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Following observation of weakly positive anticardiolipin (aCL) antibodies in four of eight patients with systemic sclerosis (SSc) and severe digital ischaemia requiring amputation, the association between the presence of these and other antibodies and severe peripheral ischaemia in patients with SSc was examined. ACL antibodies (IgG and IgM), anticentromere and anti-Scl-70 antibodies were measured in a further 60 patients with SSc over a one year period. Thirty one of the 68 patients in whom aCL antibodies were assayed had 'severe ischaemia', having suffered digital ischaemia severe enough to warrant amputation (13 patients), surgical debridement or admission for intravenous vasodilator therapy. There was no difference in aCL positivity between those with severe ischaemia and those without, nor between those who had amputations and those who had not. Three of the 31 patients (10%) with severe ischaemia had IgG and eight (26%) IgM aCL antibodies in weak to moderate titre compared to 10 (27%) and 6 (16%) respectively of the remaining patients (p = 0.06 for IgG and p = 0.25 for IgM, Fisher's exact test). Seventeen of the 31 patients (55%) with severe ischaemia were anticentromere antibody positive compared with nine of 37 (24%) without ischaemia (p = 0.01). Six patients with severe ischaemia had anti-Scl-70 antibodies compared with two of the 37 without ischaemia (p = 0.08).

The findings do not support an association between aCL antibodies and severe ischaemia in SSc, but confirm the previously reported association between anticentromere antibodies and severe peripheral ischaemia. Although anti-Scl-70 antibodies were present only in a small number of patients, there was also a tendency for these to be associated with severe ischaemia, suggesting that patients with either anticentromere or anti-Scl-70 antibodies should be considered at risk of digital loss.

Although transition from proliferation to hypertrophic differentiation of chondrocytes is a crucial step for endochondral ossification in physiological skeletal growth and pathological disorders like osteoarthritis, the underlying mechanism remains an enigma. This study investigated the role of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) in chondrocytes during endochondral ossification. Mouse embryos with homozygous deficiency in C/EBPbeta (C/EBPbeta-/-) exhibited dwarfism with elongated proliferative zone and delayed chondrocyte hypertrophy in the growth plate cartilage. In the cultures of primary C/EBPbeta-/- chondrocytes, cell proliferation was enhanced while hypertrophic differentiation was suppressed. Contrarily, retroviral overexpression of C/EBPbeta in chondrocytes suppressed the proliferation and enhanced the hypertrophy, suggesting the cell cycle arrest by C/EBPbeta. In fact, a DNA cell cycle histogram revealed that the C/EBPbeta overexpression caused accumulation of cells in the G0/G1 fraction. Among cell cycle factors, microarray and real-time RT-PCR analyses have identified the cyclin-dependent kinase inhibitor p57(Kip2) as the transcriptional target of C/EBPbeta. p57(Kip2) was co-localized with C/EBPbeta in late proliferative and pre-hypertrophic chondrocytes of the mouse growth plate, which was decreased by the C/EBPbeta deficiency. Luciferase-reporter and electrophoretic mobility shift assays identified the core responsive element of C/EBPbeta in the p57(Kip2) promoter between -150 and -130 bp region containing a putative C/EBP motif. The knockdown of p57(Kip2) by the siRNA inhibited the C/EBPbeta-induced chondrocyte hypertrophy. Finally, when we created the experimental osteoarthritis model by inducing instability in the knee joints of adult mice of wild-type and C/EBPbeta+/- littermates, the C/EBPbeta insufficiency caused resistance to joint cartilage destruction.

C/EBPbeta transactivates p57(Kip2) to promote transition from proliferation to hypertrophic differentiation of chondrocytes during endochondral ossification, suggesting that the C/EBPbeta-p57(Kip2) signal would be a therapeutic target of skeletal disorders like growth retardation and osteoarthritis.

Osteoarthritis (OA) is the most common joint disease worldwide. In the past decade, mesenchymal stem cells (MSCs) have been used widely for the treatment of OA. A potential mechanism of MSC-based therapies has been attributed to the paracrine secretion of trophic factors, in which exosomes may play a major role. In this study, we aimed to compare the effectiveness of exosomes secreted by synovial membrane MSCs (SMMSC-Exos) and exosomes secreted by induced pluripotent stem cell-derived MSCs (iMSC-Exos) on the treatment of OA. Induced pluripotent stem cell-derived MSCs and synovial membrane MSCs were characterized by flow cytometry. iMSC-Exos and SMMSC-Exos were isolated using an ultrafiltration method. Tunable resistive pulse-sensing analysis, transmission electron microscopy, and western blots were used to identify exosomes. iMSC-Exos and SMMSC-Exos were injected intra-articularly in a mouse model of collagenase-induced OA and the efficacy of exosome injections was assessed by macroscopic, histological, and immunohistochemistry analysis. We also evaluated the effects of iMSC-Exos and SMMSC-Exos on proliferation and migration of human chondrocytes by cell-counting and scratch assays, respectively. The majority of iMSC-Exos and SMMSC-Exos were approximately 50-150 nm in diameter and expressed CD9, CD63, and TSG101. The injection of iMSC-Exos and SMMSC-Exos both attenuated OA in the mouse OA model, but iMSC-Exos had a superior therapeutic effect compared with SMMSC-Exos. Similarly, chondrocyte migration and proliferation were stimulated by both iMSC-Exos and SMMSC-Exos, with iMSC-Exos exerting a stronger effect.

The present study demonstrated that iMSC-Exos have a greater therapeutic effect on OA than SMMSC-Exos. Because autologous iMSCs are theoretically inexhaustible, iMSC-Exos may represent a novel therapeutic approach for the treatment of OA.

Recent evidence suggests a role of fibrogenesis in intervertebral disc (IVD) degeneration. We aim to explore if fibrotic genes may serve as IVD degeneration indicators, and if their expression is associated with myofibroblast activity. Transcriptional expression of fibrosis markers (COL1A1, COL3A1, FN1, HSP47, MMP12, RASAL1) were analyzed in degenerated (D) and non-degenerated (ND) human nucleus pulposus (NP) and annulus fibrosus (AF) cells, along with traditional (SOX9, ACAN) and newly established degeneration markers (CDH2, KRT19, KRT18, FBLN1, MGP, and COMP). Protein expression was investigated by immunohistochemistry in human IVDs, and in rodent IVDs undergoing natural ageing or puncture-induced degeneration. Co-expression with myofibroblast markers was examined by double staining on human and rat specimens. Disc degeneration severity and extent of fibrosis were determined by histological scoring and picrosirius red staining respectively. Human D-NP showed more intensive staining for picrosirius red than ND-NP. Among the genes examined, D-NP showed significantly higher MMP12 expression along with lower KRT19 expression. Protein expression analysis revealed increased MMP12(+) cells in human D-IVD. Histological scoring indicated mild degeneration in the punctured rat discs and discs of ageing mouse. Higher MMP12 positivity was found in peripheral NP and AF of the degenerative rat discs and in NP of the aged mice. In addition, human D-NP and D-AF showed increased α-SMA(+) cells, indicating enhanced myofibroblast activity. MMP12 was found co-expressed with α-SMA, FSP1 and FAP-α in human and rat degenerative IVDs.

Our study suggests that in addition to a reduced KRT19 expression, an increased expression of MMP12, a profibrotic mediator, is characteristic of disc degenerative changes. Co-expression study indicates an association of the increased MMP12 positivity with myofibroblast activity in degenerated IVDs. Overall, our findings implicate an impact of MMP12 in disc cell homeostasis. The precise role of MMP12 in IVD degeneration warrants further investigation.

Biologic disease modifying antirheumatic drugs (bDMARDs) and Janus Kinase (JAK) inhibitors are prescribed in adult and paediatric rheumatology. Due to age-dependent changes, disease course, and pharmacokinetic processes paediatric patients with inflammatory rheumatic diseases (PiRD) differ from adult rheumatology patients. A systematic literature search for randomized clinical trials (RCTs) in PiRD treated with bDMARDs/JAK inhibitors was conducted on Medline, clinicaltrials.gov , clinicaltrialsregister.eu and conference abstracts as of July 2020. RCTs were included if (i) patients were aged ≤20 years, (ii) patients had a predefined rheumatic diagnosis and (iii) RCT reported predefined outcomes. Selected studies were excluded in case of (i) observational or single arm study or (ii) sample size ≤5 patients. Study characteristics were extracted. Out of 608 screened references, 65 references were selected, reporting 35 unique RCTs. All 35 RCTs reported efficacy while 34/3 provided safety outcomes and 16/35 provided pharmacokinetic data. The most common investigated treatments were TNF inhibitors (60%), IL-1 inhibitors (17%) and IL-6 inhibitors (9%). No RCTs with published results were identified for baricitinib, brodalumab, certolizumab pegol, guselkumab, risankizumab, rituximab, sarilumab, secukinumab, tildrakizumab, or upadacitinib. In patients with juvenile idiopathic arthritis (JIA) 25/35 RCTs were conducted. The remaining 10 RCTs were performed in non-JIA patients including plaque psoriasis, Kawasaki Disease, systemic lupus erythematosus and non-infectious uveitis. In JIA-RCTs, the control arm was mainly placebo and the concomitant treatments were either methotrexate, non-steroidal anti-inflammatory drugs (NSAID) or corticosteroids. Non-JIA patients mostly received NSAID. There are ongoing trials investigating abatacept, adalimumab, baricitinib, brodalumab, certolizumab pegol, etanercept, guselkumab, infliximab, risankizumab, secukinumab, tofacitinib and tildrakizumab.

Despite the FDA Modernization Act and support of major paediatric rheumatology networks, such as the Pediatric Rheumatology Collaborative Study Group (PRCSG) and the Paediatric Rheumatology International Trials Organization (PRINTO), which resulted in drug approval for PiRD indications, there are limited RCTs in PiRD patients. As therapy response is influenced by age-dependent changes, pharmacokinetic processes and disease course it is important to consider developmental changes in bDMARDs/JAK inhibitor use in PiRD patients. As such it is critical to collaborate and conduct international RCTs to appropriately investigate and characterize efficacy, safety and pharmacokinetics of bDMARDs/JAK inhibitors in paediatric rheumatology.

Lupus nephritis is characterised by intrarenal inflammation and lymphocyte activation. To examine the profile of cytokine gene expression in glomerulus and tubulointerstitium in patients with lupus nephritis. 36 consecutive patients with systemic lupus erythematosus having active renal disease were recruited, and they were required to undergo kidney biopsy. Glomerular and tubulointestitial cytokine expression of interleukin (IL)2, 4, 10, 12, 18, interferon gamma (IFN)gamma, T-bet (the Th1 transcription factor), GATA-3 (the Th2 transcription factor), transforming growth factor beta and monocyte chemoattractant protein (MCP)1 were studied by laser microdissection of the renal biopsy specimen, followed by real-time quantitative PCR. There were 13 patients with World Health Organization class III nephritis, 14 patients with class IV nephritis and 9 patients with class V nephritis. There was a significant correlation between serum C3, C4 and anti-double strand DNA antibody level with glomerular expression of T-bet, IFNgamma and IL2. There was a significant correlation between histological activity index and glomerular expression of IL12, IL18, IL10 and MCP1. In addition, the degree of glomerular leucocyte infiltration significantly correlated with glomerular expression of IFNgamma, IL10, IL12 and IL18. By contrast, histological chronicity index correlated with the tubulointerstitial expression of IL2, MCP1 and GATA-3.

Intraglomerular expression of certain target genes correlate with the severity of systemic as well as histological activity, whereas the tubulointerstitial expression of other target genes correlate with the degree of chronic kidney scarring. This result may shed light on the immunopathogenesis of lupus nephritis.

The purpose of this study was to determine the expression of related genes in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX), to identify hub genes, and to systematically analyse the functions, pathways, and networks of these genes. The PubMed identifiers (PMIDs) of relevant publications were obtained from the PubMed database, and gene data were extracted from these documents using the text mining software PubTator. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to obtain enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway information. In addition, the STRING database was used to construct a protein-protein interaction (PPI) network. Genes with which at least 10 other genes interacted were identified as hub genes. A total of 216 genes were identified as being associated with treatment efficacy for MTX, of which 14 pathways exhibited significant correlation (p<0.05, FDR<0.05). In addition, the constructed MTX treatment-related network consisted of 267 interactions. Fourteen genes were found to interact with at least 10 other genes (p<0.05, FDR<0.05) and identified as hub genes in the PPI network. These genes were JAK1, MAPK1, JUN, AKT1, MAPK14, MAPK8, FGB, FN1, ALB, B2M, IL2RB, GGH, IL2RA, and TP53.

This study will assist in elucidating the molecular mechanisms associated with the treatment efficacy of MTX for RA and provide a scientific rationale for guiding patient medication. However, the relationship between particular genes and the efficacy of MTX treatment for RA patients requires additional investigation.

To compare the reliability of 3 different simplified joint counts with the gold standard 66 swollen/68 tender joint count (JC66/68) for assessing clinical response in patients with polyarticular psoriatic arthritis (PsA). The 28-joint count (JC28), in the same way that it is used in rheumatoid arthritis, and 2 measures including distal interphalangeal (DIP) joints (the 32-joint count [JC32], including all finger joints as well as wrists and knees, and 36-joint count [JC36], which additionally included elbows and ankles), were compared with the JC66/68 in 182 patients using data from the Infliximab Multinational Psoriatic Arthritis Controlled Trial 2 trial database. Pearson's correlation coefficients were calculated to compare the swollen and tender JC28, JC32, and JC36 with the corresponding results of the total JC66/68. American College of Rheumatology (ACR) responses based on the individual measures were compared, and their ability in predicting a clinical response of ACR 20% improvement (ACR20) based on the JC66/68 was assessed by calculating the area under the receiver operating characteristic curve via logistic regression and the maximum Youden indices at weeks 14 and 24. All simplified joint counts were highly correlated to the standard JC66/68 both for tenderness and swelling at each individual visit (Pearson's correlation coefficients consistently >0.8, n = 182-200; P < 0.0001). Logistic regression for ACR20 response showed that area under the curve was constantly >0.91, with comparable results for Youden indices of the simplified joint counts.

All simplified joint counts considered seemed sufficiently sensitive and specific to measure clinical response in trial patients with polyarticular PsA when compared with the JC66/68, no matter whether DIP joints were included (the JC36 and JC32) or excluded (the JC28). Further research will be needed to clarify this issue.

Ultrasonography (US) is a sensitive tool in the diagnosis of major salivary gland abnormalities in primary Sjögren's syndrome (pSS). The aim of this systematic review was to assess the metric properties of this technique. PUBMED and EMBASE databases were searched. All publications between January 1988 and January 2013 were considered. Data were extracted from the articles meeting the inclusion criteria according to US definition of salivary gland scoring system and metric properties studied. The type and number of glands tested, study design and metric properties according to OMERACT filter (truth, discrimination, feasibility) were assessed. Of 167 publications identified initially with PUBMED and EMBASE, 31 met the inclusion criteria. The number of pSS patients varied among the studies from 16 to 140. The diagnosis of pSS was in line in most of the cases with the American-European Consensus Group (AECG) classification criteria for Sjögren's syndrome. The US examination was performed in suspected pSS only in studies in which the sensitivity ranged from 45.8 to 91.6% and specificity from 73 to 98.1%. There was heterogeneity in regard to the definition of US in B-mode and few studies used US in colour Doppler. Few studies reported reliability of US and sensitivity to change in pSS.

US is a valuable tool for detecting salivary gland abnormalities in pSS. Its reliability has been poorly investigated and there is considerable variation in the definition of US abnormalities. Further studies are required to validate and standardize the US definition of salivary gland in pSS.

To gain clinical experience on the effectiveness and safety of switching from infliximab-Remicade(INX) to infliximab-biosimilar-CT-P13(INB) in patients with established rheumatic disease. Patients receiving INX treatment at a rheumatology clinic consented to switching from INX to INB. Patient reported outcomes (PROs), disease-activity, and inflammatory markers were recorded at every visit. Generalized estimating equation models and time-dependent area under the curve (AUC) before/during INX and INB treatments were employed. Thirty-nine consecutive patients [mean (SD) age 53 (11), 17 F] with various rheumatic diseases were switched to INB after a mean (SD) of 4.1 (2.3) years on INX. Thirty-one patients were on concomitant methotrexate. At a median (range) of 11 (7.5-13) months following the first administration of INB, AUCs for disease activity and PROs were similar for INX and INB. They were better compared to those prior to INX. Eleven patients (28.2%) discontinued INB, due to INX antidrug antibodies detected prior to INB infusion (n = 3); latent tuberculosis (n = 1); new-onset neurofibromatosis (n = 1); subjective reasons with no objective deterioration of disease (n = 6).

The clinical effectiveness of INB in both PROs and disease-activity measures was comparable to INX during the first year of switching, with no immediate safety signals. Subjective reasons (negative expectations) may play a role among discontinuations of biosimilars. Larger patient numbers and longer follow-up are necessary for confirming this clinical experience.

To examine the kinetic features in patients with knee osteoarthritis (OA) after intra-articular hyaluronic acid (IAHA) injections in different time periods. A single group repeated measures study. Gait laboratory in a tertiary hospital. Twenty-five subjects with bilateral symptomatic knee OA and 15 healthy control subjects. Gait analyses were performed in both control and OA groups before (baseline), and after the completion of IAHA injections (1 week, 3 months, and 6 months). Knee pain and functional indices were assessed using a visual analogue scale (VAS) and the Lequesne function Index (LI). Joint kinetic changes were analyzed in the frontal and sagittal planes with 6-camera motion analysis system and two AMTI force plates. VAS and LI scores were both improved in OA group after IAHA injections (p<0.001). In the frontal plane, increased knee adduction moment (p<0.001) after IAHA treatment was observed and would last up to a period of 6 months. In the sagittal plane, lower knee extension moments at early stance, and larger knee flexion moments at terminal stance were demonstrated after the completion of IAHA injections (p<0.05).

This study revealed that IAHA injections can provide significant pain relief and improvement in activity of daily living function for patients with knee OA. However, the reduction in pain and the increase in knee adduction moment may last up to 6 months. This may cause excessive loading on the knee joints, which may further accelerate the rate of knee degeneration. As a result, longer study time is needed to determine whether the observed kinetic findings in this study are associated with detrimental outcomes on the knee joints.

