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Current Status on the Clinical Usefulness of Apheresis in Patients with Inflammatory Bowel Disease

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Current Status on the Clinical Usefulness of Apheresis in Patients with Inflammatory Bowel Disease 100 ANNALS OF GASTROENTEROLOGYJ.K. TRIANTAFILLIDIS, 2003, 16(2):100-104 et al Current view Current status on the clinical usefulness of apheresis in patients with inflammatory bowel disease J.K. Triantafillidis, P. Cherakakis 2-10 SUMMARY USA and Europe. This kind of treatment, termed apheresis, has been In this review the current aspects concerning the applica- investigated in several diseases such as rheumatoid ar- tion of leukocytapheresis in patients with inflammatory thritis, ophthalmic Graves disease, Behcets disease, bowel disease are briefly discussed. Leukocytapheresis has pemphigus vulgaris, systemic lupus erythematosus, renal already been applied in patients suffering mainly from dis- disorders, multiple sclerosis, acute leukemia, and inflam- eases affecting the immunological balance. The procedure matory bowel disease.11,12 It seems, however, that today a has recently been tried in patients with ulcerative colitis new era has arrived concerning the application of leuko- and Crohns disease as well, with promising results. Leu- cytapheresis in inflammatory bowel disease, because of kocytapheresis is gaining in interest as a therapeutic pro- the tremendous progress achieved in the field of patho- cedure of the near future, because it removes - in a short physiology of IBD and the understanding of the role of time- a number of immunologically active cells, which are immunocytes and their products in the initiation and well known to actively participate in the inflammatory cas- perpetuation of inflammation in the intestinal wall. cade, leading to tissue damage. However, further studies are needed in order to better clarify the role of leukocyta- Technique pheresis in the maintenance treatment of patients with in- Two methods of removal of leukocytes from the cir- flammatory bowel disease, either alone, or in combination culation have been reported. The first uses extracorpo- with drugs of known efficacy in IBD. real circulation (on-line system) and the second leuko- Key words: Apheresis, Leucocytapheresis, Inflammatory cyte elimination filters for blood transfusion to leuko- bowel disease, Ulcerative colitis, Crohns disease cytapheresis without the use of extracorporeal circula- tion (off-line leukocytapheresis system). The latter meth- od was applied by Endo et al4 who collected each time INTRODUCTION 400 ml of peripheral blood and re-infused it through a leukocyte elimination filter once weekly for 5 weeks. The Efforts to remove plasma and/or various cells from extracorporeal device that has been developed for selec- the circulation of patients with inflammatory bowel dis- ease, can be recorded back to 1989.1 During the last 10 tive adsorption of granulocytes, and monocytes/ mac- years efforts aiming to introduce this kind of treatment rophages from peripheral blood of patients with ulcer- ative colitis contains a column, which is filled with carri- in patients with inflammatory bowel disease were suc- ers (G-1 beads) of 2mm diameter, made from cellulose cessful only in Japan, whilst little work has been done in diacetate.10 According to Sawada et al3 whole blood is pumped out from 1 cubital vein at a 50 ml/min flow rate Department of Gastroenterology, Saint Panteleimon General State with a Plasauto 1000 apheresis unit. (Asahi Medical Co., Hospital, Nikea, Greece Ltd, Tokyo, Japan). Mafamostat mesilate anticoagulant Author for correspondence: is added to it. Then the anticoagulant whole blood is John K. Triantafyllidis, MD, 8 Kerasountos str., 124 61 Haidari, passed through a leukocyte removal filter (Cellsorba, Athens, Greece, Tel.: 210-5819481, Fax: 210-5810970, Asahi Medical Co. Ltd., Tokyo, Japan), and the treated e-mail: [email protected] blood returns to the patient. Three thousand milliliters Current status on the clinical usefulness of apheresis in patients with inflammatory bowel disease 101 of whole blood is processed during each session. Thera- cytokines (Tumor Necrosis Factor-alpha, interleukin- py is usually performed once weekly for 5 weeks as acute 1beta, interleukin-6 and interleukin-8) produced by leu- treatment and then every 2 to 6 weeks as on-going main- kocytes, a reduction in neutrophil chemotaxis, and down- tenance therapy. regulation of adhesion to interleukin-1beta-activated endothelial cells. They also found that after apheresis, The removal of leukocyte components has also been the number of CD10-negative premature granulocytes achieved by the centrifugal method, using fiber technol- increased, indicating increased turnover of these cells in ogy or column technology, leukocyte components can the circulation. They suggest that selective granulocyte be