Successful Treatment of Metastatic Crohn Disease With Infliximab

Abstract

Extraintestinal manifestations of Crohn disease are not uncommon and may precede the emergence of gastrointestinal symptoms. Dermatologic manifestations, reported in 1% to 10% of children with Crohn disease (1), can occur without specific histopathologic abnormalities (i.e., erythema nodosum, pyoderma gangrenosum) or may be referred to as metastatic Crohn disease, with characteristic granulomatous skin lesions affecting the groins, the male and female genitalia, or submammary regions. Several case reports describe children with isolated symptoms of the penile and scrotal skin (2–5,7). Medical treatment of this rare condition has been of limited value. We describe a boy with cutaneous, metastatic Crohn disease of the penile and scrotal skin who was the first to be treated with anti–tumor necrosis factor-α antibody (infliximab). CASE REPORT At the age of 10 years, an otherwise healthy boy had a 6-week history of a swollen penis and scrotum, which caused only minor discomfort while playing tennis but caused major embarrassment in the shower after school gymnastics. During the past 2.5 years, he had experienced episodes of minimal rectal bleeding associated with firm stools in the presence of a small anal fissure. The patient had no history of malaise, anorexia, weight loss, fever, profuse sweating, diarrhea, dysuria, or hematuria. At examination, the boy was in excellent condition and of normal height and weight for his age. A diffuse nonpainful soft swelling of the prepubertal penis and scrotum was seen, and the scrotal skin was slightly red. The perianal region showed one indolent perianal tag, a small anal fissure, but no fistula. All hematologic laboratory values were normal, demonstrating no signs of an acute infection or inflammatory disease. His urine contained no bacteria and no white or red blood cells. Local genital symptoms increased after a biopsy specimen was taken from the penile skin, which showed granulomas in the dermis and lymphatic spaces (Fig. 1). A biopsy specimen from the perianal skin showed similar abnormalities. Appropriate tests ruled out local anatomic or vascular abnormalities, infectious causes such as tuberculosis or atypical mycobacterial infection, syphilis, chlamydia, fungal infection or leishmaniasis, or immune-mediated disease such as histiocytosis or sarcoidosis.FIG. 1.: Histopathology of penile skin biopsy; granulomatous infiltrate.Expecting to establish a diagnosis of inflammatory bowel disease, a thorough gastrointestinal workup was performed. However, ultrasound, enteroclysis, upper endoscopy, and ileocolonoscopy with multiple biopsies failed to show any evidence of intestinal inflammation. Magnetic resonance imaging scan of the sacral region demonstrated a slight thickening of the rectal mucosa. Ileocolonoscopy and histology, repeated 1.5 years after the initial presentation were still normal. On the basis of these findings, Crohn disease with metastatic genital granulomatous lymphangitis was diagnosed. Treatment with oral prednisolone alone or in combination with azathioprine or courses of intravenous cyclosporine only transiently reduced this patient's genital lymphedema (Fig. 2A). Based on previous experience with therapy-resistant perineal metastatic Crohn disease (6), treatment was begun with a monoclonal anti–tumor necrosis factor antibody (anti–TNF-α, infliximab, 5 mg/kg infusions at weeks 0, 4, and 12) in combination with oral azathioprine, 1 year and 10 months after onset of the symptoms. Within 1 week after a single infusion, swelling and variable redness decreased (Fig. 2B). With two repeat infusions (at weeks 4 and 12), treatment success was maintained (Fig. 2C). The boy experienced moderate fatigue in the first 2 days after the second and third infusions, but had no other side effects. Maintenance treatment with azathioprine (2.5 mg/kg daily) was continued.FIG. 2.: Result after treatment with prednisolone and cyclosporine (A), result after treatment with infliximab and azathioprine one week after start (B), result after 12 weeks (C).Relapse of genital swelling occurred 14 months after cessation of the infliximab infusions, and treatment was begun again with an infusion every 8 weeks. Again, symptoms resolved within 2 weeks, and still no signs of gastrointestinal Crohn disease were present. Currently, the boy receives infliximab maintenance treatment (an infusion every 6–8 weeks for the past 12 months) and has some remaining indurated swelling of the scrotum and penis. For cosmetic reasons, surgery is being planned. Now more than 4 years after the first genital manifestations, no bowel symptoms are present. DISCUSSION The symptom of isolated genital edema in a boy has a differential diagnosis (Table 1) that normally would not include metastatic Crohn disease. In this case, other conditions were certainly considered, but all were ruled out on the basis of either laboratory results or clinical condition. After the skin biopsy, the differential diagnosis could be narrowed down to granulomatous skin infiltration, as listed in Table 2. Positive signs of Crohn disease in this case were the characteristic granulomatous infiltrate of the scrotal skin and the presence of subtle perianal lesions, such as a tag and a minor fissure. Four cases very similar to this have been described (2–5,7), but all patients had bowel symptoms (and gastrointestinal inflammation) either before (2), during (3,7), or years after the onset of genital symptoms (4,5). In an excellent review and additional case reports, Ploysangam et al. (7) described 80 cases of cutaneous Crohn disease, 14 of which were in children. Two thirds of the children had genital involvement, and in 11 of the children, cutaneous Crohn disease preceded intestinal Crohn disease by weeks to 6 years.TABLE 1: Differential diagnosis of genital edemaTABLE 2: Differential diagnosis of granulomatous skin lesions in genital regionMetastatic Crohn disease in the skin of male genitals presents differently in children (2–5) than in adults (8–10). Children have genital edema, whereas adult men have ulceration of the penile or scrotal skin, often in conjunction with perianal disease, such as extensive fistulae. Recently, however, two young adult patients were described with genital swelling as well (11). Cases of metastatic Crohn disease also have been described in the face (12), retroauricular area (13), upper or lower extremities (14–20), perineal area (6), vulva (7,21–24), and lungs (25). Treating metastatic Crohn disease with various chemotherapeutic agents, including oral steroids (2–5,7,10,18), topical steroids (7,8), azathioprine (3,4,10,13), sulfasalazine (3), metronidazole (3,4,12), or tetracyclines (21), has demonstrated variable success. In general, treatment seems to be less effective when metastatic Crohn disease has been of long duration. Two adults with therapy-resistant metastatic Crohn disease in the perineum have been successfully treated with anti–tumor necrosis factor antibody (6), and this experience led us to use similar treatment in our patient. Table 3 shows the various treatment options for metastatic Crohn disease in the skin of the penis and scrotum.TABLE 3: Treatment options for metastatic Crohn disease in penis and scrotumThis unusual manifestation of metastatic Crohn disease in a child is the first case to demonstrate a beneficial effect of immunomodulatory treatment with infliximab and azathioprine for genital lymphedema, even if treatment begins almost 2 years after onset. Whether this child will have further intestinal inflammation in the coming years is of course unknown.