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Arthritis Research & Therapy - Latest Articles

Biomarkers as tools for improved diagnostic and therapeutic monitoring in SLE
Michael SmithFalk HiepeThomas DornerGerd Burmester Thu, 19 Nov 2009 00:00:00 -0000
One of the major challenges in rheumatology is to overcome the classification criteria that previously defined SLE since the heterogeneity of the disease(s) appears to represent a complexity that likely substantially contributed to the failure of a number of recent trials. For those engaged in clinical trials, validated disease activity biomarkers which respond rapidly to treatment and are predictive of clinical response would greatly facilitate early decision making around futility and dose selection. Likewise, use of validated patient stratification biomarkers possibly in conjunction with autoantibody profiles and disease manifestations will result in the recruitment of more homogenous patient populations during later stage clinical studies thereby decreasing size, costs, and risks in pivotal studies.
Connective tissue growth factor promotes articular damage by increased osteoclastogenesis in patients with rheumatoid arthritis
Kazuhisa NozawaMaki FujishiroMikiko KawasakiHiroshi KanekoKazuhisa IwabuchiMitsuaki YanagidaFujihiko SuzukiKeiji MiyazawaYoshinari TakasakiHideoki OgawaKenji TakamoriIwao Sekigawa Wed, 18 Nov 2009 00:00:00 -0000
IntroductionA protein analysis using a mass spectrometry indicated that there are serum proteins showing significant quantitative changes after the administration of infliximab. Among them, connective tissue growth factor (CTGF) seems to be related to the pathogenesis of rheumatoid arthritis (RA). Therefore, this study was conducted to investigate how CTGF is associated with the disease progression of RA. Methods: Serum samples were collected from RA patients in active or inactive disease stages, and before or after treatments with infliximab. CTGF production was evaluated by ELISA, RT-PCR, indirect immunofluorescence microscopy, and immunoblotting. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase (TRAP) staining, a bone resorption assay and osteoclasts specific catalytic enzymes productions. Results: The serum concentrations of CTGF in RA were greater than in normal healthy controls and disease controls. Interestingly, those were significantly higher in active RA patients compared to inactive RA patients. Furthermore, the CTGF levels significantly were decreased by infliximab concomitant with the disease amelioration. In addition, tumour necrosis factor (TNF)alpha can induce the CTGF production from synovial fibroblasts even though TNFalpha can oppositely inhibit the production of CTGF from chondrocytes. CTGF promoted the induction of the quantitative and qualitative activities of osteoclasts in combination with M-CSF and receptor activator of NF-kappaB ligand (RANKL). In addition, we newly found integrin aVb3 on the osteoclasts as a CTGF receptor. Conclusions: These results indicate that aberrant CTGF production induced by TNFalpha plays a central role for the abnormal osteoclastic activation in RA patients. Restoration for dysregulation of CTGF production may contribute to the inhibition of articular destruction in infliximab treatment.
