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Bilateral parotid enlargement are presenting features of some metabolic and systemic disease but also of chronic emesis. A 24-year old woman consulted during three years many physicians asking for the treatment of a painless parotid swelling confusing with a Sjogren's syndrome. After an initial denial, the weight history, alteration of tooth wear and hypokaliemia conducted to admit a self inducing vomiting with bulimia nervosa.

Gender, young age, weight history, tooth alteration and electrolytic disorders are the main diagnostic tool of this dissimulated etiology of parotid swelling.

Scaphoid excision and 4-corner arthrodesis is a salvage option for patients with advanced carpal collapse. This study aims to compare the clinical outcomes of 4-corner arthrodesis (FCA) at one year, 2 years, and a minimum of 10 years. A cohort study was performed of patients having scaphoid excision and FCA procedure by a single surgeon. Thirty-one of 35 recruited were followed up for 10 years. The mean patient age was 47 years. All patients had scaphoid excision and FCA, using bone graft and 3M Shapiro staples (3M, St Paul, MN). Patients were followed up prospectively at one year, 2 years, and a minimum of 10 years after surgery by an independent observer. Three patients were lost to follow-up between the 2-year and 10-year assessments because they were untraceable, and one patient died at 7 years, without any further intervention. Before surgery, pain scores measured with a visual analog scale, range of wrist movement, grip and pinch strength, and scores from a self-assessment functional questionnaire were recorded prospectively. These measures were repeated at each time point, in addition to patient satisfaction scores measured on a visual analog scale. The pain scores decreased from a median preoperative score of 6/10 to 0/10 at one year. Grip strength did not change significantly. Wrist flexion decreased significantly after surgery, by an average of 22%. The average patient-reported satisfaction score was 8/10. There was no significant change in pain, wrist function, satisfaction, or arc of motion between one and 10 years. Two of 35 patients recruited had gone on to a total wrist arthrodesis for ongoing pain.

The outcome of scaphoid excision and 4-corner arthrodesis is favorable at one year and does not deteriorate significantly between one and 10 years. There is a low rate of conversion to total wrist arthrodesis. Pain scores are reduced at the cost of reduced wrist flexion.

To investigate functional consequences of the Toll-like receptor 4 (TLR4) variant (Asp299Gly) in rheumatoid arthritis (RA). Peripheral blood mononuclear cells from 28 patients with RA carrying or not carrying the TLR4 variant were incubated with lipopolysaccharide (LPS) and heat shock protein B8 (HSPB8). Concentrations of interleukin 6 (IL-6), tumor necrosis factor-alpha(TNF-alpha), and IL-10 were determined along with TLR4 and CD14 expression. TLR4 expression was similar in patients carrying or not carrying the variant. In contrast, both LPS and HSPB8 resulted in significantly lower secretion of IL-6, TNF-alpha, and IL-10 in those who carried the variant, whereas the frequency of CD14+ cells was higher in these individuals.

TLR4 variant clearly reduces its potency to mediate signaling. Correction for CD14+ cells is necessary in comparable experiments.

Fibromyalgia (FM) is a disease of unknown etiology. Inflammation could be one of the mechanisms behind this disease. We studied the frequency and clinical relevance of metal allergy in FM patients. Fifteen female FM patients were included in the study. Metal allergy was measured by a lymphocyte transformation test, MELISA®. Ten healthy age-matched women were used as controls for in vitro studies. Reduction of metal exposure in the FM patients was achieved by replacement of dental metal restorations and by the avoidance of known sources of metal exposure. Objective health assessment was performed 5 years after treatment. Subjective health assessment was established by a questionnaire, completed 2, 5 and in some cases 10 years after the start of the study. Follow-up MELISA was also performed. All FM patients tested positive to at least one of the metals tested. The most frequent reactions were to nickel, followed by inorganic mercury, cadmium and lead. Some healthy controls responded to inorganic mercury in vitro but most of the tests were negative. Objective examination 5 years later showed that half of the patients no longer fulfilled the FM diagnosis, 20% had improved and the remaining 30% still had FM. All patients reported subjective health improvement. This correlated with the normalisation of metal-specific responses in vitro.

Metal allergy is frequent in FM patients. The reduction of metal exposure resulted in improved health in the majority of metal-sensitized patients. This suggests that metal-induced inflammation might be an important risk factor in a subset of patients with FM.

This study evaluates cytokines production in bone and bone marrow of patients with an osteoporotic fracture or with osteoarthritis by real time PCR, Western blot and immunohistochemistry. We demonstrate that the cytokine pattern is shifted towards osteoclast activation and osteoblast inhibition in patients with osteoporotic fractures. Fragility fractures are the resultant of low bone mass and poor bone architecture typical of osteoporosis. Cytokines involved in the control of bone cell maturation and function are produced by both bone itself and bone marrow cells, but the roles of these two sources in its control and the amounts they produce are not clear. This study compares their production in patients with an osteoporotic fracture and those with osteoarthritis. We evaluated 52 femoral heads from women subjected to hip-joint replacement surgery for femoral neck fractures due to low-energy trauma (37), or for osteoarthritis (15). Total RNA was extracted from both bone and bone marrow, and quantitative PCR was used to identify the receptor activator of nuclear factor kB Ligand (RANKL), osteoprotegerin (OPG), macrophage colony stimulating factor (M-CSF), transforming growth factor β (TGFβ), Dickoppf-1 (DKK-1) and sclerostin (SOST) expression. Immunohistochemistry and Western blot were performed in order to quantify and localize in bone and bone marrow the cytokines. We found an increase of RANKL/OPG ratio, M-CSF, SOST and DKK-1 in fractured patients, whereas TGFβ was increased in osteoarthritic bone. Bone marrow produced greater amounts of RANKL, M-CSF and TGFβ compared to bone, whereas the production of DKK-1 and SOST was higher in bone.

We show that bone marrow cells produced the greater amount of pro-osteoclastogenic cytokines, whereas bone cells produced higher amount of osteoblast inhibitors in patients with fragility fracture, thus the cytokine pattern is shifted towards osteoclast activation and osteoblast inhibition in these patients.

Interleukin-23 (IL-23) is a pro-inflammatory cytokine that is thought to be central to the development of autoimmune diseases. This study was conducted to determine whether or not the serum concentration of IL-23 is elevated in patients with rheumatoid arthritis (RA), and to determine the relationship between the IL-23 level and disease activity in RA patients. Serum samples were obtained from 59 patients with RA and 30 healthy controls. The clinical parameters of disease activity were determined, including the 28-joint disease activity score (DAS28), C-reactive protein (CRP), rheumatoid factor (RF) levels, and the degree of bony erosions based on X-rays. The levels of IL-23 and IL-17 were determined by enzyme-linked immunosorbent assay (ELISA). The correlations between the serum levels of IL-23 and disease activity parameters of patients with RA were determined. The serum IL-23 level was significantly elevated in patients with RA compared to healthy controls. The serum IL-23 levels in the RA patients correlated with IL-17 and CRP levels, and the DAS28. The levels of IL-23 based on X-ray classification phase I, II, III, and IV were gradually elevated in RA patients.

The levels of serum IL-23 in RA patients were higher than in healthy controls. Thus, elevated serum IL-23 levels may be useful markers to detect active RA. In addition, IL-23 is involved in disease progression and bony erosions in patients with RA.

Variable clinical outcomes of tibial tuberosity transfer surgery have been reported. The biomechanical outcome of surgery is patient-specific; no single procedure produces superior results for all patients. Use of patient-specific computer models can optimize choice of procedure. Computer simulation study using clinical data. We used patient-specific multibody models of the patellofemoral joints of 20 patients with a diagnosis of patellar subluxation and osteoarthritis. Four tibial tuberosity transfer procedures (two anterior and two anteromedial) were simulated for each patient and compared with their preoperative model. When results for all patients were averaged, all simulated operations produced a statistically significant decrease in surface-wide mean contact stress, although no significant difference was found among them. Computer simulation may serve as a valuable tool for tailoring procedures to specific patients.

The simulated surgical outcomes were patient-specific: no single procedure was consistently superior at decreasing peak or mean stress and each procedure produced a potentially detrimental outcome, an increase in either mean stress or peak stress, in at least one patient.

Methotrexate-associated lymphoproliferative disorder (MTX-LPD) can present as a benign lymphoid proliferation or a malignant lymphoma in patients taking MTX. Almost 50% of MTX-LPD cases show spontaneous remission after withdrawal of MTX treatment. Studies have suggested that the hyper-immune state of rheumatoid arthritis, the immunosuppressive state associated with MTX, and the carcinogenicity of the Epstein-Barr virus might contribute to MTX-LPD development. Although most cases of MTX-LPD occur at extranodal sites, few cases of MTX-LPD affecting the stomach and duodenum have been reported. To our knowledge, no other study has reported on the endoscopic observations of dramatic withdrawal and appearance of multiple digestive tract lesions in a short period of time. Herein, we report the clinical course and imaging findings of our case, which may be useful for understanding the pathological condition of MTX-LPD. We describe the case of a 70-year-old woman with MTX-LPD of the stomach and duodenum. Disease regression was temporarily achieved after cessation of MTX treatment; however, it subsequently recurred, and complete response was only achieved after six cycles of rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (R-CHOP) chemotherapy.

The first-choice therapy for patients taking MTX who develop suspected MTX-LPD should be the withdrawal of MTX treatment. Even after remission is achieved, patients should be kept under careful observation, and if the disease recurs, chemotherapy should be commenced promptly.

To describe the ambulatory care utilization by patients with gouty arthritis (gout) in the United States using a nationally representative sample. A cross-sectional survey design based on the ambulatory care data from the 2002 US National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey was used to examine the ambulatory care burden for gout, the characteristics of gout patients, the types of providers who see gout patients, and prescribing patterns associated with the management of gout. Weighted analyses were performed to estimate the effect of age, sex, and ethnicity on the association with gout and prescription of allopurinol. Of the 973 million ambulatory care visits in the United States, 3.9 million were for gout. The majority of visits were for men. The average age for men with gout was lower than that for women with gout (65 vs 70 years of age). Over two-thirds of these gout visits were attended to by primary care providers, whereas visits to rheumatologists constituted only a very small proportion of these visits (1.3%). There were 2.8 million prescriptions for allopurinol, 700,000 prescriptions for nonsteroidal antiinflammatory drugs, 381,000 prescriptions for colchicine, and 341,000 prescriptions for prednisone. After adjusting for age and sex, Asians were 2.7 times more likely than Caucasians to have a gout visit. Yet these patients had lower probability of receiving allopurinol (odds ratio 0.04, 95% confidence interval 0.01-0.27).

The majority of patients with gout are seen by generalist physicians. Asian ethnicity is associated with higher number of visits for gout, but a lower frequency of allopurinol treatment.

To analyse the association between the type of work (productive vs reproductive work) and the levels of physical activity and sedentary behaviour in women with fibromyalgia. This cross-sectional study involved 258 women with fibromyalgia from southern Spain. Of them, 55% performed reproductive work (unpaid, associated with caregiving and domestic roles) exclusively, while 45% had productive job (remunerated, that results in goods or services). Physical activity of light, moderate and vigorous intensity in the leisure time, at home, at work, and totally were measured through the leisure time physical activity instrument and with the physical activity at home and work instrument, respectively. Sedentary behaviour was measured by the Sedentary Behaviour Questionnaire. After adjusting for age, fat percentage, education level and marital status, the multivariate analysis of covariance model informed the existence of significant differences between type of work groups (p<0.001). Women with productive work engaged in more light physical activity at work (mean difference =448.52 min; 95 % CI 179.66 to 717.38; p

Women with productive work had greater levels of physical activity compared with those who only did reproductive work, except for physical activity at home. Having productive work might facilitate movement of women with fibromyalgia towards a more active lifestyle.

To analyze disease burden in osteoarthritis (OA) according to Multidimensional Health Assessment Questionnaire (MDHAQ)/Routine Assessment of Patient Index Data 3 (RAPID3) scores at the initial visit and the 6-month follow-up visit, compared with rheumatoid arthritis (RA) as a benchmark for high disease burden. All patients with all diagnoses at the Rush University Medical Center Division of Rheumatology complete a paper MDHAQ at all visits, saved as a PDF in the electronic health record. MDHAQ 0-10 scores for physical function, pain, and patient global assessment (compiled into RAPID3 0-30 scores) and additional scales at the initial and 6-month follow-up visits, for new OA and RA patients seen from 2011 to 2017, were compared. OA and RA patients were classified as self-referred or physician-referred, and RA patients were classified as disease-modifying antirheumatic drug (DMARD)-naive or having prior-DMARD treatment. Patient groups were compared using t-tests and analysis of variance, adjusted for age, disease duration, body mass index (BMI), education, and ethnicity. Compared with RA patients, OA patients had higher age, BMI, and disease duration. At initial visit, the mean RAPID3 did not differ significantly in OA versus DMARD-naive RA patients, whether self- or physician-referred (range 14.8-16.4 [P = 0.38]), or in all OA patients versus DMARD-naive RA patients versus prior-DMARD RA patients (15.0, 15.7, and 15.8, respectively [P = 0.49]). After 6 months, RAPID3 was improved to 13.3, 10.3, and 10.8, respectively, which represented substantially greater improvement in RA patients than OA patients (P < 0.001). Similar results were seen for most self-reported measures and in adjusted analyses.

MDHAQ/RAPID3 scores are similar in OA and RA patients at the initial visit, but higher in OA patients than in RA patients 6 months later, reflecting superior RA treatments. The same MDHAQ/RAPID3 allows comparisons of disease burdens in different diseases.

A high prevalence of obesity in fibromyalgia syndrome (FMS) predisposes patients to metabolic changes. It is not clear how the clinical manifestations of the disease affect metabolism. This study aimed to investigate leptin, growth hormone (GH), and insulin-like growth factor (IGF-1) levels in FMS, and their relationship with body mass index (BMI) and disease severity. This case-control study included 60 patients with FMS and 42 age- and sex-matched healthy controls. BMIs were recorded for all participants. The disease severity was assessed using the Fibromyalgia Impact Questionnaire (FIQ) and a visual analog scale (VAS). The serum levels of leptin, GH, and IGF-1 of all participants were measured using specific enzyme-linked immunosorbent assays. Both groups had similar age (p = 0.058), sex (p = 0.25), and BMI (p = 0.29) distribution. The mean age of the FMS and the control groups was 40.7 ± 10.8 years and 36.2 ± 13.6 years, respectively. The mean BMI was 26.7 kg/m

We found that leptin (high), GH (low), and IGF-1 (low) levels were statistically different, together with being independent of disease severity (FIQ, VAS), and correlated with BMI in the FMS group. These findings may be related with hypothalamo-pituitary axis dysfunction, BMI, and energy metabolism.

To systematically review the evidence for a relationship between sex hormones and structural changes in osteoarthritis (OA). Electronic searches of MEDLINE were performed in November-December 2010 and in February 2011 for studies of sex hormones and OA that met a predefined set of criteria. Both controlled trials and observational studies were eligible for inclusion. Two independent reviewers extracted the data and assessed the methodological quality of the included studies. Due to the heterogeneity of the studies, we were unable to perform a best evidence synthesis. However we have provided summaries for each section. Twenty-seven studies were included in this review, of which 11 were considered high quality. The evidence suggests an association between endogenous oestrogen and cartilage turnover and radiographic OA, and between testosterone and cartilage volume. There is also evidence for an association between exogenous oestrogen and cartilage and bone turnover, although its effects on radiographic and MRI structure as well as joint replacement are unclear. The evidence also supports an association between oestrogen receptor α and β gene polymorphisms and OA.

Although the heterogeneity of the studies means that there is insufficient evidence to form strong conclusions, the available evidence supports an effect of endogenous and exogenous oestrogen as well as oestrogen receptor polymorphisms on joint health.

This study examined whether gentle Hatha yoga reduced fibromyalgia-related symptoms for a convenience sample of 10 participants ranging in age from 39 to 64 years who received yoga instruction 2 times per week for 8 weeks. Respondents completed the Fibromyalgia Impact Questionnaire 1 time per week and provided weekly journal reports regarding their health status. Pre- and post-intervention manual tender point evaluations were also conducted. Findings provide evidence of association between participating in gentle Hatha yoga classes and reduced fibromyalgia - related symptoms.

Additional randomized controlled trials with larger sample sizes and greater empirical rigor are needed to more fully understand this relationship.

To study the effects of experimentally created unilateral anterior crossbite prosthesis on the expression of parathyroid hormone-related peptide (PTHrP) and parathyroid hormone receptor-1 (PTH1R) in mandibular condylar cartilage of SD rat. In experimental groups, the unilateral anterior crossbite metal prosthesis was cemented to the left incisors of the maxilla and mandible of 6-week-old SD rats, respectively. Animals were sacrificed at 2, 4, 8 weeks. Hematoxylin-eosin (HE) staining were carried out for studying the morphological changes of the condylar cartilage. Immunohistochemical staining and real-time polymerase chain reaction (PCR) analysis were performed to detect the levels of expression of PTHrP and PTH1R in the condylar cartilages. The obvious degenerative changes were found in the condylar cartilages in experimental group at 8 weeks. Comparing to the control group, the expression of PTHrP mRNA (P < 0.01) and protein(P < 0.01) in the experimental group were increased, whereas PTH1R mRNA (P < 0.01) and protein (P < 0.01) levels were decreased.

The expression of PTHrP was increased in the condylar cartilage of rat with unilateral anterior crossbite metal prosthesis but its effects might be limited because of decreased expression of PTH1R in the condylar cartilage. The low level expression of PTH1R should be a part of the constitution of the molecular pathomechanism of temporomandibular joint osteoarthritis (TMJOA)-like lesion.

