Abdominal pain is associated with an increased risk of future healthcare resource utilization in inflammatory bowel disease.

BACKGROUND: Numerous factors influence healthcare resource utilization (HRU) in inflammatory bowel disease (IBD). We previously demonstrated an association between the presence of certain IBD-related symptoms and HRU. We conducted a longitudinal study to identify the clinical variables and IBD-related symptoms predictive of HRU. METHODS: This investigation utilized clinical encounters at an IBD center within a tertiary care referral center between 10/29/2015-12/31/2019. Participants were assessed over two time points (index and follow-up office visits) separated by a minimum of 6 months. Demographics, endoscopic disease severity, totals and sub-scores of surveys assessing for IBD-related symptoms, HRU, and substance use, and IBD-related medications. HRU was defined as any IBD-related emergency room visit, hospitalization, or surgery during the 6 months prior to follow-up appointment. We identified patients exhibiting HRU (at follow-up) and computed descriptive statistics and contingency table analyses of index appointment clinical data to identify predictors of HRU. Multivariable logistic regression models were fit incorporating significant demographic and clinical factors. RESULTS: 162 consecutively enrolled IBD patients (mean age 44.0 years; 99f:63 m; 115 Crohn's disease [CD], 45 ulcerative colitis [UC], 2 indeterminate colitis) were included. 121 patients (74.7%) exhibited HRU (mean age 43.6 years; 73f:48 m; 84 CD, 36 UC, 1 IC) preceding follow-up appointment. Abdominal pain (OR = 2.18, 95% CI 1.04-4.35, p = 0.04) at the index appointment was the only study variable significantly associated with HRU on bivariate analysis (Table 1). However, none of the clinical factors evaluated in this study were independently associated with HRU in our multivariable logistic regression model. CONCLUSIONS: In this longitudinal study, abdominal pain was the only clinical variable that demonstrated an association with future HRU (even when considering other symptoms and key variables such as disease activity, IBD-medications, and psychiatric comorbidities (i.e., anxious or depressed state). These findings reinforce the importance of regularly screening for and effectively treating abdominal pain in IBD.

Lifestyle Factors Associated with Abdominal Pain in Quiescent Inflammatory Bowel Disease.

BACKGROUND: Lifestyle factors, including diet, exercise, substance use, and sexual activity, have been shown to influence risk of inflammation and complications in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Little is known about their potential role in abdominal pain generation in IBD. AIMS: We performed this study to evaluate for relationships between lifestyle factors and abdominal pain in quiescent IBD (QP-IBD). METHODS: We performed a retrospective analysis utilizing data from our institution's IBD Natural History Registry (January 1, 2017-December 31, 2022). Endoscopic evaluation, concurrent laboratory studies and surveys were completed by participants. Demographic and clinical data were also abstracted. RESULTS: We identified 177 consecutive patients with quiescent disease (105 females:72 males; 121 with CD:56 with UC) for participation in this study, 93 (52.5%) had QP-IBD. Compared to patients with quiescent IBD without pain (QNP-IBD, patients with QP-IBD exhibited no significant differences in IBD type, location, severity or complication rate. Patients with QP-IBD were more likely to have anxiety/depression (55.9% vs. 32.1%, p = 0.002) and to use antidepressants/anxiolytics (49.5% vs. 21.4%, p < 0.001). They were also less likely to engage in exercise at least three times per week (39.8% vs. 54.8%, p = 0.05) or participate in sexual activity at least monthly (53.8% vs. 69.1%, p = 0.04). On logistic regression analysis, antidepressant and/or anxiolytic use was independently associated with QP-IBD [2.72(1.32-5.62)], while monthly sexual activity was inversely associated [0.48(0.24-0.96)]. CONCLUSION: Lifestyle factors, including the lack of sexual activity and exercise, are significantly associated with QP-IBD. Further study is warranted to clarify the relationships between these factors and the development of abdominal pain in quiescent IBD.

