Introduction

Capsule retention is the main adverse event of SBCE. Current guidelines support the use of conservative/medical treatment for asymptomatic patients. However, the appropriate duration of conservative and medical therapy, the optimal regimens, and the timing to perform DAE/surgery in asymptomatic patients is still largely undefined.

Aims & Methods

Through a systematic search of multiple electronic databases until November 2023, studies including CD patients undergoing capsule endoscopy (CE) were identified. Capsule retention was defined according to ICCE criteria.

Results

We included 42 studies, totaling 196 capsule retentions in CD patients. Of these, 50 underwent anti-inflammatory therapy, consisting of corticosteroids (n= 34); corticosteroids + antibiotics (n=1), and corticosteroids + infliximab (n= 15). Steroids allowed for spontaneous passage in 44% (n=22): 3 out of 16 asymptomatic patients; 3 out of 5 symptomatic without complete small bowel
occlusion (SBO); 2 in 3 with complete SBO. Combination with infliximab solved the retention in further 6 out of 15 patients. Mean time to resolution was 6,9 days (R 15h-21d), which was reported in 6 patients. Steroid administration route was reported in 2 patients (intravenous) and dosage in 3 patients: 100mg for 3 days, 1.2 mg/kg/day for 17 days, 0.5 mg/kg/day for 17 days, the latter being unsuccessful. Conservative treatment only or after failed medical therapy was used in 19 asymptomatic patients, with spontaneous passage in 6. One study reports retention of a capsule for 8.5 years. Of patients undergoing medical treatment 3 underwent urgent and 15 programed surgeries.

Conclusion

Evidence was of low quality. Treatment duration, regimen and time to spontaneous passage was underreported. We were unable to find predictors of the need to perform DAE/surgery in asymptomatic patients. As capsule retentions are increasingly rarer, the available evidence is unlikely to change.

Introduction

5-aminosalicylates (5-ASAs) are commonly used in patients with Crohn’s disease (CD), especially in mild-to-moderate disease. Over half of patients receive 5-ASA during their disease course, with up to 30% continuing long-term therapy for either active (induction of remission) or quiescent (maintenance of remission) disease. However, the evidence regarding their efficacy is mixed, with conflicting findings in systematic reviews (SRs). In preparation for the results of the STATIC trial (NCT 03261206)¹, we conducted an umbrella review to consolidate existing knowledge by identifying, evaluating, and synthesizing findings from published SRs on the use of 5-ASA in patients with active or quiescent CD.

Aims & Methods

Following Cochrane guidelines for "Overviews of Reviews" and adhering to the Preferred Reporting Items for Overviews of Reviews (PRIOR), we systematically searched major databases for relevant SRs published in English until February 28, 2024, summarizing data on 5-ASA use in induction, maintenance, or withdrawal trials of CD. We excluded SRs focusing solely on post-surgical patients or studying the chemoprevention effects of 5-ASA. Two independent reviewers screened articles, extracted data, and assessed quality using AMSTAR 2.

Results

Of 795 screened references, 8 SRs met our inclusion criteria, with the number of included RCTs ranging from 2 to 22 (Table). Most SRs included RCTs of patients with mild-to-moderate ileo-colonic CD. Three SRs focused on induction of remission, two on maintenance of medically induced remission, and three included both, while none investigated withdrawal of therapy. Two SRs were network meta-analyses (NMA) comparing 5-ASAs with other active treatments or placebo; four were Cochrane systematic reviews comparing 5-ASAs with placebo, corticosteroids, or thiopurines (AZA or 6-MP). One SR, published in 2017,used the outdated Jadad scale to assess the risk of bias of RCTs; only Cochrane reviews assessed the level of certainty of evidence. The latest NMA in 2017, including 22 RCTs for induction of remission, suggested that high-dose mesalamine was more effective than placebo, ranking higher than low-dose budesonide and sulfasalazine, though lower than systemic corticosteroid and high-dose budesonide. Conversely, the latest Cochrane review in 2016, including 12 RCTs for maintenance of remission, found no evidence of benefit for oral 5-ASAs over placebo for maintaining medically induced remission. No SRs performed subgroup analysis for duration of remission upon enrollment. Only the NMA conducted a sensitivity analysis to evaluate baseline disease activity, indicating that high-dose mesalamine was superior to placebo when restricted to RCTs with an enrollment CDAI between 150 to 450.

