High-dose Dexamethasone Treatment Research Articles

Leptin Increase During Dexamethasone and Its Association With Hunger and Fat in Pediatric Acute Lymphoblastic Leukemia.

During treatment, children with acute lymphoblastic leukemia (ALL) receive high doses dexamethasone, which induce acute side effects. To determine the influence of a 5-day dexamethasone course on changes in leptin, fat mass, BMI, hunger, sleep, and fatigue and to explore associations between these changes. Pediatric ALL patients were included during maintenance treatment. Data were collected before (T1) and after (T2) a 5-day dexamethasone course (6 mg/m2/day). At both time points, BMI, fat mass (bioelectrical impedance analysis), and leptin were assessed, as well as parent-reported questionnaires regarding hunger, fatigue, and sleep problems. Changes between T1 and T2 were assessed using paired tests. Correlation coefficients were calculated to assess associations between these changes (Delta scores: T2-T1). Univariable regression models were estimated to study associations between covariates and elevated leptin. We included 105 children, with median age 5.4 years (range, 3.0-18.8). Leptin and fat mass, as well as hunger scores, fatigue, and sleep deteriorated after 5 days of dexamethasone (P < .001), in contrast to BMI (P = .12). No correlations between delta leptin and delta fat mass, BMI, hunger, fatigue, or sleep were found. Elevated leptin on T1 was associated with older age (odds ratio [OR] 1.51; 95% CI, 1.28-1.77), higher fat mass (OR 1.19; 95% CI, 1.07-1.33), and earlier maintenance week (OR 0.96; 95% CI, 0.92-0.99). Five days of high-dose dexamethasone treatment led to direct and significant changes in leptin, hunger scores, and fat mass. Since children with ALL are at increased risk for metabolic adverse events, understanding underlying mechanisms is important, and a dexamethasone-induced state of acute leptin resistance might play a role.

MST4 kinase regulates immune thrombocytopenia by phosphorylating STAT1-mediated M1 polarization of macrophages.

Primary immune thrombocytopenia (ITP) is an autoimmune hemorrhagic disorder in which macrophages play a critical role. Mammalian sterile-20-like kinase 4 (MST4), a member of the germinal-center kinase STE20 family, has been demonstrated to be a regulator of inflammation. Whether MST4 participates in the macrophage-dependent inflammation of ITP remains elusive. The expression and function of MST4 in macrophages of ITP patients and THP-1 cells, andof a macrophage-specific Mst4-/- (Mst4ΔM/ΔM) ITP mouse model were determined. Macrophage phagocytic assays, RNA sequencing (RNA-seq) analysis, immunofluorescence analysis, coimmunoprecipitation (co-IP), mass spectrometry (MS), bioinformatics analysis, and phosphoproteomics analysis were performed to reveal the underlying mechanisms. The expression levels of the MST4 gene were elevated in the expanded M1-like macrophages of ITP patients, and this elevated expression of MST4 was restored to basal levels in patients with remission after high-dose dexamethasone treatment. The expression of the MST4 gene was significantly elevated in THP-1-derived M1 macrophages. Silencing of MST4 decreased the expression of M1 macrophage markers and cytokines, and impaired phagocytosis, whichcould be increased by overexpression of MST4. In a passive ITP mouse model, macrophage-specific depletion of Mst4 reduced the numbers of M1 macrophages in the spleen and peritoneal lavage fluid, attenuated the expression of M1 cytokines, and promoted the predominance of FcγRIIb in splenic macrophages, which resulted in amelioration of thrombocytopenia. Downregulation of MST4 directly inhibited STAT1 phosphorylation, which is essential for M1 polarization of macrophages. Our study elucidates a critical role for MST4 kinase in the pathology of ITP and identifies MST4 kinase as a potential therapeutic target for refractory ITP.

The effect of dexamethasone on functional pain following Transoral Robotic Surgery: a randomized double blinded clinical trial

Background Pain is prevalent after most TransOral Robotic Surgery (TORS) procedures and may limit function i.e. swallowing. Currently, there is limited knowledge regarding optimal pain treatment in TORS. Aims/objectives This clinical trial randomized patients to either a high-dose dexamethasone or low-dose dexamethasone treatment in addition to a multimodal basic analgesic protocol. The aim of the trial was to investigate the pain intensity during rest and swallowing using the Visual Analogue Scale (VAS) after TORS lingual tonsillectomy. Secondary outcomes were acceptable food consistency, nausea, vomiting, opioid rescue usage, length of hospitalization, feeding tube placements, readmissions, blood glucose levels and postoperative complications. Methods The trial was conducted between August 2020 and October 2022. Eligible patients were patients scheduled for TORS-L treatment of obstructive sleep apnea syndrome or as part of the diagnostic work-up of head and neck carcinoma of unknown primary. Results Eighteen patients were and randomized 1:1. There were overall no significant differences between groups in the reported VAS scores during rest or swallowing (p ≥ .05). Overall, there were no differences in the secondary outcomes. Conclusion There were no differences in the pain intensity in the two treatment groups allocated to a basic multimodal analgesic package and either high-dose dexamethasone or low-dose dexamethasone treatment. The trial is the first RCT to include pain measurement during a procedure-relevant activity, thus creating a platform for future recovery studies.

