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Cell Communication and Signaling : CCS Jun 2022Autoimmune hepatitis (AIH) is a chronic, immune-mediated liver dysfunction. The gut microbiota and T follicular helper (Tfh) cells play critical roles in the...
BACKGROUND
Autoimmune hepatitis (AIH) is a chronic, immune-mediated liver dysfunction. The gut microbiota and T follicular helper (Tfh) cells play critical roles in the immunopathogenesis and progression of AIH. We aimed to investigate the effect of gut microbiota combined with prednisone therapy on Tfh cell response in AIH.
METHODS
Samples from AIH patients and mouse model of experimental autoimmune hepatitis (EAH) were analyzed using real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, flow cytometry, and hematoxylin-eosin staining to determine the role of gut microbiota on AIH.
RESULTS
Lactobacillus significantly increased the levels of Bacteroides fragilis, Clostridium, Clostridium leptum, Bifidobacterium, and Lactobacillus and significantly enhanced the suppressive effects of prednisone on the levels of AIH clinical indexes in AIH patients. Lactobacillus exerts the same prptective effects as prednisone in EAH mice and enhanced the effects of prednisone. Lactobacillus also reinforced the inhibitory effects of prednisone on the levels of serum IL-21 and the proportions of Tfh cells in peripheral blood mononuclear cells. Mechanistically, prednisone and Lactobacillus regulated Tfh cell response in EAH mice in an MyD88/NF-κB pathway-dependent manner.
CONCLUSION
Our results suggested a therapeutic potential of Lactobacillus in the prednisone-combined treatment of AIH. Video Abstract.
Topics: Animals; Gastrointestinal Microbiome; Hepatitis, Autoimmune; Humans; Lactobacillus; Leukocytes, Mononuclear; Mice; Prednisone; T Follicular Helper Cells
PubMed: 35658901
DOI: 10.1186/s12964-021-00819-7 -
Lupus Jul 2021Systemic lupus erythematosus (SLE) management objectives include preventing disease flares while minimizing glucocorticoid exposure. Pooled data from the phase 3 TULIP-1... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Systemic lupus erythematosus (SLE) management objectives include preventing disease flares while minimizing glucocorticoid exposure. Pooled data from the phase 3 TULIP-1 and TULIP-2 trials in patients with moderate to severe SLE were analyzed to determine anifrolumab's effect on flares, including those arising with glucocorticoid taper.
METHODS
TULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks for 48 weeks). For patients receiving baseline glucocorticoid ≥10 mg/day, attempted taper to ≤7.5 mg/day prednisone or equivalent from Weeks 8-40 was required and defined as sustained reduction when maintained through Week 52. Flares were defined as ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B scores versus the previous visit. Flare assessments were compared for patients receiving anifrolumab versus placebo.
RESULTS
Compared with placebo (n = 366), anifrolumab (n = 360) was associated with lower annualized flare rates (rate ratio 0.75, 95% confidence interval [CI] 0.60-0.95), prolonged time to first flare (hazard ratio 0.70, 95% CI 0.55-0.89), and fewer patients with ≥1 flare (difference -9.3%, 95% CI -16.3 to -2.3), as well as flares in organ domains commonly active at baseline (musculoskeletal, mucocutaneous). Fewer BILAG-based Composite Lupus Assessment responders had ≥1 flare with anifrolumab (21.1%, 36/171) versus placebo (30.4%, 34/112). Of patients who achieved sustained glucocorticoid reductions from ≥10 mg/day at baseline, more remained flare free with anifrolumab (40.0%, 76/190) versus placebo (17.3%, 32/185).
CONCLUSIONS
Analyses of pooled TULIP-1 and TULIP-2 data support that anifrolumab reduces flares while permitting glucocorticoid taper in patients with SLE.TULIP-1 NCT02446912 (clinicaltrials.gov/ct2/show/NCT02446912);TULIP-2 NCT02446899 (clinicaltrials.gov/ct2/show/NCT02446899).
