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Objectively measured differences in physical activity (PA) and sleep have been documented among people with osteoarthritis (OA) and rheumatoid arthritis (RA) compared to non-arthritic controls. However, it is not clear whether OA and RA subgroups also differ on these indexes or the extent to which distinct arthritis subgroups versus controls can be accurately identified on the basis of objective PA and sleep indexes compared to self-report responses on questionnaires. This study addressed these gaps. This case-control study comprised Chinese adults with OA (N = 40) or RA (N = 40) diagnoses based on physician assessments as well as a control group of adults without chronic pain (N = 40). All participants wore a Sensewear Armband (SWA) for consecutive 7 days and completed the International Physical Activity Questionnaire Short Form-Chinese as well as Pittsburgh Sleep Diary to obtain objective and subjective PA and sleep data, respectively. There were no differences between the three groups on any self-report indexes of PA or sleep. Conversely, OA and RA subgroups displayed significantly lower PA levels and more sleep problems than controls did on a majority of SWA indexes, though arthritis subgroups were not differentiated from one another on these measures. Logistic regression analyses indicated four non-multicollinear SWA indexes (i.e., steps, active energy expenditure, vigorous activity, time awake after sleep onset) correctly identified the subgroup membership of 75.0-82.5% of participants with RA or OA while classification accuracy results were attenuated for controls.

Where possible, objective measures should be used to assess PA and sleep of adults with OA and RA while particular self-report PA questionnaires should be used sparingly.

Proteinase-activated receptor 2 (PAR(2)) is a G protein-coupled receptor activated by serine proteinases with proinflammatory activity. A study was undertaken to investigate the presence and functional significance of PAR(2) expression on rheumatoid arthritis (RA)-derived leucocyte subsets. Venous blood was obtained from patients with RA and osteoarthritis (OA) as well as healthy control subjects. Surface expression of PAR(2) on peripheral blood mononuclear cells (PBMCs) was analysed by flow cytometry and interleukin 6 (IL-6) generation by ELISA. Patients with RA had elevated but variable surface expression of PAR(2) on CD14+ monocytes compared with control subjects (median (1st to 3rd quartiles) 1.76% (0.86-4.10%) vs 0.06% (0.03-0.81%), p<0.0001). CD3+ T cells showed a similar pattern with significantly higher PAR(2) expression in patients with RA compared with controls (3.05% (0.36-11.82%) vs 0.08% (0.02-0.28%), p<0.0001). For both subsets, PAR(2) expression was significantly higher (p<0.00001) in patients with high levels of disease activity: PAR(2) expression for both CD14+ and CD3+ cells correlated to C reactive protein and erythrocyte sedimentation rate. Furthermore, in a cohort of patients with newly diagnosed RA, elevated PAR(2) expression in both CD14+ and CD3+ cells was significantly reduced 3 months after methotrexate or sulfasalazine treatment and this reduction correlated significantly with the reduction in the 28-joint Disease Activity Scale score (p<0.05). PAR(2) expression on cells from patients with OA was low, similar to levels seen in control subjects. Generation of IL-6 by monocytes in response to a selective PAR(2) agonist was significantly greater in patients with RA than in patients with OA and control subjects (p<0.05).

These findings are consistent with a pathogenic role for PAR(2) in RA.

A previous whole-genome scan (WGS) of 182 UK rheumatoid arthritis (RA) affected sibling pair (ASP) families suggested linkage to HLA and 11 other chromosome regions. Replication of such findings in an independent cohort can help to distinguish true linkages from false-positive linkages. Since RA is a heterogeneous disease, some loci may be linked only in subsets of patients. Thus, the aim of this study was to investigate in an additional set of RA ASP families linkage to regions showing deviation in expected allele-sharing ratios in the UK WGS and to perform subset analysis on the combined cohort. Twenty loci were investigated for linkage in 217 Caucasian UK RA ASPs. Stratification analysis was performed on the combined cohort of 377 RA ASP families to account for sex, RA severity, and the shared epitope (SE). None of the regions of linkage identified in the initial WGS achieved statistical significance in the second cohort. In contrast, after stratification analysis, 14 regions showed nominal evidence of linkage (logarithm of odds score >0.8) in one or more subgroups. In particular, the strength of evidence for linkage to chromosome 16p was increased in subsets of ASPs with younger age at disease onset (LOD score 2.38) and for linkage to chromosome 6q in female-female ASPs (LOD score 2.31) and in ASPs in which both siblings had 2 copies of the SE (LOD score 3.03).

These results support the evidence for heterogeneity of RA. This information will inform the future design of association-based investigations as the search for disease genes in the linked regions begins.

To evaluate active inflammatory lesions (AIL) and structural changes (SC) in patients with active non-radiographic axial spondyloarthritis (nr-axSpA) compared with patients with ankylosing spondylitis (AS) on whole-body MRI (wb-MRI). 75 patients with active disease and a symptom duration of <5 years (39 with AS and 36 with nr-axSpA) were investigated with a comprehensive wb-MRI protocol and scored for AIL and SC in the spine, sacroiliac joints (SIJs) and non-axial manifestations. 92% of patients with AS showed active inflammation in the SIJ, 53% in the spine and 94% and 39%, respectively, in the nr-axSpA group. There was a non-significant trend towards more inflammation in patients with AS compared with patients with nr-axSpA in SIJs and spine. Peripheral enthesitis/osteitis was more common in patients with AS (n=22) than in those with nr-axSpA (n=12) (p=0.05). SC were more common in patients with AS than in those with nr-axSpA, with significantly higher scores for SIJ fatty bone marrow deposition (FMD) in patients with AS (4.8±3.2) compared with those with nr-axSpA (2.4±2.7; p=0.001) and more frequent bone proliferation in the spine and the SIJ (p=0.02 and p=0.005, respectively). SIJ erosions were more common in AS (score 4.2±2.3) than in nr-axSpA (score 3.8±1.8) patients (not significant).

Wb-MRI detects active inflammation and SC more frequently in the SIJs than in the spine. Half of the patients showed inflammation in non-axial sites. Active inflammatory and structural lesions were present both in patients with AS and those with nr-axSpA, being only slightly more common in patients with AS.

To study the effect of rheumatoid arthritis (RA) on working capabilities and social participation, including non-paying jobs, during the first 6 yr of disease. Cross-sectional study. In April 1996, a self-reporting questionnaire was sent to 424 participants of a population-based clinical trial of therapeutic strategies for early RA initiated in 1990. A total of 363 completed questionnaires were returned (response = 86%). Disease duration varied from < 1 to 6 yr (mean 2.8 yr). The employment rate was low in the RA population compared to the Dutch population. In the male 45- to 64-yr-old group, 63% of RA patients were not employed compared to 32% of the Dutch population (P < 0.01). In the female 45- to 64-yr-old group, 76% of the RA population vs 67% of the Dutch were not employed (P < 0.05). Of the employed patients, 59% reported that RA affected their working capabilities, e.g. they worked an average of 21 h per week less due to RA. Of the patients without a paying job, 41% believed that this was (partly) due to RA. In addition, fewer RA patients had non-paying jobs and they performed fewer household activities compared to the general Dutch population.

RA already has a negative influence on the working capabilities, social participation and household activities of these patients during the first 6 yr of disease.

To investigate the risk of rheumatoid arthritis (RA) in the first degree relatives and to investigate whether the sex of the parent influences the pattern of inheritance. An interview based case-control study, with subjects serially matched for age and sex. We analyzed 126 cases (hospital cases) and 94 controls (derived from the same hospitals), who gave information for family history of RA. Data concerning RA history among siblings and parents were computerized and analyzed univariately and multivariately. The odds ratio (OR) for developing RA is 4.4 (p < 0.001) if a first degree relative reported having the disease and 5.4 (p < 0.01) if a female first degree relative reported having the disease. For females the OR is 7.0 (p < 0.01) if the first degree relative is female. When the analysis was restricted to parents only, it was found that mothers with RA predispose their daughters and sons to develop RA more (OR = 8.6, p < 0.01, for daughters and 4.8, p < 0.05, for both sexes) than fathers (OR = 1.1 and 1.9, respectively).

This case-control study confirms the familial clustering of RA and suggests that mothers confer susceptibility to RA on their offspring more often than fathers.

The frequent use of chiropractic, naturopathic, and physical and occupational therapy by patients with fibromyalgia has been emphasized repeatedly, but little is known about the attitudes of these therapists towards this challenging condition. We administered a cross-sectional survey to 385 senior Canadian chiropractic, naturopathic, physical and occupational therapy students in their final year of studies, that inquired about attitudes towards the diagnosis and management of fibromyalgia. 336 students completed the survey (response rate 87%). While they disagreed about the etiology (primarily psychological 28%, physiological 23%, psychological and physiological 15%, unsure 34%), the majority (58%) reported that fibromyalgia was difficult to manage. Respondants were also conflicted in whether treatment should prioritize symptom relief (65%) or functional gains (85%), with the majority (58%) wanting to do both. The majority of respondents (57%) agreed that there was effective treatment for fibromyalgia and that they possessed the required clinical skills to manage patients (55%). Chiropractic students were most skeptical in regards to fibromyalgia as a useful diagnostic entity, and most likely to endorse a psychological etiology. In our regression model, only training in naturopathic medicine (unstandardized regression coefficient = 0.33; 95% confidence interval = 0.11 to 0.56) and the belief that effective therapies existed (unstandardized regression coefficient = 0.42; 95% confidence interval = 0.30 to 0.54) were associated with greater confidence in managing patients with fibromyalgia.

The majority of senior Canadian chiropractic, naturopathic, physical and occupational therapy students, and in particular those with naturopathic training, believe that effective treatment for fibromyalgia exists and that they possess the clinical skillset to effectively manage this disorder. The majority place high priority on both symptom relief and functional gains when treating fibromyalgia.

To determine whether the presence of psoriatic arthritis (PsA) is associated with greater comorbidity, in particular cardiovascular morbidity, compared to psoriasis without arthritis. Six hundred eleven patients with PsA were recruited from the University of Toronto Psoriatic Arthritis Clinic and 449 psoriasis without arthritis patients were recruited from the University of Toronto Psoriasis Cohort. The clinical database was used to identify the prevalence of cardiovascular and other comorbidities in both PsA and psoriasis without arthritis patients. Univariate and multivariate logistic regression analyses were conducted to estimate odds ratios (ORs), comparing the odds of ever having a given comorbid disease in PsA patients with those in psoriasis without arthritis patients. Covariates included age, sex, education, smoking status, severity and duration of psoriasis, medication status, and other comorbidities. The prevalence of hypertension, obesity, hyperlipidemia, type 2 diabetes mellitus, and at least 1 cardiovascular event in PsA patients was 37.1%, 30.0%, 20.7%, 12.0%, and 8.2%, respectively. This was significantly higher than in psoriasis without arthritis patients, with unadjusted ORs ranging from 1.54 to 2.59. In the multivariate analyses, hypertension remained significantly elevated (adjusted OR 2.17). PsA was also significantly associated with infections not treated with antibiotics (presumably viral), neurologic conditions, gastrointestinal disorders, and liver disease (adjusted ORs 2.83, 4.76, 21.53, and 7.74, respectively). Infections treated with antibiotics and depression/anxiety were relatively common in PsA, with a prevalence of 30.5% and 20.7%, respectively. However, this was not significantly different from psoriasis without arthritis after multivariate adjustments.

The results suggest that inflammatory joint disease may play a role in both cardiovascular and noncardiovascular morbidity in PsA.

Anti-tumour necrosis factor alpha (anti-TNFalpha) treatment may be associated with the production of autoantibodies, including lupus-specific autoantibodies. To investigate the prevalence of autoantibodies in biological agent naive patients with psoriatic arthritis (PsA). 94 consecutive, prospectively collected, biological agent naive patients with PsA at the University of Toronto PsA clinic underwent clinical and laboratory assessment. Disease activity was assessed by the number of actively inflamed joints, and the Psoriasis Activity and Severity Index (PASI) score. Antinuclear antibodies (ANA), rheumatoid factor (RF), double stranded DNA (dsDNA), Ro, La, Smith, and RNP were tested. Descriptive statistics and non-parametric tests were used to analyse the data. 44/94 (47%) patients with PsA were ANA positive (>/=1/40); 13/94 (14%) had a clinically significant titre of >/=1/80. Three per cent had dsDNA antibodies, 2% had RF and anti-Ro antibodies, 1% had anti-RNP antibodies, and none had anti-La or anti-Smith antibodies.

The background prevalence of ANA >/=1/80 in patients with PsA was 14%, with very few patients having specific lupus antibodies. This should serve as a baseline figure for the frequency of autoantibodies in biological agent naive patients with PsA for studies of the use of anti-TNFalpha agents.

To investigate changes in gene expression in fibrillated and intact human osteoarthritis (OA) cartilage for evidence of an altered chondrocyte phenotype and hypertrophy. Paired osteochondral samples were taken from a high-load site and a low-load site from 25 OA joints and were compared with eight similar paired samples from age-matched controls. Gene expression of key matrix and regulatory genes was analysed by quantitative real-time reverse transcription-polymerase chain reaction on total RNA extracted from the cartilage. There was a major change in chondrocyte gene expression in OA cartilage. SOX9 (38-fold) and aggrecan (4-fold) gene expression were both lower in OA (p<0.001), and collagen I (17-fold) and II (2.5-fold) gene expression were each increased in a subset of OA samples. The major changes in gene expression were similar at the fibrillated high-loaded site and the intact low-loaded site. There was no evidence of a generalised change in OA to proliferative or hypertrophic phenotype as seen in the growth plate, as genes associated with either stage of differentiation were unchanged (PTHrPR), or significantly downregulated (collagen X (14-fold, p<0.002), VEGF (23-fold, p<0.02), BCL-2 (5.6-fold, p<0.001), matrilin-1 (6.5-fold, p<0.001)). In contrast MMP-13 was significantly upregulated in the OA cartilage samples (5.3-fold, p<0.003).

The expression of key chondrocyte genes, including aggrecan and SOX9, was decreased in OA cartilage and the changes were similar in both fibrillated high-loaded and intact low-loaded cartilage on the same joint. However, there was no significant upregulation of type X collagen, and other genes associated with chondrocyte further differentiation and hypertrophy.

In developmental dysplasia of the hip (DDH), the centers of hip rotation move in the superior and lateral direction. In total hip arthroplasty for such cases, movement of the center of hip rotation is in the inferior and medial direction. It causes an increase in leg length and a decrease in acetabular offset. We therefore evaluated the change of hip offset and leg length before and after surgery with two stems having a high offset option. The preoperative diagnosis was secondary osteoarthritis due to DDH excluded Crowe IV. A stem selection was decided based on preoperative two-dimensional templating. Total 55 hips in 50 patients were followed up for minimum 10 years. Pre- and postoperative clinical evaluations were performed using a hip joint function scoring system. Radiographic evaluations were used for offset and leg length measurements and other associated factors. Both stems showed excellent clinical results. A high offset option was used in 60% of all cases. No postoperative dislocations were observed. The biological fixation was stable in all cases. The hip offset was restored without excessive leg lengthening in most cases.

Anatomical consistency could be maintained by using a stem which matched geometry of the proximal part and had offset option. These cementless tapered stems having a high offset option are suitable for Crowe I to III hip dysplasia if two-dimensional X-ray templates fit the shape of the proximal femurs. They were associated with excellent clinical results and biological fixation. The offset option may be useful to adjust leg length and offset in DDH patients.

The lower extremity function scale (LEFS) is widely used to investigate patients' functional status due to musculoskeletal dysfunction of the lower extremity. The aims of this study were to translate and cross-culturally adapt the LEFS into simplified Chinese (SC-LEFS) and evaluate the psychometric properties in patients with knee osteoarthritis (OA). The SC-LEFS was translated and cross-culturally adapted on the basis of guideline. Patients scheduled for knee arthroplasty (108) were invited in this study. The Cronbach's alpha coefficient was employed to assess the internal consistency. The test-retest reliability was determined by intra-class correlation coefficient (ICC). Pearson's correlation coefficient was detected to evaluate the criterion validity between the SC-LEFS and WOMAC/SF-36/range of motion (ROM). Construct validity was assessed by exploratory factorial analysis. Additionally, responsiveness analysis was conducted with effect size (ES) and standardized response mean (SRM). The results revealed good internal consistency (Cronbach's alpha = 0.975) and good test-retest reliability (ICC = 0.937). Strong correlations were observed between the SC-LEFS and WOMAC pain/function/total, physical component summary of SF-36, and ROM. We confirmed the SC-LEFS as a two-factor structure with factor 1 and factor 2 explaining 73.781% and 5.546% of the variance, respectively. The ES (1.74) and SRM (1.95) indicated a good responsiveness.

The SC-LEFS has been nicely adapted into simplified Chinese. It was proved to be reliable and valid for knee OA patients from China mainland who are undergoing arthroplasty. Furthermore, additional research should be conducted to assess these findings in other dysfunctions of lower extremity in a larger sample size. Key Points • The present study firstly cross-culturally adapted the lower extremity function scale (LEFS) into simplified Chinese and applied for patients with knee osteoarthritis in China mainland. • The psychometric properties including reliability, validity, and responsiveness were evaluated in SC-LEFS. • The SC-LEFS turned out to be a reliable and valid tool for clinical physicians and researchers assessing patients with knee osteoarthritis.

Hyperuricemia is the only biochemical index in the classification of acute gouty arthritis in American Rheumatism Association 1977 and the main basis of clinical diagnosis for most doctors. However, nearly half of the time gout occurs without hyperuricemia, especially in an acute attack，which leads to an urgent need to find a new substitute diadynamic criteria of gout. Xanthine and hypoxanthine, as precursors of uric acid, have been reported to be high in gout patients with hyperuricemia and presumed to be gout biomarkers. To further explore the possibility of xanthine and hypoxanthine to be gout biomarkers as substitutes for uric acid. A reversed-phase HPLC-UV method was employed for simultaneous quantitative detection of uric acid (UA), xanthine (X), and hypoxanthine (HX) in gout patients' (with and without hyperuricemia) and healthy persons' serum. The xanthine and hypoxanthine concentrations in gout patients with hyperuricemia and without hyperuricemia are higher than in healthy persons with a P < 0.001.

