Effectiveness and safety of tofacitinib for ulcerative colitis: two-year results of the ICC Registry.

BACKGROUND: Tofacitinib is an oral Janus kinase (JAK) inhibitor and is registered for the treatment of ulcerative colitis (UC). The effectiveness of tofacitinib has been evaluated up to 12 months of treatment. AIM: The aim of this study was to assess the effectiveness and safety of 24 months of tofacitinib use in UC patients in the Netherlands. METHODS: Patients initiating tofacitinib treatment were included in the ICC Registry, a nationwide, observational registry. Patients were prospectively evaluated for up to 24 months. The primary outcome was corticosteroid-free clinical remission (CSFR, Simple Clinical Colitis Activity Index [SCCAI] ≤2) at week 104. Secondary outcomes included biochemical remission (C-reactive protein (CRP) ≤5 mg/L and faecal calprotectin (FC) ≤250 µg/g), safety, and discontinuation rate. RESULTS: We included 110 patients of whom 104 (94.5%) were anti-TNF experienced. After 104 weeks of tofacitinib, 31.8% (34/107) were in CSFR, 23.4% (25/107) in biochemical remission and 18.7% (20/107) in combined clinical and biochemical remission. Of the patients in CSFR at week 52, 76.5% (26/34) remained so after 104 weeks of treatment. Sixty-one patients (55.5%) discontinued tofacitinib after a median duration of 13 weeks (IQR 7-34). The main reasons for discontinuation were non-response (59%), loss of response (14.8%), and adverse events (18%). There were 33.9 possible tofacitinib-related adverse events per 100 patient-years during follow-up. Adverse events most probably related to tofacitinib were skin reactions and headaches. There were 6.4 herpes zoster infections per 100 patient-years. CONCLUSION: Tofacitinib was effective in 31.8% of patients after 24 months of treatment.

Gene expression responses reflecting 5-FU-induced toxicity: Comparison between patient colon tissue and 3D human colon organoids.

Capecitabine is a chemotherapeutic drug that is widely used as a monotherapy option in advanced cancer patients. After administration, it is converted into its active metabolite 5-fluorouracil (5-FU), a cytotoxic compound that may also induce adverse side effects in the gastrointestinal (GI) tract. Although these side effects can interfere with the continuation of the chemotherapy, diagnostic tools to detect early onset and prevention strategies are not available. In this explorative case study, we aim to identify differentially expressed genes (DEGs) that provide insight into the molecular mechanisms of toxicity induced by 5-FU in healthy colon tissue of breast cancer patients receiving capecitabine. Gene expression responses observed in patients were compared with those established in an in vitro model of healthy colon organoids. Colon biopsies from two patients with advanced breast cancer were collected before and after the treatment with capecitabine and used for RNA sequencing to determine transcriptomic responses. Differential expression analysis resulted in 31 affected genes, showing that the most affected pathways were transport of small molecules, cellular responses to stress, folate metabolism, NF-kB signalling pathway and immune system responses. The most biologically relevant genes were haemoglobin subunits encoding genes, involved in several processes; ATP12A, SLC26A3 and AQP8, involved in the transport of ions and water; TRIM31, a regulator of NF-kB signalling pathway; MST1P2 and MST1L, stimulators of macrophages. Comparison of human in vitro and in vivo responses showed that the gene expression of TRIM31 was similarly altered in the colon organoids exposed to 5-FU. Therefore, this gene constitutes a potential biomarker of colon toxicity that might be used in future in vitro drug safety design and screening.

Feasibility and Efficiency of the BEFORE (Better Exercise and Food, Better Recovery) Prehabilitation Program.

Prehabilitation has been postulated as an effective preventive intervention to reduce postoperative complications, particularly for elderly patients with a relatively high risk of complications. To date, it remains to be determined whether prehabilitation increases physical capacity and reduces postoperative complications. The aim of this study was to assess the feasibility of a 4-week multimodal prehabilitation program consisting of a personalized, supervised training program and nutritional intervention with daily fresh protein-rich food for colorectal cancer patients aged over 64 years prior to surgery. The primary outcome was the feasibility of this prehabilitation program defined as ≥80% compliance with the exercise training program and nutritional intervention. The secondary outcomes were the organizational feasibility and acceptability of the prehabilitation program. A compliance rate of ≥80% to both the exercise and nutritional intervention was accomplished by 6 patients (66.7%). Attendance of ≥80% at all 12 training sessions was achieved by 7 patients (77.8%); all patients (100%) attended ≥80% of the available training sessions. Overall, compliance with the training was 91.7%. Six patients (66.7%) accomplished compliance of ≥80% with the nutritional program. The median protein intake was 1.2 (g/kg/d). No adverse events occurred. This multimodal prehabilitation program was feasible for the majority of patients.

