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To identify risk factors for opioid consumption after arthroscopic meniscectomy using a large national database. Patients undergoing primary arthroscopic meniscectomy from 2007 to 2016 were retrospectively accessed from the Humana database. Patients were categorized as those who filled opioid prescriptions within 3 months (OU), within 1 month (A-OU), between 1 and 3 months (C-OU), and never filled opioid prescriptions (N-OU) before surgery. Rates of opioid use were evaluated preoperatively and longitudinally tracked for each cohort. Prolonged opioid use was defined as continued opioid prescription filling at ≥3 months after surgery. Multiple logistic regression analysis was used to identify factors associated with opioid refills at 12 months after surgery. There were 88,120 patients (53.7% female) who underwent arthroscopic meniscectomy, of whom 46.1% (n = 39,078) were N-OU. About a quarter (25.3%) of patients continued filling opioid prescriptions at 1 year postoperatively. In addition, opioid fill rate at 1 year was significantly greater in the OU group compared with the N-OU group with a relative risk of 2.89 (40.7% vs 14.1%; 95% confidence interval 2.81-2.98; P < .0001). Multiple logistic regression model identified C-OU (odds ratio 3.67; 95% confidence interval 3.53-3.82; P < .0001) as the strongest predictor of opioid use at 12 months postoperatively. Furthermore, male sex, A-OU, knee osteoarthritis, diabetes mellitus, hypertension, chronic obstructive pulmonary disease, fibromyalgia, anxiety or depression, alcohol use disorder, and tobacco use (P < .02 for all) had significantly increased odds of opioid use at 12 months postoperatively. However, patients <40 years (P < .0001) had significantly decreased odds of opioid use 12 months postoperatively. Level-III, Retrospective Cohort Study.

Preoperative opioid filling is a significant risk factor for opioid use at 12 months postoperatively. Male sex, preexisting knee osteoarthritis, and diagnosis of anxiety or depression were independent risk factors for opioid use 12 months following arthroscopic meniscectomy.

To assess which clinical features are most important for patients, parents, and clinicians in the course of juvenile idiopathic arthritis (JIA). Forty-nine people participated in 6 audience-specific focus group discussions and 112 reciprocal interviews in 3 Canadian cities. Participants included youth with JIA, experienced English- and French-speaking parents, novice parents (<6 mos since diagnosis), pediatric rheumatologists, and allied health professionals. Participants discussed the importance of 34 JIA clinical features extracted from medical literature. Transcripts and interview reports underwent qualitative analysis to establish relative priorities for each group. Most study participants considered medication requirements, medication side effects, pain, participant-defined quality of life, and active joints as high priority clinical features of JIA. Active joint count was the only American College of Rheumatology core variable accorded high or medium priority by all groups. Rheumatologists and allied health professionals considered physician global assessment as high priority, but it had very low priority for patients and parents. The parent global assessment was considered high priority by clinicians, medium to high by parents, and low by patients. Child Health Assessment Questionnaire scores were considered low priority by patients and parents, and moderate or high by clinicians. The number of joints with limited motion was given low to very low priority by all groups. Parents gave high priority to arthritis flares.

If our findings are confirmed, medication requirements, medication side effects, pain, participant-defined quality of life, and active joint counts should figure prominently in describing the course of JIA.

Visual disorders, even blindness, are serious complications of polymyalgia rheumatica (PMR) associated with temporal arteritis. Their early recognition in patients at high risk is essential to avoid the development of such visual disorders. It was the aim of this study to identify these risk factors. Clinical and laboratory data and biopsy findings in 131 patients (94 women, 37 men; mean age 74 years) with PMR and concomitant temporal arteritis were analysed retrospectively. Visual disorders occurred in 61 of the 131 patients. Temporal artery biopsy was not sufficient to detect those at high risk. But this was possible by identifying a typical clinical pattern in that most patients with visual disorders had severe cerebral symptoms, while they had only minor forms of PMR and few generalized symptoms. There was no correlation between any of the laboratory tests and high risk.

A typical pattern of clinical manifestations can provide early identification of those patients who have PMR associated with temporal arteritis and are at high risk of developing visual disorders.

To describe a semi-quantitative scoring method for multi-feature, whole-organ evaluation of the knee in osteoarthritis (OA) based on magnetic resonance imaging (MRI) findings. To determine the inter-observer agreement of this scoring method. To examine associations among the features included in the scoring method. Nineteen knees of 19 patients with knee OA were imaged with MRI using conventional pulse sequences and a clinical 1.5 T MRI system. Images were independently analyzed by two musculoskeletal radiologists using a whole-organ MRI scoring method (WORMS) that incorporated 14 features: articular cartilage integrity, subarticular bone marrow abnormality, subarticular cysts, subarticular bone attrition, marginal osteophytes, medial and lateral meniscal integrity, anterior and posterior cruciate ligament integrity, medial and lateral collateral ligament integrity, synovitis/effusion, intraarticular loose bodies, and periarticular cysts/bursitis. Intraclass correlation coefficients (ICC) were determined for each feature as a measure of inter-observer agreement. Associations among the scores for different features were expressed as Spearman Rho. All knees showed structural abnormalities with MRI. Cartilage loss and osteophytes were the most prevalent features (98% and 92%, respectively). One of the least common features was ligament abnormality (8%). Inter-observer agreement for WORMS scores was high (most ICC values were >0.80). The individual features showed strong inter-associations.

The WORMS method described in this report provides multi-feature, whole-organ assessment of the knee in OA using conventional MR images, and shows high inter-observer agreement among trained readers. This method may be useful in epidemiological studies and clinical trials of OA.

To investigate the patterns of healthcare use (HCU) at the last year of life in persons with osteoarthritis (OA). Using linked registers, we identified persons aged≥ 65 years who died during 2003-2014 and were resided in the Skåne region during 5-year prior to death. Among these, we randomly matched decedents with a principal OA diagnosis prior to the last year of life (OA cohort, n = 17,993) with up to 4 comparators without OA by sex, age at death, and year of death (n = 59,945). We measured monthly HCU for each decedent during last year of life and applied two-part regression models to estimate HCU attributable to OA. Group-based trajectory modelling (GBTM) was used to detect distinct trajectories of HCU within the OA cohort. During last 12-month of life, each person with OA had, on average, 2.5 (95% CI 2.2, 2.7) excess healthcare consultations and 1.8 (95% CI 1.3, 2.2) more inpatient days than those without OA. While both cohorts observed increasing trends in HCU towards death, excess healthcare consultations attributable to OA declined and inpatient days increased as death approached. For both healthcare consultations and inpatient days, GBTM identified four distinct trajectory classes. While underlying cause of death and age were the most important predictors of class membership, the overall predictive accuracy was poor.

OA was associated with excess HCU especially hospital-based care during the last year of life. However, there seem to be distinct trajectory classes within the OA patient population.

To determine the clinical value of a novel osteoarthritis (OA) biomarker in detecting canine cruciate disease. Cross sectional clinical study. Dogs (n=22) with cranial cruciate ligament (CCL) rupture and 12 control dogs. Concentrations of collagenase-generated cleavage epitope of type II collagen (Col2-3/4C(long mono), or C2C) in serum, urine, and joint fluid were compared between a group of dogs with CCL rupture and a control group. Correlation of C2C concentrations to the clinical stage of stifle OA was also evaluated. There were no significant differences in C2C concentrations in serum, urine, and joint fluid between groups (P>.05). Subjective scores of lameness, joint effusion, osteophytosis were significantly more severe in the CCL rupture group compared with the control group (P<.05). There was no significant correlation of C2C concentrations with clinical stage of stifle OA (P>.05). C2C is not clinically useful in detecting CCL rupture in dogs.

This OA biomarker did not detect pathology associated with CCL rupture. Our results suggest that collagenase-specific degradation of type II collagen in articular cartilage may not be involved in the early stage of naturally occurring canine cruciate disease, and that pathology associated with naturally occurring CCL rupture is different from that of experimental OA model.

Genome-wide association studies in rheumatoid arthritis (RA) have failed to examine the FCGR gene cluster because of the confounding effects of segmental duplication. This study aimed to replicate previous candidate gene studies that had identified a significant association between the FCGR3A-158V allele and RA and then sought to estimate specific subgroup effects. FCGR3A-158F/V genotyping was undertaken in a UK Caucasian replication cohort comprising 2049 patients with RA and 1156 controls. Subgroup analyses assessing the magnitude of association according to gender and autoantibody (rheumatoid factor (RF) and cyclic citrullinated peptide (CCP)) status were undertaken in a pooled cohort of 2963 patients with RA and 1731 controls. Logistic regression was used to test for interaction between FCGR3A and HLA-DRB1 shared epitope (SE) alleles. In the combined RA cohort, borderline association with homozygosity was found for the FCGR3A-158V allele (OR 1.2, p=0.05), which was stronger in men (OR 1.7, p=0.01). Stratification by autoantibody status showed an increased risk in RF and CCP positive RA. Analysis of the FCGR3A-158V and HLA-DRB1 SE interaction revealed roles for both genes in susceptibility to autoantibody positive RA, with no evidence of interaction.

FCGR3A is a risk factor for the development of autoantibody positive RA, particularly in men, with evidence of a multiplicative effect with HLA-DRB1 SE.

To examine trends in the prevalence of rheumatoid vasculitis in a national US population comprising both hospitalized and ambulatory patients with rheumatoid arthritis (RA). In this serial cross-sectional study, we analyzed data on hospitalized and ambulatory patients spanning 22 years (1985-2006) and 10 years (1997-2006), respectively, to determine the prevalence of rheumatoid vasculitis, as defined by the International Classification of Diseases, Ninth Revision. Our search encompassed data collected on a predominantly male study population during 10 million hospitalizations and outpatient visits, and included annual data on >37,000 RA patients. To test for a decrease in rheumatoid vasculitis prevalence, breakpoint analysis was performed using stepwise Chow and Durbin-Watson tests. There was a clear decline in the prevalence of rheumatoid vasculitis, and this decline remained evident even after accounting for a decreased number of hospitalizations among RA patients. Peak prevalence occurred among hospitalized patients in the 1980s, and prevalence gradually declined throughout the 1990s. Furthermore, simultaneous breakpoints representing a significant drop in rheumatoid vasculitis prevalence between the years 2000 and 2001 were demonstrated for both inpatients (P < 0.000) and outpatients (P < 0.003). The prevalence of vasculitis dropped 53% among inpatients and 31% among outpatients between 2000 and 2001.

Our results demonstrate a significant decline in rheumatoid vasculitis prevalence after 2000 in this nationwide sample of hospitalized and ambulatory patients. The clear, consistent drop in prevalence provides an opportunity for the formulation of causal hypotheses, including consideration of the impact of biologic agents used to treat RA, on rheumatoid vasculitis.

Cardiovascular mortality is increased in patients with rheumatoid arthritis (RA). RA is associated with an increased left ventricular mass index (LVMI), a strong marker of cardiovascular mortality, and vessel abnormalities. Experimental studies have suggested that tumour necrosis factor α (TNFα) may induce LV hypertrophy. To study the effect of medium-term (3- and 6-months) treatment with the TNFα inhibitor etanercept (ETN) and synthetic disease-modifying antirheumatic drugs (sDMARDs) on LV morphological features and arterial stiffness in patients with RA. Consecutive female patients with active RA requiring treatment with ETN (n=28) or sDMARDs (n=20) were included. Clinical and biological monitoring, echocardiography and pulse wave velocity (PWV) assessment were performed at inclusion and at 3 and 6 months after the start of treatment. Paired t tests and multivariate linear regression analysis were used. Mean LVMI tended to be higher at baseline in the ETN group than in the sDMARD group (96.5±19.8 vs 84.3±26.8 g/m2; p=0.11 for the ETN and sDMARD groups, respectively). In patients with ETN treatment, mean LVMI was significantly decreased at 3 and 6 months (-6.3±7.6 and -14.2±9.3 g/m2; p<0.001), with no change from baseline for patients with sDMARD treatment (-2.2±10.9 and -2.7±10.2 g/m2, respectively). Blood pressure (BP) and aortic PWV were not changed by either treatment.

ETN induced a significant decrease in LVMI with medium-term treatment with no change in BP or PWV. TNFα may be an important factor of LV hypertrophy, which may explain the benefit of TNF inhibitors on cardiovascular morbidity and mortality in RA. These results need to be confirmed by larger studies and with other TNF inhibitors.

Patients with rheumatoid arthritis (RA) have an increased cardiovascular event rate, mainly due to the arterial stiffness which leads to coronary atherosclerosis and concentric left ventricular (LV) geometry. These conditions predispose to LV systolic dysfunction (LVSD), which can be detected by stress-corrected mid-wall shortening (sc-MS), an early prognosticator of cardiovascular events in asymptomatic patients with arterial hypertension and/or diabetes. In these subjects, sc-MS is frequently impaired even though LV ejection fraction (LVEF) is preserved. In this study, we analyzed the prevalence and the factors associated with asymptomatic LVSD measured by sc-MS among patients with RA and verified whether RA per se was independently related to LVSD. We prospectively recruited 198 outpatients with RA without overt cardiac disease between January and June 2014 and compared them to 198 controls matched for age, gender, body mass index, and prevalence of hypertension and diabetes. sc-MS was taken as index of LVSD and considered impaired if <86.5%. Impaired sc-MS was detected in 110 (56%) RA patients and in 30 (15%) controls (P < 0.001), whereas LVEF was impaired (value <50%) in six (3%) RA patients and in two (1%) controls (P = ns). Multiple logistic regression analysis revealed that RA was independently associated with impaired sc-MS (Exp β 2.01 [CI 1.12-3.80], P = 0.02) together with increased LV mass and concentric geometry.

More than half RA patients without overt cardiac disease have LVSD detectable by sc-MS. RA emerges as a condition closely related to LVSD. These findings might explain the high risk for adverse cardiovascular events in RA patients.

Infliximab, a monoclonal antibody directed against tumour necrosis factor, is widely used in the treatment of chronic inflammatory conditions including Crohn's disease and rheumatoid arthritis. Its use is limited by development of anti-infliximab antibodies, which can lead to loss of therapeutic efficacy. Serum infliximab and anti-infliximab antibody measurements have recently become routinely available in the UK. The study aimed to assess the clinical utility of antibodies as an adjunct to trough infliximab. Serum trough infliximab was measured in 201 samples from 108 gastroenterology and rheumatology patients on maintenance infliximab therapy. Results were correlated with C-reactive protein concentrations. Total anti-infliximab antibodies were measured in 164 samples. The median (25th-75th percentile) trough infliximab was 3.7 µg/mL (1.2-5.2 µg/mL) and 23% of samples had a concentration ≤1 µg/mL. A notable proportion had positive anti-infliximab antibodies: 84/164 (51%), which subdivided to 85% and 28% with infliximab ≤1 and >1 µg/mL, respectively.Serum C-reactive protein was found to be significantly higher where infliximab was ≤1 compared to >1 µg/mL (10 mg/L [<5-24 mg/L] vs. <5 mg/L [<5-8 mg/L], P < 0.01), although a strict correlation was not observed. The relationship between trough infliximab and C-reactive protein differed depending on antibody status and there was no association between C-reactive protein and the presence or absence of antibodies.

Our findings support measurement of anti-infliximab antibodies only in the context of low infliximab concentrations <1 µg/mL. A higher therapeutic cut-off may be relevant in patients with negative antibodies. Further work is indicated to investigate the clinical significance of positive antibodies with therapeutic infliximab concentrations.

To assess the prevalence of rheumatic diseases in Greek urban, suburban, and rural adult general populations. This cross-sectional population based epidemiological study of rheumatic diseases in Greece (the ESORDIG Study) was conducted on the total adult population of 2 urban, one suburban, and 4 rural communities (8547 subjects), as well as on 2100 out of 5686 randomly selected subjects in one suburban and one rural community. The study, based on a standardized questionnaire and clinical evaluation and laboratory investigation when necessary, was carried out by rheumatologists who visited the target population at their homes. Either established classification criteria or criteria set for the purposes of the study were used for diagnosis. A total of 8740 subjects participated in the study (response rate 82.1%). The overall age and sex adjusted prevalence (prevalence(asa)) of rheumatic diseases in the total target adult population was 26.9% (95% CI 26.2-27.6), being significantly higher among women (33.7%) than men (19.9%) (p < 0.0005). Disease prevalence(asa) increased significantly with age (p < 0.0005). The most common disease group was low back pain, with a prevalence(asa) of 11.0%, followed by symptomatic peripheral osteoarthritis (7.9%), neck pain (4.8%), miscellaneous rheumatic disorders (4.4%), soft tissue rheumatism disorders (4.3%), and inflammatory rheumatic disease (2.1%). Logistic regression analysis showed a significant positive association of female or male sex, age >or= 50 years, high body mass index, low level of education, moderate or heavy alcohol consumption, and high socioeconomic level with particular diseases or disease groups.

These findings indicate rheumatic diseases are very common in the general adult population of Greece; 26.9% of adults currently have active or chronic rheumatic disease in remission.

Women with endometriosis may also have associated disorders related to autoimmune dysregulation or pain. This study examined whether the prevalence of autoimmune, chronic pain and fatigue and atopic disorders is higher in women with endometriosis than in the general female population. A cross-sectional survey was conducted in 1998 by the Endometriosis Association of 3680 USA members with surgically diagnosed endometriosis. Almost all responders had pain (99%), and many reported infertility (41%). Compared with published rates in the general USA female population, women with endometriosis had higher rates of hypothyroidism (9.6 versus 1.5%, P < 0.0001), fibromyalgia (5.9 versus 3.4%, P < 0.0001), chronic fatigue syndrome (4.6 versus 0.03%, P < 0.0001), rheumatoid arthritis (1.8 versus 1.2%, P = 0.001), systemic lupus erythematosus (0.8 versus 0.04%, P < 0.0001), Sjögren's syndrome (0.6 versus 0.03%, P < 0.0001) and multiple sclerosis (0.5 versus 0.07%, P < 0.0001), but not hyperthyroidism or diabetes. Allergies and asthma were more common among women with endometriosis alone (61%, P < 0.001 and 12%, P < 0.001 respectively) and highest in those with fibromyalgia or chronic fatigue syndrome (88%, P < 0.001 and 25%, P < 0.001 respectively) than in the USA female population (18%, P < 0.001 and 5%, P < 0.001 respectively).

