Refractory Colitis Research Articles

INTERLEUKIN 21-INDUCED METABOLIC REPROGRAMMING DRIVES CD4 T CELL INFLAMMATORY RESPONSE DURING INTESTINAL INFLAMMATION

Abstract BACKGROUND Significant proportion of inflammatory bowel disease (IBD) patients continue to respond inconsistently to therapies, underscoring disease complexity and the need for efficacious treatment. Interleukin 21 (IL-21), which is known to support T helper (Th) cell function, is highly expressed within inflamed tissues of IBD patients compared to healthy controls. Also, inflammatory regulatory T cells (Tregs) have been linked to refractory human IBD, and the complete induction of IBD in mice has been shown to require IL-21. Given that healthy Tregs are critical for self-tolerance and prevention of IBD, we investigated the metabolic role of IL-21 in instigating Treg dysfunction and the therapeutic ramifications of targeting metabolic pathways during IBD. METHODS Human Tregs as well as relevant control Th cells were generated from naïve CD4+ T cells isolated from healthy blood donors. Microarray analysis was utilized for targeted transcriptional profiling. Immune phenotyping was assessed by fluorescence-activated cell sorting. Metabolic phenotyping of cells was assessed by Seahorse flux analysis and mass spectrometry-based targeted metabolomics. Colitis was induced in Rag1-/- (T and B cell deficient) mice by adoptive transfer of pathogenic naïve CD4+ T cells. RESULTS Acute IL-21 stimulation of human Tregs induced glycolysis and fluctuations in mitochondrial respiration (i.e. oxidative phosphorylation – OXPHOS), as assessed by Seahorse flux analysis. In agreement, microarray analysis, validated by qPCR, revealed IL-21-induced alterations in the expression of genes associated with glycolysis and OXPHOS metabolism. Prolonged IL-21 stimulation rendered Tregs susceptible to inflammatory response, as evidenced by the production of inflammatory Th cytokines such as interferon γ, tumor necrosis factor, IL-17A, and IL-17F. Exploring the mechanisms underlying IL-21-induced effects, we observed reduced expression of inactive glycogen synthase kinase 3 (GSK3) β, a protein known to prevent pyruvate entry into the mitochondria. This reduction in inactive GSK3β in response to IL-21 was accompanied by high abundance of intracellular pyruvate and lactate, as assessed by targeted metabolomics. Importantly, GSK3 inhibition or exogenous membrane-permeable methyl pyruvate abrogated IL-21-induced metabolic rewiring and Treg inflammatory response. Moreover, GSK3 inhibition diminished the metabolic and inflammatory function of Th cells. Lastly, GSK3 inhibition prevented pathogenic CD4+ T cell-induced colitis in mice, as evidenced by reduced Disease Activity Index, Mouse Colon Histology Index, and serum inflammatory cytokines. CONCLUSIONS IL-21 potently engages human Tregs in a metabolic state that subsequently augments an inflammatory phenotype. Therefore, desensitizing CD4+ T cells to detrimental cues, such as IL-21, may augment Treg function during human IBD.

COMBINATION BIOLOGIC AND SMALL MOLECULE THERAPY FOR REFRACTORY ULCERATIVE COLITIS

Abstract INTRODUCTION Some inflammatory bowel disease (IBD) patients do not achieve remission with maximal medical therapy. We present a case of refractory UC who achieved clinical, endoscopic, and histologic remission after combining biologic and small molecule therapy. CASE DESCRIPTION A 25-year-old Caucasian male was referred to our clinic for refractory UC. Since diagnosis four years prior, he failed mesalamine, azathioprine (intolerant), adalimumab (secondary nonresponse), vedolizumab (secondary nonresponse) with inability to taper prednisone. Upon presentation to our clinic he was at week 14 of infliximab therapy without clinical improvement. Therapeutic drug monitoring revealed adequate infliximab levels without antibodies. Colonoscopy revealed mayo 2-3 disease with discrete ulcerations (Figure 1). Due to primary non-response, he was initiated on ustekinumab (UST). He remained clinically active despite dose escalation up to evey four weeks and prednisone use. Tofacitinib was initiated with initial clinical improvement, then worsening after 3 months. The Tofacitinib dosing was increased from twice daily to three times daily and repeat colonoscopy revealed pan-colitis with Mayo 2 disease. Due to refractory disease the patient was started on combined therapy of tofacitinib twice daily with UST. On dual therapy the patient experienced progressive clinical improvement. After a year of dual treatment colonoscopy showed no disease activity, and biopsies showed no evidence of cryptitis, or crypt abscesses or active inflammatory infiltrate (Figure 2). DISCUSSION This case highlights the benefit of combination biologic therapy with small molecule therapy in medically refractory IBD. There are limited prospective data to endorse the widespread implementation of combination therapy. A meta-analysis of thirty studies, involving 279 patients, reported 59% were able to achieve clinical remission and 34% achieved endoscopic remission with treatment of dual biologic or small molecule therapy1. Concerns involving safety of combination biologic and small molecule therapy continue to be evaluated. In our case, the patient achieved clinical, endoscopic, and histologic remission with tofacitinib and UST without adverse effects. We present this case to support the safety and efficacy of combination therapy in medically refractory patients. REFERENCES Ahmed W, Galati J, Kumar A et al. Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2021. https://doi.org/10.1016/j.cgh.2021.03.034.