COVID-19 Vaccine Hesitancy in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: COVID-19 vaccine hesitancy varies across the USA. Data on COVID-19 vaccine hesitancy in patients with inflammatory bowel disease (IBD) are lacking. We assessed COVID-19 vaccine hesitancy and its associated variables in patients with IBD. METHODS: We evaluated voluntary patient survey responses during routine clinical visits to our IBD center. Data collected included demographic and clinical characteristics. Descriptive statistics, univariate and multivariate analyses were performed to evaluate significant associations with COVID-19 vaccine hesitancy. RESULTS: A total of 239 individuals completed the survey. Over a third of respondents (35.6%) expressed hesitancy toward receiving the COVID-19 vaccine due to vaccine safety concerns (49.4%) and efficacy (23.5%), while others reported non-specific concerns (34.1%). On univariate analysis, Crohn's disease (OR 2.33 CI 1.28-4.25 p = 0.0056), use of biologic medications (OR 1.93 CI 1.16-3.23, p = 0.012), previous self-reported vaccine refusal (OR 8.13 CI 2.90-22.82 p = 0.0001), earlier date of survey administration (OR 2.01 CI 1.17-3.44 p = 0.011), and self-reported COVID infection (OR 2.55 CI 1.16-5.61 p = 0.0056) were more likely to be associated with COVID-19 vaccine hesitancy. On multivariate analysis, patient age, previous vaccine refusal and date of survey administration were more likely to be associated with COVID-19 vaccine hesitancy. CONCLUSIONS: Over one-third of patients with IBD expressed COVID-19 vaccine hesitancy. Vaccine safety and efficacy were the most common reasons. Younger age, previous vaccine refusal and earlier date of survey were more likely to be associated with hesitancy. Our findings suggest that there is room for targeted education to improve COVID-19 vaccine uptake in patients with IBD.

Abdominal pain in quiescent inflammatory bowel disease.

OBJECTIVES: Inflammation is an important driver of abdominal pain in inflammatory bowel disease (IBD). However, some patients in remission still experience pain. We aimed to identify risk factors associated with abdominal pain in quiescent IBD (QP-IBD) and to characterize differences from patients with active disease experiencing pain (AP-IBD). METHODS: We performed a retrospective analysis utilizing data from our institution's IBD Natural History Registry (January 1, 2015-August 31, 2018). Endoscopic evaluation, concurrent laboratory studies, and validated surveys were completed by participants. Demographic and clinical data were also abstracted. RESULTS: We recruited 122 patients with quiescent disease (65f:57 m; 93CD:26UC:3Indeterminate) for participation in this study, 74 (60.7%) had QP-IBD. QP-IBD patients were more likely to have anxiety/depression (71.6% vs. 25.0%, p < 0.001) or to use antidepressants (47.3% vs. 22.9%, p < 0.010), opiates (18.9% vs. 2.1%, p < 0.010), other pain medications (50.0% vs. 18.8%, p < 0.010), or corticosteroids (18.9% vs. 2.1%, p < 0.010). On logistic regression analysis, corticosteroid use, anxious/depressed state, and female gender were each independently associated with QP-IBD (p < 0.050 or less). Compared with AP-IBD patients (n = 110, 59f:51 m; 69CD:38UC:3Indeterminate), QP-IBD patients were more likely to use antidepressants (45.6% vs. 26.4%, p < 0.010). Platelet, white blood cell, C-reactive protein, and sedimentation rate levels were all less likely to be elevated in QP-IBD (all p < 0.050), though 44% exhibited pathological elevation in at least one. DISCUSSION: QP-IBD was independently associated with corticosteroid use, anxiety/depression, and female gender. Compared with AP-IBD, QP-IBD patients were more likely to use antidepressants and less likely to exhibit elevated inflammatory markers. However, many QP-IBD patients still demonstrated pathological elevation of these tests, demonstrating the need to develop new noninvasive screening methods for this condition.

Anxiety, depression, and inflammation after restorative proctocolectomy.

