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Rheumatology Physician Jobs in Eastern North Carolina. :: North Carolina :: MedPro Search - Recruiting For Physician Jobs

Rheumatology Physician Jobs in Eastern North Carolina. Our Rheumatology division has an immediate opening. We currently have three board certified rheumatologists. MRI, CT, nuclear, BMD, x-ray, ultrasound,

Rheumatology Physician Job for Coastal North Carolina :: North Carolina :: MedPro Search - Recruiting For Physician Jobs

Med Pro Search is seeking a Rheumatologist (Rheum) to join a Rheumatology Division with a premier multi-specialty group in Eastern North Carolina. We now have more than 50 providers and our new; state

Metro Western Louisiana :: Louisiana :: Medical Search International

A prestigious Regional Medical Center located in a metropolitan community in Western Louisiana is seeking a BC/BE Rheumatologist to join their specialty group. State license is preferred but eligibility

Greater Santa Fe Area :: New Mexico :: Medical Search International

A regional medical center located in the greater Santa Fe area of New Mexico is seeking a BC/BE Rheumatologist to join their specialty group. State license is preferred but eligibility is acceptable.

Excellent Location :: Tennessee :: Spot On Recruiting

Rheumatologist needed 30 miles from Chattanooga, TN: H1 Visa's are accepted. Medical Center is aggressively seeking a board certified/board eligible rheumatologist to either join an established employed

North of Boston :: Massachusetts :: New England Physician Recruitment Center

Rheum 122 -World-renowned teaching hospital affiliated with Tufts Medical School seeking Rheumatologist to join group of 5 Rheumatologists in large physician run group, consisting of 500 physicians.

Greater Chicago :: Illinois :: Medical Search International

A busy medical center located in a beautiful community in greater Chicago is seeking BC/BE Rheumatologist to joint their specialty group. State license is preferred but eligibility is acceptable. Residents

Greater Jackson :: Mississippi :: Medical Search International

A large Medical Center located in greater Jackson is seeking a BC/BE Rheumatologist to joint their specialty group. State license is preferred but eligibility is acceptable. Residents and fellows are

Florham Park :: New Jersey :: Medical Search International

A prestigious medical center located in a beautiful community in C PA is seeking a BC/BE Rheumatologist to join their group. Reasonable call schdule plus bonus program. State license is preferred but

Boston subs :: Massachusetts :: New England Physician Recruitment Center

Subject: Rheumatology-Boston area Rheumatology-Boston- established multi-specialty group with teaching available; seeking 3rd Rheumatologist for expanding practice. New office space . Outpatient.

Springfield :: Massachusetts :: New England Physician Recruitment Center

RHEUM 119 -Join one other Rheumatologist is busy practice located in Western MA (close to Springfield)office is on the campus of the Medical Center and is currently staffed with one physician, one registered

Manchester :: Connecticut :: New England Physician Recruitment Center

RHEUM 140-Rheumatologist needed to join multi-specialty group practice with more than 50 providers. Practice 100% Rheumatology. Employed position. No call. EMR. Reputable group with several office locations

Kingston :: New York :: Winston Staffing

Seeking BC physician to join a multi-speciality group practice, serving the healthcare needs of patients in Upstate New York and Hudson Valley region. in dicsipline areas above mentioned. They offer

Southern :: Michigan :: Medical Search International

BC/BE Rheumatologist-Southern Michigan Two board-certified rheumatologists want to add a third rheumatologist to their expanding consultative practice which includes a PA. The partners participate in

Hyannis :: Massachusetts :: New England Physician Recruitment Center

RHEUM 125 - Rheumatologist needed to join expanding group in Cape Cod region. Beautiful coastal area. One hour to Boston. Well established group of 4 Rheumatologists currently. Office hours 4 day work

Western :: Massachusetts :: New England Physician Recruitment Center

Western MA College Town rated very high in living. Practice Rheumatology. well established multi-specialty group (50 years old) . Total office staff is 28, which includes NP's and PA's. They have the

El Paso :: Texas :: Absolute Staffers

Absolute Staffers is currently seeking a full-time Rheumatologis for a potential Government contact at a Military Treatment Facility in El Paso, TX. As a Government Contractor you will receive great

Central :: South Carolina :: Medical Search International

RHEUMATOLOGY - PARTNERSHIP TRACK - PRIVATE GROUP - LAKE FRONT COMMUNITY - GREAT PLACE TO LIVE & PRACTICE - Join 1 Rheumatologist in a very busy growing community based practice. The practice resides

Boston :: Massachusetts :: New England Physician Recruitment Center

I am doing a Rheumatology search for academic oriented Lahey clinic in Boston. Please provide your resume and a time to speak for all the comparitive inforamation, ie.. salary, benefits etc. Boston-Lahey

Boston :: Massachusetts :: New England Physician Recruitment Center

RHEUM 127- Practice 100% Rheumatology. Well established multi-specialty group (50 years old) is adding a Rheumatologist to their current group which includes the following specialties: Pediatrics, Internal

Immunocytokines: the long-awaited therapeutic magic bullet in rheumatoid arthritis?

Modulatory cytokines such as IL-4 and IL-10 looked promising biologicals, but suffered from poor exposure at the inflamed joints, when administered via the patient friendly subcutaneous route. Immunocytokines have now been engineered with tissue targeting potential and are a challenging solution to this problem. Local inflammatory processes cause destruction of extracellular matrix components (ECM) leading to neo-eptitopes and/or elicit the synthesis of new ECM components. This makes ECM elements interesting targets for antibody mediated recognition and retention, to achieve higher levels of immunocytokines at the site of therapeutic interference. The study presented by Schwager et al. showed that targeted delivery of IL-10 is more efficacious in experimental arthritis. Clinical studies are warranted to show whether this strategy works for all RA-patients or better in subgroups with a defined ECM phenotype. In principle the scFv-tageting system is plastic enough to allow for personalized strategies.

SAPHO syndrome: is a range of pathogen-associated rheumatic diseases extended?

SAPHO syndrome, representing a constellation of synovitis, acne, palmo-plantar pustulosis, hyperostosis and osteitis, is now recognized as a distinct medical entity, a reactive infectious osteitis. Genetic, immunological and bacterial mechanisms are implicated in the development of the disease. Diagnostic problems may rise due to non complete manifestations of SAPHO: acne and arthritis, or acne and anterior wall osteitis with an unclear pustulosis history. The interventional study of Assman et al. is a significant addition to a long range of publications, showing an association of SAPHO with P. acnes. Randomized control studies are needed to confirm the effects of antibiotic therapy.

Effect of small interference RNA for ADAMTS5 on intervertebral disc degeneration in the rabbit anular needle puncture model

IntroductionThe etiology of degenerative disc disease is unknown. Several investigators have reported the presence of proteolytic enzymes, such as the matrix metalloproteinase (MMP) and ADAMTS (a disintegrin and metalloprotease with thrombospondin-like repeats) families, in degenerated human discs. Glasson et al. have recently reported that there is a significant reduction in the severity of cartilage destruction in ADAMTS5 knockout mice compared with wild-type mice. The purpose of this study was to evaluate the suppressive effects of injections of ADAMTS5 small interference RNA (siRNA) oligonucleotide on intervertebral disc degeneration in the rabbit anular needle puncture model. Methods: Rabbit nucleus pulposus (NP) cells were transfected with siRNA oligonucleotides specific for ADAMTS5 or the control. The suppression of the ADAMTS5 gene by siRNA transfection was assessed using real-time polymerase chain reaction (PCR), both in monolayer and alginate bead cultures with or without interleukin-1beta (IL-1beta) stimulation. The effect of siRNA was determined in vivo using the rabbit anular needle puncture model (control group: n=8; ADAMTS5 group: n=8). One week after the initial anular puncture, the animals received an injection of the control or anti-ADAMTS5 oligonucleotide (100 ug each at the L2/3 and L4/5 level; 16 discs/group). Disc height, magnetic resonance imaging (MRI) (Thompson classification and signal intensity) and safranin-O staining (histological grade) were assessed. Results: IL-1beta treatment significantly increased the ADAMTS5 mRNA level in NP cells (P<0.01). ADAMTS5 gene suppression was 70% compared with the control oligonucleotide in both monolayer and alginate bead culture with or without stimulation with IL-1beta. The injection of anti-ADAMTS5 oligonucleotide in vivo resulted in improved MRI scores with increased signal intensity and improved histological grade scores with statistical significance (P<0.05). No significant change in disc height was observed. Conclusions: A single injection of ADAMTS5 siRNA induced the suppression of degradation in NP tissues as shown by significantly improved MRI and histological grades. The mechanism of response to siRNA may be worthy of exploration for possible therapeutic purposes.

Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes: inhibition of interleukin-1beta-induced nuclear factor-kappaB-mediated inflammation and apoptosis

IntroductionCurrently available treatments for osteoarthritis (OA) are restricted to non-steroidal anti-inflammatory drugs (NSAIDs), which exhibit numerous side effects and are only temporarily effective. Thus novel, safe and more efficacious anti-inflammatory agents are needed for OA. Naturally occurring polyphenolic compounds, such as curcumin and resveratrol, are potent agents for modulating inflammation. Both compounds mediate their effects by targeting the nuclear factor-kappaB (NF-kappaB) signalling pathway. Methods: We have recently demonstrated that in chondrocytes resveratrol modulates the NF-kappaB pathway by inhibiting the proteasome, while curcumin modulates the activation of NF-kappaB by inhibiting upstream kinases (Akt). However, the combinational effects of these compounds in chondrocytes has not been studied and/or compared with their individual effects. The aim of this study was to investigate the potential synergistic effects of curcumin and resveratrol on interleukin (IL)-1beta-stimulated human chondrocytes in vitro using immunoblotting and electron microscopy. Results: Treatment with curcumin and resveratrol suppressed NF-kappaB regulated gene products involved in inflammation (cyclooxygenase-2 (COX-2) and matrix metalloproteinase (MMP)-3, -9, vascular endothelial growth factor (VEGF)), inhibited apoptosis (Bcl-2, Bcl-xL, and tumor necrosis factor receptor-associated factor 1 (TRAF1)) and prevented activation of caspase-3. IL-1beta-induced NF-kappaB activation was suppressed directly by cocktails of curcumin and resveratrol through inhibition of Ikappakappa- and proteasome-activation, inhibition of Ikappa-Balpha phosphorylation and degradation and inhibition of nuclear translocation of NF-kappaB. The modulatory effects of curcumin and resveratrol on IL-1beta-induced expression of cartilage-specific matrix and pro-inflammatory enzymes are mediated in part by the cartilage specific transcription factor Sox-9. Conclusions: We propose that combining these natural compounds may be a useful strategy in OA therapy as compared to separate treatment with each individual compound.

Sinus aspergilloma in rheumatoid arthritis before or during tumor necrosis factor-alpha antagonist therapy

IntroductionIn 2008, the FDA required manufacturers of tumor necrosis factor-alpha (TNF-alpha) antagonists to strengthen their warnings about the risk of serious fungal infections in patients with rheumatoid arthritis (RA). Sinus aspergilloma occurs occasionally in RA patients and can progress to invasive Aspergillus disease. The purpose of this study was to describe symptomatic sinus aspergilloma in RA patients treated with TNF-alpha antagonists. Methods: Retrospective descriptive study of symptomatic cases of sinus aspergilloma in patients with RA followed in three French university hospitals. A systematic literature review was performed. Results: Among 550 RA patients treated with TNF-alpha antagonists, 6 (1.1%) had symptomatic maxillary aspergilloma diagnosed by computed tomography before or during TNF-alpha antagonist therapy. None had chronic neutropenia. Aspergilloma treatment was with surgery only in all 6 patients. In the literature, we found 20 reports of Aspergillus infection in patients with chronic inflammatory joint diseases (including 10 with RA). Only 5/20 patients were treated with TNF-alpha antagonists (invasive lung aspergillosis, n=3; intracranial aspergillosis, n=1; and sphenoidal sinusitis, n=1). Conclusions: Otorhinolaryngological symptoms must be evaluated before starting or switching TNF-alpha antagonists. Routine computed tomography of the sinuses before starting or switching TNF-alpha antagonists may deserve consideration.

ACR70-disease activity score remission achievement from switches between all the available biological agents in rheumatoid arthritis: a systematic review of the literature

IntroductionThe aim of our analysis was to compare the gaining of a major response (disease activity score (DAS) remission or ACR 70) by switching between all the available biological therapies in rheumatoid arthritis. Methods: A systematic review was performed including studies, published before December 2008, in which a second biological agent was used and clinical outcomes were evaluated after a first biological failure. Results: 9 articles were included: switch from etanercept and/or infliximab and/or to adalimumab is effective with an ACR70 response from 5% to 33%. Rituximab may be slightly more effective than switching to a second anti-tumor necrosis factor alpha (TNF-alpha) reaching an ACR70 or DAS remission response in 12% and 9% respectively. Clinical trials confirmed the efficacy in switching to abatacept (gain of effect 10.2%). Tocilizumab allows to reach DAS28 remission in 30.1% but ACR70 only in 12.4% of patients refractory to anti-TNFalpha. Conclusions: The efficacy of a second biologic agent, irrespective of the mode of action, in reaching an ACR70 or DAS-remission after a first biologic is observed from 5 to 15% and from 9% to 15.4% respectively (except in two studies).

Dual energy X-ray absorptiometry analysis contributes to the prediction of hip osteoarthritis progression

IntroductionThe objective was to determine if structural bone parameters obtained from dual energy X-ray absorptiometry (DXA) contribute to the prediction of progression of hip osteoarthritis (OA) and to test if the difference between the most affected (OA) hip and the contralateral hip adds to this prediction. Methods: The study group involves a prospective cohort of 189 patients that met the ACR classification criteria for hip osteoarthritis. Progression was defined as 20% joint space narrowing or total hip replacement within a two years follow up. Software was developed to calculate geometrical aspects and bone mineral density (BMD) in different regions of interest of the proximal femur. Logistic regression was used to test if Kellgren and Lawrence (K-L) scores and DXA parameters can predict "progression" of OA. Models were compared using -2log likelihood tests, R^2 Nagelkerke and areas under the Receiver Operator Characteristic curves, assessed using 10-fold cross validation. Results: The model that included the DXA variables was significantly better in predicting hip OA progression than the model with K-L score of the affected side alone (P<0.01). The addition of the differences in DXA parameters between the most affected and contralateral hip in the superior part of the femoral head, trochanteric and intertrochanteric area further improved the prediction of progression (P<0.05). K-L score of the affected side was still the most significant single variable in the models. Conclusions: DXA parameters can significantly contribute to the prediction of progression in patients with hip osteoarthritis. The analysis of the DXA differences between the hips of the patient represents a small but significant contribution to this prediction. These analyses show the importance of bone density changes in the etiology of OA.

Adiponectin may contribute to synovitis and joint destruction in rheumatoid arthritis by stimulating vascular endothelial growth factor, matrix metalloproteinase-1, and matrix metalloproteinase-13 expression in fibroblast-like synoviocytes more than proinflammatory mediators

IntroductionThe role of adiponectin in the pathogenesis of arthritis is still controversial. This study was performed to examine whether adiponectin is involved in joint inflammation and destruction in rheumatoid arthritis (RA) in relation to the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs). Methods: Synovial cells from RA patients were treated with adiponectin or interleukin (IL)-1beta for 24 hr. The culture supernatant was collected and analyzed for the levels of IL-6, IL-8, prostaglandin E2 (PGE2), VEGF, and MMPs by enzyme-linked immunosorbent assay (ELISA). The levels of adiponectin, VEGF, MMP-1 and MMP-13 in the joint fluids from 30 RA or osteoarthritis (OA) patients were also measured. Results: Adiponectin at the concentration of 10 ug/ml stimulated the production of IL-6, IL-8, and PGE2 in RA fibroblast-like synoviocytes (FLSs) although the level of these was much lower than with 1 ng/ml IL-1beta. However, adiponectin stimulated the production of VEGF, MMP-1, and MMP-13 at the same level as IL-1beta. In addition, the level of adiponectin and MMP-1 in the joint fluid of RA patients was significantly higher than in OA patients. Adiponectin was positively correlated with VEGF in RA patients but not in OA patients, while the level of MMPs in joint fluid was not correlated with adiponectin in either RA or OA patients. Conclusions: Adiponectin may play a significant role in the pathogenesis of RA by stimulating the production of VEGF and MMPs in FLSs, leading to joint inflammation and destruction, respectively.

Progress in spondylarthritis. Progress in studies of the genetics of ankylosing spondylitis

The advent of high-throughput SNP genotyping methods has advanced research into the genetics of common complex genetic diseases such as ankylosing spondylitis (AS) rapidly in recent times. The identification of associations with the genes IL23R and ERAP1 have been robustly replicated, and advances have been made in studies of the major histocompatibility complex genetics of AS, and of KIR gene variants and the disease. The findings are already being translated into increased understanding of the immunological pathways involved in AS, and raising novel potential therapies. The current studies in AS remain underpowered, and no full genomewide association study has yet been reported in AS; such studies are likely to add to the significant advances that have already been made.

