Statins Are Associated With a Decreased Risk of Severe Liver Disease in Individuals With Noncirrhotic Chronic Liver Disease.

BACKGROUND & AIMS: Little is known about the potential impact of statins on the progression of noncirrhotic chronic liver diseases (CLDs) to severe liver disease. METHODS: Using liver histopathology data in a nationwide Swedish cohort, we identified 3862 noncirrhotic individuals with CLD and statin exposure, defined as a statin prescription filled for 30 or more cumulative defined daily doses. Statin users were matched to 3862 (statin) nonusers with CLD through direct 1:1 matching followed by propensity score matching. Cox regression was used to estimate hazard ratios (HRs) for the primary outcome of incident severe liver disease (a composite of cirrhosis, hepatocellular carcinoma, and liver transplantation/liver-related mortality). RESULTS: A total of 45.3% of CLD patients had nonalcoholic fatty liver disease, 21.9% had alcohol-related liver disease, 17.7% had viral hepatitis, and 15.1% had autoimmune hepatitis. During follow-up evaluation, 234 (6.1%) statin users vs 276 (7.1%) nonusers developed severe liver disease. Statin use was associated with a decreased risk of developing severe liver disease (HR, 0.60; 95% CI, 0.48-0.74). Statistically significantly lower rates of severe liver disease were seen in alcohol-related liver disease (HR, 0.30; 95% CI, 0.19-0.49) and in nonalcoholic fatty liver disease (HR, 0.68; 95% CI, 0.45-1.00), but not in viral hepatitis (HR, 0.76; 95% CI, 0.51-1.14) or autoimmune hepatitis (HR, 0.88; 95% CI, 0.48-1.58). Statin use had a protective association in both prefibrosis and fibrosis stages at diagnosis. Statin use was associated with lower rates of progression to cirrhosis (HR, 0.62; 95% CI, 0.49-0.78), hepatocellular carcinoma (HR, 0.44; 95% CI, 0.27-0.71), and liver-related mortality (HR, 0.55; 95% CI, 0.36-0.82). CONCLUSIONS: Among individuals with noncirrhotic CLD, incident statin use was linked to lower rates of severe liver disease, suggesting a potential disease-modifying role.

Association of Proton Pump Inhibitor Use With All-Cause and Cause-Specific Mortality.

BACKGROUND & AIMS: The use of proton pump inhibitors (PPIs) has increased rapidly in the past 2 decades. Concerns about the regular use of PPIs contributing to mortality have been raised. METHODS: We conducted a prospective cohort study using data collected from the Nurses' Health Study (2004-2018) and the Health Professionals Follow-up Study (2004-2018). Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% CIs for mortality according to PPI use. We used a modified lag-time approach to minimize reverse causation (ie, protopathic bias). RESULTS: Among 50,156 women and 21,731 men followed for 831,407 person-years and a median of 13.8 years, we documented 22,125 deaths, including 4592 deaths from cancer, 5404 from cardiovascular diseases, and 12,129 deaths from other causes. Compared with nonusers of PPIs, PPI users had significantly higher risks of all-cause mortality (HR, 1.19; 95% CI, 1.13-1.24) and mortality due to cancer (HR, 1.30; 95% CI, 1.17-1.44), cardiovascular diseases (HR, 1.13; 95% CI, 1.02-1.26), respiratory diseases (HR, 1.32; 95% CI, 1.12-1.56), and digestive diseases (HR, 1.50; 95% CI, 1.10-2.05). Upon applying lag times of up to 6 years, the associations were attenuated and no longer statistically significant (all-cause: HR, 1.04; 95% CI, 0.97-1.11; cancer: HR, 1.07; 95% CI, 0.89-1.28; cardiovascular diseases: HR, 0.94; 95% CI, 0.81-1.10; respiratory diseases: HR, 1.20; 95% CI, 0.95-1.50; digestive diseases: HR, 1.38; 95% CI, 0.88-2.18). Longer duration of PPI use did not confer higher risks for all-cause and cause-specific mortality. CONCLUSIONS: After accounting for protopathic bias, PPI use was not associated with higher risks of all-cause mortality and mortality due to major causes.

Lifestyle factors for the prevention of inflammatory bowel disease.

