Archives of the Balkan Medical Union vol. 50, no. 3, pp. 399-405 Copyright © 2015 CELSIUS September 2015

REVIEW

THE GENESIS OF INFLAMMATORY BOWEL DISEASE YESTERDAY, TODAY, TOMORROW

DORINA CALAGIU1, MIRCEA DICULESCU1,2, ROXANA MARIA NEMEÆ3, CORINA SILVIA POP1,4 1„Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 2Gastroenterology and Hepatology Center, Fundeni Clincal Insitute, Bucharest, Romania 3”Marius Nasta” Institute National of Pneumology, Bucharest, Romania 4Emergency University Hospital, Bucharest, Romania

SUMMARY RÉSUMÉ

The discovery of Inflammatory Bowel Disease (IBD) has had a La genèse de la maladie inflammatoire de l’intestin hier, à tumultuous trajectory, beginning with its recognition as a medical présent, demain entity to defining and understanding. The genesis of the two diseases included in the spectrum of IBD is the same with the La découverte de la maladie inflammatoire de l'intestin (MII) a eu one of humanity, the earliest descriptions belonging to ancient une trajectoire tumultueuse, en commençant par sa reconnais- Greeks, but the differentiation between them and other intestinal sance comme une entité médicale à la définition et la pathologies took place years later. Even establishing the names of compréhension. La genèse de ces deux maladies incluses dans le Ulcerative colitis (UC) and Crohn’s disease (CD) encountered spectre de l'IBD est la même avec celle de l'humanité, les difficulties. With the beginning of the modern era, remarkable premières descriptions appartenant aux Grecs anciens, mais la progress has been made in the field of medicine - both in under- différenciation entre eux et d'autres pathologies intestinales a eu standing the diseases and in treating it. Outstanding medical and lieu des années plus tard. Même établir les noms de rectocolite surgical techniques have led to significant improvement in hémorragique (RCH) et la maladie de Crohn (CD) a rencontré des prognosis and quality of life, so nowadays IBD is no longer seen difficultés. Avec le début de l'ère moderne, des progrès as a medical curiosity but as a manageable chronic condition. remarquables ont été accomplis dans le domaine de la médecine - This article is a review of the history and treatment of Inflam- à la fois dans la compréhension des maladies et leur traitement. matory Bowel Disease up to the present time, when, despite all D’éminentes techniques médicales et chirurgicales ont conduit à the advances made, the etiopathology and cure remain unknown. une amélioration significative dans le pronostic et la qualité de vie, Key words: inflammatory bowel disease, ulcerative colitis, ainsi que de nos jours MII n’est plus considérée comme une Crohn’s disease, regional ileitis, history curiosité médicale, mais comme une maladie chronique gérable. Cet article est une revue de l'histoire et du traitement des maladies inflammatoires de l'intestin à l'heure actuelle, car, en dépit de tous les progrès réalisés, l'étiopathologie et la guérison restent inconnus. Mots clés: maladie inflammatoire de l'intestin, rectocolite hémorragique, maladie de Crohn, iléite regional, l'histoire

Ulcerative Colitis - First there was darkness! (who worked at Mayo Clinic and was the President of the American Gastroenterological Association) maintained From discovery to definition în 1966 that ”as long as the cause of UC remains hrough the ages there have been numerous unknown, defining the disease would be impossible and controversies regarding the nomenclature and shouldn’t even be attempted”. Nevertheless, subsequent TT etiopathogenesis of IBD. Dr. J Arnold Bargen advances have made defining the disease as truthfully an

Correspondence address: Roxana Maria Nemes, MD, PhD “Marius Nasta” Institute of Pneumology, Bucharest Head of Pulmonary Function Tests Department e-mail: [email protected] THE GENESIS OF INFLAMMATORY BOWEL DISEASE YESTERDAY, TODAY, TOMORROW - CALAGIU et al vol. 50, no. 3, 400 imperative need as possible. UC is a chronic inflammation January, at a symposium held by the Royal Medical Society of the colon (large intestine) lining, of unknown cause, in London, 317 cases recorded in London hospitals were often characterized clinically by blood in stool, diarrhea, reviewed – they revealed many important observations rectal tenesmus and abdominal pain, by ongoing involve- regarding: risk factors, disease onset symptoms, treatment ment of the mucosa, and a centripetal extension from attempts (antiseptics, antidiarrheal, sedatives, tried with no rectum up to the cecum [1]. real benefit) [11]. Dr. John Percy Lockart Mummery (a UC is the first disease among those included in the IBD surgeon at St. Mark’s Hospital, Hunterian Professor at the spectrum that was defined as a distinct entity. The early Royal College of Surgeons, the first secretary of