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Arthritis Research & Therapy - Latest Articles

IL-10 produced by B cells is crucial for the suppression of Th17/ Th1 responses, induction of Tr1 cells and reduction of collagen-induced arthritis
Natalie CarterElizabeth RosserClaudia Mauri Wed, 08 Feb 2012 00:00:00 -0000
IntroductionInterleukin-10 (IL-10) producing B cells, also known as regulatory B (Breg) cells, play a key role in controlling autoimmunity. Our laboratory and others have demonstrated a pivotal role for Bregs in rheumatological disorders including experimental models of arthritis and lupus. The aim of this study was to identify the role of endogenous IL-10 secreting B cells in vivo in controlling the induction and disease progression of collagen- induced arthritis (CIA). Methods: We generated chimeric mice that had IL-10 knocked out specifically in the B cell population. These mice were compared with wild-type (WT) B cell chimeric mice for their susceptibility to CIA. Results: Here we report that chimeric mice specifically lacking IL-10 producing B cells (IL-10-/- B cell) developed an exacerbated CIA compared to chimeric wild type B cell (WT B cell) mice. A marked increase in inflammatory Th1 and Th17 cells were detected in IL-10-/-B cell mice compared to WT B cell mice. Furthermore there was a reduction in IL-10 secreting CD4+ Tr1 cells in these animals. Conclusions: IL-10 producing B cells restrain inflammation by promoting differentiation of immuno-regulatory over pro-inflammatory T cells and hence act to maintain tolerance.
Direct transplantation of mesenchymal stem cells into the knee joints of Hartley Strain guinea pig with spontaneous osteoarthritis
Mitsuhiko SatoKenzo UchidaHideaki NakajimaTsuyoshi MiyazakiAlexander Rodriguez GuerreroShuji WatanabeSally RobertsHisatoshi Baba Tue, 07 Feb 2012 00:00:00 -0000
IntroductionMesenchymal stem cells (MSCs) can differentiate into various connective tissue cells. Several techniques have been used for the clinical application of MSCs in articular cartilage repair, however, there are many issues associated with the selection of the scaffold material, including its ability to support cell viability and differentiation and its retention and degradation in situ. The application of MSCs via a scaffold also requires a technically demanding surgical procedure. The aim of this study was to test the outcome of intra-articular transplantation of mesenchymal stem cells suspended in hyaluronic acid (HA) in the knee joints of Hartley strain guinea pigs with spontaneous osteoarthritis (OA). Methods: Commercially-available human MSCs were cultured, labeled with carboxyfluorescein diacetate succinimidyl ester (CFDA-SE), suspended in either phosphate-buffered-saline (PBS) or HA, and injected into the knee joints of 7-month-old animals. The control animals were injected with either PBS or HA alone. The animals were sacrificed at 1, 3, and 5 weeks post-transplantation and the knee joints harvested, fluorescent microscopic analysis was performed. Histological and immunohistochemical analysis were performed at 5 weeks post-transplantation. Results: At 5 weeks post-transplantation, partial cartilage repair was noted in the HA-MSC group but not in the other groups. Examination of CFDA-SE-labeled cells demonstrated migration, differentiation and proliferation of MSC in the HA-MSC group. There was strong immunostaining for type-II collagen around both residual chondrocytes and transplanted MSCs in the OA cartilage. Conclusions: This scaffold-free and technically un-demanding technique appears to result in the regeneration of articular cartilage in the spontaneous OA animal model. Although further examination of the long-term effects of transplantation is necessary, the findings suggest that intra-articular injection of a mixture of MSCs-HA is potentially beneficial for OA.
