Abdominal pain in patients with inflammatory bowel disease in remission: A prospective study on contributing factors.

BACKGROUND: Abdominal pain is highly prevalent in patients with inflammatory bowel disease (IBD) in remission, but the aetiology is incompletely understood. AIM: To investigate the association of clinical, lifestyle and psychosocial factors with abdominal pain in patients with IBD in remission. METHODS: We performed a prospective multicentre study enrolling consecutive patients with IBD. Data were collected between 1 January 2020 and 1 July 2021, using myIBDcoach, an established remote monitoring platform for IBD. Chronic abdominal pain in IBD in remission (IBDremissionPain+) was defined as abdominal pain score ≥3 (0-10 NRS) on ≥1/3 of all assessments, combined with faecal calprotectin <150 µg/g in 90 days around periodic assessments. Disease activity, lifestyle and psychosocial factors were assessed every 1-3 months during 18 months. Using linear mixed models, the association of these factors with abdominal pain over time was analysed. RESULTS: We included 559 patients, of whom 429 (76.7%) remained in biochemical remission. Of these, 198 (46.2%) fulfilled the criteria for chronic abdominal pain. IBDremissionPain+ patients were characterised by female sex, younger age, higher BMI, and shorter disease duration. They reported more often or higher levels of stress, fatigue, depressive and anxiety symptoms, and life events (all p < 0.001). In the multivariable analysis, sex, disease entity, fatigue, depressive symptoms and life events were associated with abdominal pain over time (all p < 0.05). CONCLUSION: In this cohort of patients with IBD in remission, abdominal pain was common and associated with psychosocial factors. A more holistic treatment approach for patients with IBD suffering from abdominal pain may improve quality of care and subjective wellbeing.

Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel disease.

BACKGROUND: Women with inflammatory bowel disease (IBD) are at increased risk of high-grade cervical intraepithelial neoplasia and cervical cancer (CIN2+). AIM: To assess the association between cumulative exposure to immunomodulators (IM) and biologic agents (BIO) for IBD and CIN2+ METHODS: Adult women diagnosed with IBD before December 31st 2016 in the Dutch IBD biobank with available cervical records in the nationwide cytopathology database were identified. CIN2+ incidence rates in IM- (i.e., thiopurines, methotrexate, tacrolimus and cyclosporine) and BIO- (anti-tumour necrosis factor, vedolizumab and ustekinumab) exposed patients were compared to unexposed patients and risk factors were assessed. Cumulative exposure to immunosuppressive drugs was evaluated in extended time-dependent Cox-regression models. RESULTS: The study cohort comprised 1981 women with IBD: 99 (5%) developed CIN2+ during median follow-up of 17.2 years [IQR 14.6]. In total, 1305 (66%) women were exposed to immunosuppressive drugs (IM 58%, BIO 40%, IM and BIO 33%). CIN2+ risk increased per year of exposure to IM (HR 1.16, 95% CI 1.08-1.25). No association was observed between cumulative exposure to BIO or both BIO and IM and CIN2+. In multivariate analysis, smoking (HR 2.73, 95%CI 1.77-4.37) and 5-yearly screening frequency (HR 1.74, 95% CI 1.33-2.27) were also risk factors for CIN2+ detection. CONCLUSION: Cumulative exposure to IM is associated with increased risk of CIN2+ in women with IBD. In addition to active counselling of women with IBD to participate in cervical screening programs, further assessment of the benefit of intensified screening of women with IBD on long-term IM exposure is warranted.

Increased Risk of High-grade Cervical Neoplasia in Women with Inflammatory Bowel Disease: A Case-controlled Cohort Study.

