Citation Acta medica Nagasakiensia. 2002, 47

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NAOSITE: Nagasaki University's Ac Title Author(s) Effectiveness Safety Leukocy Colitis Matsuo, Kengo; Murase, Kunihiko; Ka Tetsuji; Nagasaki, Yoshikazu; Koga, Takeshima, Fuminao; Omagari,

1 NAOSITE: Nagasaki University's Ac Title Author(s) Effectiveness Safety Leukocy Colitis Matsuo, Kengo; Murase, Kunihiko; Ka Tetsuji; Nagasaki, Yoshikazu; Koga, Takeshima, Fuminao; Omagari, Katsuh Kohno, Shigeru Citation Acta medica Nagasakiensia. 2002, 47 Issue Date URL Right This document is downloaded

2 Acta Med. Nagasaki 47 : Effectiveness Safety Leukocytapheresis Therapy for Ulcerative Colitis Kengo MATSUO1,3), Kunihiko MURASE2), Shinichirou KANZAKI1), Tetsuji AKIYAMA1), Yoshikazu NAGASAKI1), Nobuhiko KOGA1), Hajime ISOMOTO2), Fuminao TAKESHIMA2), Katsuhisa OMAGARI2), Yohei MIZUTA2), Ikuo MURATA2), Shigeru KOHNO2) 1) Department Internal Medicine, Koga Hospital 2) Second Department Internal Medicine, Nagasaki University School Medicine 3) Department Internal Medicine, Nagasaki Municipal Medical Center 4) Department Pharmacorapeutics, Nagasaki University Graduate School Pharmaceutical Science Leukocytapheresis () was performed in seven moderate or severe active ulcerative colitis (UC) at Koga Hospital. was considered as having been effective in all seven (excellent clinical response in five moderate clinical response in two ). The excellent or moderate clinical response continued throughout maintenance in three seven. None required discontinuation, despite appearance some side effects, including facial redness, low-grade fever, discomfort, headache hypotension during rapy. The results this study indicate that may be a safe effective intensive maintenance rapy for UC. ACTA MEDICA NAGASAKIENSIA 47: , 2002 Key Words: leukocytapheresis, ulcerative colitis. Introduction Corticosteroids are effective for inducing clinical in ulcerative colitis (UC) (1,2). However, in severely relapsed cases, corticosteroids are not always effective, even when a high dosage is administered (3,4). In addition, long-term use corticosteroids ten causes serious side effects, including hormonal derangements, peptic ulcers psychological problems (5,6). Therefore, an alternative treatment for active ulcerative colitis is desirable in order to avoid se clinical problems. Recently, efficacy leukocytapheresis () was reported for inflammatory bowel disease, using a Address Correspondence: Kunihiko Murase, M.D. Department Internal Medicine, Nagasaki University School Medicine, Sakamoto Nagasaki , Japan Tel: Fax: murasek@net.nagasaki-u.ac.jp leukocyte removal filter or centrifugal method (7-10). In our hospital, was performed in seven severe UC, in this report we present effects this rapy. Patients Methods was performed in seven UC (four males three females) between November 1995 June 1998 in Koga Hospital. Three moderate active UC four severe active UC, showed insufficient response to conventional rapy. Informed consent was obtained from all prior to inclusion in study. 1 provides clinical prile participating. Imugard (Terumo Corporation, Tokyo, Japan) was used as a leukocyte removal filter (Fig. 1 A,B). Heparin or nafamostat mesilate was used as anticoagulant 1575 ml whole blood were processed a blood flow rate 35 ml/min for each procedure for a duration 45 min. was usually performed once each week for five weeks in severely affected UC requiring intensive rapy. For maintenance rapy, was usually performed once every four to six weeks until steroids were discontinued or dose tapered, or for up to six months. was discontinued clinical course patient was followed after steroids were discontinued or tapered to a maintenance dose 5-10 mg. For evaluation, we classified response to using criteria Egashira et al. (11); excellent, moderately improved, no change, or deterioration.

