Side Effects Of Glucocorticoids Research Articles

Intermittent pulses of methylprednisolone with low-dose prednisone attenuate lupus symptoms in B6.MRL-Faslpr/J mice with fewer glucocorticoid side effects

Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressant medications and remain the cornerstone of systemic lupus erythematosus (SLE) therapy. However, ongoing exposure to GCs has the potential to elicit multiple adverse effects. Considering the irreplaceability of GCs in SLE therapy, it is important to explore the optimal regimen of GCs. Here, we compared the long-term efficacy and safety of pulsed and oral GC therapy in a lupus-prone mouse model. Mice were grouped using a randomized block design. We monitored survival rates, proteinuria, serum autoantibodies, and complement 3 (C3) levels up to 28 weeks of age, and assessed renal damage, bone quality, lipid deposition in the liver and marrow, glucose metabolic parameters, and levels of hormones of the hypothalamic-pituitary-adrenal (HPA) axis. Finally, we explored the mechanisms underlying the superior efficacy of the pulse regimen over oral prednisone regimen. We found that both GC regimens alleviated the poor survival rate, proteinuria, and glomerulonephritis, while also reducing serum autoantibodies and increasing the level of C3. The pulsed GC regimen showed less resistance to insulin, less suppression of the HPA axis, less bone loss, and less bone marrow fat deposition than the oral GC regimen. Additionally, GC-induced leucine zipper (GILZ) was significantly overexpressed in the GC pulse group. These results suggest that the GC pulse regimen ameliorated symptoms in lupus-prone mice, with fewer side effects, which may be related to GILZ overexpression. Our findings offer a potentially promising GC treatment option for SLE.

Discovery of novel ocotillol derivatives modulating glucocorticoid receptor/NF-κB signaling for the treatment of sepsis

Glucocorticoids (GCs) have been used in the treatment of sepsis because of their potent anti-inflammatory effects. However, their clinical efficacy against sepsis remains controversial because of glucocorticoid receptor (GR) downregulation and side effects. Herein, we designed and synthesized 30 ocotillol derivatives and evaluated their anti-inflammatory activities. Ocotillol 24(R/S) differential isomers were stereoselective in their pharmacological action. Specifically, 24(S) derivatives had better anti-inflammatory activity than their corresponding 24(R) derivatives. Compound 20 most effectively inhibited NO release (85.97% reduction), and it exerted dose-dependent inhibitory effects on interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels. Mechanistic studies revealed that compound 20 reduces the degradation of GR mRNA and GR protein. Meanwhile, compound 20 inhibited the activation of nuclear factor-κB (NF-κB) signaling, thereby inhibiting the nuclear translocation of p65 and attenuating the inflammatory response. In vivo studies revealed that compound 20 attenuated hepatic, pulmonary, and renal pathology damage in mice with sepsis and suppressed the production of inflammatory mediators. These results indicated that compound 20 is a promising lead compound for designing and developing anti-sepsis drugs.

Polymyalgia rheumatica-Achallenge in geriatrics : Interdisciplinary presentation of diagnostics and treatment

Polymyalgia rheumatica is the second most frequent inflammatory rheumatic disease in people aged over 50years, after rheumatoid arthritis. It is characterized by pain and morning stiffness in the region of the shoulders, hip girdle and neck. It can be associated with giant cell arteritis (CGA). Treatment with glucocorticoids is indispensable. The duration of treatment varies and often exceeds 1year. The additive administration of methotrexate is an option for saving glucocorticoids. The biologicals tocilizumab or secukinumab are very promising alternatives. The course of treatment should be closely monitored for inflammation parameters, glucocorticoid side effects, pain, visual acuity, depression, activities of daily living and especially related to functions of the upper extremities. The geriatric assessment plays an important role in the management of this condition.

Renal and survival benefits of seventeen prescribed Chinese herbal medicines against oxidative-inflammatory stress in systemic lupus erythematosus patients with chronic kidney disease: a real-world longitudinal study.

