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ID PMID Title PublicationDate abstract
23876791 Reduction of biological agent dose in rheumatic diseases: descriptive analysis of 153 pati 2014 Jan OBJECTIVE: To analyze the frequency and characteristics of dose reduction of biological agents in a cohort of patients with chronic arthritis, in clinical practice conditions in a tertiary level hospital. MATERIAL AND METHODS: Descriptive, cross-sectional study, which included all patients, followed consecutively during 6 months (June 2011-November 2011), by one investigator, with patients who at least have received one dose of biological agents in 2011. RESULTS: We included 153 patients: Rheumatoid arthritis (RA) (n=82), ankylosing spondylitis (n=29), psoriatic arthritis (n=20), and miscellaneous group (n=22). Mean disease duration was 14.9±7.7 years. At the time of analysis, 70 patients (45.7%) were receiving low doses of biological therapy (50% in miscellaneous group group, 50% in psoriatic arthritis, 48.2% in ankylosing spondylitis, and 42.6% in RA). Mean time of dosage reduction was 17.4±17.5 months. The most common biological agents used in low dose were: etanercept, adalimumab and tocilizumab; 57.6%, 54.9% and 40% respectively, in patients with a reduced dose of biological therapy. The patients at low dose of biological therapy compared with standard dose, had similar mean disease duration, but received significantly less DMARDs, glucocorticoids and NSAIDs, and similar biological agent duration. RA patients with reduced biological treatment, at the time of analysis, had higher remission rates versus patients receiving a standard dose (82.9% vs 34%, p<0.0001). The medical decision at the time of analysis was to maintain low-dosage biological treatment in almost all patients. CONCLUSION: In our clinical practice, 45.7% of our chronic arthritis patients receive low dose of biological therapy, after achieving remission or low activity at standard doses, maintaining a good control of the disease.
25228497 Impaired degradation and aberrant phagocytosis of necrotic cell debris in the peripheral b 2015 Jan Aberrant removal of necrotic debris is considered a feature with inflammatory consequences in SLE. Herein, primary Sjögren's syndrome (SS) patients were investigated for the first time for the capacity of their sera to degrade secondary necrotic cell remnants (SNEC) and DNA (endonuclease DNase1 activity), as well as for uptake of SNEC by blood-borne phagocytes. For comparison, specimens from unselected SLE and RA patients and from healthy blood donors (HBD) were also studied. Compared to HBD, the sera from SS and SLE patients studied (but not RA) were found to exhibit significantly impaired capacity for degradation of SNEC (both for p = 0.007) and deficient DNase1 activity (both for p < 0.0001). The deficient DNase1 activity in SS and SLE sera did not owe to decreased DNase1 protein levels. It correlated inversely with increased serum levels of circulating nucleosomes and cell-free DNA (p < 0.0001), as well as with the disease activity indices of SS (r = -0.445, p = 0.0001) and SLE (r = -0.500, p = 0.013). In ex-vivo whole blood analyses, SS and SLE patients (but not RA) also manifested significantly increased SNEC-phagocytosis by monocytes and granulocytes (all for p < 0.0001) that also correlated with disease severity indices of SS (p = 0.001) and SLE (p = 0.01). In various cross-admixture experiments, such aberration was found to reside in the hyperfunctional activity of phagocytes, the impaired degrading activity of serum DNase1 and the SNEC-binding capacity of serum IgG of SS and SLE patients. The sera of SS and SLE patients (but not of RA) induced significant SNEC-phagocytosis by healthy monocytes that correlated inversely with the DNase1 activity (r = -0.634, p < 0.0001) of these sera. In line with this, the inhibition of DNase1 in HBD sera by G-actin was found to lead to significantly diminished SNEC degradation and increased SNEC uptake by healthy phagocytes (p = 0.0009), supporting the important physiologic role of serum DNase1 in the prevention of SNEC-phagocytosis. Purified serum IgG preparations from SS and SLE patients manifested increased binding to SNEC and were able to enhance significantly the engulfment of SNEC by healthy phagocytes both directly (under serum-free conditions, p ≤ 0.009) and via the prevention of physiologic degradation of SNEC by serum, most likely due to their "shielding" against endonuclease digestion (p = 0.0005). These data indicate that upon cell necrosis, the immune system of SS and SLE patients may be overly exposed to the necrotic debris, a fact that probably holds a key role in the pathogenesis of inflammatory and autoimmune reactions observed in these disorders.
