bluuebunny/crossref_metadata_2025_split huggingface dataset:
The knee pain map: Reliability of a method to identify knee pain location and pattern
Authors: Thompson Laura R. , Boudreau Robert , Hannon Michael J. , Newman Anne B. , Chu Constance R. , Jansen Mary , Nevitt Michael C. , Kwoh C. Kent 
Published: May 2009

AbstractObjectiveTo describe the location and pattern of knee pain in patients with chronic, frequent knee pain using the Knee Pain Map, and to evaluate the inter‐ and intrarater reliability of the map.MethodsA cohort of 799 participants from the University of Pittsburgh Osteoarthritis Initiative Clinical Center who had knee pain in the last 12 months were studied. Trained interviewers assessed and recorded participant‐reported knee pain patterns into 8 local areas, 4 regional areas, or as diffuse. Inter‐ and intrarater reliability were assessed using Fleiss' kappa.ResultsParticipants most often reported localized (69%) followed by regional (14%) or diffuse (10%) knee pain. In those with localized pain, the most commonly reported locations were the medial (56%) and lateral (43%) joint lines. In those with regional pain, the most commonly reported regions were the patella (44%) and medial region (38%). There was excellent interrater reliability for the identification of localized and regional pain patterns (κ = 0.7–0.9 and 0.7–0.8, respectively). The interrater reliability for specific locations was also excellent (κ = 0.7–1.0) when the number of participants with pain in a location was >4. For regional pain, the kappa for specific regions varied from 0.7–1.0.ConclusionThe majority of participants could identify the location of their knee pain, and trained interviewers could reliably record those locations. The variation in locations suggests that there are multiple sources of pain in knee OA. Additional studies are needed to determine whether specific knee pain patterns correlate with discrete pathologic findings on radiographs or magnetic resonance images.
Ligands for retinoic acid receptors are elevated in osteoarthritis and may contribute to pathologic processes in the osteoarthritic joint
Authors: Davies Mark R. , Ribeiro Lyn Rosenbrier , Downey‐Jones Mark , Needham Maurice R. C. , Oakley Caroline , Wardale John 
Published: May 2009

AbstractObjectiveVitamin A derivatives, including all‐trans‐retinoic acid (ATRA), have a well‐established role during skeletal development and limb formation and have been shown to have profound effects on chondrocyte phenotype. The aim of this study was to elucidate the effects of retinoids and components of the retinoid metabolic pathway on chondrocyte phenotype in the tibiofemoral joints of patients with osteoarthritis (OA), to show that the retinoids can have multiple effects relevant to the OA disease process.MethodsHuman explant tissue and a chondrocyte‐like cell line were treated with ATRA, and the responses of 4 key markers of chondrocyte phenotype were analyzed. In addition, the effects of ATRA on a number of novel genes associated with OA were assessed using a low‐density microarray containing 80 disease marker genes.ResultsVitamin A metabolite levels were elevated in synovial fluid, serum, and cartilage from patients with OA. Expression profiling of a retinoic acid receptor α coactivator protein, P/CAF, demonstrated elevated expression in patients with OA, suggesting the potential for increased signaling via the retinoid receptors in the disease. ATRA increased the levels of matrix metalloproteinase 13 and aggrecanase activity in human cartilage explants and in a human chondrocyte cell line. Furthermore, ATRA altered the expression of a wide range of relevant genes, including the types I, II, IX, and XI collagen genes, toward a nonchondrogenic and OA‐like phenotype.ConclusionThese results suggest that retinoid signaling could have a central role in OA, and that components of the pathway may provide potential disease biomarkers or targets for therapeutic intervention.
The relationship between focal erosions and generalized osteoporosis in postmenopausal women with rheumatoid arthritis
Authors: Solomon Daniel H. , Finkelstein Joel S. , Shadick Nancy , LeBoff Meryl S. , Winalski Carl S. , Stedman Margaret , Glass Roberta , Brookhart M. Alan , Weinblatt Michael E. , Gravallese Ellen M. 
Published: May 2009

