José Luis Cabriada ¹ , Gastroenterol Hepatol. 2012 Jan;35(1):22-31.

Leukocyte apheresis works by purifying distinct populations of active leukocytes and by modifying inflammatory mediators. Based on their theoretical immunomodulatory effect, these techniques have begun to be used in inflammatory bowel disease. There are two types of devices: granulocytapheresis, which performs selective granulocyte and monocyte absorption, and leukocytapheresis, which carries out non-selective filtration. Conventional treatment regimens consist of between 5 and 10 sessions, normally one session per week, to induce remission. Although the indications for apheresis have not been clearly defined, this technique can be considered a valid option in selected patients with ulcerative colitis, mainly those with corticosteroid-dependent or corticosteroid-refractory disease when other, better-established immunosuppressive or biological treatments have failed. In addition to avoiding the use of corticosteroids, due to its excellent safety profile, apheresis is an attractive option to avoid the risks of immunosuppressive and biological treatments and for use in the pediatric population. The present reviews analyzes the data on the safety and efficacy of apheresis in those patients with inflammatory bowel diseases who could benefit from this technique.

https://pubmed.ncbi.nlm.nih.gov/22169354/

D J Gracie ¹, A C Ford Minerva Gastroenterol Dietol. 2012 Jun;58(2):87-99.

Ulcerative colitis (UC) is a chronic inflammatory disorder of the gastrointestinal tract, the exact etiology of which remains unknown. The prevalence in the general population is around 0.25%, and the condition represents a considerable financial burden to the health service. The natural history of the condition is one of periods of remission, punctuated by relapses of disease activity. Medical therapy aims to minimise the frequency of these relapses, as well as the need for glucocorticosteroids, which have potentially deleterious effects. In those with acute severe disease, however, glucocorticosteroids are probably effective, as are infliximab and cyclosporine. In those with a mild to moderate flare of disease activity, oral or topical 5-ASAs, or in combination, are more effective than placebo for induction of remission. Doses of oral 5-ASAs in excess of 2g/day appear to lead to higher likelihood of successful remission. Once remission has been achieved, there is evidence to support the use of oral or topical 5-ASAs, and azathioprine to prevent relapse of disease activity. Again, doses of 5-ASA in excess of 2g/day are associated with a lower risk of relapse. Individuals with chronic relapsing and remitting disease activity are difficult to manage, and may require colectomy with ileal pouch anal anastamosis. Granulocyte/monocyte adsorptive apheresis could be of benefit in this setting, but most trials have been conducted in the Far East, so the efficacy in Western UC patients is unclear.

https://pubmed.ncbi.nlm.nih.gov/22643593/

https://www.minervamedica.it/en/journals/gastroenterology/article.php?cod=R08Y2012N02A0087

Premchand P, Ford L, Venkama DPWE-236 White cell aphaeresis (WCA) with adacolumn is effective in selected cases of chronic refractory colitis with high histological activityGut 2012;61:A394.

