{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T14:02:48Z","timestamp":1793714568076,"version":"4.6.1"},"reference-count":93,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T00:00:00Z","timestamp":1738540800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn\u2019s disease (CD), are chronic and complex autoimmune conditions. Despite the advancements in biologics and small molecules, the therapeutic ceiling persists, posing significant treatment challenges and contributing to the concept of difficult-to-treat IBD. Dual-targeted therapy (DTT), combining two biologic agents or biologics with small molecules, has emerged as a novel approach to address this unmet need by targeting multiple inflammatory pathways simultaneously. Evidence suggests that DTT holds promise in improving clinical and endoscopic outcomes, especially in patients with refractory disease or extraintestinal manifestations. Safety data, while consistent with monotherapy profiles, highlight the importance of vigilant monitoring for infections and other adverse events. Continued research and high-quality trials are crucial to defining optimal DTT regimens and broadening its clinical applicability. This review explores the efficacy and safety of DTT in IBD, reporting data from clinical trials, systematic reviews, and real-world studies.<\/jats:p>","DOI":"10.3390\/biom15020222","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T05:36:32Z","timestamp":1738560992000},"page":"222","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Dual Therapy in Inflammatory Bowel Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7635-221X","authenticated-orcid":false,"given":"Gabriele","family":"Altieri","sequence":"first","affiliation":[{"name":"Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy"},{"name":"Faculty of Medicine and Surgery, Vita Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Zilli","sequence":"additional","affiliation":[{"name":"Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso Lorenzo","family":"Parigi","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Surgery, Vita Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariangela","family":"Allocca","sequence":"additional","affiliation":[{"name":"Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Furfaro","sequence":"additional","affiliation":[{"name":"Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5623-2968","authenticated-orcid":false,"given":"Gionata","family":"Fiorino","sequence":"additional","affiliation":[{"name":"Gastroenterology and Digestive Endoscopy, San Camillo-Forlanini Hospital, 00152 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5400-2765","authenticated-orcid":false,"given":"Clelia","family":"Cicerone","sequence":"additional","affiliation":[{"name":"Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Peyrin-Biroulet","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, INFINY Institute, INSERM NGERE, CHRU de Nancy, Universit\u00e9 de Lorraine, F-54500 Vand\u0153uvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvio","family":"Danese","sequence":"additional","affiliation":[{"name":"Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy"},{"name":"Faculty of Medicine and Surgery, Vita Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8591-6995","authenticated-orcid":false,"given":"Ferdinando","family":"D\u2019Amico","sequence":"additional","affiliation":[{"name":"Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1016\/S0140-6736(16)32126-2","article-title":"Ulcerative Colitis","volume":"389","author":"Ungaro","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1016\/S0140-6736(16)31711-1","article-title":"Crohn\u2019s Disease","volume":"389","author":"Torres","year":"2017","journal-title":"Lancet"},{"key":"ref_3","first-page":"e41120","article-title":"Advancements in Inflammatory Bowel Disease: A Narrative Review of Diagnostics, Management, Epidemiology, Prevalence, Patient Outcomes, Quality of Life, and Clinical Presentation","volume":"15","author":"Muzammil","year":"2023","journal-title":"Cureus"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"jjae091","DOI":"10.1093\/ecco-jcc\/jjae091","article-title":"ECCO Guidelines on Therapeutics in Crohn\u2019s Disease: Medical Treatment","volume":"18","author":"Gordon","year":"2024","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1093\/ecco-jcc\/jjab178","article-title":"ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment","volume":"16","author":"Raine","year":"2022","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/S2468-1253(21)00065-0","article-title":"Breaking the Therapeutic Ceiling in Drug Development in Ulcerative Colitis","volume":"6","author":"Alsoud","year":"2021","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1111\/j.1365-2036.2011.04599.x","article-title":"Review Article: Remission Rates Achievable by Current Therapies for Inflammatory Bowel Disease","volume":"33","year":"2011","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/S2468-1253(21)00141-2","article-title":"Defining