AbstractObjectiveAmong rheumatoid arthritis (RA) patients who have had the disease for 10 years, more than half have focal erosions, and the risk of fracture is doubled. However, there is little information about the potential relationship between focal erosions and bone mineral density (BMD). The aim of this study was to determine whether lower BMD is associated with higher erosion scores among patients with RA.MethodsWe enrolled 163 postmenopausal women with RA, none of whom were taking osteoporosis medications. Patients underwent dual x‐ray absorptiometry at the hip and spine and hand radiography, and completed a questionnaire. The hand radiographs were scored using the Sharp method, and the relationship between BMD and erosions was measured using Spearman's correlation coefficients and adjusted linear regression models.ResultsPatients had an average disease duration of 13.7 years, and almost all were taking a disease‐modifying antirheumatic drug. Sixty‐three percent were rheumatoid factor (RF) positive. The median modified Health Assessment Questionnaire score was 0.7, and the average Disease Activity Score in 28 joints was 3.8. The erosion score was significantly correlated with total hip BMD (r = −0.33,P< 0.0001), but not with lumbar spine BMD (r = −0.09,P= 0.27). Hip BMD was significantly lower in RF‐positive patients versus RF‐negative patients (P= 0.02). In multivariable models that included age, body mass index, and cumulative oral glucocorticoid dose, neither total hip BMD nor lumbar spine BMD was significantly associated with focal erosions.ConclusionOur results suggest that hip BMD is associated with focal erosions among postmenopausal women with RA, but that this association disappears after multivariable adjustment. While BMD and erosions may be correlated with bone manifestations of RA, their relationship is complex and influenced by other disease‐related factors.
The critical role of kinase activity of interleukin‐1 receptor–associated kinase 4 in animal models of joint inflammation
Authors: Koziczak‐Holbro Magdalena , Littlewood‐Evans Amanda , Pöllinger Bernadette , Kovarik Jiri , Dawson Janet , Zenke Gerhard , Burkhart Christoph , Müller Matthias , Gram Hermann 
Published: May 2009

AbstractObjectiveWe have previously reported that the kinase activity of interleukin‐1 receptor–associated kinase 4 (IRAK‐4) is important for Toll‐like receptor and interleukin‐1 receptor signaling in vitro. Using mice devoid of IRAK‐4 kinase activity (IRAK‐4 KD mice), we undertook this study to determine the importance of IRAK‐4 kinase function in complex disease models of joint inflammation.MethodsIRAK‐4 KD mice were subjected to serum transfer–induced (K/BxN) arthritis, and migration of transferred spleen lymphocytes into joints and cartilage and bone degradation were assessed. T cell response in vivo was tested in antigen‐induced arthritis (AIA) by measuring the T cell–dependent antigen‐specific IgG production and frequency of antigen‐specific T cells in the spleen and lymph nodes. T cell allogeneic response was tested in vitro by mixed lymphocyte reaction (MLR).ResultsLipopolysaccharide‐induced local neutrophil influx into subcutaneous air pouches was impaired in IRAK‐4 KD mice. These mice were also protected from inflammation in the K/BxN and AIA models, as shown by reduced swelling of joints. Histologic analysis of joints of K/BxN serum–injected mice revealed that bone erosion, osteoclast formation, and cartilage matrix proteoglycan loss were reduced in IRAK‐4 KD mice. Assessment of T cell response by MLR, by frequency of antigen‐specific clones, and by production of antigen‐specific IgG did not reveal substantial differences between IRAK‐4 KD and wild‐type mice.ConclusionThese results demonstrate that IRAK‐4 is a key component for the development of proarthritis inflammation, but that it is not crucial for T cell activation. Therefore, the kinase function of IRAK‐4 appears to be an attractive therapeutic target in chronic inflammation.
Impact of medicare part D on access to and cost sharing for specialty biologic medications for beneficiaries with rheumatoid arthritis
Authors: Polinski Jennifer M. , Mohr Penny E. , Johnson Lorraine 
Published: May 2009

