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To evaluate the safety, efficacy and therapeutic mechanism of BI 655064, an antagonistic anti-CD40 monoclonal antibody, in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR). In total, 67 patients were randomised to receive weekly subcutaneous doses of 120 mg BI 655064 (n=44) or placebo (n=23) for 12 weeks. The primary endpoint was the proportion of patients who achieved 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Safety was assessed in patients who received at least one dose of study drug. At week 12, the primary endpoint was not met, with 68.2% of patients treated with BI 655064 achieving an ACR20 vs 45.5% with placebo (p=0.064); using Bayesian analysis, the posterior probability of seeing a difference greater than 35% was 42.9%. BI 655064 was associated with greater changes in CD40-CD40L pathway-related markers, including reductions in inflammatory and bone resorption markers (interleukin-6, matrix metalloproteinase-3, receptor activator of nuclear factor-κB ligand), concentration of autoantibodies (immunoglobulin [Ig]G rheumatoid factor [RF], IgM RF, IgA RF) and CD95+ activated B-cell subsets. No serious adverse events (AEs) related to BI 655064 treatment or thromboembolic events occurred; reported AEs were mainly of mild intensity. NCT01751776.

Although blockade of the CD40-CD40L pathway with BI 655064 in MTX-IR patients with RA resulted in marked changes in clinical and biological parameters, including reductions in activated B-cells, autoantibody production and inflammatory and bone resorption markers, with a favourable safety profile, clinical efficacy was not demonstrated in this small phase IIa study.

To examine the effects of depressive symptoms and spouse empathic responding on patient disability and marital quality over time and to identify factors that contribute to patients perceiving their spouses as responding empathically to their rheumatoid arthritis (RA). Patients diagnosed with RA and their spouses (n = 133 couples) independently completed mailed questionnaires at baseline and 1 year later. Patients completed measures of functional impairment, marital quality, depressive symptoms, and perceived empathic responding from their spouse. Spouses reported their own depressive symptoms and empathic responding behavior. Perceived empathic responding was found to interact with spouse depressive symptoms, contributing significantly to the prediction of patient functional impairment at followup. Only when spouse empathic responding was low was spouse depression associated with greater patient functional impairment 1 year later. Similarly, in the model predicting patient marital quality at followup, there were significant 2-way interactions between perceived empathic responding and both spouse depressive symptoms and patient depressive symptoms. Only when spouse empathic responding was low did patient or spouse depression significantly predict poorer marital quality at followup. Patient perceptions of spouse empathic responding were found to depend on spouse reports of their own empathic responding, patient marital satisfaction, and the interaction of patient depressive symptoms and marital satisfaction.

Empathic responding from the spouse was found to buffer against the negative effects of spouse depression on functional and marital outcomes for patients with RA. In developing couple-oriented RA treatments, increasing perceived empathic responding could serve as a useful target for intervention.

To assess the psychological, behavioural and social adjustment of children (7-11 years) and adolescents (12-16 years) with juvenile chronic arthritis (JCA). Higher rates of maladjustment were expected to be found in these patients. Self report questionnaires were used within the context of personal interviews. Family functioning and social support were studied as well. Forty seven patients with JCA, 52 healthy peers and their respective parents participated in the study. Self esteem, perceived competence and body image in patients with JCA were as positive as they were in healthy participants. There were no differences between ill and healthy youngsters with respect to the incidence of psychopathology. Patients with JCA, in general, perceived themselves as socially competent, but they seemed to have somewhat less opportunity or energy to participate in social activities. Children with JCA showed a high level of aspiration to cope with social expectations. This aspiration seemed to be even stronger in case the disease caused more strains, for example, in periods of inflammation and in the systemic onset type. The high level of social adjustment in children with JCA seemed to be supported by highly cohesive family structures. Generally, adolescents with JCA experienced much social support.

In contrast with our expectation, children and adolescents with JCA seemeed to cope quite well with the psychological and social consequences of their long term condition. For future studies, it is hypothesised that the high levels of adaptation might imply an enduring psychological strain, which is reflected in an altered function of the autonomic nervous system.

To determine the short-term and medium-term risks of cancer in patients receiving anti-tumor necrosis factor alpha (anti-TNFalpha) therapies that have proven effective in the treatment of chronic inflammatory conditions. By linking together data from the Swedish Biologics Register, Swedish registers of RA, and the Swedish Cancer Register, we identified and analyzed for cancer occurrence a national cohort of 6,366 patients with RA who first started anti-TNF therapy between January 1999 and July 2006. As comparators, we used a national biologics-naive RA cohort (n = 61,160), a cohort of RA patients newly starting methotrexate (n = 5,989), a cohort of RA patients newly starting disease-modifying antirheumatic drug combination therapy (n = 1,838), and the general population of Sweden. Relative risks (RRs) were estimated using Cox regression analyses, examining overall RR as well as RR by time since the first start of anti-TNF therapy, by the duration of active anti-TNF therapy, and by the anti-TNF agent received. During 25,693 person-years of followup in 6,366 patients newly starting anti-TNF, 240 first cancers occurred, yielding an RR of 1.00 (95% confidence interval 0.86-1.15) versus the biologics-naive RA cohort, and similar RRs versus the other 2 RA comparators. RRs did not increase with increasing time since the start of anti-TNF therapy, nor with the cumulative duration of active anti-TNF therapy. During the first year following the first treatment start, but not thereafter, dissimilar cancer risks for adalimumab, etanercept, and infliximab were observed.

During the first 6 years after the start of anti-TNF therapy in routine care, no overall elevation of cancer risk and no increase with followup time were observed.

Bone marrow lesions are a radiographic indication of bony pathology closely associated with advanced osteoarthritis of the adjacent joint. Injection of autologous orthobiologic products, including bone marrow concentrate and platelet-rich plasma, have demonstrated safety and efficacy in treating both advanced osteoarthritis (via intraarticular injection) and associated bone marrow lesions (via intraosseous injection). The relative efficacy of intraarticular versus intraosseous injection of orthobiologics has not been evaluated at the present time. The objective was to evaluate differences in orthobiologic bone marrow lesions treatment, either as a collateral result of intraarticular injection with bone marrow concentrate and platelet products alone, or intraosseous plus intraarticular injection as measured by patient reported outcomes. This study employed a prospective case-matched cohort design. This study took place at a single outpatient interventional orthopedic pain clinic. Using data from a prospective orthobiologic treatment registry of knee patients, a population of knee osteoarthritis with bone marrow lesions patients who had undergone only intraarticular knee injections of bone marrow concentrate and platelets (for symptomatic advanced osteoarthritis) were age, gender, and disease severity case-matched to a series of advanced osteoarthritis and bone marrow lesions patients who underwent intraosseous plus intraarticular injections. Self-reported patient outcomes for Numeric Pain Scale, International Knee Documentation Committee, lower extremity functional scale, and a modified single assessment numeric evaluation were compared between the 2 treatment groups. Eighty patients were included, 40 in each group. Although pain and functional outcome scores were significantly improved in both treatment groups, there was no statistically significant differences in patient reported outcomes based on the type of treatment. There are several limitations to this study, including multiple providers performing the injections, varying onset of symptoms to treatment, and additional injections after their initial treatment, that were not controlled. In addition, increasing the sample size may be beneficial as well, particularly with the large bone marrow lesions group, which did suggest possible improvement with intraosseous plus intraarticular over the intraarticular, although was not statistically significant in our sample. Limited data availability for this cohort as well as some missing data are other limitations to consider.

Treating knee bone marrow lesions with intraosseous bone marrow concentrate and platelet products did not affect patient reported outcomes.

The psychometric properties of Patient Reported Outcomes Measurement Information System (PROMIS) instruments have been explored in a number of general and clinical samples. No study, however, has evaluated the psychometric function of these measures in individuals with symptomatic knee osteoarthritis (KOA). The aim of this project was to evaluate the construct (structural) validity and floor/ceiling effects of four PROMIS measures in this population. We conducted a secondary analysis of baseline data from a randomized trial comparing Tai Chi and physical therapy. Participants completed four PROMIS static short-form instruments (i.e., Anxiety, Depression, Physical Function, and Pain Interference) as well as six well-validated (legacy) measures that assess pain, function, and psychological health. We calculated descriptive statistics and percentages of participants scoring the minimum (floor) and maximum (ceiling) possible scores for PROMIS and legacy measures. We also estimated the association between PROMIS scores and scores on legacy measures using Spearman's rank correlations coefficients. Data from 204 participants were analyzed. Mean age of the sample was 60 years; 70% were female. The PROMIS Anxiety and Depression had floor effects with 17 and 24% of participants scoring the minimum, respectively. PROMIS Anxiety and Depression scores had strongest associations with general mental health, including stress (Perceived Stress Scale, r ≥ 0.65) and depression (Beck Depression Index-II, r = 0.70). PROMIS Pain Interference scores correlated most strongly with measures of whole body pain (Short-Form 36 Bodily Pain, r = -0.73) and physical health (Short-Form 36 Physical-Component Summary, r = -0.73); their correlations were lower with other legacy measures, including with the WOMAC knee-specific pain (r = 0.47). PROMIS Physical Function scores had stronger associations with scores on the Short-Form 36 Physical Function (r = 0.79) than with scores on other legacy measures. Clinicaltrials.gov NCT01258985. Registered 10 December 2010.

The four PROMIS static-short forms performed well among individuals with symptomatic knee osteoarthritis as evidenced in correlations with legacy measures. PROMIS Anxiety and Depression target general mental health (e.g., stress, depression), and PROMIS Pain Interference and Physical Function static-short forms target whole-body outcomes among participants with symptomatic knee osteoarthritis. Floor effects in the PROMIS Anxiety and Depression scores should be considered if needing to distinguish among patients with very low levels of these outcomes.

To compare the accuracy of daily and recalled pain measurements in hip and knee osteoarthritis (OA). A prospective study investigating pain intensity over 29 days in patients with painful OA. Pain was assessed on days 1 and 29 during visits. Between these two visits, daily (worst, least, usual, mean, at rest and during daily life) and recalled pain intensities were randomly recorded by telephone interview with a numerical rating scale. We studied 129 patients, with a mean age of 67.7 ± 10.0 years, 27.1% males. Daily prospective assessments demonstrated that the strongest correlations were between 'mean daily' and 'usual' pain (r=0.88) and between 'mean daily' and 'worst' pain (r=0.86). Retrospective assessments demonstrated a strong correlation between recalled pain intensities and calculated mean of daily assessments over the seven and 28 days (0.78 and 0.67, respectively), but weakened by adjustment for pain intensity on the day of recalled pain assessment. Anxiety and depression scores did not affect pain recall for 7 and 28 days.

In hip and knee OA, prospective daily pain assessment can be performed either by assessing 'usual pain' or 'worst pain' of the day. When recalled over one and four weeks, recall pain intensity is well correlated with calculated mean of prospective daily pain assessments during the same period, but correlations are weaker as the length of period increases. Either for 1 and 4 weeks, retrospective assessments are influenced by current pain intensity at the end of the period.

To study the effects of three different laser treatments (650 nm alone, 10.6 μm alone and combined laser of 650 nm and 10.6 μm) on experimental osteoarthritis of the knees in C57 black mice. Sixty C57 black mice were divided randomly into 6 groups. Ten mice were assigned to a normal control group (no intervention) and the other 5 groups were subjected to a forced running regimen to induce osteoarthritis. One group was set as the model control group. The other 4 groups were given 90 s of a 650 nm laser, 90 s of a 10.6 μm laser, 90 s of a combined laser, or a sham treatment on acupoint Dubi (ST35) of the rear left leg 3 times per week for 4 weeks. The modified Mankin score was used to evaluate the degree of cartilage degradation. Immunohistochemical staining for heat shock protein (HSP) 70 was conducted. Mankin scores of the model control group and the sham control group were significantly higher than that of the normal control group (P<0.01). Mankin score of the combined laser group was significantly lower than that of the model control group (P<0.01). Compared with the normal control group, there was a significant induction of HSP70 in the arthritic chondrocytes of the combined laser group.

The arthritic cartilage induced in C57 black mice improved significantly after combined laser treatment of 650 nm and 10.6 μm lasers. This effect may be related to the induction of HSP70 in the arthritic chondrocytes. The two different lasers appear to have a synergistic effect.

Recent findings suggest that acute-phase rheumatic fever (RF) patients present with higher frequencies of obsessive-compulsive disorder (OCD) and tic disorders. Until now, there have been no such studies in RF in non-acute phases. To verify whether patients with a history of RF with or without Sydenham's chorea (SC) present with higher rates of OCD, tic disorders, and other obsessive-compulsive (OC) spectrum disorders (such as body dysmorphic disorder [BDD]) than controls. Between February 1999 and December 2002, 59 consecutive outpatients with non-acute RF (28 with and 31 without SC) from an RF clinic and 39 controls from an orthopedics clinic were blindly assessed for OC spectrum disorders using structured interviews to assign DSM-IV diagnosis. Data were analyzed with Fisher exact and chi(2) tests to compare frequencies of disorders, and Kaplan-Meier survival analyses were used to obtain age-corrected rates. The age-corrected rates of tic disorders were higher in patients with RF without SC (N = 3; 14.39%) (p =.003) when compared with controls. Age-corrected rates for OC spectrum disorders (OCD, tic disorders, and BDD) combined were higher both in RF without SC (N = 4; 20.65%) and RF with SC (N = 5; 19.55%) groups than in controls (N = 1; 2.56%) (p =.048).

RF, even in the non-acute phase, may increase the risk for some OC spectrum disorders, such as OCD, tic disorders, and BDD. These data, although preliminary, reinforce the idea that OC spectrum disorders may share common underlying pathophysiologic mechanisms and vulnerability factors with RF or that RF could trigger central nervous system late manifestations such as OC spectrum disorders.

This study aimed to determine the prevalence of ultrasound-detected tendon abnormalities in healthy subjects (HS) across the age range. Adult HS (age 18-80 years) were recruited in 23 international Outcome Measures in Rheumatology ultrasound centres and were clinically assessed to exclude inflammatory diseases or overt osteoarthritis before undergoing a bilateral ultrasound examination of digit flexors (DFs) 1-5 and extensor carpi ulnaris (ECU) tendons to detect the presence of tenosynovial hypertrophy (TSH), tenosynovial power Doppler (TPD) and tenosynovial effusion (TEF), usually considered ultrasound signs of inflammatory diseases. A comparison cohort of patients with rheumatoid arthritis (RA) was taken from the Birmingham Early Arthritis early arthritis inception cohort. 939 HS and 144 patients with RA were included. The majority of HS (85%) had grade 0 for TSH, TPD and TEF in all DF and ECU tendons examined. There was a statistically significant difference in the proportion of TSH and TPD involvement between HS and subjects with RA (HS vs RA p<0.001). In HS, there was no difference in the presence of ultrasound abnormalities between age groups.

Ultrasound-detected TSH and TPD abnormalities are rare in HS and can be regarded as markers of active inflammatory disease, especially in newly presenting RA.

To examine the association of serum CRP and ESR with muscle strength in patients with knee OA. Cross-sectional data from 285 patients with knee OA from the Amsterdam Osteoarthritis (AMS-OA) cohort were analysed. CRP (mg/l) and ESR (mm/l) were measured in serum from patients' blood samples and the values were dichotomized for the analyses. Strength of quadriceps and hamstring muscles was assessed using an isokinetic dynamometer. Univariable and multivariable linear regression analyses were used to assess the association of CRP and ESR with muscle strength, adjusting for relevant confounders. Elevated levels of serum CRP (β = -0.10; P = 0.04) and ESR (β = -0.12; P = 0.02) were associated with lower muscle strength after adjustment for age, sex, comorbidities and NSAID use. The associations were no longer significant when BMI was incorporated in the adjusted model.

Inflammation might influence muscle strength in patients with knee OA. Moreover, the link between inflammation and obesity might explain the effect that BMI has in the associations between inflammatory markers (i.e. CRP and ESR) and muscle strength.

The aim of this study is to investigate the prognostic value of tibial component coverage (over-hang and under-hang) and the alignment of total knee arthroplasty (TKA) components 1 week after surgery. We select patient-reported outcome measures (PROMS) (the Knee Society score (KSS score) and the Western Ontario and McMaster Universities Osteoarthritis Index-pain score (WOMAC pain score)) and tibial bone resorption (TBR) 2 years after surgery as the end points. The study retrospectively analyzed 109 patients undergoing TKA (fixed-bearing prosthesis with asymmetrical tibial tray) from January 2014 to December 2017 in Huashan Hospital. By using standard long-leg X-rays, anteroposterior (AP) and lateral X-rays of the knee, tibial component coverage (under-hang or over-hang), AP tibial-femoral anatomical angle (AP-TFA), AP femoral angle (AP-FA), AP tibial angle (AP-TA), and lateral tibial angle (L-TA) were measured at 1 week after surgery, while TBR was measured through postoperative 1-week and 2-year AP and lateral radiographs of the knee on three sides (medial side, lateral side on AP radiograph, and anterior side on lateral radiograph). The Pearson correlation analysis, simple linear regression, multiple linear regression, the Student's t test, and one-way ANOVA together with Tukey's post hoc test (or Games-Howell post hoc test) were used in the analyses. Tibial under-hang was more likely to appear in our patients following TKA (42%, medially, 39%, laterally, and 25%, anteriorly). In multivariate linear regression analysis of TBR, tibial under-hang (negative value) 1 week after surgery was positively correlated with TBR 2 years later on the medial (p = 0.003) and lateral (p = 0.026) side. Tibial over-hang (positive value) 1 week after surgery on the medial side was found negatively related with KSS score (p = 0.004) and positively related with WOMAC pain score (p = 0.036) 2 years later in multivariate linear regression analysis of PROMS. Both scores were better in the anatomically sized group than in the mild over-hang group (or severe over-hang) (p < 0.001). However, no significant relationship was found between the alignment of TKA components at 1 week after surgery and the end points (TBR and PROMS) 2 years later.

Under-hang of the tibial component on both the medial and lateral sides can increase the risk of TBR 2 years later. Over-hang of tibial component on the medial side decreases the PROMS (KSS score and WOMAC pain score) 2 years later. An appropriate size of tibial component during TKA is extremely important for patient's prognosis, while the alignment of components might not be as important.

