Precision medicine: how multiomics will shape the future of inflammatory bowel disease?

PURPOSE OF REVIEW: In this article, we provide an overview of studies examining multiomic profiling in various clinical scenarios in the management of inflammatory bowel diseases (IBDs). RECENT FINDINGS: IBD arises as a result of an interplay between genetic, environmental, microbial and immunologic perturbations. The access to high throughput technology as well as the decrease in costs associated with such studies has led to a growing wealth of literature examining the utility of single or multiomic profiles in the management of IBD. Such studies have commonly examined the genome (and less frequently the epigenome), transcriptome, metabolome, proteome and the gut microbial metagenome in the context of overall IBD status or specific clinical scenarios, including the disease progression or response to treatment. The findings have provided important insight into how each of these compartments reflect underlying disease pathophysiologic processes and, in turn, can influence stratification of patients for clinical management. SUMMARY: Multiomic profiling in IBD has the potential to advance the field of personalized precision medicine in the management of IBDs.

Alterations in Fecal Microbiomes and Serum Metabolomes of Fatigued Patients With Quiescent Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Fatigue is frequent and disabling in patients with inflammatory bowel diseases (IBD) but its mechanisms are poorly understood. We investigated alterations in fecal microbiomes and serum metabolomes and proteomes in patients with quiescent IBD, with vs without fatigue. METHODS: We performed a prospective observational study of patients (44% women; mean age, 39.8 y) with clinically and endoscopically quiescent Crohn's disease (n = 106) or ulcerative colitis (n = 60) at a tertiary hospital, from March 2016 through December 2018. Fatigue was assessed using the functional assessment of chronic illness therapy-fatigue scoring system and defined as a score of 43 or less. We performed metabolomic analysis of serum samples using liquid chromatography-mass spectrometry methods and proteomic analysis using multiplex proximity extension assay (PEA) technology. Stool samples were obtained from 50 patients and analyzed by shotgun metagenomic sequencing on Illumina HiSeq platform. RESULTS: Of the 166 study participants, 91 (55%) were fatigued. Serum samples from patients with fatigue (n = 59) did not have significant increases in levels of inflammatory cytokines compared with serum samples from nonfatigued patients (n = 72). We found a statistically significant difference in a cluster of 18 serum metabolites between patients with fatigue (n = 84) vs without fatigue (n = 72) (P = .033); serum samples from patients with fatigue had significant reductions in levels of methionine (P = .020), tryptophan (P = .042), proline (P = .017), and sarcosine (P = .047). Fecal samples from patients with fatigue had a less diverse gut microbiome, with significant reductions in butyrate-producing bacteria, including Faecalibacterium prausnitzii (P = .0002, q =.007) and Roseburia hominis (P = .0079, q = 0.105). This fatigue-like microbiome was associated with fatigue scales and correlated with progressive depletion of metabolites from serum samples. CONCLUSIONS: In an analysis of fecal and serum samples from 166 patients with IBD, we found alterations in serum metabolites and fecal microbes that were associated with fatigue.

Longitudinal Trajectory of Fatigue in Patients With Inflammatory Bowel Disease: A Prospective Study.

BACKGROUND: Fatigue is a disabling symptom in patients with inflammatory bowel disease (IBD). Its prevalence, mechanism, and impact remain poorly understood. We determined changes in fatigue status over time and identified predictors of incident or resolving fatigue. METHODS: This was a prospective study nested within the IBD Partners cohort. Participants prospectively completed the Multidimensional Fatigue Inventory and the Functional Assessment of Chronic Illness Therapy-Fatigue at baseline, 6 months, and 12 months. A Functional Assessment of Chronic Illness Therapy-Fatigue score ≤43 defined significant fatigue. Multivariable regression models using baseline covariates were used to identify risk factors for incident fatigue at 6 months and to predict the resolution of fatigue. RESULTS: A total of 2429 patients (1605 with Crohn disease, 824 with ulcerative colitis) completed a baseline assessment, and 1057 completed a second assessment at 6 months. Persistent fatigue (at baseline and at 6 months) was the most common pattern, affecting two-thirds (65.8%) of patients. One-sixth (15.7%) of patients had fatigue at 1 timepoint, whereas fewer than one-fifth (18.5%) of patients never reported fatigue. Among patients not fatigued at baseline, 26% developed fatigue at 6 months. The strongest predictor of incident fatigue was sleep disturbance at baseline (odds ratio, 2.91; 95% confidence interval, 1.48-5.72). In contrast, only 12.3% of those with fatigue at baseline had symptom resolution by month 6. Resolution was more likely in patients with a diagnosis of ulcerative colitis, quiescent disease, and an absence of significant psychological comorbidity. CONCLUSIONS: Fatigue is common in patients with IBD. However, only a few fatigued patients experience symptom resolution at 6 or 12 months, suggesting the need for novel interventions to ameliorate its impact.

