Introduction

To compare the efficacy of different modalities of FMT to induce clinical remission in patients with ulcerative colitis (UC).

Aims & Methods

We performed a systematic review and network analysis (random effects model) of randomized controlled trials including at least one arm of FMT in
adult patients with active UC.
Primary endpoint, i.e. clinical remission (total Mayo score ≤ 2 with Mayo endoscopic score ≤ 1), was assessed between week 6 and 12. Results are expressed as relative risk with 95% confidence intervals, adjusted for bowel cleansing and pre-FMT antibiotics therapy.
Ranking of FMT modalities for clinical remission was calculated as their surface under the cumulative ranking (SUCRA), which represents the percentage of efficacy achieved by an agent compared with an imaginary agent that is always the best without uncertainty. Heterogeneity among studies was evaluated by τ (global statistical heterogeneity across all comparisons).

Results

Among the 12 selected studies, patients were exclusively bio-naïve in 4 studies (4/12), while between 9 and 32% had prior biologics exposure in the other trials. Risk of bias was low across all domains in 7 studies. Global heterogeneity was negligible (τ = 0). After adjustment on bowel cleansing and pre-FMT antibiotics, oral capsule (RR=7.1[1.8-33.3]), lower GI FMT (RR=4.5[1.7-12.5] and combination of both (RR=12.5[2.1-100]) were more effective than placebo to induce clinical remission contrary to upper GI FMT (RR=1.1[0.2-7.7]) and autologous FMT (RR = 0.8 [0.2-3.8]. The combination of lower GI FMT and oral capsule was significantly more effective than upper GI FMT to induce clinical remission (RR=10.7[1.1-104.2]). Combination of lower GI FMT and oral capsule ranked highest for the induction of clinical remission (SUCRA=0.93), followed by oral capsule (SUCRA=0.82) and lower GI FMT (SUCRA=0.72). Autologous FMT ranked lower than placebo (SUCRA=0.12 vs 0.22). We performed a sensitivity analysis distinguishing single donor FMT and multi-donor FMT (pooled samples from different donors). Combination of lower GI FMT and oral capsule ranked highest for the induction of clinical remission (SUCRA=0.89), followed by single donor lower GI FMT (SUCRA = 0.70), multi-donor (pooled samples) lower GI FMT (SUCRA = 0.65), multi-donor (pooled samples) oral capsule (SUCRA = 0.61), single donor oral capsule (SUCRA = 0.60).

Conclusion

In this network meta-analysis, we confirmed the efficacy of FMT to induce clinical remission in patients with UC. The combination of lower GI and oral capsule FMT seems to be the best modality of FMT for patients with UC while upper GI FMT is not suitable. In clinical trials, autologous FMT should be avoided due to a potential detrimental effect.

Disclosure

Anthony BUISSON: Consulting fees for Abbvie, Amgen, Arena, Biogen, Celltrion Healthcare, CTMA, Galapagos/Alfa Sigma, GutyCare/Resilience, Janssen, MSD, Nexbiome, Pfizer, Roche, Sandoz, Takeda, Tillotts. And Viatris. Lecture fees for Abbvie, Amgen, Biogen, Celltrion Healthcare, Galapagos/Alfa Sigma, Janssen, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma. Research grants from: Abbvie, Celltrion Healthcare, Galapagos/Alfa Sigma, Janssen, Lessaffre, Lilly, Pfizer, Takeda.

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

The therapeutic landscape for ulcerative colitis (UC) is rapidly evolving, with an increasing number of biologic agents available.

Aims & Methods

This systematic review and meta-analysis synthesised randomised controlled trials (RCTs) data on biologic therapies for achieving key endoscopic and histologic endpoints in moderate to severe UC. A systematic search of MEDLINE, EMBASE, Cochrane Library, Web of Science and grey literature was conducted through November 2024. Separate meta-analyses were performed for induction and maintenance. A random-effects model was used to estimate relative risks (RR), with 95% confidence intervals (CI) and confidence in estimates was evaluated with the GRADE approach (Grading of Recommendation Assessment, Development and Evaluation).

