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ID PMID Title PublicationDate abstract
26749999 [MID- AND LONG-TERM EFFECTIVENESS OF THIRD-GENERATION CERAMIC-ON-CERAMIC TOTAL HIP ARTHROP 2015 Sep OBJECTIVE: To analyze the mid- and long-term effectiveness of the 3rd-generation ceramic-on-ceramic (CoC) total hip arthroplasty (THA) in the younger patients. METHODS: A retrospective analysis was made on the clinical data of 68 younger patients (73 hips) who accepted the 3rd-generation CoC THA between March 2001 and May 2009. Of 68 cases, 39 was male and 29 was female with the average age of 38.6 years (range, 18-50 years); there were 15 cases (15 hips) of osteonecrosis of the femoral head, 9 cases (9 hips) congenital dysplasia of the hip, 5 cases (8 hips) of ankylosing spondylitis, 10 cases (10 hips) of osteoarthritis of the hip joint, 12 cases (12 hips) of traumatic hip arthritis, 12 cases (12 hips) of femoral neck fracture, 4 cases (6 hips) of rheumatoid hip arthritis, and 1 case (1 hip) of tumor of the femoral neck. The Harris score and University of California Los Angeles (UCLA) score were used to evaluate the hip joint function and activity level respectively. The visual analogue scale (VAS) was used to assess postoperative thigh pain. Radiological signs of osteolysis, loosening, and alumina ceramic related complications were evaluated continuously. And the Kaplan-Meier survival analysis was used to assess the prosthesis survival. RESULTS: The average duration of follow-up was 9.7 years (range, 6-14 years). Sandwich ceramic liners fracture was observed in 3 cases (3 hips), and revision was performed; 1 case had "squeaking" hip because of physical activity. At last follow-up, Harris score and UCLA score were significantly improved when compared with preoperative scores (P<0.05). Bony healing was obtained in all patients, without osteolysis, loosening, and thigh pain. The VAS score was 0. The 5-year and 10-year cumulative survival rates for ceramic fracture revision were 98.6% and 95.9%, and the 5-year and 10-year cumulative survival rates for osteolysis and loosening revision both were 100%. CONCLUSION: The 3rd-generation CoC prosthesis offer an excellent option for younger patients in THA and the mid- and long-term effectiveness are satisfactory.
26360530 Association of Elevations of Specific T Cell and Monocyte Subpopulations in Rheumatoid Art 2016 Jan OBJECTIVE: Coronary artery disease (CAD) is the leading cause of excess deaths in rheumatoid arthritis (RA). However, identification of features denoting patients with a risk of developing CAD is lacking. The composition of circulating peripheral blood mononuclear cell (PBMC) subsets in RA patients differs markedly from that in healthy controls with regard to the extent of T cell activation, with clonal expansion and differentiation to effector memory status, and presence of inflammatory monocytes. In this study, we sought to evaluate whether elevations in these PBMC subpopulations in RA patients could denote those with an increased risk of subclinical CAD, as determined by the presence of coronary artery calcification (CAC). METHODS: The study cohort comprised 72 patients with RA who underwent cardiac computed tomography to assess CAC. PBMC subsets were determined by multiparameter flow cytometry. Multivariable logistic regression was used to determine the associations between PBMC subpopulations and the presence of CAC. RESULTS: Among the 72 patients with RA, 33% had CAC and exhibited significant increases in the levels of circulating CD4 T cell subsets denoting activation and differentiation to the effector memory phenotypes. Analogous increases in the levels of CD8 T cell subsets, as well as in the CD14(high)CD16+ intermediate monocyte subset, were also present in these patients, as compared to those without CAC. The increases in the CD4 and CD8 T cell subsets were highly intercorrelated, whereas the increases in CD14(high)CD16+ monocytes were independent of elevations in the CD4 T cell subsets. After adjustments for relevant confounders, the levels of CD4+CD56+CD57+ T cells and CD14(high)CD16+ monocytes remained associated with the presence of CAC. CONCLUSION: These findings indicate that PBMC subsets are markers for the presence of CAC and suggest that mechanisms of atherogenesis in RA may operate in part through the elevations in these subsets, raising further questions about the mechanisms underlying the presence of such alterations in cell composition in patients with RA and the potential for shared etiologic pathways between RA and cardiovascular disease.
