High Glucocorticoid Research Articles

Favourable outcome of acute hepatitis E infection in patients with ANCA-associated vasculitis

BackgroundHepatitis E virus (HEV) infection is a frequent cause of acute viral hepatitis. Immunocompromised patients are at increased risk for viral infection and chronic courses of hepatitis. Whether patients with autoimmune diseases are at risk of developing clinically relevant hepatitis or even chronic liver disease after HEV infection is discussed controversially. ANCA-associated vasculitis is a rare autoimmune disease with potentially life-threatening organ involvement, thus requiring intensive immunosuppression with glucocorticoids, cyclophosphamide, or rituximab. As there are no reports available on the infection with HEV in patients with ANCA-associated vasculitis, clinical decision making in such cases is based on experiences from other disease entities. Therefore, in this study we analyzed the course of liver disease and the therapeutic management of autoimmune vasculitis in a retrospective cohort of five patients with ANCA-associated vasculitis and acute hepatitis E.ResultsFour patients were on immunosuppressive maintenance therapy and one patient was on remission induction therapy with cyclophosphamide and high dose glucocorticoids. All patients had at least one potentially hepatotoxic co-medication at the time of hepatitis. Hepatitis-associated clinical symptoms were recorded in four of five patients. The course of hepatitis was characterized by strongly elevated transaminases, a temporary liver failure was observed in one case. The management of hepatitis E included cessation of the immunosuppressants in all patients, whereas oral glucocorticoids were not discontinued. Under this regime, all patients cleared the virus without additional anti-viral treatment. Liver enzymes normalized one month after they peaked. In the follow-up period of at least 1.5 years (range 1.5–12 years), no chronic liver disease was observed, although one patient died of cholangiocarcinoma with liver metastases some years after HEV infection. Vasculitis was not active in our patient cohort at the time of HEV infection. However, inflammatory flares occured in three of five patients after discontinuation of the immunosuppressive therapy. Immunosuppressants were paused for a median time of 4 weeks and after their resumption vasculitic disease activity was controlled in all patients.ConclusionsAcute HEV infection in patients with ANCA-associated vasculitis shows a favorable outcome of liver disease but bears the risk of inflammatory flares due to cessation of immunosuppression.

225P Ovarian cancer-cell glucocorticoid receptor activity modulates cytokine secretion promoting infiltration of immunosuppressive cells into the tumor microenvironment

Immunosuppressive myeloid-derived suppressor cells (MDSCs) have recently been identified as a heterogeneous cell population that expand during tumor-associated inflammation and are significantly increased in the tumor, peripheral blood, as well as ascites of ovarian cancer patients. MDSCs contribute to tumor immune tolerance via inhibition of T-cell proliferation and activation. Signals from the tumor microenvironment in the form of soluble cytokines lead to MDSC infiltration. It is also known that high tumor cell glucocorticoid receptor (GR) expression is associated with a relatively poor prognosis in ovarian cancer patients.

Senescence-associated secretory proteins induced in lung adenocarcinoma by extended treatment with dexamethasone enhance migration and activation of lymphocytes.

There is a need to improve response rates of immunotherapies in lung adenocarcinoma (AC). Extended (7-14days) treatment of high glucocorticoid receptor (GR) expressing lung AC cells with dexamethasone (Dex) induces an irreversible senescence phenotype through chronic induction of p27. As the senescence-associated secretory phenotype (SASP) may have either tumor supporting or antitumor immunomodulatory effects, it was interest to examine the effects of Dex-induced senescence of lung AC cells on immune cells. Dex-induced senescence resulted in sustained production of CCL2, CCL4, CXCL1 and CXCL2, both in vitro and in vivo. After Dex withdrawal, secretion of these chemokines by the senescent cells attracted peripheral blood monocytes, T-cells, and NK cells. Following treatment with Dex-induced SASP protein(s), the peripheral blood lymphocytes exhibited higher cell count and tumor cytolytic activity along with enhanced Ki67 and perforin expression in T and NK cells. This cytolytic activity was partially attributed to NKG2D, which was upregulated in NK cells by SASP while its ligand MICA/B was upregulated in the senescent cells. Enhanced infiltrations of T and NK cells were observed in human lung AC xenografts in humanized NSG mice, following treatment with Dex. The findings substantiate the idea that induction of irreversible senescence in high-GR expressing subpopulations of lung AC tumors using Dex pretreatment enhances tumor immune infiltration and may subsequently improve the clinical outcome of current immunotherapies.