Infliximab Trough Levels Are Not Predictive of Relapse in Patients with IBD in Endoscopic Remission: A Multicenter Cohort Study.

BACKGROUND: Therapeutic drug monitoring (TDM) is important in optimizing use of biologics in inflammatory bowel diseases (IBD). However, the role of proactive TDM during remission remains uncertain. METHODS: This retrospective study included patients receiving infliximab (IFX) therapy at Massachusetts General Hospital or Erasmus University Medical Center. All eligible patients had completed induction phase of IFX and were in clinical and endoscopic remission. Our primary outcome was clinical relapse within 2 years after baseline. Multivariable regression models examined the association between infliximab trough levels during remission and relapse, need for IBD-related surgery or hospitalization. RESULTS: Our study cohort included 110 patients with IBD (72 CD, 38 UC) on IFX maintenance therapy. In total, 12 patients (10.9%) experienced relapse of disease over 2 years. The mean IFX trough level at baseline was 8.0 µg/mL (± 8.6) and did not differ between the institutions. 49.1% of patients had levels < 5 µg/mL and 2.7% had antibodies to infliximab at baseline. There was no difference in the mean IFX trough levels between patients who relapsed (7.5 µg/mL ± 3.7 µg/mL) over 24 months compared to those who did not (8.1 µg/mL ± 7.9 µg/mL, p = 0.815). On multivariable logistic regression analysis, IFX trough levels at baseline were not associated with relapse of disease over 24 months (OR 1.01, 95% CI 0.93-1.09, p = 0.856). CONCLUSION: This retrospective multicenter study provides evidence that IFX trough levels during quiescent disease do not predict relapse over 2 years, suggestive that proactive TDM in this setting is not warranted.

Multi-"-Omics" Profiling in Patients With Quiescent Inflammatory Bowel Disease Identifies Biomarkers Predicting Relapse.

BACKGROUND: Inflammatory bowel diseases (IBD) are characterized by intermittent relapses, and their course is heterogeneous and unpredictable. Our aim was to determine the ability of protein, metabolite, or microbial biomarkers to predict relapse in patients with quiescent disease. METHODS: This prospective study enrolled patients with quiescent Crohn disease and ulcerative colitis, defined as the absence of clinical symptoms (Harvey-Bradshaw Index ≤ 4, Simple Clinical Colitis Activity Index ≤ 2) and endoscopic remission within the prior year. The primary outcome was relapse within 2 years, defined as symptomatic worsening accompanied by elevated inflammatory markers resulting in a change in therapy or IBD-related hospitalization or surgery. Biomarkers were tested in a derivation cohort, and their performance was examined in an independent validation cohort. RESULTS: Our prospective cohort study included 164 patients with IBD (108 with Crohn disease, 56 with ulcerative colitis). Upon follow-up for a median of 1 year, 22 patients (13.4%) experienced a relapse. Three protein biomarkers (interleukin-10, glial cell line-derived neurotrophic factor, and T-cell surface glycoprotein CD8 alpha chain) and 4 metabolomic markers (propionyl-L-carnitine, carnitine, sarcosine, and sorbitol) were associated with relapse in multivariable models. Proteomic and metabolomic risk scores independently predicted relapse with a combined area under the curve of 0.83. A high proteomic risk score (odds ratio = 9.11; 95% confidence interval, 1.90-43.61) or metabolomic risk score (odds ratio = 5.79; 95% confidence interval, 1.24-27.11) independently predicted a higher risk of relapse over 2 years. Fecal metagenomics showed an increased abundance of Proteobacteria (P = 0.0019, q = 0.019) and Fusobacteria (P = 0.0040, q = 0.020) and at the species level Lachnospiraceae_bacterium_2_1_58FAA (P = 0.000008, q = 0.0009) among the relapses. CONCLUSIONS: Proteomic, metabolomic, and microbial biomarkers identify a proinflammatory state in quiescent IBD that predisposes to clinical relapse.

