Chie Kurihara, Toshihide Ohmori, Kenichi Inaba, Nao Sugihara, Yoshinori Hanawa, Kazuki Horiuchi, Akinori Wada, Shin Nishii, Akinori Mizoguchi, Suguru Ito, Rina Tanemoto, Akira Tomioka, Yoshikiyo Okada, Yoshihiro Akita, Kazuyuki Narimatsu, Masaaki Higashiyama, Shunsuke Komoto, Kengo Tomita, Ryota Hokari

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, mucosal healing has been emerged as a therapeutic goal for IBD. It has been reported that growth factors play a role in improvement of mucosal repair and regeneration in animal colitis models, and tight junction proteins which impact mucosal permeability play a crucial role in mucosal healing. We investigated that changes in mRNA expression levels of these molecules 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) were enrolled in this study. All UC patients received 10-11 times of GMA, and colonoscopies were applied before the first GMA (preGMA) and after the last GMA (post-GMA). Assessment of GMA therapeutic efficacy and colonic mucosal healing were determined based on Mayo score. Growth factors such as EGF and HGF, and tight junction proteins such as occludin and ZO-1 mRNA expressions were determined by quantitative RT-PCR using biopsy specimen of colonic mucosa. Results: After GMA treatment, 11 patients (34.4%) achieved clinical remission, 17 patients (53.1%) showed clinical response and 4 patients (12.5%) showed non-response. All patients of the clinical remission group achieved mucosal healing, whereas none of patients in non-response group achieved mucosal healing. Baseline characteristics such as sex, location of disease, CRP, WBC and Mayo score were not significantly different according to GMA efficacy. In both pre-GMA and post-GMA, the clinical remission group showed significantly higher expressions of occludin, ZO-1 and EGF mRNA in mucosal tissue than those of the nonresponse group (P <0.05). Post-GMA, HGF mRNA expression tended to be lower in the remission group than those in non-response group. In the non-response group, levels of occludin and ZO-1 mRNA significantly decreased post-GMA compared to their pre-GMA levels (P <0.05), but they were not decreased in the clinical remission group. In contrast, HGF mRNA level decreased post-GMA compared to its pre-GMA level in the remission group, but it was not decreased in the non-response group. Conclusion: In UC patients who achieved clinical remission by GMA, expressions of EGF and tight junction molecules were higher significantly, and mRNA level of HGF decreased after GMA treatment. These results suggest that these molecules play an important role in mucosal healing, and could be helpful for choosing patients who are respond to GMA before treatment

https://www.gastrojournal.org/article/S0016-5085(21)01910-7/pdf

Masanao Nakamura ¹, Takeshi Yamamura ¹, Keiko Maeda ², Tsunaki Sawada ², Yasuyuki Mizutani ¹, Eri Ishikawa ¹, Ayako Ohashi ¹, Go Kajikawa ¹, Kazuhiro Furukawa ¹, Eizaburo Ohno ¹, Takashi Honda ¹, Hiroki Kawashima ¹, Masatoshi Ishigami ¹, Mitsuhiro Fujishiro ¹

Intern Med. 2020 Dec 1;59(23):3009-3014. doi: 10.2169/internalmedicine.5302-20. Epub 2020 Jul 28.

Granulocyte and monocyte adsorptive apheresis (GMA) is occasionally introduced as an alternative combination therapy after loss of response to biologics in ulcerative colitis (UC) patients. However, there have been no reports of the concomitant use of vedolizumab (VDZ) and GMA for the initial induction of UC. A 20-year-old man with refractory UC was admitted for recrudescence. VDZ monotherapy had previously been introduced but was ineffective. Therefore, he received scheduled combination of VDZ and GMA and achieved clinical remission. The combination of two different approaches to inhibit the migration of leukocytes into the inflamed tissue led to satisfactory clinical outcomes.

https://pubmed.ncbi.nlm.nih.gov/32727993/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759717/

Lorenzo Bertani ¹, Federico Rossari ², Brigida Barberio ³, Maria Giulia Demarzo ⁴, Gherardo Tapete ¹, Eleonora Albano ¹, Giovanni Baiano Svizzero ¹, Linda Ceccarelli ⁵, Maria Gloria Mumolo ⁵, Chiara Brombin ⁶, Nicola de Bortoli ¹, Massimo Bellini ¹, Santino Marchi ¹, Giorgia Bodini ⁴, Edoardo Savarino ³, Francesco Costa ⁵

Inflamm Bowel Dis. 2020 Sep 18;26(10):1579-1587. doi: 10.1093/ibd/izaa062.

