bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of dehydroepiandrosterone on articular cartilage during the development of osteoarthritis
Authors: Jo Hyunchul , Ahn Hyun Jeong , Kim Eun Mi , Kim Hee Joong , Seong Sang Cheol , Lee InBum , Lee Myung Chul
Published: August 2004

Objective

To investigate the in vivo effects of dehydroepiandrosterone (DHEA) on knee joints during the development of experimentally induced osteoarthritis (OA).

Methods

Twenty‐two mature NZW rabbits underwent bilateral anterior cruciate ligament transection (ACLT) and received 0.3‐ml intraarticular injections of DHEA (at a concentration of 100 μM in phosphate buffered saline) and control solution in the right and left knees, respectively, beginning 4 weeks after ACLT and continuing once weekly for 5 weeks. All animals were killed 9 weeks after surgery, and the knee joints were assessed by gross morphologic, histologic, histomorphometric, and biochemical methods.

Results

Gross morphologic inspection following India ink application showed that the right femoral condyles, which received DHEA, demonstrated less severe cartilage damage than did the contralateral condyles. The thickness, area, and roughness of the DHEA‐treated femoral condyles provided evidence of a cartilage‐protecting effect of DHEA following ACLT. These results were supported by gene expression analysis. Messenger RNA expression of a proinflammatory cytokine, interleukin‐1β, and catabolic enzymes, matrix metalloproteinases 1 and 3, was reduced in the cartilage of the DHEA‐treated knee joints, and expression of tissue inhibitor of metalloproteinase 1 was increased.

Conclusion

Results of the present study demonstrate a cartilage‐protecting effect of DHEA during the development of OA following ACLT in a rabbit model.
Detection of anti–type 3 muscarinic acetylcholine receptor autoantibodies in the sera of Sjögren's syndrome patients by use of a transfected cell line assay
Authors: Gao Juehua , Cha Seunghee , Jonsson Roland , Opalko Jeffrey , Peck Ammon B.
Published: August 2004

Objective

Sjögren's syndrome (SS) is an autoimmune disease affecting primarily the salivary and lacrimal glands, leading to dry mouth and dry eyes. Recent studies have suggested that autoantibodies reactive with the type 3 muscarinic acetylcholine receptors (M3Rs) expressed on salivary and lacrimal gland cells may be highly specific for SS. To test this hypothesis, we constructed a cell line expressing the human M3R gene in order to screen for anti‐M3R autoantibodies in sera from SS patients.

Methods

Complementary DNA encoding the open‐reading frame (ORF) of the human M3R gene was amplified, ligated into the pcDNA5/FRT/V5‐His‐TOPO TA vector, and then used to transform Escherichia coli bacteria. Plasmid DNA containing the M3R ORF with the correct orientation was transfected into Flp‐In Chinese hamster ovary (CHO) cells using Flp recombinase–mediated site‐specific recombination. An M3R‐transfected CHO cell line, selected and propagated in hygromycin, was used to detect anti‐M3R autoantibodies in SS patient and healthy control sera by flow cytometry.

Results

Testing of sera for the presence of anti‐M3R autoantibodies bound to CHO‐transfected cells revealed the presence of anti‐M3R autoantibodies in SS patients (9 of 11) but not in healthy controls (0 of 11). Although the anti‐M3R autoantibodies detected in patient sera were of multiple isotypes, the most consistently detected were IgG1, IgG3, and IgA.

Conclusion

Using a newly constructed cell line expressing human M3R, anti‐M3R autoantibodies were easily detected in sera from SS patients. These autoantibodies were skewed toward the IgG1, IgG3, and IgA isotypes, probably recognizing a tertiary epitope created by extracellular domains of the receptor protein. Anti‐M3R autoantibodies represent a highly promising clinical marker for the identification of SS.
The genetic epidemiology of joint hypermobility: A population study of female twins
Authors: Hakim Alan J. , Cherkas Lynn F. , Grahame Rodney , Spector Tim D. , MacGregor Alexander J.
Published: August 2004

Objective

To estimate the genetic influence on joint hypermobility in an unselected population using a classic twin study design.

Methods

A self‐report questionnaire on joint hypermobility as well as data on age, height, weight, estrogen replacement therapy, and menopause status were obtained from 483 monozygotic (MZ) and 472 dizygotic (DZ) unselected female twin pairs ages 21–81 years who were registered with the St Thomas' Adult Twin Registry in the UK.

Results

The overall prevalence of hypermobility was 19.5% in MZ twins and 22.1% in DZ twins. The prevalence of hypermobile joints declined with age, falling from 34% in subjects ages 20–30 years to 18.4% in those ages 60 years or older. Significantly greater concordance for joint hypermobility was observed in the MZ twins when compared with the DZ twins (60% versus 36%), consistent with a genetic influence. In variance components analysis, the age‐ and body mass index–adjusted heritability of joint hypermobility was estimated to be 70% (95% confidence interval 57–89%).

Conclusion

Genetic factors have a substantial contribution to joint hypermobility in the adult female population.
Cartilage atrophy in the knees of patients after seven weeks of partial load bearing
Authors: Hinterwimmer S. , Krammer M. , Krötz M. , Glaser C. , Baumgart R. , Reiser M. , Eckstein F.
Published: August 2004

Objective

It is currently unknown whether human cartilage properties change during short periods of partial load bearing. We used a post–ankle fracture model to explore whether changes in cartilage morphology occur in the knee under conditions of partial load bearing.

