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Background Combination therapy with an immunomodulator (IMM) and an anti-TNF agent (specifically infliximab) is recommended in Crohn’s disease (CD) and ulcerative colitis (UC) patients to improve efficacy and reduce anti-TNF immunogenicity. Combo therapy increases the risk of adverse events and therefore attempts are made to de-escalate therapy in clinical practice. There are scarce data about relapse rates after discontinuation of either IMM or anti-TNF among patients with long-term remission under combination therapy. The aims of this study were to assess the risk of relapse in a cohort of UC and CD patients with long-standing remission after discontinuation of IMM or anti-TNF and to identify predictive factors for relapse. Methods This is a retrospective unicentric study that included patients with UC or CD on combination therapy and sustained clinical remission at least for 6 months. IMM or anti-TNF were stopped upon treating-physician decision and data were collected until relapse or last follow-up. Relapse was defined as the onset of clinical, biological, endoscopic or radiological activity, leading to therapeutic intervention. The survival without relapse is represented by Kaplan–Meier curve and analyzed by log rank test. Hazard ratios (HR) for relapse were estimated by Cox proportional hazard regression analyses and are reported with 95% confidence intervals (CI). Results Eighty-eight patients (60 CD (68.2%), 28 UC (31.8%) were included. Demographic data and clinical characteristics are shown in tables 1 and 2. Forty-eight patients (54.5%) discontinued IMM and 40 (45.5%) anti-TNF. Median time of follow-up was 33 months (IQR 18.00-55.75). During follow-up, relapse rate was 16.7% in the IMM discontinuation group and 52.5% in the anti-TNF discontinuation group (p Conclusion Discontinuation of anti-TNF in patients on combination therapy with IMM and anti-TNF and long-standing remission led to significantly higher relapse rates compared to discontinuation of IMM. Retreatment after anti-TNF discontinuation was effective and safe.

Background It has been suggested that the transition of patients from paediatric to adult care units may be key in the outcomes of inflammatory bowel disease (IBD). However, the impact of transition in real clinical practice has been barely studied. Aims: Principal: to evaluate the impact of transition on clinical outcomes in IBD. Secondary: to describe the prevalence of transition programs in Spain; to identify predictive factors of poor clinical outcomes; and to evaluate the percentage of patients with loss to follow-up. Methods Multicenter, retrospective, and observational study of IBD patients transferred between 2017-2020. Two groups (transition/no-transition) were compared retrospectively. Transition was defined as a structured process with at least 1 join visit involving the gastroenterologist, paediatrician, and a program coordinator, as well as the parents and the patient. Outcomes within the first 12 months after transfer were analysed. The main variable was the presence of “poor clinical outcome” defined as an IBD flare, hospitalisation, surgery or any change of the treatment due to an IBD flare. Predictive factors of poor clinical outcome were identified in multivariate analysis. Results A total of 278 patients from 34 Spanish hospitals were included: 185 patients (67%) from 22 hospitals (65%) performed a structured transition. In hospitals without transition, 91% of the patients were transferred to an IBD-specialist. In 66% of the patients in the transition group, 1 joint visit was performed. The median age of transfer was 16 years [interquartile range (IQR)=12-20]. Baseline characteristics of both groups are detailed in Figure 1. At 1-year after transfer, hospitalisations and corticosteroid treatment were more frequent in the no-transition group (10 vs. 3%; p=0.025; 16 vs. 5%; p=0.002). At 1-year after transfer, 89 patients (27% transition vs. 43% no-transition; p=0.005) had poor clinical outcome [median time: 9.3 months; 95% confidence interval (CI)=8.4-10.1 in no-transition; 10.4 months (95%CI 9.9-10.9) in the transition group]. In the multivariate analysis, the lack of transition [Hazard Ratio (HR)=2.1; 95%CI=1.4-3.3], IBD activity at transfer (HR=4.9; 95%CI=3.1-7.9), BMI Conclusion In the present study, to our knowledge the largest performed so far, the benefit of paediatric to adult transition program on patients’ outcomes has been demonstrated. The importance of achieving remission before transfer has also been highlighted.

