Infliximab rescue therapy in a case of severe granulomatous colitis associated with rituximab use.

Colitis occurs in about 4% of individuals treated with rituximab. Optimal management of rituximab-induced colitis, which does not improve with cessation of the drug and supportive care alone, is poorly defined due to limited evidence. Severe refractory disease can lead to colectomy. We present a case of suspected rituximab-induced colitis occurring in a woman in her 70s suffering from rheumatoid arthritis. The patient achieved full clinical, endoscopic and histological remission of colitis with infliximab therapy. The use of biological therapy to treat rituximab-induced colitis can be a potentially organ-saving rescue therapy; however, it must be balanced against the increased risks of immunosuppression in patients already exposed to rituximab. While more evidence is required to fully understand the efficacy and risks of antitumour necrosis factor therapy in this scenario, our case provides an example of the successful use of infliximab for rituximab-induced colitis, which likely helped the patient avoid a colectomy.

Clinical impact of syndromic molecular point-of-care testing for gastrointestinal pathogens in adults hospitalised with suspected gastroenteritis (GastroPOC): a pragmatic, open-label, randomised controlled trial.

BACKGROUND: Single-occupancy isolation rooms are a finite resource in UK hospitals but are crucial in preventing transmission of infection. Patients with suspected gastroenteritis are nursed in single-occupancy rooms, but delays in laboratory testing lead to non-infectious patients remaining isolated for prolonged periods unnecessarily. Rapid molecular test panels for gastrointestinal pathogens have a run time of around 1 h but their clinical impact is unknown. We aimed to evaluate the clinical impact of syndromic molecular point-of-care testing (mPOCT) for gastrointestinal pathogens in adult patients presenting to hospital with suspected gastroenteritis on single-occupancy room use and a range of other outcome measures. METHODS: In this pragmatic, open-label, randomised controlled trial, we enrolled adults hospitalised with suspected gastroenteritis in a large UK hospital. Patients were randomly allocated (1:1) to receive syndromic mPOCT of stool or rectal samples, or to routine clinical care (control) with laboratory testing. The primary outcome was the duration of time in single-occupancy rooms assessed on a modified intention-to-treat basis. Secondary outcomes included the time to results, time to de-isolation, antibiotic use, and safety outcomes. The study was registered with ISRCTN, ISRCTN88918395, and is complete. FINDINGS: Between March 20, 2017 and March 17, 2020, from 455 patients assessed for eligibility, we enrolled 278 patients, 138 assigned to mPOCT (one withdrawal) and 140 to the control group. The duration (geometric mean) of single-occupancy room isolation was 1·8 days (95% CI 1·5-2·2) in the mPOCT group compared with 2·6 days (2·2-3·0) in the control group (exponentiated coefficient 0·70 [95% CI 0·56 to 0·87]; p=0·0017). The median (IQR) time to results was 1·7 h (1·5-2·0) for mPOCT and 44·7 h (21·2-66·1) for the control group (p<0·0001). Time to de-isolation was 0·6 days (0·3-1·8) in the mPOCT group compared with 2·2 days (1·2-3·2) in the control group, (p<0·0001). Antibiotics were given in 89 (65%) of 137 in the mPOCT group and 66 (47%) of 140 in the control group (p=0·0028). There were no differences between groups in length of hospital stay, or in safety outcomes including mortality, intensive care unit admission, or readmission to hospital. INTERPRETATION: mPOCT for gastrointestinal pathogens in patients with suspected gastroenteritis returned results more rapidly than conventional testing and was associated with a reduction in single-occupancy room use. However, these benefits need to be balanced against a potential increase in antibiotic use. FUNDING: University Hospital Southampton NHS Foundation Trust.

Impact of direct-access IBD physician delivered endoscopy on clinical outcomes: a pre-implementation and post-implementation study.

