Mild Crohn's Disease: Definition and Management.

PURPOSE OF REVIEW: Crohn's Disease (CD) is a chronic inflammatory disease that can lead to progressive damage to the gastrointestinal tract and significant disability. Early, "top-down" biologic therapy is recommended in moderate-to-severe CD to induce remission and to prevent hospitalization and complications. However, an estimated 20-30% of patients with CD have a mild disease course and may not garner sufficient benefit from expensive, immunosuppressing agents to justify their risks. Herein, we review characteristics of patients with mild CD, the available options for disease treatment and monitoring, and future directions of research. RECENT FINDINGS: For ambulatory outpatients with low-risk, mild, ileal or ileocolonic CD, induction of remission with budesonide is recommended. For colonic CD, sulfasalazine is a reasonable choice, although other aminosalicylates have no role in the treatment of CD. No large, randomized trial has supported the use of antibiotics or antimycobacterials in the treatment of CD. Partial Enteral Nutrition and Crohn's Disease Exclusion Diets may be appropriate for inducing remission in some adult patients, with trials ongoing. Select patients with mild-to-moderate CD may benefit from maintenance therapy with azathioprines or gut specific biologics, such as vedolizumab. The role of complementary and alternative medicine is not well defined. The identification, risk stratification, and monitoring of patients with mild CD can be a challenging clinical scenario. Some patients with low risk of disease progression may be appropriate for initial induction of remission with budesonide or sulfasalazine, followed by close clinical monitoring. Future research should focus on pre-clinical biomarkers to stratify disease, novel therapies with minimal systemic immune suppression, and validation of rigorous clinical monitoring algorithms.

Comorbidity Influences the Comparative Safety of Biologic Therapy in Older Adults With Inflammatory Bowel Diseases.

INTRODUCTION: There are limited data on comparative risk of infections with various biologic agents in older adults with inflammatory bowel diseases (IBDs). We aimed to assess the comparative safety of biologic agents in older IBD patients with varying comorbidity burden. METHODS: We used data from a large, national commercial insurance plan in the United States to identify patients 60 years and older with IBD who newly initiated tumor necrosis factor-α antagonists (anti-TNF), vedolizumab, or ustekinumab. Comorbidity was defined using the Charlson Comorbidity Index (CCI). Our primary outcome was infection-related hospitalizations. Cox proportional hazards models were fitted in propensity score-weighted cohorts to compare the risk of infections between the different therapeutic classes. RESULTS: The anti-TNF, vedolizumab, and ustekinumab cohorts included 2,369, 972, and 352 patients, respectively, with a mean age of 67 years. The overall rate of infection-related hospitalizations was similar to that of anti-TNF agents for patients initiating vedolizumab (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.84-1.04) and ustekinumab (0.92, 95% CI 0.74-1.16). Among patients with a CCI of >1, both ustekinumab (HR: 0.66, 95% CI: 0.46-0.91, p-interaction <0.01) and vedolizumab (HR: 0.78, 95% CI: 0.65-0.94, p-interaction: 0.02) were associated with a significantly lower rate of infection-related hospitalizations compared with anti-TNFs. No difference was found among patients with a CCI of ≤1. DISCUSSION: Among adults 60 years and older with IBD initiating biologic therapy, both vedolizumab and ustekinumab were associated with lower rates of infection-related hospitalizations than anti-TNF therapy for those with high comorbidity burden.

Multi-omics reveal microbial determinants impacting responses to biologic therapies in inflammatory bowel disease.

The intestinal microbiome is a key determinant of responses to biologic therapy in inflammatory bowel disease (IBD). However, diverse therapeutics and variable responses among IBD patients have posed challenges in predicting clinical therapeutic success. In this prospective study, we profiled baseline stool and blood in patients with moderate-to-severe Crohn's disease or ulcerative colitis initiating anti-cytokine therapy (anti-TNF or -IL12/23) or anti-integrin therapy. Patients were assessed at 14 weeks for clinical remission and 52 weeks for clinical and endoscopic remission. Baseline microbial richness indicated preferential responses to anti-cytokine therapy and correlated with the abundance of microbial species capable of 7α/ß-dehydroxylation of primary to secondary bile acids. Serum signatures of immune proteins reflecting microbial diversity identified patients more likely to achieve remission with anti-cytokine therapy. Remission-associated multi-omic profiles were unique to each therapeutic class. These profiles may facilitate a priori determination of optimal therapeutics for patients and serve as targets for newer therapies.

