Adverse Effects Of Glucocorticoids Research Articles

LEDT and Idebenone treatment modulate autophagy and improve regenerative capacity in the dystrophic muscle through an AMPK-pathway.

Considering the difficulties and challenges in Duchenne muscular dystrophy (DMD) treatment, such as the adverse effects of glucocorticoids, which are the main medical prescription used by dystrophic patients, new treatment concepts for dystrophic therapy are very necessary. Thus, in this study, we explore the effects of photobiomodulation (PBM; a non-invasive therapy) and Idebenone (IDE) treatment (a potent antioxidant), applied alone or in association, in dystrophic muscle cells and the quadriceps muscle, with special focus on autophagy and regenerative pathways. For the in vitro studies, the dystrophic primary muscle cells received 0.5J LEDT and 0.06μM IDE; and for the in vivo studies, the dystrophic quadriceps muscle received 3J LEDT and the mdx mice were treated with 200mg/kg IDE. LEDT and IDE treatment modulate autophagy by increasing autophagy markers (SQSTM1/p62, Beclin and Parkin) and signaling pathways (AMPK and TGF-β). Concomitantly, the treatments prevented muscle degeneration by reducing the number of IgG-positive fibers and the fibers with a central nucleus; decreasing the fibrotic area; up-regulating the myogenin and MCH-slow levels; and down-regulating the MyoD and MHC-fast levels. These results suggest that LEDT and IDE treatments enhance autophagy and prevented muscle degeneration in the dystrophic muscle of the experimental model. These findings illustrate the potential efficacy of LEDT and IDE treatment as an alternative therapy focused on muscle recovery in the dystrophic patient.

Introducing the general management of glomerular disease from a pediatric perspective based on the updated KDIGO guidelines

In 2021, a new chapter on the general management of glomerulonephritis (GN) was added to the Kidney Disease: Improving Global Outcomes (KDIGO). It emphasizes the importance of early general management of GN for improving long-term kidney outcomes and prognosis. The chapter introduces the management of glomerular diseases in 18 subchapters. Here, kidney biopsy for the diagnosis and evaluation of kidney function and the management of complications, such as hypertension, infection, and thrombosis, are presented. Moreover, the adverse effects of glucocorticoids and immunosuppressive therapy, which are commonly used drugs for glomerular disease, are mentioned, and a guideline for drug selection is presented. Each subtheme focused on items reflecting the interpretation of the “practice points” of the expert working group are introduced. In this review of the general treatment for GN in the KDIGO guidelines, excluding pregnancy and reproductive health, we focused on and compared various references pertaining to pediatric GN management.

Glucocorticoids (GCs) are widely accessible over-the-counter (OTC), liberally recommended by locals medical practitioner, and freEpidemiological and Socio-demographic Characters of Glucocorticoids Misuse among Premenopausal Women in Thi-Qar, Southern Iraq

Glucocorticoids (GCs) are widely accessible over-the-counter (OTC), liberally recommended by locals medical practitioner, and frequently misused by women for the purpose of treatment of skin conditions, joint pains, febrile illnesses and asthma. Unfortunately, ladies misuse a lot of over-the-counter GCs and glucocorticoids containing cosmetic creams, both imported and locally blended in order to deposit fat as a connection between beauty and propensity. The objectives of the study were to evaluate the epidemiological and socio-demographic characteristics of GCs misuse among reproductive women in the South of Iraq.
 Methods: a cross-sectional study was conducted on 251 reproductive-aged women who were misusing GCs for any cause and attending Thi-Qar Specialized Diabetes, Endocrine and Metabolism Center (TDEMC) in Nasiriya City. They were evaluated for demographic characteristics, medical and social histories, and then examined carefully for any signs of GCs misuse.
 Results: The mean ages of women were 33.21±8.6 years, BMI 30.68±7.3 Kg/m², and 208 (82.9%) women were either overweight or obese. More than half (51.3%) of the women were misusing two or more forma of GCs and one quarter (26.7%) of them were misusing tablets. The types of GCs misused were presented as 77.7% dexamethasone, 19.5% prednisolone, 22.3% hydrocortisone, 21.1% betamethasone, 17.5% local GCs types, and 13.5% Inhaler GCs types. The major source of GCs misuse was pharmacy 201 (80.1%) and 18 (7.2%) from street vendors. Approximately, all women had many features of GCs-induced adverse effects and there were many misconceptions about their safety like 41.8% thought that using GCs was safe, and 45.8% did not really feel guilty about using those medications. About 90 of them (35.9%) were still misusing drugs during the time of meeting, 53 (21.1%) reported that physicians recommended them at the first time for using glucocorticoids and the majority 198 (78.9%) were misusing GCs by themselves, friends, or first-degree family to become beautiful or marry.
 Conclusions: The relatively high rate of misuse of these drugs can be attributed to the lack of awareness of their chronic adverse effects, their widespread availability at pharmacies, plus their dramatic and quick response. Therefore, educational programs have to be implemented to inform the public about the adverse effects of GCs and the problems of misuse of drugs.