25989191 Ability of Interleukin-33- and Immune Complex-Triggered Activation of Human Mast Cells to 2015 Sep OBJECTIVE: Mast cells have been implicated in the pathogenesis of rheumatoid arthritis (RA). In particular, their activation by interleukin-33 (IL-33) has been linked to the development of arthritis in animal models. The aim of this study was to evaluate the functional responses of human mast cells to IL-33 in the context of RA. METHODS: Human mast cells were stimulated with IL-33 combined with plate-bound IgG or IgG anti-citrullinated protein antibodies (ACPAs), and their effects on monocyte activation were evaluated. Cellular interactions of mast cells in RA synovium were assessed by immunofluorescence analysis, and the expression of messenger RNA (mRNA) for mast cell-specific genes was evaluated in synovial biopsy tissue from patients with early RA who were naive to treatment with disease-modifying antirheumatic drugs. RESULTS: IL-33 induced the up-regulation of Fcγ receptor type IIa and enhanced the activation of mast cells by IgG, including IgG ACPAs, as indicated by the production of CXCL8/IL-8. Intriguingly, mast cell activation triggered with IL-33 and IgG led to the release of mediators such as histamine and IL-10, which inhibited monocyte activation. Synovial mast cells were found in contact with CD14+ monocyte/macrophages. Finally, mRNA levels of mast cell-specific genes were inversely associated with disease severity, and IL-33 mRNA levels showed an inverse correlation with the levels of proinflammatory markers. CONCLUSION: When human mast cells are activated by IL-33, an immunomodulatory phenotype develops, with human mast cells gaining the ability to suppress monocyte activation via the release of IL-10 and histamine. These findings, together with the presence of synovial mast cell-monocyte interactions and the inverse association between the expression of mast cell genes at the synovial level and disease activity, suggest that these newly described mast cell-mediated inhibitory pathways might have a functional relevance in the pathogenesis of RA.
24471764 Potential of capsaicin-loaded transfersomes in arthritic rats. 2015 In the present study, the biopotential of capsaicin (an active principle of capsicum) as a topical antiarthritic agent was studied in arthritic rats. Transfersomal vesicular system was employed for the topical administration of capsaicin in experimental rats. The characterization of prepared capsaicin-loaded transfersomes reveals their nano size (94 nm) with negative surface charge (-14.5 mV) and sufficient structural flexibility, which resulted in 60.34% entrapment efficacy, penetration across the biomembrane (220 µm) and 76.76% of drug release from vesicular system in 24 h in their intact form as evident from confocal laser scanning micrographic study. Results of transfersomal nanoformulation (capsaicin loaded, test) were compared with that of conventional gel formulation available in the market (Thermagel, standard), with an aim to assess the antiarthritic efficacy of our prepared capsaicin-loaded transfersomal formulation. In vivo antiarthritic activity study shows that our formulation possesses superior inhibitory activity than the marketed Thermagel formulation at the same dosage level, which could probably be due to the lesser permeability of Thermagel across the dermal barriers compared to our specially designed transfersomal delivery system. Moreover, the better tolerance of prepared vesicular formulation in biological system further enlightens the suitability of the transfersomal vesicle to be used as a novel carrier system for the topical administration of such highly irritant substance.
26646950 Interleukin-21 induces migration and invasion of fibroblast-like synoviocytes from patient 2016 May Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial fibroblast hyperplasia and bone erosion. Fibroblast-like synoviocytes (FLS) play a pivotal role in RA pathogenesis through aggressive migration and matrix invasion, and certain proinflammatory cytokines may affect synoviocyte invasion. Whether interleukin (IL)-21 influences this process remains controversial. Here, we evaluated the potential regulatory effect of IL-21 on the migration, invasion and matrix metalloproteinase (MMP) expression in RA-FLS. We found that IL-21 promoted the migration, invasion and MMP (MMP-2, MMP-3, MMP-9, MMP-13) production in RA-FLS. Moreover, IL-21 induced activation of the phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription-3 (STAT-3) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathways, and blockage of these pathways [PI3K/protein kinase B (AKT) inhibitor LY294002, STAT-3 inhibitor STA-21 and ERK1/2 inhibitor PD98059] attenuated IL-21-induced migration and secretion of MMP-3 and MMP-9. In conclusion, our results suggest that IL-21 promotes migration and invasion of RA-FLS. Therefore, therapeutic strategies targeting IL-21 might be effective for the treatment of RA.
