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Journal of Crohn's and Colitis: 10 (10)

Editor-in-Chief

Laurence J. Egan, Ireland

Associate Editors

Shomron Ben-Horin, IsraelSilvio Danese, ItalyPeter Lakatos, HungaryMiles Parkes, UKJesús Rivera-Nieves, USABritta Siegmund, GermanyGijs van den Brink, NLSéverine Vermeire, Belgium

6.585
5.586

Published on behalf of

A large-scale, prospective, observational study of leukocytapheresis for ulcerative colitis: Treatment outcomes of 847 patients in clinical practice

Yoko Yokoyama, Katsuyoshi Matsuoka, Taku Kobayashi, Koji Sawada, Tateshi Fujiyoshi, Takafumi Ando, Yoshifumi Ohnishi, Tetsuya Ishida, Masashi Oka, Masahiro Yamada, Takashi Nakamura, Tomoko Ino, Toyoko Numata, Hirofumi Aoki, Jun-ichi Sakou, Masahiro Kusada, Tomoki Maekawa, Toshifumi Hibi
DOI: http://dx.doi.org/10.1016/j.crohns.2014.01.027 981-991 First published online: 1 September 2014

Abstract

Background and aims Leukocytapheresis is an extracorporeal therapy for ulcerative colitis. However, no large-scale study on leukocytapheresis has been reported. This large-scale, prospective, observational study aimed to evaluate the treatment outcomes of leukocytapheresis for active ulcerative colitis in clinical practice.

Methods Patients with active ulcerative colitis treated with leukocytapheresis using a Cellsorba E column between May 2010 and December 2012 were enrolled from 116 medical facilities in Japan.

Results A total of 847 patients were enrolled, and 623 were available for efficacy analysis. Out of 847 patients, 80.3% of the patients had moderate to severe disease activity, and 67.6% were steroid refractory. As concomitant medications, 5-aminosalicylic acids, corticosteroids, and thiopurines were administered to 94.8%, 63.8%, and 32.8% of the patients, respectively. In addition, infliximab and tacrolimus were concomitantly used in 5.8% and 12.3%, respectively. Intensive leukocytapheresis (≥ 4 leukocytapheresis sessions within the first 2 weeks) was used in > 70% of the patients. Adverse events were seen in 10.3% (87/847), which were severe in only 5 patients (0.6%). Any concomitant medications did not increase the incidence of adverse events. Intensive leukocytapheresis was as safe as the conventional weekly procedure. The overall clinical remission rate was 68.9% (429/623), and the mucosal healing rate was 62.5% (145/232). Clinical remission was achieved more frequently and rapidly in the intensive group than in the weekly group.

Conclusions This large-scale study indicates that leukocytapheresis, including intensive procedure, is a safe and effective therapeutic option for active ulcerative colitis.

Keywords
  • Ulcerative colitis
  • Leukocytapheresis
  • Large-scale observational study
  • Safety
  • Treatment outcomes

1 Introduction

Ulcerative colitis (UC) is an inflammatory bowel disease that mainly affects the mucosa of the colon, causing erosion and ulceration.1 UC is a chronic disease with repeated relapses and remissions; its typical clinical symptoms include bloody stools and abdominal pain. Although the etiology of UC is not fully understood, inflammatory cytokines produced by leukocytes (including neutrophils, monocytes, and lymphocytes) that infiltrate the mucosa of the intestine are considered key factors in the pathogenesis of the condition.2,3

Conventional medications for active UC typically include the use of 5-aminosalicylic acid (5-ASA),4,5 but corticosteroids are often used in patients refractory to 5-ASA.6,7 Corticosteroids are effective in many patients, but their long-term use may result in various adverse effects, including Cushingoid facies, infections, and osteoporosis.8 Therefore, long-term use of corticosteroids should be limited.

Leukocytapheresis (LCAP) using a Cellsorba E column (Asahi Kasei Medical Co., Ltd., Tokyo, Japan), which is filled with nonwoven polyester fiber, is a blood purification therapy that exerts anti-inflammatory effects by removing activated leukocytes or platelets from the peripheral blood through an extracorporeal circulation.912 An open-label multicenter randomized control study showed that LCAP with low-dose corticosteroids (26.9 mg/day on average) in the treatment of active UC had significantly higher efficacy (29/39, 74%) than high-dose corticosteroids (47.9 mg/day on average; 14/37, 38%) and had significantly lower (24%) incidence of adverse events than high-dose steroid treatment (68%).13 In a multicenter, double-blind, prospective, case–control study with sham apheresis as placebo treatment, the response rate with LCAP was 80% in 19 patients with active UC, which was significantly higher than that in the sham group.14 Recently, LCAP has been shown to be effective not only in the improvement of clinical symptoms but also in the induction of mucosal healing.15 However, the numbers of subjects in these studies were small and no large-scale study evaluating the efficacy and safety of LCAP has been conducted.

Recently, biological drugs such as infliximab (IFX) and immunosuppressive drugs such as tacrolimus (Tac) have been used for treating UC.1618 The efficacy and safety of LCAP with concomitant use of these drugs has not been reported. Furthermore, in Japan, patients were previously only allowed to receive LCAP once per week. However, the revision of public insurance coverage in 2010 removed the restrictions on the frequency of LCAP and has enabled patients to receive ≥ 2 LCAP treatments per week (referred to as intensive LCAP) in clinical practice. However, the safety and efficacy of intensive LCAP have not been reported in the literature. Therefore, we conducted a large-scale, prospective, observational, postmarketing study to evaluate the treatment outcomes of LCAP, including intensive LCAP, as currently used in clinical practice.

