Hiroyuki Hanai 1 , Eur J Gastroenterol Hepatol. 2008 Jul;20(7):596-600.
Tag: ulcerative colitis
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Leucocytapheresis for inflammatory bowel disease in the era of biologic therapy
The development of biologicals such as infliximab to intercept TNF-alpha validates the current perception that certain cytokines are major factors in the immunopathogenesis of inflammatory bowel disease (IBD), ulcerative colitis and Crohn’s disease. Furthermore, major sources of inflammatory cytokines include activated peripheral granulocytes and monocytes (GM), which in patients with IBD are elevated with increased survival time and are found in vast numbers within the inflamed intestinal mucosa. Hence, elevated GM should be appropriate targets of therapy in IBD. Accordingly, in recent years technologies such as the Adacolumn have been developed for selective depletion of elevated GM by extracorporeal adsorption (GMA). Published data show that GMA in patients with steroid-dependent or steroid-refractory IBD is associated with striking efficacy and tapering or discontinuation of steroids, whereas in steroid-naïve patients GMA spared patients from steroids. Likewise, GMA at appropriate intervals in patients at a high risk of clinical relapse significantly suppressed relapse, thus sparing the patients from the morbidity associated with active IBD. First ulcerative colitis episode, steroid naivety and short disease duration seem to be good predictors of response to GMA and on the basis of our experience, GMA seems to have an excellent safety profile.
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Granulocytapheresis versus methylprednisolone in patients with acute ulcerative colitis: 12-month follow up
Giampaolo Bresci 1, Giuseppe Parisi, Alessandro Mazzoni, Fabrizio Scatena, Alfonso Capria, J Gastroenterol Hepatol. 2008 Nov;23(11):1678-82.
GCAP results were superior to MP for the treatment of UC, even though no statistically significant difference was observed. Side-effects in the GCAP group were significantly lower than in the MP group. This new therapeutic approach seems able to maintain the condition of remission for a longer time after a flare. In fact, the patients who had obtained a remission after a course of CGAP showed fewer relapses during the follow up compared to the patients treated with MP.
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Selective white cell apheresis reduces relapse rates in patients with IBD at significant risk of clinical relapse
Laurence Maiden 1, Ken Takeuchi, Rosie Baur, Ingi Bjarnason, John O’Donohue, Ian Forgacs, Guy Chung-Faye, Jeremy Sanderson, Ingvar Bjarnason, Inflamm Bowel Dis. 2008 Oct;14(10):1413-8.
This study represents a new approach to the treatment of IBD by targeting a group of asymptomatic patients for treatment who are at significant risk of relapse based on high fecal calprotectin concentrations. Selective leukocytapheresis significantly reduced the number of, and increased the time to, clinical relapse in these patients without serious side effects.
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Granulocytapheresis in the treatment of patients with active ulcerative colitis
Giampaolo Bresci 1 , Expert Rev Gastroenterol Hepatol. 2008 Oct;2(5):639-43.
In recent years, considering the role of inflammatory processes and the involvement of the immune system in ulcerative colitis, granulocytapheresis, a technique for removing circulating leukocytes and preventing their migration into the intestinal mucosa, has been proposed for the treatment of acute ulcerative colitis. Initially introduced for the treatment of patients who did not respond to conventional therapy only, this new therapy may become a useful and safe method to induce clinical remission in patients with acute disease. This article will review the clinical applications and issues concerning the use of granulocytapheresis in ulcerative colitis.
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A multi center study of granulocyte and monocyte adsorption apheresis therapy for ulcerative colitis—Clinical efficacy and production of interleukin-1 receptor antagonist
Hiroaki Takeda,Yasukuni Suzuki,Yuji Takeda,Shoichi Nishise,Tadahisa Fukui,Shoichiro Fujishima,Tomohiko Orii,Sayaka Otake,Takeshi Sato,Koji Suzuki,Yukiko Nakamuara,Sumio Kawata (2008) J.Clin. Apher. 23, 3; 105-110 https://doi.org/10.1002/jca.20164
Granulocyte and monocyte adsorption apheresis (GCAP) is a useful strategy for intractable ulcerative colitis, but its mechanisms of therapy is not fully explained. Previously, depleting activated granulocytes and monocytes (GMs) and modifying product of proinflammatory cytokines had been proposed. In addition, activated GMs are releasing anti-inflammatory cytokines, interleukin-1 receptor antagonist (IL-1ra) that may contribute to the clinical efficacy of GCAP therapy. Hence, to investigate contribution of IL-1ra as well as to confirm clinical efficacy of this therapy based on clinical activity index (CAI), we performed a multicenter study. Twenty-five of 38 (65.8%) patients achieved remission state (CAI ≤ 4) and two of 38 (5.3%) revealed clinical improvement. Almost effective cases significantly decreased CAI even at 3rd session of GCAP. Plasma level of IL-1ra from outflow of the GCAP column at 30 min was significantly increased rather than inflow. Median exact elevated level of IL-1ra was 221 pg/ml and median of increasing ratio was 1.6 times. Furthermore, the responsive patients, who well released the IL-1ra at outflow more than 100 pg/ml compared with inflow, tended to show clinical effectiveness. While, the increased ratio of IL-1ra in effective cases did not differ from ineffective cases, and there were no significant relationship with improvement of CAI score. These conflict results suggest that the increase of IL-1ra at outflow is not a direct factor to the clinical improvement, but the induction of clinical improvement is accompanied by the release of IL-1ra. The IL-1ra may be involved in the multiple steps for the improvement induced by GCAP.
