Farah Yasmin ¹, Hala Najeeb ¹, Unaiza Naeem ¹, Abdul Moeed ¹, Thoyaja Koritala ², Salim Surani ^3 4

World J Clin Cases  2022 Jul 26;10(21):7195-7208. doi: 10.12998/wjcc.v10.i21.7195.

Inflammatory Bowel Disease (IBD) is a hallmark of leukocyte infiltration, followed by the release of cytokines and interleukins. Disease progression to Ulcerative Colitis (UC) or Crohn’s Disease (CD) remained largely incurable. The genetic and environmental factors disrupt enteral bacteria in the gut, which hampers the intestinal repairing capability of damaged mucosa. Commonly practiced pharmacological therapies include 5-aminosalicylic acid with corticosteroids and tumor necrosis factor (TNF)-α. New interventions such as CDP571 and TNF-blocking RDP58 report the loss of patient response. This review discusses the non-pharmacologic selective granulocyte-monocyte-apheresis (GMA) and leukocytapheresis (LCAP) that have been proposed as treatment modalities that reduce mortality. GMA, an extracorporeal vein-to-vein technique, presents a strong safety profile case for its use as a viable therapeutic option compared to GMA’s conventional medication safety profile. GMA reported minimal to no side effects in the pediatric population and pregnant women. Numerous studies report the efficacious nature of GMA in UC patients, whereas data on CD patients is insufficient. Its benefits outweigh the risks and are emerging as a favored non-pharmacological treatment option. On the contrary, LCAP uses a general extracorporeal treatment that entraps leukocytes and suppresses cytokine release. It has been deemed more efficacious than conventional drug treatments, the former causing better disease remission, and maintenance. Patients with UC/CD secondary to complications have responded well to the treatment. Side effects of the procedure have remained mild to moderate, and there is little evidence of any severe adverse event occurring in most age groups. LCAP decreases the dependence on steroids and immunosuppressive therapies for IBD. The review will discuss the role of GMA and LCAP.

https://pubmed.ncbi.nlm.nih.gov/36158031/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353887/

Daniel Vasile Balaban and Mariana Jinga Crohn’s Disease Recent Advances book, October 15th, 2020 DOI: 10.5772/intechopen.93605

Inflammatory bowel diseases (IBD) have become a major focus for gastroenterologists worldwide, with the increasing incidence and complexity of cases, which pose therapeutic challenges. Currently available approaches fail in controlling the disease activity in a significant proportion of patients and some of the therapies are associated with significant adverse events. Although new molecules are on the horizon and treatment strategies have been optimized, novel therapeutic tools are much needed in IBD for patients who fail to attain control of the disease. Apheresis is now a common non-pharmacological therapeutic modality used in several pathologies, IBD also. In the current review, we summarize currently available evidence with respect to selective apheresis in IBD.

https://www.intechopen.com/chapters/73330

Abbi R Saniabadi ¹, Tomotaka Tanaka ¹, Toshihide Ohmori ¹, Koji Sawada ¹, Takayuki Yamamoto ¹, Hiroyuki Hanai  World J gastroenterol. 2014 Aug 7;20(29):9699-715

Ulcerative colitis and Crohn’s disease are the major phenotypes of the idiopathic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms, impairing function and quality of life. Current medications are aimed at reducing the symptoms or suppressing exacerbations. However, patients require life-long medications, and this can lead to drug dependency, loss of response together with adverse side effects. Indeed, drug side effects become additional morbidity factor in many patients on long-term medications. Nonetheless, the efficacy of anti-tumour necrosis factors (TNF)-α biologics has validated the role of inflammatory cytokines notably TNF-α in the exacerbation of IBD. However, inflammatory cytokines are released by patients’ own cellular elements including myeloid lineage leucocytes, which in patients with IBD are elevated with activation behaviour and prolonged survival. Accordingly, these leucocytes appear logical targets of therapy and can be depleted by adsorptive granulocyte/monocyte apheresis (GMA) with an Adacolumn. Based on this background, recently GMA has been applied to treat patients with IBD in Japan and in the European Union countries. Efficacy rates have been impressive as well as disappointing. In fact the clinical response to GMA seems to define the patients’ disease course, response to medications, duration of active disease, and severity at entry. The best responders have been first episode cases (up to 100%) followed by steroid naïve and patients with a short duration of active disease prior to GMA. Patients with deep ulcers together with extensive loss of the mucosal tissue and cases with a long duration of IBD refractory to existing medications are not likely to benefit from GMA. It is clinically interesting that patients who respond to GMA have a good long-term disease course by avoiding drugs including corticosteroids in the early stage of their IBD. Additionally, GMA is very much favoured by patients for its good safety profile. GMA in 21st century reminds us of phlebotomy as a major medical practice at the time of Hippocrates. However, in patients with IBD, there is a scope for removing from the body the sources of pro-inflammatory cytokines and achieve disease remission. The bottom line is that by introducing GMA at an early stage following the onset of IBD or before patients develop extensive mucosal damage and become refractory to medications, many patients should respond to GMA and avoid pharmacologics. This should fulfill the desire to treat without drugs.

