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Treatment of inflammatory bowel disease by leukocytapheresis
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Treatment of inflammatory bowel disease by leukocytapheresis Emre Gerc¸eker a,∗ , Hakan Yüceyar b , Elmas Kasap b , Ufuk Demirci c , Burcu Ceren Ekti c , I˙ smet Aydo˘gdu d , Mine Miskio˘glu d Departments of Gastroenterology, Gazi Hospital, I˙ zmir, Turkey Departments of Gastroenterology, Medical Faculty, Celal Bayar University, Manisa, Turkey c Departments of Internal Medicine, Medical Faculty, Celal Bayar University, Manisa, Turkey d Departments of Hematology, Medical Faculty, Celal Bayar University, Manisa, Turkey a
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Article history: Received 17 November 2016 Received in revised form 25 March 2017 Accepted 30 March 2017 Available online xxx Keywords: Crohn’s disease Inflammatory bowel disease Leukocytapheresis Ulcerative colitis
a b s t r a c t Studies about leukocytapheresis have emerged with the need of search for alternatives to conventional treatment in inflammatory bowel diseases (IBD). Leukocytapheresis is a novel non-pharmacologic approach for active ulcerative colitis (UC) and Crohn’s disease (CD), in which leukocytes are mechanically removed from the circulatory system. Patients with active IBD treated with leukocytapheresis using a Cellsorba E column between 2012 and 2015, were enrolled in Turkey. In our experience, the results of leukocytapheresis therapy in 6 patients with CD and 20 patients with active UC were overviewed. Leukocytapheresis (10 sessions for remission induction therapy, 6 sessions for maintenance therapy) was applied to the patients with their concomitant medications. Intensive leukocytapheresis (≥4 leukocytapheresis sessions within the first 2 weeks) was used in 30% patients with active severe UC. The overall clinical remission rate in patients with UC was 80%, and the mucosal healing rate was 65%. Patients were followed for an average of 24 months. It was observed that clinical remission has continued in 65% of patients with UC. Mild relapse was observed in 3 patients with UC during follow up period. In 5 patients with CD significant clinical remission was achieved except only one patient. Surgical needs were disappeared in 3 patients with obstructive type Crohn’s disease. Adverse events were seen in only 4.3% of 416 sessions. Any concomitant medications did not increase the incidence of adverse events. Our results indicate that leukocytapheresis is efficacious in improving remission rates with excellent tolerability and safety in patients with IBD. © 2017 Elsevier Ltd. All rights reserved.
1. Introduction Inflammatory bowel disease (IBD) (ulcerative colitis (UC) and Crohn’s disease (CD)) is a chronic inflammatory disease of gastrointestinal tract associated with the relapses and remissions [1]. Inflammation in IBD is emerging results of an unusual series of exaggerated immune reaction developing against unknown peripheral antigens in genetically susceptible individuals. It is thought that encountering with pro-inflammatory antigens depending on the increased permeability of the intestinal epithelium, irregularities in the activation of T helper 1 (Th1) and T
Abbreviations: AZA, azathioprine; CD, Crohn’s disease; CsA, cyclosporine; CMV, cytomegalovirus; IBD, inflammatory bowel disease; UC, ulcerative colitis. ∗ Corresponding author. E-mail addresses: [email protected] (E. Gerc¸eker), [email protected] (H. Yüceyar), [email protected] (E. Kasap), [email protected] (U. Demirci), [email protected] (B.C. Ekti), [email protected] (I˙ . Aydo˘gdu), [email protected] (M. Miskio˘glu).
helper 2 (Th2) lymphocytes, disorder in cytokine regulation indicating increase in favor of pro-inflammatory cytokines are playing role in IBD immune pathogenesis [2–7]. In IBD therapy, ensuring and maintaining of clinical remission is expected. It’s also aimed to improve quality of patient’s life and safety. Effort is also made to prevent or reduce the complications (bleeding, perforation, fistula, stricture and cancer, etc.). Main targets are reduction of drug toxicity, reducing the need for hospitalization and eliminating the surgical intervention [8–10]. It is intended to suppress lymphocytes and cytokines responsible from inflammation and to maintain this suppression. Conventional medical treatment agents used for this purpose are mesalazine, corticosteroids, azathioprine (AZA), cyclosporine (CsA), tacrolimus, anti TNF alpha (infliximab, adalimumab) [8–10]. Corticosteroids are effective in many IBD patients. However, their long-term use may cause various adverse effects, including diabetes mellitus, Cushingoid appearance, infections, osteoporosis and vertebral fracture. Therefore, long-term use of corticosteroids in the medical therapy of IBD should be limited. Dosage and timing of the therapy cannot be adjusted optimally
http://dx.doi.org/10.1016/j.transci.2017.03.016 1473-0502/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Gerc¸eker E, et al. Treatment of inflammatory bowel disease by leukocytapheresis. Transfus Apheresis Sci (2017), http://dx.doi.org/10.1016/j.transci.2017.03.016
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in conventional medical treatments due to the side effects of the drugs. Therefore, this problem is the most important issue causes difficulties to ensure the induction and maintenance of remission. The majority of these drugs present several severe side effects, requiring careful attention in drug dosage and duration [9,10]. Leukocytapheresis has emerged as a non-pharmacological treatment with few side effects [8]. The mechanism of action consists of the removal of the cell population involved in the induction and perpetuation of bowel inflammation from the peripheral blood [11]. Circulating cytokines and specific inflammatory cells can be removed from blood by the use of the specific filters in extracorporeal leukocyteapheresis systems [12]. There are limited number of studies indicating the use of extracorporeal leukocytapheresis systems which are used in the treatment of IBD, combined with the conventional therapies in induction and maintenance of remission in IBD [13]. It is observed that the experience is increasing gradually in literature. Besides limited experience in the CD patients; there is also available increasing data regarding significant benefits are achieved especially in the patients with severe ulcerative colitis [14]. Leukocytapheresis was initiated into the treatment of steroid dependent or resistant patients with active inflammatory bowel disease [15]. We performed a retrospective study of patients with IBD. The results were evaluated for its efficiency, reliability and feasibility by the way of retrospective analysis. 2. Material-method 2.1. Study design, localization of study and patients This post-marketing study was conducted in accordance with the Turkish Ministry of Health. This study is carried out by the approval of Scientific Research Ethics Committee of Celal Bayar University Medical Faculty with number 356 and dated 30/09/2015. Patients were recruited from Gastroenterology Department of Medical Faculty in Celal Bayar University between January 2012 and May 2015. Leukocytapheresis was performed for steroid dependent or steroid resistant patients who were histologically, clinically and endoscopically proven IBD. The treatment strategy for each patient, including the course of leukocytapheresis, was determined by the attending physicians. Twenty six patients with IBD were enrolled. Twenty patients with UC and six patients with CD were overviewed. The observation period spanned from 4 weeks before the first leukocytapheresis session to 2 weeks after the last leukocytapheresis session. After the observation period, the participating physician entered all data of patients. 2.2. Leukocytapheresis treatment Consent form was taken from each patient before commencing to leukocytapheresis treatment. Each patient was evaluated and received approval for process conformity by hematologist. Leukocytapheresis was performed using Cellsorba E, a column filled with nonwoven polyester fiber that removes leukocytes. Leukocytapheresis was performed 10 sessions (2–3 times per week) for remission induction and 6 sessions (once per month) for maintenance therapy 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. Totally 16 sessions of leukocytapheresis therapy were applied. 2.3. Concomitant medical treatment The baseline patient information routinely recorded included mesalazine, steroid, AZA, anti TNF alpha agents. All agents were continued with leukocytapheresis in all patients. After leukocytapheresis treatment, steroid agents were interrupted in patients