Nutrition in the Management of Inflammatory Bowel Diseases.

With the increasing global prevalence of inflammatory bowel diseases, research in this field is expanding to better understand the multifactorial etiologies of this complex disease. Nutrition and diet, as modifiable risk factors, have been shown to play an important role in disease activity and prognosis. This article reviews the role of nutrition in inflammatory bowel disease, including appropriate nutrition screening in this at-risk population, and associated micronutrient deficiencies. We provide recommendations on dosing supplementation. We briefly review diet as a risk factor for inflammatory bowel disease and the currently proposed published dietary intervention studies.

Assessment of Body Weight Changes in Patients with Inflammatory Bowel Diseases Initiating Biologic Therapy: A Prospective Cohort Study.

BACKGROUND: Prior studies have inconsistently suggested that biologic therapy may be associated with weight gain in inflammatory bowel disease patients (IBD). Our aim was to compare weight gain across different biologic therapy classes with distinct mechanisms of action. METHODS: This prospective cohort study recruited patients with moderate to severe IBD initiating outpatient biologic therapy with anti-TNF (infliximab, adalimumab), vedolizumab, or ustekinumab. Weight measurements were performed at weeks 0, 14, 30, and 54. Changes in weight between baseline and each of the follow-up visits were modeled as a continuous variable, and multivariate regression assessed the independent effect of therapeutic class on this outcome. RESULTS: Our study enrolled 269 patients (163 CD, 106 UC) initiating biologic therapy [99 anti-TNF (37%), 122 vedolizumab (45%), 48 ustekinumab (18%)]. From baseline, the weight significantly increased at week 14 with a mean of 0.36 kg (± 3.8 kg, p = 0.004) and continued to increase compared to baseline with 0.96 kg (± 3.9 kg, p < 0.001) and 1.29 kg (± 4.2 kg, p < 0.001) at week 30 and 54, respectively. On univariate and multivariable analysis, no significant differences between any of the biologic therapies for weight gain were seen at any time point (weight gain anti-TNF: 0.31 kg, 1.06 kg, 1.33 kg; VDZ: 0.30 kg, 0.83 kg, 1.10 kg; UST: 0.63 kg, 1.21 kg, 2.31 kg at wk 14, wk 30, and wk 54, respectively). None of the disease activity parameters showed any statistical association with weight gain. CONCLUSION: There was no difference in weight gain among the different biologic therapeutic classes.

Longitudinal Trajectory of Fatigue With Initiation of Biologic Therapy in Inflammatory Bowel Diseases: A Prospective Cohort Study.

BACKGROUNDS AND AIMS: Fatigue is prevalent in patients with inflammatory bowel diseases [IBD]. Biologic therapy is effective in achieving symptomatic and endoscopic remission, but its impact on fatigue is less well established. Our aim is to define the longitudinal trajectory of fatigue over 1 year in patients initiating biologic therapy. METHODS: This prospective cohort enrolled patients diagnosed with Crohn's disease [CD] or ulcerative colitis [UC] initiating biologic therapy with infliximab, adalimumab, ustekinumab, or vedolizumab. Fatigue was quantified using the seven-point fatigue question in the Short Inflammatory Bowel Disease Questionnaire [SIBDQ]. A score of ≤4 for this question was used to define fatigue. Multivariable regression models adjusting for relevant confounders examined the independent association between attaining clinical remission and resolution of fatigue. RESULTS: Our study included 326 patients [206 CD, 120 UC] initiating biologic therapy [144 anti-tumour necrosis factor, 129 vedolizumab, 63 ustekinumab]. A total of 61% of the included patients reported significant fatigue at baseline. This was associated with female gender, depressive symptoms, active disease, and disturbed sleep [p < 0.001]. Among the 198 patients who were fatigued at therapy initiation, 86 [70%], 55 [63%], and 44 [61%] remained fatigued at Week 14, 30, and 54, respectively. At each of these time points, achieving clinical remission was associated with lower likelihood of persistent fatigue. However, despite achieving remission, 35%, 30%, and 28% of patients experienced persistent fatigue at Week 14, 30, and 54, respectively. CONCLUSIONS: Fatigue is common in IBD. Though biologic therapy improves fatigue parallel symptomatic improvement, a significant proportion continue to experience persistent fatigue up to 1 year.

