Targeting neutrophils in inflammatory bowel disease: revisiting the role of adsorptive granulocyte and monocyte apheresis
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.
An Update on Current Pharmacotherapeutic Options for the Treatment of Ulcerative Colitis
The main goals of Ulcerative Colitis (UC) treatment are to both induce and maintain the clinical and endoscopic remission of disease, reduce the incidence of complications such as dysplasia and colorectal carcinoma and improve quality of life. Although a curative medical treatment for UC has not yet been found, new therapeutic strategies addressing specific pathogenetic mechanisms of disease are emerging. Notwithstanding these novel therapies, non-biological conventional drugs remain a mainstay of treatment. The aim of this review is to summarize current therapeutic strategies used as treatment for ulcerative colitis and to briefly focus on emerging therapeutic strategies, including novel biologic therapies and small molecules. To date, multiple therapeutic approaches can be adopted in UC and the range of available compounds is constantly increasing. In this era, the realization of well-designed comparative clinical trials, as well as the definition of specific therapeutic models, would be strongly suggested in order to achieve personalized management for UC patients. They also presented other non-Pharmacological Therapies for UC including probiotics, cytapheresis and fecal transplantation.
Treatment of Inflammatory Bowel Disease: A Comprehensive Review
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.
The New Molecules Are Changing the Course of Pediatric Chronically Active Ulcerative Colitis: A Series of Pediatric Cases
Rafael Martín-Masot, MD, *Pilar Ortiz Pérez, MD, *Encarnación Torcuato Rubio, MD,
*Javier Blasco Alonso, PhD, *Marta Herrador López, †Carmen Gallego Fernández, PhD,
and *Víctor Manuel Navas-López, PhD, DOI: 10.1097/PG9.0000000000000100
Chronically active ulcerative colitis (UC) constitutes a challenge in an era where medical therapeutic options have increased while experience with colectomies has decreased. The change in the therapeutic paradigm of the disease means that patients with chronically active UC are being managed waiting to find their therapeutic target. We present 2 cases of children with chronically active UC who did not respond to intravenous steroids nor sequential therapy. A response was obtained with ustekinumab and tofacitinib, 2 drugs widely used in adults but still with little evidence in children. Highlighting the important role of patients and their families helped decision making, facilitating the work of the medical team. With multidisciplinary
management and close follow-up, they have been able to avoid surgery entering complete clinical remission.
Chronic Antibiotic-Refractory Pouchitis: Management Challenges
Pouchitis can be suspected based on clinical symptoms and laboratory findings, but should be confirmed with endoscopy and histology. Clear definitions should be used to classify pouchitis into acute versus chronic, and responsive versus dependent versus refractory to antibiotics. Before treatment is started for chronic antibiotic-refractory pouchitis, secondary causes should be ruled out. Also, scoring the disease, taking into account the quality of life of the patient, should guide you in choosing the best treatment option for your patient.
Managing patients with chronic antibiotic-refractory pouchitis remains a challenge for the treating gastroenterologist or abdominal surgeon. Because chronic antibiotic-refractory pouchitis is mainly immune mediated, therapeutic options are similar to the treatment strategies for inflammatory bowel diseases. Treatments with antibiotics, aminosalicylates, steroids, immunomodulators and biologics has been shown to be effective for chronic antibiotic-refractory pouchitis. Also, treatments with AST-120, hyperbaric oxygen therapy, tacrolimus enemas, and granulocyte and monocyte apheresis suggested some efficacy. The available data are weak but suggest that therapeutic options for chronic antibiotic-refractory pouchitis are similar to the treatment strategies for inflammatory bowel diseases. However, randomized controlled trials are warranted to further identify the best treatment options in this patient population.
S-05-06 Efficacy of Adsorptive Granulocyte/Monocyte Apheresis in Inflammatory Bowel Disease Patients Experiencing Loss of Response to Infliximab (poster)
To our knowledge this is the first report of adding GMA to restore the efficacy of infliximab in patients with LoR. However, the efficacy outcomes following addition of a non-drug GMA to infliximab is potentially very interesting in therapeutic settings and should inspire further studies
Cytapheresis for pyoderma gangrenosum associated with inflammatory bowel disease: A review of current status
Pyoderma gangrenosum (PG) is a neutrophilic dermatosis clinically characterized by the presence of painful skin ulcerations with erythematous. As it is frequently associated with inflammatory bowel diseases, including ulcerative colitis, gastroenterologists should be familiar with the disease including therapeutic options. Pyoderma gangrenosum is one of the neutrophilic dermatoses often complicated with ulcerative colitis. The corticosteroid and other immune modulator have been used for the treatment, however, as its disease mechanism has not been clarified, there is no additional option for those who showed poor response and refractory to the conventional therapies. Therefore, we have conducted a review focusing on the cytapheresis for PG in cases of inflammatory bowel diseases. A literature search was conducted to extract studies published in the last 20 years, with information on demographics, clinical symptoms, treatment, and the clinical course from a total of 22 cases reported and our recent case. In most patients, cytapheresis was associated with improvement or resolution of PG after failure of conventional therapeutic options such as corticosteroids, antibiotics, immunosuppressive agents and immunoglobulin. Based on the recent reports, we have summarized the clinical course of 23 cases and efficacy of cytapheresis..Cytapheresis is helpful in the majority of patients with PG refractory to medical treatment associated with inflammatory bowel diseases and could be further studied in a multicenter, randomized trial.
GS1-04 The apheresis guidelines for digestive diseases
Kazuaki Inoue, Tomoki Furuya, Yoko Yokoyama
The apheresis guidelines for digestive diseases are divided into the following four fields: acute liver failure (ALF); ascites; acute pancreatitis (AP); inflammatory bowel disease (IBD).
