Regional enteritis K50.9

Lesniowski 1903, Crohn 1932

Crohn's disease is an idiopathic systemic disease with a chronic relapsing course that manifests as disease of the entire gastrointestinal tract with segmental involvement and transmural inflammation. Inflammation can occur in any segment of the gastrointestinal tract but is most common in the terminal ileum and proximal colon.

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

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.

Crohn's disease is thought to be mediated by autoimmunological dysfunction. In addition to genetic influences, dietary factors, environmental factors, the intestinal microbiome, and increased and impaired permeability of the intestinal wall play a role.

Genetics: About 25% of Crohn's disease is explained by the presence of risk mutations (Franke A et al. 2010). There is a stronger genetic association in Crohn's disease than in ulcerative colitis. This is illustrated by twin studies: in monozygotic twins there is a concordance of 38-50%, in dizygotic twins of 4%. If the disease manifests in infancy or early childhood, monogenetic disease should be ruled out by exome sequencing.

• Genes that regulate cellular processes, such as XBP1, ORMDL 3 (Pramanik J et al. 2018; Davis D et al. 2018).
• Genes regulating antimicrobial responses of Paneth or goblet cells to commensal microbiota
• Genes responsible for immunity and relevant in defense against bacteria and viruses (e.g. NOD2, ATG16L 1, STAT 3 see under Kurreeman FA et al. 2012, Fritz T et al. 2011).
• Genes that provide balance between pro- and anti-inflammatory cytokines (e.g., IL-23 R, IL-10).
• Genes involved in the initiation and termination of cellular inflammatory responses (e.g., MST 1 = macrophage-stimulating protein 1, CCR6) (Wang MH et al. 2002).

• It is possible that mutations in the genes of the so-called NOD-like receptors play a pathogenetic role. A surprising finding came from genetic studies that identified risk loci for complicated courses but showed no overlap with risk loci for disease development (Lee JC et al 2017).

• Autophagy genes: The proteins encoded by the ATG17L1 (Autophagy related 17 like 1) and ATG16L1 (Autophagy related 16 like 1) genes are portions of a large protein complex required for autophagy. Associations are detectable (Teimoori-Toolabi L et al. 2018).

Microbiota: The human intestinal microbiome establishes a stable configuration by 3 years of age. Composition and function vary among individuals and are 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 mucin layer overlying the epithelium. This cellular assembly responds to intestinal microbiota luminally through the production of mucins, through a broad arsenal of antimicrobial peptides (lysozyme, alpha-defensins, tumor necrosis factor-alpha, phospholipase A2, ECF), and mucosally through control of the immune cell compartment. Dysregulation of this complex system may be caused by an altered microbiome, a pathologic mucin layer, by a primary epithelial cell defect, and by 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 translocating antigens. This is accomplished by a particular form of antigen presentation within an anti-inflammatory milieu. In addition to antigen-presenting cells, T cell subpopulations are of particular importance here. The relevance of individual subtypes is clearly illustrated by the example of FoxP3 + regulatory T cell deficiency associated with a severe autoimmune phenotype. Among the proinflammatory subtypes, Th1 cells, Th2 cells, and Th17 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).

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

T cells: Pro-inflammatory T cells induce increased homing of inflammatory cells to the lamina propria, which in turn explains the therapeutic benefit of the integrin antibody vedolizumab.Bacterial antigens: Various data suggesting that the disease may be triggered or maintained by bacterial antigens are gaining momentum. Mycobacterium avium paratuberculosis (MAP) is considered the main suspect.Other risk factors:

• Smoking increases the risk of developing Crohn's disease in the Caucasian population. Smoking is likewise main risk factor for postoperative recurrence after ileocecal resection.
• Oral anticonceptives: Less well established is the increase in risk from taking oral contraceptives.
• Antibiotics: Antib iotic use within the first year of life is associated with increased risk.
• Breastfeeding possibly exerts a protective role.
• Infectious gastroenteritis with pathogen detection also increases the risk.

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.

Crohn's disease presents clinically very differently:

Leading symptoms are abdominal pain and diarrhea, usually non-bloody. Occasionally constipation, meteorism. Symptoms such as appendicitis with colicky pain in the right lower abdomen may occur, possibly with mild temperature elevations. However, weight loss or developmental delay may be the only symptoms. In addition, perianal or enterocutaneous fistulas indicate complications.

