Excess non-COVID-19-related mortality among inflammatory bowel disease decedents during the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic disrupted healthcare in the United States. AIM: To investigate COVID-19-related and non-COVID-19-related death and characteristics associated with excess death among inflammatory bowel disease (IBD) decedents. METHODS: We performed a register-based study using data from the National Vital Statistics System, which reports death data from over 99% of the United States population, from January 1, 2006 through December 31, 2021. IBD-related deaths among adults 25 years and older were stratified by age, sex, race/ethnicity, place of death, and primary cause of death. Predicted and actual age-standardized mortality rates (ASMRs) per 100000 persons were compared. RESULTS: 49782 IBD-related deaths occurred during the study period. Non-COVID-19-related deaths increased by 13.14% in 2020 and 18.12% in 2021 [2020 ASMR: 1.55 actual vs 1.37 predicted, 95% confidence interval (CI): 1.26-1.49; 2021 ASMR: 1.63 actual vs 1.38 predicted, 95%CI: 1.26-1.49]. In 2020, non-COVID-19-related mortality increased by 17.65% in ulcerative colitis (UC) patients between the ages of 25 and 65 and 36.36% in non-Hispanic black (NHB) Crohn's disease (CD) patients. During the pandemic, deaths at home or on arrival and at medical facilities as well as deaths due to neoplasms also increased. CONCLUSION: IBD patients suffered excess non-COVID-19-related death during the pandemic. Excess death was associated with younger age among UC patients, and with NHB race among CD patients. Increased death at home or on arrival and due to neoplasms suggests that delayed presentation and difficulty accessing healthcare may have led to increased IBD mortality.

The impact of nonalcoholic fatty liver disease on inflammatory bowel disease-related hospitalization outcomes: a systematic review.

Evidence suggests that patients with inflammatory bowel disease are at higher risk of developing nonalcoholic fatty liver disease (NAFLD). However, there is limited information currently available on how NAFLD may affect the clinical course of IBD. Thus, we conducted a systematic review to evaluate the impact of NAFLD on IBD-related hospitalization outcomes. All observational studies assessing IBD-related hospitalization outcomes in patients with NAFLD were included. Exclusion criteria were studies published in languages other than English or French, or those involving pediatric population. Outcomes included IBD-related hospitalization and readmission rates, need for surgery, length of stay, inpatient mortality, and costs. Overall, 3252 citations were retrieved and seven studies met the inclusion criteria (1 574 937 patients); all were observational, of high quality, and originated in the United States. Measurable outcomes reported in these studies were few and with insufficient similarity across studies to complete a quantitative assessment. Only one study reports NAFLD severity. Two studies suggested a higher rate of hospitalization for patients with both NAFLD and IBD compared to IBD alone (incidence rate ratio of 1.54; 95% confidence interval: 1.33-1.79). This is the first systematic review to date that evaluates any possible association of NAFLD with IBD-related hospitalization outcomes. Despite the paucity and low quality of available data, our findings indicate that NAFLD may be associated with worse outcomes amongst IBD patients (especially Crohn's disease). Further and higher certainty of evidence is needed for better characterization of such clinical impact.

Pleural AA amyloidosis preceding the diagnosis of inflammatory bowel disease / Amioloidosis AA pleural que precede el diagnóstico de una enfermedad inflamatoria intestinal

Pleural amyloidosis constitutes a rare presentation of a rare disease. We report a case of amyloidotic pleural effusion that preceded the diagnosis of inflammatory bowel disease by six months. The patient had a paucisymptomatic gastrointestinal disease but an exuberant AA amyloidosis that progressed to involve multiple organs, including lung, kidney and heart. Despite immunomodulatory treatment with corticosteroids and infliximab with good gastrointestinal response, the patient eventually passed away 2 years after diagnosis. (AU)

Antibiotic use differentially affects the risk of anti-drug antibody formation during anti-TNFα therapy in inflammatory bowel disease patients: a report from the epi-IIRN.

