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El-Baz AM, Khodir AE, Adel El-Sokkary MM, Shata A. The protective effect of Lactobacillus versus 5-aminosalicylic acid in ulcerative colitis model by modulation of gut microbiota and Nrf2/Ho-1 pathway. Life Sci 2020; 256:117927. [PMID: 32526285 DOI: 10.1016/j.lfs.2020.117927] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 06/02/2020] [Accepted: 06/05/2020] [Indexed: 02/06/2023]
Abstract
AIMS Ulcerative colitis (UC) has many complications, from colonic damage to colorectal cancer. The mystery of both etiology and effective treatment of UC still challenging process. The role of gut microbiota in UC is still unclear. In the current study we compare the difference in gut microbiota abundance in both UC and normal colon besides the therapeutic effect of Lactobacillus spp. in treating UC versus the standard drug. MATERIALS AND METHODS The experimental panel included five group of rats; normal control, UC diseased rats, sterilizing rats, ASA treated and Lactobacillus treated. The change in the microbiota abundance was investigated using conventional and real time PCR. In parallel, clinical evaluation of UC and macroscopic examination scoring was also done. Colonic oxidants/antioxidant stress biomarkers; MDA, GSH, catalase, myeloperoxidase activity, and SOD activity were assessed. Colon Nrf2, HO-1 contents and TNF-α was evaluated. KEY FINDINGS The current study revealed a significant difference in the relative abundance of microbiota where, UC is associated with massive increase of E. coli and Fusobacterium spp., while enormous decrease in Bifidobacteria spp. in contrast with negative control. Both 5-ASA and Lactobacillus show a significant amelioration of all antioxidant enzymes and marked decline of inflammatory and oxidative stress markers. Both Lactobacillus and 5-ASA show significant increase of NrF2 and HO-1 and marked decrease of TNF-α. SIGNIFICANCE Lactobacillus spp. exerted a beneficial effect on the inflammation, oxidative stress and the symbiosis of gut microbiota that improve structural intestinal defect and promote healing in UC.
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Affiliation(s)
- Ahmed M El-Baz
- Microbiology and Biotechnology Department, Faculty of Pharmacy, Delta University for Science and Technology, International Coastal Road, Gamasa City, Mansoura, Dakhaliya, Egypt.
| | - Ahmed E Khodir
- Pharmacology and Biochemistry Department, Faculty of Pharmacy, Delta University for Science and Technology, International Coastal Road, Gamasa City, Mansoura, Dakhaliya, Egypt
| | | | - Ahmed Shata
- Clinical Pharmacology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt; Clinical Pharmacy Department, Faculty of Pharmacy, Delta University for Science and Technology, International Coastal Road, Gamasa City, Mansoura, Dakhaliya, Egypt
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Computer-Aided Prediction of Long-Term Prognosis of Patients with Ulcerative Colitis after Cytoapheresis Therapy. PLoS One 2015; 10:e0131197. [PMID: 26111148 PMCID: PMC4481415 DOI: 10.1371/journal.pone.0131197] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 05/29/2015] [Indexed: 12/13/2022] Open
Abstract
Cytoapheresis (CAP) therapy is widely used in ulcerative colitis (UC) patients with moderate to severe activity in Japan. The aim of this study is to predict the need of operation after CAP therapy of UC patients on an individual level using an artificial neural network system (ANN). Ninety UC patients with moderate to severe activity were treated with CAP. Data on the patients' demographics, medication, clinical activity index (CAI) and efficacy of CAP were collected. Clinical data were divided into training data group and validation data group and analyzed using ANN to predict individual outcomes. The sensitivity and specificity of predictive expression by ANN were 0.96 and 0.97, respectively. Events of admission, operation, and use of immunomodulator, and efficacy of CAP were significantly correlated to the outcome. Requirement of operation after CAP therapy was successfully predicted by using ANN. This newly established ANN strategy would be used as powerful support of physicians in the clinical practice.
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Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel JF, Allez M, d'Haens G, d'Hoore A, Mantzanaris G, Novacek G, Öresland T, Reinisch W, Sans M, Stange E, Vermeire S, Travis S, van Assche G. [Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 2: Current management (Spanish version)]. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2015; 80:32-73. [PMID: 25769217 DOI: 10.1016/j.rgmx.2014.10.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 10/23/2014] [Indexed: 02/06/2023]
Affiliation(s)
- A Dignass
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso.
| | | | - A Sturm
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - A Windsor
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - J-F Colombel
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - M Allez
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - G d'Haens
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - A d'Hoore
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - G Mantzanaris
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - G Novacek
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - T Öresland
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - W Reinisch
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - M Sans
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - E Stange
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - S Vermeire
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
| | - S Travis
- Contribuyeron por igual a este trabajo; Coordinadores del Consenso
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Schultheiß C, Weischenberg R, Herrmann A, Haller B, Schmid RM, Reindl W, Huber W. Dose-intensified granulocyte-monocyte apheresis in therapy refractory ulcerative colitis. Artif Organs 2014; 39:187-92. [PMID: 24981894 DOI: 10.1111/aor.12329] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Granulocyte-monocyte apheresis (GMA) is an emerging therapeutic option in active course of ulcerative colitis (UC). Appropriate GMA dose, including total number, frequency, and duration of the individual GMA session, is a matter of debate. It was the aim of the present study to evaluate the efficacy of a dose-intensified GMA regimen in patients with moderately to severely active UC. A prospective open-label, single-center study was performed in 10 patients with active UC (Rachmilewitz Clinical Activity Index [CAI] ≥ 8 points; Rachmilewitz Endoscopic Index ≥ 7 points). Patients had failed to improve after treatment with steroids and/or immunomodulators. GMA was performed twice weekly for 2 h to a maximum of 10 sessions. In each GMA session, the adsorber was changed after 1 h of treatment time. Four patients achieved remission with a CAI ≤ 4 points. Three patients had a response with an improvement of CAI of ≥3 points. Three patients showed no benefit from GMA. The quality of life score determined by the inflammatory bowel disease questionnaire-Deutschland increased by 26 points in median. First and second filters had similar efficiency in granulocyte and monocyte adsorption. No major adverse effects were observed. Dose-intensified GMA as reported in this study provided an encouraging short-term response rate of 70% in patients with moderately to severely active UC not responding to standard steroid or immunomodulator therapy. Although all patients relapsed not later than 16 weeks, GMA might be useful to reduce steroid and immunomodulator usage, or to delay surgery in this patient group.
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Affiliation(s)
- Caroline Schultheiß
- II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, München, Germany
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Bamba T, Yamamoto T, Umegae S, Matsumoto K. Effects of preoperative leukocytapheresis on inflammatory cytokines following surgery for ulcerative colitis: a prospective randomized study. J Clin Apher 2013; 29:107-12. [PMID: 24000140 DOI: 10.1002/jca.21299] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2013] [Revised: 07/22/2013] [Accepted: 08/08/2013] [Indexed: 12/17/2022]
Abstract
Targeted extracorporeal granulocyte and monocyte apheresis (GMA) has produced clinical efficacy together with down modulation of specific inflammatory cytokines in patients with ulcerative colitis (UC). This study was to investigate if preoperative GMA produces immunological effect on dysregulated immune activity after restorative proctocolectomy (RPC) in patients with UC. Forty patients requiring RPC were included. Twenty randomly selected patients received five GMA sessions with the Adacolumn over two consecutive weeks before RPC (GMA group). RPC was performed within 2 weeks following the last GMA session. The other 20 patients did not receive GMA before RPC (non-GMA group). Blood samples were obtained immediately before surgery, at 1 h after surgery, and on postoperative Days 1, 3, and 7 from all patients. Abdominal exudate was obtained from the drainage tube at 1 h after surgery, and on postoperative Days 1, 3, and 7. Concentrations of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in plasma and peritoneal fluid from a drainage tube were measured by enzyme linked immunosorbent assay. Between the two groups, patients were matched with respect to age, sex, UC duration, severity, extent and the dose of prednisolone at surgery. IL-1β, IL-6, and TNF-α levels in plasma and peritoneal fluid were not significantly different between the two groups during the entire study period. Based on the assays of IL-1β, IL-6, and TNF-α levels in the plasma and the peritoneal fluid, this study did not find any effect on these inflammatory cytokines by preoperative GMA in patients with UC who underwent RPC.
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Affiliation(s)
- Takuya Bamba
- Department of Surgery, Inflammatory Bowel Disease Center, Yokkaichi Social Insurance Hospital, Yokkaichi, Mie, Japan
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Takayama T, Kanai T, Matsuoka K, Okamoto S, Sujino T, Mikami Y, Hisamatsu T, Yajima T, Iwao Y, Ogata H, Hibi T. Long-term prognosis of patients with ulcerative colitis treated with cytapheresis therapy. J Crohns Colitis 2013; 7:e49-54. [PMID: 22633997 DOI: 10.1016/j.crohns.2012.05.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2012] [Revised: 04/02/2012] [Accepted: 05/04/2012] [Indexed: 02/06/2023]
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 (> 4-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. 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.
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Affiliation(s)
- Tetsuro Takayama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Vecchi M, Vernia P, Riegler G, D'Incà R, Annese V, Bagnoli S. Therapeutic landscape for ulcerative colitis: where is the Adacolumn(®) system and where should it be? Clin Exp Gastroenterol 2013; 6:1-7. [PMID: 23323022 PMCID: PMC3541711 DOI: 10.2147/ceg.s33275] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Granulocyte-monocyte apheresis is a relatively new therapy that has been proposed, sometimes with controversial results, for the treatment of inflammatory bowel disease, particularly ulcerative colitis. The aim of the present study was to perform a thorough review of the literature on the application of this type of treatment in ulcerative colitis and discuss the results, in order to provide an opinion on its use which is shared by the involved experts. The review of the literature was performed by searching PubMed with appropriate key words. The results obtained suggest that the major role for this treatment at this moment is for those patients with steroid dependency or with major contraindications to use of steroids. However, promising, albeit very preliminary, results have also been observed in steroid-naïve subjects, and this is of particular interest in consideration of the safety profile of this therapeutic method. As such, the Adacolumn may prove useful in specific subgroups of patients. Future phenotypic, genotypic, and molecular characterization of patients with inflammatory bowel disease might prove useful in defining better those subjects who might benefit most from this treatment modality.