This study supplements previous researches by confirming that xanthine and hypoxanthine are significantly elevated in gout patients' serum especially in patients' with normouricemia, which supported xanthine and hypoxanthine may have clinical application for the diagnosis of gout.

To examine the impact of an electronic data capture system on patient satisfaction and patient-physician interactions in a rheumatology clinical setting. In this multicenter study, 1079 patients with rheumatoid arthritis completed questionnaires quarterly about their health and satisfaction with care using a computer. At 6 months, 901 eligible patients were randomized 2:1 to receive or not to receive graphical summarized health information or Health Tracker (HT) reports. Data collected at each visit included patient satisfaction with care; patient-physician interaction assessments; a 56-joint self-assessment for patients; a 28-joint assessment for physicians; patient pain, fatigue, and global assessments (visual analogue scale, physician global assessment, Health Assessment Questionnaire, and Short Form-12) all of which were cumulatively recorded in the HT report. Patient demographics at baseline were similar between groups. Changes from baseline to 1 year showed that patients in the HT-viewers group were significantly more satisfied with their care (p < 0.001) than those in the HT-nonviewers group (p = 0.131). Physicians reported improved interactions with patients at 1 year in both the HT-viewers (p < 0.001) and HT-nonviewers groups (p = 0.002); however, the improvement was significantly larger for the HT-viewers group than for the HT-nonviewers group (p < 0.001). Adverse events were comparable between groups.

Patient access to systematically collected patient data reports promoted self-involvement and improved patient satisfaction and patient-physician interactions more in the HT-viewers than in HT-nonviewers groups at 1 year (p < 0.001). This was an open, observational study; no formal hypothesis testing was conducted. The HT system was not validated and some bias may have existed with respect to patient comfort level with a computer, user error, and timing of data entry of the physicians' assessments.

This study investigates the effects of an aqueous extract of TNF-α-induced RA-derived fibroblast-like synoviocyte MH7A cells were incubated with ACR (0.1-2 mg/mL) for 24 h. The proliferation was tested using CCK-8 and colony formation assays. The migration and invasion abilities were measured using transwell tests and wound healing assays. Apoptosis and cell cycle were examined by flow cytometry. The potential mechanisms were determined by western blotting and quantitative real-time PCR. UPLC-QE-MS/MS was used for chromatographic analysis of ACR and its compounds were identified. Molecular docking strategy was used to screen the potential anti-RA active compounds of ACR. We found that ACR induced apoptosis in MH7A cells at concentrations of 0.4, 0.8, and 1.2 mg/mL. The proliferation of MH7A cells was reduced and the cell cycle was blocked in the G2/M phase at concentrations of 0.2, 0.4, 0.6 mg/mL. Migration and invasion of MH7A cells were reduced through inhibiting the expression of MMP-1, MMP-2, and MMP-3. The molecular docking strategy results showed that 9 compounds in ACR have good affinity with protein crystal, and benzyl cinnamate (10-100 µg/mL) could inhibit cell migration and induce apoptosis.

The anti-RA effect of ACR may be attributed to its anti-proliferative and anti-migration effects on synovial fibroblasts. These data suggest that

To evaluate the risk of venous thromboembolism (VTE) in rheumatoid arthritis (RA) patients receiving tofacitinib versus those receiving tumor necrosis factor (TNF) inhibitors. RA patients who were initiating treatment with tofacitinib or a TNF inhibitor and had not previously received any biologic agent or tofacitinib were identified from the Truven MarketScan database (2012-2016) or Medicare claims (parts A, B, and D) database (2012-2015). Patients were followed up until treatment discontinuation, treatment switch, insurance disenrollment, or administrative censoring. The outcome of VTE was identified using inpatient claims for pulmonary embolism or deep vein thrombosis. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were determined using a Cox proportional hazards model after accounting for confounding through propensity score-based fine-stratification weighting. HRs were pooled across databases using the inverse variance meta-analytic method. A total of 34,074 RA patients (mean age 50 years; 5.6% tofacitinib initiators) and 17,086 RA patients (mean age 71 years; 5.8% tofacitinib initiators) were identified from the Truven and Medicare databases, respectively. The crude incidence rates of VTE per 100 person-years were 0.60 (95% CI 0.26-1.19) and 0.34 (95% CI 0.27-0.41) in Truven and 1.12 (95% CI 0.45-2.31) and 0.92 (95% CI 0.76-1.11) in Medicare for patients receiving tofacitinib and patients receiving TNF inhibitors, respectively. Propensity score-adjusted HRs showed no significant differences in the risk of VTE between tofacitinib-treated and TNF inhibitor-treated patients in either database, with a pooled HR of 1.33 (95% CI 0.78-2.24).

Occurrence of VTE in a total of 50,865 RA patients initiating treatment with tofacitinib or a TNF inhibitor was infrequent (<1 per 100 person-years). We observed a numerically higher, but statistically nonsignificant, risk of VTE in RA patients receiving tofacitinib versus those receiving TNF inhibitors.

This review discusses the rationale and experimental data that led to clinical trials of certain botanical lipids, mainly gammalinolenic acid (GLA), for the treatment of rheumatoid arthritis (RA). Pertinent articles and reviews, and a bibliographic database in English using the following indexing terms: rheumatoid arthritis, fatty acids, gammalinolenic acid, lymphocytes, and monocytes, were used. All clinical trials in which GLA was used to treat arthritis are included in this review. Data from appropriately peer reviewed in vitro and animal experiments evaluating the effects of botanical lipids as regulators of cell activation and immune responses are also reviewed. GLA treatment is associated with clinical improvement in patients with RA, as evaluated by duration of morning stiffness, joint pain and swelling, and ability to reduce other medications. However, studies vary in terms of duration, GLA dose, whether or not they were placebo controlled, and, if so, what placebo was used, criteria for evaluation, and use of concomitant medication. Studies done in vitro generally indicated that GLA reduces lymphocyte activation and production of mediators of inflammation.

A small number of studies suggest that GLA is effective treatment for RA patients. Further controlled studies of its use in RA seem warranted.

To investigate the prevalence of calcium phosphate mineral salt accumulation in degenerative supraspinatus 'tendinitis' compared with a normal sample of human tendons, and to determine whether there is an association of calcium salt deposition with pathological changes in the tendon extracellular matrix. Cadaver tendons (supraspinatus and common biceps tendons, n = 96) and fragments of supraspinatus tendons obtained during shoulder surgery (n = 31) were analysed for calcium content by atomic absorption spectroscopy, phosphorous content using a spectrophotometric assay, and matrix composition (collagen, glycosaminoglycans and DNA) using standard biochemical techniques. We established baseline values of calcium concentration in macroscopically normal cadaver tendons (mean 1.1 (SD 0.35) micrograms/mg dry wt, n = 60) and found that 33% (nine of 27) of ruptured tendons from patients with 'degenerative tendinitis' contained an excess of calcium (more than 2SD greater than the normal sample mean). Five of these specimens had increased concentrations of phosphorous and calcium:phosphorous (molar) ratios consistent with a variety of possible calcium crystals, including calcium pyrophosphate, hydroxyapatite, and tricalcium phosphate, in addition to mixed or amorphous calcium phosphate deposits. Four of these specimens contained normal concentrations of phosphorous, consistent with deposits of calcium oxalate or calcium carbonate, although this was not confirmed biochemically. In contrast, surgical specimens (n = 4) from patients with 'calcifying tendinitis' (radiographically detected calcium deposits) all contained salts with a mineral composition consistent with hydroxyapatite. The presence and identity of crystal deposits was subsequently confirmed in five specimens by radiographic microanalysis. Analysis of the tendon matrix demonstrated a number of significant differences between normal and degenerate (ruptured) tendons, including a reduction in collagen content, an increase in sulphated glycosaminoglycans (predominantly dermatan sulphate) and an increase in DNA (cellular) content. However, there were no significant differences between degenerate tendons that were 'calcified' and those degenerate specimens that contained normal concentrations of calcium.

Although there was a relatively high prevalence of calcium salts in degenerate tendons, which might contribute to the pathological process (such as increased matrix collagen degradation), these data are consistent with the hypothesis that 'dystrophic calcification' of degenerate tendon matrix is a pathological entity distinct from cell mediated 'calcifying tendinitis'. Calcification is probably one possible outcome (or end point) of chronic tendon injury, although the possibility exists that in many cases, the presence of calcium salts may contribute to the tendon matrix degeneration.

The genus Rhodiola has been used to treat cough, hemoptysis, fever, pain, bruise and other symptoms which are related to injury and inflammation over a thousand years in traditional Tibetan medicine. Salidroside (p-hydroxyphenethyl-β-D-glucoside) is one of the most potent bioactive ingredients of the genus Rhodiola. The present study aimed to explore whether salidroside could alleviate the clinical symptom and sign in the early acute stage of osteoarthritis (OA) in monosodium iodoacetate (MIA) rat model, and its underlying mechanisms. Osteoarthritis (OA) was induced in rat knees by intra-articular injection of MIA; simultaneously salidroside was administered by intravenous injection. Pain behaviors were evaluated by knee-bend test, hind limb weight-bearing asymmetry and hind paw mechanical withdrawal threshold. The joint swelling was determined by the difference of knee joint diameter. Inflammatory exudates in synovial fluid were evaluated by leukocyte counting and protein content. Cytokines, chemokines, reactive oxygen species (ROS) and reactive nitrogen species (RNS) markers were determined by Enzyme-linked immunosorbent assay (ELISA) and colorimetric assay in synovial fluid. Pro-inflammatory gene expressions in synovial tissue were detected by quantitative real time RT-PCR (qRT-PCR). Nuclear factor kappa-B (NF-κB) DNA binding assay and western blot were used to determine NF-κB activation and ROS marker protein expression in synovial tissue. Glycosaminoglycan (GAG) content in the cartilage was measured by dimethylmethylene blue method. Hematoxylin and eosin (H&E), Safranin O-fast green and a modified Mankin grading system were used to evaluate the histology of articular cartilage. Salidroside could alleviate pain and joint swelling in the early acute stage of OA in rat model, reduced the number of leukocytes, total protein content, proinflammatory mediators and ROS/RNS markers in synovial fluid, down regulated the expression of proinflammatory genes in synovium, inhibited the activation of NF- κ B and oxidative stress response in synovium, promoted the synthesis of cartilage GAG, prevented the loss of proteoglycan and chondrocyte degeneration.

Salidroside effectively alleviates acute symptom and sign of OA in rat model by its anti-inflammatory and antioxidant affects to inhibit synovial inflammation, which provides a new strategy to prevent the onset and progression of OA.

To quantify the incidence of symptomatic hand, hip, and knee osteoarthritis (OA) among members of the Fallon Community Health Plan, a health maintenance organization located in central Massachusetts. Incident OA was defined as the first evidence of OA by radiography (grade > or = 2 on the Kellgren-Lawrence scale of 0-4) plus joint symptoms at the time the radiograph was obtained or up to 1 year before the radiograph was obtained. The age- and sex-standardized incidence rate for hand OA was 100/100,000 person-years (95% confidence interval [95% CI] 86, 115), for hip OA 88/100,000 person-years (95% CI 75, 101), and for knee OA 240/100,000 person-years (95% CI 218, 262). The incidence of hand, hip, and knee OA increased with age, and women had higher rates than men, especially after age 50. A leveling off or decline occurred for both groups around the age of 80.

In a large study of symptomatic OA we observed incidence rates that increased with age. In women ages 70-89, the incidence of knee OA approached 1% per year.

The purpose of this study was to determine if oral administration of the interleukin (IL) 12/IL-23 inhibitor, STA-5326, is effective in experimental autoimmune uveoretinitis (EAU). C57BL/6J mice were immunised with human interphotoreceptor retinoid binding protein peptide (IRBP 1-20). STA-5326 at a dose of either 5 mg/kg or 20 mg/kg, or vehicle alone, was orally administered once a day for six days a week from day 0 to day 14. Fundus examination was performed on day 14 and day 18 after immunisation. Mice were euthanased on day 18 and the eyes were enucleated for histopathological examination. In vivo-primed draining lymph node cells were stimulated with IRBP 1-20 and culture supernatant was harvested for assay of interferon (IFN)-gamma and IL-17 by ELISA. Intracellular expression of IFN-gamma and IL-17 in CD4+ T cells of cultured draining lymph node cells was assessed by flow cytometry. The level of IL-12 p40 in serum was examined in STA-5326-treated or vehicle-treated mice receiving immunisation. The level of IL-12 p40 in serum was decreased in mice treated with STA-5326. Oral administration of either 5 mg/kg or 20 mg/kg STA-5326 reduced the severity of EAU on day 14 and 18. In addition, mice treated with 20 mg/kg STA-5326 showed significantly decreased severity of EAU by histopathological analysis. Although IFN-gamma production of draining lymph node cells was increased in STA-5326-treated mice by ELISA analysis, the proportion of IFN-gamma-producing cells was not significantly altered. However, IL-17 production and the proportion of IL-17-producing cells were significantly reduced in STA-5326-treated mice. Furthermore, oral administration of STA-5326 during the effector phase reduced the severity of EAU.

These results indicate that oral administration of the IL-12/IL-23 inhibitor STA-5326 is effective in suppressing inflammation in the EAU model, and reduces the expansion of IL-17-producing cells. STA-5326 may represent a new therapeutic modality for human refractory uveitis.

Hip osteoarthritis is a major cause of pain and disability, especially in the elderly. As part of a study investigating factors that could be associated with advanced osteoarthritis of the hip, we compared the health status of patients awaiting arthroplasty for hip osteoarthritis with controls. We further investigated the interaction of hip osteoarthritis with other variables (age, gender, social class and concurrent pain) in relation to health status. A case-control study was performed in two English health districts (Portsmouth and North Staffordshire) during 1993-1995. A total of 611 patients (210 men and 401 women) listed for hip replacement because of osteoarthritis over an 18-month period formed the case group and were compared with an equal number of controls selected from the general population and individually matched for age, gender and general practice. Cases and controls completed a structured interviewer-administered questionnaire, which included queries about their medical condition, occupation (from which a measure of social class was derived), and general health status using the SF36. Physical function (t=32.1, P<0.001), social function (t=16.8, P<0.001) and perceived general health (t=4.1, P<0.001) were worse in the case group, but energy/vitality and mental health showed little difference between cases and controls. Cases were more likely to report knee pain than controls, but case-control status was not associated with pain in the fingers or shoulders, or with social class. However, differences in physical and social function between cases and controls did vary with socio-demographic factors and concurrent knee pain status.

Patients awaiting hip-replacement because of osteoarthritis were more likely to be restricted in their physical and social life than adults in the general population, but mental state and vitality appear unimpaired in this group. This contrasts with findings from other chronic pain disorders. Manual social class is not linked to being on a waiting list for osteoarthritic hip replacement but does add to the burden on health status, particularly social functioning in those with osteoarthritis of the hip.

Data on the disease course and ultimate outcome of adult-onset Still's disease (AOSD) are limited. We analyzed the clinical manifestations, disease course, and complications of patients with AOSD in Taiwan. A retrospective cohort design with prospective follow-up was used. Eighty two patients with AOSD diagnosed between 1983 and 2003 were evaluated. Their clinical features and laboratory findings at presentation, disease course, and complications were analyzed. Fifty nine patients (72%) were female and 55 (67.1%) were aged between 16-35 years at onset. The most common clinical manifestations were fever (100%), articular symptoms (100%), evanescent rash (87%), and sore throat (84%). Dermatographism was noted in 59% of patients. Elevation of erythrocyte sedimentation rate and C-reactive protein, which were significantly correlated with disease activity score (both p < 0.01) occurred in more than 90% of AOSD patients. Elevation of serum ferritin, which was significantly correlated with disease activity score and hepatic enzyme levels, was present in 91% of patients. Polycyclic systemic course was the most common (45%), followed by monocyclic systemic course (34%); only 20% of patients progressed to chronic arthropathy.

The multisystemic involvement and various patterns of disease course in this series illustrate the heterogenic nature of AOSD. Serum ferritin levels can be used as a marker for monitoring disease activity in AOSD.

To estimate the incidence of psoriatic arthritis (PsA) in patients with psoriasis, and to identify risk factors for its development. The study was designed as a prospective cohort study involving psoriasis patients who did not have a diagnosis of arthritis at the time of study enrollment. Information was collected about lifestyle habits, comorbidities, psoriasis activity, and medications. Patients who developed inflammatory arthritis or spondylitis were classified as having PsA if they fulfilled the criteria of the Classification of Psoriatic Arthritis Study group. The annual incidence of PsA was estimated using an event per person-years analysis. Cox proportional hazards models, involving fixed and time-dependent explanatory variables, were fitted to obtain estimates of the relative risk (RR) of the onset of PsA, determined in multivariate models stratified by sex and controlled for age at onset of psoriasis. The data obtained from the 464 patients who were followed up for 8 years were analyzed. A total of 51 patients developed PsA during the 8 years since enrollment. The annual incidence rate of PsA was 2.7 cases (95% confidence interval 2.1-3.6) per 100 psoriasis patients. The following baseline variables were associated with the development of PsA in multivariate analysis: severe psoriasis (RR 5.4, P = 0.006), low level of education (university/college versus high school incomplete RR 0.22, P = 0.005; high school graduate versus high school incomplete RR 0.30, P = 0.049), and use of retinoid medications (RR 3.4, P = 0.02). In multivariate models with time-dependent variables, psoriatic nail pitting (RR 2.5, P = 0.002) and uveitis (RR 31.5, P = 0.0002) were associated with the development of PsA.

The incidence of PsA in patients with psoriasis is higher than previously reported. A severe psoriasis phenotype, presence of nail pitting, low level of education, and uveitis are predictive of the development of PsA in patients with psoriasis.

