Granulocyte/monocyte Adsorptive Apheresis Research Articles

Induction of mucosal healing by intensive granulocyte/monocyte adsorptive apheresis (GMA) without use of corticosteroids in patients with ulcerative colitis: long-term remission maintenance after induction by GMA and efficacy of GMA re-treatment upon relapse.

This study examined the long-term maintenance rate after inducing remission by intensive granulocyte/monocyte adsorptive apheresis (GMA) without use of corticosteroids (CS) and GMA re-treatment efficacy in the same patients upon relapse with ulcerative colitis. Patients who achieved clinical remission and mucosal healing (MH) by first-time intensive GMA (first GMA) without CS were enrolled. The cumulative non-relapse survival rate up to week 156 was calculated. Patients with relapse during the maintenance period underwent second-time intensive GMA (second GMA) without CS. Clinical remission and MH rates following second GMA were compared to those following first GMA in the same patients. Of the 84 patients enrolled, 78 were followed until week 156 and 34 demonstrated relapse. The cumulative non-relapse survival rate by week 156 was 56.4%. Clinical remission and MH rates after second GMA did not differ from those after first GMA in the same patients (week 6: clinical remission, 100% vs 88.4%, p = 0.134; MH, 100% vs 84.8%, p = 0.074). In conclusion, MH induction by intensive GMA without use of CS in ulcerative colitis patients contributes to subsequent long-term clinical remission maintenance. GMA re-treatment efficacy was comparable to that of first GMA in the same patients who had relapse.

Granulocyte and monocyte adsorptive apheresis induces apoptosis of neutrophils and release of a novel chemoattractant for desensitization of interleukin-8 response – In vitro and in vivo results

ObjectiveApoptotic 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. MethodsTo 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. ResultsL-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. ConclusionsGMA may regulate the immune system in patients with an immune-mediated disorder by inducing a biological response of neutrophils with a PICD-like reaction.

Granulocyte/monocyte adsorptive apheresis for the treatment of therapy-refractory chronic active ulcerative colitis

Objectives: Current options for patients with steroid-dependent, chronic-active ulcerative colitis (UC) with insufficient response/intolerance to immunosuppressants (ISs) and/or biologics are limited. The aim of this study was to assess the long-term outcome of granulocyte/monocyte adsorptive (GMA) apheresis (Adacolumn®) in this population.Materials and methods: Ninety five adults with steroid-dependent active UC and insufficient response/intolerance to IS and/or TNF inhibitors received 5–8 aphereses in a single induction series of ≤10 weeks. Endpoints included rates of remission (clinical activity index [CAI] ≤ 4) at weeks 24 and 48.Results: Of 94 patients (ITT population), remission and response rates were 34.0% and 44.7% at week 24, and 33.0% and 39.4% at week 48. Among 30 patients with prior failure of IS and biologics, 33.3% and 20.0% were in remission at weeks 24 and 48. At both weeks, 19.2% of patients achieved steroid-free remission. Sustained remission or response occurred in 27.7% of patients at 48 weeks. The cumulative colectomy rate at week 96 was 23.4%. Safety was consistent with previous findings.Conclusions: This study confirms findings of the 12-week interim analysis and demonstrates that GMA apheresis provides a safe and beneficial long-term outcome for patients with chronic active UC resistant/intolerant to IS and/or TNF inhibitors.

P-034 Intensive Granulocyte-monocyte Adsorptive Apheresis Twice a Week for the Treatment of Steroid-naïve Ulcerative Colitis

P-034 Intensive Granulocyte-monocyte Adsorptive Apheresis Twice a Week for the Treatment of Steroid-naïve Ulcerative Colitis

Crohn's disease complicated by hepatitis B virus successfully treated with the use of adsorptive depletion of myeloid lineage leucocytes to suppress inflammatory cytokine profile

