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British Society of Gastroenterology British Society of Gastroenterology Document Transcript

  • British Society of Gastroenterology Post Graduate Teaching Day Inflammatory Bowel Disease Monday, 14th March 2005International Convention Centre Birmingham
  • POSTGRADUATE COURSE ‘Inflammatory Bowel Disease’ – Hall 1Setting the Scene: Chair – Professor JC Atherton and Professor S Ghosh10.00 Prevalence and pattern of IBD, including … Is Crohn’s disease increasing? Professor RFA Logan, Nottingham10.25 Bridging the gap : from genes to function, including … What does Nod2 do? Professor DP Jewell, Oxford10.50 Breaking down barriers : bacterial : epithelial crosstalk, including … Is this the basis of inflammation? Professor IR Sanderson, London11.15 CoffeeClinical controversies - illustrated with cases11.35 Growing pains : IBD in adolescence Professor IW Booth, Birmingham12.00 Timing of colectomy in severe ulcerative colitis Dr SP Travis, Oxford12.25 PSC – What treatment and when to transplant? Dr RW Chapman, Oxford12.50 Lunch (with opportunities to quiz the experts)Interdisciplinary: Chair – Dr MD Hellier and Dr SP Travis14.00 Getting the most from your pathologist, including … Reducing reports of non-specific colitis and … Does low grade dysplasia matter? Professor M Novelli, London14.25 Imaging for Crohn’s disease today and tomorrow, including … The places of wireless Endoscopy and MRI Dr S Jackson, Plymouth14.50 Surgery and postoperative prophylaxis for Crohn’s disease, including … Does the operation matter? Professor R MacLeod, Toronto15.20 TeaBack to the future:15.45 Probiotics, first or last Professor F Shanahan, Cork16.15 Crohn’s disease treatment: infliximab and beyond Professor S Ghosh, London
  • Professor RFA Logan Prevalence and pattern of IBD Professor R F A Logan Professor of Epidemiology, University of NottinghamRichard Logan is Professor of Clinical Epidemiology at the University ofNottingham and an Honorary Consultant Gastroenterologist at the Queen’sMedical Centre.He qualified from Edinburgh University and did most of his training in clinicalgastroenterology in Edinburgh and Scotland. After postgraduate training inepidemiology at the London School of Hygiene and Tropical Medicine, he movedto Nottingham in 1982 as a Wellcome Research Fellow to work with ProfessorMichael Langman. He was appointed Senior Lecturer in 1983 and Professor in1997.His research has concerned the application of epidemiological methods toproblems in gastrointestinal disease. He has a particular interest in coeliacdisease, inflammatory bowel disease and in the epidemiological aspect ofcolorectal and oesophageal cancer. 1
  • Professor RFA Logan Prevalence and pattern of IBD It has become commonplace to describe inflammatory bowel diseases (IBD) as “complex genetic disorders of unknown aetiology”. Nonetheless it is worth reminding ourselves that the overall objective of most epidemiological research is to contribute insights into aetiology, if not to generate full hypotheses. Such research can be divided into descriptive studies – describing IBD occurrence by place, time and person across populations and analytic studies – assessing risk factors or exposures within populations. Place IBD are diseases of economically developed ‘Western’ societies; what is not known is how much their absence in less developed countries is due to lack of recognition. The European community IBD study showed that the North/South incidence gradient was less than once was thought with the incidence of UC being 37% higher and CD 80% higher in the North. Even so CD incidence in developed mainland Italy was only half that of similar areas in the North. Within this broad pattern there are consistent curiosities such as the high CD but low UC incidence in northern France and the high UC and very low CD incidence of NW Greece. The incidence of both diseases appears much lower in Eastern Europe but there is a lack of good data. What is striking is that the range of variation in incidence across W.Europe is considerably less than that for some digestive cancers. There are relatively few studies of IBD incidence from the rest of the world. In many places case series indicate the occurrence of both diseases. Careful studies from Japan and Korea have shown rates about half those of Europe as also seems to be the case for whites in South Africa. While UC has been regarded as rare in India a recent study from N.India estimated annual incidence to be 6.0/105, a figure not much lower than those reported from some W.European centres. Time The incidence of both diseases in W.Europe and N.America showed a marked increase during the 20th century. Generally UC incidence appeared to rise first with CD incidence increasing 3-4 fold between 1950 and 1980. What is disputed is how much the incidence of CD in adults is continuing to increase. Several areas that have a long-run of data have reported modest increases in keeping with greater case ascertainment and more intensive investigation (>90% of CD patients now have a colonoscopy at diagnosis). In contrast in northern France CD incidence has shown a 20% increase during the 1990s. UC incidence has attracted less attention but the routinely collected Danish and UK hospital admission statistics and figures from areas with prolonged data suggest UC incidence has been stable since the 1970s. Person In W.Europe CD incidence in adults tends to be slightly higher (around 25%) in women than men but the reverse is true in children. CD incidence is highest at ages 15-24 in both sexes. UC incidence now shows a less pronounced peak with rates remaining high in men but not women. In the UK people of Asian origin appear to have higher incidences of both diseases in contrast to the Afro- Caribbean population where IBD incidence appears low. How far this pattern applies in the rest of Europe is unclear. Clearly the overall pattern of IBD incidence is in keeping with environmental factors related to economic development playing an important role. The narrow range of incidence variation suggests that these factors are widely distributed. Some factors acting close to IBD onset (smoking, NSAID use, and oral contraceptive use) have been identified but smoking is the only one irrefutably established. Attention recently has turned to factors in childhood, particularly ones that might reflect early exposure (or lack of) to enteric infection and later impact on immunological tolerance. Appendicectomy has emerged (protecting2
  • Professor RFA Loganagainst UC) as the only consistent finding. Indeed two large studies of childhoodIBD have recently reported disparate, if not conflicting findings. Armitage et al inan ecological analysis of childhood IBD in Scotland found significantly more CDbut not UC in affluent areas while Baron et al in a case-control study in northernFrance found no relationship with higher socio-economic status for either diseasebut did find positive associations with certain vaccinations. It is difficult to avoidmaking the banal conclusion ‘more research is needed’.References1. Logan RFA. Inflammatory bowel disease incidence: up, down or unchanged? GUT 1998;42:309-311.2. Ekbom A. The epidemiology of IBD: a lot of data but little knowledge. How shall we proceed? Inflamm Bowel Dis 2004;10 Suppl 1:S32-4.3. Ekbom A, Montgomery SM. Environmental risk factors (excluding tobacco and microorganisms): critical analysis of old and new hypotheses. Best Pract Res Clin Gastroenterol 2004;18(3):497-508.4. Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 2004;126(6):1504-17.5. Farrokhyar F, Swarbrick ET, Irvine EJ. A critical review of epidemiological studies in inflammatory bowel disease. Scand J Gastroenterol 2001;36(1):2- 15.6. Armitage EL, Aldhous MC, Anderson N, Drummond HE, Riemersma RA, Ghosh S, et al. Incidence of juvenile-onset Crohns disease in Scotland: association with northern latitude and affluence. Gastroenterology 2004;127(4):1051-7.7. Baron S, Turck D, Leplat C, Merle V, Gower-Rousseau C, Marti R, et al. Environmental risk factors in paediatric inflammatory bowel diseases: a population based case control study. Gut 2005;54(3):357-63.8. Shivananda S, Lennard-Jones J, Logan RFA, Fear N, Price A, Carpenter L, et al. Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European collaborative study on inflammatory bowel disease (EC-IBD). GUT 1996;39:690-697.9. Molinie F, Gower-Rousseau C, Yzet T, Merle V, Grandbastien B, Marti R, et al. Opposite evolution in incidence of Crohns disease and ulcerative colitis in Northern France (1988-1999). Gut 2004;53(6):843-8. 3
