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ID PMID Title PublicationDate abstract
26238620 Novel biomarkers of atherosclerosis and cardiovascular risk in autoimmune diseases: Genomi 2009 Feb Atherosclerosis (AT) and cardiovascular disease (CVD) are enhanced in autoimmune diseases such as antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). The reason for this accelerated process is still debatable and, although traditional risk factors are more prevalent in those patients than in general population, they do not fully explain that enhanced risk. Inflammatory components of the immune response, mainly interleukins, TNF-α, and IFN-γ, as well as some autoantibodies, including anti-oxidized low density lipoproteins (anti-oxLDL), anti-beta-2-Glycoprotein 1 (anti- β2GPI), anti-Heat shock proteins 60/65 (anti-HSP60/65), and anti-oxLDL/β2GPI have been shown to play a leading role in the pathogenesis of both, AT and CVD. However, the role of the autoantibodies in accelerated AT in autoimmune disease patients is still controversial. Recently, DNA microarray and proteomic-based approaches have made substantial breakthrough into the study of various rheumatic diseases, thus allowing for the discovery of previously unknown proteins involved in CVD including some that may be suitable to be used as biomarkers. Herein, we review recent genomics and proteomic approaches that have been applied to the study of autoimmune diseases with atherosclerotic and CV risk. The pharmacogenomics and pharmacoproteomics studies given over to the analysis of ancient and new drugs used to relieve the physiopathology associated to these complex diseases are also discussed.
20664576 Attenuation of TNF-driven murine ileitis by intestinal expression of the viral immunomodul 2010 Nov Tumor necrosis factor α (TNFα) is a key pathogenic factor in Crohn's disease and rheumatoid arthritis. TNF(ΔARE) mice express high levels of TNFα and present Crohn's-like ileitis and arthritis. Alterations in the chemokine network could underline the TNF-driven ileitis. The aim of this study was to evaluate the role of TNF and chemokines in ileitis using ectromelia virus cytokine response modifier D (CrmD), a protein that binds TNFα and a limited number of chemokines. We generated transgenic mice expressing CrmD in intestinal epithelial cells (vCrmD mice) and crossed them with the TNF(ΔARE) mice to test whether CrmD could affect TNF-driven inflammatory processes. During homeostasis, only the number of B cells in the lamina propria was reduced by CrmD expression. Interestingly, CrmD expression in the intestine markedly attenuated the inflammatory infiltrates in the ileum of TNF(ΔARE) mice, but did not affect development of arthritis. Our results suggest that CrmD affects development of ileitis by locally affecting both TNF and chemokine function in the ileum.
20955443 Risk factors for NSAID-associated upper GI clinical events in a long-term prospective stud 2010 Nov BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAID)-related GI effects vary based on patient characteristics. AIMS: To assess risk factors for NSAID-associated upper GI clinical events and dyspepsia. METHODS: Patients ≥50 years with osteoarthritis or rheumatoid arthritis were randomized to etoricoxib or diclofenac in a prespecified intent-to-treat analysis of three double-blind randomized trials. Potential risk factors for upper GI clinical events (bleeding, perforation, obstruction, or ulcer), complicated events (perforation, obstruction, bleeding) and discontinuations due to dyspepsia were assessed with Cox proportional hazard models. RESULTS: Significant predictors of clinical events and complicated events included age ≥65 years [hazards ratios (HRs) = 2.25 (1.84-2.76), 4.09 (2.82-5.92)], prior event [HRs = 2.57 (1.94-3.39), 3.23 (2.09-5.00)], low-dose aspirin [HRs = 2.34 (1.87-2.92), 3.41 (2.33-5.00)] and corticosteroid [HRs = 1.85 (1.41-2.43), 2.09 (1.29-3.38)]. Predictors of discontinuation due to dyspepsia included prior dyspepsia [HR = 1.78 (1.44-2.00)], prior event [HR = 1.78 (1.40-2.27)] and age ≥65 years [HR = 1.35 (1.16-1.57)]. CONCLUSIONS: Assessment for age ≥65 years, prior upper GI clinical events and low-dose aspirin use are key in identifying patients who should either avoid NSAIDs or employ management strategies to reduce NSAID-associated upper GI events. Prior dyspepsia or upper GI clinical events and age ≥65 years also predict an increased risk of developing dyspepsia severe enough to necessitate discontinuation of NSAIDs.
