Behçet disease (BD) is a chronic-relapsing systemic vasculitis characterized most commonly by oral aphthous ulceration, skin lesions, and ocular inflammation. It is less commonly characterized by lesions in the central nervous system, the gastrointestinal tract, and the cardiovascular system. The prevalence of intestinal BD appears to vary regionally, with reported frequencies ranging from 0% in a study in Israel to 60% in a study in Japan (1). The gastrointestinal manifestations of BD usually appear 4 to 6 years after the onset of the oral ulcers (2). Any part of the intestine may be affected, but the ileocecum is the most common area involved (3). Although the etiology of BD is unknown, it appears that tumor necrosis factor-α (TNF-α) plays an important role in its immunopathogenesis. Infliximab (IFX), a murine-human chimeric monoclonal antibody that neutralizes the biologic activity of TNF-α by binding to the soluble and membrane-bound precursors of TNF-α (4), has been reported to show rapid and dramatic effects in the treatment of refractory ocular, mucocutaneous, joint, gastrointestinal, and central nervous system manifestations of BD in several case reports and case series (5). There are only a few reports describing the effects of IFX for treatment of intestinal BD in adults and even fewer in pediatric patients with BD. We report a 15-year-old girl with immunosuppressive-resistant BD whose symptoms were successfully controlled by IFX.
A 15-year-old Japanese girl was referred to our tertiary care medical center with a 1-month history of unexplained right lower-quadrant abdominal pain. Medical history revealed that she had undergone appendectomy 5 months earlier with apparent relief of her abdominal complaints. Two months later, she developed severe bilateral shin pain with erythema. She was examined by a dermatologist and a diagnosis of erythema nodosum was made. She was treated with prednisolone, 10 mg 3 times daily, and her symptoms improved. The prednisolone dose was tapered to 5 mg once daily, and she experienced recurrence of these symptoms. Despite the recurrence, the decision was made to discontinue the prednisolone entirely. She then developed lower abdominal pain and was referred to our center for further evaluation. When initially seen by us, she was being treated with a nonsteroidal anti-inflammatory drug for the recurrent leg pain. Review of systems revealed no complaints of weight loss, fever, diarrhea, hematochezia, tarry stools, or visual problems. Her family history was unremarkable. On examination, her vital signs were normal. There was an aphthous ulcer on her lower lip. Her abdomen was soft, with tenderness to palpation in the right lower quadrant; there was no guarding or rebound. There was no erythema on her lower extremities. Neurologic and ophthalmologic examinations were unremarkable. Laboratory studies revealed a total white blood cell count of 16,800 cells/mm3, hemoglobin of 11.5 g/dL, platelet count of 608,000 cells/mm3, erythrocyte sedimentation rate (ESR) of 23 mm/hour (normal range 3–11 mm/hour), serum albumin level of 3.6 g/dL (normal range 3.8–5.3 g/dL), and C-reactive protein (CRP) of 8.65 mg/dL (normal range 0–0.3 mg/dL). Liver and renal function tests, serum electrolytes, glucose, calcium, phosphate, and globulin levels were normal. HLA-B51 was negative. Computed tomography of the abdomen showed intestinal wall thickening from the terminal ileum to the ascending colon. Ileocolonoscopy revealed multiple aphthoid ulcerations in the terminal ileum (Fig. 1A). There were no ulcerations in the colon. Esophagogastroduodenoscopy revealed normal findings. Histologic studies of the biopsy specimens showed atrophy and reduction of crypts and infiltration with lymphocytes, neutrophils, and eosinophils. There were no granulomatous lesions (Fig. 1B).
She was diagnosed as having Crohn disease. Mesalazine (500 mg 3 times daily) was initiated. Her symptoms improved for 2 months, but then the leg pain and abdominal pain recurred. She also complained of vulvar pain and ulceration on the labia majus was recognized. There was significant tenderness in the right lower quadrant. Serum CRP and ESR were elevated again.
The patient was diagnosed as having BD based on the criteria recommended by the International Study Group of BD (6). Colchicine (0.5 mg twice daily) was initiated, but it was not found to be effective. She was hospitalized because of severe abdominal pain and high fever. Prednisolone (15 mg 3 times daily) was again initiated and her symptoms improved dramatically. Tapering of the prednisolone dose to 5 mg once daily resulted in recurrence of her symptoms. Azathioprine (50 mg once daily) was added to the lower-dose prednisolone for maintenance therapy. Four months later, she redeveloped severe abdominal pain and high fever. CRP and ESR were again elevated. Exacerbation of BD was suspected. She refused to allow treatment with higher-dose prednisolone therapy again. Cyclosporine was initiated at a dose of 1 mg/kg twice daily, then increased to 2 mg/kg twice daily. At a dose of 2 mg/kg twice daily, the trough level was 77.1 ng/mL. Her symptoms and serum CRP and ESR levels did not improve. We believed that cyclosporine had not been effective as an induction therapy and we also believed that azathioprine was not effective as a maintenance therapy.
