Enteritis regionalis, skin alterations K50.9

Author: Prof. Dr. med. Peter Altmeyer

All authors of this article

Last updated on: 07.04.2021

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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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Idiopathic, discontinuously and segmentally occurring, chronic inflammatory granulomatous intestinal disease of unclear etiology of the entire gastrointestinal tract with preferred localization of the ileum. The disease can be accompanied by a variety of granulomatous, often ulcerated skin symptoms. Complications are stenoses, fistulas, malnutrition (s.a.Eneritis regionalis).

Occurrence/Epidemiology
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Incidence: 6/100.000 inhabitants/year.

Etiopathogenesis
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Crohn's disease is probably mediated by autoimmunological processes. Besides genetic influences (mutations in chromosome 12 and 16 are discussed), dietary factors, oral anticonceptives, smoking, the intestinal flora and the permeability of the intestinal wall play a role. A disturbed permeability of the mucosa seems to be etiologically significant. Mutations of the so-called NOD-receptors are thought to play a pathogenetic role. First data that the disease could be caused by bacterial antigens are gaining increasing importance. The main suspect is Mycobacterium avium paratuberculosis (MAP).

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

Manifestation
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Usually before the age of 30 with emphasis on the 2nd and 3rd decade of life. In 4-20% of the patients the oral mucosa is involved. No sex preference. In the relatively rare metastatic Crohn's disease, women are in the majority (about 75% of the clients). The average age of manifestation is 34.5 years. Children are an extreme exception (20 cases in world literature).

Clinical features
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Abdominal pain with (mostly non-bloody) mucous diarrhoea, meteorism, constipation, weight loss. Abdominal pain also appendicitis-like or colicky in the right lower abdomen with a slight increase in temperature.

Classification of the clinic according to the Montreal classification:

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

Skin / skin-near mucous membrane symptoms:

  • Fistulas (40%), perianal aphthous ulcerations, anorectal abscesses (25%) - Note: often anal fistulas are the first monitoring signs of regional enteritis!
  • Acne-like abscesses on buttocks, lower abdomen and thighs.
  • Erythema nodosum, erythema exsudativum multiforme, vasculitis leukocytoclastic, palmarerythema, uncharacteristic pustulosis of the skin.
  • Persistent genital edema
  • Recurrent or permanent, usually deep, extensive and very painful ulcers in the oral mucosa area (4-20% of Crohn's disease cases) frequency more frequently 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 possible
  • occurrence of arthritis and ankylosing spondylitis (80% HLA-B27 positive)
  • Individual coincident cases of Sweet's syndrome have been described.

eyes (7%)

  • Episcleritis, iritis, concomitant

Joints (20%)

  • Arthritis, ankylosing spondylitis, sacroilitis

Liver

Growth disorders in children

Malabsorption syndrome with weight loss

intestinal stenoses with signs of (sub)ileus, rarely perforations

Laboratory
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Special immunological parameters: pANCA is 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. Other antibodies are found against tropomyosin in ulcerative colitis, but not in Crohn's disease.

Histology
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The oral mucous membrane changes show granulomatous inflammations.

Diagnosis
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  • Typical endoscopic findings: Disseminated mucosal lesions with often segmental involvement and often involvement of the small intestine.
  • Histology with epitheloid cell granulomas including all wall layers.
  • Small intestine contrast examination according to Sellink with the typical findings of a stenosis in the terminal ileum.
  • The floridity can be controlled by the inflammation parameters below the laboratory values (BSG, CRP, alpha2-globulin, fibrinogen).

Differential diagnosis
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Tuberculosis, sarcoidosis, ulcerative colitis.


The main clinical differential diagnoses of the most common granulomatous and non-granulomatous skin diseases.

Granulomatous

Non-granulomatous

Disease Clinical/histological markers Disease Clinical signs
Tuberculosis Inflammation, cheese necrosis pyoderma gangraenosum ulceration with probably undermined purple margins
Sarcoidosis Non-caustic granuloma Behcet's disease Multiple ulcerations, arthralgia, pathergy
Melkersson-Rosenthal syndrome Non-caustic granuloma Vulvovaginitis/vaginal infections (venereal and non-venereal, bacterial/fungal) ulceration, nodules, swelling, vaginal discharge
Idiopathic granulomatous vulvitis Non-caustic granuloma Bartholinitis/Bartholin cyst Painful swelling of the labia majora
Foreign body granuloma Foreign body granuloma acuminate condyloma Exophytic painless lesions
venereal lymphogranuloma Small, non-hardened ulcers or poplar, inguinal lymph nodes suppurative hidradenitis Nodular abscess, multiple lesions
Syphilis Solitary painless ulcerations Rosacea Pustules, erythema
CD1a-positive Langerhans cell histiocytosis with eosinophilia Shortness of breath, joint pain and arthritis, red bump on the skin, hepatomegaly and dry eyes (asymptomatic in several cases) Vulva edema / lymphedema medical history post-radiotherapy, neoplastic lymph vessel obstruction
Allergic granulomatous reactions

Itchy, more generalized rash: Patch test

Lymphangioma Swelling
Traumatic bleeding Pushing pain, local heaviness

Therapy
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  • Therapy of skin and mucous membrane changes requires prior treatment of the inflammatory bowel disease (therapy of first choice: 5-aminosalicylic acid preparations + systemic glucocorticoids.
  • TNF-alpha blockers(Infliximab and Adalimumab)
  • AK against Interleukin 10
  • Vedolizumab (Entyvio®) is an enteric-selective integrin antagonist approved since May 2014 for use in patients with active moderate to severe forms of Crohn's disease and ulcerative colitis. Vedolizumab blocks the adhesion molecule alpha4beta7 integrin (see also integrins).
  • Surgical therapy for obstruction, perforation, abscess and fistula formation.

