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The fixed combination of diclofenac sodium and misoprostol (Arthrotec) is the only nonsteroidal antiinflammatory drug (NSAID) that contains a gastroprotective component and is available in 2 formulations:(1) an enteric coated core of diclofenac sodium 50 mg surrounded by a mantle of misoprostol 200 microg, and (2) a 75 mg enteric coated diclofenac core also surrounded by a 200 microg mantle of misoprostol. This article reviews the European clinical experience with both formulations in patients with arthritis. Three randomized, blinded, multicenter studies, including one in general practice, evaluated the efficacy of combination diclofenac/misoprostol versus diclofenac or ibuprofen in a total of 1824 patients with rheumatoid arthritis (RA) or osteoarthritis (OA). Four additional studies assessed antiarthritic efficacy and employed endoscopy to compare the gastroduodenal safety of combined diclofenac50/misoprostol with that of diclofenac, naproxen, piroxicam, or indomethacin in 1459 patients with RA, OA, or ankylosing spondylitis. The gastroduodenal safety and antiarthritic efficacy of diclofenac75/misoprostol was compared with that of diclofenac in one endoscopy study involving 514 patients with RA or OA. The efficacy and safety data obtained from these European clinical trials show that both formulations diclofenac50/misoprostol and diclofenac75/misoprostol are effective antiinflammatory drugs, with clinical efficacy equivalent to that of diclofenac. Diclofenac50/misoprostol is at least as effective as naproxen, piroxicam, indomethacin, and ibuprofen. Both formulations of the combination were associated with significantly fewer gastroduodenal ulcers compared with diclofenac. In separate studies, the tolerability of diclofenac50/misoprostol (as determined by withdrawal rates) was shown to be equivalent to that of diclofenac, naproxen, piroxicam, and ibuprofen, and the tolerability of diclofenac75/misoprostol was shown to be equivalent to that of diclofenac. The diclofenac50/misoprostol was associated with fewer decreases in hemoglobin concentration compared with diclofenac in the general practice study as well as in hospital patients.

Diclofenac50/misoprostol and diclofenac75/misoprostol are effective in treating the signs and symptoms of RA and OA and are well tolerated by the majority of patients. Both of these formulations achieve a significant reduction in the incidence of both gastric and duodenal ulcers compared with other NSAID.

To evaluate the effectiveness of multidisciplinary foot-care, and to evaluate the methodological considerations of a trial of multidisciplinary care in juvenile idiopathic arthritis. Exploratory randomised controlled trial. Children/adolescents with juvenile idio-pathic arthritis and inflammatory joint disease affecting the foot/ankle. Standard medical care was compared with a 12 month program of multidisciplinary foot-care informed by musculoskeletal ultrasound. This program was centred on strict disease control through rigorous examination and interventions delivered by a team comprised of a paediatric rheumatologist, podiatrist, physiotherapist and musculoskeletal ultrasonographer. Patients were assessed on foot impairment and disability scores using the Juvenile Arthritis Foot Disability Index. Forty-four participants, aged 3-17 years were randomly assigned to receive the experimental (n = 21) or usual care (n = 23) interventions. There was an overall improvement in levels of foot related impairments in both groups over 12 months. Between-group differences in change scores for the Juvenile Arthritis Foot Disability Index were not statistically significant at 6 or 12 month follow-ups.

The integrated multidisciplinary foot care interventions described in this trial were safe, but did not improve foot impairment levels relative to usual care. This trial identified several methodological challenges including recruitment/retention, difficulties with outcome tools and potential confounders.

To develop a pharmacokinetic-pharmacodynamic disease progression (PK/PD/DIS) model to characterize the effect of etanercept in collagen-induced arthritis (CIA) rats on rheumatoid arthritis (RA) progression. The CIA rats received either 5 mg/kg intravenous (IV), 1 mg/kg IV, or 5 mg/kg subcutaneous (SC) etanercept at day 21 post-disease induction. Effect on disease progression was measured by paw swelling. Plasma concentrations of etanercept were assayed by enzyme-linked immunosorbent assay (ELISA). PK profiles were fitted first; parameter estimates were applied to fit paw edema data for PD and DIS-related parameter estimation using ADAPT 5 software. The model contained a two-compartment PK model with Michaelis-Menten elimination. For SC administration, two additional mathematical functions for absorption were added. The disease progression component was an indirect response model with a time-dependent change in paw edema production rate constant (k(in)) assumed to be inhibited by etanercept.

Etanercept has modest effects on paw swelling in CIA rats. The PK and PD profiles were well described by the developed PK/PD/DIS model, which may be used for other anti-cytokine biologic agents for RA.

To explore the link between a patient acceptable symptom state (PASS) and patient-perceived impact in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). This was a cross-sectional study of unselected patients with definite RA or PsA. Pain, functional capacity, fatigue, coping, and sleep disturbance were assessed using a numeric rating scale (0-10) and compared between patients in PASS or not (Cohen's effect sizes). The domains of health associated with PASS status were assessed by multivariate forward logistic regression, and PASS thresholds were determined using the 75th percentile method and receiver operating characteristic analyses. Among 977 patients (531 with RA, 446 with PsA), the mean ± SD age was 53.4 ± 13.2 years, mean ± SD disease duration was 11.2 ± 10.0 years, and 637 (65.8%) were women. In all, 595 patients (60.9%) were in PASS; they had lower symptom levels, and all domains of health except sleep disturbance discriminated clearly between patients in PASS or not (effect sizes 0.73-1.45 in RA and 0.82-1.52 in PsA). In multivariate analysis, less pain and better coping were predictive of being in PASS. Odds ratios were: RA pain 0.80 (95% confidence interval [95% CI] 0.67-0.96), PsA pain 0.63 (95% CI 0.52-0.75), RA coping 0.84 (95% CI 0.74-0.96), and PsA coping 0.83 (95% CI 0.71-0.97). The cutoffs of symptom intensity (range 0-10), corresponding to PASS for the 5 domains of health and the 2 diseases were similar, i.e., approximately 4-5.

In RA and PsA, PASS was associated with the 5 domains of health analyzed, and in particular with less pain and better coping.

To describe the clinical features and familial distribution of rheumatoid arthritis (RA) in the Pima Indians. From 1965 through 1990, all cases of RA as defined by the American College of Rheumatology (formerly, the American Rheumatism Association) 1987 criteria or all cases of seropositive, erosive disease as defined by the Rome criteria were identified in individuals who were age 20 years and older and were of 50% or more Pima/Tohono-O'odham heritage. Radiographs were reviewed by 2 musculoskeletal radiologists who were blinded to case status. Kinship coefficients were used to evaluate familial aggregation. Eighty-eight RA cases were identified from this population-based sample. Over 66% of the cases had seropositive disease, over 60% had erosive disease, and over 40% had subcutaneous nodules. Of the 88 RA cases, 40 were members of families with more than 1 RA case. The remainder were simplex cases.

In this population, clinical markers of severe RA were present in a majority of cases. The presence of familial aggregation for RA in the Pima Indians suggests underlying genetic factors in disease pathogenesis.

To compare the accuracy of serum biomarkers for the diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA) during tocilizumab therapy. Serum cytokine levels of neopterin, IL-18, C-X-C motif chemokine ligand 9, soluble tumor necrosis factor receptor (sTNFR)-I, and sTNFR-II were determined by enzyme-linked immunosorbent assay in 36 patients with MAS complicating s-JIA including 12 patients receiving tocilizumab. Furthermore, the serum sTNFR-II/I ratio was compared with the clinical features of MAS. The levels of all serum cytokines at MAS diagnosis were significantly lower in the tocilizumab-treated group than in the tocilizumab-untreated group. In contrast, the serum sTNFR-II/I ratio at MAS diagnosis was comparable between the tocilizumab-treated and the tocilizumab-untreated groups. The receiver operating characteristic curve analysis revealed that the area under the curve and cut-off values of sTNFR-II/I ratio were 0.9722 and 4.71, respectively. The serum sTNFR-II/I ratio, which was significantly elevated in patients with MAS complicating s-JIA, was correlated positively with disease activity. This is the first study to analyze the role of tocilizumab in modifying the serum levels of biomarkers used for the diagnosis of MAS complicating s-JIA. We found the biomarker for the diagnosis of MAS complicating s-JIA during tocilizumab therapy. We hope our results might be useful for the development of a new criteria for the diagnosis of MAS complicating s-JIA in patients treated with tocilizumab in future.

These findings suggest that the serum sTNFR-II/I ratio might be a useful indicator to evaluate disease activity in MAS complicating s-JIA and a useful diagnostic marker for the transition from active-phase s-JIA to MAS even in tocilizumab-treated patients.

To summarise important findings from biomarker studies relevant to osteoarthritis (OA), published between April 2016 and March 2017; to consider these findings in the context of new discoveries and technologies, and clinical and scientific need in OA. Studies were selected by PubMed search, conducted between 01/04/2016 and 01/03/2017. MeSH terms [biomarker] AND [OA] were used; the search was restricted to Human, English language and Full Text Available publications, which yielded 50 eligible publications. Any biomarker was considered, including non-proteins and other clinical measurements. Three main areas are overviewed: 1) Studies examining highly validated biomarkers, in the FNIH OA Biomarkers Consortium and elsewhere, particularly their ongoing application and validation. Control reference intervals, work on predictive validity and other longitudinal studies examining prognostic value of biomarkers in large cohorts are reviewed. 2) Novel studies relating to biomarkers of inflammation are discussed, including complement, the performance of markers of so-called 'cold inflammation' and results from clinical trials including biomarkers. 3) Discovery studies, including whole blood RNA, proteomics and metabolomics are reviewed, with an emphasis on new technologies.

Discovery, characterisation and qualification of various biomarkers is ongoing; several novel protein and non-protein candidate biomarkers have been reported this year. Biomarkers provide us with an opportunity to better diagnose and stratify the disease, via established panels or new discovery approaches. Improving quality of sampling and testing, and measuring large numbers of markers simultaneously in large cohorts would seem likely to identify new clinically applicable biomarkers, which are still much needed in this disease.

To describe a scoring system for quantification of cartilage lesions (Cartilage Lesion Score [CaLS]), to determine its reproducibility, to examine the association of CaLS-detected longitudinal change with known risk factors for osteoarthritis (OA) progression by comparing a group of subjects with OA risk factors with a group of subjects without OA risk factors, and to compare the CaLS system with the established semiquantitative Whole-Organ Magnetic Resonance Imaging Score (WORMS) and Boston-Leeds Osteoarthritis Knee Score (BLOKS) systems in terms of detection of cartilage defect progression. All subjects provided written informed consent, and the local institutional review board approved this HIPAA-compliant study. Fifty-two subjects with and 25 subjects without risk factors for knee OA were randomly selected from the Osteoarthritis Initiative. Inclusion criteria were age of 45-60 years, body mass index of 19-27 kg/m(2), and no knee pain or OA on radiographs at baseline. Baseline and 24-month follow-up right knee 3-T magnetic resonance images were analyzed with WORMS, BLOKS, and CaLS systems. Progression of cartilage lesions with each scoring system was compared by using multilevel mixed-effects linear-regression models. κ values were calculated to determine reliability. Intraclass coefficient values for inter- and intraobserver reliability of the CaLS system were 0.86 and 0.91, respectively. Interobserver κ value range for individual features was 0.81-0.94. The CaLS system enabled significantly higher detection of cartilage lesion progression than did WORMS or BLOKS systems (P < .001); 51.8% (56 of 108), 17.6% (19 of 108), and 13.0% (14 of 108) of the lesions progressed when analyzed with the CaLS, WORMS, and BLOKS systems, respectively. With the CaLS system, subjects with OA risk factors had significantly higher odds of progression than did subjects without risk factors (odds ratio, 2.78; P = .005).

The CaLS system is a reproducible scoring system for cartilage lesions that yields an improved detection rate for monitoring progression when compared with detection rates of semiquantitative WORMS and BLOKS systems.

The interferon (IFN) signature is related to disease activity and vascular disease in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) and represents a promising therapeutic target. Quantification of the IFN signature is currently performed by gene expression analysis, limiting its current applicability in clinical practice. Therefore, the objective of this study was to establish an easy to measure biomarker for the IFN signature. Serum levels of galectin-9, CXCL-10 (IP-10) and tumour necrosis factor receptor type II (TNF-RII) were measured in patients with SLE, SLE+APS and primary APS (PAPS) and healthy controls (n=148) after an initial screening of serum analytes in a smaller cohort (n=43). Analytes were correlated to measures of disease activity and the IFN signature. The performance of galectin-9, CXCL-10 and TNF-RII as biomarkers to detect the IFN signature was assessed by receiver operating characteristic curves. Galectin-9, CXCL-10 and TNF-RII were elevated in patients with SLE, SLE+APS and PAPS (p<0.05) and correlated with disease activity and tissue factor expression. Galectin-9 correlated stronger than CXCL-10 or TNF-RII with the IFN score (r=0.70, p<0.001) and was superior to CXCL-10 or TNF-RII in detecting the IFN signature (area under the curve (AUC) 0.86). Importantly, in patients with SLE(±APS), galectin-9 was also superior to anti-dsDNA antibody (AUC 0.70), or complement C3 (AUC 0.70) and C4 (AUC 0.78) levels in detecting the IFN signature.

Galectin-9 is a novel, easy to measure hence clinically applicable biomarker to detect the IFN signature in patients with systemic autoimmune diseases such as SLE and APS.

Explore the potential use of a cytokine panel as biochemical markers of disease activity in rheumatoid arthritis (RA) patients. 57 adult RA patients were assessed using five validated clinical disease activity tools: Health Assessment Questionnaire (HAQ), standard 28-joint Disease Activity Score (DAS28), DAS28 using C-reactive protein (DAS28-CRP), Clinical Disease Activity Index (CDAI), and Simple Disease Activity Index (SDAI). Plasma cytokine levels (IL-2, IL-4, IL-6, IL-8, IL-10, VEGF, IFN-γ, TNF-α, IL1α, IL1β, MCP1, and EGF) were measured in 47 of the 57 patients and correlated with clinical indicators. We found significant correlations between plasma levels of IL-6 and all clinical measures of disease activity; Spearman coefficients (p values) were: HAQ: 0.347(0.017); DAS28: 0.409(0.005); DAS-CRP: 0.378(0.011); CDAI: 0.312(0.033); SDAI: 0.310(0.039); ESR: 0.448(0.002); and CRP: 0.513(0.001). IFN-γ also correlated with DAS-CRP: 0.309(0.039) and SDAI: 0.301(0.044). Furthermore, the levels of IL-6 and IFN-γ increased significantly with worsening disease, as defined by the European League Against Rheumatism (EULAR) classification of disease activity.

A significant correlation between plasma levels of IL-6 and clinical disease activity in patients with RA suggests a future role of IL6 as a disease activity marker.

Recurrent macrophage activation syndrome (MAS) is rarely reported. To describe recurrent MAS in a 2.5-year-old girl with systemic juvenile idiopathic arthritis and heterozygous perforin mutation, which may have a role in the patient's first recurrence despite use of the HLH-2004 treatment protocol. In the presented case, MAS was initially controlled after the addition of etoposide to the treatment regimen. However, recurrence occurred 6.5 months after cessation of the HLH-2004 protocol. Subsequent recurrences may have occurred because of the family's noncompliance with treatment.

The patient's extremely high serum ferritin level (267,054 ng/mL) and the recurrent course of MAS may have been because of the coexistence of juvenile idiopathic arthritis and heterozygous perforin W374X mutation. We suggest to search for mutations in HLH genes in recurrent MAS cases.

The aim of this study was to investigate factors that predict a decrease in serum 25(OH)D among Japanese patients with rheumatoid arthritis (RA). In 2011 and 2013, serum 25(OH)D was evaluated in the same 2534 Japanese patients with RA (2179 women and 355 men) who participated in the Institute of Rheumatology Rheumatoid Arthritis (IORRA) cohort study. A vitamin D deficiency was defined as serum 25(OH)D levels <20 ng/mL. Predictive factors resulting in decreased serum 25(OH)D over a 2-year period were evaluated using multivariate logistic regression. The prevalence of vitamin D deficiency was 73.3% in 2011 and 68.2% in 2013. Serum 25(OH)D levels decreased by >5 ng/mL from 2011 to 2013 in 224 (8.8%) patients. A serum 25(OH)D decrease of >5 ng/mL was significantly associated with female gender, younger age, and disuse of bisphosphonates among all patients, and younger age, higher Japanese health assessment questionnaire disability index (JHAQ-DI), increased tender joint counts, and disuse of bisphosphonates and/or active vitamin D

Female gender, younger age, JHAQ-DI, tender joint counts, and disuse of bisphosphonates and/or active vitamin D

Leptin is an adipokine that participates in the regulation of the immune and inflammatory response. Chronic systemic inflammation contributes to the development of cardiovascular (CV) disease in rheumatoid arthritis (RA). In this study, we aimed to assess the short-term effect of the anti-IL-6 receptor tocilizumab (TCZ) administration on circulating leptin concentrations in patients with RA, as well as the potential association of leptin with CV risk factors and demographic and clinical characteristics of these patients. We recruited 50 consecutive non-diabetic patients with RA undergoing periodic treatment with TCZ. Leptin serum levels were determined by a commercial immunoassay kit in samples obtained immediately prior to (pre-infusion) and 60 minutes after the end of a TCZ intravenous infusion (post-infusion). A significant reduction of leptin levels was observed following the TCZ infusion (9.24±7.98 ng/mL vs. 7.92±7.32 ng/mL, pre- and post-infusion, respectively, p=0.002). Additionally, there was a strong positive correlation between body mass index of RA patients and basal levels of leptin (r=0.56; p=0.0001). Moreover, high basal levels of leptin in RA patients were associated with female sex (p=0.006), obesity (p<0.001) and rheumatoid factor negative status (p=0.006).

Our study disclosed a short-term effect of anti-IL-6 therapy on leptin serum levels in RA patients. Decreased leptin levels may explain the beneficial effect of anti-IL-6 blockade on CV disease associated to RA.

