Early management of acute severe UC in the biologics era: development and international validation of a prognostic clinical index to predict steroid response.

OBJECTIVES: We aimed to determine whether changes in acute severe colitis (ASC) management have translated to improved outcomes and to develop a simple model predicting steroid non-response on admission. DESIGN: Outcomes of 131 adult ASC admissions (117 patients) in Oxford, UK between 2015 and 2019 were compared with data from 1992 to 1993. All patients received standard treatment with intravenous corticosteroids and endoscopic disease activity scoring (Ulcerative Colitis Endoscopic Index of Severity (UCEIS)). Steroid non-response was defined as receiving medical rescue therapy or surgery. A predictive model developed in the Oxford cohort was validated in Australia and India (Gold Coast University Hospital 2015-2020, n=110; All India Institute of Medical Sciences, New Delhi 2018-2020, n=62). RESULTS: In the 2015-2019 Oxford cohort, 15% required colectomy during admission vs 29% in 1992-1993 (p=0.033), while 71 (54%) patients received medical rescue therapy (27% ciclosporin, 27% anti-tumour necrosis factor, compared with 27% ciclosporin in 1992-1993 (p=0.0015). Admission C reactive protein (CRP) (false discovery rate, p=0.00066), albumin (0.0066) and UCEIS scores (0.015) predicted steroid non-response. A four-point model was developed involving CRP of ≥100 mg/L (one point), albumin of ≤25 g/L (one point), and UCEIS score of ≥4 (1 point) or ≥7 (2 points). Patients scoring 0, 1, 2, 3 and 4 in the validation cohorts had steroid response rates of 100, 75.0%, 54.9%, 18.2% and 0%, respectively. Scoring of ≥3 was 84% (95% CI 0.70 to 0.98) predictive of steroid failure (OR 11.9, 95% CI 10.8 to 13.0). Colectomy rates in the validation cohorts were were 8%-11%. CONCLUSIONS: Emergency colectomy rates for ASC have halved in 25 years to 8%-15% worldwide. Patients who will not respond to corticosteroids are readily identified on admission and may be prioritised for early intensification of therapy.

Interferon-Gamma-Producing CD8+ Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor-Colitis.

BACKGROUND & AIMS: The pathogenesis of immune checkpoint inhibitor (ICI)-colitis remains incompletely understood. We sought to identify key cellular drivers of ICI-colitis and their similarities to idiopathic ulcerative colitis, and to determine potential novel therapeutic targets. METHODS: We used a cross-sectional approach to study patients with ICI-colitis, those receiving ICI without the development of colitis, idiopathic ulcerative colitis, and healthy controls. A subset of patients with ICI-colitis were studied longitudinally. We applied a range of methods, including multiparameter and spectral flow cytometry, spectral immunofluorescence microscopy, targeted gene panels, and bulk and single-cell RNA sequencing. RESULTS: We demonstrate CD8+ tissue resident memory T (TRM) cells are the dominant activated T cell subset in ICI-colitis. The pattern of gastrointestinal immunopathology is distinct from ulcerative colitis at both the immune and epithelial-signaling levels. CD8+ TRM cell activation correlates with clinical and endoscopic ICI-colitis severity. Single-cell RNA sequencing analysis confirms activated CD8+ TRM cells express high levels of transcripts for checkpoint inhibitors and interferon-gamma in ICI-colitis. We demonstrate similar findings in both anti-CTLA-4/PD-1 combination therapy and in anti-PD-1 inhibitor-associated colitis. On the basis of our data, we successfully targeted this pathway in a patient with refractory ICI-colitis, using the JAK inhibitor tofacitinib. CONCLUSIONS: Interferon gamma-producing CD8+ TRM cells are a pathological hallmark of ICI-colitis and a novel target for therapy.

The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release.

