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ID PMID Title PublicationDate abstract
29181029 Incidence and Risk Factors for Infections Requiring Hospitalization, Including Pneumocysti 2017 OBJECTIVE: Rheumatoid arthritis (RA) may be complicated by different infections, but risk factors for these are not fully elucidated. Here, we assessed the incidence of and risk factors for infections requiring hospitalization (IRH) including pneumocystis pneumonia (PCP) in patients with RA. METHODS: We retrospectively surveyed all RA patients treated at our hospital from 2009 to 2013, for whom data were available on demographic features, medications, comorbidities, and severity of RA. Multivariate logistic regression analysis was applied to calculate adjusted odds ratios (ORs) for factors associated with the occurrence of IRH. RESULTS: In a total of 9210 patient-years (2688 patients), there were 373 IRH (3.7/100 patient-years). Respiratory tract infections were most frequent (n = 154, and additionally 16 PCP), followed by urinary tract infections (n = 50). Significant factors for PCP included higher age (≥70 years; OR 3.5), male sex (6.6), underlying lung disease (3.0), use of corticosteroids (4.8), and use of biologics (5.4). Use of methotrexate (5.7) was positively associated with PCP but negatively with total infections (0.7). Additionally, functional disorders and higher RA disease activity were also related to total infections. CONCLUSIONS: Risk factors for infection should be taken into account when deciding treatment for the individual RA patient.
30886947 Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets 2017 In recent years, the landscape of pro- and anti-inflammatory cytokines has rapidly expanded with the identification of new members proven to be involved at different extent in the pathogenesis of chronic immune mediated inflammatory diseases including rheumatoid arthritis (RA). The advance of our understanding of mediators involved in the pathogenesis of RA and in consequence, the development of novel targeted therapies is necessary to provide patients not responding to currently available strategies with novel compounds. The aim of this review article is to provide an overview on recently identified cytokines, emphasizing their pathogenic role and therapeutic potential in RA. A systematic literature review was performed to retrieve articles related to every cytokine discussed in the review. In some cases, evidence from animal models and RA patients is already consistent to move forward into drug development. In others, conflicting observation and the paucity of data require further investigations.Forty years after the discovery of IL-1, the landscape of cytokines is continuously expanding with increasing possibilities to develop novel therapeutic strategies in RA.
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.
29112329 In Vitro and In Vivo Investigation of Potential for Complex CYP3A Interaction for PF-00251 2018 Mar The dissociated agonists of the glucocorticoid receptor are a novel class of agents in clinical development for rheumatoid arthritis. PF-04171327 (fosdagrocorat) is a phosphate ester prodrug of PF-00251802 (dagrocorat), a selective high-affinity partial agonist of the glucocorticoid receptor, which is further metabolized to PF-04015475. This study evaluated the cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) potential of PF-00251802 and PF-04015475 in vitro and used model-based prediction approaches to estimate clinical impact. PF-00251802 is a reversible inhibitor of several CYPs, but modeling has suggested no clinically relevant interaction. PF-00251802 and PF-04015475 are time-dependent inhibitors and inducers of CYP3A in vitro; PF-00251802 is also a time-dependent inhibitor of CYP2D6. Model-based prediction suggested the potential for weak inhibition of CYP3A in vivo. A clinical DDI study was conducted with midazolam, a sensitive CYP3A substrate. A phase 1 open-label, multiple-dose study evaluated the effect of PF-04171327 on midazolam pharmacokinetics and safety in 12 healthy volunteers. Administration of midazolam alone or concomitantly with PF-04171327 resulted in equivalent pharmacokinetic profiles (AUC(inf) , 21.17 vs 20.28 ng·h/mL, respectively), indicating that PF-04171327 had no net effect on CYP3A activity in vivo. These findings support the further development of PF-00251802 and PF-04171327 as potential treatments for patients with rheumatoid arthritis (NCT00987038).