We sought to investigate the long-term outcomes of patients who develop immune checkpoint inhibitor (ICI)-induced inflammatory arthritis (IA), to define factors associated with IA persistence after ICI cessation, the need for immunosuppressants and the impact of these medications on underlying malignancies. We conducted a prospective observational study of patients referred for IA associated with ICIs. Patients were recruited from June 2015 to December 2018. Information was obtained at the baseline visit, and follow-up visits occurred at varying intervals for up to 24 months from ICI cessation. Kaplan-Meier curves were developed to characterise IA persistence. Cox proportional hazards models were used to assess the influence of various factors on IA persistence. Logistic regression was used to evaluate the impact of IA treatment on tumour response. Sixty patients were monitored with a median follow-up after ICI cessation of 9 months. A majority (53.3%) had active IA at their most recent follow-up. IA was less likely to improve in those with longer duration of ICI use, in those receiving combination ICI therapy, and in patients with multiple other immune-related adverse events. Tumour response did not appear to be impacted by immunosuppression. Although not statistically significant, persistent IA was correlated with a better tumour response (complete or partial response).

ICI-induced IA can become a long-term disease necessitating management by rheumatology for immunomodulatory treatment. Importantly, the use of immunomodulatory treatment has not been shown to impact cancer outcomes in this study.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects approximately 1.5 million people in the US. Tumour necrosis factor (TNF)-α inhibitors have been shown to effectively treat and maintain remission in patients with moderately to severely active RA compared with conventional agents. The high acquisition cost of TNF-α inhibitors prohibits access, which mandates economic investigations into their affordability. The lack of head-to-head comparisons between these agents makes it difficult to determine which agent is the most cost effective. This study aimed to determine which TNF-α inhibitor was the most cost-effective agent for the treatment of moderately to severely active RA from the US healthcare payer's perspective. A Markov model was constructed to analyse the cost utility of five TNF-α inhibitors (in combination with methotrexate [+MTX]) versus MTX monotherapy using Bayesian methods for evidence synthesis. The model had a cycle length of 3 months and an overall time horizon of 5 years. Transition probabilities and utility scores were based on published studies. Total direct costs were adjusted to year 2009 $US using the medical component of the Consumer Price Index. All costs and QALYs were discounted at a rate of 3% per year. Patient response to the different strategies was determined by the American College of Rheumatology (ACR)50 criteria. One-way and probabilistic sensitivity analyses (PSAs) were performed to test the robustness of the base-case scenario. The base-case scenario was changed to ACR20 criteria (scenario 1) and ACR70 criteria (scenario 2) to determine the model's robustness. Cost-effectiveness acceptability curves and cost-effectiveness frontiers were used to estimate the cost-effectiveness probability of each treatment strategy. A willingness-to-pay (WTP) threshold was defined as three times the US GDP per capita ($US139,143 per additional QALY gained). Primary results were presented as incremental cost-effective ratios (ICERs). Etanercept+MTX was the most cost-effective treatment strategy in the base-case scenario up to a WTP threshold of $US2 185,497 per QALY gained. At a WTP threshold of greater than $US2 185,497 per QALY gained, certolizumab+MTX was the most cost-effective treatment strategy. One-way analyses showed that the base-case scenario was sensitive to the probability of achieving ACR50 criteria for MTX and each TNF-α inhibitor, and changes in the utility score for patients who achieved the ACR50 criteria. With the exception of infliximab, all of the TNF-α inhibitors were sensitive to drug cost per cycle. In the scenario analyses, certolizumab+MTX was a dominant treatment strategy using ACR20 criteria, but etanercept+MTX was a dominant treatment strategy using ACR70 criteria.

Etanercept+MTX was a cost-effective treatment strategy in the base-case scenario; however, the model was sensitive to parameter uncertainties and ACR response criteria. Although Bayesian methods were used to determine transition probabilities, future studies will need to focus on head-to-head comparisons of multiple TNF-α inhibitors to provide valid comparisons.

Sjogren's syndrome (SS) is among the most frequent autoimmune diseases and one of its most severe extraglandular manifestations is peripheral neuropathy. There is no consensus about peripheral neuropathy treatment in SS. Our aim is to identify studies proving the efficiency of immunosuppressive treatment on peripheral neuropathies in SS. The search was conducted on the PubMed (MEDLINE) database. Studies with patients diagnosed with SS and peripheral neuropathy were included. Treatment with one of the following was among inclusion criteria: glucocorticoids (GC), rituximab (RTX), azathioprine (AZA), mycophenolic acid (MMF), cyclophosphamide (CP), methotrexate (MTX), plasmapheresis or iv immunoglobulins (IV IG). A total of 116 results were found and abstracts were examined. 103 papers were excluded, and the remaining 13 papers were analyzed. They were 3 case series and 10 case reports, retrospective, totalizing 62 patients of which 22 (35.5%) received IV IG, 8 (13%) received RTX, 7 (11%) CP, and 5 (8%) received only GC. Drug associations containing corticosteroids were frequent. Of those 22 treated with IV IG, 18 patients improved (82%), and 4 stabilized (18%). IV IG was useful in sensory, motor and sensorimotor neuropathies. CP had good results in mononeuritis multiplex, while autonomic neuropathies responded well to GC or RTX. AZA, RTX, MTX, MMF or plasmapheresis were not used alone. Follow-up periods were heterogenous and the evaluation of the neuropathy was not systematic.

There is only low level evidence (retrospective case reports and case series). In most cases, IV IG treatment in patients with peripheral neuropathies and SS resulted in clinical improvement, while other therapies, such as RTX, corticosteroids and CP proved to be useful in a handful of cases.

Calcitonin is well-known for its inhibitory actions on bone-resorbing osteoclasts and recently potential beneficial effects on cartilage were shown. We investigated effects of salmon calcitonin (sCT) on the articular cartilage and bone, after destabilization of the medial meniscus (DMM) in normal and sCT over-expressing mice. Bone phenotype of transgenic (TG) C57Bl/6 mice over-expressing sCT at 6 months and 12 months was investigated by (1) serum osteocalcin and urinary deoxypyridinoline and (2) dynamic and normal histomorphometry of vertebrae bodies. In subsequent evaluation of cartilage and subchondral bone changes, 44 10-week old TG or wild-type (WT) mice were randomized into four groups and subjected to DMM or sham-operations. After 7 weeks animals were sacrificed, and knee joints were isolated for histological analysis. Trabecular bone volume (BV/TV) increased 150% after 6 months and 300% after 12 months in sCT-expressing mice when compared to WT controls (P<0.05). Osteoblast number, bone formation rate and osteocalcin measurements were not affected in TG mice over-expressing sCT. In WT animals, a 5-fold increase in the quantitative erosion index was observed after DMM, and the semi-quantitative OARSI score showed over 400% (P<0.001) increase, compared to sham-operated WT mice. DMM-operated TG mice were protected against cartilage erosion and showed a 65% and 64% (P<0.001) reduction, respectively, for the two histopathological evaluation methods.

sCT over-expressing mice had higher bone volume, and were protected against cartilage erosion. These data suggest that increased levels of sCT may hamper the pathogenesis of osteoarthritis (OA). However more studies are necessary to confirm these preliminary results.

To conduct a systematic review and longitudinal meta-analysis of early rheumatoid arthritis (RA) cohorts with long-term data on pain, fatigue or mental well-being. Searches using PUBMED, EMBASE and PyscInfo were performed to identify all early RA cohorts with longitudinal measures of pain, fatigue or mental well-being, along with clinical measures. Using longitudinal meta-analyses, the progression of each outcome over the first 60-months was estimated. Cohorts were stratified based on the median recruitment year to investigate secular trends in disease progression. Of 7,319 papers identified, 75 met the inclusion criteria and 46 cohorts from 41 publications provided sufficient data on 18,046 patients for meta-analysis. The Disease Activity Scores (DAS28) and the Short-Form 36 (SF-36) Physical Component Score (PCS) indicated that post-2002 cohorts had statistically significant improvements over the first 60-months compared to pre-2002 cohorts, with standardised mean differences (SMD) of 0.86 (95% Confidence Intervals 0.34 to 1.37) and 0.76 (95% CI 0.25 to 1.27) respectively at month-60. However, post-2002 cohorts indicated statistically non-significant improvements in pain, fatigue, functional disability and SF-36 Mental Component Score (MCS) compared to pre-2002 cohorts, with SMD of 0.24 (95% CI -0.25 to 0.74), 0.38 (95% CI -0.11 to 0.88), 0.34 (95% CI -0.15-0.84) and -0.08 (95% CI -0.41 to 0.58) at month-60 respectively.

Recent cohorts indicate improved levels of disease activity and physical quality of life, however this has not translated into similar improvements in levels of pain, fatigue and functional disability by 60-months.

Autophagy dysfunction has been reported in osteoarthritis (OA) cartilage. The objective of this study was to investigate the role of microRNA-155 (miR-155), which is overexpressed in OA, in the regulation of autophagy in human chondrocytes. Rapamycin (50 nM) and 2-deoxyglucose (2-DG) (5 mM) were used to stimulate autophagy in primary human articular chondrocytes and in the T/C28a2 human chondrocyte cell line. Cells were transfected with LNA GapmeR or mimic specific for miR-155 and autophagy flux was assessed by LC3 western blotting and by Cyto-ID(®) dye quantification in autophagic vacuoles. Expression of predicted miR-155 targets in the autophagy pathway were analyzed by real-time PCR and western blotting. Autophagy flux induced by rapamycin and 2-DG was significantly increased by miR-155 LNA, and significantly decreased after miR-155 mimic transfection in T/C28a2 cells and in human primary chondrocytes. These effects of miR-155 on autophagy were related to suppression of gene and protein expression of key autophagy regulators including Ulk1, FoxO3, Atg14, Atg5, Atg3, Gabarapl1, and Map1lc3.

MiR-155 is an inhibitor of autophagy in chondrocytes and contributes to the autophagy defects in OA.

We had noted cogwheel rigidity in a number of patients with rheumatoid arthritis (RA). Based on this finding, we aimed to investigate formally the presence of rigidity and cogwheeling in RA patients. Our secondary aim was to survey the co-existence of RA and Parkinson's disease (PD). A total of 87 consecutive patients with a diagnosis of RA, 78 patients with PD and 67 otherwise healthy patients attending a dedicated headache clinic participated in the study. Rigidity was observed in 24% of RA, 60% of PD and 2% of headache patients. The frequency among the RA patients was significantly higher compared to that of patients with headache (chi 2 = 15.2; P = 0.00009). The frequency of PD among the RA patients was 2/87 (2.3%), while the frequency of RA among the PD patients was 6/78 (7.7%).

Rigidity can be observed in approximately a quarter of patients with RA.

Antinuclear antibodies (ANA) and their identification are important diagnostic tools in rheumatic diseases. We aimed to determine their prevalence in samples referred for ANA testing and to identify factors predicting more specific reactivities. We analyzed the first sample of 6422 consecutive patients for ANA. Positive samples were analyzed by indirect immunofluorescence (IIF) on Crithidia luciliae and by line immunoassay. We used multivariate logistic regression to detect predicting variables. 42.6% of all patients were ANA positive of which 13.0% showed > or = one extractable nuclear antigen (ENA) reactivity with anti-SSA/Ro (5.5%), anti-SSB/La (2.9%), anti-Cenp-B (2.5%) and anti-histones (2.2%) as the most prevalent antibodies. Anti-double-stranded DNA antibodies (dsDNA) were present in 1.0%. The strongest overall predictor was ANA intensity regardless of pattern. Cenp-B however was best predicted by pattern. Anti-dsDNA and anti-histone were more frequent in samples with a homogenous as compared with a speckled pattern. Anti-SSA and anti-SSB were more frequent in females and anti-Sm in patients < or = 30 years.

The best overall predictor of antibodies to ENA or dsDNA is ANA intensity. Anti-Cenp-B is however best predicted by pattern. Samples with low ANA intensity (1+) may not need further testing unless a high clinical suspicion of ANA-associated disease.

To determine prognostic factors of disability in early rheumatoid arthritis (RA) and to investigate the radiological and functional course of the disease. A total of 191 patients with early RA (diagnosed for less than one year) according to American College of Rheumatology criteria were followed prospectively for 5 years. At baseline and at endpoint, Stanford Health Assessment Questionnaire (HAQ) scores and radiological scores (Sharp's score modified by van der Heijde) were performed. Correlations between numerous baseline data and HAQ score at endpoint were analyzed, using nonparametric tests. A multilinear regression model was performed to select independent prognostic factors of HAQ disability. During the 5-year followup, mean HAQ decreased from 1.3 (+/- 0.7) to 0.6 (+/- 0.6). There were 98 (65.3%) patients with a score > 1 point at baseline, but only 46 (27.4%) after 3 years and 34 (21.8%) after 5 years. Moreover, 90% of the patients had an improvement of the disability score. Final HAQ disability was associated with baseline values of HAQ score, Pain, Ritchie index, tender joint count, Disease Activity Score, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and erosion. Multivariate analysis selected baseline HAQ score, Ritchie index, ESR, CRP, and presence of erosion as independent prognostic factors of HAQ disability. The probability cutoff in the logistic model was selected to minimize the sum of false positive and false negative values: negative predictive value = 92.71%, positive predictive value = 46.15%, p = 0.408. Sex, age, IgM and IgA rheumatoid factors, other tested autoantibodies, and HLA class II genes did not contribute significantly to prediction of the disability after 5 years. At baseline, mean scores were 3.6 units (+/- 7.7) for total radiological score, 1.7 (+/- 4.5) for erosion score, and 1.9 (+/- 3.7) for joint space narrowing score. After 5 years, they were 17.9 +/- 22.3, 6.9 +/- 9.5, and 11.0 +/- 15.4, respectively. No erosion was present at the start in 58.0% of patients, compared to 24.2% and 22.4% at 3 and 5 years. Global radiographic progression concerned 87 patients (55.8%) during the 5 years.

During the first 5 years of RA, radiological damage increased progressively in half of the patients, whereas HAQ disability improved in most of them during the same period of time and could be predicted by baseline values of HAQ score, Ritchie index, ESR, CRP, and presence (or absence) of erosion.

To review the assessment and management of gout by general practitioners (GPs) and medical officers (MOs) within the Illawarra Network, Australia. A survey was sent to GPs and MOs within the Illawarra Network. Of 110 GPs, 45 responded. Of 129 MOs, 42 responded. The overall response was 32.6%. On analysis, 65.1% felt their knowledge of gout to be adequate and 61.6% thought they had been educated well. In acute assessment, 59.1% of GPs responded that the diagnosis of gout best be confirmed with a joint aspiration and 36.4% clinical suspicion. Differing, 85.7% of MOs chose a joint aspiration. In acute management, if colchicine were used, 59.1% of GPs would give 1 mg followed by 0.5 mg an hour later, then 0.5 mg twice daily, compared to 9.5% of MOs, while 20.5% of GPs would use 1 mg twice daily. Chronic management was answered poorly. After an acute attack, urate lowering therapy (ULT) would be started 14 days after by 47.7% of GPs, compared to 69.0% of MOs. GPs were more likely to start ULT within 7 days (52.3% vs. 31.0%). With dosing of ULT, 45.3% would treat to target, while 46.5% would dose to the creatinine clearance. Prophylactic therapy with ULT would be started by 81.8%, although only 17.4% would continue it for 3-6 months.

There is poor adherence to recommended practice for dosing of colchicine in acute gout. Also in the management of chronic gout, in particular, the timing of starting ULT and the use of prophylaxis when initiating ULT.

Traditional surgical techniques for radiolunate arthrodesis typically result in an unsatisfactory primary stability. Thus cast immobilisation is implemented until bone healing is complete. Nonunion and implant dislocation are frequent complications. Eighteen patients (20 wrists) with rheumatoid disease who had undergone a radiolunate arthrodesis procedure using a mini-titanium-T-plate with an oblique screw were examined. The high primary stability of this fusion depends on three point fixation. Complete bone healing was achieved in all wrists. Dislocation of a screw occurred in one wrist which subsequently healed in mild dislocation. Grip strength improved in 12 hands with pain relief in 19 wrists. 18 patients rated the result of the operation as "very good" or "good" and would agree to have the operation again.

The mini-titanium-T-plate with oblique screw achieves high primary stability via three point fixation of the lunate at the radius. Thus, postoperative immobilisation in a cast is unnecessary. The procedure is well tolerated by patients with a high satisfaction rating.

In previous studies, 50%-70% of patients referred to orthopedic surgeons for total knee replacement (TKR) were not surgical candidates at the time of initial assessment. The purpose of our study was to identify and cross-validate patient self-reported predictors of suitability for TKR and to determine the clinical utility of a predictive model to guide the timing and appropriateness of referral to a surgeon. We assessed pre-consultation patient data as well as the surgeon's findings and post-consultation recommendations. We used multivariate logistic regression to detect self-reported items that could identify suitable surgical candidates. Patients' willingness to undergo surgery, higher rating of pain, greater physical function, previous intra-articular injections and patient age were the factors predictive of patients being offered and electing to undergo TKR. Dans des études précédentes, de 50 % à 70 % des patients dirigés vers des chirurgiens orthopédistes pour une arthroplastie totale du genou (ATG) n’étaient pas des candidats à la chirurgie au moment de l’évaluation initiale. Notre étude visait à recenser et à contrevalider les facteurs prédictifs de l’opportunité d’une ATG fondés sur des renseignements fournis par les patients, ainsi qu’à déterminer l’utilité clinique d’un modèle de prévision qui évaluerait le moment et la pertinence de diriger un patient vers un chirurgien. Nous avons évalué les données des patients préconsultation ainsi que les conclusions du chirurgien et ses recommandations postconsultation. Nous avons mené une analyse de régression logistique multivariée pour détecter les éléments autodéclarés qui permettraient de reconnaître les candidats pour la chirurgie. Les facteurs permettant de prédire si un patient se ferait offrir une ATG et choisirait de subir l’intervention étaient la disposition favorable du patient à se faire opérer, une douleur d’intensité élevée, des capacités physiques fonctionnelles supérieures, des antécédents d’injections intra-articulaires et l’âge.

The application of the model developed in our study would effectively reduce the proportion of nonsurgical referrals by 25%, while identifying the vast majority of surgical candidates (> 90%). Using patient-reported information, we can correctly predict the outcome of specialist consultation for TKR in 70% of cases. To reduce long waits for first consultation with a surgeon, it may be possible to use these items to educate and guide referring clinicians and patients to understand when specialist consultation is the next step in managing the patient with severe osteoarthritis of the knee. Concrètement, l’application du modèle élaboré durant notre étude réduirait le nombre de patients dirigés vers un chirurgien sans motif valable dans une proportion de 25 %, tout en permettant de reconnaître la vaste majorité des candidats à la chirurgie (> 90 %). À partir des renseignements fournis par les patients, nous pouvons prédire correctement le résultat d’une consultation avec un spécialiste pour une ATG dans 70 % des cas. Les conclusions de notre étude pourraient servir à réduire les longs délais d’attente pour une première consultation avec un chirurgien en aidant les professionnels de la santé et les patients à déterminer quand il convient de consulter un spécialiste pour la prise en charge d’une gonarthrose grave.