Methods

The knees of 20 patients with Weber type B and type C fractures were examined using magnetic resonance imaging. The first scan was obtained shortly (mean ± SD 3.2 ± 3.0 days) after the injury, and a second scan was obtained 7 weeks later (mean ± SD 50.7 ± 5.5 days). The morphology (mean and maximum thickness, volume, and surface area) of the patellar, tibial, and femoral cartilage was determined from coronal and axial magnetic resonance images (fat‐suppressed gradient‐echo).

Results

Between week 0 and week 7, the cross‐sectional area of the quadriceps muscle was reduced by 11% (P< 0.001). Changes in the mean (±SD) cartilage thickness ranged from −2.9 ± 3.2% in the patella to −6.6 ± 4.9% in the medial tibia. No significant change in cartilage morphology of the contralateral knee was observed.

Conclusion

Results of this study demonstrate that in a post–ankle fracture model of partial load bearing, cartilage morphology in all knee compartments is subject to significant change. Changes in the femorotibial joint exceeded those in the patella, whereas no change was observed in the contralateral knee. These findings raise the question of whether cartilage is mechanically less competent and particularly vulnerable after states of partial or complete immobilization.
In vivo imaging of protease activity in arthritis: A novel approach for monitoring treatment response
Authors: Wunder Andreas , Tung Ching‐Hsuan , Müller‐Ladner Ulf , Weissleder Ralph , Mahmood Umar
Published: August 2004

Objective

Sensitive noninvasive strategies for monitoring treatment response in rheumatoid arthritis (RA) would be valuable for facilitating appropriate therapy and dosing, evaluating clinical outcome, and developing more effective drugs. Because different proteases are highly up‐regulated in RA and contribute significantly to joint destruction, in the present study we investigated whether such enzymes are suitable in vivo imaging biomarkers for early evaluation of treatment response in a murine model of RA.

Methods

Using a protease‐activated near‐infrared fluorescence (NIRF) imaging “smart” probe, we examined the presence and distribution of fluorescence in arthritic joints of mice with collagen‐induced arthritis by both noninvasive fluorescence imaging and histology. Proteases that target the Lys–Lys cleavage site, including cathepsin B, activate probe fluorescence. Treatment monitoring data were obtained following methotrexate (MTX) therapy.

Results

Twenty‐four hours after intravenous injection of the protease sensor, affected toes and paws of arthritic mice showed significantly higher fluorescence intensity than did toes and paws of healthy mice. Fluorescence from the protease probe and cathepsin B antibody histologic staining were localized in the vast majority of cells in the inflamed synovium. In arthritic animals treated with MTX (35 mg of MTX/kg 48 hours prior to probe injection), a significantly lower fluorescent signal (inflamed paws 50%, inflamed toes 70%) was observed as compared with untreated arthritic animals.

Conclusion

Protease‐activated NIRF probes are sensitive means of imaging the presence of target enzymes in arthritic joints and can be used for early monitoring of treatment response to antirheumatic drugs such as MTX.
Lack of requirement of osteopontin for inflammation, bone erosion, and cartilage damage in the K/BxN model of autoantibody‐mediated arthritis
Authors: Jacobs Jonathan P. , Pettit Allison R. , Shinohara Mari L. , Jansson Marianne , Cantor Harvey , Gravallese Ellen M. , Mathis Diane , Benoist Christophe
Published: August 2004

Objective

Osteopontin (OPN) is a secreted glycoprotein involved in a range of physiologic processes, including inflammation, immunity mediated by Th1 cells, and bone remodeling. It is expressed in the joints of rheumatoid arthritis patients and has been the subject of conflicting reports concerning its role in arthritis induced by antibodies against type II collagen. This study assessed the role of OPN in the K/BxN serum‐transfer model of autoantibody‐induced arthritis.

Methods

Expression of OPN gene transcripts was assessed by microarray analysis of ankle RNA taken at 6 time points after transfer of K/BxN serum. OPN‐sufficient or OPN‐deficient littermates backcrossed for 10 generations onto the C57BL/6 genetic background were given K/BxN serum. Arthritis severity was measured by ankle thickening and a clinical index. Hind limb sections were stained with hematoxylin and eosin or toluidine blue and scored for inflammation, cartilage damage, and bone erosion.

Results

OPN messenger RNA transcripts progressively increased in ankle joints during the course of K/BxN serum‐transferred arthritis. OPN‐deficient mice receiving K/BxN serum developed arthritis with kinetics and clinical severity comparable with those of OPN‐sufficient littermates. Histologic assessment of arthritic joints from OPN‐deficient mice revealed synovial hyperplasia, pannus formation, mononuclear cell infiltration, bone erosion, cartilage damage at sites adjacent to and distal from pannus invasion, and tartrate‐resistant acid phosphatase–positive multinucleated cells at sites of bone erosion. Histopathologic scoring demonstrated comparable levels of inflammation, cartilage damage, and bone erosion in OPN‐sufficient and OPN‐deficient mice.

