bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Objective

To 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.

Methods

Human 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.

Results

We 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.

Conclusion

Anti‐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

Objective

To 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).

Methods

We 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.

Results

Forty‐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.

Conclusion

These 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

Objective

Fibroblast‐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.

Methods

RA 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.

Results

FKN 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.

Conclusion

These 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

The 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

Objective

Patients 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.

Methods

The 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.

Results

First‐, 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.

Conclusion

Patients 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

Objective

To identify susceptibility genes in a rat model of rheumatoid arthritis (RA) and to determine whether the corresponding human genes are associated with RA.

Methods

Genes 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.

Results

Congenic 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.

Conclusion

Rat 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

Objective

Recent 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.

Methods

Modified 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.

Results

An 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.

Conclusion

The 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.
Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis
Authors: Bang Holger , Egerer Karl , Gauliard Anke , Lüthke Kirsten , Rudolph Paul E. , Fredenhagen Gert , Berg Wigbert , Feist Eugen , Burmester Gerd‐R.
Published: July 2007

Objective

Modification of antigens represents a trigger for the generation of autoantibodies. In the pathogenesis of rheumatoid arthritis (RA), citrullination of proteins has been shown to be a critical process, and the determination of antibodies against citrullinated antigens has been a diagnostic milestone. We undertook this study to determine whether antibodies to mutated and citrullinated vimentin (MCV) could serve as a diagnostic and prognostic marker for RA.

Methods

We identified novel isoforms of human MCV in the synovial fluid of RA patients. The significance of these disease‐related modifications was investigated by the analysis of autoantibody reactivities. In a group of 1,151 RA patients, the diagnostic significance and the prognostic value of an anti‐MCV enzyme‐linked immunosorbent assay (ELISA) were compared with that of an anti–cyclic citrullinated peptide (anti‐CCP) ELISA.

Results

In RA, sensitivities of 82% and 72% were calculated for the anti‐MCV and anti‐CCP assays, respectively. The specificity of both assays was comparable (98% and 96%, respectively). In followup analyses of 16 RA patients with moderate disease activity (mean Disease Activity Score in 28 joints [DAS28] of 2.72) and 26 RA patients with active disease (mean DAS28 of 5.07), disease stratification of RA was possible using the anti‐MCV assay (P = 0.0084). A significant correlation of anti‐MCV antibodies with the DAS28 was documented (r = 0.5334, P = 0.0003), in 42 RA patients (n = 427 antibody determinations at different time points).

Conclusion

Antigenic properties of vimentin were determined by mutation and citrullination. Anti‐MCV antibodies are a novel diagnostic marker for RA. Furthermore, they may allow monitoring and—if confirmed in even larger series of patients—stratification of disease.
Identification of previously unrecognized predisposing factors for ankylosing spondylitis from analysis of HLA–B27 extended haplotypes in sardinia
Authors: Cascino Isabella , Paladini Fabiana , Belfiore Francesca , Cauli Alberto , Angelini Claudia , Fiorillo Maria Teresa , Mathieu Alessandro , Sorrentino Rosa
Published: July 2007

Objective

To define the contribution of HLA genes other than HLA–B27 in conferring susceptibility to ankylosing spondylitis (AS), through analysis of HLA–B27 haplotypes in Sardinian subjects.

Methods

Ninety‐eight patients with AS, 133 HLA–B27–positive controls (of whom 33 were positive for HLA–B*2709), and 190 randomly selected controls were genotyped for microsatellites and single‐nucleotide polymorphisms (SNPs) spanning the HLA region.

Results

Haplotypes carrying either the B*2705 or the B*2709 allele were found to share a conserved region downstream of the HLA–B gene and a functional polymorphism in the HLA–E gene (R128G), while differing in all other markers. Notably, the presence of an A at SNP rs1264457, encoding for Arg‐128, was significantly increased in the cohort of patients (P= 6 × 10−6, correctedP= 3 × 10−5) but not in B*2705‐ or B*2709‐positive controls. Comparing the alleles co‐occurring at each HLA marker, we identified a region differentiating patients with AS and B*2705‐matched controls. In particular, there was a markedly increased prevalence of heterozygosity at rs1264457 among B27‐positive controls (74%, versus 47% in patients and 54% in random controls), suggesting a protective role of G128 in AS. Moreover, other markers around the HLA–B gene were also differentially represented.