Background: Systemic lupus erythematosus (SLE) significantly links to LN, a type of CKD with high mortality despite modern Western treatments. About 70% of SLE patients develop LN, and 30% advance to end-stage renal disease (ESRD). Concerns about glucocorticoid side effects and LN worsening due to oxidative stress prompt alternative treatment searches. In Taiwan, over 85% of SLE patients opt for complementary methods, especially Chinese herbal medicine (CHM). We pinpointed seventeen CHMs for SLE (PRCHMSLE) with antioxidative and anti-inflammatory properties from national health insurance data (2000-2017). Our primary aim was to assess their impact on renal and survival outcomes in SLE patients progressing to CKD (SLE-CKD), with a secondary focus on the risks of hospitalization and hyperkalemia. Methods: We established a propensity-matched cohort of 1,188 patients with SLE-CKD, comprising 594 PRCHMSLE users and 594 nonusers. We employed Cox proportional hazards models and restricted mean survival time (RMST) analyses to assess the renal and survival outcomes of PRCHMSLE users. Moreover, we performed pooling and network analyses, specifically focusing on the renal effects linked to PRCHMSLE. Results: PRCHMSLE use was associated with decreased adjusted hazard ratios for ESRD (0.45; 95% confidence interval, 0.25-0.79, p = 0.006), all-cause mortality (0.56; 0.43-0.75, p < 0.0001), non-cardiovascular mortality (0.56; 0.42-0.75, p < 0.0001), and hospitalization (0.72; 0.52-0.96, p = 0.009). Hyperkalemia risk did not increase. Significant differences in RMST were observed: 0.57 years (95% confidence interval, 0.19-0.95, p = 0.004) for ESRD, 1.22 years (0.63-1.82, p < 0.0001) for all-cause mortality, and 1.21 years (0.62-1.80, p < 0.0001) for non-cardiovascular mortality, favoring PRCHMSLE use. Notably renoprotective PRCHMSLE included Gan-Lu-Ying, Anemarrhena asphodeloides Bunge [Asparagaceae; Rhizoma Anemarrhenae] (Zhi-Mu), Rehmannia glutinosa (Gaertn.) DC. [Orobanchaceae; Radix Rehmanniae] (Sheng-Di-Huang), Jia-Wei-Xiao-Yao-San, and Paeonia suffruticosa Andr. [Paeoniaceae; Cortex Moutan] (Mu-Dan-Pi). Network analysis highlighted primary treatment strategies with central components like Liu-Wei-Di-Huang-Wan, Paeonia suffruticosa Andr. [Paeoniaceae; Cortex Moutan] (Mu-Dan-Pi), Anemarrhena asphodeloides Bunge [Asparagaceae; Rhizoma Anemarrhenae] (Zhi-Mu), Rehmannia glutinosa (Gaertn.) DC. [Orobanchaceae; Radix Rehmanniae] (Sheng-Di-Huang), and Zhi-Bai-Di-Huang-Wan. Conclusion: This work underscores the pronounced renal and survival benefits associated with the seventeen PRCHMSLE in the treatment of SLE-CKD, concurrently mitigating the risks of hospitalization and hyperkalemia. This highlights their potential as alternative treatment options for individuals with this condition.

Neuropsychiatric Adverse Effects of Synthetic Glucocorticoids: A Systematic Review and Meta-Analysis.

Synthetic glucocorticoids are widely used to treat patients with a broad range of diseases. While efficacious, glucocorticoids can be accompanied by neuropsychiatric adverse effects. This systematic review and meta-analysis assesses and quantifies the proportion of different neuropsychiatric adverse effects in patients using synthetic glucocorticoids. Six electronic databases were searched to identify potentially relevant studies. Randomized controlled trials, cohort studies, and cross-sectional studies assessing psychiatric side effects of glucocorticoids measured with validated questionnaires were eligible. Risk of bias was assessed with RoB 2, ROBINS-I, and AXIS appraisal tool. For proportions of neuropsychiatric outcomes, we pooled proportions, and when possible, differences in questionnaire scores between glucocorticoid users and nonusers were expressed as standardized mean differences (SMD). Data were pooled in a random-effects logistic regression model. We included 49 studies with heterogeneity in study populations, type, dose, and duration of glucocorticoids. For glucocorticoid users, meta-analysis showed a proportion of 22% for depression (95% CI, 14%-33%), 11% for mania (2%-46%), 8% for anxiety (2%-25%), 16% for delirium (6%-36%), and 52% for behavioral changes (42%-61%). Questionnaire scores for depression (SMD of 0.80 [95% CI 0.35-1.26]), and mania (0.78 [0.14-1.42]) were higher than in controls, indicating more depressive and manic symptoms following glucocorticoid use. The heterogeneity of glucocorticoid use is reflected in the available studies. Despite this heterogeneity, the proportion of neuropsychiatric adverse effects in glucocorticoid users is high. The most substantial associations with glucocorticoid use were found for depression and mania. Upon starting glucocorticoid treatment, awareness of possible psychiatric side effects is essential. More structured studies on incidence and potential pathways of neuropsychiatric side effects of prescribed glucocorticoids are clearly needed.