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Affiliation(s)
- Maurizio Vecchi
- University of Milan, Department of Biomedical Sciences for Health, San Donato Milanese, Milan
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Dignass A, Lindsay JO, Sturm A, Windsor A, Colombel JF, Allez M, D'Haens G, D'Hoore A, Mantzaris G, Novacek G, Oresland T, Reinisch W, Sans M, Stange E, Vermeire S, Travis S, Van Assche G. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohns Colitis 2012; 6:991-1030. [PMID: 23040451 DOI: 10.1016/j.crohns.2012.09.002] [Citation(s) in RCA: 692] [Impact Index Per Article: 53.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2012] [Accepted: 09/03/2012] [Indexed: 02/07/2023]
Affiliation(s)
- Axel Dignass
- Department of Medicine 1, Agaplesion Markus Hospital, Wilhelm-Epstein-Str. 4, D-60431 Frankfurt/Main, Germany.
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Shiraki M, Yamamoto T. Steroid-sparing strategies in the management of ulcerative colitis: Efficacy of leukocytapheresis. World J Gastroenterol 2012; 18:5833-8. [PMID: 23139598 PMCID: PMC3491589 DOI: 10.3748/wjg.v18.i41.5833] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Revised: 06/05/2012] [Accepted: 06/15/2012] [Indexed: 02/06/2023] Open
Abstract
Active ulcerative colitis (UC) is frequently associated with infiltration of a large number of leukocytes into the bowel mucosa. Leukocytapheresis is a novel nonpharmacologic approach for active UC, in which leukocytes are mechanically removed from the circulatory system. Current data indicate that leukocytapheresis is efficacious in improving response and remission rates with excellent tolerability and safety in patients with UC. Corticosteroid therapy remains a mainstay in the treatment of active UC; however, long-term, high doses of corticosteroids usually produce predictable and potentially serious side effects. If leukocytapheresis can spare patients from exposure to corticosteroids, the risk of steroid-induced adverse events should be minimized. This may be of great benefit to patients because severe side effects of steroids seriously impair health-related quality of life. In this article, we reviewed current evidence on whether leukocytapheresis can avoid or reduce the use of corticosteroids in the management of patients with UC. Several studies have shown that leukocytapheresis was effective for steroid-naïve patients with active UC. Furthermore, both short-term and long-term studies have demonstrated the steroid-sparing effects of leukocytapheresis therapy in patients with UC. Although the evidence level is not striking, the available data suggest that leukocytapheresis can avoid or reduce the use of corticosteroids in the management of UC. Large, well-designed clinical trials are necessary to more accurately evaluate the steroid-sparing effects of leukocytapheresis in the management of UC.
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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. [PMID: 22398094 DOI: 10.1016/j.crohns.2011.12.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Revised: 11/21/2011] [Accepted: 12/13/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS The efficacy of granulocyte and monocyte adsorptive apheresis (GMA) for patients with a first episode of ulcerative colitis (UC) has been scarcely reported. This study was to see if the introduction of GMA at an early stage reduces corticosteroid administration and steroid dependency in the long term clinical course of UC. METHODS Forty consecutive patients with moderately active symptoms as the first attack of UC were included. Twenty patients were treated with GMA, with or without corticosteroids (GMA group), and the other 20 were given corticosteroids without GMA (steroid group). All patients were monitored for 5 years. Relapses were treated in the same manner as the first attack in both groups. The total dose of steroid administered and the appearance of steroid-dependency were to be compared between the two groups. RESULTS All patients in both groups achieved clinical remission after the first attack. The mean number of relapses per patient was 2.8 in the GMA group and 2.9 in the steroid group (P=0.86). During this study, 5 patients in the GMA group did not require corticosteroids. The mean dose of steroid administered during the 5 years was 2141 mg in the GMA group vs 5443 mg in the steroid group (P=0.002). One patient in the GMA group and 7 in the steroid group were steroid-dependent at the end of the study (P=0.048). CONCLUSIONS In patients with the first UC episode, GMA therapy at an early stage significantly reduces steroid administration and steroid-dependency in the long-term clinical course.
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Affiliation(s)
- Takayuki Yamamoto
- Inflammatory Bowel Disease Centre, Yokkaichi Social Insurance Hospital, Yokkaichi, Mie, Japan.
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Fukunaga K, Matsumoto T. Current status and future perspectives of leukocytapheresis for inflammatory bowel disease. J Gastroenterol Hepatol 2012; 27:997-1003. [PMID: 22414250 DOI: 10.1111/j.1440-1746.2012.07119.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) comprise the idiopathic inflammatory bowel diseases (IBD) of the gut. The etiology of IBD is poorly understood, but an autoimmune disturbance has been suggested to play an important role in this incurable disease. Extracorporeal leukocytapheresis (CAP) is an additional adjunct for IBD patients refractory to other conventional therapies, including steroids. The primary aim of CAP should be to suppress such unwanted immunological response by removing circulating inflammatory cells from the blood stream. The first decade has been passed since CAP was approved by Japanese social health insurance policy. It is therefore now an appropriate opportunity to upgrade and summarize our current understandings and/or future perspectives of this unique non-pharmacological and non-surgical strategy for IBD patients. According to several clinical and basic research reports, an early introduction of CAP should produce higher efficacy as compared with CAP applied sometime after a clinical relapse. Likewise, CAP therapy adjusted to patients' body-weight as well as two treatment sessions per week (intensive regimen) should benefit the efficacy rate. The etiology of IBD is not fully elucidated yet. As a result, the major therapeutic strategies in the Western world have been immunosuppressive therapy, including biologics. CAP is an unusual treatment modality for IBD because it seems to have both effectiveness and safety, which should generally be balanced in this type of illness. We now have to develop future strategies with and without combining biologics to improve the quality of life of IBD patients.
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Affiliation(s)
- Ken Fukunaga
- Departments of Lower Gastroenterology and Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
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Cabriada JL, Domènech E, Ibargoyen N, Hernández V, Clofent J, Ginard D, Gutiérrez-Ibarluzea I, Hinojosa J. Leukocytapheresis for steroid-dependent ulcerative colitis in clinical practice: results of a nationwide Spanish registry. J Gastroenterol 2012; 47:359-65. [PMID: 22105230 DOI: 10.1007/s00535-011-0499-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2011] [Accepted: 10/12/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND Several small, prospective, open studies suggest that leukocytapheresis might be efficient in patients with steroid-dependent ulcerative colitis (UC). AIM To evaluate the short- and long-term effectiveness of leukocytapheresis for the management of steroid-dependent UC in clinical practice. METHODS A Web-based, nationwide database specifically designed to record the efficacy and safety data of leukocytapheresis therapy in UC was available from September 2007 in Spain. Clinical data were collected at treatment baseline, 1 month after the last apheresis session (initial efficacy), and 6 and 12 months thereafter (long-term efficacy). Remission was defined as a Mayo Clinic index ≤2 together with complete steroid withdrawal and response as a decrease of ≥3 from the baseline score. RESULTS A total of 142 steroid-dependent UC patients were included in the registry, most of them treated with the Adacolumn™ system. In 69% of patients thiopurine therapy failed to achieve steroid-free clinical remission. Initial clinical remission was obtained in 37% of cases. The initial corticosteroid dose, the number and frequency of apheresis sessions, or the previous failure of thiopurines and/or infliximab did not influence the initial remission rate, but a greater decrease in CRP levels was associated with a higher probability to obtain initial remission. At 6 and 12 months, 41 and 36% of patients were in clinical remission, respectively. Only one serious adverse effect was recorded. CONCLUSIONS In clinical practice, apheresis allows long-term steroid-free clinical remission in up to one third of steroid-dependent UC patients, even in those with prior failure of thiopurines.
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Affiliation(s)
- J L Cabriada
- Hospital Galdakao-Usansolo, Galdakao, Vizcaya, Spain
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Cabriada JL. Aféresis en enfermedad inflamatoria intestinal. ¿Una opción válida? GASTROENTEROLOGIA Y HEPATOLOGIA 2012; 35:22-31. [DOI: 10.1016/j.gastrohep.2011.10.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Accepted: 10/19/2011] [Indexed: 12/16/2022]
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Processed blood volume impacts clinical efficacy in patients with ulcerative colitis undergoing adsorptive depletion of myeloid lineage leucocytes. J Gastroenterol 2012; 47:49-55. [PMID: 21915624 DOI: 10.1007/s00535-011-0464-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2011] [Accepted: 08/03/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hitherto, therapeutic depletion of granulocytes and monocytes by adsorption (GMA) has been associated with significant and insignificant efficacy in patients with ulcerative colitis (UC). Further, the processed blood volume in one GMA session has been fixed at 30 mL/min × 60 min, regardless of patients' body weight (BW). We were interested to see the efficacy and safety of GMA when administered in relation to patients' BW. METHODS Sixty patients were randomly assigned to the routine GMA (n = 30) and to GMA adjusted to patients' BW, 60 mL/kg (n = 30). GMA was done with the Adacolumn, up to 10 sessions over 10 weeks. At entry and 1 week post last GMA, patients were clinically and endoscopically evaluated. Remission was defined as clinical activity index (CAI) ≤4, whereas mucosal remission was defined as endoscopic index (EI) ≤3. RESULTS In the BW group, the processed volume/session was 3,260 ± 581 versus 1,800 mL in the routine group (P < 0.001). In the BW group, 25 of 30 patients (83.3%) achieved remission versus 19 of 30 patients (63.3%) in the routine group. The average CAI in the BW group fell from 9.6 ± 2.6 to 2.3 ± 2.1 versus from 9.1 ± 2.4 to 4.0 ± 2.1 (P < 0.05) in the routine group. Similarly, the EI in the BW group fell from 9.4 ± 1.3 to 2.1 ± 2.1 versus from 9.2 ± 1.8 to 4.5 ± 2.3 (P < 0.01). CONCLUSIONS GMA adjusted to patients' BW and at a vastly greater processed volume produces significantly higher efficacy as compared with the routine GMA protocol. Further, in this study, up to twofold higher processed volume caused no safety concern.
