Browse

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

ID PMID Title PublicationDate abstract
27537204 Inflammation as a Risk of Developing Chronic Kidney Disease in Rheumatoid Arthritis. 2016 OBJECTIVE: The relationship between chronic inflammation and the incidence of chronic kidney disease (CKD) remained not-clear in patients with rheumatoid arthritis (RA). This study aims to examine the relationship between persistently high C-reactive protein (CRP), a marker of inflammation, and the incidence of CKD in RA. METHODS: We retrospectively examined the relationship between the levels of CRP and incidence of CKD in 345 RA patients. The outcome of interest was incidence of CKD, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and/or positive dipstick testing for proteinuria for ≥3 months. We defined high CRP, as >3.0 mg/L. On the basis of three measurements of CRP for 6-months period, patients were divided into three groups: group 1, including patients with no high CRP values; group 2, patients with transient high CRP values (once or twice) and group 3, patients with persistently high CRP values. RESULTS: During a median follow-up period of 89 months, 14% of all patients developed CKD. The cumulative incidence of CKD was 7% in group 1, 14% in group 2 and 22% in group 3 (P = 0.008, log-rank test). In a multivariate analysis, including classical risk factors for CKD, persistently high CRP was an independent predictor of the incidence of CKD (hazard ratio, 3.00; 95% confidence interval, 1.23-8.53; P = 0.01). CONCLUSIONS: Persistently high CRP was a significant risk factor for the incidence of CKD. Results suggest that persistent inflammation is a marker for the high risk of CKD in RA.
26935126 Low levels of inflammation and the absence of subclinical atherosclerosis in rheumatoid ar 2016 Apr Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease. Patients with RA have an increased risk for the development of cardiovascular diseases, however, the pathophysiological mechanisms of arterial complications in RA remain to be fully elucidated. Understanding the early markers of vascular damage may aid in preventing cardiovascular complications in patients with RA. The current study investigated this by recruiting 30 patients with RA and 30 healthy subjects. Intima‑media thickness (IMT) was used to detect the presence of atherosclerotic disease and was measured in the carotid and femoral arteries. Tumor necrosis factor α, interleukin‑6 (IL‑6), IL‑8, IL‑10 and matrix metalloproteinase‑2 were measured as markers of inflammation. An IMT ≥0.9 mm was observed in 7/30 patients with RA, however, no significant differences between patients with RA and the controls were observed in the inflammatory markers analyzed. Of note, these results indicated that the appropriate management of RA may have affected the inflammatory status of these patients and consequently may have impacted upon subclinical atherosclerosis.
26866424 Subclinical Atherosclerosis in Systemic Sclerosis: Not Less Frequent Than Rheumatoid Arthr 2016 Oct OBJECTIVE: To determine the frequency of subclinical atherosclerosis in patients with systemic sclerosis (SSc; scleroderma) compared to healthy subjects (HS) and rheumatoid arthritis (RA) patients and to determine the ability of cardiovascular (CV) risk indices in detecting SSc patients with subclinical atherosclerosis. METHODS: A total of 110 SSc patients (102 females and 8 males, mean ± SD age 50.5 ± 11.9 years), 110 age- and sex-matched RA patients, and 51 HS without CV disease were examined with ultrasonography (US). Carotid intima-media thickness (cIMT) >0.90 mm and/or carotid plaques were used as the gold standard for subclinical atherosclerosis (US+). Systematic Coronary Risk Evaluation (SCORE), QRisk II, and 2013 American College of Cardiology (ACC)/American Heart Association (AHA) CV risk indices were calculated. RESULTS: Twenty-one (19.1%) SSc patients, 24 (21.8%) RA patients, and 3 (5.9%) HS had subclinical atherosclerosis (SSc versus RA: P = 0.62, SSc versus HS: P = 0.029). cIMT in SSc was higher compared to HS (0.68 ± 0.15 mm versus 0.61 ± 0.10 mm; P = 0.008) but similar to RA patients (0.66 ± 0.14 mm; P = 0.82). Subclinical atherosclerosis in SSc was associated with age (odds ratio [OR] 1.07, P = 0.013), elevated erythrocyte sedimentation rate (OR 3.4, P = 0.045), and pulmonary arterial hypertension (OR 4.27, P = 0.012). Concerning CV risk indices, of the 21 US+ SSc patients only 0, 3 (14.2%), and 6 (28.6%) were classified as high CV risk according to SCORE, QRisk II, and ACC/AHA risk indices, respectively. CONCLUSION: Subclinical atherosclerosis in SSc patients is more frequent than in HS, but is as frequent as in RA patients in which accelerated atherosclerosis is clearly defined. CV risk indices for the general population are considerably insufficient to detect SSc patients with atherosclerosis.
