A Prediction Model for Successful Increase of Adalimumab Dose Intervals in Patients with Crohn's Disease: Secondary Analysis of the Pragmatic Open-Label Randomised Controlled Non-inferiority LADI Trial.

BACKGROUND: In the pragmatic open-label randomised controlled non-inferiority LADI trial we showed that increasing adalimumab (ADA) dose intervals was non-inferior to conventional dosing for persistent flares in patients with Crohn's disease (CD) in clinical and biochemical remission. AIMS: To develop a prediction model to identify patients who can successfully increase their ADA dose interval based on secondary analysis of trial data. METHODS: Patients in the intervention group of the LADI trial increased ADA intervals to 3 and then to 4 weeks. The dose interval increase was defined as successful when patients had no persistent flare (> 8 weeks), no intervention-related severe adverse events, no rescue medication use during the study, and were on an increased dose interval while in clinical and biochemical remission at week 48. Prediction models were based on logistic regression with relaxed LASSO. Models were internally validated using bootstrap optimism correction. RESULTS: We included 109 patients, of which 60.6% successfully increased their dose interval. Patients that were active smokers (odds ratio [OR] 0.90), had previous CD-related intra-abdominal surgeries (OR 0.85), proximal small bowel disease (OR 0.92), an increased Harvey-Bradshaw Index (OR 0.99) or increased faecal calprotectin (OR 0.997) were less likely to successfully increase their dose interval. The model had fair discriminative ability (AUC = 0.63) and net benefit analysis showed that the model could be used to select patients who could increase their dose interval. CONCLUSION: The final prediction model seems promising to select patients who could successfully increase their ADA dose interval. The model should be validated externally before it may be applied in clinical practice. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377.

Cost-Effectiveness Analysis of Increased Adalimumab Dose Intervals in Crohn's Disease Patients in Stable Remission: The Randomized Controlled LADI Trial.

BACKGROUND AND AIMS: We aimed to assess cost-effectiveness of increasing adalimumab dose intervals compared to the conventional dosing interval in patients with Crohn's disease [CD] in stable clinical and biochemical remission. DESIGN: We conducted a pragmatic, open-label, randomized controlled non-inferiority trial, comparing increased adalimumab intervals with the 2-weekly interval in adult CD patients in clinical remission. Quality of life was measured with the EQ-5D-5L. Costs were measured from a societal perspective. Results are shown as differences and incremental net monetary benefit [iNMB] at relevant willingness to accept [WTA] levels. RESULTS: We randomized 174 patients to the intervention [n = 113] and control [n = 61] groups. No difference was found in utility (difference: -0.017, 95% confidence interval [-0.044; 0.004]) and total costs (-€943, [-€2226; €1367]) over the 48-week study period between the two groups. Medication costs per patient were lower (-€2545, [-€2780; -€2192]) in the intervention group, but non-medication healthcare (+€474, [+€149; +€952]) and patient costs (+€365 [+€92; €1058]) were higher. Cost-utility analysis showed that the iNMB was €594 [-€2099; €2050], €69 [-€2908; €1965] and -€455 [-€4,096; €1984] at WTA levels of €20 000, €50 000 and €80 000, respectively. Increasing adalimumab dose intervals was more likely to be cost-effective at WTA levels below €53 960 per quality-adjusted life year. Above €53 960 continuing the conventional dose interval was more likely to be cost-effective. CONCLUSION: When the loss of a quality-adjusted life year is valued at less than €53 960, increasing the adalimumab dose interval is a cost-effective strategy in CD patients in stable clinical and biochemical remission. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377.

Increased versus conventional adalimumab dose interval for patients with Crohn's disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial.