PSAT277 Glucocorticoid Therapy for Management of Hypoglycemia in the context of Non-Islet Cell Tumor-Induced Hypoglycemia

Abstract Background Non-islet cell tumor-induced hypoglycemia (NICTH) is a rare paraneoplastic syndrome which can cause recurrent hypoglycemia. There is no clear standard of care for management of hypoglycemia. Often, these patients have high morbidity and therefore surgical tumor resection is not always possible. Clinical case: This is the case of a 69 year-old male presenting with altered mental status in the context of hypoglycemia without clear etiology with an initial serum glucose level of 32 mg/dL (normal range 60-100 mg/dL) which quickly corrected after administration of intravenous glucose. He was found to have a large bowel obstruction with CT abdomen revealing an underlying neoplasm. Biopsy of suspected lesion on colonoscopy revealed colorectal adenocarcinoma. Repeated episodes of hypoglycemia complicated by seizures required inpatient management. Workup included serum insulin level which resulted in suppressed level (<1. 0 uU/mL, normal range 1.9-23. 0 uU/mL), low c-peptide level (0.1 ng/mL, normal range 1.1-4.4 ng/mL), low beta hydroxybutyrate level (0. 07 mmol/L, normal level <0.3 mmol/L), cortisol level of 43.7 mcg/dL, undetectable insulin like growth factor-1 (IGF-1) level (<10 ng/mL, normal range 59-230 ng/mL) and low insulin like growth factor-2 (IGF-2) level (66 ng/mL, normal range 333 - 967 ng/mL). IGF2: IGF1 ratio was 66 (ratio >10 is indicative for diagnosis of non-islet cell tumor hypoglycemia). Due to extremely poor oral intake and recurrent episodes of hypoglycemia despite continuous dextrose infusion, the patient was started on 20 mg prednisone daily. Eventually, 40 mg of intravenous methylprednisolone in addition to dextrose infusion was needed as maintenance therapy effectively preventing hypoglycemia. Given his poor functional status, the surgical and oncology team decided he was no longer a surgical or chemotherapy candidate. Eventually, palliative medicine was consulted and the patient was transitioned to comfort care with a plan for outpatient hospice. Conclusion NICTH should be suspected in any patient with hypoglycemia without clear etiology, especially if there are suggestions to NICTH such as known malignancy or newly diagnosed mass. Once NICTH is identified and a primary tumor is found, complete tumor resection represents ideal management, however, not always attainable. In such cases, dextrose infusion might be insufficient to prevent hypoglycemia and is not always the preferred option given the required long-term venous access. In these circumstances, early high dose glucocorticoids are safe and appear to successfully prevent hypoglycemic events. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

OR22-6 Ovarian Cancer Cell Glucocorticoid Receptor Activity Is Associated With Cytokine Secretion Promoting Infiltration of Immunosuppressive Cells Into the Tumor Microenvironment

