Expanding targeted immune modulators in ulcerative colitis

Over the past decade, the treatment options for moderately to severely active ulcerative colitis have increased rapidly, with the regulatory approval of multiple non-tumour necrosis factor (TNF)-targeting biologics and small molecule inhibitors, including vedolizumab in 2014, tofacitinib in 2018, and ustekinumab in 2019. 1 Singh S Allegretti JR Siddique SM Terdiman JP AGA technical review on the management of moderate to severe ulcerative colitis. Gastroenterology. 2020; 158 (96.e17): 1465 Summary Full Text Full Text PDF PubMed Scopus (54) Google Scholar Among these, tofacitinib (a Janus kinase [JAK]-inhibitor which targets JAK1, JAK2, and JAK3) is particularly attractive since it is conveniently administered orally, is not immunogenic, and has a fairly rapid onset of action. 2 Hanauer S Panaccione R Danese S et al. Tofacitinib induction therapy reduces symptoms within 3 days for patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2019; 17: 139-147 Summary Full Text Full Text PDF PubMed Scopus (92) Google Scholar , 3 Shivaji UN Nardone OM Cannatelli R Smith SC Ghosh S Iacucci M Small molecule oral targeted therapies in ulcerative colitis. Lancet Gastroenterol Hepatol. 2020; 5: 850-861 Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar However, tofacitinib is associated with dose-dependent bone marrow suppression, risk of serious infections (particularly shingles), and thromboembolism. These adverse effects are partly due to inhibition of multiple JAKs and limit the use of tofacitinib at high doses, even though this may be more efficacious for patients with refractory ulcerative colitis. 4 Olivera PA Lasa JS Bonovas S Danese S Peyrin-Biroulet L Safety of Janus kinase inhibitors in patients with inflammatory bowel diseases or other immune-mediated diseases: a systematic review and meta-analysis. Gastroenterology. 2020; 158 (73.e12): 1554 Summary Full Text Full Text PDF PubMed Scopus (105) Google Scholar To overcome some of these limitations, selective JAK1 inhibitors such as filgotinib and upadacitinib have been developed, and are at various stages of approval for multiple immune-mediated inflammatory diseases. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trialFilgotinib 200 mg was well tolerated, and efficacious in inducing and maintaining clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. Full-Text PDF