Efficacy and safety of intravenous glucocorticoid therapy for IgG4-related ophthalmic disease.

To evaluate and compare the efficacy and safety of intravenous (IV) glucocorticoid therapy with those of oral glucocorticoids as a first-line treatment for IgG4-related ophthalmic disease (IgG4-ROD). We retrospectively reviewed the medical records of patients who underwent systemic glucocorticoid therapy for biopsy-proven IgG4-ROD from June 2012 to June 2022. Glucocorticoids were given either oral prednisolone at an initial dose of 0.6 mg/kg/day for four weeks with subsequent tapering or once weekly IV methylprednisolone (500 mg for six weeks, then 250 mg for six weeks), according to the date of treatment. Clinicoserological features, initial response, relapse during follow-ups, cumulative doses of glucocorticoids, and adverse effects of glucocorticoids were compared for the IV and oral steroid groups. Sixty one eyes of 35 patients were evaluated over a median follow-up period of 32.9 months. The complete response rate was significantly higher in the IV steroid group (n = 30 eyes) than in the oral steroid group (n = 31 eyes) (66.7% vs. 38.7%, p = 0.041). Kaplan-Meier analysis showed that the 2-year relapse-free survival was 71.5% (95% confidence interval: 51.6-91.4) and 21.5% (95% confidence interval: 4.5-38.5) in the IV steroid and oral steroid group, respectively (p < 0.001). Although the cumulative dose of glucocorticoids was significantly higher in the IV steroid group than in the oral steroid group (7.8 g vs. 4.9 g, p = 0.012), systemic and ophthalmic adverse effects were not significantly different between the two groups throughout follow-ups (all p > 0.05). As a first-line treatment for IgG4-ROD, IV glucocorticoid therapy was well-tolerated, led to better clinical remission and more effectively prevented inflammatory relapse than oral steroids. Further research is needed to establish guidelines on dosage regimens.

Abstract 453: Targeting FOXL2C402Gvulnerabilities in adult type ovarian granulosa cell tumors