BACKGROUND AND AIMS: Women with inflammatory bowel disease [IBD] may be at higher risk for cervical intraepithelial neoplasia [CIN]. However, data are conflicting. The aim of this study was to assess the risk of high-grade dysplasia and cancer [CIN2+] in IBD women and identify risk factors. METHODS: Clinical data from adult IBD women in a multicentre Dutch IBD prospective cohort [PSI] from 2007 onwards were linked to cervical cytology and histology records from the Dutch nationwide cytology and pathology database [PALGA], from 2000 to 2016. Patients were frequency-matched 1:4 to a general population cohort. Standardised detection rates [SDR] were calculated for CIN2+. Longitudinal data were assessed to calculate CIN2+ risk during follow-up using incidence rate ratios [IRR] and risk factors were identified in multivariable analysis. RESULTS: Cervical records were available from 2098 IBD women [77%] and 8379 in the matched cohort; median follow-up was 13 years. CIN2+ detection rate was higher in the IBD cohort than in the matched cohort (SDR 1.27, 95% confidence interval [CI] 1.05-1.52). Women with IBD had an increased risk of CIN2+ [IRR 1.66, 95% CI 1.21-2.25] and persistent or recurrent CIN during follow-up (odds ratio [OR] 1.89, 95% CI 1.06-3.38). Risk factors for CIN2+ in IBD women were smoking and disease location (ileocolonic [L3] or upper gastrointestinal [GI] [L4]). CIN2+ risk was not associated with exposure to immunosuppressants. CONCLUSIONS: Women with IBD are at increased risk for CIN2+ lesions. These results underline the importance of human papillomavirus [HPV] vaccination and adherence to cervical cancer screening guidelines in IBD women, regardless of exposure to immunosuppressants.

Genetic Risk Scores Identify Genetic Aetiology of Inflammatory Bowel Disease Phenotypes.

BACKGROUND AND AIMS: Inflammatory bowel disease [IBD] phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores [GRS] to disentangle the genetic contributions to IBD phenotypes. METHODS: Clinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts [cohort A, n = 1097; cohort B, n = 2156]. Genetic risk scoring [GRS] was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS-phenotype (false-discovery rate [FDR] corrected p <0.05) associations identified in cohort A were put forward for replication in cohort B. RESULTS: Crohn's disease [CD] GRS were associated with fibrostenotic CD [R2 = 7.4%, FDR = 0.02] and ileocaecal resection [R2 = 4.1%, FDR = 1.6E-03], and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis [UC] GRS [R2 = 7.1%, FDR = 0.02] and primary sclerosing cholangitis [PSC] GRS [R2 = 3.6%, FDR = 0.03] were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour [R2 = 1.7%, FDR = 0.04]. CONCLUSIONS: Patients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, whereas colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes.

The Impact of Ethnicity and Country of Birth on Inflammatory Bowel Disease Phenotype: a Prospective Cohort Study.

BACKGROUND AND AIMS: The number of patients with inflammatory bowel disease [IBD], of non-Caucasian descent in Western Europe, is increasing. We aimed to explore the impact of ethnicity and country of birth on IBD phenotype. METHODS: IBD patients treated in the eight University Medical Centers in The Netherlands [Dutch IBD Biobank] were divided into two groups according to their ethnicity: 1] Caucasian patients of Western and Central European descent [CEU]; and 2] patients of non-Caucasian descent [non-CEU]. The non-CEU group was subdivided according to country of birth, into: born in The Netherlands or Western Europe [non-CEU European born]; or born outside Western-Europe who migrated to The Netherlands [non-CEU non-European born]. Both comparisons were analysed for phenotype differences [by chi-square test]. RESULTS: The Dutch IBD Biobank included 2921 CEU patients and 233 non-CEU patients. Non-CEU Crohn's disease [CD] patients more often had upper gastro-intestinal disease [16% vs 8%, p = 0.001] and anal stenosis [10% vs 4%, p = 0.002] than CEU CD patients. The use of anti-tumour necrosis factor [TNF] agents and immunomodulators was higher in non-CEU IBD patients than in CEU IBD patients [45% vs 38%, p = 0.042] and [77% vs 66%, p = 0.001], respectively. Non-CEU IBD patients born in Europe [n = 116] were diagnosed at a lower age than non-CEU IBD patients born outside Europe [n = 115] [at 22.7 vs 28.9 years old, p < 0.001]. CONCLUSION: Non-Caucasians had more severe disease behaviour than Caucasians. Non-CEU patients born in Europe were diagnosed at a lower age with IBD than those born outside Europe who migrated to The Netherlands.

