[Crohn disease: before and after 1932 year].

The article describes the historical milestones in the study of Crohn's disease from the time of its original description in the 17th century, the revolution in the medical community after the landmark paper in 1932, to the present day. The history of Crohn's disease testifies to the discoveries of the past years, which open up to us the advantages of a scientific approach to the diagnosis and treatment of this disease.

What the early pathologists got wrong, and right, about the pathology of Crohn's disease: a historical perspective.

Surgeons, who documented what they had seen and felt in the abdomen of the patient, made the earliest descriptions of Crohn's disease (CD). Dalziel wrote the first pathology description in 1913. Crohn and his coworkers reinvented what Dalziel had written about and called it by a different name, 'regional enteritis'. Later others elaborated on the histologic features, at first the lymphoid follicles, later the granulomas. Some thought the latter were comprised of lymphatic endothelial cells and that endothelial plugs obstructed the lymphatics. Tonelli and others recognized that lymphedema was important and caused by obstructions to lymphatic vasculature. Some lymphatics they described contained lymphocyte plugs and others granulomas. Immunohistochemistry (IHC) has now shown that endothelial cells are not the cause of lymphatic obstruction, but rather CD68-positive macrophages, concluding that the 'lymphocyte thrombi' are passive, caught upstream of granuloma-obstructed lymphatics. Numerous authors recognized that transmural edema was the most significant change in Crohn's disease and that this was later followed by fibrosis and contracture of the diseased segment. Key descriptive papers spoke of the segmental lymphedema. Most recently, attention has been given to attachments of the intralymphatic CD68+ granulomas to a focal point where endothelial damage occurred, damage suggesting infectious penetration of the mucosa, necrosis of lymphatic endothelium and then granulomatous response, both inside and outside the lymphatics, of submucosa, muscularis, and subserosa. D2-40 IHC outlines the endothelium, and anti-CD68 shows the granulomas. IHC adds a valuable perspective when reviewing CD resections.

Año 1932: descripción inicial detallada de la enteritis regional / Year 1932: The first detailed description of regional enteritis

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Is Crohn's Disease a Rightly Used Eponym?

In 1932 Burrill B. Crohn, a gastroenterologist at Mount Sinai Hospital in New York City, described, together with two surgical colleagues, a series of 14 patients with an inflammatory condition of the terminal ileum. All patients were operated on by Dr Albert Berg, the Chief Surgeon of the hospital, whose name did not appear on the initial publication. The 'new' disease was called 'regional ileitis', but was rapidly referred to as 'Crohn's disease'. From earlier accounts and publications it has become clear that the condition had already existed for many centuries and was 'discovered' several times before 1932, most notably by Giovanni Morgagni in 1769, Antoni Lesniowski in 1903 and Thomas K. Dalziel in 1913. 'Crohn's disease' might reasonably be known by another eponym. Nevertheless, the 1932 publication of Crohn was pivotal, as were his later contributions to the knowledge of 'his' disease. Therefore the worldwide use of the eponym is rightly to be continued. Present researchers and clinicians with an interest in inflammatory bowel disease [IBD] might learn from the complicated story summarised in this contribution. Apart from an interesting historical overview, there are some lessons for today: the importance of thorough clinical observation and pattern recognition, the need for communication between colleagues and multidisciplinary approaches, and the need for broad access to valuable data, past or present, regardless of the journal or language of publication. It should ultimately bring us some humility, despite great achievements in treating this chronic disease, which defies all our efforts yet to find a cure.

Evolving primary and secondary endpoints in randomized controlled trials leading to approval of biologics and small molecules in IBD: an historical perspective.

Introduction: Therapeutic goals in inflammatory bowel diseases (IBD) have evolved, over the last decades, from clinical response to complete remission (clinical and endoscopic remission).Areas covered: Development of biologics and small molecules has been associated with the development of new endpoints in IBD trials that could not have been achieved in the pre-biologics era. Herein, we focus on evolving endpoints for approved biologics and small molecules. We searched for relevant publications using Medline/PubMed, Embase and the Cochrane Library from their inception to 1 July 2019.Expert opinion: Endpoints differ between induction (clinical and endoscopic response) and maintenance trials (clinical and endoscopic remission) because the goal is to evaluate the anti-inflammatory effect of a given drug during induction, whereas full disease control is the ultimate goal during the maintenance phase in order to change patients' life and disease course. Histological healing has recently emerged as a new co-primary endpoint in ulcerative colitis, and is now part of the definition of mucosal healing in these trials. Whether new endpoints such as transmural and radiologic healing could become an endpoint and replace endoscopy in Crohn's disease trials in the near future requires further investigation.