BACKGROUND: Despite its effectiveness in treating Crohn's disease, adalimumab is associated with an increased risk of infections and high health-care costs. We aimed to assess clinical outcomes of increased adalimumab dose intervals versus conventional dosing in patients with Crohn's disease in stable remission. METHODS: The LADI study was a pragmatic, open-label, multicentre, non-inferiority, parallel, randomised controlled trial, done in six academic hospitals and 14 general hospitals in the Netherlands. Adults (aged ≥18 years) diagnosed with luminal Crohn's disease (with or without concomitant perianal disease) were eligible when in steroid-free clinical and biochemical remission (defined as Harvey-Bradshaw Index [HBI] score <5, faecal calprotectin <150 µg/g, and C-reactive protein <10 mg/L) for at least 9 months on a stable dose of 40 mg subcutaneous adalimumab every 2 weeks. Patients were randomly assigned (2:1) to the intervention group or control group by the coordinating investigator using a secure web-based system with variable block randomisation (block sizes of 6, 9, and 12). Randomisation was stratified on concomitant use of thiopurines and methotrexate. Patients and health-care providers were not masked to group assignment. Patients allocated to the intervention group increased adalimumab dose intervals to 40 mg every 3 weeks at baseline and further to every 4 weeks if they remained in clinical and biochemical remission at week 24. Patients in the control group continued their 2-weekly dose interval. The primary outcome was the cumulative incidence of persistent flares at week 48 defined as the presence of at least two of the following criteria: HBI score of 5 or more, C-reactive protein 10 mg/L or more, and faecal calprotectin more than 250 µg/g for more than 8 weeks and a concurrent decrease in the adalimumab dose interval or start of escape medication. The non-inferiority margin was 15% on a risk difference scale. All analyses were done in the intention-to-treat and per-protocol populations. This trial was registered at ClinicalTrials.gov, NCT03172377, and is not recruiting. FINDINGS: Between May 3, 2017, and July 6, 2020, 174 patients were randomly assigned to the intervention group (n=113) or the control group (n=61). Four patients from the intervention group and one patient from the control group were excluded from the analysis for not meeting inclusion criteria. 85 (50%) of 169 participants were female and 84 (50%) were male. At week 48, the cumulative incidence of persistent flares in the intervention group (three [3%] of 109) was non-inferior compared with the control group (zero; pooled adjusted risk difference 1·86% [90% CI -0·35 to 4·07). Seven serious adverse events occurred, all in the intervention group, of which two (both patients with intestinal obstruction) were possibly related to the intervention. Per 100 person-years, 168·35 total adverse events, 59·99 infection-related adverse events, and 42·57 gastrointestinal adverse events occurred in the intervention group versus 134·67, 75·03, and 5·77 in the control group, respectively. INTERPRETATION: The individual benefit of increasing adalimumab dose intervals versus the risk of disease recurrence is a trade-off that should take patient preferences regarding medication and the risk of a flare into account. FUNDING: Netherlands Organisation for Health Research and Development.

Long-term effectiveness and safety of ustekinumab in Crohn's disease: a prospective cohort study.

BACKGROUND: Real-world data showed that ustekinumab is an effective treatment for Crohn's disease for up to 52 weeks. Yet, long-term effectiveness and safety outcomes beyond 52 weeks are limited. This study aimed to evaluate the corticosteroid-free clinical remission for up to 104 weeks. Secondary aims were focused on biochemical disease, dosing adjustments and safety outcomes. METHODS: This multicentre prospective cohort study enrolled Crohn's disease patients who started ustekinumab between May 2016 and September 2019. Participants had scheduled outpatient visits at week 0, 13, 26, 52 and 104. Data on clinical disease [Harvey Bradshaw Index (HBI) = 4 points = remission], biochemical disease (faecal calprotectin = 200 µg/g or C-reactive protein = 10 mg/l = remission), dose adjustments and adverse drug reactions (ADRs) were recorded. RESULTS: We included 101 Crohn's disease patients. In all patients, the proportion of patients in corticosteroid-free clinical remission was 35 and 36% at week 52 and 104. Of patients achieving corticosteroid-free remission at week 52, more than half maintained corticosteroid-free remission throughout week 104. Biochemical remission rates were 25 and 30% at week 52 and 104, respectively. In the first year of treatment, 33% required their first dose escalation, and 15% in the second year. Overall, 7% of patients discontinued ustekinumab due to ADRs. Ustekinumab persistency rates were 68% at week 52 and 59% at week 104. CONCLUSION: Ustekinumab is an effective and well-tolerated treatment for Crohn's disease. More than half of all patients continued ustekinumab treatment after 104 weeks whereas one-third achieved corticosteroid-free remission.