upon the achievement of clinical and mucosal remission. The maintenance treatment strategy was determined by gastroenterologists. In some patients with IBD, CMV (cytomegalovirus) infection was determined in the colon samples by PCR. Leukocytapheresis and intravenous antiviral agent (ganciclovir) was simultaneously performed. Per oral ganciclovir was given as a maintenance treatment. 2.4. Assessment of treatment outcomes Age, sex, another systemic diseases, duration of disease, extend of disease, extra-intestinal involvement, concomitant medications before leukocytapheresis, the presence/absence of corticosteroid resistance/dependence were recorded. Steroid refractoriness was defined as active disease despite prednisone up to 0.75-1.00 mg/kg per day over a period of at least 4 week. Steroid dependence patients were defined; who are either unable to reduce steroids below the equivalent of prednisolone 10 mg/day within 3 months of starting steroids, without recurrent active disease or who have a relapse within 3 months of stopping steroids [16,17]. All adverse events during the observational periods were recorded for the safety evaluation by the attending physicians. Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA/J version 15.1). Mayo Clinical Score in patients with UC, CDAI (Crohn’s disease activity index) score in patients with CD; were recorded at baseline (before the first leukocytapheresis) and 2 weeks after the last leukocytapheresis (tenth) session. All patients were examined after 6th and 12th mounts at the end of 16th sessions. Blood tests, radiological and colonoscopic examinations were recorded along the observation period. Patients were followed during the average period of 24 mounts after leukocytapheresis. Mayo Clinical Score ≤ 4 at 2 weeks after the last leukocytapheresis session was defined as clinical remission. Clinical remission or a decrease in scores that were at least half of the pre- leukocytapheresis value was defined as clinical improvement. The Endoscopic Index (EI) of the Disease Activity Index (DAI) at baseline and at 2 weeks after the last leukocytapheresis session was recorded in all patients. An EI ≤ 1 at 2 weeks after the last leukocytapheresis session was defined as mucosal healing. 3. Results 3.1. Demographic background of patients with IBD All of the patients with IBD (20 patients with UC and 6 patients with CD) were evaluated retrospectively. 84.6% (n = 22) of patients were men, 16.4% (n = 4) were women. Average ages were 41.85. The average time of UC diagnosis was 6.71 years (min-max; 2–12 years). 65% (n = 13) of these patients were pancolitis, 35% (n = 7) left colitis. All patients had symptoms with active colitis. Steroid refractoriness was found in all patients. Before leukocytapheresis application, all of patients had a treatment history with steroid, mesalazine and AZA. In addition, 15% (n = 3) of the patients had a treatment history with anti-TNF alpha (adalimumab). The average Mayo Clinical Score was 10.20 (min-max: 8–12) before leukocytapheresis. The average CRP level was 31.34 mg/dL (minmax: 24.4–37.8 mg/dL). Before leukocytapheresis applications, 30% (n = 6) of patients with UC had colectomy risk. Before leukocytapheresis, CMV had been determined in 30% of patients with UC by PCR with colon biopsy. Intravenous and per oral antiviral ganciclovir agents were used for CMV colitis (Table 1). In this study, 6 patients with CD were enrolled. The average time of CD diagnosis was 7.66 years (min-max; 3–15 years). Only one patient with CD had isolated ileal involvement, 5 of 6 patients had ileal and colonic involvement. We encountered severe dis-
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Fig. 1. Mayo Clinic Score of patients with UC during treatment period.
Table 1 Demographic background of patients with UC (n = 20). Disease duration (Year average, min-max)
6.71 (2–12)
Extend of UC (Pancolitis/left colitis) Mayo Score average; min-max Disease CRP severity Patient with pancolitis and total colectomy risk Patient with steroid refractory Medication before leukocytapheresis (With/without Anti TNF alpha) CMV colitis before leukocytapheresis
13/7 (65%/35%) 10.20 (8–12) 31.34 (24.4–37.8) 6 (30%) 20 (100%) 3/17 (15%/85%) 6 (30%)
Table 2 Demographic background of patients with CD (n = 6). Disease duration (Year average; min-max)
7.66 (3-15)
Extend of CD (Only ileum/ileum and colon) Disease Severity (CDAI Score average, min-max) Medication before leukocytapheresis (steroid + mesalasine + AZA + anti TNF alpha)
1/5 412.1 (320–482) 6 (100%)
ease activities in all of them (CDAI ≥ 220, annual attack number ≥ 2, persistence CD symptoms with long period). The average CDAI was 412.1 (min-max; 320–482) before leukocytapheresis. 3 of 6 patients had obstructive type of CD. In one of all patients, perianal fistula was visualized radiologically. Conventional therapeutic agents (such as mezalazine, steroid, AZA, anti TNF alpha) were recorded (Table 2).
rate was evaluated after tenth sessions and sixteenth sessions. Mayo clinic scores and CRP levels were dramatically dropped after leukocytapheresis treatment (Fig. 1 and 2). Clinical response was observed in 80% (n = 16) of patients with UC. Both clinical response and mucosal healing were observed in 65% (n = 13) of patients with UC. Steroid therapy was gradually reduced and interrupted in these patients (%65 and n = 13). Patients were followed along average period of 24 months. Exacerbation of colitis was not observed in these patients during the follow-up period. In 15% of patients (n = 3) had not mucosal healing. Partial clinical response was determined. Mild colitis attack was observed with responding to temporary low dose steroids and anti-TNF alpha therapy in these patients. Both clinical response and mucosal healing did not appear in 20% (n = 4) of patients with UC. In these patients, clinical remission was achieved upon beginning anti TNF alpha (adalimumab) therapy. 30% (n = 6) of patients had high colectomy risk due to severe pancolitis. Dramatic clinical response and mucosal healing was observed in 5 of 6 patients (Picture 1A and B). Steroid therapy was completely interrupted after intensive leukocytapheresis period in these patients. Sustained remission was observed also in followup for 24 months. In this group, colectomy needs disappeared after leukocytapheresis. But in only one patient, clinical remission and mucosal healing were not detected. In this patient, clinical remission was achieved with starting anti TNF alpha (adalimumab) therapy. Acute pancreatitis due to UC was determined in two patients before leukocytapheresis. One patient had anchylosing spondylitis as comorbid condition with UC. In these patients with extraintestinal manifestations, dramatic remission had been achieved with leukocytapheresis and anti TNF alpha therapy combination. Relapse was not observed in follow-up period.
3.2. Leukocytapheresis outcomes in patients with UC 3.3. Leukocytapheresis outcomes of patients with CD Leukocytapheresis was performed 2 sessions per week in 14 of 20 patients. After 10 sessions the maintenance leukocytapheresis had been continued along six months in all patients. Intensive leukocytapheresis for remission induction (≥4 leukocytapheresis sessions within the first 2 weeks) was applied in 30% (n = 6) of patients with high colectomy risk. Leukocytapheresis response
Leukocytapheresis was performed in 6 patients with CD. Remission induction (2 times per week) and maintenance leukocytapheresis therapy was applied similar as patients with UC group. Clinical remission was observed in 5 of 6 patients after leukocytapheresis. It was observed that remission was determined
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Fig. 2. CRP levels of patients with UC during treatment period.
