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Background Crohn’s disease (CD)-related rectovaginal fistulas (RVFs) and anovaginal fistulas (AVFs) are rare, debilitating conditions that present a substantial disease and treatment burden for women. This systematic literature review (SLR) assessed the burden of Crohn’s-related RVF and AVF, summarizing evidence from observational studies and highlighting knowledge gaps. Methods This SLR identified articles in PubMed and Embase that provide data and insight into the patient experience and disease burden of Crohn’s-related RVF and AVF. Two trained reviewers used pre-specified eligibility criteria to identify studies for inclusion and evaluate risk of bias using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies. Results Of the 582 records identified, 316 full-text articles were assessed, and 16 studies met a priori eligibility criteria and were included. Few epidemiology studies were identified, with one study estimating the prevalence of RVF to be 2.3% in females with Crohn’s disease. Seven of 12 treatment pattern studies reported that patients had or required additional procedures before and/or after the intervention of interest, demonstrating a substantial treatment burden. Seven of 11 studies assessing clinical outcomes reported fistula healing rates between 50 and 75%, with varying estimates based on population and intervention. Conclusions This SLR reports the high disease and treatment burden of Crohn’s-related RVF and AVF and identifies multiple evidence gaps in this field. The literature lacks robust, generalizable data, and demonstrates a compelling need for substantial, novel research into these rare and debilitating sequelae of CD. Registration The PROSPERO registration number for the protocol for this systematic literature review is CRD42020177732.

Background: Proton-pump inhibitors (PPIs) are widely prescribed as acid-suppression therapy. Some observational studies suggest that long-term use of PPIs is potentially associated with certain adverse kidney outcomes. We conducted a systematic literature review to assess potential bias in non-randomized studies reporting on putative associations between PPIs and adverse kidney outcomes (acute kidney injury, acute interstitial nephritis, chronic interstitial nephritis, acute tubular necrosis, chronic kidney disease, and end-stage renal disease). Methods: We searched the medical literature within 10 years of 17 December 2020. Pre-specified criteria guided identification of relevant English language articles for assessment. Risk of bias on an outcome-specific basis was evaluated using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool by two independent reviewers. Results: Of 620 initially identified records, 26 studies met a priori eligibility criteria and underwent risk of bias assessment. Nineteen studies were judged as having a moderate risk of bias for reported adverse kidney outcomes, while six studies were judged as having a serious risk of bias (mainly due to inadequate control of confounders and selection bias). We were unable to determine the overall risk of bias in two studies (one of which was assessed as having a moderate risk of bias for a different adverse kidney outcome) due to insufficient information presented. Effect estimates for PPIs in relation to adverse kidney outcomes varied widely (0.24–7.34) but associations mostly showed increased risk. Conclusion: Using ROBINS-I, we found that non-randomized observational studies suggesting kidney harm by PPIs have moderate to serious risk of bias, making it challenging to establish causality. Additional high-quality, real-world evidence among generalizable populations are needed to better understand the relation between PPI treatment and acute and chronic kidney outcomes, accounting for the effects of varying durations of PPI treatment, self-treatment with over-the-counter PPIs, and potential critical confounders.

