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Clinical, endoscopic and histological remission in paediatric chronically active ulcerative colitis after prolonged treatment with selective granulocyte–monocyte adsorptive apheresis
Journal of Crohn's and Colitis (2009) 3, 216–217
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
LETTER TO THE EDITOR Clinical, endoscopic and histological remission in paediatric chronically active ulcerative colitis after prolonged treatment with selective granulocyte– monocyte adsorptive apheresis Dear Sir, Treatment of paediatric ulcerative colitis (UC) unresponsive to conventional treatment constitutes a challenge. According to the classical step-up strategy, flare-ups that do not respond to oral and/or topical 5-ASA, are tributary of systemic steroids. Although treatment with oral or intravenous corticosteroids is effective in most patients, severe cases of steroid-refractory pancolitis will need colectomy even at diagnosis.1 Wide experience with cyclosporine A has shown its efficacy in preventing emergency colectomy, although its effect seems to be poorer in the long-term, most of these patients needing colectomy within a few months or years period. Recent experience with the antiTNF-α monoclonal chimeric antibody (Infliximab) has shown also its efficacy as rescue therapy in preventing colectomy in patients with fulminant paediatric UC.2 On the other hand, a significant proportion of the paediatric UC patients who respond to steroid treatment will develop steroid-resistance (29%) or steroid-dependence (14%) during the follow-up.3 Early introduction of immunomodulators (azathioprine, 6mercaptopurine) have proved to be steroid-sparing and to heal the mucosa as well.4 Nevertheless, there are still a group of patients in whom the disease behaves in a chronically active manner and who will need additional course of 5-ASA or even steroids to the maintenance treatment in order to control the inflammatory activity. As opposed to adults, subsequent re-treatments with steroids are not a reasonable strategy in children. Thus, the finding of new secure, steroid-sparing and long acting treatments for these cases are mandatory. Selective granulocyte–monocyte adsorptive (GMA) apheresis with the Adacolumn device has shown conflicting results in these patients. While it has shown its utility in small series of both adult steroid-refractory and steroid-dependent UC,5,6 recent studies performed in heterogeneous groups of patients have failed to show any advantages over a sham device in moderate-to-severe UC.7 The available experience with Adacolumn in paediatric UC suggests that, because of its slow mechanism of action and its immunomodulatory effect, it can be useful in very carefully selected patients.8 Instead of offering Adacolumn to prolonged severe UC unresponsive
to previous treatments, it would be interesting to investigate its utility in new indications. We report our experience with a long-term therapeutic strategy with Adacolumn in a chronically active paediatric UC patient. A 9 year-old boy presented with a one-month story of bloody diarrhoea, fever and elevated inflammatory markers. The colonoscopy and the histological studies confirmed the diagnosis of UC involving the entire colon. Intravenous methyl-prednisolone was started with a good response, the patient entering remission. Change to oral steroids, progressive tapering, and initiation of azathioprine (AZA) as maintenance treatment (2.5 mg/kg/day) was successfully achieved. After 14 months in clinical remission, he presented with intermittent episodes of bloody stools, with a generally maintained well-being, slight elevation of inflammatory markers and ferropenia. These episodes were successfully treated with addition of oral and/or rectal mesalamine, with good response but rapid recurrence after changing back to AZA monotherapy. After 2 years with this pattern of chronically active UC, on maintenance treatment with AZA and oral mesalamine, a colonoscopy was performed, showing moderately active extensive UC, from the rectum up to the mid-transverse colon. Two possible therapeutic options were considered at that time; infliximab or selective GMA apheresis. Due to his maintained clinical situation, a five-session initial strategy with a weekly Adacolumn apheresis and posterior maintenance with a session every 8 weeks, was decided. The 8-week interval was decided in order to establish a scheduled treatment regimen similar to infliximab and considering it could be an acceptable one. The patient has received 10 maintenance sessions through a peripheral vein in a 1 year period without complications. Mesalamine was successfully tapered after the 3rd session and stopped after the 5th session, without posterior reappearance of rectal bleeding. A new colonoscopy after the tenth maintenance session showed complete endoscopic and histological remission (Fig. 1). Maintenance on AZA treatment without new sessions of apheresis was agreed with the patients and his parents. The patient is now doing well on AZA monotherapy three months after the last apheresis session. This case shows the utility of prolonged Adacolumn treatment in chronically active UC patients. One of the most controversial aspects of GMA apheresis is its presumed slow mechanism of action, which limits its role in moderate to severe flare-ups unresponsive to other treatments needing a rapid improvement. After 14 months of remission on AZA maintenance treatment, our patient presented with
1873-9946/$ - see front matter © 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.crohns.2009.03.003
Letter to the Editor
217
Figure 1 Endoscopic view before (left) and after (right) Adacolumn treatment. The initial pattern of moderately active ulcerative colitis in the sigmoid colon has disappeared, with an endoscopically normal aspect after the maintenance treatment.
