T Hibi 1, Y Sameshima, Y Sekiguchi, Y Hisatome, F Maruyama, K Moriwaki, C Shima, A R Saniabadi, T Matsumoto
Tag: Safety
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Treating ulcerative colitis by Adacolumn therapeutic leucocytapheresis: clinical efficacy and safety based on surveillance of 656 patients in 53 centres in Japan
Background/aim: The Adacolumn selectively depletes granulocytes and monocytes/macrophages, which are thought to be part of the immunopathogenesis of ulcerative colitis. This work aims at evaluating the safety and clinical efficacy of the Adacolumn in patients with ulcerative colitis in large population-based data sets. Methods: The Adacolumn post marketing surveillance in Japan was undertaken on 697 patients in 53 medical institutions over 7 years from 29 October 1999 to 28 October 2006. Clinical efficacy and safety data were provided by patients‘ physicians in the participating institutes. Results: Safety was evaluated in all the 697 patients and efficacy in 656 patients. At entry, 92% of the patients were on salicylates, 74% on prednisolone and only 9% on immunomodulators. Approximately 40% of patients had severe ulcerative colitis and over 70% had ulcerative colitis that was refractory to conventional medications. There was no serious adverse events; mild to moderate adverse events were seen in 7.7% of the patients. The overall response (remission or significantly improved) was 77.3%; the remission rate based on clinical activity index was 71.1%, while 17.1% remained unchanged and 5.6% worsened. Patients were subgrouped into severe, moderate and mild ulcerative colitis based on clinical activity index (n=578), the response rates were 63.2%, 65.7% and 80.4%, respectively (P<0.001). Endoscopic assessment of efficacy showed very significant mucosal healing, Matts‘ endoscopic index improved from 3.2+/-0.04 to 2.1+/-0.7 (n=219, P<0.001); reduction in prednisolone dose (P<0.0001); leucocyte count (n=358, P<0.0001) and C-reactive protein (n=314, P<0.0001). Patients who received > or =6 Adacolumn sessions (n=319) did better than patients who received < or =5 sessions (n=188, P=0.004) and multivariate logistic regression analysis revealed that baseline granulocyte count was the strongest predictor of clinical response to Adacolumn (P=0.0191, odds ratio 1.151). Conclusion: This post marketing surveillance provides the largest ever efficacy and safety data on the Adacolumn therapeutic leucocytapheresis in patients with ulcerative colitis. As a non-pharmacologic treatment for patients with active ulcerative colitis most of whom were refractory to conventional drug therapy, the observed efficacy was very significant. Baseline granulocyte count was convincingly an independent predictor of clinical response.
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Ulcerative colitis associated with Vogt-Koyanagi-Harada disease (in Spanish)
Gema de la Poza Gomez,, Antonio Lopez-San Román, Jaime Masjuan Vallejo,Gemma Arranz de la Mata, Teresa Angueira Lapeña, Daniel Boixeda de Miquel, Gastroenterol Hepatol. 2009;32(5):343–345
We report the case of a female patient who was diagnosed with Vogt-Koyanagi-Harada disease at the age of 14 years and who developed myelopathy, resulting in paraparesis. A cerebral magnetic resonance imaging scan revealed the presence of T2-hyperintense lesions in the periventricular white matter, suggesting demyelinization. Twelve years later, ulcerative colitis was diagnosed during workup for abdominal pain associated with bloody diarrhea. The association of these two diseases has previously been reported anecdotically .The management of the ulcerative colitis was complicated by the patient’s neurological manifestations. Even though recent reports support the use of anti-TNF drugs in the management of Vogt-Koyanagi-Harada-associated uveitis, because of the lack of experience in patients with neurological symptoms, and the presence of apparently demyelinating lesions in our patient, we did not use these drugs in this case.