Terapia biológica na doença de Crohn: quando iniciar? / Biologic therapy for Crohn's disease: when to initiate?

A doença de Crohn se caracteriza como uma doença inflamatória, que acomete qualquer porção do trato gastrintestinal, resultante da desrregulação imunológica, gerenciada por fatores endógenos e exógenos. As formas de abordagem terapêutica da doença variam conforme sua apresentação clínica e gravidade, bem como o impacto na qualidade de vida do portador. A terapia biológica vem se tornando uma das principais classes utilizadas no contexto desta enfermidade, mas não está claro quando deve ser iniciada ou em que momento a própria doença deve ser considerada moderada ou grave. Sua forma de apresentação multiforme dificulta a classificação dos pacientes nestes grupos. Neste trabalho, foi realizada revisão de literatura sobre a introdução de terapia biológica como tratamento da doença inflamatória intestinal em curso. (AU)

Crohn's Disease (CD) is an inflammatory disease that can affect any portion of the gastrointestinal tract, caused by immune dysregulation, managed by endogenous and exogenous factors. The forms of therapeutic approach of the disease vary significantly according to its clinical presentation and severity, as well as to the impact on patient's quality of life. Biologic therapy has become one of the main classes used in the context of this disease; however, when it should be initiated or at what time the disease itself should be considered moderate or severe is not clear. Its multiform presentation makes it difficult to classify patients in these groups. In this work, a literature review was carried out about the introduction of the biologic therapy as a treatment of the ongoing inflammatory bowel disease. (AU)

Prof Ronan O'Connell Festschrift: Stricture pathogenesis in Crohn's disease-the role of intestinal fibroblasts.

Approximately one-third of patients with Crohn's disease have a distinct fibrostenosing phenotype predisposing them to recurrent intestinal stricture formation. The intestinal fibroblast was thought to play a critical role in the abnormal wound healing which ends in stricture formation. Recognising this, a laboratory-based research study was initiated at the Mater Misericordiae Hospital and University College Dublin with the aim of investigating the key steps in intestinal fibroblast-mediated stricture pathogenesis. An in vitro model was developed using cultured fibroblasts taken from sites of stricture in patients undergoing surgery. In summary, these fibroblasts were shown to carry multiple distinct pro-fibrotic phenotypic changes which may explain the abnormal wound healing and scar formation found at their sites of origin. This paper reviews that body of work, undertaken by series of surgical researchers and scientists, and driven by the insight, guidance and mentorship of Professor Ronan O'Connell.

[History of surgical treatment of non-specific inflammatory bowel diseases]. / Historie chirurgické lécby nespecifických zánetu strevních.

Treatment of non-specific inflammatory bowel diseases was from the start accompanied by forced operations. In the 19th and early 20th century operations were burdened with high mortality, but most were more successful than the limited possibilities of conservative treatment. Gradually developed principles for the treatment of Crohns disease, a length of bowel sparing surgery are still valid today. Surgical treatment of ulcerative colitis passed the time of colonic irrigation, bypass surgery, limited resection to todays gold standard - proctocolectomy with ileo-pouch-anal anastomosis.

Clinical trials in luminal Crohn's disease: a historical perspective.

It goes back to 1932 when Dr. Burrill Bernard Crohn and co-workers published their landmark paper, describing regional ileitis as a disease entity. However, clinical trial research has been developing rather slowly in luminal Crohn's disease. It took until the early seventies before the first randomized clinical trial was set up by the National Co-operative Crohn's Disease Study (NCCDS) group. Although the efforts of this group triggered a first wave of clinical trials in Crohn's disease, the lack of guidelines for conducting a clinical trial in this research area resulted in a variety of study designs and much criticism. Besides having a rather small sample size and a short follow-up time, they were often characterized by vague and subjective assessment of disease activity and treatment response. Following the advent of a new and very potent drug class in the late nineties, the anti-TNF agents, investigators started to re-think their study protocols and the first guidelines were set up by the regulatory authorities. Over the last 15years, clinical trials in luminal Crohn's disease have been evolving significantly. Inclusion criteria have been shifting from clinical scores such as Crohn's Disease Activity Index (CDAI) to more objective disease activity parameters such as biomarkers (C-reactive protein and faecal calprotectin) and endoscopic lesions. Primary endpoints have been developing from clinical response to corticosteroid-free remission and more ambitious end-points such as mucosal healing. In this paper, we will give a historical overview on clinical trials in luminal Crohn's disease, before and within the biologic era, and provide insight into how they have shaped our current understanding of trial designs in Crohn's disease.