Assessment of Body Weight Changes in Patients with Inflammatory Bowel Diseases Initiating Biologic Therapy: A Prospective Cohort Study.

BACKGROUND: Prior studies have inconsistently suggested that biologic therapy may be associated with weight gain in inflammatory bowel disease patients (IBD). Our aim was to compare weight gain across different biologic therapy classes with distinct mechanisms of action. METHODS: This prospective cohort study recruited patients with moderate to severe IBD initiating outpatient biologic therapy with anti-TNF (infliximab, adalimumab), vedolizumab, or ustekinumab. Weight measurements were performed at weeks 0, 14, 30, and 54. Changes in weight between baseline and each of the follow-up visits were modeled as a continuous variable, and multivariate regression assessed the independent effect of therapeutic class on this outcome. RESULTS: Our study enrolled 269 patients (163 CD, 106 UC) initiating biologic therapy [99 anti-TNF (37%), 122 vedolizumab (45%), 48 ustekinumab (18%)]. From baseline, the weight significantly increased at week 14 with a mean of 0.36 kg (± 3.8 kg, p = 0.004) and continued to increase compared to baseline with 0.96 kg (± 3.9 kg, p < 0.001) and 1.29 kg (± 4.2 kg, p < 0.001) at week 30 and 54, respectively. On univariate and multivariable analysis, no significant differences between any of the biologic therapies for weight gain were seen at any time point (weight gain anti-TNF: 0.31 kg, 1.06 kg, 1.33 kg; VDZ: 0.30 kg, 0.83 kg, 1.10 kg; UST: 0.63 kg, 1.21 kg, 2.31 kg at wk 14, wk 30, and wk 54, respectively). None of the disease activity parameters showed any statistical association with weight gain. CONCLUSION: There was no difference in weight gain among the different biologic therapeutic classes.

Longitudinal Trajectory of Fatigue With Initiation of Biologic Therapy in Inflammatory Bowel Diseases: A Prospective Cohort Study.

BACKGROUNDS AND AIMS: Fatigue is prevalent in patients with inflammatory bowel diseases [IBD]. Biologic therapy is effective in achieving symptomatic and endoscopic remission, but its impact on fatigue is less well established. Our aim is to define the longitudinal trajectory of fatigue over 1 year in patients initiating biologic therapy. METHODS: This prospective cohort enrolled patients diagnosed with Crohn's disease [CD] or ulcerative colitis [UC] initiating biologic therapy with infliximab, adalimumab, ustekinumab, or vedolizumab. Fatigue was quantified using the seven-point fatigue question in the Short Inflammatory Bowel Disease Questionnaire [SIBDQ]. A score of ≤4 for this question was used to define fatigue. Multivariable regression models adjusting for relevant confounders examined the independent association between attaining clinical remission and resolution of fatigue. RESULTS: Our study included 326 patients [206 CD, 120 UC] initiating biologic therapy [144 anti-tumour necrosis factor, 129 vedolizumab, 63 ustekinumab]. A total of 61% of the included patients reported significant fatigue at baseline. This was associated with female gender, depressive symptoms, active disease, and disturbed sleep [p < 0.001]. Among the 198 patients who were fatigued at therapy initiation, 86 [70%], 55 [63%], and 44 [61%] remained fatigued at Week 14, 30, and 54, respectively. At each of these time points, achieving clinical remission was associated with lower likelihood of persistent fatigue. However, despite achieving remission, 35%, 30%, and 28% of patients experienced persistent fatigue at Week 14, 30, and 54, respectively. CONCLUSIONS: Fatigue is common in IBD. Though biologic therapy improves fatigue parallel symptomatic improvement, a significant proportion continue to experience persistent fatigue up to 1 year.

