bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for a pathogenetic role of interleukin‐18 in cutaneous lupus erythematosus
Authors: Wang Dong , Drenker Melanie , Eiz‐Vesper Britta , Werfel Thomas , Wittmann Miriam 
Published: September 2008

AbstractObjectiveCutaneous manifestations are the most common clinical features of lupus erythematosus (LE). The aim of this study was to analyze differences in the inflammatory response of keratinocytes from patients with cutaneous LE (CLE) compared with healthy controls.MethodsKeratinocytes from LE patients and controls were cultured from epidermal stem cells of the hair follicle of anagen head hairs. Functional responses of keratinocytes to cytokine stimulation were determined by flow cytometry and enzyme‐linked immunosorbent assay. Biopsy samples of lesional skin were analyzed by immunohistochemistry.ResultsKeratinocytes from CLE patients expressed higher levels of IL‐18 receptor on their cell surface in response to tumor necrosis factor α (TNFα) or interferon‐γ stimulation. In response to IL‐18 stimulation, these cells produced large amounts of TNFα. Of note, in the presence of IL‐18, CLE keratinocytes failed to express IL‐12. IL‐12 has previously been shown to protect keratinocytes from ultraviolet irradiation–induced apoptosis. Keratinocytes from LE patients were more prone to die upon exposure to IL‐18, and this increased apoptosis was abrogated by blockade of endogenously produced TNFα as well as by the addition of exogenous IL‐12. IL‐18 was highly expressed in biopsy samples of lesional skin from CLE patients.ConclusionOur results demonstrate an intrinsic difference in the inflammatory response of keratinocytes and indicate an autocrine feedback loop involving TNFα, IL‐18, and IL‐12 family members. Our results suggest that IL‐18 may occupy an important position in the cytokine hierarchy in CLE, indicating the potential benefit of a local agent that blocks IL‐18 activity in the treatment of the manifestations of CLE.
Expression of the CD85j (leukocyte Ig‐like receptor 1, Ig‐like transcript 2) receptor for class I major histocompatibility complex molecules in idiopathic inflammatory myopathies
Authors: Schleinitz Nicolas , Cognet Celine , Guia Sophie , Laugier‐Anfossi Fanny , Baratin Myriam , Pouget Jean , Pelissier Jean‐Francois , Harle Jean‐Robert , Vivier Eric , Figarella‐Branger Dominique 
Published: September 2008

AbstractObjectiveExpression of class I major histocompatibility complex (MHC) molecules on the surface of muscle cells is a biologic feature of idiopathic inflammatory myopathies (IIM). Class I MHC–transgenic mouse models support a causative role for class I MHC expression by muscle cells in the pathogenesis of IIM. The muscle lesions are characterized by leukocyte infiltration. We undertook this study to analyze the expression in muscle lesions of various class I MHC–specific receptors on leukocytes and natural killer (NK) cells.MethodsWe generated a panel of cell transfectants to control the immunofluorescence analysis of class I MHC receptor expression. We then analyzed the expression of CD158 (killer cell Ig‐like receptors [KIRs]) and CD85j (leukocyte Ig‐like receptor 1, Ig‐like transcript 2) on muscle sections prepared from 14 patients with IIM (5 with dermatomyositis [DM], 5 with polymyositis [PM], and 4 with sporadic inclusion body myositis [IBM]).ResultsWe could not detect the presence of NK cells in inflammatory lesions. However, the class I MHC receptor CD85j, but no KIRs, was expressed by inflammatory cells infiltrating muscle lesions in IIM.ConclusionCD85j is expressed in PM and sporadic IBM at the sites of partial invasion and in DM in perivascular inflammation, paving the way for dissecting the role of CD85j in the pathogenesis of inflammatory myopathies.
Vascular endothelial growth factor is highly expressed in muscle tissue of patients with polymyositis and patients with dermatomyositis
Authors: Grundtman Cecilia , Tham Emma , Ulfgren Ann‐Kristin , Lundberg Ingrid E. 
Published: September 2008

