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To evaluate the acetabular cup and graft survival in patients who underwent total hip arthroplasty (THA) with the diagnosis of dysplastic hip osteoarthritis and received a femoral head autograft due to acetabular coverage deficiency. Between January 2005 and December 2016, 83 hip prostheses of 80 patients who underwent THA using femoral head autografts and were followed up for at least 2 years were retrospectively evaluated. Seventy-four hips of the remaining 71 patients (57 female (80%)) were included. Mean patient age at surgery was 51 ± 16 (range 18-76) years. The mean follow-up duration was 76 ± 25 (range 25-161) months. Acetabular inclination and graft thickness, contact length, percentage of coverage, and graft resorption were examined on postoperative and final follow-up radiographs. The presence of a radiolucent area around the acetabular and femoral components indicating loosening was also evaluated. The mean postoperative acetabular component inclination was 44 ± 5.1° (range 30-48°) with mean graft coverage of 34 ± 4.8% (range 24-46%). In all patients, autograft union with the pelvis was seen and the lateral overflow was remodeled. Fifteen patients (20%) underwent revision surgery due to aseptic acetabular component loosening in four, nontraumatic recurrent dislocations in eight, periprosthetic infection in one, acetabular component protrusion in one, and traumatic hip dislocation in one.
In patients with osteoarthritis secondary to developmental hip dysplasia, the use of femoral head autografts to eliminate acetabular coverage deficiency during THA achieves acceptable midterm postoperative radiological outcomes. Increased acetabular bone stock may be beneficial in possible future revision surgeries.
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The purpose of this study was to investigate the risk of myopathy when statins are coadministered with colchicine in patients with gout. In gout patients who received colchicine with or without statin, clinical data collected included medications and history of hypertension, chronic kidney disease, and liver cirrhosis. Myopathy was defined as the presence of muscle symptoms with elevated creatine kinase or myoglobin. Multivariate analysis was performed to identify risk factors for myopathy. Inverse probability of treatment weighting (IPTW)-adjusted analysis was used to evaluate the influence of concomitant colchicine and statin use on myopathy. Of 674 patients, 486 received colchicine alone and 188 also received statin. The incidence of myopathy was not significantly higher in those on both drugs than in those on colchicine alone (2.7% vs 1.4%, P = .330). On multivariate analysis, chronic kidney disease (hazard ratio [HR] 29.056; 95% confidence interval [CI], 4.387-192.450; P <.001), liver cirrhosis (HR 10.676; 95% CI, 1.279-89.126; P = .029), higher colchicine dose (HR 20.960; 95% CI, 1.835-239.481; P = .014), and concomitant CYP3A4 inhibitor (HR 12.027; 95% CI, 2.743-52.725; P = .001) were associated with increased risk of myopathy. Concomitant use of statins, however, was not, even after adjusting for confounders (HR 1.123; 95% CI, 0.262-4.814; P = .875; IPTW-adjusted HR 0.321; 95% CI, 0.077-1.345; P = .120).
Concomitant use of statin and colchicine was not associated with increased risk of myopathy. Thus, concomitant use of statin with colchicine seems to be safe from myotoxicity in gout patients.
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Haplotypes of PADI4, encoding for a citrullinating enzyme, were associated with rheumatoid arthritis in a Japanese population. It was suggested they were related to the presence of anticitrullinated protein antibodies (ACPA). To explore the relation between PADI4 haplotypes, the presence of rheumatoid arthritis specific intracellular citrullinated proteins in synovial membrane, and serum ACPA titres. Synovial biopsies and peripheral blood samples were obtained in 59 patients with rheumatoid arthritis. Synovial intracellular citrullinated proteins were detected by immunohistochemistry. Serum ACPA titres were measured by anti-CCP2 ELISA. PADI4 haplotypes were determined by direct sequencing of the four exonic PADI4 single nucleotide polymorphisms. PADI4 haplotype frequencies and the presence of synovial intracellular citrullinated proteins and ACPA were comparable with previous studies. There was no significant association between PADI4 haplotype 1 or 2 and the presence of synovial intracellular citrullinated proteins, although these proteins were associated with higher serum ACPA. There was no correlation between PADI4 haplotypes and serum ACPA, either by continuous analysis using the titres or by dichotomous analysis using the diagnostic cut off. Further analyses in homozygotes for haplotype 1 or 2 or in heterozygotes (1/2) also failed to show an association between PADI4 polymorphisms and ACPA. This contrasted with the clear association between ACPA levels and HLA-DR shared epitope.
The link between synovial intracellular citrullinated proteins and ACPA emphasises the role of deimination of synovial proteins in rheumatoid arthritis, but the biological relevance of the PADI4 haplotypes for this autoimmune process is questionable, at least in a European population.
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Research objective - comparative analysis of incidence and structure of anxiety-depressive spectrum disorders (ADD) in patients with various rheumatic diseases (RD). 613 patients with RD were enrolled in the study: 180 with a reliable diagnosis of systemic lupus erythematosus (SLE), 128 with rheumatoid arthritis (RA), 110 with systemic sclerosis (SSc), 115 with Behcet's disease (BD), 80 with primary Sjögren's syndrome (pSS). Female prevailed in all groups (95% of patients with pSS, 88,2% - SSc, 87,2% - RA, 85,5% of SLE) except BD patients (70% male). The mean age was 42.3±1.54 years and was lower in patients with BD (33.3±0.98 years) and SLE (34.6±0.93 years) compared to patients with SSc (49.9±2.47 years), RA (47.4±0.99 years) and pSS (46.2±2.3 years). The mean RD duration was 130,0±8,65 months and was more at BD - 148,5±10,4 months, pSS - 141,6±8,92 months, RA - 138,4±10,1months, and less at SLE - 134,9±8,8 months and SSc - 87,0±5,04 months. The mean SLE activity index SLEDAI was 9,13±0,63 points (high), RA (DAS28) - 5,26±0,17 points (high), BD (BDCAF) - 3,79±0,2 points (moderate) and SSc by G. Valentini - 1,1±0,20 points (moderate). Glucocorticoids took 100% of patients with pSS, 91,1% - SLE, 90% - SSc, 87% - BD and 67,2% - RA patients; conventional disease modifying anti-rheumatic drugs (cDMARDs) took 90% of patients with SSc, 84% - BD, 79,6% - RA, 68% - pSS, 40,6% - SLE. Biologic DMARDs took 32% of patients with RA, 17,4% - BD, 7,3% - SSc and 7,2% - SLE. Mental disorders were diagnosed by psychiatrist as a result of screening by the hospital anxiety and depression scale (HADS) and in semi-structured interview in accordance with the ICD-10/ DSM-IV. The severity of depression was evaluated by Montgomery-Asberg Depression Rating Scale (MADRS) and anxiety - by Hamilton Anxiety Rating Scale (HAM-A). Projective psychological methods were used for cognitive impairment detection. Screening of depressive disorders (HADS-D≥8) was positive in 180 (29,4%) patients with RD, including 74 (41%) patients with SLE, 38 (35%) - SSc, 29 (23%) - RA, 23 (20%) - BD and 16 (20%) - pSS; anxiety disorders (HADS-A≥8) - in 272 (44,4%) patients, including 66 (52%) patients with RA, 40 (50%) - pSS, 77 (43%) - SLE, 45 (41%) - SSc and 44 (38%) - BD. In accordance with the ICD-10/ DSM-IV depressive disorders have been identified in 389 (63%) patients, including 94 (73%) patients with RA, 71 (64,5%) - SSc, 69 (60%) - BD, 90 (50%) - SLE and 39 (49%) - pSS; anxiety disorders - in 377 (61,5%) patients, including 20 (25%) patients with pSS, 44 (24,5%) - SLE, 29 (23%) - RA, 20 (17%) - BD and 7 (6,4%) - SSc.
Anxiety-depressive spectrum disorders are typical for most patients with RA, SLE, SSc, pSS and BD. ADDs diagnosis in RD patients with the use of the HADS did not reveal a significant proportion. To obtain objective data on the frequency and structure of ADDs, psychopathological and clinical psychological diagnosis is necessary.
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To investigate the relationship between nonselective nonsteroidal antiinflammatory drugs (NS NSAID), rofecoxib, celecoxib, and risk of edema and blood pressure destabilization in patients with rheumatoid arthritis (RA) and osteoarthritis (OA) receiving ordinary clinic care. Patients participating in a longterm outcome study reported drug use, as well as the presence of edema and blood pressure increases occurring during the previous 6 months. To measure pure drug effect, analyses were restricted to 8538 patients who exclusively used a NS NSAID, rofecoxib, or celecoxib, and compared to nonusers of NS NSAID, rofecoxib, or celecoxib. We evaluated blood pressure destabilization using patient-reported increases in blood pressure and/or difficulty in controlling blood pressure. Compared with nonusers, after adjusting for age, sex, presence of RA, and history of heart disease and hypertension, patients using rofecoxib, but not celecoxib or NS NSAID, had an increased rate of edema (23.3% vs 18.0%), while the rates for celecoxib and NS NSAID were 17.5% and 18.2%, respectively. The adjusted risk of edema was significantly increased for rofecoxib compared to celecoxib (OR 1.33, 95% CI 1.08-1.64). For blood pressure increases, among patients who did not report having hypertension, no significant increase was noted for NS NSAID and celecoxib compared with nonusers. However a significant increased risk of blood pressure increase was seen for rofecoxib (OR 2.08, 95% CI 1.41-3.06). Among patients who reported having hypertension, patients taking rofecoxib had a significant increased risk of blood pressure increase compared to nonusers (OR 1.55, 95% CI 1.23-1.96), while the risks of blood pressure increase for users of celecoxib and NS NSAID were not significantly different than among nonusers. After controlling for age, sex, RA, and new starts on NSAID, the risk of blood pressure increase was significantly higher for users of rofecoxib than celecoxib (OR 1.21, 95% CI 1.03-1.61) among patients with hypertension, and numerically higher for nonhypertensives (OR 1.42, 95% CI 0.96-2.22). The increased risk for hypertension and edema of rofecoxib compared to celecoxib users was further confirmed by analysis of specific reported side effects during 2 separate 6-month periods (July 1 to December 31, 1999, and January 1 to June 30, 2000). During these 2 periods, rofecoxib-treated patients were 2.16 to 3.82 times more likely to report edema or blood pressure increase side effects compared to celecoxib-treated patients.
Rofecoxib, but not celecoxib and NS NSAID, is associated with an increased risk of edema and blood pressure increase compared to nonusers of NSAID.
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To determine whether smoking is protective against the development of osteoarthritis (OA). Observational studies for the association between smoking and OA were systematically searched through Medline (1950-), Embase (1980-), Web of Science (1960-), PubMed, Google and relevant references. ORs and 95% CIs were directly retrieved or calculated. Current standards for reporting using MOOSE were followed. Quality-related aspects such as study design, setting, sample selection and confounding bias were recorded. Stratified and meta-regression analyses were undertaken to examine the covariates. Of 48 studies (537 730 participants) identified from the systematic literature search, 8 were cohort, 21 cross-sectional and 19 case-control. There was an overall negative association between smoking and OA (OR=0.87; 95% CI 0.80 to 0.94) and subgroup analysis confirmed this in case-control studies (OR=0.82; 95% CI 0.70 to 0.95), but not in cohort (OR=0.92; 95% CI 0.81 to 1.06) or cross-sectional studies (OR=0.89; 95% CI 0.78 to 1.01). Within case-control studies a negative association occurred only in hospital settings (OR=0.65; 95% CI 0.52 to 0.81), not in community settings (OR=0.90; 95% CI 0.75 to 1.08). The association was also seen in knee OA, radiographic OA and smoking as a secondary exposure (covariate or confounding factor). Meta-regression analysis demonstrated that a hospital setting and smoking as a secondary exposure were the major source of the negative association.
The protective effect of smoking in OA observed in some epidemiological studies is likely to be false. It may be caused by selection bias, often in a hospital setting where control subjects have smoking-related conditions and studies that are not primarily designed to investigate smoking. Critical appraisal of such studies is needed.
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MRL/MpJ mice spontaneously develop lacrimal gland inflammation and are a model for the human disorder Sjögren's syndrome. MRL/MpJ-lpr/lpr (MRL/lpr) and MRL/Mp-+/+ (MRL/+) mice are congenic substrains, which differ only by a single autosomal recessive gene, the lpr mutation. This mutation results in defective Fas protein, defective lymphocytic apoptosis, and accelerated autoimmune lacrimal gland disease in MRL/lpr mice. We evaluated apoptosis in the lacrimal glands of MRL/lpr and MRL/+ mice. Inflammatory cells in the lacrimal glands of MRL/lpr and MRL/+ mice were evaluated for apoptosis with TUNEL staining and Fas and Fas ligand expression with immunohistochemistry. MRL/lpr mice had a greater percentage of the lacrimal gland replaced by inflammatory infiltrate (30.3% +/- 7.0%) than did MRL/+ mice (13.0% +/- 3.0%, P = 0.02). However, similar amounts of lymphocytic apoptosis were present in the lacrimal glands of MRL/lpr and MRL/+ mice. The mean number of apoptotic cells per unit area of inflammation was 23.8 +/- 2.4 in MRL/lpr mice and 24.6 +/- 6.0 in MRL/+ mice (P = 0.91). Fas expression was absent on lymphocytes in MRL/lpr mice but was present on lymphocytes in MRL/+ mice. Fas ligand expression was present on epithelial structures in both substrains.
The accelerated lacrimal gland disease inflammation in MRL/lpr mice does not appear to be due to decreased apoptosis in the microenvironment of the lacrimal gland of MRL/lpr mice. It appears that in MRL/lpr mice there is defective extrathymic lymphoid apoptosis, permitting a relatively greater expansion of autoreactive T cells, which subsequently invade the lacrimal gland.
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To summarize the research progress of pathological manifestations and mechanism of endochondral ossification in osteoarthritis (OA). The literature about endochondral ossification, bone-cartilage remodeling in OA, and joints development was reviewed, analyzed, and summarized. Chondrocyte hypertrophy and apoptosis, vascular invasion, replication of the tidemark, thickening calcified cartilage, and thinning superficial cartilage are the characteristics of cartilage degeneration in OA. Articular cartilage and growth plate are similar in structure, and cartilage degeneration in OA is similar to a process of endochondral ossification of the growth plate. 综述骨关节炎(osteoarthritis,OA)软骨内骨化的病理表现和机制研究进展。. 查阅有关OA软骨内骨化、骨-软骨重塑及关节发育的相关文献,并进行分析总结。. 软骨细胞的肥大、凋亡,血管的侵入,潮线的复制,软骨钙化层不断增厚和软骨表层的相对变薄是OA软骨退变的重要特征。关节软骨与生长板在结构上类似,OA的软骨退变是一种类似于生长板的软骨内骨化过程。. 关节软骨失去稳定表征,从静息代谢平衡状态转为临时软骨的高转换状态,继而发生软骨不断钙化和钙化软骨不断骨化重塑,可能是导致OA发生发展的中心环节。.
Loss of stability characterization from resting metabolic balance to a high conversion state of temporary cartilage in stimulation of abnormal mechanical stresses and cytokines would subsequently contributed to continual calcification and remodeling of articular cartilage, which may be the key link of the initiation and development of OA.
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To assess the safety and effectiveness of leflunomide (LNF) using 100 mg/week in patients with rheumatoid arthritis (RA). Patients who were clinically active using the American College of Rheumatology criteria for RA were enrolled. They received a loading dose of 100 mg of LFN for 3 days, followed by 100 mg of LFN weekly. Efficacy and adverse events (AE) were recorded. Fifty patients were enrolled; 46 (93.6%) were women with a mean age of 45.6 years (range: 24 to 83). Disease duration was 3.7 years (range: 0.5 to 12). Twenty patients (40.8%) had previously taken disease modifying antirheumatic drugs. Outcomes achieved after 24 weeks of treatment were as follows: ACR20 (74%), ACR50 (64%), and ACR70 (28%). Five patients were withdrawn due to AE: 2 due to urticaria, 2 patients had elevated liver enzymes, and one had thrombocytopenia. Six patients (12%) were lost to followup. No severe AE were seen.
The results in our preliminary report indicate that using a 100 mg/week dose achieves a similar benefit to the LFN 20 mg/day treatment, and there were no severe AE. In addition, a single LFN weekly dose has better treatment compliance. A secondary important benefit is the reduction of the monthly cost of medication. Comparative and blind trials are necessary in order to confirm longterm improvement and benefits on this regimen.
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To develop a set of clinical criteria that identifies patients with a potential autoinflammatory IFNopathy. Based on a literature review, a set of clinical criteria identifying genetically confirmed monogenic IFNopathies was selected. For validation, the clinical score was assessed in healthy controls (HCs) and 18 disease controls, including 2 known autoimmune IFNopathies, juvenile systemic lupus erythematosus (JSLE, n = 4) and dermatomyositis (JDM, n = 4); adenosine deaminase 2 deficiency (DADA2, n = 4); and oligoarticular juvenile idiopathic arthritis (oJIA, n = 6). We assessed an IFN score (IRG-S) in whole blood by NanoString using a previously published 28-gene-IRG-S and a reduced 6-gene-IRG-S. The 12 patients with a possible IFNopathy had higher clinical scores (3-5) than the patients with sJLE, JDM, DADA2, and oJIA and in HCs. Both the 28-IRG-S and 6-IRG-S were significantly higher in the autoinflammatory IFNopathy patients compared to HCs and oJIA and DADA2 patients but not different from patients with JSLE and JDM. Subsequently, genetic analysis revealed mutations in genes previously reported in genes related to the IFN pathway in 9 of the 12 patients.
We developed a clinical score to identify patients with possible autoinflammatory IFNopathies. A clinical score was associated with a high IRG-S and may serve to identify patients with an autoinflammatory IFNopathy.
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Mikulicz's disease (MD) has been considered as one manifestation of Sjögren's syndrome (SS). Recently, it has also been considered as an IgG(4)-related disorder. To determine the differences between IgG(4)-related disorders including MD and SS. A study was undertaken to investigate patients with MD and IgG(4)-related disorders registered in Japan and to set up provisional criteria for the new clinical entity IgG(4)-positive multiorgan lymphoproliferative syndrome (IgG(4)+MOLPS). The preliminary diagnostic criteria include raised serum levels of IgG(4) (>135 mg/dl) and infiltration of IgG(4)(+) plasma cells in the tissue (IgG(4)+/IgG+ plasma cells >50%) with fibrosis or sclerosis. The clinical features, laboratory data and pathologies of 64 patients with IgG(4)+MOLPS and 31 patients with typical SS were compared. The incidence of xerostomia, xerophthalmia and arthralgia, rheumatoid factor and antinuclear, antiSS-A/Ro and antiSS-B/La antibodies was significantly lower in patients with IgG(4)+MOLPS than in those with typical SS. Allergic rhinitis and autoimmune pancreatitis were significantly more frequent and total IgG, IgG(2), IgG(4) and IgE levels were significantly increased in IgG(4)+MOLPS. Histological specimens from patients with IgG(4)+MOLPS revealed marked IgG(4)+ plasma cell infiltration. Many patients with IgG(4)+MOLPS had lymphocytic follicle formation, but lymphoepithelial lesions were rare. Few IgG(4)+ cells were seen in the tissue of patients with typical SS. Thirty-eight patients with IgG(4)+MOLPS treated with glucocorticoids showed marked clinical improvement.