25894436 Pulmonary Langerhans Histiocytosis: an uncommon cause of interstitial pneumonia in a patie 2016 Mar Sjögren syndrome is a chronic, systemic, and autoimmune disorder that targets exocrine glands by remarkable B cell hyperactivity. Eventually, it is associated with extra-glandular clinical manifestations that affect essentially any organ system, including pulmonary involvement. Interstitial lung disease is one of the most serious pulmonary complications, and the early diagnosis is essential to initiate a prompt therapy. On the other hand, Sjögren syndrome could present concomitantly with several rheumatologic diseases such as systemic lupus erythematosus or rheumatoid arthritis. Pulmonary Langerhans Histiocytosis is a rare clonal proliferative disease characterized by pulmonary involvement by cells phenotypically similar to Langerhans cells. We describe the case of a nonsmoker 62-year-old woman with Sjögren syndrome who presented concomitantly a Pulmonary Langerhans Histiocytosis mimicking a pulmonary complication of its Sjögren. Fortunately, she had a well response to corticosteroids and azathioprine regimen. The aim of the paper is to emphasize the importance of the good differential diagnosis related to the pulmonary involvement. To the best of our knowledge, this is the first description of these two entities in the literature.
25486906 miR-148a is upregulated by Twist1 and T-bet and promotes Th1-cell survival by regulating t 2015 Apr Repeatedly activated T helper 1 (Th1) cells present during chronic inflammation can efficiently adapt to the inflammatory milieu, for example, by expressing the transcription factor Twist1, which limits the immunopathology caused by Th1 cells. Here, we show that in repeatedly activated murine Th1 cells, Twist1 and T-bet induce expression of microRNA-148a (miR-148a). miR-148a regulates expression of the proapoptotic gene Bim, resulting in a decreased Bim/Bcl2 ratio. Inhibition of miR-148a by antagomirs in repeatedly activated Th1 cells increases the expression of Bim, leading to enhanced apoptosis. Knockdown of Bim expression by siRNA in miR-148a antagomir-treated cells restores viability of the Th1 cells, demonstrating that miR-148a controls survival by regulating Bim expression. Thus, Twist1 and T-bet not only control the differentiation and function of Th1 cells, but also their persistence in chronic inflammation.
26360137 Circulating Apoptotic Microparticles in Systemic Lupus Erythematosus Patients Drive the Ac 2016 Feb OBJECTIVE: Circulating chromatin-containing apoptotic material and/or neutrophil extracellular traps (NETs) have been proposed to be an important driving force for the antichromatin autoimmune response in patients with systemic lupus erythematosus (SLE). The aim of this study was to determine the exact nature of microparticles in the circulation of SLE patients and to assess the effects of the microparticles on the immune system. METHODS: We analyzed microparticles isolated from the plasma of patients with SLE, rheumatoid arthritis (RA), and systemic sclerosis (SSc), as well as from healthy subjects. The effects of the microparticles on blood-derived dendritic cells (DCs) and neutrophils were assessed by flow cytometry, enzyme-linked immunosorbent assay, and immunofluorescence microscopy. RESULTS: In SLE patients, we identified microparticles that were highly positive for annexin V and apoptosis-modified chromatin that were not present in healthy subjects or in RA or SSc patients. These microparticles were mostly CD31+/CD45- (endothelial), partly CD45+/CD66b+ (granulocyte), and negative for B and T cell markers. Microparticles isolated from the plasma of SLE patients increased the expression of the costimulatory surface molecules CD40, CD80, CD83, and CD86 and the production of proinflammatory cytokines interleukin-6, tumor necrosis factor, and interferon-α by blood-derived plasmacytoid DCs (PDCs) and myeloid DCs (MDCs). SLE microparticles also primed blood-derived neutrophils for NETosis. Microparticles from healthy subjects and from RA or SSc patients exhibited no significant effects on MDCs, PDCs, and NETosis. CONCLUSION: Circulating microparticles in SLE patients include a population of apoptotic cell-derived microparticles that has proinflammatory effects on PDCs and MDCs and enhances NETosis. These results underline the important role of apoptotic microparticles in driving the autoimmune response in SLE patients.