Picture 1. Colonoscopy images of patient with ulcerative colitis before and after leukocytapheresis treatment (1A: Before leukocytapheresis, 1B: After the 10th leukocytapheresis).
Picture 2. Colonoscopy images of patient with Crohn’s disease before and after leukocytapheresis treatment (2A: Before leukocytapheresis, 2B: After the 10th leukocytapheresis).
during follow-up period in these 5 patients. Steroid treatment was interrupted in these patients. Despite of all treatment agents and methods, inadequate response was observed only in one patient with CD. Severe colonic involvement and obstructive findings were encountered in 3 of 6 patients with CD. Surgical needs were disappeared in 3 patients with obstructive type of CD (Picture 2A and B). Colchicine-refractory FMF (Familial Mediterranean Fever) attacks were observed in one patient with CD. After leukocytapheresis sessions and anti TNF alpha treatment, FMF attacks were also successfully disappeared. In another patient with CD, pyo-
derma gangrenosum healed with leukocytapheresis and anti TNF alpha treatment. 3.4. Safety of leukocytapheresis in patients with IBD Leukocytapheresis was performed 73.1% (n = 19) of 26 patients via peripheral vascular access. Leukocytapheresis sessions was able to successfully applied by placing the jugular vein catheter because of failure to implement the optimal leukocytapheresis with peripheral vascular access in only 26.9% (n = 7) of patients. Leukocytapheresis was applied a total 416 sessions of 26 patients.
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Serious complications such as infection, thrombosis, embolism, anaphylactic reactions were not observed during leukocytapheresis applications. Mild hypotension responsive to fluid replacement was observed in the only 4.3% (n = 18) of leukocytapheresis sessions.
4. Discussion IBD is a complex disease which arises as a result of the interaction of genetic, immunological and environmental factors [18]. In the literature, current data showed that alterations of immunological reactions of the patients with IBD to their own enterable bacteria may contribute to inflammation [19]. It is demonstrated that mucosal and submucosal inflammation perpetuated by infiltration of activated leukocytes [2,8,20]. The ideal therapeutic goal is to achieve steroid free long lasting remission in patient with UC or CD [8–10]. As therapeutic alternative the main mediators of IBD, namely the activated pro-inflammatory cytokine producing leukocytes can be selectively removed via leukocytapheresis [8]. Leukocytapheresis is a novel non-pharmacologic approach for active ulcerative colitis (UC) and Crohn disease (CD), in which leukocytes are mechanically removed from the circulatory system [8,14,21–25]. Leukocytapheresis is a method often used to treatment IBD, particularly UC, in Japan. Over the last decade, they have also attracted much attention in Europe and North America. There are studies showing that leukocytapheresis is an effective alternative treatment with current drug therapies on steroid dependent or refractory patients in the treatment of IBD [13–15,26–28]. Until now, a number of uncontrolled studies using leukocytapheresis has been published over the last years with clinical response rates ranging from 62% to 84% and mucosal healing rate 62.5% [14,21]. No large-scale study in Turkey on leukocytapheresis has been reported. This present study was a retrospective study to investigate the treatment outcomes of leukocytapheresis for active UC and CD in the clinical practice setting. We were able to obtain short and long follow up period (24 months) results regarding to status of leukocytapheresis use for active UC and complicated CD with steroid refractory or dependent cases. Patients with active IBD (n = 26) treated with leukocytapheresis using a Cellsorba E column between January 2012 and May 2015 were enrolled in Turkey. Leukocytapheresis (10 sessions for remission induction therapy, 6 sessions for maintenance therapy) were applied to the patients with their concomitant medications. Leukocytapheresis can be performed for a maximum 16 times. Intensive leukocytapheresis was as safe as the conventional weekly procedure [14]. Intensive leukocytapheresis (≥4 leukocytapheresis sessions within the first 2 weeks) was used in %30 (n = 6) of patients with active UC. The overall clinical remission rate in patients with UC was 80% (16/20) but the mucosal healing rate was 65% (13/20). Clinical remission was achieved more rapidly in the intensive group than in the weekly group (2 times in a week). In our experience, adverse events (mild hypotension) were seen in only %4.3 of leukocytapheresis sessions (18/416). Serious complications such as infection, thrombosis, embolism, anaphylactic reactions were not observed during leukocytapheresis applications. Any concomitant medications did not increase the incidence of adverse events. Leukocytapheresis has been considered a safe treatment because it does not incorporate immunosuppression [14,26,29]. Our results indicate that leukocytapheresis is efficacious in improving remission rates with excellent tolerability and safety in patients with IBD. Therefore, as a non-pharmacological treatment strategy, leukocytapheresis has the potential to be a useful treatment option for patients, with active UC without increasing the incidence of adverse events. Patients were followed for an average of 24 months. It was observed that clinical remission has continued in 80% (n = 16) but
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the mucosal healing rate was only 65% (13/20). However, mucosal healing has been determined as an important goal of treatment patients with IBD [30]. In the literature, mucosal healing has been proposed to be an important measure of treatment efficacy. Some evidence has currently accumulated to show that mucosal healing can alter the course of IBD. In patients with ulcerative colitis, mucosal healing may represent ultimate therapeutic goal because inflammation is limited to colonic mucosa [31]. This study, however had no control group, we could not clearly define the efficacy of leukocytapheresis based on its results. The results of this study are based on 20 patients with UC whose had been monitored scheduled 24 months follow-up. These results may reflect the actual outcomes of leukocytapheresis as a treatment strategy in clinical practice. CMV colitis often occurs in UC, particularly in patients who have recently been treated with high-dose steroids and immunosuppressive agents. Patients with UC and CMV colitis seem to have a poorer prognosis, as indicated by the greater need for rescue therapy. Many studies have reported the prevalence of CMV infection in patients with IBD. The prevalence of CMV infection in patients with severe UC and steroid-refractory colitis has been reported as 21-38%. The human CMV infection rates in patients with severe UC and patients with steroid-dependent UC are higher than those in patients with active Crohn’s disease. In the literature, histological evaluation of biopsy specimens is essential to examine human CMV infection in colonic mucosa of active UC [32,33]. In present study, 6 patients with UC, CMV was determined in colon tissue by PCR. In present study, the detection of CMV in biopsy specimens by histologic examinations, the detection of inclusion bodies and immunohistochemistry had not been performed. Patients with UC and CMV colitis were easily treated with intravenous and per oral ganciclovir treatment. Anti-CMV therapy may probably cause an additive efficacy of leukocytapheresis. In this regard, the application of the mucosal PCR method for evaluating CMV infection should be considered in patients with steroid refractory UC. Although the majority of clinical studies enrolled only small numbers of patients with CD, leukocytapheresis showed clinical efficacy with an excellent safety profile [34,35]. In present study, significant clinical remission was achieved in 5 patients with CD. Only in one patient mild relapse was observed during follow up period. Surgical needs were disappeared in 3 patients with obstructive type Crohn’s disease. 