Despite similarities in the involved organs, there are considerable clinical and pathological differences between IgG(4)+MOLPS and SS. Based on the clinical features and good response to glucocorticoids, we propose a new clinical entity: IgG(4)+MOLPS.
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To investigate whether periodontitis, characterized by marginal jawbone loss, precedes the onset of symptoms of rheumatoid arthritis (RA), and to analyze plasma levels of RANKL (a cytokine that is crucial for bone resorption) and anti-citrullinated peptide antibodies (ACPAs) in presymptomatic individuals compared with matched referent controls. Marginal jawbone loss was measured on dental radiographs of the premolar/molar regions in the jaws in 176 subjects, 93 of whom subsequently developed RA. Among these participating subjects, 46 had documented radiographs predating symptom onset, and 45 cases could be matched to controls, according to sex, age, and smoking status. Plasma RANKL concentrations were analyzed using enzyme-linked immunosorbent assay. A receiver operating characteristic curve was used to define the cutoff value for RANKL positivity. Bone loss was significantly greater in presymptomatic subjects classified as never smokers compared with that in controls, and increasing levels of bone loss were associated with a higher risk of the subsequent development of RA (hazard ratio 1.03, 95% confidence interval 1.01-1.05). No association between jawbone loss and RA was observed in smokers. A significantly greater extent of marginal jawbone loss was detected in RANKL-positive presymptomatic subjects, and even more pronounced jawbone loss was observed in those who were positive for both RANKL and ACPA.
Marginal jawbone loss preceded the clinical onset of RA symptoms, but this was observed only in nonsmokers. Moreover, marginal jawbone loss was significantly greater in RANKL-positive presymptomatic subjects compared with RANKL-negative presymptomatic subjects and was highest in presymptomatic subjects positive for both ACPA and RANKL.
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Rheumatoid factor (RF) is a well-established diagnostic and prognostic biomarker in rheumatoid arthritis (RA). However, ∼20% of RA patients are negative for this anti-IgG antibody. To date, only variation at the HLA-DRB1 gene has been associated with the presence of RF. This study was undertaken to identify additional genetic variants associated with RF positivity. A genome-wide association study (GWAS) for RF positivity was performed using an Illumina Quad610 genotyping platform. A total of 937 RF-positive and 323 RF-negative RA patients were genotyped for >550,000 single-nucleotide polymorphisms (SNPs). Association testing was performed using an allelic chi-square test implemented in Plink software. An independent cohort of 472 RF-positive and 190 RF-negative RA patients was used to validate the most significant findings. In the discovery stage, a SNP in the IRX1 locus on chromosome 5p15.3 (SNP rs1502644) showed a genome-wide significant association with RF positivity (P = 4.13 × 10(-8) , odds ratio [OR] 0.37 [95% confidence interval (95% CI) 0.26-0.53]). In the validation stage, the association of IRX1 with RF was replicated in an independent group of RA patients (P = 0.034, OR 0.58 [95% CI 0.35-0.97] and combined P = 1.14 × 10(-8) , OR 0.43 [95% CI 0.32-0.58]).
To our knowledge, this is the first GWAS of RF positivity in RA. Variation at the IRX1 locus on chromosome 5p15.3 is associated with the presence of RF. Our findings indicate that IRX1 and HLA-DRB1 are the strongest genetic factors for RF production in RA.
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To define the pathogenesis of bone marrow (BM) involvement in systemic lupus erythematosus (SLE). Tumor necrosis factor α (TNFα) levels, cell death, and cellular damage in BM from SLE patients, controls, and mice with pristane-induced lupus were analyzed using a morphometric technique and immunohistochemistry. The pathogenesis of BM abnormalities was studied in wild-type (WT), TNFα(-/-) , Toll-like receptor-deficient (TLR-7(-/-) ), interferon (IFN)-α/β/ω receptor-knockout (IFNAR(-/-) ), and B cell-deficient (μmt) mice treated with pristane. Flow cytometry was used to examine TNFα production (by intracellular staining) and plasma cell/plasmablast development. CXCL12 expression was determined by quantitative polymerase chain reaction. BM from SLE patients exhibited striking death of niche and hematopoietic cells associated with TNFα overproduction. BM from mice with a type I IFN-mediated lupus syndrome induced by pristane showed similar abnormalities. TNFα was produced mainly by BM neutrophils, many with phagocytosed nuclear material (lupus erythematosus cells). TNFα production was abolished in pristane-treated TLR-7(-/-) and μmt mice but was restored in μmt mice by infusing normal plasma. Pristane-treated WT and IFNAR(-/-) mice developed anemia, BM hypocellularity, and extramedullary hematopoiesis, which were absent in TLR-7(-/-) and TNFα(-/-) mice. Additionally, the expression of CXCL12, which is produced by stromal cells and mediates homing of hematopoietic cells and plasmablasts, was decreased in BM from pristane-treated WT mice but was normal in BM from pristane-treated TNFα(-/-) mice.
Although autoantibodies and glomerulonephritis are type I IFN dependent, lupus-associated BM abnormalities were TLR-7 and TNFα driven but type I IFN independent, suggesting that lupus is a disorder of innate immunity in which TLR-7 activation by phagocytosed nuclei causes relentless type I IFN and TNFα production mediating glomerulonephritis and hematologic involvement, respectively.
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To investigate balance, gait, falls, and fear of falling in patients with the hypermobility type of Ehlers-Danlos syndrome (EDS-HT). Twenty-two women with EDS-HT and 22 sex- and age-matched healthy control subjects participated in the study. Each subject performed the modified Clinical Test of Sensory Interaction on Balance (mCTSIB) and the Tandem Stance test (TS) on an AccuGait force platform to assess balance by center of pressure-based postural sway measures. The GAITRite walkway system was used to record spatial-temporal gait variables during 3 walking conditions (single task, cognitive task, and functional task). Data about fall frequency and circumstances were collected by retrospective recall, and fear of falling was assessed by the modified Falls Efficacy Scale. Compared with healthy subjects, EDS-HT subjects showed significantly impaired balance, reflected by increased sway velocity, mediolateral and anteroposterior sway excursion, and sway area during mCTSIB and TS. Gait velocity, step length, and stride length were significantly smaller during all walking conditions, and a significant dual-task-related decrement was found for gait velocity, step and stride length, and cadence in the EDS-HT subjects compared to the control group. Ninety-five percent of the patients fell during the past year, and some fear of falling was measured.
To our knowledge, this study is the first to establish that EDS-HT is associated with balance and gait impairments, increased fall frequency, and poorer balance confidence, implying a decrease in the safety of standing in everyday life situations. Whether these deficits can be improved by appropriate exercise programs needs to be addressed in future research.
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To examine the rate of incident malignancies excluding non-melanoma skin cancer (NMSC) in patients with rheumatoid arthritis (RA) newly treated with tocilizumab versus other biologic drugs. We conducted a cohort study using data from 3 U.S. insurance claims databases - Medicare (2010-2015), 'IMS' PharMetrics Plus (2011-2015) and Truven 'MarketScan' (2011-2015). Adults with RA who newly started tocilizumab or a TNF inhibitor (TNFi) after failing a different TNFi, abatacept or tofacitinib were included. The primary outcome was development of any malignancies excluding NMSC. For confounding control, tocilizumab starters were propensity score (PS)-matched to TNFi starters with a variable ratio of 1:3 within each database. Hazard ratios (HR) from the 3 PS-matched cohorts were combined by an inverse variance-weighted, fixed-effects model. We conducted a secondary analysis where we compared tocilizumab initiators with abatacept initiators. We included 13,102 tocilizumab initiators PS-matched to 26,727 TNFi initiators in all three databases. The incidence rate of malignancies per 1,000 person-years ranged from 8.27 (IMS) to 23.18 (Medicare) in the tocilizumab group and from 9.64 (MarketScan) to 21.46 (Medicare) in the TNFi group. The risk of incident malignancies was similar between tocilizumab and TNFi initiators across all three databases, with a combined HR of 0.98 (95%CI 0.80-1.19) in tocilizumab versus TNFi. The secondary analysis comparing tocilizumab versus abatacept showed similar results (combined HR 0.97, 95%CI 0.74-1.27).
This large multi-database cohort study found no difference in the risk of malignancies excluding NMSC in RA patients who newly started tocilizumab compared with TNFi or abatacept.
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To identify the genetic cause of chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) using whole-exome sequencing in a child who had typical clinical features but who was NLRP3 mutation negative based on conventional Sanger sequencing. We performed whole-exome sequencing on DNA from peripheral blood, using Illumina TruSeq Exome capture and the HiSeq sequencing platform. Exome data were analyzed in the Galaxy Web-based suite. Whole-exome sequencing findings were confirmed by massively parallel sequencing. Analysis of variants in known autoinflammatory genes led to the identification of the pathogenic p.F556L NLRP3 missense mutation in 17.7% of Illumina reads (25 of 141). No new candidate genes were identified. Massively parallel sequencing of DNA from peripheral blood (performed in duplicate) unequivocally confirmed the presence of this mutation in 14.5% of alleles. Reexamination of the original Sanger chromatograms revealed a small peak at nucleotide position c.1698 corresponding to the mutated allele. This had initially been regarded as background noise, but in retrospect is completely consistent with somatic mosaicism for the p.F556L NLRP3 mutation in this child with CINCA syndrome.
This is the first description of somatic NLRP3 mosaicism detected using whole-exome sequencing in a "mutation-negative" patient with CINCA syndrome. Our findings suggest that whole-exome sequencing could be an important diagnostic tool for detecting somatic mosaicism, as well as for the discovery of novel causative gene mutations, in patients with clinical features of cryopyrin-associated periodic syndromes who are NLRP3 mutation negative by conventional sequencing. This approach could also be applicable to patients with other autosomal-dominant autoinflammatory diseases characterized by gain-of-function mutations who are mutation negative by conventional Sanger sequencing.
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To investigate the effect of suppressing inflammation on retinal microvascular health in patients with RA. Two groups of patients with RA were recruited and studied concurrently. Group A included patients with moderate to high disease activity [28-joint DAS with CRP (DAS28-CRP) >3.2] requiring treatment escalation, while group B had stable low disease activity (DAS28-CRP ≤3.2) not requiring treatment escalation. Retinal photography was performed at baseline and weeks 6 and 24 in group A and at baseline and week 12 in group B. Group A included 26 patients with a mean age of 50.7 years (s.d. 3.5) and a mean disease duration of 7.1 years (s.d. 8.0). Disease activity significantly improved during follow-up and was accompanied by a significant reduction in retinal venular calibre at week 6 [mean difference (MD) -7.9 μm (95% CI -13.3, -2.5)] and at week 24 [MD -6.8 μm (95% CI -12.2, -1.4)]. No significant change in retinal arteriolar calibre was identified at week 6 [MD -0.6 μm (95% CI -4.5, 3.28)] or week 24 [MD 0.7 μm (95% CI -3.1, 4.5)]. Group B included 27 patients with a mean age of 54.6 years (s.d. 1.8) and a mean disease duration of 14.5 years (s.d. 10.9). Disease activity and therapy remained unchanged during follow-up and no significant changes in retinal venular [MD 1.81 μm (95% CI -2.32, 5.95)] or arteriolar [MD 0.54 μm (95% CI -2.77, 3.86)] calibre were observed.
We demonstrated that suppression of inflammation in RA is associated with a reduction of retinal venular calibre, suggesting that therapies targeting inflammation could improve vascular health in RA.
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High prolactin (PRL) levels have been reported in systemic lupus erythematosus, Reiter's syndrome, and psoriatic arthritis. However, results of PRL investigations in rheumatoid arthritis (RA) are contradictory. We evaluated the PRL status in men with RA and the possible effect on bone mineral density (BMD). We studied 91 men with RA and 68 controls. PRL serum levels were analyzed under standardized conditions. Sex hormones (testosterone, androstenedione, and DHEAS) were also studied. BMD was analyzed at L2-L4 and the femoral neck by Hologic QDR1000. Comparative tests, linear correlations, and multiple regression analysis were performed. Serum PRL levels were significantly higher in men with RA (249+/-162 mU/l) than in controls (189+/-85 mU/l) (p=0.0015). High PRL levels were significantly correlated with the duration of RA (r=0.23; p=0.01) and with functional stage according to the Steinbrocker classification (r=0.24; p=0.01). High PRL concentrations were not correlated with the low levels of androgens observed in males with RA. Femoral BMD showed a negative correlation with PRL concentrations (r=0.20; p=0.04). Nevertheless, PRL was not a significant determinant of BMD.
Men with RA have high serum PRL levels and concentrations increase with longer disease evolution and worse functional stage. Prolactin levels do not have a direct effect on BMD.
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Meniscus injury increases the risk of osteoarthritis; however, the biologic mechanism remains unknown. We hypothesized that pro-inflammatory stimulation of meniscus would increase production of matrix-degrading enzymes, cytokines and chemokines which cause joint tissue destruction and could contribute to osteoarthritis development. Meniscus and cartilage tissue from healthy tissue donors and total knee arthroplasties (TKAs) was cultured. Primary cell cultures were stimulated with pro-inflammatory factors [IL-1β, IL-6, or fibronectin fragments (FnF)] and cellular responses were analyzed by real-time PCR, protein arrays and immunoblots. To determine if NF-κB was required for MMP production, meniscus cultures were treated with inflammatory factors with and without the NF-κB inhibitor, hypoestoxide. Normal and osteoarthritic meniscus cells increased their MMP secretion in response to stimulation, but specific patterns emerged that were unique to each stimulus with the greatest number of MMPs expressed in response to FnF. Meniscus collagen and connective tissue growth factor (CTGF) gene expression was reduced. Expression of cytokines (IL-1α, IL-1β, IL-6), chemokines (IL-8, CXCL1, CXCL2, CSF1) and components of the NF-κB and tumor necrosis factor (TNF) family were significantly increased. Cytokine and chemokine protein production was also increased by stimulation. When primary cell cultures were treated with hypoestoxide in conjunction with pro-inflammatory stimulation, p65 activation was reduced as were MMP-1 and MMP-3 production.
Pro-inflammatory stimulation of meniscus cells increased matrix metalloproteinase production and catabolic gene expression. The meniscus could have an active biologic role in osteoarthritis development following joint injury through increased production of cytokines, chemokines, and matrix-degrading enzymes.
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Spinal gout is rarely encountered in clinical practice, is easily misdiagnosed, and often remains undiagnosed. This paper aims to provide some clues that are the salient diagnostic features of spinal gout, particularly axial pain, radiculopathy, and myelopathy, as determined on the basis of our experience with a few cases as well as a literature review. We retrospectively reviewed the clinical data of 5 patients that were treated for axial pain and neurological symptoms associated with spinal gout between 2014 and 2017 in our hospital. Herein, we systematically describe the clinical characteristics of 5 patients with spinal gout. The 5 patients included 4 men and 1 woman, aged between 24 and 75 years. The most common clinical presentation included spinal pain, radiculopathy, and myelopathy. Four of the 5 patients had a history of gout and elevated serum uric acid levels. Four patients underwent surgery, while the remaining patient underwent conservative treatment and biopsy due to poor general condition. Pathological examination of the surgical samples in the 4 surgical cases and the biopsy sample in the remaining case confirmed the presence of spinal gout tophi. The neurological symptoms of all 5 patients were relieved after treatment.
Due to its rarity and lack of typical defining criteria, the diagnosis of spinal gout is quite difficult. We recommend that patients presenting with axial pain; radicular pain or myelopathy; and especially high uric acid levels, with or without a history of gout, should be evaluated for spinal gout. Timely pathological examination of surgical or biopsy samples would help confirm the diagnosis and enable practitioners to provide the appropriate treatment to prevent disease progression.
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Until now there have been no appropriate models for metacarpophalangeal osteoarthritis (OA), even though OA in this joint is a significant medical and economic problem in horses. A good model would be useful to evaluate progression and treatment of OA, particularly in this joint. Therefore, we translated the canine Groove model to the ovine metacarpophalangeal (fetlock) joint. Cartilage surfaces of the metacarpal side of one fetlock joint were surgically damaged (grooved), followed by intermittent forced loading of the experimental joint. After 15 and 37 weeks, cartilage, synovial tissue and subchondral bone were analyzed by the use of macroscopy, histology, biochemistry and micro-CT. Technically, the model was difficult to use because cartilage surfaces were very thin. Nonetheless, all macroscopic, histologic, and biochemical cartilage parameters demonstrated adverse changes in chondrocyte activity and matrix integrity. Decreased proteoglycan content suggested slow progression of cartilage degeneration over time, while synovial inflammation diminished. Impaired subchondral bone quality and osteophyte formation were found. Although osteophyte formation was progressive, subchondral bone changes diminished over time.
The canine Groove model appears to a limited extent transferable to the ovine fetlock joint. However, despite development of adverse changes consistent with early changes of OA, use of the Groove model in the ovine fetlock joint has technical limitations. Using larger animals, such as horses, may significantly improve the technical procedures and with that may provide a more reliable model of metacarpophalangeal OA that is based primarily on intrinsic cartilage damage, appropriate to evaluate the progression and treatment of OA in this particular joint.
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To investigate the role of HLA-DRB1 genotypes and HLA-DRB1*0401-DQB1*03 haplotypes in the expression of extraarticular manifestations and rheumatoid factor (RF) in rheumatoid arthritis (RA). 189 patients with RA were classified according to the presence of vasculitis and seropositivity for RF. IgM RF were determined by at least 2 of the following methods: standard latex agglutination, the Waaler-Rose test, and nephelometry. HLA genotyping was performed by reverse dot blot hybridization for DRB1 alleles and the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for DQB1 alleles. The QKRAA susceptibility sequence, which characterizes the HLA-DRB1*0401 allele, was observed in 71.5% of the 21 patients with vasculitis and 57.6% of the 158 RF positive patients. The influence of a 2nd allele within the major histocompatibility complex was observed but the allele differed according to the clinical features examined. Higher risk for vasculitis was observed in patients who carried 2 DRB1 susceptibility alleles, one characterized by the QKRAA sequence and the other by the QRRAA sequence (OR = 3). Conversely, the higher risk for IgM RF positivity was observed in patients who carried the QKRAA sequence of the DRB1 alleles with the DQB1*0301 alleles of the DQ region (OR = 4.7).
Our data suggest that a distinct immunogenetic association is involved in the extraarticular manifestations of RA and in the expression of RF.
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To determine whether stromal cell-derived factor-1 (SDF-1) concentrations in serum, plasma, and synovial fluid differed among untrained, race-trained, and osteochondral-injured Thoroughbred racehorses. 22 racehorses without osteochondral injury and 37 racehorses with osteochondral injury. Horses without osteochondral injury were examined before and after 5 to 6 months of race training. Horses with osteochondral injury were undergoing arthroscopic surgery for removal of osteochondral fragments from carpal or metacarpophalangeal or metatarsophalangeal joints (fetlock joints). Serum, plasma, and fetlock or carpal synovial fluid samples were obtained and analyzed for SDF-1 concentration by use of an ELISA. In horses with fetlock or carpal joint injury, mean synovial fluid SDF-1 concentrations were significantly higher, serum SDF-1 concentrations were significantly lower, and synovial fluid-to-serum SDF-1 ratios were significantly higher than in untrained and trained horses. Synovial fluid SDF-1 concentrations were not significantly different between trained and untrained horses. Plasma SDF-1 concentrations were not different among the 3 groups. Results obtained with serum, compared with synovial fluid and plasma, had better sensitivity for differentiating between osteochondral-injured horses and uninjured horses. In horses with fetlock joint osteochondral injury, serum SDF-1 concentrations were correlated with radiographic and arthroscopic inflammation scores, but not arthroscopic cartilage scores.
