Evaluation of endoscopic disease severity is a key component in the management of ulcerative colitis (UC) patients. However, endoscopic assessment suffers from substantial intra- and interobserver variation, up to 75 %, thereby limiting the reliability of individual assessments. Our aim was to develop an artificial intelligence (AI) model capable of distinguishing active from healed mucosa as well as to differentiate different levels of endoscopic disease activity.Methods
1484 unique endoscopic images from 467 patients were extracted for classification. Two experts classified all images independent of each other according to the Mayo endoscopic subscore (MES). In case of disagreement, a third expert classified the images.
Different convolutional neural network architectures were implied in the development of the AI model. Five-fold cross-validation was employed to select the best model. Unseen test data were used for evaluation.
The final model was evaluated on its performance for distinguishing MES 0 from 1–3, MES 0–1 (i.e. mucosal healing) from 2–3, and distinguish between all MES.
The accuracy, sensitivity, specificity, positive and negative predictive value, and Cohen’s Kappa were used to evaluate the final models.Results
Our final model achieved at the most difficult task (distinguishing between all 4 categories of MES) a mean accuracy of 0.82, mean AUC of 0.99, test accuracy of 0.84, a sensitivity of 0.88, and a specificity of 0.81 and a weighted Cohens Kappa of 0.83 (p<0.001 compared to the experts).
The results from the other tasks are shown in table 1.
|Task||Test accuracy||Sensitivity||Specificity||PPV||NPV||Cohens Kappa||P-value|
|Distinguish between all MES||0.84|
|MES 0 from 1–3||0.94|
|MES 0–11 from 2–3||0.93|
|*(95 % confidence interval); MES = Mayo endoscopic subscore; PPV = Positive predictive value; NPV = Negative predictive value|
We propose a new standardised way of evaluating endoscopic images from UC patients for both clinical and academic purposes. The proposed AI model demonstrated a very good capability of distinguishing between all 4 MES levels of activity. This will optimize and unify the evaluation of the disease severity measured by the Mayo endoscopic subscore across all centres and hospitals no matter the level of medical expertise.
Treating beyond endoscopic remission, aiming for histological remission, has shown to reduce relapse and hospitalization rates in patients with ulcerative colitis (UC). However, very little is known on how histological remission associates with patient reported outcomes (PROMs).Methods
PROMs (Simple clinical colitis activity index [SCCAI], IBD disk and Visual Analogue Scales [VAS]) were prospectively collected through a digital questionnaire in all patients with UC undergoing colonoscopy between July 21st 2020-Jan 21st 2021. Mayo endoscopic sub score and UCEIS were determined, as well as the Nancy histologic index (NHI) of the most affected area. Endoscopic remission was defined as Mayo endoscopic sub score 0 and UCEIS 0; histologic remission as NHI 0, absence of active inflammation as NHI ≤ 1. PRO2 remission was defined as stool frequency ≤ 1 (absolute stool frequency ≤ 3 OR 1-2 stools more than usual) and rectal bleeding score of 0.Results
Fifty-six paired assessments were collected in 48 unique patients (Table 1), with a histologic, endoscopic and PRO-2 remission rate of 23.2%, 28.6% and 38.2% respectively. Patients with histologic remission or absence of histologic inflammation had a significantly lower overall IBD disability (p=0.007, p=0.003) and disease activity score (p=0.003, p<0.001), as compared to patients without. In line, NHI correlated with the overall IBD disk (r=0.40, p=0.002) and SCCAI score (r=0.50, p<0.001). Many individual components of both scores (abdominal pain, arthralgia, impact on education and work/interpersonal interactions/sexual function, regulation of defecation, blood loss, general wellbeing, joint pain, numbers of stools during night/day, urgency) differed significantly between patients with and without histologic remission. VAS scores assessing general wellbeing (r=0.33, p=0.01), impact on daily activities (r=0.41, p=0.002), UC-related symptoms (r=0.42, p=0.001) and worries (r=0.40, p=0.002) correlated with histology. Quartile analysis of the overall IBD disk and SCCAI scores confirmed the highest likelihood for histologic remission in patients with the lowest scores (Q1-Q2 vs Q3-Q4 39.3% vs 7.1%, p=0.01; 40.0% vs 9.7%, p=0.01) (Figure 1). Nevertheless, the overall accuracy of the IBD disk (0.75) or SCCAI score (0.76) for histologic remission is lower (p<0.05) than the accuracy of the Mayo endoscopic (0.90) or UCEIS (0.90) score.
Table 1 : Baseline features
In patients with UC, PROMs for disability and clinical disease activity reflect histologic disease activity and should therefore be further explored in (trial) endpoint discussions. However, they cannot fully replace endoscopic and histologic findings, and should be considered complementary.
