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Inflammatory bowel disease: dogmas and heresies
UIEWPOINT
Inflammatory
DIGEST LIVER DIS 2002;34:306-11
bowel disease:
C. Fiocchi
dogmas
and heresies
Perception of a disease state by the practising physician is based on how easily the diagnosis can be made and how predictable the outcome of the chosen therapy is. The academic investigator perceives the same disease based on how well its cause and mechanism are understood, and how rational pathophysiology-based treatments are. Because of incomplete knowledge, neither the practising physician nor the academic investigator are comfortable in dealing with inflammatory bowel disease, and both seek help in the dogmas and heresies inof unknown aetiology evitably associated with chronic disease
Digest
liver
Key words:
Ois 2002;34:306-11 Crohn’s
disease;
inflammatory
bowel
disease:
ulcerative
colitis
Introduction
1 Flvm Divisionof Gastmenterology, University Hospitalsof Cleveland, CaseWestern ReserveUniversitySchoolof Medicine, Cleveland, Ohio,USA.
M&we hr mwmepedeece Or. C. Fiocchi, Division of Gestroenterology, Case Western Reserve University School of Medicine (8R8-4251, 10900 Euclid Avenue, Cleveland, Ohio 441064952, USA. Fax: +I-216-368-1674. E-mail: cxflE@po. cwru. edu
306
The longer certain diseases succeed in hiding their cause and mechanisms from the relentless pursuit of investigators, the greater the risk that such diseases become surrounded by unproven assumptions and theories about why they appear and how they should be treated. During this process dogmas and heresies (“true” and “false” notions, respectively) are inevitably generated. With time, such dogmas and heresies become generally accepted, but this assent serves more to relief the anxieties of preoccupied patients and frustrated physicians than to impartially track down the cause, the mechanisms, and possibly the cure. Unfortunately, the list of diseases plagued by dogmas and heresies is long, and prominent among them features inflammatory bowel disease (IBD). Both forms of IBD, Crohn’s disease (CD) and ulcerative colitis (UC), have been around long enough that they have already succeeded in creating certain beliefs of what is true and false about them. True or false, beliefs and impressions tend to become entrenched in our minds and we end up embracing them at face value. This is obviously at the detriment of an “absolute truth” still to be uncovered some time in the future, or at the risk of becoming skeptical that the whole truth will ever be found I. The purpose of this review is to candidly discuss some of the dogmas and heresies about CD and UC, with the hope that this will keep us as objective as possible in our professional attitude towards these conditions, and as honest as possible in discriminating between true and false convictions 2. IBD represents multiple and obviously complex clinical entities where genetic, environmental and microbial factors interact, leading to the activation of the immune and non-immune systems in the gut, and the subsequent production of multiple substances (antibodies, cytokines, growth factors, eicosanoids, neuropeptides, reactive oxygen and nitrogen metabolites, proteolytic enzymes) that initiate and sustain an inflammatory tissue injury 3. Often, by the time the diagnosis of IBD is made, the disease is already chronic, culminating a process that started at the time of conception, when the genetic make up of the future patient is already imprinted in his/her DNA”. If genetic predisposition is matched to the right environmental and priming factors, microscopic disease ensues that progresses from a clini-
C. Fiocchi
tally silent stage to the first mild and inconsistent symptoms, and eventually to a clinically overt disease.
Epidemiological, environmental and genetic factors In the mind of the writer, one of the first dogmas to be considered is that IBD is a “new” disease or, in other words, not an entity under or misdiagnosed until a few decades ago, but one that was virtually absent or truly rare until the Second World War. In support of this dogma is indisputable evidence that the types of diseases causing mortality and morbidity among humans have dramatically changed during the last century 5. In the early 1900’s tuberculosis, pneumonia and infectious diarrhoeas accounted for 50% of deaths, whereas by the end of the century, heart disease, cancer and stroke were responsible for three-fourths of all demises. Why so? What could explain such remarkable changes in such a brief period of time? What may have caused the rapid decline in infectious diseases? A very logical explanation lays in the dramatic social and economical improvements that society has experienced since the beginning of last century. Better housing, better nutrition and antibiotics have led to a decrease in host susceptibility, while safer food and water, hygiene and sanitation, as well as immunisations have contributed to a decrease in disease transmission. If this were only the case, our planet should have been transformed into a disease-free heaven, but mankind is not destined to free rides, and the good news always comes with the bad news. At the same time that good changes occurred, other subtle but ominous changes also happened. Sheltered housing, lack of parasites and exposure to new antigens have caused an increase in host susceptibility which, coupled to a restricted stimulation of the immune system due to clean food and water, hygiene and sanitation, and selective nutrition, have resulted in a net increase in autoimmune or chronic inflammatory diseases, including IBD. There is little question that environmental changes increase the risk of IBD 6 ‘. Among a myriad of environmental factors, dietary changes are among the best candidate culprits to explain the increasing incidence of IBD worldwide. In countries like Japan, where IBD has been and still is relatively uncommon but certainly on the rise, changes in dietary habits are evident and indirectly associated with IBD 8. During the last 25 years, there has been a steady increase in meat and dairy product consumption while the use of seafood has remained stable. During the same period of time, the increase in UC incidence has paralleled the expanded use of these western-type foods. These epidemiological observations, of course, do not establish a cause-and-effect relationship, but their close associa“-.