The relationship between disease activity, sleep, psychiatric distress and pain sensitivity in rheumatoid arthritis: a cross-sectional study

IntroductionDespite recent advances in anti-inflammatory therapy, rheumatoid arthritis (RA) patients continue to rate pain as a priority. The etiology of RA pain is likely multifactorial, including both inflammatory and non-inflammatory components. In this study, we examine the association between disease activity, sleep, psychiatric distress and pain sensitivity in RA. Methods: Fifty-nine female RA patients completed questionnaires and underwent pressure pain threshold testing to assess hyperalgesia/allodynia at joint and non-joint sites. Blood samples were taken to measure C-reactive protein (CRP). The association between disease activity, sleep problems, psychiatric distress and pain threshold was assessed using Pearson/Spearman correlations and multivariable linear regression. Disease activity levels, sleep problems and psychiatric distress were compared between RA patients with fibromyalgia and RA patients without fibromyalgia. Results: In unadjusted analyses, CRP was not correlated with pain threshold, but tender joint count was inversely correlated with pain threshold at all sites (P ≤ 0.004). Sleep problems were associated with low pain threshold at all sites (P ≤ 0.0008). Psychiatric distress was associated with low pain threshold at the wrist and thumbnail (P ≤ 0.006). In multivariable linear regression models, CRP was inversely associated with wrist pain threshold (P = 0.003). Sleep problems were inversely associated with pain threshold at all sites (P ≤ 0.01), but psychiatric distress was not. Despite differences in pain threshold, CRP levels and sleep problems between RA patients with fibromyalgia and those without fibromyalgia, associations between these variables did not change when patients with fibromyalgia were excluded. Conclusions: Multivariable models are essential in analyses of pain. Among RA patients, inflammation is associated with heightened pain sensitivity at joints. In contrast, poor sleep is associated with diffuse pain sensitivity, as noted in central pain conditions such as fibromyalgia. Future studies examining pain sensitivity at joint and non-joint sites may identify patients with different underlying pain mechanisms and suggest alternative approaches to treating RA pain.

Despair on disparities

Musculoskeletal manifestations of lysosomal storage disorders

Lysosomal storage disorders (LSDs), a heterogeneous group of inborn metabolic disorders, are far more common than most doctors presume. Although patients with a severe LSD subtype are often readily diagnosed, the more attenuated subtypes are frequently missed or diagnosis is significantly delayed. The presenting manifestations often involve the bones and/or joints and therefore these patients are frequently under specialist care by (paediatric) rheumatologists, receiving inadequate treatment. Since effective disease-specific treatments, including enzyme replacement therapy and stem cell transplantation, have become available for certain LSDs and timely initiation of these treatments is necessary to prevent the development of severe, disabling and irreversible manifestations, early diagnosis has become essential. The challenge is to raise awareness for better recognition of the presenting signs and symptoms of LSDs by all doctors who may encounter these patients, including rheumatologists.

Disparities in rheumatoid arthritis disease activity according to gross domestic product in 25 countries in the QUEST-RA database

Objective: To analyse associations between the clinical status of patients with rheumatoid arthritis (RA) and the gross domestic product (GDP) of their resident country. Methods: The Quantitative Standard Monitoring of Patients with Rheumatoid Arthritis (QUEST–RA) cohort includes clinical and questionnaire data from 6004 patients who were seen in usual care at 70 rheumatology clinics in 25 countries as of April 2008, including 18 European countries. Demographic variables, clinical characteristics, RA disease activity measures, including the disease activity score in 28 joints (DAS28), and treatment-related variables were analysed according to GDP per capita, including 14 "high GDP" countries with GDP per capita greater than US$24 000 and 11 "low GDP" countries with GDP per capita less than US$11 000. Results: Disease activity DAS28 ranged between 3.1 and 6.0 among the 25 countries and was significantly associated with GDP (r = –0.78, 95% CI –0.56 to –0.90, r2 = 61%). Disease activity levels differed substantially between "high GDP" and "low GDP" countries at much greater levels than according to whether patients were currently taking or not taking methotrexate, prednisone and/or biological agents. Conclusions: The clinical status of patients with RA was correlated significantly with GDP among 25 mostly European countries according to all disease measures, associated only modestly with the current use of antirheumatic medications. The burden of arthritis appears substantially greater in "low GDP" than in "high GDP" countries. These findings may alert healthcare professionals and designers of health policy towards improving the clinical status of patients with RA in all countries.

Association of bone scintigraphic abnormalities with knee malalignment and pain

Objective: The information content of knee bone scintigraphy was evaluated, including pattern, localisation and intensity of retention relative to radiographic features of knee osteoarthritis, knee alignment and knee symptoms. Methods: A total of 308 knees (159 subjects) with symptomatic and radiographic knee osteoarthritis of at least one knee was assessed by late-phase 99mTechnetium methylene disphosphonate bone scintigraph, fixed-flexion knee radiograph, full limb radiograph for knee alignment and for self-reported knee symptom severity. Generalised linear models were used to control for within-subject correlation of knee data. Results: The compartmental localisation (medial vs lateral) and intensity of knee bone scan retention were associated with the pattern (varus vs valgus) (p<0.001) and severity (p<0.001) of knee malalignment and localisation and severity of radiographic osteoarthritis (p<0.001). Bone scan agent retention in the tibiofemoral, but not patellofemoral, compartment was associated with severity of knee symptoms (p<0.001) and persisted after adjusting for radiographic osteoarthritis (p<0.001). Conclusion: To the authors’ knowledge, this is the first study describing a relationship between knee malalignment, joint symptom severity and compartment-specific abnormalities by bone scintigraphy. This work demonstrates that bone scintigraphy is a sensitive and quantitative indicator of symptomatic knee osteoarthritis. Used selectively, bone scintigraphy is a dynamic imaging modality that holds great promise as a clinical trial screening tool and outcome measure.

Elaboration of the preliminary Rheumatoid Arthritis Impact of Disease (RAID) score: a EULAR initiative

Background: Current response criteria in rheumatoid arthritis (RA) usually assess only three patient-reported outcomes (PROs): pain, functional disability and patient global assessment. Other important PROs such as fatigue are not included. Objective: To elaborate a patient-derived composite response index for use in clinical trials in RA, the RA Impact of Disease (RAID) score. Methods: Ten patients identified 17 domains or areas of health relevant for inclusion in the score, then 96 patients (10 per country in 10 European countries) ranked these domains in order of decreasing importance. The seven most important domains were selected. Instruments were chosen for each domain after extensive literature research of psychometric properties and expert opinion. The relative weight of each of the domains was obtained from 505 patients who were asked to "distribute 100 points" among the seven domains. The average ranks of importance of these domains were then computed. Results: The RAID score includes seven domains with the following relative weights: pain (21%), functional disability (16%), fatigue (15%), emotional well-being (12%), sleep (12%), coping (12%) and physical well-being (12%). Weights were similar across countries and across patient and disease characteristics. Proposed instruments include the Health Assessment Questionnaire and numerical ratings scales. Conclusion: The preliminary RAID score is a patient-derived weighted score to assess the impact of RA. An ongoing study will allow the final choice of questionnaires and assessment of validity. This score can be used in clinical trials as a new composite index that captures information relevant to patients.

Adaptation and cross-cultural validation of the rheumatoid arthritis work instability scale (RA-WIS)

Background: Despite recent advances, work disability in rheumatoid arthritis (RA) remains common. Work disability is frequently preceded by a period of work instability characterised by a mismatch between an individual’s functional abilities and job demands. This could raise the risk of work disability if not resolved. A work instability scale for RA (RA–WIS) has previously been developed to screen for this risk. The objective of this study was the adaptation of this scale into French, Dutch and German. Method: Different language versions of the RA–WIS were produced through a process of forward and back translations. The new scales were tested for face validity. English data from the original developmental study was pooled with data generated through postal surveys in each country. The internal construct and cross-cultural validity of the new scales were assessed using Rasch analysis, including differential item functioning (DIF) by culture. Results: The pooled data showed good fit to the Rasch model and demonstrated strict unidimensionality. DIF was found to be present for six items, but these appeared both to cancel out at the test level and have only a marginal effect on the test score itself. Conclusions: The RA–WIS was shown to be robust to adaptation into different languages. Data fitted Rasch model expectations and strict tests of unidimensionality. This project and the continuing work on further cross-cultural adaptations have the potential to help ensure clinicians across Europe are able to support RA patients to achieve their potential in work through early identification of those most at risk.

Subtle changes in individual joints result in both positive and negative change scores in a patient: results from a clinical trial in patients with rheumatoid arthritis

Background: Radiographic progression in clinical trials is assessed by interpreting changes in total radiographic joint score, and the reliability of those scores depends on an evaluation of sum scores. It is not known how consistently changes in individual joints are identified by independent readers and in independent readings. Patients and Methods: 7255 single joints from 178 patients who participated in the Trial of Etanercept and Methothrexate with Radiographic Patient Outcomes (TEMPO) trial were evaluated. Every image was independently scored twice according to the Sharp–van der Heijde method by two independent readers, so that four scores per joint were available. Absolute agreement and consistency of negative and positive erosion change scores across readers and readings were compared on a per-joint level, as well as on a per-patient level. Results: The number of joints showing a change for erosion was very low in this trial: 691/7255 analysed joints had at least one non-zero change score out of four readings. Absolute agreement between readings was remarkably poor: only 12 joints showed a consistently positive or negative change in all four readings. Change scores in opposite directions in the same joint across independent readings were rare (25 joints). Frequency of opposite joint scores in the same patient (mixed change patterns) was reader dependent. Conclusion: Substantial intra and interreader disagreement in scoring change in individual joints is common. Opposite joint scores in the same patient, however, are rare and reader dependent. Notwithstanding these subtle inconsistencies on the individual joint level, the total Sharp score is a useful and discriminatory outcome measure.

Hand osteoarthritis in older women is associated with carotid and coronary atherosclerosis: the AGES Reykjavik study

Objective: There is evidence that atherosclerosis may contribute to the initiation or progression of osteoarthritis. To test this hypothesis, the presence and severity of hand osteoarthritis (HOA) was compared with markers of atherosclerotic vascular disease in an elderly population. Patients and Methods: The AGES Reykjavik Study is a population-based multidisciplinary study of ageing in the elderly population of Reykjavik. In a study of 2264 men (mean age 76 years; SD 6) and 3078 women (mean age 76 years; SD 6) the severity of HOA, scored from photographs, was compared with measures of atherosclerosis. These included carotid intimal thickness and plaque severity, coronary calcifications (CAC) and aortic calcifications and reported cardiac and cerebrovascular events. Results: After adjustment for confounders, both carotid plaque severity and CAC were significantly associated with HOA in women, with an odds ratio of 1.42 (95% CI 1.14 to 1.76, p = 0.002) for having CAC and 1.25 (95% CI 1.04 to 1.49, p = 0.016) for having moderate or severe carotid plaques. Both carotid plaques and CAC also exhibited significant linear trends in relation to HOA severity in women in the whole AGES Reykjavik cohort (p<0.001 and p = 0.027, respectively, for trend). No significant associations were seen in men. Despite this evidence of increased atherosclerosis, women with HOA did not report proportionally more previous cardiovascular or cerebrovascular events. Conclusions: The results indicate a linear association between the severity of HOA and atherosclerosis in older women. The pathological process of HOA seems to have some components in common with atherosclerosis. Prospective studies may help elucidate the possible mechanisms of this relationship.

Comparison of the Bath Ankylosing Spondylitis Disease Activity Index and a modified version of the index in assessing disease activity in patients with ankylosing spondylitis without peripheral manifestations

Objective: To compare the original Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) with a modified BASDAI without questions about peripheral arthritis (question 3) and enthesitis (question 4), here termed the mini-BASDAI, as an instrument to assess disease activity in patients with ankylosing spondylitis (AS) without peripheral manifestations. Methods: The mini-BASDAI was calculated by omitting questions 3 and 4. The correlation of the original BASDAI and the mini-BASDAI with patient global and other disease parameters was assessed in a total of 692 patients from three AS cohorts including one observational AS cohort and two clinical trial populations treated with non-steroidal anti-inflammatory drugs and tumour necrosis factor alpha inhibitors. Sensitivity to change was assessed by calculating effect sizes. Results: Up to 70% of AS patients did not have peripheral involvement. Patients with peripheral involvement had higher disease activity in all activity parameters. The mini-BASDAI had higher values compared with the original BASDAI, also in the subgroup with peripheral manifestations. However, the mini-BASDAI did not correlate better with other markers of disease activity compared with the original BASDAI. Furthermore, effect sizes of the original BASDAI and mini-BASDAI were comparable in the treatment trials. Interestingly, approximately 5% of active AS patients with pure axial disease manifestation were identified whose disease activity was underestimated by the original BASDAI. Conclusion: On a group level using the mini-BASDAI did not result in an advantage to assess disease activity or in the subgroup without peripheral involvement. In only approximately 5% of AS patients was the mini-BASDAI superior to the original BASDAI.

The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial

Objective: To assess the safety, tolerability and efficacy of abatacept in patients with rheumatoid arthritis (RA) who had failed anti-tumour necrosis factor (TNF) therapy and were switched to abatacept directly or after completing washout. Methods: In this international, 6-month, open-label trial, patients had active RA, an inadequate response to anti-TNF therapy for 3 months or longer and a disease activity score in 28 joints (DAS28 (C-reactive protein; CRP) of 5.1 or greater. "Washout" patients discontinued anti-TNF therapy 2 months or longer pre-screening; "direct-switch" patients began abatacept (~10 mg/kg) at their next scheduled anti-TNF therapy dose. Results: 1046 patients were treated (449 washout, 597 direct-switch; baseline characteristics were similar between groups). At 6 months, adverse events (AE; 78.0% vs 79.2%), serious AE (11.1% vs 9.9%) and discontinuations due to AE (3.8% vs 4.0%) and serious AE (2.0% vs 1.3%) were comparable in washout versus direct-switch patients. There were no opportunistic infections. At 6 months, in washout versus direct-switch patients, similar clinically meaningful improvements were seen in DAS28 (CRP) (>=1.2 unit improvement, 59.5% vs 53.6%, respectively; low disease activity state, 22.5% vs 22.3%; DAS28-defined remission, 12.0% vs 13.7%), physical function (health assessment questionnaire disability index >=0.22 improvement; 46.3% vs 47.1%) and health-related quality of life (mean change in short-form 36 scores: physical component summary, 5.5 vs 6.1; mental component summary, 4.8 vs 5.4). Conclusion: Abatacept demonstrated acceptable safety and tolerability and clinically meaningful efficacy over 6 months in patients with inadequate response to anti-TNF therapy. Results were comparable with or without a washout, supporting direct switching from anti-TNF therapy to abatacept as an option in clinical practice. Trial registration number: NCT00124982.

Efficacy of prednisone 1-4 mg/day in patients with rheumatoid arthritis: a randomised, double-blind, placebo controlled withdrawal clinical trial

Objective: A randomised double-blind placebo controlled withdrawal clinical trial of prednisone versus placebo in patients with rheumatoid arthritis (RA), treated in usual clinical care with 1–4 mg/day prednisone, withdrawn to the same dose of 1 mg prednisone or identical placebo tablets. Methods: All patients were from one academic setting and all trial visits were conducted in usual clinical care. Patients were taking stable doses of 1–4 mg prednisone with stable clinical status, documented quantitatively by patient questionnaire scores. The protocol included three phases: (1) equivalence: 1–4 study prednisone 1 mg tablets taken for 12 weeks to ascertain their efficacy compared with the patient’s usual tablets before randomisation; (2) transfer: substitution of a 1 mg prednisone or identical placebo tablet every 4 weeks (over 0–12 weeks) to the same number as baseline prednisone; (3) comparison: observation over 24 subsequent weeks taking the same number of either placebo or prednisone tablets as at baseline. The primary outcome was withdrawal due to patient-reported lack of efficacy versus continuation in the trial for 24 weeks. Results: Thirty-one patients were randomised, 15 to prednisone and 16 to placebo, with three administrative discontinuations. In "intent-to-treat" analyses, 3/15 prednisone and 11/16 placebo participants withdrew (p = 0.03). Among participants eligible for the primary outcome, 3/13 prednisone and 11/15 placebo participants withdrew for lack of efficacy (p = 0.02). No meaningful adverse events were reported, as anticipated. Conclusion: Efficacy of 1–4 mg prednisone was documented. Evidence of statistically significant differences with only 31 patients may suggest a robust treatment effect.

Baseline and 1-year magnetic resonance imaging of the sacroiliac joint and lumbar spine in very early inflammatory back pain. Relationship between symptoms, HLA-B27 and disease extent and persistence

Background: The precise anatomical location of pathology associated with inflammatory back pain (IBP) in early spondyloarthropathy (SpA) remains unclear. Objective: To use MRI to study the sacroiliac joint (SIJ) and lumbar spine (LS) and explore the relationship between sites and extent of inflammation and HLA-B27 status over 12 months. Methods: 54 patients with IBP; median duration 24 weeks (54% HLA-B27 positive; median Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 5.65) and 22 control subjects (11 with mechanical back pain; 11 volunteers) were recruited and 63% (n = 34) were reassessed at 1 year. Fat saturation and T1-weighted MRI was performed with images being scored for active bone marrow oedema (BMO) lesions representative of inflammation. Results: At baseline 46/54 (85%) patients had BMO (SIJs and LS) compared with 40% in the control group. The majority of affected patients had inflammation at the SIJ level (96% (n = 44); 23.5% (n = 12) LS) and 28.3% (n = 13) at both sites simultaneously. The SIJ activity score confirmed more severe inflammation (BMO grade 2 or 3: 52.2%) in the IBP group (controls = BMO grade 1: 100%; p<0.001). HLA-B27 was associated with both the severity (p = 0.009) and number of baseline SIJ lesions (p = 0.045) and with persistence (SIJ or LS) at 1 year (p = 0.02). 90% of reattenders fulfilled European Spondyloarthropathy Study Group criteria; 73.5% showed MRI inflammation despite clinical improvement (median BASDAI 5.65 to 3.05; p<0.009). Conclusion: LS and SIJ involvement may occur simultaneously in very early SpA and may be differentiated from non-inflammatory back pain by the severity of MRI lesions. HLA-B27 is associated with both the severity of osteitis and its persistence.

