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Treatment of Inflammatory Bowel Disease: A Comprehensive Review

Zhaobei Cai 1 2Shu Wang 3Jiannan Li 1 Front Med (Lausanne)  2021 Dec 20;8:765474. doi: 10.3389/fmed.2021.765474. eCollection 2021.

Inflammatory bowel disease (IBD), as a global disease, has attracted much research interest. Constant research has led to a better understanding of the disease condition and further promoted its management. We here reviewed the conventional and the novel drugs and therapies, as well as the potential ones, which have shown promise in preclinical studies and are likely to be effective future therapies. The conventional treatments aim at controlling symptoms through pharmacotherapy, including aminosalicylates, corticosteroids, immunomodulators, and biologics, with other general measures and/or surgical resection if necessary. However, a considerable fraction of patients do not respond to available treatments or lose response, which calls for new therapeutic strategies. Diverse therapeutic options are emerging, involving small molecules, apheresis therapy, improved intestinal microecology, cell therapy, and exosome therapy. In addition, patient education partly upgrades the efficacy of IBD treatment. Recent advances in the management of IBD have led to a paradigm shift in the treatment goals, from targeting symptom-free daily life to shooting for mucosal healing. In this review, the latest progress in IBD treatment is summarized to understand the advantages, pitfalls, and research prospects of different drugs and therapies and to provide a basis for the clinical decision and further research of IBD.

https://pubmed.ncbi.nlm.nih.gov/34988090/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8720971/

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Apheresis in Inflammatory Bowel Disease: Current Evidence

Daniel Vasile Balaban and Mariana Jinga Crohn’s Disease Recent Advances book, October 15th, 2020 DOI: 10.5772/intechopen.93605

Inflammatory bowel diseases (IBD) have become a major focus for gastroenterologists worldwide, with the increasing incidence and complexity of cases, which pose therapeutic challenges. Currently available approaches fail in controlling the disease activity in a significant proportion of patients and some of the therapies are associated with significant adverse events. Although new molecules are on the horizon and treatment strategies have been optimized, novel therapeutic tools are much needed in IBD for patients who fail to attain control of the disease. Apheresis is now a common non-pharmacological therapeutic modality used in several pathologies, IBD also. In the current review, we summarize currently available evidence with respect to selective apheresis in IBD.

https://www.intechopen.com/chapters/73330

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Adsorptive granulocyte and monocyte apheresis: A potentially relevant therapeutic option for COVID-19

Takuro Kanekura 1Koichi Kawahara 2 , Int J Infect Dis 2020 Oct;99:1-2. 

To our knowledge, GMA has a good safety profile; serious adverse effects are rarely reported. Its modes of action together with the findings of this case report support our notion that GMA is a relevant therapeutic option for patients with COVID-19 and warrants an immediate clinical trial to evaluate its full therapeutic efficacy in a large cohort of COVID-19 patients.

https://pubmed.ncbi.nlm.nih.gov/32721534/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834290/pdf/main.pdf

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Recommendations for Therapeutic Apheresis by the Section “Preparative and Therapeutic Hemapheresis” of the German Society for Transfusion Medicine and Immunohematology

Nina Worel 1Behrouz Mansouri Taleghani 2Erwin Strasser 3 Transfus Med Hemother 2019 Dec;46(6):394-406. doi: 10.1159/000503937. Epub 2019 Nov 6.

The section “Preparative and Therapeutic Hemapheresis” of the German Society for Transfusion Medicine and Immunohematology (DGTI) has reviewed the actual literature and updated techniques and indications for evidence-based use of therapeutic apheresis in human disease. The recommendations are mostly in line with the “Guidelines on the Use of Therapeutic Apheresis in Clinical Practice” published by the Writing Committee of the American Society for Apheresis (ASFA) and have been conducted by experts from the DACH (Germany, Austria, Switzerland) region.

https://pubmed.ncbi.nlm.nih.gov/31933569/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944925/

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Granulocitoaféresis en 2017. Puesta al día (Spanish)

Cabriada, J.L.Rodríguez-Lago, I.