Osteoarthritis is associated with cell death and extracellular matrix degradation in articular cartilage. Autophagy is an essential cellular homeostasis mechanism that was found to be deficient in ageing and osteoarthritic cartilage. This study determined whether pharmacological inhibition of the mammalian target of rapamycin (mTOR), a key inhibitor of autophagy, has disease-modifying activity in experimental osteoarthritis. Experimental osteoarthritis was induced by transection of the medial meniscotibial ligament and the medial collateral ligament in 2-month-old C57Bl/6 mice (n=36). Rapamycin (1 mg/kg weight/day) (n=18 mice) or dimethyl sulphoxide vehicle control (n=18 mice) was administered intraperitoneally for 10 weeks. Histopathological changes in articular cartilage and synovium were examined by using semiquantitative scoring systems. Rapamycin effects on mTOR signalling, autophagy, cartilage homeostasis and inflammation were analysed by immunohistochemistry and immunofluorescence staining. Rapamycin affected the mTOR signalling pathway in mouse knee joints as indicated by the inhibition of ribosomal protein S6 phosphorylation, a target of mTOR and activation of LC3, a main marker of autophagy. The severity of cartilage degradation was significantly (p<0.01) reduced in the rapamycin-treated group compared with the control group and this was associated with a significant (p<0.05) decrease in synovitis. Rapamycin treatment also maintained cartilage cellularity and decreased ADAMTS-5 and interleukin-1β expression in articular cartilage.

These results suggest that rapamycin, at least in part by autophagy activation, reduces the severity of experimental osteoarthritis. Pharmacological activation of autophagy may be an effective therapeutic approach for osteoarthritis.

Planning a family is a complex decision. For women with chronic conditions such as rheumatoid arthritis (RA), there are additional concerns about their own and their baby's health. This qualitative study examined women's experiences of negotiating their family decisions in the context of RA. A qualitative study was conducted in 14 women who provided a written account of their motherhood decisions and experiences. Those 'stories' were then thematically analysed. RA was found to affect women's motherhood decisions and experiences. Three key themes were identified for both the process of decision making and the experience of that decision: capacity, uncertainty and acceptance. Only two of the women decided not to have children, while for others the decision centred on changing expectations from the number of children they planned to have, to parenting within the restrictions of their physical abilities.

While many women struggled through the negotiations of their motherhood choices, those who chose to have children reported great joy in that experience. The challenges faced by women with RA contemplating motherhood, however, highlight the need for understanding and support from health professionals and the provision of resources so that women can make informed choices.

The objective of this study was to investigate which genes are regulated by osteogenic protein-1 (OP-1) in human articular chondrocytes using Affimetrix gene array, in order to understand the role of OP-1 in cartilage homeostasis. Chondrocytes enzymatically isolated from 12 normal ankle cartilage samples were cultured in high-density monolayers and either transfected with OP-1 antisense oligonucleotide in the presence of lipofectin or treated with recombinant OP-1 (100 ng/ml) for 48 hours followed by RNA isolation. Gene expression profiles were analyzed by HG-U133A gene chips from Affimetrix. A cut-off was chosen at 1.5-fold difference from controls. Selected gene array results were verified by real-time PCR and by in vitro measures of proteoglycan synthesis and signal transduction. OP-1 controls cartilage homeostasis on multiple levels including regulation of genes responsible for chondrocyte cytoskeleton (cyclin D, Talin1, and Cyclin M1), matrix production, and other anabolic pathways (transforming growth factor-beta (TGF-β)/ bone morphogenetic protein (BMP), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), genes responsible for bone formation, and so on) as well as regulation of cytokines, neuromediators, and various catabolic pathways responsible for matrix degradation and cell death. In many of these cases, OP-1 modulated the expression of not only the ligands, but also their receptors, mediators of downstream signaling, kinases responsible for an activation of the pathways, binding proteins responsible for the inhibition of the pathways, and transcription factors that induce transcriptional responses.

Gene array data strongly suggest a critical role of OP-1 in human cartilage homeostasis. OP-1 regulates numerous metabolic pathways that are not only limited to its well-documented anabolic function, but also to its anti-catabolic activity. An understanding of OP-1 function in cartilage will provide strong justification for the application of OP-1 protein as a therapeutic treatment for cartilage regeneration and repair.

Fibromyalgia syndrome (FMS) is a chronic pain condition associated with a substantial decrease in health-related quality of life (HRQoL). This study investigated the relationships of HRQoL with clinical parameters of FMS (pain, insomnia and fatigue) and affective variables (depression and anxiety). Women with FMS (n=145) and healthy women (n=94) completed the Short-Form Health Survey (SF-36) to evaluate HRQoL, and self-report questionnaires pertaining to clinical pain, symptoms of anxiety and depression, fatigue and insomnia. Patterns of associations were assessed by correlation, multiple linear regression, and mediation analyses. FMS patients showed lower scores on all SF-36 scales than healthy individuals. Clinical and emotional factors were inversely associated with SF-36 scores. Although depression was the strongest predictor of global HRQoL (explaining 36% of its variance), clinical pain and fatigue were the main predictors of physical components of HRQoL; depression and trait-anxiety were the main predictors of mental HRQoL components. Results of mediation analysis showed that depression, trait-anxiety and fatigue mediated the effect of clinical pain on HRQoL. Additionally, depression, trait-anxiety and fatigue mutually influenced each other, increasing their negative effects on the different areas of HRQoL. Among all emotional factors, only anxiety and depression were considered.

Our results suggest that FMS pain and related functional disability may increase depression and anxiety, in turn aggravating the primary symptoms of FMS and indirectly increasing the negative influence of pain on HRQoL. These results showed the need to evaluate and treat negative affective states in FMS.

To examine the factor structure of the Center for Epidemiologic Studies Depression Scale (CES-D) in a sample of patients with rheumatoid arthritis (RA), testing all of the alternative models suggested by the previous evidence. The CES-D was administered to a group of RA patients (n = 685) during a structured telephone interview. The telephone interview was repeated 6 months later (n = 537) and 12 months later (n = 453). Confirmatory factor analyses were conducted to test alternative models. The correlated 4-factor model and the second-order 4-factor model were the best fitting models.

The factor structure of the CES-D previously found in the general population was replicated in an RA sample. The results are consistent with previous evidence of criterion contamination in the CES-D when used in an RA sample and provide support for the view that a single summary score may not be the most informative index of the CES-D.

The study investigated the association between plasma homocysteine, folate and vitamin B12 with 5,10 methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), thymidylate synthase (TYMS 2R → 3R) and methionine synthase (MTR A2756G) polymorphisms and methotrexate (MTX) treatment and toxicity in Tunisian Rheumatoid arthritis (RA) patients. A total of 185 patients with RA were included. Homocysteine (Hcy) was assessed by fluorescence polarization immunoassay, and folate and vitamin B12 were measured by chemiluminescence immunoassays. The genetic polymorphisms were analyzed by PCR or PCR-RFLP. Hyperhomocysteinemia (HHC) was considered for Hcy > 15 µmol/L. MTHFR C677T polymorphism was associated with HHC in RA patients (multi-adjusted OR, 95% CI 2.18, [1.07-4.57]; p = 0.031). No association was detected with the remaining polymorphisms. Plasma Hcy, folate, and vitamin B12 did not differ according to each polymorphism, or with MTX treatment or toxicity. However, HHC was more prevalent in patients with than those without MTX toxicity (32.7 vs. 16.7%; p = 0.035).

The MTHFR 677TT genotype is an independent risk factor for HHC in Tunisians RA patients. HHC could be a useful marker of MTX toxicity in RA patients.

Intervertebral disc degeneration (IDD) represents major cause of low back pain. Quercetin (QUE) is one of the approved senolytic agents. In this study, we evaluated the protective effects of QUE on IDD development and its underlying mechanism. Effects of senolytic agent QUE on the viability of nucleus pulposus cells (NPCs) were measured by CCK-8 assays and EdU staining. The senescence associated secreted phenotype (SASP) factors expressions were measured by qPCR, western blot, and ELISA; and NF-κB pathway was detected by immunofluorescence and western blot. Molecular docking was applied to predict the interacting protein of QUE; while Nrf2 was knocked down by siRNAs to confirm its role in QUE regulated senescence phenotype. X-ray, MRI, Hematoxylin-Eosin and Safranin O-Fast green staining were performed to evaluate the therapeutic effects of QUE on IDD in the puncture-induced rat model. In in vitro experiments, QUE inhibited SASP factors expression and senescence phenotype in IL-1β-treated NPCs. Mechanistically, QUE suppressed IL-1β induced activation of the NF-κB pathway cascades; it was also demonstrated in molecular docking and knock down studies that QUE might bind to Keap1-Nrf2 complex to suppress NF-κB pathway. In vivo, QUE ameliorated the IDD process in the puncture-induced rat model.

Together the present work suggests that QUE inhibits SASP factors expression and senescence phenotype in NPCs and ameliorates the progression of IDD via the Nrf2/NF-κB axis, which supports senolytic agent QUE as a potential therapeutic agent for the treatment of IDD.

The present study sought to identify dietary nutrients associated with the prevalence of radiographic knee osteoarthritis (OA) in the Japanese elderly of a population-based cohort of the Research on Osteoarthritis Against Disability (ROAD) study. From the baseline survey of the ROAD study, 719 participants >or=60 years of age (270 men, 449 women) of a rural cohort were analyzed. Dietary nutrient intakes for the previous 1 month were assessed by a self-administered brief diet history questionnaire. The radiographic severity at both knees was determined by the Kellgren/Lawrence (KL) system. The prevalence of knee OA of KL >or=2 was 70.8%. Age, body mass index, and female sex were positively associated with the prevalence. Among the dietary factors, only vitamin K intake was shown to be inversely associated with the prevalence of radiographic knee OA by multivariate logistic regression analysis. The presence of joint space narrowing of the knee was also inversely associated with vitamin K intake. The prevalence of radiographic knee OA for each dietary vitamin K intake quartile decreased with the increased intake.

The present cross-sectional study using a population-based cohort supports the hypothesis that low dietary vitamin K intake is a risk factor for knee OA. Vitamin K may have a protective role against knee OA and might lead to a disease-modifying treatment.

The aim was to compare the prevalence of periodontal conditions in patients with juvenile idiopathic arthritis (JIA) (n=78, age 14.4 years) with those revealed in a healthy control group (n=75, age 15.5 years). In both groups, the approximal plaque index (API), the modified sulcular bleeding index (SBI), and the clinical attachment loss (CAL) were determined. Laboratory parameters for JIA activity included the capsule-reactive protein (CRP) and the immunoglobulins A, G, M. JIA patients had a significantly higher API (64.6%versus 49.9%, p=0.004) and slightly higher mean percentages of sites with CAL>3.5 mm (0.58%versus 0.22%, p=0.041). There was no significant difference in the prevalence of patients and controls who had sites with CAL >3.5 mm (25.6%versus 17.3%, p=0.212). The mean CAL was slightly greater (0.2 mm; p=0.030) in patients with CRP> or =5.0 mg/l compared with patients with CRP<5.0 mg/l. Patients who took non-steroidal anti-inflammatory drugs (NSAIDs) had a significantly decreased SBI (26.2%versus 51.1%, p=0.019).

After adjustment for microbial plaque, JIA is not a risk factor for periodontitis.

The presence of anti-citrullinated peptide antibodies is the most specific serological marker known of rheumatoid arthritis (RA). The PADI4 gene, encoding a haematopoietic isoform of the peptidylarginine deiminase citrullinating enzyme, has recently been associated with susceptibility to RA in the Japanese population. A subsequent UK report could not confirm this association, and a later French study also yielded a negative result. Given this discrepancy and the importance of antibodies against citrullinated peptides in the early course of the disease, we performed a replication study. Three hundred and fifty-four Spanish RA patients and 498 Spanish controls were recruited from two Madrid hospitals. The padi4_104 and padi4_94 single-nucleotide polymorphisms (SNP) were analysed by TaqMan assays. Similarly to what was described in the British and French population, the less frequent allele of this SNP was not associated with the disease (genotype TT, 16.1% in RA patients vs 14.3% in controls; P = 0.46, odds ratio 1.15, 95% confidence interval 0.78-1.71). A confirmatory negative result was obtained on analysing another SNP in the same gene, padi4_94, in 248 RA patients and 394 controls.

The results of our group and from the British and French studies strongly suggest that polymorphisms of the PADI4 gene do not play a role in susceptibility to RA in European populations.

In adult patients with arthritis, use of the tumor necrosis factor (TNF) inhibitor etanercept (ETN) is often associated with a reduction in the utilization of co-medications, particularly steroids. Comparatively little is known about the utilization of co-medications when ETN is initiated in pediatric patients with juvenile idiopathic arthritis (JIA). This study analyzed Canadian longitudinal claims level data spanning January 2007 to April 2017. Data were collated from the IQVIA Private Drug Plan, Ontario Public Drug Plan, and the Quebec Public Drug Plan (Régie de l'assurance maladie du Québec) databases. Patients < 18 years of age were indexed when filling a prescription for ETN between January 2008 and January 2016. Those who met the inclusion and exclusion criteria were assessed for methotrexate (MTX), and prednisone (PRD) use in the 6 months prior to and 12 months following initiation of ETN. Longitudinal claims data for 330 biologic-naive pediatric patients initiating ETN therapy were included. The majority of patients were female (67%), aged 10-17 years (64%), and with a drug history consistent with JIA (96%). Most patients were from Quebec (36%) or Ontario (33%). Dosing of ETN was weight-based with a mean dosage over the first year of 31 mg per week. ETN dosing was relatively consistent over the first year. In total, 222 (67%) patients did not use MTX and 223 (68%) did not use PRD before or after starting ETN. A total of 17% (18/103) of MTX-treated and 50% (46/92) of PRD-treated patients discontinued use of those medications upon initiation of ETN treatment. In patients continuing MTX or PRD, significant reductions in the weekly dosage from 14.3 to 6.8 mg per week for MTX and from 56 to 23 mg per week for PRD were observed (P < 0.01).

This study of Canadian claims-level data is the first large prespecified analysis of co-medication utilization following the initiation of ETN therapy in pediatric patients. A decline in both MTX and PRD use and dosage was observed and may be associated with benefits related to safety, tolerability, and overall healthcare costs.

Minimally invasive implantation of unicompartmental knee prostheses can shorten rehabilitation time and lead to better functional results than conventional implantation. Exact positioning of the implant should be achieved, as this is a factor for the long-term survival of the prosthesis, although malpositioning can result due to the poor intraoperative view when using the minimally invasive approach. Navigation of the unicompartmental prosthesis could lead to a better implant positioning without losing the advantages of a minimally invasive approach. The same unicondylar knee prosthesis was implanted in a total of 40 patients, of whom 20 were implanted using navigation (kinematic navigation) and 20 using a conventional technique. The operating time was assessed in both groups. The orientation of the tibial and femoral implants was assessed radiologically postoperatively. We analysed these results according to the optimal positioning range proposed by the manufacturer. Furthermore, we examined the clinical results with the knee society score (KSS). A good positioning of the prosthesis was observed in both techniques with only 11% of the radiologic measurements out of the proposed optimal range in each group. The operating time was significantly longer in the navigation group (17 min). The KSS did not differ between both groups at a follow-up of 16 resp. 18 months (navigated group: 184 points, conventional group: 178 points).

Navigation did not lead to a better positioning of the prosthesis than the conventional method and the operating time was longer. The clinical results were similar in both groups. The navigation may be a useful help for surgeons performing less unicompartmental knee arthroplasty using a minimally invasive approach.

Anterior cruciate ligament (ACL) injury incurred from high-impact activities leads to an increased risk of osteoarthritis. Impact forces that cause ACL failure can also inflict cartilage damage, whereby its extent and distribution may be influenced by the ligament failure mechanism. Descriptive laboratory study. Six porcine knee specimens were mounted to a material testing system at 70 degrees of flexion. During compression, rotational and translational data of the specimens were recorded with a motion-capture system. Compression was successively repeated with increasing actuator displacement until a significant drop in compressive force response was observed; ligament failure was assessed by dissection. Osteocartilage explants were extracted from the meniscus-covered sites (anterior, exterior, and posterior) and exposed (interior) sites on both tibial compartments. The explants were sectioned, stained, and histologically scored using the modified Mankin grading system. Five of the 6 specimens incurred ACL failure. On failure, a significant compressive force drop (1812.5-2659.3 N) was observed together with considerable posterior femoral translation; 2 specimens underwent external rotation, while 2 had internal rotation and 1 had no substantial rotation. Generally, the meniscus-covered sites displayed significant surface fraying and occasional deep clefts; the exposed site did not present substantial surface irregularities but indicated more tidemark disruption. Higher Mankin scores observed at certain sites illustrated a localized presence of contact and shear forces, which may be caused by pivoting and sliding of the femoral condyles during rotation. Cartilage injury arising at the time of ACL injury may lead to an accelerated risk of joint degeneration.

The porcine model can be a tenable preliminary option for assessing the role of the human ACL during joint compression. Impact loads that result in ligament failure can potentially inflict considerable cartilage damage; the damage profile may be affected by the type of failure mechanism.

To study the frequency of remission using 3 sets of criteria in patients with rheumatoid arthritis (RA) at 5 years after the diagnosis. All adult patients with recent onset inflammatory arthritis who did not meet criteria or show clinical signs of other specific arthritides were included in the RA1997 inception cohort at Jyväskylä Central Hospital, Finland, and were assessed for remission at 5-year control examination. Remission was defined as (1) American College of Rheumatology (ACR) remission (fatigue excluded), (2) clinical remission with no tender and no swollen joints and normal erythrocyte sedimentation rate, and (3) radiographic remission with no worsening of erosions and no new erosions from baseline to 5 years. The study included 127 patients with early RA (mean age 56 yrs, 61% female, 54% with positive rheumatoid factor, and 25% with erosions). At 5 years, 111 patients were examined, 17% (95% CI 11%-25%) of whom met ACR remission criteria, 37% (95% CI 28%-47%) met clinical remission criteria, and 55% (95% CI 49%-68%) met radiographic remission criteria. Only 13 (12%) patients met all 3 sets of remission criteria. The rate of remission was statistically significantly different (p < 0.001) using the 3 sets.

The rate of remission in RA depends on the criteria used. No gold standard exists for defining remission in RA. A set of criteria including no sign of inflammatory activity and no radiographic progression might be a basis for development of clinically relevant remission criteria for RA.