[Changes in the treatment of Crohn's disease: fewer hospitalizations, less surgery, and reduced glucocorticoid use]. / Veranderingen in de behandeling van ziekte van Crohn.

OBJECTIVE: To study changes in treatment and disease course in patients with Crohn's disease (CD) in the South Limburg region of the Netherlands between 1991 and 2014. DESIGN: Population-based cohort study. METHODS: All 1162 CD patients in the 'IBD South Limburg cohort' were divided across three subcohorts on the basis of year of diagnosis: 1991-1998 (N = 316), 1999-2005 (N = 387) and 2006-2011 (N = 459). We compared the risk of hospitalization, bowel resection and the development of strictures and/or fistulas across the subcohorts. We also compared cumulative corticosteroid use and the relationship between the outcome measures and maintenance medication. RESULTS: In the period 1991-2014 there was an increase in the number of patients treated within 5 years with immunomodulators from 30.6% to 70.8%. For treatment with biologicals there was an increase from 3.1% to 41.2%. In parallel, the risk of hospitalization decreased from 65.9% to 44.2% and the risk of bowel resection decreased from 42.9% to 17.4%. The risk of developing strictures or fistulas remained stable (21.2%). There was no significant association between the outcome measures and the use of immunomodulators or biologicals. Furthermore, corticosteroid use decreased over time; this was linked to use of immunomodulators and biologicals. CONCLUSION: Treatment of Crohn's disease has changed over the past two decades, and the disease course has improved. We found no association between changes in maintenance medication and disease course.

The potential of volatile organic compounds for the detection of active disease in patients with ulcerative colitis.

BACKGROUND: To optimise treatment of ulcerative colitis (UC), patients need repeated assessment of mucosal inflammation. Current non-invasive biomarkers and clinical activity indices do not accurately reflect disease activity in all patients and cannot discriminate UC from non-UC colitis. Volatile organic compounds (VOCs) in exhaled air could be predictive of active disease or remission in Crohn's disease. AIM: To investigate whether VOCs are able to differentiate between active UC, UC in remission and non-UC colitis. METHODS: UC patients participated in a 1-year study. Clinical activity index, blood, faecal and breath samples were collected at each out-patient visit. Patients with clear defined active faecal calprotectin >250 µg/g and inactive disease (Simple Clinical Colitis Activity Index <3, C-reactive protein <5 mg/L and faecal calprotectin <100 µg/g) were included for cross-sectional analysis. Non-UC colitis was confirmed by stool culture or radiological evaluation. Breath samples were analysed by gas chromatography time-of-flight mass spectrometry and kernel-based method to identify discriminating VOCs. RESULTS: In total, 72 UC (132 breath samples; 62 active; 70 remission) and 22 non-UC-colitis patients (22 samples) were included. Eleven VOCs predicted active vs. inactive UC in an independent internal validation set with 92% sensitivity and 77% specificity (AUC 0.94). Non-UC colitis patients could be clearly separated from active and inactive UC patients with principal component analysis. CONCLUSIONS: Volatile organic compounds can accurately distinguish active disease from remission in UC and profiles in UC are clearly different from profiles in non-UC colitis patients. VOCs have demonstrated potential as new non-invasive biomarker to monitor inflammation in UC.

High risk of drug-induced microscopic colitis with concomitant use of NSAIDs and proton pump inhibitors.

