Facilitators and barriers in the implementation and adoption of Patient Reported Outcomes Measurements in daily practice.

OBJECTIVES: At the Erasmus MC, Patient Reported Outcome Measures (PROMs) are implemented on a hospital-wide scale. However, less than half of the patients and healthcare professionals (HCP) utilize these PROMs. Therefore, this study aimed to investigate facilitators and barriers for adoption of PROMs to develop guidance around implementation. METHODS: A mixed-methods study with a combination of interviews and focus groups, and questionnaires was conducted, involving patients, both PROM non-responders and PROM responders, HCPs, and medicine students and nurse specialists in training (hereafter 'students'). (Group)interview transcripts were subjected to thematic content analysis. Subsequently, questionnaires were developed and presented to all stakeholders to validate the findings. Last, identified themes and implementation recommendations were presented in a final questionnaire to the Value Based Healthcare Erasmus MC expert group to prioritize findings. RESULTS: Interviews were conducted with 15 patients, 14 HCPs and 4 students, and 2 focus groups with 5 students. The questionnaire was completed by 370/999 responders (37.0%), 173/1395 non-responders (12.5%), 44/194 HCPs (22.7%) and 40 students were reached via an open link. The identified facilitators and barriers were grouped into four overarching themes; training on PROMs at different levels in the education of (future) HCPS, motivate and reduce the burden for the HCP, implement generic and disease-specific PROMs simultaneously and motivate, activate and reduce the patient burden. CONCLUSIONS: Providing end-users with digital tools, implementation support and a clear hospital-wide vision are important, yet this does not guarantee successful adoption of PROMs. Successful adoption necessitates ongoing efforts to engage, motivate and train end-users.

Early fecal calprotectin levels at week 8 may guide therapeutic decisions on Ustekinumab therapy in patients with Crohn's disease.

BACKGROUND: Response evaluation after induction therapy with ustekinumab (UST) in Crohn's disease (CD) is important for decisions on maintenance therapy. We aimed to assess the potential of fecal calprotectin (FC) levels to predict endoscopic response at week 16. METHODS: CD patients with FC >100 µg/g and endoscopic active disease (SES-CD> 2, Rutgeerts' score ≥ i2) at initiation of UST therapy were enrolled. FC was determined at weeks 0, 2, 4, 8 and 16 and patients underwent a colonoscopy at week 16. The primary outcome was an endoscopic response at week 16 (SES-CD score ≥50% decrease or a decrease of ≥1 points in Rutgeerts' score). The optimal cut-off levels of FC and change in FC to predict endoscopic response were determined using ROC statistics. RESULTS: 59 CD patients were included. Endoscopic response was observed in 21/59 (36%) patients. The diagnostic accuracy for FC levels at week 8 to predict endoscopic response at week 16 showed a predictive value of 0.71. A decrease in FC levels ≥500 µg/g between baseline at week 8 indicates endoscopic response (PPV = 89%), whereas absence of any decrease indicates endoscopic non-response after induction (NPV = 81%). CONCLUSIONS: Continuation of UST therapy without endoscopic response evaluation may be considered in patients with a decrease in FC levels of ≥500 µg/g at week 8. The decision on continuation of UST therapy or therapy optimization needs reconsideration in patients without a decrease of FC level. In all other patients, endoscopic response evaluation of induction therapy remains essential for therapeutic decisions.

Physical fitness and physical activity in fatigued and non-fatigued inflammatory bowel disease patients.

OBJECTIVE: To assess physical fitness and physical activity in inflammatory bowel disease (IBD) patients and whether fatigue is associated with impaired physical fitness and impaired physical activity. MATERIALS AND METHODS: Ten patients with quiescent IBD and fatigue (fatigue group [FG]) based on the Checklist Individual Strength-Fatigue score of ≥35 were matched for age (±5 years) and sex with a non-fatigue group (NFG) with IBD. Physical fitness was measured with a cyclo-ergometric-based maximal exercise test, a submaximal 6-min walk test, and a dynamometer test to quantify the isokinetic muscle strength of the knee extensors and flexors. Level of physical activity was measured with an accelerometer-based activity monitor. RESULTS: The patients in both groups did not differ in regard to medication use, clinical characteristics, and body composition. However, medium-to-large effect sizes for impaired physical fitness (both cardiorespiratory fitness and muscle strength) and physical activity were seen between the patients in the FG and the NFG. Especially, intensity of physical activity was significantly lower in the FG patients compared with the NFG patients (effect size: 1.02; p = 0.037). Similar results were seen when outcomes of the FG and NFG were compared with reference values of the normal population. CONCLUSION: Fatigued IBD patients show an impaired physical fitness and physical activity compared with non-fatigued IBD patients. This gives directions for a physical component in fatigue in IBD patients. Therefore, these new insights into fatigue indicate that these patients might benefit from an exercise program to improve physical fitness and physical activity.