Exposure to Thioguanine During 117 Pregnancies in Women With Inflammatory Bowel Disease.

BACKGROUND: Safety of thioguanine in pregnant patients with inflammatory bowel disease [IBD] is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and birth. METHODS: In this multicentre case series, IBD patients treated with thioguanine during pregnancy were included. Data regarding disease and medication history, pregnancy course, obstetric complications, and neonatal outcomes were collected. RESULTS: Data on 117 thioguanine-exposed pregnancies in 99 women were collected. Most [78%] had Crohn's disease and the mean age at delivery was 31 years. In 18 pregnancies [15%], IBD flared. Obstetric and infectious complications were seen in 15% [n = 17] and 7% [n = 8] of pregnancies, respectively. Ten pregnancies [8.5%] resulted in a first trimester miscarriage, one in a stillbirth at 22 weeks of gestational age and one in an induced abortion due to trisomy 21. In total, 109 neonates were born from 101 singleton pregnancies and four twin pregnancies. One child was born with a congenital abnormality [cleft palate]. In the singleton pregnancies, 10 children were born prematurely and 10 were born small for gestational age. Screening for myelosuppresion was performed in 16 neonates [14.7%]; two had anaemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from three Dutch cohort studies on the use of conventional thiopurines in pregnant IBD patients. CONCLUSION: In this large case series, the use of thioguanine during pregnancy is not associated in excess with adverse maternal or neonatal outcomes.

Impact of Biological Therapies and Tofacitinib on Real-world Work Impairment in Inflammatory Bowel Disease Patients: A Prospective Study.

BACKGROUND: There are limited real-world data on the change in total work impairment (TWI) in biological-treated patients with inflammatory bowel disease (IBD). This study aimed to evaluate the real-world effects of initiating biological therapy or tofacitinib on change in TWI in IBD patients. METHODS: This multicenter prospective cohort study enrolled IBD patients who started treatment with biological therapy or tofacitinib. Subjects completed the work productivity and activity impairment (WPAI) questionnaire and short inflammatory bowel disease questionnaire at therapy initiation and at week 26. Total work impairment comprises working hours missed due to sick leave and impact of disease during working hours (range 0%-100%). Clinical disease activity was assessed using the Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index (SCCAI). RESULTS: We included 137 IBD patients for analyses (median age 38 years, 58% Crohn's disease [CD]). The median baseline TWI was 50% and decreased by a median of 10%-points of points after 26 weeks. Patients with continued biological therapy or tofacitinib use, clinical disease activity at baseline, and clinical response or remission at week 26 showed a greater median TWI reduction (22%-points) than the remaining study patients (7%-points; P = .014). Ulcerative colitis (UC) and IBD-unclassified (IBD-U) patients showed a greater median TWI reduction (26%-points) than CD patients (6%-points); P = .041. Correlations were observed between decrease in TWI and decrease in SCCAI, decrease in fatigue and increase in quality of life. CONCLUSIONS: Work impairment in IBD patients decreased following biological therapy or tofacitinib initiation. Patients achieving clinical remission or response showed the greatest improvement, especially UC and IBD-U patients.

De-escalation of biological therapy in inflammatory bowel disease patients following prior dose escalation.

