Comprehensive genetic study of the insulin resistance marker TG:HDL-C in the UK Biobank.

Insulin resistance (IR) is a well-established risk factor for metabolic disease. The ratio of triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) is a surrogate marker of IR. We conducted a genome-wide association study of the TG:HDL-C ratio in 402,398 Europeans within the UK Biobank. We identified 369 independent SNPs, of which 114 had a false discovery rate-adjusted P value < 0.05 in other genome-wide studies of IR making them high-confidence IR-associated loci. Seventy-two of these 114 loci have not been previously associated with IR. These 114 loci cluster into five groups upon phenome-wide analysis and are enriched for candidate genes important in insulin signaling, adipocyte physiology and protein metabolism. We created a polygenic-risk score from the high-confidence IR-associated loci using 51,550 European individuals in the Michigan Genomics Initiative. We identified associations with diabetes, hyperglyceridemia, hypertension, nonalcoholic fatty liver disease and ischemic heart disease. Collectively, this study provides insight into the genes, pathways, tissues and subtypes critical in IR.

Genetic Defects in Early-Onset Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) represents a spectrum of disease, which is characterized by chronic gastrointestinal inflammation. Monogenic mutations driving IBD pathogenesis are more highly represented in early-onset compared to adult-onset disease. The pathogenic genes which dysregulate host immune responses in monogenic IBD affect both the innate (ie, intestinal barrier, phagocytes) and adaptive immune systems (ie, T cells, B cells). Advanced genomic and targeted functional testing can improve clinical decision making and present increased opportunities for precision medicine approaches in this important patient population.

An Assessment of Comparative Medication Durability in Inflammatory Bowel Disease Patients With and Without Co-morbid Psoriasis, Rheumatoid Arthritis, and/or Enteropathic Arthritis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk for many co-morbid diseases. However, little is known about durability of IBD medications in patients with co-morbid diseases. AIMS: Determine medication durability in IBD patients with and without psoriasis, rheumatoid arthritis, and/or enteropathic arthropathy. METHODS: All patients with at least three ICD-9 or 10 diagnoses for IBD were included in the cohort. The risk factors of interest were a co-morbid diagnosis of psoriasis (IBD-Ps), rheumatoid arthritis (IBD-RA), and/or enteropathic arthritis (IBD-EA). Medication durability was defined as days of medication use, calculated using order start and stop dates from the electronic medical record. Significant differences were tested using the Wilcoxon rank sum test for continuous variables and Fisher's exact test or Pearson's Chi-squared test, as appropriate, for categorical variables. Boxplots were constructed for graphical interpretation of results. RESULTS: In the psoriasis group, there were 481 patients with 831 medication exposures [131 IBS-Ps (16%), 700 IBD only (84%)]. The median days of medication use were numerically higher in the IBD-Ps group for all therapies [anti-TNF: 1109 vs 861 (p = 0.17); anti-IL-12/23: 984 vs 834 (p = 0.33); JAKi: 682 vs 230 (p = 0.13)], anti-TNF/IM: 370 vs 202 (p = 0.57), except anti-integrin therapy [214 vs 470 (p = 0.08)]. When restricting to UC only, patients with co-morbid again Ps had a significantly shorter duration on anti-integrin therapy (84 vs 456 days, p = 0.02). While not reaching statistical significance, there was a distinctly longer medication duration on JAKi therapy (910 vs 317, p = 0.10). When restricting to patients with CD only, no results reached statistical significance though there was a trend towards longer anti-TNF durability in CD-Ps (1340 vs 1000 days, p = 0.098). There were no differences in medication durability in IBD-RA or IBD-EA patients. DISCUSSION: Larger studies investigating medication durability of JAKi and anti-integrin therapy in IBD patients with psoriasis would be beneficial given noteworthy trends towards increased and decreased durability, respectively.