Seasonality and trends in the incidence and prevalence of gout in England and Wales 1994-2007

Objectives: To examine seasonality and long-term trends in the incidence and prevalence of gout. Methods: A retrospective study (1994–2007) using routinely collected surveillance data from the Royal College of General Practitioners Weekly Returns Service sentinel general practice network in England and Wales. New cases and acute attacks of gout per 10 000 population were calculated for age groups 0–44, 45–64, 65–74 and >=75 years. Long-term trends of annual incidence were assessed by regression analysis. Seasonality indices were calculated using 4-weekly data, and the relative risk of gout incidence during the summer was estimated. Annual prevalence was estimated from the consulting patient population (2001–7) and from prescribing data on defined daily doses (DDD) of allopurinol (2003–7). Results: The annual incidence rate of new gout cases was stable over the period 1998–2007; acute attacks decreased on average 4% per annum. New gout cases and acute attacks combined into 4-weekly incidence rates peaked during the "summer" period of each year. There was an increased risk of gout diagnosis during summer months (late April to mid-September; odds ratio 1.22, 95% CI 1.18 to 1.26). The annual prevalence of gout in 2001–7 was 0.46%, with highest rates in men >=75 years (2.57%). Estimated prevalence based on a DDD of 400 mg allopurinol was 0.37%. Conclusion: The incidence of gout is seasonal. This has implications for the management of patients who currently have gout, and for those who are at risk of future attacks. The decreasing trend in the incidence of acute attacks suggests that patient management is improving.

Progressive increase in body mass index is not associated with a progressive increase in joint space narrowing in obese women with osteoarthritis of the knee

Objective: Given that obesity is a risk factor for osteoarthritis (OA) of the knee, a study was undertaken to determine whether progressively higher body mass index (BMI) among obese women is associated with progressive increases in joint space narrowing (JSN). Methods: Medial compartment JSN over 12 months in Lyon Schuss radiographs of 60 obese women (BMI 30.0–50.5 kg/m2) with radiographic and symptomatic OA was compared with that in 81 non-obese women (BMI <28 kg/m2) with normal radiographs and minimal or no symptoms of knee OA. Results: Among the patients with OA, higher BMI tended to be associated with a higher Kellgren and Lawrence (KL) grade of OA severity. JSN in the non-obese controls was negligible, but in the 30 patients with KL grade 2 and KL grade 3 knees, mean (SD) JSN was 0.12 (0.31) mm and 0.32 (0.50) mm, respectively (p<0.005 and p<0.001). No association was seen between baseline BMI and 12-month JSN in patients with OA; indeed, the regression plot suggested a slight inverse relationship between the two. Conclusions: In obese patients with OA, progressively higher BMI values were not accompanied by a progressively increasing rate of JSN. Joint loading was not evaluated, but it is possible that marked obesity limited the functional capacity of some subjects with OA, protecting their knees from loading. For investigators considering eligibility criteria for a trial of a structure-modifying OA drug, these data suggest that recruitment of patients with a BMI much higher than 30 kg/m2 will not enrich the sample of subjects who will have more rapid JSN than those with a BMI of only 30 kg/m2.

Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis

Background: Tumour necrosis factor (TNF) neutralising antibody constructs are increasingly being used to treat rheumatoid arthritis (RA). Objective: To determine potential differences in clinical responses, soluble drug levels and antibody formation between patients with RA receiving infliximab and adalimumab. Methods: 69 patients with RA fulfilling the 1987 American College of Rheumatology criteria and about to start treatment with infliximab or adalimumab, were enrolled consecutively. All patients had active disease (28-joint count Disease Activity Score >3.2). Infliximab was given intravenously at 3 mg/kg at baseline and after 2, 6 and 14 weeks. Adalimumab was administered as 40 mg biweekly subcutaneously. Concomitant drug treatment was monitored and continued at constant dosage during the study. All serum samples were tested for infliximab/adalimumab levels and anti-infliximab/anti-adalimumab antibodies. Results: 35 patients received infliximab, 34 received adalimumab. At 6 months, 15 (43%), 6 (17%) and 14 (40%) of the infliximab-treated patients fulfilled the EULAR criteria for good, moderate and non-responders, respectively, whereas the corresponding figures for adalimumab-treated patients were 16 (47%), 8 (24%) and 10 (29%). Clinical responses correlated with the levels of S-infliximab/adalimumab and the formation of anti-infliximab/anti-adalimumab antibodies. Conclusion: The clinical response to two anti-TNF biological agents closely follows the trough drug levels and the presence of antibodies directed against the drugs. Further studies that focus on the underlying pathways leading to antibody formation are warranted to predict immunogenicity of these expensive biological agents and treatment outcomes.

STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk

Objectives: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus (SLE), investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. Methods: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in five new sets of cases and controls for replication. STAT4 cDNA was analysed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. Results: In the fine mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals, represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. Transcription of alternative tissue-specific exons 1, indicating the presence of tissue-specific promoters of potential importance in the expression of STAT4, was also detected. No interaction with associated SNPs of IRF5 was observed using regression analysis. Conclusions: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. The results also indicate that the genes STAT4 and IRF5 act additively to increase the risk for SLE.

Genetic variation in the GDF5 region is associated with osteoarthritis, height, hip axis length and fracture risk: the Rotterdam study

Background: A polymorphism (rs143383; T to C) near the GDF5 gene has been associated with height and osteoarthritis (OA), but debate exists about whether its primary biological action is directed to cartilage or bone. Objective: To study the association between genetic variation in the GDF5 region and radiographic osteoarthritis (ROA) susceptibility, height, bone size parameters and fracture risk in a large population-based cohort of Caucasian elderly subjects. Methods: 6365 men and women had genotype data available. ROA was defined as a Kellgren/Lawrence (K/L) score >=2 for hand, knee and hip joints. CTX-II levels, height, bone mineral density (BMD), bone size and fracture risk were also assessed. Results: rs143383 and three highly correlated single nucleotide polymorphisms (SNPs) in the GDF5 region were found to be independently associated with OA, height, bone size and fracture risk in women. Women with homozygotes for the rs143383 C allele had a 37% lower risk for hand OA (p = 8x10–6) and a 28% lower risk for knee OA (p = 0.003). In addition, they were 1.1 cm taller (p = 0.001), had a larger hip axis length (HAL) (p = 4x10–4) and had a 29% increased risk of incident non-vertebral fractures (p = 0.02). No associations with hip OA or BMD were detected. No associations were found in men. Conclusion: This population-based study shows that GDF5 gene variants are associated with hand OA, knee OA and fracture risk in elderly women. It also replicates previous association between GDF5 variation and height. Furthermore, our findings for HAL suggest that GDF5 action is primarily directed to the long bones, rather than the axial skeleton.

Bortezomib attenuates murine collagen-induced arthritis

Objectives: Nuclear factor kappa B (NF-B) is a major regulator of pivotal proinflammatory cytokines in the pathogenesis of rheumatoid arthritis (RA). Bortezomib inhibits NF-B activation by blocking the degradation of the NF-B inhibitor, I-B. In this study, the efficacy of bortezomib on murine collagen-induced arthritis (CIA) was investigated. Methods: Thirty-five male DBA/1 mice were divided into five groups. All mice except controls were injected with type II collagen. Mice in the bortezomib-treated groups were injected intraperitoneally with 0.01, 0.1 and 1 mg/kg bortezomib twice a week for 2 weeks. Controls and mice in the untreated group were also injected intraperitoneally with phosphate-buffered saline in the same manner. Arthritis score and paw thickness were measured and histopathological assessment of joint sections was performed. The expression of proinflammatory cytokines and enzymes was evaluated by immunohistochemical staining. Joint destruction was confirmed using three-dimensional micro-computerised tomography (CT). Blood cells were counted and liver and kidney functions were monitored. Results: Bortezomib significantly attenuated the severity of arthritis and histopathological findings in CIA mice. The expression of tumour necrosis factor alpha, IL-1β, IL-6, matrix metalloproteinase 3, cyclooxygenase 2 and inducible nitric oxide synthase decreased in bortezomib-treated mice compared with untreated mice. In addition, micro-CT confirmed that bortezomib reduced joint destruction. No adverse effects in blood cells, liver or kidneys were observed with bortezomib treatment. Conclusions: These data suggest that bortezomib may play an anti-inflammatory role in the pathophysiology of RA and serve as a new therapeutic modality for RA.

Elevated synovial expression of triggering receptor expressed on myeloid cells 1 in patients with septic arthritis or rheumatoid arthritis

Objective: To determine whether synovial expression of triggering receptor expressed on myeloid cells 1 (TREM-1) is upregulated in patients with distinct types of inflammatory or non-inflammatory arthritis. Methods: Synovial fluid (SF) samples were analysed for levels of soluble TREM-1 (sTREM; n = 132), tumour necrosis factor alpha (TNF, n = 78) and leucocyte TREM-1 messenger RNA (n = 48). Synovial tissue from four rheumatoid arthritis (RA) patients, two patients with Crohn’s-associated arthritis, one patient with ankylosing spondylitis and one patient with osteoarthritis were examined for TREM-1 expression by immunohistology, and three of the RA samples were also analysed by Western blotting. Results: Synovial fluid sTREM-1 levels in septic arthritis and RA were similar to each other and were each greater than those in gouty arthritis, non-septic/non-RA inflammatory arthritis and non-inflammatory arthritis. Synovial fluid TNF and sTREM-1 levels correlated with each other, and sTREM-1 and leucocyte TREM-1 mRNA levels each correlated with SF leucocyte counts. TREM-1 in RA was expressed in situ in synovial tissue by cells of myelomonocytic lineage but was not detectably expressed in control osteoarthritis synovial tissue. Conclusions: Synovial TREM-1 expression is increased in septic arthritis and RA. In patients with acute inflammatory arthritis, elevated SF sTREM-1 levels may point the clinician to a diagnosis of septic arthritis or RA. In RA patients, targeting TREM-1 may have therapeutic benefits by reducing local proinflammatory cytokine and chemokine release.

Contribution of Fc{gamma} receptor IIIA gene 158V/F polymorphism and copy number variation to the risk of ACPA-positive rheumatoid arthritis

Background: Fc receptors (FcRs) are potent immune modulators. FcR genes encompass a complex region, polymorphic by both single nucleotide polymorphisms (SNPs) and copy number variation (CNV). The heterogeneity of rheumatoid arthritis (RA) combined with the genetic complexity of FcR genes may be the cause of inconsistent findings in previous RA studies on FcR SNPs. There is increasing evidence that anti-citrullinated peptide antibody (ACPA)-positive RA and ACPA-negative RA have a different genetic background. Objective: To investigate whether FcRIIIA 158V/F SNP associates differently with ACPA-positive and ACPA-negative RA and to assess if the FcRIIIA gene CNV affects the association of the FcRIIIA 158V/F SNP with RA and whether the FcRIIIA gene CNV confers risk for RA. Methods: 945 patients with RA and 388 healthy controls, all Dutch-Caucasians, were included in the study. FcRIIIA 158V/F SNP was genotyped using Sequenom. CNV of the FcRIIIA gene was determined in 456 patients with RA and 285 controls using multiplex ligation-dependent probe amplification. Associations between genotypes and RA were analysed, stratifying for the presence/absence of ACPA and CNV. Results: In all patients with RA the FcRIIIA 158V/F SNP was not associated with RA. In ACPA-positive RA (n = 358), the VV genotype was more prevalent in cases than in controls (18.4% vs 13.2%, OR = 1.5, p = 0.05). After stratification for CNV the VV genotype was associated with RA in general (n = 426) (OR = 1.6, 95% CI 0.97 to 2.6, p = 0.05) and with ACPA-positive RA (n = 135) (OR = 2.1, 95% CI 1.2 to 3.8, p = 0.009) but not with ACPA-negative RA. The distribution of CNV was not significantly different between patients with RA and controls. Conclusion: The FcRIIIA 158 VV genotype confers risk for ACPA-positive RA; this association increased slightly after correction for CNV of the FcRIIIA gene. CNV itself is not associated with RA susceptibility.

Genetic polymorphisms of the matrix metalloproteinase-3 (MMP-3) and tissue inhibitors of matrix metalloproteinases-1 (TIMP-1) modulate the development of ankylosing spondylitis

Background: The aetiology of ankylosing spondylitis (AS) remains unclear. Inflammation progresses to fibrosis and calcification of the spine and sacroiliac joints in AS development. Fibrosis results from excessive accumulations of the extracellular matrix (ECM). ECM turnover depends on the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Objective: To evaluate the effects of the MMP-3 -1171 and TIMP-1 372 T>C polymorphisms on the modified risk of AS. Methods: Genotypes of 241 patients with AS and 241 controls were identified by PCR. Disease activity and functional status were assessed by the Bath Ankylosing Spondylitis Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Global (BAS-G) Score. Results: MMP-3 6A/6A carriers had a 2.41-fold (95% confidence interval (CI) 1.55 to 3.74) increased risk of AS compared with 6A/5A and 5A/5A carriers. TIMP-1 C alleles had a greater risk of AS, but this was not significant (odds ratio (OR) = 1.28, 95% CI 0.92 to 1.77). Pairwise analysis of the MMP-3/TIMP-1 alleles showed that 6A/C (OR = 3.23, 95% CI 1.50 to 6.95) and 6A/T (OR = 2.55, 95% CI 1.17 to 5.54) had a significantly greater risk of AS than the 5A/T alleles. After adjustment for the effects of age, gender and disease duration, the MMP-3/TIMP-1 5A/T alleles had the lowest BASDAI (p = 0.02), BASFI (p = 0.05) and BAS-G (p = 0.02) among all MMP-3/TIMP-1 alleles. Conclusion: The findings highlight the importance of the MMP-3 and TIMP-1 genes as crucial elements in AS development.

Decreased clinical response to adalimumab in ankylosing spondylitis is associated with antibody formation

MRSA infections in patients treated with tumour necrosis factor inhibitors

Association of IL2RA and IL2RB with rheumatoid arthritis: a replication study in a Dutch population

Rapidity of rheumatology consultation for people in an early inflammatory arthritis cohort

Antinuclear antibodies directed against proliferating cell nuclear antigen are not specifically associated with systemic lupus erythematosus

Etanercept during pregnancy and lactation in a patient with rheumatoid arthritis: drug levels in maternal serum, cord blood, breast milk and the infant's serum

A patient's wish: anakinra in pregnancy

Fall incidence and fall risk factors in people with rheumatoid arthritis

Health insurance and out-of-pocket expenses

No abstract.

US bone and joint decade prepares for the future

No abstract.

Anti-citrullinated peptide antibody assays and their role in the diagnosis of rheumatoid arthritis

No abstract.

Erythrocyte sedimentation rate, C-reactive protein level, and serum amyloid a protein for patient selection and monitoring of anti-tumor necrosis factor treatment in ankylosing spondylitis

To study the usefulness of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum amyloid A (SAA) for response prediction and monitoring of anti-tumor necrosis factor (anti-TNF) treatment in ankylosing spondylitis (AS) patients.Patients were included consecutively before starting etanercept or infliximab treatment. ASsessment in Ankylosing Spondylitis (ASAS) response, defined as a 50% improvement or an absolute improvement of 2 points of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; 0-10 scale), was assessed at 3 months. Inflammatory markers and the BASDAI were collected at baseline and 1 and 3 months. Longitudinal data analysis was performed to compare associations between inflammatory markers and the BASDAI over time by calculating standardized betas. Predictive values of baseline levels of inflammatory markers for ASAS response were calculated.In total, 155 patients were included, of whom, after 3 months of treatment, 70% in the etanercept cohort and 71% in the infliximab cohort responded. All markers, notably SAA, decreased significantly (P < 0.0001). Standardized betas were 0.49 for ESR, 0.43 for CRP, and 0.39 for SAA. Normal baseline levels of CRP and SAA were significantly associated with nonresponse. A combination of elevated CRP and SAA levels at baseline revealed the highest predictive value (81%) for ASAS response.ESR, CRP, and SAA were significantly associated with the BASDAI over 3 months, and the association with ESR was the strongest. Elevated baseline CRP and SAA levels revealed the highest predictive value for response. Together, this study demonstrates that inflammatory markers, and notably CRP and SAA, may facilitate patient selection and monitoring of efficacy of anti-TNF treatment in AS, and could be added to response criteria.

