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ID PMID Title PublicationDate abstract
25057003 Modulation of TNF-induced macrophage polarization by synovial fibroblasts. 2014 Sep 1 Mesenchymal stromal cells have emerged as powerful modulators of the immune system. In this study, we explored how the human macrophage response to TNF is regulated by human synovial fibroblasts, the representative stromal cell type in the synovial lining of joints that become activated during inflammatory arthritis. We found that synovial fibroblasts strongly suppressed TNF-mediated induction of an IFN-β autocrine loop and downstream expression of IFN-stimulated genes (ISGs), including chemokines CXCL9 and CXCL10 that are characteristic of classical macrophage activation. TNF induced the production of soluble synovial fibroblast factors that suppressed the macrophage production of IFN-β, and cooperated with TNF to limit the responsiveness of macrophages to IFN-β by suppressing activation of Jak-STAT signaling. Genome-wide transcriptome analysis showed that cocultured synovial fibroblasts modulate the expression of approximately one third of TNF-regulated genes in macrophages, including genes in pathways important for macrophage survival and polarization toward an alternatively activated phenotype. Pathway analysis revealed that gene expression programs regulated by synovial fibroblasts in our coculture system were also regulated in rheumatoid arthritis synovial macrophages, suggesting that these fibroblast-mediated changes may contribute to rheumatoid arthritis pathogenesis. This work furthers our understanding of the interplay between innate immune and stromal cells during an inflammatory response, one that is particularly relevant to inflammatory arthritis. Our findings also identify modulation of macrophage phenotype as a new function for synovial fibroblasts that may prove to be a contributing factor in arthritis pathogenesis.
24832836 Efficacy and safety of infliximab-biosimilar compared to other biological drugs in rheumat 2014 May OBJECTIVE: The aim of this meta-analysis was to compare the efficacy and safety of infliximab-biosimilar and other available biologicals for the treatment of rheumatoid arthritis (RA), namely abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, rituximab and tocilizumab. METHODS: A systematic literature review of MEDLINE database until August 2013 was carried out to identify relevant randomized controlled trials (RCTs). Bayesian mixed treatment comparison method was applied for the pairwise comparison of treatments. Improvement rates by the American College of Rheumatology criteria (ACR20 and ACR50) at week 24 were used as efficacy endpoints, and the occurrence of serious adverse events was considered to assess the safety of the biologicals. RESULTS: Thirty-six RCTs were included in the meta-analysis. All the biological agents proved to be superior to placebo. For ACR20 response, certolizumab pegol showed the highest odds ratio (OR) compared to placebo, OR 7.69 [95% CI 3.69-14.26], followed by abatacept OR 3.7 [95% CI 2.17-6.06], tocilizumab OR 3.69 [95% CI 1.87-6.62] and infliximab-biosimilar OR 3.47 [95% CI 0.85-9.7]. For ACR50 response, certolizumab pegol showed the highest OR compared to placebo OR 8.46 [3.74-16.82], followed by tocilizumab OR 5.57 [95% CI 2.77-10.09], and infliximab-biosimilar OR 4.06 [95% CI 1.01-11.54]. Regarding the occurrence of serious adverse events, the results show no statistically significant difference between infliximab-biosimilar and placebo, OR 1.87 [95% CI 0.74-3.84]. No significant difference regarding efficacy and safety was found between infliximab-biosimilar and the other biological treatments. CONCLUSION: This is the first indirect meta-analysis in RA that compares the efficacy and safety of biosimilar-infliximab to the other biologicals indicated in RA. We found no significant difference between infliximab-biosimilar and other biological agents in terms of clinical efficacy and safety.
