Crohn disease is an inflammatory condition that can affect any portion of the gastrointestinal tract from the mouth to the perianal area. It is transmural in nature.

It most commonly manifests in the small intestine, in particular the terminal ileum.

The disease exhibits aggressive activity of the gastrointestinal immune system

The transmural nature of the inflammatory process results in fibrotic strictures. These strictures often lead to repeated episodes of small bowel, or less commonly colonic, obstruction. A patient with disease limited to the distal ileum frequently presents with right lower quadrant pain. Occasionally, patients will have no clinical manifestations of CD until luminal narrowing causes constipation and early signs of obstruction with abdominal pain.

Crohn’s most commonly affects the end of the small bowel (the ileum) and the beginning of the colon, but it may affect any part of the gastrointestinal (GI) tract, from the mouth to the anus.

The lesions are discontinuous.

The hallmark of Crohn disease is granulomas that may be present throughout the bowel wall and involve the lymph nodes, mesentery, peritoneum, liver, and pancreas. Although pathognomonic for Crohn disease, granulomas are only found in about half of surgical resections.

Crohn’s disease belongs to a group of conditions known as Inflammatory Bowel Diseases (IBD). Crohn’s disease is a chronic inflammatory condition of the gastrointestinal tract.

Crohn’s disease is not the same thing as ulcerative colitis, another type of IBD. The symptoms of these two illnesses are quite similar, but the areas affected in the gastrointestinal tract (GI tract) are different.

Crohn’s disease can also affect the entire thickness of the bowel wall, while ulcerative colitis only involves the innermost lining of the colon. Finally, in Crohn’s disease, the inflammation of the intestine can “skip”-- leaving normal areas in between patches of diseased intestine. In ulcerative colitis this does not occur.

Watch this webcast to learn more about Crohn's disease.

 

Crohn's Disease represents a disturbed relationship between the commensal microbiota, intestinal epithelial cells (IECs), and the immune system within the epithelium and lamina propria modified by genetic and environmental risk factors.

Numerous genetic and environmental factors have been identified that modify the risk for IBD development by specifically affecting the composition and function of the aforementioned critical core elements of disease pathogenesis (commensal microbiota, intestinal epithelium, or immune system).

Environmental factors have clearly been proven to either modify these diseases or regulate the lifetime risk of developing them. These include tobacco use, enteropathogenic exposures, appendectomy, antibiotic use, and oral contraceptive pills.

These do not, in and of themselves, cause the disease but likely modify the genetically defined or undefined aspects of the most critical components that underlie the immunopathogenesis of this disease: intestinal bacteria, epithelial barrier, and mucosal immune response. Of the latter three factors, the best understood influence—which has, to date, generated the most information, resulting in novel and exciting new forms of therapy—involves the mucosal immune response associated with these disorders.

 

 

Examples of factors that are involved in these pathways are shown. HSP, heat shock proteins; NSAID, nonsteroidal anti-inflammatory drugs; PRR, pattern recognition receptors; RA, retinoic acid; ROS, reactive oxygen species; TSLP, thymic stromal lymphopoietin; Genes’ names in red are Crohn disease specific, blue are ulcerative colitis specific, and black are those that affect both diseases. (Adapted, with permission, from Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573–621.)

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The major operating paradigm of our current understanding of IBD is that this disease represents hyperreactivity or loss of (oral) tolerance of the mucosal immune system to one’s own mucosal microbiota. This is consistent with the general localization of the disease, both UC and CD, to the regions of the intestine where microbes are mostly present. This concept is mainly derived from observations with numerous animal models of IBD, as well as a lesser number of human clinical studies. The latter have revealed some response to antibiotics, especially in CD, and the lack of any identifiable pathogens in both clinical subtypes of IBD. Thus, IBD likely represents a dysregulated mucosal immune response in a genetically susceptible host to commensal microbial antigens. At the same time, the commensal microbiota provides numerous protective signals that assist in the maintenance of homeostasis and the prevention of inflammation. Thus, IBD is associated with an increase in microbiota that tend to promote inflammation (eg, proteobacteria such as enteroadherent and invasive Escherichia coli) relative to the quantity of microbes that are inclined to prevent inflammation (eg, Firmicutes such as Faecalibacterium prausnitzii).

