Antidepressant treatment in inflammatory bowel disease: a systematic review and meta-analysis.

Around 25% of patients with inflammatory bowel disease (IBD) have depressive symptoms, yet antidepressants have been poorly studied in IBD. We systematically searched IBD studies testing antidepressants in four databases. Outcomes were depressive symptoms, anxiety, IBD disease activity, quality of life (QoL) and adverse events. For randomized controlled trials (RCTs), we performed random-effects meta-analysis of the standardized mean difference (SMD) in posttreatment scores between antidepressant and placebo groups. Risk of bias was assessed using the Cochrane Common Mental Disorders Depression Anxiety and Neurosis Group tool (clinical trials) and Newcastle-Ottawa scale (cohort studies). We included 11 studies ( n  = 327): three placebo-controlled RCTs, two nonrandomized trials, and six other study types. In the pooled analysis, antidepressants improved depressive symptoms [SMD = -0.71 (95% confidence interval (CI) -1.32 to -0.10), P  = 0.02, I2  = 51%] and QoL [SMD = 0.88 (95% CI 0.30-1.45), P  = 0.003, I2  = 44%] more than placebo. Serotonin and noradrenaline reuptake inhibitors (SNRIs) alone improved depressive symptoms [SMD = -0.95 (95% CI -1.45 to -0.45, P  < 0.001, I2  = 11%], anxiety [SMD = -0.92 (95% CI 1.72 to -0.13), P  = 0.023, I2  = 65%] and QoL [SMD = 1.14 (95% CI 0.66-1.62), P  < 0.001, I2  = 0%]. The three RCTs were of good quality. In conclusion, based on three small but good-quality studies, antidepressants improve depressive symptoms and QoL compared to placebo in IBD. SNRI antidepressants may also improve anxiety. A fully powered study of antidepressants in IBD is needed.

Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine.

INTRODUCTION: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments. METHODS AND ANALYSIS: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk. TRIAL REGISTRATION NUMBER: ISRCTN96296121.

Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis.

BACKGROUND: Checkpoint inhibitor-induced hepatitis (CPI-hepatitis) is an emerging problem with the widening use of CPIs in cancer immunotherapy. Here, we developed a mouse model to characterize the mechanism of CPI-hepatitis and to therapeutically target key pathways driving this pathology. METHODS: C57BL/6 wild-type (WT) mice were dosed with toll-like receptor (TLR)9 agonist (TLR9-L) for hepatic priming combined with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) plus anti-programmed cell death 1 (PD-1) ("CPI") or phosphate buffered saline (PBS) control for up to 7 days. Flow cytometry, histology/immunofluorescence and messenger RNA sequencing were used to characterize liver myeloid/lymphoid subsets and inflammation. Hepatocyte damage was assessed by plasma alanine transaminase (ALT) and cytokeratin-18 (CK-18) measurements. In vivo investigations of CPI-hepatitis were carried out in Rag2-/- and Ccr2rfp/rfp transgenic mice, as well as following anti-CD4, anti-CD8 or cenicriviroc (CVC; CCR2/CCR5 antagonist) treatment. RESULTS: Co-administration of combination CPIs with TLR9-L induced liver pathology closely resembling human disease, with increased infiltration and clustering of granzyme B+perforin+CD8+ T cells and CCR2+ monocytes, 7 days post treatment. This was accompanied by apoptotic hepatocytes surrounding these clusters and elevated ALT and CK-18 plasma levels. Liver RNA sequencing identified key signaling pathways (JAK-STAT, NF-ΚB) and cytokine/chemokine networks (Ifnγ, Cxcl9, Ccl2/Ccr2) as drivers of CPI-hepatitis. Using this model, we show that CD8+ T cells mediate hepatocyte damage in experimental CPI-hepatitis. However, their liver recruitment, clustering, and cytotoxic activity is dependent on the presence of CCR2+ monocytes. The absence of hepatic monocyte recruitment in Ccr2rfp/rfp mice and CCR2 inhibition by CVC treatment in WT mice was able to prevent the development and reverse established experimental CPI-hepatitis. CONCLUSION: This newly established mouse model provides a platform for in vivo mechanistic studies of CPI-hepatitis. Using this model, we demonstrate the central role of liver infiltrating CCR2+ monocyte interaction with tissue-destructive CD8+ T cells in the pathogenesis of CPI-hepatitis and highlight CCR2 inhibition as a novel therapeutic target.

