Role Of Glucocorticoids Research Articles

The Role of Glucocorticoids in Enhancing Exposure Therapy for Phobias: A Systematic Review

Phobias, a common subset of anxiety disorders, are commonly treated with psychological therapies. However, there are limits to the achievements of these therapies and in some severe or treatment-resistant cases, there are requirements for adjuncts. Glucocorticoids (GC), such as cortisol, can enhance the therapy by modulating the fear responses and facilitating the extinction of the fear memories. This systematic review (SR) examined the role of GCs as adjuncts to psychologies therapies in several phobias. A total of seven papers, eight studies met the inclusion criteria with findings that showed GCs had some effect on improvement and this was seen particularly in spider phobia. Neuroimaging data was also included and showed similar findings such as the normalisation of fear-processing networks with the use of GCs, particularly the salience network. However, the results for social phobia and acrophobia were more variable as some inconsistencies in long-term effectiveness were noted. This SR found that GCs may have potential in the treatment of phobias but further research is required to determine their efficacy, optimal dosing and long-term impact.

9264 The interplay of FOXO1 and NR3C1 in the development and function of pituitary somatotropes

Abstract Disclosure: P. Das: None. D.A. Jabal: None. D.A. Sunny: None. B.S. Ellsworth: None. Our research focuses on the role of glucocorticoid (GC) in regulating the maturation of pituitary somatotropes. We previously demonstrated that deletion of the forkhead transcription factor, FOXO1, affects the development of somatotropes both in vivo and in vitro. Our studies reveal that treating pregnant mice with the synthetic glucocorticoid, dexamethasone leads to premature somatotrope maturation. Interestingly, we have observed that the ability of GC to promote Gh1 expression is compromised in the absence of FOXO1 in a somatotrope-like cell line. This finding leads to further investigation into the GC receptor, NR3C1, and its developmental role in the pituitary gland. In mouse embryos, we detect NR3C1-positive cells localized primarily in the nucleus, initially in small numbers at embryonic day (e)12.5 and becoming more abundant by e14.5. At e14.5 there is a subset of cells where NR3C1 co-localizes with POU1F1, a marker of pre-somatotropes, suggesting the importance of NR3C1 in the formation of the somatotrope lineage. In dexamethasone-treated animals, we observe an increase in NR3C1-positive cells. However, no significant change was noted in POU1F1 expression. Significantly, the premature somatotropes identified are NR3C1 and POU1F1-positive, suggesting the pituitary cells expressing both POU1F1 and NR3C1 at e14.5 are likely differentiating into somatotropes when exposed to GC. Normally, by e16.5, GH-positive cells begin to appear in mice. Double immunostaining reveals that some of these cells also express NR3C1. Further supporting this finding, the deletion of Nr3c1 results in a decreased number of GH-positive cells at e16.5. Altogether these findings demonstrate that NR3C1 and FOXO1 are key factors regulating somatotrope maturation. Presentation: 6/2/2024

5152 The interplay of FOXO1 and NR3C1 in the development and function of pituitary somatotropes

Abstract Disclosure: P. Das: None. D.A. Jabal: None. D.A. Sunny: None. B.S. Ellsworth: None. Our research focuses on the role of glucocorticoid (GC) in regulating the maturation of pituitary somatotropes. We previously demonstrated that deletion of the forkhead transcription factor, FOXO1, affects the development of somatotropes both in vivo and in vitro. Our studies reveal that treating pregnant mice with the synthetic glucocorticoid, dexamethasone leads to premature somatotrope maturation. Interestingly, we have observed that the ability of GC to promote Gh1 expression is compromised in the absence of FOXO1 in a somatotrope-like cell line. This finding leads to further investigation into the GC receptor, NR3C1, and its developmental role in the pituitary gland. In mouse embryos, we detect NR3C1-positive cells localized primarily in the nucleus, initially in small numbers at embryonic day (e)12.5 and becoming more abundant by e14.5. At e14.5 there is a subset of cells where NR3C1 co-localizes with POU1F1, a marker of pre-somatotropes, suggesting the importance of NR3C1 in the formation of the somatotrope lineage. In dexamethasone-treated animals, we observe an increase in NR3C1-positive cells. However, no significant change was noted in POU1F1 expression. Significantly, the premature somatotropes identified are NR3C1 and POU1F1-positive, suggesting the pituitary cells expressing both POU1F1 and NR3C1 at e14.5 are likely differentiating into somatotropes when exposed to GC. Normally, by e16.5, GH-positive cells begin to appear in mice. Double immunostaining reveals that some of these cells also express NR3C1. Further supporting this finding, the deletion of Nr3c1 results in a decreased number of GH-positive cells at e16.5. Altogether these findings demonstrate that NR3C1 and FOXO1 are key factors regulating somatotrope maturation. Presentation: 6/2/2024