Genetic Basis

It has been known for almost 50 years that IBD in humans has a strong genetic basis. Specifically, 10–30% of patients will have a positive family history. There is also an extremely strong concordance of CD and, to a lesser extent (but which is still significant), of UC in monozygotic twins. The risk that both monozygotic twins will develop CD is approximately 60% (or 800-fold increased risk). However, even in monozygotic twins, there is environmental contribution to the development of both CD and UC. The genetic contribution to the development of IBD exists on a continuum (Figure 2–3). At one extreme are the forms of IBD that have a monogenic basis and typically develop during the early periods of life. This includes early onset (<10 years of age), very early onset (<6 years of age), and infantile (1–2 years of age) types of IBD that derive from environmental interactions with, in some cases, highly penetrant single gene defects that control the ability of the host to regulate inflammatory responses. Examples include inadequate production of or responses to inhibitory cytokines such as IL-10 or defective expression of inhibitory molecules on the surface of T cells such as CTLA-4. The majority of IBD, however, occurs in the second and third decades of life and represents a complex genetic disorder in which approximately 10% have a familial origin based on a positive family medical history. In these cases, the number of genes involved in the pathogenesis is unknown but likely to be a significant number. A genetic basis for IBD is further supported by observations in animal models in light of the similarity between these genetically induced models and the human disease especially in the case of the instances in which IBD begins in early human life.

The syndromic nature of inflammatory bowel disease (IBD). IBD can vary from presenting as a monogenic disorder early in life, a familial disorder in approximately 10% of adolescent or adult cases or a sporadic disorder in 90% of cases. In the majority of patients IBD is a complex disorder with varying contributions from genetic and environmental elements. Undiagnosed infections still remain as a possibility in the differential diagnosis of IBD. IL10, interleukin-10 gene; IL10A, interleukin-10 receptor A gene; IL10B, interleukin-10 receptor B gene. (Adapted, with permission, from Kaser A, Zeissig S, Blumberg RS. Genes and environment: how will our concepts on the pathophysiology of IBD develop in the future? Dig Dis. 2010;28(5):395–405.)

Genome-wide association studies and candidate gene studies with DNA sequencing have identified more than 160 genetic susceptibility loci throughout the human genome which increasingly points toward the existence of critical pathways in the pathogenesis of these disorders (Table 2–3)Genetic risk appears to be an important, if not essential, variable in driving the causation of IBD. It should be noted, however, that the mechanism by which genetic risk factors impose risk for the development of IBD remains largely unknown and environmental factors are equally required. It can be surmised but not proven that any one of these genes alone cannot cause IBD, as is strongly supported by the well-known observation that deletion of NOD2/CARD15, the strongest genetic risk factor for CD in mice, does not result in spontaneous inflammation.

Table 2–3. Immunogenetic pathways to inflammatory bowel disease.

  • Innate immunity (eg, NOD2, CARD9): inappropriate bacterial sensing and clearance by innate immune cells

  • Adaptive immunity (eg, IL23R, JAK2, STAT3, PTPN2, IL10): imbalance between effector and regulatory pathways

  • Inflammation pathways (eg, MST1, CCR6): dysfunction in leukocyte recruitment and inflammatory mediator production and response

  • ER stress pathways, autophagy, & epithelium (eg, XBP1, ORMDL3, ATG16L1, IRGM): abnormal intestinal epithelial cell regulation and sensing of bacteria

  • Metabolic pathways (eg, SLC22A5): inappropriate energy metabolism in hypermetabolic cells

Human genes are listed in italics. ER, endoplasmic reticulum.

Data from Kaser AK, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573–621.

Several interesting observations have been derived from the susceptibility loci identified to date. First, as predicted by a wide variety of immunologic studies, the genetic evaluation of humans shows very clearly that components of the immune system associated with innate immunity (eg, NOD2 which is expressed by dendritic cells) and adaptive immunity (eg, IL-10 which is produced by T cells which regulate the immune response) and their relationships with the microbiota are clearly involved in the pathogenesis of these diseases. Moreover, genetic studies show that alterations of intestinal epithelial cell function and especially that of Paneth cells, which secrete antimicrobial peptides into the lumen, contribute to the pathogenesis of these diseases. This occurs through genes such as ATG16L1 (which regulates autophagy), XBP1(which regulates the unfolded protein response), and NOD2 (which regulates intracellular bacterial sensing). In addition, the genes identified to date seem to associate with specific functional pathways that may be shared by CD and UC, as well as other immune-mediated diseases such as multiple sclerosis, type 1 diabetes mellitus, asthma, and others.

