Silvio Danese ¹, Erika Angelucci, Tommaso Stefanelli, Paolo Omodei, Carmelo Luigiano, Silvia Finazzi, Nico Pagano, Alessandro Repici, Maurizio Vecchi, Alberto Malesci, Digestion. 2008;77(2):96-107.

Ulcerative colitis and Crohn’s disease are inflammatory bowel diseases with a chronic relapsing course. Management of both conditions is far from being fully satisfactory. For this reason in the last decade a large number of biological therapies, targeting cytokines involved in intestinal inflammation, has been developed with various results in terms of efficacy, safety and costs. Activated granulocytes and monocytes represent the major sources of pro-inflammatory cytokines in the intestinal mucosa, playing a pivotal role in inducing and maintaining intestinal inflammation. Leukocytapheresis using an adsorptive carrier-based system (Adacolumn) or a removal filter column (Cellsorba) has been proposed as a feasible, safe and effective therapy for ulcerative colitis and Crohn’s disease. The objective of this paper is to provide an overview on the current knowledge about mechanisms of action, available clinical data and the possible future perspectives for the use of Adacolumn and Cellsorba in the management of inflammatory bowel diseases.

https://pubmed.ncbi.nlm.nih.gov/18382085/

David Schwartz ¹, John R Ferguson, Curr Med Res Opin . 2007 Nov;23(11):2715-28.

Background: A broad range of pharmacologic therapies are available to treat active inflammatory bowel disease (IBD), including 5-aminosalicylate preparations, corticosteroids, and immunosuppressants (e.g., azathio prine/6-mercaptopurine [AZA/6-MP] or methotrexate). Although these therapies are effective, up to 60% of patients are refractory or intolerant. Biologic therapies, such as the anti-TNF agent infliximab, offer promise but are not without controversy; despite many positive reports, steroid-refractory patients are less likely than other individuals to respond to infliximab. Effective, long-term therapies that do not add to the adverse-effects burden in patients with IBD are needed. Of these, granulocyte/monocyte apheresis (GMA) is one promising approach.

Scope: PubMed and relevant congresses databases were searched using the terms ‘granulocyte/monocyte apheresis,’ ‘GMA,’ ‘leukocytapheresis,’ ‘Adacolumn,’ and ‘Cellsorba.’ These studies were further selected to include only those focusing on IBD. A time frame of 2000-2006 was used.

Findings: Data from open-label trials show that patients with moderate-to-severe IBD refractory to conventional pharmacologic treatment achieved clinical response and/or remission after treatment with GMA. Furthermore, recent small open-label trials of GMA show increased rates of induction and maintenance of response/remission in steroid-naïve IBD patients.

Conclusions: The remission rates seen in these open-label clinical trials of GMA are consistent with those of currently available pharmacologic therapies for IBD. However, the majority of these trials enrolled only small numbers of patients, were largely open-label, and were of limited duration. These data must be confirmed in well-controlled, large-scale clinical trials

https://pubmed.ncbi.nlm.nih.gov/17894921/

Tarja Ruuska, Marja-Leena Lähdeaho, Yelda Sutas, Merja Ashorn, Juhani Grönlund Scand J Gastroenterol 2007 Nov; 42(11):1390-1. doi: 10.1080/00365520701231116.

Recent studies show corticosteroid dependency in 45% of paediatric ulcerative colitis (UC) patients despite using other medicaments, including immunomodulators This patient group is problematic as corticosteroids have numerous side effects when used long term. New biological approaches have proved effective in the treatment of inflammatory bowel disease (IBD), but as the side effects can be severe, especially in young patients, their use is restricted in UC.

In UC, circulating activated granulocytes and macrophages/monocytes are increased and can infiltrate the bowel and cause tissue injury by producing inflammatory cytokines, being thus involved in the initiation and perpetuation of an inflammatory disorder. Periodic removal of activated granulocytes and monocytes/ macrophages with selective leucocyte apheresis (Adacolumn; JIMRO, Japan) is expected to reduce leucocyte-dependent tissue injury. Preliminary reports show promising results in the treatment of IBD, in children with corticosteroid-dependent or -resistant UC.

