Regional enteritis K50.9

Authors: Prof. Dr. med. Peter Altmeyer, Prof. Dr. med. Guido Gerken

Our authors

Last updated on: 29.10.2020

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Synonym(s)

Crohn-Ginsburg-Oppenheimer disease; Crohn`s disease; Crohn's disease; Crohn's disease cutaneous; Crohn's disease Skin changes; Cutaneous Crohn's disease; (e) Cutaneous Crohn's disease; M.Crohn's skin changes; M. Crohn the skin; Metastatic Crohn`s disease; Metastatic Crohn's disease; regional enteritis; regional enterocolitis; Sclerosing chronic enteritis; terminal ileitis

History
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Lesniowski 1903, Crohn 1932

Definition
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Crohn's disease is an idiopathic systemic disease with a chronic recurrent course, which preferentially manifests itself as an intestinal disease with segmental involvement and transmural inflammation. Inflammation can occur in any section of the gastrointestinal tract, but is most commonly localized at the ileocecal junction.

Classification
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The disease is classified according to the Montreal Classification.

The Montreal Classification distinguishes between age at first diagnosis, the pattern of infection and behaviour. If a perianal infestation is added, a "p" is added.

  • A: age of manifestation: A1<16Lj; A2 17-40Lj; A3>40Lj.
  • L: Location: L1=ilium; L2=colon; L3=ileocolonic; L4=upper GI tract
  • B: Biological behaviour: B1= not structuring/penetrating; B2= stricting; B3 internally penetrating; B3p: perianal pentrating

Occurrence/Epidemiology
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Epidemiological figures show a continuous increase in the incidence of Crohn's disease over the last decades, with the prevalence being highest in western countries. The incidence of Crohn's disease in Europe ranges from 0.3 to 12.7/100 000 inhabitants, with an estimated prevalence of 0.6 to 322/100 000 inhabitants. The correlating figures for Asia are significantly lower, but also show an increase.

Etiopathogenesis
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Crohn's disease is probably mediated by autoimmunological misreactions. In addition to genetic influences, dietary factors, environmental factors, the intestinal microbiome and increased and disturbed permeability of the intestinal wall play a role.

The following genloci are involved in the pathogenesis of the disease:

  • genes that regulate cellular processes, such as endosplasmic reticulum stress and metabolism e.g. XBP1, ORMDL 3 (Pramanik J et al. 2018; Davis D et al. 2018)
  • genes that regulate the antimicrobial response of Paneth or goblet cells to commensal microbiota
  • genes responsible for immunity and autophagy and relevant in the defence against bacteria and viruses (e.g. NOD2, ATG16L 1, STAT 3 see under Kurreeman FA et al. 2012, Fritz T et al. 2011). The protein encoded by the ATG16L1 gene is part of a large protein complex required for autophagy.
  • Genes that ensure the balance between pro- and anti-inflammatory cytokines (e.g. IL-23 R, IL-10)
  • genes involved in the initiation and termination of cellular inflammatory reactions (e.g. MST 1 = macrophage-stimulating protein 1, CCR6) (Wang MH et al. 2002)

Microbiota: The human intestinal microbiome establishes a stable configuration by the age of 3 years. Its composition and function varies from individual to individual and is controlled by diet, genetic factors and environment.

Intestinal barrier: The intestinal barrier is formed by the cell layer of epithelial, goblet and Paneth cells (Adolph TE et al. 2013), intraepithelial lymphocytes and the mucin layer overlying the epithelium. This cell network reacts to intestinal microbiota luminally by the production of mucins, by a broad arsenal of antimicrobial peptides (lysozyme, alpha-defensins, tumor necrosis factor-alpha, phospholipase A2, ECF) and mucosally by the control of the immune cell compartment. The misregulation of this complex system can be caused by an altered microbiome, a pathological mucin layer, a primary epithelial cell defect as well as by an increased production of pro-inflammatory cytokines from mucosal.

Immune cells of the lamina propria: An important function of the immunological mucosal systems is to maintain tolerance to the translocating antigens. This is achieved by a special form of antigen presentation within an anti-inflammatory milieu. In addition to the antigen-presenting cells, the T-cell subpopulations are of particular importance here. The relevance of individual subtypes is clearly demonstrated by the example of the deficiency of FoxP3 + regulatory T cells, which is associated with a severe autoimmune phenotype. In proinflammatory subtypes Th 1 cells, Th 2 cells and Th 17 cells play a role. The latter are responsible for neutrophil recruitment.

