The second Irish Helicobacter pylori Working Group consensus for the diagnosis and treatment of Helicobacter pylori infection in adult patients in Ireland.

BACKGROUND: There has been an increase in resistance to many of the antimicrobials used to treat Helicobacter pylori ( H. pylori ) nationally and internationally. Primary clarithromycin resistance and dual clarithromycin and metronidazole resistance are high in Ireland. These trends call for an evaluation of best-practice management strategies. OBJECTIVE: The objective of this study was to revise the recommendations for the management of H. pylori infection in adult patients in the Irish healthcare setting. METHODS: The Irish H. pylori working group (IHPWG) was established in 2016 and reconvened in 2023 to evaluate the most up-to-date literature on H. pylori diagnosis, eradication rates and antimicrobial resistance. The 'GRADE' approach was then used to rate the quality of available evidence and grade the resulting recommendations. RESULTS: The Irish H. pylori working group agreed on 14 consensus statements. Key recommendations include (1) routine antimicrobial susceptibility testing to guide therapy is no longer recommended other than for clarithromycin susceptibility testing for first-line treatment (statements 6 and 9), (2) clarithromycin triple therapy should only be prescribed as first-line therapy in cases where clarithromycin susceptibility has been confirmed (statement 9), (3) bismuth quadruple therapy (proton pump inhibitor, bismuth, metronidazole, tetracycline) is the recommended first-line therapy if clarithromycin resistance is unknown or confirmed (statement 10), (4) bismuth quadruple therapy with a proton pump inhibitor, levofloxacin and amoxicillin is the recommended second-line treatment (statement 11) and (5) rifabutin amoxicillin triple therapy is the recommend rescue therapy (statement 12). CONCLUSION: These recommendations are intended to provide the most relevant current best-practice guidelines for the management of H. pylori infection in adults in Ireland.

HLA-DQA1*05 Allele Carriage and Anti-TNF Therapy Persistence in Inflammatory Bowel Disease.

INTRODUCTION: Carriage of the HLA-DQA1*05 allele is associated with development of antidrug antibodies (ADAs) to antitumor necrosis factor (anti-TNF) therapy in patients with Crohn's disease. However, ADA is not uniformly associated with treatment failure. We aimed to determine the impact of carriage of HLA-DQA1*05 allele on outcome of biologic therapy evaluated by drug persistence. METHODS: A multicenter, retrospective study of 877 patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy with HLA-DQA1*05 genotypes were generated by imputation from whole genome sequence using the HIBAG package, in R. Primary end point was anti-TNF therapy persistence, (time to therapy failure), segregated by HLA-DQA1*05 allele genotype and development of a risk score to predict anti-TNF therapy failure, incorporating HLA-DQA1*05 allele genotype status (LORisk score). RESULTS: In all, 877 patients receiving anti-TNF therapy were included in our study; 543 (62%) had no copy, 281 (32%) one copy, and 53 (6%) 2 copies of HLA-DQA1*05 allele. Mean time to anti-TNF therapy failure in patients with 2 copies of HLA-DQA1*05 allele was significantly shorter compared with patients with 0 or 1 copy at 700 days' follow-up: 418 vs 541 vs 513 days, respectively (P = .012). Factors independently associated with time to anti-TNF therapy failure included carriage of HLA-DQA1*05 allele (hazard ratio [HR], 1.2, P = .02; female gender HR, 1.6, P < .001; UC phenotype HR, 1.4, P = .009; and anti-TNF therapy type [infliximab], HR, 1.5, P = .002). The LORisk score was significantly associated with shorter time to anti-TNF therapy failure (P < .001). CONCLUSIONS: Carriage of 2 HLA-DQA1*05 alleles is associated with less favorable outcomes for patients receiving anti-TNF therapy with shorter time to therapy failure. HLA-DQA1*05 genotype status in conjunction with clinical factors may aid in therapy selection in patients with IBD.