  • Professor RFA Logan Anderson et al, NEJM 2001 Recent Time Trends in Incidence of Crohns Disease ABERDEEN(7) BLACKPOOL(70) CARDIFF(8) DERBY(71) STOCKHOLM(18) OREBRO,SWE(72) ROCHESTER,US(6) COPENHAGEN(73) 120 100 80 rate per million 60 40 20 0 YEAR 1961 1963 1965 1967 1969 1971 1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 YEAR4
  • Professor RFA Logan Recent Time Trends in Incidence of Ulcerative Colitis CARDIFF(74) COPENHAGEN(75) OREBRO, SWE(76) UPPSALA, SWE(77) ROCHESTER, US(78) 160 140 120Incidence / million / year 100 80 60 40 20 0 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 YEAR 5
  • Space for Notes6
  • Professor D Jewell Bridging the gap: from genes to function Professor Derek Jewell University of Oxford, Radcliffe Infirmary, OxfordD.P. Jewell is Professor of Gastroenterology in Oxford. Much of his training was inOxford and his interest in Gastroenterology was stimulated by Dr SidneyTruelove. He spent over a year in the Gastroenterology Department of StanfordUniversity before returning as Senior Lecturer in Medicine at the Royal FreeHospital. He has been back in Oxford since 1980. Research interests havemainly centred around inflammatory bowel disease and coeliac disease andinclude clinical, therapeutic, immunological and genetic aspects. He has beenChairman of the International Organisation for the Study of Inflammatory BowelDisease and is a past-President of the British Society of Gastroenterology. 7
  • Professor D Jewell Bridging the gap: from genes to function Both ulcerative colitis and Crohn’s disease are under genetic control to a degree. Several genes are involved and current evidence suggests that they predominantly determine disease location and behaviour. Possession of certain alleles within the HLA region (Chr 6p) will put individuals at risk of developing extra-intestinal manifestations. The NOD2/CARD1 gene on Chr 16 is the only gene to be identified so far with sufficient certainty and three mutations within this gene have been consistently associated with Crohn’s disease, but not with ulcerative colitis. Studies from France, Germany, UK and USA have shown that up to 40% of patients with Crohn’s disease will have one or more of these mutations. However, in Ireland, Scotland, Iceland and Scandinavia the frequency is much lower (8-15%) and NOD2 mutations are not found in patients with Crohn’s disease in China, Korea or Japan. Jewish patients tend to have an increased frequency of these mutations. A consistent finding is that NOD2/CARD15 mutations are particularly associated with ileal disease and many, but not all, studies show an association with stricturing disease. Colonic Crohn’s disease appears to be mainly influenced by genes within the HLA locus (Chr 6p) rather than by NOD2/CARD15 mutations. How NOD2/CARD15 mutations render individuals susceptible to ileal Crohn’s disease is unclear. The mutations are found at the C-terminal encoding the leucine rich region of the protein. This region is an intra-cytoplasmic receptor for the muramyl dipeptide (MDP) moiety of peptidoglycan which is found within the walls of many bacteria. The protein is expressed in monocytes but expression tends to be lost as monocytes migrate into the intestinal lamina propria and mature into tissue macrophages. NOD2/CARD15 is also constitutively expressed in Paneth cells which are found predominantly in the terminal ileum. Our knowledge of the function of NOD2/CARD15 is rapidly expanding but the results are dependant on the experimental model used. They can be summarised as follows:- Epithelial cell lines transfected with mutated NOD2/CARD15 gene fail to up- regulate NFκβ, and hence gene transcription, in response to MDP compared with cells transfected with wild type NOD2/CARD15. Furthermore, intracellular killing of Salmonella is impaired with cell lines expressing the mutated gene. Genetically-engineered mice deficient in the NOD2/CARD15 gene are healthy and have no intestinal inflammation. However, compared with mice expressing wild- type NOD2/CARD15, the deficient mice are more susceptible to infection with Listeria monocytogenes when administered intragastrically. More organisms were present in the liver and spleen than in the wild-type mice but no intestinal inflammation was observed. Interestingly, the expression of certain cryptidins (equivalent to human α-defensins) was low in the mice containing the mutated gene and was even lower following infection. No changes compared with wild- type were seen if Listeria were given IV or IP. In humans, peripheral blood mononuclear cells produce several cytokines (TNFα, IL-1β) in response to activating toll-like receptors with their appropriate ligands. This response is augmented in the presence of MDP in individuals with wild-type NOD2/CARD15 genotype but not in individuals who possess one or more mutations. It has also been shown that Paneth cells fail to secrete much α- defensins 4 and 5 in biopsy specimens from patients with NOD2 mutations, a finding analogous to the NOD2 deficient mice.8
  • Professor D JewellIn summary, the identification of NOD2/CARD15 mutations in many patients withileal Crohn’s disease and the observation that this may be associated with adeficient anti-microbial defence, highlights the interaction between environmentand genetic susceptibility and in particular, the role of bacterial molecules (e.g.peptidoglycan, LPS, flagellin, CpG DNA) and pattern-recognition receptors withincells.ReferencesAhmad T, Armuzzi A, Bunce M, Mulcahy-Hawes K, Marshall SE, Orchard TR, et al.The molecular classification of the clinical manifestations of Crohns disease.Gastroenterology 2002;122(4):854-66.Ahmad T, Tamboli CP, Jewell D, Colombel JF. Clinical relevance of advances ingenetics and pharmacogenetics of IBD. Gastroenterology 2004;126(6):1533-49.Bonen DK, Ogura Y, Nicolae DL, Inohara N, Saab L, Tanabe T, et al. Crohnsdisease-associated NOD2 variants share a signaling defect in response tolipopolysaccharide and peptidoglycan. Gastroenterology 2003;124(1):140-6.Gollop JH, Phillips SF, III LJM, Zinsmeister AR. Epidemiologic aspects of Crohnsdisease: a population-based study in Olmsted County, Minnesota, 1943-1982.Gut 1988;29:49-56.Hisamatsu T, Suzuki M, Reinecker HC, Nadeau WJ, McCormick BA, Podolsky DK.CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelialcells. Gastroenterology 2003;124(4):993-1000.Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, et al. Hostrecognition of bacterial muramyl dipeptide mediated through NOD2. Implicationsfor Crohns disease. J Biol Chem 2003;278(8):5509-12.Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, et al.Nod2-dependent regulation of innate and adaptive immunity in the intestinaltract. Science 2005;307(5710):731-4.Lala S, Ogura Y, Osborne C, Hor SY, Bromfield A, Davies S, et al. Crohns diseaseand the NOD2 gene: a role for paneth cells. Gastroenterology 2003;125(1):47-57.Maeda S, Hsu LC, Liu H, Bankston LA, Iimura M, Kagnoff MF, et al. Nod2 mutationin Crohns disease potentiates NF-kappaB activity and IL-1beta processing.Science 2005;307(5710):734-8.Watanabe T, Kitani A, Murray PJ, Strober W. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol 2004;5(8):800-8.Wehkamp J, Harder J, Weichenthal M, Schwab M, Schaffeler E, Schlee M, et al.NOD2 (CARD15) mutations in Crohns disease are associated with diminishedmucosal alpha-defensin expression. Gut 2004;53(11):1658-64. 9
