Ryosuke Kasuga 1, Po-Sung Chu 1, Nobuhito Taniki 1, Aya Yoshida 1, Rei Morikawa 1, Takaya Tabuchi 1, Fumie Noguchi 1, Karin Yamataka 1, Yukie Nakadai 1, Mayuko Kondo 1, Hirotoshi Ebinuma 1 2, Takanori Kanai 1, Nobuhiro Nakamoto 1

Background: Patients with severe alcohol-associated hepatitis (SAH) have a high short-term mortality rate. Unmet needs exist in patients who are refractory to corticosteroids (CS) or are ineligible for early liver transplantation.

Methods: This was a prospective, open-label, nonrandomized pilot study conducted at a liver transplant center in Tokyo, Japan, starting in October 2015. Lille model and Model for End-stage Liver Disease (MELD) score-defined CS nonresponsive or CS-intolerant patients with SAH who fulfilled the inclusion criteria (leukocytosis over 10,000/μL, etc.) were considered for enrollment. The median duration from admission to enrollment was 23 days (IQR, 14-31 days), after standard of care. Granulocyte-monocyte/macrophage apheresis (GMA) performed with Adacolumn twice per week, up to 10 times per treatment course, was evaluated.

Results: 13 GMA treatments were conducted through December 2021. Maddrey Discriminant Function was 53.217.7 at admission. The overall survival rate was 90.9% at 90 and 180 days. MELD scores significantly improved, from median (IQRs) of 23 (20-25) to 15 (13-21) after GMA (p<0.0001). Estimated mortality risks using the Lille model and MELD scores significantly improved from 20.9%±16.5% to 7.4%±7.3% at 2 months and from 30.4%±21.3% to 11.6%±10.8% at 6 months, respectively (both p<0.01), and were internally validated. The cumulative rate of alcohol relapse was 35.9% per year. No severe adverse events were observed. In exploratory analysis, granulocyte colony-stimulating factor levels were significantly correlated with prognostic systems such as MELD-Sodium scores after GMA (correlation coefficient= -0.9943, p<0.0001) but not before GMA (p=0.62). Conclusions: Compared to published studies, GMA is associated with a lower-than-expected 90- and 180-day mortality in patients with CS-nonresponsive or CS-intolerant SAH. GMA may meet the needs as a salvage anti-inflammatory therapy for SAH. (Trial registration: UMIN000019351 and jRCTs No.032180221) (274 words).

I Rodríguez-Lago, D Ginard, R J Díaz Molina, M Vicuña, E Domenech, M Abanades, O Moralejo Lozano, G Bastida, A D Sánchez Capilla, E Iglesias, F Rancel-Medina, M D M Blasco, M Bosca-Watts, M Calvo Iñiguez, C Herrera deGuisé, E Leo, A Viejo Almanzor, V Hernández Ramirez, C Suárez Ferrer, L Quilez Pérez, M Muñoz, F Fernández Pérez, J M Huguet, P Fradejas, C López Ramos, A M Fuentes Coronel, C Reygosa Castro, N Rull Murillo, P Zapico, J L Cabriada
Journal of Crohn’s and Colitis, Volume 18, Issue Supplement_1, January 2024, Page i1011, doi.org=10.1093/ecco-jcc/jjad212.0641

Background
The clinical efficacy of granulocyte and monocyte adsorptive apheresis (GMA) with Adacolumn in patients (pts) with inflammatory bowel disease (IBD) has been reported in several clinical trials (CT), with significant clinical remission rates. However, evidence on real-world effectiveness of GMA with Adacolumn in ulcerative colitis (UC) or Crohn’s disease (CD) patients who were underrepresented in CT is still limited.

Methods
GRACE is a multicentric, prospective observational study conducted at 31 centres in Spain. The study included adults (≥18 years) diagnosed with UC or CD who had been scheduled to receive GMA with Adacolumn in clinical practice. The study consisted of a baseline (GMA initiation) and 3 follow-up visits at 4, 24, and 48 weeks after the last GMA session. The primary endpoint is the steroid-free remission rate at 24 weeks. This interim analysis is focused on clinical characterization of patients and their management and outcome 4 weeks after GMA treatment.

Results
A total of 95 evaluable patients were included at data cut-off date (25 Sept 2023) (median age: 54 years; 50% men: 81% outpatients). Overall, 89.4% (n=84) of patients had UC, being moderate-to-severe in 85.5%; 57,8% had pancolitis, and the median Mayo score was 5 (interquartile range [IQR], 3-6). Out of the 10 patients (10.6%) with CD, all had B1, and 3 patients had L1, 4 L2 and 3 L3. Overall, 17% had extraintestinal manifestations. Regarding IBD-related therapy, 52.6% of patients had previously received anti-TNF agents, 37.9% thiopurines, and 17.8% JAK inhibitors. Overall, 85.3% of patients received concomitant treatment with GMA, most commonly 5-ASA (60%), corticosteroids (51,6%), ustekinumab (20%), vedolizumab (17.9%), and anti-TNF therapy (11.6%). A total of 71 patients reached the 4-week visit after receiving a median of 10 (IQR, 8-10) GMA sessions (weekly: 26.3%, biweekly: 36.8%, and weekly/biweekly: 31.6%). At week 4, clinical remission was achieved by 50.7% of patients (UC: 49.2%; CD: 66.7%), being 50% and 53.3% in patients concomitantly treated with ustekinumab and vedolizumab. Steroid-free remission rate was 26.1% (UC: 22.2%; CD: 66.7%) at week 4. Overall, 11,2% of patients experienced AEs related to GMA, most of them being mild (73%) or moderate (22.4%). Most common AEs were headache and asthenia. No SAEs were observed.