Abstract Immunosuppressive cells abundantly infiltrate tumors during cancer progression. Notably, immunosuppressive myeloid-derived suppressor cells (MDSCs) have recently been identified as a heterogeneous cell population that expand during tumor-associated inflammation and are significantly increased in the tumor, peripheral blood, as well as ascites of ovarian cancer patients. MDSCs contribute to tumor immune tolerance via inhibition of T-cell proliferation and activation. Signals from the tumor microenvironment in the form of soluble cytokines are proposed to lead to MDSC infiltration. It is also known that high tumor cell glucocorticoid receptor (GR) expression is associated with a relatively poor prognosis in ovarian cancer patients. We hypothesized that ovarian cancer cell GR expression and activity may modulate tumor cell cytokine secretion thereby leading to increased MDSC generation and recruitment to the tumor, thereby creating an immunosuppressive environment. Our preliminary data confirm that GR activation in two high-grade ovarian cancer cell lines (HeyA8 and SKOV3) modulates the cytokine secretome. Our results demonstrate GR-mediated secretion of several pro-tumorigenic and immunosuppressive proteins including G-CSF, M-CSF, TGF-b, and MCP-1 in those ovarian cancer models. We also observed downregulation of potent cytotoxic T-cell activating cytokines required for anti-tumor T-cell function including IL-2, IFN-g and MIP1 upon GR activation. Importantly, treatment of cells with a selective GR modulator (SGRM) reverses this immunosuppressive secretome effect. Furthermore, upon culturing healthy peripheral blood mononuclear cells (PBMCs) with tumor conditioned media from GR activated ovarian cancer cells, we show that secreted immunomodulatory factors have the capacity to promote differentiation of human MDSCs from progenitor myeloid cells. The resulting MDSC population was characterized via expression of activation markers including Arginase-1, iNOS, VEGF and TGF-b. Most importantly, the suppressive function of these MDSCs is being evaluated by determining their inhibitory potential on cytotoxic T-cell proliferation and/or activation. Based on the insight provided by these data, we propose to determine whether ovarian tumor cell-intrinsic GR activation and resulting MDSC generation contributes to earlier relapse of GR-positive ovarian cancers, and eventually whether this mechanism may be targeted to improve patient outcomes in this subset of ovarian cancers. Presentation: Monday, June 13, 2022 12:15 p.m. - 12:30 p.m.

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.

Brain structure in autoimmune Addison's disease.

Long-term disturbances in cortisol levels might affect brain structure in individuals with autoimmune Addison's disease (AAD). This study investigated gray and white matter brain structure in a cohort of young adults with AAD. T1- and diffusion-weighted images were acquired for 52 individuals with AAD and 70 healthy controls, aged 19-43years, using magnetic resonance imaging. Groups were compared on cortical thickness, surface area, cortical gray matter volume, subcortical volume (FreeSurfer), and white matter microstructure (FSL tract-based spatial statistics). Individuals with AAD had 4.3% smaller total brain volume. Correcting for head size, we did not find any regional structural differences, apart from reduced volume of the right superior parietal cortex in males with AAD. Within the patient group, a higher glucocorticoid (GC) replacement dose was associated with smaller total brain volume and smaller volume of the left lingual gyrus, left rostral anterior cingulate cortex, and right supramarginal gyrus. With the exception of smaller total brain volume and potential sensitivity of the parietal cortex to GC disturbances in men, brain structure seems relatively unaffected in young adults with AAD. However, the association between GC replacement dose and reduced brain volume may be reason for concern and requires follow-up study.

FKBP5 intron 7 methylation is associated with higher anxiety proneness and smaller right thalamus volume in adolescents.

Dysregulation of stress response systems may mediate the detrimental effects of childhood trauma (CT) on mental health. FKBP5 regulates glucocorticoid receptor sensitivity and exerts pleiotropic effects on intracellular signaling, neurobiology and behavior. We investigated whether CT, alone and in combination with rs1360780 genotype, is associated with altered FKBP5 methylation and whether CT-associated methylation profiles are associated with anxiety proneness (AP) and structural brain volumes. Ninety-four adolescents completed the Childhood Trauma Questionnaire, and a composite AP score was generated from the Childhood Anxiety Sensitivity Index and the State-Trait Anxiety Inventory-Trait measure. Mean methylation values for 12 regulatory regions and 25 individual CpG sites were determined using high-accuracy measurement via targeted bisulfite sequencing. FKBP5 rs1360780 genotype and structural MRI data were available for a subset of participants (n = 71 and n = 75, respectively). Regression models revealed an inverse association between methylation of three intron 7 CpG sites (35558438, 35558566 and 35558710) and right thalamus volume. CpG35558438 methylation was positively associated with AP scores. Our data indicate that an intron 7 methylation profile, consistent with lower FKBP5 expression and elevated high sensitivity glucocorticoid receptor levels, is associated with higher AP and smaller right thalamus volume. Research into the mechanisms underlying the intron 7 methylation-thalamus volume relationship, and whether it confers increased risk for long-term psychopathology by altering the regulatory threshold of stress responding, is required.