Topics: Antibodies, Monoclonal, Humanized; Glucocorticoids; Humans; Lupus Erythematosus, Systemic; Prednisone
PubMed: 33977796
DOI: 10.1177/09612033211014267 -
Pediatric Nephrology (Berlin, Germany) Feb 2022The therapeutic efficacy of B cell-depleting anti-CD20 treatment in both pediatric and adult steroid-sensitive nephrotic syndromes (SSNS) suggests that B cells play a...
BACKGROUND
The therapeutic efficacy of B cell-depleting anti-CD20 treatment in both pediatric and adult steroid-sensitive nephrotic syndromes (SSNS) suggests that B cells play a pathogenic role in the disease. In adults with minimal change disease (MCD), only circulating plasmablasts are increased during the active phase of the disease, among B cell subsets. These cells have not been studied yet in children with SSNS.
METHODS
We retrospectively quantified by flow cytometry analysis circulating plasmablasts in 107 pediatric patients with SSNS (51 at disease onset, 27 during relapse, and 29 in remission). Data were compared with an equal number of age- and sex-matched healthy donors (HD).
RESULTS
Circulating plasmablast levels, expressed as percentage of total CD19 B cells or as percentage of total lymphocytes, were normal in all SSNS subgroups, compared to HD. Patients in remission had significantly fewer circulating plasmablasts compared to patients at disease onset. No significant correlation was observed between plasmablast levels and proteinuria or serum proteins, at onset. Treatment with prednisone and mycophenolate mofetil significantly reduced circulating levels of plasmablasts, unlike treatment with prednisone and calcineurin inhibitors.
CONCLUSIONS
The B cell phenotype of children with SSNS differs from that of adults with MCD. This may justify different therapeutic approaches.
Topics: Child; Female; Humans; Male; Nephrosis, Lipoid; Nephrotic Syndrome; Plasma Cells; Prednisone; Retrospective Studies
PubMed: 34661744
DOI: 10.1007/s00467-021-05273-8 -
Journal of Cardiac Failure Dec 2021Cardiac sarcoidosis (CS) is a major cause of morbidity and mortality in patients with systemic sarcoidosis. Steroid-sparing agents are increasingly used, despite a lack...
BACKGROUND
Cardiac sarcoidosis (CS) is a major cause of morbidity and mortality in patients with systemic sarcoidosis. Steroid-sparing agents are increasingly used, despite a lack of randomized trials or published guidelines to direct treatment.
METHODS AND RESULTS
This retrospective study included 77 patients with CS treated with prednisone monotherapy (n = 32) or a combination with mycophenolate mofetil (n = 45) between 2003 and 2018. Baseline characteristics and clinical outcomes were evaluated. The mean patient age was 53 ± 11 years at CS diagnosis, 66.2% were male, and 35.1% were Black. The total exposure to maximum prednisone dose (initial prednisone dose × days at dose) was lower in the combination therapy group (1440 mg [interquartile range (IQR), 1200-2760 mg] vs 2710 mg [IQR, 1200-5080 mg]; P = .06). On F-fluorodeoxyglucose positron emission tomography scans, both groups demonstrated a significant decrease in the cardiac maximum standardized uptake value after treatment: a median decrease of 3.9 (IQR 2.7-9.0, P = .002) and 2.9 (IQR 0-5.0, P = .001) for prednisone monotherapy and combination therapy, respectively. Most patients experienced improvement or complete resolution in qualitative cardiac F-fluorodeoxyglucose uptake (92.3% and 70.4% for the prednisone and combination therapy groups, respectively). Mycophenolate mofetil was well tolerated.
CONCLUSIONS
Mycophenolate mofetil in combination with prednisone for the treatment of CS may minimize corticosteroid exposure and decrease cardiac inflammation without significant adverse effects.
Topics: Adult; Heart Failure; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prednisone; Retrospective Studies; Sarcoidosis
PubMed: 34166800
DOI: 10.1016/j.cardfail.2021.06.010 -
Journal of Veterinary Internal Medicine May 2020Glucocorticoids cause hypercoagulability, but it is unknown if they counteract clopidogrel's antiplatelet effects.
BACKGROUND
Glucocorticoids cause hypercoagulability, but it is unknown if they counteract clopidogrel's antiplatelet effects.