Novel endoscopic scoring system for immune mediated colitis: A Multicenter Retrospective Study of 674 Patients.

BACKGROUND & AIMS: No endoscopic scoring system has been established for immune-mediated colitis (IMC). This study aimed to establish such a system for IMC and explore its utility in guiding future selective immunosuppressive therapy (SIT) use compared to clinical symptoms. METHODS: This retrospective international 14-center study included 674 patients who developed IMC after immunotherapy and underwent endoscopic evaluation. Ten endoscopic features were selected by group consensus and assigned one point each to calculate an IMC endoscopic score (IMCES). IMCES cutoffs were chosen to maximize specificity for SIT use. This specificity was compared between IMCES, and clinical symptoms graded according to a standardized instrument. RESULTS: A total of 309 (45.8%) patients received SIT. IMCES specificity for SIT use was 82.8% with a cutoff of 4 . The inclusion of ulceration as a mandatory criterion resulted in higher specificity (85.0% for a cutoff of 4). In comparison, the specificity of a Mayo Endoscopy Score (MES) of 3 was 74.6% while specificity of clinical symptom grading was much lower at 27.4% and 12.3% respectively. Early endoscopy was associated with timely SIT use (p<0.001, r=0.4084). CONCLUSIONS: This is the largest, multi-center study to devise an endoscopic scoring system to guide IMC management. An IMCES cutoff 4 has a higher specificity for SIT use than clinical symptoms, supporting early endoscopic evaluation for IMC.

Antibody responses to Influenza vaccination are diminished in patients with inflammatory bowel disease on infliximab or tofacitinib.

BACKGROUND AND AIMS: We sought to determine whether six commonly used immunosuppressive regimens were associated with lower antibody responses after seasonal influenza vaccination in patients with IBD. METHODS: We conducted a prospective study including 213 IBD patients and 53 healthy controls; 165 who had received seasonal influenza vaccine and 101 who had not. IBD medications included infliximab, thiopurines, infliximab and thiopurine combination therapy, ustekinumab, vedolizumab or tofacitinib. The primary outcome was antibody responses against influenza/A H3N2 and A/H1N1, compared to controls, adjusting for age, prior vaccination and interval between vaccination and sampling. RESULTS: Lower antibody responses against influenza A/H3N2 were observed in patients on infliximab (Geometric Mean Ratio 0.35 [95% CI 0.20-0.60], p=0.0002), combination of infliximab and thiopurine therapy (0.46 [0.27-0.79], p=0.0050) and tofacitinib (0.28 [0.14-0.57], p=0.0005) compared to controls. Lower antibody responses against A/H1N1 were observed in patients on infliximab (0.29 [0.15-0.56], p=0.0003), combination of infliximab and thiopurine therapy (0.34 [0.17-0.66], p=0.0016), thiopurine monotherapy (0.46 [0.24-0.87], p=0.017) and tofacitinib (0.23 [0.10-0.56], p=0.0013). Ustekinumab and vedolizumab were not associated with reduced antibody responses against A/H3N2 or A/H1N1. Vaccination in the previous year was associated with higher antibody responses to A/H3N2. Vaccine-induced anti-SARS-CoV-2 antibody concentration weakly correlated with antibodies against H3N2 (r=0.27; p=0.0004) and H1N1 (r=0.33; p<0.0001). CONCLUSIONS: Vaccination in both the 2020-2021 and 2021-2022 seasons was associated with significantly higher antibody responses to influenza/A than no vaccination or vaccination in 2021-2022 alone. Infliximab and tofacitinib are associated with lower binding antibody responses to Influenza/A, similar to COVID-19 vaccine-induced antibody responses.

Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis.

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.

Neutralising antibody responses against SARS-CoV-2 Omicron BA.4/5 and wild-type virus in patients with inflammatory bowel disease following three doses of COVID-19 vaccine (VIP): a prospective, multicentre, cohort study.