2 Materials and methods

2.1 Study design

This postmarketing study was conducted in accordance with the Good Postmarketing Study Practice (GPSP) ordinance of the Japanese Ministry of Health, Labour and Welfare. The GPSP ordinance is the authorized standard for postmarketing studies of approved drugs and medical devices in clinical practice.

Patients were recruited from 116 medical facilities in Japan between May 2010 and December 2012. To eliminate any selection bias, a continuous registration method was adopted, where all patients treated with LCAP in participating facilities were enrolled. The treatment strategy for each patient, including the course of LCAP, was determined by the attending physician. The observation period spanned from 2 weeks before the first LCAP session to 2 weeks after the last LCAP session. After the observation period, the participating physician entered the information in the case report form (CRF).

2.2 LCAP treatment

LCAP was performed using Cellsorba E, a column filled with nonwoven polyester fiber that removes leukocytes. LCAP was performed 5–10 times during the treatment period at a blood flow rate of 30–50 mL/min and at a blood processing volume ≥ 30 mL/kg body weight. Intensive LCAP was defined as performing ≥ 4 LCAP treatments within the first 2 weeks, and weekly LCAP was defined as performing < 4 LCAP treatments within the first 2 weeks.

2.3 Assessment of treatment outcomes

The baseline patient information routinely collected for this study included age, body weight, sex, duration after UC onset, extent of disease, the presence/absence of corticosteroid resistance/dependence, and concomitant medications. The information recorded about each LCAP session included the date LCAP was performed, blood processing volume, and any anticoagulants used. During the observation period, we measured the leukocyte count, erythrocyte count, platelet count, hemoglobin level, C-reactive protein (CRP) level, and erythrocyte sedimentation rate.

Steroid resistance was defined when active UC failed to respond to a daily systemic corticosteroid dose of 1–1.5 mg/kg of body weight given over at least 1 week. Steroid dependence was defined when an attempt to taper corticosteroids had been unsuccessful in patients with active UC.

All adverse events during the observational periods were recorded for the safety evaluation, and any event in which association with LCAP could not be disproved was defined as adverse events of LCAP. Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA/J version 15.1).

The Lichtiger Clinical Activity Index (CAI)19 was recorded at baseline (before the first LCAP), at the 5th LCAP, and at 2 weeks after the last LCAP session. In addition, the CAI was recorded at the 3rd, 7th, and 9th LCAP when possible. A CAI ≤ 4 at 2 weeks after the last LCAP session was defined as clinical remission. Clinical remission or a decrease in scores that were at least half of the pre-LCAP value was defined as clinical improvement. The Endoscopic Index (EI) of the Disease Activity Index (DAI)20 at baseline and at 2 weeks after the last LCAP session was recorded in the patients whose endoscopic findings were available. An EI ≤ 1 or 0 at 2 weeks after the last LCAP session was defined as mucosal healing.

2.4 Statistical analyses

The Wilcoxon rank sum test for continuous data and Fisher exact test for categorical data were used to compare patient backgrounds, adverse events, and efficacy outcomes. A comparison between the pretreatment and posttreatment CAI values was performed using the Wilcoxon signed-rank test. Comparisons of efficacy outcomes between disease activities and steroid refractory were performed using the Fisher exact test and Bonferroni correction. The Kaplan–Meier curves of time (days) to achieve clinical remission were compared using the log-rank test. The mean times to remission in the patients who achieved clinical remission were compared using the Wilcoxon rank sum test. Missing data were excluded for respective analyses. In all the statistical analyses, p < 0.05 (2-sided test) was considered significant.

3 Results

3.1 Patients' background and LCAP treatment status

The CRFs of a total of 847 patients were retrieved, and all the patients were included in the safety assessment. Of the 847 patients, 81 who had a baseline CAI ≤ 4 and 143 who were concomitantly treated with IFX, Tac, or cyclosporine (CyA) were excluded; the remaining 623 patients were eligible for the efficacy outcome assessment (Fig. 1). The patients' baseline backgrounds and concomitant medications, and the therapeutic variables of the LCAP treatment for the 847 and 623 patients are shown in Table 1 .

Figure 1

Study design. CAI, clinical activity index; CyA, cyclosporin; IFX, infliximab; Tac, tacrolimus.

View this table:
Table 1

Baseline demographic data, concomitant medications, and LCAP treatment status of the 847 patients for the safety assessment and the 623 patients for the efficacy assessment.