the British history of IBD begins with the history of UC, nonetheless Proctological Society) proved the same year that sigmoi- that is not to say that UC predates CD - both diseases had doscopy was a safe method of evaluating and diagnosing the afflicted patients long before modern medicine was able to intestinal involvement, while in March the British Medical discover and define them [2]. The first description of UC Journal published the work of Dr. Herbert P. Hawkins (St. still remains a matter of controversy. Starting with Greek Thomas Hospital) that confirmed the chronic and relapsing antiquity, there have been mentions of chronic nonconta- nature of the disease and its insidious onset with mild, often gious diarrhea - Hippocrates himself (460-370 BC) discussed unnoticed bleedings, accompanied by constipation [12]. the possible etiology of diarrhea [3]. Several other reports of Later on, Sir Arthur Hurst (a neurologist at Guy’s the disease were susequently attributed to Soranus (117 AD) Hospital, a pioneer in the diagnosis and treatment of and Aretaeus of Cappadocia (300 AD) [4]. Although the psychoneuroses, who introduced the term dyschezia) name of UC is not entirely accurate – insomuch as ulcera- proposed a more elaborate description of UC, including the tions are not necessarily present, and as the disease quite sigmoid colon changes (muscular tension and stretching), as often involves the rectum and the sigmoid colon - it became well as its distinction from bacillary dysentery. Although its widely accepted [1]. etiology remained controversial, infectious or psychosomatic The 19th century medical school of thought increasingly factors were taken into consideration as possible primary concerned itself with intestinal inflammation – Prof. causes [13]. Francois Joseph Victor Broussais 1772-1838 (professor of Ulcerative Colitis – And then there was light ! general pathology of the Academy of Medicine) and Dr. John Brown 1810-1882 (Fellow of the Royal College of Physicians New treatments and curiosities of Edinburgh) supported the theory that all diseases derive their cause from the GI tract inflammation, a theory From 1909 onwards, as the decades passed, the medical reinforced by the advent of the microscope, with its impor- community was making advances in their knowledge tance for entomological examinations [5]. The cholera about UC. These included the detailed descriptions of epidemics raging at that time worldwide drew attention to familial predisposition made by Dr. Richard Lewisohn the transmissible causes of diarrhea [6]. (known for the storage of blood in blood banks, who Although it was suggested that in 1745 young Prince worked at Mount Sinai Hospital), the association of UC Charles (known in Britain as The Young Pretender) with colon polyps described by Dr Hewitt JH. (a physician developed bloody diarrhea following his defeat at the Battle in Cleveland) and Dr. Owen H. Wangensteen’s (a surgeon of Culloden and was cured from UC by a milk-free diet, [7] at Minnesota Hospital - the developer of the suction Dr Samuel Wilks (a physician at Guy’s Hospital London) is apparatus, 1931) observation that UC can lead to colon the one credited with the first description of the disease in cancer. Helmholz, in 1923, was the first to describe UC 1859, when he identified it as being distinct from bacillary in children (ages 8 to 15) [2]. dysentery and named it idiopathic colitis [8]. He, as well as Treatments were also making progress, with ileostomy Dr. Walter Moxon (1875) (a physician at Guy’s Hospital and and blood transfusions validated as useful means of therapy a lecturer in comparative anatomy and pathology) and Dr. in UC. At first, the surgical treatment of UC was used infre- William Henry Allchin (1885) (a physician and a lecturer in quently and mostly in an experimental manner, but starting comparative anatomy, physiology, pathology and medicine with the 1930s the surgical approach gradually became the at Westminster Hospital) afterwards outlined the clinical standard of care. Some of the therapeutic practices were and pathological features of the disease: severe extensive abandoned over time (therapeutic pneumoperitoneum, colon inflammation with areas of dilated or narrowed lumen appendicectomy, pelvic autonomic neurectomy, thymus [9]. resection, vagotomy), but others have stood the test of time In 1888 Sir William Hale White (a physician at Guy’s and are still in use to this day: ileostomy, partial or total Hospital, president of the Association of Physicians of Great colectomy [14]. Medical approaches also ranged from benign Britain and Ireland and of The Royal Society of Medicine) to unusual ones, to say the least: administering porcine raw published in London a detailed description of his UC cases, small intestine (the