Rodolfo Sacco ¹, Tomotaka Tanaka, Takayuki Yamamoto, Giampaolo Bresci, Abbi R Saniabadi, Expert Rev Gastroenterol Hepatol. 2015 Mar;9(3):327-33.

The authors’ view is that in patients with UC, there is an evolving scope for therapeutic opportunity based on taking away the sources of inflammatory cytokines, also considering the favorable safety profile of GMA.

https://pubmed.ncbi.nlm.nih.gov/25160857/

Chiara De Cassan ¹, Edoardo Savarino ¹, Piero Marson ¹, Tiziana Tison ¹, Giorgia Hatem ¹, Giacomo Carlo Sturniolo ¹, Renata D’Incà ¹ , World J Gastroenterol. 2014 Dec 7;20(45):17155-62.

Patients with mild UC benefit from GMA more than patients with moderate to severe disease in the short-term period. GMA should be considered a valid therapeutic option in cases of contraindications to immunosuppressants, corticosteroids and/or biologics.

https://pubmed.ncbi.nlm.nih.gov/25493030/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258586/pdf/WJG-20-17155.pdf

Nobuhito Kashiwagi

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

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/

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/

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/

B.J. Rembacken,H.E. Newbould,S.J. Richards,S.A. Misbah,M.E. Dixon,D.M. Chalmers,A.T.R. Axon THERAP APHERE DIAL (2007) 2 (2) 93-96  https://doi.org/10.1111/j.1744-9987.1998.tb00082.x

We have studied the effects of granulocyte apheresis in 18 patients with ulcerative colitis and 6 with Crohn’s disease who had failed to respond to conventional therapy. Patients were treated with weekly apheresis using a granulocyte removal column. We found a mean reduction in circulating granulocytes of 1.29 × 10⁹ cells/L with no significant alterations in red blood cell monocyte, total lymphocyte, absolute T-helper, or T-cytotoxic lymphocyte counts. There were no significant changes in complement levels or immunoglobulin subclasses. There was a signifycant increase in granulocyte adhesion and a reduction in L-selectin expression. The removal of granulocytes is unlikely to explain the effect of granulocytapheresis. The markedly increased expression of α_m integrin/Mac-1 and low L-selectin expression alter the capability of granulocytes to migrate to sites of inflammation and may be responsible for the improvement observed in patients treated with granulocyte apheresis.

https://pubmed.ncbi.nlm.nih.gov/10225706/

https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1744-9987.1998.tb00082.x

Takuro Kanekura ¹, Katsuya Hiraishi, Koichi Kawahara, Ikuro Maruyama, Tamotsu Kanzaki

Ther Apher Dial 2006 Jun;10(3):247-56. doi: 10.1111/j.1744-9987.2006.00369.x.

In the present study, we have shown that granulocyte and monocyte adsorption apheresis (GCAP), an extracorporeal apheresis instrument whose column contains cellulose acetate (CA) beads, is useful for skin diseases attributable to activated granulocytes and psoriatic arthritis (PsA). We assessed the clinical effectiveness of GCAP and investigated the mechanisms underlying the adsorption of pathogenic granulocytes. The effect of GCAP was assessed in 14 patients with neutrophilic dermatoses and 16 with PsA. The mechanisms by which the instrument adsorbs activated granulocytes were investigated using an in vitro mini-column system that mimics the GCAP. Skin lesions and arthropathy improved in 22 of 29 patients (75.9%) and 14 of 18 (77.8%), respectively. Mac-1 (CD11b/CD18) expression on the peripheral neutrophils, increased compared with normal subjects, was reduced by GCAP. In the mini-column system, CA beads adsorbed 50% neutrophils; and adsorption was inhibited significantly by treating plasma with EDTA and blood cells with antihuman CD11b monoclonal antibody. GCAP was useful for treating neutrophilic dermatoses and PsA. GCAP adsorbs Mac-1-expressing neutrophils to the CA beads by the binding of complement component (iC3b) on CA beads and CD11b expressed on activated neutrophils.

https://pubmed.ncbi.nlm.nih.gov/16817789/

Y. Takeda, N. Shiobara, A. R. Saniabadi, M. Adachi & K. Hiraishi, Inflammation Research volume 53, pages 277–283 (2004)

Objective: Evolving evidence of anti-inflammatory effects is observed in patients with rheumatoid arthritis or ulcerative colitis following periodic adsorptive granulocyte and monocyte (GM) apheresis with a column containing cellulose acetate (CA) beads as apheresis carriers. This study was undertaken to obtain insights into mechanisms of anti-inflammatory actions of adsorptive GM apheresis with CA beads. Methods: In a series of in-vitro experiments, we investigated the effects of plasma proteins and the leucocytes β2 integrin (CD18) on granulocyte adsorption to CA beads. Results: Granulocyte adsorption to CA beads required plasma IgG, the complement C3 and was inhibited by an antibody to leucocytes CD18. Further, hepatocyte growth factor (HGF) and interleukin-1 receptor antagonist (IL-1ra) which have strong anti-inflammatory actions were released by granulocytes that adhered to CA beads. Conclusions: Plasma IgG, C3 derived complement activation fragments and leucocytes CD18 are involved in granulocyte adhesion to CA beads and hence the release of HGF and IL-1ra.

https://link.springer.com/article/10.1007/s00011-004-1253-5

Takuro Kanekura ¹, Hisashi Kawabata, Ikuro Maruyama, Tamotsu Kanzaki

J Am Acad Dermatol  2004 Feb;50(2):242-6. doi: 10.1016/s0190-9622(03)02474-5.

Granulocyte and monocyte adsorption apheresis (GCAP) is a new extracorporeal apheresis treatment modality that removes pathogenic granulocytes. Recently, we found that GCAP is useful for treating pyoderma gangrenosum and pustular psoriasis. We thought that this treatment may also be effective for treating other disorders attributable to activated granulocytes and studied the efficacy of GCAP in 4 patients with psoriatic arthritis. Treatment with GCAP resulted in remarkable clearing of joint pain, suggesting that GCAP is valuable for treating arthritis as well as skin disorders. We present a detailed description of these patients and this novel therapy.

https://pubmed.ncbi.nlm.nih.gov/14726879/