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The randomised placebo-controlled GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) trial evaluated the benefits and harms of prednisolone 5 mg/day added to standard care for 2 years in patients aged 65+ years with rheumatoid arthritis (RA). Here, we studied disease activity, flares and possible adrenal insufficiency after blinded withdrawal of study medication. Per protocol, patients successfully completing the 2-year trial period linearly tapered and stopped blinded study medication in 3 months. We compared changes in disease activity after taper between treatment groups (one-sided testing). Secondary outcomes (two-sided tests) comprised disease flares (DAS28 (Disease Activity Score 28 joints) increase >0.6, open-label glucocorticoids or disease-modifying antirheumatic drug (DMARD) increase/switch after week 4 of tapering) and symptoms/signs of adrenal insufficiency. In a subset of patients from 3 Dutch centres, cortisol and ACTH were measured in spot serum samples after tapering. 191 patients were eligible; 36 met treatment-related flare criteria and were only included in the flare analysis. Mean (SD) DAS28 change at follow-up: 0.2 (1.0) in the prednisolone group (n=76) vs 0.0 (1.2) in placebo (n=79). Adjusted for baseline, the between-group difference in DAS28 increase was 0.16 (95% confidence limit -0.06, p=0.12). Flares occurred in 45% of prednisolone patients compared with 33% in placebo, relative risk (RR) 1.37 (95% CI 0.95 to 1.98; p=0.12). We found no evidence for adrenal insufficiency. Tapering prednisolone moderately increases disease activity to the levels of the placebo group (mean still at low disease activity levels) and numerically increases the risk of flare without evidence for adrenal insufficiency. This suggests that withdrawal of low-dose prednisolone is feasible and safe after 2 years of administration.

Abstract Background and Aims Glucocorticoid-induced adrenal insufficiency (GC-AI) is a potentially life-threatening side effect of glucocorticoid therapy. Currently, there is no consensus on monitoring and treating GC-AI in inflammatory bowel disease (IBD) patients. This systematic review and meta-analysis aimed to determine the prevalence of GC-AI in IBD patients following glucocorticoid use. Additionally, a Delphi panel was conducted to develop evidence-based expert opinions on evaluating and managing GC-AI in IBD patients. Methods Thirty-four articles were included in this study. Of these, 26 articles reported the prevalence of GC-AI in IBD patients. Statements were generated and rated by a panel of adult and pediatric gastroenterologists using a 1-9 scale. Statements were classified as inappropriate, uncertain, or appropriate based on the median panel rating and the degree of disagreement. Results The prevalence of GC-AI across all studies was 26.9% (95% CI: 18.9-36.8, I2: 96%). The panel emphasized the importance of maintaining a high suspicion for GC-AI in IBD patients treated with systemic glucocorticoids and considering risk factors such as exogenous glucocorticoid use ≥4 weeks at doses ≥5 mg of prednisone-equivalent. Recommendations for initial screening and management of GC-AI are provided. The management of GC-AI in special populations, such as those in the perioperative setting is also addressed. The panel underscored the need to consider GC-AI assessment in clinical trial design. Conclusions GC-AI is a serious, often underrecognized side effect of glucocorticoid use. This study presents expert opinions on the evaluation and management of GC-AI in IBD patients, emphasizing the need for vigilance and appropriate management strategies. Lay Summary Glucocorticoid-induced adrenal insufficiency (GC-AI) occurs in approximately 25% of IBD patients after stopping corticosteroids. This study adds expert guidance on GC-AI evaluation and management, aiming to improve awareness and reduce associated risks.