Conclusion

OPN does not have a required role in inflammation, bone erosion, and cartilage damage in the K/BxN serum‐transfer model.
An analysis of CTLA‐4 and proinflammatory cytokine genes in Wegener's granulomatosis
Authors: Zhou Yihua , Huang DeRen , Paris Pamela L. , Sauter Craig S. , Prock Kristin A. , Hoffman Gary S.
Published: August 2004

Objective

The precipitating event(s) that triggers Wegener's granulomatosis (WG) is unknown. Cytokines, costimulatory molecules, and counterregulatory molecules control the quality and intensity of immune responses. Thus, they are relevant candidates for genetic studies of immune dysregulation in WG, the pathogenesis of which may be facilitated by multiple acquired and/or inherited factors. This study was undertaken to investigate possible genetic associations of various proinflammatory cytokines and CTLA‐4, a receptor for T cell inhibition, with WG.

Methods

Using polymerase chain reaction–based DNA genotyping, we investigated the polymorphisms located in the genes encoding a variety of proinflammatory cytokines and CTLA‐4 in 117 American patients with WG and 123 ethnically matched healthy controls.

Results

Compared with controls, patients with WG had a significantly lower frequency of homozygosity for the shortest allele (designated allele 86) of the Ctla4 microsatellite polymorphism (AT)n located in the 3′‐untranslated region (3′‐UTR) of exon 3 (47.0% versus 69.9%; P = 0.0005). Significant differences between patients and controls in the allelic and genotypic frequencies of polymorphisms in the other cytokine and cytokine receptor genes studied (tumor necrosis factor α [TNFα], TNF receptor I [TNFRI], TNFRII, interleukin‐1β [IL‐1β], IL‐6) were not found.

Conclusion

The Ctla4 (AT)n 86 allele has been previously demonstrated to be crucial for maintenance of normal levels of CTLA‐4 expression and balance between T cell activation and inhibition. Our results in American patients confirm findings from a Scandinavian cohort in which a positive association between WG and longer alleles of (AT)n in the Ctla4 3′‐UTR was demonstrated. Diminished frequencies of the most effective allele for CTLA‐4 expression may represent a WG‐related susceptibility mutation that accounts, in part, for increased T cell activation and clonal expansion in WG. Blockade of T cell costimulation using CTLA‐4Ig might be a useful therapeutic intervention, providing an alternative or complementary approach to conventional treatment with immunosuppressive agents.
Effects of hypoxia on the expression and activity of cyclooxygenase 2 in fibroblast‐like synoviocytes: Interactions with monocyte‐derived soluble mediators
Authors: Demasi Maryanne , Cleland Leslie G. , Cook‐Johnson Rebecca J. , James Michael J.
Published: August 2004

Objective

Rheumatoid synovium is characterized by hyperplasia of fibroblast‐like (type B) synoviocytes (FLS), infiltration with mononuclear leukocytes, and tissue hypoxia. Although the latter is well documented, it has received little attention in dissection of the biochemical events that mediate the inflammatory lesion in rheumatoid arthritis (RA). Therefore, this study was designed to assess the effect of hypoxia on FLS responses to the monokine interleukin‐1β (IL‐1β) and to monocyte conditioned medium.

Methods

FLS obtained from serial cultures of synovial fluid aspirates were treated with IL‐1β or monocyte conditioned medium, under normoxia and hypoxia.

Results

In hypoxia, transcription of cyclooxygenase 2 (COX‐2), expression of COX‐2 protein, and production of COX‐2–derived eicosanoids and matrix metalloproteinase (MMP) activity by FLS were all increased in response to IL‐1β. In contrast to our recent observations concerning monocytes, there was no change in COX‐2 message stability and cytosolic phospholipase A2 activity in the FLS under hypoxia. Treatment of monocyte conditioned medium with an IL‐1β blocking antibody showed that most of the effect of the conditioned medium was attributable to IL‐1β.

Conclusion

The findings suggest that hypoxia is an important factor in aggravating the inflammatory lesion in RA, through increased production of COX‐2–derived nociceptive eicosanoids and increased release of tissue‐damaging MMPs.
B cell depletion as a novel treatment for systemic lupus erythematosus: A phase I/II dose‐escalation trial of rituximab
Authors: Looney R. John , Anolik Jennifer H. , Campbell Debbie , Felgar Raymond E. , Young Faith , Arend Lois J. , Sloand James A. , Rosenblatt Joseph , Sanz Iñaki
Published: August 2004

Objective

Safer and more effective therapies are needed for the treatment of systemic lupus erythematosus (SLE). B lymphocytes have been shown to play fundamental pathogenic roles in SLE, and therefore, elimination of B cells with the use of rituximab may represent a new therapy for SLE.

Methods

A phase I/II dose‐escalation trial of rituximab added to ongoing therapy in SLE was conducted. Rituximab was administered as a single infusion of 100 mg/m2 (low dose), a single infusion of 375 mg/m2 (intermediate dose), or as 4 infusions (1 week apart) of 375 mg/m2 (high dose). CD19+ lymphocytes were measured to determine the effectiveness of B cell depletion. The Systemic Lupus Activity Measure (SLAM) score was used as the primary outcome for clinical efficacy.

Results

Rituximab was well tolerated in this patient population, with most experiencing no significant adverse effects. Only 3 serious adverse events, which were thought to be unrelated to rituximab administration, were noted. A majority of patients (11 of 17) had profound B cell depletion (to <5 CD19+ B cells/μl). In these patients, the SLAM score was significantly improved at 2 and 3 months compared with baseline (P = 0.0016 and P = 0.0022, respectively, by paired t‐test). This improvement persisted for 12 months, despite the absence of a significant change in anti–double‐stranded DNA antibody and complement levels. Six patients developed human antichimeric antibodies (HACAs) at a level ≥100 ng/ml. These HACA titers were associated with African American ancestry, higher baseline SLAM scores, reduced B cell depletion, and lower levels of rituximab at 2 months after initial infusion.

