Polygenic risk score predicts risk of primary sclerosing cholangitis in inflammatory bowel disease.

BACKGROUND: Forty distinct primary sclerosing cholangitis (PSC) genomic loci have been identified through multiancestry meta-analyses. The polygenic risk score (PRS) could serve as a promising tool to discover unique disease behaviour, like PSC, underlying inflammatory bowel disease (IBD). AIM: To test whether PRS indicates PSC risk in patients with IBD. MATERIALS AND METHODS: Mayo Clinic and Washington University at St Louis IBD cohorts were used to test our hypothesis. PRS was modelled through the published PSC loci and weighted with their corresponding effect size. Logistic regression was applied to predict the PSC risk. RESULTS: In total, 63 (5.6%) among 1130 patients with IBD of European ancestry had PSC. Among 381 ulcerative colitis (UC), 12% had PSC; in contrast to 1.4% in 761 Crohn disease (CD). Compared with IBD alone, IBD-PSC had significantly higher PRS (PSC risk: 3.0% at the lowest PRS quartile vs 7.2% at the highest PRS quartile, Ptrend =.03). In IBD subphenotypes subgroup analysis, multivariate analysis shows that UC-PSC is associated with more extensive UC disease (OR, 5.60; p=0.002) and younger age at diagnosis (p=0.02). In CD, multivariate analysis suggests that CD-PSC is associated with colorectal cancer (OR, 50; p=0.005). CONCLUSIONS: We found evidence that patients with IBD with PSC presented with a clinical course difference from that of patients with IBD alone. PRS can influence PSC risk in patients with IBD. Once validated in an independent cohort, this may help identify patients with the highest likelihood of developing PSC.

Novel Genetic Risk Variants and Clinical Predictors Associated With Primary Sclerosing Cholangitis in Patients With Ulcerative Colitis.

INTRODUCTION: Patients with ulcerative colitis (UC) who are likely to have primary sclerosing cholangitis (PSC) should be identified because PSC can influence UC clinical behavior and outcomes.The aim of this study was to establish a model incorporating clinical and genetic risk predictors that identifies patients with UC at risk of developing PSC. METHODS: We conducted a retrospective case-control study. Inflammatory bowel disease cohorts from multiple institutions were used as discovery and replicate datasets. Quality control criteria, including minor allele frequency, call rates, Hardy-Weinberg equilibrium, cryptic relatedness, and population stratification (through principal components), were used. Discriminative accuracy was evaluated with area under the receiver operating characteristic curve. RESULTS: Fifty-seven of 581 patients (9.8%) with UC had PSC. Multivariate analysis showed that patients with UC-PSC had more extensive disease (odds ratio [OR], 5.42; P = 1.57E-04), younger diagnosis age (younger than 20 years; OR, 2.22; P = 0.02), and less smoking (OR, 0.42; P = 0.02) than those with UC. After linkage disequilibrium pruning and multivariate analyses, 3 SNPs (rs3131621 at 6p21.33; rs9275596 and rs11244 at 6p21.32) at the HLA region were found associated with a 2- to 3-fold increased risk of PSC. Our model demonstrated good discriminatory power (area under the receiver operating characteristic curve, 88%). DISCUSSION: Three variants in HLA (6p21.3) region significantly distinguished patients with UC-PSC from patients with UC alone. Once further validated in an independent large cohort, our model could be used to identify patients with UC at risk of PSC, and it could also help guide disease management.

Novel Genetic Variant Predicts Surgical Recurrence Risk in Crohn's Disease Patients.

