Y-ECCO Literature Review: Mohammed Tauseef Sharip
Mohammed Tauseef Sharip
Vedolizumab for the treatment of chronic pouchitis
Travis S, Silverberg MS, Danese S, et al., EARNEST Study Group
N Engl J Med 2023;388:1191–1200. doi:10.1056/NEJMoa2208450.
Proctocolectomy is a curative treatment for medically refractory Ulcerative Colitis (UC). However, a significant number of patients prefer to have continuity of their bowel and undergo a restorative ileal pouch–anal anastomosis (IPAA), after having had an initial subtotal colectomy. Unfortunately, pouchitis is a most common complication in patients with an IPAA: 81% of patients experience pouchitis in their lifetime, with 40% experiencing it in their first year of pouch formation . Multiple factors associated with pouchitis include mutations in NOD2/CARD15, genetic polymorphisms of interleukin-1 receptor antagonists [2–4], tumour necrosis factor allele 2 and toll-like receptor 1 .
The cause of pouchitis is multifactorial, including abnormal immune reaction to newly formed IPAA, change in the vascularity and anatomy of the bowel, faecal stasis and many other postulated factors. Single-cell analysis of CD45+ haematopoietic cells in the colon and pouch of UC patients has also highlighted genetic pathways that might contribute to the inflammation and disease severity seen in this condition . However, the aetiology of pouchitis remains poorly understood and this may explain why treatment of this condition has emerged as an important area of unmet research need in the field of IBD. The treatment currently ranges from probiotics, antibiotics, steroids and immunomodulators through to use of biologics. Unfortunately, 50% of patients develop recurrent pouchitis, and up to 20% develop chronic pouchitis. Typically, cases of medically refractory pouchitis have been treated with anti-tumour necrosis factor (anti-TNF), vedolizumab and ustekinumab, but the evidence base for this approach has been very limited, typically comprising only case series and retrospective studies. Until recently, there had been no double-blind, randomised placebo-controlled trial supporting use of any therapeutic in pouchitis. Therefore, there has been significant interest in the study by Travis et al., reporting the first placebo-controlled trial for treatment of pouchitis, with use of vedolizumab. The findings from this trial help to provide evidence supporting the use of gut-selective vedolizumab for patients living with an IPAA.
Methods and key findings
The EARNEST trial is the first randomised, placebo-controlled and blinded study to compare the efficacy of vedolizumab to a placebo. The trial itself was conducted across North America and Europe, with a rigorous endpoint of clinical response and remission. Patients were eligible if they were aged 18–80 years, had undergone a proctocolectomy and IPAA for UC that had been performed at least one year before screening and had active chronic pouchitis. Active chronic pouchitis was defined by ongoing inflammation using the modified Pouchitis Disease Activity Index (mPDAI), with a required score of at least 5 and a minimum subscore of 2 on the endoscopic domain. The primary endpoint was mPDAI-defined remission (an mPDAI score of ≤4 and a reduction from baseline of ≥2 points in the mPDAI total score) at week 14. The trial also assessed multiple secondary endpoints, including mPDAI-defined remission at week 34, PDAI-defined remission (a PDAI score of ≤6 and a reduction from baseline of ≥3 points) at weeks 14 and 34, and PDAI endoscopic and histological domain subscores at weeks 14 and 34.
The demographic and clinical characteristics of both groups at baseline were comparable. Fifteen patients in the vedolizumab-treated group and 12 in the placebo group had a history of treatment failure with anti-TNF therapy. Of note, though, most patients in this trial had not been exposed to anti-TNF treatment for their pouchitis. The trial demonstrated that 31% of patients treated with vedolizumab achieved clinical remission at week 14 compared to 10% of placebo-treated patients, irrespective of their antibiotic use during the study. The high remission rate was maintained at week 34 (the between-group difference in the incidence of mPDAI-defined remission at week 34 was 17 percentage points). The PDAI response rate of vedolizumab-treated patients was also high and held true at both week 14 and week 34. Moreover, the endoscopic remission rate was higher in vedolizumab-treated patients and remained high throughout the study. Subgroup analysis showed that among patients previously exposed to anti-TNF therapy, the mPDAI remission rate was higher in the vedolizumab-treated group than in the placebo group. However, for vedolizumab-treated patients who had anti-TNF treatment in the past, the remission rate at week 34 was not significantly different from that in the placebo control group.