Background Tofacitinib is an oral JAK1 and JAK3 inhibitor approved for the treatment of moderate to severe ulcerative colitis (UC). The aim of this study is to identify the relevant cellular subsets and genes involved in response and/or resistance to tofacitinib using temporal single-cell RNA sequencing (scRNA-seq). Methods Colon biopsies from patients with active moderate to severe UC starting tofacitinib 10 mg bid for 8 weeks and 5 or 10 mg bid thereafter were collected at baseline (n=11) and during follow-up (week 8, 16, 24 and/or 48; n=12 samples) and processed by scRNA-seq. Patients were classified as responders (R) or non-responders (NR) based on the decrease in the endoscopic Mayo score of at least 1 point from baseline during follow-up. Additional biopsies were used for bulk RNA qPCR analysis (baseline n=24, follow-up n=39) and histology. Blood samples were also collected at baseline (n=15) and during follow-up (n=30) for transcriptional analysis. Results Fourteen out of twenty-four patients enrolled in this study responded to tofacitinib treatment. No baseline demographics or clinical differences were observed between R and NR. In blood, tofacitinib did not significantly modulate the expression of genes related to total T cells, Tregs, B cells, neutrophils or inflammatory monocytes independently of response. However, in R, JAK/STAT pathway targets SOCS1 and SOCS3 were significantly decreased both in blood and in tissue. ScRNA-seq analysis demonstrated partial recovery of the epithelium and a decrease of plasma cells, inflammatory fibroblasts and neutrophils in R. Importantly, the proportion of T cells remained unaltered. These findings were transcriptionally and histologically validated. In contrast, in NR, tofacitinib did not drive epithelial repair or significant remodeling of the stromal compartment, instead ongoing inflammation induced a small but significant increase in the proportions of neutrophils and inflammatory fibroblasts. Furthermore, NR M2 macrophages upregulated the expression of M1-related genes (CLEC5A, SPP1 and INHBA) during follow-up, while in R tofacitinib induced upregulation of IGF1 and IL10RA in this population of macrophages. Conclusion Our study suggest that tofacitinib has little effect on systemic cells. Beyond changes in the mucosa of R that are associated to mucosal healing (increased epithelial and decrease inflammatory cells), scRNAseq analysis reveals previously undescribed effects of tofacitinib on macrophage populations in NR. This suggests a bias towards pro-inflammatory phenotypes in these patients as a potential cause of sustained inflammation in tofacitinib refractory patients. This is an independent study promoted by IDIBAPS and financed by a Pfizer Independent Medical Grant (grant 54549477).

Background Perianal fistulizing disease (PFD) is a complication occurring in about 20% of Crohn’s Disease (CD) patients. It consists of the formation of new epithelised tracks connecting the intestine with the outer perianal region, which dramatically worsens a patient's quality of life. The mechanisms driving fistula formation have not been elucidated and therefore, there are currently no specific treatments for PFD. Methods We collected rectum biopsies of CD patients with and without PFD in the absence of rectal inflammation (CD and CD+PFD), and with active rectal inflammation (CDinf and CD+PFDinf) (Fig.1). Rectal tissue samples were processed for RT-qPCR, or histologic analysis, and single-cell RNA sequencing (scRNAseq) for each patient. Results Differential expression gene (DEG) analysis of CD4+ and CD8+ T cells comparing CD vs CD+PFD and CDinf vs CD+PFDinf patients, respectively, revealed increased expression of TGFB1 in patients with fistulae. To investigate the main cellular subsets TGFB1 was interacting with, we performed ligand-receptor interaction analysis using CellphoneDB, which indicated that T-cell derived TGFB1 was primary interacting with the stromal compartment (Fig.2). 365 DEG were found in lamina propria (LP) fibroblasts of CD+PFD compared to CD, including TGFβ1-inducible genes such as TFPI2, SERPINE2 and MMPs 1 and 3. These changes were validated by bulk RT-qPCR, underscoring their potential use as PFD biomarkers (Fig.3). Moreover, we also identified a signature of elastin fibre assembly genes dysregulated in CD+PFD fibroblasts, suggesting molecular changes in the formation of elastin fibres in these patients. To determine whether the differentiation of fibroblasts was altered in the context of PFD, we conducted trajectory analysis using RNA velocity. Whilst fibroblasts in CD patients preferentially differentiate towards myofibroblasts, patients with PFD are biased towards LP fibroblasts, indicating an overall structural rearrangement of the mesenchyme in the rectum of patients with PFD, regardless of their inflammatory status (Fig.4). Importantly, analysis of an independent scRNAseq dataset of CD and ulcerative colitis (UC) patients showed higher expression of TGFB1 in T cells of active CD compared to active UC patients, suggesting that these alterations are already present in CD patients before the onset of a fistulizing phenotype and might potentially contribute to explain the absence of PFD in UC patients. Conclusion Based on these results, we suggest that the rectum of patients suffering from PFD present cellular and transcriptomic differences compared to CD patients without PFD. These changes are inflammation independent and point towards the TGFβ pathway as the main driver of this complication.

