Updates on the management of inflammatory bowel disease from periconception to pregnancy and lactation.

Inflammatory bowel disease (IBD) affects reproductive planning due to psychological effects and mechanical problems related to surgery. Children of people with IBD have an increased risk of about 10% if one parent has IBD and up to 33% if both parents have IBD. The fertility of people with IBD is similar to the general population, but fertility might be reduced in individuals with active IBD, ileal pouch-anal anastomosis, or perianal Crohn's disease. Flaring disease during pregnancy increases complications, such as preterm birth. Thus, disease management with appropriate medications can optimise outcomes. As most medications have minimal fetal risks, people with IBD should be informed about the risks of stopping medications and the importance of maintaining remission. A period of disease remission is advisable before pregnancy and could reduce the risks for both the pregnant person and the fetus. Flexible endoscopy, intestinal ultrasound, and gadolinium-free magnetic resonance enterography are safe during pregnancy. We provide state-of-the-art knowledge on the basis of the latest evidence to ensure successful pregnancy outcomes in controlled IBD.

Differential expression of small bowel TGFß1 and TGFß3 characterizes intestinal strictures in patients with fibrostenotic Crohn's disease.

Small bowel strictures remain a debilitating consequence of Crohn's disease and contribute to poor outcomes for patients. Recently, TGFß has been identified as an important driver of intestinal fibrosis. We studied the localization of TGFß isoforms in ileal strictures of patients with Crohn's disease using in situ hybridization to understand TGFß's role in stricture formation. The mucosa of strictures was characterized by higher TGFß1 while the stricture submucosa showed higher TGFß3 compared to normal ileum from patients without Crohn's disease (p = 0.02 and p = 0.044, respectively). We correlated these findings with single-cell transcriptomics which demonstrated that TGFß3 transcripts overall are very rare, which may partially explain why its role in intestinal fibrosis has remained unclear to date. There were no significant differences in fibroblast or B cell TGFß1 and/or TGFß3 expression in inflamed vs. noninflamed ileum. We discuss the implications of these findings for therapeutic development strategies to treat patients with fibrostenotic Crohn's disease.

Some Drugs Have Two Faces: Paradoxical Colitis in a Patient with Psoriatic Arthritis Previously Treated with Etanercept and IL-17 Inhibitors.

Tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17) inhibitors are among the most potent treatments for inflammatory arthropathies including rheumatoid arthritis, psoriasis, and spondyloarthropathies. The availability of these biologic agents have revolutionized the management of these conditions and improved patient outcomes. Though generally safe, these biologics may contribute to the induction or exacerbation of colitis. This paradoxical colitis has been observed in patients on TNF-α inhibitor etanercept and IL-17 inhibitors (secukinumab and ixekizumab). We report a case of a 46-year-old female with psoriasis and psoriatic arthritis who presented with gastrointestinal symptoms after treatment with etanercept and IL-17 inhibitors. She was later diagnosed with paradoxical indeterminate colitis that was masked and treated by subsequent biologics given for her RA and psoriatic arthritis. In this report, we will discuss the importance of considering paradoxical colitis in the differential diagnosis for patients even several years after TNF-α/IL-17 inhibitor initiation and explain why careful consideration must be made when initiating these colitis-inducing agents to treat patients with inflammatory disorders.

Paternal Medications in Inflammatory Bowel Disease and Male Fertility and Reproductive Outcomes: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Studies evaluating reproductive outcomes among male patients with inflammatory bowel disease (IBD) are limited. We evaluated use of IBD medications and association with semen parameters, a proxy of male fertility, and adverse pregnancy outcomes (early pregnancy loss [EPL], preterm birth [PB], congenital malformations [CM]). METHODS: We searched Medline, Embase, Scopus, and Web of Science (PROSPERO CRD42020197098) from inception to April 2022 for studies reporting semen parameters and adverse pregnancy outcomes among male patients exposed to biologics, thiopurine, or methotrexate. Standardized mean difference, prevalence, and odds ratios (ORs) of outcomes were pooled and analyzed using a random effects model. RESULTS: Ten studies reporting semen parameters (268 patients with IBD) and 16 studies reporting adverse pregnancy outcomes (over 25,000 patients with IBD) were included. Biologic, thiopurine, or methotrexate use were not associated with decreased sperm count, motility, or abnormal morphology compared with nonexposed patients. The prevalence of adverse pregnancy outcomes with paternal biologic (5%), thiopurine (6%), or methotrexate (6%) exposure was comparable to nonexposed patients (5%). Biologic use was not associated with risk of EPL (OR, 1.26; I2 = 0%; P = .12), PB (OR, 1.10; I2 = 0%; P = .17), or CM (OR, 1.03; I2 = 0%; P = .69). Thiopurine use was not associated with risk of EPL (OR, 1.31; I2 = 19%; P = .17), PB (OR, 1.05; I2 = 0%; P = .20), or CM (OR, 1.07; I2 = 7%; P = .34). Methotrexate use was not associated with risk of PB (OR, 1.06; I2 = 0%; P = .62) or CM (OR, 1.03; I2 = 0%; P = .81). CONCLUSIONS: Biologic, thiopurine, or methotrexate use among male patients with IBD are not associated with impairments in fertility or with increased odds of adverse pregnancy outcomes.