Our study found carriage of 2 copies of the HLA-DQA1*05 allele is associated with a less favorable response to anti-TNF therapy with shorter time to therapy failure. HLA-DQA1*05 genotype status in conjunction with clinical factors may aid in therapy selection in IBD patients.

Effect of cigarette smoke extract on the intestinal microenvironment of ulcerative colitis tissue.

BACKGROUND AND AIM: Ulcerative colitis (UC) is an autoimmune disease characterized by inflammation in the gastrointestinal tract. The severity of UC is higher in nonsmokers than smokers; however, the biological mechanisms controlling this effect remain unknown. The aim of this study was to examine the effect of cigarette smoke extract (CSE) on inflamed and noninflamed colonic tissue from UC patients and to determine if inflammatory mediators, transcription factors, and T cell phenotypes are altered by CSE. METHODS: Blood and colonic biopsies were obtained from UC patients undergoing endoscopy. Biopsies were cultured in the presence or absence of CSE. Multiplex enzyme-linked immunosorbent assay (ELISA) measured secreted levels of inflammatory mediators. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Hypoxia-inducible factor 1-alpha (HIF-1α) expression were measured by DNA-binding ELISA. T cell phenotypes were assessed by flow cytometry in matched blood and biopsies. RESULTS: Secreted levels of interleukin 2 (IL-2), interleukin 6 (IL-6), tumor necrosis factor - alpha (TNF-α), chemokine (C-C motif) ligand 2 (CCL2), and interleukin 10 (IL-10) were significantly (all P < 0.05) decreased following treatment with CSE. This effect was specific to inflamed tissue and was not observed in noninflamed tissue. CSE did not alter the expression of NF-κB or HIF-1α. Assessment of T cell phenotypes in blood and tissue revealed that there were significantly more activated and exhausted T cells in the colonic tissue compared to matched blood. These profiles were not altered following CSE treatment. CONCLUSION: These data suggest that observed effects of CSE in reducing inflammatory mediators ex vivo are specific to inflamed colonic tissue but are not due to the activation of NF-κB or HIF-1α and are not caused by alterations in subpopulations of T cells in these UC tissues.

Comparison of medium to long-term outcomes of acute severe ulcerative colitis patients receiving accelerated and standard infliximab induction.

INTRODUCTION: Accelerated dose infliximab (IFX) induction is associated with reduced short-term colectomy rate in acute severe ulcerative colitis (ASUC). Data on medium/long-term outcomes of this strategy are limited. AIMS: Evaluate medium/long-term outcomes in patients receiving IFX induction for ASUC, comparing accelerated dose (AD) and standard dose (SD) induction. METHODS: Retrospective study of consecutive patients admitted with corticosteroid-refractory ASUC in four tertiary referral centres within INITIative IBD research network (www.initiativeibd.ie). IFX rescue was given either as SD (weeks 0, 2, 6) or AD (<28 days) from January 2010 to September 2017. AD induction has been utilised in participating centres since 2014. Consequently SD patients were subdivided based on time period of IFX rescue: historical SD group (SD1) (2010-2013) and current SD group (SD2) (2014-2017). Primary endpoint was time to colectomy; secondary endpoint was time to IFX discontinuation if induction was complete. RESULTS: 145 patients received rescue IFX (AD=58, SD1=32, SD2=55). Disease severity at induction was comparable between AD and SD1 groups; however, SD2 group had less severe disease: median C-reactive protein (CRP) 39, 44 and 20 mg/L for AD, SD1 and SD2 groups, respectively (p=0.026, Kruskal-Wallis); median CRP: albumin ratio was 1.4, 1.8 and 0.6 (p=0.016). Median follow-up for AD, SD1 and SD2 groups was 1.6 (IQR 1.1-3.1), 4.9 (IQR 2.6-5.5) and 1.5 (IQR 0.9-2.3) years. Time to colectomy was shorter in SD1 (log rank p=0.0013); no significant difference in time to colectomy was observed comparing AD and SD2 groups (log rank p=0.32). 123 patients (84%) completed IFX induction and received maintenance therapy. Time to IFX discontinuation was shorter in SD1 (log rank p=0.009). CONCLUSION: Time to colectomy is significantly prolonged with use of AD IFX in selected ASUC patients with more severe disease. Historical use of standard IFX induction for all ASUC patients is associated with inferior long-term outcomes.