Immunologic Factors

It remains incompletely understood how the previously noted genetically imposed risk factors result in the development of IBD. However, it can be reasonably predicted that these genetic factors modify the intestinal epithelial cell barrier and have major effects on the function of innate and adaptive immune systems. They likely also regulate the composition of the microbiota itself. Furthermore, these genetic risk factors resolve into a final common pathway characterized by highly polarized T-cell responses associated with excess cytokine production derived from differentiated CD4-positive T helper cells and proinflammatory APC subsets (dendritic cells and macrophages). In addition, unique populations of T lymphocytes that sense host and microbial lipids (natural killer T cells) and innate-like lymphoid cells (ILC) that do not express T-cell markers are also increasingly recognized to regulate intestinal inflammation. Animal models have shown the essential importance of the microbiota in these responses, as no disease is often observed under germ-free conditions (ie, in the absence of intestinal bacteria); although some intestinal bacteria also prevent the development of inflammation by preventing the responses of both innate and adaptive immune cells. Finally, animal models have also revealed the importance of regulatory (anti-inflammatory) pathways and T regulatory cells, in particular, in both the prevention and resolution of IBD.

Given the importance of CD4-positive T helper (Th) cell polarization in IBD pathogenesis, some discussion of this topic is appropriate (Figure 2–4). T cells leave the thymus and migrate into peripheral tissues, such as the intestines, as naïve (antigen-inexperienced) cells. As such, they are considered to be Th0 cells without a bias for cytokine production other than the ability to secrete IL-2 upon stimulation through their antigen-specific receptor, the T-cell receptor (TCR), together with a costimulatory signal (so-called signal 2) that is classically delivered by cell surface molecules, such as CD80 or CD86 on APCs, to CD28 on the T cell (seeFigure 2–4). When T cells are presented the antigen for which they are specific through their TCR (signal 1) by professional APCs (eg, dendritic cells in peripheral tissues such as the intestines) together with signal 2, they are induced to deviate to one of several polarized fates under the control of cytokines produced by the APC (eg, dendritic cell) itself or other surrounding cells, or both. Importantly, these immune-deviating cytokines or other factors are typically produced by innate immune factors and cells (see Table 2–2 and Figure 2–4). Thus, cytokines associated with innate immune responses (eg, IL-12, IL-23) guide the adaptive immune response to one of several outcomes characterized by the development of T cells that are polarized to secrete a specific signature of cytokines, as shown in Figure 2–4 (eg, Th1, Th2, Th17, or T regulatory), through the actions of specific transcription factors (eg, T-bet in the case of Th1 cells).


Differentiation of T cells. Naïve CD4-positive T cells that have never experienced an antigen (Th0) are stimulated by an antigen-presenting cell (APC) such as a dendritic cell. The APC presents the antigen on a major histocompatibility complex (MHC) class II molecule to the T-cell receptor (TCR) on a T cell (signal 1). In the presence of costimulatory signals (so-called signal 2) provided by CD80 (B7.1) and CD86 (B7.2) on the APC to CD28 on the Th0 cell, the T cell is properly activated. The activated T cell is induced then to differentiate into one or more different fates that depend on the local cytokine milieu. This cytokine milieu is mainly derived from the APC itself and thus the innate immune response (boxed area in figure). In this manner, interleukin-12 (IL-12) induces Th1 cells; IL-4 induces Th2 cells; IL-23 induces transforming growth factor-β (TGFβ), IL-6 and IL-1 induce Th17 cells; TGF β, IL-6, and retinoic acid promote induced (i) T regulatory (Treg) cells; and interferon-α (IFN-α) induces T regulatory 1 cells (Tr1). Each T cell is maintained in its differentiated state by intracellular transcription factors. These include T-bet (Th1), GATA-3 (Th2), RORγt (Th17), and FoxP3 (nTreg). The differentiated T cells secrete a characteristic profile of cytokines (shown above the T cells). Cells in red are effector cells, and cells in gray are regulatory cells that inhibit inflammation. nTreg, natural T regulatory cell (see Figure 2–5).

