High-dose Glucocorticoid Treatment Research Articles

OR19-5 The Impact Of High Dose Glucocorticoids On The Outcome Of Immune Checkpoint Inhibitor-related Thyroid Disorders And The Baseline TSH As A Predictive Biomarker

Thyroid disorders have emerged as one of the most common immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICI) therapy, yet optimum management and biomarkers to predict vulnerable individuals remain unknown. High dose glucocorticoid (HDG) therapy is routinely recommended for irAEs. However, systemic analysis of the impact of glucocorticoid therapy on the outcome of ICI-induced thyroid disorders is lacking. Our study analyzed presentation of thyroid disorders caused by different ICIs and examined the effects of systemic HDG treatment on the outcome of thyroid disorders. We analyzed 151 patients with or without ICI-related thyroid disorders. We divided the patients with ICI-related thyroid disorders into two subgroups: HDG and no HDG treatment. We evaluated the effects of HDG on the duration of thyrotoxicosis, the converting time from thyrotoxicosis to hypothyroidism, the onset time of hypothyroidism, and maintenance dose of levothyroxine. We explored the association of baseline TSH level with ICI-related thyroid disorders. Our results showed there were no significant differences between HDG and no HDG groups in terms of the median duration of thyrotoxicosis: 28 (range: 7-85) and 42 (range: 14-273) days, the median time to conversion from thyrotoxicosis to hypothyroidism: 39 days (range: 14-169) and 42 days (range: 14-315) days, the median time to onset of hypothyroidism: 63 (range: 21-190) and 63 (range: 14-489) days, and the median maintenance dose of levothyroxine: 1.5 (range: 0.4 - 2.3) μg/kg/day, and 1.3 (range: 0.3 - 2.5) μg/kg/day. The median pretreatment TSH levels were 2.3 (range: 0.3 - 5.2) mIU/L and 1.7 (range: 0.5 - 4.5) mIU/L in patients with and without ICPi-related thyroid disorders, respectively. The baseline TSH levels were significantly higher in patients who developed ICPi-related thyroid disorders (P = 0.05). Our results show that HDG treatment did not improve the outcome of ICPi-related thyroid disorders and higher baseline TSH increased the risk for the development of ICPi-related thyroid disorders.

High-Dose Glucocorticoid Treatment Does Not Induce Severe Hyperglycemia in Young Patients with Autoimmune Diseases by Cgms

High-dose glucocorticoids (HDG) are used in the treatment of autoimmune diseases. Glucocorticoids-induced hyperglycemia (GIH) is often described in elderly patients. In young patients with autoimmune diseases, however, the risk for GIH has not been well characterized. We recruited 24 inpatients (median age, 32 years; interquartile range, 25-42) with exacerbations of autoimmune diseases, receiving 1 to 2 mg/kg/day prednisone or equivalent methylprednisone. Fourteen subjects were naïve to glucocorticoids (group 1) and 10 subjects were on glucocorticoid maintenance (≤15 mg/day prednisone at least 3 months) (group 2) prior to HDG. All subjects were monitored by continuous glucose monitoring system (CGMS) for 3 days. GIH developed in 21 (91%) subjects, 11/13 in group 1 and 10/10 in group 2. The main peak of glucose excursion (128.7 ± 6.4 mg/dL, group 1; 143.9 ± 10.0 mg/dL, group 2) occurred at 2 to 3 pm. Another peak occurred before sleep. Two-hour mean postprandial glucose levels were normal in both groups: breakfast, 105.0 ± 28.4 versus 125.6 ± 24.4 mg/dL, P = .065; lunch, 115.7 ± 21.1 versus 135.9 ± 29.0 mg/dL, P = .082; dinner, 122.8 ± 18.5 versus 137.8 ± 26.4 mg/dL, P = .144 in groups 1 and 2, respectively. There was a positive association between pretreatment hemoglobin A1C and peak glucose levels ( P<.0001). Notably, 35% of our subjects experienced early morning hypoglycemia (65.2 ± 2.8 mg/dL). In hospitalized young patients with auto-immune diseases, CGMS data revealed that short-term consistent HDG treatment induced mild hyperglycemia, peaking in the early afternoon and before sleep. Early morning hypoglycemia was found in 35%. A1C = hemoglobin A1C; AUC = the area under the curve; BG = blood glucose; BMI = body mass index; CGMS = continuous glucose monitoring system; DM = diabetes mellitus; FBG = fasting blood glucose; GA = glycated albumin; GCs = glucocorticoids; GIH = glucocorticoids-induced hyperglycemia; HDG = high-dose glucocorticoids; HOMA-IR = Homeostasis Model Assessment-Insulin Resistance; IG = interstitial glucose; IQR = interquartile range; PUMCH = Peking Union Medical College Hospital; SLE = systemic lupus erythematosus.

