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/

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

Toshimi Chibaa, Mikiya Endob, Shoko Matsushitab, Mika Sasakib, Shoichi Chidab, Yosuke Toyaa, Satoshi Kasugaia, Nozomi atsudaa, Shunsuke Orikasaa, Yukito Abikoa, Norihiko Kudaraa, Shuhei Oanaa, Masaki Endoa, Kazuyuki Suzukia© 2011 S. Karger AG, BaselISSN 1662–0631

Granulocyte and monocyte adsorptive apheresis (GMA) is reportedly useful as induction therapy for Crohn’s disease (CD). However, the effects of GMA on CD64 have not been well characterized. We report here our assessment of CD64 expression on neutrophils before and after treatment with GMA in two patients with CD. The severity of CD was assessed with the CD activity index (CDAI). The duration of each GMA session was 60 min at a flow rate of 30 ml/min as per protocol. CD64 expression on neutrophils was measured by analyzing whole blood with a FACScan flow cytometer. In case 1, CD64 levels after each session of GMA tended to decrease compared to pretreatment levels, whereas in case 2, CD64 levels dropped significantly after treatment. The CDAI decreased after GMA in both cases 1 and 2. A significant correlation was noted between CDAI scores and CD64 levels in both cases. In conclusion, GMA reduced blood CD64 levels, which would be an important factor for the decrease of CDAI scores.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250654/pdf/crg0005-0667.pdf

Nobuhito Kashiwagi

Japanese Journal of Apheresis 30(1): 39-47, 2011

Ken Fukunaga,Yoko Yokoyama,Koji Kamikozuru,Koji Yoshida,Risa Kikuyama,Kazuko Nagase,Shiro Nakamura,Yoshiyuki Takei,Hiroto Miwa,Takayuki Matsumoto

J. Clin. Apheresis, 2010;25(4):226-8. doi: 10.1002/jca.20242.

Background: This is the first report on a case of Crohn’s disease (CD), who was successfully maintained with a combination of infliximab (IFX) and selective depletion of granulocytes/monocytes by adsorption (GMA). Case: A 33-year-old female with CD activity index (CDAI) 294.2 responded to iv IFX (5mg/kg) administered at weeks 0, 2, and 6 in combination with 3000 mg/day oral 5-aminosalicylic acid (5-ASA; CDAI = 118). Then IFX at 8 week intervals was given as maintenance therapy. Two weeks before the 5th scheduled IFX, the patient worsened with an increase in stool frequency and a rise in CDAI. GMA was administered at weeks 5, 6, and 7 after her 6th iv IFX. Her CDAI decreased from 166.2 to 126.3 and 111.9 before 2nd and 3rd GMA sessions. She received her 7th iv IFX while the CDAI was 83.6. GMA course was repeated before 8th and 9th IFX. The patient remained in stable clinical and endoscopic remission without experiencing any serious side effect. After achieving mucosal healing, the patient decided to cease IFX therapy while continuing with GMA. Conclusions: IFX appears to induce and maintain remission of CD, but it may lose its efficacy after repeated administration. GMA is safe and by selectively depleting elevated/activated leukocytes may be a useful adjunct for IFX efficacy.

https://pubmed.ncbi.nlm.nih.gov/20544712/

https://onlinelibrary.wiley.com/doi/10.1002/jca.20242

Piero Vernia ¹, Valeria D’Ovidio, Donatella Meo, Transfus Apher Sci. 2010 Oct;43(2):227-9.

Therapeutic apheresis, a novel approach for immunodisorders, has been used in the last decade for the treatment of ulcerative colitis with promising result, and represents an alternative to conventional pharmacological therapy. Selective apheresis is aimed at reducing the number of circulating lymphocytes, interfering with recruitment and activation of mucosal granulocytes and macrophages, reducing cytokine and chemokine production which are thought to contribute to induction and perpetuation of inflammation. The article briefly reports indications, treatment schedule and clinical results of leukocytapheresis in ulcerative colitis. Available data for the two selective adsorption devices so far approved for clinical use (granulocyte-monocyte apheresis- Adacolumn- and leukocytapheresis-Cellsorba) are partially conflicting, and the number of controlled studies too small to draw definitive conclusions. Nonetheless apheresis definitely appears to be an effective non-conventional tool for the treatment of steroid refractory and steroid dependent UC patients with moderately active disease. The excellent safety profile of the procedure makes this approach attractive, both in adult and in pediatric patients, more so in those refractory to conventional drug therapy, who are presently treated with immunosuppressive and biological therapies.

https://pubmed.ncbi.nlm.nih.gov/20817610/

G Bresci ¹, A Romano, A Mazzoni, F Scatena, E Altomare, A Capria, R Sacco, Gastroenterol Clin Biol. 2010 Dec;34(12):682-6.