21572631 Use of recombinant human bone morphogenetic protein-2 as an adjunct for instrumented poste 2010 Jul BACKGROUND: There have been few reports on the use of recombinant human bone morphogenetic protein (rhBMP)-2 in posterior spine. However, no study has investigated the dosing, safety, and efficacy of its use in the posterior atlantoaxial, and/or craniovertebral junction. Recent case report of the cytokine-mediated inflammatory reaction, following off label use of rhBMP-2 as an adjunct for cervical fusion, particularly in complex cases, has increased concern about complications associated with the product. OBJECTIVE: To assess the safety, efficacy, and dosing of rhBMP-2 as an adjunct for instrumented posterior atlantoaxial and/or craniovertebral junction arthrodesis. MATERIALS AND METHODS: We included all patients treated by the senior author that included posterior atlantoaxial and/or craniovertebral junction instrumented fusion using rhBMP-2 from 2003 to 2008 with a minimum two year follow-up. Diagnosis, levels fused, rhBMP-2 dose, complications, and fusion were assessed. RESULTS: Twenty three patients with a mean age of 60.9 years (range 4 - 89 years) and an average follow-up of 45 months (range 27 to 84 months) met inclusion criteria. The indications for surgery included, atlantoaxial instability (n = 16), basilar invagination (n = 6), and kyphoscoliosis (n = 1). The specific pathologic diagnosis included type 2 dens fracture (n = 7), complex C1 and C2 ring fracture (n = 2), chordoma (n = 2), degenerative/osteoporosis (n = 3), rheumatoid disease (n = 8), and pseudogout (n = 1). The average rhBMP-2 dose was 2.38 mg/level, with a total of 76 levels treated (average 3.3 levels, SD= 1.4 levels). There were no complications. During the most recent follow-up, all patients had achieved fusion. CONCLUSIONS: In a series of patients with complex pathology and/or rheumatoid arthritis, 100% fusion rate was achieved with adjunct use of rhBMP-2, with a safe and effective average rhBMP-2 dose of 2.38 mg per level.
19505573 Cyclic AMP regulates extracellular matrix gene expression and metabolism in cultured prima 2009 Jul In osteo- and rheumatoid arthritis, the synovial fluid surrounding chondrocytes contains increased levels of prostaglandin E(2) (PGE(2)), an agent known to elevate intracellular cyclic AMP (cAMP). However, the effect of PGE(2)/cAMP on mRNA expression in chondrocytes is largely unknown. In this report, we assess the effect of the cell-permeable cAMP analog adenosine 8-(4-chloro-phenylthio)-3',5'-cyclic monophosphate (CPT-cAMP) and PGE(2) on mRNA expression in primary neonatal rat chondrocytes. CPT-cAMP decreased type II collagen, link protein, parathyroid hormone/parathyroid hormone-related peptide receptor and alkaline phosphatase, increased glyceraldehyde-3-phosphate dehydrogenase mRNA and lactate efflux, but did not alter type X collagen or aggrecan mRNA. The effect of CPT-cAMP on type II collagen and link protein mRNAs and chondrocyte metabolism were attenuated by the transcriptional inhibitor actinomycin D, indicating that the ability of CPT-cAMP to suppress mRNA expression was not due to alterations in mRNA stability, but were instead likely due to transcriptional mechanisms. CPT-cAMP-treatment induced GSK3 beta phosphorylation and beta-catenin-mediated transcriptional activity. Pharmacological inhibition of GSK3 beta paralleled the effects of CPT-cAMP on type II collagen, link protein and chondrocyte metabolism, suggesting that the effect of CPT-cAMP on chondrocytes may be GSK3 beta/beta-catenin-dependent. The effects of CPT-cAMP on beta-catenin-mediated transcription, cell metabolism and mRNA expression were mimicked by the cAMP-elevating agent PGE(2), providing a physiologically relevant context for our studies. Collectively, these results suggest that agents that elevate cAMP signaling may impair chondrocyte function in conditions such as arthritis.
