High-dose Glucocorticoid Treatment Research Articles

Combined application of mesenchymal stem cells and different glucocorticoid dosing alleviates osteoporosis in SLE murine models.

Bone mesenchymal stem cells (BMSCs) have been tentatively applied in the treatment of glucocorticoid-induced osteoporosis (GIOP) and systemic lupus erythematosus (SLE). However, the effects of BMSCs on osteoporosis within the context of glucocorticoid (GC) application in SLE remain unclear. Our aim was to explore the roles of BMSCs and different doses of GC interventions on osteoporosis in SLE murine models. MRL/MpJ-Faslpr mice were divided into eight groups with BMSC treatment and different dose of GC intervention. Three-dimensional imaging analysis and hematoxylin and eosin (H&E) staining were performed to observe morphological changes. The concentrations of osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) in serum were measured by enzyme-linked immunosorbent assay (ELISA). The subpopulation of B cells and T cells in bone marrows and spleens were analyzed by flow cytometry. Serum cytokines and chemokines were assessed using Luminex magnetic bead technology. BMSCs ameliorated osteoporosis in murine SLE models by enhancing bone mass, improving bone structure, and promoting bone formation through increased bone mineral content and optimization of trabecular morphology. BMSC and GC treatments reduced the number of B cells in bone marrows, but the effect was not significant in spleens. BMSCs significantly promoted the expression of IL-10 while reducing IL-18. Moreover, BMSCs exert immunomodulatory effects by reducing Th17 expression and rectifying the Th17/Treg imbalance. BMSCs effectively alleviate osteoporosis induced by SLE itself, as well as osteoporosis resulting from SLE combined with various doses of GC therapy. The therapeutic effects of BMSCs appear to be mediated by their influence on bone marrow B cells, T cell subsets, and associated cytokines. High-dose GC treatment exerts a potent anti-inflammatory effect but may hinder the immunotherapeutic potential of BMSCs. Our research may offer valuable guidance to clinicians regarding the use of BMSC treatment in SLE and provide insights into the judicious use of GCs in clinical practice.

Modulation of cytokine response in post-cardiac arrest syndrome through prehospital high-dose glucocorticoid treatment

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation Research Foundation of Rigshospitalet. Background Post-cardiac arrest syndrome (PCAS) following out-of-hospital cardiac arrest (OHCA) is a life-threatening condition, characterized by a cascade of pathological events, including the development of a severe cytokine response. This inflammatory response may be associated with secondary brain injury and multi-organ dysfunction. In the randomized STEROHCA trial, high-dose glucocorticoid was administered immediately following resuscitation in the prehospital setting. The intervention exhibited a significant decrease in interleukin (IL) 6 levels, but its effect on other cytokines has yet to be assessed. Purpose We aimed to investigate the effects of high-dose glucocorticoid treatment in mitigating the cytokine response observed in PCAS after OHCA. Methods The modified intention-to-treat population of the double-blind, randomized STEROHCA trial consisted of 137 OHCA patients, who were randomized to a single prehospital injection of methylprednisolone 250 mg or placebo. Of these, this sub-study included 112 patients who were comatose and admitted to an ICU. Cytokine profiling was performed with a 17-plex assay, including pro- and anti-inflammatory cytokines, which were measured at 0, 24, 48, and 72h after admission. We applied mixed-model analyses to assess the effect of the intervention over time with log-transformed data. To maintain an exploratory approach, we chose not to correct for multiple testing. Results The intervention induced a reduction in the levels of several cytokines, with a significant treatment over time effect for IL-4, IL-8, IL-10, Monocyte Chemoattractant Protein-1 (MCP-1), Macrophage Inflammatory Protein-1 Beta (MIP-1β), and Tumor Necrosis Factor Alpha (TNF-α), all p<0.01. These cytokines, except for IL-10, exhibited lower values in the glucocorticoid group after 24h, Figure 1. Higher levels of IL-10 were observed in the glucocorticoid group at 0h. We found no differences in cytokine levels after 48-, and 72h between the two groups. Conclusion High-dose glucocorticoid treatment administered promptly after resuscitation from OHCA reduced several pro-inflammatory cytokines after 24h. TNF-α has previously been associated with poor outcomes following OHCA, whereas the exact role of the other cytokines following OHCA is unclear.Cytokines at 0-, 24-, 48-, and 72 hours

Effect of prehospital high-dose glucocorticoid on hemodynamics in patients resuscitated from out-of-hospital cardiac arrest: a sub-study of the STEROHCA trial

