bluuebunny/crossref_metadata_2025_split huggingface dataset:
Late‐onset tumor necrosis factor receptor–associated periodic syndrome in multiple sclerosis patients carrying the TNFRSF1A R92Q mutation
Authors: Kümpfel Tania , Hoffmann Lisa‐Ann , Rübsamen Heike , Pöllmann Walter , Feneberg Wolfgang , Hohlfeld Reinhard , Lohse Peter 
Published: July 2007

AbstractObjectiveTumor necrosis factor receptor–associated periodic syndrome (TRAPS) is an autosomal‐dominantly inherited autoinflammatory disorder caused by mutations in the TNFRSF1A gene. It is characterized by episodes of autoinflammation usually associated with fever, abdominal pain, myalgia, exanthema, arthralgia/arthritis, and ocular involvement. We undertook this study to investigate the prevalence of TRAPS in patients with multiple sclerosis (MS) who reported, in addition to their neurologic symptoms, at least 2 other symptoms compatible with TRAPS.MethodsTwenty‐five unrelated MS patients were prospectively screened for TNFRSF1A mutations. In addition, blood samples from 365 unrelated MS patients and 407 unrelated Caucasian controls were analyzed to determine the R92Q carrier frequency.ResultsSix of 25 adult MS patients (24%) with symptoms suggestive of TRAPS were found to carry the identical arginine‐to‐glutamine substitution at amino acid position 92 (R92Q or p.Arg121Gln) encoded by exon 4 of the TNFRSF1A gene. All R92Q heterozygotes had similar symptoms, including arthralgias/arthritis, myalgias, urticarial rash, and severe fatigue, which began before the onset of MS. In 5 of the 6 patients, we could identify family members who had TRAPS symptoms and had inherited the identical mutation. The R92Q exchange was also detected in 17 of 365 unselected MS patients (4.66%) and in 12 of 407 controls (2.95%) (P = 0.112). Three patients were heterozygous carriers of MEFV variants, in 1 patient in combination with the R92Q mutation.ConclusionAutoinflammatory syndromes and especially late‐onset TRAPS should be considered in MS patients who report symptoms such as arthralgias/arthritis, myalgias, urticarial rash, and severe fatigue.
The effect of oral calcitonin on cartilage turnover and surface erosion in an ovariectomized rat model
Authors: Sondergaard Bodil‐Cecilie , Oestergaard Svetlana , Christiansen Claus , Tankó Laszló B. , Karsdal Morten Asser 
Published: July 2007

AbstractObjectiveTo investigate whether oral calcitonin treatment influences the increases in type II collagen (CII) degradation and related surface erosions of articular cartilage in ovariectomized rats.MethodsFifty rats were randomly allocated into 1 of the 5 following intervention groups: sham‐operated, ovariectomy, ovariectomy plus subcutaneously implanted 17β‐estradiol pellet, ovariectomy plus 2 mg/kg salmon calcitonin plus 50 mg/kg 5CNAC (carrier), or ovariectomy plus 50 mg/kg 5CNAC. Each treatment was administered for 9 weeks after the ovariectomy. Blood samples for biochemical marker analysis were collected from fasting animals at baseline, on day 3, and after 1, 2, 4, 6, and 9 weeks. CII degradation was quantified by specific immunoassay, and the changes in severity scores of articular cartilage erosions were visualized and scored in histologic sections of the knees.ResultsOvariectomy resulted in a marked increase in serum levels of C‐telopeptide of type II collagen (CTX‐II) (P < 0.001), which could be effectively reversed by 17β‐estradiol supplementation. Oral administration of calcitonin elicited similar decreases in serum levels of CTX‐II (P < 0.001). Histologic scoring of cartilage erosion showed significantly less cartilage erosion in calcitonin‐treated ovariectomized rats versus control ovariectomized rats that were untreated or treated with 5CNAC alone. (P < 0.01).ConclusionThe in vivo effects of calcitonin in rats suggest that calcitonin is able to counteract CII degradation and the accompanying structural disintegration of articular cartilage promoted by estrogen deficiency. Clinical assessment of the chondroprotective potential of calcitonin in postmenopausal women seems warranted.
Improved survival in psoriatic arthritis with calendar time
Authors: Ali Yaser , Tom Brian D. M. , Schentag Catherine T. , Farewell Vernon T. , Gladman Dafna D. 
Published: July 2007