Xerostomia (dry mouth) is a clinical symptom due to a number of factors, including Sjögren syndrome and radiation treatment to the head and neck region. It has been reported that acupuncture increases the salivary flow rate (SFR) in healthy subjects and in patients with xerostomia. A prognostic tool that would allow the care provider to identify patients who may respond to acupuncture treatment will aid in early intervention and thus lead to normalized SFR or relief of symptoms. To determine the prognostic value of a test using pilocarpine chloride to identify those patients with xerostomia who may achieve a long-term increase in SFR in response to acupuncture. Cohort clinical study of 10 months' duration. School of dentistry in a large, urban, research institute. Thirty-two consecutive patients with xerostomia due to radiation treatment (n = 21) or Sjögren syndrome (n=11). Salivary flow rates for unstimulated whole saliva and paraffin-chewing stimulated whole saliva were measured before and after the administration of individualized doses of pilocarpine. All patients were then given 24 acupuncture treatments and followed up at 1 and 6 months. The effects of acupuncture treatment on SFR were recorded and response compared with the results of the pilocarpine test. Sensitivity, specificity, and positive and negative predictive value of the pilocarpine test based on changes in SFR, defined as a 20% increase or greater, following acupuncture treatment, compared with response to the pilocarpine test. At the 1-month follow-up, 18 (72%) of 25 patients with a positive pilocarpine test result had defined significant changes in SFR; 4 (67%) of 6 patients with a negative pilocarpine test result had an unchanged SFR. At this point, the sensitivity of the pilocarpine test was 0.90 (95% confidence interval [CI], 0.68-0.99) and the specificity was 0.36 (95% CI, 0.11-0.69). The positive predictive value was 0.72 (95% CI, 0.51-0.88), and the negative predictive value was 0.67 (95% CI, 0.22-0.96). At the 6-month follow-up, 17 (74%) of 23 patients with a positive pilocarpine test result had defined significant changes in SFR; 3 (60%) of 5 patients with a negative pilocarpine test result had an unchanged SFR. At this point, the sensitivity of the pilocarpine test was 0.89 (95% CI, 0.67-0.99), and the specificity was 0.33 (95% CI, 0.07-0.70). The positive predictive value was 0.74 (95% CI, 0.52-0.90), and the negative predictive value was 0.60 (95% CI, 0.15-0.95).

The pilocarpine test was found to have a high sensitivity and good positive predictive value in identifying patients who may respond to acupuncture for the treatment of xerostomia.

Patients with hyperuricemia or gout often have metabolic syndrome. Few prospective studies have examined the risk of incident diabetes mellitus (DM) in patients with gout, and there are no data to indicate whether the risk of DM in gout differs by sex. Therefore, this cohort study was undertaken to examine the overall and sex-specific incidence rates of DM in patients with gout. Using data from a US commercial insurance plan (2003-2012), the overall and sex-specific incidence rates of DM in patients with gout (ages ≥40 years) were compared to those in patients with osteoarthritis (OA). Incident DM was defined as a diagnosis of DM and at least one dispensing of an antidiabetic drug. The sex-specific effect of gout on DM risk was also examined. The primary study cohorts consisted of 54,075 patients with gout and 162,225 patients with OA, matched for age, sex, and index date. In both cohorts, the mean age of the patients was 56.2 years, and 84.8% were men. Over a mean followup of 1.9 years, the incidence rate of DM was 1.91 per 100 person-years in patients with gout and 1.12 per 100 person-years in patients with OA. Multivariable Cox models adjusted for age, comorbidities, medications, and health care utilization factors revealed that gout was associated with an increased risk of DM (hazard ratio 1.45, 95% confidence interval [95% CI] 1.37-1.54) in both sexes. The impact of gout on the risk of incident DM was greater in women (hazard ratio 1.78, 95% CI 1.51-2.09) than in men (hazard ratio 1.41, 95% CI 1.33-1.50), with a significant interaction between gout and sex in relation to the risk of incident DM (P = 0.0009).

Gout was associated with an increased risk of developing DM compared to that in patients with OA after adjustment for potential confounders. In addition, the risk of incident DM associated with gout was higher among women than among men.

The goal of this study was to compare three types of mobile-bearing posterior cruciate ligament (PCL)-sacrificing TKA. The hypothesis was that the three designs provide differences in flexion stability and femoral rollback and improved clinical score at 2-year follow-up. Three groups of patients, divided according to implant design, were analysed retrospectively. All operations were guided by a non-image-based navigation system that recorded relative femoral and tibial positions in native and implanted knees during: passive range of motion and anterior drawer test at 90° flexion. WOMAC, KSS and SF36 scores were collected pre-operatively and at 2-year follow-up. There are no differences in kinematic or clinical performance of the three implants, except for the antero-posterior translation during stress test in flexion: only Cohort B had comparable pre- and post-operative laxity test values (p < 0.001). All three TKA designs allowed to maintain pre-operative tibial rotation pattern through all range of knee flexion. All clinical scores of the three patient cohorts were significantly improved post-operatively compared to the pre-operative values (p < 0.001). Moreover, we found no differences among post-operative results of the three designs. III.

Despite design variations, mobile-bearing PCL-sacrificing TKA reproduces femoral rollback and screw-home with little or no difference in clinical or functional scores at a follow-up of 2 years.

Although incidence and survival are frequent topics within the solid organ transplantation (SOT) literature, the size of the surviving SOT population is not well known. Existing studies of gout in patients with SOT have focused on the incident SOT population. This analysis was performed to characterize the prevalent SOT population and the prevalence of gout within it. This study includes the 2017 United States (US) population size of recipients of kidney, heart, liver, and lung transplants that was estimated by combining primary transplant recipient cohort sizes (1988-2017) with previously published survival rates for each annual cohort's time since transplantation (0-29 years). Gout among prevalent patients with SOT was assessed using Medicare and commercial claims. A total of 637,231 US patients received a primary kidney (393,953), liver (142,186), heart (66,637), or lung (34,455) transplant between 1988 and 2017. An estimated 356,000 (55.8%) recipients were alive in 2017 (233,000 kidney; 78,700 liver; 29,300 heart; 14,700 lung). Gout was identified in 11% of prevalent patients with SOT in 2016. Higher rates of gout were seen in recipients of kidney (13.1%) and heart (12.7%) compared to recipients of liver (6.7%) and lung (5.6%) (P < .0001 in both datasets). Active diagnosed gout prevalence in the US population without a SOT history was 1.1% in 2016.

Hundreds of thousands of US patients are living with a transplanted organ today and these numbers are likely to increase. In patients with SOT, gout is a frequent comorbidity of which physicians should be aware. This study suggests a markedly higher rate of gout among transplant recipients compared to the general US population.

We aimed to assess the relationship between bone inflammation in multi-pinhole single-photon emission computed tomography (MPH-SPECT) and synovitis detected by magnetic resonance imaging (MRI) in early rheumatoid arthritis patients. MPH-SPECT with technetium dicarboxypropanedisphosphonate (Tc-99mDPD) and 3 Tesla MRI were performed in 10 early rheumatoid arthritis patients. Eighty finger joint sites were assessed for increased osteoblastic activity using visual and region-of-interest (ROI) analysis. Presence of joint inflammation in MRI was investigated using the subscores of the rheumatoid arthritis MRI score. Tc-99mDPD uptake was increased in 38 (47.5%) and 22 (27.5%) joint sites as determined by visual and ROI analysis, respectively. A total of 32 (84.2%) sites with increased bone metabolism showed a normal MRI bone signal. The MPH-SPECT uptake ratio was elevated only in the subgroup with severe synovitis (P < 0.001).

In early rheumatoid arthritis, molecular imaging with MPH-SPECT detects higher rates of inflammatory bone involvement compared to MRI. Our preliminary data suggest that osteitis is related to severe synovitis.

To evaluate in patients with knee osteoarthritis (OA) the size changes in bone oedema and cysts over 24 months, and to contrast these changes with cartilage volume loss using quantitative magnetic resonance imaging. 107 patients with knee OA, selected from a large trial evaluating the effect of a bisphosphonate, were analysed by magnetic resonance imaging at baseline and 24 months. Assessments of subchondral bone oedema and cysts, and cartilage volume were done. At baseline, 86 patients showed the presence of at least one type of bone lesion: 71 oedema, 61 cysts and 51 both. At 24 months, although not statistically significant, the oedema total size change increased by 2.09 (SD 15.03) mm, and the cyst by 1.09 (8.13) mm; mean size change for the oedema was +0.38 (2.18) mm and -0.10 (4.36) mm for the cyst. When analysed according to subregions, an increase was found for the cyst size in the trochlea (+0.67 (2.74) mm, p = 0.02) and in the lateral tibial plateau (+0.15 (0.83) mm, p = 0.09), and for the oedema size in the medial tibial plateau (+1.73 (8.11) mm, p = 0.05). At 24 months, significant correlations were seen between the loss of cartilage volume and oedema size change in the medial condyle (-0.40, p = 0.0001) and the medial tibial plateau (-0.23, p = 0.03), and the changes in cyst size in the medial condyle (-0.29, p = 0.01). A multivariate analysis showed that the oedema size change was strongly and independently associated with medial cartilage volume loss (-0.31, p = 0.0004).

These data demonstrate that bone lesions are prevalent in knee OA. The correlation of the oedema and cyst size increase in the medial compartment over time with a greater loss of cartilage volume in this area underlines the importance of subchondral bone lesions in OA pathophysiology.

To determine whether the human herpes viruses, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6), are detectable in serum and peripheral blood mononuclear cells (PBMCs) of patients with rheumatoid arthritis (RA). 133 PBMC samples (61 RA, 72 healthy donors) and 136 serum samples (59 RA, 77 healthy donors) were analysed by quantitative real time polymerase chain reaction for DNA prevalence and viral load of HHV-6, EBV, and CMV. For PBMC samples significant differences were found for EBV in DNA prevalence (56% in RA v 33% in controls, p = 0.009) and viral load (copies/microg DNA 0-592.3 for RA v 0-40.4 for controls, p = 0.001). For serum samples a significant difference was found for HHV-6 DNA prevalence (10% in RA v 0% in controls, p = 0.006) and viral load (copies/microg DNA 0-529.1 for RA v 0 for controls, p = 0.007).

Herpes viruses may have a role in RA, although alternative explanations are possible: (a) defects in cellular immunity in patients with RA may result in a relatively high viral load; (b) patients with RA may be more prone to infection/reactivation. The usefulness of monitoring the DNA viral load in patients with RA is questioned by these data.

Lupus disease measures such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the British Isles Lupus Assessment Group (BILAG) index are challenging to interpret. The Lupus Foundation of America-Rapid Evaluation of Activity in Lupus (LFA-REAL) is intended to provide an efficient application of anchored visual analog scores, each representing the individual severity of active symptoms, with the sum of individual scores deriving an overall disease activity assessment. Our objective was to compare the performance of LFA-REAL to systemic lupus erythematosus disease activity assessments and compare scores between trained lupus clinical investigators and clinicians. Investigators scored the SLEDAI, BILAG, physician's global assessment (PGA), and LFA-REAL, while the clinicians scored the LFA-REAL. The level of agreement between physicians and instruments was determined. The study included 99 patients (93% women, 31% white, mean ± SD ages 43.4 ± 13.2 years). At the first visit, the mean ± SD SLEDAI score was 5.5 ± 4.5, BILAG score 6.7 ± 7.8, and PGA score 33.6 ± 24.5. The mean ± SD investigator LFA-REAL score was 46.2 ± 42.9, and clinician LFA-REAL score 56.1 ± 53.6. At the second visit, the mean ± SD investigator LFA-REAL score was 41.3 ± 36.7, and clinician LFA-REAL score 48.3 ± 42.6. Total LFA-REAL scores correlated positively with PGA, SLEDAI, and BILAG (ρ = 0.58-0.88, P < 0.001). LFA-REAL scores produced correlation coefficients of ρ > 0.7 for musculoskeletal, mucocutaneous, and renal BILAG domains. The intraclass correlation coefficient between the LFA-REAL scores of investigators and clinicians was 0.79 for visit 1 (P < 0.001) and 0.86 for visit 2 (P < 0.001).

The LFA-REAL provides a reliable surrogate for more complicated disease activity measures when used by lupus clinical investigators or clinicians.

In order to evaluate the prevalence of angiographically significant coronary artery disease (CAD) in patients with predominant mitral stenosis (mitral valve area < or = 1.5 cm2), coronary angiograms of the 837 consecutive patients with mitral stenosis (482 women and 355 men; median age = 50 years [ranging from 35 to 77]) were retrospectively analysed. Significant CAD was defined as at least 50% diameter narrowing of a major coronary artery. Significant CAD was detected in 63 patients (7.5%, 30 men and 33 women). Patients with CAD were significantly older than those without CAD (median: 59 vs. 49 years; p < 0.0001, respectively). With respect to coronary risk factors, diabetes mellitus (28.6% vs. 9.4%; p < 0.0001), hypertension (46% vs. 16.7%; p < 0.0001) and family history of CAD (34.9% vs. 17.3%; p = 0.001) were significantly more frequent in the CAD+ group as compared to the CAD- group. Serum levels of cholesterol were significantly higher in CAD+ group as compared to the CAD-patients (median: 199 vs. 176 mg/dl; p = 0.003). No significant differences were noted between the two groups in both serum levels of HDL-cholesterol (p = 0.12) and triglycerides (p = 0.08). Of the 63 patients with CAD, 21 (33.3%) had angina pectoris (AP) and, in patients free of CAD, AP was present in 106 (13.7%). The sensitivity and specificity of AP for the presence of significant CAD were 33.3% and 86.3%, respectively. The positive predictive value of AP for the presence of CAD was 16.5% and the negative predictive value of its absence was 94.1%.

It is concluded that routine coronary angiography is not necessarily indicated in predominant mitral stenosis particularly in patients who are younger than 40 years and have no coronary risk factors and typical chest pain.

To investigate the association of single nucleotide polymorphisms (SNPs) of the peptidylarginine deiminase IV (PADI4) and HLA-DRB1 shared epitope (SE) alleles with rheumatoid arthritis(RA) in a Chinese population. Four exonic SNPs of the PADI4 gene (PADI 4_89*A/G, PADI 4_90*C/T, PADI 4_92*C/G and PADI 4_104*C/T) were genotyped in 67 unrelated patients with RA and 81 healthy controls, using cDNA sequencing and T vector cloning. HLA-DRB 1*01, *04 and *10 subtypes were determined by polymerase chain reaction with sequence specific primers (PCR-SSP). The distributions of the 4 SNPs were different in the two groups, and increased RA susceptibility was significantly associated with the minor alleles of PADI 4_89*G (P was 0.023), PADI 4_90*T (P was 0.004), PADI 4_104*T (P was 0.003), and the haplotypes carrying the 4 minor alleles (P was 0.008). HLA-DRB1 SE alleles are composed of HLA-DRB 1*0101, *0102, *0401, *0404, *0405, *0408, *0409, *0410 and *1001. Individuals carrying the SE alleles were associated with increased RA susceptibility (P was 0.002). Individuals carrying both the SE alleles and minor alleles of the 4 SNPs were more susceptible to RA than individuals carrying neither the minor SNP alleles nor the SE alleles.

The PADI4 SNPs and haplotypes are associated with RA susceptibility in Chinese. HLA-DRB1 shared epitope is also an important risky factor for RA. There may exist certain synergistic effect between the PADI4 minor alleles and the HLA-DRB1 shared epitope.

To investigate responsiveness, discrimination, and construct validity of a composite change index (CCI) for the assessment of single-joint involvement in inflammatory arthritis. Evaluation of standardized response means (SRM), Guyatt effect size, and Spearman rank correlation coefficient in a randomized controlled trial investigating the effect of an intraarticular etanercept injection. The CCI showed a high SRM (1.68) and high Guyatt effect size (2.72). Both visual analog scale of pain and functionality had a moderate Guyatt effect size (2.06, 2.44) and high SRM (0.81, 0.97). NTR-1210.

This study supports the use of the CCI as a single-joint assessment after single-joint intervention.

To assess whether the American College of Rheumatology response criteria ACR20 should be replaced by another definition of response with enhanced discriminant validity. We worked with statisticians to define over 100 different ways of defining response, including dichotomous definitions (e.g., ACR20; ACR50; ACR70; low disease activity), ordinal definitions (EULAR response; ACR20, ACR50, ACR70), disease activity indexes [Disease Activity Score (DAS); Disease Activity Index, SDAI], continuous definitions (mean percentage improvement in all core set measures; nACR, ACRn), and hybrid definitions (ACR20, ACR50, ACR70 defined for a patient as 0, 1, 2, 3 scale with continuous measures between intervals) along with variations on each of these approaches (e.g., percentage vs absolute change in DAS; e.g., measures requiring vs not requiring joint count improvement). To test clinical validity, we administered a survey using patients from a trial who had various levels of improvement and asked rheumatologists whether and by how much these patients improved. For Sn-to-Chge, we are collecting data from large disease modifying antirheumatic drug multicenter trials in rheumatoid arthritis and ranking candidate definitions of response on their average p values in distinguishing active treatment from placebo or combination compared to single comparator. We surveyed 52 rheumatologists about which trial patients had improved and by how much. Trial data were obtained and tested for sensitivity to change.

A rigorous data-driven consensus process was used to reassess the ACR20.

The aims of this study were to describe the prevalence of previous lumbar surgery in patients who undergo total hip arthroplasty (THA) and to investigate their patient-reported outcomes (PROMs) one year post-operatively. Data from the Swedish Hip Arthroplasty Register and the Swedish Spine Register gathered between 2002 and 2012 were merged to identify a group of patients who had undergone lumbar surgery before THA (n = 997) and a carefully matched one-to-one control group. We investigated differences in the one-year post-operative PROMs between the groups. Linear regression analyses were used to explore the associations between previous lumbar surgery and these PROMs following THA. The prevalence of prior lumbar surgery was calculated as the ratio of patients identified with previous lumbar surgery between 2002 and 2012, and divided by the total number of patients who underwent a THA in 2012. The prevalence of lumbar surgery prior to THA in 2012 was 3.5% (351 of 10 082). Linear regression analyses showed an association with more pain (B = 4.35, 95% confidence interval (CI) 2.57 to 6.12), worse EuroQol (EQ)-5D index, (B = -0.089, 95% CI -0.112 to -0.066), worse EQ VAS (B = -6.75, 95% CI -8.58 to -4.92), and less satisfaction (B = 6.04, 95% CI 4.05 to 8.02).