Background Main aim: To evaluate the retention rate of ustekinumab compared to vedolizumab in Crohn’s disease patients who failed anti-TNF therapy in clinical practice. Secondary aims: To compare the short-term and long-term effectiveness, and the safety of both treatments. Methods Crohn’s disease patients who had received either vedolizumab or ustekinumab after failure or intolerance to anti-TNF agents from ENEIDA registry were included. ENEIDA is a prospectively maintained database promoted by GETECCU. A total of 755 patients from 30 centres were included at time of data extraction. Clinical activity was classified based on Harvey-Bradshaw index both at short (during induction) and in the long-term. Kaplan-Meier curves, Cox regression models, inverse probability weighting and propensity matching score analyses were performed to compare both drugs and to identify predictive factors of treatment effectiveness and durability. Results 755 patients were included (195 in the vedolizumab cohort and 560 in the ustekinumab cohort). After a median of 20 months (IQR 7.4–30) of follow-up, the survival rate for ustekinumab therapy was higher than vedolizumab (Figure 1). The propensity matching score verified the differences between both therapies. The short-term proportion of patients on clinical remission, steroid-free remission and clinical response was also superior in the ustekinumab cohort (Figure 2). In the long-term, significant differences were observed 2 years after the beginning of the treatments, although no differences in clinical response and remission rates were detected in patients who achieved clinical response at week 16 between both cohorts. Vedolizumab was discontinued in 142 patients and ustekinumab in 185, mainly due to primary non-response (52% in the vedolizumab and 58% in the ustekinumab cohort) and loss of response (34% and 25%, respectively) despite the fact that 35% of the patients required intensification. The predictive factors associated to the discontinuation of the therapy are described in table 1. Adverse events were observed, overall, in 12% of the patients, without differences between both groups (Table 2). Following the discontinuation of the treatment with vedolizumab/ustekinumab, other biologic agents were prescribed in 56% of the patients, and 27% underwent surgery. Conclusion In clinical practice, a relatively high proportion of Crohn’s disease patients who received ustekinumab or vedolizumab for anti-TNF failure, maintained these drugs in the medium-long term, although ustekinumab retention rate was higher in comparison with vedolizumab.

Background The ALI (air liquid-interface) culture derived from human primary intestinal epithelium is generating considerable interest for closely reproducing the mature cell features of the differentiated epithelium in a 2D configuration. However, the phenotypic changes occurring in the human ALI culture during cell differentiation have thus far not been explored in depth. Here, we aimed to characterize the cell composition of human ALI culture over time. Methods 3D epithelial organoids (n=3) were expanded from human colonic samples and organoid-derived single cells were seeded on a Transwell. After reaching confluence, the submerged 2D was switched to ALI and maintained for 7 days. The ALI culture was analysed every 24h by qPCR, membrane staining (H&E and immunofluorescence) and trans-epithelial resistance (TER) (Figure 1). Results The confluent pre-ALI (TER>200 Ω*cm2) showed high mRNA expression of stem cell markers (i.e., LGR5, AXIN2), while several differentiation markers (i.e., ZG16, CLCA1, ANPEP, AQP8, BEST4, CHGA) were almost undetectable, thus resembling the stem cell niche compartment. Air exposure of the 2D culture induced an early and transient (limited to ALI-day 1) transcriptional up-regulation of proliferation markers (i.e., MKI67, CDCA7) and OLFM4, followed by a concomitant marked downregulation of stem cell markers, thus mimicking the Transit Amplifying compartment. OLFM4 protein, as observed by immunofluorescence, showed an early cytoplasmic accumulation followed by secretion at later time points (from ALI-day 5). Differentiation towards absorptive and secretory lineages increased gradually from ALI-day 5 and ALI-day 7 onward, respectively, at both the transcriptional and protein level. Expression changes were accompanied by the progressive transition of the ALI monolayer from a squamous to a columnar morphology. In parallel, TER promptly increased upon ALI switch, thus indicating the early establishment of cell-cell junctions. Conclusion By recapitulating the cell composition identified along the crypt, the ALI culture holds promise to be a versatile in vitro model for studying how the different epithelial cell compartments respond to specific environmental stimuli, like those present during an inflammatory flare.

