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ID PMID Title PublicationDate abstract
28598291 Spinal navigation for posterior instrumentation of C1-2 instability using a mobile intraop 2017 Sep OBJECTIVE Spinal navigation techniques for surgical fixation of unstable C1-2 pathologies are challenged by complex osseous and neurovascular anatomy, instability of the pathology, and unreliable preoperative registration techniques. An intraoperative CT scanner with autoregistration of C-1 and C-2 promises sufficient accuracy of spinal navigation without the need for further registration procedures. The aim of this study was to analyze the accuracy and reliability of posterior C1-2 fixation using intraoperative mobile CT scanner-guided navigation. METHODS In the period from July 2014 to February 2016, 10 consecutive patients with instability of C1-2 underwent posterior fixation using C-2 pedicle screws and C-1 lateral mass screws, and 2 patients underwent posterior fixation from C-1 to C-3. Spinal navigation was performed using intraoperative mobile CT. Following navigated screw insertion in C-1 and C-2, intraoperative CT was repeated to check for the accuracy of screw placement. In this study, the accuracy of screw positioning was retrospectively analyzed and graded by an independent observer. RESULTS The authors retrospectively analyzed the records of 10 females and 2 males, with a mean age of 80.7 ± 4.95 years (range 42-90 years). Unstable pathologies, which were verified by fracture dislocation or by flexion/extension radiographs, included 8 Anderson Type II fractures, 1 unstable Anderson Type III fracture, 1 hangman fracture Levine Effendi Ia, 1 complex hangman-Anderson Type III fracture, and 1 destructive rheumatoid arthritis of C1-2. In 4 patients, critical anatomy was observed: high-riding vertebral artery (3 patients) and arthritis-induced partial osseous destruction of the C-1 lateral mass (1 patient). A total of 48 navigated screws were placed. Correct screw positioning was observed in 47 screws (97.9%). Minor pedicle breach was observed in 1 screw (2.1%). No screw displacement occurred (accuracy rate 97.9%). CONCLUSION Spinal navigation using intraoperative mobile CT scanning was reliable and safe for posterior fixation in unstable C1-2 pathologies with high accuracy in this patient series.
28597514 Macrophage Migration Inhibitory Factor Induces Inflammation and Predicts Spinal Progressio 2017 Sep OBJECTIVE: To investigate the role of macrophage migration inhibitory factor (MIF) in the pathogenesis of ankylosing spondylitis (AS). METHODS: Patients who met the modified New York criteria for AS were recruited for the study. Healthy volunteers, rheumatoid arthritis patients, and osteoarthritis patients were included as controls. Based on the annual rate of increase in modified Stoke AS Spine Score (mSASSS), AS patients were classified as progressors or nonprogressors. MIF levels in serum and synovial fluid were quantitated by enzyme-linked immunosorbent assay. Predictors of AS progression were evaluated using logistic regression analysis. Immunohistochemical analysis of ileal tissue was performed to identify MIF-producing cells. Flow cytometry was used to identify MIF-producing subsets, expression patterns of the MIF receptor (CD74), and MIF-induced tumor necrosis factor (TNF) production in the peripheral blood. MIF-induced mineralization of osteoblast cells (SaOS-2) was analyzed by alizarin red S staining, and Western blotting was used to quantify active β-catenin levels. RESULTS: Baseline serum MIF levels were significantly elevated in AS patients compared to healthy controls and were found to independently predict AS progression. MIF levels were higher in the synovial fluid of AS patients, and MIF-producing macrophages and Paneth cells were enriched in their gut. MIF induced TNF production in monocytes, activated β-catenin in osteoblasts, and promoted the mineralization of osteoblasts. CONCLUSION: Our findings indicate an unexplored pathogenic role of MIF in AS and a link between inflammation and new bone formation.