PNPLA3 Genotype and Diabetes Identify Patients With Nonalcoholic Fatty Liver Disease at High Risk of Incident Cirrhosis.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) can progress to cirrhosis and hepatic decompensation, but whether genetic variants influence the rate of progression to cirrhosis or are useful in risk stratification among patients with NAFLD is uncertain. METHODS: We included participants from 2 independent cohorts, they Michigan Genomics Initiative (MGI) and UK Biobank (UKBB), who had NAFLD defined by elevated alanine aminotransferase (ALT) levels in the absence of alternative chronic liver disease. The primary predictors were genetic variants and metabolic comorbidities associated with cirrhosis. We conducted time-to-event analyses using Fine-Gray competing risk models. RESULTS: We included 7893 and 46,880 participants from MGI and UKBB, respectively. In univariable analysis, PNPLA3-rs738409-GG genotype, diabetes, obesity, and ALT of ≥2× upper limit of normal were associated with higher incidence rate of cirrhosis in both MGI and UKBB. PNPLA3-rs738409-GG had additive effects with clinical risk factors including diabetes, obesity, and ALT elevations. Among patients with indeterminate fibrosis-4 (FIB4) scores (1.3-2.67), those with diabetes and PNPLA3-rs738409-GG genotype had an incidence rate of cirrhosis comparable to that of patients with high-risk FIB4 scores (>2.67) and 2.9-4.8 times that of patients with diabetes but CC/CG genotypes. In contrast, FIB4 <1.3 was associated with an incidence rate of cirrhosis significantly lower than that of FIB4 of >2.67, even in the presence of clinical risk factors and high-risk PNPLA3 genotype. CONCLUSIONS: PNPLA3-rs738409 genotype and diabetes identified patients with NAFLD currently considered indeterminate risk (FIB4 1.3-2.67) who had a similar risk of cirrhosis as those considered high-risk (FIB4 >2.67). PNPLA3 genotyping may improve prognostication and allow for prioritization of intensive intervention.

Risk Variants in or Near ZBTB40 AND NFATC1 Increase the Risk of Both IBD and Adverse Bone Health Outcomes Highlighting Common Genetic Underpinnings Across Both Diseases.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with an increased risk of osteoporosis and bone fracture. The aims of this study were to (1) confirm the association between IBD and low bone density and (2) test for shared risk variants across diseases. METHODS: The study cohort included patients from the Michigan Genomics Initiative. Student's t tests (continuous) and chi-square tests (categorical) were used for univariate analyses. Multivariable logistic regression was performed to test the effect of IBD on osteoporosis or osteopenia. Publicly available genome-wide association summary statistics were used to identify variants that alter the risk of IBD and bone density, and Mendelian randomization (MR) was used to identify causal effects of genetically predicted IBD on bone density. RESULTS: There were 51 405 individuals in the Michigan Genomics Initiative cohort including 10 378 (20.2%) cases of osteoporosis or osteopenia and 1404 (2.7%) cases of IBD. Patients with osteoporosis or osteopenia were more likely to be older (64 years of age vs 56 years of age; P < .001), female (67% vs 49%; P < .001), and have a lower body mass index (29 kg/m2 vs 30 kg/m2; P < .001). IBD patients with (odds ratio, 4.60; 95% confidence interval, 3.93-5.37) and without (odds ratio, 1.77; 95% confidence interval, 1.42-2.21) steroid use had a significantly higher risk of osteoporosis or osteopenia. Twenty-one IBD variants associated with reduced bone mineral density at P ≤ .05 and 3 IBD risk variants associated with reduced bone mineral density at P ≤ 5 × 10-8. Of the 3 genome-wide significant variants, 2 increased risk of IBD (rs12568930-T: MIR4418;ZBTB40; rs7236492-C: NFATC1). MR did not reveal a causal effect of genetically predicted IBD on bone density (MR Egger, P = .30; inverse variance weighted, P = .63). CONCLUSIONS: Patients with IBD are at increased risk for low bone density, independent of steroid use. Variants in or near ZBTB40 and NFATC1 are associated with an increased risk of IBD and low bone density.

Patients with inflammatory bowel disease (IBD) are at an increased risk of osteopenia, osteoporosis, and bone fracture. Herein, we identify risk variants in or near ZBTB40 and NFATC1 which associate with risk of both IBD and low bone density. Therefore, a subset of patients with IBD may be at risk for osteopenia and osteoporosis regardless of steroid use.