25760298 Finding a place for interleukin-1 inhibitors in the treatment of rheumatologic diseases. 2015 Interleukin-1 inhibitors were tested in large arthritis trials with less than impressive results, despite having convincing disease expression data and pre-clinical animal model supporting the potential pathogenic role of this cytokine in these settings. Despite disappointing beginnings, some IL-1 pathway blocking drugs are now beginning to find a place in the pharmacopoeia of rheumatologists. Drug developers utilised rapidly growing understanding of the molecular pathway and the genetic basis of key diseases to seek out conditions in which IL-1 pathway activation was much more likely to have a pivotal role in disease pathogenesis compared to the major arthritides. This review details the crucial advances in understanding of the IL-1 pathway activation which enabled this progress, particularly the advent of inflammasome biology. The drug development of IL-1 biologics in rheumatological diseases makes a fascinating case study illustrating major changes in drug development strategy encompassing closer synergies between translational biology, underlying molecular pathophysiology of disease, and novel clinical development pathways of biologic therapeutics.
25862815 DEC205+ Dendritic Cell-Targeted Tolerogenic Vaccination Promotes Immune Tolerance in Exper 2015 May 15 Previous studies in mouse models of autoimmune diabetes and encephalomyelitis have indicated that the selective delivery of self-antigen to the endocytic receptor DEC205 on steady-state dendritic cells (DCs) may represent a suitable approach to induce Ag-specific immune tolerance. In this study, we aimed to examine whether DEC205(+) DC targeting of a single immunodominant peptide derived from human cartilage proteoglycan (PG) can promote immune tolerance in PG-induced arthritis (PGIA). Besides disease induction by immunization with whole PG protein with a high degree of antigenic complexity, PGIA substantially differs from previously studied autoimmune models not only in the target tissue of autoimmune destruction but also in the nature of pathogenic immune effector cells. Our results show that DEC205(+) DC targeting of the PG peptide 70-84 is sufficient to efficiently protect against PGIA development. Complementary mechanistic studies support a model in which DEC205(+) DC targeting leads to insufficient germinal center B cell support by PG-specific follicular helper T cells. Consequently, impaired germinal center formation results in lower Ab titers, severely compromising the development of PGIA. Overall, this study further corroborates the potential of prospective tolerogenic DEC205(+) DC vaccination to interfere with autoimmune diseases, such as rheumatoid arthritis.