BackgroundFollowing resuscitated out-of-hospital cardiac arrest (OHCA), inflammatory markers are significantly elevated and associated with hemodynamic instability and organ dysfunction. Vasopressor support is recommended to maintain a mean arterial pressure (MAP) above 65 mmHg. Glucocorticoids have anti-inflammatory effects and may lower the need for vasopressors. This study aimed to assess the hemodynamic effects of prehospital high-dose glucocorticoid treatment in resuscitated comatose OHCA patients.MethodsThe STEROHCA trial was a randomized, placebo-controlled, phase 2 trial comparing one prehospital injection of methylprednisolone 250 mg with placebo immediately after resuscitated OHCA. In this sub-study, we included patients who remained comatose at admission and survived until intensive care unit (ICU) admission. The primary outcome was cumulated norepinephrine use from ICU admission until 48 h reported as mcg/kg/min. Secondary outcomes included hemodynamic status characterized by MAP, heart rate, vasoactive-inotropic score (VIS), and the VIS/MAP-ratio as well as cardiac function assessed by pulmonary artery catheter measurements. Linear mixed-model analyses were performed to evaluate mean differences between treatment groups at all follow-up times.ResultsA total of 114 comatose OHCA patients were included (glucocorticoid: n = 56, placebo: n = 58) in the sub-study. There were no differences in outcomes at ICU admission. From the time of ICU admission up to 48 h post-admission, patients in the glucocorticoid group cumulated a lower norepinephrine use (mean difference − 0.04 mcg/kg/min, 95% CI − 0.07 to − 0.01, p = 0.02). Moreover, after 12–24 h post-admission, the glucocorticoid group demonstrated a higher MAP with mean differences ranging from 6 to 7 mmHg (95% CIs from 1 to 12), a lower VIS (mean differences from − 4.2 to − 3.8, 95% CIs from − 8.1 to 0.3), and a lower VIS/MAP ratio (mean differences from − 0.10 to − 0.07, 95% CIs from − 0.16 to − 0.01), while there were no major differences in heart rate (mean differences from − 4 to − 3, 95% CIs from − 11 to 3). These treatment differences between groups were also present 30–48 h post-admission but to a smaller extent and with increased statistical uncertainty. No differences were found in pulmonary artery catheter measurements between groups.ConclusionsPrehospital treatment with high-dose glucocorticoid was associated with reduced norepinephrine use in resuscitated OHCA patients.Trial registration: EudraCT number: 2020-000855-11; submitted March 30, 2020. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04624776.Graphic

Current Therapeutic Options in Active Moderate-to-Severe Thyroid-Associated Ophthalmopathy

Abstract Active moderate-to-severe TAO is a disease, the treatment of which requires a multidisciplinary team, an individualized approach and strict follow-up, yet it is often suboptimal. Recent knowledge about the pathogenesis of the disease and the randomized controlled trials conducted in recent years made it possible to use new therapeutic combinations and biological agents. The currently recommended first-line therapy for active moderate-to-severe TAO is the combination of intravenous glucocorticoids (GCs) in moderate doses and mycophenolate or, in more severe cases, a high-dose GC treatment alone. There are several options for second-choice therapy, if needed: a new course with GCs, combination of orbital radiotherapy and GCs (preferably intravenous), cyclosporine and oral GCs, azathioprine and oral GCs, rituximab, tocilizumab or teprotumumab. The clinical manifestations of TAO should also be considered when choosing second-line treatment. Thus, for example, teprotumumab best affects diplopia, orbital radiotherapy – visual disturbances and diplopia, while intravenous GCs, mycophenolate, cyclosporine, rituximab and tocilizumab – the inflammatory manifestations of TAO. However, the question of the availability of the new drugs in routine clinical practice remains unsolved.

Imaging for assessment of cancer treatment response to immune checkpoint inhibitors can be complementary in identifying hypophysitis.

Hypophysitis is reported in 8.5%-14% of patients receiving combination immune checkpoint inhibition (cICI) but can be a diagnostic challenge. This study aimed to assess the role of routine diagnostic imaging performed during therapeutic monitoring of combination anti-CTLA-4/anti-PD-1 treatment in the identification of hypophysitis and the relationship of imaging findings to clinical diagnostic criteria. This retrospective cohort study identified patients treated with cICI between January 2016 and January 2019 at a quaternary melanoma service. Medical records were reviewed to identify patients with a documented diagnosis of hypophysitis based on clinical criteria. Available structural brain imaging with magnetic resonance imaging (MRI) or computed tomography (CT) of the brain and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography with computed tomography (FDG-PET/CT) were assessed retrospectively. The main radiological outcome measures were a relative change in pituitary size or FDG uptake temporally attributed to cICI. There were 162 patients (median age 60 years, 30% female) included. A total of 100 and 134 had serial CT/MRI of the brain and FDG-PET/CT, respectively. There were 31 patients who had a documented diagnosis of hypophysitis and an additional 20 who had isolated pituitary imaging findings. The pituitary gland enlargement was mild, and the largest absolute gland size was 13 mm, with a relative increase of 7 mm from baseline. There were no cases of optic chiasm compression. Pituitary enlargement and increased FDG uptake were universally transient. High-dose glucocorticoid treatment for concurrent irAEs prevented assessment of the pituitary-adrenal axis in 90% of patients with isolated imaging findings. Careful review of changes in pituitary characteristics on imaging performed for assessment of therapeutic response to iICI may lead to increased identification and more prompt management of cICI-induced hypophysitis.

