Rheumatology RSS : Gourt

Southern Academic Pediatric Rheumatology,One of the South’s Top Children’s Hospitals,#5611 :: Mississippi :: Timeline Recruiting

As the only childrens hospital in the state, our more than 100 pediatric medical faculty provide outstanding medical services to millions of patients in our draw area. We are part of the Southeast

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

1 Hour to the Bay Area :: California :: Fidelis Partners

100% RHEUMATOLOGY NORTHERN CALIFORNIA ONE HOUR TO THE BAY AREA Large and Instant Referral Base 100% Rheumatology Opportunity Financials: * Two-year Income guarantee based on experience.

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.

Central Florida :: Florida :: Nationwide Physician Recruitment

Excellent Rheumatology Opportunity within two hours of the Gulf of Mexico, Atlantic Ocean, and Orlando. Growing Community with a strong need - Excellent opportunity in a great market without competition.

Great Location :: Arkansas :: MedBizJob.com

Join a well established multi-specialty group or establish a solo practice. Rheumatology has been identified as a need by the community and our medical staff. This is an opportunity to work with the

Williamsport :: Pennsylvania :: New England Physician Recruitment Center

Rheumatology Central PA - Join large hospital system including 3 hospitals serving patients from an 11-county region. We are considered a healthcare leader and offers a broad array of services that

Southbridge :: Massachusetts :: New England Physician Recruitment Center

Rheumatology West of Boston - Seeking Rheumatologist for full time Rheum/ IM position or part time Rheumatology only. Joining one other Rheumatologist. Hospital employed. Modern 113-bed hospital which

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

Pittsfield :: Massachusetts :: New England Physician Recruitment Center

Rheumatology--Western Massachusetts-302-bed community teaching hospital and Level II Trauma Center -academic teaching facility with excellent schools and lifestyle .Where quality of life and quality

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

Greenville :: North Carolina :: Horton Smith Associates

Join an established 80+ provider multi-specialty group based in Greenville, NC. We are a multi-campus physician-owned practice offering a wide range of specialties. Our Rheumatology division has an

Kingston :: New York :: New England Physician Recruitment Center

Rheumatology-Southern NY 100 percent Rheumatology-- 20 year established practice looking to expand services. They are located just north of NYC and 1 hour south of Albany. Groups currently has 6 physicians.

Hartford :: Connecticut :: New England Physician Recruitment Center

Within twenty minutes of New Haven and Hartford, a short drive to Boston and New York, approximately two hours, the coast and twenty-five minutes to an International Airport. The area is filled with some

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

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

East :: North Carolina :: Healthcare Recruitment Counselors, LLC

an established 80+ provider multi-specialty group based in east, NC. We are a multi-campus physician-owned practice offering a wide range of specialties. Our Rheumatology division has an immediate opening.

Regulation of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase-activating protein/5-lipoxygenase by 4-hydroxynonenal in human osteoarthritic chondrocytes

IntroductionThis study aimed to investigate whether hydroxynonenal (HNE) depletion is responsible for the switch from cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase-1 (mPGES-1) to 5-lipoxygenase-activating protein (FLAP) and 5-lipoxygenase (5-LOX). Methods: For COX-2 and mPGES-1 studies, human osteoarthritic (OA) chondrocytes were stimulated at different incubation times (up to 24 hours) with a single or repetitive addition of 10 microM HNE to the cultures at 2 hour intervals, up to 14 hours. For 5-LOX and FLAP studies, cells were treated with a single addition of 10 microM HNE for 24 hours, 48 hours, and 72 hours in the presence or absence of naproxen (a nonspecific COX-2 inhibitor) or antibody anti-transforming growth factor-beta 1 (TGF-beta1. The protein levels of COX-2, mPGES-1 and early growth response factor-1 (Egr-1) transcription factor were evaluated by Western blot and that of prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and TGF-beta1were determined with commercial kits. The levels of mPGES-1, FLAP and 5-LOX mRNA were measured by real-time RT-PCR. Transient transfection was performed to determine promoter activities of mPGES-1 and 5-LOX. Results: Single addition of 10 microM HNE to cultured chondrocytes induced PGE2 release as well as COX-2 and mPGES-1 expression at the protein and mRNA levels, with a plateau reached respectively at 8 and 16 hours of incubation, followed by a subsequent decline. However, repeated treatments with HNE prevented the decline of COX-2 and mPGES-1 expression that occurred with a single aldehyde addition. HNE induced mPGES-1 promoter activity, possibly through transcription factor Egr-1 activation. After 48 hours, when COX-2 expression decreased, LTB4 level rose through 5-LOX and FLAP up-regulation. The addition of naproxen to cultured chondrocytes revealed that FLAP and 5-LOX regulation by HNE required PGE2 production. Furthermore, our data showed that HNE significantly induced TGF-beta1 production. The addition of anti-TGF-beta1 antibody reduced HNE-induced 5-LOX and FLAP expression by 40%, indicating the partial involvement of a TGF-beta1-dependent mechanism. Conclusions: Our data demonstrate that the shunt to the FLAP and 5-LOX pathway in HNE-induced human OA chondrocytes is attributed to COX-2 and mPGES-1 inhibition, probably due to HNE depletion. PGE2 and TGF-beta1 are suggested to be involved in this regulation.

Local leptin production in osteoarthritis subchondral osteoblasts may be responsible for their abnormal phenotypic expression

IntroductionLeptin is a peptide hormone with a role in bone metabolism and rheumatic diseases. The subchondral bone tissue plays a prominent role in the pathophysiology of osteoarthritis (OA), related to abnormal osteoblast (Ob) differentiation. Although leptin promotes the differentiation of Ob under normal condition, a role for leptin in OA Ob has not been demonstrated. Here we determined if endogenous leptin produced by OA Ob could be responsible for the expression of the abnormal phenotypic biomarkers observed in OA Ob. Methods: We prepared primary normal and OA Ob from subchondral bone of tibial plateaus removed for knee surgery of OA patients or at autopsy. We determined the production of leptin and of the long, biologically active, leptin receptors (OB-Rb) using RT-PCR, ELISA and Western blot analysis. We determined the effect of leptin on cell proliferation by BrdU incorporation and MTT assays, and we determined by Western blot analysis phospho 42/44 MAPK (p42/44 Erk1/2) and phospho p38 levels. We then determined the effect of the addition of exogenous leptin, leptin receptor antagonists, inhibitors of leptin signaling or siRNA techniques on the phenotypic features of OA Ob. Phenotypic features of Ob were determined by measuring alkaline phosphatase activity (ALP), osteocalcin release (OC), collagen type 1 production (CICP) and of Transforming growth factor-beta1 (TGF-beta1). Results: Leptin expression was increased ~5-fold and protein levels ~2-fold in OA Ob compared to normal. Leptin stimulated its own expression and the expression of OB-Rb in OA Ob. Leptin dose-dependently stimulated cell proliferation of OA Ob and also increased phosphorylated p42/44 Erk1/2 and p38 levels. Inactivating antibodies against leptin reduced ALP, OC, CICP and TGF-beta1 levels in OA Ob. Tyrphostin (AG490) and piceatannol (Pce), inhibitors of leptin signaling, reproduced this effect. Inhibition of endogenous leptin levels using siRNA for leptin or inhibiting leptin signaling using siRNA for OB-Rb expression both reduced ALP and OC about 60%. Exogenous leptin addition stimulated ALP, yet this failed to further increase OC or CICP. Conclusions: These results suggest that abnormal production of leptin by OA Ob could be responsible, in part, for the elevated levels of ALP, OC, collagen type 1 and TGF-beta1 observed in these cells compared to normal. Leptin also stimulated cell proliferation, and Erk 1/2 and p38 signaling. Taken together, these data suggest leptin could contribute to abnormal osteoblast function in OA.

Is Phytalgic(R) a goldmine for osteoarthritis patients or is there something fishy about this nutraceutical? A summary of findings and risk of bias assessment

A food supplement containing fish oils, urtica dioica, Zinc, and Vitamin E (Phytalgic(R)) for osteoarthritis (OA) has now been tested in a placebo-controlled trial for three months and according to the authors has a very large clinical effect, considerably larger than any other known product. Even experts endorsing nutraceuticals for OA symptoms would probably agree that a nutraceutical with an effect size above .5 is rarely seen. Despite our concern about the trial registration taking place after the study was completed, and the likelihood that patients would note the taste of fish, thus leading to detection bias, we consider these data promising although with a high risk of bias.

Autophagy induction and CHOP under-expression promotes survival of fibroblasts from rheumatoid arthritis patients under endoplasmic reticulum stress

IntroductionSynovial fibroblasts from rheumatoid arthritis show resistance to apoptotic stimuli, indicating they may be difficult to treat. To clearly understand these mechanisms of resistance, rheumatoid and osteoarthritis synovial fibroblasts (RASF and OASF) were exposed to endoplasmic reticulum (ER) stress such as thapsigargin, Ca2+-ATPase inhibitor. Methods: Fibroblasts were assessed microscopically for cell viability by trypan blue exclusion and for autophagic cells by LC-3II formation. Caspase-3 activity was measured as aminomethyl-coumarin (AMC) liberated from AC-DEVD-AMC. Immunoblotting was performed to compare protein expression in OASF and RASF. Results: ER stress caused cell death in OASF but not in RASF. Thapsigargin, a Ca2+-ATPase inhibitor, did not change the expression of GRP78, an ER chaperone in OASF and RASF, but induced another ER stress protein, CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) differently, showing high levels in OASF and low levels in RASF. Thapsigargin increased the autophagy response in RASF, with autophagosome formation, beclin expression, and LC3-II conversion. Transfection with beclin siRNA inhibited autophagy and increased the susceptibility to ER stress-induced cell death. On the other hand, CHOP siRNA increased autophagy and improved cell survival, especially in RASF, indicating that CHOP is involved in regulation of autophagy and cell death, but that low expression of CHOP protects RASF from apoptosis. Conclusions: Autophagy induction and CHOP under-expression increases cell resistance against ER stress-induced cell death in fibroblasts from rheumatoid arthritis patients.

From the item to the outcome: the promising prospects of PROMIS

Evaluation of patient reported outcomes, and in particular physical function, have gained increasing importance in research and therapy of patients with rheumatic diseases. Most instruments that are used for that purpose are rigid and suffer from floor and ceiling effects when used in patients whose physical function differs from the average. A new approach to the assessment of physical function uses computerised adaptive testing, by which precision and reliability of the measurement can be achieved for most patients, while even requiring less time for the assessment. Well calibrated and tested item and large item data banks are a prerequisite for this purpose, a process that is summarised in the present report by Bruce and colleagues.

A role for age-related changes in TGF-beta signalling in aberrant chondrocyte differentiation and osteoarthritis.

Transforming growth factor beta (TGFβ) is a growth factor with many faces. In our osteoarthritis (OA) research we have found that TGFβ can be protective as well as deleterious for articular cartilage. We postulate that the dual effects of TGFβ on chondrocytes can be explained by the fact that TGFβ can signal via different receptors and related Smad signaling routes. On chondrocytes, TGFβ not only signals via the canonical type I receptor ALK5 but also via the ALK1 receptor. Notably, signaling via ALK5 (Smad2/3 route) results in markedly different chondrocyte responses than ALK1 signaling (Smad1/5/8), and we postulate that the balance between ALK5 and ALK1 expression on chondrocytes will determine the overall effect of TGFβ on these cells. Importantly, signaling via ALK1, but not ALK5, stimulates MMP-13 expression by chondrocytes. In cartilage of ageing mice and in experimental OA models we have found that the ALK1/ALK5 ratio is significantly increased, favoring TGFβ signaling via the Smad1/5/8 route, changes in chondrocyte differentiation and MMP-13 expression. Moreover, human OA cartilage showed a significant correlation between ALK1 and MMP-13 expression. In this paper we summarize concepts in OA, its link with ageing and disturbed growth factor responses, and a potential role of TGFβ signaling in OA development.

A peptidyl-glucosamine derivative affects IKKalpha kinase activity in human chondrocytes

IntroductionNuclear factor-kappaB (NF-kappaB) transcription factor regulates several cell signaling pathways, such as differentiation and inflammation, which are both altered in osteoarthritis. Inhibitor kappaB kinase (IKK)alpha and IKKbeta are kinases involved in the activation of the NF-kappaB transcription factor. The aim of the present study was to determine the effects of glucosamine (GlcN), which is administered in the treatment of osteoarthritis, and of its 2-(N-Acetyl)-L-phenylalanylamido-2-deoxy-beta-D-glucose (NAPA) derivative on IKK kinases and, consequently, on NF-kappaB activation in human chondrocytes. Methods: The human chondrosarcoma cell line HTB-94 and human primary chondrocytes were stimulated with tumor necrosis factor (TNF)alpha after pre-treatment with GlcN or NAPA. Gene mRNA expression level was evaluated by real time-PCR. IkappaBalpha phosphorylation and p65 nuclear re-localization were analyzed by Western blotting, IKKalpha nuclear re-localization was also investigated by immunocytochemistry and Western blotting. IKK kinase activity was studied by in vitro kinase assay. Results: After TNFalpha stimulation, the mRNA expression level of some of the genes under NF-kappaB control, such as interleukin (IL)-6 and IL-8, increased, while treatment with GlcN and NAPA reverted the effect. We investigated the possibility that GlcN and NAPA inhibit IKK kinase activity and found that NAPA inhibits the IKKalpha kinase activity, whereas GlcN does not. Interestingly, both GlcN and NAPA inhibit IKKalpha nuclear re-localization. Conclusions: Our results demonstrate that glucosamine and its peptidyl-derivative can interfere with NF-kappaB signaling pathway by inhibiting IKKalpha activity in human chondrocytes. However, the mechanism of action of the two molecules is not completely overlapping. While NAPA can both specifically inhibit the IKKalpha kinase activity and IKKalpha nuclear re-localization, GlcN only acts on IKKalpha nuclear re-localization.

Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: implication in the pathogenesis of the disease

IntroductionFibromyalgia is a chronic pain syndrome with unknown etiology. Recent studies have shown some evidence demonstrating that oxidative stress may have a role in the pathophysiology of fibromyalgia. However, it is still not clear whether oxidative stress is the cause or the effect of the abnormalities documented in fibromyalgia. Furthermore, the role of mitochondria in the redox imbalance reported in fibromyalgia is also controversial. We undertook this study to investigate the role of mitochondrial dysfunction, oxidative stress and mitophagy in fibromyalgia. Methods: We studied 20 patients (2 males and 18 females) recruited from the database of the Sevillian Fibromyalgia Association and 10 healthy controls. We evaluated mitochondrial function in blood mononuclear cells from fibromyalgia patients measuring coenzyme Q10 levels by high performance liquid chromatography (HPLC), and mitochondrial membrane potential by flow cytometry. Oxidative stress was determined by measuring mitochondrial superoxide production by MitoSOXTM, and lipid peroxidation in blood mononuclear cells and plasma from fibromyalgia patients. Autophagy activation was evaluated by quantifying the fluorescence intensity of LysoTrackerTM Red staining of blood mononuclear cells. Mitophagy was confirmed by measuring citrate synthase activity and electron microscopy examination of blood mononuclear cells. Results: We found reduced levels of coenzyme Q10, decreased mitochondrial membrane potential, increased level of mitochondrial superoxide in blood mononuclear cells, and increased levels of lipid peroxidation in both blood mononuclear cells and plasma from fibromyalgia patients. Mitochondrial dysfunction was also associated with increased expression of autophagic genes and the elimination of dysfunctional mitochondria by mitophagy. Conclusions: These findings may support the role of oxidative stress and mitophagy in the pathophysiology of fibromyalgia.

S100A8 and S100A9 in experimental osteoarthritis

IntroductionThe objective was to evaluate the changes in S100A8 S100A9, and their complex (S100A8/S100A9) in cartilage during the onset of osteoarthritis (OA) as opposed to inflammatory arthritis. Methods: S100A8 and S100A9 protein localization were determined in antigen-induced inflammatory arthritis in mice, mouse femoral head cartilage explants stimulated with interleukin-1 (IL-1), and in surgically-induced OA in mice. Micro-array expression profiling of all S100 proteins in cartilage was evaluated at different times after initiation of degradation in femoral head explant cultures stimulated with IL-1 and surgically-induced OA. The effect of S100A8, S100A9 or the complex on the expression of aggrecan (Acan), collagen II (Col2a1), disintegrin and metalloproteases with thrombospondin motifs (Adamts1, Adamts 4 & Adamts 5), matrix metalloproteases (Mmp1, Mmp3, Mmp13 & Mmp14) and tissue inhibitors of metalloproteinases (Timp1, Timp2 & Timp3), by primary adult ovine articular chondrocytes was determined using real time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results: Stimulation with IL-1 increased chondrocyte S100a8 and S100a9 mRNA and protein levels. There was increased chondrocyte mRNA expression of S100a8 and S100a9 in early but not late mouse OA. However, loss of the S100A8 staining in chondrocytes occurred as mouse OA progressed, in contrast to the positive reactivity for both S100A8 and S100A9 in chondrocytes in inflammatory arthritis in mice. Homodimeric S100A8 and S100A9, but not the heterodimeric complex, significantly upregulated chondrocyte Adamts1, Adamts4 and Adamts 5, Mmp1, Mmp3 and Mmp13 gene expression, while collagen II and aggrecan mRNAs were significantly decreased. Conclusions: Chondrocyte derived S100A8 and S100A9 may have a sustained role in cartilage degradation in inflammatory arthritis. In contrast, while these proteins may have a role in initiating early cartilage degradation in OA by upregulating MMPs and aggrecanases, their reduced expression in late stages of OA suggests they do not have an ongoing role in cartilage degradation in this non-inflammatory arthropathy.

