. Pharmaceuticals (Basel). 2021; 14: 637.

[234] Jefremow A, Neurath MF. Novel Small Molecules in IBD: Current State and Future Perspectives. Cells. 2023; 12: 1730.

[235] Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs. 2017; 77: 521-46.

[236] Liu E, Aslam N, Nigam G, Limdi JK. Tofacitinib and newer JAK inhibitors in inflammatory bowel disease - where we are and where we are going. Drugs Context. 2022; 11: 2021-11-4.

[237] Fansiwala K, Sauk JS. Small Molecules, Big Results: How JAK Inhibitors Have Transformed the Treatment of Patients with IBD. Dig Dis Sci. 2025; 70: 469-77.

[238] Xu Q, He L, Yin Y. Risk of herpes zoster associated with JAK inhibitors in immune-mediated inflammatory diseases: a systematic review and network meta-analysis. Front Pharmacol. 2023; 14: 1241954.

[239] Núñez P, Quera R, Yarur AJ. Safety of Janus Kinase Inhibitors in Inflammatory Bowel Diseases. Drugs. 2023; 83: 299-314.

[240] Janus Kinase (JAK) inhibitors: Drug Safety Communication - FDA Requires Warnings about Increased Risk of Serious Heart-related Events, Cancer, Blood Clots, and Death [Internet]. [cited 2025 Jul 20]. Available from: https://www.fda.gov/safety/medical-product-safety-information/janus-kinase-jak-inhibitors-drug-safety-communication-fda-requires-warnings-about-increased-risk

[241] Feagan BG, Danese S, Loftus EV Jr, Vermeire S, Schreiber S, Ritter T, et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet. 2021; 397: 2372-84.

[242] Vermeire S, Schreiber S, Rubin DT, D’Haens G, Reinisch W, Watanabe M, et al. Efficacy and safety of filgotinib as induction and maintenance therapy for Crohn’s disease (DIVERSITY): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Gastroenterol Hepatol. 2025; 10: 138-53.

[243] Chen B, Zhong J, Li X, Pan F, Ding Y, Zhang Y, et al. Efficacy and Safety of Ivarmacitinib in Patients With Moderate-to-Severe, Active, Ulcerative Colitis: A Phase II Study. Gastroenterology. 2022; 163: 1555-68.

[244] Efficacy and Safety of Deucravacitinib, an Oral, Selective Tyrosine Kinase 2 Inhibitor, in Patients With Moderately to Severely Active Ulcerative Colitis: 12-Week Results From the Phase 2 LATTICE-UC Study. Gastroenterol Hepatol (N Y). 2022; 18: 6.

[245] D’Haens G, Danese S, Panaccione R, Rubin DT, Peyrin-Biroulet L, Matsuoka K, et al. Deucravacitinib in patients with inflammatory bowel disease: 12-week efficacy and safety results from 3 randomized phase 2 studies in Crohn’s disease and ulcerative colitis. J Crohns Colitis. 2025; 19: jjaf080.

[246] Proia RL, Hla T. Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest. 2015; 125: 1379-87.

[247] Xiao S, Peng K, Li C, Long Y, Yu Q. The role of sphingosine-1-phosphate in autophagy and related disorders. Cell Death Discov. 2023; 9: 380.

[248] Saleh O, Abuelazm MT, Mohamed I, Ramadan A, Assaf M, Alzoubi A, et al. Etrolizumab as an induction and maintenance therapy for ulcerative colitis: A systematic review and meta-analysis of randomized controlled trials. JGH Open. 2024; 8: e13056.

[249] Paik J. Ozanimod: A Review in Ulcerative Colitis. Drugs. 2022; 82: 1303-13.

[250] Bristol Myers Squibb Provides Update on the First Phase 3 YELLOWSTONE Trial Evaluating Oral Zeposia (ozanimod) in Patients with Moderate to Severe Active Crohn’s Disease [Internet]. Bristol-Myers Squibb Company; c2025 [cited 2025 Jul 20]. Available from: https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Provides-Update-on-the-First-Phase-3-YELLOWSTONE-Trial-Evaluating-Oral-Zeposia-ozanimod-in-Patients-with-Moderate-to-Severe-Active-Crohns-Disease/default.aspx

[251] Choden T, Cohen NA, Rubin DT. Sphingosine-1 Phosphate Receptor Modulators: The Next Wave of Oral Therapies in Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y). 2022; 18: 265-71.