so-called organotherapy), Dr. Thomas dismissing all the other causes discussed earlier: bacterial Sydenham’s (a physician in London, known as the “English overgrowth, dysentery, tuberculosis, typhus etc. From that Hippocrates”) therapy (3 glasses per day of milk soured with moment on, the UC entered the general medical vocabulary lactic acid), opium, silver nitrate, kerosene, ionizing therapy, [10]. hypnosis, hot water enemas, vaccines and extracts prepared 1909 was an important year in the history of UC. In from animal intestines, irigography using a zinc solution and Archives of the Balkan Medical Union September 2015, 401 an electrical impulse sent through it. [18] This period (1934- A major conceptual change was brought on by the 1944) also saw the first retrospective epidemiological study accidental discovery, in 1940, of Swedish doctor Nanna on UC, performed in Rochester, Minnesota, that revealed Svartz (professor at Karolinska Institute of Pathology in an incidence rate of 6 to 100,000 [15]. Stockholm) of the impressive symptomatic remission of From the 1940s onwards medical interest in UC UC when treated with sulphasalazines – in her attempt to extended to all specialties. Thus, Dr. Shields Warren and treat the King’s (Gustav V) arthritis, Svartz synthesized a Dr. Sheldon C. Sommers (who worked together at New new drug by the chemical linking of sulphapyridines with England Deaconess Hospital, Laboratory of Pathology, in 5-amino salicylic acid and she noticed symptoms improv- Boston) published the first ample description of UC ing in patients with arthritis and UC. She also found pathology, with photographic and micrographic illustra- similar changes in the connective tissue underlying the tions of vasculitis, cryptitis, distrophies and abscesses [16]. muscularis mucous lining and the articular connective Radiology was increasingly being used to evaluate the tissue, but she thought that the therapy had worked disease extension and identify strictures [17]. Although through a bactericidal effect and she held the streptococ- the etiology of UC still remains unknown, that decade cus responsible for the pathogenesis of both rheumatoid saw numerous attempts at solving this problem. The best- arthritis and UC. The clinical trials undertaken at the known theories took into consideration an infectious University of Chicago after 1940 and those led by Prof. cause (Mycobacterium tuberculosis - Dr. Thomas K. Klotz U. (Institute of Clinical Pharmacology in Stuttgart) Dalziel, Dr. J.A. Bargen’s diplostreptococcus (Mayo in 1970 proved the inefficiency of sulphapyridines and the Clinic), parasites, fungi and viruses – Dr. Fradkin (1937 - low bactericidal activity of sulphasalazines. The 5-ASA Entamoeba Hystolitica), Dr. Richard Henderson with Dr. derivatives (mesalazine, mesalamine) are still in use today Henry Pinkerton and Dr. Louis Moore (1942 - fungus - due to their antiinflammatory and antichemotactic Histoplasma Capsulatum), Dr. Victor R.J., Dr. Kirsner J.B. properties, their capacity for inhibition of lymphocyte and Dr. Palmer W. (1950 - viral etiology), an allergic activation and superoxide and hydroxyl radicals formation (cow’s milk - Dr. Andersen was the first in 1925, then Dr. [14]. Truelove and Dr. Taylor in 1961 at Radcliffe Infirmary, The discovery by Dr. Phillip Hench (professor Oxford) or dietary one (carbohydrates, fats), a metabolic rheumathologist) et al. (Dr. Charles Slocumb, MD and one (mucinoses - elevated lysozyme in stools, Dr. Meyer K. Dr. Edward Kendall, Ph.D., from the Department of and his colleagues Dr. Gellhorn A. and Dr. Prudden J. F. in Biochemistry of the Mayo Clinic) in 1950 of the adreno- 1947 at the New York Hospital), an autoimmune corticotropic hormone (ACTH) (that brought them the (anti-colon antibodies - Dr. Ove Broberger and Dr. Peter Nobel Prize), and the subsequent development of gluco- Perlmann were the first to sustain the hypothesis in 1959) or corticoid hormones – cortisone, prednisone, ushered in a toxic one (diets rich in sulphur compounds – Professor Dr. the era of steroid therapy of IBD. The remarkable W. E. W. Roediger, Department of Surgery at Queen short-term results of ACTH therapy even led some to Elizabeth Hospital, toothpaste components – Dr. Powell J. J. consider a possible corticoid deficit as an etiology in the 1990s) [1,18]. alternative. In 1955 Professor Sidney Charles Truelove Also from an etiologic point of view many works of (from the Nuffield Department of Clinical Medicine - psychiatry supported the link between UC and psychiatric University of Oxford, to whom we owe the first prog- pathology - Wittkower’s study showed that 28 out of 40 UC nostic classification of colitis) and Professor Leslie Witts patients had suffered a major emotional trauma before (who invited Dr. Truelove