28589334 Are There Differences in Gait Mechanics in Patients With A Fixed Versus Mobile Bearing Tot 2017 Oct BACKGROUND: Total ankle arthroplasty (TAA) is an alternative to arthrodesis, but no randomized trial has examined whether a fixed bearing or mobile bearing implant provides improved gait mechanics. QUESTIONS/PURPOSES: We wished to determine if fixed- or mobile-bearing TAA results in a larger improvement in pain scores and gait mechanics from before surgery to 1 year after surgery, and to quantify differences in outcomes using statistical analysis and report the standardized effect sizes for such comparisons. METHODS: Patients with end-stage ankle arthritis who were scheduled for TAA between November 2011 and June 2013 (n = 40; 16 men, 24 women; average age, 63 years; age range, 35-81 years) were prospectively recruited for this study from a single foot and ankle orthopaedic clinic. During this period, 185 patients underwent TAA, with 144 being eligible to participate in this study. Patients were eligible to participate if they were able to meet all study inclusion criteria, which were: no previous diagnosis of rheumatoid arthritis, a contralateral TAA, bilateral ankle arthritis, previous revision TAA, an ankle fusion revision, or able to walk without the use of an assistive device, weight less than 250 pounds (114 kg), a sagittal or coronal plane deformity less than 15°, no presence of avascular necrosis of the distal tibia, no current neuropathy, age older than 35 years, no history of a talar neck fracture, or an avascular talus. Of the 144 eligible patients, 40 consented to participate in our randomized trial. These 40 patients were randomly assigned to either the fixed (n = 20) or mobile bearing implant group (n = 20). Walking speed, bilateral peak dorsiflexion angle, peak plantar flexion angle, sagittal plane ankle ROM, peak ankle inversion angle, peak plantar flexion moment, peak plantar flexion power during stance, peak weight acceptance, and propulsive vertical ground reaction force were analyzed during seven self-selected speed level walking trials for 33 participants using an eight-camera motion analysis system and four force plates. Seven patients were not included in the analysis owing to cancelled surgery (one from each group) and five were lost to followup (four with fixed bearing and one with mobile bearing implants). A series of effect-size calculations and two-sample t-tests comparing postoperative and preoperative increases in outcome variables between implant types were used to determine the differences in the magnitude of improvement between the two patient cohorts from before surgery to 1 year after surgery. The sample size in this study enabled us to detect a standardized shift of 1.01 SDs between group means with 80% power and a type I error rate of 5% for all outcome variables in the study. RESULTS: This randomized trial did not reveal any differences in outcomes between the two implant types under study at the sample size collected. In addition to these results, effect size analysis suggests that changes in outcome differ between implant types by less than 1 SD. Detection of the largest change score or observed effect (propulsive vertical ground reaction force [Fixed: 0.1 ± 0.1; 0.0-1.0; Mobile: 0.0 ± 0.1; 0.0-0.0; p = 0.0.051]) in this study would require a future trial to enroll 66 patients. However, the smallest change score or observed effect (walking speed [Fixed: 0.2 ± 0.3; 0.1-0.4; Mobile: 0.2 ± 0.3; 0.0-0.3; p = 0.742]) requires a sample size of 2336 to detect a significant difference with 80% power at the observed effect sizes. CONCLUSIONS: To our knowledge, this is the first randomized study to report the observed effect size comparing improvements in outcome measures between fixed and mobile bearing implant types. This study was statistically powered to detect large effects and descriptively analyze observed effect sizes. Based on our results there were no statistically or clinically meaningful differences between the fixed and mobile bearing implants when examining gait mechanics and pain 1 year after TAA. LEVEL OF EVIDENCE: Level II, therapeutic study.
29296554 Serum components and clinical efficacies of autologous serum eye drops in dry eye patients 2017 Oct PURPOSE: Autologous serum eye drops are considered safe and efficient for the treatment of various ocular surface disorders, including dry eye diseases (DED) caused by the primary and secondary Sjogren syndrome (SS). However, the serum components in patients of SS may be different from those of normal patients and can thus lead to unpredictable therapeutic effects. This study divided the SS patients into active and inactive types based on the erythrocyte sedimentation rate and the presence or absence of active rheumatoid arthritis. METHODS: We compared the serum components of these two groups with standard and multiplex enzyme linked immunosorbent assay arrays and predicted the therapeutic effects of topical autologous serum for the treatment of DED with ocular surface disease index (OSDI) and Oxford Schema scale (OSS). RESULTS: Hyaluronic acid and transforming growth factor b1 levels were significantly higher in the active SS group compared to the inactive SS group (P < 0.01), whereas epidermal growth factors, insulin growth factor 1, and fibroblast growth factor b had no significant differences between these two groups. Active SS group had significantly higher expressions of interleukin (IL) 1 beta, IL 6, and tumor necrosis factor alpha compared to inactive SS patients (P < 0.05). There were no statistical differences in therapeutic effects between these two groups, as measured with the OSDI or OSS. CONCLUSION: Dividing the Sjogren dry eye patients into active and inactive groups may appear as a reasonable method to predict the quality of autologous serum eye drops, but there seems to be no significant predictability to the therapeutic effects.
