FOXO1 Single-Nucleotide Polymorphisms Are Associated with Bleeding Severity and Sensitivity of Glucocorticoid Treatment of Pediatric Immune Thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune-mediated hemorrhagic disease. Emerging evidence indicates that FOXO1 SNPs are related to the immune dysregulation of several autoimmune diseases suggesting that FOXO1 may be involved in inflammation and pathologic activities in patients with ITP. This study aimed to evaluate whether FOXO1 gene single-nucleotide polymorphisms (SNPs) are associated with susceptibility to ITP and clinical priorities of concern include bleeding severity and sensitivity of glucocorticoid treatment. This study recruited 327 newly diagnosed ITP and 220 healthy controls. Four SNPs (rs17446593, rs17446614, rs2721068, and rs2721068) of the FOXO1 gene were detected using the Sequenom MassArray system. Bleeding severity were classified into the mild and severe groups based on the bleeding scores. ITP patients were classified as sensitive and insensitive to glucocorticoid treatment according to the practice guideline for ITP (2019 version). The frequencies of the four SNPs did not show any significant differences between the ITP and healthy control groups. Patients with AA genotype at rs17446593 (p = 0.009) and GG genotype at rs17446614 (p = 0.009) suffered more severe bleeding than patients without them. Carriers of haplotype Grs17446593Ars17446614Crs2721068Trs2755213 were protective to severe bleeding (p = 0.002). The AA genotype at rs17446593 was significantly higher in ITP patients sensitive to glucocorticoid treatment than in those insensitive to glucocorticoid treatment (p = 0.03). Haplotype Grs17446593Grs17446614Trs2721068Trs2755213 increases the risk of glucocorticoid resistance (p = 0.007). Although FOXO1 gene polymorphisms were not associated with susceptibility to ITP, the AA genotype at rs17446593 and GG genotype at rs17446614 were associated with bleeding severity. Haplotype GACT have a protective effect against severe bleeding. Patients with AA genotype at rs17446593 may tend to have good responds to glucocorticoid treatment. However, the FOXO1 gene haplotype GGTT increases the risk of glucocorticoid-resistant. Trial registration: ChiCTR1900022419.

The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy.

Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (-0.80%) and SF (-0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (-11.01 mL/m2, p = 0.03) while for dp116 were correlated with decreased EF (-4.14%, p = <0.001). The rs10880 genotype in the LTBP4 gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, p = 0.002, and -10.62 mL/m2, p = 0.008) with a recessive model. Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD.

[Detection of molecular affecting sensitivity to local glucocorticoid therapy in oral lichen planus through transcriptome sequencing].

OBJECTIVE: To detect key genes of local glucocorticoid therapy in oral lichen planus (OLP) through transcriptome sequencing. METHODS: The study prospectively enrolled 28 symptomatic patients who visitied Department of Oral Mucosa, Peking University Hospital of Stomatology from November 2019 to March 2023. Topical inunction of 0.1 g/L of dexamethasone was applied for 1 min, 3 times daily for 4 weeks. The patients' signs and pain symptoms were recorded and they were classified as effective group and ineffective group according to the treatment outcome. Their mucosa samples were collected before treatment. After isolating total RNA, transcriptome sequencing was performed. The gene expression data obtained by sequencing were analyzed differently using the DESeq2 package in R software, and the Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis was performed on the basis of the hypergeometric distribution algorithm to describe the biological function of differentially expressed genes (DEGs), accordingly detecting sensitivity related molecular affecting therapeutic effect of dexamethasone. RESULTS: After 4 weeks treatment by topical dexamethasone, 13 cases of the 28 OLP patients responding well with the sign score reducing from 7.0 (4.5, 9.0) to 5.0 (3.0, 6.3), pain score decreasing from 5.0 (2.0, 5.5) to 2.0 (0.0, 3.5), oral health impact profile lessening from 5.0 (3.5, 9.0) to 1.0 (0.0, 5.0) significantly (P<0.01) were classified as effective group and 15 cases with poor response to the drug were sorted as ineffective group. There were no significant differences of demographic and baseline levels of clinical features, especially disease severity between these two groups. A total of 499 DEGs including 274 upregulated and 225 downregulated genes were identified between effective group and ineffective group. KEGG enrichment analysis showed that upregulated genes in effective group compared with ineffective group including CLDN8, CTNNA3, MYL2 and MYLPF were associated with leukocyte transendothelial migration, while downregulated genes were significantly enriched in tumor necrosis factor (TNF), interleukin-17 (IL-17), nuclear factor kappa B (NF-κB) signaling pathways, and cortisol synthesis and secretory. CONCLUSION: High expressions of CLDN8, CTNNA3, MYL2 and MYLPF genes in patients with oral lichen planus have a good clinical response to topical dexamethasone, while patients with high expression genes of inflammation pathway such as TNF, IL-17, NF-κB and cortisol synthesis and secretion received poor effect.