Fatigue management in patients with IBD: a randomised controlled trial.

OBJECTIVE: To assess the effectiveness of solution-focused therapy (SFT) on fatigue and quality of life (QoL) in patients with fatigued inflammatory bowel disease (IBD). DESIGN: Randomised controlled trial in two Dutch hospitals. Patients with IBD with quiescent IBD and with a Checklist Individual Strength--Fatigue (CIS--fatigue) score of ≥ 35 were enrolled. Patients were 1:1 randomised to receive SFT or care as usual (CAU) for 3 months. Patients were followed for a further 6 months after the SFT. Primary endpoint was defined as changes in fatigue and QoL during follow-up. Secondary endpoints included change in anxiety and depression, medication use, side effects to medication, disease activity, laboratory parameters (C-reactive protein, leucocytes and haemoglobin) and sleep quality. RESULTS: Ninety-eight patients were included, of whom 63% were women, mean age was 40.1 years. After the SFT course, 17 (39%) patients in the SFT group had a CIS-fatigue score below 35 compared with eight (18%) of patients in the CAU group (p=0.03). The SFT group also showed a greater reduction in fatigue across the first 6 months compared with the CAU group (CIS-fatigue: p=<0.001 and CIS-total: p=0.001). SFT was associated with a significant higher mean IBD questionnaire change at 3 months (p=0.020). At 9 months, no significant differences between the two groups were observed. CONCLUSIONS: SFT has a significant beneficial effect on the severity of fatigue and QoL in patients with quiescent IBD. However, this effect diminished during follow-up.

Validation of endoscopic activity scores in patients with Crohn's disease based on a post hoc analysis of data from SONIC.

BACKGROUND & AIMS: Mucosal healing might alter midterm and long-term outcomes of patients with Crohn's disease (CD) and has become an important end point in clinical trials. However, the minimal degree of mucosal improvement (endoscopic response) required to alter midterm outcomes is not known. We aimed to determine the best definition of endoscopic response by evaluating data on the Simple Endoscopic Score for Crohn's Disease (SES-CD) and the Crohn's Disease Endoscopic Index of Severity (CDEIS) from the Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease (SONIC trial). METHODS: We analyzed data from 172 patients who participated in the SONIC trial, were found to have endoscopic lesions at baseline, and underwent a second endoscopic examination at week 26 of treatment with infliximab, azathioprine, or both. Mucosal healing was defined as absence of ulcers. A central reader calculated SES-CD and CDEIS results. Different cutoff values were set for endoscopic response based on the SES-CD or CDEIS. The diagnostic ability of these different cutoff values was evaluated using receiver operating characteristic (ROC) curves, positive likelihood ratios (PLR), and negative likelihood ratios (NLR). Corticosteroid-free clinical remission (CFREM) at week 50 was used as a binary classifier. RESULTS: Based on analyses of ROC curves, PLR, and NLR, endoscopic response was defined as a decrease from baseline in SES-CD of at least 50%. At week 26, mucosal healing and endoscopic response were achieved in 48% and 65% of patients, respectively. Mucosal healing at week 26 was associated with CFREM at week 50, with 56% sensitivity, 65% specificity, a PLR of 1.60, and an NLR of 0.67. Endoscopic response at week 26 was associated with CFREM at week 50, with 74% sensitivity, 48% specificity, a PLR of 1.42, and an NLR of 0.54. Endoscopic response, defined as a decrease from baseline in CDEIS of at least 50%, yielded similar results. CONCLUSIONS: In patients with CD, mucosal healing and endoscopic response (defined as a decrease from baseline in SES-CD or CDEIS of at least 50%) at week 26 of treatment identified those most likely to be in CFREM at week 50. The ability of the proposed endoscopic response cutoff value to predict midterm CFREM should be validated in an independent, prospective cohort. Its correlation with changes in long-term disease progression still needs to be demonstration. ClinicalTrials.gov, Number: NCT00094458.