3 Kengo treated 1. by Demography ulcerative colitis Matsuo et al : Leukocytapheresis Therapy Resul Age (mean ± SEM) All 51.4 ± 12.3 included in study active UC (pancolitis [n=5], left-side colitis [n=2]). Six (87.5%) seven achieved clinical in four weeks undergoing apheresis, remained in Male/Female 4/3 Duration disease (years) 5.5 ± 3.5 for an average eight months out any additional corticosteroid rapy. As intensive rapy, was effective in all seven (excellent Severity UC severe 4 [n=5] moderately = 100%). Maintenance effective [n=2]; effectiveness rate was also effective in three moderate 3, who progressed to a stage ( 2). Side effects, such as facial redness, low grade fever, pancolitis 5 discomfort headache occurred in some none required discontinuation left-side colitis 2 ( 3). Blood biochemical parameters did not change significantly between before after. No ef- Types clinical course 2. Effectiveness. one only attack type 1 relapse-remitting type 4 excellentclinical response chronic persistent type 2 moderateclinical response 2(28.6) no clinicalresponse changefor worse A. Intensive rapy n (%) Data are number B. Maintenancerapy 3. Side continuous 3(100) changefor worse effects Side effect Figure 1. Imugard after (B). leukocyte removal filter cases, but before (A) n (%) Facial redness Fever Discomfort 3(42.8) Headache 3(42.8) Hypotension 2(28.6) Abdominal pain 1 (14.3) Arthralgia 1(14.3) Nausea, vomiting 1(14.3)

Kengo Matsuo et al : Leukocytapheresis Therapy function. months, amination Case left lower abdomen. Laboratory studies moderate anemia (hemoglobin 9.8 g/dl) vated CRP (15.0 mg/dl).

4 Kengo Matsuo et al : Leukocytapheresis Therapy function. months, amination Case left lower abdomen. Laboratory studies moderate anemia (hemoglobin 9.8 g/dl) vated CRP (15.0 mg/dl). showed fects rapy A 41-year-old were male noted was on admitted April, 1998 a history bloody stools 5-6 hepatic to our melena. times/day, or hospital renal in On admission, he abdominal pain, slight fever hypoproteinemia. Prior to admission, condition not improved for about nine mia, The (Fig. despite various on admission drug rapies. mild oozing blood, diffuse diagnosis was established 2A). After admission, IVH Physical tenderness showed an elehypere- mucosal ulcerations. as severe pancolitis steroid rapy (40 mg methylprednisolone) was performed for weeks, but both were ineffective. was formed once a week for five courses. The patient came asymptomatic ratory data reverted ex after two to in courses, normal limits treatments. that he entered after (Fig. 2B). two perbe- laboafter five confirmed Discussion Ulcerative colitis inflammatory neutrophils. is characterized cells such Immune by infiltration as monocytes, lymphocytes effector mechanisms are cen- tral to disease process in inflammatory bowel disease, but it is not clear wher mucosal or systemic immunological abnormalities are primary phenomena, or are secondary to disease activity (12). Activated neutrophils, as well as lymphocytes, are thought to play an important role in pathogenesis Fig UC. The exact mechanism by which reduces severe colonic inflammation in active UC is obscure. One possible mechanism using Imugard filter may 2-A be removal leukocytes. are removed in a single pass x 109 leukocytes single procedure that in cases treatment including 70% leukocytes this filter, 3 are calculated to be removed in a (13). A few reports have suggested where pro-inflammatory IL-6, IL-8 creased, whereas About through is effective, production cytokines, such as interleukin (IL)-1, tumor necrosis factor (TNF)-a, dethis did not occur in cases where was ineffective (14,15). is reported to be beneficial in or diseases, rheumatoid arthritis, erythroderma, Crohn's disease, in which mune cycle" relieve it can halt "vicious imlocal inflammation (16-18). One report, based on flow cytometric analysis stated that among UC repeated recurrences, tended to be effective in those elevated acfig Figure 2. blood, five out ulceration. Endoscopic on diffuse treatments appearance admission mucosal tivated counts 2-B ulceration. almost sigmoid hyperemia, B. colon. A. oozing normal mucosa after - leukocyte counts, but not in those minimal active inflammation our study included tive UC, effect only in low (7). Since severe mild could not be determined. This is probably repeated recurrences progression to acuc because chronic UC,