Flow cytometric characterization of freshly isolated and culture expanded human synovial cell populations in patients with chronic arthritis

IntroductionThe synovium is a major target tissue in chronic arthritis and is intensively studied at the cellular and molecular level. The aim of this study was to develop flow cytometry for the quantitative analysis of synovial cell populations pre and post culture and to characterize mesenchymal cell populations residing in the inflammatory synovium. Methods: Knee synovium biopsies from 39 patients with chronic arthritis and from 15 controls were treated in a short, standardized tissue digestion procedure. Stored thawed digests were routinely analyzed with flow cytometry including live-dead staining and use of the markers CD45, CD3, CD14, CD20, CD34, CD73, CD105, CD90, CD146, CD163 and HLA-DR to distinguish inflammatory and stromal cells. The influence of the digestion method on the detection of the different surface markers was studied separately. In addition, we studied the presence of a specific cell population hypothesized to be mesenchymal stem cells (MSC) based on the CD271 marker. Cell expansion cultures were set up and a MSC-related surface marker profile in passages 3 and 6 was obtained. Immunohistochemistry for CD34 and von Willebrand factor (vWF) was done to obtain additional data on synovium vascularity. Results: The cell yield and viability normalized to tissue weight were significantly higher in inflammatory arthritis than in controls. Within the hematopoietic CD45-positive populations, we found no differences in relative amounts of macrophages, T-lymphocytes and B-lymphocytes between patient groups. Within the CD45-negative cells, more CD34-positive cells were seen in controls than in arthritis patients. In arthritis samples a small CD271 positive population was detected. Culture expanded cells were found to fulfill the multipotent mesenchymal stromal cell marker profile, except for CD34 negativity. Detection of peripheral blood macrophage and B-cell markers was decreased after enzymatic exposure and mechanical forces, respectively, but stromal markers were not affected. Conclusions: Flow cytometry can distinguish synovial cell populations in tissue digests. The preparation method can influence the detection levels of macrophage and B-cell populations. However, stromal cell markers seem not affected and quantification is possible, supporting flow cytometry tissue analysis as a tool to study these cell populations in arthritis.

Rheumatoid arthritis and pregnancy; not only for rheumatologists interested in female health issues

Anti-endothelial cell antibodies in systemic sclerosis

Anti-endothelial cell antibodies (AECA) are a heterogeneous class of antibodies whose role in the pathogenesis of autoimmune diseases with vascular involvement has been extensively studied. Systemic sclerosis (SSc) is one of the systemic autoimmune diseases in which endothelial dysfunction is well defined and important in the development of the disease. AECA are present in the serum samples of many patients with SSc. Depending on the detection method and on patient selection, 22–86% of patients test positive for AECA. Among the demonstrated clinical associations, lung and peripheral vascular involvement are the most common. In this paper, the methods of detection, various molecular specificities and the possible pathogenic mechanisms of AECA in SSc are reviewed.

EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis

Objectives: To develop evidence-based EULAR recommendations for cardiovascular (CV) risk management in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Methods: A multidisciplinary expert committee was convened as a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), comprising 18 members including rheumatologists, cardiologists, internists and epidemiologists, representing nine European countries. Problem areas and related keywords for systematic literature research were identified. A systematic literature research was performed using MedLine, Embase and the Cochrane library through to May 2008. Based on this literature review and in accordance with the EULAR’s "standardised operating procedures", the multidisciplinary steering committee formulated evidence-based and expert opinion-based recommendations for CV risk screening and management in patients with inflammatory arthritis. Results: Annual CV risk assessment using national guidelines is recommended for all patients with RA and should be considered for all patients with AS and PsA. Any CV risk factors identified should be managed according to local guidelines. If no local guidelines are available, CV risk management should be carried out according to the SCORE function. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower the CV risk. Conclusions: Ten recommendations were made for CV risk management in patients with RA, AS and PsA. The strength of the recommendations differed between RA on the one hand, and AS and PsA, on the other, as evidence for an increased CV risk is most compelling for RA.

Postpartum onset of rheumatoid arthritis and other chronic arthritides: results from a patient register linked to a medical birth registry

Background: It is known that onset of rheumatoid arthritis (RA) is increased post partum. Objective: To compare incidence rates between RA and other chronic arthritides (OCA) 0–24 months after delivery, and to compare the incidence rates within each group 0–24 versus 25–48 months post partum. Methods: Premenopausal women from a Norwegian patient register were linked with the Medical Birth Registry of Norway to study the interval between delivery and time of diagnosis. Cox regression analysis with adjustments for age at delivery and birth order was applied to compare proportions of incident cases of RA and OCA with onset 0–24 months post partum. Poisson regression analysis with adjustment for the population at risk was applied to estimate the incidence rate ratio (IRR) 0–24 versus 25–48 months post partum. Results: Of 183 RA and 110 patients with OCA diagnosed after delivery, 69 (37.7%) had RA and 31 (28.2%) OCA during the first 24 months post partum (p = 0.09). The IRR (95% CI) for diagnosis during 0–24 months versus 25–48 months was 1.73 (1.11 to 2.70) (p = 0.01) for RA, 1.05 (0.59 to 1.84) (p = 0.86) for OCA. The IRR was 2.23 (1.06 to 4.70) and 1.87 (0.67 to 5.21), respectively, when only considering diagnoses after the first pregnancy. Clinical characteristics were similar within each diagnostic group. Conclusion: The proportions of incident cases with onset 0–24 months after delivery were not different between RA and OCA. A peak in incidence during 0–24 months was seen in the RA group, both when considering all pregnancies and only the first pregnancy.

Correction

Does anti-mutated citrullinated vimentin have additional value as a serological marker in the diagnostic and prognostic investigation of patients with rheumatoid arthritis? A systematic review

Objective: To review the diagnostic and prognostic value of anti-mutated citrullinated vimentin (MCV) in rheumatoid arthritis, taking into account the already available serology. Methods: Medline was searched via PubMed (1966 to May 2008) for anti-MCV and related terms, arthritis and arthropathies. Studies with anti-MCV, arthritis/arthropathy, and primary data on diagnosis and/or prognosis were included. Their methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) instrument for diagnostic studies and the modified Hayden list for prognostic studies. Results: Of 14 eligible studies, 11 included diagnostic data and 3 included prognostic data. No study evaluated anti-MCV as an added diagnostic test to the already available anti-cyclic citrullinated peptide (CCP) and rheumatoid factor serology. One study included the optimal patient spectrum resulting in a sensitivity of 0.59 and specificity of 0.98. A total of 10 diagnostic case-control studies using the same anti-MCV kit showed a sensitivity of 0.64–0.84 and a specificity of 0.79–0.96. This almost equalled the performance of anti-CCP in the same studies. The prognostic evaluation of anti-MCV was limited by differences in study methodology, outcome and statistical modelling. Individual studies showed moderate associations for anti-MCV and radiological progression with the strength of the association comparable to that of anti-CCP. Conclusions: Study heterogeneity, choice of study population and methodological limitations limited overall conclusions about the true diagnostic and prognostic test performance of anti-MCV. Evidence from the diagnostic case-control studies suggests that anti-MCV may be used as an alternative for anti-CCP.

Prediction of radiographic progression in rheumatoid arthritis and the role of antibodies against mutated citrullinated vimentin: results from a 10-year prospective study

Objectives: Anti-citrullinated peptide antibodies (ACPAs) are established as useful predictors of radiographic progression in rheumatoid arthritis (RA). The main objective of this study was to test the prognostic capacity of the recently developed test for anti-mutated citrullinated vimentin (anti-MCV). Methods: A cohort of 238 patients with RA was followed longitudinally for 10 years; 125 patients with complete x ray sets were included in the main analyses. Radiographs were scored according to the van der Heijde modified Sharp score (SHS). Patients were analysed for anti-MCV and anti-cyclic citrullinated peptide (CCP), and were genotyped for human leukocyte antigen (HLA)-DRB1 "shared epitope" (SE) and protein tyrosine phosphatase, non-receptor type 22 (PTPN22) 1858T. Results: Anti-MCV and anti-CCP were strongly associated with regard to status and level. Both antibodies were associated with SE, but only anti-MCV was significantly associated with PTPN22 1858T. A positive anti-MCV test increased the odds of radiographic progression by 7.3 (95% confidence interval (CI) 3.2 to 16.5) compared to 5.7 (95% CI 2.6 to 12.5) for a positive anti-CCP. Presence of MCV antibodies gave an average increase in the total SHS of 30 U compared to an average increase of 25 U for the presence of CCP antibodies. Anti-MCVs were more strongly associated to progression in erosions than joint space narrowing. Associations remained after adjustment for other predictors of radiographic progression. The odds of progression increased with increasing anti-MCV level. Conclusions: Presence of anti-MCV predicted joint damage, and the strength of this prediction was at least as strong as for anti-CCP. Antibody status showed a stronger association to bone than to cartilage destruction. This study also indicates that higher anti-MCV levels add prognostic information compared to their mere presence or absence.

Rapid and sustained health utility gain in anti-tumour necrosis factor-treated inflammatory arthritis: observational data during 7 years in southern Sweden

Background: Rheumatoid arthritis (RA), psoriatic arthritis (PsA) and other spondylarthritides impose a great impact on the individual in addition to the costs on society, which may be reduced by effective pharmacological treatment. Industry-independent health economic studies should complement studies sponsored by industry. Objective: To study secular trends in baseline health utilities in patients commencing tumour necrosis factor (TNF) blockade for arthritis in clinical practice over 7 years; to address utility changes during treatment; to investigate the influence of previous treatment courses; to study the feasibility of health utility measures and to compare them across diagnostic entities. Methods: EuroQoL 5 dimensions (EQ-5D) utility data were collected from a structured clinical follow-up programme of anti-TNF-treated patients with RA (N = 2554), PsA (N = 574) or spondylarthritides (N = 586). Time trends were calculated. Completer analysis was used. Results: There were weak or non-significant secular trends for increasing baseline utilities over time for RA, PsA and spondylarthritides. The maximum gain in utilities had already occurred after 2 weeks for all diagnoses and remained stable for patients remaining on therapy. The first and second anti-TNF courses performed similarly. Conclusions: Utilities at inclusion remained largely unchanged for RA, PsA and spondylarthritides over 7 years. Improvement occurred early during treatment and not beyond 6 weeks at the group level. Improvement during the first course was not consistently greater than the second. There were no major differences between RA, PsA and spondylarthritides. EQ-5D proved feasible and applicable across these diagnoses. These "real world" data may be useful for health economic modelling.

National cohort study of reproductive risk factors for rheumatoid arthritis in Denmark: a role for hyperemesis, gestational hypertension and pre-eclampsia?

Objectives: While reproductive factors might plausibly be involved in the aetiology of rheumatoid arthritis (RA), the female predominance remains unexplained. A study was undertaken to address the possible impact of live births, pregnancy losses and pregnancy complications on the subsequent risk of RA in a nationwide cohort study. Methods: National register data were used to link reproductive histories and later RA hospitalisations in a cohort of 4.4 million Danes. As a measure of relative risk associated with different reproductive histories, ratios of first inpatient RA hospitalisation rates (RRs) were used with 95% confidence intervals (CIs) obtained by Poisson regression analysis. Results: Overall, 7017 women and 3041 men were admitted to hospital with RA in 1977–2004 (88.8 million person-years). The risk of RA was inversely associated with age at birth of first child in both women and men (p for trend <0.001). Overall, nulliparity and a history of pregnancy loss were not associated with RA risk but, compared with one-child mothers, women with two (RR 0.84; 95% CI 0.78 to 0.90) or three (RR 0.83; 95% CI 0.77 to 0.91) children were at reduced risk. The risk of RA was increased in women with a history of hyperemesis (RR 1.70; 95% CI 1.06 to 2.54), gestational hypertension (RR 1.49; 95% CI 1.06 to 2.02) or pre-eclampsia (RR 1.42; 95% CI 1.08 to 1.84). Conclusions: One-child mothers and young parents are at increased risk of RA later in life, possibly due to socioeconomic factors. The novel finding of a significantly increased risk of RA in women whose pregnancies were complicated by hyperemesis, gestational hypertension or pre-eclampsia might reflect reduced immune adaptability to pregnancy in women disposed to RA or a role of fetal microchimerism in the aetiology of RA.

Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy

Objective: To determine the efficacy and safety of pamapimod in adult patients with active rheumatoid arthritis (RA) who had an inadequate clinical response to methotrexate (MTX). Methods: Patients receiving stable doses of MTX were randomised to one of six dose groups and received 12 weeks of double-blind pamapimod (up to 300 mg once daily) or matching placebo. The primary efficacy measure was the proportion of patients with >=20% improvement in RA based on the American College of Rheumatology criteria (ACR20) at 12 weeks. Secondary measures were ACR50, Disease Activity Score (DAS)/European League Against Rheumatism (EULAR) responses and the individual ACR core set of parameters. Safety measures included adverse events (AEs), laboratory testing and immunology assessments. Results: On a background of MTX, the percentage of patients with an ACR20 response at week 12 in the pamapimod groups (31% to 43%) was not significantly different from placebo (34%). Secondary efficacy end points showed a similar pattern. AEs were typically mild and included infections, gastrointestinal disturbances, dizziness and rashes; AEs resulting in discontinuation of study drug were primarily attributed to infections. Conclusion: In patients with active RA receiving stable doses of MTX, pamapimod showed non-significant improvement in efficacy outcomes compared to placebo.

Association study of TRAF1-C5 polymorphisms with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese

Objective: The primary aim of this study was to investigate the association of polymorphisms of TRAF1-C5, a newly identified rheumatoid arthritis (RA) risk locus in Caucasians, with susceptibility to RA and systemic lupus erythematosus (SLE) in Japanese populations. Gene expression levels of TRAF1 and C5 to assess the functional significance of genotypes were also analysed. Methods: A multicentre association study consisting of 4 RA case-control series (4397 cases and 2857 controls) and 3 SLE case-control series (591 cases and 2199 shared controls) was conducted. Genotyping was performed using TaqMan genotyping assay for two single nucleotide polymorphisms (SNPs) that showed the best evidence of association in the previous Caucasian studies. Quantifications of TRAF1 and C5 expression were performed with TaqMan expression assay. Results: Significant differences in allele frequency for both SNPs were observed between RA and control subjects (combined odds ratio = 1.09), while no significant difference was detected between patients with SLE and controls. Interestingly, alleles rs3761847 A and rs10818488 G had increased the risk for RA in the present study, while they decreased the risk in the original studies. A significant difference was found between risk allele carriers and non-carriers of rs10818488 for the expression level of TRAF1 in phorbol myristate acetate-stimulated lymphoblastoid cell lines (p = 0.04). Conclusion: Association of TRAF1-C5 locus with RA susceptibility was detected in the Japanese populations with modest magnitude, while no significant association was observed for SLE. Significant positive effect of genotype on the expression of TRAF1 might support the genetic association between TRAF1 and RA.

Responder analysis for pain relief and numbers needed to treat in a meta-analysis of etoricoxib osteoarthritis trials: bridging a gap between clinical trials and clinical practice

Background: Population mean changes from clinical trials are difficult to apply to individuals in clinical practice. Responder analysis may be better, but needs validating for level of response and treatment duration. Methods: The numbers of patients with pain relief over baseline (>=15%, >=30%, >=50%, >=70%) at 2, 4, 8 and 12 weeks of treatment were obtained using the WOMAC 100 mm visual analogue pain subscale score for each treatment group in seven randomised placebo-controlled trials of etoricoxib in osteoarthritis lasting >=6 weeks. Dropouts were assigned 0% improvement from baseline from then on. The numbers needed to treat (NNTs) were calculated at each level of response and time point. Results: 3554 patients were treated with placebo, etoricoxib 30 mg and 60 mg, celecoxib 200 mg, naproxen 1000 mg or ibuprofen 2400 mg daily. Response rates fell with increasing pain relief: 60–80% experienced minimally important pain relief (>=15%), 50–60% moderate pain relief (>=30%), 40–50% substantial pain relief (>=50%) and 20–30% extensive pain relief (>=70%). NNTs for etoricoxib, celecoxib and naproxen were stable over 2–12 weeks. Ibuprofen showed lessening of effectiveness with time. Conclusion: Responder rates and NNTs are reproducible for different levels of response over 12 weeks and have relevance for clinical practice at the individual patient level. An average 10 mm improvement in pain equates to almost one in two patients having substantial benefit.

Association of methotrexate and tumour necrosis factor antagonists with risk of infectious outcomes including opportunistic infections in the CORRONA registry

Objective: To examine the association of methotrexate (MTX) and tumour necrosis factor (TNF) antagonists with the risk of infectious outcomes including opportunistic infections in patients with rheumatoid arthritis (RA). Methods: Patients with RA enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) registry prescribed MTX, TNF antagonists or other disease-modifying antirheumatic drugs (DMARDs) were included. The primary outcomes were incident overall and opportunistic infections. Incident rate ratios were calculated using generalised estimating equation Poisson regression models adjusted for demographics, comorbidities and RA disease activity measures. Results: A total of 7971 patients with RA were followed. The adjusted rate of infections per 100 person-years was increased among users of MTX (30.9, 95% CI 29.2 to 32.7), TNF antagonists (40.1, 95% CI 37.0 to 43.4) and a combination of MTX and TNF antagonists (37.1, 95% CI 34.9 to 39.3) compared with users of other non-biological DMARDs (24.5, 95% CI 21.8 to 27.5). The adjusted incidence rate ratio (IRR) was increased in patients treated with MTX (IRR 1.30, 95% CI 1.12 to 1.50) and TNF antagonists (IRR 1.52, 95% CI 1.30 to 1.78) compared with those treated with other DMARDs. TNF antagonist use was associated with an increased risk of opportunistic infections (IRR 1.67, 95% CI 0.95 to 2.94). Prednisone use was associated with an increased risk of opportunistic infections (IRR 1.63, 95% CI 1.20 to 2.21) and an increased risk of overall infection at doses >10 mg daily (IRR 1.30, 95% CI 1.11 to 1.53). Conclusions: MTX, TNF antagonists and prednisone at doses >10 mg daily were associated with increased risks of overall infections. Low-dose prednisone and TNF antagonists (but not MTX) increased the risk of opportunistic infections.