Aceclofenac is an orally administered phenylacetic acid derivative with effects on a variety of inflammatory mediators. Through its analgesic and anti-inflammatory properties, aceclofenac provides symptomatic relief in a variety of painful conditions. In patients with osteoarthritis of the knee, the drug decreases pain, reduces disease severity and improves the functional capacity of the knee to a similar extent to diclofenac, piroxicam and naproxen. Aceclofenac reduces joint inflammation, pain intensity and the duration of morning stiffness in patients with rheumatoid arthritis, and is similar in efficacy to ketoprofen, diclofenac, indomethacin and tenoxicam in these patients. The duration of morning stiffness and pain intensity are reduced, and spinal mobility improved, by aceclofenac in patients with ankylosing spondylitis, with improvements being similar to those observed with indomethacin, naproxen or tenoxicam. Aceclofenac is also effective in other painful conditions (e.g. dental and gynaecological). In contrast to some other NSAIDs, aceclofenac has shown stimulatory effects on cartilage matrix synthesis. Aceclofenac is well tolerated, with most adverse events being minor and reversible, and affecting mainly the GI system. Although the incidence of GI adverse events with aceclofenac was similar to those of comparator NSAIDs in individual clinical trials, withdrawal rates due to these events were significantly lower with aceclofenac than with ketoprofen and tenoxicam. Superior overall and/or GI tolerability of the drug relative to other NSAIDs has been indicated by a nonrandomised comparison with sustained release diclofenac in 10,142 patients, a meta-analysis of 13 comparisons with diclofenac, naproxen, piroxicam, indomethacin, tenoxicam or ketoprofen in 3574 patients, and preliminary details of a comparison with 10 other NSAIDs in 142,776 patients. Further analysis of the above meta-analytical data has indicated that costs incurred as a result of adverse event management are lower with aceclofenac than with a range of comparator NSAIDs.

Trials of 2 to 6 months' duration have shown aceclofenac to be an effective agent in the management of pain and rheumatic disease. Data from in vitro studies indicate properties of particular interest with respect to cartilage matrix effects and selectivity for cyclo-oxygenase-2. Aceclofenac is well tolerated, with encouraging reports of improved general and GI tolerability relative to other NSAIDs from a meta-analysis of double-blind trials and from large nonblind studies.

Juvenile Arthritis (JA) is one of the most common autoimmune diseases in children. A variety of sociocultural factors that influence health outcomes in children with JA have been examined in previous research. However, clinical guidelines to guide the care of these children lack support because this research has not been systematically examined and synthesized. Primary research articles from five internet databases were included if they were peer-reviewed articles in English of studies conducted in the U.S. or Canada and referenced one or more determinants of health, quality of life, socioeconomic status, or health disparities in children with JA. The final sample included 16 articles representing 2139 children and 939 parents. Topics covered in the studies included medication compliance, electronic medical records, environmental risk factors, economic hardship, parental coping, leisure activities, and their effects on patient outcomes including disability and quality of life. Patients with Medicaid experienced more severe outcomes than patients with private insurance despite equivalent levels of healthcare utilization. Other important topics, such as effects of the physical environment and alcohol use, were missing from the literature. Sociocultural factors should be taken into consideration when developing care plans, research studies, and policies in order to remove barriers and promote the best outcomes for this vulnerable population.

Five categories of health determinants were found to influence outcomes: biology, individual behaviors, social environment, physical environment, and health services. Disparities continue to exist for racial and ethnic minority children with JA and those of low socioeconomic status.

Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with numerous cancers. However, these therapies are associated with immune-related adverse events (irAEs), which are inflammatory side effects potentially affecting any organ. Cases of ICI-induced inflammatory arthritis have also been reported. In general, mild irAEs are treated with corticosteroids, while tumour necrosis factor-α (TNFα) inhibitors are reserved for refractory cases. However, prolonged use of TNFα inhibitor (TNFαi) can induce widespread, significant immunosuppression, which can negatively impact the antitumour efficacy of ICI therapy. Therefore, in clinical scenarios where patients develop severe immunotherapy-induced irAEs, an unmet need exists for alternative therapeutic strategies that are effective and without immune dampening effects. The anti-interleukin (IL)-6 receptor antibody, tocilizumab, is a biological agent Food and Drug Administration approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Here, we report on three patients who developed severe polyarthritis while receiving ICI therapy and were treated with tocilizumab. All three patients demonstrated significant clinical improvement; one patient maintained a durable antitumour response derived from checkpoint inhibition.

These three cases suggest that anti-IL-6 receptor antibody may be an effective alternative to corticosteroids or TNFαi for the treatment of arthritis irAEs.

To clarify the significance of increased adenosine deaminase (ADA) isozyme activities in synovial fluid (SF) from patients with rheumatoid arthritis (RA). ADA isozyme activities were measured using colorimetric assays. Concentrations of matrix metalloproteinase-9 (MMP-9) were measured by ELISA. Levels of ADA isozyme activities in RA SF were significantly higher than those from patients with osteoarthritis and patients with traumatic injuries. Significant positive correlations between MMP-9 concentration and ADA activities were observed in RA SF (MMP-9 vs total ADA: r = 0.880; vs ADA1: r = 0.829; vs ADA2: r = 0.823; p < 0.001).

Elevated levels of ADA activities were found in SF from patients with RA. There were significant positive correlations between MMP-9 and ADA isozymes. These results may reflect the inflammatory condition of patients with RA.

Treatment persistence is an important consideration when selecting a therapy for chronic conditions such as rheumatoid arthritis (RA). We assessed the long-term persistence of abatacept or a tumor necrosis factor inhibitor (TNFi) following (1) inadequate response to a conventional synthetic disease-modifying antirheumatic drug (first-line biologic agent) and (2) inadequate response to a first biologic DMARD (second-line biologic agent). Data were extracted from the Rhumadata® registry for patients with RA prescribed either abatacept or a TNFi (adalimumab, certolizumab, etanercept, golimumab, or infliximab) who met the study selection criteria. The primary outcome was persistence to abatacept and TNFi treatment, as first- or second-line biologics. Secondary outcomes included the proportion of patients discontinuing therapy, reasons for discontinuation, and predictors of discontinuation. Persistence was defined as the time from initiation to discontinuation of biologic therapy. Baseline characteristics were compared using descriptive statistics; cumulative persistence rates were estimated using Kaplan-Meier methods, compared using the log-rank test. Multivariate Cox proportional hazard models were used to compare the persistence between treatments, controlling for baseline covariates. Overall, 705 patients met the selection criteria for first-line biologic agent initiation (abatacept, n = 92; TNFi, n = 613) and 317 patients met the criteria for second-line biologic agent initiation (abatacept, n = 105; TNFi, n = 212). There were no clinically significant differences in baseline characteristics between the treatments with either first- or second-line biologics. Persistence was similar between the first-line biologic treatments (p = 0.7406) but significantly higher for abatacept compared with TNFi as a second-line biologic (p = 0.0001). Mean (SD) times on first-line biologic abatacept and TNFi use were 4.53 (0.41) and 5.35 (0.20) years, and 4.80 (0.45) and 2.82 (0.24) years, respectively, as second-line biologic agents. The proportion of patients discontinuing abatacept and TNFi in first-line was 51.1% vs. 59.5% (p = 0.1404), respectively. In second-line, it was 57.1% vs. 74.1% (p = 0.0031). The main reasons for stopping both treatments were inefficacy and adverse events.

Abatacept and TNFi use demonstrated similar persistence rates at 9 years as a first-line biologic agent. As a second-line biologic agent, abatacept had better persistence rates over a TNFi.

To investigate the risk of total hip replacement (THR) due to primary osteoarthritis in relation to cumulative occupational mechanical exposures and lifestyle factors. Using register information, we identified first-time THR cases within the Danish working population in 2005-2006. For each case, 2 age- and sex-matched controls were drawn. Persons within 2,500 randomly selected case-control sets received a questionnaire about job history, weight at age 25 years, present weight and height, smoking, and sports activities at age 25 years. The job history was combined with a job exposure matrix. Cumulative exposure estimates were expressed according to the pack-year concept of smoking (e.g., cumulative lifting was expressed as ton-years). We used conditional logistic regression for statistical analyses. In total, 1,776 case-control sets (71%) were available for analysis. The adjusted odds ratio (OR) for exposure to ≥20 ton-years was 1.35 (95% confidence interval [95% CI] 1.05-1.74) for men and 1.00 (95% CI 0.73-1.41) for women. Standing/walking and whole body vibration showed no associations. The adjusted OR for body mass index (BMI) ≥30 kg/m(2) at age 25 years was 2.44 (95% CI 1.38-4.32) for men and 5.12 (95% CI 2.30-11.39) for women. The corresponding adjusted ORs for an increase in BMI of ≥10 kg/m(2) since age 25 years were 2.16 (95% CI 1.25-3.70) and 2.46 (95% CI 1.47-4.13). Sports participation showed weak positive associations, while pack-years of smoking showed no associations.

The results indicated a modest increase in risk of THR in relation to cumulative lifting among men and an increased risk in relation to a high BMI at age 25 years and to a gain in BMI in both sexes.

Benign lymphoepithelial lesions of the parotid include a spectrum of disorders ranging from lymphoepithelial sialadenitis (LESA) of Sjögren syndrome to lymphoepithelial cysts (LEC) and both human immunodeficiency virus (HIV)-related and -unrelated cystic lymphoid hyperplasia (CLH). They share a common microscopic appearance characterized by epimyoepithelial islands and/or epithelial lined cysts in a lymphoid stroma. However, they differ greatly regarding their etiology, clinical presentation, and management. The purpose of this study was to establish specific immunophenotypic profiles for these diverse disease entities. Four cases of HIV+ CLH, 5 cases of HIV- CLH, 3 cases of LESA of Sjögren syndrome, and 3 cases of sporadic LEC were quantitatively analyzed for distribution of lymphoreticular cell subpopulations, using antibodies against CD20, CD45RO, CD4, CD8, CD57, and CD68. The cystic lesions in both the HIV+ and HIV- cases were microscopically analogous. However, a marked decrease in the interfollicular CD4:CD8 ratio was observed in all HIV+ CLH cases, which was statistically significant when compared with the HIV- cases (P = .02) and cases of LESA of Sjögren syndrome (P = .03). No significant differences regarding the distribution of CD20+ B lymphocytes in epithelial cyst lining or the interfollicular or follicular distribution of CD20+, CD45RO+, CD57+, and CD68+ cells were present among the different groups.

Analysis of the interfollicular CD4:CD8 ratio may offer a simple immunophenotypic approach in the distinction of HIV+ from other lymphoepithelial lesions of the parotid gland, when HIV status is unknown and p24 immunohistochemistry is not readily available.

To investigate mitochondrial membrane integrity, lipid peroxidation and cytotoxicity in peripheral lymphocytes (PL) from rheumatoid arthritis (RA) patients. South African black RA patients (HIV(-)) were recruited into the study. Mitochondrial membrane potential (Deltapsi(m)) was analysed in PL using the JC-1 dye distribution assay and flow cytometry. Correlations between Deltapsi(m) and clinical parameters were tested for statistical significance. Cytotoxicity (LDH) and lipid peroxidation (thiobarbituric acid reactive substances (TBARS)) was also determined. Our findings show significantly elevated levels of cytotoxicity (p=0.0029) and lipid peroxidation (p=0.0030) in RA. A significantly higher percentage of circulating PL contained depolarised mitochondria (p=0.0003) which correlated with disease activity and C-reactive protein levels in patients. Collapse of Deltapsi(m) also negatively correlated to absolute lymphocyte counts (r=-0.4041; p=0.0197).

These findings suggest a possible role for mitochondrial membrane alterations in the pathology of RA.

Knee osteoarthritis (KOA) is one of the most common chronic muscular diseases in old people. In recent years, people are more and more interested in the use of Chinese herbal medicine (CHM) in the treatment of KOA, such as kidney-tonifying and blood-activating medicinal herbs (KTBAMs) in the treatment of KOA. Many studies have confirmed that KTBAMs are effective in the treatment of KOA. However, it is still unknown whether KTBAMs and NSAIDs are more effective in the treatment of KOA. Therefore, we evaluated the efficacy and safety of KTBAMs and NSAIDs in the treatment of KOA. Randomized controlled trials (RCTs) from online databases including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wanfang Data, and Chinese Biomedical Literature Database that compared the efficacy of KTBAMs and NSAIDs in the treatment of KOA were retrieved. The main outcomes included the evaluation of functional outcomes, pain and adverse effects. The Cochrane risk of bias (ROB) tool was used to assess methodological quality. The literature will provide a high-quality analysis of the current evidence supporting KTBAMs for KOA based on various comprehensive assessments including the total effective rate, visual analog scale scores, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequence scores, Knee Society Scale (KSS) scores, and adverse effects.

This proposed systematic review will provide up-to-date evidence to assess the effect of KTBAMs in the treatment for patients with KOA. RESEARCH REGISTRY REGISTRATION NUMBER: : reviewregistry 783.

Studies suggest that apoptosis plays a major role in destruction of salivary glands in Sjögren's syndrome. We hypothesise that apoptosis results in the exposure of cryptic T cell epitopes and an autoimmune response which is pathway-specific. To activate the extrinsic or intrinsic apoptotic pathway to examine morphology, adhesion molecules, markers of antigen processing, and autoantigens on apoptotic bodies in vitro. Tumor necrosis factor-alpha (TNF-alpha) or staurosporine, a protein kinase inhibitor, was used to trigger the extrinsic or intrinsic apoptotic pathway in a Human Salivary Gland cell line (HSG), in vitro. Activated genes were profiled by cDNA array. Apoptotic bodies were visualised using light and SEM. Proteins were evaluated by immunofluorescence and confirmed by functional binding assays with Jurkat lymphocytes. TNF-alpha-triggered extrinsic apoptosis resulted in "sticky" aggregated, apoptotic bodies which displayed cleaved alpha-fodrin autoantigen. In contrast, intrinsic apoptosis induced by staurosporine, resulted in dispersed cell blebs which were alpha-fodrin-negative. cDNA arrays revealed that TNF-alpha, but not staurosporine, upregulated transcriptional expression of Intercellular Adhesion Molecule-1 (ICAM-1) and Macrophage Inflammatory Protein-3 (CCL20).

The apoptotic pathway controls morphological, structural and functional properties of apoptotic bodies. Collectively, TNF-alpha-dependent activation of the extrinsic apoptotic pathway leads to upregulation of ICAM-1 and CCL20 in HSG in vitro. This suggests that pathogenesis in Sjögren's syndrome may involve a TNF-controlled cross-talk between apoptotic ductal and CCL20-attracted dendritic cells via the CD137/CD137L signalling pathway.

joint space assessment on roentgenograms is considered reliable for evaluating the anatomic severity of hip osteoarthritis. Methods for measuring this parameter include the scoring system developed by Kellgren and Lawrence, joint space width measurement, and joint space surface area measurement after digitalization of roentgenograms. to compare the sensitivity to change of the three above-listed methods. the study included patients with hip osteoarthritis meeting ACR criteria for whom two roentgenograms showing evidence of hip osteoarthritis taken 10 to 15 months apart were available. Roentgenograms were read by a single investigator who was unaware of the chronological order of films. Sensitivity to change of the three measurement techniques was determined by calculating standardized response mean (mean change/standard deviation of change). the study evaluated 34 hips (68 roentgenograms) in 22 patients (12 females and ten males, mean age 63 +/- 10 years) with osteoarthritis of one (n = 10) or both (n = 12) hips. Standardized response mean were 0.37, 0.33, and 0.16 for joint space width, joint space surface area, and the Kellgren-Lawrence score, respectively.

this study suggests that joint space width or surface area may be more sensitive than the Kellgren-Lawrence score for monitoring the course of hip osteoarthritis.

To address the role of the nuclear receptor 4A (NR4A) family of orphan nuclear receptors in synoviocyte transformation, hyperplasia, and regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in models of inflammatory arthritis. NR4A messenger RNA levels in synovial tissue and primary synoviocytes were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). NR4A2 was stably overexpressed in normal synoviocytes, and cell proliferation, survival, anchorage-independent growth, migration, and invasion were monitored in vitro. MMP and TIMP expression levels were analyzed by quantitative RT-PCR, and MMP-13 promoter activity was measured using reporter assays. Stable depletion of endogenous NR4A levels was achieved by lentiviral transduction of NR4A short hairpin RNA (shRNA), and the effects on proliferation, migration, and MMP-13 expression were analyzed. NR4A2 was expressed at elevated levels in normal, OA, and RA synovial tissue and in primary RA synoviocytes. Tumor necrosis factor α (TNFα) rapidly and selectively induced expression of NR4A2 in synoviocytes. Ectopic expression of NR4A2 in normal synoviocytes significantly increased proliferation and survival, promoted anchorage-independent growth, and induced migration and invasion. MMP-13 gene expression was synergistically induced by NR4A2 and TNFα, while expression of TIMP-2 was antagonized. NR4A2 directly transactivated the proximal MMP-13 promoter, and a point mutation in the DNA binding domain of NR4A2 abolished transcriptional activation. Depletion of endogenous NR4A receptors with shRNA reduced synoviocyte proliferation, migration, and MMP-13 expression.

The orphan nuclear receptor NR4A2 is a downstream mediator of TNFα signaling in synovial tissue. NR4A2 transcriptional activity contributes to the hyperplastic and invasive phenotype of synoviocytes that leads to cartilage destruction, suggesting that this receptor may show promise as a therapeutic target in inflammatory arthritis.

