Dianne Gelien Bouwknegt

Background: Pregnancy is associated with altered pharmacokinetics for several drugs. The blood concentration of infliximab increases during pregnancy, whereas that of vedolizumab tends to decrease. As autoimmune disease activity during pregnancy can lead to adverse pregnancy outcomes, monitoring drug concentrations during pregnancy is important. Methods: This study reports a 32-year-old female patient with severe juvenile idiopathic arthritis and Crohn disease who was treated with dual biologic therapy throughout her pregnancy. The measurements were performed as part of routine care. Results: The patient was treated with vedolizumab and infliximab during the course of her pregnancy. Both autoimmune diseases remained unaffected throughout pregnancy, and therapeutic drug concentrations were monitored to guide treatment. The patient had gestational diabetes and mild polyhydramnios. Ultimately, the pregnancy was complicated by preterm delivery at 33 weeks and 5 days of gestation, with a good birth weight of 2425 g at p85 without growth retardation. Conclusions: Therapeutic drug monitoring (TDM) supports optimal dosing and effective disease control, highlighting the importance of individual interpretations. All TDM-initiated dosing changes were based on expert opinions, owing to the lack of validated guidelines on dosing during pregnancy. However, preterm birth could not be avoided and may be influenced by underlying autoimmune diseases, gestational diabetes, and mild polyhydramnios. Multidisciplinary care is essential in pregnant women with autoimmune disorders. Prospective research focusing on drug concentrations, disease activity, and the risk of adverse pregnancy outcomes is needed to understand the safety and implications of dual biologic therapies during pregnancy.

Background: Over recent decades, there has been a more pronounced shift towards earlier therapeutic intervention in luminal Crohn's disease (CD). However, it remains unclear if similar strategies apply to active perianal fistulizing CD (pCD). This study explores the patient journey by assessing pCD management across diagnostic time periods in a large national cohort. Methods: Patients with active pCD were included in a multicentre cohort across 41 Dutch academic and non‐academic hospitals. Diagnostic modalities, medical and surgical treatments were evaluated over the pCD disease course, particularly within the first year after pCD diagnosis, and compared across four time periods: < 2010, 2010–2015, 2015–2020 and > 2020. Results: Four hundred and forty patients were included (53.0% female; median pCD disease course 4.1 years). 12% were diagnosed before 2010, 11% in 2010–2015, 31% in 2015–2020, 46% after 2020. Over time, imaging (MRI or EUS) within the first year after pCD diagnosis was used in 37% of cases diagnosed before 2010 to 66%, 83% and 95% in subsequent periods. Endoscopic evaluation for proctitis was performed in 23%, 40%, 57% and 60%. First‐line anti‐TNF use was initiated in 27% followed by 58%, 68% and 69%. A seton was placed in 27% initially and in 42%, 51% and 52% in later years. Fistula surgery aimed at closure was performed in 14%, 4%, 8% and 19% over time. Conclusions: This national cohort illustrates substantial progress in early pCD management over time. These shifts likely reflect growing clinical awareness of the importance of early and multidisciplinary interventions. However, surgical procedures aimed at fistula closure remain infrequently performed in the early disease course, which may be related to the inclusion of a predominantly therapy‐refractory patient group.

Background: Risankizumab, a monoclonal antibody targeting interleukin-23, is approved for the treatment of Crohn’s disease (CD). Real-world evidence on its effectiveness remains limited. We assessed 1-year effectiveness and safety of risankizumab in a prospective cohort of patients with CD, emphasizing difficult-to-treat disease. Methods: Data were retrieved from the Dutch Initiative on Crohn and Colitis Registry. At baseline and at weeks 12, 24, and 52, clinical remission (Harvey-Bradshaw Index ≤4), biochemical remission (fecal calprotectin ≤250 µg/g and C-reactive protein levels ≤5 mg/L), systemic corticosteroids use, and safety outcomes were determined. The primary outcome was corticosteroid-free clinical remission (CSFCR) at week 24. Difficult-to-treat disease was defined as the failure of advanced therapies with at least 2 different mechanisms of action. Results: In total, 151 patients initiated risankizumab before August 1, 2025; 136 (90.1%) of 151 patients had difficult-to-treat disease. At baseline, 90 (59.6%) patients had Harvey-Bradshaw Index >4. Of those, at week 24, 31 (50%) of 62 patients were in CSFCR; this rate was 53.3% when including all patients. Analysis including only patients with difficult-to-treat disease revealed that 51.8% of these patients were in CSFCR at week 24. Twenty-two (14.6%) patients discontinued treatment after a median of 183.5 days (Q1-Q3: 90.0-295.2 days), most following nonresponse. Regarding adverse events, 35.3 possibly and 16.6 probably risankizumab-related events per 100 person-years were reported. Conclusion: In this prospective multicenter study, risankizumab demonstrated favorable effectiveness and safety profile in patients with CD, including those with difficult-to-treat disease, bowel surgery, and stoma. These findings support the use of risankizumab in patients with difficult-to-treat disease.