Baseline serum MMP-3 levels in patients with rheumatoid arthritis are still independently predictive of radiographic progression in a longitudinal observational cohort at 8 years follow up
Mark HousemanCatherine PotterNicola MarshallRachel LakeyTim CawstonIan GriffithsSteven Young-MinJohn Isaacs Tue, 07 Feb 2012 00:00:00 -0000
IntroductionAt present, there is no reliable tool for predicting disease outcome in patients with rheumatoid arthritis (RA). We previously demonstrated an association between specific baseline biomarkers/clinical measures including matrix metalloproteinase-3 (MMP-3) and 2-year radiographic progression in patients with RA. This study further evaluates the predictive capability of these baseline variables with outcome extended over 8-years. Methods: Fifty-eight of the original cohort (n=118) had radiographic progression from baseline to mean 8.2-years determined using the van der Heijde modified Sharp method. The contribution of each predictor variable towards radiographic progression was assessed with univariate and multivariate analyses. Results: Traditional factors (including erythrocyte sedimentation rate, C-reactive protein, anti-cyclic citrullinated peptide (anti-CCP), and rheumatoid factor) and biomarkers of tissue destruction (including MMP-3, C-telopeptide of type II collagen, cartilage oligomeric matrix protein, and tissue inhibitor of metalloproteinase 1) measured at baseline were associated with radiographic progression at endpoint. Multivariate logistic regression identified anti-CCP seropositivity [OR 9.29, 95%CI: 2.29-37.64], baseline elevated MMP-3 [OR 8.25, 95%CI: 2.54-26.78] and baseline radiographic damage [OR 5.83, 95%CI: 1.88-18.10] as the strongest independent predictors of radiographic progression. A model incorporating these variables had a predictive accuracy of 0.87, assessed using the area under the receiver operating characteristic curve. Conclusion: In our cohort with onset of RA symptoms <2-years, multivariate analysis identified anti-CCP status and baseline MMP-3 as the strongest independent predictors of radiographic disease outcome at 8.2-years. This finding suggests determination of baseline MMP-3, in conjunction with traditional serologic markers, may provide additional prognostic information for patients with RA. Furthermore, these findings highlight the importance of continued research into a broad range of biomarkers as potential predictors of joint damage.
The neuropeptide neuromedin U promotes autoantibody-mediated arthritis
Sindhuja RaoJennifer AugerPhilippe GaillardRalph WeisslederEtsuko WadaRichard TorresMasayasu KojimaChristophe BenoistDiane MathisBryce Binstadt Tue, 07 Feb 2012 00:00:00 -0000
IntroductionNeuromedin U (NMU) is a neuropeptide with pro-inflammatory activity. The primary objective of this study was to determine if NMU promotes autoantibody-induced arthritis. Additional studies addressed the cellular source of NMU and sought to define the NMU receptor responsible for its pro-inflammatory effects. Methods: Serum containing arthritogenic autoantibodies from K/BxN mice was used to induce arthritis in mice genetically lacking NMU. Parallel experiments examined whether NMU deficiency impacted the early mast-cell-dependent vascular leak response induced by these autoantibodies. Bone-marrow chimeric mice were generated to determine whether pro-inflammatory NMU is derived from hematopoietic cells or stromal cells. Mice lacking the known NMU receptors singly and in combination were used to determine susceptibility to serum-transferred arthritis and in vitro cellular responses to NMU. Results: NMU-deficient mice developed less severe arthritis than control mice. Vascular leak was not affected by NMU deficiency. NMU expression by bone-marrow-derived cells mediated the pro-arthritogenic effect. Deficiency of all of the known NMU receptors, however, had no impact on arthritis severity and did not affect the ability of NMU to stimulate intracellular calcium flux. Conclusions: NMU-deficient mice are protected from developing autoantibody-induced inflammatory arthritis. NMU derived from hematopoietic cells, not neurons, promotes the development of autoantibody-induced inflammatory arthritis. This effect is mediated by a receptor other than the currently known NMU receptors.