Neoplasia and Precursor Lesions of the Female Genital Tract in IBD: Epidemiology, Role of Immunosuppressants, and Clinical Implications.

In this review the risk of breast, ovarian, and endometrial cancer and cervical and vulvovaginal (pre)malignant abnormalities in patients with inflammatory bowel disease (IBD) with or without immune suppressive treatment will be discussed. So far, this has not been studied thoroughly and large studies taking into account diverse potential confounding factors are lacking. IBD per se has not been associated with development of cervical cancer, yet patients with Crohn's disease who smoke, have a younger age at diagnosis or who use(d) thiopurines might be more at risk. Other immunosuppressive medication seems not to increase this risk, however, as evidence at this point is incomplete, physician awareness and prevention by lifestyle counseling, HPV vaccination and (intensified) screening are warranted. The risk for breast, endometrial, ovarian, and vulvovaginal cancer in IBD patients appears to be comparable to the background population, although for breast cancer this may even be decreasedin Crohn's disease specifically. Immunosuppressive medication in general does not seem to alter this risk. Earlier and more frequent screening for breast cancer than currently conducted in general nationwide screening programs is not recommended at this moment. Current literature suggests a much lower overall malignancy recurrence rate in IBD patients than has been observed previously. More importantly, immune suppressive medication does not appear to increase the recurrence risk. Robust epidemiologic data on female genital tract cancer are needed.

High Risk of Advanced Colorectal Neoplasia in Patients With Primary Sclerosing Cholangitis Associated With Inflammatory Bowel Disease.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC, termed PSC-IBD) are at increased risk for colorectal cancer, but their risk following a diagnosis of low-grade dysplasia (LGD) is not well described. We aimed to determine the rate of advanced colorectal neoplasia (aCRN), defined as high-grade dysplasia and/or colorectal cancer, following a diagnosis of indefinite dysplasia or LGD in this population. METHODS: We performed a retrospective, longitudinal study of 1911 patients with colonic IBD (293 with PSC and 1618 without PSC) who underwent more than 2 surveillance colonoscopies from 2000 through 2015 in The Netherlands or the United States (9265 patient-years of follow-up evaluation). We collected data on clinical and demographic features of patients, as well as data from each surveillance colonoscopy and histologic report. For each surveillance colonoscopy, the severity of active inflammation was documented. The primary outcome was a diagnosis of aCRN during follow-up evaluation. We also investigated factors associated with aCRN in patients with or without a prior diagnosis of indefinite dysplasia or LGD. RESULTS: Patients with PSC-IBD had a 2-fold higher risk of developing aCRN than patients with non-PSC IBD. Mean inflammation scores did not differ significantly between patients with PSC-IBD (0.55) vs patients with non-PSC IBD (0.56) (P = .89), nor did proportions of patients with LGD (21% of patients with PSC-IBD vs 18% of patients with non-PSC IBD) differ significantly (P = .37). However, the rate of aCRN following a diagnosis of LGD was significantly higher in patients with PSC-IBD (8.4 per 100 patient-years) than patients with non-PSC IBD (3.0 per 100 patient-years; P = .01). PSC (adjusted hazard ratio [aHR], 2.01; 95% CI, 1.09-3.71), increasing age (aHR 1.03; 95% CI, 1.01-1.05), and active inflammation (aHR, 2.39; 95% CI, 1.63-3.49) were independent risk factors for aCRN. Dysplasia was more often endoscopically invisible in patients with PSC-IBD than in patients with non-PSC IBD. CONCLUSIONS: In a longitudinal study of almost 2000 patients with colonic IBD, PSC remained a strong independent risk factor for aCRN. Once LGD is detected, aCRN develops at a higher rate in patients with PSC and is more often endoscopically invisible than in patients with only IBD. Our findings support recommendations for careful annual colonoscopic surveillance for patients with IBD and PSC, and consideration of colectomy once LGD is detected.

Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: a randomised controlled, open-label, multicentre trial.

BACKGROUND: Treatment of patients with ileocaecal Crohn's disease who have not responded to conventional therapy is commonly scaled up to biological agents, but surgery can also offer excellent short-term and long-term results. We compared laparoscopic ileocaecal resection with infliximab to assess how they affect health-related quality of life. METHODS: In this randomised controlled, open-label trial, in 29 teaching hospitals and tertiary care centres in the Netherlands and the UK, adults with non-stricturing, ileocaecal Crohn's disease, in whom conventional therapy has failed were randomly allocated (1:1) by an internet randomisation module with biased-coin minimisation for participating centres and perianal fistula to receive laparoscopic ileocaecal resection or infliximab. Eligible patients were aged 18-80 years, had active Crohn's disease of the terminal ileum, and had not responded to at least 3 months of conventional therapy with glucocorticosteroids, thiopurines, or methotrexate. Patients with diseased terminal ileum longer than 40 cm or abdominal abscesses were excluded. The primary outcome was quality of life on the Inflammatory Bowel Disease Questionnaire (IBDQ) at 12 months. Secondary outcomes were general quality of life, measured by the Short Form-36 (SF-36) health survey and its physical and mental component subscales, days unable to participate in social life, days on sick leave, morbidity (additional procedures and hospital admissions), and body image and cosmesis. Analyses of the primary outcome were done in the intention-to-treat population, and safety analyses were done in the per-protocol population. This trial is registered at the Dutch Trial Registry (NTR1150). FINDINGS: Between May 2, 2008, and October 14, 2015, 73 patients were allocated to have resection and 70 to receive infliximab. Corrected for baseline differences, the mean IBDQ score at 12 months was 178·1 (95% CI 171·1-185·0) in the resection group versus 172·0 (164·3-179·6) in the infliximab group (mean difference 6·1 points, 95% CI -4·2 to 16·4; p=0·25). At 12 months, the mean SF-36 total score was 112·1 (95% CI 108·0-116·2) in the resection group versus 106·5 (102·1-110·9) in the infliximab group (mean difference 5·6, 95% CI -0·4 to 11·6), the mean physical component score was 47·7 (45·7-49·7) versus 44·6 (42·5-46·8; mean difference 3·1, 4·2 to 6·0), and the mean mental component score was 49·5 (47·0-52·1) versus 46·1 (43·3-48·9; mean difference 3·5, -0·3 to 7·3). Mean numbers of days of sick leave were 3·4 days (SD 7·1) in the resection group versus 1·4 days (4·7) in the infliximab group (p<0·0001), days not able to take part in social life were 1·8 days (6·3) versus 1·1 days (4·5; p=0·20), days of scheduled hospital admission were 6·5 days (3·8) versus 6·8 days (3·2; p=0·84), and the number of patients who had unscheduled hospital admissions were 13 (18%) of 73 versus 15 (21%) of 70 (p=0·68). Body-image scale mean scores in the patients who had resection were 16·0 (95% CI 15·2-16·8) at baseline versus 17·8 (17·1-18·4) at 12 months, and cosmetic scale mean scores were 17·6 (16·6-18·6) versus 18·6 (17·6-19·6). Surgical intervention-related complications classified as IIIa or worse on the Clavien-Dindo scale occurred in four patients in the resection group. Treatment-related serious adverse events occurred in two patients in the infliximab group. During a median follow-up of 4 years (IQR 2-6), 26 (37%) of 70 patients in the infliximab group had resection, and 19 (26%) of 73 patients in the resection group received anti-TNF. INTERPRETATION: Laparoscopic resection in patients with limited (diseased terminal ileum <40 cm), non-stricturing, ileocaecal Crohn's disease in whom conventional therapy has failed could be considered a reasonable alternative to infliximab therapy. FUNDING: Netherlands Organisation for Health Research and Development.

Clinical Predictors of Future Nonadherence in Inflammatory Bowel Disease.