Which subgroup of patients with rheumatoid arthritis benefits from switching to rituximab versus alternative anti-tumour necrosis factor (TNF) agents after previous failure of an anti-TNF agent?

Background: Patients with rheumatoid arthritis (RA) with an inadequate response to TNF antagonists (aTNFs) may switch to an alternative aTNF or start treatment from a different class of drugs, such as rituximab (RTX). It remains unclear in which clinical settings these therapeutic strategies offer most benefit. Objective: To analyse the effectiveness of RTX versus alternative aTNFs on RA disease activity in different subgroups of patients. Methods: A prospective cohort study of patients with RA who discontinued at least one aTNF and subsequently received either RTX or an alternative aTNF, nested within the Swiss RA registry (SCQM-RA) was carried out. The primary outcome, longitudinal improvement in 28-joint count Disease Activity Score (DAS28), was analysed using multivariate regression models for longitudinal data and adjusted for potential confounders. Results: Of the 318 patients with RA included; 155 received RTX and 163 received an alternative aTNF. The relative benefit of RTX varied with the type of prior aTNF failure: when the motive for switching was ineffectiveness to previous aTNFs, the longitudinal improvement in DAS28 was significantly better with RTX than with an alternative aTNF (p = 0.03; at 6 months, –1.34 (95% CI –1.54 to –1.15) vs –0.93 (95% CI –1.28 to –0.59), respectively). When the motive for switching was other causes, the longitudinal improvement in DAS28 was similar for RTX and alternative aTNFs (p = 0.40). These results were not significantly modified by the number of previous aTNF failures, the type of aTNF switches, or the presence of co-treatment with a disease-modifying antirheumatic drug. Conclusion: This observational study suggests that in patients with RA who have stopped a previous aTNF treatment because of ineffectiveness changing to RTX is more effective than switching to an alternative aTNF.

Effectiveness of adalimumab in treating patients with active psoriatic arthritis and predictors of good clinical responses for arthritis, skin and nail lesions

Objectives: To evaluate the effectiveness of adalimumab in patients with psoriatic arthritis (PsA) and identify predictors of good clinical response for joint and skin lesions. Methods: Patients received adalimumab 40 mg every other week in addition to standard therapy in this prospective, 12-week, open-label, uncontrolled study. Four definitions of good clinical response were used: >=50% improvement in American College of Rheumatology response criteria (ACR50), good response according to European League Against Rheumatism (EULAR) guidelines, a >=3-grade improvement in Physician Global Assessment of psoriasis (PGA) and a >=50% improvement in the Nail Psoriasis Severity Index (NAPSI). Response predictors were determined by logistic regression with backward elimination (selection level was 5%). Results: Of 442 patients, 94% completed 12 weeks of treatment. At week 12, 74%, 51% and 32% of the patients had achieved ACR20, 50 and 70, respectively; 87% and 61% experienced moderate and good responses according to EULAR criteria, respectively. The percentage of patients with PGA results of "clear/almost clear" increased from 34% (baseline) to 68%. The mean NAPSI score was reduced by 44%. No new safety signals were detected. A lower Health Assessment Questionnaire Disability Index (HAQ-DI) score, greater pain assessment, male sex and absence of systemic glucocorticoid therapy were strongly associated with achievement of ACR50 and good response according to EULAR criteria. In addition, greater C-reactive protein concentration and polyarthritis predicted ACR50, and non-involvement of large joints predicted a good response according to EULAR criteria. Conclusions: Adalimumab was effective in patients with PsA. Lower impairment of physical function, greater pain, male sex and no systemic treatment with glucocorticoids were factors that increased the chance of achieving a good clinical response.

Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry

Objective: To describe cases of lymphoma associated with anti-TNF therapy, identify risk factors, estimate the incidence and compare the risks for different anti-TNF agents. Methods: A national prospective registry was designed (Research Axed on Tolerance of bIOtherapies; RATIO) to collect all cases of lymphoma in French patients receiving anti-TNF therapy from 2004 to 2006, whatever the indication. A case–control analysis was conducted including two controls treated with anti-TNF per case and an incidence study of lymphoma with the French population was used as the reference. Results: 38 cases of lymphoma, 31 non-Hodgkin’s lymphoma (NHL) (26 B cell and five T cell), five Hodgkin’s lymphoma (HL) and two Hodgkin’s-like lymphoma were collected. Epstein–Barr virus was detected in both of two Hodgkin’s-like lymphoma, three of five HL and one NHL. Patients receiving adalimumab or infliximab had a higher risk than those treated with etanercept: standardised incidence ratio (SIR) 4.1 (2.3–7.1) and 3.6 (2.3–5.6) versus 0.9 (0.4–1.8). The exposure to adalimumab or infliximab versus etanercept was an independent risk factor for lymphoma in the case–control study: odds ratio 4.7 (1.3–17.7) and 4.1 (1.4–12.5), respectively. The sex and age-adjusted incidence rate of lymphoma was 42.1 per 100 000 patient-years. The SIR was 2.4 (95% CI 1.7 to 3.2). Conclusion: The two to threefold increased risk of lymphoma in patients receiving anti-TNF therapy is similar to that expected for such patients with severe inflammatory diseases. Some lymphomas associated with immunosuppression may occur, and the risk of lymphoma is higher with monoclonal-antibody therapy than with soluble-receptor therapy.

Clinical response, pharmacokinetics, development of human anti-chimaeric antibodies, and synovial tissue response to rituximab treatment in patients with rheumatoid arthritis

Objectives: To analyse whether persistence of synovial B lineage cells and lack of clinical response to rituximab treatment in patients with rheumatoid arthritis (RA) are associated with low rituximab serum levels and anti-rituximab antibody (ARA) formation. Methods: Fifty-eight patients with RA were treated with rituximab. The clinical response was determined 24 weeks after each treatment course using the Disease Activity Score evaluated in 28 joints (DAS28) and EULAR response criteria. Rituximab serum levels, ARAs and synovial B lineage cell numbers were determined before and after treatment. Results: Four weeks after treatment rituximab serum levels were highly variable. Low rituximab levels were associated with ARA formation (in five patients (8.6%)) and high baseline erythrocyte sedimentation rate. Interestingly, serum rituximab levels were not related to persistence of synovial B lineage cells or clinical response. Furthermore, response to treatment and re-treatment was similar in ARA-positive and ARA-negative patients. Conclusion: There is clear variability in serum levels after rituximab treatment, but rituximab levels are not lower in patients with persistence of synovial B lineage cells or lack of clinical response. The current treatment schedule suffices to induce and maintain a clinical response, even when ARAs are formed.

Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebo-controlled trial

Objectives: To determine the efficacy of CP-690,550 in improving pain, function and health status in patients with moderate to severe active rheumatoid arthritis (RA) and an inadequate response to methotrexate or a tumour necrosis factor inhibitor. Methods: Patients were randomised equally to placebo, CP-690,550 5, 15 or 30 mg twice daily for 6 weeks, with 6 weeks’ follow-up. The patient’s assessment of arthritis pain (pain), patient’s assessment of disease activity, Health Assessment Questionnaire-Disability Index (HAQ-DI) and Short Form-36 (SF-36) were recorded. Results: At week 6, significantly more patients in the CP-690,550 5, 15 and 30 mg twice-daily groups experienced a 50% improvement in pain compared with placebo (44%, 66%, 78% and 14%, respectively), clinically meaningful reductions in HAQ-DI (>=0.3 units) (57%, 75%, 76% and 36%, respectively) and clinically meaningful improvements in SF-36 domains and physical and mental components. Conclusions: CP-690,550 was efficacious in improving the pain, function and health status of patients with RA, from week 1 to week 6.

A diagnostic algorithm for persistence of very early inflammatory arthritis: the utility of power Doppler ultrasound when added to conventional assessment tools

Objectives: The aim of this study was to assess the value of power Doppler ultrasound (PDUS) in combination with routine management in a cohort of patients with very early inflammatory arthritis (IA). Methods: 50 patients with <=12 weeks of inflammatory symptoms with or without signs had clinical, laboratory and imaging assessments. Diagnosis was recorded at 12 months. Assuming a 15% pre-test probability of IA, post-test probabilities for various assessments were calculated and used to develop a diagnostic algorithm. Results: All patients positive for rheumatoid factor (RF) and/or cyclic citrullinated peptide (CCP) developed persistent IA, so the added value of PDUS was assessed in the seronegative (RF and CCP negative) group. The probability of IA in a seronegative patient was 6%. The addition of clinical and radiographic features raised the probability of IA to 30% and, with certain ultrasound features, this rose to 94%. Conclusions: In seronegative patients with early IA, combining PDUS with routine assessment can have a major impact on the certainty of diagnosis.

Women with rheumatoid arthritis negative for anti-cyclic citrullinated peptide and rheumatoid factor are more likely to improve during pregnancy, whereas in autoantibody-positive women autoantibody levels are not influenced by pregnancy

Objectives: To determine whether changes in levels of anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) are associated with the spontaneous improvement of rheumatoid arthritis (RA) during pregnancy and with the subsequent flare post partum. Methods: Disease activity scores from the Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) study of 118 patients were available for analysis. Before conception (if applicable), at each trimester and at 6, 12 and 26 weeks post partum, levels of the autoantibodies anti-CCP, IgM-RF, IgG-RF and IgA-RF were determined. Responses in disease activity were classified according to European League Against Rheumatism (EULAR) response criteria during pregnancy and post partum, and associated with the presence or absence of autoantibodies. Results: The median levels of anti-CCP and all subclasses of RF during pregnancy were stable, whereas post partum the levels of anti-CCP, IgM-RF and IgA-RF declined. A significantly higher percentage of women without autoantibodies (negative for anti-CCP and RF) improved compared with women positive for either or both autoantibodies (75% vs 39%, p = 0.01). The occurrence of a flare post partum was comparable between these groups. Conclusions: Improvement of disease activity of RA during pregnancy was not associated with changes in levels of autoantibodies during pregnancy, however, improvement may occur more frequently in the absence of anti-CCP and RF.

Cost effectiveness of two therapeutic regimens of infliximab in ankylosing spondylitis: economic evaluation within a randomised controlled trial

Objective: To determine the incremental cost-effectiveness ratios (ICERs) of two therapeutic regimens of infliximab for ankylosing spondylitis (AS). Methods: 230 patients with active AS who were participating in a randomised controlled trial comparing two infliximab infusion modalities—every 6 weeks (Q6) and on demand (DEM)—were included in an economic evaluation within the trial. Data were collected by phone every 3 months for 1 year. Direct and indirect costs were calculated from a payer perspective. Health-related quality of life was assessed with a general health rating scale. ICERs were calculated for one 20% improvement (ASAS20), for one partial remission and for one quality-adjusted life year (QALY) gained. Results: The Q6 regimen was significantly more efficacious than the DEM regimen but also more costly (22 388 vs 17 596; p<0.001), because it required significantly more infliximab infusions per patient (8.4 vs 6.2). The ICERs of the Q6 to DEM regimen were 15 841 for one ASAS20 response, 23 296 for one partial remission and 50 760 for one QALY gained. Conclusion: The administration of infliximab every 6 weeks is cost effective as compared with a DEM regimen; however, the ICER is close to the acceptability threshold of 50 000 for one QALY gained. Trial registration number: NCT 00439283.

Antifibroblast antibodies from systemic sclerosis patients bind to {alpha}-enolase and are associated with interstitial lung disease

Objective: To identify target antigens of antifibroblast antibodies (AFA) in systemic sclerosis (SSc) patients. Patients and Methods: In the first part, sera from 24 SSc patients (12 with pulmonary arterial hypertension (PAH) and 12 without) and 36 idiopathic PAH patients, tested in pooled sera for groups of three, were compared with a sera pool from 14 healthy controls (HC). Serum IgG reactivity was analysed by the use of a two-dimensional electrophoresis and immunoblotting technique with normal human fibroblasts antigens. In the second part, serum IgG reactivity for two groups: 158 SSc, 67 idiopathic PAH and 100 HC; and 35 SSc and 50 HC was tested against -enolase from Saccharomyces cerevisiae and recombinant human (rHu) -enolase, respectively, on ELISA. Results: In the first part, -enolase was identified as a main target antigen of AFA from SSc patients. In the second part, 37/158 (23%) SSc patients, 6/67 (9%) idiopathic PAH patients and 4/100 (4%) HC (p<0.001) had anti-S cerevisiae -enolase antibodies; 12/35 (34%) SSc patients and 3/50 (6%) HC had anti-rHu -enolase antibodies (p = 0.001). In SSc, the presence of anti-S cerevisiae -enolase antibodies was associated with interstitial lung disease (ILD), decreased total lung capacity (73.2% vs 89.7%; p<0.001) and diffusion capacity for carbon monoxide (47.4% vs 62.3%; p<0.001), and antitopoisomerase 1 antibodies (46% vs 21%; p = 0.005) but not anticentromere antibodies (11% vs 34%; p = 0.006). Results were similar with rHu -enolase testing. Conclusion: In SSc, AFA recognise -enolase and are associated with ILD and antitopoisomerase antibodies.

Increased expression of the endothelin system in arterial lesions from patients with giant-cell arteritis: association between elevated plasma endothelin levels and the development of ischaemic events

Objective: Approximately 15–20% of patients with giant-cell arteritis (GCA) develop ischaemic complications often preceded by transient ischaemia. The expression of the endothelin (ET) system in GCA lesions was investigated to assess its relationship with the development of ischaemic complications. Methods: Plasma ET-1 was quantified by immunoassay in 61 patients with biopsy-confirmed GCA and 16 healthy donors. ET-1, endothelin-converting enzyme (ECE-1) and endothelin receptor (ETAR and ETBR) messenger RNA were measured by real-time quantitative reverse transcriptase–PCR in temporal arteries from 35 of these patients and 19 control arteries. Proteins were measured by immunoassay and Western blot. Results: ET-1 concentration was increased at the protein level in temporal artery samples from GCA patients compared with controls (0.98 (SEM 0.32) vs 0.28 (SEM 0.098) fmol/mg, p = 0.028). ECE-1, ETAR and ETBR/actin ratios (Western blot) were also significantly higher in GCA patients. Intriguingly, mRNA expression of ET-1, ECE-1 and both receptors was significantly reduced in GCA lesions compared with control arteries. When investigating mechanisms underlying these results, platelet-derived growth factor and IL-1β, present in GCA lesions, were found to downregulate ET-1 mRNA in cultured human temporal artery-derived smooth muscle cells. Glucocorticoid treatment for 8 days did not result in significantly decreased endothelin tissue concentration (0.87 (SEM 0.2) vs 0.52 (SEM 0.08); p = 0.6). Plasma endothelin concentrations were higher in patients with ischaemic complications (1.049 (SEM 0.48) vs 1.205 (SEM 0.63) pg/ml, p = 0.032). Conclusions: The endothelin system is increased at the protein level in GCA lesions creating a microenvironment prone to the development of ischaemic complications. Recovery induced by glucocorticoids is delayed, indicating persistent exposure to endothelin during initial treatment.

Anti-inflammatory and cartilage-protecting effects of an intra-articularly injected anti-TNF{alpha} single-chain Fv antibody (ESBA105) designed for local therapeutic use

Objectives: (1) To show that a single-chain Fv antibody (scFv) against tumour necrosis factor (TNF) (ESBA105) has efficacy comparable to a full length anti-TNF IgG (infliximab); (2) to evaluate whether ESBA105 has all the properties required for the local treatment of arthritis; and (3) to investigate its discriminative tissue penetration properties. Methods: In vivo efficacy was measured in arthritis of the knee joint induced by the intra-articular injection of recombinant human TNF (rhTNF) in Lewis rats. Cartilage penetration of scFv (ESBA105) and full length IgG (infliximab) were studied in bovine cartilage specimens ex vivo. Tissue penetration, biodistribution and pharmacokinetics of ESBA105 were followed and compared after intra-articular and intravenous administration. Results: In cell culture, ESBA105 showed similar TNF inhibitory potency to infliximab. In vivo, ESBA105 inhibited rhTNF-induced synovial inflammation in rats with efficacy again comparable to infliximab. An 11-fold molar excess of ESBA105 over rhTNF resulted in 90% inhibition of knee joint swelling, inflammatory infiltrates and proteoglycan loss from cartilage. In ex vivo studies of bovine cartilage, ESBA105 penetrated well into the cartilage whereas infliximab remained on the surface. In vivo, rapid penetration into the synovial tissue, cartilage and surrounding tissues was observed following intra-articular injection of [125I]-ESBA105 into the knee joint of rabbits. Conclusions: ESBA105 potently inhibits inflammation and prevents cartilage damage triggered by TNF. In contrast to a full length IgG, ESBA105 also penetrates into cartilage and can be expected to reverse the TNF-induced catabolic state of articular cartilage in arthritides.

Mesenchymal stem cells in rheumatoid synovium: enumeration and functional assessment in relation to synovial inflammation level

Objective: Achieving joint regeneration in rheumatoid arthritis (RA) represents a future challenge. Autologous synovial mesenchymal stem cells (MSCs) could be therapeutically exploited. However, the inflammatory milieu in the RA synovium could adversely affect endogenous MSC function. To test this hypothesis, the frequency and multipotency of RA synovial MSCs was evaluated in relation to existing synovial inflammation. Methods: Synovial inflammation was measured using the arthroscopic visual analogue score (VAS) and further validated using immunohistochemistry and flow cytometry. Highly proliferative clonogenic in vivo MSCs were enumerated following fluorescence-activated cell sorting and expansion for 20 population doublings. MSC multipotency was quantified following standard in vitro culture expansion and trilineage differentiation assays. Real-time PCR, flow cytometry and ELISA were used to evaluate pro- and anti-chondrogenic molecules in standard polyclonal synovial MSCs. Results: The arthroscopic VAS significantly correlated with synovial macrophage infiltration. In RA, synovial MSC chondrogenesis was inhibited in direct relation to VAS (r = –0.777, p<0.05) and reduced compared with control osteoarthritis (OA)-MSCs (p<0.05). In vivo, MSCs resided in the synovial fibroblastic/stromal fraction (CD45–CD31–) and were reduced in frequency in relation to VAS (r = –0.695, p<0.05). In RA-MSCs, CD44 levels correlated negatively with inflammation and positively with chondrogenesis (r = –0.830 and r = 0.865, respectively). Cytokine production and Sox9 expression was similar in RA-MSCs and OA-MSCs. Conclusions: There is a negative relationship between synovial MSC chondrogenic and clonogenic capacities and the magnitude of synovitis in RA. Effective suppression of joint inflammation is therefore necessary for the development of autologous MSC treatments aimed at cartilage regeneration in RA.

