Granulocyte/monocyte Adsorption Research Articles

Comparison of adsorption efficiency of leukocytes in single needle GMA with or without PSL treatment in patients with active ulcerative colitis

Granulocyte monocyte adsorption (GMA) is considered one of the modalities for the remission induction of ulcerative colitis (UC). We previously reported that single-needle GMA (SN-GMA) could simplify the GMA. In the present study, the efficiency of SNGMA was examined according to the administration of corticosteroids (PSL) in UC patients. Blood sample were taken at proximal and distal side of the column during the SN-GMA treatment. Disease activity score (partial Mayo score: pMayo score) before and after the SN-GMA was investigated. The data of 18 patients with active UC (11 and 7 patients with PSL naïve and PSL use groups, respectively) treated with SN-GMA was analyzed. The mean pMayo score before the GMA treatment was comparable between the PSL naïve group (p = 0.26), whereas the score after the GMA treatment was significantly lower in PSL naïve group (0.8 + 0.6) than in PSL use group (3.0 + 2.1) (p = 0.04). Patients achieving the clinical remission were more observed in the PSL naive group (90.9%) than in the PSL use group (42.9%) (p = 0.047). The adsorption efficiency in the PSL naïve and PSL use groups were as follows: leukocytes (34.45 ± 7.43% vs 23.14 ± 7.56%: p = 0.008), granulocytes (41.74 ± 10.07% vs 27.99 ± 15.11%: p = 0.04), monocytes (32.59 ± 24.07% vs 33.16 ± 24.18%: p = 0.95), and lymphocytes (−1.87 ± 18.17% vs −3.79 ± 22.52%: p = 0.84), with a significant difference of the absorption efficiency in leukocytes and granulocytes. These data collectively indicate that the SN-GMA can be applied for the remission induction to active UC patients with a higher clinical remission rate in PSL naïve patients compared to PSL use patients.

Valutazione economica del sistema di aferesi per la rimozione di granulociti e macrofagi (Adacolumn®) rispetto a biologico nel trattamento della colite ulcerosa moderata-severa in pazienti steroido-dipendenti o resistenti in Italia

The treatment of chronic inflammatory bowel disease (IBD) is always a challenge for gastroenterologists dealing with this type of condition. The development of granulocyte-monocyte apheresis (GMA) appears to be an innovative approach, comprising both treatment safety and therapeutic potential. To assess the cost-consequence of granulocyte monocyte adsorption—apheresis (GMA-Apheresis; Adacolumn®) versus infliximab in the treatment of moderate-to-severe ulcerative colitis (UC) in steroid-dependent or steroid-resistant patients. One-year cost-consequence analysis from the Italian National Health Service (NHS) perspective using a decision tree model was carried out. Probabilities of each event were derived from literature and an expert panel. Direct medical costs were obtained from official sources (€2013). The average annual cost per patient who started the treatment with GMA-Apheresis was estimated to be €13,931.33; the cost was estimated to be €15,179.08, starting the treatment with infliximab. The sensitivity analysis confirmed the results of the base case. We performed a cost-consequence analysis focused on the use of GMA-Apheresis (Adacolumn®) in the therapeutic management of moderate-to-severe UC in steroid-dependent or steroid-resistant patients. From the Italian NHS perspective, GMA-Apheresis is a cost-saving strategy compared with infliximab.

Treatment of children and adolescents with ulcerative colitis by adsorptive depletion of myeloid lineage leucocytes as monotherapy or in combination with low dose prednisolone after failure of first-line medications