Hypothyroidism, fibromyalgia, chronic fatigue syndrome, autoimmune diseases, allergies and asthma are all significantly more common in women with endometriosis than in women in the general USA population.

The purpose of this study was to examine the safety and efficacy of anti-tumour necrosis factor (TNF) agents (etanercept, infliximab and adalimumab) in HIV-positive patients with rheumatic diseases refractory to standard therapy. Patients were treated with anti-TNF blocker with rheumatic diseases refractory to disease modifying antirheumatic drugs who had a CD4 count of >200 mm3 and an HIV viral load of <60 000 copies/mm3 and no active concurrent infections. Changes in CD4 counts, HIV viral loads, or other adverse effects while on anti-TNF agents and clinical response were monitored for 28.1 (SD 20.9) months (range 2.5-55). Eight HIV-positive patients were treated with anti-TNF blockers (two patients with rheumatoid arthritis, three with psoriatic arthritis, one with undifferentiated spondyloarthritis, one with reactive arthritis and one with ankylosing spondylitis). No significant clinical adverse effect was attributed to this treatment in any patient. CD4 counts and HIV viral load levels remained stable in all patients. Three patients on etanercept therapy and two patients on infliximab had sustained clinical improvement in their rheumatic diseases.

This retrospective series of eight patients suggests that treatment with anti-TNF-alpha therapy is a viable alternative in HIV patients without advanced disease with associated rheumatic diseases refractory to standard therapy.

To determine the adequacy of calcium, folic acid, vitamin E, zinc, and selenium intake in patients with rheumatoid arthritis (RA). We conducted an observational study on 48 patients (13 men, 35 women; mean age, 64.5 years) with RA attending a specialty clinic in New Zealand comparing their dietary intake as measured by a 5-day dietary survey with recommended dietary intake (RDI) guidelines. Information on disease activity, functional ability, and drug therapy also was obtained. The percentage of patients who achieved the RDI was 23% for calcium, 46% for folic acid, 29% for vitamin E, 10% for zinc, and only 6% for selenium. Patients on methotrexate had a significantly reduced intake of folic acid as a percentage of RDI (P < .05) compared with those on other therapies. In contrast, dietary intake of iron and protein was largely adequate and unrelated to anemia.

Patients with RA should receive dietary education or supplementation to bring their intake of calcium, folic acid, vitamin E, zinc, and selenium up to the RDI.

The long-term results of rheumatoid arthritis are unsatisfactory despite the mono or combination therapy of conventional "disease-modifying antirheumatic drugs". Therefore in the recent past the administration of a combination of Methotrexate with Leflunomide takes place more frequently. To what extent the perioperative infection rate is influenced by the individual immune-modulating drugs, is still disputed and should quantified on the basis the rheumatism orthopaedic patient collective of an orthopaedic university clinic. The clinical progresses of patients after operative treatment in the orthopaedic hospital, since introduction of the Leflunomide, were evaluated with regard to perioperative infection. Of 16 patients, who were observed during a period of 1,5 years under a combination therapy by MTX/Leflunomide, three exhibited a heavy infection of the musculoskeletal system.

The combination of the two above mentioned drugs affects different pathophysiological processes. Synergistic effects in therapy but also with regard to side effects must be expected. First available reports on this combination therapy do not refer to a increased infection/risk. The observation of three serious infections under the combination MTX/Leflunomide prompted us to call attention to this risk. In particular with infection-susceptible bone-surgical operations such a combination of immune-modulating medicines should be employed with caution. The recent literature is discussed.

To identify variables and evaluate methods for assessing chronic pain in dogs. Prospective study. 41 dogs with canine hip dysplasia (CHD), and 24 apparently healthy dogs with no history of pain. 2 veterinarians evaluated the dogs' locomotion and signs of pain. Owners of dogs with CHD and control dogs answered a questionnaire regarding their dogs' demeanor, behavior, and locomotion (descriptive scales) and assessed pain and locomotion (visual analog scales). Plasma concentrations of several stress-related hormones were determined, and 13 radiologic variables were assessed in affected hip joints. For many of the questions, answers provided by owners of dogs with CHD differed significantly from those of owners of control dogs. Stress hormone concentrations differed significantly between dogs with CHD and controls, but individual variation was too great for them to be of value in pain assessment. None of the radiologic variables examined correlated well with owner or veterinarian pain scores.

Chronic pain could be assessed in dogs with CHD through completion of the study questionnaire by a person familiar with the pet (eg, owner) after receiving appropriate education in its use. Eleven variables were identified as being potentially useful in assessment of chronic pain in dogs.

To define the interaction between cigarette smoking and HLA polymorphisms in seropositive rheumatoid arthritis (RA), in the context of a recently identified amino acid-based HLA model for RA susceptibility. We imputed Immunochip data on HLA amino acids and classical alleles from 3 case-control studies (the Swedish Epidemiological Investigation of Rheumatoid Arthritis [EIRA] study [1,654 cases and 1,934 controls], the Nurses' Health Study [NHS] [229 cases and 360 controls], and the Korean RA Cohort Study [1,390 cases and 735 controls]). We examined the interaction effects of heavy smoking (>10 pack-years) and the genetic risk score (GRS) of multiple RA-associated amino acid positions (positions 11, 13, 71, and 74 in HLA-DRβ1, position 9 in HLA-B, and position 9 in HLA-DPβ1), as well as the interaction effects of heavy smoking and the GRS of HLA-DRβ1 4-amino acid haplotypes (assessed via attributable proportion due to interaction [AP] using the additive interaction model). Heavy smoking and all investigated HLA amino acid positions and haplotypes were associated with RA susceptibility in the 3 populations. In the interaction analysis, we found a significant deviation from the expected additive joint effect between heavy smoking and the HLA-DRβ1 4-amino acid haplotype (AP 0.416, 0.467, and 0.796, in the EIRA, NHS, and Korean studies, respectively). We further identified the key interacting variants as being located at HLA-DRβ1 amino acid positions 11 and 13 but not at any of the other RA risk-associated amino acid positions. For residues in positions 11 and 13, there were similar patterns between RA risk effects and interaction effects.

Our findings of significant gene-environment interaction effects indicate that a physical interaction between citrullinated autoantigens produced by smoking and HLA-DR molecules is characterized by the HLA-DRβ1 4-amino acid haplotype, primarily by positions 11 and 13.

Sleep disturbance is common among adults with osteoarthritis (OA), but little is known about patterns over time. In this cohort study, we identified restless sleep trajectories and associated factors in adults with or at high risk for knee OA. Longitudinal (2004-2014) restless sleep (≥3 nights/week) annual reports over 8 years from 4359 Osteoarthritis Initiative participants were analyzed. Group-based trajectory modeling identified heterogeneous temporal patterns. Logistic regression identified baseline health and behavioral predictors of trajectory membership. Four restless sleep trajectory groups were identified: good (69.7%, persistently low restless sleep probabilities), worsening (9.1%), improving (11.7%), and poor (9.5%, persistently high). Among 2 groups initially having low restless sleep prevalence, the worsening trajectory group had an increased likelihood of baseline cardiovascular disease (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.01-2.33), pulmonary disease (OR, 1.48; 95% CI, 1.07-2.05), lower physical activity (OR, 1.29; 95% CI, 1.03-1.61), knee pain (OR, 1.04; 95% CI, 1.00-1.07), depressive symptoms (OR, 1.03; 95% CI, 1.01-1.06), and a decreased likelihood of better mental health (OR, 0.97; 95% CI, 0.95-0.98) at baseline. Among 2 groups initially having high restless sleep prevalence, the poor group had an increased likelihood of baseline depressive symptoms (OR, 1.03; 95% CI, 1.00-1.05).

Four trajectories of restless sleep over 8 years were identified using data collected from over 4000 older adults aged 45 to 79 years with or at higher risk for knee OA. The presence of depressive symptoms, less physical activity, knee pain, poor mental health, cardiovascular disease, or pulmonary disease was each associated with unfavorable trajectories.

To assess relationships of acetabular volume (AV), femoral head volume (FV), and portion of the femoral head within in the acetabulum (FVIA) with each other and with degrees of hip joint laxity and degenerative joint disease from youth to maturity in dogs predisposed to developing hip joint osteoarthritis (OA). 46 mixed-breed half- or full-sibling hound-type dogs. The distraction index (DI), AV, FV, FVIA, and degree of osteoarthritis (OA score) were quantified in 1 hip joint at 16, 32, and 104 weeks of age. Relationships among variables were evaluated within and between ages. Ratios corresponding to OA scores were compared within ages. Differences among 16-week ratios corresponding to 32-week OA scores and among 16- and 32-week ratios corresponding to 104-week OA scores were evaluated. Significant positive relationships existed between FV and AV across ages as well as between FVIA/FV and FVIA/AV and between DI and OA score across and within most ages. Such relationships also existed within these variables across most ages. Negative relationships of DI and OA scores with FVIA/FV and FVIA/AV within and among all ages were significant. Sixteen-week AVs, FVs, and FVIAs were greater and FV/AVs and OA scores were less than 32- and 104-week values. The 32-week FVIA/FV was less than 16- and 104-week values, and the 32-week FVIA/AV was less than the 104-week value. The FVIA/FV and FVIA/AV were lower and the DI was higher with higher OA scores within and among most ages.

Structural volumes in lax canine hip joints changed predictably relative to each other during growth, despite degenerative changes. Measures developed in this study may augment current diagnosis and treatment strategies for hip dysplasia in dogs.

To evaluate the relationship between postoperative knee function and the sagittal position of tibial component in unicompartmental knee arthroplasty (UKA). We retrospectively enrolled the patients who underwent UKA from January 2016 to May 2020. They were assigned into 2 groups according to postoperative posterior tibial slope (PTS): the normal PTS group (PTS≥3° and PTS < 8°) and the abnormal PTS group (PTS < 3° or ≥8°). The patients were followed up for at least 12 months. The postoperative Knee Society Clinical Score (KSS-C), Knee Society Functional Score (KSS-F) and knee range of motion (ROM) were compared between the two groups. A total of 72 patients (82 knees) were included with 51 patients (58 knees) in PTS normal group and 21 patients (24 knees) in PTS abnormal group. All the patients were followed up with median of 23.6 months. There was no significant difference in the general data [gender, age, body mass index (BMI)], pre-operative knee range of motion, preoperative KSS-C score and KSS-F score (

The posterior tibial slope between 3° and < 8° can be recommended to improve knee joint function in mobile UKA, and excessive or insufficient PTS should be avoided.

Inflammatory arthritides including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) are associated with increased risk of cardiovascular disease. This process may be driven by systemic inflammation, and the use of tumour necrosis factor (TNF) inhibitors could therefore potentially reduce cardiovascular risk by reducing this inflammatory burden. The aims of this study were to evaluate whether the risk of cardiovascular events (CVEs) in patients with inflammatory arthritis is associated with treatment with anti-TNF therapy, compared with other biologics or non-biologic therapy, and to compare the CVE risk between participants with RA, PsA and AS. Data from consecutive participants in the Australian Rheumatology Association Database with RA, PsA and AS from September 2001 to January 2015 were included in the study. The Cox proportional hazards model using the counting process with time-varying covariates tested for risk of having CVEs, defined as angina, myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention, other heart disease, stroke/transient ischaemic attack or death from cardiovascular causes. The model was adjusted for age, sex, diagnosis, methotrexate use, prednisone use, non-steroidal anti-inflammatory use, smoking, alcohol consumption, hypertension, hyperlipidaemia, diabetes and functional status (Health Assessment Questionnaire Disability Score). There were 4140 patients included in the analysis, totalling 19,627 patient-years. After multivariate adjustment, the CVE risk was reduced with anti-TNF use (HR 0.85, 95% CI 0.76-0.95) or other biologic therapies (HR 0.81, 95% CI 0.70-0.95), but not in those who had ceased biologic therapy (HR 0.96, 95% CI 0.83-1.11). After adjustment, no significant difference in CVE risk was observed between participants with RA and PsA (HR 0.92, 95% CI 0.77-1.10) or AS (HR 1.14, 95% CI 0.96-1.36).

Current biologic use was associated with a reduction in major CVEs. No reduction in CVE risk was seen in those who had ceased biologic therapy. After adjustment, the CVE risk was not significantly different between RA, AS or PsA.

Most cases of chronic urticaria (CU) are idiopathic. Circumstantial evidence suggests that some CU cases have an autoimmune pathogenesis. Previous research indicates that a substantial percentage of patients with CU have an atopic background. This study aims to examine the association between CU, and atopic and autoimmune diseases. This population-based retrospective cohort study identified 9,332 patients with CU and 37,328 controls matched for age, sex, and number of dermatological clinic visits from the Taiwan National Health Insurance Research Database for 2004-2009. Using multiple logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for associations of CU with atopic and autoimmune diseases. CU was most strongly associated with Kawasaki disease (modified OR, 2.76; 95% CI 1.15-6.63), followed by Henoch-Schönlein purpura (HSP), atopic dermatitis (AD), systemic lupus erythematosus (SLE), allergic rhinitis (AR), autoimmune thyroid diseases, Sjögren syndrome, inflammatory bowel disease (IBD), and asthma, which had the lowest adjusted OR (1.11; 95% CI 1.01-1.22) among comorbidities significantly associated with CU. The associations varied in relation to age, group, and sex. Among women, CU was significantly associated with AD, AR, autoimmune thyroid diseases, SLE, vitiligo, and HSP. Among men, CU was significantly associated with AD, AR, autoimmune thyroid diseases, Kawasaki disease, and IBD.

CU is associated with atopic/autoimmune diseases. Increased awareness of atopic and autoimmune comorbidities may be warranted for patients with CU.

To examine the use of metho-trexate (MTX) in rheumatoid arthritis (RA) patients during the perioperative period. Systematic review of studies retrieved by a sensitive search strategy in Medline (1961-July 2007), Embase (1961-July 2007), Cochrane Library (up to July 2007), and from the abstracts of the ACR (2005, 2006) and EULAR (2005-2007) annual scientific meetings. (population) studies had to include patients with RA undergoing surgery; (intervention and control) studies had to test continuing MTX versus stopping MTX; and (outcomes), studies had to report complications within a year after the surgery including infections, wound morbidity, surgery complications, and RA flares. Only randomized controlled trials (RCT) or high quality cohort studies with a control group were included. Patients from the four included studies were mostly women with mean ages around 60. All of them underwent elective orthopaedic surgery and were taking MTX doses mainly from 5 mg/week to 10 mg/week. By order of level of evidence, we found two RCTs, in which continuing on MTX was not associated with increasing risk of surgery complications, but it was statistically associated with less RA flares. In a prospective cohort study, four infections were observed in the MTX group while none were observed in the control group. No disease flare was reported in any group. A retrospective study showed that patients on MTX reported fewer cases of wound morbitity (p=0.038), RA flares (p=0.050), and no differences related to infections compared to those who stopped MTX.

Continuing with low doses of MTX seems to be a safe option during the perioperative period in RA patients without relevant comorbidities and/or risk factors of infections, undergoing elective orthopaedic surgery, while maintaining disease control.

To investigate whether concurrent administration of misoprostol reduces the occurrence of serious upper gastrointestinal complications, such as perforation, gastric outlet obstruction, or bleeding, in patients with rheumatoid arthritis who are receiving nonsteroidal anti-inflammatory drugs (NSAIDs). 6-month randomized, double-blind, placebo-controlled trial. 664 clinical practices of family medicine, internal medicine, or rheumatology in the United States and Canada. 8843 men and women (mean age, 68 years) receiving continuous therapy with any of 10 specified NSAIDs for control of symptoms of rheumatoid arthritis. Patients were enrolled between July 1991 and August 1993. Patients were randomly assigned to receive 200 micrograms of misoprostol or placebo four times a day. Development of serious upper gastrointestinal complications detected by clinical symptoms or findings (not by scheduled endoscopy). Serious upper gastrointestinal complications were reduced by 40% (odds ratio, 0.598 [95% CI, 0.364 to 0.982; P = 0.049]) among patients receiving misoprostol (25 of 4404 patients) compared with those receiving placebo (42 of 4439 patients). During the first month, more patients receiving misoprostol (20%) than placebo (15%) withdrew from the study, primarily because of diarrhea and related problems (P < 0.001). Risk factors for serious upper gastrointestinal complications were increasing age, history of peptic ulcer or bleeding, and cardiovascular disease. Patients with all four risk factors would have a 9% risk for a major complication in 6 months.

In older patients with rheumatoid arthritis, misoprostol reduced serious NSAID-induced upper gastrointestinal complications by 40% compared with placebo.

The trapeziometacarpal joint provides important functions for the hand. This joint is often involved in primary osteoarthritis. From November 1982 to December 1995, we encountered 42 patients (47 hands) with osteoarthritis (OA). All the patients were Chinese. Thirty-six patients (36 hands) were treated surgically. Ligament reconstruction and tendon interposition arthroplasty were done with total removal of the trapezium or partial removal of trapeziometacarpal joint depending on the stage of the disease. These patients were monitored for an average of 106 months and evaluated both clinically and roentgenographically. Of three stage II cases, the results of two were excellent and one was good. Of the 18 stage III patients, 14 had excellent (77.8%) and four had good (22.2%) results. In the 15 stage IV patients, 10 had excellent (66.6%), four had good (26.7%) and one had fair (6.7%) results. No patient had poor results.

Ligament reconstruction and tendon interpositional arthroplasty is a good alternative in treating degenerative arthritis of the trapeziometacarpal joint of the thumb. Partial removal of the diseased joint is indicated for stage II, and total removal of the trapezium is indicated for stage III and IV patients. Men seek treatment more often than women due to their need to work, even though women are more commonly afflicted with this disorder.

