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IntroductionUstekinumab, an interleukin-12 and interleukin-23 antagonist, is licensed for the treatment of Crohn’s disease (CD) and ulcerative colitis (UC) after the phase III trial programs demonstrated efficacy over placebo. However, these findings may not be directly transferable to the real-world due to the stringent inclusion criteria of clinical trials.MethodsWe conducted a systematic review and meta-analysis of the safety and effectiveness of ustekinumab in inflammatory bowel disease (IBD). A systematic literature search was conducted via Medline and Embase from inception to April 21, 2020. Observational studies assessing ustekinumab’s safety and effectiveness by reporting response, remission and/or adverse events (AE) in either CD or UC were included. Two reviewers independently assessed risk of bias and extracted study data. Random-effects meta-analysis was performed to pool rates of clinical response, remission, and safety data.ResultsFollowing deduplication, 2147 records were identified of which 41 studies (38 CD, 3 UC) comprising 4400 patients were included for quantitative analysis. Pooled clinical remission rates for CD were 34% (95% CI, 26%–42%) following induction and 31% (95% CI, 25%–38%) at one year. For UC, post-induction clinical remission rates were 39% (95% CI, 23%–56%). Serious AEs were reported in 5.6% of patients. Pregnancy outcomes were similar to the general population. One-third of patients with active baseline perianal disease responded or had fistula healing with ustekinumab.ConclusionsIn the most comprehensive systematic review and meta-analysis to date, and the first to include UC, ustekinumab was shown to be effective and safe in the real-world treatment of IBD.

Immune checkpoint inhibitors (CPIs) are a relatively newly licenced cancer treatment, which make a once previously untreatable disease now amenable to a potential cure. Combination regimens of anti-CTLA4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. To probe the impact of immune checkpoints on intestinal homoeostasis, mice are challenged with anti-CTLA4 and anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. The immune profile of the colon of these mice with CPI-colitis is analysed using bulk RNA sequencing, single-cell RNA sequencing and flow cytometry. CPI-colitis in mice is dependent on the composition of the intestinal microbiota and by the induction of lymphocytes expressing interferon-γ (IFNγ), cytotoxicity molecules and other pro-inflammatory cytokines/chemokines. This pre-clinical model of CPI-colitis could be attenuated following blockade of the IL23/IFNγ axis. Therapeutic targeting of IFNγ-producing lymphocytes or regulatory networks, may hold the key to reversing CPI-colitis. Immune checkpoint inhibitors (CPI) could effectively target cancers that are resistant to traditional therapy but may initiate immune related adverse effects, such as colitis. Here, authors characterise the gut immune microenvironment during CPI-colitis by bulk RNA sequencing, single-cell RNA sequencing and flow cytometry, and find that interleukin 23 plays an important role in promoting inflammation via cytotoxic polyfunctional IFNγ-producing lymphocytes.

IntroductionImmune Checkpoint Inhibitors (CPI) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce.MethodsWe conducted a multi-centre (six cancer centres), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with CTCAE grade 0 for diarrhoea at 12 weeks after IFX initiation. We also assessed cancer outcomes at one year using RECIST criteria.Results127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhoea CTCAE grade >2 and 115 (90.6%) required hospitalisation for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistical regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04-0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13-8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared to patients with IFX-responsive enterocolitis (37.5%; p=0.013).ConclusionThis is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Utilizing pre-defined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI-therapy.

IntroductionImmune checkpoint inhibitors (CPI) have transformed the treatment of many advanced cancers but cause immune related adverse events including enterocolitis (CPI-E). The conventional inflammatory bowel diseases ulcerative colitis (UC) and Crohn’s disease (CD) are associated with unfavourable health-related quality of life (HRQoL) outcomes, but there are currently no data on HRQoL in the setting of CPI-E. This study aimed to investigate HRQoL in CPI-E.MethodsA prospective study was conducted across two London hospital trusts between February-April 2021. UC, CD and CPI-E patient cohorts were recruited from outpatient clinics and the biologic infusion unit. Disease activity was assessed using non-invasive scoring systems: modified-Partial Mayo Score (m-PMS), modified-Harvey Bradshaw Index (m-HBI), Simple Crohn’s and Colitis Activity Index (SCCAI) and Common Terminology Criteria for Adverse Events (CTCAE). HRQoL outcomes were assessed using validated questionnaires: Patient Health Questionnaire-8 (PHQ-8), Generalised Anxiety Disorder-7 (GAD-7), IBD-Questionnaire (IBD-Q) and Multidimensional Assessment of Fatigue (MAF).ResultsSeventy-five patients (33 CD, 21 UC, 21 CPI-E) were recruited. 33 CD patients (100%) and 20 UC patients (95.2%) were receiving biologic therapy. Thirteen CPI-E patients (61.9%) received Anti-PD1/PDL1 monotherapy and (38.1%) received combination anti-PD1 and anti-CTLA-4 therapy. Twenty-four CD patients (72.7%), 11 UC patients (52.4%) and 16 CPI-E patients (76.2%) were shielding due to the COVID-19 pandemic. Using m-PMS, m-HBI, SCCAI and CTCAE, >80% in each of the three cohorts were either classed as being in remission or having mild disease activity. Three CPI-E patients (14.3%) had moderate depression (PHQ-8 ≥10) and a further 9 (42.9%) had mild depression (PHQ-8 score 5-9). Nine CPI-E patients (42.9%) had significant fatigue (MAF score ≥30) and 6 (28.6%) had mild or moderate anxiety (GAD-7 ≥5). There were no significant differences in PHQ-8, GAD-7, IBD-Q and MAF between CPI-E, CD and UC patients, suggesting comparable levels of psychological morbidity in the three groups. Significant correlations were found between CPI-E disease activity and IBD-Q and GAD-7 scores.ConclusionOur study suggests that psychological morbidity in CPI-E is common and comparable to rates in CD and UC, even in the setting of clinical remission. Clinicians should be aware of this complication and take a holistic approach to this patient group.

