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Arthritis Research & Therapy - Latest articles

Circulating immune complexes contain citrullinated fibrinogen in rheumatoid arthritis
Xiaoyan Zhao, Nwora L Okeke, Orr Sharpe, Franak M Batliwalla, Annette T Lee, Peggy P Ho, Beren H Tomooka, Peter K Gregersen and William H Robinson Mon, 18 Aug 2008 00:00:00 -0000
IntroductionThere is increasing evidence that autoantibodies and immune complexes (ICs) contribute to synovitis in rheumatoid arthritis (RA), yet the autoantigens incorporated in ICs in RA remain incompletely characterized. Methods: We utilized C1q to capture ICs from plasma derived from human RA and control patients, followed by detection with antibodies specific for: (i) immunoglobulin to detect ICs, and (ii) fibrinogen to detect fibrinogen-containing ICs. RA and control plasma were separated by liquid chromatography, and fractions characterized by ELISA, immunoblotting and mass spectrometry. Immunohistochemical staining was performed on rheumatoid synovial tissue. Results: C1q-immunoassays demonstrated increased levels of IgG (P = 0.01) and IgM (P = 0.0002) ICs in plasma derived from RA patients possessing anti-cyclic citrullinated peptide autoantibodies (CCP+) as compared to healthy controls. About one-half of the CCP+ RA possessed circulating ICs containing fibrinogen (P = 0.0004). Fractionation of whole RA plasma revealed citrullinated fibrinogen in the high molecular weight fractions that contained immune complexes. Positive correlations were observed between fibrinogen containing immune complex and anti-citrullinated fibrinogen autoantibodies, anti-CCP antibody, rheumatoid factor and certain clinical characteristics. Immunohistochemical staining demonstrated co-localization of fibrinogen, immunoglobulin and complement component C3 in RA pannus tissue. Mass spectrometry analysis of immune complexes immunoprecipitated from RA pannus tissue lysates demonstrated the presence of citrullinated fibrinogen. Conclusions: Circulating ICs containing citrullinated fibrinogen are present in one-half of CCP+ RA patients, and these immune complexes co-localize with C3 in the rheumatoid synovium suggesting that they contribute to synovitis in a subset of RA patients.
TH-17 cells in rheumatoid arthritis
Shiva Shahrara, QiQuan Huang, Arthur M. Mandelin and Richard M. Pope Mon, 18 Aug 2008 00:00:00 -0000
IntroductionThis study was conducted to quantify the number of TH-17 cells present in rheumatoid arthritis (RA) synovial fluid (SF) and the to determine the level of IL-17 cytokine in RA, osteoarthritis (OA) and normal synovial tissue, as well as to examine SF macrophages for the presence of IL-23, IL-27 and interferon (IFN)-g. Methods: Peripheral blood (PB) mononuclear cells from normal and RA donors and mononuclear cells from RA SF were examined either without stimulation, or after pretreatment with IL-23 followed by stimulation with PMA plus ionomycin (P/I). The abundance of TH-17 cells in RA SF was determined by flow cytometry. IL-17 levels were quantified in synovial tissue from RA, OA and normal individuals by ELISA. IL-23 was identified in SFs by ELISA. RA SF and control in vitro differentiated macrophages were either untreated or treated with the Toll like receptor (TLR)2 ligand peptidoglycan, and then IL-23, IL-27 and IFN-g mRNA levels were quantified by real-time RT-PCR. Results: Treatment with P/I alone or combined with IL-23 significantly increased the number of TH-17 cells in normal and RA PB and in RA SF. With or without P/I plus IL-23, the percentage of TH-17 cells was higher in RA SF compared to normal and RA PB. IL-17 levels were comparable in OA and normal synovial tissues, and these values were significantly increased in RA synovial tissue. Although IL-17 was readily detected in RA SFs, IL-23 was rarely identified in RA SF. However, IL-23 mRNA was significantly increased in RA SF macrophages compared to control macrophages, with or without TLR2 ligation. IL-27 mRNA was also significantly higher in RA SF compared to control macrophages, but there was no difference in IL-27 levels between RA and control macrophages following TLR2 ligation. IFN-g mRNA was also detectable in RA SF macrophages but not control macrophages and the increase of IFN-g mRNA following TLR2 ligation was greater in RA SF macrophages compared to control macrophages. Conclusions: These observations support a role for TH-17 cells in RA. Our observations do not strongly support a role or IL-23 in the generation to TH-17 cells in the RA joint, however, they suggest that strategies which enhance IL-27 or IFN-g might modulate the presence of TH-17 cells in RA.