Recent studies have suggested that the tumor necrosis factor-α (TNF-α) pathway is a potential target for the management of osteoarthritis (OA). Transforming growth factor (TGF)-β-activated kinase 1 (TAK1) is essential in several cytokine-mediated cascades, including the TNF-α, interleukin-1 (IL-1), and TGF-β pathways. The role of TAK1 in synovial tissue in OA is not fully understood. Using synovial cells harvested from OA patients during surgery, we investigated whether TAK1 inhibition suppresses production of TNF-α-induced extracellular matrix degrading enzymes and expression of pain-related molecules. Synovial tissues were harvested from ten subjects with radiographic evidence of osteoarthritis (OA) during total knee arthroplasty. Synovial cells were cultured and stimulated with control (culture media), 10 ng/mL human recombinant TNF-α, or 10 ng/mL TNF-α and 10 μM of the TAK1 inhibitor (5Z)-7-oxozeaenol for 24 h. Real-time polymerase chain reaction (PCR) analysis was used to monitor expression of mRNA of the extracellular matrix degrading enzymes matrix metalloproteinase-3 (MMP-3) and a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 4 (ADAMTS-4); and of the pain-related molecules cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), and nerve growth factor (NGF). MMP-3 and NGF protein concentrations in cell supernatant were measured by enzyme-linked immunosorbent assay (ELISA). COX-2, mPGES-1 and ADAMTS-4 protein expression was also evaluated by western blotting. TNF-α stimulated increases in ADAMTS-4 and MMP3 mRNA (2.0-fold and 1.6-fold, respectively, p < 0.05) and protein expression (21.5-fold and 2.0-fold, respectively). Treatment with the TAK1 inihibitor (5Z)-7-oxozeaenol reduced ADAMTS-4 and MMP3 mRNA (0.5-fold and 0.6-fold, respectively) and protein expression (1.4-fold and 0.5-fold, respectively) in OA synovial cells. COX-2, mPGES-1 and NGF mRNA (11.2-fold, 3.1-fold and 2.7-fold, respectively) and protein expression (3.0-fold, 2.7-fold and 2.2-fold, respectively) were increased by TNF-α. (5Z)-7-oxozeaenol treatment reduced mPGES1 and NGF mRNA (1.5-fold and 0.8-fold, respectively) and protein (1.5-fold and 0.5-fold, respectively).

TAK1 plays an important role in the regulation of TNF-α induced extracellular matrix degrading enzymes and pain-related molecule expression. TAK1 may be a potential target for therapeutic strategies aimed at preventing osteoarthritis progression and pain.

The retention of the anti-rheumatic agent tocilizumab (TCZ) has not been well documented in patients with rheumatoid arthritis (RA). We conducted an observational study to compare the retention of TCZ and anti-tumour necrosis factor (TNF) drugs in the treatment of patients with RA. We reviewed continuation rates and causes of discontinuation of biological agents (biologics) by assessing medical records of patients with RA who were administered biologics at our institute from September 1999 to April 2012, using the Osaka University Biologics for Rheumatic Diseases (BiRD) registry. A total of 401 patients were included. TCZ, infliximab (IFX), etanercept (ETN), and adalimumab (ADA) were administered to 97, 103, 143, and 58 patients, respectively. There were some differences between the baseline characteristics of the groups. The median duration (range) of TCZ, IFX, ETN, and ADA administration was 2.5 (0.1-12.6), 1.9 (0.0-7.7), 2.9 (0.0-11.3), and 1.3 (0.0-3.4) years, respectively. Continuation rates for TCZ and ETN were significantly higher than those for IFX and ADA. Multivariate analyses showed that discontinuation due to lack or loss of efficacy was significantly less common in the TCZ group than in the other groups. Discontinuation due to overall adverse events was not significantly different between treatment groups.

TCZ and ETN show better retention than IFX or ADA in the treatment of RA.

The goal of this study was to differentiate between normal, degenerative meniscus, and meniscal tears using monoexponentially and biexponentially calculated T2*. Meniscal disease, characterized by an altered collagen fiber matrix, might be detectable in vivo using quantitative T2* mapping. A 3D Cartesian spoiled gradient echo technique was adapted to enable the use of a variable echo time approach in combination with a highly asymmetric readout. T2* was calculated monoexponentially and biexponentially using three- and five-parametric non-linear fits, respectively. From a total of 68 evaluated menisci, 48 were normal, 12 were degenerated, and eight had tears. Mean values for the short (T2*s) and long (T2*l) T2* components were as follows: in normal menisci, 0.82 ± 0.38/15.0 ± 5.4 ms, respectively; in degenerated menisci, 1.29 ± 0.53/19.97 ± 5.59 ms, respectively; and, in meniscal tears, 2.05 ± 0.73 and 26.83 ± 7.72 ms, respectively. Biexponentially fitted T2* demonstrated a greater ability to distinguish normal and degenerated menisci using receiver operating characteristic (ROC) analysis (higher area under curve as well as higher specificity and sensitivity).

This study suggests that biexponential fitting, used for T2* calculation in the menisci, provides better results compared to monoexponential fitting. Observed changes in T2* result from the matrix reorganization in degenerative processes in the menisci, which affects the collagen fiber orientation, as well as content.

Knee osteoarthritis (KOA) refers to a chronic deteriorating disease distinguished by degeneration of joint cartilage. Many clinical studies have demonstrated that isokinetic muscle strength training can improve muscle function in patients with KOA. However, although such studies deduce an excellent effect, the results remain controversial. Therefore, the present systematic review seeks to explore the curative effects of isokinetic muscle strength training to establish if it can improve muscle function in patients experiencing KOA. This review will entail a systematic review and a comprehensive examination to establish all randomized controlled studies covering curative effects of isokinetic muscle strength training to improve muscle function in patients with KOA. We will obtain data from PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure, and WanFang databases from inception to September 2021. In addition, the study will employ the criterion postulated by Cochrane to ascertain a quality evaluation and risk assessment of the studies included for analysis. Also, we will employ relative risk, mean differences, and standardized mean differences with 95% confidence intervals to estimate the effective measures. Also, we will employ Cochran Q test and I2 statics to assess heterogeneity among the 2 studies. Overall, this study anticipates providing accurate results and balanced inferences on curative effects of isokinetic muscle strength training for improving muscle function in patients with KOA.

The study's inferences will offer evidence to decide whether isokinetic muscle strength training is an effective measure for improving muscle function in patients with KOA.

To investigate the effect of a single intravenous treatment with glucocorticoids (GC) encapsulated in long-circulating PEG-liposomes on both joint inflammation and cartilage destruction and to investigate the phenomenon of selective homing of these liposomes in the inflamed synovium. Mice with collagen type II-induced arthritis (CIA) were intravenously treated with liposomal and free prednisolone phosphate (PLP) a few days after the first signs of the disease. Joint inflammation was scored during 1 week after treatment, after which sections of the knee joints were prepared for assessment of cartilage damage. In addition, arthritic mice were treated with liposomes containing colloidal gold. 24 hours after injection, knee joint sections were prepared in which the location of liposomes was visualised. Treatment of CIA with 10 mg/kg liposomal PLP resulted in a strong and lasting resolution of joint inflammation. 10 mg/kg free PLP only became slightly effective after repeated daily injections. Although joint inflammation recurred 1 week after treatment with liposomal PLP, knee joint sections prepared at this time indicated that the cartilage damage was still reduced. Localisation of gold labelled liposomes in the inflamed joints was seen in the proximity of blood vessels, in the cellular infiltrate, but mainly in the synovial lining. Unaffected joints did not take up liposomes.

By using the property of long-circulating liposomes to target the synovial lining selectively in inflamed joints, the anti-inflammatory activity of GC can be greatly increased, showing also the beneficial effect of reduced cartilage destruction.

To develop responder definitions for fibromyalgia (FM) clinical trials using key symptom and function domains. Twenty-four candidate responder definitions were developed by expert consensus and were evaluated in 12 randomized, placebo-controlled trials of 4 medications for the treatment of FM. For each definition, the treatment effects of the medication compared with placebo were analyzed using Cochran-Mantel-Haenszel tests or chi-square tests. A meta-analysis of the pooled results for the 4 medications established risk ratios to determine the definitions that best favored medication over placebo. Two definitions performed best in the analyses. Both definitions included ≥30% reduction in pain and ≥10% improvement in physical function. The definitions differed in that one (≥30% improvement in FM [FM30] short version) included ≥30% improvement in sleep or fatigue, and the other (FM30 long version) required ≥30% improvement in 2 of the following symptoms: sleep, fatigue, depression, anxiety, or cognition. In the analysis of both versions, the response rate was ≥15% for each medication and was significantly greater compared with placebo. The risk ratio favoring drug over placebo in the pooled analysis for FM30 version 3 (short version) was 1.50 (95% confidence interval [95% CI] 1.24-1.82; P ≤ 0.0001); the risk ratio for FM30 version 6 (long version) was 1.60 (95% CI 1.31-1.96; P ≤ 0.00001).

Among the 24 responder definitions tested, 2 were identified as most sensitive in identifying response to treatment. The identification of responder definitions for FM clinical trials that include assessments of key symptom and function domains may improve the sensitivity of clinical trials to identify meaningful improvements, leading to improved management of FM.

Patients with idiopathic chronic pancreatitis and Sjögren's syndrome show immune responses against a 60-kilodalton protein isolated from human pancreas extracts. Monoclonal antibody SP3-1, raised against the 60-kilodalton protein, reacts with ductal cells in several exocrine organs and cross-reacts with human carbonic anhydrase II. The present study evaluated serum from patients with these diseases for antibodies to human carbonic anhydrase I and II. An enzyme-linked immunosorbent assay was used to quantify serum antibody against carbonic anhydrase I and II. Serum antibodies against carbonic anhydrase I and II were detected in 7 and 11 of 33 patients with idiopathic chronic pancreatitis, respectively, and in 8 and 13 of 21 patients with Sjögren's syndrome, respectively. The positive prevalence rates of patients with antibodies of carbonic anhydrase II were significantly different among patients with idiopathic chronic pancreatitis and Sjögren's syndrome compared with normal patients (1 of 21). There were no significant differences in the prevalence rates of patients with alcoholic chronic pancreatitis (3 of 20), gallstone-related chronic pancreatitis (0 of 7), and primary biliary cirrhosis (1 of 11).

The results suggest that carbonic anhydrase II is one candidate target antigen recognized during the autoimmune pathophysiology observed in idiopathic chronic pancreatitis and Sjögren's syndrome.

Stress fractures are common in military recruits and athletes and are thought to be secondary to stress and overuse. Less often they are associated with metabolic disorders such as osteoporosis, hypophosphataemia, and diabetes mellitus. Analysis of 19 patients with systemic lupus erythematosus and antiphospholipid antibodies presenting consecutively with foot pain. All had metatarsal fractures (six bilateral) without any obvious history of trauma. 13 of the 19 patients had antiphospholipid syndrome. Among the whole group, 13 had normal bone mineral density, one had osteopenia, and five others had osteoporosis as defined by WHO criteria; 10 had received steroids, mostly in low dosage; 13 were receiving warfarin. There was no evidence that a metabolic bone abnormality was a unifying factor in the pathogenesis.

Atraumatic metatarsal stress fractures may occur in SLE, particularly in association with the antiphospholipid syndrome. The pathogenesis of these fractures remains uncertain but microinfarcts in the metatarsal bones are a possible cause.

To quantify the gene expression of aggrecan core protein and type II collagen in an experimental animal model of osteoarthritis (OA). Total RNA was extracted from the articular cartilage of unoperated knee joints and from OA joints produced by anterior cruciate ligament transection. The relative amounts of type II collagen and aggrecan core protein messenger RNA (mRNA) were evaluated by Northern blot analysis. Total RNA was elevated 2.5 times, aggrecan mRNA was elevated 2 times, and type II collagen mRNA was elevated 8 times, in OA knees compared to unoperated controls.

Chondrocytes are activated metabolically in response to joint injury. Discoordinate gene expression of aggrecan and type II collagen is characteristic of early experimental OA, and we speculate that it may contribute to its pathogenesis.

The multiple disease domains affected in psoriatic arthritis (PsA) may make composite endpoints appropriate for assessing changes in disease activity over time. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Data from two phase 3 studies of patients with PsA were used to evaluate the effect of tofacitinib on composite endpoints. Oral Psoriatic Arthritis triaL (OPAL) Broaden was a 12-month study of tumor necrosis factor inhibitor (TNFi)-naïve patients with an inadequate response to at least one conventional synthetic disease-modifying anti-rheumatic drug; OPAL Beyond was a 6-month study of patients with inadequate response to TNFi. Patients with active PsA received tofacitinib 5 or 10 mg doses twice daily (BID), adalimumab 40 mg subcutaneous injection once every 2 weeks (OPAL Broaden only), or placebo advancing at month 3 to tofacitinib 5 or 10 mg BID. The disease-specific composites were Psoriatic Arthritis Disease Activity Score (PASDAS), Disease Activity Index for Reactive Arthritis/Psoriatic Arthritis (DAPSA), and Composite Psoriatic Disease Activity Index (CPDAI). Change from baseline in composite endpoints was also assessed for minimal disease activity (MDA) responders versus non-responders. Overall, 422 patients from OPAL Broaden and 394 patients from OPAL Beyond were treated. The mean changes from baseline to month 3 for tofacitinib 5 mg BID, tofacitinib 10 mg BID (standard error; effect size) were OPAL Broaden: PASDAS, -2.0 (0.14; 1.73), -2.4 (0.14; 2.4); DAPSA, -20.2 (1.72; 0.9), -24.4 (1.73; 1.23); and CPDAI, -2.9 (0.34; 1.03), -4.2 (0.36; 1.53); OPAL Beyond: PASDAS, -1.9 (0.14; 1.53), -2.1 (0.14; 1.84); DAPSA, -22.5 (1.67; 0.81), -21.0 (1.70; 0.84); and CPDAI, -3.3 (0.31; 1.41), -3.4 (0.31; 1.45). Greater changes from baseline to month 3 (P ≤0.05) were seen with both doses of tofacitinib versus placebo for all endpoints except CPDAI for tofacitinib 5 mg BID in OPAL Broaden. Effect sizes generally increased from 3 to 6 months. Mean changes from baseline were greater in MDA responders than MDA non-responders for all composite endpoints across all time points and treatments. OPAL Broaden: ClinicalTrials.gov Identifier: NCT01877668 , first posted June 12, 2013; OPAL Beyond: ClinicalTrials.gov Identifier: NCT01882439 , first posted June 20, 2013.

This analysis suggests that disease-specific composite measures are appropriate for evaluating treatment efficacy on multiple disease domains in PsA.

Basic fibroblast growth factor (FGF2) is a mitogen for articular chondrocytes. Cell death frequently occurs upon cartilage wounding and is evident during the progression of osteoarthritis. We hypothesised that incubation of wounded articular cartilage with exogenously added FGF2 would enhance cartilage repair, replacing dead cells through increased cell proliferation. Articular cartilage from the metacarapalphalangeal joint of immature bovine steers was wounded in situ, then incubated in vitro in the continual presence or absence of FGF2. Cellular proliferation was expressed as a ratio of cell density of a fixed area between wounded and adjacent cartilage. Immunolabelling revealed the incorporation of bromodeoxyuridine and localisation of collagen type VI and Notch1 epitopes. gamma-secretase inhibitor N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester and soluble Jagged1 ligand (sJ1) were used to analyse the function of Notch signalling in this wound model. FGF2 induced cellular proliferation at the margins of wounded articular cartilage, where proliferative chondrocytes adopted a cluster configuration. Collagen type VI protein was expressed by chondrocytes in clusters, as was Notch1. Cellular proliferation was not affected by inhibition of gamma-secretase dependent Notch1 signalling. Binding of sJ1 to Notch1 receptors in FGF2 treated cartilage inhibited proliferation.

Addition of FGF2 induces rapid chondrocyte proliferation in wounded cartilage, chondrocytes adopt a cluster morphology and also express Notch1. Binding of sJ1 to Notch1 causes apoptosis overriding a proliferative response. This study may shed some light on the significance of increased Notch1 expression and its localisation in chondrocyte clusters in osteoarthritic cartilage.

The prevalence of radiographic osteoarthritis (OA) after anterior cruciate ligament reconstruction (ACLR) approaches 50%, yet the prevalence of significant knee pain is unknown. We applied three different models of Knee injury and Osteoarthritis Outcome Score (KOOS) thresholds for significant knee pain to an ACLR cohort to identify prevalence and risk factors. Multicenter Orthopaedic Outcomes Network (MOON) prospective cohort patients with a unilateral primary ACLR and normal contralateral knee were assessed at 2 and 6 years. Independent variables included patient demographics, validated Patient Reported Outcomes (PRO; Marx activity score, KOOS), and surgical characteristics. Models included: (1) KOOS criteria for a painful knee = quality of life subscale <87.5 and ≥2 of: KOOSpain <86.1, KOOSsymptoms <85.7, KOOSADL <86.8, or KOOSsports/rec <85.0; (2) KOOSpain subscale score ≤72 (≥2 standard deviations below population mean); (3) 10-point KOOSpain drop from 2 to 6 years. Proportional odds models (alpha ≤ 0.05) were used. 1761 patients of median age 23 years, median body mass index (BMI) 24.8 kg/m(2) and 56% male met inclusion, with 87% (1530/1761) and 86% (1506/1761) follow-up at 2 and 6 years, respectively. At 6 years, n = 592 (39%), n = 131 (9%) and n = 169 (12%) met criteria for models #1 through #3, respectively. The most consistent and strongest independent risk factor at both time-points was subsequent ipsilateral knee surgery. Low 2-year Marx activity score increased the odds of a painful knee at 6 years.

Significant knee pain is prevalent after ACLR; with those who undergo subsequent ipsilateral surgery at greatest risk. The relationship between pain and structural OA warrants further study.

Rapamycin, an inhibitor of the serine/threonine protein kinase mTOR, is an immunosuppressant used to treat renal transplant recipients, but it can cause endothelial and mitochondrial dysfunction. Metformin is used for the treatment of type 2 diabetes and was reported to exert therapeutic effects against rheumatoid arthritis and obesity by improving mitochondrial dysfunction via the activation of fibroblast growth factor 21. We investigated the therapeutic effects of rapamycin-metformin combination therapy in obese mice with collagen-induced arthritis (CIA). Mouse embryonic fibroblasts were treated with rapamycin, metformin, or rapamycin-metformin, and their respiratory level and mitochondrial gene expression were assayed. Mice were fed a high-fat diet, immunized with type II collagen, and subsequently treated with rapamycin-metformin daily for 10 weeks. Rapamycin-treated cells exhibited dysfunction of mitochondrial respiration and decreased mitochondrial gene expression compared with rapamycin-metformin-treated cells. Moreover, rapamycin-metformin reduced the clinical arthritis score and the extent of histological inflammation and improved the metabolic profile in obese mice with CIA. Rapamycin-metformin enhanced the balance between T helper 17 and regulatory T cells in vitro and in vivo.

