To the Editor: Crohn’s Disease (CD) in a 53-year-old man that was localized to sigmoid and descendent colon was diagnosed in February 2001. The patient was admitted to the hospital because of bloody diarrhea, severe oral and pharyngeal aphthous lesions, and pyoderma. The diagnosis of CD and its extension was based on clinical findings, colonoscopy, histology, and small bowel follow-through. After the diagnosis was made, a course of methylprednisolone was begun, with the patient experiencing clinical remission. When treatment was stopped, clinical relapse was observed. Steroids together with azathioprine at a dosage of 2 mg/kg were then started, but the appearance of severe arthritic pains and myalgias led to the suspension of azathioprine. Infliximab was started at a dosage of 5 mg/kg at 0, 15, and 45 days with a complete clinical response (CD Activity Index score < 150 with disappearance of extraintestinal manifestations). A maintenance treatment with infliximab at a dosage of 5 mg/kg was continued every 8 weeks. During the first year of treatment, the clinical response to infliximab lasted about 7 weeks, with relapses characterized mainly by extraintestinal manifestations (oral ulcers and pyoderma). After the first year of treatment, the duration of the response gradually shortened despite the increase in dosage of infliximab to 10 mg/kg; the remission-free periods lasted approximately 1 month with the need to add steroids to control the symptoms. In March 2003, methotrexate at an intramuscular dosage of 25 mg weekly was added to infliximab. In April 2003, the patient had a severe clinical relapse, and colonoscopic evaluation showed a worsening of colonic lesions with extension of the disease to the rectum. The steroid dependence, the refractoriness to methotrexate, and the intolerance to azathioprine associated with the shortening of time response duration to infliximab were considered an indication to surgery (temporary colostomy or left colectomy with definitive colostomy), which the patient refused. High-dose immunosuppression with autologous hematopoietic stem cell rescue was then proposed to the patient who accepted the procedure. We decided to start the program at least 2 months after the last infliximab infusion, and the patient received steroids up to the end of June. In July, hematopoietic stem cells were mobilized from peripheral blood using cyclophosphamide (Cy) 2 g/m2 and G-CSF (lenograstim) 10 μg /kg. A total of 9.9 × 106/kg CD34+ cells were collected by 2 apheresis procedures and the cells were then enriched by CD34+ positive selection using the CliniMAX device. After the selection procedure a total of 3.3 × 106/kg CD34+ cells were recovered with a T-cell content of 0.17 × 104 /kg CD3+, 0.1 × 104 /kg CD4, and 0.06 × 10 4 /kg CD8+ (>4 log T-cell depletion). After the mobilization phase, the patient achieved a complete clinical remission with disappearance of extraintestinal manifestations, and steroids were stopped. However, a colonoscopy performed in August 2003 before hematopoietic stem cell transplantation (HSCT) showed no improvement of the lesions. In August, the patient underwent high-dose immunosuppression followed by autologous hematopoietic stem cell rescue. The immunosuppressive conditioning consisted of cyclophosphamide 50 mg/kg on Days -5, -4, -3, and -2 and equine ATG (Merieux) at the dosage of 90 mg/kg from Day -4 to Day -2 followed on day 0 by the infusion of CD34+ selected cells. Premedication with metilprednisone at dosage of 60 mg intravenously was administered prior to each ATG infusion. From Day + 1 until a neutrophil count above 0.5 × 109/L, he received G-CSF (lenograstim) 5 μg/kg subcutaneously. From admission until 3 months after HSCT supportive care included fluconazole, ciprofloxacin, oral acyclovir, and metronidazole as anti-infective prophylaxis. The posttransplantation course was uneventful with only one episode of culture-positive fever (Staphylococcus epidermidis) treated with specific antibiotic therapy while he was neutropenic. Severe neutropenia (ANC < 500/L) lasted 10 days, whereas platelets never went under 25 × 109/L and reached 50 and 100 × 109/L on Day +9. The transfusional support consisted of 2 irradiated packed red cells. After HSCT, the patient remained on clinical remission. In October, a new colonoscopic evaluation was performed: a reduction of the degree and the extension of the lesions and healing of mucosa in the rectum was observed. Histologically a clear improvement was also observed (Figs. 1A and 1B). Five months after undergoing transplantation the patient is still in complete clinical remission without any extraintestinal manifestations and in a partial endoscopic and histologic remission. In the last month the patient did not take any drug. Histologic findings: patchy transmural inflammation, intense cellular infiltrate, mucin depletion, and crypt distortion. In this patient with colonic CD who was refractory or intolerant to all immunomodulator and immunosuppressive therapies, HSCT obtained the following results: (1) a complete clinical response lasting 5 months (from the beginning of mobilization therapy) with the disappearance of all extraintestinal manifestations; (2) the complete withdrawal of steroids; (3) the improvement of endoscopic lesions mainly in the rectum; and (4) significant histologic improvement. Such a long remission duration had never been achieved with any of the previous treatments. In the present case, we choose to apply ex vivo T-cell depletion by the mean of CD 34+ positive selection together with in vivo ATG infusion, as in the cases reported by Burt et al. 1 This was done on theoretical grounds to avoid the reinfusion of autoreactive T cells and to enhance and prolong the clinical response. However, T-cell depletion of the graft both is an expensive procedure and may increase the risk for opportunistic infections, so that the issue of T-cell depletion in the setting of autoimmune disease remains unresolved. However, it is not possible to draw the conclusion that HSCT in this case has been responsible for the remission because cyclophosphamide alone has been reported to be effective in active steroid-refractory inflammatory bowel disease. 2 Furthermore, as G-CSF treatment polarizes T-lymphocytes toward type-2 cytokine production 3 and CD manifested as a TH1-mediated disease, 1 one cannot exclude that, in our case, the use of G-CSF might have also played a role in the clinical response. However, the observation that endoscopic and histologic improvement was observed only after the completion of the whole therapeutic program suggests the main role of HSCT in this case. In this case it is important to underline that the improvement obtained in the rectal lesions could, in the future, allow a less invasive surgical intervention (cyclophosphamide anastomosis). This case confirms the possible role of HSCT in the management of severe steroid-resistant CD. 1 The presence of extraintestinal symptoms which suggest a more relevant autoimmune component could be one of the criteria for selecting patients with severe resistant CD disease for HSCT. Histologic findings after HSCT: reduction of all histologic signs of inflammation. Despite the fact that allogenic marrow transplantation was shown to maintain remission in CD patients by Lopez-Cubera et al, 4 the risk of allogenic transplantation is the transfer of the susceptibility to the recipient of his or her hematopoietic cells as shown in a recent case report of fulminant CD colitis after allogenic transplantation. 5 HSCT, avoiding this risk, may be an alternative treatment for some patients with intractable CD and a poor quality of life.
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Scimè et al. (2004) studied this question.
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