Arthritic pain among Latinos: Results from a community-based survey

To examine factors associated with pain among Latinos with arthritis, identify common coping strategies and potentially effective interventions, and determine whether pain levels affect the level of interest in potentially useful programs.Using a convenience sampling approach and a combination of face-to-face and telephone surveys, 588 Latino adults in Oregon with arthritis were interviewed. The intensity of pain during a typical day was assessed using a scale ranging from 0 (no pain) to 10 (worst pain). A score of [ge]7 was defined as severe pain.More than 60% of Latinos reported severe pain. Results from an ordinary least square regression indicated that among Latinos with arthritis, women, those with lower levels of education, and those reporting poor or fair self-rated health and functional limitations had higher levels of pain, after controlling for confounders. Those with severe pain were more likely than those with lower levels of pain to use over the counter medicine and home remedies to manage their arthritis. In addition, Latinos with greater pain were more likely to be interested in arthritis management programs.These findings have important implications for public health policy. The strong interest of Latinos in various arthritis and joint pain management programs could prove to be an important avenue for supporting a population with high levels of arthritic pain and lack of health insurance. These pain management programs are all the more appealing, given the availability of a number of evidence-based, low-cost interventions.

Comparison of clinical versus ultrasound-determined synovitis in juvenile idiopathic arthritis

To compare clinical evaluation and ultrasonography (US) in the assessment of joint synovitis in children with juvenile idiopathic arthritis (JIA).Thirty-two patients underwent clinical evaluation of 52 joints by 2 pediatric rheumatologists. Joints were assessed for swelling, tenderness/pain on motion, and restricted motion. The same joints were scanned independently by an experienced sonographer for synovial hyperplasia, joint effusion, and power Doppler (PD) signal.In total, 1,664 joints were assessed both clinically and with US. On clinical examination, 98 joints (5.9%) were swollen, 59 joints (3.5%) were tender, and 40 joints (2.4%) had restricted motion. On US evaluation, 125 joints (7.5%) had synovial hyperplasia, 153 joints (9.2%) had joint effusion, and 53 joints (3.2%) had PD signal. A total of 104 (6.3%) and 167 (10%) joints had clinical and US synovitis, respectively. Of the 1,560 clinically normal joints, 86 (5.5%) had subclinical synovitis (i.e., had synovitis on US). US led to classifying 5 patients as having polyarthritis who were classified as having oligoarthritis or were found to have no synovitis on clinical evaluation. US variables were moderately correlated with clinical measures of joint swelling, but poorly correlated with those of joint tenderness/pain on motion and restricted motion. Overall, correlations were lower for PD signal than for synovial hyperplasia and joint effusion.We found that subclinical synovitis as detected by US is common in children with JIA. This finding may have important implications for patient classification and may affect the choice of the optimal therapeutic strategy in individual patients.

Improved influenza and pneumococcal vaccination in rheumatology patients taking immunosuppressants using an electronic health record best practice alert

To examine whether an electronic health record (EHR) best practice alert (BPA), a clinical reminder to help guideline adherence, improved vaccination rates in rheumatology patients receiving immunosuppressants. Guidelines recommend yearly influenza and pneumococcal vaccination with revaccination for patients age >65 years who are taking immunosuppressive medications.A vaccination BPA was developed based on immunosuppressant treatment, age, and prior vaccinations. At site 1, a hospital-based academic practice, physicians ordered vaccinations. At site 2, a community-based practice, physicians signed orders placed by nurses. Demographics, vaccination rates, and documentation (vaccination or no administration) were obtained. Chi-square and Fisher's exact test analysis compared vaccination and documentation rates for October 1 through December 31, 2006 (preBPA), and October 1 through December 31, 2007 (postBPA). Breslow-Day statistics tested the odds ratio of improvement across the years between the sites.PostBPA influenza vaccination rates significantly increased (47% to 65%; P < 0.001), with significant improvement at both sites. PostBPA pneumococcal vaccination rates likewise significantly increased (19% to 41%; P < 0.001). PostBPA documentation rates for influenza and pneumococcal vaccinations also increased significantly. Site 2 (nurse-driven) had significantly higher preBPA vaccination rates for influenza (69% versus 43%; P < 0.001) than pneumococcal (47% versus 15%; P < 0.001).The use of a BPA significantly increased influenza and pneumococcal vaccination and documentation rates in rheumatology patients taking immunosuppressants. A nurse-driven process offered higher efficacy. An EHR programmed to alert providers is an effective tool for improving quality of care for patients receiving immunosuppressants.

UK-based physical therapists' attitudes and beliefs regarding exercise and knee osteoarthritis: Findings from a mixed-methods study

Within the UK, differences exist between physical therapists' use of exercise for patients with knee osteoarthritis (OA) and recent exercise recommendations. This may be explained by their underlying attitudes and beliefs. We aimed to describe UK physical therapists' attitudes and beliefs regarding exercise and knee OA, and understand and explain them.A survey was mailed to 2,000 UK-based chartered physical therapists that included 23 attitude statements derived from recently published recommendations. Semistructured telephone interviews were conducted with a purposeful sample of questionnaire respondents (n = 24), and were recorded and analyzed thematically.The questionnaire response rate was 58% (n = 1,152); 538 respondents reported treating a patient with knee OA in the last 6 months. The survey highlighted uncertainty about potential benefits of exercise for knee OA: only 56% largely/totally agreed that knee problems are improved by local exercise. Although exercise adherence was deemed important, it was seen as the patient's, not the therapist's, responsibility. Interviews revealed an underlying biomedical model of care of knee pain, with knee OA viewed as a progressive degenerative condition. A paternalistic treatment approach was evident. Health care systems presented a number of barriers to best practice, including limited opportunity to provide followup.Although the attitudes and beliefs of physical therapists may help to explain differences between current practice and recent exercise recommendations, the wider health care system also plays a part. Further research is needed to support meaningful shifts in physical therapy care in line with the best practice recommendations.

Functional and work outcomes improve in patients with rheumatoid arthritis who receive targeted, comprehensive occupational therapy

Work disability is a serious consequence of rheumatoid arthritis (RA). We conducted a 6-month, prospective randomized controlled trial comparing assessments of function, work, coping, and disease activity in employed patients with RA receiving occupational therapy intervention versus usual care.Employed patients with RA with increased perceived work disability risk were identified by the RA Work Instability Scale (WIS; score [ge]10). Patients were stratified into medium- (score [ge]10 and <17) and high-risk ([ge]17) groups, then randomized into occupational therapy or usual care groups. Assessments were conducted at baseline and 6 months. The primary outcome was the Canadian Occupational Performance Measure (COPM), a standardized patient self-report of function. Other outcomes included the disability index (DI) of the Health Assessment Questionnaire (HAQ); Disease Activity Score in 28 joints (DAS28); RA WIS; EuroQol Index; visual analog scales (VAS) for pain, work satisfaction, and work performance; and days missed/month. Independent sample t-tests and Mann-Whitney U tests were used.We recruited 32 employed patients with RA. At baseline the groups were well matched. At 6 months the improvement in the occupational therapy group was significantly greater than that in the usual care group for all functional outcomes (COPM performance P < 0.001, COPM satisfaction P < 0.001, HAQ DI P = 0.02) and most work outcomes (RA WIS [P = 0.04], VAS work satisfaction [P < 0.001], VAS work performance [P = 0.01]). Additionally, Arthritis Helplessness Index (P = 0.02), Arthritis Impact Measurement Scales II pain subscale (P = 0.03), VAS pain (P = 0.007), EuroQol Index (P = 0.02), EuroQol global (P = 0.02), and DAS28 (P = 0.03) scores significantly improved.Targeted, comprehensive occupational therapy intervention improves functional and work-related outcomes in employed RA patients at risk of work disability.

Medical decision making in patients with knee pain, meniscal tear, and osteoarthritis

Meniscal tears and osteoarthritis (OA) frequently coexist, but to our knowledge, no data exist to identify who will benefit from arthroscopic partial meniscectomy (APM) versus nonoperative management. Our objective was to evaluate the capability of preoperative information to predict APM outcomes in OA.Using a mathematical model and published data, we combined 2 clinical (mechanical symptoms and pain pattern) and 2 magnetic resonance imaging (tear type and bone marrow lesions) indicators into 36 possible combinations and ranked each combination according to the likelihood of having primarily tear- versus OA-related pain in individuals ages 45-65 years with knee pain, OA, and meniscal tears. By considering alternative thresholds for performing APM, we identified the cutoff rank that maximized the overall population International Knee Documentation Committee (IKDC) score (0-100 scale).Rank 1 (e.g., displaced tear, locking, increased pain, no bone marrow lesions) represented the highest likelihood of APM benefit; rank 36 (e.g., oblique tear, no mechanical symptoms, static pain, severe bone marrow lesions) represented the lowest likelihood of APM benefit. Indeterminate middle ranks included individuals with mixed findings (i.e., 2 findings consistent with high and 2 with low likelihood of APM benefit). APM thresholds between ranks 17 and 23 resulted in >82% of the population receiving treatment producing the greatest possible IKDC improvement, with mean incremental gains in IKDC score of >24 points. Findings were robust across a broad range of indicator assumptions, but were sensitive to outcome assumptions.Among individuals with degenerative meniscal tears and OA, easily obtainable clinical information can differentiate those who are more likely to benefit from APM.

Cartilage loss occurs in the same subregions as subchondral bone attrition: A within-knee subregion-matched approach from the multicenter osteoarthritis study

By magnetic resonance imaging (MRI), subchondral bone attrition (SBA) can be seen in early osteoarthritis (OA), but the significance of this is unknown. We therefore evaluated whether SBA was associated with cartilage loss within the same subregion of the knee.The Multicenter Osteoarthritis Study is a cohort of individuals who have or are at high risk for knee OA. At baseline and 30 months, participants' knee MRIs were graded using the Whole-Organ Magnetic Resonance Imaging Score in the 10 subregions of the tibiofemoral joint for cartilage morphology and SBA. We conducted analyses within a knee to eliminate between-person confounding, using an M:N (cases:controls) matched case-control approach with the 10 subregions of a person's knee forming a matched set. Cases within a knee were defined as subregions with cartilage loss, while controls were subregions in that same knee without cartilage loss. We evaluated the association of cartilage loss over 30 months with the presence of baseline SBA in the same subregion within that knee using conditional logistic regression.SBA was associated with an odds ratio of 7.5 (95% confidence interval 5.6-9.9, P < 0.0001) for cartilage loss in the same subregion compared with subregions without any baseline SBA in our sample of 459 knees from participants, 64% of whom were women, with a mean age of 63 years and a mean body mass index of 30.5 kg/m2.SBA is strongly associated with cartilage loss within the same subregion of a knee. SBA may directly influence overlying cartilage loss or serve as a marker of an area undergoing great compressive stress and in which cartilage loss is inevitable.

Tai Chi is effective in treating knee osteoarthritis: A randomized controlled trial

To evaluate the effectiveness of Tai Chi in the treatment of knee osteoarthritis (OA) symptoms.We conducted a prospective, single-blind, randomized controlled trial of 40 individuals with symptomatic tibiofemoral OA. Patients were randomly assigned to 60 minutes of Tai Chi (10 modified forms from classic Yang style) or attention control (wellness education and stretching) twice weekly for 12 weeks. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at 12 weeks. Secondary outcomes included WOMAC function, patient and physician global assessments, timed chair stand, depression index, self-efficacy scale, and quality of life. We repeated these assessments at 24 and 48 weeks. Analyses were compared by intent-to-treat principles.The 40 patients had a mean age of 65 years and a mean body mass index of 30.0 kg/m2. Compared with the controls, patients assigned to Tai Chi exhibited significantly greater improvement in WOMAC pain (mean difference at 12 weeks -118.80 mm [95% confidence interval (95% CI) -183.66, -53.94; P = 0.0005]), WOMAC physical function (-324.60 mm [95% CI -513.98, -135.22; P = 0.001]), patient global visual analog scale (VAS; -2.15 cm [95% CI -3.82, -0.49; P = 0.01]), physician global VAS (-1.71 cm [95% CI -2.75, -0.66; P = 0.002]), chair stand time (-10.88 seconds [95% CI -15.91, -5.84; P = 0.00005]), Center for Epidemiologic Studies Depression Scale (-6.70 [95% CI -11.63, -1.77; P = 0.009]), self-efficacy score (0.71 [95% CI 0.03, 1.39; P = 0.04]), and Short Form 36 physical component summary (7.43 [95% CI 2.50, 12.36; P = 0.004]). No severe adverse events were observed.Tai Chi reduces pain and improves physical function, self-efficacy, depression, and health-related quality of life for knee OA.

The robust association between childhood physical abuse and osteoarthritis in adulthood: Findings from a representative community sample

Research suggests a role of early-life trauma in the development of arthritis. This study investigated the relationship between childhood physical abuse and osteoarthritis (OA) while controlling for age, sex, race, and socioeconomic status (SES), in addition to the following types of risk factors for OA: 1) concurrent childhood stressors, 2) adult health behaviors, and 3) depression.Data from the provinces of Manitoba and Saskatchewan were selected from the 2005 Canadian Community Health Survey (n = 13,093). Respondents with missing arthritis data or with arthritis types other than OA were excluded (n = 1,985). Of the 11,108 remaining respondents, 6.9% (n = 854) reported childhood physical abuse by someone close to them, and 10.1% (n = 1,452) reported that they had been diagnosed with OA by a health professional. The regional-level response rate was 84%.When adjusting for all 3 types of risk factors, a significant association between childhood physical abuse and OA was found (odds ratio [OR] 1.56, 95% confidence interval [95% CI] 1.21-2.00). In contrast, when adjusting for age, sex, race, and SES only, the OR was 1.99 (95% CI 1.57-2.52).The association between childhood physical abuse and OA remained significant, even after controlling for many risk factors that may mediate the relationship. Further research is needed to investigate potential pathways through which arthritis develops as a consequence of childhood physical abuse.

Out-of-pocket expenses and their burden in patients with rheumatoid arthritis

To describe and understand the burden of out-of-pocket expenses in patients with rheumatoid arthritis (RA).We studied out-of-pocket expenses and their burden in 8,545 US patients with RA. We determined direct medical costs, out-of-pocket expenses, the burden of out-of-pocket expenses, household income, and measures of RA severity and outcome. In addition, patients were classified into 3 groups based on the level of burden caused by out-of-pocket expenses: no or limited problem (I am able to pay the bills without much problem); moderate problem (paying the bills takes away some money I need for other activities); and a great problem (I can't purchase all of the medications or medical care that I need).A total of 43.6% of patients reported problems paying medical bills after insurance payments and 9.0% reported severe or great problems. Problems with expenses were associated with measures of RA severity, but also and particularly with lower household income and absence of health insurance. The proportion of household income that was consumed by out-of-pocket spending for the 3 groups was 2.4%, 7.2%, and 19.2%, respectively, and the percentage of patients meeting the 185% poverty level for these groups was 12.3%, 24.4%, and 51.3%, respectively.The out-of-pocket burden is substantial, particularly in those <65 years of age. Out-of-pocket expenses exert their severity predominantly on those with the most severe RA who have the least ability to pay. Household income is the primary determinant of out-of-pocket burden, followed by RA severity, and type of health insurance.

Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study

Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease (CVD), but longitudinal observations are limited and the precise magnitude is unknown. We prospectively assessed the incidence of CVD in patients with RA compared with patients with type 2 diabetes mellitus (DM) and the general population.The 3-year incidence rate of CVD was determined in a prospective cohort (the Cardiovascular Research and Rheumatoid Arthritis Study) of 353 outpatients with RA, and was compared with that in 1,852 population-based cohort study participants (155 had type 2 DM). We investigated fatal and nonfatal CVD (according to International Classification of Diseases, Ninth Revision criteria) and used Cox proportional hazards models to assess the incidence of CVD in RA, type 2 DM, and the general population.The 3-year incidence of CVD was 9.0% in patients with RA and 4.3% in the general population, corresponding with an incidence rate of 3.30 per 100 patient-years (95% confidence interval [95% CI] 2.08-4.25) and 1.51 per 100 person-years (95% CI 1.18-1.84), respectively. Compared with the general population, the age- and sex-adjusted hazard ratio (HR) for RA was 1.94 (95% CI 1.24-3.05, P = 0.004). Neither exclusion of patients with prior CVD at baseline nor adjustment for cardiovascular risk factors significantly influenced this. Compared with the nondiabetic population, nondiabetic patients with RA and those with type 2 DM had comparable HRs, 2.16 (95% CI 1.28-3.63, P = 0.004) and 2.04 (95% CI 1.12-3.67, P = 0.019), respectively.The risk of CVD in RA was significantly elevated compared with the general population, and comparable with the magnitude of risk in type 2 DM.