Background aimsIn patients with inflammatory bowel disease infected with hepatitis B virus (HBV), immunosuppressive therapy required to suppress active inflammatory bowel disease may promote HBV reactivation. MethodsA 27-year-old corticosteroid-naive woman with Crohn's disease (CD) activity index of 249.8 complicated by HBV infection was offered Entecavir to control HBV reactivation during immunosuppressive therapy for CD. The patient refused Entecavir, fearing that it might adversely affect her pregnancy outcome. Instead, we applied intensive granulocyte/monocyte adsorptive apheresis (GMA) at two sessions per week to deplete inflammatory cytokine-producing leucocytes as an immunosuppressive therapy in this case. ResultsGMA induced stable remission (CD activity index, I 105) and endoscopic improvement without HBV reactivation or safety concern. Furthermore, CD remission was paralleled by suppression of tumor necrosis factor and interleukin as measured in serum samples. ConclusionsImmunosuppressive therapy required to treat an active CD potentially can promote HBV reactivation and worsen liver function. In this study involving a CD case complicated by chronic HBV infection, intensive GMA as a non-pharmacologic treatment intervention was associated with clinical remission and endoscopic improvement without HBV reactivation. Furthermore, GMA was well-tolerated and was without any safety concern. However, suppression of tumor necrosis and interleukin-6by GMA in this clinical setting is potentially very interesting.

P-028 Investigation of the Availability of Granulocyte–monocyte Adsorptive Apheresis for Treating Crohn’s Disease

P-028 Investigation of the Availability of Granulocyte–monocyte Adsorptive Apheresis for Treating Crohn’s Disease

Granulocytapheresis

Inflammatory Bowel Diseases (IBD), whose main clinical syndromes are ulcerative colitis and Crohn's disease, are widespread conditions in Western countries. The etiology of IBD is multifactorial, involving both a genetic predisposition and an immunological dysregulation of the gut that activate the intestinal wall's inflammatory process. The pharmacological therapy available for IBD includes aminosalicylates, corticosteroids, immunosuppressants, cyclosporine, and biological agents; however, not all patients respond adequately to the therapy and most of these medications have a severe long-term toxicity. Since activated granulocytes and monocytes, together with proinflammatory cytokines and deregulated activity of the Regulatory T lymphocytes (Treg), seem to play a central role in the chronic enteric inflammation, granulocyte/monocyte adsorptive apheresis (GMA), an extracorporeal technique that removes activated leucocytes from the blood, may represent a safe and effective therapeutic tool. According to several multicentric studies on the therapeutic efficacy of GMA, this procedure is a safe and well-tolerated option for patients resistant to pharmacological therapy, or may be an adjunctive treatment to conventional therapeutic schemes, able to induce prolonged periods of clinical remission and a significant reduction of corticosteroids' intake. Further studies are required to better define the frequency of the treatment and the volume of blood to process, as well as the pharmacological therapy that is better associated with GMA and the possibility to treat other autoimmune diseases with this therapeutic tool.

The efficacy of intensive granulocyte and monocyte adsorption apheresis in a patient with Crohn's disease complicated by extensive subcutaneous aseptic neutrophilic abscesses

Background and aimsSubcutaneous aseptic abscess is one phenotype of neutrophilic dermatitis. We were interested to see if a case of steroid refractory Crohn's disease (CD) complicated by subcutaneous aseptic neutrophilic abscesses responds to intensive granulocyte/monocyte adsorptive apheresis (GMA). MethodsThe patient was a 21-year-old male with worsening severe CD while on oral prednisolone (30mg/day). His symptoms included fever, bloody diarrhoea and multiple painful subcutaneous nodules throughout his body. Skin biopsy showed chronic panniculitis with neutrophilic infiltrates. Further, colonoscopy showed oedematous sigmoid colon, while colonic biopsy showed non-caseous granuloma. Because biologics were feared to increase the risk of bacteraemia as the result of germ culture on his pus was not known at the time, we decided to treat this case with GMA. Five GMA sessions with the Adacolumn over 5 consecutive days (daily GMA) were initiated. ResultsOn admission, his CD activity index (CDAI) was 355, C-reactive protein (CRP) 11.2mg/dL. After 5 GMA sessions, CDAI decreased to 170, and CRP fell to 5.0mg/dL, with no fever. GMA was restarted at 2 sessions/week (total 10 sessions). The patient's CDAI fell to <150, and the skin lesions re-epithelialized. ConclusionsIn this CD case complicated by subcutaneous aseptic neutrophilic abscesses, GMA appeared to be effective. Our impression is that when biopsy reveals neutrophil infiltrate is a major feature of the lesions, GMA should be considered. As GMA appears to have no safety concerns, a frequent GMA protocol, like daily followed by 2 to 3 times/week should be preferred over the routine weekly GMA.