Effect of dexamethasone dose on outcomes in acute COVID-19 disease: A systematic review and meta-analysis

The impact of different doses of dexamethasone on outcomes from acute COVID-19 pneumonia is unknown. We performed a systematic review and meta-analysis of randomised control trials comparing different doses of dexamethasone in adult patients with COVID-19. High dose dexamethasone treatment was defined as 12-24mg daily, whereas low-dose treatment was 6-8mg daily. Primary outcome was 28-day mortality. Eight trials including 3469 patients were identified, with 1775 patients receiving high dose dexamethasone. There was no difference in mortality between patients receiving high dose or low-dose dexamethasone (22.0% vs. 20.2%; odds ratio 1.20 [95% confidence interval 0.86-1.67]; p=0.29; I2 =63%; TSA-adjusted CI [0.31-4.66]; very low QoE). Meta-regression did not demonstrate a dose-dependent effect of steroids on mortality. High dose dexamethasone was associated with an increased risk of hyperglycaemia (23.6% vs. 17.2%; 1.51 [1.19-1.92]; p=0.0008; I2 =0%; TSA-adjusted CI [0.90-2.54]; low QoE) but not secondary infections (14.3% vs. 15.0%; 0.87 [0.56-1.37]; p=0.56; I2 =72%; very low QoE). Risk of bias was low for seven of the eight studies. The mortality of patients with acute COVID-19 receiving high-dose dexamethasone is similar to patients receiving low-dose dexamethasone, although high-dose dexamethasone is associated with an increased risk of hyperglycaemia.

Effect of glucocorticoids on the development of COVID-19-associated pulmonary aspergillosis: A meta-analysis of 21 studies and 5174 patients.

COVID-19-associated pulmonary aspergillosis (CAPA) remains a high mortality mycotic infection throughout the pandemic, and glucocorticoids (GC) may be its root cause. Our aim was to evaluate the effect of systemic GC treatment on the development of CAPA. We systematically searched the PubMed, Google Scholar, Scopus and Embase databases to collect eligible studies published until 31 December 2022. The pooled outcome of CAPA development was calculated as the log odds ratio (LOR) with 95% confidence intervals (CI) using a random effect model. A total of 21 studies with 5174 patients were included. Of these, 20 studies with 4675 patients consisting of 2565 treated with GC but without other immunomodulators (GC group) and 2110 treated without GC or other immunomodulators (controls) were analysed. The pooled LOR of CAPA development was higher for the GC group than for the controls (0.54; 95% CI: 0.22, 0.86; p < .01). In the subgroups, the pooled LOR was higher for high-dose GC (0.90; 95% CI: 0.17, 1.62: p = .01) and dexamethasone (0.71; 95% CI: 0.35, 1.07; p < .01) but had no significant difference for low-dose GC (0.41; 95% CI: -0.07, 0.89; p = .09), and non-dexamethasone GC (0.21; 95% CI: -0.36, 0.79; p = .47), treated patients versus controls. GC treatment increases the risk of CAPA development, and this risk is particularly associated with the use of high-dose GC or dexamethasone treatment.

Low-dose decitabine promotes M2 macrophage polarization in patients with primary immune thrombocytopenia via enhancing KLF4 binding to PPARγ promoter.

The first-line therapy is effective for the treatment of primary immune thrombocytopenia (ITP); however, maintaining the long-term responses remains challenging. Low-dose decitabine (DAC) has been adopted to treat refractory ITP, while its role in macrophage polarization has not been fully understood. We aimed to investigate the mechanistic role of DAC in M2 macrophage polarization and evaluated its therapeutic effect in ITP. The M2 monocytes were identified by flow cytometry from peripheral blood mononuclear cells in healthy controls (HCs) and ITP patients. The expression of PPARγ, Arg-1, DNMT3b and NLRP3, together with IL-10 plasma levels was measured to examine its function. Bisulfite-sequencing PCR was used to evaluate the methylation status of PPARγ promoter, and the binding affinity of KLF4 was measured by Cut&Tag. A sh-PPARγ THP-1 cell line was created to verify if low-dose DAC-modulated M2 macrophage polarization was PPARγ-dependent. The passive ITP models were used to investigate the therapeutic effects of low-dose DAC and its role in modulating polarization and immunomodulatory function of macrophages. NLRP3 inflammasome and reactive oxygen species were also tested to understand the downstream of PPARγ. The M2 monocytes with impaired immunoregulation were observed in ITP. After high-dose dexamethasone (HD-DXM) treatment, M2 monocytes increased significantly with the elevated expression of PPARγ, Arg-1 and IL-10 in CR patients. Low-dose DAC promoted M2 macrophage polarization in a PPARγ-dependent way via demethylating the promoter of PPARγ, especially the KLF4 binding sites. Low-dose DAC alleviated ITP mice by restoring the M1/M2 balance and fine-tuning immunomodulatory function of macrophages. The downstream of the PPARγ modulation of M2 macrophage polarization might physiologically antagonize NLRP3 inflammasome. Low-dose DAC promoted M2 macrophage polarization due to the demethylation within the promoter of PPARγ, thus enhanced the KLF4 binding affinity in ITP.