Severe fibrotic changes and altered expression of angiogenic factors in maternal scleroderma: placental findings

Objective: Pregnant women with systemic sclerosis (SSc; scleroderma) have an increased risk of premature delivery and small full-term infants. During placental development, angiogenesis and vascular remodelling are essential for a successful pregnancy outcome. An analysis was made of the pathological changes and expression of angiogenic factors in SSc placentas. Methods: Placenta biopsies were obtained from three patients with SSc and four healthy uncomplicated pregnancies after delivery at 34–38 weeks of gestation. The sections were stained with Masson’s trichrome and phosphotungstic-acid-haematoxylin and immunostained for connective tissue growth factor (CTGF), -smooth muscle actin (-SMA), vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and receptors VEGFR-1 and VEGFR-2. Results: The pathological findings were signs of decidual vasculopathy, increased syncytiotrophoblast knotting, placental infarcts and villous hypoplasia. Severe and diffuse perivascular and stromal fibrosis of decidua and chorionic villi, and extensive deposition of fibrinoid material around decidual vessels and in intervillous spaces were observed. Strong CTGF expression in the vessel wall, decidual cells and fibroblasts and -SMA+ myofibroblasts were found. VEGF and VEGFR-2 expression was stronger in SSc than in healthy placentas, while VEGFR-1 expression was similar to controls. PlGF immunopositivity was weaker in SSc. Conclusion: In SSc placentas, severe fibrosis and abnormal vascular remodelling were detected. This may result in reduced blood flow leading to deep sufferance of maternal placenta and possible premature delivery.

Bcl-2 antagonist killer 1 (BAK1) polymorphisms influence the risk of developing autoimmune rheumatic diseases in women

Objective: Bcl-2 antagonist killer 1 (BAK1) is a Bcl-2 family proapoptotic member suggested as a candidate gene for autoimmune diseases. The influence of BAK1 polymorphisms on the risk of developing autoimmune rheumatic diseases (AIRDs) in women was investigated. Methods: A total of 719 Colombian women were included in the present study: 209 had systemic lupus erythematosus, 99 primary Sjögren syndrome, 159 rheumatoid arthritis and 252 were healthy matched controls. Tag single nucleotide polymorphisms (SNPs) and potentially functional variants were typed by TaqMan allele discrimination assays. HLA-DRB1 and HLA-DQB1 typing was performed by reverse dot-blot hybridisation and linkage disequilibrium (LD) with BAK1 SNPs was assessed. Results: SNPs rs513349 (odds ratio (OR) 0.57, 95% CI 0.46 to 0.72, p = <0.001) and rs5745582 (OR 1.61, 95% CI 1.26 to 2.04, p = <0.001) were associated with the AIRDs included in this study. There was a significant increase of the rs513349G-rs561276C-rs5745582A (GCA) haplotype in each patient cohort as compared to controls (OR 1.95, 95% CI 1.50 to 2.54, p = <0.001). These SNPs were not in LD with HLA-DRB1 or HLA-DQB1 genes. Conclusions: The results indicate that the BAK1 polymorphisms influence the risk of acquiring AIRDs in the population studied and are consistent with the paradigm that autoimmune diseases are likely to share common susceptibility variants.

IL1-receptor antagonist anakinra provides long-lasting efficacy in the treatment of refractory adult-onset Still's disease

Clinical evaluation of hsPR3-ANCA ELISA for detection of antineutrophil cytoplasmatic antibodies directed against proteinase 3

Are anti-cyclic citrullinated peptide autoantibodies seromarkers for rheumatoid vasculitis in a cohort of patients with systemic vasculitis?

Rituximab in the spondyloarthropathies: data of eight patients followed up in the French Autoimmunity and Rituximab (AIR) registry

The child, grown, becomes independent

No abstract.

Getting them even earlier: Identifying individuals before clinical presentation with rheumatoid arthritis

No abstract.

Each measure of patient-reported change provides useful information and is susceptible to bias: The need to combine methods to assess their relative validity

No abstract.

A patient's perspective on multidisciplinary treatment gain for fibromyalgia: An indicator for pre-post treatment effects?

Increasing attention is devoted to the patient's perspective in clinical research and practice. However, the relationship between the patient's view on treatment progress and standardized pre-post changes in health outcomes is not well understood. The objective of this study was to investigate whether the patient's perception of treatment gain converges with pre-post treatment effects of a multidisciplinary treatment as assessed by standardized self-report measures.During a tailored multidisciplinary treatment for fibromyalgia, validated self-report questionnaires were assessed at baseline and posttreatment on the outcome measures of pain, functional disability, fatigue, anxiety, and negative mood. In addition, the participants were asked to fill in a questionnaire at the end of the treatment assessing the patient's perception of improvement on core outcomes, as well as satisfaction and usefulness of the treatment.Moderate to relatively high correlations were found between the patient's perception of improvement and pre-post changes on the physical outcomes, in contrast to small or nonsignificant correlations for psychological outcomes. In addition, satisfaction and usefulness were significantly related to pre-post changes on physical outcomes, but no relationship was found with respect to psychological outcomes.Results suggest that the patient's perception of treatment gain and pre-post changes in outcomes during treatment assess different aspects of the patient's treatment progress, particularly with regard to psychological functioning. Future research on clinical improvements should consider the patient's perception of treatment gain as an independent and clinically relevant outcome, in addition to standardized trial data of pre-post assessments of health outcomes.

The importance of allocation concealment and patient blinding in osteoarthritis trials: A meta-epidemiologic study

To evaluate the association of adequate allocation concealment and patient blinding with estimates of treatment benefits in osteoarthritis trials.We performed a meta-epidemiologic study of 16 meta-analyses with 175 trials that compared therapeutic interventions with placebo or nonintervention control in patients with hip or knee osteoarthritis. We calculated effect sizes from the differences in means of pain intensity between groups at the end of followup divided by the pooled SD and compared effect sizes between trials with and trials without adequate methodology.Effect sizes tended to be less beneficial in 46 trials with adequate allocation concealment compared with 112 trials with inadequate or unclear concealment of allocation (difference -0.15; 95% confidence interval [95% CI] -0.31, 0.02). Selection bias associated with inadequate or unclear concealment of allocation was most pronounced in meta-analyses with large estimated treatment benefits (P for interaction < 0.001), meta-analyses with high between-trial heterogeneity (P = 0.009), and meta-analyses of complementary medicine (P = 0.019). Effect sizes tended to be less beneficial in 64 trials with adequate blinding of patients compared with 58 trials without (difference -0.15; 95% CI -0.39, 0.09), but differences were less consistent and disappeared after accounting for allocation concealment. Detection bias associated with a lack of adequate patient blinding was most pronounced for nonpharmacologic interventions (P for interaction < 0.001).Results of osteoarthritis trials may be affected by selection and detection bias. Adequate concealment of allocation and attempts to blind patients will minimize these biases.

Identification of undiagnosed inflammatory arthritis in a community health fair screen

To identify individuals with undiagnosed inflammatory arthritis (IA) and rheumatoid arthritis (RA) in a community health fair screen, and to establish in a health fair setting the diagnostic accuracy of combinations of the Connective Tissue Disease Screening Questionnaire (CSQ) and autoantibody testing for IA.Screening for IA/RA was performed at health fair sites using a combination of the CSQ, joint examination, rheumatoid factor, and anti-cyclic citrullinated peptide (anti-CCP) antibody testing. IA was defined as [ge]1 swollen joint suggestive of synovitis on joint examination by a trained clinician.Six hundred one subjects were screened; 51.0% participated because of joint symptoms (pain, stiffness, or swelling). Eighty-four subjects (14.0%) had [ge]1 swollen joint, designated as IA on joint examination. Of the 601 subjects screened, 9 (1.5%) had IA and met [ge]4 of 7 American College of Rheumatology criteria for RA but had no prior diagnosis of RA, and 15 (2.5%) had IA and RF and/or anti-CCP positivity, suggesting early RA. The diagnostic accuracy of combinations of the CSQ and autoantibody testing for the identification of IA yielded maximal sensitivity, specificity, and positive and negative predictive values of 95.3%, 99.2%, 71.4%, and 97.7%, respectively.Health fair screening may be an effective approach for the identification of individuals with undiagnosed IA/RA. A combination of the CSQ and autoantibody testing alone has clinically useful diagnostic accuracy for the detection of IA. Decisions regarding which methodology to use for future health fair IA/RA screening will depend on goals of screening and funding.

Understanding the lack of understanding: Invalidation from the perspective of the patient with fibromyalgia

Patients with fibromyalgia have difficulty with the invisibility and medically unexplained character of the syndrome. Disbelief, lack of acceptance, and stigmatization by their spouse, family, colleagues, the health care system, and society are key issues in their lives. Nevertheless, the components of this phenomenon that we term "invalidation" are not clear. The aim of our study was to identify the definition and structure of invalidation as perceived by patients with fibromyalgia.A hierarchical cluster analysis was applied to examine everyday invalidation experiences of patients with fibromyalgia. Ninety-four statements about invalidation that were derived from interviews and a card-sorting (Q-sort) technique provided the input for this cluster analysis.The hierarchical structure of invalidation showed a higher-order distinction between statements reflecting "discounting" and "understanding." Discounting was subdivided into the components "denying" and "patronizing" (consisting of "lecturing" and "overprotecting"). Understanding was subdivided into "supporting" and "acknowledging." These higher-order constructs were further subdivided into 15 lower-order clusters that reflected cognitive, affective, and behavioral aspects of invalidation.Invalidation as perceived by patients with fibromyalgia includes active negative social responses (denying, lecturing, and overprotecting) as well as a lack of positive social responses (supporting and acknowledging) with respect to the patient and the condition of the patient. This definition of invalidation provides a basis to quantify invalidation and to study its impact on symptom severity, quality of life, therapy adherence, therapy outcome, and other important aspects of fibromyalgia.

Modeling the need for hip and knee replacement surgery. Part 1. A two-stage cross-cohort approach

To explore inequalities in the need for hip/knee replacement surgery using a 2-stage cross-cohort approach.In the first stage, a small-area population-based survey, the Somerset and Avon Survey of Health, was used to provide a high-quality measure of need for hip/knee replacement using the New Zealand (NZ) score. Receiver operating characteristic curve analyses were used to validate a simplified NZ score, excluding information from clinical examination. In the second stage, a nationally representative population-based survey, the English Longitudinal Study of Ageing, was used to explore inequalities in need for hip/knee replacement using the simplified NZ score. Multilevel Poisson regression modeling was used to estimate rates of need for surgery. Exposures considered were age, sex, social class, ethnicity, obesity, Index of Multiple Deprivation 2004 deprivation quintiles, rurality, and ethnic mix of area.Rates of need for hip/knee replacement increase with age and are lower in men than in women (rate ratio [RR] 0.7, 95% confidence interval [95% CI] 0.6-0.9 for hips; RR 0.8, 95% CI 0.7-1.0 for knees). Those of lowest social class have greater need. Need was greatest for people living in more deprived areas. Individual ethnic group did not predict the need for surgery. For hip replacement, there was no rurality effect; for knee replacement, those in town and fringe areas had greater need. Obesity was a strong predictor of need for surgery (RR 2.3, 95% CI 1.9-2.8 for hips; RR 2.4, 95% CI 2.0-2.8 for knees).This study provides evidence of greater variations of inequalities in need for hip/knee replacement than previous studies. Further research should explore geographic variation and produce small-area estimates of need to inform local health planning. It is important to complement data on need with willingness to undergo surgery.

Modeling the need for hip and knee replacement surgery. Part 2. Incorporating census data to provide small-area predictions for need with uncertainty bounds

To develop methods to produce small-area estimates of need for hip and knee replacement surgery to inform local health service planning.Multilevel Poisson regression modeling was used to estimate rates of need for hip/knee replacement by age, sex, deprivation, rurality, and ethnic mix using a nationally representative population-based survey (the English Longitudinal Study of Ageing, n = 11,392 people age [ge]50 years). Estimates of need from the regression model were then combined with stratified census population counts to produce small-area predictions of need. Uncertainty in the predictions was obtained by taking a Bayesian simulation-based approach using WinBUGS software. This allows correlations in parameter estimates to be appropriately incorporated in the credible intervals for the small-area predictions.Small-area estimates of need for hip/knee replacement have been produced for wards and districts in England. Rates of need are adjusted for the sociodemographic characteristics of an area and include 95% credible intervals. Need for hip/knee replacement varies geographically, dependant on the sociodemographic characteristics of an area.For the first time, small-area estimates of need for hip/knee replacement surgery have been produced together with estimates of uncertainty to inform local health planning. The methodologic approach described here could be reproduced in other countries and for other disease indicators. Further research is required to combine small-area estimates of need with provision to determine whether there is equitable access to care.

Patient responsibility for medical decision making and risky treatment options

Studies have shown that increasing patient participation in decision making decreases utilization of risky procedures. It has been demonstrated that risk perception is increased under conditions that emphasize volition, or the act of choosing. The objective of this study was to examine whether emphasizing volition increases patients' risk perception and decreases their willingness to accept risk.Consecutive patients attending outpatient clinic appointments viewed a video in which a physician described the availability of a new medication associated with a rare risk of a serious side effect. Patients' willingness to accept treatment and worry about the risk of the serious side effect were measured under 2 different conditions: one that minimized patient involvement and the one that maximized patient involvement in the decision-making process.The willingness of the subject to take the proposed medication was lower (mean ± SD 4.2 ± 3.7 versus 5.3 ± 3.7; P < 0.001) and their worry about the risk of the adverse event was greater in the high compared with the low involvement condition (mean ± SD 6.1 ± 3.7 versus 5.5 ± 3.8; P < 0.001).Increasing patient responsibility in medical decision making may decrease the patient's willingness to accept risky treatment options.

Clinical appropriateness and not race predicted referral for joint arthroplasty

To understand the reasons behind racial disparities in the use of total joint arthroplasty (TJA), we sought to examine the predictors of time to referral to orthopedic surgery for consideration of joint replacement.In this prospective, longitudinal study of 676 primary care clinic patients with at least a moderately severe degree of hip or knee osteoarthritis (OA), we examined the effects of race, health beliefs (i.e., perceived benefits and risks) of TJA, and clinical appropriateness of TJA on referral to orthopedic surgery.The sample included 255 African Americans (38%) and 421 whites (62%); 523 patients had knee OA (78%) and 153 had hip OA (22%). Subjects were 60% male, with a mean ± SD age of 64 ± 9 years, a mean ± SD body mass index of 33.6 ± 8 kg/m2, and a mean ± SD summary Western Ontario and McMaster Universities Osteoarthritis Index score of 56 ± 14, suggesting moderately severe OA. At baseline, African Americans perceived fewer benefits and greater risk from TJA than whites. There were no significant racial group differences in the proportions of cases deemed clinically appropriate for TJA. After controlling for potential confounders, clinical appropriateness (hazard ratio [HR] 1.95, 95% confidence interval [95% CI] 1.15-3.32; P = 0.01) predicted referral to orthopedic surgery. Neither race (HR 1.30, 95% CI 0.94-2.05; P = 0.1) nor health beliefs (HR 1.0, P = 0.5) were associated with referral status.In this sample of primary care clinic patients, African Americans and whites were equally likely to be referred by their physicians to orthopedic surgery. Clinical appropriateness predicted future referral to orthopedic surgery, and not race or TJA-specific health beliefs.

The New York City Rheumatology Objective Structured Clinical Examination: Five-year data demonstrates its validity, usefulness as a unique rating tool, objectivity, and sensitivity to change

Traditional means of testing rheumatology fellows do not adequately assess some skills that are required to practice medicine well, such as humanistic qualities, communication skills, or professionalism. Institution of the New York City Rheumatology Objective Structured Clinical Examination (ROSCE) and our sequential 5 years of experience have provided us with a unique opportunity to assess its usefulness and objectivity as a rheumatology assessment tool.Prior to taking the examination, all of the fellows were rated by their program directors. Fellows from the participating institutions then underwent a multistation patient-interactive examination observed and rated by patient actors and faculty raters. Assessments were recorded by all of the participants using separate but overlapping sets of instruments testing the Accreditation Council of Graduate Medical Education (ACGME) core competencies of patient care, interpersonal and communication skills, professionalism, and overall medical knowledge.Although the program directors tended to rate their fellows more highly than the ROSCE raters, typically there was agreement between the program directors and the ROSCE faculty in distinguishing between the highest- and lowest- performing fellows. The ROSCE faculty and patient actor assessments of individual trainees were notable for a high degree of concordance, both quantitatively and qualitatively.The ROSCE provides a unique opportunity to obtain a patient-centered assessment of fellows' ACGME-mandated competencies that traditional knowledge-based examinations, such as the rheumatology in-service examination, cannot measure. The ability of the ROSCE to provide a well-rounded and objective assessment suggests that it should be considered an important component of the rheumatology training director's toolbox.