Background: Anti-tumor necrosis factor drugs (anti-TNFs) are widely used for the treatment of ulcerative colitis (UC). However, many patients experience loss of response during the first year of therapy. An early predictor of clinical remission and mucosal healing is needed. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are markers of subclinical inflammation poorly evaluated in UC patients treated with anti-TNFs. The aim of this multicenter study was to evaluate whether NLR and PLR could be used as prognostic markers of anti-TNF treatment response. Methods: Patients with UC who started anti-TNF treatment in monotherapy were evaluated. Patients with concomitant corticosteroid treatment ≥20 mg were excluded. We calculated NLR, PLR, and fecal calprotectin before treatment and after induction. The values of NLR and PLR were correlated with clinical remission and mucosal healing at the end of follow-up (54 weeks) using the Mann-Whitney U test and then multivariate analysis was conducted. Results: Eighty-eight patients were included. Patients who reached mucosal healing after 54 weeks of therapy displayed lower levels of both baseline NLR and PLR (P = 0.0001 and P = 0.04, respectively); similar results were obtained at week 8 (P = 0.0001 and P = 0.001, respectively). Patients who presented with active ulcers at baseline endoscopic evaluation had higher baseline NLR and PLR values compared with those without detected ulcers (P = 0.002 and P = 0.0007, respectively). Conclusions: Both NLR and PLR showed a promising role as early predictors of therapeutic response to anti-TNF therapy in UC patients. If confirmed in larger studies, classification and regression trees proposed in this article could be useful to guide clinical decisions regarding anti-TNF treatment.

https://pubmed.ncbi.nlm.nih.gov/32232392/

Satoshi Tanida ¹, Keiji Ozeki ¹, Tsutomu Mizoshita ¹, Mika Kitagawa ¹, Takanori Ozeki ¹, Mamoru Tanaka ¹, Hirotada Nishie ¹, Takaya Shimura ¹, Eiji Kubota ¹, Hiromi Kataoka ¹ , J Clin Med Res, 2020 Jan;12(1):36-40.

Based on these outcomes, combination therapy with TOF plus intensive GMA was well tolerated and may be useful for induction of clinical remission in patients with refractory UC.

https://pubmed.ncbi.nlm.nih.gov/32010420/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968921/pdf/jocmr-12-036.pdf

Satoshi Tanida

poster at ISFA 2019 pag 56

Background and Aim: A monotherapy with intensive GMA, biologics or a JAK inhibitor are limited in patients with intractable Crohn’s disease (CD) or ulcerative colitis (UC). We retrospectively evaluated the 10- and 52-week efficacy and safety of combination therapy of intensive GMA with biologics or a JAK inhibitor for intractable UC or CD.
Method: A combination of intensive GMA (2 sessions a week, total 10 times) with tofacitinib (TOF) for active UC was performed and that of intensive GMA with ustekinumab (UST) for active CD was done. Results: Of 6 consecutive UC patients receiving a combination therapy of TOF (20 mg daily for 8 weeks as induction therapy and subsequently 10 mg daily) plus intensive GMA for moderately-to-severely active UC and loss of response to corticosteroids, azathioprine, and/ or biologic therapies, 67% (4 cases) displayed clinical remission according to Mayo score and 100% displayed mucosal healing at 10 weeks. A temporary increase in CPK were seen. Of 5 consecutive CD patients receiving a combination therapy of ustekinumab (every 8 weeks) plus intensive GMA for moderately-to-severely active CD and loss of response to corticosteroids, azathioprine, and/or biologic therapies, 75% displayed cumulative steroid-free clinical remission at 10 weeks and did such remission over 52 weeks under subsequent maintenance monotherapy of UST. The mean CDAI at baseline were 257. Its values at 10 and 52 weeks after the combination therapy with UST plus intensive GMA were 48 and 68, respectively. One case showed mucosal healing at 52 weeks according to SES-CD. No adverse events were observed. Conclusions: Combination therapy of intensive GMA with biologics or a JAK inhibitor appeared to be effective and safe for refractory UC or CD.

