Complete Endoscopic Healing Is Associated With Lower Relapse Risk After Anti-TNF Withdrawal in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Discontinuation of anti-tumor necrosis factor-α treatment (anti-TNF) (infliximab and adalimumab) in patients with inflammatory bowel disease (IBD) is associated with a high relapse risk that may be influenced by endoscopic activity at the time of stopping. We assessed the relapse rate after anti-TNF withdrawal in patients with endoscopic healing and studied predictors of relapse including the depth of endoscopic healing. METHODS: This was a multicenter, prospective study in adult patients with Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU), with ≥6 months of corticosteroid-free clinical remission (confirmed at baseline) and endoscopic healing (Mayo <2/SES-CD <5 without large ulcers), who discontinued anti-TNF between 2018 and 2020 in the Netherlands. We performed Kaplan-Meier and Cox regression analyses to assess the relapse rate and evaluate potential predictors: partial (Mayo 1/SES-CD 3-4) versus complete (Mayo 0/SES-CD 0-2) endoscopic healing, anti-TNF trough levels, and immunomodulator and/or mesalamine use. RESULTS: Among 81 patients (CD: n = 41, 51%) with a median follow-up of 2.0 years (interquartile range, 1.6-2.1), 40 patients (49%) relapsed. Relapse rates in CD and UC/IBDU patients were comparable. At 12 months, 70% versus 35% of patients with partial versus complete endoscopic healing relapsed, respectively (adjusted hazard rate [aHR], 3.28; 95% confidence interval [CI], 1.43-7.50). Mesalamine use was associated with fewer relapses in UC/IBDU patients (aHR, 0.08; 95% CI, 0.01-0.67). Thirty patients restarted anti-TNF, and clinical remission was regained in 73% at 3 months. CONCLUSIONS: The relapse risk was high after anti-TNF withdrawal in IBD patients with endoscopic healing, but remission was regained in most cases after anti-TNF reintroduction. Complete endoscopic healing and mesalamine treatment in UC/IBDU patients decreased the risk of relapse.

Lower Risk of Recurrence with a Higher Induction Dose of Mesalazine and Longer Duration of Treatment in Ulcerative Colitis: Results from the Dutch, Non-Interventional, IMPACT Study.

BACKGROUND AND AIMS: The dose and duration of mesalazine treatment for ulcerative colitis (UC) is a potentially important determinant of effectiveness, with evidence suggesting that continuing the induction dose for 6-12 months may improve outcomes; however, real-world data are lacking. We assessed mesalazine use in Dutch clinical practice, including how differences in dose and duration affected UC outcomes. METHODS: Adults with mild-to-moderate UC who received oral prolonged-release mesalazine de novo or had a dose escalation for an active episode were followed for 12 months in this non-interventional study (ClinicalTrials.gov identifier: NCT02261636). The primary endpoint was time from start of treatment to dose reduction (TDR). Secondary endpoints included recurrence rate, adherence, and work productivity. RESULTS: In total, 151 patients were enrolled, of whom 108 (71.5%) were newly diagnosed with UC. The majority (120; 79.5%) received a dose of ≥4 g/day. Nearly one-third (48; 31.8%) underwent dose reduction, with mean TDR being 8.3 months. Disease extent and endoscopic appearance did not influence duration of induction therapy, while TDR increased with higher baseline UCDAI scores. TDR was longer in patients without (mean 8.8 months) than with (4.1 months) recurrence, although not significantly (p=0.09). Patients on ≥4 g/day had a significantly lower chance of recurrence versus those on 2-<4 g/day (26.6% vs 62.5%, respectively; p=0.04). Longer treatment duration was associated with significantly reduced recurrence risk [hazard ratio >6 months vs 3-6 months: 0.19 (95%CI: 0.08-0.46); p<0.05], particularly for those on ≥4 g/day [0.15 (0.06-0.40) vs 0.26 (0.01-11.9) for 2-<4 g/day). Patients reported significantly increased work productivity, which was maintained throughout follow-up. CONCLUSIONS: Mesalazine was effective induction therapy, with treatment duration not meaningfully influenced by disease extent and endoscopic appearance at initiation. A higher induction dose of oral mesalazine (≥4 g/day) and longer duration of treatment (>6 months) was associated with a lower recurrence risk.