P283 Infliximab re-challenge: could it be an option in refractory IBD patients?

Abstract Background Infliximab (IFX) is effective in treatment of inflammatory bowel disease (IBD). However, primary non-response and secondary loss-of-response rates go up to 30–40% and intolerance may occur leading to treatment switch. Unfortunately, even with increased availability of new molecules, some patients remain refractory to all currently available medical options. This study assesses the effect of IFX re-challenge in a real-life cohort of highly refractory IBD patients. Methods A retrospective observational study was set up to analyse the effect of IFX rechallenge in IBD patients previously treated with IFX and found refractory to other biologics. Cases between August 2018 and June 2021 with at least one year of follow-up (FU) were analysed. Clinical, biological (CRP and faecal calprotectin [FC]) and endoscopic response was evaluated, as well as adverse events (AE). Results Ten patients with refractory IBD were included (9 Crohn’s disease [CD], 1 ulcerative colitis [UC]). Details on previous treatment before IFX re-challenge are shown in Table 1. All patients had active disease at the start of IFX re-challenge. Median baseline CRP was 12.6mg/L [4.9–24.1] and FC 396mg/kg [64–2786.8]. IFX was started in combination with systemic steroids, immunosuppressants and ustekinumab in 50%, 70% and 10% of patients, respectively. Baseline endoscopy showed severe active disease in 7/8 patients. Clinical and endoscopic response rates are shown in Table 2. Biological response is shown in Figure 1. After 1 year FU, all (7/7) required intensified dosing (4-weekly), in 3/7 corticosteroid free clinical remission was reached. IFX re-challenge was discontinued after the second administration in 2/10, due to a severe allergic reaction despite premedication with antihistamines and corticosteroids (1 anaphylactic shock admitted to intensive care unit, fully recovered). IFX was continued in 8/10. Other AE (not in all cases considered to be related to IFX) included: disease flare-up requiring hospitalization (3/10), liver test abnormalities (1/10), new perianal abcedation (1/10), subobstruction (1/10), C. difficile infection (1/10), EBV infection (1/10) and Addison crisis (1/10). Conclusion IFX re-challenge was efficient in inducing clinical and endoscopic response in this highly refractory IBD population. However, there is a non-negligible risk of AE including infusion reaction.

P438 The Efficacy and Safety of ustekinumab Therapy in refractory Inflammatory Bowel Disease (IBD) patients with co-morbidities and old age

Abstract Background Ustekinumab is approved for treatment of active Crohn’s Disease (CD) and Ulcerative Colitis (UC) with a more favourable safety profile to anti-TNF therapy however it is still used with caution in the elderly and those with comorbidities. We present our data on safety and efficacy of Ustekinumab in our IBD population including consideration of age and existing medical conditions. Methods Clinical data on all IBD patients treated with Ustekinumab within our population between, 2016 and, 2021 were retrospectively collected from electronic records. This included baseline characteristics, diagnosis, previous medical and surgical history, comorbidities, clinical response, endoscopic response and adverse events (AEs). Results 120 (M=57, F=63) patients were identified, 98 CD, 17 UC and, 5 IBDU with a median follow up of, 13.9 months (IQR, 3–20.5) The median age of starting Ustekinumab was, 35.5 years (16–81) with, 65% (78/120) previously treated with two or more biologics suggestive of refractory disease. Clinical response was achieved in, 18.0% (16/89) of patients at, 8 weeks, 39.3% (24/61) at, 24 weeks, 42.0% (21/50) at, 1 year and endoscopic response and/or with imaging was seen in, 9/23 (39.1%) at, 24 weeks and, 3/18 (16.7%) at, 1 year. 10% (14/120) were >60 at time of starting Ustekinumab, this group had an average of, 1.4 comorbidities compared to, 0.3 in the <, 60 group (p value -0.00001), 7% (8/, 120) patients had had a prior malignancy (Non-melanoma Skin Ca, 4, Solid organ, 2, melanoma, 1, haematological, 1) and, 5 of these were in the >60 group with a median of, 10 years (IQR, 5–11) since being cured and no episodes of recurrence, with, 1 patient developing a malignancy post Ustekinumab. Adverse events (AEs) were seen in, 5.8% (7/120) of patients and a serious adverse event (SAE) in, 5% (6/120), this included, 4 patients in the <60 age group requiring admission for Intravenous antibiotics vs, 1 in the >, 60 age group (p value, 0.57). Conclusion This study contributes to the real-world data being presented regarding Ustekinumab. The efficacy demonstrated in clinical response is comparable to previous studies, the majority of patients having already been treated with two or more biologics. We have demonstrated a favourable safety profile in the over, 60 age group who had a greater number of comorbidities and a higher rate of previous malignancy. With an ageing IBD population the safety and efficacy of Biologics in the older age groups need to be further examined.