Inflammatory mediators and premature coronary atherosclerosis in rheumatoid arthritis

Rheumatoid arthritis (RA) is an inflammatory disease associated with premature atherosclerosis. We hypothesized that mediators of inflammation associated with atherosclerosis in other populations (interleukin-6 [IL-6], tumor necrosis factor [alpha] [TNF[alpha]], serum amyloid A [SAA], vascular endothelial growth factor, neutrophil count, IL-1[alpha], E-selectin, intercellular adhesion molecule 1 [ICAM-1], myeloperoxidase [MPO], matrix metalloproteinase 9, and vascular cell adhesion molecule 1) would be increased and associated with the severity of coronary atherosclerosis in patients with RA.Clinical variables, concentrations of inflammatory mediators, and coronary artery calcification were measured in 169 patients with RA and 92 control subjects. Differences in concentrations of inflammatory mediators were compared using median quantile regression. The relationship of inflammatory mediators with the severity of coronary calcification in RA and control subjects was examined using proportional odds logistic regression, allowing for interaction with disease status. Models were adjusted for traditional cardiovascular risk factors.Median serum concentrations of IL-6, SAA, ICAM-1, E-selectin, TNF[alpha], and MPO and peripheral blood neutrophil count were higher in patients with RA than controls (all P < 0.05), independent of Framingham risk score and diabetes mellitus (DM). IL-6 (main effect odds ratio [OR] 1.72; 95% confidence interval [95% CI] 1.12, 2.66) and TNF[alpha] (main effect OR 1.49; 95% CI 1.16, 1.90) concentrations were significantly associated with higher amounts of coronary calcium, independent of Framingham risk score and DM, and such main effects significantly differed from controls (P = 0.001 and 0.03 for interaction, respectively).TNF[alpha] and IL-6 are significantly associated with the severity of subclinical atherosclerosis, independent of Framingham risk score, in RA.

Predictors of depression in a multiethnic cohort of patients with rheumatoid arthritis

Patients with rheumatoid arthritis (RA) who experience depression have worse health outcomes. This study identifies predictors of depression in an ethnically and racially diverse population of patients with RA.Patients with RA in a prospective cohort at the San Francisco General Hospital outpatient rheumatology clinic were included if they were age [ge]18 years, met the American College of Rheumatology classification criteria for RA, had a Health Assessment Questionnaire (HAQ) score collected, and had the RA-specific Disease Activity Score performed by a rheumatologist. The outcome variable was a depression score measured by the Patient Health Questionnaire 9 (PHQ-9), a self-report questionnaire validated to correlate with a diagnosis of major depression.Three hundred forty-nine clinical visits for 172 patients were included in the analysis. Forty percent of patients scored [ge]10 on the PHQ-9 during at least one clinic visit, which corresponds to a symptom severity of at least moderate depression. The mean PHQ-9 score was 7, corresponding to a symptom severity of mild depression. In the multivariate analysis, higher HAQ scores were associated with depression, and Asians had lower depression scores compared with Hispanic, white, and African American subjects.Identifying associated predictors of depression in a diverse population of patients with RA can help guide treatment, which should include preventing disability and decreased function as well as targeting depressive symptoms more specifically in patients with RA.

Effect of certolizumab pegol with methotrexate on home and work place productivity and social activities in patients with active rheumatoid arthritis

To assess the impact of certolizumab pegol (CZP), a novel PEGylated anti-tumor necrosis factor, in combination with methotrexate (MTX) on productivity outside and within the home, and on participation in family, social, and leisure activities in adult patients with rheumatoid arthritis (RA).The efficacy and safety of CZP (200 mg and 400 mg) plus MTX were assessed in 2 phase III, multicenter, double-blind, placebo-controlled trials (Rheumatoid Arthritis Prevention of Structural Damage [RAPID] 1 and RAPID 2). The novel, validated, RA-specific Work Productivity Survey (WPS-RA) was used to assess work place and home productivity. WPS-RA responses were collected at baseline and every 4 weeks until withdrawal/study completion.At baseline, 41.6% and 39.8% of subjects were employed outside the home in RAPID 1 and RAPID 2, respectively. Compared with placebo plus MTX, CZP plus MTX significantly reduced work absenteeism and presenteeism among patients working outside the home. Significant reductions in number of household days lost, household days with productivity reduced by [ge]50%, and days lost due to RA for participation in family, social, and leisure activities were reported by patients in active treatment relative to placebo plus MTX. Improvements in all measures were observed with CZP plus MTX as early as week 4, and maintained until the study end (12 months in RAPID 1, 6 months in RAPID 2). Findings were consistent with clinical improvements with CZP plus MTX in both trials.CZP plus MTX improved productivity outside and within the home and resulted in more participation in social activities compared with placebo plus MTX. These observations suggest that considerable indirect cost gains might be achieved with this therapeutic agent in RA.

Impaired sexual function in women with systemic sclerosis: A cross-sectional study

To compare sexual functioning and distress in women with systemic sclerosis (SSc) with that in healthy controls and determine the association between disease characteristics and sexual function.We conducted a cross-sectional study of 69 women with SSc (ages 18-60 years) and 58 healthy, age-matched controls. Assessment included the Female Sexual Function Index (FSFI), Female Sexual Distress Scale (FSDS), Hospital Anxiety and Depression Scale, Short Form 36 health survey, sociodemographic characteristics, and in patients only, the Health Assessment Questionnaire.Of 69 eligible patients with SSc, 37 (54%) responded, in addition to 37 (64%) of 58 controls. The FSFI total score and the subscale scores for lubrication, orgasm, arousal, and pain were significantly lower and the FSDS scores were significantly higher in patients with SSc. Longer disease duration and higher levels of marital dissatisfaction were significantly associated with low sexual function in patients with SSc. Longer disease duration, more depressive symptoms, and the use of antidepressants were significantly associated with sexual distress. Multivariate analyses indicated that marital distress was the only variable significantly associated with low sexual function in patients with SSc ([beta] = 0.40, P < 0.05), whereas depression was the only variable significantly associated with sexual distress ([beta] = 0.32, P < 0.05). The same pattern of associations was found in the healthy control group.Women with SSc reported significantly impaired sexual functioning and more sexual distress then healthy controls. Impaired sexual functioning and sexual distress were associated with marital distress and depressive symptoms. These results indicate that in daily practice, inquiring about sexuality and screening for depressive symptoms is indicated in every patient with SSc, irrespective of their clinical characteristics.

Thrombotic microangiopathy and purtscher-like retinopathy associated with adult-onset still's disease: A role for glomerular vascular endothelial growth factor?

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Protective effect of hydroxychloroquine on renal damage may be biased: Comment on the article by Pons-Estel et al

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Have some beneficial effects of hydroxychloroquine been overestimated? Potential biases in observational studies of drug effects: Comment on the article by Pons-Estel et al

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Reply

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The cost-utility analysis of the BeSt trial: Is a camel in fact a horse with abnormalities in the distribution of dorsal fat? Comment on the article by van den Hout et al

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Reply

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Submissions invited for themed issue of Arthritis Care & Research: Quality of care in the rheumatic diseases

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ARHP announcements

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In this issue

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Interpreting registry-derived drug studies: Does societal context matter?

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Human osteoclastogenic T cells and human osteoclastology

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The price of silence

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Endothelial progenitor cells: Novel players in the pathogenesis of rheumatic diseases

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Cancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor [alpha] therapies: Does the risk change with the time since start of treatment?

To determine the short-term and medium-term risks of cancer in patients receiving anti-tumor necrosis factor [alpha] (anti-TNF[alpha]) therapies that have proven effective in the treatment of chronic inflammatory conditions.By linking together data from the Swedish Biologics Register, Swedish registers of RA, and the Swedish Cancer Register, we identified and analyzed for cancer occurrence a national cohort of 6,366 patients with RA who first started anti-TNF therapy between January 1999 and July 2006. As comparators, we used a national biologics-naive RA cohort (n = 61,160), a cohort of RA patients newly starting methotrexate (n = 5,989), a cohort of RA patients newly starting disease-modifying antirheumatic drug combination therapy (n = 1,838), and the general population of Sweden. Relative risks (RRs) were estimated using Cox regression analyses, examining overall RR as well as RR by time since the first start of anti-TNF therapy, by the duration of active anti-TNF therapy, and by the anti-TNF agent received.During 25,693 person-years of followup in 6,366 patients newly starting anti-TNF, 240 first cancers occurred, yielding an RR of 1.00 (95% confidence interval 0.86-1.15) versus the biologics-naive RA cohort, and similar RRs versus the other 2 RA comparators. RRs did not increase with increasing time since the start of anti-TNF therapy, nor with the cumulative duration of active anti-TNF therapy. During the first year following the first treatment start, but not thereafter, dissimilar cancer risks for adalimumab, etanercept, and infliximab were observed.During the first 6 years after the start of anti-TNF therapy in routine care, no overall elevation of cancer risk and no increase with followup time were observed.

Brain involvement in rheumatoid arthritis: A magnetic resonance spectroscopy study

Tumor necrosis factor [alpha] was recently implicated as an important mediator of communication between the peripheral and cerebral immune systems in an animal model of chronic inflammation. The purpose of this study was to examine by proton magnetic resonance spectroscopy (1H-MRS) the influence of inflammation on cerebral metabolism in patients with rheumatoid arthritis (RA).Single-voxel 1H-MRS of the centrum semiovale was performed on 35 RA patients (6 men and 29 women; mean ± SD age 51.8 ± 14.6 years) and 28 healthy age- and sex-matched control subjects (9 men and 19 women; mean ± SD age 50.2 ± 10.4 years). None of the study subjects had any neurologic signs or symptoms. Clinical markers of disease activity were correlated with the 1H-MRS findings.Patients with active RA, as reflected by an elevated erythrocyte sedimentation rate (ESR), had a significantly higher ratio of choline to creatine and a significantly lower ratio of N-acetylaspartate to choline than did patients with inactive RA, as reflected by a normal ESR. Moreover, the ratios of choline to creatine and NAA to choline were significantly correlated with the ESR after correction for age, sex, smoking status, handedness, alcohol consumption, medication use, and disease duration. Medication use had no additional effect on these associations.Our data show that systemic inflammation in RA is associated with metabolic changes in the brain.

Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: Results of a national prospective study

To determine the outcome of pregnancy in women with rheumatoid arthritis (RA) in relation to disease activity and medication use during the pregnancy.In a prospective study, pregnant women with RA were evaluated before conception (when possible), during each trimester of the pregnancy, and postpartum. Clinical characteristics, disease activity, medication use, and pregnancy outcome were analyzed. To examine the independent influence of prednisone use and disease activity on birth weight, regression analyses were performed, with adjustments for gestational age of the child at delivery, the sex of the newborn, and the mother's smoking status, education level, parity, and use of an assisted reproduction technique. Kaplan-Meier curve analyses were performed to examine the association between medication use and gestational age at delivery.Data from 152 Caucasian RA patients with singleton pregnancies were available. Both the mean ± SD birth weight (3,379 ± 564 gm) and the mean ± SD birth weight standard deviation score (SDS; +0.1 ± 1.1), which is the birth weight adjusted for the gestational age and sex of the newborn, were comparable with those in the general population. On multiple linear regression analyses of birth weight and birth weight SDS, both of which were adjusted for covariates, only disease activity was associated with lower birth weight (P = 0.025). The gestational age at delivery was significantly lower in women who were taking prednisone (38.8 versus 39.9 weeks; P = 0.001), and their delivery was more often premature (<37 weeks; P = 0.004).Pregnancy outcome in women with well-controlled RA is comparable with that in the general population. The effect of prednisone on birth weight is mediated by a lower gestational age at delivery, whereas a higher level of disease activity independently influences birth weight negatively, suggesting an immune-mediated mechanism.

Epitope-specific immunotherapy of rheumatoid arthritis: Clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double-blind, placebo-controlled, pilot phase II trial

Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis (RA). Accordingly, we are developing a tolerization approach to dnaJP1, a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA. We undertook this study to test 2 hypotheses: 1) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype, and 2) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement.One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial. They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months.The dnaJP1 peptide was safe and well-tolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor [alpha] and a corresponding trend toward an increased percentage of T cells producing interleukin-10. Coexpression of a cluster of molecules (programmed death 1 and its ligands) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders. Analysis of the primary efficacy end point (meeting the American College of Rheumatology 20% improvement criteria at least once on day 112, 140, or 168) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations. Differences in clinical responses were also found between treatment groups on day 140 and at followup. Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine (HCQ) was superior to the combination of HCQ and placebo.Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy. Susceptibility to treatment relies on the coexpression of molecules that can down-regulate adaptive immunity.

The relationship between synovial lymphocyte aggregates and the clinical response to infliximab in rheumatoid arthritis: A prospective study

Some patients with rheumatoid arthritis (RA) exhibit lymphocyte aggregates in the synovium. This study was undertaken to address whether the presence of lymphocyte aggregates before treatment could serve as a biomarker for the clinical response to tumor necrosis factor (TNF) blockade, and to confirm whether the aggregation of synovial lymphocytes is reversible after anti-TNF treatment.Synovial tissue biopsy samples were obtained from 97 patients with active RA before the initiation of infliximab treatment. Lymphocyte aggregates in the synovial tissue were counted and also graded for size. Logistic regression analysis was performed to identify whether the presence of lymphocyte aggregates could be a predictor of the clinical response at week 16. Furthermore, the effects of TNF blockade on lymphocyte aggregates were compared between patients with RA and patients with psoriatic arthritis (PsA).Fifty-seven percent of RA synovial tissue samples contained lymphocyte aggregates, and 32% of the patients had large aggregates. Aggregates were found in 67% of clinical responders compared with 38% of nonresponders. The presence of aggregates at baseline was a highly significant predictor of the clinical response to anti-TNF treatment (R2 = 0.10, P = 0.008). Positivity for lymphocyte aggregates increased the power to predict the clinical response (R2 = 0.29), when analyzed in a prediction model that included baseline disease activity evaluated by the Disease Activity Score in 28 joints, anti-cyclic citrullinated peptide antibody positivity, and synovial TNF[alpha] expression. There was a reduction in lymphocyte aggregates after anti-TNF antibody therapy in both RA and PsA.RA patients with synovial lymphocyte aggregates have, on average, a better response to infliximab treatment than those with only diffuse leukocyte infiltration. Moreover, the aggregation of synovial lymphocytes is reversible after anti-TNF antibody treatment.

Progressive multifocal leukoencephalopathy following rituximab treatment in a patient with rheumatoid arthritis

Progressive multifocal leukoencephalopathy (PML) is a rare brain disease caused by reactivation of the JC virus. Herein, a case of PML in association with rituximab treatment in a patient with chronic rheumatoid arthritis (RA) and Sjögren's syndrome is described. The patient received 4 courses of rituximab (2 1,000-mg infusions administered 2 weeks apart) over a period of [sim]40 months, during a phase III trial and safety extension study. PML was diagnosed [sim]18 months after the last rituximab course, and the patient died 1 month later. Determination of the cause of PML was confounded by the fact that the patient had developed oropharyngeal cancer, which was treated with chemoradiotherapy, 9 months prior to the development of PML. Although there was no direct evidence that linked rituximab to the development of PML, this case highlights the need to consider a diagnosis of PML in patients with RA who have been treated with rituximab and who subsequently develop new neurologic symptoms.

Gadd45[beta] deficiency in rheumatoid arthritis: Enhanced synovitis through JNK signaling

JNK-mediated cell signaling plays a critical role in matrix metalloproteinase (MMP) expression and joint destruction in rheumatoid arthritis (RA). Gadd45[beta], which is an NF-[kappa]B-regulated gene, was recently identified as an endogenous negative regulator of the JNK pathway, since it could block the upstream kinase MKK-7. This study was carried out to evaluate whether low Gadd45[beta] expression in RA enhances JNK activation and overproduction of MMPs in RA, and whether Gadd45[beta] deficiency increases arthritis severity in passive K/BxN murine arthritis.Activation of the NF-[kappa]B and JNK pathways and Gadd45[beta] expression were analyzed in human synovium and fibroblast-like synoviocytes (FLS) using quantitative polymerase chain reaction, immunoblotting, immunohistochemistry, electrophoretic mobility shift assay, and luciferase reporter constructs. Gadd45[beta]-/- and wild-type mice were evaluated in the K/BxN serum transfer model of inflammatory arthritis, and clinical signs of arthritis, osteoclast formation, and bone erosion were assessed.Expression levels of the Gadd45[beta] gene and protein were unexpectedly low in human RA synovium despite abundant NF-[kappa]B activity. Forced Gadd45[beta] expression in human FLS attenuated tumor necrosis factor-induced signaling through the JNK pathway, reduced the activation of activator protein 1, and decreased the expression of MMP genes. Furthermore, Gadd45[beta] deficiency exacerbated K/BxN serum-induced arthritis in mice, dramatically increased signaling through the JNK pathway, elevated MMP3 and MMP13 gene expression in the mouse joints, and increased the synovial inflammation and number of osteoclasts.Deficient Gadd45[beta] expression in RA can contribute to activation of JNK, exacerbate clinical arthritis, and augment joint destruction. This process can be mitigated by enhancing Gadd45[beta] expression or by inhibiting the activity of JNK or its upstream regulator, MKK-7.

