Granulocyte and monocyte apheresis as an adjunctive therapy to induce and maintain clinical remission in ulcerative colitis: a systematic review and meta-analysis
BMJ open. 2021;11(5):e042374
OBJECTIVE The goal of treatment in ulcerative colitis (UC) is to induce and maintain remission. The addition of granulocyte and monocyte apheresis (GMA) to conventional therapy may be a promising therapeutic alternative. In this meta-analysis, we aimed to assess the efficacy and safety profile of GMA as an adjunctive therapy. DESIGN Systematic review and meta-analysis. METHODS We searched four databases (MEDLINE, Embase, Web of Science and Cochrane Central Register of Controlled Trials) for randomised or minimised controlled trials which discussed the impact of additional GMA therapy on clinical remission induction and clinical remission maintenance compared with conventional therapy alone. Primary outcomes were clinical remission induction and maintenance, secondary outcomes were adverse events (AEs) and steroid-sparing effect. ORs with 95% CIs were calculated. Trial Sequential Analyses were performed to adjusts for the risk of random errors in meta-analyses. RESULTS A total of 11 studies were eligible for meta-analysis. GMA was clearly demonstrated to induce and maintain clinical remission more effectively than conventional therapy alone (598 patients: OR: 1.93, 95% CI 1.28 to 2.91, p=0.002, I(2)=0.0% for induction; 71 patients: OR: 8.34, 95% CI 2.64 to 26.32, p<0.001, I(2)=0.0% for maintenance). There was no statistically significant difference in the number of AEs (OR: 0.27, 95% CI 0.05 to 1.50, p=0.135, I(2)=84.2%). CONCLUSION GMA appears to be more effective as an adjunctive treatment in inducing and maintaining remission in patients with UC than conventional therapy alone. PROSPERO REGISTRATION NUMBER CRD42019134050.
Novel Leucocyte/Thrombocyte Apheresis for Induction of Steroid-Free Remission in Ulcerative Colitis: A Controlled Randomized Pilot Study
Journal of Crohn's & colitis. 2019
BACKGROUND AND AIMS In active ulcerative colitis [UC] refractory to mesalazine, escalation to either steroids or immunosuppression is common practice. The efficacy and safety of alternative escalation therapy with a novel leukocyte apheresis device were studied. METHODS This was a prospective, randomized, controlled multicentre pilot study comparing leukocyte apheresis with prednisolone in refractory UC (disease activity index [DAI] ≥ 4 and ≤8). Group A received weekly apheresis over five consecutive weeks. Group P received oral prednisolone 40 mg/day tapered to 0 mg at week 6. The primary end point was steroid-free clinical remission [DAI ≤ 2] at week 12. Clinical response was also analysed. RESULTS Twenty-four patients were enrolled, 13 of whom were randomized into group A and 11 into group P. Clinical remission off steroids at week 12 was achieved in 3/12 patients [25.0%] with apheresis and 2/10 [20.0%] with prednisolone [p = 1.0]. The response rate after 12 weeks was 75.0% in group A and 50.0% in group P. Mean DAI scores improved in both treatment groups [p = 0.008]. C-reactive protein decreased from 6.0 +/- 5.3 to 3.8 +/- 3.7 mg/L at 12 weeks in group A and increased from 5.2 +/- 6.0 to 6.3 +/- 7.9 mg/mL in group P. Both treatments were well tolerated. No unexpected serious adverse events were seen in group A. In group P one symptomatic infection with Clostridium difficile occurred. CONCLUSIONS In patients with active UC refractory to mesalazine a novel leukocyte apheresis showed promising results. A comparison with prednisolone revealed similar therapeutic effectivity and excellent safety, providing the chance to escalate without systemic steroids. CIV-12-01-003581.
