british society of gastroenterology
TRANSCRIPT
British Society of Gastroenterology
Post Graduate Teaching Day
Inflammatory Bowel Disease
Monday, 14th March 2005
International Convention Centre Birmingham
Professor RFA Logan
POSTGRADUATE COURSE ‘Inflammatory Bowel Disease’ – Hall 1
Setting the Scene: Chair – Professor JC Atherton and Professor S Ghosh 10.00 Prevalence and pattern of IBD, including … Is Crohn’s disease
increasing? Professor RFA Logan, Nottingham
10.25 Bridging the gap : from genes to function, including … What does
Nod2 do? Professor DP Jewell, Oxford
10.50 Breaking down barriers : bacterial : epithelial crosstalk, including …
Is this the basis of inflammation? Professor IR Sanderson, London
11.15 Coffee Clinical controversies - illustrated with cases 11.35 Growing pains : IBD in adolescence
Professor IW Booth, Birmingham
12.00 Timing of colectomy in severe ulcerative colitis Dr SP Travis, Oxford
12.25 PSC – What treatment and when to transplant?
Dr RW Chapman, Oxford 12.50 Lunch (with opportunities to quiz the experts) Interdisciplinary: Chair – Dr MD Hellier and Dr SP Travis 14.00 Getting the most from your pathologist, including … Reducing
reports of non-specific colitis and … Does low grade dysplasia matter?
Professor M Novelli, London 14.25 Imaging for Crohn’s disease today and tomorrow, including … The
places of wireless Endoscopy and MRI Dr S Jackson, Plymouth
14.50 Surgery and postoperative prophylaxis for Crohn’s disease,
including … Does the operation matter? Professor R MacLeod, Toronto
15.20 Tea Back to the future: 15.45 Probiotics, first or last
Professor F Shanahan, Cork 16.15 Crohn’s disease treatment: infliximab and beyond
Professor S Ghosh, London
Prevalence and pattern of IBD
Professor R F A Logan Professor of Epidemiology, University of Nottingham
Richard Logan is Professor of Clinical Epidemiology at the University of Nottingham and an Honorary Consultant Gastroenterologist at the Queen’s Medical Centre. He qualified from Edinburgh University and did most of his training in clinical gastroenterology in Edinburgh and Scotland. After postgraduate training in epidemiology at the London School of Hygiene and Tropical Medicine, he moved to Nottingham in 1982 as a Wellcome Research Fellow to work with Professor Michael Langman. He was appointed Senior Lecturer in 1983 and Professor in 1997. His research has concerned the application of epidemiological methods to problems in gastrointestinal disease. He has a particular interest in coeliac disease, inflammatory bowel disease and in the epidemiological aspect of colorectal and oesophageal cancer.
Professor RFA Logan
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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 (protecting
Professor RFA Logan
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against UC) as the only consistent finding. Indeed two large studies of childhood IBD have recently reported disparate, if not conflicting findings. Armitage et al in an ecological analysis of childhood IBD in Scotland found significantly more CD but not UC in affluent areas while Baron et al in a case-control study in northern France found no relationship with higher socio-economic status for either disease but did find positive associations with certain vaccinations. It is difficult to avoid making the banal conclusion ‘more research is needed’. References 1. 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 Crohn's 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 Crohn's disease and ulcerative colitis in Northern France (1988-1999). Gut 2004;53(6):843-8.