OBJECTIVE: To estimate the proportion of cases of Crohn's disease (CD) and ulcerative colitis (UC) that could be prevented by modifiable lifestyle factors. DESIGN: In a prospective cohort study of US adults from the Nurses' Health Study (NHS; n=72 290), NHSII (n=93 909) and Health Professionals Follow-up Study (HPFS; n=41 871), we created modifiable risk scores (MRS; 0-6) for CD and UC based on established lifestyle risk factors, and healthy lifestyle scores (HLS; 0-9) derived from American healthy lifestyle recommendations. We calculated the population attributable risk by comparing the incidence of CD and UC between low-risk (CD-MRS≤1, UC-MRS≤2, HLS≥7) and high-risk groups. We externally validated our findings in three European cohorts: the Swedish Mammography Cohort (n=37 275), Cohort of Swedish Men (n=40 810) and European Prospective Investigation into Cancer and Nutrition (n=404 144). RESULTS: Over 5 117 021 person-years of follow-up (NHS, HPFS: 1986-2016; NHSII: 1991-2017), we documented 346 CD and 456 UC cases. Adherence to a low MRS could have prevented 42.9% (95% CI 12.2% to 66.1%) of CD and 44.4% (95% CI 9.0% to 69.8%) of UC cases. Similarly, adherence to a healthy lifestyle could have prevented 61.1% (95% CI 16.8% to 84.9%) of CD and 42.2% (95% CI 1.7% to 70.9%) of UC cases. In our validation cohorts, adherence to a low MRS and healthy lifestyle could have, respectively, prevented 43.9%-51.2% and 48.8%-60.4% of CD cases and 20.6%-27.8% and 46.8%-56.3% of UC cases. CONCLUSIONS: Across six US and European cohorts, a substantial burden of inflammatory bowel diseases risk may be preventable through lifestyle modification.

Risk Factors for Incident Inflammatory Bowel Disease According to Disease Phenotype.

BACKGROUND & AIMS: We examined whether relationships between known risk factors for Crohn's disease (CD) and ulcerative colitis (UC) differ according to disease phenotype, defined by Montreal classification, at the time of diagnosis. METHODS: We performed a prospective cohort study of 208,070 adults from the Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-Up Study (HPFS). Dietary, lifestyle, and medical data were obtained at baseline and every 2-4 years. We confirmed cases of inflammatory bowel disease (IBD) and their phenotypes via medical record review. We tested for heterogeneity across CD subtypes using the likelihood ratio test and for linear heterogeneity across UC subtypes using the meta-regression method. RESULTS: We ascertained 346 cases of CD and 456 cases of UC over 5,117,021 person-years of follow-up (1986-2016 for NHS and HPFS; 1991-2017 for NHSII). Fiber intake was associated with decreased risk for ileocolonic but not ileal or colonic CD (Pheterogeneity = .04). Physical activity was associated with decreased risk of nonstricturing and nonpenetrating CD but not of penetrating CD (Pheterogeneity = .02). Higher body mass index and current smoking were associated with decreased risk of proctitis and left-sided UC but not of pan-UC (Plinear heterogeneity= .004 and .02, respectively). The associations between other risk factors examined and risk of CD and UC did not differ by disease phenotype (all Pheterogeneity > .06). CONCLUSIONS: In 3 large prospective cohorts, we observed that dietary and lifestyle risk factors for IBD may differ according to disease phenotype. These findings highlight the need for disease stratification in future epidemiologic studies.

Frequency of Bowel Movements and Risk of Diverticulitis.

OBJECTIVE: The etiology of diverticulitis is poorly understood. The long-held belief that constipation and low-fiber diet are risk factors for diverticulosis has recently been challenged by studies that suggest that more frequent bowel movements predispose to diverticulosis. We aim to prospectively explore the association between bowel movement frequency and incident diverticulitis. DESIGN: We studied participants of the Nurses' Health Study (NHS) and Health Professional Follow-up Study (HPFS). Participants' medical history, lifestyle factors and diet were used in Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios(HRs) and 95% confidence intervals(CI). RESULTS: In the NHS during over 24 years of follow-up encompassing 1,299,922 person-years, we documented 5,214 incident cases of diverticulitis, and in the HPFS over 14 years encompassing 368,661 person-years of follow-up, we documented 390 incident cases of diverticulitis. We observed an inverse association between the frequency of bowel movements and risk of diverticulitis. In the NHS, compared with women who had daily bowel movements, those with more than once daily bowel movements had a HR of 1.30 (95% CI, 1.19, 1.42) and those with less frequent bowel movements had a HR of 0.89 (95% CI, 0.82, 0.95; p-trend < 0.0001). In the HPFS, the corresponding HRs were 1.29 (95% CI, 1.04, 1.59) and 0.61 (95% CI, 0.36, 1.03; p-trend = 0.003). The association between bowel movements and diverticulitis was not modified by categories of age, BMI, physical activity, laxative use or fiber intake. CONCLUSION: More frequent bowel movements appear to be a risk factor for subsequent diverticulitis both in men and women. Further studies are needed to understand the potential mechanisms that may underlie this association.