26702877 Antibodies to age-β2 glycoprotein I in patients with anti-phospholipid antibody syndrome. 2016 May Anti-phospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized clinically by arterial and/or venous thromboses, recurrent abortions or fetal loss and serologically by the presence of 'anti-phospholipid antibodies' (aPL). The main target antigen of the antibodies is β2 glycoprotein I (β2 GPI). Post-translational oxidative modifications of the protein have been widely described. In this study we aimed to analyse sera reactivity to glucose-modified β2 GPI (G-β2 GPI). Sera collected from 43 patients with APS [15 primary APS (PAPS) and 28 APS associated with systemic lupus erythematosus (SLE) (SAPS)], 30 with SLE, 30 with rheumatoid arthritis (RA) and 40 healthy subjects were analysed by an enzyme-linked immunosorbent assay (ELISA) using a G-β2 GPI. Nine of 15 consecutive PAPS out-patients (60%) and 16 of 28 SAPS (57.1%) showed serum antibodies [immunoglobulin (Ig)G class] against G-β2 GPI (anti-G-β2 GPI) by ELISA. The occurrence of anti-G-β2 GPI was significantly higher in APS patients compared to patients suffering from SLE. No RA patients or control healthy subjects resulted positive for anti-G-β2 GPI. Of note, aG-β2 GPI prompted to identify some APS patients (four PAPS and seven SAPS), who were negative in the classical anti-β2 GPI test. Moreover, in APS patients, anti-G-β2 GPI titre was associated significantly with venous thrombosis and seizure in APS patients. This study demonstrates that G-β2 GPI is a target antigen of humoral immune response in patients with APS, suggesting that β2 GPI glycation products may contain additional epitopes for anti-β2 GPI reactivity. Searching for these antibodies may be useful for evaluating the risk of clinical manifestations.
27920336 Reasons for Discontinuation and Adverse Effects of TNFα Inhibitors in a Cohort of Patient 2017 May BACKGROUND: The introduction of anti-tumor necrosis factor α (anti-TNFα) drugs has improved the clinical outcomes in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, these drugs may cause adverse effects that motivate a change in or discontinuation of the treatment. OBJECTIVE: To evaluate the causes of discontinuation or changes in the dosage regimen in a cohort of patients with RA and AS treated with infliximab, adalimumab, etanercept, and golimumab under clinical practice conditions. METHODS: This was a retrospective observational study that included patients with RA or AS treated with anti-TNFα drugs between 2008 and 2013. Changes in the dosage regimen, reasons for treatment discontinuation, and adverse effects were recorded and analyzed. Time to discontinuation was estimated using Kaplan-Meier survival analysis. RESULTS: A total of 123 patients with RA and 93 patients with AS were treated with anti-TNFα therapy. During the study, 55.3% of RA patients and 41.7% of AS patients had stopped the treatment. The most frequent changes were modifications in the dosing, and the most frequent adverse effects were reactions after the infusion or injection (53.8% and 66.7% in RA and AS, respectively). Drug survival of etanercept in RA (67.9%) is greater than for adalimumab and infliximab, whereas drug survival of infliximab in AS (70.0%) is greater than for etanercept and adalimumab at 5 years, although there were no significant differences ( P = 0.098 in RA and 0.194 in AS). CONCLUSIONS: The main cause of discontinuation of anti-TNFα is therapeutic failure in both diseases. Etanercept and infliximab have the best survival rates in RA and AS, respectively.
