Sara N. Horst

Functional Abdominal Pain in Childhood and Long-term Vulnerability to Anxiety Disorders

BACKGROUND: Cross-sectional studies link functional abdominal pain (FAP) to anxiety and depression in childhood, but no prospective study has evaluated psychiatric status in adulthood or its relation to pain persistence. METHODS: Pediatric patients with FAP (n = 332) and control subjects (n = 147) were tracked prospectively and evaluated for psychiatric disorders and functional gastrointestinal disorders (FGIDs) at follow-up in adolescence and young adulthood (mean age = 20.01 years). Participants were classified according to presence (FGID-POS) or absence (FGID-NEG) of FGIDs at follow-up. RESULTS: Lifetime and current risk of anxiety disorders was higher in FAP than controls (lifetime: 51% vs 20%; current: 30% vs 12%). Controlling for gender and age, the odds ratio was 4.9 (confidence interval = 2.83–7.43) for lifetime anxiety disorder and 3.57 (confidence interval = 2.00–6.36) for current anxiety disorder at follow-up for FAP versus controls. Lifetime risk of depressive disorder was significantly higher in FAP versus controls (40% vs. 16%); current risk did not differ. In most cases, initial onset of anxiety disorders was before pediatric FAP evaluation; onset of depressive disorders was subsequent to FAP evaluation. Within the FAP group, risk of current anxiety disorders at follow-up was significantly higher for FGID-POS versus FGID-NEG (40% vs 24%), and both were higher than controls (12%); current depressive disorders did not differ across FGID-POS, FGID-NEG, and controls. CONCLUSIONS: Patients with FAP carry long-term vulnerability to anxiety that begins in childhood and persists into late adolescence and early adulthood, even if abdominal pain resolves.

Somatic Complaints in Childhood Functional Abdominal Pain Are Associated With Functional Gastrointestinal Disorders in Adolescence and Adulthood

Objectives: Nongastrointestinal (non-GI) somatic complaints are common in children and adults with functional gastrointestinal disorders (FGIDs). The aim of the present study was to determine whether non-GI somatic complaints in children with functional abdominal pain (FAP) were associated with FGIDs in adolescence and young adulthood. Patients and Methods: In a prospective clinic-based study, children and adolescents (ages 8–16 years) with FAP (n = 188) and well controls (n = 61) completed a validated measure of somatic symptoms. Participants were assessed 4 to 15 years later (as older adolescents and young adults) for presence of current FGIDs as defined by the Rome III criteria. Results: Of the 188 youths with pediatric FAP, 35.6% met criteria for FGIDs at follow-up. Initial levels of non-GI somatic symptoms were significantly higher in pediatric FAP participants who subsequently met criteria for FGIDs at follow-up compared with controls and pediatric FAP participants who did not meet criteria for FGIDs at follow-up. Conclusions: The association of non-GI somatic symptoms with FAP in children may identify a group that is at risk for FGIDs later in life.

Predicting Persistence of Functional Abdominal Pain From Childhood Into Young Adulthood

BACKGROUND & AIMS Pediatric functional abdominal pain has been linked to functional gastrointestinal disorders (FGIDs) in adulthood, but little is known about patient characteristics in childhood that increase the risk for FGID in young adulthood. We investigated the contribution of gastrointestinal symptoms, extraintestinal somatic symptoms, and depressive symptoms in pediatric patients with functional abdominal pain and whether these predicted FGIDs later in life. METHODS In a longitudinal study, consecutive new pediatric patients, diagnosed with functional abdominal pain in a subspecialty clinic, completed a comprehensive baseline evaluation of the severity of their physical and emotional symptoms. They were contacted 5 to 15 years later and evaluated, based on Rome III symptom criteria, for abdominal pain-related FGIDs, including irritable bowel syndrome, functional dyspepsia, functional abdominal pain syndrome, and abdominal migraine. Controlling for age, sex, baseline severity of abdominal pain, and time to follow-up evaluation, multivariable logistic regression was used to evaluate the association of baseline gastrointestinal, extraintestinal somatic, and depressive symptoms in childhood with FGID in adolescence and young adulthood. RESULTS Of 392 patients interviewed an average of 9.2 years after their initial evaluation, 41% (n = 162) met symptom criteria for FGID; most met the criteria for irritable bowel syndrome. Extraintestinal somatic and depressive symptoms at the initial pediatric evaluation were significant predictors of FGID later in life, after controlling for initial levels of GI symptoms. Age, sex, and abdominal pain severity at initial presentation were not significant predictors of FGID later in life. CONCLUSIONS In pediatric patients with functional abdominal pain, assessment of extraintestinal and depressive symptoms may be useful in identifying those at risk for FGID in adolescence and young adulthood.