at Oxford in 1947) published disease onset. Psychotherapy was deemed capable of solving in the British Medical Journal the first blinded some UC cases and of contributing to the remission of controlled study that proved disease improvement and others [1,19]. lower mortality in the corticosteroid treated group when It is well known nowadays that the symptoms of IBD compared to the control group [14,21]. can cause major psychological distress and there is proof The discovery of the double-stranded DNA helix by that emotional factors have a crucial role in maintaining Drs. James Watson and Francis Crick in 1950 signaled the and prolonging disease flare-ups. Current treatment guide- beginning of the genetic research era. Over the following lines encourage doctors to deal with the psychosocial decades it was the science of immunology that concerned aspect of the disease, as well as with the organic one itself most with the pathogenesis of UC. In the 1960s, Dr. [1,20]. Bean in Australia discovered that 6MP - an immunosup- pressive drug- is effective in UC by inhibiting DNA Ulcerative Colitis –What can we do today? synthesis, in particular in those cells with a high mitotic Treatment and immunophysiology in the modern med- rate, such as inflammatory cells [22]. In 1966, Dr. Bowen ical era G. E. and Professor Dr. Kirsner Joseph Barrett (at the University of Chicago- he was the first to document the After World War II, randomized clinical studies increased risk of colon cancer in IBD) compared the became widely used, ushering in the era of evidence-based efficiency of a similar chemical compound – azathioprine, modern medicine, and thus discarding local or systemic determining also the adequate dosage needed to prevent empirical therapies and vaccines without any benefit [2]. its adverse effects and proving its success in eliminating THE GENESIS OF INFLAMMATORY BOWEL DISEASE YESTERDAY, TODAY, TOMORROW - CALAGIU et al vol. 50, no. 3, 402 the need for steroid therapy, partially or even completely in 1882, there was a description of ileocecal inflammation [23]. supplied, since CD inflammation is very similar to intestinal In the last 60 years there has been a major break- tuberculosis, but it lacks the presence of the mycobacterium through in medicine on our understanding of IBDs, due [30]. Much like the symposium of 1909 in London for UC, to the impact of molecular biology and genetics. The a series of 13 cases of CD was first published in the British numerous data offered by these two fields of research Medical Journal in 1913 by the Scottish surgeon Thomas give evidence of the complexity and elusiveness of their Kennedy Dalziel (a surgeon in the Western Infirmary] – he etiology [2]. Molecular investigations have proven linked the intestine consistency and surface features to those TNFα to be a key factor involved in the inflammatory of a « fish-snake in rigor mortis » and he named the affliction pathways of intestinal diseases, thus leading to the « non-tuberculous chronic enteritis » [31]. Although some development of biological drugs – monoclonal anti TNFα patients succumbed to the severity of the strictures and antibodies, increasingly used nowadays in the treatment of extensive involvement, other cases of localized disease were severe of refractory cases. These researches also led to the successfully controlled with partial resections. Dr. T. discovery of multiple immunological markers and provided Kennedy Dalziel also pointed out the possible involvement information regarding the pathogenic mechanisms of of the colon in CD. When analyzing Dalziel’s surgery cases, IBDs- the immune response in UC is the result of type 2 T the pathologists found eosinophilic infiltrates, giant cells, helper lymphocytes activation, while in Crohn’s disease type submucosal edema and granulomas, without evidence for an 1 T helper cells are involved [24]. infectious agent, and they named the disease « hyperplastic enteritis » [32,35]. Crohn’s disease - first there was darkness! Other important reports of the disease came from Dr. Discovery and delineation Weiner 1914, Drs. Eli Moschcowitz and A. O. Wilensky in Although historical figures such as Prince Bonnie 1923 published a clinical and pathological study of intesti- Charles and King Alfred The Great were reported as nal granulomas, and Dr. S. J. Goldfarb and Dr. M. Sussman suffering from UC and CD, respectively, it is now clear in 1931 - in their paper “The Roentgen Diagnosis of Lesions that these clinical entities were rare before the 20th of the Small Intestine” [26,30]. century. King Alfred (849-900) suffered from a “painful Nevertheless, it was not until 1932 that the landmark illness for much of his life”- its identity being the cause of article that identified CD as a “ terminal regional ileitis ” much speculation among Anglo-Saxons. The disease brought the disease to the attention of the entire medical started at about the age of 18 with a perianal onset, world, when published in the Journal of the American followed by abdominal symptoms and ran a protracted Medical Association by Dr Burrill Bernard Crohn (the course with many relapses up to his death at the age of 51 first Head of Gastroenterology at Mt. Sinai Hospital) in [25]. 