OBJECTIVE: Anti-drug antibodies (ADA) to anti-tumour necrosis factor (anti-TNF) therapy drive treatment loss of response. An association between intestinal microbial composition and response to anti-TNF therapy was noted. We therefore aimed to assess the implications of antibiotic treatments on ADA formation in patients with inflammatory bowel disease (IBD). DESIGN: We analysed data from the epi-IIRN (epidemiology group of the Israeli IBD research nucleus), a nationwide registry of all patients with IBD in Israel. We included all patients treated with anti-TNF who had available ADA levels. Survival analysis with drug use as time varying covariates were used to assess the association between antibiotic use and ADA development. Next, specific pathogen and germ-free C57BL mice were treated with respective antibiotics and challenged with infliximab. ADA were assessed after 14 days. RESULTS: Among 1946 eligible patients, with a median follow-up of 651 days from initiation of therapy, 363 had positive ADA. Cox proportional hazard model demonstrated an increased risk of ADA development in patients who used cephalosporins (HR=1.97, 95% CI 1.58 to 2.44), or penicillins with ß-lactamase inhibitors (penicillin-BLI, HR=1.4, 95% CI 1.13 to 1.74), whereas a reduced risk was noted in patients treated with macrolides (HR=0.38, 95% CI 0.16 to 0.86) or fluoroquinolones (HR=0.20, 95% CI 0.12 to 0.35). In mice exposed to infliximab, significantly increased ADA production was observed in cephalosporin as compared with macrolide pretreated mice. Germ-free mice produced no ADA. CONCLUSION: ADA production is associated with the microbial composition. The risk of ADA development during anti-TNF therapy can possibly be reduced by avoidance of cephalosporins and penicillin-BLIs, or by treatment with fluoroquinolones or macrolides.

The Influence of Corticosteroids, Immunosuppressants and Biologics on Patients With Inflammatory Bowel Diseases, Psoriasis and Rheumatic Diseases in the Era of COVID-19: A Review of Current Evidence.

Patients with inflammatory bowel disease, psoriasis or other rheumatic diseases treated with corticosteroids, immunomodulators and biologics might face additional risk during COVID-19 epidemic due to their immunocompromised status. However, there was still no unanimous opinion on the use of these therapy during COVID-19 epidemic. Current studies suggested that systemic corticosteroids might increase the risk of hospitalization, as well as risks of ventilation, ICU, and death among patients with immune-mediated inflammatory diseases. Anti-TNF agent was associated with lower rate of hospitalization, as well as lower risks of ventilation, ICU, and death. No significant changes in rates of hospitalization, ventilation, ICU and mortality were observed in patients treated with immunomodulators or biologics apart from anti-TNF agents. The underlying mechanism of these results might be related to pathway of antiviral immune response and cytokine storm induced by SARS-COV-2 infection. Decision on the use of corticosteroids, immunomodulators and biologics should be made after weighing the benefits and potential risks based on individual patients.

Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 2: Inactivated Vaccines.

BACKGROUND AND AIMS: The effectiveness and safety of vaccinations can be altered by immunosuppressive therapies, and perhaps by inflammatory bowel disease (IBD) itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on inactivated vaccines. METHODS: Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative online platform, and voted on by a multidisciplinary group. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS: Consensus was reached on 15 of 20 questions. Recommendations address the following vaccines: Haemophilus influenzae type b, recombinant zoster, hepatitis B, influenza, pneumococcus, meningococcus, tetanus-diphtheria-pertussis, and human papillomavirus. Most of the recommendations for patients with IBD are congruent with the current Centers for Disease Control and Prevention and Canada's National Advisory Committee on Immunization recommendations for the general population, with the following exceptions. In patients with IBD, the panel suggested Haemophilus influenzae type b vaccine for patients older than 5 years of age, recombinant zoster vaccine for adults younger than 50 year of age, and hepatitis B vaccine for adults without a risk factor. Consensus was not reached, and recommendations were not made for 5 statements, due largely to lack of evidence, including double-dose hepatitis B vaccine, timing of influenza immunization in patients on biologics, pneumococcal and meningococcal vaccines in adult patients without risk factors, and human papillomavirus vaccine in patients aged 27-45 years. CONCLUSIONS: Patients with IBD may be at increased risk of some vaccine-preventable diseases. Therefore, maintaining appropriate vaccination status in these patients is critical to optimize patient outcomes. In general, IBD is not a contraindication to the use of inactivated vaccines, but immunosuppressive therapy may reduce vaccine responses.

Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 1: Live Vaccines.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) may be at increased risk of some vaccine-preventable diseases. The effectiveness and safety of vaccinations may be altered by immunosuppressive therapies or IBD itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on live vaccines. METHODS: Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative process and voted on by a multidisciplinary panel. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS: Three good practice statements included reviewing a patient's vaccination status at diagnosis and at regular intervals, giving appropriate vaccinations as soon as possible, and not delaying urgently needed immunosuppressive therapy to provide vaccinations. There are 4 recommendations on the use of live vaccines. Measles, mumps, rubella vaccine is recommended for both adult and pediatric patients with IBD not on immunosuppressive therapy, but not for those using immunosuppressive medications (conditional). Varicella vaccine is recommended for pediatric patients with IBD not on immunosuppressive therapy, but not for those using immunosuppressive medications (conditional). For adults, recommendations are conditionally in favor of varicella vaccine for those not on immunosuppressive therapy, and against for those on therapy. No recommendation was made regarding the use of live vaccines in infants born to mothers using biologics because the desirable and undesirable effects were closely balanced and the evidence was insufficient. CONCLUSIONS: Maintaining appropriate vaccination status in patients with IBD is critical to optimize patient outcomes. In general, live vaccines are recommended in patients not on immunosuppressive therapy, but not for those using immunosuppressive medications. Additional studies are needed to evaluate the safety and efficacy of live vaccines in patients on immunosuppressive therapy.

Increasing Prevalence of Frailty and Its Association with Readmission and Mortality Among Hospitalized Patients with IBD.

BACKGROUND: Although age is often used as a clinical risk stratification tool, recent data have suggested that adverse outcomes are driven by frailty rather than chronological age. AIMS: In this nationwide cohort study, we assessed the prevalence of frailty, and factors associated with 30-day readmission and mortality among hospitalized IBD patients. METHODS: Using the Nationwide Readmission Database, we examined all patients with IBD hospitalized from 2010 to 2014. Based on index admission, we defined IBD and frailty using previously validated ICD codes. We used univariable and multivariable regression to assess risk factors associated with all-cause 30-day readmission and 30-day readmission mortality. RESULTS: From 2010 to 2014, 1,405,529 IBD index admissions were identified, with 152,974 (10.9%) categorized as frail. Over this time period, the prevalence of frailty increased each year from 10.20% (27,594) in 2010 to 11.45% (33,507) in 2014. On multivariable analysis, frailty was an independent predictor of readmission (aRR 1.16, 95% CI: 1.14-1.17), as well as readmission mortality (aRR 1.12, 95% CI 1.02-1.23) after adjusting for relevant clinical factors. Frailty also remained associated with readmission after stratification by IBD subtype, admission characteristics (surgical vs. non-surgical), age (patients ≥ 60 years old), and when excluding malnutrition, weight loss, and fecal incontinence as frailty indicators. Conversely, we found older age to be associated with a lower risk of readmission. CONCLUSIONS: Frailty, independent of age, comorbidities, and severity of admission, is associated with a higher risk of readmission and mortality among IBD patients, and is increasing in prevalence. Given frailty is a potentially modifiable risk factor, future studies prospectively assessing frailty within the IBD patient population are needed.