NOD2 is an intracellular sensor that contributes to immune defense and inflammation. Here we investigated whether NOD2 mediates its effects through control of microRNAs (miRNAs). miR-29 expression was upregulated in human dendritic cells (DCs) in response to NOD2 signals, and miR-29 regulated the expression of multiple immune mediators. In particular, miR-29 downregulated interleukin-23 (IL-23) by targeting IL-12p40 directly and IL-23p19 indirectly, likely via reduction of ATF2. DSS-induced colitis was worse in miR-29-deficient mice and was associated with elevated IL-23 and T helper 17 signature cytokines in the intestinal mucosa. Crohn's disease (CD) patient DCs expressing NOD2 polymorphisms failed to induce miR-29 upon pattern recognition receptor stimulation and showed enhanced release of IL-12p40 on exposure to adherent invasive E. coli. Therefore, we suggest that loss of miR-29-mediated immunoregulation in CD DCs might contribute to elevated IL-23 in this disease.

Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles.

BACKGROUND: Immune checkpoint blockers (ICBs) activate CD8+ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear. METHODS: Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab-sICB) or combination (nivolumab and ipilimumab-cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8+ T cells was sequenced and differential gene expression according to irAE development assessed. RESULTS: 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9-33.4) versus not-reached (P = 2.8 × 10-6). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8+ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment. CONCLUSIONS: Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.

Immune checkpoint inhibitor-related colitis assessment and prognosis: can IBD scoring point the way?

BACKGROUND: Immune checkpoint inhibitors (ICI) improve survival but cause immune-related adverse events (irAE). We sought to determine if CTCAE classification, IBD biomarkers/endoscopic/histological scores correlate with irAE colitis outcomes. METHODS: A dual-centre retrospective study was performed on patients receiving ICI for melanoma, NSCLC or urothelial cancer from 2012 to 2018. Demographics, clinical data, endoscopies (reanalysed using Mayo/Ulcerative Colitis Endoscopic Index of Severity (UCEIS) scores), histology (scored with Nancy Index) and treatment outcomes were analysed. RESULTS: In all, 1074 patients were analysed. Twelve percent (134) developed irAE colitis. Median patient age was 66, 59% were male. CTCAE diarrhoea grade does not correlate with steroid/ infliximab use. G3/4 colitis patients are more likely to need infliximab (p < 0.0001) but colitis grade does not correlate with steroid duration. CRP, albumin and haemoglobin do not correlate with severity. The UCEIS (p = 0.008) and Mayo (p = 0.016) scores correlate with severity/infliximab requirement. Patients with higher Nancy indices (3/4) are more likely to require infliximab (p = 0.03). CONCLUSIONS: CTCAE assessment does not accurately reflect colitis severity and our data do not support its use in isolation, as this may negatively impact timely management. Our data support utilising endoscopic scoring for patients with >grade 1 CTCAE disease, and demonstrate the potential prognostic utility of objective histologic scoring.

Pattern recognition receptor mediated downregulation of microRNA-650 fine-tunes MxA expression in dendritic cells infected with influenza A virus.

MicroRNAs are important posttranscriptional regulators of gene expression, which have been shown to fine-tune innate immune responses downstream of pattern recognition receptor (PRR) signaling. This study identifies miR-650 as a novel PRR-responsive microRNA that is downregulated upon stimulation of primary human monocyte-derived dendritic cells (MDDCs) with a variety of different microbe-associated molecular patterns. A comprehensive target search combining in silico analysis, transcriptional profiling, and reporter assays reveals that miR-650 regulates several well-known interferon-stimulated genes, including IFIT2 and MXA. In particular, downregulation of miR-650 in influenza A infected MDDCs enhances the expression of MxA and may therefore contribute to the establishment of an antiviral state. Together these findings reveal a novel link between miR-650 and the innate immune response in human MDDCs.

Beyond endoscopic mucosal healing in UC: histological remission better predicts corticosteroid use and hospitalisation over 6†years of follow-up.