Cia5d regulates a new fibroblast-like synoviocyte invasion-associated gene expression signature
Teresina Laragione, Max Brenner, Wentian Li and Percio S. Gulko Fri, 15 Aug 2008 00:00:00 -0000
IntroductionThe in vitro invasive properties of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) have been shown to correlate with disease severity and radiographic damage. We have recently determined that FLS obtained from pristane-induced arthritis (PIA)-susceptible DA rats are also highly invasive in the same in vitro assay through Matrigel. The transfer of alleles derived from the arthritis-resistant F344 strain at the arthritis severity locus Cia5d (RNO10), as in DA.F344(Cia5d) congenics, was enough to significantly and specifically reduce the invasive properties FLS. This genetically controlled difference in FLS invasion involves increased production of soluble membrane-type 1 matrix metalloproteinase (MT1-MMP) by DA, and is dependent on increased activation of matrix metalloproteinase-2 (MMP-2). In the present study we aimed at characterizing the pattern of gene expression that correlates with differences in invasion in order to identify pathways regulated by the Cia5d locus. Methods: Synovial tissues were collected from DA and DA.F344(Cia5d) rats 21 days after the induction of PIA. Tissues were digested and FLS isolated. After a minimum of four passages FLS were plated on Matrigel-covered dishes at similar densities for 24h, followed by RNA extraction. Illumina RatRef-12 expression BeadChip arrays were used. Expression data were normalized, followed by t-test, logistic regression and cluster analysis. Real-time quantitative polymerase chain reaction (QPCR) was used for validation of the microarray data. Results: 7,665 genes out of the 22,523 RefSeq gene probes present in the array were expressed by the FLS. The expression of 66 genes was significantly different between the DA and DA.F344(Cia5d) FLS (P<0.01). Nineteen of the 66 differentially expressed genes (28.7%) are genes involved in the regulation of cell cycle progression or cancer-associated phenotypes such as invasion and contact inhibition. These included Cxcl10, Vil2 and Nras, three genes up-regulated in DA and known to regulate MMP-2 expression and activation. Nine of the 66 genes (13.6%) are involved in the regulation of the estrogen receptor signaling or transcription. Five candidate genes located within the Cia5d interval were also differentially expressed. Conclusions: We have identified a novel FLS invasion-associated gene expression signature regulated by Cia5d. Many of the genes differentially expressed have been previously implicated in cancer cell phenotypes, including invasion, suggesting a parallel in the behavior of arthritis FLS and cancer cells, and raising novel pathways and genes for therapeutic intervention and prognostication.