Systematic Review and External Validation of Prediction Models Based on Symptoms and Biomarkers for Identifying Endoscopic Activity in Crohn's Disease.

BACKGROUND & AIMS: Endoscopic healing, an important target of treatment for Crohn's disease (CD), requires ileocolonoscopy, which is costly and burdensome. We investigated whether published noninvasive models (based on symptoms and biomarkers) to evaluate CD activity have sufficient accuracy to replace ileocolonoscopy. METHODS: We performed a systematic review of published noninvasive diagnostic models to evaluate CD activity that used endoscopic features of activity (endoscopic activity) or healing as the reference standard. We externally validated these models for the outcome endoscopic activity (CD endoscopic index of severity scores, ≥3) using data from the a randomized controlled trial investigating tailored treatment with infliximab for active luminal Crohn's disease (TAILORIX) study (346 ileocolonoscopies in 155 patients) and the Utrecht Activity Index (UAI) study (93 ileocolonoscopies in 82 patients). We calculated the area under the receiver operating characteristic curves (AUROCs) for the models using data from these studies, and compared the performance of these models against measurements of fecal calprotectin (FC) and C-reactive protein (CRP). RESULTS: We screened 5303 articles and identified 27 models (from 21 studies) for our analysis. Seven models could be validated externally; in the TAILORIX data set, these models identified patients with endoscopic activity with AUROC values ranging from 0.61 (95% CI, 0.51-0.70) to 0.81 (95% CI, 0.76-0.86). In this data set, the AUROC value for FC concentration was 0.79 (95% CI, 0.74-0.85) and the AUROC value for CRP level was 0.72 (95% CI, 0.66-0.77). The AUROC values for the validation in the UAI data set were similar. In the TAILORIX and/or UAI data set, 4 of the 7 models, as well as the FC and CRP assays, were able to identify patients with endoscopic activity with positive predictive values of 90% or more. Two of the 7 models (but not the FC or CRP values) identified patients without endoscopic activity with a negative predictive value (NPV) of 90% or more, leading to correct prediction of endoscopic healing in 3.2% to 11.3% of all patients. For example, applying the Herranz-Bachiller model (1 of 7 models) at a NPV of 92.1% and a positive predictive value of 91.9% correctly identified 35.7% of all patients in whom ileocolonoscopy could be avoided for expected endoscopic activity or healing but incorrectly identified 3.2% of all patients. Most ileocolonoscopies (66.5% in TAILORIX and 72.6% in the UAI of all ileocolonoscopies) could be avoided correctly based on concentrations of FC of 100 µg/g or less and 250 µg/g or higher. However, using this range of FC concentrations to identify patients who do not require ileocolonoscopy caused 18.7% of all patients in the TAILORIX cohort and 19.8% of all patients in the UAI cohort to be predicted incorrectly to have endoscopic activity or healing. CONCLUSIONS: In a systematic review and external validation of noninvasive models to identify patients with endoscopic activity of CD, we found only 2 of 7 models evaluated to have NPVs of 90% or more, however, leading to correctly predicted EH in only a small proportion of patients. Ileocolonoscopy therefore remains the mainstay to evaluate CD mucosal disease activity and healing.

Variation in palliative care of esophageal cancer in clinical practice: factors associated with treatment decisions.