BACKGROUND: Limited data are available on biological therapy de-escalation after prior escalation in inflammatory bowel disease (IBD) patients. This study aimed to assess the frequency and success rate of de-escalation of biological therapy in IBD patients after prior dose escalation and to evaluate which measures are used to guide de-escalation. METHODS: This multicentre retrospective cohort study enrolled IBD patients treated with infliximab (IFX), adalimumab (ADA) or vedolizumab (VEDO) in whom therapy was de-escalated after prior biological escalation. De-escalations were considered pharmacokinetic-driven if based on clinical symptoms combined with therapeutic or supratherapeutic trough levels, and disease activity-driven if based on faecal calprotectin less than or equal to 200 µg/g or resolution of perianal fistula drainage or closure or endoscopic remission. Successful de-escalation was defined as remaining on the same or lower biological dose for greater than or equal to 6 months after de-escalation without the need for corticosteroids. RESULTS: In total, 206 IFX users, 85 ADA users and 55 VEDO users underwent therapy escalation. Of these patients, 34 (17%) on IFX, 18 (21%) on ADA and 8 (15%) on VEDO underwent therapy de-escalation. De-escalation was successful in 88% of IFX patients, 89% of ADA and 100% of VEDO. The probability of remaining on the de-escalated regimen or further de-escalation after 1 year was 85% for IFX, 62% for ADA and 100% for VEDO. Disease activity-driven de-escalations were more often successful (97%) than pharmacokinetic- and no marker-driven de-escalations (76%); P = 0.017. CONCLUSION: De-escalation after biological dose escalation was successful in the majority of carefully selected IBD patients. Objective assessment of remission increased the likelihood of successful de-escalation.

Discrepancy between patient- and healthcare provider-reported adverse drug reactions in inflammatory bowel disease patients on biological therapy.

BACKGROUND: Only limited data is available on the extent and burden of adverse drug reactions (ADRs) to biological therapy in inflammatory bowel disease (IBD) patients in daily practice, especially from a patient's perspective. OBJECTIVE: The aim of this study was to systematically assess patient-reported ADRs during biological therapy in IBD patients and compare these with healthcare provider (HCP)-reported ADRs. METHODS: This multicentre, prospective, event monitoring study enrolled IBD patients on biological therapy. Patients completed bimonthly comprehensive web-based questionnaires regarding description of biological induced ADRs, follow-up of previous ADRs and experienced burden of the ADR using a five-point Likert scale. The relationship between patient-reported ADRs and biological therapy was assessed. HCP-reported ADRs were extracted from the electronic healthcare records. RESULTS: In total, 182 patients (female 51%, mean age 42.2 [standard deviation 14.2] years, Crohn's disease 77%) were included and completed 728 questionnaires. At baseline, 60% of patients used infliximab, 30% adalimumab, 9% vedolizumab and 1% ustekinumab. Fifty percent of participants reported at least one ADR with a total of 239 unique ADRs. Fatigue (n = 26) and headache (n = 20) resulted in the highest burden and a correlation in time with the administration of the biological was described in 56% and 85% respectively. Out of 239 ADRs, 115 were considered biological-related. HCPs reported 119 ADRs. Agreement between patient-reported ADRs and HCP-reported ADRs was only 13%. CONCLUSION: IBD patients often report ADRs during biological therapy. We observed an important significant difference between the type and frequency of patient-reported ADRs versus HCP-reported ADRs, leading to an underestimation of more subjective ADRs and patients' ADR-related burden.

Adverse Drug Reactions from Real-World Data in Inflammatory Bowel Disease Patients in the IBDREAM Registry.