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Daily granulocyte and monocyte adsorptive apheresis in patients with active ulcerative colitis: a prospective safety and feasibility study. J Gastroenterol 2011; 46:1003-9. [PMID: 21681409 DOI: 10.1007/s00535-011-0428-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2011] [Accepted: 05/08/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND This prospective study was to assess the safety and feasibility of daily granulocyte and monocyte adsorptive apheresis (GMA) therapy in patients with active ulcerative colitis (UC). METHODS Thirty consecutive patients with moderately or severely active UC received daily GMA treatment (5 sessions over 5 consecutive days) with the Adacolumn. Adverse events (AE), patient tolerability, and clinical symptoms were monitored daily. RESULTS Sixteen patients (53%) experienced AE during at least one GMA session. The most frequent AE was mild headache followed by fatigue and fever. None of the AE was serious, and all patients completed the 5 consecutive GMA sessions. Clinical symptoms (stool frequency and/or rectal bleeding) were improved in 21 patients (70%) during the course of GMA therapy. Clinical remission defined as normal stool frequency and no rectal bleeding was achieved in 7 patients (23%) after 5 GMA sessions. Seven of 20 patients (35%) with moderately active disease achieved clinical remission, whereas none of the 10 patients with severely active disease achieved clinical remission. Total and differential leukocyte counts, platelet count, and hemoglobin level did not significantly change, but C-reactive protein level significantly decreased during the course of GMA therapy. CONCLUSIONS This is the first report on daily GMA in the treatment of patients with UC. Daily GMA was safe and well tolerated without serious AE. Furthermore, daily GMA was associated with rapid improvement of clinical symptoms in patients with moderately active UC. However, controlled trials are warranted to assess a definite efficacy for daily GMA therapy.
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Yamamoto T. Granulocyte and monocyte adsorptive apheresis in the management of ulcerative colitis. Aliment Pharmacol Ther 2011; 33:288; author reply 289. [PMID: 21155856 DOI: 10.1111/j.1365-2036.2010.04521.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Thanaraj S, Hamlin PJ, Ford AC. Systematic review: granulocyte/monocyte adsorptive apheresis for ulcerative colitis. Aliment Pharmacol Ther 2010; 32:1297-306. [PMID: 21050231 DOI: 10.1111/j.1365-2036.2010.04490.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Patients with ulcerative colitis (UC) that is chronically active despite 5-aminosalicylates or immunomodulators, or who are dependent on corticosteroids to maintain remission, have limited treatment options. Granulocyte/monocyte adsorptive apheresis (GMAA) may have a role in this situation. AIM To conduct a systematic review of GMAA in UC. METHODS MEDLINE, EMBASE and the Cochrane central register of controlled trials were searched to identify randomized controlled trials (RCTs) comparing GMAA with conventional medical therapy, sham procedure or 'intensive' with 'conventional' GMAA regimens in adult UC patients. Studies reported clinical remission or response rates. RESULTS Ten RCTs were eligible. Formal meta-analysis was not undertaken due to concerns about methodological quality of identified studies. Compared with medical therapy, remission rates with GMAA were generally higher, and corticosteroid-sparing effects were observed. Compared with sham procedure, GMAA did not achieve significantly higher remission rates. 'Intensive' GMAA regimens demonstrated generally higher remission rates, and time to remission was shorter compared with 'conventional' regimens. Only two RCTs were at low risk of bias. Six were conducted in Japanese patients, which may limit generalizability. CONCLUSIONS Granulocyte/monocyte adsorptive apheresis appears of some benefit in UC. High-quality RCTs comparing granulocyte/monocyte adsorptive apheresis with conventional medical therapy or sham procedure in Western populations, with disease activity confirmed endoscopically, are required.
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Affiliation(s)
- S Thanaraj
- Leeds General Infirmary, Leeds Gastroenterology Institute, UK
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Yamamoto T, Umegae S, Matsumoto K. Mucosal healing in patients with ulcerative colitis during a course of selective leukocytapheresis therapy: a prospective cohort study. Inflamm Bowel Dis 2010; 16:1905-11. [PMID: 20310015 DOI: 10.1002/ibd.21260] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND During active ulcerative colitis (UC), vast numbers of granulocytes, monocytes/macrophages (GM) infiltrate the mucosal tissue and can potentially exacerbate inflammation and injury. Accordingly, we were interested to see if selective depletion of GM by adsorption (GMA) impacts mucosal healing (MH) in UC patients. METHODS In all, 124 patients with clinically and endoscopically active UC received 5 or 10 GMA sessions at one or two sessions/week. The endoscopic severity of mucosal inflammation at entry and 1 week after the last GMA session were scored as follows: 0 = normal mucosa and inactive disease; 1 = mild inflammation; 2 = moderate inflammation; 3 = severe inflammation. Likewise, a score 0 or 1 at post-GMA course was defined as MH. RESULTS At entry the endoscopic severity of the mucosal inflammation was 2 in 100 patients (81%) and 3 in 24 patients (19%). Following the course of GMA, 56 patients (45%) achieved clinical remission (normal stool frequency and no rectal bleeding). Thirty-four of these 56 responders achieved MH; 32 (94%) of the 34 patients with MH had an endoscopic score of 2 (moderate inflammation) at entry. The maintained clinical remission rate was significantly higher in the 34 patients who achieved MH as compared with 22 patients who achieved clinical remission without MH (P = 0.0005). CONCLUSIONS MH is achieved more frequently in patients with moderate than with severe endoscopic severity at entry. Further, patients with MH have a reduced risk of future clinical relapse as compared with patients who achieve remission without MH.
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Affiliation(s)
- Takayuki Yamamoto
- Inflammatory Bowel Disease Center, Yokkaichi Social Insurance Hospital, Yokkaichi, Mie, Japan.
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Tanaka T, Okanobu H, Kuga Y, Yoshifuku Y, Fujino H, Miwata T, Moriya T, Nishida T, Oya T. Clinical and endoscopic features of responders and non-responders to adsorptive leucocytapheresis: a report based on 120 patients with active ulcerative colitis. ACTA ACUST UNITED AC 2010; 34:687-95. [PMID: 20934287 DOI: 10.1016/j.gcb.2010.08.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2010] [Accepted: 08/06/2010] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND OBJECTIVE Elevated/activated myeloid leucocytes, like the CD14(+)CD16(+) monocytes are sources of TNF-α, and therefore, selective depletion of these cells by granulocyte/monocyte (GM) adsorption (GMA) should promote remission or enhance drug efficacy. However, studies in ulcerative colitis (UC) reported contrasting efficacy, from an 85% to statistically insignificant level. We investigated patients' demography in responders and non-responders. METHODS In 120 UC patients, 61 steroid naive and 59 steroid dependent, we looked for entry clinical or endoscopic features to identify responders (or non-responders) to GMA. Patients received up to an 11 Adacolumn GMA sessions over 12 weeks. Patients were clinically and endoscopically evaluated, allowing each patient to serve as her/his own control. Immunohistochemistry on colonic biopsies was to reveal the impact of GMA on leucocyte infiltration of the mucosa. RESULTS Entry average clinical activity index (CAI) was 12.6, 10-16. An 80 of 120 patients responded (CAI≤4); 45 steroid naïve (73.8%) and 35 steroid dependent (59.3%). Over 900 biopsies were processed. Infiltrating leucocytes were overwhelmingly polymorphonuclear and macrophages around and within crypt abscesses. There was a marked reduction of infiltrating leucocytes in responders. Most non-responders had extensive colonic lesions with virtually no mucosal tissue left at the lesions. CONCLUSIONS Steroid naïve patients with short duration of UC were the best responders, while patients with deep colonic lesions and extensive loss of the mucosal tissue were non-responders.
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Affiliation(s)
- Tomotaka Tanaka
- Department of Internal Medicine, Chugoku Rosai Hospital, Hirotagaya 1-5-1, Kure, Hiroshima 737-0193, Japan.
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Szczepiorkowski ZM, Winters JL, Bandarenko N, Kim HC, Linenberger ML, Marques MB, Sarode R, Schwartz J, Weinstein R, Shaz BH. Guidelines on the use of therapeutic apheresis in clinical practice--evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher 2010; 25:83-177. [PMID: 20568098 DOI: 10.1002/jca.20240] [Citation(s) in RCA: 354] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The American Society for Apheresis (ASFA) Apheresis Applications Committee is charged with a review and categorization of indications for therapeutic apheresis. Beginning with the 2007 ASFA Special Issue (fourth edition), the subcommittee has incorporated systematic review and evidence-based approach in the grading and categorization of indications. This Fifth ASFA Special Issue has further improved the process of using evidence-based medicine in the recommendations by refining the category definitions and by adding a grade of recommendation based on widely accepted GRADE system. The concept of a fact sheet was introduced in the Fourth edition and is only slightly modified in this current edition. The fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis. The article consists of 59 fact sheets devoted to each disease entity currently categorized by the ASFA as category I through III. Category IV indications are also listed.