Conclusion

These results demonstrate a significant difference in the frequency of some HLA markers between AS patients and B*2705‐positive controls, which could be attributed to the opposite chromosome. In particular, the differential distribution of a functional polymorphism in the HLA–E gene suggests a possible role of natural killer function in AS pathogenesis.
In vivo inhibition of angiogenesis by interleukin‐13 gene therapy in a rat model of rheumatoid arthritis
Authors: Haas Christian S. , Amin M. Asif , Ruth Jeffrey H. , Allen Brittany L. , Ahmed Salahuddin , Pakozdi Angela , Woods James M. , Shahrara Shiva , Koch Alisa E.
Published: July 2007

Objective

Interleukin‐13 (IL‐13) is a pleiotropic cytokine that can affect vessel formation, an important component of the rheumatoid arthritis (RA) synovial tissue pannus. The purpose of this study was to use a gene therapy approach to investigate the role of IL‐13 in angiogenesis in vivo, using a rat adjuvant‐induced arthritis model of RA.

Methods

Ankle joints of female rats were injected preventatively with an adenovirus vector containing human IL‐13 (AxCAIL‐13), a control vector with no insert (AxCANI), or phosphate buffered saline (PBS). Joints were harvested at the peak of arthritis, and histologic and biochemical features were evaluated.

Results

AxCAIL‐13–treated joint homogenates had lower hemoglobin levels, suggesting reduced joint vascularity, and both endothelial cell migration and tube formation were significantly inhibited (P < 0.05). Similarly, AxCAIL‐13 inhibited capillary sprouting in the rat aortic ring assay and vessel growth in the Matrigel plug in vivo assay. IL‐13 gene delivery resulted in up‐regulation and association of phosphorylated ERK‐1/2 and protein kinase Cα/βII, suggesting a novel pathway in IL‐13–mediated angiostasis. The angiostatic effect of AxCAIL‐13 was associated with down‐regulation of proangiogenic cytokines (IL‐18, cytokine‐induced neutrophil chemoattractant 1/CXCL1, lipopolysaccharide‐induced CXC chemokine/CXCL5) and up‐regulation of the angiogenesis inhibitor endostatin. The expression and activity of matrix metalloproteinases 2 and 9, which participate in angiogenesis, was impaired in response to IL‐13 as compared with AxCANI and PBS treatment.

Conclusion

Our findings support a role for IL‐13 as an in vivo antiangiogenic factor and provide a rationale for its use in RA to control pathologic neovascularization.
Modified aquaporin 5 expression and distribution in submandibular glands from NOD mice displaying autoimmune exocrinopathy
Authors: Soyfoo Muhammad S. , De Vriese Carine , Debaix Huguette , Martin‐Martinez Maria D. , Mathieu Chantal , Devuyst Olivier , Steinfeld Serge D. , Delporte Christine
Published: July 2007

Objective

To investigate the expression and localization of aquaporin 5 (AQP5) in salivary glands and salivary gland function in the NOD mouse.

Methods

All experiments were performed using NOD and BALB/c mice (ages 8 weeks and 24 weeks). Real‐time reverse transcription–polymerase chain reaction, Western blotting, and immunohistochemical analysis were used to study the expression and distribution of AQP5 in salivary glands. In addition, salivary gland function was determined.

