Inflammatory Bowel Disease

Translating Basic Science into Clinical Practice

Stephan R. Targan, Fergus Shanahan, Loren C. Karp

• Publisher: Wiley-Blackwell
• Year: 2011
• ISBN:
  9781444359114
• Edition: 1
• Topic: Medicine
• Subtopic: Gastroenterology & Hepatology

This is the state-of–the-art book on inflammatory bowel disease you have been waiting for

Written and edited by international experts in gastroenterology this up-to-date volume provides a complete review of the basic science behind inflammatory bowel disease (IBD), as well as evidence-based clinical guidance on diagnosis, treatment and long-term management of IBD.

In 50 chapters the authors cover the latest and most promising treatment modalities and the science behind them. There are chapters which cover the advances in the medical and surgical treatment of conditions such as Crohn's disease and ulcerative colitis, as well as chapters focusing on nutrition, imaging and complementary medicine.

This is an invaluable information resource for all those in the medical team treating patients with IBD. Whether you are a gastroenterologist, gastrointestinal surgeon or GI nurse specialist this book deserves a place in your library.

Chapter 1

Introduction: the Science and the Art of Inflammatory Bowel Disease

Fergus Shanahan¹, Loren C. Karp² & Stephan R. Targan²

¹University College Cork, National University of Ireland, Cork, Ireland

²Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

This book is about the science and the art and the science of the art of gastroenterology as it pertains to inflammatory bowel disease. Once described as disabling and under-researched diseases, the inflammatory bowel diseases now attract intense interest from clinical and basic investigators, but remain an important cause of suffering and a major burden on healthcare resources.

Why another textbook, in this era of rapid information access? The answer is simple – there is a continuing need for informed opinion and perspective on the deluge of data generated in recent years spanning a diversity of aspects of inflammatory bowel disease. Many wish for a single repository of information from authoritative sources. With this in mind, the authors for this textbook were selected because they are expert and currently active contributors to their respective areas of the field. Each was charged with delivering a crisp, timely and opinionated account of their area with a futuristic perspective.

A recurring theme within modern biology in general and inflammatory bowel disease, in particular, is the need to think across traditional boundaries of intellectual pursuit and to be aware of research at the interface of disparate disciplines. The convergence of different research avenues in inflammatory bowel disease is represented by the host–microbe interface; other pertinent examples have been variably expressed as the brain–gut axis, immunoepithelial dialogue and neuroimmunology. Each is embraced in this textbook in various chapters dealing with disease mechanisms.

One of the great lessons of the recent past in gastroenterology was the failure of traditional epidemiologic and biologic approaches to identify a transmissible agent as the cause of peptic ulcer disease. A more important lesson was that the solution to some complex diseases may never be found by research focused exclusively on the host, without due regard for host–environment interactions, particularly host–microbe interactions. In the future, investigators involved in epidemiologic, genetic or other areas of research in inflammatory bowel disease will have to approach their challenge with some form of rapprochement with disease mechanisms. It is noteworthy, for example, that the genetic risk factors for inflammatory bowel disease are responsible for sensing and interpreting the microenvironment (e.g. NOD2/CARD15) or are involved in the regulation of the host immune response to that microenvironment (e.g. autophagy, IL23R). The complexity and clinical implications of these interactions are discussed by several authors in this volume.

Advances in technology have greatly facilitated research in inflammatory bowel disease. These include automated approaches to gene sequencing and genotyping large numbers of study subjects and molecular strategies for studying the intestinal microbiota, most of which is still unculturable and, therefore, neglected or considered until recently to be obscure. The human organism is now viewed as a composite of the human genome and its commensal microbial genome (microbiome), both of which interact with environmental and lifestyle modifying factors. As the human microbiome project and other similar metagenomic collaborations around the world deliver new information on the diversity and individual variations in the intestinal microbiota, it is anticipated that some of the heterogeneity of inflammatory bowel disease may be resolved. Thus, genetic risk factors will have to be reconciled with variations in microbial composition and with patterns of immunologic responsiveness to the microbiota. The challenge for epidemiologists and biologists will be to relate the aspects of a modern lifestyle with changes in the microbiota and thence with immunologic behavior and susceptibility to disease. Thus, the elucidation of the “IBD genome” provides the foundation for micro- and macro-environmental epidemiologic investigation. The contributing authors to this text have provided the background to this futuristic scenario.