Dietary Gluten Intake Is Not Associated With Risk of Inflammatory Bowel Disease in US Adults Without Celiac Disease.

BACKGROUND & AIMS: Diet is thought to play a role in the development of inflammatory bowel disease (IBD), though it is unknown whether gluten intake confers risk of IBD. The aim of this study was to determine the relationship between gluten intake and risk of incident Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We performed a prospective cohort study of 208,280 US participants from the Nurses' Health Study (1986-2016), Nurses' Health Study II (1991-2017), and the Health Professionals Follow-up Study (1986-2016) who did not have IBD at baseline or celiac disease, and who completed semiquantitative food frequency questionnaires. We used Cox proportional hazards modeling to estimate the risk of IBD according to quintiles of cumulative average energy-adjusted dietary gluten intake over the follow-up period. RESULTS: We documented 337 CD cases and 447 UC cases over 5,115,265 person-years of follow-up evaluation. Dietary gluten intake was not associated with risk of IBD. Compared with participants in the lowest quintile of gluten intake, the adjusted hazard ratios and 95% CIs for participants in the highest quintile of gluten intake were 1.16 (95% CI, 0.82-1.64; Ptrend = .41) for CD and 1.04 (95% CI, 0.75-1.44; Ptrend = .64) for UC. Adjusting for primary sources of gluten intake did not materially change our estimates. CONCLUSIONS: In 3 large adult US prospective cohorts, gluten intake was not associated with risk of CD or UC. Our findings are reassuring at a time when consumption of gluten has been increasingly perceived as a trigger for chronic gastrointestinal diseases.

Obesity is Associated With Increased Risk of Crohn's disease, but not Ulcerative Colitis: A Pooled Analysis of Five Prospective Cohort Studies.

BACKGROUND AND AIMS: It is unclear whether obesity is associated with the development of inflammatory bowel disease despite compelling data from basic science studies. We therefore examined the association between obesity and risk of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We conducted pooled analyses of 5 prospective cohorts with validated anthropometric measurements for body mass index (BMI) and waist-hip ratio and other lifestyle factors. Diagnoses of CD and UC were confirmed through medical records or ascertained using validated definitions. We used Cox proportional hazards modeling to calculate pooled multivariable-adjusted HRs (aHRs) and 95% confidence intervals (CIs). RESULTS: Among 601,009 participants (age range, 18-98 years) with 10,110,018 person-years of follow-up, we confirmed 563 incident cases of CD and 1047 incident cases of UC. Obesity (baseline BMI ≥30 kg/m2) was associated with an increased risk of CD (pooled aHR, 1.34; 95% CI, 1.05-1.71, I2 = 0%) compared with normal BMI (18.5 to <25 kg/m2). Each 5 kg/m2 increment in baseline BMI was associated with a 16% increase in risk of CD (pooled aHR, 1.16; 95% CI, 1.05-1.22; I2 = 0%). Similarly, with each 5 kg/m2 increment in early adulthood BMI (age, 18-20 years), there was a 22% increase in risk of CD (pooled aHR, 1.22; 95% CI, 1.05-1.40; I2 = 13.6%). An increase in waist-hip ratio was associated with an increased risk of CD that did not reach statistical significance (pooled aHR across quartiles, 1.08; 95% CI, 0.97-1.19; I2 = 0%). No associations were observed between measures of obesity and risk of UC. CONCLUSIONS: In an adult population, obesity as measured by BMI was associated with an increased risk of older-onset CD but not UC.

Ultra-processed Foods and Risk of Crohn's Disease and Ulcerative Colitis: A Prospective Cohort Study.

