Ellen J. Scherl

A Randomized Trial of Ustekinumab, a Human Interleukin-12/23 Monoclonal Antibody, in Patients With Moderate-to-Severe Crohn's Disease

BACKGROUND & AIMS Interleukin-12 and interleukin-23 are inflammatory cytokines implicated in Crohns disease pathophysiology. Ustekinumab is a monoclonal antibody against the p40 subunit of interleukin-12/23. METHODS We performed a double-blind, cross-over trial of the clinical effects of ustekinumab in 104 patients with moderate-to-severe Crohns disease (population 1). Patients were given subcutaneous placebo at weeks 0-3, then ustekinumab at weeks 8-11; subcutaneous ustekinumab at weeks 0-3, then placebo at weeks 8-11; intravenous placebo at week 0, then ustekinumab at week 8; or intravenous ustekinumab at week 0, then placebo at week 8. Furthermore, an open-label trial evaluated the effects of 4 weekly subcutaneous injections or 1 intravenous infusion of ustekinumab in 27 patients who were primary or secondary nonresponders to infliximab (population 2). RESULTS In population 1, clinical response rates for the combined groups given ustekinumab and placebo were 53% and 30% (P = .02), respectively at weeks 4 and 6, and 49% and 40% (P = .34), respectively at week 8. In a subgroup of 49 patients who were previously given infliximab (neither primary nor secondary nonresponders), clinical response to ustekinumab was significantly greater than the group given placebo (P < .05) through week 8. In population 2, the clinical responses at week 8 to subcutaneous and intravenous ustekinumab were 43% and 54%, respectively. There was no increase in the number of adverse or serious adverse events in patients given ustekinumab through week 8 compared with placebo. CONCLUSIONS Ustekinumab induced a clinical response in patients with moderate-to-severe Crohns disease, especially in patients previously given infliximab.

Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn's disease involving the ileum

Intestinal bacteria are implicated increasingly as a pivotal factor in the development of Crohns disease, but the specific components of the complex polymicrobial enteric environment driving the inflammatory response are unresolved. This study addresses the role of the ileal mucosa-associated microflora in Crohns disease. A combination of culture-independent analysis of bacterial diversity (16S rDNA library analysis, quantitative PCR and fluorescence in situ hybridization) and molecular characterization of cultured bacteria was used to examine the ileal mucosa-associated flora of patients with Crohns disease involving the ileum (13), Crohns disease restricted to the colon (CCD) (8) and healthy individuals (7). Analysis of 16S rDNA libraries constructed from ileal mucosa yielded nine clades that segregated according to their origin (P<0.0001). 16S rDNA libraries of ileitis mucosa were enriched in sequences for Escherichia coli (P<0.001), but relatively depleted in a subset of Clostridiales (P<0.05). PCR of mucosal DNA was negative for Mycobacterium avium subspecies paratuberculosis, Shigella and Listeria. The number of E. coli in situ correlated with the severity of ileal disease (ρ 0.621, P<0.001) and invasive E. coli was restricted to inflamed mucosa. E. coli strains isolated from the ileum were predominantly novel in phylogeny, displayed pathogen-like behavior in vitro and harbored chromosomal and episomal elements similar to those described in extraintestinal pathogenic E. coli and pathogenic Enterobacteriaceae. These data establish that dysbiosis of the ileal mucosa-associated flora correlates with an ileal Crohns disease (ICD) phenotype, and raise the possibility that a selective increase in a novel group of invasive E. coli is involved in the etiopathogenesis to Crohns disease involving the ileum.

CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22

Intestinal CX3CR1+ mononuclear phagocytes regulate ILC3 in vivo in response to colitis associated microbial signals.

Microsomal Prostaglandin E Synthase-1 Is Overexpressed in Inflammatory Bowel Disease EVIDENCE FOR INVOLVEMENT OF THE TRANSCRIPTION FACTOR Egr-1

Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the conversion of cyclooxygenase-derived prostaglandin (PG) H2 to PGE2. Increased amounts of mPGES-1 were detected in inflamed intestinal mucosa from patients with inflammatory bowel disease (IBD). Treatment with tumor necrosis factor (TNF)-α stimulated mPGES-1 transcription in human colonocytes, resulting in increased amounts of mPGES-1 mRNA and protein. The inductive effect of TNF-α localized to the GC box region of the mPGES-1 promoter. Binding of Egr-1 to the GC box region of the mPGES-1 promoter was enhanced by treatment with TNF-α. Notably, increased Egr-1 expression and binding activity were also detected in inflamed mucosa from IBD patients. Treatment with TNF-α induced the activities of phosphatidylcholine-phospholipase C (PC-PLC) and protein kinase (PK) C and enhanced NO production. A pharmacological approach was used to implicate PC-PLC → PKC → NO signaling as being important for the induction of mPGES-1 by TNF-α. TNF-α also enhanced guanylate cyclase activity and inhibitors of guanylate cyclase activity blocked the induction of mPGES-1 by TNF-α. YC-1, an activator of guanylate cyclase, induced mPGES-1. Overexpressing a dominant negative form of PKG blocked TNF-α-mediated stimulation of the mPGES-1 promoter. Taken together, these results suggest that overexpression of mPGES-1 in IBD is the result of Egr-1-mediated activation of transcription. Moreover, TNF-α induced mPGES-1 by stimulating PC-PLC → PKC → NO → cGMP → PKG signal transduction pathway.