Low copy number of the FCGR3B gene and rheumatoid arthritis: a case control study and meta-analysis
Scott GrafSue LesterHans NossentCatherine HillSusanna ProudmanAnita LeeMaureen Rischmueller Tue, 07 Feb 2012 00:00:00 -0000
IntroductionLow copy number (CN) of the Fc gamma receptor 3B (FCGR3B) gene has been associated with systemic autoimmune disease. This receptor for IgG is present almost exclusively on neutrophils and plays a role in their interaction with immune complexes. At present the relationship between FCGR3B and rheumatoid arthritis (RA) is unclear. The aim of this study was to investigate whether low CN of the FCGR3B gene is associated with susceptibility to RA.MethodFCGR3B CN was determined using a custom Taqman(R) copy number assay (Applied Biosystems, Hs04211858) in 197 RA patients, recruited from a tertiary setting, and 162 population matched controls. Odds ratios for low CN (2), both relative to the normal diploid two CN, were estimated by logistic regression. Results: A significant association between RA and low FCGR3B CN was observed, with frequencies of 13.7% in RA patients compared to 6.2% in controls (OR 2.5 95%CI 1.2-5.4 p=0.017). No association was observed between low CN and the presence of rheumatoid factor (RF), anti-CCP antibodies or radiographic erosions in RA patients. A meta-analysis, including six previous studies, confirmed an association between RA and low FCGR3B CN (OR 1.47, 95% CI 1.13, 1.92, p = 0.004) Conclusions: This study confirms that low CN of the FCGR3B gene is associated with susceptibility to RA. The association may be stronger in patients recruited from a tertiary setting, which may relate to disease severity and/or complications. The mechanism of susceptibility remains unclear and further study is required.
Pre-disease pregnancy complications and systemic sclerosis: pathogenic or pre-clinical?
Eliza Chakravarty Mon, 06 Feb 2012 00:00:00 -0000
The fetal microchimerism theory for the pathogenesis of systemic sclerosis (SSc) has compelling biologic support, including the female predominance of the disease, the mean age of onset after childbearing years, similarities between diffuse cutaneous SSc and graft-versus-host disease, as well as the detection of microchimeric cells in peripheral blood and skin of SSc patients. The previous issue of Arthritis Research and Therapy presents findings of a positive association between pregnancy complications and future diagnosis of SSc in parous women. Before interpreting the results of this epidemiologic study as support for fetal microchimerism, however, other theories for the observed associations must be considered.

Annals of the Rheumatic Diseases current issue

Inflammation and ankylosis: still an enigmatic relationship in spondyloarthritis
Lories, R. J. U., Dougados, M. Mon, 06 Feb 2012 23:37:03 -0800
The introduction of targeted therapies against cytokine tumour necrosis factor (TNF) alpha has dramatically changed the management, prognosis and perspectives of patients with ankylosing spondylitis (AS) and related forms of spondyloarthritis.1 Both the soluble TNF receptor etanercept and the different anti-TNF antibodies are highly successful in reducing the signs and symptoms of disease, thereby improving quality of life, participation in the work force and the overall wellbeing of patients.2 3 Clinical evidence suggests that anti-TNF therapies are more successful and the effect more sustained than in other diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease.4 However, in contrast to what is seen in patients with RA, anti-TNF does not appear to have an impact on the structural progression of disease, a process characterised by ankylosis of the spine and sacroiliac joints in spondyloarthritis patients.5–A systematic literature review of drug therapies for the treatment of psoriatic arthritis: current evidence and meta-analysis informing the EULAR recommendations for the management of psoriatic arthritis
Ash, Z., Gaujoux-Viala, C., Gossec, L., Hensor, E. M., FitzGerald, O., Winthrop, K., van der Heijde, D., Emery, P., Smolen, J. S., Marzo-Ortega, H. Mon, 06 Feb 2012 23:37:03 -0800
Objectives To review the available evidence for the efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs), synthetic and biological drug therapies for the different clinical manifestations of psoriatic arthritis (PsA) in order to provide data for the development of treatment recommendations by the European League Against Rheumatism (EULAR) taskforce. Methods A systematic literature review (SLR) of available treatments for PsA was performed using the largest electronic databases (MEDLINE, EMBASE and COCHRANE) by two working groups formed within the EULAR taskforce. This comprised a comprehensive sample of rheumatologists, dermatologists, epidemiologists and patients. The available evidence was reviewed for NSAIDs, synthetic disease modifying antirheumatic drugs (DMARDs), local and systemic corticosteroids and biologic drugs. All articles and abstracts published between 1962 and January 2010 were reviewed and considered and a meta-analysis of data on biological therapies was performed. Results While little data are available on NSAIDs, glucocorticoids and synthetic DMARDs, the available evidence suggests an acceptable efficacy and safety profile of both NSAIDs and synthetic DMARDs (methotrexate, cyclosporine A, sulfasalazine and leflunomide) in PsA. More evidence is available (level 1B) supporting the efficacy of anti-tumour necrosis factor (anti-TNF) agents (adalimumab, etanercept, golimumab and infliximab) in treating the signs and symptoms of PsA as well as reducing radiographic progression. Registry data show no new safety concerns, although the numbers studied to date are relatively small. Conclusions This SLR reveals some evidence to support the use of NSAIDs and synthetic DMARDs and good evidence for the efficacy of anti-TNF therapy in PsA.