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Affiliation(s)
- Zbigniew M Szczepiorkowski
- Transfusion Medicine Service, Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, USA.
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Adsorptive depletion of alpha4 integrin(hi)- and CX3CR1hi-expressing proinflammatory monocytes in patients with ulcerative colitis. Dig Dis Sci 2010; 55:1886-95. [PMID: 19908144 DOI: 10.1007/s10620-009-0974-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2009] [Accepted: 08/28/2009] [Indexed: 02/06/2023]
Abstract
BACKGROUND Two main functionally distinct monocytes phenotypes are known: the CD14(hi)CD16(-) "classical" and the CD14(+)CD16(+) "proinflammatory" phenotypes. The latter phenotype is elevated in patients with ulcerative colitis (UC) and is suspected to have a major role in the immunopathogenesis of UC. AIM To selectively deplete circulating proinflammatory CD14(+)CD16(+) monocyte phenotype. METHODS Seven corticosteroid-naïve patients with UC (clinical activity index = 8.7 +/- 1.3) and seven healthy subjects were included. In patients with UC, granulocyte/monocyte adsorption (GMA) was done with an Adacolumn that selectively adsorbs leucocytes of the myeloid lineage. Blood from all subjects at baseline and from the patients immediately after the first GMA session was processed. Isolated monocytes were subjected to fluorescence-activated cell sorter analyses. RESULTS The seven UC patients achieved remission (CAI <or=4) after 5-10 GMA sessions. GMA induced a strong fall in the ratio (%) of CD14(+)CD16(+) to CD14(hi)CD16(-) monocytes, from 10.0 +/- 1.4 to 3.0 +/- 0.9. Further, expressions of alpha4 integrin (374.8 +/- 26.1 mean fluorescence intensity, MFI) and CX(3)CR1 (49.5 +/- 4.6 MFI) were significantly high on CD14(+)CD16(+)monocytes as compared with on CD14(hi)CD16(-) monocytes (169.2 +/- 17.2 and 33.2 +/- 3.6 MFI, respectively). Additionally, GMA significantly increased the ratio of the CD14(hi)CD16(-)CCR2(low) "immature" monocytes from 3.74 +/- 0.62 to 8.11 +/- 0.56 MFI. CONCLUSIONS We found high expressions of alpha4 integrin and CX(3)CR1 on monocytes in patients with active UC, known to promote the extravasation of CD14(+)CD16(+) monocytes into the mucosa. GMA effectively depletes CD14(+)CD16(+) monocytes and concomitantly increases CD14(hi)CD16(-)CCR2(low) "immature" monocytes; thus GMA was associated with the emergence of less inflammatory monocyte phenotype in circulation.
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The GRADE approach for assessing new technologies as applied to apheresis devices in ulcerative colitis. Implement Sci 2010; 5:48. [PMID: 20553616 PMCID: PMC2908057 DOI: 10.1186/1748-5908-5-48] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2009] [Accepted: 06/16/2010] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND In the last few years, a new non-pharmacological treatment, termed apheresis, has been developed to lessen the burden of ulcerative colitis (UC). Several methods can be used to establish treatment recommendations, but over the last decade an informal collaboration group of guideline developers, methodologists, and clinicians has developed a more sensible and transparent approach known as the Grading of Recommendations, Assessment, Development and Evaluation (GRADE). GRADE has mainly been used in clinical practice guidelines and systematic reviews. The aim of the present study is to describe the use of this approach in the development of recommendations for a new health technology, and to analyse the strengths, weaknesses, opportunities, and threats found when doing so. METHODS A systematic review of the use of apheresis for UC treatment was performed in June 2004 and updated in May 2008. Two related clinical questions were selected, the outcomes of interest defined, and the quality of the evidence assessed. Finally, the overall quality of each question was taken into account to formulate recommendations following the GRADE approach. To evaluate this experience, a SWOT (strengths, weaknesses, opportunities and threats) analysis was performed to enable a comparison with our previous experience with the SIGN (Scottish Intercollegiate Guidelines Network) method. RESULTS Application of the GRADE approach allowed recommendations to be formulated and the method to be clarified and made more explicit and transparent. Two weak recommendations were proposed to answer to the formulated questions. Some challenges, such as the limited number of studies found for the new technology and the difficulties encountered when searching for the results for the selected outcomes, none of which are specific to GRADE, were identified. GRADE was considered to be a more time-consuming method, although it has the advantage of taking into account patient values when defining and grading the relevant outcomes, thereby avoiding any influence from literature precedents, which could be considered to be a strength of this method. CONCLUSIONS The GRADE approach could be appropriate for making the recommendation development process for Health Technology Assessment (HTA) reports more explicit, especially with regard to new technologies.
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Cabriada JL, Ibargoyen N, Hernández A, Bernal A, Castiella A. Sustained remission after steroids and leukocytapheresis induced response in steroid-dependent ulcerative colitis: results at 1 year. Dig Liver Dis 2010; 42:432-5. [PMID: 19833566 DOI: 10.1016/j.dld.2009.09.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2009] [Revised: 09/01/2009] [Accepted: 09/09/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND Leukocytapheresis (LAP) could be an alternative treatment for steroid-dependent ulcerative colitis (UC). AIMS To assess the duration of response at 1 year after this treatment. PATIENTS AND METHODS A prospective study in 18 patients with steroid-dependent UC treated with LAP plus steroids after failure or intolerance to immunomodulators. Clinical and endoscopic (Mayo Clinic index) examinations were performed at 1 month after the last apheresis and at 12 months. The clinical, endoscopic remission and the relapse during the 1-year follow-up were evaluated based on standard parameters. RESULTS Induction of remission: clinical remission: 10/18 (55%). Partial response: 4. Endoscopic remission: 9 (50%), always accompanied by clinical remission. A significant correlation was observed between clinical remission and endoscopic remission (r(s)=0.894; p< or =0.001). At 1 year: sustained steroid-free clinical remission in 9 (50%), all of whom presented initial endoscopic remission. Remission and relapse before 1 year in 17%. A tendency for sustained remission at 1 year was observed when initial endoscopic remission was achieved. CONCLUSIONS Initial remission can be maintained at 1 year in half of the patients without the need for additional steroids. Complete remission and endoscopic mucosal healing is proposed as an objective for achieving a lasting response.
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Affiliation(s)
- Jose L Cabriada
- Gastroenterology and Hepatology Service, Hospital Galdakao-Usánsolo, Galdakao (Vizcaya), Spain.
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Yamaguchi T, Yoshida S, Tanaka S, Takemura Y, Oka S, Yoshihara M, Yamada H, Chayama K. Predicting the clinical response to cytapheresis in steroid-refractory or -dependent ulcerative colitis using contrast-enhanced ultrasonography. Scand J Gastroenterol 2010; 44:831-7. [PMID: 19811342 DOI: 10.1080/00365520902839659] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To evaluate the usefulness of transabdominal ultrasound (US), including contrast-enhanced ultrasonography (CEUS), in predicting the response to cytapheresis therapy in patients with steroid-refractory or -dependent ulcerative colitis (UC). MATERIAL AND METHODS Between January 2005 and June 2008, 26 consecutive patients with steroid-refractory or -dependent UC were treated with granulocyte and monocyte adsorption apheresis (GCAP) or leukocytapheresis (LCAP) at our institute. The clinical activity of UC was evaluated by patients' C-reactive protein (CRP) levels and clinical activity index (CAI) scores. All patients were evaluated by grey-scale US, power Doppler US (PDUS), and CEUS. In CEUS, the color signal patterns were classified as 1 of 2 patterns. In pattern 1, color signals were partially detected in the bowel wall (excluding muscularis propria, the outer thin layer of the bowel wall), whereas in pattern 2, color signals were detected in the entire bowel wall (excluding muscularis propria). Differences between remission or clinical response (group R) and no response (group N) were ascertained for clinical features, clinical activities, and US findings. RESULTS Differences between the two groups were not considered significant for the clinical features, clinical activities, and grey-scale US and PDUS findings. Using CEUS, 4 patients in group R showed pattern 2 (21%), while in group N, all patients showed this pattern, indicating a significant difference between the two groups (p<0.01). CONCLUSION CEUS findings may be helpful in predicting the clinical response to cytapheresis for steroid-refractory or -dependent UC.
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Affiliation(s)
- Toshiki Yamaguchi
- Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
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Abstract
Ulcerative colitis is a chronic inflammatory disease that affects the colon and rectum. Its pathogenesis is probably multifactorial including the influx of certain cytokines into the colonic mucosa, causing disease activity and relapse. The hypothesis of removing such cytokines from the circulation by leukocytapheresis was implemented to reduce disease activity, maintain remission, and prevent relapse. Many recent reports not only in Japan, but also in the West, have highlighted its beneficial effects in both adult and pediatric patients. Large placebo-controlled studies are needed to confirm the available data in this regard. In this article, we shed some light on the use of leukocyte apheresis in the management of autoimmune diseases, especially ulcerative colitis.