Life expectancy and health-adjusted life expectancy in people with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) may be life-threatening and often reduces quality of life. We determined trends in life expectancy and health-adjusted life expectancy in people with and without IBD. METHODS: We conducted a retrospective cohort study of population-level health administrative, demographic and health survey data available from databases in Ontario. We matched people with a diagnosis of IBD to those without a diagnosis of IBD. We used period life tables that were generated using age- and sex-specific 5-year mortality rates to calculate life expectancy (for 1996, 2000, 2008 and 2011). We incorporated the Health Utility Index (National Population Health Study; Canadian Community Health Survey) to estimate health-adjusted life expectancy (for 1996, 2000 and 2008). RESULTS: Life expectancy in patients with IBD increased between 1996 and 2011 (females: from 75.5 to 78.4 yr, difference: 2.9 yr [95% confidence interval (CI) 1.3 to 4.5]; males: from 72.2 to 75.5 yr, difference: 3.2 yr [95% CI 2.1 to 4.4]). Between 1996 and 2008, health-adjusted life expectancy decreased among males by 3.9 years (95% CI 1.2 to 6.6). There was no statistically significant change in health-adjusted life expectancy among females with IBD (difference: 2.0 yr, 95% CI -1.6 to 5.7). Life expectancy and health-adjusted life expectancy were lower in people with IBD compared with those without IBD. Differences in life expectancy in people with and without IBD ranged from 6.6 to 8.1 years in females and 5.0 to 6.1 years in males, depending on the year. Differences in health-adjusted life expectancy for people with and without IBD ranged from 9.5 to 13.5 years in females and 2.6 to 6.7 years in males. INTERPRETATION: Whilst life expectancy has increased among people with IBD, a gap in life expectancy between those with and without IBD remains, and the effect of pain on daily functioning contributes substantially to reduced health-adjusted life expectancy, suggesting that improved pain mitigation strategies should be implemented.

Frailty is independently associated with mortality in 11 001 patients with inflammatory bowel diseases.

BACKGROUND: The prevalence of older adults with inflammatory bowel diseases (IBD) is increasing. Frailty is an important predictor of outcomes in many chronic disease states. The implications of frailty have not been well-delineated in IBD. AIMS: To report the prevalence of a frailty-associated diagnosis and determine the association between frailty and mortality in a cohort of IBD patients. METHODS: In a cohort of 11 001 IBD patients, we applied a validated definition of frailty using International Classification of Disease codes. We compared frail IBD patients to those without a frailty-related code ("fit"). We constructed multivariable logistic regression models adjusting for clinically pertinent confounders (age, gender, race, IBD type, follow-up, IBD-related surgery, ≥1 comorbidity in the Charlson comorbidity index [CCI], and immunosuppression use) to determine whether frailty predicts mortality. RESULTS: A total of 675 (6%) IBD patients had a frailty-related diagnosis. The prevalence of frailty increased with age, rising from 4% in 20-29 year olds to 25% in patients 90 years or older. The most prevalent frailty diagnosis was protein-energy malnutrition. The strongest predictors of frailty were non-IBD comorbidity, all-cause and IBD-related, hospitalisations. Frailty remained independently associated with mortality after adjusting for age, sex, duration of follow-up, comorbidity, need for IBD-related surgery and immunosuppression (OR: 2.90, 95% CI: 2.29-3.68). CONCLUSIONS: Frailty is prevalent in IBD patients and increases with age. Frailty nearly triples the odds of mortality for IBD patients. Risk stratifying patients by frailty may improve outcomes.

Corticosteroids, But Not TNF Antagonists, Are Associated With Adverse COVID-19 Outcomes in Patients With Inflammatory Bowel Diseases: Results From an International Registry.