BACKGROUND: We aimed to identify a model of clinical and genetic risk factors through hypothesis-free search across genome that can predict the surgical recurrence risk after the first abdominal surgery in CD patients. MATERIALS AND METHODS: Two independent inflammatory bowel disease (IBD) cohort studies were used to derive and validate the genetic risk profile. The study subjects were genotyped using Illumina Immunochip custom genotyping array. Surgical recurrence was defined as having the second or more abdominal bowel resections after the first abdominal surgery at the time of study enrollment; nonsurgical recurrence was defined as having no further abdominal resection after the first abdominal surgery. RESULTS: Among 372 CD patients who had at least 1 abdominal surgery at the study enrollment, 132 (35.5%) had subsequent surgical recurrence after their first abdominal surgery, and 240 (64.5%) required no subsequent abdominal surgery at the end of follow up. Among clinical factors, multivariable analysis showed that history of immunomodulatory use (odds ratio [OR], 3.96; P = 0.002) and early era of CD first surgery (OR, 1.12; P = 1.01E-04) remained significant. Genotypic association tests identified a genome-wide significant locus rs2060886 in TCF4 at chr18q21.2 associated with surgical recurrence risk (OR, dom, 4.10 [2.37-7.11]; P = 4.58E-08). CONCLUSIONS: Novel genetic locus rs2060886 in TCF4 was associated with surgical recurrence risk at genome-wide significance level among CD patients after their first abdominal surgery. Early era of CD first intestinal surgery predicts higher surgical recurrence risk. These results suggest that genetic variants may help guide the CD management strategy in patients at the highest risk of repeated abdominal surgeries.

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.

Novel Genetic Risk Variants Can Predict Anti-TNF Agent Response in Patients With Inflammatory Bowel Disease.

BACKGROUND: It is important to identify patients with inflammatory bowel disease [IBD] refractory to anti-tumour necrosis factor [TNF] therapy, to avoid potential adverse effects and to adopt different treatment strategies. We aimed to identify and validate clinical and genetic factors to predict anti-TNF response in patients with IBD. MATERIALS AND METHODS: Mayo Clinic and Washington University IBD genetic association study cohorts were used as discovery and replicate datasets, respectively. Clinical factors included sex, age at diagnosis, disease duration and phenotype, disease location, bowel resection, tobacco use, family history of IBD, extraintestinal manifestations, and response to anti-TNF therapy. RESULTS: Of 474 patients with IBD treated with anti-TNF therapy, 41 [8.7%] were refractory to therapy and 433 [91.3%] had response. Multivariate analysis showed history of immunomodulator use (odds ratio 10.2, p = 8.73E-4) and bowel resection (odds ratio 3.24, p = 4.38E-4) were associated with refractory response to anti-TNF agents. Among genetic loci, two [rs116724455 in TNFSF4/18, rs2228416 in PLIN2] were successfully replicated and another four [rs762787, rs9572250, rs144256942, rs523781] with suggestive evidence were found. An exploratory risk model predictability [area under the curve] increased from 0.72 [clinical predictors] to 0.89 after adding genetic predictors. Through identified clinical and genetic predictors, we constructed a preliminary anti-TNF refractory score to differentiate anti-TNF non-responders (mean [standard deviation] score, 5.49 [0.99]) from responders (2.65 [0.39]; p = 4.33E-23). CONCLUSIONS: Novel and validated genetic loci, including variants in TNFSF, were found associated with anti-TNF response in patients with IBD. Future validation of the exploratory risk model in a large prospective cohort is warranted.

Beliefs about GI medications and adherence to pharmacotherapy in functional GI disorder outpatients.

OBJECTIVES: Pharmacotherapy is a mainstay in functional gastrointestinal (GI) disorder (FGID) management, but little is known about patient attitudes toward medication regimens. Understanding patient concerns and adherence to pharmacotherapy is particularly important for off-label medication use (e.g., antidepressants) in FGID. METHODS: Consecutive tertiary GI outpatients completed the Beliefs About Medications questionnaire (BMQ). Subjects were categorized as FGID and structural GI disease (SGID) using clinician diagnoses and Rome criteria; GI-specific medications and doses were recorded, and adherence to medication regimens was determined by patient self-report. BMQ domains (overuse, harm, necessity, and concern) were compared between FGID and SGID, with an interest in how these beliefs affected medication adherence. Psychiatric measures (depression, anxiety, and somatization) were assessed to gauge their influence on medication beliefs. RESULTS: A total of 536 subjects (mean age 54.7±0.7 years, range 22-100 years; n=406, 75.7% female) were enrolled over a 5.5-year interval: 341 (63.6%) with FGID (IBS, 64.8%; functional dyspepsia, 51.0%, ≥2 FGIDs, 38.7%) and 142 (26.5%) with SGID (IBD, 28.9%; GERD, 23.2%). PPIs (n=231, 47.8%), tricyclic antidepressants (TCAs) (n=167, 34.6%), and anxiolytics (n=122, 25.3%) were common medications prescribed. FGID and SGID were similar across all BMQ domains (P>0.05 for overuse, harm, necessity, and concern). SGID subjects had higher necessity-concern framework (NCF) scores compared with FGID subjects (P=0.043). FGID medication adherence correlated negatively with concerns about medication harm (r=-0.24, P<0.001) and overuse (r=-0.15, P=0.001), whereas higher NCF differences predicted medication compliance (P=0.006). Medication concern and overuse scores correlated with psychiatric comorbidity among FGID subjects (P<0.03 for each). FGID patients prescribed TCAs (n=142, 41.6%) expressed a greater medication necessity (17.4±0.4 vs. 16.2±0.4, P=0.024) and found their GI regimen to be more helpful (P=0.054). FGID subjects not on TCAs expressed a greater apprehension about medication overuse (10.7±0.3 vs. 9.7±0.2, P=0.002) on the BMQ. CONCLUSIONS: FGID subjects report medication necessity and concern scores comparable to patients with SGID but have negative perceptions about medications, particularly in the presence of psychiatric comorbidity; these factors may affect treatment adherence and willingness to initiate neuromodulator regimens.