AbstractObjectiveTo determine whether there has been a change in mortality rates over the last 3 decades in patients with psoriatic arthritis (PsA) whose cases were followed prospectively.MethodsPatients receiving followup care according to a standard protocol at the University of Toronto PsA Clinic between 1978 and 2004 were included. Information on patient deaths was collected prospectively. Mortality data for the general population of Ontario, Canada, stratified by 5‐year age bands, sex, and calendar year from 1978 to 2004, were used to calculate the reference rates. Standardized mortality ratios (SMRs) were calculated through use of Poisson regression models for the number of observed deaths. Time trend analyses were performed through the use of 10‐year “rolling‐average” SMRs and followup period–specific SMRs stratified by the period of entry into clinic.ResultsOf 680 patients with PsA, 106 (15.6%) (55 women and 51 men) have died. Major causes of death were disease of the circulatory system, neoplasms, diseases of the respiratory system, diseases of the gastrointestinal system, injuries/poisoning, and unknown. The overall SMR for the period 1978–2004 was 1.36 (95% confidence interval 1.12, 1.64). The estimated number of life‐years lost by the PsA patient cohort overall was 2.99 years (95% confidence interval 1.14, 4.77). For patients who entered the cohort during the years 1978–1986, the SMRs were 1.89, 1.83, and 1.21 for followup periods 1978–1986, 1987–1995, and 1996–2004, respectively. For patients who entered the cohort during the years 1987–1995, the SMRs were 0.55 and 0.82, while the SMR for those who entered during 1996–2004 was 0.56.ConclusionThe drop in SMRs in this PsA clinic population suggests that the mortality risk has improved over time. This improved survival may reflect disease severity at presentation in the earlier cohort as well as earlier diagnosis and more aggressive treatment in the more recent followup period.
Reactivity of γ/δ T cells to human 60‐kd heat‐shock protein and their cytotoxicity to aortic endothelial cells in Takayasu arteritis
Authors: Chauhan Sunil Kumar , Singh Mahavir , Nityanand Soniya 
Published: July 2007

AbstractObjectiveIncreased numbers of circulating γ/δ T cells with a restricted T cell receptor repertoire, as well as colocalization of the expression of heat‐shock protein Hsp60/65 and γ/δ T cells in the arterial lesions of patients with Takayasu arteritis (TA), indicate that γ/δ T cells may react to Hsp60 and cause damage to the arterial endothelium. In this study we investigated the proliferative responses of γ/δ T cells to human Hsp60 and their cytotoxicity to human aortic endothelial cells (ECs) in patients with TA.MethodsBlood samples were obtained from 12 patients with TA, 8 patients with systemic lupus erythematosus (SLE) (as disease controls), and 10 healthy control subjects. Proliferative responses of circulating γ/δ T cells to human Hsp60 were detected by flow cytometry–based bromodeoxyuridine incorporation assay. Cytotoxicity of the γ/δ T cells to human aortic ECs was analyzed by colorimetric lactate dehydrogenase release assay.ResultsThe γ/δ T cells of 11 of 12 patients with TA exhibited reactivity to Hsp60, whereas none of the γ/δ T cells from patients with SLE or healthy controls showed reactivity (both P < 0.001). The mean ± SD proliferative response of γ/δ T cells in patients with TA was 21.4 ± 11.3%, compared with 4.2 ± 1.2% in patients with SLE and 4.01 ± 1.82% in healthy controls (both P < 0.001). In addition, compared with the control groups, the γ/δ T cells of patients with TA had increased spontaneous cytotoxicity to aortic ECs (22.1 ± 15.0% versus 9.6 ± 2.13% in SLE patients and 8.1 ± 4.7% in healthy controls; both P < 0.005), which was further enhanced following stimulation of γ/δ T cells with Hsp60. The cytotoxicity of the γ/δ T cells was significantly inhibited by treatment of these cells with concanamycin A and anti–Fas ligand–blocking antibodies.ConclusionThe results show that γ/δ T cells in patients with TA are reactive to Hsp60 and exhibit cytotoxicity to aortic ECs, suggesting a key role of Hsp60 and γ/δ T cells in the pathogenesis of TA.
Anti–β2‐glycoprotein I antibodies induce monocyte release of tumor necrosis factor α and tissue factor by signal transduction pathways involving lipid rafts
Authors: Sorice Maurizio , Longo Agostina , Capozzi Antonella , Garofalo Tina , Misasi Roberta , Alessandri Cristiano , Conti Fabrizio , Buttari Brigitta , Riganò Rachele , Ortona Elena , Valesini Guido 
Published: July 2007