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Affiliation(s)
- Ahmed Helmy
- Section of Gastroenterology, Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
| | - Maheeba Abdulla
- Section of Gastroenterology, Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Ingvar Kagevi
- Section of Gastroenterology, Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
| | - Khalid Al Kahtani
- Section of Gastroenterology, Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
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Nos P, Domènech E. Tratamiento con aféresis en la enfermedad inflamatoria intestinal. GASTROENTEROLOGIA Y HEPATOLOGIA 2009; 32:509-18. [DOI: 10.1016/j.gastrohep.2009.01.183] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2008] [Accepted: 01/13/2009] [Indexed: 02/07/2023]
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Granulocyte–monocyte apheresis for the treatment of ulcerative colitis—is this the end of the road? ACTA ACUST UNITED AC 2008; 6:6-7. [DOI: 10.1038/ncpgasthep1299] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2008] [Accepted: 10/06/2008] [Indexed: 12/14/2022]
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Bresci G. Granulocytapheresis in the treatment of patients with active ulcerative colitis. Expert Rev Gastroenterol Hepatol 2008; 2:639-43. [PMID: 19072341 DOI: 10.1586/17474124.2.5.639] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
In recent years, considering the role of inflammatory processes and the involvement of the immune system in ulcerative colitis, granulocytapheresis, a technique for removing circulating leukocytes and preventing their migration into the intestinal mucosa, has been proposed for the treatment of acute ulcerative colitis. Initially introduced for the treatment of patients who did not respond to conventional therapy only, this new therapy may become a useful and safe method to induce clinical remission in patients with acute disease. This article will review the clinical applications and issues concerning the use of granulocytapheresis in ulcerative colitis.
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Affiliation(s)
- Giampaolo Bresci
- U.O. Gastroenterologia, Azienda Ospedaliera-Universitaria Pisana, Via A. Della Spina, Pisa 1156125, Italy.
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Tanaka T, Okanobu H, Yoshimi S, Murakami E, Kogame A, Imagawa H, Numata Y, Kuga Y, Moriya T, Ohya T, Kajiyama G. In patients with ulcerative colitis, adsorptive depletion of granulocytes and monocytes impacts mucosal level of neutrophils and clinically is most effective in steroid naïve patients. Dig Liver Dis 2008; 40:731-6. [PMID: 18387860 DOI: 10.1016/j.dld.2008.02.012] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2007] [Revised: 12/19/2007] [Accepted: 02/14/2008] [Indexed: 12/11/2022]
Abstract
BACKGROUND The aetiology of ulcerative colitis is inadequately understood, and drug therapy has been empirical rather than based on sound understanding of disease aetiology. This has been a major factor for refractoriness and adverse drug effects as additional complications. However, ulcerative colitis by its very nature is exacerbated and perpetuated by inflammatory cytokines, which are released by peripheral granulocytes and monocytes as well. Additionally, active ulcerative colitis is often associated with elevated peripheral granulocytes and monocytes with activation behaviour and are found in vast numbers within the colonic mucosa. Hence, from the clinicopathologic viewpoint, granulocytes and monocytes are appropriate targets for therapy in ulcerative colitis. Based on this thinking, an Adacolumn has been developed for depleting excess granulocytes and monocytes by adsorption. METHODS By colonoscopy, biopsy and histology, we investigated the impact of granulocyte and monocyte adsorption (GMA) on the mucosal level of granulocytes and monocytes in patients with active ulcerative colitis. Forty-five patients (26 steroid naïve and 19 steroid-dependent), mean age 44.7 yr, were included. Twenty patients had total colitis and 25 had left-sided colitis. Each patient was given up to 11 GMA sessions over 12 weeks. No patient received additional medications within 4 weeks (steroid) to 8 weeks (other immunosuppressants) prior to entry or during the GMA course. Colonoscopy together with biopsy was done at entry and within 2 weeks after the last GMA session. RESULTS At entry, the mean clinical activity index was 12.6; range 10-16. A total of 400 colonic biopsies were examined, which revealed massive infiltration of the colonic mucosa by granulocytes, and GMA was associated with striking reduction of granulocytes in the mucosa. At week 12, 33 of 45 patients (73.3%, P<0.01) had achieved clinical remission (the mean clinical activity index <or= 4). Colonoscopy revealed that most non-responders had deep colonic ulcers and extensive loss of the mucosal tissue. The response rate in steroid naïve subgroup was 22 of 26 patients (84.6%, P<0.005) and in steroid-dependent was 11 of 19 (57.9%, P<0.05 and P=0.02154 for steroid naïve vs. steroid-dependent). Patients who achieved remission could continue with their salicylates. On average, remission was sustained for 7.8 months in all 33 responders. CONCLUSIONS This is the first report showing a striking difference in clinical response to GMA between steroid naïve and steroid-dependent patients. Further, patients with deep colonic ulcers together with extensive loss of the mucosal tissue are not like to respond to GMA.
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Affiliation(s)
- T Tanaka
- Internal Medicine, Chugoku Rosai Hospital, Hirotagaya 1-5-1, Kure, Hiroshima 737-0193, Japan.
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Leukocytapheresis for the treatment of IBD. ACTA ACUST UNITED AC 2008; 5:509-16. [PMID: 18665138 DOI: 10.1038/ncpgasthep1209] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2008] [Accepted: 06/24/2008] [Indexed: 02/06/2023]
Abstract
Leukocytapheresis is a controversial nonpharmacologic treatment for IBD, in which white blood cells--the effector cells of the inflammatory process--are mechanically removed from the circulation. Current controversy centers on the uncontrolled nature of the leukocytapheresis trials performed and their use of different outcome measures in patient groups that have very variable disease activity and severity. Nonetheless, the efficacy data obtained are generally quite consistent: an excellent response (remission >80%) has been achieved in corticosteroid-naïve patients with ulcerative colitis and an average remission rate of more than 50% has been achieved in patients who have steroid-dependent or refractory ulcerative colitis. Interestingly, the largest randomized, double-blind, sham-controlled study of granulocyte-monocyte apheresis in patients with moderate to severe ulcerative colitis failed to demonstrate efficacy for the induction of clinical remission or response. Regardless, leukocytapheresis seems to be remarkably safe. The precise positioning of leukocytapheresis in the treatment of ulcerative colitis is uncertain at present and will vary according to geography and patient preference for a safe, nonpharmacologic treatment. Further efficacy studies are required to assess what the optimal number and frequency of treatments is, in addition to the need for head-to-head comparisons with established drugs.
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Hanai H, Iida T, Takeuchi K, Watanabe F, Maruyama Y, Kageoka M, Ikeya K, Yamada M, Kikuyama M, Iwaoka Y, Hirayama K, Nagata S, Sato Y, Hosoda Y. Intensive granulocyte and monocyte adsorption versus intravenous prednisolone in patients with severe ulcerative colitis: an unblinded randomised multi-centre controlled study. Dig Liver Dis 2008; 40:433-40. [PMID: 18296130 DOI: 10.1016/j.dld.2008.01.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2007] [Revised: 12/06/2007] [Accepted: 01/07/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Several uncontrolled studies have reported on the efficacy of adsorptive depletion of peripheral blood granulocytes and monocytes/macrophages (GM) in patients with moderate or severe ulcerative colitis. This study was to compare the efficacy and safety of intensive GMA with intensive intravenous prednisolone in patients with severe ulcerative colitis. METHODS Seventy patients with clinical activity index 10-23 were randomly assigned to intensive GMA with the Adacolumn, at 2 sessions/week in the first 3 weeks and then 1 session/week for up to 11 sessions (n = 35) or intravenous prednisolone, 40-60 mg/day for 5-10 days (n = 35). No patient received immunomodulators within 8 weeks prior to entry. Clinical response based on intention to treat was assessed at weeks 2, 6 and 12. RESULTS Four patients in the prednisolone group and two patients in the GMA group discontinued in week 1. At weeks 2, 6 and 12, the remission (clinical activity index < or = 4) rates (%) in the GMA group were 17.1, 54.4, 74.3, respectively. The corresponding values in the prednisolone group were 25.7, 51.4 and 48.6. Further, at week 12, 27 patients (77%) in the GMA group and 5 patients (14%) in the prednisolone group were steroid free (P = 0.0076). In the GMA group, flushing and light-headedness were observed in 5 patients versus typical steroid side effects in 29 patients of the prednisolone group. CONCLUSIONS In this clinical response to GMA was comparable or better than prednisolone. Further, the response to GMA was slower than to intravenous prednisolone, but was more sustainable than the latter.
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Affiliation(s)
- H Hanai
- Centre for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, 26 Shirowacho, Hamamatsu 430-0846, Japan.
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Travis SPL, Stange EF, Lémann M, Oresland T, Bemelman WA, Chowers Y, Colombel JF, D'Haens G, Ghosh S, Marteau P, Kruis W, Mortensen NJM, Penninckx F, Gassull M. European evidence-based Consensus on the management of ulcerative colitis: Current management. J Crohns Colitis 2008; 2:24-62. [PMID: 21172195 DOI: 10.1016/j.crohns.2007.11.002] [Citation(s) in RCA: 402] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2007] [Accepted: 11/23/2007] [Indexed: 02/08/2023]
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Matsumoto T, Fukunaga K, Kamikozuru K, Tozawa K, Yokoyama Y, Kusaka T, Onishi K, Miwa H, Nakamura S. Cytapheresis as a Non-Pharmacological Therapy for Inflammatory Bowel Disease. Transfus Med Hemother 2007; 35:18-23. [PMID: 21547106 DOI: 10.1159/000111763] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2007] [Accepted: 10/09/2007] [Indexed: 01/01/2023] Open
Abstract
SUMMARY: Although inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic recurrent disease with unknown etiology. Recent immunological studies suggest close relation to autoimmune status featured by antibodies against colonic epithelial cells. For patients with IBD, 5-aminosalycilates are often used in case of mild disease, and corticosteroids are standard therapy for moderate-to-severe disease. However, we often encounter patients who are resistant to or dependent of conventional therapy, which are likely to lead to future problems in quality of life due to adverse effects of drugs used, especially corticosteroids. Extracorporeal leukocyte removal therapy (cytapheresis) is one of the adjunctive therapies for IBD patients refractory to steroids. By removing circulating activated leukocytes, especially granulocytes and lymphocytes, impaired immune response is suppressed. In the present article recently published studies are reviewed in order to reflect the current state of the art in the use of cytapheresis for treating IBD, especially UC and CD. Although there are only few randomized controlled trials, clinical experience so far suggests that cytapheresis has superior efficiency than conventional therapies in steroid-resistant moderate-to-severe UC. Moreover, cytapheresis features its safety characteristic compared with other conventional medications for severe UC, cytapheresis is regarded as safe treatment regimen.