Difficult-to-Treat Inflammatory Bowel Disease: Why and How","volume":"6","author":"Danese","year":"2021","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/S2468-1253(23)00154-1","article-title":"Difficult-to-Treat Inflammatory Bowel Disease: Results from an International Consensus Meeting","volume":"8","author":"Parigi","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_10","first-page":"845","article-title":"Feasibility Study of Pyrrolitinib-Based Dual-Target Therapy for Neoadjuvant Treatment of HER2-Positive Breast Cancer Patients","volume":"16","author":"Zhao","year":"2024","journal-title":"Breast Cancer (Dove Med. Press)"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"468","DOI":"10.7326\/M13-2526","article-title":"Effectiveness of Combination Therapy with Statin and Another Lipid-Modifying Agent Compared with Intensified Statin Monotherapy","volume":"160","author":"Gudzune","year":"2014","journal-title":"Ann. Intern. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1001\/jamaneurol.2014.808","article-title":"Effectiveness of Antiepileptic Drug Combination Therapy for Partial-Onset Seizures Based on Mechanisms of Action","volume":"71","author":"Margolis","year":"2014","journal-title":"JAMA Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"637","DOI":"10.7326\/M16-2575","article-title":"Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection: A Systematic Review","volume":"166","author":"Nelson","year":"2017","journal-title":"Ann. Intern. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1730","DOI":"10.14309\/ajg.0000000000002968","article-title":"ACG Clinical Guideline: Treatment of Helicobacter Pylori Infection","volume":"119","author":"Chey","year":"2024","journal-title":"Am. J. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1053\/j.gastro.2021.09.078","article-title":"Breaking Through the Therapeutic Ceiling: What Will It Take?","volume":"162","author":"Raine","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"103017","DOI":"10.1016\/j.autrev.2021.103017","article-title":"The Influence of Cytokines on the Complex Pathology of Ulcerative Colitis","volume":"21","author":"Nakase","year":"2022","journal-title":"Autoimmun. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1038\/nature08949","article-title":"Innate Lymphoid Cells Drive Interleukin-23-Dependent Innate Intestinal Pathology","volume":"464","author":"Buonocore","year":"2010","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1084\/jem.20101712","article-title":"IL-23-Responsive Innate Lymphoid Cells Are Increased in Inflammatory Bowel Disease","volume":"208","author":"Geremia","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/s41575-021-00574-7","article-title":"Alimentiv Translational Research Consortium (ATRC) Sphingosine 1-Phosphate Modulation and Immune Cell Trafficking in Inflammatory Bowel Disease","volume":"19","author":"Verstockt","year":"2022","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1053\/j.gastro.2021.04.068","article-title":"Rational Combination Therapy to Overcome the Plateau of Drug Efficacy in Inflammatory Bowel Disease","volume":"161","author":"Stalgis","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Battat, R., Chang, J.T., Loftus, E.V., and Sands, B.E. (2024). IBD Matchmaking\u2014Rational Combination Therapy. Clin. Gastroenterol. Hepatol.","DOI":"10.1016\/j.cgh.2024.05.051"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/S2468-1253(22)00085-1","article-title":"Difficult-to-Treat Inflammatory Bowel Disease: Results from a Global IOIBD Survey","volume":"7","author":"Parigi","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17562848211006669","DOI":"10.1177\/17562848211006669","article-title":"Novel Trends with Biologics in Inflammatory Bowel Disease: Sequential and Combined Approaches","volume":"14","author":"Privitera","year":"2021","journal-title":"Therap Adv. Gastroenterol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1093\/ecco-jcc\/jjaa149","article-title":"Dual Targeted Therapy: A Possible Option for the Management of Refractory Inflammatory Bowel Disease","volume":"15","author":"Privitera","year":"2021","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1093\/ecco-jcc\/jjx008","article-title":"Third European Evidence-Based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-Intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-Anal Pouch Disorders","volume":"11","author":"Magro","year":"2017","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1093\/ecco-jcc\/jjv213","article-title":"The First European Evidence-Based Consensus on Extra-Intestinal Manifestations in Inflammatory Bowel Disease","volume":"10","author":"Harbord","year":"2016","journal-title":"J. Crohns Colitis"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.suc.2007.03.003","article-title":"Extra-Intestinal Manifestations of Crohn\u2019s Disease","volume":"87","author":"Ephgrave","year":"2007","journal-title":"Surg. Clin. N. Am."