To investigate the influence of gender on osteoarthritic knee rehabilitation outcome of osteoarthritis patient undergoing total knee arthroplasty (TKA). We prospectively studied thirty male and thirty female knee primary osteoarthritis patients receiving unilateral TKA with posterior stable-fixed plateau prosthesis at our hospital from March 2003 to March 2008. The age and body mass index of male and female patients were matched. The surgical and rehabilitation clinical factors were compared between two groups. There was no significant difference in postoperative hospitalization time, surgical tourniquet time, and wound drainage volume between two groups (P>0.05). The extension/flexion degrees of knee joint before operation, 1-week, 2-week and 1-year after operation for male patients were 6.0 +/- 3.3 degrees/114.0 +/- 10.0 degrees, 2.0 +/- 1.6 degrees/93.0 +/- 7.4 degrees, 0.6 +/- 0.6 degrees/104.0 +/- 9.9 degrees and 0.3 +/- 0.5 degrees/125.0 +/- 8.8 degrees, for female patients were 7.0 +/- 3.4 degrees/112.0 +/- 14.0 degrees, 2.0 +/- 1.3 degrees/89.0 +/- 10.9 degrees, 0.9 +/- 0.8 degrees/101.0 +/- 11.8 degrees, 0.4 +/- 0.5 degrees/124.0 +/- 7.1 degrees. The range of motion before operation, 1-week, 2-week, and 1-year after operation for male patients was 108.0 +/- 9.5 degrees, 91.0 +/- 7.1 degrees, 103.0 +/- 9.9 degrees, and 125.0 +/- 8.9 degrees, for female patients was 105.0 +/- 14.1 degrees, 87.0 +/- 11.4 degrees, 100.0 +/- 11.9 degrees, and 124.0 +/- 7.0 degrees. The preoperative and 1-year postoperative HSS scores were 55.8 +/- 13.3 and 89.6 +/- 6.7 for males and 54.5 +/- 13.8 and 89.2 +/- 4.1 for females. No significant statistical difference was observed between two gender groups in regards to degree of extension and flexion, range of motion and HSS score (P>0.05).

Gender does not influence postoperative knee function of osteoarthritis patients. TKA significantly improves knee joint function and relieve osteoarthritis-related pain.

Seventeen knees in 13 patients with rheumatoid arthritis (RA) were studied with MRI to clarify the dynamics of Gd-DTPA administered intravenously and to determine an optimal imaging time. Dynamic gradient recalled echo imaging with bolus intravenous injection of Gd-DTPA was performed following unenhanced T1- and T2-weighted SE imaging. Late-phase SE or serial gradient recalled echo images were obtained following dynamic study. There was rapid enhancement of synovium with maximal enhancement ratio of 96-499% (mean 214 +/- 111%) with Tmax ranging from 120 to 660 s (mean 253 s). The synovial enhancement persisted over 80% of the peak enhancement for 6-27 min (average 12 min) with eventual enhancement of joint effusion from the periphery to the center beginning at 6 min to 8 min, 20 s after contrast medium injection. Complete enhancement of joint effusion was noted in four joints at 24-86 min.

We conclude that enhancement of synovium in patients with RA is a time-dependent phenomenon, and an optimal imaging time would be within 5 min following contrast medium administration.

The presence of YKL-40 (human cartilage glycoprotein 39) in synovium, cartilage and synovial fluid (SF) from knee joints of patients with rheumatoid arthritis and osteoarthritis (OA) were related to histopathological changes in synovium and cartilage and to serum YKL-40 and other biochemical markers. The localization of YKL-40 in synovium and cartilage was determined by immunohistochemistry. Synovial inflammation was estimated histologically and by magnetic resonance imaging (MRI). Biochemical markers of inflammation, neutrophil activation and cartilage metabolism were analysed. YKL-40 concentrations in serum and SF were determined by RIA and ELISA. In the synovium YKL-40 positive cells were found in lining and stromal cells (macrophages) and the number of YKL-40 positive cells was related to the degree of synovitis. In arthritic cartilage, YKL-40 was located to chondrocytes. YKL-40 levels in SF were higher in RA patients with moderate/severe or none/slight synovitis of the knee joint compared to OA patients with moderate/severe or none/slight synovitis. SF YKL-40 correlated with the synovial membrane and the joint effusion volumes determined by magnetic resonance imaging (MRI) and with other biochemical markers of intercellular matrix metabolism. SF YKL-40 was higher than serum YKL-40, and a relationship existed between the YKL-40 levels in SF and serum. Intraarticular glucocorticoid injection was followed by clinical remission and a decrease in serum YKL-40, which increased again at clinical relapse.

YKL-40 in SF is derived from cells in the inflamed synovium, chondrocytes and SF neutrophils. Joint derived YKL-40 influences serum YKL-40. YKL-40 may be involved in the pathophysiology of the arthritic processes and reflect local disease activity.

To study the therapeutic effect of chitosan-coated basic fibroblast growth factor (bFGF) slow-releasing microspheres on the knee osteoarthritis in the rabbit. From November 2008 to July 2009, 54 New Zealand rabbits were divided into 6 groups at random, which were the control group, the model group, the PBS-M group, the bFGF-S group, the 10-bFGF-M group and the 100-bFGF-M group, respectively. The model of knee osteoarthritis was induced by the injection of papain in the rabbit. Except the control and model groups, all the experimental groups were implanted 1 ml intervention solution at the third and sixth weeks, including the PBS microspheres, bFGF solution, 10 µg bFGF microspheres and 100 µg bFGF microspheres, respectively. The rabbits were sacrificed at the ninth week after operation, and then articular cartilage was conducted the morphological and histopathological evaluation. The damage of articular cartilage in the model group was more serious than that in the control group, with statistical differences according to the Ink score (t = 8.22, P = 0.00) and Mankin score (t = 17.20, P = 0.00). The damage of articular cartilage in the PBS-M and bFGF-S groups were similar with that in the model group, according to the Ink score (t = 0.26, P = 0.79; t = 0.80, P = 0.45) and Mankin score (t = 1.51, P = 0.17; t = 0.56, P = 0.60). The Ink and Mankin scores in the 10-bFGF-M and 100-bFGF-M groups were better than that in the model group (Ink score: t = 3.58, P = 0.01; t = 6.82, P = 0.00; Mankin score: t = 3.41, P = 0.01; t = 5.00, P = 0.00), with the 100-bFGF-M group much better (t = 5.29, P = 0.00; t = 2.80, P = 0.02).

The bFGF slow-releasing microsphere can keep its effective intra-articular concentration, which may accelerate the synthesis of proteoglycan and inhibit its decomposition to reverse the damage of articular cartilage.

To evaluate the prevalence of undiagnosed rheumatic diseases in the first trimester of pregnancy. We screened for rheumatic diseases in 1210 consecutive pregnant women during the first trimester of pregnancy using a 10-item questionnaire. A university hospital in northern Italy. One hundred and thirty-seven (11.3%) women who answered positively to at least one question constituted the cases and were compared with 107 negative controls. Cases and controls were tested for rheumatic autoantibodies (antinuclear antibody, anti-double-stranded DNA, anti-extractable nuclear antigen, anticardiolipin antibody, anti-beta2-glycoprotein I antibodies and lupus anticoagulant) and were evaluated by a rheumatologist for a definite diagnosis of rheumatic disease. Prevalence of undiagnosed rheumatic disease in the first trimester of pregnancy. The overall rate of positivity to the antibodies tested was 43.1% (59/137) among cases and 9.3% (10/107) in the controls (P < 0.001). A definitive diagnosis of rheumatic disease was made in 35 cases (25.5%) and in none of the controls (P <0.001). In stepwise logistic regression analysis, photosensitivity (adjusted OR 5.72; 95% CI 2.38-13.8), erythema or malar rash (adjusted OR 3.91; 95% CI 1.53-10) and history of two or more miscarriages (adjusted OR 5.6; 95% CI 1.55-20.6) were independent predictors of a definitive diagnosis of rheumatic disease (area under receiving operator curve = 0.814; 95% CI 0.76-0.86). Birthweight was lower (3180 g +/- 475 compared with 3340 g +/- 452, P= 0.008), and overall serious pregnancy complications (miscarriage, fetal growth restriction, delivery before 34 weeks of pregnancy and severe pre-eclampsia) were higher among cases (12/137) than controls (2/107) (adjusted OR 5.60; 95% CI 1.29-24.3; P= 0.021).

A two-step screening process with a self-administered questionnaire proved to be a useful method to screen for undiagnosed rheumatic diseases during the first trimester of pregnancy.

In the oligoarticular subgroup of juvenile idiopathic arthritis, a strong association has been found with the expression of human leukocyte antigen class II molecules HLA-DQA1 *0401-DQB1*0402 and DQA1*0501-DQB1*0301, whereas DQA1*0501-DQB1*0201 is neutral and DQA1 *0201-DQB1*0201 protective. A presentation of different peptides by these DQ alleles would support their role in the disease process. Using a synthetic nonapeptide library, a peptide binding motif was determined for the associated DQA1*0501-DQB1*0301 molecule and compared to the neutral and the protective DQ molecules. A differential motif for the three molecules could be deduced, suggesting that peptides preferentially binding to the associated vs. the neutral/protective DQ-molecules are mutually exclusive.

These results imply a role for differential peptide presentation in the pathogenesis of oligoarthritic JIA. The search for peptides initiating the disease process might be facilitated which could then lead to therapeutical interventions.

To determine whether the expression of IL17A and CD21L genes in inflamed rheumatoid synovia is associated with the neogenesis of ectopic lymphoid follicle-like structures (ELS), and if this aids the stratification of rheumatoid inflammation and thereby distinguishes patients with rheumatoid arthritis that might be responsive to specific targeted biologic therapies. Expression of IL17A and CD21L genes was assessed by RT-PCR, qRT-PCR and dPCR in synovia from 54 patients with rheumatoid arthritis. A subset of synovia (n = 30) was assessed by immunohistology for the presence of CD20+ B-lymphocytes and size of CD20+ B-lymphocyte aggregates as indicated by maximum radial cell count. The molecular profiles of six IL17A+/CD21L+ and six IL17A-/CD21L- synovia were determined by complementary DNA microarray analysis. By RT-PCR, 26% of synovia expressed IL17A and 52% expressed CD21L. This provided the basis for distinguishing four subgroups of rheumatoid synovia: IL17A+/CD21L+ (18.5% of synovia), IL17A+/CD21L- (7.5%), IL17A-/CD21L+ (33.3%) and IL17A-/CD21L- (40.7%). While the subgroups did not predict clinical outcome measures, comparisons between the synovial subgroups revealed the IL17A+/CD21L+ subgroup had significantly larger CD20+ B-lymphocyte aggregates (P = 0.007) and a gene expression profile skewed toward B-cell- and antibody-mediated immunity. In contrast, genes associated with bone and cartilage remodelling were prominent in IL17A-/CD21L- synovia.

Rheumatoid synovia can be subdivided on the basis of IL17A and CD21L gene expression. Ensuing molecular subgroups do not predict clinical outcome for patients but highlight high inflammation and the predominance of B-lymphocyte mediated mechanisms operating in IL17A+/CD21L+ synovia. This may provide a rationale for more refined therapeutic selection due to the distinct molecular profiles associated with IL17A+/CD21L+ and IL17A-/CD21L- rheumatoid synovia.

Primary Sjögren syndrome (pSS) is a common autoimmune condition which primarily affects epithelial tissue, often including the kidney causing either tubulointerstitial nephritis (TIN) or more rarely, an immune complex related glomerulonephritis. We describe the clinical, biochemical and histological characteristics of 12 patients with pSS related TIN and their response to treatment with antiproliferative agents. All 12 patients were investigated and treated at the UCL Centre for Nephrology in London. All patients had TIN demonstrated via needle biopsy; immunophenotyping showed that the interstitial infiltrate was predominantly a CD4+ T-cell infiltrate. Urinary acidification testing demonstrated distal renal tubular acidosis in 8 patients. Proximal tubular dysfunction was present in 5 patients. All but 1 patient were treated with antiproliferative agents and most also with a reducing course of steroids. In the treated patients, there was a significant improvement in the serum creatinine and measured GFR.

Patients with pSS TIN have significant renal impairment and other functional tubular defects. There is a mononuclear lymphocytic infiltrate on renal biopsy and this appears to be mainly a CD4+ T-cell infiltrate. Treatment with mycophenolate (and corticosteroids) improves the renal function in patients with pSS TIN.

Identifying drivers of pain that can serve as novel drug targets is important for improving perioperative analgesia. Total knee arthroplasty (TKA) is associated with significant postoperative pain. Cytokines contribute to the pathophysiology of osteoarthritis (OA) and associated pain. However, the influence of perioperative cytokine levels after TKA surgery upon postoperative pain remains unexplored. We designed a prospective observational study to profile three proinflammatory cytokines, interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and leptin in serum, synovial, and cerebrospinal fluid of TKA patients perioperatively to determine associations between cytokine levels and pain. We characterized time-trajectories in cytokines pre- and post-surgery and explored their relationships to pain across gender. Preoperative pain, measured by functional pain disability scores (PDQ), was predictive of postoperative pain. There were no gender differences in severity of preoperative pain or acute postoperative pain. Serum IL-6, serum leptin, and synovial fluid leptin were positively correlated with body mass index and preoperative pain severity. Stratification of patients by gender revealed strong correlations between serum IL-6, leptin, and PDQ only in females, suggesting that females may be more sensitive to the nociceptive actions of these cytokines. Although serum IL-6 increased dramatically (and TNFα increased modestly) four hours after surgery and remained elevated at 72h; they were not associated with the severity of acute postoperative pain.

Our data suggest that while preoperative chronic pain is predictive of the severity of acute postoperative pain in TKA patients, the pre- and post-operative inflammatory status does not predict postoperative pain.

Several studies have reported an association between the presence of the shared epitope (SE) and susceptibility to rheumatoid arthritis (RA). Recent studies have shown that certain HLA-DRB1 alleles in combination with predisposing DQB1 and DQA1 alleles may protect against the development of RA. This model is known as the rheumatoid arthritis protection (RAP) hypothesis. To determine the distribution of HLA-DRB1 and DQB1/DQA1 alleles in a cohort of patients with RA in remission and to determine the association between these HLA alleles and the persistence of remission. HLA-DRB1 and DQB1 typings were performed in 167 patients with RA in remission, defined according to the American College of Rheumatology criteria. The disease course, as defined by the persistence of remission during a follow up of two years, was compared between subgroups. According to the RAP hypothesis patients were divided into three subgroups: patients carrying predisposing DQ alleles, patients carrying predisposing alleles in combination with protective alleles (DQ(RA+)/DERAA phenotype), and patients lacking the predisposing alleles. According to the SE hypothesis, patients were divided into three subgroups based on whether they were carrying two, one, or no predisposing alleles (SE alleles). Predisposing DQ alleles along with a DERAA-bearing allele were present in 14 (8%) of the 167 patients. At least one SE allele was present in 116 (69%) patients; 34 of them (20%) were carrying two copies. The disease course was not significantly different between the subgroups according to the SE and RAP hypothesis, respectively.

The frequency of DQ(RA+)/DERAA combinations and of SE alleles in patients with RA clinically in remission was similar to that found in other RA populations. Persistent remission of RA was not associated with any particular HLA subtypes, indicating that HLA typing is not useful for predicting persistent clinical remission.

Controversy exists regarding the safety of simultaneous vs. staged bilateral total knee arthroplasty (TKA). The purpose of this study was to compare postoperative complication rate and clinical outcomes of simultaneous vs. staged bilateral TKA. A consecutive series of 1074 patients who underwent either simultaneous (759 patients) or staged bilateral (315 patients) TKA from 2004 to 2013 were enrolled in this study. Postoperative complications were categorized as minor or major. Clinical outcome was evaluated at the last follow-up using Knee Society Score (KSS), Western Ontario and McMaster Universities Arthritis Index (WOMAC), and range of motion (ROM). Major complication rate was not statistically different between the two groups. However, minor complication rate was significantly (p < 0.05) higher in the staged TKA group compared to that in the simultaneous TKA group. The median length of stay (LOS) in hospital was 18.0 days after simultaneous TKA vs. cumulated LOS of 34.1 days in the staged group (p < 0.05). Clinical outcome results revealed that there was no significant difference in KSS, WOMAC scores, or ROM between the two groups.

Therefore, simultaneous bilateral TKA has some advantage such as less length of stay in hospital compared to staged bilateral TKA. However, this procedure should be conducted very carefully, particularly in high-risk patients.

Interferon (IFN) beta displays anti-inflammatory and immunosuppressive activity and has been considered for the treatment of rheumatoid arthritis (RA). Information about the effects of this molecule on joint cells is scarce, however. To investigate the effects of IFNbeta on the production of interleukin-1 receptor antagonist (IL1Ra) in human articular chondrocytes and synovial fibroblasts. Chondrocytes and synovial fibroblasts were stimulated with IFNbeta alone or in combination with interleukin (IL) 1beta. IL1Ra concentrations in culture supernatants and cell lysates were determined by ELISA. Expression of mRNA encoding the secreted sIL1Ra or the intracellular icIL1Ra1 isoforms was quantified by real time reverse transcriptase-polymerase chain reaction. In chondrocytes, IFNbeta alone had no effect, but dose dependently enhanced the secretion of IL1Ra induced by IL1beta. Chondrocyte cell lysates contained undetectable or low levels of IL1Ra, even after stimulation with IL1beta and IFNbeta. Consistently, IL1beta and IFNbeta induced sIL1Ra mRNA expression in chondrocytes, while expression of icIL1Ra1 was not detectable. Human articular chondrocytes thus mainly produce secreted IL1Ra. In synovial fibroblasts, IFNbeta alone dose dependently increased IL1Ra secretion. In addition, IFNbeta enhanced the stimulatory effect of IL1beta on IL1Ra production. In synovial cell lysates, IFNbeta and IL1beta also increased IL1Ra levels. Consistently, IFNbeta and IL1beta induced the expression of both sIL1Ra and icIL1Ra1 mRNA in synovial fibroblasts.

IFNbeta increases IL1Ra production in joint cells, which may be beneficial in cartilage damaging diseases such as RA or osteoarthritis.