Background and objective: This study evaluated the feasibility and safety of granulocytapheresis (GCAP) in inducing and maintaining remission in refractory Crohn’s disease. The relationship between the clinical outcomes and the location (ileal or ileocolonic) of disease was also assessed. Patients: We evaluated 16 patients with ileal location (group A), 14 with ileocolonic location (group B). The patients underwent five sessions (1 session/wk) of GCAP (Adacolumn(TM)). CDAI was measured at the end of the GCAP, at 6, 9 and 12 months. Results and conclusions: No major complications were observed. At the end of GCAP, 19 (63.3%) patients showed a clinical remission: 10 (62.5%) in group A versus 9 (64.2%) in group B. At 6 months, 16 (53.3%) of the cases had maintained remission: 9 (56.2%) in group A versus 7 (50.0%) in group B. At 9 months, 13 (43.3%) patients had maintained remission: 7 (43.7%) in group A versus 6 (42.8%) in group B. At 12 months, 12 (40%) patients were still in clinical remission: 7 (43.7%) in group A versus 5 (35.7%) in group B. Risk of relapse was not related to disease location. The procedure was well tolerated and feasible in an important percentage of Crohn’s disease patients.

https://pubmed.ncbi.nlm.nih.gov/21075574/

https://www.researchgate.net/publication/47791004_Feasibility_and_safety_of_granulocytapheresis_in_Crohn’s_disease_A_prospective_cohort_study

Annelie Lindberg ¹, Michael Eberhardson, Mats Karlsson, Per Karlén, BMC Gastroenterol. 2010 Jul 6;10:73.

Background: Patients with IBD and chronic inflammation refractory to conventional therapy often demonstrate higher risk of serious complications. Combinations of immunosuppression and biological treatment as well as surgical intervention are often used in this patient group. Hence, there is need for additional treatment options. In this observational study, focused on re-treatment and long-term results, Granulocyte/Monocyte Adsorption (GMA, Adacolumn) treatment has been investigated to study efficacy, safety and quality of life in IBD-patients with chronic activity.

Methods: 15 patients with ulcerative colitis and 25 patients with Crohn’s disease, both groups with chronically active inflammation refractory to conventional medication were included in this observational study. The patients received 5-10 GMA sessions, and the clinical activity was assessed at baseline, after each completed course, and at week 10 and 20 by disease activity index, endoscopy and quality of life evaluation. Relapsed patients were re-treated by GMA in this follow-up study up to 58 months.

Results: Clinical response was seen in 85% and complete remission in 65% of the patients. 10 patients in the UC-group (66%) and 16 patients in the CD-group (64%) maintained clinical and endoscopic remission for an average of 14 months.14 patients who relapsed after showing initial remission were re-treated with GMA and 13 (93%) went into a second remission. Following further relapses, all of 7 patients were successfully re-treated for the third time, all of3 patients for the fourth time and 1 for a fifth time.

Conclusions: IBD-patients with chronic inflammation despite conventional therapy seem to benefit from GMA. Re-treatment of relapsing remission patients seems to be effective.

https://pubmed.ncbi.nlm.nih.gov/20604939/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914086/pdf/1471-230X-10-73.pdf

Atsushi Sakuraba ¹, Satoshi Motoya, Kenji Watanabe, Masakazu Nishishita, Kazunari Kanke, Toshiyuki Matsui, Yasuo Suzuki, Tadayuki Oshima, Reiko Kunisaki, Takayuki Matsumoto, Hiroyuki Hanai, Ken Fukunaga, Naoki Yoshimura, Toshimi Chiba, Shinsuke Funakoshi, Nobuo Aoyama, Akira Andoh, Hiroshi Nakase, Yohei Mizuta, Ryoichi Suzuki, Taiji Akamatsu, Masahiro Iizuka, Toshifumi Ashida, Toshifumi Hibi, Am J Gastroenterol. 2009 Dec;104(12):2990-5.

Background: Granulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active Crohn’s disease (CD). However, with routine weekly therapy, it may take several weeks to achieve remission. This study was performed to assess clinical efficacy and safety of intensive GMA in patients with active CD. Methods: In an open-label, prospective, randomized multicentre setting, 104 patients with CD activity index (CDAI) of 200 to 450 received intensive GMA, at two sessions per week (n = 55) or one session per week (n = 49). Clinical remission was defined as a CDAI score <150. Patients in each arm could receive up to 10 GMA sessions. However, GMA treatment could be discontinued when CDAI decreased to <150 (clinical remission level). Results: Of the 104 patients, 99 were available for efficacy evaluation as per protocol, 45 in the weekly GMA group, and 54 in the intensive GMA group. Remission was achieved in 16 of 45 patients (35.6 %) in the weekly GMA and in 19 of 54 (35.2 %) in the intensive GMA (NS). Further, the mean time to remission was 35.4 ± 5.3 days in the weekly GMA and 21.7 ± 2.7 days in the intensive GMA (P = 0.0373). Elevated leucocytes and erythrocyte sedimentation rate were significantly improved by intensive GMA, from 8005/μL to 6950/μL (P = 0.0461) and from 54.5 mm/hr to 30.0 mm/hr (P = 0.0059), respectively. In both arms, GMA was well tolerated and was without safety concern. Conclusions: In this study, with respect to remission rate, intensive GMA was not superior to weekly GMA, but the time to remission was significantly shorter in the former without increasing the incidence of side effects. UMIN registration # 000003666.

https://pubmed.ncbi.nlm.nih.gov/26585569/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653849/