BACKGROUND AND AIMS: The impact of Coronavirus disease 2019 (COVID-19) on patients with inflammatory bowel disease (IBD) is unknown. We sought to characterize the clinical course of COVID-19 among patients with IBD and evaluate the association among demographics, clinical characteristics, and immunosuppressant treatments on COVID-19 outcomes. METHODS: Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) is a large, international registry created to monitor outcomes of patients with IBD with confirmed COVID-19. We calculated age-standardized mortality ratios and used multivariable logistic regression to identify factors associated with severe COVID-19, defined as intensive care unit admission, ventilator use, and/or death. RESULTS: 525 cases from 33 countries were reported (median age 43 years, 53% men). Thirty-seven patients (7%) had severe COVID-19, 161 (31%) were hospitalized, and 16 patients died (3% case fatality rate). Standardized mortality ratios for patients with IBD were 1.8 (95% confidence interval [CI], 0.9-2.6), 1.5 (95% CI, 0.7-2.2), and 1.7 (95% CI, 0.9-2.5) relative to data from China, Italy, and the United States, respectively. Risk factors for severe COVID-19 among patients with IBD included increasing age (adjusted odds ratio [aOR], 1.04; 95% CI, 1.01-1.02), ≥2 comorbidities (aOR, 2.9; 95% CI, 1.1-7.8), systemic corticosteroids (aOR, 6.9; 95% CI, 2.3-20.5), and sulfasalazine or 5-aminosalicylate use (aOR, 3.1; 95% CI, 1.3-7.7). Tumor necrosis factor antagonist treatment was not associated with severe COVID-19 (aOR, 0.9; 95% CI, 0.4-2.2). CONCLUSIONS: Increasing age, comorbidities, and corticosteroids are associated with severe COVID-19 among patients with IBD, although a causal relationship cannot be definitively established. Notably, tumor necrosis factor antagonists do not appear to be associated with severe COVID-19.

Safety of Janus Kinase Inhibitors in Patients With Inflammatory Bowel Diseases or Other Immune-mediated Diseases: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis. METHODS: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990, through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events. RESULTS: We identified 973 studies; of these, 82 were included in the final analysis, comprising 66,159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared with patients given placebo or active comparator (relative risk 0.72; 95% confidence interval 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% confidence interval 1.04-2.37). CONCLUSIONS: In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.

Short-term and long-term outcomes of indigo naturalis treatment for inflammatory bowel disease.

BACKGROUND AND AIM: Indigo naturalis (IN) is a traditional Chinese herbal medicine reported to be effective in inducing remission in ulcerative colitis (UC). We conducted a retrospective observational study to investigate the efficacy and safety of IN for induction and maintenance therapy in patients with inflammatory bowel disease. METHODS: Data were collected from the electric medical records of patients with inflammatory bowel disease who had started IN treatment between March 2015 and April 2017 at Kyushu University Hospital. Clinical response and remission rates were assessed based on the clinical activity index determined by Rachmilewitz index or Crohn's disease (CD) activity index. Cumulative IN continuation rates were estimated using the Kaplan-Meier method. Overall adverse events (AEs) during follow-up were also analyzed. RESULTS: Seventeen UC patients and eight CD patients were enrolled. Clinical response and remission rates at week 8 were 94.1% and 88.2% in UC patients and 37.5% and 25.0% in CD patients, respectively. Clinical remission rates, as assessed through non-responders imputation analyses at weeks 52 and 104, were 76.4% and 70.4% in UC patients and 25.0% and 25.0% in CD patients, respectively. Ten patients (40%) experienced AEs during follow-up. Three patients (12%) experienced severe AEs, including acute colitis requiring hospitalization in two patients and acute colitis with intussusception requiring surgery in one patient. CONCLUSIONS: Indigo naturalis showed favorable therapeutic efficacy in UC, whereas its therapeutic efficacy in CD appeared to be modest. The risk of severe AEs should be recognized for IN treatment.

Trends and risk factors of mortality analysis in patients with inflammatory bowel disease: a Taiwanese nationwide population-based study.

