bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reciprocal cross‐talk between RANKL and interferon‐γ–inducible protein 10 is responsible for bone‐erosive experimental arthritis
Authors: Kwak Han Bok , Ha Hyunil , Kim Ha‐Neui , Lee Jong‐Ho , Kim Hun Soo , Lee Seungbok , Kim Hyun‐Man , Kim Jung Yeon , Kim Hong‐Hee , Song Yeong Wook , Lee Zang Hee 
Published: April 2008

AbstractObjectiveInterferon‐γ–inducible protein 10 (IP‐10; also called CXCL10), a chemokine important in the migration and proliferation of T cells, is induced in a wide variety of cell types. However, the role of IP‐10 in rheumatoid arthritis (RA) remains largely unknown. The purpose of this study was to examine the potential role of IP‐10 in bone resorption and RA through examination of a mouse model of collagen‐induced arthritis (CIA).MethodsThe effects of IP‐10 on mouse T cells during osteoclast differentiation were examined in migration assays. The bone‐erosive activity of IP‐10 was determined in vivo in a mouse model of CIA by histologic and immunostaining analyses. Cytokine levels in serum and culture medium were measured with sandwich enzyme‐linked immunosorbent assays.ResultsSerum concentrations of IP‐10 were significantly higher in mice with CIA than in control mice. RANKL greatly induced IP‐10 expression in osteoclast precursors, but not in mature osteoclasts. IP‐10 stimulated the expression of RANKL and tumor necrosis factor α (TNFα) in CD4+ T cells and induced osteoclastogenesis in cocultures of CD4+ T cells and osteoclast precursors. However, IP‐10 did not induce RANKL or TNFα in CD8+ T cells. Treatment with neutralizing antibody to IP‐10 significantly inhibited the infiltration of CD4+ T cells and F4/80+ macrophages into the synovium and attenuated bone destruction in mice with CIA. Furthermore, levels of RANKL and TNFα were inhibited by antibody to IP‐10. Bone erosion was observed in mice infected with an IP‐10 retrovirus.ConclusionOur findings suggest that IP‐10 plays a critical role in the infiltration of CD4+ T cells and F4/80+ macrophages into inflamed joints and causes bone destruction. Our results provide the first evidence that IP‐10 contributes to the recruitment of inflammatory cells and is involved in bone erosion in inflamed joints.
Autoantibody prevalence and lupus characteristics in a unique African American population
Authors: Kamen Diane L. , Barron Mia , Parker Tia M. , Shaftman Stephanie R. , Bruner Gail R. , Aberle Teresa , James Judith A. , Scofield R. Hal , Harley John B. , Gilkeson Gary S. 
Published: April 2008

AbstractObjectiveThe Gullah population of the Sea Islands of South Carolina is a unique group of African Americans who, due to geographic and cultural factors, remained isolated with minimal genetic admixture until the 1950s. Because of the unique homogeneous nature of the Gullah, we sought to define the genetic and environmental factors contributing to systemic lupus erythematosus (SLE) in this population.MethodsUsing data from our ongoing cohort study of lupus in the Gullah population, which we established in 2003, disease characteristics and serologic profiles were summarized for 184 patients with SLE, 144 unaffected first‐degree relatives, and 144 matched unrelated, unaffected control subjects. These findings were compared with those in 2 other large cohorts of African Americans with SLE.ResultsIn the Gullah cohort, we observed a high prevalence of SLE multiplex families (26.6%), malar rash (56.0%), discoid rash (34.2%), photosensitivity (60.9%), and oral/nasal ulcerations (43.5%), but a lower prevalence of hematologic and pleuropericardial disease than has been reported in other African American cohorts. Overall renal and central nervous system involvement, number of American College of Rheumatology disease criteria met, and SLE Damage Index scores were similar to those reported in other cohorts. Of interest, male and female first‐degree relatives and male and female control subjects in this cohort had similar rates of antinuclear antibody positivity, whereas lupus‐specific antibodies were more prevalent in the women than in the men.ConclusionThese data indicate that the severity of lupus in the Gullah population is similar to that in other African American populations, whereas skin disease and familial disease prevalence are increased in the Gullah. These findings suggest that there is an increased genetic influence on overall disease in this cohort compared with that in other African American cohorts, which confirms the unique nature of this cohort.
Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: A twelve‐month, multicenter, randomized, double‐blind, placebo‐controlled, phase II clinical trial
Authors: Cohen Stanley B. , Dore Robin K. , Lane Nancy E. , Ory Peter A. , Peterfy Charles G. , Sharp John T. , van der Heijde Désirée , Zhou Lifen , Tsuji Wayne , Newmark Richard ,   Denosumab Rheumatoid Arthritis Study Group
Published: April 2008

