The Relationship Between Mucosal Microbiota, Colitis, and Systemic Inflammation in Chronic Granulomatous Disorder.

PURPOSE: Chronic granulomatous disorder (CGD) is a primary immunodeficiency which is frequently complicated by inflammatory colitis and is associated with systemic inflammation. Herein, we aimed to investigate the role of the microbiome in the pathogenesis of colitis and systemic inflammation. METHODS: We performed 16S rDNA sequencing on mucosal biopsy samples from each segment of 10 CGD patients' colons and conducted compositional and functional pathway prediction analyses. RESULTS: The microbiota in samples from colitis patients demonstrated reduced taxonomic alpha-diversity compared to unaffected patients, even in apparently normal bowel segments. Functional pathway richness was similar between the colitic and non-colitic mucosa, although metabolic pathways involved in butyrate biosynthesis or utilization were enriched in patients with colitis and correlated positively with fecal calprotectin levels. One patient with very severe colitis was dominated by Enterococcus spp., while among other patients Bacteroides spp. abundance correlated with colitis severity measured by fecal calprotectin and an endoscopic severity score. In contrast, Blautia abundance is associated with low severity scores and mucosal health. Several taxa and functional pathways correlated with concentrations of inflammatory cytokines in blood but not with colitis severity. Notably, dividing patients into "high" and "low" systemic inflammation groups demonstrated clearer separation than on the basis of colitis status in beta-diversity analyses. CONCLUSION: The microbiome is abnormal in CGD-associated colitis and altered functional characteristics probably contribute to pathogenesis. Furthermore, the relationship between the mucosal microbiome and systemic inflammation, independent of colitis status, implies that the microbiome in CGD can influence the inflammatory phenotype of the condition.

Autoantibody predictors of gastrointestinal symptoms in systemic sclerosis.

OBJECTIVES: To assess the prevalence and burden of SSc-related gastrointestinal dysfunction (SSc-GI) and to evaluate associations with demographic, clinical and serological characteristics. METHODS: Patients completed the UCLA SCTC GIT 2.0 questionnaire for SSc-GI disease to assess the burden of GI disease across multiple functional and psychological domains. Questionnaire scores were assessed using non-parametric and quantile regression analyses. RESULTS: Our cohort included 526 patients with SSc, with a typical distribution of disease-associated autoantibodies (ACA, ARA, ATA, PM-Scl, U1RNP, U3RNP). We demonstrated associations between hallmark antibodies and the domain-specific burden of GI disease. In particular, ACA, ARA and ENA-negative demonstrated increased SSc-GI disease burden, while PM-Scl conferred relative protection. In a distributional analysis, associations with autoantibodies were particularly marked in those with the highest burden of GI disease. CONCLUSION: There is a significant burden of SSc-GI disease in patients with SSc; reflux and bloating symptoms are most prominent. SSc hallmark antibodies may predict increased risk of SSc-GI disease, in particular ACA and ARA, while PM-Scl may be protective.

Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab.

OBJECTIVE: Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections. DESIGN: Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4ß7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020. RESULTS: Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2-5.6) vs 37.0 (15.2-76.1), p<0.0001). CONCLUSIONS: Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy. TRIAL REGISTRATION NUMBER: ISRCTN45176516.

Adaptations to the British Society of Gastroenterology guidelines on the management of acute severe UC in the context of the COVID-19 pandemic: a RAND appropriateness panel.

OBJECTIVE: Management of acute severe UC (ASUC) during the novel COVID-19 pandemic presents significant dilemmas. We aimed to provide COVID-19-specific guidance using current British Society of Gastroenterology (BSG) guidelines as a reference point. DESIGN: We convened a RAND appropriateness panel comprising 14 gastroenterologists and an IBD nurse consultant supplemented by surgical and COVID-19 experts. Panellists rated the appropriateness of interventions for ASUC in the context of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Median scores and disagreement index (DI) were calculated. Results were discussed at a moderated meeting prior to a second survey. RESULTS: Panellists recommended that patients with ASUC should be isolated throughout their hospital stay and should have a SARS-CoV-2 swab performed on admission. Patients with a positive swab should be discussed with COVID-19 specialists. As per BSG guidance, intravenous hydrocortisone was considered appropriate as initial management; only in patients with COVID-19 pneumonia was its use deemed uncertain. In patients requiring rescue therapy, infliximab with continuing steroids was recommended. Delaying colectomy because of COVID-19 was deemed inappropriate. Steroid tapering as per BSG guidance was deemed appropriate for all patients apart from those with COVID-19 pneumonia in whom a 4-6 week taper was preferred. Post-ASUC maintenance therapy was dependent on SARS-CoV-2 status but, in general, biologics were more likely to be deemed appropriate than azathioprine or tofacitinib. Panellists deemed prophylactic anticoagulation postdischarge to be appropriate in patients with a positive SARS-CoV-2 swab. CONCLUSION: We have suggested COVID-19-specific adaptations to the BSG ASUC guideline using a RAND panel.