 

, but the exact cause is unknown.

 

 


[ Although aminosalicylates are attractive because of low toxicity, it is unclear if these drugs are superior to placebo in preventing relapse.]As a result, immunomodulators (6-MP/AZA or MTX) or anti-TNF antibodies are generally used for

maintenance therapy for patients with moderate or severe disease.
¶ For patients with severe disease, enteral nutrition therapy might be used in combination with glucocorticoids or other medical treatments for induction of remission.
Δ In our practice, we consider early use of anti-TNF antibodies in the following types of patients, based on limited data that suggest that they are at high risk for complicated disease:[1-3]

  • Severe perianal disease
  • Steroid unresponsive
  • Deep fissuring ulcers in the colon
  • Extensive disease involving the mid-small bowel
  • Growth failure (if severe and/or occurring in late puberty)
◊ In general, patients requiring more than one course of glucocorticoids within one year should be advanced to a different immunomodulator or to an anti-TNF antibody.
References:
  1. Walters TD, Kim MO, Denson LA, et al. Increased effectiveness of early therapy with anti-tumor necrosis factor-α vs an immunomodulator in children with Crohn's disease. Gastroenterology 2014; 146:383.
  2. Turner D, Griffiths AM, Veerman G, et al. Endoscopic and clinical variables that predict sustained remission in children with ulcerative colitis treated with infliximab. Clin Gastroenterol Hepatol 2013; 11:1480.
  3. Ruemmele FM, Veres G, Kolho KL, et al. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. J Crohns Colitis 2014.

Similarly, avoidance of lactose-containing products is often beneficial advice for patients with Crohn disease

 

Pain Control and Anti-Inflammatory Agents

The treatment of Crohn disease can be divided into four areas of management: dealing with symptoms, treating mucosal inflammation, nutritional management, and surgery. Abdominal pain and diarrhea are dealt mostly by addressing intestinal inflammation. Pain may be due to the stretching of nerve endings as a result of distention from obstruction or inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided, and narcotics lead to addiction in this chronic condition. Acetaminophen, Tramadol, and Darvocet are used most frequently for pain control. 5-Aminosalicylic acid derivatives such as Azulfidine, Asacol, Pentasa, and Rowasa are used widely and have some effect. They are more effective in ulcerative colitis than in Crohn disease.

Steroids

Corticosteroids have been the mainstay in the acute treatment of Crohn disease for many years. Steroids should be used only when more conservative measures fail. The strategy employed is to induce remission by using high doses (prednisolone 60 mg per day) in the short term, followed by a temporary regime as soon as remission is induced. Maintenance therapy should employ the lowest dose possible.

Second-Line Agents

Steroid sparing in long-term management can be achieved with 6-mercaptopurine. This drug is slow to act and unpredictable in terms of achieving a therapeutic response. In doses of 50 to 125 mg daily, bone marrow suppression and other side effects are rare. The antibiotic metronidazole is also used as second-line therapy with a degree of success, particularly in treating fistulae. In addition to its properties as an antibiotic, the drug has an effect on the immune system. Other antibiotics that have been used to some effect are ciprofloxacin and clarithromycin.

Immune Suppressants

The immune suppressants methotrexate and cyclosporine have been shown to confer some benefit in the short term. The latest, still experimental, strategy in the treatment of Crohn disease involves the role of cytokines. Antitumor necrosis factor has been shown to be effective. Other cytokine therapies, such as the use of interleukin-11 (IL-11) and IL-10, have been reported to be efficacious in approximately 30 percent of cases.

Surgery

The cumulative risk of undergoing surgery sometime in the lives for patients with Crohn disease is approximately 90 percent,and the cumulative risk of recurrent disease at 20 years is 70 percent. Many recurrences may be asymptomatic, however. The major indication for surgery is failed medical therapy, usually in the presence of obstruction, fistula formation, and electrolyte or nutritional problems.