Rituximab for refractory granulomatosis with polyangiitis (Wegener's granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations
Holle, J. U., Dubrau, C., Herlyn, K., Heller, M., Ambrosch, P., Noelle, B., Reinhold-Keller, E., Gross, W. L. Mon, 06 Feb 2012 23:37:03 -0800
Objective First, to investigate the overall efficacy and safety of rituximab (RTX) in refractory granulomatosis with polyangiitis (GPA) in a tertiary referral centre. Second, to compare the efficacy of RTX in granulomatous and vasculitic manifestations in GPA. Patients and methods This study comprised a retrospective, standardised data collection from all patients who received RTX for refractory Wegener's granulomatosis from 2002 to 2010. Patients were assessed by a standardised interdisciplinary diagnostic procedure (including ear, nose and throat and ophthalmology assessment, MRI, immunodiagnostics, B-cell levels and Birmingham Vasculitis Activity Score) and were treated by standardised therapeutic regimens according to available evidence. Results 59 patients received 75 cycles of RTX. 9.3% achieved complete remission. A response was documented in 61.3% (improvement in 52%, unchanged disease activity in 9.3%), 26.7% had refractory disease. Birmingham Vasculitis Activity Score, disease extent index, erythrocyte sedimentation rate, C-reactive protein and prednisolone demand decreased significantly. All patients achieved B-cell depletion. Granulomatous manifestations such as orbital granuloma and pachymeningitis were more frequently refractory to RTX than vasculitis or other granulomatous manifestations. Thus, for example, complete remission/improvement was found in 89.2% of patients with renal disease and in only 44.4% of those with orbital masses (p=0.003). The relapse rate was 44.4% after a median period of 13.5 months. Adverse events occurred in 29%, pneumonia in 15% and death in 3%. Conclusion The overall response rate of refractory GPA to RTX was high (61.3% complete remission or improvement). Response rates of vasculitic manifestations were excellent; failure of response/progress was mostly due to granulomatous manifestations, especially orbital masses. Relapse rates were high (40%) despite maintenance treatment.
Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern
Ambrosi, A., Salomonsson, S., Eliasson, H., Zeffer, E., Skog, A., Dzikaite, V., Bergman, G., Fernlund, E., Tingstrom, J., Theander, E., Rydberg, A., Skogh, T., Ohman, A., Lundstrom, U., Mellander, M., Winqvist, O., Fored, M., Ekbom, A., Alfredsson, L., Kallberg, H., Olsson, T., Gadler, F., Jonzon, A., Kockum, I., Sonesson, S.-E., Wahren-Herlenius, M. Mon, 06 Feb 2012 23:37:03 -0800
Objective Congenital heart block may develop in the fetuses of Ro/SSA-positive and La/SSB-positive mothers. Recurrence rates of only 10–20% despite persisting maternal antibodies indicate that additional factors are critical for the establishment of heart block. The authors investigated the influence of other maternal and fetal factors on heart block development in a Swedish population-based cohort. Methods The influence of fetal gender, maternal age, parity and time of birth on heart block development was analysed in 145 families, including Ro/La-positive (n=190) and Ro/La-negative (n=165) pregnancies. Results There was a recurrence rate of 12.1% in Ro/La-positive women, and no recurrence in Ro/La-negative women. Fetal gender and parity did not influence the development of heart block in either group. Maternal age in Ro/La-positive pregnancies with a child affected by heart block was, however, significantly higher than in pregnancies resulting in babies without heart block (p<0.05).Seasonal timing of pregnancy influenced the outcome. Gestational susceptibility weeks 18–24 occurring during January–March correlated with a higher proportion of children with heart block and lower vitamin D levels during the same period in a representative sample of Swedish women and a corresponding higher proportion of children with heart block born in the summer (p<0.02). Maternal age or seasonal timing of pregnancy did not affect the outcome in Ro/La-negative pregnancies. Conclusion This study identifies maternal age and seasonal timing of pregnancy as novel risk factors for heart block development in children of Ro/La-positive women. These observations may be useful for counselling when pregnancy is considered.