British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic.

The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government's advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials.

Chronic Granulomatous Disorder-Associated Colitis Can Be Accurately Evaluated with MRI Scans and Fecal Calprotectin Level.

PURPOSE: Colitis is a common and serious complication of chronic granulomatous disorder (CGD) and requires assessment. Colonoscopy is invasive and carries risks of serious complication. We therefore assessed non-invasive monitoring via magnetic resonance imaging (MRI). We also evaluated fecal calprotectin (FCP), the Harvey-Bradshaw index (HBI) clinical score, and serum cytokines. METHODS: We recruited 10 patients with CGD (8 males, mean age 29.6 years), scored a modified HBI, and obtained stool for FCP. The following day we took blood for cytokine measurement via Luminex, performed MR enterography (scored by two independent radiologists using three systems: London score, CDMI, and MaRIA) followed by colonoscopy with disease activity measurement via ulcerative colitis endoscopic index of severity (UCEIS). We assessed patient experience after each investigation and overall preference with follow-up questionnaires. RESULTS: MRI scores correlated well with colonoscopic gold standard (for London score R2 0.91, p < 0.0001; for CDMI R2 0.83, p = 0.0006; for MaRIA R2 0.89, p = 0.0002). MRI was better tolerated and generally preferred, quicker, and visualized the entire large bowel whereas colonoscopy did not reach the terminal ileum in 3 participants. Elevated FCP accurately differentiated patients with colitis from those without, and log(calprotectin) correlated well with disease activity (R2 0.71, p = 0.009). Serum interleukin (IL)-12 concentration correlated with colitis activity but IL-1ß and TNF did not. Harvey-Bradshaw index did not correlate with colitis activity. CONCLUSIONS: MRI and fecal calprotectin are useful methods for monitoring CGD colitis and should reduce the need for colonoscopy in these patients. IL-12 may represent an appropriate target for treatment.

A New Look at Familial Risk of Inflammatory Bowel Disease in the Ashkenazi Jewish Population.

BACKGROUND AND AIMS: The inflammatory bowel diseases (IBD) are particularly common among the Ashkenazi Jewish (AJ) population. Population-specific estimates of familial risk are important for counseling; however, relatively small cohorts of AJ IBD patients have been analyzed for familial risk to date. This study aimed to recruit a new cohort of AJ IBD patients, mainly from the UK, to determine the familial occurrence of disease. METHODS: A total of 864 AJ IBD patients were recruited through advertisements, hospital clinics, and primary care. Participants were interviewed about their Jewish ancestry, disease phenotype, age of diagnosis, and family history of disease. Case notes were reviewed. RESULTS: The 864 probands comprised 506 sporadic and 358 familial cases, the latter with a total of 625 affected relatives. Of the UK cases, 40% had a positive family history with 25% having at least one affected first-degree relative. These percentages were lower among those recruited through hospital clinics and primary care (33% for all relatives and 22% among first-degree relatives). Examining all probands, the relative risk of IBD for offspring, siblings, and parents was 10.5, 7.4, and 4, respectively. Age of diagnosis was significantly lower in familial versus sporadic patients with Crohn's disease. CONCLUSIONS: This study reports familial risk estimates for a significant proportion of the AJ IBD population in the UK. The high rate of a positive family history in this cohort may reflect the greater genetic burden for IBD among AJs. These data are of value in predicting the likelihood of future recurrence of IBD in AJ families.

UK guideline on transition of adolescent and young persons with chronic digestive diseases from paediatric to adult care.