29249839 A Calibrated Power Prior Approach to Borrow Information from Historical Data with Applicat 2017 Nov A biosimilar refers to a follow-on biologic intended to be approved for marketing based on biosimilarity to an existing patented biological product (i.e., the reference product). To develop a biosimilar product, it is essential to demonstrate biosimilarity between the follow-on biologic and the reference product, typically through two-arm randomization trials. We propose a Bayesian adaptive design for trials to evaluate biosimilar products. To take advantage of the abundant historical data on the efficacy of the reference product that is typically available at the time a biosimilar product is developed, we propose the calibrated power prior, which allows our design to adaptively borrow information from the historical data according to the congruence between the historical data and the new data collected from the current trial. We propose a new measure, the Bayesian biosimilarity index, to measure the similarity between the biosimilar and the reference product. During the trial, we evaluate the Bayesian biosimilarity index in a group sequential fashion based on the accumulating interim data, and stop the trial early once there is enough information to conclude or reject the similarity. Extensive simulation studies show that the proposed design has higher power than traditional designs. We applied the proposed design to a biosimilar trial for treating rheumatoid arthritis.
29249121 Matrix metalloproteinase 1: a better biomarker for squamous cell carcinoma by multiple mic 2019 Jun BACKGROUND: The present study aimed to validate MMP1 role in the development of squamous cell carcinoma (SCC) by bioinformatics methods. METHODS: Gene expression data of 10 GSE series (5 HNSCCs and 5 cSCCs) were obtained from the Gene Expression Omnibus (GEO) database and used to identify differentially expressed genes (DEGs). RESULTS: Higher expression of MMP1 was found rank number one in 9/10 GSE series of SCC. MMP1 was mainly focused on Gene Ontology (GO) terms of collagen catabolic process, extracellular matrix disassembly. The analysis results of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways mainly involved Rheumatoid arthritis, Bladder cancer and Pathways in cancer. Also, MMP1 was identified as a hub protein in the PPI network by using Cytoscape software. In addition, others MMPs members of family were analyzed. CONCLUSIONS: These results suggested that MMP1 may be pivotal to the transition from normal skin to premalignant lesions to SCC, thus representing a potential therapeutic target gene of diagnosis and prevention in SCC.
29101714 Changes in Healthcare Spending After Diagnosis of Comorbidities Among Endometriosis Patien 2017 Nov INTRODUCTION: We sought to characterize changes in healthcare spending associated with the onset of 22 endometriosis-related comorbidities. METHODS: Women aged 18-49 years with endometriosis (N = 180,278) were extracted from 2006-2015 de-identified Clinformatics(®) DataMart claims data. For 22 comorbidities, comorbidity patients were identified on the basis of having a first comorbidity diagnosis after their initial endometriosis diagnosis. Controls were identified on the basis of having no comorbidity diagnosis and were matched 1:1 to comorbidity patients on demographics and baseline spending. Total medical and pharmacy spending was measured during 12 months before and after each patient's index date (first comorbidity diagnosis for comorbidity patients, and equal number of days after earliest endometriosis claim for controls). Pre-post spending differences were compared using difference-in-differences linear regression. Total and comorbidity-related cumulative spending per patient for all endometriosis patients were calculated annually for the 5 years following endometriosis diagnosis. RESULTS: The number of endometriosis patients with each comorbidity varied between 121 for endometrial cancer and 16,177 for fatigue. Healthcare spending increased significantly with the onset of eight comorbidities: breast cancer, ovarian cancer, pregnancy complications, systemic lupus erythematosus/rheumatoid arthritis/Sjogren's/multiple sclerosis, infertility, uterine fibroids, ovarian cyst, and headache [p < 0.001 except for headache (p = 0.045)]. Spending decreased significantly for fatigue, cystitis/UTI, and eczema [p < 0.001 except for fatigue (p = 0.048)] and was not statistically different for the other 11 comorbidities. Difference-in-differences estimates were significantly higher for comorbidity patients for all comorbidities except eczema (p ≤ 0.003). Mean 5-year total cumulative spending was $58,191 per endometriosis patient, of which between 11% and 23% was attributable to comorbidity-related medical claims. CONCLUSION: For all but one of the 22 comorbidities associated with endometriosis, comorbidity onset was associated with a relative increase in total healthcare spending. FUNDING: AbbVie Inc.