BACKGROUND & AIMS: The rising incidence of inflammatory bowel disease in regions undergoing Westernization has coincided with the increase in ultra-processed food (UPF) consumption over the past few decades. We aimed to examine the association between consumption of UPFs and the risk of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We performed a prospective cohort study of 3 nationwide cohorts of health professionals in the United States-the Nurses' Health Study (1986-2014), the Nurses' Health Study II (1991-2017), and the Health Professionals Follow-up Study (1986-2012). We employed Cox proportional hazards models with adjustment for confounders to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for CD and UC according to self-reported consumption of UPFs. RESULTS: The study included 245,112 participants. Over 5,468,444 person-years of follow-up, we documented 369 incident cases of CD and 488 incident cases of UC. The median age at diagnosis was 56 years (range, 29-85 years). Compared with participants in the lowest quartile of simple updated UPF consumption, those in the highest quartile had a significantly increased risk of CD (HR, 1.70; 95% CI, 1.23-2.35; Ptrend = .0008). Among different UPF subgroups, ultra-processed breads and breakfast foods; frozen or shelf-stable ready-to-eat/heat meals; and sauces, cheeses, spreads, and gravies showed the strongest positive associations with CD risk (HR per 1 standard deviation increase in intake, 1.18 [95% CI, 1.07-1.29], 1.11 [95% CI, 1.01-1.22], and 1.14 [95% CI, 1.02-1.27], respectively). There was no consistent association between UPF intake and UC risk. CONCLUSIONS: Higher UPF intake was associated with an increased risk of incident CD. Further studies are needed to identify specific contributory dietary components.

Histological differences between lumbar and tail intervertebral discs in mice.

Both the lumbar and tail intervertebral discs (IVD) of mice serve as models for the pathogenesis and histologic progression of degenerative disc disease. Recent studies in mature mice, however, demonstrate that the mechanics and physical attributes of lumbar and tail IVD-endplate (EP)-interfaces are strikingly different. We hypothesized that these structural disparities are associated with differences in the composition and organization of soft tissue elements that influence the biomechanical properties of the spine. Lumbar and tail vertebral segments and discs were collected from the same C57BL/6N and C57BL/6JRj mice, respectively for histological comparison of coronal sections at the ages of 4 weeks (weaned, both strains, C57BL/6N: n = 7; C57BL/6JRj: n = 4), three (mature, C57BL/6N: n = 7; C57BL/6JRj: n = 4), twelve (middle aged, C57BL/6JRj only: n = 3) and eighteen (old, C57BL/6JRj only: n = 3) months old. The histology of lumbar and tail IVD-EP-interfaces of mature mice differed markedly. The lumbar IVD-EP-interphase was characterized by a broad cartilaginous EP, while the tail IVD-EP-interphase comprised a thin layer of cartilage cells adjacent to a broad bony layer abutting the vertebral growth plate. Furthermore, the composition of the nuclei pulposi (NP) of lumbar and tail IVD in mature mice differed greatly. Lumbar NP consisted of a compact cluster of mainly large, uni-vacuolated cells centered in an amorphous matrix, while tail NP were composed of a loose aggregate of vacuolated and non-vacuolated cells. The anuli fibrosi also differed, with more abundant and sharply defined lamellae in tail compared to lumbar discs. The observed histological differences in the EP were even most prominent in weaned mice but were still discernible in middle-aged and old mice. An appreciation of the histological differences between lumbar and tail IVD components in mice, including nucleus pulposus, annulus fibrosus, and endplates, is essential to our understanding of spinal biomechanics in these animals and should inform the design and interpretation of future IVD-studies.

Plasma concentrations of perfluoroalkyl substances and risk of inflammatory bowel diseases in women: A nested case control analysis in the Nurses' Health Study cohorts.

BACKGROUND: Perfluoroalkyl substances (PFASs) are synthetic compounds used in a wide variety of industrial and consumer applications. An association between PFAS exposure and risk of ulcerative colitis (UC) has been reported in a highly exposed population. However, data are limited on risk of inflammatory bowel diseases (IBD) among individuals with background population levels of PFAS exposure. OBJECTIVES: We set out to examine the association between plasma PFAS concentrations and risk of IBD among women in two population-based, prospective cohort studies in which pre-diagnostic blood specimens were available. METHODS: We conducted a nested case-control study in the Nurses' Health Study and Nurses' Health Study II cohorts. We identified 73 participants with incident Crohn's disease (CD) and 80 participants with incident UC who had provided blood samples before diagnosis. Cases were matched 1:2 to IBD-free controls. Plasma concentrations of five major PFASs were measured by liquid chromatography and tandem mass spectrometry. We used conditional logistic models to estimated odds ratios for risk of IBD according to log10-transformed PFAS concentrations, adjusting for potential confounders. RESULTS: In multivariable models, we observed inverse associations between plasma concentrations of three PFASs and risk of CD (all P ≤ 0.012 for a standard deviation increase in log10PFAS). The inverse association with CD was strongest for perfluorodecanoate, where, compared to the lowest tertile, the odds ratio (OR) for the highest tertile was 0.39 (95% confidence interval, 0.17-0.92). No associations were observed between PFAS concentrations and UC risk. DISCUSSION: Our results do not support the hypothesis that elevated PFAS exposure is associated with higher risk of UC. Contrary to expectation, our data suggest that circulating concentrations of some PFASs may be inversely associated with CD development.