To investigate the role of humoral immunity to mycobacterial hsp65 in the aetiology of rheumatoid arthritis. Levels of IgG antibodies to recombinant mycobacterial hsp65 were measured by enzyme linked immunosorbent assay (ELISA) in serum samples of 152 twin pairs discordant for RA and in serum samples from 62 normal blood donors. No significant differences between antibody levels in the subjects with RA compared either with their unaffected twins or with a group of normal blood donors was observed. In the monozygotic twins there was a strong but negative association between levels of antibody to hsp65 and disease status. Zygosity, sex, and HLA status did not significantly affect levels of antibody to hsp65.

Previous reports of an association between hsp65 and RA were not confirmed.

Patellofemoral arthroplasty (PFA) can be a successful, bone-sparing treatment for isolated patellofemoral arthritis. However, progression of tibio-femoral arthritis or incorrect indications may predispose patients to early conversion to total knee arthroplasty (TKA). The purpose of this study was to review the clinical cases and perform retrieval analysis of PFA conversions to TKA at our institution. Twenty one patellofemoral arthroplasties in 18 patients that were converted to TKA were identified through our implant retrieval registry. Sixteen implants were available for review by biomechanical engineers, who recorded surface markings, wear patterns, and integrity of fixation. Patient charts were reviewed and time to conversion, tourniquet time, conversion implant, additional surgeries, infections, and Kellgren & Lawrence grade of the tibio-femoral joint on pre-operative radiographs were recorded. PFAs converted to TKAs at our institution were implanted for an average of 2.7years. The most common reason for conversion was pain, but most patients had significant tibio-femoral arthritis, as indicated by an average Kellgren & Lawrence grade of 2.6. The average tourniquet time for these conversions was 67min. These patients underwent an average of one additional surgery per PFA converted, and the infection rate of these conversions was approximately 14%. IV.

Success of PFA depends upon correct patient selection rather than implant failure or wear. Conversion of PFA to TKA is technically similar to primary TKA, with similar post-operative pain relief and range of motion. However, infection rates and complications requiring further surgery are more consistent with results seen in revision TKA.

Both genetic and environmental factors are associated with susceptibility to juvenile idiopathic arthritis (JIA). Many studies have reported that both a 'shared epitope' (SE) encoded by several HLA-DRB1 alleles and the peptidyl arginine deiminase type 4 (PADI4) gene polymorphisms are associated with susceptibility to rheumatoid arthritis (RA). However, it is uncertain whether JIA and RA share the latter genetic risk factor. Therefore, here we investigated relationships between HLA-SE and PADI4 polymorphisms with clinical subtypes of JIA. JIA patients (39 oligoarthritis, 48 RF-positive polyarthritis, 19 RF-negative polyarthritis and 82 systemic) and 188 healthy controls were genotyped for HLA-DRB1 by PCR-sequence-specific oligonucleotide probe methodology. Three PADI4 gene single nucleotide polymorphisms (SNPs), rs2240340, rs2240337 and rs1748033, were genotyped using TaqMan SNP Genotyping Assays. Frequencies of the HLA-SE were higher in RF-positive polyarticular JIA than in healthy controls. RF-positive polyarticular JIA was associated with HLA-SE (OR = 5.3, 95% CI = 2.5-11.9, pc < 0.001). No associations were found between clinical subtypes of JIA and PADI4 allele frequency. Nonetheless, rs2240337 in the PADI4 gene was significantly associated with anti-cyclic citrullinated peptide antibody (ACPA)-positivity in JIA. The A allele at rs2240337 was a significant risk factor for ACPA positivity in JIA (OR = 5.6, 95% CI = 1.71-23.7 pc = 0.03).

PADI4 gene polymorphism is associated with ACPA-positivity in JIA. The association of HLA-SE with RF-positive polyarticular JIA as well as RA is confirmed in Japanese. Thus, HLA-SE and PADI4 status both influence JIA clinical manifestations.

In late 2017, the American Academy of Orthopaedic Surgeons (AAOS) published an appropriateness classification system using the RAND/University of California, Los Angeles (UCLA) approach for patients with hip osteoarthritis (OA). We determined the contribution of predictor variables in the system to final classification, rated as "appropriate," "may be appropriate," or "rarely appropriate" for hip arthroplasty. An AAOS-appointed expert panel developed 270 clinical vignettes incorporating all permutations of 5 evidence-driven indication variables associated with hip arthroplasty outcome or need. Indication variables were age, function-limiting pain severity, radiographic hip OA severity, hip motion, and presence of modifiable prognostic risk factors. Multinomial regression determined the relative contribution of each variable and a classification tree method determined variable combinations contributing to final classification. Patient age and hip OA severity were the dominant predictors of appropriateness classification in both statistical models. Function-limiting pain made a slight contribution relative to age and hip OA severity while hip motion and the presence of modifiable prognostic factors did not meaningfully contribute to final classification. The regression model explained about 99% of the variance and the classification tree had an accuracy of 87.8%.

Classification for hip arthroplasty appropriateness in the AAOS system is driven almost exclusively by age and OA severity. Function-limiting pain, a major reason patients seek surgery, contributes only slightly to the AAOS appropriateness criteria. The system relies heavily on traditional variables of patient age and radiographic hip OA severity. Future study of actual patient outcomes is needed to further test the validity of the AAOS system.

Little is known about systemic B-cell activation in early rheumatoid arthritis (RA). We therefore evaluated the serum levels of markers of B-cell activation in patients included in the ESPOIR early arthritis cohort. In the ESPOIR early arthritis cohort (at least 2 swollen joints for more than 6 weeks but less than 6 months), 710 patients were assessed at 1 year and either met the 1987 American College of Rheumatology criteria for RA (n = 578) or had undifferentiated arthritis (n = 132). Baseline serum samples of patients naïve to corticosteroid and disease-modifying antirheumatic drug treatment were assessed for beta2-microglobulin, IgG, IgA, IgM, immunoglobulin free light chains of immunoglobulins, and B-cell activating factor of the tumor necrosis factor family (BAFF). The BAFF gene 871T>C polymorphism was genotyped in all patients. All markers of B-cell activation except BAFF and IgM were significantly higher in patients with early RA than those with undifferentiated arthritis. Anti-cyclic citrullinated peptide (anti-CCP) and beta2-microglobulin were associated with a diagnosis of early RA in the multivariate analysis. Markers of B-cell activation, except BAFF, were associated with disease activity, rheumatoid factor and anti-CCP secretion. The BAFF gene polymorphism was not associated with early RA.

Markers of B-cell activation are elevated in patients with early RA, compared with undifferentiated arthritis, independently of any systemic increase in BAFF secretion, and correlate with disease activity. This study sheds new light on the early pathogenic role of B-lymphocytes in RA and suggests that targeting them might be a useful therapeutic strategy in early RA.

The impact of long-term therapy for rheumatoid arthritis (RA) in elderly (> or = 65 years of age) and younger (< 65 years of age) patients, especially on patient-reported outcomes, has not been well studied. We evaluated patient-reported outcomes in elderly patients treated with etanercept, in contrast to outcomes in younger patients, using data from multiple controlled and open-label extension studies of patients with early RA (ERA; < or = 3 years) and late RA (LRA; disease-modifying antirheumatic drug [DMARD]-refractory RA). This post hoc analysis included adult patients with RA enrolled in controlled, double-blind studies (up to 2 years) and subsequent open-label extension studies (up to 4 years). Patients were evaluated according to age at baseline of the original study. Patients may have received etanercept, placebo or methotrexate during the blinded treatment phases, but all patients had been receiving etanercept 25 mg twice weekly for at least 4 years. Both ERA and LRA extension studies are ongoing. Patient-reported outcome assessments included improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI), proportions of patients achieving an improvement in HAQ-DI > or = 0.22 points, patients exhibiting worsening of HAQ-DI and patients achieving an HAQ-DI score of 0. Elderly patients, with either ERA or LRA, had significantly worse baseline mean HAQ-DI scores than younger patients (p < 0.05, Student's t-test) in most studies, indicating greater disability. Improvement in HAQ-DI was greatest during the first 3 months after starting etanercept treatment in the controlled phase and appeared to be sustained over 3-6 months in patients with early or DMARD-refractory RA. Across the various controlled trials, mean improvements from baseline in HAQ-DI ranged from 0.39 to 0.92 points in elderly patients and from 0.57 to 1.00 points in younger patients. Patients with ERA and LRA, regardless of age group, maintained their improvement in HAQ-DI throughout the open-label extension trials for up to a total of 6 years of etanercept therapy. Change from baseline in HAQ-DI was moderately correlated with 28-joint Disease Activity Score within each age group across the multiple trials.

Both elderly and younger patients with RA treated with etanercept exhibited similar and rapid improvements in functional status during controlled studies, and these improvements were sustained during open-label extension trials.

To determine the effect of blood flow restriction with strengthening exercises on knee osteoarthritis patients. The case-control study was conducted at the Department of Physical Medicine and Rehabilitation, Combined Military Hospital, Okara, Pakistan, from June to December 2018, and comprised knee osteoarthritis patients who were assigned to two equal groups. The cases in Group A received strengthening exercises with blood flow restriction, while the controls in Group B received strengthening exercises without blood flow restriction. Both groups were given 4 sessions of treatment per week with 5-minute warm-up on a stationary bike for 4 weeks. Outcome was measured using visual analogue scale, Kujala scoring questionnaire and muscle girth measurement. Data was analysed using SPSS 20. Of the 30 patients, 15(50%) were in each of the two groups. There were 20(66.7%) females and 10(33.3%) men with an overall mean age of 66.5}6.5 years. Also, 18(60%) subjects were overweight on the basis of body mass index. There were significant improvement in terms of pain and disability in both the groups (p<0.05)), but only Group A showed significant improvement in muscle girth (p<0.05). Overall there was no significant difference between the groups (p>0.05).

Strengthening exercises reduced pain and disability, but the addition of blood flow restriction had no significant impact except in terms of muscle size.

Methotrexate (MTX) is the anchor drug for the treatment of rheumatoid arthritis (RA). MTX is associated with adverse events that limit its use. The MTX intolerance severity score (MISS) was developed to identify symptoms related to MTX use in juvenile idiopathic arthritis and RA patients. The aim of this study is to translate and validate the MISS in the Arabic language. Forward and backward translation of the MISS were performed by two fluent Arabic translators and reviewed by three rheumatologists. Consecutive patients with RA who used MTX for ≥3 months were recruited from two tertiary care centers in Riyadh, Saudi Arabia. A test was considered positive if the patient scored ≥6 points. The internal consistency and stability of the items were evaluated using Cronbach's alpha and the test-retest method. A total of 185 patients were recruited. Of those patients, 158 (85.4%) were female. The mean (±SD) age and disease duration were 49.7 (±12.67) and 8.67 (±7.1) years, respectively. The mean Disease Activity Score of 28 joints was 3.2 (±1.3). Fifty-five (30%) patients were illiterate. Seventy-three (39.5%) patients had a positive MISS. Of those patients, 55 (75.3%) and 18 (24.7%) were using the oral and subcutaneous forms of MTX, respectively. The Arabic MISS had good internal consistency (Cronbach's alpha = 0.792) and a factorable study size for test-retest and factor analysis (Kaiser-Meyer-Olkin = 0.745).

The Arabic MISS showed validity and good reliability in detecting MTX intolerance in RA patients. MTX intolerance is prevalent among RA patients. Larger studies are needed to confirm these findings.

Few studies have evaluated the impact of age on patient-reported outcomes in the long-term follow-up after high tibial valgus osteotomy (HTO). The purpose of this study is to assess the association between age at surgery and patient-reported clinical outcomes in the mid-term to long-term follow-up of HTO. We mailed the 2011 Knee Society score (KSS) questionnaires to 234 consecutive patients (295 knees) who had undergone closing-wedge HTO, and 158 patients (202 knees, 68.5%) returned a completed questionnaire. The cohort was divided into two groups depending on the age at the time of surgery, and pairs matched the follow-up period and sex was created. The mean follow-up period was approximately 12 years. KSS scores at the final follow-up were compared between two groups using the Student t test and chi-square test, and the survival rates were calculated using Kaplan-Meier survival curves. The symptom, satisfaction, and expectation scores were not significantly different between the ≤64-year-old patients and ≥65-year-old patients. The functional activities score was significantly lower in older patients than in younger patients. The overall survival rates of HTO were 99.1 ± 0.4% at 5 years, 94.4 ± 1.2% at 10 years, and 84.6 ± 2.7% at 15 years. There was no significant difference in the survival rate after HTO between the two groups divided by the age (p = 0.602).

Pain relief and satisfaction after HTO in older patients were comparable to those in younger patients in the mid-term to long-term follow-up, although the functional activity was affected by age.

Tophus burden is currently measured using physical examination and imaging methods. The aim of this study was to develop a patient-reported outcome (PRO) tool to assess tophus burden in people with gout. The responses from interviews with 25 people with tophaceous gout were used to generate items for a preliminary PRO tool. Following cognitive testing of each item, a preliminary 34-item questionnaire was administered to 103 people with tophaceous gout. Rasch analysis generated a 20-item Tophus Impact Questionnaire (TIQ-20). Test-retest reproducibility and construct validity of the TIQ-20 were assessed. The TIQ-20 responses fit the Rasch model and demonstrated unidimensionality, adequate precision, absence of differential item functioning and adequate person separation index. The TIQ-20 included items related to pain, activity limitation, footwear modification, participation, psychological impact and healthcare use due to tophi. In the 103 patients with tophaceous gout, floor effects were observed in 4.9% and ceiling effects in 1%. The TIQ-20 test-retest intraclass correlation coefficient was 0.76 (95% CI 0.61 to 0.85). All predicted correlations for construct validity testing were observed, including weak correlation with serum urate concentrations (r<0.30), moderate correlation with subcutaneous tophus count and dual energy CT urate volume (r=0.30-0.50), and stronger correlation with Health Assessment Questionnaire scores (r>0.50).

We have developed a tophus-specific PRO in patients with tophaceous gout. The TIQ-20 demonstrates acceptable psychometric properties. Initial results show internal, face and construct validity, reproducibility and feasibility. Further research is required to determine responsiveness to change.

The purpose of this study was to investigate whether the effect of treatment with hyaluronic acid (HA) on cartilage in osteoarthritis (OA) can be determined by measuring the magnetic resonance (MR) T2 value of cartilage in an anterior cruciate ligament transection (ACLX) animal model. Eighteen male Sprague Dawley rats were separated randomly into three groups (n=6 for each group). Group 1 was given ACLX and intra-articular (IA) normal saline (NS) injection (ACLX+NS), group 2 was given ACLX and IA HA injection (ACLX+HA), and group 3 was the sham control. The ACLX+NS and ACLX+HA groups received ACLX on the right knee at 8 weeks of age and were then treated with IA NS or HA injection once a week, respectively, for 4 weeks starting at 13 weeks of age. In the sham-control group, the right knee joint was opened surgically but ACLX was not performed at 8 weeks of age. MR T2 measurements were obtained on all rats at 8, 12, and 21 weeks of age, and histological Mankin scoring was performed at 21 weeks of age. Five weeks after the 4-week treatment, the MR T2 value of the ACLX right knee cartilage was significantly lower in ACLX+HA (29.58+/-1.12ms) than in ACLX+NS (32.04+/-1.39ms) (P<0.05). Five weeks after the 4-week treatment, the Mankin score of the ACLX right knee was significantly lower in ACLX+HA (3.3+/-0.81) than in ACLX+NS (7.3+/-1.03) (P<0.001). The T2 value was significantly and positively correlated with the Mankin score in the ACLX+NS (rho=0.77, P<0.05) and ACLX+HA (rho=0.69, P<0.05) groups.

This study demonstrates the feasibility of quantitative MR T2 measurement in the early assessment of HA treatment efficiency in a cartilage degeneration model.

Vibratory perception threshold (VPT) is impaired in patients with knee osteoarthritis (OA). It is, however, not known if sensory deficits precede or follow as a consequence of OA. The aim of this study was to investigate VPT in 2 independent groups of patients with high risk of future OA (young anterior cruciate ligament [ACL]-injured patients and middle-aged meniscectomized patients) and compare them to age-matched controls. VPT was assessed at the medial malleolus (MM) and medial femoral condyle (MFC) in 2 independent groups of patients and matched controls: ACL-injured patients (n = 39, mean ± SD age 24.0 ± 5.2 years, mean ± SD BMI 24.0 ± 2.9 kg/m(2) , mean ± SD time since injury 21.9 ± 21.6 months) and controls (n = 28, mean ± SD age 25.6 ± 4.4 years, mean ± SD BMI 23.6 ± 2.2 kg/m(2) ), and meniscectomized patients (n = 22, mean ± SD age 49.6 ± 4.8 years, mean ± SD BMI 24.7 ± 2.7 kg/m(2) , mean ± SD time since surgery 49.6 ± 5.0 months) and controls (n = 25, mean ± SD age 49.4 ± 5.2 years, mean ± SD BMI 25.2 ± 4.9 kg/m(2) ). ACL-injured patients had a better VPT than controls at the MM (P = 0.030), which persisted after adjusting for age and sex (P = 0.034). At the MFC, there was a similar trend in favor of ACL injured patients (unadjusted P = 0.093, adjusted P = 0.122). No differences were seen in VPT at the MM between meniscectomized patients and controls, whereas there was a tendency for better VPT in meniscectomized patients at the MFC (unadjusted P = 0.085, adjusted P = 0.092).

Impaired vibratory sensation could not be confirmed in 2 independent groups of patients compared to age-matched controls, suggesting that impaired vibratory sense is not present in knee-injured patients at high risk or in the very early phase of knee OA.