Biologics are being used increasingly in the treatment of Inflammatory Bowel Disease. However, up to 40% of patients do not respond to biologics. Therefore, methods to predict response are imperative. We aimed to identify novel genes and pathways predictive of anti-TNF response in patients with Ulcerative Colitis (UC) undergoing electronic chromoendoscopy and probe confocal laser endomicroscopy (pCLE). We further evaluated the ex-vivo binding of fluorescent labelled biologics as markers of responseMethods
26 UC patients starting anti-TNF therapy as standard of care were recruited. Pre-treatment colonoscopy, with electronic chromoendoscopy and pCLE (Cellvizio, Mauna Kea) by injecting intravenous fluorescein (2.5-5mls), was performed to assess disease activity. Targeted biopsies were taken for fluorescein isothiocyanate (FITC)-labelled infliximab staining and RNA extraction and gene expression analysis. Ex vivo labelling was evaluated by an automated analysis: after a first pre-processing step to remove biases, the labelled regions were identified using statistical multi-level thresholding, and evaluated as area and intensity. To assess response, the same endoscopic procedure was repeated at week 12-14 after anti-TNF. cDNA libraries were prepared using QIAseq UPX 3’Transcriptome reagents and sequenced. Normalised gene expressions were obtained through the CLC Genomics Workbench. Differentially expressed genes (DEGs) (FDR-corrected P-value<0.05) were determined using the Limma package and PLS-DA modelling performed to calculate their importance (VIP score). Functionally related genes were identified and classified using DAVID tools. Strongest indicators of response were predicted by Random Forest area under the curve (AUC) analysis in this cohort and a similar validation cohortResults
At baseline increased binding of the labelled biologic was associated with a higher likelihood of response to treatment (AUROC81%, accuracy77%, PPV100%, NPV63%). 342 DEGs (75 up-regulated, 267 down-regulated) distinguished responders from non-responders, 76 fell within enriched pathways. Pathways related to inflammation, chemotaxis, TGF-beta signalling, extracellular matrix and carbohydrate metabolism were reduced and cell-cell adhesion increased in responders pre-treatment. Among the 37 genes with VIP>1, CRIP2, CXCL6,EMILIN1,GADD45B, LAMA4 and MAPKAPK2 were upregulated in non-responders pre-treatment and were good predictors of response (AUROC>0.7) in this cohort and validation cohort
A higher mucosal binding of the biologics before treatment was observed in anti-TNF responders. Responsive UC patients have a less inflamed and fibrotic state pre-treatment. Chemotactic pathways, involving CXCL6 may be novel targets to treat non-responders
Interventions targeting key inflammatory mechanisms have expanded the therapeutic repertoire for ulcerative colitis (UC). However, exact molecular mechanisms associated with clinical response remain elusive. We conducted a multiplex-immunohistochemistry (IHC) study to monitor immune cell composition in biopsies from UC patients under 2 approved therapies targeting TNF (infliximab) and integrin (vedolizumab), and a phase IIa clinical trial with the selective IL-6 transsignalling inhibitor olamkicept, to identify spatiotemporal changes of mucosal immune cell compartments in relation to each mechanism of action.Methods
Sigmoid biopsies from UC patients exposed to infliximab, vedolizumab or olamkicept (26 patients in total) at baseline and week 2, 6 and 14 after therapy induction were subjected to multiplex IHC for CD3, CD15, CD20, CD68, pSTAT3, and pan-cytokeratin (OPAL/Vectra Polaris, Akoya). Quantitative and spatial immune cell patterns captured by advanced image analysis (inForm, Akoya; R package PhenoptrReports) were analysed for differences between baseline and subsequent time points using Dunnett’s multiple comparisons test (GraphPad Prism 8.4.3). Accepted significance levels: *p<0.05,**p<0.01, ***p<0.001.Results
Targeted therapies resulted in overall decrease of immune cell infiltrates (range 1.15-1.22 fold; p=0.017-0.007), irrespective of drug or specified endpoint (remission at week 14) (Fig. 1). Significant drug-specific changes of spatial immune cell distributions were discernible (Fig. 2). Anti-TNF treatment was mainly associated with decrease in CD3+ T cells (p=0.005) localized in the submucosa close to epithelium or in tertiary lymphoid organs. In contrast, integrin targeting resulted in fewer CD15+ neutrophils, mainly in the submucosal compartment (p=0.046). Olamkicept treatment resulted in unique depletion of pSTAT3+ cells in patients achieving remission at week 14 (not observed in remission after infliximab or vedolizumab). To decipher drug-independent features of clinical remission we assessed distance metrics between immune and intestinal epithelial cells in remission and non-remission patients and observed increase (endpoint compared to baseline) of the average distance to the nearest CD20 or CD15 cell in the remission (p=0.0054, p=0.0004) but not in the non-remission group (n.s.).
Our study strongly suggests that multiplexed spatiotemporally resolved immune cell phenotyping may provide novel insights into the dynamic shifts of immune cell compartments in UC patients undergoing targeted therapy. We propose that such highly resolved digital maps of immune cells could lead to novel tools for therapeutic stratification of IBD patients.
In Crohn’s disease (CD), biologics can induce mucosal healing and stable remission. After reaching this target, treatment de-escalation could be considered but the risk of relapse needs to be estimated. Current biomarkers used to predict relapse (C-reactive protein: CRP, faecal calprotectin) offer a limited prognostic capacity. Furthermore, they only monitor inflammation while we recently highlighted various and distinct pathological processes associated with the risk of short-term (<6 months) and mid/long-term (>6 months) relapse in CD patients stopping infliximab. Herein, the aim of our study was to further characterise this distinction.Methods
Serum abundance of 92 proteins were measured by proximity extension assay (immune response panel, Olink)at baseline of the STORI cohort (infliximab diScon-Tinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors, n=102). Association of markers with the risk of relapse was determined by univariable Cox model in stratified (relapse <6 months or >6 months) and non-stratified datasets. Study of protein characteristics and enrichment analyses were performed to find biological patterns differentiating short-term from mid/long-term relapsers. To evaluate the predictive capacity of markers, we combined them systematically by pairs (‘AND’ or ‘OR’ logical operators) and used log-rank statistics with false discovery rate (FDR) correction (Benjamini-Hochberg).Results
The risk of mid/long-term relapse was associated with a decreased circulating level of anti-inflammatory effectors while the risk of short-term relapse was associated with an increased circulating level of pro-inflammatory effectors (Fig. 1A, 1B).
The risk associated with the downstream signalling of cytokine and pattern recognition receptors showed an opposite pattern in the short-term versus mid/long-term relapsers (Fig. 1D, 1E).
The risk of short-term relapse was characterised by a perturbed circulating level of proteins inducing tolerance and immunity in antigen presenting cells (Fig. 2A, 2B).
The risk of mid/long-term relapse was characterised by an increased circulating level of proteins promoting lymphocyte tolerance (Fig. 2D, 2E) and a decreased circulating level of cellular junction proteins (Fig. 3).We found 1223 (short-term relapse dataset), 233 (mid/long-term relapse dataset) and 101 (non-stratified dataset) novel marker combinations with FDR<0.05 and higher Z-scores than CRP and faecal calprotectin. The best combinations are showed in Fig. 4.Conclusion
In CD patients stopping infliximab, blood proteins linked to immunoregulation or cellular junctions support the distinct profiles of short-term and mid/long-term relapsers. These proteins showed a capacity to predict the relapse.
Innate Lymphoid Cells (ILC) develop from Common Lymphoid Precursors in the bone marrow, and ILC precursors (ILCP) migrate to mucosa where they mature, promote homeostasis, and provide a potent, antigen-non-specific sources of cytokines. Deciphering what local stimuli drive the final stages of ILCP maturation in these tissues remains a pressing question, as ILC frequencies can become dysregulated during chronic infection and inflammatory diseases. For example, Type-1 innate lymphoid cells (ILC1) are enriched in the mucosa of patients with active inflammatory bowel disease (IBD) and the impact of this accumulation remains elusive.