24401767 Comprehensive analysis of miRNA expression in T-cell subsets of rheumatoid arthritis patie 2014 Mar Disturbed expression of microRNAs (miRNAs) in regulatory T cells (Tregs) leads to development of autoimmunity in experimental mouse models. However, the miRNA expression signature characterizing Tregs of autoimmune diseases, such as rheumatoid arthritis (RA) has not been determined yet. In this study, we have used a microarray approach to comprehensively analyze miRNA expression signatures of both naive Tregs (CD4+CD45RO-CD25++) and memory Tregs (CD4+CD45RO+CD25+++), as well as conventional naive (CD4+CD45RO-CD25-) and memory (CD4+CD45RO+CD25-) T cells (Tconvs) derived from peripheral blood of RA patients and matched healthy controls. Differential expression of selected miRNAs was validated by TaqMan-based quantitative reverse transcription-PCR. We found a positive correlation between increased expression of miR-451 in T cells of RA patients and disease activity score (DAS28), erythrocyte sedimentation rate levels and serum levels of interleukin-6. Moreover, we found characteristic, disease- and treatment-independent, global miRNA expression signatures defining naive Tregs, memory Tregs, naive Tconvs and memory Tconvs. The analysis allowed us to define miRNAs characteristic for a general naive phenotype (for example, miR-92a) and a general memory phenotype (for example, miR-21, miR-155). Importantly, the analysis allowed us to define miRNAs that are specifically expressed in both naive and memory Tregs, defining as such miRNA signature characterizing the Treg phenotype (that is, miR-146a, miR-3162, miR-1202, miR-1246 and miR-4281).
23007924 Association of rheumatoid arthritis risk alleles with response to anti-TNF biologics: resu 2013 Apr In this study, we investigated whether genetic variants known to be related with susceptibility to rheumatoid arthritis (RA) are also associated with response to therapy with anti-tumor necrosis factor (anti-TNF) biologics; 233 patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) RA registry were studied. Findings were combined with results from an international collaborative study (N = 1,283) in a meta-analysis (N = 1,516). Multivariate models investigating the association between single nucleotide polymorphisms (SNPs) and change in RA disease activity were adjusted for age, gender, concomitant methotrexate, and baseline disease activity. In the CORRONA cohort, nominal associations with disease activity improvement were observed for the rs1980422 SNP of the CD28 gene in multivariate models (coefficient -0.377, p = 0.005) but were not significant after adjustment for multiple comparisons (q = 0.10). In the meta-analysis, the only SNP with nominal associations with change in DAS28 was the rs2812378 SNP of the CCL21 gene (coefficient 1.9195, p = 0.0068). This association was not significant after adjustment for multiple comparisons (q = 0.143). We conclude that the established RA risk alleles studied were not significantly associated with response to anti-TNF biologics in the CORRONA cohort or the meta-analysis.
24943354 Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. 2014 Oct OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk for herpes zoster (HZ) (i.e., shingles). The aim of this study was to determine whether treatment with tofacitinib increases the risk of HZ in patients with RA. METHODS: HZ cases were identified as those reported by trial investigators from the databases of the phase II, phase III, and long-term extension (LTE) clinical trials in the Tofacitinib RA Development Program. Crude incidence rates (IRs) of HZ per 100 patient-years (with 95% confidence intervals [95% CIs]) were calculated by exposure group. Logistic regression analyses were performed to evaluate potential risk factors for HZ (e.g., age, prednisone use). RESULTS: Among 4,789 participants, 239 were identified as having tofacitinib-associated HZ during the phase II, phase III, and LTE trials, of whom 208 (87%) were female and whose median age was 57 years (range 21-75 years). One HZ case (0.4%) was multidermatomal; none of the cases involved visceral dissemination or death. Twenty-four patients with HZ (10%) permanently discontinued treatment with tofacitinib, and 16 (7%) were either hospitalized or received intravenous antiviral drugs. The crude HZ IR across the development program was 4.4 per 100 patient-years (95% CI 3.8-4.9), but the IR was substantially higher within Asia (7.7 per 100 patient-years, 95% CI 6.4-9.3). Older age was associated with HZ (odds ratio 1.9, 95% CI 1.5-2.6), and IRs for HZ were similar between patients receiving 5 mg tofacitinib twice daily (4.4 per 100 patient-years, 95% CI 3.2-6.0) and those receiving 10 mg twice daily (4.2 per 100 patient-years, 95% CI 3.1-5.8). In the phase III trials among placebo recipients, the incidence of HZ was 1.5 per 100 patient-years (95% CI 0.5-4.6). CONCLUSION: In the Tofacitinib RA Development Program, increased rates of HZ were observed in patients treated with tofacitinib compared with those receiving placebo, particularly among patients within Asia. Complicated HZ among tofacitinib-treated patients was rare.