Lymphatic Dysfunction and Perirenal Adiposity: Role of Glucocorticoids

Lymphatic Dysfunction and Perirenal Adiposity: Role of Glucocorticoids

The Role of Glucocorticoid and Nicotinic Acetylcholine Receptors in the Reward-Enhancing Effects of Nicotine in the ICSS Procedure in Male and Female Rats.

Tobacco use disorder is a chronic disorder that affects more than one billion people worldwide and causes the death of millions each year. The rewarding properties of nicotine are critical for the initiation of smoking. Previous research has shown that the activation of glucocorticoid receptors (GRs) plays a role in nicotine self-administration in rats. However, the role of GRs in the acute rewarding effects of nicotine are unknown. In this study, we investigated the effects of the GR antagonist mifepristone and the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine on the reward-enhancing effects of nicotine using the intracranial self-stimulation (ICSS) procedure in adult male and female rats. The rats were prepared with ICSS electrodes in the medial forebrain bundle and then trained on the ICSS procedure. Nicotine lowered the brain reward thresholds and decreased response latencies similarly in male and female rats. These findings suggest that nicotine enhances the rewarding effects of ICSS and has stimulant properties. Treatment with the GR antagonist mifepristone did not affect the reward-enhancing effects of nicotine but increased response latencies, suggesting a sedative effect. Mecamylamine did not affect the brain reward thresholds or response latencies of the control rats, but prevented the nicotine-induced decrease in brain reward thresholds and reward latencies. These findings indicate that the rewarding effects of nicotine are mediated via the activation of nAChRs, and that the activation of GRs does not contribute to the acute rewarding effects of nicotine. These studies enhance our understanding of the neurobiological mechanisms underlying tobacco use disorder.

Augmented prehabilitation - is there a role for glucocorticoids and/or anabolic steroids to improve surgical outcomes?

Augmented prehabilitation - is there a role for glucocorticoids and/or anabolic steroids to improve surgical outcomes?

Role of glucocorticoids in pneumocystis pneumonia in patients with non-HIV infection/AIDS (HIV/AIDS) and related mechanisms

Pneumocystis pneumonia (PCP) is an opportunistic infection caused by Pneumocystis carinii and is the most common fungal infection in HIV/AIDS patients. With the routine use of antiretroviral therapy (ART), the incidence of PCP infection in HIV/AIDS patients has decreased and the prognosis has improved significantly. On the other hand, the use of chemoradiotherapy and immunotherapy in patients with cancer, post-transplantation and autoimmune diseases are increasing dramatically, which has led to a similar increase in the incidence of PCP in these non-HIV/AIDS patients. There is a global shift in research on PCP from HIV-infected co-infected PCP (HIV-PCP) to non-HIV-infected co-infected PCP. The clinical course of non-HIV-PCP is rapid and severe, and the morbidity and mortality rates are higher than those of HIV-PCP. Studies have shown that 90% of non-HIV-PCP patients have a history of glucocorticoid use prior to infection, such as in patients with hematologic malignancies, solid organ transplants, and rheumatic diseases, and that long-term high-dose glucocorticoid use is an important risk for PCP susceptibility. Clinical practice has shown that PCP often occurs during the tapering of glucocorticoids, and a higher proportion of patients develop diffuse pulmonary lesions and, in more severe cases suffer from life-threatening acute respiratory failure. The pathogenesis of non-HIV infections associated with PCP is not yet clarified, and there is a lack of effective therapeutic practices that require further investigation.

The Control of Neuroendocrine Mechanisms in Livestock to Facilitate Adaptation to Stress

This article discusses the concept of stress in animals, which is a complex set of physiological and behavioral responses to aversive stimuli.