Subclinical cardiac involvement diagnosis is important for long term management of rheumatoid arthritis (RA) patients. Recently, 2D speckle tracking echocardiography (STE) allows non invasive and angle-independent measurement of left ventricular (LV) dimensions and regional myocardial strain (ε). The aim of this study was to assess whether STE can be useful to detect subclinical cardiac involvement in RA patients. We studied 22 RA patients (10 M, 12 F, aged 46 ± 12 years) without clinical evidence of coronary artery disease (CAD) and 20 healthy controls matched for age and sex by STE. LV end-systolic longitudinal and radial ε from apical 4-chamber view were analyzed using available software (QLAB 6.0). Standard echo and Doppler parameters did not differ between the 2 groups. Tissue Doppler Imaging (TDI) showed a significant reduction of S', E' and E'/A' ratio from the basal septum and lateral mitral annulus in RA patients. LV end-systolic radial and longitudinal ε of basal-lateral, basal- and mid-septal, mid-lateral and apical segments were significantly reduced compared to controls.

Our data indicate that LV end-systolic radial and longitudinal ε are reduced in RA patients without CAD despite normal standard echo. Non invasive evaluation of LV function by STE appears to be useful to detect subclinical cardiac involvement in comparison to conventional 2D echoDoppler, representing a promising new modality to follow-up RA patients for cardiac involvement.

To examine for a possible relationship between osteoarthritis and cardiovascular disease. A systematic review and meta-analysis. Published and unpublished literature from: MEDLINE, EMBASE, CINAHL, the Cochrane Library, OpenGrey and clinical trial registers. Search to 22 November 2014. Cohort, case-control, randomised and non-randomised controlled trial papers reporting the prevalence of cardiovascular disease in osteoarthritis were included. Fifteen studies with 32,278,744 individuals were eligible. Pooled prevalence for overall cardiovascular disease pathology in people with osteoarthritis was 38.4% (95% confidence interval (CI): 37.2% to 39.6%). Individuals with osteoarthritis were almost three times as likely to have heart failure (relative risk (RR): 2.80; 95% CI: 2.25 to 3.49) or ischaemic heart disease (RR: 1.78; 95% CI: 1.18 to 2.69) compared with matched non-osteoarthritis cohorts. No significant difference was detected between the two groups for the risk of experiencing myocardial infarction or stroke. There was a three-fold decrease in the risk of experiencing a transient ischaemic attack in the osteoarthritis cohort compared with the non-osteoarthritis group.

Prevalence of cardiovascular disease in patients with osteoarthritis is significant. There was an observed increased risk of incident heart failure and ischaemic heart disease in people with osteoarthritis compared with matched controls. However, the relationship between osteoarthritis and cardiovascular disease is not straightforward and there is a need to better understand the potential common pathways linking pathophysiological mechanisms.

Evaluation of hepatic lesions in patients treated with methotrexate (MTX) generally used the Roenigk histological score. However, the sensitivity of the method for hepatic fibrosis assessment has been discussed. The semi-quantitative histological scoring system (SSS) offers a sensitive and specific evaluation of liver fibrosis. Both scores have been evaluated in liver biopsies of patients with rheumatoid arthritis. Seventy-four liver biopsies were obtained in 57 rheumatoid arthritis patients before initiation of MTX (group 1, 38 cases), in cases of a persistently high level of transaminases during 1 yr of treatment (group 2, 10 cases) and after a MTX total dose of 2 g (group 3, 26 cases). Eleven biopsies of groups 1 and 3 originated from the same patient in 11 cases. Specimens were examined blindly by two anatomopathologists. The three groups were compared with an ANOVA. Sequential biopsies performed in 11 patients were compared with the Wilcoxon paired test. The Roenigk score and the SSS were significantly correlated (P<0.0001). Only a mild fibrosis was found in 33.8% (25/74) of the biopsies with the Roenigk score. Liver fibrosis, graded as mild (48.6%), moderate (41.8%) or severe (4%), was demonstrated in 94.6% (70/74) of the biopsies with the SSS. The Roenigk score and the SSS of the three patient groups were not statistically significantly different. The scores did not progress in the 11 patients who had serial biopsies.

SSS is much more sensitive than the Roenigk score for the evaluation of hepatic fibrosis. However, SSS did not show progression of hepatic fibrosis in patients with rheumatoid arthritis treated with MTX.

To examine the role of adenosine receptor 2a gene (ADORA2a) polymorphisms on outcome of MTX treatment in RA. Subjects included 309 RA patients with a defined response to MTX. Patients were included if they were (i) good responders (n = 147) (ESR <20 for >6/12 on stable dose of MTX) (ii) inefficacy failures (n = 101) (physician statement and failure to reduce ESR/CRP by 20%) or (iii) adverse event (AE) failures (n = 61) (verified by medical record review). AEs were sub-divided into gastrointestinal (GI) (n = 24), abnormal LFTs (n = 20) or other (n = 17). 8 single nucleotide polymorphisms (SNPs) within ADORA2a were genotyped using the Sequenom MALDI-TOF platform. Five SNPs within ADORA2a were associated with stopping MTX for AEs (OR 2.1-3.07, P < 0.05 for all). Analysis by AE type showed that the association was specific for GI toxicity. No association was observed between ADORA2a and inefficacy outcomes.

Genetic variation within ADORA2a is significantly associated with AEs on MTX, specifically GI AEs. Knowledge of the ADORA2a genotype may help to improve identification of patients at high risk of GI toxicity with MTX.

To evaluate and compare the efficacy of pharmacological and nonpharmacological treatments of fibromyalgia syndrome (FMS). This meta-analysis of 49 fibromyalgia treatment outcome studies assessed the efficacy of pharmacological and nonpharmacological treatment across four types of outcome measures-physical status, self-report of FMS symptoms, psychological status, and daily functioning. After controlling for study design, antidepressants resulted in improvements on physical status and self-report of FMS symptoms. All nonpharmacological treatments were associated with significant improvements in all four categories of outcome measures with the exception that physically-based treatment (primarily exercise) did not significantly improve daily functioning. When compared, nonpharmacological treatment appears to be more efficacious in improving self-report of FMS symptoms than pharmacological treatment alone. A similar trend was suggested for functional measures.

The optimal intervention for FMS would include nonpharmacological treatments, specifically exercise and cognitive-behavioral therapy, in addition to appropriate medication management as needed for sleep and pain symptoms.

It is unclear whether postoperative outcomes are associated with the cartilage regeneration after open wedge high tibial osteotomy (OWHTO) combined with microfracture. The purpose of this study was to evaluate the regeneration of the articular cartilage, radiologic, and clinical outcomes after OWHTO with and without microfracture. Eighty-seven patients who underwent OWHTO from 2014 to 2015 were retrospectively included in this study. Fifty-seven OWHTOs with microfracture on medial femoral condyle (MFC) (group 1) and 30 OWHTOs without microfracture (group 2) were compared at a mean 2-year follow-up. The regeneration of the articular cartilage was evaluated using International Cartilage Repair Society (ICRS) grade on the second-look arthroscopy and the magnetic resonance observation of cartilage repair tissue (MOCART) score on magnetic resonance imaging (MRI). The weight-bearing line (WBL) ratio, hip-knee-ankle (HKA) angle, joint line convergence angle (JLCA) and Ahlbäck grade were evaluated. The clinical outcomes were evaluated using the Western Ontario and McMaster University (WOMAC) scores and the Knee Society (KS). The articular cartilage in the MFC were regenerated in 67.8% of group 1 (43/57) and 58.6% of group 2 (16/30), respectively (p = 0.014). However, change of the ICRS grades of the medial tibial plateau, lateral and patellofemoral compartments showed no statistical difference between the groups. Total MOCART score in group 1 was superior to that in the group 2 at postoperative 2 years (41.8 ± 18.6 vs. 31.8 ± 19.8, p = 0.023). Regarding MOCART score, microfracture was only effective in the defect filling and integration to the border zone of the MFC (p < 0.001 and p = 0.035, respectively). Other radiologic and clinical outcomes showed no statistical differences between the groups.

Microfracture of the MFC during OWHTO only helped the filling of the degenerative cartilage defect and the integration of the cartilage with adjacent cartilage. However, the clinical and radiologic outcome could not be improved by mircrofracture in the OWHTO.

Report on radiographic effects and maintenance of clinical benefit with intravenous golimumab 2 mg/kg+methotrexate (MTX) for up to week (wk) 52 in active rheumatoid arthritis (RA). Patients (n=592) with active RA (≥6/66 swollen, ≥6/68 tender joints, C reactive protein (CRP) ≥1.0 mg/dL and positive for rheumatoid factor and/or anticyclic citrullinated protein antibody at screening) despite MTX ≥3 months (stable dose of 15-25 mg/week for ≥4 weeks) participated in this multicentre, international, randomised, double blind, placebo controlled, phase 3 study. Patients were randomised (2:1) to receive intravenous golimumab 2 mg/kg or placebo infusions at weeks 0 and 4 and then every 8 weeks; patients continued their stable MTX regimen. Placebo patients started golimumab 2 mg/kg at wk16 (early escape; <10% improvement in tender and swollen joints) or wk24 (crossover by design). Week 24 and wk52 radiographic (van der Heijde-Sharp (vdH-S) scores), clinical efficacy and safety data up to 1 year are reported here. Significant and rapid clinical improvement was observed up to wk24 of intravenous golimumab therapy. Golimumab+MTX treated patients demonstrated less radiographic progression than placebo treated patients at wk24 (vdH-S score mean change 0.03 vs 1.09; p<0.001) and wk52 (0.13 vs 1.22; p=0.001). Among patients with ≥20% improvement in the American College of Rheumatology response criteria or who achieved a 'good' or 'moderate' response according to the 28 joint Disease Activity Score employing CRP at wk24, approximately 80% maintained this response up until wk52. Through an average of 43.5 weeks of follow-up, 64.6% of patients receiving golimumab+MTX reported adverse events, most commonly non-serious infections. NCT00973479, EudraCT 2008-006 064-11.

In patients with active RA despite MTX, intravenous golimumab+MTX yielded significant inhibition of structural damage at wk24 and wk52, and sustained clinical improvement in signs and symptoms with no new safety signals up to 1 year.

The ALIGN study (NCT01061723) evaluated the efficacy and safety of sarilumab, the first fully human monoclonal antibody against interleukin-6 receptor-α (IL-6Rα), in patients with ankylosing spondylitis (AS). Patients with active AS despite conventional treatment were randomised to placebo, or one of five subcutaneous dose regimens of sarilumab (100, 150 or 200 mg every other week, or 100 or 150 mg every week), for 12 weeks. The primary efficacy end point was the percentage of patients achieving the Axial SpondyloArthritis international Society (ASAS) 20 response criteria at week 12. Secondary endpoints included ASAS40 response, ASAS partial remission, AS Disease Activity Score, high-sensitivity C-reactive protein (hs-CRP) value, and safety. Baseline demographic and disease characteristics of the 301 patients enrolled were similar across treatment groups. At week 12, there was no statistically significant difference in ASAS20 response rate between placebo (ASAS20 = 24.0%) and any sarilumab dose group. A significantly greater reduction in hs-CRP value was achieved with the higher sarilumab doses versus placebo. No other statistically significant differences were evident for secondary efficacy endpoints. The most common treatment-emergent adverse events reported for sarilumab included infections (non-serious), neutropenia, and increase in alanine aminotransferase. No cases of tuberculosis, opportunistic, or fungal infections, or bowel perforations were reported. Seven patients experienced a treatment-emergent serious adverse event (all in sarilumab treatment groups). No deaths occurred.

The ALIGN study shows that IL-6Rα blockade with sarilumab was not an effective treatment for AS. Sarilumab was generally well tolerated with a manageable safety profile.

To analyze the influence of 2 different treatment strategies on general and specific damage accrual in patients with systemic lupus erythematosus (SLE). Two cohorts were identified according to the responsible physicians: patients treated at the autoimmune diseases unit (ADU), and patients treated by other members of the internal medicine (IM) department. Members of the ADU worked with a protocol including the universal prescription of hydroxychloroquine (HCQ), the use of maximum oral prednisone dosages ≤30 mg/day and maintenance therapy with ≤5 mg/day, by using methylprednisolone pulses and/or early immunosuppressive (IS) drugs. We analyzed the influence of these 2 treatment strategies on damage accrual, both general and domain specific, attributed to glucocorticoids, cardiovascular (CV) disease, SLE, and unclassified, since the diagnosis of disease in patients with a followup ≥5 years. A total of 74 patients were included in the ADU group and 213 in the IM group. They were comparable for most demographic and lupus-related variables. ADU patients received prednisone later and at lower doses, more methylprednisolone pulses, earlier IS drugs and more HCQ (P < 0.05 for all comparisons). The Systemic Lupus Erythematosus Disease Activity Index score decreased similarly in both cohorts (P = 0.4). Patients in the ADU group were less likely to accrue any damage (P = 0.007). They accrued less glucocorticoid-related (adjusted hazard ratio [HR] 0.23 [95% confidence interval (95% CI) 0.07-0.80]), CV disease (adjusted HR 0.28 [95% CI 0.08-0.95]), and unclassified damage (adjusted HR 0.58 [95% CI 0.3-1.1]). Both groups accrued similar SLE-related damage (adjusted HR 0.84 [95% CI 0.40-1.75]).

The use of reduced oral prednisone doses, which was possible by combining different therapies, reduced glucocorticoid-related damage and improved CV prognosis without increasing damage caused by SLE.

In this large population-based study we aimed to assess:(1)mortality in ankylosing-spondylitis(AS) patients compared to the general population.Considering demographics,comorbidities and treatment.(2)factors associated with mortality within AS patients. This study was designed as a retrospective-cohort study utilizing the electronic-database of the largest health maintenance organization in Israel.All AS patients diagnosed between 2002-2018 were included.Controls were matched by age,gender,clinic, and enrollment-time.Follow-up continued until death or end of study. The study comprised 5,930 AS patients and 29,018 matched controls that were followed-up for a median period of 7.5 years.There were 667 deaths within the AS cohort and 2,919 deaths within controls,the mean age-at-death was 76.9 years and 77.1 years respectively(p=0.74). 3,249(55.8%) of AS patients were treated only with non-steroidal-anti-inflammtory-drugs(NSAIDs), 1,760(30.2%) were treated with tumor-necrosis-factor-α-inhibitors(TNFi),and 1,687(29.0%) with disease-modifying-antirheumatic-drugs(DMARDs).Mortality rates were increased among AS patients compared to controls with an age-and-sex-adjusted HR of 1.19(95%CI1.10-1.30).The association was significant for men(HR=1.15,95%CI 1.04-1.27) and women(HR=1.32,95%CI 1.13-1.54), and after adjusting for background comorbidities (HR=1.14,95%CI 1.05-1.24).AS patients treated with TNFi or with a combination of TNFi and DMARDs did not have significant difference in mortality rates compared to controls(HR=0.67,95%CI 0.38-1.18;HR=0.93,95%CI 0.69-1.25;respectively).Age,male-gender,mean C-reactive-protein(CRP) levels and general comorbidities were predictors of mortality within the AS cohort.

AS patients had increased mortality risk compared to the general population after adjusting for age, sex, and baseline comorbidities.AS patients treated with TNFi did not demonstrate excess mortality compared to matched controls.Within the AS cohort age, male-gender, background comorbidities, and higher CRP levels were identified as risk factors for mortality.

To quantify the effects of possible risk factors for herpes zoster at different ages. Case-control study. UK Clinical Practice Research Datalink primary care data. 144 959 adults diagnosed with zoster between 2000 and 2011; 549,336 age, sex, and practice matched controls. Conditional logistic regression was used to generate adjusted odds ratios to estimate the strength of association of each potential risk factor with zoster and assess effect modification by age. The median age of the cases and controls was 62 years. Factors associated with increased risk of zoster included rheumatoid arthritis (3111 (2.1%) v 8029 (1.5%); adjusted odds ratio 1.46, 99% confidence interval 1.38 to 1.55), inflammatory bowel disease (1851 (1.3%) v 5118 (0.9%); 1.36, 1.26 to 1.46), chronic obstructive pulmonary disease (6815 (4.7%) v 20 201 (3.7%); 1.32, 1.27 to 1.37), asthma (10 243 (7.1%) v 31 865 (5.8%); 1.21, 1.17 to 1.25), chronic kidney disease (8724 (6.0%) v 29 437 (5.4%); 1.14, 1.09 to 1.18), and depression (6830 (4.7%) v 22 052 (4.0%); 1.15, 1.10 to 1.20). Type 1, but not type 2, diabetes showed some association with zoster (adjusted odds ratio 1.27, 1.07 to 1.50). The relative effects of many assessed risk factors were larger in younger patients. Patients with severely immunosuppressive conditions were at greatest risk of zoster-for example, patients with lymphoma (adjusted odds ratio 3.90, 3.21 to 4.74) and myeloma (2.16, 1.84 to 2.53), who are not eligible for zoster vaccination.

A range of conditions were associated with increased risk of zoster. In general, the increased risk was proportionally greater in younger age groups. Current vaccines are contraindicated in people at the greatest risk of zoster, highlighting the need for alternative risk reduction strategies in these groups.

Duloxetine hydrochloride is a reuptake inhibitor of 5-hydroxytryptamine and norepinephrine used to treat depression, generalized anxiety disorder, neuropathic pain, and stress incontinence in women. We investigated the efficacy of duloxetine in painful diabetic neuropathy and fibromyalgia to allow comparison with other antidepressants. We searched PubMed, EMBASE (via Ovid), and Cochrane CENTRAL up to June 2008 for randomised controlled trials using duloxetine to treat neuropathic pain. We identified six trials with 1,696 patients: 1,510 were treated with duloxetine and 706 with placebo. All patients had established baseline pain of at least moderate severity. Trial duration was 12 to 13 weeks. Three trials enrolled patients with painful diabetic neuropathy (PDN) and three enrolled patients with fibromyalgia. The number needed to treat (NNT) for at least 50% pain relief at 12 to 13 weeks with duloxetine 60 mg versus placebo (1,211 patients in the total comparison) was 5.8 (95% CI 4.5 to 8.4), and for duloxetine 120 mg (1,410 patients) was 5.7 (4.5 to 5.7). There was no difference in NNTs between PDN and fibromyalgia. With all doses of duloxetine combined (20/60/120 mg) there were fewer withdrawals for lack of efficacy than with placebo (number needed to treat to prevent one withdrawal 20 (13 to 42)), but more withdrawals due to adverse events (number needed to harm (NNH) 15 (11 to 25)). Nausea, somnolence, constipation, and reduced appetite were all more common with duloxetine than placebo (NNH values 6.3, 11, 11, and 18 respectively). The results for duloxetine are compared with published data for other antidepressants in neuropathic pain.

