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ID PMID Title PublicationDate abstract
30147981 Hepatitis E during Tocilizumab Therapy in a Patient with Rheumatoid Arthritis: Case Report 2018 Hepatitis E is an acute self-limiting disease caused by hepatitis E virus (HEV). Recent reports show that HEV can induce chronic hepatitis or be reactivated in immunocompromised hosts. We report a 63-year-old woman with rheumatoid arthritis (RA) who developed hepatitis E during treatment with tocilizumab. Analysis of serially stocked serum samples confirmed that hepatitis was caused by primary infection with HEV and not by viral reactivation. Her liver function improved after discontinuing tocilizumab and remained within the normal range without reactivation of HEV for >5 years after restarting tocilizumab. We also reviewed the published cases of hepatitis E that developed during RA treatment.
29681970 K Nearest Neighbor Algorithm Coupled with Metabonomics to Study the Therapeutic Mechanism 2018 As a traditional Mongolian medicine, Sendeng-4 (SD) has been widely used to treat rheumatoid arthritis (RA) in Inner Mongolia and exhibits a good curative effect. Unfortunately, due to geographical factors, it is difficult to popularize this drug throughout the whole country, and the mechanism of action of SD has been unclear. In this study, a serum metabolite profile analysis was performed to identify potential biomarkers associated with adjuvant-induced RA and investigate the mechanism of action of SD. Ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was performed for the metabonomics analysis. K nearest neighbor (KNN) models were established in both positive and negative spectra for classifying data from the control, model, and SD administration groups. Accuracy rate for classification was 95.8% in positive ion mode and 91.7% in negative ion mode. Orthogonal partial least squares discriminant analysis (OPLS-DA) enabled the identification of 12 metabolites as potential biomarkers of adjuvant-induced RA. After treatment with SD, the levels of uridine triphosphate, calcitroic acid, dynorphin B (6-9), and docosahexaenoic acid were restored to normal, indicating that SD likely ameliorated RA by regulating the levels of these biomarkers. This study identified early biomarkers of RA and elucidated the underlying mechanism of action of SD, which is worth further investigation for development as a clinical therapy.
29910742 Obesity, Fat Mass and Immune System: Role for Leptin. 2018 Obesity is an epidemic disease characterized by chronic low-grade inflammation associated with a dysfunctional fat mass. Adipose tissue is now considered an extremely active endocrine organ that secretes cytokine-like hormones, called adipokines, either pro- or anti-inflammatory factors bridging metabolism to the immune system. Leptin is historically one of most relevant adipokines, with important physiological roles in the central control of energy metabolism and in the regulation of metabolism-immune system interplay, being a cornerstone of the emerging field of immunometabolism. Indeed, leptin receptor is expressed throughout the immune system and leptin has been shown to regulate both innate and adaptive immune responses. This review discusses the latest data regarding the role of leptin as a mediator of immune system and metabolism, with particular emphasis on its effects on obesity-associated metabolic disorders and autoimmune and/or inflammatory rheumatic diseases.
29770718 A systematic literature review comparing methods for the measurement of patient persistenc 2018 Sep OBJECTIVES: A systematic literature review was conducted comparing different approaches estimating persistence and adherence in chronic diseases with polypharmacy of oral and subcutaneous treatments. METHODS: This work followed published guidance on performing systematic reviews. Twelve electronic databases and grey literature sources were used to identify studies and guidelines for persistence and adherence of oral and subcutaneous therapies in hypercholesterolemia, type 2 diabetes, hypertension, osteoporosis and rheumatoid arthritis. Outcomes of interest of each persistence and adherence data collection and calculation method included pros: accurate, easy to use, inexpensive; and cons: inaccurate, difficult to use, expensive. RESULTS: A total of 4158 records were retrieved up to March 2017. We included 16 observational studies, 5 systematic reviews and 7 guidelines, in patients with hypercholesterolemia (n = 8), type 2 diabetes (n = 4), hypertension (n = 2), rheumatoid arthritis (n = 1) and mixed patient populations (n = 13). Pharmacy and medical records offer an accurate, easy and inexpensive data collection method. Pill count, medication event monitoring systems (MEMs), self-report questionnaires and observer report are easy to use. MEMS and biochemical monitoring tests can be expensive. Proportion of days covered (PDC) was recommended as a gold standard calculation method for long-term treatments. PDC avoids use of days' supply in calculation, hence is more accurate compared to medication possession ratio (MPR) to assess adherence to treatments in chronic diseases. CONCLUSIONS: Decisions on what method to use should be based on considerations of the route of medication administration, the resources available, setting and aim of the assessment. Combining different methods may provide wider insights into adherence and persistence, including patient behavior.
