Systemic Glucocorticoid Exposure Research Articles

Systemic glucocorticoid exposure and postoperative infection risk in 143,782 appendectomy patients—a Danish longitudinal nationwide study

BackgroundGlucocorticoids are conventionally associated with increased postoperative infection risk. It is necessary to clarify if preoperative glucocorticoid exposure is associated with postoperative infection in appendectomy patients and if the association is different for open and laparoscopic appendectomies.MethodsA Danish nationwide study of appendectomy patients between 1996 and 2018. Exposures were defined as high (≥ 5 mg) versus no/low (< 5 mg) glucocorticoid exposure in milligram prednisone-equivalents/day preoperatively. The main outcome was any postoperative infection. Then, 90-day cumulative incidences (absolute risk) and adjusted hazard ratios (relative risk) of the outcome were calculated for high versus no/low glucocorticoid exposure within all appendectomies and within open and laparoscopic subgroups. Propensity-score matching was used for sensitivity analysis.ResultsOf 143,782 patients, median age was 29 years, 74,543 were female, and 7654 experienced at least one infection during the 90-day follow-up. The 90-day cumulative incidence for postoperative infection was 5.3% within the no/low glucocorticoid exposure group and 10.0% within the high glucocorticoid exposure group. Compared to no/low glucocorticoid exposure, adjusted hazard ratios for 90-day postoperative infection with high glucocorticoid exposure were 1.25 [95% CI 1.02–1.52; p = 0.03] for all appendectomies, 1.59 [1.16–2.18; p = 0.004] for laparoscopic appendectomies, and 1.09 [0.85–1.40; p = 0.52] for open appendectomies (pinteraction < 0.001). The results were robust to sensitivity analyses.ConclusionPreoperative high (≥ 5 mg/day) glucocorticoid exposure was associated with increased absolute risk of postoperative infections in open and laparoscopic appendectomies. The relative risk increase was significant for laparoscopic but not open appendectomies, possibly due to lower absolute risk with no/low glucocorticoid exposure in the laparoscopic subgroup.

Trends in Systemic Glucocorticoid Utilization in the United Kingdom from 1990 to 2019: A Population-Based, Serial Cross-Sectional Analysis.

Associations between systemic glucocorticoid (SGC) exposure and risk for adverse outcomes have spurred a move toward steroid-sparing treatment strategies. Real-world changes in SGC exposure over time, after the introduction of steroid-sparing treatment strategies, reveal areas of successful risk mitigation as well as unmet needs. A population-based ecological study was performed from the Optimum Patient Care Research Database to describe SGC prescribing trends of steroid-sparing treatment strategies in primary care practices before and after licensure of biologics in the United Kingdom from 1990 to 2019. Each analysis year included patients aged ≥5 years who were registered for ≥1 year with a participating primary care practice. The primary analysis was SGC exposure, defined as total cumulative SGC dose per patient per year, for asthma, severe asthma, chronic obstructive pulmonary disease (COPD), nasal polyps, Crohn's disease, rheumatoid arthritis, ulcerative colitis, and systemic lupus erythematosus. Secondary outcomes were percentages of patients prescribed SGCs and number of SGC prescriptions per patient per year. The number of patients who met study inclusion criteria ranged from 219,862 (1990) to 1,261,550 (2019). At the population level, patients with asthma or COPD accounted for 67.7% to 73.2% of patients per year with an SGC prescription. Over three decades, decreases in SGC total yearly dose ≥1000 mg have been achieved in multiple conditions. Patients with COPD prescribed SGCs increased from 5.8% (1990) to 34.8% (2017). SGC prescribing trends for severe asthma, Crohn's disease, and ulcerative colitis show decreased prescribing trends after the introduction of biologics. Decreases in total yearly SGC doses have been shown in multiple conditions; however, for conditions such as severe asthma and COPD, an unmet need remains for increased awareness of SGC burden and the adoption or development of SGC-sparing alternatives to reduce overuse.

Invasive pulmonary aspergillosis real-world outcomes: Clinical features and risk factors associated with increased mortality.