Aggrecanolysis and in vitro matrix degradation in the immature bovine meniscus: mechanisms and functional implications
Christopher WilsonEric VanderploegFengrong ZuoJohn SandyMarc Levenston Tue, 17 Nov 2009 00:00:00 -0000
IntroductionLittle is known about endogenous or cytokine-stimulated aggrecan catabolism in the meniscal fibrocartilage of the knee. The objectives of this study were to characterize the structure, distribution, and processing of aggrecan in menisci from immature bovines, and to identify mechanisms of extracellular matrix degradation that lead to changes in the mechanical properties of meniscal fibrocartilage. Methods: Aggrecanase activity in the native immature bovine meniscus was examined by immunolocalization of the aggrecan NITEGE neoepitope. To investigate mechanisms of cytokine-induced aggrecan catabolism in this tissue, explants were treated with interleukin-1alpha (IL-1) in the absence or presence of selective or broad spectrum metalloproteinase inhibitors. The sulfated glycosaminoglycan (sGAG) and collagen contents of explants and culture media were quantified by biochemical methods, and aggrecan catabolism was examined by Western analysis of aggrecan fragments. The mechanical properties of explants were determined by dynamic compression and shear tests. Results: The aggrecanase-generated NITEGE neoepitope was preferentially localized in the middle and outer regions of freshly isolated immature bovine menisci, where sGAG density was lowest and blood vessels were present. In vitro treatment of explants with IL-1 triggered the accumulation of NITEGE in the inner and middle regions. Middle region explants stimulated with IL-1 exhibited substantial decreases in sGAG content, collagen content, and mechanical properties. A broad spectrum metalloproteinase inhibitor significantly reduced sGAG loss, abrogated collagen degradation, and preserved tissue mechanical properties. In contrast, an inhibitor selective for ADAMTS-4 and ADAMTS-5 was least effective at blocking IL-1-induced matrix catabolism and loss of mechanical properties. Conclusions: Aggrecanase-mediated aggrecanolysis, typical of degenerative articular cartilage, may play a physiologic role in the development of the immature bovine meniscus. IL-1-induced release of sGAG and loss of mechanical properties can be ascribed primarily to the activity of MMPs or aggrecanases other than ADAMTS-4 and ADAMTS-5. These results may have implications for the clinical management of osteoarthritis.
TWEAK: a novel biomarker for lupus nephritis?
Neeraj DhaunDavid Kluth Tue, 17 Nov 2009 00:00:00 -0000
Renal involvement is common in systemic lupus erythematosus. Early diagnosis of lupus nephritis (LN), allowing the instigation of appropriate therapy, remains an important clinical challenge. Current biomarkers in clinical practice are less than ideal lacking both sensitivity and specificity. In this issue of the Journal Schwartz and colleagues demonstrate the potential value of urinary TWEAK (uTWEAK) as a biomarker for LN. They show that uTWEAK is elevated in subjects with LN at diagnosis compared to those with SLE but no renal disease, and correlates with the degree of clinical disease activity. These data are thought provoking and provide the platform for future longer term studies.
Intradiscal injection of simvastatin retards progression of intervertebral disc degeneration induced by stab injury
Huina ZhangLin WangJun Beom ParkPaul ParkVictor YangScott HollisterFrank La MarcaChia-Ying Lin Fri, 13 Nov 2009 00:00:00 -0000
IntroductionEarlier work indicates that the cholesterol-lowering drug, simvastatin, is anabolic to chondrogenic expression of rat intervertebral disc (IVD) cells, which suggests a potential role for simvastatin in IVD regeneration. In this study, we expand on our earlier work to test the effectiveness of simvastatin on disc degeneration utilizing a rat tail disc degeneration model. Methods: 30 rats that underwent 21 G needle-puncture at rat tail discs were injected with simvastatin-loaded poly(ethylene glycol)-poly(lactic acid-co-glycolic acid)-poly(ethylene glycol) (PEG-PLGA-PEG) gel (5mg/ml) or vehicle control at 4 weeks after needle injury. All animals were sacrificed 2 weeks after simvastatin injection. Bone morphogenetic protein-2 (BMP-2), aggrecan, collagen type II, and collagen type I messenger ribonucleic acid (mRNA) expression in the rat nucleus pulposus (NP) were measured by real-time polymerase chain reaction (PCR). In vivo magnetic resonance imaging (MRI) was performed to monitor changes in disc degeneration. Rat discs were also assessed by histology using hematoxylin and eosin (H&E) and safranin O staining. In addition, the NP weight, glycosaminoglycan (sGAG) and DNA content were also measured. Results: A single dose of simvastatin loaded in thermo-sensitive PEG-PLGA-PEG gel injected into the NP had the trend to increase aggrecan expression and sGAG content, and significantly increased mRNA levels of BMP-2, collagen type II, and the differentiation index (the ratio of collagen type II to collagen type I). The decreased NP weight, T2 intensity, as well as MRI index in the rat tail discs induced by needle puncture were significantly reversed after 2 weeks of simvastatin treatment. In addition, simvastatin treatment also improved histological changes induced by needle puncture. Conclusions: A single injection of simvastatin loaded in PEG-PLGA-PEG gel into rat tail discs had the potential to retard or regenerate the degenerative disc.