25475778 Role of salivary anti-SSA/B antibodies for diagnosing primary Sjögren's syndrome. 2015 Mar 1 The diagnosis of primary Sjögren's syndrome (pSS) is complex, and the saliva test is a potential method to improve the existing diagnostic criteria. OBJECTIVE: To estimate the diagnostic accuracy of salivary anti-SSA/B antibodies in primary Sjögren's syndrome (pSS), and to analyze their correlations with clinical and laboratory profiles. STUDY DESIGN: This study enrolled 100 pSS patients and 140 non-pSS controls, including 40 rheumatoid arthritis (RA) patients, 40 systemic lupus erythematosus (SLE) patients, and 60 healthy controls. Unstimulated whole saliva and stimulated parotid saliva samples were collected from the subjects. Salivary anti-SSA/B antibodies were measured using an enzyme-linked immunosorbent assay (ELISA). Clinical and laboratory data were retrieved from the medical records. RESULTS: In the pSS group, the sensitivity of anti-SSA and anti-SSB antibodies in whole saliva was 49% and 29%, respectively, and the specificity was 87.5% and 95%. The sensitivity of anti-SSA and anti-SSB antibodies in parotid saliva was 32% and 8%, respectively, and the specificity was 95.52% and 97.86%, respectively. In the pSS group, the diagnostic accuracy of anti-SSA/B antibodies in whole saliva was significantly higher than in parotid saliva (p<0.05), but was significantly lower than in serum (p<0.05). The salivary flow rate in the pSS group positive for whole salivary anti-SSA was significantly lower than in the negative group (p<0.05). The prevalence of rheumatoid factor and antinuclear factor were significantly higher in salivary SSB-positive pSS patients than in SSB-negative patients (p<0.05). CONCLUSIONS: Compared to parotid saliva, whole saliva is a more suitable diagnostic fluid. Using salivary anti-SSA/B antibodies as a single test item is insufficient given the relatively low sensitivity. Further studies should investigate the possibility of combining tests for different salivary autoantibodies as a method for diagnosing pSS.
25524130 Capsaicin-sensitive sensory nerves exert complex regulatory functions in the serum-transfe 2015 Mar OBJECTIVE: The K/BxN serum-transfer arthritis is a widely-used translational mouse model of rheumatoid arthritis, in which the immunological components have thoroughly been investigated. In contrast, little is known about the role of sensory neural factors and the complexity of neuro-immune interactions. Therefore, we analyzed the involvement of capsaicin-sensitive peptidergic sensory nerves in autoantibody-induced arthritis with integrative methodology. METHODS: Arthritogenic K/BxN or control serum was injected to non-pretreated mice or resiniferatoxin (RTX)-pretreated animals where capsaicin-sensitive nerves were inactivated. Edema, touch sensitivity, noxious heat threshold, joint function, body weight and clinical arthritis severity scores were determined repeatedly throughout two weeks. Micro-CT and in vivo optical imaging to determine matrix-metalloproteinase (MMP) and neutrophil-derived myeloperoxidase (MPO) activities, semiquantitative histopathological scoring and radioimmunoassay to measure somatostatin in the joint homogenates were also performed. RESULTS: In RTX-pretreated mice, the autoantibody-induced joint swelling, arthritis severity score, MMP and MPO activities, as well as histopathological alterations were significantly greater compared to non-pretreated animals. Self-control quantification of the bone mass revealed decreased values in intact female mice, but significantly greater arthritis-induced pathological bone formation after RTX-pretreatment. In contrast, mechanical hyperalgesia from day 10 was smaller after inactivating capsaicin-sensitive afferents. Although thermal hyperalgesia did not develop, noxious heat threshold was significantly higher following RTX pretreatment. Somatostatin-like immunoreactivity elevated in the tibiotarsal joints in non-pretreated, which was significantly less in RTX-pretreated mice. CONCLUSIONS: Although capsaicin-sensitive sensory nerves mediate mechanical hyperalgesia in the later phase of autoantibody-induced chronic arthritis, they play important anti-inflammatory roles at least partially through somatostatin release.
