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Inflammatory bowel disease (IBD) and celiac disease are the two most common immune-mediated gastrointestinal diseases. There is limited knowledge regarding the course of IBD in those with coexisting celiac disease. We conducted this study to determine whether patients with coexisting celiac disease present a unique phenotype of IBD and to examine the frequency of co-occurrence of celiac disease and IBD in comparison with other autoimmune disorders. This was a case-control study performed at two tertiary referral centers. Cases comprised of patients with known diagnoses of celiac disease and IBD. Two random IBD controls without celiac disease were selected for each case after matching for IBD type. Disease phenotype and natural history for both Crohn's disease (CD) and ulcerative colitis (UC) were noted from medical record review, and were compared between IBD patients with and without celiac disease. We identified a total of 51 patients with IBD (22 UC, 1 indeterminate colitis, 28 CD) and celiac disease. There was no significant difference in the age, gender, or ethnicity between celiac-IBD and controls. Pancolitis was more common in celiac-UC patients as compared with controls (odds ratio (OR) 3.30, 95% confidence interval (CI) 1.05-21.50). There was also a trend toward increased use of immunomodulators (IMMs) among celiac-UC patients than in non-celiac UC controls (OR 2.83, 95% CI 0.95-8.48). No phenotypic differences were found in celiac-CD patients. There were no significant differences in IBD-related medication usage, hospitalizations, or surgeries. Patients with UC and celiac disease were more likely to have pancolitis and had a trend toward greater use of IMMs. Coexisting celiac disease did not influence natural history of CD.

Cigarette smoking is a well-established environmental risk factor for Crohn's disease (CD) and ulcerative colitis (UC). The exact mechanism of its effect remains unexplained. Genetic polymorphisms in metabolizing enzymes may influence susceptibility to the effect of smoking and shed light on its mechanism of action.MethodsWe used a prospective cohort of patients with CD, UC, and healthy controls. Smoking status was defined as current, former, or never smoking. Patients were genotyped for polymorphisms in CYP2A6, glutathione transferase enzymes (GSTP1 and GSTM1), NAD(P)H quinone oxidoreductase (NQO), and heme oxygenase 1 using a Sequenom platform. Multivariate logistic regression models with CD or UC as the outcome, stratified by genotype, were developed and interaction P-values calculated.ResultsOur study included 634 patients with CD, 401 with UC, and 337 healthy controls. Ever smokers had an increased risk of CD (odds ratio = 3.88, 95% confidence interval = 2.35–6.39) compared with nonsmokers among patients with AG/AA genotypes at CYP2A6. However, ever smoking was not associated with CD among patients with the AA genotype (Pinteraction = 0.001). Former smoking was associated with an increased risk for UC only in the presence of GG/AG genotypes for GSTP1 but not in those with the AA genotype (Pinteraction = 0.012). Polymorphisms at the NQO and HMOX loci did not demonstrate a statistically significant interaction with smoking and risk of CD or UC.ConclusionsGenetic polymorphisms in metabolizing enzymes may influence the association between smoking and CD and UC. Further studies of gene–environment interaction in inflammatory bowel disease are warranted.

The specific pathogenesis underlying inflammatory bowel disease is complex, and it is even more difficult to decipher the pathophysiology to explain for the similarities and differences between two of its major subtypes, Crohn's disease and ulcerative colitis (UC). Animal models are indispensable to pry into mechanistic details that will facilitate better preclinical drug/therapy design to target specific components involved in the disease pathogenesis. This review focuses on common animal models that are particularly useful for the study of UC and its therapeutic strategy. Recent reports of the latest compounds, therapeutic strategies, and approaches tested on UC animal models are also discussed.

BackgroundThe brush border enzyme intestinal alkaline phosphatase (IAP) functions as a gut mucosal defense factor and is protective against dextran sulfate sodium (DSS)-induced acute injury in rats. The present study evaluated the potential therapeutic role for orally administered calf IAP (cIAP) in two independent mouse models of chronic colitis: 1) DSS-induced chronic colitis, and 2) chronic spontaneous colitis in Wiskott-Aldrich Syndrome protein (WASP)-deficient (knockout) mice that is accelerated by irradiation.MethodsThe wildtype (WT) and IAP knockout (IAP-KO) mice received four cycles of 2% DSS ad libitum for 7 days. Each cycle was followed by a 7-day DSS-free interval during which mice received either cIAP or vehicle in the drinking water. The WASP-KO mice received either vehicle or cIAP for 6 weeks beginning on the day of irradiation.ResultsMicroscopic colitis scores of DSS-treated IAP-KO mice were higher than DSS-treated WT mice (52 ± 3.8 versus 28.8 ± 6.6, respectively, P < 0.0001). cIAP treatment attenuated the disease in both groups (KO = 30.7 ± 6.01, WT = 18.7 ± 5.0, P < 0.05). In irradiated WASP-KO mice cIAP also attenuated colitis compared to control groups (3.3 ± 0.52 versus 6.2 ± 0.34, respectively, P < 0.001). Tissue myeloperoxidase activity and proinflammatory cytokines were significantly decreased by cIAP treatment.ConclusionsEndogenous IAP appears to play a role in protecting the host against chronic colitis. Orally administered cIAP exerts a protective effect in two independent mouse models of chronic colitis and may represent a novel therapy for human IBD. (Inflamm Bowel Dis 2011)

