Standard Immunosuppressive Therapy Research Articles

Efficacy of plasma exchange on top of standard immunosuppressive therapy in adult autoimmune inflammatory rheumatic diseases-associated macrophage activation syndrome, a single center real-world analysis

BackgroundThere is a lack of documented real-world evidence about the efficacy of current therapeutics for autoimmune inflammatory rheumatic diseases (AIIRD)-associated adult macrophage activation syndrome (MAS). ObjectiveTo analyze the efficacy of different treatments, especially plasma exchange (PE), in AIIRD-associated MAS. MethodsAmong 5775 patients with AIIRD in Tongji Hospital from 2014 to 2020, 62 AIIRD-associated MAS cases were collected. Unadjusted logistic regression, least absolute shrinkage and selection operator (LASSO), and inverse probability of treatment weight (IPTW) analyses were used to characterize the clinical features and potential factors related to the prognosis. Paired t-test was used to compared the changes of inflammatory indicators before and after PE treatment. ResultsThe baseline data was defined as the data collected at the onset of MAS, and all of the 62 patients were diagnosed as AIIRD before MAS onset. The prevalance rate of MAS in AIIRD was 1.1%, and the most common types of AIIRD were systemic lupus erythematosus (45.2%) and adult-onset Still's disease (33.9%). All 62 MAS patients received glucocorticoids, 87.1% patients used at least one immunosuppressive agent, and 54.8% received PE. LASSO regression indicates a positive effect of PE on the basis of variables. After PE treatment, serum levels of multiple inflammatory cytokines were rapidly reduced, accompanied by improvements in clinical symptoms and laboratory indecies including ferritin, lactate dehydrogenase, and C-reactive protein. LASSO regression indicates that PE treatment was associated with a marked reduction of mortality (from 53.6% to 11.8%), with a hazard ratio (HR) of 0.148 (p < 0.001) after adjustment for confounding factors using IPTW analysis. ConclusionWith the background therapy of glucocorticoids and immunosuppressive agents, PE is an effective approach to rapidly clear inflammatory cytokines and reduce mortality of AIIRD-associated MAS. Clinical implicationThis study provided real-world information on the efficacy of PE in AIIRD-associated MAS.

The first experience of cord blood stem cells application in kidney transplantation: A descriptive study

Abstract. Kidney transplantation is recognized as the optimal method of end-stage kidney disease treatment, but chronic renal allograft rejection remains an unresolved issue and leads to transplanted organ function loss. Recent studies show positive effects of stem cell injections in a variety of diseases, including kidney transplantation.&#x0D; The present study aimed to analyze the first experience of umbilical cord blood stem cells application in living-related kidney transplantation in Shalimov’s National Institute of Surgery and Transplantation, give a preliminary assessment of their effectiveness and safety, evaluate the clinical course and especially the dynamics of laboratory parameters in the recipient’s postoperative period.&#x0D; Methods. The study group included 6 male, adult recipients of kidney transplants, who performed the first kidney allotransplantation from a living family donor in the Shalimov’s National Institute of Surgery and Transplantology in 2020 – 2021. Before surgery, all patients received intravenous administration of a fraction of nuclear cells from human umbilical cord blood at a dose of 2-3 x 106/kg body weight in combination with standard three-component immunosuppressive therapy. Immune system studies were performed before kidney transplantation, on the first and third days of the postoperative period, at the end of the first and second week, as well as on the first, third, sixth, and twelfth months, following kidney transplantation. Renal graft function was assessed by serum creatinine and glomerular filtration rate. Monitoring of clinical and laboratory parameters of blood and urine, the concentration of calcineurin inhibitors (C0) was carried out regularly three times a week for the first month, twice a month for 2-3 months, and once a month until the end of the year.&#x0D; Puncture biopsy of the transplanted kidney was performed three months after surgery to diagnose the pathology of the graft, namely the manifestations of acute and chronic rejection, the nature and degree of which were determined according to the Banff classification.&#x0D; The state of the immune system of the recipients was characterized by indicators of cellular and humoral immunity.&#x0D; Statistical processing of research results was performed using the statistical package StatSoft (2010) STATISTICA 9.1 for Windows StatSoft Inc, Tusla.&#x0D; Results. All patients received cord blood stem cells without complications. On the first day after surgery, an average diuresis was 9415 ± 928.1 ml. Normalization of graft function was observed on the second or third day (GFR more than 90 ml/ min/1.73 m2). There were no rejections of grafts and signs of opportunistic infections in the patients during 1 year follow-up period. Morphological studies did not reveal signs of significant pathological changes in transplanted kidneys in patients who received stem cells as induction therapy.&#x0D; The study of the state of the immune system of recipients in the dynamics, given the insufficient number of patients, requires further research.&#x0D; Conclusions. The administration of cord blood stem cells to recipients prior to kidney transplantation is safe and promotes rapid recovery of renal allograft function. There were no signs of morphological proven chronic graft rejection, which allows us to predict its long-term functioning in the future. To assess the response of the recipient's immune system to the application of cord blood stem cells requires the accumulation of additional data.