Invasive pulmonary aspergillosis (IPA) is a severe fungal infection that primarily affects immunocompromised patients and is associated with high mortality. Contemporary clinical characteristics of IPA and "real-world" estimates and predictors of associated mortality are inadequate. TriNetX, a global research network, was queried to identify adult patients with IPA diagnoses based on the ICD-10 code B44.0. We performed a propensity score-matched analysis comparing clinical characteristics among patients who survived versus non-survivors at 1 year. We identified 4371 patients with IPA. We found neoplasms, solid organ transplant recipients, hematologic malignancies, and aplastic anemia as the most predominant risk factors. The overall 1-year mortality was 32% for IPA. 1-year mortality was highest for patients with COVID-19 in the ICU, followed by those with acute myeloid leukemia and aplastic anemia (54%, 50%, and 39%, respectively). After propensity score matching, severe sepsis, pleural effusion, and candidiasis were mortality contributors within a year after diagnosis. Liver injury, systemic glucocorticoid exposure over the previous 6 months, lower lymphocyte and CD4 counts, elevated ferritin, LDH, thrombocytopenia, anemia, or elevated glycosylated hemoglobin (HbA1c) were independent predictors of mortality at 1 year. Voriconazole was the most common treatment (67%). The annual incidence of IPA was 0.001%, increasing to 0.02% among critically ill patients in the ICU. IPA continues to have a very high mortality. We encourage prospective studies to validate and refine the identified clinical markers linked to increased mortality.

Systemic Prenatal Stress Exposure through Corticosterone Application Adversely Affects Avian Embryonic Skin Development.

Prenatal stress exposure is considered a risk factor for developmental deficits and postnatal behavioral disorders. While the effect of glucocorticoid-associated prenatal stress exposure has been comprehensively studied in many organ systems, there is a lack of in-depth embryological investigations regarding the effects of stress on the integumentary system. To approach this, we employed the avian embryo as a model organism and investigated the effects of systemic pathologically-elevated glucocorticoid exposure on the development of the integumentary system. After standardized corticosterone injections on embryonic day 6, we compared the stress-exposed embryos with a control cohort, using histological and immunohistochemical analyses as well as in situ hybridization. The overarching developmental deficits observed in the stress-exposed embryos were reflected through downregulation of both vimentin as well as fibronectin. In addition, a deficient composition in the different skin layers became apparent, which could be linked to a reduced expression of Dermo-1 along with significantly reduced proliferation rates. An impairment of skin appendage formation could be demonstrated by diminished expression of Sonic hedgehog. These results contribute to a more profound understanding of prenatal stress causing severe deficits in the integumentary system of developing organisms.

In utero exposure to glucocorticoids and risk of anxiety and depression in childhood or adolescence

Glucocorticoid use is prevalent in pregnant women, but whether in utero exposure impacts mental health in the offspring has not been fully explored. The aim of this study was to investigate if in utero exposure to synthetic glucocorticoids increases the risk of anxiety and depression in childhood or adolescence. The study was conducted as a nationwide cohort study, including negative control exposure analyses and a sibling design to optimize control of confounding. The study population comprised 1,275,909 children born in 1996–2015 in Denmark (median follow-up of 13 years). Exposure was divided into systemic and local glucocorticoid exposure, levels of cumulative dose, generic type and according to trimester of exposure. The comparison cohort was children without exposure born to maternal never-users. Negative control exposures included children without glucocorticoid exposure born to: maternal users of non-steroidal anti-inflammatory drugs or immunotherapy during pregnancy, maternal former users of systemic glucocorticoids, maternal users of systemic glucocorticoids in the postnatal period, and fathers who were prescribed glucocorticoids. The sibling design compared siblings with and without exposure. 9307 (0.7%) children were exposed to systemic glucocorticoids and 116,389 (9.1%) children were exposed to local glucocorticoids. High-dose systemic glucocorticoids (≥500 mg prednisolone equivalents) increased the risk of anxiety compared to the comparison cohort [aIRR 1.79 (95% CI: 1.36–2.37), cumulative risk 16% vs. 7.8% by age 20]. A similar result was found for depression [aIRR 1.45 (95% CI: 0.80–2.63), cumulative risk 3.6% vs. 2.6% by age 20]. The association with anxiety was consistent in the sibling design [aIRR 1.83 (95% CI: 1.03–3.66), exposed siblings (≥ 500 mg) vs. unexposed]. Sex did not modify the associations. Negative control exposure analyses indicated robustness towards confounding from genetics and family environment. No association was found with low doses of systemic exposure or local use. In conclusion, potential adverse mental health effects of in utero exposure to high-dose glucocorticoids merit clinical attention.