28893837 Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) RNAs in the Porphyromona 2017 Dec 1 The CRISPR-Cas (clustered regularly interspaced short palindromic repeat-CRISPR-associated protein) system is unique to prokaryotes and provides the majority of bacteria and archaea with immunity against nucleic acids of foreign origin. CRISPR RNAs (crRNAs) are the key element of this system, since they are responsible for its selectivity and effectiveness. Typical crRNAs consist of a spacer sequence flanked with 5' and 3' handles originating from repeat sequences that are important for recognition of these small RNAs by the Cas machinery. In this investigation, we studied the type I-C CRISPR-Cas system in Porphyromonas gingivalis, a human pathogen associated with periodontitis, rheumatoid arthritis, cardiovascular disease, and aspiration pneumonia. We demonstrated the importance of the 5' handle for crRNA recognition by the effector complex and consequently activity, as well as secondary trimming of the 3' handle, which was not affected by modifications of the repeat sequence.IMPORTANCEPorphyromonas gingivalis, a clinically relevant Gram-negative, anaerobic bacterium, is one of the major etiologic agents of periodontitis and has been linked with the development of other clinical conditions, including rheumatoid arthritis, cardiovascular disease, and aspiration pneumonia. The presented results on the biogenesis and functions of crRNAs expand our understanding of CRISPR-Cas cellular defenses in P. gingivalis and of horizontal gene transfer in bacteria.
28668652 An integrative investigation of the toxicity of Aconiti kusnezoffii radix and the attenuat 2017 Oct 25 Aconiti kusnezoffii radix (AKR), the root of Aconitum kusnezoffii Reichb., is commonly used in the treatment of the rheumatoid arthritis. However, the clinical application is limited due to its potential toxicity. Therefore, to investigate the mechanism of its potential neurotoxicity and nephrotoxicity, a comprehensive metabolomics study combined with serum biochemistry and histopathology measurements was carried out. A UHPLC-Q-TOF mass spectrometry based metabolomics approach was applied to characterize the AKR toxicity, while the toxicity attenuation effects of Aconiti kusnezoffii radix cocta (AKRC) on Wistar rats were also investigated. Two chromatographic techniques involving reversed-phase chromatography and hydrophilic interaction chromatography were combined for the serum and urine detection, which balanced the integrity and selectivity of the two matrices. Principal component analysis was used to determine the groups, and principal component analysis discriminant analysis was carried out to confirm the important variables. Then, the developed integrative toxicity evaluation method was applied to assess the toxicity of AKR and the attenuation effect of AKRC. The highly sensitive and specific toxic biomarkers, which can provide practical bases were identified for the diagnosis of the neurotoxicity and nephrotoxicity induced by AKR. In all, a total of 19 putative biomarkers were characterized, and related metabolic pathways were identified. The study demonstrated that the established metabolomics strategy is a powerful approach for investigating the mechanisms of herbal toxicity and the attenuation effect of a processing method and would provide medical solutions for other toxic herbal medications and further clinical evidence on how AKR improves symptoms of rheumatoid arthritis patients.
29141196 ASIC2a overexpression enhances the protective effect of PcTx1 and APETx2 against acidosis- 2018 Feb 5 Acid hydrarthrosis is another important pathological character in rheumatoid arthritis (RA), and acid-sensing ion channel 1a (ASIC1a) plays a destructive role in acidosis-induced articular chondrocyte cytotoxicity. Recently, ASIC2a has been reported to possess neuroprotective effect on acidosis-induced injury of neuronal cells. However, whether ASIC2a has an enhanced effect on the protective effect of blocking ASIC1a and ASIC3 against acid-induced chondrocyte apoptosis is still unclear. The aim of present study was to investigate the chondroprotective effect of ASIC2a with PcTx1 (ASIC1a specific blocker) and APETx2 (ASIC3 specific blocker) on acidosis-induced chondrocyte apoptosis. Our results revealed that acid (pH 6.0) decreased the cell viability and induced apoptosis of articular chondrocytes. PcTx1 and APETx2 combination significantly attenuated acidosis-induced chondrocyte cytotoxicity due to inhibit apoptosis, and this role could be enhanced by ASIC2a overexpression compared with the PcTx1 and APETx2 combination alone group. Moreover, both the [Ca(2+)](i) levels and the levels of phosphorylated ERK1/2 as well as p38 were further reduced in acidosis-induced chondrocytes after ASIC2a overexpression in the presence of PcTx1 and APETx2. Furthermore, ASIC2a overexpression also reduced acid-induced the expression of ASIC1a. In addition, ASIC2a overexpression further promoted the PcTx1 and APETx2-increased levels of type II collagen in acidosis-induced chondrocytes. Taken together, the current data suggested that ASIC2a overexpression might enhance the anti-apoptotic and protective role of PcTx1 and APETx2 against acid-induced rat articular chondrocyte apoptosis by regulating ASIC1a expression and the [Ca(2+)](i) levels and at least in part, suppressing p38 and ERK1/2 MAPK signaling pathways.