HYPOTHESIS/OBJECTIVES
Determine the effects of clopidogrel and prednisone on platelet function.
ANIMALS
Twenty-four healthy dogs.
METHODS
Double-blinded, placebo-controlled randomized trial. Platelet function was evaluated using a platelet function analyzer and impedance aggregometry (days 0, 14, and 28) for dogs treated with placebo, clopidogrel (2-3 mg/kg/d), prednisone (2 mg/kg/d), or prednisone with clopidogrel PO for 28 days. Results were categorized as nonresponder versus responder (platelet function analyzer), and inadequate, ideal, or excessive response (aggregometry). Results were compared using mixed model, split-plot repeated measures analysis of variance and generalized estimating equation proportional odds models. P < .05 was considered significant.
RESULTS
Closure times differed by treatment (F [3, 20] = 10.5; P < .001), time (F [2, 40] = 14.3; P < .001), and treatment-by-time (F [6, 40] = 3.4; P = .01). Area under the curve (AUC) differed by treatment (F [3, 20] = 19.6; P < .001), time (F [2, 40] = 35.4; P < .001), and treatment-by-time (F [6, 40] = 13.5; P < .001). Based on closure times, 5/6 dogs each in the clopidogrel and prednisone/clopidogrel groups were responders. All dogs in the prednisone/clopidogrel group were overcontrolled based on AUC (days 14 and 28), whereas 5/6 (day 14) and 2/6 (day 28) dogs treated with clopidogrel were overcontrolled. Compared to clopidogrel, dogs receiving prednisone/clopidogrel were 11 times (P = .03) more likely to have an excessive response.
CONCLUSIONS AND CLINICAL IMPORTANCE
Administration of clopidogrel/prednisone increases platelet dysfunction in healthy dogs.
Topics: Animals; Blood Platelets; Clopidogrel; Dogs; Drug Interactions; Female; Glucocorticoids; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prednisone
PubMed: 32246893
DOI: 10.1111/jvim.15759 -
Therapeutic Drug Monitoring Apr 2021Prednisolone (PL) is a standard component of most immunosuppressive protocols after solid organ transplantation (Tx). Adverse effects are frequent and well known. The... (Observational Study)
Observational Study
BACKGROUND
Prednisolone (PL) is a standard component of most immunosuppressive protocols after solid organ transplantation (Tx). Adverse effects are frequent and well known. The aim of this study was to characterize the pharmacokinetics (PKs) of PL and prednisone (PN), including cortisol (CL) and cortisone (CN) profiles, after PL treatment in renal Tx recipients in the early post-Tx phase.
METHODS
This single-center, prospective, observational study included stable renal Tx recipients, >18 years of age, and in the early postengraftment phase. Blood samples were obtained predose and during a 24-hour dose interval [n = 26 samples per area under the curve (AUC0-24)], within the first 8 weeks post-Tx. PL, PN, CL, and CN concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry.
RESULTS
In renal Tx recipients (n = 28), our results indicated a relatively high PL exposure [median, range AUC0-24 = 3821 (2232-5382) mcg h/L], paralleled by strong suppression of endogenous CL profile, demonstrated by a low CL evening-to-morning ratio [median, range 11 (3-47)%]. A negative correlation (r = -0.83) between PL AUC0-24 and morning CL levels was observed. The best single PK variable to predict PL AUC0-24 was PL C6 (r2 = 0.82). An algorithm based on 3 PK sampling time points: trough, 2, and 4 hours after PL dosing, predicted PL AUC0-24 with a low percentage prediction error (PPE = 5.2 ± 1.5%) and a good correlation of determination (r2 = 0.91). PL AUC0-24 varied 3-fold among study participants, whereas CL AUC0-24 varied by 18-fold.
CONCLUSIONS
The large interindividual variability in both PL exposure and suppression of endogenous CL implies a possible role for therapeutic drug monitoring. An abbreviated profile within the first 4 hours after PL dosing provides a good prediction of PL exposure in renal Tx recipients. The strong negative correlation between PL AUC0-24 and morning CL levels suggests a possible surrogate marker for drug exposure for further evaluation.