Results

Compared with the levels in BALB/c mice, relative AQP5 messenger RNA levels were not significantly modified in the parotid glands from NOD mice of both ages but were significantly increased in the submandibular glands from NOD mice of both ages. Western blot analyses of both salivary gland membranes revealed that the level of AQP5 protein was increased in 24‐week‐old NOD mice. Important inflammatory infiltrates were observed in the submandibular glands, but not in the parotid glands, from 24‐week‐old NOD mice. The 8‐week‐old and 24‐week‐old BALB/c mice and the 8‐week‐old NOD mice showed AQP5 primarily at the apical membrane of the salivary gland acinus. In contrast, in acini from the submandibular glands (but not the parotid glands) from 24‐week‐old NOD mice, AQP5 staining was reduced at the apical membrane but was increased at the basal membrane. A moderately statistically significant decrease in pilocarpine‐stimulated salivary flow was observed in 24‐week‐old NOD mice compared with that in age‐matched BALB/c mice.

Conclusion

Submandibular glands from 24‐week‐old NOD mice displayed inflammatory infiltrates, increased AQP5 protein expression, and impaired AQP5 distribution. However, the moderately statistically significant decrease in the salivary flow rate in these mice did not match the extent of AQP5 misdistribution.
Low salivary dehydroepiandrosterone and androgen‐regulated cysteine‐rich secretory protein 3 levels in Sjögren's syndrome
Authors: Laine Mikael , Porola Pauliina , Udby Lene , Kjeldsen Lars , Cowland Jack B. , Borregaard Niels , Hietanen Jarkko , Ståhle Mona , Pihakari Antti , Konttinen Yrjö T.
Published: July 2007

Objective

Sjögren's syndrome (SS), an autoimmune disease of exocrine glands, typically starts at the time of adrenopause. We undertook this study to test the hypothesis that SS is characterized by an insufficient androgen effect at the target tissue level.

Methods

We searched for androgen response elements (AREs) in the cysteine‐rich secretory protein 3 (crisp‐3) gene. Dehydroepiandrosterone (DHEA) responsiveness was experimentally studied using quantitative reverse transcriptase–polymerase chain reaction and immunofluorescence staining of human submandibular gland–derived acinar cells and labial salivary gland explants with or without DHEA. Finally, glandular and salivary CRISP‐3 in healthy controls and SS patients was analyzed using immunohistochemistry, in situ hybridization, and enzyme‐linked immunosorbent assay. Serum DHEA sulfate (DHEAS) and salivary DHEA levels were measured using a radioimmunometric method.

Results

Literature analysis and a search for AREs in gene banks suggested androgen dependency of human CRISP‐3, and this was verified by studies of human submandibular gland acinar cells cultured with or without DHEA, in which DHEA increased CRISP‐3 messenger RNA (mRNA) levels (P = 0.018). This finding was confirmed by the results of DHEA stimulation of labial salivary gland explants. Glandular CRISP‐3 mRNA and protein labeling was weak and diffuse, coupled with low secretion in saliva (mean ± SEM 21.1 ± 2.7 μg CRISP‐3/15 minutes in SS patients versus 97.6 ± 12.0 μg CRISP‐3/15 minutes in healthy controls; P < 0.0001). Compared with healthy controls, SS patients had low serum levels of DHEAS (P = 0.008) and also low salivary levels of DHEA (mean ± SEM 224 ± 33 pmoles versus 419 ± 98 pmoles; P = 0.005).

Conclusion

CRISP‐3 pathology was seen in acini remote from lymphocyte foci and is apparently not secondary to local inflammation, but may represent some systemic effect in SS. Indeed, androgen deprivation in the salivary glands of SS patients is evidenced both by low salivary levels of DHEA and by low levels of DHEA‐regulated CRISP‐3. This may explain some of the characteristic features of SS.
Development and validation of a disease‐specific health‐related quality of life measure, the LupusQol, for adults with systemic lupus erythematosus
Authors: McElhone Kathleen , Abbott Janice , Shelmerdine Joanna , Bruce Ian N. , Ahmad Yasmeen , Gordon Caroline , Peers Kate , Isenberg David , Ferenkeh‐Koroma Ada , Griffiths Bridget , Akil Mohamed , Maddison Peter , Teh Lee‐suan
Published: July 2007

Objective

To develop and validate a disease‐specific health‐related quality of life (HRQOL) instrument for adults with systemic lupus erythematosus (SLE).

