Adacolumn®

Granulocyte-monocyte apheresis (GMA) acts specifically by preventing the migration of activated granulocytes (neutrophils) and monocytes to the gastrointestinal wall

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Scientific corner

GMA Apheresis time

The rationale for the use of granulocyte-monocyte apheresis (GMA) in the treatment of IBD

In any immune-mediated disease there is an initial and essential step for inflammation to occur in any of the affected organs: the recruitment of inflammatory cells from the bloodstream into inflamed tissues.

Once there, these inflammatory cells secrete a variety of substances whose function will be, on the one hand, to recruit more inflammatory cells and, on the other, to cause tissue damage typical of each disease.

Initially, the treatment used in immune-mediated diseases was based on the administration of non-selective corticosteroids and immunosuppressants, whose mechanism of action affected multiple levels and had a high rate of side effects.

In the last two decades, the treatment of these diseases has evolved towards the use of much more selective therapies and, therefore, more predictable therapeutic as well as collateral effects.

Role of granulocytes and monocytes in IBD

In the case of Immflamatory Bowel Disease (IBD), although other cells such as lymphocytes and monocytes have a certain role, the main inflammatory cells involved in the pathogenic mechanism are neutrophils, white blood cells, also called granulocytes.

Neutrophils are actively recruited from the bloodstream into the mucous layer of the intestine, causing the typical lesions of this disease through their degranulation and the release of various proteinases and chemokines.

In fact, the neutrophil’s significance in this disease is such that several studies have shown a strong correlation between the presence of neutrophils in the gastrointestinal wall of patients with IBD and the risk of clinical relapse (disease “flare-up”) or colon cancer.

Another fact that demonstrates the relevance of neutrophil presence in the intestinal linen of patients with IBD is the utility of faecal calprotectin measurement regarding the prediction of relapses or the diagnosis of disease activity even in the absence of symptoms. Faecal calprotectin is the main protein in the cytoplasm of neutrophils and is detectable in stools, as long as the intestinal tract mucosa is infiltrated by neutrophils. The physicochemical characteristics of this protein and its resistance to degradation by bacteria of the colon have allowed its use in clinical practice, making it the most used and reliable parameter for the management and evaluation of patients with IBD, specially with UC.

MoA Granulocyte Monocyte Adsorption Apheresis

Granulocyte-monocyte apheresis (GMA): Adacolumn®

Granulocyte-monocyte apheresis (GMA) acts specifically by preventing the migration of granulocytes (neutrophils) and activated monocytes to the gastrointestinal wall (1). Adacolumn® cellulose acetate beads have been shown to absorb circulating immunocomplexes and IgGs in addition to activating certain complement fragments (specifically C3a and C5a); this allows the system to selectively absorb granulocytes (via Fc receptors) and monocytes (via complement receptors). In addition to this “mechanical effect”, it has been found that cellulose beads can activate neutrophil apoptosis (which is reduced in UC).

Various studies have shown that cellulose beads and the presence of neutrophil apoptotic bodies also increase the synthesis of anti- inflammatory cytokines (IL-10, IL-1ra, HGF) and achieve the reduction of pro-inflammatory cytokines (TNF-α, IL-6, IL-8, IL-1β) (2). Due to the mobilization of white blood cells from the bone marrow, this “withdrawal” of activated neutrophils and monocytes from the bloodstream does not follow a reduction in the total number of these cells in the blood, because they are replaced by immature or inactive cells.

This would explain why the application of GMA is not accompanied by an increased risk of infections or tumours observed with most immunosuppressive drugs (1).

1.- Hanai H1, Takeda Y, Eberhardson M, Gruber R, Saniabadi AR, Winqvist O, Lofberg R. The mode of actions of the Adacolumn therapeutic leucocytapheresis in patients with inflammatory bowel disease: a concise review, Clin Exp Immunol. 2011 Jan;163(1):50-8.DOI: 10.1111/j.1365-2249.2010.04279.x. 2.- Saniabadi AR1, Hanai H, Takeuchi K, Umemura K, Nakashima M, Adachi T, Shima C, Bjarnason I, Lofberg R. Adacolumn, an adsorptive carrier based granulocyte and monocyte apheresis device for the treatment of inflammatory and refractory diseases associated with leukocytes. Ther Apher Dial. 2003 Feb;7(1):48-59. DOI: 10.1046/j.1526-0968.2003.00012.x

GENERAL OVERVIEW

Mechanism of action of GMA(1)

Activation of complement fragments (C3a, C5a).
Adsorption of circulating IgG and immunocomplexes by cellulose acetate beads.
Granulocyte and monocyte adsorption via (1) Fc receptors (IgC and IC), and (2) biding sites of leukocyte complement receptors (not in lymphocytes).
Reduction of activated neutrophils and monocytes.
ACs interact with regulatory B-cells, producing IL-10 and mature regulatory B-cells.
Return of substances relased by adsorpted cells: IL-1 ra (control intestinal inflammation) and HGF (mucosal epitelial regeneration).
Generation of apoptotic cells (ACs), mostly neutrophils, >40% re-entering the patients’ circulation.

MORE ABOUT ADACOLUMN® MECHANISM OF ACTION

Approved Indications

Adacolumn^® is a medical device approved for:

Inducing of remission in patients with inflammatory bowel disease (active ulcerative colitis and Crohn’s disease).
Suppressing of both subjective and objective symptoms in patients with rheumatoid arthritis in the inflammatory stage whose symptoms might be resistant to standard drug therapy.
Treatment of patients with ocular Behçet disease.
Treatment of patients with systemic lupus erythematosus (SLE).
Improvement of the clinical symptoms in patients with pustular psoriasis (PP).

CE certificate: CE 0123 by TÜV SÜD, risk class IIb.

GMA Safety and Contraindications

GMA is a safe technique. Side effects affect a low percentage of patients (1-15%) and are generally mild and transient. Headache, dizziness, fatigue, muscle pain, facial flushing, hypotension, palpitations, etc. are the most common.

Contraindications are scarce.

This procedure cannot be indicated in patients allergic to heparin (used to prevent blood clotting in the circuit) and when the patient has a low number of platelets in the blood.

In addition, precautions should be taken in patients with low white blood cell count, severe anemia, infection, severe heart or kidney disease, blood clotting problems or dehydration.

In summary,

GMA achieves(1):

• a reduction of activated neutrophils and monocytes in the bloodstream.
• an increase of anti-inflammatory cytokines.
• a decrease of pro-inflammatory cytokines.

This is done without inducing immunosuppression, therefore GMA offers a therapeutic effect without the debilitating side effects usually associated with immunosuppressive drugs.

The Adacolumn® is a Class IIb medical device intended to perfom selective leukocyte apheresis for the therapeutic removal of granulocytes and monocytes/macrophages from peripheral blood.

The Adacolumn® is approved in Japan and in Europe Union from 1999 and in China from 2011.

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