Background This study aimed to understand awareness, knowledge, and perception of mesenchymal stem cells (MSCs) among physicians, with particular focus on the complex perianal fistula (CPF) in Crohn’s disease (CD) indication. Methods A cross-sectional, web-based survey of currently practicing and registered gastroenterologists (GIs) and colorectal surgeons (CRs) across 15 countries in North America, Europe and Asia Pacific was undertaken. Descriptive analyses of data on awareness, knowledge, and perception of MSCs, willingness to use them in clinical practice and potential concerns were conducted overall and by medical specialty. Missing responses were allowed, thus denominators differed among questions (N values reported throughout). Multivariable logistic regression was used to examine factors associated with moderate/strong awareness of MSCs. Results Of 146 physicians, 115 (79%) were aware of MSCs (63% strong/moderate; 37% limited awareness), including 101 GIs (88%) and 14 CRs (12%). Of these, 21 physicians (19%, N=112) had treated ≥1 patient with MSCs. Among the aware physicians, the majority were moderately/largely interested in MSCs (87%, N=113), were willing to use them for patients with CD and CPF (82%, N=108) and believed MSCs address an unmet need for these patients (93%, N=101). However, there was a marked heterogeneity as to the assumed definition and mechanism of action (MoA) of MSCs (Figure 1). By specialty group, more CRs (50%) than GIs (31%) defined correctly MSCs as an immunomodulatory therapy. The majority of the physicians aware of MSCs stated that they have limited/no knowledge of this therapy (64%), its efficacy (51%), safety (53%) and MoA (65%) in patients with CPF in CD (N=105 for all questions). Many physicians (46%; N=107) also expressed concerns about using MSCs in these patients. In physicians with concerns, long-term efficacy, long-term safety, and cost were the most frequently reported concerns, both overall (Figure 2) and by each specialty group (data not shown). The multivariable logistic regression showed that attendance at discussions or presentations on MSCs in the past 2 years (p Conclusion In this study, the majority of physicians demonstrated interest and willingness to use MSCs in clinical practice. However, the survey showed a perceived lack of knowledge of what MSCs are and how they work in patients with CPF in CD. This may explain physicians’ concerns about using MSCs in this indication. Increased communication and education regarding MSCs are required to alleviate physicians’ concerns and increase the uptake of this therapy in routine practice. Sponsor: Takeda Pharmaceuticals USA, Inc.

Background Studies suggest that complex cryptoglandular fistulas (CCF) are difficult to treat, resulting in higher intervention failure rates and functional disability. This systematic literature review (SLR) assessed the epidemiology of cryptoglandular fistula and outcomes associated with local, surgical and intersphincteric ligation procedures for treatment of CCF. Methods PubMed and Embase were searched to identify articles published in the past 5 years (2015–2020) relating to incidence or prevalence of cryptoglandular fistula and outcomes of surgical interventions for CCF (PROSPERO registration number CRD42020177732). Outcomes of interest included fistula closure/healing, recurrence, surgery failure, post-operative pain and faecal incontinence. The interventions included anal flap procedures, fistulectomy, fistulotomy, primary sphincteroplasty, modified Park’s technique, LIFT or BIOLIFT, and TROPIS. Two trained reviewers used pre-specified eligibility criteria to identify studies for inclusion and evaluate risk of bias using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies. Data were extracted for a range of variables, including study type and design, population, outcomes and limitations. Results In total, 148 studies were identified that met a priori eligibility criteria for all cryptoglandular fistulas and all intervention types. Of these, two reported incidence or prevalence of cryptoglandular fistulas and 18 reported outcomes for the interventions of interest in CCF. Prevalence of cryptoglandular fistulas was reported as 1.35 per 10 000 patients without Crohn’s disease, and 52.6% of patients without IBD were found to progress from anorectal abscess to fistula over 12 months. Studies examining the clinical outcomes reported primary healing rates of 57.4–100.0%, recurrence rates of 4.9–61.0% and failure rates of 2.8–18.0% of patients. Only five studies reported post-operative pain as a clinical outcome. Overall, these studies suggest patients experience no or minimal longer-term post-operative pain. In studies reporting post-operative faecal incontinence following anal mucosal flap procedures, observed incontinence rates were low, as measured using Wexner or Miller scoring. None of the studies involving fistulectomy measured faecal incontinence. Conclusion This SLR provides a summary of outcomes from a selected group of surgical interventions for CCF. Healing rates vary according to surgery type; however, differences in study design and heterogenous definitions prevent direct comparison. Overall, the published literature indicates low to modest rates of CCF recurrence and limited data on faecal incontinence and longer-term post-operative pain. Sponsor: Takeda Pharmaceuticals USA, Inc.