AbstractObjectiveRANKL is essential for osteoclast development, activation, and survival. Denosumab is a fully human monoclonal IgG2 antibody that binds RANKL, inhibiting its activity. The aim of this multicenter, randomized, double‐blind, placebo‐controlled, phase II study was to evaluate the effects of denosumab on structural damage in patients with rheumatoid arthritis (RA) receiving methotrexate treatment.MethodsRA patients received subcutaneous placebo (n = 75), denosumab 60 mg (n = 71), or denosumab 180 mg (n = 72) injections every 6 months for 12 months. The primary end point was the change from baseline in the magnetic resonance imaging (MRI) erosion score at 6 months.ResultsAt 6 months, the increase in the MRI erosion score from baseline was lower in the 60‐mg denosumab group (mean change 0.13; P = 0.118) and significantly lower in the 180‐mg denosumab group (mean change 0.06; P = 0.007) than in the placebo group (mean change 1.75). A significant difference in the modified Sharp erosion score was observed as early as 6 months in the 180‐mg denosumab group (P = 0.019) as compared with placebo, and at 12 months, both the 60‐mg (P = 0.012) and the 180‐mg (P = 0.007) denosumab groups were significantly different from the placebo group. Denosumab caused sustained suppression of markers of bone turnover. There was no evidence of an effect of denosumab on joint space narrowing or on measures of RA disease activity. Rates of adverse events were comparable between the denosumab and placebo groups.ConclusionAddition of twice‐yearly injections of denosumab to ongoing methotrexate treatment inhibited structural damage in patients with RA for up to 12 months, with no increase in the rates of adverse events as compared with placebo.
Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis
Authors: Lovell Daniel J. , Reiff Andreas , Ilowite Norman T. , Wallace Carol A. , Chon Yun , Lin Shao‐Lee , Baumgartner Scott W. , Giannini Edward H. ,   Pediatric Rheumatology Collaborative Study Group
Published: April 2008

AbstractObjectiveTo evaluate the safety and efficacy of up to 8 years of etanercept treatment in patients with polyarticular‐course juvenile rheumatoid arthritis (JRA).MethodsPatients with JRA who previously participated in a randomized controlled trial (RCT) of etanercept were eligible to receive etanercept in a long‐term open‐label extension (OLE) trial. Safety end points included the incidences of serious adverse events (SAEs), medically important infections (MIIs), and death. Efficacy end points included the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement.ResultsOf the 69 patients originally enrolled in the RCT, 58 (84%) participated in the OLE, for a total of 318 patient‐years of etanercept exposure. A total of 42 of the 58 patients (72%) entered the fourth year of continuous etanercept treatment, and 26 patients (45%) entered the eighth year. Sixteen patients (23% of those entering the RCT) reported 39 SAEs. The overall rate of SAEs (0.12 per patient‐year) did not increase with long‐term exposure to etanercept. The rate of MIIs (0.03 per patient‐year) remained low; 1 new MII was reported in patients with ≥5 years of etanercept exposure. No cases of tuberculosis, opportunistic infections, malignancies, lymphomas, lupus, demyelinating disorders, or deaths were reported. An ACR Pedi 70 response or higher was achieved by 100% of patients with 8 years of data (11 of 11) and by 61% of patients according to the last observation carried forward data (28 of 46).ConclusionThese data suggest that the acceptable safety profile of etanercept therapy is maintained for up to 8 years in this population of JRA patients. Improvements in the signs and symptoms of JRA were also maintained for up to 8 years.
The shared epitope hypothesis in rheumatoid arthritis: Evaluation of alternative classification criteria in a large UK Caucasian cohort
Authors: Morgan Ann W. , Haroon‐Rashid Lubna , Martin Stephen G. , Gooi Hock‐Chye , Worthington Jane , Thomson Wendy , Barrett Jennifer H. , Emery Paul 
Published: April 2008

