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Fri, 03 Sep 2010 10:14:27 -0500
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Southern Academic Pediatric Rheumatology,One of the South’s Top Children’s Hospitals,#5611 : MS
Fri, 03 Sep 2010 10:14:27 -0500
As the only childrens hospital in the state, our more than 100 pediatric medical faculty provide outstanding medical services to millions of patients in our draw area. We are part of the Southeast
Immediate Access to Philadelphia, EMR, Infusion and X-Ray – All in Clinic, #5624 : PA
Fri, 03 Sep 2010 10:14:27 -0500
Join us in beautiful north central Pennsylvania as we grow! Our highly regarded, established practice conveniently shares offices with fellowed Orthopaedic Surgeons. Physical Therapy is across the

Arthritis Research & Therapy - Latest Articles

Predictors of interstitial lung disease in early systemic sclerosis: a prospective longitudinal study of the GENISOS cohort
Shervin AssassiRoozbeh SharifRobert LaskyTerry McNearneyRosa Estrada-Y-MartinHilda DraegerDeepthi NairMarvin FritzlerJohn ReveilleFrank ArnettMaureen MayesThe GENISOS Study Thu, 02 Sep 2010 00:00:00 -0000
IntroductionThe objective was to examine the association of baseline demographic and clinical characteristics with sequentially obtained measurements of forced vital capacity (FVC, expressed as a percentage of the predicted value) and to identify predictors of decline rate in FVC over time in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS). Methods: To date, 266 patients were enrolled in GENISOS, a prospective, observational cohort of patients with early systemic sclerosis. In addition to pulmonary function tests (PFT), clinical and laboratory data were obtained from each patient. We analyzed 926 FVC measurements utilizing generalized linear mixed models. The predictive significance of baseline variables for the decline rate in FVC was investigated by the interaction term between the variable and follow up time within the first 3 years after enrollment as well as throughout the entire follow up time. Results: The cohort consisted of 125 white, 54 African American, and 77 Hispanic patients with average disease duration of 2.5 years at enrollment. The mean follow up time was 3.8 years, ranging up to 11.4 years. A number of baseline variables including antibody status, African American ethnicity, disease type, baseline PFT values, modified Rodnan Skin Score, fibrosis on chest radiograph, lung and skin subscores of Severity Index were associated with serially measured FVC levels. However, only presence of anti-topoisomerase I antibodies (ATA) was associated with lower FVC levels (P<0.001) as well as accelerated decline rate in FVC within the first 3 years of follow up (P=0.02). None of the baseline variables predicted the rate of decline in FVC on long term follow up. However, patients with rapidly progressive ILD were underrepresented in the long term follow up group because the accelerated rate of decline in FVC was associated with poor survival (P=0.001). Conclusions: ATA was the only baseline variable, associated with differential FVC levels, predicting the rate of decline in FVC within the first three years of follow up. The association of faster decline in FVC with poor survival further emphasizes the need for identification of predictive biomarkers by collection of genetic information and serial blood samples in cohort studies.
New developments in osteoarthritis. Prevention of injury-related knee osteoarthritis: opportunities for the primary and secondary prevention of knee osteoarthritis
Charles RatzlaffMatthew Liang Tue, 31 Aug 2010 00:00:00 -0000
Where risk factors have been identified in knee and hip osteoarthritis (OA), with few exceptions, no prevention strategies have proven beneficial. The major risk factors for knee OA are advanced age, injury and obesity. However, there is limited or no evidence that they are modifiable or to what degree modifying them is effective in preventing development of knee OA or in preventing symptoms and progressive disease in persons with early OA. The notable exception is the growing epidemic of (sports) injury related knee OA. This review details the biological and clinical data indicating the efficacy of interventions targeting neuromuscular and biomechanical factors that make this subset of OA an attractive public health target, and highlights research opportunities for the future.
