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GMA in Inflammatory Bowel Disease (IBD)

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.

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 adsorb circulating immunocomplexes and IgGs in addition to activating certain complement fragments (specifically C3a and C5a); this allows the system to selectively adsorb 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.

What is it Leukocytapheresis / Granulocyte And Monocyte Apheresis treatment?

Apheresis is an extracorporeal blood purification procedure. GMA apheresis is intended for treating patients with autoimmune disorders or chronic inflammatory disease. It enables the selective adsorption of granulocytes and monocytes/macrophages from the peripheral blood.

Leukocytapheresis is an important procedure that can help alleviate symptoms and improve the quality of life in people with IBD and other autoimmune diseases. It is therefore considered a useful treatment for chronic autoimmune disorders, avoiding or reducing the use of drug therapies that, in some cases, can lead to serious side effects. What’s more, its use in combination with other IBD treatment may open the door to more effective & safer IBD therapies.

If leukocytapheresis is recommended, ask the healthcare provider to walk you through the procedure so that you have a better understanding of what to expect.

By asking all of your questions ahead of time, you’ll likely feel less stressed and be more comfortable on the day of the procedure.

Leukocytapheresis can be performed by a blood specialist/ nephrologists/ hematologist or a qualified medical technologist, nurse, or doctor certified in apheresis

Most apheresis machines are mobile and roughly the size of a small/medium size box. A video screen on the unit will monitor your progress. The room where the procedure will be applied will also be equipped with a reclining chair with armrest or a bed and an IV pole. If you are hospitalized, the apheresis machine can be rolled next to your bed.

You will be seated in a reclining chair or you will lay in a bed with a blanket and pillows.The venip

To Take into account before the leukocytapheresis /granulocyte and monocyte apheresis

Before starting GMA treatment, your doctor will ensure that you do not find yourself in a situation that contraindicates its use, at least temporarily, or requires special precautions up1.

For the procedure it is best to wear loose-fitting clothes with short sleeves or sleeves you can easily roll.

Since you will be sitting for a while, you can also bring slippers to make you more comfortable. Sweat pants with stretchy waistbands are also suitable. If you are incontinent or have an overactive bladder, you may want to consider wearing adult diapers since you won’t be able to move once the procedure begins.

Most healthcare providers will recommend that you drink plenty of fluids several days in advance of a leukocytapheresis procedure. Caffeine should be avoided as it promotes urination and can reduce the relative pressure in the veins.

On the day before the procedure, avoid any caffeinated beverages, foods (including dark chocolate), or medications (including pain relievers like Aspirin…). Eat a hearty meal prior to the procedure but not one that is large enough to cause you discomfort.

It is advisable to perform arm exercises (with weight or tensors) some days prior to the GMA session to improve venous circulation.

Avoid unnecessary blood extractions during this period.

You might want to bring something to read or watch while you are sitting (some apheresis rooms offer TV and reading materials to help pass the time).

Plan on having someone drive you home after the procedure as you may feel dizzy or faint. Though the staff will not stop you from driving yourself home, they may insist that you rest until you seem reasonably recovered.

If you have experienced body temperature (fever) before the GMA session, contact your doctor. It would be better to delay it until resolution.

The leukocytapheresis /granulocyte and monocyte apheresis procedure

Once you’ve been cleared for the procedure—and your blood pressure, temperature, pulse, and respiration rate have all checked OK—you will be taken to the apheresis room.

The nurse or technologist will recommend that you go to the bathroom beforehand. Once the procedure starts, you will not be able to go to the bathroom since you will be connected to the machine.

If you are undergoing a continuous procedure, an IV line will be placed in each arm (usually the antecubital vein near the crook of the arm). Intermittent procedures require only one arm.13

Once an IV line is placed in the antecubital vein, you will not be able to bend the arm until the needle is removed. If that’s a problem, let the staff member know. A larger vein in the forearm may be used 2.

The procedure itself is relatively straightforward and is similar to what you would have experienced if you ever donated blood.

  1. You will be seated in a reclining chair or you will lay in a bed with a blanket and pillows.
  2. The venipuncture site(s) will be cleaned with a sterile swab. If a catheter is used, the line will be flushed with normal saline.
  3. To reduce discomfort, a local anesthetic may be offered prior to the insertion of the needle, which can numb the area in around one minute.
  4. An IV line is inserted into the vein(s) with a needle. People with catheters are connected to the machine via attachment to the lumens.
  5. To ensure that blood doesn’t clot and clog the lines during the procedure, an anticoagulant (blood thinner) like heparin or sodium citrate is injected into IV or catheter line.
  6. The machine is then turned on. As the blood is extracted and delivered to a collection chamber, it is spun low speeds (30 ml/minute) to adsorb the leukocyte cells from the rest of the blood, which is re-infused into the patient through one of the contralateral antecubital veins.
  7. After a minimum of 60 min procedure (on average 90 min.), enough blood will have been processed, the machine will be turned off and the IV/catheter lines disconnected after returning to your body the remaining blood in the catheter.
  8. The IV needle and catheters will then be removed and discarded3.

You should not feel anything during the procedure. If you experience numbness or a tingling sensation, let the nurse know.

1.-  If a central catheter was placed, wear a loose button-down shirt to provide easy access to the shoulder area.

2.- If you were provided a central catheter, the line will be attached to the machine via two exterior tubes, which alternately deliver and return blood to the body.

3.-The central catheter would be cleaned and secured to the chest with an adhesive dressing.

Post-Procedure

Following the completion of leukocytapheresis, you will be asked to relax awhile to ensure that you are neither dizzy, faint, or nauseous. Once you are cleared by the nurse, you can leave.

For safety sake, have someone drive you home.

It is not uncommon to feel tired after leukocytapheresis.

To get back on your feet faster, limit your activities for the 12 to 24 hours.

Your arm may also feel sore after being kept in place for the duration of the procedure. If so, you can take an over-the-counter pain reliever like acetaminophen which is less likely to promote bruising than nonsteroidal anti-inflammatory drugs like aspirin or ibuprofen.

Be sure to keep well hydrated by drinking at least eight 8-ounce glasses of water or non-caffeinated beverages. If you feel dizzy or lightheaded, lie down and elevate your feet until the feeling passes.

Avoid activities with a high risk of traumatism for 12 to 24 h after the GMA session.

Call your healthcare provider immediately if you experience persistent or worsening pain at the injection site as well as increased swelling, redness, fever, chills, or discharge.

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 approved in Japan and in Europe Union from 1999 and in China from 2011.

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

Adacolumn® is 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).
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