{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:45:24Z","timestamp":1759970724725,"version":"build-2065373602"},"reference-count":61,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T00:00:00Z","timestamp":1738108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Introduction: Crohn\u2019s disease is a chronic inflammatory bowel disease characterized by abdominal pain, diarrhea, and other symptoms. It can lead to significant complications and impact patients\u2019 quality of life. Therefore, effective management strategies are essential for improving outcomes. Methods: To assess the efficacy of the treatments for Crohn\u2019s disease, this umbrella review systematically addresses systematic reviews and meta-analyses on Crohn\u2019s disease management published between 2013 and 2023. The quality of the included studies was assessed using the National Institutes of Health\u2019s quality assessment tool. Results: Sixteen studies were included, evaluating various interventions for the induction and maintenance of remission. These included biologic agents (anti-TNF agents, anti-IL-12\/23p40 antibodies, and integrin receptor antagonists), antimetabolites, and corticosteroids. Conclusions: The findings suggest that biologic agents may be promising options for both the induction and maintenance of remission in Crohn\u2019s disease. Antimetabolites and corticosteroids may be effective in certain cases, but their efficacy and safety profiles require further investigation. The included studies varied in quality and sample size. More research is needed to confirm the findings and establish optimal treatment strategies. Moreover, while biologic agents show promise, the optimal management of Crohn\u2019s disease requires further research. A personalized approach considering patient factors and disease characteristics is crucial for optimizing outcomes.<\/jats:p>","DOI":"10.3390\/medsci13010012","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T07:45:12Z","timestamp":1738136712000},"page":"12","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Placebo-Controlled Trials in the Management of Crohn\u2019s Disease: An Umbrella Review of Meta-Analyses"],"prefix":"10.3390","volume":"13","author":[{"given":"Richard","family":"Silva","sequence":"first","affiliation":[{"name":"Cl\u00ednica M\u00e9dica Dr. Richard, 3700-317 S\u00e3o Jo\u00e3o da Madeira, Portugal"}]},{"given":"Jos\u00e9 Nunes de","family":"Azevedo","sequence":"additional","affiliation":[{"name":"TECSAM, Tecnologia e Servi\u00e7os M\u00e9dicos SA, 5370-530 Mirandela, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4570-5445","authenticated-orcid":false,"given":"Jorge Pereira","family":"Machado","sequence":"additional","affiliation":[{"name":"ICBAS, School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal"},{"name":"CBSin\u2014Center of BioSciences in Integrative Health, 4000-105 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5892-1855","authenticated-orcid":false,"given":"Jorge Magalh\u00e3es","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"ICBAS, School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal"},{"name":"CBSin\u2014Center of BioSciences in Integrative Health, 4000-105 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1136\/bmj.g6670","article-title":"Crohn\u2019s disease","volume":"349","author":"Kalla","year":"2014","journal-title":"BMJ"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Reider, S., Binder, L., F\u00fcrst, S., Hatzl, S., and Blesl, A. (2022). Hematopoietic Stem Cell Transplantation in Refractory Crohn\u2019s Disease: Should It Be Considered?. Cells, 11.","DOI":"10.3390\/cells11213463"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1016\/S0140-6736(12)60026-9","article-title":"Crohn\u2019s disease","volume":"380","author":"Baumgart","year":"2012","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"s1","DOI":"10.1136\/gutjnl-2019-318484","article-title":"British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults","volume":"68","author":"Lamb","year":"2019","journal-title":"Gut"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1111\/j.1365-2036.2006.02854.x","article-title":"Meta-analysis: Colorectal and small bowel cancer risk in patients with Crohn\u2019s disease","volume":"23","author":"Canavan","year":"2006","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1136\/gut.2007.143453","article-title":"High frequency of early colorectal cancer in inflammatory bowel disease","volume":"57","author":"Lutgens","year":"2008","journal-title":"Gut"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/ajg.2010.343","article-title":"Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort","volume":"106","author":"Vavricka","year":"2011","journal-title":"Am. J. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1111\/apt.13190","article-title":"Systematic review with network meta-analysis: Comparative efficacy and safety of budesonide and mesalazine (mesalamine) for Crohn\u2019s disease","volume":"41","author":"Moja","year":"2015","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/j.dld.2003.07.002","article-title":"Burden of illness of Crohn\u2019s disease in Spain","volume":"35","author":"Juan","year":"2003","journal-title":"Dig. Liver Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S28","DOI":"10.1097\/00005176-199904001-00004","article-title":"Inflammatory bowel disease in children and adolescents: Mental health and family functioning","volume":"28","author":"Engstrom","year":"1999","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1038\/ajg.2011.142","article-title":"Increased risks of developing anxiety and depression in young patients with Crohn\u2019s disease","volume":"106","author":"Loftus","year":"2011","journal-title":"Am. J. Gastroenterol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1002\/ibd.22916","article-title":"Mood disorders in inflammatory bowel disease: Relation to diagnosis, disease activity, perceived stress, and other factors","volume":"18","author":"Goodhand","year":"2012","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1016\/j.cgh.2006.09.027","article-title":"The relationship of inflammatory bowel disease type and activity to psychological functioning and quality of life","volume":"4","author":"Graff","year":"2006","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1111\/j.1742-1241.2008.01763.x","article-title":"State and trait anxiety and depression in patients affected by gastrointestinal diseases: Psychometric evaluation of 1641 patients referred to an internal medicine outpatient setting","volume":"62","author":"Addolorato","year":"2008","journal-title":"Int. J. Clin. Pract."