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Affiliation(s)
- Takayuki Matsumoto
- Division of Lower Gl Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
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Noguchi A, Watanabe K, Narumi S, Yamagami H, Fujiwara Y, Higuchi K, Oshitani N, Arakawa T. The production of interferon-gamma-inducible protein 10 by granulocytes and monocytes is associated with ulcerative colitis disease activity. J Gastroenterol 2007; 42:947-56. [PMID: 18085351 DOI: 10.1007/s00535-007-2118-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2006] [Accepted: 09/18/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND To clarify which types of cells produce interferon-gamma-inducible protein 10 (IP-10) and whether IP-10 is associated with the development of ulcerative colitis (UC), we investigated IP-10 production in UC patients. METHODS Serum IP-10 levels were measured using enzyme-linked immunosorbent assay in 29 patients with active and 21 with inactive UC and in 20 controls. The production of IP-10 by granulocytes and monocytes adsorbed to G-1 beads was examined. In 21 active UC patients treated with granulocyte and monocyte/macrophage adsorptive apheresis (GMA), serum IP-10 levels were measured before and after treatment. IP-10-positive cells in UC mucosa were also examined immunohistochemically using tissues obtained by surgical resection and colonoscopic biopsies. RESULTS Serum IP-10 levels in active UC patients were significantly higher than those in inactive patients, although even in the latter the levels were increased compared with those in controls. IP-10 production by granulocytes and monocytes in active UC patients was significantly higher than that in controls. Furthermore, the number of IP-10-positive cells was elevated in the colonic mucosa of patients with active UC, and one of the main subpopulations of IP-10-positive cells was granulocytes. Serum IP-10 levels decreased following GMA treatment in responders, but not in nonresponders. Interestingly, serum IP-10 levels before GMA were higher in responders than in nonresponders. In parallel with the serum levels, IP-10-positive cells also decreased following GMA treatment. CONCLUSIONS Serum IP-10 levels reflected UC disease activity, and the source of IP-10 was granulocytes and monocytes. Furthermore, serum IP-10 levels may be a marker for the responsiveness of patients to GMA treatment.
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Affiliation(s)
- Atsushi Noguchi
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan
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35
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Yokoyama Y, Fukunaga K, Fukuda Y, Tozawa K, Kamikozuru K, Ohnishi K, Kusaka T, Kosaka T, Hida N, Ohda Y, Miwa H, Matsumoto T. Demonstration of low-regulatory CD25High+CD4+ and high-pro-inflammatory CD28-CD4+ T-Cell subsets in patients with ulcerative colitis: modified by selective granulocyte and monocyte adsorption apheresis. Dig Dis Sci 2007; 52:2725-31. [PMID: 17404876 DOI: 10.1007/s10620-006-9560-z] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2006] [Accepted: 08/03/2006] [Indexed: 12/12/2022]
Abstract
Low-CD25(High+)CD4(+), a subset of regulatory CD25(+)CD4(+) T cells and high-inflammatory CD28(-)CD4(+) T cells can exacerbate ulcerative colitis (UC). This study sought to investigate the frequency of CD25(High+)CD4(+) and CD28(-)CD4(+) T cells in patients with UC and the changes in these cells during Adacolumn granulocyte and monocyte adsorption apheresis (GMA). Subjects were 12 patients with active UC, 11 with quiescent UC, and 14 healthy volunteers (HVs). The mean clinical activity index was 15.7 +/- 2.2 in active UC and 4.5 +/- 1.1 in quiescent UC. Peripheral blood samples were stained with CD4, CD25, and CD28 antibodies for flow cytometry. Patients with active UC received GMA and blood samples were examined before and after the first GMA session. Patients with active UC (P < 0.04) or quiescent UC (P < 0.02) had a higher percentage of CD28(-)D4(+)T cells compared with HVs, while the percentage of CD28(+)CD4(+) T cells was lower in both UC groups compared with HVs (P = 0.03 and P < 0.02). Patients with active UC had a lower percentage of CD25(High+)CD4(+)T cells compared with quiescent UC patients (P < 0.001). A significant increase in CD25(High+)CD4(+) T cells was associated with GMA (P < 0.03). Low CD25(High+)CD4(+) and high CD28(-)CD4(+) are prominent features in UC. The increase in CD25(High+)CD4(+) T cells induced by GMA should contribute to improved immune function. Additional studies are warranted, since a low frequency of CD25(High+)CD4(+) (-) and a high frequency of CD28(-)CD4(+) (-) expressing T cells might be a predictor of clinical response to GMA.
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Affiliation(s)
- Yoko Yokoyama
- Division of Lower Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
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Yamamoto T, Saniabadi AR, Maruyama Y, Umegae S, Matsumoto K. Factors affecting clinical and endoscopic efficacies of selective leucocytapheresis for ulcerative colitis. Dig Liver Dis 2007; 39:626-33. [PMID: 17532273 DOI: 10.1016/j.dld.2007.04.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2006] [Revised: 02/18/2007] [Accepted: 04/18/2007] [Indexed: 12/11/2022]
Abstract
BACKGROUND Granulocyte, monocyte/macrophage adsorptive apheresis is a novel treatment for active ulcerative colitis. However, as yet no study has reported on a subset of patients who might respond well to granulocyte, monocyte/macrophage adsorptive apheresis therapy. AIM To identify factors affecting clinical and endoscopic efficacies of granulocyte, monocyte/macrophage in patients with ulcerative colitis. METHODS Fifty consecutive patients with active ulcerative colitis initially received five granulocyte, monocyte/macrophage adsorptive apheresis sessions with the Adacolumn over five consecutive weeks. Patients who improved without achieving remission received five additional granulocyte, monocyte/macrophage adsorptive apheresis sessions. RESULTS One week after the last granulocyte, monocyte/macrophage adsorptive apheresis session, 26 (52%) and 17 patients (34%) achieved clinical and endoscopic remission, respectively. In the multivariate analysis, the dose of prednisolone administered at entry and the cumulative dose of prednisolone administered before entry were independent significant factors for both clinical and endoscopic remission, negatively impacted the efficacy of granulocyte, monocyte/macrophage adsorptive apheresis. Age, gender, duration of ulcerative colitis, number of prior relapses, duration of current exacerbation, extent and severity of ulcerative colitis, extra-intestinal manifestations, entry haematology values and C-reactive protein did not affect the outcome. CONCLUSIONS Based on the outcomes of this study, it appears that steroid-naïve patients and patients on low dose steroid and short duration of exposure respond to granulocyte, monocyte/macrophage adsorptive apheresis. Further studies in larger cohorts of patients should strengthen our findings.
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Affiliation(s)
- T Yamamoto
- Inflammatory Bowel Disease Centre, Yokkaichi Social Insurance Hospital, 10-8 Hazuyamacho, Yokkaichi, Mie 510-0016, Japan.
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Aoki H, Nakamura K, Yoshimatsu Y, Tsuda Y, Irie M, Fukuda K, Hosoe N, Takada N, Shirai K, Suzuki Y. Adacolumn selective leukocyte adsorption apheresis in patients with active ulcerative colitis: clinical efficacy, effects on plasma IL-8, and expression of Toll-like receptor 2 on granulocytes. Dig Dis Sci 2007; 52:1427-33. [PMID: 17394078 DOI: 10.1007/s10620-006-9406-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2006] [Accepted: 04/23/2006] [Indexed: 12/12/2022]
Abstract
Adacolumn selective granulocyte and monocyte apheresis (GMA) depletes activated leukocytes in patients with ulcerative colitis (UC). However, this per se cannot fully explain the efficacy of GMA. We have investigated the effects of GMA on the expression of toll-like receptors (TLRs) and plasma interleukin-8 (IL-8). Twenty-two patients with clinical activity index (CAI) of 5-17, 15 with total colitis and 7 with left-sided colitis, were included. Each patient could receive up to 10 GMA sessions, at 1 or 2 sessions per week. GMA was added to the patients' ongoing medication following a relapse or worsening UC, but no additional medication was given. Further, at entry and pre-GMA, blood samples were taken for full blood cell count, expression of TLRs on leukocytes, and plasma IL-8. Seventy-five percent of patients achieved remission after the 10th session (CAI, < or =4; P < 0.005) and there was a marked fall in C-reactive protein (P < 0.01), plasma IL-8 (P < 0.001), and granulocytes (P < 0.05) but an increase in lymphocytes (P < 0.05). The expression of TLR2 on granulocytes was down-modulated (P < 0.05) together with suppression of inflammatory cytokines produced by peripheral blood leukocytes. In conclusion, GMA appears to be an effective adjunct therapy to induce remission in the majority of patients, who are then spared from excess drug therapy. The procedure is associated with sustained immunomodulation. Control studies should strengthen these findings.
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Affiliation(s)
- Hiroshi Aoki
- Department of Internal of Medicine, Sakura Hospital, Toho University, 564-1 Shimoshizu, Sakura City, Chiba, Japan
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Caprilli R, D'Ovidio V. Leukocytapheresis as promising therapy for inflammatory bowel disease. Dig Liver Dis 2007; 39:435-7. [PMID: 17379590 DOI: 10.1016/j.dld.2007.02.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2007] [Accepted: 02/09/2007] [Indexed: 12/11/2022]
Affiliation(s)
- R Caprilli
- Department of Clinical Sciences, GI Unit, Policlinico Umberto I, University of Rome, La Sapienza, Rome, Italy.