Rates and Predictors of Long-term Clinical Outcomes in Patients With Perianal Crohn's Disease on Biologic Therapy.

BACKGROUND AND GOALS: Perianal Crohn's disease (pCD) represents an aggressive phenotype with limited studies on long-term outcomes. We evaluated 5-year outcomes of these patients on biologic therapies. METHODS: We performed a retrospective analysis of patients with pCD at a tertiary medical center. We used Kaplan-Meier curves to estimate rates and multivariate logistic regression to identify predictors of long-term outcomes. RESULTS: We included 311 patients with pCD of which 168 patients were started on biologics [138 anti-tumor necrosis factor (TNF) α, 14 vedolizumab, 16 ustekinumab] at the time of diagnosis. Anti-TNF use at the time of diagnosis was associated with decreased rates of perianal abscess recurrence [hazard ratio (HR)=0.48, 95% confidence interval (CI): 0.32-0.74], whereas ustekinumab use was associated with increased rates of perianal fistula closure (HR=3.58, 95% CI: 1.04-12.35) and decreased rates of perianal abscess recurrence (HR=0.20, 95% CI: 0.07-0.56) at follow-up. Among patients who failed their first anti-TNF, switching to another anti-TNF was associated with decreased rates of colectomy (HR=0.20, 95% CI: 0.04-0.90) and permanent diversion (HR=0.16, 95% CI: 0.03-0.94) compared with ustekinumab, whereas vedolizumab use was associated with decreased perianal fistula closure (HR=0.22, 95% CI: 0.05-0.96) compared with ustekinumab. Predictors of colectomy included colonic disease (odds ratio=2.71, 95% CI: 1.36-5.38) and anal stenosis (odds ratio=4.44, 95% CI: 1.59-12.43). CONCLUSION: Type of biologic use at the time of pCD diagnosis or after first anti-TNF failure may be associated with long-term outcomes in patients with pCD.

Biologics for Inflammatory Bowel Disease and Their Safety in Pregnancy: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Biologics are used routinely in pregnant women with inflammatory bowel disease (IBD), but large-scale data reporting adverse pregnancy outcomes among biologic users are lacking. We sought to estimate the prevalence of adverse pregnancy outcomes in women with IBD on biologic therapies. METHODS: We searched major databases from inception to June 2020 for studies estimating the prevalence of adverse pregnancy outcomes in IBD when using biologics (anti-tumor necrosis factor [TNF], anti-integrins, and anticytokines). Prevalence and relative risk (RR) were pooled using a random-effects model. RESULTS: Forty-eight studies were included in the meta-analysis comprising 6963 patients. Biologic therapy in IBD pregnancies was associated with a pooled prevalence of 8% (95% CI, 6%-10%; I2 = 87.4%) for early pregnancy loss, 9% (95% CI, 7%-11%; I2 = 89.9%) for preterm birth, 0% (95% CI, 0%-0%; I2 = 0%) for stillbirth, 8% (95% CI, 5%-10%; I2 = 87.0%) for low birth weight, and 1% (95% CI, 1%-2%; I2 = 78.3%) for congenital malformations. These rates are comparable with those published in the general population. In subgroup analyses of a small number of studies, the prevalence of early pregnancy loss and preterm birth were higher in vedolizumab vs anti-TNF users. Meta-regression did not show an association of disease activity or concomitant thiopurine on adverse outcomes. Continued TNF inhibitor use during the third trimester was not associated with risk of preterm birth (RR, 1.41; 95% CI, 0.77-2.60; I2 = 0%), low birth weight (RR, 1.32; 95% CI, 0.80-2.18; I2 = 0%), or congenital malformations (RR, 1.28; 95% CI, 0.47-3.49; I2 = 0%). CONCLUSIONS: Adverse pregnancy outcomes among pregnant IBD women using biologics are comparable with that of the general population. PROSPERO protocol #CRD42019135721.