A tale of two diseases: the history of inflammatory bowel disease.

'Inflammatory bowel disease' (IBD) sounds like a straightforward term - a disease of inflammation in the bowel. However, the history of IBD reveals a story of a nefariously complex set of idiopathic conditions. IBD defies definition, in part because its pathophysiology is not completely understood. For the same reason and despite substantial advances in research, IBD also defies cure. At best, IBD can be defined as a disease of disruption - disrupted physiology, microbiology, immunology and genetics. The term 'IBD' is most often used to describe two separate conditions: ulcerative colitis (UC) and Crohn's disease (CD). This paper reviews the history of IBD, considering the ever-evolving understanding of both UC and CD. Beyond its intrinsic interest, the history of IBD exemplifies a pattern that is becoming increasingly familiar in the 21st century - the story of a chronic, incurable disease that defies the best efforts to treat it.

[Cell adhesion molecules in evaluation of Crohn's disease therapy].

The treatment of inflammatory bowel diseases (IBD), which include ulcerative colitis (UC) and Crohn's disease (CD) is one of actual problems of modern gastroenterology and coloproctology. In recent years a great attention is paid to the molecules of adhesion. Adhesion proteins play a significant role in the development of inflammation in patients with IBD. They cause the migration of cells from the capillaries into the center of inflammation, i.e. do much to increase the inflammatory infiltration of the mucosa and homing of lymphocytes. Changes in the levels of adhesion factors under the influence of biological therapy have been insufficiently studied. So the aim of our study was to determine the diagnostic value of adhesion molecules--integrin-sVCAM-1 and selectins P-, E-, L- for the assessment of the effectiveness of therapy in patients with UC and CD and prognosis of the disease. 15 patients with IBD were examined (15 patients with Crohn's disease (CD)). 9 patients were treated using infliximab 5 mg/kg according to the standard scheme (0-2-6 and then every 8 weeks). 3 patients with IBD received anti-inflammatory therapy with the introduction of the culture of MSC in the number of 150 x 108 cells suspended in 200 ml of physiological solution with the addition of heparin (10 IU/ml). 3 patients received azathioprine (2 mg/kg) and glucocorticosteroids (GCS) 1 mg/kg. The clinical symptoms, the level of leukocytes, erythrocyte sedimentation rate, C-reactive protein and also were analyzed before and after the treatment with infliximab and transplantation of MSC. The status of the colonic mucosa was evaluated using colonoscopy with biopsy. The concentration of adhesion molecules L-selectin, E-selectin, P-selectin, integrin-sVCAM-1 in blood serum was analyzed using immunoenzyme method twice before the beginning of treatment and after 2 months. It is established that after the standard therapy with the use of corticosteroids and azathioprine clinical and laboratory signs of IBD activity and increased levels of adhesion molecules remained in all patients. It is reliably determined that under the influence of infliximab the levels of P-selectin, E-selectin and integrin-sVCAM-1 decrease to 8.9 +/- 1.0 ng/ml, 5.5 +/- 1.7 ng/ml, 9.5 +/- 4.4 ng/ml, respectively (p < 0.001) in all patients with IBD. This point to the suppression of the synthesis of the main inflammatory cytokine alpha-TNF. Transplantation of MSC causes significant decrease of P-selectin, E-selectin to 6.9 +/- 1.1 ng/ml and 5.7 +/- 1.3 ng/ml, respectively (p < 0.001). Integrin-sVCAM-1 has decreased slightly to 12.2 +/- 2.2 ng/ml, p > 0.1. This is associated with the onset of the maximum therapeutic effect only in 1-2 months after transplantation. The levels of P-selectin, E-selectin, integrin-sVCAM-1, reflecting the acute phase of inflammation, decreased after MSC transplantation and infliximab induction therapy. The level of L-selectin, reflecting a chronic autoimmune inflammation, practically does not decrease after the MSC transplantation (8.9 +/- 0.5 ng/ml, p < 0.05) and infliximab induction therapy (9.6 +/- 0.8 ng/ml, p > 0.1). These include the appointment of long-term infliximab therapy and repeated MSC transplantations. P-selectin, E-selectin, L-selectin, integrin-sVCAM-1 are modern markers of inflammation and may be used to assess the effectiveness of standard and biological therapy in patients with IBD, and to predict the course of the disease.