After discussion with the patient and her family, an infusion of IFX (200 mg, 4 mg/kg) was administered. Within only a few days of receiving the first infusion, an improvement in symptoms was noticed. Repeat infusions of IFX (300 mg, 6 mg/kg) were given 2 and 7 weeks after the initial infusion. Prednisolone and azathioprine were discontinued after the second infusion. Before the first infusion of IXF, her ESR was 42 mm/hour and serum CRP level was 8.79 mg/dL. Two weeks after the third IFX infusion, they had decreased to 7 mm/hour and 0.12 mg/dL, respectively. Repeated ileocolonoscopy 7 weeks after the third infusion showed marked improvement in the degree of inflammation and ulcer healing (Fig. 1C). Biopsy specimens also showed a reduction in inflammation (Fig. 1D). At the time of the present report, 3 months after the third IFX infusion, she remains without evidence of recurrent gastrointestinal symptoms, with normal ESR and CRP values.
Although the exact pathogenesis of BD is not completely understood, substantial evidence suggests that TNF-α plays a pathogenic role in the development of BD. A subpopulation of T cells expressing the γδ receptor is increased in patients with BD as compared with healthy individuals. This subset of T cells produces extreme amounts of TNF-α (>5000 pg/mL compared with <100 pg/mL by γδ T cells from normal donors) when stimulated with phorbol myristate acetate or anti-CD3 (7). This may account for the response to IFX in our patient.
Gastrointestinal involvement in BD is often uncontrollable, frequently characterized by relapse, and sometimes contributes to poor outcomes. The overall frequency of BD in Japan is almost the same as that in Mediterranean countries, but a higher frequency of gastrointestinal involvement appears in Japanese patients (8,9), especially in children (10). In these studies, the gastroenterology patients with BD showed a high corticosteroid dependency with severe adverse effects. They did not respond to the usual anti-inflammatory drugs such as azathioprine, colchicine, cyclosporine, sulfasalazine, and methotrexate. Successful medical treatment for gastrointestinal involvement in patients with BD has not been firmly established. In 7 patients with BD with gastrointestinal involvement, Yasui et al (11) reported a modest response to thalidomide, which is known to inhibit the transcription of TNF-α. Anti-TNF-α monoclonal antibodies are used widely in the therapy of rheumatoid arthritis, spondyloarthropathies, Crohn disease, and psoriasis, with an acceptable safety profile. Although the published reports of anti-TNF-α treatment for patients with BD have been limited to independent investigator-initiated trials and uncontrolled case series, the therapeutic response to anti-TNF-α treatment in the vast majority of the patients in these reports has been considered favorable. In 2007, Sfikakis et al (12) formulated the following inclusion criteria for selecting patients eligible for anti-TNF-α treatment of BD: a definite diagnosis of BD; presence of active disease, including objective signs of inflammation; previous failure of drugs that have a documented efficacy in controlling BD manifestations, combined or not with low-dose corticosteroids (equivalent to prednisolone dose of 7.5 mg/day); presence of contraindications or intolerance to these conventional regimens; and absence of contraindications to anti-TNF-α treatment. Our patient fulfilled their criteria. BD is a systemic inflammatory disease, but the degree of inflammation may vary between organs. In our patient, treatment with IFX led to a complete remission of all disease manifestations, and there was no recurrence after steroid discontinuation. We postulate that the terminal ileum may be the site of greatest production of TNF-α in our patient. This may be the explanation for the localized effect to the intestinal region of IFX in our patient. Furthermore, our patient has not experienced recurrence of genital ulcers, oral ulcers, or erythema nodosum since steroids have been stopped, implying that her extraintestinal manifestations of BD also may have been effectively treated with IFX.
We believe that IFX may be considered in the treatment of BD, especially if more traditional medical therapy has not been successful. There are no official guidelines regarding IFX treatment regimen and duration, with treatment in reported cases ranging from a single dose (13) to a total of 30 doses with a maximum duration of 5 years (14). Further confirmation of the beneficial effects of anti-TNF-α treatment as a maintenance treatment and an induction treatment in randomized controlled double-blind studies is recommended.
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