Lumbar spinal surgery prior to THA is associated with less reduction of pain, worse health-related quality of life, and less satisfaction one year after THA. This is useful information to share in the decision-making process and may help establish realistic expectations of the outcomes of THA in patients who also have previously undergone lumbar spinal surgery. Cite this article:

Bleeding on probing (BOP) is a frequent observation in patients with Sjögren's syndrome and a sialagogue is routinely prescribed for these patients. The objective of this study was to evaluate the effect of sialagogue (muscarinic cholinergic agonists) on BOP in patients with Sjögren's syndrome. This observational study included 57 subjects. Study population was divided into two groups: Subjects on sialagogue (n = 32) and subjects not on sialagogue due to their side-effects (non-sialagogue, n = 25). The number of sites with BOP was recorded on all teeth. The subjects on sialagogue had a significantly lower mean (standard error) number of sites with BOP 22.97 (2.65) as compared with the non-sialagogue group 46.59 (6.20), P < 0.001. After adjusting for the use of remineralizing rinse the subjects on sialagogue had a significantly lower number of sites with BOP (P < 0.001).

In this observational study treatment with sialagogue may prevent BOP in patients with Sjögren's syndrome.

Pro-inflammatory cytokines are important in rheumatoid arthritis (RA) and their production is mainly regulated by NF-κB and inflammasomes. Carboxyamidotriazole (CAI) exhibits potent anti-inflammatory activities by decreasing cytokines. Here, we have investigated NACHT, LRR and PYD domains-containing protein (NALP) inflammasomes in a rat model of RA and explored the therapeutic effects of CAI in this model and the involvement of NF-κB and inflammasomes in the actions of CAI. The anti-arthritic effects of CAI were assessed in the adjuvant arthritis (AA) model in rats, using radiological and histological techniques. NALP1 and NALP3 inflammasomes, NF-κB pathway and pro-inflammatory cytokines levels were measured with Western blots, immunohistochemistry and ELISA. CAI decreased the arthritis index, improved radiological and histological changes, and reduced synovial IL-1β, IL-6, IL-18 and TNF-α levels in rats with AA. Compared with normal rats, the 70 kDa NALP1 isoform was up-regulated, NALP3 was down-regulated, and levels of the 165 kDa NALP1 isoform and the adaptor protein ASC were unchanged in synovial tissue from AA rats. CAI reduced the 70 kDa NALP1 isoform and restored NALP3 levels in AA rats; CAI inhibited caspase-1 activation in AA synovial tissue, but not its enzymic activity in vitro. In addition, CAI reduced expression of p65 NF-κB subunit and IκBα phosphorylation and degradation in AA rats.

NALP1 inflammasomes were activated in synovial tissues from AA rats and appeared to be a novel therapeutic target for RA. CAI could have therapeutic value in RA by inhibiting activation of NF-κB and NALP1 inflammasomes and by decreasing pro-inflammatory cytokines.

Juvenile fibromyalgia (JFM) is a chronic musculoskeletal pain condition that is associated with reduced physical function. Recent research has demonstrated that cognitive-behavioral therapy (CBT) is effective in improving daily functioning among adolescents with JFM. However, it is not known whether these improvements were accompanied by increased physical activity levels. Our objective was to analyze secondary data from a randomized clinical trial of CBT to examine whether CBT was associated with improvement in objectively measured physical activity and whether actigraphy indices corresponded with self-reported functioning among adolescents with JFM. Participants were 114 adolescents (ages 11-18 years) recruited from pediatric rheumatology clinics that met criteria for JFM and were enrolled in a clinical trial. Subjects were randomly (1:1) assigned to receive either CBT or fibromyalgia education (FE). Participants wore a hip-mounted accelerometer for 1 week as part of their baseline and posttreatment assessments. The final sample included 68 subjects (94% female, mean age 15.2 years) for whom complete actigraphy data were obtained. Actigraphy measures were not found to correspond with self-reported improvements in functioning. While self-reported functioning improved in the CBT condition compared to FE, no significant changes were seen in either group for activity counts, sedentary, moderate, or vigorous activity. The CBT group had significantly lower peak and light activity at posttreatment.

Actigraphy monitoring provides a unique source of information about patient outcomes. CBT intervention was not associated with increased physical activity in adolescents with JFM, indicating that combining CBT with interventions to increase physical activity may enhance treatment effects.

We aimed to develop a questionnaire assessing fears and beliefs of patients with knee OA. We sent a detailed document reporting on a qualitative analysis of interviews of patients with knee OA to experts, and a Delphi procedure was adopted for item generation. Then, 80 physicians recruited 566 patients with knee OA to test the provisional questionnaire. Items were reduced according to their metric properties and exploratory factor analysis. Reliability was tested by the Cronbach α coefficient. Construct validity was tested by divergent validity and confirmatory factor analysis. Test-retest reliability was assessed by the intra-class correlation coefficient (ICC) and the Bland and Altman technique. 137 items were extracted from analysis of the interview data. Three Delphi rounds were needed to obtain consensus on a 25-item provisional questionnaire. The item-reduction process resulted in an 11-item questionnaire. Selected items represented fears and beliefs about daily living activities (3 items), fears and beliefs about physicians (4 items), fears and beliefs about the disease (2 items), and fears and beliefs about sports and leisure activities (2 items). The Cronbach α coefficient of global score was 0.85. We observed expected divergent validity. Confirmation factor analyses confirmed higher intra-factor than inter-factor correlations. Test-retest reliability was good, with an ICC of 0.81, and Bland and Altman analysis did not reveal a systematic trend.

We propose an 11-item questionnaire assessing patients' fears and beliefs concerning knee OA with good content and construct validity.

To evaluate the safety and efficacy of sodium oxybate for management of the symptoms of fibromyalgia syndrome (FMS). Patients with FMS (according to the American College of Rheumatology 1990 criteria) were randomized, after discontinuing their prestudy medications for FMS, to receive 4.5 gm or 6 gm of sodium oxybate or matching placebo once per night for 8 weeks. The primary outcome variable (POV) was a composite score for changes from baseline in 3 coprimary self-report measures: patient's pain rating (in daily electronic diaries) on a visual analog scale (PVAS), the Fibromyalgia Impact Questionnaire (FIQ) score, and the Patient Global Impression of Change (PGI-C). A beneficial response rate for the POV composite score was defined as >or=20% improvement in the PVAS and FIQ scores plus a rating of "much better" or "very much better" on the PGI-C. Secondary measures included subjective sleep outcomes (on the Jenkins Scale for Sleep) and quality-of-life measures. The analyses were based on an intent-to-treat (ITT) population. The ITT population included 188 patients with FMS, 78% of whom completed the trial. Significant benefit was observed with both dosages of sodium oxybate, according to changes in the POV and subjective sleep quality. Improvements in the PVAS score were significantly correlated with sleep outcomes. Sodium oxybate was well tolerated overall; dose-related nausea (<or=28% of patients) and dizziness (<or=18% of patients) tended to resolve with continued therapy.

Sodium oxybate therapy was well tolerated and significantly improved the symptoms of FMS. Further study of sodium oxybate as a novel therapeutic option for FMS is warranted.

Rheumatoid arthritis (RA) is characterized by hyperplasia of fibro-blast-like synoviocytes (FLSs), in part due to apoptosis resistance. Adrenomedullin, an anti-apoptotic peptide, is secreted more by RA than osteoarthritis FLSs. Adrenomedullin binds to a heterodimeric functional receptor, of calcitonin receptor-like receptor (CRLR) coupled with a receptor activity-modifying protein-2 (RAMP-2), which is also overexpressed by rheumatoid synoviocytes. Since adrenomedullin decreases RA FLS apoptosis, possibly contributing to the development of pannus, study of adrenomedullin and its receptor genes might reveal a linkage and association in French Caucasian RA trio families. Within each of 100 families, one RA-affected patient and both parents underwent genotyping for polymorphisms of adrenomedullin, CRLR and RAMP-2, by PCR-restricted fragment-length polymorphism (RFLP) or Taqman 5' allelic discrimination assay. Statistical analysis relied on the transmission disequilibrium test, the affected family-based controls and the genotype relative risk. Haplotypes of CRLR were inferred, and linkage and association studies were performed. No significant transmission disequilibrium or association between the three genes and RA was observed. CRLR haplotypes revealed two major haplotypes, but no significant linkage with RA.

Our findings provided no significant linkage or association of adrenomedullin and CRLR-RAMP-2 genes with RA in the studied trio families. The two CRLR polymorphisms rs3771076 and rs3771084 should be investigated in larger samples.

Existent biomechanical studies on hip osteoarthritic gait have primarily focused on the end stage of disease. Consequently, there is no clear consensus on which specific gait parameters are of most relevance for hip osteoarthritis patients with mild to moderate symptoms. The purpose of this study was to explore sagittal plane gait characteristics during the stance phase of gait in hip osteoarthritis patients not eligible for hip replacement surgery. First, compared to healthy controls, and second, when categorized into two subgroups of radiographic severity defined from a minimal joint space of ≤/>2 mm. Sagittal plane kinematics and kinetics of the hip, knee and ankle joint were calculated for total joint excursion throughout the stance phase, as well as from the specific events initial contact, midstance, peak hip extension and toe-off following 3D gait analysis. In addition, the Western Ontario and McMaster Universities Osteoarthritis Index, passive hip range of motion, and isokinetic muscle strength of hip and knee flexion and extension were included as secondary outcomes. Data were checked for normality and differences evaluated with the independent Student's t-test, Welch's t-test and the independent Mann-Whitney U-test. A binary logistic regression model was used in order to control for velocity in key variables. Fourty-eight hip osteoarthritis patients and 22 controls were included in the final material. The patients walked significantly slower than the controls (p=0.002), revealed significantly reduced joint excursions of the hip (p<0.001) and knee (p=0.011), and a reduced hip flexion moment at midstance and peak hip extension (p<0.001). Differences were primarily manifested during the latter 50% of stance, and were persistent when controlling for velocity. Subgroup analyses of patients with minimal joint space ≤/>2 mm suggested that the observed deviations were more pronounced in patients with greater radiographic severity. The biomechanical differences were, however, not reflected in self-reported symptoms or function.

Reduced gait velocity, reduced sagittal plane joint excursion, and a reduced hip flexion moment in the late stance phase of gait were found to be evident already in hip osteoarthritis patients with mild to moderate symptoms, not eligible for total hip replacement. Consequently, these variables should be considered as key features in studies regarding hip osteoarthritic gait at all stages of disease. Subgroup analyses of patients with different levels of radiographic OA further generated the hypothesis that the observed characteristics were more pronounced in patients with a minimal joint space ≤2 mm.

Malrotation of the femoral component after primary total knee arthroplasty (TKA) is one of the most important problems leading to painful TKA requiring revision surgery. A comprehensive systematic review of the literature was performed to present current evidence on how to optimally place the femoral component in TKA. Several landmarks and techniques for intraoperative determination of femoral component placement and examination of their reliability were analyzed. 2806 articles were identified and 21 met the inclusion criteria. As there is no unquestioned gold standard, numerous approaches are possible which come along with specific advantages and disadvantages. In addition, imaging modalities and measurements regarding postoperative femoral component rotation were also investigated. Femoral component rotation measurements on three-dimensional (3D) reconstructed computerised tomography (CT) images displayed intraclass correlation coefficients (ICC) above 0.85, significantly better than those performed in radiographics or two-dimensional (2D) CT images. Thus, 3D CT images to accurately evaluate the femoral prosthetic component rotation are recommended, especially in unsatisfied patients after TKA. III.

The EKA Femoral Rotation Focus Group has not identified a single best reference method to determine femoral component rotation, but surgeons mostly prefer the measured resection technique using at least two landmarks for cross-checking the rotation.

Lymphoid neogenesis seems to play an important role in the persistence of chronic inflammation and has been shown in various disorders characterized by chronic inflammation including rheumatoid arthritis. Arthritis of Behçet's disease is characterized by non-erosive arthritis in which the disease course is considered to be subacute and self limiting. However, molecular mechanisms underlying those features of Behçet's arthritis have not been defined yet. In order to determine the contribution of lymphoid neogenesis in the disease course of Behçet's arthritis, we investigated the synovial fluid (SF) levels of CXCL 12, CXCL 13, CCL 21 homeostatic chemokines and the percentage of SF naive lymphocytes expressing their receptors such as CXCR4+ and CCR7+. We further measured the SF TGF-Beta and INF-Beta levels which are known to contribute lymphoid neogenesis via leading persistent expression of CXCR4 on T cells and inhibiting T cell apoptosis, respectively. Fifty-one [15 BD, 17 RA, and 19 osteoarthritis (OA)] patients with at least one- sided knee arthritis were enrolled in the study. Patients with BD constituted the study group, and RA, OA patients were used as positive and negative control groups, respectively. The SF levels of CXCL 12, CXCL 13, CCL 21, TGF-Beta and INF-Beta were measured by ELISA. CXCR4, CCR7 chemokine receptors on SF lymphocytes were tested by Flow- cytometry. Kruskal-Wallis test and Mann-Whitney U test were used for statistical analysis where appropriate. Synovial fluid CCL 21 levels were found to be increased in RA patients as compared to BD and OA patients (p = 0.003, and p = 0.013, respectively). No significant difference was detected between BD and OA patients with respect to CCL 21 levels. Both CXCL 12 and CXCL 13 SF levels were found to be higher in RA and BD patients as compared to OA patients (CXCL-12; p = 0.012, and p = 0.024), (CXCL 13; p < 0.001, and p = 0.007). However, no difference with regard to SF levels of both CXCL 12 and CXCL 13 were found between RA and BD patients. Percentages of both CD3+CXCR4+ lymphocytes and CD3+CCR7+ lymphocytes in the SF of RA patients were detected to be increased as compared to those of BD and OA patients (CD3+CXCR4+; p = 0.019, p = 0.048, respectively), (CD3+CCR7+; p = 0.023, p = 0.001, respectively). However, no differences with respect to the percentages of SF lymphocytes expressing CD3+CXCR4+ or CD3+CCR7+ were found between BD and OA patients. Both TGF-Beta and INF-Beta SF levels were found to be higher in RA patients as compared to BD and OA patients (TGF-Beta; p = 0.041, and p = 0.003), (INF-Beta; p = 0.012, and p = 0.016). However, no differences with regard to SF levels of both TGF-Beta and INF-Beta were found between BD and OA patients.

Considering the subacute, self limiting and non-erosive course of arthritis observed in BD, our finding of detection of lower levels of CCL21 and TGF-Beta1 and IFN-Beta in BD patients, seems to prevent the development of LN and chronic inflammation in Behçet's synovitis. In support of this view, percentages of SF naïve T lymphocytes were found to be lower in BD patients comparing with those of the RA. Absence of tertiary lymphoid structures in BD patients, may explain the spontaneous resolution of Behçet's arthritis in most of the cases.

Failed conservative treatments of knee osteoarthritis (OA) in the elderly have traditionally been treated with TKA (Total Knee Arthroplasty). Although TKA is a gold standard and cost-effective treatment in elderly patients, it should be considered as the last resource for patients with pain that cannot be controlled by the usual conservative therapeutic approaches. Numerous studies showed that intra-articular Sodium Hyaluronate (IA-HA) (Hyalgan) is effective for treatment in various stages of knee OA. To compare cost of treatment between two groups of knee OA patients who failed conservative treatments. The first group includes the patients who responded to IA-HA treatment leading to delay or cancel surgical treatments (response group). The second group includes the patients who did not respond to IA-HA treatment and they had to undergo surgical procedures (non-response group). A cost analysis from the retrospective data in Police General Hospital from year 2001-2004. One hundred and eighty three patients with knee OA (208 knees) who failed conservative treatments and did not have contraindications for surgery were enrolled. All patients were treated with one course of three IA-HA injections (500-730 KDA, Hyalgan) at weekly intervals and followed up for a minimum 2-year period. In case of successful treatment (response group), repeated doses were recommended. If the patients did not improve in the average Western Ontario and McMaster Universities Osteoarthritis Index (the average WOMAC) score within one month after completion of the injections, they would be classified as a non-response group and the surgical procedures would be considered. Cost of direct medical costs (drugs), hospitalization, and resource utilization were recorded and analyzed. One hundred and forty six patients (164 knees) responded to the treatment and did not need any surgical procedures within the 2-year follow-up period. Thirty-seven patients (44 knees) did not respond and needed surgical procedures. In the response group, 83 patients repeated the second course of treatment and 14 patients repeated the third course. The total average cost for the response group were 47,044.18 Baht per patient, which was an average cost of IA-HA; 12,240.41 Baht and an average cost of other medications following the injection of 34, 803.77 Baht. The ratio of the IA-HA cost and medications following the injection cost was 1:2.84. In the non-response group, the total average cost was 144,884 Baht per patient including average cost of surgery of 135,559.95 Baht per patient or 113,993.59 Baht per knee and cost of IA-HA treatment of 9,324 Baht per patient, which was only 6.44% of the total costs of treatment. However, when considered in the response group, the IA-HA treatment provided cost saving from cancellation or delayed surgical procedures at 63.26%.

IA-HA should be considered as a medical intervention before surgical procedures in knee OA patients who failed conservative treatments. Even though the cost of IA-HA treatment would increase the total costs of treatment and some patients might fail, it was only 6.44% of the total costs. On the other hand, if patients responded to IA-HA treatment, then the surgical procedures were not required. This treatment could save the cost from cancellation or delayed surgical procedures at 63.26%.

In rehabilitation, treatment is individually tailored to each patient's goals. Individualized instruments allow patients to choose domains that they consider important, which may make them particularly appropriate as evaluative tools in this setting. We aimed to evaluate the psychometric properties of the Norwegian version of the patient generated index (PGI) in patients with rheumatic diseases participating in inpatient rehabilitation or self-management programmes. Patients completed the PGI together with other outcome measures at arrival and 5 and 52 weeks after arrival. The PGI was assessed for data quality by completion rates, reliability by the intraclass correlation coefficient (ICC), agreement by standard error of measurement (SEM) and smallest detectable change (SDC). Construct validity was assessed by testing a priori hypotheses regarding correlation between PGI scores and other outcome measures. Responsiveness was assessed by an a priori hypothesis regarding the correlation of different change scores and standardized response means (SRMs). A total of 145 patients participated and 118 (81%) completed the PGI correctly. The ICC was 0.87, SEM 7.25 and SDC 20.10. Ninety-three per cent of the hypotheses of correlation were confirmed in tests for construct validity. Responsiveness was confirmed in 53% and 71% of hypotheses tested at 5 and 52 weeks. SRMs were 0.2 and 0.4, respectively.