23404327 [Topical application of TNF-blockers]. 2013 Feb In 1998, the first TNF-blocker was approved in the USA and a year later in Germany. Treatment with TNF-blocking agents has significantly expanded therapeutic options for patients with chronic inflammatory diseases in rheumatology, dermatology and gastroenterology. However, it is not always possible to achieve a local clinical improvement by systemically administered TNF-blockers. Many approaches to topical therapy with TNF blockers have been published in recent years. The main objective of these off-label applications is the injection of a larger quantity of TNF-blocker in the inflamed tissue than it is achievable with systemic therapy. This summary provides an overview of the variety of topical therapy trials and reports own experiences in patients with Crohn's disease.
23892891 IL-18 in inflammatory and autoimmune disease. 2013 Dec Inflammation serves as the first line of defense in response to tissue injury, guiding the immune system to ensure preservation of the host. The inflammatory response can be divided into a quick initial phase mediated mainly by innate immune cells including neutrophils and macrophages, followed by a late phase that is dominated by lymphocytes. Early in the new millennium, a key component of the inflammatory reaction was discovered with the identification of a number of cytosolic sensor proteins (Nod-like receptors) that assembled into a common structure, the 'inflammasome'. This structure includes an enzyme, caspase-1, which upon activation cleaves pro-forms of cytokines leading to subsequent release of active IL-1 and IL-18. This review focuses on the role of IL-18 in inflammatory responses with emphasis on autoimmune diseases.
24952375 CD45RA-Foxp3(low) non-regulatory T cells in the CCR7-CD45RA-CD27+CD28+ effector memory sub 2014 Jul Increased numbers of regulatory T (Treg) cells are found in synovial fluid from patients with rheumatoid arthritis (RASF) compared with peripheral blood. However, Treg cells in RASF have been shown to have a decreased capacity to suppress T cells. Here we phenotypically classified CD4+ T cells in RASF into six subsets based on the expression of CD45RA, CCR7, CD27 and CD28, and demonstrated that the CCR7-CD45RA-CD27+CD28+ TEM subset was significantly increased in synovial fluid compared with peripheral blood. In addition, the proportion of Foxp3+ Treg cells in the CCR7-CD45RA-CD27+CD28+ TEM subset was significantly increased in RASF. Furthermore, most of the Foxp3+ Treg cells in RASF were non-suppressive CD45RA-Foxp3(low) non-Treg cells, and the frequency of the non-Treg cells in the CCR7-CD45RA-CD27+CD28+ TEM subset was significantly increased in RASF. Our findings suggest that the pro-inflammatory environment in RA joints may induce the increase of CD45RA-Foxp3(low) non-Treg cells in synovial fluid.
23814065 Niemann-pick type C2 deficiency in human fibroblasts confers robust and selective activati 2013 Aug 16 Activated fibroblasts, also known as myofibroblasts, are mediators of several major human pathologies including proliferative fibrotic disorders, invasive tumor growth, rheumatoid arthritis, and atherosclerosis. We previously identified Niemann-Pick type C2 (NPC2) protein as a negative regulator of fibroblast activation (Csepeggi, C., Jiang, M., Kojima, F., Crofford, L. J., and Frolov, A. (2011) J. Biol. Chem. 286, 2078-2087). Here we report that NPC2-deficiency leads to a dramatic up-regulation of the arachidonic acid (AA) metabolic pathway in human fibroblasts. The major enzymes in this pathway, cPLA2 type IVA, COX-2, and mPGES-1, were dramatically up-regulated at both the transcriptional and translational levels. The specific phenotypic changes resulted in a >10-fold increase in the production and secretion of a key modulator of inflammation and immunity, prostaglandin E2. More importantly, AA metabolome profiling by liquid chromatography/tandem mass-spectrometry revealed the very specific nature of prostaglandin E2 up-regulation as the other analyzed AA metabolites derived from the COX-2, cytochrome P450, 5/15-lipoxygenase, and non-enzymatic oxidative pathways were mostly down-regulated. Blocking activity of cPLA2 efficiently suppressed expression of inflammatory cytokines, IL-1β and IL-6, thereby identifying cPLA2 as an important regulator of the inflammatory program in NPC2-null cells. Altogether, these studies highlight NPC2 as a specific regulator of AA metabolism and inflammation that suggests potential for NPC2 protein or its related signaling in the treatment of inflammatory diseases characterized by the presence of activated fibroblasts.