Background Rectovaginal fistulas (RVF) and anovaginal fistulas (AVF) in Crohn’s disease (CD) are rare, debilitating conditions that present substantial disease and treatment burdens for women. In this systematic literature review (SLR), articles relating to the epidemiology and burden of CD-related RVF and AVF were assessed in order to summarize evidence from observational studies and highlight knowledge gaps. Methods Articles published in the past 10 years in PubMed and Embase that provide data on incidence, prevalence and insight into the patient experience and disease burden of CD-related RVF and AVF (PROSPERO registration number CRD42020177732) were identified. Two trained reviewers used pre-specified eligibility criteria to identify studies for inclusion and evaluate risk of bias using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies. Data were extracted for a range of variables, including study type and design, population, outcomes and limitations. Results Of the 582 records identified, 316 full-text articles were assessed, and 16 studies that met a priori eligibility criteria were included (Figure). Three epidemiology studies were identified, with one study estimating the prevalence of RVF to be 2.3% in women with CD. No studies relating to the incidence or prevalence of AVF were identified. Seven of 12 treatment-pattern studies reported that patients had or required additional procedures before and/or after the intervention of interest, demonstrating substantial treatment burden. Of the nine studies that reported healing/success across multiple surgical types, rates ranged from 14.4% to 81.0%. In the seven studies that assessed clinical outcomes, healing rates were in the range 50–75%, with varying estimates dependent on population and intervention. Two studies reported recurrence rates of 13.3–55.8% across multiple surgical interventions. Patient-reported outcomes obtained using standardized measures were reported in only one of the 16 studies and were limited to overall health related quality of life, faecal incontinence-related quality of life and female sexual function index. None of the 16 studies included reported healthcare-resource utilization in this patient population. Conclusion This SLR shows the high disease and treatment burdens of RVF and AVF in patients with CD and identifies multiple evidence gaps in this field. The published literature lacks robust, generalizable data and demonstrates a compelling need for substantial novel research into these rare and debilitating sequelae of CD. Sponsor: Takeda Pharmaceuticals USA, Inc.

ObjectiveTo generate real-world evidence for the epidemiology of gastroparesis in the UK, we evaluated the prevalence, incidence, patient characteristics and outcomes of gastroparesis in the Clinical Practice Research Datalink (CPRD) database.DesignThis was a retrospective, cross-sectional study. Prevalence and incidence of gastroparesis were evaluated in the CPRD database, with linkage to Hospital Episodes Statistics Admitted Patient Care and Office for National Statistics mortality data. Prevalence and incidence were age and sex standardised to mid-2017 UK population estimates. Descriptive analyses of demographics, aetiologies, pharmacological therapies and mortality were conducted.ResultsStandardised prevalence of gastroparesis, as documented in general practice records, was 13.8 (95% CI 12.6 to 15.1) per 100 000 persons in 2016, and standardised incidence of gastroparesis rose from 1.5 (95% CI 1.1 to 1.8) per 100 000 person-years in 2004 to 1.9 (95% CI 1.4 to 2.3) per 100 000 person-years in 2016. The most common disease aetiologies were idiopathic (39.4%) and diabetic gastroparesis (37.5%), with a similar distribution of type 1 and type 2 diabetes among the 90% who had type of diabetes documented. Patients with diabetic gastroparesis had a significantly higher risk of mortality than those with idiopathic gastroparesis after diagnosis (adjusted HR 1.9, 95% CI 1.2 to 3.0). Of those with gastroparesis, 31.6% were not offered any recognised pharmacological therapy after diagnosis.ConclusionThis is, to our knowledge, the first population-based study providing data on epidemiology and outcomes of gastroparesis in Europe. Further research is required to fully understand the factors influencing outcomes and survival of patients with gastroparesis.

Background & Aims While gastroparesis carries a considerable healthcare and patient burden, associated epidemiological data are limited. To provide new real-world evidence for gastroparesis, we estimated disease prevalence, and investigated patient demographics and disease etiology in a large US claims database. Methods This retrospective, cross-sectional analysis used de-identified, longitudinal patient-level enrollment and billing data for adults from the Optum® Clinformatics® Data Mart database, a large US national administrative health insurance claims database. Prevalence was age-, sex-, and geographical region-standardized using the 2018 US census. Descriptive analyses of demographic and clinical variables and underlying disease etiologies were performed. Results The overall standardized prevalence of gastroparesis was 267.7 (95% confidence interval [CI] 264.8–270.7) per 100 000 persons in US adults, while prevalence of ‘definite’ gastroparesis (individuals diagnosed within three months of gastric emptying scintigraphy testing with persistent symptoms for over three months) was 21.5 (95% CI 20.6–22.4) per 100 000 persons. Patients with gastroparesis had an overall Charlson Comorbidity Index score of 4.2, indicating substantial comorbidity burden. The most frequently documented comorbidities were chronic pulmonary disease (46.4%), diabetes with chronic complication (37.3%), and peripheral vascular disease (30.4%). Patients most commonly had a diabetic etiology (57.4%; type 1, 5.7% and type 2, 51.7%), followed by post-surgical (15.0%), drug-induced (11.8%), and idiopathic (11.3%) etiologies. Conclusions New evidence is provided regarding the prevalence, patient demographics, and etiology of gastroparesis in the US general population. Wider availability of reliable objective gastric emptying measures and further education of medical professionals in recognizing and diagnosing gastroparesis would benefit future studies and improve understanding of disease epidemiology.