29050128 [Lung transplantation for connective tissue disease-associated interstitial lung disease r 2017 Oct 12 Objective: To investigate the timing and complications of lung transplantation for the treatment of connective tissue disease-associated interstitial lung disease (CTD-ILD). Method: The clinical data of connective tissue-associated disease lung transplantation recipients from September, 2015 to February, 2017 were collected. Results: 11 patients with CTD-ILD were evaluated by lung transplantation and were treated with lung transplantation. Including 2 cases dermatomyositis/polymyositis and interstitial lung disease (PM/DM-ILD), 4 cases rheumatoid arthritis and interstitial lung disease (RA-ILD), 4 cases of primary Sjgren's syndrome and interstitial lung disease (pSS-ILD), 1 case of systemic sclerosis and interstitial lung disease (SSc-ILD). There are 6 cases are CTD-ILD-PAH patients of all. There were 5 males and 6 females, aged 37-70 years, with an average age of (52.73±9.53) years. 7 patients received single lung transplantation, 4 patients received double lung transplantation. 3 patients died in the early postoperative period, one for pulmonary embolism, one for septic shock and heart failure, one for severe primary graft failure (PGD). The remaining patients were followed up (4-24 months) with good survival, no acute and chronic rejection and other complications were observed. The survival rate was similar to that of other disease sources. Conclusion: There is no recurrence, acute and chronic rejection and other complications were observed in CTD-ILD and/or PAH lung transplant recipients. And the survival rate was comparable to that of other disease sources.Lung transplantation is a safe and effective choice for selected CTD-ILD patients.
29033895 Autoimmune Thyroid Diseases in Patients Treated with Alemtuzumab for Multiple Sclerosis: A 2017 Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for the treatment of active relapsing-remitting multiple sclerosis (MS). Alemtuzumab induces a rapid and prolonged depletion of lymphocytes from the circulation, which results in a profound immuno-suppression status followed by an immune reconstitution phase. Secondary to reconstitution autoimmune diseases represent the most common side effect of Alemtuzumab treatment. Among them, Graves' disease (GD) is the most frequent one with an estimated prevalence ranging from 16.7 to 41.0% of MS patients receiving Alemtuzumab. Thyrotropin (TSH) receptor (R)-reactive B cells are typically observed in GD and eventually present this autoantigen to T-cells, which, in turn, secrete several pro-inflammatory cytokines and chemokines. Given that reconstitution autoimmunity is more frequently characterized by autoantibody-mediated diseases rather than by destructive Th1-mediated disorders, it is not surprising that GD is the most commonly reported side effect of Alemtuzumab treatment in patients with MS. On the other hand, immune reconstitution GD was not observed in a large series of patients with rheumatoid arthritis treated with Alemtuzumab. This negative finding supports the view that patients with MS are intrinsically more at risk for developing Alemtuzumab-related thyroid dysfunctions and in particular of GD. From a clinical point of view, Alemtuzumab-induced GD is characterized by a surprisingly high rate of remission, both spontaneous and after antithyroid drugs, as well as by a spontaneous shift to hypothyroidism, which is supposed to result from a change from stimulating to blocking TSH-receptor antibodies. These immune and clinical peculiarities support the concept that antithyroid drugs should be the first-line treatment in Alemtuzumab-induced Graves' hyperthyroidism.