AbstractObjectiveMany classification systems for the HLA–DRB1 allelic association with rheumatoid arthritis (RA) have been reported, but few have been validated in additional populations. We sought to evaluate 3 different DRB1 allele classification systems in a large cohort of Caucasian RA patients and control subjects in the UK.MethodsHLA–DRB1 typing was undertaken in 1,325 Caucasian RA patients and 462 healthy Caucasian controls who were residents of the UK. Logistic regression analyses were performed to investigate the different classification systems.ResultsWe confirmed the association between the susceptibility alleles S2 and S3P, as proposed by Tezenas du Montcel, and the presence of RA in UK Caucasians. A significant hierarchy of risk was observed within the S3P allele group. There was no evidence of a significant association between DRB1*1001 and RA. Our data did not support the hypothesis that an isoleucine at position 67 conferred protection against RA, other than in contrast to the susceptibility alleles. However, the presence of an aspartic acid at amino acid 70 did appear to confer some degree of protection.ConclusionWe were unable to fully substantiate any of the 3 recent revisions of the shared epitope hypothesis in this large cohort of Caucasian RA patients and control subjects in the UK. This reinforces the importance of evaluating disease susceptibility alleles in different Caucasian populations as well as in other ethnic groups. In particular, it will be important to clarify the precise DRB1 association in a given population before DRB1 genotyping is incorporated into clinical diagnostic or treatment algorithms.
Profound and paradoxical impact on arthritis and autoimmunity of the rat antigen‐presenting lectin‐like receptor complex
Authors: Guo Jian Ping , Bäckdahl Liselotte , Marta Monica , Mathsson Linda , Rönnelid Johan , Lorentzen Johnny C. 
Published: April 2008

AbstractObjectiveThe antigen‐presenting lectin‐like receptor complex (APLEC) was recently identified as a genetic determinant for arthritis susceptibility. We undertook this study to define mechanisms underlying the impact of APLEC on arthritis, to determine whether sex effects occur, and to determine whether APLEC influences different types of arthritis and phenotypes other than susceptibility.MethodsArthritis‐susceptible DA rats were compared with sex‐matched congenic rats in which APLEC alleles were substituted with alleles from arthritis‐resistant PVG rats. Six different arthritogenic agents were injected at the base of the tail: Freund's incomplete adjuvant, pristane, squalene, killed mycobacteria, yeast β‐glucan, or rat type II collagen (CII). Arthritis was visually scored, body weight was measured, and anti‐CII IgG and cytokine messenger RNA (mRNA) levels were determined by enzyme‐linked immunosorbent assay and reverse transcription–polymerase chain reaction, respectively.ResultsIn 5 models of rheumatoid arthritis (RA), congenic rats deviated profoundly from DA rats by having reduced arthritis susceptibility, delayed onset, decreased severity, and/or reduced body weight loss. Paradoxical opposite genetic effects were noted, including a more severe disease course in congenic males in pristane‐induced arthritis and decreased clinical signs in collagen‐induced arthritis despite increased autoantibody levels. Interestingly, the anti‐CII IgG isotype profile was skewed in congenic rats, and markedly reduced lymph node mRNA levels for interleukin‐17 suggested that the cytokine profile of autoreactive T helper cells was also skewed in a less pathogenic direction.ConclusionRat APLEC regulates autoimmunity and multiple phenotypes in several types of arthritis. However, delineating the genetic impact may require stratification for sex or mode of arthritis induction. This pathogenetic complexity should be considered when evaluating APLEC in inflammatory and autoimmune diseases, including RA.
Src kinases in systemic sclerosis: Central roles in fibroblast activation and in skin fibrosis
Authors: Skhirtladze Catherine , Distler Oliver , Dees Clara , Akhmetshina Alfiya , Busch Nicole , Venalis Paulius , Zwerina Jochen , Spriewald Bernd , Pileckyte Margarita , Schett Georg , Distler Jörg H. W. 
Published: April 2008