Methods

The work consisted of 6 stages. Stage 1 included item generation for questionnaire content from semistructured interviews with SLE patients. In stage 2 item selection for the draft questionnaire was performed by thematic analysis of the patient interview transcripts and expert panel agreement. In stage 3 the content validity of the draft questionnaire was assessed by patients completing the questionnaire and providing critical feedback. In stages 4 and 5 construct validity and internal reliability of the 3 versions of the LupusQoL were evaluated using principal component analysis with varimax rotation and Cronbach's alpha coefficients, respectively. In stage 6 discriminatory validity, concurrent validity, and test–retest reliability were evaluated.

Results

Stages 1, 2, and 3 resulted in a preliminary instrument containing 63 items. In stage 4, 8 domains were identified. This factor structure, accounting for 82% of the variance, was confirmed in stage 5. The domains and Cronbach's alpha coefficients were physical health (0.94), emotional health (0.94), body image (0.89), pain (0.92), planning (0.93), fatigue (0.88), intimate relationships (0.96), and burden to others (0.94). Discriminant validity was demonstrated for different levels of disease activity (British Isles Lupus Assessment Group Index) and damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). High correlations (r = 0.71–0.79) between comparable domains of the Short Form 36 and the LupusQoL assured acceptable concurrent validity. Good test–retest reliability (r = 0.72–0.93) was demonstrated.

Conclusion

The LupusQoL is a validated SLE‐specific HRQOL instrument with 34 items across 8 domains defined by patients as being important.
Delay in access to appropriate care for children presenting with musculoskeletal symptoms and ultimately diagnosed with juvenile idiopathic arthritis
Authors: Foster H. E. , Eltringham M. S. , Kay L. J. , Friswell M. , Abinun M. , Myers A.
Published: July 2007

Objective

To document pathways of care, management, and interval from onset of symptoms to first pediatric rheumatology multidisciplinary team (PRhMDT) assessment for children with incident juvenile idiopathic arthritis (JIA).

Methods

We conducted a retrospective observational study of children with incident JIA over a 3‐year period.

Results

The study included 152 patients with JIA (87 females). The median interval from symptom onset to first PRhMDT assessment was 20 weeks (range 0–416), with significant variation between JIA subtypes (P = 0.0097); children with extended oligoarticular JIA had the longest interval (median 60 weeks, range 12–320). Prior to pediatric rheumatology assessment, many children had referrals to multiple secondary care specialties and had been subjected to multiple and often invasive procedures including arthroscopy/synovial biopsy (18 [11.8%] of 152), but none were referred for ophthalmologic screening, physical therapy, or nursing input and a diagnosis of JIA was rarely made (98%). At first PRhMDT assessment, most patients had untreated active disease with active joint count ≥1 (135 [89%] of 152), restricted joint count ≥1 (135 [89%] of 152), and functional disability by Child Health Assessment Questionnaire score >0 (53 [68%] of 118); 1 child had undetected uveitis. Following PRhMDT assessment, interventions were invariably indicated, including joint injections (69 [45%] of 152), methotrexate (49 [32%] of 152), and physical therapy programs (all patients).

Conclusion

Delay in access to pediatric rheumatology assessment is common with complex pathways of referral. Many children were subjected to inappropriate invasive investigations and many had prolonged untreated active disease at the initial PRhMDT assessment. This delay is likely to affect long‐term outcome and warrants further exploration.
Comparison of the EuroQol and short form 6D in Singapore multiethnic asian knee osteoarthritis patients scheduled for total knee replacement
Authors: Xie Feng , Li Shu‐chuen , Luo Nan , Lo Ngai‐nung , Yeo Seng‐jin , Yang Kuang‐ying , Fong Kok‐yong , Thumboo Julian
Published: July 2007

Objective

To compare the EuroQol (EQ‐5D) and Short Form 6D (SF‐6D) among multiethnic Asian patients with knee osteoarthritis (OA) scheduled for total knee replacement in Singapore.