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W1254 The Decreased TLR2 Expression and Elevated IL-8 Production On Peripheral Leukocytes in Patients with Active Ulcerative Colitis: the Modulation of the Leukocyte Sensitivity to Pgn By Granulocyte and Monocyte Apheresis
Suzuki, Yasuo; Yamada, Akihiro; Aoki, Hiroshi; Osamura, Aisaku; Nakamura, Kentaro; Yoshimatsu, Yasushi; Hosoe, Nobuo; Takada, Nobuo; Tsuda, Yukio; Shirai, Koji (2008). W1254 The Decreased TLR2 Expression and Elevated IL-8 Production On Peripheral Leukocytes in Patients with Active Ulcerative Colitis: the Modulation of the Leukocyte Sensitivity to Pgn By Granulocyte and Monocyte Apheresis. Gastroenterology, 134(4), A-665–. doi:10.1016/S0016-5085(08)63105-4
BACKGROUND & AIM: Mucosal lesions of active ulcerative colitis (UC) are characterized by acute inflammatory cell (polymorphonuclear granulocyte, PMN) infiltrate and ulceration. Granulocyte and monocyte apheresis (GMA) using a column device, Adacolumn, selectively adsorbs and removes leukocytes from the peripheral blood, and has been reported to be effective in patients with active UC. The aim of this study was to investigate the expression of toll like receptor 2 (TLR2) on PMNs and monocytes in patients with active UC as compared to the level in healthy subjects and see the impact of GMA on TLR2. METHODS: Fortyeight patients with active UC, Clinical Activity Index (CAI, Lichtiger index) ≥5, were included in this study. Patients received several GMA sessions (maximum 10 sessions), and CAI ≤ 3 was considered remission. Blood samples were obtained from patients at each GMA session and also from healthy subjects (n=14), after obtaining informed consent. The expression of TLR2 was investigated by flowcytometry. In several samples, IL-8 production by cultured blood upon stimulation with peptidoglycan (PGN, a ligand for TLR2) was measured (n=21). RESULTS: An average of CAI at the entry was 11.0 (n=48), and remission rate by GMA was 56.3%(27/48). At the baseline, the expression of TLR2 on PMN of patients with active UC was significantly less than the level in healthy subjects (p<0.001). Further, the improvement in CAI was accompanied by a trend towards normalization of TLR2 on PMN (up-regulation, p<0.05) together with a significant fall (P<0.01) of plasma IL-8 level. However, as for the patients with still active symptoms (CAI>5) in course of GMA therapy, the decreased TLR2 on PMN and the elevated release of IL-8 from PGN-stimulated leukocytes were kept on. By exposing blood to the column carriers In Vitro, TLR2 expression on the cell surface of PMN was decreased, but increased within the cellular of PMN. Similarly, in the blood on column outflow of GMA, the TLR2 expression on PMN and IL-8 production by PGN-stimulation were significantly decreased (TLR2:P<0.001, IL-8:P<0.001), indicating that leukocyte sensitivity to PGN is weakened by GMA column. CONCLUSION: The expression of TLR2 on PMN in patients with active UC is significantly decreased compared with remission status or healthy subjects. In connection with the decreased TLR2 expression, the IL-8 production by PGN-stimulated leukocytes is elevated in patients with active UC. These changes seem to reflect PMN activation based on UC disease activity. GMA or exposure of blood to GMA carriers is associated with down-modulation of the TLR2 expression on PMN and also leukocyte sensitivity to PGN
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In patients with ulcerative colitis, adsorptive depletion of granulocytes and monocytes impacts mucosal level of neutrophils and clinically is most effective in steroid naïve patients
T Tanaka 1, H Okanobu, S Yoshimi, E Murakami, A Kogame, H Imagawa, Y Numata, Y Kuga, T Moriya, T Ohya, G Kajiyama