tions are enough to sustain the dogma that IBD is an environmentally induced condition. Hence, a logical heresy is that IBD is not linked to the environment. Perhaps with the exception of overt contamination of the human habitat by toxic pollutants, such as mercury poisoning in Japan in the past, environmental factors seldom cause disease by themselves. An accommodating genetic make-up in the host is also indispensable for an autoimmune or chronic inflammatory disease to develop. Again, this is also true for IBD. Presently, there is no question that both CD and UC are associated with genetic predisposition, and an increasing number of genetic links or associations have been reported 9. At least 12 chromosomal loci have been suggested as possibly harbouring genes potentially related to IBD pathogenesis, and up to 7 “IBD loci” have been postulated. It is unlikely that all of them are relevant because of lack of consistency among reports and different ethnic populations, but these reports raise the key question of how the various IBD-conditioning genes put into motion the effector branch of the immune system, induce an abnormal, excessive or defective response that initiates or maintains gut inflammation. An answer to this critical issue appeared distant until two landmark papers last year described the first genetic mutation formally associated with CD lo I’. Two independent groups found a frameshift mutation of the Nod2 gene in about 20% of CD patients, but not in UC patients. This finding is remarkable not so much for the identification of the first IBD gene, but because the specific function of this gene, the product of which is a cytoplasmic protein found in monocytes that is involved in lipopolysaccharide-induced activation of NF-KB r2. This creates a link between the innate immune response and products of gram-negative bacteria, such as those of the enteric flora, and considerably strengthens the increasingly accepted view (another emerging dogma) that the IBD is caused by abnormal immune reactivity to components of the lumenal flora 13,the topic of our next discussion. Thus, how strong is the dogma that IBD is a genetically induced condition? How many heretics would openly claim that IBD is not a genetic disease? A dogma for the importance of the Nod2 gene will soon be created, but what about all other genes (perhaps another half dozen or so) that are necessary to explain the other 80% of CD cases? And what about the still to be discovered genes for UC? Will they help strengthening the dogma and easily fit into current concepts of IBD pathogenesis? Considering the advances of the human genome project and the speed of new genetic and genomic screening systems, the answers may be just around the corner. Another puzzling dogma is that altered intestinal permeability presumably contributes to CD pathogenesis 14. Creation of this dogma is justified since increased per307
Dogmas and heresies in ILK!
meability is consistently found, and seems specific for CD since no evidence exists for a similar phenomenon in UC patients and their relatives. However, a far more interesting question is whether increased intestinal permeability in healthy CD relatives is a primary event leading to inflammation through a postulated excessive antigen absorption, or simply a secondary event due to the existence of low level, asymptomatic and still undetected mucosal inflammation. Histological and endoscopic evidence of active inflammation can be found in symptom-free relatives, but it is still unsettled whether this correlates with altered permeability “. Completion of these difficult studies may transform the dogma that increased permeability predisposes to CD into a heresy.
loss of tolerance to autologous flora 2s, and animal models of IBD 26 strongly supports the dogma that components of the enteric flora are contributing to IBD pathogenesis. Curiously, this dogma was probably considered a heresy only a few decades ago, when Shorter et al. first proposed that “IBD results from the establishment of a state of hypersensitivity to antigen(s) of bacteria normally present in the individual gastrointestinal tract and the pathologic and clinical features of IBD then result from a predominantly cell-mediated hypersensitivity reaction in the bowel walYz7. The suggestive results of a few experiments and a sharp intuition go a long way in proposing a dogma, but only time and a lot of hard work by many laboratories can make the dogma survive and prevent it from becoming a heresy.