[252] Sands BE, Panaccione R, D’Haens G, Schreiber S, Jairath V, DuVall A, et al. Tamuzimod in patients with moderately-to-severely active ulcerative colitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 induction trial. Lancet Gastroenterol Hepatol. 2025; 10: 210-21.

[253] Spadaccini M, D’Alessio S, Peyrin-Biroulet L, Danese S. PDE4 Inhibition and Inflammatory Bowel Disease: A Novel Therapeutic Avenue. Int J Mol Sci. 2017; 18: 1276.

[254] Picchianti-Diamanti A, Spinelli FR, Rosado MM, Conti F, Laganà B. Inhibition of Phosphodiesterase-4 in Psoriatic Arthritis and Inflammatory Bowel Diseases. Int J Mol Sci. 2021; 22: 2638.

[255] Danese S, Neurath MF, Kopoń A, Zakko SF, Simmons TC, Fogel R, et al. Effects of Apremilast, an Oral Inhibitor of Phosphodiesterase 4, in a Randomized Trial of Patients With Active Ulcerative Colitis. Clin Gastroenterol Hepatol. 2020; 18: 2526-34.e9.

[256] Schreiber S, Keshavarzian A, Isaacs KL, Schollenberger J, Guzman JP, Orlandi C, et al. A randomized, placebo-controlled, phase II study of tetomilast in active ulcerative colitis. Gastroenterology. 2007; 132: 76-86.

[257] Hussain A, Singhal P, Wong J, Goodwin B, Abhyankar B, Soo C, et al. P1002 Changes in circulating lymphocyte subsets and CCR9 transcripts as mechanistic biomarkers of the small molecule α4β7 inhibitor MORF-057 in patients with Ulcerative Colitis. J Crohns Colitis. 2025; 19: i1854-5.

[258] Brooks A. 25% of Patients Achieve Endoscopic Remission in Phase 2a EMERALD-1 Trial for MORF-057 [Internet]. MJH Life Sciences^® ; 2025 [cited 2025 Jul 20]. Available from: https://www.hcplive.com/view/-of-patients-achieve-endoscopic-remission-in-phase-2a-emerald-1-trial-for-morf-057#:~:text=Data%20from%20the%20phase%202a%20trial%20showed%2025.7%25,and%2045.7%25%20achieved%20clinical%20response%20after%20week%2012

[259] Fourie AM, Cheng X, Chang L, Greving C, Li X, Knight B, et al. JNJ-77242113, a highly potent, selective peptide targeting the IL-23 receptor, provides robust IL-23 pathway inhibition upon oral dosing in rats and humans. Sci Rep. 2024; 14: 17515.

[260] Icotrokinra meets primary endpoint of clinical response in ulcerative colitis study and shows potential to transform the treatment paradigm for patients [Internet]. Johnson & Johnson and its affiliates; c2025 [cited 2025 Jul 20]. Available from: https://www.jnj.com/media-center/press-releases/icotrokinra-meets-primary-endpoint-of-clinical-response-in-ulcerative-colitis-study-and-shows-potential-to-transform-the-treatment-paradigm-for-patients

[261] Ihara S, Hirata Y, Koike K. TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota. J Gastroenterol. 2017; 52: 777-87.

[262] Levitte S, Khan I, Iyahen V, Ziai J, Gubatan J, Sheng R, et al. Differential expression of small bowel TGFβ1 and TGFβ3 characterizes intestinal strictures in patients with fibrostenotic Crohn’s disease. Histochem Cell Biol. 2024; 162: 225-30.

[263] Sáez-Borderías A, Van Kaem T, Alberti J, Stiers PJ, Sabadie C, Van Heeswijk R, et al. P0334 AGMB-129, an investigational ALK5 inhibitor for the treatment of Fibrostenosing Crohn’s Disease (FSCD), shows gastrointestinal (GI) restricted pharmacokinetics (PK) and a favorable safety profile in healthy subjects. J Crohns Colitis. 2025; 19: i796.