25939534 Sinomenine potentiates degranulation of RBL-2H3 basophils via up-regulation of phospholipa 2015 Oct Sinomenine (SIN), an alkaloid derived from the Chinese medicinal plant Sinomenium acutum, is the major component of Zhengqing Fongtong Ning (ZQFTN), a pharmaceutical drug produced by Hunan Zhengqing Pharmaceutical Co. Ltd. in China for the treatment of rheumatoid arthritis and other autoimmune diseases. Some clinic reports indicate that ZQFTN may induce an anaphylactic reaction via potentiating the degranulation of immune cells. In the current study, we aimed to examine whether SIN is capable of inducing the degranulation of basophilic leukemia 2H3 (RBL-2H3) cells to elucidate how the anaphylactic reaction occurs. The results revealed that SIN could up-regulate β-hexosaminidase levels in RBL-2H3 cells without significant cytotoxicity, suggesting that SIN could induce the degranulation of RBL-2H3 cells. Furthermore, SIN increased the release of prostaglandin D2 (PGD2) and prostaglandin E2 (PGE2) in RBL-2H3 cells via promoting the expression of phosphorylated-extracellular signal-regulated kinase (P-ERK), the cleavage of Annexin A1 (ANXA1), and phosphorylated-cytosolic phospholipase A2 (P-cPLA2), as well as cyclooxygenase-2 (COX-2). The ERK inhibitor, PD98059, significantly attenuated the up-regulatory effect of SIN on cPLA2 phosphorylation. Interestingly, SIN did not significantly increase Ca(2+) influx in the cells. These findings not only explored the anaphylactic reaction and underlying mechanism of ZQFTN in RBL-2H3 cells, but may promote the development of relevant strategies for overcoming the adverse effects of the drug.
27864476 Anti-Hinge Antibodies Recognize IgG Subclass- and Protease-Restricted Neoepitopes. 2017 Jan 1 Anti-hinge Abs (AHAs) target neoepitopes exposed after proteolytic cleavage of IgG. In this study, we explored the diversity of protease- and IgG subclass-restricted AHAs and their potential as immunological markers in healthy donors (HDs) and patients with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). AHA reactivity against IgG-degrading enzyme of Streptococcus pyogenes (IdeS)- or pepsin-generated F(ab')(2) fragments of all four human IgG subclasses was determined. AHA reactivity against one or more out of eight F(ab')(2) targets was found in 68% (68 of 100) of HDs, 69% (68 of 99) of SLE patients, and 81% (79 of 97) of RA patients. Specific recognition of hinge epitopes was dependent on IgG subclass and protease used to create the F(ab')(2) targets, as confirmed by inhibition experiments with F(ab')(2) fragments and hinge peptides. Reactivity against IdeS-generated F(ab')(2) targets was found most frequently, whereas reactivity against pepsin-generated F(ab')(2) targets better discriminated between RA and HDs or SLE, with significantly higher AHA levels against IgG1/3/4. In contrast, AHA levels against pepsin-cleaved IgG2 were comparable. No reactivity against IdeS-generated IgG2-F(ab')(2)s was detected. The most discriminatory AHA reactivity in RA was against pepsin-cleaved IgG4, with a 35% prevalence, ≥5.8-fold higher than in HDs/SLE, and significantly higher levels (p < 0.0001). Cross-reactivity for F(ab')(2)s generated from different IgG subclasses was only observed for subclasses having homologous F(ab')(2) C termini (IgG1/3/4). For IgG2, two pepsin cleavage sites were identified; anti-hinge reactivity was restricted to only one of these. In conclusion, AHAs specifically recognize IgG subclass- and protease-restricted hinge neoepitopes. Their protease-restricted specificity suggests that different AHA responses developed under distinct inflammatory or infectious conditions and may be markers of, and participants in, such processes.
28502139 Serum Interleukin-33 in Behcet's Disease: Its Relation to Disease Activity and Clinical Ma 2015 Jun Behcet's disease (BD) is a chronic systemic inflammatory disorder characterized by a ‎‎course of remissions and exacerbations of unpredictable frequency and duration‎. Pro-‎inflammatory cytokines seem to be responsible for the enhanced inflammatory ‎‎response in BD. AIM OF THE WORK: This study aimed to investigate serum levels of IL-33 in patients with Behcet's disease (BD) and their relationship to disease activity and clinical manifestations. Thirty patients with BD were enrolled and subjected to assessment of disease activity according to Behcet's Disease Current Activity Form (BDCAF) score. Serum IL-33 levels were determined using Enzyme-Linked-Immunosorbent Assay (ELISA). Thirty age and sex matched rheumatoid arthritis patients and thirty healthy volunteers were included in this study as control groups. Serum IL-33 level was 132.5±19 pgml, 101.2±20.1 pgml and 31.5±10.5 pgml in RA, BD and healthy control groups respectively. IL-33 was significantly higher in BD patients (101.2±20.1pg/ml) as compared to healthy controls (31.5±10.5 pg/ml) but lower than rheumatoid arthritis patients (132.5±19.1 pg/ml). Levels of IL-33 were significantly increased in BD patients with skin lesions (Erythema nodosum & Acneiform lesions) and ocular lesions (retinal vasculitis) (P<0.05), and a positive correlation was found between BDCAF score and IL-33serum levels (r=0.9, P<0.001). In conclusions, serum IL-33 level is elevated in active BD patients with skin and ocular affection and correlates with disease activity.