These results suggest that rapamycin-metformin is a potential therapeutic option for autoimmune arthritis.

In cases where the femur or tibial deformity is not correctly analysed, the corrective osteotomies may result in an oblique joint line. The aim of this study was to assess the preoperative deformity of patients due to undergo corrective osteotomy and the resulting abnormal tibial and femoral morphologies after the planned correction using 3D software. CT scans of 327 patients undergoing corrective osteotomy were retrospectively included. Each patient was planned using a software application and the simulated correction was validated by the surgeon. Following the virtual osteotomy, tibial and femoral coronal angular values were considered abnormal if the values were outside 97.5% confidence intervals for non-osteoarthritis knees. After virtual osteotomy, morphological abnormalities were split into two types. Type 1 was an under/overcorrection at the site of the osteotomy resulting in abnormal bone morphology. A type 2 was defined as an error in the site of the correction, resulting in an uncorrected abnormal bone morphology. The global rate of planned abnormalities after tibial virtual osteotomy was 50.7% (166/327) with abnormalities type 1 in 44% and type 2 in 6.7%. After femoral virtual osteotomy the global rate was 6.7% (22/327) with only abnormalities type 1. A lower preoperative HKA was significantly associated with a non-anatomical correction (R III; retrospective cohort study.

Non-anatomical correction was found in more than half the cases analysed more frequently for preoperative global varus alignment. These results suggest that surgeons should considered anatomical angular values to avoid joint line obliquity.

Markers of inflammation have recently been shown to be predictive of cardiovascular disease (CVD). Furthermore, the excess mortality in rheumatoid arthritis (RA), a disease characterized by chronic polyarthritis, is chiefly due to death from CVD. With this background, we studied the effect of inflammation, as reflected by the number of joints with soft tissue swelling, and rheumatoid factor (RF) seropositivity on CVD-related mortality. Mortality rates and rate ratios for all-cause and CVD-related deaths were computed in a longitudinal, population-based cohort of Pima Indians in Arizona from 1965 through 1994. Repeated health examinations were performed, involving systematic assessment of the features of RA, cardiovascular risk factors, serum titers of RF, as well as mortality. The cohort comprised 4,120 subjects (1,861 men, 2,259 women) who were examined an average of 3.5 times during a mean followup of 14 years. During the followup period, 182 CVD-related deaths ocurred. The age- and sex-adjusted CVD-related mortality rates increased significantly with the presence of a higher number of joints with soft tissue swelling (Ptrend = 0.04), and were 2.07 (95% confidence interval [95% CI] 1.30-3.31) times as high in those subjects who had 2 or more swollen joints as in those who had none. There were no significant additional effects on CVD-related mortality when seropositivity for RF or a previous diagnosis of RA were considered. In age- and sex-adjusted proportional hazards analyses, which were controlled for possible confounders, the effect of swollen joints remained significant (mortality rate ratio 1.33, 95% CI 1.04-1.71 per category increase [no swollen joints, 1 swollen joint, at least 2 swollen joints]).

Joint swelling is a significant risk factor for CVD-related death, independent of other known risk factors including a diagnosis of RA. This finding supports the hypothesis that inflammatory mechanisms are important for the development of CVD.

To characterize the clinical and immunologic patterns of expression, response to therapy, and outcome of patients with Sjögren's syndrome (SS) and associated hepatitis C virus (HCV) infection who developed B cell lymphoma. Various international reference centers constituted a multicenter study group with the purpose of creating a registry of patients with SS-HCV who developed B cell lymphoma. A protocol form was used to record the main characteristics of SS, chronic HCV infection, and B cell lymphoma. Twenty-five patients with SS-HCV with B cell lymphoma were included in the registry. There were 22 (88%) women and 3 (12%) men (mean age 55, 58, and 61 years at SS, HCV infection, and lymphoma diagnosis, respectively). The main extraglandular SS manifestations were cutaneous vasculitis in 15 (60%) patients and peripheral neuropathy in 12 (48%); the main immunologic features were positive rheumatoid factor (RF) in 24 (96%) and type II cryoglobulins in 20 (80%). The main histologic subtypes were mucosa-associated lymphoid tissue (MALT) lymphoma in 11 (44%) patients, diffuse large B cell lymphoma in 6 (24%), and follicular center cell lymphoma in 6 (24%). Fifteen (60%) patients had an extranodal primary location, most frequently in the parotid gland (5 patients), liver (4 patients), and stomach (4 patients). Twelve (52%) of 23 patients died after a median followup from the time of lymphoma diagnosis of 4 years, with lymphoma progression being the most frequent cause of death. Survival differed significantly between the main types of B cell lymphoma.

Patients with SS-HCV and B cell lymphoma are clinically characterized by a high frequency of parotid enlargement and vasculitis, an immunologic pattern overwhelmingly dominated by the presence of RF and mixed type II cryoglobulins, a predominance of MALT lymphomas, and an elevated frequency of primary extranodal involvement in organs in which HCV replicates (exocrine glands, liver, and stomach).

To study efficacy of the chondroprotector chondroitin sulphate (structum, Pier Fabr Medicament Production, France) in patients with rheumatoid arthritis (RA) and secondary osteoarthrosis of the knee joints. 15 women with a long history of RA (mean duration 11.9 years) entered an open non-randomized trial of structum. The patients had a severe progressive highly active RA with a definite x-ray stage of the disease. 13 patients had a positive rheumatoid factor (1:80 to 1:1280) and involved knee joints which had been affected for 1 to 10 years (mean 5.3 years). The second x-ray stage was in 8 patients, the third stage of knee joints arthrosis was in 7 ones. A marked pain syndrome in the knee joints upon movement (mean 64.7 mm by VAS) was observed in all the examinees and at rest (mean 28 mm by VAS) in 13 of 15 patients. Structum was given according to a standard scheme: 500 mg 3 times a day for 3 weeks than 500 mg 2 times a day for up to 6 months. Basic drugs for RA were the same for all the observation period. Structum noticeably improved knee joint function (mean Leken's index 12.8, 11.3 and 9.4 scores before the treatment, on treatment month 3 and 6. Movement pain syndrome VAS reduced from 64.7 mm at the start to 51 mm 3 months and 37.5 mm 6 months later, rest VAS--from 19 to 10.3 and 6.4 mm, respectively. The demand in intraarticular glucocorticoids went down from 52 injections at the start of therapy to 6 after 6 months. Side effects for 6 months were absent. Overall efficacy was good (73.3% and 80%) as judged by the doctors and patients, respectively. After 6 months of therapy control x-rays found no progression of destructive changes in the knee joints (by MRI--in 4 patients).

Structum has a marked positive therapeutic effect in patients with severe and long-term course of RA with associated pronounced secondary joint arthrosis.

To make an inventory of the opinions about professional duties and of the cooperation of general practitioners (GPs) and rheumatologists in the care of patients with rheumatoid arthritis (RA), after the publication of the standard 'Rheumatoid arthritis' issued by the Dutch College of General Practitioners in 1994. Descriptive. Maastricht University, the Netherlands. Information was collected by means of a written questionnaire submitted to a random sample of 500 GPs and all 148 (assistant) rheumatologists in the Netherlands, and by means of focus group interviews with GPs, rheumatologists and RA patients. This information focused on the opinion of both groups of professionals on their professional duties in diagnosis and management of RA, existing models of cooperation, the satisfaction with mutual consultations, experienced problems and possibilities to improve cooperation. Substantial differences existed between both groups of professionals in their views on the duties of the GP and the rheumatologist respectively, in the care of RA patients. GPs tended to an expectative policy in cases of suspected or even diagnosed RA, whereas rheumatologists preferred early referral. Hardly any cooperation model was found with agreements committed to paper on the mutual duties regarding RA patients.

Inadequate mutual contacts and inadequate insight of both parties into each other's abilities appeared to be major problems impeding improvement of the mutual communication. Both groups recognized the need to improve the mutual cooperation.

Two of the most common joint diseases are rheumatoid arthritis (RA) and osteoarthritis (OA). Cartilage degradation and erosions are important pathogenetic mechanisms in both joint diseases and have presently gained increasing interest. The aim of the present study was to investigate the effects of the synovial fluid environment of OA patients in comparison with synovial fluids of RA patients on human chondrocytes in vitro. Primary human chondrocytes were incubated in synovial fluids gained from patients with OA or RA. The detection of vital cell numbers was determined by histology and by using the Casy Cell Counter System. Cytokine and chemokine secretion was determined by a multiplex suspension array. Microscopic analysis showed altered cell morphology and cell shrinkage following incubation with synovial fluid of RA patients. Detection of vital cells showed a highly significant decrease of vital chondrocyte when treated with RA synovial fluids in comparison with OA synovial fluids. An active secretion of cytokines such as vascular endothelial growth factor (VEGF) of chondrocytes treated with OA synovial fluids was observed.

Significantly increased levels of various cytokines in synovial fluids of RA, and surprisingly of OA, patients were shown. Activation of pro-inflammatory cytokines of human chondrocytes by synovial fluids of OA patient supports a pro-inflammatory process in the pathogenesis of OA.

Cardiovascular (CV) disease is the most common cause of mortality in patients with rheumatoid arthritis (RA). We assessed the contribution of epidemiologic features, clinical features, routine laboratory markers of inflammation, and HLA-DRB1 alleles to CV mortality in patients with RA prospectively followed at a single referral center in Spain. Patients fulfilling the 1987 American College of Rheumatology classification criteria for RA seen at the rheumatology outpatient clinic of Hospital Xeral-Calde, Lugo between March and September 1996 were included. HLA-DRB1 phenotype, epidemiologic data, and clinical data were assessed at that time. Patients were prospectively followed and clinical records were examined until patient's death or September 1, 2005. A total of 182 consecutive patients were assessed. Compared with the general Spanish population, the age- and sex-standardized mortality ratio by CV cause was 1.78. CV mortality adjusted by age at disease onset and sex was associated with chronic inflammation determined by C-reactive protein level (CRP; hazard ratio [HR] 1.14, P < 0.001) and erythrocyte sedimentation rate (ESR; HR 1.05, P = 0.003). Patients with HLA-DRB1*04 shared epitope alleles (HR 4.15, P = 0.030), in particular those HLA-DRB1*0404 positive (HR 6.65, P = 0.002), had increased risk of CV mortality. Increased risk of CV events was also associated with CRP level (HR 1.09, P = 0.001), ESR (HR 1.03, P = 0.003), and HLA-DRB1*0404 (HR 4.47, P = 0.002).

Our results suggest that a chronically high inflammatory response in genetically predisposed individuals promotes an increased risk of CV events and CV mortality in RA.

Knowledge about predictors of new spinal bone formation in patients with ankylosing spondylitis (AS) is limited. AS-related spinal alterations are more common in men; however, knowledge of whether predictors differ between sexes is lacking. Our objectives were to study spinal radiographic progression in patients with AS and investigate predictors of progression overall and by sex. Swedish patients with AS, age (mean ± SD) 50 ± 13 years, were included in a longitudinal study. At baseline and at 5-year follow up, spinal radiographs were graded according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Predictors were assessed by questionnaires, spinal mobility tests and blood samples. Of 204 patients included, 166 (81%) were re-examined and 54% were men. Men had significantly higher mean mSASSS at baseline and higher mean increase in mSASSS than women (1.9 ± 2.8 vs. 1.2 ± 3.3; p = 0.005) More men than women developed new syndesmophytes (30% vs. 12%; p = 0.007). Multivariate logistic regression analyses with progression ≥ 2 mSASSS units over 5 years or development of new syndesmophytes as the dependent variable showed that presence of baseline AS-related spinal radiographic alterations and obesity (OR 3.78, 95% CI 1.3 to 11.2) were independent predictors of spinal radiographic progression in both sexes. High C-reactive protein (CRP) was a significant predictor in men, with only a trend seen in women. Smoking predicted progression in men whereas high Bath Ankylosing Spondylitis Metrology Index (BASMI) and exposure to bisphosphonates during follow up (OR 4.78, 95% CI 1.1 to 20.1) predicted progression in women. ClinicalTrials.gov , NCT00858819 . Registered on 9 March 2009. Last updated 28 May 2015.

This first report on sex-specific predictors of spinal radiographic progression shows that predictors may partly differ between the sexes. New predictors identified were obesity in both sexes and exposure to bisphosphonates in women. Among previously known predictors, baseline AS-related spinal radiographic alterations predicted radiographic progression in both sexes, high CRP was a predictor in men (with a trend in women) and smoking was a predictor only in men.

Anti-mutated citrullinated vimentin (MCV) antibodies have been reported as a fairly sensitive serological marker of rheumatoid arthritis (RA). We evaluated the diagnostic value of anti-MCV in a large cohort of Chinese patients with early RA. One hundred seventy patients with early RA (<1 yr duration), 66 with other rheumatic diseases, 10 with infectious diseases, and 60 healthy individuals were included in our study. Serum anti-MCV and second-generation anti-cyclic citrullinated peptide antibodies (anti-CCP2) were measured by ELISA, and rheumatoid factor (RF) was measured by rate nephelometry. The associated clinical data of patients with early RA were also evaluated. Then disease activity was scored by the formula for Disease Activity Score (DAS)28, and the degree of radiological changes was assessed by Sharp score. The prevalence of serum anti-MCV in patients with early RA (78.2%, 133/170) was significantly higher than that of other rheumatologic patients and patients with infectious diseases. It was 12% (3/25) in systemic lupus erythematosus, 9.5% (2/21) in primary Sjögren's syndrome, 10% (1/10) in systemic sclerosis, 20% (2/10) in ankylosing spondylitis, 12.5% (1/8) in viral hepatitis type B, and 0% (0/2) in tuberculosis. Anti-MCV was not found in the serum of healthy subjects. The sensitivities of anti-MCV, anti-CCP2, and RF tests for early RA were 78.2%, 61.8%, and 72.4%, respectively, and the specificities were 93.4%, 96.3%, and 80.1%. The combination of anti-MCV and anti-CCP2 positivity showed a very high specificity (97.8%) and positive predictive value (97.1%), but a low sensitivity (58.8%). The sensitivity reached 81.2% when the union of anti-MCV and anti-CCP2 positivities was used as one combined criterion. Statistically, anti-MCV had significant correlation with anti-CCP2 (r=0.587, p=0.01, 2-tailed) and RF (r=0.389, p=0.01, 2-tailed). In addition, it had an interesting correlation with radiological assessment (r=0.349, p=0.05, 2-tailed). The anti-MCV had no significant correlation with other factors, such as erythrocyte sedimentation rate, C-reactive protein, antikeratin antibody, antiperinuclear factor, global visual analog scale score for joint pain, IgA, IgG, IgM, C3, C4, hidden rheumatoid factor for IgA (HRFIgA), HRFIgG, and DAS28.

Anti-MCV is a novel diagnostic marker for early RA. It may be more useful if the anti-CCP2 assay is performed concomitantly to diagnose patients with early RA.

To investigate the clinical course of patients with elderly-onset rheumatoid arthritis (RA). We compared the characteristics, and clinical course of 55 patients who developed RA at over 80 years of age (elderly-onset [EO] group) with 119 patients who developed RA at 40-59 years of age (non-elderly onset [non-EO] group). We also investigated the characteristics and clinical course of 19 patients who developed RA at over 80 and who received biological disease-modifying anti-rheumatic drugs (bDMARDs). The mean DAS28-ESR (DAS) and HAQ-DI (HAQ) of the EO were significantly higher in comparison to the non-EO group (4.91±1.31 vs 4.41±1.47, p=0.043, 1.2±0.9 vs 0.5±0.6, p<0.01). For the first treatment, 87.3% in the EO group received conventional synthetic DMARDs (csDMARDs), none received MTX. The rate of prednisolone (PSL) administration in the EO group was significantly higher than the non-EO group (56.4% vs 30.3%, p<0.01). The DAS and HAQ were significantly decreased in both groups, while the HAQ of the EO group was higher than the non-EO group. The decrease in DAS and HAQ of the PSL users was significantly greater than the non-PSL users (ΔDAS: 2.55±1.83 vs 1.83±1.23, p<0.01, ΔHAQ: 0.9±1.0 vs 0.3±0.6, p=0.027). Among the 19 patients with bDMARDs, the mean DAS and HAQ at baseline were significantly decreased 6 months later.

Early use of csDMARDs and PSL was effective for functional disability of elderly-onset RA; however, some of them required bDMARDs. Further study should be performed to investigate the effectiveness of the early induction of MTX and bDMARDs.

Data on the effects of cigarette smoking with osteoarthritis (OA) are inconsistent and no study has examined the effect of smoking cessation. We examined smoking status, duration, dosage and cessation in association with risk of total knee replacement (TKR) for severe knee OA among elderly Chinese in Singapore. We used data from the Singapore Chinese Health Study, a population-based prospective cohort of 63,257 Chinese men and women aged 45-74 years during enrollment between 1993 and 1998. Detailed information on smoking, current diet and lifestyle factors were obtained through in person interviews. As of 31 December 2011, 1,973 incident TKR cases for severe knee OA had been identified via linkage with nationwide hospital discharge database. We used Cox regression methods to examine smoking in relation to TKR risk with adjustment for age, gender, education, body mass index (BMI), comorbidities and physical activity level. Compared to never smokers, current smokers had a 51% decrease in risk of TKR [Hazards ratio (HR) = 0.49; 95% confidence interval (CI) = 0.40-0.60]. Among current smokers, there was a very strong dose-dependent association between increasing duration and dosage of smoking with decreasing risk of TKR (P for trend <0.0001). Among former smokers, there was a dose-dependent response between decrease in duration of smoking cessation and reduction in TKR risk (P for trend = 0.034).

Our findings strongly implicate smoking as a protective factor for TKR indicated for severe knee OA. This concurs with experimental data that nicotine promotes proliferation and collagen synthesis in chondrocytes.