In the routine setting of the 20-bed orthopaedic ward of a regional hospital in Netherlands, we developed, implemented, and evaluated a new, function-tailored perioperative care pathway for patients receiving total knee replacement (TKR), aimed at faster functional recovery by reduction of inactivity and stimulation of self-efficacy of the patients. To assess effectiveness, we compared, using prospectively collected data from medical files, patient groups before (n = 127) and after (n = 108) introduction of the new care pathway with respect to time to recovery of physical functioning during hospitalisation (five milestones), length of hospital stay (LoS), referrals to an inpatient rehabilitation facility, and readmissions. Multivariable regression was used to adjust results for differences between the two groups in preoperatively assessed risk factors for delayed recovery. Comparison of patient groups before (n = 127) and after (n = 108) introduction of the tailored care pathway showed that the tailored rehabilitation pathway decreased the time to recovery of physical functioning (from 4.5 to 4.1 days, P < 0.05), the mean LoS (from 5.2 days to 4.2 days, P < 0.01).

We demonstrated that the introduction of a function-tailored care pathway shortens the hospital stay and accelerates the recovery of physical functioning.

Early intervention with mesenchymal stem cells (MSCs) after articular trauma has the potential to limit progression of focal lesions and prevent ongoing cartilage degeneration by modulating the joint environment and/or contributing to repair. Integrin α10β1 is the main collagen type II binding receptor on chondrocytes, and MSCs that are selected for high expression of the α10 subunit have improved chondrogenic potential. The ability of α10β1-selected (integrin α10 To investigate integrin α10 Controlled laboratory study. Focal cartilage injuries were created on the tali of horses (2-5 years, n = 8) by using an impacting device equipped to measure impact stress. Joints were treated with 20 × 10 Integrin α10 This preclinical study indicates that intra-articular therapy with integrin α10

Intra-articular administration of integrin α10

To evaluate the effects of pool-based exercises on pain symptomatology among adults with fibromyalgia syndrome. A systematic review and meta-analysis were carried out using PRISMA guidelines. Database search was conducted by two independent reviewers. For meta-analysis, the visual analogue scale (VAS) score for pain was used as the primary outcome and the Fibromyalgia Impact Questionnaire (FIQ) score was utilized as the secondary outcome. A total of 42 out of 292 potentially eligible studies were selected for being read in full by reviewers, 14 of which were included in meta-analysis, being 10 of them used in sensitivity analysis of either the primary or secondary outcome. Data pooled from 10 randomized controlled trials (n = 508) revealed that patients who underwent pool-based exercises exhibited a significantly lower mean in VAS score as compared to controls (SMD = -0.27, 95% CI: -0.45 to -0.09). Regarding FIQ scores, data from 10 randomized controlled trials were pooled (n = 578) and a lower mean score was also shown in the group that underwent a pool-based exercise program (SMD = -0.29, 95% CI: -0.49 to -0.09). Limitations of this study include the small sample size and moderate dropout rates in currently available clinical trials. Collectively, these findings suggest that pool-based exercise deserves further attention as a potential adjuvant therapeutic option for adults with fibromyalgia. PROSPERO registration number: CRD42019136755.

Pool-based exercise may provide some additional benefit for pain relief in adults with fibromyalgia as compared to either land-based or no physical exercise.

To assess the impact of escalating conventional therapy in patients with RA who satisfy BSR/NICE criteria for biologics. A total of 308 consecutive patients referred to a tertiary centre for biological therapy between January 1999 and February 2001 were studied prospectively. They were considered by their own consultant to have failed standard therapy. Prior to biologics, conventional therapy was escalated to include combination and parenteral methotrexate treatment. Patients were assessed at 12-weekly intervals for 1 yr and therapy was changed if response was not satisfactory. The subsequently released BSR/NICE biologic eligibility criteria were applied retrospectively. Response (disease activity, disability and quality of life) to escalated therapy in those patients who did or did not satisfy current eligibility criteria were compared. In total, 159 satisfied BSR/NICE criteria and would have been eligible for immediate treatment with biologics [DAS28 > 5.1, failed methotrexate (20 mg/week or lower dose owing to toxicity) and one other DMARD]; however, 93 of these responded to escalated conventional therapy and did not require biologics [significant improvement (P < 0.01) in disease activity, disability and quality of life]. However, mild disease activity (DAS28 < 3.2) was only achieved in 7% of these patients at 12 months.

Although over half the patients who satisfied standard criteria for biologics responded satisfactorily to escalated therapy, only a minority achieved mild disease activity. The savings achieved by treating with conventional therapies need to be weighed against the risk of persistent disease activity.

Leflunomide is a relatively new disease modifying antirheumatic drug (DMARD) and a number of studies evaluating its effectiveness and safety in daily medical practice is limited. Evaluation of effectiveness and safety of leflunomide treatment in patients with active rheumatoid arthritis in whom methotrexate was ineffective or contraindicated. Eighty one patients (66 women and 15 men) with RA diagnosed according to ARA (The American Rheumatism Association) criteria were included in the study. The mean age was 57.6+/-11.7 years and the mean disease duration was 7.7+/-7.1 years. The inclusion criteria were: disease activity according to DAS28 (Disease Activity Score)>3.2 and contraindications to methotrexate or ineffective methotrexate treatment for at least 3 months. At the beginning of the study 49 of patients were treated with methotrexate in weekly dose of 17+4.2mg and 32 were not treated with DMARDs. Oral glicocorticosteroids in stable doses of 5-15mg of prednisone were given to 66 (77.7%) of them. There was no statistically significant difference in radiological progression of the disease according to Steinbrocker's scale between groups (treated and not treated with methotrexate). Monotherapy with leflunomide was started with loading dose of 100mg for 3 days, and then 20mg daily. Combination therapy was introduced without loading dose. Evaluation was performed monthly and included: duration of morning stiffness, pain and disease activity according to VAS (visual-analogue) scale, the number of tender and swollen joints, blood count, ESR, CRP, aminotransferases activity, and the presence and intensity of adverse reactions. The results of treatment were evaluated after 5 months in 37 of patients and adverse reactions which happened until the end of 5th month were evaluated in all included patients. The mean DAS28 values improved exponentially during consecutive months and the difference between them was statistically significant. Adverse reactions during 5 months of treatment were observed in 36(44,4%) of patients and in 6(7,4%) of cases the treatment had to be stopped because of side effects. The frequency of adverse reactions was similar in monotherapy and combination therapy group.

Leflunomide therapy can be effective in patients with active rheumatoid arthritis in whom methotrexate is contraindicated or insufficient. Combination of leflunomide with methotrexate is safe and does not increase the frequency of adverse reactions.

Muscle weakness is associated with osteoarthritis pathology. A recent study demonstrated that measuring muscle volume using computed tomography (CT)-based analysis and comparing bilateral muscles in the same patient allowed for accurate evaluation of muscle volume in unilateral hip osteoarthritis (OA) patients. Here, we evaluated muscle volume using CT-based analysis and compared bilateral muscles in knee OA (KOA) patients. CT images were obtained from 35 female radiographic KOA patients the day prior to total knee replacement surgery. Muscle volume (MV) was semi-automatically analyzed. Knee extension muscle strength (MS) was determined using a hand-held dynamometer. The severity of KOA patients' clinical symptoms was examined using four domains of the Japanese Orthopedic Association (JOA) score. We compared the difference in MS (ΔMS) and MV (ΔMV) between the operated side (OS), which exhibited severe radiographic OA or severe pain, and the contralateral side (CS). JOA score was significantly lower in the OS than CS. MV and MS were also significantly lower in the OS than CS. There was no correlation between MV and MS or between MV and MS as a percentage of body weight on either side. However, ΔMV was positively correlated with ΔMS and pain on walking in the JOA.

We evaluated MV and MS using bilateral CT images of the legs of KOA patients. A reduction in MV was observed on the OS, and was correlated with a reduction in MS and pain on walking. Bilateral CT image analysis may be useful for evaluating the relationship between OA pathology and muscle atrophy.

Despite a health care system that is free at the point of delivery, ethnic minorities may not always get care equitable to that of White patients in England. We examined whether ethnic differences exist in joint replacement rates and surgical practice in England. 373,613 hip and 428,936 knee National Joint Registry (NJR) primary replacement patients had coded ethnicity in Hospital Episode Statistics (HES). Age and gender adjusted observed/expected ratios of hip and knee replacements amongst ethnic groups were compared using indirect standardisation. Associations between ethnic group and type of procedure were explored and effects of demographic, clinical and hospital-related factors examined using multivariable logistic regression. Adjusted standardised observed/expected ratios were substantially lower in Blacks and Asians than Whites for hip replacement (Blacks 0.33 [95% CI, 0.31-0.35], Asians 0.20 [CI, 0.19-0.21]) and knee replacement (Blacks 0.64 [CI, 0.61-0.67], Asians 0.86 % [CI, 0.84-0.88]). Blacks were more likely to receive uncemented hip replacements (Blacks 52%, Whites 37%, Asians 44%; P < 0.001). Black men and women aged <70 years were less likely to receive unicondylar or patellofemoral knee replacements than Whites (men 10% vs 15%, P = 0.001; women 6% vs 14%, P < 0.001). After adjustment for demographic, clinical and hospital-related factors, Blacks were more likely to receive uncemented hip replacement (OR 1.43 [CI, 1.11-1.84]).

In England, hip and knee replacement rates and prosthesis type given differ amongst ethnic groups. Whether these reflect differences in clinical need or differential access to treatment requires urgent investigation.

To investigate the function of Fas ligand (Fas-L) positive T cells in rheumatoid synovium, we analyzed the T cell receptor (TCR) CDR3 region and examined the expression of cytokines in both Fas-L+ and Fas-L- single T cells. Synovial fluid (SF) samples were collected from 2 patients with rheumatoid arthritis. TCR BV8+ T cells were sorted into a 96 well plate at a density of one cell per well. Expression of Fas-L, interferon-gamma, interleukin 2 (IL-2), IL-4, IL-6, and IL-10 was analyzed by reverse transcription-polymerase chain reaction and Southern blot and the TCR BV8 junctional region was sequenced. Twenty-two of 30 TCR BV8+ T cells from Patient 1 and 20 of 43 TCR BV8+ T cells from Patient 2 were Fas-L+ T cells, while the others were Fas-L-. Junctional sequence analysis showed the presence of some conserved amino acid motifs in the CDR3 region (SRQ, GFG, SSG, SGS, LGTSGTL, TLSS) in 13 clones of Fas-L+ T cells from Patient 1, whereas no conserved amino acid motif in Fas-L-T cells was found. In Patient 2, conserved amino acid motifs (PGQ, GQG, TTWGA) in the CDR3 region were found in 6 clones of Fas-L+ T cells, while only one was found in 2 clones of Fas-L-cells. In Fas-L+ T cells, 90-93% expressed both IL-2 and IL-10 mRNA.

Fas-L+ TCR BV8+ T cells revealed the conserved amino acids motif in the CDR3 region, suggesting that Fas-L+ T cells might expand by antigen stimulation and play a crucial role as Th0-type T cells in triggering autoimmunity in rheumatoid synovium.

To identify novel genes involved in osteoarthritis (OA), by means of a genome-wide association study. We tested 500,510 single-nucleotide polymorphisms (SNPs) in 1,341 Dutch Caucasian OA cases and 3,496 Dutch Caucasian controls. SNPs associated with at least 2 OA phenotypes were analyzed in 14,938 OA cases and approximately 39,000 controls. Meta-analyses were performed using the program Comprehensive Meta-analysis, with P values <1 x 10(-7) considered genome-wide significant. The C allele of rs3815148 on chromosome 7q22 (minor allele frequency 23%; intron 12 of the COG5 gene) was associated with a 1.14-fold increased risk (95% confidence interval 1.09-1.19) of knee and/or hand OA (P = 8 x 10(-8)) and also with a 30% increased risk of knee OA progression (95% confidence interval 1.03-1.64) (P = 0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (68 kb upstream of GPR22), which is associated with GPR22 expression levels in lymphoblast cell lines (P = 4 x 10(-12)). Immunohistochemistry experiments revealed that G protein-coupled receptor protein 22 (GPR22) was absent in normal mouse articular cartilage or synovium. However, GPR22-positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged with in vivo papain treatment or methylated bovine serum albumin treatment. GPR22-positive chondrocyte-like cells were also found in osteophytes in instability-induced OA.

Our findings identify a novel common variant on chromosome 7q22 that influences susceptibility to prevalence and progression of OA. Since the GPR22 gene encodes a G protein-coupled receptor, this is potentially an interesting therapeutic target.

To investigate the predictive value of early functional disability in patients with inflammatory polyarthritis (IP), for all-cause and cardiovascular disease (CVD) mortality. 1010 subjects with new-onset IP from the Norfolk Arthritis Register were studied. All were seen at baseline and at 1 year. Health Assessment Questionnaire (HAQ) scores were obtained at both time points. Vital status at 10 years from registration was established through central records. Mortality (all-cause and CVD) per 1000 person-years were calculated by HAQ stratum (HAQ scores<1, 1-2 and>or=2). The predictive value of HAQ (per unit increase) at the two time points, adjusted for age at onset of symptom, sex and other factors found to predict mortality, was assessed using Cox regression models. The analysis was repeated for those who satisfied the 1987 American College of Rheumatology criteria for rheumatoid arthritis (RA) by 5 years. By 10 years, 171 (16.9%) subjects had died. 89 deaths (52%) were attributed to CVD. Mortality was greatest in the highest HAQ group at both time points. Following adjustment for other predictors, HAQ score at year 1 remained a significant predictor of all-cause mortality (HR 1.46; 95% CI 1.15 to 1.85) and CVD mortality (HR 1.49; 95% CI 1.12 to 1.97). The predictive value of HAQ at year 1 was similar in the RA subgroup.

Our data show that at 1 year of follow-up, HAQ score is an important independent predictor of subsequent all-cause and CVD mortalities in people with IP and RA. Baseline HAQ scores are of less value.

The objective of this study was to determine the capacity of chondrocyte- and mesenchymal stem cell (MSC)-laden hydrogel constructs to achieve native tissue tensile properties when cultured in a chemically defined medium supplemented with transforming growth factor-beta3 (TGF-beta3). Cell-laden agarose hydrogel constructs (seeded with bovine chondrocytes or MSCs) were formed as prismatic strips and cultured in a chemically defined serum-free medium in the presence or absence of TGF-beta3. The effects of seeding density (10 vs 30 million cells/mL) and cell type (chondrocyte vs MSC) were evaluated over a 56-day period. Biochemical content, collagenous matrix deposition and localization, and tensile properties (ramp modulus, ultimate strain, and toughness) were assessed biweekly. Results show that the tensile properties of cell-seeded agarose constructs increase with time in culture. However, tensile properties (modulus, ultimate strain, and toughness) achieved on day 56 were not dependent on either the initial seeding density or the cell type employed. When cultured in medium supplemented with TGF-beta3, tensile modulus increased and plateaued at a level of 300-400 kPa for each cell type and starting cell concentration. Ultimate strain and toughness also increased relative to starting values. Collagen deposition increased in constructs seeded with both cell types and at both seeding densities, with exposure to TGF-beta3 resulting in a clear shift toward type II collagen deposition as determined by immunohistochemical staining.

These findings demonstrate that the tensile properties, an important and often overlooked metric of cartilage development, increase with time in culture in engineered hydrogel-based cartilage constructs. Under the free-swelling conditions employed in the present study, tensile moduli and toughness did not match that of the native tissue, though significant time-dependent increases were observed with the inclusion of TGF-beta3. Of note, MSC-seeded constructs achieved tensile properties that were comparable to chondrocyte-seeded constructs, confirming the utility of this alternative cell source in cartilage tissue engineering. Further work, including both modulation of the chemical and mechanical culture environment, is required to optimize the deposition of collagen and its remodeling to achieve tensile properties in engineered constructs matching the native tissue.

Eosinophilic granulomatosis with polyangiitis (EGPA) is part of antineutrophil cytoplasmic antibodies (ANCAs)-associated vasculitides. In EGPA small-vessel vasculitis is associated with eosinophilia and asthma. About 40% of EGPA patients are ANCA-positive, suggesting a role for B cells in the pathogenesis of EGPA. B cell-depleting therapy with rituximab (RTX) can be effective in ANCA-positive EGPA, but very few patients have been published to date. The role of RTX in the treatment of ANCA-negative EGPA is unclear. We report a single-center cohort of patients with eosinophilic granulomatosis with polyangiitis. Of these patients, nine (six ANCA-positive, three ANCA-negative) had been treated with RTX for relapsing or refractory disease on standard immunosuppressive treatment. In a retrospective analysis, data on treatment response, frequency of relapses, adverse events, and peripheral B-cell reconstitution were evaluated. Furthermore, serum immunoglobulin concentrations, ANCA status, and peripheral B cell subpopulations were assessed after RTX treatment. All patients had high disease activity before RTX treatment. At presentation 3 months after RTX therapy, all ANCA-positive and ANCA-negative patients had responded to RTX, with one patient being in complete remission, and eight patients being in partial remission. After a mean follow-up of 9 months, C-reactive protein concentrations had normalized, eosinophils had significantly decreased, and prednisone had been tapered in all patients. In all patients, RTX therapy was combined with a standard immunosuppressive therapy. Within the 9-month observation period, no relapse was recorded. Three patients were preemptively retreated with RTX, and during the median follow-up time of 3 years, no relapse occurred in these patients. During the follow-up of 13 patient-years, five minor but no major infections were recorded.

In our analysis on nine patients with EGPA resistant to standard therapy, rituximab proved to be an efficient and safe treatment for ANCA-positive and ANCA-negative patients. Preemptive retreatment with RTX, combined with standard maintenance immunosuppressants, resulted in a sustained treatment response. Prospective, randomized trials evaluating the use of RTX in EGPA are warranted.

To conduct a cross-sectional review of non-selected consecutive outpatients with rheumatoid arthritis (RA) as part of standard clinical care in 15 countries for an overview of the characteristics of patients with RA. The review included current disease activity using data from clinical assessment and a patient self-report questionnaire, which was translated into each language. Data on demographic, disease and treatment-related variables were collected and analysed using descriptive statistics. Variation in disease activity on DAS28 (disease activity score on 28-joint count) within and between countries was graphically analysed. A median regression model was applied to analyse differences in disease activity between countries. Between January 2005 and October 2006, the QUEST-RA (Quantitative Patient Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis) project included 4363 patients from 48 sites in 15 countries; 78% were female, >90% Caucasian, mean age was 57 years and mean disease duration was 11.5 years. More than 80% of patients had been treated with methotrexate in all but three countries. Overall, patients had an active disease with a median DAS28 of 4.0, with a significant variation between countries (p<0.001). Among 42 sites with >50 patients included, low disease activity of DAS28 <or=3.2 was found in the majority of patients in seven sites in five countries; in eight sites in five other countries, >50% of patients had high disease activity of DAS28 >5.1.