P472 Changes in colectomy for Ulcerative Colitis during the last two decades: an in-depth retrospective analysis

Abstract Background The management of ulcerative colitis (UC) has been improved due to progresses in medical and surgical practices during the past twenty years. Yet the impact of new therapies on the evolution of the three colectomy’s indications in UC (severe acute colitis, refractory ulcerative colitis and (pre-)neoplastic complication) is still not well established. The aim of this study was to compare the evolution of the surgical indications within the last two decades. Methods This was an observational retrospective study carried out in two tertiary hospitals. All patients with UC who underwent total or segmental colectomy between 2001 and 2020 were included, without age restriction. Two periods were compared: 2001–2010 and 2011–2020. Endpoints were to compare the colectomy indications, patients’ characteristics, surgical procedures, and rates of postoperative complication between the two cohorts. Results Among the 286 patients included (57% were men; median age of 40 years; 60.5% of extensive and 35.7% of distal colitis), 87 (30.4%) underwent colectomy in 2001–2010 and 199 patients (69.6%) in 2011–2020. Patients’ characteristics were similar between the two periods, including duration of UC and the severity according to the global Mayo score. Colectomy rate for refractory UC significantly decreased over time (n=119) (50.6% vs. 37.7%; p=0.042), while it increased for acute severe colitis (n=116) (36.8% vs. 42.2%; p=0.390) and (pre-)neoplastic indication (n=51) (12.6% vs. 20.1%; p=0.130) (Figure 1). Regarding surgery, there was an increased use of laparoscopic colectomy (47.7% vs. 81.4%; p<0.001) during the latter period and the median length of stay in hospital after surgery has decreased from 13 to 10 days (p=0,098). There were less early (12.6% vs. 5.5%; p=0.038) and late severe complications (1.6% vs. 0.8%; p< 0.001) and less surgical revisions (38.6% vs. 19.5%; p<0.001) without change on 30-day mortality rate (2.3% vs. 1%; p=0.391). The rate of extraintestinal postoperative infections (especially urinary, pulmonary and catheters infections) increased during the second period (27% vs; 45.7%; p=0.018). As expected, the mean number of past biotherapies was higher during the second period (1.2 versus 0.6; p<0.001), as well as the rate of pre-operative exposition to TNFα antagonists (68.4% vs. 50.6%; p=0.016). Conclusion The rate of surgery for refractory colitis has significantly decreased while the rate of colectomy for cancer and acute severe colitis has risen during the last twenty years. In the same time, surgical technics have changed with more laparoscopic surgeries associated with a reduction of postoperative morbidity despite the larger use of biotherapies.

P308 Quadruple oral antibiotic treatment in refractory Paediatric Inflammatory Bowel Disease – incidence and analysis of responders from a, 10 year cohort

