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Therapeutic Granulomonocytapheresis as a Non-pharmacologic Treatment Option for Inflammatory Bowel Disease: Efficacy Reports on a Wide Age Range and Disease Profile

Tomotaka Tanaka

Cureus 2023 Nov 16;15(11):e48913. doi: 10.7759/cureus.48913. eCollection 2023 Nov.

The major phenotypes of inflammatory bowel disease (IBD) include ulcerative colitis (UC) and Crohn’s disease (CD), which cause debilitating symptoms, including bloody diarrhea, abdominal discomfort, and fever. Patients require life-long immunosuppressive medications, which cause adverse side effects as additional morbidity factors. However, IBD is initiated and perpetuated by inflammatory cytokines, and given that in patients with IBD myeloid lineage leukocytes are elevated with activation behavior and release inflammatory cytokines, selective depletion of elevated granulocytes and monocytes by granulomonocytapheresis is a relevant therapeutic option for IBD patients. Therefore, a column filled with specially designed beads as granulomonocytapheresis carriers for selective adsorption of myeloid lineage leukocytes (Adacolumn) has been applied to treat patients with active IBD. Patients receive up to 10 granulomonocytapheresis sessions at one or two sessions per week. During each session, the carriers adsorb up to 60% of the myeloid leukocytes from the blood that passes through the granulomonocytapheresis column. Efficacy rates in the UC setting have been as high as 85% in steroid-naïve patients, and 100% in drug-naïve, first-episode cases, but patients with a long duration of active IBD and extensive colonic lesions that have become refractory to pharmacological treatment have not responded well. However, granulomonocytapheresis has a favorable safety profile. Given that immunosuppressive medications used to treat IBD potentially may increase the risk of severe viral infection, non-drug granulomonocytapheresis should be a favorable treatment strategy. Further, by targeting granulomonocytapheresis to patients with background features and identifying a patient as a likely responder, futile use of medical resources is avoided.

Therapeutic Granulomonocytapheresis as a Non-pharmacologic Treatment Option for Inflammatory Bowel Disease: Efficacy Reports on a Wide Age Range and Disease Profile – PubMed (

Therapeutic Granulomonocytapheresis as a Non-pharmacologic Treatment Option for Inflammatory Bowel Disease: Efficacy Reports on a Wide Age Range and Disease Profile – PMC (

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Sweet Syndrome With Vasculitis: Time To Adopt a New Criteria?

Muhammad Hassan Shakir 1 2, Salman A Basit 1, Syed Muhammad Hussain Zaidi 1, Sarasija Natarajan 1, Omar Z Syed 1, Mohammad Asim Amjad 1, Douglas Klamp, Cureus. 2023 Nov 6;15(11):e48399. doi: 10.7759/cureus.48399. eCollection 2023

Sweet syndrome (SS) is an acute febrile neutrophilic dermatosis. Although perceived to be rare, the disease may well have been underreported due to lack of exposure in low-volume clinical settings and due to the use of rather strict clinical criteria for diagnosis. It presents as cutaneous papules, plaques, or nodules in an asymmetric distribution that follows fever and flu-like symptoms. Data on the disease is ever-expanding. Several associations have been identified, including drugs, infections, malignancies, and autoimmune diseases. Different disease patterns and histological variants have been identified. Pathophysiology is complex and multifactorial but appears to involve mechanisms that negatively influence neutrophil apoptosis and facilitate neutrophil recruitment. The existing diagnostic criteria exclude cases with vasculitis; over time, cases of neutrophilic dermatoses with vasculitis have been reported as SS as long as other criteria were met. Newer diagnostic models have been proposed, some arguing against the exclusion of vasculitis. Steroids continue to be the mainstay of treatment, and steroid responsiveness continues to be a part of the diagnostic criteria, although newer treatment modalities have been used and have shown promise. No established guidelines exist for management. We present a case of Idiopathic SS with vasculitis along with a brief review of the existing literature. We agree to the inclusion of vasculitis as proposed by the newer diagnostic criteria.

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Treatment Strategies in Neutrophilic Dermatoses: A Comprehensive Review

Grisell Starita-Fajardo 1, David Lucena-López 1, María Asunción Ballester-Martínez 2, Montserrat Fernández-Guarino 2, Andrés González-García Int J Mol Sci. 2023 Oct 26;24(21):15622. doi: 10.3390/ijms242115622

Neutrophilic dermatoses (NDs) are a group of noninfectious disorders characterized by the presence of a sterile neutrophilic infiltrate without vasculitis histopathology. Their physiopathology is not fully understood. The association between neutrophilic dermatoses and autoinflammatory diseases has led some authors to propose that both are part of the same spectrum of diseases. The classification of NDs depends on clinical and histopathological features. This review focuses on the recent developments of treatments in these pathologies.