Impact of glucocorticoids on the incidence of lupus-related major organ damage: a systematic literature review and meta-regression analysis of longitudinal observational studies

ObjectiveIn systemic lupus erythematosus (SLE), disease activity and glucocorticoid (GC) exposure are known to contribute to irreversible organ damage. We aimed to examine the association between GC exposure and organ...

Low prevalence of bone mineral density testing in patients with systemic lupus erythematosus and glucocorticoid exposure.

SummaryPatients with systemic lupus erythematosus (SLE) have an increased risk of developing osteoporosis and fractures due to systemic inflammation and glucocorticoids (GCs). Professional organizations recommend bone mineral density (BMD) testing in SLE patients on GCs, especially within 6 months of initiation. Using a validated algorithm, we identified SLE patients in an electronic health record cohort with long-term GC exposure (≥90 days). Our primary outcome was ever BMD testing. We assessed the impact of patient and provider factors on testing. We identified 693 SLE cases with long-term GC exposure, 41% of whom had BMD testing performed. Only 18% of patients had BMD testing within 6 months of GC initiation. In a logistic regression model for BMD testing, male sex (OR = 0.49, 95% CI 0.27 - 0.87, p = 0.01) was associated with being less likely to have BMD testing after adjusting for race and ethnicity. In contrast, older age (OR = 1.04, p < 0.001) and nephritis (OR = 1.83, p = 0.003) were associated with being more likely to have BMD testing after adjusting for race and ethnicity. Bone health in SLE patients remains an area in need of improvement with attention to patients who are younger and male.

Clinical investigation on the related factors for the application of systemic glucocorticoids in patients with acute exacerbation of chronic obstructive pulmonary disease with carbon dioxide retention

To investigate the factors affecting the application of systemic glucocorticoids in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with carbon dioxide (CO2) retention, and to guide the formulation of a strategy to reduce systemic glucocorticoid exposure. The AECOPD patients with CO2 retention admitted to the Ningde Municipal Hospital of Fujian Medical University from January 2017 to December 2019 were enrolled. The general information, past history, times of acute exacerbations within 1 year, pneumonia on admission, causes of COPD, heart failure, blood gas analysis, eosinophil count (EOS), albumin (Alb) and apolipoprotein E (ApoE) levels, exhaled nitric oxide (FeNO) level, inhaled glucocorticoid and non-invasive mechanical ventilation treatment at acute exacerbation were collected. The patients were divided into recommended dosage group (exposure levels in the recommended dosage range, cumulative prednisone dosage ≤ 200 mg) and exceeded group (exposure levels exceeded the recommended dose, cumulative prednisone dosage > 200 mg) according to cumulative systemic glucocorticoid exposure dosage of the patients during hospitalization. The clinical data of patients between the two groups were compared, and possible factors with P < 0.1 in univariate analysis were included in multivariate Logistic regression analysis to screen the related factors of systemic glucocorticoid exposure level in AECOPD patients with CO2 retention. According to the order of hospitalization, 151 AECOPD patients with CO2 retention were enrolled, 8 patients were excluded, and 143 patients were enrolled in the analysis. Of the 143 patients, 68 received the recommended dose of systemic glucocorticoid, and 75 received excessive systemic glucocorticoid. Age, percentage of forced expiratory volume in 1 second (FEV1%) at stable phase, frequency of acute exacerbation within 1 year, heart failure ratio, oxygen index (PaO2/FiO2), arterial partial pressure of carbon dioxide (PaCO2), serum EOS and ApoE levels at admission, the ratio of aerosolized inhaled glucocorticoids and non-invasive mechanical ventilation showed statistical differences between the two groups. Multivariate Logistic regression analysis showed that related factors affecting systemic glucocorticoid exposure levels of AECOPD patients with CO2 retention were FEV1% at stable phase [odds ratio (OR) = 0.957, 95% confidence interval (95%CI) was 0.921-0.994, P = 0.023], acute exacerbation frequency within 1 year (OR = 1.530, 95%CI was 1.121-2.088, P = 0.007), heart failure (OR = 3.022, 95%CI was 1.263-7.231, P = 0.013), PaCO2 (OR = 1.062, 95%CI was 1.010-1.115, P = 0.018) and EOS at admission (OR = 0.103, 95%CI was 0.016-0.684, P = 0.019), aerosolized inhaled glucocorticoids (OR = 0.337, 95%CI was 0.145-0.783, P = 0.011) and non-invasive mechanical ventilation at acute exacerbation (OR = 0.422, 95%CI was 0.188-0.948, P = 0.037), of which high FEV1% at stable phase, high EOS at admission, aerosolized inhaled glucocorticoid and non-invasive mechanical ventilation at acute exacerbation were protective factors, while high frequency of acute exacerbation within 1 year, heart failure and high PaCO2 were risk factors. For AECOPD patients with CO2 retention, high FEV1% at stable phase, high EOS level at admission, aerosolized inhaled glucocorticoid and non-invasive mechanical ventilation at acute exacerbation can reduce systemic glucocorticoid exposure. In addition, high frequency of acute exacerbation within 1 year, heart failure, and high PaCO2 can increase systemic glucocorticoid exposure.