E47 as a novel glucocorticoid-dependent gene mediating lipid metabolism in patients with endogenous glucocorticoid excess.

E47 has been identified as a modulating transcription factor of glucocorticoid receptor target genes, its loss protecting mice from metabolic adverse effects of glucocorticoids. We aimed to analyze the role of E47 in patients with endogenous glucocorticoid excess [Cushing's syndrome (CS)] and its association with disorders of lipid and glucose metabolism. This is a prospective cohort study including 120 female patients with CS (ACTH-dependent = 79; ACTH-independent = 41) and 26 healthy female controls. Morning whole blood samples after an overnight fast were used to determine E47 mRNA expression levels in patients with overt CS before and 6-12 months after curative surgery. Expression levels were correlated with the clinical phenotype of the patients. Control subjects underwent ACTH stimulation tests and dexamethasone suppression tests to analyze short-term regulation of E47. E47 gene expression showed significant differences in patient cohorts with overt CS vs. patients in remission (p = 0.0474) and in direct intraindividual comparisons pre- vs. post-surgery (p = 0.0353). ACTH stimulation of controls resulted in a significant decrease of E47 mRNA expression 30min after i.v. injection compared to baseline measurements. Administration of 1 mg of dexamethasone overnight in controls did not change E47 mRNA expression. E47 gene expression showed a positive correlation with total serum cholesterol (p = 0.0036), low-density lipoprotein cholesterol (p = 0.0157), and waist-arm ratio (p = 0.0138) in patients with CS in remission. E47 is a GC-dependent gene that is upregulated in GC excess potentially aiming at reducing metabolic glucocorticoid side effects such asdyslipidemia.

Topical Spironolactone in the Treatment of Ocular Graft-Versus-Host Disease.

This two-part study aimed to investigate the therapeutic potential of topical spironolactone in ocular graft-versus-host disease (oGVHD). While off-label use of topical spironolactone has been described in dry eye, its efficacy in managing signs and symptoms of oGVHD remains unstudied. Preclinically, we tested the hypothesis that spironolactone induces corneal lipid synthesis in a mouse model. Clinically, we assessed patient response to spironolactone with a retrospective observational design. Both immortalized and primary human corneal epithelial cells were stained with oil red O after 9 days of treatment with spironolactone. C57BL/6 mice were dosed thrice daily with one drop in each eye for 18 days. Corneal tissue was stained with oil red O and BODIPY™. Twenty eyes with oGVHD, as defined by the International Chronic oGVHD Consensus Group, were studied. Corneal fluorescein staining, lid margin vascularity, meibomian gland obstruction, meibum turbidity, zone A posterior lid margin vascularity, and oGVHD diagnostic criteria severity grading were compared in a pre-post study. Follow-up times ranged from 7 to 21 weeks, with a median time of 12 weeks. Statistical analysis was done with STATA 17 by fitting data to a non-parametric model. In vitroresults showed an increased number and density of oil red O staining granules in the treatment group versus control in both primary and immortalized human corneal epithelium.In vivo, results showed translation to the mouse model with increased corneal epithelial BODIPY™ signal compared to untreated control. oGVHD patients had improved lid margin vascularity (p= 0.046), corneal fluorescein staining (p= 0.021), and International oGVHD Consensus Group severity scores (p= 0.011) after treatment with topical spironolactone. Minimal adverse effects were noted, the most common being mild stinging lasting less than a minute after instillation. The improved severity scores, lid margin inflammation, and corneal fluorescein staining after weeks of treatment support the rationale that topical spironolactone may benefit oGVHD. The observed lipid production by the corneal epithelium is thought to contribute to this protective effect against ocular surface erosive disease in oGVHD. A mineralocorticoid receptor antagonist, spironolactone may offer therapeutic benefits in oGVHD while avoiding undesirable side effects of topical or systemic glucocorticoids.