Controversy still exists over how radical the surgeon should be in treating Crohn disease. Some studies show that the more disease-free the margins are after the resection, the less likely there is to be recurrent disease. Conversely, there is a danger that overly radical resections will leave the patient with the short bowel syndrome and its nutritional consequences. Conservative surgery in the form of stricturoplasty for short stenotic lesions that are producing obstructions can be helpful without the loss of any bowel. For longer diseased segments, resection is preferred to bypass. For colonic Crohn disease with severe rectal and anal involvement, a proctocolectomy with ileostomy may be required. Meticulous care is required in performing anastomoses in patients with Crohn disease, as healing is often impaired and the risk of anastomotic leakage therefore is increased.

 

Dysregulated mucosal immune response to antigenic components of the normal commensal microbiota that reside within the intestine.

The principal stimulus for diarrhea is the mucosal immune response in association with cytokine release.

 

 Diarrhea is a common presentation, but often fluctuates over a long period of time.

A history of prolonged diarrhea without bleeding but with other features suggestive of inflammatory bowel disease (IBD) (eg, skin, eye, or joint problems, or a family history of IBD) should suggest the diagnosis of CD. Diarrhea associated with CD may have multiple causes, including:

●Excessive fluid secretion and impaired fluid absorption by inflamed small or large bowel

●Bile salt malabsorption due to an inflamed or resected terminal ileum

●Steatorrhea related to loss of bile salts

●Small intestinal bacterial overgrowth

●Overlapping irritable bowel syndrome

●Enterocutaneous fistulas causing bypass of portions of absorptive surface area

 

Published studies in the United States report incidence rates that vary between 1.2 and 8.8 per 100,000 population; the prevalence is 44 to 106 per 100,000. The condition is more common in the cold climates of the northeastern United States than in the south. Those of Jewish ethnicity have a high incidence. The disorder, which is slightly more common in females, has a bimodal age distribution, peaking in the early twenties and again emerging in the mid-sixties.

Theories regarding pathogenesis have referred to genetics, infection, autoimmune or allergic processes, thromboembolic disorders, and dietary disorders.

 

  • Malabsorption and malnutrition, fibrous strictures of the intestine, and fistulae to other organs, such as from bowel to skin or bowel to bladder

 

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Content 3

Content 11

 

Which of the therapies listed below is used most often to treat an individual with a history of Crohn disease who acutely develops abdominal pain and bloody diarrhea but has no clinical evidence of obstruction or fistula formation?

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The correct answer is D. You answered D.

D. In the absence of bowel obstruction or fistula formation, several types of medical therapies have been used to treat the acute inflammation associated with Crohn disease. Corticosteroids, such as high-dose prednisolone, have been used commonly to treat the acute symptoms and induce remissions. In contrast, the antibiotic metronidazole may be used to treat patients with fistula formation, whereas the use of cytokines such as interleukin-10 is experimental. Surgical resection of bowel usually is done to treat problems such as obstruction.

 

Content 2

Which of the following is a contraindication to use of sulfasalazine in Crohn disease?
A
Aspirin allergy.

B
Heme positive stools.

C
Fever.

D
Platelet count <100,000.

https://www.ouh.nhs.uk/rheumatology/information/health-professionals/documents/5.GPdruginfosulphasalazineNov2010.pdf

A 44-year-old man presents with multiple episodes of bloody diarrhea accompanied by cramping abdominal pain. A colonoscopy reveals the rectum and distal colon to be unremarkable, but x-ray studies find areas of focal thickening of the wall of the proximal colon, producing a characteristic "string sign." Biopsies from the abnormal portions of the colon revealed histologic features that were diagnostic of Crohn disease. Which of the following histologic features is most characteristic of Crohn disease?

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The correct answer is C. You answered C.

C. Microscopic examination of the abnormal bowel from an individual with Crohn disease will reveal transmural inflammation with fibrosis, but the histologic feature that is most diagnostic of Crohn disease is the presence of noncaseating granulomas. This characteristic histologic feature, however, may be present in only approximately 50 percent of patients; however, the diagnosis of Crohn disease can still be made without finding granulomas by the characteristic clinical presentation, which includes the production of fissures, fistulae, and bowel obstruction by the transmural inflammation.

62% of users answered correctly.

 

 

Named after Dr. Burrill B. Crohn, who first described the disease in 1932 along with colleagues Dr. Leon Ginzburg and Dr. Gordon D. Oppenheimer,

 

 

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