263 Pre-hospital high-dose glucocorticoid treatment for post-cardiac arrest syndrome following resuscitated out-of-hospital cardiac arrest (the sterohca trial)

263 Pre-hospital high-dose glucocorticoid treatment for post-cardiac arrest syndrome following resuscitated out-of-hospital cardiac arrest (the sterohca trial)

High-Dose Hydrocortisone Treatment Does Not Affect Serum C-Reactive Protein (CRP) Concentrations in Healthy Dogs.

Measuring C-reactive protein (CRP) in serum is a useful surrogate marker for assessing disease progression and treatment response in dogs with autoinflammatory diseases. Affected dogs often receive high-dose glucocorticoid treatment, but the effect of such treatment alone on serum CRP concentrations is unknown. We evaluated serum CRP concentrations via immunoassay (sandwich enzyme-linked immunosorbent assay and particle-enhanced turbidimetric immunoassay) in 12 healthy beagle dogs administered high-dose hydrocortisone (8 mg/kg q12 h) per os vs. placebo over 28 days (days 0, 1, 5, and 28) in a randomized parallel study design. Serum CRP concentrations slightly decreased during treatment or placebo but without a significant association with hydrocortisone administration (p = 0.761). Compared to baseline, serum CRP concentrations were decreased by >2.7-fold (minimum critical difference) in three hydrocortisone-treated dogs and two dogs in the placebo group on day 28, whereas an increase to >2.7-fold was seen in one dog receiving placebo. These results suggest a lack of confounding effects of high-dose hydrocortisone administration on serum CRP concentrations in healthy dogs. This might also hold in dogs with autoinflammatory conditions and/or administration of other high-dose corticosteroids, suggesting that CRP presents a suitable biomarker to monitor inflammatory disease processes. However, this needs confirmation by further studies evaluating corticosteroid-induced cellular (e.g., hepatic) transcriptome and proteome changes.

Effect of high-dose glucocorticoid treatment on human brown adipose tissue activity: a randomised, double-blinded, placebo-controlled cross-over trial in healthy men

Glucocorticoids (GCs) are widely applied anti-inflammatory drugs that are associated with adverse metabolic effects including insulin resistance and weight gain. Previous research indicates that GCs may negatively impact brown adipose tissue (BAT) activity in rodents and humans. We performed a randomised, double-blinded cross-over trial in 16 healthy men (clinicaltrials.govNCT03269747). Participants received 40mg of prednisone per day for one week or placebo. After a washout period of four weeks, participants crossed-over to the other treatment arm. Primary endpoint was the increase in resting energy expenditure (EE) in response to a mild-cold stimulus (cold-induced thermogenesis, CIT). Secondary outcomes comprised mean 18F-FDG uptake into supraclavicular BAT (SUVmean) as determined by FDG-PET/CT, volume of the BAT depot as well as fat content determined by MRI. The plasma metabolome and the transcriptome of supraclavicular BAT and of skeletal muscle biopsies after each treatment period were analysed. Sixteen participants were recruited to the trial and completed it successfully per protocol. After prednisone treatment resting EE was higher both during warm and cold conditions. However, CIT was similar, 153 kcal/24h (95% CI 40-266 kcal/24h) after placebo and 186 kcal/24h (95% CI 94-277 kcal/24h, p=0.38) after prednisone. SUVmean of BAT after cold exposure was not significantly affected by prednisone (3.36g/ml, 95% CI 2.69-4.02g/ml, vs 3.07g/ml, 95% CI 2.52-3.62g/ml, p=0.28). Results of plasma metabolomics and BAT transcriptomics corroborated these findings. RNA sequencing of muscle biopsies revealed higher expression of genes involved in calcium cycling. No serious adverse events were reported and adverse events were evenly distributed between the two treatments. Prednisone increased EE in healthy men possibly by altering skeletal muscle calcium cycling. Cold-induced BAT activity was not affected by GC treatment, which indicates that the unfavourable metabolic effects of GCs are independent from thermogenic adipocytes. Grants from Swiss National Science Foundation (PZ00P3_167823), Bangerter-Rhyner Foundation and from Nora van der Meeuwen-Häfliger Foundation to MJB. A fellowship-grant from the Swiss National Science Foundation (SNF211053) to WS. Grants from German Research Foundation (project number: 314061271-TRR 205) and Else Kröner-Fresenius (grant support 2012_A103 and 2015_A228) to MR.