Background The use of ustekinumab (UST) and vedolizumab (VDZ) as first line therapy for inflammatory bowel disease (IBD) is increasing due to safety reasons and contraindications of anti-TNFs. However, there are no studies evaluating their efficacy and safety in clinical practice under these circumstances. Thus, our aims were to describe bionaïve patients’ characteristics starting VDZ or UST and to evaluate treatment persistence of these drugs and their safety profile in this scenario. Methods Descriptive, retrospective and multicenter study based on the ENEIDA registry (a large, prospectively maintained database of the Spanish Working Group in IBD –GETECCU). All IBD patients never exposed to biological agents who started VDZ or UST as first-line biological treatment were identified. Results Out of 29,450 IBD patients ever exposed to biological drugs included in the ENEIDA registry, 924 patients met the inclusion criteria. Of these, 366 (40%) started UST and 558 (60%) VDZ as first line biological therapy. UST group: 48% women, 90% Crohn's disease (43% ileal; 13% colic; 43.5% ileocolic; 31% upper gastrointestinal involvement; 25% stricturing behaviour; 12% penetrating, 18% perianal disease), 10% ulcerative colitis (74% extensive, 17% left-sided, 9% proctitis), 27% had extraintestinal manifestations (EIM). Median age at the beginning of UST was 57 years (IQR 57-70), 17% patients had a past history of malignancy and, 34% had associated comorbidities. UST indication was luminal activity except in 2% for perianal disease and 5% for EIM. At the end of follow-up (median 14 months [IQR 6-30]), 12 patients (3.3%) developed adverse effects (AEs) that led to treatment discontinuation in the majority of them (92%). VDZ group: 44% women, 42% Crohn's disease (44% ileal; 18% colic; 38% ileocolic; 25% upper gastrointestinal involvement; 28% stricturing behaviour; 13% penetrating; 7% perianal disease), 58% ulcerative colitis (50% extensive, 42% left-sided, 8% proctitis), 17% had EIM. The median age at the beginning was 61 years (IQR 48-71), 24% had past history of malignancy and, 34% associated comorbidities. The indication was exclusively luminal activity. At the end of follow-up (median 21 months [IQR 8-36]), 36 patients (6.5%) had AEs, that lead to treatment withdrawal in 67% of them (24 patients). Cumulative treatment persistence rates were 78%, 60% and 50% for VDZ and 85%, 75% and 66% for UST at 12, 24 and 36 months, respectively (P Conclusion In clinical practice, VDZ and UST are used first-line particularly in elderly patients with comorbidities. Both treatments have a good safety profile and a high persistence of treatment, being superior for ustekinumab.

Background Over the last years significant advances have arisen in CD. New therapies with different mechanisms of action have been approved for the management of Crohn’s disease (CD). However, there is limited evidence on optimal positioning of agents as first-or second-line therapies due to the lack of head-to-head robust comparative data. Our aim was to establish feasible and practical recommendations for the management of patients with moderate to severe CD with the use of anti-tumour necrosis factor (TNF) drugs, with special focus on controversial areas. Methods A group of 9 expert gastroenterologists identified current relevant clinical controversies in the management of CD with anti-TNF therapies. A comprehensive literature review was performed to analyze them and a survey was launched to examine current clinical practice. This was a structured survey organized in 2 main sections that included several questions: 1) Sociodemographic and practice related questions; 2) Opinion and attitude in daily practice related to: the use of anti-TNFs, vedolizumab or ustekinumab in naïve and refractory patients, the role of HLA-DQA105, or monitoring of drug levels. An invitation to participate was emailed to a representative number of 244 IBD treating physicians all over the country. The results of the literature review and survey were discussed in a nominal group meeting, and a set of statements were proposed for a Delphi process. The participants of the survey were also invited to the Delphi. Agreement was defined if at least 70% of the participants voted ≥7 (from 1, totally disagree to 10, totally agree). For each statement, the level of evidence and grade of recommendation was established based on the Oxford Evidence Based Medicine categorization. Results A total of 14 statements were generated (table 1 depicts the statements and the results of the Delphi). All but two achieved required level of agreement. The statements cover the following areas: 1) use of first-line non-anti-TNF biologic therapy; 2) role of HLA-DQA1*05 in daily practice; 3) attitudes in primary nonresponse and loss of response to anti-TNF therapy due to immunogenicity; 4) ustekinumab or vedolizumab if a change of mechanism of action is considered; 5) anti-TNF drug levels monitoring during induction; 6) combined therapy with an immunomodulator and anti-TNF monotherapy. Conclusion This document sought to pull together the experts’ attitudes when dealing with different clinical scenarios of patients with CD on anti-TNF.