Ustekinumab Tissue and Serum Levels in Patients With Crohn's Disease Are Closely Correlated Though Not Consistently Associated With Objective Response After Induction.

BACKGROUND: Ustekinumab (UST), which targets p40/interleukin (IL)-23 and IL-12, is an effective treatment for Crohn's disease (CD). Therapeutic drug monitoring may optimize UST posology. The aim of this study was to investigate UST and IL-23 serum and tissue concentrations in relation to mucosal inflammation and treatment response at an early time point. METHODS: CD patients starting UST between December 2016 and November 2018 were prospectively enrolled. Endoscopies were performed at baseline and week 16. UST and IL-23 serum and tissue concentrations were measured at week 16. Clinical and biochemical response were defined as decline of ≥3 points in Harvey-Bradshaw Index and reduction of ≥50% in fecal calprotectin levels. Endoscopic response was defined as a ≥50% decline in Simple Endoscopic Score or a decline of ≥1 points in Rutgeerts score. Histological remission was defined as Global Histologic Disease Activity Score ≤4. RESULTS: Of 56 included patients, 17 (30%) of 56 showed clinical response, 16 (30%) of 53 showed biochemical response, and 20 (36%) of 56 showed endoscopic response. UST, but not IL-23, concentration in biopsies was correlated to levels in corresponding sera (P < .0001). No correlation was found between UST tissue levels and treatment response. Patients achieving biochemical response showed significantly higher UST serum levels (3.12 µg/mL vs 1.41 µg/mL; P = .01). Tissue IL-23-to-UST ratio correlated with mucosal inflammation (P = .01). CONCLUSIONS: This is the first study to demonstrate a correlation between serum and tissue UST levels. While tissue IL-23-to-UST ratio correlated with mucosal inflammation, UST serum levels were more indicative for biochemical response. The role of UST levels for therapeutic drug monitoring in inflammatory bowel disease needs further research.

Ustekinumab (UST) serum levels correlate with UST tissue levels in patients with Crohn's disease. Tissue interleukin-23-to-UST ratio correlates with histological inflammation (Global Histologic Disease Activity Score). Serum UST levels correlate with biochemical response (reduction of ≥50% in fecal calprotectin levels).

Impact of the First SARS-CoV-2 Lockdown on Adherence to Biological Treatment in Patients with Immune-Mediated Inflammatory Diseases in the Netherlands.

Purpose: During the SARS-CoV-2 pandemic, national and international societies have recommended continuing biological agents in patients with immune-mediated inflammatory diseases (IMID) in the absence of SARS-CoV-2 symptoms. However, adherence to biological treatment might decrease, because these recommendations contradict patients' beliefs. Especially an increased concern about side effects could have influenced the adherence to biological treatment during the first lockdown. The primary objective was to investigate the impact of the first SARS-CoV-2 lockdown on adherence to biological treatment in IMID patients. Patients and Methods: In this prospective cohort study, IMID patients who received a biological agent before and during the first SARS-CoV-2 lockdown (March 2020- June 2020) were included. Patients were excluded if they did not complete the medication adherence report scale-5 (MARS-5) questionnaire at ≥1 visit before the lockdown and ≥1 visit during the lockdown. Adherence to biological treatment was measured with the MARS-5 and Medication Possession Ratio (MPR). Results: We included 157 IMID patients. The percentage of adherent patients, defined as MARS-5 score >21, was significantly lower during the lockdown compared to the period before the lockdown (88.5% vs 84.1%, p<0.001). Additionally, the overall percentage of adherent patients during the lockdown based on the MPR ≥90% was significantly lower compared to adherence based upon the MARS-5 (65.1% vs 84.1%, p<0.001). Conclusion: This study showed that the first SARS-CoV-2 lockdown negatively impacts adherence to biological treatment in IMID patients. Therefore, treating physicians should be aware of this problem to minimize the potential harmful effects of non-adherence.

Histomorphometric analysis reveals reduced bone mass and bone formation in patients with quiescent Crohn's disease.