HLA-E gene polymorphism associates with ankylosing spondylitis in Sardinia
Fabiana PaladiniFrancesca BelfioreElisa CoccoCarlo CarcassiAlberto CauliAlessandra VaccaMaria Teresa FiorilloAlessandro MathieuIsabella CascinoRosa Sorrentino Fri, 13 Nov 2009 00:00:00 -0000
IntroductionAnkylosing spondylitis (AS) is a severe, chronic inflammatory disease strongly associated with HLA-B27. The presence of additional HLA risk factors has been suggested by several studies. The aim of the current study is to assess the occurrence of an additional HLA susceptibility locus in the region between HLA-E and HLA-C in the Sardinian population. Methods: 200 random controls, 120 patients with AS and 175 HLA-B27 positive controls were genotyped for six single nucleotide polymorphisms (SNPs) spanning the HLA region between HLA-E and HLA-C loci previously shown to harbour an additional susceptibility locus for AS. Allele, genotype and haplotype frequencies were compared. Results: The data confirm our previous finding of a significant increase in patients with AS of allele A at SNP rs1264457 encoding for an Arg at the functional HLA-E polymorphism (Arg128/Gly128). This was due to a remarkable increase in the frequency of genotype A/A in patients vs HLA-B27-matched controls (51% vs 29%; P for trend: 5x10-5). Genotype distribution of three other SNPs mapping in genes (GNL1, PRR3 and ABCF-1) close to HLA-E and showing high LD with it, was also significantly skewed. Accordingly, haplotype distribution was also remarkably different. The frequency of the haplotype AAGA, is 42% in random controls, increases to 53% in the HLA-B27-positive controls, and reaches 68% in patients with AS (P values: 2x10-11 vs random and 3x10-4 vs HLA-B27 controls). Conclusions: There is a strong association between the presence of a haplotype in genes mapping between HLA-E and HLA-C and AS due to an increase of homozygous markers in patients. The strongest association however, is with the HLA-E functional polymorphism rs1264457. Since HLA-E is the ligand for the NKG2A receptor, these data point to the natural killer (NK) activity as possible player in the pathogenesis of AS.

Annals of the Rheumatic Diseases current issue

Quality indicators in rheumatology: valid for whom?
Vliet Vlieland, T. P M, Huizinga, T. W J
Use of "spydergrams" to present and interpret SF-36 health-related quality of life data across rheumatic diseases
Strand, V, Crawford, B, Singh, J, Choy, E, Smolen, J S, Khanna, D The Medical Outcomes Study Short Form-36 (SF-36) is a generic measure of health-related quality of life (HRQOL), validated and cross-culturally translated, which has been extensively utilised in rheumatology. In randomised controlled trials and observational studies, SF-36 provides rich data regarding HRQOL; but as typically portrayed, patterns of disease and treatment-associated effects can be difficult to discern. "Spydergrams" offer a simplified means to visualise complex results across all domains of SF-36 in a single figure: depicting disease and population-specific patterns of decrements in HRQOL compared with age and gender-matched normative data, as well as providing a tool for interpreting complex treatment-associated or longitudinal changes. Utilising spydergrams as a standard format to illustrate and report changes in SF-36 across different rheumatic diseases can greatly facilitate analyses and interpretations of clinical trial results, as well as providing patients an accessible means to compare baseline scores and treatment-associated improvements with normative data from individuals without arthritis. Furthermore, SF-6D utility scores based on mean changes across all eight domains of SF-36 are suggested as a quantitative means of summarising changes illustrated by spydergrams, offering a universal metric for cost-effectiveness analyses of therapeutic interventions.