5. Conclusions UC and CD are chronically inflammatory bowel diseases that significantly impair quality of life with severe relapses. This demanding patient group warrants the search for new treatment strategies beside conventional therapies. By this study, we conclude that leukocytapheresis can be a safe and effective treatment option in maintaining steroid unresponsive severe relapses in UC and also in CD. Larger studies are needed to show the effect of leukocytapheresis in inducing remission in IBD. References [1] Loftus Jr EV. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 2004;126:1504–17. [2] Quetglas EG, Mujagic Z, Wigge S, Keszthelyi D, Wachten S, Masclee A, et al. Update on pathogenesis and predictors of response of therapeutic strategies used in inflammatory bowel disease. World J Gastroenterol 2015;21:12519–43. [3] Schreiber S, Nikolaus S, Hampe J, Hamling J, Koop I, Groessner B, et al. Tumour necrosis factor alpha and interleukin 1beta in relapse of Crohn’s disease. Lancet 1999;353:459–61. [4] Papadakis KA, Targan SR. Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med 2000;51:289–98. [5] Nikolaus S, Bauditz J, Gionchetti P, Witt C, Lochs H, Schreiber S. Increased secretion of pro-inflammatory cytokines by circulating polymorphonuclear
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6
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18] [19] [20]
neutrophils and regulation by interleukin 10 during intestinal inflammation. Gut 1998;42:470–6. Tibble JA, Sigthorsson G, Bridger S, Fagerhol MK, Bjarnason I. Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease. Gastroenterology 2000;119:15–22. Lugering N, Kucharzik T, Stoll R, Domschke W. Current concept of the role of monocytes/macrophages in inflammatory bowel disease–balance of proinflammatory and immunosuppressive mediators. Ital J Gastroenterol Hepatol 1998;30:338–44. Leitner GC, Vogelsang H. Pharmacological- and non-pharmacological therapeutic approaches in inflammatory bowel disease in adults. World J Gastrointest Pharmacol Ther 2016;7:5–20. Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel JF, Allez M, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohns Colitis 2012;6:991–1030. Dignass A, Van Assche G, Lindsay JO, Lemann M, Soderholm J, Colombel JF, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: current management. J Crohns Colitis 2010;4:28–62. Vecchi M, Vernia P, Riegler G, D’Inca R, Annese V, Bagnoli S. Therapeutic landscape for ulcerative colitis: where is the Adacolumn((R)) system and where should it be? Clin Exp Gastroenterol 2013;6:1–7. Suemitsu J, Yoshida M, Yamawaki N, Yamashita Y. Leukocytapheresis therapy by extracorporeal circulation using a leukocyte removal filter. Ther Apher 1998;2:31–6. Saniabadi AR, Tanaka T, Ohmori T, Sawada K, Yamamoto T, Hanai H. Treating inflammatory bowel disease by adsorptive leucocytapheresis: a desire to treat without drugs. World J Gastroenterol 2014;20:9699–715. Yokoyama Y, Matsuoka K, Kobayashi T, Sawada K, Fujiyoshi T, Ando T, et al. A large-scale, prospective, observational study of leukocytapheresis for ulcerative colitis: treatment outcomes of 847 patients in clinical practice. J Crohns Colitis 2014;8:981–91. Shiraki M, Yamamoto T. Steroid-sparing strategies in the management of ulcerative colitis: efficacy of leukocytapheresis. World J Gastroenterol 2012;18:5833–8. Dignass A, Eliakim R, Magro F, Maaser C, Chowers Y, Geboes K, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. J Crohns Colitis 2012;6:965–90. Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, Allez M, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: definitions and diagnosis. J Crohns Colitis 2010;4:7–27. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011;474:307–17. Mukhopadhya I, Hansen R, El-Omar EM, Hold GL. IBD-what role do Proteobacteria play? Nat Rev Gastroenterol Hepatol 2012;9:219–30. Grisham MB, Yamada T. Neutrophils, nitrogen oxides, and inflammatory bowel disease. Ann N Y Acad Sci 1992;664:103–15.
[21] Arseneau KO, Cominelli F. Leukocytapheresis in ulcerative colitis: a possible alternative to biological therapy? Dig Liver Dis 2009;41:551–2. [22] Hanai H, Watanabe F, Yamada M, Sato Y, Takeuchi K, Iida T, et al. Adsorptive granulocyte and monocyte apheresis versus prednisolone in patients with corticosteroid-dependent moderately severe ulcerative colitis. Digestion 2004;70:36–44. [23] Emmrich J, Petermann S, Nowak D, Beutner I, Brock P, Klingel R, et al. Leukocytapheresis (LCAP) in the management of chronic active ulcerative colitis–results of a randomized pilot trial. Dig Dis Sci 2007;52:2044–53. [24] Cabriada JL, Domenech E, Ibargoyen N, Hernandez V, Clofent J, Ginard D, et al. Leukocytapheresis for steroid-dependent ulcerative colitis in clinical practice: results of a nationwide Spanish registry. J Gastroenterol 2012;47:359–65. [25] Yamamoto T, Umegae S, Matsumoto K. Long-term clinical impact of early introduction of granulocyte and monocyte adsorptive apheresis in new onset, moderately active, extensive ulcerative colitis. J Crohns Colitis 2012;6:750–5. [26] Tominaga K, Nakano M, Hoshino M, Kanke K, Hiraishi H. Efficacy, safety and cost analyses in ulcerative colitis patients undergoing granulocyte and monocyte adsorption or receiving prednisolone. BMC Gastroenterol 2013;13:41. [27] De Cassan C, Savarino E, Marson P, Tison T, Hatem G, Sturniolo GC, et al. Granulo-monocyto apheresis is more effective in mild ulcerative colitis than in moderate to severe disease. World J Gastroenterol 2014;20:17155–62. [28] Fukunaga K, Nagase K, Kusaka T, Hida N, Ohda Y, Yoshida K, et al. Cytapheresis in patients with severe ulcerative colitis after failure of intravenous corticosteroid: a long-term retrospective cohort study. Gut Liver 2009;3:41–7. [29] Mitsuyama K, Andoh A, Masuda J, Yamasaki H, Kuwaki K, Takedatsu H, et al. Mobilization of bone marrow cells by leukocytapheresis in patients with ulcerative colitis. Ther Apher Dial 2008;12:271–7. [30] Pineton de Chambrun G, Peyrin-Biroulet L, Lemann M, Colombel JF. Clinical implications of mucosal healing for the management of IBD. Nat Rev Gastroenterol Hepatol 2010;7:15–29. [31] Froslie KF, Jahnsen J, Moum BA, Vatn MH. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133:412–22. [32] Nakase H, Honzawa Y, Toyonaga T, Yamada S, Minami N, Yoshino T, et al. Diagnosis and treatment of ulcerative colitis with cytomegalovirus infection: importance of controlling mucosal inflammation to prevent cytomegalovirus reactivation. Intest Res 2014;12:5–11. [33] Lee HS, Park SH, Kim SH, Kim J, Choi J, Lee HJ, et al. Risk Factors and Clinical Outcomes Associated with Cytomegalovirus Colitis in Patients with Acute Severe Ulcerative Colitis. Inflamm Bowel Dis 2016. [34] Matsui T, Nishimura T, Matake H, Ohta T, Sakurai T, Yao T. Granulocytapheresis for Crohn’s disease: a report on seven refractory patients. Am J Gastroenterol 2003;98:511–2. [35] Fukuda Y, Matsui T, Suzuki Y, Kanke K, Matsumoto T, Takazoe M, et al. Adsorptive granulocyte and monocyte apheresis for refractory Crohn’s disease: an open multicenter prospective study. J Gastroenterol 2004;39:1158–64.