20713891 Evolution of ectopic lymphoid neogenesis and in situ autoantibody production in autoimmune 2010 Sep 15 A pivotal role for tertiary lymphoid structures (TLSs) in promoting Ag-specific humoral responses during chronic inflammation is emerging in several autoimmune conditions, including rheumatoid arthritis, Sjogren's syndrome, and autoimmune thyroiditis. However, there is limited evidence on the cellular and molecular mechanisms underlying TLS formation and their contribution to autoimmunity in the pancreas during autoimmune insulitis. In this study, we performed a detailed and comprehensive assessment of the evolution of TLSs during autoimmune insulitis in 126 female NOD mice from 4 to 38 wk of age. We demonstrated that during progression from peri- to intrainsulitis in early diabetic mice, T and B cell infiltration follows a highly regulated process with the formation of lymphoid aggregates characterized by T/B cell segregation, follicular dendritic cell networks, and differentiation of germinal center B cells. This process is preceded by local upregulation of lymphotoxins alpha/beta and lymphoid chemokines CXCL13 and CCL19, and is associated with infiltration of B220(+)/IgD(+)/CD23(+)/CD21(-) follicular B cells expressing CXCR5. Despite a similar incidence of insulitis, late diabetic mice displayed a significantly reduced incidence of fully organized TLSs and reduced levels of lymphotoxins/lymphoid chemokines. Upon development, TLSs were fully functional in supporting in situ autoreactive B cell differentiation, as demonstrated by the expression of activation-induced cytidine deaminase, the enzyme required for Ig affinity maturation and class switching, and the presence of CD138(+) plasma cells displaying anti-insulin reactivity. Overall, our work provides direct evidence that TLSs are of critical relevance in promoting autoimmunity and chronic inflammation during autoimmune insulitis and diabetes in NOD mice.
20635230 Comparison of health-related quality of life and associated psychological factors between 2010 Sep OBJECTIVES: To compare health-related quality of life (HRQOL) between younger and older patients with established rheumatic disorders and to assess the relative impact of a number of psychosocial parameters on HRQOL. METHODS: In a cross-sectional study of 320 patients (245 < 65 and 75 > or = 65 years old, response rate: 74.9%) with various rheumatic disorders (rheumatoid arthritis, 168; systemic lupus, 56; scleroderma, 56; and Sjogren's syndrome, 40) attending a follow-up clinic, HRQOL was assessed by the WHOQOL-BREF. Functional limitations (Health Assessment Questionnaire), psychological distress (Symptom Distress Checklist-90-R), defense mechanisms (Defense Style Questionnaire and Life Style Index), sense of coherence, and interpersonal difficulties (Inventory of Interpersonal Problems-40) were also assessed. RESULTS: Older patients presented more impaired physical HRQOL (p = 0.018) and social relationships HRQOL (p = 0.041) independent of disease type, education, and pain. Functional limitations were more prominent in the older group (p = 0.030). Pain, functional limitations, and psychological distress were independently associated with physical HRQOL in both groups. Psychological distress was the only common independent correlate of social relationships HRQOL. Personality factors were significant correlates of physical and social relationships HRQOLs only in the younger group, while the impact of pain in physical HRQOL was greater for younger than older patients, as shown by a moderator analysis. CONCLUSION: Older patients with rheumatic diseases experience more impaired HRQOL than the younger ones, and the management and prevention of functional limitations and psychological distress should be a priority, since they are strongly associated with HRQOL. Pain also warrants attention in all age groups, but especially in younger patients. Personality factors impact on HRQOL in younger patients, and this might be relevant to psychological interventions.