Microbial factors Immune and non-immune mechanisms When UC was first being defined at around the turn of the last century, and CD a few decades later, all diseases were infectious, and early investigators had little doubt that both forms of IBD were caused by common infectious agents, a dogma then that is nearly a heresy today. The search for putative infectious agents in IBD has been going on forever, and every decade or so a new bacterium, virus or yeast emerges as “the cause” of IBD, more often CD. Unlike any other organ of the body, the gut is non sterile and contains so many different and abundant microorganisms that there are approximately 10 prokaryotic cells in a human being for every single eukaryotic cell. This means that, if a rare, but still unknown, agent causes IBD, the chances of identifying it are infinitesimally small, and, consequently, we still can not rule out the existence of relevant infectious agents in a CD- or UC-afflicted intestine. The two most recent agents supporting an infectious hypothesis for CD have been M. parutuberculosis and the measles virus I6 17.After a couple of decades of intense investigation, multiple controversial reports, uncontrolled and inconclusive experiments, and tenuous results from epidemiological studies, the hypothesis that CD is caused by M. paratuberculosis or the measles virus appears destined to be added to the list of heresies lg. While faith in these microbial agents is fading away, the concept that the normal bacterial flora is somehow involved in IBD pathogenesis is currently a widely accepted dogma i9. What is broadly accepted today was not so only three decades ago when the idea first emerged that “because of the always present germs... it is very difficult to imagine that bacteria should not influence the reaction of the mucosa and its pattern of regeneration” 20. Evidence from faecal diversion studies *I, pouchitis 22, use of antibiotics and probiotics 2324, 308
Some dogmas are based on rather soft and indirect evidence, while others are sitting comfortably on a huge pile of data collected over decades by highly respected investigators. The latter case is the best chance a dogma has of transforming itself in a “truth”, as has been happening for immunological factors in IBD. Thus, dogmas are never born as such and, as mentioned before, there is the need for a suggestion to be pushed forward by its novelty and be sustained by continuous studies in a defined research field to give initial credence to a new pathogenic concept. Immunology was still a newborn field only 30 years ago, when Arend and Martini wrote that “immunological mechanisms recently have been considered as least as important (to IBD pathogenesis) as psychological and bacterial influences” *O.It is ironic that in this intuitive but unsubstantiated statement that immune factors, that still are by far the most cogent ones in IBD research, were directly compared to “psychological influences”, generally accepted as important up until the 1970’s and now relegated to the realm of heresies. The literature on the importance of immune factors both in CD and UC is so vast that there is no need to discuss specific points or cite major papers to document credibility, and the dogma that IBD is an immunologically mediated disease is perhaps the most securely established 28. As a corollary, nobody would now dare to declare that IBD is not immunologically mediated, an obvious heresy today. In spite of the dogma, immunological heresies continue to emerge from time to time. A notable one is that CD is caused by an immune reaction to toothpaste, derived from the simple observation of finding silica-like particles in granulomas of CD-involved tissue 29. Integrated in the dogma that IBD is an immunologically
C. Fiocchi
mediated condition are various observations that contribute to the creation of the dogma. A strongly grounded one is that CD is a state of immunological hyper-reactivity, where T-cells work too hard and too long 3o31, this leading to inflammation and tissue damage. This generally accepted view does not prevent the rise of alternate thinking such as the one recently proposed that CD is a state of immunological hypo-reactivity, i.e., an immunodeficiency condition j2, a challenging idea presently relegated to the heresy category. Finally, another new concept that is just being recognized as relevant to IBD pathogenesis is one suggesting that non-immune cells, including epithelial, endothelial, mesenchymal and nerve cells, may be as important as immune factors to IBD pathogenesis 33. Perhaps because of a greater complacency that all is possible until the true cause of IBD is discovered and evidence gathered from other conditions such as rheumatoid arthritis, the idea that non-immune cells are important in an immune-mediated process does not quite fit to the definition of heresy, but many doubts still exist regarding whether and when (early or only late in the disease process) non-immune cells become truly important.
Psychological factors What about stress and emotional factors? Where do they tit in IBD? Which category do they belong to: dogmas or heresies? We previously mentioned that psychological factors were widely accepted as relevant to the pathogenesis of IBD, mainly UC, until the 1970’s. With the advent and subsequent dominance of immunology from the 1970’s until the present time, the belief that stress and emotions contribute to IBD has progressively dwindled and stating today that these factors cause IBD will be equated to a heresy. But, should they be totally dismissed as irrelevant to IBD? The answer is yes and no 34. Yes, if evidence derives from vague studies suggesting a link between some psychological conditions and immune markers of uncertain significance 35. But no, if evidence is based on studies showing that stress is reliably associated with colitis in established animal models investigated under strict scientific conditions 36. Stress, when measured by objective parameters such as neuropeptide levels, oxygen consumption, or metabolic status, is nothing more than a physiological response induced by environmental or endogenous factors, and firm evidence exists to show that stress modulates intestinal inflammation, at least in animal models 3738. Thus, as studies evolve in this field, what once were heresies may be progressively transformed into valuable areas of study, and perhaps future dogmas.