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1053\/j.gastro.2013.10.052","article-title":"Combination Therapy with Infliximab and Azathioprine Is Superior to Monotherapy with Either Agent in Ulcerative Colitis","volume":"146","author":"Panaccione","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1136\/gutjnl-2019-319758","article-title":"Addition of Azathioprine to the Switch of Anti-TNF in Patients with IBD in Clinical Relapse with Undetectable Anti-TNF Trough Levels and Antidrug Antibodies: A Prospective Randomised Trial","volume":"69","author":"Roblin","year":"2020","journal-title":"Gut"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1016\/j.cgh.2018.09.033","article-title":"Combination Therapy with Infliximab and Azathioprine Improves Infliximab Pharmacokinetic Features and Efficacy: A Post Hoc Analysis","volume":"17","author":"Colombel","year":"2019","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S2468-1253(22)00427-7","article-title":"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","volume":"8","author":"Feagan","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e361","DOI":"10.1016\/j.cgh.2021.03.034","article-title":"Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis","volume":"20","author":"Ahmed","year":"2022","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2604","DOI":"10.1007\/s10620-023-07837-0","article-title":"Efficacy and Safety of Dual Targeted Therapy for Partially or Non-Responsive Inflammatory Bowel Disease: A Systematic Review of the Literature","volume":"68","author":"Berinstein","year":"2023","journal-title":"Dig. Dis. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1093\/ibd\/izx110","article-title":"Combining Anti-TNF-\u03b1 and Vedolizumab in the Treatment of Inflammatory Bowel Disease: A Case Series","volume":"24","author":"Buer","year":"2018","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.cgh.2021.02.043","article-title":"Efficacy and Safety of Tofacitinib in Ulcerative Colitis Based on Prior Tumor Necrosis Factor Inhibitor Failure Status","volume":"20","author":"Sandborn","year":"2022","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"861","DOI":"10.14309\/ajg.0000000000002129","article-title":"REMIT-UC: Real-World Effectiveness and Safety of Tofacitinib for Moderate-to-Severely Active Ulcerative Colitis: A Canadian IBD Research Consortium Multicenter National Cohort Study","volume":"118","author":"Ma","year":"2023","journal-title":"Off. J. Am. Coll. Gastroenterol. ACG"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1093\/ibd\/izab011","article-title":"Real-World Effectiveness and Safety of Tofacitinib in Patients with Ulcerative Colitis: Systematic Review with Meta-Analysis","volume":"28","author":"Taxonera","year":"2022","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"S460","DOI":"10.14309\/01.ajg.0000705628.04061.db","article-title":"S0895 Is Two Better Than One? Combination Therapy with Vedolizumab and Tofacitinib for the Treatment of Patients with Inflammatory Bowel Disease","volume":"115","author":"Scheinberg","year":"2020","journal-title":"Off. J. Am. Coll. Gastroenterol. ACG"},{"key":"ref_39","first-page":"S107","article-title":"Dual Biological Therapy for Ulcerative Colitis with Intractable Pyoderma Gangrenosum","volume":"35","author":"Lee","year":"2023","journal-title":"Ann. Dermatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1093\/ecco-jcc\/jjx142","article-title":"Co-Treatment with Golimumab and Vedolizumab to Treat Severe UC and Associated Spondyloarthropathy","volume":"12","author":"Roblin","year":"2018","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1056\/NEJMoa0904492","article-title":"Infliximab, Azathioprine, or Combination Therapy for Crohn\u2019s Disease","volume":"362","author":"Colombel","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/ibd.20014","article-title":"Safety and Tolerability of Concurrent Natalizumab Treatment for Patients with Crohn\u2019s Disease Not in Remission While Receiving Infliximab","volume":"13","author":"Sands","year":"2007","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1056\/NEJMoa1107829","article-title":"Risk of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy","volume":"366","author":"Bloomgren","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1111\/apt.15719","article-title":"Efficacy and Safety of Simultaneous Treatment with Two Biologic Medications in Refractory Crohn\u2019s Disease","volume":"51","author":"Yang","year":"2020","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1111\/apt.14487","article-title":"Long-Term Efficacy and Safety of Ustekinumab in 122 Refractory Crohn\u2019s Disease Patients: A Multicentre Experience","volume":"47","author":"Wils","year":"2018","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1097\/MCG.0000000000001729","article-title":"Rates and Predictors of Long-Term Clinical Outcomes in Patients with Perianal