INTRODUCTION: Inflammatory bowel disease (IBD) frequently requires chronic immunosuppressive treatment and active involvement from patients during treatment decision making. Information about the risk of developing adverse drug reactions (ADRs) to IBD therapies is required in this process. OBJECTIVE: The aim of this study was to describe the ADRs reported in IBD patients from real-world data, using the Dutch nationwide IBDREAM registry, and compare the occurrence and cumulative incidences with the Summary of Product Characteristics (SmPC) of the associated drugs. METHODS: In this retrospective multicentre study, ADRs related to IBD medication were assessed. Only reports associated with the use of drugs used for the maintenance treatment of IBD were included. All ADRs were verified by healthcare professionals and coded by trained pharmacovigilance assessors. RESULTS: In total, 3080 ADRs were reported in 1179 patients. Twenty-three new drug-ADR associations related to the use of azathioprine, mercaptopurine, infliximab, oral mesalamine and thioguanine were reported in the IBDREAM registry that were not mentioned in the corresponding SmPCs. The most frequently reported new association was pyrexia for azathioprine (3.1%) and mercaptopurine (4.9%). In addition, there were seven ADRs with a higher cumulative incidence in IBDREAM compared with the SmPC, and included, among others, arthralgia during mercaptopurine use (2.5%), and diarrhoea (1.4%), alopecia (1.2%) and infections (1.6%) during azathioprine use. CONCLUSIONS: Based on real-world data, ADR reporting demonstrated new ADRs and higher incidences of ADRs to IBD therapies. This information will contribute to drug safety by updating the SmPCs, allowing better risk assessment and communication towards patients.

Clinical Outcomes of Covid-19 in Patients With Inflammatory Bowel Disease: A Nationwide Cohort Study.

BACKGROUND AND AIMS: The COVID-19 risk and disease course in inflammatory bowel disease [IBD] patients remains uncertain. Therefore, we aimed to assess the clinical presentation, disease course, and outcomes of COVID-19 in IBD patients. Second, we determined COVID-19 incidences in IBD patients and compared this with the general population. METHODS: We conducted a multicentre, nationwide IBD cohort study in The Netherlands and identified patients with COVID-19. First, we assessed the COVID-19 disease course and outcomes. Second, we compared COVID-19 incidences between our IBD study cohort and the general Dutch population. RESULTS: We established an IBD cohort of 34 763 patients. COVID-19 was diagnosed in 100/34 763 patients [0.29%]; 20/100 of these patients [20%] had severe COVID-19 defined as admission to the intensive care unit, mechanical ventilation, and/or death. Hospitalisation occurred in 59/100 [59.0%] patients and 13/100 [13.0%] died. All patients who died had comorbidities and all but one were ≥65 years old. In line, we identified ≥1 comorbidity as an independent risk factor for hospitalisation (odds ratio [OR] 4.20, 95% confidence interval [CI] 1.58-11.17,; p = 0.004). Incidences of COVID-19 between the IBD study cohort and the general population were comparable (287.6 [95% CI 236.6-349.7] versus 333.0 [95% CI 329.3-336.7] per 100000 patients, respectively; p = 0.15). CONCLUSIONS: Of 100 cases with IBD and COVID-19, 20% developed severe COVID-19, 59% were hospitalised and 13% died. A comparable COVID-19 risk was found between the IBD cohort [100/34 763 = 0.29%] and the general Dutch population. The presence of ≥1 comorbidities was an independent risk factor for hospitalisation due to COVID-19.

Cross-cultural translation and validation of the IBD-control questionnaire in The Netherlands: a patient-reported outcome measure in inflammatory bowel disease.

