Comparative analysis of the 2016 ACR-EULAR and the 2002 AECG classification criteria for Sjögren's syndrome: Findings from the NIH cohort.

INTRODUCTION: The introduction of new classification criteria for Sjögren's syndrome, known as the 2016 American College of Rheumatology/European League against Rheumatism Classification Criteria (ACR-EULAR), created a need for the evaluation of its performance in an external cohort. The purpose of this study was to compare the performance of the 2016 ACR-EULAR classification set with the widely used American-European Consensus Group Classification criteria (AECG) in the cohort at the National Institutes of Health, USA, and to compare the performance of the sets in classifying both primary and secondary Sjögren's syndrome (pSS and sSS). METHODS: The study cohort at the NIH (N = 1,303) was enrolled for clinical suspicion of SS. Participants were classified as SS, pSS, and sSS according to both classification sets. Performance of 2016 ACR-EULAR and AECG sets was compared holding each as gold standard to the other. Statistical analysis of test diagnostics and agreement between the two sets were undertaken. RESULTS: By the AECG set, 701 were classified as having SS (627 pSS, 74 sSS) and 714 were classified with SS (647 pSS, 67 sSS) by the 2016 ACR-EULAR set. Sensitivity and specificity of the two sets were comparable in classifying SS, pSS, and sSS. There was high agreement between the two sets for classifying SS (κ = 0.79), pSS (κ = 0.81), and sSS (κ = 0.87). The specificity of the 2016 ACR-EULAR set was significantly higher for classifying sSS than pSS, while the sensitivity was similar for the two disease groups. However, this pattern was also exhibited by the AECG set. CONCLUSION: There was high agreement between the two classification sets with comparable performance diagnostics. There was no evidence of superior performance value by the new 2016 ACR-EULAR set over the AECG set, and the two sets were found to be equivalent. Findings from our cohort indicate that 2016 ACR-EULAR classification could be extended to classification of sSS.

Elucidating the role of hyposalivation and autoimmunity in oral candidiasis.

INTRODUCTION: Oral candidiasis (OC) is a potential oral complication in Sjögren's syndrome (SS). Some studies indicate that the low stimulated salivary flow and not low unstimulated salivary flow is associated with OC in SS, while others report that the underlying autoimmune disorders contribute to OC, based solely on correlation coefficients. Given the conflicting and limited existing evidence, we purposed to ascertain the role of both salivary gland dysfunction (hyposalivation based on unstimulated and stimulated flow rates) and autoimmunity (SS, other autoimmune disorders) in OC among those with SS, other salivary gland dysfunction, and non-salivary gland dysfunction controls (NSGD). METHODS: A nested case-control study was designed within a larger NIH/NIDCR cohort. Descriptive analyses, nonparametric tests, comparative analyses, and multivariate logistic regression analyses were undertaken. RESULTS: Data on 1526 subjects (701 SS, 247 ISS, 355 Sicca, and 223 NSGD) were obtained from the source cohort of 2046 and analyzed for this study. The median whole unstimulated salivary flow rate (WUS, ml 15 min-1 ) was lower in SS (0.8, interquartile range (IQR) 1.8) compared to ISS (5.5, IQR: 5.2, P < 0.001) and NSGD (3.8, IQR: 3.8, P < 0.001) but comparable with that of Sicca (1.0, IQR: 1.5, P = 0.777) participants. The median total stimulated salivary flow rate (TSS, ml 15 min-1 ) was lowest in SS (7.0, IQR: 12.4, P < 0.001) compared to other groups. Of the 45 OC cases in this cohort, 71.1% (n = 32) were from the SS group. The prevalence of OC was highest in the SS group (4.6%, P = 0.008). SS group had twice the risk of OC than NSGD (OR = 2.2, 95%CI: 1.1-4.2, P = 0.02) and Sicca (OR = 2.2, 95% CI: 1.0-4.8, P = 0.03), adjusting for confounders; hyposalivation [WUS (OR = 5.1, 95%CI: 2.5-10.4, P < 0.001), TSS (OR = 1.9, 95%CI: 1.0-3.5, P = 0.04)], history of other autoimmune disorders (OR = 4.4, 95%CI: 1.7-11.3, P = 0.002), medications for extraglandular manifestations (OR = 2.3, 95%CI: 1.1-4.9, P = 0.03), and diabetes mellitus (4.2, 95%CI: 1.2-15.2, P = 0.02) were independent predictors of OC; females had a lower risk than males (OR = 0.29, 95%CI: 0.13-0.67, P = 0.004). Age, race, anti-SSA/SSB autoantibodies, focus score, other medications, anxiety, fatigue, cigarette smoking, alcohol, and caffeine use were not associated with oral candidiasis. CONCLUSION: Salivary gland dysfunction (hyposalivation with WUS being a stronger predictor than TSS) and autoimmunity (SS, other autoimmune disorders, medications, i.e., DMARDS) are both independent predictors of OC. Diabetes mellitus is an independent predictor of OC among those with salivary gland dysfunction. Our findings suggest that these independent predictors should be considered in the prevention and management of OC in this population.

Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction.

We evaluated late effects of AdhAQP1 administration in five subjects in a clinical trial for radiation-induced salivary hypofunction (http://www.clinicaltrials.gov/ct/show/NCT00372320?order=). All were identified as initially responding to human aquaporin-1 (hAQP1) gene transfer. They were followed for 3-4 years after AdhAQP1 delivery to one parotid gland. At intervals we examined salivary flow, xerostomic symptoms, saliva composition, vector presence and efficacy in the targeted gland, clinical laboratory data and adverse events. All displayed marked increases (71-500% above baseline) in parotid flow 3-4.7 years after treatment, with improved symptoms for ~2-3 years. There were some changes in [Na+] and [Cl-] consistent with elevated salivary flow, but no uniform changes in secretion of key parotid proteins. There were no clinically significant adverse events, nor consistent negative changes in laboratory parameters. One subject underwent a core needle biopsy of the targeted parotid gland 3.1 years post treatment and displayed evidence of hAQP1 protein in acinar, but not duct, cell membranes. All subjects responding to hAQP1 gene transfer initially had benefits for much longer times. First-generation adenoviral vectors typically yield transit effects, but these data show beneficial effects can continue years after parotid gland delivery.

Dose-response effects of TPI ASM8 in asthmatics after allergen.

BACKGROUND: TPI ASM8 contains two modified antisense oligonucleotides (AON) targeting the beta subunit (ß(c) ) of the IL-3, IL-5, GM-CSF receptors and the chemokine receptor CCR3. A previous study suggested that TPI ASM8 had broader effects than just inhibition of eosinophils in asthmatics. OBJECTIVE: We assessed whether TPI ASM8 caused a dose-dependent attenuation in the inflammatory and physiological changes after inhaled allergen challenge (AIC). METHODS: This single-center, open-label, stepwise-ascending dose study was conducted in fourteen stable, mild allergic asthmatics. Following placebo AIC, subjects underwent AIC after 4 days treatment with 1, 2, and 4 mg BID and finally 8 mg once daily (OD) of TPI ASM8, inhaled via the I-Neb™ nebuliser. Treatments were separated by 2-3-week washout periods. RESULTS: TPI ASM8 was safe and well tolerated at all doses. TPI ASM8 8 mg OD reduced eosinophils in sputum after AIC (by 60.9% at 7 h and 68.4% at 24 h post-AIC, P=0.016 and P=0.007, respectively). Additionally, TPI ASM8 8 mg OD significantly attenuated the early and late airway responses as shown by the reduction in the area under the curve by 45% (P=0.016) and 59%, (P=0.0015), respectively, the increase in eosinophil cationic protein (ECP) by up to 57% (P=0.021), and airway responsiveness to methacholine by more than 1 doubling dose (P=0.012). A dose-response relationship was noted, and efficacy was maintained with once per day administration. CONCLUSIONS: TPI ASM8 attenuated a broad range of inflammatory and physiological changes after AIC, suggesting that CCR3, IL-3, and GM-CSF also are important targets for the management of asthma.

Protection against methacholine-induced bronchospasm: salbutamol pMDI versus Clickhaler DPI.

Passive dry-powder inhalers (DPIs) have been developed as an alternative to pressurised metered-dose inhalers (pMDIs) to improve aerosol delivery on inhalation and eliminate the need for propellants. However, new DPI formulations of generic drugs must be rigorously compared with conventional pMDI therapy. This randomised, double-blind, double-dummy, placebo-controlled, seven-way crossover study evaluated bronchoprotection from methacholine challenge in order to compare a novel salbutamol DPI (Clickhaler) with a reference salbutamol pMDI (Ventolin). Adult asthma patients with airway hyperresponsiveness to methacholine (provocative concentration of methacholine causing a 20% fall in the forced expiratory volume in one second (PC20) <4 mg x mL(-1)) were treated on separate days with 0, 100, 200 or 400 microg of salbutamol via the DPI or pMDI. Methacholine challenge was performed before and after salbutamol treatment and the PC20 ratios analysed by Finney's bioassay to test for therapeutic equivalence of the inhalers. Eighteen patients completed the study and showed significant dose-related responses to salbutamol. The relative potency of DPI:pMDI was 1.29 (90% confidence interval 1.04-1.63). There were no treatment differences in safety (cardiac frequency, blood pressure, adverse events). Methacholine-challenge methodology provides a sensitive bioassay and has demonstrated therapeutic equivalence of the salbutamol Clickhaler dry-powder inhaler with the conventional salbutamol pressurised metered-dose inhaler.