Enfermedad Inflamatoria Intestinal 20017 (16) 2, 62-69 DOI: 10.1016/j.eii.2016.12.001 

Granulocyte apheresis is a procedure that allows the removal of different activated leukocyte populations and it also modifies some circulating inflammatory mediators. These effects, along with its immunomodulatory potential, make it an attractive therapeutic option in inflammatory bowel disease. Previous studies with this technique have had significant limitations, but recent data is emerging about the ideal clinical setting in which granulocyte apheresis should be indicated. Most of the evidence supports its use in conditions that are dependent or refractory to corticosteroids, especially when treatments with immunomodulators or biologics has failed and when it is necessary to reduce or avoid the use of systemic corticosteroids. Its excellent safety profile gives it a role in cases of comorbidity or risk in the use of immunosuppressive drugs or in paediatric patients. In this review, we provide an update on the role of granulocyte apheresis in inflammatory bowel disease.

https://www.elsevier.es/es-revista-enfermedad-inflamatoria-intestinal-al-dia-220-articulo-granulocitoaferesis-2017-puesta-al-dia-S1696780116300999

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Therapeutic Granulocyte and Monocyte Apheresis (GMA) for Treatment Refractory Sarcoidosis: A Pilot Study of Clinical Effects and Possible Mechanisms of Action.

H H Olsen 1V MuratovK CederlundJ LundahlA EklundJ 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/

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Granulocyte and monocyte adsorption apheresis as an effective treatment for Reiter disease

J L Cabriada 1E DomènechN IbargoyenV HernándezJ ClofentD GinardI Gutiérrez-IbarluzeaJ Hinojosa, J clin. Exp.dermatology 2012 (37),3, 241-244 doi.org/10.1111/j.1365-2230.2011.04181.x

Reiter disease (RD) is characterized by a triad of sterile arthritis, urethritis and conjunctivitis. The conditions occur concomitantly or sequentially, and are associated with mucocutaneous features such as circinate balanitis and stomatitis. Arthritis usually occurs in attacks followed by recovery, but it sometimes progresses to permanent damage of the affected joints. Because the symptoms of this disorder are attributable to activated neutrophils, we assessed the efficacy of granulocyte and monocyte adsorption apheresis (GCAP) in a 73-year-old man with RD who had skin rashes on his penis, scrotum and right hand, with severe arthralgia. The patient’s skin rash and joint pain responded dramatically to five sessions of GCAP delivered at intervals of 5 days. We present a detailed description of the patient and discuss the mechanisms of GCAP, and suggest that GCAP may be useful for treating RD.

https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2230.2011.04181.x

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Current and emerging drugs for the treatment of inflammatory bowel disease

John K TriantafillidisEmmanuel Merikas, and Filippos Georgopoulos Drug Des Devel Ther. 2011; 5: 185–210. doi: 10.2147/DDDT.S11290

During the last decade a large number of biological agents against tumor necrosis factor-α (TNF-α), as well as many biochemical substances and molecules specifically for the medical treatment of patients with inflammatory bowel disease (IBD), have been developed. This enormous progress was a consequence of the significant advances in biotechnology along with the increased knowledge of the underlying pathophysiological mechanisms involved in the pathogenesis of IBD. However, conventional therapies remain the cornerstone of treatment for most patients. During recent years conventional and biologic IBD therapies have been optimized. Newer mesalazine formulations with a reduced pill size and only one dose per day demonstrate similar efficacy to older formulations. New corticosteroids retain the efficacy of older corticosteroids while exhibiting a higher safety profile. The role of antibiotics and probiotics has been further clarified. Significant progress in understanding thiopurine metabolism has improved the effective dose along with adjunctive therapies. Quite a large number of substances and therapies, including biologic agents other than TNF-α inhibitors, unfractionated or low-molecular-weight heparin, omega-3 polyunsaturated fatty acids, microbes and microbial products, leukocytapheresis, and other substances under investigation, could offer important benefits to our patients. In this paper we review the established and emerging therapeutic strategies in patients with Crohn’s disease and ulcerative colitis.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084301/

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Biological Effect of Anaphylatoxin C5a on the Generation of Anti-inflammatory Substances in Leukocyte Adsorption