BackgroundCurrently available drugs for the treatment of ulcerative colitis (UC) include salicylates, thiopurines, corticosteroids and new anti-tumour necrosis factor (TNF)-α biologics. Among these medications, corticosteroids in children and adolescents may adversely affect the patients’ growth and development. Further, UC patients have elevated and activated myeloid lineage leucocytes including the CD14 + CD16+ monocytes, which release TNF-α as a significant exacerbating factor. Accordingly, depletion of these cells by granulocyte/monocyte adsorption (GMA) should alleviate inflammation and promote UC remission. The objective of this study was to evaluate the efficacy of GMA in children and adolescents in whom conventional first-line medications had failed to induce remission.MethodsIn a single centre setting, between 2007 and 2012, a total of 24 consecutive children and adolescents, age 11–19 years were given mesalazine or sulphasalazine as a first-line medication. Seventeen patients relapsed or did not respond to the first-line medications, and received GMA with the Adacolumn, 2 sessions in the first week, and then weekly, up to 11 sessions. Patients who achieved a decrease of ≥5 in the clinical activity index (CAI) were to continue with GMA, while non-responders were to receive 0.5 to 1.0 mg/kg/day prednisolone (PSL) plus additional GMA sessions similar to GMA responder cases. At entry and week 12, patients were clinically and endoscopically evaluated, allowing each patient to serve as her/his own control.ResultsSeven patients achieved remission with the first-line medications and did not receive GMA. Five patients did not respond to the first 5 GMA sessions and received PSL plus GMA, while 12 patients responded to the first 5 GMA sessions and received additional sessions. At entry, the average CAI was 12.7 ± 2.5, range 8–17, and the average endoscopic index was 8.5 ± 1.5, range 7–11. The corresponding values at week 12 were 2.1 ± 0.2, range 1–4 (P < 0.001) and 2.4 ± 0.2, range 1–4 (P < 0.001). PSL was tapered to 0 mg within 3 months.ConclusionsWith the strategy we applied in this study, all 24 consecutive patients achieved remission. In growing patients with active UC refractory to first-line medications, GMA was associated with clinical remission and mucosal healing, while in non-responders to GMA monotherapy, addition of a low dose PSL enhanced the efficacy of GMA and tapering of the PSL dose soon after remission was not associated with UC relapse. Therefore, the majority of young corticosteroid naive UC patients in whom first-line salicylates have failed may respond to GMA and be spared from additional drug therapy. Avoiding corticosteroids at an early stage of UC should ensure better long-term clinical course.

Efficacy, safety and cost analyses in ulcerative colitis patients undergoing granulocyte and monocyte adsorption or receiving prednisolone

BackgroundPatients with ulcerative colitis (UC) are treated with prednisolone (PSL), which causes adverse side effects. Extracorporeal granulocyte/monocyte adsorption (GMA) with an Adacolumn depletes elevated/activated myeloid lineage leucocytes as sources of inflammatory cytokines. We were interested to evaluate the efficacy, safety and the treatment cost for PSL and GMA.MethodsForty-one patients with active UC had achieved remission with GMA, at 1 or 2 sessions/week, up to 10 sessions (n=24) or with orally administered PSL (1mg/kg bodyweight, n=17). Clinical activity index (CAI) ≤4 was considered clinical remission. Following remission, patients received 5-aminosalicylic acid (2250-3000mg/day) or sulphasalazine (4000-6000mg/day) as maintenance therapy and were followed for 600 days. The total treatment cost was assessed based on 1€=150JPY.ResultsPSL was tapered after two weeks, and discontinued when a patient achieved remission. The average time to the disappearance of at least one major UC symptom (haematochezia, diarrhoea, or abdominal discomfort) was 15.3 days in the GMA group and 12.7 days in the PSL group, while time to remission was 27.9 days in the GMA group and 27.6 days in the PSL group, CAI 0.8 and 2.0, respectively. The Kaplan-Meier plots showed similar remission maintenance rates over the 600 days follow-up period. The average medical cost was 12739.4€/patient in the GMA group and 8751.3€ in the PSL group (P<0.05). In the GMA group, 5 transient adverse events were observed vs 10 steroid related adverse events in the PSL group (P<0.001).ConclusionsIn appropriately selected patients, GMA has significant efficacy with no safety concern. The higher cost of GMA vs PSL should be compromised by good safety profile of this non-pharmacological treatment intervention.