Review Type (NMA or SR+MA or SR only)	Author, year	Search date (up to)	Searched database	Number of included studies/ study designs	Study Eligibility	Adults or pediatric	Induction trials, maintenance trials, or both	Intervention (5ASA) / dose/treatment duration/follow-up duration (range)	Comparisons (Control regimens, dose)/duration	Key conclusions related to 5-ASA
NMA	Coward, 2017	Nov 2015	Cochrane reviews, Medline, EMBASE, CENTRAL	22 RCTs (mesalamine =9, sulfasalazine=4)	RCTs comparing budesonide, sulfasalazine, mesalamine, or systemic corticosteroids with placebo in CD	Adults	Induction	Sulfasalazine: 1 g/15 kg /d to 3 g /d; 6 - 17 wk Mesalamine: 1- 4 g /d; 8-16 wk (above and below 2.4 g/d as high vs low dose)	Placebo, systemic corticosteroids, budesonide	Treatment ranking for induction from best to worst: systemic corticosteroid> high dose budesonide > high dose mesalamine > (low dose budesonide = sulfasalazine)> low dose mesalamine > placebo. Mesalamine at doses above 2.4 g/day was more effective than placebo for the induction of remission in CD, this finding was shown in NMA but not the traditional MA. High dose mesalamine may be an option among patients preferring to avoid steroids. Sulfasalazine was not significantly superior to any therapy including placebo.
SR + MA	Chen, 2017	May 2014	Pubmed/Medline, EMBASE, ISI Web of Knowledge, CINAHL, COCHRANE Database of Systematic Reviews, CBM, CNKI, ChiCTR	Total 8 RCTs, but 6 for CD	RCTs of AZA or 6-MP vs 5-ASA	Adults	Both	AZA: 2-3 mg/kg/d; 1-3 yr 6-MP: 50 mg/d; 2 yr	Mesalamine: 3-4 g/d ; 1-3 yr	Thiopurines (AZA/6-MP) are more effective that 5-ASA for the treatment of CD (clinical relapse rate and remission rate).
SR+MA (Cochrane review)	Akobeng, 2016	Jun 2016	MEDLINE, EMBASE, CENTRAL, Cochrane IBD group specialized register	12 RCTs	5-ASA agents vs either placebo or sulfasalazine in quiescent CD	Both	Maintenance	5-ASA: 1.6 g to 4 g/d; 12-24 mo dose 50 mg/kg/d />6 mo	Placebo	No evidence to suggest that oral 5-ASA preparations are superior to placebo for the maintenance of medically induced remission in patients with CD.
SR+MA (Cochrane review)	Chande, 2016	Oct 2015	MEDLINE, EMBASE and the Cochrane Library	13 RCTs, only two compared vs 5-ASA	RCTs of AZA and 6-MP for induction of remission in active CD (5-ASA as one of the comparative arms). One study 6-MP vs 5-ASA, one study AZA vs sulfasalazine; the two studies were pooled together	Adults	Induction	AZA and 6MP: NR ;NR	Mesalamine: 3 g/d; 30 wk Sulfasalazine: NR; 17 wk	Overall quality of the evidence for both outcomes was low to very low due to sparse data.
