Leukocyte removal therapy for ulcerative colitis does not affect postoperative complications

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  • J Gastroenterol 2006; 41:848854DOI 10.1007/s00535-006-1875-1

    Leukocyte removal therapy for ulcerative colitis does not affectpostoperative complications

    Hiroki Ikeuchi1, Takehira Yamamura1, Masato Kusunoki2, Hiroki Nakano1, Motoi Uchino1,Mitsuhiro Nakamura1, Masafumi Noda1, Hidenori Yanagi1, and Takayuki Matsumoto3

    1 Second Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan2 Second Department of Surgery, Mie University School of Medicine, Tsu, Japan3 Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan

    Introduction

    The etiology of ulcerative colitis (UC) remains un-known, and a fundamental therapy has not been estab-lished. The disease is generally treated medically withdrugs such as mesalazine and corticosteroids, and occa-sionally with immunosuppressive agents. However, theside effects of drug therapy can present problems, par-ticularly with long-term use. Thus, alternative therapiesare considered to be necessary and desirable.

    Leukocyte removal therapy (LRT) has been reportedto be effective for various disorders related to autoim-mune responses, especially UC.1,2 Further, apheresis,which removes plasma components, is considered to bean effective nondrug strategy for the management ofimmune disorders. The Japan Ministry of Health hasapproved leukocyte apheresis (LCAP) with a leukocyteremoval filter (Cellsorba; Asahi Medical, Tokyo,Japan), granulocytemonocyte adsorptive apheresis(GCAP) using an Adacolumn (Japan ImmunoresearchLaboratories, Takasaki Japan), and centrifugal leuko-cyte apheresis using a centrifugal cell separator (Com-ponent Collection System; Haemonetics, Braintree,MA, USA) for treatment of active UC. Recently, LRThas been shown by our hospital and others to reduce theneed for surgery in patients with steroid-resistant dis-ease, though an operation may eventually be requiredfor those who are not helped by that treatment.3,4

    The aim of this study was to compare the postopera-tive complication rates between patients who receivedand those that did not receive preoperative LRT. This isthe first known report of the relationship between pre-operative LRT and postoperative complications in UCpatients. We considered that if LRT did not have aneffect on postoperative complications, then physicianswould be able to treat acute UC patients confidentlywith the procedure.

    Received: April 6, 2006 / Accepted: July 23, 2006Reprint requests to: H. Ikeuchi

    Background. We investigated the incidence of postop-erative complications in patients treated with or withoutpreoperative leukocyte removal therapy (LRT). Meth-ods. The case notes of 387 patients with ulcerative coli-tis (UC) who underwent surgical intervention wereretrospectively reviewed. One hundred nine patientswere treated with LRT within 8 weeks before surgery(LRT group), and 278 had not received LRT since atleast 8 weeks before surgery (without LRT group). Wereviewed the postoperative complications according totype of initial operation. Results. Of the patients whounderwent an ileal J-pouch anal anastomosis (IPAA)without an ileostomy, 3 (6.5%) in the LRT group devel-oped pouch-related complications (PRC), while 11(7.5%) in the without LRT group developed PRC. Theoverall postoperative complication rates were 28.3% inthe LRT group and 21.8% in the without LRT group.For patients who underwent an IPAA with an ileo-stomy, the overall rates of postoperative complicationswere 39.1% in the LRT group and 31.8% in the withoutLRT group. Among those undergoing a total colec-tomy, 33.3% in the LRT group and 18.2% in the with-out LRT group had postoperative complications. Nostatistically significant differences were demonstratedbetween the two groups with respect to postoperativecomplications. Conclusions. Our results suggest thatpreoperative LRT does not influence the rate of postop-erative complications in UC patients.