Risk-benefit analysis of primary prophylaxis against Pneumocystis jirovecii pneumonia in patients with rheumatic diseases receiving rituximab.

To identify a specific population of patients with rheumatic diseases receiving rituximab treatment for whom the benefit from primary prophylaxis against Pneumocystis jirovecii pneumonia (PJP) outweighs the risk of adverse events (AEs) METHODS: This study included 818 patients treated with rituximab for rheumatic diseases. Of these, 419 received prophylactic trimethoprim-sulfamethoxazole (TMP-SMX) with rituximab while the remainder did not. Differences in 1-year PJP incidence between the groups were estimated using Cox regression. Risk-benefit assessment was performed in the subgroup stratified according to risk factors based on the number needed to treat (NNT) to prevent one case of PJP and the number needed to harm (NNH) due to severe AEs. Inverse probability of treatment weighting was applied to minimize the confounding by indication. During the 663.1 person-years, there were 11 PJP cases, with a mortality rate of 63.6%. Concomitant use of high-dose glucocorticoids (≥30mg/day of prednisone during 4 weeks after rituximab administration) was the most important risk factor. The PJP incidence (per 100 person-years) was 7.93 (2.91-17.25) in the subgroup receiving high-dose glucocorticoids, compared with 0.40 (0.01-2.25) in the subgroup without high-dose glucocorticoids. Although prophylactic TMP-SMX significantly reduced the overall PJP incidence (HR 0.11 [0.03-0.37]), the NNT to prevent one PJP was higher than the NNH (146 vs. 86). In contrast, the NNT fell to 20 (10.7-65.7) in patients receiving concomitant high-dose glucocorticoids. The benefit associated with primary PJP prophylaxis overweighs the risk of severe AEs in patients receiving rituximab and concomitant high-dose glucocorticoid treatment. This article is protected by copyright. All rights reserved.

Sarcopenia in patients with rheumatic musculoskeletal diseases.

To investigate the impact of high-dose glucocorticoid therapy on sarcopenia in hospitalized patients with rheumatic musculoskeletal diseases (RMDs). We included patients with RMDs who were hospitalized between 2020 and 2022 for remission induction treatment and collected information on skeletal mass index (SMI) before high-dose glucocorticoid therapy and 1 month later. We divided the patients into 2 groups according to the progression of sarcopenia, defined as a >10% decrease in SMI, and compared their clinical characteristics. Forty-nine patients were included in this analysis. The mean age was 53.3 years, 73.5% were female, and the mean SMI was 5.3 kg/m2 . Before treatment, 83.7% had already met the definition of sarcopenia, and 57.1% experienced further sarcopenia progression after 1 month of high-dose glucocorticoid treatment. Patients with sarcopenia progression were predominantly male (P = 0.025), had a higher body weight (P = 0.048), and showed a higher SMI than those without sarcopenia at baseline (P = 0.008). Multivariable analysis revealed that body weight increase from 0 to week 1 of high-dose glucocorticoid treatment was associated with sarcopenia progression (odds ratio: 0.22, 95% CI: 0.04-0.61, P = 0.007) with a cut-off of -1.8 kg. During a mean observation period of 30.2 days, the incidence of infection was significantly higher in patients with progressive sarcopenia (P = 0.042). One-month hospitalization with high-dose glucocorticoid therapy is associated with sarcopenia progression in patients with RMDs. An early decrease in body weight can be used to predict muscle volume loss.

Steroid-loaded reconstituted high-density lipoprotein nanocarrier: A new treatment for systemic lupus erythematosus.

Glucocorticoids (GCs) are the most effective and commonly used drugs for the treatment of systemic lupus erythematosus (SLE). However, a large number of side effects occur after long-term or high-dose glucocorticoid treatment, which severely restricts the use of glucocorticoids. Reconstituted high-density lipoprotein (rHDL), an emerging nanocarrier, is promising for targeted delivery to sites of inflammation and macrophages. Here, we prepared a steroid-loaded recombinant high-density lipoprotein and evaluated its therapeutic efficacy in a murine macrophage cell line (RAW264.7) and a lupus (MRL/lpr mice) mouse model. The obtained corticosteroid-loaded nanomedicine, named PLP-CaP-rHDL, exhibited desirable characteristics. Pharmacodynamics studies revealed that the nanoparticles could significantly reduce the levels of inflammatory cytokines in the macrophages in vitro and also effectively alleviate lupus nephritis in MRL/lpr mice without causing obvious side effects at a dose of 0.25mg/kg. Thus, our newly developed steroid-loaded rHDL nanocarriers hold a great potential for anti-inflammatory therapy with reduced side effects and may provide a precise targeted therapy for SLE.

