Background Glucocorticoids Research Articles

Efficacy and safety of emapalumab in macrophage activation syndrome

ObjectivesMacrophage activation syndrome (MAS) is a severe, life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD). The objective of this study was to confirm the adequacy...

Baricitinib for the treatment of intestinal Behçet's disease: A pilot study

ObjectivesThe pilot study aims to explore the efficacy and safety of baricitinib in treating refractory intestinal Behçet's disease (BD). MethodsWe consecutively enrolled patients with refractory intestinal BD from October 2020 to September 2022. They were treated with baricitinib 2-4 mg daily, with background glucocorticoids and immunosuppressants. Efficacy assessment included the global gastrointestinal symptom scores, the endoscopy scores, the Disease activity index for intestinal Behçet's disease (DAIBD), and the inflammatory parameters. Side effects were recorded. ResultsThe thirteen patients (six males and seven females) had a median follow-up of eleven months, 76.92% (10/13) patients achieved complete remission of global gastrointestinal symptom scores, and 66.7% (6/9) had mucosal healing on endoscopy. The DAIBD scores decreased significantly, as well as the C-reactive protein level. Baricitinib showed a glucocorticoid-sparing effect, and the safety profile is favorable. ConclusionBaricitinib might be a potential choice in treating refractory intestinal BD.

Does methylprednisolone provide protective effect in total aortic arch replacement requiring hypothermia circulatory arrest and selective cerebral perfusion?

Glucocorticoids (GC)were applied in total aortic arch replacement (TAAR) at various dosages in many centers, but with limited evidence. The retrospective study was aimed to evaluate whether methylprednisolone was associated with better postoperative outcomes in patients undergoing TAAR. Patients undergoing TAAR with moderate hypothermia and selective cerebral perfusion between 2017.1 to 2018.12 in Fuwai hospital were classified into three groups according to doses of methylprednisolone given in the surgery: large-GC group (1500-3000mg); medium-GC group (500-1000mg) and no-GC group (0mg). Postoperative outcomes were compared among three groups. Multivariable analysis was performed to identify the association of methylprednisolone with outcomes. Three hundred twenty-eight patients were enrolled. Two hundred twenty-eight were in the large-GC group, 34 were in the medium-GC group, and 66 were in the no-GC group. The incidences of major adverse outcomes in large-GC, medium-GC and no-GC groups were 22.8%, 17.6% and 18.2%, respectively, with no statistical difference. A significant difference was observed in post-cardiopulmonary bypass (CPB) fresh frozen plasma (FFP) transfusion (p < .001) and chest drainage volume (p < .001). Multivariable analysis demonstrated that methylprednisolone was not associated with better outcomes (p = .455), while large doses of methylprednisolone were significantly associated with excessive chest drainage (over 2000mL) [OR (99% CI) 4.282 (1.66-11.044), p < .001] and excessive post-CPB FFP transfusion (over 400mL) [OR (99% CI) 2.208 (1.027-4.747), p = .008]. Large doses of methylprednisolone (1500-3000mg) did not show a protective effect in TAAR with moderate hypothermia arrest plus selective cerebral perfusion and might increase postoperative bleeding and FFP transfusion.

Treatment with low-dose prednisone in refractory obstetric antiphospholipid syndrome: A retrospective cohort study and meta-analysis.

Glucocorticoids have been suggested as a potential therapy in refractory obstetric antiphospholipid syndrome (oAPS). Our aims were to describe a cohort of patients with oAPS treated with low-dose glucocorticoids and to perform a systematic review and meta-analysis evaluating the effects of additional glucocorticoids on the pregnancy outcomes in oAPS patients. Retrospective study that included 11 women diagnosed with primary antiphospholipid syndrome. The meta-analysis was conducted by fitting random effects models and was checked for heterogeneity. All women had suffered from early pregnancy losses and two also had a history of fetal deaths. We studied 47 pregnancies that resulted in 32 abortions (68.1%) and 3 fetal deaths (6.4%). Twenty-six pregnancies were under treatment, mainly LDA and LMWH. Low-dose glucocorticoids were indicated in 13 pregnancies (always in association with LDA and LMWH). There was a decrease in pregnancy loss in those patients treated with LDA and LMWH. Treatment with glucocorticoids significantly increased the rate of successful pregnancy (38.5% abortions in treated vs 85.3% abortions in non-treated pregnancies; p=0.003). After multivariate GEE analysis, only glucocorticoids remained inversely associated with pregnancy loss (OR=0.157, (CI 0.025-0.968, p=0.046)). The meta-analysis showed that glucocorticoids tended to improve the frequency of successful pregnancy (OR= 0.509 (0.252-1.028), p=0.06). Three cases of gestational diabetes and one of preeclampsia were observed in our cohort. The meta-analysis, which mostly included studies using high-dose steroids, showed that glucocorticoids increased not only the frequency of preeclampsia and gestational diabetes, but also the rate of pre-term birth. The efficacy of low-dose glucocorticoids in addition to the standard therapy in patients with refractory oAPS should be confirmed in well-designed clinical trials. However, high doses of steroids significantly increase the frequency of maternal and fetal morbidities, making their use strongly inadvisable.