Differential mechanism of NF-[kappa]B inhibition by two glucocorticoid receptor modulators in rheumatoid arthritis synovial fibroblasts

To investigate and compare the molecular mechanisms by which 2 glucocorticoid receptor (GR)-activating compounds, dexamethasone (DEX) and Compound A (CpdA), interfere with the NF-[kappa]B activation pathway in rheumatoid arthritis (RA) synovial cells.Quantitative polymerase chain reaction was performed to detect the tumor necrosis factor [alpha] (TNF[alpha])-induced cytokine gene expression of interleukin-1[beta] (IL-1[beta]) and to investigate the effects of DEX and CpdA in RA fibroblast-like synoviocytes (FLS) transfected with small interfering RNA (siRNA) against GR (siGR) compared with nontransfected cells. Immunofluorescence analysis was used to detect the subcellular distribution of NF-[kappa]B (p65) under the various treatment conditions, and active DNA-bound p65 was measured using a TransAM assay and by chromatin immunoprecipitation analysis of IL-1[beta]. Signaling pathways were studied via Western blotting of siGR-transfected cells, compared with nontransfected and nontargeting siRNA-transfected control cells, to detect the regulation of phospho-IKK, I[kappa]B[alpha], phospho-p38, phospho-ERK, and phospho-JNK.Both DEX and CpdA efficiently inhibited IL-1[beta] gene expression in a GR-dependent manner. In addition, CpdA attenuated the TNF[alpha]-induced nuclear translocation and DNA binding of p65 in RA FLS, via the attenuation of IKK phosphorylation and subsequent I[kappa]B[alpha] degradation. CpdA also displayed profound effects on TNF[alpha]-induced MAPK activation. The effects of CpdA on TNF[alpha]-induced kinase activities occurred independently of the presence of GR. In sharp contrast, DEX did not affect TNF[alpha]-induced IKK phosphorylation, I[kappa]B[alpha] degradation, p65 nuclear translocation, or MAPK activation in RA FLS.DEX and CpdA display a dissimilar molecular mechanism of interaction with the NF-[kappa]B activation pathway ex vivo. A dual pathway, partially dependent and partially independent of GR (nongenomic), may explain the gene-inhibitory effects of CpdA in RA FLS.

American College of Rheumatology Office Has Moved

No abstract.

Clinical and histologic evidence of salivary gland restoration supports the efficacy of rituximab treatment in Sjögren's syndrome

To assess the effect of rituximab (anti-CD20 antibody) therapy on the (immuno)histopathology of parotid tissue in patients with primary Sjögren's syndrome (SS) and the correlation of histologic findings with the flow rate and composition of parotid saliva.In a phase II study, an incisional parotid biopsy specimen was obtained from 5 patients with primary SS before and 12 weeks after rituximab treatment (4 infusions of 375 mg/m2). The relative amount of parotid parenchyma, lymphocytic infiltrate, and fat, and the presence/quantity of germinal centers and lymphoepithelial duct lesions were evaluated. Immunohistochemical characterization was performed to analyze the B:T cell ratio of the lymphocytic infiltrate (CD20, CD79a, CD3) and cellular proliferation in the acinar parenchyma (by double immunohistologic labeling for cytokeratin 14 and Ki-67). Histologic data were assessed for correlations with the parotid flow rate and saliva composition.Four patients showed an increased salivary flow rate and normalization of the initially increased salivary sodium concentration. Following rituximab treatment, the lymphocytic infiltrate was reduced, with a decreased B:T cell ratio and (partial) disappearance of germinal centers. The amount and extent of lymphoepithelial lesions decreased in 3 patients and was completely absent in 2 patients. The initially increased proliferation of acinar parenchyma in response to inflammation was reduced in all patients.Sequential parotid biopsy specimens obtained from patients with primary SS before and after rituximab treatment demonstrated histopathologic evidence of reduced glandular inflammation and redifferentiation of lymphoepithelial duct lesions to regular striated ducts as a putative morphologic correlate of increased parotid flow and normalization of the salivary sodium content. These histopathologic findings in a few patients underline the efficacy of B cell depletion and indicate the potential for glandular restoration in SS.

Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis

Osteocytes are considered to be sensors of bone damage and regulators of bone mass by specifically expressing sclerostin, an inhibitor of bone formation. The contribution of osteocytes in regulating local bone remodeling in arthritis is unknown. The aim of this study was to investigate the role of osteocytes as contributors to bone remodeling in ankylosing spondylitis (AS).Sclerostin expression and osteocyte death were assessed by immunohistochemistry in joints derived from patients with AS, patients with rheumatoid arthritis (RA), and patients with osteoarthritis (OA), as well as from control subjects. In addition, the serum level of sclerostin was assessed by enzyme-linked immunosorbent assay in healthy subjects and patients with AS; this assessment included the longitudinal correlation of sclerostin serum levels and radiographic progression in the spine of patients with AS.Sclerostin expression was confined exclusively to osteocytes. Whereas the majority of osteocytes in healthy individuals and patients with RA were sclerostin positive, expression was significantly reduced in patients with OA and was virtually absent in patients with AS. Moreover, serum levels of sclerostin were significantly lower in patients with AS than in healthy individuals. Importantly, low serum sclerostin levels in patients with AS were significantly associated with the formation of new syndesmophytes (P = 0.007).Sclerostin expression is impaired in patients with AS, suggesting a specific alteration of osteocyte function in this disease. A low serum level of sclerostin in the setting of AS is linked to increased structural damage, emphasizing the role of sclerostin in the suppression of bone formation.

Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population

The results of a recent genome-wide association study have shown that ERAP1 and IL23R are associated with ankylosing spondylitis (AS) in Caucasian populations from North America and the UK. Based on these findings, we undertook the current study to investigate whether single-nucleotide polymorphisms (SNPs) covering the genes ERAP1 and IL23R are associated with AS in a Han Chinese population.A case-control study was performed in Han Chinese patients with AS (n = 527) and controls (n = 945) from Shanghai and Nanjing. All patients met the modified New York criteria for AS. The Sequenom iPlex platform was used to genotype cases and controls for 21 tag SNPs covering IL23R and 38 tag SNPs covering ERAP1. Statistical analysis was performed using the Cochran-Armitage test for trend.Multiple SNPs in ERAP1 were significantly associated with AS (for rs27980, P = 0.0048; for rs7711564, P = 0.0081). However, no association was observed between IL23R and AS (for all SNPs, P > 0.1). The nonsynonymous SNP in IL23R, rs11209026, widely thought to be the primary AS-associated SNP in IL23R in Europeans, was found not to be polymorphic in Chinese.Our results demonstrate that genetic polymorphisms in ERAP1 are associated with AS in Han Chinese, suggesting a common pathogenic mechanism for the disease in Chinese and Caucasian populations, and that IL23R is not associated with AS in Chinese, indicating a difference in the mechanism of disease pathogenesis between Chinese and Caucasian populations. This may result from the fact that rs11209026, the nonsynonymous SNP in IL23R, is not polymorphic in Chinese patients, providing further evidence that rs11209026 is the key polymorphism associated with AS (and likely inflammatory bowel disease and psoriasis) in this gene.

Identification of RGS1 as a candidate biomarker for undifferentiated spondylarthritis by genome-wide expression profiling and real-time polymerase chain reaction

To compare gene expression profiles between ankylosing spondylitis (AS) and undifferentiated spondylarthritis (uSpA) patients with inflammatory low back pain.Peripheral blood mononuclear cells (PBMCs) from patients with AS, patients with uSpA, and healthy subjects were screened using genome-wide microarrays, followed by validation by real-time polymerase chain reaction (PCR).Microarray profiling and real-time PCR assays showed only minor differences between AS patients and healthy subjects. In contrast, 20 genes were strikingly more highly expressed in uSpA patients. Regulator of G protein signaling 1 (RGS1) was identified as the most useful biomarker for distinguishing uSpA patients, and to a lesser extent AS patients, from control subjects (P = 2.3 × 10-7 and 6.7 × 10-3, respectively). These findings were verified in an independent cohort that also included patients with rheumatoid arthritis and patients with mechanical low back pain. The receiver operating characteristic area under the curve values in the first and second cohorts of uSpA patients were 0.99 and 0.93, respectively (P = 1 × 10-4). To evaluate the possible derivation of RGS1, we cultured a monocyte-derived cell line with a panel of cytokines and chemokines. RGS1 was significantly induced either by tumor necrosis factor [alpha] (TNF[alpha]) or by interleukin-17 (IL-17).Our findings indicate that uSpA PBMCs carry strikingly more highly expressed genes compared with PBMCs from AS patients or healthy subjects, and that TNF[alpha]- and IL-17-inducible RGS1 is a potential biomarker for uSpA, and to a lesser extent for AS, with inflammatory low back pain.

Impaired myofibrillar function in the soleus muscle of mice with collagen-induced arthritis

Progressive muscle weakness is a common feature in patients with rheumatoid arthritis (RA). However, little is known about whether the intrinsic contractile properties of muscle fibers are affected in RA. This study was undertaken to investigate muscle contractility and the myoplasmic free Ca2+ concentration ([Ca2+]i) in the soleus, a major postural muscle, in mice with collagen-induced arthritis (CIA).Muscle contractility and [Ca2+]i were assessed in whole muscle and intact single-fiber preparations, respectively. The underlying mechanisms of contractile dysfunction were assessed by investigating redox modifications using Western blotting and antibodies against nitric oxide synthase (NOS), superoxide dismutase (SOD), 3-nitrotyrosine (3-NT), carbonyl, malondialdehyde (MDA), and S-nitrosocysteine (SNO-Cys).The tetanic force per cross-sectional area was markedly decreased in the soleus muscle of mice with CIA, and the change was not due to a decrease in the amplitude of [Ca2+]i transients. The reduction in force production was accompanied by slowing of the twitch contraction and relaxation and a decrease in the maximum shortening velocity. Immunoblot analyses showed a marked increase in neuronal NOS expression but not in inducible or endothelial NOS expression, which, together with the observed decrease in SOD2 expression, favors peroxynitrite formation. These changes were accompanied by increased 3-NT, carbonyl, and MDA adducts content in myofibrillar proteins from the muscles of mice with CIA. Moreover, there was a significant increase in SNO-Cys content in myosin heavy-chain and troponin I myofibrillar proteins from the soleus muscle of mice with CIA.These findings show impaired contractile function in the soleus muscle of mice with CIA and suggest that this abnormality is due to peroxynitrite-induced modifications in myofibrillar proteins.

Amelioration of experimental arthritis by a telomerase-dependent conditionally replicating adenovirus that targets synovial fibroblasts

Synovial fibroblasts (SFs) play a pivotal role in the pathogenesis of rheumatoid arthritis (RA). It has been documented that the phenotype of rheumatoid synovium is similar, in many respects, to that of an aggressive tumor. In this study, a novel, genetically engineered adenovirus was designed to lyse SFs that exhibit high telomerase activity and p53 mutations, and its effects as a novel therapeutic strategy were assessed in an experimental arthritis model.An E1B-55-kd-deleted adenovirus driven by the human telomerase reverse transcriptase promoter was constructed (designated Ad.GS1). Cytolysis of SFs and productive replication of Ad.GS1 in the SFs of rats with collagen-induced arthritis (CIA), as well as the SFs of patients with RA (RASFs), were assessed in vitro and in vivo. Treatment responses, as well as the presence of disease-related cytokines and enzymes in the ankle joints, were determined in the murine model.Ad.GS1 replicated in and induced cytolysis of human RASFs and SFs from arthritic rats, but spared normal fibroblasts. Bioluminescence imaging in vivo also demonstrated replication of Ad.GS1 in arthritic rat joints, but not in normal rat joints. Intraarticular administration of Ad.GS1 significantly reduced the ankle circumference, articular index scores, radiographic scores, and histologic scores and decreased the production of interleukin-1[beta], matrix metalloproteinase 9, and prolyl 4-hydroxylase in rats with CIA compared with their control counterparts.This study is the first to demonstrate the amelioration of arthritic symptoms by a novel, telomerase-dependent adenovirus in the rat CIA model, an experimental model that resembles human RA. In addition, the results suggest that because of its ability to induce cytolysis of SFs, this virus may be further explored as a therapeutic agent in patients with RA.

DNA demethylation at specific CpG sites in the IL1B promoter in response to inflammatory cytokines in human articular chondrocytes

To determine whether changes in the DNA methylation status in the promoter region of the gene encoding interleukin-1[beta] (IL-1[beta]) account for expression of IL1B messenger RNA (mRNA) after long-term treatment of human articular chondrocytes with inflammatory cytokines.IL-1[beta], tumor necrosis factor [alpha] (TNF[alpha]) plus oncostatin M (OSM), or 5-azadeoxycytidine (5-aza-dC) was added twice weekly for 4-5 weeks to primary cultures of normal human articular chondrocytes derived from the femoral head cartilage of patients with a fracture of the femoral neck. Expression of MMP13, IL1B, TNFA, and DNMT1 was determined by SYBR Green-based quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis of genomic DNA and total RNA extracted from the same sample before and after culture. Bisulfite modification was used to identify which CpG sites in the IL1B promoter showed differential methylation between IL1B-expressing and IL1B-nonexpressing cells. The percentages of cells that were methylated at that critical CpG site (-299 bp) were quantified by a method that depended on methylation-sensitive restriction enzymes and real-time RT-PCR. Secretion of IL-1[beta] into the culture media was assessed by enzyme-linked immunosorbent assay.Healthy chondrocytes did not express IL1B mRNA, but the levels were increased 5-fold by treatment with 5-aza-dC and were increased 100-1,000-fold by treatment with TNF[alpha]/OSM. The percentage CpG methylation was decreased by 5-aza-dC treatment but was reduced considerably more by IL-1[beta] and was almost abolished by TNF[alpha]/OSM. The mRNA was translated into protein in cytokine-treated chondrocytes.These novel findings indicate that inflammatory cytokines can change the DNA methylation status at key CpG sites, resulting in long-term induction of IL1B in human articular chondrocytes.

Screening of chondrogenic factors with a real-time fluorescence-monitoring cell line ATDC5-C2ER: Identification of sorting nexin 19 as a novel factor

To establish a cell culture system for noninvasive and real-time monitoring of chondrogenic differentiation in order to screen for chondrogenic factors.The optimum reporter construct transfected into chondrogenic ATDC5 cells was selected by a luciferase reporter assay and fluorescence analysis during cultures with insulin. The established cell line was validated according to its fluorescence following stimulation with SOX proteins, bone morphogenetic protein 2 (BMP-2), or transforming growth factor [beta] (TGF[beta]) and was compared with the level of messenger RNA for COL2A1 as well as with the degree of Alcian blue staining. Screening of chondrogenic factors was performed by expression cloning using a retroviral expression library prepared from human tracheal cartilage. The expression pattern of the identified molecule was examined by in situ hybridization and immunohistochemistry. Functional analysis was performed by transfection of the identified gene, the small interfering RNA, and the mutated gene.We established an ATDC5 cell line with 4 repeats of a highly conserved enhancer ligated to a COL2A1 basal promoter and the DsRed2 reporter (ATDC5-C2ER). Fluorescence was induced under the stimulations with SOX proteins, BMP-2, or TGF[beta], showing good correspondence to the chondrogenic markers. Screening using the ATDC5-C2ER system identified several chondrogenic factors, including sorting nexin 19 (SNX19). SNX19 was expressed in the limb cartilage of mouse embryos and in the degraded cartilage of adult mouse knee joints during osteoarthritis progression. The gain-of-function and loss-of-function analyses revealed a potent chondrogenic activity of SNX19.We established the ATDC5-C2ER system for efficient monitoring of chondrogenic differentiation by fluorescence analysis, and we identified a novel chondrogenic factor (SNX19) using this system. This system will be useful for elucidating the molecular network of chondrogenic differentiation.

A novel T cell cytokine, secreted osteoclastogenic factor of activated T cells, induces osteoclast formation in a RANKL-Independent manner

Chronic T cell activation is central to the etiology of rheumatoid arthritis (RA), an inflammatory autoimmune disease that leads to severe focal bone erosions and generalized systemic osteoporosis. Previous studies have shown novel cytokine-like activities in medium containing activated T cells, characterized by potent induction of the osteoblastic production of interleukin-6 (IL-6), an inflammatory cytokine and stimulator of osteoclastogenesis, as well as induction of an activity that directly stimulates osteoclast formation in a manner independent of the key osteoclastogenic cytokine RANKL. This study was undertaken to identify the factors secreted by T cells that are responsible for these activities.Human T cells were activated using anti-human CD3 and anti-human CD28 antibodies for 72 hours in AIM V serum-free medium to obtain T cell-conditioned medium, followed by concentration and fractionation of the medium by fast-protein liquid chromatography. Biologically active fractions were resolved using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Major bands were analyzed by mass spectrometry, and a major candidate protein was identified. This novel cytokine was cloned, and its expression was analyzed using recombinant DNA technologies.A single novel cytokine that could induce both osteoblastic IL-6 production and functional osteoclast formation in the absence of osteoblasts or RANKL and that was insensitive to the effects of the RANKL inhibitor osteoprotegerin was identified in the activated T cell-conditioned medium; this cytokine was designated secreted osteoclastogenic factor of activated T cells (SOFAT). Further analysis of SOFAT revealed that it was derived from an unusual messenger RNA splice variant coded by the threonine synthase-like 2 gene homolog, which is a conserved gene remnant coding for threonine synthase, an enzyme that functions only in microorganisms and plants.SOFAT may act to exacerbate inflammation and/or bone turnover under inflammatory conditions such as RA or periodontitis and in conditions of estrogen deficiency.