BACKGROUND: Inflammatory bowel disease (IBD) was emerging as a worldwide epidemic disease, and the advanced therapy changed the clinical course and possibly the outcomes. Our previous study reported a higher mortality rate from (IBD) in Taiwan than in Western countries. We proposed to analyze the trend and risk factors of mortality in order to improve the care quality of IBD patients. METHODS: This retrospective study was conducted to analyze data for January 2001 to December 2015 from a registered database, compiled by the Taiwan's National Health Insurance. RESULTS: Between 2001 and 2015, a total of 3806 IBD patients [Crohn's disease (CD): 919; ulcerative colitis (UC): 2887] were registered as having catastrophic illness, and 8.2% of these patients died during follow-up. The standardized mortality ratios (SMRs) of CD and UC were 3.72 (95% CI 3.02-4.55) and 1.44 (95% CI 1.26-1.65), respectively, from 2001 to 2015, respectively. A comparison of the periods of 2011-2015 and 2001-2005 revealed a decrease in the mortality rates from both UC and CD. Multivariate Cox proportional hazards analysis identified elderly individuals; sepsis and pneumonia were the risk factors for IBD mortality. The specific risk factors of mortality were liver cancer for UC and surgeries for CD. CONCLUSION: For further decreasing IBD-related mortality in Taiwan, we need to pay special attention toward elderly individuals, infection control, cancer screening and improvement in perioperative care.

Therapeutic Effects of Mesenchymal Stem Cells Derived From Bone Marrow, Umbilical Cord Blood, and Pluripotent Stem Cells in a Mouse Model of Chemically Induced Inflammatory Bowel Disease.

Acute inflammatory bowel disease (AIBD) is a wide clinical entity including severe gastrointestinal pathologies with common histopathological basis. Epidemiologically increasing diseases, such as necrotizing enterocolitis (NEC), gastrointestinal graft versus host disease (GVHD), and the primary acute phase of chronic inflammatory bowel disease (CIBD), exhibit a high necessity for new therapeutic strategies. Mesenchymal stem cell (MSC) cellular therapy represents a promising option for the treatment of these diseases. In our study, we comparatively assess the efficacy of human MSCs derived from bone marrow (BM), umbilical cord blood (UCB), human embryonic stem cells (ESCs), or human-induced pluripotent stem cells (iPSCs) in a mouse model of chemically induced acute enterocolitis. The laboratory animals were provided ad libitum potable dextrane sulfate sodium solution (DSS) in order to reproduce an AIBD model and then individually exposed intraperitoneally to MSCs derived from BM (BM-MSCs), UCB (UCB-MSCs), ESCs (ESC-MSCs), or iPSCs (iPSC-MSCs). The parameters used to evaluate the cellular treatment efficacy were the animal survival prolongation and the histopathological-macroscopic picture of bowel sections. Although all categories of mesenchymal stem cells led to statistically significant survival prolongation compared to the control group, significant clinical and histopathological improvement was observed only in mice receiving BM-MSCs and UCB-MSCs. Our results demonstrated that the in vivo anti-inflammatory effect of ESC-MSCs and iPSC-MSCs was inferior to that of UCB-MSCs and BM-MSCs. Further investigation will clarify the potential of ESCs and iPSC-derived MSCs in AIBD treatment.

Mortality After First Hospital Admission for Inflammatory Bowel Disease: A Nationwide Registry Linkage Study.

BACKGROUND: The goal of this study was to determine long-term mortality and causes of death in patients after hospitalization for inflammatory bowel disease (IBD). METHODS: A cohort of patients admitted to the hospital because of IBD for the first time between 1998 and 2010 was identified by linkage of nationwide Dutch registries. Mortality risks and causes of death in Crohn's disease (CD) and ulcerative colitis (UC) patients were compared with a large random sample of individuals from the general population. Multivariable Cox regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: In total, 23,003 patients (56.1% women; mean age, 44.8 years) were hospitalized for IBD. Patients admitted for IBD had a higher risk of death than those from the general population. Adjusted HRs for 5-year all-cause mortality were 2.42 (95% CI, 1.15-5.12) and 1.45 (95% CI, 1.26-1.66) in men and women hospitalized for CD, respectively. Corresponding HRs for UC were 1.59 (95% CI, 1.39-1.83) and 1.13 (95% CI, 0.98-1.31). Mortality among patients after hospitalization for IBD decreased between 1998-2004 and 2005-2010. Patients admitted for UC had a higher risk of all-cause mortality than those admitted for CD. Inflammatory bowel disease patients died more often from (colorectal) cancer and gastrointestinal disease and less often from cardiovascular disease relative to the general population. CONCLUSIONS: Mortality of patients after hospitalization for IBD has decreased over time. Causes of death in CD and UC patients differ from those in the general population.