Reproducibility of bronchodilator response for a reservoir dry powder inhaler following routine clinical use.

The performance of dry powder inhaler (DPI) devices, particularly reservoir DPIs, may be influenced by environmental conditions. This study compared the bronchodilator efficacy and in vitro aerosol characteristics of salbutamol, delivered via a novel reservoir DPI (Clickhaler) and a conventional pressurized metered-dose inhaler (MDI) before and after use of the DPI in clinical practice. Following a screening visit, patients received cumulative doses of salbutamol (100, 200, and 400 microg) via DPI or MDI on separate days in a double-blind, crossover design before and after a 4-week period, during which the DPI was used as the patients' first-line bronchodilator. Lung function responses (forced expiratory volume in 1 sec [FEV1], forced vital capacity [FVC], and peak expiratory flow [PEF]) to salbutamol delivered by DPI and MDI and in vitro aerosol characteristics were not significantly different before and after the period of DPI patient use. DPI performance, assessed in vivo and in vitro, is maintained following an extended period of patient use.

Clickhaler (a novel dry powder inhaler) provides similar bronchodilation to pressurized metered-dose inhaler, even at low flow rates.

STUDY OBJECTIVE: Comparison of the bronchodilator response to an albuterol novel dry powder inhaler (DPI) (Clickhaler [CH]; ML Laboratories PLC; St. Albans, UK) activated at various inspiratory flow rates and to an albuterol pressurized metered-dose inhaler (pMDI) by patients with moderate to moderately severe stable asthma. DESIGN: Randomized, double-blind, placebo-controlled comparison of the bronchodilator response to albuterol DPI (200 microg) at inspiratory flow rates of approximately 15, 30, and 60 L/min in patients with stable asthma with demonstrated reversibility to albuterol. Active (albuterol via pMDI inhaled at 30 L/min) and placebo controls were included. SETTING: Single center study at the chest/allergy unit of a teaching hospital in Canada. PATIENTS: Sixteen patients with moderate to moderately severe stable asthma. MEASUREMENTS AND RESULTS: Efficacy end points were FEV1, FVC, FEV1/FVC, maximum expiratory flow, and forced expiratory flow between 25% and 75% of vital capacity. Safety end points included heart rate, BP, and tremor. There was no significant difference between the bronchodilator response to albuterol via the CH at 15, 30, and 60 L/min inspiratory flow rate and, at all flow rates, no significant difference was found comparing albuterol CH with the pMDI. All of the techniques for delivering albuterol provided significantly better bronchodilatation than placebo. Adverse events were minimal and did not differ between CH and pMDI or between the various flow rates inhaled through the CH. CONCLUSION: A novel passive albuterol DPI (CH) provides a similar bronchodilator response at 15, 30, and 60 L/min inspiratory flow rates compared with a pMDI used optimally.

Outsourcing: considerations for healthcare protection managers.

The author discusses the use of contract services--myths, advantages, and disadvantages. He provides tips on what to look out for and what questions to ask before making a change to contract security.

Design, development and performance of a novel multidose dry-powder inhaler.

The authors describe the design and development of a breath-actuated multidose dry-powder inhaler and summarize the in vitro and in vivo data demonstrating its robustness and performance in the laboratory and during clinical use. Drugs for the treatment of asthma--including budesonide, beclomethasone dipropionate and salbutamol--when formulated with lactose powder as a carrier and dispensed via this device, have exhibited clinical efficacy and safety profiles comparable with standard pressurized metered-dose inhalers and dry-powder formulations.

Furosemide decreases the sensitivity of glucose transport to insulin in skeletal muscle in vitro.

The effects of the diuretic furosemide on the sensitivity of glucose disposal to insulin were investigated in rat soleus muscle in vitro. At basal levels of insulin, the rates of 3-O-methylglucose transport, 2-deoxyglucose phosphorylation and lactate formation were not affected significantly by furosemide (0.5 mmol/l). However, furosemide significantly decreased these rates at physiological and maximal levels of insulin. The contents of 2-deoxyglucose and glucose 6-phosphate in the presence of furosemide were not significantly different from those in control muscles at all levels of insulin studied. It is concluded that furosemide decreases the sensitivity of glucose utilization to insulin in skeletal muscle by directly inhibiting the glucose transport process.