Systemic lupus erythematosus (SLE) has one of the highest 30-day hospital readmission rates among chronic diseases in the US. This quality improvement initiative developed and assessed the feasibility of a multidisciplinary postdischarge intervention to reduce 30-day readmission rates among SLE patients. A retrospective study was performed using electronic health records of patients with SLE admitted to a university hospital prior to (nonintervention group) and after initiation of the study intervention (intervention group). The study population included patients with a diagnosis of SLE who were admitted to the hospital for any reason during an 8-month time period. The intervention involved sending a templated message at the time of discharge to the rheumatology clinic nurses, which prompted the nurses to call the patient to coordinate future visits and provide education. The primary outcome was the 30-day hospital readmission rate. Data were analyzed using a multivariate mixed binomial regression model. There were 59 hospitalizations in the nonintervention group and 73 hospitalizations in the intervention group during the 8-month study period. The 30-day readmission rate was 29% in the nonintervention group and 19% in the intervention group. The difference in readmission rates between the 2 groups was not statistically significant based on the multivariate model.

Our study demonstrates the feasibility of implementing a multidisciplinary postdischarge intervention to reduce readmission rates for patients with SLE in a large academic medical center. Further investigation is warranted to determine if this approach reduces the unacceptably high hospital readmission rates among SLE patients.

Mesenchymal stem cells (MSCs) are used for the treatment of osteoarthritis (OA), and MSC genetic engineering is expected to enhance cartilage repair. Here, we aimed to investigate the effect of MSCs overexpressing platelet-derived growth factor (PDGF) or heme oxygenase-1 (HO-1) in chondrocytes and synovial cells with an OA phenotype and assess the in vivo efficacy of intra-articular injections of these MSCs in canine OA models. Canine adipose-derived MSCs were transfected with canine PDGF (PDGF-MSCs) or HO-1 (HO-1-MSCs) using lentiviral vectors. Canine chondrocytes or synovial cells were stimulated with lipopolysaccharide (LPS) to mimic the inflammatory OA model and then co-cultured with MSCs, PDGF-MSCs, or HO-1-MSCs for 24 h and 72 h. The mRNA levels of pro-inflammatory, extracellular matrix-degradative/synthetic, or pain-related factors were measured after co-culture by real-time PCR. Furthermore, a surgery-induced canine OA model was established and the dogs were randomized into four groups: normal saline (n = 4), MSCs (n = 4), PDGF-MSCs (n = 4), and HO-1-MSCs (n = 4). The OA symptoms, radiographic OA severity, and serum matrix metallopeptidase (MMP)-13 levels were assessed before and 10 weeks after treatment, to evaluate the safety and efficacy of the modified MSCs. PDGF or HO-1 overexpression significantly reduced the expression of pro-inflammatory factors, MMP-13, and nerve growth factor elicited by LPS and increased that of aggrecan and collagen type 2 in chondrocytes (P < 0.05). In addition, the expression of aggrecanases was significantly downregulated in synovial cells, whereas that of tissue inhibitor of metalloproteinases was upregulated (P < 0.05). Furthermore, the co-cultured MSCs highly expressed genes that contributed to the maintenance of joint homeostasis (P < 0.05). In vivo studies showed that OA symptoms improved after administration of all MSCs. Also, PDGF-MSCs significantly improved limb function and reduced pain (P < 0.05). The results of the radiographic assessment and serum MMP-13 levels did not vary significantly compared to those of the control.

Genetically modifying PDGF and HO-1 in MSCs is an effective strategy for treating OA, suggesting that PDGF-MSCs can be novel therapeutic agents for improving OA symptoms.

Depleting pathogenic B cells could treat systemic lupus erythematosus (SLE). However, depleting B cells in an inflammatory setting such as lupus is difficult. This study was undertaken to investigate whether a type II anti-CD20 monoclonal antibody (mAb) with a different mechanism of action, obinutuzumab (GA101), is more effective than a type I anti-CD20 mAb, rituximab (RTX), in B cell depletion in lupus, and whether efficient B cell depletion results in amelioration of disease. We treated lupus-prone MRL/lpr mice expressing human CD20 on B cells (hCD20 MRL/lpr mice) with either RTX or GA101 and measured B cell depletion under various conditions, as well as multiple clinical end points. A single dose of GA101 was markedly more effective than RTX in depleting B cells in diseased MRL/lpr mice (P < 0.05). RTX overcame resistance to B cell depletion in diseased MRL/lpr mice with continuous treatments. GA101 was more effective in treating hCD20 MRL/lpr mice with early disease, as GA101-treated mice had reduced glomerulonephritis (P < 0.05), lower anti-RNA autoantibody titers (P < 0.05), and fewer activated CD4+ T cells (P < 0.0001) compared to RTX-treated mice. GA101 also treated advanced disease, and continual treatment prolonged survival. Using variants of GA101, we also elucidated B cell depletion mechanisms in vivo in mice with lupus.

Albeit both anti-CD20 antibodies ameliorated early disease, GA101 was more effective than RTX in important parameters, such as glomerulonephritis score. GA101 proved beneficial in an advanced disease model, where it prolonged survival. These data support clinical testing of GA101 in SLE and lupus nephritis.

Dysregulation of T cells mediated immune responses is a hallmark in the development of systemic lupus erythematosus (SLE). Recent genome wide association study (GWAS) revealed the genetic contribution of variants located in the cytotoxic T lymphocyte-associated protein-4 (CTLA4)-inducible T cell co-stimulator (ICOS) intergenic region to SLE susceptibility. Our aim is to find a functional variant in this region. The genetic association results in the CTLA4-ICOS region from previous GWAS were adopted to select the potential variant which was further replicated in two independent cohorts (Henan cohort 2053 SLE patients and 1845 healthy controls, Beijing cohort 2303 SLE patients and 19,262 healthy). In order to explore the functional significance in SLE, bioinformatics with validation experiments (including electrophoretic mobility shift assay and luciferase reporter assay) and mRNA expression analysis were also performed. A variant located in the CTLA4-ICOS intergenic region, rs17268364, was associated with susceptibility to SLE patients in Chinese populations (risk allele, p

The present study confirmed the functional role of rs17268364 in the CTLA4-ICOS intergenic region that increased SLE susceptibility in the Chinese population.

The present cross sectional study was performed to test the hypothesis that in osteoarthritis (OA) of the knee severity of this disease is related to local levels of inflammatory metabolites and their corresponding enzymes. From 41 patients with OA of the knee (age range 45-79 years) undergoing arthroscopy blood, synovial fluid (SF) and synovial membrane (SM) were collected. Clinical conditions were primarily assessed by the WOMAC-index and radiographic grading (K&L-grade). Concentrations of PGE(2), TxB(2)and NO(2/3)and that of IL-6, IL-1 alpha, IL-1 beta, TNF alpha, COX-2 and iNOS were determined in SF and SM, respectively. With advancing age K&L-grade and COX-2 in SM increased significantly (P=0.005 and P=0.01, respectively). TNF alpha and IL-1 alpha were not detectable in SM samples. Apart from a correlation between PGE(2)and WOMAC-index (r=0.36, P=0.035) no significant relationships could be found between the various inflammatory parameters and any of the assessed clinical signs.

Apparently no direct relationships exist between the measured markers of inflammation (e.g. PGE(2), NO(2/3)) or the involved enzymes (e.g. COX-2, iNOS) and the severity of OA of the knee. The degenerative condition of this disease might be due to the more local, mainly mechanical injury with little systemic upset. However, further longitudinal studies are needed to clarify whether the assessed biochemical markers could serve as predictors for the progression of OA.

Autoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting. The ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an 'observer-nested-within-subject' design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach's alpha. The ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items.

The ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies.

Although the Foot and Ankle Outcome Score (FAOS) is commonly used in several languages for a variety of foot disorders, it has not been validated specifically for foot and ankle arthritic conditions. The aims of the present study were to translate the original English FAOS into Thai and to evaluate the validity and reliability of the Thai version of the FAOS for the foot and ankle arthritic conditions. The original FAOS was translated into Thai using forward-backward translation. The Thai FAOS and validated Thai Short Form-36 (SF-36 The Thai FAOS score demonstrated sufficient correlation with SF-36 total score in Pain (Pearson's correlation coefficient (r)=0.45, p=0.002), Symptoms (r=0.45, p=0.002), Activities of Daily Living (ADL) (r=0.47, p=0.001), and Quality of Life (QOL) (r=0.38, p=0.011) subscales. The Sports and Recreational Activities (Sports & Rec) subscale did not correlate significantly with the SF-36

The Thai FAOS demonstrated sufficient levels of construct and content validity for the evaluation of foot and ankle arthritis. Although reliability was satisfactory for the major subscale ADL, it was not sufficient for the minor subscales. Our findings suggest that it can be used as a disease-specific instrument to evaluate foot and ankle arthritis and can complement other reliable outcome surveys.

This randomized, placebo-controlled, double-blind, Phase 1 study assessed the magnitude, onset, and duration of response with intravenous (i.v.) and subcutaneous (s.c.) adalimumab (Humira, Abbott Laboratories) combined with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite previous MTX therapy. Fifty-four patients were randomized to two injections of i.v. or s.c. adalimumab (1 mg/kg) or placebo while continuing on MTX (mean dose, 15.7 mg/week). Dosing intervals were determined by the European League Against Rheumatism (EULAR) response criteria, and were allowed to range from 1 to 3 months. Efficacy was mainly assessed using the EULAR response criteria and the American College of Rheumatology (ACR) response criteria. Moderate EULAR response was achieved at least once within 29 days after the first injection in 83% and 61% of patients receiving i.v. and s.c. adalimumab respectively, compared with 44% for placebo [probability (p) < or = 0.05 for i.v. adalimumab versus placebo]. A 20% improvement in disease activity according to the ACR criteria (ACR20 response) was achieved by 72% and 67% of patients receiving i.v. and s.c. adalimumab respectively, compared with 28% for placebo (p < or = 0.01 and p < or = 0.05, respectively, versus placebo). By Day 15 after the first and second injections, statistically significant moderate EULAR and ACR20 response rates were achieved with either i.v. or s.c. adalimumab compared with placebo (p < or = 0.05). The mean times to second injection for i.v. adalimumab, s.c. adalimumab, and placebo were 42.2 days (range: 27-84 days), 38.3 days (range: 26-85 days), and 28.4 days (range: 26-32 days), respectively (minimum time allowed by the protocol between the first and second injections was 4 weeks). Adalimumab in combination with MTX was well tolerated, with no patients being withdrawn because of adverse events.

Either i.v. or s.c. adalimumab added to MTX significantly improved the signs and symptoms of RA compared with MTX alone. Subcutaneously administered adalimumab appeared to provide a response that was as great, as rapid, and as enduring as that with i.v. adalimumab.

Rheumatoid arthritis (RA) cause major functional, psychological, social and occupational repercussions for patients and has important economic consequences for society. The principal objective of this work was to determine the economic pertinence of a staff nurse specialised in preventive management for these patients. The COMEDRA multicentre randomised controlled clinical trial, conducted from March 2011 to June 2012, showed the effectiveness of a nurse-led programme dedicated to the management of comorbidities trough the promotion of 11 preventive procedures. A cost-benefit analysis, from a societal perspective and based on direct medical cost, was conducted to assess the equivalence of the cost of the nurse-led programme and the cost of the additional preventive procedures performed, engendered by the programme. The programme was considered effective if its cost was less than or equal to the costs of the additional preventive procedures. The costs were calculated from the approved health insurance charges. From the total costs induced, a contributive share was measured, corresponding to the ratio of the total costs of each type of procedure to the overall total cost. The cost of the intervention was assessed at €16,804.2. This intervention contributed to the performance of 747 additional preventive procedures, at a cost of €30,184.8. This intervention with these patients is financially balanced when at least 37 patients follow the recommendations for every preventive procedure.

From the hospital's perspective and from both a medical and economic point of view, a nurse-led programme to manage the comorbidities of RA is useful.

Due to concerns of infection and medication disruptions during the COVID-19 pandemic, rheumatology patients at the pandemic epicenter were at risk of distress and poor health outcomes. We sought to investigate medication disruptions and COVID-19-related distress in the Bronx, New York shortly after the peak of the pandemic and determine whether factors related to the pandemic were associated with flares, disease activity, and overall health. In the month following the epidemic peak, we surveyed adult patients and parents of pediatric patients from rheumatology clinics in the Bronx regarding medication access, medication interruptions, COVID-19 infection, COVID-19 hospitalization, and COVID-19-related distress. We examined which factors were associated with patient-reported flares, disease activity, and overall health scores in regression models accounting for sociodemographic characteristics and rheumatologic disease type. Of the 1,692 patients and parents of pediatric patients that were contacted, 361 (21%) responded; 16% reported medication access difficulty, 14% reported medication interruptions, and 41% reported experiencing flare(s). In a multivariable logistic regression model, medication access difficulty was associated with increased odds of flare (odds ratio [OR] 4.0 [95% confidence interval (95% CI) 1.5, 10.4]; P = 0.005), as was high COVID-19-related distress (OR 2.4 [95% CI 1.2, 4.6]; P = 0.01). In multivariable linear regression models, medication access difficulty and high COVID-19-related distress were associated with worse disease activity scores, and high COVID-19-related distress was associated with worse health scores.

Medication access difficulties and flares were common among rheumatology patients from the Bronx, New York in the month following the peak of the epidemic. Medication access difficulty and COVID-19-related distress were highly associated with flare and disease activity. COVID-19-related distress was associated with overall health scores.

Peroxynitrite (ONOO(-)) is formed in the inflamed and degenerating human joint. Peroxynitrite-modified collagen-II (PMC-II) was recently discovered in the serum of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Therefore we investigated the cellular effects of PMC-II on human mesenchymal progenitor cells (MPCs) as a model of cartilage and cartilage repair cells in the inflamed and degenerating joint. MPCs were isolated from the trabecular bone of patients undergoing reconstructive surgery and were differentiated into a chondrogenic lineage. Cells were exposed to PMC-II and levels of the proinflammatory mediators nitric oxide (*NO) and prostaglandin E(2) (PGE(2)) measured. Levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), phosphorylated mitogen activated protein kinases (MAPKs) and nuclear factor kappa B (NF-kappaB) activation were measured by enzyme linked immunosorbent assay (ELISA) together with specific MAPK and NF-kappaB inhibitors. PMC-II induced ()NO and PGE(2) synthesis through upregulation of iNOS and COX-2 proteins. PMC-II also lead to the phosphorylation of MAPKs, extracellularly regulated kinase 1/2 (ERK1/2) and p38 [but not c-Jun NH(2)-terminal kinase (JNK1/2)] and the activation of proinflammatory transcription factor NF-kappaB. Inhibitors of p38, ERK1/2 and NF-kappaB prevented PMC-II induced ()NO and PGE(2) synthesis, iNOS and COX-2 protein expression and NF-kappaB activation.

iNOS, COX-2, NF-kappaB and MAPK are known to be activated in the joints of patients with OA and RA. PMC-II induced iNOS and COX-2 synthesis through p38, ERK1/2 and NF-kappaB dependent pathways suggesting a previously unidentified pathway for the synthesis of the proinflammatory mediators, ()NO and PGE(2), further suggesting that inhibitors of these pathways may be therapeutic in the inflamed and degenerating human joint.

This research aims to explore differentially expressed circRNA between OA and KBD and potential diagnostic biomarkers. Total RNA was extracted from 5 pairs of KBD and OA knee joint cartilage specimens, and the expression of circRNAs was analyzed by Chip Scanning Analysis. The microarray data was verified by quantitative polymerase chain reaction (qRT-PCR). CircRNA-miRNA network was constructed to predict targeting microRNAs of circRNA genes. Peripheral blood samples from 25 KBD patients and 25 OA patients were collected for verification by qRT-PCR. Diagnostic value was evaluated by the area under the receiver operator characteristic (ROC) curve. A total of 1627 circRNAs were differentially expressed between OA and KBD. Five bone and joint disease-related circRNAs were chosen for qRT-PCR validation. The difference in expression profile of hsa_circRNA_0020014 was confirmed by qRT-PCR, and its circRNA-miRNA regulation network was set up. The ROC curve demonstrated that hsa_circ_0020014_CBC1 in peripheral blood could distinguish patients with KBD and OA.

The expression profiles of circRNA were significantly different between OA and KBD. hsa_circRNA_0020014 is a potential biomarker for differential diagnosis between these two diseases.

To compare the radiographic outcomes after 36 months in patients with early erosive rheumatoid arthritis (RA) who were treated with methotrexate (MTX) or gold sodium thiomalate (GSTM). In a randomized, double-blind fashion, 174 patients from two centres were assigned to receive weekly intramuscular injections of either 15 mg MTX or 50 mg GSTM. After 12 months, the study was continued as an open prospective study for an additional 2 yr, administering the same amount of MTX and half of the GSTM dose. Radiographic outcomes were assessed by standardized methods in all patients at baseline and after 6, 12, 24 and 36 months. Intention-to-treat analysis showed that patients treated with MTX had higher radiographic scores and more erosive joints at all follow-up points. However, there was no statistically significant difference between the two treatment groups. The progression rate was significantly slower during the second and third years of follow-up in both groups. Baseline and time-integrated (area under the curve over 6 months) disease activity parameters were good predictors of radiographic outcome after 3 yr. Seropositivity was not an independent predictor of progression. However, patients who were positive for rheumatoid factor had higher time-integrated disease activity (with less response to treatment) and thus their disease was significantly more progressive.

Both of the disease-modifying compounds used in this study, MTX and GSTM, were able to reduce the slope of radiographic progression during 3 yr of follow-up. There was some advantage for parenteral gold but no significant intergroup difference.

To identify whether or not there are clinical markers that correlate with Helicobacter pylori (H. pylori) infection in patients with Sjogren's syndrome (SS) and its implication to handling this group of patients. Four groups of patients were studied. Group 1, 36 patients with primary SS; group 2, 31 patients with secondary SS; group 3, 46 patients with various connective tissue diseases not suffering from sicca symptoms, and group 4, 64 healthy controls. Clinical assessment was done and a score for disease manifestation was given for every SS patient. Serum IgG and IgM antibodies to H. pylori were assessed by ELISA. The prevalence and mean titer of H. pylori infection in patients with SS in group 1 (80.6%) and 2 (71%) were significantly higher than in group 3 (60.9%) and 4 (56.3%) (P < 0.01). There was significant correlation between H. pylori infection and age, disease duration, global score for disease status and C-reactive protein (CRP) in SS patients. On the other hand, there was no significant correlation with body mass index, and erythrocyte sedimentation rate (ESR).