Duloxetine is equally effective for the treatment of PDN and fibromyalgia, judged by the outcome of at least 50% pain relief over 12 weeks, and is well tolerated. The NNT of 6 for 50% pain relief suggests that this is likely to be a useful drug in these difficult-to-treat conditions, where typically only a minority of patients respond. Comparing duloxetine with antidepressants for pain relief in DPN shows inadequacies in the evidence for efficacy of antidepressants, which are currently recommended in PDN care pathways.

There is a need to incorporate multiple tissues into in vitro OA models to evaluate novel therapeutics. This approach is limited by inherent donor variability. We present an optimized research tool: a human OA cartilage-synovium explant co-culture model (OA-EXM) that employs donor-matched lower and upper limit response controls combined with statistical approaches to address variability. Multiple rapid read-outs allow for evaluation of therapeutics while cataloguing cartilage-synovium interactions. 48-h human explant cultures were sourced from OA knee arthroplasties. An OA-like cartilage-synovium co-culture baseline was established relative to donor-matched upper limit supraphysiological pro-inflammatory cytokine and lower limit OA cartilage or synovium alone controls. 100 nM dexamethasone treatment validated possible "rescue effects" within the OA-EXM dual tissue environment. Gene expression, proteoglycan loss, MMP activity, and soluble protein concentrations were analyzed using blocking and clustering methods. The OA-EXM demonstrates the value of the co-culture approach as the addition of OA synovium increases OA cartilage proteoglycan loss and expression of MMP1, MMP3, MMP13, CXCL8, CCL2, IL6, and PTGS2, but not to the extent of supraphysiological stimulation. Conversely, OA cartilage does not affect gene expression or MMP activity of OA synovium. Dexamethasone shows dual treatment effects on synovium (pro-resolving macrophage upregulation, protease downregulation) and cartilage (pro-inflammatory, catabolic, and anabolic downregulation), and decreases soluble CCL2 levels in co-culture, thereby validating OA-EXM utility.

The OA-EXM is representative of late-stage OA pathology, captures dual interactions between cartilage and synovium, and combined with statistical strategies provides a rapid, sensitive research tool for evaluating OA therapeutics.

Chinese herbal medicine (CHM) has been commonly used for treating osteoarthritis in Asia for centuries. This study aimed to conduct a large-scale pharmaco-epidemiologic study and evaluate the frequency and patterns of CHM used in treating osteoarthritis in Taiwan. A complete database (total 22,520,776 beneficiaries) of traditional Chinese medicine (TCM) outpatient claims offered by the National Health Insurance program in Taiwan for the year 2002 was employed for this research. Patients with osteoarthritis were identified according to the diagnostic code of the International Classification of Disease among claimed visiting files. Corresponding prescription files were analyzed, and an association rule was applied to evaluate the co-prescription of CHM for treating osteoarthritis. There were 20,059 subjects who visited TCM clinics for osteoarthritis and received a total of 32,050 CHM prescriptions. Subjects between 40 and 49 years of age comprised the largest number of those treated (19.2%), followed by 50-59 years (18.8%) and 60-69 years group (18.2%). In addition, female subjects used CHMs for osteoarthritis more frequently than male subjects (female: male = 1.89: l). There was an average of 5.2 items prescribed in the form of either an individual Chinese herb or formula in a single CHM prescription for osteoarthritis. Du-zhong (Eucommia bark) was the most commonly prescribed Chinese single herb, while Du-huo-ji-sheng-tang was the most commonly prescribed Chinese herbal formula for osteoarthritis. According to the association rule, the most commonly prescribed formula was Du-huo-ji-sheng-tang plus Shen-tong-zhu-yu-tang, and the most commonly prescribed triple-drug combination was Du-huo-ji-sheng-tang, Gu-sui-pu (Drynaria fortune (Kunze) J. Sm.), and Xu-Duan (Himalaya teasel). Nevertheless, further clinical trials are needed to evaluate the efficacy and safety of these CHMs for treating osteoarthritis.

This study conducted a large scale pharmaco-epidemiology survey of Chinese herbal medicine use in OA patients by analyzing the NHIRD in Taiwan in year 2002.

Which is the best strategy to achieve (drug-free) inactive disease in juvenile idiopathic arthritis (JIA)? In a randomised, single-blinded, study in disease-modifying anti-rheumatic drug (DMARD)-naive patients with JIA, three treatment-strategies were compared: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX +etanercept. Treatment-to-target entailed 3-monthly DMARD/biological adjustments in case of persistent disease activity, with drug tapering to nil in case of inactive disease.After 24 months, primary outcomes were time-to-inactive-disease and time-to-flare after DMARD discontinuation. Secondary outcomes were adapted ACRPedi30/50/70/90 scores, functional ability and adverse events. 94 children (67 % girls) aged median (IQR) 9.1 (4.6-12.9) years were enrolled: 32 in arms 1 and 2, 30 in arm 3. At baseline visual analogue scale (VAS) physician was mean 49 (SD 16) mm, VAS patient 53 (22) mm, erythrocyte sedimentation rate 12.8 (14.7), active joints median 8 (5-12), limited joints 2.5 (1-4.8) and Childhood Health Assessment Questionnaire score mean 1.0 (0.6).After 24 months, 71% (arm 1), 70% (arm 2) and 72% (arm 3) of patients had inactive disease and 45% (arm 1), 31% (arm 2) and 41% (arm 3) had drug-free inactive disease. Time-to-inactive-disease was median 9.0 (5.3-15.0) months in arm 1, 9.0 (6.0-12.8) months in arm 2 and 9.0 (6.0-12.0) months in arm 3 (p=0.30). Time-to-flare was not significantly different (overall 3.0 (3.0-6.8) months, p=0.7). Adapted ACR pedi-scores were comparably high between arms. Adverse events were similar. 1574.

Regardless of initial specific treatments, after 24 months of treatment-to-target aimed at drug-free inactive disease, 71% of recent-onset patients with JIA had inactive disease (median onset 9 months) and 39% were drug free. Tightly controlled treatment-to-target is feasible.

To study the direct physiological and emotional impact of an animal-assisted activity (AAA) session (a form of complementary and integrative medicine) in patients with fibromyalgia (FM). The study population consisted of 221 participants with FM who were attending Mayo Clinic's Fibromyalgia Treatment Program between August 5, 2017, and September 1, 2018. This was a randomized controlled trial. Participants were randomly assigned to either the treatment group (a 20-minute session with a certified therapy dog and handler) or the control group (a 20-minute session with a handler only). To gain a better understanding of the direct physiological and emotional effects of AAA in patients with FM, we used multiple noninvasive physiologic-emotional biomarkers, including salivary cortisol and oxytocin concentrations, tympanic membrane temperatures, and various cardiac parameters, in addition to standardized pain and mood-based questionnaires. Results show a decrease in heart rate, an increase in heart rate variability, an increase in well-being survey scores, an increase in salivary oxytocin, and subsequent tympanic membrane temperature changes, suggesting that participants in the treatment group were in a more positive emotional-physiologic state as a result of the AAA session compared with the control group.

Our results suggest that a 20-minute therapy dog visit in an outpatient setting can significantly and positively impact the physical and mental health of patients with FM.

There is consistent evidence from observational studies of an association between occupational lifting and carrying of heavy loads and the diagnosis of hip osteoarthritis. However, due to the heterogeneity of exposure estimates considered in single studies, a dose-response relationship between cumulative physical workload and hip osteoarthritis could not be determined so far. This study aimed to analyze the dose-response relationship between cumulative physical workload and hip osteoarthritis by replacing the exposure categories of the included studies with cumulative exposure values of an external reference population. Our meta-regression analysis was based on a recently conducted systematic review (Bergmann A, Bolm-Audorff U, Krone D, Seidler A, Liebers F, Haerting J, Freiberg A, Unverzagt S, Dtsch Arztebl Int 114:581-8, 2017). The main analysis of our meta-regression comprised six case-control studies for men and five for women. The population control subjects of a German multicentre case-control study (Seidler A, Bergmann A, Jäger M, Ellegast R, Ditchen D, Elsner G, Grifka J, Haerting J, Hofmann F, Linhardt O, Luttmann A, Michaelis M, Petereit-Haack G, Schumann B, Bolm-Audorff U, BMC Musculoskelet Disord 10:48, 2009) served as the reference population. Based on the sex-specific cumulative exposure percentiles of the reference population, we assigned exposure values to each category of the included studies using three different cumulative exposure parameters. To estimate the doubling dose (the amount of physical workload to double the risk of hip osteoarthritis) on the basis of all available case-control-studies, meta-regression analyses were conducted based on the linear association between exposure values of the reference population and the logarithm of reported odds ratios (ORs) from the included studies. In men, the risk to develop hip osteoarthritis was increased by an OR of 1.98 (95% CI 1.20-3.29) per 10,000 tons of weights ≥20 kg handled, 2.08 (95% CI 1.22-3.53) per 10,000 tons handled > 10 times per day and 8.64 (95% CI 1.87-39.91) per 10

Under specific conditions, the application of an external reference population allows for the derivation of a dose-response relationship despite high exposure heterogeneities in the pooled studies.

To study granulocyte adhesion to E-selectin, VCAM-1 and ICAM-1 in patients with primary Sjögren's syndrome (pSS). In previous studies diminished neutrophil adhesion has been shown as measured by the nylon fiber method. Neutrophil and eosinophil adhesion to the adhesion molecules E-selectin, VCAM-1 and ICAM-1 were measured using transfected fibroblasts. The cell surface expression of the integrin proteins CD11a, CD11b, CD18 and CD29 on neutrophils was assayed by means of flow cytometry. Neutrophils and eosinophils from patients with pSS had elevated basal adhesion in the presence of Mn2+ as compared with controls (basal adhesion was considered to be the adhesion to untransfected fibroblasts). Granulocyte adhesion to E-selectin was also elevated. No differences were seen between patients and controls in cell surface expression of the integrin proteins CD11a, CD11b, CD18 and CD29 on neutrophils, nor was there any difference in these parameters between patients with and without extra glandular symptoms.

These results suggest that blood neutrophils and eosinophils are activated in pSS. Accordingly they do not confirm results from earlier studies of impaired neutrophil adhesion in pSS.

Antibodies that react with citrullinated proteins (anti-mutated citrullinated vimentin [anti-MCV] and second-generation anti-cyclic citrullinated peptide antibodies [anti-CCP2]) are markers for rheumatoid arthritis. Recent studies have demonstrated that these antibodies are present in other arthropathies including the spondyloarthritis, psoriatic arthritis, and juvenile idiopathic arthritis. Arthritis associated with inflammatory bowel disease (IBD) takes various forms, with some shared similarities with classic spondylarthropathies. Our objective was to investigate the role of anti-MCV and anti-CCP2 as potential biomarkers in IBD and related arthritis. In all, 125 IBD patients (71 males, 54 females) were compared to 81 age- and sex-matched healthy controls. Anti-MCV and Anti-CCP2 IgG were measured using an enzyme linked immunosorbent assay. In the 125 IBD patients (mean age 32.6 ± 12.3 years), 44 (35.2%) had ulcerative colitis and 81 (64.8%) had Crohn's disease. Forty-four (35.2%) IBD patients developed arthritic manifestations. Antibody positivity was observed in 24/125 (19.2%) IBD patients and in 18/81 (22.2%) healthy subjects. The proportion of anti-MCV positivity among IBD patients and healthy individuals were similar: 16.8% vs. 16.0%, P = 0.887. Anti-CCP2 positivity among IBD patients and healthy individuals was also comparable: 6.4% vs. 6.2%, P = 0.948. Similarly, the presence of anti-MCV and anti-CCP2 antibodies was not different among IBD patients with and without arthritis. The mean titers of antibodies were low: anti-MCV (29.6 ± 7.5 U/mL) and anti-CCP2 (27.6 ± 4.0 U/mL) in IBD patients with arthritis.

Autoantibodies to citrullinated proteins were low in IBD-related arthritis. These findings suggest that these antibodies are not useful biomarkers in IBD to predict who may develop IBD-related arthropathy.

To study the prevalence, impact and dose-response relationship of comorbid chronic conditions on quality of life of type 2 diabetes patients. Cross-sectional data of 1676 type 2 diabetes patients, aged 31-96 years, and treated in primary care, were analyzed. Quality of life (QoL) was measured using the mental component summary (MCS) and the physical component summary (PCS) scores of the Short Form-12. Diagnosis of type 2 diabetes was obtained from medical records and comorbidities from self-reports. Only 361 (21.5%) of the patients reported no comorbidities. Diabetes patients with comorbidities showed significantly lower mean difference in PCS [-8.5; 95% confidence interval (CI) -9.8 to -7.3] and MCS scores (-1.9; 95% CI -3.0 to -0.9), compared to diabetes patients without. Additional adjustments did not substantially change these associations. Both MCS and PCS scores decrease significantly with the number of comorbid conditions, yet most pronounced regarding physical QoL. Comorbidities that reduced physical QoL most significantly were retinopathy, heart diseases, atherosclerosis in abdomen or legs, lung diseases, incontinence, back, neck and shoulder disorder, osteoarthritis and chronic rheumatoid arthritis, using the backwards stepwise regression procedure.

Comorbidities are highly prevalent among type 2 diabetes patients and have a negative impact on the patient's QoL. A strong dose-response relationship between comorbidities and physical QoL was found. Reduced physical QoL is mainly determined by musculoskeletal and cardiovascular disorders.

To investigate a cohort of professional ballet dancers for evidence of early signs of osteoarthritis (OA). One radiologist and 1 orthopedic surgeon specialized in musculoskeletal disorders analyzed magnetic resonance imaging scans independently. University Teaching Hospital. Fifteen professional ballet dancers (4 males and 11 females; age range, 19-36 years) experiencing chronic pain in the hip, knee, spine, ankle, or foot joints. Presence of osteophytes, subchondral sclerosis, joint space narrowing, cysts, and bone marrow changes; the Kellgren and Lawrence scale was used to quantify the knee OA. In the knee, there was thinning and irregularity of the articular cartilage over the medial femoral condyle and bone marrow changes within the lateral femoral condyle. In the hip, there was a loss of joint space and a frayed labrum with deep recess. The first metatarsophalangeal joint showed evidence of osteophytic development.

Early signs of OA, in different joints, were present in a small but highly selected cohort of professional ballet dancers. In future, prospective studies among a number of ballet companies should control for medical and natural history alongside the visual analysis of images and plain radiographs to confirm these preliminary results.

Rheumatoid arthritis (RA) is associated with an increased cardiovascular disease (CVD) risk which may start even before diagnosis. To explore this CVD risk prior to RA, we determined multiple risk factors and two 10-year clinical risk scores in a cohort of individuals at-risk of RA. We also analyzed associations with arthritis development and autoantibody status and compared a subset of at-risk individuals to an age and sex matched seronegative control group. In a cohort of 555 consecutive arthralgia patients positive for rheumatoid factor (RF) and / or anti-citrullinated protein antibody (ACPA) we retrospectively identified patients with preclinical arthritis (i.e. those who developed arthritis), and non-arthritis patients (those without arthritis development during maximum 5 years follow up). Demographics, CVD risk factors and the 10-year cardiovascular risk according to the SCORE and QRISK3 system were determined at baseline. Preclinical arthritis patients (n = 188) had a higher heart rate (68 vs 63 bpm, p = 0.048) and lower cholesterol (5.2 mmol/l vs 5.5, p = 0.006), HDL (1.0 mmol/l vs 1.1, p0.003) and ApoB (0.85 g/l vs 0.91, p = 0.011) compared to non-arthritis patients (n = 367). Lipid levels were associated with ACPA status in both the preclinical arthritis and non-arthritis group. Ten-year CVD risk scores did not differ between preclinical arthritis and non-arthritis patients, in total, 7% (SCORE) and 8% (QRISK3) of seropositive arthralgia patients were classified as high risk. Seropositive at-risk patients (n = 71) had higher total cholesterol (5.4 vs 4.9, p<0.001), TC/HDL ratio (4.0 vs 3.0, p<0.001), triglycerides (1.4 vs 1.0, p = 0.001), ApoB (1.0 vs 0.9, p = 0.019) and 10-year risk scores (median SCORE 1.0 vs 0.0, p = 0.030 and median QRISK3 4.4 vs 3.1, p<0.001) compared to seronegative controls.

Our results suggest that lipid changes commence prior to RA diagnosis and that ACPAs might play a role.

To explore the significance and evaluate the early structural erosion through the expressions of Th17 cells in peripheral blood of patients with rheumatoid arthritis (RA) in clinical remission. A total of 41 active RA patients without structural erosion were selected. Intracelluar flow cytometric detection of Th17 cells in peripheral blood was performed. And the supernatant level of interleukin (IL)-17A was determined simultaneously in RA patients and control groups at baseline and endpoint of 24-month therapy. The correlations were analyzed between Th17 cells and RA disease activity index DAS28. They were classified into radiographic progression (P, n = 10) and radiographic non-progression groups (NP, n = 26) by the Sharp/van der Heijde score (SHS) at the endpoint. The differences of Th17 cells and IL-17A levels were analyzed between P (SHS > 0.5) and NP groups (SHS ≤ 0.5). The expression of Th17 cells in active RA patients was significantly higher than that of controls [(1.63 ± 0.45)% vs (0.91 ± 0.26)%, P < 0.01]. And the results of IL-17A level were similar [1510 ± 280) vs (320 ± 31) ng/L, P < 0.05]. The expression of Th17 cells was positively correlated with DAS28 score (r = 0.87, P < 0.01). Thirty-six RA patients were followed up at the endpoint and all of them stayed in clinical remission (DAS28 < 2.6). The peripheral blood expressions of Th17 cells of P group were significantly higher than those of NP group . At the same time, no differences of IL-17A levels existed between two groups.

Structural erosion still progresses in some RA patients despite an apparent clinic remission. And a high-level peripheral expression of Th17 hints at structural erosion.