intermittent episodes of rectal bleeding but with a stable general well-being. This clinical stability although the almost continuous episodes of rectal bleeding once adjuvant treatment with 5-ASA was stopped and the endoscopic and histological confirmation of maintained colonic inflammation, made us think of Adacolumn as a possible stabilization agent useful in ameliorating symptoms and permitting a successful switch to AZA monotherapy. These two aspects have been achieved without reappearance of rectal bleeding after oral mesalamine suppression. But perhaps the most interesting and promising finding is the confirmation of GMA apheresis effect on mucosal healing after prolonged treatment. After more than 3 years of treatment with AZA (an agent with potential capacity of ameliorating mucosal inflammation), our patient showed endoscopic and histological evidence of sustained inflammation. Maintenance treatment with Adacolumn has been effective in achieving a complete endoscopic and histological remission.
References 1. Hyams JS, Davis P, Lere T, et al. Clinical outcome of ulcerative colitis in children. J Pediatr 1996;129:81–8. 2. Martín de Carpi J, Vilar P, Varea V. Infliximab as rescue therapy in severe steroid-resistant ulcerative colitis. An Pediatr (Barc) 2008;69:351–4. 3. Tung J, Loftus EV, Freese DK, et al. A population-based study of the frequency of corticosteroid resistance and dependence in pediatric patients with Crohn's disease and ulcerative colitis. Inflamm Bowel Dis 2006;12:1093–100.
4. Banerjee S, Bishop WP. Evolution of thiopurine use in pediatric inflammatory bowel disease in an academic center. J Ped Gastroenterol Nutr 2006;43:324–30. 5. Kruis W, Dignass A, Steingahen-Thiessen E, et al. Open label trial of granulocyte apheresis suggests therapeutic efficacy in chronically active-steroid refractory ulcerative colitis. World J Gastroenterology 2005;11:7001–6. 6. Yamamoto T, Umegae S, matsumoto K. Safety and clinical efficacy of granulocyte and monocyte adsorptive apheresis therapy for ulcerative colitis. World J Gastroenterology 2006;12:520–5. 7. Sands BE, Sandborn WJ, Feagan B, et al. A randomized, doubleblind, sham-controlled study of granulocyte/monocyte apheresis for active ulcerative colitis. Gastroenterology 2008;135:400–9. 8. Martín de Carpi J, Vilar P, Prieto G, et al. Safety and efficacy of granulocyte and monocyte adsorption apheresis in paediatric inflammatory bowel disease: a prospective pilot study. J Pediatr Gastroenterol Nutr 2008;46:386–91.