A multicentre trial of intensive immunosuppressive therapy combined with umbilical cord blood for the treatment of severe aplastic anaemia

Immunosuppressive therapy (IST) is an effective treatment regimen for severe aplastic anaemia (SAA) patients without HLA-identical donors. This study further compared the outcomes between IST and IIST-UCB in SAA on the basis of research shown that IST combined with umbilical cord blood infusion (IIST-UCB) treated effectively. A total of 123 patients from 11 hospitals in China were enrolled. Sixty-nine patients in IIST-UCB group were treated with ATG + CsA + CTX combined with cord blood, while 54 patients in IST group with ATG + CsA. The overall remission rates (ORRs), complete remission (CR) rates and partial response (PR) rates of IIST-UCB group and IST group at 3 months were 69.67% vs 51.85% (P = .045), 21.74% vs 3.7% (P = .004) and 47.83% vs 48.15% (P = .972), respectively. After 6 months of treatment, they were 76.81% vs 57.41% (P = .022), 37.68% vs 11.11% (P = .001) and 39.13% vs 46.30% (P = .425), respectively. After 1 year of treatment, they were 85.51% vs 61.11% (P = .002), 59.42% vs 25.93% (P = .000) and 26.09% vs 35.19% (P = .275), respectively. The ORRs and CR rates of IIST-UCB group were both significantly higher than IST group after 3 months, 6 months and 1 year of treatment. The neutrophil granulocyte, platelet and haemoglobin recovery times of IIST-UCB group were significantly shorter than IST group. Compared with standard IST, IIST-UCB as an effective therapy for SAA patients without HLA-identical donors accelerated the haematopoietic reconstitution, resulting in higher early CR rates.

New Trends in Nontransplant Therapy for Acquired Aplastic Anemia.

Aplastic anemia (AA) is a hematological disease characterized by pancytopenia and hypofunctional bone marrow hematopoiesis. Patients with AA are treated with either immunosuppressive therapy (IST) using anti-thymocyte globulin (ATG) and cyclosporine (CsA) or hematopoietic stem cell transplantation (HSCT), if a matched donor is available. The standard IST regimen for AA patients results in response rates up to 70% and even higher overall survival. However, primary and secondary failures after IST remain frequent, and to date, all attempts aiming to overcome this problem have been unfruitful. The nontransplant therapeutic options for AA have significantly expanded during the last few years. Here, we review the new trends of nontransplant therapy for AA and summarize the current therapeutic effect of AA.

Pathogenic T-Cell Responses in Immune-Mediated Glomerulonephritis.

Glomerulonephritis (GN) comprises a group of immune-mediated kidney diseases affecting glomeruli and the tubulointerstitium. Glomerular crescent formation is a histopathological characteristic of severe forms of GN, also referred to as crescentic GN (cGN). Based on histological findings, cGN includes anti-neutrophil cytoplasmic antibody (ANCA)-associated GN, a severe form of ANCA-associated vasculitis, lupus nephritis associated with systemic lupus erythematosus, Goodpasture’s disease, and IgA nephropathy. The immunopathogenesis of cGN is associated with activation of CD4+ and CD8+ T cells, which particularly accumulate in the periglomerular and tubulointerstitial space but also infiltrate glomeruli. Clinical observations and functional studies in pre-clinical animal models provide evidence for a pathogenic role of Th1 and Th17 cell-mediated immune responses in cGN. Emerging evidence further argues that CD8+ T cells have a role in disease pathology and the mechanisms of activation and function of recently identified tissue-resident CD4+ and CD8+ T cells in cGN are currently under investigation. This review summarizes the mechanisms of pathogenic T-cell responses leading to glomerular damage and renal inflammation in cGN. Advanced knowledge of the underlying immune mechanisms involved with cGN will enable the identification of novel therapeutic targets for the replacement or reduction in standard immunosuppressive therapy or the treatment of refractory disease.