26713507 X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in S 2016 May OBJECTIVE: More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ∼1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. METHODS: All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. RESULTS: We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients. CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was ∼2.5 and ∼2.9 times higher, respectively, than that in women with 46,XX and ∼25 and ∼41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.
25028707 Disease-regulated local IL-10 gene therapy diminishes synovitis and cartilage proteoglycan 2015 Nov OBJECTIVES: Rheumatoid arthritis is a chronic destructive autoimmune disease, but the course is unpredictable in individual patients. An attractive treatment would provide a disease-regulated therapy that offers personalised drug delivery. Therefore, we expressed the anti-inflammatory interleukin-10 (IL-10) gene under the control of inflammation-dependent promoters in a mouse model of arthritis. METHODS: Proximal promoters of S100a8, Cxcl1, Mmp13, Saa3, IL-1b and Tsg6 were selected by whole-genome expression analysis of inflamed synovial tissues from arthritic mice. Mice were injected intraarticularly in knee joints with lentiviral vectors expressing a luciferase reporter or the therapeutic protein IL-10 under control of the Saa3 or Mmp13 promoter. After 4 days, arthritis was induced by intraarticular injection of streptococcal cell walls (SCW). At different time points after arthritis induction, in vivo bioluminescent imaging was performed and knee joints were dissected for histological and RNA analysis. RESULTS: The disease-regulated promoter-luciferase reporter constructs showed different activation profiles during the course of the disease. The Saa3 and Mmp13 promoters were significantly induced at day 1 or day 4 after arthritis induction respectively and selected for further research. Overexpression of IL-10 using these two disease-inducible promoters resulted in less synovitis and markedly diminished cartilage proteoglycan depletion and in upregulation of IL-1Ra and SOCS3 gene expression. CONCLUSIONS: Our study shows that promoters of genes that are expressed locally during arthritis can be candidates for disease-regulated overexpression of biologics into arthritic joints, as shown for IL-10 in SCW arthritis. The disease-inducible approach might be promising for future tailor-made local gene therapy in arthritis.
26076982 IL-1R1 is expressed on both Helios(+) and Helios(-) FoxP3(+) CD4(+) T cells in the rheumat 2015 Oct Synovial fluid from rheumatic joints displays a well-documented enrichment of forkhead box protein 3 (FoxP3)(+) regulatory T cells (tissue Tregs ). However, we have previously demonstrated that the mere frequency of FoxP3 expressing cells cannot predict suppressive function. Instead, extrinsic factors and the functional heterogeneity of FoxP3(+) Tregs complicate the picture. Here, we investigated FoxP3(+) Tregs from blood and synovial fluid of patients with rheumatic disease in relation to Helios expression by assessing phenotypes, proliferative potential and cytokine production by flow cytometry. Our aim was to investigate the discriminatory potential of Helios when studying FoxP3(+) Tregs in an inflammatory setting. We demonstrate that the majority of the synovial FoxP3(+) CD4(+) T cells in patients with inflammatory arthritis expressed Helios. Helios(+) FoxP3(+) Tregs displayed a classical Treg phenotype with regard to CD25 and cytotoxic T lymphocyte-associated antigen (CTLA)-4 expression and a demethylated Treg -specific demethylated region (TSDR). Furthermore, Helios(+) FoxP3(+) T cells were poor producers of the effector cytokines interferon (IFN)-γ and tumour necrosis factor (TNF), as well as of the anti-inflammatory cytokine interleukin (IL)-10. The less abundant Helios(-) FoxP3(+) T cell subset was also enriched significantly in the joint, displayed a overlapping phenotype to the double-positive Treg cells with regard to CTLA-4 expression, but differed by their ability to secrete IL-10, IFN-γ and TNF upon T cell receptor (TCR) cross-linking. We also demonstrate a striking enrichment of IL-1R1 expression in synovial CD4(+) T cells that was restricted to the CD25-expressing FoxP3 population, but independent of Helios. IL-1R1 expression appears to define a tissue Treg cell phenotype together with the expression of CD25, glucocorticoid-induced TNF receptor family-related gene (GITR) and CTLA-4.