Minimally invasive total hip arthroplasty is purported to allow an improved and faster rehabilitation in the immediate postoperative period because of reduced soft-tissue damage compared with total hip arthroplasty performed with use of a standard approach. In the present study, a minimally invasive approach was compared with a traditional standard approach in terms of the effect on gait kinematics as demonstrated with gait analysis and electromyography. Twenty randomized patients who underwent a primary total hip replacement with use of a minimally invasive modified Watson-Jones approach (minimally invasive group) were compared with a group of twenty patients who underwent a total hip arthroplasty with use of a standard transgluteal Hardinge approach (standard group). All patients received the same cementless implant, inserted with use of standard instruments, and all operations were performed by a single, experienced surgeon. The patients were evaluated with use of three-dimensional gait analysis and dynamic electromyograms at three time points: preoperatively, ten days postoperatively, and twelve weeks postoperatively. Temporospatial and joint-kinematic parameters were evaluated. There were no significant differences between the two groups with regard to the temporospatial variables of velocity, cadence, step length, and stride length at any tested time point. With regard to the range of motion of the operatively treated hip, the minimally invasive group had a smaller decrease at the ten-day time point in comparison with the standard group. However, this finding was not significant. The reduction in the range of motion was mainly caused by reduced hip extension. A compensatory increase in the pelvic tilt was observed in both groups. One patient in the standard group showed a positive Trendelenburg gait ten days postoperatively; it had disappeared completely at the twelve-week time point.

With regard to gait kinematics in the early postoperative period (three months), the present study showed no significant benefit for patients who underwent a total hip arthroplasty through a minimally invasive Watson-Jones approach in comparison with those who were managed with a standard transgluteal approach.

Both overall and central obesity have been associated with the risk of psoriasis in a prospective study. Data on the association between obesity and psoriatic arthritis (PsA) have been sparse and no evidence on obesity measures and the risk of incident PsA is available now. This study aimed to evaluate the association between obesity and the risk of incident PsA in a large cohort of women. 89,049 participants were included from the Nurses Health Study II over a 14-year period (1991-2005). Information on body mass index (BMI), weight change and measures of central obesity (waist circumference, hip circumference and waist-hip ratio) was collected during the follow-up. The incidence of clinician-diagnosed PsA was ascertained and confirmed by supplementary questionnaires. 146 incident PsA cases were identified during 1,231,693 person-years of follow-up. Among all participants, BMI was monotonically associated with an increased risk of incident PsA. Compared with BMI less than 25.0, the RR was 1.83 for BMI 25.0-29.9 (95% CI 1.15 to 2.89), 3.12 for BMI 30.0-34.9 (95% CI 1.90 to 5.11) and 6.46 for BMI over 35.0 (95% CI 4.11 to 10.16). There was a graded positive association between weight change from age 18 years, measures of central obesity and risk of PsA (p for trend <0.001). The analysis among participants developing psoriasis during follow-up revealed a similar association (p for trend <0.01), indicating an increased risk of PsA associated with obesity among patients with psoriasis.

This study provides further evidence linking obesity with the risk of incident PsA among US women.

Activated fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) share many characteristics with tumour cells and are key mediators of synovial tissue transformation and joint destruction. The glycoprotein podoplanin is upregulated in the invasive front of several human cancers and has been associated with epithelial-mesenchymal transition, increased cell migration and tissue invasion. The aim of this study was to investigate whether podoplanin is expressed in areas of synovial transformation in RA and especially in promigratory RA-FLS. Podoplanin expression in human synovial tissue from 18 RA patients and nine osteoarthritis (OA) patients was assessed by immunohistochemistry and confirmed by Western blot analysis. The expression was related to markers of synoviocytes and myofibroblasts detected by using confocal immunofluoresence microscopy. Expression of podoplanin, with or without the addition of proinflammatory cytokines and growth factors, in primary human FLS was evaluated by using flow cytometry. Podoplanin was highly expressed in cadherin-11-positive cells throughout the synovial lining layer in RA. The expression was most pronounced in areas with lining layer hyperplasia and high matrix metalloproteinase 9 expression, where it coincided with upregulation of α-smooth muscle actin (α-sma). The synovium in OA was predominantly podoplanin-negative. Podoplanin was expressed in 50% of cultured primary FLSs, and the expression was increased by interleukin 1β, tumour necrosis factor α and transforming growth factor β receptor 1.

Here we show that podoplanin is highly expressed in FLSs of the invading synovial tissue in RA. The concomitant upregulation of α-sma and podoplanin in a subpopulation of FLSs indicates a myofibroblast phenotype. Proinflammatory mediators increased the podoplanin expression in cultured RA-FLS. We conclude that podoplanin might be involved in the synovial tissue transformation and increased migratory potential of activated FLSs in RA.

To determine the construct validity and responsiveness of the Lysholm knee scoring scale and the WOMAC osteoarthritis index in adolescents and young adults with knee complaints in general practice. In the framework of a prospective cohort study with 1-year follow-up, we included 314 patients aged 12-35 years consulting the general practitioner for incident knee complaints. Subgroup analyses of traumatic and nontraumatic knee complaints and of adolescents and adults were performed. Construct validity was adequate for both questionnaires both in traumatic and nontraumatic patients (aged 12-35) and in adolescents (12-17) and young adults (18-35). Effect size (ES) and standardized response mean (SRM) for both Lysholm and WOMAC global scores were moderate in nontraumatic patients and high in traumatic patients. Guyatt's responsiveness statistic was high in both subpopulations. Adolescents showed high responsiveness with all measures on the Lysholm scale, and moderate (Guyatt's statistic) to high responsiveness (ES and SRM) on the WOMAC index. Young adults showed high responsiveness with all measures on both instruments.

Although neither of the scales was developed for use in adolescents and young adults in general practice, both scales show adequate responsiveness, content, and construct validity in this population.

Glenoid bone stock and morphology and rotator cuff muscle quality and tendon integrity affect the outcome of total shoulder arthroplasty. We hypothesized that glenoid bone loss correlates with rotator cuff muscle fatty infiltration (FI), tendinopathy, and atrophy. Forty-three 3D CT scans and MRIs of 43 patients (mean age 62 years; SD 13 years; range 22-77 years) referred for primary shoulder pain were evaluated. Measurements of glenoid bone stock, version, and posterior humeral subluxation index (HSI) were assessed on an axial CT image reconstructed in the true scapular plane. Measurements utilized the Friedman line to approximate the pre-pathologic surface. Glenoid morphology was assigned by modified Walch classification. Rotator cuff FI, atrophy, and tendon integrity were assessed on corresponding MRIs. There was a very strong negative correlation between increasing glenoid version and HSI (r = - 0.908; p < 0.0001). There was a moderately negative correlation between anterior bone loss and HSI (r = - 0.562; p < 0.0001) and a moderately positive correlation between posterior bone loss and HSI (r = 0.555; p < 0.0001). Subscapularis muscle FI correlated moderately with increased anterior and central bone loss and increased humeral head medialization (r = 0.512, p = 0.0294; r = 0.479, p = 0.033; r = 0.494, p = 0.0294; respectively). Inter-observer reliability (intra-class correlation coefficient [ICC] and kappa) was good to excellent for all measurements and grading.

Glenoid anteversion and anterior and posterior bone loss are associated with varying HSI. Subscapularis muscle FI, not tendon integrity, correlates to anterior and central glenoid erosion. The study adds evidence that neither rotator cuff tendinopathy nor muscle atrophy exhibits a significant relationship to HSI.

Osteoarthritis of the knee affects millions of people. Elastic knee sleeves aim at relieving symptoms. While symptomatic improvements have been demonstrated as a consequence of elastic knee sleeves, evidence for biomechanical alterations only exists for the sagittal plane. We therefore asked what effect an elastic knee sleeve would have on frontal plane gait biomechanics. 18 subjects (8 women, 10 men) with osteoarthritis of the medial tibiofemoral joint walked over ground with and without an elastic knee sleeve. Kinematics and forces were recorded and joint moments were calculated using an inverse dynamics approach. Conditions with sleeve and without sleeve were compared with paired t-Tests. With the sleeve, knee adduction angle at ground contact was reduced by 1.9 ± 2.1° (P = 0.006). Peak knee adduction was reduced by 1.5 ± 1.6° (P = 0.004). The first peak knee adduction moment and positive knee adduction impulse were decreased by 10.1% (0.74 ± 0.9 Nm • kg-1; P = 0.002) and 12.9% (0.28 ± 0.3 Nm • s • kg-1; P < 0.004), respectively.

Our study provides evidence that wearing an elastic knee sleeve during walking can reduce knee adduction angles, moments and impulse in subjects with knee osteoarthritis. As a higher knee adduction moment has previously been identified as a risk factor for disease progression in patients with medial knee osteoarthritis, we speculate that wearing a knee sleeve may be beneficial for this specific subgroup.

To investigate the incidence rate of anterior knee pain after total knee arthroplasty (TKA) and identify the related factors. This prospective, double-blind clinical trial involved a total of 128 patients scheduled for primary ipsilateral cemented three-component TKA for osteoarthrosis. The patients were randomized into two groups to receive operations for TKA with patellar resurfacing (experimental group) or not (control). The incidence of anterior knee pain was observed in these patients and the factor affecting the occurrence of anterior knee pain and knee was analyzed. The patients were followed up for a mean of 16.5 months (range 6~24 months). The incidence rate of anterior knee pain was 10.9% (7/64) in the experimental group, showing no significant difference from the rate of 14.1% (9/64) in the control group. But the 52 patients with varus or valgus knee showed a significantly higher incidence rate of anterior knee pain (21.2%, 11/52).

TKA with patellar resurfacing can not decrease the incidence of anterior knee pain, and varus or valgus before the operation is associated with a higher risk of anterior knee pain.

Approximately 10% of patients with rheumatoid arthritis (RA) have interstitial lung disease (ILD), and one-third have subclinical ILD on chest CT scan. In this study, we aimed to further characterize functional decrements in a spectrum of RA-associated ILD. All subjects were enrolled in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS). The presence of interstitial lung abnormalities (ILAs) on clinically indicated chest CT scans was determined using a previously validated sequential reading method. Univariate and multivariate analyses were used to assess the association between degree of ILAs and physiologic, functional, and demographic variables of interest. Of 1,145 BRASS subjects, 91 subjects (8%) were included in this study. Twelve had radiologically severe ILAs, 34 had ILAs, and 38 had no ILAs on CT scan. Subjects with radiologically severe ILAs were older (P = .0037), had increased respiratory symptoms (cough, P = .027; dyspnea, P = .010), and more severe RA disease (rheumatoid factor, P = .018; total swollen joints, P = .046) compared with subjects with no ILAs. Participants also had a trend toward having an increased smoking history (P = .16) and having lower FVC % predicted (77% vs 94%, P = .097) and diffusion capacity of carbon monoxide % predicted (52% vs 77%, P = .068). Similar but attenuated increases in respiratory symptoms, functional decrements, and RA disease severity were observed in subjects with ILAs compared with those with no ILAs.

We have shown that patients with RA have varying degrees of ILAs that are associated with a spectrum of functional and physiologic decrements. Our findings suggest that improved risk stratification and detection of ILAs will provide a therapeutic window that could improve RA-ILD outcomes.

To compare the histological characteristics of the synovium between seropositive and seronegative rheumatoid arthritis (RA), synovial tissue was obtained from 19 patients with rheumatoid factor-positive (RF+) RA, 11 with rheumatoid factor-negative (RF-)RA and 11 non-RA controls. There were no differences in the frequency of each histological feature or histological scores between RF+ and RF-RA. However, significant differences in the frequency of histological findings such as lining cell proliferation and inflammatory cell infiltration were found both between RF+ RA and non-RA controls, and between RF-RA and non-RA controls. Analysis of clinical parameters and histology in all RA patients revealed that the level of serum C-reactive protein and the erythrocyte sedimentation rate were directly correlated with the inflammatory cellular infiltration score. Immunohistological staining using a monoclonal antibody against IgM rheumatoid factor (RF) was positive in some plasma cells in the synovium of both RF+ and RF-RA patients, while no IgM-RF-positive cells were observed in the synovium of non-RA controls.

RF serostatus does not necessarily reflect the histology of synovial inflammation.

To establish feasible and practical recommendations for the management of the psychological needs of patients with rheumatoid arthritis (RA) from the moment of diagnosis through the course of the disease. A nominal group meeting was held with an RA expert team including rheumatologists and psychologists, at which a guided discussion addressed the most important psychological and emotional needs in RA. Based on the comments collected, and a literature review, a matrix document of recommendations for telematics discussion was prepared, as well as a Delphi survey to test agreement with these recommendations. Agreement was defined if at least 80% of participants voted ≥ 7 (from 1, totally disagree to 10, totally agree). For each recommendation, the level of evidence and grading of recommendations was established following the Oxford criteria, and the degree of agreement through the Delphi. Thirteen recommendations were established, addressing several key processes: (1) identification of psychological problems and needs in patients with RA, and a guideline for their management in daily practice; (2) communication with patients; (3) referral criteria to mental health professionals.

These recommendations are intended to help health care professionals openly address the psychological aspects of patients in daily practice to follow and treat them properly.

To study the gene expressions of suppressors of cytokine signaling (SOCS1, 2, 3) and cytokine-inducible SH2-domain 1(CIS-1) in chondrocytes of osteoarthritis (OA) patients and healthy controls, and also analyze the effects of IL-1β and TNF-α on the levels of mRNA encoding these SOCS family members. Chondrocytes were isolated from patients of OA and joint replacement due to traffic accident by sequential treatment with trypsin, hyaluronidase and collagenase B. Total RNA was extracted from the same chondrocytes, and the levels of SOCS1, 2, 3 and CIS-1 mRNA were determined by real-time qRT-PCR. In addition, healthy chondrocytes were cultured with and without a mixture of IL-1β and oncostatin M (OSM, both 2.5 ng/mL) or TNF-α (10 ng/mL). The short-term cultures with single cytokine treatment were harvested 24 and 72 h after treatment, and the long-term cultures were maintained for 4-5 weeks until confluent with periodical cytokine stimulation. Total RNA was extracted and mRNA levels of SOCS1, 2, 3 and CIS-1 mRNA were detected by qRT-PCR. The SOCS2 and CIS-1 mRNA levels were reduced by approximately 8-fold in OA samples compared to controls (P<0.01), whereas SOCS1 and SOCS3 showed similar expression patterns in OA and control chondrocytes (P>0.05). The SOCS2 and CIS-1 mRNA levels declined by 5-fold and 3-fold with long-term treatment with IL-1β and OSM or IL-1β and TNF-α, respectively (P<0.05).

In OA patients, the expressions of SOCS2 and CIS-1 decreased, while SOCS1 and SOCS3 were unaffected. Long-term treatment with inflammatory cytokines mimicking OA effect attenuated the expressions of SOCS2 and CIS-1 in chondrocytes.

Women with systemic lupus erythematosus (SLE) have an increased incidence of premature cardiovascular disease (CVD). A relationship between depression and increased inflammation leading to CVD has been proposed. The aim of this study was to evaluate the relationship between depression and the progression of subclinical atherosclerosis in women with SLE. In this prospective case-control study, 149 participants with SLE and 126 controls were followed over 5 years. Evaluation included laboratory studies, assessment of CVD risk factors, depression screening, ultrasound evaluations of carotid intima-media thickness (CIMT) and carotid plaque, and assessment of SLE disease activity for the SLE cases. The SLE group had a higher rate of depression: 29% compared with 11% in the control group (P = 0.003). When controlling for traditional CVD risk factors, the presence of baseline depression correlated with increased progression of CIMT in the SLE group, but not in the control group. The mean increase in CIMT was 0.026 mm in the SLE group without depression versus 0.064 mm in the depressed SLE group (P = 0.0096). There was no association between depression and carotid plaque in either group, with a calculated odds ratio for plaque progression in the depressed SLE group of 1.118 (95% confidence interval 0.476, 2.623) in the adjusted model.

Women with SLE and concomitant depression have an increased risk of developing subclinical atherosclerosis, as measured by CIMT, but not by carotid plaque. The data suggest that depression, a potentially modifiable risk factor, may contribute to the increased risk of subclinical atherosclerosis in women with SLE.

Immune checkpoint inhibitors (ICIs) are improving prognoses in advanced stage cancers, but they also lead to immune-related adverse events (IRAEs). IRAEs targeting many organ systems have been reported, but musculoskeletal and rheumatic IRAEs have not been well-characterized. We systematically reviewed published literature on musculoskeletal and rheumatic IRAEs to better understand prevalence and clinical characteristics. Medline and CENTRAL databases were searched for articles reporting rheumatic and musculoskeletal IRAEs secondary to ICI treatment. After screening abstracts and full texts in duplicate, clinical features, prevalence, and treatment data were extracted and summarized. A total of 1,725 unique abstracts were screened; 231 contained original data and were about ICIs and went to full-text screening. Fifty-two of these contained information about musculoskeletal or rheumatic IRAEs or about treatment with ICIs in preexisting autoimmune disease. Of these, 33 were clinical trials, 3 were observational studies, and 16 were case reports or series. Arthralgia prevalence in clinical trials ranged 1-43%, and myalgia was reported in 2-20%. Arthritis was reported in 5 of 33 clinical trials, and vasculitis was reported in only 2. One observational study and 3 case reports described patients with preexisting autoimmune disease treated with ICIs. Case reports included development of inflammatory arthritis, vasculitis, myositis, and lupus nephritis.

Arthralgia and myalgia have been reported commonly in patients treated with ICIs. The prevalence of rheumatic IRAEs such as inflammatory arthritis, vasculitis, and sicca syndrome is less clear from current evidence. There is limited observational and case-level evidence describing ICI use in patients with preexisting autoimmune disease.

CD40 is a costimulatory molecule for B cells, and CD154 is a marker of CD4+ T cells activation. CD40-CD154 interaction promotes pro-inflammatory cytokines secretion and autoantibodies production. PTPN22 gene encodes LYP protein, an inhibitor of T- and B-cell activation. PTPN22 1858C>T polymorphism confers rheumatoid arthritis (RA) susceptibility. Hence, we evaluate the relationship between 1858C>T polymorphism with CD40 and CD154 expression and IFN-γ secretion in RA patients. PTPN22 1858C>T polymorphism was genotyped in 315 RA patients and 315 control subjects (CS) using PCR-RFLP method. Later, we selected only ten anti-CCP-positive RA patients, naïve to disease-modifying antirheumatic drugs and ten CS, all with known 1858C>T PTPN22 genotype. The CD40 and CD154 membrane expressions were determined by flow cytometry in peripheral B and T cells, correspondingly. The B cells percentage and mCD40 expression were similar between RA and CS (P > 0.05) and we did not find an association between these variables and the 1858C>T polymorphism. The CD4+ T cells percentage was higher in RA patients than CS (P = 0.003), and in the RA group, the CD4+ T cells percentage and mCD154 expression were higher in the 1858 T allele carriers (P = 0.008 and P = 0.032, respectively). The IFN-γ levels were lower in RA patients carrying the PTPN22 risk allele (P = 0.032).