Bacteremia after endoscopic injection sclerosis

Endoscopic injection sclerosis is a therapeutic alternative in the management of esophageal varices. Complications of sclerotherapy have been minor, including fever, bacteremia, and abnormal chest x-ray. We performed a prospective study to evaluate the frequency of postsclerosis bacteremia. Bacteremia was detected in 14 procedures (50%). There were no cases of bacteremia in a group of control patients with esophageal varices undergoing upper gastrointestinal endoscopy without sclerosis (p less than 0.05). Bacteremia was transient and unrelated to the presence of fever or other clinical complications. The organism most commonly cultured from blood, alpha-hemolytic streptococcus, probably represents a contaminant from the oropharynx, introduced into the bloodstream during sclerosis. We conclude that injection sclerotherapy of esophageal varices is associated with a higher incidence of bacteremia than routine upper endoscopy and that selected patients may require antibiotic prophylaxis when undergoing this procedure.

Inflammation Drives Dysbiosis and Bacterial Invasion in Murine Models of Ileal Crohn’s Disease

Background and Aims Understanding the interplay between genetic susceptibility, the microbiome, the environment and the immune system in Crohn’s Disease (CD) is essential for developing optimal therapeutic strategies. We sought to examine the dynamics of the relationship between inflammation, the ileal microbiome, and host genetics in murine models of ileitis. Methods We induced ileal inflammation of graded severity in C57BL6 mice by gavage with Toxoplasma gondii, Giardia muris, low dose indomethacin (LDI;0.1 mg/mouse), or high dose indomethacin (HDI;1 mg/mouse). The composition and spatial distribution of the mucosal microbiome was evaluated by 16S rDNA pyrosequencing and fluorescence in situ hybridization. Mucosal E. coli were enumerated by quantitative PCR, and characterized by phylogroup, genotype and pathotype. Results Moderate to severe ileitis induced by T. gondii (day 8) and HDI caused a consistent shift from >95% Gram + Firmicutes to >95% Gram - Proteobacteria. This was accompanied by reduced microbial diversity and mucosal invasion by adherent and invasive E. coli, mirroring the dysbiosis of ileal CD. In contrast, dysbiosis and bacterial invasion did not develop in mice with mild ileitis induced by Giardia muris. Superimposition of genetic susceptibility and T. Gondii infection revealed greatest dysbiosis and bacterial invasion in the CD-susceptible genotype, NOD2−/−, and reduced dysbiosis in ileitis-resistant CCR2−/− mice. Abrogating inflammation with the CD therapeutic anti-TNF-α-mAb tempered dysbiosis and bacterial invasion. Conclusions Acute ileitis induces dysbiosis and proliferation of mucosally invasive E. coli, irrespective of trigger and genotype. The identification of CCR2 as a target for therapeutic intervention, and discovery that host genotype and therapeutic blockade of inflammation impact the threshold and extent of ileal dysbiosis are of high relevance to developing effective therapies for CD.

Inflammatory bowel disease in patients with celiac disease

Background: Several case reports and series report an association between celiac disease and inflammatory bowel disease (IBD); however, there is no current data assessing this association. We therefore studied the occurrence of these conditions in a cohort of patients with celiac disease seen at a referral center. Methods: A database of patients with celiac disease seen between 1981 and 2002 was analyzed. Only biopsy‐proven adults were included. Patients who had endoscopic and pathologic evidence of IBD were identified, and their pathology was reviewed. Age‐ and sex‐adjusted prevalence rate ratios were determined by comparing results with population‐based prevalence data. Results: Among 455 patients with celiac disease, IBD was identified in 10 (5 had ulcerative colitis and 5 had Crohns disease). This represented an age‐ and sex‐adjusted prevalence rate ratio for ulcerative colitis of 3.56 (95% confidence interval, 1.48‐8.56) and for Crohns disease of 8.49 (95% confidence interval, 3.53‐20.42). Conclusion: Within our cohort of patients with celiac disease, IBD was significantly more common than in the general population.

