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

Objectives: Granulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active ulcerative colitis (UC). However, with routine weekly treatment, it may take several weeks to achieve remission, and to date, the efficacy of a more frequent treatment schedule remains unknown. The aim of this study was to assess the clinical efficacy and safety of intensive GMA treatment in patients with active UC. Methods: This was an open-label, prospective, randomized multicenter study to compare an intensive, two GMA sessions per week, with the routine, one GMA session per week. A total of 163 patients with mild-to-moderately active UC were randomly assigned to routine weekly treatment or intensive treatment. The maximum number of sessions of GMA permitted was 10. However, when patients achieved remission, GMA was discontinued. Remission rate at the end of the study, time to remission, and adverse events were assessed in both groups. Results: Of the 163 patients, 149 were available for efficacy analysis as per protocol, 76 were in weekly GMA, and 73 were in intensive GMA. At the end of the study period, clinical remission was achieved in 41 of 76 patients (54.0%) in weekly GMA and in 52 of 73 patients (71.2%) in intensive GMA (P=0.029). The mean time to remission was 28.1+/-16.9 days in the weekly GMA treatment group and 14.9+/-9.5 days in the intensive GMA group (P<0.0001). Intensive GMA was well tolerated without GMA-related serious adverse side effects. Conclusions: Intensive GMA in patients with active UC seems to be more efficacious than weekly treatment, and significantly reduced the patients‘ morbidity time without increasing the incidence of side effects.

)https://pubmed.ncbi.nlm.nih.gov/19724269/

Shoichi Nishise,Yuji Takeda,Yuko Nishise,Shoichiro Fujishima,Tomohiko Orii,Sayaka Otake,Takeshi Sato,Yu Sasaki,Hiroaki Takeda,Sumio Kawata

Biological Effect of Anaphylatoxin C5a on the Generation of Anti-inflammatory Substances in Leukocyte Adsorption. Therap. Apher. Dial. 2009 13(6), 509–514. doi:10.1111/j.1744-9987.2009.00779.x 

Anaphylatoxins, which are involved in both pro-inflammatory processes and a variety of anti-inflammatory effects, are produced during granulocyte and monocyte adsorptive apheresis. We noticed the anti-inflammatory effects of C5a, the strongest anaphylatoxin, in granulocyte and monocyte adsorptive apheresis. The aim of this study was to investigate the effect of C5a on interleukin-1 receptor antagonist (IL-1ra) and hepatocyte growth factor (HGF) generation in granulocyte and monocyte adsorption. Peripheral blood containing nafamostat mesilate as an endogenous complement activation inhibitor was divided into four groups: (1) no recombinant C5a added, no contact with cellulose acetate (CA) beads (control group); (2) no C5a added, contact with CA beads; (3) C5a added, no contact with CA beads; and (4) C5a added, contact with CA beads. After incubation, IL-1ra and HGF in plasma were measured. IL-1ra was significantly higher in group 3, in which only C5a was added in the absence of CA beads, compared to groups 2 (P < 0.01) and 4 (P < 0.05). HGF was significantly higher only in group 4, in which C5a was added in the presence of CA beads (P < 0.05), but did not increase in the absence of CA beads. C5a can directly induce IL-1ra generation without the granulocyte and monocyte adsorption stimuli to CA beads, but can synergistically induce HGF generation with the adsorption stimuli, indicating C5a has different effects on IL-1ra and HGF generation.

https://onlinelibrary.wiley.com/doi/10.1111/j.1744-9987.2009.00779.x

Shin-ichiro Takeda, Toru Sato, Tatsuro Katsuno, Tomoo Nakagawa, Yoshiko Noguchi, Osamu Yokosuka & Yasushi Saito

Dig Dis Sci 55, 1886–1895 (2010). https://doi.org/10.1007/s10620-009-0974-2

Background:  Two main functionally distinct monocytes phenotypes are known: the CD14hiCD16− “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 ≤4) after 5–10 GMA sessions. GMA induced a strong fall in the ratio (%) of CD14+CD16+ to CD14hiCD16− monocytes, from 10.0 ± 1.4 to 3.0 ± 0.9. Further, expressions of α4 integrin (374.8 ± 26.1 mean fluorescence intensity, MFI) and CX3CR1 (49.5 ± 4.6 MFI) were significantly high on CD14+CD16+monocytes as compared with on CD14hiCD16− monocytes (169.2 ± 17.2 and 33.2 ± 3.6 MFI, respectively). Additionally, GMA significantly increased the ratio of the CD14hiCD16−CCR2low “immature” monocytes from 3.74 ± 0.62 to 8.11 ± 0.56 MFI. Conclusions: We found high expressions of α4 integrin and CX₃CR1 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 D14^hiCD16⁻CCR2^low “immature” monocytes; thus, GMA was associated with the emergence of less inflammatory monocyte phenotype in circulation.

https://link.springer.com/article/10.1007%2Fs10620-009-0974-2#citeas

Luca Pastorelli ¹, Theresa T Pizarro, Fabio Cominelli, Maurizio Vecchi Expert Opin Emerg Drugs. 2009 Sep;14(3):505-21. doi: 10.1517/14728210903146882.