Introduction Treatment options for patients with chronic refractory colitis are limited. White cell aphaeresis (WCA) is effective in inducing clinical remission in chronic refractory colitis in patients with a strong inflammatory burden at baseline and histologically active disease. Previous multinational sham controlled trials have demonstrated significant improvement when patients with high histological activity (modified Rileys score) are selected for treatment. Methods A prospective study was conducted in 30 patients with severe steroid -dependent or steroid -refractory ulcerative colitis referred for WCA. Inclusion criteria were (i) High disease activity score (partial Mayo score ≥6) (ii) Intractable symptoms despite treatment with steroids and/or immunosuppressants (iii) Severe disease at endoscopy and histologically. The aim was to induce clinical and IBD-Q remission at 12 weeks. A Mayo score ≤3 defined clinical remission. The 32 item Inflammatory Bowel Disease questionnaire (IBD-Q) was used to assess quality of life prior to treatment and at 12 weeks. Results Patient Characteristics: Prior to treatment 28 patients (93.3%) were prescribed 5-ASA compounds. 12 patients (40%) were prescribed topical therapies (5-ASA enemas or suppositories/steroids enemas). 27 patients (90%) were steroid dependent (Prednisolone mean dose 21.1 mg, median 20 mg). Three patients (10%) were steroid refractory (no response to high dose oral steroids). 13 patients (43.3%) were prescribed Azathioprine of the remainder all had documented intolerance or a contraindication. One patient (3.3%) was prescribed six Mercaptopurine. Five patients had failed Infliximab (16.6%) and in one patient (3.3%) it was contraindicated. 1 patient (3.3%) had failed intramuscular Methotrexate. Outcomes: At week 12 clinical remission (Mayo score ≤3) was achieved in 22 patients (73.3%), 18 patients (60%) were no longer prescribed oral steroids. IBD-Q remission at week 12 was achieved in 19 patients (63.3%). Of the remainder, five patients (16.6%) achieved an IBD-Q response. Of eight patients (26.6%) who failed to achieve clinical remission at 12 weeks, one achieved delayed remission at 20 weeks. Of the remaining seven treatment failures, five underwent colectomy (16.6%). Conclusion WCA can be effective in inducing clinical remission and improving quality of life (IBD-Q) indices in chronic severe steroid refractory ulcerative colitis with highly active disease histologically. This data series suggests WCA should be considered before colectomy in this challenging patient group

https://gut.bmj.com/content/61/Suppl_2/A394.1.info

Ludvig Linton ¹, Mats Karlsson, Jeanette Grundström, Eric Hjalmarsson, Annelie Lindberg, Emma Lindh, Hans Glise, Ragnar Befrits, Izabella Janczewska, Per Karlén, Ola Winqvist, Michael Eberhardson, Clin Transl Gastroenterol. 2012 Dec 20;3(12):e29.

CD14(+)HLA-DR(hi) blood monocytes were increased in patients with active IBD. These monocytes exhibit a pro-inflammatory, gut-homing phenotype with regard to their TNF-α production and expression of CCR9. Our results suggest that these monocytes are important in mediating intestinal inflammation, and provide potential therapeutic targets in IBD.

https://pubmed.ncbi.nlm.nih.gov/23254312/

Risa Kikuyama,Ken Fukunaga,Mikio Kawai,Yoko Yokoyama,Koji Kamikozuru,Nobuyuki Hida,Yoshio Ohda,Naohisa Takeda,Koji Yoshida,Masaki Iimuro,Kyoichi Kato,Tomoaki Kono,Koji Nogami,Kazuko Nagase,Shiro Nakamura,Yoshiyuki Takei,Hiroto Miwa,Takayuki Matsumoto, https://doi.org/10.1111/j.1744-9987.2011.00968.x

Granulocyte/monocyte adsorption (GMA) has been introduced as an adjunct intervention for active ulcerative colitis (UC) patients. The processed blood volume (PV) per GMA session is an important factor for its efficacy because depletion of elevated/activated myeloid leukocytes is its main action. Hitherto, this aspect of GMA has been largely ignored. Thirty-three patients were enrolled for remission induction therapy with five weekly GMA sessions at a standard PV of 1800 mL, regardless of patients’ bodyweight (BW). The patients were divided into three groups: high (H)BW (≥65 kg, n = 11), 50 kg ≤ medium (M)BW < 65 kg (n = 12), and low (L)BW (≤50 kg, n = 10). UC clinical activity index (CAI) was according to Lichtiger, and the clinical efficacies were evaluated at both one week post 3^rd GMA (Week 4) and one week post 5^th GMA (Week 6). The average BW was 70.9 ± 6.2 kg in HBW, 55.8 ± 4.5 kg in MBW, and 46.8 ± 1.2 kg in LBW, indicating the mean PV/BW in the three groups being 25.6 ± 2.12, 32.5 ± 2.50, and 38.7 ± 1.0 (mL/kg, P < 0.05), respectively. The LBW group consisted of female patients only. Significant improvements of CAI were seen before treatment at either Week 4 or Week 6 in all groups. A significantly higher remission rate was achieved in the LBW (80.0%) vs. MBW (33.3%) or HBW (27.3%) at Week 6 (P < 0.03). According to this GMA evaluation, the lower-limit of optimum PV/kg should be higher than 38.7 mL/kg for its potential clinical efficacy to be significantly greater than the routine GMA method. Additional BW-oriented GMA studies in larger and gender controlled cohorts of patients should strengthen our findings. 