Methods

Patients were asked to complete questionnaires including the EQ‐5D, Short Form 36, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Lequesne knee index. EQ‐5D and SF‐6D utility scores were calculated using the scoring algorithms developed from the UK general population. Agreement between the 2 instruments was assessed by comparing their score distributions, means, medians, intraclass correlation coefficients (ICCs), and a Bland‐Altman plot. Correlations of the EQ‐5D and SF‐6D with WOMAC and Lequesne knee index scores were also examined.

Results

A consecutive sample of 258 knee OA patients (127 English‐speaking and 131 Chinese‐speaking) participated. The mean ± SD EQ‐5D utility score was 0.49 ± 0.31 (range −0.25–1.00) and the mean SF‐6D utility score was 0.63 ± 0.12 (range 0.32–0.89). In a hypothetical example, this 0.14‐point difference in mean utility scores yielded a difference of $10,000/quality‐adjusted life year (QALY) in cost‐effectiveness ratios. The score distribution was bimodal for the EQ‐5D and normal for the SF‐6D. This poor agreement was also demonstrated by the Bland‐Altman plot and the low ICC (range 0.18–0.54). Correlations of the WOMAC and Lequesne index with the EQ‐5D were higher than with the SF‐6D.

Conclusion

Using different preference‐based health‐related quality of life instruments may yield different utility scores, which could have a great impact on QALY estimates. This highlights the importance of selecting appropriate instruments for economic evaluation. Additional research is needed to determine which instrument (the EQ‐5D or the SF‐6D) should be used in OA patients.
High prevalence of subclinical atherosclerosis in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors
Authors: Gonzalez‐juanatey Carlos , Llorca Javier , Amigo‐Diaz Encarnacion , Dierssen Trinidad , Martin Javier , Gonzalez‐Gay Miguel A.
Published: July 2007

Objective

To assess the presence of subclinical atherosclerosis in patients with psoriatic arthritis (PsA) without clinically evident atherosclerosis or its complications, and to assess whether demographic or clinical factors affect the development of atherosclerotic disease in a series of patients with PsA attended to in a community hospital.

Methods

Fifty‐nine patients with PsA who fulfilled the Moll and Wright criteria were recruited from Hospital Xeral‐Calde (Lugo, Spain). Patients seen during the period of recruitment who had classic cardiovascular risk factors or had experienced cardiovascular or cerebrovascular events were excluded. Fifty‐nine healthy matched controls were also studied. Carotid artery intima‐media thickness (IMT) and carotid plaques were measured in the right common carotid artery. The study was performed using high‐resolution B‐mode ultrasound.

Results

Patients with PsA exhibited greater carotid artery IMT than did matched controls (mean ± SD 0.699 ± 0.165 mm versus 0.643 ± 0.111 mm; P = 0.031; difference of means 0.056; 95% confidence interval 0.005–0.108). Adjusted for age, the carotid IMT was correlated with age at the time of PsA diagnosis (partial correlation coefficient [r] = −0.264, P = 0.04), disease duration (r = 0.264, P = 0.04), total cholesterol (r = 0.233, P = 0.01), and low‐density lipoprotein cholesterol (r = 0.243, P = 0.01).

Conclusion

The present study demonstrates that patients with PsA without cardiovascular risk factors or clinically evident cardiovascular disease have a high prevalence of macrovascular disease in the form of increased carotid artery IMT compared with ethnically matched controls.
Using the health assessment questionnaire to estimate preference‐based single indices in patients with rheumatoid arthritis
Authors: Bansback Nick , Marra Carlo , Tsuchiya Aki , Anis Aslam , Guh Daphne , Hammond Tony , Brazier John
Published: July 2007

Objective

To estimate the relationship between preference‐based measures, EuroQol (EQ‐5D) and SF‐6D, and the Health Assessment Questionnaire (HAQ) disability index (DI) in patients with rheumatoid arthritis (RA), and to characterize components that are predictors of health utility.