22492023 A series of patients on anti-TNF therapy referred to a multidisciplinary lung cancer servi 2013 Mar BACKGROUND: Biological therapies have significantly improved the quality of life of patients with aggressive collagen vascular diseases. Blocking TNF activity may potentially confer a higher malignant potential for patients. AIMS: To identify patients to whom anti-TNF therapies were recently prescribed and were referred to a multidisciplinary lung cancer service. METHODS: Retrospective review of patients over an 18-month period who were referred to a multidisciplinary lung cancer service. RESULTS: Three patients who underwent recent anti-TNF therapies and presented with solid organ tumours. All had significant additional risks for cancer including smoking and family history and active connective tissue diseases with a past history of immunosuppressive therapies. CONCLUSIONS: Our series highlights the potential malignant risk of anti-TNF theraphy to a general medical audience.
25358907 A unification of models for meta-analysis of diagnostic accuracy studies without a gold st 2015 Jun Several statistical methods for meta-analysis of diagnostic accuracy studies have been discussed in the presence of a gold standard. However, in practice, the selected reference test may be imperfect due to measurement error, non-existence, invasive nature, or expensive cost of a gold standard. It has been suggested that treating an imperfect reference test as a gold standard can lead to substantial bias in the estimation of diagnostic test accuracy. Recently, two models have been proposed to account for imperfect reference test, namely, a multivariate generalized linear mixed model (MGLMM) and a hierarchical summary receiver operating characteristic (HSROC) model. Both models are very flexible in accounting for heterogeneity in accuracies of tests across studies as well as the dependence between tests. In this article, we show that these two models, although with different formulations, are closely related and are equivalent in the absence of study-level covariates. Furthermore, we provide the exact relations between the parameters of these two models and assumptions under which two models can be reduced to equivalent submodels. On the other hand, we show that some submodels of the MGLMM do not have corresponding equivalent submodels of the HSROC model, and vice versa. With three real examples, we illustrate the cases when fitting the MGLMM and HSROC models leads to equivalent submodels and hence identical inference, and the cases when the inferences from two models are slightly different. Our results generalize the important relations between the bivariate generalized linear mixed model and HSROC model when the reference test is a gold standard.
23508298 A matrix metalloproteinase 1-cleavable composite peptide derived from transforming growth 2013 Jul OBJECTIVE: Transforming growth factor β-inducible gene h3 (βIG-H3), which is abundantly expressed in rheumatoid synovium, and matrix metalloproteinases (MMP) play important roles in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to determine the therapeutic efficacy of βIG-H3-derived peptides using MMP-1-dependent target tissue delivery in chronic inflammatory arthritis. METHODS: Peptides developed from βIG-H3 derivatives, including the second and fourth YH peptides, the fourth fas-1 domain, the fourth fas-1 domain truncated for H1 and H2 sequences (dhfas-1), and an MMP-1- cleavable composite peptide (MFK24), were cloned. We confirmed the specificity of MFK24 cleavage by immunoblot analysis after treatment with different proteases. RESULTS: The YH18 peptide in the fourth fas-1 domain of βIG-H3 was weakly effective in suppressing arthritis severity in mice with collagen-induced arthritis (CIA). Treatment with higher-dose dhfas-1 (30 mg/kg) showed remarkable efficacy, whereas treatment with a lower dose (10 mg/kg) resulted in only partial improvement. MFK24, a composite peptide consisting of dhfas-1 and RGD peptide linked by MMP-1 substrate, was cleaved specifically by MMP-1. The adhesion and migration of NIH3T3 cells mediated by βIG-H3 were inhibited by MFK24 at a low concentration. MFK24 suppressed the adhesion of NIH3T3 cells more efficiently compared with murine dhfas-1 (MFK00) or RGD, either alone or in combination. The therapeutic efficacy of MFK24 in mice with CIA was remarkably enhanced, with consistently reduced expression of inflammatory mediators within joint tissue. CONCLUSION: This proof-of-concept study showed that an MMP-cleavable composite peptide, based on βIG-H3 derivatives, had markedly improved therapeutic efficacy in chronic inflammatory arthritis, implicating a new expandable strategy for enhancement of the efficacy of 2 different active molecules in RA.