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Anderson et al, NEJM 2001
Recent Time Trends in Incidence of Crohn's Disease
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YEAR 1961 1963 1965 1967 1969 1971 1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997
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ABERDEEN(7) BLACKPOOL(70) CARDIFF(8) DERBY(71) STOCKHOLM(18)OREBRO,SWE(72) ROCHESTER,US(6) COPENHAGEN(73)
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Recent Time Trends in Incidence of Ulcerative Colitis
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16019
6019
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8019
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denc
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illio
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CARDIFF(74) COPENHAGEN(75) OREBRO, SWE(76)UPPSALA, SWE(77) ROCHESTER, US(78)
Professor RFA Logan
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Space for Notes
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Bridging the gap: from genes to function
Professor Derek Jewell University of Oxford, Radcliffe Infirmary, Oxford
D.P. Jewell is Professor of Gastroenterology in Oxford. Much of his training was in Oxford and his interest in Gastroenterology was stimulated by Dr Sidney Truelove. He spent over a year in the Gastroenterology Department of Stanford University before returning as Senior Lecturer in Medicine at the Royal Free Hospital. He has been back in Oxford since 1980. Research interests have mainly centred around inflammatory bowel disease and coeliac disease and include clinical, therapeutic, immunological and genetic aspects. He has been Chairman of the International Organisation for the Study of Inflammatory Bowel Disease and is a past-President of the British Society of Gastroenterology.
Professor D Jewell
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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.
Professor D Jewell
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In summary, the identification of NOD2/CARD15 mutations in many patients with ileal Crohn’s disease and the observation that this may be associated with a deficient anti-microbial defence, highlights the interaction between environment and genetic susceptibility and in particular, the role of bacterial molecules (e.g. peptidoglycan, LPS, flagellin, CpG DNA) and pattern-recognition receptors within cells. References Ahmad T, Armuzzi A, Bunce M, Mulcahy-Hawes K, Marshall SE, Orchard TR, et al. The molecular classification of the clinical manifestations of Crohn's disease. Gastroenterology 2002;122(4):854-66. Ahmad T, Tamboli CP, Jewell D, Colombel JF. Clinical relevance of advances in genetics and pharmacogenetics of IBD. Gastroenterology 2004;126(6):1533-49. Bonen DK, Ogura Y, Nicolae DL, Inohara N, Saab L, Tanabe T, et al. Crohn's disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan. Gastroenterology 2003;124(1):140-6. Gollop JH, Phillips SF, III LJM, Zinsmeister AR. Epidemiologic aspects of Crohn's disease: 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 epithelial cells. Gastroenterology 2003;124(4):993-1000. Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's 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 intestinal tract. Science 2005;307(5710):731-4. Lala S, Ogura Y, Osborne C, Hor SY, Bromfield A, Davies S, et al. Crohn's disease and 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 mutation in Crohn's 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 Crohn's disease are associated with diminished mucosal alpha-defensin expression. Gut 2004;53(11):1658-64.
Professor D Jewell
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Interaction between Gene Products and Environment
Bacterial recognition receptors - Toll-like receptors
Intracellular receptors - NOD1, NOD2
Antigen processing - HLA Class II
Epithelial integrity - Organic cationtransporters
CARD15 protein variants associated with Crohn’s disease
Hugot JP et al. Nature 2001
CARD1 CARD2 NBD LRR1 121 129 217 260 570 744 10201040
R702W G908R 1007fs
Apoptosis Oligomerization Ligand-binding
• Expressed in monocytes
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Functional Significance of NOD2 mutations
1. Failure to kill intracellular organisms in vitroHisamatsu et al, 2003
2. 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
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Space for Notes
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Breaking down barriers - Bacterial epithelial cross - talk
Ian R Sanderson Professor of Paediatric Gastroenterology
Barts & The London, London, UK Ian Sanderson is Professor of Paediatric Gastroenterology and Head of Adult & Paediatric Gastroenterology at Barts & The London, Queen Mary’s School of Medicine. He first became interested in the intestine as a graduate student under Dennis Parsons where he examined the exit of absorbed amino acids from the enterocyte. After finishing his medical studies he worked as a house officer to Dr Anthony Dawson and trained as a paediatrician. He was the CICRA Clinical Research Fellow at St Bartholomew’s Hospital where he demonstrated that an elemental diet was as effective as high dose steroids in children with Crohn’s disease. 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 in Dr Allan Walker’s department. He become Assistant Professor of Paediatrics and Director of the Developmental Gastroenterology Laboratory at the Harvard Clinical Nutrition Research Centre. He developed the concept that luminal factors regulate genes in the epithelium that signal to the mucosal immune system. By this means, changes in diet can act through enterocytes altering inflammatory mechanisms in the intestine. Professor Sanderson was awarded the Crohn’s and Colitis Foundation of American Silver Jubilee medal for his work in childhood Crohn’s disease and the Norman Kretchmer Award in Nutrition and Development for his work on the affect of diet on genes in the developing intestine. His current laboratory in London examines how dietary factors act on genes in the epithelium both through promoter-based mechanisms and through changes in chromosomal structure.