Dose-related cardiac outcomes in response to postnatal dexamethasone treatment in premature lambs.

Postnatal corticosteroids are used in the critical care of preterm infants for the prevention and treatment of bronchopulmonary dysplasia. We aimed to investigate the effects of early postnatal dexamethasone therapy and dose on cardiac maturation and morphology in preterm lambs. Lambs were delivered prematurely at ~128 days of gestational age and managed postnatally according to best clinical practice. Preterm lambs were administered dexamethasone daily at either a low-dose (n=9) or a high-dose (n=7), or were naïve to steroid treatment and administered saline (n=9), over a 7-day time-course. Hearts were studied at postnatal Day 7 for gene expression and assessment of myocardial structure. High-dose dexamethasone treatment in the early postnatal period led to marked differences in cardiac gene expression, altered cardiomyocyte maturation and reduced cardiomyocyte endowment in the right ventricle, as well as increased inflammatory infiltrates into the left ventricle. Low-dose exposure had minimal effects on the preterm heart. Neonatal dexamethasone treatment led to adverse effects in the preterm heart in a dose-dependent manner within the first week of life. The observed cardiac changes associated with high-dose postnatal dexamethasone treatment may influence postnatal growth and remodeling of the preterm heart and subsequent long-term cardiac function.

Şiddetli COVID-19 Pnömonisi Olan Hastalarda Yüksek Doz Metilprednizolon ve 6 mg Deksametazonun Tedavi Etkinliğinin Karşılaştırılması

Introduction: The course of SARS-CoV-2 disease has a clinical spectrum ranging from mild upper respiratory tract infection to fulminant pneumonia. The use of corticosteroids is recommended in the treatment of severe COVID-19 pneumonia. The present study aimed to compare the efficacy of high-dose methylprednisolone and dexamethasone treatment in patients hospitalized with severe COVID-19 pneumonia. Materials and Methods: The participants were divided into Group M, receiving ≥250 mg intravenous methylprednisolone therapy, and Group D receiving 6 mg intravenous dexamethasone therapy. The efficacy of treatments, length of hospital stays, ventilator requirements, anti-cytokine treatment requirements, and mortality rates were evaluated in both groups. Results: Two hundred eighty-eight (69.1%) patients received dexamethasone and 129 (30.9%) received methylprednisolone. While overall mortality in the study was 11%, this rate was 10.4% in Group D and 12.4% in Group M (p&gt; 0.05). The rate of patients requiring intensive care was 15.8% in total, with a rate of 14.6% in Group D and 18.6% in Group M (p&gt; 0.05). However, the total length of hospital stay was nine (7-39) days in Group M and 13 (7-29) days in Group D (p= 0.009). Anticytokines were required in 14.4% of the patients during treatment [40 in Group D, 20 in Group M (p&gt; 0.05)]. Conclusion: In this study, it was determined that early methylprednisolone treatment shortened the hospital stay. In addition, there was no statistically significant difference between Group M and Group D in terms of mechanical ventilation requirement, which showed an additional positive effect. However, mortality rates in patients receiving dexamethasone were found to be lower than in those receiving methylprednisolone, yet this difference did not reach statistical significance.

Vestibulotoxicity in Patients Undergoing Cisplatin-Based Cancer Treatment: A Phase IIIB Randomized Controlled Clinical Trial

Introduction: This study aimed to evaluate the incidence of balance disorders and the efficacy of dexamethasone in protecting patients undergoing cisplatin-based cancer treatment against vestibulototoxicity. Methods: This study was a randomized controlled phase IIIB clinical trial. The subjects participating in the clinical trial were patients with a neoplastic disease whose treatment protocol included cisplatin. The average dose of cisplatin was 444.87 mg (SD 235.2 mg). Treatment consisted of intratympanically administering dexamethasone via a passive diffusion device called Microwick (8 mg/24 h dose) from the start of treatment with cisplatin to 3 weeks after the last cycle. Patients were administered the medication to one ear, and the contralateral ear was used as the control. The treated ears were randomly chosen using a computer system (randomization). Vestibular system was evaluated by video head impulse test before each cisplatin cycle. Results: Thirty-four patients were recruited over a 2-year period at a reference tertiary hospital, of whom 11 were excluded. Forty-six ears were analyzed (23 treated and 23 control ears). Vestibular analysis presented no changes in the mean increase in the vestibulo-ocular response in all patients evaluated, both in treated and control ears. Both 8.69% infection complications during treatment and 34.8% permanent perforation at 6 months were detected after device removal. Conclusion: Ototoxicity related to cisplatin-based treatment does not affect the vestibular system. Long-term high-dose intratympanic dexamethasone treatment is safe for the vestibular system.