AbstractObjectiveSrc kinases are nonreceptor tyrosine kinases, which have been implicated in cytoskeletal organization and cell mobility. This study was undertaken to evaluate the potential of Src kinases as novel targets of antifibrotic therapies.MethodsFibroblast cultures were obtained from 10 patients with systemic sclerosis (SSc) and 5 healthy subjects. Src signaling was inhibited using small‐molecule inhibitors and overexpression of a dominant‐negative mutant of Src and of the endogenous inhibitor Csk. The expression of extracellular matrix proteins was analyzed by real‐time polymerase chain reaction and by SirCol collagen assay. Toxic effects were excluded by MTT assay and staining for annexin V and propidium iodide. The mouse model of bleomycin‐induced dermal fibrosis was used to assess the role of Src kinases in dermal fibrosis in vivo.ResultsStimulation with transforming growth factor β and platelet‐derived growth factor activated Src signaling in dermal fibroblasts from patients with SSc and healthy donors. Incubation with the Src kinase inhibitors or overexpressed mutant Src or Csk reduced the synthesis of messenger RNA for COL1A1, COL1A2, and fibronectin 1. A dose‐dependent reduction in collagen release was also observed at the protein level. No inhibitory effects on proliferation and no increase in the number of apoptotic or necrotic fibroblasts were observed. Consistent with the in vitro data, inhibition of Src kinases prevented experimental dermal fibrosis. Dermal thickness, the amount of collagen protein, and the number of myofibroblasts were reduced in a dose‐dependent manner.ConclusionThese findings indicate that Src kinases play important roles in the activation of fibroblasts and in the development of experimental fibrosis. Thus, Src kinases might be interesting targets for novel antifibrotic therapies in SSc.
The pattern of response to anti–interleukin‐1 treatment distinguishes two subsets of patients with systemic‐onset juvenile idiopathic arthritis
Authors: Gattorno Marco , Piccini Alessandra , Lasigliè Denise , Tassi Sara , Brisca Giacomo , Carta Sonia , Delfino Laura , Ferlito Francesca , Pelagatti Maria Antonietta , Caroli Francesco , Buoncompagni Antonella , Viola Stefania , Loy Anna , Sironi Marina , Vecchi Annunciata , Ravelli Angelo , Martini Alberto , Rubartelli Anna 
Published: April 2008

AbstractObjectiveTo assess the clinical response to interleukin‐1 (IL‐1) blockade and in vitro IL‐1β and IL‐18 secretion in patients with systemic‐onset juvenile idiopathic arthritis (JIA).MethodsTwenty‐two patients with systemic‐onset JIA were treated with the IL‐1 receptor antagonist (IL‐1Ra) anakinra. Monocytes from 18 patients and 20 healthy donors were activated by different Toll‐like receptor ligands. Intracellular and secreted IL‐1β and IL‐18 were analyzed by Western blotting and enzyme‐linked immunosorbent assay.ResultsTen patients with systemic‐onset JIA exhibited a dramatic response to anakinra and were classified as complete responders. Eleven patients had an incomplete response or no response, and 1 patient could not be classified in terms of response. Compared with patients who had an incomplete response or no response, complete responders had a lower number of active joints (P = 0.02) and an increased absolute neutrophil count (P = 0.02). In vitro IL‐1β and IL‐18 secretion in response to various stimuli was not increased and was independent of treatment efficacy. Likewise, secretion of IL‐1Ra by monocytes from patients with systemic‐onset JIA was not impaired. An overall low level of IL‐1β secretion upon exposure to exogenous ATP was observed, unrelated to treatment responsiveness or disease activity.ConclusionTwo subsets of systemic‐onset JIA can be identified according to patient response to IL‐1 blockade. The 2 subsets appear to be characterized by some distinct clinical features. In vitro secretion of IL‐1β and IL‐18 by monocytes from patients with systemic‐onset JIA is not increased and is independent of both treatment outcome and disease activity.
Identification of the molecular response of articular cartilage to injury, by microarray screening: Wnt‐16 expression and signaling after injury and in osteoarthritis
Authors: Dell'Accio Francesco , De Bari Cosimo , Eltawil Noha M. , Vanhummelen Paul , Pitzalis Costantino 
Published: April 2008

AbstractObjectiveTo characterize the molecular response of adult human articular cartilage to acute mechanical injury.MethodsAn established ex vivo model was used to compare gene expression of adult human articular cartilage explants 24 hours after mechanical injury with that of uninjured controls by microarray analysis of gene expression. Confirmation for selected genes was obtained by real‐time polymerase chain reaction and immunohistochemical analysis. Expression of selected genes was also investigated in preserved and osteoarthritic (OA) cartilage.ResultsSix hundred ninety genes were significantly regulated at least 2‐fold following mechanical injury. They included genes previously reported to be differentially expressed in OA versus normal cartilage or having allelic variants genetically linked to OA. Significant functional clusters included genes associated with wound healing, developmental processes, and skeletal development. The transforming growth factor β, fibroblast growth factor, and Wnt pathways were modulated. A systematic analysis of the Wnt signaling pathway revealed up‐regulation of Wnt‐16, down‐regulation of FRZB, up‐regulation of Wnt target genes, and nuclear localization of β‐catenin in injured cartilage. In addition, in OA, Wnt‐16 and β‐catenin were barely detectable in preserved cartilage areas, but were dramatically up‐regulated in areas of the same joint with moderate to severe OA damage.ConclusionOur findings indicate that mechanical injury to adult human articular cartilage results in the activation of a signaling response, with reactivation of morphogenetic pathways. Therapeutic targeting of such pathways may improve current protocols of joint surface defect repair and/or prevent the evolution of such lesions into posttraumatic OA.
Triple therapy in early active rheumatoid arthritis: A randomized, single‐blind, controlled trial comparing step‐up and parallel treatment strategies
Authors: Saunders S. A. , Capell H. A. , Stirling A. , Vallance R. , Kincaid W. , McMahon A. D. , Porter D. R. 
Published: April 2008