[264] Late-Breaking Interim STENOVA Data Presented at Digestive Disease Week^® 2025 Demonstrate Potential of AGMB-129 in Fibrostenosing Crohn’s Disease [Internet]. [cited 2025 Jul 20]. Available from: https://www.agomab.com/wp-content/uploads/2025/05/20250507_AGMB-129-DDW-presentation_Final.pdf

[265] Wang W, Guo DY, Lin YJ, Tao YX. Melanocortin Regulation of Inflammation. Front Endocrinol (Lausanne). 2019; 10: 683.

[266] Dodd J, Jordan R, Makhlina M, Barnett K, Roffel A, Spana C, et al. A novel oral formulation of the melanocortin-1 receptor agonist PL8177 resolves inflammation in preclinical studies of inflammatory bowel disease and is gut restricted in rats, dogs, and humans. Front Immunol. 2023; 14: 1083333.

[267] Palatin Announces Positive Topline Results from Phase 2 Ulcerative Colitis (UC) Study of Oral Melanocortin-1 Receptor Agonist PL8177 [Internet]. PALATIN; c2025 [cited 2025 Jul 20]. Available from: https://palatin.com/press_releases/palatin-announces-positive-topline-results-from-phase-2-ulcerative-colitis-uc-study-of-oral-melanocortin-1-receptor-agonist-pl8177

[268] Li Y, Xu F, Fang Y, Cui Y, Zhu Z, Wu Y, et al. Inflammation-fibrosis interplay in inflammatory bowel disease: mechanisms, progression, and therapeutic strategies. Front Pharmacol. 2025; 16: 1530797.

[269] Cosín-Roger J. Inflammatory Bowel Disease: Immune Function, Tissue Fibrosis and Current Therapies. Int J Mol Sci. 2024; 25: 6416.

[270] Raine T, Danese S. Breaking Through the Therapeutic Ceiling: What Will It Take? Gastroenterology. 2022; 162: 1507-11.

[271] Greco R, Farge D. CART Cells and Other Cell Therapies (ie MSC, Tregs) in Autoimmune Diseases. In: Sureda A, Corbacioglu S, Greco R, Kröger N, Carreras E, editors. The EBMT Handbook: Hematopoietic Cell Transplantation and Cellular Therapies. Cham: Springer International Publishing; 2024. pp. 837-48.

[272] Bulliard Y, Freeborn R, Uyeda MJ, Humes D, Bjordahl R, de Vries D, et al. From promise to practice: CAR T and Treg cell therapies in autoimmunity and other immune-mediated diseases. Front Immunol. 2024; 15: 1509956.

[273] Boix-Amorós A, Monaco H, Sambataro E, Clemente JC. Novel technologies to characterize and engineer the microbiome in inflammatory bowel disease. Gut Microbes. 2022; 14: 2107866.

[274] Castro-Dopico T, Colombel JF, Mehandru S. Targeting B cells for inflammatory bowel disease treatment: back to the future. Curr Opin Pharmacol. 2020; 55: 90-8.

[275] Neurath MF, Sands BE, Rieder F. Cellular immunotherapies and immune cell depleting therapies in inflammatory bowel diseases: the next magic bullet? Gut. 2025; 74: 9-14.

[276] Li YR, Lyu Z, Chen Y, Fang Y, Yang L. Frontiers in CAR-T cell therapy for autoimmune diseases. Trends Pharmacol Sci. 2024; 45: 839-57.

[277] Cui Y, Boulakirba S, David M, Bouchareychas L, Rouquier S, Sajuthi S, et al. OP02 IL23R-CAR-Tregs: creating a therapeutic breakthrough for Crohn’s Disease. J Crohns Colitis. 2024; 18: i3.

[278] Shaikh S, Shaikh H. CART Cell Therapy Toxicity. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025.

[279] Testa U, Castelli G, Pelosi E, Galli E, Chiusolo P. Toxicities Associated with CAR-T Cell Therapies. Mediterr J Hematol Infect Dis. 2025; 17: e2025039.

[280] Ozdemirli M, Loughney TM, Deniz E, Chahine JJ, Albitar M, Pittaluga S, et al. Indolent CD4+ CAR T-Cell Lymphoma after Cilta-cel CAR T-Cell Therapy. N Engl J Med. 2024; 390: 2074-82.

[281] Hamilton MP, Sugio T, Noordenbos T, Shi S, Bulterys PL, Liu CL, et al. Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy. N Engl J Med. 2024; 390: 2047-60.