Adsorptive Granulocyte/Monocyte Apheresis for the Maintenance of Remission in Patients with Ulcerative Colitis: A Prospective Randomized, Double Blind, Sham-Controlled Clinical Trial

Background/AimsWeekly granulocyte/monocyte adsorption (GMA) to deplete elevated and activated leucocytes should serve as a non-pharmacological intervention to induce remission in patients with ulcerative colitis (UC). This trial assessed the efficacy of monthly GMA as a maintenance therapy to suppress UC relapse.MethodsThirty-three corticosteroid refractory patients with active UC received 10 weekly GMA sessions as a remission induction therapy. They were then randomized to receive one GMA session every 4 weeks (True, n=11), extracorporeal circulation without the GMA column every 4 weeks (Sham, n=11), or no additional intervention (Control, n=11). The primary endpoint was the rate of avoiding relapse (AR) over 48 weeks.ResultsAt week 48, the AR rates in the True, Sham, and Control groups were 40.0%, 9.1%, and 18.2%, respectively. All patients were steroid-free, but no statistically significant difference was seen among the three arms. However, in patients who could taper their prednisolone dose to <20 mg/day during the remission induction therapy, the AR in the True group was better than in the Sham (p<0.03) or Control (p<0.05) groups.ConclusionsMonthly GMA may potentially prevent UC relapse in patients who have achieved remission through weekly GMA, especially in patients on <20 mg/day PSL at the start of the maintenance therapy.

Production of Interleukin‐10 by Combining a Granulocyte and Monocyte Adsorption Carrier With Ulinastatin

Interleukin (IL)-10 is an anti-inflammatory cytokine mainly produced by monocytes and is essential for the induction of anti-inflammatory intestinal macrophages with macrophage colony-stimulating factor (M-CSF). Thus, IL-10- and M-CSF-rich conditions in colonic tissues seem to contribute to the improvement of pathological conditions in patients with inflammatory bowel diseases (IBD). We have already reported that ulinastatin, a serine protease inhibitor, increases M-CSF production during granulocyte/monocyte (GM) adsorption to cellulose acetate (CA) beads (carriers for Adacolumn therapy). However, the effects of ulinastatin on IL-10 production have not been clarified. The aim of the present study was to clarify the effects of ulinastatin on IL-10 production during GM adsorption by in vitro experiments. Peripheral blood was divided into four groups: (Control) no ulinastatin added, no contact with CA beads; (1) no ulinastatin added, contact with CA beads; (2) ulinastatin added, no contact with CA beads; and (3) ulinastatin added, contact with CA beads. After incubation, IL-10 in the plasma was measured. Compared with the level in the Control group, plasma IL-10 was significantly higher only in group 3, in which ulinastatin was added in the presence of CA beads, but did not increase in the absence of CA beads. These results suggest that ulinastatin synergistically increases IL-10 production with monocyte adsorption stimuli. By increasing not only M-CSF but also IL-10, a combination of ulinastatin and Adacolumn therapy may improve clinical efficacy for the treatment of IBD in terms of the induction of anti-inflammatory intestinal macrophages.

Relevance of the Processed Blood Volume per Granulocyte and Monocyte Apheresis Session to its Clinical Efficacy in Patients With Ulcerative Colitis