Interferon-induced protein IFIT4 is associated with systemic lupus erythematosus and promotes differentiation of monocytes into DC-like cells
Xiangyang Huang, Nan Shen, Chunde Bao, Yueying Gu, Li Wu and Shunle Chen Fri, 15 Aug 2008 00:00:00 -0000
IntroductionA multitude of interferon (IFN)-inducible genes (IFIGs) was found highly expressed in the peripheral blood mononuclear cells (PBMC) of most patients with systemic lupus erythematosus (SLE) via oligonucleotide microarray. Among these IFIGs, interferon-induced protein with tetratricopeptide repeats 4 (IFIT4) is a novel gene with function unknown. Methods: In this study, we studied the role of IFIT4 in monocyte differentiation and the correlation between IFIT4 expression and the clinical manifestation of SLE using plasmid transfection, flow cytometry, mixed leukocyte responses (MLRs), ELISA, quantitative RT-PCR and Western blotting. Results: We found that both IFIT4 mRNA and protein expression levels were significantly higher in PBMCs and monocytes from SLE patients than those from healthy controls. IFIT4 expression was positively correlated with ANA, anti-dsDNA, and anti-Sm auto-immune antibodies in SLE. SLE patients with higher expression of IFIT4 had a higher prevalence of leucopenia, thrombocytopenia, and C3/C4 decrease. IFIT4 protein was localized exclusively in the cytoplasm, and significantly up-regulated by IFN-alpha in normal PBMCs. To determine the role of IFIT4 in monocyte differentiation, the monocytic cell line THP-1 was transfected with pEGFP-IFIT4 expression plasmid and stimulated with GM-CSF/IL-4 to generate IFIT4-primed DC-like cells (DCLCs). IFIT4-primed DCLCs acquired morphological characteristics of DCs more quickly with a greater resemblance to DCs and had higher expression of CD40, CD86, CD80, HLA-DR, and CD83, along with lower expression of CD14; increased IL-12 secretion; and an increased ability to stimulate T cell proliferation than DCLCs primed with a pEGFP-C1 control plasmid trasfection. Besides, IFIT4-primed DCLCs enhanced the IFN-gamma secretion (about 2.4 fold) by T cells compared with controls. Conclusions: Our findings suggested that IFIT4 might play a role in promoting monocyte differentiation into DCLCs and directing DCLCs to modulate Th1 cells differentiation, all of which might contribute to the autoimmunity and pathogenesis of SLE.
The role of fibroblast growth factor-8 (FGF8) in animal models of osteoarthritis
Masako Uchii, Tadafumi Tamura, Toshio Suda, Masakazu Kakuni, Akira Tanaka and Ichiro Miki Tue, 12 Aug 2008 00:00:00 -0000
IntroductionFibroblast growth factor-8 (FGF8) is isolated as an androgen-induced growth factor and recently has shown to contribute to limb morphogenesis. The aim of this study was to clarify the role of FGF8 in animal models of osteoarthritis (OA). Methods: The expression of FGF8 in the partial meniscectomy model of OA in the rabbit knee was examined by immunohistochemistry. The effect of intraperitoneal administration of anti-FGF8 antibody was tested in a model of OA that employed injection of monoiodoacetic acid (MIA) or FGF8 into the knee joint of rats. Effect of FGF8 was also tested using cultured chondrocytes. Rabbit articular chondrocytes were treated with FGF8 for 48 hours, and the production of matrix metalloproteinase and the degradation of sulfated glycosaminoglycan in the extracellular matrix (ECM) were measured. Results: The expression of FGF8 in hyperplastic synovial cells and fibroblasts was induced in the meniscectomized OA model, whereas little or no expression was detected in normal synovium. Injection of FGF8 into rat knee joints induced the degradation of ECM, which was suppressed by anti-FGF8 antibody. In the MIA-induced arthritis model, anti-FGF8 antibody reduced ECM release into the synovial cavity. In cultured chondrocytes, FGF8 induced the release of matrix metalloproteinase 3 and prostaglandin E2 and caused degradation of ECM. The combination of FGF8 and interleukin-1alpha accelerated the degradation of ECM. Anti-FGF8 antibody suppressed the effects of FGF8 on the cells. Conclusions: FGF8 is produced by injured synovium and it enhances the production of protease and PGE2 from inflamed synoviocytes. Degradation of ECM is enhanced by FGF8. Therefore, FGF8 may participate in the degradation of cartilage and exacerbation of osteoarthritis.