Low-dose Methotrexate has Similar Outcomes to High-dose Methotrexate in Combination with Anti-TNF Therapy in Inflammatory Bowel Diseases.

BACKGROUND AND AIMS: Methotrexate [MTX] is a well-known immunomodulator in the treatment of inflammatory bowel disease [IBD] and is often combined with biologic agents. The ideal MTX dose for combination therapy has not been determined. This study aimed to investigate the effect of varying doses of MTX on efficacy and safety outcomes when used with anti-TNF agents in IBD. METHODS: This study included patients with Crohn's disease [CD] or ulcerative colitis [UC] receiving care between January 2005 and June 2018. Low-dose MTX was defined as ≤12.5 mg/week and high-dose as >12.5 mg/week. The primary efficacy outcome was a composite of need for IBD-related hospitalization or surgery, steroid initiation, or change of biologic agent within 1 year. Safety outcomes included side effects related to MTX, serious infections, malignancy, and need to discontinue MTX therapy within 1 year. Multivariable logistic regression models adjusting for relevant covariates were used to assess independent association between MTX dose and outcomes. RESULTS: Our study included 222 patients with IBD [163 CD, 59 UC]. Just under a third were receiving low-dose MTX [28%]. The primary efficacy composite outcome was noted in 75 patients [47%] in the high-dose MTX group compared with 23 patients [37%] in the low-dose MTX group [p = 0.15]. We found no significant associations between MTX dose and any side effect [odds ratio 1.59, 95% confidence interval 0.77-3.31, p = 0.21] or development of serious infections [odds ratio 1.19, 95% confidence interval 0.41-3.45, p = 0.76]. CONCLUSIONS: Low-dose and high-dose MTX combination therapy were equally effective, and no difference in infection or malignancy rates was observed.

Comparative safety and effectiveness of tumor necrosis factor α antagonists and vedolizumab in elderly IBD patients: a multicentre study.

BACKGROUND: The older patient group with inflammatory bowel diseases (IBD) is particularly vulnerable to consequences of disease and therapy-related side effects but little is known about the best treatment options in this population. AIM: To compare safety and efficacy of tumor necrosis factor α antagonist (anti-TNF) or vedolizumab (VDZ) in patients with IBD >60 years of age. METHODS: This retrospective study included patients with Crohn's disease (CD) or ulcerative colitis (UC) initiating anti-TNF or VDZ therapy ≥60 years of age at three study sites. We examined occurrence of infection or malignancy within 1 year after therapy as our primary outcome. Our efficacy outcomes included clinical remission at 3, 6 and 12 months. Multivariable logistic regression models adjusting for relevant confounders estimated odds ratios (OR) and 95% confidence intervals. RESULTS: The study included 131 anti-TNF and 103 VDZ initiated patients (age range 60-88 years). Approximately half had CD. At 1 year, there were no significant differences in safety profile between the two therapeutic classes. Infections were observed in 20% of anti-TNF-treated and 17% of VDZ-treated patients (P = 0.54). Pneumonia was the most common infection in both groups. While more anti-TNF-treated CD patients were in remission at 3 months compared to VDZ (OR 2.82, 95% CI 1.18-6.76), this difference was not maintained at 6 and 12 months suggesting similar efficacy of both classes. CONCLUSIONS: Both anti-TNF and VDZ therapy were similarly effective and safe in elderly IBD patients.