Abstract Background: Nearly all adult-type granulosa cell tumors of the ovary (aGCTs) carry the same oncogenic mutation affecting the second winged helix domain of the Forkhead family transcription factor FOXL2 (c.C402G; p.C134W). There are no currently available therapies that exploit the high prevalence of FOXL2 mutations in this disease. Objectives: Exploit FOXL2-C402G oncogenic addiction in order to identify FDA-approved compounds with differential potency in KGN-FOXL2WT/C402G cells and isogenic KGN-FOXL2—/— cells. Methods: CRISPR/Cas9 was used to generate isogenic derivatives of KGN, a cell line derived from a recurrent aGCT. Parental cells (KGN-FOXL2WT/C402G) or isogenic cells lacking both FOXL2 alleles (KGN-FOXL2—/—) were functionally characterized and loss of Foxl2 protein was confirmed by immunoblot. Two drug libraries comprising a total of 2,416 compounds (majority FDA approved) were screened for effectiveness in KGN-FOXL2WT/C402G cells and KGN-FOXL2—/— cells. Our assay included staining with DAPI, followed by automated image analysis of each well to enumerate nuclei/cell numbers. Based on Fraction Affected (FA) statistics, compounds were ranked according to effectiveness in KGN-FOXL2WT/C402G cells. FA-area under the curve (FA-AUC) cutoff &amp;gt;0.1 yielded 152 drug candidates, categorized into 13 drug classes. 40 drug candidates, including the top 1-4 hits in each drug class were chosen for further validation. Validation rate in the confirmatory screen was at 95%. A novel primary tumor organoid culture system for aGCT was developed and validated using whole exome sequencing and immunophenotype. Selected candidate compounds were further investigated in aGCT organoid cultures from two relapsed tumors. Results: We identified classes of drugs such as the inhibitors of Bromodomain family proteins and Hydroxy-Camptothecin analogs, with enhanced activity in KGN-FOXL2WT/C402G cells relative to KGN-FOXL2—/— cells. Unexpectedly glucocorticoids as a class were found to stimulate proliferation of KGN-FOXL2WT/C402G cells whereas they lacked this activity in KGN-FOXL2—/— cells. For 36 glucocorticoids present in the screen, FA-AUC ranged from -0.3191 to -0.1342 (highest proliferation index among all test compounds) in KGN-FOXL2WT/C402G cells compared to -0.0353 to +0.1667 in KGN-FOXL2—/— cells. In recurrent aGCT organoids, the high-potency glucocorticoid dexamethasone induced cell proliferation and co-treatment with glucocorticoids increased the IC50 of paclitaxel in KGN-FOXL2WT/C402G cells from 1.43 nM to 4.04 nM. Conclusion: Mutant FOXL2 mediates a proliferative response to glucocorticoids in cultured cells and primary aGCT organoids. Paclitaxel is a standard of care chemotherapy in the treatment of aGCTs and is often administered with glucocorticoid pre-medication. The adverse effect of glucocorticoids on paclitaxel efficiency shown here should thus be taken into consideration in the clinic. Citation Format: Thomas Welte, Veena Vuttaradhi, Eleonora Khlebus, Barrett Lawson, Robert T. Hillman, Nghi Nguyen, Mary Sobieski, Reid T. Powell, Clifford Stephan. Targeting FOXL2C402Gvulnerabilities in adult type ovarian granulosa cell tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 453.

Extensive Expertise in Endocrinology: Advances in the Management of Glucocorticoid-Induced Osteoporosis.

Osteoporosis is a common consequence of long-term oral glucocorticoid therapy and the resulting fractures cause significant morbidity. Bone loss occurs rapidly after initiation of glucocorticoid therapy; the accompanying increase in risk of fracture is dose-dependent and occurs within a few months of starting therapy. The adverse effects of glucocorticoids on bone are mediated by inhibition of bone formation accompanied by an early but transient increase in bone resorption, due both to direct and indirect effects on bone remodelling. Fracture risk assessment should be performed as soon as possible after long-term glucocorticoid therapy (≥3 months) is initiated. FRAX can be adjusted for the dose of prednisolone but does not currently take fracture site, recency or number into account and therefore may underestimate fracture risk, particularly in individuals with morphometric vertebral fractures. Vertebral fracture assessment should therefore be regarded as a routine part of fracture risk estimation in individuals receiving long-term glucocorticoid therapy. Bone protective therapy should be started promptly in individuals at high-risk, together with calcium and vitamin D supplements. Bisphosphonates are generally regarded as first line options on the grounds of their low cost, but anabolic therapy should be considered as an alternative first line option in very high-risk individuals.

Glucocorticoid therapy as first-line treatment in primary hypophysitis: a systematic review and individual patient data meta-analysis.