Suppression of bone morphogenetic protein inhibitors promotes osteogenic differentiation: therapeutic implications
Manolis Heliotis and Eleftherios Tsiridis Tue, 12 Aug 2008 00:00:00 -0000
Bone morphogenetic proteins (BMPs) are expressed during osteogenesis and their action is regulated by corresponding BMP inhibitors. Chordin (a well recognized BMP inhibitor) and BMP-2 are expressed during osteogenic differentiation of human mesenchymal stem cells. Chordin inhibition induces human mesenchymal stem cell differentiation and reduces their proliferation by increasing BMP-2 bioavailability. The potential of suppressing BMP inhibitors is emerging as a biological therapeutic target in bone tissue engineering, because it results in an unopposed synergy between the various growth factors that are involved in osteogenesis, within their physiological milieu.

Annals of the Rheumatic Diseases current issue

[Editorials] Arthritis and endogenous glucocorticoids: the emerging role of the 11{beta}-HSD enzymes
Buttgereit, F., Zhou, H., Seibel, M. J Tue, 12 Aug 2008 00:00:00 -0000

[Extended reports] Local and systemic glucocorticoid metabolism in inflammatory arthritis
Hardy, R, Rabbitt, E H, Filer, A, Emery, P, Hewison, M, Stewart, P M, Gittoes, N J, Buckley, C D, Raza, K, Cooper, M S Tue, 12 Aug 2008 00:00:00 -0000
Background: Isolated, primary synovial fibroblasts generate active glucocorticoids through expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme produces cortisol from inactive cortisone (and prednisolone from prednisone). Objective: To determine how intact synovial tissue metabolises glucocorticoids and to identify the local and systemic consequences of this activity by examination of glucocorticoid metabolism in patients with rheumatoid arthritis (RA). Methods: Synovial tissue was taken from patients with RA during joint replacement surgery. Glucocorticoid metabolism in explants was assessed by thin-layer chromatography and specific enzyme inhibitors. RT-PCR and immunohistochemistry were used to determine expression and distribution of 11β-HSD enzymes. Systemic glucocorticoid metabolism was examined in patients with RA using gas chromatography/mass spectrometry. Results: Synovial tissue synthesised cortisol from cortisone, confirming functional 11β-HSD1 expression. In patients with RA, enzyme activity correlated with donor erythrocyte sedimentation rate (ESR). Synovial tissues could also convert cortisol back to cortisone. Inhibitor studies and immunohistochemistry suggested this was owing to 11β-HSD2 expression in synovial macrophages, whereas 11β-HSD1 expression occurred primarily in fibroblasts. Synovial fluids exhibited lower cortisone levels than matched serum samples, indicating net local steroid activation. Urinary analyses indicated high 11β-HSD1 activity in untreated patients with RA compared with controls and a significant correlation between total body 11β-HSD1 activity and ESR. Conclusions: Synovial tissue metabolises glucocorticoids, the predominant effect being glucocorticoid activation, and this increases with inflammation. Endogenous glucocorticoid production in the joint is likely to have an impact on local inflammation and bone integrity.
[Extended reports] Treatment with a CO-releasing molecule (CORM-3) reduces joint inflammation and erosion in murine collagen-induced arthritis
Ferrandiz, M L, Maicas, N, Garcia-Arnandis, I, Terencio, M C, Motterlini, R, Devesa, I, Joosten, L A B, van den Berg, W B, Alcaraz, M J Tue, 12 Aug 2008 00:00:00 -0000
Objective: CO-releasing molecules (CO-RMs) are a novel class of anti-inflammatory agents. We have examined the possible therapeutic effects of CORM-3 in collagen-induced arthritis (CIA). Methods: Arthritis was induced in DBA-1/J mice by type II collagen. Animals were treated with CORM-3 (5 and 10 mg/kg/day, intraperitoneally) or the inactive compound iCORM-3 (10 mg/kg/day, intraperitoneally) unable to release CO, from days 22 to 31. Production of anti-type II collagen antibodies, cytokines and cartilage olimeric matrix protein (COMP) was evaluated by enzyme-linked immunosorbent assay, and prostaglandin E2 (PGE2) by radioimmunoassay. Localisation of cyclooxygenase-2 (COX-2), haem oxygenase-1 (HO-1), intercellular adhesion molecule-1 (ICAM-1) and receptor activator of nuclear factor B ligand (RANKL) was examined by immunohistochemistry. Results: Therapeutic administration of CORM-3 suppressed clinical and histopathological manifestations of disease. The levels of PGE2, interleukin (IL)1β, IL2, IL6, IL10 and tumour necrosis factor (TNF) in joint tissues were inhibited by CORM-3. By contrast, CORM-3 augmented IL4. Anti-type II collagen antibodies and COMP levels in serum were reduced by CORM-3. Treatment with CORM-3 decreased cellular infiltration, joint inflammation and destruction, as well as the expression of COX-2, ICAM-1 and RANKL, whereas HO-1 increased. These beneficial effects were due to CO release, as iCORM-3 was ineffective. Conclusion: This study reveals the antiarthritic properties of CORM-3 in the CIA model and supports the notion that CO-RMs could be developed as a novel strategy for the treatment of inflammatory and arthritic conditions.