BACKGROUND: There is a need for easy-to-use patient-reported outcome measures (PROMS) in inflammatory bowel disease (IBD) practice. The 'IBD-control' is a short IBD-specific questionnaire capturing disease control from the patient's perspective. The International Consortium for Health Outcomes Measurement (ICHOM) recommends the use of the IBD-control even though it has only been validated in the United Kingdom. We aimed to cross-culturally translate and validate the IBD-control in the Netherlands using IBDREAM, a prospective multicentre IBD registry. METHODS: Lack of ambiguity and acceptability were verified in a pilot patient group (n = 5) after forward-backward translation of the IBD-control. Prospective validation involved completion of the IBD-control, Short Form-36, short IBDQ and disease activity measurement by Physician Global Assessment (PGA) and Simple Clinical Colitis Activity Index or Harvey-Bradshaw Index. Test-retest (2-week repeat) was used for measuring reliability. RESULTS: Questionnaires were completed by 998 IBD patients (674 Crohn's disease, 324 ulcerative colitis). Internal consistency (Cronbach's alpha) was 0.82 for the sub-group of 8 questions (IBD-control-8-sub-score). Mean completion time was 105 s. Construct validity analyses demonstrated moderate-to-strong correlations of the IBD-control-8-subscore and the other instruments (0.49-0.81). Test-retest reliability for stable patients was high (intraclass correlation coefficient 0.95). The IBD-control-8-subscore showed good discriminant ability between the PGA categories (ANOVA, p<.001). Sensitivity to change analyses showed large effect sizes of 0.81-1.87 for the IBD-control-8 subscore. CONCLUSIONS: These results support the IBD-control as a rapid, reliable, valid and sensitive instrument for measuring disease control from an IBD patient's perspective in the Netherlands.

Inflammatory bowel disease patients provide reliable self-reported medical information: A multicentre prospective pharmacovigilance monitoring system.

PURPOSE: To assess the agreement between patient-reported and health care provider-reported medical information in inflammatory bowel disease (IBD). METHODS: This multicentre, prospective, event monitoring study enrolled adult Crohn's disease (CD) and ulcerative colitis (UC) patients treated with a biological in four medical centers in the Netherlands. At two-monthly intervals, patients completed questionnaires on biological use, combination therapy and indication. The patient-reported information was compared with their electronic health records (EHRs) and analysed for percentage agreement and Cohen's kappa. A reference population from a prospective IBD registry was used to assess the representativeness of the study population. RESULTS: In total, 182 patients (female 50.5%, mean age 42.2 years, CD 76.9%) were included in the analysis. At baseline, 51.0% of the patients were prescribed an immunomodulator (43.9% thiopurines, 7.1% methotrexate), and patients were prescribed biologicals as follows: 59.3% infliximab, 30.2% adalimumab, 9.3% vedolizumab, and 1.1% ustekinumab. Agreement on patient-reported indication and biological use was almost perfect (κ = 0.878 and κ = 1.000, respectively); substantial for combination therapy (κ = 0.672). Gender, age, type of IBD, biological use and combination therapy were comparable with the reference population. CONCLUSION: Systematic patient-reporting by questionnaires was reliable in retrieving indication and treatment specific information from IBD patients. These results indicate that the use of patient-reporting outcomes in daily IBD practice can ensure reliable information collection.

Limited relevance and progression of histological alterations in the liver during thioguanine therapy in inflammatory bowel disease patients.

Background: Thioguanine is associated with liver toxicity, especially nodular regenerative hyperplasia (NRH). We assessed if liver histology alters during long-term maintenance treatment with thioguanine in patients with inflammatory bowel disease (IBD). Methods: Liver specimens of thioguanine treated IBD patients with at least two liver biopsies were revised by two independent liver pathologists, blinded to clinical characteristics. Alterations in histopathological findings between first and sequential liver specimen were evaluated and associated clinical data, including laboratory parameters and abdominal imaging reports, were collected. Results: Twenty-five IBD patients underwent sequential liver biopsies prior to, at time of, or after cessation of thioguanine treatment. The median time between the first and second biopsy was 25 months (range: 14-54). Except for one normal liver specimen, any degree of irregularities including inflammation, steatosis, fibrosis and some vascular disturbances were observed in the biopsies. The rates of perisinusoidal fibrosis (91%), sinusoidal dilatation (68%) and nodularity (18%) were the same in the first and second liver biopsies. A trend towards statistical significance was observed for phlebosclerosis (36% of the first vs. 68% of the second biopsies, p = .092). Presence of histopathological liver abnormalities was not associated with clinical outcomes. Furthermore, two patients in this cohort had portal hypertension in presence of phlebosclerosis. In another two patients, nodularity of the liver resolved upon thioguanine withdrawal. Conclusion: Vascular abnormalities of the liver were commonly observed in thioguanine treated IBD patients, although these were not progressive and remained of limited clinical relevance over time.