Various treatments are available for the palliation of esophageal cancer, but the optimal therapeutic approach is unclear. This study aimed to assess the palliative treatment modalities used in patients with inoperable esophageal cancer and to identify factors associated with treatment decisions. A population-based, retrospective cohort study was conducted using data from the nationwide Netherlands Cancer Registry and medical records of seven participating hospitals. Patients diagnosed with stage III-IV inoperable esophageal or gastric cardia cancer in the central part of the Netherlands between 2001 and 2010 were included. Logistic regression analyses were performed to identify determinants of treatment choices. In total, 736 patients were initially treated with best supportive care (21%), stent placement (19%), chemotherapy (18%), external beam radiotherapy (EBRT) (16%), brachytherapy (6%), a combination of EBRT and brachytherapy (6%), a combination of chemotherapy and EBRT (5%) or another treatment (9%). The palliative approach varied for disease stage (P < 0.01) and hospital of diagnosis (P < 0.01). Independent factors affecting treatment decisions were age, degree of dysphagia, tumor histology, tumor localization, disease stage, and hospital of diagnosis. For example, patients diagnosed in one hospital were less likely to be treated with EBRT than with stent placement compared to patients in another hospital (odds ratio 0.20, 95% confidence interval 0.07-0.59). In conclusion, the initial palliative approach of patients with inoperable esophageal cancer varies widely and is not only associated with patient- and disease-related factors, but also with hospital of diagnosis. These findings suggest a lack of therapeutic guidance and highlight the need for more evidence on palliative care strategies for esophageal cancer.

Predicting Endoscopic Disease Activity in Crohn's Disease: A New and Validated Noninvasive Disease Activity Index (The Utrecht Activity Index).

BACKGROUND: Mucosal healing is presently considered one of the primary goals in treatment of Crohn's disease (CD), but this can only be confirmed by endoscopy. We aimed to design and validate a new disease activity index based on a combination of clinical characteristics and readily available laboratory parameters, which reliably predicts the presence and severity of endoscopic disease activity in patients with CD. METHODS: Thirteen clinical characteristics and laboratory variables were selected for analysis. Endoscopic disease activity was assessed by the Crohn's disease Endoscopic Index of Severity. A linear regression model was based on 93 ileocolonoscopies performed in 82 patients with CD and internally validated by bootstrap resampling. Subsequently, the newly developed model was validated in a cohort of 99 patients. RESULTS: The number of liquid stools during 1 day × 0.25 + C-reactive protein (in milligrams per liter) × 0.1 + platelet count (× 10(9)/L) × 0.01 + fecal calprotectin (in milligrams per liter) × 0.001 - mean platelet volume (in femtoliters) × 0.2 optimally predicted the severity of endoscopic disease activity (bootstrap adjusted R2 = 0.50). The model demonstrated good agreement in the external validation (r = 0.7), especially for (ileo)colonic CD (r = 0.8). Using receiver operator characteristic statistics, a cutoff point of 3 on the new index indicated endoscopic disease activity with a sensitivity of 80% and a specificity of 92%. CONCLUSIONS: This newly developed, noninvasive, index was found to reliably predict endoscopic disease activity in patients with CD. This tool can facilitate clinical decision making and might prove valuable in clinical trials.

Substantial impact of illness perceptions on quality of life in patients with Crohn's disease.

BACKGROUND AND AIMS: Crohn's disease (CD) negatively impact patients' health-related quality of life (HRQOL). We used the common sense model to examine the contribution of illness perceptions and coping to HRQOL, in addition to clinical and socio-demographic characteristics. This provides insight into potential targets for psychological interventions aimed at improving HRQOL. METHODS: Consecutive CD patients undergoing colonoscopy were included. Disease activity was assessed by a clinical and an endoscopic index. Patients completed questionnaires assessing illness perceptions (IPQ-R), coping (Utrecht Coping List), self-perceived health, neuroticism, and HRQOL. Hierarchical multiple regression analyses were performed to assess the contribution of illness perceptions and coping to HRQOL. Illness perceptions were compared to patients with rheumatoid arthritis, myocardial infarction (MI), and head and neck cancer (HNC). RESULTS: Of 82 CD patients, mean age was 42±14years. Clinical and endoscopic active disease was present in 42 (52%) and 49 (60%) patients, respectively. HRQOL was strongly impaired by clinical active disease (r=-0.79), self-perceived health (r=-0.60), and perceived consequences of CD (r=-0.54), but correlated poorly with endoscopic disease activity (r=-0.29). Illness perceptions significantly contributed 3-27% to HRQOL. Coping had no contributory role. CD patients perceived similarly strong consequences of their illness as patients with MI and HNC and had the strongest thoughts about the chronic nature of their illness. CONCLUSIONS: CD has a similar impact on patients' daily lives as was observed in patients with MI and HNC. Illness perceptions contribute to HRQOL and should therefore be incorporated in clinical practice, thereby improving HRQOL.