Extraintestinal manifestations may occur with an episode, but also before the initial manifestation:

Skin/skin mucosal manifestations:

• Fistula formations (40%), perianally located aphthous ulcerations, anorectal abscesses (25%) - Note: often anal fistulas are the first monitoring signs of enteritis regionalis! Remark: The little meaningful 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 the underlying disease (metastatic!); on the other hand, it fails to recognize that Crohn's disease is a "non-monotopic" granulomatous systemic disease.
• Acne-like, granulomatous (not abscess-like) papules and nodules on the buttocks, lower abdomen and thighs (see below Crohn's disease, skin changes).
• Other: erythema nodosum, erythema exsudativum multiforme, vasculitis leukocytoclastic, palmar erythema, uncharacteristic pustulosis of the skin.
• Persistent genital edema
• Aphthae/ulcers: Recurrent or permanent, usually deep, extensive, and very painful ulcers of the oral mucosa (4-20% of Crohn's disease cases). Frequency more frequent than in habituated aphthae. They are significantly larger and more painful.
• Cheilitis granulomatosa: Chronic, inflammatory swelling of the lips (see below Cheilitis granulomatosa or orofacial granulomatosis). Coincidence with pyoderma gangraenosum has been described. Occurrence of acrodermatitis enteropathica is possible. Isolated coincident cases of Sweet 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: int estinal stenosis with signs of (sub)ileus, rarely perforations

Growth disorders in childhood

Malabsorption syndrome with weight loss

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

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

The majority of patients will require long-term immunosuppressive therapy. This is the most important message that should be presented to the patient in all candor. The following parameters should be clarified:

• Imfp status, latent infections: At initial diagnosis, check vaccination status, add live vaccines if necessary, and rule out chronic infections such as hepatitis B and C, HIV and latentTuberculosis (interferon-α release assay and chest X-ray). Caution: live vaccines in case of immunosuppressive long-term therapy!
• Autoantibodies: In up to 30 % of cases, a clear 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.

Secondary treatment failure: If patients initially respond to treatment with TNF antibodies and then lose their efficacy in the course of treatment, this is referred to as secondary treatment failure. Either the given dose is too low and the required effect level is not reached (dose adjustment is necessary),

or

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

Fecal calprotectin (fecal calprotectin level): This value reflects the infiltration of neutrophilic granulocytes into the mucosa and is a very good way to assess progression for ulcerative colitis. Due to the segmental involvement in Crohn's disease, the fecal calprotectin value is only useful in individual cases.

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.

At initial diagnosis, a liver laboratory should be performed to exclude coexisting primary sclerosing cholangitis (PSC). In addition, routine diagnostics should include blood count, renal function, albumin, C-reactive protein, and coagulation parameters!

Deficiencies may occur with the infestation or after resection of the ileocecal region, but also with other infestation patterns. Therefore, vitamin B12, folic acid, vitamin D, transferrin saturation (for evaluation of iron storage) and zinc should be determined at regular intervals.

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.

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

In the first manifestation of isolated ileitis terminalis, yersinia 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.

Furthermore, regardless of the pattern of infestation, other forms of infectious colitis (travel history, think of Clostridium difficile ) must be excluded.

• Bacterial infections: classic enteritis pathogens, typical and atypical mycobacteria (with appropriate history). In isolated Crohn's disease, infection with Yersinia should be excluded.
• Infections (infestations) by parasites: amoebae, Isospora, Trichuris trichura
• Viral infections: CMV (CMV colitis), HIV, HSV

Segmental colitis associated with diverticulosis (SCAD): In SCAD, inflammation of the peridiverticular mucosa is present, sometimes associated with stenosis. Differentiation from other chronic inflammatory bowel diseases can be difficult.

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

Ischemic colitis: This may be difficult to distinguish from Crohn's disease, as longitudinal ulcerations may also occur, usually localized anti-mesenterically. The diagnosis should be made in the clinical context.

Intestinal vasculitis: If there are other symptoms besides the intestinal inflammation that suggest the possibility of vasculitis (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 colonic involvement in the setting of inflammatory bowel disease.

Radiation enteritis/colitis: In this case, a corresponding history is present. The original radiation field will correspond to the localization of the colitis/enteritis.