Irish data on the safety and efficacy of vedolizumab in the treatment of inflammatory bowel disease.

SUMMARY: This study reviews the safety and efficacy of treatment with vedolizumab for patients with inflammatory bowel disease across 9 Irish hospitals. It generates valuable and timely real-world data on treatment outcomes to add to the existing evidence base. Our population represents a refractory cohort with most patients previously exposed to at least one anti-TNFa agent and expressing an inflammatory phenotype. Results are reassuringly similar to larger international studies with additional insights into potential predictors of treatment response. This study further supports the safety and efficacy of vedolizumab in the treatment of inflammatory bowel disease. Key SummaryVedolizumab has growing real world data on its safety and efficacy in the treatment of IBD. Data on predictors of response are lacking. Studies such as VARSITY require new real-world data to help identify the place VDZ will occupy in the treatment algorithm for IBDThis study provides national Irish data on the safety and efficacy of VDZ in the treatment of IBD. It gives insight into various predictors of response for both UC and CD. It strengthens the available body of evidence on the use of VDZ and helps us determine its position on the treatment algorithm.

Prevalence of coexisting autoimmune thyroidal diseases in coeliac disease is decreasing.

BACKGROUND: Coeliac disease (CD) is associated with an increased risk of other immune-mediated conditions. Aim: To investigate the prevalence of coexistent immune-mediated diseases in CD patients, and changes in the prevalence of autoimmune thyroidal diseases over the last 50 years. METHODS: Medical record data were collected retrospectively from 749 CD patients in Ireland. Prevalence of autoimmune diseases was compared with previously published results from general populations. Patients were divided into four groups based on the year of diagnosis to analyse changes in the prevalence of autoimmune thyroidal disease over time. RESULTS: Median age at the time of CD diagnosis was 56 years (range 18-91 years). A total of 233 (31.1%) patients had a coexistent immune-mediated condition (IMC). Autoimmune thyroidal diseases were seen in 149 (19.9%) patients, hypothyroidism in 110 (14.7%), type 1 diabetes in 27 (3.6%), psoriasis in 20 (2.7%), inflammatory bowel disease in 14 (1.9%) and rheumatoid arthritis in 12 (1.6%). All conditions were more common in CD patients than in the general population. Type 1 diabetes was diagnosed mainly before CD, whereas there was no such trend in other conditions. Autoimmune thyroidal diseases became less common in female CD patients over time. CONCLUSIONS: Prevalence of autoimmune diseases is increased in adult CD patients compared with the general population. However, concomitant autoimmune thyroidal diseases became less common over time in women.

Histological Markers of Clinical Relapse in Endoscopically Quiescent Ulcerative Colitis.

BACKGROUND: In ulcerative colitis (UC) patients who have achieved mucosal healing, active microscopic colonic mucosal inflammation is commonly observed. We aimed to assess the association between histological activity and disease relapse in endoscopically quiescent UC. METHODS: Ulcerative colitis patients with endoscopically quiescent disease and ≥12 months of follow-up were included. Biopsies were reviewed for the presence of basal plasmacytosis (BPC) and active histological inflammation, defined as a Geboes score (GS) ≥3.2. Primary outcome measures were disease relapse at 18 months and time to first relapse after index colonoscopy. RESULTS: Seventy-six UC patients (51% male; mean age, 38.6 years; median follow-up [range], 75.2 [2-118] months) were included. Sixty-two percent had an endoscopic Mayo score of 0 at index colonoscopy. Basal plasmacytosis was present in 46% and active histological inflammation in 30% of subjects. Presence of BPC was associated with a significantly shorter time to disease relapse (P = 0.01). Active histological inflammation was significantly associated with clinical relapse at 18 months (P = 0.0005) and shorter time to clinical relapse (P = 0.0006). Multivariate analysis demonstrated active histological inflammation to be independently associated with clinical relapse at 18 months and time to clinical relapse. CONCLUSIONS: In endoscopically quiescent UC, active histological inflammation and the presence of BPC are adjunctive histological markers associated with increased likelihood of disease relapse. Although prospective studies are required, the presence of these histological markers should be a factor considered when making therapeutic decisions in UC.