20637100 Risk factors for total joint arthroplasty infection in patients receiving tumor necrosis f 2010 INTRODUCTION: The objective of this study was to assess natural microbial agents, history and risk factors for total joint arthroplasty (TJA) infections in patients receiving tumor necrosis factor (TNF)α-blockers, through the French RATIO registry and a case-control study. METHODS: Cases were TJA infections during TNFα-blocker treatments. Each case was compared to two controls (with TJA and TNFα-blocker therapy, but without TJA infection) matched on age (±15 years), TJA localization, type of rheumatic disorder and disease duration (±15 years). Statistical analyses included univariate and multivariate analyses with conditional logistic regression. RESULTS: In the 20 cases (18 rheumatoid arthritis), TJA infection concerned principally the knee (n = 12, 60%) and the hip (n = 5, 25%). Staphylococcus was the more frequent microorganism involved (n = 15, 75%). Four patients (20%) were hospitalized in an intensive care unit and two died from infection. Eight cases (40%) versus 5 controls (13%) had undergone primary TJA or TJA revision for the joint subsequently infected during the last year (P = 0.03). Of these procedures, 5 cases versus 1 control were performed without withdrawing TNFα-blockers (P = 0.08). In multivariate analysis, predictors of infection were primary TJA or TJA revision for the joint subsequently infected within the last year (odds ratio, OR = 88.3; 95%CI 1.1-7,071.6; P = 0.04) and increased daily steroid intake (OR = 5.0 per 5 mg/d increase; 1.1-21.6; P = 0.03). Case-control comparisons showed similar distribution between TNFα-blockers (P = 0.70). CONCLUSIONS: In patients receiving TNFα-blockers, TJA infection is rare but potentially severe. Important risk factors are primary TJA or TJA revision within the last year, particularly when TNFα-blockers are not interrupted before surgery, and the daily steroid intake.
20600535 Luteolin suppresses IL-1beta-induced cytokines and MMPs production via p38 MAPK, JNK, NF-k 2010 Oct Matrix metalloproteinases (MMPs) play an important role in tissue degradation in rheumatoid synovium and inflammatory cytokines are essential in the pathogenesis of rheumatoid arthritis (RA). This study was conducted to evaluate the efficacy of luteolin in regulating interleukin-1beta (IL-1beta)-induced production of MMPs (MMP-1 and -3) and cytokines (tumor necrosis factor (TNF)-alpha and IL-6) in human synovial cell line, SW982. Treatment with luteolin at 1 or 10 microM significantly (P<0.05) inhibited IL-1beta-induced MMPs (MMP-1 and -3) and cytokines (TNF-alpha and IL-6) production when measured by enzyme-linked immunosorbent assay (ELISA). The mitogen-activated protein kinases (MAPKs) represent an attractive target for RA because they can regulate MMP and cytokine expression. The effects of luteolin on the activation of MAPKs and transcription factors were also examined in SW982 cells by ELISA. IL-1beta-induced JNK and p38 activation were inhibited by luteolin. Moreover, IL-1beta-induced activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) activation were inhibited by luteolin. These results suggest that luteolin reduces the production of MMPs and cytokines in SW982 cells by inhibiting MAPKs (JNK and p38) and transcription factors (AP-1 and NF-kappaB).