Javier Martín-Carpi⁎ Vicente Varea Paediatric IBD Unit, Department of Paediatric Gastroenterology, Hepatology and Nutrition, Hospital Sant Joan de Déu, Barcelona (Spain) ⁎Corresponding author. Tel.: +34 93 600 61 03. E-mail address: [email protected] (J. Martín-Carpi). 4 March 2009
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
LETTER TO THE EDITOR Clinical, endoscopic and histological remission in paediatric chronically active ulcerative colitis after prolonged treatment with selective granulocyte– monocyte adsorptive apheresis Dear Sir, Treatment of paediatric ulcerative colitis (UC) unresponsive to conventional treatment constitutes a challenge. According to the classical step-up strategy, flare-ups that do not respond to oral and/or topical 5-ASA, are tributary of systemic steroids. Although treatment with oral or intravenous corticosteroids is effective in most patients, severe cases of steroid-refractory pancolitis will need colectomy even at diagnosis.1 Wide experience with cyclosporine A has shown its efficacy in preventing emergency colectomy, although its effect seems to be poorer in the long-term, most of these patients needing colectomy within a few months or years period. Recent experience with the antiTNF-α monoclonal chimeric antibody (Infliximab) has shown also its efficacy as rescue therapy in preventing colectomy in patients with fulminant paediatric UC.2 On the other hand, a significant proportion of the paediatric UC patients who respond to steroid treatment will develop steroid-resistance (29%) or steroid-dependence (14%) during the follow-up.3 Early introduction of immunomodulators (azathioprine, 6mercaptopurine) have proved to be steroid-sparing and to heal the mucosa as well.4 Nevertheless, there are still a group of patients in whom the disease behaves in a chronically active manner and who will need additional course of 5-ASA or even steroids to the maintenance treatment in order to control the inflammatory activity. As opposed to adults, subsequent re-treatments with steroids are not a reasonable strategy in children. Thus, the finding of new secure, steroid-sparing and long acting treatments for these cases are mandatory. Selective granulocyte–monocyte adsorptive (GMA) apheresis with the Adacolumn device has shown conflicting results in these patients. While it has shown its utility in small series of both adult steroid-refractory and steroid-dependent UC,5,6 recent studies performed in heterogeneous groups of patients have failed to show any advantages over a sham device in moderate-to-severe UC.7 The available experience with Adacolumn in paediatric UC suggests that, because of its slow mechanism of action and its immunomodulatory effect, it can be useful in very carefully selected patients.8 Instead of offering Adacolumn to prolonged severe UC unresponsive
to previous treatments, it would be interesting to investigate its utility in new indications. We report our experience with a long-term therapeutic strategy with Adacolumn in a chronically active paediatric UC patient. A 9 year-old boy presented with a one-month story of bloody diarrhoea, fever and elevated inflammatory markers. The colonoscopy and the histological studies confirmed the diagnosis of UC involving the entire colon. Intravenous methyl-prednisolone was started with a good response, the patient entering remission. Change to oral steroids, progressive tapering, and initiation of azathioprine (AZA) as maintenance treatment (2.5 mg/kg/day) was successfully achieved. After 14 months in clinical remission, he presented with intermittent episodes of bloody stools, with a generally maintained well-being, slight elevation of inflammatory markers and ferropenia. These episodes were successfully treated with addition of oral and/or rectal mesalamine, with good response but rapid recurrence after changing back to AZA monotherapy. After 2 years with this pattern of chronically active UC, on maintenance treatment with AZA and oral mesalamine, a colonoscopy was performed, showing moderately active extensive UC, from the rectum up to the mid-transverse colon. Two possible therapeutic options were considered at that time; infliximab or selective GMA apheresis. Due to his maintained clinical situation, a five-session initial strategy with a weekly Adacolumn apheresis and posterior maintenance with a session every 8 weeks, was decided. The 8-week interval was decided in order to establish a scheduled treatment regimen similar to infliximab and considering it could be an acceptable one. The patient has received 10 maintenance sessions through a peripheral vein in a 1 year period without complications. Mesalamine was successfully tapered after the 3rd session and stopped after the 5th session, without posterior reappearance of rectal bleeding. A new colonoscopy after the tenth maintenance session showed complete endoscopic and histological remission (Fig. 1). Maintenance on AZA treatment without new sessions of apheresis was agreed with the patients and his parents. The patient is now doing well on AZA monotherapy three months after the last apheresis session. This case shows the utility of prolonged Adacolumn treatment in chronically active UC patients. One of the most controversial aspects of GMA apheresis is its presumed slow mechanism of action, which limits its role in moderate to severe flare-ups unresponsive to other treatments needing a rapid improvement. After 14 months of remission on AZA maintenance treatment, our patient presented with
1873-9946/$ - see front matter © 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.crohns.2009.03.003
Letter to the Editor
217
Figure 1 Endoscopic view before (left) and after (right) Adacolumn treatment. The initial pattern of moderately active ulcerative colitis in the sigmoid colon has disappeared, with an endoscopically normal aspect after the maintenance treatment.