Safety of Biologic Therapy in Older Patients With Immune-Mediated Diseases: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Management of immune-mediated inflammatory diseases often requires lifelong immunosuppression. Increasing numbers of older patients have inflammatory diseases and are particularly vulnerable to risks of immune suppressive therapies-particularly infections and malignancies. METHODS: We systematically searched PubMed/Medline and Embase to identify eligible studies that examined the safety of biologic therapies in older patients with immune-mediated inflammatory diseases (inflammatory bowel disease, rheumatoid arthritis, psoriasis). Included studies provided information on patients who began receiving therapy with a biologic agent when they were older than 60 years and a control population (either younger users of biologics or older patients who did not use biologics). Information of on overall pooled rates of infections, malignancy, and mortality were extracted. A DerSimonian and Laird random effects model was used to calculate pooled odds ratios (ORs) and 95% CIs. RESULTS: Our meta-analysis included 14 unique studies that comprised 4719 older users of biologics, 13,305 younger users of biologics, and 3961 older patients who did not use biologics. The pooled prevalence of infections in older and younger users of biologics was 13% and 6% respectively, yielding a pooled random effects odds ratio of 2.28 (95% CI, 1.57-3.31). Older age was associated with a significant increase in risk of malignancy (OR, 3.07; 95% CI, 1.98-4.62) compared to younger age. Older users of biologics had a 3-fold increase in risk of infection compared to patients who did not use biologics (OR, 3.60; 95% CI, 1.62-8.01), but there were no significant differences in odds of malignancy (0.54, 95% CI, 0.28-1.05) or death (OR, 1.52; 95% CI, 0.44-5.28) compared to older patients who did not use biologics. CONCLUSION: In a systematic review and meta-analysis of studies on the safety of biologic therapies in older patients with inflammatory diseases, we found that older users of biologic agents have an increased risk of infections compared with younger users or older patients who do not use biologics. Large, prospective cohort studies are needed to examine safety of biologic therapy in older patients with immune-mediated diseases.

Cancer risk in microscopic colitis: a retrospective cohort study.

BACKGROUND: The long-term natural history of microscopic colitis (MC) (collagenous colitis (CC), lymphocytic colitis (LC)), traditionally considered relapsing but non-progressive diseases, is poorly defined. Whether persistent histologic inflammation in such diseases is associated with an increased risk of colorectal neoplasia (CRN) or extracolonic cancers has not been robustly established. METHODS: This retrospective cohort included diagnosed with MC at a referral center. Rates of CRN and extracolonic cancer were compared to patients undergoing screening colonoscopy (n = 306) and to the United States population using data from the Surveillance, Epidemiology, and End-Results (SEER) program. Standardized incidence ratios (SIR) and 95% confidence intervals were calculated and multivariable regression models used to identify the effect of MC diagnosis and severity on cancer risk. RESULTS: Our study included 221 patients with microscopic colitis (112 CC, 109 LC) among whom 77% were women. Compared to the colonoscopy control population, MC was associated with similar odds of tubular adenoma (Odds ratio (OR) 1.07, 95% CI 0.69-1.66) or villous adenoma (OR 1.26, 95% CI 0.17-9.42). Compared to patients with a single episode of MC, those with 2 or more episodes had similar risk of colon cancer (OR 0.83, 95% CI 0.20-3.39) or tubular adenoma (OR 1.49 95% CI 0.83-2.67). We also identified no statistical increase in the rates of cancer in the MC population compared to US-SEER data. CONCLUSION: Microscopic colitis was not associated with increased risk of CRN and extracolonic cancers when compared to controls undergoing colonoscopy or the US SEER population.

Second-Look Endoscopy in Hospitalized Severe Ulcerative Colitis: A Retrospective Cohort Study.

BACKGROUND: Acute severe ulcerative colitis (ASUC) is a serious complication of ulcerative colitis (UC). Management of partial responders to steroids or rescue therapy remains challenging. Whether there is a role for re-look sigmoidoscopic evaluation in disease management is unknown. METHODS: Our study cohort consisted of patients who underwent 2 sigmoidoscopic procedures during the same index hospitalization for ASUC at our center. Reasons for repeat endoscopic evaluation and endoscopic and histologic severity of inflammation during both procedures were noted. Multivariable regression models were performed to identify predictors of improvement at the second endoscopic assessment and to determine the independent effect of such an improvement on in-hospital colectomy and at 3, 6, and 12 months. RESULTS: Our study included 49 patients (mean age, 42 years; 52% women). Just under one-third of patients (30%) were noted to have improved endoscopic appearance at the second sigmoidoscopy, at a median of 9 days after initial exam. None of the patients who had improvement on the second endoscopy underwent in-hospital colectomy, compared with 46% of those with worsening or persistent disease (P = 0.002). Similar differences in the improved group persisted at 3 months (P = 0.007) and 6 months (P = 0.027). Histologic severity at the first endoscopy was associated with increased risk of colectomy in-hospital (odds ratio, 3.8; 95% confidence interval, 1.02-14.21) and at 3 and 6 months. CONCLUSIONS: After a median interval of 9 days, endoscopic improvement was noted in 30% of patients with ASUC undergoing a second sigmoidoscopy, which predicted lower rates of colectomy in-hospital and at 3 and 6 months.