    Key words: leukocyte removal therapy, ulcerative coli-tis, complications

    Editorial on page 923

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  • H. Ikeuchi et al.: Leukocyte removal therapy and postoperative complications 849

    Patients and methods

    Patients

    We reviewed the records of 387 patients who underwenta restorative proctocolectomy with an ileal J-pouch analanastomosis (IPAA) for UC at our institution betweenJanuary 2000 and December 2004. Each satisfied thediagnostic criteria for UC established by the ExpertCommittee on Inflammatory Bowel Disease appointedby the Japan Ministry of Health.3 Preoperative condi-tions were determined using a clinical activity index(CAI score) for evaluation of patients with ulcerativecolitis.4

    Methods

    This study was a retrospective analysis of outcomes in aseries of consecutive patients who underwent opera-tions performed by a single surgical team. We reviewedpostoperative complications, including infectiouscomplications, pouch-related complications, intestinalobstructions, urinary complications, and stoma-relatedcomplications, according to type of initial operation at 3weeks after the initial operation.

    Definitions of groups

    The patients were divided into two groups, those whoreceived LRT no more than 8 weeks before surgery(LRT group) and those who did not undergo LRTwithin 8 weeks before surgery (without LRT group).

    Operative procedures

    All of the ileal pouches were created with a J-shapedreservoir, 15 to 20 cm in axial length. In 324 (83.7%) ofthe patients, an IPAA with or without an ileostomy wasperformed as the initial operation. In 318 (98.1%) ofthose, the pouch was anastomosed to the dentate linewith a mucosectomy using a hand-sewn suture. The pro-cedure used for complete transanal mucosectomy withan ultrasonically activated scalpel (harmonic scalpel)has been described previously.5 In the remaining sixcases (1.9%), the pouch was anastomosed to the uppermargin of the anal canal by a double stapling method.

    LCAP and GCAP

    LCAP was performed using a Plasauto 1000 apheresisunit (Asahi Medical, Tokyo, Japan) equipped with aCellsorba leukocyte removal filter, because leukocyteremoval in LCAP is accomplished by adherence of leu-kocytes to fibers in the filter. Leukocyte adsorptiveapheresis was performed using an Adacolumn filled

    with cellulose acetate beads, each 2 mm in diameter. Inthat system, the beads selectively absorb granulocytesand monocytes/macrophages, whereas lymphocytes arenot removed in significant numbers. This system isa direct blood perfusion device, in which blood isaccessed from the antecubital vein of one arm andreturned via the antecubital vein of the contralateralarm. Nafamostat mesylate was commonly used as theanticoagulant.

    Statistical analysis

    Grouped data are described by median and range. Theresults were compared using Mann-Whitney U and -squared tests, with probability values less than 0.05 con-sidered to be significant.

    Results

    Patient backgrounds

    Characteristics of the 387 patients are shown in Table 1.There were 109 in the LRT group and 278 in the withoutLRT group. Sex and age were not significantly differentbetween the groups, whereas the duration of disease inthe without LRT group was significantly longer. Fur-ther, the incidence of total colitis type, severe or fulmi-nant, and the CAI score were significantly greater in theLRT group than in the without LRT group.

    Preoperative medical treatments

    The preoperative medical treatments utilized are shownin Table 2. Daily doses of steroids in the LRT groupwere significantly higher than those in the without LRTgroup.

    Type of LRT procedure

    In the LRT group, 56 (51.4%) of 109 patients weretreated with LCAP and 47 (43.1%) were treated withGCAP. The remaining six patients were treated pre-operatively with both LCAP and GCAP. None ofthe patients were treated with centrifugal leukocyteapheresis.

    Number of LRT procedures

    The numbers of preoperative LRT procedures for eachpatient are shown in Table 3. Four of 9 patients whowere treated as emergency cases after being transferredfrom another hospital for treatment of fulminant colitisunderwent a single LRT procedure immediately priorto the operation. Further, 14 (17.3%) of 81 (17.3%) who

  • 850 H. Ikeuchi et al.: Leukocyte removal therapy and postoperative complications

    underwent elective surgery were originally indicated foremergency surgery at the time of hospitalization. How-ever, LRT was effective for those patients, and theywere able to avoid an emergency operation.

    Surgical indications

    Surgical indications are shown in Table 4. The incidenceof emergency operations in the LRT group (25.7%) wassignificantly greater than that in the without LRT group(14.7%). Four patients in the LRT group were origi-nally transferred from other hospitals because of fulmi-nant colitis and underwent a single LRT procedureprior to emergency surgery. Of these, three underwentan IPAA with an ileostomy and one a total colectomy.