23942232 Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory art 2013 Sep 11 In rheumatoid arthritis (RA), macrophage is one of the major sources of inflammatory mediators. Macrophages produce inflammatory cytokines through toll-like receptor (TLR)-mediated signalling during RA. Herein, we studied macrophages from the synovial fluid of RA patients and observed a significant increase in activation of inositol-requiring enzyme 1α (IRE1α), a primary unfolded protein response (UPR) transducer. Myeloid-specific deletion of the IRE1α gene protected mice from inflammatory arthritis, and treatment with the IRE1α-specific inhibitor 4U8C attenuated joint inflammation in mice. IRE1α was required for optimal production of pro-inflammatory cytokines as evidenced by impaired TLR-induced cytokine production in IRE1α-null macrophages and neutrophils. Further analyses demonstrated that tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6) plays a key role in TLR-mediated IRE1α activation by catalysing IRE1α ubiquitination and blocking the recruitment of protein phosphatase 2A (PP2A), a phosphatase that inhibits IRE1α phosphorylation. In summary, we discovered a novel regulatory axis through TRAF6-mediated IRE1α ubiquitination in regulating TLR-induced IRE1α activation in pro-inflammatory cytokine production, and demonstrated that IRE1α is a potential therapeutic target for inflammatory arthritis.
24264477 Myeloid-derived suppressor cells protect mouse models from autoimmune arthritis via contro 2014 Jun Myeloid-derived suppressor cells (MDSCs) have been reported to participate in immune suppression and autoimmune disorders. However, its role in autoimmune arthritis remains to be determined. We explored whether adoptive transfer of MDSCs in vivo would block joint inflammation and histological damage using collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA) models. CD11b(+) Gr-1(+) MDSCs were isolated from the single cells from the spleens of CIA mice on day 41 or AIA mice on day 35. MDSCs (2 × 10(6)) were then transferred to AIA and CIA mice via tail vein before arthritis establishment at indicated time points. Phosphate buffered saline (PBS) was injected as control. Arthritis was evaluated by severity score and histology. The levels of TNF-α, IL-6, IL-17 and IL-10 in the serum and joints were detected by enzyme-linked immunosorbent assay (ELISA). The number of Th17 cells and macrophages in draining lymph nodes and joint tissues was assessed by flow cytometric analysis. Adoptive transfer of MDSCs significantly reduced the clinical score of arthritis, alleviated joint inflammation and histological damage both in AIA and CIA models compared with PBS-treated control groups. The levels of TNF-α, IL-6, IL-17, and IL-10 in the serum and joints were down-regulated by transfer of MDSCs. In addition, adoptive transfer of MDSCs significantly reduced the number of Th17 cells and macrophages in draining lymph nodes and joint tissues. Altogether, we demonstrate that adoptive transfer of MDSCs prevented autoimmune arthritis in mouse models of RA through inhibiting Th17 cells and macrophages. These new findings provide insights into the inhibitory functions of MDSCs and MDSCs may be used as a cell-based biotherapy in RA.
23333834 RANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthriti 2013 Apr 25 Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for RANKL binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for RANKL induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide YR-11 (YLEIEFSLKHR), obtained by direct substitution of cysteine with a serine residue in the template sequence, significantly (p<0.05) inhibited RANK-RANKL binding, and RANKL induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of YR-11 peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1β, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that YR-11 peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on RANKL induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects.