BACKGROUND: Microscopic colitis (MC) is a chronic bowel disorder characterised by watery diarrhoea. Nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), selective serotonin reuptake inhibitors (SSRIs) and statins have been associated with MC. However, underlying mechanisms remain unclear. AIM: To study the association between exposure to these drugs and MC, with attention to time of exposure, duration, dosage and combined exposure, and to test hypotheses on underlying pharmacological mechanisms. METHODS: A case-control study was conducted using the British Clinical Practice Research Datalink. MC cases (1992-2013) were matched to MC-naive controls on age, sex and GP practice. Drug exposure was stratified according to time of exposure, duration of exposure or dosage. Conditional logistic regression analysis was applied to calculate adjusted odds ratios (AORs). RESULTS: In total, 1211 cases with MC were matched to 6041 controls. Mean age was 63.4 years, with 73.2% being female. Current use of NSAIDs (AOR 1.86, 95% CI 1.39-2.49), PPIs (AOR 3.37, 95% CI 2.77-4.09) or SSRIs (AOR 2.03, 95% CI 1.58-2.61) was associated with MC compared to never or past use. Continuous use for 4-12 months further increased the risk of MC. Strongest associations (fivefold increased risk) were observed for concomitant use of PPIs and NSAIDs. Statins were not associated with MC. CONCLUSIONS: Current exposure to NSAIDs, PPIs or SSRIs and prolonged use for 4-12 months increased the risk of MC. Concomitant use of NSAIDs and PPIs showed the highest risk of MC. Acid suppression related dysbiosis may contribute to the PPI effect, which may be exacerbated by NSAID-related side-effects.

Smoking is Associated With Extra-intestinal Manifestations in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Smoking affects the course of disease in patients with ulcerative colitis (UC) and Crohn's disease (CD). We aimed to study the association between smoking and extra-intestinal manifestations (EIMs) in inflammatory bowel disease (IBD). METHODS: We cross-sectionally explored the association between smoking and EIMs in IBD in three cohort studies: (1) the COIN study, designed to estimate healthcare expenditures in IBD; (2) the Groningen study, focused on cigarette smoke exposure and disease behaviour in IBD; and (3) the JOINT study, evaluating joint and back manifestations in IBD. RESULTS: In the COIN, Groningen and JOINT cohorts, 3030, 797 and 225 patients were enrolled, of whom 16, 24 and 23.5% were current smokers, respectively. Chronic skin disorders and joint manifestations were more prevalent in smoking IBD patients than in non-smokers (COIN, 39.1 vs 29.8%, p <0.01; Groningen, 41.7 vs 30.0%, p <0.01) in both CD and UC. In the JOINT cohort, smoking was more prevalent in IBD patients with joint manifestations than in those without (30.3 vs 13.0%, p <0.01). EIMs appeared to be more prevalent in high- than in low-exposure smokers (56.0 vs 37.1%, p = 0.10). After smoking cessation, the prevalence of EIMs in IBD patients rapidly decreased towards levels found in never smokers (lag time: COIN cohort, 1-2 years; Groningen cohort, within 1 year). CONCLUSIONS: There is a robust dose-dependent association between active smoking and EIMs in both CD and UC patients. Smoking cessation was found to result in a rapid reduction of EIM prevalence to levels encountered in never smokers.

Review article: the association of diet with onset and relapse in patients with inflammatory bowel disease.

BACKGROUND: The role of diet in inflammatory bowel disease (IBD) is supported by migration studies and increasing incidences in line with Westernisation. AIM: To give a complete overview of studies associating habitual diet with the onset or relapses in ulcerative colitis (UC) or Crohn's disease (CD). METHODS: A structured search in Pubmed, the Cochrane Library and EMBASE was performed using defined key words, including only full text papers in English language. RESULTS: Forty-one studies were identified, investigating onset (n = 35), relapses (n = 5) or both (n = 1). Several studies reported high intake of sugar or sugar-containing foods (n = 7 UC, n = 12 CD), and low intake of fruits and/or vegetables (n = 5 UC, n = 10 CD) to be associated with an increased onset risk. However, these findings could not be confirmed by similar or higher numbers of other studies. A possible protective role was found for grain-derived products in CD onset, but results were inconsistent for dietary fibre in UC and CD and grain-derived products in UC. No definite conclusions could be drawn for unsaturated fatty acids (UFA), protein and energy intake due to limited and/or inconsistent results. Six studies reported on diet and relapse risk, of which only two (n = 1 UC, n = 1 CD) had a prospective follow-up. CONCLUSIONS: The current evidence is not sufficient to draw firm conclusions on the role of specific food components or nutrients in the aetiology of IBD. Furthermore, large prospective studies into the role of habitual diet as a trigger of relapses are needed, to identify new therapeutic or preventive targets.