Granulocyte/monocyte adsorption (GMA) has been introduced as an adjunct intervention for active ulcerative colitis (UC) patients. The processed blood volume (PV) per GMA session is an important factor for its efficacy because depletion of elevated/activated myeloid leukocytes is its main action. Hitherto, this aspect of GMA has been largely ignored. Thirty-three patients were enrolled for remission induction therapy with five weekly GMA sessions at a standard PV of 1800 mL, regardless of patients' bodyweight (BW). The patients were divided into three groups: high (H)BW (≥ 65 kg, n = 11), 50 kg ≤ medium (M)BW < 65 kg (n = 12), and low (L)BW (≤ 50 kg, n = 10). UC clinical activity index (CAI) was according to Lichtiger, and the clinical efficacies were evaluated at both one week post 3(rd) GMA (Week 4) and one week post 5(th) GMA (Week 6). The average BW was 70.9 ± 6.2 kg in HBW, 55.8 ± 4.5 kg in MBW, and 46.8 ± 1.2 kg in LBW, indicating the mean PV/BW in the three groups being 25.6 ± 2.12, 32.5 ± 2.50, and 38.7 ± 1.0 (mL/kg, P < 0.05), respectively. The LBW group consisted of female patients only. Significant improvements of CAI were seen before treatment at either Week 4 or Week 6 in all groups. A significantly higher remission rate was achieved in the LBW (80.0%) vs. MBW (33.3%) or HBW (27.3%) at Week 6 (P < 0.03). According to this GMA evaluation, the lower-limit of optimum PV/kg should be higher than 38.7 mL/kg for its potential clinical efficacy to be significantly greater than the routine GMA method. Additional BW-oriented GMA studies in larger and gender controlled cohorts of patients should strengthen our findings.

Mucosal healing of esophageal involvement of Crohn's disease with granulocyte/monocyte adsorption

We report a case of a 16-year-old male who suffered from Crohn's disease (CD) with esophageal involvement, showing remarkable improvement with granulocyte/monocyte adsorption (GMA). The patient had been diagnosed as ileocolic CD and was treated with 5-aminosalicylate. He was admitted to our hospital with symptoms of fever, diarrhea, and odynophagia. Endoscopic examinations revealed that the exacerbation of ileocolic ulcers, and advent of ulcers in esophagus. Because of the patient's refusal to receive corticosteroids, immunomodulators, or biologics, he underwent GMA twice a week. After 10 sessions of GMA, he entered remission with significant decrease in clinical activity. In addition, endoscopic examinations showed remarkable improvement of ileocolic ulcers and disappearance of esophageal lesions. No adverse events were observed. GMA could be effective for manifestations of CD in gastrointestinal tract other than ileum or colon.

The mode of actions of the Adacolumn therapeutic leucocytapheresis in patients with inflammatory bowel disease: a concise review

Patients with active inflammatory bowel disease (IBD) have elevated and activated myeloid leucocytes which infiltrate the colonic mucosa in vast numbers. Myeloid leucocytes such as the CD14(+) CD16(+) monocytes are major sources of tumour necrosis factor (TNF)-α, and therefore selective granulocyte/monocyte (GM) adsorption (GMA) should promote remission or enhance efficacy of pharmacological therapy. However, studies in IBD have reported both impressive as well as disappointing efficacy outcomes, indicating that patients' demographic factors might determine responders or non-responders to GMA. Nonetheless, this non-drug intervention has an excellent safety profile, and therapeutic GMA is expected to expand. In this review, attempts have been made to compile an update on the mode of actions (MoA) of the Adacolumn GMA. The MoA of GMA appears to be more than adsorption of excess neutrophils and TNF-producing CD14(+) CD16(+) monocytes per se. Adsorbed GMs release interleukin (IL)-1 receptor antagonist, hepatocyte growth factor and soluble TNF receptors, which are anti-inflammatory. Additionally, a sustained increase in lymphocytes including the regulatory CD4(+) CD25(+) T cells (lymphocyte sparing) is seen post-GMA. The impact of GMA on the immune system is potentially very interesting in the context of treating immune-related diseases. Future studies are expected to add intriguing insights to the MoA of GMA.

Clinical and endoscopic features of responders and non-responders to adsorptive leucocytapheresis: A report based on 120 patients with active ulcerative colitis