Background: Thiopurines are used to maintain remission in inflammatory bowel disease (IBD). These drugs are metabolized into 6‐thioguanine nucleotides (6‐TGN), associated with efficacy, and 6‐methylmercaptopurine ribonucleotides (6‐MMPR), associated with adverse drug reactions. Pregnancy has been linked to a shift in thiopurine metabolism, characterized by reduced 6‐TGN and increased 6‐MMPR levels. The clinical impact of these changes remains unclear. To explore the association between changes in 6‐TGN and 6‐MMPR levels with disease activity and toxicity markers in women with IBD during pregnancy. Methods: This retrospective cohort study included pregnant women with IBD who used thiopurines from six Dutch hospitals (2017–2022). Linear mixed‐effects models were used to model changes of 6‐TGN and 6‐MMPR before, during and after pregnancy, and to identify associations with markers of disease activity (faecal calprotectin) and toxicity (alanine aminotransferase [ALT], leukocytes, platelets). Results: A total of 87 women with 100 pregnancies were included (64.4% Crohn's disease, 32.2% ulcerative colitis). A significant reduction in 6‐TGN was found in the second and third trimester, but no associations with changes in faecal calprotectin were detected. There were no significant increases in 6‐MMPR. Increases in 6‐MMPR were associated with modest elevations in ALT, but none of the other toxicity markers. Transient thrombocytopenia and leukopenia occurred thrice, and elevated liver enzymes were observed in nine pregnancies. Conclusions: Although 6‐TGN levels decreased during pregnancy, these fluctuations were not associated with increased disease activity or toxicity. No significant increase in 6‐MMPR levels was observed. Proactive monitoring may therefore not be warranted in the pregnant population.

Background: Filgotinib is a preferential Janus kinase 1 (JAK‐1) inhibitor registered for the treatment of ulcerative colitis (UC). Real‐world effectiveness of filgotinib, especially for difficult‐to‐treat (DTT, failure of ≥ 2 prior advanced therapies) patients, has been scarcely reported. Objective: This study aimed to assess the effectiveness and safety of filgotinib for UC patients in routine care. Methods: The Dutch ICC registry enrolled UC patients initiating filgotinib and prospectively evaluated outcomes up to 52 weeks. The primary outcome was corticosteroid‐free clinical remission (CSFR, Simple Clinical Colitis Activity Index [SCCAI] ≤ 2 without steroid use) at week 52. Secondary outcomes included clinical remission (SCCAI ≤ 2), biochemical remission (C‐reactive protein serum concentration < 5 mg/L and/or faecal calprotectin level < 250 μg/g), treatment persistence and safety. Results: A total of 96 UC patients were included. At 52 weeks, 39.5% (34/76) of patients with disease activity at baseline were in CSFR. Out of the patients that met the criteria for DTT disease ( n = 68; 71%), 36.4% achieved CSFR. Treatment persistence at 52 weeks was 71.4% (CI 56.5–90.3) and 53.4% (CI 42.6–67.0) for non‐DTT and DTT patients, respectively. The main reasons for discontinuation of filgotinib were primary non‐response ( n = 21, 54%) or secondary loss of response ( n = 8, 23%). No severe infections were documented. Most reported adverse events included headache ( n = 5), nausea ( n = 3) and hypercholesterolemia ( n = 3). Conclusion: Filgotinib is an effective and well‐tolerated treatment option for UC, including DTT disease. No new safety signals were found.