23011084 Soluble CD163 serum levels are elevated and correlated with IL-12 and CXCL10 in patients w 2013 Apr CD163, a membrane glycoprotein restricted to monocyte-macrophage cell lineage, is released in the terminal phase of acute inflammation and during chronic inflammation, with anti-inflammatory and antiangiogenic role. The proteolytically detached ectodomain of CD163 is the soluble component sCD163. A few studies were performed regarding circulating sCD163 in human diseases. Only two were accomplished in patients with rheumatoid arthritis (RA). Our concern was (1) to evaluate sCD163 serum concentrations in active RA patients with long-standing evolution, (2) to correlate them with clinical parameters, laboratory markers, disease activity, and (3) to search possible relationships with some cytokines (IL-12, IL-17) and chemokine (CXCL10), involved in RA pathogenesis. First and third topics were not achieved until now, and the second one points out discordant findings and unspecified aspects. It was achieved immunoassay of serum sCD163, IL-12, IL-17, CXCL10 and traditional methods for RA laboratory markers. The mean sCD163 level of 33 patients was significantly higher than in 20 normal controls (p = 0.0001), 59.3 % of them with concentrations above normal cut-off value. sCD163 levels were weakly correlated with CRP and RF but not with ERS and disease activity. IL-12 and CXCL10 serum levels strongly correlated with sCD163 concentrations, while IL-17 positively but insignificantly correlated. In conclusion, serum sCD163 levels are significantly elevated in long-standing RA patients, but sCD163 has no role as a biomarker of disease activity. High correlation of sCD163 with IL-12 and CXCL10 suggests the association of their well-known anti-inflammatory function in long-standing RA patients.
24463110 [Role of NK-22 cells and interleukin-22-related molecules in proliferation of fibroblast- 2014 Jan OBJECTIVE: To investigate the role of natural killer-22 (NK-22) cells in the synovial fluid in the proliferation of fibroblast-like synoviocytes (FLS) in patients with rheumatoid arthritis (RA) and explore the possible signal pathway involved. METHODS: NK-22 cells in the SF of RA patients were sorted by flow cytometry. NK-22 cells were cultured for two weeks and the purity was detected by flow cytometry before stimulation with 20 ng/ml phorbol 12-myristate 13-acetate and 0.5 µmol/L ionomycin for 4 h. The level of interleukin-22 (IL-22) in the culture medium supernatant was then measured with ELISA. The proliferation of FLS in the presence of the culture supernatant of NK-22 cells was assessed with MTT assay at 24, 48 and 72 h, and the effect of IL-22 antibody on FLS proliferation was also observed. Real-time PCR and Western blotting were used to detect Stat3 mRNA and p-Stat3 protein levels, respectively, in the FLS exposed to rhIL-22 and AG490. RESULTS: NK-22 cells were successfully sorted by flow cytometry with a purity exceeding 90%. The levels of IL-22 in the supernatant of NKp44(+)NK cell culture averaged 1273.42∓254.48 pg/ml. The FLS proliferated rapidly 24, 48, and 72 h after the addition of culture supernatant of NK-22 cells (P<0.05). IL-22 antibody obviously inhibited the proliferation of FLS induced by NK-22 cell culture supernatant (P<0.05). Exposure of the FLS to rhIL-22 obviously increased cellular Stat3 expression levels, which were significantly lowered by the addition of AG490 (P<0.05). CONCLUSION: NK-22 cells in the SF of RA patients can produce high concentrations of IL-22 to promote the proliferation of FLS through the STAT3 signal pathway.
23381558 Genetics and epigenetics of rheumatoid arthritis. 2013 Mar Investigators have made key advances in rheumatoid arthritis (RA) genetics in the past 10 years. Although genetic studies have had limited influence on clinical practice and drug discovery, they are currently generating testable hypotheses to explain disease pathogenesis. Firstly, we review here the major advances in identifying RA genetic susceptibility markers both within and outside of the MHC. Understanding how genetic variants translate into pathogenic mechanisms and ultimately into phenotypes remains a mystery for most of the polymorphisms that confer susceptibility to RA, but functional data are emerging. Interplay between environmental and genetic factors is poorly understood and in need of further investigation. Secondly, we review current knowledge of the role of epigenetics in RA susceptibility. Differences in the epigenome could represent one of the ways in which environmental exposures translate into phenotypic outcomes. The best understood epigenetic phenomena include post-translational histone modifications and DNA methylation events, both of which have critical roles in gene regulation. Epigenetic studies in RA represent a new area of research with the potential to answer unsolved questions.