Risk of Bloodstream Infection in Patients with Systemic Lupus Erythematosus Exposed to Prolonged Medium-to-High-Dose Glucocorticoids.

This study aimed to investigate the incidence rate and risk factors of bloodstream infection (BSI) in patients with systemic lupus erythematosus (SLE) exposed to medium to high doses of glucocorticoids. This study included 1109 treatment episodes with prolonged (≥4 weeks) medium-to-high-dose glucocorticoids (≥15mg/day prednisolone) in 612 patients with SLE for over 14 years. Clinical features regarding systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K), immunosuppressant use, and laboratory results were obtained from the electronic medical database. The primary outcome of this study was the 1-year incidence of BSI. The effect of clinical factors on the outcome was investigated using a generalized estimating equation. During a total of 1078.64 person-years, 30 cases of BSI occurred, with an incidence rate of 2.78 (95% confidence interval (CI) 1.88-3.97) per 100 person-years. Mortality rate of the treatment episodes with BSI was 16.7%, which was significantly higher than that in the other episodes (incidence rate ratio (IRR) 19.59, 95% CI 7.33-52.44). When the incidence rate of BSI was stratified by baseline glucocorticoid dose and SLEDAI-2K score, a higher incidence rate of BSI occurred as disease activity or baseline glucocorticoid dose increased. In the multivariable analysis, SLEDAI-2K ≥20 (adjusted IRR (aIRR) 4.66, 95% CI 2.17-10.00), initial baseline prednisolone ≥ 60mg/day (aIRR 2.42, 95% CI 1.11-5.32), and cumulative prednisolone dose ≥15mg/day during the previous 6 months (aIRR 2.13, 95% CI 1.03-4.40) significantly increased the risk of BSI. In patients with SLE exposed to prolonged medium-to-high-dose glucocorticoids, the 1-year incidence rate of BSI was significantly higher than previously reported in the general patients with SLE. Severe disease activity, and high-dose glucocorticoid treatment previously or at baseline increased the risk of BSI.

Perioperative Low-Dose Prednisolone Treatment Has Beneficial Effects on Postoperative Recovery and Anastomotic Healing in a Murine Colitis Model.

High-dose glucocorticoid treatment has been identified as a risk factor for anastomotic leakage in patients with inflammatory bowel disease [IBD] undergoing bowel resection surgery. By contrast, active disease during surgery is also associated with elevated morbidity. Perioperative low-dose treatment might be beneficial regarding postoperative outcomes by controlling disease activity. The present study is the first to investigate the dose-dependent effect of perioperative prednisolone therapy in a murine IBD model combining dextran sodium sulphate [DSS] colitis with intestinal anastomosis surgery. In 84 10-week-old wild-type mice, a colorectal anastomosis was performed using a microsurgical technique. Half the animals received induction of chemical colitis with 2% DSS via drinking water prior to surgery. In both groups, one-third of the animals received daily oral administration of high-dose [0.533 mg/kg] and one-third low-dose [0.133 mg/kg] prednisolone. Evaluation was performed on postoperative days 3 and 7. While high-dose prednisolone treatment led to an increased anastomotic leakage rate in mice under colitis, low-dose prednisolone treatment limited preoperative disease activity and did not influence the leakage rate. Histological examination showed a beneficial effect of low-dose prednisolone treatment on microscopic abscess formation at the anastomotic site in DSS mice as well as an increased anastomotic healing score. We demonstrate a beneficial effect of perioperative short-term low-dose prednisolone treatment on intestinal anastomotic healing in the context of colitis. Perioperative use of short-term low-dose prednisolone treatment might be beneficial in IBD patients who need to undergo surgery during active disease.

Continuous Glucose Monitoring of Steroid-Induced Hyperglycemia in Patients With Dermatologic Diseases.

Systemic administration of glucocorticoids is a mainstay therapy for various inflammatory diseases and may lead to hyperglycemia, which carries the risk of worsening preexisting diabetes and triggering steroid-induced diabetes. Therefore, we aimed to identify patients at risk and to quantify severity of steroid-induced hyperglycemia (SIH) by continuous glucose monitoring (CGM) in hospitalized patients needing systemic glucocorticoid treatment. This prospective study included 51 steroid-naive, dermatological patients requiring systemic high-dose glucocorticoid treatment at the Department of Dermatology of the University Hospital Essen. After careful diabetes-specific assessment at admission, glucose monitoring was performed using a CGM system and glucose profile was analyzed in patients with and without SIH. SIH occurred in 47.1% of all treated patients, and a relevant part of patients with initial normoglycemia developed SIH (2/10 patients). Doubling of SIH incidence was observed with each severity grade of dysglycemia (4/10 in prediabetes; 9/10 in diabetes). Patients with SIH spend nearly 6 hours daily above targeted glucose range, and severe hyperglycemia was observed for 1.2 hours/day. Our study underlines the need for dedicated glucose monitoring in dermatologic patients on systemic glucocorticoid therapy by demonstrating its impact on glucose metabolism.