Single-stage bilateral total knee replacement (TKR) has the advantages of requiring only one hospital stay and one anesthesia session, having a shorter rehabilitation period, and reducing the cost of patient care. However, this strategy is controversial because of the perioperative risk. We hypothesized that this strategy did not cause early perioperative mortality and that the early morbidity and readmission rates would be low when patients are selected based on their ASA score. This single-center retrospective study analyzed a cohort of ASA-1 and ASA-2 patients who underwent single-stage bilateral TKR over an 8-year period (2009 to 2016). The study cohort consisted of 116 patients, mainly women with mean age of 69 years at inclusion; 22.4% of patients were ASA-1 and 77.6% were ASA-2. Death and early complications during the first 90 days postoperative, the early readmission rate and the blood-sparing strategy were analyzed using the clinical and paraclinical data collected during the hospital stay, during the convalescent care center stay, and during the follow-up visits at 6 weeks and 3 months postoperative. The analysis was completed using the intrahospital software Clinicom, which allowed us to trace all the events and episodes for each patient. The early mortality rate was 0%. There were five major complications (4.3%) and thirteen minor complications (11%). The early readmission rate was 5.2%. Homologous blood transfusion was performed in 36% of patients. Administration of tranexamic acid reduced this rate to 24.3% versus 44% in patients not taking it (p=0.06). IV, retrospective cohort study.

The perioperative mortality in this selected population is zero and the early morbidity is acceptable. The early readmission rate is also low. Thus proposing single-stage bilateral TKR to patients meeting the criteria defined in this study is a valid strategy.

To determine the effect of physical activity on knee osteoarthritis (OA) development in persons without knee injury and according to knee alignment. We combined data from Multicenter Osteoarthritis (MOST) and Osteoarthritis Initiative (OAI), studies of persons with or at high risk of OA. Subjects had long limb and repeated posteroanterior knee radiographs and completed the physical activity survey for the elderly (PASE). We studied persons without radiographic OA and excluded knees with major injury and without long limb films. We followed subjects 30 months (in MOST) and 48 months (in OAI) for one of two incident outcomes: (1) symptomatic tibiofemoral OA (radiographic OA and knee pain), or (2) tibiofemoral narrowing. 'Active' persons were those with PASE score in the highest quartile by gender. We examined risk of OA in active group using logistic regression adjusting for age, gender, body mass index (BMI), Western Ontario and McMaster Arthritis Index (WOMAC) pain score, Kellgren and Lawrence (KL) grade (0 or 1), and study of origin. We also analyzed knees from malaligned and neutrally aligned limbs. The combined sample comprised 2,073 subjects (3,542 knees) with mean age 61 years. The cumulative incidence of symptomatic tibiofemoral OA was 1.12% in the active group vs 1.82% in the others (odds ratio (OR) among active group 0.6, 95% confidence interval (CI) 0.3, 1.3). Joint space narrowing occurred in 3.41% of knees in the active group vs 4.04% in the others (OR among active group 0.9 (95% CI 0.5, 1.5)). Results did not differ by alignment status.

Physical activity in the highest quartile did not affect the risk of developing OA.

To explore the natural course of knee osteoarthritis (OA) in a middle-aged population with chronic knee pain. A population-based sample of 143 subjects (mean age 45 (range 35-54), 44% women) with knee pain (>3 months) at inclusion was studied. Weight-bearing posteroanterior tibiofemoral (TF) radiographs were obtained at baseline and 12 years later, and classified according to Kellgren/Lawrence (K/L). Patellofemoral (PF) OA was determined at 5- and 12-years' follow-up using a skyline view and a cut-off point of <5 mm joint space width. The ACR clinical criteria were used at baseline. Seventy-six (53%) had no TF OA (K/L 0) at baseline, but 49 had clinical OA. Overall, 65/76 (86%) developed incident TF OA over 12 years (K/L >or=1): 44/49 (90%) of the subjects with clinical OA and 21/27 (78%) without clinical OA. Progression was found in 65/67 (97%) with TF OA at baseline. Of the 84 with no PF OA at the 5-year examination, 26 (31%) developed PF OA over 7 years.

A majority of the subjects with chronic knee pain developed knee OA over 12 years. It is concluded that knee pain is often the first sign of knee OA.

Cinnamomum cassia (C. cassia, Lauraceae family), commonly used for treating dyspepsia, gastritis, blood circulation, and inflammatory diseases is considered as one of the 50 fundamental herbs in traditional Chinese medicine. The anti-inflammatory action of an ethanol extract of C. cassia (CA), and its underlying mechanisms were explored in both in vitro cellular and in vivo murine models. Bone marrow-derived macrophages (BMDMs) were used to study the regulatory effect of CA on inflammasome activation. A lipopolysaccharide (LPS)-induced sepsis mouse model and a monosodium urate (MSU)-induced gout model were employed to study the effect of CA on in vivo efficacy. CA improved the survival rate in the LPS-induced septic shock mouse model and inhibited inflammasome activation including NLRP3, NLRC4, and AIM2, leading to suppression of interleukin-1β secretion. Further, ASC oligomerization and its speck formation in cytosol were attenuated by CA treatment. Furthermore, CA improved both survival rate of LPS-induced septic shock and gout murine model.

CA treatment significantly attenuated danger signals-induced inflammatory responses via regulation of inflammasome activation, substantiating the traditional claims of its use in the treatment of inflammation-related disorders.

This study aimed to assess total influenza mortality among the elderly (> or = 75 years old) in France, and to evaluate how many deaths may have been avoided through vaccination during the past 10 years. The monthly mortality rates related to different causes among the elderly were obtained from the national mortality statistics for the period 1978-90. For each cause, the proportion of the registered death rate attributable to influenza was estimated using time series models. Each model analysed the registered death rate for the considered cause as a linear function of the registered influenza death rate for that month, the secular trend, and the seasonal variations. This yielded yearly regression coefficients for influenza. Formulas were subsequently developed to estimate the death rates avoided as a result of influenza vaccination according to the level of vaccine coverage and the hypothetical effectiveness of the vaccine. Between 1980 and 1990 registered influenza death rates ranged from 11-81 per 100,000. The number of deaths attributable to influenza but registered as resulting from another cause was up to eight times the number of deaths registered as influenza. Total influenza death rates were estimated as ranging from 28 per 100,000 (1988-89) to 482 per 100,000 (1985-86). At the same time it was estimated that the use of influenza vaccine avoided from 7 per 100,000 deaths in 1981-82 to 697 per 100,000 deaths in 1989-90, depending on the intensity of the epidemic, the vaccine coverage, and the vaccine effectiveness.

These results support the policy of promoting influenza vaccination among the elderly.

To further explore deiodinase iodothyronine type 2 (DIO2) as a therapeutic target in osteoarthritis (OA) by studying the effects of forced mechanical loading on in vivo joint cartilage tissue homeostasis and the modulating effect herein of Dio2 deficiency. Wild-type and C57BL/6-Dio2(-/-) -mice were subjected to a forced running regime for 1 h per day for 3 weeks. Severity of OA was assessed by histological scoring for cartilage damage and synovitis. Genome-wide gene expression was determined in knee cartilage by microarray analysis (Illumina MouseWG-6 v2). STRING-db analyses were applied to determine enrichment for specific pathways and to visualise protein-protein interactions. In total, 158 probes representing 147 unique genes showed significantly differential expression with a fold-change ≥1.5 upon forced exercise. Among these are genes known for their association with OA (eg, Mef2c, Egfr, Ctgf, Prg4 and Ctnnb1), supporting the use of forced running as an OA model in mice. Dio2-deficient mice showed significantly less cartilage damage and signs of synovitis. Gene expression response upon exercise between wild-type and knockout mice was significantly different for 29 genes.

Mice subjected to a running regime have significant increased cartilage damage and synovitis scores. Lack of Dio2 protected against cartilage damage in this model and was reflected in a specific gene expression profile, and either mark a favourable effect in the Dio2 knockout (eg, Gnas) or an unfavourable effect in wild-type cartilage homeostasis (eg, Hmbg2 and Calr). These data further support DIO2 activity as a therapeutic target in OA.

To identify the organisms causing delayed deep infection following primary total knee arthroplasty (TKA) and to compare the differences in outcome based on the infecting organism. Between the period April 1998 and March 2004 inclusive, patients presenting with delayed deep infection following primary TKA and/or those who underwent a salvage procedure (amputation or arthodesis) were retrospectively studied. Organisms were isolated in 27 patients; 44% were methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. When the organism was resistant, the mean number of surgical procedures per patient was significantly higher and the proportion of patients with satisfactory outcomes was significantly lower.

Deep infection with methicillin-resistant S. aureus or S. epidermidis is increasing. Strict infection control measures must be in place to combat such problems.

The objective of the present study was to assess the frequency of self-reported psoriasis in a hip osteoarthritis (OA) cohort, and a secondary objective was to assess the course of hip OA with psoriasis. ECHODIAH was a 3-year, randomised double-blind controlled trial evaluating diacerein vs. placebo in hip OA. During the 36 months of the trial, the Lequesne algofunctional index and pain visual analog scale (VAS) and joint space width (JSW) were assessed every 3 months. From month 36 to 120, the requirement for total hip replacement (THR) was collected annually via a phone call. At the end of 10 years of follow-up, the prevalence of self-reported psoriasis, family psoriasis was assessed by letter, retrospectively--(retrolective design). Of the 507 ECHODIAH patients, 279 were followed-up 10 years; 192 (68.8%) answered the psoriasis questionnaire. Twenty-two (11.4%) of 192 patients had self-reported psoriasis. Eighteen patients (9.4%) had family history of psoriasis. Eleven (50%) of 22 patients were diagnosed by a dermatologist. Baseline characteristics were similar between responders and non-responders, and between psoriasis and no psoriasis patients. The disease course was not different according to the presence of psoriasis, though total hip replacement was more frequent with psoriasis (77.2% after 10 years) than without (58.8%), no statistical difference (p=0.10).

The prevalence of self-reported psoriasis was high in this cohort, almost twice the frequency reported in the general population. The disease course was not modified by the presence of psoriasis. These data should be further confirmed.

To obtain the perspective of individuals with systemic lupus erythematosus (SLE) regarding the role of poverty, neighborhood, and chronic stress in SLE outcomes. Through annual structured interviews as part of the Lupus Outcomes Study, 723 persons with SLE were followed from 2003 to 2015 in order to establish the effect of combinations of poverty, persistent poverty, residence in an area of concentrated poverty, access to health care, and chronic stress on accumulated damage. We obtained a sample of 28 of the 723 individuals on the basis of household income, geography, and outcomes in their last interview, and administered qualitative interviews to explore their perspectives on the impact of these factors on SLE outcomes. The interviews were recorded, transcribed, and analyzed using a grounded theory approach. Persons in poverty frequently reported that poverty necessitated a choice to deal with food, medical care, and housing insecurity on a daily basis and to relegate their management of SLE to occurrences of disease flares. They also reported that exposure to crime in their neighborhoods was a stressor that triggered worse disease activity. Affluent participants reported that neighborhood neither helped nor hindered dealing with SLE, because they relied on networks not tied to neighborhoods to deal with SLE.

Mitigating poverty and reducing exposure to crime through moving to safer neighborhoods are factors identified by individuals with SLE as potentially critical in disease outcomes.

To determine the minimal clinically important differences (MCID) in the patient-reported outcomes of activity (0-30, number of days of limitation), fatigue (0 = none, 100 = complete), and sleep quality (0 = no problems, 100 = worst case) for patients with rheumatoid arthritis (RA). Two randomized controlled trials comparing abatacept to placebo in RA patients were considered: ATTAIN (n = 391) and AIM (n = 652). An internal anchor-based approach was used to derive the MCID using the Health Assessment Questionnaire, patient global assessment, and pain as anchors. Minimal important change in activity, fatigue, and sleep were determined by estimating mean changes in these outcomes in patients showing change in a narrow range about the MCID of the internal anchor. Correlation analysis was used to determine the consistency of the changes in the outcomes and anchors, and a Delphi process was used to determine the final MCID values. For the 2 trials, consistent patterns of change for activity, fatigue, and sleep and the internal anchors were found with correlations in the range of 0.5, 0.7, and 0.4, respectively. The mean changes for activity, fatigue, and sleep in a narrow range about the MCID of the 3 internal anchors corresponding to the 2 trials were: 3.4 to 4.3 for activity; 6.7 to 17.0 for fatigue; and 4.1 to 7.3 for sleep. Following the Delphi process the MCID determined were 4 for activity, 10 for fatigue, and 6 for sleep.

These MCID for activity limitation, fatigue, and sleep problems can be used in designing clinical trials and providing benchmarks in assessing patient improvement.

There is evidence that omega-3 polyunsaturated fatty acids alleviate the progression of osteoarthritis (OA). However, little work has been done to investigate the effect of fatty acids on bone marrow lesions and knee cartilage in healthy subjects. We examined this in a cohort of healthy middle-aged subjects without clinical knee OA. Two hundred and ninety-three healthy adults without knee pain or injury were recruited from an existing community-based cohort. Intakes of fatty acids and food sources of these were estimated from a food frequency questionnaire at baseline. Tibial cartilage volume, tibial plateau bone area, tibiofemoral cartilage defects and bone marrow lesions were assessed approximately 10 years later using magnetic resonance imaging. In multivariate analyses, higher intakes of monounsaturated fatty acids (OR=2.14, 95% CI 1.04-4.39, P=0.04), total (OR=1.77, 95% CI 1.13-2.77, P=0.01) and n-6 polyunsaturated fatty acids (OR=1.69, 95% CI 1.10-2.61, P=0.02) were associated with an increased risk of bone marrow lesions. Intake of fatty acids was not significantly associated with cartilage volume or cartilage defects.

These findings support the dietary recommendation towards a shift to foods rich in n-3 polyunsaturated fatty acids in order to maintain an optimal balance between dietary n-3 and n-6 polyunsaturated fatty acids, which is also important in the prevention of atherosclerosis. Although our findings will need to be confirmed in longitudinal studies, they suggest the potential of fatty acids to adversely effect the knee joint.

Mass cytometry has recently emerged as a promising tool for clinical research. However, few studies have demonstrated its benefit for patient stratification and biomarker identification. Primary Sjögren's syndrome (pSS) is a prototype of chronic autoimmune disease, the pathogenesis of which remains unclear and for which treatment does not exist. This observational case-control study was designed to discover new cellular biomarkers and therapeutic targets in patients with pSS. Forty-nine patients with pSS and 45 control subjects were enrolled for clinical evaluation and mass cytometry quantification of 34 protein markers in blood. For a third of these subjects, matched labial salivary gland biopsy specimens were also analyzed by mass cytometry and immunohistochemistry. In salivary gland biopsy specimens from patients with pSS, we identified a high number of activated CD8(+) T cells, terminally differentiated plasma cells, and activated epithelial cells, pointing to new pathogenic mechanisms for future clinical intervention. In blood, we identified a 6-cell disease signature defined by decreased numbers of CD4 and memory B lymphocytes, decreased plasmacytoid dendritic cell numbers, and increased representation of activated CD4 and CD8 T cells and plasmablasts. These blood cellular components correlated with clinical parameters and, when taken together, clustered patients into subsets with distinct disease activity and glandular inflammation.

This first application of mass cytometry to a well-stratified clinical cohort and small biopsy tissues establishes the benefits of such an approach for the discovery of new biomarkers and therapeutic targets. Similar high-dimensional immunophenotyping strategies could be implemented in longitudinal and interventional clinical settings in this and other disease areas.

To identify changes in joint pain, stiffness, and functional ability in patients with knee osteoarthritis (OA) after use of a knee sleeve that prevents loss of body heat by the joint. Subjects with symptomatic knee OA (n = 52) were randomized to 2 treatment groups: verum sleeve (specially fabricated to retain body heat) or placebo sleeve (standard cotton/elastane sleeve). Subjects wore the sleeve over the more painful OA knee for at least 12 hours daily for 4 weeks. Pain, stiffness, and functional impairment (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) in the index knee were measured at baseline and after 4 weeks of wear, after which sleeve use was discontinued. Telephone followup interviews were conducted 2 and 4 weeks later. After 4 weeks of sleeve wear, subjects in the active treatment group reported a 16% decrease in mean WOMAC pain score relative to baseline (P = 0.001). Those who wore the placebo sleeve reported a 9.7% decrease from baseline (P = 0.002). The difference between treatment groups was not statistically significant (P = 0.12). However, it was found that the 12 subjects who believed correctly that they had received the verum sleeve reported a highly significant decrease in WOMAC pain score (-27.5% relative to baseline, P = 0.0001). In comparison, subjects who received the verum sleeve but believed they had received the placebo sleeve exhibited only a marginally significant improvement in pain (-13.0% relative to baseline, P = 0.07). In the placebo group, the modest improvement in pain scores appeared unrelated to the subject's impression of the type of sleeve worn.

This pilot study was insufficiently powered to be a definitive trial of the heat-retaining sleeve. Given the magnitude of changes in knee pain in the active treatment group, heat retention merits further scientific investigation as a treatment modality for patients with knee OA.

Painful hip following hip dislocation or acetabular fracture can be an important signal for early degeneration and progression to osteoarthritis due to intraarticular pathology. However, there is limited literature discussing the use of arthroscopy for the treatment of painful hip. The purpose of this retrospective study was to analyze the effectiveness and benefit of arthroscopic treatment for patients with a painful hip after major trauma. From July 2003 to February 2013, we reviewed 13 patients who underwent arthroscopic treatment after acetabular fracture or hip dislocation and were followed up for a minimum of 2 postoperative years. The degree of osteoarthritis based on the Tonnis classification pre- and postoperatively at final follow-up was determined. Clinical outcomes were evaluated using visual analogue scale for pain (VAS) and modified Harris hip score (MHHS), and range of motion (ROM) of the hip pre- and postoperatively at final follow-up. There were nine male and four female patients with a mean age at surgery of 28 years (range, 20 to 50 years). The mean follow-up period of the patients was 59.8 months (range, 24 to 115 months), and the mean interval between initial trauma and arthroscopic treatment was 40.8 months (range, 1 to 144 months). At the final follow-up, VAS and MHHS improved significantly from 6.3 and 53.4 to 3.0 and 88.3, respectively (p = 0.002 and p < 0.001, respectively). However, there were no significant differences in hip flexion, abduction, adduction, external rotation, and internal rotation as minor improvements from 113.1°, 38.5°, 28.5°, 36.5°, and 22.7° to 118.5°, 39.0°, 29.2°, 38.9°, and 26.5° were observed, respectively (p = 0.070, p = 0.414, p = 0.317, p = 0.084, and p = 0.136, respectively). None of the patients exhibited progression of osteoarthritis of the hip at the final follow-up.