https://pubmed.ncbi.nlm.nih.gov/25110409/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123360/

Takeshi Tomomasa ¹, Hitoshi Tajiri, Seiichi Kagimoto, Toshiaki Shimizu, Atsushi Yoden, Kosuke Ushijima, Keiichi Uchida, Hiroaki Kaneko, Daiki Abukawa, Mutsuko Konno, Shun-ichi Maisawa, Takao Kohsaka, Akio Kobayashi, Japanese Study Group for Pediatric Ulcerative Colitis. J Pediatr Gastroenterol Nutr. 2011 Jul;53(1):34-9. doi: 10.1097/MPG.0b013e31821058bc.

Objective: Leukocytapheresis (LCAP) is a nonpharmacologic therapy that has recently been used to treat ulcerative colitis (UC). This multicenter open-label study prospectively assessed the efficacy and safety of LCAP in pediatric patients with UC. Patients and methods: Twenty-three patients ages 8 to 16 years with moderate (n = 19) to severe (n = 4) steroid-resistant UC were enrolled. One of 2 LCAP columns with different volumes (model EX and the half-volume model EI) was selected, according to body weight. LCAP was performed once per week for 5 consecutive weeks. Clinical and laboratory data were collected at predetermined time points. The primary endpoint was decreased stool frequency/hematochezia score, and secondary endpoints were clinical, laboratory, and endoscopic improvements. Results: The stool frequency/hematochezia score decreased significantly from 4.5 ± 1.2 before treatment to 1.6 ± 1.9 after the fifth treatment. Clinical parameters, including stool frequency, presence of visible blood, abdominal pain, and body temperature, were significantly improved. Fecal calprotectin decreased significantly. Endoscopic findings evaluated using Matts score also improved (P < 0.01). The steroid dose decreased from 1.1 ± 0.4 mg/kg before treatment to 0.8 ± 0.5 mg/kg after treatment. There were no significant differences in changes between the EX and EI columns. The incidence of adverse effects was 61%, although none was serious. The most common adverse effects were decreased hematocrit and hemoglobin concentration. Conclusions: The present study showed that LCAP was well tolerated in children with UC, mostly moderate, and was as effective as in adults. The types of pediatric patients best suited to LCAP remain to be determined.

https://pubmed.ncbi.nlm.nih.gov/21694533/

Leukocytapheresis in Pediatric Patients With Ulcerative Coli… : Journal of Pediatric Gastroenterology and Nutrition (lww.com)

Takeshi Tomomasa ¹, Hitoshi Tajiri, Seiichi Kagimoto, Toshiaki Shimizu, Atsushi Yoden, Kosuke Ushijima, Keiichi Uchida, Hiroaki Kaneko, Daiki Abukawa, Mutsuko Konno, Shun-ichi Maisawa, Takao Kohsaka, Akio Kobayashi, Japanese Study Group for Pediatric Ulcerative Colitis J Pediatr Gastroenterol Nutr. 2011 Jul;53(1):34-9. doi: 10.1097/MPG.0b013e31821058bc.