  • Professor D Jewell Interaction between Gene Products and Environment Bacterial recognition receptors - Toll-like receptors Intracellular receptors - NOD1, NOD2 Antigen processing - HLA Class II Epithelial integrity - Organic cation transporters CARD15 protein variants associated with Crohn’s disease Apoptosis Oligomerization Ligand-binding CARD1 CARD2 NBD LRR 1 121 129 217 260 570 744 10201040 • Expressed in monocytes R702W G908R 1007fs Hugot JP et al. Nature 200110
  • Professor D Jewell Functional Significance of NOD2 mutations1. Failure to kill intracellular organisms in vitro Hisamatsu et al, 20032. Failure to activate NFκβ on stimulation with PG or MDP Inokara et al, 20033. PBMNC from patients with NOD2 mutations have impaired TNFa and IL-8 responses to MDP van Heel et al, 2005 11
  • Space for Notes12
  • Professor I SandersonBreaking down barriers - Bacterial epithelial cross - talk Ian R Sanderson Professor of Paediatric Gastroenterology Barts & The London, London, UKIan Sanderson is Professor of Paediatric Gastroenterology and Head of Adult &Paediatric Gastroenterology at Barts & The London, Queen Mary’s School ofMedicine.He first became interested in the intestine as a graduate student under DennisParsons where he examined the exit of absorbed amino acids from theenterocyte. After finishing his medical studies he worked as a house officer to DrAnthony Dawson and trained as a paediatrician. He was the CICRA ClinicalResearch Fellow at St Bartholomew’s Hospital where he demonstrated that anelemental diet was as effective as high dose steroids in children with Crohn’sdisease. He also showed that those taking the enteral feeds grew faster.After completing his training as a paediatrician and paediatric gastroenterologist,Professor Sanderson moved to Harvard Medical School as a Fulbright Scholar inDr Allan Walker’s department. He become Assistant Professor of Paediatrics andDirector of the Developmental Gastroenterology Laboratory at the HarvardClinical Nutrition Research Centre. He developed the concept that luminal factorsregulate genes in the epithelium that signal to the mucosal immune system. Bythis means, changes in diet can act through enterocytes altering inflammatorymechanisms in the intestine.Professor Sanderson was awarded the Crohn’s and Colitis Foundation of AmericanSilver Jubilee medal for his work in childhood Crohn’s disease and the NormanKretchmer Award in Nutrition and Development for his work on the affect of dieton genes in the developing intestine. His current laboratory in London examineshow dietary factors act on genes in the epithelium both through promoter-basedmechanisms and through changes in chromosomal structure. 13
  • Professor I Sanderson Breaking down the barriers - Bacterial epithelial cross - talk There is increasing evidence for the role of commensal bacteria in the pathogenesis of inflammatory bowel disease. Clinical studies with ileal diversion or the use of antibiotics can reduce disease activity. Animal models of inflammatory bowel disease require microflora for inflammation to be present. Animals such as the IL-2 knockout mouse or the HLA-B27 transgenic rat show no signs of inflammation when born into a germ-free environment. Introduction of commensal bacteria result in establishment of inflammation. There is little evidence for a specific bacterial pathogen in inflammatory bowel disease; however, resident enteric flora may be altered. For example, E.coli strains have been reported to be more adherent in Crohn’s disease than in controls. The question arises therefore, whether patients with inflammatory bowel disease have an altered response to the normal gut flora. Intermittent chronic stress in rats affects barrier function resulting in ultrastructural changes in the epithelium and bacterial penetration and inflammation. The molecular basis of these changes are not fully understood. However, increasing work has demonstrated receptors that recognise bacterial products in the intestine. These include the toll-like receptors which are present on the surface of many cell types including the epithelium and card/NOD proteins which recognise bacterial products that have entered the cell. Both sets of recognition molecules cause stimulation of inflammatory pathways. The card 15/NOD-2 is involved in the recognition of bacterial polymers (peptinglycan-M-VP). Mutations in this receptor centre susceptibility to Crohn’s disease. No mutations have been found in the Toll-like receptors that definitively classes one of them as a disease susceptibility gene. However, recent data inducing inflammation in mice that are defective in the Toll- like receptor signalling pathway show increased inflammation. This suggests that Toll-like receptors may play a homeostatic role in protecting against inflammation. In summary, the evidence that bacteria play a role in the pathogenesis of inflammatory bowel disease is increasing. The role of microbial receptors in inflammatory bowel disease is an area of active research.14
  • Professor I Sanderson Signalling mechanisms in gut innate immunity Pathogen-associated molecular patterns (PAMPs) Toll-like Receptors + Nucleotide-binding site-leucine-rich repeat family Didierlaurent et al. Cellular Microbiol 2002Signalling through TLRs reducesinflammation in mice given DSS Wild-type mice survive inflammation from DSS. Mice in whom signalling through TLRs is impaired (lacking MyD88; TLR2 or TLR4) have worse inflammation and die Rakoff-Nahoum et al., 2004 15
  • Professor I Sanderson Dendritic cells express a chemokine receptor that controls bacterial clearance The CX3CR1 (Green) is expressed on intestinal dendritic cells. Arrows indicate inter-epithelial cell projections Niess et al., 200516
  • Space for Notes 17
  • Professor I Booth Growing pains : IBD in adolescence Professor Ian Booth Leonard Parsons Professor of Paediatrics and Child Health The Medical School, Edgbaston, Birmingham Ian Booth qualified at Kings College Hospital in 1972, and after training at Great Ormond Street, where he held the Royal College of Physicians Eden Fellowship, he moved to Birmingham in 1985. He held a personal Chair in Paediatric Gastroenterolgy and Nutrition before appointment to the Leonard Parsons Chair of Paediatrics and Child Health in 1997. In addition to inflammatory bowel disease in children, his other clinical interests include the management of intestinal failure, small bowel transplantation and neonatal gastroenterology.18