Development of quality indicators for monitoring of the disease course in rheumatoid arthritis
van Hulst, L T C, Fransen, J, Broeder, A A d., Grol, R, van Riel, P L C M, Hulscher, M E J L Objectives: To suppress rheumatoid arthritis (RA) patients’ disease activity, it should be periodically measured and patients should be treated on the basis of the disease activity outcomes. Insight into the actual care, by using quality indicators, is the first step in achieving optimal care. The objective of this study was to develop a set of quality indicators to evaluate RA disease course monitoring of rheumatologists in daily clinical practice. Methods: A RAND-modified Delphi method in a five-step procedure was applied: a literature search for quality indicators and recommendations about disease course monitoring; a first questionnaire round; a consensus meeting; a second questionnaire round and drawing up the final set. Results: The systematic procedure resulted in the development of 18 quality indicators: 10 process, five structure and three outcome indicators that describe seven domains of disease course monitoring: schedule follow-up visits; measure disease activity; functional impairment; structural damage; change medication; preconditions for measuring disease activity and outcome measures in terms of disease activity. Conclusions: This quality indicator set can be used to assess the quality of disease course monitoring of rheumatologists in daily clinical practice, and to determine for which aspects of disease course monitoring rheumatologists perform well, or where there is room for improvement. This information can be used to improve the quality of disease course monitoring.
ASDAS, a highly discriminatory ASAS-endorsed disease activity score in patients with ankylosing spondylitis
van der Heijde, D, Lie, E, Kvien, T K, Sieper, J, Van den Bosch, F, Listing, J, Braun, J, Landewe, R, for the Assessment of SpondyloArthritis international Society (ASAS) Objectives: To evaluate various validity aspects of four disease activity scores (ASDAS) for ankylosing spondylitis (AS) in comparison with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), its individual components and physician and patient global assessment of disease activity. Methods: The analyses were performed in two cohorts of patients with AS: (1) the NOR-DMARD database which includes patients starting on a disease-modifying antirheumatic drug or tumour necrosis factor (TNF) blocker and (2) patients participating in double-blind placebo controlled randomised clinical trials with TNF blockers in four centres. Discrimination between patients with low versus high disease activity according to various definitions and between various levels of change were analysed as the standardised mean difference (difference in the group means divided by the pooled SD of the group means) and t score. Results: The four ASDAS versions were highly discriminatory in differentiating patients with different levels of disease activity and patients with different levels of change. The ASDAS scores outperformed the BASDAI and its single components in all settings: patient- or physician-based, reflecting status or change, with normal or raised C-reactive protein (CRP), in the presence or absence of peripheral arthritis. There were no major differences between the four ASDAS scores. Based on feasibility, the ASAS membership selected the ASDAS version which included back pain, duration of morning stiffness, patient global assessment, peripheral joint complaints and CRP as the preferred version. Conclusions: The ASDAS is a validated, highly discriminatory instrument for assessing disease activity in AS, including patient-reported outcomes and CRP levels.
Malignancies in the rheumatoid arthritis abatacept clinical development programme: an epidemiological assessment
Simon, T A, Smitten, A L, Franklin, J, Askling, J, Lacaille, D, Wolfe, F, Hochberg, M C, Qi, K, Suissa, S Objective: To provide context for the malignancy experience in the rheumatoid arthritis (RA) abatacept clinical development programme (CDP) by performing comparisons with similar RA patients and the general population. Methods: Malignancy outcomes included total malignancy (excluding non-melanoma skin cancer (NMSC)), breast, colorectal, lung cancers and lymphoma. Comparisons were made between the observed incidence in patients within the abatacept CDP and RA patients on disease-modifying antirheumatic drugs (DMARD) identified from five data sources: the population-based British Columbia RA Cohort, the Norfolk Arthritis Register, the National Data Bank for Rheumatic Diseases, the Sweden Early RA Register and the General Practice Research Database. Age and sex-adjusted incidence rates (IR) and standardised incidence ratios (SIR) were used to compare events in the abatacept trials with the RA DMARD cohorts and the general population. Results: A total of 4134 RA patients treated with abatacept in seven trials and 41 529 DMARD-treated RA patients in the five observational cohorts was identified for study inclusion. In the abatacept-treated patients, the 51 malignancies (excluding NMSC), seven cases of breast, two cases of colorectal, 13 cases of lung cancer and five cases of lymphoma observed were not greater than the range of expected cases from the five RA cohorts. The SIR comparing RA patients with the general population were consistent with those reported in the literature. Conclusions: The IR of total malignancy (excluding NMSC), breast, colorectal, lung cancers and lymphoma in the abatacept CDP were consistent with those in a comparable RA population. These data suggest no new safety signals with respect to malignancies, which will continue to be monitored.