MO999: Intra-Patient Variability of Tacrolimus in Kidney Transplant Patients: An Experience of a Kidney Disease Specialist Hospital

Abstract BACKGROUND AND AIMS The complexity of tacrolimus pharmacokinetics results in a unique tacrolimus recommendation in transplant centers and global level [1]. Intra-patient variability (IPV) of tacrolimus has become a simple and interesting marker to predict transplant outcomes in addition to minimum concentration (Cmin) monitoring [2–4]. As differences in ethnic affecting tacrolimus pharmacokinetics and patient response, we investigated a pilot study of tacrolimus IPV in our institution. METHOD The cohort study was conducted in all new kidney transplant patients receiving twice-daily tacrolimus as a standard immunosuppressive therapy. Patients were switched from twice-daily tacrolimus to other immunosuppressive agents were excluded from the study. All patients were followed-up at an outpatient clinic with routine monitoring. A one-year follow-up period was evaluated in the study. The primary outcome was the IPV of tacrolimus during the 3–12 months after transplantation. IPV of tacrolimus Cmin was calculated by [SD/(mean tacrolimus dose-normalized Cmin)] × 100.5 We categorized the IPV of tacrolimus into three levels: low (0%–10%), intermediate (11%–30%) and high IPV (&amp;gt;30%). The secondary outcomes were to assess renal function by eGFR and pre-defined factors associated with the IPV of tacrolimus. The study protocol was reviewed and approved by the Thai Clinical Trial Registry (TCTR20210519005). RESULTS There were 56 patients who underwent kidney transplantation during the study period. Of these 56 patients, 12 patients experienced late conversion from twice-daily to once-daily tacrolimus or were combined with sirolimus, and 4 patients became lost to follow-up. A total of 40 patients completed the one-year study period and were included in the analysis. The mean age of patients was 50.85 ± 11.07 years. A total of 39 patients received basiliximab, and one patient received anti-thymoglobulin as an induction therapy. Baseline characteristics are shown in Table 1. At 3–12 months after transplantation, the mean IPV of tacrolimus was 23.77% ± 11.23%. When categorized patients according to %IPV of tacrolimus, we found that most patients were in the intermediate IPV. The percentage of patients in each category was 7.5%, 65% and 27.5% of patients in low, intermediate and high IPV of tacrolimus, respectively (Fig. 1). The eGFR at discharge of patients with high IPV was significantly lower than that with low to intermediate IPV (P = .0282). For pre-defined factors associated with IPV of tacrolimus, the hemoglobin level at 3 months of patients with high IPV (11.23 ± 1.72 g/dL) was significantly lower than that of patients with low to intermediate IPV (12.54 ± 1.77, P = .0425). All patients were compliant as measured by pill counts and no difference in drug interaction between groups. Renal function remained stable and was similar between groups at one year of follow-up (52.03 ± 14.74 and 57.93 ± 16.40 mL/min/1.73 m2P = .3254 for high IPV and low to intermediate IPV, respectively). CONCLUSION Our findings showed that most patients were in low to intermediate IPV of tacrolimus. A low level of eGFR at discharge and a low level of hemoglobin in the early-post transplant period were associated with high IPV of tacrolimus. Therefore, clinicians should be cautious to monitor levels and adjust the dose of tacrolimus, especially if patients at risk of tacrolimus variability. A practical calculation of IPV provides a tremendous benefit for clinicians to individualized tacrolimus therapeutic drug monitoring. This study was a starting point and would expand for our large patient population. Clinical correlation with IPV of tacrolimus and IPV-directed interventions for Asian population are needed to improve tacrolimus using for achieving transplant outcomes.

MO1005: Analysis of Expression of Immune System Genes that are Responsible for Activation and Inhibition of T-Cell Immune Response in Renal Transplant Recipients after Extracorporeal Photochemotherapy

Abstract BACKGROUND AND AIMS Due to the increasing need for kidney transplantation, there is a demand for new methods of preventing rejection of the transplant based on the mechanisms of natural regulation of the immune response. Extracorporeal photopheresis (ECP) is one of these technologies whose clinical efficacy in the prevention and treatment of acute renal transplant rejection has been confirmed by many studies, but the mechanism of its effect has not been fully understood. Characterization of the genes responsible for the activation and inhibition of the immune response during ECP is an important step towards the modification of immunosuppressive therapy. The aim of this study was to analyze the changes in the expression level of the genes responsible for the activation and inhibition of the T-cell response in the recipients of the renal graft after ECP. METHOD An open cohort randomized trial was conducted with 20 patients who underwent a single group cadaver kidney transplantation from an unrelated donor. The recipients of the compared groups received standard immunosuppressive therapy and the same therapy in combination with ECP procedures, according to the study protocol. Each recipient of the main group received 15 sessions of ECP within 6 months. The level of gene expression was analyzed by real-time RT-PCR. Comparison of the study groups was carried out at point 1 (1st–4th day) and 2 (30th day). RESULTS The analysis of clinical data did not show statistically significant clinical differences, but in the specific consideration of each pair of cases, the tendency to some improvement in the transplant organ engraftment rate in the early terms after the transplant, and better survival of the graft and the recipient was revealed. For instance, patients of the main group revealed no transplant rejection by clinical laboratory signs as well as the results of histological examination of biopsy specimens. In the comparison group, acute graft rejection was clinically diagnosed and was confirmed by histological examination as humoral type rejection. The level of expression of genes involved in immune response regulation (CD28, CTLA4, PDL1 and FOXP3) and cytokine genes (TNFA, IL1, IL2, IL10 and IFNG) in the studied groups was determined. A decrease in the level of expression of the genes for the proinflammatory cytokines IL1, IL2 and IFNG was noted by the 30th day after transplantation. At the same time, the expression of the genes PDL1 and FOXP3, which regulate the development of the regulatory response, significantly increased by the 30th day after transplantation. Correlations of the level of gene expression with the presence/absence of rejection episodes have not been established. To assess the effect of the ECP on these gene expression, a comparison was made of the level sof transcript representation of patients receiving standard immunotherapy and immunotherapy in combination with ECP, and a significant increase in the expression of PDL1 and FOXP3 genes (Fig. 1A and B) was found in the group of patients who underwent ECP procedures (P = .0009 and .0013, respectively). CONCLUSION According to the results of comparative analysis, the level of expression of pro-inflammatory cytokines' genes IL1, IL2 and IFNG decreased to the 30th day after transplantation. A 30-day comparison between groups shows an increase in the expression level of the PDL1 and FOXP3 genes. Increased expression of these genes may be associated with the activation of regulatory T-cells and the development of peripheral tolerance and can become a criterion for the modification of immunosuppressive therapy.