25436661 A comparison of two podiatric protocols for metatarsalgia in patients with rheumatoid arth 2014 Nov OBJECTIVES: In rheumatoid arthritis (RA) and osteoarthritis (OA) forefoot involvement causes disability and metatarsalgia. Our objective was to evaluate, in RA and OA patients, the efficacy of two protocols combining insoles in polypropylene terephtalate (PPT) and custom silicone orthoses for toes on disability and metatarsalgia. METHODS: Twenty-four women (13 with OA, 11 with RA) with metatarsalgia were treated with two protocols: group A (protocol A) wore PPT insoles (T1) for 30 days and for another 30 days silicone orthosis for toes were added (T2). Group B (protocol B) wore PPT insoles and silicone orthosis (T1) for 30 days and in the following 30 days only insoles (T2). At T0, T1 and T2, pain, disability and function (Foot Function Index - FFI), pressure (KPA) and plantar contact areas (cm2) (baropodometer), and gait spatial-temporal parameters (GAITRite®) were assessed. RESULTS: At T0 versus T2, both protocols reduced FFI-pain, -disability and -functional limitation (p<0.05), with better results of protocol A than protocol B (p<0.05) for FFI-pain and -disability. Both protocols reduced baropodometer foot plantar pressures (p<0.001), with better results for protocol A for right foot pressures (p<0.05) and increased foot contact areas (p<0.05), with no difference between them (p=NS). Gait parameters were not significantly changed by both protocols (p=NS). CONCLUSIONS: In patients with RA and OA with metatarsalgia, the synergic action of silicone toe orthosis and PPT insoles improves FFI, reduces foot plantar pressures and increases foot plantar contact areas. Protocol A, using firstly insoles and then adding silicone toe orthoses, is the more efficacious.
24448858 [Effects of hydroxychloroquine on insulin sensitivity and lipid profile in patients with r 2013 Aug BACKGROUND: Rheumatoid arthritis (RA) is associated with a decrease in insulin sensitivity (IS), which has been identified as an independent risk factor for the development of early atherosclerosis. Hydroxychloroquine (HCQ) may have beneficial effects on glucose homeostasis and lipid profile. AIM: To assess the effect of HCQ on IS and lipid profile in patients with RA. MATERIAL AND METHODS: An open clinical trial was performed in 15 patients aged between 35 and 56 years. During three months, patients received 400 mg/day of HCQ orally. Before and after the pharmacological intervention, demographic and anthropometric variables, serum glucose, total cholesterol (TC), triglycerides (TG), HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, insulin and uric acid were measured. IS was estimated as the rate of glucose clearance per minute obtained with the insulin tolerance test (KITT). RESULTS: Baseline and final KITT values were 4.3 ± 1.2 and 4.80 ± 1.1%/min, respectively (p = 0.03). Significant reductions in serum TC (p = 0.04) and TG (p = 0.01) were also observed. No other significant differences were observed. CONCLUSIONS: Oral administration of 400 mg/day of HCQ during three months in RA patients is associated with an improvement in IS, TC and TG.