Risk of fracture according to glucocorticoid use after renal biopsy: a nationwide population-based study

Few data are available regarding fracture risk in patients treated with glucocorticoids, including patients with kidney disease. A population-based retrospective cohort study was performed using Health Insurance Review and Assessment Service database, a South Korean nationwide cohort set. This study identified 44,702 patients with diagnosis code of kidney diseases who received a renal biopsy between January 1, 2012 and December 31, 2017. A total of 8,624 patients met all study inclusion criteria. A total of 1,406 fractures of any site were observed in the study period. The glucocorticoid-exposed group had more fractures than the unexposed (14.4% vs 8.8%, P < 0.0001). Vertebral fractures were the most common, followed by upper limb, and lower limb fractures. The exposed group showed a remarkably higher hazard ratio of fracture risk (HR 6.0, 95% CI 5.01–7.23) than the unexposed group, indicating systemic glucocorticoid exposure was highly associated with fracture risk. Although HR increased at doses even less than 5 mg/day, it was independent of dose. Older age showed a significant effect on fracture risk (HR 1.2, 95% CI 1.05–1.44), even after adjusting for systemic glucocorticoid exposure. Glucocorticoids was associated with higher risk of fracture even at a low daily dose and short term exposure.

SUN-739 Next Generation AR Antagonists Increase Systemic Active Glucocorticoid Exposure by Altering Glucocorticoid Metabolism

Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Despite the increased survival benefits of these agents, resistance normally occurs and the disease transitions to its lethal form. We hypothesized that enzalutamide and apalutamide suppress 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations and increased ratio of active to inactive glucocorticoids. We measured cortisol and cortisol/cortisone ratio (substrate/product of 11β-HSD2) in serum using mass spectrometry before and 1 month on-treatment in 3 clinical trials: 1) neoadjuvant apalutamide + leuprolide (n=25) 2) enzalutamide +/- PROSTVAC for metastatic castration-resistant prostate cancer (n=54) and 3) enzalutamide +/- PROSTVAC for non-metastatic castration-sensitive prostate cancer (n=38 patients). Progression-free survival (PFS) was determined in the metastatic CRPC study of enzalutamide +/- PROSTVAC for those with glucocorticoid changes above and below the median. A statistically significant rise in cortisol concentration and cortisol/cortisone ratio with AR antagonist treatment occurred uniformly across all 3 clinical trials. For example, a rise in cortisol/cortisone ratio occurred in 23/25 (92%) patients (p < 0.001), 36/54 (67%) patients (p < 0.001), and 30/38 (79%) patients (p = 0.051), in the 3 respective trials. In the trial of enzalutamide +/- PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved PSA progression-free survival and radiographic progression-free survival. However, in the enzalutamide + PROSTVAC arm, the opposite trend was observed. In conclusion, treatment with enzalutamide or apalutamide increases systemic exposure to active glucocorticoids. These findings have potential consequences for immune suppression and the efficacy of treatment combinations using next-generation AR antagonists. On-treatment, glucocorticoid changes might serve as a pharmacodynamic biomarker.