BLUE FINGERS, EOSINOPHILIC LUNGS: ACUTE EOSINOPHILIC PNEUMONIA FOLLOWING COVID-19 INFECTION

BLUE FINGERS, EOSINOPHILIC LUNGS: ACUTE EOSINOPHILIC PNEUMONIA FOLLOWING COVID-19 INFECTION

Intracranial Bleeding as Primary Manifestation of Antiphospholipid Syndrome: Case Report

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder usually resulting in an increased risk of blood clots in the arterial-, venous-, or microvascular system. Various antibodies have been identified causing the activation and aggregation of thrombocytes and endothelial dysfunction resulting in a wide range of symptoms. Frequent manifestation may be arterial or venous clots in extremities or internal organs, neurological manifestation or pregnancy morbidities. Rarely, APS can manifest in the form of hemorrhage. We discuss the case of a 40-year-old male presenting with a severe headache, fatigue and fever. Head CT confirmed a subdural hematoma. Laboratory findings showed anemia, thrombocytopenia and elongated coagulation times. Immunoserology found the strong presence of lupus anticoagulant, anti-cardiolipin-, and anti-β2glycoprotein-I IgG antibodies confirming the diagnosis of primary antiphospholipid syndrome, specifically LA - hypoprothrombinemia syndrome. Following the administration of high dose glucocorticoids, we chose to give intravenous immunoglobulin followed by rituximab. Although his symptoms regressed and there was no further hemorrhaging, we chose to perform plasmapheresis due to continuously high concentration of anti- phospholipid antibodies to lower the antibody titer, which proved to be effective. Antithrombotic treatment can be challenging in such cases due to the co-occurrence of hypoprothrombinemia and prothrombotic antibodies. We decided to administer low-dose aspirin, with which the patient has no bleeding or blood clots for over 6 years. We find the case worth presenting due to the rare occurance of bleeding as primary manifestation of APS and due to the challenging treatment.

Individual variation, personality, and the ability of animals to cope with climate change

The Sixth Assessment of the Intergovernmental Panel on Climate Change describes negative effects of climate change on animals occurring on a larger scale than previously appreciated. Animal species are increasingly experiencing more frequent and extreme weather in comparison with conditions in which the species evolved. Individual variation in behavioural and physiological responses of animals to stimuli from the environment is ubiquitous across all species. Populations with relatively high levels of individual variation are more likely to be able to survive in a range of environmental conditions and cope with climate change than populations with low levels of variation. Behavioural and physiological responses are linked in animals, and personality can be defined as consistent individual behavioural and physiological responses of animals to changes in their immediate environment. Glucocorticoids (cortisol and corticosterone) are hormones that, in addition to metabolic roles, are released when the neuroendocrine stress system is activated in response to stimuli from the environment perceived to be threatening. The size of a glucocorticoid response of an animal is an indication of the animal’s personality. Animals with reactive personalities have relatively high glucocorticoid responses, are relatively slow and thorough to explore new situations, and are more flexible and able to cope with changing or unpredictable conditions than animals with proactive personalities. Animals with reactive personalities are likely to be better able to cope with environmental changes due to climate change than animals with proactive personalities. A reaction norm shows the relationship between phenotype and environmental conditions, with the slope of a reaction norm for an individual animal a measure of phenotypic plasticity. If reaction norm slopes are not parallel, there is individual variation in plasticity. Populations with relatively high individual variation in plasticity of reaction norms will have more animals that can adjust to a new situation than populations with little variation in plasticity, so are more likely to persist as environments change due to climate change. Future studies of individual variation in plasticity of responses to changing environments will help understanding of how populations of animals may be able to cope with climate change.