Ambulatory visit utilization in a national, population-based sample of adults with osteoarthritis

To estimate the proportion of adults with osteoarthritis (OA) seeing various medical providers and ascertain factors affecting the likelihood of a patient seeing an OA specialist.We used data from the Medical Expenditures Panel Survey, a stratified random sample of the noninstitutionalized civilian population. We classified adults as having symptomatic OA if their medical conditions included at least 1 occurrence of the International Classification of Diseases, Ninth Revision Clinical Modification, codes 715, 716, or 719, and if they reported joint pain, swelling, or stiffness during the previous 12 months. For the purpose of our analysis, we defined rheumatologists, orthopedists, and physical therapists as OA specialists. We first estimated the proportion of OA individuals seen by OA specialists and other health care providers in a 1-year period. We then used logistic regression to estimate the impact of demographic and clinical factors on the likelihood of an individual seeing an OA specialist.A total of 9,933 persons met the definition of OA, representing 22.5 million adults in the US. Of these persons, 92% see physicians during the year, 34% see at least 1 OA specialist, 25% see an orthopedist, 11% see a physical therapist, and 6% see a rheumatologist. Higher educational attainment, having more comorbidities, and residing in the northeastern US are significant positive predictors for a patient seeing an OA specialist. Significant negative predictors for seeing an OA specialist are being unmarried but previously married and having no health insurance.Most adults with OA do not visit OA specialists. Those without insurance and with lower levels of education are less likely to see these specialists.

Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: A systematic review and meta-analysis

To compare the efficacy of intraarticular hyaluronic acid with corticosteroids for knee osteoarthritis (OA).Our data sources were Medline, EMBASE, CINAHL, BIOSIS, and the Cochrane database, as well as hand- searched reviews, manuscripts, and supplements. For unpublished data we used author contacts. Randomized trials that reported effects of intraarticular hyaluronic acid versus corticosteroids on knee OA were selected based on inclusion criteria. Two reviewers extracted data independently. Using a random-effects model, we computed effect sizes for pain change from baseline at 2, 4, 8, 12, and 26 weeks. We also performed multivariate analyses accounting for within and between-study covariance. We performed sensitivity analyses for trials that reported intent-to-treat (ITT) analysis and blinding, and directly compared Hyalgan with methylprednisolone.The 7 eligible trials included 606 participants. Five reported ITT analyses. At week 2 the effect size was -0.39 (95% confidence interval [95% CI], -0.65, -0.12) favoring corticosteroids; at week 4 it was -0.01 (95% CI -0.23, 0.21) suggesting equal efficacy. At week 8 the effect size was 0.22 (95% CI -0.05, 0.49) favoring hyaluronic acid, and at week 12 it was 0.35 (95% CI 0.03, 0.66) favoring hyaluronic acid. At week 26 the effect size was 0.39 (95% CI 0.18, 0.59), favoring hyaluronic acid. The multivariate analyses and sensitivity analyses generated consistent results.From baseline to week 4, intraarticular corticosteroids appear to be relatively more effective for pain than intraarticular hyaluronic acid. By week 4, the 2 approaches have equal efficacy, but beyond week 8, hyaluronic acid has greater efficacy. Understanding this trend is useful to clinicians when treating knee OA.

Do mothers and fathers hold similar views about their child's arthritis?

Evaluations of the well-being of children with juvenile idiopathic arthritis (JIA) typically rely on parents as proxy respondents. An assumption of several studies appears to be that mothers' and fathers' ratings are interchangeable, as reports do not always specify which parent completed the assessments nor, in repeated measures, whether they were completed by the same parent. The aim of this study was to examine the level of agreement between mothers' and fathers' ratings of their child's quality of life (QOL) and to identify possible predictors of disagreement.Mothers and fathers (n = 82) of children with JIA completed ratings of their child's symptoms, QOL, and measures of their mood and beliefs about their child's illness and treatment. The number of active and limited joints and the physician's global assessment were also recorded.Intraclass correlation coefficients between mothers' and fathers' ratings of physical and psychosocial QOL were high (0.824 and 0.755, respectively). However, calculation of difference scores revealed that 70.6% and 65.9%, respectively, were classified as discordant. Where parents differed, the direction of difference was not systematic. Discordance in parents' mood states and in their illness and treatment beliefs explained a small amount of the variance in discordance in QOL.It should not be assumed that proxy ratings of a child's well-being can be generalized from one parent to the other. Studies that take repeated assessments should ensure that the same parent completes assessments at all time points. Other factors that may explain discordance between parents' ratings need to be explored.

Can patellar tape reduce the patellar malalignment and pain associated with patellofemoral osteoarthritis?

Patellar taping is a conservative treatment that may reduce patellar malalignment and pain in people with patellofemoral joint osteoarthritis (OA). This study aimed to compare patellar alignment in people with and without patellofemoral joint OA and to evaluate immediate effects of patellar taping on patellar alignment and pain in people with patellofemoral joint OA.Patellar malalignment was measured from magnetic resonance imaging (MRI; 15° knee flexion) in 28 individuals (14 with patellofemoral joint OA and 14 asymptomatic, age-matched controls). In the patellofemoral joint OA group, MRI data were collected in 2 randomly allocated conditions (tape and no tape). Patellar alignment indices were measured from deidentified axial scans by 1 examiner. Pain during squatting was recorded in the 2 conditions (tape and no tape).People with patellofemoral joint OA exhibited greater lateral displacement and bisect offset compared with controls (P < 0.001). Lateral patellar tilt angle did not differ between groups. In the patellofemoral joint OA group, patellar tape resulted in a significant lessening of lateral alignment, with reduced lateral displacement (P = 0.028) and increased lateral patellar tilt angle (P < 0.001). Mean pain during squatting decreased with patellar tape by 15 mm on a 100-mm scale (P = 0.045).Patellar tape may reduce malalignment and pain associated with patellofemoral joint OA.

Effects of high-intensity resistance training in patients with rheumatoid arthritis: A randomized controlled trial

To confirm, in a randomized controlled trial (RCT), the efficacy of high-intensity progressive resistance training (PRT) in restoring muscle mass and function in patients with rheumatoid arthritis (RA). Additionally, to investigate the role of the insulin-like growth factor (IGF) system in exercise-induced muscle hypertrophy in the context of RA.Twenty-eight patients with established, controlled RA were randomized to either 24 weeks of twice-weekly PRT (n = 13) or a range of movement home exercise control group (n = 15). Dual x-ray absorptiometry-assessed body composition (including lean body mass [LBM], appendicular lean mass [ALM], and fat mass); objective physical function; disease activity; and muscle IGFs were assessed at weeks 0 and 24.Analyses of variance revealed that PRT increased LBM and ALM (P < 0.01); reduced trunk fat mass by 2.5 kg (not significant); and improved training-specific strength by 119%, chair stands by 30%, knee extensor strength by 25%, arm curls by 23%, and walk time by 17% (for objective function tests, P values ranged from 0.027 to 0.001 versus controls). In contrast, body composition and physical function remained unchanged in control patients. Changes in LBM and regional lean mass were associated with changes in objective function (P values ranged from 0.126 to <0.0001). Coinciding with muscle hypertrophy, previously diminished muscle levels of IGF-1 and IGF binding protein 3 both increased following PRT (P < 0.05).In an RCT, 24 weeks of PRT proved safe and effective in restoring lean mass and function in patients with RA. Muscle hypertrophy coincided with significant elevations of attenuated muscle IGF levels, revealing a possible contributory mechanism for rheumatoid cachexia. PRT should feature in disease management.

A prospective approach to investigating the natural history of preclinical rheumatoid arthritis (RA) using first-degree relatives of probands with RA

To describe a large, multicenter prospective cohort study of first-degree relatives (FDRs) of probands with rheumatoid arthritis (RA), and outline the use of such a study in investigating the natural history of RA development.A total of 1,058 FDRs, none of whom met the American College of Rheumatology criteria for RA, were enrolled in a prospective study investigating genetic and environmental influences on the development of RA-related autoimmunity. Demographic, epidemiologic, genetic, autoantibody, and physical examination data from the initial study enrollment visit were described for these FDRs, and the relationship was examined between genetic factors, autoantibodies, inflammation, and joint disease.Fifty-five percent of the FDRs had [ge]1 copy of the shared epitope, 20% had [ge]1 copy of the PTPN22 polymorphism, and [sim]16% were positive for rheumatoid factor (RF; including isotypes) and/or anti-cyclic citrullinated peptide antibody. IgM-RF positivity is associated with [ge]1 tender joint on examination (odds ratio [OR] 2.50, 95% confidence interval [95% CI] 1.27-4.89; P < 0.01) and elevated C-reactive protein (CRP) levels (OR 5.31, 95% CI 1.45-19.52; P = 0.01).FDRs without RA demonstrate high prevalences of genetic risk factors and RA-related autoantibodies. Additionally, an RF association with tender joints and elevated CRP levels suggests that autoantibodies are a valid intermediate marker of RA-related autoimmunity in this cohort. This prospective FDR cohort will be a valuable resource for evaluating the relationship between genetic and epidemiologic factors and the development of RA-related autoimmunity.

Neurologic outcome of surgical and conservative treatment of rheumatoid cervical spine subluxation: A systematic review

Rheumatoid arthritis commonly involves the upper cervical spine and can cause significant neurologic morbidity and mortality. However, there is no consensus on the optimal timing for surgical intervention: whether surgery should be performed prophylactically or once neurologic deficits have become apparent.A systematic review of the literature was performed to analyze neurologic outcome (Ranawat) and survival time (Kaplan-Meier) after surgical or conservative treatment using the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) and GRADE (Grading of Recommendations, Assessment, Development and Evaluation system) criteria.Twenty-five observational studies were selected. No randomized controlled trials (RCTs) could be found. All of the studies had a high risk of bias. Twenty-three studies reported the neurologic outcome after surgery for 752 patients. Neurologic deterioration rarely occurred in Ranawat I and II patients. Ranawat III patients did not fully recover. The 10-year survival rates were 77%, 63%, 47%, and 30% for Ranawat I, II, IIIA, and IIIB, respectively. The Ranawat IIIB patients had a significantly worse outcome. Another 185 patients treated conservatively were described in 7 studies. Neurologic deterioration rarely occurred in Ranawat I patients, but was almost inevitable in Ranawat II, IIIA, and IIIB patients. The Kaplan-Meier analysis showed a 10-year overall survival rate of 40%.There are no RCTs that compared surgery with conservative treatment. In observational studies, surgical neurologic outcomes were better than conservative treatment in all patients with cervical spine involvement, and in asymptomatic patients with no neurologic impairment (Ranawat I) the outcomes were similar; however, the evidence is weak. Survival time of surgical and conservative treatment could not be compared.

"Should I tell my employer and coworkers I have arthritis?" A longitudinal examination of self-disclosure in the work place

To examine arthritis self-disclosure at work, factors associated with disclosure, and prospective relationships of self-disclosure and work place support with changes to work place interactions, work transitions, and work place stress.Using a structured questionnaire, participants with osteoarthritis or inflammatory arthritis were interviewed at 4 time points, 18 months apart. At time 1, all participants (n = 490; 381 women, 109 men) were employed. Of the entire sample, 71% were retained throughout the study. Respondents were recruited using community advertising and from rheumatology and rehabilitation clinics. Self-disclosure and perceived support from managers and coworkers was assessed, as well as demographic, illness, work-context, and psychological variables. Generalized estimating equations modeled associations of disclosure and support on changes at work (e.g., job disruptions, work place stress).At each time point, 70.6-76.6% of participants had self-disclosed arthritis to their manager and 85.2-88.1% had told a coworker. Intraindividual variability in disclosure was considerable. Factors associated with self-disclosure were often inconsistent over time, with the exception of variables assessing the need to self-disclose (e.g., activity limitations) and perceived coworker support. Self-disclosure was not associated with changes to work. However, coworker support was related to fewer job disruptions, help with work tasks, and being less likely to reduce hours. Perceived managerial support was associated with less work place stress.Greater awareness is needed about issues related to self-disclosing arthritis at work. This study emphasizes the importance of a supportive work place, especially supportive coworkers, in decisions to discuss arthritis at work and in changes to work that might enable people to remain employed.

Erratum

No abstract.

Successful treatment of reactive arthritis with a humanized anti-interleukin-6 receptor antibody, tocilizumab

No abstract.

Prevalence and clinical correlates of pruritus in patients with systemic sclerosis

There are no studies of pruritus prevalence or clinical correlates in systemic sclerosis (SSc). The objectives of this study were to document the proportion of SSc patients with pruritus on most days, to determine when in the course of the disease pruritus is most prevalent, and to identify clinical correlates.We performed a cross-sectional, multicenter study of 400 SSc patients from the Canadian Scleroderma Research Group Registry [ge]1 year after Registry enrollment. Patients indicated whether they experienced pruritus during the past month on most days and underwent clinical histories and medical examinations. Multiple logistic regression was used to assess the association between sociodemographic and clinical variables and pruritus.A total of 179 patients (45%) reported pruritus on most days, including 69% (11 of 16) among patients 1.0-1.9 years from onset of non-Raynaud's symptoms, 41% (38 of 93) for 2.0-4.9 years, 47% (44 of 94) for 5.0-9.9 years, 43% (60 of 140) for 10.0-19.9 years, and 46% (26 of 57) for [ge]20 years. In post hoc analysis, patients 1.0-1.9 years from disease onset were significantly more likely to report pruritus (P = 0.049). Patients with pruritus had significantly more skin involvement (P = 0.029), more gastrointestinal (GI) symptoms (P < 0.001), worse breathing problems (P = 0.001), worse Raynaud's symptoms (P = 0.002), and more severe finger ulcers (P = 0.009). Only the number of GI symptoms predicted pruritus in multiple logistic regression analysis (odds ratio 1.25, 95% confidence interval 1.13-1.37; P < 0.001).Pruritus is common in SSc and is independently associated with GI symptoms. Focused research on sources of pruritus and its management in SSc is needed.

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

No abstract.

Reviewers 2009

ARHP announcements

No abstract.

In this issue

No abstract.

Shaping our own future

Lawrence E. Shulman, MD, PhD, 1919-2009

No abstract.

The history of erosions in rheumatoid arthritis: Are erosions history?

No abstract.

The HLA-B27 peptidome: Building on the cornerstone

Excessive interleukin-1 signaling determines the development of Th1 and Th17 responses in chronic inflammation

No abstract.

Confirmation of an association between rs6822844 at the Il2-Il21 region and multiple autoimmune diseases: Evidence of a general susceptibility locus

Autoimmune diseases often have susceptibility genes in common, indicating similar molecular mechanisms. Increasing evidence suggests that rs6822844 at the IL2-IL21 region is strongly associated with multiple autoimmune diseases in individuals of European descent. This study was undertaken to attempt to replicate the association between rs6822844 and 6 different immune-mediated diseases in non-European populations, and to perform disease-specific and overall meta-analyses using data from previously published studies.We evaluated case-control associations between rs6822844 and celiac disease (CD) in subjects from Argentina; rheumatoid arthritis (RA), type 1 diabetes mellitus (DM), primary Sjögren's syndrome (SS), and systemic lupus erythematosus (SLE) in subjects from Colombia; and Behçet's disease (BD) in subjects from Turkey. Allele and gene distributions were compared between cases and controls. Meta-analyses were performed using data from the present study and previous studies.We detected significant associations of rs6822844 with SLE (P = 0.008), type 1 DM (P = 0.014), RA (P = 0.019), and primary SS (P = 0.033) but not with BD (P = 0.34) or CD (P = 0.98). We identified little evidence of population differentiation (FST = 0.01) within cases and controls from Argentina and Colombia, suggesting that association was not influenced by population substructure. Disease-specific meta-analysis indicated significant association for RA (Pmeta = 3.61 × 10-6), inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis) (Pmeta = 3.48 × 10-12), type 1 DM (Pmeta = 5.33 × 10-5), and CD (Pmeta = 5.30 × 10-3). Overall meta-analysis across all autoimmune diseases reinforced association with rs6822844 (23 data sets; Pmeta = 2.61 × 10-25, odds ratio 0.73 [95% confidence interval 0.69-0.78]).Our results indicate that there is an association between rs6822844 and multiple autoimmune diseases in non-European populations. Meta-analysis results strongly reinforce this robust association across multiple autoimmune diseases in both European-derived and non-European populations.

Periarticular bone structure in rheumatoid arthritis patients and healthy individuals assessed by high-resolution computed tomography

To define the nature of structural bone changes in patients with rheumatoid arthritis (RA) compared with those in healthy individuals by using the novel technique of high-resolution microfocal computed tomography (micro-CT).Fifty-eight RA patients and 30 healthy individuals underwent a micro-CT scan of the proximal wrist and metacarpophalangeal joints. Bone lesions such as cortical breaks, osteophytes, and surface changes were quantified on 2-dimensional (2-D) slices as well as by using 3-D reconstruction images, and exact localization of lesions was recorded.Micro-CT scans could detect bone lesions 1.9 mm in diameter were highly specific for RA. Cortical breaks were mostly found along the radial sites of the metacarpal heads. No significant difference in the presence of osteophytes between healthy individuals and RA patients was found. Cortical surface changes, presumably cortical thinning and fenestration, became evident from 3-D reconstructions and were more pronounced in RA patients.Micro-CT allows exact detection of morphologic changes of juxtaarticular bone in healthy individuals and RA patients. Even healthy individuals occasionally show bone changes, but the severity of these lesions, with the exception of osteophytes, is greater in RA patients. Thus, micro-CT allows accurate differentiation among physiologic bone changes in joints and among types of pathologic bone damage resulting from RA.

Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque model

An increased risk of tuberculosis has been documented in humans treated with tumor necrosis factor [alpha] (TNF[alpha])-neutralizing agents. In murine models, impaired signaling by TNF causes exacerbation of both acute and chronic infection associated with aberrant granuloma formation and maintenance. This study was undertaken to investigate immune modulation in the setting of TNF neutralization in primary and latent tuberculosis in a non-human primate model.Cynomolgus macaques 4 years of age or older were infected with Mycobacterium tuberculosis and subjected to clinical, microbiologic, immunologic, and radiographic examinations. Monkeys were classified as having active or latent disease 6-8 months after infection, based on clinical criteria. Monkeys used in acute infection studies were randomized to receive either adalimumab (prior to and during infection) or no treatment. Monkeys with latent infection that were randomized to receive TNF-neutralizing agent were given either an inhibitor of soluble TNF, recombinant methionyl human soluble TNF receptor I (p55-TNFRI), or adalimumab. Control monkeys with latent infection were given no treatment or saline. Data from previously studied monkeys with active or latent disease were also used for comparison.Administration of TNF-neutralizing agents prior to M tuberculosis infection resulted in fulminant and disseminated disease by 8 weeks after infection. Neutralization of TNF in latently infected cynomolgus macaques caused reactivation in a majority of animals as determined by gross pathologic examination and bacterial burden. A spectrum of dissemination was noted, including extrapulmonary disease. Surprisingly, monkeys that developed primary and reactivation tuberculosis after TNF neutralization had similar granuloma structure and composition to that of control monkeys with active disease. TNF neutralization was associated with increased levels of interleukin-12, decreased levels of CCL4, increased chemokine receptor expression, and reduced mycobacteria-induced interferon-[gamma] production in blood but not in the affected mediastinal lymph nodes. Finally, the first signs of reactivation often occurred in thoracic lymph nodes.These findings have important clinical implications for determining the mechanism of TNF neutralization-related tuberculosis.

The selective estrogen receptor [alpha] agonist Org 37663 induces estrogenic effects but lacks antirheumatic activity: A phase IIa trial investigating efficacy and safety of Org 37663 in postmenopausal female rheumatoid arthritis patients receiving stable background methotrexate or sulfasalazine

Multiple lines of evidence suggest that sex hormones may play a role in the pathogenesis or clinical expression of rheumatoid arthritis (RA). Studies on the effects of exogenous estrogens in RA patients have yielded contradictory results. We undertook this study to determine the effects of the selective estrogen receptor [alpha] (ER[alpha]) agonist Org 37663 in patients with RA, in terms of both its estrogenic effects and its ability to ameliorate disease activity.A 10-week, multicenter, randomized, double-blind, placebo-controlled, parallel group, dose-finding, proof-of-concept trial was initiated to obtain data on the efficacy and safety of Org 37663 in postmenopausal female patients with RA who were receiving background treatment with either methotrexate or sulfasalazine. Patients were randomized to receive placebo or Org 37663 at doses of 4 mg/day, 15 mg/day, or 50 mg/week. The primary efficacy variable was the Disease Activity Score in 28 joints (DAS28).Org 37663 induced a clear biologic, estrogenic response in several organ systems, including a dose-related increase in levels of sex hormone binding globulin. However, the DAS28 decreased similarly for all treatment groups including placebo, indicating lack of clinical efficacy of Org 37663 in this trial.The observed lack of clinical benefit in RA patients treated with an ER[alpha] agonist, in association with a clear biologic response to the study drug, provides evidence that a biologically relevant ER[alpha]-mediated estrogenic effect is not associated with a clinically relevant effect on RA symptoms and signs.

Methotrexate polyglutamate concentrations are not associated with disease control in rheumatoid arthritis patients receiving long-term methotrexate therapy

There are limited data suggesting that methotrexate polyglutamate (MTXGlu) concentrations can guide MTX dosing in patients with rheumatoid arthritis (RA). The aim of this study was to define a therapeutic range of red blood cell (RBC) MTXGlun concentrations (where n refers to the number of glutamate groups), including threshold values for efficacy and adverse effects in patients receiving long-term oral MTX treatment.A cross-sectional study of 192 patients receiving oral MTX was undertaken. Disease activity was assessed by the swollen and tender joint counts, the C-reactive protein level, and the Disease Activity Score in 28 joints (DAS28). High disease activity was defined as a DAS28 of >3.2. A standardized questionnaire regarding common MTX adverse effects was completed.The MTX dosage was significantly higher in patients in whom the swollen joint count and DAS28 were higher. The MTXGlu4, MTXGlu5, MTXGlu3-5, and MTXGlu1-5 concentrations were significantly higher in patients with high disease activity. After correction for age, the estimated glomerular filtration rate, and the MTX dosage, the association remained significant for MTXGlu5. RBC folate concentrations were significantly higher in the group with high disease activity. There was no association between any MTXGlun concentration and adverse effects.In contrast to other studies, the results of the present study did not show a relationship between the MTXGlun concentration and reduced disease activity in patients with RA who were receiving long-term MTX therapy. However, disease activity was influenced by the RBC folate level, which may be a more important factor than MTXGlun concentrations for disease control. In accordance with the findings of previous studies, we were unable to show a relationship between MTXGlun concentrations and adverse effects. Prospective studies will be important to determine whether there is a role for measuring MTXGlun concentrations in patients receiving long-term treatment with MTX.

Smoking increases rheumatoid arthritis susceptibility in individuals carrying the HLA-DRB1 shared epitope, regardless of rheumatoid factor or anti-cyclic citrullinated peptide antibody status

Smoking is associated with rheumatoid arthritis (RA) in individuals with the HLA-DRB1 shared epitope (SE). SE alleles have been shown to be predominantly associated with anti-cyclic citrullinated peptide (anti-CCP)-positive RA. These risk factors have not been identified for anti-CCP-negative RA. The aim of this study was to investigate whether SE-containing HLA-DRB1 alleles, smoking, or the combination of these factors contributes to the development of RA, depending on the presence or absence of serologic markers, in a Korean population.All of the patients with RA (n =1,482) and all of the control subjects (n = 1,119) were Korean. Four-digit HLA-DRB1 typing was performed by a conventional polymerase chain reaction-sequence-based typing method. Information about smoking history was obtained through a questionnaire. The patients with RA were tested for anti-CCP antibodies and rheumatoid factor (RF).The SE alleles had significant effects on anti-CCP antibody and RF formation. The DRB1*0901 allele was associated with the presence of anti-CCP antibodies (odds ratio [OR] 2.49) and RF (OR 2.09). SE alleles and smoking were associated with both anti-CCP-positive and anti-CCP-negative RA. The combination of smoking and double copies of the SE allele increased the risk of anti-CCP-positive RA 36.11-fold and increased the risk of anti-CCP-negative RA 12.29-fold, compared with the risk among nonsmokers not carrying SE alleles. Interactions between SE alleles and smoking were observed for both anti-CCP-positive and RF-positive RA, although the associations of RF-positive RA could be consequences of the underlying anti-CCP antibody status.We demonstrated that the combination of SE alleles and smoking is associated with RA susceptibility regardless of anti-CCP antibody or RF status, but that the combination shows stronger effects in anti-CCP-positive/RF-positive patients with RA than in anti-CCP-negative/RF-negative patients with RA. The SE-smoking interactions were present in anti-CCP-positive and RF-positive RA.

Could accelerated aging explain the excess mortality in patients with seropositive rheumatoid arthritis?

To determine whether the mortality pattern in patients with seropositive rheumatoid arthritis (RA) is consistent with the concept of accelerated aging, by comparing the observed mortality rates in patients with RA with the age-accelerated mortality rates from the general population.A population-based inception cohort of patients with seropositive RA (according to the American College of Rheumatology 1987 criteria) was assembled and followed up for vital status until July 1, 2008. The expected mortality rate was obtained by applying the death rates from the general population to the age, sex, and calendar year distribution of the RA population. The observed mortality was estimated using Kaplan-Meier methods. Acceleration factors for the expected mortality were estimated in accelerated failure time models.A total of 755 patients with seropositive RA (mean age 55.6 years, 69% women) were followed up for a mean of 12.5 years, during which 315 patients died. The expected median survival was age 82.4 years, whereas the median survival of the RA patients was age 76.7 years. Results of statistical modeling suggested that, in terms of mortality rates, patients with RA were effectively 2 years older than actual age at RA incidence, and thereafter the patients underwent 11.4 effective years of aging for each 10 years of calendar time.The overall observed mortality experience of patients with seropositive RA is consistent with the hypothesis of accelerated aging. The causes of accelerated aging in RA deserve further investigation.

Clinical Image: Massive bony erosions in the shoulder

No abstract.

Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis

To identify whether cytokines, cytokine-related factors, and chemokines are up-regulated prior to the development of rheumatoid arthritis (RA).A nested case-control study was performed in 86 individuals who had donated blood samples before experiencing any symptoms of disease (pre-patients) and 256 matched control subjects (1:3 ratio). In 69 of the pre-patients, blood samples were also obtained at the time of the diagnosis of RA. The plasma levels of 30 cytokines, related factors, and chemokines were measured using a multiplex system.The levels of several of the cytokines, cytokine receptors, and chemokines were significantly increased in individuals before disease onset compared with the levels in control subjects; i.e., those representing signs of general immune activation (interleukin-1[beta] [IL-1[beta]], IL-2, IL-6, IL-1 receptor antagonist, and tumor necrosis factor), activation of Th1 cells (interferon-[gamma], IL-12), Th2 cells (IL-4, eotaxin), Treg cells (IL-10), bone marrow-derived factors (IL-7, granulocyte-macrophage colony-stimulating factor, and granulocyte colony-stimulating factor), as well as chemokines (monocyte chemotactic protein 1 and macrophage inflammatory protein 1[alpha]). The levels were particularly increased in anti-cyclic citrullinated peptide antibody- and rheumatoid factor-positive individuals, and the concentration of most of these increased further after disease onset. The concentration of IL-17 in individuals before disease onset was significantly higher than that in patients after disease onset. Individuals in whom RA subsequently developed were discriminated from control subjects mainly by the presence of Th1 cells, Th2 cells, and Treg cell-related cytokines, while chemokines, stromal cell-derived cytokines, and angiogenic-related markers separated patients after the development of RA from individuals before the onset of RA.Individuals in whom RA later developed had significantly increased levels of several cytokines, cytokine-related factors, and chemokines representing the adaptive immune system (Th1, Th2, and Treg cell-related factors); after disease onset, the involvement and activation of the immune system was more general and widespread.

Association of the response to tumor necrosis factor antagonists with plasma type I interferon activity and interferon-[beta]/[alpha] ratios in rheumatoid arthritis patients: A post hoc analysis of a predominantly Hispanic cohort

Despite the substantial clinical efficacy of tumor necrosis factor [alpha] (TNF[alpha]) antagonist therapy in patients with rheumatoid arthritis (RA), some patients respond poorly to such agents. Since an interferon (IFN) signature is variably expressed among RA patients, we investigated whether plasma type I IFN activity might predict the response to TNF antagonist therapy.RA patients (n = 35), the majority of whom were Hispanic, from a single center were evaluated before and after initiation of TNF antagonist therapy. As controls, 12 RA patients from the same center who were not treated with a TNF antagonist were studied. Plasma type I IFN activity was measured using a reporter cell assay, and disease status was assessed using the Disease Activity Score in 28 joints (DAS28). Levels of interleukin-1 receptor antagonist (IL-1Ra) were determined in baseline plasma samples using a commercial enzyme-linked immunosorbent assay. The clinical response was classified according to the European League Against Rheumatism criteria for improvement in RA.Plasma type I IFN activity at baseline was significantly associated with clinical response (odds ratio 1.36 [95% confidence interval 1.05-1.76], P = 0.020), with high baseline IFN activity associated with a good response. Changes in DAS28 scores were greater among patients with a baseline plasma IFN[beta]/[alpha] ratio >0.8 (indicating elevated plasma IFN[beta] levels). Consistent with the capacity of IFN[beta] to induce IL-1Ra, elevated baseline IL-1Ra levels were associated with better therapeutic outcomes (odds ratio 1.82 [95% confidence interval 1.1-3.29], P = 0.027).The plasma type I IFN activity, the IFN[beta]/[alpha] ratio, and the IL-1Ra level were predictive of the therapeutic response in TNF antagonist-treated RA patients, indicating that these parameters might define clinically meaningful subgroups of RA patients with distinct responses to therapeutic agents.

Interleukin-27 inhibits human osteoclastogenesis by abrogating RANKL-mediated induction of nuclear factor of activated T cells c1 and suppressing proximal RANK signaling

Interleukin-27 (IL-27) has stimulatory and regulatory immune functions and is expressed in rheumatoid arthritis (RA) synovium. This study was undertaken to investigate the effects of IL-27 on human osteoclastogenesis, to determine whether IL-27 can stimulate or attenuate the osteoclast-mediated bone resorption that is a hallmark of RA.Osteoclasts were generated from blood-derived human CD14+ cells. The effects of IL-27 on osteoclast formation were evaluated by counting the number of tartrate-resistant acid phosphatase-positive multinucleated cells and measuring the expression of osteoclast-related genes. The induction of nuclear factor of activated T cells c1 (NFATc1) and the activation of signaling pathways downstream of RANK were measured by immunoblotting. The expression of key molecules implicated in osteoclastogenesis (NFATc1, RANK, costimulatory receptors, and immunoreceptor tyrosine-based activation motif-harboring adaptor proteins) was measured by real-time reverse transcription-polymerase chain reaction. Murine osteoclast precursors obtained from mouse bone marrow and synovial fluid macrophages derived from RA patients were also tested for their responsiveness to IL-27.IL-27 inhibited human osteoclastogenesis, suppressed the induction of NFATc1, down-regulated the expression of RANK and triggering receptor expressed on myeloid cells 2 (TREM-2), and inhibited RANKL-mediated activation of ERK, p38, and NF-[kappa]B in osteoclast precursors. Synovial fluid macrophages from RA patients were refractory to the effects of IL-27. In contrast to the findings in humans, IL-27 only moderately suppressed murine osteoclastogenesis, and this was likely attributable to low expression of the IL-27 receptor subunit WSX-1 on murine osteoclast precursors.IL-27 inhibits human osteoclastogenesis by a direct mechanism that suppresses the responses of osteoclast precursors to RANKL. These findings suggest that, in addition to its well-known antiinflammatory effects, IL-27 plays a homeostatic role in restraining bone erosion. This homeostatic function is compromised under conditions of chronic inflammation such as in RA synovitis.

Activation of AMP-activated protein kinase by adiponectin rescues salivary gland epithelial cells from spontaneous and interferon-[gamma]-induced apoptosis

Primary Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltrates associated with destruction of salivary gland epithelial cells (SGECs) induced mainly by apoptosis. Adiponectin is an immunoregulatory hormone. We have previously shown that SGECs from patients with primary SS as well as from controls differentially express adiponectin. SGECs derived from patients with primary SS constitutively produce and secrete adiponectin in higher quantities. The aim of this study was to investigate the effect of adiponectin on the proliferation and apoptosis of SGECs.Cultured, non-neoplastic SGECs were treated with recombinant human adiponectin, and the rate of cell proliferation was assessed. Spontaneous and interferon-[gamma] (IFN[gamma])-induced apoptosis was evaluated with a specific single-stranded DNA enzyme-linked immunosorbent assay. The AMP-activated protein kinase (AMPK) inhibitor Compound C was used to test the involvement of AMPK in adiponectin effects. Western blotting was applied to detect the phosphorylation levels of AMPK after adiponectin treatment.Adiponectin treatment resulted in a dose-dependent suppression of proliferation of SGECs from patients with primary SS and control donors. Adiponectin protected cells from spontaneous as well as from IFN[gamma]-induced apoptosis. Furthermore, the antiapoptotic effects of adiponectin were dependent upon AMPK phosphorylation at Thr172, since pretreatment of SGECs with Compound C abolished the adiponectin protective effect.Adiponectin exerted antiproliferative effects on SGECs without inducing apoptosis and protected SGECs from spontaneous as well as from IFN[gamma]-induced apoptosis through an AMPK-dependent pathway. Our observations suggest that adiponectin may protect SGECs in this specific inflammatory milieu, providing a potential pathway through which AMPK may regulate cell survival under energy stress conditions such as autoimmune inflammation.

Clinical Image: Primary actinomycosis of the hand

No abstract.

The HLA-B*2705 peptidome

The HLA-B27 allele is strongly associated with the group of inflammatory diseases known as the spondylarthritides (SpA). The aim of this study was to perform a large-scale, direct biochemical analysis of the HLA-B*2705 peptidome in order to identify candidates for mimicry between HLA-B27 peptides derived from cartilage proteins and arthritogenic bacterial sequences and to refine the consensus binding motif of this important allele.The peptides were recovered by recombinant expression of soluble HLA-B27 molecules secreted from cultured chondrocytic cells or HeLa cells. Analysis was based on capillary chromatography and tandem mass spectrometry in combination with stable isotope labeling with amino acids in cell culture or chemical labeling with iTRAQ to enhance the validity of the data.Over 1,268 B27 peptides were identified, with 569 of them at high certainty, thus enabling better refinement of the B27 motif. This enabled the prediction of both short peptides and long peptides whose middle residues likely bulge out of the binding groove. Moreover, we identified a number of human B27 peptide sequences derived from human cartilage proteins, some of which are similar to common bacterial sequences.The peptides we identified may provide the missing link between bacterial infections and the resulting SpA.

Tumor necrosis factor [alpha] blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cells

Patients with psoriasis and psoriatic arthritis respond well to tumor necrosis factor [alpha] (TNF[alpha]) blockers in general; however, there is now mounting evidence that a small cohort of patients with rheumatoid arthritis who receive TNF[alpha] blockers develop psoriasis. This study was undertaken to explore the mechanisms underlying TNF[alpha] blockade-induced exacerbation of skin inflammation in murine psoriasis-like skin disease.Skin inflammation was induced in BALB/c scid/scid mice after they received CD4+CD45RBhighCD25- (naive CD4) T cells from donor mice. These mice were treated with either anti-interleukin-12 (anti-IL-12)/23p40 antibody or murine TNFRII-Fc fusion protein and were examined for signs of disease, including histologic features, various cytokine levels in the serum, and cytokine or FoxP3 transcripts in the affected skin and draining lymph node (LN) cells. In a separate study, naive CD4+ T cells were differentiated into Th1 or Th17 lineages with anti-CD3/28 magnetic beads and appropriate cytokines in the presence or absence of TNF[alpha]. Cytokine gene expression from these differentiated cells was also determined.Neutralization of TNF[alpha] exacerbated skin inflammation and markedly enhanced the expression of the proinflammatory cytokines IL-1[beta], IL-6, IL-17, IL-21, and IL-22 but suppressed FoxP3 expression in the skin and reduced the number of FoxP3-positive Treg cells in the draining LNs. TNF[alpha] also demonstrated a divergent role during priming and reactivation of naive T cells.These results reveal a novel immunoregulatory role of TNF[alpha] on Th17 and Treg cells in some individuals, which may account for the exacerbation of skin inflammation in some patients who receive anti-TNF treatments.