AbstractObjectiveThe Tight Control of Rheumatoid Arthritis study previously demonstrated that an intensive step‐up disease‐modifying antirheumatic drug (DMARD) treatment strategy targeting persistent disease activity was superior to routine care in the management of early rheumatoid arthritis (RA). We undertook this study to test the hypothesis that early parallel triple therapy achieves better outcomes than step‐up therapy within an intensive disease management regimen.MethodsNinety‐six patients with early RA (mean disease duration 11.5 months) were randomized to receive step‐up therapy (sulfasalazine [SSZ] monotherapy, then after 3 months, methotrexate [MTX] was added, and when the maximum tolerated dosage of MTX was reached, hydroxychloroquine [HCQ] was added) or parallel triple therapy (SSZ/MTX/HCQ). All patients were assessed monthly for 12 months. If their disease activity score in 28 joints (DAS28) was ≥3.2, the dosage of DMARDs was increased according to protocol, and swollen joints were injected with triamcinolone acetonide (maximum dosage 80 mg per month). A metrologist who was blinded to the treatment allocation performed assessments every 3 months. The primary outcome measure was the mean decrease in the DAS28 score at 12 months.ResultsBoth groups showed substantial improvements in disease activity and functional outcome. At 12 months, the mean decrease in the DAS28 score was −4.0 (step‐up therapy group) versus −3.3 (parallel therapy group) (P = 0.163). No significant differences in the percentages of patients with DAS28 remission (step‐up therapy group 45% versus parallel triple therapy group 33%), DAS28 good response (60% versus 41%, respectively), or American College of Rheumatology criteria for 20% improvement (ACR20) (77% versus 76%, respectively), ACR50 (60% versus 51%, respectively), or ACR70 (30% versus 20%, respectively) responses were seen. Radiologic progression was similar in both groups.ConclusionThis study confirms that highly effective control of disease activity can be achieved using conventional DMARDs as part of an intensive disease management strategy. Within this setting, step‐up therapy is at least as effective as parallel triple therapy.
Assessment of unmet needs and the lack of generalizability in the design of randomized controlled trials for scleroderma treatment
Authors: Villela Renata , Yuen Sai Yan , Pope Janet E. , Baron Murray 
Published: April 2008

AbstractObjectiveTo determine the generalizability of randomized controlled trials (RCTs) in the treatment of systemic sclerosis (SSc) using the Canadian Scleroderma Research Group (CSRG) database.MethodsWe identified articles related to SSc published from 1958 to 2006. Key points on trial design were recorded. The inclusion/exclusion criteria were used in conjunction with the CSRG database to determine the proportion of patients with SSc who would theoretically be eligible for these trials. Articles were classified into subcategories according to the target system. The CSRG database contains 438 patients with SSc from 14 Canadian centers. Results were in median (%) and mean (%) with 95% confidence intervals (95% CIs).ResultsIn total, 210 articles were evaluated and 73 were selected for inclusion in this study. The mean percentage of eligible patients with SSc associated with other conditions was 35% (95% CI 17–53) for Raynaud's phenomenon, 24% (95% CI 1–47) for digital ulcers, 48% (95% CI 27–68) for gastrointestinal (GI) involvement, 32% (95% CI 20–43) for overall disease modification, 6% (95% CI 4–8) for pulmonary arterial hypertension, 2% (95% CI 0–4) for interstitial lung disease, and 38% (95% CI 12–64) for other categories.ConclusionExcept for GI trials, <38% of the identified patients with SSc would have been suitable to enter the RCTs. Although some patients would be ineligible because they lack certain organ involvement, RCTs designed to include appropriate patients with SSc are needed; there are few proven treatments and trials typically do not include the majority of those who could potentially benefit from the intervention.