Long-term prognosis of patients with ulcerative colitis treated with cytapheresis therapy

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Journal of Crohn's and Colitis (2013) 7, e49 e54 Available online at www.sciencedirect.

Yohei Mikami a, Tadakazu Hisamatsu a, Tomoharu Yajima a, Yasushi Iwao c, Haruhiko Ogata c, Toshifumi Hibi a, a Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio

1 Journal of Crohn's and Colitis (2013) 7, e49 e54 Available online at Long-term prognosis of patients with ulcerative colitis treated with cytapheresis therapy Tetsuro Takayama a, b, Takanaori Kanai a, Katsuyoshi Matsuoka a, Susumu Okamoto a, Tomohisa Sujino a, Yohei Mikami a, Tadakazu Hisamatsu a, Tomoharu Yajima a, Yasushi Iwao c, Haruhiko Ogata c, Toshifumi Hibi a, a Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan b Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan c Center for Diagnostic and Therapeutic Endoscopy, Keio University Hospital, Tokyo, Japan Received 6 January 2012; received in revised form 2 April 2012; accepted 4 May 2012 KEYWORDS Inflammatory bowel disease; Ulcerative colitis; Cytapheresis therapy; Long-term prognosis Abstract Background: Although accumulating studies in Japan show that cytapheresis (CAP) therapy is safe and effective for the induction of remission of moderate or severe ulcerative colitis (UC), the long-term prognosis of UC patients treated with CAP is unknown. The aim of this study was to determine the long-term prognosis of UC patients treated with CAP. Methods: Ninety patients treated previously with CAP and followed for more than 3 years were evaluated. The rates of operation, readmission, and use or dose-up of corticosteroid were analyzed as long-term prognosis. Results: Following the first course of CAP treatment, 64% of patients showed clinical improvement (N4-point decrease in the clinical activity index (CAI)), and 49% of patients achieved clinical remission (CAI 4). Longer disease duration and lower age at the first CAP treatment correlated significantly with the therapeutic effects of CAP (p =0.003 and 0.035, respectively). The rates of operation and readmission were significantly lower in patients who showed previous clinical effects of CAP than in those who did not respond to CAP. The rates of operation and readmission were also significantly lower in patients whose treatment was combined with immunomodulators after the initiation of CAP than in patients who did not use immunomodulators. Importantly, the second course of CAP was also effective in most of the patients who showed a clinical response to the first CAP. Corresponding author at: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo , Japan. Fax: address: thibi@sc.itc.keio.ac.jp (T. Hibi) /$ - see front matter 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi: /j.crohns

