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Induction of mucosal healing by intensive granulocyte/monocyte adsorptive apheresis (GMA) without use of corticosteroids in patients with ulcerative colitis: long-term remission maintenance after induction by GMA and efficacy of GMA re-treatment upon relapse

Takumi Fukuchi Kousaku Kawashima Hideaki Koga Ran UtsunomiyaKohei Sugiyama Keiji Shimazu Takaaki Eguchi Shunji Ishihara J Clin Biochem Nutr. 2022 Mar;70(2):197-204. doi: 10.3164/jcbn.21-112. Epub 2021 Dec 25.

This study examined the long-term maintenance rate after inducing remission by intensive granulocyte/monocyte adsorptive apheresis (GMA) without use of corticosteroids (CS) and GMA re-treatment efficacy in the same patients upon relapse with ulcerative colitis. Patients who achieved clinical remission and mucosal healing (MH) by first-time intensive GMA (first GMA) without CS were enrolled. The cumulative non-relapse survival rate up to week 156 was calculated. Patients with relapse during the maintenance period underwent second-time intensive GMA (second GMA) without CS. Clinical remission and MH rates following second GMA were compared to those following first GMA in the same patients. Of the 84 patients enrolled, 78 were followed until week 156 and 34 demonstrated relapse. The cumulative non-relapse survival rate by week 156 was 56.4%. Clinical remission and MH rates after second GMA did not differ from those after first GMA in the same patients (week 6: clinical remission, 100% vs 88.4%, p = 0.134; MH, 100% vs 84.8%, p = 0.074). In conclusion, MH induction by intensive GMA without use of CS in ulcerative colitis patients contributes to subsequent long-term clinical remission maintenance. GMA re-treatment efficacy was comparable to that of first GMA in the same patients who had relapse.

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Complete Resolution of Mucosal Neutrophils Associates With Improved Long-Term Clinical Outcomes of Patients With Ulcerative Colitis

Rish K Pai 1Douglas J Hartman 2Claudia Ramos Rivers 3Miguel Regueiro 4Marc Schwartz 3David G Binion 3Reetesh K Pai Clin Gastroenterol Hepatol 2020 Oct;18(11):2510-2517.e5. doi: 10.1016/j.cgh.2019.12.011. Epub 2019 Dec 14.

Background & aims: We investigated correlations between histologic features of the colonic mucosa in patients with ulcerative colitis (UC) and clinical outcomes during a 3-year follow-up period. Methods: We obtained baseline biopsies from all colorectal segments (n = 889) from 281 patients with UC enrolled in a prospective study at a single center from 2009 through 2013. Biopsies were assessed in a blinded manner using validated histologic scoring systems (the Geboes score, Nancy histopathologic index, and Robarts histopathologic index). Clinical, endoscopic, and histologic data were collected and tested for correlations with systemic corticosteroid use, hospitalization, and colectomy within 3 years of the index colonoscopy. Results: We found histologic evidence of UC activity (Geboes score ≥ 2B.1) in biopsies from 182 patients (65%) and endoscopic evidence of UC activity in 149 patients (53%) (substantial agreement, κ = 0.60). Histologic features of UC activity were associated with increased rates of systemic corticosteroid use, colectomy, and hospitalization in the entire cohort (P < .05 for all) and associated with increased rates of systemic corticosteroid use in an analysis limited to patients in endoscopic remission (P < .001). In patients in endoscopic remission, only histologic activity was independently associated with use of systemic corticosteroids (multivariate odds ratio, 6.34; 95% CI, 2.20-18.28; P = .001). Similar results were seen when the entire cohort was analyzed. Compared with patients without histologic evidence of UC activity, patients with only a small number of mucosal neutrophils still had higher rates of systemic corticosteroid use (P < .001). Conclusions: Histologic evidence of UC activity, including small numbers of neutrophils in the colonic mucosa, is the only factor independently associated with use of systemic corticosteroids. Complete resolution of neutrophil-associated inflammation should be a target for treatment of UC.