Professor I Sanderson
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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.
Professor I Sanderson
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Signalling mechanisms in gut innate immunity
Didierlaurent et al. Cellular Microbiol 2002
Pathogen-associated molecular patterns (PAMPs)
Toll-like Receptors+
Nucleotide-binding site-leucine-rich repeat family
Signalling through TLRs reduces inflammation in mice given DSS
Wild-type mice survive inflammation from DSS.
Mice in whom signallingthrough TLRs is impaired (lacking MyD88; TLR2 or TLR4) have worse inflammation and die
Rakoff-Nahoum et al., 2004
Professor I Sanderson
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Dendritic cells express a chemokine receptor that controls bacterial
clearanceThe CX3CR1 (Green) is expressed on intestinal dendritic cells. Arrows indicateinter-epithelial cell projections
Niess et al., 2005
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Space for Notes
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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.
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Growing Pains: IBD in Adolescence Effective treatment of IBD in adolescents depends more on a knowledge of the physiology and psychology of adolescents than a familiarity with altered responses to treatment, which are few. In general, adolescents respond to conventional therapies in the same way as adults. In many ways, the style of management 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 by energetic nutritional support and/or judicious surgery are in themselves, important aims of therapy. In addition to a growth spurt, adolescence is also characterised by psychological changes which have major implications for adherence to treatment and therefore to growth and nutritional status. An ability to perceive the long-term implications of current actions is still being acquired in adolescence and there is a strong feeling of self-invincibility. In marked contrast with the need to affiliate with one’s peer group, there is an increased frequency of conflict with parents and other authority figures including doctors, regarding boundaries of appropriate behaviour. Chronic gastrointestinal disease, with a perceived need for dependence on others, is often complicated by symptoms of anxiety and depression, together with poor school work and social interactions. Specific problems, such as incontinence, diarrhoea or a stoma may also be present, although a stoma is by no means a psychosocial disaster in children and adolescents. Certainly, colectomy should not be deferred because of a fear of the emotional consequences of stoma surgery in children and adolescents. New problems such as poor drug or dietary compliance, or erratic outpatient attendance, may arise, and a formal authoritarian approach on the part of attending doctors and their colleagues is almost invariably fruitless. Whilst adolescent patients require sympathetic handling and extra support, so do their parents, most of whom find it difficult to relinquish the responsibility for the care of a sick child to the patient themselves. This is particularly so if the patient shows little interest in self-care and the parents require extra help while undergoing this difficult process. References Suris J.C., Michaud P.A., Viner R, – The Adolescent with a Chronic Condition. Part 1: Developmental Issues Arch Dis Child 2004; 89: 934-42Michaud P.A., Suris J.C., Viner R, – The Adolescent with a Chronic Condition. Part 2: Health Care Provision Arch Dis Child 2004; 89: 943-49. Christie D, Viner R, - Adolescent Development BMJ 2005; 330: 301-304 Booth I.W., Hills S, - Best Practice in Crohns Disease in Children and Adolescents in the Effective Management of Crohns Disease (Hawkey et al eds) 2003. Viner R, - Transition from Paediatric to Adult Care. Bridging the Gaps for Passing the Buck? Arch Dis Child 1999; 81: 271-275. Heuschkel R.B., et al – Enteral Nutrition and Corticosteroids in the Treatment of Acute Crohns Disease in Children, JPEN 2000; 31: 8-15
Professor I Booth
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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 socioculturalenvironment
(Christie and Viner BMJ 2005; 330:301-304)
The challenges for young people
• Challenging authority• Taking risks • Experimenting with drugs, alcohol,
and sex• Challenging the moral and social