The results support the validity, reliability and responsiveness of the Norwegian version of the PGI in patients with rheumatic diseases and its application as an outcome measure in rehabilitation or self-management programmes. Further research is needed to improve completion rates for the PGI.

Amylin, which is co-secreted with insulin, plays a role in glycemic regulation and is impaired in type 2 diabetes. In the present study we assess, for the first time, the implication of amylin in the development of insulin resistance (IR) in rheumatoid arthritis (RA). This was a cross-sectional study involving 361 non-diabetic individuals, 151 patients with RA and 210 sex-matched controls. Insulin, C-peptide, amylin, lipoprotein serum concentrations, and IR indexes by homeostatic model assessment (HOMA2) were evaluated in patients and controls. A multivariable analysis, adjusted for IR-related factors, was performed to determine the differences between patients and controls vis-à-vis amylin and how it is related to IR in RA. Insulin, C-peptide and HOMA2-IR indexes were higher in RA patients than in controls. Amylin serum levels were found to be upregulated in RA patients compared to controls (1.36 ± 0.81 vs. 1.79 ± 1.51 ng/ml, p=0.011), although this difference was lost after adjusting for covariates (p=0.46). While amylin positively correlated with the presence of rheumatoid factor (beta coef. 0.90 [95%CI -0.23-1.56], p=0.009) and SDAI (beta coef 0.01 [95%CI 0.00-0.03], p=0.034), no significant association with other disease activity scores, glucocorticoid intake, methotrexate use or TNF-alpha inhibitors was found.

IR in RA does not appear to be mediated by amylin. This would imply that the mechanisms associated with IR in RA patients differ from those at work in type 2 diabetes.

Intra-articular (IA) injection of hyaluronic acid (HA) has been shown to relieve osteoarthritis (OA)-related pain and improve joint structure within a 1-year period. We examined the mid-term (2-year) efficacy of IA-HA in Japanese subjects by using a large-scale population-based cohort of the Research on Osteoarthritis/Osteoporosis Against Disability study. We performed a nested case control study of 60 case control pairs matched for age (within 1 year), sex, Kellgren and Lawrence grade, and history of knee pain. The mean follow-up period after IA-HA series was 2.9 years in case patients. We examined the association of IA-HA with knee radiographic severity and knee pain. To estimate radiographic severity of OA, six distinct features--joint space area and the minimum joint space width at medial and lateral sides, osteophyte area, and tibiofemoral angle--were measured using a fully automatic computer-assisted program. Comparison of the radiographic parameters between case patients and controls showed that the medial and lateral joint space areas were significantly bigger in case patients than in controls. After constructing a multivariate logistic regression model to examine the correlation of knee pain, IA-HA, and radiographic features, we found that unlike radiographic features, IA-HA was protectively associated with the presence of pain.

IA-HA might effectively improve joint structure and relieve pain in patients with knee OA.

To evaluate the effect of viral IL-10 on the lacrimal gland immunopathologic response in the ocular surface disease, induced autoimmune dacryoadenitis. Disease was induced in rabbits by injecting inferior lacrimal glands with peripheral blood lymphocytes activated by 5 days of coculture with autologous acinar cells in a mixed-cell reaction. In the treated group, an adenoviral vector carrying the vIL-10 gene was concurrently injected with activated lymphocytes. Tears were collected periodically for quantitation of IL-10 by ELISA. Two weeks after disease induction, tear production, tear film breakup time, and rose bengal staining score were determined. Sectioned glands were immunostained for expression of CD4, CD8, rabbit thymic lymphocyte antigen (RTLA), CD18 and major histocompatibility complex class II. The titer of vIL-10 in tears was at its maximum on day 3, started to decline by day 7, and was undetectable by day 14. In the diseased group, the tear production rate and tear film breakup time were significantly decreased, and rose bengal staining was significantly increased. Diseased glands had immune cell infiltrates containing CD4+, RTLA+, and CD18+ cells, and major histocompatibility complex class II expression was increased. These changes were significantly ameliorated by expression of vIL-10.

In vivo transduction of the lacrimal gland with AdvIL-10 resulted in the transient appearance of vIL-10 in tears. The presence of vIL-10 partially suppressed the appearance of Sjögren-syndrome-like features of reduced tear production, accelerated tear breakup, ocular surface disease, and immunopathologic response. Anti-inflammatory cytokine gene expression may offer a therapeutic modality for the treatment of autoimmune dacryoadenitis, once suitable vectors become available.

To evaluate efficacy, serological responses, and predictors of response in patients with severe and refractory systemic lupus erythematosus (SLE) treated with rituximab plus cyclophosphamide. 16 patients entered a treatment protocol using rituximab plus cyclophosphamide. Disease activity was assessed by the SLE disease activity index (SLEDAI) and by the British Isles Lupus Assessment Group (BILAG) index. At six months follow up, mean SLEDAI values decreased significantly from (mean (SD)) 12.1 (2.2) to 4.7 (1.1). Clinical improvement (50% reduction in SLEDAI) occurred in all but three patients. All but one patient responded according to BILAG. Remission defined as SLEDAI <3 was achieved in nine of 16 patients. Isotype analysis of anti-dsDNA antibodies revealed preferential decreases of IgG and IgA, but not IgM. Higher absolute numbers of CD19+ cells at baseline were correlated with shorter depletion time (r = -0.6).

The majority of patients improved following rituximab plus cyclophosphamide. The differential downregulation of anti-DNA of the IgG and IgA but not the IgM isotypes supports the hypothesis that cells producing pathogenic autoantibodies are preferentially targeted by the treatment. The fact that greater absolute numbers of CD19+ cells at baseline predict a less impressive clinical and serological response suggests that more flexible dosing could be advantageous.

To evaluate the contributions of radiographic knee osteoarthritis (OA) and knee pain severity to self-reported disability performing upper and lower extremity tasks in a rural, population based sample. Data from 1192 African-American and Caucasian participants in the Johnston County Osteoarthritis Project were analyzed with multiple logistic regression to examine the roles of Kellgren-Lawrence radiographic knee OA grade and knee pain severity in self-reported difficulty performing 20 activities of the Health Assessment Questionnaire. Potential confounders included age, sex, race, marital status, education, and body mass index. Forty-three percent reported difficulty performing at least one task. Mild knee pain was independently associated with difficulty performing 16 upper and lower extremity tasks, and moderate/severe knee pain with all 20 tasks, with little change after adjustment (p < 0.0001). In contrast, mild radiographic knee OA was associated with difficulty in only 4 mobility and transfer tasks: climbing 5 steps, taking a tub bath, getting in/out of a car, and performing chores. Moderate/severe radiographic knee OA was associated with difficulty in 17 of 20 tasks (in 10 of 17, p < 0.0001), except lifting a cup, opening car doors, and turning faucets. However, no associations between radiographic knee OA and difficulty were statistically significant after adjustment for knee pain and the above factors.

Knee pain severity was the strongest risk factor for self-reported difficulty performing tasks of upper and lower extremity function. Future studies of disability should include data on knee pain severity.

Reverse shoulder arthroplasty (RSA) was introduced in 1985 by Grammont for patients with gleno-humeral osteoarthritis and severe rotator cuff damage. Internal rotation (IR) is limited in some patients after RSA. The objective of this study was to identify pre- and intra-operative factors associated with good IR outcomes 6 months after RSA. The condition of the residual cuff (usually the sub-scapularis and teres minor) and inferior glenosphere overhang are the main factors associated with IR outcomes after RSA. A total of 36 patients who underwent RSA between 2 November 2015 and 10 January 2017 were enrolled prospectively. The inclusion criterion was massive rotator cuff tear with or without osteoarthritis and gleno-humeral osteoarthritis with asymmetrical glenoid wear. The pre-operative work-up included determination of the Constant score, Subjective Shoulder Value (SSV), and passive and active motion ranges; standard radiographs; and computed tomography. The same clinical and radiological parameters were recorded in all patients during a visit 6 months after surgery. After surgery, all motion ranges were improved except IR with the elbow by the side (IR1, ability to place the hand on the back). IR1 to or above L3 was significantly associated with a lower body mass index (p=0.04), good passive IR before surgery (p=0.056), a smaller pre-operative glenoid inclination angle, and greater glenosphere overhang (p=0.03). Neither the condition of the sub-scapularis nor sub-scapularis repair were significantly associated with post-operative IR1. IR1 was significantly more limited in patients whose teres minor was normal. IV, prospective observational cohort study.

Satisfactory active IR1 correlated with good passive IR1. IR1 was better in thin individuals who had non-concentric gleno-humeral osteoarthritis. Inferior glenosphere overhang of 6mm or more was associated with a greater range of IR.

To study trends in the incidence of juvenile rheumatoid arthritis (JRA). The study covered subjects who were entitled under the nation-wide sickness insurance scheme to receive specially reimbursed medication for juvenile rheumatic diseases in 11 of 21 central hospital districts in Finland (the base population comprised about 445,000 children <16 yr of age) in 1995. Data from the years 1980, 1985 and 1990 were compared with data from 1995 concerning the central part of the area, which had been included in a previous study by us. A total of 87 incident cases (58 girls and 29 boys) satisfied criteria for JRA in 1995 in the study area. The incidence of JRA was 19.5 per 100 000 [95% confidence interval (CI) 15.6-24.1] of the population <16 yr of age for the whole area. It was 22.7 per 100,000 (95% CI 17.3-29.2) for the area that had been covered by the earlier study (five districts) and 14.9 per 100,000 (95% CI 9.8-21.7) for the new area (six additional districts). The incidence of JRA was significantly higher than in the earlier years (1980, 1985 and 1990) in the same district (trend, P=0.024). The highest incidence, 60.3 per 100,000 (95% CI 35.8-95.4), was noted in 1995 among girls in the age group 10-15 yr in the southernmost part of the study area.

There was both temporal and regional variation in the incidence of JRA. Results of the present study suggest that environmental factors may influence the frequency of JRA.

The Stanford Health Assessment Questionnaire Disability Index (HAQ) is the gold standard functional status questionnaire in rheumatology, but it is lengthy. Three shorter versions, the modified HAQ (MHAQ), the Multidimensional HAQ (MDHAQ), and the HAQII are often used in outcomes research as HAQ substitutes. We developed conversion formulas between these modified versions and the original HAQ. Analysis was limited to the comparison of rheumatoid arthritis (RA) patients at a random observation when the HAQ was recorded in conjunction with the MHAQ (n = 29,596), the MDHAQ (n = 13,665), or the HAQII (n = 15,823). Development models were randomly limited to 80% of the data (development sample) and the remaining 20% was used for model validation. Two conversion formulas were developed for each of the MHAQ, the MDHAQ, and the HAQII: a short model and a long model inclusive of questions common to both the modified measures and the original HAQ. Short models explained 81-83%, and long models 82-86%, of the variance. Predicted HAQ values of zero were assigned to all cases with an MDHAQ or HAQII score of zero, with remaining cases used for model estimation. Bland-Altman plots demonstrated good concordance between actual and predicted values for each measure. The validation sample closely approximated the results from the development sample (0.005 ≤ ΔR² ≤ 0.009) for each measure.

We have developed and validated highly accurate conversion formulas from the MHAQ, MDHAQ, and HAQII to the original HAQ in a large sample of RA patients. The developed models are useful for conversion of measures in the research setting. Because of substantial variability at the individual patient level, application of the formulas to individual patients is inadvisable.

Fibromyalgia (FM) is a syndrome whose primary symptoms include chronic widespread muscle pain and fatigue. The treatment of patients with FM aims to provide symptomatic relief and improvement in physical capacities to perform daily tasks and quality of life. Invasive or non-invasive electric stimulation (ES) is used for pain relief in patients with FM. This systematic review aimed to assess the effects of treatment with ES, combined or not combined with other types of therapy, for pain relief in patients with FM. Systematic review and meta-analysis. Electronic search was conducted on databases (from the inception to April 2016): MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (Cochrane CENTRAL), and Physiotherapy Evidence Database (PEDro). Two independent reviewers assessed the eligibility of studies based on the inclusion criteria: randomized controlled trials (RCTs) examining the effects of ES combined or not with other types of treatment for pain relief in patients with FM (according to the American College of Rheumatology), regardless of the ES dosages. The primary outcome was pain, assessed by the visual analogue scale (VAS). The secondary outcomes extracted were quality of life, assessed by short form-36 health survey (SF- 36), and fatigue, assessed by VAS. Nine studies were included, with 301 patients. The meta-analysis for pain showed positive effect of ES treatment versus control [-1.24 (95% CI: -2.39 to -0.08; I²: 87%, P = 0.04) n = 8 RCTs]. The sensitivity analysis for pain showed significant results for invasive ES, combined or not with other types of therapy [-0.94 (95% CI, -1.50 to -0.38; I² 0%, P = 0.001) n = 3 RCTs]. No significant improvement was found regarding quality of life [-3.48 (95% CI: -12.58 to 5.62; I²: 0%, P = 0.45), n = 2 RCTs] or fatigue [-0.57 (95% CI, -1.25 to 0.11; I² 34%, P = 0.100; n = 4 RCTs]. This systematic review included a small number of studies and reduced number of participants in each study. Furthermore, most of the studies showed some biases and lack of methodological quality. PROSPERO under the identification CRD42015025323Key words: Electric stimulation, electroacupuncture, transcutaneous electric nerve stimulation, pain, fibromyalgia, review, physical therapy, rehabilitation.

This meta-analysis indicates that there is low-quality evidence for the effectiveness of ES for pain relief in patients with FM. However, moderate-quality evidence for the effectiveness of electroacupuncture (EA), combined or not combined with other types of treatment, was found for pain relief.

To report a case of systemic lupus erythematosus (SLE) in a patient with human immunodeficiency virus (HIV) infection. We also reviewed the medical literature for similar cases to assess the role of "lupus-specific antibodies" in the diagnosis of SLE in the presence of HIV infection. We described the presentation, clinical course, and serologic studies of our patient and reviewed the English language medical literature from 1966 to 1999 using MEDLINE with the keywords "SLE," "HIV," "acquired immune deficiency syndrome (AIDS)," and "autoantibodies." Our patient with long-standing HIV infection presented with fever, arthralgias and arthritis, photosensitive rash, oral ulcers, alopecia, headache, pleuritic chest pain, and lymphadenopathy. Laboratory testing showed leukopenia, thrombocytopenia, antibodies against ribonucleoprotein, Smith, and ribosomal-P, as well as immunoglobulin G anticardiolipin antibodies. Review of the literature revealed only 25 cases of concomitant SLE and HIV. In these cases, rheumatologic signs and symptoms were common in HIV and overlapped significantly with SLE. Autoantibodies also occurred frequently in both diseases.

There are very few reported cases of concomitant HIV and SLE. These diseases may be largely mutually exclusive, but distinguishing the two can be difficult because of the high degree of rheumatic complaints and autoantibodies in HIV-positive patients. As illustrated by the patient presented, SLE should be considered in HIV-positive patients with rheumatologic complaints.

We investigated the in vitro immunomodulatory effects of sulfasalazine on B cells in rheumatoid arthritis (RA). Reversed hemolytic plaque assay and 3H-thymidine incorporation were measured. B cells from patients with RA showed hyperactivity to stimulation by Staphylococcus aureus Cowan I. Sulfasalazine significantly inhibited this B cell hyperactivity in a dose dependent manner. The kinetic study and a decrease in 3H-thymidine incorporation on Day 3 indicate that sulfasalazine inhibited the early phase (0-48 h) of B cell proliferation in these patients. Sulfapyridine also inhibited B cell hyperactivity in these patients, but 5-aminosalicylic acid and N-acetylsulfapyridin had no significant effect.

Sulfasalazine exhibited a direct immunosuppressive effect on B cell hyperactivity in patients with RA, which may be responsible for its therapeutic effectiveness in this disorder.

To compare recovery kinematics following trip-simulated perturbation during gait between three groups: adults without knee Osteoarthritis (OA) and adults with OA, scheduled and not scheduled for Total Knee Replacement (TKR). People with OA scheduled for TKR (TKR group; N = 19) and not scheduled (NTKR group; N = 17) were age-matched with People without OA (N = 19). Outcome measures included: joint range of motion (ROM), Timed Up and Go (TUG), joint pain levels, Oxford score, Instrumental Activities of Daily Living Questionnaire, and the Activities-specific Balance Confidence Scale. Also, spatiotemporal gait parameters and joint kinematics were recorded during perturbed and unperturbed gait. The perturbed gait data were normalized by unperturbed gait data. There were no differences between the two OA groups in the four questionnaire scores and joint ROM. The TUG score of the TKR group was higher than that of the NTKR group. There were no statistically significant between-group differences in the normalized spatiotemporal parameters. The OA groups showed statistically significant lower anterior pelvic tilt ranges and higher maximal hip adduction of the contralateral limb compared to the Non-OA group. When the contralateral limb was perturbed, the TKR group showed significantly lower pelvic rotation range compared to the NTKR and Non-OA groups. When the OA limb was perturbed, the maximal hip flexion of the injured limb was significantly lower and the maximal knee flexion higher in the OA groups compared with the Non-OA group.

The recovery strategy from trip-simulated perturbation of individuals with OA differs from that of individuals without OA. This may emphasize the importance of devising a treatment plan that focuses on improving balance and reactions to gait perturbation.

To determine prior authorization (PA) impact on healthcare utilization, costs, and pharmacologic treatment patterns for painful diabetic peripheral neuropathy (pDPN) and fibromyalgia (FM). This retrospective, observational, longitudinal cohort study used medical and pharmacy claims data. Newly diagnosed patients treated for FM or pDPN between 7/1/2007 and 12/31/2011 were included. PA and no PA groups were matched by propensity score 4:1. Medical resource utilization, direct medical and pharmacy costs, and treatment pattern differences were compared. Pre and postindex differences between PA and no PA cohorts were determined by difference in difference analysis. Analysis of 2,315 FM patients (1,852 PA; 463 no PA) demonstrated greater increases in postindex all-cause costs ($197; P = 0.6673) and disease-related costs ($72; P = 0.4186) in the PA cohort. Analysis of 1,300 pDPN patients (1,040 PA; 260 no PA) demonstrated postindex all-cause cost increases of $1,155 more in the no PA cohort (P = 0.6248); disease-related costs decreased $2,809 more in the no PA cohort (P = 0.4312). Treatment patterns were similar between cohorts; opioid usage was higher in the FM PA cohort (P = 0.0082).