Therapy Dogmas and heresies in IBD are not limited to its obscure aetiology and still uncertain pathogenesis. There are also plenty of them when considering treatment of IBD. In this area, not only dogmas and heresies exist, but also a major paradox: in spite of all the undeniable advances occurring in the few decades, IBD is still treated with over half-century-old drugs. Sulphasalazine has been in use since the 1940’s, when its beneficial effect on UC was accidentally discovered in rheumatoid arthritis patients with both conditions. In the 1950’s, cortisone and adrenocorticotropic hormone (ACTH) made their debut, and in the 1960’s azathioprine started to be adopted as the first immunosuppressive medication for IBD. In the 1970’s, 5aminosalicylic acid (5ASA) was found to be the active anti-inflammatory moiety of sulphasalazine, and various new 5-ASA formulations were born. The first antibiotic to be used regularly in CD, metronidazole, appeared on the scene in the 1980’s, the same time when elemental diets appeared. In the early 1990’s, additional immunosuppressive drugs, including cyclosporine and methotrexate, began to be used together with less toxic corticosteroids (budesonide) and novel antibiotics (ciprofloxacin). This was followed by the long awaited fruits of IBD immunological research coupled to wondrous biotechnological achievements, and the new biologicals were born in the late 1990’s 39, a period of time when the potential value of probiotics in modulating intestinal flora also began to be seriously considered. What is amazing in this quest for a better IBD therapy is that, unlike theories about IBD aetiopathogenesis that came and went, all the above therapeutic strategies arrived, but never went away. All of the above medications are still being actively used today, posing the new therapeutic challenge for the 2000’s of learning how, when, and best to use them in a combinatorial way. In other words, how do we optimally customise therapy for individual patients or groups of patients? The long evolution of IBD therapy in time and the continuous use of the same drugs during this evolution has greatly facilitated the creation of two parallel dogmas: the first is that most of the above drugs are, indeed, useful in managing IBD, and the second is that they should be used progressively in a step-by-step fashion. Once a dogma has been created and accepted, anything deviating from it is consequently a heresy. This has hindered, but certainly not eliminated, the continuous surge of alternative, or heretic, therapies. As an example, lymphocyte apheresis has been heralded as a useful approach to treatment of CD ‘O. No credible, large scale and controlled clinical trial has ever demonstrated the effectiveness of this biomechanical approach
Dogmas and heresies in MO
that, nevertheless, is frequently employed in countries like Japan. The use of hyperbaric oxygen for CD is considered by most as another example of an unorthodox therapy 4’, as a vacation on the Dead Sea for treatment of CD would inevitably be 42, but a biologically valid explanation may lay behind it and help transforming this heresy into something more credible 43. In some Asian countries, like China and Japan, herbs are commonly used as adjuvant therapies to standard drugbased therapies. These would be among the most striking examples of therapeutic heresies, which are now appearing in Western societies under a thin layer of scientific painting, as is the proposed use of green tea for maintenance of remission in CD 44. As mentioned above, one of the most established therapeutic dogmas is that patients with IBD should be treated initially with one drug, most often sulphasalazine and, when a predictable failure occurs, corticosteroids should be added until the next flare-up, when immunosuppressive drugs and antibiotics are called into action. Next in line are now biologicals, to which all hopes are devoted that miraculously a chronically active patient with CD or UC is suddenly brought into permanent remission. More often than not, failure occurs, hope disappears, and surgery starts looming as the next therapeutic horizon. This dogmatic system is now being challenged by evidence that old and new drugs, until not long ago relegated to the “last to be used category”, are far more beneficial that previously suspected when used early in the therapeutic game. Spurred by successes obtained in the treatment of related disorders like rheumatoid arthritis 45, recent studies have shown that the early use of 6-mercaptopurine combined with corticosteroids provides more sustained remission in CD 46. In addition to challenging the dogma of single therapy, the dogma that new “more potent” drugs should be relegated to the last step of treatment should also be challenged. A report on the use of infliximab in children with the first manifestation of CD also shows a much better outcome in number and time compared to the use of the same biological in children with chronic disease 47.Thus, the heresy that IBD should be treated with an “all out” approach may be changing, perhaps slowly transforming itself into the next therapeutic dogma.
Conclusion Have we learned anything from this dissertation on dogmas and heresies in IBD? There are always some hidden lessons even in an eccentric and a bit cynical thought exercise like the one herein being concluded. Realistically speaking, there are still no absolute “truths” in IBD and, therefore, dogmas and heresies 310
will continue to flourish, even though more dogmas and fewer heresies are likely to be created because of a continuously increasing body of scientific knowledge. However, at least for the foreseeable future, as “beauty is in the eye of the beholder”, truth (in IBD) will remain in the eye of the beholder. I
List of abbreviations 5ASA: 5aminosalicylic 1 CD: Crphn’s disease: We colltis. L --------
acid; ACTH: adrenocorticotropic IBD: inflammatory bowel disease; -~--
~_~~_~_
hormone; UC: ulcera-
(
_~_I
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Digestive and Liver Disease and The Italian Journal of Gastroenterology (Volumes 29-34) are available on-line at the web site:
http://www.dldjournal.it Possibility of on-line subscriptions.