Clinical Images: Burst fracture in "flowing wax" spine

No abstract.

Bim-Bcl-2 homology 3 mimetic therapy is effective at suppressing inflammatory arthritis through the activation of myeloid cell apoptosis

Rheumatoid arthritis (RA) is a destructive autoimmune disease characterized by an increased inflammation in the joint. Therapies that activate the apoptotic cascade may have potential for use in RA; however, few therapeutic agents fit this category. The purpose of this study was to examine the potential of Bim, an agent that mimics the action of Bcl-2 homology 3 (BH3) domain-only proteins that have shown success in preclinical studies of cancer, in the treatment of autoimmune disease.Synovial tissues from RA and osteoarthritis patients were analyzed for the expression of Bim and CD68 using immunohistochemistry. Macrophages from Bim-/- mice were examined for their response to lipopolysaccharide (LPS) using flow cytometry, real-time polymerase chain reaction analysis, enzyme-linked immunosorbent assay, and immunoblotting. Bim-/- mice were stimulated with thioglycollate or LPS and examined for macrophage activation and cytokine production. Experimental arthritis was induced using the K/BxN serum-transfer model. A mimetic peptide corresponding to the BH3 domain of Bim (TAT-BH3) was administered as a prophylactic agent and as a therapeutic agent. Edema of the ankles and histopathologic analysis of ankle tissue sections were used to determine the severity of arthritis, its cellular composition, and the degree of apoptosis.The expression of Bim was reduced in RA synovial tissue as compared with controls, particularly in macrophages. Bim-/- macrophages displayed elevated expression of markers of inflammation and secreted more interleukin-1[beta] following stimulation with LPS or thioglycollate. TAT-BH3 ameliorated arthritis development, reduced the number of myeloid cells in the joint, and enhanced apoptosis without inducing cytotoxicity.These data demonstrate that BH3 mimetic therapy may have significant potential for the treatment of RA.

Enhanced Th1 and Th17 responses and arthritis severity in mice with a deficiency of myeloid cell-specific interleukin-1 receptor antagonist

The balance between interleukin-1 (IL-1) and its specific inhibitor, the IL-1 receptor antagonist (IL-1Ra), plays a major role in the development of arthritis. The purpose of this study was to investigate the role of IL-1Ra produced specifically by myeloid cells in the control of collagen-induced arthritis (CIA) by using myeloid cell-specific IL-1Ra-deficient mice (IL-1Ra[Delta]M).IL-1Ra[Delta]M mice were generated by using the loxP/Cre recombinase system. CIA was induced in IL-1Ra[Delta]M mice and littermate control mice by a single immunization with bovine type II collagen (CII) in Freund's complete adjuvant. Arthritis severity was assessed by clinical and histologic scoring. Draining lymph node (DLN) cell responses were examined ex vivo, and ankle extracts were used in the quantification of cytokines and chemokines.Clinical and histopathologic evaluations revealed an early disease onset and a severe form of CIA in IL-1Ra[Delta]M mice. This was characterized by increased production of interferon-[gamma] (IFN[gamma]) and IL-17 by CII-stimulated DLN cells. We also observed that the CII-specific CD4+ T cell response shifted in vivo, from a dominant Th1 response early in the course of the arthritis to the presence of both Th1 and Th17 cytokines later in the disease course. Interestingly, IL-1Ra levels were higher in the arthritic joints of IL-1Ra[Delta]M mice as compared with the controls, indicating that nonmyeloid cells strongly contribute to the local production of IL-1Ra. However, this enhanced IL-1Ra production was not sufficient to limit joint inflammation and tissue damage.Our results suggest that myeloid cell-derived IL-1Ra plays a critical role in the control of the development and the severity of CIA by modulating Th1 and Th17 responses in lymphoid organs.

A longitudinal analysis of urinary biochemical markers and bone mineral density in STR/Ort mice as a model of spontaneous osteoarthritis

To investigate the longitudinal changes both in the urinary concentrations of biochemical markers and in bone mineral density (BMD) during disease progression in the STR/Ort mouse model of osteoarthritis (OA).Male STR/Ort mice were studied, with CBA mice used as nonarthritic controls. Radiographic evaluation and grading of the knee and measurements of urinary C-terminal crosslinking telopeptide of type II collagen (CTX-II), pyridinoline (Pyr), and deoxypyridinoline were performed between 8 weeks and 40 weeks of age. The BMD of the femoral shaft was measured from 20 weeks to 40 weeks of age and adjusted for body weight. Histologic evaluation and grading were performed at 40 weeks of age. STR/Ort mice were divided into 2 subgroups (STR OA and STR non-OA) based on histologic grading.No significant differences between STR/Ort and CBA mice were observed for any biochemical marker or BMD at any time point. Urinary CTX-II levels and BMD in the STR OA subgroup were higher than those in the STR non-OA subgroup before radiographic changes of OA were apparent. Higher urinary Pyr levels in the STR OA subgroup were observed at the advanced stage of OA.Urinary CTX-II could be a useful marker in the early diagnosis and predicting the progression of OA, and urinary Pyr may be a potential marker to assess the severity of OA at an advanced stage. An increase in BMD prior to the establishment of radiographic OA may be related to the induction of OA.

Apolipoprotein E-deficient mice are resistant to the development of collagen-induced arthritis

To determine whether elevated serum lipid levels resulting from feeding animals a high-fat diet can affect the inflammatory process in C57BL/6 (B6) wild-type (WT) and B6 ApoE-/- mouse models of collagen-induced arthritis (CIA).Male B6 WT or ApoE-/- mice were fed either a normal chow diet or a high-fat diet. CIA was induced in mice at 12 weeks of age using type II chicken collagen, Freund's complete adjuvant, and, on occasion, a lipopolysaccharide boost. Expression levels of autoantibodies and cytokines were measured using enzyme-linked immunosorbent assay and multiplex assay, respectively.Whereas B6 WT mice developed severe articular inflammation after collagen immunization, ApoE-/- mice developed no clinical or histologic evidence of disease regardless of whether they had been fed a high-fat diet or a normal chow diet. The fact that arthritis was not present in ApoE-/- mice did not result from inadequate production of serum IgG2a collagen antibodies, since levels observed in ApoE-/- mice were similar to those observed in arthritic B6 WT control mice. Critically, development of atherosclerosis in ApoE-/- mice was not affected by the CIA protocol.Our findings suggest that ApoE-/- mice are resistant to the development of CIA. Intriguingly, induction of host autoimmunity in the absence of articular inflammation had no effect on atherosclerosis progression, suggesting that articular inflammatory load may be a critical risk factor in vascular pathology.

Nonsteroidal antiinflammatory drugs and prostaglandin E2 modulate the synthesis of osteoprotegerin and RANKL in the cartilage of patients with severe knee osteoarthritis

Although the osteoprotegerin (OPG)/RANK/RANKL system is the main modulator of bone remodeling, it remains unclear whether it is regulated in cartilage during osteoarthritis (OA). The aim of this study was to examine whether nonsteroidal antiinflammatory drug (NSAID) treatment modulates the synthesis of OPG and RANKL in the cartilage of patients with OA, and to investigate whether prostaglandin E2 (PGE2) modifies this system in human OA chondrocytes in culture.A 3-month clinical trial was carried out in 20 patients with severe knee OA, all of whom were scheduled to undergo knee replacement surgery. Ten of these patients were treated with celecoxib, and the other 10 patients, who did not want to be treated, served as the control group. After surgery, cartilage was processed for molecular biology studies. We also used human OA chondrocytes to examine the effects of PGE2 on OPG/RANKL synthesis, examining which surface receptors were affected by PGE2.In patients with OA, celecoxib decreased RANKL synthesis in the cartilage, thereby increasing the OPG:RANKL ratio. In human OA chondrocytes in culture, PGE2 elicited a dose- and time-dependent increase in the synthesis of RANKL, the extent of which was greater than that of OPG. Confocal microscopy revealed that PGE2 induced RANKL transport to the cell membrane. Only EP2/EP4 agonists reproduced the effects of PGE2 on OPG and RANKL induction.Long-term NSAID treatment inhibited the resorptive signal synthesized by chondrocytes. In vitro, PGE2 regulated the expression and release of these key mediators of bone metabolism by articular chondrocytes. The role of OPG/RANK/RANKL in OA cartilage metabolism is still unknown, although the synthesis of these proteins would enable the cartilage to control the activity of subchondral bone cells.

Proliferative remodeling of the spatial organization of human superficial chondrocytes distant from focal early osteoarthritis

Human superficial chondrocytes show distinct spatial organizations, and they commonly aggregate near osteoarthritic (OA) fissures. The aim of this study was to determine whether remodeling or destruction of the spatial chondrocyte organization might occur at a distance from focal (early) lesions in patients with OA.Samples of intact cartilage (condyles, patellofemoral groove, and proximal tibia) lying distant from focal lesions of OA in grade 2 joints were compared with location-matched nondegenerative (grade 0-1) cartilage samples. Chondrocyte nuclei were stained with propidium iodide, examined by fluorescence microscopy, and the findings were recorded in a top-down view. Chondrocyte arrangements were tested for randomness or significant grouping via point pattern analyses (Clark and Evans Aggregation Index) and were correlated with the OA grade and the surface cell densities.In grade 2 cartilage samples, superficial chondrocytes were situated in horizontal patterns, such as strings, clusters, pairs, and singles, comparable to the patterns in nondegenerative cartilage. In intact cartilage samples from grade 2 joints, the spatial organization included a novel pattern, consisting of chondrocytes that were aligned in 2 parallel lines, building double strings. These double strings correlated significantly with an increased number of chondrocytes per group and an increased corresponding superficial zone cell density. They were observed in all grade 2 condyles and some grade 2 tibiae, but never in grade 0-1 cartilage.This study is the first to identify a distinct spatial reorganization of human superficial chondrocytes in response to distant early OA lesions, suggesting that proliferation had occurred distant from focal early OA lesions. This spatial reorganization may serve to recruit metabolically active units as an attempt to repair focal damage.

A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22

To identify novel genes involved in osteoarthritis (OA), by means of a genome-wide association study.We tested 500,510 single-nucleotide polymorphisms (SNPs) in 1,341 Dutch Caucasian OA cases and 3,496 Dutch Caucasian controls. SNPs associated with at least 2 OA phenotypes were analyzed in 14,938 OA cases and [sim]39,000 controls. Meta-analyses were performed using the program Comprehensive Meta-analysis, with P values <1 × 10-7 considered genome-wide significant.The C allele of rs3815148 on chromosome 7q22 (minor allele frequency 23%; intron 12 of the COG5 gene) was associated with a 1.14-fold increased risk (95% confidence interval 1.09-1.19) of knee and/or hand OA (P = 8 × 10-8) and also with a 30% increased risk of knee OA progression (95% confidence interval 1.03-1.64) (P = 0.03). This SNP is in almost complete linkage disequilibrium with rs3757713 (68 kb upstream of GPR22), which is associated with GPR22 expression levels in lymphoblast cell lines (P = 4 × 10-12). Immunohistochemistry experiments revealed that G protein-coupled receptor protein 22 (GPR22) was absent in normal mouse articular cartilage or synovium. However, GPR22-positive chondrocytes were found in the upper layers of the articular cartilage of mouse knee joints that were challenged with in vivo papain treatment or methylated bovine serum albumin treatment. GPR22-positive chondrocyte-like cells were also found in osteophytes in instability-induced OA.Our findings identify a novel common variant on chromosome 7q22 that influences susceptibility to prevalence and progression of OA. Since the GPR22 gene encodes a G protein-coupled receptor, this is potentially an interesting therapeutic target.

Association of 25-hydroxyvitamin D with prevalent osteoarthritis of the hip in elderly men: The osteoporotic fractures in men study

To examine the cross-sectional association of serum levels of 25-hydroxyvitamin D, or 25(OH)D, with prevalent radiographic hip osteoarthritis (OA) in elderly men.In a cohort of 1,104 elderly men from the Osteoporotic Fractures in Men Study, 25(OH)D serum levels were determined by mass spectrometry, followed by pelvic radiographs [sim]4.6 years later. Categories of vitamin D levels were defined as follows: deficiency as [le]15 ng/ml, insufficiency as 15.1-30 ng/ml, and sufficiency as >30 ng/ml. Radiographs were assessed for severity of hip OA using a summary grade of 0-4 for individual features of hip OA. Logistic regression was used to assess associations of serum 25(OH)D levels with prevalent radiographic hip OA; covariates included age, clinic site, season at the time of blood withdrawal, self-reported hip pain for >30 days, timed 6-meter walk, presence of at least 1 coexisting condition, and self-rated health status.Men with radiographic hip OA had a slower 6-meter walking time (P < 0.0001), reported more hip pain (P = 0.0001), had a lower vitamin D level (P = 0.0002), and had a higher prevalence of vitamin D insufficiency (P = 0.002) and vitamin D deficiency (P = 0.012) compared with controls. Higher 25(OH)D levels were associated with a lower prevalence of radiographic hip OA (odds ratio [OR] 1.39 per 1 SD decrease in 25[OH]D, 95% confidence interval [95% CI] 1.11-1.74) after adjusting for age, season, and clinic site. Men with vitamin D insufficiency had an increased likelihood of prevalent radiographic hip OA (OR 2.19, 95% CI 1.21-3.97) compared with men with sufficient levels of 25(OH)D, and in men with vitamin D deficiency, there was a tendency toward an increased likelihood of radiographic hip OA (OR 1.99, 95% CI 0.83-4.74).Men with vitamin D deficiencies are twice as likely to have prevalent radiographic hip OA, and therefore vitamin D therapy to augment skeletal health in the elderly is warranted.

Effect of interleukin-32[gamma] on differentiation of osteoclasts from CD14+ monocytes

Interleukin-32 (IL-32) induces various inflammatory molecules in human monocytes and differentiation of monocytes into macrophage-like cells. This study was undertaken to evaluate the effects of IL-32[gamma], the most biologically active isoform, on the differentiation and activation of osteoclasts.CD14+ monocytes were obtained from healthy volunteers, and samples of synovial tissue and synovial fluid were obtained from patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA). The concentration and expression levels of IL-32[gamma] in RA and OA samples were evaluated by enzyme-linked immunosorbent assay and immunoblotting, respectively. To examine the osteoclastogenic effects and functional activities, isolated monocytes were treated with either IL-32[gamma] or IL-17 in the presence or absence of soluble RANKL (sRANKL) on a culture system and on Osteologic disks. The expression of RANKL and osteoprotegerin (OPG) messenger RNA (mRNA) in RA fibroblast-like synoviocytes (FLS) was measured using reverse transcription-polymerase chain reaction (PCR) and real-time PCR.The concentration and expression levels of IL-32[gamma] were higher in the RA samples than in the OA samples. Upon costimulation with sRANKL, the osteoclast count and resorbed area increased more significantly in the IL-32[gamma]-stimulated cultures than in those stimulated with IL-17. In the IL-32[gamma]-treated group without sRANKL stimulation, osteoclasts were differentiated, but the cells displayed low resorption activity. In RA FLS, RANKL mRNA expression increased in the presence of both IL-32[gamma] and IL-17. However, transcription of OPG decreased following IL-32[gamma] stimulation, resulting in a significant increase in the RANKL:OPG ratio.Our results suggest that IL-32[gamma] is a potent mediator of active osteoclast generation in the presence of sRANKL. Moreover, this novel cytokine creates more favorable conditions for osteoclastogenesis in the RA joint by increasing the RANKL:OPG ratio in FLS.

Amelioration of collagen-induced arthritis and immune-associated bone loss through signaling via estrogen receptor [alpha], and not estrogen receptor [beta] or G protein-coupled receptor 30

The effects of estrogen may be exerted via the nuclear estrogen receptors (ERs) ER[alpha] or ER[beta] or via the recently proposed transmembrane estrogen receptor G protein-coupled receptor 30 (GPR-30). The purpose of this study was to elucidate the ER specificity for the ameliorating effects of estrogen on arthritis and bone loss in a model of postmenopausal rheumatoid arthritis (RA).Female DBA/1 mice underwent ovariectomy or sham operation, and type II collagen-induced arthritis was induced. Mice were treated subcutaneously 5 days/week with the specific agonists propylpyrazoletriol (PPT; for ER[alpha]), diarylpropionitrile (DPN; for ER[beta]), G1 (for GPR-30), or with a physiologic dose of estradiol. Clinical arthritis scores were determined continuously. At termination of the study, bone mineral density (BMD) was analyzed, paws were collected for histologic assessment, serum was analyzed for cytokines and markers of bone and cartilage turnover, and bone marrow was subjected to fluorescence-activated cell sorting.Treatment with PPT as well as estradiol dramatically decreased the frequency and severity of arthritis. Furthermore, estradiol and PPT treatment resulted in preservation of bone and cartilage, as demonstrated by increased BMD and decreased serum levels of bone resorption markers and cartilage degradation markers, whereas no effect was seen after DPN or G1 treatment.In a well-established model of postmenopausal RA, ER[alpha], but not ER[beta] or GPR-30 signaling, was shown to ameliorate the disease and the associated development of osteoporosis. Since long-term treatment with estrogen has been associated with significant side effects, increased knowledge about the mechanisms behind the beneficial effects of estrogen is useful in the search for novel treatments of postmenopausal RA.