http://www.atalacia.com/isfa/data/abstract.pdf

Taku Kobayashi

poster at ISFA 2019 pag 53

There are two types of extracorporeal therapy for treating active ulcerative colitis (UC), granulocyte and monocyte adsorption (GMA) and leukocytapheresis (LCAP). Although Sawada et al reported the efficacy of LCAP by the randomized controlled trial (Sawada K et al. Am J Gastroenterol 2005), the larger sham-controlled multicenter trial of GMA failed to prove its efficacy (Sands BE et al. Gastroenterol 2008). Therefore, evidence to show their efficacy relies more on the real-world data, including the post-marketing surveillance (PMS). The large-scale PMS for LCAP was named as REFINE study, involving 847 patients from 116 medical facilities in Japan (Yokoyama Y, Kobayashi T et al. J Crohn Colitis 2014). Adverse events were seen only in 10.3% and the vast majority were mild. The overall clinical remission rate was 68.9%, and the mucosal healing rate was 62.5%. These results were very consistent with the results from PMS of 697 patients treated with GMA, which also demonstrated its real-world effectiveness and safety (Hibi T et al. Dig Liver Dis 2008). In addition, a retrospective observational study aimed to evaluate the clinical outcome at 1 year and identify risk factors for relapse after LCAP was recently conducted among patients who had achieved remission in the PMS (Kobayashi T et al. J Gastroenterol 2018). The 1-year cumulative relapse free rate was 63.6%. Following LCAP, a high clinical activity and a high leukocyte count were associated with a greater risk of relapse. Intensive LCAP was associated with favorable long-term outcomes in corticosteroidrefractory patients. The response rate of re-treatment upon relapse was as high as 85%. These results on the risks of relapse as well as effectiveness of re-treatment may help to overcome the weakness of cytapheresis therapy in maintaining remission. Results from the clinical trial evaluating the clinical efficacy of intermittent maintenance cytapheresis therapy are also warranted.

http://www.atalacia.com/isfa/data/abstract.pdf

Chie Kurihara, Toshihide Ohmori, Hirotaka Furuhashi, Kenichi Inaba, Nao Sugihara, Yoshinori Hanawa, Gastroenterology 2019 156 (6) Suppl. S-1146

Background: Granulocyte and monocyte adsorptive apheresis (GMA) is non-pharmacological therapy which selective depletion of activated granulocytes and monocytes/macrophages from peripheral blood. GMA is effective and safe as induction therapy in ulcerative colitis (UC) of moderate to severe patients, and commonly used in Asia and north Europe. However, therapeutic mechanism of GMA, especially its effect on mucosal healing, has not been well characterized. Since moderate to severe patients with UC sometimes become fulminant, it is important to select an appropriate induction therapy. GMA treatment efficacy is reported about 60% patients respond, whereas, there is not useful parameter that predicts GMA therapeutic efficacy before treatment. In this study, we attempted to identify predictive factors of clinical response to GMA treatment in UC patients. 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 or 11 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 disease activity and colonic mucosal healing were determined based on Mayo score. Inflammation-related molecules mRNA expressions were determined by quantitative RT-PCR using biopsy specimen of colonic mucosa. ROC curves analysis was used to assess sensitivity and specificity in prediction of GMA therapeutic efficacy. 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. Mucosal healing was observed in 18 patients (56.3%) and it was not observed in 14 patients (43.7%). Baseline characteristics were not significantly different according to GMA efficacy. Before the first GMA session, the clinical remission group showed significantly higher expressions of TNFα, MAdCAM-1 and MIP-1β mRNA than those of the non-response group (P <0.05). Patients in the response group who highly expressed these mRNA achieved mucosal healing. In the mucosal healing group, the mRNA levels of TNFα, IL-1β, IL-8, MIP-1β, TGFβ and IL-10 were significantly higher than those in the non-mucosal healing group (P <0.05). TNFα and MIP-1β had 0.83 and 0.79 of area under the curve with 83.3% and 66.7% sensitivity, 71.4% and 100% specificity, 78.9% and 100%positive predictive value, and 76.9% and 70.0% negative predictive value, respectively, for prediction of mucosal healing. Conclusion: Mucosal expression of TNFα and MIP-1β mRNA before treatment in the remission group and the mucosal healing group was significantly higher than non-responder to GMA treatment. We propose that measuring of these molecules’ expression is useful to expect GMA therapeutic efficacy in patients with UC.