Hepatic decompensation is accelerated in patients with cirrhosis and alpha-1 antitrypsin Pi∗MZ genotype.

Background & Aims: Alpha-1 antitrypsin deficiency is caused by mutations in SERPINA1, most commonly homozygosity for the Pi∗Z variant, and can present as liver disease. While heterozygosity for Pi∗Z (Pi∗MZ) is linked to increased risk of cirrhosis, whether the Pi∗MZ genotype is associated with an increased rate of decompensation among patients who already have compensated cirrhosis is not known. Methods: This was a retrospective study of Michigan Genomics Initiative participants with baseline compensated cirrhosis. The primary predictors were Pi∗MZ or Pi∗MS genotype (vs. Pi∗MM). The primary outcomes were hepatic decompensation with ascites, hepatic encephalopathy, or variceal bleeding, or the combined endpoint of liver-related death or liver transplant, both modeled with Fine-Gray competing risk models. Results: We included 576 patients with baseline compensated cirrhosis who had undergone genotyping, of whom 474 had Pi∗MM, 49 had Pi∗MZ, and 52 had Pi∗MS genotypes. Compared to Pi∗MM genotype, Pi∗MZ was associated with increased rates of hepatic decompensation (hazard ratio 1.81; 95% CI 1.22-2.69; p = 0.003) and liver transplant or liver-related death (hazard ratio 2.07; 95% CI 1.21-3.52; p = 0.078). These associations remained significant after adjustment for severity of underlying liver disease, and were robust across subgroup analyses based on etiology, sex, obesity, and diabetes status. Pi∗MS was not associated with decompensation or death/transplantation. Conclusions: The SERPINA1 Pi∗MZ genotype is associated with an increased rate of hepatic decompensation and decreased transplant-free survival among patients with baseline compensated cirrhosis. Lay summary: There is a mutation in the gene SERPINA1 called Pi∗MZ which increases risk of liver scarring (cirrhosis); however, it is not known what effect Pi∗MZ has if someone already has cirrhosis. In this study, we found that people who had cirrhosis and Pi∗MZ developed complications from cirrhosis faster than those who did not have the mutation.

Inflammatory Bowel Disease Risk Variants Are Associated with an Increased Risk of Skin Cancer.

BACKGROUND: Inflammatory bowel disease is associated with an increased risk of skin cancer. The aims of this study were to determine whether IBD susceptibility variants are also associated with skin cancer susceptibility and if such risk is augmented by use of immune-suppressive therapy. METHODS: The discovery cohort included participants in the UK Biobank. The validation cohort included participants in the Michigan Genomics Initiative. The primary outcome of interest was skin cancer, subgrouped into nonmelanoma skin cancers (NMSC) and melanoma skin cancers (MSC). Multivariable logistic regression with matched controls (3 controls:1 case) was performed to identify genomic predictors of skin malignancy in the discovery cohort. Variants with P < .05 were tested for replication in the validation cohort. Validated Single nucleotide polymorphisms were then evaluated for effect modification by immune-suppressive medications. RESULTS: The discovery cohort included 10,247 cases of NMSC and 1883 cases of MSC. The validation cohort included 7334 cases of NMSC and 3304 cases of MSC. Twenty-nine variants were associated with risk of NMSC in the discovery cohort, of which 5 replicated in the validation cohort (increased risk, rs7773324-A [DUSP22; IRF4], rs2476601-G [PTPN22], rs1847472-C [BACH2], rs72810983-A [CPEB4]; decreased risk, rs6088765-G [PROCR; MMP24]). Twelve variants were associated with risk of MSC in the discovery cohort, of which 4 were replicated in the validation cohort (increased risk, rs61839660-T [IL2RA]; decreased risk, rs17391694-C [GIPC2; MGC27382], rs6088765-G [PROCR; MMP24], and rs1728785-C [ZFP90]). No effect modification was observed. CONCLUSIONS: The results of this study highlight shared genetic susceptibility across IBD and skin cancer, with increased risk of NMSC in those who carry risk variants in IRF4, PTPN22, CPEB4, and BACH2 and increased risk of MSC in those who carry a risk variant in IL2RA.