structure of society• Demanding rights• Taking responsibility for self and
others
• Seeking spiritual paths (organised or cult religions)
• Getting a job• Changing schools and educational
environment• Developing relationships• Understanding sexuality• Renegotiating rules at home
(Christie and Viner BMJ 2005; 330:301-304)
Professor I Booth
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Bridging the gap
Paediatric paradigm• family centered• developmentally
focused• ignores independence
and increasingly adult behaviour
Adult medical culture• acknowledges
autonomy, reproduction, jobs
• ignores growth, development and family concerns
Transition clinics
Professor I Booth
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Space for Notes
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Timing of colectomy in severe ulcerative colitis
Simon TRAVIS DPhil FRCP Consultant Physician and Gastroenterologist
John Radcliffe Hospital, Oxford Consultant Physician and Gastroenterologist, John Radcliffe Hospital. Fellow, Linacre College, Oxford. Clinical Director of Gastroenterology, Oxford. Chairman of IBD Section and member of Council, British Society of Gastroenterology. UK representative and member of scientific committee, European Crohn's and Colitis Organisation. Secretary to Medical Advisers and Trustee, National Association of Colitis and Crohn's Disease. Qualified St Thomas' Hospital, London 1981. Research interests in therapeutics and clinical prediction of IBD. Principal investigator for RDP58 (novel anti-cytokine decapeptide). Peripheral interest in gastrointestinal physiology at high altitude.
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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.
Dr S Travis
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Lennard-Jones JE, Ritchie JK, Hilder W, Spicer CC. Assessment of severity in colitis: a preliminary study. Gut 1975; 16:579-84. Lindgren SC, Flood LM, Kilander AF, et al. Early predictors of gluticorticoid treatment 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 ulcerative colitis. Gut 1996; 38:905-910 Travis SPL. Predicting outcome in severe colitis Dig Liver Dis 2004; 36:448-50.
Dr S Travis
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National experience: 29/45 UK centres
116
33 36(28%) (31%)
47(41%)
Colectomy
Remission
Partial response
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/dthen 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 1998
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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
Dr S Travis
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Space for Notes
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Primary Sclerosing Cholangitis - What treatment and when to refer?
Dr Roger Chapman BSc, MD, MBBS, FRCP John Radcliffe Hospital Headington Oxford
Roger Chapman trained in liver disease at the Royal Free Hospital with the late Dame Sheila Sherlock, before moving to Oxford in 1981,obtaining an MD on Iron metabolism in liver disease. In addition he developed a life long interest in liver problems associated with inflammatory bowel disease particularly PSC. In 1984 he spent a year at the University of Washington as visiting scientist. His current research interests include combination medical therapy with UDCA and antibiotics in PSC and the role of retroviruses in the aetiology of autoimmune liver diseases.
Dr R Chapman
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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.
Dr R Chapman
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The timing of liver transplantation in PSC is particularly difficult,and prognostic models have not proved to be useful in individual cases. Indications for transplantation include deepening jaundice (bilirubin > 100umol/l), hepatic decompensation, refractory itching and possibly biliary dysplasia. Hepatic transplantation in PSC is associated with a good 5 year survival although recurrence of PSC occurs in about 30%.
References
1. Harnois DM, Angulo P, Jorgencen RA, LaRusso NF, Lindor KD High dose Ursodeoxycholic Acid as a therapy for patients with PSC. Am J Gasteroenterol 2001; 96:1558-1662
2. Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, Chapman RW A preliminary trial of high dose Ursodeoxycholic Acid in primary sclerosing cholangitis. Gastroenterology 2001; 121:900-909
Dr R Chapman
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Management of PSCcomplicated!
