Apheresis:A cell-based therapeutic tool for the inflammatory bowel disease

Inflammatory Bowel Disease(IBD)is a hallmark of leukocyte infiltration,followed by the release of cytokines and interleukins.Disease progression to Ulcerative Colitis(UC)or Crohn’s Disease(CD)remained largely incurable.The genetic and environmental factors disrupt enteral bacteria in the gut,which hampers the intestinal repairing capability of damaged mucosa.Commonly practiced pharmacological therapies include 5-aminosalicylic acid with corticosteroids and tumor necrosis factor(TNF)-α.New interventions such as CDP571 and TNF-blocking RDP58 report the loss of patient response.This review discusses the non-pharmacologic selective granulocyte–monocyte-apheresis(GMA)and leukocytapheresis(LCAP)that have been proposed as treatment modalities that reduce mortality.GMA,an extracorporeal vein-to-vein technique,presents a strong safety profile case for its use as a viable therapeutic option compared to GMA's conventional medication safety profile.GMA reported minimal to no side effects in the pediatric population and pregnant women.Numerous studies report the efficacious nature of GMA in UC patients,whereas data on CD patients is insufficient.Its benefits outweigh the risks and are emerging as a favored nonpharmacological treatment option.On the contrary,LCAP uses a general extracorporeal treatment that entraps leukocytes and suppresses cytokine release.It has been deemed more efficacious than conventional drug treatments,the former causing better disease remission,and maintenance.Patients with UC/CD secondary to complications have responded well to the treatment.Side effects of the procedure have remained mild to moderate,and there is little evidence of any severe adverse event occurring in most age groups.LCAP decreases the dependence on steroids and immunosuppressive therapies for IBD.The review will discuss the role of GMA and LCAP.

case of familial hyperlipoproteinemia type Ⅲ hypertriglyceridemia induced acute pancreatitis: role for outpatient apheresis maintenance therapy

Hypertriglyceridemic pancreatitis(HTGP) accounts for up to 10% of acute pancreatitis presentations in nonpregnant individuals and is the third most common cause of acute pancreatitis after alcohol and gallstones. There are a number of retrospective studies and case reports that have suggested a role for apheresis and insulin infusion in the acute inpatient setting. We report a case of HTGP in a male with hyperlipoproteinemia type Ⅲ who was treated successfully with insulin and apheresis on the initial inpatient presentation followed by bi-monthly outpatient maintenance apheresis sessions for the prevention of recurrent HTGP. We also reviewed the literature for the different inpatient and outpatient management modalities of HTGP. Given that there are no guidelines or randomized clinical trials that evaluate the outpatient management of HTGP, this case report may provide insight into a possible role for outpatient apheresis maintenance therapy.

Efficacy of cytapheresis in patients with ulcerative colitis showing insufficient or lost response to biologic therapy

For the optimal management of refractory ulcerative colitis(UC),secondary loss of response(LOR)and primary non-response to biologics is a critical issue.This article aimed to summarize the current literature on the use of cytapheresis(CAP)in patients with UC showing a poor response or LOR to biologics and discuss its advantages and limitations.Further,we summarized the efficacy of CAP in patients with UC showing insufficient response to thiopurines or immunomodulators(IM).Eight studies evaluated the efficacy of CAP in patients with UC with inadequate responses to thiopurines or IM.There were no significant differences in the rate of remission and steroid-free remission between patients exposed or not exposed to thiopurines or IM.Three studies evaluated the efficacy of CAP in patients with UC showing an insufficient response to biologic therapies.Mean remission rates of biologics exposed or unexposed patients were 29.4%and 44.2%,respectively.Fourteen studies evaluated the efficacy of CAP in combination with biologics in patients with inflammatory bowel disease showing a poor response or LOR to biologics.The rates of remission/response and steroid-free remission in patients with UC ranged 32%-69%(mean:48.0%,median:42.9%)and 9%-75%(mean:40.7%,median:38%),respectively.CAP had the same effectiveness for remission induction with or without prior failure on thiopurines or IM but showed little benefit in patients with UC refractory to biologics.Although heterogeneity existed in the efficacy of the combination therapy with CAP and biologics,these combination therapies induced clinical remission/response and steroid-free remission in more than 40%of patients with UC refractory to biologics on average.Given the excellent safety profile of CAP,this combination therapy can be an alternative therapeutic strategy for UC refractory to biologics.Extensive prospective studies are needed to understand the efficacy of combination therapy with CAP and biologics.