A study on high-dose dexamethasone versus prednisolone as frontline therapy in newly diagnosed immune thrombocytopenia in children

Objectives: Treatment for children with newly diagnosed immune thrombocytopenia (ITP) includes corticosteroids, out of which prednisolone is commonly used. High-dose dexamethasone (HD-DXM) treatment for children with newly diagnosed ITP can produce better outcomes than prednisone, as stated by many studies. A few articles compare HD-DXM and prednisolone as frontline therapies in newly diagnosed adult ITP but data on pediatric ITP comparing these two drugs are scarce. Material and Methods: It was a randomized, prospective, and cohort study. After enrolment, checking the inclusion and exclusion criteria, each child was randomly distributed into two groups; one cohort was treated with HD-DXM in the dose of 40 mg/m2 (maximum daily dose 40 mg) for 4 days once every 28 days for three cycles; and one with prednisolone in the dose of 2 mg/kg/day (maximum 60 mg/day) for 2 weeks, with quick tapering. A total of 42 children were enrolled, 21 in each cohort. Results: The overall response (OR) was 42.9% with HD-DXM therapy. The OR and median time to response were similar in both HD-DXM and prednisolone cohorts. There was also no significant difference in incidences of adverse effects between the two cohorts. Conclusion: Thus, this study confirms that HD-DXM is a safe, effective, and non-inferior option compared to prednisolone as frontline therapy in newly diagnosed ITP in children.

Systemic high-dose dexamethasone treatment may modulate the efficacy of intratumoral viral oncolytic immunotherapy in glioblastoma models

BackgroundIntratumoral viral oncolytic immunotherapy is a promising new approach for the treatment of a variety of solid cancers. CAN-2409 is a replication-deficient adenovirus that delivers herpes simplex virus thymidine kinase...

High-dose dexamethasone injection disordered metabolism and multiple protein kinases expression in the mouse kidney.

Glucocorticoids (GCs) have been widely used in clinical treatment as anti-inflammatory, anti-shock and immunosuppressive medicines. However, the effect of excessive GCs on immune response and metabolism of kidney remains unclear. Here, we profiled the gene expression of kidney from mice with high-dose dexamethasone (DEX) treatment. A total of 1193 differentially expressed genes (DEGs) were screened in DEX treatment group compared with the saline group, including 715 down- regulated and 478 up-regulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of these DEGs showed extracellular matrix (ECM)–receptor interaction, cell adhesion molecules signaling pathway were significantly enriched, and that the vast majority of DEGs were involved in monocarboxylic acid metabolism, leukocyte cell–cell adhesion and fatty acid metabolism. Gene set enrichment analysis (GSEA) revealed that DEGs were strongly associated with immune-response and cell adhesion gene sets, such as Fc γ R-mediated phagocytosis, leukocyte transendothelial migration, T-cell receptor signaling pathway, cell adhesion, ECM–receptor interaction and focal adhesion-associated pathways. KEGG pathway analysis of differentially expressed kinases (DEKs) showed T-cell receptor and forkhead box class O signaling pathway were enriched. Furthermore, we found multiple protein kinases expression were dysregulated greatly after dexamethasone treatment, including classical effector of GCs stimulation-serum and GC-regulated kinase. These protein kinases are involved in multiple signaling pathways in mice kidney, such as mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. We profiled the gene expression of the kidney from high-dose dexamethasone-treated mice and provided important information for further study the mechanism of side effects of GCs in clinical therapy.

High-dose dexamethasone treatment for COVID-19 severe acute respiratory distress syndrome: a retrospective study