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Treatment of inflammatory bowel disease by leukocytapheresis Emre Gerc¸eker a,∗ , Hakan Yüceyar b , Elmas Kasap b , Ufuk Demirci c , Burcu Ceren Ekti c , I˙ smet Aydo˘gdu d , Mine Miskio˘glu d Departments of Gastroenterology, Gazi Hospital, I˙ zmir, Turkey Departments of Gastroenterology, Medical Faculty, Celal Bayar University, Manisa, Turkey c Departments of Internal Medicine, Medical Faculty, Celal Bayar University, Manisa, Turkey d Departments of Hematology, Medical Faculty, Celal Bayar University, Manisa, Turkey a
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a r t i c l e
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Article history: Received 17 November 2016 Received in revised form 25 March 2017 Accepted 30 March 2017 Available online xxx Keywords: Crohn’s disease Inflammatory bowel disease Leukocytapheresis Ulcerative colitis
a b s t r a c t Studies about leukocytapheresis have emerged with the need of search for alternatives to conventional treatment in inflammatory bowel diseases (IBD). Leukocytapheresis is a novel non-pharmacologic approach for active ulcerative colitis (UC) and Crohn’s disease (CD), in which leukocytes are mechanically removed from the circulatory system. Patients with active IBD treated with leukocytapheresis using a Cellsorba E column between 2012 and 2015, were enrolled in Turkey. In our experience, the results of leukocytapheresis therapy in 6 patients with CD and 20 patients with active UC were overviewed. Leukocytapheresis (10 sessions for remission induction therapy, 6 sessions for maintenance therapy) was applied to the patients with their concomitant medications. Intensive leukocytapheresis (≥4 leukocytapheresis sessions within the first 2 weeks) was used in 30% patients with active severe UC. The overall clinical remission rate in patients with UC was 80%, and the mucosal healing rate was 65%. Patients were followed for an average of 24 months. It was observed that clinical remission has continued in 65% of patients with UC. Mild relapse was observed in 3 patients with UC during follow up period. In 5 patients with CD significant clinical remission was achieved except only one patient. Surgical needs were disappeared in 3 patients with obstructive type Crohn’s disease. Adverse events were seen in only 4.3% of 416 sessions. Any concomitant medications did not increase the incidence of adverse events. Our results indicate that leukocytapheresis is efficacious in improving remission rates with excellent tolerability and safety in patients with IBD. © 2017 Elsevier Ltd. All rights reserved.
1. Introduction Inflammatory bowel disease (IBD) (ulcerative colitis (UC) and Crohn’s disease (CD)) is a chronic inflammatory disease of gastrointestinal tract associated with the relapses and remissions [1]. Inflammation in IBD is emerging results of an unusual series of exaggerated immune reaction developing against unknown peripheral antigens in genetically susceptible individuals. It is thought that encountering with pro-inflammatory antigens depending on the increased permeability of the intestinal epithelium, irregularities in the activation of T helper 1 (Th1) and T
Abbreviations: AZA, azathioprine; CD, Crohn’s disease; CsA, cyclosporine; CMV, cytomegalovirus; IBD, inflammatory bowel disease; UC, ulcerative colitis. ∗ Corresponding author. E-mail addresses: [email protected] (E. Gerc¸eker), [email protected] (H. Yüceyar), [email protected] (E. Kasap), [email protected] (U. Demirci), [email protected] (B.C. Ekti), [email protected] (I˙ . Aydo˘gdu), [email protected] (M. Miskio˘glu).
helper 2 (Th2) lymphocytes, disorder in cytokine regulation indicating increase in favor of pro-inflammatory cytokines are playing role in IBD immune pathogenesis [2–7]. In IBD therapy, ensuring and maintaining of clinical remission is expected. It’s also aimed to improve quality of patient’s life and safety. Effort is also made to prevent or reduce the complications (bleeding, perforation, fistula, stricture and cancer, etc.). Main targets are reduction of drug toxicity, reducing the need for hospitalization and eliminating the surgical intervention [8–10]. It is intended to suppress lymphocytes and cytokines responsible from inflammation and to maintain this suppression. Conventional medical treatment agents used for this purpose are mesalazine, corticosteroids, azathioprine (AZA), cyclosporine (CsA), tacrolimus, anti TNF alpha (infliximab, adalimumab) [8–10]. Corticosteroids are effective in many IBD patients. However, their long-term use may cause various adverse effects, including diabetes mellitus, Cushingoid appearance, infections, osteoporosis and vertebral fracture. Therefore, long-term use of corticosteroids in the medical therapy of IBD should be limited. Dosage and timing of the therapy cannot be adjusted optimally
http://dx.doi.org/10.1016/j.transci.2017.03.016 1473-0502/© 2017 Elsevier Ltd. All rights reserved.
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in conventional medical treatments due to the side effects of the drugs. Therefore, this problem is the most important issue causes difficulties to ensure the induction and maintenance of remission. The majority of these drugs present several severe side effects, requiring careful attention in drug dosage and duration [9,10]. Leukocytapheresis has emerged as a non-pharmacological treatment with few side effects [8]. The mechanism of action consists of the removal of the cell population involved in the induction and perpetuation of bowel inflammation from the peripheral blood [11]. Circulating cytokines and specific inflammatory cells can be removed from blood by the use of the specific filters in extracorporeal leukocyteapheresis systems [12]. There are limited number of studies indicating the use of extracorporeal leukocytapheresis systems which are used in the treatment of IBD, combined with the conventional therapies in induction and maintenance of remission in IBD [13]. It is observed that the experience is increasing gradually in literature. Besides limited experience in the CD patients; there is also available increasing data regarding significant benefits are achieved especially in the patients with severe ulcerative colitis [14]. Leukocytapheresis was initiated into the treatment of steroid dependent or resistant patients with active inflammatory bowel disease [15]. We performed a retrospective study of patients with IBD. The results were evaluated for its efficiency, reliability and feasibility by the way of retrospective analysis. 2. Material-method 2.1. Study design, localization of study and patients This post-marketing study was conducted in accordance with the Turkish Ministry of Health. This study is carried out by the approval of Scientific Research Ethics Committee of Celal Bayar University Medical Faculty with number 356 and dated 30/09/2015. Patients were recruited from Gastroenterology Department of Medical Faculty in Celal Bayar University between January 2012 and May 2015. Leukocytapheresis was performed for steroid dependent or steroid resistant patients who were histologically, clinically and endoscopically proven IBD. The treatment strategy for each patient, including the course of leukocytapheresis, was determined by the attending physicians. Twenty six patients with IBD were enrolled. Twenty patients with UC and six patients with CD were overviewed. The observation period spanned from 4 weeks before the first leukocytapheresis session to 2 weeks after the last leukocytapheresis session. After the observation period, the participating physician entered all data of patients. 2.2. Leukocytapheresis treatment Consent form was taken from each patient before commencing to leukocytapheresis treatment. Each patient was evaluated and received approval for process conformity by hematologist. Leukocytapheresis was performed using Cellsorba E, a column filled with nonwoven polyester fiber that removes leukocytes. Leukocytapheresis was performed 10 sessions (2–3 times per week) for remission induction and 6 sessions (once per month) for maintenance therapy 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. Totally 16 sessions of leukocytapheresis therapy were applied. 2.3. Concomitant medical treatment The baseline patient information routinely recorded included mesalazine, steroid, AZA, anti TNF alpha agents. All agents were continued with leukocytapheresis in all patients. After leukocytapheresis treatment, steroid agents were interrupted in patients