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Leukocytapheresis for the treatment of IBD
Fridrik Thor Sigurbjörnsson & Ingvar Bjarnason, Nature Clinical Practice Gastroenterology & Hepatology volume 5, pages509–516 (2008)
Leukocytapheresis is a controversial nonpharmacologic treatment for IBD, in which white blood cells–the effector cells of the inflammatory process–are mechanically removed from the circulation. Current controversy centers on the uncontrolled nature of the leukocytapheresis trials performed and their use of different outcome measures in patient groups that have very variable disease activity and severity. Nonetheless, the efficacy data obtained are generally quite consistent: an excellent response (remission >80%) has been achieved in corticosteroid-naïve patients with ulcerative colitis and an average remission rate of more than 50% has been achieved in patients who have steroid-dependent or refractory ulcerative colitis. Interestingly, the largest randomized, double-blind, sham-controlled study of granulocyte-monocyte apheresis in patients with moderate to severe ulcerative colitis failed to demonstrate efficacy for the induction of clinical remission or response. Regardless, leukocytapheresis seems to be remarkably safe. The precise positioning of leukocytapheresis in the treatment of ulcerative colitis is uncertain at present and will vary according to geography and patient preference for a safe, nonpharmacologic treatment. Further efficacy studies are required to assess what the optimal number and frequency of treatments is, in addition to the need for head-to-head comparisons with established drugs.
Enthusiasm for the use of leukocytapheresis in the treatment of patients with IBD (mainly ulcerative colitis) is fueled by the lack of serious adverse effects and tempered by the lack of conventional placebo-controlled data or head-to-head comparisons with potential competitors
Leukocytapheresis induces clinical remission in more than 80% of corticosteroid-naïve patients who have ulcerative colitis
Average remission rates are in excess of 50% in patients with moderate or severe ulcerative colitis and in patients with corticosteroid-dependent or corticosteroid-resistant ulcerative colitis
Data in Crohn’s disease are sparse and further studies are required
Leukocyte apheresis clearly has potential use in patients with ulcerative colitis, but to decide its precise positioning in treatment algorithms will require targeted studies
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Leukocytapheresis for the treatment of active pouchitis: a pilot study
Yasumi Araki 1, Keiichi Mitsuyama, Takaaki Nagae, Yuji Tou, Motonori Nakagawa, Yasue Iwatani, Masakazu Harada, Hiroyuki Ozasa, Michio Sata, Toshihiro Noake, J Gastroenterol. 2008;43(7):571-5.
Background: Pouchitis is a major long-term complication of ileal pouch-anal anastomosis for ulcerative colitis. The aim of this study is to investigate the efficacy of leukocytapheresis for the treatment of active pouchitis. Methods: Eight patients with active pouchitis received leukocytapheresis weekly for 5 weeks in an open-label treatment protocol together with baseline therapy. Results: Patients showed significant improvement in their pouchitis disease activity index scores, from 9.5 (range, 8-10) to 4.0 (range, 2-8) (P < 0.05). Six (75%) of the 8 treated patients achieved remission. No adverse events were observed. Conclusions: Leukocytapheresis therapy could be a new therapeutic strategy for patients with pouchitis after ileal pouch-anal anastomosis for ulcerative colitis. These encouraging results lead us to propose a randomized controlled trial.
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Leukocytapheresis in a girl with severe ulcerative colitis refractory to corticosteroids, infliximab, and cyclosporine A
Katalin Dittrich, Markus Richter, Wolfgang Rascher, Henrik Köhler Inflamm Bowel Dis 2008 Oct;14(10):1466-7. doi: 10.1002/ibd.20464.
Although medical therapy remains the first-line treatment for UC, colectomy may be required for patients with severe medically refractory disease. Leukocytapheresis (LCAP) has been reported as a new line of therapy in
patients with UC. Only 2 pediatric case series, not including patients on immunosuppressive therapy or biologicals, treated with granulocytapheresis have been reported. The patient reported by us is the youngest to the best of our knowledge in which this LCAP technique was used . She had severe colitis refractory to corticosteroids, infliximab and yclosporine A. We were able to avoid colectomy and the procedure was well tolerated.