Low-dose dexamethasone reduces mortality in patients with coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS). We retrospectively analyzed the efficacy of high-dose dexamethasone in patients with COVID-19-related ARDS and evaluated factors affecting the composite outcome (death or invasive mechanical ventilation). From March 4th to April 1st 2020, 98 patients with COVID-19 pneumonia were included. Those who after at least 7 days from symptom onset presented a worsening of the respiratory function or of inflammatory biomarkers were started on intravenous high-dose dexamethasone (20 mg daily for 5 days, followed by 10 mg daily for 5 days). Most patients were males (62%) with a mean age of 69 years. Hypertension and cardiovascular disease (CVD) were prevalent. Following dexamethasone treatment, a significant improvement in PaO2/FiO2 (277.41 [178.5–374.8] mmHg vs. 146.75 [93.62–231.16] mmHg, p < 0.001), PaO2 (88.15 [76.62–112.0] mmHg vs. 65.65 [57.07–81.22] mmHg, p < 0.001), and SpO2 (96 [95–98]% vs. 94 [90–96]%, p < 0.001) was observed. A concomitant decrease in C-reactive protein and ferritin levels was found (132.25 [82.27–186.5] mg/L vs. 7.3 [3.3–24.2] mg/L and 1169 [665–2056] ng/mL vs. 874.0 [569.5–1434] ng/mL, respectively; p < 0.001 for both vs. baseline). CVD was found to increase the risk of the composite outcome (RR 7.64, 95% CI 1.24–47.06, p = 0.028). In hospitalized patients with COVID-19-related ARDS, high-dose dexamethasone rapidly improves the clinical status and decreases inflammatory biomarkers. CVD was found to increase the risk of the composite outcome. These data support the importance of randomized clinical trials with high-dose dexamethasone in COVID-19 patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11739-021-02800-1.

Early Increased Platelet Count Is a Predictive Factor for a Long-Term Response in High-Dose Dexamethasone Treatment for Newly-Diagnosed Immune Thrombocytopenia Patients.

Background: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by increased destruction of platelets. Guidelines recommend corticosteroids with or without intravenous immunoglobulin as an initial therapy for ITP patients who are required treatment. Prednisone (or predonisolone) has been widely used as a first-line treatment. High-dose dexamethasone (HD-DXM) is an alternative corticosteroid for prednisone. Recently, a randomized clinical trial, in which four-days HD-DXM was compared with standard prednisone in newly diagnosed ITP patients. The results showed that higher remission rate was obtained in patients treated with four -days HD-DXM, suggesting that HD-DXM is preferred in certain ITP patients. However, long-term outcomes of the patents treated with HD-DXM has not been fully evaluated. In this study, we retrospectively analyzed ITP patients who received HD-DXM as initial therapy to evaluate a long-term efficacy of HD-DXM and to find out predictive factors for long-term response.Patients and methods: We reviewed clinical records of patients who were diagnosed as ITP from Aug 2005 to Feb 2015 in Tokyo Women's Medical University Hospital. Patients who received HD-DXM because of a platelet count of less than 20,000 per cubic millimeter or a platelet count less than 50,000 per cubic millimeter with clinically significant bleeding, were included this study. An initial response was defined as an increase number of platelets, 30,000 per cubic millimeter or more and at least 2-fold increase of the baseline count and absence of bleeding between day 8-18 days after HD-DXM. Sustained response was defined as follows: platelet count was maintained 30,000 per cubic millimeter or more and absence of bleeding after achievement of initial response.Results: A total of 30 patients were analyzed in this study. Median age of patients was 63 years (range, 23 to 91). The mean platelet count before treatment was 11,000 (range, 2,000 to 50,000) per cubic millimeter. Median follow up period is 35 months (range, 0.7 to 129.5). Dexamethasone (30-40mg per day) was administrated for 4 days for 1-3 cycles. Initial response was obtained in 17 of 30 patients (56.7 %). In responder group (n=17), sustained response rates at 6, 36, and 60 months was 92.8% (13/14), 87.5 % (7/8), and 100 % (6/6). Among non- responders within 18 days (n=13), long-term response rates at 6, 36, and 60 months was 58.3% (7/12), 100 % (3/3), and 100 % (2/2). We investigate clinical characteristics of the patients obtained long-term response, including duration of HD-DXM, age, platelet count before HD-DXM, lymphocyte count before HD-DXM, number of HD-DXM, to find out predictive factors for long-term response. In some patients obtained long-term response, early increase platelet count within a week was observed. Interestingly, among non-responders, early increased platelet count within a week was observed in seven patients, and five of these seven patients (71.4%) obtained response at six months. In a logistic regression model, univariable and multivariable analysis indicates early increased platelet count within a week after initiation of HD-DEX was significantly efficacy associated with long-term response (P=0.02, P=0.01, respectively).Conclusion: In this study, HD-DXM is an effective initial therapy for ITP patients. Long-term response was obtained in substantial number of patients. The present result suggests that increased platelet count within a week after HD-DXM initiation predicts long-term response. DisclosuresNo relevant conflicts of interest to declare.