2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

To develop recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP). We conducted a systematic review to synthesize the evidence for the benefits and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long-term (≥3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long-term GC treatment, as well as in special populations of long-term GC users. Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate-to-high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high-dose GC treatment, are also made. This guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision-making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

To develop recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP). We conducted a systematic review to synthesize the evidence for the benefits and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long-term (≥3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long-term GC treatment, as well as in special populations of long-term GC users. Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate-to-high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high-dose GC treatment, are also made. This guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision-making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

THE INFLUENCE OF AMIODARONE ON THYROID FUNCTION – A CASE REPORT

Amiodarone is an antiarrhythmic drug, commonly used in the treatment of ventricular and supraventricular arrhythmias. It can cause many side effects, including thyroid dysfunction, which can lead to either hypo- or hyperthyroidism. There are two types of amiodarone-induced hyperthyroidism. Type 1 affects patients with preexisting thyroid pathology and is the consequence of iodine excess. Type 2 is not related to preexisting thyroid pathology and is characterised by the presence of destructive thyroid inflammation. A 55-year old male was admitted to our hospital because of chest pain. He was diagnosed with atrial fibrillation and three vessel coronary artery disease, serum TSH concentration was normal. The patient later underwent coronary artery bypass surgery and was subsequently prescribed amiodarone. Two years later he became hyperthyroid, thyroid ultrasonography was consistent with autoimmune thyroid disease, however thyroid autoantibodies were negative. Amiodarone was discontinued and antithyroid drugs were introduced, leading to remission of hyperthyroidism. One month after the discontinuation of the antithyroid drugs the patient had a primary cardiac arrest, there were signs of diffuse ischemic cerebral injury. Due to nonsustained ventricular tachycardias an implantable cardioverter defibrillator was inserted, the patient was again prescribed amiodarone, and after three years of continuous amiodarone treatment hyperthyroidism recurred. As amiodarone discontinuation in conjunction with antithyroid drugs and high-dose glucocorticoid treatment did not result in remission, total thyroidectomy was safely performed. Pathohistological examination of the thyroid revealed pathologic changes consistent with amiodarone-induced hyperthyroidism type 2. Substitution therapy with levothyroxine was introduced on the 17th postoperative day. Peroral glucocorticoid therapy is the first line treatment of type 2 amiodarone-induced hyperthyroidism. However, in a selected group of patients, where medication therapy is unsuccessful, total thyroidectomy is an effective and safe modality, despite high-dose glucocorticoid treatment and other possible comorbidities. Furthermore, total thyroidectomy makes continuous amiodarone therapy possible, when it is necessary. It is important to keep in mind that high serum concentrations of free triiodothyronine and free thyroxine may persist for several days after total thyroidectomy.

Vpliv amiodarona na delovanje ščitnice – Prikaz primera

Amiodarone is an antiarrhythmic drug, commonly used in the treatment of ventricular and supraventricular arrhythmias. It can cause many side effects, including thyroid dysfunction, which can lead to either hypo- or hyperthyroidism. There are two types of amiodarone-induced hyperthyroidism. Type 1 affects patients with preexisting thyroid pathology and is the consequence of iodine excess. Type 2 is not related to preexisting thyroid pathology and is characterised by the presence of destructive thyroid inflammation.A 55-year old male was admitted to our hospital because of chest pain. He was diagnosed with atrial fibrillation and three vessel coronary artery disease, serum TSH concentration was normal. The patient later underwent coronary artery bypass surgery and was subsequently prescribed amiodarone. Two years later he became hyperthyroid, thyroid ultrasonography was consistent with autoimmune thyroid disease, however thyroid autoantibodies were negative. Amiodarone was discontinued and antithyroid drugs were introduced, leading to remission of hyperthyroidism. One month after the discontinuation of the antithyroid drugs the patient had a primary cardiac arrest, there were signs of diffuse ischemic cerebral injury. Due to nonsustained ventricular tachycardias an implantable cardioverter defibrillator was inserted, the patient was again prescribed amiodarone, and after three years of continuous amiodarone treatment hyperthyroidism recurred. As amiodarone discontinuation in conjunction with antithyroid drugs and high-dose glucocorticoid treatment did not result in remission, total thyroidectomy was safely performed. Pathohistological examination of the thyroid revealed pathologic changes consistent with amiodarone-induced hyperthyroidism type 2. Substitution therapy with levothyroxine was introduced on the 17th postoperative day.Peroral glucocorticoid therapy is the first line treatment of type 2 amiodarone-induced hyperthyroidism. However, in a selected group of patients, where medication therapy is unsuccessful, total thyroidectomy is an effective and safe modality, despite high-dose glucocorticoid treatment and other possible comorbidities. Furthermore, total thyroidectomy makes continuous amiodarone therapy possible, when it is necessary. It is important to keep in mind that high serum concentrations of free triiodothyronine and free thyroxine may persist for several days after total thyroidectomy.