28748389 Predisposing factors associated with atypical femur fracture among postmenopausal Korean w 2017 Nov The risk factors for atypical femur fracture in patients exposed to bisphosphonates for at least 1 year were examined. Prolonged and continuous use of bisphosphonates, long-term use of glucocorticoids, and a higher body mass index were associated with increased risk of atypical femur fracture. INTRODUCTION: The purpose of the present study is to determine whether rheumatoid arthritis (RA) and other clinical factors are associated with an increased risk of bisphosphonate (BP)-related atypical femur fracture (AFF). METHODS: A retrospective nested case-control study of patients who had taken BPs for at least 1 year was conducted. Patients with AFF were identified by reviewing surgical and radiographic records. Three controls with no history of AFFs were randomly selected and age- and sex-matched to each patient with AFFs. Cox proportional hazard models were used to analyze the independent contribution of risk factors to BP-related AFF. RESULTS: Among the 35,104 patients prescribed BPs for at least 1 year, 43 females (mean age, 68 years) suffered AFFs (0.12%). Patients with AFFs were exposed to BPs for a mean of 7.3 years. Patients with AFFs were exposed to BPs for longer than those without AFFs and continued treatment without a drug holiday. More patients with AFF than controls had taken glucocorticoids and disease-modifying anti-rheumatic drugs. Multivariate Cox regression analyses estimated that long-term use of glucocorticoids, prolonged exposure to BP without cessation, and every 1 kg/m(2) increase in the body mass index (BMI) increased the hazard ratio for AFFs by 3.0, 5.2, and 1.2, respectively. CONCLUSIONS: Prolonged and continuous use of BPs, long-term use of glucocorticoids, and a higher BMI increase the risk of AFFs. Switching long-term BP and glucocorticoid users to other bone-protective agents should be considered.
29127458 Safety, pharmacokinetics and pharmacodynamics of single rising doses of BI 655064, an anta 2018 Feb PURPOSE: The CD40-CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and lupus nephritis. The safety, pharmacokinetics and pharmacodynamics of BI 655064, a novel humanised antagonistic anti-CD40 monoclonal antibody, were investigated in this first-in-human trial. METHODS: Healthy male subjects (n = 72) were randomised 3:1, within each BI 655064 dose group, to single intravenous (IV; 0.2-120 mg) or subcutaneous (SC; 40-120 mg) doses of BI 655064 or placebo. Safety, plasma exposure, CD40 receptor occupancy and CD40L-induced CD54 upregulation were assessed over 12 weeks. RESULTS: Adverse events (AEs) were reported in 43% of subjects (n = 31). Frequency and intensity of AEs were generally similar between BI 655064 and placebo and showed no dose relationship. The most frequent AEs were headache and nasopharyngitis. One mild rash and one local reaction occurred with SC BI 655064; two serious AEs were reported, both judged unrelated to BI 655064. Pharmacokinetic evaluation demonstrated a more than proportional increase in plasma exposure relative to BI 655064 dose, with a terminal half-life between 4 h and 4 days IV and approximately 5 days SC; doses ≥ 20 mg IV and 120 mg SC showed > 90% CD40 receptor occupancy and inhibition of CD54 upregulation, which lasted 7 days in the 120 mg IV and SC groups. CONCLUSIONS: Single doses up to 120 mg BI 655064 IV and SC were well tolerated and showed a high potential to block the CD40-CD40L pathway, supporting further clinical development of BI 655064 in patients with autoimmune disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01510782.
29037480 Linking energy sensing to suppression of JAK-STAT signalling: A potential route for repurp 2018 Feb Exaggerated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling is key to the pathogenesis of pro-inflammatory disorders, such as rheumatoid arthritis and cardiovascular diseases. Mutational activation of JAKs is also responsible for several haematological malignancies, including myeloproliferative neoplasms and acute lymphoblastic leukaemia. Accumulating evidence links adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), an energy sensor and regulator of organismal and cellular metabolism, with the suppression of immune and inflammatory processes. Recent studies have shown that activation of AMPK can limit JAK-STAT-dependent signalling pathways via several mechanisms. These novel findings support AMPK activation as a strategy for management of an array of disorders characterised by hyper-activation of the JAK-STAT pathway. This review discusses the pivotal role of JAK-STAT signalling in a range of disorders and how both established clinically used and novel AMPK activators might be used to treat these conditions.