Clinical remission / Corticosteroids / cyclosporine A / gma / Infliximab / intensive / Leukocytapheresis / pediatric / Safety / severe / steroid / ulcerative colitis /
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Comparison of the efficacy of granulocyte and monocyte/macrophage adsorptive apheresis and leukocytapheresis in active ulcerative colitis patients: a prospective randomized study
Yasuhisa Sakata 1, Ryuichi Iwakiri, Sadahiro Amemori, Kanako Yamaguchi, Takehiro Fujise, Hibiki Otani, Ryo Shimoda, Seiji Tsunada, Hiroyuki Sakata, Yuji Ikeda, Takashi Ando, Yuji Nakafusa, Kazuma Fujimoto
Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease associated with recurring inflammation of the colorectal mucosa. Recently, cytapheresis has emerged as a new treatment for patients with UC. Removal methods are mainly performed with beads [granulocyte and monocyte/macrophage adsorptive apheresis (GMCAP)] or filters [leukocytapheresis (LCAP)]. Both treatments have been reported to be effective for active UC. There have been few trials, however, comparing the efficacy of GMCAP and LCAP. In this study, we prospectively evaluated the efficacy of LCAP and GMCAP for the treatment of active UC. Methods: Thirty-nine patients [18 male, 21 female; mean age 38.7 years; duration of disease 6 years; clinical activity index (CAI) >6 points] with moderate-to-severe active UC were randomly assigned to the LCAP (n=21) or GMCAP group (n=17). Adacolumn (cellulose acetate beads; Japan Immunoresearch Laboratories, Takasaki, Japan) for GMCAP and Cellsorba EX (polyethylene phthalate fibers; Asahi Medical Co. Ltd, Tokyo, Japan) for LCAP were used for leukocyte removal. Patients received two sessions of cytapheresis in the first week, followed by four weekly administrations. Steroid doses were tapered if patients achieved clinical improvement. When the CAI score had decreased by 5 points or more, the patient was considered to have improved. Results: Thirteen patients in the GMCAP group and 14 in the LCAP group achieved clinical improvement. No significant difference was found in clinical response and clinical course between LCAP and GMCAP. Hemoglobin levels were significantly decreased immediately after one session of cytapheresis in the LCAP group. No severe adverse effects were observed in any of the patients. No significant differences were observed in any clinical parameters predictive of a response to either LCAP or GMCAP. But in all patients receiving cytapheresis, a high CAI score was a significant risk factor for treatment failure. All of the cytapheresis nonresponders had CAI scores >or=16. Conclusion: Both GMCAP and LCAP were effective treatments for active UC. Patients with severe UC and a high CAI score were, however, refractory to treatment.
Clinical trial / COMPARISON / efficacy / gma / hyporesponsiveness / Leukocytapheresis / MOA / Safety / T-lymphocytes / ulcerative colitis /
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Leucocyte apheresis in the treatment of paediatric ulcerative colitis
Tarja Ruuska, Marja-Leena Lähdeaho, Yelda Sutas, Merja Ashorn, Juhani Grönlund Scand J Gastroenterol 2007 Nov; 42(11):1390-1. doi: 10.1080/00365520701231116.
Recent studies show corticosteroid dependency in 45% of paediatric ulcerative colitis (UC) patients despite using other medicaments, including immunomodulators This patient group is problematic as corticosteroids have numerous side effects when used long term. New biological approaches have proved effective in the treatment of inflammatory bowel disease (IBD), but as the side effects can be severe, especially in young patients, their use is restricted in UC.
In UC, circulating activated granulocytes and macrophages/monocytes are increased and can infiltrate the bowel and cause tissue injury by producing inflammatory cytokines, being thus involved in the initiation and perpetuation of an inflammatory disorder. Periodic removal of activated granulocytes and monocytes/ macrophages with selective leucocyte apheresis (Adacolumn; JIMRO, Japan) is expected to reduce leucocyte-dependent tissue injury. Preliminary reports show promising results in the treatment of IBD, in children with corticosteroid-dependent or -resistant UC.
We design a pilot study where 11 children (7 corticosteroid-dependent, 3 corticosteroid-resistant and 1 refusing corticosteroids) were treated with apheresis and their data analysed. Treatment was given once a week, a total of 5-9 sessions. 8 out of the remaining 11 patients responded well to the treatment. Corticosteroids could be tapered-off either totally or to minimal doses in all cases. Treatment was well tolerated.
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The logics of leukocytapheresis as a natural biological therapy for inflammatory bowel disease
Takanori Kanai 1, Toshifumi Hibi, Mamoru Watanabe, Expert Opin Biol Ther. 2006 May;6(5):453-66.