Addition of granulocyte/monocyte apheresis to oral prednisone for steroid-dependent ulcerative colitis: A randomized, multicentre, clinical trial
Journal of Crohn's & Colitis. 2018;12((6):):687-694
Background and Aims: Steroid-dependency occurs in up to 30% of patients with ulcerative colitis (UC). In this setting, few drugs have demonstrated efficacy in inducing steroid-free remission. The aim was to evaluate the efficacy and safety of adding granulocyte/monocyte apheresis (GMA) to oral prednisone in patients with steroid-dependent UC. Methods: Randomized, multicentre, open trial comparing 7 weekly sessions of GMA plus oral prednisone (40mg/day and tapering) to prednisone alone in patients with active, steroid-dependent UC (Mayo score 4-10 and inability to withdraw corticosteroids in 3 months or relapse within the first 3 months after discontinuation). Patients were stratified by concomitant use of thiopurines at inclusion. A 9-week tapering schedule of prednisone was pre-established in both study groups. The primary end point was steroid-free remission (defined as a total Mayo score ≤2, with no subscore >1) at week 24, with no reintroduction of corticosteroids. Results: One hundred and twenty-three patients were included (63 GMA group, 62 prednisone alone). In the ITT analysis, steroid-free remission at week 24 was achieved in 13% (95%CI 6-24) in the GMA group and 7% (95%CI 2-16) in the control group (P=0.11). In the GMA group, time to relapse was significantly longer (HR 1.7 [1.16-2.48], P=0.005) and steroid-related adverse events were significantly lower (6% vs. 20%, P<0.05). Conclusions: In a randomized trial, the addition of 7 weekly sessions of GMA to a conventional course of oral prednisone did not increase the proportion of steroid-free remissions in patients with active steroid-dependent UC, though it delayed clinical relapse. ClinicalTrials.gov ID: NCT00702611.
Shorter Relapse-Free Period after Leukocyte Removal Therapy in Younger than Older Patients with Ulcerative Colitis
BACKGROUND Leukocyte removal therapy (LRT) is an effective treatment for active ulcerative colitis (UC). The present study was performed to evaluate the relapse-free period after LRT and identify risk factors for relapse. METHODS In total, 94 patients who underwent first-time LRT for remission of moderate to severe UC from April 2004 to March 2016 were enrolled in the present study. The patients were randomly assigned to one of 2 treatments: leukocytapheresis (LCAP; n = 43) or granulocyte and monocyte/macrophage adsorptive apheresis (GMA; n = 51). The 5-year cumulative relapse-free rate and risk factors for relapse were evaluated. RESULTS The therapeutic response rate was 82% for GMA and 70% for LCAP without a statistically significant difference. The 5-year relapse-free rate was 34.7% in the LRT group. The 5-year relapse-free rate in patients aged > 40 years was 49.9%, which was significantly higher than that in patients aged ≤40 years (22.9%, p < 0.01). The relapse-free period was longer in the older than younger patients. CONCLUSIONS The relapse-free period after LRT was examined in patients with UC, and 34.7% of patients achieved clinical remission within a 5-year period. The risk factor for early relapse after LRT was younger age.
Randomised, Double-blind, Placebo-controlled Trial of CCR9-targeted Leukapheresis Treatment of Ulcerative Colitis Patients
Journal of Crohn's & Colitis. 2017;11((5)):534-542.
Background and Aims: Ulcerative colitis patients display increased numbers of circulating pro-inflammatory monocyte human leukocyte antigen-DR [HLA-DRhi] monocytes expressing high levels of the gut-homing C-C chemokine receptor 9 [CCR9] and tumour necrosis factor [TNF]-alpha. The aim of this first-in-human, double-blind, randomised, placebo-controlled trial was to evaluate selective removal of circulating CCR9-expressing monocytes by leukapheresis in patients with moderate to severe ulcerative colitis, with regards to safety, tolerability, and immunological response. Methods: Patients with ulcerative colitis were treated every second day with leukapheresis during five sessions with a C-C chemokine ligand 25 [CCL25; CCR9 ligand] column or a placebo column. Results: No major safety concerns were raised and the procedure was well tolerated. Pro-inflammatory HLA-DRhi cells decreased significantly in the active treatment group [p = 0.0391] whereas no statistically significant change was seen in the placebo group [p = 0.4688]. There was a significant decrease of HLA-DRhi monocytes in the active group compared with the placebo group when corrected for the imbalance in weight between the groups [p = 0.0105]. Mayo score decreased in the active group [p = 0.0156] whereas the change in the placebo group was not significant [p = 0.1250]. Mayo score ≤ 3 was observed in five out of 14 patients [35.7%] in the active group compared with one out of eight [12.5%] receiving placebo. The number of responders in the active treatment group was eight out of 14 patients [57.1%], whereas in the corresponding placebo group three out of eight patients [37.5%] responded to placebo. A dose-response correlation was observed between the blood volume processed and clinical outcome. Conclusion: This clinical induction trial using CCL25-tailored leukapheresis demonstrates a safe and effective removal of activated monocytes with a clinical effect in patients with ulcerative colitis.