25941031 Tumor necrosis factor and interleukin-6 differentially regulate Dkk-1 in the inflamed arth 2015 May OBJECTIVE: Tumor necrosis factor (TNF) drives bone destruction, but it also inhibits new bone formation by inducing Dkk-1, an inhibitor of the Wnt pathway. Accordingly, blocking of Dkk-1 reverses the phenotype in experimental arthritis from a pattern of bone destruction to a pattern of bone formation. To delineate the potential role of Dkk-1 in the structural phenotype of human arthritis, we analyzed the expression of Dkk-1 and its regulation by proinflammatory cytokines in the inflamed peripheral joints of patients with spondyloarthritis (SpA) and rheumatoid arthritis (RA). METHODS: Expression of Dkk-1 and proinflammatory cytokines was determined by enzyme-linked immunosorbent assay and microarray analysis in synovial fluid (SF) and synovial tissue, respectively. Regulation of Dkk-1 production by proinflammatory cytokines was assessed in fibroblast-like synoviocyte (FLS) cultures. RESULTS: TNF and interleukin-1β (IL-1β) levels, were higher in RA SF than in SpA SF (P < 0.001 for both), whereas levels of IL-6 were not. Levels of Dkk-1 were similar in SpA SF and RA SF and were not correlated with TNF and IL-1β levels. However, Dkk-1 levels showed an inverse correlation with IL-6 levels in both SpA SF (r = -0.31, P = 0.04) and RA SF (r = -0.39, P = 0.01); this result was reproduced at the messenger RNA level in synovial tissue. In vitro experiments with FLS confirmed that Dkk-1 production was strongly induced by TNF but clearly suppressed by IL-6. Moreover, IL-6 was able to suppress the TNF-induced up-regulation of Dkk-1 production by FLS. CONCLUSION: The inverse correlation of Dkk-1 levels with IL-6 levels observed in vivo in the inflamed joints was mirrored by the differential regulation of Dkk-1 production by TNF and IL-6 in vitro. The relative balance between these and other factors in the arthritic joints may determine functional Wnt signaling and tissue remodeling.
25348220 Human papillomavirus and chlamydia trachomatis infections in rheumatoid arthritis under an 2015 Mar The objective of this study was to evaluate human papillomavirus (HPV) and Chlamydia trachomatis (CT) infections in RA patients pre- and post-TNF blocker. Fifty female RA patients (ACR criteria), who were eligible to anti-TNF therapy [n = 50 at baseline (BL) and n = 45 after 6 months of treatment (6 M)], and 50 age-matched healthy controls were prospectively enrolled. They were assessed for demographic data, gynecologic, sexual, cervical cytology and histological evaluations, disease parameters and current treatment. HPV DNA and CT DNA testing in cervical specimens were done using Hybrid Capture II assays. At BL, the median current age of RA patients and controls was 49 (18-74) versus 49 (18-74) years, p = 1.0. A trend of lower frequency of HPV infection was observed in AR patients pre-anti-TNF compared with controls (14 vs. 30%, p = 0.054). Further evaluation of AR patients with and without HPV infection before anti-TNF therapy showed that the former group had higher frequency of sexual intercourses (100 vs. 48%, p = 0.014), higher median number of sexual partners [1 (1-1) vs. 0 (0-1), p = 0.032] and higher frequency of abnormal cervical cytology (43 vs. 7%, p = 0.029). Current age, disease duration, disease parameters and treatments were alike in both groups (p > 0.05). At 6 M after TNF blockage, HPV infection remained unchanged in five patients, whereas two became negative and one additional patient turned out to be positive (p = 1.0). CT infection was uniformly negative in RA patients pre- and post-TNF blockage and in controls. Anti-TNF does not seem to increase short-term risk of exacerbation and/or progression of HPV and CT infections in RA patients.