Conclusion

Rituximab therapy appears to be safe for the treatment of SLE and holds significant therapeutic promise, at least for the majority of patients experiencing profound B cell depletion. Based on these results, controlled trials of rituximab appear to be warranted.
Increased levels of C‐reactive protein in serum from blood donors before the onset of rheumatoid arthritis
Authors: Nielen Markus M. J. , Van Schaardenburg Dirkjan , Reesink Henk W. , Twisk Jos W. R. , Van De Stadt Rob J. , Van Der Horst‐Bruinsma Irene E. , De Gast Truus , Habibuw Moud R. , Vandenbroucke Jan P. , Dijkmans Ben A. C.
Published: August 2004

Objective

We previously reported that approximately half of the patients with rheumatoid arthritis (RA) have specific serologic abnormalities (elevated serum concentrations of IgM rheumatoid factor and/or anti–cyclic citrullinated peptide antibodies) starting several years before the onset of symptoms. In this study, the presence of serologic signs of inflammation in patients with preclinical RA was investigated with serial measurements of C‐reactive protein (CRP).

Methods

Seventy‐nine patients (61% female; mean age at onset of symptoms 51 years) who had been blood donors before the onset of RA were identified. Frozen serum samples from each donor were retrieved, together with 1 sample from a control donor matched for age, sex, and date of donation. CRP was measured using a highly sensitive latex‐enhanced assay. The dates of donation were categorized into 15 1‐year periods preceding the onset of RA symptoms. For each period, the median CRP levels in the patient and control groups were compared using the Mann‐Whitney U test. The course of CRP concentrations over time in the patient group was estimated with random coefficient analysis.

Results

A median of 13 samples (range 1–51) per patient were available; the earliest donation was made a median of 7.5 years (range 0.4–14.5 years) before the onset of symptoms. A total of 1,078 patient samples and 1,071 control samples were tested. For all 1‐year periods, the median CRP concentration was increased in the patient group compared with the control group, but this difference was statistically significant only for the periods 0–1 year, 1–2 years, and 4–5 years before the onset of symptoms. The CRP concentration increased significantly over time in patients with preclinical RA; levels were slightly higher in the group of patients who had serologic abnormalities before the onset of symptoms than in those without such serologic abnormalities.

Conclusion

After observing specific serologic abnormalities 5 years before the onset of RA symptoms, we now report increased levels of CRP in blood donors in whom RA later developed; these increases were most common within the 2 years before the onset of symptoms. The preclinical increase in CRP levels was observed both in donors with and in those without serologic abnormalities.
Antiphospholipid syndrome nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies: Prevalence, clinical associations, and long‐term outcome
Authors: Tektonidou Maria G. , Sotsiou Flora , Nakopoulou Lidia , Vlachoyiannopoulos Panayiotis G. , Moutsopoulos Haralampos M.
Published: August 2004

Objective

To evaluate the prevalence, clinical associations, and outcome of antiphospholipid syndrome (APS) nephropathy in patients with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL) and in SLE patients without aPL.

Methods

Kidney biopsy specimens obtained from 81 patients with aPL (18 of whom had APS) and 70 patients without aPL were retrospectively examined for the presence of APS nephropathy. Clinical and serologic data obtained at the time of kidney biopsy and during a mean followup of 7 years were recorded. In cases for which serial kidney biopsy specimens were available, the evolution of APS nephropathy was examined.

Results

APS nephropathy existed in 39.5% of patients with aPL, compared with only 4.3% of patients without aPL. APS nephropathy was associated with both lupus anticoagulant and anticardiolipin antibodies. Among aPL‐positive SLE patients, APS nephropathy was found in two‐thirds of those with APS and in one‐third of those without APS. A strong association between APS nephropathy and the presence of arterial thrombosis and livedo reticularis was noted. Patients with APS nephropathy had a higher frequency of hypertension and elevated serum creatinine levels at the time of kidney biopsy but did not have a higher frequency of renal insufficiency, end‐stage renal disease, or death at the end of followup. Serial kidney biopsy specimens were available from 11 patients and showed progression of APS nephropathy lesions. During followup, manifestations of APS (especially arterial thromboses) developed more frequently in the SLE/non‐APS patients with APS nephropathy than in those without APS nephropathy.

Conclusion

Among patients with SLE, APS nephropathy occurs almost exclusively in those with aPL, suggesting an important role of aPL in the pathogenesis of APS nephropathy. Patients with APS nephropathy develop hypertension, raised serum creatinine levels, and progression of histologic lesions, all of which are associated with a poor renal outcome. Manifestations of APS also tend to develop in these patients. APS nephropathy should be included in the APS classification criteria, and the use of appropriate anticoagulant therapy should be tested.
Association of PDCD1 with susceptibility to systemic lupus erythematosus
Authors: Ferreiros‐Vidal Isabel , Gomez‐Reino Juan J. , Barros Francisco , Carracedo Angel , Carreira Patricia , Gonzalez‐Escribano Francisca , Liz Myriam , Martin Javier , Ordi Josep , Vicario Jose L. , Gonzalez Antonio
Published: August 2004

Objective

The A allele of the PD1.3 single‐nucleotide polymorphism (SNP) on the programmed cell death gene PDCD1 was markedly more frequent in patients with systemic lupus erythematosus (SLE) than in unaffected controls in a recent study involving large sets of Swedish, European American, and Mexican families. This study sought to determine the role of PDCD1 in susceptibility to SLE in the Spanish population.