High mobility group box 1 potentiates the pro-inflammatory effects of interleukin-1beta in osteoarthritic synoviocytes
Isabel Garcia-ArnandisMaria Isabel GuillenFrancisco GomarJean-Pierre PelletierJohanne Martel-PelletierMaria Jose Alcaraz Fri, 27 Aug 2010 00:00:00 -0000
IntroductionHigh mobility group box 1 (HMGB1) is released by necrotic cells or secreted in response to inflammatory stimuli. Extracellular HMGB1 may act as a pro-inflammatory cytokine in rheumatoid arthritis. We have recently reported that HMGB1 is released by osteoarthritic synoviocytes after activation with interleukin-1beta (IL-1beta). The present study investigated the role of HMGB1 in synovial inflammation in osteoarthritis (OA). Methods: HMGB1 was determined in human synovium using immunohistochemistry, comparing normal to OA. OA synoviocytes were incubated with HMGB1 at 15 or 25 ng/ml in the absence or presence of IL-1beta (10 ng/ml). Gene expression was analyzed by quantitative PCR and protein expression by Western Blot and ELISA. Matrix metalloproteinase (MMP) activity was studied by fluorometric procedures and nuclear factor (NF)-kappaB activation by transient transfection with a NF-kappaB-luciferase plasmid. Results: In the normal synovium, HMGB1 was found in the synovial lining cells, sublining cells, and in the vascular wall cells. The distribution of HMGB1 in OA synovium was similar but the number of HMGB1 positive cells was higher and HMGB1 was also present in infiltrated cells. In normal synovial membrane cells, HMGB1 was found mostly in the nuclei, whereas in OA, HMGB1 was generally found mostly in the cytoplasm. In OA synoviocytes, HMGB1 alone at concentrations of 15 or 25 ng/ml did not affect the production of IL-6, IL-8, CCL2, CCL20, MMP-1 or MMP-3, but in the presence of IL-1beta, a significant potentiation of protein and mRNA expression, as well as MMP activity was observed. HMGB1 also enhanced the phosphorylated ERK1/2 and p38 levels, with a lower effect on phosphorylated Akt. In contrast, JNK1/2 phosphorylation was not affected. In addition, HMGB1 at 25 ng/ml significantly potentiated NF-kappaB activation in the presence of IL-1beta. Conclusions: Our results indicate that HMGB1 is overexpressed in OA synovium and mostly present in extracellular form. In OA synoviocytes, HMGB1 cooperates with IL-1beta to amplify the inflammatory response leading to the production of a number of cytokines, chemokines and MMPs. Our data support a pro-inflammatory role for this protein contributing to synovitis and articular destruction in OA.
Circulating mediators of bone remodeling in psoriatic arthritis: implications for disordered osteoclastogenesis and bone erosion
Nicola DalbethBregina PoolTimothy SmithKaren CallonMaria LoboWilliam TaylorPeter JonesJillian CornishFiona McQueen Thu, 26 Aug 2010 00:00:00 -0000
IntroductionDiverse bone pathologies are observed in patients with psoriatic arthritis (PsA). Uncoupling of bone remodeling with disordered osteoclastogenesis has been implicated in the pathogenesis of PsA. The aim of this study was to examine the role of soluble mediators of bone remodeling within the circulation of patients with PsA. Methods: Patients with PsA (n=38), with psoriasis (n=10) and healthy controls (n=12) were studied. Serum was obtained for testing of Dikkopf-1 (Dkk-1), macrophage-colony stimulating factor (M-CSF), osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) by ELISA. Patients with PsA also had bone densitometry, plain radiographs of the hands and feet, and assessment of peripheral blood osteoclast precursors. Radiographs were scored for erosion, joint space narrowing, osteolysis and new bone formation. Results: Compared with psoriasis and healthy controls, patients with PsA had higher circulating concentrations of Dkk-1 and M-CSF. In patients with PsA, M-CSF and RANKL, but not Dkk-1, concentrations positively correlated with radiographic erosion, joint space narrowing and osteolysis scores. Mediators of bone remodeling did not correlate with the number of joints with new bone formation or with total hip bone mineral density. Peripheral blood CD14+/CD11b+ cells, and the number of osteoclast-like cells and resorptive pits following culture with RANKL and M-CSF also correlated with radiographic damage scores. Circulating M-CSF concentrations correlated with the percentage of peripheral blood CD14+/CD11b+ cells. Conclusions: Systemic expression of soluble factors that promote osteoclastogenesis is disordered in patients with PsA, and may contribute to periarticular bone loss in this disease.