1920 and his associates Dr. Leon Ginzburg (a surgeon at Nowadays CD is identified by the transmural inflamma- Mount Sinai) and Dr. Gordon D. Oppenheimer (patholo- tion of any part of the digestive tract mucosa, of unknown gist) of Mount Sinai Hospital in New York. They focused cause, clinically manifesting as diarrhea, abdominal pain, on “terminal ileitis” as a distinct and chronic clinical muscle aches and stiffness, weight loss and involvement of entity identified in 14 patients, of ages between 17 and 52 discontinuous segments of the intestine - skip lesions [2]. CD [33]. This designation proved later on inadequate, as it is a relatively newly-discovered disease – its first official was shown that the disease can involve the colon as well. description dating from 1932, although isolated cases had Moreover, many patients were terrified by the resonance of been reported much earlier and obvious clinical and the word “terminal”, whose medical significance they histopathological aspects of the disease had been mentioned sometimes misunderstood. The term “regional enteritis” as far back as two centuries before [26]. What is more, matched the focal character of the inflammatory process Professor John Fielding (Department of Clinical Medicine, but it did not allow for an accurate description of the Trinity College and St. James’s Hospital, Dublin) pointed out possible variable involvements: small intestine as well as the possibility that the first case of UC reported by Dr. Wilks large intestine or only large intestine. The term “granulo- in 1859 had actually been CD [27]. matous enterocolitis” was likewise dismissed after it was Many reports in the medical literature predating 1932 proven that the presence of granulomas was not mandato- refer to the disease as enteritis or regional ileitis [28]. The ry for establishing the diagnosis [34]. earliest and most complete description of the disease dates Dr. Ginzburg (adjunct surgeon at that time, under the back to 1761 and it belongs to Giovanni Battista Morgagni, eminent Dr. A.A. Berg) claimed that 12 out of 14 patients who is known as the father of modern anatomic pathology, included in the article had initially been selected by for his accurate and rigorous dissections and writings. Years himself and by Dr. Oppenheimer from the Surgery later, in 1828, Dr. J. Abercrombie (Edinburgh) reported a Department of Dr A.A. Berg’s at Mount Sinai Hospital. case of ileitis and skip lesions affecting the ascending colon Dr A.A. Berg having declined to further participate in and cecum, but the cause was not known [29]. the preparation and publication of the manuscript, the Only after Professor Robert Koch (the founder of modern two doctors sought the help of a pathologist to increase bacteriology, known for identifying the agents of tuberculo- their number of cases and they were put in contact with sis, cholera and anthrax) discovered the tubercle bacillus (TB) Dr. Crohn at the suggestion of pathologist Dr. Paul Archives of the Balkan Medical Union September 2015, 403

Klemperer. Dr. Crohn apparently took the manuscript and himself, disagreed that CD could affect the colon [40]. was not heard of for two years, after which he published In the past 50 years our understanding of CD has been the article including two additional cases (a 16-year-old revolutionized by the advances made in the fields of boy and his sister) and with him as first author. Dr. Crohn immunology, genetics and molecular biology, which have possibly never expected the disease to receive this eponym led to the discovery of over 50 genome polymorphisms as the article’s title had actually suggested the name of linked to the disease, that determine different phenotypes “regional ileitis” for it. But the publishing policy at that with distinct prognosis [41]. time was to list the authors alphabetically by their last Unlike UC, CD was found to be effectively controlled name [35]. by Methotrexate - the study published in 1988 that proved The difference between Dr. Dalziel’s 1913 article and it also won the Nobel prize [42]. Alongside the biological the 1932 article was of timing and publicity: Dr. Crohn’s therapy with Infliximab, Adalimumab is a newer biological paper was presented to a large medical audience whose agent, fully human and with fewer adverse reactions that interest had already been awakened and it was