28986674 Surgical overreduction and hyperlordotic fusion of C1-C2 joint are associated with cervica 2017 Dec INTRODUCTION: Previous studies have shown that hyperlordotic C1-C2 fusion was related to postoperative subaxial kyphosis. However, most of the patients in these studies were complicated with rheumatoid arthritis (RA). Moreover, no studies have specifically evaluated the relationship between C1-C2 fusion angle and cervical sagittal vertical axis (cSVA), T1 slope or cranial tilt (CRT) after posterior C1-C2 fusion. This study aimed to investigate the cervical sagittal alignment in non-RA patients following posterior C1-C2 fusion and the correlation between C1-C2 fusion angle and postoperative cervical sagittal alignment. MATERIALS AND METHODS: From August 2004 to December 2015, twenty-eight consecutive patients with an average age of 39.2 years (range 6-70 years) who underwent posterior C1-C2 fusion from a single institution were enrolled. The mean follow-up period was 30.7 months (range 12-77 months). Angles of Oc-C1, C1-C2, C2-C3 and C2-C7, cSVA, T1 slope and CRT were measured in lateral cervical radiographs in neutral position before surgery and at the final follow-up. RESULTS: C1-C2 angle significantly increased from 13.6° ± 12.4° to 22.0° ± 8.1° at the final follow-up (P < 0.001). A significant decrease was found both in Oc-C1 and C2-C7 angles from pre-operation to the final follow-up (P < 0.001 and P = 0.011, respectively). Moreover, cSVA and CRT dramatically increased from pre-operation to the final follow-up (P < 0.001). C1-C2 fusion angle was significantly associated with Oc-C1, C2-C7 angle, cSVA and CRT at the final follow-up. A significant correlation was also observed between postoperative change of C1-C2 angle and that of Oc-C1, C2-C7 angle, cSVA and CRT. CONCLUSIONS: Apart from decreased subaxial lordosis, posterior C1-C2 fusion in hyperextension may also lead to kyphotic change of atlanto-occipital alignment and increased tilting forward of the cervical spine. Therefore, intraoperative overreduction of C1-C2 angle and hyperlordotic C1-C2 fusion should be avoided to maintain the physiologic cervical sagittal alignment.
28613962 Significant association between renal function and area of amyloid deposition in kidney bi 2017 Jun The kidney is a major target organ for systemic amyloidosis, which results in proteinuria and an elevated serum creatinine level. The clinical manifestations and precursor proteins of amyloid A (AA) and light-chain (AL) amyloidosis are different, and the renal damage due to amyloid deposition also seems to differ. The purpose of this study was to clarify haw the difference in clinical features between AA and AL amyloidosis are explained by the difference in the amount and distribution of amyloid deposition in the renal tissues. A total of 119 patients participated: 58 patients with an established diagnosis of AA amyloidosis (AA group) and 61 with AL amyloidosis (AL group). We retrospectively investigated the correlation between clinical data, pathological manifestations, and the area occupied by amyloid in renal biopsy specimens. In most of the renal specimens the percentage area occupied by amyloid was less than 10%. For statistical analyses, the percentage area of amyloid deposition was transformed to a common logarithmic value (Log(10)%amyloid). The results of sex-, age-, and Log(10)%amyloid-adjusted analyses showed that systolic blood pressure (SBP) was higher in the AA group. In terms of renal function parameters, serum creatinine, creatinine clearance (Ccr) and estimated glomerular filtration rate (eGFR) indicated significant renal impairment in the AA group, whereas urinary protein indicated significant renal impairment in the AL group. Pathological examinations revealed amyloid was predominantly deposited at glomerular basement membrane (GBM) and easily transferred to the mesangial area in the AA group, and it was predominantly deposited at in the AL group. The degree of amyloid deposition in the glomerular capillary was significantly more severe in AL group. The frequency of amyloid deposits in extraglomerular mesangium was not significantly different between the two groups, but in AA group, the degree amyloid deposition was significantly more severe, and the deposition pattern in the glomerulus was nodular. Nodular deposition in extraglomerular mesangium leads to renal impairment in AA group. There are significant differences between AA and AL amyloidosis with regard to the renal function, especially in terms of Ccr, eGFR and urinary protein, even after Log10%amyloid was adjusted; showing that these inter-group differences in renal function would not be depend on the amount of renal amyloid deposits. These differences could be explained by the difference in distribution and morphological pattern of amyloid deposition in the renal tissue.