[282] Sharma A, Rudra D. Emerging Functions of Regulatory T Cells in Tissue Homeostasis. Front Immunol. 2018; 9: 883.

[283] Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of Treg-mediated T cell suppression. Front Immunol. 2012; 3: 51.

[284] Voskens C, Stoica D, Rosenberg M, Vitali F, Zundler S, Ganslmayer M, et al. Autologous regulatory T-cell transfer in refractory ulcerative colitis with concomitant primary sclerosing cholangitis. Gut. 2023; 72: 49-53.

[285] Desreumaux P, Foussat A, Allez M, Beaugerie L, Hébuterne X, Bouhnik Y, et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease. Gastroenterology. 2012; 143: 1207-17.e2.

[286] Luu K, Dahl ME, Hare E, Sibley C, Lizzul P, Randazzo B. Rosnilimab, a Novel PD-1 Agonist Monoclonal Antibody, Reduced T Cell Proliferation, Inflammatory Cytokine Secretion, and PD-1+ Expressing CD4 and CD8 T Cells: Results From a Phase 1 Healthy Volunteer Clinical Trial. In: Proceedings of DDW Annual Meeting; 2024 May 18-21; Washington DC, USA.

[287] Hodder A, Mishra AK, Enshaei A, Baird S, Elbeshlawi I, Bonney D, et al. Blinatumomab for First-Line Treatment of Children and Young Persons With B-ALL. J Clin Oncol. 2024; 42: 907-14.

[288] Zhai Y, Hong J, Wang J, Jiang Y, Wu W, Lv Y, et al. Comparison of blinatumomab and CAR T-cell therapy in relapsed/refractory acute lymphoblastic leukemia: a systematic review and meta-analysis. Expert Rev Hematol. 2024; 17: 67-76.

[289] Hedin CR, Creignou M, MacKay J, Jucaite A, Cselényi Z, Johnström P, et al. P1116 Imaging of CCR9 in the small bowel of patients with Crohn’s disease: effects of the CCR9-depleting monoclonal antibody AZD7798. J Crohns Colitis. 2025; 19: i2048-9.

[290] Hu KA, Gubatan J. Gut microbiome-based therapeutics in inflammatory bowel disease. Clin Transl Disc. 2023; 3: e182.

[291] Biedermann L, Kreienbühl A, Rogler G. Microbiota Therapy in Inflammatory Bowel Disease. Visc Med. 2024; 40: 92-101.

[292] Fang H, Fu L, Wang J. Protocol for Fecal Microbiota Transplantation in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. Biomed Res Int. 2018; 2018: 8941340.

[293] Lopez-Siles M, Duncan SH, Garcia-Gil LJ, Martinez-Medina M. Faecalibacterium prausnitzii: from microbiology to diagnostics and prognostics . ISME J. 2017; 11: 841-52.

[294] VE202 [Internet]. Vedanta Biosciences, Inc.; c2025 [cited 2025 Jul 20]. Available from: https://www.vedantabio.com/pipeline-programs/ve202/

[295] Pandey H, Tang DWT, Wong SH, Lal D. Helminths in alternative therapeutics of inflammatory bowel disease. Intest Res. 2025; 23: 8-22.

[296] Summers RW, Elliott DE, Qadir K, Urban JF Jr, Thompson R, Weinstock JV. Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease . Am J Gastroenterol. 2003; 98: 2034-41.

[297] Summers RW, Elliott DE, Urban JF Jr, Thompson RA, Weinstock JV. Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial . Gastroenterology. 2005; 128: 825-32.

[298] Sultany A, Noori H, Sultany HS, Eltobgy A, Gamal H, Khan SA, et al. Beyond the Bacterial Microbiome: Exploring the Gut Virome and Mycobiome in Health and Disease. Curr Trends Biomedical Eng & Biosci. 2025; 23: CTBEB.MS.ID.556119.

[299] Wu Y, Cheng R, Lin H, Li L, Jia Y, Philips A, et al. Gut virome and its implications in the pathogenesis and therapeutics of inflammatory bowel disease. BMC Med. 2025; 23: 183.