ItemSafety assessment (No. of patients)Efficacy assessment (No. of patients)
Age, years40.6 ± 16.0 [6–88] (847)41.7 ± 16.2 [11–88] (623)
Body weight, kg56.8 ± 11.1 [13.3–117.0] (767)57.3 ± 11.1 [23.0–117.0] (571)
Sex, male/female57.6% (488/847)/42.4% (359/847)59.2% (369/623)/40.8% (254/623)
UC duration, years6.8 ± 7.4 [0.0–64.4] (819)6.9 ± 7.6 [0.0–64.4] (603)
Lichtiger CAI9.7 ± 3.7 (847)10.3 ± 3.1 (623)
Clinical activity
CAI ≤ 49.6% (81/847)
Mild, CAI = 5–610.2% (86/847)11.7% (73/623)
Moderate, CAI = 7–1148.8% (413/847)55.5% (346/623)
Severe, CAI ≥ 1231.5% (267/847)32.7% (204/623)
Disease extent
Total57.2% (483/844)54.8% (340/621)
Left-sided37.4% (316/844)39.8% (247/621)
Others5.3% (45/844)5.5% (34/621)
Response to corticosteroid
Resistant31.0% (261/843)27.7% (172/620)
Dependent36.7% (309/843)36.9% (229/620)
Nonrefractory32.4% (273/843)35.3% (219/620)
History of corticosteroid administration76.0% (642/845)73.8% (458/621)
Concomitant medications
5-ASA94.8% (803/847)95.5% (595/623)
Corticosteroids63.8% (540/847)62.9% (392/623)
Thiopurine32.8% (278/847)31.5% (196/623)
Infliximab5.8% (49/847)
Tacrolimus12.3% (104/847)
Cyclosporin1.1% (9/847)
Laboratory data
Leukocyte count, /mm38930.3 ± 3760.6 (815)8918.5 ± 3828.6 (596)
Erythrocyte count, × 104/mm3428.5 ± 63.8 (812)430.2 ± 62.5 (595)
Platelet count, × 104/mm333.2 ± 12.0 (812)33.1 ± 11.9 (595)
Hemoglobin level, g/dL12.3 ± 2.1 (814)12.3 ± 2.1 (595)
CRP level, mg/dL2.3 ± 4.2 (809)2.4 ± 4.4 (592)
Erythrocyte sedimentation rate, mm/h34.3 ± 28.1 (473)36.2 ± 29.5 (333)
LCAP treatment status
Mean number of LCAP sessions8.4 ± 2.5 (847)8.6 ± 2.4 (623)
Frequency of LCAP treatment
Weekly29.5% (236/800)29.3% (174/594)
Intensive70.5% (564/800)70.7% (420/594)
Blood processing volume per weight, mL/kg44.3 ± 13.7 (760)44.2 ± 13.5 (567)
Anticoagulant used
Nafamostat masilate86.2% (715/829)85.0% (517/608)
Heparin13.8% (114/829)15.0% (91/608)
  • 5-ASA, 5-aminosalicylic acid; CAI, Clinical Activity Index; CRP, C-reactive protein; LCAP, leukocytapheresis; UC, ulcerative colitis.

  • The data shown are percentages (%) or mean ± standard deviation values. In the brackets, the minimum and maximum values are given.

In the 847 patients, steroid-refractory UC patients with moderate to severe disease were mainly enrolled in this study, in which LCAP was used across a wide range of ages. Approximately 95% of the patients were treated with concomitant 5-ASA. The rates of concomitant use of corticosteroids (prednisolone or betamethasone via oral administration or intravenous injection) and thiopurines (azathioprine or 6-mercaptopurine) were 63.8% and 32.8%, respectively. The rates of concomitant use of IFX, Tac, and CyA were 5.8%, 12.3%, and 1.1%, respectively.

The mean number of LCAP treatments performed was 8.4 ± 2.5; the most frequent number of treatments received was 10 (59.9%), with the next being 5 (13.2%). Intensive LCAP was performed in > 70% of the patients. The anticoagulant nafamostat mesilate was used in 86.2% of the patients, and heparin was used in 13.8%.

3.2 Safety

The overall incidence of adverse events was 10.3% (87/847). The main adverse events observed were headache (2.2%), nausea (1.4%), and fever (1.3%; Table 2). These adverse events are commonly associated with extracorporeal circulation. Adverse events related to infections were seen only in 3 patients (0.4%). Almost all the adverse events were mild to moderate, and all the patients either recovered from the events or showed significant improvement.

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Table 2

Common adverse events (≥ 0.5%) in the 847 patients.

Adverse eventNo. of patients (%)
Patients with ≥ 1 adverse event87 (10.3)
General disorders and administration site conditions
Fever11 (1.3)
Pain in vascular access site6 (0.7)
Chill5 (0.6)
Gastrointestinal disorders
Nausea12 (1.4)
Abdominal pain4 (0.5)
Nervous system disorders
Headache19 (2.2)
Vascular disorders
Hypotension5 (0.6)
Skin and subcutaneous tissue disorders
Rash5 (0.6)
Investigations
Platelet count decrease7 (0.8)
Respiratory, thoracic, and mediastinal disorders
Nasal congestion6 (0.7)
Respiratory distress6 (0.7)
Immune system disorders
Anaphylactic shock4 (0.5)

Six severe adverse events were reported in 5 patients (0.6%). These included deep vein thrombosis (2 patients), hypotension (1 patient), anaphylactic shock (1 patient), and infective endocarditis/candidemia (1 patient). All the patients recovered from these events after appropriate treatments. Oral corticosteroids were administered to both patients with deep vein thrombosis. For the patient who developed anaphylactic shock, nafamostat mesilate was used as the anticoagulant; after the event, the patient was able to receive LCAP by changing the anticoagulant to heparin. An episode of candidemia and infective endocarditis was observed in a 6-year-old male patient, who was also treated with sulfasalazine, oral corticosteroids, azathioprine, and CyA; this suggests that the patient was highly immunosuppressed. The patient needed a catheter insertion for vascular access for the LCAP therapy, which could have also been a cause of infection. Therefore, the infection might not be due to the leukocyte removal by LCAP. He recovered after removal of the catheter and antifungal therapy.