Background and Aims: Inflammatory bowel disease (IBD) often coincides with pregnancy, and disease activity during pregnancy increases the risk of adverse outcomes. We aimed to determine how disease course before conception influences relapse risk during pregnancy, adjusting for established risk factors. Methods: In this multicenter, retrospective cohort study, we included adult women with IBD who were pregnant during treatment at one of three university hospitals between 2017 and 2022. Using generalized estimating equations, we evaluated associations between relapse during pregnancy and pre-conceptional flares, categorized into three time intervals. Analyses were adjusted for phenotype, disease duration, surgical history, biologic use, smoking, and assisted reproduction. Interaction analyses were conducted with matched non-pregnant women. Results: We included 386 women (63.4% Crohn’s disease, 36.6% ulcerative colitis) with 476 pregnancies. Pre-conceptional flares were significantly associated with relapse if they occurred <3 months [adjusted odds ratio (aOR) 5.289, 95% CI 2.6-10.8, P < .001] or 3-6 months prior to conception (aOR 2.910, 95% CI 1.0-8.2, P = .043), but not 6-12 months prior (aOR 1.636, 95% CI 0.8-3.2, P = .146). Other predictors were not significantly associated with relapse. There was no significant interaction between pregnancy and pre-conceptional disease activity. Conclusions: This large multicenter study demonstrates that disease activity within 6 months before conception significantly increases the risk of relapse during pregnancy in women with IBD. Our study is the first to assess both the pre-conceptional disease course and a broad set of known risk factors in a real-world cohort.

Background and Aims: Complex gene-environment interaction (GXE) for inflammatory bowel disease (IBD) remains elusive. This systematic review aims to summarize the current evidence of GXE in IBD. Methods: PubMed, EMBASE, Web of Science, and Scopus were systematically searched from inception through April 30, 2024, to identify publications examining the interaction effect of genetic variants and environmental factors in IBD. All eligible studies were graded using STREGA guideline. Results: Four thousand eight hundred thirty-three publications were identified and screened, resulting in 39 eligible studies, and 17 studies reported statistically significant interactions. NOD2-smoking interaction was most frequently investigated and showed variant-specific effect at rs2066847 regarding the risk of Crohn’s disease. Gene-smoking interactions were further identified in other IBD risk genes (ATG16L1, IL23R, and CALM3), detoxification genes (GSTP1 and HMOX1), smoking-associated genes (CHRNA3, CHRNA5, PPP1R3C, and BDNF), and the inflammatory cytokine (IL1B) through a candidate gene approach. Immunochip-wide interaction analyses yielded 64 smoking interacting variants. Gene-diet interactions were observed across multiple nutritional measures, including fatty acid intake with CYP4F3 and FADS2, serum selenium with SEPHS1 and SEPSECS, potassium intake with IL21, alcohol consumption with IL12B, heme iron intake with FCGR2A, and serum vitamin D with VDR. Conclusions: Current evidence indicated that the IBD risk conferred by environmental factors can vary among the individuals carrying certain genetic variants. Further efforts, including genome wide environment interaction studies and genotype-based nutrition/lifestyle clinical trials, are needed to unravel the missing heritability influenced by environmental exposures and to construct personalized recommendations of lifestyle/dietary modification based on an individual genetic background.

Background: Inflammatory bowel disease (IBD) is often diagnosed in young adults, and therefore frequently coincides with pregnancy. Patients may require surgery that includes (temporary) stoma placement. Literature on the occurrence of stoma-complications during pregnancy and the effect on pregnancy outcomes is limited. To evaluate stoma- complications peri- and postpartum, a retrospective study was performed in women who were pregnant while having a stoma. Methods: This multicentre cohort and survey study included all pregnant patients with IBD and a stoma who delivered between 2016 and 2023 from 5 Dutch university hospitals. Stoma-complications and pregnancy outcomes were retrospectively collected from electronic patient files. A questionnaire assessed patient-reported complications and long-term stoma-related complaints. Results: In total, 50 patients were included (median age at conception 31.0 years; 55.2% Crohn’s disease and 44.8% ulcerative colitis), comprising 67 pregnancies, 5 of which ended in pregnancy loss. Stoma complications occurred in 44 full-term pregnancies (71.0%), most commonly obstruction (35.5%) and decreased output (29.0%). Surgery was required in four pregnancies due to obstruction (n = 3) and prolapse (n = 2). In the first-year postpartum, 7 patients required surgery for stoma-complications. Amongst 29 women who completed the questionnaire, 10 (34.5%) reported unresolved complications 6 months postpartum. Cesarean sections were performed in 31 (50.0%) pregnancies. Adverse pregnancy outcomes included prematurity (n = 9, 14.5%), low birth weight (n = 9, 14.5%), and dysmaturity (n = 5, 8.1%). Conclusions: Pregnancy with a stoma is feasible, though manageable complications often occur. Counseling before pregnancy and close monitoring of symptoms during pregnancy and postpartum are essential for women with IBD and a stoma.