Use of granulocyte/monocytapheresis in ulcerative colitis:A practical review from a European perspective

Half of the patients with ulcerative colitis require at least one course of systemic corticosteroids in their lifetime.Approximately 75%of these patients will also require immunosuppressive drugs(i.e.,thiopurines or biological agents)in the mid-term to avoid colectomy.Immunosuppressive drugs raise some concerns due to an increased risk of serious and opportunistic infections and cancer,particularly in elderly and co-morbid patients,underlining the unmet need for safer alternative therapies.Granulocyte/monocytapheresis(GMA),a CE-marked,non-pharmacological procedure for the treatment of ulcerative colitis(among other immune-mediated diseases),remains the only therapy targeting neutrophils,the hallmark of pathology in ulcerative colitis.GMA has proven its efficacy in different clinical scenarios and shows an excellent and unique safety profile.In spite of being a first line therapy in Japan,GMA use is still limited to a small number of centres and countries in Europe.In this article,we aim to give an overview from a European perspective of the mechanism of action,recent clinical data on efficacy and practical aspects for the use of GMA in ulcerative colitis.

Selective granulocyte and monocyte apheresis in inflammatory bowel disease:Its past,present and future

The etiology and pathogenesis of inflammatory bowel disease(IBD),including ulcerative colitis and Crohn’s disease,are not fully understood so far.Therefore,IBD still remains incurable despite the fact that significant progress has been achieved in recent years in its treatment with innovative medicine.About 20 years ago,selective granulocyte and monocyte apheresis(GMA)was invented in Japan and later approved by the Japanese health authority for IBD treatment.From then on this technique was extensively used for IBD patients in Japan and later in Europe.Clinical trials from Japan and European countries have verified the effectiveness and safety of GMA therapy in patients with IBD.In 2013,GMA therapy was approved by China State Food and Drug Administration for therapeutic use for the Chinese IBD patients.However,GMA therapy has not been extensively used in China,although a few clinical studies also showed that it was effective in clinical and endoscopic induction of remission in Chinese IBD patients with a high safety profile.This article reviews past history,present clinical application as well as the future prospective of GMA therapy for patients with IBD.

Case of severe alcoholic hepatitis treated with granulocytapheresis

Severe alcoholic hepatitis(AH) has a high mortality,and it is associated with encephalopathy,acute renal failure,sepsis,gastrointestinal bleeding,and endotoxemia.The 28-d mortality remains poor(34%-40%),because no effective treatment has been established.Recently,corticosteroids(CS) have been considered effective for significantly improving the prognosis of those with AH,as it prevents the production of pro-inflammatory cytokines.However,CS are not always appropriate as an initial therapeutic option,such as in cases with an infection or resistance to CS.We describe a patient with severe AH complicated by a severe infection caused by the multidrug resistance bacteria(Pseudomonas aeruginosa),and was successfully treated with granulocytapheresis monotherapy without using CS.The experience of this case will provide understanding of the disease and information treating cases without using CS.

ANCA-Associated Vasculitis: Value of Apheresis in Initial Treatment

Introduction: Vasculitis associated with anti-neutrophil cytoplasm antibodies (ANCA) can be grouped with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MAP), and eosinophilic granulomatosis with polyangiitis (EGPA). Diagnosis of these rare pathologies is based on clinical presentation, the positivity of ANCA, and, if possible, histological proof of vasculitis. Our study describes a series of six cases of ANCA-associated vasculitis where due to the severity of symptoms apheresis sessions were started from the beginning of the therapy. Patients and methods: We conducted a retrospective, single-center observational, monocentric study on all patients treated by apheresis for ANCA vasculitis in the period January 01, 2016 to December 01, 2019. Results: We identified six cases of ANCA vasculitis treated by apheresis over a 3-year period. The mean age was 61 ± 19 years;M/F gender ratio was 1:1. Initial renal damage in all patients was rapidly progressive glomerulonephritis. Inflammatory syndrome occurred in all patients with average CRP of 82 mg/L. All patients had positive ANCA at diagnosis. Four patients required renal replacement therapy at the time of diagnosis. The induction regimen consisted of rituximab associated with IV boluses of methylprednisolone. The apheresis techniques used were the same for all patients, i.e. plasmapheresis. Outcomes were favorable for five patients;only one patient became dependent on hemodialysis. No mortality occurred. Conclusion: This study analyzed practices for the management of patients with ANCA vasculitis. No patient was treated with cyclophosphamide as a first approach but rituximab instead. Plasmapheresis was given because of symptoms severity at initial diagnosis.