3.3 Factors influencing the safety of LCAP

Table 3 shows the comparisons of the incidence rates of adverse events between the subgroups of the backgrounds, concomitant medications, and LCAP treatment status of the patients. The incidence rate of adverse events in the patients aged 65 years or older was 8.0% (6/75), which was not different from that in the patients younger than 65 years. Any concomitant medications, including IFX and Tac, did not increase the incidence rate of adverse events compared with the concomitant use of only 5-ASA. The incidence rate of adverse events was 9.9% (17/172) in the conventional weekly LCAP group and 5.9% (24/409) in the intensive LCAP group (≥ 4 LCAP sessions within the first 2 weeks), indicating an insignificant difference between the 2 groups. In addition, the types of adverse events did not significantly differ between the groups. With regard to the anticoagulant used, the incidence rate of adverse events was 2.8% (163/5770 treatments) in the nafamostat mesilate group and 2.3% (26/1151 treatments) in the heparin group; these rates were not significantly different. No serious bleeding events were observed in the heparin group.

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Table 3

Comparison of the incidence of adverse events.

Item (No. of patients)No. of patients (%)p value
Age, years
< 65 (772)81 (10.5)0.689
≥ 65 (75)6 (8.0)
Clinical activity
Mild, CAI = 5–6 (86)13 (15.1)0.443
Moderate, CAI = 7–11 (413)42 (10.2)
Severe, CAI ≥ 12 (267)24 (9.0)
Concomitant medications
Only 5-ASA (188)23 (12.2)
Corticosteroids (540)51 (9.4)0.266a
Thiopurines (278)24 (8.6)0.213a
Infliximab (49)4 (8.2)0.614a
Tacrolimus (104)13 (12.5)1.000a
Cyclosporin (9)2 (22.2)0.320a
Frequency of LCAP treatment
Weekly (172)17 (9.9)0.109
Intensive (409)24 (5.9)
Anticoagulant used
Nafamostat masilate (5770 treatments)163 treatments (2.8)0.322
Heparin (1151 treatments)26 treatments (2.3)
  • 5-ASA, 5-aminosalicylic acid; CAI, Clinical Activity Index; LCAP, leukocytapheresis.

  • The p values were calculated using the Fisher exact test.

  • a Compared with only 5-ASA.

3.4 Overall efficacy outcomes

The patients' baseline backgrounds and concomitant medications, and the therapeutic variables of the LCAP treatment for the 623 patients are shown in Table 1. In the 623 patients, the overall rate of clinical improvement was 73.8% (460/623) and the rate of clinical remission was 68.9% (429/623) at 2 weeks after the last LCAP session (Fig. 2a). The mean CAI significantly decreased from a baseline level of 10.3 ± 3.1 to 3.4 ± 3.2 at 2 weeks after the last LCAP session (p < 0.001; Fig. 2b). In patients who were concomitantly treated with corticosteroids, the rate of their withdrawal at 2 weeks after the last LCAP session was 13.5% (53/392). In the patients whose endoscopic findings were available (n = 232), the mucosal healing rates signified by an EI of 0 and ≤ 1 were 19.8% (46/232) and 62.5% (145/232), respectively (Fig. 2c). The backgrounds of the 232 patients were not significantly different from those of the 623 patients (data not shown).

Figure 2

Overall efficacy outcomes of LCAP in the 623 patients. (a) Clinical improvement and remission rates at 2 weeks after the last LCAP session. (b) Comparison of the CAI scores between before and after the LCAP treatments. (c) Mucosal healing rates in the patients whose endoscopic findings were available (n = 232). The data shown are mean ± standard deviation values.

The clinical remission rates in the patients with mild (baseline CAI, 5–6), moderate (CAI, 7–11), and severe disease activities (CAI, ≥ 12) were 79.5% (58/73), 67.6% (234/346), and 67.2% (137/204), respectively, showing no significant difference between the groups. The clinical remission rates in the steroid-resistant, steroid-dependent, and nonrefractory patients were 70.9% (122/172), 64.6% (148/229), and 71.2% (156/219), respectively, showing no significant difference between the groups.

The clinical remission rates in the patients who were respectively concomitantly treated with IFX, Tac, and CyA were 69.0% (29/42), 57.1% (56/98), and 44.4% (4/9), respectively. The clinical remission rate was 68.9% (356/517) in the patients who received nafamostat mesilate as an anticoagulant and 68.1% (62/91) in the patients who received heparin; no significant difference was found between the 2 groups.

A total of 169 patients were treated with LCAP monotherapy (only concomitant use of 5-ASA). Approximately 85% of the patients had moderate to severe UC. In the 169 patients, clinical improvement and clinical remission were achieved in 66.9% (113/169) and 62.7% (106/169) of the patients, respectively (Fig. 3). The mean CAI significantly decreased from a baseline level of 9.8 ± 3.0 to 3.7 ± 3.3 at 2 weeks after the last LCAP session. In the patients whose endoscopic findings were available (n = 62), the mucosal healing rates signified by an EI of 0 and ≤ 1 were 16.1% (10/62) and 61.3% (38/62), respectively.

Figure 3

Efficacy outcomes of LCAP monotherapy (concomitant use of only 5-aminosalicylic acid). The data shown are mean ± standard deviation values.

3.5 Factors influencing the efficacy outcomes

To clearly compare the efficacy outcomes, the patients who were not able to undergo at least 5 LCAP sessions (n = 42) were excluded; the remaining 581 patients were further evaluated to identify factors influencing the efficacy outcomes after LCAP. The main reasons why the patients were not able to undergo at least 5 LCAP sessions were adverse events (35.7%, 15/42), feasibility problems (26.2%, 11/42), and insufficient effect (14.3%, 6/42).