High-dose glucocorticoids are associated with improved recovery of deficits in primary autoimmune hypophysitis (PAH), but optimal dosing, route, and duration are unclear. We reviewed literature for first-line glucocorticoid treatment in PAH until December 2021 and performed an individual-patient data meta-analysis to analyze clinical, hormonal, and radiological outcomes with respect to route, dose, and duration (<6.5 vs. 6.5-12 vs. >12 weeks) of glucocorticoid treatment according to disease severity. 153 PAH patients from 83 publications were included. The median age at presentation was 41(32.5-48) years with a female preponderance (70.3%). Visual field recovery was significantly better with intravenous (91.7%) as compared to oral (54.5%) route, high dose (100%) and very-high dose (90.9%) as compared to medium dose (20%) of glucocorticoids. Corticotroph axis recovery was greater in intravenous (54.8% vs. 28.1% oral, p=0.033) route and increasing glucocorticoid dose group (0% vs. 38.1% vs. 57.1%), attaining statistical significance (p=0.012) with very high-dose. A longer duration of treatment (>6.5 weeks) was associated with better corticotroph and thyrotroph recovery. Need for rescue therapy with lower with intravenous route (38% vs 17.5%, p=0.012) and with increasing glucocorticoid doses (53.3% vs. 34.3% vs. 17.3%, p=0.016). In severe disease, visual field and corticotroph axis recovery was significantly higher with intravenous route and very-high dose steroids. The adverse effects of glucocorticoids were independent of dose and duration of treatment. Very high-dose glucocorticoids by intravenous route and cumulative longer duration (>6.5 weeks) lead to better outcomes and could be considered as first-line treatment of severe PAH cases.

Giant cell arteritis successfully treated with subcutaneous tocilizumab monotherapy.

Glucocorticoid remains the mainstay for treatment of large vessel vasculitis (LVV) including giant cell arteritis (GCA); however, the disease affects the elderly for whom the adverse effects of glucocorticoid are problematic. Recently, some reports have suggested that intravenous tocilizumab (TCZ) monotherapy is effective for this disease. To date, it remains unknown whether subcutaneous TCZ monotherapy is also effective. Here, we present a first case of GCA successfully treated with subcutaneous TCZ monotherapy. A 75-year-old woman presented with shoulder and hip pain. She was diagnosed with polymyalgia rheumatica (PMR) and treated with low-dose prednisolone (15mg daily); however, she discontinued glucocorticoid therapy at her discretion due to the psychiatric adverse effect (cognitive dysfunction). Seven months later, her shoulder and hip pain relapsed. Furthermore, 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) revealed uptake in the descending thoracic aorta, indicating a complication of LVV. She refused to take glucocorticoid for fear of psychiatric adverse effects and chose subcutaneous TCZ monotherapy (162mg weekly) for treating this life-threatening urgent condition. Nine months later, her shoulder and hip pain resolved and FDG-PET/CT demonstrated no uptake in the descending thoracic aorta, indicating a successful treatment with subcutaneous TCZ monotherapy for the disease. No adverse events and disease relapse were found during observation period. Our case and the literature review suggest that not only intravenous injection but also subcutaneous injection of TCZ monotherapy can serve as an alternative treatment for patients with GCA who have comorbidities or refuse to take glucocorticoid.

P293 Tocilizumab for refractory or relapsing giant cell arteritis: audit data from the Bristol and Bath regional multidisciplinary meetings 2018-2021