    Initial operation

    Details regarding the initial operations are shown inTable 5. In the LRT group, 46 patients (42.2%) under-went an IPAA without an ileostomy, 46 (42.2%) anIPAA with an ileostomy, and 15 (13.8%) a total colec-tomy. In the without LRT group, the respective num-bers were 147 (52.9%), 85 (30.6%), and 33 (11.9%)patients.

    Postoperative complications

    Among all 387 patients, 193 (49.9%) underwent anIPAA without a diverting ileostomy (Table 6). Of those,the mean CAI score for the LRT group (8; range, 317)was significantly greater than that for the without LRTgroup (7.5; range, 216). We found infectious complica-tions in 6 (13.0%) of 46 patients in the LRT groupand 10 (6.8%) of 147 in the without LRT group, adifference that was not significant. In the LRT group,three (6.5%) patients developed pouch-related compli-cations (PRC), though only one (2.2%) underwent asecondary ileostomy. Further, 11 (7.5%) patients in thewithout LRT group developed PRC, of whom 4 (2.7%)underwent a reoperation. Intestinal obstructions oc-curred in three (6.5%) patients in the LRT group andseven (7.5%) in the without LRT group. Two of threepatients in the LRT group and one of seven patients inthe without LRT group required a laparotomy withdivision of adhesions, while the remaining patients re-sponded to conservative treatment. Thus, a total of13 (28.3%) patients in the LRT group and 32 (21.8%)in the without LRT group experienced postoperativecomplications.

    Of all 387 patients, 131 (33.9%) underwent an IPAAwith an ileostomy (Table 7). The mean CAI score forthose in the LRT group (8; range, 419) was signifi-cantly greater than that of those in the without LRT

    Table 1. Patient characteristics and data at time of operation

    LRT (+) LRT ()

    Number of patients 109 278Age 31 (1570) 34 (1474)Sex (M/F) 56/53 164/114Duration of disease (months) 46 (1301) 83 (0.2393)*Pancolitis (%) 90 (82.6)* 203 (73.0)Severe or fulminant type (%) 30 (27.5)* 35 (12.6)Clinical activity index score 8 (319)* 8 (219)RBC (104/mm3) 389 (208510)* 420 (217553)WBC (/mm3) 8100 (2 80028 400) 8000 (200025 500)Platelets (104/mm3) 29.1 (10.052.2) 27.3 (6.969.2)CRP (mg/dL) 0.4 (019.2)* 0.3 (017.1)Total protein (g/dL) 5.8 (2.67.6) 6.3 (3.08.4)*

    LRT, leukocyte removal therapy; RBC, red blood cell count; WBC, white blood cell count; CRP,C-reactive protein*P < 0.05

    Table 3. Preoperative LRT procedures and emergencyoperation

    Operations (no. of patients)

    Elective Emergency

    Once 22 925 times 43 13610 times 16 4>11 times 0 2Total 81 28

    Table 2. Preoperative medical treatment

    LRT (+) LRT ()

    Steroids (total dose) (mg) 11 000 12 000(1 400110000) (0110 000)

    Steroids (daily dose) (mg) 30 (070)* 15 (080)Immunosuppressants, 17 (15.6) 32 (11.5)

    no. of patients (%)

    *P < 0.05

  • H. Ikeuchi et al.: Leukocyte removal therapy and postoperative complications 851

    Table 6. Postoperative complications after IPAA without ileostomy

    LRT (+) LRT ()n = 46 n = 147 P value

    CAI score (range) 8 (317) 7.5 (216)

  • 852 H. Ikeuchi et al.: Leukocyte removal therapy and postoperative complications

    LRT group had complications associated with the ileo-stomy, while intestinal obstructions related to a stomadeveloped in five patients, a peristomal fistula was seenin one patient, and intestinal prolapse developed in onepatient. No postoperative infectious complications oc-curred in the three patients who were transferred fromother hospitals because of fulminant colitis and under-went a single LRT procedure prior to emergency sur-gery. Two of those three patients later experiencedintestinal obstruction and responded to conservativetreatment. The overall rate of postoperative complica-tions was not statistically significant between the groups(LRT, 39.1%, vs without LRT, 31.8%).