28158305 Higher efficacy of anti-IL-6/IL-21 combination therapy compared to monotherapy in the indu 2017 Th17 cells and their cytokines are linked to the pathogenesis of rheumatoid arthritis, a chronic autoimmune disease characterized by joint inflammation. Th17 development is initiated by combined signaling of TGF-β and IL-6 or IL-21, and can be reduced in the absence of either IL-6 or IL-21. The aim of this study was to assess whether combinatorial IL-6/IL-21 blockade would more potently inhibit Th17 development, and be more efficacious in treating arthritis than targeting either cytokine. We assessed in vitro Th17 differentiation efficacy in the absence of IL-6 and/or IL-21. To investigate in vivo effects of IL-6/IL-21 blockade on Th17 and arthritis development, antigen-induced arthritis (AIA) was induced in IL-6-/- x IL-21R-/- mice. The therapeutic potential of this combined blocking strategy was assessed by treating mice with collagen-induced arthritis (CIA) with anti-IL-6R antibodies and soluble (s)IL-21R.Fc. We demonstrated that combined IL-6/IL-21 blocking synergistically reduced in vitro Th17 differentiation. In mice with AIA, absence of IL-6 and IL-21 signaling more strongly reduced Th17 levels and resulted in stronger suppression of arthritis than the absence of either cytokine. Additionally, anti-IL-6/anti-IL-21 treatment of CIA mice during the arthritis induction phase reduced disease development more potent than IL-6 or IL-21 inhibition alone, as effective as anti-TNF treatment. Collectively, these results suggest dual IL-6/IL-21 inhibition may be a more efficacious therapeutic strategy compared to single cytokine blockade to suppress arthritis development.
28490909 Determining early referral criteria for patients with suspected inflammatory arthritis pre 2017 OBJECTIVE: Early diagnosis and initiation of treatment for inflammatory arthritis can greatly improve patient outcome. We aimed to provide standardized and validated criteria for use by primary care physicians (PCPs) in the identification of individuals requiring referral to a rheumatologist. PATIENTS AND METHODS: We analyzed the predictive value of a wide variety of demographic variables, patient-reported complaints, physical examination results, and biomarkers in order to identify the most useful factors for indicating a requirement for referral. Patients for this cross-sectional study were enrolled from various centers of the city of Jeddah, Saudi Arabia, if they were ≥18 years of age and presented to a PCP with small joint pain that had been present for more than 6 weeks. A total of 203 patients were enrolled, as indicated by the sample size calculation. Each patient underwent a standardized physical examination, which was subsequently compared to ultrasound findings. Biomarker analysis and a patient interview were also carried out. Results were then correlated with the final diagnosis made by a rheumatologist. RESULTS: A total of 9 variables were identified as having high specificity and good predictive value: loss of appetite, swelling of metacarpophalangeal joint 2 or 5, swelling of proximal inter-phalangeal joint 2 or 3, wrist swelling, wrist tenderness, a positive test for rheumatoid factor, and a positive test for anti-citrullinated protein antibodies. CONCLUSION: Nine variables should be the basis of early referral criteria. It should aid PCPs in making appropriate early referrals of patients with suspected inflammatory arthritis, accelerating diagnosis and initiation of treatment.
27749230 Characterisation of peripheral blood mononuclear cell microRNA in early onset psoriatic ar 2017 Jan OBJECTIVES: To evaluate the micro-RNA (miRNA) expression profile in patients with early psoriatic arthritis (PsA) in order to assess the role of miRNAs as potential PsA biomarkers. METHODS: The expression of 723 mature miRNAs in peripheral blood mononuclear cells of early PsA patients in comparison with early-rheumatoid arthritis (ERA) patients and healthy controls (HC) was evaluated using a miRNA microarray. All patients had active disease and were naïve from treatment. The results were validated for a specific miRNA (miR-21-5p) in the entire series of patients plus an additional group of early PsA, ERA and HC using droplet digital PCR. RESULTS: In PsA, microarray analysis revealed a distinct pattern of 19 (vs. HC) and 48 (vs. ERA) deregulated miRNAs (p<0.05). The significant up-regulation of miR-21-5p both in early PsA and in ERA in comparison with HC was validated and confirmed. In PsA, miR-21-5p was found significantly down regulated after 12 weeks of therapy, which significantly correlated with the reduction of DAPSA score. CONCLUSIONS: In early PsA, a 19- (vs. HC) and 48- (vs. ERA) miRNA signature was identified. A differential expression of miRNAs in patients with active disease makes them attractive biomarkers of psoriatic disease. MiR-21-5p was found up-regulated both in early PsA and ERA, a finding which highlights its role in the inflammatory process in general and its potential role as a therapeutic target in different inflammatory disorders. A potential role of miR-21-5p as a response to treatment biomarker in early PsA has been identified.