Use of Biologic Therapy by Pregnant Women With Inflammatory Bowel Disease Does Not Affect Infant Response to Vaccines.

BACKGROUND & AIMS: In women with inflammatory bowel diseases (IBDs), exposure to immunomodulator or biologic therapy has not been associated with adverse events during pregnancy or outcomes of newborns. We investigated whether exposure of patients to these agents during pregnancy affects serologic responses to vaccines in newborns. METHODS: We collected data from the Pregnancy in IBD and Neonatal Outcomes registry, which records outcomes of pregnant women with diagnosis of IBD receiving care at multiple centers in the United States, from 2007 through 2016. Serum samples collected from infants at least 7 months old were analyzed for titers of antibodies to Haemophilus influenzae B (HiB) or tetanus toxin; mothers completed a survey of vaccine practices and outcomes from July 2013 through October 2016. Umbilical cord blood samples from 33 infants were assayed for concentration of biologic agents. Vaccination response was compared between infants born to mothers exposed to biologic therapy (infliximab, adalimumab, certolizumab pegol, golimumab, natalizumab, vedolizumab, or ustekinumab-either as a single agent or in combination with an immunomodulator, at any time between conception and delivery) and infants born to unexposed mothers. RESULTS: A total of 179 women completed the vaccine survey (26 biologic unexposed, 153 exposed to a biologic agent). We found no significant difference in proportions of infants with protective antibody titers against HiB born to exposed mothers (n = 42, 71%) vs unexposed mothers (n = 8, 50%) (P = .41). We also found no difference in the proportion of infants with protective antibody titers to tetanus toxoid born to exposed mothers (80%) vs unexposed mothers (75%) (P = .66). The median concentration of infliximab in cord blood did not differ significantly between infants with vs without protective antibody titers to HiB (P = .30) or tetanus toxoid (P = .93). Mild reactions were observed in 7/40 infants who received rotavirus vaccine and whose mothers had been exposed to biologic therapies. CONCLUSIONS: Vaccination of infants against HiB and tetanus toxin, based on antibody titers measured when infants were at least 7 months old, does not appear to be affected by in utero exposure to biologic therapy.

Gut Microbiome Function Predicts Response to Anti-integrin Biologic Therapy in Inflammatory Bowel Diseases.

The gut microbiome plays a central role in inflammatory bowel diseases (IBDs) pathogenesis and propagation. To determine whether the gut microbiome may predict responses to IBD therapy, we conducted a prospective study with Crohn's disease (CD) or ulcerative colitis (UC) patients initiating anti-integrin therapy (vedolizumab). Disease activity and stool metagenomes at baseline, and weeks 14, 30, and 54 after therapy initiation were assessed. Community α-diversity was significantly higher, and Roseburia inulinivorans and a Burkholderiales species were more abundant at baseline among CD patients achieving week 14 remission. Several significant associations were identified with microbial function; 13 pathways including branched chain amino acid synthesis were significantly enriched in baseline samples from CD patients achieving remission. A neural network algorithm, vedoNet, incorporating microbiome and clinical data, provided highest classifying power for clinical remission. We hypothesize that the trajectory of early microbiome changes may be a marker of response to IBD treatment.

Modifiable Environmental Factors in Inflammatory Bowel Disease.

PURPOSE OF REVIEW: Environmental factors may influence predisposition to develop inflammatory bowel diseases (Crohn's disease, ulcerative colitis) or alter its natural history by modification of both the host immune response and intestinal microbial composition. The purpose of this review is to translate such evidence into clinical practice by a focus on interventional studies that have modified such environmental influences to improve disease outcomes. RECENT FINDINGS: Several environmental influences have been identified in the recent literature including tobacco use, diet, antibiotics, vitamin D deficiency, stress, appendectomy, and oral contraceptive use. Some risk factors have similar influences on both Crohn's disease and ulcerative colitis while others are disease-specific or have divergent effects. Emerging epidemiologic evidence has confirmed the association of many of these factors with incident disease using prospective data. In addition, laboratory data has supported their mechanistic plausibility and relevance to intestinal inflammation.

Older Age- and Health-related Quality of Life in Inflammatory Bowel Diseases.