Glucocorticoid receptor modulates myeloid-derived suppressor cell function via mitochondria respiration and metabolism in immune thrombocytopenia

Abstract Methods We collected 27 immune thrombocytopenia (ITP) patients who had received high-dose dexamethasone treatment. The myeloid-derived suppressor cells (MDSCs) were induced in vitro and CHIP-qPCR assays were performed. Seahorse XF analyzer was used to analyze oxygen consumption rate and parameters of mitochondrial function of MDSCs. MDSCs were treated with CPT-1 inhibitor, etomoxir, to explore the effect of inhibiting fatty acid oxidation. Glucocorticoid receptor (GR) expression was blocked in murine MDSCs which were transplanted into ITP mice. Results The mRNA expression of GR and mtDNA-encoded genes (ATP8, COX1, CYTB, ND1, ND5), as well as the binding of GR to mtDNA in MDSCs were decreased in steroid-resistant ITP group compared to steroid-responsive ITP group and healthy controls. MDSCs in steroid-resistant patients had decreased levels of basal respiration, maximal respiration and ATP production, suggesting that the mitochondria of MDSCs in steroid-resistant group had lower activities of electron transport chains and oxidative phosphorylation. The function of MDSCs to inhibit T-cell proliferation was decreased in steroid-resistant group. Etomoxir reduced the ability of MDSCs to block T-cell proliferation in steroid-responsive group, but did not alter the suppressive function of MDSCs on T cells in steroid-resistant group. ITP mice transplanted with GR siRNA-treated MDSCs showed lower platelet counts than those with control siRNA-treated MDSCs, suggesting that the function of MDSCs to ameliorate ITP relied on GR. Conclusions This study demonstrated that GR-associated MDSCs impairments are involved in the pathogenesis of ITP. It might be related to the modulation of mitochondrial respiration and metabolism by GR.

The abnormal function of CD39+ regulatory T cells could be corrected by high-dose dexamethasone in patients with primary immune thrombocytopenia.

Primary immune thrombocytopenia is an autoimmune disease, characterized with decreased platelet and increased risk of bleeding. Recent studies have shown the reduction and dysfunction of regulatory T (Treg) cells in ITP patients. CD39 is highly expressed on the surface of Treg cells. It degrades ATP to AMP and CD73 dephosphorylates AMP into adenosine. Then adenosine binds with adenosine receptor and suppresses immune response by activating Treg cells and inhibiting the release of inflammatory cytokines from effector T (Teff) cells. Adenosine receptor has several subtypes and adenosine A2A receptor (A2AR) plays a crucial role especially within lymphocytes. The CD39+ Treg cells and the expression of A2AR showed abnormality in some autoimmune disease. But knowledge of CD39+ Treg cells and A2AR which are crucial in the adenosine immunosuppressive pathway is still limited in ITP. Thirty-one adult patients with newly diagnosed ITP were enrolled in this study. CD39 and A2AR expression was measured by flow cytometry and RT-PCR. The function of CD39 was reflected by the change of ATP concentration detected by CellTiter-Glo Luminescent Cell Viability Assay. CD39 expression within CD4+CD25+ Treg cells in ITP patients was decreased compared to normal controls. After high-dose dexamethasone therapy, response (R) group showed increased CD39 expression within Treg cells while non-response (NR) group did not show any difference in contrast to those before treatment. The expression of A2AR in CD4+CD25- Teff and CD4+CD25+ Treg cells was both lower in ITP patients than that of normal controls. After therapy, CD4+CD25- Teff cells had higher A2AR expression while CD4+CD25+ Treg cells did not show any difference in comparison to that before treatment. The enzymatic activity of CD39 was damaged in ITP patients and improved after high-dose dexamethasone therapy. In ITP, there was not only numerical decrease but also impaired enzymatic activity in CD39+ Treg cells. After high-dose dexamethasone treatment, these two defects could be reversed. Our results also suggested that ITP patients had reduced A2AR expression in both CD4+CD25+ Treg cells and CD4+CD25- Teff cells. CD4+CD25- Teff cells had increased A2AR expression after treatment.

High-Dose Dexamethasone Corrects the Elevated Level of IL-16 in Immune Thrombocytopenia