25640101 Comparison of total hip and knee joint replacement in patients with rheumatoid arthritis a 2015 Jan INTRODUCTION: Patients with rheumatoid arthritis (RA) and osteoarthritis (OA) may require total hip replacement (THR) or total knee replacement (TKR). The present study aimed to compare the demographic characteristics and medical costs of RA and OA patients from Taiwan who underwent either THR or TKR. METHODS: The medical records of patients who had undergone THR or TKR from 1 January 1996 to 31 December 2010 were obtained from the Taiwan National Health Insurance Research Database (NHIRD). In all, we found 49 and 146 RA patients who received THR and TKR, respectively, and 1,191 and 6,574 OA patients who received THR and TKR, respectively. The gender, age, Charlson comorbidity index (CCI), hospital grade, age at registration in the catastrophic illness dataset, and medical utilisation costs of the different groups were compared. RESULTS: There were statistically significant differences in age, CCI score, drug costs and surgery costs between RA and OA patients. Joint replacement incidence was lower in RA patients than in OA patients, and among patients who underwent THR, total medical costs incurred were higher for RA patients than OA patients. RA patients who underwent THR incurred a significantly greater total medical utilisation cost in the outpatient department (3 months before surgery and 12 months after surgery) than OA patients who underwent THR. CONCLUSION: Analysis of Taiwan NHIRD with regard to patients who had undergone either THR or TKR indicated that RA patients were younger than OA patients, and that significantly more medical resources were used for RA patients before, during and after hospitalisation for these procedures.
27193031 A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheu 2017 Jan OBJECTIVES: During the last years, genome-wide association studies (GWASs) have identified a number of common genetic risk factors for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the genetic overlap between these two immune-mediated diseases has not been thoroughly examined so far. The aim of the present study was to identify additional risk loci shared between RA and SLE. METHODS: We performed a large-scale meta-analysis of GWAS data from RA (3911 cases and 4083 controls) and SLE (2237 cases and 6315 controls). The top-associated polymorphisms in the discovery phase were selected for replication in additional datasets comprising 13 641 RA cases and 31 921 controls and 1957 patients with SLE and 4588 controls. RESULTS: The rs9603612 genetic variant, located nearby the COG6 gene, an established susceptibility locus for RA, reached genome-wide significance in the combined analysis including both discovery and replication sets (p value=2.95E-13). In silico expression quantitative trait locus analysis revealed that the associated polymorphism acts as a regulatory variant influencing COG6 expression. Moreover, protein-protein interaction and gene ontology enrichment analyses suggested the existence of overlap with specific biological processes, specially the type I interferon signalling pathway. Finally, genetic correlation and polygenic risk score analyses showed cross-phenotype associations between RA and SLE. CONCLUSIONS: In conclusion, we have identified a new risk locus shared between RA and SLE through a meta-analysis including GWAS datasets of both diseases. This study represents the first comprehensive large-scale analysis on the genetic overlap between these two complex disorders.