The SF-36 is a very commonly used generic measure of health outcome in osteoarthritis (OA). An important, but frequently overlooked, aspect of validating health outcome measures is to establish if items work in the same way across subgroup of a population. That is, if respondents have the same 'true' level of outcome, does the item give the same score in different subgroups or is it biased towards one subgroup or another. Differential item functioning (DIF) can identify items that may be biased for one group or another and has been applied to measuring patient reported outcomes. Items may show DIF for different conditions and between cultures, however the SF-36 has not been specifically examined in an osteoarthritis population nor in a UK population. Hence, the aim of the study was to apply the DIF method to the SF-36 for a UK OA population. The sample comprised a community sample of 763 people with OA who participated in the Somerset and Avon Survey of Health. The SF-36 was explored for DIF with respect to demographic, social, clinical and psychological factors. Well developed ordinal regression models were used to identify DIF items. DIF items were found by age (6 items), employment status (6 items), social class (2 items), mood (2 items), hip v knee (2 items), social deprivation (1 item) and body mass index (1 item). Although the impact of the DIF items rarely had a significant effect on the conclusions of group comparisons, in most cases there was a significant change in effect size.

Overall, the SF-36 performed well with only a small number of DIF items identified, a reassuring finding in view of the frequent use of the SF-36 in OA. Nevertheless, where DIF items were identified it would be advisable to analyse data taking account of DIF items, especially when age effects are the focus of interest.

Lesional skin of patients with discoid lupus erythematosus (DLE) contains macrophages, whose polarization has yet to be investigated. To test our hypothesis that M1 macrophages would be increased in DLE skin, we examined transcriptome alterations in immune cell gene expression and macrophage features in DLE and normal skin by using gene expression and histochemical approaches. Gene expression of RNA from DLE lesional and normal control skin was compared by microarrays and quantitative real-time polymerase chain reaction (RT-PCR). Both skin groups were analyzed for CD163 expression by immunohistochemistry. Double immunofluorescence studies were performed to characterize protein expression of CD163+ macrophages. DLE skin had twice as many upregulated genes than downregulated genes compared with normal skin. Gene set enrichment analysis comparing differentially expressed genes in DLE and normal skin with previously published gene sets associated with M1 and M2 macrophages showed strong overlap between upregulated genes in DLE skin and M1 macrophages. Quantitative RT-PCR showed that several M1 macrophage-associated genes--e.g., chemokine (C-X-C motif) ligand 10 (CXCL10), chemokine (C-C motif) ligand 5 (CCL5), and signal transducer and activator of transcription 1 (STAT1)-had amplified mRNA levels in DLE skin. CD163+ macrophages were increased near the epidermal-dermal junction and perivascular areas in DLE skin compared with normal skin. However, double immunofluorescence studies of CD163+ macrophages revealed minor co-expression of M1 (CXCL10, tumor necrosis factor-alpha, and CD127) and M2 (CD209 and transforming growth factor-beta) macrophage-related proteins in DLE skin.

Whereas a subset of CD163+ macrophages displays mixed polarizations in DLE skin, other immune cells such as T cells can contribute to the expression of these macrophage-related genes.

Antibodies to citrullinated proteins are a hallmark of rheumatoid arthritis (RA). Porphyromonas gingivalis peptidylarginine deiminase (PPAD) has been implicated in the initiation of RA by generating citrullinated neoantigens and due to its ability to autocitrullinate. To define the citrullination status and biology of PPAD in P gingivalis and to characterise the anti-PPAD antibody response in RA and associated periodontal disease (PD). PPAD in P gingivalis cells and culture supernatant were analysed by immunoblotting and mass spectrometry to detect citrullination. Recombinant PPAD (rPPAD), inactive mutant PPAD (rPPAD(C351S)), and N-terminal truncated PPAD (rPPAD(Ntx)) were cloned and expressed in Escherichia coli. Patients with RA and healthy controls were assayed for IgG antibodies to citrullinated rPPAD and unmodified rPPAD(C351S) by ELISA. Anti-PPAD antibodies were correlated with anti-cyclic citrullinated peptide (third-generation) antibody levels, RA disease activity and PD status. PPAD from P gingivalis is truncated at the N-terminal and C-terminal domains and not citrullinated. Only when artificially expressed in E coli, full-length rPPAD, but not truncated (fully active) rPPAD(Ntx), is autocitrullinated. Anti-PPAD antibodies show no heightened reactivity to citrullinated rPPAD, but are exclusively directed against the unmodified enzyme. Antibodies against PPAD do not correlate with anti-cyclic citrullinated peptide levels and disease activity in RA. By contrast, anti-PPAD antibody levels are significantly decreased in RA patients with PD.

PPAD autocitrullination is not the underlying mechanism linking PD and RA. N-terminal processing protects PPAD from autocitrullination and enhances enzyme activity. Anti-PPAD antibodies may have a protective role for the development of PD in patients with RA.

Clinical and autopsy studies have shown that patients with temporomandibular joint dysfunction are more likely to have enlargement and deformity of the condyle and subsequently occlusal disharmony. However, it is not known what causes this enlargement. This study was designed to test the hypothesis that surgical induction of anterior disc displacement (ADD) in the rabbit craniomandibular joint (CMJ) could lead to enlargement and deformity of the condyle. The right CMJ was exposed surgically, and the discal attachments were severed except for the posterior discal attachment (bilaminar zone). Then, the disc was repositioned anteriorly and sutured to the zygomatic arch. The left joint served as a sham-operated control. CMJ tissues then were removed after fixation at 24 hours (5 rabbits), 1 week (10 rabbits), 2 weeks (10 rabbits), or 6 weeks (10 rabbits), processed, and stained with hematoxylineosin. Histomorphometric assessment was used to evaluate changes in condylar volume, and thickness of the fibrous, reserve cell, and condylar cartilage layers. The results showed a progressive enlargement of the condylar volume in all experimental joints compared with controls (P < .01). The enlargement was attributable to a significant increase in the cartilage thickness and surface area of the nonarticulating portion of the condyle in the 1-week group (P < .01). In the 2- and 6-week groups, there were significant, progressive increases in cartilage thickness and surface area of the articulating portion of the condyle (P < .01). In all animals, increased cartilage thickness was associated with a decrease in the thickness of the fibrous and the reserve cell layers (P < .01).

It is concluded that surgical induction of ADD in the rabbit CMJ causes enlargement of the condyle, which is in part caused by hyperplasia of the condylar cartilage.

Hyperprolactinemia (hyperPRL) has been associated with autoimmune rheumatic disorders and the presence of thyroid autoantibodies (tAb). The interrelation between these variables was the focus of this prospective study. The study assessed six groups of individuals: 26 with systemic lupus erythematosus (SLE), 20 with rheumatoid arthritis (RA), 28 with tAb (tAb+), 14 with untreated hyperprolactinemia (hyperPRL), 10 with treated hyperPRL, and a control group (n = 28). Prolactin (PRL), free thyroxin, TSH, antibodies against thyroglobulin (TgAb), thyroid microsomal antigen (MsAb) and/or thyroid peroxidase (TPOAb) were determined in all patients. Those with hyperPRL had macroprolactin investigated by the polyethylene glycol (PEG) precipitation method. PRL (ng/mL) levels in the SLE, RA, and tAb+ groups were, respectively, 21.3 +/- 12.6, 11.5 +/- 7.4, and 12.5 +/- 8.6, and were significantly greater in the SLE group (p = 0.006) than in the controls (12.5 +/- 6.5) and in the other groups. Five patients had hyperPRL: three with SLE, one with RA, and one with tAb+. Macroprolactinemia was detected in three of the untreated hyperprolactinemic patients and in the hyperprolactinemic patient of the tAb+ group. Positivity for any of the tAb was 15% in the SLE, 15% in the RA, 57.1% in the untreated hyperPRL, 10% in the hyperPRL on treatment, and 3.6% in the control group. The presence of antibodies was significantly more frequent in the untreated hyperPRL group than in the control group (p = 0.001).

The results indicate that the PRL level is higher in SLE patients and that in the presence of hyperPRL there is increased prevalence of antithyroid antibodies, evidencing the association of PRL and autoimmunity and pointing to the appropriateness of assessing and monitoring the progress of these markers in patients affected by these disorders.

To observe the therapeutic effects of acupuncture on gouty renal damage. 72 cases of gouty renal damage were randomly divided into a treatment group of 42 cases and a control group of 30 cases to observe the therapeutic effects and the changes in 24-hour urinary protein content, blood creatinine, uric acid and urea nitrogen in blood before treatment and one month after treatment. The total effective rate in the treatment group reached 95.24%, which was remarkably higher than 63.33% in the control group. After one month of treatment, the indexes were found reduced in both groups, but the reduction rate in the treatment group was obviously superior to that in the control group.

The patients with repeated attacks of gout may have a higher possibility to suffer from renal damage. Therefore, attention should be paid to its early diagnosis and treatment. Acupuncture may exert good therapeutic effects on early gout complicated with renal damage by adjusting the metabolism and improving the renal function.

Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is caused by TNFRSF1A mutations, known to induce intracellular retention of the TNFα receptor 1 (TNFR1) protein, defective TNFα-induced apoptosis, and production of reactive oxygen species. As downregulation of autophagy, the main cellular pathway involved in insoluble aggregate elimination, has been observed to increase the inflammatory response, we investigated whether it plays a role in TRAPS pathogenesis. The possible link between TNFRSF1A mutations and inflammation in TRAPS was studied in HEK-293T cells, transfected with expression constructs for wild-type and mutant TNFR1 proteins, and in monocytes derived from patients with TRAPS, by investigating autophagy function, NF-κB activation and interleukin (IL)-1β secretion. We found that autophagy is responsible for clearance of wild-type TNFR1, but when TNFR1 is mutated, the autophagy process is defective, probably accounting for mutant TNFR1 accumulation as well as TRAPS-associated induction of NF-κB activity and excessive IL-1β secretion, leading to chronic inflammation. Autophagy inhibition due to TNFR1 mutant proteins can be reversed, as demonstrated by the effects of the antibiotic geldanamycin, which was found to rescue the membrane localisation of mutant TNFR1 proteins, reduce their accumulation and counteract the increased inflammation by decreasing IL-1β secretion.

Autophagy appears to be an important mechanism in the pathogenesis of TRAPS, an observation that provides a rationale for the most effective therapy in this autoinflammatory disorder. Our findings also suggest that autophagy could be proposed as a novel therapeutic target for TRAPS and possibly other similar diseases.

Monosodium urate monohydrate (MSU) crystals synergize with various toll-like receptor (TLR) ligands to induce cytokine production via activation of the NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLPR3) inflammasome. This has been demonstrated in vitro using human cell lines or monocytes of healthy volunteers. In the present study, we have investigated the effect of MSU crystals and of their combination with TLR ligands in peripheral blood mononuclear cells (PBMC) of patients with gout. PBMCs from 18 patients with primary gout and 12 healthy donors were exposed to MSU crystals in the presence or absence of saturated fatty acid C18:0 (free fatty acid, TLR2 ligand), palmitoyl-3-cystein (Pam₃Cys, TLR1/2 ligand) and fibroblast stimulating factor-1 (FSL-1, TLR 2/6 ligand). Production of IL-1β, IL-6, IL-8, IL-17 and tumor necrosis factor alpha (TNFα) was determined by ELISA. mRNA transcripts of IL-1β were measured by real-time PCR. MSU crystals alone failed to induce IL-1β, IL-6 or TNFα in both patients and control groups, but a stronger synergy between MSU/Pam₃Cys and MSU/C18:0 for the induction of IL-1β was found in patients with gout compared to healthy controls. IL-6, but not IL-8, followed the kinetics of IL-1β. No production of the neutrophil-recruiting IL-17 was detectable after stimulation of the patients' PBMCs with MSU in both the presence or absence of TLR ligands. No change of gene transcripts of IL-1β after stimulation with MSU and Pam₃Cys or with MSU and C18:0 was found. A positive correlation was found between synergy in IL-1β production from PBMCs of patients between C18:0 and MSU crystals, as well as the annual number of attacks of acute gouty arthritis (rs: +0.649, P: 0.022).

The synergy between MSU crystals and TLR-2 ligands is more prominent in patients with gout than in controls. This is likely mediated by the enhanced maturation of pro-IL-1β into IL-1β.

To define a novel RNA epitope recognized by serum from a patient with Sjögren's syndrome (SS) from a randomized RNA epitope library and investigate the epitope reactivity of the anti-RNA antibodies in patients with various connective tissue diseases. Serum from a patient with SS was used to select ligands from a library of RNA oligomers with a central region of 25 degenerate nucleotides. Bound RNA was recovered by reverse transcription, PCR amplification, and subcloning. The relationship between the antibodies to the selected RNA and disease specificity was studied using immunoprecipitation. From the random RNA library, several unique RNA sequences were obtained. Sera from 32 of 61 patients with SS (52.5%) precipitated with one of the selected RNA (TS1-RNA), whereas sera from 8 of 41 patients with systemic lupus erythematosus (19.5%) and 3 of 25 patients with rheumatoid arthritis (12.0%) precipitated. Although the frequency of reactivity to the TS1-RNA was higher in anti-SSA/Ro positive sera, the presence of either native or recombinant SSA/Ro antigen showed no detectable competition, and no apparent sequence homology was found between the TS1-RNA and hY RNA.

These data suggest that anti-TS1-RNA is a novel antibody against sequence-specific RNA in many patients with SS.

The mechanism(s) of nociceptive dysfunction and potential roles of opioid neurotransmitters are unresolved in the chronic pain syndromes of fibromyalgia and chronic low back pain. History and physical examinations, tender point examinations, and questionnaires were used to identify 14 fibromyalgia, 10 chronic low back pain and 6 normal control subjects. Lumbar punctures were performed. Met-enkephalin-Arg6-Phe7 (MEAP) and nociceptin immunoreactive materials were measured in the cerebrospinal fluid by radioimmunoassays. Fibromyalgia (117.6 pg/ml; 85.9 to 149.4; mean, 95% C.I.; p = 0.009) and low back pain (92.3 pg/ml; 56.9 to 127.7; p = 0.049) groups had significantly higher MEAP than the normal control group (35.7 pg/ml; 15.0 to 56.5). MEAP was inversely correlated to systemic pain thresholds. Nociceptin was not different between groups. Systemic Complaints questionnaire responses were significantly ranked as fibromyalgia > back pain > normal. SF-36 domains demonstrated severe disability for the low back pain group, intermediate results in fibromyalgia, and high function in the normal group.

Fibromyalgia was distinguished by higher cerebrospinal fluid MEAP, systemic complaints, and manual tender points; intermediate SF-36 scores; and lower pain thresholds compared to the low back pain and normal groups. MEAP and systemic pain thresholds were inversely correlated in low back pain subjects. Central nervous system opioid dysfunction may contribute to pain in fibromyalgia.

To examine the therapeutic efficacy of caspase inhibitors in experimental osteoarthritis (OA). Experimental OA was induced in rabbits by anterior cruciate ligament transection (ACLT). Rabbits were treated with intraarticular (i.a.) injections of caspase inhibitors 3 times per week starting 1 week postoperatively. Animals were killed 9 weeks after ACLT, for macroscopic, histologic, and immunohistochemical assessment of the knee joints. I.a. administration of the pan-caspase inhibitor Z-VAD-FMK significantly reduced cartilage degradation, as assessed by macroscopic and microscopic criteria. Untreated knees showed large numbers of chondrocytes with active caspase 3 and the p85 fragment of poly(ADP-ribose) polymerase (PARP p85) that is generated during apoptosis. The frequency of cells positive for PARP p85 and active caspase 3 was reduced in Z-VAD-FMK-treated knees. Inhibitors specific for caspase 3 or caspase 8 showed no significant efficacy. Caspase 1 inhibitor and the combination of caspase 3 and caspase 8 inhibitors reduced OA pathology.

These results provide direct support for a role of cell death in OA pathogenesis. Caspase inhibitors reduced the severity of cartilage lesions in experimental OA, suggesting that they may have disease-modifying activity in human OA.

This study analyses our results after revision surgery for failed trapezectomy and suspension arthroplasty with painful proximalisation of the 1(st) metacarpal using the Mini TightRope(®). In a prospective observational study, 5 patients (4 women and 1 man) with an average age of 62 years were treated with the Mini TightRope(®) for revision of a failed Epping arthroplasty with painful proximalisation of the first ray. The mean time between initial surgery and revision was 23.1 (12.5-31.5) months; the mean follow-up was 25±7.7 (12-32) months. The pain level (visual analogue scale - VAS), pinch grip, and qDASH score were evaluated preoperatively and postoperatively. In addition, the Conolly score was used postoperatively. Directly after surgery and at the last follow-up exam, the degree of proximalisation of the first metacarpal was measured radiologically. At the last follow-up, there was significant mean pain relief during everyday stress, from 5.2 preoperatively to 1.6 (p<0.01) postoperatively, and a significant increase in pinch grip, from 0.5 kg to 3 kg (p<0.01). qDASH improved significantly, from 54 to 20 (p<0.001). The Conolly score showed 2 good and 3 fair results. Renewed proximalisation could not be entirely prevented, but was limited to an average of 2 mm.

Mini TightRope(®) revision surgery after failed trapezectomy and suspension arthroplasty showes good results with significant pain reduction and gain of function. Renewed proximalisation of the first ray cannot be completely avoided.

This prospective study analyzed influence of patient's sex on early rheumatoid arthritis (RA) within one year of disease onset and after 2 years' followup. A total of 844 consecutive patients, 538 women, with RA of less than 12 months were studied. Standardized clinical and radiographic assessments were performed at study entry and after 2 years. The association of several variables at study entry with the outcome variables Disease Activity Score (DAS28), functional disability measured by the Health Assessment Questionnaire (HAQ), and, in 390 patients, Larsen score at the 2-year followup were analyzed in men and women separately. At study entry the women were younger compared with the men and the sexes showed different age distributions. The women had higher DAS28 and HAQ scores. However, women below 50 years of age at study entry had milder disease than older women and close to that of men. At 2-year followup the women still had higher DAS28 and HAQ scores compared to men, who had achieved remission in a higher frequency. Larsen score showed no sex difference either at study entry or after 2 years. Presence of rheumatoid factor (RF) was associated with lower age at study entry and higher DAS28 at followup in men only. Higher DAS28 and HAQ scores at entry were more strongly correlated with severe disease at followup in women than in men. Presence of the "shared epitope" was not associated with age or the outcome variables DAS28 and Larsen score in either sex.

The disease phenotype in early RA was significantly different between men and women, particularly concerning age, disease activity, and functional capacity. There were differences between the sexes concerning early disease characteristics associated with outcome at 2 years of followup.