Distinct response of adipocyte progenitors to glucocorticoids determines visceral obesity via the TEAD1-miR-27b-PRDM16 axis.

Visceral obesity contributes to obesity-related complications; however, the intrinsic mechanism of depot-specific adipose tissue behavior remains unclear. Despite the pro-adipogenesis role of glucocorticoids (GCs) in adipogenesis, the role of GCs in visceral adiposity rather than in subcutaneous adipose tissue is not established. Because adipocyte progenitors display a striking depot-specific pattern, the regulatory pathways of novel progenitor subtypes within different depots remain unclear. This study describes a cell-specific mechanism underlying visceral adiposity. A diverse panel of novel depot-specific adipose progenitors was screened in mice and human samples. The transcriptome distinction and various responses of novel progenitor subtypes of GCs were further measured using the GC receptor-chromatin immunoprecipitation assay and RNA sequencing. The mechanism of novel subtypes was identified using transposase-accessible chromatin analysis and bisulfite sequencing and further confirmed using precise editing of CpG methylation. Platelet-derived growth factor receptor α (PDGFRα+ ) progenitors, which were dominant in the visceral adipose tissue, were GC-sensitive beige adipose progenitors, whereas CD137+ progenitors, which were dominant in the subcutaneous adipose tissue, were GC-passive beige adipose progenitors. Expression of miR-27b, an inhibitor of adipocyte browning, was significantly increased in PDGFRα+ progenitors treated with GCs. Using transposase-accessible chromatin analysis, bisulfite sequencing, and precise editing of CpGmethylation, TEA domain transcription factor 1 (TEAD1) was discovered to be uniquely hypomethylated in PDGFRα+ progenitors. GCs inhibited the PDGFRα+ progenitors' browning process via miR-27b, which was transcriptionally activated by the collaboration of TEAD1 with the GC receptor. These data provide insights into the mechanism of depot-specific variations in high-fat diet-induced obesity.

The role of glucocorticoids in increasing cardiovascular risk.

Different studies provide conflicting evidence regarding the potential for glucocorticoids (GCs) to increase the risk of cardiovascular diseases. This study performed a systematic review and meta-analysis to determine the correlation between GCs and cardiovascular risk, including major adverse cardiovascular events (MACE), death from any cause, coronary heart disease (CHD), heart failure (HF), and stroke. We performed a comprehensive search in PubMed and Embase (from inception to June 1, 2022). Studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of interest were included. A total of 43 studies with 15,572,512 subjects were included. Patients taking GCs had a higher risk of MACE (RR = 1.27, 95% CI: 1.15-1.40), CHD (RR = 1.25, 95% CI: 1.11-1.41), and HF (RR = 1.92, 95% CI: 1.51-2.45). The MACE risk increased by 10% (95% CI: 6%-15%) for each additional gram of GCs cumulative dose or by 63% (95% CI: 46%-83%) for an additional 10 μg daily dose. The subgroup analysis suggested that not inhaled GCs and current GCs use were associated with increasing MACE risk. Similarly, GCs were linked to an increase in absolute MACE risk of 13.94 (95% CI: 10.29-17.58) cases per 1,000 person-years. Administration of GCs is possibly related with increased risk for MACE, CHD, and HF but not increased all-cause death or stroke. Furthermore, it seems that the risk of MACE increased with increasing cumulative or daily dose of GCs.

Glucocorticoids improve the balance of M1/M2 macrophage polarization in experimental autoimmune uveitis through the P38MAPK-MEF2C axis