This international multicentre cross-sectional database provides an overview of clinical status and treatments of patients with RA in standard clinical care in 2005-6 including countries that are infrequently involved in clinical research projects.

Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily. Its ligand, 1,25-(OH)2D, is a metabolically active hormone derived from vitamin D3. The levels of vitamin D3 are decreased in patients with systemic sclerosis (SSc). Here, we aimed to analyse the role of VDR signalling in fibrosis. VDR expression was analysed in SSc skin, experimental fibrosis and human fibroblasts. VDR signalling was modulated by siRNA and with the selective agonist paricalcitol. The effects of VDR on Smad signalling were analysed by reporter assays, target gene analyses and coimmunoprecipitation. The effects of paricalcitol were evaluated in the models of bleomycin-induced fibrosis and fibrosis induced by overexpression of a constitutively active transforming growth factor-β (TGF-β) receptor I (TBRI(CA)). VDR expression was decreased in fibroblasts of SSc patients and murine models of SSc in a TGF-β-dependent manner. Knockdown of VDR enhanced the sensitivity of fibroblasts towards TGF-β. In contrast, activation of VDR by paricalcitol reduced the stimulatory effects of TGF-β on fibroblasts and inhibited collagen release and myofibroblast differentiation. Paricalcitol stimulated the formation of complexes between VDR and phosphorylated Smad3 in fibroblasts to inhibit Smad-dependent transcription. Preventive and therapeutic treatment with paricalcitol exerted potent antifibrotic effects and ameliorated bleomycin- as well as TBRI(CA)-induced fibrosis.

We characterise VDR as a negative regulator of TGF-β/Smad signalling. Impaired VDR signalling with reduced expression of VDR and decreased levels of its ligand may thus contribute to hyperactive TGF-β signalling and aberrant fibroblast activation in SSc.

The purposes of this study were 1) to quantify the proteoglycan 4 (PRG4) and hyaluronan (HA) content in synovial fluid (SF) from normal donors and from patients with chronic osteoarthritis (OA) and 2) to assess the cartilage boundary-lubricating ability of PRG4-deficient OA SF as compared to that of normal SF, with and without supplementation with PRG4 and/or HA. OA SF was aspirated from the knee joints of patients with symptomatic chronic knee OA prior to therapeutic injection. PRG4 concentrations were measured using a custom sandwich enzyme-linked immunosorbent assay (ELISA), and HA concentrations were measured using a commercially available ELISA. The molecular weight distribution of HA was measured by agarose gel electrophoresis. The cartilage boundary-lubricating ability of PRG4-deficient OA SF, PRG4-deficient OA SF supplemented with PRG4 and/or HA, and normal SF was assessed using a cartilage-on-cartilage friction test. Two friction coefficients (μ) were calculated: static (μ(static, Neq) ) and kinetic (<μ(kinetic, Neq) >) (where N(eq) represents equilibrium axial load and angle brackets indicate that the value is an average). The mean ± SEM PRG4 concentration in normal SF was 287.1 ± 31.8 μg/ml. OA SF samples deficient in PRG4 (146.5 ± 28.2 μg/ml) as compared to normal were identified and selected for lubrication testing. The HA concentration in PRG4-deficient OA SF (mean ± SEM 0.73 ± 0.08 mg/ml) was not significantly different from that in normal SF (0.54 ± 0.09 mg/ml). In PRG4-deficient OA SF, the molecular weight distribution of HA was shifted toward the lower range. The cartilage boundary-lubricating ability of PRG4-deficient OA SF was significantly diminished as compared to normal (mean ± SEM <μ(kinetic, Neq) > = 0.043 ± 0.008 versus 0.025 ± 0.002; P < 0.05) and was restored when supplemented with PRG4 (<μ(kinetic, Neq) > = 0.023 ± 0.003; P < 0.05).

These results indicate that some OA SF may have decreased PRG4 levels and diminished cartilage boundary-lubricating ability as compared to normal SF and that PRG4 supplementation can restore normal cartilage boundary lubrication function to these OA SF.

To provide guidance on the implementation of recommended American College of Rheumatology (ACR) rheumatoid arthritis (RA) disease activity and functional status assessment measures in telehealth settings. An expert panel was assembled from the recently convened ACR RA disease activity and functional status measures working groups to summarize strategies for implementation of ACR-recommended RA disease activity (the Clinical Disease Activity Index [CDAI], Disease Activity Score in 28 joints using the erythrocyte sedimentation rate or the C-reactive protein level [DAS28-ESR/CRP], Patient Activity Scale II [PAS-II], Simplified Disease Activity Index [SDAI], and Routine Assessment of Patient Index Data 3 [RAPID3]) and functional status (the Health Assessment Questionnaire II [HAQ-II], Multidimensional Health Assessment Questionnaire [MDHAQ], and PROMIS physical function 10-item short form [PROMIS PF-10]) measures in telehealth settings. Measures composed of patient-reported items (disease activity: PAS-II, RAPID3; functional status: HAQ-II, MDHAQ, PROMIS PF-10) require minimal modification for use in telehealth settings. Measures requiring formal joint counts (the CDAI, DAS28-ESR/CRP, and SDAI) can be calculated using patient-reported swollen and tender joint counts. When the feasibility of laboratory testing is limited, the CDAI can be used in place of the SDAI, and scoring modifications of the DAS28-ESR/CRP without the acute-phase reactant are available. Assessment of the validity of these modifications is limited. Implementation of these measures can be facilitated by electronic health record collection, mobile applications, and provider/staff administration during telehealth visits.

The ACR-recommended RA disease activity and functional status measures can be adapted for use in telehealth settings to support high-quality clinical care. Research is needed to better understand how telehealth settings may impact the validity of these measures.

Among people coping with chronic illness, tangible social support sometimes has unintended negative consequences on the recipient's psychological health. Identity processes may help explain these effects. Individuals derive self-worth and a sense of competence by enacting social roles that are central to the self-concept. This study tested a model drawing from some of these theoretical propositions. The central hypothesis was that tangible support in fulfilling a highly valued role undermines self-esteem and a sense of self-efficacy, which, in turn, affect psychological adjustment. Structured interviews were conducted with 98 Latina women with arthritis who rated the homemaker identity as being of central importance to the self-concept. A path analysis indicated that, contrary to predictions, tangible housework support was related to less psychological distress. Emotional support predicted greater psychological well-being. These relationships were not mediated by self-esteem or self-efficacy. Qualitative data revealed that half of the sample expressed either ambivalent or negative feelings about receiving housework support.

Results may reflect social and cultural norms concerning the types of support that are helpful and appropriate from specific support providers. Future research should consider the cultural meaning and normative context of the support transaction. This study contributes to scarce literatures on the mechanisms that mediate the relationship between social support and adjustment, as well as illness and psychosocial adaptation among Latina women with chronic illness.

To evaluate the efficacy and safety of ustekinumab (UST) in giant cell arteritis (GCA). We conducted a prospective, open-label trial of UST in patients with active new-onset or relapsing GCA. Active disease was defined as the presence of GCA symptoms and elevation of erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level within 6 weeks of baseline. All patients received a 24-week prednisone taper and subcutaneous UST 90 mg at baseline and at weeks 4, 12, 20, 28, 36, and 44. The primary endpoint, prednisone-free remission, was defined as the absence of relapse through week 52 and normalization of the ESR and CRP level. Relapse was defined as the recurrence of GCA symptoms requiring treatment intensification. A sensitivity analysis excluding ESR/CRP level normalization from the prednisone-free remission definition was performed. The study enrolled 13 patients (target sample size 20). Enrollment was closed prematurely after 7 of the initial 10 patients relapsed. Five patients (39%) had new-onset disease. The initial prednisone doses were 20 mg (1 patient), 40 mg (9 patients), and 60 mg (3 patients). All patients entered disease remission within 4 weeks of baseline. Only 3 (23%) achieved the primary endpoint. Of the 10 patients (77%) who failed to achieve the primary endpoint, 7 relapsed after a mean period of 23 weeks. The remaining 3 patients met the alternative definition of prednisone-free remission that did not require ESR/CRP level normalization. One serious adverse event occurred.

UST combined with 24 weeks of prednisone was associated with a high rate of treatment failure in this prospective GCA trial.

Histamine receptors are known to participate in spinal cord nociceptive transmission, and previous studies have suggested that histaminergic receptors are involved in the analgesic effects of morphine. Herein, we investigated the effect of intrathecal injection of histaminergic agonists and antagonists in a model of acute articular inflammation and their interaction with morphine. After carrageenan injection in the right knee joint, articular incapacitation was measured hourly, for up to 6 hours, by the paw elevation time during 1-minute periods of stimulated walking. Inflammatory edema was also assessed hourly by determining an increase in articular diameter. Spinal treatments were administered 20 minutes before knee-joint carrageenan injection and were compared with the saline-treated control group. Intrathecally injected histamine increased incapacitation and articular edema, whereas the H1R antagonist, cetirizine, decreased both parameters. The H3R agonist, immepip, decreased both incapacitation and edema, but the H3R antagonist, thioperamide, increased both incapacitation and edema. Morphine inhibited both incapacitation and edema. Furthermore, combining a subeffective dose of morphine with cetirizine or immepip potentiated the analgesic and antiedematogenic effect.

Histamine seems to act at the spinal level via H1 and H3 receptors to modulate acute arthritis in rats. An H1R antagonist and H3R agonist were found to potentiate the analgesic and antiedematogenic effects of morphine, suggesting that histaminergic and opioid spinal systems may be explored for means of improving analgesia, as well as peripheral anti-inflammatory effects.

Rheumatoid arthritis (RA) is a chronic, painful disease with many injurious psychological effects. Acceptance is an important component of pain management and is associated with improved quality of life, and lower levels of pain and depression. While studies have begun to identify the stages of acceptance, little is known about factors influencing the ease and speed with which patients pass through these stages. To explore the main stages through which RA patients pass and the strategies they adopt to learn to live with the pain, and to identify factors shaping patients' capacities to achieve acceptance. A qualitative study involving 20 semistructured interviews with RA patients in the Italian-speaking region of Switzerland was conducted. Analysis of the data followed the precepts of grounded theory. Although the present study revealed that acceptance is not a smooth or linear process, five main stages in patients' struggles to accommodate the newly imposed limitations were, nonetheless, identified: naming the illness; realizing the illness; resisting the illness; 'hitting the bottom'; and integrating the illness. Diagnosis proved to be an especially tortuous stage in the case of RA, and the effects of delayed diagnosis continued to be felt during the subsequent stages. Patients' understanding of the notion of acceptance and the strategies that they used to achieve it were also explored.

Diagnosis of RA is notoriously difficult. Beyond the clinical difficulties, structural reasons for late diagnosis (symptoms being neglected by patients and medical professionals) were identifed. Delayed diagnosis hindered the acceptance process throughout, and led to more resistant behaviour and to a struggle to achieve the optimal formula for acceptance - accepting the losses of prepain life while still pursuing personal goals.

The aim of the study was to identify sociodemographic, disease-related, physical and mental health-related determinants of fatigue at 2-year follow-up in individuals with symptomatic knee osteoarthritis (OA). A longitudinal analysis of participants with symptomatic knee OA from the Multicenter Osteoarthritis Study (MOST) was conducted to identify predictors of fatigue at 2-year follow-up. Participants self-reported fatigue at baseline for the first time in the MOST cohort and at follow-up using a 0-10 visual analog scale. At baseline, questionnaires on sociodemographics, disease-related symptoms, physical and mental health factors were completed. Data were analyzed using linear regressions with a backwards elimination approach. Of the 2330 individuals in the MOST cohort at baseline, 576 had symptomatic knee OA and of these, 449 with complete fatigue values at baseline and follow-up were included in this analysis. Minimally important fatigue change (ie, worsening [≥1.13], no change [<0.82 or <1.13] and improvement [≥-0.82]) from baseline to follow-up were unequal within the population (34.5%, 26.9%, 38.5%; χ

Fatigue is strongly associated with physical- and mental-related health factors. Individualized treatments that include combined psychological and physical function rehabilitation might be modalities for fatigue management.

Anti-citrullinated peptide antibodies (ACPAs) are established as useful predictors of radiographic progression in rheumatoid arthritis (RA). The main objective of this study was to test the prognostic capacity of the recently developed test for anti-mutated citrullinated vimentin (anti-MCV). A cohort of 238 patients with RA was followed longitudinally for 10 years; 125 patients with complete x ray sets were included in the main analyses. Radiographs were scored according to the van der Heijde modified Sharp score (SHS). Patients were analysed for anti-MCV and anti-cyclic citrullinated peptide (CCP), and were genotyped for human leukocyte antigen (HLA)-DRB1 "shared epitope" (SE) and protein tyrosine phosphatase, non-receptor type 22 (PTPN22) 1858T. Anti-MCV and anti-CCP were strongly associated with regard to status and level. Both antibodies were associated with SE, but only anti-MCV was significantly associated with PTPN22 1858T. A positive anti-MCV test increased the odds of radiographic progression by 7.3 (95% confidence interval (CI) 3.2 to 16.5) compared to 5.7 (95% CI 2.6 to 12.5) for a positive anti-CCP. Presence of MCV antibodies gave an average increase in the total SHS of 30 U compared to an average increase of 25 U for the presence of CCP antibodies. Anti-MCVs were more strongly associated to progression in erosions than joint space narrowing. Associations remained after adjustment for other predictors of radiographic progression. The odds of progression increased with increasing anti-MCV level.

Presence of anti-MCV predicted joint damage, and the strength of this prediction was at least as strong as for anti-CCP. Antibody status showed a stronger association to bone than to cartilage destruction. This study also indicates that higher anti-MCV levels add prognostic information compared to their mere presence or absence.

To investigate the diagnostic value of single-source dual-energy computed tomography (SDECT) in gouty arthritis and to compare its capability to detect urate depositions with digital radiography (DR) and conventional computed tomography (CT). Forty-four patients who underwent SDECT volume scans of the feet for suspected gouty arthritis were retrospectively analyzed. SDECT, CT (both n=44) and DR (n=36) were scored by three blinded readers for presence of osteoarthritis, erosions, and tophi. A diagnosis was made for each imaging modality. Results were compared to the clinical diagnosis using the American College of Rheumatology (ACR) classification criteria. The patient population was divided into a gout (n=21) and control (n=23) group based on final clinical diagnosis. Osteoarthritis was evident in 15 joints using CT and 30 joints using DR (p=0.165). There were 134 erosions detected by CT compared to 38 erosions detected by DR (p<0.001). In total 119 tophi were detected by SDECT, compared to 85 tophi by CT (p=0.182) and 25 tophi by DR (p<0.001). SDECT had best diagnostic value for diagnosis of gout compared to DR and conventional CT (sensitivity and specificity for SDECT: 71.4% and 95.7%, CT: 71.4% and 91.3% and DR: 44.4% and 83.3%, respectively). For all three readers, Cohen's kappa for DR and conventional CT were substantial for all scoring items and ranged from 0.75 to 0.77 and 0.72-0.76, respectively. For SDECT Cohen's kappa was good to almost perfect with 0.77-0.84.

SDECT is capable to detect uric acid depositions with good sensitivity and high specificity in feet, therefore diagnostic confidence is improved. Using SDECT, inter-reader variance can be markedly reduced for the detection of gouty tophi.

Controversy exists over the appropriate use of total hip arthroplasty in patients with significant neuromuscular disease. This study investigated the use of THR in neuromuscular disease patients. A criterion for patient inclusion was a diagnosis of mental retardation, cerebral palsy or Down's syndrome. The study population consisted of nine patients (12 hips), average age, 42 years. Average follow-up was 3.5 years. (1) 100% of patients demonstrated decreased pain, expanded range of motion and improved overall function. (2) All institutionalized patients were cared for more easily. (3) There were no infections, dislocations or major complications.

Total hip arthroplasty is a reasonable and safe therapeutic option for the treatment of painful osteoarthritis of the hip in select patients with neuromuscular disease.

Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase-2 without affecting platelet aggregation. The goal of this study was to assess the efficacy and tolerability of meloxicam under natural prescribing conditions for up to 6 months. This was a multicenter, prospective, observational cohort study. Participating centers were randomized to 1 of 2 groups: the meloxicam-only group, and the group who received comparator NSAIDs (ie, diclofenac, ibuprofen, piroxicam, or indomethacin). A total of 4526 patients received either meloxicam (n = 2530) or a comparator NSAID (n = 1996). Treatment groups were comparable in terms of observed efficacy measures. Meloxicam patients had significantly lower rates of reported gastrointestinal (GI) adverse drug reactions (1.80% vs 3.20%; P = 0.003), including dyspepsia (0.08% vs 0.35%; P = 0.049), abdominal pain (0.91% vs 1.90%; P = 0.006), gastritis (0.08% vs 0.60%; P = 0.002), and GI bleeding (0.08% vs 0.50%; P = 0.007), compared with those receiving comparator NSAIDs.

There was evidence that meloxicam was prescribed preferentially to patients who had not responded to NSAIDs previously, who had previously experienced NSAID-induced side effects (and so were at high risk for developing NSAID-induced GI toxicity), or who were more seriously impaired. The nonrandomized and unblinded nature of this study limits the conclusions that can be drawn concerning efficacy or tolerability. Nevertheless, the study results are consistent with the favorable GI tolerability seen with meloxicam in double-blind comparative trials.