Detection of molecular affecting sensitivity to local glucocorticoid therapy in oral lichen planus through transcriptome sequencing / 北京大学学报(医学版)

Objective:To detect key genes of local glucocorticoid therapy in oral lichen planus(OLP)through transcriptome sequencing.Methods:The study prospectively enrolled 28 symptomatic patients who visitied Department of Oral Mucosa,Peking University Hospital of Stomatology from November 2019 to March 2023.Topical inunction of 0.1 g/L of dexamethasone was applied for 1 min,3 times daily for 4 weeks.The patients'signs and pain symptoms were recorded and they were classified as effective group and ineffective group according to the treatment outcome.Their mucosa samples were collected before treatment.After isolating total RNA,transcriptome sequencing was performed.The gene expression data obtained by sequencing were analyzed differently using the DESeq2 package in R software,and the Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analysis was performed on the basis of the hypergeometric distribution algorithm to describe the biological function of differentially expressed genes(DEGs),accordingly detecting sensitivity related molecular affecting therapeutic effect of dexamethasone.Results:After 4 weeks treatment by topical dexamethasone,13 cases of the 28 OLP pa-tients responding well with the sign score reducing from 7.0(4.5,9.0)to 5.0(3.0,6.3),pain score decreasing from 5.0(2.0,5.5)to 2.0(0.0,3.5),oral health impact profile lessening from 5.0(3.5,9.0)to 1.0(0.0,5.0)significantly(P＜0.01)were classified as effective group and 15 cases with poor response to the drug were sorted as ineffective group.There were no significant differences of demographic and baseline levels of clinical features,especially disease severity between these two groups.A total of 499 DEGs including 274 upregulated and 225 downregulated genes were identified between ef-fective group and ineffective group.KEGG enrichment analysis showed that upregulated genes in effective group compared with ineffective group including CLDN8,CTNNA3,MYL2 and MYLPF were associated with leukocyte transendothelial migration,while downregulated genes were significantly enriched in tumor necrosis factor(TNF),interleukin-17(IL-17),nuclear factor kappa B(NF-κB)signaling pathways,and cortisol synthesis and secretory.Conclusion:High expressions of CLDN8,CTNNA3,MYL2 and MYLPF genes in patients with oral lichen planus have a good clinical response to topical dexamethasone,while patients with high expression genes of inflammation pathway such as TNF,IL-17,NF-κB and corti-sol synthesis and secretion received poor effect.

Role of Chondroitin Sulfate Proteoglycan 5 in Steroid-Induced Cataract.

Steroid-induced cataracts (SIC) are defined as cataracts associated with the administration of corticosteroids. Long-term glucocorticoid treatment for inflammatory diseases reportedly increases the risk of SIC, and steroids can induce cataracts by disrupting ocular growth factor balance or homeostasis. In this study, we verified the effect of chondroitin sulfate proteoglycan 5 (CSPG5) using dexamethasone (dexa)-treated human lens epithelial (HLE-B3) cells and the lens epithelium from the anterior capsule of SIC patients obtained during cataract surgery. CSPG5 expression increased in the lens epithelium of SIC patients. The downregulation of CSPG5 suppressed the dexa-induced epithelial-mesenchymal transition (EMT)-related protein expression and motility in HLE-B3 cells. The disruption of the transcription factors EZH2 and B-Myb downregulated CSPG5, dexa-induced fibronectin expression, and cell migration in HLE-B3 cells, reaffirming that CSPG5 expression regulates EMT in lens epithelial cells. Taken together, these results indicate that the steroid-induced effects on lens epithelial cells are mediated via alterations in CSPG5 expression. Therefore, our study emphasizes the potential of CSPG5 as a therapeutic target for the prevention and treatment of SIC.