Polymyalgia rheumatica-Achallenge in geriatrics : Interdisciplinary presentation of diagnostics and treatment

Polymyalgia rheumatica is the second most frequent inflammatory rheumatic disease in people aged over 50years, after rheumatoid arthritis. It is characterized by pain and morning stiffness in the region of the shoulders, hip girdle and neck. It can be associated with giant cell arteritis (CGA). Treatment with glucocorticoids is indispensable. The duration of treatment varies and often exceeds 1year. The additive administration of methotrexate is an option for saving glucocorticoids. The biologicals tocilizumab or secukinumab are very promising alternatives. The course of treatment should be closely monitored for inflammation parameters, glucocorticoid side effects, pain, visual acuity, depression, activities of daily living and especially related to functions of the upper extremities. The geriatric assessment plays an important role in the management of this condition.

Glucocorticoid Treatment in Acute Respiratory Distress Syndrome: An Overview on Mechanistic Insights and Clinical Benefit.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), triggered by various pathogenic factors inside and outside the lungs, leads to diffuse lung injury and can result in respiratory failure and death, which are typical clinical critical emergencies. Severe acute pancreatitis (SAP), which has a poor clinical prognosis, is one of the most common diseases that induces ARDS. When SAP causes the body to produce a storm of inflammatory factors and even causes sepsis, clinicians will face a two-way choice between anti-inflammatory and anti-infection objectives while considering the damaged intestinal barrier and respiratory failure, which undoubtedly increases the difficulty of the diagnosis and treatment of SAP-ALI/ARDS. For a long time, many studies have been devoted to applying glucocorticoids (GCs) to control the inflammatory response and prevent and treat sepsis and ALI/ARDS. However, the specific mechanism is not precise, the clinical efficacy is uneven, and the corresponding side effects are endless. This review discusses the mechanism of action, current clinical application status, effectiveness assessment, and side effects of GCs in the treatment of ALI/ARDS (especially the subtype caused by SAP).

Rituximab as Initial Therapy in Adult Patients With Minimal Change Disease

Rituximab as Initial Therapy in Adult Patients With Minimal Change Disease

Rare localization of avascular necrosis during treatment of COVID-19 with glucocorticosteroids

The development of bony avascular necrosis induced by glucocorticoid treatment of COVID-19 is a common adverse effect, with femoral head being the most commonly affected. Timely detection of avascular necrosis is important in the prevention of osteoarthrosis and other complications.&#x0D; We present a clinical case of a 54-year-old patient hospitalized for novel coronavirus infection with complaints of severe pain in both knees 2 weeks after the disease onset. Magnetic resonance imaging revealed pronounced changes in both knees, corresponding to avascular necrosis. The results of conservative therapy, including non-steroidal anti-inflammatory drugs and bisphosphonate bone resorption inhibitors, produced a pronounced positive result. At follow-up examination 3 months later, there was no pain, but the knee joints still had slight restrictions of movement. Magnetic resonance imaging showed a significant decrease in the previously detected changes.&#x0D; The side effects of glucocorticoids (impaired glucose tolerance, increased blood pressure, tachycardia, gastrointestinal erosive ulcers, sleep disorders, etc.) are widely known, but knee osteonecrosis caused by steroid intake rarely comes to the attention of clinicians. This clinical case emphasizes the complex nature of osteonecrosis pathogenesis and demonstrates a wide range of complications in corticosteroid therapy.