Introduction: Patients with suspected inflammatory bowel disease (IBD) referred from primary care often face diagnostic and treatment delays. This study aimed to compare a novel direct-access IBD endoscopy pathway with the traditional care model. Method: Single centre real-world study analysing primary care referrals with suspected IBD. Group A: patients triaged to direct-access IBD endoscopy. Group B: patients undergoing traditional outpatient appointments before the availability of direct-access IBD endoscopy. Demographics, fecal calprotectin (FCP), C-reactive protein (CRP), disease activity score, endoscopy findings, treatment and follow-up were collected and statistically analysed. Ranked semantic analysis of IBD symptoms contained within referral letters was performed. Results: Referral letters did not differ significantly in Groups A and B. Demographic data, FCP and CRP values were similar. Referral to treatment time (RTT) at the time of IBD endoscopy was reduced from 177 days (Group B) to 24 days (Group A) (p<0.0001). Diagnostic yield of IBD was 35.6% (Group B) versus 62.0% (Group A) (p=0.0003). 89.2% of patients underwent colonoscopy in Group B versus 46.4% in Group A. DNA rates were similar in both groups. The direct to IBD endoscopy pathway saved 100% of initial IBD consultant clinics with a 2.5-fold increase in IBD nurse-led follow-up. Conclusion: Our novel pathway resulted in an 86% reduction in RTT with associated increased diagnostic yield while saving 100% of initial IBD consultant outpatient appointments. Replication in other trusts may improve patient experience and accelerate time to diagnosis/treatment while optimising the use of healthcare resources.

Transitioning from Intravenous to Subcutaneous Vedolizumab in Patients with Inflammatory Bowel Disease [TRAVELESS].

BACKGROUND AND AIMS: Subcutaneous [SC] vedolizumab presents the opportunity for inflammatory bowel disease [IBD] patients to manage their treatment at home. There are currently no data on the process of transitioning patients established on intravenous [IV] to SC vedolizumab as part of routine clinical care. The aim of this programme is to evaluate the clinical and biochemical outcomes of switching a cohort of IBD patients established on IV vedolizumab to SC, at 12 weeks following the transition. METHODS: In all, 178 adult patients were offered the opportunity to transition to SC vedolizumab. Patients who agreed were reviewed prior to switching and at Week 12 [W12] after their first SC dose. Evaluation outcomes included disease activity scores, the IBD-Control Patient-Reported Outcome Measures [PROMs], and faecal calprotectin [FCP]. Reasons for patients declining or accepting transitioning, pharmacokinetics, adverse drug reactions, and risk factors for a poor outcome in SARS-CoV-2 infection were also assessed. RESULTS: A total of 124 patients agreed to transition, of whom 106 patients had been on IV vedolizumab for at least 4 months. There were no statistically significant differences in disease activity scores or IBD-Control PROMs between baseline and W12. A statistically significant increase in FCP was observed [31 µg/g vs. 47 µg/g; p = 0.008], although this was unlikely to be clinically relevant. The most common adverse drug reaction reported was injection site reactions [15%]. Based on this cohort of patients, an expected reduction of £572,000 per annum is likely to be achieved. CONCLUSIONS: Transitioning patients established on IV vedolizumab to SC appears to be safe and effective, with high patient satisfaction and multiple benefits for the health service.

Management of Crohn's disease in an immunosuppressed COVID-19-positive patient: safety-driven prioritisation of nutritional therapy as a bridge to restarting immunosuppression.

Active inflammatory bowel disease (IBD), combined immunosuppression and corticosteroid therapy have all been identified as risk factors for a poor outcome in COVID-19 infection. The management of patients with both COVID-19 infection and active IBD is therefore complex. We present the case of a 31-year-old patient with Crohn's disease, on dual immunosuppression with infliximab and mercaptopurine presenting with inflammatory small bowel obstruction and COVID-19 infection. The case highlights the use of nutritional therapy, which remains underused in the management of adults with IBD, to manage his flare acutely. Following negative SARS-CoV-2 PCR testing and SARS-CoV-2 IgG testing confirming an antibody response, ustekinumab (anti-interleukin 12/23) was prescribed for long-term maintenance.

High incidence of glucocorticoid-induced hyperglycaemia in inflammatory bowel disease: metabolic and clinical predictors identified by machine learning.