Arthroscopic treatment after acetabular fracture or hip dislocation is effective and delays the progression of traumatic osteoarthritis.

Rheumatoid arthritis (RA) is a chronic auto-immune disease with extensive articular cartilage destruction. Aggrecan depletion, mediated by aggrecanases is one of the first signs of early cartilage erosion. We investigated, whether measurement of aggrecan and fragments thereof in serum, could be used as biomarkers for joint-disease in RA patients and furthermore characterized the fragments found in the circulation. The study consisted of 38 patients, 12 males (62.2 +/- 16.0 years) and 26 females (59.8 +/- 20.7 years) diagnosed with RA: 41.5 +/- 27.5 mm/h erythrocyte sedimentation rate (ESR), 38.4 +/- 34.7 mg/ml C-reactive protein (CRP) and 4.8 +/- 1.7 disease activity score (DAS) and 108 healthy age-matched controls. Aggrecan levels were measured using two immunoassays, i.e. the (374)ARGSVI-G2 sandwich ELISA measuring aggrecanase-mediated aggrecan degradation and the G1/G2 sandwich assay, detecting aggrecan molecules containing G1 and/or G2 (total aggrecan) We further characterized serum samples by western blots, by using monoclonal antibodies F-78, binding to G1 and G2, or by BC-3, detecting the aggrecanase-generated N-terminal 374ARGSVI neo-epitope. Total aggrecan levels in RA patients were significantly decreased from 824.8 +/- 31 ng/ml in healthy controls to 570.5 +/- 30 ng/ml (31% decrease, P < 0.0001), as measured by the G1/G2 ELISA. Western blot analysis with F-78 showed one strong band at 10 kDa, and weaker bands at 25 and 45 kDa in both healthy controls and RA patients. In contrast, staining for aggrecanase-activity revealed only one strong band in RA patients of 45 kDa.

This is the first study, which characterizes different aggrecan fragments in human serum. The data strongly suggests that total aggrecan levels, i.e. aggrecan molecules containing G1 and/or G2 are lower in RA patients, and that RA patients have at least one specific subpopulation of aggrecan fragments, namely aggrecanse generated 374ARGSVI fragments. Further clinical studies are needed to investigate the potential of G1/G2 as a structure-related biochemical marker in destructive joint-diseases.

The pathogenesis of rheumatoid arthritis (RA) reflects an ongoing imbalance between proinflammatory and antiinflammatory cytokines. Interleukin-20 (IL-20) has proinflammatory properties for keratinocytes. In this study, we sought to determine whether IL-20 is involved in RA. We analyzed IL-20 levels in synovial fluid from RA patients. IL-20 and its receptors were detected in RA synovial fibroblasts (RASFs), using immunohistochemical staining. The effect of IL-20 on endothelial cells, neutrophils, and RASFs was investigated using MTT and migration assays. The expression of IL-20 and its receptors in healthy rats and in rats with collagen-induced arthritis (CIA) was also analyzed. Soluble IL-20 receptor type I (sIL-20RI) or sIL-20RII was administered to rats with CIA by intramuscular electroporation, and the severity of arthritis was monitored. RA patients expressed significantly higher levels of synovial fluid IL-20 than did the rheumatic disease controls. IL-20 and its receptors were expressed in the synovial membranes and RASFs. IL-20 induced RASFs to secrete monocyte chemoattractant protein 1, IL-6, and IL-8, and it promoted neutrophil chemotaxis, RASF migration, and endothelial cell proliferation. Both IL-20 and IL-20RI were up-regulated in the rat CIA model. In vivo, electroporated sIL-20RI plasmid DNA decreased the severity of arthritis in the rats with CIA.

IL-20 was up-regulated in the synovial fluid of RA patients and acted as a chemokine that attracted the migration of neutrophils and RASFs in vitro. The rat CIA model demonstrated that IL-20 was involved in the pathogenesis of arthritis, because sIL-20RI significantly reduced arthritis in rats with CIA. Thus, IL-20 may modulate the incidence and severity of arthritis and play important roles at local sites of inflammation.

The aim of our study was to evaluate the influence of aerobic training on the dyslipedemia in patients with knee osteoarthritis (KOA). Prospective observational six-month study performed on 40 patients with KOA, fulfilling the inclusion criteria, classified according to their participation in specific aerobic training program (30 minutes/day, 5 days/ week) in two subgroups. A standard evaluation protocol was followed assessing lipid parameters (total cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol levels) at baseline, three and six months. Statistical analysis was performed in SPSS 16.0, p < 0.05. Subgroup analysis has demonstrated a statistical significant improvement in plasma lipids levels in all patients performing regular aerobic training (cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol) (p < 0.05). Although the difference reported for total cholesterol, triglycerides and LDL-cholesterol after six months between subgroups was not significant (p > 0.05), the mean level of HDL-cholesterol was significantly higher in patients performing aerobic training, reaching the cardio-vascular protective levels.

Regular aerobic exercise has a positive effect on plasma lipoprotein concentrations; further research is needed for the assessment of long-term effects of physical exercises for both KOA and lipid pattern.

There is relatively little direct evidence for the roles of interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) in activating endothelium in vivo. The aim of this study was to use in vitro and in vivo models to investigate the contribution of these cytokines to both E-selectin expression and the recruitment of polymorphonuclear cells (PMN) in monosodium urate monohydrate (MSU) crystal-induced inflammation. MSU crystals were incubated with freshly isolated mononuclear cells, after which the harvested supernatants were tested for their ability to induce E-selectin expression during coculture with human umbilical vein endothelial cells. Subsequent experiments were performed with the addition of neutralizing anticytokine antibodies/antisera. The role of TNF alpha was then studied in an MSU crystal-induced monarthritis model, in the presence or absence of anti-TNF alpha (5 mg/kg intravenously). 99mtechnetium (99mTc)-labeled PMN cells and (111)indium (111In)-labeled anti-E-selectin monoclonal antibody (MAb) 1.2B6 were intravenously administered 4 hours after intraarticular injection to quantify PMN recruitment and E-selectin expression in inflamed joints. MSU crystals were a potent stimulus for IL-1 and TNF alpha production by monocytes in vitro, and these cytokines fully accounted for MSU crystal-stimulated, monocyte-mediated endothelial activation. In the MSU crystal-induced monarthritis model, TNF alpha blockade was very effective in suppressing both E-selectin expression and PMN emigration into the inflamed joints, as judged by gamma-camera image analysis and postmortem tissue counting following the intravenous injection of 99mTc-PMN and 111In-anti-E-selectin MAb.

IL-1 and TNF alpha appear to be the only factors released by monocytes following incubation with MSU crystals, which induce E-selectin expression in vitro. Anti-TNF alpha is effective in suppressing endothelial activation and PMN recruitment in vivo E-selectin imaging can be used to assess the endothelial response to therapy and may prove useful for clinical studies.

To compare the ratings given by the caregivers regarding the health status of their rheumatoid arthritis (RA) patients to those recorded by the patients themselves and to assess the effect of caring for a patient with RA on the mental health of the caregiver. This is a non-interventional, cross-sectional, multi-center epidemiological study conducted at the outpatient clinics of two hospitals in Saudi Arabia. The patients included were diagnosed with RA, over 18 years of age with 1-5 years of disease duration, and all had an identifiable single caregiver who was willing to participate in the study. 40 patients of whom 92.5% were women and the mean age of 44.6 years. The mean visual analogue scale (VAS) score was 4.98 for general health. The mean Health Assessment Questionnaire (HAQ) for the patients according to themselves was 1.31 (±0.68), while that stated by caregivers was 1.40 (±0.69); thus, the mean scores given by the caregivers was 0.091 points higher than that provided by the patients themselves (95% confidence interval [CI], 0.167-0.014) (p=0.0214). Further, 43% of the caregivers gave higher HAQ scores to their related patients than the patients themselves, while 30% gave similar HAQ scores. The caregivers scored a mean of 21 points in the Zarit Burden Interview (±12.1), with 47.5% reporting mild to moderate burden, and 5% reporting moderate to severe burden.

RA patients showed a tendency to understate their disease burden and as compared to that observed by caregivers who suffer from considerable level of burden.

Aromatase inhibitor therapy is often effective for breast cancer, yet it can be accompanied by musculoskeletal pain and stiffness. This prevalence assessment aimed to characterize a rheumatologist's view of frequency and clinical features, including associated disability, within a breast cancer clinic panel of 77 patients. The "aromatase inhibitor arthralgia" frequency was estimated at 50%, including both those with new and worsened discomfort. Substantial functional disability was associated, whether measured by individual functional disability (frequencies ranging from 39% to 61%) or composite score of 7 functional disability areas (median score 5 compared with median 0 in the comparison group; P = .00003). The frequency of clinical hand osteoarthritis appeared somewhat increased in the aromatase inhibitor arthralgia group (28% vs. 14%; not statistically significant). Yet the distribution of aromatase inhibitor-related symptoms and functional disabilities appeared to parallel those joint regions commonly affected by osteoarthritis. Using clinical criteria to assess 5 common rheumatic disorders (hand osteoarthritis, trigger finger, carpal tunnel syndrome, Raynaud's phenomenon, and sicca syndrome), the aromatase inhibitor arthralgia group tended to have more common rheumatic disorders (P < .05), consistent with nociceptive mechanisms making latent disorders symptomatic.

Aromatase inhibitor therapy for postmenopausal breast cancer might be associated with common musculoskeletal symptoms and with substantial functional disability and should prompt patient education. In view of the potential relevance of estrogen deprivation to osteoarthritis onset and severity, future studies of natural history should include systematic assessment of osteoarthritis frequency and severity.

To compare the effect of a single infusion of zoledronic acid (ZA) with placebo on knee pain and bone marrow lesions (BMLs). Adults aged 50-80 years (n=59) with clinical knee osteoarthritis and knee BMLs were randomised to receive either ZA (5 mg/100 ml) or placebo. BMLs were determined using proton density-weighted fat saturation MR images at baseline, 6 and 12 months. Pain and function were measured using a visual analogue scale (VAS) and the knee injury and osteoarthritis outcome score (KOOS) scale. At baseline, mean VAS score was 54 mm and mean total BML area was 468 mm(2). VAS pain scores were significantly reduced in the ZA group compared with placebo after 6 months (-14.5 mm, 95% CI -28.1 to -0.9) but not after 3 or 12 months. Changes on the KOOS scales were not significant at any time point. Reduction in total BML area was greater in the ZA group compared with placebo after 6 months (-175.7 mm(2), 95% CI -327.2 to -24.3) with a trend after 12 months (-146.5 mm(2), 95% CI -307.5 to +14.5). A greater proportion of those in the ZA group achieved a clinically significant reduction in BML size at 6 months (39% vs 18%, p=0.044). Toxicity was as expected apart from a high rate of acute phase reactions in treatment and placebo arms. ACTRN 12609000399291.

ZA reduces knee pain and areal BML size and increases the proportion improving over 6 months. Treatment of osteoarthritis may benefit from a lesion specific therapeutic approach.

Patients with osteoarthritis (OA) take a variety of health supplements in an attempt to reduce pain and improve function. The aim of this study was to determine the efficacy of methylsulfonylmethane (MSM) in treating patients with knee OA. This study was a prospective, randomized, double-blind, controlled clinical trial. Forty nine men and women 45-90 (mean 68 ± SD 7.3) years of age with knee OA according to the American College of Rheumatology clinical criteria for OA of the knee and with radiographic confirmed knee OA were enrolled in the study and randomly assigned into 2 groups: One received MSM in doses of 1.125 grams 3 times daily for 12 weeks and the other received a placebo in the same dosing frequency. The primary outcomes were the WOMAC Osteoarthritis Index for pain, stiffness and physical function, the Aggregated Locomotor Function (ALF) test that evaluates each patient's physical function, the SF-36 quality of life health survey and the visual-analogue-scale (VAS) for pain. The secondary outcomes were Knee Society Clinical Rating System for Knee Score (KSKS) and Function Score (KSFS). Patients were assessed at baseline, 6 weeks and 12 weeks. All continuous variables were tested by the Kolmogorov-Smirnov test for Normal distribution. Changes within the groups and differences between the groups were calculated by repeated measures of analysis (ANOVA) with one nested variable. There were significant differences between treatment groups over time in WOMAC physical function (14.6 mm [CI: 4.3, 25.0]; p = 0.04) and in WOMAC total score (15.0 mm [CI: 5.1, 24.9]; p = 0.03). Treatment groups did not differ significantly in WOMAC pain (12.4 mm [CI: 0.0, 24.8]); p = 0.08) or WOMAC stiffness (27.2 mm [CI: 8.2, 46.2]; p = 0.08). There was a non-significant difference in SF-36 total score between treatment groups (11.6 [CI: 1.0, 22.1]; p = 0.54). A significant difference was found between groups in VAS for pain (0.7 s [CI: -0.9, 2.4]; p = 0.05). Secondary outcomes showed non-significant differences between the two groups. ClinicalTrials.gov: NCT01188213.

Patients with OA of the knee taking MSM for 12 weeks showed an improvement in pain and physical function. These improvements, however, are small and it is yet to be determined if they are of clinical significance.

Intra-articular steroid hip injection (IASHI) has been prescribed for painful hip arthritis since the 1950s, but with advances in medical and surgical management its role is less certain today. There are very few published data on the utility or prescribing patterns of IASHI. We developed a questionnaire to seek expert opinion on IASHI that we distributed to practising Ontario-based members of the Canadian Orthopaedic Association. We systematically describe the current practices and expert opinion of 99 hip surgeons (73% response rate), focusing on indications, current use and complications experienced with IASHI. Only 56% of surgeons felt that IASHI was therapeutically useful, with 72% of surgeons estimating that 60% or less of their patients achieved even transient benefit from IASHI. One-quarter of the surgeons believe that IASHI accelerates arthritis progression, most of whom had stated that it would be no great loss if IASHI was no longer available. Nineteen percent of the surgeons believed that the infection rate related to total hip arthroplasty (THA) may be increased after IASHI, and this was associated with fewer IASHIs ordered per year, compared with the number prescribed by those who did not feel that infection rates would increase.

This systematic collection of expert opinions demonstrates that substantial numbers of surgeons felt that, in their patients, IASHI was not therapeutically helpful, may accelerate arthritis progression or may cause increased infectious complications after subsequent THA.

Previous studies have indicated that joint hypermobility may affect the development of clinical and radiological hand osteoarthritis (OA), but this question has not been addressed in epidemiological studies. Our objective was to investigate this relationship in a population-based study. The study group consisted of 384 unselected older participants in the Age, Gene/Environment Susceptibility-Reykjavik Study (161 males, median age 76, range 69-90, and 223 females median age 75, range 69-92). The criterion used for joint mobility was the single maximal degree of hyperextension of digits 2 and 5 on both hands (HYP degrees). HYP degrees was more prevalent in females and on the left hand in both men and women. Both genders had a positive association between the degree of mobility measured by HYP degrees and radiological scores for the first carpometacarpal joint (CMC1) OA. Thus, those with HYP degrees >or=70 had an odds ratio of 3.05 (1.69-5.5, P<0.001) of having a Kellgren-Lawrence score of >or=3 in a CMC1 joint. There was also a trend towards a negative association between HYP degrees and proximal interphalangeal joint scores.

Hand joint mobility, defined as hyperextension in the metacarpophalangeal joints (HYP degrees ) is more prevalent in females and on the left side. It was associated with more severe radiographic OA in the CMC1 joints in this population. The reasons for this relationship are not known, but likely explanations involve ligament laxity and CMC1 joint stability. These findings may relate to the left-sided predominance of radiographic OA in the CMC1 joints observed in many prevalence studies.

The aim of this study was to compare ultrasound (US) grading and laboratory measures in patients with rheumatoid arthritis. Two-hundred four patients with rheumatoid arthritis who received US evaluation for synovitis were included after excluding those using tocilizumab. Ultrasound grading of synovial hypertrophy (SH) and power Doppler (PD) at the most severe site were recorded. An assessment of the correlation of laboratory measures and US grading was conducted by reviewing the electronic medical records. High-titer anti-cyclic citrullinated peptide (anti-CCP) antibodies positivity was associated with SH grade ≥2 (odds ratio [OR], 6.00; 95% confidence interval [CI], 1.78-20.2) and PD grade ≥2 (OR, 5.56; 95% CI, 1.82-16.9). Recent C-reactive protein (CRP) levels ≥0.3 mg/dL were associated with SH grade ≥2 (OR, 3.13; 95% CI, 1.38-7.10) and PD grade ≥2 (OR, 2.38; 95% CI, 1.31-4.31). Anti-CCP antibody levels correlated with US scores better than the levels of CRP with higher Spearman ρ correlation coefficients. Most of the patients with recent CRP levels <0.3 mg/dL had US synovitis. In logistic regression, high levels of anti-CCP antibodies and CRP were both independently associated with SH grade ≥2 and PD grade ≥2.

Higher levels of anti-CCP antibodies and CRP may predict synovitis on US, whereas discrepancies existed between inflammatory markers and US grading. These findings suggest that US has a role in the comprehensive assessment of disease activity, especially for patients with high-titer positive anti-CCP antibodies.