28948358 Pregnancy outcome in 162 women with rheumatic diseases: experience of a university hospita 2017 Dec PURPOSE: To evaluate the distribution and the obstetric outcomes of pregnancies with different types of rheumatic diseases managed in our unit. METHODS: Pregnancies of 162 women with rheumatic diseases, seen for their antenatal care at our department for the period between 2013 and 2017 were included in this retrospective clinical study. Obstetric and perinatal outcomes were main outcome measures. RESULTS: The most encountered rheumatic diseases were SLE (37.7%) followed by Behcet's disease (20.4%) and rheumatoid arthritis (17.3%) in our series. The mean maternal age was 30.6 ± 5.3 and the rate of nulliparity was 38.3% in the overall group. Disease activation occurred in 14.1% of patients. Mean gestational age at delivery was 37.4 ± 3.1 and mean birth weight was 3004 ± 762 g. Stillbirth, neonatal death, fetal growth restriction, preeclampsia and preterm delivery rates were 1.2, 2.4, 17.3, 7.4 and 17.9%, respectively. Antiphospholipid syndrome had the highest incidences for fetal growth restriction (42.9%), preeclampsia (28.6%) and delivery ≤ 34 gestational weeks (42.9%). Pathologic uterine artery Doppler velocimetry was identified in 15 cases (15/162, 9.3%) in which 10 (66.7%) developed preeclampsia and/or fetal growth restriction during follow-up. CONCLUSION: A majority of women with rheumatic diseases have successful pregnancies and deliver healthy babies, with the close and appropriate rheumatological, obstetric and neonatal monitoring.
28798075 Cytokines of the IL-1 family: recognized targets in chronic inflammation underrated in org 2017 Sep 1 Interleukin 1 (IL-1) family is a group of cytokines with multiple local and systemic effects, which regulates both innate and adaptive immune responses. Generally, most IL-1 family cytokines express prevailing pro-inflammatory activities (IL-1α, IL-1β, IL-18, IL-33, IL-36 α, β, γ), whereas others are anti-inflammatory (IL-1Ra (IL-1 receptor antagonist), IL-36Ra, IL-38, IL-37). In addition to their immunomodulatory roles, some of them are also involved in the physiological modulation of homeostatic processes and directly affect mRNA transcription. IL-1 family cytokines bind to specific receptors composed of a ligand-binding chain and an accessory chain. The pro-inflammatory effects of IL-1 family cytokines are regulated on the level of transcription, enzymatic processing of precursors, release of soluble antagonists, and expression of decoy receptors. Members of the IL-1 family regulate the recruitment and activation of effector cells involved in innate and adaptive immunity, but they are also involved in the pathogenesis of chronic disorders, including inflammatory bowel disease, rheumatoid arthritis, and various autoimmune and autoinflammatory diseases. There are only limited data regarding the role of IL-1 cytokines in transplantation. In recent years, targeted therapeutics affecting IL-1 have been used in multiple clinical studies. In addition to the recombinant IL-1Ra, anakinra (highly effective in autoinflammatory diseases and tested for other chronic diseases), the monoclonal antibodies canakinumab, gevokizumab, and rilonacept (a long-acting IL-1 receptor fusion protein) provide further options to block IL-1 activity. Furthermore, new inhibitors of IL-18 (GSK 1070806, ABT-325, rIL-18BP (IL-18 binding protein)) and IL-33 (CNTO-7160) are presently under clinical studies and other molecules are being developed to target IL-1 family cytokines.
28630629 The CEDAR Study: A Longitudinal Study of the Clinical Effects of Conventional DMARDs and B 2017 OBJECTIVES: To observe the choices of conventional disease modifying antirheumatic drugs (cDMARDs) and biologic DMARDs (bDMARDs) in the management of rheumatoid arthritis (RA) in Australian routine clinical practice, to assess treatment survival and determine the effect of cDMARDs/bDMARDs on disease activity. METHODS: Routinely collected, deidentified clinical data was sourced from 20 Australian rheumatology practices. RA patients aged ≥18 years, who had received cDMARDs/bDMARDs and a recorded subsequent visit, were included. A linear mixed model was used to determine the change over time and the percentage reduction in disease activity was summarized. RESULTS: 12,526 RA patients were included: 72% females, mean age 62 years. cDMARDs and bDMARDs were used in 92% and 30% of patients, respectively. The most commonly prescribed cDMARD was methotrexate (76% patients); median time to stopping treatment was 337 months [95% CI: 279-ND]. Etanercept was the most commonly prescribed bDMARD (12% patients); median time to stopping treatment was 79 months [95% CI: 57-93]. Of 5,341 patients with a first change in medication (cDMARD or bDMARD), 87% had therapy escalation and 13% deescalation. Reduction in DAS28-ESR, 6-month post-DMARDs initiation ranged from 3%, adalimumab, to 14%, leflunomide and tocilizumab. CONCLUSIONS: In this large Australian cohort of unselected community RA patients, the choices of cDMARDs/bDMARDs are aligned with current international guidelines.