Systemic Lupus Erythematosus Flare-Up Manifestation as Intramedullary and Posterior Pharynx Hemorrhage.

Systemic lupus erythematosus (SLE) is a common clinical condition, and one of its more common complications is bleeding. Intramedullary and posterior pharynx hemorrhage in SLE is rare and disastrous. We present a patient with a predominantly neurological clinical presentation, which on examination was thought to be the result of active SLE complicated by intramedullary and pharynx hemorrhage. Intravenous glucocorticoids were administered for the acute SLE flare-up. The patient's neurological deficits improved gradually. She could walk independently when she was discharged. Early magnetic resonance imaging detection and early glucocorticoid treatment can halt the progression of neuropsychiatric SLE.

Compromised Adult Height in Females with Non-Classical Congenital Adrenal Hyperplasia Diagnosed in Childhood.

INTRODUCTION: Data on adult height (AHt) in individuals with non-classical congenital adrenal hyperplasia (NCCAH) are inconsistent. METHODS: We conducted a retrospective study of 109 females diagnosed with NCCAH at age <18 years who reached AHt. We studied AHt compared to target height (THt) and the correlation of AHt with clinical parameters. RESULTS: The mean age at diagnosis was 9.7 ± 4.4 years; the mean follow-up was 10.9 ± 6.3 years. Hydrocortisone treatment (11.0 ± 5.0 mg/m2) was initiated at age 9.7 ± 4.0 years. Bone age was more advanced in girls who presented with central precocious puberty or early puberty (CPP/EP) (n = 43) than with timely puberty. AHt-standard deviation score (SDS) was lower than Ht-SDS at diagnosis (-0.8 ± 1.0 vs. +0.2 ± 1.3; p < 0.001) and -0.3 SDS shorter than THt (p < 0.001). Height, weight, and body mass index-SDS at last visits were similar between patients treated with glucocorticoids (n = 92) and those never treated (n = 17). AHt was comparable between patients with timely puberty and with CPP/EP, with no difference between those treated or not by GnRH analogue. AHt was similar between patients who were fully pubertal (Tanner 5), pre-pubertal (Tanner 1), and pubertal (Tanner 2-4) at diagnosis (158.0 ± 7.6, 158.1 ± 6.1, and 157.5 ± 6.5, respectively; p = 0.9). AHt-SDS was correlated with THt (R = 0.67, p < 0.001) and Ht-SDS at diagnosis (R = 0.7, p < 0.001) but not with age at diagnosis (R = -0.05, p = 0.6), the extent of bone age advancement (R = -0.04, p = 0.72), glucocorticoid treatment duration (R = -0.11, p = 0.34), or dose (R = -0.04, p = 0.70). CONCLUSION: AHt of females diagnosed with NCCAH in childhood was lower than their THt. Glucocorticoid treatment duration and dose, pubertal status at diagnosis, and having CPP or EP were not correlated with AHt.

Sialocele and Its Association with Hypercortisolism and Long-Term Glucocorticoid Treatment in Dogs: Retrospective Case-Control Study.