Long-term prognosis of focal segmental glomerulosclerosis treated with therapeutic low-density lipoprotein-apheresis in patients with severe kidney dysfunction and proteinuria

Background:The prognosis of focal segmental glomerulosclerosis patients with nephrotic syndrome is estimated to be 10%-20%in 5 years and 30%-50%in 10 years,leading to end-stage kidney disease.The response rate with steroid therapy is 40%-60%.Therapeutic low-density lipoprotein-apheresis(LDL-A)may be effective in patients with steroid resistance.Information regarding the long-term prognosis of patients with focal segmental glomerulosclerosis receiving this therapy is scarce.Methods:We investigated the effectiveness of treatment in 50 patients with primary focal segmental glomerulosclerosis diagnosed between 1961 and 2017 at Kanazawa University Hospital and related facilities.The patients were observed at least 12 months after biopsy or until end-stage kidney disease occurrence or death.Results:LDL-A was performed in four patients who presented with steroidresistant nephrotic syndrome(two patients had concurrent acute renal failure for which hemodialysis was performed).In comparison with 17 patients who did not receive LDL-A after 1989,the LDL-A group had higher urinary protein excretion(13.7 vs.5.2 g/day,P=0.053)and serum creatinine(4.11 vs.1.65 mg/dL)levels at onset,and a numerically higher remission rate(75.0%vs.58.7%)compared with the nonlipoprotein-apheresis group.Conclusion:Therapeutic LDL-A can be performed for critical cases and may improve the remission rate.

Perioperative Single-Donor Platelet Apheresis and Red Blood Cell Transfusion Impact on 90-Day and Overall Survival in Living Donor Liver Transplantation

Background： Although many previous studies have confirmed that perioperative blood transfusion is associated with poor outcomes after liver transplantation （LT）, few studies described the influence of single-donor platelet apheresis transfusion in living donor LT （LDLT）. This study aimed to assess the effect of blood products on outcomes for LDLT recipients, focusing on apheresis platelets. Methods： This retrospective study included 126 recipients who underwent their first adult-to-adult LDLT. Twenty-four variables including consumption of blood products of 126 LDLT recipients were assessed for their link to short-term outcomes and overall survival. Kaplan-Meier survival curve and the log-rank test were used for recipient survival analysis. A multivariate Cox proportional-hazard model and a propensity score analysis were applied to adjust confounders after potential risk factors were identified by a univariate Cox analysis. Results： Patients who received apheresis platelet transfusion had a lower 90-day cumulative survival （78.9% vs. 94.2%, P = 0.009）, but had no significant difference in overall survival in the Cox model, compared with those without apheresis platelet transfusion. Units of apheresis platelet transfusion（hazard ratio[HR]=3.103,95% confidence interval[CI]：1.720–5.600,P〈0.001）and preoperative platelet count（HR=0.170,95% CI：0.040–0.730,P=0.017）impacted 90-day survival independently.Multivariate Cox regression analysis also found that units of red blood cell（RBC）transfusion（HR=1.036,95% CI：1.006–1.067,P=0.018）,recipient＇s age（HR=1.045,95% CI：1.005–1.086,P=0.025）,and ABO blood group comparison（HR=2.990,95% CI：1.341–6.669,P=0.007）were independent risk factors for overall survival after LDLT. Conclusions： This study suggested that apheresis platelets were only associated with early mortality but had no impact on overall survival in LDLT. Units of RBC, recipient＇s age, and ABO group comparison were independent predictors of long-term outcomes.