2 e50 T. Takayama et al. Conclusions: Patients who achieve remission after the first CAP therapy may have a good long-term prognosis and a good response to a second CAP therapy even after relapse European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. 1. Introduction Ulcerative colitis (UC) is a chronic and recurrent inflammatory disease of the colon that impairs the quality of life (QOL). Several treatments for UC have been developed. 1 3 For instance, prednisolone (PSL) is used in induction therapy with great efficacy but has several severe side effects. 4 Immunomodulators (IM) such as 6-mercaptopurine (6-MP) and azathioprine (AZA) are effective agents for the maintenance of remission. 5 However, IM also have severe side effects such as myelosuppression and the development of lymphoma. 4 Recent advances include the use of biologics, such as infliximab, for the induction therapy and maintenance of severe UC, but the long-term safety of this medication is not known. 1,2 In most patients, UC can be controlled by these medications without any complications, although some patients require an operation. Nearly all UC patients prefer to avoid colectomy, even for severe symptoms, although QOL is usually improved after an operation. 6 Chronic inflammation elevates the risk of developing colitic cancer, which severely impairs QOL and threatens the patient's life. 7 Therefore, it is important to choose therapies that can effectively avoid recurrences and that have the fewest side effects. Therefore, it is very critical to know the long-term prognosis by specific treatment with predicted life of each patient. UC is often associated with an increase in peripheral blood granulocytes and monocytes. 8 Accordingly, cytapheresis (CAP) therapy is used widely in Japan in UC patients with moderate to severe activity. Several studies have shown the efficacy and safety of CAP, with most demonstrating that about 60% of patients have a clinical response to CAP therapy However, there are few reports on the long-term prognosis of UC patients treated with CAP therapy and the number of patients is relatively small. 20 Although some UC patients receive multiple courses of CAP therapy throughout their life, the efficacy of a second course of CAP therapy has not been reported. Therefore we here analyzed the long-term prognosis of UC patients treated with CAP therapy and assessed the efficacy of multiple courses of CAP. 2. Materials and methods 2.1. Patients Retrospective data were collected for 114 patients with active UC who were treated with CAP by granulocytapheresis (GCAP; JIMRO Co. Ltd., Takasaki, Japan) and/or leukocytapheresis (LCAP; Asahi Kasei Kuraray Medical Co. Ltd., Tokyo, Japan) and who could be followed up for N3 years (including seven lost patients). Ninety patients (55 men, 35 women; mean age, 36.4 years) with full clinical records were enrolled for further analysis that included information about their background, medication, and long-term prognosis. The average observation period was 4.6 years. Clinical efficacy was evaluated using the clinical activity index (CAI) according to Rachmilewitz's criteria applied to information collected from questionnaires completed by the patients. 21 We defined a CAI of 4 pointsas remission and a decrease in CAI of N4 points as effective treatment, as reported previously. 22 To determine the longterm prognosis, we evaluated the rates of operation, readmission, and use or dose-up of steroid. This historical cohort study was conducted at Keio University Hospital and the study was approved by the Keio University School of Medicine review board and the permission was obtained. All patients who underwent CAP for UC with moderate to severe activity between 2001 and 2006 were enrolled. Written or oral informed consent was obtained from all patients and/or the parents of patients younger than 20 years of age. The questionnaire was designed to collect demographic data including age, gender, disease extent, disease duration, clinical type, CAI before the first course of CAP, and medication (use of PSL and/or IM). Outcomes (rates of operation: total colectomy, readmission, and use or dose-up of PSL) were obtained from the hospital medical records Inclusion and exclusion criteria The inclusion criteria were age between 14 and 77 years; an endoscopic and histological diagnosis of UC but not indeterminate colitis; and a CAI scoren 5 for patients with colonic involvement. The exclusion criteria were evidence of toxic megacolon; malignancy with serious concomitant cerebral, pulmonary, cardiac, hepatic, or renal disease; and a history of hypersensitivity reaction during apheresis Cytapheresis Patients with moderately active disease were treated in our outpatient clinic, and those with severe disease were hospitalized and treated. Each patient received five or 10 GCAP or LCAP once or twice per week, respectively. Each GCAP session time was 60 min at 30 ml/min and each LCAP session time was 60 min at ml/min. In patients who were receiving PSL at entry, the dose of PSL was tapered or discontinued according to clinical improvement during the CAP Data analysis Multiple logistic regression analysis was performed using JMP version (SAS Institute Japan, Co., Ltd, Tokyo, Japan) and GraphPad Prism software version 4.0 (GraphPad Software Inc., San Diego, CA). Differences at pb 0.05 were considered significant. The log-rank test was used to compare the Kaplan Meier survival curves. The data are expressed as mean± SEM where appropriate.

3 Long term prognosis after CAP therapy e51 3. Results 3.1. Effects of the first course of CAP One hundred fourteen patients with UC received CAP therapy. Ninety patients followed for more than 3 years after the first CAP course (CAP administered 5 10 times) with full clinical data (55 men and 35 women, mean age 36.4 years [range 14 77]) were enrolled for further analysis (Table 1). Following the first course of CAP, 58 patients (64%) showed clinical improvement (remission: a CAI 4, and effective: N4-point decrease in the CAI) and 44 of these 58 patients (49%) achieved clinical remission (CAI 4). The duration of the disease correlated significantly with the therapeutic effects of CAP (p=0.04); CAP therapy was most effective in patients with a longer disease duration (Table 2). Other factors such as age, sex, disease extent, clinical type, CAI at the start of the study, and use of PSL and IM before the study had little effect on the response to therapy (Table 2) Long-term prognosis We next analyzed the rates of operation, readmission, and use or dose-up of PSL after the first course of CAP in terms of long-term prognosis. The average observation period was 4.6 years. Because of disease recurrence, 62 patients (69%) relapsed and received treatment to induce remission (PSL, admission, and second course of CAP) during the observation period; of these 29 patients (32%) were readmitted to our hospital, 39 patients (43%) were given PSL or received doseup of PSL, and 12 patients (13%) received an operation (total colectomy) for uncontrollable disease after the first course of CAP (578±478.4, ) (mean ±SD, range). The rate of readmission was significantly lower in patients who showed clinical effects with the first CAP treatment than in those who did not respond to CAP (pb0.001) (Fig. 1). Multiple logistic regression analysis showed that the CAI before CAP and the effects of the first course of CAP were significant predictors of readmission (p = 0.01 and 0.001, respectively) Table 1 Subject characteristics in this study. Total n=90 Age (years) 38.5 ± 15.8 (14 77) Gender Male 55, Female 35 Disease extent Proctosigmoiditis 5, left-sided colitis 26, pancolitis 55, others 4 Disease duration (years) 7.6 ± 7.1 (0 32) Clinical type One-attack 6, relapsing remitting 79, chronic continuous 5 CAI (pre 1st course of CAP) 9.2±3.5 Medication (pre 1st course of CAP) PSL Yes 59, no 31 Immunomodulator (IM) Yes 14, no 76 (Both PSL and IM) (9 patients) Continuous data are expressed as mean with range or number in parentheses. CAI: clinical activity index, CAP: cytapheresis, PSL: prednisolone. Table 2 (Table 2). The rate of use or dose-up of PSL was not significant but was relatively low in patients who achieved remission with CAP (p =0.07). The CAI before CAP and the use of PSL before CAP were significantly related to the use or dose-up of steroid (p = 0.03 and 0.03, respectively) (Table 2). The rate of operation was also significantly lower in patients who responded to the first course of CAP than in those who did not respond (pb0.001) (Fig. 2). We could not perform multiple logistic regression analysis because few patients received an operation Effects of IM Results of multiple logistic regression analysis. Factor χ 2 Effect of 1st course of CAP p Re-admission χ 2 p Use or dose-up of steroid χ 2 p Age Gender Disease extent Duration * Clinical type Pre CAI * * Effect of 1st CAP n/a n/a * Pre use of PSL * Pre use of IM Our group and other groups have previously reported the efficacy of 6-MP/AZA for disease control in patients with UC, 2 4,6 and here we analyzed the use of IM in patients who received CAP. The rate of readmission was significantly lower in patients who used IM after CAP than in those who did not (Fig. 3). The rates of use or dose-up of PSL and operation did not differ significantly between patients who used or did not use IM, although there was a trend toward a difference (p = 0.17 and 0.12, respectively) (Fig. 3). p< (remission vs no effect) p= (effective vs no effect) Figure 1 Kaplan Meier analysis of readmission after CAP. The readmission rate was significantly lower in patients who showed remission or improvement with the first course of CAP (pb0.001 and pb 0.001, respectively).