Efficacy of Ustekinumab in Crohn's Disease With and Without Concurrent Autoimmune Skin Disease.

BACKGROUND: Approximately 33% of Crohn's disease (CD) patients have associated autoimmune skin disease. The pathophysiology of the latter frequently involves interleukin-12/interleukin-23 signaling pathways that may also impact gut inflammation. Ustekinumab is an anti-IL-12/23 FDA-approved biologic for psoriasis and inflammatory bowel disease. However, its relative efficacy has never been studied in CD with autoimmune skin disease (CD-ASD) vs CD without autoimmune skin disease (CD-none). METHODS: This is a retrospective, single-center, case-control study comparing markers of disease activity between CD-ASD and CD-none. Biomarkers (fecal calprotectin [FCP], C-reactive protein [CRP]) prior to drug initiation and after at least 5 months of standard IBD dose ustekinumab therapy were extracted from the medical record. In addition, 2 blinded observers performed 5-point Likert scoring before and after endoscopic, pathologic, and imaging reports. RESULTS: In all, 395 CD patients received ustekinumab therapy (79 CD-ASD, 316 CD-none). Patients were similar in age; gender; ethnicity; CD severity, phenotype, and duration; tobacco, immunomodulator, and steroid use. Ustekinumab had greater efficacy in CD-ASD when evaluated by FCP (P = .0337) and CRP (P = .078). The CD-ASD group also showed better outcomes in Likert scores of endoscopy (P = .016), histopathology (P = .074), and imaging (P = .094). In all Likert parameters, CD-ASD had more patients with complete resolution of moderate/severe disease (P < .05). Additional subanalyses for surgeries, ulcers, abscesses, fistulas, and colitis were conducted, with colitis reaching statistical significance (P = .0011). CONCLUSIONS: Concurrent autoimmune skin disease in CD is associated with greater ustekinumab effectiveness in controlling intestinal inflammation.

Corrigendum to: Assessment of Benefit of Advanced Inflammatory Bowel Disease Training: Challenges and Solutions.

[This corrects the article DOI: 10.1093/crocol/otaa019.].

Tofacitinib for Biologic-Experienced Hospitalized Patients With Acute Severe Ulcerative Colitis: A Retrospective Case-Control Study.

BACKGROUND & AIMS: Despite rescue therapy, more than 30% of patients with acute severe ulcerative colitis (ASUC) require colectomy. Tofacitinib is a rapidly acting Janus kinase inhibitor with proven efficacy in ulcerative colitis. Tofacitinib may provide additional means for preventing colectomy in patients with ASUC. METHODS: A retrospective case-control study was performed evaluating the efficacy of tofacitinib induction in biologic-experienced patients admitted with ASUC requiring intravenous corticosteroids. Tofacitinib patients were matched 1:3 to controls according to gender and date of admission. Using Cox regression adjusted for disease severity, we estimated the 90-day risk of colectomy. Rates of complications and steroid dependence were examined as secondary outcomes. RESULTS: Forty patients who received tofacitinib were matched 1:3 to controls (n = 113). Tofacitinib was protective against colectomy at 90 days compared with matched controls (hazard ratio [HR], 0.28, 95% confidence interval [CI], 0.10-0.81; P = .018). When stratifying according to treatment dose, 10 mg three times daily (HR, 0.11; 95% CI, 0.02-0.56; P = .008) was protective, whereas 10 mg twice daily was not significantly protective (HR, 0.66; 95% CI, 0.21-2.09; P = .5). Rate of complications and steroid dependence were similar between tofacitinib and controls. CONCLUSIONS: Tofacitinib with concomitant intravenous corticosteroids may be an effective induction strategy in biologic-experienced patients hospitalized with ASUC. Prospective trials are needed to identify the safety, optimal dose, frequency, and duration of tofacitinib for ASUC.

Management of Crohn Disease: A Review.

