Introduction

Leaks and strictures on the anastomotic site of the lower gastrointestinal tract increase morbidity and mortality of colorectal surgery. Multiple endoscopic methods have been described to treat anastomotic leaks, namely, endoscopic vacuum-assisted therapy, over-the-scope clips and sealants (fibrin glue and cyanoacrylate). As for anastomotic strictures, lumen apposing metal stents, self-expandable metal stents, balloon dilatation, intralesional steroid injection and endoscopic stricturotomy have all been proposed.

Aims & Methods

We aimed to report the indications and the overall clinical efficacy of endoscopic therapies applied for anastomotic leaks and/or strictures following colorectal surgery. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines were followed and a literature search was performed by two independent reviewers using relevant search terms in the databases PubMed and Scopus. A total of 14 studies were found and 21 additional reports were obtained from their references, overall, containing 992 patients.

Results

The overall clinical success rate of all endoscopic methods to treat leaks and strictures was 78.3%. For the treatment of leaks in 572 patients 83.4% long-term success was achieved. In 68 patients over-the-scope clips reached 67.2% symptom relief, in 473 patients the endoscopic vacuum therapy had 86.3% success rate and in 31 individuals sealants reached 79.8% efficacy. A sum of 420 cases with strictures were identified. Clinical success was reported at 72.3% for this group. A total of 101 cases with strictures were managed with self-expanding metal stents and 54.7% experienced clinical improvement. The introduction of lumen apposing metal stents for the treatment of strictures in 19 patients produced 92.4% clinical efficacy. Migration rate for fully covered stents was 46.1% and for lumen apposing metal stents 9.1%. Balloon dilatation was applied in 182 patients reporting clinical improvement in 94% of cases and in 71 cases the strictures were treated with endoscopic stricturotomy, leading to symptom relief in 41% of patients. Forty-four patients had anastomotic strictures with concomitant leaks and were managed with self-expanding metal stents reaching clinical success in 82.1% of cases. Major complications, namely bleeding or perforation, were recorded in 2.4% and the highest rate (7.2%) was reported for stricturotomy.

Conclusion

Patients with anastomotic colorectal strictures should be treated with balloon dilation initially. Self-expandable metal stent deployment, either fully-covered or uncovered or lumen-apposing metal stents, can be used in refractory cases, with the latest expressing lower rates of migration. Colorectal anastomotic leaks with concomitant cavity can be treated with endoscopic vacuum therapy and avoid re-surgery. In the case of no cavity, sealants represent an appropriate alternative method. Strictures with leaks should be considered for treatment with fully-covered metal stent deployment. Stricturotomy is associated with high rates of complications and it is not recommended unless the technique is modified appropriately to guarantee safety.

References

1. Kwon YH, et al. Endoscopic management of refractory benign colorectal strictures. Clin Endosc 2013 Sep;46(5):472-5 [DOI: 10.5946/ce.2013.46.5.472 PMCID: PMC3797928 PMID: 24143305]
2. Rahbari NN, et al. Definition and grading of anastomotic leakage following anterior resection of the rectum: a proposal by the International Study Group of Rectal Cancer. Surgery 2010 Mar;147(3):339-51 [PMID: 20004450 DOI: 10.1016/j.surg.2009.10.012]
3. Shalaby M, et al. Systematic review of endoluminal vacuum-assisted therapy as salvage treatment for rectal anastomotic leakage. BJS Open 2018 Dec 26;3(2):153-160 [PMID: 30957061 PMCID: PMC6433422 DOI: 10.1002/bjs5.50124]
4. E. Girard, et al. Anastomotic leakage after gastrointestinal surgery: Diagnosis and management. J Visc Surg. 2014 Dec;151(6):441-50 [PMID: 25455960 DOI: 10.1016/j.jviscsurg.2014.10.004]
5. Yuan-Yao Tsai, et al. Management of anastomotic leakage after rectal surgery: a review article. J Gastrointest Oncol 2019 Dec;10(6):1229-1237 [PMID: 31949944 PMCID: PMC6955017 DOI: 10.21037/jgo.2019.07.07]
6. Bartell N, et al. Clinical efficacy of the over-the-scope clip device: A systematic review. World J Gastroenterol 2020 Jun 28;26(24):3495-3516 [PMID: 32655272 PMCID: PMC7327783 DOI: 10.3748/wjg.v26.i24.3495]

Introduction

The prevention of postoperative recurrence (POR) after ileocolonic resection is one of the most relevant issues in the management of Crohn's disease (CD). The role of ustekinumab (UST) and vedolizumab (VEDO) especially in the context of real-life studies is still not entirely clear, often due to small sample sizes, thus requiring further investigation and confirmation.