PURPOSE: Anxiety and depression (A&D) are more common in inflammatory bowel disease (IBD) and in IBD patients who undergo proctocolectomy with ileal pouch-anal anastomosis (IPAA). Our aim was to test the hypothesis that chronic inflammatory conditions in IPAA are associated with increased incidence of A&D. METHODS: Retrospective cohort study at a single tertiary care referral center using a consented IBD and colon cancer natural history registry. Demographic and clinical factors, including surgical and psychiatric history, were abstracted. RESULTS: We compared A&D rate in three cohorts: (1) ulcerative proctocolitis with IPAA (UC) (n = 353), (2) Crohn's disease/indeterminate proctocolitis with IPAA (CDIC) (n = 49), and (3) familial adenomatous polyposis with IPAA (FAP) (n = 33). Forty-six CDIC patients (93.9%) demonstrated pouch-related inflammation, while 126 UC patients (35.7%) and 2 FAP patients (6.1%) developed pouchitis. CDIC had a higher rate of A&D co-diagnosis compared to UC and FAP (20.4 vs.12.7 vs.12.1% respectively; p < 0.05). UC patients with pouchitis also exhibited a higher rate of A&D than UC without pouchitis (19.8 vs.8.8%; p < 0.05). Multivariable analysis demonstrated that pre-operative corticosteroid use (OR = 4.46, CI = 1.34-14.87, p < 0.05), female gender (OR = 2.19, CI = 1.22-3.95, p < 0.01), tobacco use (OR = 2.92, CI = 1.57 = 5.41, p < 0.001), and pouch inflammation (OR = 2.37, CI = 1.28-4.39, p < 0.05) were each independently associated with A&D in these patients. CONCLUSIONS: Anxiety and depression were more common in patients experiencing inflammatory conditions of the pouch. UC without pouchitis and FAP patients demonstrated lower rates of A&D (that were comparable to the general population), implying that having an IPAA alone was not enough to increase risk for A&D. Factors independently associated with A&D in IPAA included an inflamed pouch, corticosteroid use, smoking, and female gender.

Economics of Emergency Department Visits by Patients With Inflammatory Bowel Disease: A Real-World Analysis.

Background: Inflammatory bowel disease (IBD) is associated with significant psychosocial, economic, and physical burden on patients. IBD care in the United States results in significant healthcare expenditure with recurring emergency department (ED) care and hospital admissions. Despite advances in therapy and improved access to specialty care, there is still room for improvement in cost-efficient care. Specialty medical homes and interdisciplinary care models have emerged as ways to improve medical care, patient outcomes, and quality of life, as well as improve the impact of healthcare costs. There is limited real-world data on cost in the United States, with many articles citing cost estimates from models. Methods: We analyzed real-world data from our tertiary care center with a focus on recurrent ED visits by IBD patients. Descriptive statistics were used for a cost analysis of multiple ED visits by IBD patients. Patients with ≥4 visits to the ED in a 6-month period were described as SuperUsers and were included in a separate analysis. The cost of hospitalization was also included. Results: Total cost associated with all ED visits from SuperUsers were $72 999.57 with an average of $6636.32 per patient. When the patients were admitted, the total cost of ED visits and hospitalizations was $721 461.52, with an average of $65 587.41 per patient. Conclusions: ED utilization by IBD patients with or without hospitalization is expensive and is typically driven by a cohort of SuperUsers. More work needs to be done to improve cost-effectiveness in IBD care, including reducing the frequency of ED visits.

Lifestyle Factors and Silent Inflammatory Bowel Disease.

Introduction: Hypoalgesic or silent inflammatory bowel disease (IBD) is a poorly understood condition that has been associated with poor clinical outcomes. There is evidence that lifestyle factors, including diet, exercise, and substance use can influence inflammatory activity and symptoms in IBD. It is unclear, though, whether these issues impact pain experience in IBD. We performed this study to evaluate the potential relationship between several key lifestyle factors and silent IBD. Methods: We performed a retrospective analysis using an IBD natural history registry based in a single tertiary care referral center. We compared demographic and clinical features in 2 patient cohorts defined using data from simultaneous pain surveys and ileocolonoscopy: (a) active IBD without pain (silent IBD) and (b) active IBD with pain. We also evaluated the relative incidence of characteristics related to diet, exercise, sexual activity, and substance abuse. Results: One hundred and eighty IBD patients had active disease and 69 (38.3%) exhibited silent IBD. Silent IBD patients exhibited incidences of disease type, location, and severity as pain-perceiving IBD patients. Silent IBD patients were more likely to be male and less likely to exhibit anxiety and/or depression or to use cannabis, analgesic medication, or corticosteroids. There were no significant differences in dietary, exercise-related, or sexual activities between silent and pain-perceiving IBD patients. Conclusions: Silent IBD was associated with reduced incidence of substance and analgesic medication use. No relationships were found between silent IBD and diet, exercise, or sexual activity, though specific elements of each require further dedicated study.

