Kirstin Taylor

Altered intestinal microbiota and blood T cell phenotype are shared by patients with Crohn's disease and their unaffected siblings

Objective Crohns disease (CD) is associated with intestinal dysbiosis, altered blood T cell populations, elevated faecal calprotectin (FC) and increased intestinal permeability (IP). CD-associated features present in siblings (increased risk of CD) but not in healthy controls, provide insight into early CD pathogenesis. We aimed to (1) Delineate the genetic, immune and microbiological profile of patients with CD, their siblings and controls and (2) Determine which factors discriminate between groups. Design Faecal microbiology was analysed by quantitative PCR targeting 16S ribosomal RNA, FC by ELISA, blood T cell phenotype by flow cytometry and IP by differential lactulose-rhamnose absorption in 22 patients with inactive CD, 21 of their healthy siblings and 25 controls. Subjects genotype relative risk was determined by Illumina Immuno BeadChip. Results Strikingly, siblings shared aspects of intestinal dysbiosis with patients with CD (lower concentrations of Faecalibacterium prausnitzii (p=0.048), Clostridia cluster IV (p=0.003) and Roseburia spp. (p=0.09) compared with controls). As in CD, siblings demonstrated a predominance of memory T cells (p=0.002) and elevated naïve CD4 T cell β7 integrin expression (p=0.01) compared with controls. FC was elevated (>50 μg/g) in 8/21 (38%) siblings compared with 2/25 (8%) controls (p=0.028); whereas IP did not differ between siblings and controls. Discriminant function analysis determined that combinations of these factors significantly discriminated between groups (χ2=80.4, df=20, p<0.001). Siblings were separated from controls by immunological and microbiological variables. Conclusions Healthy siblings of patients with CD manifest immune and microbiological abnormalities associated with CD distinct from their genotype-related risk and provide an excellent model in which to investigate early CD pathogenesis.

Optimization of conventional therapy in patients with IBD

The majority of patients with IBD use conventional therapy (namely, aminosalicylates, antibiotics, corticosteroids and immunomodulatory agents) for prolonged periods of time, to both induce and maintain remission. Treatment paradigms in IBD have evolved towards a rapid escalation of therapy to achieve stringent goals, including mucosal healing and a reduction in the need for hospital admission and surgery. In this context, the failure to optimize conventional therapy can lead to a potentially effective treatment being abandoned too early, which is undesirable when only a limited number of drugs are effective in the management of IBD, and could also lead to patients being unnecessarily exposed to potentially toxic and/or expensive biologic drugs. This Review provides an overview of the many ways in which conventional therapy can be optimized, and describes strategies to improve adherence to drug regimens, such as simplifying the dosing regimen, optimizing drug delivery and dose, and tailoring medication on the basis of metabolite levels.

A role for gut-associated lymphoid tissue in shaping the human B cell repertoire

Transitional 2 B cells home to gut-associated lymphoid tissue and present an activated phenotype in healthy subjects, but gut immune compartments are depleted in SLE.

Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes

The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn’s disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10−10, OR = 2.3[95% CI = 1.75–3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1–5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.

UK national curriculum for undergraduate oral surgery subgroup for teaching of the Association of British Academic Oral and Maxillofacial Surgeons

This article describes a curriculum in oral surgery for undergraduate dental education in the United Kingdom prepared by the Education Subgroup of The British Academic Oral and Maxillofacial Surgeons. This group is made up of representatives from each of the 13 UK Dental Schools, one Irish Dental School and one Post-graduate Institute. The document represents a group consensus of an undergraduate UK oral surgery curriculum that is founded on the frameworks outlined by the General Dental Council, the Quality Assurance Agency for Higher Education and the Association for Dental Education in Europe. Our curriculum document is more prescriptive than the information available in the aforementioned documents. It is based on UK undergraduate oral surgery experience and thus attempts to set achievable core competencies and, in a few areas, challenges the available curriculum and related documentation.

