Dawn B. Beaulieu

Inflammatory bowel disease in pregnancy.

Crohns disease and ulcerative colitis affect women in their child-bearing years. Family planning has come to be a common discussion between the gastroenterologist and the inflammatory bowel disease (IBD) patient. Disease control prior to desired conception and throughout pregnancy is the most important thing to keep in mind when caring for the IBD patient. Continued medical management during pregnancy is crucial in optimizing outcomes. Studies indicate that quiescent disease prior to conception infer the best pregnancy outcomes, similar to those in the general population. Active disease prior to and during pregnancy, can lead to complications such as pre-term labor, low birth weight, and small for gestational age infants. Although there are no definitive long term effects of pregnancy on IBD, there are some limited studies that suggest that it may alter the disease course. Understanding the literature and its limitations is important in the modern era of IBD care. Educating the patient and taking a team approach with the obstetrician will help achieve successful outcomes for mother and baby.

Patients with Refractory Crohn's Disease Successfully Treated with Ustekinumab.

Background:Ustekinumab is a new biologic therapy targeting interleukin-12 and interleukin -23. It is currently approved for the treatment of psoriasis, but clinical trials have shown that it can induce and maintain remission in Crohns disease (CD). We aim to evaluate effectiveness of ustekinumab in the treatment of CD. Methods:A retrospective chart review was performed including patients (pts) from 2 academic medical centers with complicated, refractory CD started on ustekinumab between June 2011 and June 2014. Pts were treated based on a novel subcutaneous dosing schedule designed to simulate the intravenous load used in clinical trials. Results:Forty-five pts were treated with ustekinumab during this study period. Of the pts who had clinical parameters available before and after medication start, 46% achieved clinical response (Harvey–Bradshaw index decrease ≥3) and 35% achieved clinical remission (Harvey–Bradshaw index ⩽3). Short inflammatory bowel disease questionnaire scores increased significantly (46 [20, 68] to 55 [32, 70], P < 0.05). Erythrocyte sedimentation rate decreased significantly (20 [3, 54] to 12 [0, 42] mm/h, P < 0.05). C-reactive protein decreased significantly (4.9 [0.3, 111] to 3.3 [0.2, 226] mg/L, P < 0.05). Seventy-six percent of patients demonstrated an endoscopic response and 24% achieved complete endoscopic remission. Twelve patients (26%) were hospitalized for IBD-related issues. Four pts had infection-related complications. Six pts (13%) underwent surgery for IBD-related issues. Three pts stopped ustekinumab, 1 for pt preference and 2 for the lack of response. Conclusions:Using a novel subcutaneous dosing schedule, ustekinumab was successful in improving clinical, laboratory, and endoscopic markers of disease activity in patients with severe, refractory CD.

High-throughput multi-analyte Luminex profiling implicates eotaxin-1 in ulcerative colitis.

Accurate and high-throughput technologies are needed for identification of new therapeutic targets and for optimizing therapy in inflammatory bowel disease. Our aim was to assess multi-analyte protein-based assays of cytokines/chemokines using Luminex technology. We have reported that Luminex-based profiling was useful in assessing response to L-arginine therapy in the mouse model of dextran sulfate sodium colitis. Therefore, we studied prospectively collected samples from ulcerative colitis (UC) patients and control subjects. Serum, colon biopsies, and clinical information were obtained from subjects undergoing colonoscopy for evaluation of UC or for non-UC indications. In total, 38 normal controls and 137 UC cases completed the study. Histologic disease severity and the Mayo Disease Activity Index (DAI) were assessed. Serum and colonic tissue cytokine/chemokine profiles were measured by Luminex-based multiplex testing of 42 analytes. Only eotaxin-1 and G-CSF were increased in serum of patients with histologically active UC vs. controls. While 13 cytokines/chemokines were increased in active UC vs. controls in tissues, only eotaxin-1 was increased in all levels of active disease in both serum and tissue. In tissues, eotaxin-1 correlated with the DAI and with eosinophil counts. Increased eotaxin-1 levels were confirmed by real-time PCR. Tissue eotaxin-1 levels were also increased in experimental murine colitis induced by dextran sulfate sodium, oxazolone, or Citrobacter rodentium, but not in murine Helicobacter pylori infection. Our data implicate eotaxin-1 as an etiologic factor and therapeutic target in UC, and indicate that Luminex-based assays may be useful to assess IBD pathogenesis and to select patients for anti-cytokine/chemokine therapies.