The PTPN22 1858 T risk allele is associated with increased CD4+ T cells percentage and high mCD154 expression in RA patients, which could favor the pro-inflammatory cytokine release and the establishment of the inflammatory response at the seropositive RA.

To determine whether hydrotherapy in a thermomineral institution is superior to the same hydrotherapy in an ordinary hospital exercise-bath. Controlled therapeutic trial. The thermomineral institution at Arcen and the exercise bath at the Maasland Hospital in Sittard, the Netherlands. 46 patients with rheumatoid arthritis were treated in a by a skilled physiotherapist, according to a standardized exercise-scheme: 27 were treated in the thermomineral institution and 19 (control-group) in the hospital exercise-bath. Each patient received 12 treatments in 12 weeks. ENDPOINTS PARAMETERS: Morning stiffness, erythrocyte sedimentation rate, Ritchie index, amount of pain, answers to 11 questions concerning the activities of daily life, and psychosocial aspects of the disease. The various subjective and objective parameters were scored by the same physician. Statistically significant improvement was observed in both groups concerning morning stiffness. Other subjective parameters improved, but did not reach significance. Objective parameters did not change significantly. Between-group differences were not found.

Hydrotherapy has a positive effect on some subjective but not on objective parameters in patients with rheumatoid arthritis, whether it is applied in a thermomineral institution or an ordinary hospital exercise bath.

The purpose of this retrospective cohort study was to investigate the influence of parameters of malalignment on knee function 5 years post TKA and, additionally, to explore alterations in patellar height after TKA. All 661 patients undergoing TKA between 2010 and 2011 were considered for inclusion. Preoperative and 1-year postoperative short-leg radiographs were assessed for malalignment parameters: coronal tibial angle (cTA), sagittal tibial angle (sTA), femoral flexion angle (FFA) and mediolateral tibial mismatch. Patellar height was measured using the modified Insall-Salvati ratio. We determined improvements in knee function utilizing the Knee Society Score (Function score, KSS-F), Oxford Knee Score (OKS) and Algofunctional index (AI). Influences of malalignment parameters were analyzed univariate and selected (p < 0.10) for multivariate linear regression analysis. Inter-observer reproducibility was assessed by test-retest analysis of 30 randomly selected radiographs and calculation of an intra-class correlation coefficient (ICC) for all radiographic parameters. Three-hundred and four patients were included. Multivariate regression showed degrees of cTA malalignment to be significantly associated with only the KSS-F (β = -3.52). Correction of coronal deformity was stronger associated with knee function (KSS-F β = 2.81; AI β = -0.36). Patellar height was significantly reduced after TKA (1.51 vs 1.44). Decrease of patellar height was weakly associated with the OKS (β = 10.69). ICC scores were: cTA 0.81, sTA 0.57, IS 0.72, FFA 0.75.

Postoperative coronal tibial plate alignment and correction of preoperative coronal deformity are associated with improved knee function 5 years post TKA. Decrease in patellar height was weakly associated with knee function. Short-leg radiography can be a sufficient screening tool for prosthesis alignment.

The association between rheumatoid arthritis (RA) and periodontitis is suggested to be linked to the periodontal pathogen Porphyromonas gingivalis. Colonization of P. gingivalis in the oral cavity of RA patients has been scarcely considered. To further explore whether the association between periodontitis and RA is dependent on P. gingivalis, we compared host immune responses in RA patients with and without periodontitis in relation to presence of cultivable P. gingivalis in subgingival plaque. In 95 RA patients, the periodontal condition was examined using the Dutch Periodontal Screening Index for treatment needs. Subgingival plaque samples were tested for presence of P. gingivalis by anaerobic culture technique. IgA, IgG and IgM antibody titers to P. gingivalis were measured by ELISA. Serum and subgingival plaque measures were compared to a matched control group of non-RA subjects. A higher prevalence of severe periodontitis was observed in RA patients in comparison to matched non-RA controls (27% versus 12%, p < 0.001). RA patients with severe periodontitis had higher DAS28 scores than RA patients with no or moderate periodontitis (p < 0.001), while no differences were seen in IgM-RF or ACPA reactivity. Furthermore, RA patients with severe periodontitis had higher IgG- and IgM-anti P. gingivalis titers than non-RA controls with severe periodontitis (p < 0.01 resp. p < 0.05), although subgingival occurrence of P. gingivalis was not different.

Severity of periodontitis is related to severity of RA. RA patients with severe periodontitis have a more robust antibody response against P. gingivalis than non-RA controls, but not all RA patients have cultivable P. gingivalis.

To identify rheumatoid arthritis (RA) specific autoantibody and its antigen in the human osteoblast-like cell line, MG-63. MG-63 cell extract was subjected to western blotting by using RA and normal serum samples as probes. The autoantigen was purified and its N-terminal sequence was determined by automated Edman degradation. The reactivity of denatured aldolase A was evaluated by immunoblotting. Screening by enzyme linked immunosorbent assay (ELISA) using the autoantibody was performed. 40 kDa protein was found only in the RA serum samples and it was identified as aldolase A. A polyclonal antibody for rabbit muscle aldolase A bound to the 40 kDa protein and reacted in preference with the denatured enzyme. Using ELISA for denatured rabbit aldolase A, the autoantibody was found in approximately 10% of RA patients, whereas it was not found in the other arthropathy and healthy adults.

This 40 kDa anti-aldolase A autoantibody, which was identified only in serum samples of RA patients with severe bone erosion, could be related to a certain event that induces RA specific joint destructions.

Transcutaneous electrical nerve stimulation (TENS) is commonly used for the management of pain; however, its effects on several pain and function measures are unclear. The purpose of this study was to determine the effects of high-frequency TENS (HF-TENS) and low-frequency TENS (LF-TENS) on several outcome measures (pain at rest, movement-evoked pain, and pain sensitivity) in people with knee osteoarthritis. The study was a double-blind, randomized clinical trial. The setting was a tertiary care center. Seventy-five participants with knee osteoarthritis (29 men and 46 women; 31-94 years of age) were assessed. Participants were randomly assigned to receive HF-TENS (100 Hz) (n=25), LF-TENS (4 Hz) (n=25), or placebo TENS (n=25) (pulse duration=100 microseconds; intensity=10% below motor threshold). The following measures were assessed before and after a single TENS treatment: cutaneous mechanical pain threshold, pressure pain threshold (PPT), heat pain threshold, heat temporal summation, Timed "Up & Go" Test (TUG), and pain intensity at rest and during the TUG. A linear mixed-model analysis of variance was used to compare differences before and after TENS and among groups (HF-TENS, LF-TENS, and placebo TENS). Compared with placebo TENS, HF-TENS and LF-TENS increased PPT at the knee; HF-TENS also increased PPT over the tibialis anterior muscle. There was no effect on the cutaneous mechanical pain threshold, heat pain threshold, or heat temporal summation. Pain at rest and during the TUG was significantly reduced by HF-TENS, LF-TENS, and placebo TENS. This study tested only a single TENS treatment.

Both HF-TENS and LF-TENS increased PPT in people with knee osteoarthritis; placebo TENS had no significant effect on PPT. Cutaneous pain measures were unaffected by TENS. Subjective pain ratings at rest and during movement were similarly reduced by active TENS and placebo TENS, suggesting a strong placebo component of the effect of TENS.

Progressive pseudorheumatoid dysplasia is a rare, autosomal recessively inherited, noninflammatory musculoskeletal disorder caused by mutations occurring in the WNT1-inducible signaling pathway protein 3 gene. Joint cartilage is the primary site of involvement, leading to arthralgia, joint stiffness, contractures, enlargement of the epiphyses and metaphysis of the hand joints, spinal abnormalities, short stature, early osteoarthritis, and osteoporosis. Juvenile idiopathic arthritis is the most common chronic rheumatic disease in childhood and has unknown etiology. Clinical features of progressive pseudorheumatoid dysplasia resemble those of juvenile idiopathic arthritis. Patients with progressive pseudorheumatoid dysplasia are usually misdiagnosed as having juvenile idiopathic arthritis. A 13-year-old Yemeni female presented to the rheumatology clinic with a history of joint pains, bone pains, and bone deformity for 7 years. Weight and height were below the third percentiles. There was no tender swelling of metacarpophalangeal and interphalangeal joints, and she presented with scoliosis. Radiographs of the hands revealed the widening of the epiphyses. Progressive pseudorheumatoid dysplasia was suspected, and genetic testing for WNT1-inducible signaling pathway protein 1, 2, and 3 was requested with these findings. A homozygous, likely pathogenic variant was identified in the WNT1-inducible signaling pathway protein 3 gene, which confirmed our diagnosis.

Progressive pseudorheumatoid dysplasia is a rare form of spondyloepimetaphyseal dysplasia and is clinically misdiagnosed as juvenile idiopathic arthritis. It is crucial to consider progressive pseudorheumatoid dysplasia, especially in patients with standard inflammatory markers who are being followed up for juvenile idiopathic arthritis and not improving with antirheumatic intervention.

To define the cytokine profile within rheumatoid subcutaneous nodules, and to determine whether the destructive inflammatory process in this lesion displays features of a lymphocyte-driven Th1 or Th2 granuloma. Subcutaneous nodules excised from 10 patients with rheumatoid arthritis were examined. Transcripts for interleukin 1beta (IL-1beta) IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-15, IL-18, and for tumor necrosis factor alpha (TNFalpha) and interferon-gamma (IFNgamma) were detected by reverse transcription-polymerase chain reaction of extracted RNA. Nine of 10 nodules contained transcripts for IFNgamma. We observed no evidence for the expression of IL-2, IL-4, or IL-5 among the lymphokine genes analyzed. Transcripts for TNFalpha, IL-1beta, IL-10, IL-15, and IL-18 were present in all 10 nodules. Transcripts for IL-12 were present in all but one nodule. Expression of IL-13 messenger RNA was observed in only 5 nodules.

The cytokine profile within the rheumatoid nodule (i.e., presence of IFNgamma but not IL-2, and prominent expression of IL-1beta and TNFalpha together with IL-12, IL-18, IL-15, and IL-10) is similar to the profile of cytokines in the synovial lesion of rheumatoid arthritis, which is generally accepted as being attributable to a Th1-mediated inflammatory mechanism. Our results suggest that damage to affected synovial membrane or subcutaneous tissue is caused by the same inflammatory mechanisms, and that the nodule is a Th1 granuloma.

To determine the psychometric properties of the Academic Medical Center (AMC) Linear Disability Scale (ALDS) item bank in a population of patients with rheumatoid arthritis (RA). 129 patients with RA completed the ALDS and Health Assessment Questionnaire Disability Index (HAQ-DI) at baseline, and after 8 and 16 weeks of anti-tumor necrosis factor-alpha treatment. Disease activity assessments at these timepoints included serum levels of C-reactive protein, Disease Activity Score 28, morning stiffness, and visual analog scales for global disease activity and fatigue. Reliability of the ALDS was excellent (homogeneity, Cronbach's alpha = 0.95; test-retest, intraclass correlation coefficient = 0.93). The ALDS results at baseline were strongly correlated with the HAQ-DI (r = -0.75). With regard to known group validity, both instruments discriminated between higher and lower disease activity (ALDS, p < 0.0001; HAQ-DI, p = 0.002) and between non-, moderate, and good responders (ALDS, p = 0.002; HAQ-DI, p < 0.0001), indicating that both instruments differentiate between groups. The ALDS was moderately to highly responsive to changes between baseline and after 8 weeks and 16 weeks of treatment (standardized response mean, range = 0.71-1.19). No substantial floor or ceiling effects were found.

Our results show that the ALDS is a promising new instrument, with at least equivalent psychometric properties compared to the HAQ-DI. Advantages of the ALDS item bank are its linear structure and an item bank that can be adapted depending on the ability level of the patient.

For establishing femoral component position, gap-balancing (GB) and measured resection (MR) techniques were compared using a force sensor. Ninety-one patients were randomized to undergo primary total knee arthroplasty using either MR (n = 43) or GB (n = 48) technique using a single total knee arthroplasty design. GB was performed with an instrumented tensioner. Force sensor data were obtained before the final implantation. GB resulted in greater range of femoral component rotation vs MR (1.5° ± 2.9° vs 3.1° ± 0.5°, P < .05) and posterior condylar cut thickness medially (10.2 ± 2.0 mm vs 9.0 ± 1.3 mm) and laterally (8.5 ± 1.9 mm vs 6.4 ± 1.0 mm). Force sensor data showed a decreased intercompartmental force difference at full flexion in GB (.8 ± 2.3 vs 2.0 ± 3.3u, 1u ≈ 15 N, P < .05).

GB resulted in a greater range of femoral component rotation and thicker posterior condylar cuts resulting in an increased flexion space relative to MR. Intercompartmental force difference trended toward a more uniform distribution between full extension and full flexion in the GB vs MR group.

Salivary gland dysfunction is one of the main clinical features of Sjögren's syndrome (SS), manifested by xerostomia with subsequent complications and well-established effects on the person's quality of life. To determine firstly whether selected tests of salivary gland function and structure, unstimulated whole salivary flow rate (UWSFR), parotid flow rate (PFR), clinical oral dryness score (CODS) and ultrasound score (USS), can discriminate SS from non-SS sicca patients and secondly whether these tests can differentiate between patients in different subgroups of SS. Unstimulated whole salivary flow rate, PFR, CODS and USS were determined in 244 patients comprised of SS patients (n = 118), SS patients at higher risk of lymphoma (n = 30) or with lymphoma (n = 26), and non-SS sicca disease controls (n = 70). All assessments showed a significant difference between the overall SS group and the disease control group, attributed mainly to the lymphoma subgroups of SS (p < 0.0001 for all parameters). There was a significant correlation (Spearman r = 0.7, p value <0.0001) and 87.3% agreement between USS and the histology focus scores of 119 patients.

The results suggest that salivary gland tests including USS can aid in differentiating between SS and non-SS dry mouth, especially the subgroups of SS with lymphoma or at higher risk of developing lymphoma.

Multiomics study was conducted to elucidate the crucial molecular mechanisms of primary Sjögren's syndrome (SS) pathology. We generated multiple data set from well-defined patients with SS, which includes whole-blood transcriptomes, serum proteomes and peripheral immunophenotyping. Based on our newly generated data, we performed an extensive bioinformatic investigation. Our integrative analysis identified SS gene signatures (SGS) dysregulated in widespread omics layers, including epigenomes, mRNAs and proteins. SGS predominantly involved the interferon signature and ADAMs substrates. Besides, SGS was significantly overlapped with SS-causing genes indicated by a genome-wide association study and expression trait loci analyses. Combining the molecular signatures with immunophenotypic profiles revealed that cytotoxic CD8 -T cells- were associated with SGS. Further, we observed the activation of SGS in cytotoxic CD8 T cells isolated from patients with SS.

Our multiomics investigation identified gene signatures deeply associated with SS pathology and showed the involvement of cytotoxic CD8 T cells. These integrative relations across multiple layers will facilitate our understanding of SS at the system level.

Bone destruction in rheumatoid arthritis is mediated by osteoclasts (OC), which are derived from precursor cells of the myeloid lineage. The role of the two monocyte subsets, classical monocytes (expressing CD115, Ly6C and CCR2) and non-classical monocytes (which are CD115 positive, but low in Ly6C and CCR2), in serving as precursors for OC in arthritis is still elusive. We investigated CCR2 We show that in hTNFtg arthritis local bone erosion and OC generation are even enhanced in the absence of CCR2. We further show the numbers of non-classical monocytes in blood are elevated and are significantly correlated with histological signs of joint destruction. Sorted non-classical monocytes display an increased capacity to differentiate into OCs. This is associated with an increased expression of signal transduction components of RANK, most importantly TRAF6, leading to an increased responsiveness to RANKL.

Therefore, non-classical monocytes are pivotal cells in arthritis tissue damage and a possible target for therapeutically intervention for the prevention of inflammatory joint damage.

The aims of this study were to evaluate the prognosis of patients with systemic rheumatic disease diagnosed in medical intensive care unit (MICU) and to determine whether the outcome is different for patients with systemic rheumatic disease previously known hospitalized in MICU. Retrospective evaluation, over a ten-year period, of 88 cases of systemic rheumatic disease selected in two groups: group I: diagnosed in MICU, group II: previously known and treated. Group I: 18 patients with necrotizing vasculitis (n = 6), extra-intestinal manifestations of inflammatory bowel disease (n = 4), systemic lupus erythematosus (n = 3), miscellaneous (n = 5). Group II: 70 patients with rheumatoid arthritis (n = 31), necrotizing vasculitis (n = 12), systemic lupus erythematosus (n = 12), polymyositis (n = 4), extra-intestinal manifestations of inflammatory bowel disease (n = 5), miscellaneous (n = 6). The main admission diagnoses were infectious diseases (p < 0.005) or iatrogenic complications in the group II (p < 0.01) and acute exacerbation of systemic rheumatic disease in the group I (p < 0.0001). Age; simplified acute physiologic score (SAPS); number of acute organ system failure; number of patients requiring mechanical ventilation, haemodialysis or right heart catheterization were not different between the two groups. The durations of mechanical ventilation and stay in the MICU were shorter in the group II (p < 0.005). MICU mortality rate was higher in the group II (p < 0.05), with a five years cumulative proportion of surviving statistically lower (p < 0.05). Mortality rate of the entire population (37.5%) was similar to that of a non-selected population with comparable SAPS. Multivariate analysis showed that SAPS, number of acute organ system failure and iatrogenic complications were the main prognostic factors (p = 0.05).

The prognosis was better for patients with systemic rheumatic disease diagnosed in MICU. Infectious diseases were the main cause of death, probably in relation with immunosuppressive treatments.