Golimumab effectiveness and safety in clinical practice for moderately active ulcerative colitis.

BACKGROUND AND AIMS: Golimumab (GLB) is an antitumour necrosis factor-α (anti-TNF) therapy that has shown efficacy as induction and maintenance therapy for ulcerative colitis (UC). We aimed to describe the outcome of GLB therapy for UC in a real-world clinical practice. PATIENTS AND METHODS: Consecutive patients receiving GLB for UC in six Irish Academic Medical Centres were identified. The primary study endpoint was the 6-month corticosteroid-free remission rate. The secondary endpoints included the 3-month clinical response, time free of GLB discontinuation and adverse events. RESULTS: Seventy-two patients were identified [57% men; median (range) age of 41.4 years (20.3-76.8); disease duration 6.6 years (0-29.9); follow-up 8.7 months (0.4-39.2)]. Sixty-four percent of patients were anti-TNF naive. The 3-month clinical response and the 6-month corticosteroid-free remission rates were 55 and 39%, respectively. Forty-four percent of patients discontinued GLB during the follow-up, median (95% confidence interval) time to GLB discontinuation 18.7 months (9.2-28.1). A C-reactive protein more than 5 mg/l at baseline was associated with failure to achieve 6-month corticosteroid-free remission and a shorter time to GLB discontinuation, odds ratio 0.2 (0.1-0.7), P=0.008, and hazard ratio (95% confidence interval) 2.8 (1.3-5.7), P=0.007, respectively. Adverse events occurred in 7% of patients (n=5), all of which were minor and self-limiting. CONCLUSION: These real-world clinical data suggest that GLB is an effective and safe therapy for a UC cohort with significant previous anti-TNF exposure. An elevated baseline C-reactive protein, likely reflective of increased inflammatory burden, is associated with a reduced likelihood of a successful outcome of GLB therapy.

Accelerated Clearance of Infliximab is Associated With Treatment Failure in Patients With Corticosteroid-Refractory Acute Ulcerative Colitis.

BACKGROUND AND AIMS: A significant proportion of patients with corticosteroid-refractory acute ulcerative colitis [UC] fail therapy. We aimed to assess the pharmacokinetics [PK] of infliximab [IFX] in patients with corticosteroid-refractory acute UC and determine the association between induction IFX PK and short- and long-term therapy outcome. METHODS: A population PK model was developed using data from 51 patients with UC [n = 42] and Crohn's disease [n = 9]. A subset of patients [n = 36] with acute corticosteroid-refractory UC (median Mayo score 11 [range 8-12]; 33 of 36 hospitalized; median corticosteroid dose at study entry 50mg prednisolone equivalent IV/oral) commencing IFX were studied to assess further correlations between PK from the first induction dose and therapy outcomes. Serial induction drug levels from the 36 UC patients were collected, facilitating population-based PK analysis. IFX and antibodies-to-infliximab [ATIs] concentrations were determined using AnsrTM IFX assay [Prometheus Inc.]. RESULTS: The Week 14 clinical response and Week 54 corticosteroid-free remission rates were 78% [28/36] and 53% [19/36], respectively. The estimated effective IFX half-life [T1/2] (median [range]) and clearance (median [range]) were 8.42 [3.94-22.03] days and 0.50 [0.19-1.41] L/day respectively. Longer induction IFX T1/2 and lower clearance were associated with the Week 14 clinical response [p = 0.005] and the Week 54 corticosteroid-free remission rates [p = 0.007]. CONCLUSIONS: Accelerated IFX clearance occurs in corticosteroid-refractory acute UC and is associated with therapy failure. These data support the use of accelerated IFX induction regimens in patients with corticosteroid-refractory acute UC failing conventional dosing regimens.