311
Inflammatory
DIGEST LIVER DIS 2002;34:306-11
bowel disease:
C. Fiocchi
dogmas
and heresies
Perception of a disease state by the practising physician is based on how easily the diagnosis can be made and how predictable the outcome of the chosen therapy is. The academic investigator perceives the same disease based on how well its cause and mechanism are understood, and how rational pathophysiology-based treatments are. Because of incomplete knowledge, neither the practising physician nor the academic investigator are comfortable in dealing with inflammatory bowel disease, and both seek help in the dogmas and heresies inof unknown aetiology evitably associated with chronic disease
Digest
liver
Key words:
Ois 2002;34:306-11 Crohn’s
disease;
inflammatory
bowel
disease:
ulcerative
colitis
Introduction
1 Flvm Divisionof Gastmenterology, University Hospitalsof Cleveland, CaseWestern ReserveUniversitySchoolof Medicine, Cleveland, Ohio,USA.
M&we hr mwmepedeece Or. C. Fiocchi, Division of Gestroenterology, Case Western Reserve University School of Medicine (8R8-4251, 10900 Euclid Avenue, Cleveland, Ohio 441064952, USA. Fax: +I-216-368-1674. E-mail: cxflE@po. cwru. edu
306
The longer certain diseases succeed in hiding their cause and mechanisms from the relentless pursuit of investigators, the greater the risk that such diseases become surrounded by unproven assumptions and theories about why they appear and how they should be treated. During this process dogmas and heresies (“true” and “false” notions, respectively) are inevitably generated. With time, such dogmas and heresies become generally accepted, but this assent serves more to relief the anxieties of preoccupied patients and frustrated physicians than to impartially track down the cause, the mechanisms, and possibly the cure. Unfortunately, the list of diseases plagued by dogmas and heresies is long, and prominent among them features inflammatory bowel disease (IBD). Both forms of IBD, Crohn’s disease (CD) and ulcerative colitis (UC), have been around long enough that they have already succeeded in creating certain beliefs of what is true and false about them. True or false, beliefs and impressions tend to become entrenched in our minds and we end up embracing them at face value. This is obviously at the detriment of an “absolute truth” still to be uncovered some time in the future, or at the risk of becoming skeptical that the whole truth will ever be found I. The purpose of this review is to candidly discuss some of the dogmas and heresies about CD and UC, with the hope that this will keep us as objective as possible in our professional attitude towards these conditions, and as honest as possible in discriminating between true and false convictions 2. IBD represents multiple and obviously complex clinical entities where genetic, environmental and microbial factors interact, leading to the activation of the immune and non-immune systems in the gut, and the subsequent production of multiple substances (antibodies, cytokines, growth factors, eicosanoids, neuropeptides, reactive oxygen and nitrogen metabolites, proteolytic enzymes) that initiate and sustain an inflammatory tissue injury 3. Often, by the time the diagnosis of IBD is made, the disease is already chronic, culminating a process that started at the time of conception, when the genetic make up of the future patient is already imprinted in his/her DNA”. If genetic predisposition is matched to the right environmental and priming factors, microscopic disease ensues that progresses from a clini-
C. Fiocchi
tally silent stage to the first mild and inconsistent symptoms, and eventually to a clinically overt disease.
Epidemiological, environmental and genetic factors In the mind of the writer, one of the first dogmas to be considered is that IBD is a “new” disease or, in other words, not an entity under or misdiagnosed until a few decades ago, but one that was virtually absent or truly rare until the Second World War. In support of this dogma is indisputable evidence that the types of diseases causing mortality and morbidity among humans have dramatically changed during the last century 5. In the early 1900’s tuberculosis, pneumonia and infectious diarrhoeas accounted for 50% of deaths, whereas by the end of the century, heart disease, cancer and stroke were responsible for three-fourths of all demises. Why so? What could explain such remarkable changes in such a brief period of time? What may have caused the rapid decline in infectious diseases? A very logical explanation lays in the dramatic social and economical improvements that society has experienced since the beginning of last century. Better housing, better nutrition and antibiotics have led to a decrease in host susceptibility, while safer food and water, hygiene and sanitation, as well as immunisations have contributed to a decrease in disease transmission. If this were only the case, our planet should have been transformed into a disease-free heaven, but mankind is not destined to free rides, and the good news always comes with the bad news. At the same time that good changes occurred, other subtle but ominous changes also happened. Sheltered housing, lack of parasites and exposure to new antigens have caused an increase in host susceptibility which, coupled to a restricted stimulation of the immune system due to clean food and water, hygiene and sanitation, and selective nutrition, have resulted in a net increase in autoimmune or chronic inflammatory diseases, including IBD. There is little question that environmental changes increase the risk of IBD 6 ‘. Among a myriad of environmental factors, dietary changes are among the best candidate culprits to explain the increasing incidence of IBD worldwide. In countries like Japan, where IBD has been and still is relatively uncommon but certainly on the rise, changes in dietary habits are evident and indirectly associated with IBD 8. During the last 25 years, there has been a steady increase in meat and dairy product consumption while the use of seafood has remained stable. During the same period of time, the increase in UC incidence has paralleled the expanded use of these western-type foods. These epidemiological observations, of course, do not establish a cause-and-effect relationship, but their close associa“-.