Objective: Leukocytapheresis (LCAP) is a nonpharmacologic therapy that has recently been used to treat ulcerative colitis (UC). This multicenter open-label study prospectively assessed the efficacy and safety of LCAP in pediatric patients with UC. Patients and methods: Twenty-three patients ages 8 to 16 years with moderate (n = 19) to severe (n = 4) steroid-resistant UC were enrolled. One of 2 LCAP columns with different volumes (model EX and the half-volume model EI) was selected, according to body weight. LCAP was performed once per week for 5 consecutive weeks. Clinical and laboratory data were collected at predetermined time points. The primary endpoint was decreased stool frequency/hematochezia score, and secondary endpoints were clinical, laboratory, and endoscopic improvements. Results: The stool frequency/hematochezia score decreased significantly from 4.5 ± 1.2 before treatment to 1.6 ± 1.9 after the fifth treatment. Clinical parameters, including stool frequency, presence of visible blood, abdominal pain, and body temperature, were significantly improved. Fecal calprotectin decreased significantly. Endoscopic findings evaluated using Matts score also improved (P < 0.01). The steroid dose decreased from 1.1 ± 0.4 mg/kg before treatment to 0.8 ± 0.5 mg/kg after treatment. There were no significant differences in changes between the EX and EI columns. The incidence of adverse effects was 61%, although none was serious. The most common adverse effects were decreased hematocrit and hemoglobin concentration. Conclusions: The present study showed that LCAP was well tolerated in children with UC, mostly moderate, and was as effective as in adults. The types of pediatric patients best suited to LCAP remain to be determined.

https://pubmed.ncbi.nlm.nih.gov/21694533/

https://journals.lww.com/jpgn/Fulltext/2011/07000/Leukocytapheresis_in_Pediatric_Patients_With.5.aspx

T Hibi ¹, Y Sameshima, Y Sekiguchi, Y Hisatome, F Maruyama, K Moriwaki, C Shima, A R Saniabadi, T Matsumoto

Dig Liver Dis. 2009 Aug;41(8):570-7. doi: 10.1016/j.dld.2008.11.020. Epub 2009 Feb 10.

Background/aim: The Adacolumn selectively depletes granulocytes and monocytes/macrophages, which are thought to be part of the immunopathogenesis of ulcerative colitis. This work aims at evaluating the safety and clinical efficacy of the Adacolumn in patients with ulcerative colitis in large population-based data sets. Methods: The Adacolumn post marketing surveillance in Japan was undertaken on 697 patients in 53 medical institutions over 7 years from 29 October 1999 to 28 October 2006. Clinical efficacy and safety data were provided by patients’ physicians in the participating institutes. Results: Safety was evaluated in all the 697 patients and efficacy in 656 patients. At entry, 92% of the patients were on salicylates, 74% on prednisolone and only 9% on immunomodulators. Approximately 40% of patients had severe ulcerative colitis and over 70% had ulcerative colitis that was refractory to conventional medications. There was no serious adverse events; mild to moderate adverse events were seen in 7.7% of the patients. The overall response (remission or significantly improved) was 77.3%; the remission rate based on clinical activity index was 71.1%, while 17.1% remained unchanged and 5.6% worsened. Patients were subgrouped into severe, moderate and mild ulcerative colitis based on clinical activity index (n=578), the response rates were 63.2%, 65.7% and 80.4%, respectively (P<0.001). Endoscopic assessment of efficacy showed very significant mucosal healing, Matts’ endoscopic index improved from 3.2+/-0.04 to 2.1+/-0.7 (n=219, P<0.001); reduction in prednisolone dose (P<0.0001); leucocyte count (n=358, P<0.0001) and C-reactive protein (n=314, P<0.0001). Patients who received > or =6 Adacolumn sessions (n=319) did better than patients who received < or =5 sessions (n=188, P=0.004) and multivariate logistic regression analysis revealed that baseline granulocyte count was the strongest predictor of clinical response to Adacolumn (P=0.0191, odds ratio 1.151). Conclusion: This post marketing surveillance provides the largest ever efficacy and safety data on the Adacolumn therapeutic leucocytapheresis in patients with ulcerative colitis. As a non-pharmacologic treatment for patients with active ulcerative colitis most of whom were refractory to conventional drug therapy, the observed efficacy was very significant. Baseline granulocyte count was convincingly an independent predictor of clinical response.

https://pubmed.ncbi.nlm.nih.gov/19211314/

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

Elena Ricart, Maria Esteve, Montserrat Andreu, Francesc Casellas, David Monfort, Miquel Sans, Natalia Oudovenko, Raúl Lafuente, and Julián Panés World J Gastroenterol. 2007 Apr 21; 13(15): 2193–2197.Published online 2007 Apr 21. doi: 10.3748/wjg.v13.i15.2193

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.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146843/

P. Irving D S Rampton 2007 chapter 29 part 3 Medical treatment: What’s Round the corner? DOI:10.1002/9780470750827.ch29

https://www.researchgate.net/publication/289900860_Leukocytapheresis_Filtering_Out_the_Facts