Targeting IL12/23 in ulcerative colitis: update on the role of ustekinumab

Abstract

As our comprehension of the pathogenic mechanisms of inflammatory bowel disease (IBD) increases, the therapeutic armamentarium for its treatment can expand, and novel target therapies join the treatment pipeline. Interleukin (IL)-12 and IL23 are two key cytokines responsible for promoting and perpetuating bowel inflammation in IBD. Ustekinumab is a monoclonal antibody directed against the shared p40 subunit of both cytokines, and it was recently approved for the treatment of ulcerative colitis (UC). In the pivotal phase III UNIFI trial, ustekinumab showed a superiority over placebo in both clinical and endoscopic outcomes; furthermore, it was characterized by a favorable safety profile, with a similar rate of adverse events as compared with placebo. Recent evidence from real-life experiences have started accumulating, generally confirming the effectiveness and safety figures emerged from the registration studies. However, most of these observational studies enrolled multirefractory patients; moreover, comparative data with other target therapies are lacking, leaving physicians without clear indications about the appropriate positioning of ustekinumab in the therapeutic pipeline for UC. This review examines the basis of targeting IL12-23 in UC therapy and summarizes the data from both clinical trials and real-life studies, to highlight the main evidence already available and the research gaps that need to be filled for the optimal usage of ustekinumab in UC.

Network meta-analysis on efficacy and safety of different biologics for ulcerative colitis

“…Pharmacokinetic analysis demonstrated that serum ustekinumab concentrations (SUCs) were proportional to dose and were not affected by concomitant immunomodulatory agents or prior exposure to biologic therapy [17]. RCTs and real-world studies with ustekinumab found Ustekinumab could potentially exhibit several advantages over other competitors in UC (anti-TNF-α drugs, vedolizumab, and tofacitinib), including a favorable profile of safety, effectiveness on certain extraintestinal manifestations, and a convenient administration mode [45]. These results suggest that Ustekinumab may be a safe and efficacious therapeutic agent for UC treatment.…”

What can inherited immunodeficiencies reveal about pyoderma gangrenosum?

“…Widely used treatments for IBD, such as TNF‐α antagonists, have been ineffective and even detrimental in CGD patients presenting with IBD suggesting that CGD‐associated IBD may be mediated by different signalling molecules than classic idiopathic IBD. IL‐23 signalling in IBD patients has been demonstrated via higher serum levels of IL‐23 and increased mucosal transcription that leads to increased levels in IBD associated with CGD 63,64,66 . Ustekinumab, an IL‐12 and IL‐23 antagonist, has been successfully utilized in IBD cases in patients with CGD and might be the agent of choice for PG in CGD patients.…”

“…IL-23 signalling in IBD patients has been demonstrated via higher serum levels of IL-23 and increased mucosal transcription that leads to increased levels in IBD associated with CGD. 63,64,66 Ustekinumab, an IL-12 and IL-23 antagonist, has been successfully utilized in IBD cases in patients with CGD and might be the agent of choice for PG in CGD patients.…”

Advanced Nanomedicine: Redefining Therapeutic Paradigms for Inflammatory Bowel Disease

“…[ 135 ] Among these drugs, Ustekinumab (UST), an antibody targets p40 subunit of both cytokines IL‐12 and IL23, has been clinically approved to be effective in moderate to severe UC treatment, and the results from a large phase III trial are expected soon. [ 136 ] Compared to the widely used placebo, Ustekinumab shows superior clinical and endoscopic outcomes with a favorable safety profile in IBD patients by either intravenous or subcutaneous injection. [ 137,138 ] Therefore, besides TNF‐ α , targeting IL­12/IL­23 or IL­23/IL­17 would also provide novel therapeutic strategy for IBD treatment.…”