Background: Patients with inflammatory bowel disease (IBD) receiving anti-TNF and JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the Omicron BA.4/5 variant. Methods: In this multicentre cohort study, we prospectively recruited 340 adults (69 healthy controls and 271 IBD) at nine UK hospitals between May 28, 2021 and March 29, 2022. The IBD study population was established (>12 weeks therapy) on either thiopurine (n = 63), infliximab (n = 45), thiopurine and infliximab combination therapy (n = 48), ustekinumab (n = 45), vedolizumab (n = 46) or tofacitinib (n = 24). Patients were excluded if they were being treated with any other immunosuppressive therapies. Participants had two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccines, followed by a third dose of either BNT162b2 or mRNA1273. Pseudo-neutralisation assays against SARS-CoV-2 wild-type and BA.4/5 were performed. The half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARS-CoV-2 neutralising response against wild-type virus and Omicron BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, vaccine type, age, and interval between vaccination and blood collection. This study is registered with ISRCTN (No. 13495664). Findings: Both heterologous (first two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both wild-type SARS-CoV-2 virus and the Omicron BA.4/5 variant in healthy participants and patients with IBD. Antibody titres against BA.4/5 were significantly lower than antibodies against wild-type virus in both healthy participants and patients with IBD (p < 0.0001). Multivariable models demonstrated that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in patients with IBD on infliximab (Geometric Mean Ratio (GMR) 0.19 [0.10, 0.36], p < 0.0001), infliximab and thiopurine combination (GMR 0.25 [0.13, 0.49], p < 0.0001) or tofacitinib (GMR 0.43 [0.20, 0.91], p = 0.028), but not in patients on thiopurine monotherapy, ustekinumab, or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against wild-type (p = 0.037) and BA.4/5 (p = 0.045). Interpretation: A third dose of a COVID-19 mRNA vaccine based on the wild-type spike glycoprotein significantly boosts neutralising antibody titres in patients with IBD. However, responses are lower against the Omicron variant BA.4/5, particularly in patients taking anti-TNF and JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed patients with IBD may receive additional benefit from bivalent vaccine boosters which target Omicron variants. Funding: Pfizer.

TRAV26-2 T-Cell Receptor Expression Is Associated With Mucosal Lymphocyte Response to Wheat Proteins in Patients With Functional Dyspepsia.

INTRODUCTION: An association between functional dyspepsia (FD) and wheat-containing foods has been reported in observational studies; however, an adaptive response has not been demonstrated. We examined whether antigens present in wheat could provoke a response from FD duodenal lymphocytes. METHODS: Lamina propria mononuclear cells (LPMCs) were isolated from duodenal biopsies from 50 patients with FD and 23 controls. LPMCs were exposed to gluten (0.2 mg/mL) or gliadin (0.2 mg/mL) for 24 hours. Flow cytometry was performed to phenotype lymphocytes. Quantitative PCR was used to measure the expression of gliadin-associated T-cell receptor alpha variant ( TRAV ) 26-2. RESULTS: In response to gliadin (but not gluten) stimulation, the effector Th2-like population was increased in FD LPMCs compared with that in controls and unstimulated FD LPMCs. Duodenal gene expression of TRAV26- 2 was decreased in patients with FD compared with that in controls. We identified a positive association between gene expression of this T-cell receptor variant and LPMC effector Th17-like cell populations in patients with FD, but not controls after exposure to gluten, but not gliadin. DISCUSSION: Our findings suggest that gliadin exposure provokes a duodenal effector Th2-like response in patients with FD, supporting the notion that food antigens drive responses in some patients. Furthermore, these findings suggest that altered lymphocyte responses to wheat proteins play a role in FD pathogenesis.

Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets.

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.

CD90 is not constitutively expressed in functional innate lymphoid cells.