Protocol for a multicentred randomised controlled trial investigating the use of personalised golimumab dosing tailored to inflammatory load in ulcerative colitis: the GOAL-ARC study (GLM dose Optimisation to Adequate Levels to Achieve Response in Colitis) led by the INITIAtive group (NCT 0268772).

INTRODUCTION: Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), often leading to an impaired quality of life in affected patients. Current treatment modalities include antitumour necrosis factor (anti-TNF) monoclonal antibodies (mABs) including infliximab, adalimumab and golimumab (GLM). Several recent retrospective and prospective studies have demonstrated that fixed dosing schedules of anti-TNF agents often fails to consistently achieve adequate circulating therapeutic drug levels (DL) with consequent risk of immunogenicity treatment failure and potential risk of hospitalisation and colectomy in patients with UC.The design of GLM dose Optimisation to Adequate Levels to Achieve Response in Colitis aims to address the impact of dose escalation of GLM immediately following induction and during the subsequent maintenance phase in response to suboptimal DL or persisting inflammatory burden as represented by raised faecal calprotectin (FCP). AIM: The primary aim of the study is to ascertain if monitoring of FCP and DL of GLM to guide dose optimisation (during maintenance) improves rates of patient continuous clinical response and reduces disease activity in UC. METHODS AND ANALYSIS: A randomised, multicentred two-arm trial studying the effect of dose optimisation of GLM based on FCP and DL versus treatment as per SMPC. Eligible patients will be randomised in a 1:1 ratio to 1 of 2 treatment groups and shall be treated over a period of 46 weeks. ETHICS AND DISSEMINATION: The study protocol was approved by the Research Ethics committee of St. Vincent's University Hospital. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. TRIAL REGISTRATION NUMBERS: EudraCT number: 2015-004724-62; Clinicaltrials.gov Identifier: NCT0268772; Pre-results.

The Irish Helicobacter pylori Working Group consensus for the diagnosis and treatment of H. pylori infection in adult patients in Ireland.

BACKGROUND: Irish eradication rates for Helicobacter pylori are decreasing and there is an increase in the prevalence of antibiotic-resistant bacteria. These trends call into question current management strategies. OBJECTIVE: To establish an Irish Helicobacter pylori Working Group (IHPWG) to assess, revise and tailor current available recommendations. METHODS: Experts in the areas of gastroenterology and microbiology were invited to join the IHPWG. Questions of relevance to diagnosis, first-line and rescue therapy were developed using the PICO system. A literature search was performed. The 'Grading of Recommendations Assessment, Development and Evaluation' approach was then used to rate the quality of available evidence and grade the resulting recommendations. RESULTS: Key resultant IHPWG statements (S), the strength of recommendation and quality of evidence include S8: standard triple therapy for 7 days' duration can no longer be recommended (strong and moderate). S9: 14 days of clarithromycin-based triple therapy with a high-dose proton pump inhibitor (PPI) is recommended as first-line therapy. Bismuth quadruple therapy for 14 days is an alternative if available (strong and moderate). S12: second-line therapy depends on the first-line treatment and should not be the same treatment. The options are (a) 14 days of levofloxacin-based therapy with high-dose PPI, (b) 14 days of clarithromycin-based triple therapy with high-dose PPI or (c) bismuth quadruple therapy for 14 days (strong and moderate). S13: culture and antimicrobial susceptibility testing should be performed following two treatment failures (weak and low/very low). CONCLUSION: These recommendations are intended to provide the most relevant current best-practice guidelines for the management of H. pylori infection in adults in Ireland.