PSAT066 Adrenal Insufficiency Associated with Amyloidosis and Sickle Cell Disease

Abstract Background Amyloidosis causes chronic inflammation by the deposition of amyloid protein fragments in multiple organs, such as kidneys, adrenal, and pituitary glands. It is a challenge to access adrenocortical function in renal amyloidosis patients due to heavy proteinuria induced hypoproteinemia and low corticosteroid-binding globulin (CBG) which may cause false positive adrenocorticotropin (ACTH) test and the reduced cortisol level uncorrelated with free cortisol. On the other hand, adrenal insufficiency also frequently occurs in Sickle Cell Disease (SCD) patients. The hypothalamic-pituitary-adrenal (HPA) axis can be affected by tissue hypoxia during recurrent small vessel occlusion, chronic anemia, and iron-overload related oxidative stress. We report a SCD patient with nephrotic syndrome due to amyloidosis, who has adrenal insufficiency. Case Presentation A 41 years old female with Nephrotic syndrome secondary to Amyloid A (AA) amyloidosis, Adrenal insufficiency, Sickle cell disease (HbSC), Graves’ Hyperthyroidism, CVA, and bilateral femoral head avascular necrosis, presented with sickle cell pain crisis and anasarca with hypotension. She was on Hydrocortisone for 12 years but was not compliant for 2 months. She was on Methimazole for several years before it was discontinued one year ago. She has amenorrhea, severe edema with anasarca from the lower extremities to the abdomen. Labs showed morning cortisol 5.46 ug/dL, low albumin 2.4 g/dL, high TSH 5.43 uIU/mL, normal FT4 1.60 ng/dL, high urine protein 996.2 mg/dL, and eGFR 21.2. CT revealed pericardial effusion, free pelvic fluid, splenomegaly, edema, and thyroid goiter. Previous labs showed persistent low cortisol 0.9 to 3.5 ug/dL, high ferritin 1007 ng/mL, and pituitary workup was normal for Prolactin 4.6 ug/L, LH 5.02 mIU/mL, FSH 9.9 mIU/mL, IGF1 216 ng/mL, and ACTH 13.1 pg/mL. NM thyroid uptake elevated 51.7% and positive TPO 79.7 IU/mL. CT head was unremarkable. The patient was managed with Lasix and Albumin infusion for anasarca, Cyclosporine for amyloidosis, and Midodrine 10 mg TID for hypotension. Hydrocortisone stress dose was given followed by Prednisone 30 mg BID. Her symptoms improved. Discussion In Amyloidosis patients with heavy proteinuria, the low serum CBG levels affect total cortisol level. Therefore, the proper assessment for the adrenal function should be used with albumin-calculated free cortisol or cortisol/CBG ratio in addition to the ACTH stimulation tests. It is essential to differentiate between adrenal insufficiency and amyloidosis-related symptoms to prevent adrenal crisis and refrain from glucocorticoid side effects by unnecessary steroid use. On the other hand, endocrine manifestations of SCD may include hypogonadism, thyroid, adrenal, and pituitary dysfunction due to vaso-occlusive episodes induced multi-organ ischemic damage. This patient has amenorrhea, adrenal insufficiency, and normalized thyroid function test in Graves’ disease. It is crucial to avoid iron-overload induced oxidative stress which would worsen endocrine dysfunctions as well. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

ODP444 The Effect of Glucocorticoid Therapy on Cardio-Metabolic Risk in Patients with Multiple Sclerosis

Abstract Multiple sclerosis (MS) often requires usage of glucocorticoids (GC). Excess of GC may affect muscles, which increases mortality. This study evaluates the effect of GC therapy on muscles and cardiovascular disease (CVD) risk factors in patients with MS. Methods 45 patients (55.5% women), 37.8 (20-45) years, were examined. 51% of patients received GC (methylprednisolone 3000-5000 mg, 3-5 days). MS duration was 5.9±1.2 years, the assessment by EDSS - 3.3±1.2. Muscle tissue was assessed by bioimpedance analysis, a chair-rising test, dynamometry. Glucose and lipid metabolism, blood pressure (BP), body mass index (BMI), waist circumference (WC),physical activity were evaluated. Statistical analysis was carried out using "Statistica 10. 0". Normal distribution was tested by the Shapiro–Wilks test, p&amp;gt;0. 05. А Mann-Whitney U-test, a t-test,χ2 test were used,p&amp;lt;0. 05. Results Patients with GC had significantly higher BMI (28.56±5. 02 vs 22.87±3.49 kg/m2), WC (98 (66-123) vs 79.9±5.27cm), lower muscle mass (36.4 (35-38) vs 40.75±2. 02 kg). A negative correlation between GC dose and a grip strength of the dominant hand among men was noted (r=-0.88, p&amp;lt;0. 0001). A normal WС was identified in 52% of patients. Comparing with others received GC, they had a lower level of low-density lipoproteins (1.35±0.39 vs 1.39(1-3,32) mmol/l), systolic BP (132.3±15.7 vs 141 (100-165)) and better handgrip strength (40 (25-47) vs 27±7.3 daN). Conclusions The negative effect of GC on cardiometabolic parameters in all patients with MS and muscle strength in men was confirmed. Metabolic healthier patients probably have a resistance to GC side effects, which may be determined genetically. It is promising for finding protective factors against GC. Presentation: No date and time listed