Randomized, double-blind, placebo-controlled trial of CCR9-targeted leukapheresis treatment of ulcerative colitis patients
Journal of Crohn's & Colitis. 2016;11((5):):534-542
BACKGROUND AND AIMS Ulcerative colitis patients display increased number of circulating pro-inflammatory HLA-DRhi monocytes expressing high levels of the gut homing chemokine receptor CCR9 and TNF-alpha. The aim of this first-in-man double blind randomized placebo controlled trial was to evaluate selective removal of circulating CCR9-expressing monocytes by leukapheresis in patients with moderate to severe ulcerative colitis with regards to safety, tolerability and immunological response. METHODS Patients with ulcerative colitis were treated every second day with leukapheresis during 5 sessions with CCL25 (CCR9 ligand) column or a placebo column. RESULTS No major safety concerns were raised and the procedure was well tolerated. Pro-inflammatory HLA-DRhi cells decreased significantly in the active treatment group (p=0.0391) while no statistically significant change was seen in the placebo group (p=0.4688). There was a significant decrease of HLA-DRhi monocytes in the active group compared to the placebo group when corrected for the imbalance in weight between the groups (p=0.0105). Mayo score decreased in the active group (p=0.0156) whereas the change in the placebo group was not significant (p=0.1250). Mayo score ≤3 was observed in five out of 14 patients (35.7%) in the active group compared to one out of eight (12.5%) receiving placebo. The number of responders in the active treatment group was eight out of 14 patients (57.1%), whereas in the corresponding placebo group three out of eight patients (37.5%) responded to placebo. A dose response correlation was observed between the blood volume processed and clinical outcome. CONCLUSION This clinical induction trial using CCL25-tailored leukapheresis demonstrates a safe and effective removal of activated monocytes with a clinical effect in patients with ulcerative colitis.
An open-label prospective randomized multicenter study of intensive versus weekly granulocyte and monocyte apheresis in active crohn's disease
BMC Gastroenterology. 2015;15((1)):163.
BACKGROUND Granulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active Crohn's disease (CD). However, with routine weekly therapy, it may take several weeks to achieve remission. This study was performed to assess clinical efficacy and safety of intensive GMA in patients with active CD. METHODS In an open-label, prospective, randomized multicentre setting, 104 patients with CD activity index (CDAI) of 200 to 450 received intensive GMA, at two sessions per week (n = 55) or one session per week (n = 49). Clinical remission was defined as a CDAI score <150. Patients in each arm could receive up to 10 GMA sessions. However, GMA treatment could be discontinued when CDAI decreased to <150 (clinical remission level). RESULTS Of the 104 patients, 99 were available for efficacy evaluation as per protocol, 45 in the weekly GMA group, and 54 in the intensive GMA group. Remission was achieved in 16 of 45 patients (35.6 %) in the weekly GMA and in 19 of 54 (35.2 %) in the intensive GMA (NS). Further, the mean time to remission was 35.4 +/- 5.3 days in the weekly GMA and 21.7 +/- 2.7 days in the intensive GMA (P = 0.0373). Elevated leucocytes and erythrocyte sedimentation rate were significantly improved by intensive GMA, from 8005/muL to 6950/muL (P = 0.0461) and from 54.5 mm/hr to 30.0 mm/hr (P = 0.0059), respectively. In both arms, GMA was well tolerated and was without safety concern. CONCLUSIONS In this study, with respect to remission rate, intensive GMA was not superior to weekly GMA, but the time to remission was significantly shorter in the former without increasing the incidence of side effects. UMIN registration # 000003666.
Granulocyte/monocyte adsorptive apheresis in moderate to severe ulcerative colitis - effective or not?