AbstractObjectiveMany worry that the use of specialty tiering for biologic disease‐modifying antirheumatic drugs (DMARDs) by Medicare Part D plans imposes a heavy financial burden on beneficiaries with rheumatoid arthritis (RA). To date, no one has examined the cost‐sharing structures for biologic DMARDs in Part D plans or the resulting cost burden for patients.MethodsWe followed 14,929 vulnerable, low‐income patients with RA who were enrolled in the Medicare Replacement Drug Demonstration (MRDD) in 2005. As the MRDD population transitioned into Part D in 2006, we examined correlates of Part D enrollment and compared the cost‐sharing provisions for biologic DMARDs in the Medicare Advantage and stand‐alone plans. We simulated the out‐of‐pocket costs of beneficiaries under 3 cost‐sharing scenarios.ResultsEighty‐one percent of MRDD beneficiaries with RA enrolled in Part D. Enrollment predictors were female sex (odds ratio [OR] 1.48, 95% confidence interval [95% CI] 1.32–1.67), prior MRDD benefit use (OR 2.29, 95% CI 2.04–2.58), other self‐reported drug coverage (OR 1.53, 95% CI 1.36–1.71), and receiving an MRDD subsidy (OR 2.00, 95% CI 1.74–2.30). Compared with stand‐alone plans, Medicare Advantage plans had lower deductibles, lower premiums, and fewer prior authorization, step therapy, and quantity limit restrictions. However, ∼75% of all plans used coinsurance as the preferred form of cost sharing. Out‐of‐pocket costs exceeded $4,000 annually in all cost‐sharing scenarios.ConclusionMost MRDD beneficiaries with RA enrolled in Part D. Although plans assume some costs for biologic DMARDs, the majority of costs are shifted to beneficiaries and to Medicare. Such cost shifting may place these medications out of the beneficiary's financial reach and expose Medicare to high financial liability.
Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis
Authors: Shen Hui , Goodall Jane C. , Hill Gaston J. S. 
Published: May 2009

AbstractObjectiveTo analyze the frequency, surface phenotype, and cytokine secretion of CD4+ T cells in peripheral blood mononuclear cells (PBMCs) from patients with ankylosing spondylitis (AS) compared with both healthy control subjects and patients with rheumatoid arthritis (RA).MethodsEight‐color flow cytometry was used to analyze the surface phenotype and cytokine production of PBMCs from 20 patients with AS, 12 patients with RA, and 16 healthy control subjects, following stimulation ex vivo with phorbol myristate acetate and ionomycin for 5 hours. Secretion of interleukin‐17 (IL‐17) by PBMCs was measured by enzyme‐linked immunosorbent assay, following stimulation with anti‐CD3/CD28 for 4 days.ResultsThe percentages of IL‐17–positive CD4+ T cells and IL‐22–positive CD4+ T cells were increased in the PBMCs of both patients with AS and patients with RA compared with healthy control subjects, whereas there were no differences in the percentages of interferon‐γ (IFNγ)–positive or IL‐10–positive CD4+ T cells. Likewise, concentrations of IL‐17 in supernatants from patients with AS were significantly higher compared with those from healthy control subjects. In patients with RA, the concentrations of IL‐17 were increased but not significantly. There was a correlation between the percentages of IL‐17–positive CD4+ T cells detected in PBMCs and the amounts of IL‐17 in culture supernatants (r = 0.414, P = 0.0034). All IL‐17–producing cells were CD4+CD45RO+; most expressed both CCR6 and CCR4, but only 50% expressed the IL‐23 receptor (IL‐23R). Nevertheless, there was a positive relationship between the percentage of IL‐23R–positive CD4+ T cells and the frequency of IL‐17–positive CD4+ T cells or IL‐22–positive CD4+ T cells (r = 0.57, P < 0.0001 and r = 0.46, P = 0.001, respectively). A significant proportion of cells that produced IL‐17 also produced IL‐22 and IFNγ, but none produced IL‐10.ConclusionThe frequencies of IL‐17–positive and IL‐22–positive CD4+ T cells were increased in PBMCs from patients with AS and patients with RA, resulting in secretion of higher quantities of IL‐17 by PBMCs following stimulation. These data support the hypothesis that Th17 cells, particularly when present in excess of IL‐10–producing cells, are involved in the pathogenesis of inflammatory arthritis.
Familial mediterranean fever with a single MEFV mutation: Where is the second hit?
Authors: Booty Matthew G. , Chae Jae Jin , Masters Seth L. , Remmers Elaine F. , Barham Beverly , Le Julie M. , Barron Karyl S. , Holland Steve M. , Kastner Daniel L. , Aksentijevich Ivona 
Published: May 2009