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Intracellular DNA sensing by neutrophils and amplification of the innate immune response

Arun K. Mankan, Paulina Czajka-Francuz, Maria Prendes, Sriram Ramanan, Marcin Koziej, Laura Vidal, Kamal S. Saini Front. Immunol., 2023, 14,

As the first responders, neutrophils lead the innate immune response to infectious pathogens and inflammation inducing agents. The well-established pathogen neutralizing strategies employed by neutrophils are phagocytosis, the action of microbicide granules, the production of ROS, and the secretion of neutrophil extracellular traps (NETs). Only recently, the ability of neutrophils to sense and respond to pathogen-associated molecular patterns is being appreciated. This review brings together the current information about the intracellular recognition of DNA by neutrophils and proposes models of signal amplification in immune response. Finally, the clinical relevance of DNA sensing by neutrophils in infectious and non-infectious diseases including malignancy are also discussed.

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Targeting neutrophils in inflammatory bowel disease: revisiting the role of adsorptive granulocyte and monocyte apheresis

Giorgos Bamias 1Evanthia Zampeli 2Eugeni Domènech 3 Expert Rev Gastroenterol Hepatol  2022 Jul 19;1-15. doi: 10.1080/17474124.2022.2100759.

Introduction: Inflammatory bowel disease (IBD) is a chronic immune-mediated disease of the gastrointestinal tract comprising Crohn’s disease (CD) and ulcerative colitis (UC). While any part of the digestive tract can be affected in CD, mucosal inflammation in UC is limited to the colon. Differences and similarities between the two conditions are reflected by their pathophysiology. Areas covered: An overview of immunological aspects, pharmacological management, and biomarkers of IBD is provided. The role of adsorptive granulocyte and monocyte apheresis (GMA) is reviewed including its primary and secondary effects on the immune system, as well as clinical studies in IBD (mainly UC), and potential biomarkers for adsorptive GMA. Expert opinion: In UC, adsorptive GMA with Adacolumn (Adacolumn®, JIMRO Co., Ltd. Takasaki, Gunma, Japan) selectively depletes elevated myeloid lineage leukocytes and has a range of beneficial secondary immune effects. Adsorptive GMA is a safe and effective non-pharmacological treatment option for UC. Pilot studies have reported promising results for adsorptive GMA in combination with biological agents, although larger studies are required. Fecal calprotectin concentrations, neutrophil counts in histological samples and/or the neutrophil/lymphocyte ratio in peripheral blood may prove to be useful biomarkers for predicting GMA effectiveness in the future.

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Inflammatory Bowel Disease and Neutrophil–Lymphocyte Ratio: A Systematic Scoping Review

Blake O. Langley 1,Sara E. Guedry 1,Joshua Z. Goldenberg 1,Douglas A. Hanes 1,Jennifer A. Beardsley 2 andJennifer Joan Ryan 1,

The findings of this systematic scoping review highlight the potential utility of NLR as an adjunctive IBD biomarker with broad applications, including differentiation from non-IBD controls, clinical and endoscopic disease activity differentiation, prediction of loss of response to treatment, and prediction of risk of complications. NLR has promise for guiding therapeutic decision making, specifically for predicting loss of response to IFX. In conclusion, NLR is an emerging IBD biomarker with potential utility at nearly every point in IBD management. As a potential IBD biomarker, NLR is particularly advantageous given that it is minimally invasive, economical, and accessible as it is easily calculated from blood count data routinely and serially monitored in patients with IBD. Additional research is justified to better understand if routine observation of NLR in research and clinical practice could beneficially impact the care of patients with IBD.

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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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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.,PICaSSO%20Histologic%20Remission%20Index%20(PHRI)%20in%20ulcerative%20colitis%3A%20development,Gut.

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Granulocyte and monocyte adsorptive apheresis induces apoptosis of neutrophils and release of a novel chemoattractant for desensitization of interleukin-8 response

Nobuhito Kashiwagi Fumio Saito Hidetaka Maegawa Kenta Kaneda, Cytokine 2021 Mar;139:155410.