AbstractObjectiveTo investigate the expression of vascular endothelial growth factor (VEGF) in muscle biopsy specimens and serum from patients with polymyositis and patients with dermatomyositis compared with that in healthy control subjects.MethodsMuscle biopsy specimens from 33 patients with polymyositis or dermatomyositis and 15 healthy control subjects and serum samples from 56 patients and 56 healthy control subjects were analyzed. Patients were categorized into 3 groups, depending on disease duration and the presence or absence of inflammatory infiltrates. The expression of VEGF and the vessel marker CD31 in muscle was analyzed by immunohistochemistry, the expression of VEGF messenger RNA (mRNA) was analyzed by in situ hybridization, and serum levels of VEGF were determined by enzyme‐linked immunosorbent assay.ResultsPatients with polymyositis or dermatomyositis in the early or chronic phase without inflammatory infiltrates had a decreased total number of capillaries compared with healthy individuals. In patients with early disease without inflammatory infiltrates, the number of VEGF‐expressing muscle fibers was increased compared with that in control subjects, whereas VEGF expression was unchanged in the chronic phase of disease. In patients with established disease with inflammatory infiltrates, total VEGF expression was high compared with that in healthy control subjects. In healthy control subjects, VEGF was expressed in endothelial cells and in occasional muscle fibers. VEGF mRNA was expressed in muscle fibers in both healthy individuals and patients. The level of serum VEGF was significantly increased in patients compared with control subjects.ConclusionOur observations support a role of VEGF in the early phases of polymyositis and dermatomyositis. A reduced number of capillaries could lead to induction of VEGF expression in muscle fibers. Furthermore, differences in molecular expression during certain phases of disease may help in the development of specific therapeutic algorithms in the treatment of myositis.
Tumor necrosis factor α drives cadherin 11 expression in rheumatoid inflammation
Authors: Vandooren Bernard , Cantaert Tineke , Borg Mariëtte Ter , Noordenbos Troy , Kuhlman Rodger , Gerlag Daniëlle , Bongartz Tim , Reedquist Kris , Tak Paul P. , Baeten Dominique 
Published: September 2008

AbstractObjectiveCadherin 11 expressed on fibroblast‐like synoviocytes (FLS) plays a key role in normal synovial architecture. The purpose of this study was to examine the expression of cadherin 11 in human synovitis.MethodsCadherin 11 expression in synovial biopsy samples from patients with various types of arthritis and in lung biopsy samples from patients with interstitial pneumonitis (IP) was examined by immunostaining. The regulation of cadherin 11 expression in human FLS was assessed by quantitative reverse transcription–polymerase chain reaction analysis and Western blotting. Therapeutic modulation of synovial cadherin 11 was assessed before and after effective antiinflammatory therapy.ResultsAbundant staining for cadherin 11 was seen in the intimal lining layer and the synovial sublining in inflamed tissues, with discrete staining in noninflammatory osteoarthritic (OA) tissues. The pattern and degree of immunostaining were similar in tissues from patients with rheumatoid arthritis (RA), nonpsoriatic spondylarthritis (SpA), psoriatic arthritis (PsA), and inflammatory OA. Clear staining for cadherin 11 was also observed in lung tissues from RA‐associated IP and idiopathic IP patients, but was very limited in normal lung tissue. Cadherin 11 staining correlated strongly with the degree of inflammatory infiltration of the tissue, as well as with the C‐reactive protein level and the erythrocyte sedimentation rate in RA patients. In vitro, cadherin 11 expression by FLS was consistently up‐regulated by tumor necrosis factor α (TNFα) at the protein, but not the messenger RNA, level. Cadherin 11 staining in vivo was strongly down‐regulated by prednisone treatment in RA patients and by TNFα blockade in SpA patients.ConclusionCadherin 11 expression is regulated by mediators of inflammation, such as TNFα. Since cadherin 11 plays an important role in cartilage destruction in experimental arthritis, down‐modulation of cadherin 11 by potent antiinflammatory therapies in humans with arthritis may contribute to halting cartilage damage.
The effects of total knee arthroplasty on physical functioning in the older population
Authors: George Linda K. , Ruiz David , Sloan Frank A. 
Published: September 2008