The aim of this study is to evaluate proinflammatory and anti-inflammatory cytokine levels in gingival crevicular fluid (GCF) and serum of rheumatoid arthritis (RA) and chronic periodontitis (CP) patients to assess whether cytokine profiles distinguish patients with RA and patients with CP while using healthy patients as background controls. A total of 49 patients, 17 patients with RA (three males and 14 females; mean age: 47.82 ± 10.74 years), 16 patients with CP (10 males and six females; mean age: 44.00 ± 7.00 years), and 16 controls (eight males and eight females; mean age: 28.06 ± 6.18 years) were enrolled. Patients with RA were under the supervision of rheumatologists; 15 of the patients with RA were being treated with methotrexate-sulfasalazine combined therapy, and two of the patients were being treated with leflunomid therapy. Periodontal parameters (plaque index, gingival index, probing depth, and clinical attachment level) were recorded. Interleukin (IL)-1β, IL-4, IL-10, and tumor necrosis factor-α (TNF-α) were determined in GCF and IL-1β and IL-10 in serum by enzyme-linked immunosorbent assay. There were significant differences found among RA, CP, and control groups for all periodontal parameters (P <0.05). The total amount and concentration of GCF IL-1 β, IL-4, IL-10, and TNF-α were similar in RA and CP patients (P >0.05). Although the total amount and concentration of serum IL-10 was not significantly different among the groups (P >0.05), serum IL-1β was significantly lower in the RA group compared to CP patients and controls and was higher in GCF of the RA group compared to the CP group.

Although clinical periodontal disease parameters indicated more severe periodontal disease in CP compared to RA patients, immunologic evaluation did not reveal consistent results regarding proinflammatory and anti-inflammatory cytokine levels. This might be a result of the use of non-steroidal anti-inflammatory drugs and rheumatoid agents by patients with RA.

To determine the incidence of falls and to investigate the consequences of falls in adults with rheumatoid arthritis (RA). A total of 559 community-dwelling adults with RA, ages 18-88 years (mean age 62 years, 69% women), participated in this prospective cohort study. After a detailed clinical assessment, patients were followed for 1 year, using monthly falls calendars and followup telephone calls. Followup took place in the participant's usual place of residence in the Northwest of England. Outcome measures included fall occurrence, reason for fall, type and severity of injuries, fractures, fall location, lie-times, use of health services, and functional ability. A total of 535 participants followed for 1 year had a total of 598 falls. Of these participants, 36.4% (95% confidence interval 32%-41%) reported falling during the 1-year followup period, with an incidence rate of 1,313 per 1,000 person-years at risk or 1.11 falls per person. Age and sex were not associated with falls. More than one-third of the falls were reportedly caused by hips, knees, or ankle joints "giving way." More than half of all the falls resulted in moderate injuries, including head injuries (n = 27) and fractures (n = 26). Treatment by general practitioners or other health professionals was required for 15.0% of falls, and emergency services were required for 8.8% of falls.

These results indicate that adults with RA are at high risk of falls and fall-related injuries, fractures, and head injuries. Strategies to prevent falls in adults with RA must be prioritized to reduce falls, fall-related injuries, and fractures.

Normal cartilage is resistant to vascular invasion and anti-angiogenic protease inhibitors may contribute to its avascular status. We hypothesized that dysregulated expression of four key anti-angiogenic protease inhibitors may contribute to increased osteochondral vascularity in osteoarthritis (OA). Medial tibial plateaux from OA patients (n=40) were compared with those from non-arthritic controls collected post-mortem (PM, n=10). Immunohistochemistry was performed for protease inhibitors TIMP-1, TIMP-3, PAI-1 and SLPI and the pro-angiogenic factor vascular endothelial growth factor (VEGF). Immunoreactivity in articular chondrocytes was scored. Chondropathy was measured as a modified Mankin score, and osteochondral vascular density as number of channels crossing each mm of tidemark. Non-parametric analyses were used for all data. All protease inhibitors and VEGF were localised to chondrocytes near the articular surface, less often in the middle zone, and rarely to deep chondrocytes. Scores for VEGF, TIMP-1, TIMP-3, SLPI and PAI-1 were all increased in OA compared with PM, and higher scores were associated with greater chondropathy. Chondrocyte expression of VEGF was associated with higher osteochondral vascular density (r=0.32, P<0.05), whereas protease inhibitors were not.

The resistance of normal articular cartilage to vascular invasion may be more due to its matrix environment than ongoing protease inhibitor expression. Upregulation of protease inhibitors by superficial chondrocytes in OA may moderate the angiogenic effects of growth factors such as VEGF. However, failure of deep chondrocytes to express anti-angiogenic protease inhibitors may permit vascular invasion into the articular cartilage.

To study the prevalence of asymptomatic activation of Epstein-Barr virus (EBV) in patients with rheumatoid arthritis (RA) and to analyse the correlation of serum EBV DNA with the disease activity. The level of EBV DNA was determined by droplet digital PCR assay from the serum of 46 DMARD naive early RA (ERA) and 22 chronic RA (CRA)-patients at study onset. Follow-up samples from 31 ERA and 16 CRA patients were obtained after starting or modifying the anti-rheumatic treatment. EBV DNA was also measured from 33 healthy controls and 9 patients with adult onset Still's disease (AOSD). Disease activity was assessed by the disease activity score (DAS28). At baseline, EBV DNA was detected in the serum of 7 of the 46 ERA patients all of whom had moderate or high disease activity. In the follow-up samples, 11 of 31 patients were EBV DNA positive. At baseline EBV positive patients had significantly higher disease activity (p=0.036) and the concentration of EBV DNA correlated significantly with DAS28 (rs=0.333, p=0.024). EBV DNA was detected in 3 of 22 CRA patients at study onset and in 8 of 16 in the follow-up samples. At follow-up EBV positive patients had significantly higher DAS28 (p=0.027) and the concentration of EBV DNA correlated significantly with DAS28 (rs=0.724, p=0.002). Only one of the healthy controls and none of the AOSD patients were positive for EBV DNA.

Active RA is associated with a lytic EBV infection which may have a role in the pathogenesis of RA.

To determine the prevalence of liver involvement in patients with primary Sjogren's syndrome (SS) and to evaluate the association of this complication with other extra-glandular manifestations and serologic markers. We examined 155 Japanese patients (150 women and 5 men, mean age 66.6 years) who met the European Epidemiology Center Criteria for primary SS. Liver involvement was considered present when abnormal liver function tests (AST, ALT, ALP, GTP, or bilirubin) were detected more than three times. 20 patients (13%) had liver involvement including 2% with clinically overt liver disease. The causes of liver involvement were primary biliary cirrhosis (PBC) 6, autoimmune hepatitis (AIH) 2, hepatitis C virus (HCV) infection 2, concurrence of AIH and HCV infection 1, fatty liver 1. In 8 patients, the cause remained unclear. Of 6 patients complicated with PBC, four patients had PBC-specific antimitochondrial antibodies (AMA). Liver dysfunction was transient in two patients. Hepatocelluar carcinoma developed in a patient whose liver involvement was due to AIH and HCV. Patients with liver involvement were more likely to have cutaneous and neurological manifestations, when compared to SS without liver involvement. A positive antinuclear antibody, rheumatoid factor, and anticentromere antibody were also associated with liver involvement. Other autoantibodies did not correlate with the prevalence of liver involvement.

Although symptomatic liver involvement is rare in SS patients, asymptomatic liver involvement is common. Clinicians must be aware of the possibility of liver involvement so that it can be treated as soon as possible.

Mesenchymal stem cell (MSC)-based therapy presents a promising approach for treating osteoarthritis (OA). However, the molecular interactions between MSCs and OA chondrocytes (OACs) are not known. This study aims to investigate the bidirectional interactions between human MSCs (hMSCs) and human OACs (hOACs) in a 3D co-culture system. hMSC-collagen microspheres were cultured in hOAC-conditioned medium or co-cultured with hOAC-collagen microspheres. Growth characteristics, glycosaminoglycan (GAG) production, gene expression of major OA-associated chondrogenic markers, including SOX9, COL2A1, ACAN and MMP13, were investigated in both cell types. Both the conditioned medium and the co-culture induced MSC chondrogenesis with enhanced GAG production, SOX9 gene and protein expression, and gene expression of ACAN and COL2A1. Meanwhile, the co-culture also induced hOACs to partially resume the lost chondrogenic phenotype as shown by reduced proliferation, enhanced GAG production when hMSCs were chondrogenically predifferentiated, and reduced MMP13 gene expression.

This work suggests that 3D co-culture of hMSCs and hOACs is mutually beneficial to each other, suggesting the potential therapeutic effect of delivering hMSC in scaffolds directly to OA defects.

Parvovirus B19 infection can be associated with arthritis in children and adults. The causative role of PB19 infection in arthritis and ulcerative synovitis would prove the etiology of juvenile idiopathic (jia) and reumatoid arthritis (ra). The aim of this study was the evaluation of the role of PB 19 infection in children's arthritis. The group of 41 children with the diagnosis of jia, arthralgia, reactive arthritis and nodular erythema according to EULAR criteria was examined. In early stage of arthritis lasting less than 3 months, there were 22 and in prolonged period lasting more than 3 months there were 19 children. No evidence of PB19 genome was detected by PCR reaction in blood of the examined patients. The possible reasons of the obtained negative results in this study were discussed.

PB19 research should be performed in more cases of children's arthritis, both using PCR and by serological methods.

To compare the toxicities of commonly employed disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA). Toxicity Index scores, computed from symptoms, laboratory abnormalities, and hospitalizations attributable to DMARD therapy, were assessed in 2,747 patients with RA receiving 3,053 courses of 6 DMARDs and 1,309 courses of prednisone over 7,278 patient-years. Results were adjusted for severity of illness and other covariates. Least toxic was hydroxychloroquine (mean +/- SEM score 1.38 +/- 0.15), followed by intramuscular gold (2.27 +/- 0.17) and the closely grouped D-penicillamine (3.38 +/- 0.36), methotrexate (3.82 +/- 0.35), and azathioprine (3.92 +/- 0.39). Auranofin (5.25 +/- 0.32) was most toxic, but this toxicity resulted from a high frequency of minor complications. Hospitalizations because of auranofin or hydroxychloroquine therapy were not noted. Prednisone (3.83 +/- 0.39) was of comparable toxicity, although it is likely that not all events of prednisone toxicity were captured. For reference, the toxicity of methotrexate and azathioprine was similar to that of the most toxic nonsteroidal antiinflammatory drugs (NSAIDs) (indomethacin 3.99, tolmetin sodium 3.96, and meclofenamate 3.86). Hydroxychloroquine showed less toxicity than the most commonly used prescription NSAIDs.

There are substantial differences in toxicity among DMARDs and less important differences in toxicity between specific DMARDs and specific NSAIDs.

Osteoporosis is a complication of rheumatoid arthritis (RA). We identified risk factors for osteoporosis during treatment with biologics. Femoral neck bone mineral density (BMD) was measured in 186 patients with biologics-treated RA. We compared the characteristics of those with BMD ≥70% of young adult mean (YAM) and those with BMD <70% of YAM, and undertook multivariable logistic regression analysis to identify risk factors for bone loss. Mean age and disease duration, the proportion of females, scores in the Modified Health Assessment Questionnaire and history of vertebral fracture were significantly greater in the BMD <70% of YAM group, but body mass index (BMI) was significantly lower in the BMD <70% of YAM group. There was no significant difference between the groups in terms of other biomarkers of RA activity, the proportion treated with methylprednisolone, or the duration or choice of biologics. The proportions of patients treated with anti-osteoporosis drugs and parathyroid hormone were significantly higher in the BMD <70% of YAM group. In the multivariable analysis, advanced age, female, longer disease duration, history of past thoracic or lumbar vertebral fracture, higher Steinbrocker classification and lower BMI were significant factors for BMD <70% of YAM. We identified risk factors for bone loss in patients with RA treated with biologics. Before suppression of disease activity by biologics, bone loss might already be advanced.

We recommend that patients with RA who possess these risk factors be considered for earlier and more intense treatment to prevent bone loss, as well as addressing RA disease progression.

We previously reported that low-dose methotrexate (MTX) was associated with an increased risk of pulmonary adverse events (AEs) in a large randomized, placebo-controlled trial. Herein, we report details on the predictors and severity of pulmonary AEs. We conducted a prespecified analysis of pulmonary AEs in the Cardiovascular Inflammation Reduction Trial. Adults with known cardiovascular disease and diabetes/metabolic syndrome were randomly allocated to receive low-dose MTX (target dose 15-20 mg/week) or placebo after a 6-8-week open-label run-in phase in which all patients received low-dose MTX. Individuals with systemic inflammatory diseases were excluded. Pulmonary AEs were adjudicated in a blinded manner. We described severe pulmonary AEs and examined associations of baseline characteristics with pulmonary AEs in patients receiving low-dose MTX. A total of 2,391 subjects were randomized to receive low-dose MTX and 2,395 to receive placebo. There were 13 severe pulmonary AEs (0.5%) and 7 cases of possible pneumonitis (0.3%) in the low-dose MTX group, compared to 8 (0.3%) and 1 (<0.1%), respectively, in the placebo group. Among those randomized to receive low-dose MTX, risk factors for any pulmonary AE included female sex (hazard ratio [HR] 1.69 versus male sex [95% confidence interval (95% CI) 1.16-2.45]), white race (HR 2.35 versus other race [95% CI 1.03-5.36]), and insulin use (HR 1.60 versus non-use [95% CI 1.11-2.30]). The only risk factor for severe pulmonary AEs was older age at baseline (HR 1.09 per year increase [95% CI 1.02-1.16]).

In this large placebo-controlled trial, pulmonary AEs, including possible pneumonitis, were uncommon but were more likely to occur in those randomized to receive low-dose MTX. White race, older age, male sex, and insulin use were associated with an increased risk of pulmonary AEs in those receiving low-dose MTX.

To review the current concepts on Achilles tendon involvement in various pathological conditions. A literature search was conducted to trace relevant literature on Achilles tendon problems in general pathologies. The Achilles tendon can be involved in inflammatory and autoimmune conditions, genetically determined collagen abnormalities, infectious diseases, tumours, and neurological conditions which are not of a primary surgical nature.

Although Achilles tendon problems are classically considered frequent in active individuals from overuse or a single acute episode, problems in the Achilles tendon can be a consequence of several conditions.

Approximately 15-20% of patients with giant-cell arteritis (GCA) develop ischaemic complications often preceded by transient ischaemia. The expression of the endothelin (ET) system in GCA lesions was investigated to assess its relationship with the development of ischaemic complications. Plasma ET-1 was quantified by immunoassay in 61 patients with biopsy-confirmed GCA and 16 healthy donors. ET-1, endothelin-converting enzyme (ECE-1) and endothelin receptor (ET(A)R and ET(B)R) messenger RNA were measured by real-time quantitative reverse transcriptase-PCR in temporal arteries from 35 of these patients and 19 control arteries. Proteins were measured by immunoassay and Western blot. ET-1 concentration was increased at the protein level in temporal artery samples from GCA patients compared with controls (0.98 (SEM 0.32) vs 0.28 (SEM 0.098) fmol/mg, p = 0.028). ECE-1, ET(A)R and ET(B)R/actin ratios (Western blot) were also significantly higher in GCA patients. Intriguingly, mRNA expression of ET-1, ECE-1 and both receptors was significantly reduced in GCA lesions compared with control arteries. When investigating mechanisms underlying these results, platelet-derived growth factor and IL-1beta, present in GCA lesions, were found to downregulate ET-1 mRNA in cultured human temporal artery-derived smooth muscle cells. Glucocorticoid treatment for 8 days did not result in significantly decreased endothelin tissue concentration (0.87 (SEM 0.2) vs 0.52 (SEM 0.08); p = 0.6). Plasma endothelin concentrations were higher in patients with ischaemic complications (1.049 (SEM 0.48) vs 1.205 (SEM 0.63) pg/ml, p = 0.032).

The endothelin system is increased at the protein level in GCA lesions creating a microenvironment prone to the development of ischaemic complications. Recovery induced by glucocorticoids is delayed, indicating persistent exposure to endothelin during initial treatment.

The aim of this study was to investigate the arthroscopic characteristics of meniscal injuries in osteoarthritic knees and explore their significance in the selection of surgical approach. Four original types of meniscal injuries were defined. The study included 87 cases; 12 Type 1, 26 Type 2, 35 Type 3 and 14 in Type 4 meniscal injuries. For Type 1 injuries, 5 cases underwent meniscal suture repair and 7 cases partial meniscal resection. Partial meniscal resection was performed in 22 cases and subtotal resection in 4 cases of Type 2 injury. For Type 3 injury, meniscal debridement was performed in 2, partial resection in 8, subtotal resection in 19 and total resection in 6 cases. For Type 4 injury, 3 cases underwent subtotal resection and 11 underwent total resection. Patients were evaluated with the Lysholm, visual analog scale, and Kellgren-Lawrence scale scores and cartilage lesions stages. Mean follow-up period was 26 (range: 8 to 51) months. Joint swelling or pain was present in 13 cases after fatigue. Twist lock symptom was observed in one Type 3 injury and one Type 4 injury. Joint flexion was limited to 20° in one Type 3 injury and two Type 4 injuries. Total knee joint replacement was performed in two Type 2 and two Type 4 injuries 2 to 3 years and 2 months after surgery.

The classification of meniscal injuries in osteoarthritic knees was designed to guide arthroscopic surgery and improve the therapeutic efficacy of minimally invasive surgery for knee osteoarthritis.

Chemerin and interleukin (IL)-8 are pro-inflammatory mediators whose role in joint inflammation and cartilage degradation has been demonstrated in in-vitro findings. Studies on their presence in synovial fluid (SF) samples may offer further information on their pathogenic role. The aim of this study was to investigate SF chemerin and IL-8 levels in patients with different joint diseases. 37 patients were enrolled: 18 with rheumatoid arthritis (RA), 8 with psoriatic arthritis (PsA) and 11 with osteoarthritis (OA). 41 SF samples were obtained by arthrocentesis in case of knee synovitis. Serum samples were obtained from 13 patients (4 with RA, 6 with PsA and 3 with OA) at the time of arthrocentesis. Chemerin, IL-8, TNF-α and IL-6 levels were measured using commercially available ELISA kits. Immunohistochemical analysis of synovial RA specimens was also performed. No difference in chemerin SF levels emerged between patients with immune-mediated inflammatory arthritides and those with OA (p=0.0656), while subjects with inflammatory arthritis displayed significantly higher levels of SF IL-8 compared to OA (p=0.0020). No significant difference emerged across the three conditions in the serum levels of both chemerin and IL-8. IL-8 strongly correlated with inflammatory markers as ESR, CRP, IL-6 and TNF-α.