upon the achievement of clinical and mucosal remission. The maintenance treatment strategy was determined by gastroenterologists. In some patients with IBD, CMV (cytomegalovirus) infection was determined in the colon samples by PCR. Leukocytapheresis and intravenous antiviral agent (ganciclovir) was simultaneously performed. Per oral ganciclovir was given as a maintenance treatment. 2.4. Assessment of treatment outcomes Age, sex, another systemic diseases, duration of disease, extend of disease, extra-intestinal involvement, concomitant medications before leukocytapheresis, the presence/absence of corticosteroid resistance/dependence were recorded. Steroid refractoriness was defined as active disease despite prednisone up to 0.75-1.00 mg/kg per day over a period of at least 4 week. Steroid dependence patients were defined; who are either unable to reduce steroids below the equivalent of prednisolone 10 mg/day within 3 months of starting steroids, without recurrent active disease or who have a relapse within 3 months of stopping steroids [16,17]. All adverse events during the observational periods were recorded for the safety evaluation by the attending physicians. Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA/J version 15.1). Mayo Clinical Score in patients with UC, CDAI (Crohn’s disease activity index) score in patients with CD; were recorded at baseline (before the first leukocytapheresis) and 2 weeks after the last leukocytapheresis (tenth) session. All patients were examined after 6th and 12th mounts at the end of 16th sessions. Blood tests, radiological and colonoscopic examinations were recorded along the observation period. Patients were followed during the average period of 24 mounts after leukocytapheresis. Mayo Clinical Score ≤ 4 at 2 weeks after the last leukocytapheresis session was defined as clinical remission. Clinical remission or a decrease in scores that were at least half of the pre- leukocytapheresis value was defined as clinical improvement. The Endoscopic Index (EI) of the Disease Activity Index (DAI) at baseline and at 2 weeks after the last leukocytapheresis session was recorded in all patients. An EI ≤ 1 at 2 weeks after the last leukocytapheresis session was defined as mucosal healing. 3. Results 3.1. Demographic background of patients with IBD All of the patients with IBD (20 patients with UC and 6 patients with CD) were evaluated retrospectively. 84.6% (n = 22) of patients were men, 16.4% (n = 4) were women. Average ages were 41.85. The average time of UC diagnosis was 6.71 years (min-max; 2–12 years). 65% (n = 13) of these patients were pancolitis, 35% (n = 7) left colitis. All patients had symptoms with active colitis. Steroid refractoriness was found in all patients. Before leukocytapheresis application, all of patients had a treatment history with steroid, mesalazine and AZA. In addition, 15% (n = 3) of the patients had a treatment history with anti-TNF alpha (adalimumab). The average Mayo Clinical Score was 10.20 (min-max: 8–12) before leukocytapheresis. The average CRP level was 31.34 mg/dL (minmax: 24.4–37.8 mg/dL). Before leukocytapheresis applications, 30% (n = 6) of patients with UC had colectomy risk. Before leukocytapheresis, CMV had been determined in 30% of patients with UC by PCR with colon biopsy. Intravenous and per oral antiviral ganciclovir agents were used for CMV colitis (Table 1). In this study, 6 patients with CD were enrolled. The average time of CD diagnosis was 7.66 years (min-max; 3–15 years). Only one patient with CD had isolated ileal involvement, 5 of 6 patients had ileal and colonic involvement. We encountered severe dis-
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Fig. 1. Mayo Clinic Score of patients with UC during treatment period.
Table 1 Demographic background of patients with UC (n = 20). Disease duration (Year average, min-max)
6.71 (2–12)
Extend of UC (Pancolitis/left colitis) Mayo Score average; min-max Disease CRP severity Patient with pancolitis and total colectomy risk Patient with steroid refractory Medication before leukocytapheresis (With/without Anti TNF alpha) CMV colitis before leukocytapheresis
13/7 (65%/35%) 10.20 (8–12) 31.34 (24.4–37.8) 6 (30%) 20 (100%) 3/17 (15%/85%) 6 (30%)
Table 2 Demographic background of patients with CD (n = 6). Disease duration (Year average; min-max)
7.66 (3-15)
Extend of CD (Only ileum/ileum and colon) Disease Severity (CDAI Score average, min-max) Medication before leukocytapheresis (steroid + mesalasine + AZA + anti TNF alpha)
1/5 412.1 (320–482) 6 (100%)
ease activities in all of them (CDAI ≥ 220, annual attack number ≥ 2, persistence CD symptoms with long period). The average CDAI was 412.1 (min-max; 320–482) before leukocytapheresis. 3 of 6 patients had obstructive type of CD. In one of all patients, perianal fistula was visualized radiologically. Conventional therapeutic agents (such as mezalazine, steroid, AZA, anti TNF alpha) were recorded (Table 2).
rate was evaluated after tenth sessions and sixteenth sessions. Mayo clinic scores and CRP levels were dramatically dropped after leukocytapheresis treatment (Fig. 1 and 2). Clinical response was observed in 80% (n = 16) of patients with UC. Both clinical response and mucosal healing were observed in 65% (n = 13) of patients with UC. Steroid therapy was gradually reduced and interrupted in these patients (%65 and n = 13). Patients were followed along average period of 24 months. Exacerbation of colitis was not observed in these patients during the follow-up period. In 15% of patients (n = 3) had not mucosal healing. Partial clinical response was determined. Mild colitis attack was observed with responding to temporary low dose steroids and anti-TNF alpha therapy in these patients. Both clinical response and mucosal healing did not appear in 20% (n = 4) of patients with UC. In these patients, clinical remission was achieved upon beginning anti TNF alpha (adalimumab) therapy. 30% (n = 6) of patients had high colectomy risk due to severe pancolitis. Dramatic clinical response and mucosal healing was observed in 5 of 6 patients (Picture 1A and B). Steroid therapy was completely interrupted after intensive leukocytapheresis period in these patients. Sustained remission was observed also in followup for 24 months. In this group, colectomy needs disappeared after leukocytapheresis. But in only one patient, clinical remission and mucosal healing were not detected. In this patient, clinical remission was achieved with starting anti TNF alpha (adalimumab) therapy. Acute pancreatitis due to UC was determined in two patients before leukocytapheresis. One patient had anchylosing spondylitis as comorbid condition with UC. In these patients with extraintestinal manifestations, dramatic remission had been achieved with leukocytapheresis and anti TNF alpha therapy combination. Relapse was not observed in follow-up period.
3.2. Leukocytapheresis outcomes in patients with UC 3.3. Leukocytapheresis outcomes of patients with CD Leukocytapheresis was performed 2 sessions per week in 14 of 20 patients. After 10 sessions the maintenance leukocytapheresis had been continued along six months in all patients. Intensive leukocytapheresis for remission induction (≥4 leukocytapheresis sessions within the first 2 weeks) was applied in 30% (n = 6) of patients with high colectomy risk. Leukocytapheresis response
Leukocytapheresis was performed in 6 patients with CD. Remission induction (2 times per week) and maintenance leukocytapheresis therapy was applied similar as patients with UC group. Clinical remission was observed in 5 of 6 patients after leukocytapheresis. It was observed that remission was determined
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Fig. 2. CRP levels of patients with UC during treatment period.
Picture 1. Colonoscopy images of patient with ulcerative colitis before and after leukocytapheresis treatment (1A: Before leukocytapheresis, 1B: After the 10th leukocytapheresis).