Huge progress has been made in understanding the biology of innate lymphoid cells (ILC) by adopting several well-known concepts in T cell biology. As such, flow cytometry gating strategies and markers, such as CD90, have been applied to indentify ILC. Here, we report that most non-NK intestinal ILC have a high expression of CD90 as expected, but surprisingly a sub-population of cells exhibit low or even no expression of this marker. CD90-negative and CD90-low CD127+ ILC were present amongst all ILC subsets in the gut. The frequency of CD90-negative and CD90-low CD127+ ILC was dependent on stimulatory cues in vitro and enhanced by dysbiosis in vivo. CD90-negative and CD90-low CD127+ ILC were a potential source of IL-13, IFNγ and IL-17A at steady state and upon dysbiosis- and dextran sulphate sodium-elicited colitis. Hence, this study reveals that, contrary to expectations, CD90 is not constitutively expressed by functional ILC in the gut.

Mirikizumab Regulates Genes Involved in Ulcerative Colitis Disease Activity and Anti-TNF Resistance: Results From a Phase 2 Study.

INTRODUCTION: Mirikizumab, a monoclonal antibody targeting the p19 subunit of interleukin (IL)-23, demonstrated efficacy and was well-tolerated in a phase 2 randomized clinical trial in patients with moderate-to-severe ulcerative colitis (UC) (NCT02589665). We explored gene expression changes in colonic tissue from study patients and their association with clinical outcomes. METHODS: Patients were randomized to receive intravenous placebo or 3 mirikizumab induction doses. Patient biopsies were collected at baseline and week 12, and differential gene expression was measured using a microarray platform and compared in all treatment groups to determine differential expression values between baseline and week 12. RESULTS: The greatest improvement in clinical outcomes and placebo-adjusted change from baseline in transcripts at week 12 was observed in the 200 mg mirikizumab group. Transcripts significantly modified by mirikizumab correlate with key UC disease activity indices (modified Mayo score, Geboes score, and Robarts Histopathology Index) and include MMP1, MMP3, S100A8, and IL1ß. Changes in transcripts associated with increased disease activity were decreased after 12 weeks of mirikizumab treatment. Mirikizumab treatment affected transcripts associated with resistance to current therapies, including IL-1ß, OSMR, FCGR3A and FCGR3B, and CXCL6, suggesting that anti-IL23p19 therapy modulates biological pathways involved in resistance to antitumor necrosis factor and Janus kinase inhibitors. DISCUSSION: This is the first large-scale gene expression study of inflamed mucosa from patients with UC treated with anti-IL23p19 therapy. These results provide molecular evidence for mucosal healing from an extensive survey of changes in transcripts that improve our understanding of the molecular effects of IL-23p19 inhibition in UC.

The gut microbiota and metabolome are associated with diminished COVID-19 vaccine-induced antibody responses in immunosuppressed inflammatory bowel disease patients.