Abstract Background Recent, albeit limited, studies indicate that combination oral antibiotic therapy may be an efficacious, immunosuppressive-free, alternative strategy to achieve remission in a subset of medically refractory IBD patients. We sought to identify incidence data and provide cohort analysis of any refractory IBD patients who subsequently responded to combination oral antibiotic therapy from a large paediatric inflammatory bowel disease [PIBD] centre. Methods We identified a regional cohort of prospectively acquired incident cases of paediatric inflammatory bowel disease (CD, UC and IBD-U) diagnosed <16 years of age in South-East Scotland over a, 10-year period (2009–2018) and conducted a retrospective review identifying all cases with treatment refractory disease who subsequently achieved remission with a quadruple oral antibiotic regimen (vancomycin/doxycycline/metronidazole/amoxicillin) as salvage therapy. We characterised demographic data, IBD disease type, classification, severity, duration, as well as prior treatment efficacy and duration. There was a minimum of, 2 years of follow data available. Results In total, 4 cases of successful treatment with a quadruple oral antibiotic regimen in refractory patients were identified from our, 10-year PIBD registry that included, 222 new cases of PIBD (cumulative incidence, 1.8%). Treatment was attempted in, 9 refractory patients over the period. All responders were male, median age at diagnosis, 13.1yrs (0.5, 11.3, 14.8, 15.7yrs), median disease duration was, 1.3yrs. All responders had chronically active moderate-severe disease., 3 had ulcerative colitis (Paris classification E4), the remainder had Crohn’s disease (Montreal classification B1, L3/4). All responders had disease refractory to a least, 2 biological therapies that were co-administered with either thiopurines or methotrexate., 3 of the, 4 had failed at least one steroid induction course., 3 of the, 4 maintained clinical remission at the minimum, 2 year follow up on regular oral vancomycin therapy. Conclusion A subset of patients with PIBD that is highly refractory to conventional therapeutics, including to steroids and multiple biologics, may achieve remission with a quadruple combination oral antibiotic regimen. Those with active colitic phenotypes at intervention were more likely to respond and longer-term disease remission may be maintained with regular oral vancomycin.

P593 Biologicals and small molecule combotherapies: promising experience in refractory IBD patients

Abstract Background It has been hypothesized that combination of two biologics or with a small molecule could ”break the ceiling” of the efficacy (~60%) of currently available biological therapies for IBD patients. The best combinations and their safety are, however, unknown. Methods A chart review of Inselspital, Bern University hospital und Crohn and colitis center Beaulieu Lausanne, of IBD patients on combination therapy have been performed. Data on disease phenotype, previous treatment and efficacy and safety of the new combinations have been collected and studied to help moving forward the use of this armentarium. Results Among 18 identified IBD patients (39% women, 10 ulcerative colitis, 8 Crohn’s disease) with extended and refractiry luminal disease (indication) who received 21 combination therapies between June 2017 and November 2021. They suffered from steroid-dependency and half of them were refractory to at least two anti-TNF alpha agents. These treatments have been started after a median duration of disease of 6 years (range 1–25) for a mean period of combo treatment of 11 months (range 1–52), 8 were still ongoing. Various combotherapies and clinical response (arrows; red=bad, green=good response) are presented in Figure 1. A partial or complete response was observed in 15/21 therapies (71%) with a mean decrease of CRP of 11 mg/l (range+23 to -59) and calprotectin of 399 mcg/g (range 0 – 1745) among the reponders. Concerning safety, 2 infections (otitis media, skin mycosis), 1 non hodgkin Lymphoma and 4 minor adverse events (tumefaction left parotide, eczema, 2x lymphopenia) have been reported, mostly when small molecules have been involved. Conclusion Ustekinumab combined with anti-TNF agents in Crohn’s disease is more effective than vedolizumab and tofactinib in ulcerative colitis. Combining with small molecules increases the risk of lymphopenia, of cancer (1 case of non hodgkin lymphoma) and minor infections in severe refractory and steroid-dependent inflammatory bowel disease patients.

DOP04 Inflammatory Bowel Disease (IBD) and Solid Organ Transplantation. Natural history of pre-existing and de novo IBD patients. (EITOS study of GETECCU)