Clinical course of pituitary function and image in IgG4-related hypophysitis.

A 76-year-old man had a hypopituitarism including adrenal insufficiency, hypogonadism and hypothyroidism. Based on various findings including the swelling of the pituitary gland, increase of serum IgG4 level and abundant IgG4-positive plasma cell infiltration in immunostaining of the pituitary gland, we diagnosed this subject as IgG4-related hypophysitis. In general, a high-dose glucocorticoid treatment is effective for IgG4-related disease. His clinical symptom, laboratory data and adrenal insufficiency were almost improved without any therapy. The serum IgG4 level was decreased and pituitary size was normalized with hydrocortisone as physiological replacement. This case report provides the possibility that IgG4 level is decreased spontaneously or with physiological dose of glucocorticoid therapy.Learning points:We performed the pituitary gland biopsy and histochemical examination glucocorticoid therapy in a subject with IgG4-related hypophysitis.This case report provides the possibility that IgG4 level is decreased spontaneously or with a physiological dose of glucocorticoid therapy. We reported the clinical course of IgG4-related hypophysitis without a high-dose glucocorticoid treatment, although there were a few reports about the retrospective examination.Although the patient had still higher IgG4 level compared to normal range, his clinical symptom disappeared and his laboratory data were improved.We should keep in mind the possibility of IgG4-related hypophysitis when we examine one of the uncertain causes of a hypopituitarism including adrenal insufficiency, hypogonadism and hypothyroidism.

Abstract #526: Clinical Vertebral Fracture and Mortality During High-Dose Glucocorticoid Treatment in Japanese Female Patients with Autoimmune Rheumatic Diseases.

Abstract #526: Clinical Vertebral Fracture and Mortality During High-Dose Glucocorticoid Treatment in Japanese Female Patients with Autoimmune Rheumatic Diseases.

STEROID-INDUCED PEDIATRIC DIABETES MELLITUS – LITERATURE REVIEW AND CASE REPORT

Glucocorticoids (GCs), one of the principal drug classes used in rheumatology, are known for their fast onset and powerful action, but also for their multiple adverse effects, the most feared ones being osteoporosis, steroidinduced diabetes (SID), cardiovascular diseases and, in children, the decrease of linear growth rate. Due to data scarcity, most SID treatment recommendations are not evidence-based. Using the minimum dose and shortest possible treatment are preventive measures generally recommended, which are frequently not followed, due to fear of GC-sparing immunosuppressive agents’ side effects (DMARDs). Physiologic dose splitting, whenever possible, can be efficient in preventing at least some of the GCs’ adverse effects, mainly the suppression of the hypothalamic-pituitary axis and SID. These are depicted by a case presentation, of a 12-year-old female patient with SID caused by high dose GC treatment for juvenile dermatomyositis (JDM), in whom this method was sufficient to control glycaemia.

Prolonged Glucocorticoid Treatment in ARDS: Impact on Intensive Care Unit-Acquired Weakness.