  • Professor I Booth Growing Pains: IBD in AdolescenceEffective treatment of IBD in adolescents depends more on a knowledge of thephysiology and psychology of adolescents than a familiarity with alteredresponses to treatment, which are few. In general, adolescents respond toconventional therapies in the same way as adults. In many ways, the style ofmanagement is at least as important as content.One third of adolescents will have growth failure, and pubertal delay,complicating their Crohn’s disease, and this adds another dimension to treatment.Consequently, induction and maintenance of growth and pubertal development byenergetic nutritional support and/or judicious surgery are in themselves,important aims of therapy.In addition to a growth spurt, adolescence is also characterised by psychologicalchanges which have major implications for adherence to treatment and thereforeto growth and nutritional status. An ability to perceive the long-term implicationsof current actions is still being acquired in adolescence and there is a strongfeeling of self-invincibility. In marked contrast with the need to affiliate withone’s peer group, there is an increased frequency of conflict with parents andother authority figures including doctors, regarding boundaries of appropriatebehaviour. Chronic gastrointestinal disease, with a perceived need fordependence on others, is often complicated by symptoms of anxiety anddepression, together with poor school work and social interactions. Specificproblems, such as incontinence, diarrhoea or a stoma may also be present,although a stoma is by no means a psychosocial disaster in children andadolescents. Certainly, colectomy should not be deferred because of a fear ofthe emotional consequences of stoma surgery in children and adolescents.New problems such as poor drug or dietary compliance, or erratic outpatientattendance, may arise, and a formal authoritarian approach on the part ofattending doctors and their colleagues is almost invariably fruitless. Whilstadolescent patients require sympathetic handling and extra support, so do theirparents, most of whom find it difficult to relinquish the responsibility for the careof a sick child to the patient themselves. This is particularly so if the patientshows little interest in self-care and the parents require extra help whileundergoing this difficult process.ReferencesSuris J.C., Michaud P.A., Viner R, – The Adolescent with a Chronic Condition. Part1: Developmental Issues Arch Dis Child 2004; 89: 934-42Michaud P.A., SurisJ.C., Viner R, – The Adolescent with a Chronic Condition. Part 2: Health CareProvision Arch Dis Child 2004; 89: 943-49.Christie D, Viner R, - Adolescent Development BMJ 2005; 330: 301-304Booth I.W., Hills S, - Best Practice in Crohns Disease in Children and Adolescentsin the Effective Management of Crohns Disease (Hawkey et al eds) 2003.Viner R, - Transition from Paediatric to Adult Care. Bridging the Gaps for Passingthe Buck? Arch Dis Child 1999; 81: 271-275.Heuschkel R.B., et al – Enteral Nutrition and Corticosteroids in the Treatment ofAcute Crohns Disease in Children, JPEN 2000; 31: 8-15 19
  • Professor I Booth The primary challenges of adolescence • The achievement of biological and sexual maturation • The development of personal identity • The development of intimate sexual relationships with an appropriate peer • Establishment of independence and autonomy in the context of the sociocultural environment (Christie and Viner BMJ 2005; 330:301-304) The challenges for young people • Challenging authority • Seeking spiritual paths (organised or • Taking risks cult religions) • Experimenting with drugs, alcohol, • Getting a job and sex • Changing schools and educational • Challenging the moral and social environment structure of society • Developing relationships • Demanding rights • Understanding sexuality • Taking responsibility for self and • Renegotiating rules at home others (Christie and Viner BMJ 2005; 330:301-304)20
  • Professor I Booth Bridging the gapPaediatric paradigm Adult medical culture• family centered • acknowledges• developmentally autonomy, reproduction, focused jobs• ignores independence • ignores growth, and increasingly adult development and family behaviour concerns Transition clinics 21
  • Space for Notes22
  • Dr S Travis Timing of colectomy in severe ulcerative colitis Simon TRAVIS DPhil FRCP Consultant Physician and Gastroenterologist John Radcliffe Hospital, OxfordConsultant Physician and Gastroenterologist, John Radcliffe Hospital. Fellow,Linacre College, Oxford. Clinical Director of Gastroenterology, Oxford. Chairmanof IBD Section and member of Council, British Society of Gastroenterology. UKrepresentative and member of scientific committee, European Crohns and ColitisOrganisation. Secretary to Medical Advisers and Trustee, National Association ofColitis and Crohns Disease. Qualified St Thomas Hospital, London 1981.Research interests in therapeutics and clinical prediction of IBD. Principalinvestigator for RDP58 (novel anti-cytokine decapeptide). Peripheral interest ingastrointestinal physiology at high altitude. 23
  • Dr S Travis Timing of colectomy in severe UC The principal clinical dilemma in managing severe UC remains how to identify at an early stage those who need colectomy, so that surgery is not inappropriately delayed. This demands the most taxing clinical judgement. As therapeutic options increase (ciclosporin, tacrolimus, or infliximab among others), so too does the opportunity for medical indecision making. The consequence is that surgery is often deferred and outcome deteriorates. Only a single patient need die from surgical complications caused by operating too late, to negate the benefits of medical therapy. Predictive factors can be broadly divided into radiological, clinical and biochemical. Radiological criteria include 1. colonic dilatation >5.5cm (associated with a 75% need for colectomy) 2. mucosal islands on a plain abdominal radiograph (75% colectomy) 3. 3 or more small bowel loops of gas (indicating ileus, 50-73% colectomy) 4. deep colonic ulcers after gentle air insufflation Clinical and biochemical markers include 1. stool frequency >12/day on day 2 (55% colectomy), 2. frequency >8/day on day 3 of intensive treatment (85% colectomy) 3. frequency 3-8/day and CRP >45mg/L on day 3 (85% colectomy) 4. frequency >4 and CRP >25mg/L on day 3 (75% colectomy) 5. albumin <33g/dL before day 4 (55% colectomy) Genetic profiles may help identify patients at high risk of colectomy in the future. The CRP and stool frequency criteria are simply a guide and neither immutable nor always reproduced. They exist to be applied as a threshold for triggering appropriate action (surgical consultation, assessment by a stomatherapist, augmenting medical treatment) at an early stage. Other criteria may do as well, but must be as simple. The message is to integrate objective measures of response into the clinical strategy, so that patients with severe UC are not blighted by procrastination. References Almer S, Bodemar G, Franzen L, et al. Use of air enema radiography to assess depth of ulceration during acute attacks of ulcerative colitis. Lancet 1996; 347:1731-5. Chew CN, Nolan DJ, Jewell DP. Small bowel gas in severe ulcerative colitis. Gut 1991; 32:1535-7. Hawthorne AB, Travis SPL and the BSG IBD Clinical Trials Network. Outcome of inpatient management of severe ulcerative colitis: a BSG IBD Clinical Trials Network Survey. Gut 2002; 50:A16 Ho GT, Mowat C, Goddard C, et al. Predicting the outcome of severe ulcerative colitis: development of a novel risk score to aid early selection of patients for second-line medical therapy or surgery. Aliment Pharmacol Ther 2004;19:1079- 87.24
  • Dr S TravisLennard-Jones JE, Ritchie JK, Hilder W, Spicer CC. Assessment of severity incolitis: a preliminary study. Gut 1975; 16:579-84.Lindgren SC, Flood LM, Kilander AF, et al. Early predictors of gluticorticoidtreatment failure in severe and moderately severe attacks of ulcerative colitis.Eur J Gastroenterol Hepatol 1998; 10:831-5.Travis SPL, Farrant JM, Ricketts C, et al. Predicting outcome in severe ulcerativecolitis. Gut 1996; 38:905-910Travis SPL. Predicting outcome in severe colitis Dig Liver Dis 2004; 36:448-50. 25
  • Dr S Travis National experience: 29/45 UK centres 116 Colectomy Partial response 33 36 (28%) Remission (31%) 47 (41%) Hawthorne & Travis Gut 2002 1955 Results (Truelove & Witts): remission 41%; improved 27%; worse 32 %....! Predicting outcome If, on day 3 of intensive treatment, stool frequency >8/day, or CRP >45mg/L and stool frequency 3-8/d then 85% come to colectomy on that admission Travis et al Gut 1996 Validated in 68 patients from 4 Scandinavian centres –day 3 frequency >4 and CRP >25mg/L: 75% Lindgren et al EJGH 199826