Abstract 55: Statin Type Does Matter: Decreasing Incorrect Statin Administration For Hospitalized Heart Transplant Patients

Background: Statin therapy has been shown to prevent the development of transplant coronary artery disease (TCAD) in heart transplant (HT) patients. Pravastatin is used in HT patients as it does not depend on CYP3A4 metabolism. Other widely used statins, such as simvastatin, have significant drug-drug interactions with the calcineurin inhibitors, which are used as standard immunosuppression therapy for all HT patients. Objective: Our goal was to increase correct statin administration for HT patients from 41-43% to 80% by June 2021 through electronic medical record (EMR) modification and interprofessional communication with the pharmacy department. Methods: Previous to our intervention, the EMR would recommend ordering simvastatin when ordering pravastatin, due to simvastatin being the hospital formulary preferred statin. The EMR did not cross reference HT status, and that pravastatin should be ordered instead. Our intervention was to remove the EMR notification for HT patients recommending simvastatin, as well as working with the clinical heart transplant pharmacists to mediate communication with primary teams. Monthly data was obtained through retrospective chart review. Results: Following our intervention in March 2021, pravastatin was ordered for 67%, 78%, and 81% of heart transplant readmissions in April, May, and June 2021, respectively (Table 1). Conclusion: Our intervention of EMR modification as well as interprofessional communication has almost doubled the correct administration of pravastatin in HT admissions from 41% to 81% over the course of seven months. Prescribing the proper statin for HT patients prevents unwanted toxicities, as well as TCAD - a major limitation to longevity amongst HT patients. Further educational interventions will be implemented for providers to achieve 100% correct statin administration to patients with heart transplant.

PcMSC Modulates Immune Dysregulation in Patients With COVID-19-Induced Refractory Acute Lung Injury.

Background and ObjectivesThe novel coronavirus disease 2019 (COVID-19) has been a pandemic health issue in 30 January 2020. The mortality rate is as high as 50% in critically ill patients. Stem cell therapy is effective for those who are refractory to standard treatments. However, the immune responses that underlie stem cell therapy have not been well reported, particularly, in patients associated with moderate to severe acute respiratory distress syndrome (ARDS).MethodsOn Days 0 and 4, an intravenous infusion of 2 × 107 placenta-derived mesenchymal stem cells (pcMSCs) (MatriPlax) were administered to five severe COVID-19 patients refractory to current standard therapies. Peripheral blood inflammatory markers and immune profiles were determined by multi-parameter flow cytometry and studied at Days 0, 4, and 8. Clinical outcomes were also observed.ResultsNone of the pc-MSC treated patients experienced 28-day mortality compared with the control group and showed a significant improvement in the PaO2/FiO2 ratio, Murray’s lung injury scores, reduction in serum ferritin, lactate dehydrogenase (LDH), and C-reactive protein (CRP) levels. The cytokine profiles also showed a reduction in IL-1β, IFN-γ, IL-2, and IL-6, and an increase in IL-13 and IL-5 type 2 cytokines within 7 days of therapy. Lymphopenia was also significantly improved after 7 days of treatment. Immune cell profiles showed an increase in the proportions of CD4+ T cells (namely, CD4+ naïve T cells and CD4+ memory T cell subtypes), Treg cells, CD19+ B cells (namely, CD19+ naïve B cells, CD27+ switched B cell subtypes) and dendritic cells, and a significant decrease in the proportion of CD14+ monocytes (namely, CD16- classical and CD16+ non-classical subtypes), and plasma/plasmablast cells. No adverse effects were seen at the serial follow-up visits for 2 months after initial therapy.Conclusionpc-MSCs therapy suppressed hyper-inflammatory states of the innate immune response to COVID-19 infection by increasing Treg cells, decreasing monocytes and plasma/plasmablast cells, and promoting CD4+ T cells and CD19+ B cells toward adaptive immune responses in severely critically ill COVID-19 patients with moderate to severe ARDS, especially those who were refractory to current standard care and immunosuppressive therapies.