Increasing incidence of eosinophilic esophagitis in Sweden: a nationwide population study.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus associated with dysphagia and esophageal fibrosis. The incidence of EoE is not precisely known, and significant heterogeneity in study design and disease definition have led to widely variable estimates. Through the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study we performed a nationwide population-based study to estimate the incidence and temporal patterns of biopsy-verified EoE. METHODS: Between October 2015 and April 2017, we contacted all pathology departments in Sweden (n = 28) to obtain biopsy report data on EoE. To assure a high degree of completeness, we restricted the study to 2004-2015. We then calculated age-specific and age-standardized incidence rates. RESULTS: We identified 1412 incident EoE cases between 2004-2015. The overall age-standardized incidence rates of EoE in Sweden was 1.22 per 100,000 person-years. During the study period, there was a significant increase of 33% [95%CI = 31-36%] (P < 0.001) per year in EoE incidence, and in the last 3 years of follow-up (2013-2015) the incidence was 2.79 per 100,000 person-years. This corresponds to a lifetime risk of biopsy-verified EoE for men of 0.33% (1 in 295 men) and for women 0.12% (1 in 813 women). We observed an early peak of EoE disgnosed at age 15-19 years for both males and females, and a second peak in the late 30 s for males, and early 40 s for females. We noted a 3:1 male-to-female predominance, which did not significantly vary over time. CONCLUSIONS: EoE seems to be increasing in Sweden, with an overall age-standardized incidence of EoE of 1.22 per 100,000 person-years in the last decade.

Risk of fractures in individuals with eosinophilic esophagitis: nationwide population-based cohort study.

BACKGROUND AND AIMS: Eosinophilic esophagitis (EoE) is an emerging, chronic immune-mediated disease for which swallowed topical steroids and proton pump inhibitors (PPIs) represent first-line treatments. Immune-mediated diseases, steroids, and PPI use have been linked to osteoporosis. We assessed the risk of fractures in patients with EoE and determined whether the most commonly used treatments for EoE were associated with increased fracture risk. METHODS: We followed a nationwide cohort of 1263 individuals in Sweden with biopsy-verified EoE diagnosed between 2005 and 2016 for first-time fracture of any type. Age- and sex-matched reference individuals were retrieved from the Total Population Register (n = 5164). We estimated hazard ratios (HRs) for fracture in relation to EoE diagnosis, steroid exposure, and PPI use. In a separate analysis, we compared fracture risk among individuals with EoE to their siblings (n = 1394). RESULTS: During 4521 person-years of follow-up, 69 individuals with EoE experienced a first-time fracture (15.3/1000 person-years) compared with 234 reference individuals (12.6/1000 person-years). After adjusting for age, sex, birth year, and county of residence, EoE was not associated with a statistically significantly increased risk of fractures (HR = 1.2, 95% CI = 0.9-1.6). Among EoE individuals, exposure to PPIs and swallowed steroids did not modify the risk of fracture (p for heterogeneity 0.20 and 0.07 respectively). There was no increased risk of fractures in EoE compared to EoE-free siblings. CONCLUSION: The risk of fracture in EoE was not statistically significantly elevated compared to non-EoE reference individuals. Fracture risk in EoE was not modified by PPIs or steroid use.