Results

We included 40 RCTs (13 therapies , 14,369 patients). Thirty-two trials provided data in induction phase and twenty-eight in maintenance phase. During induction phase, all biologic therapies except for mirikizumab and filgotinib 100 mg demonstrated superiority over placebo (RR 2.02, 95% CI:1.76–2.31, I²=72%) for endoscopic improvement. Upadacitinib showed the highest efficacy (RR 5.53, 95% CI: 3.78-8.09). In biologic-naive patients and in patients with no previous biologic failure status upadacitinib 30mg had the highest efficacy (RR 4.07, 95% CI:2.69-6.16). In biologic-exposed patients or those with previous biologic failure, upadacitinib 30mg also showed the greatest benefit (RR 10.52, 95% CI:4.55-24.34). For induction of mucosal healing, all interventions were superior to placebo (RR 2.95, 95% CI:2.11–4.13,I²=61%), except for filgotinib 100 mg. Risankizumab showed the highest efficacy (RR 10.25, 95% CI:2.49-42.11). In maintenance phase, all therapies showed superiority over placebo for endoscopic improvement. Upadacitinib showed the highest efficacy (RR 4.18, 95% CI: 2.79–6.27). In biologic-naïve patients or those without prior biologic failure, all interventions—except filgotinib 100 mg and vedolizumab—were significantly superior to placebo, with etrasimod showing the highest efficacy (RR 3.12, 95% CI: 1.79–5.43). Among biologic-exposed patients or those with prior biologic failure, upadacitinib, mirikizumab, ustekinumab, etrasimod, tofacitinib, and risankizumab 180 mg were significantly superior to placebo. Upadacitinib showed the highest efficacy (RR 7.58, 95% CI: 3.42–16.8). For mucosal healing all therapies were superior to placebo, except for risankizumab. Upadacitinib showed the highest efficacy (RR 4.01 ,95% CI: 1.81–8.87). In biologic-naïve patients or those without prior biologic failure, only etrasimod, mirikizumab, upadacitinib 30 mg and subcutaneous infliximab were significantly superior to placebo, with upadacitinib showing the highest efficacy (RR 3.02, 95% CI: 1.18–7.71). Among biologic-exposed patients or those with prior biologic failure, only etrasimod, mirikizumab, and upadacitinib were significantly superior to placebo, with etrasimod demonstrating the highest efficacy (RR 9.45, 95% CI: 1.31–68.36).

Conclusion

Biologic and small-molecule therapies demonstrated substantial efficacy in achieving key endoscopic and histologic endpoints in moderate to severe UC. Upadacitinib consistently showed the highest efficacy across both induction and maintenance phases. Stratified analyses revealed enhanced response rates in biologic-naïve patients, supporting early initiation of advanced therapies. Our findings highlight the importance of individualised treatment strategies and the urgent need for standardised endpoint definitions to enhance comparability across future trials.

Introduction

Refractory ulcerative proctitis (UP) represents a clinical conundrum, often necessitating systemic therapy for localised disease. Faecal microbiota transplant (FMT) has proven efficacy for remission induction ulcerative colitis, yet has not been evaluated in UP.

Aims & Methods

Aims: To undertake a prospective open-label study examining the safety and efficacy of Faecal Microbiota Transplant (FMT) enema therapy for management of resistant ulcerative proctitis (UP).
Methods: Patients with mild-moderately active UP (total Mayo score 3-10 with endoscopic Mayo subscore ≥ 1) resistant to 5-Aminosalicylates (5-ASA) were prospectively enrolled. After an initial conditioning phase of vancomycin therapy and dietary education, participants received six anaerobically prepared single donor FMT retention enemas over an eight-week period. The primary end point was clinical and endoscopic remission (total Mayo score ≤2) at 8 weeks. Secondary endpoints included safety, histological remission and patient reported outcomes (Inflammatory Bowel Disease Questionnaire). Disease activity assessments including clinical, endoscopic, histological and quality of life measures were performed at week 0 and week 8 to assess response to FMT therapy. Systematic adverse event reporting was completed at each study visit.