Background and aim Postoperative infection (POI) is a major source of morbidity and prolongation of hospitalization in inflammatory bowel disease (IBD) patients. This large observational study was conducted to further describe risk factors and to quantify the proportion of POIs that are preventable. Methods We conducted a retrospective cohort analysis of the Optum US health insurance claims database. The study population included adults with ulcerative colitis (UC) or Crohn's disease (CD) who underwent lower gastrointestinal (GI) surgery of small intestine, colon, rectum, or anus during September 2014 to September 2016. Multiple logistic regression was used to identify and quantify risk factors and determine the proportion of infections that are preventable. Results A total of 3360 adult IBD patients with lower GI surgery were included in the study. Their mean age was 51 years, 52.5% were women, and 59.5% had CD. The 30-day POI incidence was 15.1% (95% confidence interval: 14.0-16.4%). We identified the following nonmodifiable or procedural risk factors: history of POI, open procedure, red blood cell transfusion within 6 months, preoperative hospital stay of at least 4 days, lower GI ostomy surgery, lower GI resection surgery, and a history of chronic obstructive pulmonary disease. Modifiable risk factors included corticosteroid use and anemia prior to surgery, but few infections were attributable to these modifiable factors. Conclusions This large, observational, real-world evidence study from the US found that the majority of the observed risk factors were nonmodifiable or procedure-related. Corticosteroid use and anemia before surgery were identified as modifiable risk factors.

Background Vedolizumab (VDZ) has demonstrated remission in ulcerative colitis (UC) and Crohn’s disease (CD), but its impact on patient (pt) fatigue is not well understood. Herein we report interim fatigue analysis data from a Belgian registry of VDZ-treated pts. Methods Ad-hoc analysis from the prospective observational Belgian VDZ registry (started, November 2016; data cutoff, February 2019), a sub-study of the European VDZ post-authorization safety study (ENcePP EUPAS6469) included pts aged ≥18 years with UC or CD with ongoing VDZ intravenous therapy (≥2 weeks) at recruitment. At baseline (recruitment) and every 6 months, physicians collected data (follow-up was 3 years or 1 year after last dose if VDZ was discontinued [whichever occurred first] and pts completed the 13-Item Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale. Clinical remission was defined as Harvey-Bradshaw Index (HBI) score 1 for UC. This analysis explored the association (using generalized estimating equations) between all available FACIT-F total scores and baseline demographic, clinical, and treatment characteristics in the treatment analysis set (TAS; pts had ≥1 VDZ dose and ≥1 year of follow-up records). Results The registry enrolled 202 VDZ-treated UC and CD pts from 19 Belgian centres. TAS included 141 pts (UC 47, CD 94); median follow-up was 537 days; 140/141 pts had ≥1 FACIT-F score. In the UC and CD groups, respectively, 68% and 42% of pts were male; median (IQR) age at index date was 51 (37–59) and 40 (29–52); and baseline median (IQR) FACIT-F total score was 39 (32–46) and 32 (24–40). Lower FACIT-F score (more fatigue) was associated with higher pMS in UC (p Conclusion These real-world data from a long-term registry study of VDZ-treated pts in Belgium demonstrate that higher pMS and HBI score, active fistulae, and EIM occurrence at baseline may be associated with more fatigue in IBD pts. Pts treated with VDZ had no significant change in FACIT-F total score over 24 months.