BACKGROUND: The burden of inflammatory bowel disease (IBD) in the older population is increasing. Older-onset disease is associated with reduced use of immunosuppressive medications. In addition, older patients may be more vulnerable to the effect of disease-related symptoms and consequently may experience worse health-related quality of life (HRQoL) compared with younger patients. METHODS: This prospective study included a cohort of patients with Crohn's disease and ulcerative colitis recruited from a single center. All patients completed the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) and the short form-12 (SF-12) questionnaire yielding general physical health (PCS) and mental health component scale subscores (MCS). Patients older than 60 years were compared with those younger than 60 years using multivariable regression analysis. RESULTS: Our study included 1607 patients, among whom 186 were older than 60 at the time of assessment. Older patients were more likely to have isolated colonic disease and less likely to use immunosuppressive therapy. On multivariable analysis, older patients with IBD had higher SIBDQ (2.34, 95% confidence interval, 0.82-3.87) and SF-12 mental subscores (3.78, 95% confidence interval, 2.26-5.30), but lower physical HRQoL (-1.80, 95% confidence interval, -3.21 to -0.38). There was no difference in the SIBDQ and PCS scores between older patients and newly diagnosed IBD or with established disease. CONCLUSIONS: Older age was associated with modestly higher SIBDQ and mental HRQoL scores, but lower physical HRQoL. Comprehensive care of the older patient with IBD should include assessment of factors impairing physical quality of life to ensure appropriate interventions.

Identification and Characterization of a Novel Association between Dietary Potassium and Risk of Crohn's Disease and Ulcerative Colitis.

BACKGROUND: Recent animal studies have identified that dietary salt intake may modify the risk and progression of autoimmune disorders through modulation of the IL-23/TH17 pathway, which is critical in the pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD). METHODS: We conducted a prospective study of U.S. women enrolled in the Nurses' Health Study (NHS) and NHSII who provided detailed and validated information on diet and lifestyle beginning in 1984 in NHS and 1991 in NHSII. We confirmed incident cases of UC and CD reported through 2010 in NHS and 2011 in NHSII. We used Cox proportional hazards models to calculate hazard ratios and 95% confidence intervals. In a case-control study nested within these cohorts, we evaluated the interaction between single nucleotide polymorphisms (SNPs) in genes involved in TH17 pathway and dietary potassium on risk of CD and UC. In a cohort of healthy volunteers, we also assessed the effect of supplemental potassium on development of naïve and memory T cells, differentiated with TGFß1 or TH17 conditions. RESULTS: Among a total of 194,711 women over a follow-up of 3,220,247 person-years, we documented 273 cases of CD and 335 cases of UC. Dietary intake of potassium (Ptrend = 0.005) but not sodium (Ptrend = 0.44) was inversely associated with risk of CD. Although, both dietary potassium and sodium were not significantly associated with risk of UC, there was a suggestion of an inverse association with dietary potassium (Ptrend = 0.08). The association of potassium with risk of CD and UC appeared to be modified by loci involved in the TH17 pathway that have previously been associated with susceptibility to CD, particularly SNP rs7657746 (IL21) (Pinteraction = 0.004 and 0.01, respectively). In vitro, potassium enhanced the expression of Foxp3 in both naïve and memory CD4+ T cells via activating Smad2/3 and inhibiting Smad7 in TH17 cells. CONCLUSION: Dietary potassium is inversely associated with risk of CD with both in vitro and gene-environment interaction data suggesting a potential role for potassium in regulating immune tolerance through its effect on Tregs and TH17 pathway.

Impact of Specialized Inpatient IBD Care on Outcomes of IBD Hospitalizations: A Cohort Study.