BACKGROUND & AIMS: Crohn's disease (CD) is associated with an increased prevalence of osteoporosis, but the pathogenesis of this bone loss is only partly understood. We assessed bone structure and remodeling at the tissue level in patients with quiescent CD. We also investigated the roles of osteocyte density and apoptosis in CD-associated bone loss. METHODS: The study included 23 patients with quiescent CD; this was a subgroup of patients from a large randomized, double-blind, placebo-controlled, multicenter trial. We obtained transiliac bone biopsy samples and performed histomorphometric analysis. Results were compared with data from age- and sex-matched healthy individuals (controls). RESULTS: Trabecular bone volume was decreased among patients with CD compared with controls (18.90% vs 25.49%; P < .001). The low bone volume was characterized by decreased trabecular thickness (120.61 vs 151.42 µm; P < .01). Bone formation and resorption were reduced, as indicated by a decreased mineral apposition rate (0.671 vs 0.746 µm/day; P < .01) and a low osteoclast number and surface area compared with controls and published values, respectively. In trabecular bone of patients with CD, osteocyte density and apoptosis were normal. The percentage of empty lacunae among patients was higher than that of published values in controls. CONCLUSIONS: In adult patients with quiescent CD, bone histomorphometric analysis revealed a reduction in bone mass that was characterized by trabecular thinning. The CD-associated bone loss was caused by reduced bone formation, possibly as a consequence of decreased osteocyte viability in the patients' past.

The risk of inflammatory bowel disease-related colorectal carcinoma is limited: results from a nationwide nested case-control study.

OBJECTIVES: The risk for inflammatory bowel disease (IBD)-related colorectal cancer (CRC) remains a matter of debate. Initial reports mainly originate from tertiary referral centers, and conflict with more recent studies. Overall, epidemiology of IBD-related CRC is relevant to strengthen the basis of surveillance guidelines. We performed a nationwide nested case-control study to assess the risk for IBD-related CRC and associated prognostic factors in general hospitals. METHODS: IBD patients diagnosed with CRC between January 1990 and July 2006 in 78 Dutch general hospitals were identified as cases, using a nationwide automated pathology database. Control IBD patients without CRC were randomly selected. Clinical data were collected from detailed chart review. Poisson regression analysis was used for univariable and multivariable analyses. RESULTS: A total of 173 cases were identified through pathology and chart review and compared with 393 controls. The incidence rate of IBD-related CRC was 0.04%. Risk factors for IBD-related CRC were older age, concomitant primary sclerosing cholangitis (PSC, relative ratio (RR) per year duration 1.05; 95% confidence interval (CI) 1.01-1.10), pseudopolyps (RR 1.92; 95% CI 1.28-2.88), and duration of IBD (RR per year 1.04; 95% CI 1.02-1.05). Using immunosuppressive therapy (odds ratio (OR) 0.3; 95% CI 0.16-0.56, P<0.001) or anti-tumor necrosis factor (TNF) (OR 0.09; 95% CI 0.01-0.68, P<0.02) was protective. CONCLUSIONS: We found a limited risk for developing IBD-related CRC in The Netherlands. Age, duration of PSC and IBD, concomitant pseudopolyps, and use immunosuppressives or anti-TNF were strong prognostic factors in general hospitals.

Malignant transformation of perianal and enterocutaneous fistulas is rare: results of 17 years of follow-up from The Netherlands.

OBJECTIVE: Malignant transformation of fistulas has been observed, particularly in perianal fistulas in Crohn's disease (CD) patients. The prevalence of adenocarcinoma in enterocutaneous fistulas and non-CD-related fistulas, however, is unknown. We investigated adenocarcinoma originating from perianal and enterocutaneous fistulas in both CD patients and non-CD patients from nine large, mostly tertiary referral, hospitals in The Netherlands. METHODS: Patients suffering from fistulizing disease and either dysplasia or adenocarcinoma between January 1990 and January 2007 were identified using the nationwide automated pathology database (PALGA). Clinical and histopathological data were collected and verified using hospital patient-charts and reported by descriptive statistics. The total CD-population comprised 6058 patients. RESULTS: In a study-period of 17 years, 2324 patients with any fistula were reported in PALGA. In 542 patients, dysplasia or adenocarcinoma was also mentioned. After initial review and additional detailed chart review, 538 patients were excluded, mainly because the adenocarcinoma was not related to the fistula. In the remaining four patients, all suffering from CD, adenocarcinoma originating from the fistula-tract was confirmed. The malignancies developed 25 years (IQR 10-38) after CD diagnosis, and 10 years (IQR 6-22) after fistula diagnosis. Median age at time of adenocarcinoma diagnosis was 48.3 years (IQR 43-58). Only one patient had clinical symptoms indicative for adenocarcinoma. In three other patients, the adenocarcinoma was found coincidently. CONCLUSIONS: Adenocarcinoma complicating perianal or enterocutaneous fistula-tracts is a rare finding. Only 4 out of 6058 CD patients developed a fistula-associated adenocarcinoma. We could not identify any malignant transformations in non-CD-related fistulas in our 17 years study-period.