Efficacy of Glucocorticoids and Glucocorticoid-Induced Hyperglycaemia in Renal Disease: A Meta-Analysis of Randomized Controlled Trials.

Background Glucocorticoids are the most effective anti-inflammatory and immunosuppressive drugs used to treat patients with renal disease. This study pooled the current evidence of the efficacy of Glucocorticoids and Glucocorticoid-induced hyperglycaemia in renal disease. Methods We conducted a systematic literature search on PubMed, Cochrane Central, and Web of Science for relevant randomized controlled trials (RCTs) up to September 1, 2021. The meta-analysis, sensitivity analysis and bias analysis were performed using Review Manager 5. 3. Results In this study, seven RCTs with 797 patients were included in our analysis. The analysis revealed that glucocorticoids had a certain alleviating effect on the reduction of renal function. (risk ratio [RR] 0.49 95% confidence interval [Cl] 0. 28 to 0.85, p =0.01) and reduction of proteinuria (weight mean difference [WMD] -0.43; 95% CI -0.57 to-0.28) when compared with the control group. Patients receiving glucocorticoids therapy did not have an increased risk of developing new-onset diabetes mellitus or impaired glucose tolerance. (RR 3.76 95% CI 0.54 to 26.10, p =0.18). For other safety outcomes, glucocorticoids therapy did not increase risk of respiratory infections (RR 1.63, 95% CI 0. 69to3. 89, p =0.27) and Gastrointestinal SAEs is relatively controversial (RR 1.10, 95% CI 0.32 to 3.79, p =0.88). Discussion. In conclusion, current clinical evidence indicates that glucocorticoids is efficacious and safe to renal disease compared with control. Further research comparing long-term glucocorticoids use is needed.

Efficacy of rituximab in patients with polymyalgia rheumatica: a double-blind, randomised, placebo-controlled, proof-of-concept trial