29725325 Mitochondria: An Organelle of Bacterial Origin Controlling Inflammation. 2018 Inflammation is a cellular and molecular response to infection and/or tissues injury. While a suited inflammatory response in intensity and time allows for killing pathogens, clearing necrotic tissue, and healing injury; an excessive inflammatory response drives various diseases in which inflammation and tissues damages/stress self-sustain each other. Microbes have been poorly implied in non-resolving inflammation, emphasizing the importance of endogenous regulation of inflammation. Mitochondria have been historically identified as the main source of cellular energy, by coupling the oxidation of fatty acids and pyruvate with the production of high amount of adenosine triphosphate by the electron transport chain. Mitochondria are also the main source of reactive oxygen species. Interestingly, research in the last decade has highlighted that since its integration in eukaryote cells, this organelle of bacterial origin has not only been tolerated by immunity, but has also been placed as a central regulator of cell defense. In intact cells, mitochondria regulate cell responses to critical innate immune receptors engagement. Downstream intracellular signaling pathways interact with mitochondrial proteins and are tuned by mitochondrial functioning. Moreover, upon cell stress or damages, mitochondrial components are released into the cytoplasm or the extra cellular milieu, where they act as danger signals when recognized by innate immune receptors. Finally, by regulating the energetic state of immunological synapse between dendritic cells and lymphocytes, mitochondria regulate the inflammation fate toward immunotolerance or immunogenicity. As dysregulations of these processes have been recently involved in various diseases, the identification of the underlying mechanisms might open new avenues to modulate inflammation.
29622995 Increased arterial stiffness in rheumatoid arthritis and Its relation to disease activity: 2018 Mar BACKGROUND: Rheumatoid arthritis (RA) is associated with elevated plasma level of inflammatory markers. Chronic inflammation is known to predispose to endothelial dysfunction and increased arterial stiffness, which is an important marker of subclinical atherosclerosis and increased cardiovascular risk. OBJECTIVE: The aim is to test for the relationship between disease activity and arterial stiffness in RA patients. METHODS: The study included 90 RA patients, at different grades of disease activity and 45 healthy subjects, as a control group. Patients were subjected to full history taking and clinical examination, laboratory investigations including serum lipid profile and high sensitivity CRP (hs-CRP) measurements and plain x-rays of hands and feet. Modified Larsen method was used as radiographic scoring method. Disease activity score (DAS 28) was used for assessment of disease activity. Transthoracic echocardiography was performed to detect aortic stiffness parameters. Duplex ultrasound imaging of both common carotid arteries was performed to measure carotid stiffness parameters. RESULTS: The mean age of RA patients was 39.86 ± 9.39 years and most of them (83.3%) were females. RA patients had higher carotid stiffness index compared to control group patients (8.57 ± 4.83 vs 4.08 ± 1.13, p < .001). Very poor correlation was found between DAS-28 and aortic (r = 0.1, p = .28) as well as carotid (r = 0.05, p = .7) stiffness indices. No statistically significant correlation was found between hs-CRP and aortic stiffness index (r = 0.64, p = .55). Disease duration was significantly correlated to intima-media thickness (p < .01) as well as with other carotid stiffness parameters. Age also show a statistically significant positive correlation with carotid stiffness parameters. CONCLUSION: RA is associated with increased arterial stiffness, a well-recognized marker of cardiovascular risk. This is attributed to the inflammatory nature of the disease. It seems that the most important factors determining stiffness are patients' age and duration of illness.
29555500 Isolated Greater Trochanteric Fracture and the Direct Anterior Approach Using a Fracture T 2018 Jul BACKGROUND: To identify the incidence, contributing factors, and outcomes of perioperative greater trochanter fractures associated with the direct anterior approach. METHODS: This is a retrospective analyses of 1401 primary THAs. Age, side, height, weight, body mass index, preoperative ambulatory status, discharge status, and hospital length of stay were identified. Radiographs were evaluated for femoral neck angle, femoral neck cut ratio (FNCR), and DORR ratio. Bivariate and logistic regression analyses were performed. RESULTS: Thirty-one hips sustained isolated greater trochanter fractures (2.2%). Multivariate analyses identified worse preoperative ambulatory status, diagnosis of slipped capital femoral epiphysis or rheumatoid arthritis, lower FNCR and greater DORR ratio as statistically significant predictors for fracture. Four intraoperative fractures underwent fixation. All postoperative fractures were treated nonoperatively. Thirty fractures healed with 1 nonunion. CONCLUSION: Worse preoperative ambulatory status, diagnosis of slipped capital femoral epiphysis or rheumatoid arthritis, greater DORR ratio, and lower FNCR were associated with increased risk of fracture. Hips with fractures had longer length of stay. Nonoperative treatment was uniformly successful.