Lung Transplantation and Extracorporeal Photopheresis as Induction Therapy in Cystic Fibrosis Patients: Immune System Profile Changes

<h3>Purpose</h3> Acute rejection (AR), common during the first year after lung transplantation (LuTx), can trigger chronic rejection (CR), the leading cause of late morbidity and mortality of LuTx. Extracorporeal photopheresis (ECP) has emerged as a promising treatment for chronic rejection. Only few studies are focus on ECP as prophylactic therapy of AR and CR. This study aims to verify, in recipients affected by cystic fibrosis (CF), whether the induction therapy with ECP can decrease the rate of AR, in order to impact positively on CR (primary end point: survival, AR). The expected results are the reduction of AR episodes in its clinical and histopathological manifestations. <h3>Methods</h3> This is a pilot clinical trial on 20 CF lung-transplanted patients, randomize, 2 parallel arms: standard immunosuppressive therapy and ECP (ECP) vs standard immunosuppressive therapy alone (CTR). We investigated the effect of ECP by the evaluation of lymphocyte immunophenotype by multiplex essay (CD4 + and CD25 +), the cytokine profile, the leukocytes subsets (by flow cytometry) in blood and BAL at different time points. AR episodes and infections were recorded, as far as ECP-related adverse events. <h3>Results</h3> No differences were detected in terms of AR episodes. Treg cells were significantly increased in the ECP group at 3 weeks post LuTx, and this difference was more evident 1 year post LuTx . Th17 cells were diminished in the ECP group. The anti-inflammatory IL10-producing NKs were significantly increased in the ECP group. Cytokine profile, both in BAL and plasma obtained at defined time points shows that in ECP group pro-inflammatory cytokines were early reduced and anti-inflammatory cytokines were upregulated. <h3>Conclusion</h3> In FC lung transplanted patients ECP was well tolerated without increasing in opportunistic infections. Its tolerogenic effect was not pointed out in terms of AR episodes, but has been confirmed in the immunological setting of ECP patients vs control: it prevents decline in Treg and NK observed with standard immunosuppressive drugs, with higher expression of anti-inflammatory cytokines (Il10, Il1RA) and less pro-inflammatory ones (Il1beta, Il6). Its effect is more evident months after the end of ECP treatment. The schedule of ECP prophylactic treatment has to be tested in an ampler cohort in order to reach its best immunomodulatory effect.

Use of Basiliximab in Recipients Who Required Dose Reduction or Discontinuation of Calcineurin Inhibitors Early After Lung Transplantation

<h3>Purpose</h3> The standard immunosuppressive therapy after lung transplantation is a combination of calcineurin inhibitors (CNIs), antimetabolites, and corticosteroids. In the cases where CNIs need to be reduced or discontinued early after transplantation due to renal dysfunction or other side effects, basiliximab is used as an alternative at our hospital. In this study, we investigated the efficacy and safety of basiliximab administered early after transplantation as an alternative of CNIs. <h3>Methods</h3> All lung transplant recipients between April 2002 and April 2021 at our hospital were retrospectively reviewed. Among 272 lung transplant recipients (108 living-donor, 163 deceased-donor, and 1 hybrid), 18 recipients were treated with basiliximab due to the need for CNI reduction or discontinuation. We reviewed indications of basiliximab and the outcome. Acute rejection was diagnosed based on radiologic and clinical parameters without transbronchial biopsy. The incidence of clinically diagnosed acute rejection and that of chronic lung allograft dysfunction (CLAD) were compared between the basiliximab group (n = 18) and the non-basiliximab group (n = 254). <h3>Results</h3> The indications of basiliximab were preoperatively existing poor renal function (n = 11) postoperative acute kidney disease (eGFR < 50, n = 4), and posterior reversible encephalopathy syndrome (PRES, n = 3) due to CNIs. The first dose of basiliximab (20 mg for adults, 10 mg for children) was administered postoperatively (median 0, range 0-7 days) and the second dose was administered 4 days later. No apparent adverse effects were encountered. None of the recipients with poor renal function required dialysis in the perioperative period, and all the recipients with PRES showed complete recovery. The incidence of clinically diagnosed acute rejection before discharge was 44.4% in the basiliximab group and 41.3% in the non-basiliximab group (<i>p</i> = 0.81). Five-year CLAD-free survival was 50% in the basiliximab group and 60.6% in the non-basiliximab group (<i>p</i> = 0.41). <h3>Conclusion</h3> The use of basiliximab as an alternative of CNIs early after lung transplantation was safe and increased neither the risk of acute rejection nor CLAD.