The objective of this study was to examine the relationship between common genetic variation of the ESR2 gene and osteoarthritis. In the discovery study, the Rotterdam Study-I, 7 single nucleotide polymorphisms (SNPs) were genotyped and tested for association with hip (284 cases, 2772 controls), knee (665 cases, 2075 controls), and hand OA (874 cases, 2184 controls) using an additive model. In the replication stage one SNP (rs1256031) was tested in an additional 2080 hip, 1318 knee and 557 hand OA cases and 4001, 2631 and 1699 controls respectively. Fixed- and random-effects meta-analyses were performed over the complete dataset including 2364 hip, 1983 knee and 1431 hand OA cases and approximately 6000 controls. The C allele of rs1256031 was associated with a 36% increased odds of hip OA in women of the Rotterdam Study-I (OR 1.36, 95% CI 1.08-1.70, p = 0.009). Haplotype analysis and analysis of knee- and hand OA did not give additional information. With the replication studies, the meta-analysis did not show a significant effect of this SNP on hip OA in the total population (OR 1.06, 95% CI 0.99-1.15, p = 0.10). Stratification according to gender did not change the results. In this study, we had 80% power to detect an odds ratio of at least 1.14 for hip OA (α = 0.05).

This study showed that common genetic variation in the ESR2 gene is not likely to influence the risk of osteoarthritis with effects smaller than a 13% increase.

To assess whether maternal cosmetic breast implants are associated with adverse health outcomes among offspring, the authors examined published findings of epidemiologic studies that addressed this hypothesis. Four epidemiologic studies, all from Scandinavia, were identified. Women with breast implants were identified from existing public and private registers of patients, and their offspring were traced through nationwide population and birth registers. The studies included a total of 11,445 women with breast implants and 3248 children born after the mothers' implantation procedures. Comparison was made with children born to mothers who had undergone other cosmetic surgery or general population controls. Outcomes under study were congenital malformations, hospitalization for esophageal and rheumatic disorders, and perinatal mortality. Overall, the studied outcomes were similar between children born to mothers with breast implants and children of controls, and between children born before and after maternal breast implantation. In the Danish studies, significantly elevated rates of esophageal disorders were observed for children born before (observed-to-expected ratio, 2.0; 95 percent confidence interval, 1.3 to 2.8) but not after (observed-to-expected ratio, 1.3; 95 percent confidence interval, 0.5 to 2.9) the mother's breast implant surgery. Similar excesses were observed among control children born before and after maternal breast reduction. In the Swedish and Finnish studies, all risk estimates for malformations and perinatal health were close to unity.

Rates of esophageal and rheumatic disorders, congenital malformations, and perinatal mortality and hospitalization were comparable between children born to mothers with breast implants and children born to mothers who had undergone other cosmetic surgery.

To report outcomes of 21 total wrist arthroplasties (TWA) using the Universal 2 prosthesis. Five men and 14 women aged 44 to 82 (mean, 62) years underwent 21 total wrist arthroplasties for rheumatoid arthritis (n=19) and post-traumatic arthritis (n=2) by a single surgeon using the Universal 2 prosthesis. Pre- and post-operative pain and function were assessed by a single surgeon using the Disabilities of the Arm, Shoulder and Hand (DASH) score and the patient-rated wrist evaluation (PRWE) score. Range of motion, stability, dislocation rate, and neurovascular status were also assessed. Radiographs were evaluated for implant alignment and fit, screw positioning, and implant loosening. The mean time to assessment of the range of motion was 3.1 (range, 1.8-3.9) years, and the mean time to assessment of the PRWE score was 4.8 (range, 2.1-7.3) years. The range of motion in each direction and the mean DASH and PRWE scores improved significantly following TWA. Two patients had restricted range of motion, which was treated by manipulation under anaesthetic (after 6 months in one and 8 weeks in the other). One patient underwent excision of a palmar bony bridge. One patient endured extensor pollicis longus rupture and underwent tendon transfer after 5 months. Radiographs revealed no evidence of implant loosening, migration, or malalignment. There was no sign of osteonecrosis in the remaining carpals or metacarpals.

The Universal 2 TWA achieved significant improvement in range of motion and functional outcome of the wrist, with reduced rates of early joint instability, dislocation, and implant loosening, compared to previous implants. The small implant size and cementless design reduce bone loss and osteonecrosis.

To review the use of animal models of osteoarthritis (OA) with regard to their utility for investigation of the mechanisms and regulation of structural pathology and pain. PubMed searches were conducted using separate clusters of terms to retrieve articles on (i) models of structural joint damage in genetically-modified (GM) mice, and (ii) models of OA joint pain. The papers were reviewed to investigate whether there was evidence that the research outcome was dependent on the model used. Out of a total of 109 separate GM mice strains identified in which an effect on OA was reported, 15 had been studied using more than one arthritis model. In 10/15 the same effect of the GM on arthritis was reported in at least two different models. In 5/15 the effect of the GM on arthritis structural pathology was different, and sometimes opposite, when comparing two or more induction methods. A total of 112 publications were retrieved in which pain/disability was examined in a model suggested to represent OA. The induction methods used most commonly to study "OA pain" were distinct from those most often used to investigate the pathophysiology and regulation of structural joint damage. Four papers directly comparing pain mechanisms in different models were identified, with 3/4 describing differences in nociceptive pathways.

The available data indicates that the molecular mechanisms of both joint structural damage and pain may be distinct in animal models of OA induced or initiated by different means. This suggests the need to continue using multiple OA animal models but that the subsequent interpretation of the data and its extrapolation to the human condition must be more precise.

Hepatitis B reactivation in patients undergoing immunosuppressive therapy can lead to liver failure and death. Prior studies have shown suboptimal hepatitis B screening rates, but few have compared screening rates across specialties or factors associated with screening. A retrospective study was performed using a hospital-based chemotherapy database and outpatient pharmacy records from January 1999 to December 2013. HBV screening rates prior to initiation of immunosuppression were determined. Multivariate analysis was used to determine predictors of HBV screening. Of the 4008 study patients, 47 % were screened prior to receiving immunosuppressive therapy; only 48 % on rituximab and 45 % of those on anti-TNF therapy were screened. Transplant specialists screened most frequently (85 %) while gastroenterologists screened the least (34 %). Factors significantly associated with HBV screening were younger age, Asian race, use of anti-rejection therapy, and treatment by a transplant specialist (p < 0.001).

HBV screening prior to immunosuppressive therapy is suboptimal, especially among gastroenterologists. Efforts to improve screening rates in at risk populations are needed.

To investigate the trends in incidence of extra-articular rheumatoid arthritis (ExRA) in a well defined community based cohort of patients with rheumatoid arthritis (RA), and to examine possible predictors of ExRA occurrence. Using the resources of the Rochester Epidemiology Project, a retrospective medical record review was conducted of a cohort of 609 cases of RA in Olmsted County, MN, diagnosed during 1955-94. These cases had been previously classified using the ACR 1987 criteria for RA. Patients were followed up from 1955 to 2000 (median follow up 11.8 years; range 0.1-42.8), and incident ExRA manifestations were recorded according to predefined criteria. Time to first presentation of ExRA was compared in patients with RA by decade of diagnosis. Possible ExRA risk factors were identified in case record reviews. ExRA occurred in 247 patients (40.6%). A subgroup of 78 patients (12.8%) had ExRA manifestations considered to be severe in a previous study from Malmö, Sweden. The incidence of severe ExRA did not change significantly over the decades (p=0.165). In a multivariate analysis the main predictors of severe ExRA were smoking at RA diagnosis (risk ratio (RR)=2.94; 95% confidence interval (95% CI) 1.68 to 5.13) and early disability (Steinbrocker class III-IV at diagnosis) (RR=2.45; 95% CI 1.51 to 4.00). The effect of smoking overwhelmed the weaker effect of rheumatoid factor seropositivity.

There was no decrease in the incidence of extra-articular manifestations in patients with RA diagnosed up to 1995. Smoking and early disability are independent risk factors for extra-articular RA.

To describe a case of joint infection by Aspergillus fumigatus in a unusual site (sacroiliac) and perform a systematic review of such cases described in the literature. We performed a Medline search of the cases of fungal joint of Aspergillus fumigatus in the period ranging from 1970 to 2009. Following PRISMA Guidelines, 15 cases including ours were reported during this period. Stem cell and solid organ transplantation, hematologic malignancy, and intra-articular steroids injection were the medical conditions found in such patients. The knee followed by the shoulder were the joints more affected. In the cases where synovial fluid analyses were reported, elevated cell count numbers could be found with a predominance of polymorphonuclear neutrophils.

Fungal joint arthritis is a rare clinical disease most frequently present in immuno-incompetent patients. Rheumatologists should be aware of this condition, where early diagnosis can be associated with good prognosis.

The aim of this study was to evaluate the prevalence of fibromyalgia (FM) in patients with diabetes mellitus (DM). The study included 100 consecutive unselected patients with DM attending our diabetes clinic. Patients were divided into two groups: 45 patients with type 1 diabetes and 55 patients with type 2 diabetes. A group of 50 healthy hospital staff members served as controls. The FM was diagnosed according to the 1990 American College of Rheumatology criteria. Counts of 18 tender points were performed by thumb palpation and assessed by dolorimeter. Routine biochemical tests and levels of HbA(1c) were recorded in each patient. The main outcome measure was the association of FM with DM. Fibromyalgia was diagnosed in 17 patients (17%) with DM and in only one (2%) healthy control ( P=0.008). No differences in patients were noted in the prevalence of FM between type 1 and type 2 diabetes (18.5% vs 15.5%, respectively). Patients with both FM and DM had significantly higher levels of HbA(1c) than DM patients without FM (9.2+/-1.1% vs 6.4+/-1.5%) ( P<0.05). Similarly, the numbers of tender points, pain scores, and the prevalence of sleep disturbances, fatigue, and headaches were higher in this group of patients. A significant correlation was observed between the numbers of tender points and HbA(1c) levels in the DM patients with FM ( r=0.72, P=0.027).

Fibromyalgia is a common finding in patients with types 1 and 2 diabetes, and its prevalence could be related to control of the disease. As with other diabetes complications, FM might be prevented by improved control of blood glucose levels.

Biologic agents are used against rheumatic diseases, however, they increase the risk of developing severe infections and diseases such as tuberculosis. We aimed to determine the benefits of IP-10 detection to diagnose latent tuberculosis infection (LTBI) in patients with inflammatory rheumatic diseases on different immunosuppressive drug regimens, and compare these results with IFN-γ detection. We included 64 patients with inflammatory rheumatic diseases. We used QuantiFERON Gold In-Tube (QFN-G-IT) and T-SPOT.TB to detect IFN-γ production, and an in-house ELISA for IP-10 detection from the previous QFN-G-IT stimulated samples. We assessed the combined use of IFN-γ release assays (IGRAs) and IP-10 test, and analyzed the influence of immunotherapy on the tests performance. We obtained 34.9% positive results by T-SPOT.TB, 25.0% by QFN-G-IT and 31.3% by IP-10 test. The combined use of IGRAs and IP-10 detection increased significantly the amount of positive results (p < 0.0001). Treatment intake had no significant effect on in vitro tests (p > 0.05).

IP-10 and IFN-γ detection is comparable and their combined use could increase the number of positive results in the diagnosis of LTBI in rheumatic patients. The tested assays were not influenced by rheumatoid immunosuppressive therapy. Thus, IP-10 could be of use in the development of new and improved LTBI diagnostic tools.

The aims of this study were as follows: (1) to analyze the literature systematically regarding the seasonal and monthly variation of the occurrence of episodes of acute gouty arthritis, and (2) to investigate the relationship between the occurrence of episodes of acute gouty arthritis and meteorological parameters. The present authors systematically reviewed databases for articles published before November 2015. Studies with quantitative data on episodes of acute gouty arthritis by months and/or seasons were included. Meteorological data such as the highest temperature, lowest temperature, diurnal temperature range, change in mean temperature between neighboring days, relative humidity and wind speed for the geographic place(s), and study period where and when each study took place were obtained from meteorological websites. Ten studies published between 1920 and 2015 were included. A meta-analysis by season showed that acute gouty arthritis occurred significantly more frequently in spring than in other seasons. Analysis by month showed an increase in episodes of acute gouty arthritis from March to July, being the highest in July. The trend reversed, and episodes of acute gouty arthritis started decreasing from July to September, being the lowest in September. The change in mean temperature between neighboring days was the only meteorological parameter that was significantly correlated with the number of monthly episodes of acute gouty arthritis.

Acute gouty arthritis seems to develop more frequently during the period in which the temperature increases significantly between neighboring days: spring by season and between March and July by month in the northern hemisphere.

To understand the differences in prevalence and incidence estimates of osteoarthritis (OA), according to case definition, in knee, hip and hand joints. A systematic review was carried out in PUBMED and SCOPUS databases comprising the date of publication period from January 1995 to February 2011. We attempted to summarise data on the incidence and prevalence of OA according to different methods of assessment: self-reported, radiographic and symptomatic OA (clinical plus radiographic). Prevalence estimates were combined through meta-analysis and between-study heterogeneity was quantified. Seventy-two papers were reviewed (nine on incidence and 63 on prevalence). Higher OA prevalences are seen when radiographic OA definition was used for all age groups. Prevalence meta-analysis showed high heterogeneity between studies even in each specific joint and using the same OA definition. Although the knee is the most studied joint, the highest OA prevalence estimates were found in hand joints. OA of the knee tends to be more prevalent in women than in men independently of the OA definition used, but no gender differences were found in hip and hand OA. Insufficient data for incidence studies didn't allow us to make any comparison according to joint site or OA definition.

Radiographic case definition of OA presented the highest prevalences. Within each joint site, self-reported and symptomatic OA definitions appear to present similar estimates. The high heterogeneity found in the studies limited further conclusions.

To evaluate new classification criteria for peripheral spondyloarthritis (SpA) in patients with SpA with peripheral manifestations only. In this Assessment of SpondyloArthritis international Society (ASAS) study, two prespecified sets of criteria were compared against the European Spondylarthropathy Study Group (ESSG) and Amor criteria in newly referred consecutive patients with undiagnosed peripheral arthritis, and/or enthesitis, and/or dactylitis that usually began before 45 years of age. The clinical diagnosis (SpA vs no SpA) made by the ASAS rheumatologist served as reference standard. In all, 24 ASAS centres included 266 patients, with a final diagnosis of SpA being made in 66.2%. After adjustments a final set of criteria showed the best balance between sensitivity (77.8%) and specificity (82.9%): arthritis and/or enthesitis and/or dactylitis plus (A) one or more of the following parameters: psoriasis, inflammatory bowel disease, preceding infection, human leucocyte antigen B27, uveitis, sacroiliitis on imaging, or (B) two or more other parameters: arthritis, enthesitis, dactylitis, inflammatory back pain in the past, family history of SpA. The new criteria performed better than modified versions of the ESSG (sensitivity 62.5%, specificity 81.1%) and the Amor criteria (sensitivity 39.8%, specificity 97.8%), particularly regarding sensitivity. In the entire ASAS population of 975 patients the combined use of ASAS criteria for axial SpA and ASAS criteria for peripheral SpA also had a better balance (sensitivity 79.5%, specificity 83.3%) than the modified ESSG (sensitivity 79.1%, specificity 68.8%) and Amor criteria (sensitivity 67.5%, specificity 86.7%), respectively.

The new ASAS classification criteria for peripheral SpA performed well in patients presenting with peripheral arthritis, enthesitis and/or dactylitis.

To systematically review and assess the efficacy and safety of hydroxychloroquine (HCQ) for treating primary Sjogren's syndrome (pSS). Five electronic databases (Pubmed, EMBASE, Web of science, Ovid, Cochrane Library) were searched for randomized controlled trials and retrospective or prospective studies published in English that reported the effect of HCQ on pSS. The subjective symptoms (sicca symptoms, fatigue and pain) and the objective indexes (erythrocyte sedimentation rate and Schirmer test) were assessed as main outcome measures. A meta-analysis and descriptive study on the efficacy and safety of HCQ were conducted. The estimate of the effect of HCQ treatment was expressed as a proportion together with 95% confidence interval, and plotted on a forest plot. Four trials with totals of 215 SS patients, including two randomized controlled trials, one double blind crossover trial and one retrospective open-label study, were analyzed in this review. For dry mouth and dry eyes, the effectiveness of HCQ treatment was essentially the same as placebo treatment. For fatigue, the effectiveness of HCQ was lower than placebo. The efficacy of HCQ in treating pain associated with pSS was superior to that of the placebo. There was no significant difference between HCQ-treated groups and controls in terms of Schirmer test results, but HCQ could reduce the erythrocyte sedimentation rate compare with placebo. A descriptive safety assessment showed that gastrointestinal adverse effects were the most common adverse effects associated with HCQ.

This systematic review showed that there is no significant difference between HCQ and placebo in the treatment of dry mouth and dry eye in pSS. Well-designed, randomized, controlled trials are needed to provide higher-quality evidence to confirm our findings, and future studies should focus on some other index or extraglandular measures, such as cutaneous manifestations, to further explore the therapeutic effect of HCQ in pSS.

To analyze the early outcomes of viscosupplementation in patients with severe knee osteoarthritis. A randomized, double-blind clinical trial of 143 knees divided into three groups: Group 1 - intra-articular injection of triamcinolone; Group 2 - hylan GF20; and Group 3 - triamcinolone + hylan GF20. Outcomes were evaluated using Lysholm and KSS scores before treatment and after one, three and six months. Within-group comparisons revealed improvements in Lysholm scores in all groups in the one month evaluation relative to pre-treatment levels (p < 0.01). This improvement was maintained in the third month after treatment (p > 0.05). Scores at six months were significantly lower than those observed in the previous follow-up assessments (p < 0.05), but still higher than pre-treatment levels (p < 0.05). KSS scores also improved after one month relative to pre-treatment levels (p < 0.01). This improvement was still present at three and six months after treatment in the corticosteroid group (p > 0.05). Patients treated with hylan GF20 showed lower scores in the last evaluation relative to month one (p < 0.05). No significant differences were observed between the treatment groups (p > 0.05).

Viscosupplementation increased functional scores in patients with severe osteoarthritis of the knee, especially within three months of injection. However, it was not superior to the use of triamcinolone.