Efficacy and safety of granulocyte, monocyte/macrophage adsorptive in pediatric ulcerative colitis

AIM: To investigate efficacy and safety for granulocyte, monocyte apheresis in a population of pediatric patients with ulcerative colitis.METHODS: The ADAPT study was a prospective, openlabel, multicenter study in pediatric patients with moderate, active ulcerative colitis with pediatric ulcerative colitis activity index(PUCAI) of 35-64. Patients received one weekly apheresis with Adacolumn granulocyte, monocyte/macrophage adsorptive(GMA) apheresis over 5 consecutive weeks, optionally followed by up to 3 additional apheresis treatments over 3 consecutive weeks. The primary endpoint was the change in mean PUCAI between baseline and week 12; the secondary endpoint was improvement in PUCAI categorized as(Significant Improvement, PUCAI decrease of ≥ 35), Moderate Improvement(PUCAI decrease of 20 < 35), Small Improvement(PUCAI decrease of 10 < 20) or No change(PUCAI decrease of < 10). RESULTS: Twenty-five patients(mean age 13.5 years; mean weight 47.7 kg) were enrolled. In the intention-to-treat set(ITT), the mean value for PUCAI improvement was 22.3 [95%CI: 12.9-31.6; n = 21]. In the per-protocol(PP) set, the mean improvement was 36.3 [95%CI: 31.4-41.1; n = 8]. Significant Improvement was recorded for 9 out of 20 patients(45%); 5 out of 20 patients(25%) had Moderate Improvement and one patient(5%) had No Change in PUCAI score at week 12. In the PP set, six out of eight patients(75%) showed Significant Improvement; and in two out of eight patients(25%) Moderate Improvement was recorded. The endoscopic activity index(EAI) decreased by 3 points on average. Seven(7) out of 21(33%) patients in ITT and 4 out of 8(50%) patients in PP have used steroids during the clinical investigation. The mean steroid dosage for these patients in the ITT set decreased from a mean 12.4 mg to 10 mg daily on average from Baseline to week 12.CONCLUSION: Adacolumn; GMA apheresis treatment was effective in pediatric patients with moderate active Ulcerative Colitis. No new safety signals were reported. The present data contribute to considering GMA apheresis as a therapeutic option in pediatric patients having failed first line therapy.

Preparation and Adsorption Properties of PAM Based Adsorbents for Plasma Lipoproteins

Crosslinked macroporous polyacrylamide (PAM) was prepared with inverse phase suspension polymerization technique. After treatment with hydrazine, the polymer was functionalized with chloroacetic acid, trifluoroacetic acid diethylenetriaminepentaacetic acid (DEPAA), and maleic acid, respectively, and PAM based adsorbents bearing carboxyl functional groups for low density lipoprotein (LDL) apheresis use were obtained. The blood compatibility and the adsorption properties for plasma lipoproteins of PAM based adsorbents were investigated.

Current protocols and outcomes of ABO-incompatible kidney transplantation

One of the principal obstacles in transplantation from living donors is that approximately 30%are immunologically incompatible because of the presence in the recipient of antibodies directed against the human leukocyte antigen system of the donor or because of the incompatibility of the ABO system.The aim of this review is to describe the more recent data from the literature on the different protocols used and the clinical outcomes of ABO-incompatible kidney transplantation.Two different strategies are used to overcome these barriers:desensitization of the recipient to remove the antibodies and to prevent their rebound after transplantation and the exchange of organs between two or more pairs.The largest part of this review is dedicated to describing the techniques of desensitization.Even if the first reports of successful renal transplantation between ABO-incompatible pairs have been published by 1980,the number of ABO-incompatible transplants increased substantially in this century because of our improved knowledge of the immune system and the availability of new drugs.Rituximab has substantially replaced splenectomy.The technique of apheresis has improved and more recently a tailored desensitization proved to be the more efficient strategy avoiding an excess of immunosuppression with the related side effects.Recent reports document outcomes for such transplantation similar to the outcomes of standard transplantation.

Not All “BAD” Cholesterol Carriers Are Necessarily Bad and Not All “GOOD” Cholesterol Carriers Are as Good as Can Be: Plasma Delipidation, a Non-Pharmacological Treatment for Atherosclerosis