Deep androgen receptor suppression in prostate cancer exploits sexually dimorphic renal expression for systemic glucocorticoid exposure

Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Metabolic, hormonal and immunologic effects of deep AR suppression are unknown. We hypothesized that enzalutamide and apalutamide suppress 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations, increased ratio of active to inactive glucocorticoids and possibly suboptimal response to immunotherapy. On-treatment glucocorticoid changes might serve as an indicator of active glucocorticoid exposure and resultant adverse consequences. Human kidney tissues were stained for AR and 11β-HSD2 expression. Patients in three trials [neoadjuvant apalutamide plus leuprolide, enzalutamide ± PROSTVAC (recombinant poxvirus prostate-specific antigen vaccine) for metastatic castration-resistant prostate cancer (CRPC) and enzalutamide ± PROSTVAC for non-metastatic castration-sensitive prostate cancer] were analyzed for cortisol and its metabolites using liquid chromatography-mass spectrometry (LC-MS/MS). Progression-free survival was determined in the metastatic CRPC study of enzalutamide ± PROSTVAC for those with glucocorticoid changes above and below the median. Concurrent AR and 11β-HSD2 expression occurs only in the kidneys of men. A statistically significant rise in cortisol concentration, cortisol/cortisone ratio and tetrahydrocortisol/tetrahydrocortisone ratio with AR antagonist treatment occurred uniformly across all three trials. In the trial of enzalutamide ± PROSTVAC for metastatic CRPC, high cortisol/cortisone ratio in the enzalutamide arm was associated with significantly improved progression-free survival. However, in the enzalutamide+ PROSTVAC arm, the opposite trend was observed. Enzalutamide and apalutamide treatment toggles renal 11β-HSD2 and significantly increases indicators of and exposure to biologically active glucocorticoids, which is associated with clinical outcomes.

Glucocorticoid Exposure and Fracture Risk in a Cohort of US Patients With Selected Conditions.

The purpose of this work was to evaluate systemic glucocorticoid exposure and fracture among patients with newly-diagnosed inflammatory and immune-modulated conditions. Using administrative data, inception cohorts of rheumatoid arthritis (RA), asthma/chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), multiple sclerosis (MS), lupus, and sarcoidosis patients age 18 to 64 years with benefits coverage ≥12 months before diagnosis (January 1, 2005 to December 31, 2012) were followed to clinical fracture, cancer diagnosis, or December 31, 2012. Glucocorticoid users were new to therapy. Fracture incidence rates (IRs) per 1000 person-years were stratified by prednisone equivalent doses. Cox's proportional hazards models assessed risk by daily and cumulative dose, and by time since discontinuation, adjusted for baseline characteristics. Most patients (72% of 403,337) had glucocorticoid exposure; 52% were under age 50. IR (95% confidence interval [CI]) of any osteoporotic fracture was elevated at doses <5 mg/day (IR 9.33; 95% CI, 7.29 to 11.77) versus 0 mg/day (IR 4.87 (95% CI, 4.72 to 5.02). Fracture rates were elevated at doses <5 mg/day in patients <50 years and those ≥50 years. In both age groups, fracture risk increased with increasing cumulative exposure, being approximately 2.5-fold higher at cumulative dose ≥5400 mg compared to <675 mg. At ≥5400 mg, IR values were 5.69 (95% CI, 4.32 to 7.35) in patients <50 years and 17.10 (95% CI, 14.97 to 19.46) in older patients. Fracture risk decreased significantly within months following glucocorticoid discontinuation. In patients with a variety of inflammatory conditions, fracture risk increased at doses as low as <5 mg/day. Risk increased with increasing cumulative exposure and decreased soon following glucocorticoid discontinuation. Trends were similar between patients older and younger than 50 years. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Intravenous immunoglobulin is an effective treatment for refractory cutaneous dermatomyositis.