We observed similar chemerin SF and serum levels in the three conditions. Although flawed by some limitations, our findings support the emerging concept of OA as an inflammatory disorder. However the increased IL-8 levels we described in patients with inflammatory arthritis suggest a selective involvement of this pro-inflammatory and angiogenic cytokine in these conditions.

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increased cardiovascular (CV) mortality. Since CD40-CD154 binding has direct consequences on inflammation process initiation, we aimed to replicate previous findings related to disease susceptibility in Spanish RA population. Furthermore, as the major complication in RA disease patients is the development of CV events due to accelerated atherosclerosis, and elevated levels of CD40L/CD154 are present in patients with acute myocardial infarction, we assessed the potential association of CD40 and CD154/CD40L gene variants with CV risk in Spanish RA patients. One thousand five hundred and seventy-five patients fulfilling the 1987 ACR classification criteria for RA and 1600 matched controls were genotyped for the CD40 rs1883832, rs4810485 and rs1535045 and CD154 rs3092952 and rs3092920 gene polymorphisms, using predesigned TaqMan single nucleotide polymorphism genotyping assays. Afterwards, we investigated the influence of CD40-CD154 gene variants in the development of CV events. Also, in a subgroup of 273 patients without history of CV events, we assessed the influence of these polymorphisms in the risk of subclinical atherosclerosis determined by carotid ultrasonography. Nominally significant differences in the allele frequencies for the rs1883832 CD40 gene polymorphism between RA patients and controls were found (p=0.038). Although we did not observe a significant association of CD40-CD154 gene variants with the development of CV events, an ANCOVA model adjusted for sex, age at the time of the ultrasonography assessment, follow-up time, traditional CV risk factors and anti-cyclic citrullinated peptide antibodies disclosed a significant association (p=0.0047) between CD40 rs1535045 polymorphism and carotid intima media thickness, a surrogate marker of atherosclerosis.

Data from our pilot study indicate a potential association of rs1883832 CD40 gene polymorphism with susceptibility to RA. Also, the CD40 rs1535045 gene variant may influence development of subclinical atherosclerosis in RA patients.

Osteoarthritis is a common disease, with a prevalence of symptomatic disease of 8.9%. One treatment option is radiotherapy. Most published samples were treated with an orthovoltage technique or with a telecobalt device. A lot of radiotherapy institutions are nowadays using linear accelerators for treatment of osteoarthritis. There is a discussion on whether the treatment results achieved with a linear accelerator are comparable to those with the orthovoltage technique. The aim of this study is to analyze the results of radiotherapy for osteoarthritis with a linear accelerator and compare the results with reference to different joints. The analysis was performed in patients of two German radiotherapy institutions and included 295 irradiated joints. Pain was documented with the numeric rating scale (NRS). Evaluation of the NRS was done before and directly after each radiation therapy course as well as for the follow-up of 24 months. The median age of the patients was 65 years, with 39.0% male and 61.0% female patients. Most frequently, osteoarthritis of the knee (34.6%) or the finger (15.9%) was treated. We could find a significant response to radiotherapy. Median pain for the whole sample was 7 on the NRS before radiotherapy, 4 after 6 weeks, and 3 after 12 and 24 months. The percentage of patients with 0 or 1 on the NRS was 33.8% 12 months after radiotherapy. All investigated subgroups had a significant reduction of pain.

Radiotherapy of osteoarthritis with a linear accelerator is an effective treatment which is very well tolerated. All analyzed subgroups show a good response to radiotherapy for at least 24 months. Orthovoltage therapy seems to be superior to treatment with a linear accelerator in a case-related analysis of the published samples. Further investigations should be performed for a definitive answer to this question.

Dietary loading has been reported to have an effect on temporomandibular joint (TMJ) remodeling via periodontal-muscular reflex. We therefore examined whether reducing dietary loading decreased TMJ degradation induced by the unilateral anterior crossbite prosthesis as we recently reported. Forty 6-week-old female C57BL/6J mice were randomly divided into two experimental and two control groups. One experimental and one control group received small-size diet and the other two groups received large-size diet. Unilateral anterior crossbite prosthesis was created in the two experimental groups. The TMJ samples were collected 3 weeks after experimental operation. Histological changes in condylar cartilage and subchondral bone were assessed by Hematoxylin & Eosin, toluidine blue, Safranin O and tartrate-resistant acid phosphatase staining. Real-time polymerase chain reaction (PCR) and/or immunohistochemistry were performed to evaluate the expression levels of Collagen II, Aggrecan, a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) and RANKL/RANK/OPG in TMJ condylar cartilage and/or subchondral bone. Thinner and degraded cartilage, reduced cartilage cellular density, decreased expression levels of Collagen II and Aggrecan, loss of subchondral bone and enhanced osteoclast activity were observed in TMJs of both experimental groups. However, the cartilage degradation phenotype was less severe and cartilage ADAMTS-5 mRNA was lower while OPG/RANKL ratio in cartilage and subchondral bone was higher in the small-size than large-size diet experimental group. No differences of histomorphology and the tested molecules were found between the two control groups.

The current findings suggest that a lower level of functional loading by providing small-size diet could reduce TMJ degradation induced by the biomechanical stimulation from abnormal occlusion.

Osteoarthritis (OA) is a joint disease characterized by osteophyte development, fibrosis, and articular cartilage damage. Effects of exogenous transforming growth factor beta (TGFbeta) isoforms and bone morphogenetic proteins (BMPs) suggest a role for these growth factors in the pathogenesis of OA. The aim of this study was to elucidate the role of endogenous TGFbeta and BMP during papain-induced OA-like changes in mice. We used adenoviral overexpression of TGFbeta and BMP antagonists to block growth factor signaling. An adenovirus expressing a secreted, pan-specific TGFbeta antagonist called murine latency-associated peptide 1 (mLAP-1) was used. In addition, we used intracellular inhibitory Smad6 as a BMP antagonist and Smad7 as a TGFbeta/BMP inhibitor. Papain was injected into the knee joints of C57BL/6 mice to induce osteophyte development, synovial thickening, and articular cartilage proteoglycan (PG) loss. Intraarticular injection of papain caused increased protein expression of several TGFbeta and BMP isoforms in synovium and cartilage. Adenovirus transfection into the joint resulted in a strong expression of the transgenes in the synovial lining. Overexpression of mLAP-1, Smad6, and Smad7 led to a significant reduction in osteophyte formation compared with that in controls. Smad6 and Smad7 overexpression also significantly decreased synovial thickening. Furthermore, the secreted TGFbeta inhibitor mLAP-1 increased articular cartilage PG loss.

Our results indicate a pivotal role of endogenous TGFbeta in the development of osteophytes and synovial thickening, implicating endogenous TGFbeta in the pathogenesis of OA. In contrast, the prevention of cartilage damage by endogenous TGFbeta signifies the protective role of TGFbeta in articular cartilage. This is the first study to demonstrate that endogenous BMPs are involved in osteophyte formation and synovial thickening in experimental OA.

To investigate effects of cartilage derived morphogenetic protein-1 and -2 (CDMP-1, CDMP-2), bone morphogenetic protein (BMP)-7 and BMP-6 on metabolism of ligament fibroblasts and their osteogenic or chondrogenic differentiation potential. Ligament fibroblasts were obtained from 3 month old calves, plated as monolayers or micromass cultures, and incubated with or without CDMP-1, CDMP-2, BMP-7, and BMP-6. Expression of the indicated growth factors was assessed by RT-PCR and western immunoblotting. The presence of their respective type I and II receptors, and lineage related markers, was investigated in stimulated and unstimulated cells by RT-PCR and northern blotting. Biosynthesis of matrix proteoglycans was assessed by [(35)S]sulphate incorporation in monolayers. Alcian blue and toluidine blue staining was done in micromass cultures. CDMP-1, CDMP-2, BMP-7, and BMP-6 were detected on mRNA and on the protein level. Type I and II receptors were endogenously expressed in unstimulated ligament fibroblasts. The growth factors significantly stimulated total proteoglycan synthesis as assessed by [(35)S]sulphate incorporation. Toluidine blue staining showed cartilage-specific metachromasia in the growth factor treated micromass cultures. Transcription analysis of stimulated ligament fibroblasts demonstrated coexpression of chondrocyte markers but no up regulation of osteogenic markers.

CDMP-1, CDMP-2, BMP-7, and BMP-6 and their receptors were expressed in ligament tissue. These growth factors induced matrix synthesis in fibroblasts derived from bovine ligament. The preferential expression of cartilage markers in vitro suggests that CDMP-1, CDMP-2, BMP-7, and BMP-6 have the potential to induce differentiation towards a chondrogenic phenotype in ligament fibroblasts. Thus, fibroblasts from ligaments may serve as a source for chondrogenesis and tissue repair.

We recently demonstrated that low-energy mechanical impact to articular cartilage, usually considered non-injurious, can in fact cause microscale cracks (widths <30μm) in the collagen network of visually pristine human cartilage. While research on macro-scale cracks in cartilage and microcracks in bone abounds, how microcracks within cartilage initiate and propagate remains unknown. We quantified the extent to which microcracks initiate and propagate in the collagen network during mechanical loading representative of normal activities. We tested 76 full-thickness, cylindrical osteochondral plugs. We imaged untreated specimens (pristine phase) via second harmonic generation and assigned specimens to three low-energy impact groups (none, low, high), and thereafter to three cyclic compression groups (none, low, high) which simulate walking. We re-imaged specimens in the post-impact and post-cyclic compression phases to identify and track microcracks. Microcracks in the network of collagen did not present in untreated controls but did initiate and propagate under mechanical treatments. We found that the length and width of microcracks increased from post-impact to post-cyclic compression in tracked microcracks, but neither depth nor angle presented statistically significant differences.

The microcracks we initiated under low-energy impact loading increased in length and width during subsequent cyclic compression that simulated walking. The extent of this propagation depended on the combination of impact and cyclic compression. More broadly, the initiation and propagation of microcracks may characterize pathogenesis of osteoarthritis, and may suggest therapeutic targets for future studies.

To study the expression level and role of apoptosis-associated speck-like protein containing a caspase recruitment domain (PYCARD) gene transcript variant mRNA in peripheral blood mononuclear cells (PBMCs) of primary gout (PG) patients with different Chinese medicine (CM) syndromes. The expressions of PYCARD gene transcript variant mRNA and interleukin-1β (IL-1β) mRNA in PBMCs were investigated in 96 PG patients with acute phase (APPG, 44 cases) and non-acute phase (NAPPG, 52 cases) and 30 healthy controls (HCs) by reverse transcription-polymerase chain reaction (PCR) and/or realtime quantitative PCR. PYCARD and nuclear factor-κB (p50) [NF-κB (p50)] protein was detected by Western blot in PBMCs respectively. IL-1β, IL-4 and IL-10 protein levels in plasma of HCs and PG patients were measured by enzyme-linked immuno sorbent assay. The main CM syndromes in APPG patients were obstruction of dampness and heat syndrome (ODHS, 36.36%) and intermingled phlegm-blood stasis syndrome (IPBSS, 27.27%), while in NAPPG patients were Pi (Spleen)-deficiency induced dampness syndrome (PDIDS, 40.38%) and qi-blood deficiency syndrome (QBDS, 26.92%). It showed statistical significances of the expressions of PYCARD gene and its transcript variant mRNA, the protein of PYCARD and NF-κB (p50) and the plasma IL-1β, IL-4 and IL-10 in APPG, NAPPG, ODHS, IPBSS, PDIDS and QBDS groups, compared with the HC group respectively (P<0.05 or P<0.01). There were also significant differences of mRNA expressions of PYCARD-1 and PYCARD-2 as well as protein expressions of IL-1β, IL-4 and IL-10 among the 4 CM syndromes groups (P<0.05 or P<0.01). Correlation analysis showed positive correlation between the mRNA expressions of PYCARD-1 gene transcript variant and IL-1β in APPG patients (r=0.3088, P=0.0183).

PYCARD gene and its transcript variant may play a critical and regulative role in the inflflammatory response of PG patients with different phases and CM syndromes.

In a large-scale ENU (N-ethyl-N-nitrosourea) mouse mutagenesis programme, we previously have identified and characterized a novel mutation Ali18 that causes inflammatory arthritis like lesions in peripheral joints. In this study, we analysed the immune system of Ali18 mice to understand mechanisms underlying the spontaneous inflammation. Humoral and cellular components of the immune system were phenotyped by ELISA and flow cytometry. The contribution of the immune system for phenotype expression was analysed in disease transfer experiments. The involvement of the adaptive immune system was investigated in Ali18;Rag1 double mutants and the influence of environmental factors was analysed in Ali18 mice reared under germ-free conditions. Bone marrow cells from Ali18 mice were able to transfer the disease phenotype to naïve wild-type recipients suggesting that cellular components of the reconstituted immune system were sufficient to induce arthritis. Ali18 mice revealed abnormal leucocyte populations including lymphocytes and granulocytes, as well as increased plasma IL-5 and IgE levels. Ali18;Rag1 double homozygous mutants, which lack mature lymphocytes, still developed arthritis, suggesting that the phenotype is independent of the adaptive immune system. In addition, the arthritis phenotype appeared to be independent from environmental conditions as demonstrated in mice reared under germ-free conditions.

The Ali18 mutation induces inflammatory arthritis through bone marrow-derived cells. However, non-pro-inflammatory cytokine cascades and mature lymphocyte independent-mechanisms are crucial for initiation and progression of the phenotype. Ali18 mice may thus represent a model to study mechanisms involved in seronegative arthritis induced by cells of the innate immune system.

Both trapeziectomy with ligament reconstruction and tendon interposition and trapeziometacarpal arthrodesis are commonly performed procedures for the treatment of trapeziometacarpal osteoarthritis. The purpose of this study was to compare the outcomes of both treatments for symptomatic osteoarthritis of the thumb trapeziometacarpal joint in a randomized trial. Women who were forty years of age or older were randomized either to trapeziectomy with ligament reconstruction and tendon interposition or to arthrodesis with plate and screws. Patients were evaluated preoperatively and at three and twelve months postoperatively with respect to pain, function (Patient-Rated Wrist/Hand Evaluation [PRWHE] and Disabilities of the Arm, Shoulder and Hand [DASH] questionnaires), joint motion, strength, complication rate, and patient satisfaction. Forty-three patients were enrolled. Since we found significantly more moderate and severe complications following arthrodesis compared with trapeziectomy with ligament reconstruction and tendon interposition (71% versus 29%; p = 0.016), the study was prematurely terminated before the sample size necessary to validly compare the two groups was reached. The higher complication rate for arthrodesis led to an increase in revision surgery (two of seventeen patients). Significantly more patients in the ligament reconstruction and tendon interposition group (86%) than in the arthrodesis group (53%) indicated they would consider the same surgery again under the same circumstances (p = 0.025). In both groups, PRWHE and DASH scores significantly improved over time; however, comparison of the groups showed that the results were similar.

Women who are forty years or older with trapeziometacarpal osteoarthritis have fewer moderate and severe complications after trapeziectomy with ligament reconstruction and tendon interposition and are more likely to consider the surgery again under the same circumstances than are those who undergo arthrodesis. Twelve months after surgery, the PRWHE and DASH scores were similar in both groups. We do not recommend routine use of arthrodesis with plate and screws in the treatment of women who are forty years or older with stage-II or III trapeziometacarpal osteoarthritis.

There is evidence that patients with rheumatoid arthritis (RA) have a higher arterial stiffness than their age-matched healthy counterparts and thus have a higher cardiovascular risk. Under National Institute for Clinical Excellence guidelines, tumor necrosis factor-α (TNF-α) antagonists are indicated clinically in patients with severe active rheumatoid disease. TNF-α antagonists have been found to reduce inflammatory markers in RA; however, it is debatable if they have favorable effects on the cardiovascular system. This review evaluates the effect of TNF-α antagonists on arterial stiffness, a predictor of cardiovascular disease, in RA patients. A search of Ovid MEDLINE and ISI Web of Knowledge databases was conducted to identify studies into the effect of TNF-α antagonists on arterial stiffness in RA patients. Eight studies matching the search criteria were included for analysis. Two methods were used to assess arterial stiffness: pulse wave velocity and augmentation index. Despite inconsistencies in augmentation index values, aortic pulse wave velocity in all but one study was significantly reduced following TNF-α antagonist treatment. Most studies had methodological limitations, including inadequate sample size, nonblinding of those involved in the measurements, and inadequate inclusion/exclusion criteria. Variation in results could be due to the use of different TNF-α antagonists, different outcome measures being used, and differences in follow-up.

The balance of evidence suggests that TNF-α antagonists may have a beneficial effect on arterial stiffness and therefore cardiovascular risk. However, larger more robust longer term studies are warranted to confirm recent findings.

To examine the degree to which shared risk factors explain the relationship of periodontitis (PD) to rheumatoid arthritis (RA) and to determine the associations of PD and Porphyromonas gingivalis with pathologic and clinical features of RA. Patients with RA (n = 287) and patients with osteoarthritis as disease controls (n = 330) underwent a standardized periodontal examination. The HLA-DRB1 status of all participants was imputed using single-nucleotide polymorphisms from the extended major histocompatibility complex. Circulating anti-P gingivalis antibodies were measured using an enzyme-linked immunosorbent assay, and subgingival plaque was assessed for the presence of P gingivalis using polymerase chain reaction (PCR). Associations of PD with RA were examined using multivariable regression. Presence of PD was more common in patients with RA and patients with anti-citrullinated protein antibody (ACPA)-positive RA (n = 240; determined using the anti-cyclic citrullinated peptide 2 [anti-CCP-2] test) than in controls (35% and 37%, respectively, versus 26%; P = 0.022 and P = 0.006, respectively). There were no differences between RA patients and controls in the levels of anti-P gingivalis or the frequency of P gingivalis positivity by PCR. The anti-P gingivalis findings showed a weak, but statistically significant, association with the findings for both anti-CCP-2 (r = 0.14, P = 0.022) and rheumatoid factor (RF) (r = 0.19, P = 0.001). Presence of PD was associated with increased swollen joint counts (P = 0.004), greater disease activity according to the 28-joint Disease Activity Score using C-reactive protein level (P = 0.045), and higher total Sharp scores of radiographic damage (P = 0.015), as well as with the presence and levels of anti-CCP-2 (P = 0.011) and RF (P < 0.001). The expression levels of select ACPAs (including antibodies to citrullinated filaggrin) were higher in patients with subgingival P gingivalis and in those with higher levels of anti-P gingivalis antibodies, irrespective of smoking status. Associations of PD with established seropositive RA were independent of all covariates examined, including evidence of P gingivalis infection.