Relevant Infections in Inflammatory Bowel Disease, and Their Relationship With Immunosuppressive Therapy and Their Effects on Disease Mortality.

BACKGROUND AND AIMS: There is controversy as to whether the risk of relevant infection in IBD is related to immunosuppressants or the disease itself. The aims of this study were to evaluate: [1] the life-long prevalence and types of relevant infections in patients with IBD related to immunosuppressive treatment, and [2] the relationship of both infection and patient comorbidity to mortality. METHODS: Observational multicentre retrospective study of IBD patients that presented a relevant infection. For each case, four periods of infection exposure were analysed: P1: pre-IBD diagnosis, P2: from IBD diagnosis to immunosuppressant initiation, P3: during immunosuppressant therapy, and P4: after treatment withdrawal. RESULTS: The life-long prevalence of relevant infection in the total cohort of patients [6914] was 3%, and 5% in immunosuppressed patients [4202]. 366 relevant infections were found in 212 patients [P1: 9, P2: 17, P3: 334, and P4: 6]. Differences between periods were significant [p < 0.0001]. The most frequent types of infection were respiratory, intestinal and urinary. The most frequent opportunistic infections were tuberculosis [prevalence: 2.6/1000] and herpes zoster [prevalence: 3.9/1000]. Herpes zoster infection was associated with thiopurines alone or in combination with anti-TNF in 75% of the cases, whereas tuberculosis was associated with anti-TNF in 94% of patients. The overall mortality was 4.2%. Infection-related mortality was 2.8% and it was not influenced by comorbidity. CONCLUSIONS: Relevant infections in IBD patients are rare and appear to be related to immunosuppression. Relevant infection is a major cause of death in IBD.

Risk Factors Associated with Clostridium difficile Infection in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIM: Clostridium difficile infection [CDI] is a significant concern in inflammatory bowel disease [IBD]. Risk factors and consequences associated with CDI in inflammatory bowel disease [IBD] patients are important to characterize. The aim of this research was to perform a systematic review and meta-analysis on risk factors and outcomes associated with CDI in IBD patients. METHODS: Multiple databases were searched for studies investigating risk factors, colectomy and mortality risk in IBD patients with and without CDI. This was stratified by short [<3 months] and long-term [>1 year] outcomes. Summary estimates were calculated using a random-effects model. Quality assessment used the Newcastle-Ottawa scale. RESULTS: Twenty-two studies met inclusion criteria. Antibiotics use within 30 days of diagnosis was associated with CDIs (odds ratio [OR]: 1.85, 95% confidence interval [CI]:1.36, 2.52). Colonic involvement in Crohn's disease patients was associated with significantly higher CDI rates [OR: 2.76, 95% CI: 1.75, 4.35]. There was a significant association between biologic medication use and CDI [OR: 1.65, 95% CI: 1.18, 2.30], with minimal heterogeneity [I2 = 4.0%]. The long-term colectomy risk was significantly higher for IBD patients with CDI compared with that for IBD patients without CDI [OR: 2.22, 95% CI: 1.17, 4.18]. Significantly higher mortality was found for CDI in IBD patients both short-term [OR: 3.84, 95% CI: 2.62, 5.61] and long-term [OR: 3.65, 95% CI: 1.58, 8.44]. Substantial heterogeneity existed. Most studies were of moderate quality. CONCLUSION: Colonic involvement, and biologic and antibiotic use appear to be risk factors associated with CDI among IBD patients. CDI is associated with increased short- and long-term mortality.