Critically ill patients often require emergency intubation. The use of etomidate as the sedative agent in this context has been challenged because it might cause a reversible adrenal insufficiency, potentially associated with increased in-hospital morbidity. We compared early and 28-day morbidity after a single dose of etomidate or ketamine used for emergency endotracheal intubation of critically ill patients. In this randomised, controlled, single-blind trial, 655 patients who needed sedation for emergency intubation were prospectively enrolled from 12 emergency medical services or emergency departments and 65 intensive care units in France. Patients were randomly assigned by a computerised random-number generator list to receive 0·3 mg/kg of etomidate (n=328) or 2 mg/kg of ketamine (n=327) for intubation. Only the emergency physician enrolling patients was aware of group assignment. The primary endpoint was the maximum score of the sequential organ failure assessment during the first 3 days in the intensive care unit. We excluded from the analysis patients who died before reaching the hospital or those discharged from the intensive care unit before 3 days (modified intention to treat). This trial is registered with ClinicalTrials.gov, number NCT00440102. 234 patients were analysed in the etomidate group and 235 in the ketamine group. The mean maximum SOFA score between the two groups did not differ significantly (10·3 [SD 3·7] for etomidate vs 9·6 [3·9] for ketamine; mean difference 0·7 [95% CI 0·0–1·4], p=0·056). Intubation conditions did not differ significantly between the two groups (median intubation difficulty score 1 [IQR 0–3] in both groups; p=0·70). The percentage of patients with adrenal insufficiency was significantly higher in the etomidate group than in the ketamine group (OR 6·7, 3·5–12·7). We recorded no serious adverse events with either study drug. Our results show that ketamine is a safe and valuable alternative to etomidate for endotracheal intubation in critically ill patients, and should be considered in those with sepsis. French Ministry of Health.

Abstract Context Vamorolone, a novel “dissociative” steroid, demonstrated similar efficacy in muscle function relative to prednisone 0.75 mg/kg/day but improved linear growth and bone turnover markers in a randomized trial of pediatric Duchenne muscular dystrophy (DMD). Objectives To determine the frequency of adrenal suppression (AS) induced by vamorolone and prednisone in pediatric DMD and to assess cortisol thresholds using a monoclonal antibody immunoassay. Methods Post hoc analysis of cortisol levels was performed on data from a randomized, double-blind, placebo- and prednisone-controlled 24-week trial of vamorolone with a 24-week crossover extension. Morning and ACTH-stimulated cortisol levels were measured using the Elecsys II immunoassay, with AS defined as a stimulated cortisol of <500 nmol/L (“historical threshold”) and <400 nmol/L (“revised threshold”). Results Mean age at enrolment was 5.41 ± 0.86 years (n = 118). At week 24, the proportion of participants with AS using the historical and revised cortisol thresholds, respectively, were as follows: prednisone 0.75 mg/kg/day = 100% (25/25) and 92.0% (23/25); vamorolone 6 mg/kg/day = 95.2% (20/21) and 90.5% (19/21); vamorolone 2 mg/kg/day = 84.2% (16/19) and 47.5% (9/19); and placebo = 20.0% (4/20) and 0% (0/20). Morning and peak ACTH-stimulated cortisol were strongly correlated in steroid-treated boys (Spearman correlation week 48 = 0.83). Conclusion AS after vamorolone and prednisone was frequent and vamorolone-associated AS appeared dose-dependent. A lower stimulated cortisol threshold may be appropriate when using a monoclonal assay. We recommend hydrocortisone for glucocorticoid stress dosing in patients receiving vamorolone.