There was no evidence of statistically significant differences between PA and no PA cohorts in either FM or pDPN populations for total all-cause or disease-related costs.

Periacetabular osteotomy has been established as an effective treatment for early or mild osteoarthritis caused by developmental dysplasia of the hip. However, the optimal method of surgical reconstruction for older patients remains controversial. The purpose of this retrospective study was to evaluate the clinical and radiographic results of a curved periacetabular osteotomy for the treatment of developmental dysplasia of the hip in patients fifty years of age or older. We evaluated forty-six consecutive hips in forty-two patients fifty years of age or older (the older group) who had developmental dysplasia of the hip and had undergone a curved periacetabular osteotomy between 1995 and 2006 with a minimum two-year follow-up period. The mean age was 54.6 years. We compared the clinical and radiographic results of this cohort with those of fifty hips in forty-four patients who were less than fifty years old (the younger group) and were managed with the same osteotomy. The mean age was 32.3 years. The patients were matched according to sex and Tönnis grade. Radiographic measurements included the center-edge angle, acetabular roof obliquity, acetabular head index, anterior center-edge angle, and head lateralization index. The mean Harris hip score improved from 69.6 points preoperatively to 90.9 points postoperatively in the older group and from 71.1 points preoperatively to 91.8 points postoperatively in the younger group. There were no significant differences in any of the radiographic measurements between the two groups preoperatively or postoperatively. The Tönnis grades improved in two hips and progressed in three hips in the older group and improved in three hips and progressed in three hips in the younger group.

Satisfactory results can be obtained clinically and radiographically after curved periacetabular osteotomy in patients fifty years of age or older with Tönnis grade-1 or 2 osteoarthritis of the hip secondary to developmental dysplasia.

During the course of acute rheumatic fever, some electrocardiographic changes are seen. First-degree atrioventricular block is the most common electrocardiographic abnormality. Second- and third-degree atrioventricular block, ventricular tachycardia, and junctional acceleration are also seen. In the present study, the specificity of accelerated junctional rhythm to acute rheumatic fever was INVESTIGATED. The study included patients with acute rheumatic fever (Group 1), healthy children who had suffered from recent group A β-haemolytic streptococcal upper respiratory tract infection but did not develop acute rheumatic fever (Group 2), and patients who had other diseases that may affect the joints and/or heart (Group 3). Accelerated junctional rhythm was detected in 10 patients in Group 1, but in none of the patients from Group 2 or 3. Specificity of accelerated junctional rhythm for acute rheumatic fever was 100% and the positive predictive value was 100%.

Accelerated junctional rhythm is specific to acute rheumatic fever. Although its frequency is low, it seems that it can be used in the differential diagnosis of acute rheumatic fever, especially in patients with isolated polyarthritis.

To determine if the arthroscopic removal of gouty crystal deposits from the first metatarsophalangeal (MTP) joint will reduce the recurrence rate and improve foot function compared to medical treatment alone. Twenty-eight male patients with hyperuricemia (>7.0 mg/dL) and repeated attacks of gouty arthritis of the first MTP joint were included in this study. Arthroscopic intervention of the first MTP joint was performed on 15 patients (group 1), while the other 13 patients were treated with medication alone (group 2). The follow-up period (mean +/- standard deviation) was 3.9 +/- 1.1 years in group 1 and 2.4 +/- 0.3 years in group 2. After treatment, both groups showed a significant improvement in the number of acute attacks of gouty arthritis and in their functional scores on the American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale. On both measures, the results for group 1 were significantly better than those for group 2.

Arthroscopic removal of gouty crystals from the first MTP joint can reduce the rate of acute repeated attacks of gouty arthritis and increase foot and ankle function.

To compare the efficacy, tolerance and safety of 50-150 micrograms orally administered iloprost given twice a day versus placebo in patients with Raynaud's syndrome. The study was multicentre (n = 3), double blind and placebo controlled. Sixty three patients who had eight or more vasospastic attacks per week were enrolled. After a one week run-in period, all patients received either iloprost or placebo treatment to a maximum tolerated dose of 150 micrograms twice a day for 10 days. Diary cards assessed the duration and severity of the vasospastic attacks. Side effects were monitored by direct questioning. A global assessment of treatment efficacy was made by the patient at the end of treatment and two weeks later. Patient opinion tended to favour iloprost at the end of the 10 day treatment phase (p = 0.09) and this was significant at day 24 (the follow up visit) (p = 0.011). Although the duration and severity of attacks tended to decrease in the iloprost treated group, these results tended not to reach statistical significance (for severity p = 0.06 at end of treatment, p = 0.09 on day 24).

Iloprost administered intravenously has been shown to be of benefit in the treatment of the Raynaud's syndrome associated with systemic sclerosis, but this route of administration is inconvenient. This study evaluated the use of iloprost administered orally to patients with Raynaud's syndrome. Patient documented improvement was significantly improved by iloprost. Diary card analysis showed a trend in favour of iloprost, but these results did not reach statistical significance.

To examine the association between obesity and knee and hip arthroplasty for osteoarthritis across a range of physical performance. The body mass index and physical performance (on the 36-item Short Form Health Survey) of 9135 Australian Diabetes, Obesity and Lifestyle Study participants were measured in 1999-2000. The incidence of knee and hip arthroplasty during 2002-2011 was determined by linking the cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. Over 9.1 ± 2.3 years (mean ± sd)) of follow-up, 317 participants had knee and 202 had hip arthroplasty for osteoarthritis. Using those with neither obesity nor significantly impaired physical performance as the reference group, participants with both obesity and significantly impaired physical performance had a higher knee arthroplasty risk [hazard ratio (HR) = 5.25, 95% confidence interval (CI) 3.85-7.14] than those with obesity alone (HR = 2.49, 95% CI 1.81-3.44) or impaired physical performance alone (HR = 2.19, 95% CI 1.59-3.02). Similar results were observed for hip arthroplasty (obesity and impaired physical performance: HR = 2.67, 95% CI 1.72-4.15; obesity alone: HR = 1.65, 95% CI 1.08-2.51; impaired physical performance alone: HR = 1.83, 95% CI 1.26-2.66). Among overweight/obese patients, 5 kg greater baseline weight increased the knee arthroplasty risk across all levels of physical performance, and hip arthroplasty risk in those with the highest level of physical performance.

Although impaired physical performance is an independent risk factor for knee and hip arthroplasty, greater weight increased knee arthroplasty for overweight/obese participants at all levels of physical performance, but hip arthroplasty only in those with good physical performance. Targeting weight loss has the potential to reduce the risk of knee arthroplasty and improve patient outcomes, even in those with poor physical performance.

Limitations in upper limb functioning are common in Musculoskeletal disorders and the Disabilities of the Arm, Shoulder and Hand scale (DASH) has gained widespread use in this context. However, various concerns have been raised about its construct validity and so this study seeks to examine this and other psychometric aspects of both the DASH and QuickDASH from a modern test theory perspective. Participants in the study were eligible if they had a confirmed diagnosis of Rheumatoid Arthritis (RA). They were mailed a questionnaire booklet which included the DASH. Construct validity was examined by fit to the Rasch measurement model. The degree of precision of both the DASH and QuickDASH were considered through their Standard Error of Measurement (SEM). Three hundred and thirty-seven subjects with confirmed RA took part, with a mean age of 62.0 years (SD12.1); 73.6% (n = 252) were female. The median standardized score on the DASH was 33 (IQR 17.5-55.0). Significant misfit of the DASH and QuickDASH was observed but, after accommodating local dependency among items in a two-testlet solution, satisfactory fit was obtained, supporting the unidimensionality of the total sets and the sufficiency of the raw (ordinal or standardized) scores. Most previous modern psychometric analyses of both the DASH and QuickDASH have failed to fully address the effect of a breach of the local independence assumption upon construct validity. Accommodating this problem by creating 'super items' or testlets, removes this effect and shows that both versions of the scale are valid and unidimensional, as applied with a bi-factor equivalent solution to an RA population. The Standard Error of Measurement of a scale can be biased by failing to take into account the local dependency in the data which inflates reliability and thus making the SEM appear better (i.e. smaller) than the true value without bias.

Having accommodated local response dependency in the DASH and QuickDASH item sets, their total scores are shown to be valid, given they satisfy the Rasch model assumptions. The Rasch transformation should be used whenever all items are used to calculate a change score, or to apply parametric statistics within an RA population.

The main objective was to determine the 2-year clinical benefit and safety of etanercept (ETN) in children with the juvenile idiopathic arthritis (JIA) categories of extended oligoarthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). CLIPPER was a 96-week, phase IIIb, open-label, multicenter study. Patients with eoJIA, ERA, or PsA received ETN 0.8 mg/kg once weekly (50 mg max) for up to 96 weeks. The proportions of patients reaching the JIA American College of Rheumatology (ACR) 30/50/70/90/100 and inactive disease responses at Week 96 were calculated. Adverse events (AE) were collected throughout the study (intention-to-treat sample). There were 127 patients (eoJIA n = 60, ERA n = 38, PsA n = 29) who received ≥ 1 dose of ETN. The mean disease duration was 31.6 (eoJIA), 23.0 (ERA), and 21.8 (PsA) months. At Week 96, JIA ACR 30/50/70/90/100/inactive disease responses (95% CI) were achieved by 84.3% (76.7, 90.1), 83.5% (75.8, 89.5), 78.7% (70.6, 85.5), 55.1% (46.0, 63.9), 45.7% (36.8, 54.7), and 27.6% (20.0, 36.2) of patients, respectively. The most common AE (no. events, events per 100 patient-yrs) overall were headache (23, 10.7), pyrexia (12, 5.6), and diarrhea (10, 4.6). The most common infections were upper respiratory tract infection (83, 38.6), pharyngitis (50, 23.2), gastroenteritis (22, 10.2), bronchitis (19, 8.8), and rhinitis (17, 7.9). No cases of malignancy, active tuberculosis, demyelinating disorders, or death were reported.

Over 96 weeks of therapy, ETN demonstrated sustained efficacy at treating the clinical symptoms of all 3 JIA categories, with no major safety issues.

The aim of this study was to investigate in situ the expression of the classic vitronectin (VN) receptor consisting of the alpha v and beta 3 subunits in synovial lining cells (SLC) of chronic synovitis occurring in osteoarthritis (OA) and in rheumatoid arthritis (RA). The expression and function of alpha v and beta 3 as VN receptor in cultured fibroblast-like synoviocytes (FBS) derived from patients with OA and RA was also compared. Expression of alpha v and beta 3 was examined immunohistochemically in normal synovial tissue and in synovial tissue from patients with OA and RA. The effect of proinflammatory cytokines and of a synovial fluid of a patient with RA on the expression of the alpha v and beta 3 subunits of cultured FBS was determined by flow cytometry. Binding of OA and RA-FBS to VN was quantified using adhesion assays and the effect of interleukin 1 beta (IL1 beta) and tumour necrosis factor alpha (TNF alpha) on adhesion was measured. The specificity of the adhesion was tested by inhibition studies using monoclonal antibodies to integrin subunits. In in situ studies normal SLC showed a parallel distribution of alpha v and beta 3 subunits. OA-SLC strongly and uniformly expressed alpha v whereas RA-SLC showed heterogeneous expression of alpha v. In situ both OA-SLC and RA-SLC lacked the expression of the integrin subunit beta 3. In in vitro studies, OA-FBS and RA-FBS did not differ as regards expression of alpha v and beta 3, and VN attachment. Binding of RA-FBS to VN was partially blocked by antibodies against alpha v, beta 1, and beta 3 subunits, whereas only antibodies against alpha v and beta 3 inhibited the binding of OA-FBS to VN. The proinflammatory cytokines TNF alpha and IL1 beta increased the expression of alpha v and beta 3, and the VN binding of OA-FBS, whereas alpha v and beta 3 expression, and VN binding were downregulated in RA-FBS. Similar effects were found when the synovial fluid of an RA patient was used.

The integrin subunit beta 3 seems to be one partner but not the major one with which the subunit alpha v forms functional vitronectin receptors in OA-FBS and RA-FBS. The interaction between synovial cells and inflammatory cytokines seems to be different for OA and RA; the basis for this difference, however, remains to be established.

To describe patient preferences in selecting specific biologics and compare clinical response using patient reported outcomes (PROs) among patients with rheumatoid arthritis (RA) started on different anti-tumor necrosis factor (TNF) therapies. Participants were enrollees in Kaiser Permanente Northern California. Patients with RA who had at least two provider visits and started a new anti-TNF therapy from 10/2010-8/2011, were eligible for participation in this longitudinal study. Using a telephone survey, patient preferences in biologic selection and RAPID3, MDHAQ, and SF-12 scores were collected at baseline and at 6 months. Patient scores rating injection/infusion-site burning and stinging (ISBS) were collected at 6 months. In all, 267 patients with RA responded to the baseline survey, of whom 57% preferred an injectable biologic, 22% preferred an infused biologic, and 21% had no preference. Motivation for injectable biologics was convenience (92%) and for infusion therapy was dislike or lack of self-efficacy for self-injection (16%). After 6 months of treatment with anti-TNF, 70% of the 177 patients who answered the ISBS question reported ISBS with the last dose; on a scale of 1 (none) to 10 (worst), 41% of these reported a score of 2-5; and 29% reported a score of 6-10. Adalimumab users experienced 3.2 times (95% confidence interval 1.2-8.6) the level of ISBS that etanercept users experienced. There were no significant differences in RAPID3, MDHAQ, or SF-12 scores between etanercept or adalimumab initiators.

Convenience and fear of self-injection were important considerations to patients selecting a biologic drug. Although more convenient, adalimumab associated with more ISBS than did etanercept, and this rate was higher than reported in clinical trials. At 6 months, PROs did not differ between etanercept and adalimumab users.

Children and young people (CYP) with juvenile idiopathic arthritis (JIA) are known to have impaired health-related quality of life (HRQoL), which is improved significantly for many by treatment with methotrexate (MTX). However, a significant proportion of CYP experience difficulties in taking MTX, which may reduce its potential benefits for HRQoL. The aim of this research was to examine how CYP with JIA perceive MTX treatment and how this relates to HRQoL. CYP aged 8-16 years taking MTX for JIA completed an adapted Parent Adherence Report Questionnaire, which contains 100 mm visual analogue scales, to assess difficulty taking MTX, adherence, frequency of negative reactions and helpfulness of MTX. They also completed the Pediatric Quality of Life Inventory (PedsQL) Generic and Rheumatology scales. We collected data on age, gender, JIA course, disease duration, MTX duration of use, route and dose. Number of inflamed and limited joints were indicators of disease severity. One hundred sixteen CYP participated. Most considered MTX helpful (median 87; interquartile range (IQR) 50.75-98) and reported adherence was high (median 98; IQR 90-100). There was greater variability on scores for difficulty (median 22; IQR 2-69) and frequency of negative reactions (median 14.5; IQR 1.25-80). Mean (S.D.) scores on the PedsQL Physical and Psychosocial subscales were 71.63 (24.02) and 71.78 (19.59) respectively, indicating poorer HRQoL than that reported by healthy children. After controlling for demographic and disease variables, poorer physical HRQoL was significantly accounted for by greater difficulty in taking MTX. Poorer psychosocial HRQoL was significantly accounted for by subcutaneous MTX administration, a lower rating of MTX helpfulness and a greater reported difficulty in taking MTX.

Taking MTX for JIA was viewed as helpful by most CYP but HRQoL was poorer in those who reported greater difficulty in taking MTX.

Two strains of guinea pig develop spontaneous osteoarthritis of the knee. Although the disease evolves at different rates in the two strains, it is not known whether these differences are reflected in the structure of the cartilage and cancellous bone. We determined whether the three-dimensional structure of the tibial-plateau cartilage and femoral cancellous bone differed between the two strains. Six Dunkin-Hartley and six GOHI/SPF guinea pigs were evaluated. The animals were sacrificed at 11 months of age. The 24 proximal tibias were used for a stereologic histomorphometric analysis of the tibial-plateau cartilage. The 24 femurs were used for a site-specific, three-dimensional quantitative analysis of the cancellous bone by micro-CT. Compared to the GOHI/SPF guinea pigs, the tibial-plateau cartilage of the Dunkin-Hartley strain had a larger lesion volume (3.8% versus 1.5%) and a thicker uncalcified cartilage layer (0.042 versus 0.035 mm), but a thinner calcified cartilage zone (0.008 versus 0.01 mm) and a thinner subchondral cortical bone plate (0.035 versus 0.039 mm). The femoral cancellous bone in the Dunkin-Hartley strain had a lower bone mineral density (477 versus 509 mg/cm(3)). However, the trabeculae were thicker (3.91 versus 3.53 pixels) and farther apart (7.8 versus 5.6 pixels). The osteoarthritic changes in the cartilage were topographically mirrored in the subchondral bone. They were most severe on the medial side of the joint, particularly in the anterior region. Three-dimensional structural information not revealed by two-dimensional radiography may help characterize the stages of osteoarthritis.

Spontaneous osteoarthritis in the guinea pig is associated with site-specific changes in the articular cartilage layer, which are topographically mirrored in the underlying subchondral bone.

The use of silicone implants in cosmetic and reconstructive surgery has been implicated in the development of autoimmune connective tissue diseases. Previous investigation of the influence of short-term silicone implantation using an experimental model of rheumatoid arthritis revealed no adverse influence upon disease despite the generation of autoantibodies against silicone bound proteins. This study was designed to examine the influence of long term implantation of different forms of silicone in collagen induced arthritis. DBA/1 mice were surgically implanted with silicone elastomers, gel or oil nine months before immunisation with type II collagen emulsified in Freund's incomplete adjuvant. The incidence and severity of arthritis, antibodies to type II collagen, and serum cytokines were assessed and compared with sham implanted mice. Silicone implants were recovered, and autoantibodies to silicone bound proteins evaluated in arthritic and non-arthritic mice. Immunisation with CII/FIA resulted in a 30% arthritis incidence in sham implanted DBA/1 mice. Long term silicone implantation resulted in an increased incidence of arthritis, with a significant increase of 90% arthritis in animals implanted with silicone elastomers. Animals implanted with silicone elastomer also developed foreign body sarcomas during the study. Serum concentrations of interleukin 10 were increased in mice implanted with elastomers and immunised with CII/FIA, while interleukin 5 concentrations were significantly diminished in these mice. The production of autoantibodies to autologous silicone bound proteins, including anti-type I collagen antibody, was also attributed to the implantation of either silicone gel or silicone elastomer in type II collagen immunised animals.