Polysubstance use in inflammatory bowel disease is associated with increased risk of emergency department visits: a longitudinal study.

Background: Polysubstance use (PSU), the simultaneous use of 2 or more substances of abuse, is common in inflammatory bowel disease (IBD). Preliminary studies suggest it may be associated with poor outcomes. This prospective study evaluated the impact of PSU on disease activity and healthcare resource utilization in IBD. Methods: This study was conducted in a tertiary IBD center between October 29, 2015, and December 31, 2019. Participants were assessed over 2 time points (index and follow-up outpatient appointments) separated by a minimum of 6 months. Demographics, endoscopic disease activity, and surveys assessing symptoms, healthcare resource utilization and substance use (tobacco, alcohol, marijuana, cocaine, methamphetamine, heroin, opioid, or benzodiazepine) were abstracted. We identified PSU during the index appointment and computed descriptive statistics and contingency table analyses, and multivariate logistic regression models at follow up to evaluate outcomes. Results: 162 consecutively enrolled IBD patients were included. Seventy-five patients (46%) were polysubstance users at the index appointment. The most common cohorts were utilizing tobacco and alcohol (n=40) or tobacco and opioids (n=13). On bivariate and multivariate analyses, PSU during the index visit was positively associated with emergency department (ED) visits (odds ratio [OR] 2.51, 95% confidence interval [CI] 1.24-5.07; P=0.01) and negatively associated with extraintestinal manifestations (OR 0.37, 95%CI 0.18-0.74; P=0.005). Age, sex, disease activity, disease subtype and IBD-related symptoms were not associated with PSU. Conclusions: IBD patients exhibiting PSU had increased risk of future ED visits. This study highlights the risks of PSU and reinforces the importance of appropriate substance use screening.

Dedicated Psychiatry Clinic for Inflammatory Bowel Disease Patients Has a Positive Impact on Depression Scores.

Background: Psychiatric disorders, including anxiety and depression, are significantly more common in patients with inflammatory bowel disease (IBD). We established an integrated psychiatry clinic for IBD patients at our tertiary center IBD clinic to provide patients with critical, but frequently unavailable, coordinated mental health services. We undertook this study to evaluate the impact of this service on psychiatric outcomes, quality of life, and symptom experience. Methods: We performed a longitudinal prospective study comparing patients who had been cared for at our integrated IBD-psychiatry clinic to those who had not. We abstracted demographic and clinical information as well as contemporaneous responses to validated surveys. Results: Thirty-six patients cared for in the IBD psychiatry clinic were compared to a control cohort of 35 IBD patients. There was a significant reduction in the Hospital Anxiety and Depression Scale (HADS) depression score over time in the study cohort (p = 0.001), though not in the HADS anxiety score. When compared to the control group, the study cohort showed a significant reduction in the HADS depression score. No significant differences were observed in the Harvey-Bradshaw Index, Simple Clinical Colitis Activity Index, or Short IBD Questionnaire. Conclusions: This is the first study to evaluate the impact of an integrated psychiatry clinic for IBD patients. Unlike their control counterparts, individuals treated in this clinic had a significant reduction in the mean HADS depression score. Larger scale studies are necessary to verify these findings. However, this study suggests that use of an integrated psychiatry IBD clinic model can result in improvement in mental health outcomes, even in the absence of significant changes in IBD activity.

Symptoms and Extraintestinal Manifestations in Active Cannabis Users with Inflammatory Bowel Disease.

