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).

H H Olsen ¹, V Muratov, K Cederlund, J Lundahl, A Eklund, J Grunewald, Clin Exp Immunol. 2014 Sep;177(3):712-9.

Sarcoidosis is a systemic, inflammatory disorder, which in a proportion of patients runs a chronic progressive course despite immunosuppressive treatment. Therapeutic granulocyte and monocyte apheresis (GMA) has been shown to be an effective treatment option for other systemic inflammatory disorders, but has not yet been investigated in sarcoidosis. The aim of this study was to evaluate the response to GMA in sarcoidosis. Seven patients with sarcoidosis refractory to standard immunosuppressive therapy received 10 GMA sessions. All patients underwent chest X-ray, spirometry, a Chronic Respiratory Disease Questionnaire (CRQ-SAS), blood tests and bronchoscopy with bronchoalveolar lavage (BAL) before treatment and at 2-4 weeks and 3 months (except bronchoscopy) after the last treatment session. Bronchoalveolar lavage fluid (BALF) cell differential counts were recorded and T cells from blood and BALF were analysed for markers of activity, differentiation and T regulatory function. Compared to baseline, five of seven patients reported an improvement in dyspnoea score. In BALF there was an increase in the percentage of macrophages and a decrease in the percentage of lymphocytes and CD4(+) /FoxP3(+) T cells. Furthermore, the decrease in BALF CD4(+) /FoxP3(+) T cells correlated significantly with an improvement in dyspnoea score. In peripheral blood there was a statistically significant increase in the percentage of CD4(+) /CD27(-) T cells and a trend towards an initial increase in the percentage of CD4(+) /FoxP3(+) T cells, followed by a statistically significant decrease. The effects of GMA on regulatory T cells are consistent with those observed in other inflammatory disorders and could potentially translate into a clinical benefit.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137856/pdf/cei0177-0712.pdf

https://pubmed.ncbi.nlm.nih.gov/24773420/

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/

Javier Martin-Carpi Martín-Carpi, Vicente Varea Journal of Crohn’s and Colitis, Volume 3, Issue 3, September 2009, Pages 216–217, https://doi.org/10.1016/j.crohns.2009.03.003

Treatment of paediatric ulcerative colitis (UC) unresponsive to conventional treatment constitutes a challenge. The finding of new secure, steroid-sparing and long acting treatments for these cases are mandatory. We report our experience with a long-term therapeutic strategy with Adacolumn in a chronically active paediatric UC patient (9 year-old boy) with the aim of achieving stabilization and ameliorating symptoms, permitting a successful switch to AZA monotherapy. These two aspects have been achieved without reappearance of rectal bleeding after oral mesalamine suppression. But the most interesting and promising finding is the confirmation of GMA apheresis effect on mucosal healing after prolonged treatment: maintenance treatment with Adacolumn has been effective in achieving a complete endoscopic and histological remission.

This case shows the utility of prolonged Adacolumn treatment in chronically active UC patients.

https://academic.oup.com/ecco-jcc/article/3/3/216/384285

Yasumi Araki ¹, Keiichi Mitsuyama, Takaaki Nagae, Yuji Tou, Motonori Nakagawa, Yasue Iwatani, Masakazu Harada, Hiroyuki Ozasa, Michio Sata, Toshihiro Noake, J Gastroenterol. 2008;43(7):571-5.

Background: Pouchitis is a major long-term complication of ileal pouch-anal anastomosis for ulcerative colitis. The aim of this study is to investigate the efficacy of leukocytapheresis for the treatment of active pouchitis. Methods: Eight patients with active pouchitis received leukocytapheresis weekly for 5 weeks in an open-label treatment protocol together with baseline therapy. Results: Patients showed significant improvement in their pouchitis disease activity index scores, from 9.5 (range, 8-10) to 4.0 (range, 2-8) (P < 0.05). Six (75%) of the 8 treated patients achieved remission. No adverse events were observed. Conclusions: Leukocytapheresis therapy could be a new therapeutic strategy for patients with pouchitis after ileal pouch-anal anastomosis for ulcerative colitis. These encouraging results lead us to propose a randomized controlled trial.

https://pubmed.ncbi.nlm.nih.gov/18648745/

Ikeda, Hitoshi; Ishimaru, Yuki; Takayasu, Hajime; Fujino, Junko; Kisaki, Yoshiyuki; Otani, Yushi; Yamagishi, Junko; Tahara, Kazunori. J Pediatr Gastroenterol Nutr 2006; 43:592-6. doi: 10.1097/01.mpg.0000237928.07729.79