A new tool for detection of type I interferon activation in systemic lupus erythematosus
Kyriakos KirouGeorge Kalliolias Thu, 26 Aug 2010 00:00:00 -0000
The IFN-I pathway is activated in systemic lupus erythematosus (SLE) and appears to be important in the pathogenesis of the disease. As a result, several clinical trials of anti-IFN monoclonal antibodies, which hold promise to control the disease, have been launched. Additionally, activation of IFN-I might be important in the prognosis and activity assessment of the disease. Therefore, new biomarkers that reflect activity of the IFN-I pathway and are simple to measure, such as the monocyte CD64 receptor, are expected to have a great impact on the management of SLE, if properly validated.
The effect of risedronate on osteogenic lineage is mediated by cyclooxygenase-2 gene upregulation
Maria Teresa ValentiSandro GianniniLuca DonatelliMirko ZanattaFrancesco BertoldoStefania SellaMaria Teresa VileiElena OssiGiuseppe RealdiVincenzo Lo CascioLuca Dalle Carbonare Wed, 25 Aug 2010 00:00:00 -0000
IntroductionThe purpose of this study was to evaluate the effects of risedronate (Ris) in the modulation of bone formation in rats with glucocorticoid (GC) - induced osteoporosis by histomorphometric, immunohistochemical and gene expression analyses. Methods: We analyzed structure, turnover and microarchitecture, cyclooxygenase 2 (COX-2) levels and osteocyte apoptosis in 40 female rats divided as follows: 1) vehicle of methylprednisolone (vGC) + vehicle of risedronate (vRis); 2) Ris 5[microg]/Kg + vGC; 3) methylprednisolone (GC) 7mg/Kg + vRis; 4) GC 7mg/Kg +Ris 5[microg]/Kg. In addition, we evaluated cell proliferation and expression of COX-2 and bone alkaline phosphatase (b-ALP) genes in bone marrow cells and MLO-y4 osteocytes treated with Ris alone or in co-treatment with the selective COX-2 inhibitor NS-398 or with dexametasone. Results: Ris reduced apoptosis induced by GC of osteocytes (41% vs 86%, P<0.0001) and increased COX-2 expression with respect to controls (IHS: 8.75 vs 1.00, P<0.0001). These positive effects of Ris in bone formation were confirmed by in vitro data as the viability and expression of b-ALP gene in bone marrow cells resulted increased in a dose dependent manner. Conclusions: These findings suggest a positive effect of Ris in bone formation and support the hypothesis that the up-regulation of COX-2 could be an additional mechanism of anabolic effect of Ris.

Annals of the Rheumatic Diseases current issue

The American College of Rheumatology/European League Against Rheumatism Criteria for the classification of rheumatoid arthritis: a game changer
Cohen, S., Emery, P.
A welcome address for the new criteria
van Schaardenburg, D., Dijkmans, B. A. C.
2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative
Aletaha, D., Neogi, T., Silman, A. J., Funovits, J., Felson, D. T., Bingham, C. O., Birnbaum, N. S., Burmester, G. R., Bykerk, V. P., Cohen, M. D., Combe, B., Costenbader, K. H., Dougados, M., Emery, P., Ferraccioli, G., Hazes, J. M., Hobbs, K., Huizinga, T. W., Kavanaugh, A., Kay, J., Kvien, T. K., Laing, T., Mease, P., Menard, H. A., Moreland, L. W., Naden, R. L., Pincus, T., Smolen, J. S., Stanislawska-Biernat, E., Symmons, D., Tak, P. P., Upchurch, K. S., Vencovsky, J., Wolfe, F., Hawker, G. Objective The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. Methods A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease—this being the appropriate current paradigm underlying the disease construct ‘RA’. Results In the new criteria set, classification as ‘definite RA’ is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0–5), serological abnormality (range 0–3), elevated acute-phase response (range 0–1) and symptom duration (two levels; range 0–1). Conclusion This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct ‘RA’.