BACKGROUND: The management of inflammatory bowel diseases (IBDs; Crohn's disease, ulcerative colitis) is increasingly complex. Specialized care has been associated with improved ambulatory IBD outcomes. AIMS: To examine if the implementation of specialized inpatient IBD care modified short-term and long-term clinical outcomes in IBD-related hospitalizations. METHODS: This retrospective cohort study included IBD patients hospitalized between July 2013 and April 2015 at a single tertiary referral center where a specialized inpatient IBD care model was implemented in July 2014. In-hospital medical and surgical outcomes as well as postdischarge outcomes at 30 and 90 days were analyzed along with measures of quality of in-hospital care. Effect of specialist IBD care was examined on multivariate analysis. RESULTS: A total of 408 IBD-related admissions were included. With implementation of specialized IBD inpatient care, we observed increased frequency of use of high-dose biologic therapy for induction (26% versus 9%, odds ratio 5.50, 95% confidence interval 1.30-23.17) and higher proportion of patients in remission at 90 days after discharge (multivariate odds ratio 1.60, 95% confidence interval 0.99-2.69). Although there was no difference in surgery by 90 days, among those who underwent surgery, early surgery defined as in-hospital or within 30 days of discharge, was more common in the study period (71%) compared with the control period (46%, multivariate odds ratio 2.73, 95% confidence interval 1.22-6.12). There was no difference in length of stay between the 2 years. CONCLUSIONS: Implementation of specialized inpatient IBD care beneficially impacted remission and facilitated early surgical treatment.

Editorial: Vitamin D and IBD: Can We Get Over the "Causation" Hump?

Vitamin D deficiency is common in patients with inflammatory bowel diseases and may even precede the disease onset contributing to an increased risk. Using comprehensive data from a large, referral IBD cohort, Kabbani et al. establish that low vitamin D levels are associated with greater disease activity, increased risk of surgery and hospitalizations, and lower health-related quality of life in patients with IBD. This expands the evidence base supporting such an association. However, there is a need for this field to evolve to interventional studies with vitamin D supplementation to confirm that vitamin D has a true therapeutic role for treating disease activity in IBD.

Zinc intake and risk of Crohn's disease and ulcerative colitis: a prospective cohort study.

BACKGROUND: Diet plays a role in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). Dietary zinc may influence risk of disease through effects on autophagy, innate and adaptive immune response and maintenance of the intestinal barrier. METHODS: We analysed data from 170 776 women from the Nurses Health Study I and Nurses Health Study II, who were followed for 26 years. Zinc intake was assessed using semi-quantitative food frequency questionnaires administered every 4 years. Incident CD and UC were ascertained by medical record review. Cox proportional hazards models adjusting for potential confounders determined the independent association between zinc intake and incident disease. RESULTS: Over 3 317 550 person-years (p-y) of follow-up, we identified 269 incident cases of CD and 338 incident cases of UC. Zinc intake ranged from 9 mg/day in the lowest quintile to 27 mg/day in the highest quintile. Compared with women with the lowest quintile of intake, the multivariate hazard ratios (HR) for CD were 0.92 [95% confidence interval (CI), 0.65 ­ 1.29) for women in the second quintile of intake, 0.60 (95% CI, 0.40 ­ 0.89) for the third quintile, 0.57 (95% CI, 0.38 ­ 0.86) for fourth quintile and 0.74 (95% CI, 0.50 ­ 1.10) for the highest quintile (Ptrend = 0.003). The association was stronger for dietary zinc (HR 0.63, 95% CI, 0.43 ­ 0.93, comparing extreme quintiles) than for zinc intake from supplements. Neither dietary nor supplemental zinc modified risk of UC. CONCLUSIONS: In two large prospective cohorts of women, intake of zinc was inversely associated with risk of CD but not UC.

Cost-effectiveness of competing strategies for management of recurrent Clostridium difficile infection: a decision analysis.

BACKGROUND: Clostridium difficile infection (CDI) is an important cause of morbidity and healthcare costs, and is characterized by high rates of disease recurrence. The cost-effectiveness of newer treatments for recurrent CDI has not been examined, yet would be important to inform clinical practice. The aim of this study was to analyze the cost effectiveness of competing strategies for recurrent CDI. METHODS: We constructed a decision-analytic model comparing 4 treatment strategies for first-line treatment of recurrent CDI in a population with a median age of 65 years: metronidazole, vancomycin, fidaxomicin, and fecal microbiota transplant (FMT). We modeled up to 2 additional recurrences following the initial recurrence. We assumed FMT delivery via colonoscopy as our base case, but conducted sensitivity analyses based on different modes of delivery. Willingness-to-pay threshold was set at $50 000 per quality-adjusted life-year. RESULTS: At our base case estimates, initial treatment of recurrent CDI using FMT colonoscopy was the most cost-effective strategy, with an incremental cost-effectiveness ratio of $17 016 relative to oral vancomycin. Fidaxomicin and metronidazole were both dominated by FMT colonoscopy. On sensitivity analysis, FMT colonoscopy remained the most cost-effective strategy at cure rates >88.4% and CDI recurrence rates <14.9%. Fidaxomicin required a cost <$1359 to meet our cost-effectiveness threshold. In clinical settings where FMT is not available or applicable, the preferred strategy appears to be initial treatment with oral vancomycin. CONCLUSIONS: In this decision analysis examining treatment strategies for recurrent CDI, we demonstrate that FMT colonoscopy is the most cost-effective initial strategy for management of recurrent CDI.