28520415 Design and Synthesis of Soluble and Cell-Permeable PI3Kδ Inhibitors for Long-Acting Inhal 2017 Jun 22 PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesized to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work, we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimization for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation. Addition of basic substituents to a region of the molecule pointing to solvent was tolerated (enzyme inhibition pIC(50) > 9), and by careful manipulation of the pK(a) and lipophilicity, we were able to discover compounds (20b, 20f) with good lung retention and cell potency that could be taken forward to in vivo studies where significant target engagement could be demonstrated.
28503066 Essential oil-mediated glycerosomes increase transdermal paeoniflorin delivery: optimizati 2017 In this study, a novel glycerosome carrier containing essential oils was prepared for topical administration of paeoniflorin (PF) to enhance its transdermal drug delivery and improve drug absorption in the synovium. The formulation of glycerosomes was optimized by a uniform design, and the final vehicle was composed of 5% (w/v) phospholipid, 0.6% (w/v) cholesterol, and 10% (v/v) glycerol, with 2% (v/v) Speranskia tuberculata essential oil (STO) as the transdermal enhancer. The in vitro transdermal flux of PF loaded in the STO-glycerosomes was 1.4-fold, 1.6-fold, and 1.7-fold higher than those of glycerosomes, liposomes, and tinctures, respectively. In vivo studies showed that the use of STO-glycerosomes was associated with a 3.1-fold greater accumulation of PF in the synovium than that of common glycerosomes. This finding was confirmed by in vivo imaging studies, which found that the fluorescence intensity of Cy5.5-loaded STO-glycerosomes in mice knee joints was 1.8-fold higher than that of the common glycerosomes 5 h after administration. The glycerosomes mediated by STO exhibited considerable skin permeability as well as improved drug absorption in the synovium, indicating that STO-glycerosomes may be a potential PF transdermal delivery vehicle for the treatment of rheumatoid arthritis caused by synovium lesions.
28490712 Application of Physiologically-Based Pharmacokinetic Modeling for the Prediction of Tofaci 2017 May 9 Tofacitinib (3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3 -oxopropanenitrile) is an oral Janus kinase inhibitor that is approved in countries including Japan and the United States for the treatment of rheumatoid arthritis, and is being developed across the globe for the treatment of inflammatory diseases. In the present study, a physiologically-based pharmacokinetic model was applied to compare the pharmacokinetics of tofacitinib in Japanese and Caucasians to assess the potential impact of ethnicity on the dosing regimen in the two populations. Simulated plasma concentration profiles and pharmacokinetic parameters, i.e. maximum concentration and area under plasma concentration-time curve, in Japanese and Caucasian populations after single or multiple doses of 1 to 30 mg tofacitinib were in agreement with clinically observed data. The similarity in simulated exposure between Japanese and Caucasian populations supports the currently approved dosing regimen in Japan and the United States, where there is no recommendation for dose adjustment according to race. Simulated results for single (1 to 100 mg) or multiple doses (5 mg twice daily) of tofacitinib in extensive and poor metabolizers of CYP2C19, an enzyme which has been shown to contribute in part to tofacitinib elimination and is known to exhibit higher frequency in Japanese compared to Caucasians, were also in support of no recommendation for dose adjustment in CYP2C19 poor metabolizers. This study demonstrated a successful application of physiologically-based pharmacokinetic modeling in evaluating ethnic sensitivity in pharmacokinetics at early stages of development, presenting its potential value as an efficient and scientific method for optimal dose setting in the Japanese population.