25204703 Mangiferin: A promising therapeutic agent for rheumatoid arthritis treatment. 2014 Nov Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial hyperplasia and progressive joint destruction. Despite aggressive treatment with anti-rheumatic drugs, progressive destruction of joints continues to occur in RA patients, who subsequently require joint surgery. A lot of evidence suggest that fibroblast-like synovial cells (FLS) play crucial role in joint degradation and the propagation of inflammation in RA. The expansion of fibroblast populations in the joint results primarily from the inhibition of pro-apoptotic pathways, rather than large scale proliferation. Because multiple factors, which contribute to fibroblast activation and enhance their destructive potential, are under control of transcription factor NF-κB, this pathway presents an interesting target for RA therapy. However, due to the lack of specificity, NF-κB inhibitors may exert severe side effects. Given the above, there has recently been more interest in natural substances of plant origin which are regarded as a safe alternatives for synthetic drugs. Mangiferin, the naturally occurring polyphenol with excellent anti-inflammatory and antioxidative properties, exhibits strong pro-apoptotic effect toward synoviocytes isolated from human synovia. Moreover, it shows no cytotoxicity toward cultivated chondrocytes and reduces the levels of matrix metalloproteinases. Considering that mangiferin is a natural constituent of foods and traditional herbal medicines, showing fewer adverse effects and low toxicity, we hypothesize that it may prove effective in the treatment of RA and prevention against joint destruction.
23604594 Safety of biologics approved for treating rheumatoid arthritis: analysis of spontaneous re 2013 Aug Despite the effectiveness of biologics approved for the treatment of rheumatoid arthritis, they have been associated with serious adverse events (AEs). Biologics are used under close supervision of health care professionals. In Portugal, they are legally required to report AEs occurring during the treatment. This study aims at investigating post-marketing safety monitoring data of biologics in Portugal by comparing the frequency of spontaneously reported adverse events between 2009 and 2011 with the frequency of such events in the summary of the product characteristics of each biologic. Sales data for biologics were obtained from IMS Health and converted into defined daily doses/1,000 inhabitants/day in order to estimate a proportion of the population treated. The frequency of AEs was estimated as the percentage of patients in which an AE may have occurred. The use of each biologic was estimated for adalimumab at 1,439 patients/year, etanercept 1,944 patients/year, and infliximab 3,211 patients/year. A total of 992 AEs were reported: 207 for adalimumab, 199 for etanercept, and 586 for infliximab. Of the 515 different spontaneously reported AEs, 194 were included for comparisons with the SPCs. Of those, 31 (16 %) were similarly frequent, and 163 (84.0 %) occurred less frequently compared with SPCs' data. These results suggest an insufficient post-marketing safety monitoring of biologics in Portugal.
24575499 Changes in anti-citrullinated protein antibody titers following treatment with infliximab 2014 Jan BACKGROUND: The presence of anti-citrullinated peptide/ protein antibody (ACPA) has a high specificity and predictive value for the development of rheumatoid arthritis (RA). Some studies have shown decreased titers of this antibody after treatment with infliximab. OBJECTIVES: To assess the changes in ACPA titers in patients with RA after treatment with infliximab as a first biological agent, and to correlate these variations with non-infusion-related adverse effects. METHODS: In a prospective multicenter observational study involving 48 research centers, we assessed 139 patients with established moderate-to-severe RA diagnosed according to American College of Rheumatology criteria. Samples were collected before and 6-12 months after treatment. RESULTS: The mean age of the study patients was 50.6 years and 118 were female (84.9%). Statistically significant variations in ACPA titers were noted in 47 patients (before and after treatment) (P = 0.012). Overall, ACPA titers were decreased in 32 (65.3%) and increased in 15 (34.7%). No correlation was found between severe or mild adverse effects in patients presenting variations in ACPA titers. CONCLUSIONS: The present study showed that infliximab affected ACPA titers, promoting mainly a decrease; however, this was not related to the occurrence of non-infusion-related adverse effects.
25475472 Hydroxychloroquine-induced cardiomyopathy: case report, pathophysiology, diagnosis, and tr 2014 Dec Drug-induced heart and vascular disease remains an important health burden. Hydroxychloroquine and its predecessor chloroquine are medications commonly used in the treatment of systemic lupus erythematosus, rheumatoid arthritis, and other connective tissue disorders. Hydroxychloroquine interferes with malarial metabolites, confers immunomodulatory effects, and also affects lysosomal function. Clinical monitoring and early recognition of toxicity is an important management strategy in patients who undergo long-term treatment with hydroxychloroquine. Retinal toxicity, neuromyopathy, and cardiac disease are recognized adverse effects of hydroxychloroquine. Immediate withdrawal of hydroxychloroquine is essential if toxicity is suspected because of the early reversibility of cardiomyopathy. In addition to recommended ophthalmological screening, regular screening with 12-lead electrocardiogram and transthoracic echocardiography to detect conduction system disease and/or biventricular morphological or functional changes should be considered in hydroxychloroquine-treated patients. Cardiac magnetic resonance imaging and endomyocardial biopsy are valuable tools to provide prognostic insights and confirm the diagnosis of hydroxychloroquine-induced cardiomyopathy. In conclusion, chronic use of hydroxychloroquine can result in an acquired lysosomal storage disorder, leading to a drug-induced cardiomyopathy characterized by concentric hypertrophy and conduction abnormalities associated with increased adverse clinical outcomes and mortality.