Effect of Accelerated Infliximab Induction on Short- and Long-term Outcomes of Acute Severe Ulcerative Colitis: A Retrospective Multicenter Study and Meta-analysis.

BACKGROUND & AIMS: In patients with acute severe ulcerative colitis (ASUC), standard infliximab induction therapy has modest efficacy. There are limited data on the short-term or long-term efficacy of accelerated infliximab induction therapy for these patients. METHODS: In a retrospective study, we collected data from 213 patients with steroid refractory ASUC who received infliximab rescue therapy at 3 centers, from 2005 through 2017. Patients were classified that received standard therapy (5mg/kg infliximab at weeks 0, 2, and 6) or accelerated therapy (>5mg/kg infliximab at shorter intervals). The primary outcome was colectomy in-hospital and at 3, 6, 12, and 24 months. Multivariable regression models were adjusted for relevant confounders. We also performed a meta-analysis of published effects of standard vs accelerated infliximab treatment of ASUC. RESULTS: In the retrospective analysis, 81 patients received accelerated infliximab therapy and 132 received standard infliximab therapy. There were no differences in characteristics between the groups, including levels of C-reactive protein or albumin. Similar proportions of patients in each group underwent in-hospital colectomy (9% receiving accelerated therapy vs 8% receiving standard therapy; adjusted odds ratio, 1.35; 95% CI, 0.38-4.82). There was no significant difference between groups in proportions that underwent colectomy at 3, 6, 12, or 24 months (P > .20 for all comparisons). Among those in the accelerated group, an initial dose of 10 mg/kg was associated with a lower rate of colectomy compared to patients who initially received 5 mg/kg followed by subsequent doses of 5mg/kg or higher. Our systematic review identified 7 studies (181 patients receiving accelerated infliximab and 436 receiving standard infliximab) and found no significant differences in short- or long-term outcomes. CONCLUSION: In a retrospective study and meta-analysis, we found no association between accelerated infliximab induction therapy and lower rates of colectomy in patients with ASUC, compared to standard induction therapy. However, confounding by disease severity cannot be excluded. Randomized trials are warranted to compare these treatment strategies.

Fatigue in IBD: epidemiology, pathophysiology and management.

Fatigue is an important clinical problem in patients with IBD, affecting nearly 50% of patients in clinical remission and > 80% of those with active disease. The resulting decrease in quality of life and impaired work productivity and functioning contribute markedly to the societal costs of fatigue. However, despite the burden and effects of fatigue, little is known about its aetiology and pathophysiology, which impairs our ability to effectively treat this symptom. Here, we review the theories behind the development of fatigue in IBD and the role of contributing factors, including nutritional deficiency, inflammation and altered metabolism. We also explore the potential role of the gut microbiome in mediating fatigue and other psychological symptoms through the gut-brain axis. We discuss the efficacy of nutrient repletion and various psychological and pharmacological interventions on relieving fatigue in patients with IBD and expand the discussion to non-IBD-related fatigue when evidence exists. Finally, we present a therapeutic strategy for the management of fatigue in IBD and call for further mechanistic and clinical research into this poorly studied symptom.

Differences in Clinical Course, Genetics, and the Microbiome Between Familial and Sporadic Inflammatory Bowel Diseases.