Picture 2. Colonoscopy images of patient with Crohn’s disease before and after leukocytapheresis treatment (2A: Before leukocytapheresis, 2B: After the 10th leukocytapheresis).
during follow-up period in these 5 patients. Steroid treatment was interrupted in these patients. Despite of all treatment agents and methods, inadequate response was observed only in one patient with CD. Severe colonic involvement and obstructive findings were encountered in 3 of 6 patients with CD. Surgical needs were disappeared in 3 patients with obstructive type of CD (Picture 2A and B). Colchicine-refractory FMF (Familial Mediterranean Fever) attacks were observed in one patient with CD. After leukocytapheresis sessions and anti TNF alpha treatment, FMF attacks were also successfully disappeared. In another patient with CD, pyo-
derma gangrenosum healed with leukocytapheresis and anti TNF alpha treatment. 3.4. Safety of leukocytapheresis in patients with IBD Leukocytapheresis was performed 73.1% (n = 19) of 26 patients via peripheral vascular access. Leukocytapheresis sessions was able to successfully applied by placing the jugular vein catheter because of failure to implement the optimal leukocytapheresis with peripheral vascular access in only 26.9% (n = 7) of patients. Leukocytapheresis was applied a total 416 sessions of 26 patients.
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Serious complications such as infection, thrombosis, embolism, anaphylactic reactions were not observed during leukocytapheresis applications. Mild hypotension responsive to fluid replacement was observed in the only 4.3% (n = 18) of leukocytapheresis sessions.
4. Discussion IBD is a complex disease which arises as a result of the interaction of genetic, immunological and environmental factors [18]. In the literature, current data showed that alterations of immunological reactions of the patients with IBD to their own enterable bacteria may contribute to inflammation [19]. It is demonstrated that mucosal and submucosal inflammation perpetuated by infiltration of activated leukocytes [2,8,20]. The ideal therapeutic goal is to achieve steroid free long lasting remission in patient with UC or CD [8–10]. As therapeutic alternative the main mediators of IBD, namely the activated pro-inflammatory cytokine producing leukocytes can be selectively removed via leukocytapheresis [8]. Leukocytapheresis is a novel non-pharmacologic approach for active ulcerative colitis (UC) and Crohn disease (CD), in which leukocytes are mechanically removed from the circulatory system [8,14,21–25]. Leukocytapheresis is a method often used to treatment IBD, particularly UC, in Japan. Over the last decade, they have also attracted much attention in Europe and North America. There are studies showing that leukocytapheresis is an effective alternative treatment with current drug therapies on steroid dependent or refractory patients in the treatment of IBD [13–15,26–28]. Until now, a number of uncontrolled studies using leukocytapheresis has been published over the last years with clinical response rates ranging from 62% to 84% and mucosal healing rate 62.5% [14,21]. No large-scale study in Turkey on leukocytapheresis has been reported. This present study was a retrospective study to investigate the treatment outcomes of leukocytapheresis for active UC and CD in the clinical practice setting. We were able to obtain short and long follow up period (24 months) results regarding to status of leukocytapheresis use for active UC and complicated CD with steroid refractory or dependent cases. Patients with active IBD (n = 26) treated with leukocytapheresis using a Cellsorba E column between January 2012 and May 2015 were enrolled in Turkey. Leukocytapheresis (10 sessions for remission induction therapy, 6 sessions for maintenance therapy) were applied to the patients with their concomitant medications. Leukocytapheresis can be performed for a maximum 16 times. Intensive leukocytapheresis was as safe as the conventional weekly procedure [14]. Intensive leukocytapheresis (≥4 leukocytapheresis sessions within the first 2 weeks) was used in %30 (n = 6) of patients with active UC. The overall clinical remission rate in patients with UC was 80% (16/20) but the mucosal healing rate was 65% (13/20). Clinical remission was achieved more rapidly in the intensive group than in the weekly group (2 times in a week). In our experience, adverse events (mild hypotension) were seen in only %4.3 of leukocytapheresis sessions (18/416). Serious complications such as infection, thrombosis, embolism, anaphylactic reactions were not observed during leukocytapheresis applications. Any concomitant medications did not increase the incidence of adverse events. Leukocytapheresis has been considered a safe treatment because it does not incorporate immunosuppression [14,26,29]. Our results indicate that leukocytapheresis is efficacious in improving remission rates with excellent tolerability and safety in patients with IBD. Therefore, as a non-pharmacological treatment strategy, leukocytapheresis has the potential to be a useful treatment option for patients, with active UC without increasing the incidence of adverse events. Patients were followed for an average of 24 months. It was observed that clinical remission has continued in 80% (n = 16) but
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the mucosal healing rate was only 65% (13/20). However, mucosal healing has been determined as an important goal of treatment patients with IBD [30]. In the literature, mucosal healing has been proposed to be an important measure of treatment efficacy. Some evidence has currently accumulated to show that mucosal healing can alter the course of IBD. In patients with ulcerative colitis, mucosal healing may represent ultimate therapeutic goal because inflammation is limited to colonic mucosa [31]. This study, however had no control group, we could not clearly define the efficacy of leukocytapheresis based on its results. The results of this study are based on 20 patients with UC whose had been monitored scheduled 24 months follow-up. These results may reflect the actual outcomes of leukocytapheresis as a treatment strategy in clinical practice. CMV colitis often occurs in UC, particularly in patients who have recently been treated with high-dose steroids and immunosuppressive agents. Patients with UC and CMV colitis seem to have a poorer prognosis, as indicated by the greater need for rescue therapy. Many studies have reported the prevalence of CMV infection in patients with IBD. The prevalence of CMV infection in patients with severe UC and steroid-refractory colitis has been reported as 21-38%. The human CMV infection rates in patients with severe UC and patients with steroid-dependent UC are higher than those in patients with active Crohn’s disease. In the literature, histological evaluation of biopsy specimens is essential to examine human CMV infection in colonic mucosa of active UC [32,33]. In present study, 6 patients with UC, CMV was determined in colon tissue by PCR. In present study, the detection of CMV in biopsy specimens by histologic examinations, the detection of inclusion bodies and immunohistochemistry had not been performed. Patients with UC and CMV colitis were easily treated with intravenous and per oral ganciclovir treatment. Anti-CMV therapy may probably cause an additive efficacy of leukocytapheresis. In this regard, the application of the mucosal PCR method for evaluating CMV infection should be considered in patients with steroid refractory UC. Although the majority of clinical studies enrolled only small numbers of patients with CD, leukocytapheresis showed clinical efficacy with an excellent safety profile [34,35]. In present study, significant clinical remission was achieved in 5 patients with CD. Only in one patient mild relapse was observed during follow up period. Surgical needs were disappeared in 3 patients with obstructive type Crohn’s disease. 