AbstractObjectiveFamilial Mediterranean fever (FMF) has traditionally been considered an autosomal‐recessive disease; however, it has been observed that a substantial number of patients with clinical FMF possess only 1 demonstrable MEFV mutation. The purpose of this study was to perform an extensive search for a second MEFV mutation in 46 patients diagnosed clinically as having FMF and carrying only 1 high‐penetrance FMF mutation.MethodsMEFV and other candidate genes were sequenced by standard capillary electrophoresis. In 10 patients, the entire 15‐kb MEFV genomic region was resequenced using hybridization‐based chip technology. MEFV gene expression levels were determined by quantitative reverse transcription–polymerase chain reaction. Pyrin protein levels were examined by Western blotting.ResultsA second MEFV mutation was not identified in any of the patients who were screened. Haplotype analysis did not identify a common haplotype that might be associated with the transmission of a second FMF allele. Western blots did not demonstrate a significant difference in pyrin levels between patients with a single mutation and those with a double mutation; however, FMF patients of both types showed higher protein expression as compared with controls and with non‐FMF patients with active inflammation. Screening of genes encoding pyrin‐interacting proteins identified rare mutations in a small number of patients, suggesting the possibility of digenic inheritance.ConclusionOur data underscore the existence of a significant subset of FMF patients who are carriers of only 1 MEFV mutation and demonstrate that complete MEFV sequencing is not likely to yield a second mutation. Screening for the set of the most common mutations and detection of a single mutation appears to be sufficient in the presence of clinical symptoms for the diagnosis of FMF and the initiation of a trial of colchicine.
Clinical disease among patients heterozygous for familial mediterranean fever
Authors: Marek‐Yagel Dina , Berkun Yackov , Padeh Shai , Abu Almogit , Reznik‐Wolf Haike , Livneh Avi , Pras Mordechai , Pras Elon 
Published: May 2009

AbstractObjectiveTo define the molecular basis of familial Mediterranean fever (FMF) in patients with only 1 mutation in the MEFV gene.MethodsGenetic analysis was performed in 20 FMF patients, including full sequencing of complementary DNA (cDNA) samples and multiplex ligation‐dependent probe amplification analysis. In patients with first‐degree relatives with FMF, haplotype analysis was also performed.ResultsA second mutation was found in 2 patients. In the other 18 patients, we could not identify additional mutations, large genomic deletions, or duplications. Analysis of single‐nucleotide polymorphisms along the cDNA ruled out a lack of expression of 1 of the alleles. In 2 of the 3 families in which more than 1 sibling had FMF, we showed that the affected siblings inherited a different MEFV allele from the parent who did not have the MEFV mutation.ConclusionThese findings are highly consistent with the existence of a clinical phenotype among some patients who are heterozygous for FMF and could explain the vertical transmission in some families. A single mutation in the MEFV gene may be much more common than was previously thought and may include up to 25% of patients who are diagnosed as having FMF.
Complete and sustained remission of juvenile dermatomyositis resulting from aggressive treatment
Authors: Kim Susan , El‐Hallak Moussa , Dedeoglu Fatma , Zurakowski David , Fuhlbrigge Robert C. , Sundel Robert P. 
Published: May 2009

AbstractObjectiveTo assess the time needed to achieve sustained, medication‐free remission in a cohort of patients with juvenile dermatomyositis (DM) receiving a stepwise, aggressive treatment protocol.MethodsBetween 1994 and 2004, a cohort of 49 children with juvenile DM who were followed up at a single tertiary care children's hospital using disease activity measures according to a specific protocol received standardized therapy with steroids and methotrexate. If a patient's strength or muscle enzyme levels did not normalize with this initial therapy, additional medications were added in rapid succession to the treatment regimen. The primary outcome measure was time to complete remission. Additional outcome measures were onset of calcinosis, effect of treatment on height, and complications resulting from medications.ResultsForty‐nine patients were followed up for a mean ± SD of 48 ± 30 months. All but 1 patient received 2 or more medications simultaneously. Transient localized calcifications occurred in 4 patients (8%), and 2 additional patients (4%) had persistent calcinosis. Despite the aggressive therapy, complications associated with treatment were mild and were primarily attributable to steroids. No persistent effect on longitudinal growth was observed. A complete, medication‐free remission was achieved in 28 patients; the median time to achievement of complete remission was 38 months (95% confidence interval 32–44 months). None of these patients experienced a disease flare that required resumption of medications during the subsequent period of observation (mean ± SD 36 ± 19.7 months).ConclusionOur findings suggest that aggressive treatment of juvenile DM aimed at achieving rapid, complete control of muscle weakness and inflammation improves outcomes and reduces disease‐related complications. In more than one‐half of the children whose disease was treated in this manner (28 of 49), a prolonged, medication‐free remission was attained within a median of 38 months from the time of diagnosis.
Gene–environment interaction between the DRB1 shared epitope and smoking in the risk of anti–citrullinated protein antibody–positive rheumatoid arthritis: All alleles are important
Authors: Lundström Emeli , Källberg Henrik , Alfredsson Lars , Klareskog Lars , Padyukov Leonid 
Published: May 2009