Here, we develop and use co-cultures of both murine and human iPSC-derived gut and lung organoids with ILCP and with mature ILC isolated from IBD patients’ intestinal biopsies.Results
Harnessing these versatile models, we demonstrate that epithelial cells provide a complex niche capable of supporting the final maturation of all helper-like ILC1, ILC2, and ILC3. Notably, organoid identity was sufficient to robustly recapitulate tissue-specific ILC imprints and frequencies, even in the absence of microbial stimuli, other cell types, or cytokine supplementation.
In addition, we show that that ILC1 drive expansion of the epithelial stem cell crypt through p38γ phosphorylation, driving a potentially pathological proliferative feedback loop between β-catenin and Cd44v6. We harnessed this model to elucidate that this phenotype was unexpectedly regulated by ILC1-derived TGFβ1. We further show that human gut ILC1 also secrete TGFβ1, and drive CD44v6 expression in both HIO epithelium and mesenchyme. As TGFβ1 is a master regulator of fibrosis, the leading indicator for surgery in IBD, we next characterised the ability of ILC1 to regulate matrix remodelling using a functionalized, synthetic hydrogel system. We show that ILC1 drive both matrix stiffening and degradation, which we posit occurs through a balance of MMP9 degradation and TGFβ1-induced fibronectin deposition.Conclusion
Taken together, our work provides unprecedented insight into in situ ILC maturation, which we show to be driven by epithelial signals, and into ILC function. We also report that intestinal ILC1 modulate epithelial and matrix remodelling, which may drive either wound healing in homeostasis, but may tip toward pathology when enriched in IBD.
Moreover, our work introduces a modular organoid platform, which provides exquisite control over both environmental stimuli and host genetics, making it a powerful tool for dissecting the interactions between complex mucosal tissues and rare cell subtypes in development and disease.
Extracellular RNAs (exRNAs) are RNA species present outside of the cells in which they were transcribed. They are found in human serum, though the exact role of circulating exRNAs remains to be established, especially in inflammatory bowel diseases (IBD). Besides their potential help in our pathophysiological understanding of disease, they might serve as liquid biopsies or non-invasive biomarkers. We characterised exRNAs in serum from IBD patients, and questioned their potential in separating ulcerative colitis (UC) from Crohn’s disease (CD).Methods
We carried out SILVER-seq (Small Input Liquid Volume Extracellular RNA-sequencing) on serum droplets (5-7ml) from a cross-sectional cohort of 26 IBD patients (15 UC, 11 CD) with active endoscopic disease (Mayo endoscopic sub score or Simple Endoscopic Score for Crohn’s disease ) (Table 1). Normalization and differential expression were done using DESeq2 R package, co-expression network analyses performed using WGCNA (FDR adjusted p ≤0.05). Using randomized generalized linear modelling (RGLM), a diagnostic exRNA marker was designed to separate UC from CD samples (15 UC, 11 CD).Results
We detected 60,675 exRNAs in serum from IBD patients, capturing 76.1% of all genes expressed in intestinal tissue, and including highly abundant intestinal genes (e.g MUC2) and intestinal barrier genes (e.g claudin 8, occludin and RETNLB). Co-expression network analysis identified 69 clusters of which 1 significantly correlated with the distinction between CD and UC (FDR p=0.003, r=-0.70). One of the hub genes within this module (consisting of 148 genes, upregulated in UC) was GNA12 (p=2.3E-4, r=0.66 for correlation with the module eigengene), encoding for a membrane bound GTPase that plays a key role in tight junction assembly and has previously been identified as UC-specific SNP in GWAS (Figure 1). Serum GNA12 expression was not associated with faecal calprotectin (p=0.55, r=0.12), disease duration (p=0.24, r=0.25), age (p=0.43, r=0.16) or gender (p=1.0), but did correlate with other UC-specific genes including TNFRSF14 (p=0.04, r=0.4), HNF4A (p=0.04, r=-0.4) and CAMK2A (p=0.004, r=0.54). Through machine learning within the UC-specific module (containing 148 genes), we identified an 8-gene exRNA panel, including GNA12, that could accurately discriminate between UC and CD patients (accuracy 96.2%).
Figure 1: Visualisation of the identified exRNA network including GNA12
Liquid biopsies are a novel non-invasive tool in IBD biomarker development. Although larger in-depth studies are required to further validate, explore and characterise the potential of serum exRNAs in the field of IBD, the current pilot project identified a new non-invasive tool to accurately distinguish CD from UC patients.
To address the question if pediatric CD patients responding to nutritional induction therapy can be maintained in remission on dietary therapy without the use of immunosuppressive drugs, we designed a prospective randomized trial (CD-HOPE) comparing cyclic exclusive enteral nutrition (EEN) to daily supplement over a 12 month period.
CD patients (6-17 years) who successfully completed at least 6 weeks of EEN with clinical remission (wPCDAI ≤12.5) were recruited in 21 sites of the French GETAID pédiatrique between 12.2014 and 09.2018. All drug therapy had to be stopped at least 4 weeks prior to inclusion. A total of 112 patients were screened with 100 patients randomized to group A cyclic EEN (100% of caloric requirement) every 8 weeks for 2 weeks or group B daily supplementary nutrition (25% of caloric requirement). Patient stratification according to age (< 10 years or older) and previous drug exposure or not. EEN and the nutritional supplement were in form of MODULEN IBD®. Except for the two weeks of EEN in group A food access was not restricted. Primary objective was the comparison of relapse rates at 12 months (defined as a wPCDAI >12.5 at two consecutive visits) between the two groups (log-rank test per protocol). Additional analyses were performed using a multivariate regression analysis and cox model.Results
49 CD patients were randomized to group A (cyclic EEN) and 51 to group B (daily supplement) with 43/49 and 44/51 newly diagnosed patients without any previous drug exposure. Baseline characteristics were comparable between the two groups. Median age was 12 and 13 years, group A and B respectively. At the final 12 months visits a total of 25/49 patients (group A) remained in remission without disease activation compared to 12/51 patients (group B) (p=0.004) with a hazard ratio of 0.48 (0.29-0.80) (p= 0.0051). Kaplan Maier survival remission rates are shown in figure 1. Mean fecal calprotectine levels showed no significant difference between the two groups (297, 399 and 469 at month 0, 3, and 12 visits in group A and 480, 606, and 283 at month 0,3, and 12 visits in group B). Mucosal healing at M12 months was achieved in 25/49 patients (group A) and 18/51 patients (group B), with a mucosal healing rate of 52% (group A) and 33% (group B). Both treatment arms showed a significant catch-up growth.