Interleukins: IL-4 and IL-23 together with IL-6 and TGFβ induce Th 2 and Th 17 cells. IL-23 inhibits the suppressive function of regulatory T cells (Treg).

Activated macrophages secrete TNF and IL-6, which explains the therapeutic benefit of TNF and IL-12/IL-23 antibodies.

The pro-inflammatory T cells induce an increased homing of inflammatory cells into the lamina propria, which in turn explains the therapeutic benefit of the integrin antibody vedolizumab.

Genetics: About 25% of Crohn's disease is explained by the presence of risk mutations (Franke A et al. 2010). Crohn's disease has a greater genetic involvement than ulcerative colitis. This is illustrated by twin studies: in monozygotic twins there is a concordance of 38-50% in Crohn's disease and 4% in fraternal twins. If the disease manifests itself in infancy or early childhood, monogenetic disease can be ruled out by exome sequencing. It is possible that mutations in the genes of the so-called NOD-like receptors play a pathogenetic role.

A surprising finding was made by genetic studies, which were able to identify risk loci for complicated courses of disease, but which do not show any overlap with risk loci for disease development (Lee JC et al. 2017).

Bacterial antigens: Various data suggesting that the disease could be caused by bacterial antigens are becoming increasingly important. The main suspect is Mycobacterium avium paratuberculosis (MAP).

Autophagy factors: Further associations are known, for example with the autophagy factor ATG17L1 and the interleukin receptor IL23R .

Smoking increases the risk of Crohn's disease in the Caucasian population. Smoking is also the main risk factor for postoperative recurrence after ileocecal resection.

Oral anticonceptives: Less well documented is the increase in risk by taking oral contraceptives.

Antibiotics: The use of antibiotics within the first year of life is associated with an increased risk.

Breastfeeding may have a protective function.

Infectious gastroenteritis with a proven pathogen also increases the risk.

Manifestation
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Usually before the age of 30 (2nd and 3rd decade of life), although the disease can occur at any age. In 4-20% of the patients the oral mucosa is involved.

There is no sex preference. However, in the relatively rare "metastatic Crohn's disease of the skin", women are in the majority (about 75% of the clientele). The average age of manifestation here is 34.5 years.

Clinical features
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  • The clinical presentation of Crohn's disease is very different. Only weight loss or a delay in development can occur. Abdominal pain, weight loss, fever, nausea and diarrhoea may occur. In addition, perianal or enterocutaneous fistulas indicate complications.

Extra-intestinal manifestations may occur with a relapse, but also before the initial manifestation:

Appearance of mucous membranes on the skin or near the skin:

  • Fistula formation (40%), perianal aphthous ulcerations, anorectal abscesses (25%) - Note: often anal fistulas are the first monitoring signs of regional enteritis! Note: The term "metastatic Crohn's disease" is defined as a sterile, granulomatous, cutaneous lesion without direct connection to the gastrointestinal tract. On the one hand, the term implies a malignant neoplastic process as an underlying disease, on the other hand it is misunderstood that Crohn's disease is a "non-monotopic" granulomatous systemic disease.
  • Acne-like abscesses of the buttocks, lower abdomen and thighs.
  • Erythema nodosum, erythema exsudativum multiforme, vasculitis leukocytoclastic, palmarerythema, uncharacteristic pustulosis of the skin.

Persistent genital edema

Ulcera: recurrent or permanent, usually deep, extensive and very painful ulcers in the oral mucosa (4-20% of Crohn's disease cases). Frequency more frequent than in habitual aphthae. They are significantly larger and more painful.

Chronic, inflammatory swelling of the lips (see below Cheilitis granulomatosa or orofacial granulomatosis). Coincidence with Pyoderma gangraenosum is described. Occurrence of acrodermatitis enteropathica is possible, and individual coincidental cases of Sweet's syndrome have been described.