23169319 Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthrit 2013 Jan OBJECTIVE: There is a need for comparative studies to provide evidence-based treatment guidance for biologic agents in rheumatoid arthritis (RA). Therefore, this study was undertaken as the first head-to-head comparison of subcutaneous (SC) abatacept and SC adalimumab, both administered along with background methotrexate (MTX), for the treatment of RA. METHODS: Patients with active RA who were naive to treatment with biologic agents and had an inadequate response to MTX were randomly assigned to receive 125 mg SC abatacept weekly or 40 mg SC adalimumab biweekly, both given in combination with MTX, in a 2-year study. The primary end point was treatment noninferiority, assessed according to the American College of Rheumatology 20% improvement response (ACR20) at 1 year. RESULTS: Of the 646 patients who were randomized and treated, 86.2% receiving SC abatacept and 82% receiving SC adalimumab completed 12 months of treatment. At 1 year, 64.8% of patients in the SC abatacept group and 63.4% in the SC adalimumab group demonstrated an ACR20 response; the estimated difference between groups was 1.8% (95% confidence interval -5.6%, 9.2%), thus demonstrating the noninferiority of abatacept compared to adalimumab. All efficacy measures showed similar results and kinetics of response between treatments. The rate of radiographic nonprogression (defined as a total modified Sharp/van der Heijde score [SHS] less than or equal to the smallest detectable change) was 84.8% for SC abatacept-treated patients and 88.6% for SC adalimumab-treated patients, while the mean change from baseline in the total SHS was 0.58 and 0.38, respectively. In the SC abatacept and SC adalimumab groups, the incidence of serious adverse events (SAEs) was 10.1% and 9.1%, respectively, and the rate of serious infections was 2.2% and 2.7%, respectively. In patients treated with SC abatacept, the frequency of discontinuations due to AEs was 3.5% and discontinuations due to SAEs was 1.3%, while in patients treated with SC adalimumab, the frequencies were 6.1% and 3%, respectively. Injection site reactions occurred in 3.8% of patients receiving SC abatacept compared to 9.1% of patients receiving SC adalimumab (P=0.006). CONCLUSION: The results demonstrate that SC abatacept and SC adalimumab have comparable efficacy in patients with RA, as shown by similar kinetics of response and comparable inhibition of radiographic progression over 1 year of treatment. The safety was generally similar, other than the occurrence of significantly more local injection site reactions in patients treated with SC adalimumab.
24285492 Free fatty acids: potential proinflammatory mediators in rheumatic diseases. 2015 Jan OBJECTIVES: Due to their role in inflammatory metabolic diseases, we hypothesised that free fatty acids (FFA) are also involved in inflammatory joint diseases. To test this hypothesis, we analysed the effect of FFA on synovial fibroblasts (SF), human chondrocytes and endothelial cells. We also investigated whether the toll-like receptor 4 (TLR4), which can contribute to driving arthritis, is involved in FFA signalling. METHODS: Rheumatoid arthritis SF, osteoarthritis SF, psoriatic arthritis SF, human chondrocytes and endothelial cells were stimulated in vitro with different FFA. Immunoassays were used to quantify FFA-induced protein secretion. TLR4 signalling was inhibited extracellularly and intracellularly. Fatty acid translocase (CD36), responsible for transporting long-chain FFA into the cell, was also inhibited. RESULTS: In rheumatoid arthritis synovial fibroblasts (RASF), FFA dose-dependently enhanced the secretion of the proinflammatory cytokine IL-6, the chemokines IL-8 and MCP-1, as well as the matrix-degrading enzymes pro-MMP1 and MMP3. The intensity of the response was mainly dependent on the patient rather than on the type of disease. Both saturated and unsaturated FFA showed similar effects on RASF, while responses to the different FFA varied for human chondrocytes and endothelial cells. Extracellular and intracellular TLR4 inhibition as well as fatty acid transport inhibition blocked the palmitic acid-induced IL-6 secretion of RASF. CONCLUSIONS: The data show that FFA are not only metabolic substrates but may also directly contribute to articular inflammation and degradation in inflammatory joint diseases. Moreover, the data suggest that, in RASF, FFA exert their effects via TLR4 and require extracellular and intracellular access to the TLR4 receptor complex.