AbstractObjectiveClinical research provides convincing evidence that total knee arthroplasty (TKA) is safe and improves joint‐specific outcomes. However, higher‐level functioning associated with self care and independent living has not been studied. Furthermore, most previous studies of the effects of TKA relied on relatively small clinical samples. We undertook this study to estimate the effects of TKA on 3 levels of physical functioning in a national sample of older adults.MethodsData were obtained from the Medicare Current Beneficiary Survey from 1992 to 2003. Medicare claims data identified participants with osteoarthritis of the knee who received TKA (n = 259) or no TKA (n = 1,816). Propensity scores were used to match treatment and no‐treatment groups according to demographic characteristics, comorbid conditions, and baseline functioning. Three levels of physical functioning were examined as outcomes of TKA. These levels were represented by items on the Nagi Disability Scale, the Instrumental Activities of Daily Living (IADL) Scale, and the Activities of Daily Living (ADL) Scale. These items were measured after TKA and at comparable intervals for the no‐treatment group. Average treatment effects were calculated for relevant Nagi Disability Scale, IADL Scale, and ADL Scale tasks.ResultsBetween baseline and outcome assessments, TKA recipients improved on all 3 levels of physical functioning; the no‐treatment group declined. Statistically significant average treatment effects for TKA were observed for one or more tasks for each measure of physical functioning.ConclusionTKA is associated with sizeable improvements in 3 levels of physical functioning among elderly Medicare beneficiaries.
Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis
Authors: Dass Shouvik , Rawstron Andy C. , Vital Edward M. , Henshaw Karen , McGonagle Dennis , Emery Paul 
Published: September 2008

AbstractObjectiveIn rheumatoid arthritis (RA), B cell depletion occurs in all patients treated with rituximab, but the clinical responses to rituximab are variable. A highly sensitive assay was used to test the hypothesis that B cell depletion is variable, and that incomplete depletion leads to a poorer outcome.MethodsSixty patients with active RA unresponsive to anti–tumor necrosis factor agents received two 1‐gram infusions of rituximab. B cell numbers were measured by highly sensitive flow cytometry before and after each infusion and at 3‐month intervals thereafter. A reduction in B cell levels below 0.0001 × 109/liter was defined as complete depletion (compared with 0.05 × 109/liter by conventional cytometry). Clinical responses were measured using the European League Against Rheumatism (EULAR) criteria.ResultsAt 6 months, 92% of patients had a moderate‐to‐good clinical response according to the EULAR criteria. B cells were detected in 63% of patients after the first infusion of rituximab (median level 0.0009 × 109/liter [range <0.0001–0.0015 × 109/liter), and these patients had poorer clinical outcomes than patients with complete depletion. At 9 months, 82% of patients with complete depletion had a moderate‐to‐ good EULAR response, compared with 43% of those with partial depletion (P = 0.01). At 12 months, 59% of complete responders had a moderate‐to‐good EULAR response, compared with 21% of those with partial depletion (P = 0.01). Patients in whom B cells were depleted only after the second infusion did no better than those in whom depletion was never complete and had poorer clinical outcomes than those in whom depletion was initially complete.ConclusionThis study is the first to show, using a highly sensitive analysis, that rituximab therapy is associated with variable diminution in B cell numbers. A lack of complete depletion of B cells after 1 infusion was associated with a poorer outcome.
Interactions of T helper cells with fibroblast‐like synoviocytes: Up‐regulation of matrix metalloproteinases by macrophage migration inhibitory factor from both Th1 and Th2 cells
Authors: Schurigt Uta , Pfirschke Christina , Irmler Ingo M. , Hückel Marion , Gajda Mieczyslaw , Janik Tobias , Baumgrass Ria , Bernhagen Jürgen , Bräuer Rolf 
Published: September 2008

AbstractObjectiveInteractions of immune cells, such as activated T helper cells, with fibroblast‐like synoviocytes (FLS) play a crucial role in the joint destruction during human rheumatoid arthritis (RA). This study was undertaken to investigate the expression of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) by T helper cells, and to assess the role of MIF in overexpression of matrix metalloproteinases (MMPs) in cocultures of FLS from arthritic mice with either Th1 or Th2 cells.MethodsMIF expression by in vitro–polarized murine Th1 and Th2 cells was determined using 2 different generation protocols. FLS were isolated from the inflamed joints of mice with antigen‐induced arthritis. MMP expression was analyzed in cocultures of the FLS with T helper cell subsets. Effects of MIF were blocked by a neutralizing anti‐MIF antibody. In addition, analyses were performed on cocultures of either Th1 or Th2 cells with FLS from MIF‐deficient mice.ResultsBoth Th1 and Th2 cells expressed high quantities of MIF. MMPs were overexpressed by FLS after coculture with both Th1 and Th2 cells. Activated T helper cells were more effective than resting cells. Neutralization of MIF by an anti‐MIF antibody led to a marked reduction in MMP expression in Th1‐ and Th2‐stimulated FLS. T helper cells generated from MIF‐deficient mice exhibited a T helper cell–specific cytokine profile comparable with that in wild‐type cells, except in the expression of MIF, but showed an impaired ability to stimulate MMP expression in FLS.ConclusionMIF is an important Th1 and Th2 cell–derived proinflammatory cytokine that stimulates MMP expression in FLS from arthritic mice, and therefore inhibition of MIF might be a promising target for novel therapeutic strategies in human RA.
Antibodies to citrullinated α‐enolase peptide 1 are specific for rheumatoid arthritis and cross‐react with bacterial enolase
Authors: Lundberg Karin , Kinloch Andrew , Fisher Benjamin A. , Wegner Natalia , Wait Robin , Charles Peter , Mikuls Ted R. , Venables Patrick J. 
Published: September 2008