Management of cholestasisManagement of cirrhosisManagement of biliary complicationsManagement of inflammatory bowel diseaseSpecific medical therapyAppropriate referral for liver transplantation
High dose Scandanavian Trial
Death /Transplantation:
7.2% UDCA vs 10.9% placebo(ns)
Dr R Chapman
32
Indications for Liver Transplantation in PSC
Persistent jaundice (bili > 100 umol /L)Hepatic decompensation
-ascites;variceal bleed;encephFatigue(?);refractory itch;malaiseBiliary dysplasia (?)
Timing of Transplant - DIFFICULT!
Dr R Chapman
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Space for Notes
34
Getting the most from your pathologist
Professor M Novelli London
Marco Novelli studied medicine at the University of Bristol qualifying in 1987. Following housejobs he took an MSc in Experimental pathology and Toxicology at the Royal Postgraduate Medical School, London. He started his pathology training in Bristol, but after 3 years moved to the Imperial Cancer Research Fund in London where he studied for a PhD on ‘Aspects of the Genetics and Biology of Colorectal Carcinoma’ under the supervision of Sir Walter Bodmer and Nick Wright. His pathology training was completed at University College Hospital, where he has since remained as a Consultant Histopathologist. In 2004 he was promoted to Professor of Gastrointestinal Pathology. His major research interests include clonality in epithelial tissues and early carcinogenesis, colorectal and small intestinal carcinogenesis in FAP, and the pathology of Barrett’s oesophagus.
Professor M Novelli
35
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.
Professor M Novelli
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Reducing 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
High grade
• Colectomy.
Low grade
• Increased surveillance.
• ? Colectomy.
Treatment of flat dysplasia in IBD
Professor M Novelli
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Adenoma-like Non adenoma-like
Outside area of colitis
• Polypectomy.• Regular
surveillance.
Colectomy.
Within area of colitis
• Polypectomy.• Confirm absence
flat dysplasia.• ? Increased
surveillance.
DALM(High and low grade)
Professor M Novelli
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Space for Notes
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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.
Dr S Jackson
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Imaging for Crohn’s disease today and tomorrow. The complexity of diagnostic imaging algorithms available for the investigation of patients with Crohn’s disease (CD), particularly when confined to the small intestine, continues to expand. For many years, barium studies including the barium follow through (small bowel meal) and enteroclysis (small bowel enema) examinations were considered the principal tools for the diagnosis and evaluation of disease extent (1). Whilst both techniques, particularly when performed by dedicated radiologists, remain accurate examinations for the diagnosis of primary and recurrent pathology, they are limited in their capacity to demonstrate both transmural and extramural extent of disease as well as assess disease activity and the presence of extra-luminal complications. The examinations also result in a significant radiation dose to patients, the majority of whom present at a young age. Since the 1980’s the use of cross sectional imaging techniques namely CT, MRI and ultrasound have become increasingly important in the patients diagnostic pathway. The modalities are used to confirm the diagnosis, localize the position and number of lesions as well as assess disease activity and severity. Importantly the presence of extra-luminal complications can be accurately evaluated as well as other factors, which may influence subsequent surgical intervention (2,3). The more limited spatial resolution of these examinations when compared with conventional enteroclysis reduces sensitivity for the diagnosis of superficial mucosal pathology. MRI
Early attempts to evaluate the small bowel were limited due to prolonged examination times. However the introduction of ultra-fast sequences as well as the excellent soft tissue contrast resolution and multi-planar imaging capabilities confer clear advantages of MRI over other diagnostic modalities for the investigation of small bowel disease. Intra-luminal contrast agents remain fundamental to a high quality examination. These may be administered either orally or directly into the small bowel via a feeding tube. This latter technique termed magnetic resonance enteroclysis (MRE) is invasive and time consuming but yields excellent results for the evaluation of both transmural and extramural small bowel disease (4,5). Capsule endoscopy
Whilst conventional imaging techniques demonstrate limited sensitivity for the diagnosis of early superficial disease, direct visualization of the small bowel intestinal mucosa is accomplished by conventional and more recently wireless capsule endoscopy (PillCamTM). Limited studies have so far been published assessing the impact of capsule endoscopy (CE) on the clinical decision making and therapeutic outcome in patients with CD (6,7,8). Results to date suggest that CE is effective in the diagnosis of patients with suspected CD who have previously undergone negative imaging. It should however be remembered that isolated superficial small bowel erosions may be secondary to other pathology. The role of CE in patients with known CD is so far undetermined. Capsule retention due to small bowel strictures remains a problem however the recent development of a patency capsule may reduce retention rates.