Systemic inflammation and duration of immobilization are strong independent risk factors for the development of intensive care unit-acquired weakness (ICUAW). Activation of the pro-inflammatory transcription factor nuclear factor-κB (NF-κB) results in muscle wasting during disuse-induced skeletal muscle atrophy (ICU bed rest) and septic shock. In addition, NF-κB-mediated signaling plays a significant role in mechanical ventilation-induced diaphragmatic atrophy and contractile dysfunction. Older trials investigating high dose glucocorticoid treatment reported a lack of a sustained anti-inflammatory effects and an association with ICUAW. However, prolonged low-to-moderate dose glucocorticoid treatment of sepsis and ARDS is associated with a reduction in NF-κB DNA-binding, decreased transcription of inflammatory cytokines, enhanced resolution of systemic and pulmonary inflammation, leading to fewer days of mechanical ventilation, and lower mortality. Importantly, meta-analyses of a large number of randomized controlled trials investigating low-to-moderate glucocorticoid treatment in severe sepsis and ARDS found no increase in ICUAW. Furthermore, while the ARDS network trial investigating methylprednisolone treatment in persistent ARDS is frequently cited to support an association with ICUAW, a reanalysis of the data showed a similar incidence with the control group. Our review concludes that in patients with sepsis and ARDS, any potential direct harmful neuromuscular effect of glucocorticoids appears outweighed by the overall clinical improvement and reduced duration of organ failure, in particular ventilator dependency and associated immobilization, which are key risk factors for ICUAW.

A High Fat diet containing Fish oil reduces weight gain and metabolic syndrome associated with glucocorticoid therapy

Obesity and metabolic syndrome are now recognized as significant health concerns for survivors of pediatric Acute Lymphoblastic Leukemia (ALL) and are consequences of their treatment. The majority of weight gain occurs during the induction phase of therapy (first 28 days), when patients receive various chemotherapies in addition to high dose glucocorticoids. Physiological levels of glucocorticoids are required for metabolic control, but chronic exposure to elevated doses has been linked to metabolic disease including type 2 diabetes and obesity. Nutrition plays an important role in the development of obesity and is also amongst the few adjustable parameters in the treatment of pediatric ALL. We therefore determined if a diet high in omega‐3 fatty acids provided by fish oil can reduce the weight gain and metabolic syndrome phenotype associated chronic high dose glucocorticoid treatment. 3 week old C57BL/6 male mice were fed a “Western type” diet (45% calories from fat (lard) (HFL)) ad libitum. At 6 weeks of age, mice received the synthetic glucocorticoid, Prednisolone, at a dose of 40 mg/m2/day for 28 days. During the Prednisolone treatment, mice either remained on the HFL diet or were switched to an isocaloric diet containing 45% fat from fish oil (HFO). Body weight, food consumption, fat deposition in the liver, accumulation of epididymal adipose tissue and adipocyte size were determined. Mice on the HFO diet gained less weight during the treatment period (P = 0.03), with a dramatic decrease in fat deposition in the liver irrespective of glucocorticoid treatment. Epididymal adipose depots were smaller in mice consuming the HFO diet (P &lt; 0.0001) with a concomitantly decrease in systemic Leptin levels (P = 0.05). Interestingly, glucocorticoid therapy caused a significant increase in adipocyte size when the mice are consuming the HFL diet (P = 0.001). The results from this study suggest that a dietary intervention in the form of fish oil during glucocorticoid treatment can reduce weight gain and metabolic syndrome and reduce long term consequences of ALL treatment.Support or Funding InformationFY16 Faculty Research Grant (University of Memphis)

Short-term assessment of BCR repertoires of SLE patients after high dose glucocorticoid therapy with high-throughput sequencing.

We analyze and assess BCR repertoires of SLE patients before and after high dose glucocorticoid therapy to address two fundamental questions: (1) After the treatment, how the BCR repertoire of SLE patient change on the clone level? (2) How to screen putative autoantibody clone set from BCR repertoire of SLE patients? The PBMCs of two SLE patients (P1 and P2) at different time points were collected, and DNA of these samples were extracted. High-throughput sequencing technology was applied in detection of BCR repertoire. Finally, we used bioinformatic methodology to analyse sequence data. We found that these two patients lost some IGHV3 family genes usage after treatment compared with before treatment. For pairing of IGHV–IGHJ gene, no significant change was shown for each patient. In addition, analyses of the composition of H-CDR3 showed overall AA compositions of H-CDR3 at three time points in each SLE patients were very similar, and the results of H-CDR3 AA usage that had the same length (14 AA) and the same position were similar. Antinuclear antibody tests of SLE patients showed that level of some antinuclear antibodies reduced after treatment; however, there was no sign that the percentage of autoantibody clones in BCR repertoires would reduce. High dose glucocorticoid treatment in short term will have little impact on composition of BCR repertoire of SLE patient. Treatment can reduce the amount of autoantibody in the protein level, but may not reduce the percentage of autoantibody clones in BCR repertoire in the clonal level.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-1709-4) contains supplementary material, which is available to authorized users.