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Tu1987 A Longitudinal Study of FDG-PET in Crohn’s Disease Patients Receiving Granulocyte/Monocyte Apheresis Therapy

Yoshioka, Shinichiro; Mitsuyama, Keiichi; Kuwaki, Kotaro; Yamauchi, Ryosuke; Yamasaki, Hiroshi; Fukunaga, Shuhei; Takedatsu, Hidetoshi; Tsuruta, Osamu; Torimura, Takuji (2016). Tu1987 A Longitudinal Study of FDG-PET in Crohn’s Disease Patients Receiving Granulocyte/Monocyte Apheresis Therapy. Gastroenterology, 2016 150(4), S998–. doi:10.1016/s0016-5085(16)33380-7 

Background: Endoscopy is the gold standard for the diagnosis and follow-up of patients with Crohn’s disease (CD). However, a less invasive approach is now being sought for the management of these patients. The objective of this study was to examine whether 18Ffluorodeoxyglucose (FDG)-positron emission tomography (PET) might be relevant for monitoring the disease activity in CD patients undergoing granulocyte/monocyte apheresis (GMA). Methods: This study was conducted in 12 patients with CD, who were receiving treatment with 10, once a week GMA sessions with the Adacolumn. The response to treatment was monitored by measuring the standard laboratory variables, the Crohn’s disease activity index (CDAI) score, the international organization for the study of inflammatory bowel diseases (IOIBD) score, and the regional and global bowel uptakes on FDG-PET. Results: In 6 of the 12 patients, significant improvement of the CDAI was observed after the final session of GMA. The patients who showed clinical response to GMA had a decrease in the regional and global bowel uptakes on FDG-PET, whereas those who did not respond showed no change. In the patients who responded to the GMA, the decrease in regional bowel uptake on FDG-PET in each disease area of the same patient varied in parallel. There was a significant correlation between decrease in the global bowel uptake on FDG-PET and improvement of
the CDAI and IOIBD scores. Conclusion: The longitudinal changes in FDG-PET uptakes are of potential clinical interest for assessing the regional and global bowel disease activity in CD patients undergoing GMA therapy.

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R. SaccoV. D’Ovidio, +18 authors G. Bresci Abstracts of the 20th National Congress of Digestive Diseases / Digestive and Liver Disease 46S (2014) S1–S144

Background and aim: Granulocyte-monocyte-apheresis (GMA) is effective in the treatment of ulcerative colitis (UC). However, all published studies evaluated a low number of patients, with an overall limited follow-up. This observational study investigates the long-term efficacy of GMA in a large number of patients included in the Italian Registry of Therapeutic Apheresis. Material and methods: Data of patients with mild/moderate UC treated with a standard protocol of GMA (5 sessions in 5 weeks) were evaluated. All patients had failed to respond to mesalamine or sulphasalazine, and were under steroid treatment. Clinical evaluations were performed at 3, 12 and 24 months since the end of GMA session. The following parameters were assessed: incidence of clinical remission (CAI [Colits Active Index] <4); CAI; erythrocyte sedimentation rate (ESR); c-reactive protein (CRP); white cells blood count (WBC). Endoscopical evaluations were performed at a 3- month follow-up: the incidence of endoscopical remission (EAI [endoscopical activity index] 0/1) was assessed. Results: Data for 347 patients (214 males, age 46.3 years; CAI 7.47) were available; 288 patients were either steroid-resistant or steroid-dependent. The proportion of patients with remission of disease was 66% at 3 months, 77% at 12 months and 78% at 24 months. At 24 months, all other efficacy parameters had improved from baseline: CAI (7.47 vs 3.47), ESR (35.87 vs 24.1 mm/h), CRP (4.31 vs 2.75 mg/dl) and WBC (8.61 vs 7.19) (p<0.001 for all comparisons). Endoscopic data were available for 107 patients. The incidence of mucosal healing was 47% and all patients with mucosal healing presented a clinical remission over the entire follow-up period. No major adverse events were reported during GMA sessions. Conclusions: Data collected on a large sample of steroid-resistant or steroidrefractory patients included in the Italian Registry of Therapeutic Apheresis show that GMA is a safe and effective procedure over a long-term follow-up. Mucosal healing appears strongly associated with clinical remission.’Ovidio/b4286829a8f80e152dc3974444e1c307c1d4e9ef#citing-papers

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Leukocytapheresis in pediatric patients with ulcerative colitis

Takeshi Tomomasa 1Hitoshi TajiriSeiichi KagimotoToshiaki ShimizuAtsushi YodenKosuke UshijimaKeiichi UchidaHiroaki KanekoDaiki AbukawaMutsuko KonnoShun-ichi MaisawaTakao KohsakaAkio KobayashiJapanese 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.

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Long-term follow-up with Granulocyte and Monocyte Apheresis re-treatment in patients with chronically active inflammatory bowel disease.