SR + MA (cochrane review)	Lim, 2016	Jun 2015	PubMed, EMBASE, MEDLINE, and the cochrane Central Library	20 RCTs	5-ASA drugs (sulfasalazine & mesalamine) vs placebo, corticosteroids, and other 5-ASA (alone or in combo with corticosteroids) in mild to moderate active CD	Adults	Induction	Mesalamine: 1 - 4.5 g /d; 6-16 wk Sulfasalazine: NR; up to 18 wk	Placebo, corticosteroids, other 5-ASA alone or in combination with corticosteroids	Sulfasalazine is modestly effective compared to placebo and inferior to corticosteroids for the treatment of mild to moderate active CD. Olsalazine and low dose mesalamine (1-2g/d) are not superior to placebo. High dose mesalamine (3.2-4g/d) is not more effective than placebo for inducing response or remission. High dose mesalamine (4-4.5g/d) has conflicting results compared to budesonide.
SR + MA (cochrane review)	Chande, 2015	Jun 2016	MEDLINE, EMBASE, and the Cochrane Library	11 RCTs (only two RCTs included mesalamine or sulfasalazine, published in 2000 and in 1979)	RCTs of AZA and 6-MP for maintenance of remission in active CD (5-ASA was one of the comparative arms). One study compared 6-MP to 5-ASA, one study compared AZA to sulfasalazine- the two studies were pooled together in meta-analysis	Adults	Maintenance	6-MP: 1 mg kg/ d Methotrexate: 10 mg/wk; 76 weeks AZA: 1- 2.5 mg/kg/ d	5-ASA: 3g/d; 76 wk	Only two RCTs; no statistically significant difference in the proportion of patients who maintained remission between AZA (1.0 to 2.5 mg/kg/day) or 6-MP (1.0 mg/day) and mesalamine (3 g/day) or sulfasalazine (0.5 g/15 kg/day) therapy.
NMA	Moja, 2015	Oct 2014	MEDLINE, EMBASE, the Cochrane library and clinicaltrials.gov	25 RCTs (induction =11, maintenance n=14)	Budesonide or mesalamine vs placebo or against each other in active or quiescent CD	Adults	Both	Mesalamine: 1 - 4 g/d; 6 wk for induction, 6 mo for maintenance Budesonide: 3 -18 mg/d; 6 wk for induction, 6 mo for maintenance	Placebo or mesalamine or budesonide in different doses	Budesonide 9mg/d or higher for induction of remission in active mild-to-moderate CD and 6mg/d for maintenance of remission appears to be the best treatment choice. Mesalamine is not effective in induction of remission and preventing relapse in mild-to moderate CD.
SR + MA	Ford, 2011	Dec 2011	MEDLINE, EMBASE, Cochrane central register	23 RCTs (active CD n=7, quiescent CD n=13, in active and quiescent CD=3)	5-ASA drugs (sulfasalazine, mesalamine, balsalazide, olsalazine) vs placebo or no treatment in quiescent or active CD.	Adults	Both	Sulfasalazine: 1 g/15 kg /d to max 5 g/d Mesalamine: 1 - 4 g/d Olsalazine: 2 g /d; 4-12 mo Duration in active CD: 6 wk - 4 mo, in quiescent CD: 6-48 mo	Placebo or no treatment	The role of 5-ASA in inducing remission of active CD and preventing relapse of quiescent CD remains uncertain.