Uveitis is a common ocular disease that can induce serious complications and sequelae. It is one of the major causes of blindness. Currently, mounting evidence suggests that glucocorticoids (GCs) can suppress ocular inflammation and promote the healing of damaged ocular tissues, but the underlying mechanism remains unclear. The present study aimed to elucidate the mechanism by which GCs modulate the homeostasis of M1/M2 macrophage polarization in experimental autoimmune uveitis (EAU) through the p38MAPK-MEF2C axis. Female Lewis rats were randomly divided into four groups: a normal control (NC) group, an EAU group, an EAU + glucocorticoid (EAU + GC) group, and an EAU + p38MAPK inhibitor (EAU + SB) group. The EAU model was induced in EAU, EAU + GC, and EAU + SB groups, followed by the treatments of normal saline, GC (predisione), and SB203580, respectively. The findings demonstrated that the rats in GC and SB groups had much less ocular inflammation, and the clinical and pathological scores decreased. Further research revealed that GC and SB treatment could inhibit iNOS and CD86 expression while promoting Arg-1 and CD206 secretion in IRBP-induced uveitis rats. Moreover, we found that the role of GC was similar to the results of SB203580, but the role of GC was masked by the C16-PAF (a p38MAPK activator) treatment. Molecular docking and western blot results confirmed that GC's therapeutic action against EAU is mediated via the p38MAPK-MEF2C axis. It regulates macrophage polarization by encouraging M1 to M2 transition and releasing anti-inflammatory factors.

Tough Decision Making in Pembrolizumab-Associated Acute Interstitial Nephritis: A Case Report

Pembrolizumab is an immune checkpoint inhibitor used as a cancer therapy. The incidence of immune related adverse events in patients receiving immune checkpoint inhibitors can be as high as 59%–85%. Renal adverse effects are uncommon, but the incidence of kidney toxicity related to pembrolizumab is rising as the use of this agent becomes more frequent. We present an uncommon case of biopsy-proven acute interstitial nephritis secondary to pembrolizumab in a patient with metastatic squamous cell carcinoma at the time of his fourth scheduled cycle. Despite the good initial tumor response, pembrolizumab had to be suspended and the patient started on corticosteroids with an initial good response. On his own initiative, the patient stopped prednisolone early, leading to a rebound acute kidney injury. Pembrolizumab was not reintroduced for the risk of further renal function worsening. His clinical status declined due to the progression of the neoplastic disease, and he was referred for palliative care. This case illustrates the importance of systematizing some key points in the approach to acute interstitial nephritis secondary to pembrolizumab: the role of the differential diagnosis of acute kidney injury in a patient under an immune checkpoint inhibitor, the role of glucocorticoids and the controversy about rechallenging this drug after a related acute interstitial nephritis.

The expression of glucocorticoid and mineralocorticoid receptors in pituitary tumors causing Cushing's disease and silent corticotroph tumors.

Pituitary neuroendocrine corticotroph tumors commonly cause Cushing's disease (CD) that results from increased adrenocorticotropic hormone (ACTH) secretion by the pituitary tumor and consequent increase of cortisol levels in blood. However, in some patients, corticotroph tumors remain clinically non-functioning. Cortisol secretion is regulated by the hypothalamic-pituitary-adrenal axis and includes a negative feedback between cortisol and ACTH secretion. Glucocorticoids reduce ACTH level both by hypothalamic regulation and acting on corticotrophs via glucocorticoid (GR) and mineralocorticoid (MR) receptors. The aim of the study was to determine the role of GR and MR expression at mRNA and protein levels in both functioning and silent corticotroph tumors. Ninety-five patients were enrolled, including 70 with CD and 25 with silent corticotroph tumors. Gene expression levels of NR3C1 and NR3C2 coding for GR and MR, respectively, were determined with qRT-PCR in the two tumor types. GR and MR protein abundance was assessed with immunohistochemistry. Both GR and MR were expressed in corticotroph tumors. Correlation between NR3C1 and NR3C2 expression levels was observed. NR3C1 expression was higher in silent than in functioning tumors. In CD patients NR3C1 and NR3C2 levels were negatively correlated with morning plasma ACTH levels and tumor size. Higher NR3C2 was confirmed in patients with remission after surgery and in densely granulated tumors. Expression of both genes and GR protein was higher in USP8-mutated tumors. Similar relationship between USP8 mutations and expression levels were observed in analysis of silent tumors that also revealed a negative correlation between GR and tumor size and higher NR3C1 expression in densely granulated tumors. Although the associations between gene/protein expression and patients clinical features are not strong, they consistently show an evident trend in which higher receptor expression corresponds to more favorable clinical characteristics.

11β-Hydroxysteroid dehydrogenase type 1 amplifies inflammation in LPS-induced THP-1 cells.