28413615 Mean Platelet Volume (MPV) as an indicator of  disease activity and severity in lupus. 2017 Background: Amongst the different clinical and laboratory parameters used to monitor disease activity in systemic lupus erythematosus (SLE), mean platelet volume (MPV) is a novel biomarker. Although MPV has been studied in other rheumatological conditions like rheumatoid arthritis, its role in adult SLE needs to be defined, especially in Pakistan. Methods: The aim of this study was to evaluate the role of MPV as a biomarker of disease activity in SLE. Fifty patients were recruited through a consecutive non-probability sampling technique for this cross-sectional study.  On the basis of their SLE disease activity index (SLEDAI) score of greater or lesser than 5, these 50 participants were divided into two equal groups respectively;25 patients with active SLE, and another 25 participants with stable, inactive lupus. MPV was measured in each group and compared using SPSS version 16. MPV was also correlated with SLEDAI and erythrocyte sedimentation rate (ESR). Independent sample t-test and Spearman's rho and Pearson's correlation tests were applied. Sensitivity and specificity of MPV were checked through ROC analysis.    Results: The MPV of patients with active SLE (n=25, mean [M]=7.12, SD=1.01) was numerically lower than those in the inactive-SLE group (n=25, M= 10.12, SD=0.97), and this was statistically significant ( P<0.001). MPV had an inverse relationship with both ESR (r=-0.93, P<0.001) and SLEDAI (r (s)= -0.89, P<0.001). However, there was a strong positive correlation between ESR and SLEDAI (r (s)=0.90, P<0.001). For MPV, a cutoff value of less than 8.5fl had a sensitivity of 92% and a specificity of 100% ( P< 0.001).  Conclusions: Higher disease activity in SLE is associated with a correspondingly low MPV.
28370169 Osteoclast differentiation gene expression profiling reveals chemokine CCL4 mediates RANKL 2017 Apr The migration of osteoclasts (OCs) from circulation and bone marrow into bone surface plays a critical role in the pathogenesis of some bone resorptive diseases, such as rheumatoid arthritis and osteoporosis. To date, how the migration of OCs remains unclear. We investigated gene expression profiling in osteoclastic differentiation of bone marrow-derived macrophages (BMMs) into OCs by microarray analysis. We identified 387 genes overexpressed in osteoclastic differentiation of BMMs. Among them, chemokine CCL4 showed a robust up-regulation signal. High expression of CCL4 was validated in primary BMMs and OC precursor cell line RAW264.7 during differentiation into OCs. The CCL4 neutralization decreased RANKL-induced OC precursor cell migration and invasion in Matrigel-coated transwell membranes assay and in vitro wound healing assay. However, CCL4 inhibition did not affect OCs differentiation and differentiation associated gene expression. The CCL4 inhibition promoted the PI3K phosphorylation at 45 to 60 minutes after RANKL stimulation in RAW264.7. This study indicated that chemokine CCL4 is an important regulator for OCs migration via PI3K pathway, providing a novel therapy target for bone resorptive diseases.
28357106 Persistent arthralgia, vomiting and hypercalcemia as the initial manifestations of hyperth 2017 Feb A 53-year-old woman presented with persistent edema and pain of the metacarpophalangeal and proximal interphalangeal joints and the wrist, knee and ankle joints, with more recent intermittent nausea and vomiting. Treatment for rheumatoid arthritis and osteoarthritis was ineffective. No clinical manifestations typical of hyperthyroidism were observed. The results of the thyroid function tests were as follows: Thyroid-stimulating hormone, 0.003 µIU/ml; triiodothyronine (T(3)), 4.44 ng/ml;, thyroxine (T(4)) >30 µg/dl; free T(3), 14.03 pg/ml; and free T(4), 8.84 ng/dl. The laboratory tests revealed an elevated serum calcium level (2.96 mmol/l); moderate hypophosphatemia (0.84 mmol/l); significantly reduced serum intact parathyroid hormone (4.8 pg/ml); normal 25-hydroxy vitamin D (52.13 nmol/l) and bone-specific alkaline phosphatase (22.1 ng/ml); and elevated osteocalcin (128.8 ng/ml). X-ray and quantitative ultrasound examinations revealed extensive osteoporosis of the hands, skull, knees and pelvis, with a bone mineral density of 0.254 g/cm(2) (T-score, -3.2). Anti-thyroid therapy (methimazole, 30 mg/day; salmon calcitonin, 50 IU/day; and alendronate, 70 mg/week) was initiated. After 2 weeks, the serum calcium and phosphate levels were normalized (2.44 and 1.19 mmol/l, respectively) and calcitonin was discontinued. After 3 months, the patient had no nausea, vomiting or joint pain, and her appetite was normal, with a weight gain of ~10 kg. Euthyroidism was achieved and the serum calcium and phosphate levels were normalized (2.31 and 1.12 mmol/l, respectively) and maintained for 6 months, by which time the osteocalcin level had diminished (80.40 ng/ml). This rare case of arthralgia, hypercalcemia and extensive osteoporosis as the first manifestations of hyperthyroidism suggests that, even without typical symptoms, hyperthyroidism should be considered in the differential diagnosis of patients with persistent arthralgia.
