I Rodríguez-Lago, C Herrera-deGuise, M Boscá-Watts, C Rodríguez, E Leo, M Calvo, F Cañete, S Chacón, C Cuarán, A Elorza, E Guerra, E Iglesias, D Sánchez, M Barreiro-de Acosta, D Ginard, J L Cabriada Journal of Crohn’s and Colitis, Volume 18, Issue Supplement_1, January 2024, Page i1135, doi.org=10.1093/ecco-jcc/jjad212.0712

Background
Granulocyte–monocyte apheresis (GMA) selectively removes activated leukocytes and immune mediators, and it has shown to be safe and effective in treating ulcerative colitis (UC). Previous reports have also described its combination with biologics, mainly with anti-TNF.

Methods
The aim of our study was to evaluate the clinical efficacy and safety of combining GMA after primary non-response (PNR) or loss of response (LOR) to ustekinumab (UST) in patients with UC. A retrospective, multicentric study was performed in 12 IBD Units, including all patients with refractory UC who received combined GMA plus UST. The number of GMA sessions, its frequency, filtered blood volume and time of each session were compiled, along with the clinical data. Efficacy was assessed 1 and 6 months after finishing the GMA by partial Mayo score, CRP and faecal calprotectin. Data regarding UST intensification, need for new immunomodulators/biologics and surgery were also compiled. Descriptive statistics and non-parametric tests were used in the statistical analysis.

Results
Nineteen patients were included (15 UC, 2 Crohn’s disease, 2 unclassified IBD; median age 48 years (IQR, 36-63); 68% male). At baseline, 78% were receiving steroids and 23% immunomodulators. Most patients (89%) had prior exposure to anti-TNF agents and 53% to vedolizumab. Baseline Mayo score was 6.5 (IQR, 5-7), with a median CRP of 9 mg/L (IQR, 4.8-20.8) and faecal calprotectin 1,612 mg/kg (IQR, 873-4,152). GMA was started mostly after PNR in 83%, the median number of GMA sessions was 16 (IQR, 11-27) and 50% of patients started maintenance GMA. Partial Mayo score significantly decreased 6 months after the last GMA session (p=0.019). During follow-up, 27% started a new biologic therapy and 13% required surgery. 64% of patients under steroids at baseline were able to stop them. Adverse events were reported in 5% of patients.

Conclusion
GMA can safely recapture the response to UST in refractory patients after PNR or LOR to this drug.

Yumiko WATANABE,Hiromichi YAMADA, https://doi.org/10.1111/j.1346-8138.2008.00572.x

https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1346-8138.2008.00572.x

UEG WEEK VIRTUAL 2021

GMA induces specific immunoregulatory changes in leukocyte’s subpopulations. We confirm the depletion of the
monocytes with proinflammatory phenotype after GMA. Treg and B effector cells shift to a more immunotolerant phenotype. The emergence of subpopulations with the atypical immunofluorescence staining (CXCR3+CRTH2+) related to immature T cells support the immunomodulatory effects of GMA. These findings could help to understand the pathology of UC and to identify targeted immune subpopulations for treatment

P0246 UEG.pdf

Chie Kurihara, Toshihide Ohmori, Kenichi Inaba, Shunsuke Komoto, Kengo Tomita, Ryota Hokari Gastroenterology 2020 158 (6) Suppl.S-1046

Background: Granulocyte and monocyte adsorptive apheresis (GMA) is non-pharmacological therapy which selective depletion of activated granulocytes and monocytes/macrophages from peripheral blood, and it is used as induction therapy for IBD. However, its therapeutic mechanism has not been well characterized. Recently, it has been reported that Th17 releases chemokines which attract neutrophils, and some neutrophils produce IL17. We investigated that changes in mRNA expression levels of inflammation associated molecules such as cytokines, chemokines in colonic mucosa of ulcerative colitis (UC) patients before and after GMA treatment in order to obtain further understanding of GMA therapeutic mechanisms. Methods: Thirty-two active UC patients (Mayo score ≥ 5 and Mayo endoscopic score ≥ 2) and 10 non-IBD control subjects were enrolled in this study. All UC patients received 10 times of GMA, and colonoscopies were applied before the first GMA and after the last GMA. Control subjects underwent colonoscopies for screening of colon cancer. Assessment of GMA therapeutic efficacy was determined based on Mayo score. Inflammation-related molecules mRNA expressions were determined by quantitative RT-PCR using biopsy specimen of colonic mucosa. Results: GMA treatment efficacy is 11 patients (34.4%) achieved clinical remission, 17 patients (53.1%) were response and 4 patients (12.5%) were non-response. Baseline characteristics such as sex, location of disease, CRP, WBC and Mayo score were not significantly different according to GMA efficacy. In the remission group, mRNA levels in mucosal tissue of IL1β, IL6, IL17, IL23 and GM-CSF which are Th17-asociated cytokines significantly decreased after the last GMA compared to the baseline levels(P<0,05) in contrast, expression of these mRNA tended to increase following GMA treatment in the non-response group. On the other hand, IL12 and IFN- γ which are associated with Th1 did not significantly decrease in the remission group. mRNA levels of leukocyte trafficking associated molecules such as MAdCAM-1, ICAM-1, integrinβ7, IL8 and MIP-1β significantly decreased following GMA treatment in the remission group(P <0.05), whereas only IL8 mRNA expression in the non-response group tended to increase. IL1 β, IL6, GM-CSF which are Th17-asociated cytokines and IL8 mRNA expressions in post-GMA treatment were significantly higher in the non-response group compared to the remission group or control group(P <0.05). Conclusion: In UC patients who achieved clinical remission by GMA, Th17- associated cytokines and leukocyte trafficking associated molecules but not Th1-asociated cytokines decreased significantly. Furthermore, Th17-asociated cytokines increased in the non-responders. These results reaffirm the involvement of neutrophil in the pathophysiology of UC and could be helpful for characterizing of GMA therapeutic mechanism.

https://www.gastrojournal.org/article/S0016-5085(20)33300-X/pdf

Jia Huang, Qian Wang, Yongjing Cheng, Yingjuan Chen, Ming Gao, Feng Yang, Bingyao Mu, Rongwei Zhou, Cibo Huang, Altern Ther Health Med. 2020 Jul;26(4):36-42.