26808746 Spontaneous Extensor Tendon Rupture in the Rheumatoid Wrist: Risk Factors and Preventive R 2016 Mar OBJECTIVE: Spontaneous extensor tendon rupture is often seen in rheumatoid arthritis (RA) patients, but the risk factors are not clearly defined. We therefore collected the data of RA patients with previous extensor tendon rupture and those with tenosynovitis and analyzed the relationship between extended tenosynovectomy and spontaneous extensor tendon rupture. METHODS: We retrospectively reviewed 17 spontaneous extensor tendon rupture episodes in 15 RA patients and 14 tenosynovitis episodes that required tenosynovectomy in 12 RA patients from 1997 to 2013. Correlations between the incidence of tendon rupture, X-ray findings, and clinical findings in the affected wrists before tendon rupture were analyzed statistically using the test for proportion. RESULTS: The following parameters were significantly correlated with spontaneous extensor tendon rupture: disease duration longer than 8 years, persistent tenosynovitis longer than 1 year duration, and Larsen grade greater than 4 (P = 0.02, 0.03, and 0.01, respectively). Dislocation of the distal end of the ulna, carpal collapse, and the scallop sign on X-ray contributed to a higher spontaneous extensor tendon rupture rate among RA patients (P = 0.01, 0.05, and 0.03, respectively). Extended tenosynovectomy was performed on 14 wrists in 12 RA patients with persistent tenosynovitis longer than 6 months, and Larsen grade did not deteriorate in this group compared with those who did not undergo the surgery. No spontaneous extensor tendon rupture occurred following the surgery. CONCLUSIONS: Risk factors of spontaneous extensor tendon rupture included disease duration longer than 8 years, persistent tenosynovitis longer than 1 year, and wrist Larsen grade greater than 4. Dislocation of the distal end of the ulna, carpal collapse, and the scallop sign on X-ray indicated a higher probability of extensor tendon rupture. Rheumatologists should consult with hand surgeons promptly to preserve hand function before tendon rupture. Prophylactic extended tenosynovectomy surgery to prevent more severe damage of extensor tendon should be recommended in patients who had the above risk factors.
26952286 Outcomes, complications, utilization trends, and risk factors for primary and revision tot 2016 Jun BACKGROUND: Using a validated database, 30-day complications of primary and revision total elbow arthroplasty (TEA) were analyzed to identify risk factors of adverse events. METHODS: Primary and revision TEAs from 2007 to 2013 were identified in the National Surgical Quality Improvement Program database. Bivariate and multivariate analyses of risk factors for 30-day adverse events were assessed using preoperative and intraoperative variables. RESULTS: The study reviewed 189 primary and 53 revision TEA patients. Fracture (34%), osteoarthritis (24%), and rheumatoid arthritis (23%) were the most common indications for TEA. Adverse event rate was similar in primary and revision TEA (12% vs. 15%; P = .49), and infectious complications occurred in 3.2% of primary TEAs and 7.5% of revision TEAs (P = .23). Bivariate analysis of risk factors for 30-day adverse events identified dependent functional status in primary TEA (P = .03) and age in revision TEA (P = .02). Multivariate analysis of primary TEA revealed that adverse events were significantly less likely with rheumatoid arthritis compared with osteoarthritis etiology (odds ratio, 0.15; P = .02), and smoking was associated with an increased chance of infection (odds ratio, 6.96; P = .03). Revision TEA was not associated with an increased 30-day adverse event or infection rate compared with primary TEA in multivariate analysis. Among primary and revision TEA patients, dependent functional status (P = .02) and hypertension (P = .04) were independent predictors for adverse events. CONCLUSION: Modifiable risk factors should be addressed before TEA to limit postoperative complications as well as cost. The risk of short-term complications after revision TEA is comparable to that of primary TEA.