28241758 Clinical trials from the patient perspective: survey in an online patient community. 2017 Feb 27 BACKGROUND: Developing new medicines relies on the successful conduct of clinical trials. As trial protocols become more arduous, it becomes harder to recruit and retain patient volunteers, although recent efforts such as OMERACT and I-SPY2 show that partnering with patients can be beneficial. We sought to describe drivers and barriers to trial participation, as well as condition-specific trial preferences. METHODS: An online survey was fielded via the patient-powered research network PatientsLikeMe to 1,621 members living with nine selected chronic health conditions. Questions included demographics, trial experience, reasons for non-participation, questions relating to aspects of trial design, and an adaptation of the Net Promoter Score (NPS) for trial satisfaction. RESULTS: Mean age of respondents was 55 years; most patients were white (93%), female (67%), and living in the United States (72%). Primary conditions were MS (21%), Parkinson's (20%), fibromyalgia (15%), ALS (10%), type 2 diabetes (10%), rheumatoid arthritis (RA, 8%), epilepsy (8%), major depressive disorder (MDD, 5%) and systemic lupus erythematosus (SLE, 3%). Most patients had not discussed a trial with their physician and only 21% had ever enrolled, with rates highest in ALS (36%), Parkinson's disease (36%) and MS (20%) and lowest among SLE (9%), MDD (11%) and Fibromyalgia (11%). Common reasons for non-participation were eligibility criteria, inconvenience of travel and concerns about side effects. NPS suggested that many patients were unsatisfied; patients with lupus, epilepsy, RA, and fibromyalgia reported negative scores, i.e. they would dissuade other patients like them from taking part in trials. The most important considerations in trial participation were the opportunity to improve one's own health and that of others, the reputation of the institution, and having medical bills covered in case of injury. Least important were remuneration and possibility of receiving a placebo. ALS patients were more willing to tolerate undesirable aspects of trials. CONCLUSIONS: Most patients are willing to enroll yet very few are invited. When they do, trial participation is often burdensome, but patients are willing to help improve their design. Researchers should let patients help design better trials to overcome recruitment and retention issues and hasten the development of new medicines.
28005437 Self nanoemulsifying granules (SNEGs) of meloxicam: preparation, characterization, molecul 2017 Apr Meloxicam, a BCS class II drug belonging to the class of NSAIDs is indicated in conditions of rheumatoid arthritis, ankylosing spondylitis and osteoarthritis in which rapid onset of drug action is desired to reduce inflammation and pain. The objective of the study was to thus develop Self Nanoemulsifying Granules (SNEGs) of Meloxicam (MLX) for enhancement of solubility; and subsequently dissolution rate, thus aiming for a faster onset of action. Preliminary studies along with molecular modeling studies were carried out for selection of appropriate lipids, surfactants and cosurfactants for the development of MLX-loaded Self Nanoemulsifying preconcentrate (SNEP). A charge inducer was incorporated into the formulation so as to increase the solubility of MLX in lipids and hence, drug loading. A three-factor D-optimal mixture design was used for optimization of MLX loaded SNEP. The role of charge inducer in increasing the drug loading of MLX in SNEDDS was studied by molecular dynamics simulation using Desmond. Optimized SNEP was adsorbed onto solid carriers to form SNEGs for improved stability and enhanced flow properties. Physical characterization studies of SNEGs, in vitro release studies, and in vivo evaluation of anti-inflammatory activity of the optimized formulation were performed. All the results indicated that MLX SNEGs can be a promising alternative to conventional oral NSAIDs therapy because of enhanced dissolution characteristics and subsequent rapid onset of action.