    Of all 387 patients, 48 (12.4%) underwent only a totalcolectomy as the initial operation (Table 8). In thesepatients, the mean CAI score in the LRT group was

    Table 8. Postoperative complications after total colectomy

    LRT (+) LRT ()n = 15 n = 33 P value

    CAI score (range) 16 (819) 16 (719) 0.89Total number of infectious complications (%) 3 (20.0) 2 (6.1) 0.14

    Laparotomy wound 2 1Septicemia 1 0Pneumonia 1 0Local septic complications 1 1Fundus endophthalmitis 1 0

    Intestinal obstruction (%) (reoperation) 1 (6.7) 3 (9.1) 0.78 (0) (1)

    Stoma-related complication 1 (6.7) 0 0.13Bleeding from remnant rectum (%) 1 (6.7) 2 (6.1) 0.94All complications 5 (40.0) 6 (18.2) 0.25

    Table 7. Postoperative complications after IPAA with ileostomy

    LRT (+) LRT ()n = 46 n = 85 P value

    CAI score (range) 8 (419) 8 (319) 0.028Total number of infectious complications (%) 5 (10.9) 7 (8.2) 0.62

    Laparotomy wound 1 2Enteritis 2 1Pneumonia 0 2Local septic complications 1 2Other infection 1 1

    Total number of PRC (%) 1 (2.2) 1 (1.2) 0.66Anastomotic dehiscence 0 0Bleeding from pouch 1 1

    Intestinal obstruction (%) (reoperation) 7 (15.2) 13 (15.3) 0.99 (0) (1)

    Intra-abdominal bleeding (%) (reoperation) 1 (2.2) 1 (1.2) 0.66 (1) (1)

    Urinary complications 2 (4.3) 1 (1.2) 0.25Stoma-related complications 5 (10.9) 7 (8.2) 0.62All complications 18 (39.1) 27 (31.8) 0.40

    16 (range, 819) and that in the without LRT group wasalso 16 (range, 719); thus no statistically significantdifference was found. Infectious complications wereobserved in three (20.0%) patients in the LRTgroup and in two (6.1%) in the without LRT group,an nonsignificant difference. No postoperative com-plications occurred in the one patient who was trans-ferred from another hospital because of fulminantcolitis and who underwent a single LRT procedureprior to an emergency total colectomy. In all, 33% ofthe patients in the LRT group and 18.2% of thosein the without LRT group had postoperative com-plications. No statistically significant differences weredemonstrated between the two groups of patientswho underwent only a total colectomy as the initialoperation.

  • H. Ikeuchi et al.: Leukocyte removal therapy and postoperative complications 853

    Patient outcomes

    Patient outcomes are shown in Table 9. One patient inthe LRT group and three in the without LRT groupdied because of postoperative sepsis. The incidence ofpouch operation and functional pouch did not differbetween the two groups. At the time of writing, pouchfunction in the four patients who underwent a singleLRT procedure prior to emergency surgery remainsgood.

    Discussion

    Since the introduction of corticosteroids and immuno-suppressive drugs, no new effective therapies for pa-tients with severe UC have been reported. The use ofsteroid-based drugs is a common strategy for treatingUC. However, since large doses are often necessary tocontrol active UC and the treatment may need to becontinued over a long period of time, the drugs becomeless effective over time. Finally, steroid-based drugtherapy may have to be stopped because of severe sideeffects, and some patients require surgery.6,7 The vari-ous side effects associated with immunosuppressivedrugs generally occur in a dose-dependent manner,though they are usually reversible. Although the risk ofteratogenesis might not be significant, it is prudent toavoid using such drugs in pregnant women.8 Therefore,alternative therapies are necessary and desirable.

    LCAP has been introduced as a new type of LRTtherapy for UC patients who show limited response tomedical therapy,2,3 while GCAP, another type of LRT,has also been reported to be effective for those withactive UC.9,10 With the use of intensive LRT proceduresfor UC patients, an excellent or moderate clinical re-sponse was recognized in 77.7% of patients, of whom71.1% maintained that response throughout the main-tenance therapy period.11 Those results demonstratedthat LRT is an effective and safe therapy for treatmentof severe UC, resulting in remission. Accordingly,LCAP and GCAP have been approved for treatment ofUC in Japan.