This is first trial indicating that children/adolescents with CD responding to EEN as induction therapy can be maintained on remission with a nutritional therapy without immunosuppressors/biologics. However, daily nutritional supplement with normal access to food was not successful with a relapse rate of 76%.
This study was supported by an unrestricted grant from Nestlé Health Science and sponsored by APHP.
Isolated colonic (L2) Crohn’s disease (CD) in adults is thought to have unique clinical and genetic features compared with ileal (L1) CD and ulcerative colitis (UC). Similar studies in paediatrics are scarce. Our goal was to characterize the clinical features of paediatric patients with isolated colonic CD and compare them to patients with ileo-cecal CD and those with UC.Methods
This was a multi-center retrospective study including 21 sites affiliated with the Porto IBD group and IBD interest group of ESPGHAN. Data of paediatric patients diagnosed between 2014-2017 with L1 or L2 CD, or with UC, was collected, including information on demographic, clinical and laboratory parameters at diagnosis, end of induction, 1 year and 3 years after diagnosis (or at last follow-up).Results
Data was collected on 300 children (102 L1, 94 L2, 104 UC) with similar demographic features. At diagnosis, bloody stools were identified in 45% of L2 patients, compared with 15% and 95% of L1 and UC patients, respectively (P<0.001), while fever was documented in 27% of L2 patients, compared to 13% and 3% of L1 and UC patients, respectively (P<0.001). At the time of diagnosis, the median pediatric Crohn’s disease activity index for patients with L1 and L2 was 25 (IQR 17.5-37) and 27.5 (20-40), respectively, while the median pediatric ulcerative colitis activity index was 40 (30-55) for patients with UC. C-reactive protein levels were significantly higher among CD patients (both L1 and L2), compared to patients with UC, and calprotectin values were comparable. ASCA was positive in 55%, 25% and 2% (P<0.001) and pANCA in 2%, 17% and 53% (P<0.001) in L1, L2 and UC patients, respectively. Granulomas were identified in 36% of L2 patients, similar to patients with L1 (33%). For induction therapy, exclusive enteral nutrition, oral steroids and mesalazine were used in 50%, 45% and 38% of patients with L2 CD, compared with 72%, 28% and 9%, and 0%, 52% and 75% of L1 and UC patients, respectively (P<0.001). Steroid-free clinical remission at the end of induction was overall similar between groups, around 55%. At 1-year post-diagnosis, 62%, 68% and 40% were on an immunomodulator (P=0.03) and 41%, 26% and 22% were receiving anti-TNFα agent (P=0.01), of patients with L1, L2 and UC, respectively. While time to initiation of an anti-TNFα agent was significantly shorter in L1 patients compared with L2 and UC (P=0.03), time to admission and time to surgery were similar.Conclusion
Paediatric patients with isolated colonic CD exhibit several clinical features which differentiate them from ileo-cecal CD and UC. Prospective studies are required to understand the pathogenesis of this unique entity and define short- and long-term outcomes.
Patients with Crohn’s disease (CD) can develop complications including stricturing and penetrating disease [1, 2]. Although reliable baseline predictors of disease progression are urgently needed to inform management strategies, few studies have comprehensively explored the phenotypic and genetic determinants of disease progression in a sufficiently powered cohort.Methods
We used data from 13,926 patients with CD in the UK IBD BioResource to investigate the effects of clinical phenotypes and genetics on CD progression. Median follow-up was 10.6 years and total follow-up was 193,033 patient-years. We applied the Montreal classification system to define disease as B1 (inflammatory), B2 (stricturing) and B3 (penetrating). Patients with B2 or B3 disease (N = 5,185) were compared to patients with B1 disease (N = 8,471) in a multivariate model fitted with both phenotype data and a polygenic score that we developed. Associations with q-values (false discovery rate adjusted p-values) less than 0.05 were defined as statistically significant.Results
CD progression occurred over time from diagnosis (Figure 1). Consistent with previous findings, we confirmed factors including smoking, disease location and perianal disease were associated with disease progression  (Table 1). The impact of a genetic influence on disease progression was confirmed and shown to be independent of genetic effects on disease location . Early prescription of medications showed a protective effect on disease progression: Infliximab, adalimumab and thiopurines significantly reduced the chance of B2/B3 progression when prescribed within two years of diagnosis. Additionally, we observed a decreased progression to B2/B3 disease in patients diagnosed recently (between 2012-2020) compared to those diagnosed before 2012. This finding persisted after conditioning on exposure to biologics and correcting for follow-up time and interval to first thiopurine prescription, and thus may be indicative of other improvements in standards of care in recent years.
Using a large, well-characterised cohort we confirm the importance of disease location, smoking status and genetics on disease progression. We highlight the positive impact of early medication prescription on disease progression and discover an independent signal relating to potential improvements in the standard of care in CD over time. These results create the framework for reliable predictors of CD progression that may better guide future CD management strategies.
1. Cosnes, J., et al., Inflamm Bowel Dis, 2002. 8(4): 244-50
2. Lo, B., et al.,J Crohns Colitis, 2018. 12(3): 265-272
3. Torres, J., et al., J Crohns Colitis, 2016. 10(12): 1385-1394
4. Cleynen, I., et al., Lancet, 2016. 387(10014): 156-67
Current guidelines on Crohn’s perianal fistulas recommend anti-TNF treatment and suggest to consider surgical closure in amendable patients. However, long-term outcome of both treatments have not been directly compared. The aim of this study was to assess MRI healing in a patient preference RCT comparing both treatment modalities.Methods
This multicentre, international trial compared surgical closure following anti-TNF induction (4 months) to anti-TNF therapy without surgery. Patients were counselled for both treatment arms and randomised if there was no preference. Due to the combination of a preference and randomised cohort, the appropriate sample size to detect a clinically relevant increase of 25% closure (from 15% to 40%) was flexible and adjusted for a possible skewed distribution (86 patients in case of 1:1 treatment allocation).