BACKGROUND: Nonadherence to medical therapy is frequently encountered in patients with inflammatory bowel disease (IBD). We aimed to identify predictors for future (non)adherence in IBD. METHODS: We conducted a multicenter prospective cohort study with adult patients with Crohn's disease (CD) and ulcerative colitis (UC). Data were collected by means of 3-monthly questionnaires on the course of disease and healthcare utilization. Medication adherence was assessed using a visual analogue scale, ranging from 0% to 100%. Levels <80% were considered to indicate nonadherence. The Brief Illness Perception Questionnaire was used to identify illness perceptions. We used a logistic regression analysis to identify patient- and disease-related factors predictive of nonadherence 3 months after the assessment of predictors. RESULTS: In total, 1558 patients with CD and 1054 patients with UC were included and followed for 2.5 years. On average, 12.1% of patients with CD and 13.3% of patients with UC using IBD-specific medication were nonadherent. Nonadherence was most frequently observed in patients using mesalazine (CD), budesonide (UC) and rectally administrated therapy (both CD and UC). A higher perceived treatment control and understanding of the disease were associated with adherence to medical therapy. Independent predictors of future nonadherence were age at diagnosis (odds ratio [OR]: 0.99 per year), nonadherence (OR: 26.91), a current flare (OR: 1.30) and feelings of anxiety/depression (OR: 1.17), together with an area under the receiver-operating-characteristics curve of 0.74. CONCLUSIONS: Lower age at diagnosis, flares, feelings of anxiety or depression, and nonadherence are associated with future nonadherence in patients with IBD. Altering illness perceptions could be an approach to improve adherence behavior.

Prevalence of- and risk factors for work disability in Dutch patients with inflammatory bowel disease.

AIM: To determine the prevalence of work disability in inflammatory bowel disease (IBD), and to assess risk factors associated with work disability. METHODS: For this retrospective cohort study, we retrieved clinical data from the Dutch IBD Biobank on July 2014, containing electronic patient records of 3388 IBD patients treated in the eight University Medical Centers in the Netherlands. Prevalence of work disability was assessed in 2794 IBD patients and compared with the general Dutch population. Multivariate analyses were performed for work disability (sick leave, partial and full disability) and long-term full work disability (> 80% work disability for > 2 years). RESULTS: Prevalence of work disability was higher in Crohn's disease (CD) (29%) and ulcerative colitis (UC) (19%) patients compared to the general Dutch population (7%). In all IBD patients, female sex, a lower education level, and extra-intestinal manifestations, were associated with work disability. In CD patients, an age > 40 years at diagnosis, disease duration > 15 years, smoking, surgical interventions, and anti-TNFα use were associated with work disability. In UC patients, an age > 55 years, and immunomodulator use were associated with work disability. In CD patients, a lower education level (OR = 1.62, 95%CI: 1.02-2.58), and in UC patients, disease complications (OR = 3.39, 95%CI: 1.09-10.58) were associated with long-term full work disability. CONCLUSION: The prevalence of work disability in IBD patients is higher than in the general Dutch population. Early assessment of risk factors for work disability is necessary, as work disability is substantial among IBD patients.

The Prevalence of Nodular Regenerative Hyperplasia in Inflammatory Bowel Disease Patients Treated with Thioguanine Is Not Associated with Clinically Significant Liver Disease.

BACKGROUND: Nodular regenerative hyperplasia (NRH) of the liver is associated with inflammatory-mediated diseases and certain drugs. There is conflicting data on the prevalence of NRH and its clinical implications in inflammatory bowel disease (IBD) patients treated with thioguanine. METHODS: A retrospective cohort study involving 7 Dutch centers comprised all IBD patients who were being treated with thioguanine and underwent a liver biopsy as part of the standard toxicity screening. Liver biopsy specimens were reviewed by 2 experienced liver pathologists. Clinical data as well as liver chemistry, blood counts, and abdominal imaging were collected. RESULTS: One hundred eleven IBD patients who submitted to liver biopsy were treated with thioguanine in a daily dose of 0.3 mg/kg for a median duration of 20 (4-64) months. NRH was detected in 6% of patients (7; 95% confidence interval, 3-14 patients). Older age (P = 0.02), elevated gamma-glutamyl transferase (P = 0.01) and alkaline phosphatase (P = 0.01) levels, a higher mean corpuscular volume (P = 0.02), and a lower platelet or leukocyte count (P < 0.01 and P = 0.02, respectively) were associated with NRH. Three of the 7 patients with NRH did not have any associated clinical symptoms or signs. The other 4 had minor biochemical abnormalities only. Ultrasonography revealed splenomegaly in 3 of the 78 patients (4%; 95% confidence interval, 0%-9%), only one of whom had NRH. There was no clinically overt portal hypertension. CONCLUSIONS: The prevalence of NRH was 6% in liver biopsies obtained from IBD patients treated with thioguanine. Histopathological irregularities including NRH were not associated with clinically significant findings over the period of observation.