The results of the univariate analyses comparing the patients' backgrounds, concomitant medications, and therapeutic variables of LCAP between the remission and nonremission groups are shown in Table 4 . The baseline leukocyte count and the use of intensive LCAP showed statistically significant differences between the groups. A multivariate logistic regression analysis including the above-mentioned 2 significant factors identified intensive LCAP as the only factor that was significantly related to remission after LCAP (p = 0.039; odds ratio, 1.524).

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Table 4

Comparison of the baseline demographic data, concomitant medications, and LCAP treatment status between the remission (n = 415) and nonremission (n = 166) groups using a univariate analysis.

ItemRemission group (No. of patients)Nonremission group (No. of patients)p value
Age, years41.7 ± 16.5 (415)42.4 ± 15.7 (166)0.454a
Body weight, kg57.4 ± 11.4 (382)56.7 ± 10.6 (150)0.438a
Sex, male/female61.2%/38.8% (415)54.8%/45.2% (166)0.162b
UC duration, years7.1 ± 8.0 (400)6.7 ± 6.8 (162)0.675a
Lichtiger CAI10.1 ± 3.1 (415)10.6 ± 3.0 (166)0.104a
Clinical activity
Mild (CAI = 5–6)/moderate (CAI = 7–11)/severe (CAI ≥ 12)13.3%/54.7%/32.0% (415)8.4%/57.2%/34.3% (166)0.266b
Disease extent
Total/left-sided/others56.0%/38.6%/5.3% (414)49.1%/44.2%/6.7% (165)0.309b
Response to corticosteroid
Resistant/dependent/nonrefractory29.4%/34.5%/36.2% (412)26.5%/43.4%/30.1% (166)0.127b
History of corticosteroid administration, yes/no72.7%/27.3% (414)77.7%/22.3% (166)0.249b
Concomitant medications
5-ASA, yes/no95.4%/4.6% (415)95.2%/4.8% (166)1.000b
Corticosteroids, yes/no63.9%/36.1% (415)57.2%/42.8% (166)0.156b
Thiopurine, yes/no32.5%/67.5% (415)30.1%/69.9% (166)0.623b
Laboratory data
Leukocyte count, /mm38966.6 ± 3594.6 (400)8271.0 ± 3685.3 (157)0.013a
Erythrocyte count, × 104/mm3430.9 ± 63.9 (400)429.5 ± 60.4 (156)0.590a
Platelet count, × 104/mm333.1 ± 12.0 (400)31.5 ± 10.9 (156)0.110a
Hemoglobin level, g/dL12.4 ± 2.1 (400)12.4 ± 2.0 (156)0.758a
CRP level, mg/dL2.5 ± 4.3 (399)1.5 ± 2.4 (154)0.439a
Erythrocyte sedimentation rate, mm/h37.0 ± 30.8 (218)33.0 ± 27.5 (90)0.394a
LCAP treatment status
Number of LCAP sessions9.0 ± 1.8 (415)8.9 ± 2.0 (166)0.597a
Intensive/weekly LCAP73.0%/27.0% (415)63.9%/36.1% (166)0.035b
Blood processing volume per weight, mL/kg44.7 ± 13.9 (381)43.8 ± 12.5 (149)0.731a
Anticoagulant used
Nafamostat masilate/heparin84.7%/15.3% (405)84.8%/15.2% (164)1.000b
  • 5-ASA, 5-aminosalicylic acid; CAI, Clinical Activity Index; CRP, C-reactive protein; LCAP, leukocytapheresis; UC, ulcerative colitis.

  • The data shown are percentages (%) or mean ± standard deviation values.

  • a Calculated using the Wilcoxon rank sum test.

  • b Calculated using the Fisher exact test.

3.6 Comparison of weekly and intensive LCAP treatments

Since intensive LCAP was identified as the most significant factor related to remission after LCAP, we compared the patients' backgrounds between the weekly and intensive LCAP groups (Table 5). The comparison showed higher levels of pretreatment CAI, leukocyte count, platelet count, and CRP level in the intensive group, suggesting that intensive LCAP was used in patients with more severe disease activity and inflammation.

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Table 5

Comparison of the baseline patient demographic data and concomitant medications between the weekly (n = 172) and intensive LCAP groups (n = 409).

ItemWeekly group (No. of patients)Intensive group (No. of patients)p value
Age, years42.4 ± 16.1 (172)41.7 ± 16.3 (409)0.624a
Body weight, kg57.7 ± 11.1 (150)57.0 ± 11.3 (382)0.506a
Sex, male/female62.8%/37.2% (172)57.9%/42.1% (409)0.309b
UC duration, years7.0 ± 6.9 (164)7.0 ± 8.0 (398)0.299a
Lichtiger CAI9.7 ± 2.9 (172)10.5 ± 3.2 (409)0.010a
Clinical activity
Mild (CAI = 5–6)/moderate (CAI = 7–11)/severe (CAI ≥ 12)15.1%/57.0%/27.9% (172)10.5%/54.8%/34.7% (409)0.136b
Disease extent
Total/left-sided/others50.9%/41.5%/7.6% (171)55.4%/39.7%/4.9% (408)0.351b
Response to corticosteroid
Resistant/dependent/nonrefractory22.1%/43.6%/34.3% (172)31.3%/34.2%/34.5% (406)0.040b
History of corticosteroid administration, yes/no76.7%/23.3% (172)73.0%/27.0% (408)0.406b
Concomitant medications
5-ASA, yes/no93.6%/6.4% (172)96.1%/3.9% (409)0.200b
Corticosteroids, yes/no52.9%/47.1% (172)65.8%/34.2% (409)0.005b
Thiopurine, yes/no36.0%/64.0% (172)30.1%/69.9% (409)0.172b
Laboratory data
Leukocyte count, /mm38181.9 ± 3556.7 (166)9020.4 ± 3637.3 (391)0.005a
Erythrocyte count, × 104/mm3436.2 ± 64.2 (166)428.1 ± 62.3 (390)0.092a
Platelet count, × 104/mm330.4 ± 10.1 (166)33.6 ± 12.3 (390)0.004a
Hemoglobin level, g/dL12.7 ± 2.0 (166)12.2 ± 2.1 (390)0.045a
CRP level, mg/dL1.3 ± 2.3 (166)2.6 ± 4.4 (387)< 0.001a
Erythrocyte sedimentation rate, mm/h26.7 ± 25.6 (83)39.2 ± 30.7 (225)< 0.001a
  • 5-ASA, 5-aminosalicylic acid; CAI, Clinical Activity Index; CRP, C-reactive protein; LCAP, leukocytapheresis; UC, ulcerative colitis.