Patients with treated autoimmune hepatitis and persistent suppression of plasmacytoid dendritic cells: A different point of view.

Objectives: Plasmacytoid dendritic cells (pDCs) have been shown to have a role in autoimmune diseases, but their role in Autoimmune Hepatitis (AIH) is not completely clear. In the present study, we assessed the frequency of pDCs in peripheral blood of AIH patients under long-term standard immunosuppressive therapy. Methods: This cross-sectional analysis enrolled 27 AIH patients and 27 healthy controls. We analyzed and compared their proportion of pDCs, CD4+, CD8+, γδ T cells, CD25+ regulatory T (Treg) cells, FoxP3+, Foxp3+CD39+ Treg cells, total B (CD19+) cells, and plasma cells (CD38+) in peripheral blood using flow cytometry immunophenotyping. Results: AIH patients had a lower percentage of pDCs (median frequencies of 0.2% vs. 0.4%; p = .002) and higher expression of CD8 T cells (32.5% vs 28.6%; p = 0.008) in peripheral blood, when compared to healthy controls. We did not find statistically significant differences between the groups regarding the other cell subtypes.Conclusion: Our data suggest a persistent suppression of pDCs in AIH patients, along with increased CD8 T cell activity, years after AIH diagnosis and despite of good clinical response to treatment, thus pointing to a role of pDCs in the AIH pathogenesis.

A New Immunosuppressive Therapy for Very Severe Aplastic Anemia in Children with Autoantibodies.

At present, a number of very severe aplastic anemia (VSAA) patients cannot receive hematopoietic stem cell transplantation (HSCT) or standard immunosuppressive therapy (IST) due to the high cost of therapy, shortage of sibling donors, and lack of resources to support the HSCT. In addition, some VSAA patients with autoantibodies have no life-threatening infections or bleeding at the time of initial diagnosis. Considering the disease condition, economics and other factors, the present study designed a new and relatively mild treatment strategy: cyclosporine A plus pulsed high-dose prednisone (CsA+HDP). The present study retrospectively analyzed 11 VSAA patients, who were treated with CsA+HDP in our hospital from August 2017 to August 2019. The median follow-up time for these patients was 24.9 months. The overall response rate was 54.5% (6/11) at six months after the initiation of IST and 81.8% (9/11) at deadline. Five patients achieved complete remission and four patients met the criteria for partial response at the last follow-up. The median time to response for responders was 110 days. Three patients underwent HSCT due to the poor effect of CsA+HDP or to find a suitable transplant donor. Recurrence and clonal evolution were not found in any of these patients. The estimated 3-year overall survival rate and 3-year failure-free survival rate were 100.0% and 72.7%, respectively. In addition, the results revealed that the cyclosporine-prednisone-associated toxicity was mild and well-tolerated by most patients. The novel CsA+HDP regimen has good therapeutic effect and safety for VSAA patients with autoantibodies, who have no serious life-threatening infections or bleeding at the time of initial diagnosis.

Cystinosis in Pediatric Renal Transplant Recipients: A Case-Control Study From Kuwait.

Cystinosis is the most frequent cause of the inherited renal Fanconi syndrome and is also potentially treatable. In this study, we have reported our single-center experience of the longterm outcomes of kidney transplant in patients with cystinosis. Pediatric patients with cystinosis (n = 17) were compared with a matched control group without cystinosis (n = 126). The 2 groups were compared with regard to demographic data, posttransplant complications, and graft and patient outcomes. Most patients with cystinosis were male teenagers (52.9%) with comparable mean age (12.4 ± 4.1 vs 14 ± 3.1 years) versus the group without cystinosis. The 2 study groups were comparable with regard to type of dialysis, type of donor, blood group, and pretransplant comorbidities (P > .05). Patients with cystinosis received significantly more potent induction therapy (P < 0.05), but both groups were maintained on comparable immunosuppressive regimens (mostly tacrolimus based) (P > .05). Most grafts in both groups displayed immediate graft function. The percentage of patients with cystinosis with primary graft function was significantly higher than the percentage of those patients without cystinosis who had primary graft function (P = .024); this was associated with a relatively lower baseline creatinine level, although this was not significant (P > .05). Posttransplant complications, especially posttransplant diabetes, cytomegalovirus viremia, or BK nephropathy, were comparable (P > .05). Moreover, patient and graft survival rates were similar in the 2 groups (P > .05). Under standard immunosuppression, renal transplant and cysteamine therapy were safe with good long-term outcomes in patients with cystinosis. Studies that can include more patients and that have longer follow-up are needed to better understand the nature of this genetic disease and to discover the best treatment options.

Sitagliptin: A promising DPP-4 inhibitor for prevention of acute graft versus host disease.