removed simply. The latter methods could be regard- and monocyte adsorption is associated with modified ed as more effective compared to the centrifugal meth- peripheral blood leukocyte function favorable to patients od in removing numbers of cells. However, it must be with ulcerative colitis. Noguchi et al16 found that the stressed that each type of leukocytapheresis removes dif- amount of Interleukin-4 production in peripheral blood ferent kind of cells. It is obvious that if, theoretically, we mononuclear cells was increased after leukocytaphere- know what kinds of cells must be removed, then we can sis. Leukocytapheresis filter-passed lymphocytes showed select the best method for removing the responsible cells. increased CD4+DR- and decreased CD4+DR+ cells in Sawada et al6 proposed that the centrifugal method comparison to peripheral blood mononuclear cells. must be called lymphocytapheresis, because it selectively Therefore, lymphocytes passed through leukocytaphere- removes 40% of neutrophils and more than 60% of lym- sis filter could produce IL-4, and may lead to bystander phocytes. The cellulose beads in a G-1 granulocyte re- suppression. However, it seems that the leucocytes re- moval column method removes only granulocytes and moval filter (cellsorba) also removes and platelets. It has monocytes but no lymphocytes, and therefore could be been shown that the platelets activation in the peripheral called granulocytapheresis. Finally the procedure in blood of ulcerative colitis patients stimulate the leuco- which the Cellsorba leukocyte removal filter is used, must cytes to secrete active oxygen. Thus removal of activated be called leukocytapheresis, because 99% of both gran- platelets may result in inhibiting production of active ulocytes and monocytes and about 70% of lymphocytes oxygen and diminution of symptoms of inflammation.18 are removed. Although reperfusion injury has not been described Recently, a non-woven polyester fiber filter has been as a major contributing factor for tissue damage in IBD, used. Using this technique, Kawamura et al,13 were able it has recently been found that leukofiltration may reduce to remove 30-70% of leukocytes and 30-68% of their reperfusion injury and rectal bleeding in inflammatory subsets. bowel disease.19 Pathophysiology Finally, modulation of leukocyte enzyme activities is one of the main effects of leukocytapheresis therapy and The effective mechanism of cytapheresis for inflam- alteration of granulocytes, monocytes and lymphocytes matory bowel disease is controversial. However, the re- in patients with rheumatoid arthritis.20 In this study treat- moval of leukocytes, including granulocytes, lymphocytes ment resulted in removal of 96% of granulocytes, 98% and monocytes may play a crucial role in restoring im- of monocytes and 61% of lymphocytes. The elastase balance between proinflammatory and inflammatory cy- activity of granulocytes was increased 4 weeks after the tokine levels.14 It seems that the suppressive effect of leu- last session only in responders. However, dipeptidylpep- kocytapheresis on patients with inflammatory bowel dis- tidase IV activity of lymphocytes was low at 4 weeks af- ease is thought to depend upon the removal of activated ter the last session in responders. inflammation-related cells that transfer inflammatory sig- nals.15 It may be that those cells removed are bound be- Despite the fact that the exact mechanism by which cause of cell stimulation caused by microorganisms or leukocytapheresis exerts its beneficial effect in patients foreign bodies. It is possible that following this proce- with IBD remains unknown, it seems that immunomo- dure, the imbalance between pro- and inflammatory cy- dulation induced by the apheresis of the responsible tokines returns to normal. Indeed, Kawamura et al13 de- inflammatory cells is the main mode of action. scribed that cytokine activity in the filter and peripheral blood was normalized after the application of apheresis. Clinical results After the application of cytapheresis, Kashiwagi et a) ulcerative colitis al10 found a significant suppression of proinflammatory So far, seven studies2,7-9,13,20,21 relating to patients with 102 J.K. TRIANTAFILLIDIS, et al steroid-dependent or resistant ulcerative colitis were low-up period of up to 12 months) (Table 1). found to contain data available for evaluation. As shown in table 1, a total number of 127 patients were treated. b) Crohns disease Remission was achieved in 110 (87%) (after application Quite a few patients with Crohns disease have been of one to five sessions) a proportion which could be char- treated with leukocytapheresis, compared with ulcerative acterized as quite significant. However, the relapse rate colitis13,22-24 (Table 2). However, the remission rate was following cessation of treatment was relatively high (42% similar to that of ulcerative colitis (77%), while
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