Modelling the benefits of an optimised treatment strategy for 5-ASA in mild-to-moderate ulcerative colitis.

OBJECTIVES: 5-aminosalicylate (mesalazine; 5-ASA) is an established first-line treatment for mild-to-moderate ulcerative colitis (UC). This study aimed to model the benefits of optimising 5-ASA therapy. METHODS: A decision tree model followed 10 000 newly diagnosed patients with mild-to-moderately active UC through induction and 1 year of maintenance treatment. Optimised treatment (maximising dose of 5-ASA and use of combined oral and rectal therapy before treatment escalation) was compared with standard treatment (standard doses of 5-ASA without optimisation). Modelled data were derived from published meta-analyses. The primary outcomes were patient numbers achieving and maintaining remission, with an analysis of treatment costs for each strategy conducted as a secondary outcome (using UK reference costs). RESULTS: During induction, there was a 39% increase in patients achieving remission through the optimised pathway without requiring systemic steroids and/or biologics (6565 vs 4725 for standard). Potential steroidal/biological adverse events avoided included: seven venous thromboembolisms and eight serious infections. Out of the 6565 patients entering maintenance following successful induction on 5-ASA, there was a 21% reduction in relapses when optimised (1830 vs 2311 for standard). This translated into 297 patients avoiding further systemic steroids and 214 biologics. Optimisation led to an average net saving of £272 per patient entering the model for the induction and maintenance of remission over 1 year. CONCLUSION: Modelling suggests that optimising 5-ASA therapy (both the inclusion of rectal 5-ASA into a combined oral and rectal regimen and maximisation of 5-ASA dose) has clinical and cost benefits that supports wider adoption in clinical practice.

Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance.

OBJECTIVE: Dysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine. DESIGN: We performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA sequencing to derive a transcriptomic signature of hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples. RESULTS: We characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing and paracrine sensing of IL-1α/IL-1ß and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (TNF) therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease. CONCLUSION: Our work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn's disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1α/IL-1ß-targeting therapies upstream of IL-23.

High mucosal cytomegalovirus DNA helps predict adverse short-term outcome in acute severe ulcerative colitis.

BACKGROUND/AIMS: Predictors of short-term outcome of intravenous (IV) steroid therapy in acute severe ulcerative colitis (ASUC) have been well described, but the impact of cytomegalovirus (CMV) infection as a predictor of outcome remains debatable. We investigated the role of quantitative CMV polymerase chain reaction (PCR) as a predictor of short-term outcome in patients with ASUC. METHODS: Consecutive patients with ASUC satisfying Truelove and Witts criteria hospitalized at All India Institute of Medical Sciences (AIIMS) from May 2016 to July 2019 were included; all received IV steroid. The primary outcome measure was steroid-failure defined as the need for rescue therapy (with ciclosporin or infliximab) or colectomy during admission. AIIMS' index (ulcerative colitis index of severity > 6 at day 1+fecal calprotectin > 1,000 µg/g at day 3), with quantitative CMV PCR on biopsy samples obtained at initial sigmoidoscopy were correlated with the primary outcome. RESULTS: Thirty of 76 patients (39%) failed IV corticosteroids and 12 (16%) underwent surgery. Patients with steroid failure had a significantly higher mucosal CMV DNA than responders (3,454 copies/mg [0-2,700,000] vs. 116 copies/mg [0-27,220]; P< 0.01). On multivariable analysis, mucosal CMV DNA load > 2,000 copies/mg (odds ratio [OR], 10.2; 95% confidence interval [CI], 2.6-39.7; P< 0.01) and AIIMS' index (OR, 39.8; 95% CI, 4.4-364.4; P< 0.01) were independent predictors of steroid-failure and need for colectomy. The combination correctly predicted outcomes in 84% of patients with ASUC. CONCLUSIONS: High mucosal CMV DNA ( > 2,000 copies/mg) independently predicts failure of IV corticosteroids and short-term risk of colectomy and it has an additional value to the established markers of disease severity in patients with ASUC.

IBD2020 global forum: results of an international patient survey on quality of care.

BACKGROUND/AIMS: IBD2020 is a global forum for standards of care in inflammatory bowel disease (IBD). The aim of the IBD2020 survey was to identify and describe variations in quality care of IBD. METHODS: Patients with IBD from Finland, Italy, France, Canada, Germany, UK, Spain and Sweden were surveyed during 2013 to 2014, covering: disease characteristics; impact on life and work; organization and perceived quality of care. RESULTS: Seven thousand five hundred and seven patients participated (median age, 39 years [range, 10-103 years]; 2,354 male [31.4%]), including 4,097 (54.6%) with Crohn's disease (CD) and 3,410 (45.4%) with ulcerative colitis (UC). Median time from symptom onset to diagnosis was 1 year for both CD (range, 0-47 years) and UC (range, 0-46 years), with no clear evidence of improvement in diagnostic delay over the preceding 24 years. Half of the patients (3,429; 50.0%) rated their care as "excellent" or "very good," with similar results for CD and UC across countries. Five factors were significantly (P<0.01) associated with perceived good quality of care: quality of specialist communication; review consultation being long enough; failure to share information; no access to a dietician; speed of advice. CONCLUSIONS: The IBD2020 survey has highlighted areas related to quality of care of IBD from the patients' perspective, with scope for improvement.

Developing a Standard Set of Patient-Centred Outcomes for Inflammatory Bowel Disease-an International, Cross-disciplinary Consensus.

BACKGROUND AND AIMS: Success in delivering value-based healthcare involves measuring outcomes that matter most to patients. Our aim was to develop a minimum Standard Set of patient-centred outcome measures for inflammatory bowel disease [IBD], for use in different healthcare settings. METHODS: An international working group [n = 25] representing patients, patient associations, gastroenterologists, surgeons, specialist nurses, IBD registries and patient-reported outcome measure [PROM] methodologists participated in a series of teleconferences incorporating a modified Delphi process. Systematic review of existing literature, registry data, patient focus groups and open review periods were used to reach consensus on a minimum set of standard outcome measures and risk adjustment variables. Similar methodology has been used in 21 other disease areas [www.ichom.org]. RESULTS: A minimum Standard Set of outcomes was developed for patients [aged ≥16] with IBD. Outcome domains included survival and disease control [survival, disease activity/remission, colorectal cancer, anaemia], disutility of care [treatment-related complications], healthcare utilization [IBD-related admissions, emergency room visits] and patient-reported outcomes [including quality of life, nutritional status and impact of fistulae] measured at baseline and at 6 or 12 month intervals. A single PROM [IBD-Control questionnaire] was recommended in the Standard Set and minimum risk adjustment data collected at baseline and annually were included: demographics, basic clinical information and treatment factors. CONCLUSIONS: A Standard Set of outcome measures for IBD has been developed based on evidence, patient input and specialist consensus. It provides an international template for meaningful, comparable and easy-to-interpret measures as a step towards achieving value-based healthcare in IBD.