Crohn’s disease: an important differential diagnosis of granulomatous skin diseases

ARTICLE

Auteur(s) : Tatjana Eames, Michael Landthaler, Sigrid Karrer

Department of Dermatology, University of Regensburg, Franz-Josef-Strauss Alle 11, D-93042 Regensburg, Germany

accepté le 28 Janvier 2009

Crohn’s disease is a chronic inflammatory granulomatous disease of the gastrointestinal tract of unclear genesis, which is typically accompanied by convulsive intermittent stomach pains and recurrent diarrhoea. Although the disease can occur at any point in the gastrointestinal tract, it is predominantly found in the terminal ileum and colon. In addition to the intestinal symptoms, Crohn’s disease is often associated with extra-intestinal manifestations. Skin lesions occur in 14 to 44% of patients with Crohn’s disease [1]. Usually, mucocutaneous lesions follow the intestinal disease, only rarely so skin lesions occur prior to bowel involvement [2, 3]. Most often the skin involvement is an extension of the intestinal disease and presents as perineal abscesses and fistulas. More rarely, metastatic cutaneous Crohn’s disease occurs at sites distant from the affected bowel.

We report the case of patient with the diagnosis of metastatic cutaneous Crohn’s disease, whose skin lesions preceded the clinical intestinal signs and we discuss Crohn’s disease as an important differential diagnosis of other granulomatous skin diseases.

Case report

On physical examination there was a large inflammatory erythematous plaque with fistulations and multiple pustules and papules on the right lower leg (figure 1A). On the right tibia there was a 1.5 cm by 1.5 cm fluctuating abscess and lateral to this there was an ulcer, several millimeters deep. On the lower part of the left leg there were only single pustules, at the sacrum and in the rima ani there was a distinct erythema. Laboratory tests showed that, at 10.37 mg/L, c-reactive protein was slightly elevated (normal value < 5 mg/L), the leukocyte count of 6.48/nL was within the normal range (4.8-10.80/nL), the hepatitis serology was negative. Histological examination of a biopsy taken from the inflammatory plaque revealed perivascular lympho-histiocytic inflammatory infiltrates with polynuclear giant cells together with numerous eosinophilic granulocytes in the dermis.

The smears repeatedly taken from the pustules and abscesses were sterile. A haemoccult test was positive twice. A colonoscopy showed a small erosive lesion at the mucous membrane in the terminal ileum. Moreover, there were several whitish stippled lesions in the mucous membranes of the rectum. Histological examinations showed an apically stressed, slight colitis in the caecum, colon ascendens, transversum and descendens which had more or less the appearance of an infectious colitis. In the rectum an erosive colitis and the interrupted inflammation pattern was consistent with both an infectious colitis and Crohn’s disease. As far as the findings in the bowels were concerned, gastroenterologists could not confirm the diagnosis of Crohn’s disease and did not recommend any therapy.

Since the clinical appearance of the skin lesions and the histological findings of the skin biopsy were compatible with the diagnosis of metastatic Crohn’s disease, the patient was treated orally with 60 mg prednisolone and topically with high-potency corticosteroids. The ulcer was treated with a hydrogel. During this treatment there was a rapid improvement of the condition and pustulation ceased (figure 1B). Skin lesions completely resolved and the corticosteroid dose was slowly tapered and stopped in July 2007.

Two months after ceasing systemic corticosteroid therapy a purulent kolpitis with vagino-cutaneous fistulas occurred together with an osteomyelitis of the os pubis (figure 1C). Also the known skin changes on the lower leg reappeared. The patient still had no gastrointestinal symptoms like diarrhoea or hematochezia. Again a colonoscopy was performed, where an intestinal affection of Crohn’s disease with aphthous lesions could now be verified histologically. The therapy included the excision of the vagino-cutaneous fistulas and the systemic antibiotic therapy of the osteomyelitis. For treatment of the cutaneous and intestinal Crohn’s disease an immunosuppressive therapy with azathioprine was proposed after healing of osteomyelitis.

Discussion

The most frequent specific skin changes, usually presenting as perianal fissures, fistules and abscesses, caused by direct spread of intestinal Crohn’s disease, occur in up to 68% of all cases and are often the first symptoms of the disease. In up to 20% of all patients, non-specific lesions occur in the mouth presenting as stomatitis and aphtose ulcers [1, 5]. However, specific oral lesions, the macroscopic and microscopic picture of which is very similar to the changes found in the rest of the gastrointestinal tract in the case of Crohn’s disease, occur more seldom and must be delineated against the above-mentioned changes in the mucous membranes. The prevalence of this “oral Crohn’s disease” varies in the literature between 0% and 9%, depending on the criteria used for diagnosis [1]. In the case of specific oral Crohn’s disease, mainly longish ulcers and partly indurated lip and cheek swellings are typical. When such linear ulcerations or fissures join together and mucous tissues have an oedematous appearance the “cobblestone-stone” pattern, which is so typical of Crohn’s disease, occurs. Apart from that, oral pseudopolyps as well as gingiva hyperplasia can also occur. Oral Crohn’s disease can also manifest as orofacial granulomatosis which presents with chronic swelling of the oral or facial tissues due to a granulomatous inflammation [2].