  • The data shown are percentages (%) or mean ± standard deviation values.

  • a Calculated using the Wilcoxon rank sum test.

  • b Calculated using the Fisher exact test.

The rate of clinical improvement was significantly higher (p = 0.005) in the intensive LCAP group (79.7%, 326/409) than in the weekly LCAP group (68.6%, 118/172). Similarly, the rate of clinical remission was significantly higher (p = 0.035) in the intensive group (74.1%, 303/409) than in the weekly group (65.1%, 112/172; Fig. 4a). In 340 patients who had all the necessary CAI data to analyze cumulative remission, a comparison of the cumulative remission rates revealed that remission was achieved more rapidly in the intensive LCAP group than in the weekly LCAP group (p < 0.001, log-rank test; Fig. 4b). The mean durations to remission in the weekly and intensive groups were 27.6 ± 14.6 days and 15.4 ± 8.6 days, respectively (p < 0.001, Wilcoxon rank sum test). In the patients whose endoscopic findings were available (n = 222), the rate of mucosal healing signified by EI ≤ 1 was achieved more frequently in the intensive LCAP group (67.0%) than in the weekly LCAP group (50.0%; p = 0.039). Similarly, the rate of mucosal healing with an EI = 0 was 10.9% in the weekly group and 23.3% in the intensive group, although these scores demonstrated no significant differences between the groups (p = 0.069; Fig. 4c).

Figure 4

Efficacy of weekly and intensive LCAP. (a) Comparison of the clinical improvement and remission rates at 2 weeks after the last LCAP session between the weekly and intensive LCAP groups, using the Fisher exact test. (b) Kaplan–Meier curve of the cumulative remission rates in the weekly and intensive LCAP groups. (c) Mucosal healing rates in the weekly and intensive LCAP groups.

4 Discussion

The present study was the first large-scale, prospective, postmarketing study to investigate the treatment outcomes of LCAP for active UC in the clinical practice setting. We were able to obtain reliable and important information regarding the status of LCAP use in current clinical practice, along with the treatment outcomes of LCAP, including intensive LCAP.

There are two types of extracorporeal therapy for treating active UC, that is, granulocyte and monocyte adsorption (GMA) and LCAP. GMA is performed using the Adacolumn (JIMRO Co., Ltd., Takasaki, Japan), which is filled with cellulose acetate beads, that enables the removal of granulocytes and monocytes, while LCAP is performed using the Cellsorba E column, which is filled with nonwoven polyester fibers that can remove leukocytes including lymphocytes. Several studies,2124 including a large-scale postmarketing study,25 have reported that GMA is a safe and effective therapy for the treatment of UC. Although a randomized, double-blind, sham-controlled study of GMA for active UC did not demonstrate the efficacy for the induction of clinical remission in patients with moderate to severe UC, the clinical remission rate in patients with severe acute disease was significantly higher in the GMA group than in the sham group.26 As regards to LCAP, an open-label multicenter randomized control study13 and a double-blind, prospective, case-controlled study with sham apheresis as placebo treatment14 demonstrated the safety and efficacy of LCAP for treating active UC. However, no large-scale postmarketing study on LCAP has been reported.

LCAP can be performed for a maximum of 10 times under public insurance coverage in Japan. In the present study, the mean number of LCAP treatments performed was 8.4 ± 2.5 and the maximum number of treatments received was 10 (59.9%), suggesting that most of the patients underwent LCAP 10 times. Intensive LCAP was performed in > 70% of the patients, demonstrating that intensive LCAP is widely preferred in clinical practice.

LCAP has been considered a safe treatment because it does not incorporate immunosuppression.13,2729 In the present study, the overall incidence rate of adverse events in the 847 patients was 10.3%, and the main adverse events were those commonly seen in association with extracorporeal circulation itself. Sever adverse events or adverse events related to infection were extremely rare. In addition, LCAP is used safely in elderly patients, and intensive LCAP is considered as safe as weekly LCAP. The findings obtained in the present study highlight a high safety profile for LCAP.

Although IFX and Tac therapies were shown to be highly effective for active UC treatment, the incidence of adverse events was relatively high.1618 Several studies have reported that the use of corticosteroids, immunosuppressives, and anti-tumor necrosis factors as well as their combination therapies are associated with an increased rate of opportunistic infections in patients with IBD.30,31 In our study, any concomitant medications, including IFX and Tac, did not increase the incidence of adverse events. Therefore, as a nonpharmacological treatment strategy, LCAP has the potential to be a useful treatment option for active UC patients, without increasing the incidence of adverse events.