Topics: Adult; Area Under Curve; Humans; Kidney Transplantation; Prednisolone; Prednisone; Prospective Studies
PubMed: 33181621
DOI: 10.1097/FTD.0000000000000835 -
Pediatric Endocrinology, Diabetes, and... 2022Steroid-induced central hypothyroidism (CH) is a frequent but under-diagnosed hormonal disturbance in children treated for acute lymphoblastic leukaemia (ALL) and...
INTRODUCTION
Steroid-induced central hypothyroidism (CH) is a frequent but under-diagnosed hormonal disturbance in children treated for acute lymphoblastic leukaemia (ALL) and lymphoma.
AIM OF THE STUDY
To determine the occurrence, frequency of symptoms, replacement therapy administration, and association of CH with glucocorticoid therapy in children treated for haematological malignancies.
MATERIAL AND METHODS
A prospective clinical survey was conducted on 21 patients (61.9% male, mean age 9.1 years) treated in the Children's Hospital Zagreb during 2019, of whom 12 were treated for for ALL and 6 for Hodgkin lymphoma (HL), based on clinical (signs and symptoms) and laboratory data (hormonal status).
RESULTS
Overt CH was verified in 15 (71.4%) and mild CH in 3 patients (14.2%). The most common symptoms and signs were fatigue, apathy, and electrolyte imbalance, observed in 50% of CH cases. Hormonal substitutional therapy was initiated in 44.4% of affected patients, during a mean of 2.08 months, with significant clinical improvement. Overt CH was more prevalent in patients with ALL than in those with HL (p = 0.025). Among children with ALL there was no difference in CH occurrence between the prednisone and dexamethasone groups; however, dexamethasone-induced CH was more frequently symptomatic (p = 0.03). The prednisone dosage played no role in CH incidence in patients with HL.
CONCLUSIONS
Further studies are needed to determine the real incidence of thyroid dysfunction during intensive chemotherapy treatment in children with ALL and lymphoma. Recommendations for optimal hormonal replacement therapy and a follow-up plan for paediatric oncology patients with CH are also urgently required.
Topics: Humans; Male; Child; Female; Prednisone; Prospective Studies; Hypothyroidism; Hematologic Neoplasms; Dexamethasone; Congenital Hypothyroidism
PubMed: 35942829
DOI: 10.5114/pedm.2022.118323 -
Molecular Metabolism Aug 2022Mitochondrial capacity is critical to adapt the high energy demand of the heart to circadian oscillations and diseased states. Glucocorticoids regulate the circadian...
OBJECTIVE
Mitochondrial capacity is critical to adapt the high energy demand of the heart to circadian oscillations and diseased states. Glucocorticoids regulate the circadian cycle of energy metabolism, but little is known about how circadian timing of exogenous glucocorticoid dosing directly regulates heart metabolism through cardiomyocyte-autonomous mechanisms. While chronic once-daily intake of glucocorticoids promotes metabolic stress and heart failure, we recently discovered that intermittent once-weekly dosing of exogenous glucocorticoids promoted muscle metabolism in normal and obese skeletal muscle. However, the effects of glucocorticoid intermittence on heart metabolism and heart failure remain unknown. Here we investigated the extent to which circadian time of dosing regulates the effects of the glucocorticoid prednisone in heart metabolism and function in conditions of single pulse or chronic intermittent dosing.
METHODS AND RESULTS
In WT mice, we found that prednisone improved cardiac content of NAD and ATP with light-phase dosing (ZT0), while the effects were blocked by dark-phase dosing (ZT12). The drug effects on mitochondrial function were cardiomyocyte-autonomous, as shown by inducible cardiomyocyte-restricted glucocorticoid receptor (GR) ablation, and depended on an intact cardiomyocyte clock, as shown by inducible cardiomyocyte-restricted ablation of Brain and Muscle ARNT-like 1 (BMAL1). Conjugating time-of-dosing with chronic intermittence, we found that once-weekly prednisone improved metabolism and function in heart after myocardial injury dependent on circadian time of intake, i.e. with light-phase but not dark-phase dosing.
CONCLUSIONS
Our study identifies cardiac-autonomous mechanisms through which circadian-specific intermittent dosing reconverts glucocorticoid drugs to metabolic boosters for the heart.