AbstractObjectiveTo investigate the association of β2‐glycoprotein I (β2GPI) with lipid rafts in monocytic cells and to evaluate the proinflammatory and procoagulant effects of anti‐β2GPI binding to its target antigen on the monocyte plasma membrane.MethodsHuman monocytes were fractionated by sucrose density‐gradient centrifugation and analyzed by Western blotting. Immunoprecipitation experiments were performed to analyze the association of β2GPI with lipid rafts and the possible interaction of β2GPI with annexin A2 and Toll‐like receptor 4 (TLR‐4). Monocytes were then stimulated with affinity‐purified anti‐β2GPI antibodies from patients with the antiphospholipid syndrome (APS). Interleukin‐1 receptor–associated kinase (IRAK) phosphorylation and NF‐κB activation were evaluated by immunoprecipitation and transcription factor assay, respectively. Supernatants from monocytes were tested for tumor necrosis factor α (TNFα) and tissue factor (TF) levels by enzyme‐linked immunosorbent assay.ResultsWe found β2GPI and its putative receptor annexin A2 in lipid raft fractions of human monocytes. Moreover, there was an association between β2GPI and TLR‐4, suggesting that it was partially dependent on raft integrity. Triggering with anti‐β2GPI antibodies induced IRAK phosphorylation and consequent NF‐κB activation, which led to the release of TNFα and TF.ConclusionAnti‐β2GPI antibodies react with their target antigen, likely in association with annexin A2 and TLR‐4, in lipid rafts in the monocyte plasma membrane. Anti‐β2GPI binding triggers IRAK phosphorylation and NF‐κB translocation, leading to a proinflammatory and procoagulant monocyte phenotype characterized by the release of TNFα and TF, respectively. These findings provide new insight into the pathogenesis of APS, improving our knowledge of valuable therapeutic targets.
Clinical and genetic risk factors for pneumonia in systemic lupus erythematosus
Authors: Kinder Brent W. , Freemer Michelle M. , King Talmadge E. , Lum Raymond F. , Nititham Joanne , Taylor Kim , Edberg Jeffrey C. , Bridges S. Louis , Criswell Lindsey A. 
Published: July 2007

AbstractObjectiveTo define the contribution of polymorphisms in genes encoding tumor necrosis factor (TNF), mannose‐binding lectin (MBL), and Fcγ receptor IIa (FCGR2A) as well as clinical factors, to the development of pneumonia in patients with systemic lupus erythematosus (SLE).MethodsWe studied 282 SLE patients from a multiethnic cohort. Pneumonia events and clinical risk factors for pneumonia were identified through medical record review. Genotyping was performed for MBL (+223, +230, and +239), TNF (–308, –238, and +488), and FCGR2A (–131H/R) polymorphisms. Univariate analyses were performed to identify clinical and genetic risk factors for pneumonia. Covariates for multivariate analysis included sex, ethnicity, treatment with immunomodulators, and leukopenia.ResultsForty‐two patients (15%) had at least 1 episode of pneumonia. Polymorphism of the TNF gene, particularly the –238A allele and a related haplotype, revealed the most striking and consistent association with pneumonia in univariate analyses. Results of multivariate analyses indicated an odds ratio (OR) for the TNF –238A allele of 3.5 (P = 0.007) and an OR for the related haplotype of 5.4 (P = 0.001). Male sex, treatment with immunomodulators, and leukopenia also influenced the risk of pneumonia.ConclusionThese findings suggest that specific TNF variants may identify SLE patients who are at particularly high risk of developing pneumonia. Given the prevalence and excessive morbidity associated with pneumonia in SLE, these findings have clinical relevance and provide insight into the pathogenesis.
Fractalkine is a novel chemoattractant for rheumatoid arthritis fibroblast‐like synoviocyte signaling through MAP kinases and Akt
Authors: Volin Michael V. , Huynh Nha , Klosowska Karolina , Chong Kyle K. , Woods James M. 
Published: July 2007