tions are enough to sustain the dogma that IBD is an environmentally induced condition. Hence, a logical heresy is that IBD is not linked to the environment. Perhaps with the exception of overt contamination of the human habitat by toxic pollutants, such as mercury poisoning in Japan in the past, environmental factors seldom cause disease by themselves. An accommodating genetic make-up in the host is also indispensable for an autoimmune or chronic inflammatory disease to develop. Again, this is also true for IBD. Presently, there is no question that both CD and UC are associated with genetic predisposition, and an increasing number of genetic links or associations have been reported 9. At least 12 chromosomal loci have been suggested as possibly harbouring genes potentially related to IBD pathogenesis, and up to 7 “IBD loci” have been postulated. It is unlikely that all of them are relevant because of lack of consistency among reports and different ethnic populations, but these reports raise the key question of how the various IBD-conditioning genes put into motion the effector branch of the immune system, induce an abnormal, excessive or defective response that initiates or maintains gut inflammation. An answer to this critical issue appeared distant until two landmark papers last year described the first genetic mutation formally associated with CD lo I’. Two independent groups found a frameshift mutation of the Nod2 gene in about 20% of CD patients, but not in UC patients. This finding is remarkable not so much for the identification of the first IBD gene, but because the specific function of this gene, the product of which is a cytoplasmic protein found in monocytes that is involved in lipopolysaccharide-induced activation of NF-KB r2. This creates a link between the innate immune response and products of gram-negative bacteria, such as those of the enteric flora, and considerably strengthens the increasingly accepted view (another emerging dogma) that the IBD is caused by abnormal immune reactivity to components of the lumenal flora 13,the topic of our next discussion. Thus, how strong is the dogma that IBD is a genetically induced condition? How many heretics would openly claim that IBD is not a genetic disease? A dogma for the importance of the Nod2 gene will soon be created, but what about all other genes (perhaps another half dozen or so) that are necessary to explain the other 80% of CD cases? And what about the still to be discovered genes for UC? Will they help strengthening the dogma and easily fit into current concepts of IBD pathogenesis? Considering the advances of the human genome project and the speed of new genetic and genomic screening systems, the answers may be just around the corner. Another puzzling dogma is that altered intestinal permeability presumably contributes to CD pathogenesis 14. Creation of this dogma is justified since increased per307
Dogmas and heresies in ILK!
meability is consistently found, and seems specific for CD since no evidence exists for a similar phenomenon in UC patients and their relatives. However, a far more interesting question is whether increased intestinal permeability in healthy CD relatives is a primary event leading to inflammation through a postulated excessive antigen absorption, or simply a secondary event due to the existence of low level, asymptomatic and still undetected mucosal inflammation. Histological and endoscopic evidence of active inflammation can be found in symptom-free relatives, but it is still unsettled whether this correlates with altered permeability “. Completion of these difficult studies may transform the dogma that increased permeability predisposes to CD into a heresy.
loss of tolerance to autologous flora 2s, and animal models of IBD 26 strongly supports the dogma that components of the enteric flora are contributing to IBD pathogenesis. Curiously, this dogma was probably considered a heresy only a few decades ago, when Shorter et al. first proposed that “IBD results from the establishment of a state of hypersensitivity to antigen(s) of bacteria normally present in the individual gastrointestinal tract and the pathologic and clinical features of IBD then result from a predominantly cell-mediated hypersensitivity reaction in the bowel walYz7. The suggestive results of a few experiments and a sharp intuition go a long way in proposing a dogma, but only time and a lot of hard work by many laboratories can make the dogma survive and prevent it from becoming a heresy.