Conclusion
Preliminary data at 4 weeks show that Adacolumn is a safe and effective treatment in a cohort of IBD refractory patients with previous failure to multiple therapies including thiopurines, biologics and JAK inhibitors. Half of patients were concomitantly treated with biologics, and their clinical remission rate was similar to the overall population. Long-term results of this study (48 weeks) are required to confirm these findings.

Kazuki Kakimoto ¹, Minoru Matsuura ², Takumi Fukuchi ³, Hitoshi Hongo ⁴, Tsuguhiro Kimura ⁴, Nobuo Aoyama ⁵, Yorihide Okuda ⁶, Kazuki Aomatsu ⁷, Noriko Kamata ⁸, Yoko Yokoyama ⁹, Chiemi Mizuno ¹⁰, Takuya Inoue ¹, Takako Miyazaki ¹, Shiro Nakamura ¹, Kazuhide Higuchi ¹, Hiroshi Nakase ¹¹ , Crohns Colitis 360. 2020 Sep 23;2(4):otaa073.

GMA shows effectiveness in inducing remission in UC patients not receiving steroid.

https://pubmed.ncbi.nlm.nih.gov/34192247/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797742/pdf/otaa073.pdf

Takayuki Yamamoto ¹, Toshiaki Tanaka ², Tadashi Yokoyama ³, Takahiro Shimoyama ¹, Hiroki Ikeuchi ⁴, Motoi Uchino ⁴, Toshiaki Watanabe ⁵ , Therap Adv Gastroenterol. 2017 Feb;10(2):199-206.

GMA has a good safety profile, but its efficacy appears to be limited in the management of chronic refractory pouchitis. However, a large controlled study should be conducted to evaluate the efficacy of GMA therapy in patients with pouchitis at an earlier clinical stage, before the disease has become refractory to conventional medical therapy.

https://pubmed.ncbi.nlm.nih.gov/28203278/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298477/pdf/10.1177_1756283X16679348.pdf

Gianni Imperiali ¹, Arnaldo Amato ¹, Maria Maddalena Terpin ², Ivo Beverina ³, Aurora Bortoli ⁴, Massimo Devani ⁴, Chiara Viganò ⁵,Gastroenterol Res Pract2017;2017:9728324.

Our study shows that a standard course of granulocyte-monocyte apheresis is associated with a 36% steroid-free clinical remission in patients with steroid-dependent, azathioprine-intolerant or resistant moderate ulcerative colitis. Apheresis might represent an alternative to biologic therapy or surgery in this specific subgroup of patients

https://pubmed.ncbi.nlm.nih.gov/29403531/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748298/pdf/GRP2017-9728324.pdf

Yusuke Okuyama,Akira Andoh,Masakazu Nishishita,Ken Fukunaga,Koji Kamikozuru,Yoko Yokoyama,Yoshitaka Ueno,Shinji Tanaka,Hiroyuki Kuge,Syusaku Yoshikawa,Atsushi Sugahara,Emi Anami,Yoshinori Munetomo,Chiyuki Watanabe,Yoshihide Fujiyama &Takayuki Matsumoto Scand. J. Gastro. 2013, 48 (4), 412-418. https://doi.org/10.3109/00365521.2012.763175

Objective. This study aimed to assess the efficacy and tolerability of leukocytapheresis (LCAP) and to investigate predictive factors for mucosal healing and a sustained clinical response in steroid-free and steroid-refractory patients with ulcerative colitis (UC). Material and methods. Thirty-one steroid-free or steroid-refractory patients with active UC were enrolled. Five or ten consecutive sessions of LCAP were performed in each patient. The efficacy and tolerability was then evaluated at weeks 3 and 6. Endoscopic examination was performed at week 6 to evaluate the mucosal healing, and the sustained cumulative response rate was evaluated at 12 months. Results. At week 6, the mean Mayo clinical activity score had decreased significantly from 8.0 to 4.6 in the steroid-free patients and from 8.3 to 3.9 in the steroid-refractory patients. Rachmilewitz’s endoscopic index had also decreased significantly from 9.1 to 6.1 in the steroid-free patients and from 10.0 to 5.7 in the steroid-refractory patients. Forty-seven percent of the steroid-free patients and 33% of the steroid-refractory patients achieved mucosal healing. The peripheral platelet counts had decreased significantly at weeks 3 and 6 in the mucosal healing group, compared with the non-mucosal healing group. The patients with a more than 15% platelet reduction had a significantly higher cumulative response rate, compared with the patients without a platelet reduction (p = 0.015). Conclusions. LCAP is beneficial for the induction of mucosal healing in steroid-free and steroid-refractory patients with UC. The degree of platelet reduction during LCAP might be a predictive marker for mucosal healing and a sustained clinical response.