Patients with SS are more prone to have H. pylori infection in comparison to other connective tissue diseases. Serum antibody titer to H. pylori correlated with index for clinical disease manifestations, age, disease duration and CRP. Assessment of H. pylori infection in older patients suffering from active SS for a relatively long duration is recommended, especially those suffering form primary SS for more than 3 years.

Exercise has beneficial effects on pain in knee osteoarthritis (OA), yet the underlying mechanisms are unclear. The purpose of this study was to investigate the effects of exercise on pressure-pain sensitivity in patients with knee OA. In a randomized controlled trial, participants were assigned to 12 weeks of supervised exercise therapy (ET; 36 sessions) or a no attention control group (CG). Pressure-pain sensitivity was assessed by cuff pressure algometry on the calf of the most symptomatic leg. The coprimary outcomes were pressure-pain thresholds (PPTs) and cumulated visual analog scale pain scores during constant pressure for 6 minutes at 125% of the PPT as a measure of temporal summation (TS) of pressure-pain. Secondary outcomes included self-reported pain using the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. Analyses were based on the "per-protocol" population (participants following the protocol). Sixty participants were randomized (31 in ET group, 29 in CG), and the per-protocol population included 48 participants (25 in ET group, 23 in CG). At followup, mean group differences in the change from baseline were 3.1 kPa (95% confidence interval [95% CI] 0.2, 6.0; P = 0.038) for the PPT, 2,608 mm × seconds (95% CI 458, 4,758; P = 0.019) for TS, and 6.8 points (95% CI 1.2, 12.4; P = 0.018) for KOOS pain, all in favor of ET.

Pressure-pain sensitivity, TS, and self-reported pain are reduced among patients completing a 12-week supervised exercise program compared to a no attention CG. These results demonstrate beneficial effects of exercise on basic pain mechanisms and further exploration may provide a basis for optimized treatment.

To investigate the combination of mild mechanical stimuli and a disease modifying osteoarthritis drug (DMOAD) in inflammatory activated chondrocytes and to study the combination of drug and mechanical tension on the cellular level as a model for an integrated biophysical approach for osteoarthritis (OA) treatments. Interleukin-1beta (IL-1β) stimulated C28/I2 cells underwent mild mechanically treatment while cultured in the presence of the DMOAD diacerein. The pharmacological input of diacerein was evaluated by cell viability and cell proliferation measurements. Inflammation and treatment induced changes in key regulatory proteins and components of the extracellular matrix (ECM) were characterized by quantitative real-time PCR (qPCR). The effects on metalloproteinase-1 (MMP-1) activity and glycosaminoglycan (GAG) concentration in cell supernatants of treated cells were investigated. C28/I2 cells demonstrated significant changes in expression of inflammatory and cartilage destructive proteins in response to IL-1β stimulation. The chondroprotective action of diacerein in mechanically stimulated cells was mediated by a decrease in interleukin-8 (IL-8), fibronectin-1 (FN-1), collagen type I (Col 1) and MMP-1 expression levels, respectively. Augmented expression of interleukin-6 receptor (IL-6R) and the fibroblast growth factor receptors (FGFRs) by diacerein was not abolished by mechanical treatment. The observed effects were accompanied by a reduced cell proliferation rate, attenuated cell viability and extenuated MMP-1 activity.

Diacerein diversely regulates the expression of main regulatory proteins as well as components important to regenerate and set up ECM. Mechanical stimulation does not negatively influence the chondroprotective effect induced by diacerein treatment in immortalized human C28/I2 chondrocytes.

Recent studies have shown an increase in both cardiovascular and all-cause mortality in ankylosing spondylitis (AS). We examined the potential survival benefit of statin use in AS within a general population context. We performed an incident user cohort study with time-stratified propensity score matching using a UK general population database between 1 January 2000 and 31 December 2014. To account for potential confounders, we compared propensity score-matched cohorts of statin initiators and non-initiators using 1-year cohort accrual blocks. The variables used to create the propensity score model included disease duration, body mass index, lifestyle factors, comorbidities and medication use. Using unmatched AS cohorts, statin initiators (n=1430) showed a 43% higher risk of mortality than non-initiators (n=1430) (HR=1.43; 95% CI 1.12 to 1.84). After propensity score matching, patients with AS who initiated statins (n=1108) had 96 deaths, and matched non-initiators (n=1108) had 134 deaths over a mean follow-up of 5.3 and 5.1 years, respectively. This corresponded to mortality rates of 16.5 and 23.8 per 1000 person-years (PY), respectively, resulting in an HR of 0.63 (95% CI 0.46 to 0.85) and an absolute mortality rate difference of 7.3 deaths per 1000 PY (95% CI 2.1 to 12.5).

This general population-based cohort study suggests that statin initiation is associated with a substantially lower risk of mortality among patients with AS. The magnitude of the inverse association appears to be larger than that observed in randomised trials of the general population and in population-based cohort studies of patients with rheumatoid arthritis.

(1) To examine the change in regional bone mineral density (BMD), including the hands, and assess its role as a predictor of outcome in patients presenting with an early undifferentiated inflammatory arthritis; (2) to examine for associations with the changes in hand BMD. 74 patients with undifferentiated hand arthritis of less than 12 months' duration were examined at baseline and then at three, six, and 12 months follow up, including BMD measurement of the femoral neck, spine (L2-4), and the whole hands using dual energy absorptiometry (DXA). During the study, 13 patients were diagnosed as having rheumatoid arthritis, 19 as having inflammatory non-rheumatoid joint disorders, and 42 as having non-inflammatory joint disorders. At the femoral neck and lumbar spine no significant bone loss was seen in any of the three subgroups. At the 12 months follow up the mean (95% confidence interval) hand BMD loss in the patients with rheumatoid arthritis was -4.27% (-1.41 to -7.13); in the inflammatory non-rheumatoid group, -0.49% (-1.33 to +0.35); and in the non-inflammatory joint disorder group, -0.87% (-1.51 to -0.23). In a multivariate linear regression model (including age, rheumatoid factor, mean C reactive protein, mean HAQ score, and cumulative glucocorticoid dose), only mean C reactive protein (p<0.001) and rheumatoid factor (p = 0.04) were independently associated with change in hand BMD during follow up.

Hand DXA provides a very sensitive tool for measuring bone loss in early rheumatoid arthritis and may be useful in identifying patients at high risk of developing progressive disease. Further studies are needed to evaluate the role of hand bone loss as a prognostic factor and outcome measure in rheumatoid arthritis.

To study the rate of common comorbidities and cardiovascular disease in patients with ankylosing spondylitis (AS) compared with the general population seeking health care. This cohort study included 935 subjects (67% men) ages ≥20 years diagnosed with AS and the adult background population in Southern Sweden. During 2004 to 2007 we recorded the occurrence of physicians' diagnostic codes for a select number of comorbidities commonly associated with AS and cardiovascular disease and risk factors. We obtained standardized morbidity-rate ratios (SMRs) by dividing the observed morbidity rate in AS patients by the expected rate based on the corresponding rate of the disease in the general population of the county seeking health care. The highest SMRs were found for uveitis (34.35, 95% confidence interval [95% CI] 28.55-40.98) and inflammatory bowel disease (9.28, 95% CI 7.07-11.97). Also, we found increased SMRs for ischemic heart diseases (2.20, 95% CI 1.77-2.70), hypertension (1.98, 95% CI 1.72-2.28), and diabetes mellitus (1.41, 95% CI 1.10-1.78). Furthermore, the SMRs for psoriasis, osteoporosis, and atrioventricular blocks were also statistically significantly elevated.

Inflammatory diseases affecting the eye and the digestive system were the most notable comorbidities in AS patients, but the rate for cardiovascular disease was also high. Using comprehensive longitudinal population-based register data is a promising tool to evaluate the excess consultation rate and total burden of rheumatic disease on patients and society.

This work was undertaken to delineate intracellular signaling pathways for the PDE4 inhibitor apremilast and to examine interactions between apremilast, methotrexate and adenosine A2A receptors (A2AR). After apremilast and LPS incubation, intracellular cAMP, TNF-α, IL-10, IL-6 and IL-1α were measured in the Raw264.7 monocytic murine cell line. PKA, Epac1/2 (signaling intermediates for cAMP) and A2AR knockdowns were performed by shRNA transfection and interactions with A2AR and A2BR, as well as with methotrexate were tested in vitro and in the murine air pouch model. Statistical differences were determined using one or two-way ANOVA or Student's t test. The alpha nominal level was set at 0.05 in all cases. A P value of < 0.05 was considered significant. In vitro, apremilast increased intracellular cAMP and inhibited TNF-α release (IC50=104nM) and the specific A2AR-agonist CGS21680 (1μM) increased apremilast potency (IC50=25nM). In this cell line, apremilast increased IL-10 production. PKA, Epac1 and Epac2 knockdowns prevented TNF-α inhibition and IL-10 stimulation by apremilast. In the murine air pouch model, both apremilast and MTX significantly inhibited leukocyte infiltration, while apremilast, but not MTX, significantly inhibited TNF-α release. The addition of MTX (1 mg/kg) to apremilast (5 mg/kg) yielded no more inhibition of leukocyte infiltration or TNF-α release than with apremilast alone.

The immunoregulatory effects of apremilast appear to be mediated by cAMP through the downstream effectors PKA, Epac1, and Epac2. A2AR agonism potentiated TNF-α inhibition by apremilast, consistent with the cAMP-elevating effects of that receptor. Because the A2AR is also involved in the anti-inflammatory effects of MTX, the mechanism of action of both drugs involves cAMP-dependent pathways and is therefore partially overlapping in nature.

To delineate the activities of decorin and biglycan in the progression of post-traumatic osteoarthritis (PTOA). Three-month-old inducible biglycan (Bgn In the DMM model, Bgn

In PTOA, decorin plays a more crucial role than biglycan in regulating cartilage degeneration, while biglycan is more important in regulating subchondral bone structure. The two have distinct activities and modest synergy in the pathogenesis of PTOA.

Posterior stabilized (PS) polyethylene inserts have been shown to have excellent long-term functional results following total knee arthroplasty (TKA). A cruciate-substituting (CS) design has been introduced to minimize bony resection and eliminate concerns regarding wear on the PS post. The purpose of this study is to compare the outcomes of patients who underwent TKA using either a PS or CS insert. We reviewed a consecutive series of 5970 patients who underwent a cruciate-sacrificing TKA and received either a PS (3,314) or CS (2,656) polyethylene liner. We compared demographics, Knee Injury and Osteoarthritis Outcome Score Jr (KOOS Jr), Short-Form 12 (SF-12) scores, and revision rates between the groups at a minimum 2 years followup. A multivariate regression was performed to identify the independent effect of design on functional outcomes. Revision rates between the groups were comparably low (0.35% for PS vs 0.51% for CS, P = .466) at an overall mean follow-up of 43 months. Patients in the PS cohort had statistically higher KOOS Jr scores at 2 years (69.8 vs 72.9, P < .001). Multivariate regression analysis found CS patients to have lower postoperative KOOS Jr scores (estimate -2.26, P = .003), and less overall improvement in KOOS Jr scores (estimate -2.42, P = .024) than PS patients, but neither was a clinically significant difference.

Patients who undergo TKA with a CS polyethylene insert have comparable functional outcomes and revision rates to those with a PS design at short-term follow-up. Longer follow-up is needed to determine whether CS can match the outstanding track record of PS TKA.

HLA-DRB1 is associated with rheumatoid arthritis (RA). However, it has recently been suggested that HLA-DRB1 is only associated with patients with RA who have anticitrullinated peptide/protein antibodies (ACPA), which are specific to RA. To elucidate whether specific HLA-DR alleles are associated with ACPA-negative RA development. HLA-DRB1 typing was carried out in 368 Japanese ACPA-negative patients with RA and 1508 healthy volunteers as the first set, followed by HLA-DRB1 typing of 501 cases and 500 controls as the second set. The HLA-DRB1 allele frequency and diplotype frequency were compared in each group, and the results of the two studies were combined to detect HLA-DRB1 alleles or diplotypes associated with ACPA-negative RA. HLA-DRB1*12:01 was identified as a novel susceptibility allele for ACPA-negative RA (p=0.000088, OR=1.72, 95% CI 1.31 to 2.26). HLA-DRB1*04:05 and *14:03 showed moderate associations with ACPA-negative RA (p=0.0063, OR=1.26, 95% CI 1.07 to 1.49 and p=0.0043, OR=1.81, 95% CI 1.20 to 2.73, respectively). The shared epitope was weakly associated with ACPA-negative RA, but no dosage effect was detected (p=0.016, OR=1.17, 95% CI 1.03 to 1.34). A combination of HLA-DRB1*12:01 and DRB1*09:01 showed a strong association with susceptibility to ACPA-negative RA (p=0.00013, OR=3.62, 95% CI 1.79 to 7.30). Homozygosity for HLA-DR8 was significantly associated with ACPA-negative RA (p=0.0070, OR=2.16, 95% CI 1.22 to 3.82). It was also found that HLA-DRB1*15:02 and *13:02 were protective against ACPA-negative RA (p=0.00010, OR=0.68, 95% CI 0.56 to 0.83 and p=0.00059, OR=0.66, 95% CI 0.52 to 0.84, respectively).

In this large-scale association study multiple alleles and diplotypes were found to be associated with susceptibility to, or protection against, ACPA-negative RA.

Patient's and physician's perspective can differ in rheumatoid arthritis (RA). The aim was to define the concept of patient-reported flares. Post-hoc analysis of a randomized controlled trial of a step-down strategy in RA patients treated with anti-TNF, in DAS28-remission for ≥6 months, randomized to either "spacing" or "maintaining" anti-TNF. The occurrence of patient-reported flares (PRF) was evaluated every 3 months for 18 months by: "Over the last 3 months, did you experience symptoms suggestive of disease exacerbation?". Visits with and without PRF were compared, using a linear mixed effects model, in terms of symptoms, disability based on the Health Assessment Questionnaire, quality of life based on Short Form 36 Health Survey and DAS28-based relapses (DBR), defined as an increase of DAS28>0.6 and an absolute value of DAS28>2.6. The agreement between PRF and DBR was measured by the kappa coefficient on repeated data. In all, 137 patients were analyzed: mean age 55±11 years, females 78%, mean RA duration 9.5±8.0 years. Over the 18 months, PRF concerned 27.2% of the 940 available visits. DBR and PRF were observed in 24% and 16% of 940 visits for 137 patients respectively. All the items were associated with PRF with standardized effect size between -0.58 (SF36 PCS) and 0.87 (DAS28). The agreement between PRF and DBR was moderate (κ=0.44).

The concept of flare refers to more than just RA disease activity.

To identify modifiable patient and provider factors associated with allopurinol adherence and the achievement of a serum urate acid (SUA) goal in gout. We identified a retrospective cohort of patients with gout, newly treated with allopurinol. All patient data came from administrative datasets at a large integrated health delivery system. Patients were ≥ 18 years old at time of initial allopurinol dispensing, and had 12 months or more of membership and drug eligibility prior to the index date. Allopurinol adherence was defined as a proportion of days covered ≥ 0.80, evaluated during the first 12 months of observation after the initial dispensing. Multivariable logistic regression was used to examine factors associated with allopurinol nonadherence and attaining an SUA concentration < 6.0 mg/dl. We identified 13,341 patients with gout with incident allopurinol use (mean age 60 yrs, 78% men). Of these, 9581 patients (72%) had SUA measured both at baseline and during followup. Only 3078 patients (32%) attained an SUA target of < 6.0 mg/dl during followup. Potentially modifiable factors associated with treatment adherence and obtaining the SUA goal in the multivariable analysis included concomitant diuretic use, prescriber specialty, and allopurinol dosing practices. Adherent patients were 2.5-fold more likely than nonadherent patients to achieve an SUA < 6.0 mg/dl during observation.

Among patients with gout initiating allopurinol in our study, 68% did not reach the SUA goal and 57% of patients were nonadherent. Modifiable factors, including allopurinol dose escalation, treatment adherence, rheumatology referral, and concomitant medication use, could be important factors to consider in efforts aimed at optimizing gout treatment outcomes.

18F-fluoro deoxy glucose PET scanner (18F-FDG-PET-CT) has shown its interest in the diagnosis of polymyalgia rheumatica (PMR) and makes possible to evaluate the metabolic activity of the entire musculoskeletal system and in particular muscular structures. The purpose of this study was to evaluate muscle involvement using 18F-FDG-PET-CT in the case of PMR, compared to a non PMR population. This is a monocentric retrospective study of patients with PMR (ACR/EULAR 2012 criteria) who had an 18F-FDG-PET-CT examination. A control group composed of subjects without rheumatological manifestations who had such an examination as part of neoplastic research or follow-up of neoplastic diseases was also evaluated. The PET assessment included 17 sites suggesting a PMR, as previously reported. Areas of muscle hypermetabolism were classified in the same way according to the same semi quantitative classification. Muscle activity sites were identified. A comparison of patients with PMR with and without muscle damage was performed using the exact Mann-Whitney or Fisher test. Two hundred and one cases were examined, involving 101 PMRs (mean age 68.6 years) and 100 controls (mean age 67.7 years). Overall, PET muscle damage was observed in 34 cases (34%) in PMR and 10 cases (10%) in controls (P=0.004). Lesions are bi or multi-focal in half of the cases. The affected muscle sites are: spinal muscles 19, scapular girdle 14, pelvic girdle 13, and thigh 6. Fasciitis was found in 3 cases. In patients with PMR, PET muscle involvement was not associated with age, CRP or overall PMR PET score.

Muscle damage assessed by 18F-Fluorodeoxyglucose PET-CT is common in PMR (1/3 of cases), located at the usual sites of disease symptoms, without association with age, CRP levels or the overall PET PMR score. The muscle must be carefully evaluated during a PET examination in cases of PMR.