64 HIGH-DOSE STEROIDS IN HAEMATOLOGICAL MALIGNANCY: A RED FLAG FOR BONE HEALTH

Abstract Background Bone-protective treatment should always be considered when commencing glucocorticoid therapy in individuals at high risk of fracture, as outlined in recent guidelines (National Osteoporosis Guideline Group, July 2018). Despite this, many patients receive high dose glucocorticoids (>7.5mg/kg/day or equivalent for >3 months) during treatment of haematological malignancy without formal assessment of bone health. Methods Twenty-five patients with Non-Hodgkin’s Lymphoma (NHL) on high dose steroid chemotherapy protocols were retrospectively assessed. The inclusion criterion was defined as any patient commenced on a cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) containing protocol from 1/8/2020 to 1/8/21. Data was collected from electronic and written patient records. Information regarding patient age, diagnosis, steroid preparation and dose, presence of risk factors for osteoporosis and calcium and vitamin D prescriptions were collected. Radiological imaging was reviewed to assess for the occurrence of fragility fractures. Each patient had a FRAX® score calculated to assess fracture risk. Results The mean age of patients studied was 67 years and equally distributed between males and females. All patients had NHL. 32% (n=25) of patients were identified to be at high risk for fracture (FRAX® score >20% ten-year probability of major osteoporotic fracture). 16% had already established fragility fractures prior to commencing steroid treatment. 28% of patients were females over the age of 70 years. Only 12% of patients received vitamin D and calcium supplementation. No patient commenced bone protection therapy. Conclusion Omission of bone health assessment prior to high dose glucocorticoid treatment is prevalent in haematological malignancy and places patients at risk of significant morbidity. Patients are not routinely considered for protective measures including calcium and vitamin D supplementation and bone protection therapy. A simple risk-assessment tool and education to staff and patients prior to glucocorticoid therapy could significantly improve practice in this area. It is now planned to introduce routine risk assessment for this cohort of patients, with re-audit following implementation.

Androgens improve ovarian follicle function impaired by glucocorticoids through an androgen-IGF1-FSH synergistic effect.

High concentrations of glucocorticoids caused by chronic stress are known to affect ovarian function and cause diminished ovarian reserve. Androgens are essential for early-stage ovarian follicle development, but the effects and mechanisms of androgens on follicle development under chronic stress remain unclear. In this study, we aim to investigate the effects of high concentrations of glucocorticoids on the function of in vitro cultured ovarian cells and mouse early-stage ovarian follicles and to validate the hypothesis that androgen-insulin-like growth factor 1 (IGF1)-follicle-stimulating hormone (FSH) synergistic signaling helps to ameliorate the damage caused by high concentrations of glucocorticoids. KGN cells (human granulosa cell line) and mouse primary cells were treated with different concentrations of glucocorticoids, and the cell proliferation, apoptosis, and sex hormone secretion were detected. The effects of glucocorticoid and androgens on IGF1 receptor (IGF1R) and FSH receptor (FSHR) expression in KGN cells were detected by Western blot. Steroidogenic synthase expressions under androgens and androgen-IGF1-FSH combination treatment were examined by qPCR after manipulation using low and high concentrations of glucocorticoids. The mechanism of androgen regulation of IGF1R and FSHR was explored by small interfering RNA (siRNA) and chromatin immunoprecipitation (ChIP)-qPCR. Damage of glucocorticoids and the treatment effects of androgens were further validated in mouse ovarian follicles cultured in vitro. The results demonstrated that prolonged treatment with high-dose glucocorticoids reduced cell viability of granulosa cells, inhibited their sex hormone secretion, and impaired their sensitivity to IGF1 and FSH signaling by affecting IGF1R and FSHR functions. Androgens at an appropriate dose range improved early-stage follicle development and their hormone secretion under high-dose glucocorticoid treatment, which was related to increased transcription of Igf1r and Fshr. This work showed that excessive glucocorticoids impaired ovarian function and validated that balanced concentrations of androgens synergized with IGF1 and FSH to improve the function of early-stage ovarian follicles under conditions of chronic stress.