Clinical evidence for allergy in orofacial granulomatosis and inflammatory bowel disease

BackgroundOrofacial granulomatosis (OFG) causes chronic, disfiguring, granulomatous inflammation of the lips and oral mucosa. A proportion of cases have co-existing intestinal Crohn’s disease (CD). The pathogenesis is unknown but has recently been linked to dietary sensitivity. Although allergy has been suggested as an aetiological factor in OFG there are few published data to support this link. In this study, we sought clinical evidence of allergy in a series of patients with OFG and compared this to a series of patients with inflammatory bowel disease (IBD) without oral involvement and to population control estimates.MethodsPrevalence rates of allergy and oral allergy syndrome (OAS) were determined in 88 patients with OFG using questionnaires, skin prick tests, total and specific serum IgE levels. Allergy was also determined in 117 patients with IBD without evidence of oral involvement (79 with CD and 38 with ulcerative colitis (UC)).ResultsPrevalence rates of allergy in patients with OFG were significantly greater than general population estimates (82% versus 22% respectively p = <0.0005). Rates of allergy were also greater in those with CD (39%) and, interestingly, highest in those with OFG and concurrent CD (87%). Conversely, whist OAS was common in allergic OFG patients (35%) rates of OAS were significantly less in patients with concomitant CD (10% vs 44% with and without CD respectively p = 0.006). Amongst CD patients, allergy was associated with perianal disease (p = 0.042) but not with ileal, ileocolonic or colonic disease location. Allergy in UC (18%) was comparable to population estimates.ConclusionWe provide compelling clinical evidence for the association of allergy with OFG whether occurring alone or in association with CD. The presence of gut CD increases this association but, conversely, reduces the expression of OAS in those with atopy. Interestingly, there is no evidence of increased allergy in UC.

A generic consensus assessment of undergraduate competence in forceps exodontia in the United Kingdom

UNLABELLED The assessment of competence in clinical skills has become more frequent in published healthcare curricula and syllabuses recently. There are agreed mechanisms for the assessment of competence in the post-graduate environment, but no consensus within the undergraduate curriculum. This paper seeks to develop an agreed generic checklist for the assessment of competence in forceps exodontia. MATERIALS AND METHODS A modified Delphi process was undertaken with representatives from all UK dental schools (n = 13) to develop a generic checklist for the assessment of competence in forceps exodontia. A content analysis of the assessments employed by each school was used to help discussion and inform the Delphi process. RESULTS Seven schools currently employ a summative assessment of competence in forceps exodontia, with the majority employing a structured clinical objective test (n = 6). From the seven assessments, there were a total of 29 putative items and 10 putative domains identified for a generic checklist. These were reduced to five domains and 19 items through the content analysis and Delphi process, and a generic overarching checklist was created. CONCLUSION Using this generic checklist, it may now be possible to pool data inter-institution to perform more powerful analyses on how our students obtain, or fail to obtain competence in forceps exodontia.

Gastrointestinal ultrasound in inflammatory bowel disease: an underused resource with potential paradigm-changing application

Evolution of treatment targets in IBD has increased the need for objective monitoring of disease activity to guide therapeutic strategy. Although mucosal healing is the current target of therapy in IBD, endoscopy is invasive, expensive and unappealing to patients. GI ultrasound (GIUS) represents a non-invasive modality to assess disease activity in IBD. It is accurate, cost-effective and reproducible. GIUS can be performed at the point of care without specific patient preparation so as to facilitate clinical decision-making. As compared with ileocolonoscopy and other imaging modalities (CT and MRI), GIUS is accurate in diagnosing IBD, detecting complications of disease including fistulae, strictures and abscesses, monitoring disease activity and detecting postoperative disease recurrence. International groups increasingly recognise GIUS as a valuable tool with paradigm-changing application in the management of IBD; however, uptake outside parts of continental Europe has been slow and GIUS is underused in many countries. The aim of this review is to present a pragmatic guide to the positioning of GIUS in IBD clinical practice, providing evidence for use, algorithms for integration into practice, training pathways and a strategic implementation framework.