Microbial factors Immune and non-immune mechanisms When UC was first being defined at around the turn of the last century, and CD a few decades later, all diseases were infectious, and early investigators had little doubt that both forms of IBD were caused by common infectious agents, a dogma then that is nearly a heresy today. The search for putative infectious agents in IBD has been going on forever, and every decade or so a new bacterium, virus or yeast emerges as “the cause” of IBD, more often CD. Unlike any other organ of the body, the gut is non sterile and contains so many different and abundant microorganisms that there are approximately 10 prokaryotic cells in a human being for every single eukaryotic cell. This means that, if a rare, but still unknown, agent causes IBD, the chances of identifying it are infinitesimally small, and, consequently, we still can not rule out the existence of relevant infectious agents in a CD- or UC-afflicted intestine. The two most recent agents supporting an infectious hypothesis for CD have been M. parutuberculosis and the measles virus I6 17.After a couple of decades of intense investigation, multiple controversial reports, uncontrolled and inconclusive experiments, and tenuous results from epidemiological studies, the hypothesis that CD is caused by M. paratuberculosis or the measles virus appears destined to be added to the list of heresies lg. While faith in these microbial agents is fading away, the concept that the normal bacterial flora is somehow involved in IBD pathogenesis is currently a widely accepted dogma i9. What is broadly accepted today was not so only three decades ago when the idea first emerged that “because of the always present germs... it is very difficult to imagine that bacteria should not influence the reaction of the mucosa and its pattern of regeneration” 20. Evidence from faecal diversion studies *I, pouchitis 22, use of antibiotics and probiotics 2324, 308
Some dogmas are based on rather soft and indirect evidence, while others are sitting comfortably on a huge pile of data collected over decades by highly respected investigators. The latter case is the best chance a dogma has of transforming itself in a “truth”, as has been happening for immunological factors in IBD. Thus, dogmas are never born as such and, as mentioned before, there is the need for a suggestion to be pushed forward by its novelty and be sustained by continuous studies in a defined research field to give initial credence to a new pathogenic concept. Immunology was still a newborn field only 30 years ago, when Arend and Martini wrote that “immunological mechanisms recently have been considered as least as important (to IBD pathogenesis) as psychological and bacterial influences” *O.It is ironic that in this intuitive but unsubstantiated statement that immune factors, that still are by far the most cogent ones in IBD research, were directly compared to “psychological influences”, generally accepted as important up until the 1970’s and now relegated to the realm of heresies. The literature on the importance of immune factors both in CD and UC is so vast that there is no need to discuss specific points or cite major papers to document credibility, and the dogma that IBD is an immunologically mediated disease is perhaps the most securely established 28. As a corollary, nobody would now dare to declare that IBD is not immunologically mediated, an obvious heresy today. In spite of the dogma, immunological heresies continue to emerge from time to time. A notable one is that CD is caused by an immune reaction to toothpaste, derived from the simple observation of finding silica-like particles in granulomas of CD-involved tissue 29. Integrated in the dogma that IBD is an immunologically
C. Fiocchi
mediated condition are various observations that contribute to the creation of the dogma. A strongly grounded one is that CD is a state of immunological hyper-reactivity, where T-cells work too hard and too long 3o31, this leading to inflammation and tissue damage. This generally accepted view does not prevent the rise of alternate thinking such as the one recently proposed that CD is a state of immunological hypo-reactivity, i.e., an immunodeficiency condition j2, a challenging idea presently relegated to the heresy category. Finally, another new concept that is just being recognized as relevant to IBD pathogenesis is one suggesting that non-immune cells, including epithelial, endothelial, mesenchymal and nerve cells, may be as important as immune factors to IBD pathogenesis 33. Perhaps because of a greater complacency that all is possible until the true cause of IBD is discovered and evidence gathered from other conditions such as rheumatoid arthritis, the idea that non-immune cells are important in an immune-mediated process does not quite fit to the definition of heresy, but many doubts still exist regarding whether and when (early or only late in the disease process) non-immune cells become truly important.
Psychological factors What about stress and emotional factors? Where do they tit in IBD? Which category do they belong to: dogmas or heresies? We previously mentioned that psychological factors were widely accepted as relevant to the pathogenesis of IBD, mainly UC, until the 1970’s. With the advent and subsequent dominance of immunology from the 1970’s until the present time, the belief that stress and emotions contribute to IBD has progressively dwindled and stating today that these factors cause IBD will be equated to a heresy. But, should they be totally dismissed as irrelevant to IBD? The answer is yes and no 34. Yes, if evidence derives from vague studies suggesting a link between some psychological conditions and immune markers of uncertain significance 35. But no, if evidence is based on studies showing that stress is reliably associated with colitis in established animal models investigated under strict scientific conditions 36. Stress, when measured by objective parameters such as neuropeptide levels, oxygen consumption, or metabolic status, is nothing more than a physiological response induced by environmental or endogenous factors, and firm evidence exists to show that stress modulates intestinal inflammation, at least in animal models 3738. Thus, as studies evolve in this field, what once were heresies may be progressively transformed into valuable areas of study, and perhaps future dogmas.