Background Glucocorticoids remain the cornerstone of polymyalgia rheumatica treatment, but their use has several drawbacks, such as long treatment duration and glucocorticoid-related adverse events. Effective glucocorticoid-sparing agents with a strong evidence base in polymyalgia rheumatica are absent. As B cells have been implicated in the pathogenesis of polymyalgia rheumatica, we aimed to evaluate the efficacy of rituximab for the treatment of polymyalgia rheumatica. Methods We did a double-blind, randomised, placebo-controlled, proof-of-concept trial at Sint Maartenskliniek, Nijmegen, Netherlands. We enrolled patients with polymyalgia rheumatica according to the 2012 European League Against Rheumatism and American College of Rheumatology criteria, who were recently diagnosed or who had relapsed on prednisolone and were unable to taper their dose to less than 7·5 mg per day. Participants were randomly assigned (1:1) to a single intravenous infusion of rituximab 1000 mg or placebo, with a 17-week glucocorticoid tapering scheme. Participants and care and research personnel were masked to treatment assignment and randomisation sequence. The primary outcome was glucocorticoid-free remission at 21 weeks after infusion in patients who completed the study. This trial is registered with EudraCT (2018-002641-11) and the Dutch trial database (NL7414). Findings Between Jan 14, 2019, and March 10, 2020, 116 patients were screened and 49 (42%) were enrolled. 47 patients (38 who were recently diagnosed, nine who had relapsed on prednisolone) completed the study: 23 (49%) in the rituximab group and 24 (51%) in the placebo group. Mean age (SD) in years was 64 (8) in the rituximab group and 66 (10) in the placebo group, the proportion of women was 11 (48%) of 23 versus 13 (54%) of 24, and all participants were White. 11 (48%) of 23 patients in the rituximab group and five (21%) of 24 in the placebo group achieved glucocorticoid-free remission at 21 weeks (difference 27% [one-sided 95% CI 4]; relative risk 2·3 [1·1]; p=0·049). Ten infusion-related complaints occurred in the rituximab group versus three in the placebo group (relative rate 3·5 [one-sided 95% CI 1·3]). One serious adverse event occurred (pulmonary embolism; in the rituximab group), and there were no deaths. Interpretation Rituximab was shown to be efficacious in combination with 17-week glucocorticoid treatment compared with glucocorticoid treatment alone in terms of glucocorticoid-free remission in patients with polymyalgia rheumatica. If these findings are confirmed by larger trials, rituximab could be a valuable glucocorticoid-sparing treatment for patients with polymyalgia rheumatica. Funding Sint Maartenskliniek. Glucocorticoids remain the cornerstone of polymyalgia rheumatica treatment, but their use has several drawbacks, such as long treatment duration and glucocorticoid-related adverse events. Effective glucocorticoid-sparing agents with a strong evidence base in polymyalgia rheumatica are absent. As B cells have been implicated in the pathogenesis of polymyalgia rheumatica, we aimed to evaluate the efficacy of rituximab for the treatment of polymyalgia rheumatica. We did a double-blind, randomised, placebo-controlled, proof-of-concept trial at Sint Maartenskliniek, Nijmegen, Netherlands. We enrolled patients with polymyalgia rheumatica according to the 2012 European League Against Rheumatism and American College of Rheumatology criteria, who were recently diagnosed or who had relapsed on prednisolone and were unable to taper their dose to less than 7·5 mg per day. Participants were randomly assigned (1:1) to a single intravenous infusion of rituximab 1000 mg or placebo, with a 17-week glucocorticoid tapering scheme. Participants and care and research personnel were masked to treatment assignment and randomisation sequence. The primary outcome was glucocorticoid-free remission at 21 weeks after infusion in patients who completed the study. This trial is registered with EudraCT (2018-002641-11) and the Dutch trial database (NL7414). Between Jan 14, 2019, and March 10, 2020, 116 patients were screened and 49 (42%) were enrolled. 47 patients (38 who were recently diagnosed, nine who had relapsed on prednisolone) completed the study: 23 (49%) in the rituximab group and 24 (51%) in the placebo group. Mean age (SD) in years was 64 (8) in the rituximab group and 66 (10) in the placebo group, the proportion of women was 11 (48%) of 23 versus 13 (54%) of 24, and all participants were White. 11 (48%) of 23 patients in the rituximab group and five (21%) of 24 in the placebo group achieved glucocorticoid-free remission at 21 weeks (difference 27% [one-sided 95% CI 4]; relative risk 2·3 [1·1]; p=0·049). Ten infusion-related complaints occurred in the rituximab group versus three in the placebo group (relative rate 3·5 [one-sided 95% CI 1·3]). One serious adverse event occurred (pulmonary embolism; in the rituximab group), and there were no deaths. Rituximab was shown to be efficacious in combination with 17-week glucocorticoid treatment compared with glucocorticoid treatment alone in terms of glucocorticoid-free remission in patients with polymyalgia rheumatica. If these findings are confirmed by larger trials, rituximab could be a valuable glucocorticoid-sparing treatment for patients with polymyalgia rheumatica.

Glucocorticoid gene signatures in systemic lupus erythematosus and the effects of type I interferon: a cross-sectional and in-vitro study.

Glucocorticoids, used as a therapy in systemic lupus erythematosus (SLE), interact with the cytoplasmic glucocorticoid receptor to modulate gene transcription. Minimising the use of glucocorticoids is a goal in SLE; however, pharmacological measures to support clinical guidelines are scarce. We evaluated glucocorticoid-regulated genes for their potential use as biomarkers of glucocorticoid exposure in SLE. We examined interactions between changes in gene expression that are induced by glucocorticoids and type I interferon. Genes regulated by glucocorticoids and type I interferon were analysed in relation to glucocorticoid exposure in adult patients meeting the American College of Rheumatology criteria for SLE from three cross-sectional cohorts: a local cohort from a tertiary hospital in Melbourne, VIC, Australia, and two public datasets (GSE49454, Hospital de la Conception, Marseille, France, and GSE88884, patients enrolled in a large, multicentre clinical trial). RNA sequencing was done using RNA from healthy donor leucocytes treated with the glucocorticoid dexamethasone, or type I interferon, or both. Glucocorticoid-regulated genes were analysed in a local SLE cohort (n=18) and public dataset GSE49454 (n=62). Five genes correlated with glucocorticoid dose in both cohorts and were combined to make a glucocorticoid gene signature. Validity of the glucocorticoid gene signature was tested in the public dataset GSE88884 (n=1756). A dose-dependent association was observed with glucocorticoid dose (p<0·0001), and the glucocorticoid gene signature had moderate ability to identify patients taking high-dose glucocorticoid (area under the curve [AUC]=0·77) although was less discriminatory when including all doses (AUC=0·69). We saw no effect of glucocorticoid dose on type I interferon -regulated gene expression. Patients with a high type I interferon gene signature had reduced glucocorticoid gene signature expression compared with patients with a low type I interferon gene signature matched for glucocorticoid dose, suggesting type I interferon inhibits glucocorticoid-stimulated gene expression. In RNA sequencing experiments, type I interferon impaired the expression of glucocorticoid-induced genes, whereas dexamethasone had minimal effect on the expression of type I interferon-stimulated genes. We identified genes regulated by dexamethasone but not affected by type I interferon; combined signatures using these genes also showed moderate ability to distinguish patients taking glucocorticoids. A gene signature for glucocorticoid exposure was identified, but the substantial effect of type I interferon on glucocorticoid-induced genes might limit its application in SLE. These data confirm the insensitivity of type I interferon-regulated genes to glucocorticoids, and together support the concept that type I interferon has a role in glucocorticoid resistance in SLE. Lupus Research Alliance and Australian National Health and Medical Research Council.

