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Original Articles: Gastroenterology

Efficacy of Granulocyte Apheresis in Pediatric Patients With Ulcerative Colitis: A Pilot Study

Ikeda, Hitoshi; Ishimaru, Yuki; Takayasu, Hajime; Fujino, Junko; Kisaki, Yoshiyuki; Otani, Yushi; Yamagishi, Junko; Tahara, Kazunori

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Journal of Pediatric Gastroenterology and Nutrition: November 2006 - Volume 43 - Issue 5 - p 592-596
doi: 10.1097/01.mpg.0000237928.07729.79
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Abstract

INTRODUCTION

Ulcerative colitis (UC), along with Crohn disease, is a major cause of chronic intestinal inflammation in children after the first few years of life (1). Epidemiological studies have shown higher risks of the disease in family members of affected patients and in monozygotic twins than in dizygotic twins. An increase in the incidence of UC in developed countries also suggests that both genetic and environmental factors are associated with its pathogenesis (2,3). Although the etiology is poorly understood, an abnormality of immunoregulation in the intestinal mucosa is considered to be of primary importance in the pathogenesis. Inflammatory mediators are apparently involved in leucocyte infiltration and resultant mucosal injuries. To interfere with these inflammatory processes and control symptoms or disease activity, 5-aminosalicylate (5-ASA) and corticosteroids, commonly prednisolone (PSL), are widely used as effective agents. However, it is difficult to control the disease in patients with steroid-refractory UC whose symptoms persist despite treatment with steroids. In patients with steroid-dependent disease, in whom steroid doses cannot be tapered, the prolonged use of steroids should be avoided because complications such as growth retardation, infection, and cosmetic effects are often observed and are sometimes serious in children.

Granulocyte apheresis (GCAP), which removes granulocytes and monocytes/macrophages from the blood, was demonstrated to effectively improve the clinical symptoms and reduce the required doses of steroids in adult patients with UC (4–7). These effects are thought to have resulted from both the reduction in circulating activated leucocytes and the modulation of inflammatory cytokine generation and chemokine activities (4,8). Granulocyte apheresis has been accepted as 1 of the treatment options for severe and moderate UC in adult patients; however, there has been a limited number of pediatric patients in whom GCAP treatment has been applied (9). As a preliminary trial, GCAP was performed in 4 pediatric patients with steroid-refractory or steroid-dependent UC to taper the dose of steroids and induce clinical remission. In this article, the effects and clinical efficacy of GCAP treatment were retrospectively examined, and its possible roles in pediatric patients with UC were discussed.

PATIENTS AND METHODS

Between September 2001 and December 2004, 3 male patients and 1 female patient, whose ages at clinical onset of ulcerative colitis ranged from 8 to 12 years, were treated with GCAP at ages ranging from 11 to 17 years (Table 1). Two of the 4 patients were included in the previous report (9). The diagnosis of UC was made according to the endoscopic and histological findings, with the presence of clinical symptoms. The disease involved the total colon at diagnosis in 3 patients and ulcerative proctitis had progressed to pancolitis before GCAP treatment was given in the fourth patient. Treatment of the 4 patients before GCAP mainly consisted of conventional doses of PSL and 5-ASA. Clinical courses were steroid dependent because symptoms recurred after tapering or discontinuation of PSL in 2 patients and steroid refractory because symptoms persisted despite conventional PSL treatment in the other 2 patients. In these 4 patients, GCAP was indicated at exacerbation of the disease, and the time interval between disease onset and GCAP treatment ranged from 28 to 58 months (median, 38.5 months). The severity of the disease at exacerbation was severe in 1 patient and moderate in 3 patients according to the modified Truelove and Witts classification, which is based on stool frequency, the presence of macroscopic blood in stools, fever, tachycardia, anaemia, and the erythrocyte sedimentation rate (ESR) (10).

TABLE 1
TABLE 1:
Characteristics of 4 pediatric patients with UC treated with GCAP

GCAP Treatment

GCAP was performed according to the protocol previously reported using an Adacolumn (Japan Immunoresearch Laboratories, Tokyo), which is a granulocyte and monocyte/macrophage adsorptive, extracorporeal apheresis system (4,8) (Fig. 1). The Adacolumn is a device with a volume of 335 mL filled with 220 g of cellulose acetate beads (approximately 35,000 pieces) of 2 mm in diameter as cell-absorbing carriers, bathed in physiological saline (8). The clinical application of the Adacolumn in active UC was approved by the Japanese Ministry of Health in 1999 (8). One course of treatment consisted of 1 apheresis per week for 5 consecutive weeks. Each apheresis was performed for 60 min at a blood perfusion rate of 30 mL/min. Blood was usually withdrawn from and returned to the veins, but an artery was accessed when an appropriate blood flow was not obtained via a venous route. The patients were admitted to hospital to receive the first few aphereses, but the following aphereses were performed in outpatient clinics when the patients were in a stable condition. Three patients received 2 courses and 1 patient received 1 course of GCAP treatment.

FIG. 1
FIG. 1:
GCAP was performed for 60 min at a blood perfusion rate of 30 mL/min according to the protocol previously reported using an Adacolumn apheresis device.

Changes in disease activity caused by GCAP treatment or therapeutic effects were evaluated by comparing the symptoms and signs, laboratory data including hemoglobin and ESR, and endoscopic findings between before and after treatment. The endoscopic findings were graded according to the classification previously reported (9). Briefly, grade 3 was defined as severe inflammation with extensive ulcers and spontaneous bleeding; grade 2, moderate inflammation with the presence of multiple aphthous lesions, ulcers and contact bleeding; grade 1, slight inflammation with invisible vascular patterns and redness of the mucosa; and grade 0, normal mucosa.