The role of glucocorticoids as anti-inflammatory and immune-stimulatory drugs has been widely reported. However, the role of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which catalyzes the conversion of inactive cortisone into active cortisol, in inflammation remains unclear. This study aimed to examine the mechanism of actions of 11β-HSD1 in lipopolysaccharide (LPS)-induced THP-1 cells. The gene expression of 11β-HSD1 and pro-inflammatory cytokines was detected via RT-PCR. The protein expression of IL-1β in cell supernatants was detected via ELISA. Oxidative stress and mitochondrial membrane potential were assessed using a reactive oxygen species (ROS) kit and a mitochondrial membrane potential (MMP) kit, respectively. The expression of Nuclear Factor- Kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) was detected via western blotting. Elevated levels of 11β-HSD1 contributed to the expression of inflammatory cytokines, whereas BVT.2733, a selective 11β-HSD1 inhibitor, ameliorated inflammatory responses, ROS, and mitochondrial damage in LPS-stimulated THP-1 cells. Furthermore, cortisone and cortisol, which are the substrate and product of 11β-HSD1, respectively, showed biphasic responses and induced the expression of pro-inflammatory cytokines at a low concentration in both LPS-stimulated or untreated THP-1 cells. The enhanced inflammation was attenuated by co-treatment with BVT.2733 and the glucocorticoid receptor (GR) antagonist RU486, but not in those treated with the mineralocorticoid receptor (MR) antagonist spironolactone. Overall, the results indicate that 11β-HSD1 amplifies inflammatory responses by activating the NF-κB and MAPK signaling pathways. Inhibition of 11β-HSD1 may serve as a potential therapeutic target against the excessive activation of inflammation.

Role of Glucocorticoids and Stress in Age-Related Mechanisms of Sarcopenia and Osteoporosis

This mini-review describes at first the ontopathogenic model based on the concept of developmental origins of health and disease (DOHaD) and thereafter explains the possible roles of glucocorticoids (GC) and stress in age-related tendencies to sarcopenia, osteoporosis, and obesity. The interactions between GC, stress and pro-inflammatory cytokines in these disorders are also considered. It is concluded that excessive exposure to stress and/or exogenous GC should be adequately prevented or controlled from the very beginning of human life.

Glucocorticoid use in rheumatoid arthritis patients and the onset of pneumonia: a systematic review and meta-analysis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that commonly affects joints. Although many treatment options exist, the most common, disease-modifying antirheumatic drugs (DMARDs), have been associated with pulmonary infections. These types of infections (specifically pneumonia) can be detrimental to RA patients. This leads providers to utilize other treatment modalities such as glucocorticoids (GCs). GCs are commonly utilized to treat RA; however, the role of GCs in the onset of pneumonia in RA patients is not fully understood. The goal of this study was to systematically review and statistically analyze pooled data documenting pneumonia as an adverse event in RA patients on DMARDs as a monotherapy vs RA patients on DMARDs and GCs as combination therapy utilizing the Population, Intervention, Comparison, and Outcomes (PICO) framework. On August 1, 2021, a search was conducted and completed on six databases: Embase, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, International Pharmaceutical Abstracts (IPA), and ClinicalTrials.gov. A total of 12 researchers were involved with the search and screening of articles (K.E., P.R.; V.A., D.P.C.; C.B., D.C.; T.A., E.S.; S.H., L.B.; K.S., C.S.). Search terms were identified utilizing Medical Subject Headings (MeSH) and Emtree and included "glucocorticoids," "rheumatoid arthritis," "pneumonia," and "respiratory tract infections," Inclusion criteria included human subjects over the age of 18 with seropositive RA, on a combination of GC (prednisone, methylprednisolone, or prednisolone) with DMARD (methotrexate [MTX], hydroxychloroquine [HCQ], or sulfasalazine [SSZ]) and developed pneumonia of bacterial, viral, or fungal origin. The control groups were on a DMARD monotherapy regimen. Articles were excluded if they were not in English, had less than 20 participants, were case reports or literature reviews, included animal subjects, and did not adhere to the established PICO framework. Five teams of two researchers individually sorted through abstracts of articles based on the inclusion and exclusion criteria. The same teams individually sorted through full-text articles of selected abstracts based on the same criteria. Conflicts between each team were resolved by a separate researcher. Odds ratios were utilized to quantify the effect sizes of combined studies from a random effects model. Chi-square tests and I2 statistics were utilized to analyze heterogeneity. A total of 3360 articles were identified from all databases, and 416 duplicate articles were removed. Thus, a total of 2944 articles abstracts were screened, of which 2819 articles either did not meet the inclusion criteria or did meet the exclusion criteria. A total of 125 articles were retrieved and assessed for full-text eligibility, of which only three observational articles were included for meta-analysis. Statistical results revealed that patients treated with DMARDs monotherapy are 95% (95% CI: 0.65-0.99) less likely to develop pneumonia compared to patients treated with a DMARD and GCs (p=0.002). Our data suggest that RA patients have a higher probability of developing pneumonia on combination therapy with GCs, compared to monotherapy with DMARDs. To our knowledge, our findings are the first to systematically review and statistically evaluate the relationship between the use of GCs and show an increased chance of developing pneumonia.