Abstract Background Limited data is available of the outcome of inflammatory bowel disease (IBD) in patients with solid organ transplantation (SOT). The aim of our study was to describe the natural history of pre-existing IBD and de novo IBD after SOT. Methods A retrospective, observational, multi-centre, nationwide study was designed. IBD patients with SOT were included. We identified two separate cohorts: (1) patients with pre-existing IBD at the time of SOT and (2) patients without IBD at the time of SOT (de novo IBD). The primary outcome was IBD progression, defined by the escalation of medical treatment, surgical therapy for medically refractory IBD or IBD-related hospitalization during follow-up. Risk factors were identified using multivariate Cox proportional hazard analysis. Results A total of 177 patients (106 pre-existing IBD and 71 de novo IBD) from 31 centres were included. Baseline characteristics are shown in Table 1. Eighty-six patients with IBD and SOT underwent liver transplantation, while 82 required renal, 4 lung, 3 heart, 1 liver/kidney and 1 pancreas/kidney transplantation. Pre-existing IBD patients were followed-up over a median of 4.8 years (range 2.6–9.4). At the time of SOT, 61 patients (59.8%) were not under maintenance treatment or were treated with 5-aminosalicylates, 10 (9.8%) were on immunosuppressive therapy and 31 (30.4%) were receiving biological agents, of which 8 were on combo therapy. At the moment of SOT, only 8 patients (7.5%) had moderate IBD activity whereas the remaining patients were in remission. During follow-up 33.7% of patients with pre-existing IBD had disease progression, with a median time between SOT and IBD progression of 2.2 years (range 1.3–4.6). No differences between Crohn′s disease and ulcerative colitis were found (Figure 1). The median time of follow-up in de novo IBD group was 5.1 years (range 2.1–8.2). In this cohort, 55.9% of patients had disease progression during follow-up (Figure 2), with a median time to flare of 1.9 years (range 0.8–3.9) from diagnosis. In pre-existing IBD cohort, multivariate Cox-regression analysis identified active IBD at the time of SOT (HR=1.80; 95%CI: 1.14–2.84; p=0.012) and the presence of extraintestinal manifestations (HR=3.10; 95%CI: 1.47–6.54; p=0.003) as predictive factors of IBD progression after SOT. Conclusion One third of patients with pre-existing IBD have disease progression, needing medical therapy escalation, surgery or hospitalization after SOT. Active IBD at the time of SOT and the presence of extraintestinal manifestations were identified as risk factors for disease progression. In de novo IBD cohort, about half of patients showed disease progression during follow-up.

VEDOLIZUMAB FOR REFRACTORY MICROSCOPIC COLITIS: A CASE SERIES

Microscopic colitis (MC) is a chronic inflammatory disease of the colon that causes non-bloody, watery diarrhea occurs up to 15 times daily in the presence of normal-appearing mucosa in the colon. There are two main subtypes of MC based on histopathologic features, collagenous colitis (CC) and lymphocytic colitis (LC)1. Treatment of each subtype is similar and should be determined by the severity of symptoms. Some patients suffer severe symptoms despite maximum dosage of budesonide, in these cases biologic therapies should be considered. Vedolizumab, a monoclonal antibody that targets α4β7-integrin, is a gut-specific biologic with an exceptional safety profile. Here, we report our experience with vedolizumab for severe, refractory MC. Eleven patients presenting to the University of Kentucky with severe microscopic colitis refractory to maximum budesonide and Imodium therapy were treated with vedolizumab. Vedolizumab was given at standard induction dosing (300mg IV at week 0, 2 and 6, and then every 8 weeks). Of the eleven patients included in this study, seven reported subjective symptomatic improvement on vedolizumab monotherapy, with four patients attaining less than 3 stools per day. Of the remaining four patients, one continues to do well on vedolizumab and budesonide combination therapy while another developed a rash after vedolizumab induction and treatment was stopped. The third patient was transitioned from vedolizumab to adalimumab and is now well controlled symptomatically and the final patient has not reached symptomatic remission of her disease. Interestingly, of the seven patients who displayed symptomatic improvement with vedolizumab monotherapy, 5/7 patients also showed improvement in albumin levels. Vedolizumab use in refractory microscopic colitis is increasingly recognized as a conceivable therapy for symptomatic improvement and disease remission. Our case series corroborates these findings, as the majority of our patients reported overall improved quality of life. Vedolizumab binds to the α4β7-integrin and prevent adhesion to its ligand, MAdCAM-1, which causes downstream prevention of T-cell adhesion. Although the exact pathophysiology of microscopic colitis remains largely unidentified, it has been postulated that exposure to a luminal antigen may trigger an inflammatory cascade, leading to activation of CD8 T suppressor cells that attack and cause luminal damage to enterocytes2. This hypothesis is supported by vedolizumab’s mechanism of action and proposed efficacy in MC. Due to low volume studies, the data supporting vedolizumab use in refractory microscopic colitis remains limited, and further studies are needed to elucidate the its potential as a first-line therapy. However, based on our experience, we recommend considering vedolizumab for patients suffering from refractory MC.

INTERLEUKIN 21-INDUCED METABOLIC REPROGRAMMING DRIVES CD4 T CELL INFLAMMATORY RESPONSE DURING INTESTINAL INFLAMMATION

Significant proportion of inflammatory bowel disease (IBD) patients continue to respond inconsistently to therapies, underscoring disease complexity and the need for efficacious treatment. Interleukin 21 (IL-21), which is known to support T helper (Th) cell function, is highly expressed within inflamed tissues of IBD patients compared to healthy controls. Also, inflammatory regulatory T cells (Tregs) have been linked to refractory human IBD, and the complete induction of IBD in mice has been shown to require IL-21.