Dogs with sialocele often have concurrent hypercortisolism or are receiving long-term glucocorticoid treatment. However, their association has not been investigated. This retrospective matched case-control study investigated the association between hypercortisolism, long-term glucocorticoid treatment, and sialocele in dogs. We retrospectively reviewed the records from 1 January 2018 to 31 December 2022. Records of 19 dogs diagnosed with sialocele were investigated for hypercortisolism and long-term glucocorticoid treatment. Two age- and breed-matched controls for each sialocele dog (38 dogs) were investigated for the same concurrent diseases. Logistic regression analysis was used. The odds of sialocele in dogs with hypercortisolism were 15.56 times those of dogs without hypercortisolism (p = 0.02; 95% CI: 1.54-156.79). The odds of sialocele in dogs with long-term glucocorticoid treatment (median, 8 months; range, 5-13) were 7.78 times those of dogs without long-term glucocorticoid treatment (p = 0.03; 95% CI: 1.23-49.40). No associations were found between age, sex, body weight, and the presence of sialocele. The results indicate that sialocele was significantly associated with hypercortisolism and long-term glucocorticoid treatment in dogs. Therefore, dogs with hypercortisolism or receiving long-term glucocorticoid therapy should be screened for possible sialocele. Additionally, dogs with sialocele should be identified for concurrent hypercortisolism and prolonged glucocorticoid exposure.

Challenges in treatment of patients with non-classic congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase deficiency (21OHD) or 11ß-hydroxylase deficiency (11OHD) are congenital conditions with affected adrenal steroidogenesis. Patients with classic 21OHD and 11OHD have a (nearly) complete enzyme deficiency resulting in impaired cortisol synthesis. Elevated precursor steroids are shunted into the unaffected adrenal androgen synthesis pathway leading to elevated adrenal androgen concentrations in these patients. Classic patients are treated with glucocorticoid substitution to compensate for the low cortisol levels and to decrease elevated adrenal androgens levels via negative feedback on the pituitary gland. On the contrary, non-classic CAH (NCCAH) patients have more residual enzymatic activity and do generally not suffer from clinically relevant glucocorticoid deficiency. However, these patients may develop symptoms due to elevated adrenal androgen levels, which are most often less elevated compared to classic patients. Although glucocorticoid treatment can lower adrenal androgen production, the supraphysiological dosages also may have a negative impact on the cardiovascular system and bone health. Therefore, the benefit of glucocorticoid treatment is questionable. An individualized treatment plan is desirable as patients can present with various symptoms or may be asymptomatic. In this review, we discuss the advantages and disadvantages of different treatment options used in patients with NCCAH due to 21OHD and 11OHD.

Reduced bone mineral density in adolescents with Duchenne Muscular Dystrophy (DMD) and scoliosis.

Duchenne muscular dystrophy is a progressive disease usually associated with loss of ambulation and progressive scoliosis. Immobilisation and glucocorticoid treatment are predisposing factors for reduced bone mineral density (BMD). Analysis of quantitative computed tomography revealed low BMD in thoracic and lumbar vertebrae in comparison to age- and sex-matched healthy controls. INTRODUCTION: Evaluation of vertebral bone mineral density (BMD) in Duchenne Muscular Dystrophy (DMD) adolescents with untreated advanced scoliosis and comparison with the BMD values of healthy age-matched controls, based on quantitative computer tomography. METHODS: Thirty-seven DMD adolescents (age 15.6 ± 2.5 years) with spinal deformity were evaluated clinically and radiologically prior to definite spinal fusion and compared to 31 male and age-matched healthy individuals (age 15.7 ± 2.3 years). Data related to previous medical treatment, physiotherapy and ambulatory status was also analysed. Scoliotic curves were measured on plain sitting radiographs of the spine. The BMD Z-scores of the thoracic and lumbar vertebrae were calculated with QCTpro® (Mindways Software Inc., USA), based on data sets of preoperative, phantom pre-calibrated spinal computed tomography scans. RESULTS: A statistically significant lower BMD could be found in DMD adolescents, when compared to healthy controls, showing an average value for the lumbar spine of 80.5 ± 30.5 mg/cm3. Z-scores deteriorated from the upper thoracic towards the lower lumbar vertebrae. All but the uppermost thoracic vertebrae had reduced BMD values, with the thoracolumbar and lumbar region demonstrating the lowest BMD. No significant correlation was observed between BMD and the severity of the scoliotic curve, previous glucocorticoid treatment, cardiovascular impairment, vitamin D supplementation, non-invasive ventilation or physiotherapy. CONCLUSION: DMD adolescents with scoliosis have strongly reduced BMD Z-scores, especially in the lumbar spine in comparison to healthy controls. These findings support the implementation of a standardised screening and treatment protocol. Level of evidence/clinical relevance: therapeutic level III.