e52 T. Takayama et al. * CAI 10.2 2.6 14 p=0.0004 (remission vs no effect) 44 (49%) CAI 10.4 2.7 Re-CAP 20 2 4 Figure 2 Kaplan Meier analysis of the operation rate after CAP.

4 e52 T. Takayama et al. * CAI p= (remission vs no effect) 44 (49%) CAI Re-CAP Figure 2 Kaplan Meier analysis of the operation rate after CAP. The operation rate was significantly lower in patients who achieved remission or improvement with the first course of CAP (pb and pb 0.001, respectively) Effects of the second course of CAP The usefulness of a second round of CAP in a patient experiencing a relapse during the disease course is unclear. To clarify it, we next assessed the effects of the second course of CAP in patients irrespective of their response to the first course of CAP. This was a crucial issue because we had to identify differences in the patients sensitivity to CAP. Thirty-three of 90 patients received a second course of CAP. Of these, the first course of CAP induced remission in 20 patients, had an effective response in eight patients, and an ineffective response in five patients (Fig. 4). The CAI s before CAP were 10.4 in patients in remission, 10.7 in patients with an effective response, and 8.4 in patients with no response to the first round of CAP. The second course of CAP produced the following effects in the 33 patients: 24 (73%) improved (remission and effective response), 19 of these 24 (58%) were in remission, and 9 (27%) had no response. The percentage of remissive and effective responses of the 2nd course of CAP was 79% in patients who had remissive and effective responses in the 1st course of CAP, whereas 40% in patients who had non-effective responses in the 1st course of CAP (pb0.05) (Fig. 4). The percentage of remissive responses to the second course of CAP increased to CAI Total 90 Re-admission Use of Steroid Operation P<0.05 p=0.17 p= (15%) 32 (36%) CAI Re-CAP 8 CAI Re-CAP 5 70% of the patients who had a remissive response in the first course of CAP (49%), instead of a higher CAI at the beginning of the second CAP than at the beginning of the first CAP (pb0.05) IM (+) IM (-) * * p<0.05 Figure 4 Efficacy of the second course of CAP. The CAI near each box shows the average CAI of each patient before the CAP. Forty-four patients achieved remission, 14 patients responded, and 32 patients did not respond to the first course of CAP. Thirtythree patients received a second course of CAP. The percentages of patients who had a remissive or effective response to the second course of CAP were 79% in patients who had a remissive and effective response in the first course of CAP and 40% in patients who had an ineffective response in the first course of CAP (pb 0.05). The remissive responses to the second course of CAP increased to 70% in patients who had a remissive response in the first course of CAP (49%) (pb0.05). * (3/27) (21/74) (6/27) (21/74) (1/27)(11/74) (Event/Total) Figure 3 Relationship between the use of IM and the long-term prognosis of UC after CAP. A: readmission, B: use or dose-up of steroid, and C: operation. The open bars represent the patients who used IM after CAP, and the solid bars show the patients who did not use IM after CAP. The readmission rate correlated significantly with the use of IM after CAP (pb0.05). The rates of the use of steroid and operation did not differ significantly but there was a trend for a relationship between these and the use of IM after CAP (p= 0.17 and p= 0.12, respectively).