To elucidate how postdiagnosis multimorbidity and lifestyle changes contribute to the excess mortality of rheumatoid arthritis (RA). We performed a matched cohort study among women in the Nurses' Health Study (1976-2018). We identified women with incident RA and matched each by age and year to 10 non-RA comparators at the RA diagnosis index date. Specific causes of death were ascertained via death certificates and medical record review. Lifestyle and morbidity factors were reported biennially; 61 chronic conditions were combined into the Multimorbidity Weighted Index (MWI). After adjusting for baseline confounders, we used inverse probability weighting analysis to examine the mediating influence of postindex MWI scores and lifestyle factors on total, cardiovascular, and respiratory mortality, comparing women with RA to their matched comparators. We identified 1,007 patients with incident RA and matched them to 10,070 non-RA comparators. After adjusting for preindex confounders, we found that hazard ratios (HRs) and 95% confidence intervals (95% CIs) were higher for total mortality (HR 1.46 [95% CI 1.32, 1.62]), as well as cardiovascular (HR 1.54 [95% CI 1.22, 1.94]) and respiratory (HR 2.75 [95% CI 2.05, 3.71]) mortality in patients with RA compared to non-RA comparators. Adjusting for postindex lifestyle factors (physical activity, body mass index, diet, smoking) attenuated but did not substantially account for this excess RA mortality. After additional adjustment for postindex MWI scores, patients with RA had HRs of 1.18 (95% CI 1.05, 1.32) for total, 1.19 (95% CI 0.94, 1.51) for cardiovascular, and 1.93 (95% CI 1.42, 2.62) for respiratory mortality.

We found that MWI scores substantially accounted for the excess total and cardiovascular mortality among women with RA. This finding underscores the importance of monitoring for the total disease burden as a whole in monitoring patients with RA.

The variable disease progression of osteoarthritis (OA) and the basis for rapid joint deterioration in some subgroups of patients are poorly understood. To explore an anatomic basis for rapidly progressive OA, this observational study compared the magnetic resonance imaging (MRI) patterns of disease between patients with neuropathic joint disease (NJD) and patients with degenerative arthritis of the ankle and foot. MR images of the foot and ankle of patients with early NJD (n = 7) and patients with OA (n = 15) were assessed. The anonomized MR images were dichotomously scored by a musculoskeletal radiologist for the presence of the following abnormalities per bone (of a total of 14 bones): cartilage defects, bone cysts, bone marrow edema, fractures, joint debris, joint effusions, tendinopathy, tendinitis, and ligament tears. Although the degree of cartilage damage and joint cyst formation was comparable between the groups, the degree of ligament tears, or change in MRI signal intensity in the ligaments, was significantly greater in patients with NJD compared with patients with OA (median of 3 tears versus 0, of 14 total bones; P < 0.01). Moreover, in patients with early NJD compared with patients with OA, there was a significantly greater degree of diffuse bone marrow edema (median of 6.5 tarsal bones versus 2 adjacent bones, of 14 total bones; P < 0.01), a greater number of bone fractures (median 4 versus 0; P < 0.01), and more frequent bone debris (median 4.5 versus 0; P = 0.013).

This analysis of NJD in the foot and ankle shows the predominance of bone and ligament abnormalities in NJD compared with the pattern of involvement in OA. These findings highlight the importance of structures other than articular cartilage in OA of the ankle and foot, and suggest that rapid joint degeneration in NJD may be more ligamentogenic or osteogenic in nature.

We propose a comparative study of urinary cortisol in a controlled simple group of patients diagnosed with fibromyalgia (FM) during a minimum time frame (3 years) vs. a normal group with the same characteristics of age and gender. Our objective is to demonstrate if urinary cortisol at lower levels than those found in the normal population, as long as FM is regarded, could help to evaluate the fatigue. We determined the urinary cortisol in a group of 47 women with a clinical diagnosis of FM using the criteria from the American College of Rheumatology (ACR) 1990, with ages between 29 and 64 years, in whom an accurate sample was collected and cortisol was determined using an FPIA method. The results were compared with the urinary cortisol obtained in a group of 88 healthy women within the same age range as those with FM. Urinary cortisol in FM was 65.0 microg/l (median), which was significantly lower than that of the healthy group (80.0 microg/l), p<0.001.

33.4% of patients with FM displayed urinary cortisol concentrations significantly lower than the group of women without FM.

Cartilage oligomeric matrix protein (COMP) has been identified as a prognostic marker of progressive joint destruction in rheumatoid arthritis. In this population based study we evaluated associations between plasma concentrations of COMP, disease activity, and growth velocity in patients with recent-onset juvenile idiopathic arthritis (JIA). COMP levels in JIA and healthy children were compared with those in healthy adults. Plasma levels of insulin-like growth factor I (IGF-1), which has been associated with COMP expression and growth velocity, were studied in parallel. 87 patients with JIA entered the study, including oligoarticular JIA (n = 34), enthesitis-related arthritis (n = 8), polyarticular rheumatoid factor (RF)-positive JIA (n = 2), polyarticular RF-negative JIA (n = 27), systemic JIA (n = 6), and undifferentiated JIA (n = 10). Plasma levels of COMP were measured by ELISA and IGF-1 by a radioimmunoassay. Significantly higher COMP levels [mean 18.9 U/l (95% CI 17.3-20.5)] were found in healthy children compared with healthy adults [mean 10.7 U/l (95% CI 9.4-12.1)] (p < 0.0001). COMP levels in the JIA patients [mean 13.5 U/l (95% CI 12.4-14.7)] were significantly reduced compared to healthy children (p < 0.0001), and correlated negatively with C-reactive protein (CRP; r = -0.29, p = 0.01) and thrombocyte count (r = -0.28, p = 0.02). COMP levels in the JIA patients correlated positively with growth velocity (cm/yr) (r = 0.38, p = 0.0003) and growth velocity (SDS) (r = 0.29, p = 0.007).

We found reduced COMP levels in children with JIA compared with healthy children. COMP levels in JIA correlated negatively with inflammatory activity as evaluated by CRP and the thrombocyte counts, and were associated with reduced growth rate.

Evidence regarding the cost-effectiveness of joint protection and hand exercises for the management of hand OA is not well established. The primary aim of this study is to assess the cost-effectiveness (cost-utility) of these management options. In addition, given the absence of consensus regarding the conduct of economic evaluation alongside factorial trials, we compare different analytical methodologies. A trial-based economic evaluation to assess the cost-utility of joint protection only, hand exercises only and joint protection plus hand exercises compared with leaflet and advice was undertaken over a 12 month period from a UK National Health Service perspective. Patient-level mean costs and mean quality-adjusted life years (QALYs) were calculated for each trial arm. Incremental cost-effectiveness ratios (ICERs) were estimated and cost-effectiveness acceptability curves were constructed. The base case analysis used a within-the-table analysis methodology. Two further methods were explored: the at-the-margins approach and a regression-based approach with or without an interaction term. Mean costs (QALYs) were £58.46 (s.d. 0.662) for leaflet and advice, £92.12 (s.d. 0.659) for joint protection, £64.51 (s.d. 0.681) for hand exercises and £112.38 (s.d. 0.658) for joint protection plus hand exercises. In the base case, hand exercises were the cost-effective option, with an ICER of £318 per QALY gained. Hand exercises remained the most cost-effective management strategy when adopting alternative methodological approaches.

This is the first trial evaluating the cost-effectiveness of occupational therapy-supported approaches to self-management for hand OA. Our findings showed that hand exercises were the most cost-effective option.

The intent of this cross-sectional study was to broaden the range of variables examined in relationship to depression in osteoarthritis (OA) to include comorbidity, stressful life events, and the ways people respond to their disease. We examined the relationship of coping behaviors and perceptions, and medical treatments received for OA and depressive symptoms. In the fifth year of a prospective cohort study, 1227 individuals >or= 62 years of age with hip/knee OA provided information about sociodemographics (age, sex, living circumstances, education), arthritis severity (WOMAC pain and function; ClinHAQ fatigue), comorbidity, life events, coping behavior, coping efficacy, treatment (pain management, treatment for depression), and depressed mood (Centre for Epidemiological Studies Depression scale, CES-D). Using hierarchical linear regression, variables were entered in blocks to predict CES-D scores. In the final block, the interaction of coping behavior and coping efficacy was tested. The response rate was 82.4% (n = 1227/1489). The mean CES-D score was 9.4, with 21.3% of individuals scoring >or= 16 (supporting depressed mood). Higher level of depressed mood was independently and significantly associated with being female, experiencing greater pain and fatigue, experiencing stressful life events, more coping behaviors, receiving treatment for depression/mental illness, and a coping behavior by coping efficacy interaction, with 63.4% of the variance accounted for in the model.

Among older adults with OA, the prevalence of depressive symptoms is high. Longitudinal studies must consider OA management strategies, including both the amount of behavioral coping and its perceived efficacy, to elucidate potential interventions designed to reduce depression in patients with OA.

Limited or absent axial rotation of the mobile insert of total knee prostheses could lead to high contact stresses and stresses at the bone-implant interface, which in turn might lead to implant loosening. The aim of this study was to assess knee kinematics and muscle activation and their possible change over time in patients with a highly congruent, mobile-bearing total knee prosthesis. A prospective series of 11 rheumatoid arthritis patients was included to participate in this fluoroscopic and EMG study; only 7 patients completed the study. Kinematic evaluations took place 7 months, 1 and 2 years post-operatively. Repeated measurements ANOVA and linear mixed-effects model for longitudinal data were used to compare the differences between the follow-ups. There are no significant changes in axial rotations between follow-up moments for the femoral component as well as the mobile insert. The insert remained mobile and followed the femoral component from 0° until approximately 60° of knee flexion. Diverging and reversed axial rotations and translations were seen during the dynamic motions. Therapeutic study, Level IV.

Knee kinematics and muscle activation do not appear to change in the first 2 post-operative years. Reversed and divergent axial rotations with increasing knee flexion indicate that as soon as the congruency decreases, the femoral component is no longer forced in a certain position by the insert and moves to a self-imposed position. At lower knee flexion angles, the femoral component might be obstructed by the highly congruent insert and therefore might not be able to move freely.

To quantify functional age-related changes in the cartilage antioxidant network in order to discover novel mediators of cartilage oxidative stress and osteoarthritis (OA) pathophysiology. We evaluated histopathologic changes of knee OA in 10-, 20-, and 30-month-old male F344BN rats and analyzed cartilage oxidation according to the ratio of reduced to oxidized glutathione. Antioxidant gene expression and protein abundance were analyzed by quantitative reverse transcription-polymerase chain reaction and selected reaction-monitoring mass spectrometry, respectively. Superoxide dismutase 2 (SOD2) activity and acetylation were analyzed by colorimetric enzyme assays and Western blotting, respectively. We examined human OA cartilage to evaluate the clinical relevance of SOD2 acetylation, and we tested age-related changes in the mitochondrial deacetylase sirtuin 3 (SIRT-3) in rats and mice. Cartilage oxidation and OA severity in F344BN rats increased with age and were associated with an increase in SOD2 expression and protein abundance. However, SOD2-specific activity decreased with age due to elevated posttranslational lysine acetylation. Consistent with these findings, SIRT-3 levels decreased substantially with age, and treatment with SIRT-3 increased SOD2 activity in an age-dependent manner. SOD2 was also acetylated in human OA cartilage, and activity was increased with SIRT-3 treatment. Moreover, in C57BL/6J mice, cartilage SIRT-3 expression decreased with age, and whole-body deletion of SIRT-3 accelerated the development of knee OA.

Our results show that SIRT-3 mediates age-related changes in cartilage redox regulation and protects against early-stage OA. These findings suggest that mitochondrial acetylation promotes OA and that restoration of SIRT-3 in aging cartilage may improve cartilage resistance to oxidative stress by rescuing acetylation-dependent inhibition of SOD2 activity.

A prospective, double-blind, randomized, and controlled trial was conducted in patients with knee osteoarthritis (OA) to evaluate the efficacy of infrared low-power Gallium-Arsenide (Ga-As) laser therapy (LPLT) and compared two different laser therapy regimes. Ninety patients were randomly assigned to three treatment groups by one of the nontreating authors by drawing 1 of 90 envelopes labeled 'A' (Group I: actual LPLT consisted of 5 minutes, 3 J total dose + exercise; 30 patients), 'B' (Group II: actual LPLT consisted of 3 minutes, 2 J total dose + exercise; 30 patients), and 'C' (Group III: placebo laser group + exercise; 30 patients). All patients received a total of 10 treatments, and exercise therapy program was continued during study (14 weeks). Subjects, physician, and data analysts were unaware of the code for active or placebo laser until the data analysis was complete. All patients were evaluated with respect to pain, degree of active knee flexion, duration of morning stiffness, painless walking distance and duration, and the Western Ontario and Mc Master Universities Osteoarthritis Index (WOMAC) at week 0, 6, 10, and 14. Statistically significant improvements were indicated in respect to all parameters such as pain, function, and quality of life (QoL) measures in the post-therapy period compared to pre-therapy in both active laser groups (P < 0.01). Improvements in all parameters of the Group I and in parameters, such as pain and WOMAC of the Group II, were more statistically significant when compared with placebo laser group (P < 0.05).

Our study demonstrated that applications of LPLT in different dose and duration have not affected results and both therapy regimes were a safe and effective method in treatment of knee OA.

To describe radiographic findings at disease onset and 3-year followup in patients with juvenile rheumatoid arthritis (JRA) and juvenile spondyloarthropathy (JSpA), to assess radiographic progression and its predictors, and to prospectively assess clinical outcome and predictors of persistent disease at 3-year followup. A total of 197 patients with JRA/JSpA were examined every 6 months for 3 years. Radiographic examination was performed at baseline and 3-year followup of knees and ankles (all patients) and of other joints on clinical indication. Remission was defined as minimum 6 months without medication and no clinical signs of active disease. Radiographic abnormalities were found in 88% of the patients at onset and in 81% after 3 years. Frequency of swelling/osteoporosis decreased and frequency of abnormal growth increased from baseline to followup. Knees, hands, and wrists had most frequently radiographic abnormalities. Radiographic progression occurred in 38% of the patients. Joints with swelling/osteoporosis on radiographs, young age, and a large number of mobility-restricted joints at baseline were predictors of radiographic progression. At 3 years, 26% of the patients were in remission and 75% had been treated with disease-modifying antirheumatic drugs. Reduced well-being, a large number of active joints and negative antinuclear antibody at baseline were predictors of persistent disease after 3 years.

After 3 years most patients had radiographic abnormalities and persistent disease. Young age, many affected joints, reduced well-being, and negative antinuclear antibody at onset increased the risk of radiographic progression and persistent disease after 3 years.

To determine whether treatment with spinal manipulative therapy (SMT) administered in addition to standard care is associated with clinically relevant early reductions in pain and analgesic consumption. 104 patients with acute low back pain were randomly assigned to SMT in addition to standard care (n = 52) or standard care alone (n = 52). Standard care consisted of general advice and paracetamol, diclofenac or dihydrocodeine as required. Other analgesic drugs or non-pharmacological treatments were not allowed. Primary outcomes were pain intensity assessed on the 11-point box scale (BS-11) and analgesic use based on diclofenac equivalence doses during days 1-14. An extended follow-up was performed at 6 months. Pain reductions were similar in experimental and control groups, with the lower limit of the 95% CI excluding a relevant benefit of SMT (difference 0.5 on the BS-11, 95% CI -0.2 to 1.2, p = 0.13). Analgesic consumptions were also similar (difference -18 mg diclofenac equivalents, 95% CI -43 mg to 7 mg, p = 0.17), with small initial differences diminishing over time. There were no differences between groups in any of the secondary outcomes and stratified analyses provided no evidence for potential benefits of SMT in specific patient groups. The extended follow-up showed similar patterns.

SMT is unlikely to result in relevant early pain reduction in patients with acute low back pain.

Articular chondrocyte senescence is responsible, at least in part, for the increased incidence of osteoarthritis (OA) with increased age. Recently, it was suggested that caveolin 1, a 21-24-kd membrane protein, participates in premature cellular senescence. Caveolin 1 is the principal structural component of caveolae, vesicular invaginations of the plasma membrane. This study was undertaken to investigate whether the catabolic factors oxidative stress and interleukin-1beta (IL-1beta) induce features of premature senescence of articular chondrocytes through up-regulation of caveolin 1 expression. Caveolin 1 expression was investigated in human OA cartilage by real-time polymerase chain reaction and in rat OA cartilage by immunohistologic analysis. We studied whether IL-1beta and H2O2 induce caveolin 1 expression in OA chondrocytes and analyzed the relationship between cellular senescent phenotypes and caveolin 1 expression in human chondrocytes. In human and rat OA articular cartilage, caveolin 1 positivity was associated with cartilage degeneration. Both IL-1beta and H2O2 up-regulated caveolin 1 messenger RNA and protein levels, and both treatments induced marked expression of senescent phenotypes: altered cellular morphology, cell growth arrest, telomere erosion, and specific senescence-associated beta-galactosidase activity. Caveolin 1 overexpression induced p38 MAPK activation and impaired the ability of chondrocytes to produce type II collagen and aggrecan. In contrast, down-regulation of caveolin 1 with antisense oligonucleotide significantly inhibited the features of chondrocyte senescence induced by catabolic factors. Caveolin 1 induction and stresses with both IL-1beta and H2O2 up-regulated p53 and p21 and down-regulated phosphorylated retinoblastoma (Rb), suggesting that the p53/p21/Rb phosphorylation pathway, as well as prolonged p38 MAPK activation, may mediate the features of chondrocyte senescence induced by stress.

Our findings suggest that IL-1beta and oxidative stress induce features of premature senescence in OA chondrocytes, mediated, at least in part, by stress-induced caveolin 1 expression. This indicates that caveolin 1 plays a role in the pathogenesis of OA via promotion of chondrocyte down-regulation.

To examine whether very late first-contact delusional disorder carries a risk for later development of dementia. By linkage of the psychiatric and the somatic nationwide registers of all out- and in-patients with hospital contact in Denmark, we included all 60+ patients with first ever from 1 January 1994 to 31 December 2001 with the index main diagnosis: delusional disorder. First contact osteoarthritis patients as well as the general population were used as controls. A total of 1,437 patients with persistent delusional disorder and 7,302 patients with osteoarthritis were included. Median follow-up time until first diagnosis of dementia at discharge was 1.87 and 4.40 years, respectively. The probability of getting a dementia diagnosis was estimated using Poisson regression models with dementia as the outcome of interest. Patients with very late first-contact delusional disorder had an 8.14 (95% CI, 6.51; 10.19) times increased rate of subsequently developing dementia compared with very late first contact osteoarthritis patients. Compared with the general population the rate ratio was 5.49 (95% CI, 4.81; 6.26).