Analysis of a pitfall in congenital adrenal hyperplasia newborn screening: evidence of maternal use of corticoids detected on dried blood spot.

Neonatal screening for congenital adrenal hyperplasia (CAH) faces many specific challenges. It must be done using a performant analytical approach that combines sensitivity and specificity to capture the potential causes of mortality during the first week of life, such as salt wasting and glucocorticoid deficiency. Here, we confirm that maternal inhaled corticosteroid intake during pregnancy is a possible cause of missed CAH diagnosis. Thanks to liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis, we were able to quantify endogenous steroid metabolites and also detect the presence of exogenous steroids in the dried blood spot of a newborn. Adding LC-MS/MS analysis as second-tier test, especially one that includes both 17-hydroxyprogesterone and 21-deoxycortisol measurements, would probably improve CAH diagnosis. In familial neonatal screening one could also look for maternal corticosteroid therapies that are hidden to prevent false-negative tests.

RIP3 blockade prevents immune-mediated hepatitis through a myeloid-derived suppressor cell dependent mechanism.

Autoimmune hepatitis (AIH) is an immune-mediated chronic inflammatory liver disease, and its pathogenesis is not fully understood. Our previous study discovered that receptor interacting protein kinase 3 (RIP3) is correlated with serum transaminase levels in AIH patients. However, its role and underlying mechanism in AIH are poorly understood. Here, we detected the increased expression and activation of RIP3 in livers of patients and animal models with AIH. The inhibition of RIP3 kinase by GSK872 prevented concanavalin A (ConA)-induced immune-mediated hepatitis (IMH) by reduced hepatic proinflammatory cytokines and immune cells including Th17 cells and macrophages. Further experiments revealed that RIP3 inhibition resulted in an increase in CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs) with immunoregulatory properties in the liver, spleen, and peripheral blood. Moreover, the depletion of Gr-1+ MDSCs abrogated the protective effect and immune suppression function of GSK872 in ConA-induced IMH. Altogether, our data demonstrate that RIP3 blockade prevents ConA-induced IMH through promoting MDSCs infiltration. Inhibition of RIP3 kinase may be a novel therapeutic avenue for AIH treatment.

Low serum osteocalcin levels are associated with diabetes mellitus in glucocorticoid treated patients.

Bone turnover markers are decreased in GC-treated subjects with DM. Decreased OC levels in GC-treated patients were associated with an increased risk of DM. These results suggest the involvement of OC in glucose homeostasis regulation in DM. INTRODUCTION: Osteocalcin (OC) is involved in the regulation of glucose homeostasis. Glucocorticoid (GC) treatment is associated with impaired osteoblast function, decreased OC levels, and the development and/or worsening of pre-existing diabetes mellitus (DM). Whether decreased OC levels in GC-treated subjects contribute to DM is not well known. The aim of this study was to analyse whether OC levels in GC-treated patients are associated with the presence of DM. METHODS: One hundred twenty-seven patients (aged 61.5 ± 17.9 years) on GC treatment were included. GC dose, treatment duration, presence of DM and bone formation (OC, bone ALP, PINP) and resorption markers (urinary NTX, serum CTX) were analysed. The cut-offs of each bone turnover marker (BTM) for the presence of DM were evaluated and optimised with the Youden index and included in the logistic regression analysis. RESULTS: Among the patients, 17.3% presented DM. No differences were observed in GC dose or duration or the presence of fractures. Diabetics showed lower levels of OC (7.57 ± 1.01 vs. 11.56 ± 1; p < 0.001), PINP (21.48 ± 1.01 vs. 28.39 ± 1; p = 0.0048), NTX (24.91 ± 1.01 vs. 31.7 ± 1; p = 0.036) and CTX (0.2 ± 1.01 vs. 0.3 ± 1; p = 0.0016). The discriminating BTM cut-offs for DM presence were < 9.25 ng/mL for OC, < 24 ng/mL for PINP, < 27.5 nMol/mM for NTX and < 0.25 ng/mL for CTX. In a multivariate logistic regression model adjusted for GC dose, BMI, age and the above four BTMs, only OC remained independently associated with DM presence. Thus, in a model adjusted for GC dose, BMI and age, OC was significantly associated with DM (OR: 6.1; 95%CI 1.87-19.89; p = 0.001). CONCLUSION: Decreased OC levels in GC-treated patients are associated with increased odds of DM, and only OC was independently associated with DM in a model including four BTMs.