Thyrotoxic Periodic Paralysis in the Post-COVID Era: A Case Report with Literature Review

Thyrotoxic Periodic Paralysis (TPP) is an acute potentially lethal emergency in patients with hyperthyroidism who present with sudden muscle weakness and hypokalemia. It is commonly precipitated by high carbohydrate or high salt content meals, strenuous exercise, stress, trauma, glucocorticoids, epinephrine, alcohol, or respiratory infections. COVID-19 infection or vaccination may represent a novel trigger for TPP. Furthermore, COVID-19 infection or vaccination may incite inflammatory processes leading to thyrotoxicosis, which can manifest as TPP. While COVID-19 causing subacute thyroiditis, euthyroid sick syndrome, Hashimoto’s disease, or Graves’ disease have been well documented in the literature; there have only been six case reports of post-COVID-19 TPP. Notably, all cases thus far have been restricted to male patients, and there is paucity of literature from North America. The purpose of this paper is to outline the first case of post-COVID-19 TPP in a female patient, who presented to the emergency department with acute paralysis and severe hypokalemia (2.2 mmol/L) three months after COVID-19 infection. Investigations in the emergency department showed thyrotoxicosis. She was treated with potassium replacement, which improved her paralysis. Subsequent investigations revealed severe hyperthyroidism from Graves’ disease, which is currently managed with metoprolol and methimazole. Her hyperthyroidism improved without recurrent hypokalemia or paralysis. In addition, we outline the epidemiology, pathophysiology, precipitants, and management of TPP, with a particular focus on COVID-19 infection or vaccination precipitating TPP. We discuss post-COVID-19 TPP cases thus far described in the literature. Knowing that North American COVID-19 infection waves lagged Asia, we could anticipate additional future TPP cases.

First Trimester Dexamethasone Treatment Is Not Associated With Alteration in Resting-state Connectivity at Adolescent or Adult Age.

ContextPrenatal treatment with dexamethasone (DEX) has been used to prevent virilization in females at risk of congenital adrenal hyperplasia (CAH). Both affected and unaffected girls, as well boys, are treated until the genotype and sex of the fetus is known (gestational weeks 10-12). After that, only affected girls are treated until term. Exposure to a high synthetic glucocorticoid dosage may alter the developmental trajectory of the brain, with alterations in resting-state functional connectivity of the brain at adult age.ObjectiveTo investigate resting-state functional connectivity in subjects at risk of having CAH, exposed to DEX treatment during the first trimester of fetal life, both in the whole brain and in 3 regions of interest (amygdala, hippocampus, and superior frontal gyrus).Design, Setting, and ParticipantsEighteen participants (8 females) at risk of having CAH, exposed to DEX treatment, and 38 controls (24 females), age range 16 to 26 years, from a single research institute, underwent functional magnetic resonance imaging of the brain during rest. We used 2 different approaches: an exploratory whole-brain analysis and seed-based analysis. For seed-based analysis, we chose 3 different brain regions (amygdala, hippocampus, and superior frontal gyrus) based on our previous findings and literature evidence.ResultsWe did not observe any differences in functional connectivity during rest, either in the whole brain nor in seed-based connectivity analyses at this adolescent and young adult age.ConclusionsOur results are reassuring; however, future studies on larger samples and with more sensitive methodologies are needed to confirm these findings.

C/EBPα regulates the fate of bone marrow mesenchymal stem cells and steroid-induced avascular necrosis of the femoral head by targeting the PPARγ signalling pathway

BackgroundThe imbalance of osteogenic/adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is closely related to steroid-induced avascular necrosis of the femoral head (SANFH). We aimed to investigate the epigenetic mechanism of intramedullary fat accumulation and continuous osteonecrosis after glucocorticoid (GC) withdrawal in SANFH.MethodsAn SANFH model was established in SD rats, which received an intermittent high GC dose for the first 4 weeks followed by an additional 4 weeks without GC. We explored the synergistic effects and mechanisms of C/EBPα and PPARγ on the differentiation of BMSCs by lentivirus-mediated gene knockdown and overexpression assays. A chromatin immunoprecipitation assay was performed to identify epigenetic modification sites on PPARγ in vivo and in vitro.ResultsIn the SANFH model, intramedullary fat was significantly increased, and the transcription factors C/EBPα and PPARγ were upregulated simultaneously in the femoral head. In vitro, C/EBPα promoted adipogenic differentiation of BMSCs by targeting the PPARγ signalling pathway, while overexpression of C/EBPα significantly impaired osteogenic differentiation. Further studies demonstrated that histone H3K27 acetylation of PPARγ played an important role in the epigenetic mechanism underlying SANFH. C/EBPα upregulates the histone H3K27 acetylation level in the PPARγ promoter region by inhibiting HDAC1. Additionally, inhibiting the histone acetylation level of PPARγ effectively prevented adipogenic differentiation, thus slowing the progression of SANFH.ConclusionsOur results demonstrate the molecular mechanism by which C/EBPα regulates PPARγ expression by acetylating histones and revealed the epigenetic phenomenon in SANFH for the first time.Graphical abstract