5 Kengo Matsuo et al : Leukocytapheresis Therapy secondary activation leukocytes triggering so-called "vicious immune cycle" (9). a dramatic effect in many cases in an uncontrolled study, although clinical evaluation was performed as early as just before fourth treatment (9). Sawada et al. (19) proposed that major inclusion criterion for rapy was insufficient response to conventional drug rapy, that could be a treatment for UC that falls between drug rapies surgery. The results present study indicate that may be useful as a rapy both in acute disease during maintenance. However, no definite consensus has been reached regard to required duration rapy. Several issues remain unresolved, including wher permanent or semipermanent is required to maintain, optimum duration rapy. In our hospital, is usually performed once every four to six weeks until steroids are discontinued or ir dose tapered, or for up to six months. is discontinued clinical course patient is followed when steroids are discontinued or tapered to a maintenance dose 5-10 mg. To date, re are no reports recurrence UC in any patient during or after. However, follow-up period in our study is only 12 months at most, longer follow-up will be necessary in future studies. With respect to safety, none required discontinuation, despite appearance side effects during rapy; to be discontinued prematurely in two due to development severe malaise. may have serious side effects such as hypotension in who are in poor general condition (19,20). It would be prudent to avoid in in poor general condition, a systolic blood pressure 80 mmhg or lower, under 10 or over 75 years age, serious hepatic or renal disorders, bleeding tendencies (19). In conclusion, rapy is useful for severe attacks ulcerative colitis, including those who fail to respond to glucocorticoid rapy. References 1. Truelove SC, Witts LJ. Cortisone in ulcerative colitis. Final report on a rapeutic trial. Br Med J 2: , Truelove SC, Jewell DP. Intensive intravenous regimen for severe attacks ulcerative colitis. Lancet is , Ardizzone S, Molteni F, Imbesi V, et al. Azathioprine in steroidresistant steroid-dependent ulcerative colitis. J Clin Gastroenterol 25: , Shinmada T, Hiwatashi N, Yamazaki H, et al. Relationship between glucocorticoid receptor response to glucocorticoid rapy in ulcerative colitis. Dis Colon Rectum 40 (suppl): S54-S58, Choi PM, Targan SR. Immunomodulator rapy in inflammatory bowel disease. Dig Dis Sci 39: , Fellerman K, Ludwig D, Stahl M, et al. Steroid unresponsive attacks inflammatory bowel disease: immunomodulation by tacrolimus (FK 506). Am J Gastroenterol 93: , Sawada K, Ohnishi K, Fukui S, et al. Leukocytapheresis rapy, performed leukocyte removal filter, for inflammatory bowel disease. J Gastroenterol 30: , Ayabe T, Ashida T, Taniguchi M, et al. A pilot study centrifugal leukocyte apheresis for corticosteroid-resistant active ulcerative colitis. Inter Med 36: , Sawada K, Ohnishi K, Fukunaga K, et al. Induction for first onset severe pancolitis treated by leukocytapheresis alone. Gastroenterol Endosc 39: , Yajima T, Takaishi H, Kauai T, et al. Predictive factors response to leukocytapheresis rapy for ulcerative colitis. Ther Apher 2: , Egashira A, Sawada K, Shimoyama T. Leukocytapheresis rapy for ulcerative colitis. Clin Gastroenterol 12: , Hawthorne AB, Hawkey CJ. Immunosuppressive drugs in inflammatory bowel disease. A review ir mechanisms efficacy place in rapy. Drugs 38: , Amano K, Amano K. Filter leukapheresis for ulcerative colitis: clinical results possible mechanism. Ther Apher 2: , Sawada K, Ohnishi K, Kosaka T, et al. Leukocytapheresis leukocyte removal filter as new rapy for ulcerative colitis. Ther Apher 1: , Shimoyama T, Sawada K, Hiwatashi N, et al. Safety efficacy granulocyte monocyte adsorption apheresis in active ulcerative colitis: a multicenter study. J Clin Apheresis 16: 1-9, Fujita S. Lymphocytapheresis using leukocyte removal filter in rheumatoid arthritis; Comparison double filtration plasmapheresis. Jpn J Clin Immun 13: , Shiraishi T, Kuribayasi F, Sato T, et al. A case report resistant erythroderma treated by successful leukocytapheresis. Jpn J Apheresis 16: , Noguchi M, Hiwatashi N, Hayakawa T, et al. Leukocyte removal filter-passes lymphocytes produce large amounts interleukin-4 in immunorapy for inflammatory bowel disease: role byster suppression. Ther Apher 2: , Sawada K, Ohnishi K, Kosaka T, et al. Leukocytapheresis for ulcerative colitis. J Jpn Surg Society 98: , Nagase K, Sawada K, Ohnishi K, et al. Complications leukocytapheresis. Ther Apher 2: , 1998

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