These data suggest that long term silicone implantation results in both the production of autoantibodies to connective tissue antigens and increased susceptibility to an experimental model of autoimmune disease.

Late-onset neutropenia following rituximab therapy is a well-recognized side effect in lymphoma patients, but only a few cases of late-onset neutropenia have been reported in patients with autoimmune disorders. The purpose of this study was to define the incidence, clinical features, and some of the underlying mechanisms of late-onset neutropenia in relation to rituximab use in several rheumatic diseases. We conducted a retrospective analysis of a cohort of 209 consecutive patients with rheumatic diseases who had been treated with rituximab at a university hospital between June 2003 and March 2009. Eleven patients with late-onset neutropenia were identified. The highest incidence was observed in granulomatosis with polyangiitis (Wegener's) and systemic lupus erythematosus patients (23% and 20%, respectively), whereas the incidence in rheumatoid arthritis patients was 3%. The median time to onset of neutropenia was 102 days (range 40-362 days) and coincided with the entire period of B lymphocyte depletion; this depletion was more pronounced in patients with late-onset neutropenia (P = 0.002) than in a control group of 20 matched patients without late-onset neutropenia. Serum IgM levels decreased during the same time and to a significantly greater amount in patients with late-onset neutropenia than in controls (P = 0.027). No patient with late-onset neutropenia displayed specific antineutrophil antibodies. Seven patients were hospitalized because of infections (6 with sepsis and 1 with febrile neutropenia) that required intravenous antibiotics. Six were treated with granulocyte colony-stimulating factor.

In patients treated with rituximab for rheumatic diseases, late-onset neutropenia is a clinically significant adverse event associated with marked B lymphocyte depletion and severe infections. The incidence of late-onset neutropenia appears to vary with autoimmune disease type.

To describe the clinical presentation and course of a relatively large group of Italian adult patients screened for mutation of the homogentisate dioxygenase gene causing alkaptonuria (AKU) and ochronosis, and to review typical and atypical facets of this condition. We reviewed the medical records of 9 patients affected by ochronotic arthropathy who were observed in our institutions between 1979 and 2001. All patients were diagnosed as having AKU through a rapid urine test with alkali. Mutation screening was performed by single-strand conformation analysis of all homogentisate dioxygenase exons, followed by sequencing of altered conformers. Our 9 cases had similar clinical features and they reflected those described in the literature: a progressive degenerative arthropathy mainly affecting axial and weight-bearing joints associated with extraarticular manifestation. Musculoskeletal symptoms began in most of our patients around the age of 30 years with back pain and stiffness: involvement of the large peripheral joints usually occurred several years after spinal changes. Ochronotic peripheral arthropathy generally was degenerative, but joint inflammation was observed in some cases; this could be attributed to an inflammatory reaction of the ochronotic shard in the synovial membrane.

Ochronosis is a model of arthropathy with known etiologic factors. Over time, AKU, the genetically determined metabolic defect, leads to the accumulation of pigment and the development of this crippling condition. Most of the clinical findings may be explained by inhibition of collagen crosslinks, but some require additional interpretation. For example, inflammatory features of the ochronotic joint only occur in a minority of cases, and may be attributable to ochronotic shards. Further studies are needed to establish the genotype-phenotype correlation to identify mutations that are predictive of severe disease. For this purpose, the Italian Study Group on Alkaptonuria (www.dfc.unifi.it/aku) is enrolling affected patients in an on-line database to characterize the molecular defects and their relationship to clinical data.

To determine the cost-effectiveness of arthroscopic surgery in addition to non-operative treatments compared with non-operative treatments alone in patients with knee osteoarthritis (OA). We conducted an economic evaluation alongside a single-centre, randomised trial among patients with symptomatic, radiographic knee OA (KL grade ≥ 2). Patients received arthroscopic debridement and partial resection of degenerative knee tissues in addition to optimised non-operative therapy, or optimised non-operative therapy only. Direct and indirect costs were collected prospectively over the 2-year study period. The effectiveness outcomes were the Western Ontario McMaster Osteoarthritis Index (WOMAC) and quality-adjusted life years (QALYs). Cost-effectiveness was estimated using the net benefit regression framework considering a range of willingness-to-pay values from the Canadian public payer and societal perspectives. We calculated incremental cost-effectiveness ratios and conducted sensitivity analyses using the extremes of the 95% CIs surrounding mean differences in effect between groups. 168 patients were included. Patients allocated to arthroscopy received partial resection and debridement of degenerative meniscal tears (81%) and/or articular cartilage (97%). There were no significant differences between groups in use of non-operative treatments. The incremental net benefit was negative for all willingness-to-pay values. Uncertainty estimates suggest that even if willing to pay $400,000 to achieve a clinically important improvement in WOMAC score, or ≥$50,000 for an additional QALY, there is <20% probability that the addition of arthroscopy is cost-effective compared with non-operative therapies only. Our sensitivity analysis suggests that even when assuming the largest treatment effect, the addition of arthroscopic surgery is not economically attractive compared with non-operative treatments only. NCT00158431.

Arthroscopic debridement of degenerative articular cartilage and resection of degenerative meniscal tears in addition to non-operative treatments for knee OA is not an economically attractive treatment option compared with non-operative treatment only, regardless of willingness-to-pay value.

Camel milk (CM) has shown beneficial anti-inflammatory actions in several experimental and clinical settings. So far, its effect on rheumatoid arthritis (RA) has not been previously explored. Thus, the current work aimed to evaluate the effects of CM in Adjuvant-induced arthritis and air pouch edema models in rats, which mimic human RA. CM was administered at 10 ml/kg orally for 3 weeks starting on the day of Freund's adjuvant paw inoculation. The levels of TNF-α and IL-10 were measured by ELISA while the protein expression of NF-κBp65, COX-2 and iNOS was detected by immunohistochemistry. The expression of MAPK target proteins was assessed by Western blotting. CM attenuated paw edema, arthritic index and gait score along with dorsal pouch inflammatory cell migration. CM lowered the TNF-α and augmented the anti-inflammatory IL-10 levels in sera and exudates of arthritic rats. It also attenuated the expression of activated NF-κBp65, COX-2 and iNOS in the lining of the dorsal pouch. Notably, CM inhibited the MAPK pathway signal transduction via lowering the phosphorylation of p38 MAPK, ERK1/2 and JNK1/2 in rat hind paws. Additionally, CM administration lowered the lipid peroxide and nitric oxide levels and boosted glutathione and total anti-oxidant capacity in sera and exudates of animals.

The observed CM downregulation of the arthritic process may support the interest of CM consumption as an adjunct approach for the management of RA.

To evaluate the midcarpal contact characteristics at the lunocapitate (LC) and scaphotrapezio-trapezoidal (STT) joints in 3 wrist conditions: intact, after simulating a radioscapholunate (RSL) arthrodesis, and after an RSL arthrodesis with distal scaphoid excision (DSE). Eight fresh-frozen cadaveric specimens were tested using a custom jig with the wrist in neutral, 15° and 30° flexion and extension, 10° radial deviation, and 20° ulnar deviation. The RSL arthrodesis was performed using 2.4-mm distal radius plates with locking screws. Using a pressure sensor, contact force, average pressure, peak pressure, and contact area at the STT and LC joints were measured for 3 conditions: intact wrist, RSL arthrodesis, and RSL arthrodesis with DSE. Following RSL arthrodesis, average and peak pressure at the LC joint increased significantly compared to the intact wrist. In the STT joint, the average and peak contact pressure increased significantly compared to the intact wrist. Following DSE, average and peak pressure at the LC joint increased further compared to the RSL arthrodesis condition. Radioscapholunate arthrodesis results in increased midcarpal contact pressures that may explain the clinical incidence of midcarpal arthritis. Excision of the distal scaphoid further increases contact pressures in the remaining midcarpal joint and may further increase the incidence of midcarpal arthritis. These alterations in contact characteristics of the midcarpal joint should be considered when excising the distal scaphoid for improved range of motion.

Our findings showed increased contact pressures in the STT and LC joint following RSL arthrodesis, which may explain the clinical findings of midcarpal arthritis. Also, although DSE may improve short-term range of motion and clinical incidence of midcarpal arthritis, our findings showed that this comes at a cost, as the remaining portions of the midcarpal joint are subject to higher forces and pressures following DSE.

Since the development of posttraumatic osteoarthritis (OA) is a relatively slow process, estimation of OA risk would be of value with regard to chondroprotective measures and medication. In this study we investigated the significance of pro-matrixmetalloproteinase-3 (proMMP-3) for this purpose. Synovial fluid (SF) and serum samples were collected from 259 patients of our trauma clinic at the time of arthroscopy. The extent of cartilage damage was assessed according to the Outerbridge-score. ProMMP-3 levels in SF and serum were determined by enzyme-linked immunosorbent assay (ELISA) using a monoclonal antibody. Additionally we determined SF and serum levels of total MMP-3 and COMP levels as well as TIMP-1 and -2 concentrations in 40 randomly selected patients by ELISA. Serum proMMP-3 levels of the total cohort were markedly increased compared to healthy controls (P<0.007). The comparison of serum and SF lavage proMMP-3 concentrations showed a significant correlation (r(s)=0.41, P<0.0001), however, only 26% of the investigated samples were increased above normal ranges. The grade of cartilage damage did not correlate with enzyme concentration neither in patients' serum nor in SF samples. ProMMP-3 SF concentration was increased early after trauma. Furthermore, proMMP-3 correlated significantly with total MMP-3 serum and SF levels as well as COMP SF levels.

The measurement of proMMP-3 in serum or SF did not reflect the present cartilage damage and thus appears to have only minor potential for clinical use, but it should be considered for longitudinal studies, since it may reflect a risk for cartilage degradation in a subset of patients.

To evaluate the effect of dialysable leucocyte extract (DLE) on pro- and anti-inflammatory profiles in a rat model of osteoarthritis (OA). Forty-eight male Wistar rats were divided into three groups: normal rats without treatment, OA rats treated with placebo, and OA rats treated with DLE. After treatment, the animals were killed to obtain cartilage for histological analysis and to determine the expression of pro- and anti-inflammatory cytokines by reverse transcription multiplex polymerase chain reaction (RT-MPCR) and immunohistofluorescence analyses. Histological analysis revealed that OA cartilage from rats treated with DLE displayed similar characteristics to non-OA cartilage from the control group. The OA cartilage treated with placebo showed alterations in the cellular architecture and in chondrocyte cluster formation. Analysis of cytokine expression by RT-MPCR showed that OA cartilage from DLE-treated rats expressed platelet-derived growth factor (PDGF), interferon (IFN)-γ, and fibroblast growth factor (FGF)-2, similar to non-OA cartilage from the control group. However, OA cartilage from rats treated with placebo expressed interleukin (IL)-1, PDGF, and I kappa B (IκB). Confocal immunodetection of FGF-2, PDGF, and non-phosphorylated IκB showed that they were distributed in the cytoplasm of most chondrocytes in OA cartilage from DLE-treated rats whereas no nuclear factor kappa B (NF-κB) expression was observed in the nuclei. Instead, in OA cartilage from the placebo group, only weak FGF-2 staining was observed, PDGF and IκB were not detected, and NF-κB was strongly observed in both cytoplasm and nuclei.

Our findings suggest that DLE treatment modifies the OA process, promoting the expression of anti-inflammatory cytokines and diminishing the inflammatory effects, avoiding the nuclear translocation of NF-κB in chondrocytes.

To determinate the diagnostic value of an antibody against a citrullinated fibrinogen peptide in Cuban patients with rheumatoid arthritis, using an enzyme immunasay. A citrullinated peptide of fibrinogen designed by informatics prediction was synthesized and used in an enzyme immunoassay. The participants were 81 patients with early disease, 81 patients with established disease, 58 patients with other rheumatic and inflammatory diseases, and 43 healthy individuals. Anti- citrullinated fibrinogen peptide, anti-mutated citrullinated vimentin, anti second generation citrullinated peptides and rheumatoid factor antibodies were determined by enzyme-linked immunosorbent assay. Determination of anti-citrullinated peptide of fibrinogen antibodies by the designed enzyme immunoassay showed the best diagnostic value in early rheumatoid arthritis patients, with the highest value sensitivity (84%), negative predictive value (85%), Youden index (0.73%) and area under the receiver operating curve (0.9192). Specificity (89%) and positive predictive value (88%) were higher than rheumatoid factor, similar to anti- mutated citrullinated vimentin, but lower than second generation anti-citrullinated peptides assay. The positivity of C-reactive protein was associated with the presence of anti- citrullinated fibrinogen peptide antibodies and the titres of these antibodies correlated with clinical activity in early disease.

The immunoassay designed with a citrullinated fibrinogen peptide has a high diagnostic value and can identify patients with greater clinical activity in early rheumatoid arthritis.

Plasmacytoid dendritic cells (PDCs) play a central role in pathogenesis of systemic lupus erythematosus (SLE) through their unique ability to produce large amounts of type I interferon (IFN) upon Toll-like receptor 7 (TLR-7) and TLR-9 triggering. PDCs express specific surface regulatory receptors involved in negative regulation of IFNα secretion. These receptors use the γ-chain of high-affinity Fc receptor (FcR) for IgE, FcɛRI. We undertook this study to test our hypothesis that IgE engagement of FcɛRI on PDCs may impact IFNα production in SLE patients. Serum levels of total IgE were measured in healthy volunteers, SLE patients, and patients with IgE-dependent allergic disorders. FcɛRI expression on PDCs from SLE patients was evaluated by flow cytometry. Purified PDCs were incubated with monoclonal IgE for 24 hours, then stimulated for 18 hours with TLR agonists or immune complexes (ICs). IFNα production by PDCs was detected by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. Expression of TLR-7, TLR-9, and IFN regulatory factor 7 (IRF-7) in PDCs was quantified by quantitative real-time PCR. We observed significantly higher IgE levels in SLE patients with quiescent disease than in those with active disease. In SLE patients, IgE levels correlated inversely with disease activity. IgE levels were not associated with the presence of antinuclear IgE. Purified PDCs treated for 24 hours with monoclonal IgE up-regulated FcɛRI expression in an IgE dose-dependent manner. IgE-treated PDCs significantly decreased IFNα secretion and down-regulated CCR7 expression upon stimulation with TLR-7 and TLR-9 ligands and ICs from lupus patients. IgE treatment down-regulated expression of TLR-9 and IRF-7.

Our results support the notion that IgE plays a protective role in SLE pathogenesis through the modulation of inflammatory response by PDCs.

Posterior glenoid bone loss is commonly encountered in total shoulder arthroplasty (TSA). The purpose of our study is to report the clinical and radiographic findings of patients with a minimum of 2 years' follow-up treated with an all-polyethylene, augmented glenoid component. Twenty-two shoulders with posterior glenoid bone loss were treated by a single surgeon. All underwent primary TSA using a posteriorly augmented, all-polyethylene, stepped glenoid component. Outcome data included visual analog scale, Western Ontario Osteoarthritis of the Shoulder index, and Short Form 36 scores. Radiographic analysis was performed to evaluate bone-cement interface lucency, implant seating, and osseous integration of the central peg. The mean follow-up period was 36 months. Average preoperative retroversion measured with computed tomography scan was 23.5°. In addition to statistically significant increases in forward flexion and external rotation, the visual analog scale score, Western Ontario Osteoarthritis of the Shoulder score, and Short Form 36 physical component summary score all improved significantly (P < .001). Twelve shoulders had osseous integration between the central-peg flanges, 6 had bone adjacent to the central-peg flanges but without identifiable osseous integration, and 1 showed osteolysis. The mean Lazarus score was 0.5. All glenoids had perfect seating scores. Two patients sustained a total of 3 episodes of prosthetic instability.

Early results of a posteriorly augmented, all-polyethylene, stepped prosthetic glenoid component to address posterior glenoid loss in TSA are encouraging. Continued evaluation will determine prosthetic longevity and maintained clinical improvement.

To investigate by high frequency ultrasonography the appearance of calcium pyrophosphate dihydrate (CPPD) calcifications, in the most commonly affected sites in CPPD disease, and the relationship between ultrasonographic CPPD deposits and the presence of CPPD crystals in synovial fluid. Three ultrasonographic patterns of CPPD calcification were identified and 11 patients enrolled. A control group comprised 13 patients with no evidence of CPPD deposits. Synovial fluid was aspirated from all patients and controls and examined for identification of crystals. All patients underwent a standard radiography examination at the same sites investigated by ultrasound. In all patients with ultrasonographically defined CPPD deposits, CPPD crystals were found in the synovial fluid. In two cases, standard radiographic examination did not show evidence of the calcific deposits that were identified by ultrasonography. CPPD crystals were not found in the synovial fluid of controls. In four control group patients, ultrasonography identified calcifications defined as deposits of another nature.

The ultrasonographic pattern used in this study for the diagnosis of CPPD disease demonstrated a very high correlation with the presence of CPPD crystals in synovial fluid. Ultrasonography demonstrated a sensitivity and specificity at least equal to that of radiography in identifying CPPD crystal calcifications.

Fibromyalgia is a prevalent musculoskeletal disorder associated with widespread mechanical tenderness, fatigue, non-refreshing sleep, depressed mood and pervasive dysfunction of the autonomic nervous system: tachycardia, postural intolerance, Raynaud's phenomenon and diarrhoea. To determine the effects of craniosacral therapy on sensitive tender points and heart rate variability in patients with fibromyalgia. A randomized controlled trial. Ninety-two patients with fibromyalgia were randomly assigned to an intervention group or placebo group. Patients received treatments for 20 weeks. The intervention group underwent a craniosacral therapy protocol and the placebo group received sham treatment with disconnected magnetotherapy equipment. Pain intensity levels were determined by evaluating tender points, and heart rate variability was recorded by 24-hour Holter monitoring. After 20 weeks of treatment, the intervention group showed significant reduction in pain at 13 of the 18 tender points (P < 0.05). Significant differences in temporal standard deviation of RR segments, root mean square deviation of temporal standard deviation of RR segments and clinical global impression of improvement versus baseline values were observed in the intervention group but not in the placebo group. At two months and one year post therapy, the intervention group showed significant differences versus baseline in tender points at left occiput, left-side lower cervical, left epicondyle and left greater trochanter and significant differences in temporal standard deviation of RR segments, root mean square deviation of temporal standard deviation of RR segments and clinical global impression of improvement.