COMBINATION BIOLOGIC AND SMALL MOLECULE THERAPY FOR REFRACTORY ULCERATIVE COLITIS

Some inflammatory bowel disease (IBD) patients do not achieve remission with maximal medical therapy. We present a case of refractory UC who achieved clinical, endoscopic, and histologic remission after combining biologic and small molecule therapy. A 25-year-old Caucasian male was referred to our clinic for refractory UC. Since diagnosis four years prior, he failed mesalamine, azathioprine (intolerant), adalimumab (secondary nonresponse), vedolizumab (secondary nonresponse) with inability to taper prednisone. Upon presentation to our clinic he was at week 14 of infliximab therapy without clinical improvement. Therapeutic drug monitoring revealed adequate infliximab levels without antibodies. Colonoscopy revealed mayo 2-3 disease with discrete ulcerations (Figure 1). Due to primary non-response, he was initiated on ustekinumab (UST). He remained clinically active despite dose escalation up to evey four weeks and prednisone use. Tofacitinib was initiated with initial clinical improvement, then worsening after 3 months. The Tofacitinib dosing was increased from twice daily to three times daily and repeat colonoscopy revealed pan-colitis with Mayo 2 disease. Due to refractory disease the patient was started on combined therapy of tofacitinib twice daily with UST. On dual therapy the patient experienced progressive clinical improvement. After a year of dual treatment colonoscopy showed no disease activity, and biopsies showed no evidence of cryptitis, or crypt abscesses or active inflammatory infiltrate (Figure 2). This case highlights the benefit of combination biologic therapy with small molecule therapy in medically refractory IBD. There are limited prospective data to endorse the widespread implementation of combination therapy. A meta-analysis of thirty studies, involving 279 patients, reported 59% were able to achieve clinical remission and 34% achieved endoscopic remission with treatment of dual biologic or small molecule therapy1. Concerns involving safety of combination biologic and small molecule therapy continue to be evaluated. In our case, the patient achieved clinical, endoscopic, and histologic remission with tofacitinib and UST without adverse effects. We present this case to support the safety and efficacy of combination therapy in medically refractory patients. Ahmed W, Galati J, Kumar A et al. Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2021. https://doi.org/10.1016/j.cgh.2021.03.034.Figure 2Colonoscopy after 1 year of dual therapyView Large Image Figure ViewerDownload Hi-res image Download (PPT)

Lamina Propria Phagocyte Profiling Reveals Targetable Signaling Pathways in Refractory Inflammatory Bowel Disease.

BACKGROUND AND AIMS:Lamina propria phagocytes are key mediators of inflammatory bowel disease (IBD). We aimed to understand the transcriptomic and functional differences in these cells based on location, disease type, inflammation state, and medication use in patients with IBD.METHODS:Phagocytic immune cells in the lamina propria, as defined by the marker CD11b, were isolated from 54 unique patients (n = 111 gut mucosal biopsies). We performed flow cytometry for cell phenotyping (n = 30) and RNA sequencing with differential gene expression analysis (n = 58). We further cultured these cells in vitro and exposed them to janus kinase inhibitors to measure cytokine output (n = 27). Finally, we matched patient genomic data to our RNA sequencing data to perform candidate gene expression quantitative trait locus analysis (n = 34).RESULTS:We found distinct differences in gene expression between CD11b+ cells from the colon vs ileum, as well as in different inflammatory states and, to a lesser degree, IBD types (Crohn’s disease or ulcerative colitis). These genes mapped to targetable immune pathways and metabolic and cancer pathways. We further explored the janus kinase-signal transducer and activator of transcription pathway, which was upregulated across many comparisons including in biopsies from anti–tumor necrosis factor refractory patients. We found that isolated CD11b+ cells treated with janus kinase inhibitors had decreased secretion of cytokines tumor necrosis factora and interleukin-8 (P ≤ .05). We also found 3 genetic variants acting as expression quantitative trait loci (P ≤ .1) within our CD11b+ data set.CONCLUSIONS:Lamina propria phagocytes from IBD mucosa provide pathogenetic clues on the nature of treatment refractoriness and inform new targets for therapy.

Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor γ-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a multifactorial autoimmune disease, representing a major clinical challenge. Herein, a strategy of dual-targeting approach employing retinoic acid receptor-related orphan receptor γ-t (RORγt) and dihydroorotate dehydrogenase (DHODH) was proposed for the treatment of IBD. Dual RORγt/DHODH inhibitors are expected not only to reduce RORγt-driven Th17 cell differentiation but also to mitigate the expansion and activation of T cells, which may enhance anti-inflammatory effects. Starting from 2-aminobenzothiazole hit 1, a series of 2-aminotetrahydrobenzothiazoles were discovered as potent dual RORγt/DHODH inhibitors. Compound 14d stands out with IC50 values of 0.110 μM for RORγt and of 0.297 μM for DHODH. With acceptable mouse pharmacokinetic profiles, 14d exhibited remarkable in vivo anti-inflammatory activity and dose-dependently alleviated the severity of dextran sulfate sodium (DSS)-induced acute colitis in mice. Taken together, the present study provides a novel framework for the development of therapeutic agents for the treatment of IBD.

Systemic delivery of siRNA to the colon using peptide modified PEG-PCL polymer micelles for the treatment of ulcerative colitis

Ulcerative colitis (UC) is a refractory inflammatory bowel disease that causes inflammation and ulcers in the digestive tract, and significantly reduces the patient's quality of life. While existing UC treatments have many challenges, nanotechnology, and small interfering RNA (siRNA) based formulations are novel and promising for UC treatment. We previously reported that intravenous administration of MPEG-PCL-CH2R4H2C nanomicelles had high inflammatory site accumulation and remarkable therapeutic effects on rheumatoid arthritis by a phenomenon similar to enhanced permeability and retention effect. In this study, we investigated the effects of siRNA delivered using MPEG-PCL-CH2R4H2C nanomicelles through intravenous administration to the inflammation site of dextran sulfate sodium-induced colitis mice. The MPEG-PCL-CH2R4H2C micelles had optimum physical properties and high siRNA compaction ability. Moreover, model-siRNA delivered through MPEG-PCL-CH2R4H2C showed higher accumulation in the inflammatory site than that of the naked siRNA. Furthermore, intravenous administration of MPEG-PCL-CH2R4H2C/siRelA micelles, targeting siRelA, a subunit of NF-κB, significantly decreased the shortening of large intestine, clinical score, and production of inflammatory cytokines compared the 5-ASA and naked siRelA. These results suggest that MPEG-PCL-CH2R4H2C is a useful carrier for the systemic delivery and accumulation of siRNA, thus improving its therapeutic effect.

Vedolizumab: An Emerging Treatment Option for Pediatric Inflammatory Bowel Disease

Vedolizumab is a humanized α4β7-integrin antagonist that is currently FDA-approved for adult inflammatory bowel disease. Limited evidence is available to guide use in pediatric patients, though off-label use is described in the form of retrospective reviews and case series. Collectively these publications begin to establish safety and efficacy data in pediatric patients < 18 years of age. Additionally, dosing regimens described in the literature serve to guide weight-based dosing, which is not established at this time. This narrative review aims to summarize the available literature and provide recommendations for vedolizumab use in the pediatric population. A literature search was performed in PubMed (January 2014–December 2020) using the keyword vedolizumab. Based on the available evidence, vedolizumab appears to be a safe and moderately effective agent for treatment of refractory pediatric inflammatory bowel disease. Prospective, randomized trials are warranted to optimize dosing regimens and to establish long-term safety.

Tofacitinib Adherence and Outcomes in Refractory Inflammatory Bowel Disease.

Tofacitinib has been approved for moderate-to-severe ulcerative colitis and studied in Crohn's disease. Understanding medication adherence to oral medications in severe disease is essential. We retrospectively reviewed adherence and real-world outcomes of inflammatory bowel disease patients who initiated tofacitinib at a single care center. Adherence was measured by proportion of days covered. Sixty-three patients were identified. All patients failed at least one prior biologic therapy. Mean proportion of days covered was 95.7% for ulcerative colitis and 93.1% for Crohn's disease. Significant clinical and endoscopic response was seen. Adherence was high in a cohort with highly refractory disease.