20096020 Is there progressive cognitive dysfunction in Sjögren Syndrome? A preliminary study. 2010 Sep OBJECTIVE: The aim of this study was to determine the progression of cognitive dysfunction in primary Sjögren Syndrome (SS). METHODS: Twelve subjects with SS were compared with ten subjects with migraine and ten healthy controls on neuropsychological, mood and fatigue tests at baseline and 8 years later. RESULTS: At follow-up, SS subjects performed below subjects with migraine on the Continuous Performance Test (CPT) but did not differ on other tasks. Compared with controls, both clinical groups obtained lower scores on simple reaction time, patients with SS obtained lower scores on the Wisconsin Card Sorting Test (WCST) and patients with migraine performed below controls on the Benton's Judgment of Line Orientation Test (JOLO). Clinical groups did not differ on cognitive changes over time, except that migraine subjects improved on verbal fluency. Compared with baseline, both SS and migraine patients were more impaired on simple reaction time, Trail Making Test part B, Stroop and JOLO. However, they showed higher scores on verbal and visual memory, WCST and CPT reaction time. SS also showed higher levels of depression and fatigue than migraine and controls, with no significant changes over time. DISCUSSION: Preliminary evidence indicates some cognitive deficits in both SS and migraine following a pattern of fronto-subcortical dysfunction without a significant cognitive decline over time.
19464655 Atrophic change of tongue papilla in 44 patients with Sjögren syndrome. 2009 Jun OBJECTIVE: The purpose of this study was to investigate the atrophic change of tongue papilla in Sjögren syndrome (SjS) patients and the correlation with characteristic features of the disease. STUDY DESIGN: Atrophic change of tongue papilla, investigated by a digital microscope, was classified from score 0 (normal) to score 6 (severe) and compared among 44 SjS patients, 20 xerostomia patients, and 20 healthy subjects. In SjS patients, correlation of the atrophic score of tongue papilla with characteristic changes in sialometry, sialography, lip biopsy, and serologic tests was also investigated. RESULTS: The atrophic score of tongue papilla was significantly higher in SjS patients and correlated with the decrease of salivary secretion, the stage on sialography, and the histologic grade of the minor salivary gland. CONCLUSION: Atrophic change of tongue papilla is significant in SjS patients and is correlated with the characteristic features of the disease.
19116902 Systems biology analysis of Sjögren's syndrome and mucosa-associated lymphoid tissue lymp 2009 Jan OBJECTIVE: To identify key target genes and activated signaling pathways associated with the pathogenesis of Sjögren's syndrome (SS) by conducting a systems analysis of parotid glands manifesting primary SS or primary SS/mucosa-associated lymphoid tissue (MALT) lymphoma phenotypes. METHODS: A systems biology approach was used to analyze parotid gland tissue samples obtained from patients with primary SS, patients with primary SS/MALT lymphoma, and subjects without primary SS (non-primary SS controls). The tissue samples were assessed concurrently by gene-expression microarray profiling and proteomics analysis, followed by weighted gene-coexpression network analysis. RESULTS: Gene-coexpression modules related to primary SS and primary SS/MALT lymphoma were significantly enriched with genes known to be involved in the immune/defense response, apoptosis, cell signaling, gene regulation, and oxidative stress. Detailed functional pathway analyses indicated that primary SS-associated modules were enriched with genes involved in proteasome degradation, apoptosis, signal peptides of the class I major histocompatibility complex (MHC), complement activation, cell growth and death, and integrin-mediated cell adhesion, while primary SS/MALT lymphoma-associated modules were enriched with genes involved in translation, ribosome biogenesis and assembly, proteasome degradation, class I MHC signal peptides, the G13 signaling pathway, complement activation, and integrin-mediated cell adhesion. Combined analyses of gene expression and proteomics data implicated 6 highly connected "hub" genes for distinguishing primary SS from non-primary SS, and 8 hub genes for distinguishing primary SS/MALT lymphoma from primary SS. CONCLUSION: Systems biology analyses of the parotid glands from patients with primary SS and those with primary SS/MALT lymphoma revealed pathways and molecular targets associated with disease pathogenesis. The identified gene modules/pathways provide further insights into the molecular mechanisms of primary SS and primary SS/MALT lymphoma. The identified disease-hub genes represent promising targets for therapeutic intervention, diagnosis, and prognosis.
