1. Historical Background: Past, Present, and Future of the Pathology

Past: the era of description
For the first time Crohn’s disease was described in 1761 by Morgagni as intestinal inflammation. In the beginning, the features of inflammatory bowel disease (IBD) were described, and medical therapeutics were guided by trial and error, misguided hypotheses about disease pathogenesis, and some measure of serendipity. With the recognition of the nosologic distinctions of Crohn’s disease and ulcerative colitis—the two major forms of idiopathic inflammatory bowel disease (IBD) came attempts to treat them surgically and medically. First treatments included treatments have included potassium permanganate, Dakin’s solution, antidysentery serum, Escherichia coli vaccine, antiamoebic drugs, and sulfonamides.

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The descriptive histology of IBD suggested that immune activation could also be targeted by therapeutic agents. The observation of acute and chronic inflammatory cells, and the common occurrence of extraintestinal immune-mediated manifestations eventually led to the use of adrenocorticotropic hormone6 and corticosteroids, which have proven to be highly effective in treating these diseases.

Present: the era of explanation

First, it is recognized that immune tolerance is the normal state of the intestinal immune system. Second, it is apparent that a wide variety of cell types are orchestrated in a tightly regulated fashion to maintain immunologic tolerance. At the same time, the capacity to mount an immune and inflammatory response within the mucosa is maintained. Third, the luminal flora is a key ingredient in the abnormal immune response of IBD. Fourth, genetic factors predispose individuals to an abnormal immune response to the flora. Finally, it is recognized that both the innate and adaptive immune responses play integrated roles in the homeostasis of the intestinal mucosal immune response. An excess of effector T cells, characterized as either Th1- or Th2-like, is associated with the distinct clinical manifestations of Crohn’s disease and ulcerative colitis, respectively. We have teased out cytokine pathways that shape and perpetuate inflammation. The process of leukocyte adhesion and recruitment has been worked out. T regulatory responses have been shown to be deficient in IBD. These detailed explanations of the pathogenesis of IBD have led to more effective and focused treatments for these diseases.

Future: the era of prediction

In spite of decades of intensive research, the pathogenesis of IBD is still not completely understood. So having a better understanding of pathogenesis of IBD would significantly help in finding new treatments.
The development of new approaches that could provide the targeted delivery of new safe drugs to the gut could increase clinical efficacy and limit potential adverse events.
Stem-cell therapies have recently been proposed as a method to address the challenges and prospective medical needs of Crohn’s disease patients in general and those with fistulas. Several studies suggest that mesenchymal stem cells (MSCs) could improve Crohn’s disease and Crohn’s fistula. Moreover, studies concerning MSC transplantation or local rejection of stem cells derived from bone marrow or adipose tissue-derived stem cells have assessed stem cell-based treatments for refractory Crohn’s disease. Many patients in these studies are now in remission.

2. Epidemiology of the Pathology

The prevalence of CD has an incidence of 3 to 20 cases per 100,000.4 Crohn disease is more common in the industrialized world, particularly in North America and Western Europe, though the incidence is rising in Asia and South America.There may be a slightly higher predominance of CD in women and it is more common in individuals of Ashkenazi Jewish origin than in non-Jews. The exact pathogenesis of CD is unknown, although there are a number of genetic and environmental factors that have been shown to increase the risk of the disease and lead to the aberrant gut immune response characteristic of the disease.

3. Signs and Symptoms of the Pathology

Crohn’s disease is a granulomatous inflammation of various parts of the digestive tract, characterized by a chronic recurrent and progressive course. For treatment purposes, it has been divided into phenotypic subtypes: inflammatory, stricturing, and fistulizing. Inflammatory CD is characterized by inflammation of the gastrointestinal tract with no evidence of stricturing or fistulizing disease. This inflammation can eventually lead to fibrosis and luminal narrowing and these patients become classified as having stricturing disease. Once fibrostenotic changes occur, there is no process that reverses this aside from surgical intervention. Ongoing transmural inflammation can also result in the development of a sinus or fistulous tract characteristic of fistulizing CD. Fistulae can develop between the bowel and any adjacent organ (including the vagina, bladder, and other areas of the bowel). If the sinus tract is not complete between the bowel and an adjacent organ, an intraabdominal abscess may develop. In addition to these subtypes, patients can develop perianal complications. Perianal disease is not considered its own phenotype but rather a complication that can develop regardless of the underlying luminal disease phenotype.

Crohn’s disease is accompanied by abdominal pain, diarrhea, intestinal bleeding. Systemic manifestations include fever, weight loss, musculoskeletal (arthropathy, sakroileitis), eye (episcleritis, uveitis), skin (erythema nodosum, pyoderma gangrenosum). Besides the common complication of intestinal obstruction, fistulas, particularly anorectal fistulas, are common in Crohn’s disease patients.

4. Diagnostic testing for the Pathology

Diagnosis of Crohn’s disease is carried out with the help of colonoscopy, intestinal X-ray, CT. Also, findings on serum and stool testing can assist with making a diagnosis. Stool studies should be obtained to rule out other causes of gastrointestinal symptoms and diarrhea. Laboratory abnormalities are seen more frequently with a longer duration and more severe disease. Patients may have an anemia from iron deficiency anemia, chronic inflammation, and B12 deficiency. Inflammatory markers including erythrocyte sedimentation rate and/or c-reactive protein may be elevated, but normal levels do not rule out CD activity. Multiple tests have been evaluated to assess for inflammation in the gastrointestinal tract including fecal calprotectin or fecal lactoferrin. However, none of these tests is unique to IBD and can be elevated with any intestinal infection or inflammatory condition.

5. Treatment Modalities: Past, Present, and Future for the Pathology

The treatment of CD depends on disease severity, location of disease, and subtype of disease (ie, inflammatory, stricturing, or penetrating). Treatment includes dietotherapy, anti-inflammatory, immunosuppressive, symptomatic therapy; with complications, surgical intervention. More recently, immunosuppressants are used in combination with anti-TNF drugs to decrease their immunogenicity and increase anti-TNF drug concentrations. The mainstay of therapy for CD has been anti-TNF agents. More recently approved drugs are monoclonal antibodies directed against certain integrins (?4 or ?4b7) or interleukins (IL-12/IL-23). The most recently approved agent, ustekinumab, an IL-12/IL-23 inhibitor, has been shown to be as effective as anti-TNF therapy at inducing and maintaining remission in moderate to severe CD.

Ultimately, the goal of medical therapy is to induce and maintain a steroid-free clinical remission, prevent complications and surgery, and improve the patient’s quality of life.