[300] Hetta HF, Ramadan YN, Alharbi AA, Alsharef S, Alkindy TT, Alkhamali A, et al. Gut Microbiome as a Target of Intervention in Inflammatory Bowel Disease Pathogenesis and Therapy. Immuno. 2024; 4: 400-25.

[301] Akhtar N, Jain C, Chauhan SB, Singh I. Gut virus axis: Unravelling viral contribution to gut microbiota dysbiosis and translational medicine in inflammatory bowel disease. Med Microecol. 2025; 26: 100148.

[302] Njoku GC, Forkan CP, Soltysik FM, Nejsum PL, Pociot F, Yarani R. Unleashing the potential of extracellular vesicles for ulcerative colitis and Crohn’s disease therapy. Bioact Mater. 2025; 45: 41-57.

[303] Saleem M, Shahzad KA, Marryum M, Singh S, Zhou Q, Du S, et al. Exosome-based therapies for inflammatory disorders: a review of recent advances. Stem Cell Res Ther. 2024; 15: 477.

[304] Tian CM, Yang MF, Xu HM, Zhu MZ, Zhang Y, Yao J, et al. Mesenchymal Stem Cell-derived Exosomes: Novel Therapeutic Approach for Inflammatory Bowel Diseases. Stem Cells Int. 2023; 2023: 4245704.

[305] Nazari H, Alborzi F, Heirani-Tabasi A, Hadizadeh A, Asbagh RA, Behboudi B, et al. Evaluating the safety and efficacy of mesenchymal stem cell-derived exosomes for treatment of refractory perianal fistula in IBD patients: clinical trial phase I. Gastroenterol Rep (Oxf). 2022; 10: goac075.

[306] Mondal J, Pillarisetti S, Junnuthula V, Surwase SS, Hwang SR, Park IK, et al. Extracellular vesicles and exosome-like nanovesicles as pioneering oral drug delivery systems. Front Bioeng Biotechnol. 2024; 11: 1307878.

[307] Syed S, Boland BS, Bourke LT, Chen LA, Churchill L, Dobes A, et al. Challenges in IBD Research 2024: Precision Medicine. Inflamm Bowel Dis. 2024; 30: S39-54.

[308] Caballero Mateos AM, Cañadas de la Fuente GA, Gros B. Paradigm Shift in Inflammatory Bowel Disease Management: Precision Medicine, Artificial Intelligence, and Emerging Therapies. J Clin Med. 2025; 14: 1536.

[309] Atreya R, Neurath MF. Biomarkers for Personalizing IBD Therapy: The Quest Continues. Clin Gastroenterol Hepatol. 2024; 22: 1353-64.

[310] Kaz AM, Venu N. Diagnostic Methods and Biomarkers in Inflammatory Bowel Disease. Diagnostics (Basel). 2025; 15: 1303.

[311] Iacucci M, Santacroce G, Yasuharu M, Ghosh S. Artificial Intelligence-Driven Personalized Medicine: Transforming Clinical Practice in Inflammatory Bowel Disease. Gastroenterology. 2025; 169: 416-31.

[312] De Bernardi A, Bezzio C, Puricelli M, Gilardi D, Saibeni S. Combining Advanced Targeted Therapy in Inflammatory Bowel Disease: Current Practice and Future Directions. J Clin Med. 2025; 14: 590.

[313] Battat R, Chang JT, Loftus EV Jr, Sands BE. IBD Matchmaking: Rational Combination Therapy. Clin Gastroenterol Hepatol. 2025; 23: 469-79.

[314] Fabisiak A, Caban M, Dudek P, Strigáč A, Małecka-Wojciesko E, Talar-Wojnarowska R. Advancements in dual biologic therapy for inflammatory bowel diseases: efficacy, safety, and future directions. Therap Adv Gastroenterol. 2025; 18: 17562848241309871.

[315] Feagan BG, Sands BE, Sandborn WJ, Germinaro M, Vetter M, Shao J, et al. ; VEGA Study Group. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. Lancet Gastroenterol Hepatol. 2023; 8: 307-20.

[316] Sands BE, Kozarek R, Spainhour J, Barish CF, Becker S, Goldberg L, et al. Safety and tolerability of concurrent natalizumab treatment for patients with Crohn’s disease not in remission while receiving infliximab. Inflamm Bowel Dis. 2007; 13: 2-11.