Methods

Seven PDCD1 SNPs were studied in 518 SLE patients and 800 healthy control subjects who had been recruited in 5 distant towns spanning continental Spain. Patients and controls were of Spanish ancestry. The diagnosis of SLE was in accordance with the American College of Rheumatology updated classification criteria.

Results

The A allele of the PD1.3 polymorphism was significantly less frequent in Spanish female patients with SLE than in Spanish female controls (9.0% versus 13.0%, odds ratio 0.67, 95% confidence interval 0.50–0.89). This difference was consistent across the 5 sets of samples grouped by town of recruitment. The other PDCD1 SNPs were not associated with SLE susceptibility. The haplotype structure of PDCD1 in the Spanish controls was different from that reported in other healthy control populations.

Conclusion

Our results confirm the association of PDCD1 with susceptibility to SLE, but the findings show a lack of involvement of the PD1.3 SNP, which is contrary to the role of the PD1.3 A allele observed previously. These contradictory results probably reflect population differences in the haplotype structure of the PDCD1 locus. More research focusing on new polymorphisms and identifying associations in other populations will be needed to clarify the role of PDCD1 in SLE susceptibility.
The Vλ–Jλ repertoire of patients with systemic lupus erythematosus manifests characteristics of the natural antibody repertoire
Authors: Lee Jisoo , Cho Young Joo , Lipsky Peter E.
Published: August 2004

Objective

To understand in detail the mechanisms of autoantibody production in patients with systemic lupus erythematosus (SLE), we performed a comprehensive analysis of the normal human immunoglobulin light chain Vλ repertoire and compared it with the Vλ repertoire in SLE patients.

Methods

The SLE Vλ repertoire of B cells obtained from 3 SLE patients was analyzed and compared in detail with the Vλ repertoire of IgM+ B cells obtained from 3 human fetal spleens and IgM+,CD5+ B cells obtained from 2 normal adults. Conventional IgM+,CD5– B cells obtained from normal adults were used as controls. Vλ–Jλ rearrangements were amplified from the genomic DNA of individual B cells by polymerase chain reaction.

Results

The expressed Vλ repertoire of SLE patients contained several similarities with the expressed repertoire of the fetus and the adult CD5+ B cells. The Vλ genes 3L and 1G were overexpressed in the fetus, the adult CD5+ B cells, and the patients with SLE. The selection for rearrangements with restricted junctional diversity by utilization of homology‐mediated joining, together with diminished N nucleotide addition, was a prominent feature of fetal, adult CD5+, and SLE B cell repertoires. Furthermore, profound expansion of Vλ clones with identical third complementarity‐determining regions was observed in the adult CD5+, fetal, and SLE B cell repertoires. Notably, significant numbers of expanded adult CD5+ B cells, fetal, and SLE Vλ clones utilized homology‐mediated joining at the Vλ–Jλ junctions.

Conclusion

These data demonstrate that the SLE Vλ–Jλ repertoire manifests characteristics of normal adult IgM+,CD5+ and fetal B cell populations that are known to be enriched for the production of natural autoantibodies.
Differential gene expression and regulation of the bone morphogenetic protein antagonists follistatin and gremlin in normal and osteoarthritic human chondrocytes and synovial fibroblasts
Authors: Tardif Ginette , Hum David , Pelletier Jean‐Pierre , Boileau Christelle , Ranger Pierre , Martel‐Pelletier Johanne
Published: August 2004

Objective

To compare gene expression in normal and osteoarthritic (OA) human chondrocytes using microarray technology. Of the novel genes identified, we selected follistatin, a bone morphogenetic protein (BMP) antagonist, and investigated its expression/regulation as well as that of 3 other antagonists, gremlin, chordin, and noggin, in normal and OA chondrocytes and synovial fibroblasts.

Methods

Basal and induced gene expression were determined using real‐time polymerase chain reaction. Gene regulation was monitored following treatment with inflammatory, antiinflammatory, growth, and developmental factors. Follistatin protein production was measured using a specific enzyme‐linked immunosorbent assay, and localization of follistatin and gremlin in cartilage was determined by immunohistochemical analysis.

Results

All BMP antagonists except noggin were expressed in chondrocytes and synovial fibroblasts. Follistatin and gremlin were significantly up‐regulated in OA chondrocytes but not in OA synovial fibroblasts. Chordin was weakly expressed in normal and OA cells. Production of follistatin protein paralleled the gene expression pattern. Follistatin and gremlin were expressed preferentially by the chondrocytes at the superficial layers of cartilage. Tumor necrosis factor α and interferon‐γ significantly stimulated follistatin expression but down‐regulated expression of gremlin. Interleukin‐1β (IL‐1β) had no effect on follistatin but reduced gremlin expression. Conversely, BMP‐2 and BMP‐4 significantly stimulated expression of gremlin but down‐regulated that of follistatin. IL‐13, dexamethasone, transforming growth factor β1, basic fibroblast growth factor, platelet‐derived growth factor type BB, and endothelial cell growth factor down‐regulated the expression of both antagonists.