Results suggested that serum SDF-1 concentrations were more sensitive than plasma and synovial fluid concentrations for detection of osteochondral injury in the fetlock or carpal joint of racehorses. Analysis of serum and synovial SDF-1 concentrations in horses with experimentally induced joint injury may help define the onset and progression of post-traumatic osteoarthritis and aid in the evaluation of anti-inflammatory treatments.
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Value-based health care is increasingly used for developing health care services by relating patient outcomes to costs. A hierarchical value scorecard for creating outcome measurements has been suggested: the 3-tier model. The objective of this study was to test the model against the patient's view of value in a chronic care setting. Semistructured interviews with 22 persons with rheumatoid arthritis were conducted, transcribed, and analyzed using qualitative content analysis. Themes were extracted, and the model was critically applied and revised. The study validates existing dimensions in the model but suggests adding information, social health, predictability, and continuity to make it more useful and representative of patients' preferences.
Although the model aims to focus on outcomes relevant to patients, it lacks dimensions important to individuals with rheumatoid arthritis. The data illustrate difficulties in finding patients' preferred outcomes and imply tactics for arriving at meaningful measurements.
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Osteoarthritis of the trapeziometacarpal joint is a common and painful affliction that can be diagnosed using conventional X‑ray imaging as well as arthroscopy and if necessary treated; however, the X‑ray classification often does not sufficiently demonstrate the cartilage damage found in arthroscopy. The aim of the study was to evaluate the diagnostic accuracy of conventional X‑ray imaging compared to arthroscopy for osteoarthritis of the trapeziometacarpal joint. The preoperative conventional X‑ray images of 23 patients were presented to 10 experienced hand surgeons who were blinded to the arthroscopy results. Their ratings were compared to the results found with arthroscopy. Of the patients 11 were found to have grade 4 cartilage lesions according to the Outerbridge classification, 8 grade 3 lesions, 4 grade 2 lesions and no grade 1 lesions. Overall, 43% (95% confidence interval, CI 37-49%) of the cartilage lesions were diagnosed correctly using conventional X‑rays. For grade 4 lesions 73% (95% CI 65-81%) of the surgeons made the correct diagnosis, in the case of grade 3 lesions 38% (95% CI 27-49%) and in grade 2 lesions 13% (95% CI 3-23%).
This study presents an arthroscopy classification system that is specific for osteoarthritis of the trapeziometacarpal joint and provides an additional method of assessment if the X‑ray grading of osteoarthritis according to Eaton and Littler is too unspecific. Arthroscopy can be used to safely differentiate the treatment-relevant stage and also includes treatment options.
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Cell-based therapies have made an impact on the treatment of osteoarthritis; however, the repair and regeneration of thick cartilage defects is an important and growing clinical problem. Next-generation therapies that combine cells with biomaterials may provide improved outcomes. We have developed modular microenvironments that mimic the composition of articular cartilage as a delivery system for consistently differentiated cells. Human bone marrow-derived mesenchymal stem cells (MSC) were embedded in modular microbeads consisting of agarose (AG) supplemented with 0%, 10% and 20% collagen Type II (COL-II) using a water-in-oil emulsion technique. AG and AG/COL-II microbeads were characterized in terms of their structural integrity, size distribution and protein content. The viability of embedded MSC and their ability to differentiate into osteogenic, adipogenic and chondrogenic lineages over 3 weeks in culture were also assessed. Microbeads made with <20% COL-II were robust, generally spheroidal in shape and 80 ± 10 µm in diameter. MSC viability in microbeads was consistently high over a week in culture, whereas viability in corresponding bulk hydrogels decreased with increasing COL-II content. Osteogenic differentiation of MSC was modestly supported in both AG and AG/COL-II microbeads, whereas adipogenic differentiation was strongly inhibited in COL-II containing microbeads. Chondrogenic differentiation of MSC was clearly promoted in microbeads containing COL-II, compared with pure AG matrices.
Inclusion of collagen Type II in agarose matrices in microbead format can potentiate chondrogenic differentiation of human MSC. Such compositionally tailored microtissues may find utility for cell delivery in next-generation cartilage repair therapies.
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Exposure to psychosocial stressors may contribute to the onset of systemic lupus erythematosus (SLE) through dysregulation of the adaptive stress response. The present study was undertaken to assess the relationship of childhood physical and sexual abuse to risk of SLE among Black women. Using data from the Black Women's Health Study, we followed 36,152 women from 1995 through 2015 with biennial questionnaires. Women reported on exposure to abuse during childhood (up to age 11) in 2005. Self-reported cases of incident SLE were confirmed as meeting the American College of Rheumatology SLE classification criteria by medical record review. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for SLE among women exposed to physical or sexual abuse during childhood, controlling for potential confounders. We confirmed 101 cases of incident SLE and identified patients who had completed questions on child abuse during 670,822 person-years of follow-up. Both physical and sexual abuse during childhood were associated with statistically significant increases in SLE incidence. The HR for SLE associated with ≥2 episodes of severe sexual abuse compared to no abuse was 2.51 (95% CI 1.29-4.85) after adjustment for alcohol consumption, smoking, body mass index, oral contraceptive use, age at menarche, and parental education. The multivariable-adjusted HR for SLE with ≥5 episodes of severe physical abuse was 2.37 (95% CI 1.13-4.99).
Our results suggest that sexual and physical abuse during childhood increase SLE risk during adulthood among Black women. Research is necessary both to confirm this finding and to understand potential mediating mechanisms.
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To test the hypothesis that joint hyperlaxity can play some role in the pathogenesis of pain in primary fibromyalgia. A total of 66 women with fibromyalgia (according to the 1990 American College of Rheumatology criteria) and 70 women with other rheumatic diseases were examined for joint laxity based on 5 criteria (The Non-Dominant Spanish modification). Individuals meeting 4 or 5 criteria were considered to be hyperlax. Joint hyperlaxity was detected in 18 (27.3%) of the patients with fibromyalgia and 8 (11.4%) of those with another rheumatic disorder. The statistical analysis revealed significant differences (P < 0.05) between both groups.
The results of this study suggest that joint hypermobility and fibromyalgia are associated. Joint hyperlaxity may play a prominent role in the pathogenesis of pain in fibromyalgia.
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To explore patients' experiences from initial symptoms to receiving a diagnosis of gout. Data from in-depth semistructured interviews were used to construct themes to describe key features of patients' experiences of gout diagnosis. A maximum variation sample of 43 UK patients with gout (29 men; 14 women; age range 32-87 years) were recruited from general practices, rheumatology clinics, gout support groups and through online advertising. Severe joint pain, combined with no obvious signs of physical trauma or knowledge of injury, caused confusion for patients attempting to interpret their symptoms. Reasons for delayed consultation included self-diagnosis and/or self-medication, reluctance to seek medical attention, and financial/work pressures. Factors potentially contributing to delayed diagnosis after consultation included reported misdiagnosis, attacks in joints other than the first metatarsophalangeal joint, and female gender. The limitations in using serum uric acid (SUA) levels for diagnostic purposes were not always communicated effectively to patients, and led to uncertainty and lack of confidence in the accuracy of the diagnosis. Resistance to the diagnosis occurred in response to patients' beliefs about the causes of gout and characteristics of the people likely to be affected. Diagnosis prompted actions, such as changes in diet, and evidence was found of self-monitoring of SUA levels.
This study is the first to report data specifically about patients' pathways to initial consultation and subsequent experiences of gout diagnosis. A more targeted approach to information provision at diagnosis would improve patients' experiences.
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The aim of this study was to develop a specific immunoassay for PIIANP and measure its serum concentration in healthy controls and in patients with osteoarthritis (OA) and rheumatoid arthritis (RA). In addition, we investigated circulating forms recognized by antiserum IIA in pools of serum from healthy adults, patients with OA and patients with RA. Using as immunogen and standard the recombinant human Glutathione S-Transferase (GST)-exon 2 fusion protein of type II collagen, we developed a competitive polyclonal antibody-based ELISA. We compare serum PIIANP levels in 43 patients with knee OA (23 women and 20 men; mean age: 62.6+/-9.6 yr), 63 women with RA (mean age: 54+/-16 yr) and 88 healthy controls (67 women, mean age: 53+/-13 yr and 21 men, mean age: 63+/-7 yr). We randomly selected serum in each group for analyze circulating forms. The immunoassay we developed demonstrated adequate intra and inter-assay precision (CV<10%) and dilution recovery (mean: 96%), allowing accurate measurements of serum PIIANP from 1.13 to 40 ng/ml. No significant cross-reactivity of the ELISA was observed with purified intact human procollagen type I N-propeptide, circulating thrombospondin and von Willebrand factor, proteins which exhibit significant sequence homology with PIIANP. Western blot analysis showed that antiserum IIA recognized two circulating immunoreactive forms of approximately 80 and 100 KDa respectively in serum from healthy adults, patients with OA and RA but also in a pool of synovial fluids from patients with OA. Serum PIIANP levels were markedly decreased in patients with knee OA (12.0+/-3.2 vs 25.8+/-7.5 ng/ml for OA and controls respectively, P<0.0001) and RA (14.1+/-2.5 ng/ml vs 21.7+/-7.6 ng/ml for RA and controls respectively, P<0.0001). In patients with RA, serum PIIANP levels were higher in those taking low-dose prednisone compared to non-users (15.0+/-2.4 vs 13.5+/-2.4 ng/ml, P<0.05).
We have developed the first specific immunoassay for serum PIIANP which exhibits adequate technical performances. This assay detects specifically two immunoreactive forms both in healthy adults and patients with arthritis and does not cross react with other proteins with sequence homology with PIIANP. Levels of PIIANP were significantly decreased in patients with knee OA and RA suggesting that type IIA collagen synthesis may be altered in these arthritic diseases. The measurement of type IIA collagen synthesis with this new molecular marker may be useful for the clinical investigation of patients with joint diseases.
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Trauma- or osteoarthritis-related cartilage damage resulted in functional decline of joints and heavy burden of public health. Recently, the reparative role of mesenchymal stem/progenitor cells (MSCs) in articular cartilage (AC) reconstruction is drawing more and more attention. To provide a review on (1) the locations and categories of joint-resident MSCs, (2) the regulation of chondrogenic capacities of MSCs, (3) the migratory approaches of MSCs to diseased AC and regulatory mechanisms. PubMed and Web of Science were searched for English-language articles related to MSC recruitment and migration for AC repair until June 2019. The presence of various MSCs in or around joints, the potential approaches to diseased AC` and the regenerative capacities of MSCs were reviewed. Various intra- and peri-articular MSCs, with inherent migratory potentials, are present in multiple stem cell niches in or around joints. The recruitment and migration of joint-resident MSCs play crucial roles in endogenous AC repair. Multiple recruiting signals, such as chemokines, growth factors, etc., emerge during the development of AC diseases and participate in the regulation of MSC mobilization. Motivated MSCs could migrate into cartilage lesions and then exert multiple reparative potentials, including extracellular matrix (ECM) reconstruction and microenvironment modulation.
In general, AC repair based on endogenous MSC recruitment and migration is a feasible strategy, and a promising research field. Furthermore, endogenous AC repair mediated by native MSCs would provide new opportunities to efficient preventative or therapeutic options for AC diseases.
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Arthroscopic knee surgery has been a topic of significant controversy in recent orthopaedic literature. Multiple studies have used administrative (Victorian Admitted Episodes Dataset and Centre for Health Record Linkage) data to identify trends in practice. This study explored the usage and reporting of arthroscopic knee surgery by conducting a detailed audit at a major Victorian public hospital. A database of orthopaedic procedures at St Vincent's Hospital Melbourne was used to retrospectively identify cases of knee arthroscopy from 1 December 2011 to 1 April 2014. Procedures were categorized as diagnostic or interventional, and native and prosthetic joints were analysed separately. Procedure codes were reviewed by comparing a registrar, auditor and hospital coders for agreement. Of the 401 cases for analysis, 375 were conducted in native knees and 26 in prosthetic joints. Of native knees, 369 (98.4%) were considered interventional. The majority of these were conducted for meniscal pathology (n = 263, 70.1%), osteoarthritis (OA) (n = 25, 6.7%) and infection (n = 28, 7.6%). Comparison of codes assigned by different parties were found to be between 57% (k = 0.324) and 70% (k = 0.572) agreement, but not statistically significant.
In this study, the most common indication for arthroscopy was meniscal pathology. Arthroscopy was rarely performed for OA in the absence of meniscal pathology. Diagnostic arthroscopy was rarely performed in the native knee, and fair to moderate agreement existed between parties in assigning Medicare Benefits Schedule procedure codes.
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The aim of this study was to define characteristic MRI findings in the spine of patients with axial spondyloarthritis (SpA) and provide a definition of a positive spinal MRI for inflammation and structural changes. Technical details of spinal MRI and the description of spinal lesions of both inflammation and structural changes were discussed in consecutive meetings of 10 experts of the Assessment in SpondyloArthritis international Society (ASAS). The discussions aimed at a broad consensus on definitions of 'a positive spinal MRI' for both types of lesions and were backed up by a systematic literature search. A total of six different types of lesions were described for inflammation--anterior/posterior spondylitis, spondylodiscitis, arthritis of costovertebral joints, arthritis of zygoapophyseal joints and enthesitis of spinal ligaments--and another four for structural changes--fatty deposition, erosions, syndesmophytes and ankylosis. In the literature review, four relevant papers were identified. Anterior/posterior spondylitis and fat depositions at vertebral edges were considered as the most typical findings in SpA. Based on expert consensus and taking the literature review into consideration, a positive spinal MRI for inflammation was defined as the presence of anterior/posterior spondylitis in ≥3 sites. Evidence of fatty deposition at several vertebral corners was found to be suggestive of axial SpA, especially in younger adults. ASAS members (n=56) approved these definitions by voting in January 2010.
This consensus statement gives clear descriptions of disease-related spinal lesions and of definitions of a positive spinal MRI for inflammatory lesions (spondylitis) and structural changes (fat deposition). These definitions can be used to describe findings of spinal MRI in patients with SpA in daily practice and clinical studies.
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Introduction The early detection of systemic sclerosis (SSc) patients at high risk of developing digital ulcers could allow preventive treatment, with a reduction of morbidity and social costs. In 2009, a quantitative score, the capillaroscopic skin ulcer risk index (CSURI), calculated according to the formula 'D×M/N(2'), was proposed, which was highly predictive of the appearance of scleroderma digital ulcers within 3 months of capillaroscopic evaluation. This multicentre study aims to validate the predictive value and reproducibility of CSURI in a large population of SSc patients. CSURI was analysed in 229 unselected SSc patients by nailfold videocapillaroscopy (NVC). All patients were re-evaluated 3 months later with regard to the persistence and/or appearance of new digital ulcers. 57 of 229 patients presented with digital ulcers after 3 months. The receiver operating characteristic curve analysis showed an area under the curve of 0.884 (95% CI 0.835 to 0.922), with specificity and sensitivity of 81.4% (95% CI 74.8 to 86.89) and 92.98% (95% CI 83.0 to 98.0), respectively, at the cut-off value of 2.96. The reproducibility of CSURI was validated on a random sample of 81 patients, with a κ-statistic measure of interrater agreement of 0.8514.
The role of CSURI was confirmed in detecting scleroderma patients with a significantly high risk of developing digital ulcers within the first 3 months from NVC evaluation. CSURI is the only method validated to predict the appearance of digital ulcers and its introduction into routine clinical practice might help optimise the therapeutic strategy of these harmful SSc complications.
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To compare the knee-alignment angle from a full-limb radiograph (mechanical axis) with the anatomic-axis angle as measured by physical examination using a goniometer and by 2 other radiographic methods. The knee-alignment angle was measured in 114 knees of 57 subjects who had radiographic osteoarthritis (OA), with a Kellgren/Lawrence grade of >/=1 in at least one knee. The mechanical axis was defined as the angle formed by the intersection of 2 lines, one from the center of the head of the femur to the center of the tibial spines, and a second from the center of the talus to the center of the tibial spines. The anatomic axis was defined as the angle formed by 2 lines, each originating from a point bisecting the femur and tibia and converging at the center of the tibial spine tips. The anatomic-axis angle was measured by 3 methods: 1) physical examination using a goniometer, 2) a posteroanterior (PA) fixed-flexion knee radiograph (anatomic(PA) axis), and 3) an anteroposterior (AP) full-limb radiograph (anatomic(AP) axis). Significant correlations were found between the mechanical-axis angle and the anatomic-axis angle measured by each of the 3 methods: by goniometer (r = 0.70, P < 0.0001), by anatomic(PA) axis (r = 0.75, P < 0.0001), and by anatomic(AP) axis (r = 0.65, P < 0.0001). The anatomic axis was offset a mean 4.21 degrees valgus from the mechanical axis (3.5 degrees in women, 6.4 degrees in men), which was consistent across all methods.
Knee alignment assessed clinically by goniometer or measured on a knee radiograph is correlated with the angle measured on the more cumbersome and costly full-limb radiograph. These alternative measures have the potential to provide useful information regarding the risk of progression of knee OA when a full-limb radiograph is not available.
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The aim of this study was to assess the differences in infection rates between rituximab (RTX) and non-RTX treatment in patients with rheumatoid arthritis (RA). A systematic review and meta-analysis was conducted by searching databases of PubMed, MEDLINE, EMBASE, Web of Science and Cochrane Library through to June 2018. We included studies that compared RTX and non-RTX treatment for patients with RA. Outcome measures were overall infections and serious infections between RTX and non-RTX treatments. A total of 11 articles, including 9502 patients (4595 with RTX treatment and 4907 with non-RTX treatment) met our inclusion criteria. The results demonstrated that RTX-related all infections and serious infections in RA patients were 43.8% and 4.4%, respectively. Pooled analysis showed no significant differences between RTX and non-RTX treatment groups in overall infections rate (43.3% vs 44.9%; odds ratio [OR] = 0.87; 95% CI = 0.70-1.08) and serious infections rate (4.1% vs 4.6%; OR = 1.05; 95% CI = 0.84-1.31). Subgroup analysis also showed no significant differences in overall infections between RTX versus placebo (OR = 0.98, 95% CI = 0.71-1.33); RTX versus tumor necrosis factor inhibitors (TNFi) (OR = 0.47, 95% CI = 0.30-1.73); RTX plus methotrexate (MTX) versus placebo plus MTX (OR = 0.98, 95% CI = 0.77-1.24), and in serious infections between RTX versus placebo (OR = 1.06, 95% CI = 0.36-3.07); RTX versus TNFi (OR = 1.25, 95% CI = 0.96-1.63); RTX plus MTX versus placebo plus MTX (OR = 0.69, 95% CI = 0.39-1.20).