A growing body of evidence suggests the involvement of the brain in FM. The purpose of this proton MRS study was to test the hypothesis that there are metabolic alterations in some brain regions processing pain (VLPFC and thalamus) in patients with FM compared with HC. Twelve patients with FM (30-54 years of age; mean age, 43.2 years), and 12 HC, matched for age and sex, underwent 1 session of single-voxel MRS performed on a 3T MR imaging scanner. MRS spectra were acquired with a PRESS for localization. The raw data from each spectrum was evaluated with an LCModel. T tests were used to evaluate differences of brain metabolites between groups. The Pearson correlation tested the relationship of metabolite ratios and clinical symptoms. Glx/Cr and Glu/Cr ratios within the VLPFC of both sides were significantly higher in patients than in HC (P < .01). No significant differences of metabolites between groups were found in the thalami. Positive correlations were found between Glu/Cr in the left thalamus and the VAS for pain (r = 0.730, P = .007) and between mIns/Cr in the right VLPFC and the VAS for pain (r = 0.607, P = .037) and the FIQ (r = 0.719, P = .008).

The presence of elevated Glu/Cr levels in VLPFC strengthens the opinion that a complex neurophysiologic imbalance of different brain areas involved in pain processing underlies FM. These data may be useful in the diagnosis and development of more effective pharmacologic treatments.

To observe the effect of Chinese herbal medicine for nourishing yin, supplementing qi, and activating blood on the expression of interferon-γ (IFN-γ)/interleukin-4 (IL-4) in peripheral blood and disease activity in primary Sjogren's syndrome (pSS) patients, and to study the relationship between the immune balance of Th1/Th2 and the disease activity. A total of 66 pSS patients were randomized with tossing coins method into two groups: the integrative therapy group (34 cases) and the control group (32 cases); and 28 healthy subjects were taken as the normal group. The integrative therapy group was treated by Chinese herbal medicines for nourishing yin, supplementing qi, and activating blood combined with hydroxychloroquine sulfate tablets and the control group was treated with hydroxychloroquine sulfate tablets. The treatment course was 3 months for both groups. The levels of serum immunoglobulin G (IgG), erythrocyte sedimentation rate (ESR), IFN-γ and IL-4 in peripheral blood were measured before and after treatment. Compared with the normal group, the levels of IgG, ESR, IFN-γ and IL-4 were significantly increased in pSS patients (P<0.05). Remarkably, after 3 months of treatment, these levels were dramatically decreased in both the integrative therapy group and the control group, although still higher than the normal group. The levels of IgG, ESR, IFN-γ and IL-4 in the integrative therapy group were lower than the control group and the same group before treatment (P<0.05). The ratio of IFN-γ/IL-4 also significantly decreased after treatment. Moreover, the level of IFN-γ and the ratio of IFN-γ/IL-4 in the integrative therapy group were significantly lower than the control group (P<0.05). For all patients the ratio of IFN-γ/IL-4 before and after treatment was positive correlated with the levels of IgG and ESR.

Chinese herbal medicine for nourishing yin, supplementing qi, and activating blood can alleviate the disease activity of pSS by regulating the immune balance of Th1/Th2.

To identify the determinants of self-report mobility measures in people with knee osteoarthritis (OA) and to compare self-report measures with physical performance. Cross-sectional, prospective. Motor performance laboratory and human mobility research center. A convenient sample of 54 participants with medial compartment knee OA (32 women, 22 men; age 68.3+/-8.7y; range, 50-87y). Three participants were excluded because of the presence of lateral knee OA on radiographs. Not applicable. Self-reports were recorded by using the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Performance measures included the six-minute walk test (6MWT), Timed Up & Go (TUG) test, and a standardized stair-climbing task (STR). Stepwise linear regression analysis identified models that included pain, quadriceps and hamstrings strength, and depression to explain 62% to 73% of the variance in scores on the physical functioning subscale of the WOMAC and the SF-36. These self-report measures had a moderate relation (r range, .46-.64) with performance measures (6MWT, TUG, STR).

Self-report measures were strongly related to pain; physical performance measures were strongly related to self-efficacy. Regression models showed that self-report scores reflect pain, knee strength, and depression. The relation between self-report and performance measures was moderate, suggesting that these examine different aspects of mobility.

To analyze aspect ratio (AP size/ (ML) size) of osteoarthritic knees at four different areas of the femur and to observe if proximalization of the femoral cut would change the ML size as well as confirm that external rotation increases the measurements for the AP dimensions of the femur. From the available MyKnee database (Medacta International, Castel San Pietro, Switzerland) 1030 patients were randomly selected within 20° of deformity consisting of 400 men with a mean (SD) age of 67.5 (9) years and 630 women with a mean (SD) age of 69 (10) years (p<0.0001). A specific software program was developed to measure AP and ML dimensions of the femur on CT-scans for (3D) planning in four areas. The AP femoral size was measured with neutral axial rotation following the epicondylar axis and without accepting anterolateral notching. Proximalization of the femur resulted in no changes except for a larger ML3 area in men. Increased axial rotation increased the AP dimensions for the same femur by a mean (SD) 2.5 (1) mm for males and females.

The crucial area for overhang of the femoral component is the anterior region (ML1) with an aspect ratio of about ±, but with an important range. Proximalization of the femoral cut is not accompanied by narrowing of the anterior femur but ML widening of the more posterior femur in men. Increased external rotation leads to a measurement of bigger AP size leading to an AP versus ML mismatch and change in aspect ratio.

To investigate prospectively long term patient relevant outcomes after unilateral total hip replacement (THR) for osteoarthritis (OA). To identify non-responders to this intervention and patient related predictors of unsatisfactory outcome. A case-control study comparing health related quality of life of 219 patients (mean age 71) after THR with that of a matched reference group of 117 subjects without hip complaints recruited from the community. Patients and reference group answered SF-36 and WOMAC questionnaires preoperatively, at 3, 6, 12 months, and at 3.6 years (range 26-65 months) postoperatively. Supplementary questions were asked at the final follow up. 198/211 (94%) of the patients and 83/109 (76%) of the reference group participated at the final follow up. At follow up, the only difference between the two groups in the SF-36 was physical function, where patients scored worse. Patients also reported worse WOMAC function. 31% of the patients had improved by <10/100 WOMAC score points for pain and/or function at final follow up, compared with preoperatively. More pain preoperatively and higher age and postoperative low back pain predicted a worse outcome in WOMAC function.

3.6 years after THR for OA, health related quality of life was similar for patients and reference group except for function, where patients had worse function. Higher age and more pain preoperatively predicted a poor outcome. Patients with hip OA with musculoskeletal comorbidities, such as low back pain and OA of the non-operated hip, have less long term functional improvement after THR.

The aim of the present study was a comparative investigation of the functional improvement reported by patients suffering from primary osteoarthritis of the knee or hip undergoing total joint replacement and assessed at 3 months. In a prospective, controlled clinical trial, 56 patients with primary osteoarthritis of the hip and 59 patients with primary osteoarthritis of the knee undergoing total joint replacement were assessed at two measuring times (day of admission = t1 and 3-month follow-up = t2) using the XSMFA-D (Extra Short Musculoskeletal Function Assessment Questionnaire--German version), WOMAC (Western Ontario and McMasters Universities) arthrosis index and FFb-H OA (Function Assessment Questionnaire Hannover Osteoarthritis). The statistical analysis included effect sizes as standardised response mean, t-test and covariance analysis. Both groups of patients demonstrated significant improvements of the musculoskeletal functions measured. The effect sizes between baseline scores and 3-month follow-up scores range from 0.4 to 2.0 and can be considered as large effects. The covariance analysis showed significant differences between patients with osteoarthritis of the hip and knee for almost every score examined. Patients with hip replacement showed large improvements. A significant influence of the presurgery baseline score on the 3-month score was found consistently. Further analysis showed that patients with medium or strong degrees of disability according to the Function index of the XSMFA-D showed the strongest effects of change at 3 months. However, their scores at t2 were less than the scores of the less disabled patients at t1.

We conclude that patients with hip replacement show more improvement 3 months after the surgery than patients with knee replacement. Furthermore, it was seen that patients who were more disabled before surgery achieved more improvement than the less-disabled patients. However, they did not achieve the level of the less disabled patients. Thus, the recommendation that total joint replacement should be performed as late as possible should be reviewed.

We have previously developed a handheld ultrasound indentation instrument for the diagnosis of cartilage degeneration. The instrument has been demonstrated to be capable of quantifying mechanical and acoustic properties of enzymatically degraded and normal bovine articular cartilage in vitro and in situ. The aim of this study was to investigate the sensitivity of the instrument to distinguish between normal and spontaneously degenerated (e.g., in osteoarthrosis) articular cartilage in vitro. Thirty articular cartilage samples were prepared from the bovine lateral patellae: 19 patellae with different degenerative stages and 11 patellae with visually normal appearance. Cartilage thickness, stiffness (dynamic modulus) and ultrasound reflection from the cartilage surface were measured with the handheld instrument. Subsequently, biomechanical, histological and biochemical reference measurements were conducted. Reproducibility of the measurements with the ultrasound indentation instrument was good. Standardized coefficient of variation was < or =6.1% for thickness, dynamic modulus and reflection coefficient. Linear correlation between the dynamic modulus, measured with the ultrasound indentation instrument, and the reference dynamic modulus was high (r=0.993, n=30, P<0.05). Ultrasound reflection coefficient, as determined from the cartilage surface, showed high linear correlations (typically r(2)>0.64, n=30, P<0.05) with the cartilage composition and histological or mechanical properties. The instrument was superior compared to visual evaluation in detecting tissue degeneration.

This study indicates that the ultrasound indentation technique and instrument may significantly improve the early diagnosis of cartilage degeneration. The results revealed that visual evaluation is insensitive for estimating the structural and mechanical properties of articular cartilage at the initial stages of degeneration.

Early diffuse cutaneous systemic sclerosis (dcSSc) has the highest case fatality among rheumatic diseases. We report baseline characteristics, current immunosuppressive therapies, progression of skin and internal organ involvement, and mortality in a multicenter prospective cohort from the United States (US) of America. We performed a longitudinal analysis of participants from 12 US centers, from April 2012 to July 2020. All participants had early dcSSc or were at-risk for dcSSc, with ≤2 years since the first non-Raynaud's phenomenon (RP) symptom. Three hundred one patients were included with a baseline median disease duration of 1.2 years since RP and a mean modified skin score of 21.1 units. At baseline, 263 (87.3%) had definite dcSSc and 38 (12.7%) were classified as at-risk; 112 (49.6%) patients were positive for anti-RNA polymerase III antibodies. The median follow-up duration was 24.5 months (IQR = 10.3-40.7 months). One hundred ninety (63.1%) participants were treated with an immunosuppressive therapy, of which mycophenolate mofetil was most used at baseline and follow-up. Of 38 who were classified as at-risk at baseline, 27 (71%) went on to develop dcSSc; these patients were characterized by higher baseline mean HAQ-DI (0.8 versus 0.4, p = 0.05) and higher baseline mRSS (8.8 versus 4.4, p < 0.01) in comparison with those who remained as limited cutaneous SSc. In the overall cohort, 48 participants (21.1%) had clinically significant worsening of skin fibrosis, mainly occurring in the first year of follow-up; 41 (23.3%) had an absolute forced vital capacity decline of ≥10%. Twenty participants (6.6%) died, of which 18 died in the first 3 years of follow-up. Cardiac involvement (33.3%), gastrointestinal dysmotility (22.2%), and progressive interstitial lung disease (ILD) (16.7%) were the main causes of death.

This US cohort highlights the management of early SSc in the current era, demonstrating progression of skin and lung involvement despite immunosuppressive therapy and high mortality due to cardiac involvement.

The medical management of JIA has advanced significantly over the past 10 years. It is not known whether these changes have impacted on outcomes. The aim of this analysis was to identify and describe trends in referral times, treatment times and 1-year outcomes over a 10-year period among children with JIA enrolled in the Childhood Arthritis Prospective Study. The Childhood Arthritis Prospective Study is a prospective inception cohort of children with new-onset inflammatory arthritis. Analysis included all children recruited in 2001-11 with at least 1 year of follow-up, divided into four groups by year of diagnosis. Median referral time, baseline disease pattern (oligoarticular, polyarticular or systemic onset) and time to first definitive treatment were compared between groups. Where possible, clinical juvenile arthritis disease activity score (cJADAS) cut-offs were applied at 1 year. One thousand and sixty-six children were included in the analysis. The median time from symptom onset and referral to first paediatric rheumatology appointment (22.7-24.7 and 3.4-4.7 weeks, respectively) did not vary significantly (∼20% seen within 10 weeks of onset and ∼50% within 4 weeks of referral). For oligoarticular and polyarticular disease, 33.8-47 and 25.4-34.9%, respectively, achieved inactive disease by 1 year, with ∼30% in high disease activity at 1 year. A positive trend towards earlier definitive treatment reached significance in oligoarticular and polyarticular pattern disease.

Children with new-onset JIA have a persistent delay in access to paediatric rheumatology care, with one-third in high disease activity at 1 year and no significant improvement over the past 10 years. Contributing factors may include service pressures and poor awareness. Further research is necessary to gain a better understanding and improve important clinical outcomes.

The purpose of this study was to develop and validate a disease-specific quality of life measurement tool for osteoarthritis (OA) of the shoulder. An instrument which could be used as the primary outcome measure in clinical trials involving patients with OA of the shoulder was developed using a specific methodological protocol: (1) identification of a specific patient population; (2) item generation; (3) item reduction; (4) pre-testing of the prototype questionnaire and (5) determining the validity, reliability and responsiveness of the final questionnaire. The final instrument contains 19 items, each with a visual analog response option for the four domains (six questions for pain and physical symptoms, five questions for sport, recreation and work, five questions for lifestyle function and three questions for emotional function). Ten of the 19 questions had not been identified previously on other shoulder measurement tools. The instrument proved to be valid by demonstrating predicted correlations with previously published shoulder measures, global health status measure and range of motion. The new instrument was also more responsive than other shoulder measurement tools, a global health status measure and range of motion.

Since the patient's own perception of changes in health status is the most important indicator of the success of treatment we suggest that this measurement tool be used as the primary outcome in clinical evaluation of various treatments for OA of the shoulder and monitoring patients over time.

To evaluate the effect of early 'aggressive' drug treatment on radiographic progression in patients with recent-onset rheumatoid arthritis (RA), compared to conventional stepwise increasing intensity of treatment. Prospective follow-up study with an experimental group and a historical control group both divided into a high-risk subgroup and a low-risk subgroup, based on prognostic factors. The effect of the 'aggressive' and the conventional treatment strategy was compared between both high-risk groups; the low-risk groups, both treated according to the conventional treatment strategy, were used to ensure internal consistency between the experimental and the historical groups. A total of 228 consecutive patients with recent-onset RA (complaints < 1 yr at study entry). The 'aggressive' drug treatment consisted of institution of relatively fast-acting disease-modifying anti-rheumatic drugs (DMARDs) (sulphasalazine, methotrexate) immediately after diagnosis, and rapid adjustment of dosage and/or drug in the case of insufficient response as measured by a change in C-reactive protein (CRP) level. Radiographic damage was assessed according to a modified version of Sharp's method and cumulative disease activity expressed as CRP-area under the curve (CRP-AUC). The occurrence of side-effects was also evaluated. After 2 yr of follow-up, comparison of the two high-risk subgroups showed the radiographic progression in the 'aggressively' treated subgroup to be significantly lower than that in the control group [Sharp score: median (range) 26 (0-100) vs 35 (1-188); P = 0.03]. Cumulative CRP values were also significantly lower than in the control high-risk subgroup [CRP-AUC: median (range) 1963 (212-8515) vs 3025 (46-15 632) mg.week/1; P = 0.002). This was achieved without an increase in the occurrence of side-effects. There was no difference between the two low-risk subgroups with regard to entry characteristics, CRP-AUC values or radiological progression, indicating comparability between the two groups.

Early 'aggressive' drug treatment, using sulphasalazine and/or methotrexate, aimed at reduction of the CRP level, significantly reduces the (rate of) radiographic progression in RA.

Arthritis and its associated joint pain act as significant barriers for adults attempting to perform land-based physical activity. Swimming can be an ideal form of exercise for patients with arthritis. Yet there is no information on the efficacy of regular swimming exercise involving patients with arthritis. The effect of a swimming exercise intervention on joint pain, stiffness, and physical function was evaluated in patients with osteoarthritis (OA). Using a randomized study design, 48 sedentary middle-aged and older adults with OA underwent 3 months of either swimming or cycling exercise training. Supervised exercise training was performed for 45 min/day, 3 days/week at 60-70% heart rate reserve for 12 weeks. The Western Ontario and McMaster Universities Arthritis Index was used to measure joint pain, stiffness, and physical limitation. After the exercise interventions, there were significant reductions in joint pain, stiffness, and physical limitation accompanied by increases in quality of life in both groups (all p < 0.05). Functional capacity as assessed by maximal handgrip strength, isokinetic knee extension and flexion power (15-30% increases), and the distance covered in the 6-min walk test increased (all p < 0.05) in both exercise groups. No differences were observed in the magnitude of improvements between swimming and cycling training. clinicaltrials.gov NCT01836380.

Regular swimming exercise reduced joint pain and stiffness associated with OA and improved muscle strength and functional capacity in middle-aged and older adults with OA. Additionally, the benefits of swimming exercise were similar to the more frequently prescribed land-based cycling training.

To examine the localisation of monocyte chemoattractant protein 1 (MCP-1) in the inflamed vessel wall in temporal arteritis (TA) and to measure MCP-1 in plasma both in patients with TA and patients with polymyalgia rheumatica (PMR). By immunohistochemical techniques MCP-1 was localised to the vessel wall in patients with TA. In TA, PMR, and healthy controls MCP-1 was quantified by enzyme linked immunosorbent assay (ELISA) in plasma. MCP-1 was localised to the majority of mononuclear cells, some smooth muscle cells, and giant cells in the arterial biopsy specimens from 12 patients with histologically verified TA. In all sections, including the vasa vasorum, the endothelium stained positive. In the intima 73% (range 57-91%), in the media 49% (range 32-67%), and in the adventitia 74% (range of 62-91%) of all cells stained positive. In plasma MCP-1 was significantly raised in untreated TA (n=33) and untreated PMR (n=27) compared with healthy controls (n=12). Untreated TA plasma levels of MCP-1 (mean 391 pg/ml (range 82-778 pg/ml)) were similar to untreated PMR plasma levels (mean 402 pg/ml (range 29-1153 pg/ml)), and no significant difference was found between the two groups of patients. In both patients with TA and patients with PMR no correlation was found between the plasma level of MCP-1 and the erythrocyte sedimentation rate, haemoglobin concentration, and CD4/CD8 ratio.