The Role of Glucocorticoids in Breast Cancer Therapy.

Glucocorticoids (GCs) are anti-inflammatory and immunosuppressive steroid molecules secreted by the adrenal gland and regulated by the hypothalamic-pituitary-adrenal (HPA) axis. GCs present a circadian release pattern under normal conditions; they increase their release under stress conditions. Their mechanism of action can be via the receptor-independent or receptor-dependent pathway. The receptor-dependent pathway translocates to the nucleus, where the ligand-receptor complex binds to specific sequences in the DNA to modulate the transcription of specific genes. The glucocorticoid receptor (GR) and its endogenous ligand cortisol (CORT) in humans, and corticosterone in rodents or its exogenous ligand, dexamethasone (DEX), have been extensively studied in breast cancer. Its clinical utility in oncology has mainly focused on using DEX as an antiemetic to prevent chemotherapy-induced nausea and vomiting. In this review, we compile the results reported in the literature in recent years, highlighting current trends and unresolved controversies in this field. Specifically, in breast cancer, GR is considered a marker of poor prognosis, and a therapeutic target for the triple-negative breast cancer (TNBC) subtype, and efforts are being made to develop better GR antagonists with fewer side effects. It is necessary to know the type of breast cancer to differentiate the treatment for estrogen receptor (ER)-positive, ER-negative, and TNBC, to implement therapies that include the use of GCs.

Hypersensitivity Reactions to Native E. coli L-Asparaginase in Children with Acute Lymphoblastic Leukemia May Vary By Treatment Schedule and Type of Glucocorticoid in Induction: Results of Trial ALL-BFM 2000