Background Magnetic resonance enterography (MRE) provides an accurate evaluation of transmural lesions in Crohn's Disease (CD). However, MRE findings associated with poor long-term outcomes in CD are not yet defined. Identification of such parameters would help in defining therapeutic goals. AIMS to identify predictors of long-term clinical outcomes based on MRE findings performed 46 weeks after biological treatment initiation in patients with CD. Methods single-center, prospective, longitudinal study conducted from 2010 to 2019. Patients with CD who had an MRE evaluation 46 weeks after biological treatment initiation and clinical follow-up of at least 3 years were evaluated. Results 89 patients were included with a median follow up of 53 months (IQR 44-76). 59 patients had ileal (66.3%), 26 ileocolic (29.2%) and 4 colonic disease (4.5%). 31 (34.8%) had inflammatory behavior, 27 (30.3%) stricturing, 9 (10.1%) fistulizing and 22 (34.7%) stricturing/fistulizing. 70 (78.7%) were treated with anti-TNFα, 5 (5.6%) vedolizumab and 14 (15.7%) ustekinumab. During follow-up, 25 (28.1%) required surgery, 17 (19.1%) hospitalization, 40 (44.9%) had clinical relapse (CDAI >150), 12 (13.5%) required corticosteroids and 12 (13.5%) required endoscopic dilatation. 32 (36.0%) patients needed resection surgery or endoscopic dilatation. MaRIA score ≥11 in any segment at week 46 was associated with a higher risk of surgery [HR 6.28 (1.42-27.84), p=0,02] or surgery/endoscopic dilatation [HR 3.76 (1.24-11.38), p=0,02]. Relative contrast enhancement (RCE) >103 was associated with higher risk of clinical relapse [HR 1,01 (1.00-1.02), p=0,03] and corticosteroids requirement [HR 1,01 (1.00-1.02), p=0,05]. Conclusion MRE findings at week 46 after biological treatment initiation predict long-term clinical outcomes in CD patients. The main determinants of poor clinical prognosis were MaRIA score ≥11 and RCE >103. Patients with these persistent findings may be candidates for treatment optimization.

Background A new formulation of biosimilar infliximab (IFX) has recently been approved for subcutaneous administration (SC) that may offer pharmacokinetic advantages resulting in higher drug exposure. Our purpose was to evaluate the efficacy, safety, pharmacokinetic changes and patients’ acceptability after switching from intravenous (IV) to SC IFX in a cohort of patients with Inflammatory Bowel Disease (IBD) in clinical practice. Methods Observational, prospective and single-center study including patients with IBD in sustained (≥6 months) clinical remission under IV IFX that were switched to SC IFX 120 mg every 2 weeks. Prospective monitoring was performed with clinical and laboratory data including IFX trough levels prior to the last IV infusion (W-IV), prior to the first SC administration (W-0), and after 16 weeks (W-16) and 52 weeks (W-52) of SC treatment. Patients’ satisfaction has been evaluated at W-52. A descriptive analysis of the data has been carried out with the R Studio statistical program using means and Wilcoxon signed rank test. Results Sixty patients have been included, all have achieved W-16 and twelve W-52. Thirty-five (58,3%) are men with a median age of 42,5 (20-71) years. Thirty-eight (63,3%) have Crohn’s disease and twenty-two (36,7%) ulcerative colitis, with a median disease duration of 11,3 years. They have been receiving IV IFX (5mg/kg/8 weeks in 95% of cases) for 5,7 (0,6-21,1) years, at a stable dose (≥6 months). Twenty-seven (45%) received concomitant immunomodulatory treatment and IFX was the first biological in 75% of patients. None of the patients presented clinical relapse during follow-up (Table 1). Median trough IFX levels under IV treatment were 3,9 µg/dl (W-IV) and 4,3 µg/dl (W-0). Compared to W-0, IFX trough levels were significantly higher both in W-16 [17,05 µg/dl (5,59–57,60), p Conclusion Switching from IV to SC IFX is safe, effective, and well accepted by patients with stable IBD. A significant increase in IFX trough levels is observed with the SC formulation.