Changes in Presentation of Celiac Disease in Ireland From the 1960s to 2015.

BACKGROUND & AIMS: Celiac disease is an immune-mediated enteropathy characterized with high heterogeneity in presentation among genetically predisposed individuals. In recent years, a change in the phenotypic presentation of celiac disease has been reported. We studied clinical presentation, from 1960 through 2015, in Ireland, which has a high incidence of celiac disease. METHODS: We performed a retrospective analysis of medical charts from patients diagnosed with celiac disease at 5 secondary referral centers in Ireland from 1960 through 2015 (n = 749; median age, 56 years; age range, 18-91 years). The cohort was divided into 5 groups based on year of diagnosis (≤1985, 1986-1995, 1996-2005, 2006-2010, or 2011 and later). We collected findings from clinical presentation at diagnosis; serology tests; small intestinal biopsy analyses; and patients' demographic, clinical, and family data. Presentations at diagnosis were classified according to the Oslo criteria as follows: classical (patients presenting with malabsorption), nonclassical (no signs or symptoms of malabsorption at presentation), or subclinical (below the threshold of clinical detection). The primary outcome was change in clinical presentation of celiac disease over time. RESULTS: Of the 749 patients studied, 512 were female and 237 were male (ratio of 2.2:1). Female patients were diagnosed at younger ages than male patients (42 vs 47 years, respectively; P = .004), and had more immune-mediated conditions than male patients (35.7% for female patients vs 21.5% for male patients; P < .001). For patients diagnosed as adults (after the age of 18 years), the median age of diagnosis increased from 34.0 years during the period ≤1985 to median ages of 44-46 years after 1985 (P < .002). A smaller proportion of patients presented with classical features of celiac disease after 2010 (48.4%) than ≤1985 (85.2%); the proportion of patients with nonclassical or subclinical celiac disease increased from 14.8% ≤1985 to 51.6% after 2010 (P = .006 for each). Biopsies categorized as Marsh 3c decreased, from 52.2% in the period 1996-2005 to 22.5% in the period after 2010 (P = .003). The prevalence of associated thyroid disease has decreased during the study period, from 36.6% ≤1985 to 17.1% after 2010 (P = .039), whereas body mass index at diagnosis increased from 21.5 kg/m2 ≤1985 to 24.8 kg/m2 after 2010 (P < .001). CONCLUSIONS: We found the clinical presentation of celiac disease changed significantly in Ireland from 1960 through 2015. The age of presentation in adulthood increased over this time period, as did the proportions of patients with nonclassical or subclinical disease.

Rates and Predictors of Endoscopic and Clinical Recurrence After Primary Ileocolic Resection for Crohn's Disease.

BACKGROUND AND AIMS: The utility of postoperative medical prophylaxis (POMP) and the treatment of mild endoscopic recurrence remain controversial. METHODS: This study is a retrospective review of patients undergoing a primary ileocolic resection for CD at a single academic center. Endoscopic recurrence (ER) was defined using the Rutgeerts score (RS), and clinical recurrence (CR) was defined as symptoms of CD with endoscopic or radiologic evidence of neo-terminal ileal disease. RESULTS: There were 171 patients who met inclusion criteria. The cumulative probability of ER (RS ≥ i-1) at 1, 2, and 5 years was 29, 51, and 77 %, respectively. The only independent predictors of ER were the absence of POMP (HR 1.50; P = 0.03) and penetrating disease behavior (HR 1.50; P = 0.05). The cumulative probability of CR at 1, 2, and 5 years was 8, 13, and 27 %, respectively. There was a higher rate of clinical recurrence in patients with RS-2 compared to RS-1 on the initial postoperative endoscopy (HR 2.50; P = 0.02). In 11 patients not exposed to POMP with i-1 on initial endoscopy, only 2 patients (18 %) progressed endoscopically during the study period while 5 patients (45 %) regressed to i-0 on subsequent endoscopy without treatment. CONCLUSIONS: Postoperative medical prophylaxis decreased the likelihood of ER while certain phenotypes of CD appear to increase the risk of developing ER and CR. There may be a role for watchful waiting in patients with mild endoscopic recurrence on the initial postoperative endoscopy.