Macromolecular Dexamethasone Prodrug Ameliorates Neuroinflammation and Prevents Bone Loss Associated with Traumatic Brain Injury.

Traumatic brain injury (TBI) is one of the leading causes of death and disability among children and young adults in the United States. In this manuscript, we assessed the utility of an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrug (P-Dex) in the treatment of TBI. Using a controlled cortical impact TBI mouse model, P-Dex was found to passively target and sustain at the traumatic/inflammatory brain tissue for over 14 days after systemic administration. The histological evidence supports P-Dex's therapeutic potential in ameliorating neuroinflammation and mitigating neurodegeneration. Behaviorally, the P-Dex-treated animals showed statistically significant improvement in balance recovery. A trend of neurological severity score improvement at the early time point post-TBI was also noted but did not achieve statistical significance. While probing the potential glucocorticoid side effects that may associate with P-Dex treatment, we discovered that the TBI mice develop osteopenia. Interestingly, the P-Dex-treated TBI mice demonstrated higher bone mineral density and better bone microarchitecture parameters when compared to free Dex and the saline control, revealing the osteoprotective effect of P-Dex in addition to its neuronal protection benefits post-TBI.

An Unusual Case of Refractory Peptic Ulcer Disease

An Unusual Case of Refractory Peptic Ulcer Disease

The treatment of sarcoidosis: translating the European respiratory guidelines into clinical practice.

Recently, the European Respiratory Society (ERS) developed new international guidelines for the treatment of sarcoidosis. This manuscript attempts to distill the ERS Sarcoidosis Treatment Guidelines to a manageable format that can be easily used by practitioners. The ERS Sarcoidosis Treatment Guidelines addressed the treatment of pulmonary, skin, cardiac, neurologic, and sarcoidosis-associated fatigue. Therapeutic drug dosing and treatment algorithms for these conditions were also addressed. Glucocorticoids were the initial recommended treatment for these conditions except for sarcoidosis-associated fatigue where a pulmonary exercise program or a neurostimulant was initially suggested. Because of the risk of glucocorticoid side-effects, the Guidelines recommended early consideration of glucocorticoid-sparing therapy including certain antimetabolites and two specific tumor necrosis alpha antagonists: infliximab and adalimumab. The ERS Sarcoidosis Treatment Guidelines used a rigorous GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology to update treatment recommendations for this condition. This manuscript summarizes the Guideline findings in practical terms for clinicians. Suggested algorithms and treatment dosing recommendations are provided.