AbstractObjectiveAn interaction effect for developing rheumatoid arthritis (RA) was previously observed between HLA–DRB1 shared epitope (SE) alleles and smoking. We aimed to further investigate this interaction between distinct SE alleles and smoking regarding the risk of developing RA with and without anti–citrullinated protein antibodies (ACPAs).MethodsWe used data regarding smoking habits and HLA–DRB1 genotypes from 1,319 patients and 943 controls from the Epidemiological Investigation of Rheumatoid Arthritis, in which 972 patients and 488 controls were SE positive. Subsequently, 759 patients and 328 controls were subtyped for specific alleles within the DRB1*04 group. Odds ratios with 95% confidence intervals (95% CIs) were calculated by means of logistic regression. Interaction was evaluated by calculating attributable proportion due to interaction, with 95% CIs.ResultsA strong interaction between smoking and SE alleles in the development of ACPA‐positive RA was observed for all DRB1*04 SE alleles taken as a group (relative risk [RR] 8.7 [95% CI 5.7–13.1]) and for the *0401 and *0404 alleles (RR 8.9 [95% CI 5.8–13.5]) and the *01 and *10 alleles (RR 4.9 [95% CI 3.0–7.8]) as specific, separate groups, with similar strength of interaction for the different groups (attributable proportion due to interaction 0.4 [95% CI 0.2–0.6], 0.5 [95% CI 0.3–0.7], and 0.6 [95% CI 0.4–0.8], respectively).ConclusionThere is a statistically significant interaction between distinct DRB1 SE alleles and smoking in the development of ACPA‐positive RA. Interaction occurs with the *04 group as well as the *01/*10 group, demonstrating that regardless of fine specificity, all SE alleles strongly interact with smoking in conferring an increased risk of ACPA‐positive RA.
Galectin 3 induces a distinctive pattern of cytokine and chemokine production in rheumatoid synovial fibroblasts via selective signaling pathways
Authors: Filer Andrew , Bik Magdalena , Parsonage Greg N. , Fitton John , Trebilcock Emily , Howlett Katherine , Cook Michelle , Raza Karim , Simmons David L. , Thomas Andrew M. C. , Salmon Mike , Scheel‐Toellner Dagmar , Lord Janet M. , Rabinovich Gabriel A. , Buckley Christopher D. 
Published: May 2009

AbstractObjectiveHigh expression of galectin 3 at sites of joint destruction in rheumatoid arthritis (RA) suggests that galectin 3 plays a role in RA pathogenesis. Previous studies have demonstrated the effects of galectins on immune cells, such as lymphocytes and macrophages. This study was undertaken to investigate the hypothesis that galectin 3 induces proinflammatory effects in RA by modulating the pattern of cytokine and chemokine production in synovial fibroblasts.MethodsMatched samples of RA synovial and skin fibroblasts were pretreated with galectin 3 or tumor necrosis factor α (TNFα), and the levels of a panel of cytokines, chemokines, and matrix metalloproteinases (MMPs) were determined using enzyme‐linked immunosorbent assays and multiplex assays. Specific inhibitors were used to dissect signaling pathways, which were confirmed by Western blotting and NF‐κB activation assay.ResultsGalectin 3 induced secretion of interleukin‐6 (IL‐6), granulocyte–macrophage colony‐stimulating factor, CXCL8, and MMP‐3 in both synovial and skin fibroblasts. By contrast, galectin 3–induced secretion of TNFα, CCL2, CCL3, and CCL5 was significantly greater in synovial fibroblasts than in skin fibroblasts. TNFα blockade ruled out autocrine TNFα‐stimulated induction of chemokines. The MAPKs p38, JNK, and ERK were necessary for IL‐6 production, but phosphatidylinositol 3‐kinase (PI 3‐kinase) was required for selective CCL5 induction. NF‐κB activation was required for production of both IL‐6 and CCL5.ConclusionOur findings indicate that galectin 3 promotes proinflammatory cytokine secretion by tissue fibroblasts. However, galectin 3 induces the production of mononuclear cell–recruiting chemokines uniquely from synovial fibroblasts, but not matched skin fibroblasts, via a PI 3‐kinase signaling pathway. These data provide further evidence of the role of synovial fibroblasts in regulating the pattern and persistence of the inflammatory infiltrate in RA and suggest a new and important functional consequence of the observed high expression of galectin 3 in the rheumatoid synovium.