Objective: Apoptotic cells participate in maintenance of homeostasis of the adaptive immune system. Granulocyte/monocyte adsorptive apheresis (GMA) performed with an Adacolumn has been shown to have clinical efficacy together with immunomodulatory effects for immune-mediated disorder cases, such as inflammatory bowel disease (IBD) or psoriatic arthritis. Although induction of apoptosis in neutrophils by GMA has been observed, the detailed mechanism remains unclear. Methods: To focus on phagocytosis-induced cell death (PICD) that induces apoptotic neutrophils, a comparative study utilizing a GMA-carrier (leukocyte adsorbing carrier for Adacolumn) and yeast particles was performed with in vitro and in vivo examinations. Results: L-selectin was significantly (P = 0.0133) shed, reactive oxygen species (ROS) production was promoted (P = 0.0019), and apoptosis induction was enhanced (P = 0.0087) by peripheral blood co-cultured with the GMA-carrier or yeast particles as compared to incubated blood alone. Furthermore, degranulation of myeloperoxidase, elastase, and lactoferrin was increased by both treatments, while the highest level of interleukin-1 receptor antagonist release was found with GMA-carrier treatment (P = 0.0087) as compared to the yeast particles. Plasma from blood treated with the GMA-carrier showed chemotactic activity, and suppressed neutrophil migration to IL-8 and LTB4. In vivo results demonstrated that neutrophil chemotaxis to IL-8 was desensitized (P = 0.0078) in rabbits following GMA apheresis, while CXCR1 and CXCR2 expressions in neutrophils were reduced by exposing peripheral blood to the GMA-carrier. Conclusions: GMA may regulate the immune system in patients with an immune-mediated disorder by inducing a biological response of neutrophils with a PICD-like reaction.

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Chie Kurihara, Toshihide Ohmori, Kenichi Inaba, Shunsuke Komoto, Kengo Tomita, Ryota Hokari Gastroenterology 2020 158 (6) Suppl.S-1046

Background: Granulocyte and monocyte adsorptive apheresis (GMA) is non-pharmacological therapy which selective depletion of activated granulocytes and monocytes/macrophages from peripheral blood, and it is used as induction therapy for IBD. However, its therapeutic mechanism has not been well characterized. Recently, it has been reported that Th17 releases chemokines which attract neutrophils, and some neutrophils produce IL17. We investigated that changes in mRNA expression levels of inflammation associated molecules such as cytokines, chemokines in colonic mucosa of ulcerative colitis (UC) patients before and after GMA treatment in order to obtain further understanding of GMA therapeutic mechanisms. Methods: Thirty-two active UC patients (Mayo score ≥ 5 and Mayo endoscopic score ≥ 2) and 10 non-IBD control subjects were enrolled in this study. All UC patients received 10 times of GMA, and colonoscopies were applied before the first GMA and after the last GMA. Control subjects underwent colonoscopies for screening of colon cancer. Assessment of GMA therapeutic efficacy was determined based on Mayo score. Inflammation-related molecules mRNA expressions were determined by quantitative RT-PCR using biopsy specimen of colonic mucosa. Results: GMA treatment efficacy is 11 patients (34.4%) achieved clinical remission, 17 patients (53.1%) were response and 4 patients (12.5%) were non-response. Baseline characteristics such as sex, location of disease, CRP, WBC and Mayo score were not significantly different according to GMA efficacy. In the remission group, mRNA levels in mucosal tissue of IL1β, IL6, IL17, IL23 and GM-CSF which are Th17-asociated cytokines significantly decreased after the last GMA compared to the baseline levels(P<0,05) in contrast, expression of these mRNA tended to increase following GMA treatment in the non-response group. On the other hand, IL12 and IFN- γ which are associated with Th1 did not significantly decrease in the remission group. mRNA levels of leukocyte trafficking associated molecules such as MAdCAM-1, ICAM-1, integrinβ7, IL8 and MIP-1β significantly decreased following GMA treatment in the remission group(P <0.05), whereas only IL8 mRNA expression in the non-response group tended to increase. IL1 β, IL6, GM-CSF which are Th17-asociated cytokines and IL8 mRNA expressions in post-GMA treatment were significantly higher in the non-response group compared to the remission group or control group(P <0.05). Conclusion: In UC patients who achieved clinical remission by GMA, Th17- associated cytokines and leukocyte trafficking associated molecules but not Th1-asociated cytokines decreased significantly. Furthermore, Th17-asociated cytokines increased in the non-responders. These results reaffirm the involvement of neutrophil in the pathophysiology of UC and could be helpful for characterizing of GMA therapeutic mechanism.

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