Thiopurine Monotherapy Is Effective in Maintenance of Mild-Moderate Inflammatory Bowel Disease.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are complex, inflammatory bowel diseases (IBD) with debilitating complications. While severe IBD typically requires biologic agents, the optimal therapy for mild-moderate IBD is less clear. AIMS: To assess the efficacy of thiopurine monotherapy for maintenance of mild-moderate IBD and clinical variables associated with treatment outcome. METHODS: This retrospective study included adults with mild-moderate IBD who were started on thiopurines without biologic therapy. The primary outcome was therapy failure, defined by disease progression based on clinical, endoscopic, and radiologic criteria. Clinical variables were extracted at time of thiopurine initiation. Univariable and multivariable Cox proportional hazards models were used to examine the independent contribution of the clinical variables on treatment response. RESULTS: From 230 CD patients, 64 (72%) were free of treatment failure with mean follow-up of 3.3 years. In our multivariable model, thiopurine failure was associated with concomitant systemic steroid administration (aHR 2.43, p = 0.001), whereas protective factors included concomitant oral 5-aminosalicylic acid (5-ASA) therapy (aHR 0.54, p = 0.02) and non-fistulizing, non-stricturing disease (aHR 0.57, p = 0.047). From 173 UC patients, 50 (71%) were free from treatment failure with mean follow-up of 3.3 years. On multivariable analysis, concomitant oral steroids were associated with thiopurine failure (aHR 2.71, p = 0.001). Only 13 (4%) discontinued thiopurines from adverse effects. CONCLUSIONS: In mild-moderate uncomplicated IBD, thiopurine monotherapy was associated with longitudinal maintenance of remission and may represent a lower-cost, convenient, and effective alternative to biologics. Multiple clinical variables were predictive of treatment response.

Cytomegalovirus infection is associated with worse outcomes in inflammatory bowel disease hospitalizations nationwide.

BACKGROUND: Cytomegalovirus (CMV) infection may complicate ulcerative colitis (UC) or Crohn's disease (CD) hospitalizations. Studies examining this relationship are often single-center examining short time periods. AIMS: To quantify the prevalence of CMV and its impact on outcomes among UC and CD hospitalizations over time using nationwide administrative databases. METHODS: The National Inpatient Sample and Nationwide Readmissions Database were analyzed to calculate CMV prevalence per 1000 UC and CD hospitalizations between 1998 and 2014. Univariable and multivariable logistic and linear regression were used to assess CMV's association with outcomes. Separate analyses examined effects from the introduction of anti-TNF therapy in UC in 2005, CD anatomic extent, and Clostridioides difficile infection. RESULTS: Among UC, from 1998 to 2014, the prevalence of CMV infection rose from 1.4 to 6.3 per 1000 UC hospitalizations (p < 0.001), although this increase was not statistically significant for the years 2006 to 2014 (p = 0.07). Among CD, prevalence rose from 0.3 to 1.8 per 1000 CD hospitalizations (p < 0.001) from 1998 to 2014. CMV was independently associated with increased inpatient mortality (UC: odds ratio (OR) 2.3, 95% confidence interval (CI) 1.2-4.5; CD: OR 4.6, CI 1.5-13.7), colectomy in UC (OR 2.5, CI 1.9-3.3), and higher length of stay and costs. CONCLUSION: CMV infection's prevalence among UC and CD hospitalizations is rising over time, but may have slowed after 2005 in UC. CMV is independently associated with increased inpatient mortality, length of stay, and hospital charges in UC and CD and with colectomy in UC.

Rising Incidence of Intestinal Infections in Inflammatory Bowel Disease: A Nationwide Analysis.