Background Ulcerative proctitis may have a mild and less aggressive course, although evidence is scarce because these patients are excluded from participation in randomized controlled clinical trials. The aim is to identify clinical characteristics and complications associated with ulcerative proctitis refractory to conventional therapy. Methods Patients included in the prospectively maintained ENEIDA registry from GETECCU with ulcerative proctitis were included. Socio-demographic data were evaluated. We defined ulcerative proctitis based on ECCO guidelines and immunosuppression as the use of immunomodulators and/or biologics. Logistic regression was used to identify the independent factors associated with immunosuppressive therapy among the different socio-demographic data. Results From a total of 34.716 patients with ulcerative colitis, 6281 (18%) patients with ulcerative proctitis were identified. Mean age was 53 ±15 years and mean duration of illness was 12 ± 9 years. Surgery was necessary only in 2% of patients, 31 (0.5%) panprotocolectomy or subtotal colectomy. The clinical characteristics of the patients with and without immunosupressive therapy are summarized at table 1. A total of 3691 patients received oral 5-ASA (58.8%) and 4652 (74.1%) topic 5ASA. 636 (10.1%) were refractory to 5-ASA and corticosteroids, necessitating immunosuppression: 459 patients with azathioprine (7%), 28 with 6-mercaptopurine (0.4%), 49 with methothrexate (0.8%), 191 with infliximab (9%), 125 with adalimumab (2%), 50 with golimumab (0.8%), 57 with vedolizumab (0.9%), 6 with ustekinumab (0.1%) and 3 with tofacitinib (0.0). 316 (5%) patients needed one biologic therapy, 95 (1.5%) needed 2 biologics and 40 (0.6%) at least three different biologics. Longer duration of illness and use of corticosteroids were associated with higher risk of immunosuppression. Conclusion Good clinical outcomes were recorded in ulcerative proctitis, with only 10% of patients treated with immunosuppression therapy. The risk factors of immunosuppression were longer duration of illness and use of corticosteroids.

Background The variability and unpredictability of drug efficacy in ulcerative colitis (UC) patients, including tofacitinib, an oral JAK1 and JAK3 inhibitor, remains a perplexing reality. The aim of this study is to identify the relevant cellular subsets and genes involved in response and/or resistance to tofacitinib using single-cell RNA sequencing (scRNA-seq). Methods Colon biopsies from UC patients starting tofacitinib treatment (10 mg twice daily) were collected from the involved region at baseline (n=9), week 8 (n=7) and week 16 (n=5). Endoscopic response was evaluated at week 16 and patients were classified as responders or non-responders based on whether they had a decrease in the endoscopic Mayo score of at least 1 point from baseline. Biopsies were immediately disaggregated and single-cell suspensions were processed using 10x Genomics Next-GEM Single Cell kit assays (Chromium 3’ v3.0). After QC filtering, a total of 61,646 cells were obtained. Additional biopsies were collected at all timepoints for validating scRNA-seq results by bulk RNA analysis (qPCR). Results Four out of nine patients enrolled in this study responded to tofacitinib treatment. Analysis of the proportions of mucosal cells identified by scRNAseq revealed a partial recovery of the epithelial and stromal cell compartments and a decrease in the total number of plasma and myeloid cells in responding patients at week 8, which was sustained at week 16 (Table 1). scRNA-seq analysis revealed a significant downregulation of SOCS1 in the CD4 and B cell populations, and of both SOCS3 and IRF1 in the neutrophil and B cell populations in all patients receiving tofacitinib treatment irrespective of endoscopic response. These results were validated by qPCR of bulk biopsy RNA (p=0.0245, p=0.0299 and p=0.0230 respectively). In contrast, S100A8 and CHI3L1 were significantly downregulated only in responders, correlating with a decrease in the proportion of mucosal inflammatory cells including neutrophils, monocytes, and inflammatory fibroblasts. Regarding prediction of outcome, a scRNA-seq comparative analysis showed that high levels of IL17A-expressing T cells at baseline significatively correlated with failure to achieve response upon tofacitinib treatment. This result was validated by qPCR of bulk biopsy RNA (p=0.0059). Conclusion Our study demonstrates the potential of using scRNAseq of intestinal biopsies not only to characterize the mechanism of action of tofacitinib, but also to describe the cellular events associated with response to this therapeutic intervention. Moreover, we show the potential of scRNAseq to identify predictors of response to tofacitinib in patients with UC.