Despite the widespread use of glucocorticoids in inflammatory and autoimmune disorders, there is uncertainty about the safe cessation of long-term systemic treatment, as data from prospective trials are largely missing. Due to potential disease relapse or glucocorticoid-induced hypocortisolism, the drug is often tapered to sub-physiological doses rather than stopped when the underlying disease is clinically stable, increasing the cumulative drug exposure. Conversely, the duration of exposure to glucocorticoids should be minimized to lower the risk of side effects. We designed a multicenter, randomized, triple-blinded, placebo-controlled trial to test the clinical noninferiority of abrupt glucocorticoid stop compared to tapering after ≥28 treatment days with ≥420 mg cumulative and ≥7.5 mg mean daily prednisone-equivalent dose. 573 adult patients treated systemically for various disorders will be included after their underlying disease has been stabilized. Prednisone in tapering doses or matching placebo is administered over 4 weeks. A 250 mg ACTH-test, the result of which will be revealed a posteriori, is performed at study inclusion; all patients are instructed on glucocorticoid stress cover dosing. Follow-up is for 6 months. The composite primary outcome measure is time to hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary outcomes include the individual components of the primary outcome, cumulative glucocorticoid doses, signs and symptoms of hypocortisolism, and the performance of the ACTH test in predicting the clinical outcome. Cox proportional hazard, linear, and logistic regression models will be used for statistical analysis. This trial aims to demonstrate the clinical noninferiority and safety of abrupt treatment cessation after ≥28 days of systemic glucocorticoid therapy in patients with stabilized underlying disease. ClinicalTrials.gov Identifier: NCT03153527; EUDRA-CT: 2020-005601-48 https://clinicaltrials.gov/ct2/show/NCT03153527?term=NCT03153527&draw=2&rank=1.

Purpose To investigate the impact of etomidate on the rate of hospital-acquired pneumonia (HAP) in trauma patients and the effects of hydrocortisone in etomidate-treated patients. Methods This was a sub-study of the HYPOLYTE multi-centre, randomized, double-blind, placebo-controlled trial of hydrocortisone in trauma patients (NCT00563303). Inclusion criterion was trauma patient with mechanical ventilation (MV) of ≥48 h. The use of etomidate was prospectively collected. Endpoints were the results of the cosyntropin test and rate of HAP on day 28 of follow-up. Results Of the 149 patients enrolled in the study, 95 (64 %) received etomidate within 36 h prior to inclusion. 79 (83 %) of 95 patients receiving etomidate and 34 of the 54 (63 %) not receiving etomidate had corticosteroid insufficiency ( p  = 0.006). The administration of etomidate did not alter basal cortisolemia ( p  = 0.73), but it did decrease the delta of cortisolemia at 60 min ( p  = 0.007). There was a correlation between time from etomidate injection to inclusion in the study and sensitivity to corticotropin ( R 2  = 0.19; p  = 0.001). Forty-nine (51.6 %) patients with etomidate and 16 (29.6 %) patients without etomidate developed HAP by day 28 ( p  = 0.009). Etomidate was associated with HAP on day 28 in the multivariate analysis (hazard ratio 2.48; 95 % confidence interval 1.19–5.18; p  = 0.016). Duration of MV with or without etomidate was not significantly different ( p  = 0.278). Among etomidate-exposed patients, 18 (40 %) treated with hydrocortisone developed HAP compared with 31 (62 %) treated with placebo ( p  = 0.032). Etomidate-exposed patients treated with hydrocortisone had fewer ventilator days ( p  < 0.001). Conclusions Among the patients enrolled in the study, etomidate did not alter basal cortisolemia, but it did decrease reactivity to corticotropin. We suggest that in trauma patients, etomidate is an independent risk factor for HAP and that the administration of hydrocortisone should be considered after etomidate use.

To evaluate the effect of an epidural corticosteroid injection of 80 mg and 40 mg of methylprednisolone acetate on the hypothalamic-pituitary-adrenal axis and on back pain. Randomized, single-blinded prospective study. Operating room of a university-affiliated hospital. 42 patients with low back pain due to radiculopathy. Group 1 received an epidural corticosteroid injection of 80 mg of methylprednisolone acetate, and Group 2 received an epidural corticosteroid injection of 40 mg of methylprednisolone acetate. All study patients underwent a stimulation test of one μg of adrenocorticotropin hormone (ACTH), and their pain levels were graded just prior to and following the epidural corticosteroid injection on weeks one, 3, and 4. Serum cortisol of the ACTH stimulation tests and back pain levels were rated using a visual analog scale (VAS). Serum cortisol levels lower than 18 ng/mL 30 minutes following the ACTH stimulation test were considered to be secondary adrenal insufficiency. 21 patients were enrolled in each group. The rate of secondary adrenal insufficiency in Group 1 was ~86%, ~ 22%, and ~17% of patients versus ~53% (P = 0.024), 15% (P = 0.874), and ~12% (P = 0.715) of Group 2 patients at weeks one, 3, and 4, respectively. About 62%, 56%, and 39% of Group 1 patients had a favorable clinical response as opposed to ~47% (P = 0362), 35% (P = 0.21), and ~6% (P = 0.049) of Group 2 patients at weeks one, 3, and 4, respectively. Epidural corticosteroid injection of methylprednisolone acetate in both groups was associated with very high rates of secondary adrenal insufficiency, but significantly more so in Group 1 at week one. This suppression was transient, with recovery of the gland in most patients noted over the ensuing weeks. An epidural corticosteroid injection of 80 mg had higher rates of favorable clinical response than a 40 mg injection, but significantly more so at week 4 only. This favorable response waned over a few weeks in both groups.