MO257: Glucocorticoid Dosing in Induction Remission Treatments for ANCA-Associated Vasculitis

Abstract BACKGROUND Anti-neutrophil cytoplasm antibodies (ANCA) associated vasculitis (AAV) is a rare and complex autoimmune disease. Induction remission and maintenance treatment typically includes glucocorticoids (GC) in addition to other immunosuppressive medications. Recent trials such as PEXIVAS (1) and ADVOCATE (2) have suggested lower dose GC as induction treatment with no significant detrimental effect on outcomes such as end-stage renal disease (ESRD) or mortality. METHOD A cohort study of biopsy-proven pauci-immune glomerulonephritis was constructed from a single centre between 2007 and 2021. Retrospective analysis of patients with AAV from a single centre in the North West, UK, compared ESRD and mortality between groups that received high dose versus low dose GC treatment at induction. High dose GC treatment was defined as 1.5 g intravenous (IV) methylprednisolone over 3 days followed by a tapering course of oral prednisolone starting with 60 mg per day. Low dose GC treatment was defined as a single dose of 250 mg pulsed IV methylprednisolone followed by a tapering course of oral prednisolone starting with 30 mg per day. Regression analysis was applied to outcomes including relapse and remission rates, glucocorticoid toxicity index (GTI) and significant adverse events. RESULTS Fifty-three patients with biopsy-proven ANCA vasculitis were identified. A total of 28 patients received high dose GC induction treatment and 25 patients received a lower dose GC induction regime. The median age for the high dose patients was 68 years (IQR 65–74), which was lower than the low dose patients; 70 years (IQR 58–78). There was a slight (60%) female preponderance in the low dose group compared with a slight male predominance in the high dose group (67%). The Charlson Comorbidity Index (CCI) was completed for all patients. The higher dose cohort had a mean CCI score of 4.8 whilst the lower dose cohort had a lower CCI of 3.8. The number of patients requiring acute dialysis was similar across both the high dose and low dose groups (29% and 32%, respectively). ESRD was also similar between the two groups at 6 months (P = .39). Time to remission was shorter in the lower dose GC cohort (P = .01) and risk of relapse was also reduced (P = .04), as shown in Fig. 1. Those that received the lower dose GC regime were on less prednisolone at 6 months than those starting with a higher induction dose and this was statistically significant when adjusting for confounders including age, gender and co-morbidities (P = .01). The risk of death was higher in the high dose GC group (21.4% versus 4%, respectively), although this did not reach statistical significance (P = .09). In addition, the risk of adverse events and GC toxicity was higher in the high dose cohort; P = .55 and P = .12, respectively. CONCLUSION Treatment of ANCA vasculitis remains complex and glucocorticoids remain the cornerstone of induction remission treatment regimes. Whilst our initial data did not show a significant difference in mortality and ESRD outcomes between those that received high versus low dose GC treatment, it demonstrated that low dose GC may be sufficient in the management of AAV. Our small size study suggests a lower dose GC induction remission treatment regime to be safe, effective and associated with fewer adverse effects relating to GC toxicity. Further large studies are needed to look at the narrow therapeutic window of GC and the role of GC-sparing treatments so as to improve outcomes in these patients.

Phase 1 results of the ODM-208 first-in-human phase 1-2 trial in patients with metastatic castration-resistant prostate cancer (CYPIDES).

18 Background: ODM-208 is a novel, oral, non-steroidal and selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. ODM-208 suppresses the production of all steroid hormones and their precursors that may activate the androgen receptor (AR) signalling pathway. This is particularly relevant in patients with AR ligand binding domain (LBD) activating somatic point mutations, a mechanism of resistance to hormone-based therapies in metastatic castration-resistant prostate cancer (mCRPC). We report the first results of the first-in-man phase I CYPIDES trial. Methods: ODM-208 was examined in a dose finding phase 1 trial with a 3+3 design in patients with progressive mCRPC who had previously received ≥1 line of AR signalling inhibitor and ≥1 line of taxane-based chemotherapy. ODM-208 was administered up to 150 mg/day with glucocorticoid (GC) and mineralocorticoid replacement therapy and androgen deprivation therapy (ADT). The phase 1 endpoints included dose-limiting toxicities (DLTs), adverse events, pharmacokinetics, pharmacodynamics, PSA and RECIST response, and exploratory genetic profiling. Results: By Jan 22 2021, 41 patients (median age 70 yrs.) had received ODM-208. The dose finding was completed and included doses ranging from 10 to 150 mg/day. 22 (54%) patients had previously received both abiraterone and enzalutamide, and 23 (56%) patients both docetaxel and cabazitaxel. Although tolerated by most patients, the main safety finding was adrenal insufficiency (AI). Overall, 15/41 (37%) patients experienced Grade 3 AI requiring short-term high-dose GC treatment. ODM-208 plasma exposure was dose proportional. Serum testosterone was undetectable after 4 weeks of start of ODM-208 in almost all patients, as were serum DHEA sulphate, androstenedione, 11β-hydroxyandrostenedione, 11-ketotestosterone and pregnenolone. Overall 12/36 (33%) evaluable patients achieved a PSA decline of ≥50%. In evaluable patients with AR LBD mutation 10/15 (67%) achieved a PSA decline of ≥50%. Clinical improvement in symptoms such as pain was also observed in some men. Conclusions: Administration of ODM-208 to mCRPC men pretreated with abiraterone/enzalutamide and taxanes was highly effective in blocking the production of steroid hormones and showed promising antitumor activity, especially in men with AR mutation-positive cancers. The phase 2 dose expansion part of CYPIDES is ongoing. Clinical trial information: NCT03436485.