Background: Asparaginase (ASNase) has become a key component of treatment for acute lymphoblastic leukemia (ALL). The ability of this agent to eliminate leukemic blasts by utilizing the special feature that such cells are largely unable to synthesize the otherwise non-essential amino acid asparagine means that blasts cannot survive in an environment in which this amino acid has been depleted. Currently, there are three ASNase products commercially available sharing the same mechanism of action. The oldest one is the purified native enzyme extracted from E. coli. This product was further developed and refined by conjugation with polyethylene glycol (PEG-L-Asparaginase, PEG-ASNase) to prolong half-life and to reduce immunogenicity. A third ASNase product derived from the bacterium Erwinia chrysanthemi (Erwinase) is structurally different from the E. coli ASNase products. The main reason for limitation in the use of ASNase is the rather frequent occurrence of hypersensitivity reactions (HSR). Such reactions require the replacement of the ASNase product used with alternative preparations. The incidence of clinical HSR to ASNase varies with the type of ASNase product, the treatment schedule (number of ASNase doses, extended ASNase-free intervals) and the administration route (intravenously [IV] or intramuscularly [IM]). This retrospective study was primarily performed to demonstrate the dynamics and the interdependence when using ASNase in a complex multiagent treatment protocol. It aimed to evaluate the incidence of clinically apparent HSR in the ALL-BFM 2000 trial which was part of the cooperative trial AIEOP-BFM ALL 2000. Methods: Clinical hypersensitivity reactions (HSR) to native E. coli ASNase were retrospectively analyzed in a cohort of children with acute lymphoblastic leukemia (ALL) focusing on the impact of concurrent chemotherapy schedules in the risk-adapted and randomized treatment protocol and evaluating the prognostic relevance of asparaginase discontinuation. Patients: Patients with ALL aged 1-18 years were treated risk-stratified with standard-risk (SR), medium-risk (MR) and high-risk (HR) regimens in trial ALL-BFM 2000. Schedule of intravenously administered native E. coli ASNase varied by risk group and randomization arm. Randomizations compared the glucocorticoids prednisolone and dexamethasone in induction and different reintensification regimens (Möricke A et al, BLOOD 127(17): 2101-2112 (2016)). In this trial, native E. coli ASNase was administered IV as first-line product during the induction and reinduction phases. In the high-risk arm, the phase of intensified consolidation included additional E. coli ASNase doses. PEG-ASNase (IV) or Erwinase (IM) were used as second- or third-line products after HSR occurring with native E. coli ASNase or the respective second-line product. Results: HSR occurred in 40% (492/1207) of all evaluable patients. One-year cumulative incidence (CI-HSR±standard error) was 42.3±1.5% (40.6±2.5% in SR, 37.0±1.9% in MR, 65.2±3.8% in HR). Dexamethasone-treated SR and MR patients had significantly higher CI-HSR (48.5±4.3% and 45.9±3.2%) than prednisolone-treated patients (32.3±3.7% [p=0.007] and 31.2±2.9% [p<0.001]); no such difference was seen among HR patients who underwent multiple exposures to the drug (Fig. 1). Post-induction randomizations showed that one week of dexamethasone before asparaginase re-exposition in reinduction did not protect from clinical HSR in the SR/MR arm. Randomization in HR revealed an effect of the type of concurrent chemotherapeutic drugs on the risk of HSR. Discontinuation of ASNase occurred in 6.1% of all patients. No disadvantage in leukemia outcome could be detected for these patients. Conclusion: The results in our study demonstrate the complex interdependencies contributing to the risk of HSR to E. coli asparaginase in a multiagent chemotherapy protocol. The differential effects of dexamethasone and prednisolone in induction generated new hypotheses about the role of glucocorticoids in sensitization or achievement of immune tolerance to asparaginase. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Glucocorticoid treatment in patients with complex regional pain syndrome: A systematic review.

The pathophysiology of complex regional pain syndrome (CRPS) is multifactorial, with an exaggerated inflammatory response being the most prominent. Treatment for CRPS is carried out according to the presenting pathophysiological mechanism. Anti-inflammatory treatment with glucocorticoids is therefore an option. The aim of this study was to systematically review the efficacy of glucocorticoids in CRPS. Embase, Medline, Web of Science and Google Scholar were systematically searched for articles focusing on glucocorticoid treatment and CRPS. Screening based on title and abstract was followed by full-text reading (including reference lists) to determine the final set of relevant articles. Bias was assessed using the revised Cochrane risk-of-bias-tool for randomized trials (Rob2). Forty-one studies were included, which reported on 1208 CRPS patients. A wide variety of glucocorticoid administration strategies were applied, with oral being the most frequently chosen. Additionally, researchers found great heterogeneity in outcome parameters, including clinical symptoms, pain relief and range of motion. The use of glucocorticoids caused an improvement of parameters in all but two studies. In particular, improvement in pain relief and range of motion were reported. Using glucocorticoids in CRPS of longer duration (i.e. more than 3 months) appears to be less effective. Based on the present review, there is evidence to support glucocorticoid treatment in CRPS. However, the ideal administration route and dose remain unclear. We therefore recommend future research via an intervention study, as well as studies on the aetiological mechanisms and corresponding optimal treatment because CRPS pathogenesis is only partially understood. Several studies point towards CRPS being an inflammatory response after tissue or nerve damage, with higher levels of pro-inflammatory cytokines in serum, plasma, cerebrospinal fluid and artificial skin blisters. Inflammation provides a possible role for glucocorticoids in treating CRPS. This systematic review provides a structured overview of glucocorticoid treatment in patients with CRPS. Improvement in pain and range of motion is shown. Systematic review registration number: PROSPERO-CRD42020144671.

Endocrine flexibility.

Endocrine flexibility.