Tulisokibart is a tumor necrosis factor-like cytokine 1A (TL1A) monoclonal antibody in development for the treatment of moderately to severely active ulcerative colitis. A genetic-based diagnostic test was designed to identify patients with an increased likelihood of response. We randomly assigned patients with glucocorticoid dependence or failure of conventional or advanced therapies for ulcerative colitis to receive intravenous tulisokibart (1000 mg on day 1 and 500 mg at weeks 2, 6, and 10) or placebo. Cohort 1 included patients regardless of status with respect to the test for likelihood of response. Cohort 2 included only patients with a positive test for likelihood of response. The primary analysis was performed in cohort 1; the primary end point was clinical remission at week 12. Patients with a positive test for likelihood of response from cohorts 1 and 2 were combined in prespecified analyses. In cohort 1, a total of 135 patients underwent randomization. A significantly higher percentage of patients who received tulisokibart had clinical remission than those who received placebo (26% vs. 1%; difference, 25 percentage points; 95% confidence interval [CI], 14 to 37; P<0.001). In cohort 2, a total of 43 patients underwent randomization. A total of 75 patients with a positive test for likelihood of response underwent randomization across both cohorts. Among patients with a positive test for likelihood of response (cohorts 1 and 2 combined), clinical remission occurred in a higher percentage of patients who received tulisokibart than in those who received placebo (32% vs. 11%; difference, 21 percentage points; 95% CI, 2 to 38; P = 0.02). Among all the enrolled patients, the incidence of adverse events was similar in the tulisokibart and placebo groups; most adverse events were mild to moderate in severity. In this short-term trial, tulisokibart was more effective than placebo in inducing clinical remission in patients with moderately to severely active ulcerative colitis. (Funded by Prometheus Biosciences, a subsidiary of Merck; ARTEMIS-UC ClinicalTrials.gov number, NCT04996797.).

Background Early life exposures may modify risk of inflammatory bowel diseases (IBD; Crohn’s disease (CD), ulcerative colitis (UC)). However, the relationship between early life exposures and natural history of IBD has not been previously examined. Methods This single center study included patients with CD or UC recruited in a prospective IBD registry. Enrolled patients completed a detailed environmental questionnaire that assessed various early life environmental exposures. Our primary outcome was requirement for disease-related surgery in CD and UC. Logistic regression models defined independent effect of early life exposures, adjusting for potential confounders. Results Our study included 333 CD and 270 UC patients. Just over half were female with a median age at diagnosis of 25 years. One-third of the cohort had history of bowel surgery (31%) and nearly half had used at least one biologic agent (47%). Among those with CD, being breastfed was associated with reduced risk of CD-related surgery (34% vs. 55%), while childhood cigarette smoke exposure was associated with increased risk. On multivariate analysis, history of being breastfed (odds ratio (OR) 0.21, 95% confidence interval [CI] 0.09–0.46) and cigarette smoke exposure as a child (OR 2.17, 95% CI 1.10–4.29) remained independently associated with surgery. None of the early life variables influenced disease phenotype or outcome in UC. Conclusion A history of being breastfed was associated with a decreased risk while childhood cigarette smoke exposure was associated with an increased risk of surgery in patients with CD. Further investigation to examine biological mechanisms is warranted.