Impaired aldosterone response to ACTH without hypoaldosteronism: An unrecognized secretory pattern in search of clinical implications.

CONTEXT: Aldosterone has been recently characterized as a 'stress hormone'. Stress per se elicits a sizable rise in aldosterone secretion, which could be replicated by the administration of a low dose (0.03-1 µg, IV) of adrenocorticotropic hormone (ACTH). Whether or not the aldosterone response to ACTH could be selectively impaired, that is, in association with intact cortisol response, is presently unknown. OBJECTIVE: To determine whether or not the aldosterone response to low dose of ACTH is impaired in subjects referred to assess the hypothalamic-pituitary-adrenal axis (HPA). DESIGN: Retrospective analysis. SETTING: Outpatient referral endocrine day care centre. PATIENTS: One hundred and ninety-five consecutive subjects who underwent the low dose (1 µg) ACTH test, in whom decreased cortisol reserve was suspected due to former/present glucocorticoid excess, pituitary disease or/and unexplained weakness. MAIN OUTCOME MEASURES: The outcome was the detection of lack of aldosterone response, defined as a rise <111 pmol/l. RESULTS: In all, 46/195 subjects had subnormal aldosterone response as compared with 52/195 subjects showing diminished cortisol response. Nine subjects had combined deficient aldosterone and cortisol response. In the 37 subjects with isolated subnormal aldosterone response common associations were the use of exogenous glucocorticoids, mostly prednisone (n = 16); former Cushing disease (n = 2); nonfunctioning pituitary adenoma (n = 8); hypothyroidism (n = 11); the use of statins (n = 11), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (n = 6), sex steroids in transgenders and orthostatic hypotension (n = 3). Twenty-seven percent (25/93) of the subjects with recent exposure to glucocorticoids had impaired aldosterone response to ACTH. CONCLUSION: Blunted aldosterone response to ACTH in the absence of hypoaldosteronism was seen in ~27% of subjects referred for HPA assessment using the low dose 1 µg ACTH test. Exposure to glucocorticoid excess was often linked to this impairment, independent of the cortisol response to ACTH.

The Initial Stage of Neutrophilic Dermatosis of the Dorsal Hands: A Case Report and Discussion of Differential Diagnoses.

Neutrophilic dermatosis of the dorsal hands (NDDH) is considered a localized variant of acute febrile neutrophilic dermatosis. It is a rare condition and presents with erythematous tender nodules and plaques on the extensor sides of the hands. Forty percent of NDDH cases occur in association with an underlying disease, with hematologic disorders being the most frequent type. Here, we describe the case of a 77-year-old male patient who presented with acute tumid, erythematous lesions of the fingers. As part of this report, we discuss possible differential diagnoses of NDDH and seek to raise awareness of this rare condition, as misdiagnoses often lead to a delay in adequate treatment and thus more dramatic disease courses.

Low-dose short synacthen test with salivary cortisol in patients with suspected central adrenal insufficiency.