Introduction: Cannabis use is common in the setting of inflammatory bowel disease (IBD). Patients frequently use cannabis to treat IBD-associated symptoms, and there is evidence that cannabis and its derivatives are helpful for this purpose. However, it is unclear how the symptom profiles of active IBD cannabis users and nonusers compare and how these symptoms may relate to their underlying disease state and/or complications. Materials and Methods: We performed a retrospective cohort study using a consented IBD natural history registry from a single tertiary care referral center between January 1, 2015 and August 31, 2020. We asked patients about current cannabis use and frequency. We also abstracted demographic and clinical characteristic information, including endoscopic severity, and totals and subscores of surveys assessing IBD characteristics, presence of anxiety/depression, and IBD-associated symptoms. We compared clinical and demographic factors of cannabis users and nonusers and developed a logistic regression model to evaluate for independent associations with cannabis use. Results: Three hundred eighty-three IBD patients met the inclusion criteria (206 females, 177 males; 258 Crohn's disease [CD], 118 ulcerative colitis, and 7 indeterminate colitis). Thirty patients (7.8%) were active cannabis users, consuming it for an average of 2.7 times per week. Cannabis users were more likely to report abdominal pain (83.3% vs. 61.7%), gas (66.7% vs. 45.6%), tenesmus (70.0% vs. 47.6%), and arthralgias (53.3% vs. 20.3%) compared to those that did not use cannabis (p<0.05 for each). Incidence of moderate-severe endoscopic inflammation was similar between cannabis users and nonusers, while CD-associated complications were more common in nonusers (39.1% vs. 69.7%, p<0.05). The only factor that demonstrated a significant association with cannabis use on multivariable analysis was arthralgia (p<0.01). Discussion: Active IBD cannabis users were more likely to report a variety of symptoms, including abdominal pain, gas, tenesmus, and arthralgias. However, they did not demonstrate more frequent active disease or IBD-associated complications, suggesting that other nonluminal factors influence their symptoms and/or decision to use cannabis. These findings demonstrate the importance of evaluating for extraintestinal contributors to symptom burden in IBD cannabis users, as well as the ongoing need to develop safer and more effective methods for recognizing and managing abdominal pain and other symptoms in this setting.

Symptoms associated with healthcare resource utilization in the setting of inflammatory bowel disease.

Several symptoms have been connected to increased healthcare resource utilization (HRU) in the context of inflammatory bowel disease (IBD), including both Crohn's disease (CD) and ulcerative colitis (UC). This study was designed to investigate the prevalence of IBD-associated symptoms and to determine whether any are independently associated with HRU. We undertook a retrospective analysis of data related to consecutive IBD patient encounters from a tertiary care referral center between 1/1/2015 and 8/31/2019. Demographics, clinical activity, endoscopic severity, IBD-related symptom scores, anxiety and depression scores, and other key clinical data were abstracted. Four hundred sixty-seven IBD patients [247f.: 220 m; 315 CD, 142 UC and 11 indeterminate colitis] were included in this study. The most common symptoms were fatigue (83.6%), fecal urgency (68.2%) and abdominal pain (63.5%). Fatigue, abdominal pain, anxiety or depression, corticosteroids, and opioids were each positively associated with HRU, while NSAID and mesalamine use were inversely associated on bivariate analysis. The only factor that demonstrated a statistically significant association with HRU in the whole cohort on multivariable analysis was abdominal pain. Abdominal pain is independently associated with HRU and should be specifically screened for in IBD patients to identify individuals at risk of undergoing expensive interventions. This study also reinforces the importance of optimizing diagnostic and therapeutic management of abdominal pain in IBD.

Combined epigenetic and immunotherapy for blastic and classical mantle cell lymphoma.

Classical MCL (cMCL) constitutes 6-8% of all B cell NHL. Despite recent advances, MCL is incurable except with allogeneic stem cell transplant. Blastic mantle cell lymphoma (bMCL) is a rarer subtype of cMCL associated with an aggressive clinical course and poor treatment response, frequent relapse and poor outcomes. We treated 13 bMCL patients with combined epigenetic and immunotherapy treatment consisting of vorinostat, cladribine and rituximab (SCR). We report an increased OS greater than 40 months with several patients maintaining durable remissions without relapse for longer than 5 years. This is remarkably better then current treatment regimens which in bMCL range from 14.5-24 months with conventional chemotherapy regimens. We demonstrate that the G/A870 CCND1 polymorphism is predictive of blastic disease, nuclear localization of cyclinD1 and response to SCR therapy. The major resistance mechanisms to SCR therapy are loss of CD20 expression and evasion of treatment by sanctuary in the CNS. These data indicate that administration of epigenetic agents improves efficacy of anti-CD20 immunotherapies. This approach is promising in the treatment of MCL and potentially other previously treatment refractory cancers.

Impact of a nurse navigator on a dedicated inflammatory bowel disease-focused gastroenterology clinic.