More than four decades ago it was established that an elevated low-density lipoprotein-cholesterol level was a risk for developing coronary artery disease. For the last two decades, statins have been the cornerstone of reducing low-density lipoprotein-cholesterol, but despite significant clinical efficacy in the majority of patients, a large number of patients suffer from side effects and cannot tolerate the required statin dose to reach their recommended low-density lipoprotein-cholesterol goals. Preliminary clinical studies indicate that monoclonal antibodies to PCSK9 appear to be highly efficacious in lowering low-density lipoprotein-cholesterol with a favourable adverse event profile. However, further longer-term clinical studies are required to determine their safety. From the early-proposed concept for high-density lipoprotein-mediated cholesterol efflux for the treatment of coronary artery disease, the concentration of the cholesterol content in high-density lipoprotein particles has been considered a surrogate measurement for the efficacy of the reverse cholesterol transport process. However, unlike the beneficial effects of the statins and monoclonal antibodies to PCSK9 in reducing low-density lipoprotein-cholesterol, no significant advances have been made to increase the levels of high-density lipoprotein-cholesterol. Here it is shown that by a non-pharmacological plasma delipidation means, the atherogenic low-density lipoproteins can be converted to anti-atherogenic particles and that the high-density lipoproteins are converted to particles with extreme high affinity to cause rapid regression of atherosclerosis.

Surface Treated Catheters for Vascular Access—Useful?

Background: Catheter-related infections (CRI), thrombosis, and stenosis are among the most frequent complications associated with catheters which are inserted in vessels as vascular access. These problems are usually related to the handling of the staff, the catheter materials, and the surface properties of the catheter. To mitigate such complications surface treatment process of the outer surface, such as ion beam assisted deposition is investigated in a retrospective study from 1992 to 2007, to prove if the surface treatment of the catheters is a sufficient solution. Methods: This study (1992-2007) evaluated silver coated and non-coated implanted large-bore catheters used for extracorporeal detoxification. In 159 patients, 54 patients received a silver coated catheter (Spi-Argent, Spire Corporation, Bedford, MA, USA) and 105 patients, an untreated catheter served as controls. The catheters were inserted into the internal jugular or subclavian veins. After removal, the catheters were cultured for bacterial colonization using standard microbiologic assays. They were also examined using a scanning electron microscope (SEM). Results: The silver coated catheters showed a tendency towards longer in situ time. The microbiologic examinations of the catheter tips were in both catheter types high positive, but not significant. Conclusion: The silver coated catheters showed no significant reduction in infection rate by evaluation of all collected data in this retrospective study. There was no association between both catheters in significantly reducing patient discomfort. Other surface treatments which include the outer and inner surface are necessary. New developed catheter materials such as the microdomain structured inner and outer surface, as an example, are considered more biocompatible because they mimic the structure of natural biological surface.

Higher efficacy of oral etoposide for mobilization of peripheral blood stem cells in patients with multiple myeloma

This study compares the efficacy,toxicity,hematopoietic recovery,and cost of stem-cell mobilization using intermediate-dose cyclophosphamide(IDCy)plus granulocyte colony-stimulating factor(G-CSF)compared with etoposide(VP-16)plus pegylated granulocyte colony-stimulating factor(PEG-rhG-CSF)in multiple myeloma(MM)patients.Two hundred forty-four consecutive patients undergoing mobilization with IDCy(3-3.5g/m^(2))plus G-CSF(n=155)were compared with patients receiving VP-16 plus PEG-rhG-CSF(n=89),including oral etoposide(n=65)and intravenous etoposide(n=24).Compared with IDCy,VP-16 use was associated with significantly higher median peak peripheral blood CD34+cell count(8.20[range:1.84-84]×10^(6)/kg vs 4.58[range:0.1-27.9]×10^(6)/kg,P=.000),and ideal CD34+cell yield of more than 6×10^(6)/kg(56.8%vs 35.1%,P=.001),notably with a higher efficacy in oral VP-16 use compared with IDCy use(CD 34+cell counts:median peak peripheral blood 5.87 vs 4.58?106/kg and≥6×10^(6)/kg[48.4%vs 35.1%]).The median number of apheresis courses was reduced from two in the IDCy group to one in the VP-16 group(P=.000).IDCy use was associated with significantly more frequent episodes of neutropenia(70.2%vs 35.2%;P=.000),intravenous antibiotic use(13.2%vs 11.4%;P=.672),and hospitalization(P=.000).The recoveries of neutrophils and platelets after autologous stem-cell transplantation were significantly faster in the VP-16 group compared with the IDCy group(P=.000).Our data indicate robust stem-cell mobilization in MM patients with VP-16 delivered either orally or intravenously.When compared with intravenous VP-16,oral VP-16 mobilization was associated with significantly more convenient,lower average total costs,and especially decreased the risk of hospital visits and exposure.