CONTEXT: The low-dose short synacthen test (LDSST) is recommended for patients with suspected central adrenal insufficiency (AI) if their basal serum cortisol (F) levels are not indicative of an intact hypothalamic-pituitary-adrenal (HPA) axis. OBJECTIVE: To evaluate diagnostic threshold for salivary F before and 30 min after administering 1 µg of synacthen, performed before 09:30 h. DESIGN: A cross-sectional study from 2014 to 2020. SETTING: A tertiary referral university hospital. PATIENTS: In this study, 174 patients with suspected AI, 37 with central AI and 137 adrenal sufficient (AS), were included. MAIN OUTCOME MEASURE: The diagnostic accuracy (sensitivity (SE), specificity (SP)) of serum and salivary F levels measured, respectively, by chemiluminescence immunoassay and liquid chromatography-tandem mass spectrometry. RESULTS: Low basal serum or salivary F levels could predict AI. For the LDSST, the best ROC-calculated threshold for serum F to differentiate AI from AS was 427 nmol/L (SE 79%, SP 89%), serum F > 500 nmol/L reached SP 100%. A salivary F peak > 12.1 nmol/L after administering synacthen reached SE 95% and SP 84% for diagnosing central AI, indicating a conclusive reduction in the likelihood of AI. This ROC-calculated threshold for salivary F was similar to the 2.5th percentile of patients with a normal HPA axis, so it was considered sufficient to exclude AI. Considering AS those patients with salivary F > 12.1 nmol/L after LDSST, we could avoid unnecessary glucocorticoid treatment: 99/150 subjects (66%) had an inadequate serum F peak after synacthen, but salivary F was >12.1 nmol/L in 79 cases, who could, therefore, be considered AS. CONCLUSIONS: Salivary F levels > 12.1 nmol/L after synacthen administration can indicate an intact HPA axis in patients with an incomplete serum F response, avoiding the need to start glucocorticoid replacement treatment.

Association of mannose-binding lectin, ficolin-2 and immunoglobulin concentrations with future exacerbations in patients with chronic obstructive pulmonary disease: secondary analysis of the randomized controlled REDUCE trial.

BACKGROUND: The innate and adaptive immune system is involved in the airway inflammation associated with acute exacerbations in patients with chronic obstructive pulmonary disease (COPD). We evaluated the association of mannose-binding lectin (MBL), immunoglobulin (Ig) and ficolin-2 concentrations with COPD exacerbations and according to the glucocorticoid treatment duration for an index exacerbation. METHODS: Post-hoc analysis of the randomized, double-blind, placebo-controlled REDUCE trial of 5 vs. 14 days of glucocorticoid treatment for an index exacerbation. MBL, ficolin-2 and total IgG/IgA and subclass concentrations were determined in stored samples drawn (n = 178) 30 days after the index exacerbation and associated with the risk of re-exacerbation during a 180-day follow-up period. RESULTS: IgG and subclass concentrations were significantly lower after 14 days vs. 5 days of glucocorticoid treatment. Patients with higher MBL concentrations were more likely to suffer from a future exacerbation (multivariable hazard ratio 1.03 per 200 ng/ml increase (95% confidence interval (CI) 1.00-1.06), p = 0.048), whereas ficolin-2 and IgG deficiency were not associated. The risk was most pronounced in patients with high MBL concentrations, IgG deficiency and 14 days of glucocorticoid treatment pointing towards an interactive effect of MBL and IgG deficiency in the presence of prolonged glucocorticoid treatment duration [Relative excess risk due to interaction 2.13 (95% CI - 0.41-4.66, p = 0.10)]. IgG concentrations were significantly lower in patients with frequent re-exacerbations (IgG, 7.81 g/L vs. 9.53 g/L, p = 0.03). CONCLUSIONS: MBL modified the short-term exacerbation risk after a recent acute exacerbation of COPD, particularly in the setting of concurrent IgG deficiency and recent prolonged systemic glucocorticoid treatment. Ficolin-2 did not emerge as a predictor of a future exacerbation risk.

Glucocorticoid Withdrawal-An Overview on When and How to Diagnose Adrenal Insufficiency in Clinical Practice.

Glucocorticoids (GCs) are widely used due to their anti-inflammatory and immunosuppressive effects. As many as 1-3% of the population are currently on GC treatment. Prolonged therapy with GCs is associated with an increased risk of GC-induced adrenal insufficiency (AI). AI is a rare and often underdiagnosed clinical condition characterized by deficient GC production by the adrenal cortex. AI can be life-threatening; therefore, it is essential to know how to diagnose and treat this disorder. Not only oral but also inhalation, topical, nasal, intra-articular and intravenous administration of GCs may lead to adrenal suppression. Moreover, recent studies have proven that short-term (<4 weeks), as well as low-dose (<5 mg prednisone equivalent per day) GC treatment can also suppress the hypothalamic-pituitary-adrenal axis. Chronic therapy with GCs is the most common cause of AI. GC-induced AI remains challenging for clinicians in everyday patient care. Properly conducted GC withdrawal is crucial in preventing GC-induced AI; however, adrenal suppression may occur despite following recommended GC tapering regimens. A suspicion of GC-induced AI requires careful diagnostic workup and prompt introduction of a GC replacement treatment. The present review provides a summary of current knowledge on the management of GC-induced AI, including diagnostic methods, treatment schedules, and GC withdrawal regimens in adults.