IntroductionSystemic corticosteroids, the mainstay of treatment for immune checkpoint inhibitor (CPI) induced enterocolitis, are associated with complications including life-threatening infection. The topically-acting oral corticosteroid Beclomethasone Dipropionate (BD) is an effective treatment for mild to moderate flares of ulcerative colitis, and has fewer side effects than systemic corticosteroids. In this study, we hypothesised that BD is a safe and effective treatment for mild and microscopic CPI enterocolitis.MethodsWe performed a retrospective analysis of all patients who started BD for CPI enterocolitis at three UK cancer centres between November 2017 & October 2020. All patients underwent endoscopic assessment and biopsy. The initial regimen of BD was 5mg once daily for 28 days. The primary outcome was clinical remission at 28 days, defined as a return to baseline stool frequency. Secondary outcomes included the rates of adverse events and clinical relapse after BD cessation.ResultsTwenty-two patients (14 male) with a median age of 64 (range 45-84) were treated with BD. At baseline, ten patients (71%) had an increase in stool frequency of greater than 3 per day above baseline (CTCAE grade 2 or more) and the median number of loose stools in a 24-hour period was six. 11 (50%) patients were dependent on systemic corticosteroids prior to starting BD. Baseline sigmoidoscopy showed mild inflammation (loss of vascular pattern, mucosal granularity, small erosions) in eleven patients (50%) and normal findings in eleven patients (50%). Twenty patients (91%) had histopathological features of inflammation. There were no adverse events attributable to BD. All 22 patients (100%) had a clinical response to BD and 21 (95.5%) achieved clinical remission with a return to baseline stool frequency. 10 patients (45.5%) had symptomatic relapse on cessation of BD, five (22.7%) within seven days of stopping. All 10 relapsing patients recaptured response on restarting BD.ConclusionsTopical BD is an appealing alternative option to systemic immunosuppressive treatments to treat colonic inflammation. In this study, BD was safe and effective at inducing remission in mild and/or microscopic CPI induced enterocolitis. Further randomised studies are needed to confirm these findings and determine the optimum dosing regimen.

IntroductionPatients with inflammatory bowel disease (IBD) are in a risk group recommended for yearly influenza (flu) immunisation. We sought to determine whether immunosuppressive treatments were associated with reduced antibody (Ab) responses to flu vaccination and if these responses correlated with responses to COVID vaccination.Methods266 adults (213 IBD, 53 healthy controls (HC); 165 vaccinated against flu, 101 unvaccinated) were recruited. Medications included infliximab (ifx; n=39), thiopurines (thio; n=43), infliximab and thiopurine combination therapy (combo; n=37), ustekinumab (uste; n=33), vedolizumab (vedo; n=39) or tofacitinib (tofa; n=22). The primary outcome was Ab responses against H3 and H1 flu, stratified by immunosuppressive therapy compared to HC, adjusting for age, and interval between vaccination and sampling.ResultsIn multivariable modelling (figure 1), lower Ab responses against H3 were observed in patients on ifx (Geometric Mean Ratio 0.41 [95% CIs 0.24,0.69], p=0.00096), combo (0.54 [0.32,0.91], p=0.021) and tofa (0.34 [0.17,0.68], p=0.0025) compared to HC. Thio (0.80 [0.48,1.32], p=0.38), uste (0.90 [0.52,1.55], p=0.70) and vedo (0.75 [0.44,1.27], p=0.28) were not associated with lower Ab responses against H3. Reduced Ab responses against H1 were observed in patients on ifx (0.32 [0.17,0.61], p=0.0006), combo (0.38 [0.20,0.72], p=0.0032), thio (0.51 [0.28,0.95], p=0.033) and tofa (0.27 [0.12,0.63], p=0.0026) relative to HC. Uste (0.73 [0.37,1.43], p=0.36) and vedo (0.74 [0.39,1.42], p=0.37) were not associated with reduced Ab responses against H1. Anti-SARS-CoV-2 Ab concentration was moderately correlated with antibodies against H3 (r=0.27; p=0.0004) and H1 (r=0.33; p<0.0001).ConclusionsIfx and tofa are associated with diminished flu vaccine-induced Ab responses and there is correlation between humoral responses to flu and COVID vaccinations. Adherence to guidelines advising annual vaccination against flu is particularly important in patients with IBD receiving anti-TNF and JAK-inhibitors.Financial support was provided as a Research Grant by Pfizer Ltd.Abstract P75 Figure 1Multivariable linear regression models of vaccine-induced antibody responses against influenza A H3 and H1, stratified by treatment group. GMR: geometric mean ratio