Very late first-contact delusional disorder increases the risk of subsequently getting a diagnosis of dementia 5-8 times compared with osteoarthritis patients and the general population.

The aims of this study are to evaluate whether improvements in functional outcome and quality of life are sustainable 10 years after total knee arthroplasty (TKA), and the age cut-off for clinical deterioration in outcomes METHODS: Prospectively collected registry data of 120 consecutive patients who underwent TKA at a tertiary hospital in 2006 was analysed. All patients were assessed at 6 months, 2 years and 10 years using the Knee Society Function Score, Knee Society Knee Score, Oxford Knee Score, Short-Form 36 Physical/Mental Component Scores and postoperative satisfaction. One-way ANOVA was used to compare continuous variables, while Chi-squared test to compare categorical variables. Multivariate logistic regression and receiver operating curve analysis was performed to evaluate the predictive factors associated with deterioration of scores postoperatively. Significant improvements were noted in all functional outcome and quality of life scores at 6 months after TKA. Between 6 months and 2 years, the KSFS and OKS continued to improve but the KSKS, PCS and MCS plateaued. Between 2 and 10 years, there was a deterioration in the KSFS and OKS, whilst KSKS, PCS and MCS were maintained. Increasing age was noted to be a significant risk factor for deterioration of KSFS at 10 years with age ≥ 68 as the cut-off value. 91.7% of patients with KSFS Minimally Clinically Important Difference(MCID) (≥ 7 points) continued to be satisfied after 10 years compared to 100.0% who did not experience KSFS MCID deterioration (p = 0.02). Retrospective study, Level III.

Patients ≥ 68 years experience deterioration in functional outcomes and quality of life from 2 to 10 years after TKA.

This study sought to ascertain whether left ventricular systolic dysfunction (LVSD) is more common among clinic patients with rheumatoid disease (RD) compared with the general population, and to assess the diagnostic utility of brain natriuretic peptide (BNP). Patients with RD are at increased risk of ischemic heart disease. However, there are few large echocardiographic studies identifying cardiac dysfunction in RD. We hypothesized that LVSD would be more prevalent in RD patients than in the general population. A total of 226 hospital out-patients with RD (65% women) underwent clinical evaluation, electrocardiography (ECG), echocardiography, and plasma BNP assay (218 patients). Prevalence of LVSD was compared with local population estimates. Definite LVSD (left ventricular ejection fraction <40%) occurred in 5.3% of the RD group: standardized prevalence ratio, 3.20; 95% confidence interval, 1.65 to 5.59. Median BNP values were higher in patients with LVSD compared with those without: 16.6 pmol/l versus 8.5 pmol/l, p < 0.005, although values between the two groups overlapped. One in nine patients with an abnormal ECG had definite LVSD.

Definite LVSD was three times more common in RD patients than in the general population. Given the prognostic benefits of treating LVSD, echocardiographic screening of RD patients with an abnormal ECG may be worthwhile.

To determine whether copy number variations (CNVs) in FCGR3A and FCGR3B are associated with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Taiwanese individuals. FCGR3A and FCGR3B CNV genotypes were determined in 846 patients with SLE, 948 patients with RA, and 1,420 healthy control subjects, using custom TaqMan CNV assays. The FCGR3A and FCGR3B CNV genotypes were compared between healthy control subjects and patients and among patients stratified according to clinical characteristics. A low (<2) FCGR3A copy number was significantly associated with SLE (for <2 copies versus 2 copies, P = 5.06 × 10(-4) , false discovery rate-corrected P [PFDR ] = 0.001, odds ratio [OR] 3.26, 95% confidence interval [95% CI] 1.68-6.35) and RA (for <2 copies versus 2 copies, P = 5.83 × 10(-4) , PFDR = 0.0012, OR 2.82, 95% CI 1.56-5.1). A low FCGR3B copy number was also significantly associated with SLE (for <2 copies versus 2 copies, P = 0.0032, PFDR = 0.0032, OR 1.59, 95% CI 1.17-2.18). Notably, a high (>2) FCGR3A copy number was also associated with SLE (for >2 copies versus 2 copies, P = 0.003, PFDR = 0.0061, OR 1.6, 95% CI 1.17-2.18). Additionally, the FCGR3A low copy number genotype was significantly enriched in subsets of patients with SLE (those with ulcer, arthritis, rash, discoid rash, photosensitivity, nephritis, leukopenia, thrombocytopenia, depressed complement levels, and autoantibody positivity) and patients with RA (those positive for rheumatoid factor) compared with healthy control subjects. The FCGR3B low copy number genotype was also significantly enriched in SLE patients with ulcer, rash, discoid rash, photosensitivity, ascites, nephritis, complement level depression, and anti-double-stranded DNA antibody positivity compared with control subjects. However, FCGR3B CNVs were not associated with RA susceptibility (for <2 copy numbers versus 2 copy numbers, P = 0.3584, OR 1.15, 95% CI 0.85-1.55) and clinical characteristics.

In Taiwanese individuals, a low FCGR3A copy number is a common risk factor for SLE and RA, while a low FCGR3B copy number confers a risk of SLE but not RA.

Patients with inflammatory arthritis (IA) have a high risk of sleep disturbances and disorders. The objective was to evaluate the evidence of non-pharmacological interventions targeting sleep disturbances or disorders in patients with IA. A systematic search was undertaken from inception to September 8 Six trials (308 patients) were included in the quantitative synthesis; three of these reported improvement in sleep in favor of the non-pharmacological intervention(s). The meta-analysis of the sleep domains indicated a large clinical effect of -0.80 (95% CI, -1.33 to -0.28) in favor of non-pharmacological interventions targeting sleep disturbances or disorders. The estimate was rated down twice for risk of bias, and unexplained inconsistency; this was assessed as corresponding to low quality evidence. None of the secondary core outcomes used in contemporary IA trials indicated clinical benefit in favor of non-pharmacological interventions targeting sleep.

Non-pharmacological interventions targeting sleep disturbances/disorders in patients with IA indicated a promising effect on sleep outcomes, but not yet with convincing evidence.

The present study aimed to review the characteristics and influencing factors of squeaking after ceramic-on-ceramic (CoC) total hip arthroplasty (THA) and to analyze the possible mechanisms of the audible noise. The data analyzed in this review were based on articles from PubMed and Web of Science. The articles selected for review were original articles and reviews found based on the following search terms: "total hip arthroplasty", "ceramic-on-ceramic", "hip squeaking", and "hip noise." The mechanism of the squeaking remains unknown. The possible explanations included stripe wear, edge loading, a third body, fracture of the ceramic liner, and resonance of the prosthesis components. Squeaking occurrence is influenced by patient, surgical, and implant factors.

Most studies indicated that squeaking after CoC THA was the consequence of increasing wear or impingement, caused by prosthesis design, patient characteristics, or surgical factors. However, as conflicts exist among different articles, the major reasons for the squeaking remain to be identified.

The risk of venous thrombosis associated with major illnesses is not well known, and neither is the risk associated with the combined effect of immobilization and thrombophilia. The aim of this study was to assess the effect on the development of venous thrombosis of several major illnesses in combination with immobilization, body mass index, and thrombophilia, to identify high-risk groups that may provide a basis for personalized prevention. This study included 4311 consecutive patients with a first episode of venous thrombosis, and 5768 controls from a case-control study (MEGA study). We calculated odds ratios (ORs) for venous thrombosis for patients with a self-reported history of major illnesses. Venous thrombosis risk was increased for all investigated major illnesses: liver disease, OR 1.7 (95% confidence interval [CI]1.0-2.9); kidney disease, OR 3.7 (95% CI 2.3-5.9); rheumatoid arthritis, OR 1.5 (95% CI 1.2-1.9); multiple sclerosis, OR 2.4 (95% CI 1.3-4.3); heart failure, OR 1.7 (95% CI 1.2-2.3); hemorrhagic stroke, OR 4.9 (95% CI 2.4-9.9); arterial thrombosis, OR 1.5 (95% CI 1.2-1.8); and the presence of any of the above major illnesses, OR 1.7 (95% CI 1.5-1.9). Combinations of major illnesses with immobilization and increased factor VIII (OR 79.9; 95% CI 33.2-192.2), increased FIX (OR 35.3; 95% CI 14.2-87.8), increased von Willebrand factor (OR 88.0; 95% CI 33.9-228.3), FV Leiden (OR 84.2; 95% CI 19.5-363.6), and blood group non-O (OR 53.1; 95% CI 30.9-91.4) were associated with increased venous thrombosis risks.

All of the major illnesses reported here were associated with an increased risk of venous thrombosis. These risks were most pronounced at the time of immobilization or in the presence of thrombophilia.

The purposes of this study were to examine patellar height at preoperation and postoperation, and compare the change of patellar height between opening wedge high tibial osteotomy (HTO) and closed wedge HTO by using Insall-Salvati (IS) ratio and our original method. Twenty patients (26 knees) were included. There were 6 males (6 knees) and 14 females (20 knees). Sixteen knees underwent closed method and 10 knees underwent opening method. Patellar height was measured at preoperation, immediately after the operation (postoperation) and 1 year after the operation according to IS ratio and modified Blumensaat (MB) ratio. We defined MB ratio as the ratio of distance from Blumensaat line to the midpoint of patellofemoral joint of patella against the length of Blumensaat line. In opening wedge HTO, though IS ratio significantly increased postoperatively compared with preoperative IS ratio, IS ratio at 1 year after operation was not significantly different from preoperative values. MB ratio at postoperation and that at 1 year after the operation significantly decreased compared with preoperative MB ratio. In closed wedge HTO, there was no difference between preoperative and postoperative values of both IS ratio and MB ratio.

In the postoperative period after opening wedge HTO, IS ratio was significantly increased, whereas MB ratio was decreased. We recommend that patients with low preoperative MB ratio must be treated with closed wedge HTO.

Delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) is used to examine the distribution of glycosaminoglycan in cartilage. This study sought to characterize dGEMRIC in the evaluation of knee osteoarthritis (OA) according to various radiographically determined disease parameters, and to examine the relationship between alignment of the knee joint and the lateral:medial dGEMRIC ratio. Thirty-one patients with knee OA underwent MRI with a dGEMRIC protocol at 1.5T. Semiflexed knee radiographs and full-limb radiographs were also obtained for assessment of alignment. Compartments of the knee joint without joint space narrowing had a higher dGEMRIC index than those with any level of narrowing (mean 408 msec versus 365 msec; P = 0.001). In knees with 1 unnarrowed (spared) and 1 narrowed (diseased) compartment, the dGEMRIC index was greater in the spared versus the diseased compartment (mean 395 msec versus 369 msec; P = 0.001). In spared compartments, there was a trend toward a lower dGEMRIC index with increasing Kellgren/Lawrence (K/L) radiographic severity grade; the spared compartments of knees with a K/L grade 2 had a higher dGEMRIC index than those of knees with a K/L grade 4 (mean 425 msec versus 371 msec; P < 0.05). There was a range of dGEMRIC values in the spared compartments within a given K/L grade, demonstrating biochemical differentiation of disease in radiographically comparable compartments. Almost all compartments with narrowing had dGEMRIC indices of <400 msec. Valgus-aligned knees tended to have lower dGEMRIC values laterally, and varus-aligned knees tended to have lower dGEMRIC values medially; as a continuous variable, alignment correlated with the lateral:medial dGEMRIC ratio (Pearson's R = 0.43, P = 0.02).

The biochemical information provided by dGEMRIC scans may augment radiography by improving the differentiation of disease status within a given radiographic grade, especially in early OA.

Osteoarthritis (OA) is initiated by pathogenic factors produced by multiple stimuli, including mechanical stress, metabolic stress, and/or inflammaging. This study was undertaken to identify novel low-grade inflammation-associated pathogenic mediators of OA. Candidate pathogenic molecules were screened using microarray data obtained from chondrocytes exposed to OA-associated catabolic factors. In mice with OA generated by destabilization of the medial meniscus (DMM), low-grade inflammation was induced by a high-fat diet or endotoxemia. Functions of candidate molecules in OA pathogenesis were examined using primary-culture chondrocytes from mice with DMM-induced OA, following intraarticular injection of adenovirus expressing the candidate gene. Specific functions of candidate genes were evaluated using whole-body gene-knockout mice. Bioinformatics analysis identified multiple candidate pathogenic factors that were associated with low-grade inflammation, including components of the Toll-like receptor (TLR) signaling pathways (e.g., TLR-2, TLR-4, lipopolysaccharide binding protein [LBP], and CD14). Overexpression of the individual TLR signaling components in mouse joint tissue did not alter cartilage homeostasis. However, the low-grade inflammation induced by a high-fat diet or endotoxemia markedly enhanced posttraumatic OA cartilage destruction in mice, and this exacerbation of cartilage destruction was significantly abrogated in LBP

LBP and CD14, which are accessory molecules of TLRs, are necessary for the exacerbation of posttraumatic OA cartilage destruction resulting from low-grade inflammation, such as that triggered by a high-fat diet or endotoxemia.

To determine fertility and pregnancy outcome in women with systemic sclerosis (SSc; scleroderma) who had disease onset before age 45 years. All living women with scleroderma who had first been evaluated at the University of Pittsburgh Scleroderma Clinic after January 1, 1972 were sent a detailed self-administered questionnaire in 1986 specifically concerning pregnancy outcomes and infertility. This group was compared with 2 race- and age-matched control groups, one comprising women with rheumatoid arthritis (RA) and one comprising healthy neighborhood women identified by random-digit dialing. We determined the number, history, treatment, and outcome of women who either had never been pregnant or had attempted to become pregnant unsuccessfully for more than 1 year. We also obtained data regarding pregnancy outcomes, including the frequency of miscarriage, premature births, small full-term infants, perinatal deaths, and births of live healthy infants. The study group comprised 214 women with SSc, 167 with RA, and 105 neighborhood controls. There were no significant differences in the overall rates of miscarriage, premature births, small full-term births, or neonatal deaths between the 3 groups. Women with SSc were more likely than those without SSc to have adverse outcomes of pregnancy after the onset of their rheumatic disease, particularly premature births (also seen in RA women after disease onset) and small full-term infants. Although a significantly greater number of women with SSc had never been pregnant, there were no significant differences in the frequency of never having been pregnant or of infertility in the 3 groups after adjustment for contributing factors.

This study indicates that women with SSc have acceptable pregnancy outcomes compared with those of women with other rheumatic disease and healthy neighborhood controls. Infertility was not a frequent problem. We believe that there are no excessive pregnancy risks to women with SSc or their infants. However, a well-timed pregnancy with careful obstetric monitoring will maximize the likelihood of a successful outcome.

Group 3 innate lymphoid cells (ILC3s) play a pivotal role in barrier tissues such as the gut and the skin, two important sites of disease in spondyloarthritis (SpA). This study was undertaken to investigate whether normal or injured human enthesis, a key target tissue in early SpA, harbors ILC3s in entheseal soft tissue and adjacent perientheseal bone. Interspinous ligament and spinous process bone from donors with no systemic inflammatory disease were collected, enzymatically digested, and immunophenotyped. The immunologic profile of entheseal cells was examined, and the transcriptional profile of sorted ILC3s was compared to that of ILC3s isolated from SpA synovial fluid (SF). To assess the ability of entheseal tissue to produce interleukin-17 (IL-17) and IL-22, entheseal digests were stimulated with IL-23 and IL-1β. Osteoarthritic and ruptured Achilles tendon tissue was examined histologically. The proportion of ILCs in human entheseal soft tissue was higher than that in peripheral blood (P = 0.008); entheseal soft tissue and perientheseal bone both had a higher proportion of NKp44+ ILC3s (P = 0.001 and P = 0.043, respectively). Studies of retinoic acid receptor-related orphan nuclear receptor γt (RORγt), STAT3, and IL-23 receptor transcript expression validated the entheseal ILC3 phenotype. Cytokine transcript expression was similar in ILC3s isolated from enthesis and from SpA SF. Stimulation of normal entheseal digests with IL-23/IL-1β led to up-regulation of IL-17A transcript, and histologic examination of injured/damaged entheses revealed the presence of RORγt-expressing cells.

This work shows that human enthesis harbors a resident population of ILC3s, with the potential to participate in the pathogenesis of SpA.

This study aimed to investigate the predictive value of synovitis and tenosynovitis detected by grayscale (GS) and by power Doppler (PD) ultrasound (US) in relation to failure of tapering disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) patients. Long-standing RA patients who de-escalated treatment were included in this prospective cohort study. All patients underwent 3 ultrasonographic and clinical assessments, at baseline and every 3 or 4 months, over a period of 6-8 months. US investigation of 32 joints was performed. Synovitis was assessed by GS and PD semiquantitative scoring (0-3) and a global score was calculated for each individual by summing single joint scores. The presence of tenosynovitis was recorded whenever detected during ultrasound assessment. Thirty-three patients completed the follow-up period (29 women; 4 men). Eight patients (25%) relapsed. Using the optimal cutoff values determined by receiver operating characteristic curve, patients with a PD synovitis ≥1 at baseline had significantly greater chances to relapse than those without PD activity. During follow-up, GS tenosynovitis was detected in 6 patients (5 with PD) who failed and in 3 patients (1 with PD) who succeeded in tapering therapy. Having at least 1 joint with PD synovitis resulted in a relative risk of 3.14 and having GS tenosynovitis resulted in a relative risk of 11.4 (95% CI: 1.03-9.60 and 2.82-45.9, respectively) for relapse in the multivariate Poisson model.

PD synovitis and GS tenosynovitis may be useful to identify RA patients in risk of relapse after DMARD tapering.

The prognosis of patients with rheumatic diseases has improved considerably following the use of biological therapies. However, an increase in the frequency of bacterial infections has been observed in patients receiving these therapies. In the present study we aimed to assess the frequency of Listeria monocytogenes infection in a large series of patients with rheumatic diseases on treatment with tumor necrosis factor (TNF)-alpha blockers because of active disease refractory to conventional therapy, included in the Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases (BIOBADASER) of the Spanish Society for Rheumatology. Assessment of the incidence of infection due to Listeria monocytogenes in the Spanish Registry Study (BIOBADASER) per 1000 patient-years and 95% confidence intervals (95% CIs) was performed. Rate from this registry was compared with that from the general population in Europe and with the rate found in patients with rheumatoid arthritis (RA) from the Spanish Rheumatoid Arthritis Registry Cohort Study (EMECAR) that assessed morbidity and clinical expression of RA and included patients treated in most cases with conventional therapies. Six patients on treatment with TNF-alpha antagonists were diagnosed as having Listeria monocytogenes infection. The incidence of this infection per 1000 patient-year (95% CI) was 0.256 (95% CI: 0.115-0.570). This was greater than the incidence observed in the general population from Europe and in the EMECAR study.