19429722 Minor salivary gland biopsy to detect primary Sjogren syndrome in patients with interstiti 2009 Oct PURPOSES: To describe a cohort of patients who presented with interstitial lung disease (ILD) of unknown cause, features of primary Sjögren syndrome (pSS), and a positive minor salivary gland biopsy (MSGB). METHODS: Thirty-eight patients with ILD evaluated at our center underwent an MSGB to confirm a diagnosis of pSS. All of the samples were reviewed by pathologists experienced in the evaluation of salivary gland histology. We defined a positive MSGB finding as a lymphocyte focus score of >1. RESULTS: At presentation, all patients had ILD, and symptoms of cough and dyspnea. None had a definable connective tissue disease (CTD) or known cause for their ILD. Thirteen patients (34%) had positive MSGB findings. Of these, the median age was 61 years (age range, 33 to 75 years); 7 patients (54%) were women; 8 patients (62%) had a smoking history; and 10 patients (77%) had sicca symptoms. In all patients, a thoracic high-resolution CT scan evaluation demonstrated bibasilar, peripheral-predominant, ground-glass, and reticular opacities. Four patients (31%) were negative for both antinuclear autoantibody (ANA) and rheumatoid factor (RF) autoantibody, and three patients (23%) were negative for ANA, RF, Sjögren syndrome (SS)-A, and SS-B autoantibodies. No patients experienced any complications from the MSGB. The identification of underlying pSS did not affect the management of ILD in these patients. CONCLUSIONS: Confirming a diagnosis of pSS-related ILD by performing MSGB allows for a more precise CTD classification. This study provides evidence that CTD may exist subclinically, and longitudinal studies are needed to determine whether identifying occult CTD impacts on management, longitudinal changes in lung function, or survival.
21319021 Syndrome of inappropriate antidiuretic hormone secretion in patients with adult Still's di 2010 Apr 20 Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a rare complication of adult Still's disease (ASD). We experienced a male ASD patient who complained of arthralgia and intermittent fever. Chest radiograph and pleural fluid analysis revealed pleurisy with effusion. We diagnosed this patient with SIADH and confirmed the disappearance of hyponatremia and pleurisy after starting treatment with nonsteroidal anti-inflammatory drugs. In this study, we reviewed previous literature and the case of our ASD patient with hyponatremia. This reported case is the fourth case of SIADH in an ASD patient. Further, we found that hyponatremia is a relatively common complication of ASD, and pleurisy has a possibility to develop SIADH in patients with ASD.
20629708 Autoimmune response and target autoantigens in Sjogren's syndrome. 2010 Nov BACKGROUND: Primary Sjogren's syndrome (pSS) is characterized by the presence of autoantibodies targeting mainly the Ro/La ribonucleoprotein complex. It is now appreciated that the production of autoantibodies is an antigen-driven immune response. DESIGN: In this review, candidate mechanisms for autoantigen presentation and perpetuation of the autoimmune response within the autoimmune tissue lesion of pSS are discussed. RESULTS: Several studies have shown that the epithelial cell in labial salivary glands of patients with Sjogren's syndrome is activated, bearing characteristics of an antigen-presenting cell, as suggested by inappropriate expression of class II HLA and co-stimulatory molecules. Other studies have confirmed that in salivary glands, there is an increased autoantigen presentation via apoptotic blebs and bodies, exosomes and heat shock protein-mediated cross-priming. There is also an increased expression of interferon (IFN)-induced genes, such as the autoantigen Ro52, which provide negative feedback regulation in inflammation. Ro60 and La autoantigens also appear to play a major role in the local autoimmune response in Sjogren's syndrome. In this regard, La and Ro60 the messenger RNA (mRNA) expression is upregulated in the affected salivary glands with different isoforms of La autoantigen mRNA to be expressed in patients with pSS. At the protein level, La/SSB in pSS salivary glands is found to be post-translationally modified. CONCLUSIONS:  Autoantigen alterations in a microenvironment of local inflammation with increased in situ apoptosis, Toll-like receptor (TLR) signalling and antigen presentation may drive the autoimmune response and local autoantibody production in pSS.