Perioperative management with biologics on severe aortic valve regurgitation caused by Behçet syndrome: the experience from a single center.

Background:To investigate the efficacy and safety of biologics in the perioperative management of severe aortic valve regurgitation (AR) caused by Behçet syndrome (BS).Methods:We retrospectively analyzed 20 patients with severe AR caused by BS who were all treated with biologics during the perioperative period of cardiac surgeries in our center between February 2016 and October 2020.Results:A total of 20 patients with severe AR were enrolled, including 19 males and 1 female, with a mean age of 39.1 ± 8.8 years and a median course of 8 [interquartile range (IQR) 5.25–10.00] years. Before biologic administration, 92.9% of the patients who underwent aortic valve replacement had failed conventional therapy and developed postoperative paravalvular leakage (PVL) at a median interval of 4 months. Biologics were administered with background glucocorticoids (GCs) and immunosuppressants during the perioperative period for 22 aortic valve surgeries, including preoperatively with a median interval of 3.5 (IQR 2.75–4.25) months in 13 cases and within 3 months postoperatively in 9 cases. After a median follow up of 21 (IQR 15–32) months, 2 out of 13 cases (15.4%) preoperatively, and 1 out of 9 cases (11.1%) postoperatively treated with biologics developed PVL, and the rest were event free. The Behçet’s Disease Current Activity Form score improved significantly (7 versus 0, median, p < 0.0001). Decrease of erythrocyte sedimentation rate [25.0 (IQR 11.00–36.25) mm/h versus 6.5 (IQR 4.0–8.8) mm/h, p < 0.001], and C-reactive protein [20.77 (IQR 7.19–29.58) mg/l versus 1.53 (IQR 0.94–2.92) mg/l, p = 0.001] were achieved rapidly and effectively. The GC dosage tapered from 40 (IQR 30–60) mg/d to 10 (IQR 5–11.25) mg/d, p < 0.0001. Immunosuppressants were tapered in number and dosage in 6 (30%) and 20 patients (100%), respectively. No serious adverse event was observed.Conclusion:Our study suggests that biologics were effective and well tolerated for the perioperative management of severe and refractory AR caused by BS, which significantly reduced the occurrence of postoperative PVL and had favorable GC- and immunosuppressant-sparing effect.

Effect of long-term glucocorticoid therapy on cardiac functions in children with congenital adrenal hyperplasia.

Glucocorticoids play an important role in cardiac physiology. Chronic exposure and higher doses may cause adverse effects on the myocardium, especially in young patients receiving long-term therapy. To assess cardiac function in children with congenital adrenal hyperplasia (CAH) and its relation to glucocorticoid dose and therapy duration. Forty-seven patients with CAH due to 21-hydroxylase deficiency were compared to 47 controls. Patients were subdivided according to treatment duration (Group A: less than 6years, Group B: more than 6years). Mean daily glucocorticoid and cumulative glucocorticoid doses were calculated. Echocardiography was performed for patients and controls to evaluate cardiac functions, chamber dimensions and tissue Doppler valvular status. Compared to controls, patients had cardiac chamber hypertrophy reflected by higher M-mode dimensions. Patients had lower fractional shortening, defective ventricular relaxation, lower average mitral and tricuspid e´/a´ ratios (e´ early diastolic, a´ late diastolic) as well as s´ (systolic) velocities, higher average mitral E/e ratio and higher left ventricle TDI Tei index (P<.05). Group B had lower average mitral e´/a´ and tricuspid s´ velocities, and higher average mitral E/e ratio (P<.05). Cumulative glucocorticoid dose significantly correlated with different echocardiographic parameters. Long-term glucocorticoid therapy even within the recommended therapeutic range adversely affects cardiac functions in children with 21-hydroxylase deficiency.