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.

Safety of Tioguanine During Pregnancy in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Conventional thiopurine [azathioprine and mercaptopurine] treatment during pregnancy in patients with inflammatory bowel disease [IBD] is considered to be safe; however data on the safety and teratogenicity of the non-conventional thiopurine tioguanine [TG] in pregnant IBD patients are lacking. We aim to describe the safety and teratogenicity of TG treatment during pregnancy in IBD patients. METHODS: This was a retrospective, multicentre descriptive case series of female IBD patients using TG during pregnancy. Data on disease and medication history, pregnancy complications, pregnancy outcome, mode of delivery, preterm birth, birthweight, congenital abnormalities, laboratory signs of myelosuppression or hepatotoxicity, and 6-thioguaninenucleotide [6-TGN] concentrations in mother and neonate were collected. RESULTS: In all, 13 patients [77% Crohn's disease, 23% ulcerative colitis] used TG [median dose 18 g/day] during pregnancy; 19 pregnancies, including 1 twin pregnancy, were included. Spontaneous abortion occurred in three pregnancies. In 7 of the 16 ongoing pregnancies a caesarean section was performed. One neonate had a mild congenital abnormality [distal shaft hypospadias]. In the singleton pregnancies, the median birthweight was 3410 g at a median of gestational age of 39 weeks. No preterm birth [< 37 weeks] or low birthweight [< 2500 g] was observed in the singleton newborns. In the twin pregnancy an induction of labour was performed at 35 + 1 weeks of gestation because of pre-eclampsia. Both neonates had a low birthweight. CONCLUSIONS: This relatively small case series supports safe use of TG in pregnant IBD patients. Still, consideration should be given to the indication and continuation of TG during pregnancy.

[Treatment of inflammatory bowel disease: what if drug therapy fails?]. / Behandeling van chronische inflammatoire darmziekten: wat als medicamenteuze therapie faalt?

The treatment of patients with chronic inflammatory bowel disease (IBD) in accordance with the current guideline is generally successful but there is still a group of patients for whom the medication does not work. If the initially prescribed medication is not sufficiently effective, the tendency is to move on to a 'higher' class of drugs relatively quickly. This is not always necessary. If therapy fails then therapy compliance and dosage should first be examined. Measurement of the metabolites of purine analogues can be helpful in determining the optimal drug dosage. The results sometimes show that a previously-prescribed drug may still be an option. Despite its proven efficacy, methotrexate appears to be being prescribed less often. For those patients who do not respond adequately to the optimum dosage of anti-tumour necrosis factor (TNF), there are new drugs on the way. Vedolizumab, a leukocyte adhesion inhibitor, in particular is showing promising results.

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.

Depressive symptoms in Crohn's disease: relationship with immune activation and tryptophan availability.

Crohn's disease (CD) is associated with immune activation and depressive symptoms. This study determines the impact of anti-tumor necrosis factor (TNF)-α treatment in CD patients on depressive symptoms and the degree to which tryptophan (TRP) availability and immune markers mediate this effect. Fifteen patients with CD, eligible for anti-TNF-α treatment were recruited. Disease activity (Harvey-Bradshaw Index (HBI), Crohn's Disease Activity Index (CDAI)), fatigue (Multidimensional Fatigue Inventory (MFI)), quality of life (Inflammatory Bowel Disease Questionnaire (IBDQ)), symptoms of depression and anxiety (Symptom Checklist (SCL-90), Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS)), immune activation (acute phase proteins (APP)), zinc and TRP availability were assessed before treatment and after 2, 4 and 8 weeks. Anti-TNF-α increased IBDQ scores and reduced all depression scores; however only SCL-90 depression scores remained decreased after correction for HBI. Positive APPs decreased, while negative APPs increased after treatment. After correction for HBI, both level and percentage of γ fraction were associated with SCL-90 depression scores over time. After correction for HBI, patients with current/past depressive disorder displayed higher levels of positive APPs and lower levels of negative APPs and zinc. TRP availability remained invariant over time and there was no association between SCL-90 depression scores and TRP availability. Inflammatory reactions in CD are more evident in patients with comorbid depression, regardless of disease activity. Anti-TNF-α treatment in CD reduces depressive symptoms, in part independently of disease activity; there was no evidence that this effect was mediated by immune-induced changes in TRP availability.