Background: The aetiology of ulcerative colitis is inadequately understood, and drug therapy has been empirical rather than based on sound understanding of disease aetiology. This has been a major factor for refractoriness and adverse drug effects as additional complications. However, ulcerative colitis by its very nature is exacerbated and perpetuated by inflammatory cytokines, which are released by peripheral granulocytes and monocytes as well. Additionally, active ulcerative colitis is often associated with elevated peripheral granulocytes and monocytes with activation behaviour and are found in vast numbers within the colonic mucosa. Hence, from the clinicopathologic viewpoint, granulocytes and monocytes are appropriate targets for therapy in ulcerative colitis. Based on this thinking, an Adacolumn has been developed for depleting excess granulocytes and monocytes by adsorption. Methods: By colonoscopy, biopsy and histology, we investigated the impact of granulocyte and monocyte adsorption (GMA) on the mucosal level of granulocytes and monocytes in patients with active ulcerative colitis. Forty-five patients (26 steroid naïve and 19 steroid-dependent), mean age 44.7 yr, were included. Twenty patients had total colitis and 25 had left-sided colitis. Each patient was given up to 11 GMA sessions over 12 weeks. No patient received additional medications within 4 weeks (steroid) to 8 weeks (other immunosuppressants) prior to entry or during the GMA course. Colonoscopy together with biopsy was done at entry and within 2 weeks after the last GMA session. Results: At entry, the mean clinical activity index was 12.6; range 10-16. A total of 400 colonic biopsies were examined, which revealed massive infiltration of the colonic mucosa by granulocytes, and GMA was associated with striking reduction of granulocytes in the mucosa. At week 12, 33 of 45 patients (73.3%, P<0.01) had achieved clinical remission (the mean clinical activity index <or= 4). Colonoscopy revealed that most non-responders had deep colonic ulcers and extensive loss of the mucosal tissue. The response rate in steroid naïve subgroup was 22 of 26 patients (84.6%, P<0.005) and in steroid-dependent was 11 of 19 (57.9%, P<0.05 and P=0.02154 for steroid naïve vs. steroid-dependent). Patients who achieved remission could continue with their salicylates. On average, remission was sustained for 7.8 months in all 33 responders. Conclusions: This is the first report showing a striking difference in clinical response to GMA between steroid naïve and steroid-dependent patients. Further, patients with deep colonic ulcers together with extensive loss of the mucosal tissue are not like to respond to GMA.
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Regulatory T cells in patients with inflammatory bowel diseases treated with adacolumn granulocytapheresis
Emilio Cuadrado 1, Marta Alonso, Maria-Dolores de Juan, Pilar Echaniz, Juan-Ignacio Arenas, World J Gastroenterol. 2008 Mar 14;14(10):1521-7.
The clinical efficacy of GMA on IBD and related extra intestinal manifestations was associated with an expansion of circulating CD4+ CD25+ Tregs and higher expression of FoxP3 in CD4+ T cells. Accordingly, an elevated CD4+ CD25+ FoxP3 may be a valuable index of remission in patients with IBD and other chronic relapsing-remitting inflammatory conditions during treatment with GMA.
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Reduction of Dendritic Cells by Granulocyte and Monocyte Adsorption Apheresis in Patients with Ulcerative Colitis
The influence of the granulocyte/monocyte apheresis (GMCAP) on cell populations participating in mechanisms of tolerance, e.g. dendritic cells (DCs), is still not very clear. In a first step, we aimed to investigate changes in the DC population of patients suffering from ulcerative colitis (UC) (n = 13) compared to healthy subjects (n = 9). In a second step, we studied the changes in peripheral DCs in a small group of patients with active UC before and after Adacolumn apheresis (n = 7). For this purpose, plasmacytoid and myeloid DCs and their maturation markers CD40, CD80, and CD86 were measured using four-color flow cytometry in the peripheral blood. After apheresis, and in acute flare-ups, we identified a significantly lower number of lymphocytes, plasmacytoid, and myeloid DCs. In conclusion, the additional removal of peripheral DCs by GMCAP, which otherwise would contribute to the inflammatory process in the gut, may lead to a higher tolerogeneic status towards luminal antigens.
dendritic cells / gma / leukocyte / MOA / plasmacytoid / T-lymphocytes / tolerogenic / 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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