Quercetin Ameliorates Lipid and Apolipoprotein Profile in High-Dose Glucocorticoid Treated Rats.

ResumoFundamento Os glicocorticóides (GCs) são amplamente prescritos para o tratamento de numerosos distúrbios clínicos devido às suas propriedades anti-inflamatórias e imunomoduladoras, e um dos efeitos indesejáveis mais comuns desses medicamentos é a dislipidemia.Objetivo Avaliar o efeito da quercetina, um flavonoide derivado de plantas, no perfil lipídico de ratos tratados com glicocorticóides em altas doses.Métodos Um total de 32 ratos Sprague-Dawley foram distribuídos aleatoriamente entre quatro grupos (8 ratos por grupo) e tratados por 6 semanas com uma das seguintes opções : (i) solução salina normal; (ii) 40 mg/kg de succinato sódico de metilprednisolona (MP); (iii) MP + 50 mg/kg de quercetina; (iv) MP + 150 mg/kg de quercetina. O MP foi injetado por via subcutânea e a quercetina foi administrada por gavagem oral 3 dias por semana. No final do estudo, o perfil lipídico dos animais foi medido através de kits enzimáticos. Os dados foram analisados e a significância estatística foi estabelecida em p <0,05.Resultados Os níveis séricos médios de colesterol total (CT), triglicerídeos (TG) e LDL aumentaram drasticamente em animais tratados com GC em comparação com o grupo controle. Ambas as doses de quercetina (50 e 150 mg/kg) melhoraram o CT (43% e 45%), LDL (56% e 56%) e TG (46% e 55%, respectivamente). A razão Apo B/A1 diminuiu mais de 20% após a ingestão de Anti-Inflamatory Agents.Conclusões Esses dados sugerem que a ingestão de quercetina Quercetin; induzida por glicocorticóides. (Arq Bras Cardiol. 2020; 115(1):102-108)

Background Glucocorticoid Therapy Has No Impact on Efficacy and Safety of Abatacept or Adalimumab in Patients with Rheumatoid Arthritis.

To date, the impact of background glucocorticoids (GC) on the efficacy and safety of abatacept or adalimumab in patients with active rheumatoid arthritis (RA) is not clearly established. This post hoc analysis of (AMPLE) trial (NCT00929864) compared efficacy and safety outcomes over 2 years in patients treated with abatacept or adalimumab plus background methotrexate (MTX), who continued GC (≤10 mg/day) versus those who were not receiving GC (no-GC). Of 646 randomized patients, 317 received abatacept + MTX (161 GC, 156 no-GC) and 326 received adalimumab + MTX (162 GC, 164 no-GC). At Year 2, the adjusted mean changes from baseline in Disease Activity Score (DAS28 C-reactive protein (CRP)) and Health Assessment Questionnaire-Disability Index (HAQ-DI) were not significantly different in the GC versus no-GC subgroups receiving abatacept or adalimumab. A similar proportion of patients achieved remission, HAQ-DI score improvement ≥0.3 and radiographic progression rates. No clinically meaningful safety differences were observed between GC versus no-GC subgroups either with abatacept or adalimumab. In patients with active RA of similar baseline disease activity treated with abatacept or adalimumab plus background MTX, there was no additional value of background GC on clinical, functional or radiographic outcomes over two years.

Effects of clopidogrel and prednisone on platelet function in healthy dogs

BackgroundGlucocorticoids cause hypercoagulability, but it is unknown if they counteract clopidogrel's antiplatelet effects.Hypothesis/ObjectivesDetermine the effects of clopidogrel and prednisone on platelet function.AnimalsTwenty‐four healthy dogs.MethodsDouble‐blinded, placebo‐controlled randomized trial. Platelet function was evaluated using a platelet function analyzer and impedance aggregometry (days 0, 14, and 28) for dogs treated with placebo, clopidogrel (2‐3 mg/kg/d), prednisone (2 mg/kg/d), or prednisone with clopidogrel PO for 28 days. Results were categorized as nonresponder versus responder (platelet function analyzer), and inadequate, ideal, or excessive response (aggregometry). Results were compared using mixed model, split‐plot repeated measures analysis of variance and generalized estimating equation proportional odds models. P < .05 was considered significant.ResultsClosure times differed by treatment (F [3, 20] = 10.5; P < .001), time (F [2, 40] = 14.3; P < .001), and treatment‐by‐time (F [6, 40] = 3.4; P = .01). Area under the curve (AUC) differed by treatment (F [3, 20] = 19.6; P < .001), time (F [2, 40] = 35.4; P < .001), and treatment‐by‐time (F [6, 40] = 13.5; P < .001). Based on closure times, 5/6 dogs each in the clopidogrel and prednisone/clopidogrel groups were responders. All dogs in the prednisone/clopidogrel group were overcontrolled based on AUC (days 14 and 28), whereas 5/6 (day 14) and 2/6 (day 28) dogs treated with clopidogrel were overcontrolled. Compared to clopidogrel, dogs receiving prednisone/clopidogrel were 11 times (P = .03) more likely to have an excessive response.Conclusions and Clinical ImportanceAdministration of clopidogrel/prednisone increases platelet dysfunction in healthy dogs.