Treating prepartum depression to improve infant developmental outcomes: a study of diabetes in pregnancy.

Whether and how the co-occurrence of depression and diabetes in pregnancy may worsen infant development has not been reported. Pregnant women with diabetes and with (n = 34) or without (n = 34) major depressive disorder (MDD) were followed during pregnancy and 6-months postpartum. The MDD subset received randomly assigned treatment with cognitive behavior therapy (CBT) or supportive counseling (SC). Depression severity was measured with the Beck Depression Inventory (BDI); infant developmental outcomes were measured with the Bayley Scales of Infant Development (BSID) and its Behavior Rating Scale (BRS). Infants of women with MDD had lower BRS scores (p = .02). Reduction in depression scores was associated with better infant outcomes on the BSID and BRS (p values <.03). These preliminary findings suggest depression occurring in pregnant women with diabetes is associated with poorer infant development and improvement in prepartum depression is associated with improvement in measures of infant development.

Improvement in sexual functioning in patients with type 2 diabetes and depression treated with bupropion.

OBJECTIVE: Major depressive disorder (MDD) and type 2 diabetes have independent adverse effects on sexual functioning (SF). Bupropion (BU) reportedly has few sexual side effects, but its use in diabetes has not been studied. RESEARCH DESIGN AND METHODS: This article reports a planned secondary analysis of SF in 90 patients with type 2 diabetes treated with BU for MDD. RESULTS: At baseline, 71.1% of patients had insufficient SF. Mean Sexual Energy Scale (SES) scores improved during treatment (P < 0.0001), as did the percentage with sufficient SF (30.6 vs. 68.1%, P = 0.001). Patients with persistent hyperglycemia had higher rates of sexual dysfunction; however, SES improvement was evident in some with persistent depression or hyperglycemia (18.2% and 25.9%, respectively). CONCLUSIONS: Insufficient SF is prevalent and may be suspected in patients with MDD and type 2 diabetes. BU treatment of MDD had few sexual side effects and was associated with significant improvements in SF.

Efficacy of sertraline in prevention of depression recurrence in older versus younger adults with diabetes.

OBJECTIVE: Sertraline maintenance therapy effectively delays recurrence of major depressive disorder in adult diabetic patients when data are examined across all age-groups. A secondary analysis was performed to assess this effect in younger and older subsets of patients. RESEARCH DESIGN AND METHODS: Younger (aged <55 years, n = 85) and older (aged > or =55 years, n = 67) subsets were identified from a multicenter, double-blind, placebo-controlled, maintenance treatment trial of sertraline in diabetic participants who achieved depression recovery with open-label sertraline treatment. Cox proportional hazards models were used to determine differences in time to depression recurrence between treatment arms (sertraline or placebo) for each age subset and between age subsets for each treatment. RESULTS: In younger subjects, sertraline conferred significantly greater prophylaxis against depression recurrence than placebo (hazard ratio 0.37 [95% CI 0.20-0.71]; P = 0.003). Benefits of sertraline maintenance therapy were lost in older participants (0.94 [0.39-2.29]; P = 0.89). There was no difference in time to recurrence for sertraline-treated subjects between age subsets (P = 0.65), but older subjects had a significantly longer time to recurrence on placebo than younger subjects (P = 0.03). CONCLUSIONS: While sertraline significantly increased the time to depression recurrence in the younger diabetic participants, there was no treatment effect in those aged > or =55 years because of a high placebo response rate. Further research is necessary to determine the mechanisms responsible for this effect and whether depression maintenance strategies specific for older patients with diabetes should be developed.