Has the relentless march of the biotech and genotech era of research delivered for the patient? Unquestionably patients are better off today than they were only a generation ago. A more coherent understanding of fundamental disease mechanisms is being translated into improved patient management with a progressive shift toward evidence-based approaches and away from therapeutic empiricism. This is reflected throughout those chapters of this book dedicated to patient care.

Although not quite at the stage of personalized health-care, the splitters are in the ascendancy over the lumpers in today’s approach to the patient with inflammatory bowel disease. Refinement of clinical phenotypes by fusing genetic variation and the functional consequences thereof will lead to the reclassification of standard clinical phenotypes into physiologically determined subgroups and ultimately to individualized therapeutic targeting. These critical steps will continue to inform the interpretation of data on the genotype. This represents just one of many opportunities for clinicians and basic scientists to engage in a mutually beneficial manner in translating bench-to-bedside research to improved management of inflammatory bowel disease.

But some things never change. Clinical care of chronic disease will always require attention to detail, compassion and a commitment to long-term follow-up. In the face of the extraordinary advances in therapeutics, which continue apace, there is substantial patient dissatisfaction with modern medicine, either because of increasing expectations or reduced tolerance of illness. Most patients place greatest emphasis on the doctor–patient relationship. In this relationship, the attitude and level of interest of the former will always be a major determinant of the outcome of the latter.

Textbooks like this cannot confer attitude, energy or enthusiasm on the reader, but they can sensitize and equip the reader with the necessary background information, opinion and perspective. Therein lies the essence of what is intended with this book – to provide stimulus and steerage for the interested clinician, scientist and clinician–scientist in what is already an intriguing and rewarding field of endeavor.

Chapter 2

Heterogeneity of Inflammatory Bowel Diseases

Loren C. Karp & Stephan R. Targan

Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Summary

• Heterogeneity in the inflammatory bowel diseases exists at the genetic, immunologic, subclinical and clinical levels.
• The mucosal inflammation that characterizes inflammatory bowel diseases is underpinned by multiple combinations of genes and innate and/or adaptive immune responses that determine disease expression and behavior.
• Serum immune responses are markers of underlying disease activity.
• Multiple genetic variants have been associated with inflammatory bowel diseases.
• Combinatorial genomics, studying the genetic variants and associated immune pathways in combination with disease markers, is leading to the development of distinct phenotypic subgroups and is identifying targets for the development of personalized therapeutic approaches.

Introduction

The chapters in this book describe the foundation of our premise about the heterogeneous nature of the inflammatory bowel diseases (IBDs). In the basic science chapters, we learn that mechanisms underlying disease expression vary genetically and immunologically and that potentially, the possibilities are as many as can be made with the known genes and variants, cells and microorganisms. In the translational and clinical chapters, we read evidence that distinct genetic and immunologic underpinnings differentiate groups of patients, setting the stage for a personalized medicine approach to treating these disorders.

Heterogeneity of inflammatory bowel diseases has been documented in the medical literature for more than a century. In 1905, Dr J.E. Summers Jr wrote, “Colitis of its different types is not uncommon; clinically, they are at some stages so much alike that a proper classification has not been made” [1]. In one simple sentence, we learn that early in the 20th century it was acknowledged by the medical field that there are many types of colitis, but defining them is confounded by their similarities and differences. Clinical heterogeneity of Crohn’s disease is mentioned in the literature as early as 1932, when Dr Burrill Crohn published the first report of what he called “regional enteritis” in JAMA [2]. Dr Crohn described four “various types of clinical course under which most of the cases may be grouped: (1) acute intra-abdominal disease with peritoneal irritation, (2) symptoms of ulcerative enteritis, (3) symptoms of chronic obstruction of the small intestine and (4) persistent and intractable fistulas in the right lower quadrant following previous drainage for ulcer or abdominal abscess.” Similarly, in 1953, Dr Bryan Brooke, writing about ulcerative colitis in reference to the likelihood that no single pathogen can be identified as causal, stated, “It is suggested that ulcerative colitis is not a specific disease, but a pathological state ...” [3]. Dr J.B. Kirsner, in noting that ulcerative colitis has symptoms similar to other diseases, said, “Ulcerative colitis is merely a name for a class of disease which hitherto had been included under the name dysentery” [4]. From this era, when original observation and description were the hallmarks of excellence in medical research, decades of scholarly activity ensued, with an emphasis on trying to categorize the vast variability in clinical expression of inflammatory bowel diseases into descriptive categories for the purpose of diagnosis and treatment.