The most uncommon specific cutaneous involvement in Crohn’s disease is metastatic Crohn’s disease, where lesions are not in contact with the gastrointestinal tract. Metastatic Crohn’s disease is well recognized in adults, but is extremely rare in children. The mean age of onset is 34.5 years [5]. The relatively small number of previously published case histories (about 100 cases) presumably represents an underestimate of the incidence of cutaneous Crohn’s disease. This could be explained by an unrecognized connection between the skin lesions and the intestinal symptoms and is often due to the time lag between the appearance of skin changes and gastrointestinal activity. In about 20% of the cases mentioned in the literature the skin changes had already been observed between 3 months and 8 years before the diagnosis of gastrointestinal Crohn’s disease [5, 8]. There is no correlation between the appearance of the skin lesions and intestinal Crohn’s disease activity. Thus, our patient had severe cutaneous fistulating, absceding and ulcerating lesions on the lower legs and the mons pubis, including vagino-cutaneous fistulas, while only minimal bowel involvement without any gastrointestinal symptoms like diarrhea or hematochezia.

The clinical picture of metastatic Crohn’s disease typically shows erythema and oedema and, at a later stage, papular, pustulous, erosive, ulcerating and fistulating lesions, which can manifest themselves anywhere, but most commonly on the limbs and particularly on the legs as well as in the genital area. Further predilection sites are the trunk, intertriginous and flexural areas and the face.

Reactive dermatoses which are associated with Crohn’s disease include erythema nodosum (up to 8%) and pyoderma gangraenosum (1-2%) (figure 2A) [1, 8]. There is also an increased frequency of psoriasis (about 10%), secondary generalized amyloidosis (up to 6%) and necrotising vasculitis [1].

Apart from the specific and reactive skin lesions of Crohn’s disease, nutritional skin changes associated with malabsorption must also be mentioned. These include insufficiency syndromes like acrodermatitis enteropathica in case of zinc deficiency, pellagra in case of nicotinic acid deficiency or disorders in nail and hair growth in case of lack of biotin (vitamin H) [1, 2, 8].

The pathogenesis of cutaneous Crohn’s disease is unclear [1, 5, 8]. Numerous theories have been proposed, including infectious agents, immunological factors including a possible immuno-deficiency state and genetic factors [4]. It is also suggested that immune complexes in the skin could be partly responsible for the granulomatous reaction. A T-lymphocyte-mediated type IV hypersensitivity reaction has been suggested as a cause of granuloma formation [8]. The diagnosis of metastatic cutaneous Crohn’s disease is quite difficult if it precedes the clinical appearance of the gastrointestinal disease. Histopathological assessment therefore has an important role in confirming the diagnosis. Characteristic for this, as in the affected sections of the digestive tract, is the occurrence of non-caseating granulomas with various giant cells mostly of the Langerhans type in the dermis and lymphomononuclear infiltrates in a perivascular distribution [4, 6, 7].

Although, in the case of cutaneous Crohn’s disease, the lesions can heal spontaneously, they tend to be chronic. The therapy for cutaneous Crohn’s disease is the same that is used for treating intestinal Crohn’s disease and includes the administration of topical, intralesional and systemic corticosteroids, metronidazole, sulfasalazine or azathioprine. Other therapeutic options are TNF-α-antagonists, such as infliximab as well as surgical measures [1, 5, 6]. The differential diagnoses of cutaneous Crohn’s disease include other non-infectious and infectious granulomatous skin disorders. These diseases are unified by similar histological findings despite having different, often unknown, causes. Non-infectious granulomas include cutaneous sarcoidosis (figure 2B), granuloma annulare (figure 2C), annular elastolytic giant cell granuloma (figure 2D), foreign body reactions, rheumatoid nodules and necrobiosis lipoidica (figure 2E). Infectious granulomas include tuberculosis (figure 3A), leprosy, late syphilis, leishmaniasis (figure 3B) and deep mycoses, such as sporotrichosis (figure 3C) (table 2).

Histologically, the granulomatous reaction pattern can be subclassified as published by David Weedon [9]:

• – Sarcoidal granulomas: epitheloid histiocytes and giant cells with surrounding lymphocytes and plasma cells, called “naked” granulomas (e.g. sarcoidosis, foreign body reactions);
• – Tuberculoid granulomas: epithelioid histiocytes and giant cells with a rim of lymphocytes and plasma cells. Ganulomas are often confluent and sometimes show central “caseation” necrosis (e.g. tuberculosis, tuberculids, leprosy, late syphilis, leishmaniasis, rosacea, perioral dermatitis, Lupus miliaris disseminatus faciei, Crohn’s disease);
• – Necrobiotic granulomas: poorly formed granulomas composed of histiocytes, lymphocytes and giant cells. The inflammatory cells are admixed or form a palisade around typical “necrobiosis”, which are areas of altered dermal connective tissue with blurring and loss of definition of collagen bundles and alteration in staining with increased basophilia or eosinophilia (e.g. granuloma annulare, necrobiosis lipoidica, necrobiotic xanthogranuloma (figure 2F), rheumatoid nodules);
• – Suppurative granulomas: collection of epitheloid histiocytes, with or without multinucleated giant cells, in the centers of which are neutrophils (e.g. non-tuberculous mycobacterial infections, lymphogranuloma venereum, pyoderma gangraenosum, chromomycosis, sprotrichosis, blastomycosis, paracoccidioidomycosis, mycetomas, nocardiosis, actinomycosis);
• – Foreign body granulomas: epithelioid histiocytes and multinucleate foreign body giant cells with either exogenous or endogenous foreign material, which can be detected under polarized light;
• – Miscellaneous granulomas: variable in appearance (e.g. Melkersson-Rosenthal syndrome (figure 2G), elastolytic granulomas, interstitial granulomatous dermatitis or drug reaction, granulomatous T-cell lymphomas) [9].

Conclusion

Acknowledgements

References

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