Results

Among 30 participants enrolled (mean age 41 years, 17 (57%) women) , 26 completed the study protocol. Clinical and endoscopic remission was achieved in 10 patients (33.3%).
Serious adverse events necessitating study withdrawal occurred in 3 enrolled patients due to flare of UP (n=2) and Clostridioides difficile (C. difficile) colitis (n=1).

Conclusion

FMT enema therapy was well tolerated and demonstrated efficacy in inducing clinical and endoscopic remission in resistant UK. The role of antibiotic preconditioning of recipients and choice of antibiotic therapy remains unclear. Further controlled studies in this area are warranted.

References

Disclosure

SSR does not have any conflicts of interest to declare. This project did not receive any financial support from any organisation or institution. FMT enemas were supplied in kind by BiomeBank. CKR has received research funding from AstraZeneca, Merck Sharp & Dohme, Eli Lilly and Company, Novartis, and Sanofi and has participated in advisory boards for Allergan (now AbbVie). SPC has received advisory, speaking fees, or research support from Ferring, Shire, Microbiotica and Janssen. RVB has received grant/research support/speaker fees (all paid to employer for research support): AbbVie, Ferring, Janssen, Shire, Takeda, Emerge Health. SPC and RVB are shareholders in BiomeBank.

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

Faecal microbiota transplantation (FMT) may induce remission in patients with ulcerative colitis (UC), however the mechanisms through which this occurs are unknown. Lipids mediate inflammation and contribute to the pathophysiology of inflammatory bowel diseases. We therefore hypothesise that the faecal lipidome mediates treatment response in UC patients undergoing FMT.

Aims & Methods

We aimed to investigate the faecal lipidome using ambient mass spectrometry to identify metabolites that mediate treatment response. Patients were recruited from a single-centre, single-blinded randomised controlled trial consisting of 18 treatment-naïve UC patients (ISRCTN58082603). All patients were pre-treated with antibiotics and underwent bowel lavage. Patients were divided into three intervention groups: 1) A single FMT enema (n=7) 2), five consecutive FMTs enema’s within five days (n=7) and 3) a control group given antibiotics and bowel lavage only (n=4). Fresh faecal samples were taken before and one-, four-, eight- and twelve weeks after FMT treatment. Response was evaluated as endoscopic remission or a drop of ≥2 points in the partial Mayo score. High-throughput laser assisted-rapid evaporative ionization mass spectrometry (LA-REIMS) set-up (Xevo G2-S QT of mass spectrometer (Waters Corporation)) as an approach for shotgun lipidomics was used. After pre-processing of the LA-REIMS data, univariate and multivariate statistics were performed using Metaboanalyst 5.0 and an in-house developed bioinformatic pipeline to build predictive models of response using leave-one-patient-out cross-validation.

Results

From 18 patients with a median age of 42 (range 18-70), male 7 (39%), 6/14 patients in the FMT intervention and 2 patients in the control group demonstrated an endoscopic response. The metabolic variance based on Partial Least-Squares Discriminant Analysis between FMT treatment and control group at baseline was not significant (R2=0.39, Q2=0.32 and diagnostic accuracy of 0.84). However, responders and non-responders demonstrated a different pre-treatment faecal lipidomic profile (R2=0.78, Q2=0.66 and diagnostic accuracy of 0.93). This persisted 12 weeks after FMT treatment (R2=0.96, Q2=0.92 and diagnostic accuracy of 1.0). Within group metabolic variances of the lipidome were also visible. For example, the pre- and post-intervention faecal lipidome discretely varied in those UC patients who responded to FMT (R2=0.63, Q2=0.52 and diagnostic accuracy of 0.92). Interestingly, a moderate variance was also seen in the control group before and after treatment with only antibiotics and bowel lavage (R2=0.87, Q2=0.78 and diagnostic accuracy of 0.98). Univariate analysis demonstrated fatty acids and glycerophospholipids explained much of this variance and they were statistically different between responders and non-responders to FMT treatment (FDR adjusted p<0.05). Tentative metabolite identification of the m/z values in statistically important metabolites suggested that cholesterol sulfate (465.304 m/z), pantothenic acid (218.102 m/z, vitamin B5) were statistically more likely to be excreted in patients who responded to an intervention, although they do not mediate inflammation per se.