Background: Intestinal infections are common in patients with inflammatory bowel disease (IBD) and may mimic IBD flares. In this study, we estimate the changing incidence of intestinal infections among IBD hospitalizations and assess the impact of intestinal infections on key hospitalization metrics. Methods: The National Inpatient Sample (NIS) was analyzed for hospitalizations from IBD between 1998 and 2014. Intestinal infections were identified using ICD-9-CM codes, and incidence for each infection was calculated for Crohn's disease (CD) and ulcerative colitis (UC). Linear and logistic regression analyses were used to assess the effects of intestinal infections on hospitalization duration, charges, and mortality. Results: There were 4,030,620 hospitalizations for IBD between 1998 and 2014. The annual incidence of intestinal infections rose from 26.2 to 70.6 infections per 1000 IBD hospitalizations (Ptrend < 0.01). A main driver of this rising incidence was Clostridium difficile infections, which increased from 7.8 to 32.1 per 1000 CD hospitalizations and from 23.0 to 84.7 per 1000 UC hospitalizations (Ptrend < 0.01). The incidence of other intestinal infections increased from 10.2 to 15.3 per 1000 CD hospitalizations and 16.5 to 25.3 per 1000 UC hospitalizations. Intestinal infections and particularly C. difficile infections were associated with longer hospitalizations, greater hospital charges, and greater all-cause mortality. Conclusions: The incidence of intestinal infections among hospitalized IBD patients has increased over the past 15 years, primarily driven by C. difficile infections. Intestinal infections are associated with length of stay, hospital charges, and all-cause mortality. More aggressive measures for prevention of C. difficile infections are needed. 10.1093/ibd/izy086_video1izy086.video15779257979001.

Prevalence and factors associated with gluten sensitivity in inflammatory bowel disease.

OBJECTIVES: Gluten sensitivity (GS) arises with celiac disease and has also been found in non-celiac disorders, although its characteristics in inflammatory bowel disease (IBD) are unclear. This study evaluated the prevalence of GS and factors associated with GS in IBD. METHODS: Adult IBD patients at a tertiary-care medical center completed a survey of their demographics, medical history, family history, social history and symptoms. Data on IBD characteristics were abstracted from the medical records. Descriptive analyses estimated the prevalence of GS. Multivariable logistic regression assessed the association between GS and patient or disease factors. RESULTS: Of 102 IBD patients (55 Crohn's disease [CD], 46 ulcerative colitis [UC] and 3 IBD-unclassified), GS was reported in 23.6 and 27.3% of CD and UC patients, respectively. Common symptoms included fatigue, abdominal pain, diarrhea, bloating and hematochezia. There was no difference in these symptoms when comparing patients with and without GS. When evaluating IBD-related factors, GS was associated with having had a recent flare (adjusted odds ratio [aOR] 7.4; 95% confidence interval [CI] 1.6-34.1), stenotic disease in CD (aOR 4.7; 95% CI 1.1-20.2) and dermatologic manifestations (aOR 5.5; 95% CI 1.2-24.1). CONCLUSION: GS was common in IBD and associated with having had a recent flare. GS may be transient for some patients, whereby dietary recommendations during and after a flare could focus on the avoidance of specific food triggers with possible reintroduction of these foods over time. This study prompts further prospective investigation into the temporal evolution of GS in IBD.

A randomized clinical trial of vitamin D3 (cholecalciferol) in ulcerative colitis patients with hypovitaminosis D3.

AIM: To prospectively evaluate the effects of vitamin D3 on disease activity and quality of life in ulcerative colitis (UC) patients with hypovitaminosis D. METHODS: The study was a prospective double-blinded, randomized trial conducted at Community Regional Medical Center, Fresno, CA from 2012-2013. Patients with UC and a serum 25(OH)D level <30 ng/ml were eligible for the study. Enrolled subjects were randomized to receive either 2,000 IU or 4,000 IU of oral vitamin D3 daily for a total of 90 days. The Short IBD Questionnaire (SIBDQ) for quality of life, the Partial Mayo Score for UC disease activity and serum lab tests were compared between the two treatment groups. Matched pair t-tests were computed to assess differences between the vitamin D levels, CRP, UC disease activity and SIBDQ scores before and after vitamin D3 therapy using SPSS version 21. RESULTS: Eight UC patients received 2,000 IU/daily and ten UC patients received 4,000 IU/daily of vitamin D3 for 90 days. Vitamin D levels increased after 90 days of oral vitamin D3 in both dose groups. However, the increase in vitamin D levels after 90 days of oral vitamin D3, in the 4,000 IU group was significantly higher 16.80 ± 9.15 (p < 0.001) compared to the 2,000 IU group of vitamin D 5.00 ± 3.12 (p = 0.008). Normal vitamin D levels (>30 ng/dl) were achieved in four out of the ten UC patients (40%) in the 4,000 IU group and in one out of the eight UC patients (12%) in the 2,000 IU group. In the group receiving 4,000 IU/day of vitamin D3 the increase in quality life scores (SIBDQ) was significant 1.0 ± 1.0 (p = 0.017) but not in the 2,000 IU vitamin D3 group 0.1 ± 1.0 (p = 0.87). In the 2,000 IU of vitamin D3 group the mean decrease in the Partial Mayo UC Score was -0.5 ± 1.5 (p = 0.38) compared to -1.3 ± 2.9 (p = 0.19) in the 4,000 IU vitamin D3 group but this was not statistically significant. CRP levels decreased after 90 days of daily vitamin D3 in both the 2,000 IU group and 4,000 IU group by -3.0 ± 9.4 (p = 0.4) and -10.8 ± 35.0 (p = 0.36) respectively. CONCLUSION: Vitamin D3 at 4,000 IU/day is more effective than 2,000 IU/day in increasing vitamin D to sufficient levels in UC patients with hypovitaminosis D, however higher doses or treatment beyond ninety days may be required. Vitamin D3 may improve the quality of life in UC patients but clinically significant improvement is not yet established. The effect of vitamin D3 on UC disease activity is still unclear. Further larger studies are needed to investigate the effects of vitamin D in ulcerative colitis.