Dr S Jackson
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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;35:564-568
Dr S Jackson
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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
Dr S Jackson
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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”
Dr S Jackson
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Space for Notes
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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.
Professor R McLeod
46
Surgery and Post-operative Prophylaxis for Crohn's Disease Surgery is an acceptable and important modality in the treatment of patients with Crohn's 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 on the criteria used to define recurrence, the method of analysis and the characteristics of the study population. Clinical or symptomatic recurrence rates are probably most clinically relevant. In a cohort of patients followed prospectively by our group, the clinical recurrence rate was 12% at one year and 47% at three years. Others have reported rates ranging from 22 to 59% at 5 years. There are also data suggesting that recurrence rates vary depending on the site of the disease, number of previous resections and the indication for surgery. Smokers also appear to have a higher risk of recurrence. Recognizing that recurrence following surgery is a significant problem, surgeons have looked at various manoeuvers which might decrease the risk of recurrence including ensuring that resection margins have normal histology, having long resection margins of normal bowel and performing different types of anastomoses. While much of the data are conflicting, it seems that differences in surgical technique have little effect on the risk of recurrence. Fazio and colleagues recently published the results of a trial where patients were randomized to short or long resection margins and after 56 months, the recurrence rates were 25% and 18% respectively. There is concern that obstruction to the fecal stream may be important in causing recurrence and the reason for most recurrences occurring in the pre-anastomotic bowel. Furthermore, it is theorized that a wide side-to side anastomosis may reduce the risk of recurrence. There are several retrospective case series which have reported divergent results and there is no firm evidence that the type of anastomosis makes a difference. There is one small trial which included patients with disease at variable sites and variable anastomotic types but 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 trials have shown that mesalamine has a modest benefit in reducing the risk of recurrence postoperatively. Another trial, reported by Korelitz and colleagues, compared mesalamine and imuran to placebo in a small trial of patients who had had an ileocolic resection. Both mesalamine and imuran were effective but imuran had a significantly greater effect. Finally, smoking is known to increase the risk of recurrence and patients should be advised to stop smoking. In summary, recurrence following surgery is an important problem. Further studies are required to assess the efficacy of both surgical techniques and medical therapies and to classify patients according to risk of recurrence so preventative strategies can be employed more rationally. As well, patient preferences must be taken into account.
Professor R McLeod
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What can the surgeon do to decrease the risk of recurrence?
1 Stoma vs. anastomosis2 Length of the resection margin3 Histology of the resection margin4 Type of anastomosis (ie:wide side to
side anastomosis)
Effect of Smoking on Crohn’s DiseaseYamamoto 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
smokers
Professor R McLeod
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• 5ASA• Metronidazole• Fish oil• Budesonide• Imuran
Post-operative MaintenanceTherapy
Professor R McLeod
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Space for Notes
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Probiotics, first or last
Fergus Shanahan Professor and Chair of the Department of Medicine at the National
University of Ireland, University College Cork
Fergus Shanahan is Professor and Chair of the Department of Medicine at the National University 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 internship and residency in internal medicine in Dublin, he trained in Clinical Immunology at McMaster University, Canada (1981-1983) and in Gastroenterology at the University of California, Los Angeles (UCLA; 1983-1985). He has been awarded Fellowships from the Royal College of Physicians in Ireland, Canada and the United Kingdom and the Fellowship of the American College of Physicians. Before returning to Ireland in 1993 he was Associate Professor of Medicine with tenure at UCLA. He has published over 300 scientific articles and several books. He recently led a team of clinicians and scientists to successfully compete for the highest research award ever given to biotechnology in Ireland, from Science Foundation Ireland. This award enabled the creation of a new research centre – the Alimentary Pharmabiotic Centre – which investigates, amongst other things, the interface between food and medicine in health and disease and the molecular basis of host-flora dialogue in the gut.