Randomised clinical trial: once- vs. twice-daily prolonged-release mesalazine for active ulcerative colitis.

BACKGROUND: Aminosalicylates are first-choice treatment for mild-to-moderately active ulcerative colitis (UC); however, multi-dosing regimens are inconvenient. AIM: To compare the efficacy and safety of once- (OD) vs. twice- (BD) daily prolonged-release mesalazine (Pentasa, Ferring, Saint-Prex, Switzerland) for active mild-to-moderate UC in a non-inferiority study. METHODS: Eligible patients (n = 206) were randomised to 8 weeks of mesalazine (4 g/day), either OD with two sachets of 2 g mesalazine granules in the morning (n = 102) or BD with one 2 g sachet in the morning and one in the evening (n = 104). Patients also received 4 weeks of mesalazine enema 1 g/day. Disease activity was assessed at randomisation, weeks 4, 8 and 12 using the UC Disease Activity Index (UC-DAI). Clinical and endoscopic remission (primary endpoint) was assessed after 8 weeks. Patients recorded stool frequency and rectal bleeding in a daily diary. RESULTS: The primary endpoint, non-inferiority in clinical and endoscopic remission with OD vs. BD mesalazine at 8 weeks, was met (intent-to-treat population: 52.1% vs. 41.8%, respectively, 95% confidence interval -3.4, 24.1; P = 0.14). Improvement of UC-DAI score (92% vs. 79%; P = 0.01) and mucosal healing (87.5% vs. 71.1%; P = 0.007) were significantly better, time to remission significantly shorter (26 vs. 28 days; P = 0.04) and safety similar with OD vs. BD dosing. CONCLUSIONS: When combined with mesalazine enema, prolonged-release mesalazine once-daily 4 g is as effective and well tolerated as 2 g twice-daily for inducing remission in patients with mild-to-moderately active ulcerative colitis (Clinicaltrials.gov: NCT00737789).

High intra-uterine exposure to infliximab following maternal anti-TNF treatment during pregnancy.

BACKGROUND: Typically, inflammatory bowel disease (IBD) patients are in their reproductive years, raising questions about safely using antitumour necrosis factor antibodies like infliximab (IFX) during pregnancy. IgG antibodies naturally cross the placenta, especially during the last trimester. To prevent foetal intra-uterine exposure, stopping IFX treatment at gestational week 30 is recommended. However, whether this limits intra-uterine and early postnatal IFX exposure is unestablished. AIM: To determine the intra-uterine exposure to IFX following maternal treatment with IFX. METHODS: Four pregnant IBD patients intentionally continued IFX during pregnancy. IFX levels were assessed in newborns' cord blood and the mothers' peripheral blood at delivery. The children's development during the first 3-6 months, infections, vaccine reactions and antibody responses to vaccinations against Haemophilus influenzae type b and Pneumococcus were assessed. RESULTS: The patients stopped IFX therapy at gestational week 21, 26, 26 and 30, respectively. In three infants, therapeutic IFX levels were present in cord blood at levels of 5.5-13.7 µg/mL and were two- to three-fold higher than in the peripheral blood of their mothers. During the 3- to 6-month follow-up, the children developed normally without signs of infections or allergic reactions, and had normal antibody titres after routine childhood vaccinations. CONCLUSION: The use of IFX until gestational week 30 leads to foetal intra-uterine exposure to IFX at levels that exceed those in the mothers' peripheral blood. Although no short-term complications were detected, the high IFX levels observed in newborns raise concerns about unknown effects of IFX on the developing immune system.