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).

Makoto Naganuma, Yoko Yokoyama, Satoshi Motoya, Kenji Watanabe, Koji Sawada, Fumito Hirai, Takayuki Yamamoto, Hiroyuki Hanai, Teppei Omori, Takanori Kanai & Toshifumi Hibi, Journal of Gastroenterology volume 55, pages390–400 (2020)

Apheresis was well tolerated as maintenance therapy for UC although the cumulative clinical remission rate at 12 months was comparable between the apheresis and control groups.

Efficacy of apheresis as maintenance therapy for patients with ulcerative colitis in an open-label prospective multicenter https://link.springer.com/article/10.1007/s00535-019-01651-0#group-1

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

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)

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/

Irene Modesto, Daniela Scimeca, Ambrogio Orlando, Mario Cottone, Inflamm Bowel Dis 12 (10), October 2006

We report the results of an open prospective study of LCAP in moderate to severe steroid-dependent UC. LCAP is an effective procedure in obtaining discontinuation of steroids in 36% of patients with UC for at least 3 months. Overall 4 of 11(36%) patients could discontinue steroids within 3 months. No relevant side effects were observed. The procedure was well tolerated. In our series, there was no endoscopic response. Most of the patients obtained a clinical temporary response, but many relapsed

https://pubmed.ncbi.nlm.nih.gov/17012976/

Wolfgang Kruis, Axel Dignass, Elisabeth Steinhagen-Thiessen, Julia Morgenstern, Joachim Mössner,
Stephan Schreiber, Maurizio Vecchi, Alberto Malesci, Max Reinshagen, Robert Löfberg

World J Gastroenterol 2005;11(44):7001-7006

AIM: To study the efficacy, safety, and feasibility of a granulocyte adsorptive type apheresis system for the treatment of patients with chronically active ulcerative colitis despite standard therapy. METHODS: An open label multicenter study was carried out in 39 patients with active ulcerative colitis (CAI 6-8) despite continuous use of steroids (a minimum total dose of 400 mg prednisone within the last 4 wk). Patients received a total of five aphereses using a granulocyte adsorptive technique (Adacolumn®, Otsuka Pharmaceutical Europe, UK). Assessments at wk 6 and during follow-up until 4 mo comprised clinical (CAI) and endoscopic (EI) activity index, histology, quality of life (IBDQ), and laboratory tests. RESULTS: Thirty-five out of thirty-nine patients were qualified for intent-to-treat analysis. After the apheresis treatment at wk 6, 13/35 (37.1%) patients achieved clinical remission and 10/35 (28.6%) patients had endoscopic remission (CAI<4, EI<4). Quality of life (IBDQ) increased significantly (24 points, P <0.01) at wk 6. Apheresis could be performed in all but one patient. Aphereses were well tolerated, only one patient experienced anemia. CONCLUSION: In patients with steroid refractory ulcerative colitis, five aphereses with a granulocyte/ monocyte depleting filter show potential short-term efficacy. Tolerability and technical feasibility of the procedure are excellent.

https://www.wjgnet.com/1007-9327/full/v11/i44/7001.htm

[Article in Korean ]Hyo Jong Kim ¹, Joo Sung Kim, Dong Soo Han, Suk-Kyun Yang, Ki Baik Hahm, Woo In Lee, Seog-Woon Kwon, Jai Hyun Choi, Won Ho Kim, Kyu Yong Choi, In Sung Song Korean J Gastroenterol  2005 Jan;45(1):34-44. PMID: 15665566

Background/aims: In chronic inflammatory conditions such as ulcerative colitis (UC), the migration of granulocytes and monocytes/macrophages from the circulation into the colonic mucosa is especially important in maintaining inflammation. The aim of this trial was to assess safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with moderate-to-severe UC refractory to conventional drug therapies. Methods: Twenty-seven patients with moderate (55.6%) to severe (44.4%) active UC refractory to conventional drug therapies who had no changes in their conventional therapy regimen in the past two weeks before the recruitment were enrolled in an open-label trial. Concomitant medications were allowed, and steroids were tapered down according to the clinical activity during the course. We used an adsorptive type extracorporeal column (Adacolumn; JIMRO, Takasaki, Japan), which selectively adsorb granulocytes and monocytes. Patients took five apheresis sessions, each with 60 minutes duration for 5 consecutive weeks. The primary efficacy variables were clinical disease activity, short inflammatory bowel disease questionnaire (SIBDQ), C-reactive protein (CRP), and endoscopic scores. These variables were scored at regular intervals, and analyzed at week 7 on an intention-to-treat (ITT) principles. Results: At 7 weeks, 70.4% of patients showed overall improvement. Clinical disease activity (p < 0.0001), endoscopic score (p < 0.001), and the quality of life as assessed by SIBDQ (p < 0.0001) were significantly improved after the therapy. In 56.3% of concomitant steroid users, tapering down or discontinuation of steroids was possible. Treatment was well tolerated, and no severe adverse events were observed. Conclusions: Adacolumn was very efficacious in patients with moderate-to-severe active UC refractory to conventional drug therapy, but further assessment is needed.

https://pubmed.ncbi.nlm.nih.gov/15665566/

E Domènech ¹, J Hinojosa, M Esteve-Comas, F Gomollón, J M Herrera, G Bastida, A Obrador, R Ruiz, C Saro, M A Gassull, Spanish Group for the Study of Crohn’s Disease and Ulcerative Colitis (GETECCU)

Aliment Pharmacol Ther. 2004 Dec;20(11-12):1347-52. doi: 10.1111/j.1365-2036.2004.02288.x.

Background: Uncontrolled studies suggest that granulocyteaphaeresis might be useful in the management of active ulcerative colitis. Aim: To assess the efficacy of granulocyteaphaeresis treatment in active steroid-dependent inflammatory bowel disease. Methods: We conducted a multicentre, prospective, open, pilot study in patients with steroid-dependent inflammatory bowel disease. All patients were started on 60 mg/day of prednisone; after 1 week, a five-session programme of granulocyteaphaeresis (once per week) was started. The steroid dose was tapered weekly if there was clinical improvement. Remission was defined as an inactive clinical activity index together with complete withdrawal of steroids at week 6. The patients were followed up for at least 6 months or until disease relapse. Results: Twenty-six patients (14 ulcerative colitis, 12 Crohn’s disease) were included. More than a half had been previously treated with immunomodulators. Remission was achieved in 62 and 70% of ulcerative colitis and Crohn’s disease, respectively. During a median follow-up of 12.6 months, six of eight ulcerative colitis patients maintained their clinical remission; however, only one Crohn’s disease patient remained in remission after the first 6 months of follow-up. Conclusions: Granulocyteaphaeresis is a safe treatment option in inflammatory bowel disease. A five-session programme of granulocyteaphaeresis seems to be efficient in the treatment of steroid-dependent ulcerative colitis, but not in Crohn’s disease.

https://pubmed.ncbi.nlm.nih.gov/15606397/

https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1365-2036.2004.02288.x