Is an increase of glucocorticoid concentrations related to the degree of arousal or valence experienced by an animal to a stimulus?

Animal welfare is the quality of life as perceived by the animal itself. It is also the state of an animal in its attempt to cope with its environment. Animal welfare has high ethics and economic importance. Thus the need to develop parameters for assessing animal welfare. An acute increase in glucocorticoid (GC) concentration is necessary for adaptation to a stressful situation. Glucocorticoids also play a significant role in metabolic, cardiovascular, and immune systems. Glucocorticoid enhances effective learning through the hippocampus and other normal body functions. That is why we remember events (either positive or negative) associated with strong emotions. Long-term secretion of GCs has catabolic effects. Thus, affecting animal health. Measuring GC is one of the ways of assessing animal welfare. But, high GC concentration does not only indicate pain or suffering. We report that stress and emotion trigger similar physiological responses. So, measuring GC levels cannot differentiate between positive and negative states. We conclude that GC shows circadian rhythms and episodic spikes in some species. Values from a single sample point are not reliable to make conclusions about a condition. Training animals for blood collection may reduce stress. Thus not causing bias in the GC concentration measured.

Abstract 1335: Ovarian cancer cell glucocorticoid receptor activity is associated with cytokine secretion promoting infiltration of immunosuppressive cells into the tumor microenvironment

Abstract Immunosuppressive cells abundantly infiltrate tumors during cancer progression. Notably, immunosuppressive myeloid-derived suppressor cells (MDSCs) have recently been identified as a heterogeneous cell population that expand during tumor-associated inflammation and are significantly increased in the tumor, peripheral blood, as well as ascites of ovarian cancer patients. MDSCs contribute to tumor immune tolerance via inhibition of T-cell proliferation and activation. Signals from the tumor microenvironment in the form of soluble cytokines are proposed to lead to MDSC infiltration. It is also known that high tumor cell glucocorticoid receptor (GR) expression is associated with a relatively poor prognosis in ovarian cancer patients. We hypothesized that ovarian cancer cell GR expression and activity may modulate tumor cell cytokine secretion thereby leading to increased MDSC generation and recruitment to the tumor, eventually creating an immunosuppressive environment. Our preliminary data confirm that GR activation in two high-grade ovarian cancer cell lines (HEYA8 and SKOV3) modulates the cytokine secretome. Our results demonstrate GR-mediated secretion of several pro-tumorigenic and immunosuppressive proteins including G-CSF, M-CSF, TGF-β, and MCP-1 in those ovarian cancer models. We also observed downregulation of potent cytotoxic T-cell activating cytokines required for anti-tumor T-cell function including IL-2, IFN-γ and MIP1 upon GR activation. Importantly, treatment of cells with a competitive GR antagonist reverses this immunosuppressive secretome effect. Furthermore, upon culturing healthy peripheral blood mononuclear cells (PBMCs) with tumor conditioned media from GR activated ovarian cancer cells, we show that secreted immunomodulatory factors have the capacity to promote differentiation of human MDSCs from PBMCs. The resulting MDSC population was characterized via expression of activation markers including Arginase-1, iNOS, VEGF and TGF-β. Most importantly, the suppressive function of these MDSCs is being evaluated by determining their inhibitory potential on cytotoxic T-cell proliferation and/or activation. Based on the insight provided by these data, we propose to determine whether ovarian tumor cell-intrinsic GR activation and resulting MDSC generation contributes to earlier relapse of GR-positive ovarian cancers, and eventually whether this mechanism may be targeted to improve patient outcomes in this subset of ovarian cancers. Citation Format: Manisha Taya, Janet Gonzalez, Lynda Bennett, Suzanne D. Conzen. Ovarian cancer cell glucocorticoid receptor activity is associated with cytokine secretion promoting infiltration of immunosuppressive cells into the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1335.