Re-induction with intravenous Ustekinumab after secondary loss of response is a valid optimization strategy in Crohn's disease.

BACKGROUND AND AIM: Re-induction with intravenous ustekinumab after secondary loss of response in Crohn's disease is a relatively new strategy to regain efficacy. This real-world cohort study aimed to evaluate its effectiveness and safety. METHODS: Crohn's disease patients with loss of response after initial response to ustekinumab and treated with a second intravenous dose of ustekinumab were included. Clinical, biochemical and endoscopic data were collected. Primary outcome was drug survival. Secondary effectiveness outcomes included clinical remission, primary nonresponse and adverse events. RESULTS: In total, 31 Crohn's disease patients were included after re-induction with intravenous ustekinumab. All patients had failed prior biologic therapy, that is 77% were exposed to two or more antitumor necrosis factor agents and 65% were exposed to vedolizumab prior to initiation of ustekinumab treatment. Median treatment duration between initial treatment and re-induction with intravenous ustekinumab was 11.1 months (interquartile range 6.9-19.5). Ustekinumab therapy after a second dose of intravenous ustekinumab was maintained in 74 and 71% of the patients at weeks 20 and 52. Clinical remission rates after re-induction at weeks 8, 20 and 52 were 37, 56 and 45%, respectively. Nonresponse occurred in 16% of the patients. Adverse events were reported in four patients. CONCLUSIONS: Re-induction with intravenous ustekinumab after secondary loss of response results in continuation of ustekinumab treatment for at least 1 year in almost three-quarters of patients and in clinical remission in half of patients after 1 year. Therefore, ustekinumab re-induction may be considered an important rescue treatment option in patients with refractory Crohn's disease.

Vedolizumab Tissue Concentration Correlates to Mucosal Inflammation and Objective Treatment Response in Inflammatory Bowel Disease.

BACKGROUND: The association between vedolizumab (VDZ) exposure and treatment response is unclear and seems insufficiently explained by serum levels. The aim of this study was to assess the correlation between VDZ concentrations in serum and intestinal tissue and their association with mucosal inflammation and response to VDZ. METHODS: This prospective study included 37 adult patients with inflammatory bowel disease with endoscopic inflammation at baseline who started VDZ. At week 16, serum and biopsies were collected for VDZ measurement by enzyme-linked immunosorbent assay. Nonlinear mixed-effects modeling was used to calculate serum trough concentrations and to assess intestinal tissue concentrations. Validated clinical and endoscopic scores were used to define clinical and endoscopic response and remission, and fecal calprotectin levels were used to assess biochemical response. Histologic remission was determined by the Nancy score. RESULTS: A positive correlation was observed between VDZ concentrations in serum and tissue (r2 = 0.83; P < 0.0001). High mucosal rather than serum VDZ levels correlated with a reduced endoscopic (P = 0.06) grade of mucosal inflammation. Furthermore, patients with a positive biochemical and endoscopic outcome had higher tissue levels of VDZ than patients without biochemical and endoscopic response (P < 0.01 and P = 0.04, respectively). CONCLUSIONS: Tissue levels of VDZ may provide a better marker than serum levels for mucosal inflammation and objective treatment outcome at week 16. The potential of VDZ tissue levels for therapeutic drug monitoring in inflammatory bowel disease warrants further exploration.

Reproductive wish represents an important factor influencing therapeutic strategy in inflammatory bowel diseases.

OBJECTIVE: Inflammatory bowel disease (IBD) affects patients in reproductive age but little is known about the peri-conceptional use of medication for IBD. The aim of this study was to assess the type of medication used by IBD patients with the desire to reproduce and changes in medication in the peri-conceptional period. MATERIAL AND METHODS: IBD patients with active conception plans and pregnant patients were prospectively recruited from the outpatient clinic of a single academic medical center. IBD-related medication and changes in this medication for reasons of a desire to conceive or pregnancy were analyzed. RESULTS: In total, 61 patients (51 females; 40 with Crohn's disease, 21 with ulcerative colitis) were included. Thirteen patients (21%) used no medication, 44 (72%) used monotherapy and four (7%) used combination treatment. Of patients on monotherapy, 11 (19%) used 5-aminosalicylates, five (9%) used steroids, 11 (19%) used thiopurines, five (9%) used methotrexate and 11 (19%) used anti-tumor necrosis factor agents. Thirty-seven patients (61%) consulted a physician prior to conception. About one-third of these patients required a change in their medication due to their conception plans. CONCLUSIONS: In a referral center, the majority of IBD patients with conception plans require medication for which limited information on the safety of peri-conceptional use is available. In addition, the desire to reproduce leads to medication changes in about one-third of these patients.