Therapy Dogmas and heresies in IBD are not limited to its obscure aetiology and still uncertain pathogenesis. There are also plenty of them when considering treatment of IBD. In this area, not only dogmas and heresies exist, but also a major paradox: in spite of all the undeniable advances occurring in the few decades, IBD is still treated with over half-century-old drugs. Sulphasalazine has been in use since the 1940’s, when its beneficial effect on UC was accidentally discovered in rheumatoid arthritis patients with both conditions. In the 1950’s, cortisone and adrenocorticotropic hormone (ACTH) made their debut, and in the 1960’s azathioprine started to be adopted as the first immunosuppressive medication for IBD. In the 1970’s, 5aminosalicylic acid (5ASA) was found to be the active anti-inflammatory moiety of sulphasalazine, and various new 5-ASA formulations were born. The first antibiotic to be used regularly in CD, metronidazole, appeared on the scene in the 1980’s, the same time when elemental diets appeared. In the early 1990’s, additional immunosuppressive drugs, including cyclosporine and methotrexate, began to be used together with less toxic corticosteroids (budesonide) and novel antibiotics (ciprofloxacin). This was followed by the long awaited fruits of IBD immunological research coupled to wondrous biotechnological achievements, and the new biologicals were born in the late 1990’s 39, a period of time when the potential value of probiotics in modulating intestinal flora also began to be seriously considered. What is amazing in this quest for a better IBD therapy is that, unlike theories about IBD aetiopathogenesis that came and went, all the above therapeutic strategies arrived, but never went away. All of the above medications are still being actively used today, posing the new therapeutic challenge for the 2000’s of learning how, when, and best to use them in a combinatorial way. In other words, how do we optimally customise therapy for individual patients or groups of patients? The long evolution of IBD therapy in time and the continuous use of the same drugs during this evolution has greatly facilitated the creation of two parallel dogmas: the first is that most of the above drugs are, indeed, useful in managing IBD, and the second is that they should be used progressively in a step-by-step fashion. Once a dogma has been created and accepted, anything deviating from it is consequently a heresy. This has hindered, but certainly not eliminated, the continuous surge of alternative, or heretic, therapies. As an example, lymphocyte apheresis has been heralded as a useful approach to treatment of CD ‘O. No credible, large scale and controlled clinical trial has ever demonstrated the effectiveness of this biomechanical approach
Dogmas and heresies in MO
that, nevertheless, is frequently employed in countries like Japan. The use of hyperbaric oxygen for CD is considered by most as another example of an unorthodox therapy 4’, as a vacation on the Dead Sea for treatment of CD would inevitably be 42, but a biologically valid explanation may lay behind it and help transforming this heresy into something more credible 43. In some Asian countries, like China and Japan, herbs are commonly used as adjuvant therapies to standard drugbased therapies. These would be among the most striking examples of therapeutic heresies, which are now appearing in Western societies under a thin layer of scientific painting, as is the proposed use of green tea for maintenance of remission in CD 44. As mentioned above, one of the most established therapeutic dogmas is that patients with IBD should be treated initially with one drug, most often sulphasalazine and, when a predictable failure occurs, corticosteroids should be added until the next flare-up, when immunosuppressive drugs and antibiotics are called into action. Next in line are now biologicals, to which all hopes are devoted that miraculously a chronically active patient with CD or UC is suddenly brought into permanent remission. More often than not, failure occurs, hope disappears, and surgery starts looming as the next therapeutic horizon. This dogmatic system is now being challenged by evidence that old and new drugs, until not long ago relegated to the “last to be used category”, are far more beneficial that previously suspected when used early in the therapeutic game. Spurred by successes obtained in the treatment of related disorders like rheumatoid arthritis 45, recent studies have shown that the early use of 6-mercaptopurine combined with corticosteroids provides more sustained remission in CD 46. In addition to challenging the dogma of single therapy, the dogma that new “more potent” drugs should be relegated to the last step of treatment should also be challenged. A report on the use of infliximab in children with the first manifestation of CD also shows a much better outcome in number and time compared to the use of the same biological in children with chronic disease 47.Thus, the heresy that IBD should be treated with an “all out” approach may be changing, perhaps slowly transforming itself into the next therapeutic dogma.
Conclusion Have we learned anything from this dissertation on dogmas and heresies in IBD? There are always some hidden lessons even in an eccentric and a bit cynical thought exercise like the one herein being concluded. Realistically speaking, there are still no absolute “truths” in IBD and, therefore, dogmas and heresies 310
will continue to flourish, even though more dogmas and fewer heresies are likely to be created because of a continuously increasing body of scientific knowledge. However, at least for the foreseeable future, as “beauty is in the eye of the beholder”, truth (in IBD) will remain in the eye of the beholder. I
List of abbreviations 5ASA: 5aminosalicylic 1 CD: Crphn’s disease: We colltis. L --------
acid; ACTH: adrenocorticotropic IBD: inflammatory bowel disease; -~--
~_~~_~_
hormone; UC: ulcera-
(
_~_I
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