26147289 Genetic Case-Control Study for Eight Polymorphisms Associated with Rheumatoid Arthritis. 2015 Rheumatoid arthritis (RA) is an autoimmune disease which has a significant socio-economic impact. The aim of the current study was to investigate eight candidate RA susceptibility loci to identify the associated variants in Egyptian population. Eight single nucleotide polymorphisms (SNPs) (MTHFR-C677T and A1298C, TGFβ1 T869C, TNFB A252G, and VDR-ApaI, BsmI, FokI, and TaqI) were tested by genotyping patients with RA (n = 105) and unrelated controls (n = 80). Associations were tested using multiplicative, dominant, recessive, and co-dominant models. Also, the linkage disequilibrium (LD) between the VDR SNPs was measured to detect any indirect association. By comparing RA patients with controls (TNFB, BsmI, and TaqI), SNPs were associated with RA using all models. MTHFR C677T was associated with RA using all models except the recessive model. TGFβ1 and MTHFR A1298C were associated with RA using the dominant and the co-dominant models. The recessive model represented the association for ApaI variant. There were no significant differences for FokI and the presence of RA disease by the used models examination. For LD results, There was a high D' value between BsmI and FokI (D' = 0.91), but the r(2) value between them was poor. All the studied SNPs may contribute to the susceptibility of RA disease in Egyptian population except for FokI SNP.
26755381 Factors affecting extension lag after tendon reconstruction for finger extensor tendon rup 2016 Jan BACKGROUND: Although extensor tendon rupture associated with distal radioulnar joint disorder is often encountered, its treatment has not yet been established. We report the postoperative results for reconstruction of finger extensor tendon rupture due to distal radioulnar lesion and analyse the factors affecting postoperative extension lag. METHODS: We examined 74 index, middle, ring, or little fingers with extensor tendon rupture of 34 hands. Primary diseases were rheumatoid arthritis in 24 hands and osteoarthritis in 10. Reconstruction methods included tendon graft in 45 fingers, extensor indicis proprius tendon transfer in 15, and end-to-side adjacent tendon suture in 14. At final postoperative follow-up ranging from 12 to 40 (mean: 18) months, we measured metacarpophalangeal (MCP) joint range of motion and extension lag and statistically evaluated the relationship between postoperative extension lag and several clinical factors. RESULTS: We encountered no cases of re-rupture or worsening of finger flexion range after reconstruction. Mean postoperative active flexion of the MCP joint was 78.1 (range: 45-95) degrees. Mean postoperative extension lag was 10.3 (range: 0-50) degrees. We observed that postoperative extension lag was significantly larger in fingers associated with extensor tendon rupture in two or three additional fingers in the affected hand or in fingers of patients aged 80 years or over. The interval from rupture to reconstruction, reconstruction method, or arthritis type did not remarkably affect outcome. CONCLUSIONS: This study uncovered that surgical intervention for extensor tendon rupture should be performed before three fingers become affected.
25472447 A new family of choline kinase inhibitors with antiproliferative and antitumor activity de 2015 Jan BACKGROUND: Choline kinase alpha (ChoKα) is a critical enzyme in the synthesis of phosphatidylcholine, a major structural component of eukaryotic cell membranes. ChoKα is overexpressed in a large variety of tumor cells and has been proposed as a target for personalized medicine, both in cancer therapy and rheumatoid arthritis. MATERIALS AND METHODS: Triterpene quinone methides (TPQ) bioactive compounds isolated from plants of the Celastraceae family and a set of their semisynthetic derivatives were tested against the recombinant human ChoKα. Those found active as potent enzymatic inhibitors were tested in vitro for antiproliferative activity against HT29 colorectal adenocarcinoma cells, and one of the active compounds was tested for in vivo antitumoral activity in mice xenographs of HT29 cells. RESULTS: Among 59 natural and semisynthetic TPQs tested in an ex vivo system, 14 were highly active as inhibitors of the enzyme ChoKα with IC50 <10 μM. Nine of these were potent antiproliferative agents (IC50 <10 μM) against tumor cells. At least one compound was identified as a new antitumoral drug based on its in vivo activity against xenographs of human HT-29 colon adenocarcinoma cells. CONCLUSIONS: The identification of a new family of natural and semisynthetic compounds with potent inhibitory activity against ChoKα and both in vitro antiproliferative and in vivo antitumoral activity supports further research on these inhibitors as potential anticancer agents. Their likely role as antiproliferative drugs deserves further studies in models of rheumatoid arthritis.
