Review ArticlesSmall molecule drugs in the treatment of inflammatory bowel diseases: which one, when and why? – a systematic reviewLucaciu, Laura A.a; Seicean, Radub; Seicean, AndradaaAuthor Information aDepartment of Gastroenterology and Hepatology, Iuliu Haţieganu University of Medicine and Pharmacy bDepartment of General Surgery, First Surgical Clinic, University of Medicine and Pharmacy, Cluj-Napoca, Romania Received 9 October 2019 Accepted 26 February 2020 Correspondence to Laura Lucaciu, MD, PhD, Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy ‘Iuliu Hatieganu’, Victor Babes Street No 8, 400162 Cluj-Napoca, Cluj County, Romania, Tel: +40745453585; fax: +0264 433 335; e-mail: firstname.lastname@example.org European Journal of Gastroenterology & Hepatology: June 2020 - Volume 32 - Issue 6 - p 669-677 doi: 10.1097/MEG.0000000000001730 Buy Metrics Abstract In the ‘treat-to-target’ era of inflammatory bowel disease (IBD) management, small molecule drugs (SMDs) represent a promising alternative to biomolecular drugs. Moreover, increasing failure rates of anti-tumor necrosis factor α agents have contributed to the development of new molecules with different mechanisms of action and bioavailability. This review focuses on the positioning of new, orally targeted therapies in the treatment algorithm of both Crohn’s disease (CD) and ulcerative colitis (UC), with special consideration to their efficacy and safety. We performed a comprehensive search of PubMed and clinical trial registries to identify randomized controlled trials assessing SMDs in adult patients with moderate-to-severe IBD, irrespective of previous exposure to other biologics. In this review, we included 15 double-blind, placebo-controlled trials that assessed the efficacy and safety of Janus kinase inhibitors, sphingosine-1-phosphate modulators (S1P), SMAD blockers, phosphodiesterase 4 inhibitors and α-4 antagonists. The primary endpoints in UC were achieved for tofacitinib in the phase III OCTAVE study and AJM-300, with a favorable safety profile. S1P receptor agonists, such as etrasimod and ozanimod, demonstrated favorable results in induction studies. For CD, filgotinib and upadacitinib also met the primary outcome criteria. Available data have demonstrated so far that SMDs have an advantageous safety and efficacy profile. However, their use in a clinical setting will eventually require a personalized, mechanism-based therapeutic approach. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.