Crohn's disease is associated with restless legs syndrome

Background: Extraintestinal manifestations of Crohns disease (CD) have not previously included the central nervous system (CNS). Restless legs syndrome (RLS) is a CNS disorder that is either idiopathic or secondary to a number of diseases. The aim of this study was to determine if RLS was associated with CD because both are associated with iron deficiency, inflammation, and bacterial overgrowth. Methods: Consecutive CD outpatients (N = 272) were prospectively surveyed at 4 centers for criteria for RLS. Incidence (having RLS at any point in time), prevalence (having RLS at time of survey), clinical characteristics, risk factors, and potential qualitative relationship between RLS and gastrointestinal symptoms were queried. Results: The incidence of RLS in patients with CD was 42.7%. Prevalence was 30.2% compared with 9% of spouses. CD patients with and without RLS had a mean age of 46.8 versus 42.6 years, small intestine involvement in 77.9% versus 66.7%, colon involvement in 39.7% versus 63.2%, and prior iron deficiency anemia in 49.3% versus 33.1%. There was no difference between the CD groups with respect to current iron deficiency, RLS family history, or rare prevalence of concomitant RLS disorders. In 91.8% of patients with RLS and CD, RLS started during or after the onset of CD diagnosis. Among 73 patients with RLS, 67 (44.5%) stated there was a relationship between qualitative RLS symptom improvement with overall CD symptom improvement. Conclusions: These results demonstrate that RLS occurs frequently in CD and appears to be a possible extraintestinal manifestation. The potential relationship of RLS with CD activity warrants further investigation. (Inflamm Bowel Dis 2009;)

Inflammation-associated adherent-invasive Escherichia coli are enriched in pathways for use of propanediol and iron and M-cell translocation.

Background:Perturbations of the intestinal microbiome, termed dysbiosis, are linked to intestinal inflammation. Isolation of adherent-invasive Escherichia coli (AIEC) from intestines of patients with Crohns disease (CD), dogs with granulomatous colitis, and mice with acute ileitis suggests these bacteria share pathoadaptive virulence factors that promote inflammation. Methods:To identify genes associated with AIEC, we sequenced the genomes of phylogenetically diverse AIEC strains isolated from people with CD (4), dogs with granulomatous colitis (2), and mice with ileitis (2) and 1 non-AIEC strain from CD ileum and compared them with 38 genome sequences of E. coli and Shigella. We then determined the prevalence of AIEC-associated genes in 49 E. coli strains from patients with CD and controls and correlated genotype with invasion of intestinal epithelial cells, persistence within macrophages, AIEC pathotype, and growth in standardized conditions. Results:Genes encoding propanediol utilization (pdu operon) and iron acquisition (yersiniabactin, chu operon) were overrepresented in AIEC relative to nonpathogenic E. coli. PduC (propanediol dehydratase) was enriched in CD-derived AIEC, correlated with increased cellular invasion, and persistence in vitro and was increasingly expressed in fucose-containing media. Growth of AIEC required iron, and the presence of chuA (heme acquisition) correlated with persistence in macrophages. CD-associated AIEC with lpfA154 (long polar fimbriae) demonstrated increased invasion of epithelial cells and translocation across M cells. Conclusions:Our findings provide novel insights into the genetic basis of the AIEC pathotype, supporting the concept that AIEC are equipped to exploit and promote intestinal inflammation and reveal potential targets for intervention against AIEC and inflammation-associated dysbiosis.

Prophylaxis against Pneumocystis pneumonia in patients with inflammatory bowel disease: toward a standard of care.

Patients with Crohns Disease and ulcerative colitis are increasingly treated with a host of immunomodulatory and immunosuppressive medications, including thiopurines and antibody‐based biologic agents. Despite the known infectious complications associated with these therapies from the HIV and solid organ transplant literature, there are currently no well‐defined concise guidelines to assist gastroenterologists and other physicians in the utility and indication for prophylaxis against Pneumocystis pneumonia and other infections in inflammatory bowel disease (IBD) patients. In this article, we discuss the evidence of various infections associated with immunocompromise in HIV/AIDS, organ transplantation, and in other immunocompromised states, and discuss the evidence for the efficacy and safety of various infectious prophylaxis protocols. In addition, we discuss the evidence for Pneumocystis and other infections in IBD patients treated with corticosteroids, azathioprine/6‐MP, biologic agents and other therapies, and we present the case for various antibiotic (and antiviral) regimens to prevent such infections. Based on the review of the literature, this discussion represents a true call for guidelines for infection prophylaxis, to help guide gastroenterologists and all practitioners who care for the challenging population of IBD patients.