intermittent episodes of rectal bleeding but with a stable general well-being. This clinical stability although the almost continuous episodes of rectal bleeding once adjuvant treatment with 5-ASA was stopped and the endoscopic and histological confirmation of maintained colonic inflammation, made us think of Adacolumn as a possible stabilization agent useful in ameliorating symptoms and permitting a successful switch to AZA monotherapy. These two aspects have been achieved without reappearance of rectal bleeding after oral mesalamine suppression. But perhaps the most interesting and promising finding is the confirmation of GMA apheresis effect on mucosal healing after prolonged treatment. After more than 3 years of treatment with AZA (an agent with potential capacity of ameliorating mucosal inflammation), our patient showed endoscopic and histological evidence of sustained inflammation. Maintenance treatment with Adacolumn has been effective in achieving a complete endoscopic and histological remission.
References 1. Hyams JS, Davis P, Lere T, et al. Clinical outcome of ulcerative colitis in children. J Pediatr 1996;129:81–8. 2. Martín de Carpi J, Vilar P, Varea V. Infliximab as rescue therapy in severe steroid-resistant ulcerative colitis. An Pediatr (Barc) 2008;69:351–4. 3. Tung J, Loftus EV, Freese DK, et al. A population-based study of the frequency of corticosteroid resistance and dependence in pediatric patients with Crohn's disease and ulcerative colitis. Inflamm Bowel Dis 2006;12:1093–100.
4. Banerjee S, Bishop WP. Evolution of thiopurine use in pediatric inflammatory bowel disease in an academic center. J Ped Gastroenterol Nutr 2006;43:324–30. 5. Kruis W, Dignass A, Steingahen-Thiessen E, et al. Open label trial of granulocyte apheresis suggests therapeutic efficacy in chronically active-steroid refractory ulcerative colitis. World J Gastroenterology 2005;11:7001–6. 6. Yamamoto T, Umegae S, matsumoto K. Safety and clinical efficacy of granulocyte and monocyte adsorptive apheresis therapy for ulcerative colitis. World J Gastroenterology 2006;12:520–5. 7. Sands BE, Sandborn WJ, Feagan B, et al. A randomized, doubleblind, sham-controlled study of granulocyte/monocyte apheresis for active ulcerative colitis. Gastroenterology 2008;135:400–9. 8. Martín de Carpi J, Vilar P, Prieto G, et al. Safety and efficacy of granulocyte and monocyte adsorption apheresis in paediatric inflammatory bowel disease: a prospective pilot study. J Pediatr Gastroenterol Nutr 2008;46:386–91.
Javier Martín-Carpi⁎ Vicente Varea Paediatric IBD Unit, Department of Paediatric Gastroenterology, Hepatology and Nutrition, Hospital Sant Joan de Déu, Barcelona (Spain) ⁎Corresponding author. Tel.: +34 93 600 61 03. E-mail address: [email protected] (J. Martín-Carpi). 4 March 2009