Both PD and P gingivalis appear to shape the autoreactivity of RA. In addition, these results demonstrate an independent relationship between PD and established seropositive RA.

The sagittal spinal alignment interacts with the lower extremity in patients with combined degenerative disease of the spine and lower extremity. This study aimed to clarify the relationships between the reciprocal changes in sagittal alignment of the knee, pelvis, and spine after total knee arthroplasty (TKA) in osteoarthritis patients. Prospectively, 36 patients who underwent primary TKA for severe knee osteoarthritis were enrolled. Their clinical and radiological evaluation included assessments of the knee flexion contracture (KFC) and standing knee flexion angle (KFA), as well as spinopelvic parameters and the global sagittal spinal alignment from standing whole-lower-extremity and whole-spine radiographs preoperatively and at postoperative 2 weeks, 6 weeks, 6 months, 1 year, and 2 years. Linear mixed models were used to assess the relationships between KFC/KFA and between spinopelvic/global sagittal spinal alignments. The KFC decreased abruptly immediately after TKA, and the correction was maintained for 2 years postoperatively. The KFA decreased gradually and approached the value of the KFC after 2 years. Of the spinopelvic parameters, sacral slope and pelvic incidence decreased significantly, in ways related to changes in KFA. There was no significant relationship between sagittal spinal alignment and postoperative changes in KFC.

Although the flexion contracture was corrected immediately after TKA, the standing KFA improved gradually over 2 years. The pelvic parameters showed compensatory changes according to the KFA. The decompensated sagittal spinal malalignment was not related to a relapse in flexion contracture.

Knee osteoarthritis (OA) has been shown to be a risk factor for falls. Reductions in foot clearance during the swing phase of walking can cause a trip and potentially lead to a fall. This study examined the swing phase mechanics of people with and without knee OA during walking. Minimum toe clearance (MTC) height, joint angles at the time of MTC and the influence of the angular changes of the hip, knee and ankle of the swing leg on foot clearance using sensitivity analysis were investigated in 50 knee OA participants and 28 age-matched asymptomatic controls. Although both groups had a similar MTC height (controls: 12.8±6.7 mm, knee OA: 13.4±7.0 mm), the knee OA group used a different strategy to achieve the same foot clearance, as evidenced by greater knee flexion (52.5±5.3° vs 49.4±4.8°, p=0.007), greater hip abduction (-3.6±3.3° vs -1.8±3.3°, p=0.03) and less ankle adduction (2.8±1.9° vs 4.2±2.1°, p=0.01).

MTC height was comparable between the groups, however a different swing phase mechanism was used by the knee OA. Although adequate MTC is an important component of safe locomotion, it does not appear to be impaired in people with knee OA. Other factors, such as inadequate responses to postural perturbation, may be responsible for falls in this group.

To determine the diverse clinical features of optic neuropathy associated with primary Sjögren's syndrome in Korean patients. Five women with acute and/or chronic optic neuropathy who were diagnosed as primary Sjögren's syndrome were retrospectively evaluated. Primary Sjögren's syndrome was diagnosed by signs and symptoms of keratoconjunctivitis sicca, positive serum anti-Ro/SSA and/or anti-La/SSB antibodies, and/or minor salivary gland biopsy. All patients underwent a complete ophthalmologic examination. Among the five patients diagnosed as optic neuropathy related to primary Sjögren's syndrome, four patients had bilateral optic neuropathy and one patient was unilateral. The clinical course was chronic in three patients and one of them showed acute exacerbation and was finally diagnosed with neuromyelitis optica spectrum disorder. The other two patients presented as acute optic neuritis and one was diagnosed with neuromyelitis optica spectrum disorder. Sicca symptoms were present in four patients, but only two patients reported these symptoms before the onset of optic neuropathy. Patients showed minimal response to systemic corticosteroids or steroid dependence, requiring plasmapheresis in the acute phase and immunosuppressive agents for maintenance therapy.

Optic neuropathy associated with primary Sjögren's syndrome may show variable clinical courses, including acute optic neuritis, insidious progression of chronic optic atrophy, or in the context of neuromyelitis optica spectrum disorders. Optic neuropathy may be the initial manifestation of primary Sjögren's syndrome without apparent sicca symptoms, which makes the diagnosis often difficult. The presence of specific antibodies including anti-Ro/SSA, anti-La/SSB, and anti-aquaporin-4 antibodies are supportive for the diagnosis and treatment in atypical cases of optic neuropathy.

Osteoarthritis (OA) is the most common joint disorder and a leading cause of disability. While early proactive management is crucial in alleviating symptoms in OA patients, currently available therapeutic approaches are yet to achieve an ideal level of efficacy. The path to the development of a potent treatment begins with the thorough understanding of the pathophysiology of OA. The present study aims to explore the mechanism by which SGK1 is involved in OA progression. Firstly, the potential target gene of SGK1 was screened and SGK1 expression was determined in OA through bioinformatics analysis. Mouse OA model was then established and chondrocytes were extracted, after which inflammation was induced with lipopolysaccharide (LPS). Following LPS treatment, the chondrocytes were transfected with synthesized plasmids to explore the impact of SGK1, CREB1, and ABCA1 on apoptosis, proliferation and inflammation in OA. ChIP-PCR and dual-luciferase reporter gene assay were conducted to determine the binding relation between SGK1 and CREB1 as well as between CREB1 and ABCA1. OA mice presented with high expression of SGK1. Interestingly, we found that SGK1 inhibited CREB1 expression in chondrocytes, thereby inducing inflammation and suppressing chondrocyte proliferation. CREB1 was found to have a positive correlation with ABCA1 expression, while down-regulation of CREB1 resulted in the inhibition of cell proliferation and aggravated inflammation, which could be reversed by overexpressed ABCA1.

Taken altogether, silencing of SGK1 alleviated OA through epigenetic regulation of CREB1 and ABCA1 expression. These findings may provide novel insight into SGK1-based strategy for OA treatment.

The goal of the study was to evaluate the long-term outcome of combined arthroscopic distal clavicle excision and subacromial decompression. Retrospective, long-term cohort evaluation. Twenty patients with an average follow-up of 6 years (range, 3.9 to 9 years) were reviewed. All patients had ipsilateral impingement syndrome and acromioclavicular joint disease at the time of surgery and underwent arthroscopic subacromial decompression combined with arthroscopic distal clavicle excision. All patients returned for evaluation in person, in addition to filling out a questionnaire incorporating the University of California, Los Angeles (UCLA), and Constant scoring systems. Preoperative and postoperative radiographs were available for all patients. Postoperatively, all patients had pain relief and were satisfied with the result. The average postoperative UCLA Shoulder score was 29.8 +/- 0.6, compared with 17.5 +/- 3.0 before surgery (P =.001). The Constant Shoulder score averaged 98.5 +/- 2.1 postoperatively, compared with 70.5 +/- 11.2 preoperatively (P =.001). There was 100% good to excellent results using both scoring systems. Individual components of the UCLA scoring system (pain, function, and power) all showed significant postoperative improvement (P =.001). Constant categories of pain, activities of daily living, range of motion, and power also improved. Follow-up radiographs showed maintenance of the resected distal clavicle in 19 patients. Five patients (25%) had radiographic evidence of calcific density distal to the resected clavicle but were asymptomatic.

The long-term results of arthroscopic resection of the distal clavicle with concomitant subacromial decompression are uniformly good or excellent. Impingement and acromioclavicular joint disease frequently coexist and should be identified and treated concurrently.

We aimed to study the risk of renal cell carcinoma (RCC) with anti-tumor necrosis factor (anti-TNF) therapy in inflammatory bowel disease (IBD) and rheumatic diseases (RD) and calculate standardized incidence ratios (SIRs) in IBD. This was a retrospective case-control and cohort study spanning 25 years, including IBD and RD patients with a diagnosis of RCC (1990-2014) identified through the electronic database of a tertiary referral center. RCC was confirmed in seven anti-TNF-exposed (TNF+) and 21 anti-TNF-naive (TNF-) IBD and one TNF+ and 26 TNF- RD patients. In IBD-RCC, younger age at RCC diagnosis [median (interquartile range) 46 (42-58) vs. 63 (52-75) years; P=0.02], immunosuppressive therapy (100 vs. 24%; P<0.0004), partial nephrectomy (86 vs. 33%; P=0.02), and surgery less than 1 month after diagnosis of RCC (71 vs. 14%; P=0.004) were associated with anti-TNF. Compared with IBD, RD patients were older at RCC diagnosis [70 (60-77) vs. 59 (47-69) years; P=0.02] with less nephron-sparing surgery (26 vs. 54%; P=0.04) and more symptomatic (44 vs. 14%; P=0.02) and advanced tumors (30 vs. 7%; P=0.04). SIRs in IBD-RCC TNF- and TNF+ were 5.4 (95% confidence interval 2.9-9.2) and 7.1 (2.3-16.5) in male patients and 8.5 (3.7-16.8) and 4.8 (0.6-17.3) in female patients, respectively. The risk for RCC associated with anti-TNF in IBD was 0.8 (0.3-2.5) in men and 1.4 (0.2-5.5) in women.

The favorable patient and tumor profiles in IBD with anti-TNF may suggest incidentally discovered RCC on abdominal imaging. SIRs for IBD-RCC were not increased after anti-TNF exposure.

The authors have previously identified a peptide of the human muscarinic acetylcholine receptor-3 (m3AChR) as a suitable antigen for the immunodetection of antimuscarinic acetylcholine receptor autoantibodies in primary Sjögren's syndrome (pSS). The aim of this study was to assess the clinical correlations and disease specificity of these antibodies. Seventy-three pSS, 40 rheumatoid arthritis (RA), 19 systemic lupus erythematosus (SLE), 14 secondary Sjögren's syndrome (sSS) patients, 22 subjects in whom pSS was suspected but in whom the diagnosis not could eventually be established (suspSS) and 40 healthy subjects were investigated. An enzyme-linked immunosorbent assay system developed by the authors using a 16-mer peptide of the m3AChR (m3AChR(213-228)) in a recombinant fusion peptide form was used as the antigen. Anti-m3AChR(213-228) antibody positivity was observed in 66 (90%) of the pSS patients. The antibody levels correlated positively with the number of extraglandular organ manifestations. Both the mean antibody levels and the occurrence of anti-m3AChR(213-228) positivity were significantly higher in pSS than in the comparison groups. The test discriminated the pSS patients from the various comparison groups with specificities of 65, 68, 71 and 50% for RA, SLE, sSS and suspSS, respectively.

The presence of m3AChR(213-228) antibodies is a common feature in pSS. Although it is significantly more common in pSS than in the comparison groups, anti-m3AChR(213-228) positivity is not exclusive to pSS.

The early recognition and management of patients with hip lesions, such as femoroacetabular impingement (FAI) and early hip osteoarthritis (OA), may preempt significant hip morbidity. The identification of reliable biomarkers may help guide decision making in an efficient and cost-effective manner. To determine the biomarkers that have been associated with FAI as well as identify serum, synovial, and urinary analytes that have shown clinical utility in the prediction or identification of hip OA. Systematic review and meta-analysis. The terms "hip arthroscopy," "femoroacetabular impingement," "labral tear," "osteoarthritis," and "biomarker" were searched in PubMed, Web of Science, Scopus, Cochrane Library, and Google Scholar, yielding 276 articles. After screening, 7 articles were included. Pooled estimates were calculated utilizing a fixed-effects inverse-variance model weighted for individual study size. A total of 1747 patients with a mean age of 37.5 ± 4.5 years (76.4% female) were identified. Forty-three unique biomarkers were assessed. Although general proinflammatory cytokines IL-1 and TNF-α exhibited inconsistent trends in arthritic hips, IL-6 demonstrated a consistent increase (+84.8% [95% CI, 81.9%-87.6%];

COMP and FAC are specific biomarkers with potential utility in the diagnosis and management of FAI and hip OA, given their ability to differentiate between controls and patients with hip lesions. Further research is necessary to identify their ability in determining disease severity, predicting the response to treatment, and establishing an association with the risk of long-term OA.

The present study was conducted to investigate whether the serum levels of interleukin 6 (IL-6), soluble IL-2 receptor (sIL-2R) and sIL-6R are associated with the morphological appearance of rheumatoid arthritis (RA). Using the ELISA technique we measured the IL-6, sIL-2R and sIL-6R concentrations in the serum of 34 patients with RA and 28 patients with osteoarthritis (OA). Histological analysis of synovial samples distinguished 2 types of rheumatoid synovitis. Twenty-one RA specimens presented diffuse infiltrates of mononuclear cells without any specific microanatomical organization. In remaining 13 samples the formation of lymphocytic follicles with germinal center-like structures was found. Serum levels of IL-6, sIL-2R and sIL-6R were elevated in patients with RA compared to the OA control group (p < 0.001, p < 0.001 and p < 0.05 respectively). Concentrations of IL-6 and sIL-2R were highest in the serum of RA patients with follicular synovitis in comparison to patients with diffuse synovitis (p < 0.001 and p < 0.01 respectively) and could distinguish RA patients with these two histological variants of the disease. Serum levels of IL-6 and sIL-2R correlated with markers of disease activity such as ESR and CRP levels. In addition, the clinical data suggest a more severe disease among RA patients with follicular synovitis.

Distinct histological types of rheumatoid synovitis associated with unique serum concentrations of IL-6 and sIL-2R reflect levels of disease activity and confirm the concept of RA heterogeneity.

Introduction: There are many methods for diagnosis and treatment of knee joints osteoarthritis in modern orthopedics. The infrared radiation is one of the most popular and effective methods though it needs experimental substantiation on rats. The aim: Experimental definition of the effectiveness of the proposed method of conservative treatment of knee joints osteoarthritis using sodium diclofenac, glucosamine hydrochloride and infrared laser radiation, on the basis of biochemical markers of connective tissue metabolism in rats. Materials and methods: Experimental studies were performed on 40 white male rats. A part of rats received infrared laser radiation in addition to diclofenac sodium and glucosamine hydrochloride. Results: Using a complex of infrared laser radiation and glucosamine hydrochloride and diclofenac sodium in conservative treatment of rats with experimentally induced knee joints osteoarthritis rats after 24 days of treatment. Treatment with the above-mentioned scheme resulted in a significant reduction in the content of glycoproteins (28.5%), chondroitin sulfates (26.1%), alkaline phosphatase activity (32.3%), and I and II fractions of glycosaminoglycans, namely chondroitin-6- (28.7%) and chondroitin-4-sulfate (40.3%). Moreover, these indicators of the studied markers approached the level of intact animals.

Conclusions: Changes in biochemical markers of connective tissue in rats during experimental knee joints osteoarthritis indicated a higher efficiency of the treatment regimen with the use of low-intensity infrared laser radiation compared with exclusively drug therapy.

Diffuse alveolar hemorrhage (DAH) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). Pristane-treated B6 mice develop severe DAH within 2 weeks of treatment. MicroRNA-155 (miR-155) is a pleiotropic microRNA that plays a crucial role in the regulation of immune responses. Recent studies have revealed a pathogenic role of miR-155 in various autoimmune disorders. The purpose of this study was to examine the role of miR-155 in the development of DAH in pristane-induced lupus using miR-155-knockout (miR-155(-/-)) mice and miR-155 antagomir to silence miR-155. DAH was induced by an intraperitoneal injection of 0.5 ml of pristane. MicroRNA-155 antagomir was administered intravenously to silence miR-155 expression. Lung tissues were collected for RNA extraction and were embedded in paraffin for sectioning. Gene expression profiling data were analyzed using Ingenuity Pathway Analysis. Real-time quantitative polymerase chain reaction analysis was used for single-gene validation. Luciferase reporter assay and argonaute 2 immunoprecipitation were performed for target validation. MicroRNA-155 expression was significantly increased during the development of DAH. Disease progression was reduced in miR-155(-/-) mice as well as by in vivo silencing of miR-155 using a miR-155 antagomir. MicroRNA-155 silencing dampened pristane-induced ectopic activation of multiple inflammatory pathways and reduced the expression of proinflammatory cytokines. Several negative regulators of NF-κB signaling were inhibited by pristane and were reactivated in miR-155(-/-) mice. In particular, the antiinflammatory factor peroxisome proliferator-activated receptor α was identified as a direct target of miR-155.

MicroRNA-155 promotes pristane-induced lung inflammation. It contributes to ectopic activation of NF-κB signaling pathways by targeting multiple negative regulators. MicroRNA-155 antagomir may be a promising therapeutic strategy for treating acute lung inflammation in lupus.

To examine the phenotype of dendritic cell subsets in synovial fluid and peripheral blood from patients with rheumatoid arthritis (RA) or spondyloarthropathy (SpA). Multiparameter flow cytometry was used to identify and characterize dendritic cells in mononuclear cell populations isolated from synovial fluid and peripheral blood. Synovial fluid contained two subsets of dendritic cells (DC), myeloid and plasmacytoid. These subsets could also be identified in peripheral blood, but there were lower numbers of DC in peripheral blood compared with synovial fluid. Plasmacytoid DC were distinguished from the myeloid subset by high expression of CD123 and lack of expression of CD11c. In comparison with myeloid dendritic cells, the plasmacytoid subset were less mature, similar to those in peripheral blood. They failed to express CD83 and DC-LAMP, and had relatively low levels of CD40 and CD86. Comparison of dendritic cells in synovial fluid from RA and SpA patients showed increased numbers of the plasmacytoid subset in SpA.

This is the first demonstration of the plasmacytoid subset of dendritic cells in synovial fluid. Since these cells are major producers of type I interferons, their increased numbers in SpA might be relevant to pathogenesis, but the immature phenotype in SpA synovial fluid may also indicate that conditions for maturation of this subset do not pertain in SpA synovium.