BACKGROUND AND AIM: Family history is the strongest risk factor for developing Crohn's disease [CD] or ulcerative colitis [UC]. We investigated whether the proximity of relationship with the affected relative and concordance for type of inflammatory bowel disease [IBD] modifies the effect of family history on phenotype and disease severity. METHOD: This cross-sectional study included patients with a confirmed diagnosis of IBD in a clinical registry. Family history of IBD was assessed by a questionnaire ascertaining presence of disease in a first-first-degree, second-second-degree or distant relative. Our primary outcomes were disease phenotype as per the Montreal classification and severity measured by need for immunomodulator, biologic, or surgical therapy. Genotyping was performed on the Immunochip and faecal samples were subjected to 16S rRNA microbiome sequencing. RESULTS: Our study included 2136 patients with IBD [1197 CD, 939 UC]. Just under one-third [32%] of cases ere familial IBD [17% first-degree, 21% second-degree]. Familial IBD was diagnosed at an earlier age, both in CD [26 vs 28 years, p = 0.0006] and UC [29 vs 32 years, p = 0.01]. Among CD patients, a positive family history for CD was associated with an increased risk for complicated disease in the presence of an affected family member (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.07-2.03). However, this effect was significant only for first-degree relatives [OR 1.82, 95% CI 1.19-2.78]. CONCLUSIONS: A family history of CD in first-degree relatives was associated with complicated CD. Family history discordant for type of IBD or in distant relatives did not influence disease phenotype or natural history.

Distance to Specialist Care and Disease Outcomes in Inflammatory Bowel Disease.

BACKGROUND: Optimal treatment of inflammatory bowel disease (IBD) requires specialized health care. Patients frequently travel long distances to obtain care for IBD, which may hinder regular care and affect outcomes adversely. METHODS: This study included patients with established Crohn's disease or ulcerative colitis receiving care at a single referral center between January 2005 and August 2016. Distance to our health care center from the zip code of residence was determined for each patient and classified into quartiles. Our primary outcome was need for IBD-related surgery with secondary outcomes being need for biological and immunomodulator therapy. Logistic regression models adjusting for relevant covariates examined the independent association between travel distance and patient outcomes. RESULTS: Our study included 2136 patients with IBD (1197 Crohn's disease, 939 ulcerative colitis), among which just over half were women (52%), and the mean age was 41 years. The mean distance from our hospital was 2.5, 8.8, 22.0, and 50.8 miles for the first (most proximal) through fourth (most distant), respectively. We observed a statistically significant and meaningful higher risk among patients in the most distant quartile in the need for immunomodulator use (OR, 1.69; 95% CI, 1.29-2.22), biological therapy (OR, 2.19; 95% CI, 1.69-2.85), and surgery (OR, 2.44; 95% CI, 1.80-3.32). Differences remained significant on multivariable analysis and by type of IBD. CONCLUSIONS: Greater distance to referral health care center was associated with increased risk for needing IBD-related surgery in patients with Crohn's disease or ulcerative colitis.

The emergence of Clostridium difficile infection in Asia: A systematic review and meta-analysis of incidence and impact.

BACKGROUND: Clostridium difficile infection (CDI) is the most common healthcare associated infection and is highly prevalent in Europe and North America. Limited data is available on the prevalence of CDI in Asia. However, secular increases in prevalence of risk factors for CDI suggest that it may be emerging as a major cause of morbidity, highlighting the urgent need for a systematic study of the prevalence of CDI in Asia. METHODS: We systematically searched PubMed/Medline and Embase for publications from Asia between 2000-16 examining prevalence of CDI. A random-effects meta-analysis was performed to calculate the pooled prevalence of CDI in Asia and to identify subgroups and regions at high risk. RESULTS: Our meta-analysis included 51 studies from throughout Asia including 37,663 patients at risk among whom confirmed CDI was found in 4,343 patients. The pooled proportion of confirmed CDI among all patients with diarrhea was 14.8% with a higher prevalence in East Asia (19.5%), compared with South Asia (10.5%) or the Middle East (11.1%). There were an estimated 5.3 episodes of CDI per 10,000 patient days, similar to rates reported from Europe and North America. Infections due to hypervirulent strains were rare. CDI-related mortality was 8.9%. CONCLUSIONS: In a meta-analysis of 51 studies, we observed similar rates of CDI in Asia in comparison to Europe and North America. Increased awareness and improved surveillance of Clostridium difficile is essential to reduce incidence and morbidity.