Conclusion

This study is the first to show the possible involvement of follistatin and gremlin in OA pathophysiology. The increased activin/BMP‐binding activities of these antagonists could affect tissue remodeling. The data suggest that follistatin and gremlin might appear at different stages during the OA process, making them interesting targets for the treatment of this disease.
Association study of candidate genes for the prevalence and progression of knee osteoarthritis
Authors: Valdes Ana M. , Hart Deborah J. , Jones Karen A. , Surdulescu Gabriela , Swarbrick Peter , Doyle David V. , Schafer Alan J. , Spector Tim D.
Published: August 2004

Objective

Osteoarthritis (OA), characterized by late‐onset degeneration of articular cartilage, is recognized to have a genetic component. We examined the role of 26 single‐nucleotide polymorphisms (SNPs) from 24 candidate genes in OA susceptibility and progression.

Methods

We compared human complementary DNA libraries from OA‐affected and normal cartilage and synovium and selected 22 genes in addition to the estrogen receptor α and vitamin D receptor genes. Based on the availability of polymorphisms, we proceeded to test whether genetic variation at those genes affected susceptibility to or progression of radiographic knee OA over a 10‐year period in 749 women (mean age 64 years) from the longitudinal Chingford Study.

Results

After adjusting for age and body mass index, we observed significant associations at ADAM12, BMP2, CD36, COX2, and NCOR2 with 3 OA susceptibility traits (presence/absence of joint space narrowing [JSN], presence/absence of osteophytes, and Kellgren/Lawrence [K/L] score). For the OA progression traits (change over 10 years in the K/L score, osteophyte grade, and JSN grade), we found significant associations with ADAM12, CILP, OPG, and TNA. Overall, we observed 15 associations with nominal significance (P < 0.05) and, by permutation analysis, found that such a number would be observed by chance only 3.8% of the time. Although these tests require replication, the stronger genetic associations observed are unlikely to be attributable simply to multiple comparisons.

Conclusion

Our results suggest that OA severity and progression have a multigenic and feature‐specific nature. These findings should encourage the development of genetic diagnostics for OA progression based on multiple SNPs and help unravel some of the complex disease mechanisms in OA.
Regional variation and differential response to therapy for knee synovitis adjacent to the cartilage–pannus junction and suprapatellar pouch in inflammatory arthritis: Implications for pathogenesis and treatment
Authors: Rhodes Laura A. , Tan Ai Lyn , Tanner Steven F. , Radjenovic Aleksandra , Hensor Elizabeth M. A. , Reece Richard , O'Connor Philip , Emery Paul , McGonagle Dennis
Published: August 2004

Objective

To use magnetic resonance imaging (MRI) to investigate the importance of knee joint synovitis at the cartilage–pannus junction (CPJ) in rheumatoid arthritis (RA) as compared with synovitis at a distant site in the suprapatellar pouch (SPP) and as compared with CPJ synovitis in the spondylarthropathies (SpA), and to assess the relative response of knee joint synovitis to therapy at the CPJ and SPP sites.

Methods

Dynamic contrast‐enhanced MRI (DEMRI) of actively involved knee joints in 24 patients (13 with RA and 11 with SpA) was undertaken. The area of synovitis was calculated at the CPJ and SPP regions of interest in patients with RA and in patients with SpA. Differences in CPJ and SPP synovitis were determined using calculated DEMRI parameters which included the initial rate of contrast enhancement (IRE) and the maximal enhancement (ME). Changes in the synovial area at the CPJ and SPP were also measured in 10 patients with early RA, following treatment with disease‐modifying antirheumatic drugs (DMARDs) (either methotrexate or leflunomide).

Results

In patients with RA or SpA, the area of synovitis was significantly larger immediately adjacent to the CPJ compared with a distant site at the SPP (in RA, mean synovitis area 162 mm2 at the CPJ versus 114 mm2 at the SPP [P = 0.010]; in SpA, mean synovitis area 214 mm2 at the CPJ versus 143 mm2 at the SPP [P = 0.002]), but the differences in the areas of synovitis at these sites were not significant between the RA and SpA patients. The IRE and ME values were also higher at the CPJ compared with the SPP, both in the RA patients (IRE P = 0.054, ME P = 0.018) and in the SpA patients (IRE P = 0.002, ME P = 0.001). A larger reduction in the area of synovitis was seen at the SPP compared with the CPJ following DMARD therapy in the RA patients (mean reduction 35% at the SPP [P = 0.023] and 12% at the CPJ [P not significant]).

Conclusion

The non–disease‐specific variations in synovitis and the differential responses to therapy in RA patients have implications for improving our understanding of CPJ synovitis. The results suggest that the pathophysiologic events at the CPJ reflect common anatomic, immune system, or biomechanical factors that play a role in modulating the severity of arthritis, and these events are not specific to RA since the same process was observed in other arthritides.
A genome scan for joint‐specific hand osteoarthritis susceptibility: The Framingham Study
Authors: Hunter D. J. , Demissie S. , Cupples L. A. , Aliabadi P. , Felson D. T.
Published: August 2004

Objective

Studies investigating hand osteoarthritis (OA) as a single entity have not shown strong linkage of the disease with any chromosomal sites. We undertook this study to test our hypothesis that phenotypes of hand OA may show stronger linkage than has been shown for overall hand OA.