Prolonged thioguanine therapy is well tolerated and safe in the treatment of ulcerative colitis.

BACKGROUND: Thioguanine has been used for the treatment of inflammatory bowel disease, in particular for patients who failed conventional thiopurine therapy. To date, thioguanine has been infrequently studied in ulcerative colitis. AIM: To evaluate the tolerability, safety and efficacy of thioguanine in the treatment of ulcerative colitis. METHODS: A database analysis was performed on inflammatory bowel disease patients who had failed conventional thiopurine therapy and were treated with thioguanine. Rates and reasons for treatment failure were assessed. Laboratory values, abdominal ultrasonography, liver biopsy and endoscopic remission rates were evaluated. RESULTS: Forty-six patients were included and median treatment duration was 22 months (range 0.3-72.0). Nine patients failed thioguanine therapy: six due to adverse events, three due to therapy resistance. Concomitant treatment with aminosalicylates protected against thioguanine failure (hazard ratio (HR) 0.11, 95% CI 0.03-0.48). When performed, ultrasonography (n = 21) revealed no suspected therapy-related pathology in all but one patient, in whom hepatomegaly was observed. Liver histology (n = 12) predominantly revealed no abnormalities (n = 4) or non-specific regeneration (n = 4); none showed nodular regenerative hyperplasia. At follow-up, 40% of colonoscopies revealed endoscopic remission as compared with 10% at baseline (P = 0.180). CONCLUSIONS: Long-term use of thioguanine appears to be well tolerated and relatively safe in ulcerative colitis patients who failed conventional thiopurine therapy.

Inflammatory Bowel Disease in South Limburg (the Netherlands) 1991-2002: Incidence, diagnostic delay, and seasonal variations in onset of symptoms.

BACKGROUND AND AIMS: Increasing incidence in Inflammatory Bowel Disease (IBD) has been suggested. Recent data on population based incidence rates within Europe are however scarce. Primary aim was to investigate prospectively the incidence of IBD within a well-defined geographical and administrative area of the Netherlands, the South Limburg IBD registry. Secondary aims were to study the duration of symptoms before diagnosis (lag time) and seasonal influences on the incidence of IBD. METHODS: The incidence was examined using standardized registration of all newly diagnosed IBD patients, between 1-1-1991 and 1-1-2003. Medical records were reviewed to verify the diagnosis. At inclusion, diagnostic lag time was registered in months. RESULTS: Age standardized incidence rates per 100,000 person-years (p-y) were: Crohn's Disease, male 4.84, female 7.58; Ulcerative Colitis, male 8.51, female 6.92; and Indeterminate Colitis, male 1.05, female 0.93. Incidence rates did not significantly changes over time in either Crohn's Disease, Ulcerative Colitis or Indeterminate Colitis. Lag time was 5 (0-360) months in Crohn's Disease, 3.0 (0-480) months in Ulcerative Colitis and 3.0 (0-180) months in Indeterminate Colitis. Lag time was not significantly different between the periods 1991-1993 and 2000-2002, and no statistical differences in the onset of symptoms per calendar month or season were found. CONCLUSIONS: Our results, from the South Limburg region (the Netherlands), show no significant change in incidence rates of IBD. The incidence found is relatively high compared to other European countries. Lag time did not change during the study period, and seasonal influence of incidence rates could not be confirmed.