Impact of double-balloon enteroscopy findings on the management of Crohn's disease.

OBJECTIVE: It is estimated that 10%-30% of Crohn's disease (CD) patients have small-bowel lesions, but the exact frequency and clinical relevance of these findings are unknown. Double-balloon enteroscopy (DBE) enables endoscopic visualization of the small bowel. The aim of this study was to evaluate the use of DBE for detecting small-bowel lesions in CD patients suspected of having small-bowel involvement. Furthermore, the clinical impact of adjusting treatment in these patients was assessed. MATERIAL AND METHODS: A prospective study was performed in a tertiary referral center. CD patients suspected of small-bowel involvement and in whom distal activity had previously been excluded were included. All patients underwent DBE, followed by step-up therapy in patients with small-bowel lesions. The presence of small-bowel lesions during DBE was noted and clinical outcome was assessed after adjusting therapy. RESULTS: Thirty-five patients (70%) showed small-bowel lesions; these lesions could not be assessed by conventional endoscopy in 23 (46%). At 1-year follow-up, step-up therapy in 26 patients (74%) led to clinical remission in 23 (88%). This was confirmed by a significant decrease in Crohn's disease activity index and mucosal repair on second DBE. CONCLUSIONS: DBE showed a high frequency of small-bowel lesions in known CD patients with clinically suspected small-bowel activity. Most of these lesions were not accessible for conventional endoscopy. Adjusting treatment in patients with small-bowel CD involvement led to clinical remission and mucosal repair in the majority of cases.

Fecal calprotectin is an early predictor of endoscopic response and histologic remission after the start of vedolizumab in inflammatory bowel disease.

BACKGROUND AND AIMS: Early prediction of the effect of vedolizumab (VDZ) in inflammatory bowel disease (IBD) is of paramount importance to guide clinical decisions. This study assessed whether early fecal calprotectin (FC) can predict endoscopic response and histologic remission after VDZ initiation. METHODS: This was a prospective study. Inclusion criteria were endoscopic inflammation and FC >100 µg/g. FC was determined at baseline and weeks 2, 4, 8 and 16. At week 16, endoscopies with ileal and colonic biopsies were performed. FC changes were assessed with Wilcoxon Rank Sum tests. ROC statistics were used to assess the diagnostic accuracy of FC. RESULTS: In total, 45 patients [27 Crohn's disease (CD), 16/2 ulcerative colitis (UC)/IBD-unclassified] [40% males, median age 39 (28-51) years] were included. Week 16 endoscopic response and histologic remission rates were 58% and 33%. A median 37% decline in FC at week 2 was observed only in endoscopic responders, p = 0.025. FC <250 µg/g at week 8 predicted endoscopic response in both UC and CD (positive predictive value 100%), whereas absence of FC decline at week 8 corresponded with absence of endoscopic response in CD [negative predictive value (NPV) 82%] and absence of histologic remission in both UC and CD (NPV 90%). CONCLUSION: The onset of a decline in FC as early as week 2 is associated with endoscopic response to VDZ induction. FC <250 µg/g at week 8 is associated with endoscopic response, whereas absence of FC decline at week 8 is associated with absence of both endoscopic response and histologic remission. FC levels 8 weeks after the start of VDZ could be used to guide clinical decisions and might substitute for endoscopic response evaluation.

Lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation.