Conclusion

The results of this umbrella review of SRs suggest that high-dose mesalamine may be considered for inducing remission in mild-to-moderate CD. However, evidence does not support the role of 5-ASA for maintaining medically induced remission. Updating SRs with new evidence is imperative to provide guidance on patient subsets who may benefit from 5-ASA use and these results will be updated with the STATIC trial ¹.

References

1. NCT03261206. Stopping Aminosalicylate Therapy in Inactive Crohn's Disease (STATIC) https://classic.clinicaltrials.gov/ct2/show/NCT03261206

Introduction

The Montreal classification reflects the varying phenotypes of Crohn’s including location and behaviour, however the majority of trials to date, despite including Montreal classification in baseline characteristics, do not report treatment efficacy by disease location. Ileal disease is associated with a higher risk of progression to stricturing and penetrating complications.

Aims & Methods

To perform a systematic review summarising the evidence for different biologic and advanced therapies available for small bowel Crohn’s disease in adult patients.
Systematic search of MEDLINE and EMBASE was conducted. Articles were then screened, duplicates removed. Inclusion criteria included trials with efficacy outcomes stratified via disease location. Primary outcome was drug efficacy, measured via endoscopic response, healing, clinical remission or improvement of MRI severity scores.

Results

A total of 868 publications were screened and assessed for eligibility following database screening and removal of duplicates. 12 studies were included with 746 patients, with a total median follow up of 52 weeks(range 14-165). All studies were included in qualitative analysis; Infliximab (6 trials n=404) Adalimumab (4 trials n=204), Vedolizumab (2 trials n=50), Ustekinumab (1 trial n=28), Filgotinib (1 trial n=60).
Of the 6 infliximab studies (n=404), 3 reported on endoscopic response (ER) and 2 endoscopic healing (EH) via double balloon enteroscopy, 2 reported on clinical outcomes only and 1 reported on improvements in MRI outcomes, as detailed in the below table. Median follow up was 52 weeks.

First author	Year	N	Design	Drug	Outcome	Follow up
Huang	2025	110 64 28 18	R	IFX UST VEDO	EH 29.6% (19/64) ER 42.2% (27/64) UH 35.9% (23/64) EH 10.7%(3/28) ER 28.6% (8/28) UH 17.9% (5/28) EH 5.5% (1/18) ER 11.1% (2/18) UH 11.1% (2/18)	52 weeks
Wei	2024	111	R	IFX	ER 42.3% (47/111) MH 29.7% (33/111)	32 months
Han	2021	91	R	IFX	DR(CR+MH) 47.2% (42/91)	14 weeks
Chen	2021	79	R	IFX	CR 46.8% (37/79)	38 months
Zorzi	2012	44 34 (I) 28 (M)	O	IFX – Induction (I) Maintenance(M)	CR 74% (20/28)	54 weeks
Van Assche	2013	15	P	IFX	MRI improvement 40% (6/15)	26 weeks

IFX=Infliximab, ADA=Adalimumab, VEDO=Vedolizumab,
EH= Endoscopic healing(defined as a modified SES-CD <3 or 0 if jejunal/proximal ileum), ER=Endoscopic Response(defined as a reduction of SES-CD by more than 50% at both segmental and complete level), UH=Ulcer Healing (defined as no inflammation, ulcers or erosions), MH=mucosal healing(SES-CD=0), DR=Deep Remission, CR=Clinical Remission

There were 4 trials for adalimumab (n=204), 2 trial outcomes reported on EH(53.3%) and ER on capsule (42%). Two trials focused on clinical response rates; 64-66%[iii][iv]. Median follow up was 52 weeks (range 24-154).
Ustekinumab data (n=28) was available from Huang et al who reported EH in 10.7%(3/28), ER in 28.6% (8/28) and UH rates of 17.9% (5/28).
Two retrospective studies reported on Vedolizumab outcomes(n=50); reporting on EH 5.5% (1/18), ER 11.1% (2/18), UH 11.1% (2/18) [v] and another study (n=36) reported on CT and MRI outcomes for ileal Crohn’s reporting a 22% (7/32) imaging response based on EMBARK scoring[vi]. Both studies had 52 week follow up.
One RCT involving two doses of Filgotinib reported rates of clinical remission (based on CDAI<150 at week 24) of 25% in both groups[vii] and secondary outcomes of MRI remission (based on MaRIAseg<7) in 6.3%(2/32) of 100mg arm and 8%(2/25) of the 200mg arm.

Conclusion

Robust retrospective data exists for small bowel mucosal healing with anti-TNF therapy. Data is lacking for vedolizumab, ustekinemab and newer smaller molecule therapies. Dedicated clinical trials are needed to specifically investigate the effectiveness of therapies in isolated ileal Crohn’s disease patients to optimise their management.