Ulcerative colitis (UC) and Crohn’s disease (CD) are debilitating idiopathic inflammatory bowel diseases (IBDs) with symptoms that impair ability to function and quality of life. The aetiology of IBD is inadequately understood and, therefore, drug therapy has been empirical instead of based on sound understanding of the disease mechanisms. This has been a major factor for poor drug efficacy and treatment-related side effects that often add to disease complications. The development of biologicals, notably infliximab, to block TNF-alpha reflects some progress, but there is major concern about their side effects and lack of long-term safety and efficacy profiles. However, IBD by its very nature is exacerbated and perpetuated by inflammatory cytokines, including TNF-alpha, IL-6 and IL-12, for which activated peripheral blood lymphocytes, monocytes/macrophages and granulocytes are major sources. Hence, activated leukocytes should be appropriate targets of therapy. At present, three strategies are available for removing excess and activated leukocytes by leukocytapheresis: centrifugation, Adacolumn and Cellsorba. Centrifugation can deplete lymphocytes or total leukocytes, whereas Adacolumn selectively adsorbs granulocytes and monocytes together with a smaller fraction of lymphocytes (FcgammaR- and complement receptor-bearing leukocytes), and Cellsorba non-selectively removes all three major leukocyte populations. Efficacy has ranged from ’none‘ to an impressive 93% together with excellent safety profiles and downmodulation of inflammation factors. Furthermore, leukocytapheresis has shown strong drug-sparing effects and reduced the number of patients requiring colectomy or exposure to unsafe immunosuppressants, such as cyclosporin A. Leukocytapheresis removes from the body cells that contribute to IBD and, therefore, unlike drugs, it is not expected to induce dependency or refractoriness.
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Selective leukocyte apheresis for the treatment of inflammatory bowel disease
Maria T Abreu 1, Scott Plevy, Bruce E Sands, Robert Weinstein, J Clin Gastroenterol. Nov-Dec 2007;41(10):874-88.
The etiology of inflammatory bowel disease (IBD) is not completely understood, thus current therapies have been empirical and directed at treating symptoms rather than addressing the cause. In IBD, the overexpression of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, leads to a persistent intestinal inflammatory response that damages the intestinal mucosa. Recent advances in pharmacologic therapies that target specific cytokines, chemokines, and adhesion molecules have proved successful in alleviating symptoms for some patients. There are 2 selective adsorption apheresis devices that remove leukocytes from whole blood, which are currently available in Japan and Europe-the Cellsorba leukocytapheresis column and the Adacolumn adsorptive extracorporeal granulocyte/monocyte apheresis device. The purported mechanisms of action of these devices have been extensively reviewed and are believed to exert an immunomodulatory and/or anti-inflammatory effect on patients with systemic inflammatory disease.The clinical trials presented here indicate that selective leukocyte apheresis effectively removes activated granulocytes and monocytes/macrophages from peripheral blood while maintaining an excellent safety profile. Despite these findings, large controlled trials of selective leukocyte apheresis in the treatment of IBD are needed to determine the true efficacy of this approach.
chemokines / Crohn's disease / cytokines / digestive / gma / IBD / immunomodulation / Leukocytapheresis / Safety / ulcerative colitis /
Scientific corner
Efficacy of granulocyte and monocyte adsorption apheresis for three cases of refractory pyoderma gangrenosum
Pyoderma gangrenosum presents with chronic skin ulcers and is histologically characterized by neutrophil infiltration throughout the dermis. It is also occasionally associated with ulcerative colitis, a type of inflammatory bowel disease, against which granulocyte and monocyte adsorption apheresis (GCAP) has recently shown remarkable efficacy. We performed GCAP on three refractory cases of pyoderma gangrenosum with painful bilateral leg ulcers and hereby report the results obtained. Patient 1 was a 43-year-old woman with a four-year history of recurrent painful skin ulcers treated with prednisolone and cyclosporine. Patient 2 was a 29-year-old woman who had been suffering from pyoderma gangrenosum with severe pain for two weeks, associated with an 11-year history of ulcerative colitis treated with prednisolone and salazosulfapyridine. Patient 3 was a 63-year-old man with a three-year history of recurrent ulcers with pain, suffering from rheumatoid arthritis treated with prednisolone and cyclophosphamide. The sizes of the lesions were reduced in all three patients following a weekly GCAP treatment for 10 or 11 consecutive weeks, and the re-epithelialization of ulcers were additionally observed in two patients. The pain disappeared dramatically in all three patients following two sessions of GCAP therapy. No adverse effects were observed for up to at least eight months after treatment. We therefore considered GCAP as one effective alternative to currently existing therapies, with regards to refractory cases of pyoderma gangrenosum.
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