Healthy Lifestyle Is Associated With Reduced Mortality in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: It is not clear whether a healthy lifestyle affects mortality of patients with inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We collected data form the Nurses' Health Study (1986-2014), Nurses' Health Study II (1991-2015), and Health Professionals Follow-up Study (1986-2014), which assess lifestyles with serial questionnaires. We estimated joint and individual associations between 5 healthy lifestyle factors after IBD diagnosis (never smoking, body mass index 18.5-24.9 kg/m2, vigorous physical activity in the highest 50% with non-zero value, alternate Mediterranean diet score ≥4, and light drinking [0.1-5.0 g/d]) and mortality using Cox proportional hazards models. RESULTS: We documented 83 deaths in 363 patients with CD during 4741 person-years and 80 deaths in 465 patients with UC during 6061 person-years. The median age of IBD diagnosis was 55 y. Compared to patients with IBD with no healthy lifestyle factors, patients with IBD with 3-5 healthy lifestyle factors had a significant reduction in all-cause mortality (hazard ratio [HR], 0.29; 95% CI, 0.16-0.52; Ptrend < .0001). This reduction was significant in patients with CD (Ptrend = .003) as well as in patients with UC (Ptrend = .0003). Individual associations were more than 25 pack-years (HR, 1.92; 95% CI, 1.24-2.97; Ptrend < .0001), physical activity (HR according to quintiles, 0.55-0.31; Ptrend = .001), Mediterranean diet (HR, 0.69; 95% CI, 0.49-0.98), and alcohol consumption (HR0.1-5 g/d 0.61; 95% CI, 0.39-0.95 vs HR>15 g/d 1.84; 95% CI, 1.02-3.32). The findings did not change when we adjusted for family history of IBD, immunomodulator use, and IBD-related surgery. CONCLUSIONS: In an analysis of data from 3 large cohort studies, we associated adherence to a healthy lifestyle with reduced mortality in patients with CD or UC.

Dietary Inflammatory Potential and Risk of Crohn's Disease and Ulcerative Colitis.

BACKGROUND & AIMS: Inflammation is a potential mechanism through which diet modulates the onset of inflammatory bowel disease. We analyzed data from 3 large prospective cohorts to determine the effects of dietary inflammatory potential on the risk of developing Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We collected data from 166,903 women and 41,931 men in the Nurses' Health Study (1984-2014), Nurses' Health Study II (1991-2015), and Health Professionals Follow-up Study (1986-2012). Empirical dietary inflammatory pattern (EDIP) scores were calculated based on the weighted sums of 18 food groups obtained via food frequency questionnaires. Self-reported CD and UC were confirmed by medical record review. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We documented 328 cases of CD and 428 cases of UC over 4,949,938 person-years of follow-up. The median age at IBD diagnosis was 55 years (range 29-85 years). Compared with participants in the lowest quartile of cumulative average EDIP score, those in the highest quartile (highest dietary inflammatory potential) had a 51% higher risk of CD (HR 1.51; 95% CI 1.10-2.07; Ptrend = .01). Compared with participants with persistently low EDIP scores (at 2 time points, separated by 8 years), those with a shift from a low to high inflammatory potential of diet or persistently consumed a proinflammatory diet had greater risk of CD (HR 2.05; 95% CI 1.10-3.79 and HR 1.77; 95% CI 1.10-2.84). In contrast, dietary inflammatory potential was not associated with the risk of developing UC (Ptrend = .62). CONCLUSIONS: In an analysis of 3 large prospective cohorts, we found dietary patterns with high inflammatory potential to be associated with increased risk of CD but not UC.

Adherence to a Mediterranean diet is associated with a lower risk of later-onset Crohn's disease: results from two large prospective cohort studies.

OBJECTIVE: To examine the relationship between Mediterranean diet and risk of later-onset Crohn's disease (CD) or ulcerative colitis (UC). DESIGN: We conducted a prospective cohort study of 83 147 participants (age range: 45-79 years) enrolled in the Cohort of Swedish Men and Swedish Mammography Cohort. A validated food frequency questionnaire was used to calculate an adherence score to a modified Mediterranean diet (mMED) at baseline in 1997. Incident diagnoses of CD and UC were ascertained from the Swedish Patient Register. We used Cox proportional hazards modelling to calculate HRs and 95% CI. RESULTS: Through December of 2017, we confirmed 164 incident cases of CD and 395 incident cases of UC with an average follow-up of 17 years. Higher mMED score was associated with a lower risk of CD (Ptrend=0.03) but not UC (Ptrend=0.61). Compared with participants in the lowest category of mMED score (0-2), there was a statistically significant lower risk of CD (HR=0.42, 95% CI 0.22 to 0.80) but not UC (HR=1.08, 95% CI 0.74 to 1.58). These associations were not modified by age, sex, education level, body mass index or smoking (all Pinteraction >0.30). The prevalence of poor adherence to a Mediterranean diet (mMED score=0-2) was 27% in our cohorts, conferring a population attributable risk of 12% for later-onset CD. CONCLUSION: In two prospective studies, greater adherence to a Mediterranean diet was associated with a significantly lower risk of later-onset CD.