Evolution of Costs of Inflammatory Bowel Disease over Two Years of Follow-Up.

BACKGROUND: With the increasing use of anti-TNF therapy in inflammatory bowel disease (IBD), a shift of costs has been observed with medication costs replacing hospitalization and surgery as major cost driver. We aimed to explore the evolution of IBD-related costs over two years of follow-up. METHODS AND FINDINGS: In total 1,307 Crohn's disease (CD) patients and 915 ulcerative colitis (UC) patients were prospectively followed for two years by three-monthly web-based questionnaires. Changes of healthcare costs, productivity costs and out-of-pocket costs over time were assessed using mixed model analysis. Multivariable logistic regression analysis was used to identify costs drivers. In total 737 CD patients and 566 UC were included. Total costs were stable over two years of follow-up, with annual total costs of €7,835 in CD and €3,600 in UC. However, within healthcare costs, the proportion of anti-TNF therapy-related costs increased from 64% to 72% in CD (p<0.01) and from 31% to 39% in UC (p < 0.01). In contrast, the proportion of hospitalization costs decreased from 19% to 13% in CD (p<0.01), and 22% to 15% in UC (p < 0.01). Penetrating disease course predicted an increase of healthcare costs (adjusted odds ratio (adj. OR) 1.95 (95% CI 1.02-3.37) in CD and age <40 years in UC (adj. OR 4.72 (95% CI 1.61-13.86)). CONCLUSIONS: BD-related costs remained stable over two years. However, the proportion of anti-TNF-related healthcare costs increased, while hospitalization costs decreased. Factors associated with increased costs were penetrating disease course in CD and age <40 in UC.

Refractory celiac disease and EATL patients show severe malnutrition and malabsorption at diagnosis.

BACKGROUND & AIMS: Refractory celiac disease type II (RCDII) and EATL (Enteropathy Associated T-cell Lymphoma) are (pre)malignant complications of celiac disease (CD). Data on malnutrition and intestinal absorption is lacking in these patients. Therefore, the aim of the study is to comprehensively assess nutritional status and intestinal absorption capacity of patients with RCDII and EATL, compared with data of newly diagnosed CD patients. METHODS: Observational study in tertiary care setting in RCDII (n = 24, 63.8 ± 8.2 y), EATL (n = 25, 62.3 ± 5.7 y) and CD patients (n = 43, 45.6 ± 14.8 y). At diagnosis, anthropometry (BMI, unintentional weight loss, fat-free mass index (FFMI), handgrip strength (HGS), nutritional intake, fecal losses and Resting Energy Expenditure (REE)) were assessed. RESULTS: Low BMI (<18.5) was more often observed in RCDII patients than in CD or EATL patients (in 33%, 12% and 12%, respectively, p = 0.029). EATL patients more frequently had unintentional weight loss (>10%) than CD or RCDII patients (in 58%, 19% and 39% of patients, respectively; p = 0.005/0.082). Energy malabsorption (<85%) was detected in 44% and 33% of RCDII and EATL patients, vs 21.6% in CD (NS). Fecal energy losses were higher in RCDII than in CD patients (589 ± 451 vs 277 ± 137 kcal/d, p = 0.017). REE was underestimated by predicted-REE with>10% in 60% of RCDII, 89% of EATL, and 38% of CD patients (p = 0.006). Low FFMI and HGS were detected in one third and two thirds of all patients, respectively. CONCLUSIONS: The nutritional status of patients with RCDII and EATL is inferior compared with untreated naïve CD patients at presentation. Both malabsorption as well as hypermetabolism contribute to malnutrition.

Comparison of Costs and Quality of Life in Ulcerative Colitis Patients with an Ileal Pouch-Anal Anastomosis, Ileostomy and Anti-TNFα Therapy.