Annelie Lindberg 1Michael EberhardsonMats KarlssonPer Karlén, BMC Gastroenterol. 2010 Jul 6;10:73.

Background: Patients with IBD and chronic inflammation refractory to conventional therapy often demonstrate higher risk of serious complications. Combinations of immunosuppression and biological treatment as well as surgical intervention are often used in this patient group. Hence, there is need for additional treatment options. In this observational study, focused on re-treatment and long-term results, Granulocyte/Monocyte Adsorption (GMA, Adacolumn) treatment has been investigated to study efficacy, safety and quality of life in IBD-patients with chronic activity.

Methods: 15 patients with ulcerative colitis and 25 patients with Crohn’s disease, both groups with chronically active inflammation refractory to conventional medication were included in this observational study. The patients received 5-10 GMA sessions, and the clinical activity was assessed at baseline, after each completed course, and at week 10 and 20 by disease activity index, endoscopy and quality of life evaluation. Relapsed patients were re-treated by GMA in this follow-up study up to 58 months.

Results: Clinical response was seen in 85% and complete remission in 65% of the patients. 10 patients in the UC-group (66%) and 16 patients in the CD-group (64%) maintained clinical and endoscopic remission for an average of 14 months.14 patients who relapsed after showing initial remission were re-treated with GMA and 13 (93%) went into a second remission. Following further relapses, all of 7 patients were successfully re-treated for the third time, all of3 patients for the fourth time and 1 for a fifth time.

Conclusions: IBD-patients with chronic inflammation despite conventional therapy seem to benefit from GMA. Re-treatment of relapsing remission patients seems to be effective.

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The expression profile of functional regulatory T cells, CD4+CD25high+/forkhead box protein P3+, in patients with ulcerative colitis during active and quiescent disease

K Kamikozuru 1K FukunagaS HirotaN HidaY OhdaK YoshidaY YokoyamaK TozawaK KawaM IimuroK NagaseA R SaniabadiS NakamuraH MiwaT Matsumoto Clin Exp Immunol 2009 May;156(2):320-7. doi: 10.1111/j.1365-2249.2009.03904.x. Epub 2009 Mar 9.

Regulatory T cells (T(reg)) have an essential role in maintaining immune tolerance in the gut. The functional CD4(+) T(reg) express the transcription factor forkhead box protein 3 (FoxP3) or a CD25(high) in humans. Further, depletion of elevated granulocytes/monocytes by extracorporeal adsorption (GMA) induces immunomodulation in patients with ulcerative colitis (UC). We investigated the impact of GMA on T(reg). Thirty-one UC patients, clinical activity index (CAI) 12.1 +/- 2.97, refractory to conventional medications including intravenous corticosteroid and 13 healthy controls (HC), were included. Patients received five GMA sessions over 5 weeks. Biopsies from the rectal mucosa and blood samples at baseline and post-GMA were immunostained with anti-CD4/FoxP3 and anti-CD4/CD25 antibodies for immunohistochemistry and flow cytometry. Following GMA, 22 of 31 patients achieved remission (CAI <or= 4, P < 0.01) and their endoscopic activity index decreased from 10.6 +/- 2.32 to 4.75 +/- 1.48 (P = 0.003). The circulating CD4(+)CD25(high+) T(reg) level was low and increased markedly in responders (P < 0.02). In the nine non-responders, the baseline CD4(+)CD25(high+) T(reg) level was about 50% of the level in the responders (P < 0.03) or in the HC (P < 0.01), and all nine had to undergo colectomy. Conversely, the number of CD4(+)/FoxP3(+) mucosal T(reg) in GMA responders decreased significantly after the fifth GMA session compared with the baseline level (P < 0.05). It is believed that the CD4(+) T(reg) has an essential role in the control of immune pathology in UC patients and a net influx of these cells from the circulation into the mucosa may proceed to suppress inflammation. GMA can impact the circulating as well as the mucosal levels of T(reg).

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Leukocytapheresis for the treatment of active pouchitis: a pilot study

Yasumi Araki 1Keiichi MitsuyamaTakaaki NagaeYuji TouMotonori NakagawaYasue IwataniMasakazu HaradaHiroyuki OzasaMichio SataToshihiro 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.

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In patients with ulcerative colitis, adsorptive depletion of granulocytes and monocytes impacts mucosal level of neutrophils and clinically is most effective in steroid naïve patients

T Tanaka 1H OkanobuS YoshimiE MurakamiA KogameH ImagawaY NumataY KugaT MoriyaT OhyaG Kajiyama

Dig Liver Dis. 2008 Sep;40(9):731-6. doi: 10.1016/j.dld.2008.02.012. Epub 2008 Apr 2.

Background: The aetiology of ulcerative colitis is inadequately understood, and drug therapy has been empirical rather than based on sound understanding of disease aetiology. This has been a major factor for refractoriness and adverse drug effects as additional complications. However, ulcerative colitis by its very nature is exacerbated and perpetuated by inflammatory cytokines, which are released by peripheral granulocytes and monocytes as well. Additionally, active ulcerative colitis is often associated with elevated peripheral granulocytes and monocytes with activation behaviour and are found in vast numbers within the colonic mucosa. Hence, from the clinicopathologic viewpoint, granulocytes and monocytes are appropriate targets for therapy in ulcerative colitis. Based on this thinking, an Adacolumn has been developed for depleting excess granulocytes and monocytes by adsorption. Methods: By colonoscopy, biopsy and histology, we investigated the impact of granulocyte and monocyte adsorption (GMA) on the mucosal level of granulocytes and monocytes in patients with active ulcerative colitis. Forty-five patients (26 steroid naïve and 19 steroid-dependent), mean age 44.7 yr, were included. Twenty patients had total colitis and 25 had left-sided colitis. Each patient was given up to 11 GMA sessions over 12 weeks. No patient received additional medications within 4 weeks (steroid) to 8 weeks (other immunosuppressants) prior to entry or during the GMA course. Colonoscopy together with biopsy was done at entry and within 2 weeks after the last GMA session. Results: At entry, the mean clinical activity index was 12.6; range 10-16. A total of 400 colonic biopsies were examined, which revealed massive infiltration of the colonic mucosa by granulocytes, and GMA was associated with striking reduction of granulocytes in the mucosa. At week 12, 33 of 45 patients (73.3%, P<0.01) had achieved clinical remission (the mean clinical activity index <or= 4). Colonoscopy revealed that most non-responders had deep colonic ulcers and extensive loss of the mucosal tissue. The response rate in steroid naïve subgroup was 22 of 26 patients (84.6%, P<0.005) and in steroid-dependent was 11 of 19 (57.9%, P<0.05 and P=0.02154 for steroid naïve vs. steroid-dependent). Patients who achieved remission could continue with their salicylates. On average, remission was sustained for 7.8 months in all 33 responders. Conclusions: This is the first report showing a striking difference in clinical response to GMA between steroid naïve and steroid-dependent patients. Further, patients with deep colonic ulcers together with extensive loss of the mucosal tissue are not like to respond to GMA.

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Evaluation of 5 versus 10 granulocyteaphaeresis sessions in steroid-dependent ulcerative colitis: A pilot, prospective, multicenter, randomized study

Elena RicartMaria EsteveMontserrat AndreuFrancesc CasellasDavid MonfortMiquel SansNatalia OudovenkoRaúl Lafuente, and Julián Panés World J Gastroenterol. 2007 Apr 21; 13(15): 2193–2197.Published online 2007 Apr 21. doi: 10.3748/wjg.v13.i15.2193

AIM: To evaluate the efficacy of 5 compared to 10 granulocyteaphaeresis sessions in patients with active steroid-dependent ulcerative colitis. METHODS: In this pilot, prospective, multicenter randomized trial, 20 patients with moderately active steroid-dependent ulcerative colitis were randomized to 5 or 10 granulocyteaphaeresis sessions. The primary objective was clinical remission at wk 17. Secondary measures included endoscopic remission and steroid consumption. RESULTS: Nine patients were randomized to 5 granulocyteaphaeresis sessions (group 1) and 11 patients to 10 granulocyteaphaeresis sessions (group 2). At wk 17, 37.5% of patients in group 1 and 45.45% of patients in group 2 were in clinical remission. Clinical remission was accompanied by endoscopic remission in all cases. Eighty-six percent of patients achieving remission were steroid-free at wk 17. Daily steroid requirements were significantly lower in group 2. Eighty-nine per cent of patients remained in remission during a one year follow-up. One serious adverse event, not related to the study therapy, was reported. CONCLUSION: Granulocyteaphaeresis is safe and effective for the treatment of steroid-dependent ulcerative colitis. In this population, increasing the number of aphaeresis sessions is not associated with higher remission rates, but affords a significant steroid-sparing effect.

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