  • Dr S Travis ConclusionsSurgical indications• Failure to improve dramatically within 24h if colonic diameter >5.5cm• Deterioration (stool frequency, pulse, or fever) during intensive treatment• Failure to improve after (about) 5 days intensive steroid treatment• Failure to improve after (about) 3 days CsA• Deterioration after reintroduction of food 27
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  • Dr R Chapman Primary Sclerosing Cholangitis - What treatment and when to refer? Dr Roger Chapman BSc, MD, MBBS, FRCP John Radcliffe Hospital Headington OxfordRoger Chapman trained in liver disease at the Royal Free Hospital with the lateDame Sheila Sherlock, before moving to Oxford in 1981,obtaining an MD on Ironmetabolism in liver disease. In addition he developed a life long interest in liverproblems associated with inflammatory bowel disease particularly PSC. In 1984he spent a year at the University of Washington as visiting scientist. His currentresearch interests include combination medical therapy with UDCA and antibioticsin PSC and the role of retroviruses in the aetiology of autoimmune liver diseases. 29
  • Dr R Chapman Primary Sclerosing Cholangitis – What treatment and when to refer? Primary sclerosing cholangitis (PSC) is a chronic cholestatic hepatobiliary disease characterised by progressive obliterating fibrosis of the biliary system leading to biliary cirrhosis, portal hypertension and liver failure. The aetiology of PSC is unknown but there is a close association with inflammatory bowel disease particularly ulcerative colitis. Recent studies have shown that PSC is a premalignant condition with an increased rate of hepatobiliary cancer which occurs in 10 – 20% of patients and colonic cancer in patients with associated ulcerative colitis. Regular colonoscopic surveillance with yearly colonoscopy is recommended. The hydrophilic bile acid ursodeoxycholic acid (UDCA) is used for the treatment of a number of cholestatic conditions. A number of groups have studied the effect of low (<10mgs/kg body weight) or medium (12-15mgs/kg body weight daily) dose UDCA in PSC. All have showed a significant improvement in liver enzymes but no studies have shown clinical benefit in terms of improvement in clinical symptoms or survival free of liver failure or transplantation. Recent evidence suggests that UDCA in medium doses reduces the incidence of colonic dysplasia, polyps and colorectal cancer in patients with associated inflammatory bowel disease. The effect of UDCA on the incidence of cholangiocarcinoma in PSC remains unclear. Novel approaches to the medical treatment of PSC have included the use of higher doses + UDCA. Two recent studies have evaluated the role of high dose UDCA (> 25mgs/kg body weight daily) in the treatment of PSC. In the first study from the Mayo Clinic 30 patients with PSC were treated for one year (1). The study showed a significantly improved expected survival at four years using the Mayo Risk Score when compared with historical placebo controls. In a second pilot study from our unit 26 patients with PSC were randomised to receive either high dose UDCA or placebo for two years (2). High dose UDCA did not influence symptoms but the study showed a significant reduction in progression of cholangiographic appearances and liver fibrosis as assessed by disease staging. In both the above studies high dose UDCA produced no significant side effects, in particular no exacerbation of inflammatory bowel disease. These promising results suggest that high dose UDCA may have a clinical benefit in PSC, and a recent large double blind placebo controlled trial from Scandanavia has shown a positive trend in favour of UDCA, although due to a power effect of small numbers this did not achieve statistical significance. Other novel approaches include the combination of UDCA with long term antibiotic therapy such as metronidazole which have provided promising results after three years of therapy. The addition of immunosuppressive agents to standard doses of UDCA have yielded evidence of efficacy. Studies from Germany using UDCA with endoscopic biliary dilatation also have provided encouraging results over a six year mean follow up period. It is likely that combination therapy probably including UDCA will provide the basis for future medical management.30
  • Dr R ChapmanThe timing of liver transplantation in PSC is particularly difficult,and prognosticmodels have not proved to be useful in individual cases. Indications fortransplantation include deepening jaundice (bilirubin > 100umol/l), hepaticdecompensation, refractory itching and possibly biliary dysplasia. Hepatictransplantation in PSC is associated with a good 5 year survival althoughrecurrence of PSC occurs in about 30%. References1. Harnois DM, Angulo P, Jorgencen RA, LaRusso NF, Lindor KD High doseUrsodeoxycholic Acid as a therapy for patients with PSC. Am J Gasteroenterol2001; 96:1558-16622. Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, ChapmanRW A preliminary trial of high dose Ursodeoxycholic Acid in primary sclerosingcholangitis. Gastroenterology 2001; 121:900-909 31
  • Dr R Chapman Management of PSC complicated! Management of cholestasis Management of cirrhosis Management of biliary complications Management of inflammatory bowel disease Specific medical therapy Appropriate referral for liver transplantation High dose Scandanavian Trial Death /Transplantation: 7.2% UDCA vs 10.9% placebo(ns)32
  • Dr R ChapmanIndications for Liver Transplantation in PSC Persistent jaundice (bili > 100 umol /L) Hepatic decompensation -ascites;variceal bleed;enceph Fatigue(?);refractory itch;malaise Biliary dysplasia (?) Timing of Transplant - DIFFICULT! 33
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  • Professor M Novelli Getting the most from your pathologist Professor M Novelli LondonMarco Novelli studied medicine at the University of Bristol qualifying in 1987.Following housejobs he took an MSc in Experimental pathology and Toxicology atthe Royal Postgraduate Medical School, London. He started his pathology trainingin Bristol, but after 3 years moved to the Imperial Cancer Research Fund inLondon where he studied for a PhD on ‘Aspects of the Genetics and Biology ofColorectal Carcinoma’ under the supervision of Sir Walter Bodmer and NickWright. His pathology training was completed at University College Hospital,where he has since remained as a Consultant Histopathologist. In 2004 he waspromoted to Professor of Gastrointestinal Pathology. His major research interestsinclude clonality in epithelial tissues and early carcinogenesis, colorectal and smallintestinal carcinogenesis in FAP, and the pathology of Barrett’s oesophagus. 35