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.crohns.2011.07.006","article-title":"Do inflammatory bowel disease patients with anxiety and depressive symptoms receive the care they need?","volume":"6","author":"Thijssens","year":"2012","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yarani, R., Shojaeian, A., Palasca, O., Doncheva, N.T., Jensen, L.J., Gorodkin, J., and Pociot, F. (2022). Differentially Expressed miRNAs in Ulcerative Colitis and Crohn\u2019s Disease. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.865777"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e2703","DOI":"10.1097\/MD.0000000000002703","article-title":"Circulating microRNA223 is a new biomarker for inflammatory bowel disease","volume":"95","author":"Wang","year":"2016","journal-title":"Medicine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"17562848221078456","DOI":"10.1177\/17562848221078456","article-title":"A review of the therapeutic management of Crohn\u2019s disease","volume":"15","author":"Kumar","year":"2022","journal-title":"Therap. Adv. Gastroenterol."},{"key":"ref_19","first-page":"308","article-title":"A Personalized Approach to Managing Inflammatory Bowel Disease","volume":"12","author":"Kingsley","year":"2016","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s13643-016-0384-4","article-title":"Rayyan-a web and mobile app for systematic reviews","volume":"5","author":"Ouzzani","year":"2016","journal-title":"Syst. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1053\/j.gastro.2021.04.022","article-title":"AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn\u2019s Disease","volume":"160","author":"Feuerstein","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_22","unstructured":"NIH NNHLBI (2023, August 10). Quality Assessment Tool for Systematic Reviews and Meta-Analyses 2014, Available online: https:\/\/www.nhlbi.nih.gov\/health-topics\/study-quality-assessment-tools."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_24","first-page":"CD012878","article-title":"Adalimumab for induction of remission in Crohn\u2019s disease","volume":"2019","author":"Abbass","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1186\/s40001-022-00817-6","article-title":"Adalimumab for induction of remission in patients with Crohn\u2019s disease: A systematic review and meta-analysis","volume":"27","author":"Yin","year":"2022","journal-title":"Eur. J. Med. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1007\/s00228-014-1702-1","article-title":"Efficacy and safety of adalimumab for the Crohn\u2019s disease: A systematic review and meta-analysis of published randomized placebo-controlled trials","volume":"70","author":"Song","year":"2014","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_27","first-page":"Cd012877","article-title":"Adalimumab for maintenance of remission in Crohn\u2019s disease","volume":"5","author":"Townsend","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_28","first-page":"Cd007572","article-title":"Anti-IL-12\/23p40 antibodies for induction of remission in Crohn\u2019s disease","volume":"11","author":"MacDonald","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_29","first-page":"Cd012804","article-title":"Anti-IL-12\/23p40 antibodies for maintenance of remission in Crohn\u2019s disease","volume":"12","author":"Davies","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"601","DOI":"10.2217\/cer-2017-0022","article-title":"Efficacy and safety of ustekinumab in the induction therapy of TNF-\u03b1-refractory Crohn\u2019s disease patients: A systematic review and meta-analysis","volume":"6","author":"Kawalec","year":"2017","journal-title":"J. Comp. Eff. Res."},{"key":"ref_31","first-page":"Cd012893","article-title":"Certolizumab pegol for induction of remission in Crohn\u2019s disease","volume":"8","author":"Yamazaki","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_32","first-page":"Cd013747","article-title":"Certolizumab pegol for maintenance of medically induced remission in Crohn\u2019s disease","volume":"6","author":"Okabayashi","year":"2022","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_33","first-page":"Cd003459","article-title":"Methotrexate for induction of remission in refractory Crohn\u2019s disease","volume":"2014","author":"McDonald","year":"2014","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_34","first-page":"Cd006884","article-title":"Methotrexate for maintenance of remission in Crohn\u2019s disease","volume":"2014","author":"Patel","year":"2014","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_35","first-page":"Cd000545","article-title":"Azathioprine or 6-mercaptopurine for induction of remission in Crohn\u2019s disease","volume":"10","author":"Chande","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_36","first-page":"Cd013611","article-title":"Vedolizumab for induction and maintenance of remission in Crohn\u2019s disease","volume":"7","author":"Hui","year":"2023","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1097\/MIB.0000000000000373","article-title":"Efficacy and Safety of Natalizumab and Vedolizumab for the Management of Crohn\u2019s Disease: A Systematic Review and Meta-analysis","volume":"21","author":"Chandar","year":"2015","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_38","first-page":"Cd002913","article-title":"Budesonide for maintenance of remission in Crohn\u2019s disease","volume":"2014","author":"Kuenzig","year":"2014","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_39","first-page":"Cd000296","article-title":"Budesonide for induction of remission in Crohn\u2019s disease","volume":"2015","author":"Rezaie","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1093\/ecco-jcc\/jjad086","article-title":"Defining Biological Remission in Crohn\u2019s Disease: Interest, Challenges and Future Directions","volume":"17","author":"Pierre","year":"2023","journal-title":"J. Crohns Colitis."