Association of host genome with intestinal microbial composition in a large healthy cohort.

Intestinal microbiota is known to be important in health and disease. Its composition is influenced by both environmental and host factors. Few large-scale studies have evaluated the association between host genetic variation and the composition of microbiota. We recruited a cohort of 1,561 healthy individuals, of whom 270 belong in 123 families, and found that almost one-third of fecal bacterial taxa were heritable. In addition, we identified 58 SNPs associated with the relative abundance of 33 taxa in 1,098 discovery subjects. Among these, four loci were replicated in a second cohort of 463 subjects: rs62171178 (nearest gene UBR3) associated with Rikenellaceae, rs1394174 (CNTN6) associated with Faecalibacterium, rs59846192 (DMRTB1) associated with Lachnospira, and rs28473221 (SALL3) associated with Eubacterium. After correction for multiple testing, 6 of the 58 associations remained significant, one of which replicated. These results identify associations between specific genetic variants and the gut microbiome.

Long-term assessment of clinical response to adalimumab therapy in refractory ulcerative colitis.

INTRODUCTION: The role of antitumour necrosis factor agents, in particular infliximab in ulcerative colitis (UC) has been well established. More recently adalimumab, a fully humanized antitumour necrosis factor α monoclonal antibody, was licensed for refractory moderately active UC in 2012. Available outcome data for adalimumab from routine clinical practice is limited. AIMS: To evaluate the clinical response and remission to adalimumab in a cohort of UC patients. METHODS: Patients with UC treated with adalimumab were identified from our inflammatory bowel disease database from 2007. A retrospective chart review was undertaken. Demographic and clinical data were recorded including a Mayo score and C-reactive protein (CRP) where available. All patients received standard induction subcutaneous therapy (160/80/40 mg) followed by a maintenance dose of 40 mg fortnightly. Clinical and biochemical response was assessed at 6 and 12 months. Clinical response was defined by a reduction in Mayo score more than or equal to 3, whereas clinical remission was defined by a total score of 2 or less. Dose adjustments and adverse events were also noted. RESULTS: In all, 52 patients were identified. Of these, 65% (n=34) were male and the mean age was 45 years (range 23-72 years). A total of 65% (n=34) had left sided disease, 31% (n=16) pancolitis and 4% (n=2) proctitis. The majority commenced adalimumab due to a loss of response to immunomodulator therapy (n=45, 87%), whereas the remaining 13% (n=7) had loss of response or been intolerant to infliximab. The mean disease duration was 8 years (1-29 years). At baseline 85% (n=44) had moderate disease and 15% (n=8) had mild disease. The baseline mean CRP was 13.5 mg/l (range 1-82 mg/l) and the mean Mayo score was 6 (range 4-10). The mean duration of treatment was 18.5 months (range 4-95 months). Follow-up data was available in 46 (88%) and 37 (71%) patients at 6 and 12 months. Overall there was a statistically significant improvement in mean partial Mayo score on follow-up; 6 months=2 [P=0.0001, 95% confidence interval (CI) 2.99-4.55], 12 months=2 (P=0.0001, 95% CI 2.74-4.46). While 65% (n=34) and 52% (n=27) had a clinical response at 6 and 12 months, respectively, 52% (n=27) and 42% (n=22) were in remission. Overall mean CRP normalized at 6 months (P=0.002, 95% CI 3.31-15.1). Of note 25% (n=13) required dose escalation during follow-up, while treatment was discontinued by seven patients, five (71%) due to a loss of response, the remaining two (29%) due to an adverse event. CONCLUSION: Our study shows adalimumab is an effective and safe long-term therapy for moderately active UC refractory to other treatments. While this data is encouraging, further work is required on patient selection and to determine the impact of treatment on both natural history and quality of life.