Subclinical renal dysfunction is independently associated with cardiovascular events in rheumatoid arthritis: the CARRE Study
van Sijl, A. M., van den Oever, I. A. M., Peters, M. J. L., Boers, M., Dijkmans, B. A. C., van Halm, V. P., Smulders, Y. M., Voskuyl, A. E., Nurmohamed, M. T. Mon, 06 Feb 2012 23:37:03 -0800
Background Patients with rheumatoid arthritis (RA) have double the risk of cardiovascular (CV) disease, largely independently of traditional CV risk factors. Renal dysfunction is associated with CV morbidity and mortality in the general population, but data on this association in RA are lacking. Objective To investigate the association between renal function and CV events in RA. Methods The CARRÉ Study is an ongoing prospective cohort study of Dutch patients with RA, which records CV events. Glomerular filtration rate (GFR) was estimated with the abbreviated Modification of Diet in Renal Disease formula. Logistic regression determined the association between estimated GFR and the occurrence of CV events. Results 353 patients were followed for 3 years, and 23 (7%) had a CV event. Patients who had an event had a significantly lower baseline GFR than those who did not (59 vs 79 ml/min, p=0.001). This association remained significant after adjustment for traditional risk factors: in this analysis, a decrease in GFR of 5 ml/min was associated with a 30% (95% CI 7% to 59%) increase in the occurrence of CV events. During follow-up, an unfavourable change in GFR was noted in patients who later had a CV event compared with those who did not. Conclusion These data confirm that, in RA, renal dysfunction is associated with a higher risk of CV disease independently of traditional CV risk factors.
Comparison of features by MRI and radiographs of the interphalangeal finger joints in patients with hand osteoarthritis
Haugen, I. K., Boyesen, P., Slatkowsky-Christensen, B., Sesseng, S., Bijsterbosch, J., van der Heijde, D., Kvien, T. K. Mon, 06 Feb 2012 23:37:03 -0800
Objectives To examine the construct validity of MRI in the detection of structural hand osteoarthritis features with conventional radiography (CR) as reference and explore the association between radiographic severity and MRI-defined pathology. Methods 106 hand osteoarthritis patients (97 women, mean age 68.9 years (SD 5.6)) had 1.0T contrast-enhanced MRI and CR of the dominant hand. The 2nd–5th interphalangeal joints were scored according to the preliminary Oslo hand osteoarthritis MRI score and Kellgren–Lawrence (KL) scale and Osteoarthritis Research Society International atlas for radiographs. The authors compared the number of joints with structural features by MRI and CR (Wilcoxon signed-rank test) and examined concordance at the individual joint level. The OR of MRI features in joints with doubtful (KL grade 1), mild (2) and moderate/severe (≥3) radiographic osteoarthritis was estimated by generalised estimating equations (KL grade 0 as reference). Results MRI detected approximately twice as many joints with erosions and osteophytes compared with CR (p<0.001), but identification of joint space narrowing, cysts and malalignment was similar. The sensitivity of MRI was very high for osteophytes (1.00) and erosions (0.95), while specificity was lower (0.22 and 0.63). The prevalence of most MRI features increased with radiographic severity, but synovitis was more frequent in joints with mild osteoarthritis (OR2.1, 95% CI 1.4 to 3.2) than in moderate/severe osteoarthritis (OR1.4, 95% CI 1.0 to 2.2). Conclusion MRI detected more osteophytes and erosions than CR, suggesting that erosive osteoarthritis may be more common than indicated by CR. Synovitis was most common in mild osteoarthritis. Whether this is due to burn-out of inflammation in late disease must be investigated further.

 

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