},{"key":"ref_41","unstructured":"Hoffman, R., Benz, E.J., Silberstein, L.E., Heslop, H.E., Weitz, J.I., and Anastasi, J. (2018). Chapter 86\u2014Plasma Cell Neoplasms. Hematology, Elsevier. [7th ed.]."},{"key":"ref_42","unstructured":"Enna, S.J., and Bylund, D.B. (2007). Antimetabolites. xPharm: The Comprehensive Pharmacology Reference, Elsevier."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/nrd2638","article-title":"Adenosine receptors: Therapeutic aspects for inflammatory and immune diseases","volume":"7","author":"Linden","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_44","first-page":"46","article-title":"Systemic Psoriasis Therapies and Comorbid Disease in Patients with Psoriasis: A Review of Potential Risks and Benefits","volume":"12","author":"Mikhaylov","year":"2019","journal-title":"J. Clin. Aesthet. Dermatol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/bcpt.13294","article-title":"Drug information centre queries and responses about drug interactions over 10 years-A descriptive analysis","volume":"126","author":"Tukukino","year":"2020","journal-title":"Basic. Clin. Pharmacol. Toxicol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1111\/j.1440-1746.2005.03832.x","article-title":"Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease","volume":"20","author":"Gearry","year":"2005","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_47","unstructured":"Drugs.com (2023, November 13). Mercaptopurine Drug Interactions 2024. Available online: https:\/\/www.drugs.com\/drug-interactions\/mercaptopurine-index.html."},{"key":"ref_48","unstructured":"Crohn\u2019s & Colitis UK (2025, January 26). Biologics and Other Targeted Medicines 2023. Available online: https:\/\/crohnsandcolitis.org.uk\/info-support\/information-about-crohns-and-colitis\/all-information-about-crohns-and-colitis\/treatments\/biologics-and-other-targeted-medicines."},{"key":"ref_49","unstructured":"Wu, J.J., Feldman, S.R., and Lebwohl, M.G. (2016). Chapter 10\u2014Adalimumab. Therapy for Severe Psoriasis, Elsevier."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1002\/ibd.20225","article-title":"Mechanism of action of certolizumab pegol (CDP870): In vitro comparison with other anti-tumor necrosis factor \u03b1 agents","volume":"13","author":"Nesbitt","year":"2007","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1136\/annrheumdis-2013-204741","article-title":"Ustekinumab, an anti-IL-12\/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: Results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trials","volume":"73","author":"Kavanaugh","year":"2014","journal-title":"Ann. Rheum. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Chen, L., Ruan, G., Cheng, Y., Yi, A., Chen, D., and Wei, Y. (2022). The role of Th17 cells in inflammatory bowel disease and the research progress. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1055914"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jaut.2017.12.004","article-title":"Th17 plasticity and its relevance to inflammatory bowel disease","volume":"87","author":"Ueno","year":"2018","journal-title":"J. Autoimmun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"333","DOI":"10.2147\/CEG.S293272","article-title":"Anti-Integrins for the Treatment of Inflammatory Bowel Disease: Current Evidence and Perspectives","volume":"14","author":"Gubatan","year":"2021","journal-title":"Clin. Exp. Gastroenterol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/ng.3760","article-title":"Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease","volume":"49","author":"Moutsianas","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1586\/14737175.4.4.571","article-title":"Natalizumab: Alpha 4-integrin antagonist selective adhesion molecule inhibitors for MS","volume":"4","author":"Rudick","year":"2004","journal-title":"Expert. Rev. Neurother."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1124\/jpet.109.153973","article-title":"The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases","volume":"330","author":"Soler","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1080\/14656566.2016.1183648","article-title":"Budesonide for the treatment of ulcerative colitis","volume":"17","author":"Abdalla","year":"2016","journal-title":"Expert. Opin. Pharmacother."},{"key":"ref_59","first-page":"813","article-title":"Mechanism of action of glucocorticoids: Role of lipocortins","volume":"145","author":"Tranchant","year":"1989","journal-title":"Rev. Neurol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1016\/S0140-6736(03)13492-7","article-title":"Adrenal insufficiency","volume":"361","author":"Arlt","year":"2003","journal-title":"Lancet"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1097\/MED.0b013e328338f608","article-title":"Adrenal insufficiency: Etiology, diagnosis and treatment","volume":"17","author":"Neary","year":"2010","journal-title":"Curr. Opin. Endocrinol. Diabetes Obes."}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/13\/1\/12\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:38:19Z","timestamp":1759919899000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/13\/1\/12"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,29]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["medsci13010012"],"URL":"https:\/\/doi.org\/10.3390\/medsci13010012","relation":{},"ISSN":["2076-3271"],"issn-type":[{"type":"electronic","value":"2076-3271"}],"subject":[],"published":{"date-parts":[[2025,1,29]]}}}