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Ricart E, Esteve M, Andreu M, Casellas F, Monfort D, Sans M, Oudovenko N, Lafuente R, Panes J. Evaluation of 5 versus 10 granulocyteaphaeresis sessions in steroid-dependent ulcerative colitis: A pilot, prospective, multicenter, randomized study. World J Gastroenterol 2007; 13:2193-7. [PMID: 17465500 PMCID: PMC4146843 DOI: 10.3748/wjg.v13.i15.2193] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the efficacy of 5 compared to 10 granulocyteaphaeresis sessions in patients with active steroid-dependent ulcerative colitis.
METHODS: In this pilot, prospective, multicenter randomized trial, 20 patients with moderately active steroid-dependent ulcerative colitis were randomized to 5 or 10 granulocyteaphaeresis sessions. The primary objective was clinical remission at wk 17. Secondary measures included endoscopic remission and steroid consumption.
RESULTS: Nine patients were randomized to 5 granulocyteaphaeresis sessions (group 1) and 11 patients to 10 granulocyteaphaeresis sessions (group 2). At wk 17, 37.5% of patients in group 1 and 45.45% of patients in group 2 were in clinical remission. Clinical remission was accompanied by endoscopic remission in all cases. Eighty-six percent of patients achieving remission were steroid-free at wk 17. Daily steroid requirements were significantly lower in group 2. Eighty-nine per cent of patients remained in remission during a one year follow-up. One serious adverse event, not related to the study therapy, was reported.
CONCLUSION: Granulocyteaphaeresis is safe and effective for the treatment of steroid-dependent ulcerative colitis. In this population, increasing the number of aphaeresis sessions is not associated with higher remission rates, but affords a significant steroid-sparing effect.
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Affiliation(s)
- Elena Ricart
- Gastroenterology Department, Hospital Clinic de Barcelona, C/Villarroel 170, 08036-Barcelona, Spain.
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Szczepiorkowski ZM, Bandarenko N, Kim HC, Linenberger ML, Marques MB, Sarode R, Schwartz J, Shaz BH, Weinstein R, Wirk A, Winters JL. Guidelines on the use of therapeutic apheresis in clinical practice—Evidence-based approach from the apheresis applications committee of the American society for apheresis. J Clin Apher 2007; 22:106-75. [PMID: 17394188 DOI: 10.1002/jca.20129] [Citation(s) in RCA: 157] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The American Society for Apheresis (ASFA) Apheresis Applications Committee is charged with a review and categorization of indications for therapeutic apheresis. This elaborate process had been undertaken every 7 years resulting in three prior publications in 1986, 1993, and 2000 of "The ASFA Special Issues." This article is the integral part of the Fourth ASFA Special Issue. The Fourth ASFA Special Issue is significantly modified in comparison to the previous editions. A new concept of a fact sheet has been introduced. The fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis. A detailed description of the fact sheet is provided. The article consists of 53 fact sheets devoted to each disease entity currently categorized by the ASFA. Categories I, II, and III are defined as previously in the Third Special Issue. However, a few new therapeutic apheresis modalities, not yet approved in the United States or are currently in clinical trials, have been assigned category P (pending) by the ASFA Clinical Categories Subcommittee. The diseases assigned to category IV are discussed in a separate article in this issue.
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Affiliation(s)
- Zbigniew M Szczepiorkowski
- Transfusion Medicine Service, Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
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Abstract
Ulcerative colitis (UC) and Crohn’s disease (CD) are the major forms of idiopathic inflammatory bowel disease (IBD). Both UC and CD are debilitating chronic disorders that afflict millions of individuals throughout the world with symptoms which impair function and quality of life. The etiology of IBD is inadequately understood and therefore, drug therapy has been empirical instead of being based on sound understanding of IBD pathogenesis. This is a major factor for poor drug efficacy and drug related side effects that often add to the disease complexity. The development of biologicals notably infliximab to intercept tumor necrosis factor (TNF)-α reflects some progress, albeit major concern about their side effects and lack of long-term safety and efficacy profiles. However, IBD seems to be perpetuated by inflammatory cytokines like TNF-α, interleukin (IL)-1β, IL-6 and IL-8 for which activated peripheral granulocytes and monocytes/macrophages (GM) are major sources. Further, in IBD, peripheral GMs are elevated with activation behavior, increased survival time and are found in vast numbers within the inflamed intestinal mucosa; they are suspected to be major factors in the immunopathogenesis of IBD. Hence, peripheral blood GMs should be appropriate targets of therapy. The Adacolumn is a medical device developed for selective depletion of GM by receptor-mediated adsorption (GMA). Clinical data show GMA, in patients with steroid dependent or steroid refractory UC, is associated with up to 85% efficacy and tapering or discontinuation of steroids, while in steroid naïve patients (the best responders), GMA spares patients from exposure to steroids. Likewise, GMA at appropriate intervals in patients at a high risk of clinical relapse suppresses relapse thus sparing the patients from the morbidity associated with IBD relapse. Further, GMA appears to reduce the number of patients being submitted to colectomy or exposure to unsafe immunosupressants. First UC episode, steroid naivety and short disease duration appear good predictors of response to GMA and based on the available data, GMA seems to have an excellent safety profile.
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Affiliation(s)
- Hiroyuki Hanai
- Center for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, 26 Shirowacho, Hamamatsu 4300846, Japan
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Suzuki Y, Yoshimura N, Fukuda K, Shirai K, Saito Y, Saniabadi AR. A retrospective search for predictors of clinical response to selective granulocyte and monocyte apheresis in patients with ulcerative colitis. Dig Dis Sci 2006; 51:2031-8. [PMID: 17004123 DOI: 10.1007/s10620-006-9199-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2005] [Accepted: 12/05/2005] [Indexed: 12/12/2022]
Abstract
Recently, selective granulocytapheresis (Adacolumn) has appeared as a new treatment for patients with inflammatory bowel disease. This study sought to determine predictors of response to this new nonpharmacologic mode of therapy by retrospectively evaluating 28 patients who received granulocytapheresis after experiencing active ulcerative colitis (UC). Between April 2000 and March 2004, 28 consecutive patients received granulocytapheresis for active UC with the Adacolumn, which is filled with cellulose acetate beads as the column leukocytapheresis carriers; the carriers adsorb granulocytes, monocytes/macrophages, and a small fraction of lymphocytes (FcgammaR and complement receptors bearing leukocytes). Each patient could receive up to 10 Adacolumn sessions, at 2 sessions per week. In 2004, clinical response was retrospectively evaluated. Seven days after the last Adacolumn session, 20 of 28 patients had remission (colitis activity index [CAI] < or =4) including all 8 patients who had their first UC episode. The mean duration of UC in the 8 first episode cases was 3.4 months compared with 40.2 months for all 28 patients and 65.4 months for the 8 nonresponders. The response to Adacolumn was independent of basal CAI. The 8 nonresponders were given conventional medication (CM) or cyclosporine (CsA) if the former failed. Two responded to CM, 3 to CsA, and 3 underwent colectomy. First UC episode and short disease duration appear good predictors of response to granulocytapheresis. Selective granulocytapheresis might be an effective first-line treatment.
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Affiliation(s)
- Yasuo Suzuki
- Department of Internal Medicine, Sakura Hospital, Toho University, Chiba University School of Medicine, Tokyo, Japan.
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Yamamoto T, Saniabadi AR, Umegae S, Matsumoto K. Impact of selective leukocytapheresis on mucosal inflammation and ulcerative colitis: cytokine profiles and endoscopic findings. Inflamm Bowel Dis 2006; 12:719-26. [PMID: 16917227 DOI: 10.1097/00054725-200608000-00008] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND This prospective study assessed the impact of selective leukocytapheresis (SLA) on mucosal inflammation in patients with active ulcerative colitis (UC) by endoscopic investigations and measurement of mucosal cytokine profiles. MATERIALS AND METHODS Twenty-eight patients with moderately active UC received 5 SLA sessions with the Adacolumn over 5 consecutive weeks. The Adacolumn leukocytapheresis carriers selectively adsorb granulocytes, monocytes/macrophages, and smaller subsets of lymphocytes (FcgammaR and complement receptors bearing leukocytes). Before and after treatment, mucosal biopsies were obtained from multiple sites in the large bowel. As control, colonic biopsies from 20 patients without bowel inflammation were examined. Mucosal cytokines were measured by enzyme-linked immunosorbent assay. RESULTS At entry, the mucosal concentrations of interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1ra), IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) were significantly higher compared with the control group, whereas IL-1ra/IL-1beta ratio was significantly lower. Clinical remission was achieved in 19 (68%) patients. In patients with clinical remission but not in those without remission, the mucosal tissue concentrations of IL-1beta, IL-1ra, IL-6, IL-8, and TNF-alpha significantly decreased, whereas the IL-1ra/IL-1beta ratio significantly increased. Furthermore, endoscopic remission of mucosal inflammation was observed in 14 (50%) patients, which was associated with a decline in mucosal IL-1beta, IL-1ra, IL-6, IL-8, and TNF-alpha and an increase in IL-1ra/IL-1beta ratio. CONCLUSIONS Depleting granulocytes and monocytes/macrophages by SLA should mitigate cytokine profiles in the intestinal mucosa and correct an imbalance between pro- and anti-inflammatory cytokines in active UC.
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Affiliation(s)
- Takayuki Yamamoto
- Inflammatory Bowel Disease Center, Yokkaichi Social Insurance Hospital, Yokkaichi, Mie, Japan.