In pediatric research, investigators rely on proxy reports of outcome, such as the proxy-completed Childhood Health Assessment Questionnaire (C-HAQ), to assess function in juvenile idiopathic arthritis (JIA). As children mature, they may self-complete the adult HAQ or the unvalidated adolescent-specific C-HAQ. It is unclear how these measures compare and whether they are directly interchangeable. The present study was undertaken to compare agreement between the proxy-completed C-HAQ, adolescent-specific C-HAQ, and the HAQ at initial presentation to pediatric rheumatologic care and 1 year following the first presentation in adolescents with JIA. Adolescents ages 11-17 years participating in the Childhood Arthritis Prospective Study (CAPS), a UK multicenter inception cohort, were included. In a CAPS substudy, adolescents self-completed the adolescent-specific C-HAQ and the HAQ, and proxies simultaneously completed the proxy-completed C-HAQ at baseline and 1 year. Correlation and agreement between scores were assessed at baseline. Agreement and ability to similarly classify clinically important changes over time were assessed at 1 year following initial presentation to rheumatologic care. A total of 107 adolescents (adolescent-specific C-HAQ and HAQ) or their proxies (proxy-completed C-HAQ) had completed all 3 measures at baseline. Median age at diagnosis was 13 years, and 61% were female. Although the 3 scores demonstrated strong correlations (r > 0.8), they were not completely interchangeable, with agreement ranging between 70% and 80%. There was similar agreement between the changes in scores between baseline and 1 year. Using proxy-completed C-HAQ minimum clinically important cutoffs, the adolescent-specific C-HAQ and the HAQ similarly classified 80% to 90% of adolescents as having improved or worsened.

While there is relatively high agreement and similar classification of change between HAQ and the 2 C-HAQ scores, these are not completely interchangeable. This impacts the comparison of function when measured in different ways over the lifespan.

Body fat is an important source of hormones and cytokines (adipokines) that not only regulate the energy balance, but also regulate the inflammatory and immune responses. This study investigated the association of clinical conditions with serum levels of adipokines in patients with rheumatoid arthritis. Serum levels of resistin, leptin, and adiponectin were measured by enzyme-linked immunosorbent assay in 141 patients (110 women) who fulfilled the 1987 revised criteria of the American Rheumatism Association for the diagnosis of rheumatoid arthritis and in 146 normal controls (124 women). Then the correlations between adipokine levels and clinical parameters were evaluated. The serum resistin level did not differ between the patients and controls. However, serum leptin levels were significantly higher in male and female rheumatoid arthritis patients than in the corresponding controls, while the serum adiponectin level was significantly higher in female patients than in female controls. Multivariate analysis revealed that predictors of an elevated resistin level were female sex and C-reactive protein (CRP), while the leptin level was related to the body mass index and CRP. Predictors of an elevated adiponectin level were the use of prednisolone and CRP, however, CRP was negatively associated with adiponectin in patients with rheumatoid arthritis.

The serum levels of resistin and leptin were positively associated with CRP level in patients with rheumatoid arthritis, suggesting that these adipokines may act as pro-inflammatory cytokines in this disease. The serum adiponectin level was elevated in the patients, however, it was negatively associated with CRP level. In addition, the serum levels of resistin, leptin, and adiponectin were also associated with female sex, BMI and the use of prednisolone, respectively.

Potent anti-inflammatory rheumatoid arthritis (RA) treatments are associated with reduced cardiovascular risk as well as increases in low-density lipoprotein (LDL) cholesterol. This apparent paradox may be explained by favorable changes in other lipid measurements. The objective of this study was to determine the longitudinal association between changes in inflammation with advanced lipoprotein measurements and high-density lipoprotein (HDL) cholesterol efflux capacity. We conducted this study in a longitudinal RA cohort from a large academic center, including subjects with high-sensitivity C-reactive protein (hs-CRP) reduction ≥10 mg/L at 2 time points 1 year apart. Subjects receiving statins during the study period or preceding 6 months were excluded. We compared total cholesterol, LDL cholesterol, HDL cholesterol, apolipoprotein B, and apolipoprotein A1 levels and HDL cholesterol efflux capacity at baseline and 1-year follow-up by using the paired t test. We also assessed the correlations between reductions in hs-CRP with percentage change in lipid parameters. We studied 90 RA subjects (mean age 57 years, 89% female), all of whom were receiving disease-modifying antirheumatic drugs. We observed a 7.2% increase in LDL cholesterol levels (P=0.02) and improvement in efflux capacity by 5.7% (P=0.002) between baseline and follow-up, with a median hs-CRP reduction of 23.5 mg/L. We observed significant correlations between reductions in hs-CRP with increases in apolipoprotein A1 (r=0.27, P=0.01) and HDL cholesterol efflux capacity (r=0.24, P=0.02).

Among RA subjects experiencing reductions in hs-CRP, we observed increased LDL cholesterol levels and concomitant improvements in HDL cholesterol efflux capacity. These findings provide further insight into lipid modulation and the beneficial effect of reduction in inflammation on lipids in vivo.

The aim of the study was to determine the prevalence and clinical significance of antibodies to individual histone components in systemic sclerosis (SSc). Serum samples from patients with limited cutaneous SSc (lSSc; n = 42) and diffuse cutaneous SSc (dSSc; n = 28) were examined for IgG and/or IgM antibodies to individual histone components and complexes by enzyme linked immunosorbent assay (ELISA). The level of IgG antibody to total histones was significantly higher in lSSc and dSSc than in normal controls. The level of IgM antibody to total histones was significantly higher in lSSc, but not in dSSc, than in normal controls. IgG antibody to total histones tended to be increased in dSSc when compared with that in lSSc. On the other hand, IgM antibody to total histones tended to be increased in lSSc when compared with that in dSSc. Although SSc showed various antihistone specificities, H2B, H2A-H2B, (H2A-H2B)-dsDNA were main antigens recognised by IgG antibodies in both lSSc and dSSc. Although IgM antibodies to H2B and H2A-H2B were also detected in both lSSc and dSSc, serum samples from lSSc patients exhibited highest IgM reactivity with H1.

SSc may be included among conditions in which heterogeneous antihistone antibodies are produced. IgM antibodies to the most accessible histone H1 may be related to mild clinical features (lSSc) and IgG antibodies to the inner core molecules of native histone such as H2B or complexes including H2B may be associated with severe clinical features (dSSc) in Ssc.

To develop a machine learning-based prediction model for incident radiographic osteoarthritis (OA) of the knee over 8 years using MRI-based cartilage biochemical composition and knee joint structure, demographics, and clinical predictors including muscle strength and symptoms. Individuals (n = 1,044) with baseline Kellgren Lawrence (KL) grade 0-1 in the right knee from the Osteoarthritis Initiative database were analyzed. 3T MRI at baseline was used to quantify knee cartilage T The 10-predictor model (Model 2, that includes cartilage and meniscus WORMS scores and cartilage T

A 10-predictor model including MRI parameters coupled with demographics, symptoms, muscle, and physical activity scores provides good prediction of incident radiographic OA over 8 years.

Rheumatoid arthritis (RA) is an inflammatory disease of the joint characterized by chronic synovitis causing pain, swelling and loss of function due to destruction of cartilage and bone. The complex series of pathological events occurring in RA is largely regulated via excessive production of pro-inflammatory cytokines, the most prominent being tumor necrosis factor (TNF). The objective of this work was to elucidate possible involvement of group IVA cytosolic phospholipase A2 (cPLA2α) in TNF-induced regulation of synovitis and joint destructive effectors in RA, to evaluate the potential of cPLA2α as a future therapeutic target. The involvement of cPLA2α in tumor necrosis factor (TNF)-induced intracellular signaling cascades in synoviocytes (synovial fibroblast-like cells) was analyzed by arachidonic acid (AA) release assay, synoviocyte enzyme activity assay, gene expression analysis by real-time PCR and ELISA immunoassay for the detection of prostaglandin E2 (PGE2), interleukin 8 (IL8) and stromelysin-1 (MMP3), respectively. Inhibitors of cPLA2α enzyme activity (AVX002, ATK) significantly reduced TNF-induced cellular release of AA, PGE2, IL8 and MMP3. This reduction was evident both at transcriptional, protein or metabolite levels. Interestingly, cPLA2α inhibition affected several key points of the arachidonyl cascade; AA-release, cyclooxygenase-2 (COX2) expression and PGE2 production. Furthermore, the results suggest that cPLA2α is subject to transcriptional auto-regulation as inhibition of cPLA2α resulted in reduced PLA2G4A gene expression in TNF-stimulated synoviocytes.

cPLA2α appears to be an important regulator of central effectors of inflammation and joint destruction, namely MMP3, IL8, COX2, and PGE2. Decreased transcription of the PLA2G4A and COX2 genes in response to cPLA2α enzyme inhibition further suggest a self-reinforcing effect of cPLA2α inhibition in response to TNF. Collectively, these results support that cPLA2α is an attractive therapeutic target candidate as its inhibition reduces the production of multiple key pro-inflammatory factors involved in RA pathogenesis.

To determine of catalytic activities of adenosine deaminase (ADA) and values of C-reactive protein (CRP) concentration in serums of patients with rheumatoid arthritis (RA), who were and were not treated with Methotrexate (MTX), and identifying the possibilities of using these biochemical parameters in diagnosing and monitoring of treatment effects in RA. The study involved 120 subjects (60 healthy ones, who are in accordance with examined groups concerning age and sex, 30 suffering from RA who were not treated with MTX and 30 suffering from RA who were treated by MTX). Catalytic activities of ADA in serum were determined by spectrophotometric method using adenosine as a substrate. CRP concentrations in serum were determined immunoturbidimetrically. A statistically significant correlation between values of ADA catalytic activities and values of CRP concentrations (r = 0.55, p < 0.01) in serums of subjects with RA without MTX treatment. At subjects with RA treated by MTX, correlation between values of ADA catalytic activities and values of CRP concentrations in serums was not statistically significant (r = 0.33, p > 0.01).

Study results have shown that ADA catalytic activity in serum can be a useful biochemical marker of inflammatory process in RA.

To establish recommendations for pharmacological treatment of knee osteoarthritis specific to France. On behalf of the French Society of Rheumatology (SFR), a bibliography group analyzed the literature on the efficacy and safety of each pharmacological treatment for knee osteoarthritis. This group joined a multidisciplinary working group to draw up recommendations. Strength of recommendation and quality of evidence level were assigned to each recommendation. A review committee gave its level of agreement. Five general principles were established: 1) need to combine pharmacological and non-pharmacological treatments, 2) personalization of treatment, 3) symptomatic and/or functional aim of pharmacological treatments, 4) need to regularly re-assess the treatments and 5) discussion about arthroplasty if medical treatment fails. Six recommendations involved oral treatments: 1) paracetamol should not necessarily be prescribed systematically and/or continuously, 2) NSAIDs, possibly as first-line, 3) weak opioids, 4) strong opioids, 5) symptomatic slow-acting drugs of osteoarthritis, and 6) duloxetine (off-label use). Two recommendations involved topical agents (NSAIDs and capsaicin<1%). Three recommendations involved intra-articular treatments: corticosteroid or hyaluronic acid injections that can be proposed to patients. The experts did not draw a conclusion about the benefits of platelet-rich plasma injections.

These are the first recommendations of the SFR on the pharmacological treatment of knee osteoarthritis.

Patients who sustain an acute anterior cruciate ligament (ACL) rupture are at increased risk to develop posttraumatic arthritis (PTA) in the injured knee whether the ACL is reconstructed or treated nonoperatively. Inflammatory cytokines and cartilage degradation biomarkers are elevated at the time of acute injury and postoperatively. This suggests that one mechanism for PTA may be an inflammatory degradative process initiated on the acute injury and sustained for some length of time independent of whether adequate joint stability is restored. Inflammatory cytokines and biomarkers of cartilage degradation are elevated in the synovial fluid several years after reconstruction of the ACL, indicating an ongoing imbalance between extracellular matrix destruction and repair. Cross-sectional study; Level of evidence, 3. In 11 patients who had undergone ACL reconstruction 8 years earlier, knee synovial fluid was aspirated from the operated knee and the contralateral nonoperated knee. The synovial fluid was analyzed for interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, sulfated glycosaminoglycans (sGAG), aggrecan neoepitope fragment (ARGS-aggrecan), and cartilage oligomeric matrix protein (COMP). At follow-up, the patients underwent bilateral weightbearing radiographs and bilateral MRIs of their knees. No significant differences between the operated and the contralateral knee were found for the synovial fluid concentrations of IL-1β, IL-6, TNF-α, sGAG, ARGS-aggrecan, or COMP. There were significantly more radiographically visible osteoarthritic changes in the operated knees compared with the contralateral knees. MRIs revealed that all grafts and all contralateral ACLs were intact and, furthermore, that there was significantly more meniscal and cartilage damage in the index knees than the contralateral knees.

Eight years after ACL reconstruction, there were no significant differences in inflammatory cytokines and biomarkers for cartilage degeneration between the nonoperated and the ACL-reconstructed knee, even though there were more osteoarthritic changes and meniscal and cartilage damage in the operated knee, as seen on weightbearing radiographs and MRI.

The aim of this study was to assess the magnitude of changes in nutritional body composition components as a consequence of rheumatoid arthritis (RA) and the extent to which these components are associated with RA clinical characteristics, serologic markers, and osteoporosis-related phenotypes (OP-RPs). Early pathologic signs, if detected, could assist in future preventative techniques. The study sample was comprised of 260 women with RA and 168 first-degree female relatives without RA who returned for body composition measurements using bioelectrical impedance analysis, from a previously established epidemiologic study conducted in Kazakhstan. In multivariate logistic regression, body composition components, the fat mass index (odds ratio [OR], 0.848; 95% confidence interval [CI], 0.786-0.913; P < 0.001) and the phase angle (PA; OR, 0.654; 95% CI, 0.467-0.826; P = 0.001), were independently and significantly negatively associated with RA after disease development. In multilinear regression analysis, PA was consistently associated with OP-RP, specifically concerning the spongial bone mineral density (BMDSPN) and cortical index, where ageing, reduced PA and increased disease duration explained 31.5% of BMDSPN and 37.3% of cortical index variation.

Data on RA in women in Kazakhstan consistently show that fat mass index and PA act as independent major covariates associated with RA affection status. These findings suggest exacerbated body composition deterioration when compared with healthy controls, potentially indicating the early appearance of sarcopenia and likely cachexic-like properties. The data also suggest that PA could serve as a potential predictor of RA prognosis, and the concomitant development of osteoporosis.

To quantify bone structure and perfusion parameters in regions of bone marrow edema pattern (BMEP), non-edematous bone marrow (NBM), and pannus tissue areas in the wrists of patients with rheumatoid arthritis (RA) using 3-Tesla (3T) magnetic resonance imaging (MRI), and high resolution peripheral quantitative computed tomography (HR-pQCT). Sixteen subjects fulfilling American College of Rheumatology classification were imaged using a HR-pQCT system and a 3T MRI scanner with an 8-channel wrist coil. Coronal T2-weighted and dynamic contrast-enhanced (DCE-MRI) images were acquired. BMEP and pannus tissue areas were segmented semiautomatically in T2-weighted images. NBM areas were placed at a similar distance from the joint space as BMEP regions. MR and HR-pQCT images were registered, and bone variables were calculated within the BMEP and NBM regions. Perfusion parameters in BMEP, pannus tissue, and NBM regions were calculated based on the signal-time curve obtained from DCE-MRI. Eighteen BMEP areas were segmented, 15 of them presented proximal to pannus-filled erosions. Significant increases in bone density and trabecular thickness and number were observed in all BMEP regions compared to NMB (p < 0.05). Significantly elevated perfusion measures were observed in both BMEP and pannus tissue regions compared to NBM (p < 0.05).

BMEP regions showed significantly increased bone density and structures as well as perfusion measures, suggesting bone remodeling and active inflammation. Combining MRI and HR-pQCT provides a powerful multimodality approach for understanding BMEP and erosions, and for potentially identifying novel imaging markers for disease progression in RA.

This work aimed at comparing the production of inflammatory and pro- and anti-angiogenic factors by normal/reactive (N/R) or inflammatory (I) areas of the osteoarthritic synovial membrane. The effects of interleukin (IL)-1β and chondroitin sulfate (CS) on the expression of pro- and anti-angiogenic factors by synovial fibroblasts cells (SFC) were also studied. Biopsies from N/R or from I areas of osteoarthritic synovial membrane were collected at the time of surgery. The inflammatory status of the synovial membrane was characterized by the surgeon according to macroscopic criteria, including the synovial vascularization, the villi formation and the hypertrophic aspect of the tissue. We assessed the expression of CD45, von Willebrand factor and vascular endothelial growth factor (VEGF) antigen by immunohistochemistry in both N/R and I biopsies. The production of IL-6, -8, VEGF and thrombospondin (TSP)-1 by N/R or I synovial cells was quantified by ELISA. SFC were cultured in the absence or in the presence of IL-1β (1 ng/ml) and with or without CS (10, 50, 200 μg/ml). Gene expression of pro-angiogenic factors (VEGF, basic fibroblast growth factor (bFGF), nerve growth factor (NGF), matrix metalloproteinase (MMP)-2 and angiopoietin (ang)-1) and anti-angiogenic factors (vascular endothelial growth inhibitor (VEGI), TSP-1 and -2) were determined by real time RT-PCR. Production of VEGI and TSP-1 was also estimated by ELISA. Immunohistochemistry showed the increase of lymphocyte infiltration, vascular density and VEGF expression in I compared to N/R synovial biopsies. Synovial cells from I areas produced more IL-6, IL-8 and VEGF but less TSP-1 than cells isolated from N/R synovial biopsies. The expression of pro-angiogenic factors by SFC was stimulated by IL-1β. A time dependent regulation of the expression of anti-angiogenic factor genes was observed. IL-1β stimulated the expression of anti-angiogenic factor genes but inhibited it after 24 h. CS reversed the inhibitory effect of IL-1β on anti-angiogenic factors, VEGI and TSP-1.

We demonstrated that synovial biopsies from I areas expressed a pro-angiogenic phenotype. IL-1β induced an imbalance between pro- and anti-angiogenic factors in SFC and CS tended to normalize this IL-1β-induced imbalance, providing a new possible mechanism of action of this drug.