Background The latest estimate of the prevalence of inflammatory bowel disease (IBD) in the United States was based on 2009 data, which indicates a need for an up-to-date re-estimation. The objectives of this study were to investigate the prevalence of all forms of IBD including ulcerative colitis (UC), Crohn’s disease (CD), and IBD unspecified (IBDU). Methods Pediatric (age 2–17) and adult (age ≥18) IBD patients were identified from 2 large claims databases. For each year between 2007 and 2016, prevalence was calculated per 100,000 population and standardized based on the 2016 national Census. A fixed-effects meta-analytical model was used for overall prevalence. Results The pediatric prevalence of IBD overall increased by 133%, from 33.0/100,000 in 2007 to 77.0/100,000 in 2016. Among children, CD was twice as prevalent as UC (45.9 vs 21.6). Prevalence was higher in boys than girls for all forms of IBD, in contrast to the adult population where the prevalence was higher in women than men. We also found that the 10–17 age subgroup was the major contributor to the rising pediatric IBD prevalence. For adults, the prevalence of IBD overall increased by 123%, from 214.9 in 2007 to 478.4 in 2016. The prevalence rates of UC and CD were similar (181.1 vs 197.7) in 2016. Conclusions Inflammatory bowel disease continues to affect a substantial proportion of the US population. In 2016, 1 in 209 adults and 1 in 1299 children aged 2–17 were affected by IBD. Prevalence of IBD has been increasing compared with previously published 2009 data.

Three cases of ileus have been published among dipeptidyl peptidase-4 (DPP-4) inhibitor users in Japan. The purpose of this study was to estimate and compare incidence rates of ileus among alogliptin users and users of other DPP-4 inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and voglibose.We used the Medical Data Vision database in Japan to conduct a retrospective cohort study among type 2 diabetes mellitus (T2DM) patients who were new users of alogliptin, other DPP-4 inhibitors, GLP-1 receptor agonists, or voglibose between 1 April 2010 and 30 April 2014. The primary outcome was an incident diagnosis of ileus. Kaplan-Meier survival curves were used to estimate ileus events over time. Adjusted Poisson regression models were used to estimate incidence rate ratios (IRR) for ileus and 95 % confidence intervals (CI) by comparing alogliptin users to users of the other study drugs.We identified 82,386 patients with T2DM. In the adjusted model, there was no difference in risk of ileus among patients exposed to alogliptin compared with patients exposed to other DPP-4 inhibitors (IRR 1.15, 95 % CI 0.75-1.75) or GLP-1 receptor agonists (IRR 0.42, 95 % CI 0.14-1.20). The risk of ileus was significantly lower among patients exposed to alogliptin compared with patients exposed to voglibose (IRR 0.55, 95 % CI 0.35-0.88).The independent risk of ileus among new users of alogliptin did not significantly differ compared with new users of other DPP-4 inhibitors or GLP-1 receptor agonists but was significantly lower than new users of voglibose.

Goals: We aimed to establish the epidemiological characteristics and documentation of diagnostic workup for gastroparesis (GP). Background: No study has used a national database to evaluate the prevalence, demographics, and associated comorbid conditions of GP, and document rates of proper diagnosis. Materials and Methods: This was a cross-sectional population-based study using the Explorys Platform to determine the prevalence of GP in a large and diverse population highly representative of the US population and to examine the diagnostic approach of GP. Data collected were individual characteristics from electronic medical records (EMRs) included age, ethnicity/race, sex, diagnostic report for esophagogastroduodenoscopy (EGD) and gastric emptying study (GES). Results: A total of 43,827,910 medical records were surveyed (1999 to 2014), of which 69,950 had a diagnosis of GP, yielding an overall prevalence of 0.16%. We identified 249,930 EMRs with type 1 diabetes mellitus (T1DM), and 2,940,280 EMR’s with type 2 diabetes mellitus (T2DM), of which 11,470 (4.59%) and 38,670 (1.31%) EMR’s had concurrent GP, respectively. The remainder 19,810 EMRs with a diagnosis of GP were classified as having idiopathic GP. In all three subgroups, women and Caucasians had the highest prevalence of GP. The diagnosis of GP was confirmed by both GES and EGD in 9,950 of patients (14.22%). For patients with T1DM, T2DM, or idiopathic GP, GP was confirmed by both diagnostic tests in 16.8%, 14.0%, and 13.2%, respectively. Conclusions: Our estimated rates of prevalence of GP in T1DM and T2DM indicate that GP is not a common clinical complication in these populations. Majority of EMRs that indicated a diagnosis of GP did not include any documentation of definitive diagnostic testing (EGD and/or GES).