We design a  pilot study where 11 children (7 corticosteroid-dependent, 3 corticosteroid-resistant and 1 refusing corticosteroids) were treated with apheresis and their data analysed. Treatment was given once a week, a total of 5-9 sessions. 8 out of the remaining 11 patients responded well to the treatment. Corticosteroids could be tapered-off either totally or to minimal doses in all cases. Treatment was well tolerated.

https://pubmed.ncbi.nlm.nih.gov/17918012/

https://www.tandfonline.com/doi/full/10.1080/00365520701231116?scroll=top&needAccess=true

F J Fernández Pérez ¹, F Rodríguez, C de Sola, N Fernández Moreno, F Vera, R Rivera, A Sánchez Cantos, Rev Esp Enferm Dig. 2007 Nov;99(11):628-35.

Introduction: Granulocytapheresis (GCAP) eliminates activated granulocytes-monocytes from peripheral blood, thus modifying the circulating pool of leukocytes and reducing intestinal inflammation. Objective: To evaluate the efficacy of GCAP in inflammatory bowel disease (IBD) using an induction and maintenance protocol. Material and method: A retrospective study including patients with active corticosteroid-dependent or refractory IBD. Induction included 5 sessions in ulcerative colitis (UC) and 7 sessions in Crohn’s disease (CD); one monthly session was used thereafter until week 32. Clinical activity indices and use of corticosteroids were monitored. Results: Eighteen patients were included (10 with UC, 8 with CD), 10 of them dependent on and 8 refractory to corticosteroids. Fourteen of them were refractory and a further 4 were intolerant to immunosuppressants (IS). Induction was not completed in 2 UC (severe relapses) and 1 CD (side-effects) patients. One UC and 3 CD patients withdrew during maintenance. Among patients who completed induction, response or remission was achieved in 87.5% of UC cases (2 and 5 patients) and 71.4% of CD cases (1 and 4 patients), respectively. At week 32 response-remission rates reached 75% in CU (3 and 3 patients) and 42.8% in CD (1 and 2 patients) cases, respectively. Corticosteroid withdrawal was possible in 14.2% of CD and in 62.5% of UC patients (25% in remission and 37.5% with response). There were two major side effects (thrombophlebitis and syncope). No colectomies were performed for UC patients who completed GCAP induction after a mean follow-up of 97.6 weeks (range: 72-128). Conclusions: Both UC and CD respond well to GCAP induction. At 32 weeks UC patients maintain similar response-remission rates (87.5 vs. 75%), whereas almost one-third of CD patients lose response. Granulocytapheresis is an alternative, steroid-sparing treatment modality to induce and maintain remission in UC, while good patient selection and a maintenance protocol not well defined yet are needed for CD.

https://pubmed.ncbi.nlm.nih.gov/18271660/

)http://www.grupoaran.com/mrmUpdate/lecturaPDFfromXML.asp?IdArt=459857&TO=RVN&Eng=1

Keiko Okuma ¹, Kouichi Mitsuishi, Toshio Hasegawa, Hitoshi Tsuchihashi, Hideoki Ogawa, Shigaku Ikeda, Ther Apher Dial. 2007 Oct;11(5):387-90.