Oral and inhaled glucocorticoid use and risk of Achilles or biceps tendon rupture: a population-based case-control study

Background. Tendinotoxicity of glucocorticoids (GC) has been shown, but evidence on how this translates into clinical practice remains scarce.Objectives. To explore the association between oral or inhaled GC use and the risk of Achilles or biceps tendon rupture (ATR/BTR).Methods. We identified patients aged 18 to 89 years with incident ATR or BTR (1995–2013) for a matched (1:4) case-control analysis using the UK-based Clinical Practice Research Datalink. We stratified oral GC use by indication, timing and duration of use, continuous versus intermittent use, cumulative dose, and average daily dose. We stratified inhaled GC use by timing and number of prescriptions.Results. Among 8,202 cases, we observed increased odds ratios (ORs) around 3.0 for continuous oral GC use, which declined shortly after therapy cessation (similarly across indications). Odds ratios increased with average daily dose (≥ 10 mg/day, OR 4.05, 95% CI 2.32–7.08) and were elevated after one cycle of high-dose oral GC (≥ 20 mg/day). There was no effect of inhaled GC at any level of exposure.Conclusion. Our results provide evidence that oral GC therapy increases the risk of tendon rupture in a dose–response relationship. A single short-term high-dose GC treatment course may be sufficient transiently to increase the risk of tendon rupture.

Current smoking is an independent risk factor for new-onset diabetes mellitus during highdose glucocorticoid treatment.

Although high-dose glucocorticoids have been reported to cause new-onset diabetes mellitus (glucocorticoid-induced diabetes mellitus), its risk factors have remained to be determined. We investigated the risk factors related to glucocorticoid-induced diabetes mellitus diagnosed within 2 months after the high-dose treatment (newly treated with an initial high dose of > 20 mg prednisolone (PSL) equivalent per day for at least more than 6 months) in collagen vascular diseases. A total of 2,631 patients with collagen vascular diseases was registered between 1986 and 2006 in the Chiba-Shimoshizu Rheumatic Cohort. We analyzed 681 patients newly treated with high-dose glucocorticoid who did not have diabetes mellitus and/or its previous diagnosis (age: 46.3 ± 16.7 years, PSL dose: 40.0 ± 14.1 mg/day). Glucocorticoid-induced diabetes mellitus was diagnosed by two or more glucose measurements in patients with fasting glycaemia ≥ 7 mmol/L and 120 minutes post-load glycaemia ≥ 11.1 mmol/L. Glucocorticoid-induced diabetes mellitus was observed in 26.3% of patients, and the glucocorticoid-induced diabetes mellitus group had higher age, higher BMI, lower rates of females and systemic lupus erythematosus, higher rates of smoking, alcohol use, and microscopic polyangiitis. Multivariate logistic regression analysis demonstrated that the risk of glucocorticoid-induced diabetes mellitus was independently higher in every 10-year increment of initial age with adjusted odds ratio (OR) 1.556 (95% confidence interval: 1.359 - 1.783), in every 1 kg/m2 increment of BMI with OR 1.062 (1.002 - 1.124), in current smoking with OR 1.664 (1.057 - 2.622), and in every 10 mg increment of initial dose of prednisolone with OR 1.250 (1.074 - 1.454). High-dose glucocorticoids caused diabetes mellitus with high prevalence within a short period, and current smokers should be considered at higher risk of glucocorticoidinduced diabetes mellitus in addition to age, BMI, and initial dose.

Short-term, high-dose glucocorticoid treatment does not contribute to reduced bone mineral density in patients with multiple sclerosis

Background: Patients with multiple sclerosis (MS) are at increased risk of reduced bone mineral density (BMD). A contributing factor might be treatment with high-dose glucocorticoids (GCs). Objectives: The objective of this paper is to assess bone mass in patients with MS and evaluate the importance of short-term, high-dose GC treatment and other risk factors that affect BMD in patients with MS. Methods: A total of 260 patients with MS received short-term high-dose GC treatment and had their BMD measured by dual x-ray absorptiometry. BMD was compared to a healthy age-matched reference population (Z-scores). Data regarding GCs, age, body mass index (BMI), serum 25(OH)D, disease duration and severity were collected retrospectively and analysed in a multiple linear regression analysis to evaluate the association between each risk factor and BMD. Results: Osteopenia was present in 38% and osteoporosis in 7% of the study population. Mean Z-score was significantly below zero, indicating a decreased BMD in our MS patients. Multiple linear regression analysis showed no significant association between GCs and BMD. In contrast, age, BMI and disease severity were independently associated with both lumbar and femoral BMD. Conclusion: Reduced BMD was prevalent in patients with MS. GC treatment appears not to be the primary underlying cause of secondary osteoporosis in MS patients.