Lateral wedge shoe insoles decrease medial knee loading, but trials have shown no effect on pain in medial knee osteoarthritis (OA). However, loading effects of insoles are inconsistent, and they can increase patellofemoral loading. We undertook this study to investigate the hypothesis that insoles would reduce pain in preselected patients. Among patients with painful medial knee OA, we excluded those with patellofemoral OA and those with a pain rating of <4 of a possible 10. We further excluded participants who, in a gait analysis using lateral wedges, did not show at least a 2% reduction in knee adduction moment (KAM), compared to wearing their shoes and a neutral insole. We then randomized subjects to lateral wedge versus neutral insole for 8-week periods, separated by an 8-week washout. The primary outcome measure was knee pain (0-10 scale) during the past week, and secondary outcome measures included activity pain and pain rated in the Knee Injury and Osteoarthritis Outcome Score questionnaire. We carried out mixed model analyses adjusted for baseline pain. Of 83 participants, 21 (25.3%) were excluded from analysis because of insufficient reduction in KAM. In the 62 patients included in analysis, the mean ± SD age was 64.2 ± 9.1 years, and 37.1% were women. Lateral wedge insoles produced a greater reduction in knee pain than neutral insoles (mean difference of 0.7 on 0-10 scale [95% confidence interval 0.1, 1.2]) (P = 0.02). Findings for secondary outcome measures were mixed.

In participants prescreened to eliminate those with patellofemoral OA and biomechanical nonresponders, lateral wedge insoles reduced knee pain, but the effect of treatment was small and is likely of clinical significance in only a minority of patients. Targeting patients may identify those who respond to this treatment.

To assess the effect of glucocorticoids (GC) on damage progression in placebo-biologic arms of rheumatoid arthritis (RA) biologics trials. Posthoc metaanalysis of 2 infliximab (IFX) trials (established and early RA) and 1 tocilizumab (TCZ) trial (established RA). The proportion of patients receiving GC was 38%-64%, baseline damage was 11-82 Sharp/van der Heijde points, and progression in the placebo groups was 0.5-4.8 points in 6 months. In the pooled IFX studies, GC cotreatment reduced 6-month progression by 2.6 points (95% CI 0.6-4.5). In the TCZ study (progression rate 0.5 Genant points), no such difference was seen.

GC cotreatment may affect results in RA trials.

Open wedge high tibial osteotomy (HTO) is an increasingly more common surgical method. A typical problem of this procedure is fracture of the lateral hinge. The aims of this article are to present the special issue of fractures of the lateral hinge after HTO and to discuss surgical hints on how to prevent and treat this problem. The results of recently published clinical studies are summarized and tips from own clinical experiences are given. Type II fractures of the lateral hinge are unstable and can create a major problem. Using short spacer plates results in a problem of stability for all types of fractures.

The classification into Takeuchi grades I-III has been proven to be suitable for fractures of the lateral hinge. The TomoFix plate is a safe implant to stabilize the osteotomy in type I and III fractures with which healing can be achieved with no problems. Type II fractures can be stabilized with the TomoFix plate; however, an autologous bone graft has to be taken into consideration. For fractures of the lateral hinge short spacer plates are not recommended due to stability issues.

To determine if the Fms-like tyrosine kinase 3 ligand (Flt-3L), a cytokine implicated in B cell ontogenesis and proliferation in hematologic malignancies, might be responsible for the increased numbers of circulating Bm2 and Bm2′ B cell subsets in patients with primary Sjögren's syndrome (SS). Serum levels of Flt-3L were measured in 64 patients with primary SS and in 20 healthy controls matched for age and sex. Flt-3L and its receptor Flt-3 were quantified in circulating B cells and in salivary gland (SG) biopsy tissues by immunofluorescence analysis. The effect of Flt-3L on circulating B lymphocytes was then determined by coculture with cells of a human SG (HSG) epithelial cell line. Serum levels of Flt-3L were increased in patients with primary SS as compared with controls (mean ± SD 135.8 ± 5.5 versus 64.4 ± 4.5 pg/ml; P < 0.001). Serum levels of Flt-3L in primary SS patients correlated with the numbers of Bm2 and Bm2′ cells (r = 0.46, P < 0.0006), and Flt-3 was selectively expressed in Bm2 and Bm2′ cells. B cell culture experiments showed that Flt-3L potentiated the proliferative effect of anti-IgM stimulation. In SGs, we found that infiltrating B cells expressed Flt-3 and epithelial cells produced Flt-3L. Finally, Flt-3L levels were associated with high disease activity scores and increased risk of developing lymphoma.

Serum levels of Flt-3L are elevated in patients with primary SS and correlate with abnormal B cell distribution. Flt-3 is mainly expressed by Bm2 and Bm2′ cells. Serum levels of Flt-3L might explain the clinical evolution of primary SS to B cell lymphoma that is observed in some patients, thus opening the possibility of new avenues for therapy.

Polymorphisms of the peptidylarginine deiminase type 4 (PADI4) gene confer susceptibility to rheumatoid arthritis (RA) in East Asian people. However, studies in European populations have produced conflicting results. This study explored the association of the PADI4 genotype with RA in a large UK Caucasian population. The PADI4_94 (rs2240340) single nucleotide polymorphism (SNP) was directly genotyped in a cohort of unrelated UK Caucasian patients with RA (n=3732) and population controls (n=3039). Imputed data from the Wellcome Trust Case Control Consortium (WTCCC) was used to investigate the association of PADI4_94 with RA in an independent group of RA cases (n=1859) and controls (n=10 599). A further 56 SNPs spanning the PADI4 gene were investigated for association with RA using data from the WTCCC study. The PADI4_94 genotype was not associated with RA in either the present cohort or the WTCCC cohort. Combined analysis of all the cases of RA (n=5591) and controls (n=13 638) gave an overall OR of 1.01 (95% CI 0.96 to 1.05, p=0.72). No association with anti-CCP antibodies and no interaction with either shared epitope or PTPN22 was detected. No evidence for association with RA was identified for any of the PADI4 SNPs investigated. Meta-analysis of previously published studies and our data confirmed no significant association between the PADI4_94 genotype and RA in people of European descent (OR 1.06, 95% CI 0.99 to 1.13, p=0.12).

In the largest study performed to date, the PADI4 genotype was not a significant risk factor for RA in people of European ancestry, in contrast to Asian populations.

To compare epicutaneous ketoprofen in Transfersome (ultra-deformable vesicles, IDEA-033) versus oral celecoxib and placebo for relief of signs and symptoms in knee osteoarthritis. This was a multicentre, randomised, double-blind, controlled trial; 397 patients with knee osteoarthritis participated and 324 completed the trial. They were randomly assigned 110 mg epicutaneous ketoprofen in 4.8 g Transfersome plus oral placebo (n = 138), 100 mg oral celecoxib plus placebo gel (n = 132), or both placebo formulations (n = 127) twice daily for 6 weeks. Primary efficacy outcome measures were the changes from baseline to end of the study on the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain subscale, physical function subscale and patient global assessment (PGA) of response. The mean WOMAC pain subscale scores in the intent to treat population were reduced by 18.2 (95% confidence interval -22.1 to -14.3), 20.3 (-24.3 to -16.2) and 9.9 (-13.9 to -5.8) in the IDEA-033, celecoxib and placebo groups, respectively, and the physical function subscale score by 14.6 (-18.1 to -11.0), 16.6 (-20.2 to -13.0) and 10.2 (-13.8 to -6.6), respectively. The mean PGA of response scores were 1.8 (1.6 to 2.1), 1.7 (1.5 to 1.9) and 1.3 (1.1 to 1.5), respectively. The differences in change between IDEA-033 and placebo were statistically significant for pain subscale (p<0.01) and PGA of response (p<0.01). Gastrointestinal adverse events for IDEA-033 were similar to placebo.

IDEA-033 is superior to placebo and comparable with celecoxib in relieving pain associated with an acute flare of knee osteoarthritis.

To determine whether the presence of varus thrust at baseline increases the risk of progression of medial tibiofemoral osteoarthritis (OA), whether knees with thrust have a greater adduction moment, whether thrust has any additional impact on top of static varus, and whether thrust is associated with poor physical function outcome. Two hundred thirty-seven patients with knee OA (definite osteophytes and symptoms) underwent baseline gait observation to assess varus thrust and full-limb radiography to assess alignment. Sixty-four of these 237 patients also underwent quantitative gait analysis to determine the maximum knee adduction moment. Two hundred thirty patients (97%) returned for followup at 18 months. At baseline and 18 months, the 230 participants had semiflexed, fluoroscopically confirmed knee radiographs (with progression defined as worsening of medial joint space grade); self-reported and performance-based measures of function were also assessed. Logistic regression with generalized estimating equations was used to estimate odds ratios (ORs) for medial OA progression, after excluding knees that were not at risk for progression. Varus thrust was present in 67 of 401 knees. Thrust increased 4-fold (age-, sex-, body mass index-, and pain-adjusted OR 3.96, 95% confidence interval [95% CI] 2.11-7.43) the odds of medial progression, with some reduction after further adjustment for varus alignment severity. In varus-aligned knees, thrust increased the odds of OA progression 3-fold (adjusted OR 3.17, 95% CI 1.60-6.31). In the gait substudy, the adduction moment was greater in knees with a thrust compared with knees without a thrust. Having a thrust in both knees versus neither knee was associated with a 2-fold increase in the OR for poor physical function outcome (P not significant).

Varus thrust is a potent risk factor, identifiable by simple gait observation, for disease progression in the medial compartment, the most common site of OA involvement at the knee. Varus thrust may also predict poor physical function outcome. Varus thrust increased the odds of progression among varus-aligned knees considered separately, suggesting that knees with a thrust are a subset of varus-aligned knees at particularly high risk for progression of OA.

The purpose of this study was to evaluate the cost and benefit of routinely submitting hammertoe specimens for histopathological examination. We hypothesized that such examination rarely shows a new diagnosis and seldom alters postoperative care. Three hundred and fourteen proximal interphalangeal (PIP) joint and 37 extensor tendon specimens from 187 consecutive hammertoe correction surgeries were submitted by 2 surgeons for histopathological examination between January 2009 and December 2011. Each patient's chart was reviewed to determine whether the histopathological examination revealed a diagnosis other than degenerative joint or degenerative tendon and whether subsequent patient management was altered. The total reimbursements for professional charges were calculated using the average reimbursement from common insurance providers for two Current Procedural Terminology (CPT) codes: 88304 (soft tissue examination) and 88311 (decalcification). Almost all of the specimens were diagnosed as degenerative: 97.5% (307/314) of the PIP specimens and all (37/37) of the tendon specimens. Seven PIP specimens (2.2%, 7/314) from 5 patients (2.7%, 5/187) and no tendon specimens had other diagnoses. These diagnoses were rheumatoid arthritis (5/314, 1.6%), osteomyelitis (1/314, 0.3%), and pigmented villonodular synovitis (PVNS) (1/314, 0.3%). Only the PVNS was a new diagnosis. A total of $56,750 was spent to determine 1 new diagnosis.

The routine submission of hammertoe specimens for pathological evaluation was not cost-efficient. Our analysis showed that new diagnoses were rarely found and patient management was not affected.

The reduced range of motion and pain are the most characteristic clinical features of osteoarthritis (OA). Hyaluronic acid (HA), which is one of the infiltrative therapies for OA treatment, and polynucleotides (PNs), which is a DNA-derived macromolecule favored cell growth and collagen production, are an ongoing debate in clinical effectiveness. We plan to perform a systematic review and meta-analysis of randomized clinical trial to evaluate efficacy of intra-articular polynucleotides associated with hyaluronic acid versus hyaluronic acid alone in the treatment of knee osteoarthritis. We will search PubMed, EMBASE, Cochrane Library using a comprehensive strategy. The related conference proceedings and reference lists of the included studies will also be checked to identify additional studies. Two reviewers will screen retrieved records, extract information and assess the risk of bias independently. Stata v15.1 software will be used to conduct data synthesis. This study will be submitted to a peer-reviewed journal for publication. Ethics approval and patient consent are not required, as this study is a systematic review and meta-analysis. CRD42020167678.

We hope it will provide a relatively comprehensive reference for clinical practice and future relevant clinical trials.

We aimed to compare second-generation patellofemoral arthroplasty (2G PFA) with total knee arthroplasty (TKA) in treating isolated patellofemoral osteoarthritis (PFOA) by assessing the percentages of revisions, complications, and patient-reported outcome measures (PROMs). Studies that compared the outcomes of 2G PFA and TKA in the treatment of isolated PFOA were searched in electronic databases, including MEDLINE, Embase, and Web of Science. Two researchers independently identified eligible studies, extracted the data, and evaluated the quality of the literature. Pooled risk ratios (RRs) or weighted mean differences with 95% confidence intervals were calculated using either fixed or random effects models. Descriptive analysis was used when data could not be pooled. A total of six studies were included in the review. For the revision percentage and complications, there were no significant differences between 2G PFA and TKA (RR = 2.29, 95% CI 0.69-7.58, P = 0.17; RR = 0.56, 95% CI 0.23-1.40, P = 0.22, respectively). Second, the results demonstrated that the differences in the Oxford Knee Score (OKS) and the University of California, Los Angeles (UCLA) activity score between 2G PFA and TKA were not significant (WMD -4.68, 95% CI -16.32 to 6.97, p = 0.43; WMD 0.16, 95% CI -1.21 to 1.53, P = 0.82). The Knee Injury and Osteoarthritis Outcome Score (KOOS), the American Knee Society Score (AKSS), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were presented in a narrative form due to methodological heterogeneity.

For isolated PFOA, 2G PFA demonstrated similar results to TKA with respect to the percentages of revisions, complications, and PROMs.

Structural interlaminar graft materials were used for atlantoaxial transarticular screw fixation (TSF), and its impact on the fusion status was investigated. Forty-two patients (10 men, 32 women, mean age 51 years, mean follow-up period 45 months; 30 with rheumatoid arthritis, and 12 with os odontoideum) underwent TSF and modified Brooks posterior wiring involving titanium cables. As interlaminar graft materials, autologous bone from posterior iliac crest alone was used in 20 patients (Group A), and a structural spacer (13 ceramic spacers, nine titanium mesh cages) in 22 (Group B). Lateral radiographs were evaluated to determine bone fusion, alignment of the cervical spine, and wire loosening. Solid osseous fusion was obtained in 95% of Group A and 96% of Group B patients. The mean atlantoaxial angle was 19.1+/-9.7 degrees and 16.7+/-10.4 degrees before surgery (p = 0.45), and 27.4+/-7.8 degrees and 22.1+/-5.5 degrees after surgery (p = 0.02) in Groups A and B, respectively. Atlantoaxial hyperlordosis (atlantoaxial angle > or = 30 degrees) was observed in 32% of Group A and 18% of Group B patients (p = 0.26). Postoperative kyphosis occurred in 40% of Group A and 23% of Group B patients (p = 0.28). Loosening of the cable was demonstrated in 50% of Group A and 36% of Group B patients(p = 0.37). In Group B patients maintenance of cervical lordosis was more likely than in those in Group A, although the differences did not reach statistical significance.

These results indicate that structural interlaminar spacers can maintain proper cervical alignment without a decease in the fusion rate; the authors recommend their use in conjunction with TSF.

A role of microRNA, which are approximately 22-nucleotide noncoding RNAs, has recently been recognized in human diseases. The objective of this study was to identify the expression pattern of microRNA-146a (miR-146a) in cartilage from patients with osteoarthritis (OA). The expression of miR-146a in cartilage from 15 patients with OA was analyzed by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and by in situ hybridization. Induction of the expression of miR-146a by cultures of normal human articular chondrocytes following stimulation with interleukin-1beta (IL-1beta) was examined by quantitative RT-PCR. All cartilage samples were divided into 3 groups according to a modification of the Mankin score (grade I = mild OA scored 0-5, grade II = moderate OA scored 6-10, and grade III = severe OA scored 11-14). In grade I OA cartilage samples, the expression of miR-146a and COL2A1 was significantly higher than that in the other groups (P < 0.05). In grades II and III OA cartilage, the expression of miR-146a and COL2A1 was decreased, whereas the expression of matrix metalloproteinase 13 (MMP-13) was elevated in grade II OA cartilage. These data showed that miR-146a is expressed intensely in cartilage with a low Mankin grade and that miR-146a expression decreases in parallel with the level of MMP-13 expression. Tissue section in situ hybridization of primary miR-146a (pri-miR-146a) revealed that pri-miR-146a was expressed in chondrocytes residing in all tissue layers, especially in the superficial layer, where it was intensely expressed. The expression of miR-146 was markedly elevated by IL-1beta stimulation in human chondrocytes in vitro.

This study shows that miR-146 is intensely expressed in low-grade OA cartilage and that its expression is induced by stimulation of IL-1beta. Thus, miR-146 might play a role in OA cartilage pathogenesis.

To determine the effect of Chuju total flavonoids (CJTF) on the secreted frizzledrelated protein 4 (SFRP4) expression in Wnt pathway in rheumatoid arthritis (RA) model rats. The role of CJTF in the treatment of RA model rats was evaluated by rat arthritis score and paw edema score. The expression regulation of the SFRP4, β-catenin and C-myc in Wnt pathway in RA model rats was detected by RT-PCR and Western blot after CJTF gavage treatment. After CJTF treatment, the rat arthritis score and paw edema score in RA model rats were significantly decreased when the RA model rats were treated with CJTF, the SFRP4 expression was significantly up-regulated, while the β-catenin and C-myc gene expression were significantly downregulated in RA model rat synovial tissues.

CJTF has significant therapeutic effect and inhibitory effect on Wnt pathway activation by targeting SFRP4 in RA model rat synovium.