With regard to efficacy outcomes, the rates of overall clinical improvement and clinical remission at 2 weeks after the last LCAP session were 73.8% and 68.9%, respectively. These results may reflect the actual outcomes of LCAP as a treatment strategy in clinical practice and were comparable with those previously reported.1315,32

In the present study, we included 169 patients who were treated with LCAP monotherapy (concomitant use of only 5-ASA), in whom a rate of clinical remission of 62.7% was achieved. Since this study had no control group, we could not clearly define the efficacy of LCAP based on its results. However, in a double-blind case–control study with sham apheresis as placebo treatment, the rate of improvement was 33% in the sham column group,14 and 10–40% efficacy rates in terms of placebo effects were achieved in several trials which treated active UC patients.1618 Compared with these results, the results of the LCAP monotherapy in our study indicate that LCAP is effective for treating active UC patients with moderate to severe disease activity.

In recent years, the importance of mucosal healing in the treatment of UC has been reported as a predictive factor of long-term outcomes.17,33,34 Okuyama et al.15 reported that mucosal healing, defined as a Mayo endoscopic subscore ≤ 1 one week after treatment, was achieved in 47% of patients with steroid-free UC and in 33% patients with steroid-resistant UC using 5 LCAP treatment sessions. In the present large-scale study, mucosal healing, defined as a DAI endoscopic subscore ≤ 1, was achieved in 62.5% patients. Moreover, even with LCAP monotherapy, mucosal healing was achieved in 61.3% of the patients, indicating that LCAP can contribute not only to the improvement of clinical symptoms but also to mucosal healing.

IFX or Tac was concomitantly used with LCAP in 42 and 98 patients, respectively. However, it was difficult to compare the definitive efficacy of each treatment because the patients' backgrounds and the timing of initiating the combined treatments differed between the individual patients. Subgroup analyses that are categorized according to patient background and determining the appropriate timing of initiating the combined treatment should be performed in future research studies.

We also investigated the factors that influenced the efficacy outcome of LCAP. In our multivariate logistic regression analysis, we identified intensive LCAP, but not weekly LCAP, as the only factor significantly related to remission after LCAP. Therefore, we extensively compared the efficacy outcomes of intensive LCAP with those of weekly LCAP. The results from the comparison of the backgrounds of the patients in the 2 groups suggest that intensive LCAP was used in patients with more severe disease. Despite this fact, the rates of clinical improvement and clinical remission were significantly higher in the intensive group than in the weekly group. These results suggest that intensive LCAP is more effective than weekly LCAP.

Furthermore, we found that in the intensive LCAP group, remission was achieved more rapidly and the time to remission was almost half as long as that in the weekly LCAP group. Sakuraba et al.23 demonstrated that the GMA therapy 2 times a week was associated with a higher rate and more rapid induction of remission than once a week of GMA therapy. Their results were consistent with our present findings in LCAP treatment. In addition, we found that the rate of mucosal healing was significantly higher in the intensive LCAP group than in the weekly LCAP group, suggesting that an intensive approach can improve the clinical and endoscopic efficacy of LCAP.

Most previous studies on LCAP have used nafamostat mesilate as the anticoagulant, in accordance with the original clinical study on LCAP.13 However, in this study, heparin was used in 13.8% of the patients. The rates of clinical improvement and clinical remission in the patients in whom heparin was used as the anticoagulant were almost equivalent to those in the patients in whom nafamostat mesilate was used. The incidence of adverse events was not significantly different between the 2 groups. Thus, the use of heparin can be feasible in terms of its effects on the efficacy and safety of LCAP.

The present study had several limitations. Since this was an observational postmarketing study, a common and predesigned treatment strategy was absent. A properly designed randomized controlled study is required to precisely compare the clinical efficacy between weekly and intensive LCAP. The results regarding mucosal healing might be biased because mucosal healing was investigated only in the patients whose endoscopic findings were available. However, the strength of this study is the large number of patients, which makes the results relevant to daily clinical practice.35

In conclusion, for the first time, we investigated the treatment outcomes of LCAP for patients with active UC in clinical practice using a large-scale, prospective study. Steroid-refractory UC patients with moderate to severe disease were mainly enrolled in this study. The overall rate of adverse events was 10.3% (87/847). Any concomitant medications and anticoagulants used did not increase the incidence of adverse events. Intensive LCAP can be as safe as weekly LCAP. The low incidence of adverse events of LCAP, including intensive LCAP, highlighted the safety profile of the procedure. The overall clinical remission rate was 68.9%, and the mucosal healing rate was 62.5% at 2 weeks after the last LCAP session, reflecting the actual outcome of LCAP as a treatment strategy in clinical practice. Superior efficacy, including remission rate, was encountered with intensive LCAP compared with weekly LCAP. Therefore, we conclude that LCAP, including intensive LCAP, is a safe and effective therapeutic option for active UC.

Conflict of interest

Y. Yokoyama, K. Matsuoka, T. Kobayashi, and T. Hibi have served as advisory board members for Asahi Kasei Medical. Y. Yokoyama, K. Sawada, M. Yamada, and T. Hibi have served as speakers of Asahi Kasei Medical. T. Nakamura, T. Ino, T. Numata, H. Aoki, J. Sakou, M. Kusada, and T. Maekawa are employees of Asahi Kasei Medical.

Acknowledgments

Role of the funding source: Asahi Kasei Medical funded this study and participated in the study design, data collection, data management, and data analysis. The authors had full access to all the data and take responsibility for the integrity of the data and the analysis. All the authors were involved in critical revisions of the manuscript and approved the final manuscript.