References

[i] ‘Mucosal Healing and Clinical Efficacy of Adalimumab in Small Intestinal Crohn’s Disease (SIMCHA Study): Final Results From a Prospective, Open-Label, Single-Arm Study’, The Turkish Journal of Gastroenterology 34, no. 6 (9 June 2023): 603–10, https://doi.org/10.5152/tjg.2023.22527.
[ii] Barry Hall et al., ‘A Prospective 52week Mucosal Healing Assessment of Small Bowel Crohn’s Disease as Detected by Capsule Endoscopy’, Journal of Crohn’s and Colitis 8, no. 12 (December 2014): 1601–9, https://doi.org/10.1016/j.crohns.2014.09.005.
[iii] Yoram Bouhnik et al., ‘Efficacy of Adalimumab in Patients with Crohn’s Disease and Symptomatic Small Bowel Stricture: A Multicentre, Prospective, Observational Cohort (CREOLE) Study’, https://doi.org/10.1136/gutjnl-2016-312581.
[iv] F. Zorzi et al., ‘Efficacy and Safety of Infliximab and Adalimumab in C Rohn’s Disease: A Single Centre Study’, https://doi.org/10.1111/j.1365-2036.2012.05100.x.
[v] Zi-Cheng Huang et al., ‘Effectiveness of Biologics for Endoscopic Healing in Patients with Isolated Proximal Small Bowel Crohn’s Disease’, https://doi.org/10.3748/wjg.v31.i7.98448.
[vi] Lukasz Kwapisz et al., ‘CT or MR Enterography to Assess Response During Vedolizumab Therapy for Small Bowel Crohn’s Disease’, https://doi.org/10.1093/crocol/otac003.
[vii] Geert R. D’Haens et al., ‘Filgotinib for the Treatment of Small Bowel Crohn’s Disease: The DIVERGENCE 1 Trial’, https://doi.org/10.1053/j.gastro.2023.03.234.

Introduction

There is an increasing diversification in the treatment landscape for Crohn’s disease (CD) driven by heterogeneity of individual phenotypes, disease courses and previous treatments. This complexity makes universal evidence-based algorithms challenging. A “treat-to-target approach” with tight inflammation monitoring after starting biologics or small molecules therapy is recommended. Intestinal ultrasound (IUS) has proven effective in monitoring treatment response in large CD cohorts. Transmural healing (TH) is a robust but puzzling endpoint that can be achieved in about one-fourth of patients treated with biological therapy and few prognostic indicators to predict it were analyzed.

Aims & Methods

We aimed to describe treatment patterns and effective therapeutic sequences to achieve TH. Secondary aim was to identify prognostic factors to predict TH. This retrospective analysis included CD patients treated with biological and small molecules therapies according to the ECCO recommendations. Patients received biological and small molecules therapies across up to four treatment lines. Biological and small molecules treatment pathways prior to achieve TH were visualized using a Sankey diagram. IUS outcomes were evaluated one year after each biological and small molecules therapy. Logistic regression analysis was performed to identify clinical predictive factors of TH, that was defined as bowel wall thickness <3 mm and no vascularization at IUS.

Results

Among 139 patients treated with biological and small molecules therapies, TH was achieved in 25.9% (n = 36). Infliximab was used as the first-line agent in 55 patients (39.6 %), adalimumab in 69 (49.6%), vedolizumab in 6 (4.4%), certolizumab pegol in 1 (0.7%), Ustekinumab in 8 (5.7%). Twenty-five patients (20%) achieved TH after the first-line therapy (n=10 with infliximab; n=9 with adalimumab; n=3 with vedolizumab; n=3 with ustekinumab). TH rates declined with each additional line of therapy. The median time to achieve TH was 25.6 months (range 12–60). Treatment sequencing analysis revealed a progressive shift toward ustekinumab in later lines, with anti-TNFs remaining the most frequent first-line agents. Multivariate analysis showed that colonic lesion and early treatment (within 2 years from diagnosis) were associated with a higher likelihood of achieving TH [OR = 7.76, p<0.001; OR 6.705, p<0.001, respectively], while perianal disease was associated with a lower likelihood of TH [OR 0.151, p=0.02].