Vedolizumab (VDZ) demonstrated efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in the GEMINI trials. Our aim was to evaluate the efficacy of VDZ at week 14 in inflammatory bowel disease in a multicenter cohort of patients.MethodsPatients at Massachusetts General Hospital and Brigham and Women's Hospital were considered for inclusion. VDZ (300 mg) was administered at weeks 0, 2, 6, and 14. Efficacy was assessed using the Harvey–Bradshaw index for CD, the simple clinical colitis activity index for UC and physician assessment, along with C-reactive protein and decrease of corticosteroid therapy. Clinical response was defined as decrease in Harvey–Bradshaw index ≥3 and simple clinical colitis activity index ≥3 and remission as Harvey–Bradshaw index ≤4, simple clinical colitis activity index ≤2 and physician assessment of response and remission.ResultsOur study included 172 patients (107 CD, 59 UC, 6 inflammatory bowel disease-unclassified, men 48.3%, mean age 40 years and disease duration 14 years). Fourteen patients had ostomy and 9 ileoanal pouch, and only 35.5% fulfilled eligibility for the GEMINI trials. Previous treatment failures with ≥ 2 anti-TNFs occurred in 70.9%, one-third were on an immunomodulator and 46% systemic steroids at baseline. In CD, 48.9% and 23.9% and in UC, 53.9% and 29.3% had clinical response and clinical remission at week 14, respectively. Adverse events occurred in 10.5%.ConclusionsVDZ is safe and well tolerated in refractory inflammatory bowel disease patients in a clinical practice with efficacy in UC and CD with responses similar to what was seen in clinical trials.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic immunologically mediated diseases with a progressive relapsing remitting course. There is considerable heterogeneity in disease course and accurate prediction of natural history has been challenging. The phenotypic implication of increasing genetic predisposition to CD or UC is unknown. The data source for our study was a prospective cohort of CD and UC patients recruited from a tertiary referral center. All patients underwent genotyping on the Illumina Immunochip. A genetic risk score (GRS) incorporating strength of association (log odds ratio) and allele dose for each of the 163 inflammatory bowel disease (IBD) risk loci was calculated and phenotypic associations examined across GRS quartiles. Our study cohort included 1,105 patients (697 CD, 408 UC). Increasing genetic burden was associated with earlier age of diagnosis of CD (Ptrend=0.008). Patients in the highest GRS quartile were likely to develop disease 5 years earlier than those in the lowest quartile. Increasing genetic burden was also associated with ileal involvement in CD (Ptrend <0.0001). The effect of genetic burden was independent of the NOD2 locus and was stronger among those with no NOD2 variants, and in never smokers. UC patients with an involved first-degree relative had a higher genetic burden, but GRS was not associated with disease phenotype in UC. Increasing genetic burden is associated with early age of diagnosis in CD, but not UC. The expanded panel of IBD risk loci explains only a fraction of variance of disease phenotype, suggesting limited clinical utility of genetics in predicting natural history.

In increasingly aging populations, awareness of outcomes of older patients treated with biologics is becoming more important. However, few studies to date have investigated the safety and durability of anti-tumor necrosis factor (TNF) therapy in this subgroup.MethodsThis was a retrospective single-center study with cases comprising all IBD patients who began anti-TNF treatment at age >60 years. Cases of Crohn's disease (CD) and ulcerative colitis (UC) were identified from medical record review. Our controls consisted of patients younger than age 60 years on anti-TNF treatment and patients >60 years on treatment with immunomodulators. Kaplan–Meier survival estimates were used to calculate the probability of remaining on anti-TNF therapy.ResultsWe identified a total of 54 IBD patients who initiated anti-TNF therapy over the age of 60 years (mean 73, range 61–97 years). Among these, a total of 38 patients (70%) discontinued anti-TNF therapy after a mean of 24.1 months. At 12 months after initiation, 75% of patients older than age 60 years were still on anti-TNF agents compared to 93% among younger users and 82% among older AZA users (P < 0.05). Compared to older AZA users, older anti-TNF users remained more likely to require early therapy cessation (hazard ratio 2.21, 95% confidence interval 1.29–3.78).ConclusionsThe IBD population older than age 60 at the time of initiation of anti-TNF therapy is at higher risk for discontinuation of therapy. They may also be particularly vulnerable to infectious complications requiring hospitalization, suggesting the need for careful monitoring during therapy.

Inflammatory bowel disease (IBD) is a well-known risk factor for venous thromboembolism (VTE). Existing guidelines for thromboprophylaxis in hospitalized patients do not extend to other clinical scenarios that may also be associated with VTE risk. Our aim was to estimate the fraction of VTE events in patients with IBD that could be prevented.MethodsA retrospective analysis assessed all patients with IBD diagnosed with VTE at a single academic medical center from 2002 to 2012. Confirmed cases were analyzed for VTE risk factors, inpatient status, the use of deep venous thrombosis prophylaxis, and when applicable the reason for omission of prophylaxis. IBD VTE cases were compared with age- and sex-matched non-IBD VTE controls with regards to risk factors and potential opportunities for VTE prevention.ResultsThere were 204 patients with IBD (108 ulcerative colitis, 96 Crohn's disease) diagnosed with VTE (110 deep venous thrombosis, 66 pulmonary embolism, 27 intra-abdominal thromboses, and 1 other). One-third of the VTE events occurred in hospitalized patients. Two-third of the medical inpatients and 44% of surgical inpatients who developed VTE did not receive prophylaxis. Importantly, 129 VTE events occurred in outpatients. The proportion of outpatients hospitalized within 4 weeks of developing venous thrombosis was higher in patients with IBD than non-IBD controls (33% versus 15%, P = 0.0003). One-third (36%) of patients were experiencing ambulatory disease flares at the time of VTE diagnosis.ConclusionsA substantial portion of VTE events in patients with IBD occurred in clinical scenarios is not routinely recommended for thromboprophylaxis. Further investigation of primary prophylaxis for patients with IBD in high-risk outpatients may be warranted.