BACKGROUND AND AIMS: More data are warranted on the economic impact of different treatment strategies in ulcerative colitis (UC) patients. We compared the costs and quality of life of UC patients with a pouch reconstruction, an ileostomy or anti-tumour necrosis factor α (TNFα) therapy. METHODS: UC patients filled out 3-monthly questionnaires for 2 years. Differences in 3-monthly healthcare costs, productivity costs and patient costs were tested using mixed model analysis. Quality of life was assessed employing the ) and the inflammatory bowel disease questionnaire (IBDQ). RESULTS: Out of 915 UC patients, 81 (9%) had a pouch and 48 (5%) an ileostomy, and 34 (4%) were on anti-TNFα therapy. Anti-TNFα-treated patients reported high UC related-healthcare costs per 3 months (€5350). Medication use accounted for 92% of healthcare costs. UC-attributable healthcare costs were 3-fold higher in ileostomy patients compared with pouch patients (€1581 versus €407; p < 0.01). Main cost drivers in ileostomy patients were healthcare costs and ileostomy supplies (2 and 23% of healthcare costs, respectively). In pouch patients, the main cost driver was hospitalization, accounting for 50% of healthcare costs. Productivity loss did not differ between pouch and ileostomy patients (€483 versus €377; p < 0.23), but was significantly higher in anti-TNFα-treated patients (€1085). No difference was found in IBDQ scores, but pouch patients were found to have higher quality-adjusted life years than ileostomy patients and anti-TNFα-treated patients (0.90 [interquartile range 0.78-1.00] versus 0.84 [0.78-1.00] and 0.84 [0.69-1.00], respectively; p < 0.01). CONCLUSION: Patients receiving anti-TNFα therapy reported the highest healthcare cost, in which medication use was the major cost driver. Ileostomy patients were three times more expensive than pouch patients due to frequent hospitalization and ileostomy supplies.

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.

Disease Outcome of Ulcerative Colitis in an Era of Changing Treatment Strategies: Results from the Dutch Population-Based IBDSL Cohort.

BACKGROUND AND AIMS: In the past decades, treatment options and strategies for ulcerative colitis [UC] have radically changed. Whether these developments have altered the disease outcome at population level is yet unknown. Therefore, we evaluated the disease outcome of UC over the past two decades in the South-Limburg area of The Netherlands. METHODS: In the Dutch population-based IBDSL cohort, three time cohorts were defined: cohort 1991-1997 [cohort A], cohort 1998-2005 [cohort B], and cohort 2006-2010 [cohort C]. The colectomy and hospitalisation rates were compared between cohorts by Kaplan-Meier survival analyses. Hazard ratios [HR] for early colectomy [within 6 months after diagnosis], late colectomy [beyond 6 months after diagnosis], and hospitalisation were calculated using Cox regression models. RESULTS: In total, 476 UC patients were included in cohort A, 587 patients in cohort B, and 598 patients in cohort C. Over time, an increase in the use of immunomodulators [8.1%, 22.8% and 21.7%, respectively, p < 0.01] and biological agents [0%, 4.3% and 10.6%, respectively, p < 0.01] was observed. The early colectomy rate decreased from 1.5% in cohort A to 0.5% in cohort B [HR 0.14; 95% confidence interval 0.04-0.47], with no further decrease in cohort C [0.3%, HR 0.98; 95% confidence interval 0.20-4.85]. Late colectomy rate remained unchanged over time [4.0% vs 5.2% vs 3.6%, respectively, p = 0.54]. Hospitalisation rate was also similar among cohorts [22.3% vs 19.5% vs 18.3%, respectively, p = 0.10]. CONCLUSION: Over the past two decades, a reduction in early colectomy rate was observed, with no further reduction in the most recent era. Late colectomy rate and hospitalisation rate remained unchanged over time.

Incidence of Interval Colorectal Cancer Among Inflammatory Bowel Disease Patients Undergoing Regular Colonoscopic Surveillance.