All Crohn’s patients ≥ 18 years with a (re)active high perianal fistula and a single internal opening were eligible. Exclusion criteria were previous failure of anti-TNF, recto-vaginal fistula, proctitis, or stoma. Patients received seton placement prior to treatment. Primary outcome was MRI healing after 18 months (defined as a complete fibrotic fistula or MAGNIFI-CD score of 0-5). Secondary outcomes included clinical healing, re-interventions and fistula recurrence.
Between September 2013 and December 2019, 7 hospitals in the Netherlands and Italy included 93 patients (59% females, median age 34 years) of which 32 were randomised. Thirty-seven patients were treated in the surgical closure group and 56 in the anti-TNF group, with comparable baseline characteristics.
After 18 months, MRI healing was significantly higher after surgical closure (41% vs 11%; P=0.002). Although a trend was seen in favour of surgical closure, clinical healing rates and surgical re-interventions were not significantly different between groups (65% vs 45%, P=0.07 and 19% vs 34%, P=0.1). After median 38 months follow-up, 12 patients in the anti-TNF group crossed over to surgical closure. Both long-term MRI healing and clinical closure in the per protocol analysis remained significantly higher for the surgical closure group (46% vs 11%, P=0.002 and 65% vs 29%, P=0.006). One patient (4%) with a MAGNIFI-CD score ≤5 developed a recurrent fistula after 46 months, whereas recurrences occurred in 37% of patients with MAGNIFI-CD score >5 (P=0.004).
These results demonstrate that surgical closure following anti-TNF induction treatment induces MRI healing more frequently than anti-TNF alone. This is associated with increased long-term clinical closure and reduced recurrences. These data suggest that Crohn’s perianal fistula patients amendable for surgical closure should be counselled for this therapeutic approach.
Limited resective surgery is used as a primary therapeutic option in patients with Crohn’s disease (CD) who present with severe symptoms or fibrostenotic complications. Recent studies suggest that surgery represents a valid alternative of biological therapy in subgroups of CD patients.1 However, only few studies have described the disease course in early resected CD patients regardless of disease location. This study aimed to investigate disease course in all early resected CD patients.Methods
Using the Danish National Patient Registry (NPR), we identified 9739 patients who were diagnosed with CD between January 1st, 1997 and December 31st, 2015. Of those, 499 patients underwent a major abdominal surgery within 30 days before or after their diagnosis. Data on re-operation, hospitalization and medication use were retrieved from the NPR and the National Prescription Registry. Trends in treatment outcomes over time were assessed using Chi-square test, Kaplan Meier survival analysis and log-rank test.Results
Overall, 217 (43.5%) patients had an initial ileocecal resection, 154 (30.9%) had a colonic resection and 112 (22.4%) had a small bowel resection and 16(3.2%) patients without classification of surgery. The cumulative risk of reoperation was 16.4% at five years after the initial surgery. Five-year risk of hospitalization and need for medical therapy was 66.1% and 61.7% (Figure 1). Among 326 (65.3%) patients who received medical therapy during follow-up, 216 (66.3%) were treated with an immunomodulator and 62 (19.0%) with a biological drug. There was no difference in the risk of re-operation (p=0.11), hospitalization (p=0.70) or medication use (p=0.37) in relation to the anatomic location of the initial surgery.
When comparing patients diagnosed before and after 2005, five-year risk of hospitalization decreased from 76.9% to 56.1% (p<0.001, Figure 2), while five-year risk of medication use decreased from 65.9% to 58.5% (p=0.01, Figure 2). In contrast, five-year risk of re-operation showed an increasing, but insignificant trend from 13.7% to 18.6% (p=0.18).
Figure 1. Cumulative risk of re-operation, hospitalization and medication use
The risk of re-operation and hospitalization after the initial surgery in this cohort of early resected CD patients are lower when compared to other CD cohorts. Furthermore, hospitalization risk and need for medical therapy decreased over time.
1.Stevens TW, Haasnoot ML, D’Haens GR, Buskens CJ, de Groof EJ, Eshuis EJ, et al. Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn’s disease: retrospective long-term follow-up of the LIR!C trial. Lancet Gastroenterol Hepatol. 2020 Oct 1;5(10):900–7.
Endoscopic remission is associated with better outcomes in ulcerative colitis (UC). However, colonoscopy (CS) is invasive and poorly tolerated by patients. Recently, we developed and externally validated non-invasive ultrasonography based criteria [Milan ultrasound criteria (MUC)] to assess and grade endoscopic activity in UC. We also confirmed that a MUC score > 6.2 is a valid cut-off to discriminate endoscopic activity, defined by a Mayo endoscopic subscore > 2.
Aim of this study was to assess the predictive role of MUC on disease course in a prospective cohort of UC patients.
UC consecutive patients were followed for at least 12 months after performing baseline bowel US. UC-related outcomes, including need of treatment escalation (defined as the need of corticosteroids or change/optimization of immunosuppressants), hospitalization and surgery, were assessed at 1 year by logistic regression analysis, and were analyzed after long term follow-up (5 years) using Kaplan-Meier survival analysis.
87 UC consecutive patients were included in the study, 31 (36%) were in endoscopic remission (Mayo endoscopic subscore 0-1) and 56 (64%) in endoscopic activity (Mayo endoscopic subscore 2-3). MUC and Mayo endoscopic subscore significantly correlated at baseline (Spearman’s rank correlations [rho]= 0.642; 95% confidence interval (CI) 0.499 to 0.751; p < 0.001). The multivariable analysis identified as independent predictors of need of treatment escalation throughout the 12-month period as being: MUC > 6.2 (OR: 5.95, 95% CI: 1.32–26.76, p < 0.020) and a partial Mayo score (PMS) > 2 (OR: 26.88, 95% CI: 5.01–144.07, p < 0.001). Kaplan-Meier survival analysis of long-term follow up demonstrated a lower cumulative probability of need for surgery and hospitalization in patients with MUC < 6.2 compared to MUC > 6.2 (Fig. 1A and 1B), as well as in patients with a Mayo endoscopic subscore of < 1 compared to Mayo endoscopic subscore of 2-3 (Fig. 1C and 1D).