25128056 Two approaches to incorporate clinical data uncertainty into multiple criteria decision an 2014 Jul BACKGROUND: The Problem formulation, Objectives, Alternatives, Consequences, Trade-offs, Uncertainties, Risk attitude, and Linked decisions (PrOACT-URL) framework and multiple criteria decision analysis (MCDA) have been recommended by the European Medicines Agency for structured benefit-risk assessment of medicinal products undergoing regulatory review. OBJECTIVE: The objective of this article was to provide solutions to incorporate the uncertainty from clinical data into the MCDA model when evaluating the overall benefit-risk profiles among different treatment options. METHODS: Two statistical approaches, the δ-method approach and the Monte-Carlo approach, were proposed to construct the confidence interval of the overall benefit-risk score from the MCDA model as well as other probabilistic measures for comparing the benefit-risk profiles between treatment options. Both approaches can incorporate the correlation structure between clinical parameters (criteria) in the MCDA model and are straightforward to implement. RESULTS: The two proposed approaches were applied to a case study to evaluate the benefit-risk profile of an add-on therapy for rheumatoid arthritis (drug X) relative to placebo. It demonstrated a straightforward way to quantify the impact of the uncertainty from clinical data to the benefit-risk assessment and enabled statistical inference on evaluating the overall benefit-risk profiles among different treatment options. CONCLUSIONS: The δ-method approach provides a closed form to quantify the variability of the overall benefit-risk score in the MCDA model, whereas the Monte-Carlo approach is more computationally intensive but can yield its true sampling distribution for statistical inference. The obtained confidence intervals and other probabilistic measures from the two approaches enhance the benefit-risk decision making of medicinal products.
25466873 Immuno-proteomics: Development of a novel reagent for separating antibodies from their tar 2015 Jun Immunoprecipitation (IP) is a widely used technique for identifying the binding partners of the target proteins of specific antibodies. Putative binding targets and their partners are usually in much lower amounts than the antibodies used to capture these target proteins. Thus antigen identification using proteomics following IP is often confounded by the presence of an overwhelming amount of interfering antibody protein. Even covalently linking antibodies to beads is susceptible to antibody leaching during IP. To circumvent this interference, we describe here a reagent, called Biotin-CDM that reversibly tags all potential target proteins in a cell lysate with biotin. The presence of biotin coupled to the target proteins allows for a secondary separation step in which antibodies are washed away from the reversibly biotinylated target proteins by binding them to an Avidin-coupled matrix. The captured target proteins are released from the Avidin matrix by reversing the Biotin-CDM link, thus releasing a pool of target proteins ready for further proteomic analysis compatible with 2D-electrophoresis. Here, we describe the synthesis and characterization of Biotin-CDM. We also demonstrate Biotin-CDM's use for immunoprecipitation of a known antigen, as well as its use for capturing an array of proteins targeted by the autoantibodies found in the serum a patient suffering from rheumatoid arthritis. The use of this reagent allows one to combine immunoprecipitation and 2D-Difference gel electrophoresis, overcoming the current limitations of Serological Proteome Analysis (SERPA) in discovering autoantigens. This article is part of a Special Issue entitled: Medical Proteomics.