27250804 Targeting CD1c-expressing classical dendritic cells to prevent thymus and activation-regul 2017 Jan OBJECTIVES: Thymus and activation-regulated chemokine (TARC) attracts cells that express the C-C chemokine receptor type 4 (CCR4), including CD4 T cells. As expression of CCR4 is increased on peripheral T cells and intra-articular interleukin (IL)-17-producing cells in patients with rheumatoid arthritis (RA), we investigated whether TARC plays a role in the attraction of T cells to the synovial compartment. In addition, we assessed the role of classical dendritic cells (cDCs) in the production of TARC in RA. METHOD: TARC was measured in synovial fluid (SF) samples from RA and osteoarthritis (OA) patients. Spontaneous and thymic stromal lymphopoietin (TSLP)-induced TARC production by mononuclear cells (MCs) and CD1c cDCs from peripheral blood (PB) and SF was assessed. The role of TARC in CD4 T-cell migration towards cDCs was assessed and the contribution of CD1c-expressing cells to TARC production was studied. RESULTS: TARC concentrations were higher in SF of RA patients compared to OA patients. MCs from SF produced TARC spontaneously and produced more TARC upon stimulation than paired PBMCs. Blocking TARC strongly inhibited CD4 T-cell chemotaxis by TSLP-stimulated cDCs, associated with decreased production of tumour necrosis factor (TNF)-α. Depletion of cDCs from SFMCs strongly reduced TARC production. CONCLUSIONS: TARC levels are increased in RA SF and our data indicate that this results from production by SFMCs and in particular CD1c cDCs. TARC attracts T cells and TARC secretion by MCs is crucially dependent on the presence of CD1c cDCs. Considering the potential of SF cDCs to activate T cells and induce pro-inflammatory cytokine secretion, targeting intra-articular cDCs constitutes a novel therapeutic approach in RA.
25950356 Localized chrysiasis, aluminum salt deposition and dystrophic calcification a decade after 2015 Aug Localized chrysiasis is rare and can occur in two settings: after localized or traumatic implantation of elemental gold or gold salts or after localized laser or light therapy in someone who has been previously exposed to systemic gold therapy. We report a unique case of localized chrysiasis with associated aluminum salt deposition and sclerosing lipogranulomas because of previous injections of aurothioglucose (Solganal®). The unique histopathologic findings seen in this case have not been previously reported.
26184541 Uveitis in adults: What do rheumatologists need to know? 2015 Oct Rheumatologists may need to establish the etiological diagnosis and handle the therapeutic management of adults with uveitis. To date, no diagnostic strategy for uveitis has been validated by prospective studies. Investigations are selected based on the clinical features and on the anatomic location of the ocular abnormalities. Infections such as syphilis, Lyme disease, tuberculosis, and Whipple's disease may cause uveitis, with concomitant joint inflammation in a few cases. In patients with a known history of chronic inflammatory joint disease, causes of uveitis include bisphosphonate therapy and immunodepression-related infections (e.g., due to Toxoplasma or a herpes virus). Sarcoidosis is an underestimated cause of uveitis, which occurs in 15% of cases, with a predilection for middle-aged women. In spondyloarthritis, uveitis is almost always acute, unilateral, and anterior. Among patients with uveitis and spondyloarthritis, about two thirds have their joint disease diagnosed during an evaluation for uveitis. Therefore, patients with inflammatory or noninflammatory back pain should be routinely evaluated for spondyloarthritis, which is the leading cause of uveitis in western countries. The risk of blindness is extremely low, and the main complication is recurrent uveitis, seen in 50% to 60% of cases. Sulfasalazine decreases the frequency, duration, and severity of uveitis and can be used prophylactically.