Craniosacral therapy improved medium-term pain symptoms in patients with fibromyalgia.

To develop fact sheets about tocilizumab, in order to assist physicians in the management of patients with inflammatory joint disease. 1. selection by a committee of rheumatology experts of the main topics of interest for which fact sheets were desirable; 2. identification and review of publications relevant to each topic; 3. development of fact sheets based on three levels of evidence: evidence-based medicine, official recommendations, and expert opinion. The 20 experts were rheumatologists and invited specialists in other fields, and they had extensive experience with the management of RA. They were members of the CRI (Club Rhumatismes et Inflammation), a section of the Société Francaise de Rhumatologie. Each fact sheet was revised by several. experts and the overall process was coordinated by three experts. Several topics of major interest were selected: contraindications of tocilizumab; the management of adverse effects and concomitant diseases that may develop during tocilizumab therapy; and the management of everyday situations such as pregnancy, surgery, and immunizations. After a review of the literature and discussions among experts, a consensus was developed about the content of the fact sheets presented here. These fact sheets focus on several points: Several topics of major interest were selected: contraindications of tocilizumab; the management of adverse effects and concomitant diseases that may develop during tocilizumab therapy; and the management of everyday situations such as pregnancy, surgery, and immunizations. After a review of the literature and discussions among experts, a consensus was developed about the content of the fact sheets presented here. These fact sheets focus on several points: 1. in RA, initiation and monitoring of tocilizumab therapy, management of patients with specific past histories, and specific clinical situations such as pregnancy; 2. diseases other than RA, such as juvenile idiopathic arthritis; 3. models of letters for informing the rheumatologist and general practitioner; 4. and patient information.

These tocilizumab fact sheets built on evidence-based medicine and expert opinion will serve as a practical tool for assisting physicians who manage patients on tocilizumab therapy. They will be available continuously at www.cri-net.com and updated at appropriate intervals.

Autologous chondrocyte implantation (ACI) aims to restore hyaline cartilage. Traditionally, ACI rehabilitation is prescribed in a concurrent (CON) format. However, it is well known from studies in asymptomatic populations that CON training produces an interference effect that can attenuate strength gains. Strength is integral to joint function, so adopting a nonconcurrent (N-CON) approach to ACI rehabilitation might improve outcomes. To assess changes in function and neuromuscular performance during 48 wk of CON and N-CON physical rehabilitation after ACI to the knee. Orthopedic Hospital NHS Foundation Trust. Randomized control, pilot study. 11 patients (9 male, 2 female; age 32.3 ± 6.6 y; body mass 79.3 ±10.4 kg; time from injury to surgery 7.1 ± 4.9 mo [mean ± SD]) randomly allocated to N-CON:CON (2:1). Standardized CON and N-CON physiotherapy that involved separation of strength and cardiovascular-endurance conditioning. Function in the single-leg-hop test, patient-reported outcomes (Knee injury and Osteoarthritis Outcome Score [KOOS], International Knee Documentation Committee subjective questionnaire [IKDC]), and neuromuscular outcomes of peak force (PF), rate of force development (RFD), electromechanical delay (EMD), and sensorimotor performance (force error [FE]) of the knee extensors and flexors of the injured and noninjured legs, measured presurgery and at 6, 12, 24, and 48 wk postsurgery. Factorial ANOVAs with repeated measures of group by leg and by test occasion revealed significantly superior improvements for KOOS, IKDC, PF, EMD, and FE associated with N-CON vs. CON rehabilitation (F(1.5,13.4 GG) = 3.7-4.7, P < .05). These results confirm increased peak effectiveness of N-CON rehabilitation (~4.5-13.3% better than CON over 48 wk of rehabilitation). N-CON and CON showed similar patterns of improvement for single-leg-hop test and RFD.

Nonconcurrent strength and cardiovascular-endurance conditioning during 48 wk of rehabilitation after ACI surgery elicited significantly greater improvements to functional and neuromuscular outcomes than did contemporary concurrent rehabilitation.

Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor α (TNFα) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs and the possible biological pathways associated with the treatment response to TNFα inhibitors. TNFα-naive patients with RA, who had available DNA and initiated TNFα inhibitor therapy between 1999 and 2008, were identified in the DANBIO registry and genotyped using the Illumina HumanHap550K Duo array. The associations between SNPs and changes in the absolute and the relative Disease Activity Score, and European League Against Rheumatism good versus no response after 14 weeks of treatment were tested. SNP data were combined with two independent cohorts in a meta-analysis. A gene-set enrichment analysis (GSEA) was carried out to identify the biological pathways associated with the treatment response. After genotyping and quality control, 486 450 SNPs were analyzed in 196 Danish patients with moderate to severe RA treated with infliximab (n=142), etanercept (n=12), and adalimumab (n=42). None of the previously identified SNPs were confirmed in our dataset or in meta-analyses of available studies. Other potential SNPs were identified, but none achieved genome-wide significance. A GSEA identified the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways to have a potential influence on the treatment response.

In a genome-wide association study of 196 genetically homogenous Danish patients with RA and in a meta-analysis, we found no SNPs associated with treatment response to TNFα inhibitors. A GSEA suggested that the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways may be associated with treatment response.

In this study, the Spondyloarthritis Research Consortium Canada (SPARCC) scoring method was used to compare treatment methods in patients with axial spondyloarthritis (SpA), a form of sacroiliitis. MRI abnormalities in bone marrow edema (BME) were compared before and after treatment in order to compare the efficacy of anti-TNF-α and DMARD, alone or in combination, as treatments for sacroiliitis. Fifty-six Chinese patients with axial SpA (mean age 22.6 years) were recruited. Patients were divided into three groups according to different treatments (anti-TNF-α alone vs. DMARDs alone vs. combined anti-TNF-α and DMARDs). MRI examinations were performed before and after treatment. The SPARCC score, clinically relevant AS Disease Activity (ASDAS) indices, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were analyzed. After treatment, ASDAS and SPARCC scores, ESR, and CRP were significantly improved (P < 0.05) in the anti-TNF-α monotherapy and combination groups; however, there were no statistically significant differences (P > 0.05) in clinical disease activity and radiological inflammation of sacroiliac joint (SIJ) in patients in the DMARDs alone group. SPARCC showed a correlation with ASDAS score pre-treatment, but not post-treatment. Furthermore, there were significant changes (P < 0.05) in these patients with axial SpA after only 3 months of treatment. Follow-up studies of patients who continued therapy for 4-6 months and 9-12 months revealed statistically significant differences from baseline (P < 0.05).

SPARCC can be used to assess severity of disease pre-treatment. Anti-TNF-α treatment resulted in effective reduction of disease activity and BME of SIJ after 3 months of therapy.

To identify the factors having the greatest effect on the Medical Outcomes Study 36-Item Short-Form Health Survey, version 2 (SF-36v2) score after total hip arthroplasty (THA). Retrospective review. Private 150-bed hospital. Patients (N=659) who underwent initial THA for osteoarthritis (OA) of the hip between April 2007 and January 2009. A total of 138 patients who fulfilled the inclusion criteria were seen at the first follow-up, while 108 patients were included in the second follow-up; all 30 patients excluded at the second follow-up underwent contralateral THA between follow-ups. The average time ± SD from surgery to first follow-up was 195.1±67.7 days, and that to second follow-up was 443.0±108.5 days. Patients' average age ± SD was 61.1±9.9 years at first follow-up and 61.3±10.3 years at second follow-up. Women accounted for 85.5% of patients at first follow-up and 85.2% at second follow-up. Not applicable. Eight subscales of the SF-36v2, age, sex, body mass index, complications, living alone, contralateral hip OA, range of hip joint motion, walking aids, and preoperative mental health (MH) values from the SF-36v2. Canonical correlation analysis showed that contralateral hip OA had a major effect on the SF-36v2 score at the first follow-up. At the second follow-up, excluding the 30 patients who had undergone contralateral THA, physical function measured by the SF-36v2 was strongly affected by age, and other items were strongly affected by preoperative MH.

When using the SF-36v2 as an assessment scale after THA, adjustments should be made for contralateral hip OA. Moreover, age and preoperative MH should also be considered.

Knee osteoarthritis (KOA) is a common progressive joint disorder in old people. Bushen huoxue (BSHX) is a classical method of TCM in treating KOA. However, there is no systematic review related to BSHX for KOA. The purpose of this study is to provide a comprehensive and reliable evaluation of the clinical evidence of BSHX in the treatment of KOA. We searched relevant studies on BSHX for KOA from the databases of PubMed, Embase, MEDLINE, Cochrane Library Central Register of Controlled Trials, China national knowledge infrastructure database (CNKI), Wan fang database, Chongqing VIP information, and SinoMed from their inception to May 2020. Two researchers will select and evaluate qualified studies independently. The primary outcomes of this review will focus on pain intensity. The meta-analyses will be performed by using the RevMan 5.3. The study will provide a comprehensive evaluation of the efficacy and safety of the BSHX method for patients with KOA.

The results of this systematic review will provide evidence to judge whether BSHX is an effective intervention for patients with KOA.

To determine if several multisystem comorbid conditions occur more frequently in subjects with tilt-table defined postural tachycardia syndrome (POTS) compared with those without. Retrospective chart review of 67 subjects aged 6-24 years, referred to a tertiary care neurogastroenterology and autonomic disorders clinic for a constellation of functional gastrointestinal, chronic pain, and autonomic complaints. All patients underwent formal autonomic testing, Beighton scores assessment for joint hypermobility (0-9), and fibromyalgia tender points (0-18) (43 subjects). Twenty-five subjects (37%) met tilt table criteria for POTS. The median age of 16 years (range, 12-24 years) in the POTS group differed from 15 years (range, 6-21 years) in the no-POTS group (P = .03). Comorbidities including chronic fatigue, sleep disturbances, dizziness, syncope, migraines, functional gastrointestinal disorders, chronic nausea, fibromyalgia, and joint hypermobility did not differ between groups. All subjects with fibromyalgia by tender point-examination had a Beighton score ≥ 4 (P = .002).

Comorbid conditions are equally prevalent in children and young adults with and without tilt-table defined POTS, suggesting that POTS itself is not a cause of the other comorbidities. Instead, POTS likely reflects another comorbid condition in children with functional disorders. Dizziness and syncope, classically associated with POTS, are not predictive of a diagnosis of POTS by tilt table, a test that is still required for formal diagnosis. These results suggest a paradigm shift in the concept of POTS as the physiological basis of many functional symptoms.

To evaluate the influence of stem offset and neck shaft angles on the range of motion before component impingement (ROMCI) and bony impingement (ROMBI), and the types of impingement in total hip arthroplasty (THA). Using the computed tomography data of 101 patients who underwent THA, three-dimensional dynamic motion analysis was performed using a modular implant (Kinectiv(®) stem) that enabled adjustment of offset and leg length independently. We defined offset as horizontal offset (HO) and leg length as vertical offset (VO), and measured the ROMCI and ROMBI in flexion (Flex), internal rotation (Int-R) and external rotation (Ext-R) with the configuration of each horizontal/vertical offset. We found that HO lengthening increased the ROMCI and ROMBI in Flex and Int-R by delaying bony impingement, although excessive lengthening had minimal effect. On the contrary, VO lengthening decreased the ROMCI and ROMBI in Flex and ROMCI in Int-R. As for Ext-R, VO lengthening had positive effects on the ROMCI and ROMBI, whereas lengthening of HO had negative effects on the ROMCI and ROMBI.

We demonstrated that the appropriate long offset with a low shaft angle increased the ROM in Flex and Int-R, and a high neck shaft angle increased the ROM in Ext-R. We should use implants properly in accordance with the types of impingement for avoiding dislocations in THA.

To determine if treatment with the sympathomimetic amine dextroamphetamine sulfate, which has been so effective in treating a variety of pain syndromes, including severe pelvic pain and interstitial cystitis in women with the sympathetic neural hyperalgesia edema syndrome would also mitigate pain from fibromyalgia which was resistant to multiple therapies. Dextroamphetamine sulfate extended release capsules once daily was gradually increased to 25 mg per day in a woman with treatment resistant fibromyalgia of 20 years duration. Within a short time, the woman experienced dramatic relief of pain. Furthermore, her edema improved resulting in a 27 pound weight loss and her chronic fatigue improved.

Fibromyalgia can be effectively treated with an innocuous dose of dextroamphetamine sulfate.

We sought to identify metabolic changes potentially related to rheumatoid arthritis (RA) pathogenesis occurring in the blood prior to its diagnosis. In a US military biorepository, serum samples collected at two timepoints prior to a diagnosis of RA were identified. These were matched to controls who did not develop RA by subject age, race and time between sample collections and RA diagnosis time to stored serum samples. Relative abundances of 380 metabolites were measured using liquid chromatography-tandem mass spectrometry. We determined whether pre-RA case versus control status predicted metabolite concentration differences and differences over time (trajectories) using linear mixed models, assessing for interactions between time, pre-RA status and metabolite concentrations. We separately examined pre-RA and pre-seropositive RA cases versus matched controls and adjusted for smoking. Multiple comparison adjustment set the false discovery rate to 0.05. 291 pre-RA cases (80.8% pre seropositive RA) were matched to 292 controls, all with two serum samples (2.7±1.6 years; 1.0±0.9 years before RA/matched date). 52.0% were women; 52.8% were White, 26.8% Black and 20.4% other race. Mean age was 31.2 (±8.1) years at earliest blood draw. Fourteen metabolites had statistically significant trajectory differences among pre-RA subjects versus controls, including sex steroids, amino acid/lipid metabolism and xenobiotics. Results were similar when limited to pre seropositive RA and after adjusting for smoking.

In this military case-control study, metabolite concentration trajectory differences in pre-RA cases versus controls implicated steroidogenesis, lipid/amino acid metabolism and xenobiotics in RA pathogenesis. Metabolites may have potential as biomarkers and/or therapeutic targets preceding RA diagnosis.

To study the effect of platelet-rich plasma (PRP) injections on pain reduction in patients with temporomandibular joint osteoarthritis (TMJ OA). The authors performed a comprehensive search of the MEDLINE, PubMed, and Web of Science databases to retrieve RCTs published up to July 2018. Pain outcomes (visual analog scale scores) were extracted to assess the effect of PRP injections on TMJ OA. All data analyses were conducted using RevMan 5.3. Six studies were included. According to the results of these trials, intra-articular injections of PRP were more effective than placebo for pain reduction (6 months postinjection: mean difference [MD] -2.82, 95% CI -3.39 to -2.25, P < .00001; 12 months postinjection: MD -3.29; 95% CI -4.07 to -2.52, P < .00001). Additionally, the comparison between PRP and hyaluronic acid injections showed a statistically significant difference in pain reduction in support of PRP (MD -0.81; 95% CI -1.22 to -0.40; P = .0001) at 12 months postinjection. All trials revealed a moderate risk of bias.

Based on current evidence, PRP injections may reduce pain more effectively than placebo injections in TMJ OA at 6 months (level of evidence: moderate) and 12 months (level of evidence: moderate) postinjection. This significant difference in pain reduction could also be seen when PRP was compared to hyaluronic acid at 12 months postinjection (level of evidence: low). It can be cautiously interpreted that PRP has a beneficial effect on the relief of TMJ OA pain. Large-scale, low-bias RCTs are needed to test whether PRP injection should be a routine treatment for patients with TMJ OA.

To investigate whether central nervous system (CNS) stimulants used for the treatment of attention deficit hyperactivity disorder (ADHD) are associated with the development of Raynaud's syndrome (RS). A case-control design was used for this study. All patients seen in a pediatric rheumatology practice during a 5-year period who had signs and symptoms of RS and met diagnostic criteria for RS as determined by pulse volume recording were studied as cases. Controls were randomly selected patients at the same clinic who did not have signs or symptoms of RS. They were matched to the cases for age, sex, and time of presentation. We tested for associations between various CNS medications and presence of RS. We also evaluated differences in laboratory test results between RS cases and matched controls. Sixty-four patients were enrolled in the study (32 cases with RS [23 female, 9 male] and 32 control patients). McNemar's test showed a significant association between the presence of RS and past or current use of ADHD stimulants (methylphenidate and dextroamphetamine) (chi(2) = 5.00, P = 0.01). The use of other CNS medications was not found to be significantly associated with RS (chi(2) = 1.33, P = 0.25 by McNemar's test). C-reactive protein levels and erythrocyte sedimentation rates were significantly higher in controls than in cases.

The results of this study indicate that there is a significant association between development of RS and therapy with CNS stimulants used for the treatment of ADHD. Although this was a small study, these findings provide preliminary evidence of an adverse effect of CNS stimulant medications in patients seen in rheumatology practice.

The aim of this study was to assess intraobserver and interobserver reliability of minor salivary gland biopsy (MSGB) in SS. All MSGBs available from the Tolerance and Efficacy of Rituximab in Primary Sjögren's Syndrome (TEARS) study were subjected to a standardized blinded assessment by a single specifically trained pathologist twice at a 2 month interval; both the Chisholm-Mason (CM) grade and the focus score (FS) were determined. Baseline histopathological reports by local pathologists at each study centre were compared with the first standardized blinded assessment. Agreement was assessed for the dichotomized FS (dFS) and dichotomized CM (dCM) grade, as well as for nine other histopathological features. Eighty-nine MSGBs were studied. Intraobserver κ values were 1 for dFS, 0.80 for dCM, 0.67 for germinal centre-like structures, 0.44 for fibrosis and 0.29 for confluent foci. Most of the local histopathological reports based their diagnosis on the CM grade, although the FS was often reported or the data needed to determine it were provided. Interobserver agreement κ values were 0.71 for dFS, 0.64 for dCM, 0.46 for focal lymphocytic sialadenitis, 0.42 for non-specific chronic inflammation and 0.16 for fibrosis.

Although FS reliability was good, disparities were noted in the assessment methods used by local pathologists. The protocol for FS determination was not followed routinely, with the result that the FS was often overestimated. Germinal centre-like structures, which predict lymphoma, showed good reliability but were inconsistently reported.

A 60-year-old man presented with left hip pain, and a radiograph showed reduced joint space. During the surgical procedure for a total hip replacement, a proximal femur mass was identified and biopsy was subsequently interpreted as grade 2 chondrosarcoma. A wide resection was needed, but he developed local recurrence after 2 years and was treated with an external hemipelvectomy.

Chondrosarcoma does not always present with a classical clinical picture or imaging, and it can be misdiagnosed. Practitioners should be highly suspicious of malignant disease as a cause for hip pain even if there is no direct indication of a neoplasm such as chondrosarcoma.