Differential Changes in Circulating Steroid Hormones in Hibernating Brown Bears: Preliminary Conclusions and Caveats.

Brown bears are obese when they enter the den, and after 6 mo of hibernation and physical inactivity, bears show none of the adverse consequences of a sedentary lifestyle in humans, such as cardiovascular disease, type 2 diabetes, and kidney failure. The metabolic mechanisms that drive hibernation physiology in bears are poorly defined, but systemic endocrine regulators are likely involved. To investigate the potential role of steroid hormones, we quantified the total levels of 12 steroid hormones, the precursor cholesterol, sex hormone-binding globulin (SHBG), and corticosterone-binding globulin (CBG) in paired serum samples from subadult free-ranging Scandinavian brown bears during the active and hibernation states. During hibernation, androstenedione and testosterone were significantly decreased in subadult female bears (), whereas they increased in all males but one () and therefore did not reach a significant difference. Despite this difference, SHBG increased more than 20-fold during hibernation for all bears. Compared with SHBG concentrations in humans, bear levels were very low in the active state, but during hibernation, levels equaled high levels in humans. The increased SHBG levels likely maintain a state of relative quiescence of the reproductive hormones in hibernating bears. Interestingly, the combination of SHBG and testosterone levels results in similar free bioavailable testosterone levels of 70-80 pM in both subadult and adult sexually active male bears, suggesting a role for SHBG in controlling androgen action during hibernation in males. Dehydroepiandrosterone sulfate, dihydrotestosterone, and estradiol levels were below the detection limit in all but one animal. The metabolically active glucocorticoids were significantly higher in both sexes during hibernation, whereas the inactive metabolite cortisone was reduced and CBG was low approaching the detection limit. A potential caveat is that the glucocorticoid levels might be affected by the ketamine applied in the anesthetic mixture for hibernating bears. However, increased hibernating cortisol levels have consistently been reported in both black bears and brown bears. Thus, we suggest that high glucocorticoid activity may support the hibernation state, likely serving to promote lipolysis and gluconeogenesis while limiting tissue glucose uptake to maintain a continuous glucose supply to the brain.

Systemic glucocorticoid-free therapy with adalimumab plus immunosuppressants versus conventional therapy in treatment-naïve Vogt-Koyanagi-Harada disease patients.

BackgroundHigh dose systemic glucocorticoid is the main therapy of treatment-naïve Vogt-Koyanagi-Harada (VKH) disease. However, series side effects induced by high dose systemic glucocorticoid frequently occur, which makes alternative therapy necessary for certain patients. This study sought to compare the efficacy and safety of systemic glucocorticoid-free (SGF) therapy with conventional therapy (CT) as an initial treatment for VKH patients.MethodsVKH patients who had not been systemically treated were enrolled. Patients were allocated into 2 therapeutic groups depending on their treatments. In CT group, patients received systemic glucocorticoid plus immunosuppressants (IS), and in SGF group, patients received adalimumab (ADA) plus IS. Patients received approximately 12 months treatment and visit monthly. The outcome parameters included the changes of best-corrected visual acuity (BCVA), intraocular inflammation (including anterior chamber cell grade and vitritis grade) and central macular thickness (CMT) (the change values define as the final-visit values subtracted from baseline counterparts). Other outcomes included the relapses times of ocular inflammation, adverse events (AEs), changes of optic nerve inflammation (ONI) and intraocular/extraocular manifestations.ResultsA total of 30 patients (60 eyes) were included. with 19 patients (38 eyes) in CT group and 11 patients (22 eyes) in SGF group. After approximately 1 year of treatment, the improvements of BCVA were slight better in the SGF group (0.57±0.23) than in the CT group (0.40±0.26), (P=0.014). In both groups, the ocular inflammatory improvements in both groups were similar, with an improvement of AC cell grade of −1.5 (−2, −0.5) in CT group versus −1 (−2, −1) in SGF group (P=0.367); improvement of vitritis grade was 0 (−1.25, 0) in CT group and −1 (−1, −1) in SGF group (P=0.050). The improvement in CMT was similar in both groups, with −523.47±412.09 µm in CT group and −362.73±375.73 µm in SGF group (P=0.572). The mean number of relapses was 1 (0, 2) in the CT group and 0 (0, 2) in the SGF group (P=0.372). No severe AEs were observed in this study.ConclusionsSGF therapy is effective, safe, and well-tolerated in treatment-naïve VKH patients. SGF therapy seems to be a feasible option in patients with existing systemic diseases intolerant to glucocorticoid.