BACKGROUND: Management of inflammatory bowel disease (IBD) patients can be very challenging. Nurse navigators (NNs) have demonstrated great promise for coordinating care of complex disorders but little is known about their impact on the setting of IBD. We undertook this study to evaluate how the introduction of a NN in a dedicated IBD clinic would influence several outcomes related to patient care. METHODS: A retrospective chart review was performed evaluating Penn State IBD clinic patients receiving care a year before and after the introduction of a dedicated NN to the clinic. No-show rates, new appointments in less than 21 days, total clinic visits per month, and patient enrolment in our IBD registry and biorepository were measured prior to and after hiring of the NN between 2 providers. Each provider and their composite data were statistically compared using univariate analysis. RESULTS: After hiring the NN, there was a statistically significant decrease in combined no-show rates (P=0.02). There was no significant difference in the combined average number of new appointments in less than 21 days (P=0.62) or total clinic visits per month (P=0.09). Enrolment in the database and biorepository increased (from 83% to 90%). Finally, 97% were satisfied with the NN's services, and 94% were satisfied with the IBD education they provided. CONCLUSIONS: Hiring a NN in our clinic was associated with high patient satisfaction, reduced no-show rates, and increased research participation. Thus, incorporation of a NN can improve care in an IBD-centered gastroenterology clinic.

Polysubstance use in inflammatory bowel disease.

OBJECTIVES: We aimed to evaluate the incidence, predisposing factors and impacts of polysubstance use (PSU) (ie, the concurrent use or abuse of two or more drugs or substances) in inflammatory bowel disease (IBD). METHODS: Data of patients enrolled between 1 January 2015 and 31 August 2019 from a single tertiary care referral center were retrospectively collected. Patients' baseline and clinical characteristics and their antidepressant and/or anxiolytic medications were abstracted. Associations between PSU and patients' characteristics were analyzed. Multivariate logistic regression models were fit, incorporating significant clinical factors. RESULTS: Altogether 315 patients with IBD (166 women, 149 men; 214 with Crohn's disease and 101 ulcerative colitis) were enrolled. Of them, 66 (21.0%) exhibited PSU (CD 21.5%, UC 19.8%); 37.5% had moderate to severe disease activity, 34.3% with extraintestinal manifestations (EIM), 41.6% with an anxious or depressed state and 69.8% had used healthcare resources in the prior 12 months. Moreover, 71.2% used two substances, while 27.3% used three substances. In the total cohort, EIM (odds ratio [OR] 1.97, 95% confidence interval [CI] 1.14-3.34, P = 0.019) and antidepressant or anxiolytic use (OR 2.51, 95% CI 1.45-4.39, P < 0.001) were positively associated with PSU on multivariate analysis. PSU was associated with increased rate of IBD-associated imaging (57.6% vs 47.0%, P < 0.05). CONCLUSIONS: PSU is common in IBD. EIM, antidepressant and/or anxiolytic use and imaging studies were independently associated with PSU. This study reinforces the importance of screening patients with IBD for substance use, particularly those with EIM and using antidepressants and/or anxiolytics.

Abdominal Pain and Anxious or Depressed State Are Independently Associated With Weight Loss in Inflammatory Bowel Disease.

BACKGROUND: Many factors impact nutritional status in inflammatory bowel disease (IBD). We undertook this study to evaluate the potential role that abdominal pain has on weight loss and dietary behavior in IBD. METHODS: This is a retrospective cohort study utilizing data from an IBD registry at our institution between January 1, 2015 and August 31, 2018. Pain scores and nutritional outcomes were derived from validated questionnaires while key associated clinical data were derived from the medical record. RESULTS: Three hundred and three patients (154 females; 206 Crohn's disease) were included in this study. Ninety-six patients (31.7%) had experienced a 6-lb or greater weight loss in the prior month. On multivariate analysis, abdominal pain and anxious/depressed state were independently associated with weight loss, while female gender and NSAID use were inversely associated with weight loss (P < 0.05). IBD patients with abdominal pain also reported significantly poorer dietary behavior than those without this symptom. CONCLUSIONS: Abdominal pain is more likely to result in negative dietary outcomes and independently associated with weight loss in IBD. IBD providers should screen for malnutrition when patients report abdominal pain.