Methods

Patients with RA participating in 2 studies in the UK (n = 151) and Canada (n = 319) completed the HAQ, EQ‐5D, and Short Form 36 (SF‐36). The SF‐36, a generic measure of quality of life, was converted into the preference‐based SF‐6D. From these results we developed models of the relationship between the HAQ and SF‐6D and EQ‐5D using various regression analyses.

Results

The optimal model developed for the EQ‐5D entered levels for each item as independent variables (model 5). A root mean square error (RMSE) of 0.18 suggested relatively good predictive ability. For the SF‐6D, RMSEs were lower (0.09), suggesting better predictions than for the EQ‐5D, but models with more explanatory variables did not improve results (model 2 or 4 optimal). The models were able to predict actual SF‐6D and EQ‐5D across the range of the HAQ DI.

Conclusion

Our approach enabled calculations of quality‐adjusted life years from existing trials where only the HAQ was measured. All aspects of the HAQ may not be reflected in the preference‐based measures, and this method is suboptimal to direct measurement of health state utility in clinical trials. Given this limitation, our approach provides an alternative for researchers who need health‐state utility values, but had not included a preference‐based measure in their clinical study because of resource constraints or a desire to limit patient burden.
Validity and reliability of the Siconolfi Step Test for assessment of physical fitness in patients with systemic lupus erythematosus
Authors: Marcora Samuele M. , Casanova Francesco , Fortes Matthew B. , Maddison Peter J.
Published: July 2007

Objective

Patients with systemic lupus erythematosus (SLE) have poor physical fitness as measured by maximal oxygen uptake (VO2max), which is associated with disability and fatigue. The purpose of this study was to validate, in this population, the Siconolfi Step Test (SST) developed to predict VO2max in healthy individuals.

Methods

Thirty patients with well‐controlled SLE were tested on a cycle ergometer until volitional exhaustion, and 25 women and 4 men (mean ± SD age 48 ± 14 years, weight 71.5 ± 13.7 kg) fulfilled the criteria for maximal effort. VO2max measured during this incremental test was compared with VO2max predicted by the SST using Bland and Altman 95% limits of agreement (LOA) and intraclass correlation coefficient (ICC). The SST was repeated twice to assess its reliability.

Results

The ICC between predicted and measured VO2max (mean ± SD 1.67 ± 0.41 liters/minute versus 1.57 ± 0.39 liters/minute) was moderately high (0.73, P < 0.001). Bland and Altman analysis revealed a trend for a positive bias (P = 0.083) and 95% LOA of ±0.58 liters/minute. There was a very high ICC (0.97, P < 0.001) between VO2max predicted by the first and second SST (mean ± SD 1.66 ± 0.40 liters/minute versus 1.67 ± 0.41 liters/minute), and no significant bias (P = 0.500). The 95% LOA were ±0.20 liters/minute.

Conclusion

The results demonstrate that the SST is well tolerated, reasonably valid, and highly reliable in patients with well‐controlled SLE. Therefore, this simple, submaximal exercise test might be useful for assessing physical fitness in clinical practice and epidemiologic studies.
Health‐related quality of life outcomes in patients with active ankylosing spondylitis treated with adalimumab: Results from a randomized controlled study
Authors: Davis John C. , Revicki Dennis , van der Heijde Désirée M. F. , Rentz Anne M. , Wong Robert L. , Kupper Hartmut , Luo Michelle P.
Published: July 2007

Objective

To evaluate the impact of adalimumab on health‐related quality of life (HRQOL) in patients with active ankylosing spondylitis (AS).

Methods

Patients ≥18 years enrolled in the Adalimumab Trial Evaluating Long‐Term Efficacy and Safety in Ankylosing Spondylitis, a randomized controlled study, were randomly assigned to receive either adalimumab 40 mg subcutaneously or placebo every other week for 24 weeks. ASsessment of Ankylosing Spondylitis (ASAS) International Working Group criteria were used to evaluate clinical efficacy. HRQOL outcomes were assessed using the Short Form 36 (SF‐36) Health Survey and Ankylosing Spondylitis Quality of Life (ASQoL) Questionnaire.