The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: Methodological Report Phase I
Funovits, J., Aletaha, D., Bykerk, V., Combe, B., Dougados, M., Emery, P., Felson, D., Hawker, G., Hazes, J. M., Huizinga, T., Kay, J., Kvien, T. K., Smolen, J. S., Symmons, D., Tak, P. P., Silman, A. Objective To apply a data-driven approach to investigate, in patients newly presenting with undifferentiated inflammatory synovitis, key variables that discriminate the subset of patients at sufficiently high risk of persistent or erosive disease for the purpose of developing new criteria for rheumatoid arthritis (RA). Methods In this first phase of the collaborative effort of the American College of Rheumatology and European League Against Rheumatism to develop new criteria for RA, a pooled analysis of early arthritis cohorts made available by the respective investigators is presented. All the variables associated with the gold standard of treatment with methotrexate during the first year after enrolment were first identified. Principal component analysis was then used to identify among the significant variables those sets that represent similar domains. In a final step, from each domain one representative variable was extracted, all of which were then tested for their independent effects in a multivariate regression model. From the OR in that final model, the relative weight of each variable was estimated. Results The final domains and variables identified by this process (and their relative weights) were: swelling of a metacarpophalangeal joint (MCP; 1.5), swelling of a proximal interphalangeal joint (PIP; 1.5), swelling of the wrist (1.5), tenderness of the hand (ie, MCP, PIP or wrist (2)), acute phase reaction (ie, C reactive protein or erythrocyte sedimentation rate and weights for moderate or high elevations of either one (1 for moderate, 2 for high elevation)) and serological abnormalities (ie, rheumatoid factors or anti-citrullinated protein antibodies, again with separate weights for moderate or high elevations (2 and 4, respectively)). Conclusion The results of this first phase were subsequently used in the second phase of the project, which is reported in a separate methodological paper, and for derivation of the final set of criteria.
EULAR points to consider when establishing, analysing and reporting safety data of biologics registers in rheumatology
Dixon, W. G., Carmona, L., Finckh, A., Hetland, M. L., Kvien, T. K., Landewe, R., Listing, J., Nicola, P. J., Tarp, U., Zink, A., Askling, J. Objectives The introduction of biological therapies for the treatment of rheumatic diseases has drawn attention to the limitations of traditional means of assessing drug safety. Consequently, a series of European academic biologics registers dedicated to this task have been established. Increasing reliance upon safety data generated from observational drug registers makes it important to convert the lessons learned from such registers into recommendations for rheumatologists embarking upon the establishment of future registers, or analysing and reporting from new and existing registers. Methods The Task Force encompassed 11 scientists from European Rheumatology drug registers. Through an informal inventory of critical elements in the establishment of existing rheumatoid arthritis drug registers, of analytical strategies used and of limitations of their results, several ‘points to consider’—beyond established generic guidelines for observational registers/studies but with particular relevance to biologics registers on safety in rheumatology—were assembled. For each ‘point to consider’, contextual and methodological background and examples were compiled. Results A set of seven points to consider was assembled for the establishment of new drug registers with a focus on purpose, population to be targeted, data collection, handling and storage as well as ethical and legal considerations. For analysis and reporting, nine points to consider were assembled (setting, participant, variable, statistical method, descriptive data, outcome data, main results, other analyses and limitations). Conclusions Thoughtful design and planning before the establishment of biologics registers will increase their sustainability, versatility and raw data quality. Harmonisation of analyses and reporting from such registers will improve interpretation of drug safety studies.
Therapeutic opportunities in systemic lupus erythematosus: state of the art and prospects for the new decade
Bertsias, G. K., Salmon, J. E., Boumpas, D. T. Immune responses against endogenous nuclear antigens are characteristic of systemic lupus erythematosus (SLE), a highly pleiomorphic disease predominantly affecting young women of reproductive age. Genome-wide association studies have confirmed the importance of genes associated with the immune response as well as genes involved in endothelial function and tissue response to injury. Immune complexes, autoantibodies, complement, cytokines, endothelial injury and a thrombophilic state associated with antiphospholipid antibodies are important for mediating tissue dysfunction. If not treated promptly, a significant proportion of patients—especially those with more aggressive disease—accumulate irreversible damage. During the past decade, novel combinations of immunosuppressive drugs and biologicals have been added to the therapeutic armamentarium. At the same time, the emphasis in the management of lupus has shifted from individual drugs to a strategy that aims at early, sustained remission tailored to disease manifestations and severity with the lowest possible toxicity. Infections and accelerated atherosclerosis (attributed to both traditional and non-traditional risk factors) and thrombosis-related clinical events (including arterial, venous and pregnancy loss) represent a major challenge in the management of the disease. To avoid fragmentation and optimise medical care, evidence and expert-based recommendations have been developed. For the future the authors predict a new taxonomy on the basis of mechanisms rather than clinical empiricism, leading to targeted therapy.

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