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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.

https://pubmed.ncbi.nlm.nih.gov/31843598/

https://www.cghjournal.org/article/S1542-3565(19)31438-7/fulltext

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PICaSSO Histologic Remission Index (PHRI) in ulcerative colitis: development of a novel simplified histological score for monitoring mucosal healing and predicting clinical outcomes and its applicability in an artificial intelligence system

Xianyong Gui # 1Alina Bazarova # 2 3Rocìo Del Amor # 4Michael Vieth  et al. Gut  2022 Feb 16;gutjnl-2021-326376. doi: 10.1136/gutjnl-2021-326376. Online ahead of print.

Histological remission is evolving as an important treatment target in UC. We aimed to develop a simple histological index, aligned to endoscopy, correlated with clinical outcomes, and suited to apply to an artificial intelligence (AI) system to evaluate inflammatory activity. Methods: Using a set of 614 biopsies from 307 patients with UC enrolled into a prospective multicentre study, we developed the Paddington International virtual ChromoendoScopy ScOre (PICaSSO) Histologic Remission Index (PHRI). Agreement with multiple other histological indices and validation for inter-reader reproducibility were assessed. Finally, to implement PHRI into a computer-aided diagnosis system, we trained and tested a novel deep learning strategy based on a CNN architecture to detect neutrophils, calculate PHRI and identify active from quiescent UC using a subset of 138 biopsies. Results: PHRI is strongly correlated with endoscopic scores (Mayo Endoscopic Score and UC Endoscopic Index of Severity and PICaSSO) and with clinical outcomes (hospitalisation, colectomy and initiation or changes in medical therapy due to UC flare-up). A PHRI score of 1 could accurately stratify patients’ risk of adverse outcomes (hospitalisation, colectomy and treatment optimisation due to flare-up) within 12 months. Our inter-reader agreement was high (intraclass correlation 0.84). Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity and 86% accuracy. Conclusions: PHRI is a simple histological index in UC, and it exhibits the highest correlation with endoscopic activity and clinical outcomes. A PHRI-based AI system was accurate in predicting histological remission.

https://pubmed.ncbi.nlm.nih.gov/35173041/#:~:text=artificial%20intelligence%20system-,PICaSSO%20Histologic%20Remission%20Index%20(PHRI)%20in%20ulcerative%20colitis%3A%20development,Gut.

https://gut.bmj.com/content/early/2022/02/23/gutjnl-2021-326376.long

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Use of granulocyte/monocytapheresis in ulcerative colitis: A practical review from a European perspective

Eugeni DomènechJoan-Ramon GrífolsAyesha Akbar, and Axel U Dignass World J Gastroenterol. 2021 Mar 14; 27(10): 908–918.

GMA is the only available therapy for UC directly targeting neutrophils. Two controlled, multicentre, European studies and a number of recent cases series found a potential therapeutic benefit of GMA in different clinical scenarios of UC with a still unmet need for optimal treatment. Moreover, GMA has an excellent safety profile and is perceived as a convenient procedure by patients, making this non-pharmacological therapy a suitable alternative or add-on therapy in UC, particularly for frail or comorbid patients.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968132/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968132/pdf/WJG-27-908.pdf

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SA6-03 MicroRNA and granulocyte and monocyte adsorption apheresis on neutrophilic skin diseases

Yuko Higashi, Munekazu Yamakuchi, Takuro Kanekura

poster at ISFA 2019 pag 126

Neutrophilic skin diseases are a group of disorders characterized by intense dermal infiltration of neutrophils without infection. They include a variety of diseases, such as pyoderma gangrenosum, pustular psoriasis, and palmoplantar pustulosis. We demonstrated that granulocyte and monocyte adsorption apheresis (GMA) is a useful treatment modality for such refractory skin diseases. Microarray analysis of microRNAs (miRNAs) was performed using sera of patients with neutrophilic skin diseases before and after GMA. Several miRNAs significantly increased in patients compared to control subjects. The expression of three
miRNAs decreased after apheresis, suggesting that these miRNAs might be involved in the pathogenesis of neutrophilic skin decreases. To prove the function of these miRNAs, HL-60, a human acute promyelocytic leukemia cell line, was differentiated by the treatment of alltrans retinoic acid (ATRA). When HL-60 was differentiated to neutrophilic cells, the HEstaining shows an increased cytoplasm to nucleus ratio, condensated chromatin, and nuclear segmentation. The expression of three miRNAs increased during the neutrophilic differentiation. Stimulation of ATRA-treated HL-60 by some cytokines altered miRNA expressions. Moreover, manipulation of these miRNAs changed proliferation of cultured keratinocytes. These data
suggest that miRNAs play an important role in regulating neutrophilic differentiation and proliferation of keratinocytes in case of neutrophilic disorders such as psoriasis. These miRNAs could be markers of disease severity and response of GMA.

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

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Adacolumn leucocytapheresis for ulcerative colitis: clinical and endoscopic features of responders and unresponders.

