Fistulising skin metastases in Crohn’s disease: a case report and review of the literature

Metastatic Crohn`s disease is a rare disease that primarily affects patients diagnosed with inflammatory bowel diseases (IBD). In rare cases, cutaneous manifestations precede gastrointestinal involvement. It most commonly occurs in the genital region, but can also affect every other part of the body. The lesions present as plaques, ulcers, fissures or papules [1] and, in rare cases, as fistulas. They are often asymptomatic but may also cause pain or itching. Despite the misleading wording, metastatic Crohn’s disease is not considered an oncologic entity. Instead, the term “metastatic” refers to the involvement of sites with no physical connection to the GI-tract. Metastatic Crohn’s disease must not be mixed up with extraintestinal manifestations of Crohn´s disease. Whereas extraintestinal manifestations such as pyoderma gangraenosum and erythema nodosum represent distinct immunologic phenomena, metastatic Crohn’s disease exhibits the same histological findings as intestinal Crohn’s disease, but on other organ sites.

Usually, a biopsy from the involved site is required for the diagnosis of metastatic Crohn’s disease. Histological findings show non-caseating, sarcoid-like granulomas, Langerhans giant cells and foreign body giant cells surrounded by inflammatory histiocytes, plasma cells and lymphocytes [2]. For a confirmed diagnosis of metastatic Crohn’s disease, other causes for granulomatous disorders have to be excluded, especially cutaneous sarcoidosis, tuberculosis, syphilis, mycobacterial infections, actinomycosis, deep fungal infections, lymphogranuloma venereum and granuloma inguinale. Also non-granulomatous skin lesions such as hidradenitis suppurativa, pyoderma gangrenosum, impetigo, erythema nodosum, factitial dermatitis from factitial injection of foreign substances, schistosomiasis, chronic lymphedema resulting from obstruction, erysipelas, chronic cellulitis and foreign body reaction need to be ruled out [3].

To objectively assess intestinal involvement, endoscopy of the upper and lower GI tract along with an abdominal magnetic resonance imaging (MRI) scan should be performed.

Currently, there is no standardized treatment of metastatic Crohn’s disease and no German or European guideline, especially for cases without GI involvement. Only individual case reports exist regarding the therapeutic use of approved medication for intestinal Crohn’s disease in metastatic conditions, including steroids, anti-TNF antibodies, azathioprine, and antibiotic therapy [4‐7].

Ustekinumab is a human monoclonal IgG1κ-antibody, which binds specifically to the p40-subunit of interleucin 12 (IL-12) and interleucin 23 (IL-23). The bioactivity of IL-12 and IL-23 is inhibited by ustekinumab by preventing the p40 subunit from binding to IL-12Rß1-receptorprotein on the surface of immune cells. It is assumed that hereby the cytokine pathways of Th1- and Th17-cells are interrupted, which both play an important role in the pathogenesis of Crohn’s disease [8].

We here report a case of metastatic Crohn’s disease successfully treated with ustekinumab at our university hospital and provide a literature review on the current therapeutic options for metastatic Crohn’s disease.

In 2020, a 29-year-old western European woman presented to the dermatology department of our university hospital with pronounced abdominal blind-ending fistulas. The initial patient contact was documented in 2019 when she sought care at the emergency department with multiple recurrent abscesses of the abdominal skin that first appeared after a tick bite a few weeks prior.

Between January 2019 and July 2020, multiple incisions of recurrent abscesses were performed in combination with antibiotic treatment. However, complete healing was not achieved. Instead, the abscess cavities expanded beneath the skin, subsequently forming a system of connected fistulas (Fig. 1), as visualized in MRI enterography (Fig. 2).

When the patient presented to the dermatology department in 2020, the fistulas showed active inflammation with secretion and were almost 2 cm in diameter. In addition, a blind ending subcutaneous fistula of the thigh could be detected, which also showed active inflammation and secretion.

Histologic examination revealed a granulomatous infiltrate with histiocytes and multinuclear giant cells, forming granulomas. In addition, lymphocytes, plasma cells, neutrophils, and eosinophils, and a granulomatous perivasculitis were observed (Fig. 3). Differential diagnoses of granulomatous diseases such as sarcoidosis, tuberculosis and immunodeficiencies were ruled out, confirming the diagnosis of metastatic Crohn’s disease.

To investigate intestinal involvement, abdominal MRI, gastroscopy, and colonoscopy were performed. However, these examinations did not reveal any gastrointestinal involvement at this time. Moreover, fecal calprotectin levels were normal. There was no history of inflammatory bowel disease in the patient’s family.