Despite the benefits associated to the use of TNF-alpha antagonists, a high level of surveillance is required to reduce the potential risk of infections related to the use of these drugs.

Platelet-rich plasma (PRP) is a blood component therapy with a supraphysiological concentration of platelets derived from allogenic or, more commonly, autologous blood. PRP has been used in different non-transfusion indications because of its role in the promotion of tissue repair and healing, in fields such as Traumatology, Dermatology and Dentistry. To provide a synthesis of the efficacy of PRP for different clinical situations. Systematic searches were carried out in MEDLINE, Embase, Cochrane Library and LILACS in July 2018 to identify systematic reviews (SRs) of randomized clinical trials (RCTs) focusing on PRP for non-transfusion use. Two authors independently screened all retrieved references in two stages (titles and abstracts at a first stage and full texts at a second stage). The methodological quality of SRs that met the eligibility criteria was appraised by AMSTAR 2. Conclusions were based on the most recent SRs with highest quality. One thousand two hundred and forty references were retrieved. After checking the inclusion criteria, 29 SRs of RCTs related to three different fields (wound care, Orthopedics and Dentistry) were included. The results suggest the benefit of PRP for different clinical situations, such as diabetic wounds, acute lesions of musculoskeletal system, rotator cuff lesions, tendinopathies, knee and hip osteoarthritis, total knee arthroplasty, allogenic bone graft for dental implants and periodontal intrabony defects.

There is low to moderate quality evidence supporting the efficacy of PRP for specific clinical situations. The low quality of the evidence limits the certainty of these findings. Well-planned and well-conducted RCTs are still needed to further assess the efficacy of PRP.

Fibromyalgia (FM) is a chronic pain disorder with patients frequently suffering from comorbid conditions, including osteoarthritis (OA). Data on how FM patients with comorbid OA respond to recommended therapies (such as pregabalin) could help their treatment. This was a pooled exploratory analysis of three randomized placebo-controlled clinical trials of pregabalin in FM patients to assess the impact of comorbid OA on the response to pregabalin. Patients were divided into those with and without comorbid OA. Difference in change in least squares (LS) mean pain score at endpoint (assessed by 0-10 numeric rating scale, controlled for baseline pain score) with pregabalin (300 mg/day and 450 mg/day) vs placebo was assessed. Changes in Patient Global Impression of Change (PGIC) responders and Fibromyalgia Impact Questionnaire (FIQ) total score were also assessed. There were 1665 patients in the analysis set (558, placebo; 552, pregabalin 300 mg/day; 555, pregabalin 450 mg/day), including 296 with comorbid OA. Pregabalin 450 mg/day significantly improved the LS mean (95% confidence interval) difference in pain score vs placebo in patients with (0.99 [0.44, 1.55], P < 0.001), and without (0.64 [0.39, 0.89], P < 0.001) OA. Improvements with pregabalin 300 mg/day with (0.31 [-0.25, 0.86], P = 0.276) and without (0.51 [0.25, 0.76], P < 0.001) OA were not consistently significant. Improvements in PGIC and FIQ total score were observed in patients with and without comorbid OA.

FM patients with or without comorbid OA respond to treatment with pregabalin 450mg/day with significant improvements in pain intensity scores. These data could provide guidance to healthcare professionals treating these patients.

The folate antagonist methotrexate (MTX) is an anchor drug in the treatment of rheumatoid arthritis (RA), but its mechanism of action with regard to the impact on folate metabolism remains elusive. The aim of the present study was to investigate the cellular pharmacologic impact of MTX on peripheral blood cells, by comparing MTX-treated RA patients to MTX-naive RA patients and healthy controls. Gene expression microarray data were used to investigate the expression of 17 folate pathway genes by peripheral blood cells from a cohort of 25 RA patients treated with MTX, 10 MTX-naive RA patients starting treatment with MTX, and 15 healthy controls (test cohort). Multiplex real-time polymerase chain reaction was used to validate the results in an independent cohort, consisting of 151 RA patients treated with MTX, 28 MTX-naive RA patients starting treatment with MTX, and 24 healthy controls (validation cohort). Multiple folate metabolism-related genes were consistently and significantly altered between the 3 groups in both cohorts. Concurrent with evidence of an immune-activation gene signature in MTX-naive RA patients, significant up-regulation of the folate-metabolizing enzymes γ-glutamyl hydrolase and dihydrofolate reductase, as well as the MTX/folate efflux transporters ABCC2 and ABCC5, was observed in the MTX-naive RA group compared to healthy controls. Strikingly, MTX treatment of RA patients normalized these differential gene expression levels to the levels observed in healthy controls.

These results suggest that under inflammatory conditions, basal folate metabolism in the peripheral blood cells of RA patients is markedly up-regulated, and treatment with MTX restores folate metabolism to normal levels. Identification of this novel gene signature provides insight into the mechanism of action of MTX, thus paving the way for development of novel folate metabolism-targeted therapies.

To validate the revised Japanese Ministry of Health criteria for the diagnosis of Sjögren's syndrome (SS) (JPN) (1999), The American-European Consensus Group classification criteria for SS (AECG) (2002), and American College of Rheumatology classification criteria for SS (ACR) (2012). The study subjects were 694 patients with SS or suspected SS who were followed-up in June 2012 at ten hospitals that form part of the Research Team for Autoimmune Diseases, The Research Program for Intractable Disease by the Ministry of Health, Labor and Welfare (MHLW). All patients had been checked for all four criteria of the JPN (pathology, oral, ocular, anti-SS-A/SS-B antibodies). We studied the clinical diagnosis made by the physician in charge and the satisfaction of the above criteria. Of the 694 patients, 499 patients did not have other connective tissue diseases (CTDs). SS was diagnosed in 476 patients (primary SS in 302, secondary SS in 174), whereas non-SS was diagnosed in 218 patients (without other CTDs in 197, with other CTDs in 21) by the physician in charge. The sensitivities of JPN, AECG, and ACR in the diagnosis of all forms of SS (both primary and secondary SS) were 79.6, 78.6, and 77.5 %, respectively, with respective specificities of 90.4, 90.4, and 83.5 %. The sensitivities of the same systems in the diagnosis of primary SS were 82.1, 83.1, and 79.1 %, respectively, with specificities of 90.9, 90.9, and 84.8 %, respectively. The sensitivities of the same systems in the diagnosis of secondary SS were 75.3, 70.7, and 74.7 %, respectively, with specificities of 85.7, 85.7, and 71.4 %, respectively.

The sensitivity of JPN to all forms of SS and secondary SS, the sensitivity of AECG to primary SS, and the specificities of JPN and AECG for all forms of SS, primary SS, and secondary SS were highest in the diagnosis of SS in Japanese patients. These results indicate that the JPN criteria for the diagnosis of SS in Japanese patients are superior to ACR and AECG.

The importance of medial compartment stability is recognized in total knee arthroplasty (TKA). To manage the medial extension-flexion gap, the posterior reference position can be changed from conventional posterior center to posterior medial in measured resection techniques. This study aimed to compare the intraoperative soft tissue balance and rotational kinematics between the posterior medial and posterior center reference groups. We enrolled 57 consecutive patients with varus osteoarthritis undergoing posterior-stabilized (PS) TKA using an image-free navigation system. The detailed surgical plan in both groups and intraoperative kinematics were recorded using navigation, and soft tissue balance measured with an offset-type tensor was statistically compared between groups. Patients were divided into the posterior center reference group (n = 32) and posterior medial reference group (n = 25). The posterior medial and posterior lateral condyles were significantly thicker in the posterior center reference group (P < .05). Although preoperative rotational kinematics were comparable between groups, the tibial rotational position was significantly more externally rotated in the posterior center reference group than in the posterior medial reference group at 45°, 60°, and 90° of flexion (P < .05). The varus angle and joint component gap were significantly smaller in the posterior medial reference group than in the posterior center reference group at 60° and 90° of flexion (P < .05).

The posterior reference position affects intraoperative kinematics and soft tissue balance in navigated PS TKA. Posterior medial reference PS TKA decreases the excessive tibial external rotation during midflexion and increases the flexion stability compared with conventional posterior center reference PS TKA.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease that affects small- to medium-sized blood vessels. Despite treatments having been improved, patients often experience disease relapses. It remains unclear how the immune cells involve in the development of vasculitis and how they fluctuate over the course of treatment. In this study, we aimed to identify the immune subsets and serum cytokines associated with disease relapse by comprehensive immuno-phenotyping in AAV patients. We reviewed consecutive patients (n = 29) from Keio University Hospital who had been newly diagnosed with AAV from January 2015 to February 2019 and chronologically followed until 52 weeks. Numbers of circulating T cells, B cells, monocytes, and granulocytes were analyzed by flow cytometry (FACS). Serum levels of cytokines were measured by electrochemiluminescence enzyme immunoassay. Clinical information was obtained from patients' records and association with time-course changes in immuno-phenotypes and serum levels of cytokines were assessed. Comprehensive immuno-phenotyping data from 161 samples from 29 AAV patients at diagnosis; at weeks 4, 12, 24, and 52 of treatment; and at time of major relapse were examined. FACS analysis from patients with relapse revealed that CD14

Chronological changes in CD14

It is well established that patients with systemic sclerosis (SSc) have a disrupted lipid profile and an increased cardiovascular risk. Cholesterol efflux capacity (CEC), the ability of high-density lipoprotein (HDL)-cholesterol to accept cholesterol from macrophages, has been linked to cardiovascular events. The aim of this study was to establish whether CEC and lipid profile were impaired in SSc patients with respect to controls and whether these changes were associated with disease-related data. Cross-sectional study encompassed 188 individuals: 73 SSc patients and 115 controls. CEC, using an in vitro assay, and lipoprotein serum concentrations were assessed in patients and controls. A multivariable analysis was performed to study the differences in CEC between patients and controls, and if SSc-related data could explain such differences. The multivariable analysis adjusted for demographic characteristics, cardiovascular risk factors, and lipid-related molecules showed that total cholesterol (beta coefficient: - 22 [95%CI - 37 to - 7], p = 0.004), triglycerides (beta coefficient: 24 [95%CI 2-47], p = 0.033), lipoprotein A (beta coefficient: 22 [95%CI 2-43], p = 0.033), and CEC (beta coefficient: - 6 [95%CI - 10 to - 2]%,p = 0.002) were significantly different between patients and controls. Skin thickness, as assessed by modified Rodnan skin score, was independently associated with a lower CEC (beta coefficient: - 0.21 [95%CI - 0.37 to - 0.05]%, p = 0.011) after multivariable adjustment.

SSc patients show an abnormal lipid profile with respect to controls including CEC. Skin thickness is independent and inversely associated with CEC in SSc patients.

To identify independent predictors of radiographic progression in psoriatic arthritis (PsA) for patients treated with adalimumab or placebo in the Adalimumab Effectiveness in PsA Trial (ADEPT). Univariate analyses and multivariate linear regression analyses assessed risk for radiographic progression (change in modified total Sharp score, DeltamTSS>0.5) from baseline to week 24 for C-reactive protein (CRP) and other baseline variables, and for 24-week time-averaged CRP (univariate analysis only). Subanalyses determined mean DeltamTSS for CRP subgroups. Analyses were post hoc, with observed data. One hundred and forty-four adalimumab-treated patients and 152 placebo-treated patients were assessed. Mean CRP was 64% lower by week 2 with adalimumab and essentially unchanged with placebo. Univariate analyses indicated that elevated CRP at baseline and time-averaged CRP were strongly associated with radiographic progression for placebo-treated patients but not for adalimumab-treated patients. Multivariate analysis confirmed that elevated baseline CRP was the only strong independent risk factor for radiographic progression (for CRP>or=1.0 mg/dl: odds ratio=3.28, 95% confidence interval=1.66 to 6.51, P<0.001). Adalimumab treatment reduced risk of progression approximately fivefold. The difference between mean DeltamTSS for adalimumab versus placebo was greatest for patients with baseline CRP>or=2.0 mg/dl (-0.5 vs. 2.6). Trial registration: NCT00195689.

Systemic inflammation in PsA, as indicated by elevated baseline CRP, was the only strong independent predictor of radiographic progression. This association was observed predominantly for placebo-treated patients. Adalimumab treatment substantially reduced the overall risk of radiographic progression, and provided greatest radiographic benefit for patients with the greatest CRP concentrations at baseline.

There is growing evidence that exposure to organic solvents can play a role in the etiology of rheumatoid arthritis (RA). This prospective cohort study aimed to investigate the association between RA and toluene exposure. The study cohort consisted of Korea Occupational Safety and Health Agency data from male workers exposed to toluene who had undergone a toluene-associated special medical examination at least once between January 1, 2000 and December 31, 2004 (n = 148,870). The morbidity from RA based on hospital admission records was estimated from 2000 to 2005 using National Health Insurance Claim Data. The standardized admission ratio (SAR) for RA was calculated with reference to the general population. Levels of urinary hippuric acid (HA), a metabolite of toluene, were measured and used for exposure assessment. Toluene-exposed workers were at an elevated risk of seropositive rheumatoid arthritis (ICD-10 code M05) with an SAR of 2.38 (95% confidence interval [CI]: 1.14-4.37) and other rheumatoid arthritis (M06) with an SAR of 1.22 (95% CI: 0.91-1.59). When data were stratified according to the duration of toluene exposure and by tertiles of urinary HA level, no significant difference was apparent.

SARs of the toluene-exposed workers are higher than that of the general reference population, indicating that exposure to toluene may contribute to an increased risk of RA. Further studies of toluene-exposed workers with longer follow-up are needed.

Methotrexate (MTX) is recommended by recent American College of Rheumatology and European League against Rheumatism guidelines as a first-line drug for rheumatoid arthritis (RA). Liver fibrosis, which occurs as a long-term side effect is of major concern. Monitoring aminotransferase and albumin is suggested in the guidelines, unfortunately this method is unreliable for detecting liver fibrosis. We try to find the association between clinical parameters, cumulative MTX dosage, liver fibrosis scoring systems and the presence of liver fibrosis assessed by transient elastography (TE; Fibroscan®). Rheumatoid arthritis patients prescribed MTX were evaluated for liver fibrosis with TE. Two subgroups of patients were compared: non-fibrosis and fibrosis (TE > 7 kPa). Univariate and multivariate logistic regression analysis was performed to identify factors associated with liver fibrosis. One hundred and eight patients were recruited. Twenty-nine patients (26.8%) were classified by transient elastography as liver fibrosis cases. The multivariate analysis demonstrated statistical significance only in the association of body mass index (odds ratio [OR] = 1.22; 95% CI 1.05-1.41; P = 0.01); fatty liver (OR = 2.32; 95% CI 1.58-9.19; P = 0.02); alanine transaminase (OR = 1.04; 95% CI 1.02-1.09; P = 0.04) and cumulative MTX dosage (OR = 1.03; 95% CI 1.01-1.04; P = 0.001).

Liver fibrosis measured with Fibroscan was associated with cumulative MTX. RA patients with metabolic syndrome including high body mass index and fatty liver, had a higher risk of MTX-induced hepatic fibrosis. RA patients with high cumulative MTX dose, especially patients with concurrent metabolic syndrome, should be cautiously monitored for liver fibrosis.

Immunosuppressed individuals present serious morbidity and mortality from influenza, therefore it is important to understand the safety and immunogenicity of influenza vaccination among them. This multicenter cohort study evaluated the immunogenicity and reactogenicity of an inactivated, monovalent, non-adjuvanted pandemic (H1N1) 2009 vaccine among the elderly, HIV-infected, rheumatoid arthritis (RA), cancer, kidney transplant, and juvenile idiopathic arthritis (JIA) patients. Participants were included during routine clinical visits, and vaccinated according to conventional influenza vaccination schedules. Antibody response was measured by the hemagglutination-inhibition assay, before and 21 days after vaccination. 319 patients with cancer, 260 with RA, 256 HIV-infected, 149 elderly individuals, 85 kidney transplant recipients, and 83 with JIA were included. The proportions of seroprotection, seroconversion, and the geometric mean titer ratios postvaccination were, respectively: 37.6%, 31.8%, and 3.2 among kidney transplant recipients, 61.5%, 53.1%, and 7.5 among RA patients, 63.1%, 55.7%, and 5.7 among the elderly, 59.0%, 54.7%, and 5.9 among HIV-infected patients, 52.4%, 49.2%, and 5.3 among cancer patients, 85.5%, 78.3%, and 16.5 among JIA patients. The vaccine was well tolerated, with no reported severe adverse events.

The vaccine was safe among all groups, with an acceptable immunogenicity among the elderly and JIA patients, however new vaccination strategies should be explored to improve the immune response of immunocompromised adult patients. (ClinicalTrials.gov, NCT01218685).

Anti-tumour necrosis factor (TNF) agents and other anti-rheumatic medications increase the risk of TB in rheumatoid arthritis (RA). Whether they increase the risk of infections with nontuberculous mycobacteria (NTM) is uncertain. To determine the effect of anti-TNF therapy and other anti-rheumatic drugs on the risk of NTM disease and TB in older patients with RA. Population-based nested case-control study among Ontario seniors aged ≥67 years with RA who were prescribed at least one anti-rheumatic medication between 2001 and 2011. We identified cases of TB and NTM disease microbiologically and identified drug exposures using linked prescription drug claims. We estimated ORs using conditional logistic regression, controlling for several potential confounders. Among 56 269 older adults with RA, we identified 37 cases of TB and 211 cases of NTM disease; each case was matched to up to 10 controls. Individuals with TB or NTM disease were both more likely to be using anti-TNF therapy (compared with non-use); adjusted ORs (95% CIs) were 5.04 (1.27 to 20.0) and 2.19 (1.10 to 4.37), respectively. Exposure to leflunomide and other anti-rheumatic drugs with high immunosuppressing potential also were associated with both TB and NTM disease, while oral corticosteroids and hydroxychloroquine were associated with NTM disease.

Anti-TNF use is associated with increased risk of both TB and NTM disease, but appears to be a relatively greater risk for TB. Several other anti-rheumatic drugs were also associated with mycobacterial infections.