Natalizumab for moderate to severe Crohn's disease in clinical practice: The Mayo Clinic Rochester experience†

Background: Not all patients with Crohns disease (CD) respond or maintain response to anti‐tumor necrosis factor (TNF) agents and alternative treatment is necessary. Natalizumab, a monoclonal antibody to alpha‐4 integrin approved for CD, has demonstrated efficacy in randomized clinical trials. We describe our experience with natalizumab in clinical practice at Mayo Clinic Rochester. Methods: Consecutive patients prescribed natalizumab for active CD were invited to participate and were followed prospectively. Incidence of infection, hospitalization, neoplasm, or other adverse events were recorded. Clinical activity was assessed using the Harvey–Bradshaw Index at each 30‐day infusion visit. Results: Between April 2008 and September 2010, 36 patients were prescribed natalizumab and 30 (83.3%) agreed to participate. Median disease duration was 9 years (range, 3–43). Twenty‐three patients had prior exposure to two anti‐TNF agents, seven to one agent. All patients experienced at least one adverse event; none of the 13 patients in whom natalizumab was stopped (43%) discontinued due to adverse events. Five patients had infusions held for infection. No patient developed progressive multifocal leukoencephalopathy (PML). Fourteen patients (46%) had clinical response. The cumulative probability of achieving complete response within 1 year was 56% (28%–73%). Four of seven patients were weaned off corticosteroids. Conclusions: In our experience with natalizumab in clinical practice, adverse events were manageable and did not result in treatment cessation. No PML cases were seen and clinical response was similar to that in clinical trials. Natalizumab results in clinical benefit in patients who have active disease and have failed anti‐TNF therapy (Inflamm Bowel Dis 2012;)

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.

Outcomes following infliximab therapy for pediatric patients hospitalized with refractory colitis-predominant IBD.

Objectives: Although randomized trials demonstrated the efficacy of infliximab for both pediatric Crohn disease and ulcerative colitis (UC), few patients in these studies exhibited colitis requiring hospitalization. The aims of this study were to determine the rate of subsequent infliximab failure and dose escalation in pediatric patients who started taking infliximab during hospitalization for colitis-predominant IBD, and to identify potential predictors of these endpoints. Methods: This is a single-center retrospective cohort study of patients admitted from 2005 to 2010 with Crohn colitis, UC, or IBD-unspecified (IBD-U) and initiated on infliximab. Results: We identified 29 patients (12 Crohn colitis, 15 UC, and 2 IBD-U; median age 14 years) with a median follow-up of 923 days. Eighteen patients (62%) required infliximab dose escalation (increased dose or decreased infusion interval). Infliximab failure occurred in 18 patients (62%) because of ineffectiveness in 12 (67%) and adverse reactions in 6 (33%). Twelve patients (41%) underwent colectomy. Subsequent need for infliximab dose escalation was associated with lower body mass index z score (P = 0.01), lower serum albumin (P = 0.03), and higher erythrocyte sedimentation rate (ESR) (P = 0.002) at baseline. ESR predicted subsequent infliximab dose escalation with an area under the curve of 0.89 (95% confidence interval [CI] 0.72–1.00) and a sensitivity and specificity at a cutoff of 38 mm/hour of 0.79 (95% CI 0.49–0.95) and 0.88 (95% CI 0.47–0.99), respectively. Conclusions: Most hospitalized pediatric patients with colitis treated with infliximab require early-dose escalation and fail the drug long term. Low body mass index and albumin and high ESR, may identify patients who would benefit from a higher infliximab starting dose.

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.