Background: Ulcerative colitis (UC) is a chronic, relapsing inflammatory disorder of the colon for which the etiology is currently unknown. At present, strategies to treat UC are primarily targeted to control inflammation during active phases of disease as well as maintain remission during quiescence. As such, several unmet needs in the treatment of UC still remain. In recent years, basic research has led to the recognition of several key factors in the pathogenesis of UC, translating into the development of several novel therapeutic agents. Objective: The aim of this study is to review emerging therapies that may advance the treatment and improve the overall care of UC patients. Methods: An extensive literature search on published manuscripts and meeting proceedings has been performed to provide a comprehensive review of future drug therapies to treat UC. Results/conclusion: The translational application of new discoveries in the basic understanding of UC pathogenesis is continuing and critical for the development of novel treatment strategies. Design of novel biologic therapies to treat UC has the challenge of addressing potential safety issues, while more traditional drugs should be further developed to facilitate patient compliance to treat this chronic, debilitating disease.

https://pubmed.ncbi.nlm.nih.gov/19656075/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4563345/

Javier Martin-Carpi Martín-Carpi, Vicente Varea Journal of Crohn’s and Colitis, Volume 3, Issue 3, September 2009, Pages 216–217, https://doi.org/10.1016/j.crohns.2009.03.003

Treatment of paediatric ulcerative colitis (UC) unresponsive to conventional treatment constitutes a challenge. The finding of new secure, steroid-sparing and long acting treatments for these cases are mandatory. We report our experience with a long-term therapeutic strategy with Adacolumn in a chronically active paediatric UC patient (9 year-old boy) with the aim of achieving stabilization and ameliorating symptoms, permitting a successful switch to AZA monotherapy. These two aspects have been achieved without reappearance of rectal bleeding after oral mesalamine suppression. But the most interesting and promising finding is the confirmation of GMA apheresis effect on mucosal healing after prolonged treatment: maintenance treatment with Adacolumn has been effective in achieving a complete endoscopic and histological remission.

This case shows the utility of prolonged Adacolumn treatment in chronically active UC patients.

https://academic.oup.com/ecco-jcc/article/3/3/216/384285

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/

Ahmed Helmy, Maheeba Abdulla, Ingvar Kagevi, and Khalid Al Kahtani, Saudi J Gastroenterol. 2009 Oct; 15(4): 283–287.

The goal of this concise report is to present the available data on the efficacy, safety, and applicability of cytapheresis in patients with UC.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981852/

Valeria Criscuoli, Filippo Mocciaro, Ambrogio Orlando, Maria Rosa Rizzuto, Maria Concetta Renda, Mario Cottone, Inflamm Bowel Dis. 2009 Jun;15(6):810-1.

https://pubmed.ncbi.nlm.nih.gov/18839422/

Ken Fukunaga ¹, Kazuko Nagase, Takeshi Kusaka, Nobuyuki Hida, Yoshio Ohda, Koji Yoshida, Katsuyuki Tozawa, Koji Kamikozuru, M Iimuro, Shiro Nakamura, Hiroto Miwa, Takayuki Matsumoto, Gut Liver. 2009 Mar;3(1):41-7. doi: 10.5009/gnl.2009.3.1.41

This study suggest that CAP is an effective therapy in patients who are refractory to conventional medications including iv corticosteroid. Increased remission rates should be expected in refractory patients with moderately severe UC.

https://pubmed.ncbi.nlm.nih.gov/20479900/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871568/pdf/gnl-3-41.pdf

K O Arseneau ¹, F Cominelli, Dig Liver Dis. 2009 Aug;41(8):551-2.

In summary, selective adsorption of granulocytes and monocytes from the peripheral blood
of patients with active ulcerative colitis using the extracorporal Adacolumn GMA appears to
be an extremely safe treatment modality. Although conflicting results have been reported
regarding the efficacy of Adacolumn GMA, this study by Hibi et al. adds to the existing
literature by providing data from the largest population of ulcerative colitis patients yet to be
studied. If the observed treatment effect of 77.7% is representative of the true response rate,
Adacolumn GMA would be a safe alternative to biological therapies for patients with
refractory ulcerative colitis. In addition, granulocyte fractions could be used to help identify
patients who are most likely to benefit from this procedure

https://pubmed.ncbi.nlm.nih.gov/19540820/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572230/pdf/nihms125646.pdf