Acid-suppressive medications and risk of colorectal cancer: results from three large prospective cohort studies.

BACKGROUND: Despite several plausible biological mechanisms linking proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) with colorectal tumorigenesis, their association with risk of colorectal cancer (CRC) has not been adequately assessed in prospective epidemiological studies. METHODS: We evaluated the association of acid-suppressive medication use with CRC risk among 175,871 (PPI) and 208,831 (H2RA) participants from three large prospective cohort studies. Medication use was assessed at baseline and updated biennially. The association was evaluated using multivariate Cox proportional hazards regression models. RESULTS: There was no significant association between baseline PPI use (hazard ratio (HR) = 0.89, 95% confidence interval (CI), 0.71-1.12) or PPI use after a lag of 8-10 years (HR = 1.12, 95% CI, 0.78-1.59) with CRC risk. We observed no significant association between H2RA use after a lag of 8-10 years and CRC risk (HR = 1.02, 95% CI, 0.81-1.28), while risk was lower for participants with baseline H2RA use (HR = 0.76, 95% CI, 0.60-0.95). Duration of PPI use or H2RA use was not associated with CRC risk (P-trend = 0.21 and 0.95, respectively). CONCLUSIONS: Among participants from three large prospective cohorts, use of PPI or H2RA was not associated with higher risk of colorectal cancer.

Identification of Menopausal and Reproductive Risk Factors for Microscopic Colitis-Results From the Nurses' Health Study.

BACKGROUND & AIMS: Microscopic colitis is a chronic inflammatory disorder of the colon primarily affecting postmenopausal women. However, the relation between hormonal determinants, including reproductive and menopausal factors, and risk of microscopic colitis has yet to be characterized. METHODS: We collected data from 227,766 women who participated in the Nurses' Health Study (NHS) and the NHSII without a baseline history of microscopic colitis. Reproductive and menopausal factors were assessed in 1988 in the NHS and 1989 in the NHSII and updated biennially. Cases of microscopic colitis were confirmed through review of pathology records. We used Cox proportional hazards modeling to estimate hazard ratios and 95% confidence intervals. RESULTS: Through 2014 in the NHS and 2015 in the NHSII, we confirmed 275 incident cases of microscopic colitis over 5,147,282 person-years. Compared with never use, current use of menopausal hormone therapy was associated with increased risk of microscopic colitis (multivariable-adjusted hazard ratio 2.64; 95% confidence interval 1.78-3.90). The risk increased with longer duration of use (P for trend < .0001) and decreased after discontinuation (P for trend = .002). The association did not differ according to disease subtype (P for heterogeneity = .34). Similarly, ever use of oral contraceptives was associated with increased risk of microscopic colitis (multivariable-adjusted hazard ratio 1.57; 95% confidence interval 1.16-2.13). There were no associations between age at menarche, parity, age at first birth, age at menopause, or menopause type and incident microscopic colitis. CONCLUSIONS: In 2 large prospective cohort studies, we observed an association between exogenous hormone use and incident microscopic colitis. Further studies are needed to determine the mechanisms underlying these associations.

No Significant Association Between Proton Pump Inhibitor Use and Risk of Stroke After Adjustment for Lifestyle Factors and Indication.

BACKGROUND & AIMS: Proton pump inhibitors (PPI) are among the top 10 most prescribed medications worldwide. We investigated the association between PPI use and ischemic stroke. METHODS: We collected data on 68,514 women (mean age, 65 ± 7 years) enrolled in the Nurses' Health Study since 2000 and 28,989 men (mean age, 69 ± 8 years) in the Health Professionals Follow-up Study since 2004, without a history of stroke. We used Cox proportional hazards models to examine the association between risk of incident stroke and PPI use among participants. The primary end point was first incident stroke. RESULTS: In the 2 cohorts, we documented 2599 incident strokes (2037 in women and 562 in men) over a 12-year period, encompassing 949,330 person-years. After adjustment for established risk factors for stroke, PPI use was associated with a significant increase in risk of ischemic stroke (hazard ratio, 1.18; 95% confidence interval, 1.02-1.37). The association was reduced after we adjusted for potential indications for PPI use, including history of peptic ulcer disease, gastroesophageal reflux disease, or gastrointestinal bleeding, and prior use of histamine-2 receptor antagonist therapy (hazard ratio, 1.08; 95% confidence interval, 0.91-1.27). Regular PPI use was not associated with increased risk of stroke overall or hemorrhagic stroke. CONCLUSIONS: In an analysis of data from the Nurses' Health Study and the Health Professionals Follow-up Study, we did not find a significant association between PPI use and ischemic stroke, after accounting for indications for PPI use. Prior reports of an increased risk of stroke may be due to residual confounding related to chronic conditions associated with PPI use.