Introduction: Adult primary immune thrombocytopenia (ITP) is an autoimmune-mediated haemorrhagic disorder characterized by excessive platelet destruction and decreased platelet production. ITP patients have a Th1 dominant profile, which was involved in the pathogenesis of ITP. Interleukin-16 (IL-16) can directly affect cellular or humoral immunity by mediating the cellular cross-talk among T cells, B cells and dendritic cells. Several studies have focused on IL-16 as an immunomodulatory cytokine that takes part in Th1 polarization in autoimmune diseases, but the roles of IL-16 in ITP remain unknown. Treatment with high-dose dexamethasone (HD-DXM) as a single-agent for four days has been widely recognized as the first-line therapy for ITP patients in need of clinical management. The aim of this study is to investigate the roles of IL-16 and effect of HD-DXM on IL-16 in ITP.Methods: We investigated the differences in IL-16 expression in the bone marrow and peripheral blood between ITP patients and healthy controls by ELISA. The mRNA expression of pro-IL-16, caspase-3 and T-bet in active ITP patients and healthy controls were quantified by real-time PCR. Furthermore, we detected changes in IL-16 concentration and gene expression before and after the 4-day HD-DXM therapy. Bone marrow samples were obtained from 23 patients and 10 healthy bone marrow donors, and peripheral blood samples were obtained from 64 patients (among them, 21 received single-agent HD-DXM therapy, the peripheral blood samples were obtained before HD-DXM therapy and 28 days after HD-DXM administration) and 38 healthy blood donors. Adult primary ITP patients with active disease were enrolled in this study between May 2015 and January 2018 at the Department of Haematology, Qilu Hospital, Shandong University, Jinan, China.Results: The concentration of IL-16 in the bone marrow supernatants and plasma of active ITP patients was significantly higher compared with that of the healthy controls (P < 0.05) (Fig. 1A, B). Gene expression of pro-IL-16 and caspase-3 in bone marrow mononuclear cells (BMMCs) in ITP patients elevated compared with healthy controls (P < 0.05) (Fig. 2A). Besides, gene expression of pro-IL-16, caspase-3 and T-bet in peripheral blood mononuclear cells (PBMCs) in ITP patients elevated (P < 0.05) (Fig. 2B). Among the 21 patients which received single-agent HD-DXM therapy, 18 responded effectively to the HD-DXM therapy according to the standard definition. The post-treatment plasma (n=21) IL-16 level decreased significantly compared with that of pre-treatment level (P < 0.05), and the level of IL-16 in the plasma of ITP patients before and after HD-DXM treatment was significantly higher than that of healthy controls (P < 0.05) (Fig. 1C). There was no correlation between IL-16 levels in the bone marrow supernatant or plasma and platelet count (data not shown). In addition, pro-IL-16, caspase-3, T-bet mRNA expression was significantly decreased after treatment with HD-DMX (P < 0.05) (Fig. 2C), although the corresponding values in patients were not statistically higher than those of healthy controls. The correlation between the plasma IL-16 concentration and pro-IL-16, caspase-3 and T-bet mRNA levels was also analysed in ITP patients (n = 21). The results demonstrated that the mRNA levels of the three detected factors were positively correlated with plasma IL-16 concentration (r2 = 0.5846, P < 0.05, r2 = 0.3980, P < 0.05 and r2 = 0.3145, P <0.05 for pro-IL-16, caspase-3 and T-bet, respectively) (Fig. 2D-F).Conclusions: ITP is an autoimmune disorder; complex interactions among antigen-presenting cells, T cells and B cells are pivotal to its pathogenesis. Our data suggest that IL-16 plays an important role in the pathogenesis of ITP by polarization of Th1. Furthermore, by modulating the abnormal IL-16 level associated with the Th1 imbalance via treatment with pulsed HD-DXM provided us with new insights into the immune regulatory mechanisms for the treatment of ITP. In our future study, we will use an in vitro study system to test and verify if the anti-IL-16 antibody can be used to treat adult ITP. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Predicting Treatment Response and Survival of Multiple Myeloma with the Xbp-1 Co-Expression Gene Module

Multiple Myeloma (MM) is a B-cell malignancy characterized by monoclonal expansion and accumulation of abnormal plasma cells in bone marrow. The extensive biological and clinical heterogeneity of MM hinders effective treatment and etiology research. Several molecular classification systems for prognosis have been proposed, but they are not predictive for treatment response. XBP-1 is a critical molecule in coordinating normal plasma cell differentiation and survival because of its role in regulating the unfolded protein response. We identified a module of 100 genes co-expressed with XBP-1 (XBP-1-M) in the dataset GSE2658 by QlucoerOmics Explore 2.2 (Qlucore AB, Lund, Sweden) software. Using unsupervised consensus clustering, we assigned 264 MMs into XBP-1 low or XBP-1 high subtype in the validation dataset GSE9782. Patients in GSE9782 were randomly assigned into bortezomib or high-dose dexamethasone (Dex) treatment arms in the APEX 3 trial (039) (Blood 2007;109:3177-88). We integrated XBP-1-M clustering-based response analysis with the choice of treatment in GSE9782, XBP-1 high MMs had lower response rate (CR+PR) than XBP-1 low group (18.5% vs 59.67%, p<0.01). In the XBP-1 high MMs, significantly different response rate between bortezomib treatment and Dex treatment (36.34% vs 0%, p<0.05) was observed, while in the XBP-1 low MMs, no significantly different response between bortezomib treatment and Dex treatment (55.88% vs 61.18%, p>0.05) was noted. We further integrated XBP-1-M clustering-based survival analysis with the choice of treatment in GSE9782, XBP-1 high MMs showed significantly poorer progression-free survival (PFS) compared with XBP-1 low MMs during the 5-8 years follow-up, using either bortezomib(p=0.0071) or Dex (p=0.0011) regimen. In the patients treated with Dex regimen, XBP-1 high MMs showed significant poorer overall survival (OS) compared with XBP-1 low MMs (p=0.0316), while there were no differences in bortezomib regimen between XBP-1 high MMs and XBP-1 low MMs (p=0.224). Next, we integrated the XBP-1-M clustering-based genetic abnormality in GSE9782, there were higher frequencies of genetic abnormalities in XBP-1 high MMs than those in XBP-1 low MMs (1q gain 49.5% vs 12.6%, p<0.01; 17p del 21.9 % vs 3.2%, p<0.01; 13q del 58.1% vs 28.5%, p<0.05; t(4,14) 22.8% vs 15.8%, p<0.05; t(11,14) 31.4% vs 3.2%, p<0.01). The higher cytogenetic abnormalities may be related to the poorer treatment response and survival in patients with XBP-1 high expression. Therefore, we conclude that XBP-1-M may enable prediction of the treatment response and clinical outcome in multiple myeloma. DisclosuresNo relevant conflicts of interest to declare.