AbstractObjectiveTo map the antibody response to human citrullinated α‐enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine cross‐reactivity with bacterial enolase.MethodsSerum samples obtained from patients with RA, disease control subjects, and healthy control subjects were tested by enzyme‐linked immunosorbent assay (ELISA) for reactivity with citrullinated α‐enolase peptides. Antibodies specific for the immunodominant epitope were raised in rabbits or were purified from RA sera. Cross‐reactivity with other citrullinated epitopes was investigated by inhibition ELISAs, and cross‐reactivity with bacterial enolase was investigated by immunoblotting.ResultsAn immunodominant peptide, citrullinated α‐enolase peptide 1, was identified. Antibodies to this epitope were observed in 37–62% of sera obtained from patients with RA, 3% of sera obtained from disease control subjects, and 2% of sera obtained from healthy control subjects. Binding was inhibited with homologous peptide but not with the arginine‐containing control peptide or with 4 citrullinated peptides from elsewhere on the molecule, indicating that antibody binding was dependent on both citrulline and flanking amino acids. The immunodominant peptide showed 82% homology with enolase from Porphyromonas gingivalis, and the levels of antibodies to citrullinated α‐enolase peptide 1 correlated with the levels of antibodies to the bacterial peptide (r2 = 0.803, P < 0.0001). Affinity‐purified antibodies to the human peptide cross‐reacted with citrullinated recombinant P gingivalis enolase.ConclusionWe have identified an immunodominant epitope in citrullinated α‐enolase, to which antibodies are specific for RA. Our data on sequence similarity and cross‐reactivity with bacterial enolase may indicate a role for bacterial infection, particularly with P gingivalis, in priming autoimmunity in a subset of patients with RA.
Nonspherical femoral head shape (pistol grip deformity), neck shaft angle, and risk of hip osteoarthritis: A case–control study
Authors: Doherty Michael , Courtney Philip , Doherty Sally , Jenkins Wendy , Maciewicz Rose A. , Muir Kenneth , Zhang Weiya 
Published: September 2008

AbstractObjectiveTo determine whether 2‐dimensional measures of femoral head shape and angle are associated with hip osteoarthritis (OA).MethodsWe compared cases with symptomatic radiographic hip OA with asymptomatic controls with no radiographic hip OA. On anteroposterior pelvis radiographs, we measured “pistol grip deformity” for each hip (visually categorized as nonspherical, indeterminate, or spherical), the femoral head–to–femoral neck ratio as an interval measure of femoral head shape, and the femoral neck shaft angle. The relative risk of hip OA associated with each feature was estimated using odds ratios (ORs) and 95% confidence intervals (95% CIs), adjusted for possible confounders using a logistic regression model.ResultsOf 1,007 cases, 965 had definite radiographic hip OA; of 1,123 controls, 1,111 had no radiographic OA. The prevalence of pistol grip deformity in at least 1 hip was 3.61% in controls and 17.71% in cases (OR 6.95 [95% CI 4.64–10.41]), and the prevalence of abnormal femoral head–to–femoral neck ratio in at least 1 hip was 3.70% in controls and 24.27% in cases (OR 12.08 [95% CI 8.05–18.15]). The risk of hip OA increased as the femoral head–to–femoral neck ratio decreased (P for trend < 0.001) and with each extreme of neck shaft angle (P < 0.05). In cases with unilateral hip OA, the prevalence of abnormal femoral head–to–femoral neck ratio in the unaffected hip was 2 times greater than that in controls (OR 1.82 [95% CI 1.07–3.07]); in contrast, an abnormally low, but not abnormally high, neck shaft angle was more common in unaffected hips than in controls (OR 1.79 [95% CI 1.03–3.14]).ConclusionOur findings indicate that pistol grip deformity is associated with hip OA. The increased prevalence of pistol grip deformity and an abnormally low neck shaft angle in unaffected hips of cases with unilateral OA suggests that they are risk factors for development of hip OA. However, both a nonspherical head shape and an increase in neck shaft angle may occur as a consequence of OA.
Interleukin‐6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease‐modifying antirheumatic drugs: The tocilizumab in combination with traditional disease‐modifying antirheumatic drug therapy study
Authors: Genovese Mark C. , McKay James D. , Nasonov Evgeny L. , Mysler Eduardo F. , da Silva Nilzio A. , Alecock Emma , Woodworth Thasia , Gomez‐Reino Juan J. 
Published: September 2008