Aims & Methods

Our real life single-centre retrospective study aims to evaluate the effect of UST and VEDO therapy on prophylaxis of endoscopic recurrence after ileo-colonic resection in CD. In the whole cohort UST or VEDO were used as first-line therapy for prophylaxis of recurrence. All patients (pts) underwent the first endoscopic evaluation within 6-12 months to assess postoperative recurrence (POR), using the Rutgeerts score and were subsequently evaluated at 24 (+-3) months with a second endoscopy. Persistence on therapy two years after the surgery was also evaluated.

Results

64 pts with a mean age of 38 years were included, 25 pts received VEDO (Cohort 1) and 39 UST (Cohort 2).
In the two cohorts, 89% and 91% of pts had been previously resected; 58% and 55% were active smokers. Notably, 100% had already been exposed to one or more biological drugs and the most frequent reason for surgery was the presence of stenosing disease in both cohorts.
In cohort 1, the first post-operative colonoscopy at 6-12 months showed severe POR (RS score >i2) in 28% of pts, all of whom underwent a treatment change at this time point (71% and 29% drug change and VEDO optimisation, respectively). Among the pts who continued the drug (22 pts), the second endoscopy performed at 24 (+-3) months showed severe ROP in 10% of pts, who underwent treatment modification. At ~2 years persistence on therapy in the cohort was 72%.
In cohort 2, the first post-operative colonoscopy at 6-12 months showed severe POR in 25.6% of patients, who changed therapy at this time. Among patients who continued the drug (29 pts), the second endoscopy performed at 24 (+-3) months showed severe POR in 10.3% of pts, who underwent treatment change. At ~2 years persistence on therapy in the cohort was 66.6%. No patients discontinued the drug due to adverse effects in both cohorts.
Comparing the two cohorts regarding severe endoscopic recurrence at 6-12 months and perisistence on therapy at ~2 years, no significant differences emerged between the two groups (p = 1.000, OR: 0.89,IC 95%: 0.29–2.75 and p = 0.86, OR:1.29, IC 95%: 0.43–3.85, respectively).

Conclusion

In our real life cohort of patients with complex CD, ustekinumab and vedolizumab showed high levels of persistence on therapy at ~2 years after surgery. Limited to the small sample population, no significant differences were observed between the two drugs.

Introduction

While three JAK inhibitors are now available in Ulcerative Colitis (UC), no direct comparison exists between these drugs making difficult the hierarchization of these therapeutic options.

Aims & Methods

We performed a systematic review and network meta-analysis to compare the short and long-term efficacy of the three available JAK inhibitors (JAKi) (Tofacitinib/TOFA, filgotinib/FILGO, upadacitinib/UPA) in patients with moderat-to-severe UC.
We performed a systematic review and network meta-analysis (PRISMAguidelines) of randomized controlled trials (including post-hoc analyses) conducted in adults, evaluating the efficacy of JAKi in moderate-to-severe UC.
The outcome mesures were 1) steroid-free clinical remission (CFREM) after induction therapy (partial Mayo score ≤ 2), 2) CFREM with endoscopic improvement (endoscopic Mayo score ≤ 1) after induction therapy, 3) CFREM at one year among induction-responders, 4) CFREM at one year among patients in clinical remission after induction.
The network meta-analysis was carried out according to a random effects model. The results are presented as relative risk (RR) with 95% confidence interval. The risk of bias of the studies was assessed according to the Cochrane risk-of-bias tool for randomized trials and overall statistical heterogeneity between studies was assessed using τ .
The SUCRA ranking method (surface under the cumulative ranking) was used to rank the treatments.