These results show that MCP-1 plays a part in the disease processes of TA and PMR.

Our prospective study aimed to demonstrate that the cumulative synovial power Doppler (PD) ultrasound scores correlate with radiographic progression better than conventional measures in patients with rheumatoid arthritis (RA). We also investigated the difference between antirheumatic agents. Sixty-nine patients with RA who had recently received either methotrexate (MTX; n = 23), tumor necrosis factor (TNF) antagonists (n = 28), or tocilizumab (TCZ; n = 18) were enrolled. Patients underwent clinical, laboratory, and ultrasonographic assessment at baseline, 12 weeks, and 24 weeks. Radiographic damage was evaluated using van der Heijde modified total Sharp score (TSS) at baseline and 24 weeks. Fifty-seven patients continued the same treatment regimen for 24 weeks and completed the study, and 21 patients (36.8%) showed radiographic progression during the study period. In all patients, ΔTSS significantly correlated both with cumulative 28-joint Disease Activity Score-C-reactive protein (DAS28-CRP; ρ = 0.342, p = 0.009) and cumulative total PD scores (ρ = 0.357, p = 0.006). In MTX-treated patients, cumulative total PD scores significantly correlated with ΔTSS (ρ = 0.679, p = 0.004), whereas cumulative DAS28-CRP did not (ρ = 0.487, p = 0.056). However, cumulative total PD scores did not correlate with ΔTSS in TNF antagonist-treated or TCZ-treated patients.

Our data confirm the evidence that synovial PD activity more accurately reflects active synovial inflammation (which actually causes joint destruction) than do conventional measures in patients treated with MTX. Our data also indicate that TNF antagonists can inhibit short-term radiographic progression in the presence of active synovitis.

To determine the reliability, validity, and responsiveness of the modified Kapandji index (MKI). Prospective study. A cohort of patients planned for surgery of the wrist and/or fingers was evaluated within 48 hours before surgery and at least 6 months after surgery. Patients were in hospitalized or private care in France. Patients with rheumatoid arthritis according to criteria of the American College of Rheumatology. Forty-two patients (36 women; mean age, 57.5y; range, 22-80y) were included in the reliability study. Fifty patients (42 women; mean age, 54.18y; range, 19-77y) were included in the validity study. Not applicable. Clinical outcome measures included the MKI, the overall mobility score of the wrist and fingers, the finger mobility score, a visual analog scale (VAS) of pain in the hands and wrists, morning stiffness duration, total score of tenderness, total score of swelling, grip and pinch strength, the Hand Functional Index (HFI), and the Cochin rheumatoid hand disability scale. Reliability was studied with the intraclass correlation coefficient (ICC) and the Bland and Altman method. Convergent and divergent validity were assessed with the Spearman correlation coefficient. Responsiveness was assessed by the paired t test, the effect size, and the standardized response mean (SRM). Interobserver reliability was good with an ICC of.90, and the Bland and Altman analysis showed homogeneous distribution of the differences, with no systematic trend. The MKI correlated well with the other mobility measures (HFI, the finger mobility score measured with the finger goniometer), indicating a good convergent validity, and the expected divergent validity with the other outcome measures (grip and pinch strength, total score of swelling, total score of Ritchie Articular Index, Cochin scale, VAS of pain) was observed. The 50 patients in the validity study were evaluated twice, before and after surgery, at a mean interval +/- standard deviation of 7.16+/-2.10 months (range, 6-15mo). Thirty-six patients (72%) were very satisfied or satisfied with the results of surgery, 7 (14%) were not satisfied or dissatisfied, and 7 (14%) were dissatisfied or very dissatisfied. The SRM and effect size values of the MKI were -.19 and -.10, respectively. Individual changes in the score had the best correlation (r(s)=.51) with overall patient satisfaction.

The MKI has excellent validity and reliability. Individual changes in the score are clinically relevant. This index can be used in clinical practice and in therapeutic trials; it needs further study concerning its use for hand surgery.

High-sensitivity C-reactive protein (hsCRP) in serum is used as a marker of risk for cardiovascular disease (CVD); however CRP is a non-specific acute phase reactant. We evaluated the association between hsCRP concentrations and the most common form of arthritis, osteoarthritis (OA), and assessed the applicability of hsCRP for CVD risk prediction. Participants (n=662) were selected from the population-based Johnston County Osteoarthritis Project, using stratified simple random sampling to achieve balance according to radiographic knee OA status, ethnic group, gender, and age group. The presence and severity of knee and hip OA were determined radiographically. CVD risk was estimated by hsCRP concentration and independently with the Framingham risk algorithm. Serum natural log-transformed hsCRP (ln hsCRP) was higher in African-Americans (P<0.0001) and women (P<0.0001), was higher in participants who had chronic pulmonary disease (P=0.01), hypertension (P<0.0001), or used pain medications (P=0.004), and correlated with body mass index (BMI) (r=0.40, P<0.0001) and waist circumference (r=0.33, P<0.0001), but not with age, CVD, or current smoking. Ln hsCRP was strongly positively associated with all definitions of radiographic OA (rOA; P<0.0001), but this association was not independent of BMI. Although 183 participants reported no CVD and were classified as low risk by the Framingham CVD score, 61% of them were classified as moderate or high risk for CVD using hsCRP; this proportion designated high risk for CVD on the basis of hsCRP consisted primarily of women (P<0.05) and individuals with OA (P<0.01).

The pathogenic significance of hsCRP elevations in this subgroup is unclear. Serum hsCRP for predicting risk of CVD is confounded by obesity, ethnicity, gender and comorbidities.

The role of HTLV-I infection in Sjögren's syndrome (SS) remains unclear. In this study, we clinically compared radiographic imaging with histological cellular infiltration between HTLV-I-seropositive and HTLV-I-sero-negative SS. Sixty primary SS patients were divided into two age-matched groups based on the seropositivity of the anti-HTLV-I antibody. We evaluated the two groups through labial salivary gland biopsy-proven cellular infiltration and sialography-proven radiographic gland destruction. In these 60 pSS patients, the incidence of abnormalities as determined by salivary gland biopsy and sialography was 51.7% (31/60) and 76.7% (46/60), respectively. Although there was no difference in the prevalence of abnormal findings between salivary gland biopsy and sialography in the whole 60 patients, there were significantly fewer abnormalities determined by sialography in HTLV-I-seropositive SS patients in comparison with HTLV-I-seronegative SS patients. Also, these findings were strengthened by the results that none of HTLV-I-seropositive SS patients with focus score 0 had abnormal sialography findings.

Our results suggest that HTLV-I infection results in resistance toward salivary gland destruction of Sjögren's syndrome.

To study the results of closing-wedge high tibial osteotomy and arthroscopy for the treatment of medial compartment osteoarthritis of the knee. From October 2005 to June 2007, 25 patients met with our inclusion criteria. All the patients with medial compartment knee osteoarthritis were treated with arthroscopy and closing-wedge high tibial osteotomy. There were 11 males and 14 females,with a mean age of 53 years old. The pre-operative HSS knee score was 67.6 +/- 2.8, FTA was (185.54 +/- 1.11) degrees, and aLPTA was (96.54 +/- 0.52) degrees in average. The patients were followed up and evaluated according to HSS knee score. The efficacy of the osteotomy was evaluated by FTA and aLPTA. All surgeries were successful without serious complication. All the patients were followed up, and the duration ranged from 5 to 7 years. The HSS was 85.5 +/- 3.7 at the 1st year and 80.3 +/- 5.4 at the latest follow-up. There was significant difference between every two scores of before operation and the two after operation (t = -33.135, P = 0.000; t = -13.215, P = 0.000). The FTA was (173.65 +/- 0.92) degrees at the 1st year and (174.34 +/- 0.53) degrees at the latest follow-up. There was significant difference between every two angles of before operation and after operation (t = 28.739, P = 0.000; t = 2.331, P = 0.048). The aLPTA was (87.32 +/- 0.33) degrees at the 1st year and (87.67 +/- 2.82) degrees at the latest follow-up. There was significant difference between every two angles of before operation and after operation (t = 37.264, P = 0.000; t = 2.469, P = 0.039).

Indication is important and good surgical technique is critical for good clinical outcome. A detailed plan before operation is essential for the operation. Arthroscopy is helpful for treating the intra-articular pathology. The osteoarthritis is still in progress but in a slow mode. The combined method of arthroscopy and closing-wedge high tibial osteotomy is a reliable way for medial compartment osteoarthritis of the knee.

To demonstrate the use of diffusion tensor magnetic resonance micro-imaging to observe adaptations of collagen fibres to mechanical compression in articular cartilage. Spin-echo and diffusion tensor images (156x156microm in-plane resolution, 2mm slice thickness) of bovine cartilage were obtained at a magnetic field of 7.0T in relaxed and compressed states. The parameters determined were: T2, maximum and mean diffusivity, direction of the maximum diffusion eigenvector and fractional anisotropy of diffusion. A correlation was found between the compressive strain applied to the cartilage and the change in both magnitude and direction of the maximum diffusivity. Compression resulted in a decrease in both the maximum and mean eigenvalues, particularly in the surface and transitional zones, while the change in orientation of the eigenvectors corresponding to maximum diffusion was greatest in the transitional region. In this region, the average orientation of the principal eigenvectors with respect to the normal to the articular surface increased by up to 40 degrees, indicating that the collagen fibre bundles were oriented more parallel to the surface when compressed.

Diffusion tensor imaging can be used to monitor the changes in the direction of the collagen fibres due to compression. It may form the basis of a new non-invasive approach to functional evaluation of cartilage, with potential applications in the diagnosis and treatment of osteoarthritis.

To prospectively use dynamic contrast material-enhanced magnetic resonance (MR) imaging and a tracer kinetic model to compare parotid gland microvascular characteristics in patients who have Sjögren syndrome (SS) with those in healthy volunteers. The local research ethics committee approved the study, and written informed consent was obtained from all participants. Twenty-one patients (19 women, two men; age range, 31-73 years) with a diagnosis of SS and 11 healthy volunteers (10 women, one man; age range, 41-68 years) underwent three-dimensional T1-weighted dynamic contrast-enhanced MR imaging of the parotid gland at 1.5 T. A voxel-wise tracer kinetic model and a model-free analysis were applied to the dynamic MR data. Parameter medians and standard deviations were computed to summarize gland microvascular characteristics and gland heterogeneity, respectively. Differences were investigated by using multivariate analysis of variance, t, or U tests. Further investigation was performed by using linear discriminant and receiver operating characteristic analyses. Compared with the healthy volunteers, the patients with SS had highly significant elevations (P << .001) in the model-free parameter initial area under the curve and in tracer kinetic model parameters, including transcapillary contrast agent transfer constant (P < .001) and extracellular extravascular volume (P < .001). Gland heterogeneity was significantly greater (P < .001) in the patients with SS. Parameter medians and standard deviations enabled excellent differentiation (areas under receiver operating characteristic curve, 0.96 and 1.00, respectively) between the patients with SS and the healthy volunteers.

Dynamic contrast-enhanced MR imaging has the potential to be used in clinical settings to quantify microvascular function in SS and to differentiate between patients with and those without SS.

Osteoarthritis of the sternoclavicular (SC) joint is a rare condition that leads to decreased function and persistent pain, ultimately altering the function of the shoulder and keeping individuals from their desired activities. SC resection in the setting of primary and posttraumatic osteoarthritis is the most common surgical treatment for these patients, but midterm results are lacking. The purpose was to assess the clinical outcomes, pain levels, return to sports rate, and survivorship after open SC joint resection in the setting of painful primary SC joint osteoarthritis. We hypothesized that an SC joint resection of maximum 10 mm would result in a significant improvement in clinical outcomes, decreased pain levels, a high rate of return to sports, and a high survivorship. Case series; Level of evidence, 4. Patients who underwent SC joint resection (maximum 10 mm) by a single surgeon between the years 2006 and 2013 with minimum 5-year follow-up were reviewed. The following clinical outcomes were collected prospectively during this time period: 12-Item Short Form Health Survey Physical Component Score (SF-12 PCS), American Shoulder and Elbow Surgeons (ASES) score, Single Assessment Numerical Evaluation (SANE) score, Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) score, and patient satisfaction. Return to sports and pain were assessed through use of a customized questionnaire. Survivorship of SC joint resection was defined as not requiring further surgery on the affected joint. A total of 21 SC joints were treated with resection of the medial clavicle and intra-articular disk and capsulorrhaphy for SC joint osteoarthritis in 19 patients with a mean age of 39.4 years (range, 12.5-66.7 years). At minimum 5-year follow-up, 19 SC joint resections were assessed in 16 of 19 patients (84%) with a mean follow-up of 6.7 years (range, 5.0-10.4 years). All outcome scores improved significantly from pre- to postoperative assessments: ASES (from 54 to 90.5;

Open SC resection arthroplasty with capsulorrhaphy in the setting of pain for SC osteoarthritis results in significant improvement in clinical outcomes, patient satisfaction, return to sports, and pain reduction at minimum 5-year follow-up.

This systematic literature review aimed to evaluate the use of conventional radiography (CR) in hand osteoarthritis (OA) and to assess the metric properties of the different radiographic scoring methods. Medical literature databases up to November 2013 were systematically reviewed for studies reporting on radiographic scoring of structural damage in hand OA. The use and metric properties of the scoring methods, including discrimination (reliability, sensitivity to change), feasibility and validity, were evaluated. Of the 48 included studies, 10 provided data on reliability, 11 on sensitivity to change, four on feasibility and 36 on validity of radiographic scoring methods. Thirteen different scoring methods have been used in studies evaluating radiographic hand OA. The number of examined joints differed extensively and the obtained scores were analyzed in various ways. The reliability of the assessed radiographic scoring methods was good for all evaluated scoring methods, for both cross-sectional and longitudinal radiographic scoring. The responsiveness to change was similar for all evaluated scoring methods. There were no major differences in feasibility between the evaluated scoring methods, although the evidence was limited. There was limited knowledge about the validity of radiographic OA findings compared with clinical nodules and deformities, whereas there was better evidence for an association between radiographic findings and symptoms and hand function.

Several radiographic scoring methods are used in hand OA literature. To enhance comparability across studies in hand OA, consensus has to be reached on a preferred scoring method, the examined joints and the used presentation of data.

To determine the clinical and biochemical characteristics of children with Juvenile Idiopathic Arthritis (JIA) at a tertiary care centre in Karachi, Pakistan. A descriptive study. Paediatric Rheumatology Clinic of The Aga Khan University Hospital (AKUH), Karachi, from January 2008 to December 2011. Clinical and laboratory profile and outcome of children less than 15 years of age attending the Paediatric Rheumatology Clinic of the Aga Khan University, Karachi with the diagnosis of Juvenile Idiopathic Arthritis according to International League against Rheumatism were studied. These children were classified into different types of JIA; their clinical and laboratory characteristics, response to therapy and outcome was evaluated. Sixty eight patients satisfying the criteria of International League against Rheumatism (ILAR) for Juvenile Idiopathic Arthritis were enrolled during the study period of four consecutive years, their age ranged from 9 months to 15 years. Mean age at onset was 6.45 ± 4.03 years while mean age at diagnosis was 7.60 ± 3.93 years. Polyarticular was the most predominant subtype with 37 (54%) patients, out of these, 9 (24%) were rheumatoid factor positive. An almost equal gender predisposition was observed. Fever and arthritis were the most common presenting symptoms, with only 2 patients presenting with uveitis.

The clinico-biochemical characteristics of JIA at the study centre showed a pattern distinct with early onset of disease, high frequency of polyarticular type and a higher rheumatoid factor (QRA) and ANA positivity in girls.

To determine the effect on pain, function, and ultrasonographic findings of ultrasonography-guided Baker's cyst aspiration followed by corticosteroid injection in a group of patients with Baker's cyst secondary to knee osteoarthritis. Prospective observational study. Twenty-six subjects participated in this study. Clinical and instrumental evaluations were performed at baseline (T0), 1 wk (T1), and 4 wks (T2) after procedure. Mean Visual Analog Scale scores significantly dropped after the procedure (T0 = 6.2 [1.2]; T1 = 4.48 [1.5]; T2 = 4.32 [1.3]; T0 vs. T1 and P < 0.0001). A significant difference between preprocedure and postprocedure Western Ontario and McMaster Universities scores was found for pain (P < 0.0001) but not for joint stiffness (P = 0.7239) and disability (P = 0.6318). Ultrasonographic evaluation showed a significant reduction for both axial (P = 0.006) and sagittal (P = 0.01) areas of Baker's cyst, but no correlation was found between pain relief and Baker's cyst volume reduction.

Cyst aspiration with corticosteroid injection give pain relief and cyst volume reduction in patients with Baker's cyst and concomitant knee osteoarthritis. However, when compared with current literature, our results are similar to those obtained with intra-articular knee corticosteroid injection.

High expression of galectin 3 at sites of joint destruction in rheumatoid arthritis (RA) suggests that galectin 3 plays a role in RA pathogenesis. Previous studies have demonstrated the effects of galectins on immune cells, such as lymphocytes and macrophages. This study was undertaken to investigate the hypothesis that galectin 3 induces proinflammatory effects in RA by modulating the pattern of cytokine and chemokine production in synovial fibroblasts. Matched samples of RA synovial and skin fibroblasts were pretreated with galectin 3 or tumor necrosis factor alpha (TNFalpha), and the levels of a panel of cytokines, chemokines, and matrix metalloproteinases (MMPs) were determined using enzyme-linked immunosorbent assays and multiplex assays. Specific inhibitors were used to dissect signaling pathways, which were confirmed by Western blotting and NF-kappaB activation assay. Galectin 3 induced secretion of interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor, CXCL8, and MMP-3 in both synovial and skin fibroblasts. By contrast, galectin 3-induced secretion of TNFalpha, CCL2, CCL3, and CCL5 was significantly greater in synovial fibroblasts than in skin fibroblasts. TNFalpha blockade ruled out autocrine TNFalpha-stimulated induction of chemokines. The MAPKs p38, JNK, and ERK were necessary for IL-6 production, but phosphatidylinositol 3-kinase (PI 3-kinase) was required for selective CCL5 induction. NF-kappaB activation was required for production of both IL-6 and CCL5.