MUC is a novel non invasive tool that predicts the course of UC in the short and long term follow-up.
Fatigue is one of the most common symptoms in IBD resulting in decreased quality of life, impaired work productivity, and higher societal costs. However, little is known about its etiology and pathophysiology. We aimed to estimate the prevalence of fatigue and to identify predictive factors for fatigue.Methods
The PREdiCCt study (https://www.predicct.co.uk) is the largest prospective study of the causes of IBD flare. 2629 patients in clinical remission were recruited from 48 UK sites. 1946 (74%) patients completed the baseline questionnaires. We assessed the prevalence of fatigue at baseline using a single item from the IBD Control questionnaire. To identify predictors for fatigue, we performed univariable and multivariable analyses including demographic, biochemical, environmental and psychosocial factors such as anxiety and depression [HADS], sleep quality [PSQI] and physical exercise [GPAQ]).Results
759/1919 IBD patients in clinical remission (39.6%) reported fatigue in the past 2 weeks, while 1034 patients (53.9%) did not report fatigue. Patients who reported fatigue were more frequently female, had more frequently CD, and were more frequently smokers (Table 1). Univariable comparisons showed higher inflammatory markers in the fatigued group, with fewer patients in clinical remission. Multivariable analyses identified female sex (OR 2.4), CRP>5 (OR 2.1), bad sleep quality (OR 2.5), anxiety (OR 1.8) and depression (OR 6.2) as independent factors associated with fatigue (Table 2).
|Variable (n [%], or median [IQR])||Often lack energy – yes(n=759)||Often lack energy – no(n=1034)||P-value|
|Female sex||504 (66.4)||508 (49.1)||<0.001|
|Current smoker||57 (8.9)||45 (4.9)||0.002|
|IBD type (CD)||431 (57.2)||492 (48.0)||<0.001|
|Haemoglobin (g/L)||136 (127-145)||140 (131-148)||<0.001|
|White cell count (x10^9/L)||6.3 (5.3-7.8)||6.0 (5.0-7.2)||<0.001|
|CRP <5 mg/L||360 (62.8)||588 (76.5)||<0.001|
|Ferritin (ug/L)||56 (27-106.5)||66 (36-116)||0.011|
|Folate (ug/L)||6.5 (4.3-10.5)||7.3 (5.0-10.9)||0.011|
|Clinical remission (HBI<4, pMayo<2)||287 (71.8)||482 (82.7)||<0.001|
|Depression (HADS>9)||224 (30.0)||49 (4.8)||<0.001|
|Anxiety (HADS>9)||336 (45.0)||165 (16.2)||<0.001|
|Physical activity (GPAQ<600)||207 (27.6)||193 (18.8)||<0.001|
|Sleep quality (PSQI>5)||633 (90.2)||693 (69.9)||<0.001|
|CRP >5 mg/L||2.1||1.3-3.5||0.004|
|Sleep quality (PSQI>5)||2.5||1.4-4.6||0.002|
We show the significant burden of fatigue in IBD patients and describe putative causes which demonstrate both the impact of residual gut inflammation and the relationship between fatigue and psychological well-being. The impact of environmental and dietary factors on fatigue is being further investigated with ongoing longitudinal data collection in the PREdiCCt study.
Upadacitinib (UPA) is a selective and reversible Janus kinase inhibitor.U-ACCOMPLISH is one of two phase 3 induction trials that evaluated the safety and efficacy of UPA 45 mg once daily (QD) in adults with ulcerative colitis (UC).Methods
U-ACCOMPLISH was a multicentre, randomized, double-blind, placebo-controlled trial (NCT03653026) that enrolled patients with moderate-to-severe UC (defined as adapted Mayo score 5–9 with centrally read endoscopic score 2–3) who had inadequate response, loss of response, or intolerance to aminosalicylates, immunosuppressants, corticosteroids and/or biologics. Patients were randomized 2:1 to UPA 45 mg QD or placebo (PBO) for 8 weeks. At week 8, responders entered the maintenance phase and non-responders entered the extended treatment period to receive open-label UPA 45 mg QD for additional 8 weeks.The primary endpoint (clinical remission per adapted Mayo Score) and ranked secondary endpoints including symptomatic, endoscopic– histologic evaluations from the 8-week PBO-controlled period are reported here. Non-responder imputation incorporating multiple imputation for missing data due to COVID-19 are reported.Results
522 patients were randomized (UPA, n=345; PBO, n=177);the intent-to-treat population included 341 patients in UPA and 174 patients in PBO group. Baseline demographics and disease characteristics were similar between groups; 50.7% and 51.1% were biologic inadequate responders in UPA and PBO groups, respectively (Table 1). A significantly higher proportion of patients receiving UPA 45 mg QD (33.5%) versus PBO (4.1%) achieved the primary endpoint (adjusted treatment difference: 29.0% [23.2, 34.7]; P<0.001). A significantly higher proportion of patients receiving UPA versus PBO also achieved all ranked secondary endpoints (all P<0.001; Figure 1).Serious adverse events were reported by 3.2% and 4.5% of patients in UPA and PBO groups, respectively (Table 2). Similar rates of serious infection were observed in both groups (0.6%); 2 events each of herpes zoster and opportunistic infection were reported in UPA group. No active tuberculosis, malignancy, adjudicated major adverse cardiovascular events, or deaths were reported in the study. One patient with venous thromboembolism (deep vein thrombosis and pulmonary embolism) and 1 patient with gastrointestinal perforation were reported in the placebo group.
In U-ACCOMPLISH, 8-week UPA 45 mg QD induction treatment led to statistically significant improvements in clinical, endoscopic, and combined endoscopic-histologic endpoints.The treatment was well tolerated, and the safety profile and AE prevalence was comparable with previous studies of UPA with no new safety signals identified.