[Extended reports] Adalimumab effectively reduces the signs and symptoms of active ankylosing spondylitis in patients with total spinal ankylosis
van der Heijde, D, Pangan, A L, Schiff, M H, Braun, J, Borofsky, M, Torre, J, Davis, J C, Wong, R L, Kupper, H, Collantes, E, for the ATLAS Study Group Tue, 12 Aug 2008 00:00:00 -0000
Objective: To evaluate the long-term safety and efficacy of adalimumab in patients with ankylosing spondylitis (AS) and total spinal ankylosis (TSA). Design: Patients (n = 315) with active AS were randomised in a 2:1 ratio to receive adalimumab 40 mg every other week or placebo for 24 weeks followed by open-label adalimumab for up to 5 years. Two-year efficacy and safety data for 11 patients with investigator-defined TSA were evaluated. The primary end point was the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at Week 12. On or after Week 12, ASAS20 non-responders could switch to open-label adalimumab. Other efficacy measurements included ASAS40, ASAS 5/6, ASAS partial remission, and 50% improvement in the Bath AS Disease Activity Index (BASDAI 50). Results: 6 of 11 TSA patients were randomised to adalimumab and 5 to placebo. At Week 12, 50% of the adalimumab-treated patients achieved an ASAS20 response and 33% achieved an ASAS40, ASAS 5/6 and BASDAI 50. No placebo-treated patients achieved any response criteria at Week 12. 4 placebo- and 2 adalimumab-treated patients switched to open-label adalimumab before Week 24. After 1 year of adalimumab treatment, 8 of 11 patients achieved an ASAS20 response. After 2 years, 6 of the remaining 8 patients with TSA reported an ASAS20 response. There were no serious adverse events or adverse event-related study discontinuations. Conclusion: In patients with TSA, adalimumab treatment resulted in rapid and clinically significant improvement in the signs and symptoms of active disease. Adalimumab effectiveness and safety were sustained for at least 2 years. Trial registration number: NCT00085644.
[Extended reports] Long-term effects of bosentan on quality of life, survival, safety and tolerability in pulmonary arterial hypertension related to connective tissue diseases
Denton, C P, Pope, J E, Peter, H-H, Gabrielli, A, Boonstra, A, van den Hoogen, F H J, Riemekasten, G, De Vita, S, Morganti, A, Dolberg, M, Berkani, O, Guillevin, L, (on behalf of the TRacleer Use in PAH associated with Scleroderma and Connective Tissue Diseases (TRUST) Investigators) Tue, 12 Aug 2008 00:00:00 -0000
Objectives: This study investigated the long-term effects of bosentan, an oral endothelin ETA/ETB receptor antagonist, in patients with pulmonary arterial hypertension (PAH) exclusively related to connective tissue diseases (CTD). Methods: A total of 53 patients with PAH related to connective tissue diseases (PAH–CTD) in World Health Organization (WHO) functional class III received bosentan 62.5 mg twice a day for 4 weeks and then 125 mg twice a day for 44 weeks in this open non-comparative study. Assessments at weeks 16 and 48 included WHO class, clinical worsening, quality of life (Short-Form Health Survey (SF-36) and health assessment questionnaire (HAQ) modified for scleroderma), and survival (week 48 only). Safety and tolerability were monitored throughout the study. Results: At week 48, WHO class improved in 27% of patients (95% CI 16–42%) and worsened in 16% (95% CI 7–29%). Kaplan–Meier estimates were 68% (95% CI 55–82%) for absence of clinical worsening and 92% (95% CI 85–100%) for survival. Overall changes in quality of life were minimal. There were no unexpected side effects observed during the study. Conclusions: In most patients, bosentan was associated with improvement or stability of clinical status. The 92% estimate for survival at 48 weeks is a significant achievement in this patient population.