  • Professor M Novelli Getting the most from your pathologist The histological reporting of pathological specimens involves a combination of pattern recognition and searching for specific histological features to confirm or exclude a diagnosis. The morphological features seen down the microscope need to be taken in the context of the clinical situation. With these principles in mind, there are a variety of ways clinicians can optimise their chances of getting clinically helpful histopathology reports and minimise non-specific diagnoses. The site and labelling of endoscopic biopsies is one important factor. The normal inflammatory cell population varies greatly within the gastrointestinal tract. Knowledge of the site of a biopsy can be very useful in the assessment of the presence/absence of inflammation. Where inflammation is found, the distribution of inflammatory changes is also crucial in making a correct diagnosis and further classifying disease (e.g. IBD). Ideally multiple biopsies should be taken from both ‘normal’ and abnormal areas, and the biopsies labelled such that their order/location within the intestine is known. An adequate clinical history is crucial in the interpretation of histological appearances. Areas of particular difficulty for the pathologist include the recognition of unusual/rare infections (history of foreign travel and/or immunosuppression) and iatrogenic pathology (including both medication and surgery-related pathological processes). The recognition and interpretation of dysplastic changes in longstanding inflammatory bowel disease provides a good example of the necessity for a combination of both appropriately labelled biopsies and a meticulous clinical history. For the assessment of such lesions it is important to know the duration of colitis, type of colitis, the site of dysplasia, and relationship of the dysplasia to areas of active colitis. These findings affect the interpretation of the histological features and have important implications for treatment (e.g. focal high grade dysplasia in a sporadic adenoma may often be treated by polypectomy, whilst low grade dysplasia in a DALM usually necessitates colectomy). Central to many of these issues is communication between the clinician and histopathologist. This routinely occurs through the provision of clinical details and history on specimen request forms. The addition of a copy of the endoscopy report is extremely helpful and is a relatively simple way of providing the pathologist with additional clinical information. In difficult cases discussion of clinical, pathological and radiological findings in the setting of an MDT meeting is perhaps the optimal way to achieve an accurate diagnosis. References Morson and Dawson’s gastrointestinal Pathology. 4th Edition, David W Day et al. Blackwell Science, Oxford. Diagnostic problems and advances in inflammatory bowel disease. Odze R. Mod Pathol. 2003; 16(4):347-58. Indeterminate colitis in clinical practice. Geboes K et al. Current Diagnostic Pathology 2003; 9: 179-187.36
  • Professor M NovelliReducing reports of non-specific colitis • Relevant clinical histories • Foreign travel • Medication • Immunosuppression • Endoscopic findings (report where available) • Multiple biopsies • ‘Normal’ and abnormal areas • Known sites • Clinician contact details • Clinicopathological correlation/MDTs Treatment of flat dysplasia in IBD Low grade High grade • Increased surveillance. • ? Colectomy. • Colectomy. 37
  • Professor M Novelli DALM (High and low grade) Adenoma-like Non adenoma-like Outside area Within area of colitis of colitis • Polypectomy. • Polypectomy. Colectomy. • Regular • Confirm absence surveillance. flat dysplasia. • ? Increased surveillance.38
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  • Dr S Jackson Imaging for Crohn’s disease today and tomorrow Dr S Jackson Consultant GI Radiologist Plymouth University Hospitals Simon Jackson was born in London, England and received his primary medical degree qualifying from St Thomas` Hospital Medical School, London. After obtaining a range of surgical experience and the FRCS (Eng) examination he commenced his training in radiology on the Southampton University Hospitals scheme in 1991. During this period he developed an interest in gastrointestinal and abdominal radiology including endoscopy and in 1996 travelled to Vancouver General Hospital, Canada where he successfully completed a fellowship in GI radiology before returning to the United Kingdom. He is currently a consultant GI radiologist at the Plymouth University Hospitals NHS Trust and Peninsula Medical School following his appointment to the post in 1998. He is an enthusiastic teacher and active researcher regularly presenting scientific work at both national and international events. In addition he has been an invited lecturer at various courses and meetings as well as a reviewer for a number of scientific journals. In recognition of his contributions, he was elected a fellow of the European Society of Gastrointestinal and Abdominal Radiology during 2003.40
  • Dr S Jackson Imaging for Crohn’s disease today and tomorrow.The complexity of diagnostic imaging algorithms available for the investigation ofpatients with Crohn’s disease (CD), particularly when confined to the smallintestine, continues to expand. For many years, barium studies including thebarium follow through (small bowel meal) and enteroclysis (small bowel enema)examinations were considered the principal tools for the diagnosis and evaluationof disease extent (1). Whilst both techniques, particularly when performed bydedicated radiologists, remain accurate examinations for the diagnosis of primaryand recurrent pathology, they are limited in their capacity to demonstrate bothtransmural and extramural extent of disease as well as assess disease activityand the presence of extra-luminal complications. The examinations also result ina significant radiation dose to patients, the majority of whom present at a youngage.Since the 1980’s the use of cross sectional imaging techniques namely CT, MRIand ultrasound have become increasingly important in the patients diagnosticpathway. The modalities are used to confirm the diagnosis, localize the positionand number of lesions as well as assess disease activity and severity.Importantly the presence of extra-luminal complications can be accuratelyevaluated as well as other factors, which may influence subsequent surgicalintervention (2,3). The more limited spatial resolution of these examinationswhen compared with conventional enteroclysis reduces sensitivity for thediagnosis of superficial mucosal pathology.MRIEarly attempts to evaluate the small bowel were limited due to prolongedexamination times. However the introduction of ultra-fast sequences as well asthe excellent soft tissue contrast resolution and multi-planar imaging capabilitiesconfer clear advantages of MRI over other diagnostic modalities for theinvestigation of small bowel disease. Intra-luminal contrast agents remainfundamental to a high quality examination. These may be administered eitherorally or directly into the small bowel via a feeding tube. This latter techniquetermed magnetic resonance enteroclysis (MRE) is invasive and time consumingbut yields excellent results for the evaluation of both transmural and extramuralsmall bowel disease (4,5).Capsule endoscopyWhilst conventional imaging techniques demonstrate limited sensitivity for thediagnosis of early superficial disease, direct visualization of the small bowelintestinal mucosa is accomplished by conventional and more recently wirelesscapsule endoscopy (PillCamTM). Limited studies have so far been publishedassessing the impact of capsule endoscopy (CE) on the clinical decision makingand therapeutic outcome in patients with CD (6,7,8). Results to date suggest thatCE is effective in the diagnosis of patients with suspected CD who have previouslyundergone negative imaging. It should however be remembered that isolatedsuperficial small bowel erosions may be secondary to other pathology. The role ofCE in patients with known CD is so far undetermined. Capsule retention due tosmall bowel strictures remains a problem however the recent development of apatency capsule may reduce retention rates. 41