Crohn\u2019s Disease on Biologic Therapy","volume":"57","author":"Gubatan","year":"2023","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"17562848241307598","DOI":"10.1177\/17562848241307598","article-title":"Efficacy and Safety of Dual-Targeted Therapy for Inflammatory Bowel Disease: A Retrospective Multicenter Study in China","volume":"18","author":"Jin","year":"2025","journal-title":"Ther. Adv. Gastroenterol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"otae080","DOI":"10.1093\/crocol\/otae080","article-title":"Dual Biologic Therapy Induces Remission in Refractory Crohn\u2019s Disease with Vedolizumab and Ustekinumab","volume":"7","author":"Hassan","year":"2025","journal-title":"Crohn\u2019s Colitis 360"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s10620-023-08182-y","article-title":"Dual-Targeted Therapy with Upadacitinib and Ustekinumab in Medically Complex Crohn\u2019s Disease","volume":"69","author":"Miyatani","year":"2024","journal-title":"Dig. Dis. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1016\/j.cgh.2023.09.010","article-title":"Vedolizumab, Adalimumab, and Methotrexate Combination Therapy in Crohn\u2019s Disease (EXPLORER)","volume":"22","author":"Colombel","year":"2024","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jaci.2015.10.023","article-title":"Alterations in Immune Function with Biologic Therapies for Autoimmune Disease","volume":"137","author":"Her","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1136\/annrheumdis-2015-207841","article-title":"Opportunistic Infections and Biologic Therapies in Immune-Mediated Inflammatory Diseases: Consensus Recommendations for Infection Reporting during Clinical Trials and Postmarketing Surveillance","volume":"74","author":"Winthrop","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1016\/j.cgh.2018.02.024","article-title":"Combining Biologics in Inflammatory Bowel Disease and Other Immune Mediated Inflammatory Disorders","volume":"16","author":"Hirten","year":"2018","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/apt.14075","article-title":"Systematic Review: The Safety of Vedolizumab for the Treatment of Inflammatory Bowel Disease","volume":"46","author":"Bye","year":"2017","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"otac002","DOI":"10.1093\/crocol\/otac002","article-title":"Systematic Review with Meta-Analysis: Safety and Effectiveness of Combining Biologics and Small Molecules in Inflammatory Bowel Disease","volume":"4","author":"Alayo","year":"2022","journal-title":"Crohn\u2019s Colitis 360"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1016\/j.cgh.2020.07.046","article-title":"Tofacitinib Is Safe and Effective When Used in Combination with Infliximab for the Management of Refractory Ulcerative Colitis","volume":"19","author":"Gilmore","year":"2021","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1002\/ueg2.12170","article-title":"Safety and Efficacy of Combining Biologics or Small Molecules for Inflammatory Bowel Disease or Immune-Mediated Inflammatory Diseases: A European Retrospective Observational Study","volume":"9","author":"Goessens","year":"2021","journal-title":"United Eur. Gastroenterol. J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"otae057","DOI":"10.1093\/crocol\/otae057","article-title":"Exploring Dual-Targeted Therapy in the Management of Moderate to Severe Inflammatory Bowel Disease: A Retrospective Study","volume":"7","author":"Bhaskar","year":"2024","journal-title":"Crohn\u2019s Colitis 360"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e000573","DOI":"10.1136\/bmjgast-2020-000573","article-title":"Risk of Common Infections in People with Inflammatory Bowel Disease in Primary Care: A Population-Based Cohort Study","volume":"8","author":"Irving","year":"2021","journal-title":"BMJ Open Gastroenterol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1093\/ibd\/izz147","article-title":"Opportunistic Infections Are More Prevalent in Crohn\u2019s Disease and Ulcerative Colitis: A Large Population-Based Study","volume":"26","author":"Sheriff","year":"2020","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Sun, Y., Liu, W., Ma, Y., Yang, H., Li, Y., Tan, B., Li, J., and Qian, J. (2024). Computerized Tomography Features Acting as Predictors for Invasive Therapy in the Management of Crohn\u2019s Disease-Related Spontaneous Intra-Abdominal Abscess: Experience from Long-Term Follow-Up. BMC Med. Imaging, 24.","DOI":"10.1186\/s12880-024-01475-2"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.cgh.2021.02.025","article-title":"Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn\u2019s Disease: The IM-UNITI Trial","volume":"20","author":"Sandborn","year":"2022","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1016\/j.cgh.2021.12.030","article-title":"Upadacitinib Was Efficacious and Well-Tolerated Over 30 Months in Patients with Crohn\u2019s Disease in the CELEST Extension