Analysis of high-dose dexamethasone in different cycles on efficacy and safety of newly diagnosed ITP

To compare the efficacy and safety of high-dose dexamethasone in treating new-diagnosed primary immune thrombocytopenia (ITP) in monocycle, di-cycle, tri-cycle. Divided by the ratio of 1:1:1, 93 newly diagnosed patients were randomly accepted monocycle (Group A:dexamethasone 40 mg once a day, from day1 to day4), dicycle (Group B:dexamethasone 40 mg once a day, from day 1 to day 4, day 15 to day 18), tri-cycle (Group C:dexamethasone 40 mg once a day, from day 1 to day 4, day 15 to day 18, day 29 to day 32) of high-dose dexamethasone treatment. Its efficacy and safety on the patients in three groups were compared. Ninety-three newly patients with new-diagnosed ITP were divided into Group A, B, and C, 31 patients in each group. In terms of short-term benefits, there was no statistically significant difference among the 7th and 14th day complete response rate after end of treatment. However, there was statistically significant difference after the end of treatment on the 7th day response rate (41.9% vs 70.0% vs 90.0%, P<0.01) and the 14th day response rate (16.1% vs 36.70% vs 63.3%, P< 0.01); in terms of long-term benefits, there was no statistically significant difference among the 120-day response rate, the complete response rate within the treatment on the 60th, 90th and 120th day and the relapse rate at 90th and 120th day; however, there was statistically significant difference among the 60- day response rate (10.0% vs 26.6% vs 53.3%, P<0.01), 90-day(0.0% vs 13.3% vs 30.0%, P<0.01) and 60-day relapse rate(88.9% vs 73.3% vs 46.7%, P<0.01). Mostly of the treatment-related adverse reactions in the three groups were mild, and most patients are tolerable. Although the complete response rate of ITP patients did not improved by increasing the cycle of high-dose dexamethasone, but improved response rate in three months, and adverse reactions were tolerable, which could be used as a reference for clinical use.

Distinct alterations of CD68+CD163+ M2-like macrophages and myeloid-derived suppressor cells in newly diagnosed primary immune thrombocytopenia with or without CR after high-dose dexamethasone treatment

BackgroundAlthough impaired myeloid-derived suppressor cells (MDSCs) recently have been studied in immune thrombocytopenia (ITP), another myeloid-derived cell population signified as M2 macrophages has not been investigated properly in ITP patients. In the present study, we intended to determine the features of circulating M2-like macrophages, to examine its relationship with MDSCs, and to explore their prognostic values in ITP.MethodsPeripheral blood mononuclear cells from healthy controls and primary ITP patients were isolated to test the circulating M2-like macrophages and MDSCs. The circulating M2-like macrophage population defined as CD68+CD163+ and circulating MDSC population as CD11b+CD33+HLA-DR− were determined by flow cytometry. Plasma inflammatory cytokines were measured by multiplex ELISA.ResultsThe percentages of MDSCs were found to be expanded in newly diagnosed patients of ITP, especially among those of the complete response (CR) group (p < 0.0001). Positive linear correlation was verified between percentages of M2-like macrophages and MDSCs. The same correlation was also determined in the CR group. After treatment, the percentages of M2-like macrophages and MDSCs were both increased significantly in CR group, while those patients among the PR + NR group manifested a significant numeric decrease of MDSCs but only a moderate decrease in M2-like macrophages. MIP-1α/CCL3 was negatively correlated with M2-like macrophages while MCP-1 possessed a positive correlation with M2-like macrophages, eotaxin-1/CCL11 was negatively correlated with MDSCs and interleukin-1β (IL-1β) was found to be negatively correlated with both M2-like macrophages and MDSCs.ConclusionsThe present findings indicated critical roles of both circulating M2-like macrophages and MDSCs in ITP. The positive correlation between them might be related to inflammatory factors-mediated bidirectional interactions or partially due to their similar background patterns during differentiation. MIP-1α/CCL3, MCP-1, eotaxin-1/CCL11 and IL-1β might play a critical role in the expansion of both M2 macrophages and MDSCs population in ITP patients, which deserves further investigation.