Eyes (7%): Episcleritis, iritis, concunctivitis

joints (20%): arthritis, ankylosing spondylitis (80% HLA-B27 positive), sacroilitis

Liver: fatty liver, primary sclerosing cholangitis (K83.0)

Intestine: intestinal stenosis with signs of (sub)ileus, rarely perforations

Children: Growth disorders , Malabsorption syndrome with weight loss

Diagnostics
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Before a therapy can be planned, the infestation pattern must be determined and complications identified:

  • an isolated infestation of the small intestine is found in 30-40% of patients
  • an infestation of the small and large intestine at 40-55
  • an isolated colon infestation at 15-25 %.
  • in small intestine infestation the terminal ileum is affected in 90 %.

The majority of patients will require long-term immunosuppressive therapy. In this respect, the following parameters must be clarified:

  • Imfpstatus, latent infections: At the first diagnosis the vaccination status has to be checked, if necessary live vaccinations have to be supplemented and chronic infections like hepatitis B and C, HIV and latent tuberculosis (interferon-α-release assay and x-ray thorax) have to be excluded.
  • Autoantibodies: In up to 30% of cases, an assignment to Crohn's disease or ulcerative colitis is not possible.
  • The determination of antibodies against Sacharomyces cerevisiae (ASCA) and of perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) can be diagnostically important.

Drug-Level and Anti-Drug-Antibodies (ADA): Secondary Therapy Failure: If patients initially respond to a therapy with TNF antibodies and then lose the response in the course of time, this is called secondary therapy failure. Here, either the given dose is too low and the required effective level is not reached. In this case a dose adjustment is necessary

or

the patient has formed anti-drug antibodies (ADA) with a consequent decrease in sensitivity to the drug

Calprotectin: Calprotectin in stool reflects the infiltration of neutrophil granulocytes into the mucosa and is a very good way to assess the course of ulcerative colitis. Due to the segmental involvement in Crohn's disease, the faecal calprotectin level is only useful in individual cases.

Imaging
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Abdominal sonography: Once the spread pattern has been established, sonography is a radiation-free option for disease control. Assessment of: (blood circulation, structures of the intestinal wall - lifting of the wall layers, motility of the intestinal sections, possible dilatations, perianal fistulas)

MRI the standard of small bowel imaging: Today, MRI imaging of the small bowel has replaced the classic small bowel imaging according to Sellink. Due to the young age of the majority of patients, MRI should be the standard and CT should only be used in emergency situations.

Instrumental Diagnostics:

Oesophago-gastro-duodenoscopy/ ileocoloscopy: To determine the infestation pattern, an oesophago-gastro-duodenoscopy (OGD) and an ileocoloscopy are performed. By means of an ÖGD, an infestation of the upper gastrointestinal tract can be excluded at the first diagnosis. In Crohn's disease, balloon dilatation may be necessary if anastomotic stenosis occurs (reoperation may be prevented).

Ileocoloscopy: Ileocoloscopy is the foundation of the diagnosis; therefore, in addition to the performance of step biopsies, the detailed diagnosis of all segments, including the terminal ileum (inflammatory quality of the intestinal mucosa, questionable stenoses) is also important. In the case of mild disease progression, only aphtae may be detectable. If the activity increases, longitudinal ulcerations are found, tend to confluence and then form the classic paving stone relief.

Capsule endoscopy: Capsule endoscopy can provide additional information in small bowel diagnostics. Note: Before use, however, stenosis must be excluded (MRI diagnosis). Since this is usually done by MRI, the small intestine is also diagnosed and capsule endoscopy is no longer necessary.

Laboratory
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Special immunological parameters:

  • pANCA are found in about 20% of cases of Crohn's disease and in about 65% of cases of ulcerative colitis.
  • Antibodies against yeasts, Saccharomyces cerevisiae, (ASCA) are frequently found in Crohn's disease, less frequently in ulcerative colitis.
  • Further antibodies against tropomyosin are found in ulcerative colitis, but not in Crohn's disease.

Histology
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The pathognomonic histological findings are non-cheesematous granulomas, which are, however, found in only about 30 % of the biopsies.

Further characteristics are subserous lymphocyte aggregates away from the inflamed regions and segmental infestation.

Differential diagnosis
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Ulcerative colitis: The most important differential diagnosis is ulcerative colitis.

At the first manifestation of an isolated terminal ileitis yersinic enterocolitis should be excluded.

Colitis indeterminata: In up to 30 % of cases a clear assignment to one of the two entities is not possible. Then the disease is called colitis indeterminata.