Study","volume":"20","author":"Louis","year":"2022","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"103331","DOI":"10.1016\/j.jaut.2024.103331","article-title":"Efficacy and Safety of Advanced Combination Treatment in Immune-Mediated Inflammatory Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","volume":"149","author":"Solitano","year":"2024","journal-title":"J. Autoimmun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1093\/rheumatology\/key335","article-title":"Temporal Relationships between Systemic Lupus Erythematosus and Comorbidities","volume":"58","author":"Kuo","year":"2019","journal-title":"Rheumatology"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Wang, J., Wu, J., and Li, L. (2024). Extra-Articular Manifestations in Rheumatoid Arthritis: Incidence and Predisposing Factors. Eur. J. Intern. Med.","DOI":"10.1016\/j.ejim.2024.11.021"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e527","DOI":"10.14309\/01.ajg.0000902200.99170.8c","article-title":"S745 Differential and Combinatorial Mechanism of Action of Golimumab and Guselkumab in Ulcerative Colitis Induction Therapy: IL-23 Blockade Drives Restoration of Normal Epithelium and Mucosal Healing","volume":"117","author":"Desai","year":"2022","journal-title":"Off. J. Am. Coll. Gastroenterol. ACG"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"102832","DOI":"10.1016\/j.autrev.2021.102832","article-title":"Combination Therapy in Inflammatory Bowel Disease\u2014From Traditional Immunosuppressors towards the New Paradigm of Dual Targeted Therapy","volume":"20","author":"Privitera","year":"2021","journal-title":"Autoimmun. Rev."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1136\/gutjnl-2022-327025","article-title":"The Future of Drug Development for Inflammatory Bowel Disease: The Need to ACT (Advanced Combination Treatment)","volume":"71","author":"Danese","year":"2022","journal-title":"Gut"},{"key":"ref_70","first-page":"55","article-title":"Translational Characterization of Immune Pathways in Inflammatory Bowel Disease: Insights for Targeted Treatments","volume":"21","author":"Faggiani","year":"2024","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/s13075-024-03380-z","article-title":"The Mode of Action of IL-23 in Experimental Inflammatory Arthritic Pain and Disease","volume":"26","author":"Lee","year":"2024","journal-title":"Arthritis Res. Ther."},{"key":"ref_72","first-page":"e70148","article-title":"Shared Pathophysiology of Inflammatory Bowel Disease and Psoriasis: Unraveling the Connection","volume":"16","author":"Tabbarah","year":"2024","journal-title":"Cureus"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1080\/14712598.2024.2428311","article-title":"An Evaluation of Risankizumab for the Treatment of Moderate-to-Severe Ulcerative Colitis","volume":"24","author":"Johnson","year":"2024","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Sands, B.E., D\u2019Haens, G., Clemow, D.B., Irving, P.M., Johns, J.T., Gibble, T.H., Abreu, M.T., Lee, S.D., Hisamatsu, T., and Kobayashi, T. (2024). Three-Year Efficacy and Safety of Mirikizumab Following 152 Weeks of Continuous Treatment for Ulcerative Colitis: Results From the LUCENT-3 Open-Label Extension Study. Inflamm. Bowel Dis., izae253.","DOI":"10.1093\/ibd\/izae253"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1080\/14712598.2022.1985999","article-title":"Bispecific Antibodies for the Treatment in Inflammatory Bowel Disease: An Avenue Worth Exploring?","volume":"22","author":"Caron","year":"2022","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Roberts, K.J., Cubitt, M.F., Carlton, T.M., Rodrigues-Duarte, L., Maggiore, L., Chai, R., Clare, S., Harcourt, K., MacDonald, T.T., and Ray, K.P. (2021). Preclinical Development of a Bispecific TNF\u03b1\/IL-23 Neutralising Domain Antibody as a Novel Oral Treatment for Inflammatory Bowel Disease. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-97236-0"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1007\/s10753-021-01449-4","article-title":"An Immuno-Blocking Agent Targeting IL-1\u03b2 and IL-17A Reduces the Lesion of DSS-Induced Ulcerative Colitis in Mice","volume":"44","author":"Yin","year":"2021","journal-title":"Inflammation"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1093\/ecco-jcc\/jjz051","article-title":"European Crohn\u2019s and Colitis Organisation Topical Review on Complementary Medicine and Psychotherapy in Inflammatory Bowel Disease","volume":"13","author":"Torres","year":"2019","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Krstulovi\u0107, J., Augustin, G., Romi\u0107, I., Tavra, A., Batinovi\u0107, F., and Hrgovi\u0107, Z. (2025). Hyperbaric Oxygen Therapy in the Treatment of Crohn\u2019s Disease. Healthcare, 13.","DOI":"10.3390\/healthcare13020128"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e564","DOI":"10.1097\/MEG.0000000000002164","article-title":"Hyperbaric Oxygen Therapy in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis","volume":"33","author":"Singh","year":"2021","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/joim.13282","article-title":"Inflammatory Bowel Disease and Psoriasis: Modernizing the Multidisciplinary Approach","volume":"290","author":"Hedin","year":"2021","journal-title":"J. Intern. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3109\/09546634.2014.880396","article-title":"Early Intervention in Psoriasis and Immune-Mediated Inflammatory Diseases: A Hypothesis Paper","volume":"26","author":"Girolomoni","year":"2015","journal-title":"J. Dermatol. Treat."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"D\u2019Amico, F., Peyrin-Biroulet, L., and Danese, S. (2024). Benefits of Biosimilars in the Management of Patients with Inflammatory Bowel Disease: An International Survey. J. Clin. Med., 13.","DOI":"10.3390\/jcm13113069"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"17562848241273066","DOI":"10.1177\/17562848241273066","article-title":"Raising the Bar in Ulcerative Colitis Management","volume":"17","author":"Fanizzi","year":"2024","journal-title":"Ther. Adv. Gastroenterol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1080\/14728222.2024.2433124","article-title":"Targeting Mucosal Healing in Crohn\u2019s Disease: Efficacy of Novel Pathways and Therapeutic Targets","volume":"28","author":"Centanni","year":"2024","journal-title":"Expert. Opin. Ther. Targets"},{"key":"ref_86","unstructured":"Takeda (2025, January 07). An Open-Label, Phase 4 Study to Evaluate the Efficacy and Safety of Dual Targeted Therapy with Vedolizumab Intravenous (IV) and Adalimumab Subcutaneous (SC) or Vedolizumab IV and Ustekinumab IV\/SC in Moderate to Severe Crohn\u2019s Disease (CD), Available online: https:\/\/clinicaltrials.gov\/study\/NCT06045754?term=NCT06045754&rank=1."},{"key":"ref_87","unstructured":"Wang, W. (2025, January 07). Evaluation of the Efficacy and Safety of Dual-Targeted Therapy with Upadacitinib and Ustekinumab Versus Intensified Ustekinumab Therapy in Crohn\u2019s Disease Patients with an Insufficient Response to Standard-Dose Ustekinumab: A Randomized Controlled Trial, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06520397?term=NCT06520397&rank=1."},{"key":"ref_88","unstructured":"Takeda (2025, January 07). A Randomized, Double-Blind, Placebo-Controlled Phase 3b Study to Evaluate the Short- and Long-Term Efficacy and Safety of Dual Targeted Therapy with Intravenous Vedolizumab and Oral Upadacitinib Compared with Intravenous Vedolizumab Monotherapy for the Treatment of Adult Participants with Moderately to Severely Active Crohn\u2019s Disease, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06227910?term=NCT06227910&rank=1."},{"key":"ref_89","unstructured":"Janssen Research & Development, LLC (2025, January 07). A Phase 2b Randomized, Double-Blind, Active-and Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Induction and Maintenance Combination Therapy with Guselkumab and Golimumab in Participants with Moderately to Severely Active Crohn\u2019s Disease, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05242471?term=NCT05242471&rank=1."},{"key":"ref_90","unstructured":"Takeda (2025, January 07). An Open-Label, Phase 4, Single-Arm, Multicenter Study to Evaluate the Induction of Response and Remission of Vedolizumab Dual Targeted Therapy with Tofacitinib in Adult Patients with Moderately to Severely Active Ulcerative Colitis, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06095128?term=NCT06095128&rank=1."},{"key":"ref_91","unstructured":"Janssen Research & Development, LLC (2025, January 07). A Phase 2b Randomized, Double-Blind, Active-and Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Induction and Maintenance Combination Therapy with Guselkumab and Golimumab in Participants with Moderately to Severely Active Ulcerative Colitis, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05242484?term=NCT05242484&rank=1."},{"key":"ref_92","unstructured":"Yao, J. (2025, January 07). Efficacy and Safety Analysis of Sequential Treatment of Moderate to Severe Ulcerative Colitis with Vedolizumab and Upadacitinib: A Multicenter Prospective Randomized Controlled Clinical Study, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06095596?term=NCT06095596&rank=1."},{"key":"ref_93","unstructured":"Talar-Wojnarowska, R. (2025, January 07). Comparison of Ustekinumab, Infliximab and Combination Therapy in Moderately to Severely Active Ulcerative Colitis (COMBO-UC), Available online: https:\/\/clinicaltrials.gov\/study\/NCT06453317?term=NCT06453317&rank=1."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/2\/222\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:26:08Z","timestamp":1760027168000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/2\/222"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,3]]},"references-count":93,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["biom15020222"],"URL":"https:\/\/doi.org\/10.3390\/biom15020222","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,3]]}}}