Durability of Infliximab in Crohn's Disease: A Single-Center Experience

Background: Infliximab is effective maintenance for moderate to severe Crohns disease (CD); however, problems with immunogenicity and decreased efficacy often complicate long‐term use. Durability of infliximab maintenance therapy over multiple years has not been defined. Methods: This was a retrospective, observational study of CD patients who received maintenance infliximab for ≥1 year with the intention of ongoing maintenance. Patients were categorized into those who either discontinued treatment or continued maintenance therapy. We examined the impact of demographic, clinical characteristics, and prior episodic exposure on long‐term durability of infliximab therapy and also examined the reasons for discontinuation of therapy. Results: A total of 153 CD patients received maintenance infliximab treatment beyond 1 year and 42 (27%) ultimately discontinued treatment. The mean duration of maintenance treatment at the time of discontinuation was 42.4 ± 19.1 months compared to a follow‐up period of 49.4 ± 19.8 months in the cohort continuing therapy (P = 0.049). The main reasons for discontinuation were allergy/adverse reaction (44.2%) and decreased efficacy (38.2%). Use of concomitant immunosuppression was similar between the 2 groups (78.6% versus 83.8%, P = NS). However, the discontinued group had a higher rate of prior episodic dosing compared to CD patients who continued maintenance (28.8% versus 11.7%, P = 0.025), while there was no difference in the rate of intensified dosing (57.2% versus 50.5%, P = NS). Conclusions: One‐quarter of CD patients on long‐term infliximab maintenance discontinued treatment. A history of prior episodic dosing was significantly associated with infliximab discontinuation, despite concomitant immunosuppression. These data emphasize the need for optimization of infliximab for successful long‐term management. Inflamm Bowel Dis 2009

MTG16 contributes to colonic epithelial integrity in experimental colitis

Objective The myeloid translocation genes (MTGs) are transcriptional corepressors with both Mtg8−/− and Mtgr1−/− mice showing developmental and/or differentiation defects in the intestine. We sought to determine the role of MTG16 in intestinal integrity. Methods Baseline and stress induced colonic phenotypes were examined in Mtg16−/− mice. To unmask phenotypes, we treated Mtg16−/− mice with dextran sodium sulphate (DSS) or infected them with Citrobacter rodentium and the colons were examined for ulceration and for changes in proliferation, apoptosis and inflammation. Results Mtg16−/− mice have altered immune subsets, suggesting priming towards Th1 responses. Mtg16−/− mice developed increased weight loss, diarrhoea, mortality and histological colitis and there were increased innate (Gr1+, F4/80+, CD11c+ and MHCII+; CD11c+) and Th1 adaptive (CD4) immune cells in Mtg16−/− colons after DSS treatment. Additionally, there was increased apoptosis and a compensatory increased proliferation in Mtg16−/− colons. Compared with wild-type mice, Mtg16−/− mice exhibited increased colonic CD4;IFN-γ cells in vehicle-treated and DSS-treated mice. Adoptive transfer of wild-type marrow into Mtg16−/− recipients did not rescue the Mtg16−/− injury phenotype. Isolated colonic epithelial cells from DSS-treated Mtg16−/− mice exhibited increased KC (Cxcl1) mRNA expression when compared with wild-type mice. Mtg16−/− mice infected with C rodentium had more severe colitis and greater bacterial colonisation. Last, MTG16 mRNA levels were reduced in human ulcerative colitis versus normal colon tissues. Conclusions These observations indicate that MTG16 is critical for colonocyte survival and regeneration in response to intestinal injury and provide evidence that this transcriptional corepressor regulates inflammatory recruitment in response to injury.