Madam, allogeneic hematopoietic stem cell transplant (HSCT) remains a life altering cure to exceptionally challenging diseases ranging from hematologic malignancies to primary immunodeficiencies and blood cancers. One of its adversities includes graft versus host disease (GVHD), a lethal immunologically mediated condition wherein the donor's T-cells attack the host's tissues. The presentation can be classified as acute or chronic. Acute GVHD is divided into four grades. Despite current prophylaxis, including a combination of calcineurin inhibitor with either methotrexate or sirolimus, the incidence of grade-II or higher GVHD is between 30% to 80%, with grade-IV GVHD approaching mortality rates up to 90%.1 A recent phase II trial by Farag et al. addresses the issue by introducing a novel combination of sitagliptin – a specific DPP-4 inhibitor used to manage type 2 diabetes in adults – along with tacrolimus and sirolimus for prevention of GVHD.2 Using the new blend, an overall marked reduction in the risks of grade-II to IV (5%) and grade-III to IV (3%) acute GVHD was shown, compared to previous studies using only sirolimus and tacrolimus.3 Moreover, no adverse effects were associated with the drug during the period of study. Advancements in the field of HSCTs are particularly crucial in developing countries such as Pakistan. The high prevalence of consanguineous marriages and insufficient genetic counselling make the country especially vulnerable to diseases like thalassemia, bone marrow failure syndromes and immunodeficiency states. Up to 9000 children require transplantation each year due to the high prevalence of beta- thalassemia major.4 The situation is further complicated by limited resources and few stem cell transplant centres, which are limited to major cities. Although HSCT efficiently treats numerous life-threatening conditions, only 719 patients underwent HSCT till mid-2017 cumulatively in Pakistan.4 In accordance with the aforementioned factors, the number of transplants performed heavily outnumbers their demand, making it essential to tackle a complication as deadly as acute GVHD. In a 2005 study conducted in Rawalpindi by Hashmi et al., the overall incidence of acute GVHD grade-II to IV after standard immunosuppressive therapy was 44.2%.5 While the results were comparable to other studies, the high f morbidity and mortality rates necessitates alternate treatment courses. Sitagliptin, a locally manufactured, cost-effective drug, will be an appropriate choice of medication in Pakistan where average income amounts to a meagre US$1000 per year.4 However, randomized trials are needed to further investigate its role in the prevention of acute GVHD. Continue....

Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia

BackgroundA single-group, phase 1–2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia.MethodsIn this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months.ResultsPatients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P=0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome.ConclusionsThe addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.)

A multicenter phase II study on the efficacy and safety of hetrombopag in patients with severe aplastic anemia refractory to immunosuppressive therapy

Background:In this single-arm phase II study (NCT03557099), we evaluated the efficacy and safety of hetrombopag, a small molecule thrombopoietin (TPO) receptor agonist, in patients with severe aplastic anemia (SAA) who were refractory to standard first-line immunosuppressive therapy (IST).Methods:SAA patients who were refractory to standard first-line IST were given hetrombopag orally at an initial dose of 7.5 mg once daily to a maximum of 15 mg once daily, for a total of 52 weeks. The primary endpoint was proportion of patients achieving hematologic responses in ⩾1 lineage at week 18.Results:A total of 55 eligible patients were enrolled and received hetrombopag treatment. This study met its primary endpoint, with 23 [41.8%, 95% confidence interval (CI) = 28.7–55.9] patients achieving hematologic response in ⩾1 lineage at week 18 after initiation of hetrombopag treatment. Twenty-four (43.6%, 95% CI = 30.3–57.7) and 27 (49.1%, 95% CI = 35.4–62.9) of the 55 patients responded in ⩾1 lineage at weeks 24 and 52, respectively. Median time to initial hematologic response was 7.9 weeks (range = 2.0–32.1). The responses were durable, with a 12-month relapse-free survival rate of 82.2% (95% CI = 62.2–92.2). Adverse events occurred in 54 (98.2%) patients, and 28 (50.9%) patients had treatment-related adverse events. Seventeen (30.9%) patients had adverse events of grade ⩾3. Serious adverse events occurred in 15 (27.3%) patients and three deaths (5.5%) were reported.Conclusion:Hetrombopag showed encouraging efficacy with durable hematologic responses in patients with SAA who were refractory to IST. Hetrombopag was well tolerant and safe for long-term use.ClinicalTrials.gov identifier:NCT03557099

Use of oral vancomycin in children with autoimmune liver disease: A single centre experience.