 Our results suggest that GCAP is a safe and useful tool for the treatment of intractable PG, and that IL-8 and G-CSF are likely to be involved in the pathogenesis of PG.

https://pubmed.ncbi.nlm.nih.gov/17845399/

Ken Fukunaga, Hiroto Miwa, Takayuki Matsumoto January 2007 Tropical gastroenterology: official journal of the Digestive Diseases Foundation 28(1):11-5

Ulcerative colitis (UC) together with Crohn’s disease (CD) constitute idiopathic inflammatory bowel diseases (IBD) of the gut. The etiology of IBD is poorly understood, but autoimmune-disturbance has been suggested to play an important role in this incurable disease. Extracorporeal leukocyte removal therapy (ELRT) is the latest adjunct for IBD patient refractory to steroids, and it aims at suppressing immunological response by removing circulating leukocytes, especially granulocytes, from the blood stream. The present paper reviews the latest evidences in order to propose the current status of ELRT in the therapeutic strategy for IBD, especially for UC and CD. Clinical experience so far suggests that ELRT has superior efficiency as a non-pharmacological immuno-modulative therapy for steroid resistant UC patients before submission to colectomy. Moreover, ELRT has been proven to be a safe therapy compared with other current medications for severe UC.

https://www.researchgate.net/publication/5947344_Role_of_leukocytapheresis_in_the_management_of_inflammatory_bowel_disease

Ikeda, Hitoshi; Ishimaru, Yuki; Takayasu, Hajime; Fujino, Junko; Kisaki, Yoshiyuki; Otani, Yushi; Yamagishi, Junko; Tahara, Kazunori. J Pediatr Gastroenterol Nutr 2006; 43:592-6. doi: 10.1097/01.mpg.0000237928.07729.79

Objectives: Granulocyte apheresis (GCAP), involving the removal of granulocytes from the blood, may improve clinical symptoms and facilitate a reduction in the dose of steroids in adult patients with ulcerative colitis. As a preliminary trial, GCAP was used to taper the dose of steroids in 4 pediatric patients with ulcerative colitis. Methods: Three males and 1 female ranging from 11 to 17 years old were treated with GCAP once per week for 5 consecutive weeks/course. The ages of patients at clinical onset ranged from 8 to 12 years and the length of time from the clinical onset to GCAP treatment ranged from 28 to 58 months (median, 38.5 months). Results: In 2 patients, symptoms and signs indicating disease activity improved after 2 courses of GCAP. Laboratory data and endoscopic findings also improved after treatment and the clinical efficacy was judged to be excellent in these patients. In 1 patient, GCAP improved laboratory and endoscopic hallmarks, but bloody stools persisted. Finally, the treatment was ineffective in the fourth patient who eventually underwent surgery. Conclusions: GCAP is effective in improving clinical symptoms and may play an important role in converting steroid therapy to other treatments in children with steroid-refractory or steroid-dependent ulcerative colitis.

https://journals.lww.com/jpgn/FullText/2006/11000/Efficacy_of_Granulocyte_Apheresis_in_Pediatric.8.aspx

Koichiro Watanabe, December 2006Alimentary Pharmacology & Therapeutics 24(1):147 – 152,

https://www.researchgate.net/publication/227900776_Efficacy_and_endoscopic_prediction_of_cytapheresis_therapy_in_patients_with_refractory_and_steroid-dependent_ulcerative_colitis

Bresci Giampaolo ¹, Parisi Giuseppe, Bertoni Michele, Mazzoni Alessandro, Scatena Fabrizio, Capria Alfonso, World J Gastroenterol. 2006 Apr 14;12(14):2201-4.

Even if the number of our patients with steroid-refractory IBDs was not big, we can assert that GCAP is well tolerated and effective, especially in the first six months after the treatment, in a significant percentage of cases. The rate of sustained response drops slightly after 6 mo and significantly after 12 mo, however the absence of severe side effects can be a stimulus for further evaluating new schedules of treatment.

https://pubmed.ncbi.nlm.nih.gov/16610021/

Takayuki Yamamoto, Satoru Umegae, Koichi Matsumoto February 2006 World Journal of Gastroenterology 12(4):520-5 DOI:10.3748/wjg.v12.i4.520

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.

https://www.researchgate.net/publication/7286897_Safety_and_clinical_efficacy_of_granulocyte_and_monocyte_adsorptive_apheresis_therapy_for_ulcerative_colitis