Combination Therapy with Adalimumab Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis Induced Clinical Remission in a Crohn's Disease Patient with the Loss of Response to Scheduled Adalimumab Maintenance Therapy: A Case Report

A 21-year-old Caucasian man with a diagnosis of Crohn's disease (CD) at the age of 14 was admitted to our hospital due to CD flare-up while under scheduled adalimumab (ADA) maintenance therapy. His symptoms remained virtually unchanged following high dose corticosteroid therapy. Seven days later, combination therapy with ADA plus intensive granulocyte/monocyte adsorptive apheresis (GMA) was initiated, which induced clinical remission. Therefore, combination therapy with ADA plus intensive GMA appears to be an effective therapeutic option for patients with severe CD while under scheduled ADA maintenance therapy.

Granulocyte and monocyte adsorptive apheresis in the management of ulcerative colitis

SIRS, We read with interest the systematic review: granulocyte ⁄monocyte adsorptive apheresis for ulcerative colitis by Thanaraj et al. It would appear that a majority of patients included in the reviewed studies were on corticosteroids. The authors found that compared with medical therapy, remission rates with granulocyte ⁄monocyte adsorptive apheresis (GMAA) were higher, and the treatment had significant corticosteroid-sparing effect. However, several uncontrolled studies 3 reported that GMAA was effective for steroid-naive patients or patients with the first episode of ulcerative colitis (UC). Recently, we completed a prospective trial aimed at identifying factors affecting clinical and endoscopic efficacies of GMAA in patients with active UC. The dose of corticosteroids at entry and the cumulative dose of corticosteroids administered before entry were independent significant factors for both clinical and endoscopic remission, negatively impacting the efficacy of GMAA. Such findings suggest that GMAA might have the effect of first-line therapy for steroid-naive patients or patients with the first UC episode. Up to now, the most common medication for UC has been corticosteroids. Most patients experience adverse side effects while on high-dose and long-term corticosteroids, adding to the disease complications and poor quality of life. In contrast, GMAA is favoured by patients for its safety, and patients with active UC can successfully be treated with GMAA without adding corticosteroids. In addition to the reported efficacy outcomes, I feel that the safety profile of GMAA is an attractive feature of this non-drug-based therapeutic intervention because adverse effects often compromise patients’ compliance with the treatment. Another factor, which must be considered when selecting a treatment option, is the treatment cost. When compared with corticosteroids, GMAA is expensive; one treatment session costs approximately €800. With this in mind, if GMAA can spare patients from corticosteroids, hospitalisation and surgery, it should be costeffective.

Systematic review: granulocyte/monocyte adsorptive apheresis for ulcerative colitis

Patients with ulcerative colitis (UC) that is chronically active despite 5-aminosalicylates or immunomodulators, or who are dependent on corticosteroids to maintain remission, have limited treatment options. Granulocyte/monocyte adsorptive apheresis (GMAA) may have a role in this situation. To conduct a systematic review of GMAA in UC. MEDLINE, EMBASE and the Cochrane central register of controlled trials were searched to identify randomized controlled trials (RCTs) comparing GMAA with conventional medical therapy, sham procedure or 'intensive' with 'conventional' GMAA regimens in adult UC patients. Studies reported clinical remission or response rates. Ten RCTs were eligible. Formal meta-analysis was not undertaken due to concerns about methodological quality of identified studies. Compared with medical therapy, remission rates with GMAA were generally higher, and corticosteroid-sparing effects were observed. Compared with sham procedure, GMAA did not achieve significantly higher remission rates. 'Intensive' GMAA regimens demonstrated generally higher remission rates, and time to remission was shorter compared with 'conventional' regimens. Only two RCTs were at low risk of bias. Six were conducted in Japanese patients, which may limit generalizability. Granulocyte/monocyte adsorptive apheresis appears of some benefit in UC. High-quality RCTs comparing granulocyte/monocyte adsorptive apheresis with conventional medical therapy or sham procedure in Western populations, with disease activity confirmed endoscopically, are required.