AbstractObjectiveTo examine the efficacy and safety of the humanized anti–interleukin‐6 receptor antibody tocilizumab combined with conventional disease‐modifying antirheumatic drugs (DMARDs) in patients with active rheumatoid arthritis (RA).MethodsA total of 1,220 patients were randomized (2:1 ratio) in the phase III, double‐blind, placebo‐controlled, multicenter TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy) study. Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo (control group) every 4 weeks for 24 weeks.ResultsAt week 24, the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20) was significantly greater in the tocilizumab plus DMARD group than in the control group (61% versus 25%; P < 0.0001). Secondary end points including 50% or 70% improvement (ACR50/70), the Disease Activity Score in 28 joints (DAS28), DAS28 remission responses (DAS28 <2.6), European League Against Rheumatism responses, and systemic markers such as the C‐reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone. Seventy‐three percent of patients in the tocilizumab group had ≥1 adverse event (AE), compared with 61% of patients in the control group. AEs leading to withdrawal from the study were infrequent (4% of patients in the tocilizumab group and 2% of those in the control group). Serious AEs occurred in 6.7% and 4.3% of patients in the tocilizumab and control groups, respectively, and serious infections occurred in 2.7% and 1.9%, respectively. Elevations in the alanine aminotransferase level, from normal at baseline to >3‐fold the upper limit of normal, occurred in 4% of patients in the tocilizumab group and 1% of those in the control group, and elevated total cholesterol levels were observed in 23% and 6% of patients, respectively. Sixteen patients started lipid‐lowering therapy during the study. Grade 3 neutropenia occurred in 3.7% of patients receiving tocilizumab and none of the patients in the control group, and no grade 4 neutropenia was reported.ConclusionTocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents.
An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis
Authors: Brown A. K. , Conaghan P. G. , Karim Z. , Quinn M. A. , Ikeda K. , Peterfy C. G. , Hensor E. , Wakefield R. J. , O'Connor P. J. , Emery P. 
Published: September 2008

AbstractObjectiveAchieving remission is the aim of treatment in rheumatoid arthritis (RA). This should represent minimal arthritis activity and ensure optimal disease outcome. However, we have previously demonstrated a high prevalence of imaging‐detected synovial inflammation in RA patients who were in clinical remission. The purpose of this study was to evaluate the long‐term significance of subclinical synovitis and its relationship to structural outcome.MethodsWe studied 102 RA patients receiving conventional treatment who had been judged by their consultant rheumatologist to be in remission, as well as 17 normal control subjects. Subjects underwent clinical, laboratory, functional, and quality of life assessments over 12 months. In addition to standard radiography of the hands and feet, imaging of the hands and wrists was performed with musculoskeletal ultrasonography (US) and conventional 1.5T magnetic resonance imaging (MRI) at baseline and 12 months, using validated acquisition and scoring techniques.ResultsDespite their being in clinical remission, 19% of the patients displayed deterioration in radiographic joint damage over the study period. Scores on musculoskeletal US synovial hypertrophy, power Doppler (PD), and MRI synovitis assessments in individual joints at baseline were significantly associated with progressive radiographic damage (P = 0.032, P < 0.001, and P = 0.002, respectively). Furthermore, there was a significant association between the musculoskeletal US PD score at baseline and structural progression over 12 months in totally asymptomatic metacarpophalangeal joints (P = 0.004) and 12 times higher odds of deterioration in joints with increased PD signal (odds ratio 12.21, P < 0.001).ConclusionSubclinical joint inflammation detected by imaging techniques explains the structural deterioration in RA patients in clinical remission who are receiving conventional therapy. Our findings reinforce the utility of imaging for the accurate evaluation of disease status and the prediction of structural outcome.