The risks of poor transition include delayed and inappropriate transfer that can result in disengagement with healthcare. Structured transition care can improve control of chronic digestive diseases and long-term health-related outcomes. These are the first nationally developed guidelines on the transition of adolescent and young persons (AYP) with chronic digestive diseases from paediatric to adult care. They were commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology under the auspices of the Adolescent and Young Persons (A&YP) Section. Electronic searches for English-language articles were performed with keywords relating to digestive system diseases and transition to adult care in the Medline (via Ovid), PsycInfo (via Ovid), Web of Science and CINAHL databases for studies published from 1980 to September 2014. The quality of evidence and grading of recommendations was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The limited number of studies in gastroenterology and hepatology required the addition of relevant studies from other chronic diseases to be included.These guidelines deal specifically with the transition of AYP living with a diagnosis of chronic digestive disease and/or liver disease from paediatric to adult healthcare under the following headings;1. Patient populations involved in AYP transition2. Risks of failing transition or poor transition3. Models of AYP transition4. Patient and carer/parent perspective in AYP transition5. Surgical perspective.

Sustained benefit from intravenous immunoglobulin therapy for gastrointestinal involvement in systemic sclerosis.

OBJECTIVE: IVIG is known to confer significant benefit in rheumatologic conditions, including inflammatory myopathy. This study aimed to assess the efficacy of IVIG across different aspects of internal organ involvement in refractory active SSc, particularly the gastrointestinal (GI) system. METHODS: SSc patients with overlap polymyositis who remained active and unresponsive to conventional disease-modifying agents and who subsequently received IVIG were identified. GI symptoms were assessed using validated questionnaires. The Medical Research Council Sum Score for muscle strength and modified Rodnan skin score (mRSS) were assessed. Serial measurements were undertaken at baseline prior to the first IVIG treatment and post-treatment in the most recent assessment. RESULTS: Fifteen SSc patients were consecutively recruited into this observational study. The mean duration of IVIG treatment was 2.3 years, with treatment frequency ranging from every 6 weeks to 4 months. Compared with baseline, there was a significant reduction in gastro-oesophageal reflux frequency and intensity mean scores (P = 0.006 and P = 0.013, respectively). Significant improvement in the Gastrointestinal Tract (GIT) 2.0 score from a baseline mean score of 1.07 (s.d. 0.67) to 0.60 (0.46) (P = 0.002) was observed. There was regression in the markers of muscle disease with a reduction in the mean (s.d.) Medical Research Council sum score and the median creatine kinase level (P = 0.001 and P = 0.025, respectively). Significant amelioration of the mean basal modified Rodnan skin score from 21.5 (s.d. 13.8) to 10 (10.6) (P = 0.005) was observed. CONCLUSION: IVIG may be a helpful adjunctive therapy in the amelioration of some key clinical aspects in refractory SSc. Sustained benefit from IVIG suggests a specific immunomodulatory effect on those with established SSc GI complications.

Intravenous immunogobulin therapy for severe gastrointestinal involvement in systemic sclerosis.

OBJECTIVES: Gastrointestinal (GI) disease is one of the major causes of morbidity in patients with systemic sclerosis (SSc). The most common manifestation of GI disease is oesophageal involvement affecting 70-90% of patients. Severe GI disease is uncommon, but results in symptoms such as early satiety, pseudo-obstruction, weight loss and malnutrition. The pathogenesis is relatively poorly understood, and management focuses on symptomatic control rather than immunomodulation. METHODS: We describe two cases of patients with SSc myositis overlap syndrome with severe GI involvement who demonstrated improvements in swallowing, early satiety and diarrhoea following the administration of intravenous immunoglobulin (IVIg). RESUTS: Clinical data related to the two cases were collected by review of medical records. CONCLUSIONS: GI complications range from mild symptoms to debilitating and life threatening. We propose that IVIg may have an immunomodulatory effect in a subset of patients with SSc myositis overlap syndrome.

Consensus best practice pathway of the UK scleroderma study group: gastrointestinal manifestations of systemic sclerosis.

Systemic sclerosis is an autoimmune connective tissue disorder, which can be progressive with multisystem involvement. Guidance on the management of complications is based on a limited data set and practice amongst clinicians can vary. The UK Scleroderma study group set up several working groups to agree some consensus pathways for the management of specific complications. Approximately nine out of ten patients with systemic sclerosis will have involvement of the gastrointestinal system and in this review article we explore the management of these complications in a symptom-based approach. The algorithms are a useful tool for clinicians, which we hope, will be a point of reference and highlight the need for further research in these areas.

METRIC (MREnterography or ulTRasound in Crohn's disease): a study protocol for a multicentre, non-randomised, single-arm, prospective comparison study of magnetic resonance enterography and small bowel ultrasound compared to a reference standard in those aged 16 and over.