Results

A total of 315 patients enrolled (208 in the adalimumab group and 107 in the placebo group). Patients in the adalimumab group showed significant improvements in SF‐36 Physical Component Summary (PCS) and ASQoL scores versus placebo at weeks 12 and 24 (P < 0.001). The observed differences between adalimumab and placebo patients exceeded the a priori minimum important difference (MID) at the group level, and significantly more adalimumab‐treated patients achieved improvements greater than the MID on the patient level. These data suggest the HRQOL improvements were clinically meaningful. No differences were observed in SF‐36 Mental Component Summary (MCS) scores. Significant differences favoring adalimumab were observed for SF‐36 domains physical function, bodily pain, role‐physical, general health, vitality, social function, and role–emotional. There was significant association between HRQOL improvements (measured by SF‐36 PCS and MCS, and ASQoL scores) and ASAS clinical responses (P < 0.001).

Conclusion

Adalimumab significantly improved physical health status and overall HRQOL through 24 weeks in patients with active AS.
Primary knee and hip arthroplasty among nonagenarians and centenarians in the United States
Authors: Krishnan Eswar , Fries James F. , Kwoh C. Kent
Published: July 2007

Objective

The number of individuals ages ≥100 years in the US is expected to increase considerably in the future along with the need for arthroplasties. This report focuses on the poorly studied epidemiology and mortality outcomes of arthroplasty among these individuals.

Methods

We describe the epidemiology of knee and hip arthroplasties among centenarians using data from a large hospital discharge database in the US (the Nationwide Inpatient Sample) during the period 1993 through 2002. We used nonagenarians as the comparison group with adjustment for differences in the prevalence of congestive heart failure, neurologic diseases such as dementia and stroke, renal and hepatic diseases, obesity, anemia, malignancy, coagulopathy, and depression and other psychiatric illnesses. Cox regression models were used to study the mortality outcomes following arthroplasty.

Results

Overall, there were 679 hip arthroplasties and 7 knee arthroplasties among centenarians in this database. The corresponding figures for nonagenarians were 33,975 and 2,050, respectively. A vast majority (83%) of hip arthroplasty recipients were women. Risk‐adjusted mortality estimates following arthroplasty for centenarians were higher than for nonagenarians (hazard ratio 1.46, 95% confidence interval 1.10–1.95). However, this was similar to differences in overall in‐hospital mortality (hazard ratio 1.36, 95% confidence interval 1.32–1.40) between these 2 age categories.

Conclusion

In the US population, hip and knee arthroplasty are very rarely performed among centenarians. Our in‐hospital mortality data suggest that arthroplasties should not be denied to centenarians solely because of short‐term postoperative life expectancy estimates.
Influences on knee movement strategies during walking in persons with medial knee osteoarthritis
Authors: SchmitT Laura C. , Rudolph Katherine S.
Published: July 2007

Objective

To investigate the movement and muscle activation strategies during walking of individuals with medial knee osteoarthritis (OA) to determine the influence of quadriceps strength, medial knee laxity, limb alignment, and self‐reported knee instability on knee motion.

Methods

Twenty‐eight persons with medial knee OA and 26 control subjects participated. Quadriceps strength, medial knee laxity, and limb alignment were measured. Knee instability (IKOSscore) was assessed with the Activities of Daily Living Scale of the Knee Outcome Survey. Knee motion and muscle activation patterns were measured with motion analysis. Group differences were detected with independent samplest‐tests and predictive relationships were determined with linear and hierarchical regression analyses.

Results

Individuals with OA were weaker, had greater medial knee laxity, and had more varus alignment. The OA group used less knee motion and higher muscle co‐contraction during weight acceptance and single‐limb support. Quadriceps strength and IKOSscore significantly strengthened the prediction of knee motion during weight acceptance and single‐limb support, whereas limb alignment and medial laxity did not.