Cutaneous dermatomyositis (DM) is often refractory to multiple systemic medications, suggesting a need for effective alternative treatments. To investigate the effects of intravenous immunoglobulin (IVIG) on patients with refractory cutaneous DM. This was a retrospective review of 42 patients treated with IVIG for refractory cutaneous DM at our institution with clinical data available at DM diagnosis. IVIG was initiated for refractory cutaneous DM alone (n = 15) or refractory cutaneous and muscle/lung disease (n = 27) in patients with various DM subtypes. Overall, 83% of patients had cutaneous DM improvement, including 87% treated for refractory skin disease alone and 81% treated for refractory skin/muscle/lung disease. Cutaneous DM improvement occurred regardless of DM subtype, and was observed after a mean of 1.82 ± 1.38 IVIG cycles. No statistically significant clinical predictors of IVIG response or lack of response were detected. IVIG use resulted in decreased systemic glucocorticoid exposure with or without a decrease in steroid-sparing immunosuppressive medications in 80% of patients. This study is limited by its retrospective nature and lack of objective cutaneous DM activity assessment. Use of IVIG resulted in improvement of refractory cutaneous DM in the vast majority of patients relatively soon after initiation and regardless of DM subtype or clinical manifestations. Additionally, IVIG allowed decrease or discontinuation of immunosuppressive medications in 80% of patients. These findings suggest that IVIG can be a clinically efficacious and cost-effective treatment for refractory cutaneous DM and warrants prospective study.

Glucocorticoid exposure and fracture risk in patients with new-onset rheumatoid arthritis.

We evaluated the impact of systemic glucocorticoid exposure on fracture risk among relatively young patients with new-onset rheumatoid arthritis (RA). Using administrative data, we identified 42,127 RA patients diagnosed January 1, 2005-December 31, 2012, age 18-64years, with benefits coverage for ≥12months before RA diagnosis. Follow-up extended to clinical fracture, cancer diagnosis, or December 31, 2012. Glucocorticoid users were new to therapy. Fracture incidence rates (IR) were stratified by glucocorticoid exposure expressed as prednisone equivalent doses. Cox's proportional hazards models estimated fracture risk adjusted for demographics and baseline clinical characteristics to assess dose-response relationships with current (daily) and prior (cumulative) dose, and by time since discontinuation. Most patients (85%) had glucocorticoid exposure. Exposed and unexposed patients were demographically similar (74% female; mean age 49.7 and 48.8years); 1% had prior fracture. Fracture IRs (95% confidence intervals) were 5 to 9 per 1000 person-years at doses <15mg/day, 16.0 (11.0, 22.6) at doses ≥15mg/day, and 13.4 (10.7, 16.7) at cumulative doses ≥5400mg. Adjusted fracture risk was approximately 2-fold higher at highest dose levels compared with 0mg/day current daily dose and <675mg cumulative dose, respectively. Fracture risk was 29% lower at 60-182days post-discontinuation compared with ongoing use and was similar to unexposed patients by 12months. Findings were similar among patients age <50years. Among younger, new-onset RA patients, fracture risk was significantly elevated at high levels of daily and cumulative dose, and was similar to unexposed patients by 12months post-discontinuation.

Time trends for alendronate prescription practices in women with chronic obstructive pulmonary disease and women exposed to systemic glucocorticoids