Author contributions: Y. Yokoyama, K. Matsuoka, and T. Kobayashi have contributed equally to this manuscript. The study was conceptualized and designed by Y. Yokoyama, K. Matsuoka, T. Kobayashi, T. Nakamura, T. Ino, H. Aoki, J. Sakou, M. Kusada, T. Maekawa, and T. Hibi. Data acquisition and analysis were carried out by Y. Yokoyama, K. Matsuoka, T. Kobayashi, K. Sawada, T. Fujiyoshi, T. Ando, Y. Ohnishi, T. Ishida, M. Oka, M. Yamada T. Nakamura, T. Ino, T. Numata, and T. Maekawa. The data were interpreted by Y. Yokoyama, K. Matsuoka, T. Kobayashi, and T. Hibi. Y. Yokoyama, K. Matsuoka, and T. Kobayashi wrote the first manuscript draft. Y. Yokoyama, K. Matsuoka, T. Kobayashi, and T. Hibi finalized the manuscript. T. Hibi supervised the study.

The authors deeply thank the participating doctors at the following 116 medical facilities for their cooperation.

Participating medical facilities: Sapporo-Kosei General Hospital, Sapporo Higashi-Tokushukai Hospital, Teine-Keijinkai Hospital, Hokuou Hospital, Asahikawa City Hospital, Obihiro-Kosei General Hospital, Date Red Cross Hospital, Aomori City Hospital, Hachinohe Red Cross Hospital, Hachinohe City Hospital, Akita Red Cross Hospital, Sendai Medical Center, Sendai Red Cross Hospital, Yamagata University Hospital, Yamagata City Hospital Saiseikan, Iwaki Kyouritsu Hospital, Niigata University, Medical & Dental Hospital, Niigata Prefecture Yoshida Hospital, Saiseikai Niigata Daini Hospital, Saitama Social Insurance Hospital, Saitama Sekishinkai Hospital, Misato Kenwa Hospital, Ohmori Toshihide gastro-intestinal Clinic, Dokkyo Medical University, Ashikaga Red Cross Hospital, University of Tsukuba Hospital, Tokyo Medical University Ibaraki Medical Center, Mito Saiseikai General Hospital, Tsuchiura Kyodo General Hospital, Chiba University Hospital, Toho University Sakura Medical Center, Jikei University School of Medicine Kashiwa Hospital, Teikyo University Chiba Medical Center, Juntendo University Urayasu Hospital, Tokyo Dental College Ichikawa General Hospital, Tsujinaka Hospital, Juntendo University Hospital, Juntendo University Nerima Hospital, Nihon University Itabashi Hospital, The Jikei University School of Medicine, Medical Hospital of Tokyo Medical and Dental University, Tokyo Medical University Hospital, Toranomon Hospital, Tokyo Teishin Hospital, Nissan Tamagawa Hospital, Nerima Hikarigaoka Hospital, Surugadai Nihon University Hospital, Ankoh Medical Clinic, Yokohama City University Medical Center, Showa University Fujigaoka Hospital, Nihon Koukan Hospital, Showa University Northern Yokohama Hospital, Saiseikai Yokohamashi Tobu Hospital, Inoue Gastrointestinal Internal Medicine Clinic, Kouhoku Koumon Clinic, Kannai-Suzuki Clinic, Hamamatsu Minami Hospital, Numazu City Hospital, Kanazawa University Hospital, Ishikawa Prefectural Central Hospital, Toyama Prefectural Central Hospital, Fukui Red Cross Hospital, Shinonoi General Hospital, Nagoya City University Hospital, Aichi Medical University Hospital, Nagoya Memorial Hospital, Midori Municipal Hospital, Meitetsu Hospital, Tosei General Hospital, Narita Memorial Hospital, Nishio Municipal Hospital, Toukai Memorial Hospital, Hosokawaonaka Clinic, Nishishita Gastroenteric Hospital, Yodogawa Christian Hospital, Hirakata Kohsai Hospital, Takatsuki General Hospital, Moriguchi Keijinkai Hospital, Minoh City Hospital, Dongo Hospital, Kobe City Medical Center General Hospital, Hyogo Prefectural Awaji Medical Center, Hyogo Prefectural Kakogawa Medical Center, Shinko Hospital, Akashi Medical Center, Aoyama Clinic: GI Endoscopy & IBD Center, Social Insurance Kinan Hospital, Nakae Hospital, Hiroshima University Hospital, Hiroshima City Asa Hospital, Okayama University Hospital, Social Insurance Tokuyama Central Hospital, Konan St. Hill Hospital, Kagawa Prefectural Central Hospital, Ehime Prefectural Central Hospital, Morita Internal Gastrointestinal Medicine Clinic, Nagasaki University Hospital, Nagasaki Medical Center, Oita Prefectural Hospital, Saga University Hospital, Saga-Ken Medical Centre Koseikan, Karatsu Red Cross Hospital, Kumamoto University Hospital, Miyazaki Medical Center Hospital, Kagoshima University Medical And Dental Hospital.

Abbreviations
5-ASA
5-aminosalicylic acid
CAI
Clinical Activity Index
CRF
case report form
CRP
C-reactive protein
CyA
cyclosporine
DAI
Disease Activity Index
GMA
granulocyte and monocyte adsorptive therapy
GPSP
Good Postmarketing Study Practice
IBD
inflammatory bowel disease
IFX
infliximab
LCAP
leukocytapheresis
MedDRA
Medical Dictionary for Regulatory Activities
Tac
tacrolimus
UC
ulcerative colitis.

References

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