An unmet therapeutic need remains in patients with ulcerative colitis (UC). U-ACHIEVE is one of two phase 3 induction trials evaluating the safety and efficacy of the selective Janus kinase–1 inhibitor upadacitinib (UPA) 45 mg once daily (QD) in adults with UC.Methods
U-ACHIEVE is a multicentre, double-blind, placebo (PBO)–controlled trial (NCT02819635) that randomized patients with moderately to severely active UC 2:1 to UPA 45 mg QD or PBO for 8 weeks. Patients were stratified by response to biologic therapy (inadequate vs non–inadequate responder), baseline corticosteroid use (yes or no), and baseline adapted Mayo score (≤7 or >7). The primary endpoint was proportion of patients achieving clinical remission (per adapted Mayo Score) at week 8.Ranked secondary endpoints included endoscopic improvement, endoscopic remission, and clinical response per adapted Mayo Score at week 8; clinical response per partial adapted Mayo Score at week 2; and histologic-endoscopic mucosal improvement at week 8. Non-responder imputation incorporating multiple imputations for missing data due to COVID-19 are reported. Safety was assessed through week 8.Results
474 patients were randomized (UPA, n=319; PBO, n=155). Baseline characteristics were well balanced between groups (Table 1). A significantly higher proportion of patients receiving UPA (26.1%) vs PBO (4.8%) achieved clinical remission at week 8 (adjusted treatment difference [95% CI], 21.6% [15.8, 27.4]; P<0.001; Figure 1). For all ranked secondary endpoints, UPA was superior to PBO (P<0.001; Figure 1). A significant difference in clinical response favouring UPA vs PBO was seen as early as week 2 (60.1% vs 27.3%) and was sustained over 8 weeks (79.0% vs 41.6%; Figure 2). There were more serious adverse events (AEs), severe AEs, and AEs leading to study drug discontinuation with PBO (Table 2). The most common AEs were acne, creatine phosphokinase elevation, and nasopharyngitis with UPA and worsening of UC and anaemia with PBO. Incidence of serious infection was similar between UPA and PBO. Neutropenia and lymphopenia were reported more frequently with UPA vs PBO (Table 2).No adjudicated gastrointestinal perforation, major cardiovascular AEs, or thrombotic events and no active tuberculosis, malignancy, or deaths were reported.
In patients with moderately to severely active UC, UPA 45 mg QD induction therapy was superior to PBO in inducing clinical remission/response, and endoscopic remission/response over 8 weeks; responses were significant and rapid. UPA 45 mg QD was well tolerated; safety was comparable with the known safety profile of UPA, and no new safety signals were identified.
Patients with ulcerative colitis (UC) often do not respond to treatment or lose response over time, and thus switch between therapies with various mechanisms of action (MoAs).1 Filgotinib (FIL) is a once-daily, oral, Janus kinase 1 preferential inhibitor in development as a UC treatment. We assessed the efficacy of FIL in biologic (bio)-naïve and bio-experienced patients with UC, and in bio-experienced patients with failure of 1 or ≥2 biologics or 1 or 2 MoAs.Methods
SELECTION (NCT02914522) was a phase 2b/3 double-blind, randomised, placebo-controlled trial comprising two induction studies and a maintenance study. Adults (18–75 years) with moderately to severely active UC were randomised 2:2:1 to FIL 200 mg, FIL 100 mg or placebo (PBO) once daily for 11 weeks in Induction Study A (bio-naïve) and B (bio-experienced). Patients in either clinical remission or Mayo Clinic Score (MCS) response at week 10 (responders) could enter the Maintenance Study. Responders who received induction FIL were re-randomised 2:1 to continue their induction regimen or PBO through week 58. Responders who received induction PBO continued PBO. We assessed clinical remission and MCS response at weeks 10 and 58 in bio-naïve patients and bio-experienced patients with failure of 1 or ≥2 biologics and 1 or 2 MoAs (TNF antagonists and vedolizumab). All p values for subgroup analyses are nominal.Results
At week 10, clinical remission was achieved by a significantly higher proportion of bio-naïve and -experienced patients treated with FIL 200 mg than PBO (Figure 1a). A higher proportion of bio-experienced patients with 1 biologic or MoA failure treated with FIL 200 mg than PBO achieved clinical remission at week 10 (p<0.05); a smaller treatment effect was seen in patients with ≥2 biologic or 2 MoA failures (Figure 1b). None of these comparisons reached p<0.05 for FIL 100 mg. Higher proportions of patients treated with either dose of FIL than PBO achieved MCS response at week 10 in all (sub)groups (Figure 2). At week 58, higher proportions of bio-naïve and -experienced responders, and bio-experienced responders with ≥2 biologic or 2 MoA failures treated with maintenance FIL 200 mg than PBO achieved clinical remission (p<0.05) (Table 1). Higher proportions of responders treated with maintenance FIL 200 mg than PBO achieved MCS response at week 58 in all (sub)groups.
FIL 200 mg was effective in inducing and maintaining clinical remission in bio-naïve and -experienced patients. Induction results suggest FIL 200 mg is most effective in bio-naïve patients, and those who switch after failure of 1 biologic or MoA. Interpretation of week 58 data is limited by low patient numbers.
1. Gemayal NC et al. Gastroenterology 2019;35:1911–23.
Guselkumab (GUS), an IL-23 antagonist, is being investigated for the treatment of IBD. GALAXI 1 is a ph2, double-blind, PBO-controlled study in pts with moderately to severely active CD with inadequate response or intolerance to conventional therapies (corticosteroid, immunosuppressant) and/or biologics (TNF antagonist, vedolizumab). Here we report early clinical outcome measures during induction with GUS vs PBO.Methods
Pts with moderate to severe CD (CDAI score 220-450) were randomized 1:1:1:1:1 to GUS 200, 600 or 1200mg IV at Wks 0, 4, 8; ustekinumab (UST) ~6mg/kg IV at Wk 0 and 90mg SC at Wk8; or PBO IV. Clinical remission (CDAI score<150), clinical response (≥100-point reduction from baseline in CDAI score or CDAI score<150), and clinical-biomarker response (clinical response and ≥50% reduction from baseline in CRP or fecal calprotectin) were evaluated at Wks 4, 8 and 12 for pooled GUS arms vs PBO. UST was a reference arm.Results
Two hundred fifty pts were evaluated; about 50% failed previous biologic therapy. Baseline demographics and disease characteristics were generally similar among treatment groups (mean CD duration, 8.8yr; mean CDAI, 306.2; median CRP, 5.4mg/L; median fecal calprotectin, 594.0mg/kg). At Wk4, clinical remission was achieved in 20.0% of GUS-treated pts compared with 11.8% of PBO-treated pts. A greater proportion of GUS-treated pts achieved clinical remission compared with PBO-treated pts at Wk8 (42.0% vs 15.7%) and Wk12 (54.0% vs 15.7%). Similarly, within each subgroup of pts who failed biologic therapy(BIO-failures) or conventional therapy(CON-failures), GUS-treated pts achieved a higher rate of clinical remission at Wks 4, 8 and 12 compared with PBO (Fig 1). The proportion of pts who achieved clinical response and clinical-biomarker response was also higher at Wks 4, 8 and 12 among GUS-treated pts compared with PBO-treated pts. From Wks 4 to 8 to 12, the proportion of GUS-treated pts in clinical response increased from 44.0% to 56.0% to 66.0%, respectively, and the proportion in clinical-biomarker response increased from 26.0% to 43.3% to 48.0%. In contrast, the proportion of PBO-treated pts who achieved clinical response and clinical-biomarker response remained stable or decreased from Wks 4 to 8 to 12: 25.5% to 25.5% to 23.5% and 13.7% to 9.8% to 7.8%, respectively (Fig 2).