Antibiotic therapy had failed in the past, but the Patient responded well to prednisolone. As maintenance therapy for metastatic Crohn’s disease, the patient initially received infliximab at a dosage of 5 mg/kg. The patient responded well to this therapy, leading to the cessation of fluid secretion by the fistulas. However, an allergic reaction with dyspnea and rash occurred after the 10th dose of infliximab in October 2021, necessitating the discontinuation of treatment.

To evaluate further treatment options, the patient was referred to the department of Gastroenterology in November 2021. Meanwhile, she had developed diarrhea and abdominal pain. MRI revealed a mild ileitis, which, however, could not be validated by colonoscopy.

Therapy was switched to adalimumab in December 2021, to which the patient did not respond. Instead, a new fistula ostium developed.

Despite the lack of evidence for ustekinumab therapy in metastatic Crohn’s disease, and given its established efficacy only for intestinal manifestation, treatment with ustekinumab was initiated in May 2022 with an initial dose of 390 mg intravenous, followed by 90 mg subcutaneous every 8 weeks. This decision was based on the suspicion that the inflammatory processes in the abdominal fistula mirrored those seen in intestinal inflammation. The patient responded well and inflammation decreased within a few weeks. However, fistulas persisted, albeit with reduced secretion.

In June 2022, the blind-ending subcutaneous fistula of the thigh could be successfully treated by surgery after the active inflammation resolved. In April 2023, the abdominal fistula also showed no remaining inflammation, so a complete excision of the abdominal fistulas was performed. At the patients last visit in August 2023, no new fistula or abscesses were detected, but ustekinumab was continued due to the long and complicated clinical history. Written informed consent for publication of their clinical details and clinical images was obtained from the patient.

Our examination summarizes patient characteristics in metastatic Crohn’s disease and outlines therapeutic options based on the presented case. However, there are some limitations.

We established the diagnosis of metastatic Crohn’s diseases based on clinical and histological findings. Other granulomatous diseases such as sarcoidosis, tuberculosis and immunodeficiencies were ruled out, and histological findings were typical for Crohn’s lesions despite there was no intestinal involvement at the time of diagnosis. However, there is no possibility of completely ruling out any other underlying immunological condition causing similar symptoms. The analyzed case reports mostly also based their diagnosis on histological findings fitting Crohn’s criteria, and often on a known underlying intestinal Crohn’s disease, but in some publications, diagnostic criteria were not discussed in detail.

Our analysis is a summary of published cases and no randomized trial, making it impossible to compare the efficiencies of different therapies. This article outlines various treatment approaches and their success rates according to literature data. However, assessing the patient's condition before and after treatment from literature data can be challenging.

Several patients responded well to antibiotic treatment (see Table 1). This was also effective in some patients with GI involvement. Nevertheless, it remains unclear if lesions described as metastatic Crohn’s disease are infectious or a manifestation of Crohn’s disease.

Despite these limitations, treatments for metastatic Crohn`s disease could be evaluated. The most effective treatments, according to the current literature, include steroids and anti-TNF-antibodies. Despite the small number of cases, also azathioprine showed good clinical results. Mesalazine also appeared to positively impact skin lesions in patients with metastatic Crohn’s disease (see Table 1).

Conclusively, mesalazine, azathioprine, steroids, and anti-TNF antibodies should be considered as first line therapy for metastatic Crohn´s disease.

In case of treatment failure, there are less common therapeutic options such as ustekinumab, surgical intervention or hyperbaric oxygen therapy, which can be offered to the patient. Although the efficacy cannot be evaluated based on the limited amount of available data, the existing literature as well as our case report suggests a positive effect of ustekinumab in patients with metastatic Crohn’s disease.

Topical tacrolimus can improve the lesions, but there is no case report where topical tacrolimus could induce remission [3, 5, 9, 24, 39, 57, 61], and can currently not be recommended as a single therapeutic option. It might be useful to support other therapies.

Metastatic Crohn’s disease can affect patients with or without GI involvement. Diagnostics include anamnesis, inspection and biopsies of the involved site as well as endoscopy and MRI.

Currently, with no German, European or American guidelines available, approved therapies for intestinal Crohn’s disease are employed, based on the suspected similar inflammatory pathophysiology in intestinal and extraintestinal sites: Steroids, anti-TNF antibodies, and antibiotics were the primary and most potent agents. Mesalazine and azathioprine as well as less common treatment options such as surgical intervention or hyperbaric oxygen therapy may also be considered in case of treatment failure.

With the increasing number of reported cases of metastatic Crohn’s disease, the need for future guidelines for treating these patients becomes apparent. Our case demonstrates successful ustekinumab treatment for metastatic Crohn’s disease, suggesting a potential new therapeutic option.