Release of Interleukin‐1 Receptor Antagonist by Combining a Leukocyte Adsorption Carrier With Ulinastatin

Both granulocyte/monocyte adsorptive apheresis (GMA) and ulinastatin, a serine protease inhibitor, are reported to be effective in patients with ulcerative colitis; however, combination therapy with GMA and ulinastatin has not been attempted. Investigating the effect of ulinastatin on GMA is required for combination therapy since the inhibition of serine protease suppresses the reaction of GMA. To clarify the effects of ulinastatin on GMA, we investigated whether granulocyte adsorption to cellulose acetate beads (carriers for GMA) and interleukin-1 receptor antagonist (IL-1ra) release were inhibited by ulinastatin. Peripheral blood containing ulinastatin, a different serine protease inhibitor (gabexate mesilate), or signal-transduction inhibitors was incubated with cellulose acetate beads in vitro, and the ratios of adsorbed granulocytes and IL-1ra release were measured. Granulocyte adsorption and IL-1ra release were significantly suppressed with increasing gabexate mesilate concentrations; however, the adsorption was not significantly inhibited by ulinastatin. Furthermore, IL-1ra release was augmented by the addition of a high dose of ulinastatin or PD98059 as compared to a low dose. The activation levels of extracellular signal-regulated protein kinase may regulate IL-1ra release induced by the carrier, because both ulinastatin and PD98059 inhibit extracellular signal-regulated protein kinase. High concentrations of ulinastatin increased IL-1ra release without inhibiting granulocyte adsorption to cellulose acetate beads. This result warrants clinical trials of a combination of ulinastatin and GMA for the treatment of ulcerative colitis.

Is the Benefit of Granulocyte Monocyte Adsorptive Apheresis in Ulcerative Colitis Overstated?

Is the Benefit of Granulocyte Monocyte Adsorptive Apheresis in Ulcerative Colitis Overstated?

Granulocyte-monocyte adsorptive apheresis in pediatric inflammatory bowel disease: Results, practical issues, safety, and future perspectives

The purpose of the study was to collect data on granulocyte-monocyte adsorptive apheresis (GMA) for the treatment of corticosteroid-dependent (SD) or corticosteroid-resistant (SR) inflammatory bowel disease (IBD) in children from 3 Nordic countries to evaluate its efficacy and safety and to assess practical issues. Retrospective data on 37 children treated with GMA were collected. In all, 22 children had ulcerative colitis (UC), 13 Crohn's disease (CD), and 2 had indeterminate colitis (IC). Their mean age was 13.2 years, range 5-17 years, and mean duration of disease was 2.4 years, range 1 month to 6 years. Indication for treatment in the UC group was SD in 11 cases, SR in 6 cases, and other reasons in 5 cases. The corresponding numbers in the CD group were SD in 8 cases, SR in 2 cases, and other reasons in 3 cases. In the IC group, 1 had SD and 1 was refractory to steroids, azathioprine, and infliximab. Efficacy was evaluated by severity indices: the Pediatric Ulcerative Colitis Activity Index (PUCAI) and the Pediatric Crohn's Disease Activity Index (PCDAI) and tapering of corticosteroids. PUCAI and PCDAI decreased significantly in both groups after 3 months (P = 0.0007, P = 0.025). The dosage of corticosteroid was significantly reduced in the UC group by the end of GMA (P = 0.004) and this response continued after 3 months. Relapse was seen in 2 patients with UC and 3 patients with CD after 3 months follow-up. GMA seems to be an effective and safe treatment in 81% of the SD or SR pediatric IBD patients, especially in those with UC.