Long-term intake of dietary fat and risk of ulcerative colitis and Crohn's disease.

INTRODUCTION: Dietary fats influence intestinal inflammation and regulate mucosal immunity. Data on the association between dietary fat and risk of Crohn's disease (CD) and ulcerative colitis (UC) are limited and conflicting. METHODS: We conducted a prospective study of women enrolled in the Nurses' Health Study cohorts. Diet was prospectively ascertained every 4 years using a validated semi-quantitative food frequency questionnaire. Self-reported CD and UC were confirmed through medical record review. We examined the effect of energy-adjusted cumulative average total fat intake and specific types of fat and fatty acids on the risk of CD and UC using Cox proportional hazards models adjusting for potential confounders. RESULTS: Among 170,805 women, we confirmed 269 incident cases of CD (incidence 8/100,000 person-years) and 338 incident cases of UC (incidence 10/100,000 person-years) over 26 years and 3,317,338 person-years of follow-up. Cumulative energy-adjusted intake of total fat, saturated fats, unsaturated fats, n-6 and n-3 polyunsaturated fatty acids (PUFAs) were not associated with risk of CD or UC. However, greater intake of long-chain n-3 PUFAs was associated with a trend towards lower risk of UC (HR 0.72, 95% CI 0.51 to 1.01). In contrast, high long-term intake of trans-unsaturated fatty acids was associated with a trend towards an increased incidence of UC (HR 1.34, 95% CI 0.94 to 1.92). CONCLUSIONS: A high intake of dietary long-chain n-3 PUFAs may be associated with a reduced risk of UC. In contrast, high intake of trans-unsaturated fats may be associated with an increased risk of UC.

Pretreatment 25-hydroxyvitamin D levels and durability of anti-tumor necrosis factor-α therapy in inflammatory bowel diseases.

INTRODUCTION: Emerging evidence supports an immunologic role for 25-hydroxyvitamin D (25(OH)D) in inflammatory bowel disease (IBD). Here we examined if pretreatment vitamin D status influences durability of anti-tumor necrosis factor (TNF)-α therapy in patients with Crohn's disease (CD) or ulcerative colitis (UC). METHODS: All IBD patients who had plasma 25(OH)D level checked <3 months prior to initiating anti-TNF-α therapy were included in this retrospective single-center cohort study. Our main predictor variable was insufficient plasma 25(OH)D (<30 ng/mL). Cox proportional hazards model adjusting for potential confounders was used to identify the independent effect of pretreatment vitamin D on biologic treatment cessation. RESULTS: Our study included 101 IBD patients (74 CD; median disease duration 9 years). The median index 25(OH)D level was 27 ng/mL (interquartile range, 20-33 ng/mL). One-third of the patients had prior exposure to anti-TNF-α therapy. On multivariate analysis, patients with insufficient vitamin D demonstrated earlier cessation of anti-TNF-α therapy (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.03-4.39; P = .04). This effect was significant in patients who stopped treatment for loss of response (HR, 3.49; 95% CI, 1.34-9.09) and stronger for CD (HR, 2.38; 95% CI, 0.95-5.99) than UC (P = NS). CONCLUSIONS: Our findings suggest that vitamin D levels may influence durability of anti-TNF-α induction and maintenance therapy. Larger cohort studies and clinical trials of supplemental vitamin D use with disease activity as an end point may be warranted.

Dyssynergic defecation: a treatable cause of persistent symptoms when inflammatory bowel disease is in remission.