24029000 Incidence of tuberculosis among anti-tumor necrosis factor users in patients with a previo 2013 Nov BACKGROUND: We aimed to investigate the results of anti-tumor necrosis factor (TNF) therapy in patients with a previous history of tuberculosis (TB). METHODS: A total of 101 patients with a previous history of TB receiving TNF antagonists between December 2004 and September 2012 at the Asan Medical Center in South Korea were retrospectively analyzed. RESULTS: The mean age of the 101 subjects was 40.4 ± 16.0 years and 51 patients (50.5%) were male. The underlying immune-mediated inflammatory diseases (IMIDs) were Crohn's disease in 55 (54.5%), rheumatoid arthritis in 27 (26.7%), and ankylosing spondylitis in 13 (12.9%) patients. Chest radiography findings were suggestive of previous TB lesions in 33 (32.7%) patients. The rates of positivity in the tuberculin skin test and interferon-gamma release assay were 21.8% (22/101) and 44.6% (45/101), respectively. Latent TB infection (LTBI) treatment was initiated in 11 subjects (10.9%) based on previous inappropriate anti-TB treatments (n = 10) or recent TB contact history (n = 1), irrespective of the LTBI test results. The median follow-up duration after the initiation of TNF antagonist therapy was 31.5 months. Active TB developed, six years after the initiation of TNF antagonist, in one patient (1.0%) who had not received LTBI treatment. The incidence rate of TB was calculated at 336 per 100,000 person-year (PY). CONCLUSIONS: Patients with IMIDs who have a previous history of TB can be treated with TNF antagonists with an acceptable incidence of TB, if LTBI treatment is performed based on clinical judgments including the adequacy of previous anti-TB treatment and recent contact history.
25014791 Immunochip identifies novel, and replicates known, genetic risk loci for rheumatoid arthri 2014 Aug 14 The aim of this study was to identify genetic variants associated with rheumatoid arthritis (RA) risk in black South Africans. Black South African RA patients (n = 263) were compared with healthy controls (n = 374). Genotyping was performed using the Immunochip, and four-digit high-resolution human leukocyte antigen (HLA) typing was performed by DNA sequencing of exon 2. Standard quality control measures were implemented on the data. The strongest associations were in the intergenic region between the HLA-DRB1 and HLA-DQA1 loci. After conditioning on HLA-DRB1 alleles, the effect in the rest of the extended major histocompatibility (MHC) diminished. Non-HLA single nucleotide polymorphisms (SNPs) in the intergenic regions LOC389203|RBPJ, LOC100131131|IL1R1, KIAA1919|REV3L, LOC643749|TRAF3IP2, and SNPs in the intron and untranslated regions (UTR) of IRF1 and the intronic region of ICOS and KIAA1542 showed association with RA (p < 5 × 10(-5)). Of the SNPs previously associated with RA in Caucasians, one SNP, rs874040, locating to the intergenic region LOC389203|RBPJ was replicated in this study. None of the variants in the PTPN22 gene was significantly associated. The seropositive subgroups showed similar results to the overall cohort. The effects observed across the HLA region are most likely due to HLA-DRB1, and secondary effects in the extended MHC cannot be detected. Seven non-HLA loci are associated with RA in black South Africans. Similar to Caucasians, the intergenic region between LOC38920 and RBPJ is associated with RA in this population. The strong association of the R620W variant of the PTPN22 gene with RA in Caucasians was not replicated since this variant was monomorphic in our study, but other SNP variants of the PTPN22 gene were also not associated with RA in black South Africans, suggesting that this locus does not play a major role in RA in this population.
24816639 Knockdown of sphingosine kinase 1 inhibits the migration and invasion of human rheumatoid 2014 Aug To investigate the potential regulation of sphingosine kinase 1 (SPHK1) on the migration, invasion, and matrix metalloproteinase (MMP) expression in human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). RA-FLS were transfected control siRNA or SPHK1 siRNA. The migration and invasion of unmanipulated control, control siRNA or SPHK1 siRNA- transfected RA-FLS in vitro were measured by the transwell system. The relative levels of SPHK1, PI3K, and AKT as well as AKT phosphorylation in RA-FLS were determined by Western blot. The levels of MMP-2/9 secreted by RA-FLS were detected by ELISA. Knockdown of SPHK1 significantly inhibited the spontaneous migration and invasion of RA-FLS, accompanied by significantly reduced levels of PI3K expression and AKT phosphorylation. Similarly, treatment with LY294002, an inhibitor of the PI3K/AKT pathway, inhibited the migration and invasion of RA-FLS. Knockdown of SPHK1 and treatment with the inhibitor synergistically inhibited the migration and invasion of RA-FLS, by further reducing the levels of PI3K expression and AKT phosphorylation. In addition, knockdown of SPHK1 or treatment with LY294002 inhibited the secretion of MMP-2 and MMP-9, and both synergistically reduced the production of MMP-2 and MMP-9 in RA-FLS in vitro. Knockdown of SPHK1 expression inhibits the PI3K/AKT activation, MMP-2 and MMP-9 expression, and human RA-FLS migration and invasion in vitro. Potentially, SPHK1 may be a novel therapeutic target for RA.