Factors influencing glycemic control in type 2 diabetes during acute- and maintenance-phase treatment of major depressive disorder with bupropion.

OBJECTIVE: Depression management in both short- and longer-term treatment studies has been associated with improvement in glycemic control. We used bupropion hydrochloride (Wellbutrin XL) to determine whether this improvement could be attributed to changes in anthropometrics or diabetes self-care. RESEARCH DESIGN AND METHODS: Ninety-three patients with type 2 diabetes and major depressive disorder (MDD) received bupropion hydrochloride in a two-phase, open-label treatment trial. Those who completed the acute phase (10 weeks; n = 75) and whose depression remitted (n = 63) continued bupropion at the remission dose and were followed in the maintenance phase (24 weeks) until attrition (n = 8) or relapse of MDD (n = 0). Self-report scales were used to measure depression symptom severity and diabetes self-care behaviors. Body composition and glycemic control were determined using dual-energy X-ray absorptiometry and serial determinations of A1C. RESULTS: BMI, total fat mass, and A1C decreased and composite diabetes self-care improved over the acute phase (-0.5 kg/m2, -0.7 kg, -0.5%, and +0.4, respectively, P < 0.01 for each), effects that persisted through the maintenance phase for BMI, A1C, and self-care (P < or = 0.01 for each). Reductions in BMI (B = 0.30, P = 0.01) and depression severity (B = 0.04, P = 0.046) independently predicted lower A1C after acute-phase treatment, whereas only reduction in depression severity (B = 0.08, P = 0.001) predicted A1C over the maintenance interval. CONCLUSIONS: In the short term, improvement in glycemic control during bupropion treatment is predicted independently by improvements in mood and body composition. Longer-term improvements in glycemic control are predicted primarily by sustained improvement in mood via mechanisms independent of anthropometric and self-care modifications.

Sertraline for prevention of depression recurrence in diabetes mellitus: a randomized, double-blind, placebo-controlled trial.

CONTEXT: In patients with diabetes mellitus, depression is a prevalent and recurrent problem that adversely affects the medical prognosis. OBJECTIVE: To determine whether maintenance therapy with sertraline hydrochloride prevents recurrence of major depression in patients with diabetes. DESIGN: A randomized, double-blind, placebo-controlled, maintenance treatment trial. Patients who recovered from depression during open-label sertraline treatment continued to receive sertraline (n = 79) or placebo (n = 73) and were followed up for up to 52 weeks or until depression recurred. SETTING: Outpatient clinics at Washington University, St Louis, MO, the University of Washington, Seattle, and the University of Arizona, Tucson. PATIENTS: One hundred fifty-two patients with diabetes (mean age, 52.8 years; 59.9% female; 82.9% with type 2 diabetes) who recovered from major depression (43.3% of those initially assigned) during 16 weeks of open-label treatment with sertraline (mean dose, 117.9 mg/d). INTERVENTION: Sertraline continued at recovery dose or identical-appearing placebo. MAIN OUTCOME MEASURES: The primary outcome was length of time (measured as the number of days after randomization) to recurrence of major depression as defined in DSM-IV. The secondary outcome was glycemic control, which was assessed via serial determinations of glycosylated hemoglobin levels. RESULTS: Sertraline conferred significantly greater prophylaxis against depression recurrence than did placebo (hazard ratio = 0.51; 95% confidence interval, 0.31-0.85; P = .02). Elapsed time before major depression recurred in one third of the patients increased from 57 days in patients who received placebo to 226 days in patients treated with sertraline. Glycosylated hemoglobin levels decreased during the open treatment phase (mean +/- SD glycosylated hemoglobin level reduction, -0.4% +/- 1.4%; P = .002). Glycosylated hemoglobin levels remained significantly lower than baseline during depression-free maintenance (P = .002) and did not differ between treatment groups (P = .90). CONCLUSIONS: In patients with diabetes, maintenance therapy with sertraline prolongs the depression-free interval following recovery from major depression. Depression recovery with sertraline as well as sustained remission with or without treatment are associated with improvements in glycosylated hemoglobin levels for at least 1 year.