Attempts by physicians and scientists to harness IBD heterogeneous expression into the foundation of a framework by which to study these disorders has evolved into the modern hypothesis of disease pathogenesis. Early theories were based on the expectation that a single pathogen was to blame, although in the 1970s and 1980s this notion was abandoned by many and the immune response became the focus. By 1989, many of the elements of the contemporary hypothesis were in place. At that time, it was hypothesized that “tissue damage might be due to a direct attack by the mucosal immune system on a specific target, such as the surface, or glandular epithelial cell” [5]. The possibility of “a non-specific outcome of disordered mucosal immune regulation” was suggested, “with uncontrolled over-reactivity to environmental antigens based on a defective downregulation of this response” [5]. It was further postulated that “genetic predisposing factors and exogenous triggers might operate at the level of the ‘target’ cell or at the level of the mucosal immune system” [5]. In 1990, Dr Stephan Targan, leading an effort by a panel of experts to set a scientific agenda for inflammatory bowel disease research, advanced the concept of “reagent grade populations” [5]. Available treatments at the time were not aimed at any particular cause of disease. In the resulting “white paper”, he described the need for defined populations of subgroups of patients with varying clinical and subclinical markers should be assembled. He further stated that:

Such “reagent-grade” populations will be invaluable in reducing the time and improving the accuracy of all studies using tissues or dependent upon clinical signals from patients. These patients would be a source of materials for the tissue banks and would serve as an extant “pure” population for clinical trials of new therapeutic agents.

Over the last 20 years, three working parties have attempted to formalize an inflammatory bowel disease classification system. In 1991, an international working party assembled in Rome devised a classification for Crohn’s disease based on anatomical distribution, surgical history and disease behavior. Seven years later, the “Rome Classification” was re-evaluated by a group attending the World Congress of Gastroenterology in Vienna. The resulting “Vienna Classification” of Crohn’s disease proposed the parameters of age of onset, disease location and disease behavior. Most recently, a group meeting in Montreal expanded upon the three phenotypic parameters and modified the criteria. The “Montreal Classification” added distinctions made by serum immune markers and genetic markers and also proposed a classification for ulcerative colitis. The changes were “supported by an evolving body of evidence demonstrating that site of disease, behavior and disease progression are all variables that are likely to be identified by genetic and serological markers” [6].

It was not until the study of serological markers and their use for identifying pathophysiologically distinct subgroups that science yielded to the biologic reality that although it may be of clinical benefit and of benefit to researchers to define subgroups, numerous types of disease expression, with unique biologic processes and distinctive genetic, immunologic and clinical manifestation, exist. Nevertheless, to rein in the possibilities, focus investigation and to test treatments, groups of patients must be identified based on common, known variables. In the current hypothesis, that IBD results in a genetically susceptible individual via a dysregulated immune response to commensal flora, it has been established that there are multiple gene variants that are conferring susceptibility and that IBD patients mount immune responses to numerous microbes.

These authors long ago proposed that the classifications of Crohn’s disease, ulcerative colitis and indeterminate colitis are somewhat false. This assertion was based on our emerging understanding of the underlying pathogenesis. Somewhat homogeneous groups of patients can be determined by similar genetic and immunologic and clinical data. Already a case is being made for deter...