5 Long term prognosis after CAP therapy e53 (Fig. 4). This indicates that the second course of CAP was effective in most of the patients who showed a clinical response to the first CAP therapy. 4. Discussion In the current study, 58 (64%) of the 90 patients who could be followed for more than 3 years after the first CAP therapy showed clinical improvement, and 44 patients (49%) achieved clinical remission after one course of CAP treatment. The duration of the disease and the age at the first CAP treatment correlated significantly with the effects of CAP. The rates of operation and readmission were significantly lower in patients who showed a previous clinical response to CAP treatment than in those who did not respond to CAP. The rates of operation and readmission were significantly lower in patients who used IM after CAP than in patients who did not use IM. The second course of CAP was also effective in most patients who showed a clinical response to the first CAP therapy. Collectively, these results provide new insight into the effects of CAP therapy in relation to the long-term prognosis of UC patients. The findings of this study should help identify patients long-term prognosis for an operation, readmission, and use of PSL Because there is no method for predicting the efficacy of CAP at present, clinicians have had no clear guidance about the likely response to the second course of CAP. Our findings suggest that patients who respond to the first course of CAP will also respond to the second course of CAP even if they have a higher CAI. By contrast, the second course of CAP will be ineffective in patients who do not respond to the first course of CAP. These observations suggest that the response to CAP varies between individuals because of the different pathogenesis. These findings may help avoid useless therapy and save time and costs by selecting patients who are likely to respond to CAP. Our data also suggest that the use of IM with CAP therapy may help avoid the need for an operation. Our data are consistent with previous findings. 2,3,6 We believe that this study provides some guidelines for the treatment and management of UC patients in terms of CAP therapy. However, this study was designed as a single-center, historical cohort study, and the number of patients was small, suggesting several confoundings and biases (in decision of medication, sessions of CAP) might be included. Since this study is designed as retrospective, we could not avoid the selection bias. However, to avoid the influence of confounding factor as much as possible, we use multiple logistic regression analysis. Though there might be many biases, suggesting a larger placebo-controlled double-blind study involving multiple centers is needed. In conclusion, patients who achieve remission after the first CAP therapy may have a good longterm prognosis and may respond well to the second CAP therapy even after relapse. Conflict of interest statement We declare that we have no conflict of interest. Acknowledgments We thank M. Hayashi, T. Monkawa, T. Matayoshi, M. Komori, M. Jinnouchi, H. Hashimoto, R. Inagaki, and S. Arai (Keio University Hospital) for assisting with the CAP therapy. This work was supported in part by a KORP project grant from Otsuka Pharmaceutical, Inc. References 1. Talley NJ, Abreu MT, Achkar JP, Bernstein CN, Dubinsky MC, Hanauer SB, et al. An evidence-based systematic review on medical therapies for inflammatory bowel disease. Am J Gastroenterol 2011;106(Suppl 1):S Hoentjen F, Sakuraba A, Hanauer S. Update on the management of ulcerative colitis. Curr Gastroenterol Rep 2011;13: Blonski W, Buchner AM, Lichtenstein GR. Inflammatory bowel disease therapy: current state-of-the-art. 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6 e54 T. Takayama et al. 17. Sakuraba A, Motoya S, Watanabe K, Nishishita M, Kanke K, Matsui T, et al. An open-label prospective randomized multicenter study shows very rapid remission of ulcerative colitis by intensive granulocyte and monocyte adsorptive apheresis as compared with routine weekly treatment. Am J Gastroenterol 2009;104: Sands BE, Sandborn WJ, Feagan B, Löfberg R, Hibi T, Wang T, et al. A randomized, double-blind, sham-controlled study of granulocyte/monocyte apheresis for active ulcerative colitis. Gastroenterology 2008;135: Hibi T, Sameshima Y, Sekiguchi Y, Hisatome Y, Maruyama F, Moriwaki K, et al. Treating ulcerative colitis by Adacolumn therapeutic leucocytapheresis: clinical efficacy and safety based on surveillance of 656 patients in 53 centres in Japan. Dig Liver Dis 2009;41: Lindberg A, Eberhardson M, Karlsson M, Karlén P. Long-term follow-up with granulocyte and monocyte apheresis re-treatment in patients with chronically active inflammatory bowel disease. BMC Gastroenterol 2010;10: Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. BMJ 1989;298: Ogata H, Matsui T, Nakamura M, Iida M, Takazoe M, Suzuki Y, et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut 2006;55:

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