Conclusion

FMT sustainably modifies the faecal lipidome in UC patients that respond to FMT, suggesting a role for the lipidome in driving remission. However, influenced by both donor and host’s faecal lipid metabolism. Future and ongoing work involve time-series analyses of significant metabolites during different time points in the course of the treatment.

Disclosure

James Kinross is an advisor to Intus Biosciences

Introduction

As no direct comparison between IBD drugs to prevent endoscopic postoperative recurrence (POR) in Crohn’s disease (CD) are available, hierarchizing these therapeutic options remains challenging.

Aims & Methods

The objective of this network meta-analysis was to compare the effectiveness of treatments to prevent endoscopic POR of CD.
We performed a systematic review and network meta-analysis of comparative studies conducted in adults, evaluating a treatment to prevent endoscopic POR after ileocecal resection. The selection of studies was made according to PRISMA guidelines. The primary endpoint was endoscopic POR at 6 months defined as Rutgeerts score ≥ i2.
The network meta-analysis was carried out according to a random effects model. The results are presented as odds ratio (OR) with 95% confidence interval, adjusted for risk factors of POR. 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

Twenty studies were included in this network meta-analysis, including a total of 2414 patients. Overall heterogeneity was moderate (τ =0.34). After adjustment for POR risk factors, ustekinumab (OR = 0.23 [0.07-0.70]), vedolizumab (OR = 0.17 [0.05 -0.59]), infliximab (OR = (0.18 [0.36-0.88]) and adalimumab (OR = 0.17 [0.07-0.42]) were superior to placebo to prevent endoscopic POR, contrary to 5-ASA (OR = 0.79 [0.42 -1.48]) and thiopurines (RR = 0.52 [0.22-1.24]) (Table 1). Ustekinumab (OR = 0.29 [0.08-0.99]), vedolizumab (OR = 0.22 [0.06-0.85]), infliximab (OR = (0.23 [0.09-0.54]) and adalimumab (OR = 0.22 [0.08-0.59]) were more effective than 5-ASA in preventing endoscopic POR. Adalimumab (OR = 0.33 [0.15-0.74]) and infliximab (OR = 0.34 [0.13-0.87]) were also more effective than thiopurines.
We observed no difference in efficacy between the 4 biologics (infliximab, adalimumab, ustekinumab and vedolizumab). The SUCRA ranking identified adalimumab (SUCRA = 0.81), infliximab (SUCRA = 0.80), vedolizumab (SUCRA = 0.79) and ustekinumab (SUCRA = 0.72) as the most effective treatments. The probability that thiopurines (SUCRA = 0.41), 5-ASA (SUCRA = 0.24), placebo (SUCRA = 0.16) and antibiotics (SUCRA = 0.08) were significantly higher weak.

Conclusion

This network meta-analysis confirms the efficacy of anti-TNF agents, vedolizumab and ustekinumab in preventing endoscopic CD POR without any difference between them. When prophylactic therapy is indicated, biologics appear as the best therapeutic option to prevent of endoscopic POR. Due to lower effectiveness, the use of 5-ASA and thiopurines should be limited in this situation.

Disclosure

Anthony BUISSON: Consulting fees for Abbvie, Amgen, Arena, Biogen, Celltrion Healthcare, CTMA, Galapagos/Alfa Sigma, GutyCare/Resilience, Janssen, MSD, Nexbiome, Pfizer, Roche, Sandoz, Takeda, Tillotts. And Viatris. Lecture fees for Abbvie, Amgen, Biogen, Celltrion Healthcare, Galapagos/Alfa Sigma, Janssen, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma. Research grants from: Abbvie, Celltrion Healthcare, Galapagos/Alfa Sigma, Janssen, Lessaffre, Lilly, Pfizer, Takeda.