Methods

We performed a factor analysis on measures of hand OA to determine patterns of disease. Using the joint regions identified by this analysis, we performed a genome‐wide linkage analysis for OA susceptibility loci using 426 original cohort members and 790 offspring cohort members in 267 pedigrees. Radiographic OA features evaluated included the Kellgren/Lawrence score, osteophytes, and joint space narrowing. Prior to linkage analysis, standardized residuals were computed from regression analysis of each phenotype on age. This was performed separately for each sex and cohort. The variance component model (GeneHunter) was then applied to the normalized scores of the residuals of both sexes and cohorts.

Results

There was evidence suggestive of linkage (logarithm of odds [LOD] score >1.5) at 16 sites. Four of these sites had LOD scores >3.0. Two of these sites (identified in the full sample) included a linkage region for OA of the distal interphalangeal (DIP) joint on chromosome 7 (155 cM; LOD score 3.06) and a linkage region for OA of the first carpometacarpal (CMC) joint on chromosome 15 (81 cM; LOD score 6.25). The other 2 sites (identified in women) included a linkage region for OA of the DIP joint on chromosome 1 (202 cM; LOD score 3.03) and a linkage region for OA of the first CMC joint on chromosome 20 (4 cM; LOD score 3.74).

Conclusion

These data suggest that several chromosomes contain hand OA susceptibility genes and that a joint‐specific approach may be more rewarding than a global approach to the genetics of hand OA. Further investigation of these regions is warranted using finer maps and other populations.
What is the most appropriate radiologic scoring method for ankylosing spondylitis?
Authors: Wanders Astrid J. B. , Landewé Robert B. M. , Spoorenberg Anneke , Dougados Maxime , van der Linden Sjef , Mielants Herman , van der Tempel Hille , van der Heijde Désirée M. F. M.
Published: August 2004

Objective

To select the most appropriate radiologic scoring method for the evaluation of radiographic progression in ankylosing spondylitis (AS) in clinical trials.

Methods

The validity of the currently available methods, the Bath Ankylosing Spondylitis Radiology Index (BASRI), the Stoke Ankylosing Spondylitis Spine Score (SASSS), and the modified SASSS (M‐SASSS), was tested according to the aspects of the Outcome Measures in Rheumatology Clinical Trials filter: truth, discrimination (reliability and sensitivity to change), and feasibility, using radiographs of 133 patients at 4 different time points (baseline, 1 year, 2 years, and 4 years). One observer scored these sets in chronological order. To assess interobserver reliability, a second observer scored radiographs of 20 patients at the 4 different time points.

Results

After 4 years, 9% and 8% of patients showed changes >0 in the sacroiliac (SI) joints and hips, respectively. Independent of the method chosen, ∼40% of patients showed changes in both the lumbar and cervical spine. Therefore, it was concluded that, for the assessment of progression, SI joints and hips are of minor importance. The intraclass correlation coefficient (ICC) varied from 0.87 to 0.98 and ICCs for intraobserver scores varied from 0.96 to 0.99. Concerning progression scores, only the ICC for the M‐SASSS measured after 2 years remained acceptable (0.82). The intraobserver scores for progression after 2 years of followup were an ICC of 0.93 for the BASRI, an ICC of 0.79 for the SASSS, and an ICC of 0.95 for the M‐SASSS. Concerning sensitivity to change, it was found that the M‐SASSS classified the highest percentage of patients with a change >0.

Conclusion

The M‐SASSS is the most appropriate method by which to score the radiographic progression in AS patients in clinical trials.
Reduced infiltration and increased apoptosis of leukocytes at sites of inflammation by systemic administration of a membrane‐permeable IκBα repressor
Authors: Blackwell Nathan M. , Sembi Phupinder , Newson Justine S. , Lawrence Toby , Gilroy Derek W. , Kabouridis Panagiotis S.
Published: August 2004

Objective

NF‐κB activation is associated with several inflammatory disorders, including rheumatoid arthritis (RA), making this family of transcription factors a good target for the development of antiinflammatory treatments. Although inhibitors of the NF‐κB pathway are currently available, their specificity has not been adequately determined. IκBα is a physiologic inhibitor of NF‐κB and a potent repressor experimentally when expressed in a nondegradable form. We describe here a novel means for specifically regulating NF‐κB activity in vivo by administering a chimeric molecule comprising the super‐repressor IκBα (srIκBα) fused to the membrane‐transducing domain of the human immunodeficiency virus Tat protein (Tat‐srIκBα).

Methods

The Wistar rat carrageenan‐induced pleurisy model was used to assess the effects of in vivo administration of Tat‐srIκBα on leukocyte infiltration and on cytokine and chemokine production.

Results

Systemic administration of Tat‐srIκBα diminished infiltration of leukocytes into the site of inflammation. Analysis of the recruited inflammatory cells confirmed uptake of the inhibitor and reduction of the NF‐κB activity. These cells exhibited elevated caspase activity, suggesting that NF‐κB is required for the survival of leukocytes at sites of inflammation. Analysis of exudates, while showing decreases in the production of the proinflammatory cytokines tumor necrosis factor α and interleukin‐1β, also revealed a significant increase in the production of the neutrophil chemoattractants cytokine‐induced neutrophil chemoattractant 1 (CINC‐1) and CINC‐3 compared with controls. This result could reveal a previously unknown feedback mechanism in which infiltrating leukocytes may down‐regulate local production of these chemokines.