Tumor necrosis factor [alpha] and interleukin-1[beta] modulate calcium and nitric oxide signaling in mechanically stimulated osteocytes

Inflammatory diseases often coincide with reduced bone mass. Mechanoresponsive osteocytes regulate bone mass by maintaining the balance between bone formation and resorption. Despite its biologic significance, the effect of inflammation on osteocyte mechanoresponsiveness is not understood. To fill this gap, we investigated whether the inflammatory cytokines tumor necrosis factor [alpha] (TNF[alpha]) and interleukin-1[beta] (IL-1[beta]) modulate the osteocyte response to mechanical loading.MLO-Y4 osteocytes were incubated with TNF[alpha] (0.5-30 ng/ml) or IL-1[beta] (0.1-10 ng/ml) for 30 minutes or 24 hours, or with calcium inhibitors for 30 minutes. Cells were subjected to mechanical loading by pulsatile fluid flow (mean ± amplitude 0.7 ± 0.3 Pa, 5 Hz), and the response was quantified by measuring nitric oxide (NO) production using Griess reagent and by measuring intracellular calcium concentration ([Ca2+]i) using Fluo-4/AM. Focal adhesions and filamentous actin (F-actin) were visualized by immunostaining, and apoptosis was quantified by measuring caspase 3/7 activity. Cell-generated tractions were quantified using traction force microscopy, and cytoskeletal stiffness was quantified using optical magnetic twisting cytometry.Pulsatile fluid flow increased [Ca2+]i within seconds (in 13% of cells) and NO production within 5 minutes (4.7-fold). TNF[alpha] and IL-1[beta] inhibited these responses. Calcium inhibitors decreased pulsatile fluid flow-induced NO production. TNF[alpha] and IL-1[beta] affected cytoskeletal stiffness, likely because 24 hours of incubation with TNF[alpha] and IL-1[beta] decreased the amount of F-actin. Incubation with IL-1[beta] for 24 hours stimulated osteocyte apoptosis.Our results suggest that TNF[alpha] and IL-1[beta] inhibit mechanical loading-induced NO production by osteocytes via abrogation of pulsatile fluid flow-stimulated [Ca2+]i, and that IL-1[beta] stimulates osteocyte apoptosis. Since both NO and osteocyte apoptosis affect osteoclasts, these findings provide a mechanism by which inflammatory cytokines might contribute to bone loss and consequently affect bone mass in rheumatoid arthritis.

Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: Thirty-six-month results of a randomized, double-blind, controlled trial

To compare the bone anabolic drug teriparatide (20 [mu]g/day) with the antiresorptive drug alendronate (10 mg/day) for treating glucocorticoid-induced osteoporosis (OP).This was a 36-month, randomized, double-blind, controlled trial in 428 subjects with OP (ages 22-89 years) who had received [ge]5 mg/day of prednisone equivalent for [ge]3 months preceding screening. Measures included changes in lumbar spine and hip bone mineral density (BMD), changes in bone biomarkers, fracture incidence, and safety.Increases in BMD from baseline were significantly greater in the teriparatide group than in the alendronate group, and at 36 months were 11.0% versus 5.3% for lumbar spine, 5.2% versus 2.7% for total hip, and 6.3% versus 3.4% for femoral neck (P < 0.001 for all). In the teriparatide group, median percent increases from baseline in N-terminal type I procollagen propeptide (PINP) and osteocalcin (OC) levels were significant from 1 to 36 months (P < 0.01), and increases in levels of C-terminal telopeptide of type I collagen (CTX) were significant from 1 to 6 months (P < 0.01). In the alendronate group, median percent decreases in PINP, OC, and CTX were significant by 6 months and remained below baseline through 36 months (P < 0.001). Fewer subjects had vertebral fractures in the teriparatide group than in the alendronate group (3 [1.7%] of 173 versus 13 [7.7%] of 169; P = 0.007), with most occurring during the first 18 months. There was no significant difference between groups in the incidence of nonvertebral fractures (16 [7.5%] of 214 subjects taking teriparatide versus 15 [7.0%] of 214 subjects taking alendronate; P = 0.843). More subjects in the teriparatide group (21%) versus the alendronate group (7%) had elevated predose serum calcium concentrations (P < 0.001).Our findings indicate that subjects with glucocorticoid-induced OP treated with teriparatide for 36 months had greater increases in BMD and fewer new vertebral fractures than subjects treated with alendronate.

Circulating mesenchymal stem cells with abnormal osteogenic differentiation in patients with osteoporosis

While the role of osteoclasts in bone loss has been well investigated, the involvement of osteoblast-lineage cells has not been completely elucidated. Several genes contribute to normal osteoblastic differentiation from mesenchymal stem cells (MSCs), but an understanding of their role in the pathogenesis of osteoporosis is still lacking. The present study was undertaken to evaluate a possible alteration of osteogenic gene expression as a mechanism contributing to bone loss.We studied the osteogenic differentiation process in MSCs obtained from the peripheral blood of 31 patients with osteoporosis and 20 normal donors. The cells were evaluated by colony-forming unit-fibroblastic assay and cultured in osteogenic medium to analyze the transcription factors runt-related transcription factor 2 (RUNX-2) and Sp7 and the bone-related genes COL1A1, SPARC, and SPP1 after 3, 8, and 15 days of differentiation. In addition, to determine possible differences between the 2 groups in terms of osteoclastic and osteoblastic activation, we quantified the osteoprotegerin (OPG) and RANKL levels in the supernatants of osteoblastic culture.Circulating MSCs were increased in osteoporosis patients compared with normal donors. In contrast, gene expression analysis revealed down-regulation of RUNX2, Sp7, COL1A1, SPARC, and SPP1 in patients with osteoporosis, associated with a lower OPG:RANKL ratio.These results suggest that an alteration of osteoblastic differentiation may contribute to the pathogenesis of osteoporosis. The noninvasive approach used in the present study could be proposed as a useful tool for studying mesenchymal involvement in bone diseases.

Whole-body bone scintigraphy provides a measure of the total-body burden of osteoarthritis for the purpose of systemic biomarker validation

To evaluate the association of serum and synovial fluid cartilage oligomeric matrix protein (COMP) with systemic and local measures of osteoarthritis (OA) activity by bone scintigraphy.Samples of serum and knee joint synovial fluid (275 knees) were obtained from 159 patients with symptomatic OA of at least 1 knee. Bone scintigraphy using 99mTc-labeled methylene diphosphonate was performed, and early-phase knee scans and late-phase whole-body bone scans of 15 additional joint sites were scored semiquantitatively. To control for within-subject correlations of knee data, generalized linear modeling was used in the correlation of the bone scan scores with the COMP levels. Principal components analysis was used to explore the contribution of each joint site to the variance in serum COMP levels.The correlation between synovial fluid and serum COMP levels was significant (r = 0.206, P = 0.006). Synovial fluid COMP levels correlated most strongly with the early-phase knee bone scan scores (P = 0.0003), even after adjustment for OA severity according to the late-phase bone scan scores (P = 0.015), as well as synovial fluid volumes (P < 0.0001). Serum COMP levels correlated with the total-body bone scan scores (r = 0.188, P = 0.018) and with a factor composed of the bone scan scores in the shoulders, spine, lateral knees, and sacroiliac joints (P = 0.0004).Synovial fluid COMP levels correlated strongly with 2 indicators of knee joint inflammation: early-phase bone scintigraphic findings and synovial fluid volume. Serum COMP levels correlated with total-body joint disease severity as determined by late-phase bone scintigraphy, supporting the hypothesis that whole-body bone scintigraphy is a means of quantifying the total-body burden of OA for systemic biomarker validation.

The infrapatellar fat pad in knee osteoarthritis: An important source of interleukin-6 and its soluble receptor

Obesity is a potent risk factor in knee osteoarthritis (OA). It has been suggested that adipokines, secreted by adipose tissue (AT) and largely found in the synovial fluid of OA patients, derive in part from the infrapatellar fat pad (IFP), also known as Hoffa's fat pad. The goal of this study was to characterize IFP tissue in obese OA patients and to compare its features with thigh subcutaneous AT to determine whether the IFP contributes to local inflammation in knee OA via production of specific cytokines.IFP and subcutaneous AT samples were obtained from 11 obese women (body mass index [ge]30 kg/m2) with knee femorotibial OA. Gene expression was measured by real-time quantitative polymerase chain reaction. Cytokine concentrations in plasma and in conditioned media of cultured AT explants were determined by enzyme-linked immunosorbent assay or by Luminex xMAP technology.In IFP tissue versus subcutaneous AT, there was a decrease in the expression of genes for key enzymes implicated in adipocyte lipid metabolism, whereas the expression levels of genes for AT markers remained similar. A 2-fold increase in the expression of the gene for interleukin-6 (IL-6), a 2-fold increase in the release of IL-6, and a 3.6-fold increase in the release of soluble IL-6 receptor (sIL-6R) were observed in IFP samples, compared with subcutaneous AT, but the rates of secretion of other cytokines in IFP samples were similar to the rates in subcutaneous AT. In addition, leptin secretion was decreased by 40%, whereas adiponectin secretion was increased by 70%, in IFP samples versus subcutaneous AT.Our results indicate that the IFP cytokine profile typically found in OA patients could play a role in paracrine inflammation via the local production of IL-6/sIL-6R and that such a profile might contribute to damage in adjacent cartilage.

Distinct subtypes of myelitis in systemic lupus erythematosus

Myelitis causes pain, weakness, and sphincteric deficits, and is 1,000-fold more prevalent in patients with systemic lupus erythematosus (SLE) than in the general population. For the last century, descriptions of SLE myelitis have been primarily limited to case reports. In contrast, larger-scale cohort studies have revealed that myelitis occurring in the idiopathic demyelinating diseases (i.e., multiple sclerosis versus neuromyelitis optica) represents distinct syndromes. This study was undertaken to determine whether SLE myelitis similarly encapsulates distinct syndromes.We analyzed a cohort of 22 patients with SLE and myelitis. Patients were assessed for neurologic variables related to myelitis and for clinical and serologic features of SLE. Magnetic resonance images of the spine, cerebrospinal fluid profiles, and autoantibody profiles were obtained.Eleven patients presented with signs of gray matter dysfunction (i.e., flaccidity and hyporeflexia), whereas 11 patients presented with signs of white matter dysfunction (i.e., spasticity and hyperreflexia). Patients with gray matter dysfunction were more likely to have irreversible paraplegia (P < 0.01), despite presenting with a monophasic versus polyphasic course (P = 0.01), higher levels of SLE activity (mean SLE Disease Activity Index 9.8 versus 2.0; P = 0.01), and a cerebrospinal fluid profile indistinguishable from bacterial meningitis. Prior to irreversible paraplegia, these patients presented with prodromes of fever and urinary retention, but were misdiagnosed by physicians of different specialties as having urinary tract infections. Patients with white matter dysfunction were more likely to meet criteria for neuromyelitis optica (P = 0.04) and were also more likely to have antiphospholipid antibodies (lupus anticoagulant) (P = 0.01).Our findings indicate that SLE myelitis encapsulates 2 distinct and previously unrecognized syndromes that can be distinguished clinically by gray matter versus white matter findings. Recognition of fever and urinary retention as prodromes of irreversible paraplegia may allow earlier diagnosis and treatment in SLE patients presenting with gray matter findings.

Macrophage activation syndrome in juvenile systemic lupus erythematosus: A multinational multicenter study of thirty-eight patients

To describe the clinical and laboratory features of macrophage activation syndrome as a complication of juvenile systemic lupus erythematosus (SLE).Cases of juvenile SLE-associated macrophage activation syndrome were provided by investigators belonging to 3 pediatric rheumatology networks or were found in the literature. Patients who had evidence of macrophage hemophagocytosis on bone marrow aspiration were considered to have definite macrophage activation syndrome, and those who did not have such evidence were considered to have probable macrophage activation syndrome. Clinical and laboratory findings in patients with macrophage activation syndrome were contrasted with those of 2 control groups composed of patients with active juvenile SLE without macrophage activation syndrome. The ability of each feature to discriminate macrophage activation syndrome from active disease was evaluated by calculating sensitivity, specificity, and area under the receiver operating characteristic curve.The study included 38 patients (20 with definite macrophage activation syndrome and 18 with probable macrophage activation syndrome). Patients with definite and probable macrophage activation syndrome were comparable with regard to all clinical and laboratory features of the syndrome, except for a greater frequency of lymphadenopathy, leukopenia, and thrombocytopenia in patients with definite macrophage activation syndrome. Overall, clinical features had better specificity than sensitivity, except for fever, which was highly sensitive but had low specificity. Among laboratory features, the best sensitivity and specificity was achieved using hyperferritinemia, followed by increased levels of lactate dehydrogenase, hypertriglyceridemia, and hypofibrinogenemia. Based on the results of statistical analysis, preliminary diagnostic guidelines for macrophage activation syndrome in juvenile SLE were developed.Our findings indicate that the occurrence of unexplained fever and cytopenia, when associated with hyperferritinemia, in a patient with juvenile SLE should raise the suspicion of macrophage activation syndrome. We propose preliminary guidelines for this syndrome in juvenile SLE to facilitate timely diagnosis and correct classification of patients.

B lymphocyte stimulator expression in pediatric systemic lupus erythematosus and juvenile idiopathic arthritis patients

To assess the expression of B lymphocyte stimulator (BLyS) in patients with pediatric systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA).Blood samples collected from patients with pediatric SLE (n = 56) and patients with JIA (n = 54) at the beginning and end of a 6-month interval were analyzed for plasma BLyS protein levels by enzyme-linked immunosorbent assay and for blood leukocyte full-length BLyS and [Delta]BLyS messenger RNA (mRNA) levels by quantitative real-time polymerase chain reaction (normalized to 18S expression). Healthy siblings (n = 34) of these patients served as controls.In pediatric SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels were each significantly elevated, and plasma BLyS protein levels, but not blood leukocyte BLyS mRNA levels, were correlated with disease activity. In contrast, plasma BLyS protein levels were normal in JIA despite blood leukocyte BLyS mRNA levels being elevated to degrees similar to those in pediatric SLE. Among JIA patients, neither BLyS parameter was correlated with disease activity. In both pediatric SLE and JIA, the BLyS expression profiles remained stable at 6 months.Our findings indicate that, as previously noted in adult SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels are elevated in pediatric SLE. The correlation of plasma BLyS protein levels with disease activity points to BLyS as a candidate therapeutic target in pediatric SLE. Contrary to previous observations in adults with rheumatoid arthritis, plasma BLyS protein levels are normal in JIA despite elevated blood leukocyte BLyS mRNA levels. The absence of correlation between either of the BLyS parameters and disease activity in JIA calls for circumspection prior to assigning BLyS as a candidate therapeutic target in this disorder.

Increased frequency of extremely skewed X chromosome inactivation in juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is a childhood rheumatic disease of unknown etiology. Two subgroups of JIA, i.e., oligoarticular and polyarticular, are thought to have an autoimmune component, and show a higher female:male ratio. Skewed X chromosome inactivation (XCI) has previously been shown to be associated with scleroderma and autoimmune thyroiditis, 2 autoimmune disorders occurring predominantly in females. This study was undertaken to extend the analysis to the pediatric age group and to determine the XCI profiles of patients with JIA.A polymorphic repeat in the androgen receptor gene was genotyped to determine XCI status in 81 female patients with JIA (21 with polyarticular disease and 60 with oligoarticular disease) and 211 healthy female controls. DNA obtained from venous blood samples was used for this analysis.Informative data were obtained on 62 JIA patients and 155 controls. Skewed XCI was observed in 14 patients (22.6%) and 11 controls (7.1%) (P = 0.0036), and extreme skewing was apparent in 8 patients (12.9%) and 2 controls (1.3%) (P = 0.0008).Our findings in the present study indicate that skewed XCI may be a risk factor for the occurrence of autoimmune disorders, including JIA.

Classification, presentation, and initial treatment of Wegener's granulomatosis in childhood

To compare the criteria for Wegener's granulomatosis (WG) of the American College of Rheumatology (ACR) with those of the European League Against Rheumatism/Pediatric Rheumatology European Society (EULAR/PRES) in a cohort of children with WG and other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs), and to describe the interval to diagnosis, presenting features, and initial treatment for WG.Eligible patients had been diagnosed by site rheumatologists (termed the "MD diagnosis") since 2004. This diagnosis was used as a reference standard for sensitivity and specificity testing of the 2 WG classification criteria. Descriptive analyses were confined to ACR-classified WG patients.MD diagnoses of 117 patients (82 of whom were female) were WG (n = 76), microscopic polyangiitis (n = 17), ANCA-positive pauci-immune glomerulonephritis (n = 5), Churg-Strauss syndrome (n = 2), and unclassified vasculitis (n = 17). The sensitivities of the ACR and EULAR/PRES classification criteria for WG among the spectrum of AAVs were 68.4% and 73.6%, respectively, and the specificities were 68.3% and 73.2%, respectively. Two more children were identified as having WG by the EULAR/PRES criteria than by the ACR criteria. For the 65 ACR-classified WG patients, the median age at diagnosis was 14.2 years (range 4-17 years), and the median interval from symptom onset to diagnosis was 2.7 months (range 0-49 months). The most frequent presenting features by organ system were constitutional (89.2%), pulmonary (80.0%), ear, nose, and throat (80.0%), and renal (75.4%). Fifty-four patients (83.1%) commenced treatment with the combination of corticosteroids and cyclophosphamide, with widely varying regimens; the remainder received methotrexate alone (n = 1), corticosteroids alone (n = 4), or a combination (n = 6).The EULAR/PRES criteria minimally improved diagnostic sensitivity and specificity for WG among a narrow spectrum of children with AAVs. Diagnostic delays may result from poor characterization of childhood WG. Initial therapy varied considerably among participating centers.