Role of Vitamin D in Inflammatory Bowel Disease.

Vitamin D is a secosteroid hormone that possesses immunomodulatory properties and has been demonstrated to potentially influence inflammatory bowel disease (IBD) pathogenesis and activity. Epidemiologic data have associated vitamin D deficiency with an increased risk of IBD, hospitalizations, surgery, and loss of response to biologic therapy. Conversely, IBD itself can lead to vitamin D deficiency. This bidirectional relationship between vitamin D and IBD suggests the need for monitoring and repletion of vitamin D, as needed, in the IBD patient. This review discusses the role of vitamin D in IBD and provides practical guidance on vitamin D repletion.

The Gastroenterology Fellowship Match: A Decade Later.

Following a period of uncertainty and disorganization, the gastroenterology (GI) national leadership decided to reinstitute the fellowship match (the Match) under the auspices of the National Residency Matching Program (NRMP) in 2006. Although it has now been a decade since the rebirth of the Match, there have been limited data published regarding progress made. In this piece, we discuss reasons for the original collapse of the GI Match, including most notably a perceived oversupply of GI physicians and a poor job market. We discuss the negative impacts the absence of the Match had on programs and on applicants, as well as the impetus to reorganize the Match under the NRMP. We then utilize data published annually by the NRMP to demonstrate that in the decade since its rebirth, the GI Match has been remarkably successful in terms of attracting the participation of applicants and programs. We show that previous misguided concerns of an oversupply of GI physicians were not realized, and that GI fellowship positions remain highly competitive for internal medicine applicants. Finally, we discuss possible implications of recent changes in the healthcare landscape on the GI Match.

Postmenopausal hormone therapy and colorectal cancer risk in relation to somatic KRAS mutation status among older women.

BACKGROUND: Postmenopausal hormone (PMH) therapy represents a controversial colorectal cancer (CRC) preventive intervention. Because colorectal carcinogenesis is a heterogeneous process, we evaluated associations between PMH therapy and incident CRC in relation to KRAS mutation status in a population-based cohort of older women [Iowa Women's Health Study (IWHS)]. METHODS: The IWHS enrolled 41,836 randomly selected women, ages 55 to 69 years, in 1986. PMH therapy and other exposure data were recorded at baseline. Tissue samples from prospectively identified CRC cases (n = 507) were analyzed for somatic KRAS mutations (exon 2, codons 12 and 13). Multivariable Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI). RESULTS: PMH therapy (ever vs. never) was inversely associated with KRAS mutation-negative (RR = 0.83; 95% CI, 0.66-1.06; P = 0.14) and KRAS mutation-positive (RR = 0.82; 95% CI, 0.58-1.16; P = 0.27) tumors, although the observed risk estimates were not statistically significant. When anatomic subsite was additionally considered, the strongest association was found for KRAS mutation-negative, distal colorectal tumors (RR = 0.64; 95% CI, 0.43-0.96; P = 0.03). CONCLUSIONS: To our knowledge, we provide the first report of KRAS-defined CRC risks associated with PMH therapy. These data suggest that PMH therapy may reduce CRC risk through mechanisms beyond KRAS mutation status but might provide greater benefits for KRAS mutation-negative than mutation-positive tumors (at least in the distal colorectum). IMPACT: Findings from this prospective cohort study provide novel insights about the molecular biology of PMH therapy-related CRC risk reduction.