Abstract Background/Aims Giant cell arteritis (GCA) is a systemic vasculitis involving large and medium-sized blood vessels. Patients can present with cranial, ocular or large vessel (LVV-GCA) involvement. Treatment is with high dose glucocorticoids. Steroid-sparing agents and tocilizumab (TCZ) are used for refractory or relapsing cases. NHS England requires all GCA patients to be discussed in a regional multidisciplinary team meeting (MDT) prior to commencing TCZ. We reviewed the case mixture of patients referred to the Bristol and Bath regional MDT. Methods The Bristol and Bath regional MDT started in November 2018 and runs monthly. A referral proforma was designed, adapted from the NHS England Blueteq approval form for TCZ in GCA (definitions of refractory and relapsing disease), with tick boxes for clinical features, investigations, treatment, glucocorticoid adverse events and a free text clinical vignette. All referral proformas were reviewed. Results Audit data from all cases referred, between November 2018 and September 2021, were analysed. 38 cases of GCA were discussed with 31 cases approved for TCZ usage. Of the approved, 100% fulfilled the criteria for either refractory (n = 11) or relapsing (n = 20) disease. Mean age of approved cases was 74 years with three quarters being female (74.2%). Average disease duration was 161.5 days for the refractory group and 827.3 days for the relapsing group. Over three quarters of cases (77.4%) had cranial GCA, 48.4% had LVV-GCA, 45.2% had visual symptoms (reduction in visual acuity, blurring or diplopia) and 25.8% had ischaemic visual loss. The positive investigations were PET-CT (48.4%), temporal artery ultrasound (41.9%) and temporal artery biopsy (32.3%). Almost two-thirds (64.5%) had previously had a steroid-sparing agent (61.3 % methotrexate, 9.7% azathioprine, 6.5% leflunomide), one third (35.5%) had received intravenous methylprednisolone and more than half (58%) were receiving greater than 40mg prednisolone at the time of referral. Common glucocorticoid adverse effects (each seen in 19.4% of cases) included osteoporosis, weight gain, cataracts or hypertension, whilst diabetes, neuropsychiatric symptoms or sleep disturbance were each reported in 16.1% of cases. The majority of patients with ocular involvement had cranial symptoms (71%). Patients with ocular involvement tended to be referred earlier than those with no ocular involvement (478.2 days vs 648.1 days), were on a higher dose of glucocorticoids at time of referral (71.4% vs 47.1% on more than 40mg) and had fewer steroid-sparing agents prior to referral. Conclusion All patients approved for TCZ in the GCA MDT fulfilled NHS England criteria for either relapsing or refractory disease. The majority of cases had cranial disease, but almost half had either ocular or large vessel vasculitis involvement, reflecting a severe spectrum of disease. Cases showed a high burden of glucocorticoid toxicity. Patients with ocular involvement were referred slightly earlier with less use of other steroid sparing treatments prior to TCZ in our cohort. Disclosure C. Jayatilleke: None. S. Janagan: None. R. Marshall: Other; Has received sponsorship from UCB Pharma to attend educational conferences in the last 2 years. S. Skeoch: None. C.M. Guly: None. F. En Sin: None. L. AL Sweedan: None. A. Anilkumar: None. K. Austin: None. A. Bourn: None. L. Clarke: None. H. Gunawardena: None. A. Johnson: None. S. Knights: None. J.D. Pauling: None. E. Reilly: None. T.D. Reynolds: None. S. Villar: None. J.C. Robson: None.

Reciprocal effect of microRNA-224 on osteogenesis and adipogenesis in steroid-induced osteonecrosis of the femoral head.

The adverse effects of glucocorticoids (GCs) on bone marrow stromal stem cells (BMSCs) play an important role in steroid-induced osteonecrosis of the femoral head (ONFH). Our previous miRNA microarray analysis indicated that microRNA-224-5p (miR-224-5p) could be a potential regulator; however, the underlying mechanism remains unclear. In the present study, we demonstrated that miR-224-5p was upregulated in GC-treated BMSCs, and functional experiments revealed that miR-224-5p could suppress osteogenic but promote adipogenic differentiation of BMSCs. Smad4 was identified as a direct target gene of miR-224-5p, and the Smad4-Taz axis was confirmed as the regulatory pathway for adipo-osteogenic differentiation of BMSCs. Our in vivo experiments further confirmed that the miR-224-5p antagomir could alleviate the inhibitory effects of GCs and facilitate bone formation in steroid-induced ONFH models. Therefore, these findings provide insight into the function of miR-224-5p as a reciprocal regulator of the adipo-osteogenic differentiation of BMSCs, and it could serve as a novel therapeutic target for steroid-induced ONFH.

Role of GILZ in the Kidney and the Cardiovascular System: Relevance to Cardiorenal Complications of COVID-19.