In patients with RA, RTX treatment has no additional risks for infections over non-RTX treatment.
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The crosstalk between the immune and nervous system in the regulation of OA pain is increasingly becoming evident. GM-CSF signals in both systems and might be a new treatment target to control OA pain. Anti GM-CSF treatment has analgesic effects in OA without affecting synovitis scores, suggesting that treatment effects are not caused by local anti-inflammatory effects. We aimed to evaluate whether expression of GM-CSF and its receptor GM-CSFrα in synovial tissue is linked to synovial inflammation and/or knee pain in knee OA patients. Cartilage and synovial tissue of knee OA patients (n = 20) was collected during total knee replacement. Cartilage damage was evaluated by histology and ex vivo matrix proteoglycan turnover. Synovial inflammation was evaluated by histology and ex vivo synovial production of TNF-α, (PGE2) and nitric oxide (NO). Numbers of synovial tissue cells expressing GM-CSF or GM-CSFrα were determined by immunohistochemistry. Pain was evaluated using WOMAC questionnaire and visual analogue scale (VAS) knee pain. Collected cartilage and synovial tissue had a typical OA phenotype with enhanced cartilage damage and synovial inflammation. GM-CSF and GM-CSFrα expressing cells in the synovial sublining correlated negatively with knee pain. Cartilage damage and synovial inflammation did not correlate with knee pain. ToetsingOnline.nl NL18274.101.07.
Unanticipated, the negative correlation between synovial tissue cells expressing GM-CSF(r) and OA knee pain suggests that local presence of these molecules does not promote pain, and that the role of GM-CSFr in OA pain is unrelated to local inflammation.
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Inbred C57BL male mice express a high incidence of spontaneous osteoarthritis of the knee joint at the age of 18 months. We used this strain of mice to find out the effects of life-long, moderate running exercise on the health of articular cartilage and the incidence of osteoarthritis. Male mice (294) were divided into controls and runners. The runners were trained daily between 2 and 18 months of age. The speed was 13.3 m/min and the distance on a flatbelt treadmill was 1,000 m/day. The mice were sacrificed at the ages of 2, 6, 10, 14, and 18 months. The knee joints were sectioned in frontal direction and the osteoarthritic changes were graded using a conventional light microscope. The reproducibility of the grading method was tested by calculating the extended kappa-coefficient for the results of six researchers. The incidence of osteoarthritis at the age of 18 months increased from 72% in controls to 88% in runners in the medial tibial condyles (P < 0.05), and from 80 to 96% in the lateral tibial condyles (P < 0.001). The incidence of the most severe osteoarthritic changes rose from 16% in controls to 36% in runners in the medial tibial condyles, and from 4 to 36% in the lateral tibial condyles.
According to our results, the moderate, long-lasting running exercise accelerates the development of osteoarthritis in the knee joints of C57BL mice.
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Anemia of chronic disorders (ACD) and iron deficiency are common features in rheumatoid arthritis (RA), but may be difficult to distinguish without marrow sampling, which is invasive, time consuming, and expensive. We sought simple laboratory measures that identified patients with absent marrow iron stores (iron deficiency). 45 anemic patients with RA underwent marrow sampling in addition to a complete blood count and serum ferritin and iron saturation measurements. 47% of patients had iron deficiency. These patients had significantly lower mean corpuscular volume (MCV), serum ferritin, and iron saturation. A 3 step algorithm was developed using these laboratory variables to identify iron deficiency. This algorithm correctly classified 94% patients with iron deficiency and 85% with ACD.
Our study demonstrates that iron deficiency may be reliably identified by measuring serum ferritin, MCV, and iron saturation in many patients with RA, thereby avoiding the trauma and expense of marrow sampling.
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The aim of this study was to assess the accuracy of Veterans Affairs (VA) databases for gout-related health care utilization. This retrospective study utilized VA administrative and clinical databases. A random sample of gout patients with visits (outpatient, inpatient or emergent/urgent care) with or without the diagnosis of gout (International Classification of Diseases, ninth revision, common modification ICD-9-CM code of 274.x or 274.xx) at the Birmingham VA hospital was selected. A blinded abstractor performed a review of VA electronic health records for the documentation of gout or gout-related terms (gouty arthritis, tophaceous gout, tophus/tophi, acute gout, chronic gout, podagra, urate stones, urate or uric acid crystals and so on) in the chief complaint, history of present illness or assessment and plan for the visit; this constituted the gold standard for gout-related utilization. The accuracy of database-derived gout-related claims was assessed by calculating sensitivity, specificity, and positive and negative predictive values (PPV and NPV). Of 108 potential visits, 85 outpatient, inpatient or urgent care/emergency room visits to a health care provider (85 patients: 84 men and 1 woman with a mean age of 63 years) and retrievable data from medical records constituted the analyzed dataset. Administrative claims for gout-related utilization with ICD-9 code for gout were accurate with a PPV of 86%, specificity of 95%, sensitivity of 86% and NPV of 95%.
VA databases are accurate for gout-related visits. These findings support their use for studies of health services and outcome studies. It remains to be seen if these findings are generalizable to other settings and databases.
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Consistent terminology to describe the diagnostic criteria for fibromyalgia (FM) and myofascial pain syndrome (MPS) is required to address the reported inadequacies in diagnosis. The present review investigated intervention studies in FM and MPS populations to determine the lexicon of the current diagnostic criteria used to identify chronic musculoskeletal pain patients. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a scoping review to review systematically the literature obtained from five scientific databases between 1997 and February 2017. Included studies consisted of intervention studies that involved symptomatic musculoskeletal pain patients, of any age or gender, presenting with FM or MPS. Included studies were evaluated for musculoskeletal condition and the diagnostic criteria used to identify patient conditions. Extraction of study criteria focused on whether diagnostic criteria were explicitly stated, the diagnostic criteria used, physical findings, symptomatic duration and the profession of the healthcare provider who confirmed diagnosis. We identified 493 interventions, of which 410 were related to FM and 83 to MPS. The lexicon of the diagnostic criteria used for MPS tended to be less consistent in comparison to FM criteria, with notable differences in all comparative categories.
The current review identified inconsistencies associated with the lexicon of the diagnostic criteria used to diagnose FM and MPS, and showed that there is wide variability in the terminology currently being used. These findings may have important implications for future development of consistent criteria to diagnose FM and MPS patients accurately.
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To verify the distribution of different types of beta 1 integrin on the plasma membrane of chondrocytes and to correlate the pattern of integrin expression to the severity of osteoarthritis (OA). The articular cartilage of ten OA patients who had undergone surgical knee replacement for "genu varum" were studied. The cartilage was separated into three zones that macroscopically and microscopically showed a decreasing degree of anatomic lesions. After enzymatic digestion, the isolated chondrocytes were immediately challenged with monoclonal antibodies against the beta 1, alpha 1-6 and alpha v chains. The phenotypic study was paralleled by a cell cycle analysis performed by flow cytometry on chondrocytes stained with propidium iodide. Chondrocytes isolated from the articular cartilage of osteoarthritic patients expressed, in different percentages, all the alpha chains (alpha 1-6 and alpha v) of the beta 1 integrins. The alpha chain most frequently expressed was alpha 1, followed by alpha 3, alpha 5, alpha 2 and alpha v, with lesser amounts of alpha 4 and alpha 6. The beta 1 chain was expressed (on average) on the 40% of the chondrocytes regardless of the zone they were isolated from. Differential phenotypic analysis of the three zones showed that beta 1 integrins correlate inversely with the severity of the anatomic lesions and the cycle phase of the chondrocytes (the G0/G1 phase prevailed in the anatomically normal cartilage of the least damaged zone, and the S-phase in the most damaged zone).
This study provides evidence of the existence of beta 1 integrins on the surface of chondrocytes from human OA cartilage, all of the alpha chains being represented, although in different percentages. Moreover, an inverse correlation was demonstrated between the severity of the anatomical changes found in the zones and the phenotypic/metabolic changes of the cells. These results, together with the well known inside-out signaling function of the adhesion molecules, highlight the key role of matrix interactions in the pathogenesis of the anatomic changes in OA.
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With the introduction of high-throughput biomarker measurements, traditional analysis of these markers is increasingly difficult. Using samples from a diverse group of patients, we tested the applicability of cluster analysis to these data. Using this method, we aim to visualize some of the patterns specific to certain disease groups. In particular, we focus on juvenile idiopathic arthritis (JIA), a multifactorial autoimmune disorder that ultimately leads to chronic inflammation of the joints. Cytokine measurements were performed using multiplex immunoassays. Using heuristic clustering methods, we set out to compare the pattern of 30 cytokines in plasma and SF of JIA, RA, OA, or diabetes type II patients and healthy controls. Analysis shows that oligo- and polyarticular JIA have similar biomarker profiles, both in plasma and SF. Systemic onset JIA (SoJIA) has a profile distinct from other JIA subtypes, suggesting that they involve different inflammatory processes. SoJIA samples do, however, cluster together with RA in SF, suggesting that these two conditions have similar cytokine profiles. Furthermore, we identify several clusters of ILs and chemokines that are co-expressed, suggesting that they are co-regulated.
We show that previously undetected clusters of cytokines and patients can be identified by applying cluster analysis to multiplex data. Cytokine clusters identified in plasma and SF samples were quite different, which underscore the differential cytokine signalling in these two compartments, and suggest that plasma samples may not be suitable for estimating joint biomarker profiles and inflammation.
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To investigate the possible association of mannose-binding lectin (MBL) genotypes with the outcome of rheumatoid arthritis (RA). MBL genotypes and plasma concentrations were retrospectively determined in 140 RA patients who were selected from a major cohort followed up prospectively for up to 32 years. MBL-insufficient patients (those with 2 defective structural MBL alleles or with 1 defective allele combined with a low-expression variant of the normal allele) had unfavorable outcomes. The relative risk of a severe radiographic outcome event (30% of maximum radiographic destruction, or an RE30) was 3.1 (95% confidence interval 1.8-5.1) in the MBL-insufficient group versus the MBL-competent group (P < 0.0001). An RE30 occurred in 50% of MBL-competent patients within 17 years, while such an event occurred 9 years earlier in MBL-insufficient patients (i.e., within 8 years) (P < 0.0001). During the first 15 years, there was a significant trend toward lower hemoglobin levels (P < 0.04), higher erythrocyte sedimentation rates (P < 0.02), and a higher number of swollen joints (P < 0.05) in the MBL-insufficient group.
MBL genotypes giving rise to MBL insufficiency are highly significant risk factors for fast progression of radiographic joint destruction.
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To study the association of antibodies to proliferating cell nuclear antigen (PCNA) in patients with chronic hepatitis B (HBV) and C (HCV) virus infection. Sera from 243 patients with chronic HBV infection; 379 patients with chronic HCV infection; 80 patients with systemic lupus erythematosus (SLE); 28 patients with rheumatoid arthritis; 15 patients with Sjogren's syndrome; eight with polymyositis; eight with primary biliary cirrhosis; and 33 healthy control subjects were tested for the presentation of anti-PCNA antibodies by enzyme linked immunosorbent assay (ELISA) and immunoblotting using recombinant PCNA as antigen. The distribution of immunoglobulin isotypes of anti-PCNA antibody was measured by ELISA assay. By ELISA, anti-PCNA antibodies were detected in 30 (12.3%) patients with chronic HBV infection, 71 (18.7%) patients with chronic HCV infection, and five (6.3%) patients with SLE. The inhibition of binding with these sera by purified PCNA was shown to exceed 71%. By immunoblotting, the frequency of anti-PCNA in patients with chronic HBV and HCV infection was 17 of 243 (7%) and 41 of 379 (11%), respectively. Absorption studies on indirect immunofluorescence showed the typical nuclear speckled staining pattern by anti-PCNA sera was abolished by preincubation of sera with PCNA. Anti-PCNA antibody was not detected in sera from patients with autoimmune diseases except SLE. Anti-PCNA antibodies in patients with chronic HBV and HCV infection were predominantly IgG.
These data suggest that anti-PCNA antibody are also present in patients with chronic HBV and HCV infection. Anti-PCNA antibody may not be specific for SLE.
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To evaluate the longterm efficacy and safety of subcutaneous tocilizumab (TCZ-SC) every 2 weeks (q2w) over 2 years in patients with rheumatoid arthritis who have an inadequate response to disease-modifying antirheumatic drugs (DMARD). Patients (n = 656) were randomized 2:1 to TCZ-SC 162 mg q2w or placebo-SC q2w plus DMARD. After a 24-week double-blind period, patients (n = 457) were rerandomized to open-label TCZ-SC q2w by means of prefilled syringe or autoinjector. Escape therapy with weekly TCZ-SC was available for patients with inadequate efficacy from Week 12. Maintenance of response and safety to 2 years was assessed. Analyses used nonresponder imputation. The American College of Rheumatology (ACR) 20 response after TCZ-SC was maintained beyond Week 24 and was > 70% at each timepoint. ACR50/70, 28-joint Disease Activity Score remission, and ≥ 0.30 decrease from baseline in the Health Assessment Questionnaire-Disability Index response rates were also maintained after Week 24 in the TCZ-SC arm (≥ 50%, > 25%,> 32% and > 56%, respectively). Following escape for inadequate efficacy, many patients achieved ACR20 at the end of the study, 35% after escape from TCZ-SC, and 63% from placebo. The rates of serious adverse events [(11.20/100 patient-years (PY)] including serious infections (3.25/100 PY) were stable through Week 96. No association between anti-TCZ antibody development and loss of efficacy or adverse events was observed.
Efficacy and safety of TCZ-SC q2w was maintained up to 2 years and remained comparable with previously published data for intravenous TCZ. Dose escalation to weekly TCZ-SC was associated with ACR responses in prior nonresponders and was well tolerated.
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According to recent reports, the synovial membrane may contain mesenchymal stem cells with the potential to differentiate into chondrocytes under appropriate conditions. In order to assess the usefulness of synovium-derived progenitor cells for the purposes of cartilage tissue engineering, we explored their requirements for the expression of chondrocyte-specific genes after expansion in vitro. Mesenchymal progenitor cells were isolated from the synovial membranes of bovine shoulder joints and expanded in two-dimensions on plastic surfaces. They were then seeded either as micromass cultures or as single cells within alginate gels, which were cultured in serum-free medium. Under these three-dimensional conditions, chondrogenesis is known to be supported and maintained. Cell cultures were exposed either to bone morphogenetic protein-2 (BMP-2) or to isoforms of transforming growth factor-beta (TGF-beta). The levels of mRNA for Sox9, collagen types I and II and aggrecan were determined by RT-PCR. When transferred to alginate gel cultures, the fibroblast-like synovial cells assumed a rounded form. BMP-2, but not isoforms of TGF-beta, stimulated, in a dose-dependent manner, the production of messenger RNAs (mRNAs) for Sox9, type II collagen and aggrecan. Under optimal conditions, the expression levels of cartilage-specific genes were comparable to those within cultured articular cartilage chondrocytes. However, in contrast to cultured articular cartilage chondrocytes, synovial cells exposed to BMP-2 continued to express the mRNA for alpha1(I) collagen.
This study demonstrates that bovine synovium-derived mesenchymal progenitor cells can be induced to express chondrocyte-specific genes. However, the differentiation process is not complete under the chosen conditions. The stimulation conditions required for full transformation must now be delineated.
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The femoral component anteversion during surgery is traditionally assessed by a visual assessment of the surgeon and has proven to be imprecise. We sought to determine the accuracy of a digital protractor and a spirit level to measure the stem anteversion during cementless THA. A prospective study was conducted among 107 patients (114 hips) who underwent primary cementless THA via posterolateral approach. A pipe with a spirit level was attached to the tibial tubercle and intermalleolar midpoint. While the leg was held perpendicularly to the floor, stem anteversion was estimated by 3 methods: method A by visual assessment; method B by a digital protractor alone; and method C by a digital protractor combined with a spirit level. The angles were compared with the true anteversion measured by postoperative CT scan. The average anteversion by method C (22.8° ± 6.9°, range -2° to 40°) was significantly lower than method A (24.6° ± 5.2°, range 0° to 30°) (p=0.033), but not different from the true anteversion (22.1° ± 8.2°, range -5.4° to 43.1°) (p=0.445). There were no significant differences between method B (23.2° ± 8.2°, range -4° to 45°) and method A, C or the true anteversion. The mean deviation of the intraoperative estimation from the true anteversion was 0.8° ± 3.7° (range -7.1° to 8.0°) by method C; 1.2° ± 5.1° (range -8.8° to 14.3°) by method B; and 2.5° ± 7.4° (range -19.0° to 16.0°) by method A. Estimation error within 5° was found in 107 hips (93.9%) with method C; 86 hips (75.4%) with method B; and 59 hips (51.8%) with method A. Thai Clinical Trials Registry ( TCTR 20180326003 ). Registered on 20 March 2018. Retrospectively registered.
Accurate estimation of stem anteversion during cementless THA can be determined intraoperatively by the use of a digital protractor and a spirit level.
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To assess the psychometric properties of the Health Assessment Questionnaire (HAQ) disability index (DI) in patients with gout. This study was conducted in a multicenter cohort of patients with gout whose data were collected at baseline (time 0) and 6 months later (time 6). Reliability was assessed by test-retest reliability (intraclass correlation coefficient [ICC]) and internal consistency (Cronbach's alpha coefficient). Construct validity was assessed with convergent validity (HAQ DI correlation with Short Form 36 [SF-36]) and discriminative validity (HAQ DI correlation with clinical features). Sensitivity to change was determined by comparing HAQ DI time 0 versus HAQ DI time 6 (percentage of change, effect size, smallest real difference [SRD], and Guyatt's responsiveness index [GRI]). We included 206 patients (96.6% men, mean +/- SD age and disease duration 56.3 +/- 12.4 years and 9.3 +/- 8.5 years, respectively). Of these, 52.4% had joint pain, 22.8% swelling, 32.5% reduced joint mobility, and 36.9% tophi. The mean HAQ DI score was 0.59 +/- 0.77 (95% confidence interval [95% CI] 0.49-0.70). ICC (n = 36, evaluations at baseline and 5 days later) was 0.76. Cronbach's alphas were 0.91 (95% CI 0.88-0.92, P = 0.000) for the 20 HAQ DI items and 0.93 (95% CI 0.92-0.94, P = 0.000) for the 8 HAQ DI categories. The HAQ DI correlated in predictable ways with SF-36 subscales and clinical variables, and discriminated between subgroups with and without any joint pain, swelling, and tophi. Concerning sensitivity to change (n = 167), the difference between HAQ DI time 0 and HAQ DI time 6 was 0.31 +/- 0.58 (effect size 0.62, SRD 0.59, and GRI 1.91). DeltaHAQ DI correlated with Deltapain (r = 0.349, P = 0.000).
The HAQ DI is a valid and reliable measure of functioning in patients with gout.