IMPORTANCE: Crohn disease, a chronic gastrointestinal inflammatory disease, is increasing in incidence and prevalence in many parts of the world. Uncontrolled inflammation leads to long-term complications, including fibrotic strictures, enteric fistulae, and intestinal neoplasia. Therefore, early and effective control of inflammation is of critical importance. OBSERVATIONS: The optimal management approach for Crohn disease incorporates patient risk stratification, patient preference, and clinical factors in therapeutic decision-making. First-line therapy generally consists of steroids for rapid palliation of symptoms during initiation of anti-tumor necrosis factor α therapy. Other treatments may include monoclonal antibodies to IL-12/23 or integrin α4ß7, immunomodulators, combination therapies, or surgery. Effective control of inflammation reduces the risk of penetrating complications (such as intra-abdominal abscesses and fistulae), although more than half of patients will develop complications that require surgery. Adverse reactions to therapy include antibody formation and infusion reactions, infections, and cancers associated with immune modulators and biologics and toxicity to the bone marrow and the liver. Both Crohn disease and corticosteroid use are associated with osteoporosis. Vaccinations to prevent infections, such as influenza, pneumonia, and herpes zoster, are important components of health maintenance for patients with Crohn disease, although live vaccines are contraindicated for patients receiving immune suppression therapy. CONCLUSIONS AND RELEVANCE: The treatment of patients with Crohn disease depends on disease severity, patient risk stratification, patient preference, and clinical factors, including age of onset and penetrating complications, and includes treatment with steroids, monoclonal antibody therapies, immunomodulators, and surgery. Physicians should be familiar with the advantages and disadvantages of each therapy to best counsel their patients.

AXL Is a Potential Target for the Treatment of Intestinal Fibrosis.

BACKGROUND: Fibrosis is the final common pathway to intestinal failure in Crohn's disease, but no medical therapies exist to treat intestinal fibrosis. Activated myofibroblasts are key effector cells of fibrosis in multiple organ systems, including the intestine. AXL is a receptor tyrosine kinase that has been implicated in fibrogenic pathways involving myofibroblast activation. We aimed to investigate the AXL pathway as a potential target for the treatment of intestinal fibrosis. METHODS: To establish proof of concept, we first analyzed AXL gene expression in 2 in vivo models of intestinal fibrosis and 3 in vitro models of intestinal fibrosis. We then tested whether pharmacological inhibition of AXL signaling could reduce fibrogenesis in 3 in vitro models of intestinal fibrosis. In vitro testing included 2 distinct cell culture models of intestinal fibrosis (matrix stiffness and TGF-ß1 treatment) and a human intestinal organoid model using TGF-ß1 cytokine stimulation. RESULTS: Our findings suggest that the AXL pathway is induced in models of intestinal fibrosis. We demonstrate that inhibition of AXL signaling with the small molecule inhibitor BGB324 abrogates both matrix-stiffness and transforming growth factor beta (TGF-ß1)-induced fibrogenesis in human colonic myofibroblasts. AXL inhibition with BGB324 sensitizes myofibroblasts to apoptosis. Finally, AXL inhibition with BGB324 blocks TGF-ß1-induced fibrogenic gene and protein expression in human intestinal organoids. CONCLUSIONS: The AXL pathway is active in multiple models of intestinal fibrosis. In vitro experiments suggest that inhibiting AXL signaling could represent a novel approach to antifibrotic therapy for intestinal fibrosis such as in Crohn's disease.

Safety and Efficacy of Tumor Necrosis Factor Antagonists in Older Patients With Ulcerative Colitis: Patient-Level Pooled Analysis of Data From Randomized Trials.