Other forms of infectious colitis (history of travel, e.g. Clostridium difficile) can be excluded regardless of the pattern of infection.

  • Bacterial infections: classic enteritis pathogens, typical and atypical mycobacteria (with corresponding anamnesis). In isolated ileitis terminalis, infection with Yersinia should be excluded.
  • Infections (infestations) by parasites: amoebae, isospora, trichuros trichura
  • Viral infections: CMV, HIV, HSV (CMV colitis)

Segmental colitis associated with diverticulosis (SCAD): In SCAD there is an inflammation of the peridiverticular mucosa, possibly associated with a stenosis. The distinction to chronic inflammatory bowel disease can be difficult.

Microscopic colitis: In this type of colitis the diagnosis can be made endoscopically. Endoscopically, the mucosa shows hardly any inflammatory changes. Histologically, there is either a widened collagen band (collagenous colitis) or an increased number of lymphocytes (lymphocytic colitis).

Ischemic colitis: It may be difficult to distinguish from Crohn's disease, as longitudinal ulcerations may occur, which are usually anti-mesenteric. The diagnosis should be made in the clinical context.

Vasculitis of the intestine: If there are other symptoms besides inflammation of the intestine which make vasculitis appear possible (y, skin involvement / purpuraSchönlein), an appropriate diagnosis should be made. A special situation is hepatitis C-associated vasculitis, which can also mimic the picture of colon involvement in the context of a chronic inflammatory bowel disease.

Radiation enteritis/colitis: In this case a corresponding anamnesis is available. The original radiation field will correspond to the location of the colitis/enteritis.

Behçet's disease: Country of origin (Mediterranean) may be an indication: Clinical leading symptoms are recurrent and clinically pronounced, painful mouth and genital ulcers in the foreground.

Medicinal:

  • NSAR: The drug history is useful here.
  • Checkpoint inhibitors (e.g. ipilimumab) can mimic the picture of a chronic inflammatory bowel disease.

Complication(s)
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Fistulas, abscesses and carcinomas can develop as complications.

Fistulas: For the therapy of perianal fistulas, please refer to the guideline. In addition, intra-abdominal fistulas can also develop in the case of a penetrating course. Depending on the course of the disease (interenteric, enterocutaneous, enterovesical, blind ending) it must be decided whether surgical repair is necessary.

In the case of an enterovesical fistula, a blind ending fistula as well as a "short circuit" (e.g. gastrocolic fistula) there is a surgical indication.

Abscesses: Abscesses are usually the result of a blind ending fistula, i.e. the section of the intestine from which the fistula originates must be rehabilitated. In the first step, the abscess should always be drained if possible, and the surgical repair should be carried out at intervals.

Carcinomas: Increased risk of developing a colon carcinoma. If the small intestine is affected, the overall very low risk of developing a small intestine carcinoma is increased, but good screening strategies for this do not exist.

Therapy
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Remission induction: The aim of remission induction is a rapid reduction of disease activity. Corticosteroids are the therapeutic agents of choice.

Local corticosteroids: For mild to moderate activity and ileocecal infestation, local budesonide is sufficient.

Systemic corticosteroids: Systemic steroids should be used if there are signs of more severe inflammation.

For moderate activity, 40 mg prednisolon/day is sufficient. Otherwise prednisolone should be given at 1 mg/kg bw. At this dose, remission can be achieved in about 90 % of patients within 8 weeks. Afterwards: spilling of the corticosteroids. In case the phasing out phase leads to a reflammation, azathioprine (1.5-2.0mg/kgkgkg p.o.) is initially applied in case of mild to moderate disease activity.

Alternatively: If there are contraindications for azathioprine, a TNF-alpha-antibody can be used(Infliximab and Adalimumab). Depending on the disease activity, they are applied monotherapeutically or as a combination therapy with a classical immunosuppressive agent.

Alternatively: Ustekinumab (anti-IL-12-/23-antibody). The induction of therapy with Ustekinumab is weight-adapted (about 6 mg/kg bw i.v.) and is continued every 8-12 weeks with a 90 mg administration s.c.

Alternatively (moderate disease activity): Vedolizumab (integrin antagonist). Vedolizumab blocks the integrin α4β7. A delayed onset of action must be explained.

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Steroid-free remission: complete elimination of the steroids is successful!