In pts with moderately to severely active CD, induction treatment with GUS combined treatments versus PBO resulted in higher rates of overall clinical remission, clinical-biomarker response, and clinical response as early as Wk4. This continued to increase through Wk12 with treatment. The early trend for achievement of clinical remission was also evident in sub-groups of pts who failed biologic or conventional therapy.
The gut microbiome directly affects the balance of pro-inflammatory and anti-inflammatory responses in the gut. As microbes thrive on dietary substrates, the question arises whether we can nourish an anti-inflammatory gut ecosystem. In this study, we investigated the relation between 173 dietary factors and the microbiome of 1425 individuals spanning four cohorts: Crohn’s disease, ulcerative colitis, irritable bowel syndrome and the general population.Methods
Shotgun metagenomic sequencing was performed to profile gut microbial composition and function. Dietary intake was assessed through food frequency questionnaires. We performed unsupervised clustering to identify dietary patterns and microbial clusters. Next, linear models were conducted between dietary intake and microbial species and pathways, adding age, sex, caloric intake and sequencing read depth as covariates. Analyses were conducted per cohort, followed by a meta-analysis and heterogeneity estimation. Multiple testing correction was performed on the obtained p-values and a FDR <0.05 was defined as significance cut-off.
We identified 38 associations between dietary patterns and microbial clusters. Moreover, 61 individual foods and nutrients were associated with 61 species and 249 metabolic pathways in the meta-analysis across healthy individuals and patients with IBS, Crohn’s disease and UC (FDR<0.05, heterogeneity p-value>0.05). Processed foods and animal-derived foods were consistently associated with higher abundances of Firmicutes, Ruminococcus species of the Blautia genus and endotoxin synthesis pathways. The opposite associations were found for clusters comprising fish, nuts, bread and legumes. Moreover, while total plant protein intake was associated with a higher Bifidobacterium abundance (FDR=0.048, coef=4.98), animal-derived protein showed a negative association (FDR=1.30x10-05, coef= -4.1). Lastly, we observed positive associations of fecal calprotectin with a fast food cluster (FDR=4.14x10-4, coef=0.24) and a cluster comprised of high-fat meat, potatoes and gravy (FDR=0.003, coef =0.22), while the opposite was seen for clusters of fish and nuts (FDR=0.038, coef= -0.1) and bread and legumes (FDR=0.005, coef= -2.48).
We identified dietary patterns that consistently correlate with groups of bacteria with shared functional roles in both, health and disease. Moreover, specific foods and nutrients were associated with species known to infer mucosal protection and anti-inflammatory effects. A decrease in these bacteria has already been associated with both IBS and IBD. We propose microbial mechanisms through which the diet affects inflammatory responses in the gut as a rationale for future intervention studies.
Faecal microbiota transplantation (FMT) administered via the lower GI tract effectively induces remission in ulcerative colitis (UC). Orally administered FMT capsules may improve patient tolerability and facilitate maintenance therapy while it is unclear if pre-FMT antibiotics enhance therapeutic efficacy.Methods
We performed a dual-centre randomised, double blind, placebo-controlled trial of oral lyophilised FMT in adults with mild-moderately active UC (total Mayo 4-10). All subjects received 2-weeks of pre-FMT antibiotics (amoxycillin, metronidazole and doxycycline) before 1:1 randomisation to either oral FMT (0.35g stool content per capsule from 1 of 2 healthy donors) or identical placebo for 8 weeks. Enforced tapering and cessation of corticosteroids was mandated. The primary endpoint was week 8 steroid-free clinical remission with endoscopic remission or response (total Mayo score ≤2 with subscores ≤ 1 for rectal bleeding, stool frequency and endoscopic appearance, and ≥1-point reduction from baseline in endoscopy subscore). Responders to FMT induction were re-randomised to either continue maintenance FMT or withdrawal of FMT with final outcomes assessed at week 56.Results
Recruitment was paused due to the COVID-19 pandemic. 37 patients were randomised. Baseline patient and disease characteristics were balanced between the randomised groups. The primary outcome was achieved in 8/16 (50%) receiving FMT versus 3/19 (16%) receiving placebo (OR: 4.63; 95%CI: 1.74-12.30; P=0.002). Steroid-free clinical remission rates and endoscopic remission rates were 69% vs 26% (P=0.012) and 44% vs 16% (P=0.074) in the FMT and placebo arms, respectively. Reported SAE were worsening colitis (2 FMT, 1 placebo) and PR bleeding relating to previous anal surgery (placebo). Ten patients entered the maintenance withdrawal study. Steroid-free clinical, endoscopic and histologic remission was achieved in 4/4 patients who continued daily oral FMT, with all 6 patients randomised to FMT withdrawal having a flare of disease with a median time to relapse of 6 months.Conclusion
Oral lyophilised FMT following antibiotic pre-treatment for mild-moderately active ulcerative colitis was associated with a significant increased rate of clinical remission with endoscopic remission or response versus antibiotic treatment alone at week 8. Pre-treatment antibiotics had an additive impact upon treatment efficacy compared with previous studies utilising FMT. Maintenance FMT therapy was associated with sustained clinical, endoscopic and histologic remission at week 56. Treatment was well tolerated and there were no new safety signals related to FMT therapy.