Adenosine A1 receptors regulate bone resorption in mice: Adenosine A1 receptor blockade or deletion increases bone density and prevents ovariectomy-induced bone loss in adenosine A1 receptor-knockout mice

Accelerated osteoclastic bone resorption plays a central role in the pathogenesis of osteoporosis and other bone diseases. Because identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and developing new treatments, we studied the effect of adenosine A1 receptor blockade or deletion on bone density.The bone mineral density (BMD) in adenosine A1 receptor-knockout (A1R-knockout) mice was analyzed by dual x-ray absorptiometry (DXA) scanning, and the trabecular and cortical bone volume was determined by microfocal computed tomography (micro-CT). The mice were ovariectomized or sham-operated, and 5 weeks after surgery, when osteopenia had developed, several parameters were analyzed by DXA scanning and micro-CT. A histologic examination of bones obtained from A1R-knockout and wild-type mice was carried out. Visualization of osteoblast function (bone formation) after tetracycline double-labeling was performed by fluorescence microscopy.Micro-CT analysis of bones from A1R-knockout mice showed significantly increased bone volume. Electron microscopy of bones from A1R-knockout mice showed the absence of ruffled borders of osteoclasts and osteoclast bone resorption. Immunohistologic analysis demonstrated that although osteoclasts were present in the A1R-knockout mice, they were smaller and often not associated with bone. No morphologic changes in osteoblasts were observed, and bone-labeling studies revealed no change in the bone formation rates in A1R-knockout mice.These results suggest that the adenosine A1 receptor may be a useful target in treating diseases characterized by excessive bone turnover, such as osteoporosis and prosthetic joint loosening.

Tocilizumab in systemic lupus erythematosus: Data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study

To assess the safety of interleukin-6 receptor inhibition and to collect preliminary data on the clinical and immunologic efficacy of tocilizumab in patients with systemic lupus erythematosus (SLE).In an open-label phase I dosage-escalation study, 16 patients with mild-to-moderate disease activity were assigned to receive 1 of 3 doses of tocilizumab given intravenously every other week for 12 weeks (total of 7 infusions): 2 mg/kg in 4 patients, 4 mg/kg in 6 patients, or 8 mg/kg in 6 patients. Patients were then monitored for an additional 8 weeks.The infusions were well tolerated. Tocilizumab treatment led to dosage-related decreases in the absolute neutrophil count, with a median decrease of 38% in the 4 mg/kg dosage group and 56% in the 8 mg/kg dosage group. Neutrophil counts returned to normal after cessation of treatment. One patient was withdrawn from the study because of neutropenia. Infections occurred in 11 patients; none was associated with neutropenia. Disease activity showed significant improvement, with a decrease of [ge]4 points in the modified Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index score in 8 of the 15 evaluable patients. Arthritis improved in all 7 patients who had arthritis at baseline and resolved in 4 of them. Levels of anti-double-stranded DNA antibodies decreased by a median of 47% in patients in the 4 mg/kg and 8 mg/kg dosage groups, with a 7.8% decrease in their IgG levels. These changes, together with a significant decrease in the frequency of circulating plasma cells, suggest a specific effect of tocilizumab on autoantibody-producing cells.Although neutropenia may limit the maximum dosage of tocilizumab in patients with SLE, the observed clinical and serologic responses are promising and warrant further studies to establish the optimal dosing regimen and efficacy.

Genetic variation at the IRF7/PHRF1 locus is associated with autoantibody profile and serum interferon-[alpha] activity in lupus patients

Interferon-[alpha] (IFN[alpha]) is a heritable risk factor for systemic lupus erythematosus (SLE). Genetic variation near IRF7 is implicated in SLE susceptibility. SLE-associated autoantibodies can stimulate IFN[alpha] production through the Toll-like receptor/IRF7 pathway. This study was undertaken to determine whether variants of IRF7 act as risk factors for SLE by increasing IFN[alpha] production and whether autoantibodies are important to this phenomenon.We studied 492 patients with SLE (236 African American, 162 European American, and 94 Hispanic American subjects). Serum levels of IFN[alpha] were measured using a reporter cell assay, and single-nucleotide polymorphisms (SNPs) in the IRF7/PHRF1 locus were genotyped.In a joint analysis of European American and Hispanic American subjects, the rs702966 C allele was associated with the presence of anti-double-stranded DNA (anti-dsDNA) antibodies (odds ratio [OR] 1.83, P = 0.0069). The rs702966 CC genotype was only associated with higher serum levels of IFN[alpha] in European American and Hispanic American patients with anti-dsDNA antibodies (joint analysis P = 4.1 × 10-5 in anti-dsDNA-positive patients and P = 0.99 in anti-dsDNA-negative patients). In African American subjects, anti-Sm antibodies were associated with the rs4963128 SNP near IRF7 (OR 1.95, P = 0.0017). The rs4963128 CT and TT genotypes were associated with higher serum levels of IFN[alpha] only in African American patients with anti-Sm antibodies (P = 0.0012). In African American patients lacking anti-Sm antibodies, an effect of anti-dsDNA-rs702966 C allele interaction on serum levels of IFN[alpha] was observed, similar to the other patient groups (overall joint analysis P = 1.0 × 10-6). In European American and Hispanic American patients, the IRF5 SLE risk haplotype showed an additive effect with the rs702966 C allele on IFN[alpha] level in anti-dsDNA-positive patients.Our findings indicate that IRF7/PHRF1 variants in combination with SLE-associated autoantibodies result in higher serum levels of IFN[alpha], providing a biologic relevance for this locus at the protein level in human SLE in vivo.

Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus

Genetic variants of the interferon (IFN) regulatory factor 5 gene (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). The contribution of these variants to IRF-5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFNs. The aim of this study was to determine the association between increased IRF-5 expression and the IRF5 risk haplotype in SLE patients.IRF-5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real-time polymerase chain reaction, minigene assay, and flow cytometry. Single-nucleotide polymorphisms rs2004640, rs10954213, and rs10488631 and the CGGGG insertion/deletion were genotyped in these patients. Genotypes of these polymorphisms defined both a common risk haplotype and a common protective haplotype.IRF-5 expression and alternative splicing were significantly up-regulated in SLE patients compared with healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 displayed the only significant independent association that correlated with increased transcription from the noncoding first exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG insertion/deletion, along with type I IFNs, in regulating IRF5 expression.This study provides the first formal proof that IRF-5 expression and alternative splicing are significantly up-regulated in primary blood cells of patients with SLE. Furthermore, the risk haplotype is associated with enhanced IRF-5 transcript and protein expression in patients with SLE.

The association of a nonsynonymous single-nucleotide polymorphism in TNFAIP3 with systemic lupus erythematosus and rheumatoid arthritis in the Japanese population

Genome-wide association (GWA) studies in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Caucasian populations have independently identified risk variants in and near the tumor necrosis factor [alpha] (TNF[alpha])-induced protein 3 gene (TNFAIP3), which is crucial for the regulation of TNF-mediated signaling and Toll-like receptor signaling. The aim of this study was to assess the role of TNFAIP3 in the development of SLE and RA in Japanese subjects.We selected 2 single-nucleotide polymorphisms (SNPs) from previous GWA studies. Rs2230926 is a nonsynonymous SNP in TNFAIP3 and is associated with SLE, while rs10499194 is an intergenic SNP associated with RA. We then performed 2 independent sets of SLE case-control comparisons (717 patients and 1,362 control subjects) and 3 sets of RA case-control comparisons (3,446 patients and 2,344 control subjects) using Japanese subjects. We genotyped SNPs using TaqMan assays.We observed a significant association between rs2230926 and an increased risk of SLE and RA in the Japanese population (for SLE, odds ratio [OR] 1.92, 95% confidence interval [95% CI] 1.53-2.41, P = 1.9 × 10-8; for RA, OR 1.35, 95% CI 1.18-1.56, P = 2.6 × 10-5). The intergenic SNP rs10499194 was also associated with SLE and RA, while the risk allele for RA in Caucasians was protective against the diseases in our population.We demonstrated a significant association between the nonsynonymous variant in TNFAIP3 and the risk for SLE and RA in the Japanese population. TNFAIP3, similar to STAT4 and IRF5, may be a common genetic risk factor for SLE and RA that is shared between the Caucasian and Japanese populations.

A four-gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosis

Improved outcome measures in systemic sclerosis (SSc) are critical to finding active therapeutics for this disease. The modified Rodnan skin thickness score (MRSS) is the current standard for evaluating skin disease in SSc, but it is not commonly used in the clinical setting, in part because it requires specialized training to perform accurately and consistently. The purpose of this study was to investigate whether skin gene expression might serve as a more objective surrogate outcome measure to supplement skin score evaluations.Skin RNAs from a group of patients with diffuse cutaneous SSc were studied for expression levels of genes known to be regulated by transforming growth factor [beta] (TGF[beta]) and interferon (IFN). These levels were correlated with the MRSS, using multiple regression analyses to obtain best-fit models.Skin expression of the TGF[beta]-regulated genes cartilage oligomeric matrix protein (COMP) and thrombospondin 1 (TSP-1) correlated moderately well with the MRSS, but the addition of other TGF[beta]-regulated genes failed to significantly improve best-fit models. IFN-regulated genes were also found to correlate with the MRSS, and the addition of interferon-inducible 44 (IFI44) and sialoadhesin (Siglec-1) to COMP and TSP-1 in multiple regression analyses significantly improved best-fit models, achieving an R2 value of 0.89. These results were validated using an independent group of skin biopsy samples. Longitudinal scores using this 4-gene biomarker indicated that it detects change over time that corresponds to changes in the MRSS.We describe a 4-gene predictor of the MRSS and validate its performance. This objective measure of skin disease could provide a strong surrogate outcome measure for patient care and for clinical trials.

Systemic sclerosis and lupus: Points in an interferon-mediated continuum

To investigate peripheral blood (PB) cell transcript profiles of systemic sclerosis (SSc) and its subtypes in direct comparison with systemic lupus erythematosus (SLE).We investigated PB cell samples from 74 SSc patients, 21 healthy controls, and 17 SLE patients using Illumina Human Ref-8 BeadChips and quantitative polymerase chain reaction confirmation. None of the study participants were receiving immunosuppressive agents other than low-dose steroids and hydroxychloroquine. In addition to conventional statistical and modular analysis, a composite score for the interferon (IFN)-inducible genes was calculated. Within the group of patients with SSc, the correlation of the IFN score with the serologic and clinical subtypes was investigated, as were single-nucleotide polymorphisms in a selected number of IFN pathway genes.Many of the most prominently overexpressed genes in SSc and SLE were IFN-inducible genes. Forty-three of 47 overexpressed IFN-inducible genes in SSc (91%) were similarly altered in SLE. The IFN score was highest in the SLE patients, followed by the SSc patients, and then the controls. The difference in IFN score among all 3 groups was statistically significant (P < 0.001 for all 3 comparisons). SSc and SLE PB cell samples showed striking parallels to our previously reported SSc skin transcripts in regard to the IFN-inducible gene expression pattern. In SSc, the presence of antitopoisomerase and anti-U1 RNP antibodies and lymphopenia correlated with the higher IFN scores (P = 0.005, P = 0.001, and P = 0.004, respectively); a missense mutation in IFNAR2 was significantly associated with the IFN score.SLE and SSc fit within the same spectrum of IFN-mediated diseases. A subset of SSc patients shows a "lupus-like" high IFN-inducible gene expression pattern that correlates with the presence of antitopoisomerase and anti-U1 RNP antibodies.

Mortality outcomes in pediatric rheumatology in the US

To describe mortality rates, causes of death, and potential mortality risk factors in pediatric rheumatic diseases in the US.We used the Indianapolis Pediatric Rheumatology Disease Registry, which includes 49,023 patients from 62 centers who were newly diagnosed between 1992 and 2001. Identifiers were matched with the Social Security Death Index censored for March 2005. Deaths were confirmed by death certificates, referring physicians, and medical records. Causes of death were derived by chart review or from the death certificate. Standardized mortality ratios (SMRs) and 95% confidence intervals (95% CIs) were determined.After excluding patients with malignancy, 110 deaths among 48,885 patients (0.23%) were confirmed. Patients had been followed up for a mean ± SD of 7.9 ± 2.7 years. The SMR of the entire cohort was significantly decreased (0.65 [95% CI 0.53-0.78]), with differences in patients followed up for [ge]9 years. The SMR was significantly greater for systemic lupus erythematosus (3.06 [95% CI 1.78-4.90]) and dermatomyositis (2.64 [95% CI 0.86-6.17]) but not for systemic juvenile rheumatoid arthritis (1.8 [95% CI 0.66-3.92]). The SMR was significantly decreased in pain syndromes (0.41 [95% CI 0.21-0.72]). Causes of death were related to the rheumatic diagnosis (including complications) in 39 patients (35%), treatment complications in 11 (10%), non-natural causes in 25 (23%), background disease in 23 (21%), and were unknown in 12 patients (11%). Rheumatic diagnoses, age at diagnosis, sex, and early use of systemic steroids and methotrexate were significantly associated with the risk of death.Our findings indicate that the overall mortality rate for pediatric rheumatic diseases was not increased. Even for the diseases and conditions associated with increased mortality, mortality rates were significantly lower than those reported in previous studies.

Age at time of corticosteroid administration is a risk factor for osteonecrosis in pediatric patients with systemic lupus erythematosus: A prospective magnetic resonance imaging study

To clarify whether age at the time of the initial administration of corticosteroids is a risk factor for corticosteroid-associated osteonecrosis in children with systemic lupus erythematosus (SLE), using magnetic resonance imaging (MRI).From 1986 to 2007, MRI was used to prospectively study 676 joints, including 72 joints (36 hips and 36 knees) in 18 pediatric patients with SLE (20 years old), beginning just after corticosteroid administration, for at least 1 year. The followup rate was 100%.In pediatric patients, osteonecrosis developed in 4 joints (6%; all hips). In adolescent patients, osteonecrosis developed in 49 joints (49%; 18 hips and 31 knees). In adult patients, osteonecrosis developed in 207 joints (41%; 95 hips and 112 knees). The rate of osteonecrosis was significantly lower in pediatric patients than in adolescent or adult patients (P = 0.0001). Logistic regression analysis revealed that adolescent and adult patients had a significantly higher risk for osteonecrosis compared with pediatric patients, with an odds ratio of 10.3 (P < 0.0001). The youngest patients with osteonecrosis in the hip and knee were 14.9 years old and 15.5 years old, respectively. Osteonecrosis did not develop in patients younger than age 14 years.Our results suggest that age at the time of the initial administration of corticosteroids is associated with osteonecrosis in pediatric patients with SLE.

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Clinical features and outcomes in 348 patients with polyarteritis nodosa: A systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French vasculitis study group database

Previous studies of polyarteritis nodosa (PAN) included patients with microscopic polyangiitis, because these entities were not distinguished prior to the Chapel Hill Consensus Conference (CHCC). This study was undertaken to describe the main characteristics of and long-term outcomes in patients with well-characterized PAN diagnoses.We conducted a systematic retrospective study of 348 patients who were diagnosed as having PAN between March 1963 and October 2005, were registered in the French Vasculitis Study Group database, and satisfied the American College of Rheumatology and CHCC criteria. Patient characteristics and outcomes were analyzed and compared according to hepatitis B virus (HBV) status.At diagnosis, the mean ± SD age was 51.2 ± 17.3 years. The most frequent findings were general symptoms (93.1%), neurologic manifestations (79%), skin involvement (49.7%), abdominal pain (35.6%), and hypertension (34.8%); 66.2% had renal artery microaneurysms; 70.1% had histologically proven PAN. Patients with HBV-related PAN (n = 123) had more frequent peripheral neuropathy, abdominal pain, cardiomyopathy, orchitis, and hypertension compared with patients with non-HBV-related PAN (n = 225). During a mean ± SD followup of 68.3 ± 63.5 months, 76 patients (21.8%) relapsed (63 with non-HBV-related PAN [28%] versus 13 with HBV-related PAN [10.6%]; P 65 years, hypertension, and gastrointestinal manifestations requiring surgery or at least consultation with a surgeon as independent predictors of death, whereas patients with cutaneous manifestations or non-HBV-related PAN had a higher risk of relapse.Our findings indicate that the rate of mortality from PAN remains high, especially for the elderly, and relapses do occur, particularly in patients with non-HBV-related PAN with cutaneous manifestations.

Cardiac involvement in Churg-Strauss syndrome

Churg-Strauss syndrome (CSS) is a rare form of systemic vasculitis. Previous studies showing cardiac involvement in CSS patients were limited in the number of patients and were often based solely on clinical manifestations. The aim of the present study was to determine in detail the incidence of cardiac involvement in a large population of ambulatory CSS patients.Thirty-two consecutive patients with CSS in remission (mean ± SD duration of disease between diagnosis and enrollment 6.1 ± 5.8 years, mean ± SD age 61 ± 10 years) who were previously unaware of cardiac involvement were compared with 32 randomly selected age- and sex-matched control subjects, using clinical evaluation, electrocardiography (EKG), echocardiography, and cardiac magnetic resonance imaging (MRI).Detailed cardiac evaluation revealed a 62% prevalence of cardiac involvement in CSS patients compared with 3% in controls (P < 0.001), with clinical symptoms in 26% and 3%, respectively (P = 0.009), EKG abnormalities in 66% and 3%, respectively (P < 0.001), and echocardiographic defects in 50% and 3%, respectively (P < 0.001). Cardiac MRI detected cardiac manifestations in 62% of CSS patients. In the presence of cardiac MRI abnormalities, echocardiography could detect cardiac involvement with a sensitivity of 83% and a specificity of 80%. The absence of symptoms or EKG abnormalities did not exclude cardiac involvement, because abnormalities could still be detected in 38% of these patients at the time of echocardiography or cardiac MRI.These results demonstrate a high incidence of cardiac involvement in CSS patients. Systematic cardiac evaluation including detailed imaging is required to properly identify CSS patients with cardiac involvement.

Does the sTNFRII biomarker mainly detect subclinical or preclinical rheumatoid arthritis?

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An increased risk of ischemic heart disease in Wegener's granulomatosis: Comment on the article by Faurschou et al

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