29389685 Cost-effectiveness of Different Intra-articular Drug Injections on Wrist and/or Elbow Comp 2018 Feb 1 BACKGROUND: Intra-articular (IA) injections are an integral part of the management of rheumatoid arthritis (RA). However, there are few reports regarding the association between drug effectiveness and cost. OBJECTIVES: The aim of this study was to assess the cost-effectiveness of various combinations of IA injections of betamethasone, hyaluronic acid (HA) or etanercept for oligoarthritis in RA. METHODS: Seventy RA patients were assigned to 4 groups according to the IA injection drug(s): betamethasone alone, betamethasone + etanercept, betamethasone + HA, or etanercept alone. Data for the following were collected before and after IA injection: erythrocyte sedimentation rate, C-reactive protein (CRP), disease activity score in 28 joints calculated with CRP, and patient global visual analog scale. In addition, power Doppler ultrasonography and gray-scale ultrasonography scores were obtained for synovitis, and passive range of motion of joints was measured. RESULTS: Sixty-eight RA patients completed the trial. Compared with patients given etanercept alone, the visual analog scale, power Doppler ultrasonography, and gray-scale ultrasonography scores of each of the other groups were significantly better at each time point. At 1 month, the passive range of motion of joints in patients given betamethasone + HA was significantly better than that of each of the other groups. Synovial hyperplasia improved significantly in all groups, but less so in those given etanercept alone. All other clinical parameters of the 4 groups were similar. The costs per joint for the betamethasone-alone, betamethasone + etanercept, betamethasone + HA, and etanercept-alone groups were, respectively, $7.55, $181.77, $42.68, and $174.22. CONCLUSIONS: Intra-articular injection of betamethasone alone was the most cost-effective treatment for oligoarthritis of RA. Betamethasone combined with HA injection resulted in the best improvement in joint function.
29067495 Short-term application of tocilizumab during myocardial infarction (STAT-MI). 2018 Jan Acute myocardial infarction (MI) occurs when blood supply falls below critical levels and normal cellular maintenance mechanisms fail. Interleukin-6 (IL-6) is a proinflammatory cytokine released in MI and associated with poor clinical outcomes. Tocilizumab (TCZ) is a humanized monoclonal antibody against the IL-6 receptor. In a randomized, double-blinded, placebo controlled trial we assigned subjects admitted with MI a single TCZ dose of 162 mg subcutaneously vs. placebo in addition to standard of care medications and interventions. Primary outcome was a change in major adverse cardiac events (MACE) 30 days after enrollment. Secondary outcomes assessed changes in CRP 30 days after enrollment, changes in QT/QTc, and monitoring for trends in adverse events. Futility analysis was performed as subject enrollment slowed and no trends were noted in either the primary or secondary outcomes. Twenty-eight subjects were enrolled; 12 to TCZ and 16 to placebo. No statistically significant differences were noted between study arms regarding demographics, comorbidities, or medical/interventional therapies received. No statistically significant differences in MACE were observed. CRP increased after administration of TCZ but this was not statistically significant. No adverse events or safety signals were observed. Though futility analysis suggested that the primary outcome was not likely achievable as our recruitment slowed, we did not observe any adverse events or safety trends. Building on this information, future studies should be conducted to assess a true benefit from TCZ as adjunct therapy for MI. The work reported herein was performed under United States Air Force Surgeon General approved Clinical Investigation FKE20140029 and has been registered at ClinicalTrials.gov under identifier NCT02419937.
30513105 Biomarkers of erosive arthritis in systemic lupus erythematosus: Application of machine le 2018 OBJECTIVE: Limited evidences are available on biomarkers to recognize Systemic Lupus erythematosus (SLE) patients at risk to develop erosive arthritis. Anti-citrullinated peptide antibodies (ACPA) have been widely investigated and identified in up to 50% of X-ray detected erosive arthritis; conversely, few studies evaluated anti-carbamylated proteins antibodies (anti-CarP). Here, we considered the application of machine learning models to identify relevant factors in the development of ultrasonography (US)-detected erosive damage in a large cohort of SLE patients with joint involvement. METHODS: We enrolled consecutive SLE patients with arthritis/arthralgia. All patients underwent joint (DAS28, STR) and laboratory assessment (detection of ACPA, anti-CarP, Rheumatoid Factor, SLE-related antibodies). The bone surfaces of metacarpophalangeal and proximal interphalangeal joints were assessed by US: the presence of erosions was registered with a dichotomous value (0/1), obtaining a total score (0-20). Concerning machine learning techniques, we applied and compared Logistic Regression and Decision Trees in conjunction with the feature selection Forward Wrapper method. RESULTS: We enrolled 120 SLE patients [M/F 8/112, median age 47.0 years (IQR 15.0); median disease duration 120.0 months (IQR 156.0)], 73.3% of them referring at least one episode of arthritis. Erosive damage was identified in 25.8% of patients (mean±SD 0.7±1.6), all of them with clinically evident arthritis. We applied Logistic Regression in conjunction with the Forward Wrapper method, obtaining an AUC value of 0.806±0.02. As a result of the learning procedure, we evaluated the relevance of the different factors: this value was higher than 35% for ACPA and anti-CarP. CONCLUSION: The application of Machine Learning Models allowed to identify factors associated with US-detected erosive bone damage in a large SLE cohort and their relevance in determining this phenotype. Although the scope of this study is limited by the small sample size and its cross-sectional nature, the results suggest the relevance of ACPA and anti-CarP antibodies in the development of erosive damage as also pointed out in other studies.
29734947 Association between Fas/FasL gene polymorphism and musculoskeletal degenerative diseases: 2018 May 7 BACKGROUND: It was reported that Fas (rs1800682, rs2234767) and FasL (rs5030772, rs763110) gene polymorphism might be related to the risk of musculoskeletal degenerative diseases (MSDD), such as osteoarthritis (OA), intervertebral disc degeneration (IVDD) and rheumatoid arthritis (RA). However, data from different studies was inconsistent. Here we aim to elaborately summarize and explore the association between the Fas (rs1800682, rs2234767) and FasL (rs5030772, rs763110) and MSDD. METHODS: Literatures were selected from PubMed, Web of Science, Embase, Scopus and Medline in English and VIP, SinoMed, Wanfang and the China National Knowledge Infrastructure (CNKI) in Chinese up to August 21, 2017. All the researches included are case-control studies about human. We calculated the pooled odds ratios (ORs) with 95% confidence intervals (95% CI) to evaluate the strengths of the associations of Fas (rs1800682, rs2234767) and FasL (rs5030772, rs763110) polymorphisms with MSDD risk. RESULTS: Eleven eligible studies for rs1800682 with 1930 cases and 1720 controls, 6 eligible studies for rs2234767 with 1794 cases and 1909 controls, 3 eligible studies for rs5030772 with 367 cases and 313 controls and 8 eligible studies for rs763110 with 2010 cases and 2105 controls were included in this analysis. The results showed that the G allele of Fas (rs1800682) is associated with an increased risk of IVDD in homozygote and recessive models. The G allele of Fas (rs2234767) is linked to a decreased risk of RA but an enhanced risk of OA in allele and recessive models. In addition, the T allele of FasL (rs763110) is correlated with a reduced risk of IVDD in all of models. However, no relationship was found between FasL (rs5030772) and these three types of MSDD in any models. CONCLUSIONS: Fas (rs1800682) and FasL (rs763110) polymorphism were associated with the risk of IVDD and Fas (rs2234767) was correlated to the susceptibility of OA and RA. Fas (rs1800682) and Fas (rs2234767) are more likely to be associated with MSDD for Chinese people. FasL (rs763110) is related to the progression of MSDD for both Caucasoid and Chinese race groups. But FasL (rs5030772) might not be associated with any types of MSDD or any race groups statistically.
30031171 NAMPT: A pleiotropic modulator of monocytes and macrophages. 2018 Sep Nicotinamide phosphoribosyltransferase (NAMPT) is the bottleneck enzyme of the NAD salvage pathway and thereby is a controller of intracellular NAD concentrations. It has been long known that the same enzyme can be secreted by a number of cell types and acts as a cytokine, although its receptor is at present unknown. Investigational compounds have been developed that target the enzymatic activity as well as the extracellular action (i.e. neutralizing antibodies). The present contribution reviews the evidence that links intracellular and extracellular NAMPT to myeloid biology, for example governing monocyte/macrophage differentiation, polarization and migration. Furthermore, it reviews the evidence that links this protein to some disorders in which myeloid cells have a prominent role (acute infarct, inflammatory bowel disease, acute lung injury and rheumatoid arthritis) and the data showing that inhibition of the enzymatic activity or the neutralization of the cytokine is beneficial in preclinical animal models.
30488002 Comparative effectiveness of subcutaneous tocilizumab versus intravenous tocilizumab in a 2018 OBJECTIVE: To compare the real-word effectiveness of subcutaneous tocilizumab (TCZ-SC) and intravenous tocilizumab (TCZ-IV) in rheumatoid arthritis (RA). METHODS: Patients with RA with TCZ from eight European registries were included. Drug retention was compared using unadjusted Kaplan-Meier and Cox models adjusted for baseline patient, disease and treatment characteristics, using a strata term for year of treatment initiation and country of registry. The proportions of patients achieving Clinical Disease Activity Index (CDAI) remission and low disease activity (LDA) at 1 year were compared using samples matched on the same covariates and corrected for attrition using LUNDEX. RESULTS: 3448 patients were retrieved, 2414 with TCZ-IV and 1034 with TCZ-SC. Crude median retention was 3.52 years (95% CI 3.22 to 3.85) for TCZ-IV and 2.12 years for TCZ-SC (95% CI 1.88 to 2.38). In a country-stratified and year of treatment initiation-stratified, covariate-adjusted analysis, hazards of discontinuation were similar between TCZ-SC and TCZ-IV treated patients (HR 0.93, 95% CI 0.80 to 1.09). The average adjusted CDAI change at 1 year was similar in both groups (-6.08). After matching, with 560 patients in each group, CDAI remission corrected for attrition at 1 year was also similar between TCZ-SC and TCZ-IV (10.4% in TCZ-IV vs 12.8% in TCZ-SC (difference: 2.4%, bootstrap 95% CI -2.1% to 7.6%)), but CDAI LDA was lower in TCZ-IV patients: 41.0% in TCZ-IV versus 49.1% in TCZ-SC (difference: 8.0 %; bootstrap 95% CI 2.4% to 12.4%). CONCLUSION: With similar retention and effectiveness, TCZ-SC is an adequate alternative to TCZ-IV for RA. When possible, considering the costs of the TCZ-IV route, TCZ-SC should be the preferred mode of administration.
29903510 Quality of life in multiple endocrine neoplasia type 2A compared with normative and diseas 2018 Sep BACKGROUND: Patient-reported outcomes are measured in chronic disease states to inform intervention and management decisions while minimizing negative outcomes. We hypothesized that health-related quality of life in patients with multiple endocrine neoplasia type 2A would be worse than the general US population but similar to other chronic diseases. METHODS: Adults ≥18 years with multiple endocrine neoplasia type 2A were recruited to complete the Patient-Reported Outcomes Measurement Information System 29-item questionnaire (n = 45). Scores based on the Patient-Reported Outcomes Measurement Information System T-score metric were compared with the general US population and with cohorts with low back pain, cancer, congestive heart failure, chronic obstructive pulmonary disease, major depressive disorder, rheumatoid arthritis, neuroendocrine tumors, primary hyperparathyroidism, and MEN1. RESULTS: Compared with US normative data, multiple endocrine neoplasia type 2A patients reported worse anxiety (58.2 ± 12.0, P < .0001), depression (55.4 ± 12.0, P < .01), fatigue (61.4 ± 10.8, P < .0001), pain interference (54.0 ± 11.5, P < .05), and sleep disturbance (56.9 ± 2.7, P < .001), as well as significantly lower physical functioning (45.7 ± 9.3, P < .01) and ability to participate in social roles (46.4 ± 9.7, P < .05). Multiple endocrine neoplasia type 2A patients reported greater fatigue than patients with cancer (P < .0001), chronic obstructive pulmonary disease (P = .01), rheumatoid arthritis (P = .0002), neuroendocrine tumors (P = .0007), and primary hyperparathyroidism (P < .0001) but higher physical functioning compared with patients with rheumatoid arthritis (P = .02), low back pain, congestive heart failure, and chronic obstructive pulmonary disease (P < .0001). CONCLUSIONS: This study is the first to use the Patient-Reported Outcomes Measurement Information System to compare patient-reported outcomes between multiple endocrine neoplasia type 2A and other chronic conditions. Individuals with multiple endocrine neoplasia type 2A reported worse health-related quality of life in all 7 domains compared with US normative data. Multiple endocrine neoplasia type 2A patients reported greater fatigue but greater physical function compared with several other conditions. Prospective longitudinal evaluation of patient-reported outcomes in multiple endocrine neoplasia type 2A should be conducted to identify treatments associated with the highest health-related quality of life.
28392572 An apoptosis-independent role of TRAIL in suppressing joint inflammation and inhibiting T- 2018 Sep Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been implicated in the regulation of inflammation in rheumatoid arthritis (RA), primarily due to its ability to promote apoptosis in synoviocytes and infiltrating lymphocytes. The aim of this study was to investigate the immunomodulatory mechanism and role of TRAIL in inflammatory arthritis. We created an animal model of inflammatory arthritis and demonstrated that TRAIL significantly inhibited joint inflammation and reduced the severity of arthritis. The suppression of joint inflammation was not due to the TRAIL-mediated induction of apoptosis in T cells, macrophages or synovial fibroblasts. In contrast, TRAIL directly inhibited T-cell proliferation and suppressed the production of cytokines, which indicated that TRAIL exerted its anti-inflammatory effects by direct inhibition of T-cell activation. Moreover, TRAIL receptor (TRAIL-R)-knockout mice developed more severe disease, and the protective effects of TRAIL were abolished in the experimental arthritis model in TRAIL-R knockout mice. From these results, we conclude that TRAIL suppresses joint inflammation via an apoptosis-independent pathway and directly inhibits T-cell activation. Our results provide a novel apoptosis-independent, immune regulatory role for TRAIL in suppressing inflammatory arthritis and shed light on the development of effective new therapies for autoimmune inflammatory diseases.
29736302 Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. 2018 Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages: (i) triggering, (ii) maturation, (iii) targeting, and (iv) fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences. Modern pharmacologic therapies (including conventional, biological, and novel potential small molecule disease-modifying anti-rheumatic drugs) remain the mainstay of RA treatment and there has been significant progress toward achieving disease remission without joint deformity. Despite this, a significant proportion of RA patients do not effectively respond to the current therapies and thus new drugs are urgently required. This review discusses recent advances of our  understanding of RA pathogenesis, disease modifying drugs, and provides perspectives on next generation therapeutics for RA.
29423022 Comprehensive analysis of gene expression and DNA methylation datasets identify valuable b 2018 Jan 9 Rheumatoid arthritis (RA) represents a common systemic autoimmune disease which lays chronic and persistent pain on patients. The purpose of our study is to identify novel RA-related genes and biological processes/pathways. All the datasets of this study, including gene expression and DNA methylation datasets of RA and OA samples, were obtained from the free available database, i.e. Gene Expression Omnibus (GEO). We firstly identified the differentially expressed genes (DEGs) between RA and OA samples through the limma package of R programming software followed by the functional enrichment analysis in the Database for Annotation, Visualization and Integrated Discovery (DAVID) for the exploring of potential involved biological processes/pathways of DEGs. For DNA methylation datasets, we used the IMA package for their normalization and identification of differential methylation genes (DMGs) in RA compared with OA samples. Comprehensive analysis of DEGs and DMGs was also conducted for the identification of valuable RA-related biomarkers. As a result, we obtained 394 DEGs and 363 DMGs in RA samples with the thresholds of |log2fold change|> 1 and p-value < 0.05, and |delta beta|> 0.2 and p-value < 0.05 respectively. Functional analysis of DEGs obtained immune and inflammation associated biological processes/pathways. Besides, several valuable biomarkers of RA, including BCL11B, CCDC88C, FCRLA and APOL6, were identified through the integrated analysis of gene expression and DNA methylation datasets. Our study should be helpful for the development of novel drugs and therapeutic methods for RA.
29202589 Interstitial lung disease in systemic autoimmune rheumatic diseases: a comprehensive revie 2018 Jan Interstitial lung diseases (ILDs) are among the most serious complications associated with systemic rheumatic diseases, and lead to significant morbidity and mortality; they may also be the first manifestation of connective tissue diseases (CTDs). The aim of this narrative review is to summarise the data concerning the pathogenesis of CTD/ILD and its distinguishing features in different rheumatic diseseas. Areas covered: The pathogenesis, clinical aspects and treatment of ILD associated with rheumatic systemic diseases and CTDs were reviewed by searching the PubMed, Medline, and Cochrane Library databases for papers published between 1995 and February 2017 using combinations of words or terms. Articles not written in English were excluded. Expert commentary: The management of CTD-ILD is challenging because of the lack of robust data regarding the treatments used, the heterogeneity of the diseases themselves, and the scarcity of well-defined outcome measures. Treatment decisions are often made clinically on the basis of functional, radiographic progression, and exacerbating factors such as age and the burden of comorbidities. Given the complexities of diagnosis and the paucity of treatment trials, the management of CTD patients with ILD requires multidisciplinary collaboration between rheumatologists and pulmonologists in CTD-ILD clinics.
29075848 Compensatory rebalancing of rice prolamins by production of recombinant prolamin/bioactive 2018 Feb Bioactive peptide was produced by fusion to rice prolamins in transgenic rice seeds. Their accumulation levels were affected by their deposition sites and by compensatory rebalancing between prolamins within PB-Is. Peptide immunotherapy using analogue peptide ligands (APLs) is one of promising treatments against autoimmune diseases. Use of seed storage protein as a fusion carrier is reasonable strategy for production of such small size bioactive peptides. In this study, to examine the efficacy of various rice prolamins deposited in ER-derived protein bodies (PB-Is), the APL12 from the Glucose-6-phosphate isomerase (GPI325-339) was expressed by fusion to four types of representative prolamins under the control of the individual native promoters. When the 14 and 16 kDa Cys-rich prolamins, which were localized in middle layer of PB-Is, were used for production of the APL12, they highly accumulated in transgenic rice seeds (~ 200 µg/grain). By contrast, fusion to the 10 and 13 kDa prolamins, which were localized in the core and outermost layer of PB-Is, resulted in lower levels of accumulation (~ 40 µg/grain). These results suggest that accumulation levels were highly affected by their deposition sites. Next, when different prolamin/APL12 fusion proteins were co-expressed to increase accumulation levels, they could not be increased so much as their expected additive levels. High accumulation of one type prolamin/APL12 led to reduction of other type(s) prolamin/APL12 to maintain the limited amounts of prolamins that can be deposited in PB-Is. Moreover, suppression of endogenous seed proteins by RNA interference also did not significantly enhance the accumulation levels of prolamin/APL12. These findings suggest that there may be compensatory rebalancing mechanism that controls the accumulation levels of prolamins deposited within PB-Is.
30185354 Using subcutaneous methotrexate to prolong duration of methotrexate therapy in rheumatoid 2018 Jul OBJECTIVE: Our study aims to determine whether the use of subcutaneous methotrexate (SC MTX) is associated with prolonged MTX use and lower incidence of hepatotoxicity in rheumatoid arthritis (RA) patients on MTX monotherapy and multiple drug therapy. METHODS: We conducted a retrospective cohort study using national databases of a large hospital system. Subjects had been diagnosed with RA and treated with MTX between September 30, 1999, and October 1, 2009. Outcomes of interest were the amount of time on MTX monotherapy or multiple disease-modifying anti-rheumatic drug (DMARD) therapy before addition of additional DMARDs or biologic agents, respectively. We conducted Cox regressions and Kaplan-Meier curves for association between SC MTX use and length of time before therapeutic change. We conducted chi-square tests for association between SC MTX use and elevated liver function tests (LFT). RESULTS: MTX monotherapy: SC MTX was associated with a significantly lower likelihood of therapeutic change (HR 0.64, 95% CI 0.52-0.78). Multiple DMARD therapy: SC MTX was not associated with a lower risk of adding a biologic (HR 1.13, 95% CI 0.97-1.31). Liver enzymes: There was no significant association between use of SC MTX and decreased frequency of abnormal LFTs [p=0.09 for alanine aminotransferase (ALT), p=0.924 for aspartate aminotransferase (AST)]. CONCLUSION: Use of SC MTX is associated with longer duration of MTX monotherapy before addition of other DMARDs/biologic agents in RA patients. Use of SC MTX is not associated with significantly longer duration of multiple DMARD therapy before addition of biologic agents. Use of oral MTX is not significantly associated with increased frequency of elevated LFTs.