Our findings indicate that galectin 3 promotes proinflammatory cytokine secretion by tissue fibroblasts. However, galectin 3 induces the production of mononuclear cell-recruiting chemokines uniquely from synovial fibroblasts, but not matched skin fibroblasts, via a PI 3-kinase signaling pathway. These data provide further evidence of the role of synovial fibroblasts in regulating the pattern and persistence of the inflammatory infiltrate in RA and suggest a new and important functional consequence of the observed high expression of galectin 3 in the rheumatoid synovium.

The vasoactive intestinal peptide (VIP) receptors VPAC1 and VPAC2 mediate anti-inflammatory and immunoregulatory responses in rheumatoid arthritis (RA). Data on the expression of these receptors could complement clinical assessment in the management of RA. Our goal was to investigate the correlation between expression of both receptors and the 28-Joint Disease Activity Score (DAS28) in peripheral blood mononuclear cells (PBMCs) from patients with early arthritis (EA). We also measured expression of IL-6 to evaluate the association between VIP receptors and systemic inflammation. We analyzed 250 blood samples collected at any of the 5 scheduled follow-up visits from 125 patients enrolled in the Princesa Early Arthritis Register Longitudinal study. Samples from 22 healthy donors were also analyzed. Sociodemographic, clinical, and therapeutic data were systematically recorded. mRNA expression levels were determined using real-time PCR. Then, longitudinal multivariate analyses were performed. PBMCs from EA patients showed significantly higher expression of VPAC2 receptors at baseline compared to healthy donors (p<0.001). With time, however, VPAC2 expression tended to be significantly lower while VPAC1 receptor expression increased in correlation with a reduction in DAS28 index. Our results reveal that more severe inflammation, based on high levels of IL-6, is associated with lower expression of VPAC1 (p<0.001) and conversely with increased expression of VPAC2 (p<0.001). A major finding of this study is that expression of VPAC1 is lower in patients with increased disease activity (p = 0.001), thus making it possible to differentiate between patients with various degrees of clinical disease activity.

Patients with more severe inflammation and higher disease activity show lower levels of VPAC1 expression, which is associated with patient-reported impairment. Therefore, VPAC1 is a biological marker in EA.

Fatigue is a common symptom of many rheumatic diseases (RDs), but more research is needed to explore the experience of fatigue and its impact on employment among people with RDs. The aim of the present study was to investigate experiences of fatigue, its impact on employment and strategies that people with RD use to continue working. Semi-structured in-depth interviews were conducted with five participants with a range of RDs living in New Zealand (three women, two men; aged 45-64 years). All participants were employed part time at the time of the interview. The transcripts were subjected to inductive thematic analysis, led by the first author, who had an RD. Four themes resulted from the analysis: (a) workplace management and coping strategies; (b) the function of positive workplace relationships; (c) barriers to understanding; and (d) collectively improving understanding. These themes act to explain how individuals with RDs in employment believe fatigue to have a bearing on their work, how they manage fatigue at work, how they believe coworkers and employers perceive and manage their fatigue, and what they believe could improve the understanding of fatigue in workplaces.

Individuals with RDs in employment describe fatigue as playing a substantial role in their experiences at work. This research expands on previous literature addressing barriers to employment in those with RDs by specifically addressing the relevance of fatigue. It is imperative to provide information to employers, and guidelines for employees with an RD who are experiencing fatigue should outline appropriate strategies for success at work.

Several authors have suggested a correlation between the fracture patterns of proximal femur fractures and the degree of hip osteoarthritis (HOA), but the current evidence to support this are insufficient. The aim of our study was to demonstrate whether there is an association between the grade of HOA and fracture pattern observed, in patients presenting with a fragility fracture of the proximal femur. We contacted a retrospective review of all patients presenting to our institution with fragility fractures involving the proximal femur, between March 2012 and October 2013. Pathological fractures, high-energy injuries and patients with less than one year of follow-up were excluded from further analysis. Admission radiographs and severity of HOA were assessed according to Kellgren and Lawrence scale (minimal: Grades 1-2; severe: Grades 3-4). Fractures were classified according to AO/OTA classification. A total of 1003 patients (725 females; 1003 fractures) met the inclusion criteria, having a mean age of 81.5 (46-106 years). With regards to fracture classification, 417 (41.6%) fractures were classified as extracapsular and 586 (58.4%) as intracapsular. A total of 939 (93.9%) patients presented with minimal HOA, whilst 61 (6.1%) of the patients presented with severe HOA. Of the 61 patients presenting with severe HOA, 42 patients (68.9%) sustained a 31A-interthrocanteric fracture and 19 patients (31.1%) sustained a 31B-intracapsular fracture. Regarding the patients presenting with minimal HOA (832 patients in total), 323 patients (38.8%) sustained 31A-intertrochanteric fracture and 509 patients (61.2%) sustained a 31B-intracapsular fracture. Patients presenting with severe HOA were found to have a statistically significant chance to present with an extracapsular fracture (p<0.01).

The degree of HOA is related to the fracture pattern in patients presenting following simple mechanical falls. More specifically, higher grades of HOA are associated with extracapsular fracture patterns, whereas lower grades of HOA are associated with intracapsular fracture patterns.

Joint lavage (JL), involves the passage of cold sterile 0.9% saline through the knee joint in order to have the fluid reach the inside of the joint capsule. This technique was evaluated as a local treatment for osteoarthritis (OA) of the knee alone (JL) and in combination with intra-articular infiltration with glucocorticoids (JLC). An overall 299 knees belonging to 205 patients (22% males, 78% females) with a mean age of 67 +/- 8 years and osteoarthritis of the knee of radiological grade II or III on the Kellgren scale were randomised in the ratio of 1:4 into two therapeutic groups, namely: JL (n = 62) and JLC (n = 237). All patients received joint lavage on day 0; in those of the JLC group, joint lavage was followed by infiltration of 40 mg of triamcinolone acetonide. The efficacy of both treatments was assessed by recording the corresponding values for the following variables: pain strength as measured by a visual analogy scale (VAS), effusion, crepitation, restricted motion, of osteoarthritis of the knee. spontaneous pain, pain on pressure, pain on passive motion and pain on active motion; all of these were recorded at the onset of the study, and after 1 and 3 months. There were no significant differences in the values of the variables at the different followup times. Also, pain severity was similar in both treatment groups. Thus, VAS for pain was 7.3 +/- 0.3 for the JL group and 7.1 +/- 0.2 for the JLC group at the onset, and decreased to 3.0 +/- 0.3 in the former and 2.8 +/- 0.2 in the latter after 1 month; the decrease was statistically significant in both cases. After 3 months, the JL and JLC groups had a VAS of 3.5 +/- 0.3 and 3.8 +/- 0.2, respectively.

The results of this work suggest the absence of significant differences between the two treatments, such that both joint lavage alone and with infiltration with corticoids can be concluded as similarly effective for the symptomatic management

We investigated the frequency of tinnitus in fibromyalgia patients and the effect of drugs used for routine fibromyalgia on tinnitus. We included 101 diagnosed fibromyalgia patients. After detailed ear nose throat examination, audiometric tests and tinnitus handicap index (THI) were performed. After the tests, routine treatment for fibromyalgia was started by the physical therapy and rehabilitation department. Two months after the beginning of the treatment, THI were repeated again and the results were statistically evaluated. All patients included in the study were women. 74.3% of the patients had tinnitus. Pregabalin and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant-treated patients were evaluated; In both groups, there was a statistically significant difference between pre- and post-treatment tinnitus levels (p < .001). However, there was no statistically significant difference between pregabalin group and diloxetine group according to treatment results.

The incidence of tinnitus is high in fibromyalgia patients. That pregabalin and duloxetine agents routinely used in fibromyalgia require further experimental and human studies in order to be able to use in tinnitus.

Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in older people. It is characterised by changes in joint structure, including degeneration of the articular cartilage, and its aetiology is multifactorial with a strong postulated genetic component. A meta-analysis was performed of four genome-wide association (GWA) studies of 2371 cases of knee OA and 35 909 controls in Caucasian populations. Replication of the top hits was attempted with data from 10 additional replication datasets. With a cumulative sample size of 6709 cases and 44 439 controls, one genome-wide significant locus was identified on chromosome 7q22 for knee OA (rs4730250, p=9.2 × 10⁻⁹), thereby confirming its role as a susceptibility locus for OA.

The associated signal is located within a large (500 kb) linkage disequilibrium block that contains six genes: PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, β), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like) and BCAP29 (B cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.

To assess the prevalence of chronic obstructive pulmonary disease (COPD) in patients with primary Sjögren syndrome (pSS) and to study the association of COPD with cigarette smoking, radiographic features, respiratory symptoms, disease activity, and laboratory inflammatory and serological features in patients with pSS. Fifty-one consecutive patients with pSS (mean age 60 yrs, range 29-82 yrs, 49 women) were assessed by pulmonary function tests (PFT). The PFT results were compared with previously studied population-based controls, standardizing results with regard to sex, age, height, weight, and cigarette smoking. In addition, patients with pSS were assessed by computed tomography of the chest, the European League Against Rheumatism Sjögren Syndrome Disease Activity Index and Patient Reported Index, the St. George's Respiratory Questionnaire (which evaluates respiratory symptoms), and by laboratory inflammatory and serological tests. Forty-one percent of all patients with pSS and 30% of the never-smoking patients with pSS fulfilled the Global Initiative for Chronic Obstructive Lung Disease criteria for COPD. Vital capacity (VC), forced expiratory volume in 1 s (FEV1), FEV1/VC ratio, and DLCO were significantly decreased while residual volume (RV) and the RV/total lung capacity ratio were significantly increased in patients with pSS. Moderate correlations between PFT results, symptoms, and disease activity were found. However, laboratory inflammatory and serological features were poorly associated with PFT results in patients with pSS.

COPD was a common finding in patients with pSS, even among never-smoking patients. An obstructive pattern was the predominant PFT finding in patients with pSS, although a superimposed restrictive lung disease could not be excluded. The results suggest that the disease per se is involved in the development of COPD in pSS.

The aim of the study was to determine the prevalence of cryoglobulinaemia and its clinical features among beta-thalassaemia patients. Eighty eight multitransfused beta-thalassaemia patients were studied. They were physically examined and asked about the presence of cryoglobulinaemia related symptoms. Hepatitis C virus (HCV) serology, HCV-RNA, HCV subtypes, viraemia, serum ferritin, liver and kidney function tests, rheumatoid factor (RF), circulating immune complexes (CIC), complement levels and autoantibodies were all evaluated. The patients were divided into four groups: HCV-RNA positive patients with and without cryoglobulinaemia (groups A and B), HCV-Ab positive/HCV-RNA negative patients (group C), HCV-Ab negative patients (group D). Cryoglobulinaemia was present in 35 of 53 (66.0%) patients with chronic HCV infection. They had higher viraemia than non-cryoglobulinaemic viral carriers, but no statistical difference relating to sex or HCV subtypes was found. In comparison with the other groups, group A patients were older, had undergone transfusion therapy for a longer period, had received a higher number of transfusions, and had increased levels of RF and CIC, as well as consumption of C4; in addition, they had a higher prevalence of cirrhosis. Cutaneous lesions (purpura, Raynaud's phenomenon, nodules and leg rash), peripheral neuropathy and sicca syndrome symptoms were present only in group A. Musculoskeletal symptoms (bone pain, arthralgia and myalgia), weakness, splenomegaly, lymphadenopathy, skin ulcers and proteinuria were also commoner in group A, but the difference did not reach statistical significance, possibly because of partial overlap between cryoglobulinaemia and beta-thalassaemia syndromes.

Because of its high prevalence in multitransfused beta-thalassaemia patients, cryoglobulinaemia needs to be systematically studied and considered in the differential diagnosis of various beta-thalassaemia manifestations.

Cross cultural validity is of vital importance for international comparisons. To investigate the validity of international Dutch-English comparisons when using the Dutch translation of the Western Ontario and McMaster Universities osteoarthritis index (WOMAC). The dimensionality, reliability, construct validity, and cross cultural equivalence of the Dutch WOMAC in Dutch and Canadian patients waiting for primary total hip arthroplasty was investigated. Unidimensionality and cross cultural equivalence was quantified by principal component and Rasch analysis. Intratest reliability was quantified with Cronbach's alpha, and test-retest reliability with the intraclass correlation coefficient. Construct validity was quantified by correlating sum scores of the Dutch WOMAC, Arthritis Impact Measurement Scales (Dutch AIMS2), Health Assessment Questionnaire (Dutch HAQ), and Harris Hip Score (Dutch HHS). The WOMAC was completed by 180 Dutch and 244 English speaking Canadian patients. Unidimensionality of the Dutch WOMAC was confirmed by principal component and Rasch analysis (good fit for 20/22 items). The intratest reliability of the Dutch WOMAC for pain and physical functioning was 0.88 and 0.96, whereas the test-retest reliability was 0.77 and 0.92, respectively. Dutch WOMAC pain sum score correlated 0.69 with Dutch HAQ pain, and 0.39 with Dutch HHS pain. Dutch WOMAC physical functioning sum score correlated 0.46 with Dutch AIMS2 mobility, 0.62 with Dutch AIMS2 walking and bending, 0.67 with Dutch HAQ disability, and 0.49 with Dutch HHS function. Differential item functioning (DIF) was shown for 6/22 Dutch items.

The Dutch WOMAC permits valid international Dutch-English comparisons after correction for DIF.

There are very few reports assessing bone mineral mass and its metabolism in the course of juvenile idiopathic arthritis (JIA). To assess the levels of selected serum markers of bone formation (OCN) and resorption (CTx) in JIA children. The study involved 52 children with JIA diagnosed according to the EULAR criteria of 1997, aged 6-18 years. All patients underwent densitometric measurements using dual-energy X-ray absorptiometry (DXA) to assess TBBMD (g/cm2), Spine BMD (g/cm2), Z-score for SBMD, TBBMC (g), and LBM (g). The following parameters were determined in blood serum: the level of osteocalcin (OCN) and C-terminal type I alpha-collagen chain telopeptide (CTx) using the Elecsys 2010 system (N-MID Osteocalcin, Beta-CrossLaps). A gender- and age-matched control group consisted of 16 healthy children. The mean concentrations of both osteocalcin (p<0.001) and CTx (p<0.005) were significantly higher in JIA patients as compared to the healthy controls (OCN 113.2+/-54.9 ng/ml vs. 70.2+/-48.3 ng/ml; CTx 1.4+/-0.5 mug/l vs. 1.2 +/-0.45 microg/l). The concentrations of the bone turnover markers were significantly reduced in children with higher degrees of joint destruction compared to those with anatomically normal joints (p<0.05). The mean concentration of CTx showed a significant negative correlation with the TB BMC/LBM Z-score (p<0.05). Reduced bone mass (Z-score for SBMD< -2.0) was found in 23.6% of the affected children.

The JIA patients had elevated levels of OCN and CTx compared to the healthy controls. Reduced bone turnover was observed in children with higher degrees of joint destruction.

To examine the effects of tumor necrosis factor inhibitors on the risk for serious infections and other influencing factors in a registry. Patients exposed for the first time to etanercept, adalimumab, or methotrexate and serious infections were identified in the German Biologic Registry for Pediatric Rheumatology (BIKER) registry. Serious infection rates per 1,000 observation-years and relative risks were calculated. Cox regression identified risk factors and provided hazard ratios (HRs) for occurrence of infections. A total of 3,350 patients with 5,919 observation-years fulfilled the inclusion criteria for the study. The first biologic agents were etanercept (1,720 cases) and adalimumab (177 cases). A total of 1,453 patients were treated with methotrexate and no biologic agent. In total, 28 serious infections were reported in 26 patients (4.7 per 1,000 patient-years), 5 with methotrexate (1.6 per 1,000 patient-years), 21 with etanercept (8.1 per 1,000 patient-years), and 2 with adalimumab (9.7 per 1,000 patient-years). Significant univariate risk factors for infection were therapy with biologic agents, disease duration before therapy start, corticosteroid medication, nonbiologic premedications, higher clinical Juvenile Arthritis Disease Activity Score including maximal 10 joints (cJADAS10) at therapy start, and higher mean cJADAS10 during therapy. In multivariate Cox regression, only biologic therapy and cJADAS10 at therapy start remained significant. Risk for infection was increased by etanercept (univariate HR 6.0 [95% confidence interval (95% CI) 2.0-17.5]) or adalimumab (HR 7.3 [95% CI 1.3-40.0]) compared to methotrexate as well as by an elevated cJADAS10 at therapy start (HR 1.1 [95% CI 1.0-1.2] per unit increase).

The total rate of serious infections reported in the BIKER registry seems low. Treatment with etanercept or adalimumab increases the risk for serious infection slightly, compared to methotrexate. Disease activity expressed by cJADAS10 appears to be an independent risk factor.

To determine the best protocol for the preparation of a tissue-engineered cartilage to investigate the potential anti-arthritic and/or anti-osteoarthritic effects of drugs. Calf articular chondrocytes, seeded in collagen sponges were grown in culture for up to 1 month. At day 14 cultures received interleukin (IL)-1beta (ranging from 0.1 to 20 ng/ml) for 1 to 3 days. Analyses of gene expression for extracellular matrix proteins, collagen-binding integrins, matrix metalloproteinases (MMPs), aggrecanases, TIMPs, IL-1Ra and Ikappa-Balpha were carried out using real-time polymerase chain reaction (PCR). Metalloproteinase activities were analysed in the culture medium using both zymography and fluorogenic peptide substrates. We selected a culture for 15 or 17 days with collagen sponges seeded with 10(7) chondrocytes showing a minimal cell proliferation, a maximal sulphated glycosaminoglycan (sGAG) deposition and a high expression of COL2A1, aggrecan and the alpha10 integrin sub-unit and low expression of COL1A2 and the alpha11 integrin sub-unit. In the presence of 1 ng/ml IL-1beta, we observed at day 15 up-regulations of 450-fold for MMP-1, 60-fold for MMP-13, 54-fold for ADAMTS-4 and MMP-3 and 10-fold for ADAMTS-5 and IL-1Ra. Down-regulations of 2.5-fold for COL2A1 and aggrecan were observed only at day 17. At the protein level a dose-dependent increase of total MMP-1 and MMP-13 was noted with less than 15% in the active form.

This in vitro model of chondrocyte culture in three dimensional (3D) seems well adapted to investigate the responses of these cells to inflammatory cytokines and to evaluate the potential anti-inflammatory effects of drugs.