Postmenopausal hormone therapy and colorectal cancer risk by molecularly defined subtypes among older women.

BACKGROUND: Postmenopausal hormone (PMH) therapy may reduce colorectal cancer (CRC) risk, but existing data are inconclusive. OBJECTIVES: To evaluate associations between PMH therapy and incident CRC, overall and by molecularly defined subtypes, in the population-based Iowa Women's Health Study of older women. METHODS: Exposure data were collected from Iowa Women's Health Study participants (55-69 years) at baseline (1986). Archived, paraffin-embedded tissue specimens for 553 CRC cases were collected and analysed to determine microsatellite instability (MSI-L/MSS or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive) and BRAF mutation (BRAF-wildtype or BRAF-mutated) status. Multivariable Cox regression models were fit to estimate RRs and 95% CIs. RESULTS: PMH therapy (ever vs never use) was inversely associated with incident CRC overall (RR=0.82; 95% CI 0.72 to 0.93), with a significantly lower risk for MSI-L/MSS tumours (RR=0.75; 95% CI 0.60 to 0.94), and borderline significantly lower risks for CIMP-negative (RR=0.79; 95% CI 0.63 to 1.01) and BRAF-wildtype (RR=0.83; 95% CI 0.66 to 1.04) tumours. For PMH therapy >5 years, the subtype-specific risk estimates for MSI-L/MSS, CIMP-negative and BRAF-wildtype tumours were: RR=0.60, 95% CI 0.40 to 0.91; RR=0.68, 95% CI 0.45 to 1.03; and RR=0.70, 95% CI 0.47 to 1.05, respectively. PMH therapy was not significantly associated with the MSI-H, CIMP-positive or BRAF-mutated CRC subtypes. CONCLUSIONS: In this prospective cohort study, PMH therapy was inversely associated with distinct molecularly defined CRC subtypes, which may be related to differential effects from oestrogen and/or progestin on heterogeneous pathways of colorectal carcinogenesis.

Cigarette smoking and colorectal cancer risk by molecularly defined subtypes.

BACKGROUND: Cigarette smoking is an established risk factor for colorectal cancer. Because colorectal carcinogenesis is a heterogeneous process, we investigated whether cigarette smoking is differentially associated with molecularly defined subtypes of colorectal cancer. METHODS: We evaluated associations between smoking and incident colorectal cancer, overall and by microsatellite instability (MSI) phenotype (MSI-high vs MSI-low or microsatellite stable), CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation status (BRAF mutation positive or BRAF mutation negative), among 37 399 participants in a population-based cohort study (the Iowa Women's Health Study). Cigarette smoking (and other exposures) was assessed by self-report at baseline in 1986, including smoking status (never and ever [former or current]), age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period. Vital status and state of residence were determined by mailed follow-up questionnaires in 1987, 1989, 1992, and 1997 and by linkage to Iowa death certificate records. Nonrespondents were checked via the National Death Index to identify descendants. Participants with newly diagnosed (ie, incident) colorectal cancer were identified through annual linkage with the Iowa Cancer Registry. Archived paraffin-embedded tumor tissue specimens were obtained for 555 patients with colorectal cancer who were diagnosed from January 1, 1986, through December 31, 2002, and MSI status, CIMP status, and BRAF status were determined. Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: Ever-smokers were at moderately increased risk for incident colorectal cancer (RR = 1.19, 95% CI = 1.05 to 1.35) compared with never-smokers. Higher risk estimates were observed for current smokers with MSI-high tumors (RR = 1.99, 95% CI = 1.26 to 3.14), CIMP-positive tumors (RR = 1.88, 95% CI = 1.22 to 2.90), and BRAF mutation-positive tumors (RR = 1.92, 95% CI = 1.22 to 3.02). Other smoking-related variables (ie, age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period) were also associated with MSI-high, CIMP-positive, and BRAF mutation-positive tumor subtypes. Conversely, cigarette smoking status (ever vs never) was not associated with the MSI-low or microsatellite stable (RR = 1.00, 95% CI = 0.79 to 1.25), CIMP-negative (RR = 1.02, 95% CI = 0.81 to 1.30), or BRAF mutation-negative subtypes (RR = 1.00, 95% CI = 0.65 to 1.27). CONCLUSIONS: In this prospective study of older women, cigarette smoking was associated with the MSI-high, CIMP-positive, and BRAF mutation-positive colorectal cancer subtypes, which indicates that epigenetic modification may be functionally involved in smoking-related colorectal carcinogenesis.