IBD Genetic Risk Profile in Healthy First-Degree Relatives of Crohn's Disease Patients.

BACKGROUND: Family history provides important information on risk of developing inflammatory bowel disease [IBD], and genetic profiling of first-degree relatives [FDR] of Crohn's disease [CD]- affected individuals might provide additional information. We aimed to delineate the genetic contribution to the increased IBD susceptibility observed in FDR. METHODS: N = 976 Caucasian, healthy, non-related FDR; n = 4997 independent CD; and n = 5000 healthy controls [HC]; were studied. Genotyping for 158 IBD-associated single nucleotide polymorphisms [SNPs] was performed using the Illumina Immunochip. Risk allele frequency [RAF] differences between FDR and HC cohorts were correlated with those between CD and HC cohorts. CD and IBD genetic risk scores [GRS] were calculated and compared between HC, FDR, and CD cohorts. RESULTS: IBD-associated SNP RAF differences in FDR and HC cohorts were strongly correlated with those in CD and HC cohorts, correlation coefficient 0.63 (95% confidence interval [CI] 0.53 - 0.72), p = 9.90 x 10(-19). There was a significant increase in CD-GRS [mean] comparing HC, FDR, and CD cohorts: 0.0244, 0.0250, and 0.0257 respectively [p < 1.00 x 10(-7) for each comparison]. There was no significant difference in the IBD-GRS between HC and FDR cohorts [p = 0.81]; however, IBD-GRS was significantly higher in CD compared with FDR and HC cohorts [p < 1.00 x 10(-10) for each comparison]. CONCLUSION: FDR of CD-affected individuals are enriched with IBD risk alleles compared with HC. Cumulative CD-specific genetic risk is increased in FDR compared with HC. Prospective studies are required to determine if genotyping would facilitate better risk stratification of FDR.

Determinants of intestinal permeability in healthy first-degree relatives of individuals with Crohn's disease.

BACKGROUND: The Genetics, Environmental, Microbial Project is a multicenter study assessing etiological factors in Crohn's disease by studying healthy first-degree relatives (FDRs) of individuals affected by Crohn's disease. We aimed to evaluate the contribution of genetic, microbial, and environmental factors to the determination of intestinal permeability in healthy FDRs. METHODS: IP was assessed using the lactulose-mannitol ratio (LacMan ratio). FDRs were genotyped for 167 inflammatory bowel disease-associated single nucleotide polymorphisms. Taxonomic profile of the fecal microbiota was determined by Illumina MiSeq pyrosequencing of 16S ribosomal RNA. The associations of LacMan ratio with demographic factors, inflammatory bowel disease-associated single nucleotide polymorphisms and the fecal microbiota were assessed. RESULTS: One thousand, one hundred ninety-six white FDRs were included [corrected]. Eleven percent of FDRs had an elevated LacMan ratio (≥0.03). A multivariate analysis demonstrated that younger subjects and nonsmokers had higher LacMan ratios, P = 3.62 × 10⁻4 and P = 0.03, respectively. The LacMan ratio was not significantly heritable, H2r, 0.13, P = 0.13. There was no association between any of the 167 inflammatory bowel disease-associated risk variants and LacMan ratio nor was there a correlation between fecal microbial composition and the LacMan ratio. CONCLUSIONS: We did not find LacMan ratio to be significantly heritable suggesting that the contribution of genetic factors to the determination of intestinal permeability in healthy FDRs is modest. Environmental factors, such as smoking, are likely more important determinants. The effect of age on intestinal barrier function has been underappreciated.