28735448 Inhibitory effects of andrographolide on activated macrophages and adjuvant-induced arthri 2018 Apr Andrographolide, a diterpenoid lactone obtained from plant Andrographis paniculata, is used in South Asian countries to relieve various inflammatory symptoms. To study the effects of this agent, the impact of andrographolide on production of inflammatory mediators were delineated in mouse peritoneal macrophages (PMϕ). Inflammatory mediators like nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin-6 and related molecular mechanisms of andrographolide-mediated inhibition of enzymes/transcription factors were studied. In addition, the in vivo anti-inflammatory activity of andrographolide was evaluated in an adjuvant-induced arthritis rat model. The results indicated that andrographolide clearly inhibited the production of NO and TNF-α in lipopolysaccharide-activated PMϕ in a dose-related manner. Immunoblot analyses revealed that andrographolide suppressed activation of both inducible NO synthase and cyclo-oxygenase-2 by directly targeting nuclear transcription factor (NF)-κB. Complete Freund's Adjuvant-induced paw edema in rats was also significantly inhibited by andrographolide treatment. From the data, we concluded that andrographolide imparted anti-inflammatory effects by suppressing two key inflammatory enzymes and a signaling pathway that mediates expression of variety of inflammatory cytokines/agents in situ. It is plausible that eventually, after further toxicologic characterization, andrographolide might be useful as a drug for the clinical treatment of various inflammatory diseases like rheumatoid arthritis or diseases associated with joint pain.
28837059 Novel Drug Delivery Systems Tailored for Improved Administration of Glucocorticoids. 2017 Aug 24 Glucocorticoids (GC) are one of the most popular and versatile classes of drugs available to treat chronic inflammation and cancer, but side effects and resistance constrain their use. To overcome these hurdles, which are often related to the uniform tissue distribution of free GC and their short half-life in biological fluids, new delivery vehicles have been developed including PEGylated liposomes, polymeric micelles, polymer-drug conjugates, inorganic scaffolds, and hybrid nanoparticles. While each of these nanoformulations has individual drawbacks, they are often superior to free GC in many aspects including therapeutic efficacy when tested in cell culture or animal models. Successful application of nanomedicines has been demonstrated in various models of neuroinflammatory diseases, cancer, rheumatoid arthritis, and several other disorders. Moreover, investigations using human cells and first clinical trials raise the hope that the new delivery vehicles may have the potential to make GC therapies more tolerable, specific and efficient in the future.
28979694 Polyene Phosphatidylcholine inhibited the inflammatory response in LPS-stimulated macropha 2017 This study sought to investigate the anti-inflammatory effect of Polyene Phosphatidylcholine (PPC), a clinical drug that is used to treat hepatopathy, on lipopolysaccharide (LPS)-stimulated macrophages and on bovine collagen II-induced arthritis (CIA) rats. In stimulated primary and Raw264.7 macrophages by LPS, PPC significantly down-regulated the relative expression of mRNA such as IL-6, TNF-α, TLR-2, TLR-4, MyD88, and NF-κB while up-regulated IL-10 and TGF-β expression. Moreover, the concentration of IL-6, TNF-α, IL-10, and TGF-β in the cultured supernatants showed the similar tendency with their mRNA alterations. In addition, PPC could significantly inhibit the LPS-induced expression of MyD88 and NF-κB p65 in both mRNA and protein levels. These results suggest that PPC could down-regulate the LPS-stimulated inflammation in macrophages through TLR-2/TLR-4/MyD88/NF-κB pathway in vitro. Furthermore, to explore its effects in vivo, PPC was administrated to CIA rats. In comparison to CIA group, PPC-treated rats showed decreased arthritis score and osteopenia. Besides, PPC exhibited its ability to alleviate the degree of synovial hyperplasia, inflammatory cell infiltration, and destruction of cartilage and bone, thus remarkably improving the condition of CIA rats. In short, this study demonstrated that PPC had the potential to be an anti-inflammatory drug to treat inflammatory disorders such as rheumatoid arthritis.