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WATANABE K, OSHITANI N, KAMATA N, INAGAWA M, YAMAGAMI H, HIGUCHI K, ARAKAWA T. Efficacy and endoscopic prediction of cytapheresis therapy in patients with refractory and steroid-dependent ulcerative colitis. ACTA ACUST UNITED AC 2006. [DOI: 10.1111/j.1746-6342.2006.00038.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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D'Ovidio V, Aratari A, Viscido A, Marcheggiano A, Papi C, Capurso L, Caprilli R. Mucosal features and granulocyte-monocyte-apheresis in steroid-dependent/refractory ulcerative colitis. Dig Liver Dis 2006; 38:389-94. [PMID: 16569521 DOI: 10.1016/j.dld.2005.12.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2005] [Revised: 12/05/2005] [Accepted: 12/13/2005] [Indexed: 12/11/2022]
Abstract
BACKGROUND Mucosa-infiltrated granulocyte neutrophils are an early characteristic of inflammation and the main histological feature of active ulcerative colitis. Mucosal healing has recently been indicated as an important tool in the evaluation of response to treatment. While several studies have stressed the efficacy of granulocyte-monocyte-apheresis in inducing clinical remission in active ulcerative colitis, few data are available on mucosal features. AIM Aim of this study was to assess the effects of granulocyte-monocyte-apheresis on clinical and mucosal features in patients with ulcerative colitis, dependent upon or refractory to steroids. MATERIAL AND METHODS From April 2004 to April 2005, 12 patients (5 females, 7 males, mean age 49 years, range 33-71 years), with mild-moderate ulcerative colitis (six left colitis, six pancolitis) dependent/refractory upon steroids were enrolled. Each patient was treated for a 5-week period with five cycles of granulocyte-monocyte-apheresis. Patients were evaluated at baseline and 1 week after the last apheresis by means of Global Physician Assessment, quality of life features, laboratory tests (erythrocyte sedimentation rate, CRP, full blood count, faecal calprotectine), endoscopy and histology. RESULTS At week 6 of follow-up, complete mucosal healing was observed in 3 out of 12 patients, partial mucosal healing in 8 patients and no change in 1 patient. Clinical response was complete in 8 out of 12 patients. CONCLUSIONS These data suggest that granulocyte-monocyte-apheresis induces an improvement both in clinical and mucosal lesions in steroid-dependent/refractory ulcerative colitis. Of note, the reduction in granulocyte infiltration and the improvement in mucosal lesions are accompanied by a reduction in faecal calprotectine.
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Affiliation(s)
- V D'Ovidio
- Department of Clinical Sciences, GI Unit, Policlinico Umberto I, University of Rome, La Sapienza, Viale del Policlinico 155, Rome, Italy.
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Manoj K, Sigurbjornsson FT, Bjarnason I. Leucocyte apheresis for ulcerative colitis: Where do we stand? Dig Liver Dis 2006; 38:394-6. [PMID: 16551515 DOI: 10.1016/j.dld.2006.02.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2006] [Accepted: 02/01/2006] [Indexed: 12/11/2022]
Affiliation(s)
- K Manoj
- Department of Medicine, King's College Hospital, Denmark Hill, London SE5 9PJ, UK
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Kruis W, Dignass A, Steinhagen-Thiessen E, Morgenstern J, Mössner J, Schreiber S, Vecchi M, Malesci A, Reinshagen M, Löfberg R. Open label trial of granulocyte apheresis suggests therapeutic efficacy in chronically active steroid refractory ulcerative colitis. World J Gastroenterol 2006; 11:7001-6. [PMID: 16437606 PMCID: PMC4717044 DOI: 10.3748/wjg.v11.i44.7001] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To study the efficacy, safety, and feasibility of a granulocyte adsorptive type apheresis system for the treatment of patients with chronically active ulcerative colitis despite standard therapy. METHODS An open label multicenter study was carried out in 39 patients with active ulcerative colitis (CAI 6-8) despite continuous use of steroids (a minimum total dose of 400 mg prednisone within the last 4 wk). Patients received a total of five aphereses using a granulocyte adsorptive technique (Adacolumn (reg), Otsuka Pharmaceutical Europe, UK). Assessments at wk 6 and during follow-up until 4 mo comprised clinical (CAI) and endoscopic (EI) activity index, histology, quality of life (IBDQ), and laboratory tests. RESULTS Thirty-five out of thirty-nine patients were qualified for intent-to-treat analysis. After the apheresis treatment at wk 6, 13/35 (37.1%) patients achieved clinical remission and 10/35 (28.6%) patients had endoscopic remission (CAI<4, EI<4). Quality of life (IBDQ) increased significantly (24 points, P<0.01) at wk 6. Apheresis could be performed in all but one patient. Aphereses were well tolerated, only one patient experienced anemia. CONCLUSION In patients with steroid refractory ulcerative colitis, five aphereses with a granulocyte/monocyte depleting filter show potential short-term efficacy. Tolerability and technical feasibility of the procedure are excellent.
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Affiliation(s)
- Wolfgang Kruis
- Evangelisches Krankenhaus Kalk, Innere Abteilung, Universität zu Köln, Germany.
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Kanai T, Hibi T, Watanabe M. The logics of leukocytapheresis as a natural biological therapy for inflammatory bowel disease. Expert Opin Biol Ther 2006; 6:453-66. [PMID: 16610976 DOI: 10.1517/14712598.6.5.453] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are debilitating idiopathic inflammatory bowel diseases (IBDs) with symptoms that impair ability to function and quality of life. The aetiology of IBD is inadequately understood and, therefore, drug therapy has been empirical instead of based on sound understanding of the disease mechanisms. This has been a major factor for poor drug efficacy and treatment-related side effects that often add to disease complications. The development of biologicals, notably infliximab, to block TNF-alpha reflects some progress, but there is major concern about their side effects and lack of long-term safety and efficacy profiles. However, IBD by its very nature is exacerbated and perpetuated by inflammatory cytokines, including TNF-alpha, IL-6 and IL-12, for which activated peripheral blood lymphocytes, monocytes/macrophages and granulocytes are major sources. Hence, activated leukocytes should be appropriate targets of therapy. At present, three strategies are available for removing excess and activated leukocytes by leukocytapheresis: centrifugation, Adacolumn and Cellsorba. Centrifugation can deplete lymphocytes or total leukocytes, whereas Adacolumn selectively adsorbs granulocytes and monocytes together with a smaller fraction of lymphocytes (FcgammaR- and complement receptor-bearing leukocytes), and Cellsorba non-selectively removes all three major leukocyte populations. Efficacy has ranged from 'none' to an impressive 93% together with excellent safety profiles and downmodulation of inflammation factors. Furthermore, leukocytapheresis has shown strong drug-sparing effects and reduced the number of patients requiring colectomy or exposure to unsafe immunosuppressants, such as cyclosporin A. Leukocytapheresis removes from the body cells that contribute to IBD and, therefore, unlike drugs, it is not expected to induce dependency or refractoriness.
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Affiliation(s)
- Takanori Kanai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
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Cabriada JL, Doménech E, Gomollón F, González-Carro P, González-Lara V, Hinojosa J, Jiménez-López CE, Nos P, Obrador A, Panès J, Saro C, Varea V, Lafuente R, Guilera M. [Consensus document on the use of granulocytapheresis in patients with inflammatory bowel disease]. GASTROENTEROLOGIA Y HEPATOLOGIA 2006; 29:85-92. [PMID: 16448611 DOI: 10.1157/13083905] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Yamamoto T, Umegae S, Matsumoto K. Safety and clinical efficacy of granulocyte and monocyte adsorptive apheresis therapy for ulcerative colitis. World J Gastroenterol 2006; 12:520-5. [PMID: 16489663 PMCID: PMC4066082 DOI: 10.3748/wjg.v12.i4.520] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Active ulcerative colitis (UC) is frequently associated with infiltration of a large number of leukocytes into the bowel mucosa. Therefore, removal of activated circulating leukocytes by apheresis has the potential for improving UC. In Japan, since April 2000, leukocytapheresis using Adacolumn has been approved as the treatment for active UC by the Ministry of Health and Welfare. The Adacolumn is an extracorporeal leukocyte apheresis device filled with cellulose acetate beads, and selectively adsorbs granulocytes and monocytes/macrophages. To assess the safety and clinical efficacy of granulocyte and monocyte adsorptive apheresis (GMCAP) for UC, we reviewed 10 open trials of the use of GMCAP to treat UC. One apheresis session (session time, 60 min) per week for five consecutive weeks (a total of five apheresis sessions) has been a standard protocol. Several studies used modified protocols with two sessions per week, with 90-min session, or with a total of 10 apheresis sessions. Typical adverse reactions were dizziness, nausea, headache, flushing, and fever. No serious adverse effects were reported during and after GMCAP therapy, and almost all the patients could complete the treatment course. GMCAP is safe and well-tolerated. In the majority of patients, GMCAP therapy achieved clinical remission or improvement. GMCAP is a useful alternative therapy for patients with steroid-refractory or -dependent UC. GMCAP should have the potential to allow tapering the dose of steroids, and is useful for shortening the time to remission and avoiding re-administration of steroids at the time of relapse. Furthermore, GMCAP may have efficacy as the first-line therapy for steroid-naive patients or patients who have the first attack of UC. However, most of the previous studies were uncontrolled trials. To assess a definite efficacy of GMCAP, randomized, double-blind, sham-controlled trials are necessary. A serious problem with GMCAP is cost; a single session costs ¥145 000 ($1 300). However, if this treatment prevents hospital admission, re-administration of steroids and surgery, and improves a quality of life of the patients, GMCAP may prove to be cost-effective.
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