  • Dr S Jackson In summary, the present and future role of various imaging modalities in patients with suspected or confirmed CD will remain complementary, with a high quality mucosal examination combined with cross sectional techniques to evaluate transmural and extramural disease extent. The future place of small bowel barium radiology is less certain however the accuracy of examinations remains high when performed by dedicated radiologists. References Maglinte DDT, Kelvin FM, O`Connor K et al. Current status of small bowel radiography. Abdom Imaging 1996;21:247-57 Zalis M, Singh AK. Imaging of inflammatory bowel disease: CT and MR. Dig Dis 2004;22:56-62 Furukawa A, Saotome T, Yamasaki M et al. Cross sectional imaging in Crohns disease. Radiographics 2004;24:689-702 Prasspopoulos P, Papanikolaou N, Grammatikakis J et al. MR Enteroclysis imaging of Crohns disease. Radiographics 2001;21:S161-172 Masselli G, Brizi GM, Parrella L et al. Crohns disease: magnetic resonance enteroclysis. Abdom imaging 2004;29:326-334 Buchman AL, Miller FH, Wallin A et al. Videocapsule endoscopy versus barium contrast studies for the diagnosis of Crohns disease recurrence involving the small intestine. Am J Gastroenterol 2004;99:2171-2177 Fireman Z, Mahajna E, Broide E et al. Diagnosing small bowel Crohns disease with wireless capsule endoscopy. Gut 2003;52:390-392 Herrerias JM, Caunedo A, Rodriguez-Tellez M et al. Capsule endoscopy in patients with suspected Crohns disease and negative endoscopy. Endoscopy 2003;35:564- 56842
  • Dr S Jackson Imaging Modalities• Plain Abdominal Film• Contrast Imaging: • Small bowel meal (barium follow through) • Small bowel enema (enteroclysis)• Cross sectional imaging: • CT • MRI • US• Endoscopy: • Conventional endoscopic techniques • Capsule endoscopy (PillCamTM)• Radionuclide imaging: • PET Cross Sectional Imaging Modalities• Advantages: • Demonstrate transmural disease extent • Assess extramural complications • Provide multi-planar and functional information • Intravenous contrast: • Assessment disease activity• Disadvantages: • Limited spatial resolution - CT • Radiation dose - CT • Operator experience - US 43
  • Dr S Jackson Future Small Bowel Imaging • Imaging techniques will remain complementary • Requirements: • High quality mucosal examination: • ? Capsule endoscopy • Cross sectional evaluation transmural/extramural disease extent: • Specific advantages MRI- • Possibility of “One stop shop”44
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  • Professor R McLeod Surgery and postoperative prophylaxis for Crohn’s disease Robin McLeod, MD, FRCSC, FACS Head of Division of Surgery – Mount Sinai Hospital, Toronto Dr Robin McLeod received a BSc and MD from the University of Alberta. Following this, she received training in General Surgery at the University of Toronto and Colorectal Surgery at the Cleveland Clinic. She currently is a Fellow of the Royal College of Physicians and Surgeons of Canada and a Fellow of the American College of Surgeons as well as a Diplomate of the American Board of Surgery and the American Board of Colorectal Surgery. She trained in clinical epidemiology at McMaster University before joining the faculty at the University of Toronto in 1985. Dr McLeod is currently Head of the Division of General Surgery at the Mount Sinai Hospital, Professor in the Departments of Surgery and Health Policy, Management and Evaluation. She is Past President of the Canadian Association of General Surgeons, Past Vice President of the American Society of Colon and Rectal Surgeons and currently is a Regent of the American College of Surgery. She is an Honorary Fellow of the Royal College of Surgeons of Edinburgh. Her clinical interests are in the areas of colorectal surgery, particularly IBD and colorectal cancer. She is on the Editorial Board of several journals including Annals of Surgery, Surgery and International Journal of Colorectal Disease. She has been the principal investigator on a number of clinical trials as well as publishing on health related quality of life, patient preferences in IBD and colorectal cancer surgery. Dr McLeod also has an interest in evidence based medicine and is the head of the Steering Committee for Evidence Based Reviews in Surgery, an internet journal club sponsored by the Canadian Association of General Surgeons and the American College of Surgeons. Dr. McLeod has published over 200 publications in peer-reviewed journals and over 50 published chapters in books as well as numerous presentations at scientific meetings and invited lectureships.46
  • Professor R McLeod Surgery and Post-operative Prophylaxis for Crohns DiseaseSurgery is an acceptable and important modality in the treatment of patients withCrohns disease. Unfortunately, while there are many beneficial effects of surgery,they may, at least in part, be negated by the risk of recurrent disease.Recurrence rates varying from 5-90% at 1 year have been reported depending onthe criteria used to define recurrence, the method of analysis and thecharacteristics of the study population. Clinical or symptomatic recurrence ratesare probably most clinically relevant. In a cohort of patients followedprospectively by our group, the clinical recurrence rate was 12% at one year and47% at three years. Others have reported rates ranging from 22 to 59% at 5years. There are also data suggesting that recurrence rates vary depending onthe site of the disease, number of previous resections and the indication forsurgery. Smokers also appear to have a higher risk of recurrence.Recognizing that recurrence following surgery is a significant problem, surgeonshave looked at various manoeuvers which might decrease the risk of recurrenceincluding ensuring that resection margins have normal histology, having longresection margins of normal bowel and performing different types ofanastomoses. While much of the data are conflicting, it seems that differences insurgical technique have little effect on the risk of recurrence. Fazio and colleaguesrecently published the results of a trial where patients were randomized to shortor long resection margins and after 56 months, the recurrence rates were 25%and 18% respectively. There is concern that obstruction to the fecal stream maybe important in causing recurrence and the reason for most recurrences occurringin the pre-anastomotic bowel. Furthermore, it is theorized that a wide side-to sideanastomosis may reduce the risk of recurrence. There are several retrospectivecase series which have reported divergent results and there is no firm evidencethat the type of anastomosis makes a difference. There is one small trial whichincluded patients with disease at variable sites and variable anastomotic typesbut the results did seem to show that a stapled anastomosis was superior.There are several trials studying the benefit of mesalamine, metronidazole,budesonide and imuran as postoperative maintenance therapy. Several trialshave shown that mesalamine has a modest benefit in reducing the risk ofrecurrence postoperatively. Another trial, reported by Korelitz and colleagues,compared mesalamine and imuran to placebo in a small trial of patients who hadhad an ileocolic resection. Both mesalamine and imuran were effective but imuranhad a significantly greater effect. Finally, smoking is known to increase the risk ofrecurrence and patients should be advised to stop smoking.In summary, recurrence following surgery is an important problem. Furtherstudies are required to assess the efficacy of both surgical techniques andmedical therapies and to classify patients according to risk of recurrence sopreventative strategies can be employed more rationally. As well, patientpreferences must be taken into account. 47