S1696 Vedolizumab Treatment of Refractory Immune Checkpoint Inhibitor Colitis

Introduction: Immune checkpoint inhibitors (ICI) are commonly associated with gastrointestinal adverse events including colitis. We present a case of severe immune checkpoint inhibitor colitis managed with vedolizumab after failing standard treatment with steroids and infliximab. Case Description/Methods: A 75-year-old male with metastatic melanoma status post brain tumor resection, radiation therapy and 2 cycles of ipilimumab/nivolumab presented with severe new onset diarrhea 3 weeks after his second cycle of ICI. Given concern for ICI induced colitis, oral prednisone was started with initial improvement of diarrhea. Severe diarrhea recurred with tapering and he was admitted to the hospital. After infectious workup was negative, he received a dose of infliximab for presumed immune-mediated colitis with mild improvement. He was discharged on prednisone 60 mg daily with a rapid 2-week taper before receiving COVID-19 vaccination. He received a second dose of infliximab 2 weeks after the first. However, a week later, he was readmitted to the hospital with grade 3 diarrhea, dehydration, weakness, hypotension, and continued weight loss. Flexible sigmoidoscopy revealed continuous mucosal ulceration with congestion and loss of vascular markings from anus to sigmoid colon (Figure 1). Biopsies showed moderate to severe active colitis with ulceration, increased crypt apoptosis, and crypt dropout-most compatible with immune checkpoint inhibitor colitis. After 1 week of poor response to high dose methylprednisolone, he was given 2 doses of vedolizumab 2 weeks apart which lead to a complete resolution of his GI symptoms. Four months later, he remains asymptomatic with a negative PET scan off vedolizumab and ICI therapy. Discussion: Immune checkpoint inhibitors (ICI) revolutionized therapeutics for malignancy in their enhancement of cytotoxic T cell survival, but the resulting robust immune response engenders adverse gastrointestinal events in 1/3 of patients around 1-2 months after the second or third dose. ICI colitis may result in abscess, perforation, and death, and it is imperative to undergo early endoscopy with biopsy plus initiation of steroids or immunotherapy, especially in severe cases. Our patient presented with grade 3 diarrhea and severe immune-mediated colitis refractory to steroids and infliximab, though vedolizumab was effective in resolution.

Celiac Disease Is Associated with Microscopic Colitis in Refractory Cases in Adults: A Systematic Review and Meta-Analysis of Observational Studies.

Microscopic colitis and Celiac disease have been shown to occur concomitantly, but their relationship has yet to be systematically evaluated. Some patients with refractory microscopic colitis may have simultaneous celiac disease, and the converse is also true. We performed a systematic review and meta-analysis of observational studies to assess the prevalence and possible association between these two conditions. PubMed, Embase, Cochrane, Web of Science, SciELO, and CINAHL Plus were systematically searched through January 26, 2021, to include relevant observational studies assessing the prevalence of microscopic colitis in celiac disease population or vice versa. DerSimonian-Laird approach using random effects was used to pool data and compare outcomes. Pooled prevalence, 95% confidence interval (CI), and p values (where applicable) were calculated. Five studies (with 2589 patients, age range 39.5-52years and females 66.6%) and 21 studies (with 7186 patients, age range 46.4-65.8years and females 76.3%) were included assessing the prevalence of microscopic colitis in refractory celiac disease and celiac disease in refractory microscopic colitis cohort. The overall prevalence was 4.5% (2.6-6.3%) and 6.7% (5.2-8.1%), respectively. Five studies showed higher odds of celiac disease diagnosis in the refractory microscopic colitis population compared to the control group (OR 8.12, CI 4.92-13.41, p < 0.001). Celiac disease and microscopic colitis are concomitantly prevalent in a subset of population with either refractory diagnosis. Clinicians should explore alternate diagnosis when one condition has been appropriately treated and patients continue to have refractory symptoms.

High anti-TNFα Concentrations Are Not Associated With More Adverse Events in Pediatric Inflammatory Bowel Disease.

Anti-tumor necrosis factor alpha (anti-TNFα) therapy is commonly used to treat refractory pediatric inflammatory bowel disease (IBD) and carry risks for adverse events. We aimed to assess the relationship between anti-TNFα trough concentrations and adverse events rate among pediatric patients with IBD. The medical records of pediatric patients with IBD who were treated with anti-TNFα agents from 2015 to 2020 and had sequential monitoring of trough concentration (TC) were reviewed retrospectively for the presence of adverse events. The study cohort included 135 eligible patients (59 [43.7%] girls, mean age at diagnosis 12.9 [±3] years, 111 [82.2%] Crohn disease) who had 1589 measurements of TCs (1037 [63%] infliximab). During a median follow-up period of 1.7 years (IQR 1.1-2.7), we recorded 156 adverse events in 50 patients (37%). Higher TCs were not associated with higher rate of anti-TNFα-related adverse events whereas these events (excluding increase in liver transaminases) were associated with younger age.

Hematopoietic Cell Transplantation Rescues Inflammatory Bowel Disease and Dysbiosis of Gut Microbiota in XIAP Deficiency

X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment. To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT. A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed. Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members afterHCT. This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency.