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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
29243903 Update on Current Care Guideline: Psoriasis (skin and joints). 2017 Psoriasis is a chronic, immune-mediated, inflammatory disorder of the skin and joints. Moderate-to-server cases are associated with an independent risk of comorbidity (cardiovascular diseases and diabetes) even after adjusting for risk factors, known to be more prevalent in psoriatics compared to normal population. The systemic underlying inflammation, analogous to that observed in rheumatoid arthritis, calls for a long-term effective treatment. Screening and treatment of cardiovascular risk factors is highly recommended. The biologic drug arsenal has new additions. Long term treatment data from clinical study extensions and independent registries are reviewed.
29181394 Corrigendum to "Serum Sclerostin Levels in Patients with Ankylosing Spondylitis and Rheuma 2017 [This corrects the article DOI: 10.1155/2017/9295313.].
28435230 Persistence with golimumab in immune-mediated rheumatic diseases: a systematic review of r 2017 PURPOSE: In immune-mediated rheumatic diseases (IMRDs), persistence to treatment may be used as a surrogate marker for long-term treatment success. In previous comparisons of persistence to tumor necrosis factor α inhibitors (TNFis), a paucity of data for subcutaneous (SC) golimumab was identified. The aim of this study was to conduct a systematic review of persistence to SC golimumab in clinical practice and contextualize these data with five-year persistence estimates from long-term open-label extension (OLE) trials of SC TNFis in IMRDs. PATIENTS AND METHODS: PubMed, Embase, MEDLINE, and conference proceedings from European League Against Rheumatism (EULAR), American College of Rheumatology (ACR), and International Society for Pharmacoeconomics and Outcomes Research (ISPOR) were searched. All studies on patients treated with SC golimumab for IMRD were included if they reported data on the persistence to golimumab. RESULTS: Of 376 available references identified through the searches, 12 studies with a total of 4,910 patients met the inclusion criteria. Furthermore, nine OLE trials were available. Among the included studies from clinical practice, at six months, one year, two years, and three years, the proportion of patients persistent to treatment ranged from 63% to 91%, 47% to 80%, 40% to 77%, and 32% to 67%, respectively. In the four studies that included comparisons to other biologics, golimumab was either statistically noninferior or statistically superior to other treatments, an observation that was supported by indirect comparisons of unadjusted point estimates of OLE trials. CONCLUSION: The data reviewed in this study indicate that golimumab may have higher persistence than other TNFis, a notion that is supported by indirect comparisons of persistence data from OLEs of randomized controlled trials (RCTs). Furthermore, the study suggests that persistence may be lower in biologic-experienced compared with biologic-naive patients and higher in axial spondyloarthritis compared with rheumatoid arthritis and psoriatic arthritis.
28983760 Chikungunya Virus-Associated Disease. 2017 Oct 5 PURPOSE OF REVIEW: Chikungunya virus (CHIKV) infection has become increasingly prevalent in the last decade not only across the southern hemisphere but also, because of a recently documented viral mutation, in southern Europe and the USA. With the global spread of CHIKV infection, practitioners should know its epidemiology, pathophysiology and clinical features. RECENT FINDINGS: The acute phase of CHIKV disease is characterised by a fever-arthralgia-rash syndrome. Chronic rheumatic manifestations can persist for months to years with very variable clinical presentations. Some cases mimic inflammatory rheumatism such as rheumatoid arthritis. Several risk factors for persistent joint pain, notably older age, have been identified in cohort studies. Despite a low mortality rate with CHIKV infection, the rate of disability with chronic joint symptoms is high, and effective treatments are lacking. Current research is focusing on the development of vaccines and antiviral drugs, and data on treatment of CHIKV-induced chronic arthritis are needed.
27988789 Systematic review of rheumatic disease phenotypes and outcomes in the Indigenous populatio 2017 Apr We performed a systematic review designed to characterize clinical phenotypes and outcomes in Indigenous populations with rheumatic disease to enhance the understanding of how rheumatic disease presents in Indigenous populations and allow for better projection of the healthcare needs of the communities affected. A systematic search was performed in medical (Medline, EMBASE, CINAHL), Indigenous and conference abstract databases (to June 2015). Search terms for Indigenous populations were combined with terms for inflammatory arthritis conditions, connective tissue disorders, crystal arthritis and osteoarthritis. Studies were included if they reported on disease features, disease activity measures, or patient-reported outcomes in Canadian, American, Australian or New Zealand Indigenous populations. Data were extracted in duplicate, and a narrative summary was prepared. A total of 5269 titles and abstracts were reviewed, of which 504 underwent full-text review and 85 met inclusion criteria. Nearly all the studies described outcomes in the North American populations (n = 77), with only four studies from Australia and four studies from New Zealand. The majority of studies were in rheumatoid arthritis (n = 31) and systemic lupus erythematosus (n = 19). Indigenous patients with rheumatoid arthritis had higher disease activity and reported more significant impact on patient-reported outcomes and quality of life than non-Indigenous patients. Spondyloarthropathy features were described in North American populations, with most patients having advanced manifestations. In systemic lupus erythematosus, nephritis was more frequent in Indigenous populations. Gout and osteoarthritis were more severe in New Zealand Maori populations. The existing literature supports differences in disease phenotype and severity in Indigenous populations of Canada, America, Australia and New Zealand. We encourage investigators in this area of research to undertake contemporary studies that disentangle differences between phenotype and severity that are biologic in etiology or merely reflecting differences in access to care and that provide a longitudinal assessment of outcomes in more diverse populations.
28959631 Effect of dietary pristane and other saturated mineral oils (MOSH) on autoimmune arthritis 2017 Pristane and other adjuvants based on mineral oil saturated hydrocarbons (MOSH) may induce autoimmunity in rodents after intradermal injection; however there is a lack of information on immune effects after oral MOSH exposure. The aim of our study was to determine the impact of dietary exposure to pristane and other MOSH on the development of autoimmune arthritis. Dark Agouti (DA) rats were given feed containing 4000 mg/kg pristane or a broad MOSH mixture in various concentrations (0-4000 mg/kg) for 90 days, or a single intradermal injection of 200 μl pristane (positive control). Arthritis scores, and serum and splenocyte markers previously associated with arthritis development, were determined. All rats injected with pristane displayed arthritis symptoms and higher levels of certain serum markers. None of the rats fed pristane or MOSH developed arthritis symptoms or demonstrated clear changes in any measured arthritis-associated biological markers in serum or splenocytes. The absence of clinical arthritis symptoms or any increase in common arthritis-associated biological markers in sera and spleen following dietary exposure to pristane or a broad MOSH mixture in a sub-chronic rat model of arthritis suggest that dietary MOSH have low capacity to promote development of autoimmunity.
28740214 Compensatory anabolic signaling in the sarcopenia of experimental chronic arthritis. 2017 Jul 24 Inflammatory activity in rheumatoid arthritis may alter the regulation of muscle mass leading to a secondary sarcopenia, commonly termed rheumatoid cachexia (RC). We characterized alterations to muscle structure and various pro-inflammatory, catabolic and regenerative markers in an animal model of RC. Antigen induced arthritis (AiA) was performed in 20 male adult rabbits. AiA animals exhibited significantly less weight gain, a markedly elevated serum C-reactive protein (CRP), lighter muscles with shorter cross-sectional diameter and increased myonuclei when compared to controls. Atrogin-1 and MuRF-1 were up-regulated alongside an increase in IL-1β, active NF-κB and a higher ratio of phosphorylated to inactive p38 MAPK. CCL-2 and TNF levels were reduced and IL-6 was unchanged between groups. We observed decreased pSTAT3, unchanged pSTAT1 and Myf5, but increased Pax7, MyoD and myogenin. AiA rabbits had a reduction in myostatin from gastrocnemii and synovium with a congruent decrease in serum myostatin compared to controls. Chronic arthritis induced an RC-like secondary sarcopenia with increased muscle protein breakdown. Elevated IL-1β may trigger proteolysis via elevated NF-κB and p38 MAPK signaling with a compensatory anabolic response suggested by myonuclear expansion, increased Pax7, MyoD and myogenin, reduced pSTAT3 as well as reduced serum, synovial and muscular myostatin.
29190705 Arthritic role of Porphyromonas gingivalis in collagen-induced arthritis mice. 2017 Epidemiological studies show an association between rheumatoid arthritis (RA) and periodontal disease. Porphyromonas gingivalis (P.gingivalis) is a well-known pathogen in periodontitis. This study investigated the pathogenic effects of P.gingivalis on autoimmune arthritis in vivo. Collagen-induced arthritis (CIA) mice were intraperitoneally injected with W83 and 2561 strains of P.gingivalis. Infection with P.gingivalis exacerbated arthritis score in CIA mice. Synovial inflammation and bone destruction in CIA mice infected with P.gingivalis were more severe than in uninfected CIA mice. Both W83 and 2561 strains were more pro-arthritic after arthritis symptom was fully activated. Interestingly, only W83 strain was arthritogenic before autoimmune reaction initiated. Citrullination was detected in synovial tissue of CIA mice and CIA mice inoculated with P.gingivalis, but not in normal control mice. The citrullinated area was greater in P.gingivalis-infected CIA mice than in non-infected CIA mice. This study showed that P.gingivalis exacerbated disease in a mouse model of autoimmune arthritis and increased the expression of citrullinated antigens in the synovium. The arthritogenic effects of P.gingivalis were at least in part, dependent upon the bacterial strain with or without fimbriae expression, route and time of infection. P.gingivalis-mediated citrullination may explain the possible link between periodontal disease and RA.
29247150 Adiposity in Juvenile Psoriatic Arthritis. 2018 Mar OBJECTIVE: Adult patients with psoriatic arthritis are at increased risk for obesity and metabolic syndrome, but data regarding adiposity in children with juvenile psoriatic arthritis (JPsA) are limited. Our study assessed adiposity in children with JPsA in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry. METHODS: Patients with JPsA in the CARRA registry were divided into nonoverweight and overweight groups using recommendations from the US Centers for Disease Control, and differences in demographic and clinical characteristics between groups at baseline and after 1-year followup were assessed using chi-square test, Fisher's exact test, T test, or Mann-Whitney U test, as appropriate. The prevalence of overweight status in the JPsA registry patients was compared to rheumatoid factor-positive and -negative polyarticular juvenile idiopathic arthritis (RF+polyJIA; RF-polyJIA) registry cohorts and the US pediatric population, using a chi-square goodness-of-fit test. RESULTS: Overweight children represented 36.3% of this JPsA cohort (n = 320). Compared to nonoverweight children, they were significantly older at symptom onset and rheumatologist's first assessment, and scored significantly worse on patient/physician outcome measures. At 1-year followup, changes in body mass index were not associated with changes in clinical features or outcome measures. The prevalence of overweight and obesity in patients with JPsA was significantly higher than in RF+polyJIA patients, RF-polyJIA patients, and the US pediatric population. CONCLUSION: In this registry, almost 1 in 5 patients with JPsA were obese and more than one-third were overweight. This is significantly more than expected compared to the US pediatric population, and appropriate longterm followup of this JPsA subgroup is warranted.
29185286 Lessons Learned from Imaging on Enthesitis in Psoriatic Arthritis. 2017 Nov Enthesitis is a term that refers to inflammation at tendon, ligament, or joint capsule insertions. The entheses are increasinlgly considered to be the primary site of joint inflammation in the spondyloarthropathies including psoriatic arthritis (PsA). Great advances have occurred in the understanding of enthesopathy, which has resulted in a better understanding of the etiopathogenesis of PsA. Enthesitis is difficult to assess on both clinical examination and on imaging because of the overlap in features between mechanical, degenerative, and inflammatory pathologies. Ultrasonography frequently detects entheseal abnormalities in patients with psoriasis, despite the absence of clinical symptoms of arthropathy and the longitudinal value of such lesions for PsA prediction remains unknown. The role of magnetic resonance imaging (MRI) in the assessment and monitoring of enthesitis is not fully agreed on but it is clearly superior for the assessment of spinal polyenthesitis and for diffuse peri-enthseal osteitis that can occur anywhere in the skeleton. Nuclear medicine, including conventional positron-emission tomography (PET) and high-resolution PET scan (hrPET), is more of a research tool for enthesitis and can, for example, help distinguish between PsA and osteoarthritis. Entheseal abnormalities are common in osteoarthritis, which creates diagnostic difficulty from PsA. Entheseal changes, especially on imaging, may also occur in rheumatoid arthritis (RA) and likely reflect the extension of the inflammatory process from the adjacent synovium. The nail is anatomically anchored to the skeleton via a mini-enthesis network. An association between ultrasonography determined distal interphalageal joint (DIP) extensor tendon enthesopathy and clinical nail disease was found, which highlights the pivotal role of the enthesis in this PsA risk factor. This review summarizes the relevant insights and implication of imaging for enthesitis, primarily in PsA but also in other arthropathies.
29435362 Long-term efficacy and safety of antitumour necrosis factor alpha treatment in rhupus: an 2017 BACKGROUND: The efficacy of antitumour necrosis factor alpha (anti-TNF-α) treatment is well recognised in rheumatoid arthritis (RA) but remains controversial in systemic lupus erythematosus (SLE). Therefore, the role of anti-TNF-α treatment in 'Rhupus', a disease sharing features of RA and SLE, is still debated. OBJECTIVE: To evaluate the efficacy and tolerance of anti-TNF-α in patients with rhupus. METHODS: Fifteen patients with rhupus with Disease Activity Score 28 (DAS 28) >3.2 despite conventional disease-modifying anti-rheumatic drugs were included in an open-label study. Patients were monitored at months (M) 3, 6, 12, 24 and 60 with SLE Disease Activity Index (SLEDAI) and DAS 28. Statistical analyses were performed using Bayesian methods and Prob >97.5% was considered significant. RESULTS: Twelve patients were treated with etanercept for a median duration of 62.5 (range: 6-112) months and three patients by adalimumab during 36.0 (range: 4-52) months. At baseline, median DAS 28 and SLEDAI were 5.94 (4.83-8.09) and 6 (4-8), respectively. DAS 28 and SLEDAI decreased significantly after 3 months, respectively, to 3.70 (1.80-6.42) and 4 (0-6) (Prob >99.9%, for both). These changes persisted at M6, M12, M24 and M60 (Prob >99.9%, for all). Median prednisone dose decreased significantly from 15 (5-35) mg/day to 5 (0-20) mg/day after 6 months and over the follow-up (Prob >99.9%, for all). Tolerance was acceptable, with a severe infection rate of 3.0 per 100 patient-years. CONCLUSION: This pilot study suggests that anti-TNF-α is effective in patients with rhupus with refractive arthritis and has an acceptable safety profile.
29143151 Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment. 2017 Nov 16 The clinical success of anti-CD20 monoclonal antibody (mAb)-mediated B cell depletion therapy has contributed to the understanding of B cells as major players in several autoimmune diseases. The first therapeutic anti-CD20 mAb, rituximab, is a murine-human chimera to which many patients develop antibodies and/or experience infusion-related reactions. A second generation of anti-CD20 mAbs has been designed to be more effective, better tolerated, and of lower immunogenicity. These include the humanized versions: ocrelizumab, obinutuzumab, and veltuzumab, and the fully human, ofatumumab. We conducted a literature search of relevant randomized clinical trials in the PubMed database and ongoing trials in Clinicaltrials.gov. Most of these trials have evaluated intravenous ocrelizumab or subcutaneous ofatumumab in rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus. Understanding how newer anti-CD20 mAbs compare with rituximab in terms of efficacy, safety, convenience, and cost is important for guiding future management of anti-CD20 mAb therapy in autoimmune diseases.
28774272 Identification of candidate protective variants for common diseases and evaluation of thei 2017 Aug 3 BACKGROUND: Human polymorphisms with derived alleles that are protective against disease may provide powerful translational opportunities. Here we report a method to identify such candidate polymorphisms and apply it to common non-synonymous SNPs (nsSNPs) associated with common diseases. Our study also sought to establish which of the identified protective nsSNPs show evidence of positive selection, taking this as indirect evidence that the protective variant has a beneficial effect on phenotype. Further, we performed an analysis to quantify the predicted effect of each protective variant on protein function/structure. RESULTS: An initial analysis of eight SNPs previously identified as associated with age-related macular degeneration (AMD), revealed that two of them have a derived allele that is protective against developing the disease. One is in the complement component 2 gene (C2; E318D) and the other is in the complement factor B gene (CFB; R32Q). Then, combining genomewide ancestral allele information with known common disease-associated nsSNPs from the GWAS catalog, we found 32 additional SNPs which have a derived allele that is disease protective. Out of the total 34 identified candidate protective variants (CPVs), we found that 30 show stronger evidence of positive selection than the protective variant in lipoprotein lipase (LPL; S447X), which has already been translated into gene therapy. Furthermore, 11 of these CPVs have a higher probability of affecting protein structure than the lipoprotein lipase protective variant (LPL; S447X). CONCLUSIONS: We identify 34 CPVs from the human genome. Diseases they confer protection against include, but are not limited to, type 2 diabetes, inflammatory bowel disease, age-related macular degeneration, multiple sclerosis and rheumatoid arthritis. We propose that those 30 CPVs with evidence of stronger positive selection than the LPL protective variant, may be considered as priority candidates for therapeutic approaches. The next step towards translation will require testing the hypotheses generated by our analyses, specifically whether the CPV arose from a gain-of-function or a loss-of-function mutation.
28342734 Integration of microbiome and epigenome to decipher the pathogenesis of autoimmune disease 2017 Sep The interaction between genetic predisposition and environmental factors are of great significance in the pathogenesis and development of autoimmune diseases (AIDs). The human mucosa is the most frequent site that interacts with the exterior environment, and commensal microbiota at the gut and other human mucosal cavities play a crucial role in the regulation of immune system. Growing evidence has shown that the compositional and functional changes of mucosal microbiota are closely related to AIDs. Gut dysbiosis not only influence the expression level of Toll-like receptors (TLRs) of antigen presenting cells, but also contribute to Th17/Treg imbalance. Epigenetic modifications triggered by environmental factors is an important mechanism that leads to altered gene expression. Researches addressing the role of DNA methylation, histone modification and non-coding RNA in AIDs have been increasing in recent years. Furthermore, studies showed that human microbiota and their metabolites can regulate immune cells and cytokines via epigenomic modifications. For example, short-chain fatty acids (SCFAs) produced by gut microbiota promote the differentiation of naïve T cell into Treg by suppressing histone deacetylases (HDACs). Therefore, we propose that dysbiosis and resulting metabolites may cause aberrant immune responses via epigenetic modifications, and lead to AIDs. With the development of high-throughput sequencing, metagenome analysis has been applied to investigate the dysbiosis in AIDs patients. We have tested the fecal, dental and salivary samples from treatment-naïve rheumatoid arthritis (RA) individuals by metagenomic shotgun sequencing and a metagenome-wide association study. Dysbiosis was detected in the gut and oral microbiomes of RA patients, but it was partially restored after treatment. We also found functional changes of microbiota and molecular mimicry of human antigens in RA individuals. By integrating the analysis of multi-omics of microbiome and epigenome, we could explore the interaction between human immune system and microbiota, and thereby unmasking specific and more sensitive biomarkers as well as potential therapeutic targets. Future studies aiming at the crosstalk between human dysbiosis and epigenetic modifications and their influences on AIDs will facilitate our understanding and better managing of these debilitating AIDs.
28273969 A Study on Association between Common Haematological Parameters and Disease Activity in Rh 2017 Jan INTRODUCTION: Rheumatoid Arthritis (RA) is a chronic systemic inflammatory disease where assessment of disease activity is essential for management of patient. Currently, many composite scoring systems are used for evaluation of disease activity but they are mainly clinical-based. As several haematological parameters are altered due to systemic inflammatory process in RA, this study was intended to evaluate role of common haematological parameters to assess disease activity in RA. AIM: To find out the association of disease activity of Rheumatoid Arthritis (RA) with platelet count, Mean Platelet Volume (MPV) and Haemoglobin (Hb) level so that these cost-effective haematological parameters can be used as additional factors to assess disease activity. MATERIALS AND METHODS: This hospital based cross-sectional study was done on newly diagnosed patients of RA along with age and sex matched healthy control population. Patients suffering from malignancies, renal failure, diabetes mellitus or RA patients on drug therapy were excluded. Clinically, disease activity of RA was measured using DAS 28-3 Score (Modified Disease Activity Score using three variables- tender joint count, swollen joint count and ESR). Haematological parameters were measured by automated cell counter. RESULTS: Total 80 cases were selected (60 female and 20 male). 48 patients with high disease activity (DAS 28-3>5.1) were labelled as Group-A and 32 with low to moderate disease activity (DAS 28-3 ≤5.1) as Group- B. Mean platelet count of patients of group A and group B were 4.53 lac/cmm and 2.17 lac/cmm respectively (p <0.001). MPV mean in group A and B were 11.86 fl and 10.19 fl respectively (p <0.001). Mean Hb (g/dl) was 10.05 and 12.25 for group A and B respectively (p=0.001) for male patients while in females it was 10.12 and 11.91 for group A and B, respectively (p=0.003). Mean platelet count and MPV in control population were 2.07 lac/cmm and 9.4 fl, respectively while mean Hb (g/dl) was 13.31 (male) and 12.01 (female). CONCLUSION: In our study it was observed that Hb is significantly lower in patients with high disease activity whereas platelet count and MPV are significantly higher with high disease activity compared to patients with low to moderate disease activity.
28189826 Targeted lipidomics reveals activation of resolution pathways in knee osteoarthritis in hu 2017 Jul OBJECTIVE: To investigate the presence of inflammation and resolution pathways in osteoarthritis (OA). DESIGN: Tissues were obtained from knee OA patients and control rheumatoid arthritis (RA) patients. Cells in synovial fluid (SF) were visualized by flow cytometry. Cytokines and chemokines were measured by multiplex assay. Lipid mediators (LMs) were determined by targeted lipidomics using liquid-chromatography mass spectrometry. RESULTS: SF of OA patients contained less cells, especially neutrophils, less cytokines and comparable levels of chemokines compared to RA controls. Thirty-seven lipids were detected in the soluble fraction of SF, including polyunsaturated fatty acids (PUFAs) and their pro-inflammatory and pro-resolving lipoxygenase (LOX) and cyclooxygenase (COX) pathway markers in both OA and RA patients. Among these, pro-inflammatory LM such as prostaglandin E(2) (PGE(2)) and thromboxane B(2), as well as precursors and pathway markers of resolution such as 17-HDHA and 18-HEPE were detected. Interestingly, the pro-resolving lipid RvD2 could also be detected, but only in the insoluble fraction (cells and undigested matrix). Ratios of metabolites to their precursors indicated a lower activity of 5-LOX and 15-LOX in OA compared to RA, with no apparent differences in COX-derived products. Interestingly, synovial tissue and SF cells could produce 5-LOX and 15-LOX metabolites, indicating these cells as possible source of LM. CONCLUSIONS: By using a state-of-the-art technique, we show for the first time that resolution pathways are present in OA patients. A better understanding of these pathways could guide us to more effective therapeutic approaches to inhibit inflammation and further structural damage in OA and RA.
28134597 Endogenous bone morphogenetic protein 2 plays a role in vascular smooth muscle cell calcif 2017 Sep Systemic inflammation is involved in vascular calcification and cardiovascular disease which is the leading cause of mortality in rheumatoid arthritis (RA). A high level of serum interleukin (IL)-6 plays a key role in local and systemic inflammation in RA. However, the underlying mechanisms remain unclear. We established a human umbilical artery smooth muscle cell (HUASMC) culturing method to investigate the possible role of IL-6 on vascular calcification. HUASMCs were obtained from umbilical arteries of healthy neonates. To detect calcification effects, HUASMCs were treated with (experimental group) or without (control group) recombinant human (rh) IL-6. The calcium deposition stain and calcium concentrations were measured, as well as the mRNA and protein levels of the regulating factor of osteogenic differentiation-bone morphogenetic protein (BMP) 2 and those calcifying related molecules including bone-specific alkaline phosphatase (BAP), osteoprotegerin (OPG), and osteopontin (OPN). Our study showed that rhIL-6 induced calcification of HUASMCs in a time- and dose-dependent manner, and upregulated expressions of BMP2, BAP, OPG, and OPN of HUASMCs. We then used the anti-BMP2 siRNA to knockdown the expression of endogenous BMP2 to confirm its role. HUASMCs were transfected with negative siRNA (control group) or the valid anti-BMP2 siRNA (experimental group) before they were treated with rhIL-6. Cells transfected with negative siRNA without IL-6 stimulating served as the blank group. The results showed that anti-BMP2 siRNA markedly decreased expressions of BMP2, BAP, OPG, and OPN, and also partly reduced the calcification of HUASMCs induced by rhIL-6. Collectively, according to our study, rhIL-6 could induce the extracellular calcification and osteogenic differentiation of human artery smooth muscle cells through upregulating endogenous BMP2 in vitro. This may be one of the underlying mechanisms of the overwhelming vascular calcification in RA.
28057550 Pharmacokinetics of LBPT and its primary metabolites, as well as tolerability in the first 2017 Mar 30 BACKGROUND: LBPT is a novel platelet-activating factor (PAF) receptor antagonist that is developed for the treatment of rheumatoid arthritis. The purpose of this first-in-human study was to evaluate the tolerability and safety of LBPT, to investigate the pharmacokinetics of LBPT and its primary metabolites, as well as to assess the food effect on the pharmacokinetics in healthy Chinese subjects. MATERIALS AND METHODS: LBPT was evaluated in 2 clinical studies. The first study was a double blind, placebo-controlled and ascending dose study. Eighty-five healthy Chinese subjects received oral dose of 2, 4, 6, 8, 15, 25, 50, 75, 100, 125, 150, 225, 300, 400 or 500mg of LBPT or placebo. The pharmacokinetics of LBPT and its primary metabolites were investigated in the last 4 dose cohorts. The tolerability was evaluated by monitoring adverse events (AEs), physical examinations, 12-lead electrocardiograms (ECG) and laboratory tests. The second study was an open-label, 2-period cross-over study with a washout interval of 3days. Twelve subjects received 300mg of LBPT after an overnight fasting or a high-fat breakfast. The pharmacokinetics of LBPT in subjects under fasted and fed conditions were compared. RESULTS: LBPT was well tolerated up to 500mg-dose and there were no serious AEs in the study. The incidence and severity of AEs were closely related to dose. Following single oral administration of 225, 300, 400 and 500mg of LBPT, plasma C(max) was reached at 0.5h and the mean t(1/2) was 0.6-1.6h. Plasma exposure increased with dose escalation but proportionality was not observed. LBPT was eliminated in forms of metabolites and 20-40% of the given dose was recovered in urine. Compared with the subjects under fasting conditions, AUC and C(max) were lower and t(max) was delayed in the fed subjects. CONCLUSION: LBPT was well tolerated in healthy subjects with a pattern of dose-related AEs. The pharmacokinetics was non-linear and was impacted by food intake.
29173945 Synthesis and in vitro evaluations of 6-(hetero)-aryl-imidazo[1,2-b]pyridazine-3-sulfonami 2018 Jan 1 Tumor necrosis factor-α is an important pro-inflammatory cytokine having a key role in hosts defensive process of immune systems and its over expression led to a diverse range of inflammatory diseases such as Rheumatoid arthritis, Cronh's disease, psoriasis, etc. This paper describes our medicinal chemistry efforts on imidazo[1,2-b]pyridazine scaffold: design, synthesis and biological evaluation. By the introducing sulfonamide functionality at 3 positions and substituting 6 positions with (hetero)-aryl groups', a small library of compounds was prepared. All synthesized compounds were screened for lipopolysaccharide (LPS) mediated TNF-α production inhibitory activity. Biological data revealed that the majority of the compounds of this series showed moderate to potent TNF-α production inhibitory activity. Compound 5u and 5v are the most potent compounds from the series with activity of IC(50) = 0.5 µM and 0.3 µM respectively. A short SAR demonstrates that 3-sulfonyl-4-arylpiperidine-4-carbonitrile moiety on imidazo[1,2-b]pyridazine showed better activity compared to the 3-(4-aryllpiperazin-1-yl) sulfonyl) in hPBMC assay. The molecular modeling studies revealed that the potent TNF-α production inhibitory activity 5v due to the extra stability of complex because of an extra pi-pi (π-π) stacking, hydrogen-bonding interactions.
28658898 Estimation of Pentraxin 3 and Porphyromonas Gingivalis Levels in Patients with Rheumatoid 2017 May INTRODUCTION: Periodontal diseases are inflammatory in nature involving interplay between the bacterial plaque and the micro-organisms, with the response of the host playing a pivotal role in either attenuating or eliminating the disease. Rheumatoid Arthritis (RA) is also a chronic inflammatory disease which shares common risk factors with periodontitis. Porphyromonas Gingivalis and Pentraxin 3 (an acute inflammatory protein) have been observed to be associated with both the diseases. AIM: This study was done to determine if there was any association between Pophyromonas Gingivalis and Pentraxin 3 levels in patients with RA and Chronic Periodontitis in comparison with Healthy controls. MATERIALS AND METHODS: This observational study was conducted on 90 subjects (42 Males and 48 Females) aged between 30-60 years. The subjects were selected from the out patient ward of a tertiary referral care hospital. The selected subjects were equally divided into three groups. Group I: Comprising of 30 patients with RA and chronic periodontitis who were in turn, subdivided into Group I- A (n=15) -Patients just diagnosed with RA and Group I- B (n=15) Patients under medications for more than three months. Group II: Patients with Chronic Periodontitis (n=30) and Group III: Healthy Controls (n=30) Intergroup comparison for continuous data was done by One-way analysis of variance test followed by Bonferroni's post-hoc test. Intragroup comparison for continuous data was done by paired t-test. RESULTS: Intergroup comparison between Group I and Group II did not show any statistical difference pertaining to the clinical parameters except for the Gingival Index (GI) which was found to be higher in Group II (Mean= 2.07) when compared to Group I (Mean=1.59). Intragroup comparison between Group IA and Group IB was statistically significant for GI, Plaque Index (PI), and Clinical Attachment Levels (CAL). Intragroup comparison between Group I-A and Group I-B showed that both Porphyromonas gingivalis and Pentraxin 3 Levels were higher in Group I- A. CONCLUSION: In this study, it was observed that there was a positive association between Porphyromonas gingivalis and Pentraxin 3 levels in patients with rheumatoid arthritis and periodontitis.