BACKGROUND AND AIMS Adsorptive granulocyte/monocyte apheresis (GMA) has shown promising efficacy in the treatment of patients with ulcerative colitis (UC). But a sham-controlled study was negative. A post-hoc analysis of this trial may haul out patients responding to GMA. METHODS A total of 168 UC patients with a disease activity (DAI) between 6 and 11 were enrolled in this study. Out of 168 patients, 112 received GMA and 56 sham apheresis. The basis for this post hoc analysis is the clinical study report issued by Otsuka America Pharmaceutical. RESULTS Baseline histology was available for 165 patients. Only 38% (63 of 165) of patients showed microscopic erosion/ulceration (group P). The remaining 62% of patients did not show microscopic erosion/ulceration (group A). The patients in group P showed significantly higher DAI, flexible proctosigmoidoscopy score and neutrophil infiltration into the colonic mucosa than those in group A (p = 0.0132, p = 0.0243 and p < 0.0001, respectively). Likewise, group P patients had a significantly (p = 0.0275) higher remission rate (11 of 46; 23.9%) when treated with GMA than with sham procedure (0 of 17; 0%). CONCLUSIONS Patients in group P who had more active UC than those in group A showed clear clinical efficacy in response to GMA. We believe that true DAI should be specified for further randomized controlled trials. © 2015 S. Karger AG, Basel.
Effects of preoperative leukocytapheresis on inflammatory cytokines following surgery for ulcerative colitis: A prospective randomized study
Journal of Clinical Apheresis. 2014;29((2):):107-12.
Targeted extracorporeal granulocyte and monocyte apheresis (GMA) has produced clinical efficacy together with down modulation of specific inflammatory cytokines in patients with ulcerative colitis (UC). This study was to investigate if preoperative GMA produces immunological effect on dysregulated immune activity after restorative proctocolectomy (RPC) in patients with UC. Forty patients requiring RPC were included. Twenty randomly selected patients received five GMA sessions with the Adacolumn over two consecutive weeks before RPC (GMA group). RPC was performed within 2 weeks following the last GMA session. The other 20 patients did not receive GMA before RPC (non-GMA group). Blood samples were obtained immediately before surgery, at 1 h after surgery, and on postoperative Days 1, 3, and 7 from all patients. Abdominal exudate was obtained from the drainage tube at 1 h after surgery, and on postoperative Days 1, 3, and 7. Concentrations of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha in plasma and peritoneal fluid from a drainage tube were measured by enzyme linked immunosorbent assay. Between the two groups, patients were matched with respect to age, sex, UC duration, severity, extent and the dose of prednisolone at surgery. IL-1beta, IL-6, and TNF-alpha levels in plasma and peritoneal fluid were not significantly different between the two groups during the entire study period. Based on the assays of IL-1beta, IL-6, and TNF-alpha levels in the plasma and the peritoneal fluid, this study did not find any effect on these inflammatory cytokines by preoperative GMA in patients with UC who underwent RPC. J. Clin. Apheresis 29:107-112, 2014. 2013 Wiley Periodicals, Inc. Copyright 2013 Wiley Periodicals, Inc.
Efficacy and safety of granulocyte and monocyte adsorption apheresis for ulcerative colitis: A meta-analysis
Digestive & Liver Disease. 2014;46((3):):219-26.
BACKGROUND Safe and effective treatments are required for patients with ulcerative colitis. It was suggested that granulocyte and monocyte adsorption apheresis might play an important role for ulcerative colitis. Therefore, a meta-analysis was performed. METHODS Medline and the Cochrane controlled trials register were used to identify randomized controlled trials comparing granulocyte and monocyte adsorption apheresis with corticosteroids, and comparing intensive with conventional apheresis in patients with ulcerative colitis. RESULTS Nine randomized trials were eligible for inclusion criteria. According to pooled data, granulocyte and monocyte adsorption apheresis is effective for inducing clinical remission in patients with ulcerative colitis compared with corticosteroids (odds ratio, 2.23; 95% confidence interval: 1.38-3.60). However, the efficacy of granulocyte and monocyte adsorption apheresis was not dependent on the number of apheresis sessions. The intensive apheresis (>2 sessions per week) is more effective for inducing clinical remission than weekly apheresis (odds ratio, 2.10; 95% confidence interval: 1.12-3.93). The rate of adverse events by apheresis was significantly lower than that by corticosteroids (odds ratio, 0.24; 95% confidence interval: 0.15-0.37). CONCLUSION Our meta-analysis reveals that intensive granulocyte and monocyte adsorption apheresis is a safe and effective treatment with higher rates of clinical remission and response for ulcerative colitis compared with corticosteroids. Copyright 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.