24287198 Management of extraglandular manifestations of primary Sjögren's syndrome. 2014 Feb Primary Sjögren's syndrome can have multiple extra-glandular manifestations ranging from mild to severe. Treatment for extra-glandular manifestations is organ specific and therapies are targeted based on the primary organs involved. Preferred treatment options used for extra-glandular manifestations of Sjögren's syndrome are usually extrapolated from the physician's experience in treating similar manifestations in other autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematous. The lack of immunomodulating disease modifying drugs in Sjögren's syndrome can be frustrating for patients dealing with extra-glandular manifestations, however recent advances in the field has made the future look promising for new therapeutic options.
25268197 Neutrophilic panniculitis: algorithmic approach to a heterogeneous group of disorders. 2014 Oct CONTEXT: Neutrophilic panniculitis encompasses an etiologically and morphologically heterogeneous group of disorders. Correct histopathologic diagnosis is important in identifying certain systemic diseases and guiding appropriate treatment. OBJECTIVE: To review the clinical and histopathologic features of different types of neutrophilic panniculitis, and to provide a diagnostic algorithm for these disorders. DATA SOURCES: A review of the literature with emphasis on the distinguishing features of different entities was performed. CONCLUSIONS: Evaluation for neutrophilic panniculitis entails paying close attention to the pattern of inflammation, the type of fat necrosis present, any evidence of vascular damage, and other relevant histopathologic features. An algorithmic approach integrating all histopathologic, clinical, and laboratory findings is required for correct diagnosis.
23460074 Changes in lipoproteins associated with methotrexate or combination therapy in early rheum 2013 Jun OBJECTIVE: To study changes in lipid profiles at 24 weeks among patients with early rheumatoid arthritis (RA) participating in the Treatment of Early RA (TEAR) trial and randomized to receive methotrexate (MTX) plus etanercept, triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or aggressively titrated MTX monotherapy. METHODS: This TEAR substudy included 459 participants with biologic specimens. Serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were measured at 0 and 24 weeks. RESULTS: At 24 weeks, there were statistically significant increases in mean cholesterol levels in the MTX plus etanercept, triple therapy, and MTX monotherapy arms. The observed increases were 31.4 mg/dl, 28.7 mg/dl, and 30 mg/dl in LDL cholesterol, 19.3 mg/dl, 22.3 mg/dl, and 20.6 mg/dl in HDL cholesterol, and 56.8 mg/dl, 53 mg/dl, and 57.3 mg/dl in total cholesterol (P < 0.0001 versus baseline for each comparison). There was a statistically significant decrease in the ratio of total cholesterol to HDL cholesterol at 24 weeks in all 3 treatment groups versus baseline. There was no difference in any lipid changes between the 3 treatment arms. After multivariable adjustment, change in C-reactive protein, but not the Disease Activity Score in 28 joints, was associated with change in LDL cholesterol (P = 0.03) and total cholesterol (P = 0.01). Baseline glucocorticoid use was associated with changes in HDL cholesterol (P = 0.03) and total cholesterol (P = 0.02). CONCLUSION: Levels of total cholesterol, LDL cholesterol, and HDL cholesterol increased comparably shortly after initiation of MTX plus etanercept, triple therapy, and MTX monotherapy among patients with early RA with active disease participating in a clinical trial. The clinical relevance of short-term changes in traditional lipids on cardiovascular outcomes remains to be determined.