https://onlinelibrary.wiley.com/doi/10.1111/j.1744-9987.2011.00968.x

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)

Masahiro Iizuka, Shiho Sagara, Takeshi Etou

https://pubmed.ncbi.nlm.nih.gov/21674727/

https://www.researchgate.net/publication/51220695_Efficacy_of_long-interval_cytapheresis_on_steroid-dependent_refractory_ulcerative_colitis

Shoichi Nishise ¹, Hiroaki Takeda, Tomohiko Orii, Takeshi Sato, Yu Sasaki, Yuko Nishise, Sumio Kawata, Ther Apher Dial. 2011 Aug;15(4):379-84.

Macrophage colony-stimulating factor (M-CSF) induces normal intestinal macrophages that have anti-inflammatory effects. Thus, M-CSF-rich conditions in colonic tissues seem to contribute to the improvement of pathological conditions in patients with inflammatory bowel diseases (IBD). However, it has not been clarified whether current therapies for IBD, including granulocyte/monocyte adsorptive apheresis using an Adacolumn, and ulinastatin, a serine protease inhibitor, affect the production of M-CSF. To clarify the effects of these therapies on M-CSF production, we investigated whether monocyte adsorption to cellulose acetate (CA) beads (carriers for Adacolumn therapy) and ulinastatin augmented M-CSF production in in vitro experiments. Peripheral blood was incubated with and without CA beads, and then M-CSF production was measured. Additionally, peripheral blood containing serial dilutions of ulinastatin was incubated with CA beads followed by measurement of M-CSF production. Monocyte adsorption to CA beads did not affect M-CSF production. A high concentration of ulinastatin augmented M-CSF production without inhibiting monocyte adsorption to CA beads, although a low concentration of ulinastatin conversely suppressed M-CSF production. The present study found that a high concentration of ulinastatin, which was administrated with CA beads, increased the production of M-CSF. Our results suggest that a combination of ulinastatin and Adacolumn therapy may provide more clinical efficacy for the treatment of IBD in terms of the production of M-CSF.

https://pubmed.ncbi.nlm.nih.gov/21884473/

H Hanai ¹, Y Takeda, M Eberhardson, R Gruber, A R Saniabadi, O Winqvist, R Lofberg , Clin Exp Immunol. 2011 Jan;163(1):50-8.

Patients with active inflammatory bowel disease (IBD) have elevated and activated myeloid leucocytes which infiltrate the colonic mucosa in vast numbers. Myeloid leucocytes such as the CD14(+) CD16(+) monocytes are major sources of tumour necrosis factor (TNF)-α, and therefore selective granulocyte/monocyte (GM) adsorption (GMA) should promote remission or enhance efficacy of pharmacological therapy. However, studies in IBD have reported both impressive as well as disappointing efficacy outcomes, indicating that patients’ demographic factors might determine responders or non-responders to GMA. Nonetheless, this non-drug intervention has an excellent safety profile, and therapeutic GMA is expected to expand. In this review, attempts have been made to compile an update on the mode of actions (MoA) of the Adacolumn GMA. The MoA of GMA appears to be more than adsorption of excess neutrophils and TNF-producing CD14(+) CD16(+) monocytes per se. Adsorbed GMs release interleukin (IL)-1 receptor antagonist, hepatocyte growth factor and soluble TNF receptors, which are anti-inflammatory. Additionally, a sustained increase in lymphocytes including the regulatory CD4(+) CD25(+) T cells (lymphocyte sparing) is seen post-GMA. The impact of GMA on the immune system is potentially very interesting in the context of treating immune-related diseases. Future studies are expected to add intriguing insights to the MoA of GMA.

https://pubmed.ncbi.nlm.nih.gov/21078086/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010911/pdf/cei0163-0050.pdf