Effect on efficacy and safety trial outcomes of also enrolling patients on ongoing glucocorticoid therapy in rheumatoid arthritis clinical trials of tocilizumab or adalimumab or methotrexate monotherapy

BackgroundIn rheumatoid arthritis (RA) trials, inclusion of patients on background treatment with glucocorticoids (GCs) might impact efficacy and safety outcomes.ObjectivesTo determine if inclusion of patients on background GC use influenced...

Tocilizumab in the treatment of severe and refractory parenchymal neuro-Behçet's syndrome: case series and literature review.

Objectives:This study aimed to investigate the efficacy and safety of tocilizumab (TCZ) in severe and refractory parenchymal neuro-Behçet’s syndrome (p-NBS).Methods:We retrospectively analyzed five patients with p-NBS treated with TCZ in our center between 2013 and 2020, and six cases from literature research with the index terms “neuro-Behçet’s syndrome” and “tocilizumab” on PubMed NCBI.Results:A total of 11 patients with p-NBS were enrolled (5 males, 6 females), with a mean age of 34.5 ± 8.0 years at the onset. All the patients had parenchymal neurological lesions, six patients (54.5%) suffered from multiple lesions, and nine patients (81.8%) were disabled. Before TCZ administration, all the patients had failed conventional therapy, eight patients (72.7%) received two or more immunosuppressants, and five patients showed insufficient response or intolerance to other biologics. TCZ was administrated at 8 mg/kg every 4 weeks, with background glucocorticoids (GCs) and immunosuppressants. After a median follow-up of 13 (interquartile range, 3.5–23.5) months, all the patients achieved both clinical and radiological improvements, and the Behçet’s Disease Current Activity Form score improved significantly (3 versus 0, median, p = 0.004), the Rankin score also decreased (4 versus 2, median, p = 0.005). Levels of interleukin-6 in the cerebrospinal fluid decreased significantly in five patients (533.4 ± 389.7 pg/ml versus 34.5 ± 27.1 pg/ml, p = 0.048), after a median of two (interquartile range, 1–4) times of TCZ infusions. Furthermore, the GC dosage (per os) reduced from 69.2 ± 16.9 mg/d to 16.4 ± 16.2 mg/d (p = 0.000), and immunosuppressants were tapered in number and dosage in seven (63.6%) and four (36.3%) patients, respectively. No serious adverse events or deaths were observed during follow-up.Conclusions:TCZ is well tolerated and effective in severe and refractory p-NBS, with a favorable GC- and immunosuppressant-sparing effect. Cerebrospinal fluid interleukin-6 might be used to monitor the effects of TCZ in p-NBS.

Glucocorticoid-induced hyperglycemia in oncohematological patients

Background Glucocorticoids are a common component of systemic chemotherapy regimens for hematological malignancy. Steroid-induced hyperglycemia remains a common potentially harmful problem that must be considered when using any type of glucocorticoids. Little is known about the impact of hyperglycemia associated with steroid use on treatment morbidity, infectious complications, as well as disease remission and mortality. Objective The aim of the current work is to study glucocorticoid-induced hyperglycemia in patients with hematologic malignancies receiving repeated short-term pulse cycles of glucocorticoids (5–7 days), to estimate its prevalence, to define the risk factors, and to assess treatment response. Patients and methods The prospective study included 30 adult patients with acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, and chronic lymphocytic leukemia attending the outpatient clinic of Al Hussein Hospital, Al Azhar University during the period between November 2015 and April 2016. During the period of the study, 30 patients received a total of 60 cycles of chemotherapy including corticosteroid. Results Out of the 30 study patients, 15 (50%) were men and 15 (50%) were women with a mean age of 44.17. Corticosteroid-induced hyperglycemia was documented in 12 patients after one or more than one cycle (12/30–40%). Among the 60 cycles, corticosteroid-induced hyperglycemia was documented after 19 cycles (19/60–31%). The age of the patient was found to be the most important factor that affected the occurrence of hyperglycemia after corticosteroid where younger patients were less likely to develop hyperglycemia (P=0.013). Patients with BMI less than or equal to 25 had the lowest chance to develop hyperglycemia after corticosteroid. However, this difference was not statistically significant. The three patients who developed persistent hyperglycemia received hypoglycemic medications. Conclusion About one-third of patients with hematological malignancies receiving glucocorticoids may develop hyperglycemia. To allow for early detection and effective treatment, these patients should be screened for hyperglycemia at least before each cycle and 4–6 h after glucocorticoids intake, especially old obese patients Appropriate guidelines for the diagnosis and treatment of steroid-induced diabetes are needed in order to prevent complications associated with the hyperglycemic state