1131-P: Progression to Diabetes Despite a Baseline Fasting Plasma Glucose = 80mg/dL: A Population-Based Case-Control Study

While elevations in baseline fasting plasma glucose (FPG) are associated with risk of type 2 diabetes mellitus (DM) , some individuals with lower FPG will also develop DM. The aim of this study was to identify factors associated with DM in people with a baseline FPG of ≤ 80mg/dL. Using the population-based Rochester Epidemiology Project medical records linkage system, we identified subjects with ≥ 2 FPG tests from 2005-17, and a baseline FPG of ≤ 80mg/dL. Subjects who developed DM (FPG > 125mg/dL) were assigned an event date as the date of the 1st diagnostic value. Those who did not develop DM were censored at their last FPG. The median duration of follow-up was 7 years. The entire cohort consisted of 2315 subjects, of whom 130 (5.6%) developed DM. Using a nested case-control design we compared all 130 who progressed to diabetes (cases) to 491 randomly selected controls. Among the cases, 121 (93%) developed type 2 DM, 4 (3%) had type 1 DM, and 5 (4%) reverted to normal FPG on repeat. Cases were older, more commonly male, and had a higher BMI (see table) . Cases were more likely to have experienced a critical health event such as a malignancy diagnosis or exposure to high dose glucocorticoids. On extended follow up, 15% of cases were deceased. In summary, progression to DM in individuals with a low-normal FPG at baseline typically occurs in the context of significant medical comorbidity and portends a poor prognosis. Disclosure S.Mohan: None. A.Vella: Advisory Panel; Crinetics Pharmaceuticals, Inc., Rezolute, Inc., vTv Therapeutics, Zealand Pharma A/S, Other Relationship; Novo Nordisk. A.M.Egan: None.

Systemic lupus erythematosus in the light of the COVID-19 pandemic: infection, vaccination, and impact on disease management.

Patients with systemic lupus erythematosus (SLE) form a vulnerable group in terms of the impact of the COVID-19 pandemic on disease management. We conducted this overview by searches through Medline/PubMed, Scopus, and the Directory of Open Access Journals (DOAJ). The prevalence and severity of COVID-19, efficacy of COVID-19 vaccination, impact on the management of SLE, and the attitudes of SLE patients to COVID-19 and vaccination were explored. After screening and due exclusions, 198 studies were included for the final review. Patients with SLE have a greater risk of acquiring COVID-19 (0.6–22%) and related hospitalization (30%), severe disease (13.5%), and death (6.5%) than the general population. Older age, male gender, comorbidities, moderate or high disease activity, and glucocorticoid, rituximab, and cyclophosphamide use are associated with unfavorable outcomes, whereas methotrexate and belimumab use showed no association with outcomes. COVID-19 vaccines are safe in SLE with minimal risk of severe flares (< 2%). Vaccine efficacy is negatively associated with glucocorticoids. The overall attitude of patients towards vaccination is positive (54–90%). The pandemic has negatively affected access to medical care, hospitalizations, procurement of drugs, employment, and the mental health of patients which need to be addressed as part of holistic care in SLE.Key Points• Lupus patients are at a greater risk of acquiring COVID-19, related hospitalization, severe disease, and death than the general population.• COVID-19 vaccines are relatively safe for lupus patients with minimal risk of severe flares.• Lupus patients’ attitude towards COVID-19 vaccination is predominantly positive.