  • Professor R McLeod What can the surgeon do to decrease the risk of recurrence? 1 Stoma vs. anastomosis 2 Length of the resection margin 3 Histology of the resection margin 4 Type of anastomosis (ie:wide side to side anastomosis) Effect of Smoking on Crohn’s Disease Yamamoto and Keighley, 2000 • 10 studies reviewed-all retrospective • smokers defined as 5 cigarettes/d x 10 years; 7 cigarettes/d x 5 years • approximately 2 fold increase in recurrence rate in smokers • dose dependent relationship • effect more pronounced in women • ex-smokers seem to have the same risk as smokers48
  • Professor R McLeodPost-operative MaintenanceTherapy • 5ASA • Metronidazole • Fish oil • Budesonide • Imuran 49
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  • Professor F Shanahan Probiotics, first or last Fergus Shanahan Professor and Chair of the Department of Medicine at the National University of Ireland, University College CorkFergus Shanahan is Professor and Chair of the Department of Medicine at the NationalUniversity of Ireland, University College Cork (UCC). He is a Dublin graduate (UCD 1977).He was awarded the gold medal in medicine from the Mater hospital, Dublin. After internshipand residency in internal medicine in Dublin, he trained in Clinical Immunology at McMasterUniversity, Canada (1981-1983) and in Gastroenterology at the University of California, LosAngeles (UCLA; 1983-1985). He has been awarded Fellowships from the Royal College ofPhysicians in Ireland, Canada and the United Kingdom and the Fellowship of the AmericanCollege of Physicians. Before returning to Ireland in 1993 he was Associate Professor ofMedicine with tenure at UCLA. He has published over 300 scientific articles and severalbooks. He recently led a team of clinicians and scientists to successfully compete for thehighest research award ever given to biotechnology in Ireland, from Science FoundationIreland. This award enabled the creation of a new research centre – the AlimentaryPharmabiotic Centre – which investigates, amongst other things, the interface between foodand medicine in health and disease and the molecular basis of host-flora dialogue in the gut. 51
  • Professor F Shanahan Probiotics in inflammatory bowel disease Abstract: Therapeutic manipulation of gut flora with probiotics has emerged as a plausible strategy for prevention and possibly treatment of a variety of infectious, inflammatory and neoplastic disorders. While the efficacy of probiotics in enteric infections and post-antibiotic syndromes appears to be established, and there is impressive support for probiotic therapy in pouchitis, convincing evidence for efficacy in other forms of inflammatory bowel disease is still awaited. More importantly, there are several problems and pitfalls that need to be resolved before guidelines for routine clinical use of probiotics can be formulated. There is, at present, no reliable in vitro biomarker of probiotic performance in vivo and there are insufficient data on a range of critical issues such as optimum strain selection for different indications, product quality and shelf life, criteria on survival and gut transit, dose, optimal delivery vehicle and monitoring. In conclusion, before the promise of probiotics can be fully realised, several gaps in knowledge regarding food-grade bacteria and the intestinal ecosystem need to be addressed.52
  • Professor F Shanahan A Network of Connectivities Flora Lymphoid Tissue Epithelium Neurone Endothelium Fibroblasts MuscleIntestinal flora Flora as an asset Defense - bacterial antagonism Priming of mucosal immunity Peristalsis Metabolism of dietary carcinogens Synthesis of B & K vitamins Epithelial nutrients e.g. SCFAs Conversion of prodrugs Flora as a liability Procarcinogens carcinogens Overgrowth syndromes Opportunism - Translocation & Essential ingredient for IBD 53
  • Professor F Shanahan enteric flora Dendritic Cell APC’s Dendritic Cell Chemokines PRRs PRRs Naïve TH cells T effector & T reg TH 1 TH 2 TNF-α IL-4 IL-10 IFN-γ IL-5 TGF-β54
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  • Professor S Ghosh Crohn’s disease treatment: infliximab and beyond Professor Subrata Ghosh Imperial College, London Subrata Ghosh trained in gastroenterology in Bristol, Tokyo and Edinburgh and took up the position as consultant gastroenterologist at the Western General Hospital, Edinburgh in 1995. As a Part-time senior lecturer with the University of Edinburgh he published over 150 articles in peer-reviewed journals. In 2002 he took up the chair in gastroenterology at the Imperial College London, Hammersmith Hospital. Professor Ghosh is currently the secretary of the British Society of Gastroenterology IBD Committee and a member of the British Society of Gastroenterology Research Committee. He sits on the editorial board of Gut, Clinical Science, World Journal of Gastroenterology, Digestive and Liver Diseases and British Medical Bulletin. Professor Ghosh also acts as a referee for a number of medical charities, and sits on the research awards committee of NACC.56
  • Professor S Ghosh Crohn’s disease treatment: infliximab and beyondBiological therapies in inflammatory bowel disease have evolved fromunderstanding of the immunopathological basis of chronic inflammation andidentification of strategic therapeutic targets.Anti-Tumour Necrosis Factor strategies, the most studied of biological therapies,include chimeric monoclonal (infliximab), humanised monoclonal (CDP571 andCDP870), fully human monoclonal (adalimumab) antibodies, p75 fusion protein(etanercept) and p55 soluble receptor (onercept). The principal use of infliximabis in treating active Crohn’s disease patients not responding to or intolerant ofconventional therapies. Infliximab is steroid sparing. The development ofantibodies against infliximab is associated with an increased risk of infusionreactions and a reduced duration of response to treatment. Concomitantimmunosuppressive therapy reduces the immunogenic response and continuationof such treatment is desirable if tolerated. Maintenance infliximab therapy resultsin fewer hospitalisation and surgeries related to Crohn’s disease and a betterquality of life compared to episodic therapy on relapse.In patients who have failed therapy with corticosteroids and immunosuppressivetherapy and are poor surgical candidates and patients with fistulising disease arelikely to require regular maintenance therapy with infliximab. Other anti-TNFtherapies which appear promising include humanised pegylated Fab’ fragmentCDP870 and adalimumab. Etanercept is ineffective in Crohn’s disease, despite itsefficacy in rheumatoid arthritis. The difference between the efficacy of infliximaband etanercept in Crohn’s disease is explained by induction of lymphocyteapoptosis after binding to membrane TNF.Side effects of anti-TNF therapy include opportunistic infections includingpredisposition to tuberculosis, infusion reactions, delayed hypersensitivityreactions, and rarely demyelination and lupus. A number of other monoclonalantibody therapies appear to be promising including a humanised monoclonalantibody against α4 integrin (natalizumab), anti IL-12p40 and anti-γ interferonantibody. Therapy with GM-CSF also appears to be promising. Appropriatepharmaco-economic analysis of the efficacy and risk of these expensive therapy isrequired relevant to actual clinical use and initial analysis of infliximab use inCrohn’s disease appears to show cost-effectiveness. 57
  • Professor S Ghosh Biological therapy • Antibody based therapies • Recombinant peptides or proteins • Nucleic acid based therapies • Cell and gene therapies Biological agents Anti-cytokine antibodies. Anti-TNF Anti-IL-12 Anti-IL-2 receptor (Daclizumab) Anti-inflammatory cytokines. Selective adhesion molecule inhibition. Growth factor peptides58
  • Professor S Ghosh Proposed Mechanisms of Action for MAbsAntibody-dependent cell-mediatedcytotoxicity (ADCC)Complement-dependent cytotoxicity(CDC)Apoptosis of lymphocytes 59
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