Results

Nine studies were included in this network meta-analysis, including a total of 2015 patients.
TOFA 10mg bid, FILGO 200 mg qd and UPA 45mg qd were more effective than placebo to induce CFREM and CFREM with endoscopic improvement. Side-by-side comparisons between JAKi found a higher efficacy of UPA 45 mg qd versus FILGO 200 mg qd (RR=0.22[0.10; 0.45]) for induction but no other significant difference between JAKi. SUCRA ranking hierarchizes induction therapies as following : UPA 45 mg qd (0.99), TOFA 10mg bid (0.75), FILGO 200 mg qd (0.27) and placebo (0.01).
Among induction-responders, all JAKi maintenance regimen (TOFA 10mg bid, TOFA 5mg, bid, FILGO 200mg qd, FILGO 100 mg qd, UPA 30 mg qd, UPA 15 mg qd) were more effective than placebo to achieve CFREM at one year with the following SUCRA ranking : UPA 30mg qd (0.85), TOFA 10mg bid (0.80), FILGO 200 mg qd (0.64), TOFA 5mg bid (0.56), UPA 15 mg (0.44), and placebo (0.01).
Among patients in CFREM after induction phase, all JAKi maintenance regimen (TOFA 10mg bid, TOFA 5mg, bid, FILGO 200mg qd, FILGO 100 mg qd, UPA 30 mg qd, UPA 15 mg qd) were more effective than placebo to achieve CFREM at one year with a different ranking (SUCRA) : TOFA 10 mg bid (0.84), FILGO 200 mg bid (0.74), TOFA (5mg bid) (0 .66), UPA 30mg qd (0.63), UPA 15 mg (0.44) and placebo (0.09).

Conclusion

While this network meta-analysis confirms the efficacy of JAKi to induce and maintain CFREM in moderate-to-severe UC, UPA seems to be the most effective JAKi to induce and maintain CFREM. However, once CFREM achieved after induction, continuing the same dose than during induction such as TOFA (10mg bid) or FILGO 200 mg seems to be more effective than reducing the dose (UPA 30 mg or UPA 15 mg) to maintain remission highlighting the dose-efficacy relationship of JAKi.

Disclosure

Consulting fees from: Abbvie, Amgen, Arena, Biocon, Biogen, Celltrion Healthcare, CTMA, Ferring, Galapagos/AlfaSigma, GutyCare/Resilience Janssen, Lilly, MSD, Nexbiome, Pfizer, Roche, Sandoz, Takeda et Tillotts
Lecture fees from: Abbvie, Amgen, Biogen, Celltrion Healthcare Galapagos/AlfaSigma, Ferring, Janssen, Lilly, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma
Research grants/fundings from: Abbvie, Celltrion Healthcare, Janssen, Lessaffre, Lilly, Pfizer, Sandoz and Takeda

Introduction

Steroid-refractory acute severe ulcerative colitis (SR-ASUC) is a life-threatening emergency that results in colectomy in approximately 40% of cases.¹ Several medical therapies have emerged as rescue treatments aimed at reducing the need for colectomy.^2-3However, direct comparative studies evaluating the relative efficacy of these therapies remain limited.⁴ This network meta-analysis aims to systematically review and compare the efficacy and safety of available rescue therapies for SR-ASUC, including biologics and small molecule treatments.

Aims & Methods

A systematic literature search was conducted using the MEDLINE, SCOPUS, and CENTRAL databases. Colectomy-free survival probabilities were extracted from Kaplan-Meier curves. A one-stage network meta-analysis using parametric Weibull regression was performed to estimate and compare the relative treatment effects of biologics and small molecule therapies. The primary outcome was colectomy-free survival at 4 and 12 weeks. This study was registered in PROSPERO (CRD420251030353).

Results

A total of 18 studies (5 randomized controlled trials and 13 cohort studies), including 1,706 patients with SR-ASUC, were included. Compared to placebo, standard-dose infliximab [hazard ratio (HR) 0.34, 95% CI: 0.20–0.60, p < 0.001], accelerated-dose infliximab [HR 0.38, 95% CI: 0.21–0.68, p = 0.001], and tofacitinib [HR 0.36, 95% CI: 0.19–0.69, p = 0.002] significantly improved colectomy-free survival. Cyclosporine also showed a trend toward reduced colectomy risk, though it did not reach statistical significance [HR 0.57, 95% CI: 0.31–1.01, p = 0.056]. There were no significant differences in overall adverse events or infection rates among the therapies. Based on SUCRA rankings, colectomy-free survival at both 4 and 12 weeks was highest for tofacitinib (SUCRA: 0.90 and 0.87), followed by accelerated-dose infliximab (0.95 and 0.85), standard-dose infliximab (0.87 and 0.83), and cyclosporine (0.81 and 0.74). (Figure 1 Colectomy free survival probability ; Kaplan-Meier curves)
Table 1. Pairwise table showing comparative efficacy in reducing colectomy risk of biologics and small molecule for SR-ASUC

Conclusion

Tofacitinib and accelerated-dose infliximab appear to be the most effective rescue therapies for improving colectomy-free survival in patients with SR-ASUC.