Note(s)
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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 the underlying disease, on the other hand it is misunderstood that Crohn's disease is a "non-monotopic" granulomatous systemic disease.

Case report(s)
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  • Case 1:
    • 13-year-old girl with intermittent occurrence of painful, itchy genito-anal swelling and redness since LJ 4. Various unsuccessful pretreatments due to lesions falsely diagnosed as erysipelas or contact allergic eczema. Last 2-4 times/day occurrence of unformed stools with blood deposits.
    • Findings: Slightly reduced AZ, slim EZ and depressive mood. Massive, doughy swelling and reddening of the labia majora and partially of the labia minora with coarse infiltration. In the area of the rima ani with preference of the perianal region an erosive, partly coarsely infiltrated, tumorous tumor-like efflorescence with greasy coatings and inflammatory component was observed.
    • Laboratory: Accelerated SPA, moderate CRP elevation, leucocytosis at 13.000/µl, Hb 10.8 g/dl, reduced corpuscular volume, markedly decreased ferritin level, ASL titre at 1157 U/ml.
    • Colonoscopy: Floride Crohn's colitis, histology of the terminal ileum with distinct lymphofollicular hyperplasia, severe chronic inflammatory signs of epithelioid-cell granulomas in the coecum and rectum and fissure necrosis.
    • Histology of the skin: Chronic lymphedema with fibrosclerosis and abundant ectatic lymphatic vessels. In the perivascular area macrophages including some giant histiocytic cells and accumulations of epithelioid-cellular granulomas associated with vessels were found in addition to a loose lympho-plasmacellular infiltration.
    • Therapy and course: Initiation of therapy with mesalazine and metronidazole (3 times/day 200 mg p.o.); reduction of stool frequency and healing of genital findings. Continued close outpatient care. Recurrence after 2 years. Combination therapy of corticosteroids (prednisolone 50 mg/day p.o.) and metronidazole (dosage see above). Improvement of findings after 3 weeks; continuation of therapy by the pediatric clinic.
  • Case 2:
    • 32-year-old female patient with painful mucosal lesions on the palate that have been present for 2 days. The patient's AZ was slightly reduced (fatigue, tiredness, loss of appetite).
    • Clinically, an oval, painful ulceration with a diameter of about 0.1 cm was found on the hard palate on the right side. In the area of the soft palate several highly inflammatory "aphthoid" areas about 0.3 cm in diameter. The gingiva, periodontium and the remaining mucosal areas were clinically o.B. A dentogenic cause of the palatal mucosal lesions could be excluded clinically and radiologically.
    • Histology of the oral mucosa: Severe acute ulcerative stomatitis with lymphocytic infiltration and few giant cells within the mucosal extravasations; no complete formation of typical epithelial cell granulomas.
    • The targeted general examination revealed a previously unknown and also currently clinically (gastro-energeologically) not active Crohn's disease. Immediate systemic therapy with prednisolone for 5 days and local analgesic irrigation with Bepanthen and subcutin solutions alternately led to complete remission within a short time.

Literature
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  1. Crohn BB, Ginzburg L, Oppenheimer GD (1932) Regional ileitis. A pathologic and clinical entity. J Am Med Ass 99: 1323-1329
  2. Dalziel TK (1913) Chronic interstitial enteritis. Br Med J 2: 1068-1070
  3. Djawari DJ (2004) Vulvitis granulomatosa in Crohn's disease. Akta Dermatol 30: 77-80
  4. Inohara N et al (2003) Nods: Intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 3: 371-382
  5. Kalmar JR (1994) Crohn's disease: orofacial considerations and disease pathogenesis. Periodontol 2000 6: 101-115
  6. Kugathasan S et al (2003) Dermatologic manifestations of Crohn's disease in children: response to infliximab. J Pediatr Gastroenterol Nutr 37: 150-154
  7. Lesniowski A (1903) Przyczynek do chirurgii kiszek. Medycyna (Warsaw) 31: 460-464, 483-489, 514-518.
  8. Mirza MM et al (2003) Genetic evidence for interaction of the 5q31 cytokine locus and the CARD15 gene in Crohn disease. Am J Hum Genet 72: 1018-1022
  9. Najarian DJ et al (2003) Connections betwen psoriasis and Crohn`s disease. JAAD 48: 805-821
  10. Saalmann R et al. (2009) Orofacial granulomatosis in childhood - a clinical entity that may indicate Crohn`s disease as well as food allergy. Acta Paediatr 98: 1162-1167
  11. Tan MH et al (2001) Improvement of Pyoderma gangrenosum and psoriasis associated with Crohn`s disease with anti-tumor necrosis factor alpha monoclonal antibody. Arch Dermatol 137: 930-933
  12. Hambardzumyan M et al (2016) Granulomatous conditions of the vulva. Gynecologic Dermatology. JP Medical Ltd: 121-128

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