Obesity and Weight Gain Since Early Adulthood Are Associated With a Lower Risk of Microscopic Colitis.

BACKGROUND & AIMS: Obesity promotes intestinal inflammation and might contribute to the pathogenesis of inflammatory bowel disease. We examined the association between obesity and risk of microscopic colitis in a prospective cohort study. METHODS: We collected data from 192,101 women enrolled in the Nurses' Health Study (NHS) (from 1986 through 2014) or the NHSII (from 1991 through 2015). Anthropomorphic and lifestyle information were self-reported biennially. Obesity was defined using body mass index (BMI). Microscopic colitis was confirmed by review of medical records. We used Cox proportional hazard models to estimate adjusted hazard ratios (aHRs) and 95% CIs. RESULTS: Among the participants in the NHS and NHSII, we confirmed 244 cases of microscopic colitis during 4,223,868 person-years of follow-up evaluation. Higher BMI was associated inversely with risk of microscopic colitis (Ptrend < .001). Compared with women with BMIs ranging from 18.5 to 20.9 kg/m2, the aHRs were 0.61 (95% CI, 0.41-0.91) for overweight women (BMI, 25-29.9 kg/m2) and 0.50 (95% CI, 0.32-0.79) for obese women (BMI ≥ 30 kg/m2). The aHR for each 5-kg/m2 increase in BMI was 0.79 (95% CI, 0.69-0.90). Weight gain since early adulthood (age, 18 y) also was associated inversely with risk of microscopic colitis (Ptrend = .001). The aHR for each 10-kg weight gain since early adulthood was 0.85 (95% CI, 0.77-0.94). The associations were not modified by age, cohort, physical activity, or smoking status (all Pinteraction ≥ .26). CONCLUSIONS: Unlike many other immune- and metabolic-related disorders, obesity and weight gain since early adulthood were associated with a lower risk of microscopic colitis, based on an analysis of participants in the NHS and NHSII.

Dietary Gluten Intake and Risk of Microscopic Colitis Among US Women without Celiac Disease: A Prospective Cohort Study.

OBJECTIVE: Microscopic colitis is a common cause of chronic watery diarrhea among the elderly. Although the prevalence of celiac disease appears to be higher in patients with microscopic colitis, the relationship between dietary gluten intake and risk of microscopic colitis among individuals without celiac disease has not been explored. METHODS: We conducted a prospective study of 160,744 US women without celiac disease enrolled in the Nurses' Health Study (NHS) and the NHSII. Dietary gluten intake was estimated using validated food frequency questionnaires every 4 years. Microscopic colitis was confirmed through medical records review. We used Cox proportional hazard modeling to estimate the multivariable-adjusted hazard ratio (HR) and 95% confidence interval (CI). RESULTS: We documented 219 incident cases of microscopic colitis over more than 20 years of follow-up encompassing 3,716,718 person-years (crude incidence rate: 5.9/100,000 person-years) in NHS and NHSII. Dietary gluten intake was not associated with risk of microscopic colitis (Ptrend = 0.88). Compared to individuals in the lowest quintile of energy-adjusted gluten intake, the adjusted HR of microscopic colitis was 1.18 (95% CI: 0.77-1.78) for the middle quintile and 1.03 (95% CI: 0.67-1.58) for the highest quintile. Additional adjustment for primary dietary sources of gluten including refined and whole grains did not materially alter the effect estimates (All Ptrend ≥ 0.69). The null association did not differ according to lymphocytic or collagenous subtypes (Pheterogeneity = 0.72) and was not modified by age, smoking status, or body mass index (All Pinteraction ≥ 0.17). CONCLUSIONS: Dietary gluten intake during adulthood was not associated with risk of microscopic colitis among women without celiac disease.