Use of whole-body plethysmography to compare bronchodilator inhaler efficacy.

Whole-body plethysmography is not included in guidelines from regulatory authorities for the development of treatments or delivery devices for lung disease, despite its potential advantages compared to spirometry. Two separate studies were undertaken to assess the use of specific airway conductance (sGaw) as a pharmacodynamic endpoint for the comparison of two bronchodilator delivery systems (a novel dry powder inhaler and a standard metered dose inhaler). The first pilot study involved delivery of a single dose of salbutamol (200 micrograms) to 12 healthy volunteers and determination of sGaw up to 120 min after treatment. The second study involved delivery of cumulative doses of salbutamol (100, 200 and 400 micrograms) to 19 healthy volunteers with demonstrated reversibility of sGaw to the bronchodilator and measurement of sGaw up to 240 min after treatment. In both studies, increases in sGaw after treatment were significant compared to placebo and larger than the recorded increases in FEV1. Increases in sGaw were similar for both delivery devices and support the therapeutic equivalence of the two products. Power calculations indicated that the second study had appropriate statistical power to discriminate between treatments. It is concluded that the assessment of sGaw in healthy volunteers may be a useful and sensitive pharmacodynamic endpoint for use in the development of bronchodilators and their delivery devices.

The effects of insulin on transport and metabolism of glucose in skeletal muscle from hyperthyroid and hypothyroid rats.

The effects of insulin on the rates of glucose disposal were studied in soleus muscles isolated from hyper- or hypothyroid rats. Treatment with triiodothyronine for 5 or 10 days decreased the sensitivity of glycogen synthesis but increased the sensitivity of lactate formation to insulin. The sensitivity of 3-O methylglucose to insulin was increased only after 10 days of treatment and was accompanied by an increase in the sensitivity of 2-deoxyglucose phosphorylation; however, 2-deoxyglucose and glucose 6-phosphate in response to insulin remained unaltered. In hypothyroidism, insulin-stimulated rates of 3-O-methylglucose transport and 2-deoxyglucose phosphorylation were decreased; however, at basal levels of insulin, 3-O-methylglucose transport was increased, while 2-deoxyglucose phosphorylation was normal. In these muscles, the sensitivity of lactate formation to insulin was decreased; this defect was improved after incubation of the muscles with prostaglandin E2. The results suggest: (a) in hyperthyroidism, insulin-stimulated rates of glucose utilization in muscle to form lactate are increased mainly because of a decrease in glycogen synthesis; when hyperthyroidism progresses in severity, increases in the sensitivity of glucose transport to insulin and in the activity of hexokinase may also be involved; (b) in hypothyroidism, the decrease in insulin-stimulated rates of glucose utilization is caused by decreased rates of glycolysis; (c) prostaglandins may be involved in the changes in sensitivity of glucose utilization to insulin observed in muscle in altered thyroid states.

Relative bioavailability of salbutamol to the lung following inhalation via a novel dry powder inhaler and a standard metered dose inhaler.

AIMS: The number of dry powder inhaler (DPI) devices could increase because they are easier to use than a metered dose inhaler (MDI). Using urinary excretion, the relative bioavailability of salbutamol to the lungs and the body for a prototype DPI has been compared with an MDI. METHODS: A randomized, double-blind, two way crossover study compared the amount of salbutamol in the urine 30 min following inhalation of 2 x 100 micrograms salbutamol from a prototype DPI (Innovata Biomed Ltd, UK) and a Ventolin (Allen and Hanburys Ltd, UK) MDI in 10 volunteers. The amount of salbutamol and its metabolite, the ester sulphate conjugate, renally excreted up to 24 h post inhalation was also determined to evaluate the relative bioavailability of salbutamol to the body. RESULTS: The mean (s.d.) 30 min post-treatment urinary excretion for the prototype DPI and MDI was 8.4 (2.6) and 5.0 (1.9) micrograms, respectively (P < 0.001). The total amount of salbutamol and its ester metabolite excreted in the urine over the 24 h period after inhalation was 187.9 (77.6) and 137.6 (40.0) micrograms (P < 0.05). CONCLUSIONS: The prototype DPI delivered more salbutamol to the body and the lungs than a conventional MDI. This finding supports further development of the prototype DPI. The urinary salbutamol method is able to discriminate between two different inhalation systems.