Objectives: Granulocyte apheresis (GCAP), involving the removal of granulocytes from the blood, may improve clinical symptoms and facilitate a reduction in the dose of steroids in adult patients with ulcerative colitis. As a preliminary trial, GCAP was used to taper the dose of steroids in 4 pediatric patients with ulcerative colitis. Methods: Three males and 1 female ranging from 11 to 17 years old were treated with GCAP once per week for 5 consecutive weeks/course. The ages of patients at clinical onset ranged from 8 to 12 years and the length of time from the clinical onset to GCAP treatment ranged from 28 to 58 months (median, 38.5 months). Results: In 2 patients, symptoms and signs indicating disease activity improved after 2 courses of GCAP. Laboratory data and endoscopic findings also improved after treatment and the clinical efficacy was judged to be excellent in these patients. In 1 patient, GCAP improved laboratory and endoscopic hallmarks, but bloody stools persisted. Finally, the treatment was ineffective in the fourth patient who eventually underwent surgery. Conclusions: GCAP is effective in improving clinical symptoms and may play an important role in converting steroid therapy to other treatments in children with steroid-refractory or steroid-dependent ulcerative colitis.

https://journals.lww.com/jpgn/FullText/2006/11000/Efficacy_of_Granulocyte_Apheresis_in_Pediatric.8.aspx

R Sanmartí ¹, S Marsal, J Valverde, E Casado, R Lafuente, N Kashiwagi, J-R Rodriguez-Cros, A Erra, D Reina, J Gratacós Rheumatology (Oxford) 2005 Sep;44(9):1140-4. doi: 10.1093/rheumatology/keh701. Epub 2005 May 31.

Objective: To assess the efficacy and safety of adsorptive granulocyte and monocyte apheresis (GCAP) in patients with refractory rheumatoid arthritis (RA). Methods: Patients with active and refractory RA were treated with weekly GCAP sessions using a column filled with acetate beads (Adacolumn) over five consecutive weeks. Clinical assessments and response to therapy were analysed at weeks 5, 7, 12 and 20 in an open multicentre trial. The primary outcome measure of clinical response was 20% improvement in the American College of Rheumatology criteria (ACR20) at week 20. EULAR (European League Against Rheumatism) response criteria, based on the disease activity score for 28 joints (DAS28) and disability using the Health Assessment Questionnaire (HAQ), were also assessed. Results: Of 27 patients, 81.5% were women with mean disease duration of 14.4 yr. The mean number of previous disease-modifying antirheumatic drugs (DMARDs) was 3.7, and 48.1% of patients had previously failed on biologicals. On an intention-to-treat basis, 40.7% of patients achieved an ACR20 and 44.4% a therapeutic EULAR response at week 20. These percentages were 50 and 54.5% in 22 patients who completed the trial. In the 10 completers who had previously failed on biologicals, an ACR response was achieved in four patients (ACR20, two; ACR50, one; ACR70, one). A significant decrease was recorded in different ACR response components, including the tender joint and swollen joint counts, pain score and patient and physician global disease assessments, as well as the DAS28 index; most of them improved after week 5. ESR and CRP, but not the HAQ score, had decreased significantly at week 20. The treatment was well tolerated and only one serious adverse event related to the study procedure was documented (sepsis due to a catheter infection). Conclusions: GCAP treatment led to significant clinical improvement in a subset of patients with RA who had failed to respond to DMARDs or biologicals. Further large, placebo-controlled studies are warranted to fully assess the therapeutic value of GCAP for refractory RA.

https://pubmed.ncbi.nlm.nih.gov/15927997/

https://academic.oup.com/rheumatology/article/44/9/1140/1784472?login=false

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

M Nagashima ¹, S Yoshino, H Tanaka, N Yoshida, N Kashiwagi, A R Saniabadi

Rheumatol Int. 1998;18(3):113-8. doi: 10.1007/s002960050068.

To investigate if granulocyte and monocyte apheresis mitigates the symptoms of rheumatoid arthritis (RA), and influences production of panmyelocytes (CD15+ CD16- cells) at the bone marrow level, 27 RA patients who had elevated granulocyte counts were recruited. The granulocyte and monocyte apheresis column (G-1 column) is an extracorporeal type device packed with 220 g cellulose acetate beads to which granulocytes and monocytes specifically adhere. Patients received apheresis of 1 hr duration twice per week, 8 times over a period of 4 weeks. To prepare CD15+CD16- cells, iliac bone marrow aspirate was obtained at baseline and at 2 weeks after completion of the apheresis course. Ex-vivo proliferation of bone marrow low density cells and production of IgM-RF were also investigated. Following granulocyte and monocyte apheresis, there was a suppressed tendency in the number of CD15+CD16- cells in patients with high bone marrow CD15+CD16- cell counts at baseline. Clinical assessments 2 weeks after the completion of apheresis therapy showed improvements in swollen joint count (P < 0.001), tender joint count (P < 0.001) and duration of morning stiffness (P < 0.005). The results suggest that granulocytes and monocytes/macrophages have a pathological role in RA and apheresis treatment to reduce or suppress these cells should benefit patients with RA.

https://pubmed.ncbi.nlm.nih.gov/9833252/

https://link.springer.com/article/10.1007%2Fs002960050068