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Fibromyalgia syndrome (FM) is a systemic disease of unknown etiology, which can cause widespread musculoskeletal pain. In patients with rheumatoid arthritis (RA), FM can cause an additional symptom burden, which can affect some variables on the RA disease activity score 28 (DAS28), a tool that evaluates 28 joints in RA patients. Compare the results of four different versions of the DAS28 and the parameters used to determine disease activity scores in RA patients with and without FM, and determine whether there are treatment differences between RA patients with and without FM. Retrospective, cross-sectional. Tertiary hospital. We identified patients diagnosed with RA between 1 September 2016 and 1 February 2020 and identified patients with and without FM. Differences between variables in the DAS28 calculations (tender joint count [TJC], patient global assessment [PGA], and others), between patients with and without FM, and differences between patients with and without FM who were using or not using biological agents. 381, including 322 females (84.5%). The frequency of FM in RA patients was 25.7% (89 females, 24.6%). In RA patients with FM, the TJC and PGA median values were significantly higher than in patients without FM ( A single center, retrospective study. None.
The presence of FM in RA patients may affect the subjective variables in different versions of DAS28 scores, causing the disease activity to score higher on the instrument, erroneously indicating worse disease than is actually present.
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Increased infection risk after total knee arthroplasty (TKA) in patients with a higher body mass index (BMI), particularly a BMI ≥40kg/m Medline and CINAHL databases were examined from Jan 2010 to May 2020 to identify high-level and/or clinically-influential evidence (systematic reviews, meta-analyses and clinical practice guidelines). The literature does not show a clear relationship between weight loss and reduction in TKA complications, and no indication that a patients' individual risk is lowered by reducing their BMI from a threshold of ≥40kg/m
Evidence to support a benefit of weight loss prior to TKA is lacking. Until knowledge gaps are clarified, it is recommended that practitioners consider individual patient needs and risk before recommending weight loss (and therefore BMI reduction).
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To generate knockin mice that express a tamoxifen-inducible Cre recombinase from the Prg4 locus (Prg4(GFPCreERt2) mice) and to use these animals to fate-map the progeny of Prg4-positive articular cartilage cells at various ages. We crossed Prg4(GFPCreERt2) mice with Rosa26(floxlacZ) or Rosa26(mTmG) reporter strains, admin-istered tamoxifen to the double heterozygous offspring at different ages, and assayed Cre-mediated recom-bination by histochemistry and/or fluorescence microscopy. In 1-month-old mice, the expression of the Prg4(GFPCreERt2) allele mirrored the expression of endogenous Prg4 and, when tamoxifen was admin-istered for 10 days, caused Cre-mediated recombination in ∼70% of the superficial-most chondrocytes. Prg4(GFPCreERt2)-expressing cells were mostly confined to the top 3 cell layers of the articular cartilage in 1-month-old mice, but descendants of these cells were located in deeper regions of the articular cartilage in aged mice. On embryonic day 17.5, Prg4(GFPCreERt2)-expressing cells were largely restricted to the superficial-most cell layer of the forming joint, yet at ∼1 year, the progeny of these cells spanned the depth of the articular cartilage.
Our results suggest that Prg4-expressing cells located at the joint surface in the embryo serve as a progenitor population for all deeper layers of the mature articular cartilage. Also, our findings indicate that Prg4(GFPCreERt2) is expressed by superficial chondrocytes in young mice, but expands into deeper regions of the articular cartilage as the animals age. The Prg4(GFPCreERt2) allele should be a useful tool for inducing efficient Cre-mediated recombination of loxP-flanked alleles at sites of Prg4 expression.
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IgG4-related systemic disease, a disorder recognized only recently, can cause lymphoplasmacytic inflammation in the thoracic aorta. The percentage of cases caused by IgG4-related systemic disease is not known. We aimed to determine the percentage of noninfectious thoracic aortitis cases that are associated with IgG4-related systemic disease and to establish pathologic criteria for identifying involvement of the thoracic aorta by this disorder. We searched our Pathology Service database to identify patients with noninfectious thoracic aortitis who underwent resection over a 5-year time span. The histologic features of these cases were reviewed. All cases of lymphoplasmacytic aortitis and representative cases of giant cell aortitis and atherosclerosis were stained by immunohistochemistry for IgG4 and for the plasma cell marker CD138. We determined the fraction of plasma cells that stained for IgG4. Of 638 resected thoracic aortas, 33 (5.2%) contained noninfectious aortitis. Four of these cases (12% of all patients with noninfectious aortitis) had histologic features of lymphoplasmacytic aortitis. Three of those 4 cases (9% of the noninfectious aortitis cases) demonstrated pathologic involvement by IgG4-related systemic disease, with an elevated proportion of plasma cells staining for IgG4 (mean +/- SD 0.82 +/- 0.08) compared with cases of giant cell aortitis (0.18 +/- 0.13) and atherosclerosis (0.19 +/- 0.08; P < 0.00001).
IgG4-related systemic disease accounted for 75% of lymphoplasmacytic aortitis cases and 9% of all cases of noninfectious thoracic aortitis in our institution during a 5-year period. Immunohistochemical assessment of the percentage of plasma cells that stained for IgG4 in resected aortas was helpful in identifying patients with IgG4-related systemic disease.
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To describe 2 cases of parvovirus B19 (B19) infection mimicking systemic lupus erythematosus (SLE) and to identify all cases of SLE imitated by and/or associated with B19 in the medical literature. A computer-assisted (PubMed) search of the medical literature from 1975 to 2003 was performed using the following key words: parvovirus, B19, SLE, lupus, antibodies, auto-immunity. Thirty-eight patients were identified: 35 women, 3 men; mean age = 28.8 years. Clinical manifestations were as follows: fever (24 patients); articular involvement (36 patients); cutaneous lesions (28 patients); lymphadenopathy (9 patients); hepato- and/or splenomegaly (6 patients); serositis (6 patients); renal involvement (4 patients); cerebral impairment (10 patients). Cytopenia was observed in 23 cases. Antinuclear antibodies were detected in 34 patients, anti-double-stranded DNA antibodies in 20 patients, anti-Sm antibodies in 4 patients, antinuclear ribonucleoprotein antibodies in 5 patients, anti-Ro-SSA antibodies in 4 patients, anti-La-SSB antibodies in 4 patients, and anticardiolipin and/or anti-beta2-glycoprotein I antibodies in 8 patients. Hypocomplementemia was found in 15 of 26 patients. In 19 cases, the B19 infection had a self-limiting course. In 6 cases, B19 infection occurred in a context of previously established SLE, simulating SLE exacerbation. In 6 observations, symptoms persisted several months after the viral infection. In 7 cases, the exact relationship between SLE and B19 could not be determined.
B19 infection may present a clinical and serological tableau making it difficult to distinguish between a viral infection and the first episode of SLE. Although B19 may modulate the clinical and biological features of rheumatic disease, studies in large series do not support a causative role for B19 in the pathogenesis of SLE.
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Identification of universal biomarkers to predict systemic lupus erythematosus (SLE) flares is challenging due to the heterogeneity of the disease. Several biomarkers have been reported. However, the data of validated biomarkers to use as a predictor for lupus flares show variation. This study aimed to identify the biomarkers that are sensitive and specific to predict lupus flares. One hundred and twenty-four SLE patients enrolled in this study and were prospectively followed up. The evaluation of disease activity achieved by the SLE disease activity index (SLEDAI-2K) and clinical SLEDAI (modified SLEDAI). Patients with active SLE were categorized into renal or non-renal flares. Serum cytokines were measured by multiplex bead-based flow cytometry. The correlation and logistic regression analysis were performed. Levels of IFN-α, MCP-1, IL-6, IL-8, and IL-18 significantly increased in active SLE and correlated with clinical SLEDAI. Complement C3 showed a weakly negative relationship with IFN-α and IL-18. IL-18 showed the highest positive likelihood ratios for active SLE. Multiple logistic regression analysis showed that IL-6, IL-8, and IL-18 significantly increased odds ratio (OR) for active SLE at baseline while complement C3 and IL-18 increased OR for active SLE at 12 weeks. IL-18 and IL-6 yielded higher sensitivity and specificity than anti-dsDNA and C3 to predict active renal and active non-renal, respectively.
The heterogeneity of SLE pathogenesis leads to different signaling mechanisms and mediates through several cytokines. The monitoring of cytokines increases the sensitivity and specificity to determine SLE disease activity. IL-18 predicts the risk of active renal SLE while IL-6 and IL-8 predict the risk of active non-renal. The sensitivity and specificity of these cytokines are higher than the anti-dsDNA or C3. We propose to use the serum level of IL-18, IL-6, and IL-8 to monitor SLE disease activity in clinical practice.
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There is an enrichment of immune response genes that are subject to copy number variations (CNVs). However, there is limited understanding of their impact on susceptibility to human diseases. CC chemokine ligand 3 like-1 (CCL3L1) is a potent ligand for the HIV coreceptor, CC chemokine receptor 5 (CCR5), and we have demonstrated previously an association between CCL3L1-gene containing segmental duplications and polymorphisms in CCR5 and HIV/AIDS susceptibility. Here, we determined the association between these genetic variations and risk of developing systemic lupus erythaematosus (SLE), differential recruitment of CD3+ and CD68+ leukocytes to the kidney, clinical severity of SLE reflected by autoantibody titres and the risk of renal complications in SLE. We genotyped 1084 subjects (469 cases of SLE and 615 matched controls with no autoimmune disease) from three geographically distinct cohorts for variations in CCL3L1 and CCR5. Deviation from the average copy number of CCL3L1 found in European populations increased the risk of SLE and modified the SLE-influencing effects of CCR5 haplotypes. The CCR5 human haplogroup (HH)E and CCR5-Delta32-bearing HHG*2 haplotypes were associated with an increased risk of developing SLE. An individual's CCL3L1-CCR5 genotype strongly predicted the overall risk of SLE, high autoantibody titres, and lupus nephritis as well as the differential recruitment of leukocytes in subjects with lupus nephritis. The CCR5 HHE/HHG*2 genotype was associated with the maximal risk of developing SLE.
CCR5 haplotypes HHE and HHG*2 strongly influence the risk of SLE. The copy number of CCL3L1 influences risk of SLE and modifies the SLE-influencing effects associated with CCR5 genotypes. These findings implicate a key role of the CCL3L1-CCR5 axis in the pathogenesis of SLE.
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Rheumatoid arthritis is characterised by progressive joint destruction and loss of periarticular bone mass. Hand bone loss (HBL) has therefore been proposed as an outcome measure for treatment efficacy. A definition of increased HBL adjusted for age- and sex-related bone loss is lacking. In this study, we aimed to: 1) establish reference values for normal hand bone mass (bone mineral density measured by digital x-ray radiogrammetry (DXR-BMD)); and 2) examine whether HBL is normalised in rheumatoid arthritis patients during treatment with tumour necrosis factor alpha inhibitors (TNFI). DXR-BMD was measured from hand x-rays in a reference cohort (1485 men/2541 women) without arthritis randomly selected from an urban Danish population. Sex- and age-related HBL/year was estimated. DXR-BMD was measured in rheumatoid arthritis patients (n = 350: at start of TNFI, and ~2 years after TNFI start), of which 135 patients had three x-rays (~2 years prior to TNFI, at start of TNFI, and ~2 years after TNFI start). Individual HBL/year prior to and during TNFI was calculated and compared to reference values. Estimated HBL/year varied strongly with age and sex. Compared to the reference values, 75 % of 135 patients had increased HBL prior to TNFI treatment and 59 % had increased HBL during TNFI treatment (p = 0.17, Chi-squared). In 38 % (38/101) of patients with increased HBL, HBL was normalised during TNFI treatment, whereas 47 % (16/34) of patients with normal HBL prior to TNFI had increased HBL during TNFI treatment. In the 350 patients, increased HBL during TNFI was associated with time-averaged 28-joint disease activity score (odds ratio 1.69 (95 % Confidence Interval 1.34-2.15)/unit increase, p < 0.001), and patients in time-averaged remission had lower HBL than patients without remission (0.0032 vs. 0.0058 g/cm(2)/year; p < 0.001, Mann-Whitney).
We established age- and sex-specific reference values for DXR-BMD in a large cohort without arthritis. HBL was increased in the majority of rheumatoid arthritis patients initiating TNFI in clinical practice, and only normalised in a minority during TNFI.
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Danger patterns and pattern recognition receptors have been targets in the investigation and treatment of systemic inflammatory response syndrome and sepsis. Lipopolysaccharide (LPS)-binding protein (LBP) presents LPS and gram-positive bacterial cell wall products to the receptors TLR4/MD-2 and TLR2, respectively. Low concentrations of LBP stimulate responses to LPS and peptidoglycan, whereas higher concentrations inhibit these responses. Soluble CD14 (sCD14) presents the LBP-LPS complex to CD14-negative cells, and it modulates the biological activity of circulating LPS. In this study, we aimed to elucidate the physiological reactions to LBP and sCD14 after total hip replacement surgery during spinal/epidural anaesthesia. Seven patients with coxarthrosis were operated upon with a total hip replacement, which is a defined trauma to bone and muscles in conjunction with a certain amount of blood loss. Venous blood samples were taken before the operation and at 1 h, 3 days and 6 days after surgery. LBP and sCD14 were measured by conventional ELISA. To correct for hemodilution, each parameter was adjusted for hematocrit. A panel of cytokines was measured using Luminex technology to evaluate the trauma reaction. IL-6 levels peaked 24 h after the operation, whereas IL-1β and IL-10 levels remained unchanged. Systemic levels of LBP were increased 24 h after surgery, whereas sCD14 remained steady. However, the dilution-corrected sCD14 values increased significantly, and the levels of both LBP and sCD14 peaked at day 3 after surgery.
Aseptic trauma primes the innate immune system for the posttraumatic release of LBP and sCD14.
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The sequential medial release technique including semimembranosus (semiM) release is effective and safe during varus total knee arthroplasty (TKA). However, there are concerns about weakening of knee flexion strength after semiM release. We determined whether semiM release to balance the medial soft tissue decreased knee flexion strength after TKA. Fifty-nine consecutive varus knees undergoing TKA were prospectively enrolled. A 3-step sequential release protocol which consisted of release of (1) the deep medial collateral ligament (dMCL), (2) the semiM, and (3) the superficial medial collateral ligament based on medial tightness. Gap balancing was obtained after dMCL release in 31 knees. However, 28 knees required semiM release or more after dMCL release. Isometric muscle strength of the knee was compared 6 months postoperatively between the semiM release and semiM nonrelease groups. Knee stability and clinical outcomes were also compared. No differences in knee flexor or extensor peak torque were observed between the groups 6 months postoperatively (P = .322 and P = .383, respectively). No group difference was observed in medial joint opening angle on valgus stress radiographs (P = .327). No differences in the Knee Society or Western Ontario and McMaster Universities Osteoarthritis Index scores were detected between the groups (P = .840 and P = .682, respectively).
These results demonstrate that semiM release as a sequential step to balance medial soft tissue in varus knees did not affect knee flexion strength after TKA.
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To analyse the levels of C-reactive protein (CRP), IL-1, IL-6 and IL-1 receptor antagonist (IRA) in the blood of patients with early gonarthrosis (GA). Clinical, x-ray and arthrosonographic examinations to stage GA, to identify knee joint synovitis, degree of pain and joint dysfunction were made in 62 males and females with early GA and 20 healthy donors. The levels of CRP, IL-1, IL-6 and IRA were measured with reference to GA stage and activity of the inflammatory process. CRP levels did not differ significantly in synovitis and no synovitis, in different GA stages, in patients and normal controls. Cytokines, except IL-6, were significantly higher in patients with knee joint osteoarthrosis (KJO). The highest levels of IL-1 and the lowest of IRA occurred in the group of roentgen-negative patients versus patients with the pathological process of stage I and II. The cytokines content did not reflect severity of inflammation in the knee joints.
In early GA inflammation may be not systemic. CRP level does not correlate with activity of local joint inflammation. Most active cartilage tissue degradation takes place at the earliest (preroentgenological) stage of KJO. This stage is most appropriate for initiation of active pathogenetic therapy of the disease.
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The aim of this study was to clarify the mechanism of leucocytapheresis (LCAP) in patients with RA. Protein profiles of blood samples from two patients with RA obtained via LCAP column inlet and outlet lines were analysed by two-dimensional fluorescence difference gel electrophoresis and mass spectrometry. The lactoferrin (LTF) levels of peripheral and circulating blood samples from seven patients obtained via the LCAP column blood circuit were then determined by ELISA. Peripheral blood samples from 14 patients with RA were exposed to unwoven polyester fibre filters and the LTF level was determined. In addition, morphological changes in neutrophils after exposure to the filter were examined by optical microscopy, electronic microscopy and LTF immunostaining. LTF levels were increased in both samples from the LCAP column outlet and peripheral blood at the end of LCAP treatment. Furthermore, peripheral blood samples exposed to the filter revealed a decreased number of neutrophils and an increased level of LTF. Morphological analysis of the exposed neutrophils showed vacuolization of the cytoplasm and degranulation of LTF-positive granules. These data suggest that LTF stored in the granules of neutrophils is released from the neutrophils caught in the LCAP column.
Because LTF has been reported to have multiple anti-inflammatory properties, increased levels of LTF may contribute to the clinical effect of LCAP in patients with RA.
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Juvenile primary fibromyalgia syndrome (JPFS) is a chronic condition characterized by widespread musculoskeletal pain and discrete tender points with no objective evidence of a muscle disease but with disordered central pain processing. Very little is known about the prevalence and treatment on inpatient psychiatric units. The purpose of this study was to determine the effect of an intervention for JPFS in adolescent females admitted to a psychiatric hospital. In total, 30 patients with JPFS were assigned to either the intervention (n = 15) or control group (n = 15). The intervention group attended a fibromyalgia seminar followed by an audio-guided total body relaxation exercise. The control group participated in a seminar on skin care. Both groups completed a visual analog scale for affective states and somatic sensations before and after the seminar. Participants in the intervention group, but not the control group, demonstrated significant improvement in concentration, self-confidence, restfulness and comfort level (p < 0.001 to p < 0.05). They also reported a reduction in stress level, muscle tightness, stomach upset and feeling down (p < 0.001 to p < 0.05) immediately after the intervention.
This study provides evidence that a combined intervention can be used in the inpatient psychiatric setting to improve functioning and overall well-being of patients with comorbid psychiatric disorders and JPFS during acute hospitalization.
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20,719
It has been reported that low skeletal muscle mass correlates with knee osteoarthritis in obese individuals. This study aimed to investigate whether lower limb skeletal muscle mass is independently associated with knee osteoarthritis in the general population. This cross-sectional study used public data from the Fourth and Fifth Korean National Health and Nutrition Examination Survey. Subjects included 4924 community-dwelling adults aged ≥50 years (821 subjects with knee osteoarthritis and 4,103 controls). Skeletal muscle mass index (SMI) was calculated from the appendicular skeletal muscle mass measured by dual energy X-ray absorptiometry. Independent effects of total and lower limb SMI values on knee osteoarthritis were determined using odds ratios (OR) adjusted for age, sex, obesity, total femur bone mineral density, serum vitamin D level, diabetes mellitus status, and physical activity on multivariate logistic regression analysis. The adjusted logistic regression model revealed that older age, female sex, and obesity were significantly associated with knee osteoarthritis. A higher serum vitamin D level was also positively correlated with knee osteoarthritis (OR, 1.015; 95% CI, 1.003-1.027; P = 0.010). Although total SMI was not significantly associated with knee osteoarthritis (OR, 0.976; 95% CI, 0.946-1.007; P = 0.127), a low lower limb SMI had an independent effect on knee osteoarthritis (OR, 0.941; 95% CI, 0.900-0.983; P = 0.006).