BACKGROUND: Glucocorticosteroids (GC) are long-established, widely used agents for induction of remission in inflammatory bowel disease (IBD). Hyperglycaemia is a known complication of GC treatment with implications for morbidity and mortality. Published data on prevalence and risk factors for GC-induced hyperglycaemia in the IBD population are limited. We prospectively characterise this complication in our cohort, employing machine-learning methods to identify key predictors of risk. METHODS: We conducted a prospective observational study of IBD patients receiving intravenous hydrocortisone (IVH). Electronically triggered three times daily capillary blood glucose (CBG) monitoring was recorded alongside diabetes mellitus (DM) history, IBD biomarkers, nutritional and IBD clinical activity scores. Hyperglycaemia was defined as CBG ≥11.1 mmol/L and undiagnosed DM as glycated haemoglobin ≥48 mmol/mol. Random forest (RF) regression models were used to extract predictor-patterns present within the dataset. RESULTS: 94 consecutive IBD patients treated with IVH were included. 60% (56/94) of the cohort recorded an episode of hyperglycaemia, including 57% (50/88) of those with no history of DM, of which 19% (17/88) and 5% (4/88) recorded a CBG ≥14 mmol/L and ≥20 mmol/L, respectively. The RF models identified increased C-reactive protein (CRP) followed by a longer IBD duration as leading risk predictors for significant hyperglycaemia. CONCLUSION: Hyperglycaemia is common in IBD patients treated with intravenous GC. Therefore, CBG monitoring should be included in routine clinical practice. Machine learning methods can identify key risk factors for clinical complications. Steroid-sparing treatment strategies may be considered for those IBD patients with higher admission CRP and greater disease duration, who appear to be at the greatest risk of hyperglycaemia.

Life in lockdown: experiences of patients with IBD during COVID-19.

OBJECTIVE: COVID-19 has disrupted the normal way of life in the UK, but for some patients with inflammatory bowel disease (IBD), the impact of this unprecedented global emergency was far greater. We aimed to assess the experience of patients with IBD during the COVID-19 lockdown. DESIGN: We designed a survey focused on the impact of COVID-19 on IBD healthcare, social and psychological well-being and quality of life. To capture those most likely to be affected we targeted survey invitations at our British Society of Gastroenterology (BSG) defined high and moderate-risk IBD population. Access to the survey was also available via our trust's social media pages. RESULTS: 685 responses were received. 76% of respondents categorised themselves in BSG defined moderate or high-risk groups, requiring stringent social distancing or shielding. 87% did not change their IBD medication, with most reported changes initiated by the IBD team. 39% were worried about their IBD care, but most services were largely uninterrupted. 90% received 'at-risk' notification often from multiple sources, but 17% not until May. The majority reported a negative impact of COVID-19 on their quality of life and significantly increased perceived stress. Patients expressed a strong wish of having future care delivered remotely. CONCLUSION: COVID-19 has had a significant negative impact on psychological well-being of patients with IBD. Local IBD services must have a robust data set of vulnerable patients and be designated future responsibility for prompt communication of advice to avoid delayed and sometimes conflicting information. Remote patient management systems should be further developed and embedded in clinical practice.

Early real-world effectiveness of ustekinumab for Crohn's disease.

OBJECTIVE: To understand the effectiveness of ustekinumab in treating Crohn's disease (CD) in a UK real-world setting. DESIGN: Retrospective cohort study using prospectively maintained clinical records. SETTING: Single UK inflammatory bowel disease centre. PATIENTS: Adult patients with an established diagnosis of CD prescribed ustekinumab outside of clinical trials at University Hospital Southampton (UHS). INTERVENTIONS: Ustekinumab, a monoclonal antibody to the shared p40 subunit of interleukin (IL) 12 and IL-23 as part of routine clinical care. MAIN OUTCOME MEASURES: Effectiveness as measured by an improvement in physician's global assessment, drug persistence and improvement in biomarkers (C-reactive protein (CRP), albumin and calprotectin). RESULTS: 84 patients were included, 72 had a postinduction review and 49 had 1-year data. At postinduction clinical review, clinical response occurred in 53% of patients and clinical remission occurred in 8%. For patients on ustekinumab at 1 year, clinical response occurred in 71% and remission in 14%. Adverse events included four patients with infections requiring admission, one drug-related rash, five CD surgeries and two CD exacerbations. CONCLUSIONS: Ustekinumab was well tolerated in a complex UK CD population and demonstrated benefit to patients in terms of clinical response and improvement of biomarkers and with some patients attaining clinical remission. No unexpected safety signals were seen.