Shoichi Nishise,Yuji Takeda,Yuko Nishise,Shoichiro Fujishima,Tomohiko Orii,Sayaka Otake,Takeshi Sato,Yu Sasaki,Hiroaki Takeda,Sumio Kawata

Biological Effect of Anaphylatoxin C5a on the Generation of Anti-inflammatory Substances in Leukocyte Adsorption. Therap. Apher. Dial. 2009 13(6), 509–514. doi:10.1111/j.1744-9987.2009.00779.x 

Anaphylatoxins, which are involved in both pro-inflammatory processes and a variety of anti-inflammatory effects, are produced during granulocyte and monocyte adsorptive apheresis. We noticed the anti-inflammatory effects of C5a, the strongest anaphylatoxin, in granulocyte and monocyte adsorptive apheresis. The aim of this study was to investigate the effect of C5a on interleukin-1 receptor antagonist (IL-1ra) and hepatocyte growth factor (HGF) generation in granulocyte and monocyte adsorption. Peripheral blood containing nafamostat mesilate as an endogenous complement activation inhibitor was divided into four groups: (1) no recombinant C5a added, no contact with cellulose acetate (CA) beads (control group); (2) no C5a added, contact with CA beads; (3) C5a added, no contact with CA beads; and (4) C5a added, contact with CA beads. After incubation, IL-1ra and HGF in plasma were measured. IL-1ra was significantly higher in group 3, in which only C5a was added in the absence of CA beads, compared to groups 2 (P < 0.01) and 4 (P < 0.05). HGF was significantly higher only in group 4, in which C5a was added in the presence of CA beads (P < 0.05), but did not increase in the absence of CA beads. C5a can directly induce IL-1ra generation without the granulocyte and monocyte adsorption stimuli to CA beads, but can synergistically induce HGF generation with the adsorption stimuli, indicating C5a has different effects on IL-1ra and HGF generation.

https://onlinelibrary.wiley.com/doi/10.1111/j.1744-9987.2009.00779.x

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Granulocyte and Monocyte Adsorption Apheresis Therapy Modulates Monocyte-Derived Dendritic Cell Function in Patients With Ulcerative Colitis

Yuko Iwakami,Atsushi Sakuraba,Toshiro Sato,Yasuhiro Takada,Motoko Izumiya,Hitoshi Ichikawa,Toshifumi Hibi Ther Apher Dial 13, 2 (2009); 138-146

The aim of this study was to elucidate the molecular mechanisms responsible for the therapeutic effects of granulocyte and monocyte adsorption apheresis (GMA). We investigated the alterations in circulating monocyte subsets and monocyte-derived dendritic cell (moDC) function after GMA therapy in ulcerative colitis (UC) patients. Eighteen patients with UC were enrolled: 14 patients were responders, and 4 patients were non-responders. Peripheral venous blood was obtained within 5 min before and 5 min after GMA therapy. Flow cytometric analysis for monocyte markers (CD14/CD16) was then performed. Monocyte-derived dendritic cells were obtained and alterations in their phenotype were analyzed by flow cytometry. Their function was also analyzed in a mixed lymphocyte reaction assay between allo-naïve T lymphocytes. Flow cytometric analysis for intracellular interferon (IFN)-γ (T-helper 1 cells) and interleukin (IL)-4 (T-helper 2 cells) was then performed for the stimulated T lymphocytes. In patients who responded to GMA, the average numbers of monocytes, especially CD16+ monocytes, were significantly decreased after therapy (P < 0.05). In responders, post-GMA moDCs expressed significantly lower CD80 and B7-DC, which are one of the stimulation and maturation markers of dendritic cells, compared to pre-GMA moDCs. CD83, CD86 and human leukocytcde antigen-DR also showed a tendency to decrease. In responders, naïve T lymphocytes stimulated with post-GMA moDCs produced significantly less IFN-γ and IL-4 compared to those stimulated with pre-GMA moDCs. The results of our study show that some of the immunosuppressive effects of GMA therapy may be associated with the modulation of monocyte subsets and moDC function.

https://pubmed.ncbi.nlm.nih.gov/19379153/

https://onlinelibrary.wiley.com/doi/10.1111/j.1744-9987.2009.00668.x

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