Professor F Shanahan
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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.
Professor F Shanahan
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A Network of Connectivities
Epithelium
Fibroblasts
Endothelium
FloraLymphoid
Tissue
Neurone
Muscle
Intestinal floraFlora as an assetDefense - bacterial antagonismPriming of mucosal immunityPeristalsisMetabolism of dietary carcinogens Synthesis of B & K vitaminsEpithelial nutrients e.g. SCFAsConversion of prodrugs
Flora as a liabilityProcarcinogens carcinogens Overgrowth syndromes Opportunism - Translocation
&Essential ingredient for IBD
Professor F Shanahan
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enteric flora
APC’s
Chemokines
DendriticCell
DendriticCell
T effector & T reg
IL-10TGF-β
IL-4IL-5
TNF-αIFN-γ
TH 1 TH 2
PRRs PRRsNaïve TH cells
Professor F Shanahan
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Space for Notes
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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.
Professor S Ghosh
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Crohn’s disease treatment: infliximab and beyond Biological therapies in inflammatory bowel disease have evolved from understanding of the immunopathological basis of chronic inflammation and identification of strategic therapeutic targets. Anti-Tumour Necrosis Factor strategies, the most studied of biological therapies, include chimeric monoclonal (infliximab), humanised monoclonal (CDP571 and CDP870), fully human monoclonal (adalimumab) antibodies, p75 fusion protein (etanercept) and p55 soluble receptor (onercept). The principal use of infliximab is in treating active Crohn’s disease patients not responding to or intolerant of conventional therapies. Infliximab is steroid sparing. The development of antibodies against infliximab is associated with an increased risk of infusion reactions and a reduced duration of response to treatment. Concomitant immunosuppressive therapy reduces the immunogenic response and continuation of such treatment is desirable if tolerated. Maintenance infliximab therapy results in fewer hospitalisation and surgeries related to Crohn’s disease and a better quality of life compared to episodic therapy on relapse. In patients who have failed therapy with corticosteroids and immunosuppressive therapy and are poor surgical candidates and patients with fistulising disease are likely to require regular maintenance therapy with infliximab. Other anti-TNF therapies which appear promising include humanised pegylated Fab’ fragment CDP870 and adalimumab. Etanercept is ineffective in Crohn’s disease, despite its efficacy in rheumatoid arthritis. The difference between the efficacy of infliximab and etanercept in Crohn’s disease is explained by induction of lymphocyte apoptosis after binding to membrane TNF. Side effects of anti-TNF therapy include opportunistic infections including predisposition to tuberculosis, infusion reactions, delayed hypersensitivity reactions, and rarely demyelination and lupus. A number of other monoclonal antibody therapies appear to be promising including a humanised monoclonal antibody against α4 integrin (natalizumab), anti IL-12p40 and anti-γ interferon antibody. Therapy with GM-CSF also appears to be promising. Appropriate pharmaco-economic analysis of the efficacy and risk of these expensive therapy is required relevant to actual clinical use and initial analysis of infliximab use in Crohn’s disease appears to show cost-effectiveness.
Professor S Ghosh
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Biological therapy• Antibody based therapies
• Recombinant peptides or proteins
• Nucleic acid based therapies
• Cell and gene therapies
Biological agentsAnti-cytokine antibodies.
Anti-TNFAnti-IL-12Anti-IL-2 receptor (Daclizumab)
Anti-inflammatory cytokines.
Selective adhesion molecule inhibition.
Growth factor peptides
Professor S Ghosh
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Proposed Mechanismsof Action for MAbs
Antibody-dependent cell-mediated cytotoxicity (ADCC)
Complement-dependent cytotoxicity(CDC)
Apoptosis of lymphocytes
Professor S Ghosh
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Space for Notes
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