22918070 Saliva as a potential diagnostic tool. 2010 Jul Saliva is a complex fluid consisting of secretions from the major and minor salivary glands. Gland-specific saliva can be used to diagnose any pathology from the specific major salivary gland. Whole saliva has serum constituents that are derived from the local vasculature of the salivary glands and gingival crevicular fluid. Saliva, as a diagnostic fluid, has distinctive advantages over serum as whole saliva can be collected non-invasively by individuals with limited training using simple equipments. This review aimed to explore the diagnostic applications of saliva in systemic and oral diseases. Analysis of saliva can offer a cost-effective approach to screen for a larger population. Salivary analysis may be useful for diagnosing systemic oral disorders, as well as for monitoring hormone and therapeutic levels of drug.
20034891 [Analysis of the risk factors of community-acquired pneumonia in patients with primary Sjo 2009 Dec OBJECTIVE: To investigate the risk factors of community-acquired pneumonia (CAP) in patients with primary Sjogren's syndrome (pSS). METHODS: The clinical data were collected from 121 inpatients with pSS and univariate analysis and logistic regression were conducted to analyze the risk factors of CAP. RESULTS: The incidence of CAP in the 121 patients with pSS was 27.3%. Age, disease course, low while blood cells, low complement levels, liver and kidney dysfunction, low albumin, hyperglobulinaemia, renal tubule acidosis, interstitial lung disease (ILD) and immunosuppressive agents were closely related to CAP in these patients. Logistic regression analysis identified ILD, low complement levels and hyperglobulinemia as the risk factors for CAP in patients with pSS. CONCLUSION: Vigorous control of pSS and minimizing the risk factors may prove effective to lower the incidence of CAP in patients with pSS.
19565513 Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopa 2009 Jul OBJECTIVE: To identify differences in peripheral blood gene expression between patients with different subclasses of juvenile idiopathic arthritis (JIA) and healthy controls in a multicenter study of patients with recent-onset JIA prior to treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents. METHODS: Peripheral blood mononuclear cells (PBMCs) from 59 healthy children and 136 patients with JIA (28 with enthesitis-related arthritis [ERA], 42 with persistent oligoarthritis, 45 with rheumatoid factor [RF]-negative polyarthritis, and 21 with systemic disease) were isolated from whole blood. Poly(A) RNA was labeled using a commercial RNA amplification and labeling system (NuGEN Ovation), and gene expression profiles were obtained using commercial expression microarrays (Affymetrix HG-U133 Plus 2.0). RESULTS: A total of 9,501 differentially expressed probe sets were identified among the JIA subtypes and controls (by analysis of variance; false discovery rate 5%). Specifically, 193, 1,036, 873, and 7,595 probe sets were different in PBMCs from the controls compared with those from the ERA, persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA patients, respectively. In patients with persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA subtypes, up-regulation of genes associated with interleukin-10 (IL-10) signaling was prominent. A hemoglobin cluster was identified that was underexpressed in ERA patients but overexpressed in systemic JIA patients. The influence of JAK/STAT, ERK/MAPK, IL-2, and B cell receptor signaling pathways was evident in patients with persistent oligoarthritis. In systemic JIA, up-regulation of innate immune pathways, including IL-6, Toll-like receptor/IL-1 receptor, and peroxisome proliferator-activated receptor signaling, were noted, along with down-regulation of gene networks related to natural killer cells and T cells. Complement and coagulation pathways were up-regulated in systemic JIA, with a subset of these genes being differentially expressed in other subtypes as well. CONCLUSION: Expression analysis identified differentially expressed genes in PBMCs obtained early in the disease from patients with different subtypes of JIA and in healthy controls, providing evidence of immunobiologic differences between these forms of childhood arthritis.