Glucocorticoids are extensively used for a variety of conditions, including those associated with dysregulation of immune and inflammatory responses as primary etiopathogenic factors. Indeed, the proinflammatory cytokine storm of coronavirus disease 2019 (COVID-19) is the latest condition for which the use of a glucocorticoid has been advocated. Recognition of serious adverse effects of glucocorticoids has led to research aimed at unraveling molecular basis by which they impact immune and inflammatory events with the ultimate objective of devising novel therapies to circumvent glucocorticoids-related adverse outcomes. Consequently, glucocorticoid-induced leucine zipper (GILZ) protein was discovered and is increasingly recognized as the pivotal regulator of the effects of glucocorticoids on immune and inflammatory responses. Importantly, the advent of GILZ-based options raises the prospect of their eventual therapeutic use for a variety of conditions accompanied with dysregulation of immune and inflammatory responses and associated target organ complications. Thus, the objective of this minireview is to describe our current understanding of the role of GILZ in the cardiovascular system and the kidney along with outcome of GILZ-based interventions on associated disorders. This information is also of relevance for emerging complications of COVID-19. SIGNIFICANCE STATEMENT: Glucocorticoid-induced leucine zipper (GILZ) was initially discovered as the pivotal mediator of immune regulatory/suppressive effects of glucocorticoids. Since the use of glucocorticoids is associated with serious adverse effects, GILZ-based formulations could offer therapeutic advantages. Thus, this minireview will describe our current understanding of the role of GILZ in the kidney and the cardiovascular system, which is of relevance and significance for pathologies affecting them, including the multiorgan complications of coronavirus disease 2019.

Efficacy of methotrexate in polymyalgia rheumatica in routine rheumatology clinical care.

Current guidelines recommend methotrexate (MTX) as a glucocorticoid-sparing agent in patients with polymyalgia rheumatica (PMR) who relapse or suffer glucocorticoid adverse effects, although there is no level 1 evidence to support this recommendation. To review the effect of MTX in PMR on inflammation and glucocorticoid dose. Patients with PMR from rheumatology outpatient clinics at two tertiary centres were identified. A structured case note review was conducted for patient characteristics at diagnosis and medications including glucocorticoid and MTX use. There were 70 patients, 61% female; mean (range) age of 70 (51-87) years. At the time of diagnosis, median (±interquartile range) erythrocyte sedimentation rate (ESR) was 38.5 (26-74) mm/h and C-reactive protein (CRP) 34.5 (6-74 mg/L) with median initiating prednisolone dose of 15 mg (range 5-60 mg). MTX was prescribed in 22 (31%) patients. Mean disease duration at MTX initiation was 2.5 years (1-7 years), with median (range) MTX dose of 10 mg (5-20 mg). At MTX initiation, median (interquartile range) (±standard deviation) ESR was 33 (13-60 mm/h) and CRP 19 (8-42 mg/L). Reasons for commencing MTX were disease relapse (34%) or inability to wean prednisolone dose (66%). Six months after MTX initiation, there was significant reduction in ESR (P = 0.012), CRP (P = 0.0003) and prednisolone dose (P < 0.0001). Eleven (50%) patients stopped MTX, five due to controlled PMR, and six due to adverse effects. In this study of PMR patients in tertiary care, 31% were co-prescribed MTX, after prolonged disease duration. MTX was associated with improved inflammatory activity and reduced prednisolone dose, with a relatively high risk of adverse events.

A pilot study to identify perceived barrier and motivating factors of primary veterinarians in the USA for specialty referral and management of atopic dermatitis with allergen-specific immunotherapy.

Allergen-specific immunotherapy (ASIT) may decrease clinical signs and potential neosensitization in dogs with canine atopic dermatitis (cAD). Identification of barriers to referral and specialty level case management may improve clinical outcome and satisfaction for both clients and primary veterinarians. The objective of this cross-sectional, descriptive, survey-based pilot study was to identify factors influencing a veterinarian's decision to recommend dermatology referral and prescribe ASIT for management of cAD. An online survey was administered to small animal veterinarians through two veterinary associations in the western United States. Participants were asked to rate factors using Likert scales. Of 60 responses, 18 (30%) rarely or never recommended ASIT. The top three factors against recommending ASIT included successful pharmaceutical management (100%), clients' concern for cost (94.4%) and veterinarians' perceptions that immunotherapy is unable to reduce pharmacological dependency (83.4%). The top three motivating factors included concerns for glucocorticoid adverse effects (83.3%), animal/owner quality of life (77.8%) and risk of antimicrobial resistant infection (55.6%). Results of the secondary objective revealed that 19 of 60 (31.7%) respondents rarely or never refer atopic pets to a dermatologist, citing cost of referral, availability of serological testing, and perception of limited benefits as the greatest barriers. Numerous factors appear to influence decisions to recommend referral or ASIT for management of pets with cAD. Further work is needed to determine if these can be generalized to larger populations with a goal of providing suggestions to bridge these gaps and improve outcomes.