BACKGROUND: Endoscopic mucosal healing is an established treatment target for UC, yet the value of achieving histological remission remains unclear. AIMS: To evaluate histological remission compared to endoscopic mucosal healing for predicting patient outcomes in UC. METHODS: Blinded assessment of endoscopic and histological measures of disease activity was performed on patients with established UC at baseline. Concordance and prognostic values of endoscopic mucosal healing (defined by Baron score ≤1) and histological remission (defined by Truelove and Richards' index) for predicting outcomes of corticosteroid use, hospitalisation and colectomy were determined over a median 6 years follow-up, including κ statistics and Cox regression multivariate analysis. RESULTS: 91 patients with UC were followed up for a median 72 months (IQR 54-75 months). Overall, concordance between endoscopic and histological remission was moderate (κ=0.56, 95% CI 0.36 to 0.77); 24% patients had persistent inflammation despite endoscopic remission. Histological remission predicted corticosteroid use and acute severe colitis requiring hospitalisation over the follow-up period (HR 0.42 (0.2 to 0.9), p=0.02; HR 0.21 (0.1 to 0.7), p=0.02; respectively), whereas endoscopic mucosal healing did not (HR 0.86, 95% CI 0.5 to 1.7, p0.65; HR 0.83 95% CI 0.3 to 2.4, p0.74; respectively). CONCLUSIONS: Histological remission is a target distinct from endoscopic mucosal healing in UC and better predicts lower rates of corticosteroid use and acute severe colitis requiring hospitalisation, over a median of 6 years of follow-up. Our findings support the inclusion of histological indices in both UC clinical trials and practice, towards a target of 'complete remission'.

Conventional drug therapy for inflammatory bowel disease.

Most patients with inflammatory bowel diseases (IBD) are offered conventional medical therapy, because emerging therapies for IBD are regulated by health-care jurisdiction and often limited to academic centres. This review distils current evidence to provide a pragmatic approach to conventional IBD therapy, including aminosalicylates, corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, infliximab and adalimumab. It addresses drug efficacy, safety and salient practice points for optimal and appropriate practice.

Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis.

The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune-related adverse effects including colitis. CPI-induced colitis is hallmarked by expansion of resident mucosal IFNγ cytotoxic CD8+ T cells, but how these arise is unclear. Here, we track CPI-bound T cells in intestinal tissue using multimodal single-cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug-bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI-bound cells were largely CD4+ T cells, including enrichment in CPI-bound peripheral helper, follicular helper, and regulatory T cells. IFNγ CD8+ T cells emerged from both tissue-resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co-localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies.

Patient-reported Outcomes: the ICHOM Standard Set for Inflammatory Bowel Disease in Real-life Practice Helps Quantify Deficits in Current Care.

BACKGROUND: Patient-reported outcome measures [PROMs] are key to documenting outcomes that matter most to patients and are increasingly important to commissioners of health care seeking value. We report the first series of the ICHOM Standard Set for Inflammatory Bowel Disease [IBD]. METHODS: Patients treated for ulcerative colitis [UC] or Crohn's disease [CD] in our centre were offered enrolment into the web-based TrueColours-IBD programme. Through this programme, e-mail prompts linking to validated questionnaires were sent for symptoms, quality of life, and ICHOM IBD outcomes. RESULTS: The first 1299 consecutive patients enrolled [779 UC, 520 CD] were studied with median 270 days of follow-up (interquartile range [IQR] 116, 504). 671 [52%] were female, mean age 42 years (standard deviation [sd] 16), mean body mass index [BMI] 26 [sd 5.3]. At registration, 483 [37%] were using advanced therapies. Median adherence to fortnightly quality of life reporting and quarterly outcomes was 100% [IQR 48, 100%] and 100% [IQR 75, 100%], respectively. In the previous 12 months, prednisolone use was reported by 229 [29%] patients with UC vs 81 [16%] with CD, p <0.001; 202 [16%] for <3 months; and 108 [8%] for >3 months. An IBD-related intervention was reported by 174 [13%] patients, and 80 [6%] reported an unplanned hospital admission. There were high rates of fatigue [50%] and mood disturbance [23%]. CONCLUSIONS: Outcomes reported by patients illustrate the scale of the therapeutic deficit in current care. Proof of principle is demonstrated that PROM data can be collected continuously with little burden on health care professionals. This may become a metric for quality improvement programmes or to compare outcomes.

Immunotherapy induced enterocolitis and gastritis - What to do and when?