Association Between Affective-Cognitive Symptoms of Depression and Exacerbation of Crohn’s Disease

OBJECTIVES:The prevalence of depression is high in patients with Crohn’s disease (CD). We examined the influence of affective-cognitive symptoms of depression on the risk of exacerbation of CD.METHODS:We studied 2,144 adult volunteers with a self-reported diagnosis of CD who completed a baseline survey that included demographics, CD status, and an affective-cognitive index of depression. Linear and logistic regression analyses were used to determine whether CD status at 12 months was associated with the baseline measure of depression. Analyses were adjusted for confounders including age, gender, race, baseline disease activity, disease duration, prior hospitalization and surgery, corticosteroid and anti-TNF use, medication adherence, body mass index, current smoking, education, and sleep quality.RESULTS:Depression was significantly associated with subsequent increases in SCDAI score in both unadjusted (P<0.001) and adjusted (P<0.001) analyses. This association was non-linear, with a shallower slope for lower levels of depression. A 10-point increase in depression t-scores from 55 to 65 was associated with a 18.6-point increase in SCDAI (95% CI 11.5–25.6) and an odds ratio of 1.27 for SCDAI>150 at follow-up (CI: 1.01–1.60). We also found a significant association between depressive symptoms and hospitalization.CONCLUSIONS:Cognitive-affective depressive symptoms were significantly associated with a risk of exacerbation of CD and hospitalization.

Use of Endoscopic Ultrasound to Guide Adalimumab Treatment in Perianal Crohn's Disease Results in Faster Fistula Healing

Background:Perianal disease is a manifestation of Crohns disease (CD) that has poor long-term treatment outcomes. The aim was to determine if rectal endoscopic ultrasound (EUS)–guided therapy with adalimumab (ADA) can improve outcomes for patients with perianal fistulizing CD. Methods:This is a randomized prospective study comparing serial EUS guidance of fistula treatment versus standard of care in fistulizing perianal CD. At enrollment, all patients underwent a rectal EUS and an EUA with seton placement and/or I&D. Treatment was maximized with immunomodulators, antibiotics, and ADA induction. Surgical interventions were determined by the surgeons discretion in the control group and assisted by every 12th week EUS in the intervention group. Primary and secondary endpoints where complete drainage cessation at week 48 was fistula status per EUS, respectively. Results:Twenty patients were enrolled: 11 control and 9 EUS guidance. At 24 weeks, 7/9 (78%) in EUS group and 3/11 (27%) in control group had drainage cessation (P = 0.04). This significant difference was lost at week 48 (P = 0.44). Three patients in the EUS and 1 in the control group had additional surgical intervention. Those in the EUS group had more rapid escalation of ADA dosing (P = 0.003). There was no difference in the change in PDAI at week 48 versus baseline (P = 0.81). Conclusions:Rectal EUS-guided ADA therapy for CD perianal fistulas showed an initial benefit at 24 weeks, which was lost at week 48. This is likely due to small sample size and higher fistula closure in the controls. However, the faster rate of fistula resolution is a clinically significant finding.

2 Pregnancy Outcomes Amongst Mothers With Inflammatory Bowel Disease Exposed to Systemic Corticosteroids: Results of the PIANO Registry

Introduction: IBD in the mother is associated with higher rates of adverse pregnancy outcomes. However, long-term effects of maternal IBD on childhood growth and development are not known. The aim of this study was to determine the impact of IBD medication exposure in utero on newborn developmental milestones. Methods: We created a prospective cohort of pregnant women at 30 US IBD centers to follow patients through pregnancy and first four years of a childs life. We ascertained IBD medications and disease activity during gestation, complications of pregnancy and delivery, and achievement of developmental milestones. Patients were classified by exposure to drugs taken between conception and delivery: 6MP/Azathioprine (Group A), infliximab, adalimumab, certolizumab (Group B), combination therapy (Group AB). We compared these groups to women who did not take any Group A or B drugs. Developmental milestones achieved by the infant, based on Denver Childhood Developmental Score, were measured by the mother at months 4, 9 and 12 and by the validated Ages and Stages Questionnaire at 1,2,3 and 4 years of age. Follow up is ongoing. Results: 1289 women are enrolled in the study as of Nov 12 2013: 1097 have completed pregnancy, 1039 with live births. There were 215 live births in Group A, 364 in Group B, 137 in Group AB and 323 to unexposed mothers. When compared to the unexposed infants, infants in Group A, B and AB always had equivalent or better achievement of milestones. These results were unchanged when controlled for maternal income and education level. Table 1 lists the milestones in which the exposed infants had better outcomes that the unexposed. Conclusions: Infants with in utero exposure to immunomodulator and biologic therapy did not exhibit developmental delay compared to infants not exposed to these agents, controlling for preterm birth. Overall, developmental scores were similar between exposed and unexposed infants, and scores of exposed infants were slightly higher in some categories. Significant Differences in Developmental Milestones by Drug Exposure