According to the 2019 updated European League Against Rheumatism (EULAR) recommendations for the treatment of systemic lupus erythematosus: debatable issues and comments

A diversity of the clinical manifestations of systemic lupus erythematosus (SLE) and its undulating course with alternating remissions and exacerbations make this disease one of the most difficult ones to diagnose, treat, and evaluate the efficiency of therapy. Despite the fact that the recently developed methods for early diagnosis and procedures for combined pathogenetic therapy and monitoring the disease course have led to increases in survival rates (≥90%) and life expectancy in patients with SLE, there are still many unsolved problems. In particular, the treatment for SLE is not yet efficient enough and the activity of the latter cannot be completely controlled. The relapsing and remitting course of SLE concurrent with comorbidity, as well as the adverse effects of glucocorticoids and immunosuppressants contribute to the accumulation of irreversible organ damages. The paper is devoted to a review of the updated EULAR recommendations for the treatment of systemic lupus erythematosus, which were published in 2019. It presents comments and debatable issues, by taking into account the Russian recommendations for the treatment of SLE.

A Jack of All Trades: Impact of Glucocorticoids on Cellular Cross-Talk in Osteoimmunology.

Glucocorticoids (GCs) are known to have a strong impact on the immune system, metabolism, and bone homeostasis. While these functions have been long investigated separately in immunology, metabolism, or bone biology, the understanding of how GCs regulate the cellular cross-talk between innate immune cells, mesenchymal cells, and other stromal cells has been garnering attention rather recently. Here we review the recent findings of GC action in osteoporosis, inflammatory bone diseases (rheumatoid and osteoarthritis), and bone regeneration during fracture healing. We focus on studies of pre-clinical animal models that enable dissecting the role of GC actions in innate immune cells, stromal cells, and bone cells using conditional and function-selective mutant mice of the GC receptor (GR), or mice with impaired GC signaling. Importantly, GCs do not only directly affect cellular functions, but also influence the cross-talk between mesenchymal and immune cells, contributing to both beneficial and adverse effects of GCs. Given the importance of endogenous GCs as stress hormones and the wide prescription of pharmaceutical GCs, an improved understanding of GC action is decisive for tackling inflammatory bone diseases, osteoporosis, and aging.

A qualitative study of patient perspectives related to glucocorticoid therapy in polymyalgia rheumatica and giant cell arteritis.

ObjectiveTo determine patient experiences of glucocorticoid (GC) therapy in polymyalgia rheumatica (PMR) and giant cell arteritis (GCA).MethodsPatients with a diagnosis of PMR or GCA were invited to participate in this qualitative study that used focus groups to explore: symptoms onset, process of diagnosis, treatment, adverse effects (AEs), and ongoing condition/s management. Data were transcribed verbatim and a “framework” approach was used for analysis and interpretation.ResultsFourteen patients participated. Weight gain, changes in face and neck shape, and bruising were commonly reported and impacts of these AEs on quality of life were highlighted. Dealing with uncertainties associated with long-term experiences of the condition/s and cycles of GC treatment were raised as were workload demands for patients in managing both the condition and other people’s expectations and recommendations related to GC therapy.ConclusionThese findings demonstrate that the patient experience of GC use is poorly captured by usual physician monitoring for GC AEs. These findings suggest that development of a patient-reported outcome instrument for inflammatory conditions treated with GCs is required.

A Survey of Glucocorticoid Adverse Effects and Benefits in Rheumatic Diseases: The Patient Perspective.