Clinical features and risk factors for myasthenia gravis crisis after impact therapy of glucocorticoid

Objective To investigate the clinical features and risk factors for myasthenia gravis crisis (MGC) after impact therapy of glucocorticoid. Methods Clinical data of 59 MG patients were retrospectively analyzed. All of them received high-dose glucocorticoid treatment, and 16 patients developed into MGC. Clinical Absolute Score (CAS) was obtained on admission, then at 4, 7, 14, 21, 28 d after treatment initiation, so as to evaluate the severity of disease. Clinical Relative Score (CRS) was used to evaluate the changes of patients' condition. The clinical features, scores and risk factors in MGC group were compared with non-MGC (NMGC) group. Results Most patients (69.49% , 41/59) had transient muscle weakness after glucocorticoid impact therapy. CAS of MGC group increased at 4 d (37.63 ± 1.80; t = 4.410, P = 0.028), then decreased at 7 d (32.94 ± 2.29), until 14 d after therapy (22.19 ± 1.75), which was significantly lower than that before treatment (31.31 ± 2.07; t = 12.701, P = 0.000). CAS of NMGC group showed a downward trend after treatment. It showed a significant decrease at 14 d after therapy (12.37 ± 1.11) compared with that before treatment (21.27 ± 1.39; t = 5.740, P = 0.000), which was consistent with its clinical manifestations. In MGC group, CRS increased gradually from 7 d [(-0.06 ± 0.06)%] after treatment till 28 d [(0.82 ± 0.03)%], which was significantly different from 4 d [(-0.23 ± 0.05)%; t = 28.232, P = 0.000). Similarly, CRS of NMGC group increased gradually and showed significant difference till 21 d [(0.53 ± 0.04)%] when compared with 4 d [(0.03 ± 0.04)%; t = 4.312, P = 0.000]. Logistic regression analysis showed relative old age, increasing CAS, infection, bulbar muscular weakness and comorbid immunological disorders were crisis-prone factors, but old age was the only factor closely related to the occurrence of MGC. Conclusions Relative old age maybe the risk factor for MGC after impact therapy of glucocorticoid. Monitoring the disease change closely, screening out high-risk patients timely, intravenous immunoglobulin (IVIg) and respiratory support are all very important for successful treatment and low mortality. doi: 10.3969/j.issn.1672-6731.2014.10.011

Modeling hemoglobin and hemoglobin:haptoglobin complex clearance in a non-rodent species–pharmacokinetic and therapeutic implications

Background: Haptoglobin (Hp) prevents hemoglobin (Hb) extravasation and attenuates Hb induced tissue oxidation and vasoconstriction. Small animal models such as mouse, rat and guinea pig appear to demonstrate proof-of-concept for Hb neutralization by Hp in diverse pre-clinical conditions. However, these species differ significantly from humans in the clearance of Hb:Hp and demonstrate long persistence of circulating Hb:Hp complexes.Objective: The focus of this study is to understand Hb:Hp clearance in a non-rodent species. In contrast to rodents, dogs maintain high plasma Hp concentrations comparable to humans and demonstrate more rapid clearance of Hb:Hp when compared to rodent species, therefore dogs may represent a relevant species to evaluate Hb:Hp pharmacokinetics and cellular clearance.Results: In this study we show, that like human macrophages, dog peripheral blood monocyte derived macrophages express a glucocorticoid inducible endocytic clearance pathways with a high specificity for the Hb:Hp complex. Evaluating the Beagle dog as a non-rodent model species we provide the first pharmacokinetic parameter estimates of free Hb and Hb:Hp complexes. The data demonstrate a significantly reduced volume of distribution (Vc) for Hb:Hp compared to free Hb, increased maximum plasma concentrations and areas under plasma concentration time curves (Cmax and AUC). Significantly reduced total body clearance (CL) and a longer terminal half-life (t1/2) of approximately 12 h were also observed for the Hb:Hp complex. Distribution and clearance were identical for dimeric and multimeric Hb:Hp complexes. We found no significant effect of a high-dose glucocorticoid treatment protocol on Hb:Hp pharmacokinetic parameter estimates.Conclusion: Collectively, our study supports the dog as a non-rodent animal model to study pharmacological and pharmacokinetic aspects of Hb clearance systems and apply the model to studying Hp as a therapeutic in diseases of hemolysis.