Effects of glucocorticoid excess on the sensitivity of glucose transport and metabolism to insulin in rat skeletal muscle.

GENBANK/dy examines the mechanisms of glucocorticoid-induced insulin resistance in rat soleus muscle. Glucocorticoid excess was induced by administration of dexamethasone to rats for 5 days. Dexamethasone decreased the sensitivity of 3-O-methylglucose transport, 2-deoxyglucose phosphorylation, glycogen synthesis and glucose oxidation to insulin. The total content of GLUT4 glucose transporters was not decreased by dexamethasone; however, the increase in these transporters in the plasma membrane in response to insulin (100 m-units/litre) was lessened. In contrast, the sensitivity of lactate formation to insulin was normal. The content of 2-deoxyglucose in the dexamethasone-treated muscle was decreased at 100 m-units/litre insulin, while the contents of glucose 6-phosphate and fructose 2,6-bisphosphate were normal at all concentrations of insulin studied. The maximal activity of hexokinase in the soleus muscle was not affected by dexamethasone; however, inhibition of this enzyme by glucose 6-phosphate was decreased. These results suggest the following. (1) Glucocorticoid excess causes insulin resistance in skeletal muscle by directly inhibiting the translocation of the GLUT4 glucose transporters to the plasma membrane in response to insulin; since the activity of hexokinase is not affected, the changes in the sensitivity of glucose phosphorylation to insulin seen under these conditions are secondary to those in glucose transport. (2) The sensitivity of glycogen synthesis and glucose oxidation to insulin is decreased, but that of glycolysis is not affected: a redistribution of glucose away from the pathway of glycogen synthesis and glucose oxidation could maintain a normal rate of lactate formation although the rate of glucose transport is decreased.

Growth hormone suppression and glutamine flux associated with cardiac surgery.

Pharmacological doses of growth hormone (GH) in humans and rats increase plasma and muscle glutamine values. As major surgery results in a physiological rise in serum GH concentration, we investigated whether this physiological increase in GH altered glutamine metabolism. Eighteen patients undergoing coronary artery bypass graft (CABG) surgery were randomly assigned to receive somatostatin, 100 micrograms subcutaneously at induction of anaesthesia and 8 hourly for 48 h, or placebo. Somatostatin effectively blocked the physiological surge of GH following injury but did not affect plasma or muscle glutamine concentrations, which fell significantly in both groups. Plasma glutamine decreased by 31% (P < 0.01) and 28% (P < 0.01) in the control and somatostatin groups respectively. Muscle glutamine was reduced 45% (P < 0.001) in the control group and 50% (P < 0.001) in the somatostatin group. There was no difference in muscle or circulating glutamate, alanine or branched chain amino acid concentrations or in metabolite values between the somatostatin-treated patients and the control group. There was no relationship between the GH response to surgery and glutamine metabolism following major surgery.

Studies on the effects of growth hormone administration in vivo on the rates of glucose transport and utilization in rat skeletal muscle.

The effects of growth hormone (GH) administration to rats in vivo on the sensitivity of the rate of glucose utilization to insulin were studied in soleus muscles isolated from these rats. A single injection of GH did not increase the rate of glucose transport within 1-2 h. However, 12 h after, the rate of glucose transport was increased at 10 mU insulin l-1 and was accompanied by a similar increase in the rate of lactate formation but no change in the rate of glycogen synthesis. Prolonged treatment with GH decreased the rate of glucose transport and glycogen synthesis and increased the content of glucose 6-phosphate at physiological levels of insulin but did not affect the rate of lactate formation. These results suggest that: (a) GH does not increase the rate of glucose transport acutely; however, after several hours, the sensitivity of glucose transport and glycolysis to insulin are increased; (b) prolonged elevations of the level of GH in plasma decrease the sensitivity of the rate of glucose transport and glycogen synthesis to insulin. However, redirection of glucose residues away from the pathway of glycogen synthesis towards that of glycolysis and a possible increase in the rate of glycogenolysis maintain a normal rate of lactate formation, although the rate of glucose transport is decreased.

The effects of growth hormone administration in vivo on skeletal muscle glutamine metabolism of the rat.

Human growth hormone administration to the rat for 3 or 10 days increased the concentrations of glutamine in both skeletal muscle and plasma and the rate of glutamine release was increased from muscle isolated from rats treated with growth hormone for 3 days. Growth hormone may therefore play an important role in the control of glutamine metabolism in muscle.