    LRT is known to be effective for the treatment of UCin patients with a relatively short disease history, re-gardless of disease severity. However, it seems to be

    ineffective for patients with a long disease history.11,12

    Sawada et al.13 reported that LCAP is effective and safefor treating patients with severe or fulminant UC withtoxic megacolon (TM). Nevertheless, LCAP should beconsidered as an option only for the management of TMor a bridging therapy to surgery, thereby avoiding ahigh-risk emergency colectomy. An LRT proceduredoes not necessarily warrant immediate surgery, thoughwhen used for treatment of steroid-refractory UC, sur-geons are required to perform a colectomy as a rescuetreatment in those patients who eventually fail torespond.

    There are some reports of the relationships betweenpreoperative steroid treatment or immunosuppressivedrugs and postoperative complications,1418 whereasnone regarding the relationship between preoperativeLRT and postoperative complications are known to us.In the present study, patients with severe or fulminantUC were more numerous in the LRT group than in thewithout LRT group. Further, CAI scores were signifi-cantly greater, as was the preoperative daily dose ofsteroids, in the LRT group than in the without LRTgroup. However, the overall rate of postoperative com-plications was not significantly different between thetwo groups. Therefore, we concluded that LRT did nothave a significant effect on postoperative complications.

    Physicians and surgeons generally hope to avoid ahigh-risk emergency colectomy when treating fulminantUC patients. LRT was introduced as a new therapy forthose patients who show a limited response to medicaltherapies. We cannot comment on its effects in all pa-tients; however, a number of studies report that it iseffective and safe for treating patients with severe orfulminant UC.2,3,9,1921 In the present study, we foundthat LRT for UC did not affect the postoperative com-plication rate; thus, it should be considered as a viableoption for the management of severe or fulminant UC,or as a bridging therapy to surgery, without fear ofpostoperative complications.

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    2. Sawada K, Ohnishi K, Kosaka T, Fukui S, Yamamura M, AmanoK, et al. Leukocytapheresis therapy with leukocyte removal filterfor inflammatory bowel disease. J Gastroenterol 1995;30(SupplVIII):1247.

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    5. Ikeuchi H, Shoji Y, Kusunoki M, Yanagi H, Noda M, YamamuraT. Clinical result after restorative proctocolectomy without

    Table 9. Patient outcomes

    LRT (+) LRT () P value

    Number of patients 109 278Death 1 (0.92%) 3 (1.1%) 0.89Pouch Operation 106 (97.3%) 264 (95.0%) 0.30Functional Pouch 106 (100%) 263 (99.6%) 0.53

  • 854 H. Ikeuchi et al.: Leukocyte removal therapy and postoperative complications

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    8. Alstead EM, Ritchie JK, Leonark-Jones JE, Farthing MJ, ClarkML. Safety of azathiopurine in pregnancy in inflammatory boweldisease. Gastroenterology 1990;99:4436.

    9. Shimoyama T, Sawada K, Hiwatashi N, Sawada T, Matsueda K,Munakata A, et al. Safety and efficacy of granulocyte and mono-cyte adsorption apheresis in patients with active ulcerative colitis:a multicenter study. J Clin Apher 2001;16:19.

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    11. Sawada K, Ohnishi K, Kosaka T, Chikano S, Egashira A,Izawa H, et al. Leukocytapheresis with leukocyte removal filteras new therapy for ulcerative colitis. Ther Apher 1997;1:20711.

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    18. Fleshner PR, Michelassi F, Rubin M, Hanauer SB, Plevy SE,Targan SR. Morbidity of subtotal colectomy in patients with se-vere ulcerative colitis unresponsive to cyclosporin. Dis ColonRectum 1995;38:12415.

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    20. Sawada K, Kusugami K, Suzuki Y, Bamba T, Munakata A, HibiT, et al. Leukocytapheresis in ulcerative colitis: results of amulticenter double-blind prospective case-control study withsham apheresis as placebo treatment. Am J Gastroenterol 2005;100:13629.

    21. Nagase K, Sawada K, Ohnishi K, Egashira A, Ohkusu K,Shimoyama T. Complication of leukocytapheresis. Ther Apher1998;2:1204.

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