Biologics During Pregnancy in Women With Inflammatory Bowel Disease and Risk of Infantile Infections: A Systematic Review and Meta-Analysis.

INTRODUCTION: Biologics, such as tumor necrosis factor inhibitors, anti-integrins and anticytokines, are therapies for inflammatory bowel disease (IBD) that may increase the risk of infection. Most biologics undergo placental transfer during pregnancy and persist at detectable concentrations in exposed infants. Whether this is associated with an increased risk of infantile infections is controversial. We performed a systematic review and meta-analysis evaluating the risk of infantile infections after in utero exposure to biologics used to treat IBD. METHODS: We searched PubMed, Embase, Scopus, Web of Science, and CENTRAL from inception to June 2020 to evaluate the association of biologic therapy during pregnancy in women with IBD and risk of infantile infections. Odds ratios of outcomes were pooled and analyzed using a random effects model. RESULTS: Nine studies met the inclusion criteria comprising 8,013 women with IBD (5,212 Crohn's disease, 2,801 ulcerative colitis) who gave birth to 8,490 infants. Biologic use during pregnancy was not associated with an increased risk of all infantile infections (odds ratio [OR] 0.91, 95% confidence interval [CI] 0.73-1.14, I2 = 30%). In a subgroup analysis for the type of infection, biologic use was associated with increased infantile upper respiratory infections (OR 1.57, 95% CI 1.02-2.40, I2 = 4%). Biologic use during pregnancy was not associated with infantile antibiotic use (OR 0.91, 95% CI 0.73-1.14, I2 = 30%) or infection-related hospitalizations (OR 1.33, 95% CI 0.95-1.86, I2 = 26%). DISCUSSION: Biologics use during pregnancy in women with IBD is not associated with the overall risk of infantile infections or serious infections requiring antibiotics or hospitalizations but is associated with an increased risk of upper respiratory infections.

Higher serum vitamin D levels are associated with protective serum cytokine profiles in patients with ulcerative colitis.

BACKGROUND & AIMS: Vitamin D has immune modulating effects on cytokines. Serum vitamin D levels are associated with the risk of relapse in patients with ulcerative colitis (UC), through unknown mechanisms. We tested the hypothesis that this beneficial role of vitamin D on UC is mediated through anti-inflammatory serum cytokine profiles. METHODS: Serum samples from a prospective cohort of seventy UC patients in clinical remission were collected and baseline histological and endoscopic scores were recorded at enrollment. Clinical relapse events were recorded over the 12-month follow-up period. Serum vitamin D and cytokines levels (IL-6, IL-8, IL-17A, TNF-α, IFN-γ, IL-4, IL-10) were quantified using ELISA. Linear regression was used to determine correlation between vitamin D and cytokine profiles. Logistic regression models were used to determine the association between serum cytokine profiles and baseline histologic mucosal healing and clinical relapse. RESULTS: Higher serum vitamin D levels positively correlated with higher ratios of IL-4 + IL-10/IL-17A + TNF-α (r = 0.37, P < .01), and IL-4 + IL-10/IL-6 + TNF-α (r = 0.32, P < .01). In multivariate analysis, IL-4 + IL-10/IL-17A + TNF-α ratios at baseline were associated with the presence of histologic mucosal healing (O.R. 1.29, 95% CI 1.02-1.62, P = .03). A higher ratio of serum IL-4 + IL-10 to IL-6 + TNF-α was associated with a reduced risk of clinical relapse (O.R. 0.72, 95% CI 0.58-0.89, P = .003), and longer time to relapse (p = .03), over the 12-month follow-up period. This ratio during remission had an AUC of 0.7 in predicting later clinical relapse. CONCLUSIONS: Vitamin D is associated with anti-inflammatory serum cytokine profiles. Anti-inflammatory cytokine patterns may mediate the protective effects of higher serum vitamin D levels in patients with ulcerative colitis.