Topics: Animals; Circadian Clocks; Glucocorticoids; Heart Failure; Mice; Myocytes, Cardiac; Prednisone
PubMed: 35717025
DOI: 10.1016/j.molmet.2022.101528 -
Hematology/oncology and Stem Cell... Dec 2022Data generated from retrospective studies on primary mediastinal B-cell lymphoma (PMBCL) outcome are valuable as no prospective phase 3 trials have been conducted in...
OBJECTIVE/BACKGROUND
Data generated from retrospective studies on primary mediastinal B-cell lymphoma (PMBCL) outcome are valuable as no prospective phase 3 trials have been conducted in this rare type of lymphoma.
METHODS
Our goal was to assess the long-term outcome of 41 patients with PMBCL who were treated at the Kuwait Cancer Center. We evaluated two types of multidrug treatment, R-CHOP (rituximab, vincristine, doxorubicin, cyclophosphamide, and prednisone) and DA-EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), and determined overall survival and complete response (CR) as primary endpoints.
RESULTS
In our cohort, 27 (66%) cases were treated with R-CHOP and 14 (34%) cases were treated with DA-EPOCH-R. The overall median follow-up time was 34 months. Among the patients treated with R-CHOP, 23 out of 27 (92.6%) patients achieved CR; similarly, 10 out of 14 patients (85.7%) in the DA-EPOCH-R group achieved CR after initial treatment. There were no differences in OS between patients treated with R-CHOP versus DA-EPOCH-R.
CONCLUSION
The findings of this study indicate that combined chemotherapy and immunotherapy results in excellent long-term outcome of patients with PMBCL. At our center, we prefer R-CHOP to DA-EPOCH-R for low-risk patients with nonbulky disease.
Topics: Humans; Rituximab; Treatment Outcome; Prednisone; Vincristine; Retrospective Studies; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin
PubMed: 34118210
DOI: 10.1016/j.hemonc.2021.05.002 -
World Journal of Pediatrics : WJP Apr 2020Tacrolimus, a calcineurin inhibitor, is recommended by the recent guidelines from the Kidney Disease Improving Global Outcomes Group as the first-line treatment for...
BACKGROUND
Tacrolimus, a calcineurin inhibitor, is recommended by the recent guidelines from the Kidney Disease Improving Global Outcomes Group as the first-line treatment for steroid-resistant nephrotic syndrome (SRNS), but its clinical application in China is still limited. We investigated the efficacy and safety of tacrolimus combined with low-dose corticosteroids in a population of Chinese children with SRNS.
METHODS
In this prospective non-randomized, non-controlled study, Chinese children with SRNS who failed the previous full-dose prednisone treatment were given tacrolimus (0.1 mg/kg/day) and low-dose prednisone (0.25-0.50 mg/kg/day). We compared the overall remission rate (ORR) and adverse events in the follow-up period with this therapeutic regimen.
RESULTS
A total of 76 children were enrolled into the study with an average follow-up period of 18 ± 6 months (maximum 36 months). ORR achieved by the first, third, and sixth months was 94.7%, 94.7%, and 96.0%, respectively. All patients who attained an initial tacrolimus trough concentration (FK506C) > 6 ng/mL (60.3%) achieved remission. The relative risk of relapse at FK506C < 3 ng/mL compared to 3-6 ng/mL, 6-9 ng/mL, and 9-12 ng/mL was 2.3, 3.2, and 16.9, respectively. During the follow-up period, adverse effects that had been previously reported were rare.
CONCLUSIONS
Combination of tacrolimus and low-dose prednisone was safe and effective for the treatment of children with SRNS, with high remission rates observed as early as the first month. Relapses were infrequent, but tended to increase significantly with decreases in FK506C.
Topics: Adolescent; Calcineurin Inhibitors; Child; Child, Preschool; China; Drug Resistance; Female; Glucocorticoids; Humans; Male; Nephrotic Syndrome; Prednisone; Prospective Studies; Tacrolimus; Treatment Outcome
PubMed: 31049814
DOI: 10.1007/s12519-019-00257-z