Background It has been reported that familial aggregation occurs in 10–20% of inflammatory bowel disease (IBD) patients1. Familial IBD has been associated with disease anticipation2 and with an increased need for immunosuppressants3 and surgery4. However, most studies were performed before the widespread use of biological agents and this may impact on the need for surgery. We aimed to compare the clinical outcomes of IBD (by means of the need for biological therapy and abdominal surgery) between familial and sporadic forms of IBD in the era of biological therapies. Methods Data were extracted from the ENEIDA registry by GETECCU, a Spanish, prospectively-maintained, IBD database in which more than 80 centers are participating. Only adult patients diagnosed with IBD since 2005 and prospectively followed in the registry since diagnosis were included. Familial IBD was defined as those cases with at least one first-degree relative diagnosed with IBD. Sporadic IBD was defined as those cases with no familial relative (of any degree) with IBD. Kaplan-Meier survival curves were performed to evaluate the cumulative probabilities of remaining biologic-free and surgery-free. Log-rank test was performed to compare them between familial and sporadic IBD forms. Chi-square test was performed for the rest of variables. Results A total of 5,263 patients (2,627 Crohn’s disease [CD]; 2,636 ulcerative colitis [UC]) were included. Of them, 507 (10%) were familial cases (274 CD, 233 UC; P=0.05). The median follow-up was 38,4 and 35.5 months, respectively (P=0.086). Familial cases were younger (P=0.022) and had a higher proportion of females among UC cases (P=0.048). No differences were observed in the need for biological therapy in both CD and UC between familial and sporadic IBD. Regarding surgery, no differences were observed in the cumulative probabilities of a first intestinal resection for CD and colectomy for UC. Similar results were obtained when all the analyses were restricted to those subgroups at high-risk for surgery (i.e. CD with ileal involvement and extensive UC). Conclusion In patients diagnosed with IBD in the era of biological therapies, familial forms have the same requirements for biological agents and resectional surgery as sporadic forms. Therefore, familial aggregation does not seem to be a factor for a more aggressive disease.

therefore aimed to find genetic and clinical factors predictive of thiopurine induced AE in patients with CD. Methods: Four hundred and sixty eight CD patients were screened and one hundred and eighty one patients treated with thiopurines were included in our study. Thiopurine AE included were myelosuppression, hepatotoxicity and pancreatitis. Clinical data collected included age, ethnicity, gender and smoking status. Patients’ DNAwas tested for specific polymorphisms in the TPMT, GSTM1and GSTT1 genes. Results: Twenty-seven patients (15%) developed AE requiring thiopurine discontinuation. The most common AE was myelosuppression (12 patients), followed by pancreatitis (9 patients) and hepatotoxicity (6 patients). Univariate analysis showed that patients developing AE were significantly older when receiving thiopurines (mean 34.19±14.0 vs. 27.95±11.7 years old, P= 0.016) and more likely to be current or past smokers (51.9% vs 30.0%, P= 0.044). Specifically, patients who developed thiopurine induced pancreatitis were more likely to be past or present smokers (p = 0.001), and patients who developed hepatotoxicity were older than patients who did not develop AE (p = 0.014). Only four patients (2.2%) were heterozygous for TPMT polymorphisms, and none developed thiopurine induced AE. No association was found between GSTM1 or GSTT1 polymorphisms and the development of AE (p = 0.08 for GSTM1 wild-type). On multi-variant analysis past or current smokers were at increased risk for developing thiopurine related AE (OR 2.84, CI 95%: 1.104 7.296). Conclusions: TPMT, GSTM1 and GSTT1 genotype did not predict development of thiopurine induced AE in our patients. Past or current smokers were at increased risk for thiopurine induced AE, specifically pancreatitis. These findings may have implications for decision making in treating CD patients with thiopurines.