Vitamin D in inflammatory bowel disease: more than just a supplement.

PURPOSE OF REVIEW: The aim of this review is to explore the protective role of vitamin D on the gastrointestinal tract, summarize the epidemiology of vitamin D deficiency in inflammatory bowel disease (IBD), and highlight recent studies examining the impact of low vitamin D and vitamin D supplementation on IBD clinical outcomes. RECENT FINDINGS: Vitamin D protects the gut barrier by regulating tight junction proteins and inhibiting intestinal apoptosis. Vitamin D enhances innate immunity by inducing antimicrobial peptides and regulates adaptive immunity by promoting anti-inflammatory T cells and cytokines. Vitamin D may also alter the gut microbiota. The prevalence of vitamin D deficiency in IBD is 30-40%. Predictors of vitamin D deficiency in IBD include non-white ethnicity, IBD-related surgery, BMI more than 30, female sex, and pregnancy. Low vitamin D is associated with increased disease activity, inflammation, and clinical relapse. The effect of vitamin D supplementation on IBD clinical outcomes is inconclusive. SUMMARY: Vitamin D plays a protective role on gut health. Vitamin D deficiency in IBD is prevalent and associated with poor outcomes. The benefits of vitamin D supplementation in IBD is unclear. Measuring novel vitamin D metabolites and vitamin D absorption in IBD patients may help guide future studies.

Low Serum Vitamin D During Remission Increases Risk of Clinical Relapse in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Vitamin D levels have been associated with disease activity in patients with ulcerative colitis (UC), but it is unclear whether they affect the risk of disease relapse. We sought to determine the association between baseline vitamin D levels during a period of clinical remission and risk of subsequent UC relapse. METHODS: We performed a physician-blinded prospective study of 70 patients with UC in clinical remission followed up after a surveillance colonoscopy at a tertiary academic medical center. Serum samples were collected at the time of colonoscopy and baseline endoscopic and histologic activity were determined. Levels of 25-hydroxy-vitamin D were measured using an enzyme-linked immunosorbent assay. The primary outcome was rate of clinical relapse, determined over 12 months. RESULTS: The mean baseline vitamin D level was lower among patients with relapse (29.5 ng/mL) than without (50.3 ng/mL) (P = .001). Remission vitamin D level (≤35 ng/mL) was associated with a risk of clinical relapse (odds ratio, 1.25; 95% confidence interval [CI], 1.01-1.56; P = .044) over 12 months, independent of endoscopic or histologic grade at enrollment. A receiver operating characteristic curve of vitamin D levels for the outcome of relapse had an area under the curve of 0.72; and a serum level of 35 ng/mL or less had a sensitivity of 70% (95% CI, 46%-88%) and a specificity of 74% (95% CI 57%-83%) for predicting risk of clinical relapse. CONCLUSIONS: Serum levels of vitamin D of 35 ng/mL or less during periods of clinical remission increase the risk of UC relapse. Clinical trials to obtain vitamin D levels higher than this threshold should be considered.

Cannabis Abuse Is Increasing and Associated with Increased Emergency Department Utilization in Gastroenterology Patients.

BACKGROUND: The role of cannabinoids in gastrointestinal diseases is controversial and of great interest, yet their use in patients has not been critically examined. AIM: To determine the prevalence and effects of cannabis abuse on healthcare utilization, as measured by emergency department (ED) visits, in a large, tertiary gastroenterology practice. METHODS: All patients seen in the gastroenterology clinic at a tertiary care center during a 27-year period (1986-2013) were included in our study to determine the overall prevalence of cannabis abuse. We matched cannabis abusers 1:2 with non-abusing controls to determine the effect of cannabis on ED utilization, our primary outcome. We used multivariate linear regression to adjust for confounders and define the independent effect of cannabis abuse on ED utilization. RESULTS: Our prevalence study cohort included 190,303 GI clinic patients with an overall cannabis abuse prevalence of 0.80 % (1520 patients). From 1986 to 2012, the prevalence of cannabis abuse in this clinic increased by 0.73 % (0.03 %/year) (p < 0.0001). From the 1520 cannabis abusers identified, 467 patients were randomly selected as cases and were matched to 934 controls. From this retrospective cohort, the median ED visits/year for cannabis abusers was 1.88 versus 0.89 for non-abusers (p < 0.0001). After multivariate adjustment, cannabis abuse was associated with a 1.47-fold increase (95 % CI 1.23-1.76, p < 0.0001) in median ED visits/year. CONCLUSIONS: Reported cannabis abuse in GI clinic patients is less prevalent than in the adult US population, but is increasing. Cannabis abuse among gastroenterology patients is associated with increased ED visits.