Background and Objective Elevated/activated myeloid leucocytes, like the CD14(+)CD16(+) monocytes are sources of TNF-α, and therefore, selective depletion of these cells by granulocyte/monocyte (GM) adsorption (GMA) should promote remission or enhance drug efficacy. However, studies in ulcerative colitis (UC) reported contrasting efficacy, from an 85% to statistically insignificant level. We investigated patients’ demography in responders and non-responders. Methods In 120 UC patients, 61 steroid naive and 59 steroid dependent, we looked for entry clinical or endoscopic features to identify responders (or non-responders) to GMA. Patients received up to an 11 Adacolumn GMA sessions over 12 weeks. Patients were clinically and endoscopically evaluated, allowing each patient to serve as her/his own control. Immunohistochemistry on colonic biopsies was to reveal the impact of GMA on leucocyte infiltration of the mucosa. Results Entry average clinical activity index (CAI) was 12.6, 10–16. An 80 of 120 patients responded (CAI ≤ 4); 45 steroid naïve (73.8%) and 35 steroid dependent (59.3%). Over 900 biopsies were processed. Infiltrating leucocytes were overwhelmingly polymorphonuclear and macrophages around and within crypt abscesses. There was a marked reduction of infiltrating leucocytes in responders. Most non-responders had extensive colonic lesions with virtually no mucosal tissue left at the lesions. Conclusions Steroid naïve patients with short duration of UC were the best responders, while patients with deep colonic lesions and extensive loss of the mucosal tissue were non-responders.

Adsorptive Depletion of α4 Integrinhi- and CX3CR1hi-Expressing Proinflammatory Monocytes in Patients with Ulcerative Colitis

Two main functionally distinct monocytes phenotypes are known: the CD14(hi)CD16(-) "classical" and the CD14(+)CD16(+) "proinflammatory" phenotypes. The latter phenotype is elevated in patients with ulcerative colitis (UC) and is suspected to have a major role in the immunopathogenesis of UC. To selectively deplete circulating proinflammatory CD14(+)CD16(+) monocyte phenotype. Seven corticosteroid-naïve patients with UC (clinical activity index = 8.7 +/- 1.3) and seven healthy subjects were included. In patients with UC, granulocyte/monocyte adsorption (GMA) was done with an Adacolumn that selectively adsorbs leucocytes of the myeloid lineage. Blood from all subjects at baseline and from the patients immediately after the first GMA session was processed. Isolated monocytes were subjected to fluorescence-activated cell sorter analyses. The seven UC patients achieved remission (CAI <or=4) after 5-10 GMA sessions. GMA induced a strong fall in the ratio (%) of CD14(+)CD16(+) to CD14(hi)CD16(-) monocytes, from 10.0 +/- 1.4 to 3.0 +/- 0.9. Further, expressions of alpha4 integrin (374.8 +/- 26.1 mean fluorescence intensity, MFI) and CX(3)CR1 (49.5 +/- 4.6 MFI) were significantly high on CD14(+)CD16(+)monocytes as compared with on CD14(hi)CD16(-) monocytes (169.2 +/- 17.2 and 33.2 +/- 3.6 MFI, respectively). Additionally, GMA significantly increased the ratio of the CD14(hi)CD16(-)CCR2(low) "immature" monocytes from 3.74 +/- 0.62 to 8.11 +/- 0.56 MFI. We found high expressions of alpha4 integrin and CX(3)CR1 on monocytes in patients with active UC, known to promote the extravasation of CD14(+)CD16(+) monocytes into the mucosa. GMA effectively depletes CD14(+)CD16(+) monocytes and concomitantly increases CD14(hi)CD16(-)CCR2(low) "immature" monocytes; thus GMA was associated with the emergence of less inflammatory monocyte phenotype in circulation.

W1123 Adsorptive Depletion of Circulating α4 Integrin Hi and Cx 3Crl Hi Expressing Proinflammatory Monocytes in Patients with Active Ulcerative Colitis