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Steroid-free remission is not possible: In about every third patient a complete elimination of steroids is not possible (2 reduction attempts fail within 6 months)

Corticosteroid + Azathioprine 2.5 mg/kg (alternative to Imurek - MTX 25 mg/week)

Alternative: TNF antibody

Alternative: Ustekinumab

Alternative: Vedolizumab

A meta-analysis showed that 50-75% of the patients achieve a remission. However, in about 20 % of patients this only occurs after 4-7 months. Remark: TNF-antibodies have an increased risk for infections, and skin side effects of various degrees can be limiting. In this situation Ustekinumab can be used as an alternative.

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Remission induction with steroids in moderate disease activity

Prednisolone+ Azathioprine 2,0-2,5 mg/kg (or MTX 15 mg/week)

Alternative: Prednisolone+ TNF antibody

Alternative: Prednisolone+ Ustekinumab

Alternative: Prednisolone+Vedolizumab

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Remission induction with high disease activity,

possibly induction with biologicals

TNF antibody ± immunosuppressant

Alternative: Ustekinumab ± immunosuppressive

Alternative:Vedolizumab± immunosuppressant

Note: If a stable remission under a combination therapy is achieved over one year, a gradual de-escalation to monotherapy can be considered.

General therapy
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The primary goal of any therapy should be the good quality of life of the patient. Naturally, due to the spectrum of side effects of immunosuppressive therapeutics, steroid-free remission should be aimed for. The therapy will basically follow the guidelines of the DGVS or the ECCO.

There is fundamental agreement that chronic inflammation of the intestine is the prerequisite for the complicating structural changes such as fistulas and stenoses. In the presence of fistulas and stenoses, surgical intervention may be necessary before drug therapy is initiated. In scarred small bowel stenoses, surgical techniques that are gentle on the bowel (stricturoplasties) are generally used (Gionchetti P et al. 2017).

Note(s)
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The topic of family planning should be discussed with patients at an early stage. Ideally, pregnancy should be in the phase of clinical remission.

Literature
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  1. Adolph TE et al (2013) Paneth cells as a site of origin for intestinal inflammation. Nature 503:272-276.
  2. Davis D et al (2018) Orm/ORMDL proteins: Gate guardians and master regulators". Advances in Biological Regulation. Sphingolipid Signaling in Chronic Disease. 70: 3–18.
  3. Feagan BG et al (1995) Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators. N Engl J Med 332: 292-297
  4. Franke A et al (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 2010; 42: 1118-1125
  5. Fritz T et al (2011) Crohn's disease: NOD2, autophagy and ER stress converge. Good. 60:1580-1588.
  6. Gionchetti P et al (2017) 3 rd European Evidence-based Consensus on the Diagnosis and Management of Crohn's Disease: Part 2: Surgical Management and Special Situations. J Crohn's colitis 11: 135-149
  7. Gomollon F et al (2017) 3 rd European Evidence-based Consensus on the Diagnosis and Management of Crohn's Disease 2016: Part 1: Diagnosis and Medical Management. J Crohn's colitis 11: 3-25
  8. Harbord M et al (2016) The First European Evidence- based Consensus on Extra-intestinal Manifestations in Inflammatory Bowel Disease. J Crohns colitis 10: 239-254
  9. Hooper KM et al (2019) Interactions Between Autophagy and the Unfolded Protein Response: Implications for Inflammatory Bowel Disease. Inflammatory Bowel Dis 25: 661-671.
  10. Kurreeman FA et al (2012) Use of a multiethnic approach to identify rheumatoid arthritis-susceptibility loci, 1p36 and 17q12 American Journal of Human Genetics. 90: 524–532.
  11. Lee JC et al (2017) Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease. Nat Genet 49: 262-268
  12. Molodecky NA et al (2012) Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142: 46-54
  13. Nguyen GC et al (2016) The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy. Gastroenterology 150: 734-757
  14. Pramanik J et al (2018) Genome-wide analyses reveal the IRE1a-XBP1 pathway promotes helper cell differentiation by resolving secretory stress and accelerating proliferation. Genome Med 10:76.
  15. Sandborn WJ et al (2013) Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 369: 711-721
  16. Wang MH et al (2002) Macrophage-stimulating protein and RON receptor tyrosine kinase: potential regulators of macrophage inflammatory activities. Scand J Immunol 56:545-553.

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Last updated on: 29.10.2020