What predicts mucosal inflammation in Crohn's disease patients?

A number of disease-specific instruments have been created over the last 30 years to assess disease activity in Crohn's disease (CD). These disease activity indices are constituted of clinical and laboratory parameters and their role in predicting disease activity and the course of disease has been reviewed various times. Currently, the severity of mucosal inflammation, assessed by endoscopy, is considered the gold standard for disease activity in CD. In the present review the most frequently used endoscopic disease activity indices and the correlation between mucosal inflammation and clinical disease activity indices, quality of life questionnaires, and biochemical markers is critically appraised. We conclude that no clinical disease activity index or single laboratory parameter of inflammation reliably predicts the mucosal inflammatory disease activity. A new, easy-to-use and robust activity index predicting mucosal inflammation is highly needed to assess the response to investigational drugs in trials and the effect of therapeutical interventions in clinical practice.

Serotonin synthesis and uptake in symptomatic patients with Crohn's disease in remission.

BACKGROUND & AIMS: Symptoms resembling irritable bowel syndrome (IBS) are reported frequently in Crohn's disease (CD) patients in remission. Studies of the mucosal content of serotonin, which is a pivotal neurotransmitter in the gut, suggest that serotonin availability is altered in IBS patients. We aimed to study the role of serotonin in the generation of IBS-like symptoms in CD patients in remission. METHODS: Ileal and colonic biopsy specimens were obtained from 20 CD patients in remission, 10 with and 10 without IBS-like symptoms, and 11 healthy controls. Enterochromaffin cells were counted, and messenger RNA expression levels of tryptophan hydroxylase (TpH)-1 and serotonin reuptake transporter were determined. RESULTS: The levels of mucosal serotonin reuptake transporter expression were significantly higher in the ileum than in the colon, in all groups studied (P < .02). When the ileum and colon were analyzed separately, TpH-1 expression in the colon of CD patients with IBS-like symptoms was found to be significantly higher compared with the 2 other studied groups (controls, P < .005; CD patients without IBS-like symptoms, P < .01). The number of enterochromaffin cells per gland was comparable for the patient groups in the ileum and colon. CONCLUSIONS: CD patients in remission who experience IBS-like symptoms have increased mucosal TpH-1 levels in the colon, suggesting that increased serotonin biosynthesis in the colon plays a role in the generation of the symptoms.

Crohn's disease, fatigue, and infliximab: is there a role for cytokines in the pathogenesis of fatigue?

AIM: To study the effect of infliximab on fatigue in relation to cytokine levels in Crohn's disease (CD) patients. METHODS: Fourteen CD patients were blinded for treatment and received placebo at baseline, and infliximab 2 wk later, with a follow-up of 4 wk. Blood samples were drawn on a regular basis, and questionnaires on fatigue, depression, quality of life, and clinical disease activity were completed at regular intervals. RESULTS: After placebo infusion, fatigue scores decreased within 3 d (3.5 points +/- 1.1, P

A pilot study on chemospecific duodenal visceral sensitivity in inflammatory bowel disease in remission.

BACKGROUND: Patients with inflammatory bowel disease (IBD) in remission frequently experience symptoms resembling irritable bowel syndrome (IBS). In IBS altered motility and visceral sensitivity are found throughout the whole gastrointestinal tract. We aimed to study chemospecific antroduodenal sensitivity in IBD patients. METHODS: Antroduodenal manometry was performed in 10 IBD patients in remission and 13 controls. Small volumes of nutrients and acid were administered intraduodenally. Motility variables and sensation scores were compared before and after each infusion. RESULTS: Acid and lipid infusion decreased the number of antral pressure waves in both groups (p < 0.05). After acid infusion the number of duodenal pressure waves in the sideholes just distal to the infusion port increased in IBD patients compared to the controls (p < 0.05). Lipid infusion increased the number of duodenal propagated pressure waves in both groups, but in controls they were also increased over longer distances (p < 0.005). None of the infusions significantly affected the sensation scores. CONCLUSION: Subtle alterations in chemospecific responses to lipids and acid in IBD patients in remission were observed, affecting duodenal motor activity but not duodenal perception. These changes are indicative of changes at the chemoreceptor level in the duodenal wall in this patient group.