19684849 Drugs Used in the Treatment of Rheumatoid Arthritis: Relationship between Current Use and 2009 Jun OBJECTIVES: Drugs used for the treatment of rheumatoid arthritis (RA) have the potential to affect cardiovascular risk factors. There is concern that corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors could affect cardiovascular risk adversely, while drugs such as the antimalarial, hydroxychloroquine, may have beneficial effects. However, there is limited information about cardiovascular risk factors in patients with RA receiving different drugs. METHODS: We measured cardiovascular risk factors including systolic and diastolic blood pressure, serum HDL and LDL cholesterol, glucose and homocysteine concentrations and urinary F(2)-isoprostane excretion in 169 patients with RA. Risk factors were compared according to current use of corticosteroids, methotrexate, antimalarials, NSAIDs, COX-2 inhibitors, leflunomide and TNF-alpha blockers. Comparisons were adjusted for age, sex, race, disease activity (DAS28 score), current hypertension, diabetes, smoking status and statin use. RESULTS: No cardiovascular risk factor differed significantly among current users and non-users of NSAIDs, COX-2 inhibitors, methotrexate and TNF-alpha blockers. Serum HDL cholesterol concentrations were significantly higher in patients currently receiving corticosteroids (42.2 +/- 10.5 vs. 50.2 +/- 15.3 mg/dL, adjusted P < 0.001). Diastolic blood pressure (75.9 +/- 11.2 vs. 72.0 +/- 9.1 mm Hg, adjusted P = 0.02), serum LDL cholesterol (115.6 +/- 34.7 vs. 103.7 +/- 27.8 mg/dL, adjusted P = 0.03) and triglyceride concentrations (157.7 +/- 202.6 vs. 105.5 +/- 50.5 mg/dL, adjusted P = 0.03) were significantly lower in patients taking antimalarial drugs. Plasma glucose was significantly lower in current lefunomide users (93.0 +/- 19.2 vs. 83.6 +/- 13.4 mg/dL, adjusted P = 0.006). CONCLUSIONS: In a cross-sectional setting drugs used to treat RA did not have major adverse effects on cardiovascular risk factors and use of antimalarials was associated with beneficial lipid profiles.
20617528 Inhibition of T cell-dependent and RANKL-dependent osteoclastogenic processes associated w 2010 Nov OBJECTIVE: T cell production of RANKL, interferon-γ (IFNγ), and other cytokines in inflammatory processes such as rheumatoid arthritis or secondary to conditions such as estrogen deficiency stimulates osteoclast activity, which leads to bone resorption and bone loss. The purpose of this study was to characterize the effects of interleukin-15 (IL-15), a master T cell growth factor whose role in bone remodeling remains unknown. METHODS: We used mice lacking the IL-15 receptor (IL-15Rα(-/-) ) to investigate the effects of IL-15 on osteoclast development, T cell and dendritic cell activation in vitro and in vivo, bone mass, and microarchitecture in intact and ovariectomized (OVX) mice. RESULTS: In wild-type (WT) animals, IL-15 and RANKL provided a costimulatory signal for osteoclast development. Spleens from IL-15Rα(-/-) mice contained few c-Kit+ osteoclast precursors, and the expression of NF-ATc1 and the osteoclastogenic response to RANKL were impaired. In addition, dendritic cell-dependent and T cell-dependent mechanisms of osteoclast activation, including RANKL and IFNγ production, were impaired in IL-15Rα(-/-) mice. In turn, IL-15Rα(-/-) T cells failed to stimulate WT osteoclasts, whereas WT T cells failed to stimulate IL-15Rα(-/-) osteoclasts. Compared with WT mice, both intact and OVX IL-15Rα(-/-) mice had significantly greater bone mineral density and microarchitecture, including a higher trabecular bone volume fraction and cortical thickness. The numbers of osteoclasts on the bone surface as well as markers of bone turnover were significantly decreased in IL-15Rα(-/-) mice. CONCLUSION: In the absence of IL-15 signaling, several converging mechanisms of osteoclastogenesis are inhibited, both directly and indirectly, through T cells, which leads to a high bone mass phenotype. Targeting the IL-15 pathway may represent a novel therapeutic approach to treating primary and secondary osteoporosis.