Observer variability in the histologic diagnosis of microscopic colitis.

BACKGROUND: Microscopic colitis is diagnosed based on histologic criteria. There has been no investigation of the reproducibility of the histologic diagnosis of microscopic colitis. Our aim was to evaluate interobserver and intraobserver variation in this diagnosis. METHODS: Colonic biopsies from 90 subjects (20 lymphocytic colitis, 20 collagenous colitis, 20 inflammatory bowel disease, and 30 normal) were blindly and independently reviewed by 4 gastrointestinal pathologists. The biopsies were classified by each pathologist into 1 of 6 diagnostic categories: lymphocytic colitis, collagenous colitis, active chronic colitis, focal active colitis, normal, or other. The slides were then relabeled and blindly reinterpreted 3 months later. The degree of agreement was determined using kappa statistics (lambda). RESULTS: Interobserver agreement with the 6 diagnostic categories was 69% (kappa = 0.76, 95% CI 0.69, 0.83) and 70% (kappa = 0.71, 95% CI 0.61, 0.79) for the first and second observations, respectively. Interobserver agreement with final diagnostic categories of microscopic colitis versus nonmicroscopic colitis was 91% (kappa = 0.90, 95% CI 0.82, 0.96) and 88% (kappa = 0.83, 95% CI 0.73, 0.92), respectively. Mean intraobserver agreement with the 6 diagnostic categories was 83% (kappa = 0.77). Mean intraobserver agreement with the final diagnostic categories of microscopic colitis versus nonmicroscopic colitis was 95% (kappa = 0.89). CONCLUSIONS: Both interobserver and intraobserver agreement were good in distinguishing among the 6 diagnostic categories, and excellent in distinguishing between microscopic colitis and nonmicroscopic colitis diagnoses. The histologic criteria for microscopic colitis provide for consistent and reproducible interindividual and intraindividual diagnoses in the evaluation of colonic biopsies.

Symptomatic overlap between irritable bowel syndrome and microscopic colitis.

BACKGROUND: Microscopic colitis is diagnosed on the basis of histologic criteria, and irritable bowel syndrome (IBS) is diagnosed by symptom-based criteria. There has been little investigation into the symptomatic overlap between these conditions. Our aim was to assess the prevalence of symptoms of irritable bowel syndrome in a population-based cohort of patients with microscopic colitis. METHODS: The Rochester Epidemiology Project (REP), a medical records linkage system providing all health care data for the defined population of Olmsted County, Minnesota, was used to identify all county residents with a diagnosis of microscopic colitis between 1985 and 2001. The medical records of these individuals were reviewed to ascertain symptoms consistent with Rome, Rome II, and Manning criteria for irritable bowel syndrome. RESULTS: One hundred thirty-one cases of microscopic colitis were identified. Median age at diagnosis was 68 years (range, 24-95); 71% were women. Sixty-nine (53%) and 73 (56%) met Rome and Rome II criteria for irritable bowel syndrome, respectively. Fifty-four (41%) had three or more Manning criteria. Forty-three (33%) had previously been diagnosed with irritable bowel syndrome. CONCLUSIONS: In this population-based cohort of histologically confirmed microscopic colitis, approximately one-half met symptom-based criteria for the diagnosis of irritable bowel syndrome. The clinical symptom-based criteria for irritable bowel syndrome are not specific enough to rule out the diagnosis of microscopic colitis. Therefore, patients with suspected diarrhea-predominant irritable bowel syndrome should undergo biopsies of the colon to investigate for possible microscopic colitis if symptoms are not well controlled by antidiarrheal therapy.