BACKGROUND: Introduction of biologic agents in inflammatory bowel disease (IBD) has increased the likelihood of disease remission. Despite resolution of active inflammation, a subset of IBD patients report persistent defecatory symptoms. AIM: To evaluate a group of patients with inflammatory bowel disease with suspected functional defecatory disorders, by use of anorectal manometric testing and subsequent biofeedback therapy. METHODS: A group of IBD patients with persistent defecatory problems despite clinical improvement were included in this study. These patients had no evidence of left-sided disease. Endoscopic and radiographic study findings and timing in relation to the manometry study were recorded. Anorectal manometry was performed by the standard protocol and included rectal sensory assessment, ability to expel a balloon, and pressure dynamics with simulated defecation. RESULTS: Thirty IBD patients (Crohn's 23 patients; ulcerative colitis six patients) presented with defecatory disorders including constipation (67%) increased stooling (10%), and rectal urgency and/or incontinence and rectal pain (6%). All but one patient had anorectal manometric criteria of dyssynergia (presence of anismus motor pattern and inability to expel the balloon). Of the patients who completed biofeedback therapy, 30% had a clinically significant (≥7-point) improvement in SIBDQ score, with a reduction in health-care utilization after a six-month period (p=0.02). CONCLUSIONS: Despite remission, some inflammatory bowel disease patients have persistent defecatory symptoms. Defecatory symptoms may not be predictive of an underlying inflammatory disorder. Lack of inflammatory activity and absence of left-sided disease should prompt investigation of functional disorders. Anorectal manometric testing and biofeedback therapy for patients with a diagnosis of dyssynergia may be a useful therapy.

Can mucosal healing be a cost-effective endpoint for biologic therapy in Crohn's disease? A decision analysis.

BACKGROUND: Observational studies have demonstrated that mucosal healing (MH) may be associated with reductions in hospitalizations and surgeries for moderate to severe Crohn's disease (CD). Whether treatment to achieve MH is a cost-effective endpoint has not been established previously. METHODS: We constructed a decision analytic model comparing two treatment strategies. In the clinical response (CR) arm, patients not in clinical remission at year 1 are dose-escalated. In the MH arm, patients with persistence of mucosal ulcerations at year 1 are escalated irrespective of clinical symptoms. Patients remain at risk for hospitalization and surgeries while they have active disease. We examined a 2-year time horizon. RESULTS: In the base case the MH strategy was more effective at 2 years (quality-adjusted life year [QALY] 0.71) compared to the CR strategy (QALY 0.69) but was also more expensive with an incremental cost-effectiveness ratio (ICER) of $49,278/QALY gained. In a hypothetical cohort of 100,000 patients assigned to each treatment arm, the MH strategy resulted in lower rates of hospitalization and surgery with a number needed to treat of 27 and 106, respectively. The results were sensitive to the ability of infliximab to achieve MH and the incremental benefit of MH over clinical remission. CONCLUSIONS: We demonstrate that MH as an endpoint is a cost-effective strategy in CD patients initiating IFX therapy. Further prospective studies on durability of MH and its incremental benefit as well as the ability of other available biologic agents to achieve MH are necessary to validate our findings.

Environmental triggers for inflammatory bowel disease.

Inflammatory bowel diseases [IBD; Crohn's disease (CD), ulcerative colitis (UC)] are chronic immunologically mediated diseases that are due to a dysregulated immune response to intestinal flora in a genetically susceptible host. Despite advances in genetics, the likelihood of occurrence of disease remains incompletely explained and there appears to be a strong role for the environment in mediating risk of disease. Smoking remains the most widely studied and replicated risk factor, contributing to increased risk and severity of CD while conferring protection against UC. Recent data has suggested novel risk factors. Lower plasma vitamin D is associated with an increased risk of Crohn's disease, and vitamin D supplementation may prevent relapse of disease. Several medications including oral contraceptives, post-menopausal hormone replacement, aspirin, NSAIDs, and antibiotics may increase risk of CD or UC with the mechanisms of effect remaining inadequately defined. There is continuing evidence that depression and psychosocial stress may play a role in the pathogenesis of both CD and UC, while at the same time also increasing risk for disease flares. There is also a growing understanding of the role of diet on IBD, in particular through its effect on the microbiome. Animal protein intake and n-6 fatty acids may increase risk of UC while n-3 fatty acids and dietary fiber may confer protection. The effect of diet on established disease remains poorly studied. There is need for routine measurement of a spectrum of environmental exposures in prospective studies to further our understanding.