25481649 Targeting the Fas/FasL system in Rheumatoid Arthritis therapy: Promising or risky? 2015 Oct Rheumatoid Arthritis (RA) is a chronic inflammatory disease affecting synovial joints. Tumor necrosis factor (TNF) α is a key component of RA pathogenesis and blocking this cytokine is the most common strategy to treat the disease. Though TNFα blockers are very efficient, one third of the RA patients are unresponsive or present side effects. Therefore, the development of novel therapeutic approaches is required. RA pathogenesis is characterized by the hyperplasia of the synovium, closely associated to the pseudo-tumoral expansion of fibroblast-like synoviocytes (FLS), which invade and destroy the joint structure. Hence, depletion of RA FLS has been proposed as an alternative therapeutic strategy. The TNF family member Fas ligand (FasL) was reported to trigger apoptosis in FLS of arthritic joints by binding to its receptor Fas and therefore suggested as a promising candidate for targeting the hyperplastic synovial tissue. However, this cytokine is pleiotropic and recent data from the literature indicate that Fas activation might have a disease-promoting role in RA by promoting cell proliferation. Therefore, a FasL-based therapy for RA requires careful evaluation before being applied. In this review we aim to overview what is known about the apoptotic and non-apoptotic effects of Fas/FasL system and discuss its relevance in RA.
24880677 Vitamin D receptor TaqI and ApaI polymorphisms: a comparative study in patients with Behç 2014 Jul Recent genetic surveys have identified vitamin D receptor (VDR) as a susceptibility gene for several autoimmune diseases. This study was designed to investigate the association of VDR gene polymorphisms with Behçet's disease (BD) and Rheumatoid arthritis (RA). A case-control study including 151 BD, 106 RA patients and an appropriate number of healthy control subjects were performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques. Association between TaqI polymorphism and BD was marginal under codominant and recessive models (P=0.078 and P=0.058, respectively). After stratification, we found evidence for a significant association between TaqI polymorphism and BD in the elderly subjects (P=0.037). The minor ApaI a allele tended to confer an increased risk for BD susceptibility (P=0.087). BD patients with VDR homozygous AA or aa genotypes were at increased risk for development of erythema nodosum (EN) skin manifestation (P=0.038). No significant association was observed for VDR ApaI and TaqI polymorphisms with RA risk (P>0.05). TaqI and ApaI polymorphisms might be modestly implicated in BD pathogenesis. They could be considered as potential biomarkers in BD rather than susceptibility genes. However, TaqI and ApaI seemed not to be implicated in RA pathogenesis.
24344811 Therapeutic effects of hybrid liposomes without drugs for rheumatoid arthritis. 2015 Hybrid liposomes (HLs) can be prepared by simply sonicating a mixture of vesicular and micellar molecules in buffer solutions. This study aims to demonstrate inhibitory effects of HLs on the growth of fibroblast-like synoviocytes along with apoptosis and therapeutic effects of HLs in a mouse model with rheumatoid arthritis (RA). HLs composed of 95 mol% L-α-dimyristoylphosphatidylcholine (DMPC) and 5 mol% polyoxyethylene(23)dodecyl ether (C12(EO)23) were prepared by the sonication method. The inhibitory effects of HLs on the growth of human fibroblast-like synoviocytes-RA (HFLS-RA) cells in vitro and their inhibitory mechanism were examined. High inhibitory effects of HLs on the growth of HFLS-RA cells were observed. The induction of apoptosis by HLs was revealed on the basis of flow cytometric analysis. Furthermore, therapeutic effects of HLs in the mouse model with RA were examined in vivo. Our results demonstrate that HLs showed inhibitory effects on the growth of HFLS-RA cells in vitro along with apoptosis and therapeutic effects in mouse models of RA in vivo.
23907781 Assessing calibration of prognostic risk scores. 2016 Aug Current methods used to assess calibration are limited, particularly in the assessment of prognostic models. Methods for testing and visualizing calibration (e.g. the Hosmer-Lemeshow test and calibration slope) have been well thought out in the binary regression setting. However, extension of these methods to Cox models is less well known and could be improved. We describe a model-based framework for the assessment of calibration in the binary setting that provides natural extensions to the survival data setting. We show that Poisson regression models can be used to easily assess calibration in prognostic models. In addition, we show that a calibration test suggested for use in survival data has poor performance. Finally, we apply these methods to the problem of external validation of a risk score developed for the general population when assessed in a special patient population (i.e. patients with particular comorbidities, such as rheumatoid arthritis).