BACKGROUND: Crohn's disease (CD) is a lifelong, relapsing and remitting inflammatory condition of the intestine. Medical imaging is crucial for diagnosis, phenotyping, activity assessment and detecting complications. Diverse small bowel imaging tests are available but a standard algorithm for deployment is lacking. Many hospitals employ tests that impart ionising radiation, of particular concern to this young patient population. Magnetic resonance enterography (MRE) and small bowel ultrasound (USS) are attractive options, as they do not use ionising radiation. However, their comparative diagnostic accuracy has not been compared in large head to head trials. METRIC aims to compare the diagnostic efficacy, therapeutic impact and cost effectiveness of MRE and USS in newly diagnosed and relapsing CD. METHODS: METRIC (ISRCTN03982913) is a multicentre, non-randomised, single-arm, prospective comparison study. Two patient cohorts will be recruited; those newly diagnosed with CD, and those with suspected relapse. Both will undergo MRE and USS in addition to other imaging tests performed as part of clinical care. Strict blinding protocols will be enforced for those interpreting MRE and USS. The Harvey Bradshaw index, C-reactive protein and faecal calprotectin will be collected at recruitment and 3 months, and patient experience will be assessed via questionnaires. A multidisciplinary consensus panel will assess all available clinical and imaging data up to 6 months after recruitment of each patient and will define the standard of reference for the presence, localisation and activity of disease against which the diagnostic accuracy of MRE and USS will be judged. Diagnostic impact of MRE and USS will be evaluated and cost effectiveness will be assessed. The primary outcome measure is the difference in per patient sensitivity between MRE and USS for the correct identification and localisation of small bowel CD. DISCUSSION: The trial is open at 5 centres with 46 patients recruited. We highlight the importance of stringent blinding protocols in order to delineate the true diagnostic accuracy of both imaging tests and discuss the difficulties of diagnostic accuracy studies in the absence of a single standard of reference, describing our approach utilising a consensus panel whilst minimising incorporation bias. TRIAL REGISTRATION: METRIC - ISRCTN03982913 - 05.11.13.

Peroral endoscopic myotomy for the management of symptomatic cricopharyngeal bar (C-POEM): a case series and video demonstration.

Background: A cricopharyngeal bar refers to a radiological description of a prominent cricopharyngeal muscle. While these may be incidental, they can lead to significant oropharyngeal dysphagia due to incoordination of the upper esophageal sphincter and true luminal narrowing. Various treatments have been used for the management of cricopharyngeal bar, including botulinum toxin injection, dilation, and surgical myotomy. Cricopharyngeal peroral endoscopic myotomy (C-POEM) is a novel procedure that uses the principles of "third-space" endoscopy to treat symptomatic cricopharyngeal bar. Methods: We report a retrospective case series of 5 patients referred with oropharyngeal dysphagia to 2 UK tertiary referral centers between 2022 and 2023 who subsequently underwent C-POEM. Technical success was defined as completion of all steps of the C-POEM procedure and clinical success as a reduction in the pre-treatment Dakkak and Bennett score to ≤1, or 0 if the pre-treatment score was 1. Results: C-POEM was associated with a technical success of 100% and clinical success of 100% over a median follow up of 2 months (interquartile range 1-8). There was 1 adverse event due to a small mucosal defect and associated leak on barium swallow, which was the result of difficult access during mucosal closure. This was managed conservatively with antibiotics. A step-by-step video demonstration of the procedure is provided. Conclusion: C-POEM offers an alternative upfront therapy for symptomatic cricopharyngeal bar, but should be undertaken by endoscopists with significant experience in third-space endoscopy in view of the difficulty of working within the hypopharynx.

The endoscopic management of oesophageal strictures.

An oesophageal stricture refers to a narrowing of the oesophageal lumen, which may be benign or malignant. The cardinal feature is dysphagia, and this may result from intrinsic oesophageal disease or extrinsic compression. Oesophageal strictures can be further classified as simple or complex depending on stricture length, location, diameter, and underlying aetiology. Many endoscopic options are now available for treating oesophageal strictures including dilatation, injectional therapy, stenting, stricturotomy, and ablation. Self-expanding metal stents have revolutionised the palliation of malignant dysphagia, but oesophageal dilatation with balloon or bougienage remains first-line therapy for most benign strictures. The increase in endoscopic and surgical interventions on the oesophagus has seen more benign refractory oesophageal strictures that are difficult to treat, and often require advanced endoscopic techniques. In this review, we provide a practical overview on the evidence-based management of both benign and malignant oesophageal strictures, including a practical algorithm for managing benign refractory strictures.

A Phenome-Wide Association Study of Drugs and Comorbidities Associated With Gastrointestinal Dysfunction in Systemic Sclerosis.