BACKGROUND & AIMS: Treatment of older patients (more than 60 years) with ulcerative colitis (UC) can be a challenge, because they might be more vulnerable to adverse events (AEs). We determined the effects of age on the safety and efficacy of anti-tumor necrosis factor (TNF) therapy in a pooled analysis of data from randomized trials. METHODS: We obtained individual patient-level data from 4 trials of anti-TNF therapy for patients with UC from the Yale Open Data Access Project. Participants were assigned to groups of older age (60 years or older) and younger age (younger than 60 years). The primary outcome was difference in serious AEs (SAEs), defined as death, life-threatening event, hospitalization, and/or significant disability. Secondary outcomes were severe infections, non-severe infections, neoplasms, and achievement of clinical remission, defined by trial investigators as Mayo score ≤ 2 with no sub-score >1 at the end of induction or maintenance therapy. A random effects logistic regression model was fitted to estimate the effect of anti-TNF therapy on safety and efficacy by age, adjusting for confounders and trial-level effects. RESULTS: The study cohort included 2257 patients (231 60 years or older). Higher proportions of older patients receiving anti-TNF therapy had SAEs (20%) and hospitalizations (14.4%), compared with younger patients (10.2% had SAEs and 5.2% were hospitalized); there were no significant differences between groups in proportions with severe or non-severe infections. Compared with placebo, there was no significant difference in safety risks associated with anti-TNF therapy (SAEs reduced by 5.4% in older patients vs reduction of 2.4% in younger patients; hospitalizations reduced by 6.7% in older patients vs reduction of 2.5% in younger patients; severe infections reduced by 3.1% vs increase of 0.7% in younger patients). There was no significant difference in between older vs younger patients in efficacy of anti-TNF therapy in inducing remission (odds risk ratio, 1.05, 95% CI, 0.33-3.39) or in maintaining remission (odds risk ratio, 0.49; 95% CI, 0.18-1.33). CONCLUSIONS: In a pooled analysis of data from randomized trials, we found that older patients with UC have an increased baseline increased risk of SAEs, but no increase in risk can be attributed to anti-TNF therapy in older vs younger patients.

Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton's tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS.

Mapping the relationships between inflammatory bowel disease and comorbid diagnoses to identify disease associations.

BACKGROUND: Massive amounts of patient data are captured daily in electronic medical records (EMR). Utilizing the power of such large data may help identify disease associations and generate hypotheses that can lead to a better understanding of disease associations and mechanisms. We aimed to comprehensively identify and validate associations between inflammatory bowel disease (IBD) and concurrent comorbid diagnoses. METHODS: We performed a cross-sectional study using EMR data collected between 1986 and 2009 at a large tertiary referral center to identify associations with a diagnosis of IBD. The resulting associations were externally validated using the Truven MarketScan database, a large nationwide dataset of private insurance claims. RESULTS: A total of 6225 IBD patients and 31 125 non-IBD controls identified using EMR data were used to abstract 41 comorbid diagnoses associated with an IBD diagnosis. The strongest associations included Clostridiodes difficile infection, pyoderma gangrenosum, parametritis, pernicious anemia, erythema nodosum, and cytomegalovirus infection. Two IBD association clusters were found, including diagnoses of nerve conduction abnormalities and nonspecific inflammatory conditions of organs outside the gut. These associations were validated in a national cohort of 80 907 patients with IBD and 404 535 age- and sex-matched controls. CONCLUSION: We leveraged a big data approach to identify several associations between IBD and concurrent comorbid diagnoses. EMR and big data provide the opportunity to explore disease associations with large sample sizes. Further studies are warranted to refine the characterization of these associations and evaluate their usefulness for increasing our understanding of disease associations and mechanisms.

Unique Phenotypic Characteristics and Clinical Course in Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis: A Multicenter US Experience.