Low skeletal muscle mass in the lower limbs but not in the whole body was independently associated with knee osteoarthritis.
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27,236
The aim of this study was to evaluate the medium-term results of total knee replacements (TKRs) after medial opening wedge valgising tibial osteotomy to those of primary TKR (TKR1). The hypothesis being that there would be no difference in results between these groups. Series 1 was made up of 45 TKRs after medial opening wedge high tibial osteotomy (MHTO)-30 men and ten women at an average age of 69 ± seven years (54-82). This was compared to a second series of TKR1s-30 men and ten women at an average age of 69 ± seven years (55-78). The average IKS scores were 91 ± 22.5 points (42-129) and 86 ± 18 points (38-116) in the two groups respectively. The average pre-operative HKA angle was 179 ± 5° (169-193°) in group 1, and 173 ± 7.5° (161-193°) in group 2. Tibial mechanical axes were 90.5 ± 4° (of which 24 knees had a valgus angle) and 85.05 ± 3.5° (79-93°) in the two groups respectively. All patients were reviewed at an average follow-up of 47 ± 24.5 months for series 1 and 185 ± 8.5 months for series 2. The average IKS score was 184 ± 6 for series 1 (172-200) and 185 ± 8.5 (163-200) for series 2 (p = 0.872). Thirty-seven patients in series 1 and 38 patients in series 2 were either extremely satisfied or satisfied with the intervention. The average post-operative HKA angle was 180.5 ± 2.5° and 181 ± 2° (p = 0.122) and the average tibial mechanical axis was 89 ± 1.5° against 90 ± 1° (p = 0.001). The results of the 24 knees with a valgus tibial mechanical axis were statistically no different.
TKRs post medial opening wedge high tibial osteotomy have identical results to primary TKRs even in knees with a valgus tibial mechanical axis.
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27,013
The purpose of this study was to assess the concurrent validity and sensitivity to change of three knee osteoarthritis (OA) grading scales. The Kellgren-Lawrence (KL) and the Osteoarthritis Research Society International (OARSI) joint space narrowing (JSN) grading scales are well-established. The third scale, the compartmental grading scale for OA (CG) is a novel scale which grades JSN, femoral osteophytes, tibial erosion and subluxation to create a total score. One sample of 72 posteroanterior (PA) fixed-flexion radiographs displaying mild to moderate knee OA was selected from the Multicenter Osteoarthritis Study (MOST) to study validity. A second sample of 75 radiograph pairs, which showed an increase in OA severity over 30 months, was selected to study sensitivity to change. The three radiographic grading scales were applied to each radiograph in both samples. Spearman's rank correlation coefficients were used to correlate the radiographic grades and the change in grades over 30 months with a Whole-organ Magnetic Resonance Imaging Score (WORMS)-based composite score which included five articular features of knee OA. Correlations between the KL, OARSI JSN and CG grading scales and the magnetic resonance image (MRI)-based score were 0.836, 0.840 and 0.773 (P < 0.0001) respectively while correlations between change in the radiographic grading scales and change in the MRI-based score were 0.501, 0.525 and 0.492 (P < 0.0001).
All three radiographic grading scales showed high validity and are suitable to assess knee OA severity. They showed moderate sensitivity to change; therefore caution should be taken when using ordinal radiographic grading scales to monitor knee OA over time.
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6,978
To assess if an integrated longitudinal analysis using all available imaging data affects the precision of estimates of change in patients with axial spondyloarthritis (axSpA), with completers analysis as reference standard. Patients from the DESIR cohort fulfilling the ASAS axSpA criteria were included. Radiographs and MRIs of the sacroiliac joints and spine were obtained at baseline, 1, 2 and 5 years. Each image was scored by 2 or 3 readers in 3 'reading-waves' (or campaigns). Each outcome was analyzed: i. According to a 'combination algorithm' (e.g. '2 out of 3' for binary scores); and ii. Per reader. Change over time was analyzed with generalized estimating equations by 3 approaches: (a)'integrated-analysis' (all patients with ≥1 score from ≥1 reader from all waves); (b1)Completers-only analysis (patients with 5-year follow-up, using scores from individual readers); (b2)Completers analysis using a 'combination algorithm' (as (b1) but with combined scores). Approaches (b1) and (b2) were considered the 'reference'. In total, 413 patients were included. The 'integrated analysis' was more inclusive with similar levels of precision of the change estimates as compared to both completers analyses. In fact, for low-incident outcomes (e.g.% mNY-positive over 5-years), an increased incidence was 'captured', with more precision, by the 'integrated analysis' compared to the completers analysis with combined scores (% change/year (95%CI): 1.1 (0.7; 1.5) vs 1.2 (0.5; 1.8), respectively).
An efficient and entirely assumption-free 'integrated analysis' does not jeopardize precision of the estimates of change in imaging parameters and may yield increased statistical power for detecting changes with low incidence.
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6,178
Rheumatoid arthritis (RA) is a risk factor for cardiovascular disease. The clinical consequences of coincident RA and coronary artery disease (CAD) are unknown. We aimed to estimate the impact of RA on the risk of adverse cardiovascular events in patients with and without CAD. A population-based cohort of patients registered in the Western Denmark Heart Registry, who underwent coronary angiography (CAG) between 2003 and 2016, was stratified according to the presence of RA and CAD. Endpoints were myocardial infarction (MI), major adverse cardiovascular events (MACE; MI, ischaemic stroke and cardiac death) and all-cause mortality. A total of 125 331 patients were included (RA: n=1732). Median follow-up was 5.2 years. Using patients with neither RA nor CAD as reference (cumulative MI incidence 2.7%), the 10-year risk of MI was increased for patients with RA alone (3.8%; adjusted incidence rate ratio (IRR
In patients undergoing CAG, RA is significantly associated with the 10-year risk of MI, MACE and all-cause mortality regardless of the presence of CAD. However, patients with RA and CAD carry the largest risk, while the additive risk of RA in patients without CAD is minor. Among patients with RA, risk stratification by presence or absence of documented CAD may allow for screening and personalised treatment strategies.
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There have been few studies of connective tissue diseases in Africa. A retrospective study was conducted in order to describe the various connective tissue diseases and their semiological profile in patients attending the dermatology and rheumatology units at Lomé hospital. Clinical examinations showed that eighty-four (0.2%) out of the 34,169 patients were suffering from connective tissue diseases. Diseases that were encountered were the following: scleroderma (18 cases), systemic lupus erythematosus (four cases), discoid lupus erythematosus (15 cases), rheumatoid arthritis (29 cases), polymyositis and dermatomyositis (16 cases), juvenile rheumatoid arthritis (one case), giant cell arteritis (one case). Raynaud's syndrome was present in six out of the 18 patients suffering from scleroderma. Nephrotic syndrome was observed in a patient suffering from systemic lupus erythematosus. A septicemia caused this patient's death. Two patients suffering from polymyositis had cancer. No etiology was found in the 14 other patients. Hip involvement was present in two patients suffering from rheumatoid arthritis. Patients with rheumatoid arthritis had no systemic involvement (nodulitis, vasculitis).
Our results are in agreement with those of previous studies on connective tissue diseases in Africa. However, further studies are required to better understand the epidemiological and semiological profiles of connective tissue diseases in Africa.
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To investigate the presence of inflammation and resolution pathways in osteoarthritis (OA). Tissues were obtained from knee OA patients and control rheumatoid arthritis (RA) patients. Cells in synovial fluid (SF) were visualized by flow cytometry. Cytokines and chemokines were measured by multiplex assay. Lipid mediators (LMs) were determined by targeted lipidomics using liquid-chromatography mass spectrometry. SF of OA patients contained less cells, especially neutrophils, less cytokines and comparable levels of chemokines compared to RA controls. Thirty-seven lipids were detected in the soluble fraction of SF, including polyunsaturated fatty acids (PUFAs) and their pro-inflammatory and pro-resolving lipoxygenase (LOX) and cyclooxygenase (COX) pathway markers in both OA and RA patients. Among these, pro-inflammatory LM such as prostaglandin E
By using a state-of-the-art technique, we show for the first time that resolution pathways are present in OA patients. A better understanding of these pathways could guide us to more effective therapeutic approaches to inhibit inflammation and further structural damage in OA and RA.
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40,118
To evaluate golimumab's effect on MRI-detected spinal inflammation in ankylosing spondylitis (AS). Patients were randomly assigned to subcutaneous injections of placebo (n=78), golimumab 50 mg (n=138), or golimumab 100 mg (n=140) every 4 weeks. An MRI substudy comprising 98 patients (placebo n=23, 50 mg n=37, 100 mg n=38) at eligible MRI substudy sites had serial spine MRI scans (sagittal plane, 1.5T scanners, T1 and short tau inversion recovery sequences) at baseline and weeks 14 and 104. Two blinded (treatment, image order) readers independently evaluated MRI spinal inflammation using AS spine MRI-activity (ASspiMRI-a) scores; reader scores were averaged. Changes from baseline to weeks 14 and 104 were compared among treatment groups using analysis of variance on van der Waerden normal scores both with (post-hoc) and without (prespecified) adjustment for baseline ASspiMRI-a scores. Median baseline ASspiMRI-a scores were lower in the 100 mg (3.5) than placebo (6.8) and 50 mg (7.8) groups. Median decreases in activity scores from baseline to week 14 were -0.5 for placebo, -3.5 for 50 mg (p=0.047 vs placebo), and -1.5 for 100 mg (p=0.14 vs placebo). After adjusting for baseline ASspiMRI-a score imbalance, significant improvements were observed with both 50 mg (p=0.011) and 100 mg (p=0.002) versus placebo. ASspiMRI-a scores improvement achieved with golimumab was maintained at week 104. Improvement in ASspiMRI-a scores correlated with improvement in the recently developed AS disease activity score (ASDAS) and C-reactive protein (CRP) levels but not with other key AS clinical outcomes.
Golimumab significantly reduced MRI-detected spinal inflammation of AS; improvements were sustained to week 104 and correlated with improvement in ASDAS and CRP.
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1,958
The Patient-Reported Outcomes Measurement Information System (PROMIS)-Plus-Osteoarthritis of the Knee (OAK) profile integrates universal PROMIS items with knee-specific items across 13 domains. We evaluated the psychometric properties of a subset of six domains associated with quality of life in people with OAK. In a cross-sectional study of OAK patients (n=600), we estimated reliability using Pearson and Spearman correlations with Knee Injury and Osteoarthritis Outcome Score (KOOS) subscores and known-groups validity with PROMIS Global Health. Measure responsiveness was tested via paired t-tests in a longitudinal study (n=238), pre/post total knee replacement. Across the six domains, internal consistency reliability (Cronbach's alpha) was 0.77-0.95 and test-retest reliability (intraclass correlation coefficients) was ≥0.90. Correlations with Knee Injury and Osteoarthritis Outcome Score (KOOS) subscores and PROMIS Global supported convergent and divergent validity. Known-groups validity testing revealed better scores in all domains for high vs. low global status groups, and knee-specific items added value in physical function and pain. All domains reflected (p<0.001) better health status scores at follow up.
The six PROMIS-Plus-OAK profile domains demonstrated good psychometric characteristics. The measure integrates universal and knee-specific content to provide enhanced relevance, measurement precision and efficient administration for patient care and clinical research.
4,872
6,675
Some uncertainty persists regarding the reproducibility of the recommended core set of performance-based tests, as well as common muscle function tests, when applied in individuals with knee osteoarthritis (KOA). The purpose of this study was to investigate the intrarater reliability and agreement of the recommended core set of performance-based tests and common muscle function tests in KOA. Participants (N=40) with radiographic and/or symptomatic KOA were evaluated twice with a 3-day interval between test sessions using the following tests: Leg extensor (LE) maximal muscle power measured in a Nottingham Power Rig; knee extensor (KE) peak isometric strength measured with a handheld dynamometer; 40-m walk test; 30-second chair-stand test; and 9-step stair climb test. Reliability was assessed using a 2-way, mixed-effects, single-measures model (3,1), absolute agreement-type intraclass correlation coefficient (ICC). Agreement was assessed using 95% limits of agreement (LOA) and LOA relative to the mean score from test and retest (LOA-%). Reliability for all tests was very high (ICC ≥ 0.97). LOA (LOA-%) was ±32.3 watt (W) (±22%) for LE power; ±22.7 N·m (±24%) for KE strength; ±0.2 m/s (±10%) for 40-m walk test; ±2.4 repetitions (±14%) for 30-second chair-stand test; and ±2 second (±20%) for stair climb test. A potential participant learning effect was found for all 3 performance-based tests, indicated by the significantly better scores at retest. The very high reliability found for the performance-based tests supports findings from previous studies and confirms discriminate reliability of these tests on a group level. Also, very high reliability estimates were demonstrated for both muscle function tests. This study also provided estimates of agreement for both performance-based and muscle function tests, which are important to consider when using these tests on an individual level in clinical practice.
When using these tests to monitor changes over time in the clinic, depending on the test, improvements of less than 10% to 24% could be a result of measurement error alone and therefore may not be considered an actual improvement after treatment.
4,873
24,042
Treg cell-mediated suppression of Teff cells is impaired in juvenile idiopathic arthritis (JIA); however, the basis for this dysfunction is incompletely understood. Animal models of autoimmunity and immunodeficiency demonstrate that a diverse Treg cell repertoire is essential to maintain Treg cell function. The present study was undertaken to investigate the Treg and Teff cell repertoires in JIA. Treg cells (CD4+CD25+CD127(low) ) and Teff cells (CD4+CD25-) were isolated from peripheral blood and synovial fluid obtained from JIA patients, healthy controls, and children with Lyme arthritis. Treg cell function was measured in suppressive assays. The T cell receptor β chain (TRB) was amplified by multiplex polymerase chain reaction and next-generation sequencing was performed, with amplicons sequenced using an Illumina HiSeq platform. Data were analyzed using ImmunoSEQ, International ImMunoGeneTics system, and the Immunoglobulin Analysis Tools. Compared to findings in controls, the JIA peripheral blood Treg cell repertoire was restricted, and clonotypic expansions were found in both blood and synovial fluid Treg cells. Skewed usage and pairing of TRB variable and joining genes, including overuse of gene segments that have been associated with other autoimmune conditions, was observed. JIA patients shared a substantial portion of synovial fluid Treg cell clonotypes that were private to JIA and not identified in Lyme arthritis.
We identified restriction and clonotypic expansions in the JIA Treg cell repertoire with sharing of Treg cell clonotypes across patients. These findings suggest that abnormalities in the Treg cell repertoire, possibly engendered by shared antigenic triggers, may contribute to disease pathogenesis in JIA.
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49,283
We examined the relationships of rheumatoid arthritis (RA), disease duration (DD), number of previous disease modifying antirheumatic drugs (DMARD), and frequency of DMARD changes, with regard to changes in function in patients with RA evaluated by modified Health Assessment Questionnaire (mHAQ) after the start of a new DMARD. In total, 889 patients with active RA from the CORRONA database [patients had mHAQ>or=0.5 and/or Disease Activity Score 28-joint count (DAS28)>or=1.6] started a new DMARD (baseline) and had at least one followup visit 6-12 mo later. Change in mHAQ from baseline to followup visit was modeled using univariate/multivariate linear regression analysis. Due to colinearity, separate multivariate regression models were performed including/excluding the predictors disease duration, number of prior DMARD, and frequency of DMARD changes. Baseline age, mHAQ, erythrocyte sedimentation rate (ESR), DAS28, and number of prior DMARD differed across DD groups. The univariate linear regression model showed that higher baseline values of mHAQ, DAS28, swollen joint count (SJC), tender joint count (TJC), Clinical Disease Activity Index (CDAI), ESR, physician global assessment, prednisone use, and subsequent addition/discontinuation of DMARD were associated with improvement of the mHAQ at followup (p=0.05). Multivariate linear regression models showed that mHAQ improvement was associated with shorter DD, higher baseline mHAQ, addition of subsequent DMARD, and the DMARD frequency index (no. previous DMARD/yrs of DD) (p<0.05). Number of DMARD patients used previously was not associated with change of mHAQ in either model.
Our study demonstrates that in clinical rheumatologic practices, more frequent changes in DMARD are associated with greater improvement in function (by mHAQ). It does not support the idea that number of previous DMARD used predicts response. Indirectly, these data support the concept that DMARD should be changed if optimal responses are not achieved within a specified time.
4,875
63,086
To examine the effect of a nonsteroidal antiinflammatory drug, carprofen, on the structure and metabolism of cartilage and subchondral bone in the experimental osteoarthritic (OA) canine model. Experimental Groups 1 and 2 received a sectioning of the anterior cruciate ligament (ACL) of the right stifle joint, and were administered carprofen (2.2 and 4.4 mg/kg/twice daily/po, respectively) for 8 weeks beginning 4 weeks postsurgery. Group 3 received ACL sectioning and no treatment. Group 4 was composed of unoperated normal dogs. Cartilage macroscopic lesions were assessed, and their histological severity was graded. Specimens of subchondral bones were fixed, decalcified, and stained with hematoxylin/eosin. The level of metalloprotease (MMP) activity in cartilage was measured. Osteoblast cells were prepared from the subchondral bone. The level of synthesis of osteoblast biomarkers (osteocalcin, alkaline phosphatase), as well as urokinase plasminogen activator (uPA) activity and insulin-like growth factor (IGF-1) in the culture medium, was estimated. Carprofen treatment decreased the width of osteophytes (p < 0.01), the size of cartilage lesions, and the histologic severity of cartilage lesions (p < 0.008). There was no difference in the levels of MMP activity in cartilage between OA and carprofen treated groups. In OA dogs, the subchondral bone plate was thinner and was the site of an extensive remodeling process with numerous lacunae. Dogs treated with carprofen showed a marked decrease in the remodeling activity with normal plate thickness, and subchondral bone morphology resembling that of normal dogs. Osteoblasts from untreated OA dogs showed slightly higher alkaline phosphatase activities and osteocalcin release that reverted back to normal upon carprofen treatment. Moreover, uPA activity and IGF-1 levels were increased in OA dogs and were significantly reduced in carprofen treated dogs.
Under therapeutic conditions, treatment with carprofen could reduce the progression of early structural changes in experimental OA. Carprofen treatment also delays and/or prevents the abnormal metabolism of subchondral osteoblasts in this model. The hypothesis of a possible link between the protective effect of carprofen and its effect on subchondral bone is of interest in the context of therapeutic intervention.
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Identification of predictors for the productivity cost components: (1) sick leave, and (2) work disability in gainfully employed and (3) impaired household productivity in unemployed patients with rheumatoid arthritis (RA) from the societal perspective. Investigation of productivity costs was linked to a multicenter, randomized, controlled trial evaluating the effectiveness of clinical quality management in 338 patients with RA. The productivity losses were assessed according to the German Guidelines on Health Economic Evaluation. By means of multivariate logistic regression analyses, predictors of sick leave, work disability (employed patients, n=96), and for days confined to bed in unemployed patient (n=242) were determined. Mean annual costs of 970 EUR arose per person taking into consideration all patients (453 EUR sick leave, 63 EUR work disability, 454 EUR impaired productivity of unemployed patients). Disease activity, disease severity, and impaired physical function were global predictors for all of the cost components investigated. Sick leave costs were predicted by prior sick leave periods and the vocational status blue collar worker, work disability costs by sociodemographic variables (marital status, schooling), and the productivity costs of unemployed patients by impaired mental health and impaired physical functions.