Serum Fatty Acids Are Correlated with Inflammatory Cytokines in Ulcerative Colitis

Background and Aims Ulcerative colitis (UC) is associated with increased dietary intake of fat and n-6 polyunsaturated fatty acids (PUFA). Modification of fat metabolism may alter inflammation and disease severity. Our aim was to assess differences in dietary and serum fatty acid levels between control and UC subjects and associations with disease activity and inflammatory cytokines. Methods Dietary histories, serum, and colonic tissue samples were prospectively collected from 137 UC subjects and 38 controls. Both histologic injury and the Mayo Disease Activity Index were assessed. Serum and tissue cytokines were measured by Luminex assay. Serum fatty acids were obtained by gas chromatography. Results UC subjects had increased total fat and oleic acid (OA) intake, but decreased arachidonic acid (AA) intake vs controls. In serum, there was less percent saturated fatty acid (SFA) and AA, with higher monounsaturated fatty acids (MUFA), linoleic acid, OA, eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA) in UC. Tissue cytokine levels were directly correlated with SFA and inversely correlated with PUFA, EPA, and DPA in UC subjects, but not controls. 5-aminosalicylic acid therapy blunted these associations. Conclusions In summary, we found differences in serum fatty acids in UC subjects that correlated with pro-inflammatory tissue cytokines. We propose that fatty acids may affect cytokine production and thus be immunomodulatory in UC.

Use of Biologic Therapy by Pregnant Women With Inflammatory Bowel Disease Does Not Affect Infant Response to Vaccines

BACKGROUND & AIMS: In women with inflammatory bowel diseases (IBDs), exposure to immunomodulator or biologic therapy has not been associated with adverse events during pregnancy or outcomes of newborns. We investigated whether exposure of patients to these agents during pregnancy affects serologic responses to vaccines in newborns. METHODS: We collected data from the Pregnancy in IBD and Neonatal Outcomes registry, which records outcomes of pregnant women with diagnosis of IBD receiving care at multiple centers in the United States, from 2007 through 2016. Serum samples collected from infants at least 7 months old were analyzed for titers of antibodies to Haemophilus influenzae B (HiB) or tetanus toxin; mothers completed a survey of vaccine practices and outcomes from July 2013 through October 2016. Umbilical cord blood samples from 33 infants were assayed for concentration of biologic agents. Vaccination response was compared between infants born to mothers exposed to biologic therapy (infliximab, adalimumab, certolizumab pegol, golimumab, natalizumab, vedolizumab, or ustekinumab—either as a single agent or in combination with an immunomodulator, at any time between conception and delivery) and infants born to unexposed mothers. RESULTS: A total of 179 women completed the vaccine survey (26 biologic unexposed, 153 exposed to a biologic agent). We found no significant difference in proportions of infants with protective antibody titers against HiB born to exposed mothers (n = 42, 71%) vs unexposed mothers (n = 8, 50%) (P = .41). We also found no difference in the proportion of infants with protective antibody titers to tetanus toxoid born to exposed mothers (80%) vs unexposed mothers (75%) (P = .66). The median concentration of infliximab in cord blood did not differ significantly between infants with vs without protective antibody titers to HiB (P = .30) or tetanus toxoid (P = .93). Mild reactions were observed in 7/40 infants who received rotavirus vaccine and whose mothers had been exposed to biologic therapies. CONCLUSIONS: Vaccination of infants against HiB and tetanus toxin, based on antibody titers measured when infants were at least 7 months old, does not appear to be affected by in utero exposure to biologic therapy.