https://www.gastrojournal.org/action/doSearch?text1=granulocyte+and+monocyte+apheresis+&field1=AllField&AfterYear=2018&BeforeYear=2021&pageSize=50&startPage=&SeriesKey=ygast

Marta Velasco Rodríguez-Belvís ¹, Javier Francisco Viada Bris ¹, Laura Palomino Pérez ¹, Rosa Ana Muñoz Codoceo ¹ , inflamm Bowel Dis. 2019 Jun 18;25(7):e82-e83.

https://pubmed.ncbi.nlm.nih.gov/30698787/

Takumi Fukuchi ¹, Hideaki Koga ¹, Shinji Kaichi ¹, Akira Ishikawa ², Takahisa Horita ³, Ryota Araki ⁴, Atsushi Yokota ⁵, Yukiomi Namba ⁶, Masahiro Kyo ⁷, Takaaki Eguchi ⁸, Keiji Shimazu ⁹ Ther Apher Dial 2019 Jun;23(3):224-232

Single-needle intensive granulocyte/monocyte adsorptive apheresis might be a novel alternative therapeutic option for elderly ulcerative colitis patients before considering corticosteroids.

https://pubmed.ncbi.nlm.nih.gov/31025824/

Takayuki Yamamoto ¹, Takayuki Iida ², Kentaro Ikeya ², Masaichi Kato ², Ai Matsuura ², Satoshi Tamura ³, Ryosuke Takano ³, Shinya Tani ⁴, Satoshi Osawa ⁴, Ken Sugimoto ³, Takahiro Shimoyama ⁵, Hiroyuki Hanai ² , Clin Transl Gastroenterol 2018 Jul 6;9(7):170.

Objectives: Adsorptive granulomonocytapheresis (GMA) with the Adacolumn has been introduced as a non-pharmacologic treatment for ulcerative colitis (UC). However, a subset of patients who might respond well to GMA needs to be targeted. This study was conducted at three IBD centers to determine factors affecting the efficacy of GMA in patients with moderately-to-severely active UC. 1234567890(); 1234567890(),; 1234567890(); 1234567890(); Methods: From January 2008 to December 2017, a total of 894 active episodes (first attack or relapse) in 593 patients were treated with GMA. Clinical remission was defined as normal stool frequency and no rectal bleeding. Multiple clinical and laboratory parameters at entry were considered for efficacy assessment. Results: Clinical remission was achieved during 422 (47%) of the 894 treatment cases. In the multivariate analysis, predictors for favorable response to GMA were age ≤60 years, UC duration <1 year, Mayo endoscopic subscore 2 (vs. 3), steroid naïve UC, and biologic naïve UC. Clinical remission rate was 70% in patients with four of the five factors, 52% in patients with three factors, 46% in patients with two factors, 39% in patients with one factor, and 18% in patients with none of these factors. Overall, the clinical remission rate was significantly higher in patients with a greater number of the five predictors (P < 0.0001). Conclusions: GMA appeared to be effective in steroid naïve and biologic naïve patients with short duration of UC. Elderly patients (>60 years) and those with severe endoscopic activity did not respond well to GMA. Additional, well designed, prospective, controlled trials should strengthen our findings.

https://pubmed.ncbi.nlm.nih.gov/29977035/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033883/pdf/41424_2018_Article_37.pdf