Uncovering a multitude of human glucocorticoid receptor variants: an expansive survey of a single gene

Background Glucocorticoids are commonly used in the clinical setting for their potent anti-inflammatory effects; however, significant variations in response to treatment have been demonstrated. Although the underlying mechanisms have yet to be fully understood, this variable response may be a result of alterations in human glucocorticoid receptor (hGR) expression and function. In addition to hGRα, the biologically active isoform, a screening of current databases and publications revealed five alternative splice isoforms and hundreds of variants that have been reported to date. Many of these changes in the hGR-coding gene, NR3C1, have been linked to pathophysiology. However, many studies focus on evaluating hGR expression in vitro or detecting previously reported variants.ResultsIn this study, blood from healthy volunteers, burn and asthma patients, as well as from peripheral blood mononuclear cells isolated from leukoreduced donor whole blood, were screened for NR3C1 isoforms. We identified more than 1500 variants, including an additional 21 unique splice isoforms which contain 15 new cryptic exons. A dynamic database, named the Universal hGR (UhGR), was created to annotate and visualize the variants.ConclusionThis identification of naturally occurring and stress-induced hGR isoforms, as well as the establishment of an hGR-specific database, may reveal new patterns or suggest areas of interest that will lead to the improved understanding of the human stress response system.

Glucocorticoid administration restores salience network activity in patients with spider phobia.

Glucocorticoids reduce phobic fear in patients with anxiety disorders. Although the neurobiology of anxiety disorders is not fully understood, convergent structural and functional neuroimaging studies have identified abnormalities in various brain regions, including those in the salience network (SN) and default mode network (DMN). Here, we examine the effects of glucocorticoid administration on SN and DMN activity during the processing of phobic stimuli. We use functional magnetic resonance imaging to record brain activity in 24 female patients with spider phobia who were administered either 20mg of cortisol or placebo while viewing pictures of spiders. Fourteen healthy female participants were tested with the same task but without substance administration. Independent component analysis (ICA) performed during stimulus encoding identified the SN and DMN as exhibiting synchronized activation in diverse brain regions; thus, we examined the effects of cortisol on these networks. Furthermore, participants had to rate their level of fear at various time points. Glucocorticoids reduced phobic fear in patients with spider phobia. The ICA performed during stimulus encoding revealed that activity in the SN and DMN was reduced in placebo-treated patients versus healthy controls. Brain activity in the SN, but not the DMN, was altered in cortisol- versus placebo-treated patients to a level that was similar to that observed in healthy controls. Activity in both the SN and DMN was reduced in patients with spider phobia. Cortisol administration altered the SN activity to a level that was comparable to that found in healthy controls. This alteration in SN activity might reflect the fear-reducing effects of glucocorticoids in phobia.

Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia.

Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate host defence against infections, which remains a cause of morbidity and death. Suppression commonly occurs in the first days after cessation of glucocorticoid therapy, but the exact duration is unclear. This review is an update of a previously published Cochrane review. To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 6, 2014), MEDLINE/PubMed (from 1945 to June 2014), and EMBASE/Ovid (from 1980 to June 2014). In addition, we searched reference lists of relevant articles, conference proceedings (the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2005 to 2013), and ongoing trial databases (the ISRCTN register and the NIH register via http://www.controlled-trials.com in June 2014). All study designs, except case reports and patient series with fewer than 10 children, examining the effect of glucocorticoid therapy for childhood ALL on the HPA axis function. Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessment, which another review author checked. We identified eight studies (total of 218 children), including two randomised controlled trials (RCTs), that assessed the adrenal function. None of the studies assessed the HPA axis at the level of the hypothalamus, pituitary, or both. Due to substantial differences between studies, we could not pool results. All of the studies had some methodological limitations. The included studies demonstrated that adrenal insufficiency occurs in nearly all children in the first days after cessation of glucocorticoid treatment for childhood ALL. The majority of children recovered within a few weeks, but a small number of children had ongoing adrenal insufficiency lasting up to 34 weeks. In the RCTs, the occurrence and duration of adrenal insufficiency did not differ between the prednisone and dexamethasone arms. In one study, it appeared that treatment with fluconazole prolonged the duration of adrenal insufficiency. Furthermore, one of the studies evaluated the presence of infections or stress episodes, or both as a risk factor for adrenal insufficiency. The authors found no relationship between the presence of infection/stress and adrenal insufficiency. We concluded that adrenal insufficiency commonly occurs in the first days after cessation of glucocorticoid therapy for childhood ALL, but the exact duration is unclear. Since no data on the level of the hypothalamus and the pituitary were available, we cannot make any conclusions regarding those outcomes. Clinicians should consider prescribing glucocorticoid replacement therapy during periods of serious stress in the first weeks after cessation of glucocorticoid therapy for childhood ALL to reduce the risk of life-threatening complications. However, more high-quality research is needed for evidence-based guidelines for glucocorticoid replacement therapy.Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as this may prolong the duration of adrenal insufficiency.Finally, it would be relevant to further investigate the relationship between present infection/stress and adrenal insufficiency in a larger, separate study specially designed for this purpose.