Conclusion

This study highlights a progressive decline in TH rates with successive lines of biological and small molecule therapies in CD patients and identifies several clinical factors that influence this outcome. Long-term follow-up and prospective studies specifically designed to evaluate sequencing in patients exposed to anti-TNFs are needed to guide challenging decisions.

Introduction

The number of patients with inflammatory bowel disease (IBD) refractory to different biologic classes and small molecules is growing. Combining mechanisms of action seems to be the key to breaking the therapeutical ceiling; however, the available evidence is still limited and of low quality.

Aims & Methods

We conducted a systematic review and meta-analysis to summarize the available data on the safety and effectiveness of different combinations of biologics and small molecules in Crohn's disease, ulcerative colitis, and indeterminate colitis.
Through a systematic search of multiple electronic databases until March 1, 2023, we included studies with two or more patients on dual biologic therapy or in combination with small molecules due to active intestinal disease.
We reported effectiveness as pooled rates of clinical and endoscopic response and remission. Safety was assessed as pooled rates of adverse events and serious adverse events for each combination. The quality of evidence was rated according to the Critical Appraisal Skills Programme checklist.

Results

We included 28 studies - 2 randomized controlled trials and 26 observational studies - with 499 patients on 7 different combinations (Anti-TNF + Vedolizumab/Ustekinumab/Tofacitinib/Natalizumab/Goselkumab or Vedolizumab + Ustekinumab/Tofacitinib). The most common was tumor Anti-TNF & anti-integrins (n=96).
In patients mostly refractory to monotherapy due to active intestinal disease, combination therapy resulted in pooled clinical and endoscopic remission rates of 48% (CI 0.44-0.52) and 32% (CI 0.26-0.39), respectively. Pooled clinical and endoscopic response rates were 76% (CI 0.65-0.85) and 52% (CI 0.46-0.58), respectively.
Pooled serious adverse event rates (SAE) were 9% (CI 0.06-0.11), with Anti-TNF + Ustekinumab (n=19)/Natalizumab (n=52) and Ustekinumab + Tofacitinib (n=22), being the safest options with no registered SAE.
Heterogeneity was significant only for pooled rates of adverse events. The certainty of the evidence was low due to the nature and inconsistencies between the included studies. Most of the studies failed to report the outcomes based on the disease subtype and specify which biological agent was used when an anti-TNF was part of the combination. Only one study had a control arm with monotherapy.

Conclusion

Combining Biologics and Small Molecules appears safe and possibly effective in patients with IBD. New trials with higher-quality data will be detrimental to generalizing access to this approach.

References

Alayo QA, Fenster M, Altayar O, Glassner KL, Llano E, Clark-Snustad K, Patel A, Kwapisz L, Yarur AJ, Cohen BL, Ciorba MA, Thomas D, Lee SD, Loftus EV Jr, Fudman DI, Abraham BP, Colombel JF, Deepak P. Systematic Review With Meta-analysis: Safety and Effectiveness of Combining Biologics and Small Molecules in Inflammatory Bowel Disease. Crohns Colitis 360. 2022 Feb 10;4(1):otac002. doi: 10.1093/crocol/otac002. PMID: 35310082; PMCID: PMC8924906.
Mas, E.B.; Calvo, X.C. Selecting the Best Combined Biological Therapy for Refractory Inflammatory Bowel Disease Patients. J. Clin. Med. 2022, 11, 1076. https://doi.org/10.3390/jcm11041076
Ahmed W, Galati J, Kumar A, Christos PJ, Longman R, Lukin DJ, Scherl E, Battat R. Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2022 Mar;20(3):e361-e379. doi: 10.1016/j.cgh.2021.03.034. Epub 2021 Mar 31. PMID: 33798711.