Modification and validation of the Birmingham Vasculitis Activity Score (version 3)
Mukhtyar, C, Lee, R, Brown, D, Carruthers, D, Dasgupta, B, Dubey, S, Flossmann, O, Hall, C, Hollywood, J, Jayne, D, Jones, R, Lanyon, P, Muir, A, Scott, D, Young, L, Luqmani, R A Background: Comprehensive multisystem clinical assessment using the Birmingham Vasculitis Activity score (BVAS) is widely used in therapeutic studies of systemic vasculitis. Extensive use suggested a need to revise the instrument. The previous version of BVAS has been revised, according to usage and reviewed by an expert committee. Objective: To modify and validate version 3 of the BVAS in patients with systemic vasculitis. Methods: The new version of BVAS was tested in a prospective cross-sectional study of patients with vasculitis. Results: The number of items was reduced from 66 to 56. The subscores for new/worse disease and persistent disease were unified. In 313 patients with systemic vasculitis, BVAS(v.3) correlated with treatment decision (Spearman’s rs = 0.66, 95% CI 0.59 to 0.72), BVAS1 of version 2 (rs = 0.94, 95% CI 0.92 to 0.96), BVAS2 of version 2 in patients with persistent disease (rs = 0.60, 95% CI 0.21 to 0.83), C-reactive protein levels (rs = 0.43, 95% CI 0.31 to 0.54), physician’s global assessment (rs = 0.91, 95% CI 0.89 to 0.93) and vasculitis activity index (rs = 0.88, 95% CI 0.86 to 0.91). The intraclass correlation coefficients for reproducibility and repeatability were 0.96 (95% CI 0.95 to 0.97) and 0.96 (95% CI 0.92 to 0.97), respectively. In 39 patients assessed at diagnosis and again at 3 months, the BVAS(v.3) fell by 17 (95% CI 15 to 19) units (p<0.001, paired t test). Conclusion: BVAS(v.3) demonstrates convergence with BVAS(v.2), treatment decision, physician global assessment of disease activity, vasculitis activity index and C-reactive protein. It is repeatable, reproducible and sensitive to change. The new version of BVAS is validated for assessment of systemic vasculitis.

Arthritis Care & Research

Health insurance and out-of-pocket expenses
Wei Zhang, Aslam H. Anis Thu, 29 Oct 2009 10:41:00 -0000
No abstract.
US bone and joint decade prepares for the future
Joshua J. Jacobs, Toby King Thu, 29 Oct 2009 10:41:00 -0000
No abstract.
Anti-citrullinated peptide antibody assays and their role in the diagnosis of rheumatoid arthritis
Rohit Aggarwal, Katherine Liao, Raj Nair, Sarah Ringold, Karen H. Costenbander Thu, 29 Oct 2009 10:41:00 -0000
No abstract.

Arthritis & Rheumatism

In this issue
Thu, 29 Oct 2009 10:39:00 -0000
No abstract.
Interpreting registry-derived drug studies: Does societal context matter?
Joel M. Kremer, Jeffrey Greenberg Thu, 29 Oct 2009 10:39:00 -0000
No abstract.
Human osteoclastogenic T cells and human osteoclastology
Shigeru Kotake, Yuki Nanke, Toru Yago, Manabu Kawamoto, Hisashi Yamanaka Thu, 29 Oct 2009 10:39:00 -0000
No abstract.

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