Gastric emptying of a solid meal starts during meal ingestion: combined study using 13C-octanoic acid breath test and Doppler ultrasonography. Absence of a lag phase in 13C-octanoic acid breath test.

Scintigraphy and the 13C-octanoic acid breath test are both applied to assess gastric emptying. Using the 13C-octanoic acid breath test, excretion curves show 13C excretion immediately after ingestion of a solid egg meal, in contrast with scintigraphy where gastric emptying is observed after a lag phase. The aim of our study was to investigate whether transpyloric flow occurs during and directly after meal ingestion. Therefore, transpyloric flow was measured during and after ingestion of an egg meal labeled with 13C-octanoic acid, using Doppler ultrasonography. The breath test was performed simultaneously, with samples taken at regular intervals. The first emptying episode was observed 6.9 (3.9-16.2) min after start of meal ingestion. A significant relation between recovery of 13C and total duration of gastric emptying during the first 20 min was observed (partial correlation coefficient r = 0.80, p < 0.001). In conclusion, transpyloric flow starts during ingestion of a solid egg meal and results in detectable excretion of 13C.

IBS-like symptoms in patients with inflammatory bowel disease in remission; relationships with quality of life and coping behavior.

The aim of this study was to assess the prevalence of irritable bowel syndrome-like symptoms in healthy controls and inflammatory bowel disease patients in remission using the Rome II criteria. Furthermore, the possible relation of irritable bowel syndrome-like symptoms with the quality of life and coping behavior was studied. Seventy-three ulcerative colitis patients in remission, 34 Crohn's disease patients in remission, and 66 healthy controls completed questionnaires on irritable bowel syndrome, quality of life, and coping. Using the Rome II criteria, irritable bowel syndrome-like symptoms were found in one-third of ulcerative colitis patients and in 42% of Crohn's disease patients in remission. The presence of irritable bowel syndrome-like symptoms impaired the quality of life of patients, while no relation was found between the presence of symptoms and coping strategies.

High prevalence of fatigue in quiescent inflammatory bowel disease is not related to adrenocortical insufficiency.

OBJECTIVES: Inflammatory bowel disease (IBD) patients, with active as well as quiescent disease, frequently complain of fatigue. This often has consequences for patients' work and daily lives. The primary aim of this study was to assess the prevalence and severity of fatigue in IBD patients in remission. Furthermore, we studied the correlation between fatigue and disease activity, quality of life, and biochemical and hematological test results, and the role of (secondary) hypocortisolism. METHODS: Eighty subjects with proven IBD were included. Disease activity was assessed using the Clinical Activity Index for Ulcerative Colitis and the Crohn's Disease Activity Index. Quality of life was measured by the Inflammatory Bowel Disease Questionnaire, and fatigue was assessed using the Multidimensional Fatigue Inventory (MFI). Routine biochemical and hematological tests were performed, and basal cortisol was determined. To evaluate adrenocortical reserve in subjects with a cortisol level of <0.4 micromol/L, a low dose adrenocorticotrophin hormone test was performed. Healthy age- and sex-matched subjects (n = 67) served as controls. RESULTS: More than 40% of the IBD patients in remission suffered from fatigue. Mean MFI scores of the IBD patients were comparable to mean MFI scores reported in cancer patients. The Inflammatory Bowel Disease Questionnaire showed a negative correlation with the MFI (r = -0.735; p < 0.001). No correlation was found between fatigue and basal cortisol levels or other laboratory parameters. CONCLUSION: Fatigue is an important feature in IBD in remission, adversely affecting the quality of life. It does not, however, affect all patients, nor does it seem to be the result of hypocortisolism.