OBJECTIVE: To explore the causes of and contributors to gastrointestinal (GI) dysfunction in systemic sclerosis (SSc) in a phenome-wide association study (PheWAS), using real-world clinical records data. METHODS: Twelve thousand five hundred thirty-five documented clinical assessments of 2058 consenting individuals with SSc at the Royal Free Hospital (UK) were available for detailed phenotyping. Diagnoses and drugs were mapped to structured dictionaries of terms (Disease Ontology project and DrugBank Open Data, respectively). A PheWAS model was used to explore links between 6 important SSc-GI domains (constipation, diarrhea, dysmotility, incontinence, gastroesophageal reflux, and small intestinal bacterial overgrowth [SIBO]) and exposure to various comorbidities and drugs. "Hits" from the PheWAS model were confirmed and explored in a subcohort reporting quantitative GI symptom scores from the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract Instrument 2.0 (GIT 2.0) questionnaire. RESULTS: One thousand five hundred forty-six individuals were entered into the PheWAS analysis. Six hundred seventy-three distinct diagnoses and 634 distinct drugs were identified in the dataset, as well as SSc-specific phenotypes such as antinuclear antibodies (ANA). PheWAS analysis revealed associations between drugs, diagnoses, and ANAs with 6 important SSc-GI outcomes: constipation, diarrhea, dysmotility, incontinence, reflux, and SIBO. Subsequently, using GIT 2.0 symptom scores links with SSc-GI were confirmed for 22 drugs, 4 diagnoses, and 3 ANAs. CONCLUSION: Using a hypothesis-free PheWAS approach, we replicated known, and revealed potential novel, risk factors for SSc-GI dysfunction, including drug classes such as opioid, antimuscarinic, and endothelin receptor antagonist, and ANA subgroup.

Metabolic and Bariatric Endoscopy: A Mini-Review.

We are currently in a worldwide obesity pandemic, which is one of the most significant health problems of the 21st century. As the prevalence of obesity continues to rise, new and innovate treatments are becoming available. Metabolic and bariatric endoscopic procedures are exciting new areas of gastroenterology that have been developed as a direct response to the obesity crisis. These novel interventions offer a potentially reversible, less invasive, safer, and more cost-effective method of tackling obesity compared to traditional bariatric surgery. Minimally invasive endoscopic treatments are not entirely novel, but as technology has rapidly improved, many of the procedures have been proven to be extremely effective for weight loss and metabolic health, based on high-quality clinical trial data. This mini-review examines the existing evidence for the most prominent metabolic and bariatric procedures, followed by a discussion on the future trajectory of this emerging subspecialty.

Safety, Effectiveness, and Treatment Persistence of Subcutaneous Vedolizumab in IBD: A Multicenter Study From the United Kingdom.

BACKGROUND AND AIMS: Despite intravenous (IV) vedolizumab being established for treatment of inflammatory bowel disease (IBD), the novel subcutaneous (SC) route of administration may provide numerous incentives to switch. However, large-scale real-world data regarding the long-term safety and effectiveness of this strategy are lacking. METHODS: IBD patients on IV vedolizumab across 11 UK sites agreed to transition to SC injections or otherwise continued IV treatment. Data regarding clinical disease activity (Simple Clinical Colitis Activity Index, partial Mayo score, and modified Harvey-Bradshaw Index), biochemical markers (C-reactive protein and calprotectin), quality of life (IBD control), adverse events, treatment persistence, and disease-related outcomes (namely corticosteroid use, IBD-related hospitalization, and IBD-related surgery) were retrospectively collected from prospectively maintained clinical records at baseline and weeks 8, 24, and 52. RESULTS: Data from 563 patients (187 [33.2%] Crohn's disease, 376 [66.8%] ulcerative colitis; 410 [72.8%] SC, 153 [27.2%] IV) demonstrated no differences in disease activity, remission rates, and quality of life between the SC and IV groups at all time points. Drug persistence at week 52 was similar (81.1% vs 81.2%; P = .98), as were rates of treatment alteration due to either active disease (12.2% vs 8.9%; P = .38) or adverse events (3.3% vs 6.3%; P = .41). At week 52, there were equivalent rates of adverse events (9.8% vs 7.8%; P = .572) and disease-related outcomes. IBD control scores were equivalent in both IV-IV and IV-SC groups. CONCLUSIONS: Switching to SC vedolizumab appears as effective, safe, and well tolerated as continued IV treatment and maintains comparable disease control and quality of life as IV treatment at 52 weeks.