BACKGROUND & AIMS: Surveillance is recommended for patients with long-term inflammatory bowel disease because they have an increased risk of colorectal cancer (CRC). To study the effectiveness of surveillance, we determined the incidence of CRC after negative findings from surveillance colonoscopies (interval CRC). METHODS: We collected data from 1273 patients with ulcerative colitis or Crohn's disease, enrolled in a surveillance program at 7 hospitals in The Netherlands, who underwent 4327 surveillance colonoscopies from January 1, 2000, through January 1, 2014. Patients were followed up from their first surveillance colonoscopy until the last surveillance colonoscopy, colectomy, or CRC. Factors that might have contributed to the occurrence of CRC were categorized as inadequate procedures (ie, inadequate bowel preparation), inadequate surveillance (CRC occurring outside the appropriate surveillance interval), or inadequate management of dysplasia (CRC diagnosed in the same colonic segment as a previous diagnosis of dysplasia). The remaining CRC cases were classified as true interval CRCs. RESULTS: CRC was diagnosed in 17 patients (1.3%), with an incidence of 2.5 per 1000 years of follow-up evaluation. Factors that might account for the occurrence of CRC were identified in 12 patients (70%). These were inadequate colonoscopies in 4 patients (24%), inadequate surveillance intervals in 9 patients (53%), and inadequate management of dysplasia in 2 patients (12%). The remaining 5 cases of CRC (30%) were classified as true interval CRCs. CONCLUSIONS: In a retrospective analysis of patients with inflammatory bowel disease participating in a surveillance program, the incidence of CRC was only 1%, which supports the implementation of longer surveillance intervals. However, the fact that 30% of CRC cases were interval cancers indicates the need for variable surveillance intervals based on risk factors for CRC.

Self-reported disability in patients with inflammatory bowel disease largely determined by disease activity and illness perceptions.

BACKGROUND: The inflammatory bowel disease (IBD) disability index has recently been introduced to measure patients' physical, psychological, familial, and social limitations associated with IBD. We assessed factors related to self-reported disability and the relationship between disability and direct health care costs. METHODS: A large cohort of patients with Crohn's disease (CD) and ulcerative colitis (UC) was prospectively followed for 2 years by 3 monthly web-based questionnaires. At 2 years, patients completed the IBD disability index, with lower score indicating more disability. Linear regression analysis was used to examine the impact of demographics, clinical characteristics, and illness perceptions on self-reported disability. Trends in direct health care costs across the disability severity groups minimal, mild, moderate, and severe, were tested. RESULTS: A total of 554 patients with CD and 424 patients with UC completed the IBD disability index (response rate, 45%). Both clinical characteristics and illness perceptions significantly contributed to self-reported disability (45%-47%, P = 0.000 and 8%-12%, P = 0.000, respectively). Patients with CD scored lower on the self-reported IBD disability index than patients with UC (0.255 versus 3.890, P < 0.000), indicating more disability in patients with CD. Factors independently associated with higher self-reported disability rates were increased disease activity, illness identity (higher number of symptoms attributed to IBD), and stronger emotional response. Disease duration and disease phenotype were not associated with self-reported disability. Direct health care costs increased with the worsening of self-reported disability (P = 0.000). CONCLUSIONS: More disability was reported by patients with CD than by UC. Self-reported disability in IBD was mainly determined by clinical disease activity and illness perceptions but not by disease duration or disease phenotype.

Intestinal vaginoplasty revisited: a review of surgical techniques, complications, and sexual function.

INTRODUCTION: Vaginal (re)construction is essential for the psychological well-being of biological women with a dysfunctional vagina and male-to-female transgender women. However, the preferred method for vagina (re)construction with respect to functional as well as aesthetic outcomes is debated. Regarding intestinal vaginoplasty, despite the asserted advantages, the need for intestinal surgery and subsequent risk of diversion colitis are often-mentioned concerns. The outcomes of vaginal reconstructive surgery need to be appraised in order to improve understanding of pros and cons. AIMS: To review literature on surgical techniques and clinical outcomes of intestinal vaginoplasty. METHODS: Electronic databases and reference lists of published articles were searched for primary studies on intestinal vaginoplasty. Studies were included if these included at least five patients and had a minimal follow-up period of 1 year. No constraints were imposed with regard to patient age, indication for vaginoplasty, or applied surgical technique. Outcome measures were extracted and analyzed. MAIN OUTCOME MEASURES: Main outcome measures were surgical procedure, clinical outcomes, and outcomes concerning sexual health and quality of life. RESULTS: Twenty-one studies on intestinal vaginoplasty were included (including 894 patients in total). All studies had a retrospective design and were of low quality. Prevalence and severity of procedure-related complications were low. The main postoperative complication was introital stenosis, necessitating surgical correction in 4.1% of sigmoid-derived and 1.2% of ileum-derived vaginoplasties. Neither diversion colitis nor cancer was reported. Sexual satisfaction rate was high, but standardized questionnaires were rarely used. Quality of life was not reported. CONCLUSION: Based on evidence presently available, it seems that intestinal vaginoplasty is associated with low complication rates. To substantiate these findings and to obtain information about functional outcomes and quality of life, prospective studies using standardized measures and questionnaires are warranted.

Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study.

OBJECTIVE: The introduction of anti tumour necrosis factor-α (anti-TNFα) therapy might impact healthcare expenditures, but there are limited data regarding the costs of inflammatory bowel diseases (IBD) following the introduction of these drugs. We aimed to assess the healthcare costs and productivity losses in a large cohort of IBD patients. DESIGN: Crohn's disease (CD) and ulcerative colitis (UC) patients from seven university hospitals and seven general hospitals were invited to fill-out a web-based questionnaire. Cost items were derived from a 3 month follow-up questionnaire and categorised in outpatient clinic, diagnostics, medication, surgery and hospitalisation. Productivity losses included sick leave of paid and unpaid work. Costs were expressed as mean 3-month costs per patients with a 95% CI obtained using non-parametric bootstrapping. RESULTS: A total of 1315 CD patients and 937 UC patients were included. Healthcare costs were almost three times higher in CD as compared with UC, €1625 (95% CI €1476 to €1775) versus €595 (95% CI €505 to €685), respectively (p<0.01). Anti-TNFα use was the main costs driver, accounting for 64% and 31% of the total cost in CD and UC. Hospitalisation and surgery together accounted for 19% and <1% of the healthcare costs in CD and 23% and 1% in UC, respectively. Productivity losses accounted for 16% and 39% of the total costs in CD and UC. CONCLUSIONS: We showed that healthcare costs are mainly driven by medication costs, most importantly by anti-TNFα therapy. Hospitalisation and surgery accounted only for a minor part of the healthcare costs.

Treatment of bone loss in osteopenic patients with Crohn's disease: a double-blind, randomised trial of oral risedronate 35†mg once weekly or placebo, concomitant with calcium and vitamin D supplementation.

OBJECTIVE: Osteoporosis and fractures are frequently encountered in patients with Crohn's disease. In order to prevent fractures, treatment with bone protecting drugs appears warranted early in the course of bone disease when bone loss is not yet prominent. We therefore aimed to demonstrate a beneficial effect on bone density of the bisphosphonate risedronate in osteopenic Crohn's disease patients. METHODS: This double-blind, placebo-controlled randomised trial of risedronate with calcium and vitamin D supplementation was performed in osteopenic Crohn's disease patients. Patients were treated for 2 years with follow-up after 3 and after every 6 months. Disease characteristics and activity and bone turnover markers were assessed at all visits; dual x-ray absorptiometry was performed at baseline, 12 and 24 months; radiographs of the spine at baseline and 24 months. RESULTS: Of 132 consenting patients, 131 were randomised (67 placebo and 64 risedronate). Patient characteristics were similar in both groups, although the risedronate group was slightly heavier (body mass index 24.3 vs 23.0 kg/m(2)). Bone mineral density at lumbar spine increased 0.04 g/cm(2) on average in the risedronate group versus 0.01 g/cm(2) in the placebo group (p=0.007). The mean increase in total hip bone mineral density was 0.03 versus 0.01 g/cm(2), respectively (p=0.071). Fracture prevalence and incidence were similar. Change of T-scores and concentrations of bone turnover markers were consistent with a beneficial effect of risedronate when compared with placebo. The effect of risedronate was primarily demonstrated in the first 12 months of treatment. No serious unexpected suspected adverse events were observed. CONCLUSIONS: A 24-month treatment course with risedronate 35 mg once weekly, concomitant with calcium and vitamin D supplementation, in osteopenic Crohn's disease patients improved bone density at lumbar spine. NTR 163 Dutch Trial Register.