27846765 Adult-onset Still's disease-like manifestation accompanied by the cancer recurrence after 2019 Jul A 72-year-old woman presented 9 months ago with skin rash on her bilateral forearms, which was followed by intermittent high fever, and stiffness and swelling of her bilateral fingers. She was diagnosed with seronegative rheumatoid arthritis (RA). She had a past history of breast cancer and had undergone breast preservation surgery 13 years previously. During admission in our hospital, she developed high fever and leukocytosis with a relapsing skin rash, sore throat, polyarthralgia and increased levels of serum ALT/AST and ferritin, all of which fulfilled Yamaguchi's criteria for adult-onset Still's disease (AOSD). While we tried to exclude other diseases that may show AOSD-like manifestations, pancytopenia rapidly developed and bone marrow biopsy strongly suggested the diagnosis of macrophage activating syndrome (MAS). Accordingly, steroid pulse therapy was begun, followed by oral glucocorticoid therapy. Thereafter, all of her symptoms improved, but systemic rash, inflammatory signs and pancytopenia gradually progressed. The results of bone marrow pathology, which returned 2 weeks after the beginning of treatment, revealed hemophagocytosis with CK7-positive/CK20-negative atypical cells that suggested recurrence of breast cancer in the bone marrow, thus all of her AOSD-like symptoms were considered to be paraneoplastic manifestations of late-onset metastatic breast cancer. She was treated successfully with chemotherapy. When we see the patients showing AOSD-like symptoms with a history of malignancy, we should consider the possibility of paraneoplastic syndrome due to cancer recurrence.
26109563 Prediction of Sjögren's Syndrome Years Before Diagnosis and Identification of Patients Wi 2015 Sep OBJECTIVE: Autoantibodies are highly characteristic of primary Sjögren's syndrome (SS) and represent important tools for studying its pathogenesis. Nonetheless, thus far, no systematic investigations have assessed the presence of autoantibodies before diagnosis. This study was undertaken to analyze how early and in what order autoantibodies appear, how predictive they are of primary SS, and whether they identify disease subsets. METHODS: A nested case-control design linking data from the Malmö primary SS registry and 3 Swedish healthcare biobanks was applied. In all, 175 serum samples obtained from 117 individuals before diagnosis of primary SS and 1 serum sample from each of 117 matched controls were analyzed for antinuclear antibodies (ANAs), rheumatoid factor (RF), and antibodies against Ro 60/SSA, Ro 52/SSA, and La/SSB. RESULTS: Considering all patients with primary SS who were autoantibody positive after diagnosis, at least one autoantibody specificity was detected in 81% up to 20 years (median 4.3-5.1 years) before diagnosis. Those found most often were ANAs, followed by RF, anti-Ro 60/SSA, anti-Ro 52/SSA, and anti-La/SSB. Anti-Ro/SSA and anti-La/SSB antibodies were strongly associated with the risk of developing primary SS, especially early-onset disease and a severe disease course. When Bayesian prior prevalence estimates for primary SS were included in the calculation, prediagnostic anti-Ro 60/SSA and anti-Ro 52/SSA had the highest positive predictive values (25% and 100%, respectively). CONCLUSION: Our findings indicate that autoantibodies are present for up to 18-20 years before the diagnosis of primary SS, but we cannot exclude even earlier seropositivity, since for most patients, the earliest sample analyzed was positive. In families with multiple cases of autoimmune disease, autoantibody profiling, along with assessment of genetic risk, enables identification of susceptible individuals in a predisease state.
27692394 What rheumatologists should know about orofacial manifestations of autoimmune rheumatic di 2016 Sep Orofacial manifestations occur frequently in rheumatic diseases and usually represent early signs of disease or of its activity that are still neglected in clinical practice. Among the autoimmune rheumatic diseases with potential for oral manifestations, rheumatoid arthritis (RA), inflammatory myopathies (IM), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), relapsing polychondritis (RP) and Sjögren's syndrome (SS) can be cited. Signs and symptoms such as oral hyposalivation, xerostomia, temporomandibular joint disorders, lesions of the oral mucosa, periodontal disease, dysphagia, and dysphonia may be the first expression of these rheumatic diseases. This article reviews the main orofacial manifestations of rheumatic diseases that may be of interest to the rheumatologist for diagnosis and monitoring of autoimmune rheumatic diseases.