AbstractObjectiveFibroblast‐like synoviocytes (FLS) are a major constituent of the hyperplastic synovial pannus that aggressively invades cartilage and bone during the course of rheumatoid arthritis (RA). Fractalkine (FKN/CX3CL1) expression is up‐regulated in RA synovium and RA synovial fluid. While RA FLS express the FKN receptor, CX3CR1, the pathophysiologic relevance of FKN stimulation of RA FLS is not understood. This study was undertaken to better characterize the relationship between FKN and the RA FLS that both produce it and express its receptor.MethodsRA FLS were subjected to chemotaxis and proliferation assays, Western blotting, enzyme‐linked immunosorbent assays, and filamentous actin staining to characterize the relationship between FKN and RA FLS.ResultsFKN secretion by RA FLS was regulated mainly by tumor necrosis factor α. Stimulation of RA FLS with FKN led to significant cytoskeletal rearrangement but no proliferation. Chemotaxis assays revealed that FKN was a novel chemoattractant for RA FLS. Stimulation of RA FLS with FKN resulted in activation of MAP kinases and Akt. JNK, ERK‐1/2, and Akt (at both Ser‐473 and Thr‐308) were each up‐regulated in a time‐dependent manner. Inhibition of ERK‐1/2–mediated signaling, but not JNK or Akt, significantly repressed FKN‐induced RA FLS migration.ConclusionThese findings indicate a novel role of FKN in regulating RA FLS cytoskeletal structure and migration. FKN specifically induces RA FLS phosphorylation of the MAP kinases JNK and ERK‐1/2, as well as full activation of Akt.
Development of psoriasis after B cell depletion with rituximab
Authors: Dass Shouvik , Vital Edward M. , Emery Paul 
Published: July 2007

AbstractThe B cell–depleting monoclonal antibody rituximab is a novel therapy for the rheumatic diseases, with an increasing body of evidence regarding its safety and efficacy in an expanding range of indications. However, there is uncertainty over its potential use in, and impact on, autoantibody‐negative diseases. We describe 3 patients, with no known risk factor for psoriasis, who developed psoriasis (and 1 who also developed features of psoriatic arthritis) after receiving rituximab for a variety of indications, namely, seropositive and seronegative rheumatoid arthritis and systemic lupus erythematosus. In all cases, the underlying disease responded well to rituximab. The interpretation of this possible side effect of rituximab remains unclear, but a B cell–depleted environment may induce abnormal T cell responses, possibly provoked either by subclinical infection or by the removal of mechanisms whereby B cells regulate T cells. These cases suggest that the pathogenesis of psoriasis may not require normal numbers of B cells and that proposed treatment of psoriasis and psoriatic arthritis with rituximab may result in unpredictable responses.
A common genetic background for inflammatory bowel disease and ankylosing spondylitis: A genealogic study in Iceland
Authors: Thjodleifsson Bjarni , Geirsson árni J. , Björnsson Sigurdur , Bjarnason Ingvar 
Published: July 2007

AbstractObjectivePatients with ankylosing spondylitis (AS) and ∼50% of their first‐degree relatives may have a genetic abnormality that results in subclinical intestinal inflammation. This study was undertaken to examine the familial occurrence and cosegregation of AS and inflammatory bowel disease (IBD) in order to determine whether there is a shared genetic risk factor in families.MethodsThe Icelandic genealogy database and population‐wide data on all living Icelanders diagnosed as having AS (n = 205) and/or IBD (n = 1,352) were used to estimate the risk ratios of AS for relatives of patients with AS, the risk ratios of IBD for relatives of patients with IBD, and the cross‐risk ratios of AS for relatives of patients with IBD or of IBD for relatives of patients with AS. The mean kinship coefficients for each disease were calculated. The control population for disease risk calculations comprised 10,000–100,000 sets of matched Icelandic subjects.ResultsFirst‐, second‐, and third‐degree relatives of patients with AS had risk ratios of 94, 25, and 3.5, respectively, indicating an increased risk of developing AS (each P < 0.0005), while first‐, second‐, and third‐degree relatives of patients with IBD had risk ratios for IBD of 4.4, 2.2, and 1.4, respectively (each P < 0.0001). The cross‐risk ratios of IBD were 3.0 and 2.1 in first‐ and second‐degree relatives of patients with AS, respectively, and were the same for AS in first‐ and second‐degree relatives of patients with IBD. With the exception of Crohn's disease, the risk of having AS, ulcerative colitis, or IBD in spouses of patients with these diseases did not differ significantly from that in controls. Calculation of the kinship coefficients confirmed these patterns of familial risk.ConclusionPatients with AS or IBD in Iceland are significantly more related to each other than are randomly sampled control subjects, in terms of an increased risk of either or both conditions developing in third‐degree relatives. These findings suggest that one or more undiscovered genetic variants may underlie the risk of both diseases.
Association of arthritis with a gene complex encoding C‐type lectin–like receptors
Authors: Lorentzen Johnny C. , Flornes Line , Eklöw Carina , Bäckdahl Liselotte , Ribbhammar Ulrica , Guo Jian Ping , Smolnikova Marina , Dissen Erik , Seddighzadeh Maria , Brookes Anthony J. , Alfredsson Lars , Klareskog Lars , Padyukov Leonid , Fossum Sigbjörn 
Published: July 2007