Regarding the clinical efficacy of GCAP treatment, it was excellent or good when the symptoms and signs improved and recovered to the point of the condition before exacerbation. In this case, the stool frequency had to be <6 times per day, visible bloody stools were almost absent, and improvements in laboratory data and endoscopic findings were also evident. Although the clinical efficacy was assessed as fair when some clinical, laboratory, and endoscopic improvements were observed, the GCAP treatment was judged ineffective when there were no improvements in symptoms and signs.

RESULTS

Effects and Clinical Efficacy of GCAP Treatment

The effects and clinical efficacy of GCAP in 4 patients with UC are summarized in Table 2. In Patients 1 and 4, the symptoms and signs improved after 2 courses of GCAP treatment (Fig. 2). Although a small number of bloody stools persisted, patient 4 resumed a stable condition, similar to that before the exacerbation of the disease. Laboratory data and endoscopic findings also improved in these patients and the clinical efficacy was assessed as excellent. In patient 2, both the laboratory data and endoscopic findings improved after 1 course of GCAP treatment; however, the patient refused the second course because of painful vascular access. Macroscopic bloody stools several times per day persisted, and the clinical efficacy of GCAP treatment was fair in this patient. In patient 3, GCAP was ineffective and total colectomy with ileoanal canal anastomosis (CIACA) was performed with an uneventful postoperative course.

TABLE 2
TABLE 2:
Effects and clinical efficacy of GCAP treatment
FIG. 2
FIG. 2:
Patient 1, a 13-year-old boy whose steroid-dependent UC was diagnosed at the age of 11 years, underwent GCAP treatment. A, Following 2 courses of GCAP, the stool frequency reduced and PSL doses were tapered. The post-GCAP course of the disease was controlled by azathioprine (AZA) and 5-aminosalicylate (5-ASA). B, Endoscopic findings improved after GCAP treatment.

Clinical Course After GCAP Treatment

After GCAP treatment, the disease was controlled by immunosuppressants, azathioprine or 6-mercaptopurine, with 5-ASA or salazosulphapyridine in 3 patients who responded to GCAP treatment. Patient 1, whose response to GCAP treatment was excellent, underwent CIACA because of strictures of the affected colon 38 months after the GCAP treatment. Symptoms have been relatively well controlled for more than 2 years in the other 2 patients (patients 2 and 4).

DISCUSSION

Periodic removal of excess and activated granulocytes and monocytes/macrophages by apheresis is expected to reduce leucocyte-dependent inflammation and resultant tissue injuries, and promote the remission of inflammatory disorders that are considered related to abnormalities of immunoregulation (8). Several clinical studies have reported promising results in adult patients with rheumatoid arthritis and skin diseases such as pyoderma gangrenosum, as well as inflammatory bowel diseases (11,12). A multicenter study in adult patients with UC showed that 26% of granulocytes, 20% of monocytes, and 2% of lymphocytes were adsorbed to carrier cellulose acetate beads (4). Approximately 60% of patients responded to GCAP treatment and showed clinical improvements, which included the remission of symptoms in 20% of patients, suggesting that the treatment may enable the tapering of the required doses of steroids, shorten the time to clinical remission, and delay relapses. Subsequent prospective studies suggested that GCAP treatment was effective in promoting clinical remissions and reducing steroids in adult patients with steroid-refractory or steroid-dependent UC (6,7).

The production of inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-β, IL-6 and IL-8) by leucocytes was markedly decreased by Adacolumn apheresis (4). In addition, the expression of leucocyte-endothelial cell adhesion molecule-1 (L-selectin) on unadsorbed leucocytes was downregulated, causing fewer leucocytes to adhere to the vascular endothelia. There is also preliminary data that Adacolumn apheresis downregulates the expression of the chemokine receptor CXCR3 (CD183), whose signaling induces the chemotactic migration of leucocytes to inflammatory sites (8). In UC, the infiltrating activated leucocytes in the colonic mucosa cause mucosal damage. Degradative proteases, reactive oxygen derivatives, and proinflammatory cytokines released by the leucocytes are responsible for the damage. Therefore, the clinical improvements by GCAP treatment in patients with UC are considered to be associated with those effects of Adacolumn aphereis, the depletion of activated leucocytes from peripheral blood, and characteristic changes or functional modulations in unadsorbed leucocytes.

A multicenter retrospective survey of pediatric patients with active UC treated with GCAP showed that clinical symptoms improved and remissions were obtained in 8 of 11 patients (9). According to the study, 4 of the 8 patients relapsed after relatively short periods and the other 4 remained in remission with maintenance therapy. Our experience with GCAP treatment in children with steroid-refractory or steroid-dependent disease also showed that the treatment effectively improved the clinical symptoms in 3 of 4 patients. These results suggest that the treatment may play an important role in converting steroid therapy to other treatments in pediatric patients, as well as adult patients with the disease. GCAP treatment was ineffective and CIACA was performed in 1 of our patients. From a surgical point of view, the postoperative course of the patient was uneventful. Presurgical GCAP could someday be applied in preventing surgical complications by reducing disease activity before surgery.

Regarding side effects of GCAP treatment, minor adverse reactions including headache, dizziness, nausea, and vomiting were reported (4). There were no major adverse reactions occurring in our patients or in patients of the previous survey (9). However, repeated puncturing to gain vascular access is painful and would be a reason for refusal of the treatment, particularly in pediatric patients.

It is obvious that our experience is too limited to draw conclusions on GCAP treatment in pediatric patients. Therefore, we propose a multicenter prospective study be performed to determine the true efficacy and feasibility of GCAP treatment in children with UC.

REFERENCES

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Keywords:

Granulocyte apheresis (GCAP); Ulcerative colitis

© 2006 Lippincott Williams & Wilkins, Inc.