Multicenter prospective study for clinical and endoscopic efficacies of leukocytapheresis therapy in patients with ulcerative colitis – PubMed (nih.gov)

Multicenter prospective study for clinical and endoscopic efficacies of leukocytapheresis therapy in patients with ulcerative colitis: Scandinavian Journal of Gastroenterology: Vol 48, No 4 (tandfonline.com)

Atsushi Sakuraba ¹, Toshiro Sato, Yuichi Morohoshi, Katsuyoshi Matsuoka, Susumu Okamoto, Nagamu Inoue, Hiromasa Takaishi, Haruhiko Ogata, Yasushi Iwao, Toshifumi Hibi,Ther Apher Dial. 2012 Jun;16(3):213-8.

The effect of granulocyte and monocyte adsorption apheresis (GMA) on prevention of relapse of ulcerative colitis (UC) is not clear. This was a pilot open-labeled, prospective, randomized, unblinded study to compare the tolerability and efficacy of intermittent GMA (once every 2 weeks) with mercaptopurine to maintain remission of UC. Twenty-one patients with UC, who had achieved remission by induction therapies were randomly assigned to receive either intermittent GMA (N = 10) or oral mercaptopurine (0.5 mg/kg per day; N = 11). The study period was 24 months. The rate of the patients maintaining remission and the incidences of adverse effects were compared between the two groups. At 24 months, seven of 10 patients (70.0%) on intermittent GMA and seven of 11 patients (63.6%, P = 1.00) on oral mercaptopurine were still in remission. Three patients relapsed in each group. One patient taking mercaptopurine, but none receiving intermittent GMA, dropped out because of adverse effects. Intermittent therapy with GMA was well tolerated and a substantial proportion of patients maintained remission. Intermittent GMA therapy in maintaining remission of UC merits further investigation.

https://pubmed.ncbi.nlm.nih.gov/22607563/

Takeshi Tomomasa ¹, Hitoshi Tajiri, Seiichi Kagimoto, Toshiaki Shimizu, Atsushi Yoden, Kosuke Ushijima, Keiichi Uchida, Hiroaki Kaneko, Daiki Abukawa, Mutsuko Konno, Shun-ichi Maisawa, Takao Kohsaka, Akio Kobayashi, Japanese Study Group for Pediatric Ulcerative Colitis. J Pediatr Gastroenterol Nutr. 2011 Jul;53(1):34-9. doi: 10.1097/MPG.0b013e31821058bc.

Objective: Leukocytapheresis (LCAP) is a nonpharmacologic therapy that has recently been used to treat ulcerative colitis (UC). This multicenter open-label study prospectively assessed the efficacy and safety of LCAP in pediatric patients with UC. Patients and methods: Twenty-three patients ages 8 to 16 years with moderate (n = 19) to severe (n = 4) steroid-resistant UC were enrolled. One of 2 LCAP columns with different volumes (model EX and the half-volume model EI) was selected, according to body weight. LCAP was performed once per week for 5 consecutive weeks. Clinical and laboratory data were collected at predetermined time points. The primary endpoint was decreased stool frequency/hematochezia score, and secondary endpoints were clinical, laboratory, and endoscopic improvements. Results: The stool frequency/hematochezia score decreased significantly from 4.5 ± 1.2 before treatment to 1.6 ± 1.9 after the fifth treatment. Clinical parameters, including stool frequency, presence of visible blood, abdominal pain, and body temperature, were significantly improved. Fecal calprotectin decreased significantly. Endoscopic findings evaluated using Matts score also improved (P < 0.01). The steroid dose decreased from 1.1 ± 0.4 mg/kg before treatment to 0.8 ± 0.5 mg/kg after treatment. There were no significant differences in changes between the EX and EI columns. The incidence of adverse effects was 61%, although none was serious. The most common adverse effects were decreased hematocrit and hemoglobin concentration. Conclusions: The present study showed that LCAP was well tolerated in children with UC, mostly moderate, and was as effective as in adults. The types of pediatric patients best suited to LCAP remain to be determined.

https://pubmed.ncbi.nlm.nih.gov/21694533/

Leukocytapheresis in Pediatric Patients With Ulcerative Coli… : Journal of Pediatric Gastroenterology and Nutrition (lww.com)

Takayuki Yamamoto ¹, Satoru Umegae, Koichi Matsumoto, J Gastroenterol 2011 Aug;46(8):1003-9.

This is the first report on daily GMA in the treatment of patients with UC. Daily GMA was safe and well tolerated without serious AE. Furthermore, daily GMA was associated with rapid improvement of clinical symptoms in patients with moderately active UC. However, controlled trials are warranted to assess a definite efficacy for daily GMA therapy.

https://pubmed.ncbi.nlm.nih.gov/21681409/

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/