Gastrointestinal hypoalgesia in inflammatory bowel disease.

BACKGROUND: Pain perception is critical for detection of noxious bodily insults. Gastrointestinal hypoalgesia in inflammatory bowel disease (IBD) is a poorly understood phenomenon previously linked to poor patient outcomes. We aimed to evaluate the risk factors associated with this condition and to discern characteristics that might differentiate these patients from pain-free quiescent counterparts. METHODS: We performed a retrospective analysis using an IBD natural history registry based in a single tertiary care referral center. We compared demographic and clinical features in 3 patient cohorts defined using data from simultaneous pain surveys and ileocolonoscopy: a) active IBD without pain (hypoalgesic IBD); b) active IBD with pain; and c) inactive IBD without pain. RESULTS: One hundred fifty-three IBD patients had active disease and 43 (28.1%) exhibited hypoalgesia. Hypoalgesic IBD patients were more likely to develop non-perianal fistulae (P=0.03). On logistic regression analysis, hypoalgesic IBD was independently associated with male sex, advancing age and mesalamine use, and inversely associated with anxious/depressed state and opiate use. Hypoalgesic IBD patients were demographically and clinically similar to the pain-free quiescent IBD cohort (n=59). Platelet count and C-reactive protein were more likely to be pathologically elevated in hypoalgesic IBD (P=0.03), though >25% did not exhibit elevated inflammatory markers. CONCLUSIONS: Hypoalgesia is common in IBD, particularly in male and older individuals, and is associated with an increased incidence of fistulae and corticosteroid use. Novel noninvasive diagnostic tools are needed to screen for this population, as inflammatory markers are not always elevated.

NKX3.1 homeodomain protein binds to topoisomerase I and enhances its activity.

The prostate-specific homeodomain protein NKX3.1 is a tumor suppressor that is commonly down-regulated in human prostate cancer. Using an NKX3.1 affinity column, we isolated topoisomerase I (Topo I) from a PC-3 prostate cancer cell extract. Topo I is a class 1B DNA-resolving enzyme that is ubiquitously expressed in higher organisms and many prokaryotes. NKX3.1 interacts with Topo I to enhance formation of the Topo I-DNA complex and to increase Topo I cleavage of DNA. The two proteins interacted in affinity pull-down experiments in the presence of either DNase or RNase. The NKX3.1 homeodomain was essential, but not sufficient, for the interaction with Topo I. NKX3.1 binding to Topo I occurred independently of the Topo I NH2-terminal domain. The binding of equimolar amounts of Topo I to NKX3.1 caused displacement of NKX3.1 from its cognate DNA recognition sequence. Topo I activity in prostates of Nkx3.1+/- and Nkx3.1-/- mice was reduced compared with wild-type mice, whereas Topo I activity in livers, where no NKX3.1 is expressed, was independent of Nkx3.1 genotype. Endogenous Topo I and NKX3.1 could be coimmunoprecipitated from LNCaP cells, where NKX3.1 and Topo I were found to colocalize in the nucleus and comigrate within the nucleus in response to either gamma-irradiation or mitomycin C exposure, two DNA-damaging agents. This is the first report that a homeodomain protein can modify the activity of Topo I and may have implications for organ-specific DNA replication, transcription, or DNA repair.

Smoking and the Risk of Pouchitis in Ulcerative Colitis Patients With Ileal Pouch-Anal Anastomosis.

BACKGROUND: Ulcerative colitis (UC) patients who undergo proctocolectomy with ileal pouch-anal anastomosis (IPAA) may develop pouchitis, a poorly understood inflammatory condition. There is controversy over whether tobacco use can protect against pouchitis. We undertook this investigation to further evaluate whether smoking reduces the risk of developing pouchitis and to determine whether other previously associated clinical factors change the risk for pouchitis. METHODS: We performed a retrospective analysis using a consented inflammatory bowel disease (IBD) natural history registry between the years 1995-2015 from a single tertiary care referral center. Demographic data, medical history, surgical information, medication use, laboratory data, and smoking history were abstracted. Former smokers had quit for at least 1 year. The primary end point was development of pouchitis. RESULTS: Of the 353 UC patients with IPAA in this study, 126 (35.6%) developed pouchitis. Prior tobacco use (P < 0.0001) was more common in patients who developed pouchitis. Former and active smokers were more likely to develop pouchitis compared with those without a history of tobacco use (63.4% vs 27.3% respectively, P < 0.001). There was no significant difference in active smoking rate between those without pouchitis and the group that did develop pouchitis. Multivariate analysis demonstrated that the only independent risk factor associated with pouchitis was a history of tobacco use. CONCLUSIONS: These results suggest that smoking cessation may increase the likelihood of developing pouchitis in tobacco users with UC and IPAA, but active smoking does not seem to be more effective in preventing this condition.