Colorectal cancer (CRC) is the second most common cause of cancer-related death, encouraging the search for novel therapeutic targets affecting tumor cell proliferation and migration. These cellular processes are under tight control of two opposing groups of enzymes; kinases and phosphatases. Aberrant activity of kinases is observed in many forms of cancer and as phosphatases counteract such "oncogenic" kinases, it is generally assumed that phosphatases function as tumor suppressors. However, emerging evidence suggests that the lipid phosphatase SH2-domain-containing 5 inositol phosphatase (SHIP2), encoded by the INPPL1 gene, may act as an oncogene. Just like the well-known tumor suppressor gene Phosphatase and Tensin Homolog (PTEN) it hydrolyses phosphatidylinositol (3,4,5) triphosphate (PI(3,4,5)P3). However, unlike PTEN, the reaction product is PI(3,4)P2, which is required for full activation of the downstream protein kinase B (PKB/Akt), suggesting that SHIP2, in contrast to PTEN, could have a tumor initiating role through PKB activation. In this work, we investigated the role of SHIP2 in colorectal cancer. We found that SHIP2 and INPPL1 expression is increased in colorectal cancer tissue in comparison to adjacent normal tissue, and this is correlated with decreased patient survival. Moreover, SHIP2 is more active in colorectal cancer tissue, suggesting that SHIP2 can induce oncogenesis in colonic epithelial cells. Furthermore, in vitro experiments performed on colorectal cancer cell lines shows an oncogenic role for SHIP2, by enhancing chemoresistance, cell migration, and cell invasion. Together, these data indicate that SHIP2 expression contributes to the malignant potential of colorectal cancer, providing a possible target in the fight against this devastating disease.

Determinants of fatigue in Crohn's disease patients.

OBJECTIVE: Crohn's disease (CD) is often associated with severe fatigue. Little is known about patients who may be at the highest risk for fatigue. Therefore, we assessed the disease phenotype and factors related to fatigue in the presence of CD in two different populations. METHODS: Patients presenting at the clinic of a referral hospital and a general hospital were included in the study. They completed questionnaires including the Checklist Individual Strength, the Hospital Anxiety and Depression Scale, a questionnaire on disease activity, and one on medication use. The Montreal classification and sociodemographics were obtained from medical records. Hemoglobin and C-reactive protein levels were measured at baseline. RESULTS: In total, 425 patients were included (276 women, mean age: 42 years). Compared with patients from the general hospital, patients at the referral hospital had worse disease activity, worse disease behavior, more bowel resections, and a higher percentage of side-effects to medication and use of anti-tumor necrosis factor (TNF). The prevalence of fatigue was significantly higher in the referral patients compared with the general patients (65.7 vs. 52.5%, respectively; P=0.01). Similar results were found in patients in remission (53.3 vs. 40.5%; P=0.061). Factors related to fatigue were the use of anti-TNF at baseline, side-effects to 5-aminosalicylic acid, disease activity, female sex, and shorter disease duration. Furthermore, we found improvement in fatigue and a trend toward lower disease activity after 1 year of anti-TNF use. CONCLUSION: A high percentage of CD patients suffer from fatigue. As a more aggressive phenotype seems to be associated with more severe fatigue and patients in remission still suffer from fatigue, a multidimensional approach for fatigue is warranted in these patients.

Majority of patients with inflammatory bowel disease in clinical remission have mucosal inflammation.

BACKGROUND: Management of inflammatory bowel disease (IBD) is increasingly focused on mucosal remission. We assessed the prevalence of mucosal inflammation during clinical remission, the clinical consequences, and the impact on disease course. METHODS: IBD patients from two referral centers who underwent a surveillance colonoscopy while clinically in remission between January 2001 and December 2003 were included. Follow-up ended May 1, 2009. Clinical data were collected from patient charts. Statistical analysis was performed using independent t-tests and nonparametric tests. RESULTS: In total, 152 IBD patients were included (98 [65%] ulcerative colitis, 46 [30%] Crohn's disease; 85 [56%] males). Median follow-up was 6.8 years (interquartile range [IQR] 6-8). Forty-seven (31%) patients had no signs of inflammation during endoscopy (group A). Of the remaining 105 (68%) patients, 51 (49%) had both endoscopic and histological inflammation (group B), 51 (49%) histological inflammation only (group C), two (2%) endoscopic lesions only (group D). Two years later, 29% of all patients had endoscopic inflammation and another 27% had only microscopic inflammation. In 39% the inflammation had resolved spontaneously. Inflammation was more often found in group B+C (n = 62/102; 61%) than in group A (n = 17/47; 36%; P = 0.21). Inflammation was not associated with more frequent clinical relapses nor with stricture formation, nor with the need for surgery. CONCLUSIONS: A large proportion of IBD patients have mucosal inflammation without clinical symptoms. Although one-third recover spontaneously, mucosal inflammation in patients who are clinically in remission is associated with more severe mucosal disease activity, but not with more complications or symptomatic flares during follow-up.