Oncological treatment has been revolutionised by the advent of immune checkpoint inhibitors (ICPi), which block inhibitory immune pathways to enhance anti-tumour responses and improve survival. This mode of action is non-specific so can cause immune-related adverse events, of which diarrhoea and enterocolitis are amongst the most common. ICPi-enterocolitis frequently leads to cancer therapy interruption. ICPi-gastritis typically occurs at a later stage of ICPi therapy and can present more insidiously with nausea and vomiting. ICPi-enterocolitis and gastritis are treated with corticosteroids, with refractory cases typically requiring biologic therapy. This review will briefly consider the pathogenesis of ICPi-induced GI disease, before focussing on the practical management of these conditions. The anticipated global increase in ICPi use across cancer types highlights the importance of prospective research in order that we can understand the immuno-microbiology of ICPi-enterocolitis and gastritis. This will lead to predictive biomarkers and help to define optimal treatment regimens.

Single-cell atlas of colonic CD8+ T cells in ulcerative colitis.

Colonic antigen-experienced lymphocytes such as tissue-resident memory CD8+ T cells can respond rapidly to repeated antigen exposure. However, their cellular phenotypes and the mechanisms by which they drive immune regulation and inflammation remain unclear. Here we compiled an unbiased atlas of human colonic CD8+ T cells in health and ulcerative colitis (UC) using single-cell transcriptomics with T-cell receptor repertoire analysis and mass cytometry. We reveal extensive heterogeneity in CD8+ T-cell composition, including expanded effector and post-effector terminally differentiated CD8+ T cells. While UC-associated CD8+ effector T cells can trigger tissue destruction and produce tumor necrosis factor (TNF)-α, post-effector cells acquire innate signatures to adopt regulatory functions that may mitigate excessive inflammation. Thus, we identify colonic CD8+ T-cell phenotypes in health and UC, define their clonal relationships and characterize terminally differentiated dysfunctional UC CD8+ T cells expressing IL-26, which attenuate acute colitis in a humanized IL-26 transgenic mouse model.

British Society of Gastroenterology endorsed guidance for the management of immune checkpoint inhibitor-induced enterocolitis.

Immune checkpoint inhibitors are a novel class of cancer treatment that have improved outcomes for a subset of cancer patients. They work by antagonising inhibitory immune pathways, thereby augmenting immune-mediated antitumour responses. However, immune activation is not cancer-specific and often results in the activation of immune cells in non-cancer tissues, resulting in off-target immune-mediated injury and organ dysfunction. Diarrhoea and gastrointestinal tract inflammation are common and sometimes serious side-effects of this type of therapy. Prompt recognition of gastrointestinal toxicity and, in many cases, rapid institution of anti-inflammatory or biologic therapy (or both) is required to reverse these complications. Management of organ-specific complications benefits from multidisciplinary input, including engagement with gastroenterologists for optimal management of immune checkpoint inhibitor-induced enterocolitis. In this British Society of Gastroenterology endorsed guidance document, we have developed a consensus framework for the investigation and management of immune checkpoint inhibitor-induced enterocolitis.

Organisational changes and challenges for inflammatory bowel disease services in the UK during the COVID-19 pandemic.

OBJECTIVE: To determine the challenges in diagnosis, monitoring, support provision in the management of inflammatory bowel disease (IBD) patients and explore the adaptations of IBD services. METHODS: Internet-based survey by invitation of IBD services across the UK from 8 to 14 April 2020. RESULTS: Respondents from 125 IBD services completed the survey. The number of whole-time equivalent gastroenterologists and IBD nurses providing elective outpatient care decreased significantly between baseline (median 4, IQR 4-7.5 and median 3, IQR 2-4) to the point of survey (median 2, IQR 1-4.8 and median 2, IQR 1-3) in the 6-week period following the onset of the COVID-19 pandemic (p<0.001 for both comparisons). Almost all (94%; 112/119) services reported an increase in IBD helpline activity. Face-to-face clinics were substituted for telephone consultation by 86% and video consultation by 11% of services. A variation in the provision of laboratory faecal calprotectin testing was noted with 27% of services reporting no access to faecal calprotectin, and a further 32% reduced access. There was also significant curtailment of IBD-specific endoscopy and elective surgery. CONCLUSIONS: IBD services in the UK have implemented several adaptive strategies in order to continue to provide safe and high-quality care for patients. National Health Service organisations will need to consider the impact of these changes in current service delivery models and staffing levels when planning exit strategies for post-pandemic IBD care. Careful planning to manage the increased workload and to maintain IBD services is essential to ensure patient safety.