References

1. Dong C, Metzger M, Holsbø E, et al. Aliment Pharmacol Ther. 2020 Jan;51(1):8-33.
2. Honap S, Jairath V, Sands BE, et al. Gut. 2024 Sep 9;73(10):1763-1773.
3. Calméjane L, Laharie D, Kirchgesner J, et al. United European Gastroenterol J. 2023 Oct;11(8):722-732.
4. Choy MC, Seah D, Faleck DM, et al. Inflamm Bowel Dis. 2019 Jun 18;25(7):1169-1186.

Introduction

Janus kinase inhibitors (JAKi), including tofacitinib (TOFA, a pan-JAK inhibitor) and filgotinib (FILGO, a selective JAK1 inhibitor), represent an emerging class of orally administered agents for moderate-to-severe ulcerative colitis (UC). Comparative real-world data on their effectiveness and safety are limited.

Aims & Methods

We conducted a multicenter, real-world, propensity score-weighted cohort study using data from the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD). All adult UC patients treated with TOFA or FILGO with ≥16 weeks of follow-up were included. The primary outcomes were steroid-free clinical remission and clinical response at weeks 8 and 24. Treatment persistence and adverse events were also assessed. Inverse Probability of Treatment Weighting (IPTW) was applied to adjust for baseline differences.

Results

A total of 263 patients were included (TOFA: n=171; FILGO: n=92). At week 8, steroid-free clinical remission was achieved in 53.2% of patients treated with TOFA and 43.4% of those treated with FILGO (IPTW-adjusted OR: 1.51; 95% CI: 0.88–2.61; p=0.14). Clinical response at 8 weeks was reported in 75.4% of TOFA-treated patients versus 69.6% in the FILGO group (IPTW-adjusted OR: 1.34; 95% CI: 0.73–2.46; p=0.34). At week 24, steroid-free clinical remission was observed in 58.8% of the TOFA group and 44.9% of the FILGO group (IPTW-adjusted OR: 1.37; 95% CI: 0.76–2.49; p=0.30). Clinical response rates at 24 weeks were 63.6% for TOFA and 59.0% for FILGO (IPTW-adjusted OR: 1.13; 95% CI: 0.62–2.08; p=0.69). IPTW-adjusted Kaplan–Meier and Cox proportional hazards analyses showed no statistically significant difference in the likelihood of treatment discontinuation (log-rank p=0.294; IPTW-adjusted HR for TOFA: 0.78; 95% CI: 0.49–1.25; p=0.30). Adverse event rates were 12.7 and 5.4 per 100 person-years for TOFA and FILGO, respectively, with no significant difference (p=0.152).

Conclusion

In this real-world, IPTW-based study, TOFA and FILGO were well tolerated and demonstrated comparable and high effectiveness and treatment persistence in patients with moderate-to-severe UC, supporting their use as viable oral options in routine clinical practice.

Disclosure

FSM served as an advisory board member and/or received lecture grants from AbbVie, Ferring, Galapagos, Giuliani, Janssen, Lilly, Liohealth s.r.l., Pfizer, Sandoz, Takeda Pharmaceuticals. WF served as an advisory board member and/or received lecture grants from Abbvie, MSD, Takeda, Pfizer, Biogen, Sandoz, Zambon, Ferring, Sofar. AV received lecture grants from Pfizer. MC served as an advisory board member for AbbVie, MSD, Takeda Pharmaceuticals, and received lecture grants from AbbVie, MSD, Chiesi, and Takeda Pharmaceuticals. MC served as an advisory board member for AbbVie, MSD, Takeda Pharmaceuticals, and received lecture grants from AbbVie, MSD, Chiesi, and Takeda Pharmaceuticals. FM served as an advisory board member for Janssen and Galapagos, and received lecture grants from Takeda Pharmaceuticals. SR served as an advisory board member for AbbVie, Janssen, and MSD Pharmaceuticals, and received lecture grants from AbbVie, Galapagos, Janssen, MSD, Pfizer, and Takeda Pharmaceuticals. AO served as an advisory board member for AbbVie, Ferring, Galapagos, Lilly, MSD, Janssen, Pfizer, Samsung Bioepis, and Takeda Pharmaceuticals, and received lecture grants from AbbVie, Fresenius Kabi, Galapagos, Lionheath s.r.l., MSD, Sofar, Chiesi, Janssen, Pfizer, and Takeda Pharmaceuticals. All other authors: nothing to disclose.