[Extended reports] The effectiveness and medication costs of three anti-tumour necrosis factor {alpha} agents in the treatment of rheumatoid arthritis from prospective clinical practice data
Kievit, W, Adang, E M, Fransen, J, Kuper, H H, van de Laar, M A F J, Jansen, T L, De Gendt, C M A, De Rooij, D-J R A M, Brus, H L M, Van Oijen, P C M, Van Riel, P C L M Tue, 12 Aug 2008 00:00:00 -0000
Aim: to evaluate the effects of adalimumab, etanercept and infliximab on disease activity, functional ability and quality of life and the medication costs in a naturalistic design. Methods: All patients from the Dutch Rheumatoid Arthritis Monitoring (DREAM) register starting on tumour necrosis factor (TNF)-blocking agents for the first time were monitored and assessed by trained research nurses every 3 months. The primary outcome was the Disease Activity Score (DAS28) course over the 12 months follow-up, analysed by linear mixed models. Secondary outcomes were the Health Assessment Questionnaire (HAQ), EuroQol five dimensions (EQ-5D) and the Short-Form 36 items (SF36) scores, and medication-related total costs. Results: The DAS28 and SF-36 physical component scale decreased in all three medication groups over 12 months, but the decrease was larger for adalimumab and etanercept in comparison to infliximab (p<0.001). The analyses of the HAQ and the EQ-5D scores showed the same (non-significant) trend, namely that at 12 months, the functionality and quality of life was better for adalimumab and etanercept patients. With regard to the medication costs, infliximab treatment resulted in significantly higher costs over the follow-up period than treatments with either adalimumab or etanercept. The comparison between adalimumab and etanercept showed a significant difference in the 12-month DAS28 course (p = 0.031). There were no additional indications for differences in effectiveness or costs between adalimumab and etanercept. Conclusion: The evaluation of the effectiveness and costs showed that adalimumab and etanercept are more or less equal and favourable compared to infliximab in the first year of treatment.

Arthritis Care & Research

Ischemic stroke: Another feature of accelerated atherosclerosis in rheumatoid arthritis?
Deborah P. M. Symmons Wed, 30 Jul 2008 10:49:00 -0000
No abstract.
On the road to adulthood for youth with rheumatic diseases: What health care professionals can do
Patience H. White Wed, 30 Jul 2008 10:49:00 -0000
No abstract.
Recommendations for use of selective and nonselective nonsteroidal antiinflammatory drugs: An American College of Rheumatology white paper
American College of Rheumatology Ad Hoc Group on Use of Selective and Nonselective Nonsteroidal Antiinflammatory Drugs Wed, 30 Jul 2008 10:49:00 -0000
No abstract.

Arthritis & Rheumatism

In this Issue
Wed, 30 Jul 2008 10:47:00 -0000
NO abstract.
The complex pathology of osteoarthritis: Even mitochondria are involved
Helmtrud I. Roach Wed, 30 Jul 2008 10:47:00 -0000
No abstract.
Molecular ablation of transforming growth factor [beta] signaling pathways by tyrosine kinase inhibition: The coming of a promising new era in the treatment of tissue fibrosis
Joel Rosenbloom, Sergio A. Jiménez Wed, 30 Jul 2008 10:47:00 -0000
No abstract.

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