An abnormality in glucocorticoid receptor expression differentiates steroid responders from nonresponders in keloid disease.

SummaryBackgroundGlucocorticoids (GCs) are first‐line treatment for keloid disease (KD) but are limited by high incidence of resistance, recurrence and undesirable side‐effects. Identifying patient responsiveness early could guide therapy.MethodsNineteen patients with KD were recruited at week 0 (before treatment) and received intralesional steroids. At weeks 0, 2 and 4, noninvasive imaging and biopsies were performed. Responsiveness was determined by clinical response and a significant reduction in vascular perfusion following steroid treatment, using full‐field laser perfusion imaging (FLPI). Responsiveness was also evaluated using (i) spectrophotometric intracutaneous analysis to quantify changes in collagen and melanin and (ii) histology to identify changes in epidermal thickness and glycosaminoglycan (GAG) expression. Biopsies were used to quantify changes in glucocorticoid receptor (GR) expression using quantitative reverse transcriptase polymerase chain reaction, immunoblotting and immunohistochemistry.ResultsAt week 2, the FLPI was used to separate patients into steroid responsive (n = 12) and nonresponsive groups (n = 7). All patients demonstrated a significant decrease in GAG at week 2 (P < 0·05). At week 4, responsive patients exhibited significant reduction in melanin, GAG, epidermal thickness (all P < 0·05) and a continued reduction in perfusion (P < 0·001) compared with nonresponders. Steroid‐responsive patients had increased GR expression at baseline and showed autoregulation of GR compared with nonresponders, who showed no change in GR transcription or protein.ConclusionsThis is the first demonstration that keloid response to steroids can be measured objectively using noninvasive imaging. FLPI is a potentially reliable tool to stratify KD responsiveness. Altered GR expression may be the mechanism gating therapeutic response.

Intratympanic Steroid Treatments May Improve Hearing via Ion Homeostasis Alterations and Not Immune Suppression.

The inner ear (IE) endothelium is capable of responding to therapeutic steroids by altering the local expression of cytokine and ion homeostasis genes that impact inflammation and fluid regulation. Glucocorticoids are often given transtympanically for hearing disorders because of their anti-inflammatory effects, but their direct impact on IE ion homeostasis and cytokine gene expression has not been studied. The middle ears of Balb/c mice were transtympanically injected with 5 μL of phosphate-buffered saline, prednisolone (Pred), or dexamethasone (Dex). Untreated mice were used as controls. Mice were euthanized at 6, 24, and 72 hours; the cochleas were harvested; and total RNA was isolated from the IE tissues. Expression of eight cytokine genes and 24 ion homeostasis genes was analyzed with quantitative real time reverse transcription polymerase chain reaction. Phosphate-buffered saline caused upregulation of inflammatory cytokine genes that peaked at 6 hours. Surprisingly, Pred and Dex also caused upregulation of most cytokine genes. Interestingly, ion homeostasis genes were predominantly upregulated with Dex and Pred, with Pred having a larger effect. In the murine model, intratympanic steroids caused an initial upregulation of inflammatory cytokine genes in the IE, as well as predominant upregulation of ion homeostasis genes. These findings suggest that glucocorticoids do not suppress IE inflammation but rather cause an initial inflammatory response in the IE. Thus, inflammatory gene suppression is not a likely mechanism for their hearing restorative effects. On the other hand, these steroids have a significant mineralocorticoid function, as demonstrated by increased function of ion homeostasis genes, implicating their ionic and fluid regulatory properties as a mechanism for their therapeutic effects.