Interventions such as reduction in disease progression and control of disease activity, early vocational rehabilitation measures and vocational retraining in patients at risk of quitting working life, and self-management programs to learn coping strategies might decrease future RA-related productivity costs.
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24,115
To evaluate the time-dependent functional outcome of patients with lateral knee osteoarthritis with increased valgus treated with lateral opening-wedge osteotomy to shift the load from the lateral to the medial compartment of the knee. Twenty-four consecutive patients with lateral knee osteoarthritis were treated with distal femoral opening-wedge varus osteotomy stabilized with the Puddu plate and bone transplantation. The mean age of the patients was 48 years (CI 40.3-55.7, range 31-62). The patients were evaluated by the Knee Injury and Osteoarthritis Outcome Score (KOOS) preoperatively and at 3 and 6 months, 1, 2, 5 and 10 years post-operatively. The knee osteoarthritis was graded according to the Kellgren-Lawrence radiological scoring system. The mean follow-up time was 7.9 years (CI 6.8-9.0, range 4.0-10.2). The mean angular correction measured on pre- and post-operative radiographs was 9.6° (CI 7.7°-11.5°, range 4°-20°). All osteotomies healed. KOOS increased significantly during the first year by 28-122 % beyond the preoperative values for all the five subscores. This improvement remained at 10-year follow-up for those with surviving osteotomy. Six knees were converted to total knee arthroplasty (TKA) mean 6.4 years (CI 3.3-9.6, range 4.0-11.8) post-operatively. The osteotomy survival rate at 5 years was 88 % and at 10 years 74 %. The preoperative osteoarthritic grade did not increase significantly during the follow-up period, but was significantly correlated (r = -0.49), P = 0.019 to the KOOS subscore symptoms at the 2-year follow-up. IV.
Distal femoral opening-wedge osteotomy for lateral knee osteoarthritis resulted in good functional recovery after 1 year and favourable midterm results. It may be a good treatment option for middle-aged patients with valgus knees and lateral osteoarthritis in order to prevent or postpone TKA.
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3,685
We aimed to assess physical activity (PA) in children with juvenile idiopathic arthritis (JIA) compared with healthy peers and to determine factors influencing PA level. This was a cross-sectional study of the measured level of PA in children with JIA, compared with age- and gender-matched healthy schoolchildren. PA was estimated using a physical activity questionnaire for children and for adolescents (cPAQ/aPAQ). Disease activity was evaluated with the Juvenile Arthritis Disease Activity Score (JADAS). Functional ability was assessed with the Childhood Health Assessment Questionnaire (CHAQ). A total of 55 children with JIA and 55 healthy control schoolchildren were included. Children with JIA had significantly lower levels of PA compared with their healthy peers as assessed with the cPAQ/aPAQ (P=0.0121). In total, 76% of the JIA group spent the day sleeping and sitting, which was significantly higher compared with the reference group (P=0.001 and P=0.055, respectively). Low PA level was associated with systemic JIA (P=0.002, OR=2.123), polyarticular JIA with positive rheumatoid factor (P=0.001, OR=2.014), JADAS-27≥6 (P=0.001, OR=2.524), patients undergoing treatment (P=0.001, OR=1.271), and higher CHAQ (P=0.002, OR=2.461).
Children with JIA were less physically active than their healthy peers and less active than recommended for general health.
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15,836
It is thought that arthroscopic ankle fusion offers improved outcomes over open fusion in terms of functional outcomes, time to fusion, length of stay and fewer complications. However, there are doubts about whether correction of established severe deformity can be achieved using the arthroscopic approach. A retrospective review of medical records and radiographs at our hospital identified consecutive tibio-talar ankle fusions between April 2009 and March 2014 with minimum 1 year follow up. Records were scrutinised for type of arthrodesis, demographics, length of stay (LOS), time to fusion (TTF), pre- and postoperative deformity, complications and unplanned procedures. Significant factors in the complication group were then compared, using multivariate binary logistic backward stepwise regression to see if any factors were predictive. There were 29 open and 50 arthroscopic ankle fusions (2 converted to open). Mean LOS was 1.93 versus 2.52 days (p=0.590). TTF was shorter after arthroscopic fusion 196d versus 146d (p=0.083). Severe deformity (>10°) was correctable to within 5° of neutral in the majority of cases (97% versus 96%, p=0.903). Union occurred in 83% versus 98% (p=0.0134). The open arthrodesis group had 9 (31%) complications (1 death-PE, 1 SPN injury, 5 non-unions, 1 delayed union and 1 wound infection) and 6 (25%) screw removals. The arthroscopic arthrodesis group had 4 (8%) complications (1 non-union, 1 reactivation of osteomyelitis and subsequent BKA, 1 wound infection, 1 delayed union) with 11 (24%) screw removals. After multi-variant regression analysis of all ankle fusions, low BMI was shown to be associated with complications (p=0.064).
Open arthrodesis was associated with a higher rate of complications and a lower rate of fusion. However, there was no significant difference in terms of LOS and ability to correct deformity compared to arthroscopic arthrodesis. Overall, low BMI was also associated with more complications.
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63,180
To assess the prevalence and clinical and serological associations of anti-ribosomal P protein antibodies (anti-P antibodies) in patients with connective tissue diseases (CTDs) and investigate the immunobiological nature of autoantibody clustering in which anti-P antibodies play a part. IgG anti-P antibodies in the sera of 267 patients with CTDs and 31 healthy subjects were analysed by immunoblotting performed on cytoplasmic extract of Raji cells. 60 patients with systemic lupus erythematosus (SLE), 32 systemic sclerosis, 46 primary Sjögren's syndrome, 16 poly/dermatomyositis, 11 rheumatoid arthritis, 8 undifferentiated CTD, 72 overlap CTD, and 22 primary antiphospholipid syndrome were studied. Anti-P antibodies were affinity purified by elution from nitrocellulose bound antigen and tested by ELISA for their binding activity to cardiolipin. Anti-P antibodies were detected in 16 (6%) patients and in none of the controls: 12/60 SLE (20%) and 4/80 undifferentiated/overlap patients with CTD (5%). A close association of IgG antibodies with P proteins and with cardiolipin was seen in lupus sera (p=0.0009, odds ratio 18.33). Anti-P antibodies from 9 of 12 anti-P lupus serum samples could be affinity purified and none of the affinity purified fractions cross reacted with ELISA plate coated cardiolipin.
Anti-P immunoreactivity is a specific marker of SLE and lupus-like disease and its detection is recommended as a powerful diagnostic tool. Anti-P antibodies are strongly clustered with IgG anticardiolipin antibodies in lupus sera, even if they are independently elicited. This suggests that their cognate autoantigens play a part in a common pathogenetic pathway in SLE.
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52,741
To determine the genetic, clinical and serological characteristics of systemic sclerosis (SSc)-rheumatoid arthritis (RA) overlap syndrome. Clinical manifestations and immunolaboratory features of 22 SSc-RA patients were assessed. The HLA-DR genotype of the 22 SSc-RA patients determined by SSP-PCR was compared with that of 38 SSc patients, 100 RA patients and 50 healthy controls. All overlap patients fulfilled the American College of Rheumatology (ACR) criteria for SSc and RA. Five of the 22 patients (23%) had diffuse cutaneous SSc (dcSSc) and 17 patients (77%) had limited cutaneous SSc (lcSSc). Antinuclear antibody, anti-Scl70, IgM rheumatoid factor and anti-CCP antibody positivity were detected in 22 (100%), 5 (23%), 16 (73%) and 18 patients (82%), respectively. Seventeen patients (77%) had pulmonary fibrosis, 12 (55%) had oesophageal dismotility, 11 (50%) had cardiac and five (23%) had renal involvement. Hand joint destruction was observed in 18 patients (82%). Significantly increased frequencies of HLA-DR3 (36% vs 5%), HLA-DR7 (9% vs 4%), HLA-DR11 (36% vs 7%) and HLA-DRw53 (23% vs 5%) were observed in SSc-RA compared with RA patients (P < 0.05). Allele frequencies of the 'shared epitope' (HLA-DR1 and -DR4) were significantly increased in SSc-RA (32% and 27%, respectively) and RA patients (46% and 31%, respectively) in comparison with SSc patients (10.5% and 16%, respectively) or healthy controls (16% and 14%, respectively) (P < 0.05).
To date this is the largest SSc-RA overlap cohort. Genetics, clinical and immunolaboratory features suggest a mixed phenotype. Our data suggest that SSc-RA overlap syndrome may be a distinct genetic, immunological and clinical entity.
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28,771
Pain is the main problem for patients with osteoarthritis (OA). Pain is linked to inflammation, but in OA a subset of patients suffers from pain without inflammation, indicating an alternative source of pain. Nerve Growth Factor (NGF) inhibition is very efficient in blocking pain during OA, but the source of NGF is unclear. We hypothesize that damaged cartilage in OA releases Transforming Growth Factor-β (TGF-β), which in turn stimulates chondrocytes to produce NGF. Murine and human chondrocyte cell lines, primary bovine and human chondrocytes, and cartilage explants from bovine metacarpal joints and human OA joints were stimulated with TGF-β1 and/or Interleukin-1 (IL-1)β. We analyzed NGF expression on mRNA level with QPCR and stained human OA cartilage for NGF immunohistochemically. Cultures were additionally pre-incubated with inhibitors for TAK1, Smad2/3 or Smad1/5/8 signaling to identify the TGF-β pathway inducing NGF. NGF expression was consistently induced in higher levels by TGF-β than IL-1 in all of our experiments: murine, bovine and human origin, in cell lines, primary chondrocytes and explants cultures. TAK1 inhibition consistently reduced TGF-β-induced NGF whereas it fully blocked IL-1β-induced NGF expression. In contrast, ALK5-Smad2/3 inhibition fully blocked TGF-β-induced NGF expression. Despite the large variation in basal NGF in human OA samples (mRNA and histology), TGF-β exposure led to a consistent high level of NGF induction.
We show for the first time that TGF-β induces NGF expression in chondrocytes, in a ALK5-Smad2/3 dependent manner. This reveals a potential alternative non-inflammatory source of pain in OA.
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30,320
Total hip replacement (THR) outcomes have been worse for patients with rheumatoid arthritis (RA) compared with those who have osteoarthritis (OA). Whether this remains true in contemporary patients with RA with a high use of disease-modifying and biologic therapy is unknown. The purpose of our study is to assess pain, function, and quality of life 2 years after primary THR, comparing patients with RA and patients with OA. Baseline and 2-year data were compared between validated patients with RA and patients with OA who were enrolled in a single-center THR registry between May 1, 2007, and February 25, 2011. There were 5666 eligible primary THR identified, of which 193 were for RA. RA THR had worse baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain (44.8 vs 53.2, p < 0.001) and function (38.7 vs 49.9, p < 0.001) compared with OA. These differences remained after surgery: pain (88.4 vs 94.0, p < 0.001) and function (82.9 vs 91.8, p < 0.001). Patients with RA were as likely to have a significant improvement as patients with OA (Δ WOMAC > 10) in pain (94% vs 96%, p = 0.35) and function (95% vs 94%, p = 0.69), but were 4 times as likely to have worse function (WOMAC ≤ 60; 19% vs 4%, p < 0.001) and pain (12% vs 3%, p < 0.001). In multivariate logistic regression controlling for multiple potential confounders, RA increased the odds of poor postoperative function (OR 4.32, 95% CI 1.57-11.9), and in patients without a previous primary THR, worse postoperative pain (OR 3.17, 95% CI 1.06-9.53).
Contemporary patients with RA have significant improvements in pain and function after THR, but higher proportions have worse 2-year pain and function. In addition, RA is an independent predictor of 2-year pain and poor function after THR, despite high use of disease-modifying therapy.
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Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have an elevated risk of cardiovascular disease (CVD). This study was undertaken to develop a clearer understanding of the association between changes in disease activity and lipid levels in AAV, which may inform CVD risk stratification in this population. Lipid levels were assessed in stored serum samples (obtained at baseline and month 6) from the Rituximab for ANCA-Associated Vasculitis (RAVE) trial, which randomized patients to receive either rituximab or cyclophosphamide followed by azathioprine. Paired t-tests and multivariable linear regression were used to assess changes in lipid levels. Of the 142 patients with serum samples available, the mean ± SD age was 52.3 ± 14.7 years, 72 (51%) were male, 95 (67%) were proteinase 3 (PR3)-ANCA positive, 72 (51%) had received a new diagnosis of AAV, and 75 (53%) were treated with rituximab. Several lipid levels increased between baseline and month 6, including total cholesterol (+12.4 mg/dl [95% confidence interval (95% CI) +7.1, +21.0]), low-density lipoprotein (+10.3 mg/dl [95% CI +6.1, +17.1]), and apolipoprotein B (+3.5 mg/dl [95% CI +1.0, +8.3]). These changes were observed among newly diagnosed and PR3-ANCA-positive patients but not among those with relapsing disease or myeloperoxidase-ANCA-positive patients. There was no difference in change in lipid levels between rituximab-treated patients and cyclophosphamide-treated patients. Changes in lipid levels correlated with changes in erythrocyte sedimentation rate but not with other inflammatory markers or glucocorticoid exposure.
Lipid levels increased during remission induction among patients with newly diagnosed AAV and those who were PR3-ANCA positive. Disease activity and ANCA type should be considered when assessing lipid profiles to stratify CVD risk in patients with AAV.
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To review the efficacy and safety of pregabalin, an alpha(2)-delta (alpha(2)-delta) ligand, for the management of fibromyalgia (FM). Review of 2 pivotal phase 3 trials that evaluated the efficacy and safety of pregabalin for the management of FM. FM is a chronic condition that is characterized by widespread musculoskeletal pain and has a greater prevalence in women than in men. In a 14-week, randomized, double-blind trial, pregabalin at all 3 doses (300, 450, and 600 mg daily) resulted in significantly greater improvements in pain and function relative to placebo. Parallel with these improvements, greater proportions of patients in the pregabalin groups reported improvement in global disease status compared with placebo. In a second study designed to evaluate the durability of response, patients were randomized to up to 6 months of treatment with pregabalin or placebo after a 6-week, open-label, dose-optimization treatment phase. Based on predefined criteria for loss of therapeutic response, patients treated with pregabalin were observed to maintain a therapeutic response for a significantly longer duration than patients treated with placebo. Pregabalin was tolerated by most patients in both trials; the incidence of the most commonly reported adverse events (dizziness, somnolence, weight gain, headache, dry mouth) appeared to be dose-related.
Pregabalin has been demonstrated to be efficacious and well-tolerated for the management of FM.
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11,828
Silicone breast implants (SBI) may induce systemic autoimmune disease as part of autoimmune syndrome induced by adjuvants (ASIA). This syndrome bears similarities to fibromyalgia and chronic fatigue syndrome (CFS). We sought to determine whether there are any associations between SBI and depression, fibromyalgia and CFS in a rheumatology clinic population. The electronic files of rheumatology clinic patients at the Royal Adelaide Hospital between 2000 and 2017 were searched for patients who had received SBI prior to rheumatological diagnosis. Demographics, diagnosis, implant history and whether the patient had depression, fibromyalgia or CFS were recorded. Controls were rheumatology clinic patients, half of whom had systemic sclerosis (SSc) and the other half had systemic lupus erythematosus (SLE). They were matched to cases 3:1 for age (within 2 years) and gender. Thirty patients had received SBI (mean age 47.9, 100% female). Twelve had a diagnosis of depression, 6 of fibromyalgia and 3 of CFS. Implant rupture was not associated with any of these (p = 1). There was no difference in the incidence of depression (p = 1), fibromyalgia (p = 0.76) or CFS (p = 0.3) between cases and SLE controls. When compared with SSc controls, there were significantly more patients with fibromyalgia and/or CFS in the case group (20.0% of cases vs 2.2% of SSc controls, p = 0.01) but no difference in depression (p = 0.12).
Fibromyalgia and CFS are more common in patients with silicone implants than SSc controls but not SLE controls. Prospective study of development of depression, fibromyalgia and CFS in recipients of SBI is required.
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Tiludronate regulates bone remodelling through a decrease of the resorptive process and should therefore ameliorate the remodelling processes active in osteoarthritis of the distal tarsal joints ('bone spavin') and alleviate pain associated with abnormal bone lysis. To confirm the efficacy of tiludronate, administered as a single infusion at a dose of 1 mg/kg bwt, in the treatment of bone spavin in the horse. A double blind placebo controlled trial on 108 clinical cases of bone spavin was undertaken. The lameness score of the lamest limb was assessed following distal tarsal analgesia of the contralateral limb and followed-up using the same procedure throughout the study. Bone spavin in the lamest limb was confirmed by distal tarsal analgesia and radiography. Horses were treated at Day 0 and reassessed 60 days later after controlled exercise. A second nonblinded treatment was given to unresponsive horses and all horses were re-examined at Day 120. Exercise levels were recorded at each examination. Eighty-seven horses completed the trial as per the protocol. The tiludronate horses were significantly less lame than the placebo horses (P = 0.0318). Horses treated at Day 60 with tiludronate showed further improvement in lameness at Day 120 (P = 0.0096 and P = 0.0034 for horses treated with tiludronate and placebo at Day 0, respectively). The only significant difference in radiographic findings between tiludronate and placebo was for presence of periarticular osteophytes (P = 0.006). Tiludronate in combination with controlled exercise offers an alternate medical treatment for bone spavin.
Tiludronate treatment is proven to be effective in bone spavin in horses in association with a controlled exercise programme.
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Conflicting findings raise questions about the role of adiponectin in osteoarthritis (OA). The current study aimed to investigate in OA patients the association between the production of adiponectin and the grade of cartilage destruction, and to provide functional evidence for a potential role of adiponectin in OA. The expression of adiponectin was examined by immunohistochemistry in cartilage obtained from healthy individuals (n = 2; ages 56 and 41 years; 1 male and 1 female) and OA patients (n = 11; ages 64-79 years; 2 male and 9 female). The association between its production in chondrocytes and the grade of cartilage destruction was established on full-depth cartilage biopsies. The functional activity of adiponectin in OA cartilage was determined from the relation between the expression of adiponectin, its receptor, cartilage-specific components and factors involved in matrix degradation, and from the chondrocyte response to the full-length or the globular form of adiponectin. Adiponectin was not detected in healthy cartilage. Conversely, the adipokine was up-regulated in damaged tissue, but no strong association with the grade of cartilage destruction was found. We showed a positive correlation between adiponectin and mPGES or MMP-13 while AdipoR1 was related to the expression of type 2 collagen, aggrecan and Sox9. The full-length form of adiponectin but not the globular isoform, stimulated the production of PGE2 and MMP-13 activity in cultured human chondrocytes.
The elevated level of adiponectin found in chondrocytes from OA patients might contribute to matrix remodelling during OA, the full-length isoform being the single active form.