INTRODUCTION: Ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC) is a rare phenotype. We aimed to assess patients with UC-PSC or UC alone and describe differences in clinical and phenotypic characteristics, antitumor necrosis factor (TNF) therapy, and long-term clinical outcomes. METHODS: This retrospective multicenter cohort study included patients who received a diagnosis of UC from 1962 through 2015. We evaluated clinical factors associated with UC-PSC vs UC alone and assessed associations by using multivariable logistic regression models. RESULTS: Among 522 patients with UC, 56 (10.7%) had PSC. Compared with UC alone, patients with UC-PSC were younger (younger than 20 years) at diagnosis (odds ratios [OR], 2.35; adjusted P = 0.02) and had milder UC severity (adjusted P = 0.05), despite having pancolonic involvement (OR, 7.01; adjusted P < 0.001). In the biologics era (calendar year 2005 to 2015), patients with UC-PSC less commonly received anti-TNF therapy compared with patients with UC (OR, 0.38; adjusted P = 0.009), but their response rates were similar. Fewer patients with UC-PSC received corticosteroids (OR, 0.24; adjusted P = 0.005) or rectal 5-aminosalicyte acid (OR, 0.26; adjusted P < 0.001). Other differences were identified that were not statistically significant in a multivariable model: patients with UC-PSC more commonly were male, had lower rates of smoking, and had higher rates of colorectal cancer and colectomy. DISCUSSION: This study identified a unique phenotype of UC with concurrent PSC, which had different clinical behavior compared with UC only. These phenotypic characteristics can help identify high-risk patients with UC before PSC is diagnosed and guide different management and monitoring strategies.

Complete histologic normalisation is associated with reduced risk of relapse among patients with ulcerative colitis in complete endoscopic remission.

BACKGROUND: Clinical and endoscopic remission are treatment targets in ulcerative colitis (UC). The value of histologic healing in altering clinical outcomes among patients with complete endoscopic healing is not well established. AIM: To quantify the association between histologic activity and clinical relapse among patients with UC who were in complete endoscopic remission. METHODS: This study included patients with UC from a prospective registry who were in complete endoscopic remission. Histologic activity was quantified by a senior gastrointestinal pathologist. Histologic activity was defined as lack of normalisation (Geboes score > 0) as well as histologically active disease (Geboes score ≥2.1 and ≥3.1). The primary outcome was clinical relapse within 2 years. Multivariable regression adjusting for potential confounders examined the independent predictive value of histologic changes. RESULTS: The study included 83 patients (51% women) (median age 44 years; median disease duration 11 years). Forty-one (49%) had complete histologic normalisation. Within two years, 26 (31%) experienced clinical relapse. Patients with complete histologic normalisation were less likely to experience relapse (5/41, 12%) compared to those without normalisation (21/42, 50%, P < 0.001) (multivariable OR 7.22, 95% confidence interval (CI) 2.48-24.70) by the Geboes score. The individual components of the Geboes score predictive of relapse were architectural changes (P = 0.03) and increased chronic inflammatory infiltrate (P < 0.001). CONCLUSIONS: Complete histologic healing using the Geboes score was associated with reduced rates of clinical relapse among patients with UC in endoscopic remission.

Assessment of Benefit of Advanced Inflammatory Bowel Disease Training: Challenges and Solutions.

Background: Advanced inflammatory bowel disease (IBD) fellowships are available for gastroenterologists who wish to increase their expertise in complex IBD. However, little is known about the outcomes of such training. The aims of this study were to assess clinical and academic outcomes following advanced training in IBD. Methods: We surveyed gastroenterologists who completed advanced IBD fellowships and compared competency and outcomes to gastroenterologists focusing in IBD who completed gastroenterology training alone. Participants completed a survey via REDCap. Continuous variables were compared using the Wilcoxon rank-sum test. Categorical variables were compared using chi-square or Fisher's exact tests. Results: A total of 104 physicians participated in the study. IBD fellowships were completed by 31 physicians (30%), of whom 29 (94%) felt their training was excellent. Management of complicated IBD (84%), research mentoring (74%), and career mentoring (71%) were felt to contribute most highly to professional development. Compared to non-advanced trained physicians, advanced trained physicians expressed higher levels of comfort with management of IBD during pregnancy (P = 0.003), complicated IBD (P = 0.057), and peri-operative IBD (P = 0.057). No significant advantage was detected in academic productivity. Common barriers to participation in IBD fellowships included feeling it was unnecessary (45%) and desire to begin a faculty position (42%). Conclusions: This study suggests there may be clinical benefit to advanced IBD training. Importantly, this study identified that there are also unique challenges to the assessment of clinical competency in IBD training. Efforts by the IBD community to establish a registry of advanced trainees and improve competency assessments are needed.