5. Conclusions UC and CD are chronically inflammatory bowel diseases that significantly impair quality of life with severe relapses. This demanding patient group warrants the search for new treatment strategies beside conventional therapies. By this study, we conclude that leukocytapheresis can be a safe and effective treatment option in maintaining steroid unresponsive severe relapses in UC and also in CD. Larger studies are needed to show the effect of leukocytapheresis in inducing remission in IBD. References [1] Loftus Jr EV. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 2004;126:1504–17. [2] Quetglas EG, Mujagic Z, Wigge S, Keszthelyi D, Wachten S, Masclee A, et al. Update on pathogenesis and predictors of response of therapeutic strategies used in inflammatory bowel disease. World J Gastroenterol 2015;21:12519–43. [3] Schreiber S, Nikolaus S, Hampe J, Hamling J, Koop I, Groessner B, et al. Tumour necrosis factor alpha and interleukin 1beta in relapse of Crohn’s disease. Lancet 1999;353:459–61. [4] Papadakis KA, Targan SR. Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med 2000;51:289–98. [5] Nikolaus S, Bauditz J, Gionchetti P, Witt C, Lochs H, Schreiber S. Increased secretion of pro-inflammatory cytokines by circulating polymorphonuclear
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[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18] [19] [20]
neutrophils and regulation by interleukin 10 during intestinal inflammation. Gut 1998;42:470–6. Tibble JA, Sigthorsson G, Bridger S, Fagerhol MK, Bjarnason I. Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease. Gastroenterology 2000;119:15–22. Lugering N, Kucharzik T, Stoll R, Domschke W. Current concept of the role of monocytes/macrophages in inflammatory bowel disease–balance of proinflammatory and immunosuppressive mediators. Ital J Gastroenterol Hepatol 1998;30:338–44. Leitner GC, Vogelsang H. Pharmacological- and non-pharmacological therapeutic approaches in inflammatory bowel disease in adults. World J Gastrointest Pharmacol Ther 2016;7:5–20. Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel JF, Allez M, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohns Colitis 2012;6:991–1030. Dignass A, Van Assche G, Lindsay JO, Lemann M, Soderholm J, Colombel JF, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: current management. J Crohns Colitis 2010;4:28–62. Vecchi M, Vernia P, Riegler G, D’Inca R, Annese V, Bagnoli S. Therapeutic landscape for ulcerative colitis: where is the Adacolumn((R)) system and where should it be? Clin Exp Gastroenterol 2013;6:1–7. Suemitsu J, Yoshida M, Yamawaki N, Yamashita Y. Leukocytapheresis therapy by extracorporeal circulation using a leukocyte removal filter. Ther Apher 1998;2:31–6. Saniabadi AR, Tanaka T, Ohmori T, Sawada K, Yamamoto T, Hanai H. Treating inflammatory bowel disease by adsorptive leucocytapheresis: a desire to treat without drugs. World J Gastroenterol 2014;20:9699–715. Yokoyama Y, Matsuoka K, Kobayashi T, Sawada K, Fujiyoshi T, Ando T, et al. A large-scale, prospective, observational study of leukocytapheresis for ulcerative colitis: treatment outcomes of 847 patients in clinical practice. J Crohns Colitis 2014;8:981–91. Shiraki M, Yamamoto T. Steroid-sparing strategies in the management of ulcerative colitis: efficacy of leukocytapheresis. World J Gastroenterol 2012;18:5833–8. Dignass A, Eliakim R, Magro F, Maaser C, Chowers Y, Geboes K, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. J Crohns Colitis 2012;6:965–90. Van Assche G, Dignass A, Panes J, Beaugerie L, Karagiannis J, Allez M, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: definitions and diagnosis. J Crohns Colitis 2010;4:7–27. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011;474:307–17. Mukhopadhya I, Hansen R, El-Omar EM, Hold GL. IBD-what role do Proteobacteria play? Nat Rev Gastroenterol Hepatol 2012;9:219–30. Grisham MB, Yamada T. Neutrophils, nitrogen oxides, and inflammatory bowel disease. Ann N Y Acad Sci 1992;664:103–15.
[21] Arseneau KO, Cominelli F. Leukocytapheresis in ulcerative colitis: a possible alternative to biological therapy? Dig Liver Dis 2009;41:551–2. [22] Hanai H, Watanabe F, Yamada M, Sato Y, Takeuchi K, Iida T, et al. Adsorptive granulocyte and monocyte apheresis versus prednisolone in patients with corticosteroid-dependent moderately severe ulcerative colitis. Digestion 2004;70:36–44. [23] Emmrich J, Petermann S, Nowak D, Beutner I, Brock P, Klingel R, et al. Leukocytapheresis (LCAP) in the management of chronic active ulcerative colitis–results of a randomized pilot trial. Dig Dis Sci 2007;52:2044–53. [24] Cabriada JL, Domenech E, Ibargoyen N, Hernandez V, Clofent J, Ginard D, et al. Leukocytapheresis for steroid-dependent ulcerative colitis in clinical practice: results of a nationwide Spanish registry. J Gastroenterol 2012;47:359–65. [25] Yamamoto T, Umegae S, Matsumoto K. Long-term clinical impact of early introduction of granulocyte and monocyte adsorptive apheresis in new onset, moderately active, extensive ulcerative colitis. J Crohns Colitis 2012;6:750–5. [26] Tominaga K, Nakano M, Hoshino M, Kanke K, Hiraishi H. Efficacy, safety and cost analyses in ulcerative colitis patients undergoing granulocyte and monocyte adsorption or receiving prednisolone. BMC Gastroenterol 2013;13:41. [27] De Cassan C, Savarino E, Marson P, Tison T, Hatem G, Sturniolo GC, et al. Granulo-monocyto apheresis is more effective in mild ulcerative colitis than in moderate to severe disease. World J Gastroenterol 2014;20:17155–62. [28] Fukunaga K, Nagase K, Kusaka T, Hida N, Ohda Y, Yoshida K, et al. Cytapheresis in patients with severe ulcerative colitis after failure of intravenous corticosteroid: a long-term retrospective cohort study. Gut Liver 2009;3:41–7. [29] Mitsuyama K, Andoh A, Masuda J, Yamasaki H, Kuwaki K, Takedatsu H, et al. Mobilization of bone marrow cells by leukocytapheresis in patients with ulcerative colitis. Ther Apher Dial 2008;12:271–7. [30] Pineton de Chambrun G, Peyrin-Biroulet L, Lemann M, Colombel JF. Clinical implications of mucosal healing for the management of IBD. Nat Rev Gastroenterol Hepatol 2010;7:15–29. [31] Froslie KF, Jahnsen J, Moum BA, Vatn MH. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133:412–22. [32] Nakase H, Honzawa Y, Toyonaga T, Yamada S, Minami N, Yoshino T, et al. Diagnosis and treatment of ulcerative colitis with cytomegalovirus infection: importance of controlling mucosal inflammation to prevent cytomegalovirus reactivation. Intest Res 2014;12:5–11. [33] Lee HS, Park SH, Kim SH, Kim J, Choi J, Lee HJ, et al. Risk Factors and Clinical Outcomes Associated with Cytomegalovirus Colitis in Patients with Acute Severe Ulcerative Colitis. Inflamm Bowel Dis 2016. [34] Matsui T, Nishimura T, Matake H, Ohta T, Sakurai T, Yao T. Granulocytapheresis for Crohn’s disease: a report on seven refractory patients. Am J Gastroenterol 2003;98:511–2. [35] Fukuda Y, Matsui T, Suzuki Y, Kanke K, Matsumoto T, Takazoe M, et al. Adsorptive granulocyte and monocyte apheresis for refractory Crohn’s disease: an open multicenter prospective study. J Gastroenterol 2004;39:1158–64.
Please cite this article in press as: Gerc¸eker E, et al. Treatment of inflammatory bowel disease by leukocytapheresis. Transfus Apheresis Sci (2017), http://dx.doi.org/10.1016/j.transci.2017.03.016