Abstract Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint clinical practice guideline provides guidance on this clinically relevant condition to aid clinicians involved in the care of patients on chronic glucocorticoid therapy.

ABSTRACTSynthetic glucocorticoids are widely used for their anti-inflammatory and immunosuppressive actions. A possible unwanted effect of glucocorticoid treatment is suppression of the hypothalamic-pituitary-adrenal axis, which can lead to adrenal insufficiency. Factors affecting the risk of glucocorticoid induced adrenal insufficiency (GI-AI) include the duration of glucocorticoid therapy, mode of administration, glucocorticoid dose and potency, concomitant drugs that interfere with glucocorticoid metabolism, and individual susceptibility. Patients with exogenous glucocorticoid use may develop features of Cushing’s syndrome and, subsequently, glucocorticoid withdrawal syndrome when the treatment is tapered down. Symptoms of glucocorticoid withdrawal can overlap with those of the underlying disorder, as well as of GI-AI. A careful approach to the glucocorticoid taper and appropriate patient counseling are needed to assure a successful taper. Glucocorticoid therapy should not be completely stopped until recovery of adrenal function is achieved. In this review, we discuss the factors affecting the risk of GI-AI, propose a regimen for the glucocorticoid taper, and make suggestions for assessment of adrenal function recovery. We also describe current gaps in the management of patients with GI-AI and make suggestions for an approach to the glucocorticoid withdrawal syndrome, chronic management of glucocorticoid therapy, and education on GI-AI for patients and providers.

Abstract Context Chronic opioid use may lead to adrenal insufficiency because of central suppression of the hypothalamic-pituitary-adrenal axis. However, the prevalence of opioid-induced adrenal insufficiency (OIAI) is unclear. Objective To determine the prevalence of OIAI and to identify predictors for the development of OIAI in patients taking opioids for chronic pain. Design Cross-sectional study, 2016-2018. Setting Referral center. Patients Adult patients taking chronic opioids admitted to the Pain Rehabilitation Center. Main outcome measure Diagnosis of OIAI was considered if positive case detection (cortisol < 10 mcg/dL, ACTH < 15 pg/mL, and dehydroepiandrosterone sulfate < 25 mcg/dL), and confirmed after endocrine evaluation. Daily morphine milligram equivalent (MME) was calculated. Results In 102 patients (median age, 53 years [range, 22-83], 67% women), median daily MME was 60 mg (3-840), and median opioid therapy duration was 60 months (3-360). Abnormal case detection testing was found in 11 (10.8%) patients, and diagnosis of OIAI was made in 9 (9%). Patients with OIAI were on a higher daily MME (median, 140 [20-392] mg vs 57 [3-840] mg, P = 0.1), and demonstrated a 4 times higher cumulative opioid exposure (median of 13,440 vs 3120 mg*months, P = 0.03). No patient taking  20 mg); however, specificity of MME cutoff >20 mg was only 19%. After opioid discontinuation, 6/7 patients recovered adrenal function. Conclusion The prevalence of OIAI was 9%, with MME cumulative exposure being the only predictor for OIAI development. Patients on MME of 20 mg/day and above should be monitored for OIAI.