Genotype characterization and delayed loss of ambulation by glucocorticoids in a large cohort of patients with Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common genetic muscle disease in human. We aimed to describe the genotype distribution in a large cohort of Chinese DMD patients and their delayed loss of ambulation by glucocorticoid (GC) treatments. This is to facilitate protocol designs and outcome measures for the emerging DMD clinical trials. RESULTS: A total of 1163 patients with DMD were recruited and genotyped. Genotype variations were categorized as large deletions, large duplications, and small mutations. Large deletions were further analyzed for those amenable to exon-skipping therapies. Participants aged 5 years or older were grouped into GC-treated and GC-naïve groups. Clinical progression among different genotypes and their responses to GC treatments were measured by age at loss of ambulation (LOA). Among the mutation genotypes, large deletions, large duplications, and small mutations accounted for 68.79%, 7.14%, and 24.07%, respectively. The mean age at diagnosis was 4.59 years; the median ages at LOA for the GC-naïve, prednisone/prednisolone-treated, and deflazacort-treated groups were 10.23, 12.02, and 13.95 years, respectively. The "deletion amenable to skipping exon 44" subgroup and the nonsense-mutation subgroup had older ages at LOA than the "other deletions" subgroup. Subgroups were further analyzed by both genotypes and GC status. All genotypes showed significant beneficial responses to GC treatment. Deletions amenable to skipping exon 44 showed a lower hazard ratio (0.155). The mean age at death was 18.57 years in this DMD group. CONCLUSION: Genotype variation influences clinical progression in certain DMD groups. Beneficial responses to GC treatment were observed among all DMD genotypes. Compared with other genotypes, deletions amenable to skipping exon 44 had a lower hazard ratio, which may indicate a stronger protective effect of GC treatments on this subgroup. These data are valuable for designing future clinical trials, as clinical outcomes may be influenced by the genotypes.

Atypical adult-onset Still's disease with an initial and sole manifestation of liver injury: A case report and review of literature.

BACKGROUND: Adult-onset Still's disease (AOSD) typically presents with a high spiking fever, polyarthritis, transient maculopapular rash, neutrophilic leukocytosis, and hepatosplenomegaly. It has a wide spectrum of clinical symptoms ranging from mild to severe, with extensive involvement of almost every organ. Although liver involvement in the form of increased hepatic enzymes and bilirubin is common, no AOSD case with liver involvement as the initial manifestation of AOSD has been reported. CASE SUMMARY: A 35-year-old woman presented to the hepatology department with progressively worsening jaundice for one week. Liver chemistry tests revealed a significantly increased liver enzymes and bilirubin level. Given that the clinical examination was unremarkable, liver biopsy was considered because the patient had a history of AOSD 6 years ago. Liver histopathology revealed that most hepatic lobules were still recognizable. Fusional necrosis was observed around most central veins. A few bridging necrotic zones were also found. Infiltration of multiple plasma cells were observed in the necrotic zone, and the reticular scaffold was still expanded. Additionally, no obvious fibrosis was observed in the portal area. Mild mixed inflammatory cell infiltration was noted in the interstitium of the portal area. Further examination was unremarkable except for a remarkably high level of ferritin. Collectively, a presumptive diagnosis of liver injury secondary to AOSD was made. The hepatic involvement responded well to glucocorticoid treatment. CONCLUSION: This case highlights that hepatic involvement as an initial and sole manifestation could be a pattern of relapsed AOSD. The diagnosis of AOSD should be considered in the case of nonresolving liver injury after the exclusion of common etiologies for liver diseases. A liver biopsy can be useful for the differential diagnosis of liver injury associated with AOSD.