Genetic Association Analysis Reveals Differences in the Contribution of NOD2 Variants to the Clinical Phenotypes of Orofacial Granulomatosis.

Background:Orofacial granulomatosis (OFG) is a rare, inflammatory disorder of the mouth, in which some patients also have intestinal Crohns disease (CD). The etiology remains largely unknown, although there is a high prevalence of atopy, and oral granulomas are also seen in other immune disorders particularly CD and sarcoidosis. We investigated whether genetic variants associated with an increased risk of CD, sarcoidosis, or atopy were also associated with susceptibility to OFG. Methods:Patients were stratified clinically as isolated oral manifestations (OFG only) or concurrent intestinal CD (OFG+CD). We genotyped 201 patients and 1023 healthy controls for risk variants in NOD2, IRGM, IL23R, ATG16L1 (CD), BTNL2 (sarcoidosis), and FLG (atopy). The coding regions of the NOD2 gene were screened for rare, potentially pathogenic variants in OFG. Results:A combined analysis of 3 CD-risk variants in NOD2 showed no association with any OFG subgroup. NOD2 p.L1007insC was associated with OFG+CD (P = 0.023) and IL23R p.R381Q with all OFG (P = 0.031). The sarcoidosis risk variant rs2076530 in BTNL2 was associated with all OFG (P = 0.013). We identified 7 rare missense NOD2 alleles in 8 individuals with OFG, 4 OFG-only patients and 4 patients with OFG+CD. There was a significant enrichment of NOD2 variants in the OFG+CD group compared to the OFG-only group (P = 0.008, common variants; P = 0.04, all common and rare variants). Conclusions:Our findings suggest that genetic variants in NOD2 are only associated with OFG in patients with concurrent intestinal disease. A genome-wide association scan is needed to fully define the genetic architecture of OFG.

PWE-067 MRI to distinguish hidradenitis suppurativa from perianal Crohn's disease

Introduction Hidradenitis suppurativa is a chronic inflammatory disease of apocrine gland-bearing skin. It has a predilection for the ano-genital skin and is characterised clinically by inflammatory abscesses and sinus tract formation. Clinically, the condition can mimic cutaneous Crohns disease, and furthermore it may co-exist with Crohns disease.1 MRI is often used to assess perianal Crohns disease and has been comprehensively described in the literature, however to date, there has only been one case report to describe the MRI features of perianal hidradenitis suppurativa.2 Methods The electronic patient records, and radiology and inflammatory bowel disease databases were searched for patients with hidradenitis suppurativa who had undergone short-tau inversion recovery (STIR) MR imaging to define disease severity, assess for fistulating disease and exclude Crohns disease, between 2005 and 2012. Results A total of 188 patients with hidradenitis suppurativa were identified (129 female, six with concomitant IBD), of whom 18 (15 male, three with comcomitant IBD) had undergone perianal MRI. On baseline MRI, multiple tracts were typically seen in the natal cleft (15/18), the perianal (11/18), the perineal (10/18) and glutaeal (8/18) regions. Abscesses were most commonly glutaeal (3/18). The overall pattern of disease was distinct to that seen in Crohns disease, with multiple sinus tracts that were superficial in nature in the majority of patients with hidradentis suppurativa, compared to perianal Crohns disease where tracts are usually centred on the anal sphincter complex. Conclusion The use of STIR MRI can help define extent of perianal disease in hidradenitis suppurativa, and typically shows a different involvement compared to Crohns disease, allowing distinction between the two, and thus appropriate management. Competing interests None declared. References 1. van der Zee HH, van der Woude CJ, Florencia EF, et al. Hidradenitis suppurativa and inflammatory bowel disease: are they associated? Results of a pilot study. Br J Dermatol 2010;162:195–7. 2. Kelly AM, Cronin P. MRI features of hidradenitis suppurativa and review of the literature. AJR Am J Roentgenol 2005;185:1201–4.