Damage extent and predictors in adult and juvenile dermatomyositis and polymyositis as determined with the myositis damage index

We undertook this study to validate the Myositis Damage Index (MDI) in juvenile and adult myositis, to describe the degree and types of damage and to develop predictors of damage.Retrospective MDI evaluations and prospective assessment of disease activity and illness features were conducted. Patients with juvenile-onset disease (n = 143) were evaluated a median of 18 months after diagnosis; 135 patients were assessed 7-9 months later, and 121 were last assessed a median of 82 months after diagnosis. Ninety-six patients with adult-onset dermatomyositis or polymyositis had a baseline assessment a median of 30 months after diagnosis; 77 patients had a 6-month followup evaluation, and 55 had a final assessment a median of 60 months after diagnosis.Damage was present in 79% of juvenile patients and in 97% of adult patients. In juveniles, scarring, contractures, persistent weakness, muscle dysfunction, and calcinosis were most frequent (23-30%) at the last evaluation. In adults, muscle atrophy, muscle dysfunction, and muscle weakness were most frequent (74-84%). MDI severity correlated with physician-assessed global damage, serum creatinine, and muscle atrophy on magnetic resonance imaging, and in juveniles also with functional disability and weakness. MDI damage scores and frequency were highest in patients with a chronic illness course and in adult patients who died. Predictors of damage included functional disability, duration of active disease, disease severity at diagnosis, physician-assessed global disease activity, and illness features, including ulcerations in children and pericarditis in adults.Damage is common in myositis after a median duration of 5 years in patients with adult-onset disease and 6.8 years in patients with juvenile-onset disease. The MDI has good content, construct, and predictive validity in juvenile and adult myositis.

Interleukin-6 and type I interferon-regulated genes and chemokines mark disease activity in dermatomyositis

Up-regulation of whole blood type I interferon (IFN)-driven transcripts and chemokines has been described in a number of autoimmune diseases. An IFN gene expression "signature" is a candidate biomarker in patients with dermatomyositis (DM). This study was performed to evaluate the capacity of IFN-dependent peripheral blood gene and chemokine signatures and levels of proinflammatory cytokines to serve as biomarkers for disease activity in adult and juvenile DM.Peripheral blood samples and clinical data were obtained from 56 patients with adult or juvenile DM. The type I IFN gene signature in the whole blood of patients with DM was defined by determining the expression levels of 3 IFN-regulated genes (IFIT1, G1P2, and IRF7) using quantitative real-time reverse transcription-polymerase chain reaction. Multiplexed immunoassays were used to quantify the serum levels of 4 type I IFN-regulated chemokines (IFN-inducible T cell [alpha] chemoattractant, IFN[gamma]-inducible 10-kd protein, monocyte chemotactic protein 1 [MCP-1], and MCP-2) and the serum levels of other proinflammatory cytokines, including interleukin-6 (IL-6).DM disease activity correlated significantly with the type I IFN gene signature (r = 0.41, P = 0.007) and with the type I IFN chemokine signature (r = 0.61, P < 0.0001). Furthermore, the serum levels of IL-6 were significantly correlated with disease activity (r = 0.45, P = 0.001). In addition, correlations between the serum levels of IL-6 and both the type I IFN gene signature (r = 0.47, P < 0.01) and the type I IFN chemokine signature (r = 0.71, P < 0.0001) were detected in patients with DM.These results suggest that serum IL-6 production and the type I IFN gene signature are candidate biomarkers for disease activity in adult and juvenile DM. Coregulation of the expression of IFN-driven chemokines and IL-6 suggests a novel pathogenic linkage in DM.

Clinical image: Adductor muscle strain in an elderly patient with suspected femoral neck fracture

No abstract.

BANK1 is a genetic risk factor for diffuse cutaneous systemic sclerosis and has additive effects with IRF5 and STAT4

To determine whether the functional BANK1 variants rs3733197 and rs10516487 are associated with systemic sclerosis (SSc) in 2 European Caucasian populations and to investigate the putative gene-gene interactions between BANK1 and IRF5 as well as STAT4.BANK1 single-nucleotide polymorphisms were genotyped in a total population of 2,432 individuals. The French cohort consisted of 874 SSc patients and 955 controls (previously genotyped for both IRF5 rs2004640 and STAT4 rs7574865). The German cohort consisted of 421 SSc patients and 182 controls.The BANK1 variants were found to be associated with diffuse cutaneous SSc (dcSSc) in both cohorts, providing an odds ratio (OR) of 0.77 for the rs10516487 T rare allele in the combined populations of dcSSc patients as compared with the combined populations of controls (95% confidence interval [95% CI] 0.64-0.93) and an OR of 0.73 (95% CI 0.61-0.87) for the rs3733197 A rare allele. BANK1 haplotype analysis found the A-T haplotype to be protective in dcSSc patients (OR 0.70 [95% CI 0.57-0.86], P = 3.39 × 10-4) and the G-C haplotype to be a risk factor (OR 1.25 [95% CI 1.06-1.47], P = 0.008). Significant differences were also observed when the limited cutaneous subset of SSc was compared with the dcSSc subset, both for the rare alleles and for the haplotypes. The BANK1, IRF5, and STAT4 risk alleles displayed a multiplicatively increased risk of dcSSc of 1.43-fold.Our results establish BANK1 as a new SSc genetic susceptibility factor and show that BANK1, IRF5, and STAT4 act with additive effects.

Dabigatran, a direct thrombin inhibitor, demonstrates antifibrotic effects on lung fibroblasts

Myofibroblasts are the principal mesenchymal cells responsible for tissue remodeling, collagen deposition, and the restrictive nature of lung parenchyma associated with pulmonary fibrosis. We previously reported that thrombin activates protease-activated receptor 1 (PAR-1) and induces a myofibroblast phenotype in normal lung fibroblasts resembling the phenotype of scleroderma lung myofibroblasts. We undertook this study to investigate whether a selective direct thrombin inhibitor, dabigatran, interferes with signal transduction in human lung fibroblasts induced by thrombin and mediated via PAR-1.Lung fibroblast proliferation was analyzed using the Quick Cell Proliferation Assay. Expression and organization of [alpha]-smooth muscle actin ([alpha]-SMA) was studied by immunofluorescence staining and immunoblotting. Contractile activity of lung fibroblasts was measured by a collagen gel contraction assay. Connective tissue growth factor (CTGF) and type I collagen expression was analyzed on Western blots.Dabigatran, at concentrations of 50-1,000 ng/ml, inhibited thrombin-induced cell proliferation, [alpha]-SMA expression and organization, and the production of collagen and CTGF in normal lung fibroblasts. Moreover, when treated with dabigatran (1 [mu]g/ml), scleroderma lung myofibroblasts produced 6-fold less [alpha]-SMA, 3-fold less CTGF, and 2-fold less type I collagen compared with untreated cells.Dabigatran restrains important profibrotic events in lung fibroblasts and warrants study as a potential antifibrotic drug for the treatment of fibrosing lung diseases such as scleroderma lung disease and idiopathic pulmonary fibrosis.

A novel inhibitor of Smad-dependent transcriptional activation suppresses tissue fibrosis in mouse models of systemic sclerosis

Tissue fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc), and an increasing number of promising molecular targets for antifibrotic therapies have been described recently. Transforming growth factor [beta] (TGF[beta]) is well known to be the principal factor that leads to tissue fibrosis. The present study was undertaken to investigate the ability of HSc025, a novel small compound that antagonizes TGF[beta]/Smad signaling through the activation of nuclear translocation of Y-box binding protein 1, to prevent tissue fibrosis in vitro or in mouse models of SSc.Human dermal fibroblasts were exposed to HSc025 at various concentrations in the presence of TGF[beta], and levels of collagen or fibronectin expression were determined. HSc025 (15 mg/kg/day for 14 days) was administered orally to tight skin mice and to mice with bleomycin-induced pulmonary fibrosis. Improvement of tissue fibrosis was evaluated by histologic or biochemical examination in each model.Pretreatment with HSc025 prevented Smad-dependent promoter activation, in a dose-dependent manner; however, HSc025 had no effect on TGF[beta]-induced phosphorylation of Smad3. The inhibitory effects of HSc025 on TGF[beta]-induced collagen or fibronectin expression were also confirmed in vitro. Orally administered HSc025 significantly reduced hypodermal thickness and hydroxyproline content in tight skin mice, and markedly decreased the histologic score and hydroxyproline content in the lungs of bleomycin-treated mice.These results demonstrate that HSc025 is a novel inhibitor of TGF[beta]/Smad signaling, resulting in the improvement of skin and pulmonary fibrosis. Orally available HSc025 might therefore be useful in the treatment of SSc.

The 423Q polymorphism of the X-linked inhibitor of apoptosis gene influences monocyte function and is associated with periodic fever

Hereditary periodic fever syndromes (HPFs) develop as a result of uncontrolled activation of the inflammatory response, with a substantial contribution from interleukin-1[beta] or tumor necrosis factor [alpha] (TNF[alpha]). The HPFs include familial Mediterranean fever (FMF), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), TNF receptor-associated syndrome (TRAPS), and cryopyrinopathies, which are attributable to mutations of the MEFV, MVK, TNFRSF1A, and CIAS1 genes, respectively. However, in many patients, the mutated gene has not been determined; therefore, the condition in these patients with an HPF-like clinical picture is referred to as idiopathic periodic fever (IPF). The aim of this study was to assess involvement of X-linked inhibitor of apoptosis (XIAP), which plays a role in caspase inhibition and NF-[kappa]B signaling, both of which are processes that influence the development of inflammatory cells.The XIAP gene (X-linked) was sequenced in 87 patients with IPF, 46 patients with HPF (13 with HIDS, 17 with TRAPS, and 16 with FMF), and 182 healthy control subjects. The expression of different alleles was evaluated by sequencing XIAP-specific complementary DNA mini-libraries and by real-time polymerase chain reaction and Western blot analyses. The functional effect of XIAP on caspase 9 activity was assessed by a fluorimetric assay, and cytokine secretion was evaluated by enzyme-linked immunosorbent assay.Sequencing disclosed a 1268A>C variation that caused a Q423P amino acid substitution. The frequency of 423Q-homozygous female patients and 423Q-hemizygous male patients was significantly higher in the IPF group than in the control group (69% versus 51%; odds ratio 2.17, 95% confidence interval 1.23-3.87, P = 0.007), whereas no significant difference was detected in the HPF group (59%) compared with controls. In primary lymphocytes and transfected cell lines, 423Q, as compared with 423P, was associated with higher XIAP protein and messenger RNA expression and lower caspase 9 activation. In lipopolysaccharide-activated monocytes, 423Q was associated with higher secretion of TNF[alpha].These results suggest that 423Q is a predisposing factor for IPF development, possibly through its influence on monocyte function.

Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand M[amacr]ori, Pacific Island, and Caucasian case-control sample sets

To examine the role of genetic variation in the renal urate transporter SLC2A9 in gout in New Zealand sample sets of M[amacr]ori, Pacific Island, and Caucasian ancestry and to determine if the M[amacr]ori and Pacific Island samples could be useful for fine-mapping.Patients (n= 56 M[amacr]ori, 69 Pacific Island, and 131 Caucasian) were recruited from rheumatology outpatient clinics and satisfied the American College of Rheumatology criteria for gout. The control samples comprised 125 M[amacr]ori subjects, 41 Pacific Island subjects, and 568 Caucasian subjects without arthritis. SLC2A9 single-nucleotide polymorphisms rs16890979 (V253I), rs5028843, rs11942223, and rs12510549 were genotyped (possible etiologic variants in Caucasians).Association of the major allele of rs16890979, rs11942223, and rs5028843 with gout was observed in all sample sets (P = 3.7 × 10-7, 1.6 × 10-6, and 7.6 × 10-5 for rs11942223 in the M[amacr]ori, Pacific Island, and Caucasian samples, respectively). One 4-marker haplotype (1/1/2/1; more prevalent in the M[amacr]ori and Pacific Island control samples) was not observed in a single gout case.Our data confirm a role of SLC2A9 in gout susceptibility in a New Zealand Caucasian sample set, with the effect on risk (odds ratio >2.0) greater than previous estimates. We also demonstrate association of SLC2A9 with gout in samples of M[amacr]ori and Pacific Island ancestry and a consistent pattern of haplotype association. The presence of both alleles of rs16890979 on susceptibility and protective haplotypes in the M[amacr]ori and Pacific Island sample is evidence against a role for this nonsynonymous variant as the sole etiologic agent. More extensive linkage disequilibrium in M[amacr]ori and Pacific Island samples suggests that Caucasian samples may be more useful for fine-mapping.

Increased incidence of cardiovascular events in patients with antineutrophil cytoplasmic antibody-associated vasculitides: A matched-pair cohort study

To explore the risk of cardiovascular disease in patients with antineutrophil cytoplasmic antibody-associated vasculitides (AAVs) and to assess contributing risk factors.In a retrospective matched-pair cohort study, 113 of 131 patients with AAVs from a vasculitis clinic registry were matched 1:1 for renal function, age at diagnosis, sex, smoking status, and previous history of a cardiovascular disease to patients with noninflammatory chronic kidney disease (CKD). Cardiovascular events were defined as acute coronary syndrome, new-onset angina, symptomatic peripheral vascular disease, stroke, and transient ischemic attack.Median followup times were 3.4 years for the AAV patients and 4.2 years for the CKD patients. More cardiovascular events occurred in the AAV group (23 of 113) than in the CKD group (16 of 113). Cox regression survival analysis showed a significantly increased risk of a cardiovascular event for AAV patients, with a hazard ratio (HR) of 2.23 (95% confidence interval [95% CI] 1.1-4.4) (P = 0.017). Within the cohort of AAV patients, the most strongly predictive factors were previous history of cardiovascular disease (HR 4 [95% CI 1.7-9.8]), history of dialysis dependency (HR 4.3 [95% CI 1.5-12.1]), ever having smoked (HR 3.9 [95% CI 1.5-10]), age at diagnosis (HR 1.038 [95% CI 1.006-1.072]), estimated glomerular filtration rate at remission (HR 0.977 [95% CI 0.957-0.998]), and serum cholesterol concentration at presentation (HR 0.637 [95% CI 0.441-0.92]).In this retrospective study, patients with AAVs appear at greater risk of cardiovascular disease, with increased risk in those with a previous history of cardiovascular disease, dialysis dependency, poor renal function at remission, or a history of smoking. Measures to reduce the risk of cardiovascular disease should be integral to the management of systemic vasculitis.

Integrated cardiac and vascular assessment in Takayasu arteritis by cardiovascular magnetic resonance

This study was undertaken to evaluate the value of cardiovascular magnetic resonance (CMR) in the assessment of patients with Takayasu arteritis (TA).Sixteen patients with TA and 2 populations comprising 110 normal volunteers were prospectively recruited. All patients with TA underwent a CMR protocol including measurement of carotid artery wall volume, assessment of left ventricular (LV) volumes and function, and late gadolinium enhancement for the detection of myocardial scarring.Carotid artery wall volume, total vessel volume, and the wall:outer wall ratio were elevated in TA patients compared with controls (wall volume 1,045 mm3 in TA patients versus 640 mm3 in controls, P < 0.001; total vessel volume 2,268 mm3 in TA patients versus 2,037 mm3 in controls, P < 0.05; wall:outer wall ratio 48% in TA patients versus 32% in controls, P < 0.001). The lumen volume was reduced in TA (1,224 mm3 versus 1,398 mm3 in controls, P < 0.05). In TA, LV function was more dynamic, with reduced end-systolic volume (mean ± 95% confidence interval ejection fraction 74 ± 3% versus 67 ± 1% in controls, P < 0.001; LV end-systolic volume 19 ± 4 ml/m2 versus 25 ± 1 ml/m2 in controls, P < 0.001). Myocardial late gadolinium enhancement was present in 4 (27%) of 15 patients, indicating previously unrecognized myocardial damage.Our findings indicate that an integrated method of cardiovascular assessment by CMR in TA not only provides good delineation of vessel wall thickening, but has also demonstrated dynamic ventricular function, myocardial scarring, and silent myocardial infarction. CMR has benefits compared with other approaches for the assessment and followup of patients with TA, and has potential to identify patients most at risk of complications, allowing early preventative therapy.

The FCRL3 -169CT promoter single-nucleotide polymorphism, which is associated with systemic lupus erythematosus in a Japanese population, predicts expression of receptor protein on CD19+B cells

No abstract.

Lipoatrophy resulting from steroid injection into the temporomandibular joint

No abstract.

The p38 MAPK pathway mediates both antiinflammatory and proinflammatory processes: Comment on the article by Damjanov and the editorial by Genovese

No abstract.

Methodology and statistical analysis in the Glucosamine/Chondroitin Arthritis Intervention Trial: Comment on the article by Sawitzke et al

No abstract.

Reply

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No evidence yet to change American Heart Association recommendations for poststreptococcal reactive arthritis: Comment on the article by van Bemmel et al

No abstract.

Reply

No abstract.

Time to prove the infective etiology of ankylosing spondylitis and related spondylarthritides: Comment on the article by Carter et al

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Autoantibodies against the platelet-derived growth factor receptor in scleroderma: Comment on the articles by Classen et al and Loizos et al

No abstract.

Clinical image: Fistulization of aortic aneurysm into the main bronchus in giant cell arteritis

No abstract.

ACR announcements

No abstract.