Portal vein thrombosis is a known risk among patients with cirrhosis, but the incidence of other thromboembolic events among patients with liver disease is inadequately delineated. This study examined the incidence of venous and arterial thromboembolic events in patients with cirrhosis and hepatitis C virus (HCV) infection and matched comparators. Patients diagnosed with HCV or cirrhosis of various etiologies were identified from a large medical claims database and matched by age and sex to comparator cohorts. New-onset diagnoses of venous and arterial thromboembolic events were determined. The incidence rate of each event was calculated and rate ratios computed using Poisson regression models, adjusting for baseline factors. The study included 22,733 HCV-infected patients and 68,198 comparators, and 15,158 cirrhosis patients and 45,473 comparators. The incidence of any thromboembolic event was 233.4 events per 10,000 person-years for the HCV cohort and 138.5 per 10,000 person-years for the comparators; the adjusted incidence rate ratio for any thromboembolic event was 1.62 (95% confidence interval [CI]: 1.48–1.77). For the cirrhosis patients and comparators, the crude rates of any thromboembolic event were 561.1 and 249.7 per 10,000 person-years, respectively. The adjusted incidence rate ratio was 2.28 (95% CI: 2.11–2.47). Arterial events, especially unstable angina and transient ischemic attack, were the most frequent events seen in both the HCV and cirrhosis cohorts, but venous events, especially portal vein thrombosis, showed a more pronounced elevation in patients with liver disease. Patients with HCV and cirrhosis of various etiologies are at increased risk of several types of thromboembolic events. Physicians should consider this increased risk when managing patients with liver disease.

Therapies for immune thrombocytopenia (ITP) may be associated with abnormal hepatobiliary laboratory (HBL) values, but the epidemiology of these abnormalities is unknown in the ITP population. The study aim was to provide prevalence and incidence rates, as well as risk factors for abnormal HBL values among a cohort of patients with chronic or persistent primary ITP. Health insurance claims data from 3,244 patients with chronic or persistent ITP was examined to estimate the prevalence of abnormal HBL values: elevated levels of Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), total bilirubin, and Alkaline Phosphatase (ALP). Incidence of abnormal HBL values was estimated in a sub cohort of 2557 (79%) patients without evidence of comorbidities related to secondary thrombocytopenia, liver disease, or abnormal HBL values during the 12-month baseline period. The baseline prevalence of ALT and AST > 3x the upper limit of normal (ULN) was 4.6 and 3.7%, respectively. The baseline prevalence of total bilirubin and ALP >1.5x ULN was 4.2 and 3.2%, respectively. The incidence rate of new HBL abnormalities (HBLA) was 1.24/1,000 person- years (95% CI: 0.52-2.56) for ALT>3x ULN and 0.41/1,000 person-years (95% CI: 0.08-1.32) for AST>3x ULN. HBLAs were significantly associated with male gender, liver disease, diabetes, congestive heart failure, lupus, hematological cancers, and HIV infection. In conclusion, the prevalence of HBLA, specifically ALT>3x ULN, among the ITP population is relatively high compared with atrial fibrillation, though within the confidence interval for that estimate. HBLAs were significantly associated with male gender, liver disease, and several other comorbidities, thus, distinguishing drug-induced liver injury in this population is clinically challenging.

Fibrosis has been reported in some patients with immune thrombocytopenia (ITP) treated with thrombopoietin receptor agonists (TPO-RA). However, fibrosis has also been reported in patients with various stages of ITP, who were TPO-RA treatment-naive. In our study, we looked for fibrosis in bone marrow trephine biopsies taken at initial diagnosis from 32 adult patients with ITP. Ten of the 32 evaluated samples (31·25%) showed increased reticulin (Grade 1-2 on Bauermeister scale and Grade 0-1 on the European Consensus scale), which showed a positive correlation with ethnicity (0·3%) but did not correlate with disease severity, any clinical features or co-morbidities.