Chronic obstructive pulmonary disease (COPD) and systemic glucocorticoid exposure are well-known risk factors of osteoporosis. We evaluated alendronate prescription practices related to COPD and exposure to systemic corticosteroids from 1996 to 2008 and showed an increasing targeting of alendronate treatment in patients with COPD and patients with systemic corticosteroid exposure. COPD and systemic glucocorticoid exposure are well-known risk factors of osteoporosis and fragility fracture, but osteoporosis is often underdiagnosed and undertreated in these patients. This study aims to evaluate alendronate prescription practices related to COPD and/or to exposure to systemic glucocorticoids among Danish women. A total of 388,314 female subjects >50years old, 64,719 of whom initiated treatment with alendronate, and 323,595 age- and gender-matched controls were retrospectively identified between 1996 and 2008 from national health registers. Multivariate logistic regression was used for examining prescription practices, specifically if these risk factors (COPD or glucocorticoid exposure) increased or decreased the likelihood of beginning alendronate therapy. A diagnosis of COPD was associated with an increased likelihood of using alendronate (odds ratio (OR) 1.4, 95% confidence interval (CI) 1.4-1.5, p < 0.001). Further, a diagnosis of COPD was associated with an increasing tendency of initiating alendronate treatment in the study period (OR 1.3 (95% CI 1.1-1.5, years 1996-1999) to 1.5 (95% CI 1.4-1.6, years 2006-2008), p < 0.01). Exposure to systemic glucocorticoids was associated with a significantly increasing (OR 3.6, 95% CI 3.3-3.9 to OR 5.5, 95% CI 5.3-5.8) probability of receiving alendronate treatment in the same observation period. This nationwide register-based study on alendronate prescription practices in Denmark shows an increasing targeting of alendronate treatment in patients with COPD and an even stronger trend for patients with systemic glucocorticoid exposure, perhaps indicating increased awareness of well-known and associated conditions.

A cell-autonomous role for the glucocorticoid receptor in skeletal muscle atrophy induced by systemic glucocorticoid exposure

Glucocorticoids (GCs) are important regulators of skeletal muscle mass, and prolonged exposure will induce significant muscle atrophy. To better understand the mechanism of skeletal muscle atrophy induced by elevated GC levels, we examined three different models: exogenous synthetic GC treatment [dexamethasone (DEX)], nutritional deprivation, and denervation. Specifically, we tested the direct contribution of the glucocorticoid receptor (GR) in skeletal muscle atrophy by creating a muscle-specific GR-knockout mouse line (MGR(e3)KO) using Cre-lox technology. In MGR(e3)KO mice, we found that the GR is essential for muscle atrophy in response to high-dose DEX treatment. In addition, DEX regulation of multiple genes, including two important atrophy markers, MuRF1 and MAFbx, is eliminated completely in the MGR(e3)KO mice. In a condition where endogenous GCs are elevated, such as nutritional deprivation, induction of MuRF1 and MAFbx was inhibited, but not completely blocked, in MGR(e3)KO mice. In response to sciatic nerve lesion and hindlimb muscle denervation, muscle atrophy and upregulation of MuRF1 and MAFbx occurred to the same extent in both wild-type and MGR(e3)KO mice, indicating that a functional GR is not required to induce atrophy under these conditions. Therefore, we demonstrate conclusively that the GR is an important mediator of skeletal muscle atrophy and associated gene expression in response to exogenous synthetic GCs in vivo and that the MGR(e3)KO mouse is a useful model for studying the role of the GR and its target genes in multiple skeletal muscle atrophy models.

Disrupted Pancreatic Exocrine Differentiation and Malabsorption in Response to Chronic Elevated Systemic Glucocorticoid

Glucocorticoids are antiinflammatory therapeutics that have potent effects on cell differentiation. The aim of this study was to establish whether systemic glucocorticoid exposure significantly affects pancreatic differentiation in vivo because hepatocyte-like cells have been documented to occur in the diseased rodent pancreas. Expression of hepatic markers was examined in pancreata from mice genetically modified to secrete elevated circulating endogenous glucocorticoid [Tg(Crh)]. Tg(Crh) mice with elevated glucocorticoid appeared cushingoid and by 21 weeks of age were obese, insulin-resistant, and had extensive areas of hepatic gene expression in exocrine tissue. Acinar cells from Tg(Crh) mice costained for both amylase and cyp2e1, suggesting direct acinar-hepatic transdifferentiation. Hepatic expression increased with age in the pancreas to such an extent that malabsorption and rapid weight loss occurred in a subset of aging mice; this effect was reversed by dietary porcine pancreatic enzyme supplementation. Indeed, pancreatic expression of hepatic markers was prevented by adrenalectomy, establishing a direct role for glucocorticoid. Elevated levels of circulating glucocorticoid therefore promote a transdifferentiation of adult exocrine pancreas into hepatocyte-like cells, and chronic exposure results in pancreatic malfunction. Glucocorticoids are thus capable of modulating the differentiation of terminally differentiated adult cells.

Hepatology highlights

Hepatology highlights