Postnatal glucocorticoid-induced hypomyelination, gliosis, and neurologic deficits are dose-dependent, preparation-specific, and reversible

Postnatal glucocorticoids (GCs) are widely used in the prevention of chronic lung disease in premature infants. Their pharmacologic use is associated with neurodevelopmental delay and cerebral palsy. However, the effect of GC dose and preparation (dexamethasone versus betamethasone) on short and long-term neurological outcomes remains undetermined, and the mechanisms of GC-induced brain injury are unclear. We hypothesized that postnatal GC would induce hypomyelination and motor impairment in a preparation- and dose-specific manner, and that GC receptor (GR) inhibition might restore myelination and neurological function in GC-treated animals. Additionally, GC-induced hypomyelination and neurological deficit might be transient. To test our hypotheses, we treated prematurely delivered rabbit pups with high (0.5mg/kg/day) or low (0.2mg/kg/day) doses of dexamethasone or betamethasone. Myelin basic protein (MBP), oligodendrocyte proliferation and maturation, astrocytes, transcriptomic profile, and neurobehavioral functions were evaluated. We found that high-dose GC treatment, but not low-dose, reduced MBP expression and impaired motor function at postnatal day 14. High-dose dexamethasone induced astrogliosis, betamethasone did not. Mifepristone, a GR antagonist, reversed dexamethasone-induced myelination, but not astrogliosis. Both GCs inhibited oligodendrocyte proliferation and maturation. Moreover, high-dose dexamethasone altered genes associated with myelination, cell-cycle, GR, and mitogen-activated protein kinase. Importantly, GC-induced hypomyelination, gliosis, and motor-deficit, observed at day 14, completely recovered by day 21. Hence, high-dose, but not low-dose, postnatal GC causes reversible reductions in myelination and motor functions. GC treatment induces hypomyelination by GR-dependent genomic mechanisms, but astrogliosis by non-genomic mechanisms. GC-induced motor impairment and neurodevelopmental delay might be transient and recover spontaneously in premature infants.

High-dose corticosterone after fear conditioning selectively suppresses fear renewal by reducing anxiety-like response

Exposure therapy is widely used to treat anxiety disorders, including posttraumatic stress disorder (PTSD). However, preventing the return of fear is still a major challenge after this behavioral treatment. An increasing number of studies suggest that high-dose glucocorticoid treatment immediately after trauma can alleviate the symptoms of PTSD in humans. Unknown is whether high-dose glucocorticoid treatment following fear conditioning suppresses the return of fear. In the present study, a typical fear renewal paradigm (AAB) was used, in which the fear response to an auditory cue can be restored in a novel context (context B) when both training and extinction occur in the same context (context A). We trained rats for auditory fear conditioning and administered corticosterone (CORT; 5 and 25mg/kg, i.p.) or vehicle with different delays (1 and 24h). Forty-eight hours after drug injection, extinction was conducted with no drug in the training context, followed by a test of tone-induced freezing behavior in the same (AAA) or a shifted (AAB) context. Both immediate and delayed administration of high-dose CORT after fear conditioning reduced fear renewal. To examine the anxiolytic effect of CORT, independent rats were trained for cued or contextual fear conditioning, followed by an injection of CORT (5 and 25mg/kg, i.p.) or vehicle at a 1 or 24h delay. One week later, anxiety-like behavior was assessed in the elevated plus maze (EPM) before and after fear expression. We found that high-dose CORT decreased anxiety-like behavior without changing tone- or context-induced freezing. These findings indicate that a single high-dose CORT administration given after fear conditioning may selectively suppress fear renewal by reducing anxiety-like behavior and not by altering the consolidation, retrieval, or extinction of fear memory.

SAT0282 Clinical and Laboratory Characteristics Associated with Visual Complications in Patients with Biopsy-Proven GIANT Cell Arteritis

BackgroundEarly diagnosis of giant cell arteritis (GCA) and prompt initiation of high-dose glucocorticoid treatment is important to avoid permanent organ damage. One of the most feared outcomes in GCA are...