AbstractObjectiveTo identify susceptibility genes in a rat model of rheumatoid arthritis (RA) and to determine whether the corresponding human genes are associated with RA.MethodsGenes influencing oil‐induced arthritis (OIA) were position mapped by comparing the susceptibility of inbred DA rats with that of DA rats carrying alleles derived from the arthritis‐resistant PVG strain in chromosomal fragments overlapping the quantitative trait locus Oia2. Sequencing of gene complementary DNA (cDNA) and analysis of gene messenger RNA (mRNA) expression were performed to attempt to clone a causal gene. Associations with human RA were evaluated by genotyping single‐nucleotide polymorphisms (SNPs) in the corresponding human genes and by analyzing frequencies of alleles and haplotypes in RA patients and age‐, sex‐, and area‐matched healthy control subjects.ResultsCongenic DA rats were resistant to OIA when they carried PVG alleles for the antigen‐presenting lectin‐like receptor gene complex (APLEC), which encodes immunoregulatory C‐type lectin–like receptors. Multiple differences in cDNA sequence and mRNA expression precluded cloning of a single causal gene. Five corresponding human APLEC genes were identified and targeted. The SNP rs1133104 in the dendritic cell immunoreceptor gene (DCIR), and a haplotype including that marker and 4 other SNPs in DCIR and its vicinity showed an indication of allelic association with susceptibility to RA in patients who were negative for antibodies to cyclic citrullinated peptide (anti‐CCP), with respective odds ratios of 1.27 (95% confidence interval [95% CI] 1.06–1.52; uncorrected P = 0.0073) and 1.37 (95% CI 1.12–1.67; uncorrected P = 0.0019). Results of permutation testing supported this association of the haplotype with RA.ConclusionRat APLEC is associated with susceptibility to polyarthritis, and human APLEC and DCIR may be associated with susceptibility to anti‐CCP–negative RA.
Association of interleukin‐6 and interleukin‐10 genotypes with radiographic damage in rheumatoid arthritis is dependent on autoantibody status
Authors: Marinou I. , Healy J. , Mewar D. , Moore D. J. , Dickson M. C. , Binks M. H. , Montgomery D. S. , Walters K. , Wilson A. G. 
Published: July 2007

AbstractObjectiveRecent evidence has highlighted a major genetic contribution to radiographic damage in rheumatoid arthritis (RA). The objective of this study was to determine whether genetic variants in the loci for interleukin‐1 (IL‐1), IL‐6, IL‐10, protein tyrosine phosphatase N22 (PTPN22), and selenoprotein S are associated with radiographic damage.MethodsModified Larsen scores of radiographic damage were determined in a cross‐sectional population of patients with RA (n = 964). Rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti‐CCP) were also assayed. The Kruskal‐Wallis nonparametric test was used to compare median radiographic damage scores across genotype groups, followed by the Cuzick nonparametric test for trend to assess gene‐dose effects.ResultsAn allele‐dose association of IL‐6 −174G with increasing radiographic damage was present (P = 0.005), but only in patients who were RF positive (P = 0.004) or anti‐CCP positive (P = 0.01). Patients with the IL‐10 −592CC genotype had more extensive radiographic damage than did those with the AC or AA genotype (P = 0.006), but this was observed only among patients who were RF negative (P = 0.002) or anti‐CCP negative (P = 0.002). However, RF status and anti‐CCP status were not associated with the IL‐6 or IL‐10 genotype. No other genetic associations were detected, apart from a marginal association of PTPN22 +1858T with increased radiographic damage.ConclusionThe reported associations of IL‐6 −174G with high IL‐6 production and IL‐10 −592 with low IL‐10 production and our own results support a role of genetically determined dysregulated cytokine production in disease severity. The lack of association of these genotypes with RF and anti‐CCP antibody status suggests that they act downstream of autoantibody production. We conclude that IL‐6 and IL‐10 genotypes may be useful in predicting disease severity in autoantibody‐positive and autoantibody‐negative patients, respectively.