Although the mechanism of action of vedolizumab remains to be fully elucidated, this anti-integrin treatment is generally considered to be a more “gut-selective” biologic, with a favourable side effect profile. When assessing safety data in the EARNEST trial, there was a slight increase in respiratory tract infections and headaches among vedolizumab-treated patients. However, crucially there was no statistically significant difference in any significant adverse events.
As acknowledged by the study group, use of mPDAI and PDAI as a tool to monitor disease activity represented a limitation of the study, but the group should be commended for clearly reporting on more objective measures of outcome, including endoscopic and histological findings. An interesting observation of the study was that the vedolizumab-treated patients received more antibiotics than their placebo counterparts despite significant differences in treatment response and remission rate. The reasons for this are not entirely clear, but the finding might be explained by the relatively easy access to prescription of antibiotics in both hospital and community-based practices and the fact that the current mainstay of treatment for symptoms of pouchitis remains a course of antibiotics.
The EARNEST trial clearly demonstrated that vedolizumab is more effective than placebo and could play an important role in treating medically refractory chronic pouchitis. Travis and colleagues should be commended for conducting the first-ever randomised, placebo-controlled, clinical trial in pouchitis. Indeed, the authors have helped to generate high-quality evidence which should facilitate improved access to treatment for patients with chronic pouchitis. Looking to the future, it is clear that more studies are needed in this field. Notably, head-to-head trials of advanced therapies for refractory pouchitis should help to achieve a better understanding of the positioning and sequencing of treatments. An important next step will be to elucidate what treatment options could be offered to patients who are unresponsive to either anti-TNF or anti-integrin therapy.
- Rabbenou W, Chang S. Medical treatment of pouchitis: a guide for the clinician. Therap Adv Gastroenterol 2021;14:17562848211023376. doi: 10.1177/17562848211023376.
- Okada S, Hata K, Shinagawa T, et al. A polymorphism in interleukin-1β gene is associated with the development of pouchitis in Japanese patients with ulcerative colitis. Digestion 2021;102:489–98. doi: 10.1159/000503283.
- Carter MJ, di Giovine FS, Jones S, et al. Association of the interleukin 1 receptor antagonist gene with ulcerative colitis in Northern European Caucasians. Gut 2001;48:461–7. doi: 10.1136/gut.48.4.461.
- Carter MJ, Di Giovine FS, Cox A, et al. The interleukin 1 receptor antagonist gene allele 2 as a predictor of pouchitis following colectomy and IPAA in ulcerative colitis. Gastroenterology 2001;121:805–11. doi: 10.1053/gast.2001.28017.
- Landy J, Al-Hassi HO, McLaughlin SD, et al. Etiology of pouchitis. Inflamm Bowel Dis 2012;18:1146–55. doi: 10.1002/ibd.21911.
- Devlin JC, Axelrad J, Hine AM, et al. Single-cell transcriptional survey of ileal-anal pouch immune cells from ulcerative colitis patients. Gastroenterology 2021;160:1679-93. doi: 10.1053/j.gastro.2020.12.030.
Mohammed Tauseef Sharip - Short Biography
Mohammed Tauseef Sharip is a higher trainee in Gastroenterology currently undertaking an IBD clinical research fellowship at Cambridge University Hospitals in the UK. Tauseef has a specific research interest in immunogenicity, the genetics of IBD and understanding the genetic heterogeneity between patients of different ethnic backgrounds. Currently he is working on a range of IBD-related projects, including a large nationwide project on better understanding the mechanisms of development of immunogenicity in biologically treated patients.