Influences and Impact of Anxiety and Depression in the Setting of Inflammatory Bowel Disease.

Background: Individuals with inflammatory bowel disease (IBD) are at increased risk of developing anxiety or depression (A&D). Crohn's disease (CD) and ulcerative colitis (UC) with comorbid A&D are both more challenging to manage. IBD providers need to better understand the causes and impact of A&D in order to improve care for IBD patients. We sought to identify clinical factors that influence development of A&D and healthcare utilization in IBD. Methods: This is a retrospective analysis using an IBD natural history registry from a single tertiary care referral center. Presence of A&D was determined based upon responses to the Hospital Anxiety and Depression Scale. Demographic and clinical factors were abstracted to evaluate for significant associations. Results: Four hundred thirty-two IBD patients (132 UC, 256 CD, and 44 indeterminate colitis) were included in this study. One hundred ninety-two (44.4%) had anxiety or depression or both, and most were female (59.4%, P < 0.05). History of surgery (P < 0.05), female gender (P < 0.05), smoking (P < 0.05), and extra-intestinal manifestations (P < 0.01) were each independently predictive of A&D. Inflammatory bowel disease patients with A&D more often underwent imaging studies (53.6% vs 36.7%, P < 0.05), visited the ED (30.7% vs 20.8%, P < 0.05), or were hospitalized (31.7% vs 21.7%, P < 0.05). They were also more frequently prescribed corticosteroids (50.5% vs 36.7%, P < 0.01) and biologic medications (62.5% vs 51.3%, P < 0.05). Finally, they were more likely to have had at least 1 "no-show" (29.2% vs 16.7%, P < 0.01) and had a higher mean number of "no-shows" (0.69 +/- 0.1 vs 0.30 +/- 0.1, P < 0.01) over the study period. Discussion: Anxiety and depression are common in the setting of IBD and are strongly associated with surgical history, disease complications (including extra-intestinal manifestations), smoking, and female gender. Inflammatory bowel disease patients with A&D are also more likely to require therapy and to utilize healthcare resources. This study refines our understanding of A&D development and its impact in IBD and provides additional considerations for management in this setting.

The role of TGF-beta and Wnt signaling in gastrointestinal stem cells and cancer.

The past three decades have seen an unremitting quest to identify and understand gastrointestinal stem cells, their plasticity in differentiating across cell types, as well as their role in normal, regenerative, and cancer cells. A fascinating hallmark of stem cells is their ability to undergo assymetric cell division, which entails replication of the DNA followed by division of the nucleus and partitioning of the cytoplasm to yield two different daughter cells: a stem cell as well as a committed progenitor cell, the latter proliferating into differentiated progeny. We are only just beginning to understand how normally quiescent, tissue-specific stem cells interpret a vast array of signals to develop into the gastrointestinal system. These signaling pathways include the transforming growth factor-beta (TGF-beta) superfamily, Wnt, FGFs, Hedgehog, Hox proteins that originate from surrounding mesodermal/stromal tissue as well as endodermal/epithelial tissue. TGF-beta and wnt proteins are key morphogens that ultimately influence cell division and cell fate, so that gut endodermal stem cells enter the cell cycle, and undergo cell division that ultimately leads to differentiated cells such as functional hepatocytes, gastric parietal cells, or gut epithelial cells. Disruptions and errors in this process usually lead to tissue-specific gastrointestinal cancers such as hepatocellular cancers, gastric adenocarcinomas, and colonic adenocarcinomas. An increasingly complex and coherent view of stem/progenitor cell signaling networks, which coordinate cell growth, proliferation, stress management, and survival, is helping to define the fragile areas where malignancies are likely to develop and shows promise for the development of better cancer therapies.