BACKGROUND: Patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy exhibit attenuated humoral immune responses to vaccination against SARS-CoV-2. The gut microbiota and its functional metabolic output, which are perturbed in IBD, play an important role in shaping host immune responses. We explored whether the gut microbiota and metabolome could explain variation in anti-SARS-CoV-2 vaccination responses in immunosuppressed IBD patients. METHODS: Faecal and serum samples were prospectively collected from infliximab-treated patients with IBD in the CLARITY-IBD study undergoing vaccination against SARS-CoV-2. Antibody responses were measured following two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccine. Patients were classified as having responses above or below the geometric mean of the wider CLARITY-IBD cohort. 16S rRNA gene amplicon sequencing, nuclear magnetic resonance (NMR) spectroscopy and bile acid profiling with ultra-high-performance liquid chromatography mass spectrometry (UHPLC-MS) were performed on faecal samples. Univariate, multivariable and correlation analyses were performed to determine gut microbial and metabolomic predictors of response to vaccination. FINDINGS: Forty-three infliximab-treated patients with IBD were recruited (30 Crohn's disease, 12 ulcerative colitis, 1 IBD-unclassified; 26 with concomitant thiopurine therapy). Eight patients had evidence of prior SARS-CoV-2 infection. Seventeen patients (39.5%) had a serological response below the geometric mean. Gut microbiota diversity was lower in below average responders (p = 0.037). Bilophila abundance was associated with better serological response, while Streptococcus was associated with poorer response. The faecal metabolome was distinct between above and below average responders (OPLS-DA R2X 0.25, R2Y 0.26, Q2 0.15; CV-ANOVA p = 0.038). Trimethylamine, isobutyrate and omega-muricholic acid were associated with better response, while succinate, phenylalanine, taurolithocholate and taurodeoxycholate were associated with poorer response. INTERPRETATION: Our data suggest that there is an association between the gut microbiota and variable serological response to vaccination against SARS-CoV-2 in immunocompromised patients. Microbial metabolites including trimethylamine may be important in mitigating anti-TNF-induced attenuation of the immune response. FUNDING: JLA is the recipient of an NIHR Academic Clinical Lectureship (CL-2019-21-502), funded by Imperial College London and The Joyce and Norman Freed Charitable Trust. BHM is the recipient of an NIHR Academic Clinical Lectureship (CL-2019-21-002). The Division of Digestive Diseases at Imperial College London receives financial and infrastructure support from the NIHR Imperial Biomedical Research Centre (BRC) based at Imperial College Healthcare NHS Trust and Imperial College London. Metabolomics studies were performed at the MRC-NIHR National Phenome Centre at Imperial College London; this work was supported by the Medical Research Council (MRC), the National Institute of Health Research (NIHR) (grant number MC_PC_12025) and infrastructure support was provided by the NIHR Imperial Biomedical Research Centre (BRC). The NIHR Exeter Clinical Research Facility is a partnership between the University of Exeter Medical School College of Medicine and Health, and Royal Devon and Exeter NHS Foundation Trust. This project is supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care.

Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): an analysis of a prospective multicentre cohort study.

BACKGROUND: Anti-TNF drugs, such as infliximab, are associated with attenuated antibody responses after SARS-CoV-2 vaccination. We aimed to determine how the anti-TNF drug infliximab and the anti-integrin drug vedolizumab affect vaccine-induced neutralising antibodies against highly transmissible omicron (B.1.1.529) BA.1, and BA.4 and BA.5 (hereafter BA.4/5) SARS-CoV-2 variants, which possess the ability to evade host immunity and, together with emerging sublineages, are now the dominating variants causing current waves of infection. METHODS: CLARITY IBD is a prospective, multicentre, observational cohort study investigating the effect of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). Patients aged 5 years and older with a diagnosis of IBD and being treated with infliximab or vedolizumab for 6 weeks or longer were recruited from infusion units at 92 hospitals in the UK. In this analysis, we included participants who had received uninterrupted biological therapy since recruitment and without a previous SARS-CoV-2 infection. The primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and omicron subvariants BA.1 and BA.4/5 after three doses of SARS-CoV-2 vaccine. We constructed Cox proportional hazards models to investigate the risk of breakthrough infection in relation to neutralising antibody titres. The study is registered with the ISRCTN registry, ISRCTN45176516, and is closed to accrual. FINDINGS: Between Sept 22 and Dec 23, 2020, 7224 patients with IBD were recruited to the CLARITY IBD study, of whom 1288 had no previous SARS-CoV-2 infection after three doses of SARS-CoV-2 vaccine and were established on either infliximab (n=871) or vedolizumab (n=417) and included in this study (median age was 46·1 years [IQR 33·6-58·2], 610 [47·4%] were female, 671 [52·1%] were male, 1209 [93·9%] were White, and 46 [3·6%] were Asian). After three doses of SARS-CoV-2 vaccine, 50% neutralising titres (NT50s) were significantly lower in patients treated with infliximab than in those treated with vedolizumab, against wild-type (geometric mean 2062 [95% CI 1720-2473] vs 3440 [2939-4026]; p<0·0001), BA.1 (107·3 [86·40-133·2] vs 648·9 [523·5-804·5]; p<0·0001), and BA.4/5 (40·63 [31·99-51·60] vs 223·0 [183·1-271·4]; p<0·0001) variants. Breakthrough infection was significantly more frequent in patients treated with infliximab (119 [13·7%; 95% CI 11·5-16·2] of 871) than in those treated with vedolizumab (29 [7·0% [4·8-10·0] of 417; p=0·00040). Cox proportional hazards models of time to breakthrough infection after the third dose of vaccine showed infliximab treatment to be associated with a higher hazard risk than treatment with vedolizumab (hazard ratio [HR] 1·71 [95% CI 1·08-2·71]; p=0·022). Among participants who had a breakthrough infection, we found that higher neutralising antibody titres against BA.4/5 were associated with a lower hazard risk and, hence, a longer time to breakthrough infection (HR 0·87 [0·79-0·95]; p=0·0028). INTERPRETATION: Our findings underline the importance of continued SARS-CoV-2 vaccination programmes, including second-generation bivalent vaccines, especially in patient subgroups where vaccine immunogenicity and efficacy might be reduced, such as those on anti-TNF therapies. FUNDING: Royal Devon University Healthcare NHS Foundation Trust; Hull University Teaching Hospital NHS Trust; NIHR Imperial Biomedical Research Centre; Crohn's and Colitis UK; Guts UK; National Core Studies Immunity Programme, UK Research and Innovation; and unrestricted educational grants from F Hoffmann-La Roche, Biogen, Celltrion Healthcare, Takeda, and Galapagos.

Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy.

The function of interleukin-22 (IL-22) in intestinal barrier homeostasis remains controversial. Here, we map the transcriptional landscape regulated by IL-22 in human colonic epithelial organoids and evaluate the biological, functional and clinical significance of the IL-22 mediated pathways in ulcerative colitis (UC). We show that IL-22 regulated pro-inflammatory pathways are involved in microbial recognition, cancer and immune cell chemotaxis; most prominently those involving CXCR2+ neutrophils. IL-22-mediated transcriptional regulation of CXC-family neutrophil-active chemokine expression is highly conserved across species, is dependent on STAT3 signaling, and is functionally and pathologically important in the recruitment of CXCR2+ neutrophils into colonic tissue. In UC patients, the magnitude of enrichment of the IL-22 regulated transcripts in colonic biopsies correlates with colonic neutrophil infiltration and is enriched in non-responders to ustekinumab therapy. Our data provide further insights into the biology of IL-22 in human disease and highlight its function in the regulation of pathogenic immune pathways, including neutrophil chemotaxis. The transcriptional networks regulated by IL-22 are functionally and clinically important in UC, impacting patient trajectories and responsiveness to biological intervention.

Faecal calprotectin is a surrogate marker of biliary inflammation in primary sclerosing cholangitis associated inflammatory bowel disease.

Objective: Faecal calprotectin (fCAL) is an established marker of intestinal inflammation in inflammatory bowel disease (IBD). Disproportionally high fCAL levels, for the severity of intestinal inflammation, have been previously observed in primary sclerosing cholangitis associated IBD (PSC-IBD). The aim of this study was to test the hypothesis that fCAL is a marker of biliary injury in PSC-IBD. Methods: We used two cohorts: (1) post hoc analysis of a colonoscopic surveillance study allowing correlation of fCAL to endoscopic severity as measured by the ulcerative colitis endoscopic index of severity (UCEIS) in PSC-IBD (n=20) and ulcerative colitis (UC, n=20) and (2) prospective recruitment of patients attending for endoscopic retrograde cholangiopancreatography allowed the correlation of fCAL to biliary calprotectin (n=8). Results: A strong correlation was seen between fCAL and UCEIS in UC (r=0.821, 95% CI (0.585 to 0.929), p<0.0001). In PSC-IBD, the correlation was weaker (r=0.596, 95% CI (0.195 to 0.8260), p=0.006). PSC-IBD patients with endoscopically quiescent colitis (UCEIS: 0-1) had higher fCAL than patients with UC (279 µg/g, IQR (68-601) vs 30 µg/g, IQR (14-107), p=0.015). This was associated with higher risk of biliary complications like need for antibiotics or instrumentation (HR 16.39, 95% CI (2.98 to 90.25)) rather than colitis flares (follow-up: 12 months). Calprotectin measured in faeces correlated positively with biliary calprotectin (r=0.898, p=0.0024). Conclusion: fCAL is a surrogate marker for biliary inflammation in PSC-IBD. Trial registration number: NCT02543021.