The pediatric glucocorticoid toxicity index

ObjectivesTo develop a Pediatric glucocorticoid toxicity index (pGTI), a standardized, weighted clinical outcome assessment that measures change in glucocorticoid (GC) toxicity over time. MethodsFourteen physician experts from 7 subspecialties participated. The physician experts represented multiple subspecialties in which GCs play a major role in the treatment of inflammatory disease: nephrology, rheumatology, oncology, endocrinology, genetics, psychiatry, and maternal-fetal medicine. Nine investigators were from Canada, Europe, or New Zealand, and 5 were from the United States. Group consensus methods and multi-criteria decision analysis were used. The pGTI is an aggregate assessment of GC toxicities that are common, important, and dynamic. These toxicities are organized into health domains graded as minor, moderate, or major and are weighted according to severity. The relative weights were derived by group consensus and multi-criteria decision analysis using the 1000MindsTM software platform. Two quantitative scores comprise the overall toxicity profile derived from pGTI data: (1) the Cumulative Worsening Score; and (2) the Aggregate Improvement Score. The pGTI also includes a qualitative, unweighted record of GC side-effects known as the Damage Checklist, which documents less common toxicities that, although potentially severe, are unlikely to change with varying GC dosing. ResultsOne hundred and seven (107) toxicity items were included in the pGTI and thirty-two (32) in the Damage Checklist. To assess the degree to which the pGTI corresponds to expert clinical judgement, the investigators ranked 15 cases by clinical judgement from highest to lowest GC toxicity. Expert rankings were then compared to case ranking by the pGTI, yielding excellent agreement (weighted kappa 0.86). The pGTI was migrated to a digital environment following its development and initial validation. The digital platform is designed to ensure ease-of-use in the clinic, rigor in application, and accuracy of scoring. Clinic staff enter vital signs, laboratory results, and medication changes relevant to pGTI scoring. Clinicians record findings for GC myopathy, skin toxicity, mood dysfunction, and infection. The pGTI algorithms then apply the weights to these raw data and calculate scores. Embedded logic accounts for the impact of age- and sex-related reference ranges on several health domains: blood pressure, lipid metabolism, and bone mineral density. Other algorithms account for anticipated changes in the height Z-scores used in the growth domain, thereby addressing a concern unique to GC toxicity in children. The Damage Checklist ensures comprehensive measurement of GC toxicity but does not contribute to pGTI scoring, because the scored domains emphasize manifestations of GC toxicity that are likely to change over the course of a trial. ConclusionsWe describe the development and initial evaluation of a weighted, composite toxicity index for the assessment of morbidity related to GC use in children and adolescents. Developing the pGTI digital platform was essential for performing the nuanced calculations necessary to ensure rigor, accuracy, and ease-of-use in both clinic and research settings.

Baricitinib in COVID-19: a coming-of-age from artificial intelligence to reducing mortality

Baricitinib in COVID-19: a coming-of-age from artificial intelligence to reducing mortality

Preclinical Testing of Dendritic Core-Multishell Nanoparticles in Inflammatory Skin Equivalents.

Human skin equivalents emerged as novel tools in preclinical dermatological research. It is being claimed that they may bridge the translational gap between preclinical and clinical research, yet only a few studies have investigated their suitability for preclinical drug testing so far. Therefore, we investigated if inflammatory skin equivalents, which emulate hallmarks of atopic dermatitis (AD), are suitable to assess the anti-inflammatory effects of dexamethasone (DXM) in a cream formulation or loaded onto dendritic core-multishell nanoparticles. Topical DXM application resulted in significantly decreased expression of the proinflammatory cytokine TSLP, increased expression of the skin barrier protein involucrin, and facilitated glucocorticoid receptor translocation in a dose-dependent manner. Further, DXM treatment inhibited gene expression of extracellular matrix components, potentially indicative of the known skin atrophy-inducing side effects of glucocorticoids. Overall, we were able to successfully assess the anti-inflammatory effects of DXM and the superiority of the nanoparticle formulation. Nevertheless the identification of robust readout parameters proved challenging and requires careful study design.

Glucocorticoids in Myositis: Initiation, Tapering, and Discontinuation.

We discuss the evidence behind the use of glucocorticoids in myositis including a discussion of mechanism of action, dosing, tapering, and duration of therapy as well as glucocorticoid-related adverse events that are particularly important in myositis patients. Studies showing reduction in mortality rates after the use of glucocorticoids, better outcomes in patients treated with glucocorticoids compared to those who did not, and reduction of inflammation in muscle biopsies provide low level evidence to support use of glucocorticoids in myositis. Early initiation of therapy is associated with better functional outcomes. Use of intravenous methylprednisolone in patients with severe disease may lead to quicker recovery and reduction in long-term glucocorticoid exposure. Steroid-related myopathy and osteoporosis are glucocorticoid side effects that are particularly relevant in myositis. The optimal dose and duration of glucocorticoid therapy in myositis currently remain elusive, and this review emphasizes the need for better quality studies in this area.