Patient-reported outcomes (PRO) in rheumatoid arthritis (RA) provide important information regarding disease effect. The study objective was to assess the frequency of PRO use in recent RA studies and compare results with a previous systematic review (SR) in 2005-2007. An SR was performed in PubMed MEDLINE (January 2015). Publications were identified using these MEdical Subject Headings terms: "arthritis, rheumatoid" with a limitation to "humans," "all adults: 19+ years," "English," "published in the last 2 years," and "clinical trials." All studies were assessed, whatever their designs. All PRO reported in publications were classified according to general domains of health by 2 authors. Statistics were descriptive. Two hundred fifty articles were analyzed. Of them, 113 (45.2%) were randomized controlled trials; 138 different PRO were reported. The most frequent PRO, similar to the 2007 SR, were function (68.0%), pain (40.0%), patient's global assessment (49.2%), and health-related quality of life (18.4%). Fatigue (14.4%), morning stiffness (10.0%), psychological status (9.6%), productivity losses (6.4%), utility (5.2%), sleep disturbance (2.4%), and coping (2.0%) were rarely reported. Although frequent domains were reported using well-validated questionnaires, the others were reported using heterogeneous questionnaires.

The PRO collected and reported in RA studies are remarkably consistent with those seen in 2005-2007, and reflect the existing RA Core Set measures. Other domains of health prioritized by patients including fatigue, psychological status, productivity losses, sleep disturbance, and coping remain rarely reported. Further, heterogeneity in outcome measures used presents challenges in interpreting true disease effect and response to therapy.

The New Zealand (NZ) Government has made a strong commitment to reduce the incidence of rheumatic fever (RF) by two thirds, to 1.4 cases per 100,000, by mid-2017. We reviewed the NZ RF surveillance sector, aiming to identify potential improvements which would support optimal RF control and prevention activities. This review used a recently developed surveillance sector review method. Interviews with 36 key informants were used to describe the sector, assess it and identify its gaps. Priorities for improvement and implementation strategies were determined following discussion with these key informants, with policy advisors and within the research team. Key improvements identified included the need for a comprehensive RF surveillance strategy, integrated reporting and an online national RF register. At a managerial level this review provided evidence for system change and built support for this across the surveillance sector.

The surveillance sector review approach can be added to the small set of tools currently available for developing and evaluating surveillance systems. This new approach is likely to prove useful as we confront the challenges of combating new emerging infectious diseases, responding to global environmental changes, and reducing health inequalities.

The aim of the present study was to ascertain the degree of occurrence of tuberculous infection in patients presenting with low back pain (LBP). Forty consecutive patients seeking primary medical attention for the main symptom of LBP and presenting to the Rheumatology Outpatient Clinic of our institution from January 2004 to June 2005, were recruited in this cohort study. All patients were thoroughly interrogated (occupational, trauma, infection, diabetes mellitus and medication history), subjected to a rigorous clinical examination and a battery of investigations Twelve of the 40 patients (33%) proved to have spinal TB as the cause of backache. Eight of these patients were above the age of 65. Five of the 12 patients with spinal TB also had concomitant osteoarthritic changes of the spine and two patients had concomitant disc prolapse. Eleven of the 12 patients with spinal TB had a completely normal chest X-ray and in 10 of these patients the plain X-ray of the lumbosacral region failed to show any significant lesion. In all 12 patients, sputum analysis failed to reveal acid-fast bacilli.

The findings of this study indicate that TB is a common cause of LBP that is liable to be overlooked in the differential diagnosis of LBP. Furthermore, evidence of concurrent active intrathoracic TB may be lacking and consequently a high level of suspicion is required. The need for prompt diagnosis and treatment of skeletal TB is of utmost importance to prevent serious bone and joint destruction and severe neurological sequelae. A reliable imaging modality for diagnosing spinal TB seems to be magnetic resonance imaging.

To simultaneously assess cardiovascular (CV) and gastrointestinal (GI) risk with traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and cyclo-oxygenase 2 (COX-2) inhibitors. Using the PHARMO Record Linkage System, including drug-dispensing and hospitalisation data of >2 million residents of The Netherlands, subjects with first hospitalisation for acute myocardial infarction (AMI), CV and GI events were identified. Use of COX-2 inhibitors and traditional non-selective NSAIDs was classified into remote, recent and current. Cases were matched to controls in a 1:4 ratio on age and event date. Multivariate analyses adjusted for gender, history of hospitalisations and medications. Compared to remote use, AMI risk was increased among current users of COX-2 inhibitors combined (adjusted odds ratio (OR) 1.73, 95% CI 1.37 to 2.19) and tNSAIDs combined (OR 1.41, 95% CI 1.23 to 1.61). AMI risk with celecoxib (OR 2.53, 95% CI 1.53 to 4.18), rofecoxib (OR 1.60, 95% CI 1.22 to 2.10), ibuprofen (OR 1.56, 95% CI 1.19 to 2.05) and diclofenac (OR 1.51, 95% CI 1.22 to 1.87) was significantly increased. CV risk with current use of individual COX-2 inhibitors and tNSAIDs was significantly increased (OR from 1.17 to 1.64), as was GI risk with current use of rofecoxib (OR 1.99, 95% CI 1.51 to 2.63), naproxen (OR 4.44, 95% CI 3.36 to 5.86), ibuprofen (OR 1.90, 95% CI 1.40 to 2.58), diclofenac (OR 4.77, 95% CI 3.94 to 5.76), other tNSAIDs (OR 2.59, 95% CI 2.08 to 3.21), but not celecoxib (OR 1.36, 95% CI 0.70 to 2.66). Compared to current use of celecoxib and AMI risk was significantly decreased with current use of naproxen (OR 0.48, 95% CI 0.26 to 0.87) only. GI risk was increased with current naproxen (OR 3.26, 95% CI 1.59 to 6.70) and diclofenac (OR 3.50, 95% CI 1.76 to 6.98).

AMI and CV risk increased similarly with individual COX-2 inhibitors and tNSAIDs, whereas GI risk was found to be greater with naproxen and diclofenac. Residual confounding and "channelling" cannot be excluded.

Hyperuricemia of gout can arise due to either overproduction or underexcretion of uric acid. Not all available urate-lowering therapies are equally effective and safe for use in patients with renal disease. The objective of this post-hoc analysis was to determine the effectiveness of the xanthine oxidase inhibitor febuxostat in reducing serum urate (sUA) levels in gouty patients who were either overproducers or underexcretors. Gouty subjects 18 to 85 years of age with sUA ≥ 8.0 mg/dl at baseline were enrolled in a Phase 2, 28-day, multicenter, randomized, double-blind, placebo-controlled trial and randomized to receive febuxostat 40 mg, 80 mg, or 120 mg daily, or placebo. The primary efficacy endpoint was the proportion of subjects with sUA < 6.0 mg/dl at Day 28. Secondary efficacy endpoints included percentage reductions in sUA and urinary uric acid (uUA) from baseline to Day 28. Of the 153 subjects, 118 (77%) were underexcretors (uUA ≤ 800 mg/24 h) and 32 (21%) were overproducers (uUA > 800 mg/24 h); baseline uUA data were missing for 3 subjects. Treatment with febuxostat led to the majority of subjects achieving sUA < 6.0 mg/dl at Day 28. Treatment with any dose of febuxostat led to significantly greater percentage reductions in uUA than that observed in the placebo group, for both underexcretors and overproducers.

Febuxostat is a highly efficacious urate-lowering therapy in patients with gout regardless of overproduction or underexcretion status.

To study effects of leflunomide on inflammatory and destructive processes in patients with early rheumatoid arthritis (RA). The trial included 33 patients (27 females and 6 males) with a significant diagnosis of RA (A CR criteria) aged 19 to 60 years and duration of the disease from 6 months to 3 years (15.97 +/- 9.70 months). The activity of the inflammatory process and treatment efficacy were assessed by severity of the articular syndrome, duration of morning stiffness (DMS), pain and the disease activity (VAS), device examination, the disease activity by DAS28 indices, etc. The articular syndrome was assessed by the number of painful joints (NPJ), number of swollen joints (NSJ), etc. The functional status of the patient was evaluated by Keitel test, HAQ and hand grip. Calculations were made of erosive arthritis progression rate (EAPR) and joint fissure narrowing progression rate (FNPR). All the patients received leflunomide (100 mg/day for 3 days, then 20 mg/day). A 12-month course was finished by 14 patients, 4 patients were withdrawn because of side effects, the rest--by social causes. To the end of the trial leflunomide reduced NPJ by 84%, NSJ--by 95%, DMS--by 88%, articular pain by VAS--by 66%, the disease activity by VAS--by 70%. A positive trend in DAS28 criterium was observed (a significant suppression of RA activity after 1 month of therapy by 18%, after 4 months--by 39%, after 6 months--by 43%, by the end of the treatment--by 48%). For the initial 6 months EAPR was 0.50 +/- 0.67, for the following 6 months it lowered to 0.37 +/- 1.00, while FNPR decreased to 1.14 +/- 1.26 vs. 1.31 +/- 2 58 for initial 6 months. A positive change of the level of type 3 matrix metalloproteinase (a 20% and 16% by month 4 and to the end of the trial, respectively) was registered.

A positive effect of leflunomide on RA inflammatory activity and progression rate of joint destruction was confirmed.

The initial degradation of collagen fibrils during osteoarthritic cartilage destruction depends on the cleavage at the collagenase site, for which there exist three major candidate enzymes: collagenase 1 (MMP-1), collagenase 2 (MMP-8), and collagense 3 (MMP-13). The objective of this study was to determine the quantitative expression as well as distribution levels in normal and osteoarthritic cartilage and synovium and in cultured articular chondrocytes with and without stimulation by Il-1 beta. Conventional and online PCR technology and immunohistochemistry were used to determine MMP-8 expression levels on the mRNA and protein level. Whereas conventional PCR analysis could demonstrate the presence of MMP-8 mRNA in normal and osteoarthritic chondrocytes, online quantitative PCR showed that only very minor amounts of MMP-8 mRNA expression is found in articular chondrocytes in vivo (and in vitro) and that there is no significant upregulation in osteoarthritic cartilage in vivo nor by Il-1 beta in vitro. The in vivo results were confirmed by the absence of significant protein staining with monoclonal antibodies for MMP-8 in normal and osteoarthritic chondrocytes.

The presented results confirm the presence of a very minor MMP-8 expression by articular chondrocytes, but clearly question the hypothesis that MMP-8 is a major cartilage matrix degrading protease and is involved in enhanced cartilage matrix breakdown in osteoarthritic cartilage degeneration or by Il-1 beta stimulation in vitro.

The aim of this work was to point out the meaning of pyrocarbon spacer as replacement of the trapezium in case of rhizarthrosis. 32 Patients (20 female, 12 male) provided in our department between January 2005 and June 2008 with pyrocarbon spacer as replacement of the trapezium as a result of a radiologic as well as clinical documented rhizarthrosis. To rate the therapy a clinical and radiological examination was done and the score of Buck-Gramcko was used. Because of a complication in two patients the spacer was taken out and a suspension arthroplasty was done. Those two patients were not considered in the study. 80% good and very good results according to the score of Buck-Gramcko, 13.3% of satisfactory and 6.7% bad results were obtained. Dislocation of the implant is the main complication of the presented procedure.

With the presented procedure it is possible to achieve in the majority of the treated patients good and very good results. 4 dislocations in the examined collective and the price of the implant of 930 Euro has to be discussed critically.

To compare health-related quality of life (HRQL) and to identify clinical determinants for poor HRQL of patients with juvenile idiopathic arthritis (JIA) coming from three geographic areas. The HRQL was assessed through the Child Health Questionnaire (CHQ). A total of 30 countries were included grouped in three geographic areas: 16 countries in Western Europe; 10 in Eastern Europe; and four in Latin America. Potential determinants of poor HRQL included demographic data, physician's and parent's global assessments, measures of joint inflammation, disability as measured by Childhood Health Assessment Questionnaire (CHAQ) and erythrocyte sedimentation rate. Poor HRQL was defined as a CHQ physical summary score (PhS) or psychosocial summary score (PsS) <2 S.D. from that of healthy children. A total of 3167 patients with JIA, younger than 18 yrs, were included in this study. The most affected health concepts (<2 S.D. from healthy children) that differentiate the three geographic areas include physical functioning, bodily pain/discomfort, global health, general health perception, change in health with respect to the previous year, self-esteem and family cohesion. Determinants for poor HRQL were similar across geographic areas with physical well-being mostly affected by the level of disability while the psychosocial well-being by the intensity of pain.

We found that patients with JIA have a significant impairment of their HRQL compared with healthy peers, particularly in the physical domain. Disability and pain are the most important determinants of physical and psychosocial well-being irrespective of the geographic area of origin.

In a flare of osteoarthritis (OA) pain, increasing the dose of standard anti-inflammatory or routine analgesic drugs may not be practical because of an increased incidence of side effects. In patients achieving inadequate pain relief from traditional non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase (COX)-2-selective inhibitors, it may be appropriate to add an analgesic agent with a different mechanism of action, thereby targeting multiple components of the pain pathway. The addition of tramadol/acetaminophen tablets to existing therapy was compared with the addition of placebo in the treatment of OA flare pain. This was a multicenter, outpatient, randomized, double-blind, placebo-controlled, parallel-group, add-on study. Patients received 1 or 2 tramadol/acetaminophen (37.5 mg/325 mg) tablets QID or matching placebo for 10 days in addition to ongoing NSAID or COX-2-selective inhibitor therapy. The primary outcome measures were average daily pain intensity and average daily pain relief scores from days 1 through 5. Three hundred eight patients were randomized to tramadoUacetaminophen (n = 197) or placebo (n = 111) and were followed for up to 10 days. Patients had a mean (+/-SD) age of 60.1 +/- 9.87 years, and were predominantly female (71.8%) and white (87.7%). Their mean (+/- SD) pain visual analog score at baseline was 73.2 +/- 11.8 mm, and their mean pain intensity score was 2.4 +/- 0.5 (on a scale from 0 = none to 3 = severe). Average daily pain intensity and pain relief scores were significantly improved with tramadol/acetaminophen compared with placebo on the primary assessment of efficacy from days 1 through 5 (both, P < 0.001) and on the assessment of efficacy from days I through 10 (both, P < 0.001) Tramadol/acetaminophen was significantly superior to placebo on the patients' and physicians' overall assessments of medication (both, P < 0.001) and on 3 of 4 subscales (pain [P = 0.004], physical function [P = 0.013], and overall [P = 0.008]) of the Western Ontario and McMaster Universities Osteoarthritis Index Questionnaire. The most common treatment-emergent adverse events with tramadol/acetaminophen were nausea, vomiting, and dizziness. No serious adverse events were reported in the tramadol/acetaminophen group.

In this study, addition of tramadol/acetaminophen to NSAID or COX-2-selective inhibitor therapy was well tolerated and effective in the treatment of OA flare pain.

Total knee arthroplasty (TKA) yields substantial improvements in quality of life for patients with severe osteoarthritis. Previous research has shown that TKA outcomes are inferior in patients with certain demographic and clinical factors. Length of stay (LOS) following TKA is a major component of costs incurred by healthcare providers. It is hypothesized that patient-related factors may influence LOS following TKA. The purpose of this systematic review and meta-analysis is to investigate these factors. Three databases (PubMed, Embase, and OVID Medline) were searched using variants of the terms "total knee arthroplasty" and "length of stay". Studies were screened and data abstracted in duplicate. The primary outcome was the effect of prognostic variables on LOS following TKA. Meta-analysis was performed using the Review Manager (RevMan) software (version 5.3. Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration, 2014). A total of 68 studies met all inclusion criteria for this review. These studies comprised 21,494,459 patients undergoing TKA with mean age 66.82 years (range, 15-95 years) and 63.8% (12,165,160 of 19,060,572 reported) females. The mean MINORS score was 7, suggesting that studies had a low quality of evidence. Mean LOS following TKA has steadily decreased over the past 4 decades, partially because of the implementation of fast-track programs. Demographic factors associated with increased LOS were age >70 years (mean difference [MD] = 0.81; 95% confidence interval [CI] = 0.38-1.24), female gender (MD = 0.32; 95% CI = 0.29-0.48), body mass index >30 (MD = 0.09; 95% CI = 0.01-0.16), and non-White race (MD = 0.20; 95% CI = 0.10-0.29). Clinical factors associated with increased LOS were American Society of Anesthesiologists score 3-4 vs 1-2 (MD = 1.12; 95% CI = 0.58 to 1.66), Charlson Comorbidity Index > 0 vs 0 (MD = 0.77; 95% CI = 0.32 to 1.22), and preoperative hemoglobin < 130 g/L (MD = 0.66; 95% CI = 0.34 to 0.98). IV, systematic review, and meta-analysis of level III and IV evidence.

This systematic review and meta-analysis showed that increased age, female gender, body mass index ≥ 30, non-White race, American Society of Anesthesiologists > 2, Charlson Comorbidity Index > 0, and preoperative hemoglobin < 130 g/L were predictors of increased LOS. Mean LOS has steadily decreased over the past decades with the implementation of perioperative "fast-track" programs. Future research should investigate the benefits of preoperative risk factor modification on LOS, in addition to novel surgical approaches, anesthetic adjuvants, and physiotherapy modifications.

The purpose of this retrospective multicentric study was to evaluate the long-term effects of lateral meniscectomy and to identify those patients who are at the most risk of developing osteoarthritis (OA). Eighty-nine arthroscopic partial lateral meniscectomies in stable knees with a mean follow-up of 22 ± 3 years were included. The following influencing factors were analyzed: age, sex, body mass index (BMI), physical activity, alignment, the types of meniscal lesions, the extent of meniscal resections and the initially associated cartilage lesions. An independent examiner reviewed all patients, using subjective (KOOS and IKDC scores) and objective clinical and radiological evaluations (IKDC score). The contralateral knee was used as a reference to calculate the prevalence and the incidence of OA. The mean age at the time of surgery was 35 ± 13 years. The main location of the lesions was the mid-section of the lateral meniscus (79% of the cases). At the latest follow-up, 48% of the patients had an active lifestyle with as many as 48% of the patients enjoying moderate to intense physical activity 22 years after the procedure (vs. 71% before surgery). The KOOS score evolved from 82 to 69% during the same period. The prevalence of OA was 56% in the affected knee and the difference of prevalence between the operated and healthy knees was 44%. In those patients presenting with an OA of the operated knee and a normal contralateral knee, the incidence of OA was 53%. Predictors of OA were an age superior to 38 years at the time of surgery, obesity (BMI >30), and valgus malalignment as well as the presence of cartilage and degenerative meniscal lesions at the time of surgery. IV.