MicroRNA-31 Targets Thymic Stromal Lymphopoietin in Mucosal Infiltrated CD4+ T Cells: A Role in Achieving Mucosal Healing in Ulcerative Colitis?

Background: Ulcerative colitis (UC) is characterized by disruption of the mucosal intestinal barrier. MicroRNAs, single-stranded noncoding RNAs of approximately 22nt, are dysregulated in UC. MicroRNAs targeting thymic stromal lymphopoietin (TSLP), a cytokine involved in T-cell maturation and polarization, may be involved in regulating UC inflammation and mucosal healing. Methods: Biopsy samples from non-UC (n = 38), inactive UC (n = 18), and active UC (n = 23) patients were analyzed for mRNA (real-time quantitative polymerase chain reaction) or TSLP protein expression (enzyme-linked immunosorbent assay). Flow cytometry was used to isolate CD4+ T cells from biopsies. The functional mechanism was shown using luciferase assays and antago-miR transfections. The TSLP/miR-31 association was analyzed on 196 subjects from a previous clinical trial that tested the anti-IL-13 drug tralokinumab, whereas mucosal healing effects were studied on a subset of patients (n = 13) from this trial. Results: We found that TSLP is reduced at both mRNA and protein levels in inflamed UC patients when compared with healthy subjects, in both whole biopsies and biopsy-isolated CD4+ CD25+ T cells. The expression of miR-31, predicted to target TSLP, inversely co-related to the levels of TSLP mRNA in T cells. Blocking miR-31 in vitro in T cells increased both TSLP mRNA expression and protein secretion. Luciferase assays showed that miR-31 directly targeted TSLP mRNA, suggesting a direct mechanistic link. We also found that TSLP is increased in patients who achieve mucosal healing, comparing biopsies before and after treatment from the tralokinumab trial. Conclusions: Our data suggest a role for TSLP in promoting mucosal healing and regulating inflammation in UC, whereas miR-31 can directly block this effect.

MicroRNA-31 and MicroRNA-155 Are Overexpressed in Ulcerative Colitis and Regulate IL-13 Signaling by Targeting Interleukin 13 Receptor α-1.

Interleukin-13 (IL-13) is an important Type 2 T helper (Th2) cytokine, controlling biological functions in epithelium and has been linked to asthma, atopic dermatitis and ulcerative colitis (UC). Interleukin-13 signals through IL-13 receptor α-1 (IL13RA1 (gene) and IL13Rα1 (protein)), a receptor that can be regulated by microRNAs (miRs). MicroRNAs are small non-coding single-stranded RNAs with a role in several pathologies. However, their relevance in the pathophysiology of UC, a chronic inflammatory condition of the colonic mucosa, is poorly characterised. Here, we determined the expression of IL13Rα1 in UC, its potential regulation by miRs and the subsequent effect on IL-13 signalling. Inflamed mucosa of UC patients showed decreased mRNA and protein expression of IL13RA1 when compared to healthy controls. We show that miR-31 and miR-155 are upregulated in inflamed UC mucosa and that both directly target the 3' untranslated region of IL13RA1 mRNA. Transfection of miR-31 and miR-155 mimics reduced the expression of IL13RA1 mRNA and protein, and blocked IL-13-dependent phosphorylation of signal transducer and activator of transcription 6 (STAT6) in HT-29 cells, a gut epithelium cell line. Interleukin-13 activation of suppressor of cytokine signaling 1 (SOCS1) and eotaxin-3 (CCL26) expression was also diminished. MicroRNA-31/microRNA-155 mimics also downregulated IL13RA1 in ex vivo human inflamed UC biopsies. We propose that miR-31 and miR-155 have an important role in limiting IL-13 signalling in UC disease.