IntroductionPatients with Inflammatory bowel disease (IBD) receiving anti-TNF or JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against Omicron BA.4/5 and wild-type strain.Methods68 healthy controls (HC) and 261 patients with IBD were sampled after 3 doses of COVID-19 vaccine. The IBD population was established (>12 weeks therapy) on either infliximab (IFX) (n=43), thiopurine (n=60), thiopurine & IFX combination (n=46), ustekinumab (n=43), vedolizumab (n=46) or tofacitinib (n=23). Pseudo neutralisation assays were performed and the half maximal inhibitory concentration (NT50) of participant sera was calculated. Primary outcome was neutralising responses against wild-type (WT) virus and BA.4/5 variant stratified by immunosuppressive therapy, adjusting for prior infection, vaccine type and age.ResultsAntibody titres against BA.4/5 were significantly lower than against WT virus in both HCs and IBD groups (figure 1. Geometric Mean Ratio (GMR) [95% CI], 0.11 [0.09, 0.15], P<0.0001 in healthy participants; GMR 0.07 [0.06, 0.08], P<0.0001 in IBD patients). Multivariable models showed that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in IBD patients on IFX (GMR 0.44 [0.20, 0.97], P=0.042), IFX and thiopurine combination (GMR 0.34 [0.15, 0.77], P=0.0098) or tofacitinib (GMR 0.37 [0.15, 0.92], P=0.032), but not in patients on thiopurine monotherapy, ustekinumab or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against WT (P=0.037) and BA.4/5 (P=0.045).ConclusionsA third dose of COVID-19 vaccine based on the WT spike glycoprotein boosts neutralising antibody titres in patients with IBD. However, responses are lower against Omicron BA.4/5, particularly in patients taking anti-TNF or JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed IBD patients may receive additional benefit from bivalent vaccine boosters which target Omicron variants.Abstract P77 Figure 150% neutralisation titre (NT50) against SARS-CoV-2 wild type (WT) and BA.4/5 in IBD patients treated with different immunosuppressant and healthy controls after 3 doses of vaccine

Immune checkpoint inhibitors (ICPis) have revolutionised survival outcomes for cancer patients by bolstering anti-tumour immunity. However, immune activation also occurs in non-cancer tissue, and a significant proportion of patients develop immune-mediated colitis, which can be fatal if not promptly recognised and managed. Diagnosis is often made by inflammation observed during lower gastrointestinal endoscopy. Little is known about microscopic inflammation (histological findings of inflammation in the absence of overt mucosal injury). Management strategies beyond the use of systemic corticosteroids, which incur a high burden of deleterious side effects, have not been extensively explored. We describe the cases of two cancer patients with ICPi-induced colitis who had isolated histoloigical features of colitis in the absence of macroscopic disease. Sustained clinical and histological remission was induced with the topical steroid preparation, beclometasone dipropionate (Clipper), with no adverse effects.

Background and AimsImmune checkpoint inhibitors (CPI) have revolutionised cancer treatment, with previously untreatable disease now amenable to potential cure. Combination regimens of anti-CTLA4 and anti-PD-1 show enhanced efficacy but are prone to off target immune-mediated tissue injury, particularly at the barrier surfaces. CPI-induced colitis is a common a serious complication.MethodsTo probe the impact of immune checkpoints on intestinal homeostasis mice were challenged with combination anti-CTLA4 and anti-PD-1 immunotherapy, manipulation of the intestinal microbiota and antibody blockade/depletion studies. Colonic immune responses were profiled using RNA-sequencing, including high-resolution single cell analyses, and flow cytometry.ResultsCPI-colitis was dependent on the composition of the intestinal microbiota and was characterized by remodelling of mucosal lymphocytes with induction of polyfunctional lymphocyte responses characterized by increased expression of interferon-γ (IFNγ), other pro-inflammatory cytokines/chemokines (Il22, Il17a Ccl3, Ccl4 and Ccl9), cytotoxicity molecules (Gzmb, Gzma, Prf1, Nkg7) and the chemokine receptor Cxcr6. In comparison with mucosal lymphocytes in the steady state, polyfunctional lymphocytes from both CD4+ and CD8+ lineages upregulated costimulatory molecules and checkpoint molecules in CPI-colitis, indicating that these cells are tightly regulated. CPI-colitis was attenuated following depletion of effector lymphocytes or following blockade of the IL23/IFNγ axis.ConclusionsThis study provides new mechanistic insights into CPI-colitis, identifying polyfunctional, cytotoxic lymphocytes as key mediators of disease. Therapeutic targeting of their effector response or regulatory networks, including the IL23/IFNγ axis holds the key to preventing and reversing CPI-colitis.