This study indicated that LCAP therapy can significantly decrease RA disease activity and is a safe and effective alternative therapy. LCAP therapy significantly reduced serum CXCL16 and serotonin levels, offering a putative mechanism by which it improves the articular symptoms of RA.

https://www.worldscientific.com/doi/10.1142/9789814749084_0031

Takuro Kanekura ¹, Mariko Seishima ², Masaru Honma ³, Takafumi Etou ⁴, Hikaru Eto ⁵, Keiko Okuma ⁶, Yukari Okubo ⁷, Yukie Yamaguchi ⁸, Takeshi Kambara ⁹, Tomotaka Mabuchi ¹⁰, Yasushi Suga ¹¹, Akimichi Morita ¹², Kiyofumi Yamanishi ¹³, Daisuke Tsuruta ¹⁴, Kei Itoh ¹⁵, Ken Yamaji ¹⁶, Shigaku Ikeda ⁶

J Dermatol 2017 Dec;44(12):1353-1359. doi: 10.1111/1346-8138.13975. Epub 2017 Aug 3.

Psoriatic arthritis (PsA), a chronic inflammatory arthropathy associated with psoriasis, is an intractable immune disorder and refractory to pharmacological intervention. We assessed efficacy of selective depletion of myeloid lineage leukocytes in patients with PsA in a multicenter setting. A total of 20 patients with moderate to severe PsA refractory to conventional and biological disease-modifying antirheumatic drugs were included. Eligible patients had 3 points or more in the classification criteria for PsA. Each patient received five sessions, once a week, of adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn^® . The primary efficacy outcome was 20% or more decrease in the American College of Rheumatology score 20 (ACR20). Partial responders could receive an additional five GMA sessions. Of 20 patients, two did not complete the study, nine responded to five GMA sessions and nine received 10 sessions. At the first evaluation 2 weeks after the last GMA session, 13 of the 20 (65.0%) patients achieved ACR20. ACR20 was maintained in seven of 10 (70%) and five of 10 (50%) patients at the follow-up evaluation points 8 and 20 weeks after the last GMA session, respectively. GMA was well tolerated without any safety concern. This study demonstrates that GMA with the Adacolumn was effective with good safety profile in patients with PsA refractory to pharmacologicals. The results indicate a major role for myeloid leukocytes in the immunopathogenesis of PsA. A large controlled study is warranted to fully evaluate the efficacy of Adacolumn GMA in patients with PsA.

https://pubmed.ncbi.nlm.nih.gov/28771892/

Shoichi Nishise ¹, Yu Sasaki, Yoshiyuki Ueno, Ther Apher Dial. 2013 Oct;17(5):564-5.

https://pubmed.ncbi.nlm.nih.gov/24107285/

Shigaku Ikeda ¹, Hidetoshi Takahashi ², Yasushi Suga ³, Hikaru Eto ⁴, Takafumi Etoh ⁵, Keiko Okuma ⁶, Kazuo Takahashi ⁷, Takeshi Kanbara ⁸, Mariko Seishima ⁹, Akimichi Morita ¹⁰, Yasutomo Imai ¹¹, Takuro Kanekura ¹²

J Am Acad Dermatol 2013 Apr;68(4):609-617. doi: 10.1016/j.jaad.2012.09.037. Epub 2013 Jan 17.

Background: Generalized pustular psoriasis (GPP) is a chronic autoimmune disease characterized by fever, erythema, and neutrophilic pustules over large areas of the skin. GPP does not respond well to pharmacologic intervention. Objective: We sought to assess efficacy of selectively depleting the myeloid lineage leukocytes in patients with GPP. Methods: Fifteen patients with persistent moderate to severe GPP despite conventional therapy were included. Eligible patients had more than 10% of their skin area covered by pustules. Treatment with oral etretinate, cyclosporine, methotrexate, prednisolone, and topical prednisolone/vitamin D3 was continued if had been initiated well in advance of study entry. Five sessions of adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn (JIMRO Co Ltd, Takasaki, Japan) were administered (1 session/wk over 5 weeks) to selectively deplete Fcγ receptor and complement receptor bearing leukocytes. Efficacy was assessed by measuring the skin areas covered by pustules at baseline and 2 weeks after the last GMA session. Results: One patient did not complete the first GMA session. Based on the GPP severity scores relative to entry, the overall scores improved (n = 14, P = .0027), and the area of erythroderma (P = .0042), pustules (P = .0031), and edema (P = .0014) decreased. Likewise, Dermatology Life Quality Index improved (P = .0016), reflecting better daily function and quality of life. Twelve patients were judged as responders (85.7%), and 10 patients maintained the clinical response for 10 weeks after the last GMA session without any change in medication. Limitations: This study was unblinded and without a placebo arm. Conclusion: GMA in this clinical setting was safe and effective, suggested a major role for granulocytes/monocytes in the immunopathogenesis of GPP.

https://pubmed.ncbi.nlm.nih.gov/23332516/

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

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