Gut Microbiome and Disorders of the Gastrointestinal Tract.

The protective intestinal epithelial barrier is constantly exposed to more than 100 trillion commensal microorganisms (bacteria, archaea, viruses, and fungi), i [...].

Network meta-analysis: Comparative onset of early effect of biologics and small molecules in moderately to severely active luminal Crohn's disease.

INTRODUCTION: Rapidity of effect of advanced therapies for patients with Crohn's disease (CD) can be an essential decision parameter; however, comparative evaluation is lacking. We aimed to compare early response for advanced CD therapies in a network meta-analysis (NMA). METHODS: We searched systematically MEDLINE, Embase, and CENTRAL up to 19 February 2024, for randomised controlled trials. The co-primary outcomes were induction of clinical remission (Crohn's Disease Activity Index (CDAI) ≤150) and clinical response (≥100-point reduction in CDAI) within the first 6 weeks of treatment. We incorporated any assessment within this time point in a Bayesian random-effects NMA following PRISMA-NMA guidance (PROSPERO ID: CRD42022368509). RESULTS: Twenty-five studies, comprising 7414 patients, were included. Infliximab combined with azathioprine or monotherapy ranked highest for induction of clinical remission within 6 weeks and was significantly superior to certolizumab, ustekinumab, guselkumab, vedolizumab, and upadacitinib. However, superiority over risankizumab 600 mg and adalimumab 160/80 mg was non-significant. Accordingly, infliximab in combination with azathioprine and guselkumab 600 mg ranked highest in the corresponding analysis of clinical response with no statistical significance demonstrated. Among bio-exposed patients, none of whom received infliximab, upadacitinib, and risankizumab induced the highest clinical responses. On the other hand, vedolizumab, certolizumab, and ustekinumab ranked lowest across the analyses. CONCLUSIONS: We found infliximab to be ranked highest and superior to all other agents but risankizumab and adalimumab, demonstrating the highest probability of early induction of remission. Upadacitinib and risankizumab induced the highest clinical responses in bio-exposed patients. However, infliximab was not investigated in this population.

Influence of vitamin D receptor signaling and vitamin D on colonic epithelial cell fate decisions in ulcerative colitis.

BACKGROUND AND AIMS: Epidemiological studies have shown that subnormal levels of vitamin D (25(OH)D) are associated with a more aggravated clinical course of ulcerative colitis (UC). Despite an increased focus on the therapeutic importance of vitamin D and vitamin D receptor (VDR) signaling, the mechanisms underlying the effects of the vitamin D-VDR axis on UC remain elusive. Therefore, we aimed to investigate whether exposure to active vitamin D (1,25(OH)2D3)/VDR signaling in human organoids could influence the maintenance of the colonic epithelium. METHODS: Intestinal VDR expression was studied by immunohistochemistry, RNA expression arrays, and single-cell RNA sequencing of colonic biopsy specimens obtained from patients with UC and healthy individuals. To characterize the functional and transcriptional effects of 1,25(OH)2D3, we used patient-derived colonic organoids. The dependency of VDR was assessed by knocking out the receptor with CRISPR/Cas9. RESULTS: Our results suggest that 1,25(OH)2D3/VDR stimulation supports differentiation of the colonic epithelium and that impaired 1,25(OH)2D3/VDR signaling thereby may compromise the structure of the intestinal epithelial barrier, leading to flares of UC. Furthermore, a transcriptional response to VDR activity was observed primarily in fully differentiated cells at the top of the colonic crypt, and this response was reduced during flares of UC. CONCLUSIONS: We identified an important role of vitamin D signaling in supporting differentiated cell states in the human colonic epithelium, and thereby maintenance of the intestinal barrier integrity. This makes the vitamin D-VDR signaling axis an interesting target for therapeutic efforts to achieve and maintain remission in patients with UC.