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Minimally-invasive total knee arthroplasty (MIS-TKA) has demonstrated very good short-term success, but its mid- to long-term results remain inconclusive. The success may be related to the tradeoff between a small incision and accurate positioning of the implant components. Patient-specific instrumentation (PSI) aims to improve the accuracy in restoring the knee axis and the clinical outcomes for MIS-TKA, but the results are yet to be confirmed by accurate assessment during functional activities. The purpose of the current study was to measure and compare the in vivo three-dimensional (3D) rigid-body and surface kinematics of MIS-TKA implanted with and without PSI during isolated knee active flexion/extension and sit-to-stand using state-of-the-art 3D model-based fluoroscopy technology. Ten patients treated for advanced medial knee osteoarthritis by MIS-TKA without PSI (non-PSI group) and nine with PSI (PSI group) participated in the current study. Each subject performed non-weight-bearing knee flexion/extension and sit-to-stand tasks while the motion of the prosthetic knee was under bi-plane fluoroscopy surveillance. The computer models of each of the knee prosthesis components were registered to the measured fluoroscopy images for each time frame via a novel validated 3D fluoroscopy method. Non-parametric 1-tailed Mann-Whitney tests were performed to detect the differences in the joint and surface kinematic variables every 10° of knee flexion between the non-PSI and PSI groups. The 1-tailed significance level was at α = 0.05. The PSI group showed clear, coupled flexion/internal rotation during activities, while the non-PSI group remained roughly at an externally rotated position with slight internal rotations. The coupled rotation in the PSI group was accompanied by an anterior displacement of the medial contact and a posterior displacement of the lateral contact, which was different from the screw-home mechanism. Neither of the two groups showed the normal roll-back phenomenon, i.e., posterior translation of the femur relative to the tibia during knee flexion.
With the state-of-the-art 3D fluoroscopy method, differences in both the rigid-body and surface kinematics of the prosthetic knees between MIS-TKA with and without PSI were identified. Patients with PSI demonstrated significant positive effects on the reconstructed rigid-body kinematics of the knee, showing clearer coupled flexion/internal rotations - an important kinematic characteristic in healthy knees - than those without PSI during activities with or without weight-bearing. However, none of them showed normal contact patterns. The current findings will be helpful for surgical instrument design, as well as for surgical decision-making in MIS total knee arthroplasty.
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To determine whether protein prenylation (farnesyl/geranylgeranylation) regulates matrix metalloproteinase (MMP) secretion from rheumatoid arthritis (RA) synovial fibroblasts (RASFs), and whether MMP-1 secretion can be regulated by statins or prenyltransferase inhibitors via effects mediated by ERK, JNK, and NF-kappaB. RASFs obtained from patients during elective knee replacement surgery were assessed by immunoblotting and/or enzyme-linked immunosorbent assay for secretion of MMP-1 and MMP-13 in the presence of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), statins, the farnesyl transferase (FT) inhibitor FTI-276 and geranylgeranyl transferase inhibitor GGTI-298, and prenyl substrates (farnesyl pyrophosphate [FPP] and geranylgeranyl pyrophosphate [GGPP]). Activities of JNK and ERK were determined by phosphoimmunoblotting, and NF-kappaB activation was determined by nuclear translocation of the p65 component. FTI-276, but not statins, inhibited RASF secretion of MMP-1, but not MMP-13, following induction with TNFalpha (P = 0.0007) or IL-1beta (P = 0.006). Loading RASFs with FPP to promote farnesylation enhanced MMP-1 secretion. FTI-276 inhibited activation of JNK (P < 0.05) and NF-kappaB (P = 0.02), but not ERK. In contrast, GGTI-298 enhanced, while GGPP inhibited, MMP-1 secretion. FTI-276 and GGTI-298 together had no effect on MMP-1 secretion. Stimulation of RASFs with TNFalpha or IL-1beta led to increased expression and activity of FT.
Protein farnesylation is required for expression and secretion of MMP-1 from RASFs, via effects on JNK and NF-kappaB. The ability of cytokines to stimulate the expression and activity of FT suggests that FT may be increased in the rheumatoid joint. In contrast, geranylgeranylation down-regulates MMP-1 expression. Statins simultaneously inhibit farnesylation and geranylgeranylation, and in consequence do not inhibit MMP-1 secretion. The ability of FTI-276 to inhibit MMP-1 secretion suggests a potential therapeutic strategy in RA.
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Copy number variants (CNVs) have been associated with the risk to develop multiple autoimmune diseases. Our objective was to identify CNVs associated with the risk to develop psoriatic arthritis (PsA) using a genome-wide analysis approach. A total of 835 patients with PsA and 1498 healthy controls were genotyped for CNVs using the Illumina HumanHap610 BeadChip genotyping platform. Genomic CNVs were characterised using CNstream analysis software and analysed for association using the χ(2) test. The most significant genomic CNV associations with PsA risk were independently tested in a validation sample of 1133 patients with PsA and 1831 healthy controls. In order to test for the specificity of the variants with PsA aetiology, we also analysed the association to a cohort of 822 patients with purely cutaneous psoriasis (PsC). A total of 165 common CNVs were identified in the genome-wide analysis. We found a highly significant association of an intergenic deletion between ADAMTS9 and MAGI1 genes on chromosome 3p14.1 (p=0.00014). Using the independent patient and control cohort, we validated the association between ADAMTS9-MAGI1 deletion and PsA risk (p=0.032). Using next-generation sequencing, we characterised the 26 kb associated deletion. Finally, analysing the PsC cohort we found a lower frequency of the deletion compared with the PsA cohort (p=0.0088) and a similar frequency to that of healthy controls (p>0.3).
The present genome-wide scan for CNVs associated with PsA risk has identified a new deletion associated with disease risk and which is also differential from PsC risk.
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Fibroblast-like synoviocytes (FLS) are a major constituent of the hyperplastic synovial pannus that aggressively invades cartilage and bone during the course of rheumatoid arthritis (RA). Fractalkine (FKN/CX(3)CL1) expression is up-regulated in RA synovium and RA synovial fluid. While RA FLS express the FKN receptor, CX(3)CR1, the pathophysiologic relevance of FKN stimulation of RA FLS is not understood. This study was undertaken to better characterize the relationship between FKN and the RA FLS that both produce it and express its receptor. RA FLS were subjected to chemotaxis and proliferation assays, Western blotting, enzyme-linked immunosorbent assays, and filamentous actin staining to characterize the relationship between FKN and RA FLS. FKN secretion by RA FLS was regulated mainly by tumor necrosis factor alpha. Stimulation of RA FLS with FKN led to significant cytoskeletal rearrangement but no proliferation. Chemotaxis assays revealed that FKN was a novel chemoattractant for RA FLS. Stimulation of RA FLS with FKN resulted in activation of MAP kinases and Akt. JNK, ERK-1/2, and Akt (at both Ser-473 and Thr-308) were each up-regulated in a time-dependent manner. Inhibition of ERK-1/2-mediated signaling, but not JNK or Akt, significantly repressed FKN-induced RA FLS migration.
These findings indicate a novel role of FKN in regulating RA FLS cytoskeletal structure and migration. FKN specifically induces RA FLS phosphorylation of the MAP kinases JNK and ERK-1/2, as well as full activation of Akt.
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2,728
This study aimed to evaluate the effect of nanoemulsion containing peppermint and rosemary essential oils in rats with osteoarthritis (OA). In this experimental study, we prepared a nanoemulsion containing peppermint and rosemary essential oils by spontaneous emulsification and evaluated the nanoemulsion's dermal irritation and toxicity. Investigating the analgesic effect of the nanoemulsion, we randomly assigned 36 male rats to 6 groups: Control (saline injection into the knee), osteoarthritis (intra-articular injection of 2 mg monosodium iodoacetate), and four groups of OA treated with nanoemulsion gel, nanoemulsion solution, rosemary and peppermint essential oil gel, or diclofenac sodium. Treatments were administered topically at a dose of 1 ml daily. Using behavioral tests, we assessed pain on days 1, 4, 7, and 14 after injection. Finally, we did the histopathological and biochemical evaluation of rats' knee joints. There were no irritation signs on the animals' skin after receiving the nanoemulsion and no changes in the hematological and biochemical parameters of rats' blood compared to the control group. Receiving nanoemulsion decreased the mechanical (P < 0.001) and thermal allodynia (P < 0.05), thermal hyperalgesia (P < 0.05), and ambulatory-evoked pain in comparison with the OA group. Also, the nanoemulsion receiving rats showed an increase in SOD and GPx activity and a decrease in MDA level. Histopathology of synovial tissues confirmed the results of behavioral and biochemical tests.
The nanoemulsion containing essential oils of peppermint and rosemary reduces osteoarthritis pain via increasing antioxidant capacity and improving the histopathological features of the rats' knee joint.
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3,522
Patients with rheumatoid arthritis (RA) commonly use oral glucocorticoids (GCs) and proton pump inhibitors (PPIs), both associated with osteoporotic fractures. We investigated the association between concomitant use of oral GCs and PPIs and the risk of osteoporotic fractures among patients with RA. This was a cohort study including patients with RA aged 50+ years from the Clinical Practice Research Datalink between 1997 and 2017. Exposure to oral GCs and PPIs was stratified by the most recent prescription as current use (<6 months), recent use (7-12 months) and past use (>1 year); average daily and cumulative dose; and duration of use. The risk of incident osteoporotic fractures (including hip, vertebrae, humerus, forearm, pelvis and ribs) was estimated by time-dependent Cox proportional-hazards models, statistically adjusted for lifestyle parameters, comorbidities and comedications. Among 12 351 patients with RA (mean age of 68 years, 69% women), 1411 osteoporotic fractures occurred. Concomitant current use of oral GCs and PPIs was associated with a 1.6-fold increased risk of osteoporotic fractures compared with non-use (adjusted HR: 1.60, 95% CI: 1.35 to 1.89). This was statistically different from a 1.2-fold increased osteoporotic fracture risk associated with oral GC or PPI use alone. Most individual fracture sites were significantly associated with concomitant use of oral GCs and PPIs. Among concomitant users, fracture risk did not increase with higher daily dose or duration of PPI use.
There was an interaction in the risk of osteoporotic fractures with concomitant use of oral GCs and PPIs. Fracture risk assessment could be considered when a patient with RA is co-prescribed oral GCs and PPIs.
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To define whether good manufacturing practice (GMP)-clinical grade adipose stem cell (ASC)-derived conditioned medium (CM) is as effective as GMP-ASC in modulating inflammatory and catabolic factors released by both osteoarthritis (OA) chondrocytes or synoviocytes. OA chondrocytes and synoviocytes were treated with ASC-CM or co-cultured with ASC. Inflammatory factors (IL6, CXCL1/GROα,CXCL8/IL8, CCL2/MCP-1, CCL3/MIP-1α and CCL5/RANTES) and proteinases, such as metalloproteinase (MMP13), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS4, ADAMTS5) and their tissue metalloproteinase inhibitors (TIMP1, TIMP3) were evaluated by qRT-PCR or immunoassays. The involvement of prostaglandin E2 (PGE2) was also analyzed. Most ASC-CM ratios tested did not decrease IL6, CCL2/MCP-1, CCL3/MIP1-α, CCL5/RANTES on basal inflamed chondrocytes or synoviocytes in contrast to what we found using ASC in co-culture. CXCL8/IL8 and CXCL1/GROα were not decreased by ASC-CM on synoviocytes but were only partially reduced on chondrocytes. Moreover, ASC-CM was less efficient both on basal inflamed OA chondrocytes and synoviocytes in reducing proteinases, such as MMP13, ADAMTS4, ADAMTS5 and increasing TIMP1 and TIMP3 compared to ASC in co-culture. The different ratios of ASC-CM contain lower amounts of PGE2 which were not sufficient to reduce inflammatory factors.
These data show that ASC-CM has a limited ability to decrease inflammatory and proteinases factors produced by OA chondrocytes or synoviocytes. ASC-CM is not sufficient to recapitulate the beneficial effect demonstrated using ASC in co-culture with inflamed OA chondrocytes and synoviocytes and shows that their use in clinical trials is fundamental to counteract OA progression.
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Clinical and in vitro studies suggest that subchondral bone sclerosis due to abnormal osteoblasts is involved in the progression of osteoarthritis (OA). Human osteoblasts isolated from sclerotic subchondral OA bone tissue show an altered phenotype, a decreased canonical Wnt/ß-catenin pathway, and a reduced mineralization in vitro as well as in vivo. These alterations were linked with an abnormal response to BMP-2. OA osteoblasts release factors such as the hepatocyte growth factor (HGF) that contribute to cartilage loss whereas chondrocytes do not express HGF. HGF can stimulate BMP-2 expression in human osteoblasts, however, the role of HGF and its effect in OA osteoblasts remains unknown. Here we investigated whether elevated endogenous HGF levels in OA osteoblasts are responsible for their altered response to BMP-2. We prepared primary human subchondral osteoblasts using the sclerotic medial portion of the tibial plateaus of OA patients undergoing total knee arthroplasty, or from tibial plateaus of normal individuals obtained at autopsy. The expression of HGF was evaluated by qRT-PCR and the protein production by western blot analysis. HGF expression was reduced with siRNA technique whereas its activity was inhibited using the selective inhibitor PHA665752. Alkaline phosphatase activity (ALPase) and osteocalcin release were measured by substrate hydrolysis and EIA respectively. Canonical Wnt/β-catenin signaling (cWnt) was evaluated both by target gene expression using the TOPflash TCF/lef luciferase reporter assay and western blot analysis of β-catenin levels in response to Wnt3a stimulation. Mineralization in response to BMP-2 was evaluated by alizarin red staining. The expression of HGF was increased in OA osteoblasts compared to normal osteoblasts and was maintained during their in vitro differentiation. OA osteoblasts released more HGF than normal osteoblasts as assessed by western blot analysis. HGF stimulated the expression of TGF-β1. BMP-2 dose-dependently (1 to 100 ng/ml) stimulated both ALPase and osteocalcin in normal osteoblasts whereas, it inhibited them in OA osteoblasts. HGF-siRNA treatments reversed this response in OA osteoblasts and restored the BMP-2 response. cWnt is reduced in OA osteoblasts compared to normal, and HGF-siRNA treatments increased cWnt in OA osteoblasts almost to normal. Smad1/5/8 phosphorylation in response to BMP-2, which is reduced in OA osteoblasts, was corrected when these cells were treated with PHA665752. The BMP-2-dependent mineralization of OA osteoblasts, which is also reduced compared to normal, was only partially restored by PHA665752 treatment whereas 28 days treatment with HGF reduced the mineralization of normal osteoblasts.
OA osteoblasts expressed more HGF than normal osteoblasts. Increased endogenous HGF production in OA osteoblasts stimulated the expression of TGF-β1 and reduced their response to BMP-2. Inhibiting HGF expression or HGF signaling restored the response to BMP-2 and Smad1/5/8 signaling. In addition, decreased HGF signaling partly corrects the abnormal mineralization of OA osteoblasts while increased HGF prevents the normal mineralization of normal osteoblasts. In summary, we hypothesize that sustained elevated HGF levels in OA osteoblasts drive their abnormal phenotype and is implicated in OA pathophysiology.
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To describe a large, multicenter prospective cohort study of first-degree relatives (FDRs) of probands with rheumatoid arthritis (RA), and outline the use of such a study in investigating the natural history of RA development. A total of 1,058 FDRs, none of whom met the American College of Rheumatology criteria for RA, were enrolled in a prospective study investigating genetic and environmental influences on the development of RA-related autoimmunity. Demographic, epidemiologic, genetic, autoantibody, and physical examination data from the initial study enrollment visit were described for these FDRs, and the relationship was examined between genetic factors, autoantibodies, inflammation, and joint disease. Fifty-five percent of the FDRs had > or =1 copy of the shared epitope, 20% had > or =1 copy of the PTPN22 polymorphism, and approximately 16% were positive for rheumatoid factor (RF; including isotypes) and/or anti-cyclic citrullinated peptide antibody. IgM-RF positivity is associated with > or =1 tender joint on examination (odds ratio [OR] 2.50, 95% confidence interval [95% CI] 1.27-4.89; P < 0.01) and elevated C-reactive protein (CRP) levels (OR 5.31, 95% CI 1.45-19.52; P = 0.01).
FDRs without RA demonstrate high prevalences of genetic risk factors and RA-related autoantibodies. Additionally, an RF association with tender joints and elevated CRP levels suggests that autoantibodies are a valid intermediate marker of RA-related autoimmunity in this cohort. This prospective FDR cohort will be a valuable resource for evaluating the relationship between genetic and epidemiologic factors and the development of RA-related autoimmunity.
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Rheumatoid arthritis (RA) is an autoimmune disease resulting in polyarthritis and systemic effects that may result in morbidity and mortality. This review provides the emergency physician with an updated analysis of acute complications seen with RA, as well as an evidence-based approach to the management of these complications. While the joint characteristics of RA are commonly recognized, the extra-articular manifestations may be overlooked. Of most concern to the emergency clinician is the involvement of the airway, cardiovascular, and pulmonary systems; however, RA can affect all organ systems. In addition, complications can arise from the specific therapies used to treat RA. Certain patient populations can have atypical presentations of the disease or may have an exaggerated response to the medications. An understanding of the involvement of these organ systems and complications can direct physicians to a broader differential that can identify disease processes that may have otherwise gone unnoticed. It is not necessarily the role of the clinician to diagnose RA in its earliest phases or initiate long-term immunosuppressive therapy from the emergency department; however, detection of some of the disease's characteristics can lead to earlier referral to specialists to begin therapy and potentially avoid life-threatening complications. If those problems are encountered in the emergency department, this review aims to provide insight into management of those conditions.
Prompt recognition of the acute complications of RA is crucial to treat these conditions. This review investigates these issues in a succinct manner for emergency clinicians.
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Computerized neuropsychological testing may facilitate screening for cognitive impairment in systemic lupus erythematosus (SLE). This study was undertaken to compare patients with SLE, patients with rheumatoid arthritis (RA), and patients with multiple sclerosis (MS) with healthy controls using the Automated Neuropsychological Assessment Metrics (ANAM). Patients with SLE (n = 68), RA (n = 33), and MS (n = 20) were compared with healthy controls (n = 29). Efficiency of cognitive performance on 8 ANAM subtests was examined using throughput (TP), inverse efficiency (IE), and adjusted IE scores. The latter is more sensitive to higher cognitive functions because it adjusts for the impact of simple reaction time on performance. The results were analyzed using O'Brien's generalized least squares test. Control subjects were the most efficient in cognitive performance. MS patients were least efficient overall (as assessed by TP and IE scores) and were less efficient than both SLE patients (P = 0.01) and RA patients (P < 0.01), who did not differ. Adjusted IE scores were similar between SLE patients, RA patients, and controls, reflecting the impact of simple reaction time on cognitive performance. Thus, 50% of SLE patients, 61% of RA patients, and 75% of MS patients had impaired performance on >or=1 ANAM subtest. Only 9% of RA patients and 11% of SLE patients had impaired performance on >or=4 subtests, whereas this was true for 20% of MS patients.
ANAM is sensitive to cognitive impairment. While such computerized testing may be a valuable screening tool, our results emphasize the lack of specificity of slowed performance as a reliable indicator of impairment of higher cognitive function in SLE patients.