28461649 Canadian Rheumatology Association Meeting, The Westin Ottawa, Ottawa, Ontario, Canada, Feb 2017 May 1 The 72nd Annual Meeting of The Canadian Rheumatology Association (CRA) was held at The Westin Ottawa, Ottawa, Ontario, Canada, February 8-11, 2017. The program consisted of presentations covering original research, symposia, awards, and lectures. Highlights of the meeting include the following 2017 award winners: Dr. Vinod Chandran, Young Investigator; Dr. Jacques P. Brown, Distinguished Investigator; Dr. David Robinson, Teacher-Educator; Dr. Michel Zummer, Distinguished Rheumatologist; Ms. Rebecca Gole, Best Abstract on SLE Research by a Trainee - Ian Watson Award; Ms. Bailey Russell, Best Abstract on Clinical or Epidemiology Research by a Trainee - Phil Rosen Award; Dr. Sahil Koppikar and Dr. Henry Averns, Practice Reflection Award; Dr. Shirine Usmani, Best Abstract on Basic Science Research by a Trainee; Ms. Carol Dou, Best Abstract for Research by an Undergraduate Student; Dr. Dania Basodan, Best Abstract on Research by a Rheumatology Resident; Dr. Claire Barber, Best Abstract on Adult Research by Young Faculty; Ms. Audrea Chen, Best Abstract by a Medical Student; Dr. Kun Huang, Best Abstract by a Post-Graduate Resident; and Dr. Ryan Lewinson, Best Abstract by a Post-Graduate Research Trainee. Lectures and other events included a Keynote Lecture by Jonathon Fowles: Exercise is Medicine: Is Exercise a Good or Bad Thing for People with Arthritis?; State of the Art Lecture by Matthew Warman: Insights into Bone Biology and Therapeutics Gleaned from the Sustained Investigation of Rare Diseases; Dunlop-Dottridge Lecture by Allen Steere: Lyme Disease: A New Problem for Rheumatologists in Canada; and the Great Debate: Be it Resolved that the Least Expensive Treatment Should be Chosen. Switch, Switch, Switch! Arguing for: Jonathan Chan and Antonio Avina, and against: Marinka Twilt and Glen Hazlewood. Topics such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjögren syndrome, psoriatic arthritis, spondyloarthritis, vasculitis, osteoarthritis, fibromyalgia, pediatric rheumatology, and their respective diagnoses, treatments, and outcomes are reflected in the abstracts, which we are pleased to publish in this issue of The Journal.
29068581 Serum ICAM-1, VCAM-1 and E-selectin levels in patients with primary and secondary Sjögren 2017 Aug BACKGROUND: Typical features of Sjögren's syndrome (SS) are severe xerostomia and xerophthalmia which are basic diagnostic criteria. OBJECTIVES: The aim of this study was to compare the serum levels of soluble (s) intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1) and sE-selectin between primary (pSS), secondary (sSS) and healthy subjects (HS). We correlated these results with selected clinical parameters of disease activity and parameters of the severity of xerostomia and xerophthalmia. MATERIAL AND METHODS: The serum levels of sICAM-1, sVCAM-1 and sE-selectin were determined by enzyme-linked immunosorbent assay (ELISA) in 16 patients with pSS, 18 with sSS and 15 HS. Eye dryness and xerostomia were assessed by the Schirmer's test, the Fox test and the visual analogue scale (VAS). RESULTS: The levels of sICAM-1 in pSS and sVCAM-1 in sSS patients were significantly higher when compared to HS (p = 0.02 and p = 0.048, respectively). There were no differences between pSS and sSS. In pSS, sVCAM-1 correlated positively with VAS (rS = 0.52, p = 0.04) and the Fox test (rS = 0.66, p=0.01). In sSS, sE-selectin correlated positively with sICAM-1 (rS = 0.54, p = 0.01), the duration of the disease (rS = 0.51, p = 0.03) and negatively with the Schirmer's test (rS = 0.59, p = 0.04). sICAM-1 correlated positively with the erythrocyte sedimentation rate (ESR) value (rS = 0.59, p = 0.01). CONCLUSIONS: sVCAM-1 reflects xerostomia in pSS. sICAM-1 and sE-selectin may be additional parameters of sSS activity.