BACKGROUND AND AIM: Circulating monocytes exist as two main functionally distinct phenotypes, the CD14hiCD16“classical” phenotype and the CD14+CD16+ “proinflammatory” phenotype for releasing large amounts of tumour necrosis factor (TNF)-α. Further, the CD14+CD16+ phenotype is elevated by up to 2 fold (or more) in patients with inflammatory bowel disease (IBD) and is suspected to have a major role in the immunopathogenesis of IBD as this phenotype is readily recruited to inflammatory as well as to non-inflammatory mucosal tissues where they differentiate into cytokine producing resident macrophages or dendritic cells. Accordingly, selectively depletion of CD14+CD16+ monocytes should be a major research objective.METHODS: Seven corticosteroid naive patients with active ulcerative colitis (UC), Lichtiger's clinical activity index (CAI) = 8.7±1.3, and 7 healthy subjects as controls were included. In patients with UC, granulocyte/monocyte adsorption (GMA) was done with an Adacolumn that selectively adsorbs leucocytes of the myeloid lineage. Peripheral blood from all subjects at baseline and from patients immediately after the first GMA session was processed. Isolated monocytes were subjected to extensive fluorescenceactivated cell sorter (FACS) analyses. RESULTS: The 7 patients with UC achieved clinical remission (CAI≤4) after 5-10 GMA sessions. GMA was associated with a striking fall in the ratio (%) of CD14+CD16+/CD14hiCD16monocytes, from 10.0±1.4 to 3.0±0.9 (P<0.05), indicating selective depletion of CD14+CD16+ monocytes. Further, FACS analyses revealed that the expressions of the adhesion molecules α4 integrin, 374.8±26.1 mean fluorescence intensity (MFI) and CX3CR1, 49.5±4.6MFI were significantly (P<0.05) high on CD14+CD16+ monocytes as compared to CD14hiCD16monocytes, 169.2±17.2 MFI and 33.2±3.6 MFI, respectively. Additionally, GMA increased the ratio of the “immature” CD14hiCD16-CCR2low monocytes from 3.74±0.62 MFI to 8.11±0.56 MFI (P<0.05), indicating that GMA was followed by an influx of immature monocytes from the bone marrow into the circulation. CONCLUSIONS: To our knowledge, this is the first report of detecting elevated levels of α4 integrin on the proinflammatory CD14+CD16+ monocytes as compared to the classical CD14hiCD16monocytes. A high level of α4 integrin on the CD14+CD16+ monocytes might promote extravasation of these myeloid cells to the mucosa as significant sources of TNFα. GMA was very effective in depleting the CD14+CD16+ monocytes and at the same time, it was associated with an increase in CD14hiCD16-CCR2low monocytes. These data should contribute to a better understanding of immune pathology in patients with IBD.

Safety and Efficacy of Granulocyte and Monocyte Adsorption Apheresis in Paediatric Inflammatory Bowel Disease: A Prospective Pilot Study

Selective granulocyte-monocyte adsorption (GMA) apheresis is a safe technique that has shown efficacy in inflammatory bowel disease (IBD), especially in adult steroid-dependent and steroid-refractory ulcerative colitis. GMA apheresis is performed with Adacolumn, a direct blood perfusion system that selectively adsorbs circulating granulocytes and monocytes. Studies on efficacy of GMA apheresis in paediatric IBD are scarce. Our aim was to evaluate efficacy, safety, and tolerability of GMA apheresis in paediatric IBD patients followed for 1 year. Nine patients with a mild to moderate flare-up (6 boys, 3 girls; 5 ulcerative colitis [UC], 4 Crohn disease [CD]) were included. Mean age at inclusion was 13 years and 9 months, and mean disease duration before inclusion was 28 months. All of our patients with UC were steroid-dependent; patients with CD had been unsuccessfully treated with other therapies. GMA apheresis consisted of 5 consecutive weekly sessions lasting 60 minutes each. After the 5 sessions, 4 of 5 patients with UC and 1 of 4 patients with CD achieved remission. This remission was maintained in 2 of 4 patients with UC and in the single patients with CD. Patients taking steroids could begin to taper their daily doses after the second apheresis, and 3 of 5 of these patients reached the end of the study steroid-free. GMA apheresis was well tolerated and no severe side effects related to the technique were observed. GMA apheresis is a safe, well-tolerated technique in paediatric IBD. As previously reported, we have observed a better efficacy in promoting and maintaining remission, and reducing conventional drugs in patients with UC than in patients with CD.