In the long term, arthroscopic partial lateral meniscectomy in stable knees without initial cartilage lesions might yield good to excellent results in young patients. Patients are at higher risk to develop symptomatic OA if they are over 40, having a high BMI, valgus malalignment and cartilage lesions at the time of surgery. This study provides precise guidelines for the surgical treatment of lateral meniscus tears.

As most of the previous studies were done to study depressive disorders and/or symptoms in patients with rheumatoid arthritis, this study was performed to investigate whether anxiety disorder is as common as depressive disorder in these patients and to look for the socio-demographic as well as the clinical characteristics of the patients developing these disorders. A detailed physical assessment of 80 patients with rheumatoid arthritis was performed. Also psychiatric assessment was done using Research Diagnostic Criteria for the International Classification of Diseases-10 (ICD-10). In addition, patients answered a Health Assessment Questionnaire (HAQ) to assess their functional capacity. Depression was diagnosed in 66.2% of the total sample while anxiety was diagnosed in 70%. Functional disability, social stress and morning stiffness were the factors highly associated with depression. Using multiple regression analysis, anxiety was highly associated with depression as well as Ritchie articular index.

Psychiatric illness is a relatively common disorder in patients with RA, with a frequency higher than that of other general medical conditions. Anxiety is a more common disorder than depression. The first step in correct management is recognition of anxiety and depression so that appropriate treatment can be tried. Particular attention has to be paid to social stress and lack of social support.

Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by new bone formation. Recent evidence suggests that new bone formation in AS may be due to upregulation of Wnt signaling in the osteoblastic pathway secondary to low serum Dickkopf homolog 1 (Dkk-1) levels. And miR-29a orchestrates osteoblast differentiation through direct targeting and negative regulation of Dkk-1. We initially validated the expression levels of miR-29a in the peripheral blood mononuclear cells (PBMCs) of AS patients (n = 30), rheumatoid arthritis (RA) patients (n = 30) and healthy controls (n = 30) using real-time quantitative reverse transcription PCR (qRT-PCR). Correlation analysis was assessed between miR-29a level in PBMCs of AS patients and disease activity indexes, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis function index (BASFI) and modified Stoke ankylosing spondylitis spinal score (mSASSS). Significantly higher expression of miR-29a was observed in PBMCs of AS patients (Ct 9.18 ± 1.96) compared with that in RA patients (10.97 ± 0.70, p < 0.001) and healthy controls (Ct 11.45 ± 1.23, p < 0.001). There was no significant difference between RA patients and healthy controls in miR-29a expression (p > 0.05). Elevated miR-29a expression is not correlated with disease activity index (p > 0.05). A weak correlation was found between elevated miR-29a expression and mSASSS (r = -0.393, p = 0.032).

We report for the first time elevated miR-29a expression in PBMCs of patients with ankylosing spondylitis, and miR-29a might be used as a useful diagnostic marker in new bone formation but cannot reflect disease activity.

Patient-reported outcome measures are increasingly recognized as an important tool in quantifying the clinical success of arthroplasty surgery. The aim of this study is to measure post-operative joint awareness and satisfaction in patients with and without a quantitatively balanced knee following primary total knee arthroplasty (TKA). In this multi-center study, a total of 318 eligible patients were assigned to one of the 2 patient groups: sensor-guided TKA or surgeon-guided TKA. In the sensor-guided group, quantitative balancing was performed according to intercompartmental tibiofemoral load measurements measured by an instrumented tibial trial component. In contrast, for the surgeon-guided group, the knees were balanced according to the surgeons' standard manual techniques while blinding the surgeon to the sensor measurements. Patients were blinded to their allocation and filled out the validated Forgotten Joint Score and 2011 Knee Society Satisfaction questionnaires at 6 weeks and 6 months. For the purposes of this study, the subjects were pooled and stratified by their state of soft tissue balance, based on the mediolateral load differential through the range of motion. In the surgeon-guided group, approximately 50% of the cases yielded a quantitatively balanced knee. Significantly more balanced knees were observed in the sensor-guided group (84.0%). More importantly, for both outcome measures, the balanced group of patients reported significantly better outcomes scores.

This demonstrates that using sensor feedback during knee arthroplasty surgery results in a more reproducible procedure, resulting in a higher percentage of balanced patients who in turn demonstrate superior clinical outcomes compared to unbalanced patients.

To observe the effect of bizhongxiao (BZX) decoction on the expression of VEGF in the synovial membrane of C II-induced arthritis(CIA) in rats and to explore the mechanism of BZX decoction in the treatment of rheumatoid arthritis RA. Seventy-five SD rats were randomly divided into four groups. The rat experimental arthritis model was established by subcutaneous injection of II collogen. The expression of VEGF was detected with immunohistochemistry in different times. The incidence of arthritis in the rats immunized with C II was approximately 88.57%. The arthritis index of the model group was rising, but that of the BZX decoction group and the methotrexate (MTX) group were decreasing on the 30th day. No expression of VEGF was found in the synovial membrane of the normal group. The expression of VEGF of the model group was notably higher than that of the BZX decoction group and the MTX group in different times (P < 0.01). The expression of VEGF of the model group rose step by step, but that of the BZX decoction group and the MTX group decreased and was significantly lower than that of the model group (P < 0.01). The expression of VEGF of the BZX decoction group was significantly lower than that of the MTX group(P < 0.05).

The expression of VEGF is relative to the synovial pannus formation in RA. BZX decoction and MTX could decrease the expression of VEGF, but the curative effect of BZX decoction is significantly better than that of MTX. BZX decoction could inhibit the formation of the synovial pannus or bone in RA by decreasing the expression of VEGF.

A large number of activated T cells are found in the joints of patients with rheumatoid arthritis (RA). Interleukin 7 (IL7), a T cell growth factor and a regulator of Th1 and Th2 cytokine production, is produced by synoviocytes from patients with RA. To investigate the effect on proinflammatory cytokine production of synovial fluid mononuclear cells (SFMC) and the mechanism by which IL7 influences CD4+ T cell activity in patients with RA. In a cross sectional group of patients with RA, IL7 levels were compared with those of healthy controls and related to disease activity. The effect of IL7 on cytokine production was tested by RA SFMC and on SF CD4+ T cells in the presence of mononuclear cells (MC). Production of tumour necrosis factor alpha (TNF alpha), IL1 beta, interferon gamma (IFN gamma), and IL4 was measured by enzyme linked immunosorbent assay (ELISA) and by single cell FACS analysis. Expression of the IL7 receptor alpha chain on CD4+ T cells (essential for IL7 signalling) was assessed. Direct effects of IL7 on isolated synovial fluid (SF) CD4+ T cells were studied by cytokine analysis. By neutralisation of IL12 in MC cultures, indirect effects of IL7 on T cells through accessory cells were studied. IL7 serum levels were higher in patients with RA than in healthy controls and correlated positively with C reactive protein levels. IL7 stimulated TNFalpha production by SFMC and very potently stimulated IFN gamma and TNF alpha production by SF CD4+ T cells. These effects were probably mediated through the IL7 receptor alpha chain, which was abundantly expressed on SF CD4+ T cells. Besides the direct stimulation of T cell cytokine production by IL7, its action was partly dependent on IL12, indicating that IL7 also stimulates accessory cell function, leading to T cell activation.

IL7 stimulates proinflammatory cytokine production of intra-articular CD4+ T cells and accessory cells from patients with RA. The correlation with measures of disease activity indicates that IL7 might substantially contribute to the perpetuation of Th1 and TNF alpha mediated proinflammatory responses in patients with RA.

Latino patients are overrepresented among cases of coronavirus disease 2019 (COVID-19) and are at an increased risk of severe disease. Prevalence of COVID-19 in Latinos with rheumatic diseases is poorly reported. This study was undertaken to characterize COVID-19 clinical features and outcomes in Latino patients with rheumatic diseases. We conducted a retrospective study of Latino patients with rheumatic diseases from an existing observational cohort in the Washington, DC area. Patients seen between April 1, 2020 and October 15, 2020 were analyzed in this study. We reviewed demographic characteristics, body mass index (BMI), comorbidities, and use of immunomodulatory therapies. An exploratory classification and regression tree (CART) analysis along with logistic regression analyses were performed to identify risk factors for COVID-19 and rheumatic disease flare. Of 178 Latino patients with rheumatic diseases, 32 (18%) were identified as having COVID-19, and the incidence rate of infection was found to be 3-fold higher than in the general Latino population. No patients required intensive care unit-level care. A CART analysis and multivariable logistic regression analysis identified a BMI of >30.35 as a risk factor for COVID-19 (odds ratio [OR] 3.37 [95% confidence interval (95% CI) 1.5-7.7]; P = 0.004). COVID-19 positivity was a risk factor for rheumatic disease flare (OR 4.57 [95% CI 1.2-17.4]; P = 0.02).

Our findings indicate that Latino patients with rheumatic diseases have a higher rate of COVID-19 compared with the general Latino population. Obesity is a risk factor for COVID-19, and COVID-19 is a risk factor for rheumatic disease flare. Latino patients with risk factors should be closely followed up, especially post-COVID-19 in anticipation of disease flare.

To contrast and compare the spectrum of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) with rheumatoid arthritis (RA) using an illustrative case. The relevant English literature of RS3PE was searched using the keywords "RS3PE" alone and in combination with terms such as neoplasia and rheumatic disease. Original and review articles were reviewed and the clinical setting was exemplified with a case report. RS3PE initially was reported to represent a form of RA. However, RS3PE has clinical features that are different from both early- and late-onset RA, such as lack of bony erosions and rheumatoid factor. RS3PE is thought to involve vascular endothelial growth factor, suggesting an infectious etiology, generally has an excellent prognosis, and is associated with neoplasia not commonly seen in RA, and the RA associated human leukocyte antigen (HLA) DRB1 genotype is absent.

Based on the clinical, laboratory, suspected infectious etiology, genetic differences, and types of associated malignancies, RS3PE appears to be a distinct entity rather than a subset of RA.

To detect the disparity of three cytokines interleukin-6 (IL-6), interferon-inducible protein 10 (IP-10) and interleukin-17 (IL-17) in peripheral blood (PB) and synovial fluid (SF) of patients with juvenile idiopathic arthritis (JIA). Serum concentrations of the three cytokines were measured in 27 patients with 13 systemic-onset JIA (sJIA), 14 polyarticular JIA (pJIA) and 28 healthy controls using enzyme-linked immunosorbent assay (ELISA). Nineteen patients with no marked arthritis symptom or only temporary arthralgia were enrolled in probable sJIA group. SF from 18 patients with 7 sJIA, 11 pJIA were examined for cytokine levels. (1) The statistically significant difference in serum IL-6 was detected between sJIA and healthy control group [28.0(4.2-59.2) ng/L vs. 12.3 (2.1-13.8) ng/L, P < 0.05], but no significant difference between probable sJIA and healthy control group [11.8(7.7-39.2) ng/L vs. 12.3 (2.1-13.8) ng/L, P > 0.05] was found. There were statistically significant differences between sJIA group and healthy control group in serum concentrations of IL-17 [14.0(9.8-34.3) ng/L vs. 9.8 (7.9-16.2) ng/L, P < 0.05], yet compared to healthy control group, no significant difference in concentration level of IL-17 was found in pJIA Group [14.2(9.9-16.9) ng/L vs. 9.8(7.9-16.2) ng/L, P > 0.05].(2) In sJIA and pJIA SF, the median IP-10 level was significantly higher compared to respective PB levels [619.7 (160.9, 873.1) ng/L vs. 64.8 (27.4-111.9) ng/L;660.9 (401.9, 1349.8) ng/L vs. 97.4 (41.9-222.1) ng/L, P < 0.01, respectively], but there was only significant difference in IL-17 between pJIA SF and PB [22.9 (17.1, 45.8) ng/L vs. 14.2 (9.9-16.9) ng/L, P < 0.01].

IL-6 may play more important role in the pathogenesis of sJIA. Moreover, IL-6 may be the biomarker associated with arthritis in early JIA stage. Both autoinflammation and autoimmune response may be involved in the pathogenesis of sJIA. IL-17 enrichment may only occur in local joint, the levels of IL-17 in PB may not be significantly increased. The prominent expression gradient between SF and PB of IP-10 maybe the basis of performing chemotaxis and further causing joint damage.

To evaluate the efficacy and tolerability of N-[4 hydroxyphenyl] retinamide (4-HPR), a synthetic retinoid, in the treatment of rheumatoid arthritis (RA). An uncontrolled, open clinical trial with synovial biopsy pre- and postmedication to evaluate the clinical effects of 4-HPR as well as its effects on metalloproteinase gene expression. Twelve patients with severe, longstanding RA were enrolled in this study. Six patients withdrew before study completion, 2 because of drug toxicity, 2 because of a flare of RA, and 2 because of intercurrent medical problems. No patient met predetermined Paulus criteria treatment response, and there was no improvement in the laboratory parameters, except for a modest decrease in C-reactive protein. No decrease in messenger RNA for the metalloproteinases collagenase and stromelysin was seen in the 2 patients in whom paired synovial biopsies were obtained.

No beneficial clinical effect was observed with the retinoid 4-HPR in the treatment of severe, longstanding RA at the 300 mg/day dosage studied. The use of higher dosages is precluded by the observed toxicities. The effect of this drug in patients with early or mild disease was not studied. Although this particular retinoid was not effective in this pilot study, the use of other retinoids in RA should still be considered.

Osteoarthritis (OA) is a degenerative chronic illness that most frequently occurs in the knee joint. Daidzein (DZ) an isoflavone has anti-inflammatory and antioxidant activity. The aim of this study was to evaluate the effectiveness of DZ as a treatment for experimental knee OA (KOA) in rats. An experimental KOA model was induced by monosodium iodoacetate (MIA) in rats. Thereafter, 49 Wistar albino male rats (250-300 g, 12-16 weeks old) were randomly divided into 7 groups: C (healthy control); DC (KOA + saline); hyaluronic acid (HA); HA+ intraarticular (ia) DZ; oral (po) DZ; ia DZ; HA + po DZ groups. DZ and/or HA were administered intraarticularly to the rats as 50 μL on days 1, 7, 14, and 21. Alternatively, the DZ was administered orally as 0.5 mL twice daily for 21 days. After the treatment, rats were sacrificed by decapitation under general anesthesia. Serum samples were analyzed to determine the total oxidant status (TOS) and total antioxidant status (TAS) and the levels of TNF-α, IL-1β, MMP-13, and DZ. Knee joint samples underwent histopathological examination, and TNF-α, IL-1β, NOS2, and MMP-13 were analyzed with immunohistochemical methods. HA, DZ, and DZ + HA effectively reduced the levels of TNF-α, IL-1β, and MMP-13 in the serum of the DC group (p < 0.001). In groups that received HA, DZ, or DZ + HA, the serum TAS increased compared with the DC group (p < 0.05). When the DZ + HA combination was used, a more pronounced reduction in the levels of TNFα, NOS2, IL-1β, and MMP-13 was observed in knee joints. In addition, the cracks on the cartilage surface and fibrillation were completely improved in the groups that received HA, DZ, or DZ + HA compared with the DC group.

DZ had anti-inflammatory and antioxidant effects in a rat OA model. Therefore, DZ, as monotherapy or especially in combination with HA, may be a promising and beneficial therapy for OA. Key Points •DZ has been shown to reduce TNF-α, IL-1β, and MMP-13 both in serum and in tissue samples taken from the knee-joints. •The cracks on the cartilage surface and fibrillation in KOA were completely improved by using DZ and DZ + HA combination. •DZ may be useful to eliminate/reduce/ameliorate inflammation and oxidative damage in the pathogenesis of KOA. •DZ, alone or in combination with HA, may be a promising natural compound with beneficial effects in the treatment of KOA.

Anti-citrullinated protein antibodies (ACPA) are associated with increased risk for rheumatoid arthritis. To investigate the effect of the presence and levels of ACPA on arthritis development in patients with arthralgia. Patients with arthralgia positive for ACPA or IgM rheumatoid factor (IgM-RF) were tested for the shared epitope (SE) and were prospectively followed up for at least 12 months. Absence of clinical arthritis at inclusion and arthritis development during follow-up were independently confirmed by two investigators. Cox regression hazard analyses were used to calculate hazard ratios (HRs) for arthritis development. 147 patients with arthralgia were included (50 ACPA positive, 52 IgM-RF positive and 45 positive for both antibodies). After a median follow-up of 28 months (interquartile range (IQR) 19-39), 29 patients developed arthritis in a median of 4 (IQR 3-6) joints and 26 (90%) of these were ACPA positive. The presence of ACPA (HR = 6.0; 95% confidence interval (95% CI) 1.8 to 19.8; p = 0.004), but not of IgM-RF (HR = 1.4, 95% CI 0.6 to 3.1) nor the SE (HR = 1.5, 95% CI 0.7 to 3.0), was associated with arthritis development. Within the group of ACPA-positive patients, the risk for arthritis was enhanced by the presence of IgM-RF (HR = 3.0; 95% CI 1.4 to 6.9; p = 0.01) and high ACPA levels (HR = 1.7; 95% CI 1.1 to 2.5; p = 0.008), but not the SE (HR = 1.0; 95% CI 0.5 to 2.1; p = 1.0).

In patients with arthralgia the presence of ACPA (but not of IgM-RF or SE) predicts arthritis development. The risk in ACPA-positive patients may be further increased by the concomitant presence of IgM-RF or high levels of ACPA.