The aim of this study was to explore, from the patient's perspective, the beneficial and adverse effects (AEs) of glucocorticoids (GCs) in patients with rheumatic diseases, to be used in the development of a patient-reported outcome measure. A cross-sectional survey, capturing benefits and AEs of GC use, was administered to 2 groups of patients: (1) those attending a tertiary rheumatology clinic with various rheumatic diseases who had used GCs within the past year and (2) patients from the Hospital for Special Surgery rheumatoid arthritis database. Cohort 1 had 55 GC users, and cohort 2 had 95 GC users and 29 nonusers. The majority of GC users in both cohorts reported at least 1 AE (100%, 86%). The AE prevalence per person was 50% higher in cohort 1 compared with GC users in cohort 2 (7.7 vs. 5.3; AE ratio, 1.5; 95% confidence interval, 1.3-1.7) and 2-fold greater in cohort 2 GC users compared with GC nonusers (5.3 vs. 2.6; AE ratio, 2.0; 95% confidence interval, 1.6-2.6). In both cohorts, AEs identified as "worst" by GC users included skin thinning/easy bruising, sleep disturbance, mood disturbance, and change in facial shape. Most felt GCs helped their disease "a lot" (78%/62%) and that the benefits were greater than the AEs (55%/64%). Many AEs were more frequent in GC users than in nonusers. Patients receiving GC therapy for rheumatic conditions report a large number of AEs and those that have the greatest life impact are often difficult for physicians to measure. These results will inform the development of a patient-reported outcome measure to capture the effects of GCs from the patient's perspective.

Will we ever have better glucocorticoids?

Glucocorticoids are cost-effective drugs with potent anti-inflammatory and immunosuppressive effects. They are used successfully to treat many disorders, including rheumatoid arthritis, polymyalgia rheumatic and other rheumatic diseases. However, these drugs also have the potential to cause adverse effects, particularly if high doses are used for prolonged periods. Therefore, continuous efforts are being made to implement recommendations for optimal dosing of glucocorticoids, monitoring for potential adverse events, adverse event prevention and management. Apart from this, novel and interesting work is underway to develop innovative glucocorticoids or glucocorticoid receptor ligands in order to improve the therapeutic balance. This article briefly mentions a recent publication discussing the question under which conditions long-term treatment with glucocorticoids has an acceptably low level of harm, and focuses then on two current approaches to minimize glucocorticoid adverse effects while keeping or even enhancing their anti-inflammatory efficacy, liposomal glucocorticoids and dissociated agonists of the glucocorticoid receptor.

Synthesis of novel steroidal agonists, partial agonists, and antagonists for the glucocorticoid receptor

Adverse effects of glucocorticoids could be limited by developing new compounds that selectively modulate anti-inflammatory activity of the glucocorticoid receptor (GR). We have synthesized a novel series of steroidal GR ligands, including potent agonists, partial agonists and antagonists with a wide range of effects on inhibiting secretion of interleukin-6. Some of these new ligands were designed to directly impact conformational stability of helix-12, in the GR ligand-binding domain (LBD). These compounds modulated GR activity and glucocorticoid-induced gene expression in a manner that was inversely correlated to the degree of inflammatory response. In contrast, compounds designed to directly modulate LBD epitopes outside helix-12, led to dissociated levels of GR-mediated gene expression and inflammatory response. Therefore, these new series of compounds and their derivatives will be useful to dissect the ligand-dependent features of GR signaling specificity.

Glucocorticoids for Management of Polymyalgia Rheumatica and Giant Cell Arteritis.

Diagnosis of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) is based on typical clinical, histologic, and laboratory features. Ultrasonographic imaging in PMR with assessment especially of subdeltoid bursitis can aid in diagnosis and in following response to treatment. In GCA, diagnosis and disease activity are supported with ultrasonographic, MRI, or [(18)F]fluorodeoxyglucose PET evaluation of large vessels. Glucocorticoids are the primary therapy for PMR and GCA. Methotrexate may be used in patients at high risk for glucocorticoid adverse effects and patients with frequent relapse or needing protracted therapy. Other therapeutic approaches including interleukin 6 antagonists are under evaluation.