afterwards is also in use in CD. Many other biological drugs are published in the Journal of the American Medical currently being developed or approved: Tofacitinib (it Association, while Dr Dalziel’s work in the British inhibits cytokine synthesis), Ustekinumab ( IL-12 and IL-23 Medical Journal was forgotten [35]. antagonist), Visilizumab (anti-CD3), Natalizumab, Vedolizumab (anti alpha4 integrins), Certolizumab, Goli- Crohn’s disease - and then there was light ! mumab (anti TNFalpha) [43]. Understanding a new disease (1932-1956) Apart from the recent pharmacological studies and ther- During this time CD was diagnosed along the entire GI apies, the nonpharmacological treatment means, such as tract – esophagus, stomach, duodenum, jejunum, ileum and nutrition and surgery, have become increasingly important colon - these findings giving support to the term CD and over the last 25 years. The use of the nutritional approach as making the terms “regional ileitis or enteritis” inadequate treatment and not just as a supportive measure has had [2]. Also, a few retrospective studies were completed during obvious benefits, not just by decreasing malnutrition in this period, such as a first one in Rochester, Minnesota, that children, but also by improving control of the disease showed an annual incidence of 1.9 per 100,000 residents activity and by helping the recovery after the surgical treat- between 1935 and 1954 [36]. There was a single study done ment. Gastroenterologists and surgeons alike, increasingly in Europe, namely in Cardiff, United Kingdom, that showed convinced by the futility of extensive intestine resections, a 0.2 per 100,000 per year incidence rate between 1935 and started acknowledging the nutritional and physiological 1945 [37]. importance of preserving the integrity of the small intestine Dr. Charles Wells (in 1952, Liverpool) was the first to as much as possible [14]. describe the lesions caused by the disease as “skip lesions” The future is yet to come ! - that is, an area uninvolved by the disease, flanked by two Advanced modern technologies involved areas [38]. An even wider recognition gained the disease after Since endoscopy plays an essential part in the President Dwight D. Eisenhower’s (the 34th President of management of IBD, the technological advances of the the United States) surgery for CD in 1956. His openness last 50 years (the development of fiberoptic endoscopy for about his affliction helped turn this previously medical colonoscopies and ileoscopies) have allowed for better curiosity into a relatively well-known and important clin- biopsy assessments of the extension and severity of the ical entity. That year, at the age of 65, nine months after disease [44]. After the video capsule was approved in 2001 having suffered a myocardial infarction and after years of by the FDA, new techniques have been developed - single enduring abdominal pains because of which he had gone and double balloon-assisted endoscopy, spiral enteroscopy through an appendectomy in 1923, he showed radiologi- – so as to surpass the limits of the video capsule and push cal signs of regional enteritis and underwent emergency enteroscopy [45]. The progresses made in the imaging surgery for ileus [39]. techniques used in endoscopy have also enabled doctors to visualize mucosal fine details, tissue features and cellular Crohn’s disease - what can we do today ? alterations. These techniques – chromoscopy, magnifica- After World War II, clinical trials and epidemiology tion endoscopy, confocal laser endomicroscopy and endo- gained a lot of interest and offered new insights into the cytoscopy, narrow band imaging – have radically changed disease: CD was found to be more prevalent in developed the medical management with regard to diagnosis, patient countries and to be rising in incidence; at the same time, follow-up and treatment decision making. relatives of patients with CD were found to be at a greater As non-invasive methods of virtual endoscopy, risk of developing the disease themselves [31]. computed tomographies and IRMs have proven their use- In 1960, Sir Hugh Evelyn Lockhart-Mummery (a sur- fulness in the evaluation of the transmucosal involvement geon at St. Thomas Hospital at that time) - the son of the and its extension and of the disease complications: surgeon that had introduced sigmoidoscopy in 1909 – fistulae, abscesses, stenoses [45]. Optical coherence made the distinction between UC and CD involvement tomography is a new technique that offers real time cross- of the colon, although many doctors, including Dr. Crohn sectional subsurface imaging at a high resolution – 10 to THE GENESIS OF INFLAMMATORY BOWEL DISEASE YESTERDAY, TODAY, TOMORROW - CALAGIU et al vol. 50, no. 3, 404

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