Comparison of characteristics, predictors and outcomes between the first and second COVID-19 waves in a tertiary care centre in Switzerland: an observational analysis.

To compare admission characteristics, predictors and outcomes of patients with confirmed coronavirus disease 2019 (COVID-19) hospitalised in a tertiary care hospital in Switzerland during the first and second waves of the pandemic. This retrospective observational analysis included adult patients with  severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection confirmed by a real-time reverse transcriptase polymerase chain reaction (RT-PCR) or rapid antigen test and hospitalised at the Cantonal Hospital Aarau from 26 February to 30 April 2020 (first wave) and from 1 October to 31 December 2020 (second wave). The primary endpoint was all-cause in-hospital mortality. The secondary endpoints were transfer to the intensive care unit (ICU) and length of hospital stay (LOS). Overall, 486 patients (mean age 65.9 years ± 14.7 SD, 65% male) were included. Ninety-two patients (19%) died during the hospital stay and 92 patients (19%) were transferred to the ICU. Admission characteristics, including comorbidities and frailty, were similar for patients of the first (n = 100) and second wave (n = 386). However, during the second wave the median time from symptom onset to presentation to the emergency department (ED) was shorter (7 days, interquartile range [IQR] 4–9 vs 8 days, IQR 4–11; p = 0.02). In the second wave, most patients received high-dose glucocorticoid treatment (0% vs 76%, p <0.01). In-hospital mortality was similar among COVID-19 patients in the first (19/100, 19%) and second wave (73/386, 19%); this finding persisted after full adjustment in multiple regression models (adjusted odds ratio [aOR] 1.18, 95% confidence interval [CI] 0.49–2.80; p = 0.71). Risk for ICU admission was also similar (24% vs 18%; aOR 0.98, 95% CI 0.46–2.06; p = 0.95). More patients were transferred to rehabilitation facilities in the second wave (18% vs 31%; aOR 2.06, 95% CI 1.04–4.07; p = 0.04) and LOS was 2.5 days shorter (9.0 vs 6.5 days; adjusted difference −2.53 days, 95%-CI −4.51 to −0.54; p = 0.01). Main predictors for in-hospital death were patient age (aOR 1.07, 95% CI 1.02–1.11; p <0.01), male sex (aOR 2.41, 95% CI 1.05–5.55; p = 0.04) and the age-adjusted Charlson comorbidity index (aOR 1.27, 95% CI 1.09–1.48 p <0.01). Despite differing treatment regimens, mortality and ICU admission remained largely unchanged for COVID-19 patients admitted during the second wave of the pandemic in our tertiary care hospital. However, discharge processes were optimised with patients leaving the hospital earlier and going to rehabilitation facilities more often. &nbsp.

Comparative effectiveness of trimethoprim-sulfamethoxazole versus atovaquone for the prophylaxis of pneumocystis pneumonia in patients with connective tissue diseases receiving prolonged high-dose glucocorticoids

We compared the prophylactic effect of trimethoprim-sulfamethoxazole (TMP-SMX) with atovaquone for pneumocystis pneumonia (PCP) in patients with connective tissue diseases (CTDs) receiving high-dose glucocorticoids. Patients with CTDs aged ≥ 18years who were treated with a prolonged course (≥ 4weeks) of glucocorticoids (≥ 20mg/day prednisone) in a Japanese tertiary center between 2013 and 2017 were included. The patients were categorized into two groups: TMP-SMX and atovaquone group. Adjusted cumulative incidence of PCP was compared between the two groups after propensity score weighting for differences in confounding factors. A total of 480 patients with a prolonged high-dose glucocorticoid treatment were identified. Out of 383 patients with TMP-SMX prophylaxis, 102 (26.8%) patients experienced adverse events leading to discontinuation within 4weeks of initiation, while no patient in the atovaquone discontinued the therapy. Two hundred eighty-one patients received TMP-SMX, while 107 received atovaquone for PCP prophylaxis. During a total of 397.0 person-years, 7 PCP cases (2 in the TMP-SMX, 5 in the atovaquone) occurred with a mortality rate of 54.5%. After adjusting for differences in baseline characteristics, the adjusted cumulative incidence of PCP was similar between the two group (HR 0.97, 95% CI 0.19-5.09, p = 0.97). Prophylactic effects for PCP in CTDs patients receiving prolonged high-dose glucocorticoids were similar between TMP-SMX and atovaquone. Atovaquone was well-tolerated with no side effects.