Effectiveness and safety of vedolizumab in inflammatory bowel disease patients aged 60 and over: an observational multicenter UK experience.

BACKGROUND: The GEMINI trials established the efficacy of vedolizumab in moderate-to-severe inflammatory bowel disease (IBD) and demonstrated a favorable safety profile, suggesting it may be advantageous in older patients at greater risk of treatment-related complications. However, there is a paucity of data exploring the outcomes of vedolizumab in this group. Our objective was to determine the clinical effectiveness and safety of vedolizumab in older IBD patients within a real-world multicenter UK cohort. METHODS: A retrospective review of electronic records across 6 UK hospitals was undertaken to evaluate the clinical effectiveness and safety outcomes of vedolizumab in IBD patients aged ≥60 at start of therapy. Rates of clinical response, remission and corticosteroid-free remission were assessed at weeks 14 and 52, using validated clinical indices, and were compared to historical controls from real-world vedolizumab-treated cohorts unstratified by age. RESULTS: Of 74 patients aged 60 years or above (median 66 years), 48 were included in our effectiveness analysis (29 ulcerative colitis, 19 Crohn's disease). Rates of clinical response, remission and corticosteroid-free remission at week 14 were 64%, 48% and 30%, respectively. By week 52, the rates of clinical response, remission, and corticosteroid-free remission were 52%, 38%, and 32%, respectively. Six (8%) patients experienced adverse effects. Effectiveness and safety outcomes were comparable to those of age-unstratified vedolizumab-treated cohorts. CONCLUSION: Our 1-year outcome data suggests that vedolizumab is safe and effective in older IBD patients and broadly comparable to cohorts unselected by age.

Immunotherapy-related hepatitis: real-world experience from a tertiary centre.

OBJECTIVE: Immune checkpoint inhibitors like anti-programmed cell death protein 1 (PD-1) drugs Nivolumab and Pembrolizumab and anti-cytotoxic T-lymphocyte associated (CTLA-4) drug Ipilimumab have become standard of care in many metastatic cancers. Immunotherapy-related hepatitis and cholangitis present a diagnostic and management challenge, being rare and incompletely characterised. We aim to report the incidence, features and treatments used for this in a real-world setting and to identify useful biomarkers, which can be used to predict effective use of steroids. DESIGN: Retrospective review of 453 patients started on immunotherapy over 7 years. SETTING: Tertiary hepatology and oncology centre. PATIENTS: 21 patients identified with immunotherapy-related hepatotoxicity. RESULTS: Hepatitis was most common in those receiving dual therapy (incidence 20%), with 75% of Grade 4 hepatitis cases occurring with ipilimumab-containing regimens. Corticosteroid monotherapy is first line treatment, but doses above 60 mg OD prednisolone do not demonstrate any additional benefit in time to hepatitis resolution. The alanine transaminase (ALT) reduction in steroid-responsive hepatitis is typically rapid (with a halving of ALT within 11 days). The commencement of additional immunosuppression (typically mycophenolate) appears safe and prompts a more rapid fall in ALT than corticosteroid use alone. Infliximab was safely used twice as hepatitis treatment. We also describe one patient with rare immunotherapy-induced biliary disease. CONCLUSIONS: Vigilance is required for detection of immunotherapy-associated liver disease as, other than dual immunotherapy, we can identify no predictive factors for its development. Our data suggest that corticosteroid response is not dependent on the higher dosing regimens. Early escalation of immunosuppression may be of benefit in the absence of a rapid response to corticosteroids.