BACKGROUNDPrevious reports showed some beneficial effect of oral vancomycin treatment (OVT) in children with primary sclerosing cholangitis; conversely, the experience in patients with other autoimmune liver diseases (AILD), including autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC), is scant. AIMTo assess the response to immunosuppressive treatment (IS) and to OVT in children diagnosed with AILD.METHODSRetrospective study of children diagnosed with AIH (normal biliary tree at cholangiography) and ASC (abnormal biliary tree at cholangiography) in the last 10 years. All underwent standard immunosuppressive therapy (IS), but non-responders received also OVT. Biochemical remission [normal aspartate aminotransferase (AST)] and immunological remission (normal IgG and negative autoantibodies) rates and Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) index were assessed and compared during the follow up.RESULTS75 children were included [69% female, median age 10.5 years (5.6-13.4 years), AIH = 54, ASC= 21]. Sixty-three patients (84%, AIH = 52, ASC = 11) were treated with standard IS and 61 achieved biochemical remission, whereas 12 not responding to IS [16%, F = 75%, median age 13.5 years, (12.2-15.7), 10 with ASC] required OVT and 8 achieved biochemical remission. Overall OVT increased the biochemical remission rate of the whole group of AILD patients from 81% (61/75) to 92% (69/75). Median values of AST, alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) decreased significantly after OVT start (P < 0.05). Complete normalization of livers enzymes (AST, ALT and GGT) was observed in 6/12 patients (50%). Decrease in SCOPE index score was reported in 5/12 patients (42%). At last follow up (median of 4.4 years, range 0.6-13.8 years) all 75 patients are alive, 6 (8%, 1 with ASC) successfully discontinued medications, 1 (with ASC) required liver transplantation.CONCLUSIONChildren with AIH and ASC respond well to IS treatment. OVT may represent a valuable treatment option to achieve biochemical remission in patients not responding to standard IS. These promising preliminary results suggest that a prospective study is indicated to define the efficacy of OVT in AILD.

Efficacy and safety analysis of eltrombopag and recombinant human thrombopoietin combined with immunosuppressive therapy for severe aplastic anemia

目的评价艾曲泊帕、重组人血小板生成素（Recombinant human thrombopoietin, rhTPO）联合标准免疫抑制治疗（Immunosuppressive therapy, IST）对重型再生障碍性贫血（Severe aplastic anemia, SAA）的疗效及安全性。方法回顾性分析2017年1月1日至2020年6月30日河南省肿瘤医院16例接受IST联合艾曲泊帕、rhTPO治疗的SAA患者，评价其疗效及安全性。结果艾曲泊帕、rhTPO联合标准IST治疗后3个月血液学反应率为81.3％，完全血液学缓解率为37.5％，6个月血液学反应率为87.5％，完全血液学缓解率为50.0％，脱离血小板输注中位时间为35（16～78）d，脱离红细胞输注中位时间为47.5（15～105）d，血小板输注中位量为5.5（3～20）U，红细胞输注中位量为6.5（2～16）U。结论艾曲泊帕联合rhTPO可提高SAA的IST血液学反应率，改善血液学缓解质量，且不良反应轻微。

Impact of graft-versus-host disease prophylaxis on immune reconstitution in patients after allogeneic hematopoietic stem cell transplantation

The graft-versus-host disease (GVHD) is among the most common complications after hematopoietic stem cell transplantation (allo-HSCT). The main tools for GVHD prevention remain calcineurin inhibitors (cyclosporin A, tacrolimus), methotrexate, mycophenolate mofetil. Upon implementation of reduced-intensity conditioning regimens, antithymocyte globulin was widely introduced. However, negative effects upon reconstitution of T-cell immunity have been noted, thus increasing risk of severe infectious complications and disease relapse. With extended practice of HSCT from alternative (partially matched or haploidentical) donors, cyclophosphamide was increasingly used. Our aim was to study reconstitution of immune cell subpopulations in the patients undergoing bone marrow transplantation (BMT), when using different GVHD prophylaxis regimens, including the schedules with post-transplant CP usage. The study concerned 44 cases classified into 2 groups. The first one included patients with standard immunosuppressive therapy, antithymocyte therapy, cyclosporine A, methotrexate, mycophenolate mofetil. The second group included the patients who received CP as immunosuppressive drug combined with other treatments (cyclosporine A, methotrexate, mycophenolate mofetil). At specified control terms, (D+14, +30, +60, +90) the blood leukocyte subpopulations were assayed by means of multicolor flow cytometry. Absolute counts of CD4+ cells in HSCT recipients treated with CP post-BMT proved to be sufficiently lower at D+14 and +30, than in those treated with classical immunosuppressive therapy. However, at later terms, (D+60, +90), these differences were not observed. Moreover, in CP-treated bone marrow recipients, absolute numbers of CD8+cells was significantly higher, compared to the patients who received conventional GVHD prophylaxis. Reconstitution of the studied lymphocyte populations in hematopoietic cell recipients did not depend on the GVHD prophylaxis regimen. Usage of CP combined with bone marrow as a source of stem cells, brings about sufficient decrease of some cell populations (CD4+; CD8+; NK cells) at early terms post-transplant. Administration of CP combined with hematopoietic stem cells as the source of hematopoietic graft seems to be more reasonable.