IBD: Ulcerative colitis (UC) and Crohn’s disease (CD) are the major forms of I BD. Although their etiology is still not fully understood, activated leukocytes are significant factors in their exacerbations. In Japan, granulocyte and monocyte apheresis (GMA) and leukocytapheresis (LCAP) are approved for IBD treatment. They are recommended for remission induction in UC
patients with mild-to-moderate activity, whether steroid-resistant or -dependent. Although GMA is recommended for remission induction in colonic type CD refractory to conventional therapy, its efficacy is lower than in UC patients.
poster at ISFA 2019 pag 100-101
Su1934-Safety of granulocyte and monocyte adsorptive apheresis in patients with inflammatory bowel disease undergoing concomitant treatment with immunosuppressant medications: a multicenter cohort study
Maki Miyakawa, Hiroki Tanaka, Tomoyoshi Shibuya,Taro Osada, Eiji Hosoi Gastroenterol. 2019 156 (6) Suppl.S-666–S-667
Background: Few studies have assessed the safety of granulocyte and monocyte adsorptive apheresis (GMA) in patients with inflammatory bowel disease (IBD) undergoing concomitant treatment with multiple immunosuppressant medications. To address this research gap, we investigated adverse effects associated with GMA in patients with IBD treated with multiple immunosuppressants who participated in the “Post-marketing surveillance study on the safety and response of GMA treatment in patients with Crohn’s disease or ulcerative colitis with at least one special situation who received Adacolumn® (PARTICULAR).” Methods: The PARTICULAR study was a retrospective, multicenter cohort study of patients with ulcerative colitis (UC) or Crohn’s disease (CD) who received GMA between November 2013 and March 2017. Patients meeting at least one of the following special situation were enrolled: elderly (<=65 years) or pediatric/adolescent (>=18 years) patients, patients with anemia, or patients undergoing concomitant treatment with multiple immunosuppressants. GMA was performed using Adacolumn® (JIMRO, Takasaki, Japan). Each patient received up to 11 GMA sessions, and all adverse events (AEs) during the study period were recorded. The incidence of AEs was investigated relative to the number and type of immunosuppressants using univariate and multivariate logistic regression analyses. Results: A total of 437 patients (368 UC, 69 CD) from 93 institutions were included. Of these, 140, 169, 101, and 27 patients received none, 1, 2, and >=3 immunosuppressants, respectively. In total, 125 patients received multiple immunosuppressants. Concomitant prednisolone, immunomodulators, anti-tumor necrosis factor agents, and calcineurin inhibitors were administered in 189, 151, 89, and 24 patients, respectively. The incidence of AEs was 11% in all 437 patients and 8%, 12%, 12%, and 26% in patients receiving none, 1, 2, and >=3 immunosuppressants, respectively. In multivariate logistic regression analysis, anemia and concomitant immunosuppressants were independently associated with the incidence of AEs. Particularly, a higher number of concomitant immunosuppressants showed an increasing trend with odds ratios related to AEs. In contrast, concomitant corticosteroids were associated with a reduced risk of AEs. Nausea/vomiting and headache were the most common AEs in patients on multiple immunosuppressant medications (5.6% and 3.2%, respectively). Conclusions: Concomitant treatment with immunosuppressants was independently associated with the incidence of AEs such as nausea/vomiting and headache in patients with IBD receiving GMA. As the number of concomitant immunosuppressants increased, the incidence of AEs also increased. However, our data also suggest that GMA is safe in patients with IBD receiving prednisolone.
Evidence-based clinical practice guidelines for inflammatory bowel disease
Katsuyoshi Matsuoka 1, Taku Kobayashi 1, Fumiaki Ueno 2 3, Toshiyuki Matsui 1, Fumihito Hirai 1, Nagamu Inoue 1, Jun Kato 1, Kenji Kobayashi 1, Kiyonori Kobayashi 1, Kazutaka Koganei 1, Reiko Kunisaki 1, Satoshi Motoya 1, Masakazu Nagahori 1, Hiroshi Nakase 1, Fumio Omata 1, Masayuki Saruta 1, Toshiaki Watanabe 1, Toshiaki Tanaka 1, Takanori Kanai 1, Yoshinori Noguchi 1, Ken-Ichi Takahashi 1, Kenji Watanabe 1, Toshifumi Hibi 1, Yasuo Suzuki 1, Mamoru Watanabe 1, Kentaro Sugano 1, Tooru Shimosegawa 1 , J Gastroenterol. 2018 Mar;53(3):305-353.
Inflammatory bowel disease (IBD) is a chronic disorder involving mainly the intestinal tract, but possibly other gastrointestinal and extraintestinal organs. Although etiology is still uncertain, recent knowledge in pathogenesis has accumulated, and novel diagnostic and therapeutic modalities have become available for clinical use. Therefore, the previous guidelines were urged to be updated. In 2016, the Japanese Society of Gastroenterology revised the previous versions of evidence-based clinical practice guidelines for ulcerative colitis (UC) and Crohn’s disease (CD) in Japanese. A total of 59 clinical questions for 9 categories (1. clinical features of IBD; 2. diagnosis; 3. general consideration in treatment; 4. therapeutic interventions for IBD; 5. treatment of UC; 6. treatment of CD; 7. extraintestinal complications; 8. cancer surveillance; 9. IBD in special situation) were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases. The guidelines were developed with the basic concept of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Recommendations were made using Delphi rounds. This English version was produced and edited based on the existing updated guidelines in Japanese.
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