Behçet's disease: Country of origin (Mediterranean) may be a clue: Leading clinical symptoms are recurrent and clinically prominent painful oral and genital ulcers in the foreground.

Drug:

• NSAIDs: Drug history is pertinent here.
• Checkpoint inhibitors (e.g. ipilimumab) can mimic the picture of inflammatory bowel disease.

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.

Remission induction: The goal of remission induction is a rapid reduction in disease activity. For this purpose, corticosteroids are the therapeutic agents of choice.

Corticosteroids locally: In cases of mild to moderate activity and ileo-cecal involvement, locally acting budesonide is sufficient.

Corticosteroids systemic: If there are signs of more severe inflammation, systemic steroids should be used.

If activity is moderate, 40 mg prednisolone/day is sufficient. Otherwise, prednisolone should be started at 1 mg/kg bw. At this dose, remission can be achieved in about 90% of patients within 8 weeks. Thereafter: tapering of corticosteroids. If the cessation phase leads to re-inflammation, azathioprine (1.5-2.0mg/kg bw p.o.) is initially used in cases of mild to moderate disease activity.

Alternatively: If contraindications to azathioprine exist, a TNF-alpha antagonist may be used(infliximab and adalimumab). Depending on disease activity, they are used monotherapeutically or as combination therapy with a classical immunosuppressant. Remarkably, paradoxical reactions can occur in the treatment of Crohn's disease with TNF-alpha antagonists (hidradenitis suppurativa, folliculitis decalvans) Salvador-Rodriguez L et al 2020).

Alternative: ustekinumab (anti-IL-12-/23 antibody). Induction of therapy with ustekinumab is weight-adapted (approximately 6 mg/kg bw i.v.) and continued every 8-12 weeks with a 90 mg administration s.c.

Alternatively (moderate disease activity): Vedolizumab (integrin antagonist). Vedolizumab blocks integrin α4β7. Delayed onset of action needs to be elucidated.

_________________________________________________________

Steroid-free remission: complete cessation of steroids succeeds!

_________________________________________________________

Steroid-free remission is not possible: complete cessation of steroids fails in about one in three patients (2 reduction attempts fail within 6 months).

Corticosteroid + azathioprine 2.5 mg/kg (alternative to azathioprine - MTX 25 mg/week).

Alternative: TNF antibody

Alternative: ustekinumab

Alternative: Vedolizumab

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

__________________________________________________________

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

___________________________________________________________

Remission induction in high disease activity,

possibly induction with biologics

TNF antibody ± immunosuppressive agent

Alternative: ustekinumab ± immunosuppressive agent

Alternative:Vedolizumab± immunosuppressive agent

Comment: If stable remission occurs with combination therapy over one year, gradual de-escalation to monotherapy may be considered.

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).

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

1. Adolph TE et al. (2013) Paneth cells as a site of origin for intestinal inflammation. Nature 503:272-276.
2. Cushing K et al.(2021) Management of Crohn's Disease: A Review. JAMA 325:69-80.
3. 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.
4. 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.
5. 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
6. Fritz T et al (2011) Crohn's disease: NOD2, autophagy and ER stress converge. Gut. 60:1580-1588.
7. 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 Crohns Colitis 11: 135-149.
8. 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 Crohns Colitis 11: 3-25.
9. 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.
10. Hooper KM et al (2019) Interactions Between Autophagy and the Unfolded Protein Response: Implications for Inflammatory Bowel Disease. Inflamm Bowel Dis 25: 661-671.
11. 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.
12. 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
13. Molodecky NA et al (2012) Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142: 46-54
14. Nguyen GC et al (2016) The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy. Gastroenterology 150: 734-757
15. Pramanik J et al. (2018) Genome-wide analyses reveal the IRE1a-XBP1 pathway promotes T helper cell differentiation by resolving secretory stress and accelerating proliferation. Genome Med 10:76.
16. Salvador-Rodriguez L et al (2020) Paradoxical hidradenitis suppurativa in patients receiving TNF-α inhibitors: case series, systematic review, and case meta-analysis. Dermatology 236:307-313
17. Sandborn WJ et al (2013) Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 369: 711-721
18. Teimoori-Toolabi L et al.(2018) Among autophagy genes, ATG16L1 but not IRGM is associated with Crohn's disease in Iranians. Gene 675:176-184.
19. 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.