Conclusion

The knee stiffening and higher muscle co‐contraction used by the OA group may be detrimental to joint integrity. IKOSscores predicted knee motion after accounting for quadriceps strength, underscoring the importance of addressing knee instability with appropriate rehabilitation strategies in persons with medial knee OA in order to promote long‐term joint integrity.
Treatment of older adult patients diagnosed with rheumatoid arthritis: Improved but not optimal
Authors: Schmajuk Gabriela , Schneeweiss Sebastian , Katz Jeffrey N. , Weinblatt Michael E. , Setoguchi Soko , Avorn Jerry , Levin Raisa , Solomon Daniel H.
Published: July 2007

Objective

The National Committee on Quality Assurance has determined that all patients with rheumatoid arthritis (RA) should be treated with disease‐modifying antirheumatic drugs (DMARDs). Our objective was to determine the rate and predictors of DMARD use in a cohort of elderly patients with RA.

Methods

We analyzed health care utilization data for 5,864 Medicare beneficiaries with RA who also participated in a state‐run pharmaceutical benefit program in Pennsylvania. Patients with RA were defined as those with at least 3 diagnoses of RA (International Classification of Diseases, Ninth Revision code 714.xx) at least 1 week apart who were enrolled in these programs for at least 12 months during 1995–2004. Multivariate logistic regression was used to assess predictors of synthetic or biologic DMARD use in the 12 months after cohort entry.

Results

Thirty percent of patients filled a DMARD prescription during 12 months of followup. Frequency of DMARD use increased steadily over time: 24% received DMARDs in 1996 compared with 43% in 2003 (P for trend <0.001). Of patients with at least 1 rheumatologist visit, 41% received a DMARD in 1996 compared with 70% in 2003 (P < 0.001). After the introduction of biologic DMARDs in 1998, 6% of all patients with RA received a biologic, including 12% who saw a rheumatologist. Patients ages 75–84 were 52% less likely to receive DMARDs (95% confidence interval [95% CI] 46–58%) and patients ages ≥85 were 74% less likely (95% CI 69–79%) compared with patients ages 65–74.

Conclusion

In this cohort of patients in the community with full prescription drug coverage, most patients diagnosed with RA did not receive a DMARD during the 12 months after cohort entry. Older patients and those not seeing a rheumatologist were less likely to receive a DMARD and may provide a target for quality improvement interventions.
Validation of a radiographic damage index in chronic gout
Authors: Dalbeth Nicola , Clark Barnaby , McQueen Fiona , Doyle Anthony , Taylor William
Published: July 2007

Objective

To identify a valid method to measure radiographic damage in patients with chronic gout.

Methods

The scoring method that best represented radiographic damage in individual joints was analyzed by comparing a gold standard rheumatologist consensus global score with recognized scoring methods, including the Sharp/van der Heijde erosion and narrowing scores, Ratingen destruction score, and Steinbrocker score. Ninety‐five proximal interphalangeal joints from 12 patients with gout were included in this analysis. Scoring of hand and feet radiographs from an additional 35 patients with gout was used to analyze the sites to be included in a scoring system and the additional features to be recorded.

Results

For individual joints, the combination of the Sharp/van der Heijde erosion and narrowing scores correlated best with the consensus global score. In addition, the limits of agreement were narrowest for the combined Sharp/van der Heijde erosion and narrowing score. All joint areas in the Sharp/van der Heijde rheumatoid arthritis score and the distal interphalangeal joints were affected by chronic gout and contributed to the total score. Additional features (extraarticular erosions, joint space widening, and ankylosis) occurred infrequently, and scoring of these features did not increase the reliability of the total score. The reliability of the total score was high: intraclass correlation coefficient for intraobserver reproducibility was 0.993–0.998 and for interobserver reproducibility was 0.963–0.966. The modified Sharp/van der Heijde score was able to discriminate between early and advanced disease.

Conclusion

A modified Sharp/van der Heijde system accurately and reliably represents radiographic joint damage in chronic gout.