To evaluate the efficacy of a 3-month exercise training program in counteracting the chronotropic incompetence and delayed heart rate recovery in patients with systemic lupus erythematosus (SLE). A 12-week randomized trial was conducted. Twenty-four inactive SLE patients were randomly assigned into 2 groups: trained (T; n = 15, 3-month exercise program) and nontrained (NT; n = 13). A sex-, body mass index-, and age-matched healthy control (C) group (n = 8) also underwent the exercise program. Subjects were assessed at baseline and at 12 weeks after training. Main measurements included the chronotropic reserve (CR) and the heart rate (HR) recovery (ΔHRR) as defined by the difference between HR at peak exercise and at both the first (ΔHRR1) and second (ΔHRR2) minutes after the exercise test. Neither the NT SLE patients nor the C group presented any change in the CR or in ΔHRR1 and ΔHRR2 (P > 0.05). The exercise training program was effective in promoting significant increases in CR (P = 0.007, effect size [ES] 1.15) and in ΔHRR1 and ΔHRR2 (P = 0.009, ES 1.12 and P = 0.002, ES 1.11, respectively) in the SLE T group when compared with the NT group. Moreover, the HR response in SLE patients after training achieved parameters comparable to the C group, as evidenced by the analysis of variance and by the Z score analysis (P > 0.05, T versus C). Systemic Lupus Erythematosus Disease Activity Index scores remained stable throughout the study.

A 3-month exercise training program was safe and capable of reducing the chronotropic incompetence and the delayed ΔHRR observed in physically inactive SLE patients.

The aim was to assess sensitization using quantitative sensory testing in mechanical and thermal modes in individuals with and without osteoarthritis (OA) of the knee. Pain thresholds were correlated with functionality, symptoms of depression and intensity of pain. Thirty control volunteers and 30 patients with OA of the knee were assessed. Punctate pain thresholds using Von Frey filaments and thermal pain thresholds using a Thermal Sensory Analyzer were evaluated in the periarticular region of the knee and forearm. Using a digital pressure algometer, pressure pain thresholds were assessed in the periarticular region of the knee and on the root exit zone on the lumbar and sacral spine. Punctate, pressure, and thermal pain thresholds differed significantly between participants with and without OA (p < 0.05). Values in those with OA were consistent with pain sensitization. Pressure pain thresholds also showed moderate and negative correlations with data on functionality, symptoms of depression and intensity of pain (-0.36 < r > -0.56), contributing up to 30% of their variability.

Allodynia and hyperalgesia were demonstrated in the OA group, suggesting central sensitization in patients with mild to moderate severity of joint damage. Correlation between mechanical hypersensitivity and psychosocial factors seems to be small, despite of its significance.

The aim of this review was to qualitatively synthesise studies that have investigated characteristics of the first metatarsophalangeal joint (1(st) MTP) in gout and to undertake a meta-analysis to estimate the average prevalence of acute 1(st) MTP arthritis across studies in people with gout. Studies published in English were included if they involved participants who had a diagnosis of gout and presented original findings relating to the following outcome measures associated with the 1(st) MTP: epidemiology; clinical features; structural and functional characteristics; and microscopic and imaging features. Forty-five studies were included in the qualitative synthesis. 1(st) MTP pain was a prominent feature in people with gout. People with 1(st) MTP gout reported walking- and general-disability. Structural and functional characteristics of 1(st) MTP gout included hallux valgus, osteoarthritis, and restricted joint motion. Successful crystal aspiration ranged from 81 to 91 % and positive crystal identification via microscopy ranged from 83 to 93 % in patients with a history of 1(st) MTP gout. Imaging features were common at the 1(st) MTP including the double contour sign, tophi and erosions. Eleven studies involving 2,325 participants were included in the meta-analysis, providing an estimate of the average prevalence of acute 1(st) MTP arthritis across studies of 73 % (95 % prediction interval 40-92 %; range 48-97 %; I(2) = 93 %).

1(st) MTP acute arthritis is highly prevalent in people with gout and has a substantial impact on patient-reported pain and disability. Gout affects the structure and function of the 1(st) MTP. Microscopic and imaging studies have demonstrated crystal deposition and joint damage at the 1(st) MTP in people with gout.

We evaluated the clinical efficacy and the tolerance of Nabumetone (N), in comparison with a pool of non-steroidal anti-inflammatory drugs (NSAIDs), in a cohort of patients affected by rheumatoid arthritis, osteoarthritis, non-articular rheumatisms and primary fibromyalgic syndrome. One hundred and seventy patients were observed in an open-non randomized study. The patients have been recruited alternatively and subdivided into two groups: 84 patients that received N and 86 patients that received one of the other NSAIDs. All the patients affected by rheumatoid arthritis received a disease-modifying anti-rheumatic drug (OH-chloroquine, d-penicillamine, auranofin, cyclosporine-A); while benzodiazepines are administered in the patients suffering from primary fibromyalgic syndrome. A follow-up not inferior to 12 consecutive weeks was realized and the following clinical parameters were studied: spontaneous pain, provoked pain, pain on active movement, pain on passive movement, pain at rising, pain at bed time, morning stiffness, limited joint mobility, number of tender points, number of affected joints and number of swollen joints. All the patients were monitored for hematological, biochemical, urinary and clotting tests. The results revealed an excellent tolerability of nabumetone with a clinical efficacy not inferior to the NSAIDs' pool. Moreover, the number of drop-outs in the N-group were significantly inferior in comparison to the NSAIDs'-pool group.

We conclude that N can be considered as effective as other NSAIDs. Moreover it seems to be better tolerated that the other NSAIDs utilized in our study.

Gouty arthritis and familial Mediterranean fever (FMF) share some clinical and pathological features such as being classified as auto inflammatory disease, association with inflammasome, short-lived intermittent arthritis, and good response to colchicine and anti-interleukin-1 treatments. As Mediterranean fever (MEFV) gene is the causative factor of FMF, we aimed to investigate the prevalence of MEFV gene mutations and their effect on disease manifestations in Turkish gouty arthritis patients. Ninety-seven patients diagnosed with primary gouty arthritis (93M and 4 F, 54 [37-84] years) and 100 healthy controls (94M and 6 F, 57 [37-86] years) included in the study. All subjects were genotyped for the MEFV variations. Number of gout attacks, diuretic use, and history of nephrolithiasis and presence of tophus were also recorded. The carriage rate of MEFV mutations for patients and controls were 22.7% (n=22) and 24% (n=24) respectively. The comparison of the patient and control groups yielded no significant difference in terms of the MEFV mutations carriage rate (p=0.87). The allelic frequencies of the MEFV mutations in patients were 11.9% (n=23) and 14% (n=28) in controls (p=0.55). The presence of MEFV variants did not show any association with clinical features of gouty arthritis. The subgroup analysis of patients revealed that gouty arthritis patients with mutations had similar frequencies of tophus, history of nephrolithiasis and podogra compared to the ones without mutations (p>0.05).

This study does not provide support for a major role of MEFV mutations in Turkish gouty arthritis patients.

To confirm the reliability and applicability of the Polymyalgia Rheumatica Disease Activity Score (PMR-AS), and to establish a threshold for remission. First, 78 patients with PMR (50 women/28 men, mean age 65.97 years) were enrolled in a cross-sectional evaluation. The PMR-AS, patient's satisfaction with disease status (PATSAT; range 1-5), erythrocyte sedimentation rate (ESR; first hour), and a visual analog scale of patients' general health assessment (VAS patient global; range 0-100) were recorded. Subsequently, another 39 PMR patients (24 women/15 men, mean age 68.12 years) were followed longitudinally. Relationships between the PMR-AS, PATSAT, ESR, and VAS patient global were analyzed by the Kruskal-Wallis test, Spearman's rank correlation, and kappa statistics. PMR-AS values in patients with a PATSAT score of 1 and a VAS patient global <10 formed the basis to establish a remission threshold. PMR-AS values were significantly related to PATSAT (P < 0.001), VAS patient global (P < 0.001), and ESR (P < 0.01). PATSAT and VAS patient global were reasonably different (kappa = 0.226). The median PMR-AS score in patients with PATSAT score 1 and VAS patient global <10 was 0.7 (range 0-3.3), and the respective 75th percentile was 1.3. To enhance applicability, a range from 0 to 1.5 was proposed to define remission in PMR. The median ESR in these patients was 10 mm/hour (range 3-28), indicating external validity.

We demonstrated the reliability, validity, and applicability of the PMR-AS in daily routine. Moreover, we proposed a remission threshold (0-1.5) founded on patient-dependent parameters.

IGF-I stimulates multiple functions of connective tissue cells and its activity is modulated by IGF-binding proteins (BPs). Some metalloproteinases are expected to modify IGF-I activity by digestion of IGF-BPs. It was decided to evaluate the concentration of IGF-I, IGF-BPs and the activity of gelatinases A and B in knee exudates of children with post-traumatic damage (PTD) and children with juvenile idiopathic arthritis (JIA) in comparison with those in the sera of the same patients. ELISA (for IGF-I assay), polyacrylamine gel electrophoresis following Western immunoblotting (for IGF-I and IGF-BPs expression), and zymography (for gelatinase detection) were used. The knee exudates, especially those taken from patients with JIA, contained large amounts of IGF-I. The exudates of PTD and JIA patients contained some forms of IGF-BP-1 of molecular weight lower than those occurring in serum. Low expression BP-3 and high activity of gelatinase B were detected in the JIA exudates.

The high gelatinase activities in exudates imply joint tissue damage. The cellular response to damage of this kind is an increase in IGF-I production, which stimulates repair processes. High proteolytic activities of gelatinase B in JIA patients may lower the amount of BP-3, possibly causing a relative decrease of IGF-I concentration and impairing the reparation processes stimulated by IGF-I.

To describe the prevalence of greater trochanteric pain syndrome (GTPS); to determine whether GTPS is associated with iliotibial band (ITB) tenderness, knee osteoarthritis (OA), body mass index (BMI), or low back pain (LBP); and to assess whether GTPS is associated with reduced hip internal rotation, physical activity, and mobility. Cross-sectional, population-based study. Multicenter observational study. Community-dwelling adults (N=3026) ages 50 to 79 years. Not applicable. Greater trochanteric tenderness to palpation in subjects with complaints of hip pain and no signs of hip OA or generalized myofascial tenderness. The prevalence of unilateral and bilateral GTPS was 15.0% and 8.5% in women and 6.6% and 1.9% men. Odds ratio (OR) for women was 3.37 (95% confidence interval [CI], 2.67-4.25), but age and race were not significantly associated with GTPS. In a multivariate model, adjusting for age, sex, ITB tenderness, ipsilateral and contralateral knee OA, BMI, and LBP, ITB tenderness (OR=1.72; 95% CI, 1.34-2.19), knee OA ipsilaterally (OR=3.47; 95% CI, 2.72-4.42) and contralaterally (OR=1.74; 95% CI, 1.32-2.28), and LBP (OR=2.79; 95% CI, 2.22-3.50) were positively related to GTPS. In this complete model, BMI was not associated with GTPS (OR=1.10; 95% CI, 0.80-1.52 when comparing >or=30 with <25kg/m(2)). Hip internal rotation range of motion did not differ based on GTPS status. After multivariate adjustment, GTPS did not alter physical activity score, but bilateal GTPS was significantly associated with a higher 20-meter walk time and chair stand time.

The higher prevalence of GTPS in women and in adults with ITB pain or knee OA indicates that altered lower-limb biomechanics may be related to GTPS. Slower functional performance in those with GTPS suggests that the study of targeted rehabilitation may be useful. A longitudinal study will be necessary to identify causal factors and outcomes of interventions.

To prospectively examine the association between leukocyte telomere length (LTL) and subsequent rheumatoid arthritis (RA) development in women. Using a case-control design nested within the prospective Nurses' Health Study (NHS), NHS II (NHSII), and Women's Health Study (WHS), each validated case of RA with a prediagnostic blood sample was matched to 3 controls by cohort, age, menopausal status, postmenopausal hormone therapy, and blood collection covariates. We measured telomere length in genomic DNA extracted from stored buffy coat samples using quantitative PCR. We used unconditional logistic regression to determine OR and 95% CI, and random-effects metaanalysis to combine study results. In total, we analyzed 296 incident RA cases and 827 matched controls. Mean age of diagnosis among women who developed RA was 60.5 in NHS/NHSII and 61.3 in WHS. Metaanalysis demonstrated that longer prediagnostic LTL was associated with increased RA risk when women in the longest versus shortest LTL tertile were compared (OR 1.51, 95% CI 1.03-2.23, Pheterogeneity = 0.27). However, statistically significant between-study heterogeneity was observed for the intermediate tertile category (Pheterogeneity = 0.008). We did not observe heterogeneity by menopausal status, inflammatory cytokine levels, age at diagnosis, age at blood collection, body mass index, seropositivity, or HLA-DRβ1 shared epitope status.

Our results do not support an involvement for short LTL preceding RA development.

To compare the efficacy and safety of intraarticular hylan and 2 hyaluronic acids (HAs) in osteoarthritis (OA) of the knee. This was a multicenter, patient-blind, randomized controlled trial in 660 patients with symptomatic knee OA. Patients were randomly assigned to receive 1 cycle of 3 intraarticular injections per knee of 1 of 3 preparations: a high molecular weight cross-linked hylan, a non-cross-linked medium molecular weight HA of avian origin, or a non-cross-linked low molecular weight HA of bacterial origin. The primary outcome measure was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at 6 months. Secondary outcome measures included local adverse events (effusions or flares) in injected knees. During months 7-12, patients were offered a second cycle of viscosupplementation. Pain relief was similar in all 3 groups. The difference in changes between baseline and 6 months between hylan and the combined HAs was 0.1 on the WOMAC pain score (95% confidence interval [95% CI] -0.2, 0.3). No relevant differences were observed in any of the secondary efficacy outcomes, and stratified analyses provided no evidence for differences in effects across different patient groups. There was a trend toward more local adverse events in the hylan group than in the HA groups during the first cycle (difference 2.2% [95% CI -2.4, 6.7]), and this trend became more pronounced during the second cycle (difference 6.4% [95% CI 0.6, 12.2]).

We found no evidence for a difference in efficacy between hylan and HAs. In view of its higher costs and potential for more local adverse events, we see no rationale for the continued use of hylan in patients with knee OA.

To investigate whether all-cause mortality and deaths due to cardiovascular disease are increased in patients who have consulted primary or secondary health care with symptoms and signs of osteoarthritis (OA). This study included 383 patients with symptomatic OA at multiple sites from the Genetics ARthrosis and Progression (GARP) study (mean age 60 years, 82% women, 3693 person-years of follow-up) and 459 patients with primary hand, knee, or hip OA from the Osteoarthritis Care Clinic (OCC) study (mean age 61 years, 88% women, 1890 person-years of follow-up). Standardized mortality ratios (SMRs) with 95% confidence intervals (CIs) were calculated for all-cause mortality and causes of deaths in comparison to the general population. Cox proportional hazard ratios (HRs) with 95% CIs were used to associate baseline characteristics with all-cause mortality. In the GARP study, 26 patients died whereas 48 deaths were expected (SMR 0.54, 95% CI 0.37-0.79). The SMR was 0.47 (95% CI 0.29-0.76) in women and 0.73 (95% CI 0.39-1.35) in men. Similar results were found in the OCC study (SMR 0.45, 95% CI 0.25-0.82). Malignancy and cardiovascular disease were the main causes of deaths in GARP. Male sex (HR 3.04, 95% CI 1.38-6.69), increasing age (HR 1.10, 95% CI 1.05-1.16), and self-reported cancer (HR 8.29, 95% CI 3.12-22.03) were associated with increased mortality in GARP.

Patients consulting health care for their OA are not at higher risk of death than the general population. These results suggest that the management of OA patients may not need to focus specifically on the treatment of cardiovascular risk factors and comorbidities.

To determine the prevalence of sicca symptoms, dry eye, and secondary Sjögren's syndrome and to evaluate the severity of dry eye in patients with mixed connective tissue disease. In total, 44 consecutive patients with mixed connective tissue disease (Kasukawa's criteria) and 41 healthy controls underwent Schirmer's test, a tear film breakup time test, and ocular surface staining to investigate dry eye. In addition, the dry eye severity was graded. Ocular and oral symptoms were assessed using a structured questionnaire. Salivary gland scintigraphy was performed in all patients. Classification of secondary Sjögren's syndrome was assessed according to the American-European Consensus Group criteria. The patients and controls had comparable ages (44.7±12.4 vs. 47.2±12.2 years) and frequencies of female gender (93 vs. 95%) and Caucasian ethnicity (71.4 vs. 85%). Ocular symptoms (47.7 vs. 24.4%) and oral symptoms (52.3 vs. 9.7%) were significantly more frequent in patients than in controls. Fourteen (31.8%) patients fulfilled Sjögren's syndrome criteria, seven of whom (50%) did not have this diagnosis prior to study inclusion. A further comparison of patients with mixed connective tissue disease with or without Sjögren's syndrome revealed that the former presented significantly lower frequencies of polyarthritis and cutaneous involvement than did the patients without Sjögren's syndrome. Moderate to severe dry eye was found in 13 of 14 patients with mixed connective tissue disease and Sjögren's syndrome (92.8%).

Sjögren's syndrome, particularly with moderate to severe dry eye, is frequent in patients with mixed connective tissue disease. These findings alert the physician regarding the importance of the appropriate diagnosis of this syndrome in such patients.

Rheumatoid arthritis (RA) is in most instances a progressive disease. Very little information is available on halting of the radiographic damage, particularly in later phases of the disease. We studied radiographic remission of RA lasting to the end of follow-up, covering the period 1973-96. Radiographs of hands and feet were taken at onset and at 1, 3, 8, 15 and 20 years from entry in 102 cases of recent onset (< 6 months) seropositive and erosive RA. A Larsen score of 0-100 was formed for 20 joints of hands and feet. If the score did not worsen by more than one point between one of the above time points and the end of the study, the patient was considered to be in remission. Remission was confirmed in 27 (26%) of the patients. In 3 cases the remission was from the 1-year check-up, in 5 from the 3-year check-up, in 6 from the 8-year check-up and in 13 cases from the 15-year check-up. Some of the remission cases had a mild disease from the outset, but there were cases in which the disease process had led to marked joint destruction before slowing down.

This data may serve as a basis for comparison with subsequent cohort studies on new treatments-of-choice.