Systemic sclerosis (SSc) and primary biliary cirrhosis (PBC) are rare polygenic autoimmune diseases (AIDs) characterized by fibroblast dysfunction. Furthermore, both diseases share some genetic bases with other AIDs, as evidenced by autoimmune gene pleiotropism. The present study was undertaken to investigate whether single-nucleotide polymorphisms (SNPs) identified by a large genome-wide association study (GWAS) in PBC might contribute to SSc susceptibility. Sixteen PBC susceptibility SNPs were genotyped in a total of 1,616 patients with SSc and 3,621 healthy controls from two European populations (France and Italy). We observed an association between PLCL2 rs1372072 (odds ratio (OR) = 1.22, 95% confidence interval (CI) 1.12 to 1.33, P adj = 7.22 × 10(-5)), nuclear factor-kappa-B (NF-κB) rs7665090 (OR = 1.15, 95% CI 1.06 to 1.25, P adj = 0.01), and IRF8 rs11117432 (OR = 0.75, 95% CI 0.67 to 0.86, P adj = 2.49 × 10(-4)) with SSc susceptibility. Furthermore, phenotype stratification showed an association between rs1372072 and rs11117432 with the limited cutaneous subgroup (lcSSc) (P adj = 4.45 × 10(-4) and P adj = 0.001), whereas rs7665090 was associated with the diffuse cutaneous subtype (dcSSc) (P adj = 0.003). Genotype-mRNA expression correlation analysis revealed that the IRF8 protective allele was associated with increased interferon-gamma (IFN-γ) expression (P = 0.03) in patients with SSc but decreased type I IFN (IFIT1) expression in patients and controls (P = 0.02). In addition, we found an epistatic interaction between NF-κB and IRF8 (OR = 0.56, 95% CI 0.00 to 0.74, P = 4 × 10(-4)) which in turn revealed that the IRF8 protective effect is dependent on the presence of the NF-κB susceptibility allele.

An analysis of pleiotropic genes identified two new susceptibility genes for SSc (NF-κB and PLCL2) and confirmed the IRF8 locus. Furthermore, the IRF8 variant influenced the IFN signature, and we found an interaction between IRF8 and NF-κB gene variants that might play a role in SSc susceptibility.

Giant cell arteritis (GCA) is the most common primary vasculitis, preferentially affecting the aorta and its large-calibre branches. An imbalance between proinflammatory CD4 A total of 41 GCA patients were classified into active disease (n=14) and disease in remission (n=27). GCA patients' and healthy blood donors' (HD) Tregs were sorted and subjected to transcriptome and phenotypic analysis. Transcriptome analysis revealed 27 genes, which were differentially regulated between GCA-derived and HD-derived Tregs. Among those, we identified transcription factors, glycolytic enzymes and IL-2 signalling mediators. We confirmed the downregulation of forkhead box P3 (FOXP3) and interferon regulatory factor 4 (IRF4) at protein level and identified the ineffective induction of glycoprotein A repetitions predominant (GARP) and CD25 as well as the reduced T cell receptor (TCR)-induced calcium influx as correlates of Treg dysfunction in GCA. Inhibition of glycolysis in HD-derived Tregs recapitulated most identified dysfunctions of GCA Tregs, suggesting the central pathogenic role of the downregulation of the glycolytic enzymes. Separate analysis of the subgroup of tocilizumab-treated patients identified the recovery of the TCR-induced calcium influx and the Treg suppressive function to associate with disease remission.

Our findings suggest that low glycolysis and calcium signalling account for Treg dysfunction and inflammation in GCA.

To systematically evaluate the association between single nucleotide polymorphism of rs2231142 genetic susceptibility and gout in East Asian population. The literature retrieval was conducted by using English databases (Medline, EMbase), Chinese databases (CNKI, Vip, Wanfang, SinaMed) and others to collect the published papers on the association between single nucleotide polymorphism of rs2231142 genetic susceptibility and gout by the end of December 2014. Meta-analysis was performed with software Stata 12.0. Nine studies were included. There were significant associations between increased risk of gout and single nucleotide polymorphism of rs2231142, the combined OR was 2.04 (95%CI: 1.82-2.28) for A allele and C allele, 1.97 (95%CI: 1.57-2.48) for CA and CC, 3.71 (95%CI: 3.07-4.47) for AA and CC. Sex and region specific subgroup analysis showed less heterogeneity.

There is significant association between gout and single nucleotide polymorphism of rs2231142 in East Asian population, and A allele is a high risk gene for gout.

To characterize and validate a novel, enzyme-linked immunoassay for measuring cross-linked dimer forms of C-terminal telopeptides of type II collagen (CTX-II) in serum and synovial fluid of rodents, and investigate whether CTX-II measurements can reflect joint status in two established animal models of destructive joint diseases. Firstly, the specificity, in vivo validity, antigen recovery, and reproducibility of the assay were investigated. Secondly, we induced arthritis in rats using either bovine collagen type II or mono-iodoacetate. CTX-II levels were measured in the serum and synovial fluid of the affected femoro-tibial joint and correlated with microscopic severity of joint lesions as determined by validated scoring systems. The F4601 monoclonal antibody (mAb) is highly specific for the EKGPDP sequence at the CTX-II. Strong CTX-II signals were detected during enzymatic degradation of articular cartilage explants by matrix metalloproteinase (MMP)-9 or MMP-13. The assay presented a good degree of precision and reproducibility (inter- and intra-assay CVs< 8.0%). In the collagen-induced arthritis (CIA) model, the assay indicated markedly increased levels of CTX-II in both the synovial fluid and the serum. Furthermore, CTX-II levels in both the synovial fluid (r = 0.76; P < 0.0001) and the serum (r = 0.85; P < 0.0001) showed strong correlations with the microscopic severity scores of joint lesions at Day 22. In the mono-iodoacetate-induced arthritis (MIA) model, CTX-II concentration in the synovial fluid (r = 0.53; P < 0.0001), but not in the serum, correlated with the microscopic severity score.

The Preclinical CTX-II assay could provide a useful supplement to currently available methods for the non-invasive assessment of cartilage status. The utility of serum CTX-II to reflect joint status appeared to be limited to systemic forms of destructive joint diseases.

Although circulating CD14brightCD16+ monocyte subsets are increased in inflammatory disease, the pathogenesis of the increase in the inflammatory condition of the cells is still unclear and the relationship to cytokines is unknown particularly in rheumatoid arthritis (RA). The purpose of this study was to investigate the influence anti-cytokine treatment has on CD14brightCD16+ monocytes in patients with RA. Thirty-two RA patients and 14 healthy volunteers (HV) were enrolled in this study. All the patients had never been treated with methotrexate (MTX) or biological agents. Peripheral blood samples and clinical information of the patients were obtained at the time of 0, 12 and 24 weeks of treatment. Peripheral blood samples were also obtained from the HV. The expression levels of CD14 and CD16 on monocytes were measured by flow cytometry (FCM). Eight patients received anti-interleukin (IL)-6 receptor antibody, tocilizumab (TCZ) treatment alone, 12 patients received anti-tumour necrosis factor (TNF)-α antibody, adalimumab (ADA) with MTX treatment and the others received only MTX treatment. FCM analysis revealed that the proportion of CD14brightCD16+ monocytes significantly increased in patients at baseline compared with HV. The proportion of CD14brightCD16+ monocytes significantly decreased after TCZ, and ADA with MTX treatment. The proportion of intermediate monocytes was significantly and positively correlated with disease activity and it improved in accordance with the proportion of CD14brightCD16+ monocytes after inhibition of signal transduction of inflammatory cytokines.

We showed that the population of CD14brightCD16+ monocytes significantly decreased with the change of disease activity by key cytokines, IL-6 or TNF-α signal blockade in RA. This result indicates that the proportion of those monocytes is important for reflecting disease activity in RA.

Matrix Gla (γ-carboxyglutamate) protein (MGP) is considered a strong inhibitor of ectopic calcification, and it has been associated with OA severity, although not conclusively. We utilized male Dunkin-Hartley (DH) guinea pigs to investigate the expression of MGP throughout aging and disease pathogenesis in a spontaneous model. Twenty-five male DH guinea pigs were obtained and nurtured to several timepoints, and then randomly and equally divided by age into five subgroups (1-, 3-, 6-, 9-, and 12-months, with the 1-month group as the reference group). DH guinea pigs in each group were euthanized at the designated month-age and the left or right medial tibial plateaus cartilages were randomly excised. OA severity was described by modified Mankin Score (MMS) at microscopy (Safranin O/Fast Green stain). Proteomic evaluation using isobaric tags for relative and absolute quantification (iTRAQ) was performed to validate the age-related changes in the MGP profiles, and immunohistochemistry (IHC) methods were applied for semi-quantitative determination of MGP expression in articular cartilage. The histopathologic findings validated the increasing severity of cartilage degeneration with age in the DH guinea pigs. The MMS showed significant, stepwise (every adjacent comparison P < 0.05) disease progression with month-age. The iTRAQ indicated that MGP levels increased significantly with advancing age (P < 0.05), as supported by the IHC result (P < 0.05).

Increased expression of MGP in male DH guinea pigs was present throughout aging and disease progression and may be link to increased OA severity. Further studies are needed to investigate and confirm the association between MGP levels and OA severity.

The enhanced liver fibrosis (ELF) test has been introduced to screen, diagnose and/or monitor liver conditions in large groups of patients with liver diseases. It has not been used in inflammatory skin or joint diseases. To evaluate the distribution of the ELF test, apply existing cut-offs for hepatic patients and healthy controls, and compare it with the procollagen-3 N-terminal peptide (P3NP) test in patients with psoriasis (PSO), psoriatic arthritis (PsA) and rheumatoid arthritis (RA), and controls. In total, 531 patients were included. Demographic, lifestyle and disease-specific data were collected. ELF and P3NP tests were performed. Prevalence of an increased ELF score (> 11) and P3NP was highest in patients with RA (7·7% and 6·1%, respectively) followed by patients with PSO (1·7% and 5·2%, respectively) and PsA (0·7% and 1·3%, respectively). Mean ± SD ELF scores for PSO, PsA and RA were, respectively, 9·09 ± 0·86, 8·96 ± 0·76 and 9·55 ± 1·04. All subgroups with moderate-to-severe disease severity had higher (> 9·8) ELF scores (PSO 27·0% vs. 18·3%; PsA 19·2% vs. 12%; RA 45·8% vs. 30·5%) and P3NP values. Distribution of the ELF score was smaller than the P3NP value [mean ± SD: 9·15 ± 0·92 (range 6·53-13·05) vs. 8·37 ± 4·30 (range 0·53-63·88)].

ELF score and P3NP are elevated in PSO, PsA and RA. ELF may be superior to P3NP alone, but further research should be done to validate the ELF test in determining susceptibility for developing liver fibrosis in PSO, PsA and RA.

To explore the potential role of Dickkopf-1 (DKK-1) in rheumatoid arthritis (RA) and to evaluate the effect of a tumor necrosis factor-α (TNF-α) inhibitor (infliximab) and an interleukin 1 receptor antagonist (IL-1Ra; anakinra) on DKK-1 secretion in patients with RA. Serum samples were collected from 100 patients with RA, 100 patients with other rheumatic diseases (e.g., osteoarthritis and ankylosing spondylitis), and 40 healthy controls. DKK-1 and osteoprotegerin (OPG) levels in serum were detected by ELISA. Serum C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR), rheumatoid factor (RF) titers, and anti-cyclic citrullinated peptide antibody were also measured in patients with RA. The serum level of DKK-1 was significantly higher in patients with RA than in healthy controls and those with other rheumatic diseases (p < 0.01); the serum DKK-1 level was correlated with levels of CRP (r = 0.488, p = 0.003) and ESR (r = 0.458, p = 2.4 x 10(-4)) and the Sharp score of radiologic change (r = 0.449, p = 0.001) in RA. In contrast to the increasing level of OPG, DKK-1 was significantly decreased in RA patients treated with TNF-α inhibitor (p < 0.01). DKK-1 was significantly decreased in RA patients treated with IL-1Ra (p < 0.01).

DKK-1, as an important mediator, was correlated with bone erosion and inflammation in RA. The change of DKK-1 level may serve as a biomarker of disease activity and bone erosion.

To assess the association of CD40/CD40 ligand (CD40L) interactions with the development of skin fibrosis and autoimmunity in tight-skin (TSK/+) mouse, which is a mouse model for human systemic sclerosis. Newly born TSK/+ mice were treated with murine anti-CD40L monoclonal antibody (100 microg intraperitoneally weekly). Hypodermal thickness of 8-week-old female mice (defined as the thickness of a subcutaneous loose connective tissue layer beneath the panniculus carnosus) was measured under a light microscope. All skin sections were taken from the para-midline, upper back region. Serum anti-topoisomerase I autoantibody levels, serum immunoglobulin levels and plasma soluble CD40L levels were determined by enzyme-linked immunosorbent assay. For analysis of lymphocyte surface molecules, single cell suspensions of lymphocytes were stained by monoclonal antibodies. Proliferation of TSK/+ B cells and fibroblasts to anti-CD40 antibodies was assessed by the uptake of [3H]-labelled thymidine and bromodeoxyuridine, respectively. The blockade of CD40/CD40L interactions by anti-CD40L monoclonal antibody significantly reduced cutaneous fibrosis (65%) and anti-topoisomerase I autoantibody in TSK/+ mice. Anti-CD40L monoclonal antibody also normalised B lymphocyte abnormal activation in TSK/+ mice, demonstrated by hyper-gamma-globulinaemia. Furthermore, augmented CD40/CD40L interactions in TSK/+ mice were suggested by upregulated expression of CD40L on CD4(+) T cells, elevated plasma soluble CD40L levels. The hyperresponsiveness to CD40 stimulation was also observed in TSK/+ B cells and fibroblasts.

Cutaneous fibrosis and autoimmunity in TSK/+ mice are closely correlated with CD40/CD40L interactions.

To define localized development of knee osteoarthritis (OA) that arises from anterior cruciate ligament (ACL) and meniscal injuries identified at magnetic resonance (MR) imaging performed a decade ago and the subsequent management of those findings in patients with subacute knee symptoms. The present study was approved by local medical ethics review boards, and written informed consent was obtained. Three hundred twenty-six patients (mean age, 42 years; 108 female) from a previously reported series of 855 patients were followed up with regard to the effect of MR imaging-guided treatment for subacute knee problems. The mean follow-up period was 10 years. Initial findings and treatment were compared with the follow-up radiograph and 3.0-T MR image findings. Odds ratios (ORs), with corresponding 95% confidence intervals, were used to identify the effects between variables. Patients with ACL ruptures had an increased risk of developing joint space narrowing (JSN), cartilaginous defects, osteophytes, bone marrow lesions, and subchondral cysts medially or laterally (OR, 2.4-9.8). Patients with medial meniscal tears had an increased risk of developing JSN, cartilaginous defects, osteophytes, and bone marrow lesions medially (OR, 2.0-15.3). Patients with lateral meniscal tears had an increased risk of developing JSN, cartilaginous defects, osteophytes, bone marrow lesions, and subchondral cysts laterally (OR, 2.1-10.5). Meniscectomy had no effect on the risk of developing OA.

Localized knee OA developed from risk factors identified from the findings of MR imaging performed a decade ago in patients with subacute knee symptoms and did not depend on the surgical treatment of those findings.

To assess the efficacy of tocilizumab for preventing damage to the joints of systemic juvenile idiopathic arthritis (sJIA) patients, we examined serial radiographs of the hands and large weight-bearing joints of these patients before and after treatment with this agent. Nine patients with sJIA receiving 8 mg/kg of tocilizumab intravenously every 2 weeks were studied. The mean follow-up period was 82 months. The number of active joints and laboratory markers of inflammation were assessed before and after tocilizumab treatment, together with radiologic evaluation of the hips, knees, ankles, shoulders, and elbows. The latter examination included soft tissue swelling, juxta-articular osteoporosis, epiphyseal irregularity, joint-space narrowing, cyst formation, erosion, and localized growth abnormalities. Modified Larsen scores for the large joints and the Poznanski score were also recorded. After tocilizumab treatment, the number of active joints and serum inflammatory markers decreased (p < 0.01). There was a decrease in radiologic abnormalities at the final follow-up (p < 0.01) with the exception of localized growth abnormalities. Radiologic improvement was observed in 47 joints (52%), but ten (11%) worsened. Total Larsen score was decreased from 15.8 to 10.9 at the final follow-up. Although the Poznanski score did not change after tocilizumab treatment, it was closely correlated with the total Larsen score (r = 0.53, p < 0.05).

We describe radiologic improvement of the majority of damaged large joints in sJIA following tocilizumab therapy, but some deteriorated further despite stabilization of systemic inflammatory responses. Further studies with a larger number of patients are needed.

Because there is controversy regarding the efficacy of acetaminophen in rheumatic diseases and because apparently safer nonsteroidal antiinflammatory drugs (NSAIDs) are being produced, we surveyed rheumatic disease patients about their preferences for these agents to determine the degree to which one type of therapeutic agent is preferred over the other. In 1998, we surveyed by mailed questionnaire 1,799 patients with osteoarthritis (OA), rheumatoid arthritis, or fibromyalgia who were participating in a long-term outcome study. Patients who had taken acetaminophen rated the effectiveness of acetaminophen, compared its effectiveness with that of NSAIDs, and then rated their overall satisfaction with acetaminophen compared with NSAIDs when both effectiveness and side effects were considered. Two-thirds of study participants had taken acetaminophen. About 37% of patients who had taken acetaminophen found it to be moderately or very effective and about 63% indicated that it was not effective or was only slightly effective. One-fourth of the patients found acetaminophen and NSAIDs to be equally effective, but >60% found acetaminophen to be much less effective or somewhat less effective. About 12% preferred acetaminophen to NSAIDs. When both effectiveness and side effects were considered together, 25% of the patients had no preference, 60% preferred NSAIDs, and 14% preferred acetaminophen.

There was a considerable and statistically significant preference for NSAIDs compared with acetaminophen among the 3 groups of rheumatic disease patients. Although this preference decreased slightly with age and was less pronounced in OA patients, the preference was noted among all categories of patients and was not altered by disease severity. If safety and cost are not issues, there would hardly ever be a reason to recommend acetaminophen over NSAIDs, since patients generally preferred NSAIDs and fewer than 14% preferred acetaminophen. If safety and costs are issues, then the recommendation of the American College Rheumatology that acetaminophen be tried first seems correct, since 38.2% found acetaminophen to be as effective or more effective than NSAIDs.