27013493 Dysregulated bioenergetics: a key regulator of joint inflammation. 2016 Dec OBJECTIVES: This study examines the relationship between synovial hypoxia and cellular bioenergetics with synovial inflammation. METHODS: Primary rheumatoid arthritis synovial fibroblasts (RASF) were cultured with hypoxia, dimethyloxalylglycine (DMOG) or metabolic intermediates. Mitochondrial respiration, mitochondrial DNA mutations, cell invasion, cytokines, glucose and lactate were quantified using specific functional assays. RASF metabolism was assessed by the XF24-Flux Analyzer. Mitochondrial structural morphology was assessed by transmission electron microscopy (TEM). In vivo synovial tissue oxygen (tpO(2) mmHg) was measured in patients with inflammatory arthritis (n=42) at arthroscopy, and markers of glycolysis/oxidative phosphorylation (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), PKM2, GLUT1, ATP) were quantified by immunohistology. A subgroup of patients underwent contiguous MRI and positron emission tomography (PET)/CT imaging. RASF and human dermal microvascular endothelial cells (HMVEC) migration/angiogenesis, transcriptional activation (HIF1α, pSTAT3, Notch1-IC) and cytokines were examined in the presence of glycolytic inhibitor 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). RESULTS: DMOG significantly increased mtDNA mutations, mitochondrial membrane potential, mitochondrial mass, reactive oxygen species and glycolytic RASF activity with concomitant attenuation of mitochondrial respiration and ATP activity (all p<0.01). This was coupled with altered mitochondrial morphology. Hypoxia-induced lactate levels (p<0.01), which in turn induced basic fibroblast growth factor (bFGF) secretion and RASF invasiveness (all p<0.05). In vivo glycolytic markers were inversely associated with synovial tpO(2) levels <20 mm Hg, in contrast ATP was significantly reduced (all p<0.05). Decrease in GAPDH and GLUT1 was paralleled by an increase in in vivo tpO(2) in tumour necrosis factor alpha inhibitor (TNFi) responders. Novel PET/MRI hybrid imaging demonstrated close association between metabolic activity and inflammation. 3PO significantly inhibited RASF invasion/migration, angiogenic tube formation, secretion of proinflammatory mediators (all p<0.05), and activation of HIF1α, pSTAT3 and Notch-1IC under normoxic and hypoxic conditions. CONCLUSIONS: Hypoxia alters cellular bioenergetics by inducing mitochondrial dysfunction and promoting a switch to glycolysis, supporting abnormal angiogenesis, cellular invasion and pannus formation.
27445458 Secukinumab for rheumatology: development and its potential place in therapy. 2016 Rheumatic disease is not a single disorder, but a group of more than 100 diseases that affect joints, connective tissues, and/or internal organs. Although rheumatic diseases like rheumatoid arthritis (RA), psoriatic arthritis, and ankylosing spondylitis (AS) differ in their pathogenesis and clinical presentation, the treatment of these inflammatory disorders overlaps. Non-steroid anti-inflammatory drugs are used to reduce pain and inflammation. Additional disease-modifying anti-rheumatic drugs are prescribed to slowdown disease progression, and is in RA more frequently and effectively applied than in AS. Biologicals are a relatively new class of treatments that specifically target cytokines or cells of the immune system, like tumor necrosis factor alpha inhibitors or B-cell blockers. A new kid on the block is the interleukin-17 (IL-17) inhibitor secukinumab, which has been recently approved by the US Food and Drug Administration for moderate-to-severe plaque psoriasis, psoriatic arthritis, and AS. IL-17 is a proinflammatory cytokine that has an important role in host defense, but its proinflammatory and destructive effects have also been linked to pathogenic processes in autoimmune diseases like RA and psoriasis. Animal models have greatly contributed to further insights in the potential of IL-17 blockade in autoimmune and autoinflammatory diseases, and have resulted in the development of various potential drugs targeting the IL-17 pathway. Secukinumab (AIN457) is a fully human monoclonal antibody that selectively binds to IL-17A and recently entered the market under the brand name Cosentyx(®). By binding to IL-17A, secukinumab prevents it from binding to its receptor and inhibits its ability to trigger inflammatory responses that play a role in the development of various autoimmune diseases. With secukinumab being the first in class to receive Food and Drug Administration approval, this article will further focus on this new biologic agent and review the milestones in its development and marketing.