Rodolfo Sacco 1Tomotaka TanakaTakayuki YamamotoGiampaolo BresciAbbi R Saniabadi, Expert Rev Gastroenterol Hepatol. 2015 Mar;9(3):327-33.

The authors’ view is that in patients with UC, there is an evolving scope for therapeutic opportunity based on taking away the sources of inflammatory cytokines, also considering the favorable safety profile of GMA.

https://pubmed.ncbi.nlm.nih.gov/25160857/

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Sa1316 Granulocyte and Monocyte Adsorptive Apheresis (GMA) Might Be Useful for Patients With Ulcerative Colitis by Inhibition of S100A12-S100a12 Correlates With Acute and Chronic Inflammation by Induction of CCL and CXCL Chemokines

Shingo Kato, Kazuhito Kani, Hidehiko Takabayashi, Ryuichi Yamamoto, Koji Yakabi Gastroenterology 2011 140(5) Suppl. S-279–S-280

Backgrounds&Aims; Granulocyte and monocyte adsorptive apheresis (GMA) adsorbs mainly granulocyte and monocytes, as well as Leukocyteapheresis (LMA) filters many cells such as granulocyte, monocytes, lymphocytes and platelets. However, there was no significant difference in clinical effectiveness between GMA and LMA (Eur J Gastroenterol Hepatol 2008;20:629). We hypothesized effectiveness of GMA and LMA might be dependent on depletion of granulocyte and monocytes. S100A12 was reported to be exclusively expressed in neutrophils and up-regulated by TNF α. The aim of this study was to investigate the changes of serum S100 A12 concentration in the GMA treatments and whether S100A12 increases the expression of adhesion molecules, CXCL and CCL chemokines. Methods; 24 patients with ulcerative colitis were treated with GMA. Serum S100A12 was estimated by ELISAmethods.Clinicalactivityindex(CAI)andserumCRPconcentrationwerealsochecked. Immunohistochemical staining of S100A12 and receptor for advanced glication end products (RAGE) were performed in the operated specimens of patients with ulcerative colitis and with colonic carcinoma (control). HUVEC were seeded into 12 well plates and confluent plates were used to experiments. Each experiment was performed in triplicate. HUVEC were treated with human recombinant S100A12 protein. RNA was extracted by RNeasy Mini Kit. 1.5μg RNA was reverse-transcriptated into cDNA. ICAM-1, VCAM-1, IL-8, CCL-2 (MCP1), CCL5 (RANTES), CXCL9 (IP-10) and CXCL10 (Mig) mRNA was quantitated by realtime PCR. Results; S100A12 staining was faintly recognized in the mucosal layer of normal control. S100A12 staining was increased in infiltrating cells in inflamed colon in patients with ulcerative colitis. Strong staining was also recognized in crypt abscess. RAGE staining was also faintly recognized in the epithelial cells in nornmal control. However, RAGE staining was increased in the inflamed epithelial cells. Significantly serum S100A12 concentration was positively correlated with CAI (n=34, p=0.02, rs=0.404). 16 patients were able to estimate S100A12 concentration in the points of pre-and post-GMA treatment. 13 patients wereGMA-respondersand3patientswere nonGMA-responders.SerumS100A12concentration was significantly decreased in GMA responders (pre-vs post-GMA, 1.34±1.08 vs 0.60±0.50, p<0.05). However, Serum S100A12 concentration of non GMA-responders was gradually increased with GMA treatments. ICAM-1, VCAM-1, IL-8, IP-10, Mig, MCP-1 and RANTES mRNA expressions were increased by S100A12 in HUVEC cell lines in time and dose-dependent manners. Conclusion; one of the mechanisms of GMA effect might be correlated with depletion of S100A12 by adsorption of activated neutrophils. S100A12 might aggravate acute and chronic inflammation by up-regulation of adhesion molecules, CXCL and CCL chemokines.

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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.

https://pubmed.ncbi.nlm.nih.gov/18387860/

https://www.dldjournalonline.com/article/S1590-8658(08)00070-4/fulltext

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In vivo modulation of leukocyte trafficking receptor following therapeutic purging of myeloid cells: implications for treatment of HIV infection and other immune disorders

Priscilla Biswas Barbara Mantelli Alberto Beretta Clinical Immunology 109 (2003) 355–358 DOI: 10.1016/j.clim.2003.07.001 

Therapeutic purging of myeloid cells (monocytes and granulocytes) (MYP) has been proposed as a treatment of severe inflammatoryconditions like ulcerative colitis and rheumatoid arthritis. Although direct purging of inflammatory cells contributes to its efficacy, the precise mechanism of action is still unclear. We have tested MYP in a pilot study on 12 patients with chronic HIV infection, of whom 6 underwent MYP. Three/6 MYP patients and none of the controls displayed a strong and long-lasting decrease of cells expressing CXCR3,a major chemokine receptor responsible for trafficking of inflammatory cells. In these three patients, the number of circulating CD4 T cells increased during treatment. The data provide a rational for the use of MYP as a therapeutic tool acting via the modulation of immune cell trafficking

https://europepmc.org/article/med/14697751

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