JIMRO Co., Ltd.

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.

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.

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.

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.

The available information on granulocyte and monocyte adsorptive apheresis (GMA) in patients with inflammatory bowel disease (IBD) under special situations remains unclear. We conducted a retrospective, multicentre cohort study to evaluate the safety and effectiveness of GMA in patients with IBD under special situations.

This study included patients with ulcerative colitis (UC) or Crohn’s disease who had at least one special situation feature and who had received GMA between November 2013 and March 2017. The incidence of adverse events (AEs) was compared in relation to the special situation, and patient background factors related to an AE were identified. For patients with UC, clinical remission was defined as a partial Mayo score of ≤2.

A total of 437 patients were included in this study. The incidence of AEs among the elderly patients (11.2%) was similar in all patients (11.4%), whereas the incidences of AEs in patients on multiple immunosuppressant medications (15.2%), patients with anaemia (18.1%) and paediatric/adolescent patients (18.9%) were higher than that in all patients (11.4%). In multivariate analysis, anaemia and concomitant immunosuppressant medications were independently associated with the incidence of AEs. Clinical remission was achieved in 46.4% of the patients with UC.

The incidence of AEs in the elderly patients was not higher than that in all patients, whereas the incidence of AE was higher in patients with anaemia and those on multiple immunosuppressant medications than that in all patients. GMA is a safe treatment option in elderly patients with IBD.

Chronic diseases like rheumatoid arthritis (RA) and inflammatory bowel diseases (IBD), which include ulcerative colitis (UC) and Crohn's disease (CD), are debilitating life-long morbid conditions caused by a dysregulated immune profile in the affected individuals.These conditions afflict millions of individuals throughout the world with symptoms that impair performance and quality of life.Considering IBD per se, the chronic nature of the immune disorders means that patients may require life-long medications often at high doses, but the currently available pharmacol. preparations are aimed at reducing the symptoms or suppressing exacerbations, without a lasting effect on the underlying cause.Further, long-term drug therapy often leads to drug dependency and loss of response together with adverse side effects.Indeed, drug side effects become an addnl. morbidity factor in many patients on long-term medications.However, the efficacy of anti-tumor necrosis factor (TNF)-α biologics has validated the role of inflammatory cytokines, notably TNF-α in the exacerbation of IBD.Given that inflammatory cytokines are released by patients' own cellular elements including myeloid lineage leukocytes, which in patients with active IBD are elevated with activation behavior and prolonged survival, selective depletion of these leukocytes should promote disease remission or at least enhance drug efficacy with the possibility of reducing drug dosage.Based on this thinking, hemoperfusion to selectively deplete excess and activated myeloid leukocytes with the Adacolumn has been applied to treat patients with dysregulated immune profile.Basically, the Adacolumn medical device is filled with specially designed cellulose acetate beads of 2mm diameter bathed in sterile saline, which serve as the column leucocytapheresis carriers.During hemoperfusion, the carriers selectively adsorb from the blood in the column FcγR (fragment crystallizable gamma receptor) and complement receptor expressing leukocytes.Hemoperfusion with the Adacolumn is popularly known as adsorptive granulocyte and monocyte apheresis (GMA).Pre-and post-column blood cell counts have shown that the carriers selectively adsorb about 65% of granulocytes and 55% of monocytes together with a significant fraction of platelets, while lymphocytes are spared; less than 2% adsorb, and red cell count is unaffected.GMA has been applied to treat patients with IBD in Japan and in the European Union countries.Efficacy outcomes have been impressive as well as disappointing.In fact the clin. response to GMA seems to define the patients' disease course and severity of the mucosal damage at entry.The best responders have been first episode cases (up to 100%) followed by steroid naïve and patients with a short duration of active IBD.Patients with deep ulcers and extensive loss of mucosal tissue do not respond well.Likewise, patients with a long duration of IBD and exposure to multiple pharmacologicals including corticosteroids are not likely to benefit from GMA if they have badly damaged mucosal tissue.It is clin. relevant to stress that patients who respond well to GMA have a good long-term disease course by avoiding drugs including corticosteroids at an early stage of their IBD.Addnl., GMA is very much favored by patients for its good safety profile, as well as for being a non-pharmacol. treatment strategy.GMA reminds us of phlebotomy as a major medical practice at the time of Hippocrates, but in patients with IBD, there is a scope for removing from the body the sources of pro-inflammatory cytokines, potentially to achieve disease remission, and this should fulfill a desire to treat without drugs.The bottom line is that by introducing GMA at an early stage following the onset of IBD or before patients develop extensive mucosal damage and become refractory to medications, many patients should respond well to GMA and be spared from pharmacologicals.