Conclusion

These results provide new insights into the etiology of inflammation and establish a strategy for developing novel therapeutics by regulating the signaling activity of pathways known to function in RA.
Fever in biopsy‐proven giant cell arteritis: Clinical implications in a defined population
Authors: Gonzalez‐Gay Miguel A. , Garcia‐Porrua Carlos , Amor‐Dorado Juan C. , Llorca Javier
Published: August 2004

Objective

To assess the frequency and clinical features of biopsy‐proven giant cell arteritis (GCA) patients who had fever at the time of diagnosis of the disease, and the relationship between fever, ischemic complications, and the systemic inflammatory response in GCA.

Methods

A retrospective study of biopsy‐proven GCA patients diagnosed between 1981 and 2001 was performed at the single referral hospital for a well‐defined population in the Lugo region of northwest Spain. Patients were considered as having fever if the axillary temperature at the time of admission or during the followup prior to the onset of corticosteroid therapy was ≥38°C.

Results

During the period of study, 21 (10%) of the 210 biopsy‐proven GCA patients had fever. Two of them fulfilled criteria for fever of unknown origin. Patients with fever had a lower frequency of severe ischemic manifestations than the rest of biopsy‐proven GCA patients. They also exhibited a more severe inflammatory disease, with significant abnormality in most laboratory variables, including higher elevation of erythrocyte sedimentation rate, lower values of hemoglobin, and higher proportion of patients with increased alkaline phosphatase. By logistic regression analysis, we observed that patients with fever had an increased risk of developing anemia (odds ratio [OR] 12.24). In contrast, a negative association between severe ischemic manifestations and fever was found (OR 0.41).

Conclusion

Biopsy‐proven GCA patients with fever constitute a subgroup of patients with more severe inflammatory response and less ischemic disease.
Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: A phase II, four‐week, multicenter, randomized, double‐blind, placebo‐controlled trial
Authors: Schnitzer Thomas J. , Beier Jannie , Geusens Piet , Hasler Paul , Patel Sanjay K. , Senftleber Ingo , Gitton Xavier , Moore Alan , Sloan Victor S. , Poór Gyula
Published: August 2004

Objective

To compare the efficacy and tolerability of the novel cyclooxygenase 2‐selective inhibitor lumiracoxib with placebo and diclofenac in osteoarthritis (OA).

Methods

Adults (n = 583) with knee or hip OA were randomized to receive for 4 weeks lumiracoxib 50, 100, or 200 mg twice daily or 400 mg once daily; placebo; or diclofenac 75 mg twice daily. Efficacy assessments included overall joint pain intensity and Western Ontario and McMaster Universities Osteoarthritis Index subscales; tolerability was evaluated by adverse event and physician reporting.

Results

All lumiracoxib doses were superior to placebo in relieving pain, improving stiffness, and improving physical function after 4 weeks. At study endpoint, pain relief was comparable among all lumiracoxib dosages and similar to diclofenac. Lumiracoxib tolerability was superior to diclofenac and comparable to placebo.

Conclusion

Lumiracoxib provides predictable and sustained relief from pain, stiffness, and impaired physical function in OA. Lumiracoxib shows clinically comparable efficacy and superior tolerability to diclofenac.
Education level and mortality in systemic lupus erythematosus (SLE): Evidence of underascertainment of deaths due to SLE in ethnic minorities with low education levels
Authors: Ward Michael M.
Published: August 2004

Objective

To determine if socioeconomic status, as measured by education level, is associated with mortality due to systemic lupus erythematosus (SLE), and to determine if these associations differ among ethnic groups.

Methods

Sex‐ and race‐specific mortality rates due to SLE by education level were computed for persons age 25–64 years using US Multiple Causes of Death data from 1994 to 1997. SLE‐specific mortality rates were compared with all‐cause mortality rates in 1997 to determine if the association between education level and mortality in SLE was similar to that in other causes of death.

Results

Among whites, the risk of death due to SLE was significantly higher among those with lower levels of education, and the risk gradient closely paralleled the 1997 all‐cause mortality risks by education level. However, in African American women and men and Asian/Pacific Islander women, the risk of death due to SLE was lower among those with lower education levels, contrary to the associations between education level and all‐cause mortality in these groups. Comparing the distribution of education levels among deaths due to SLE and all deaths in 1997, persons with lower education levels were underrepresented among deaths due to SLE in African Americans and Asian/Pacific Islanders.

Conclusion

Among whites, higher education levels are associated with lower mortality due to SLE. These associations were not present in ethnic minorities, likely due to underascertainment of deaths due to SLE in less‐well educated persons. This underascertainment may be due to underreporting of SLE on death certificates, but may also represent underdiagnosis of SLE in ethnic minorities with low education levels.
Costs of workups for the diagnosis of early arthritis: Results of a nationwide survey
Authors: Fautrel Bruno , Saraux Alain , Maillefert Jean‐Francis , Kaye Olivier , Lafforgue Pierre , Flipo René‐Marc , Penrod John R. , Guillemin Francis ,   for the Club Rhumatisme & Inflammation of the French Society for Rheumatology
Published: August 2004

Objective

To evaluate the costs of workups to diagnose early arthritis.

Methods

In 2000, the French Society for Rheumatology conducted a survey of a representative sample of French and Belgian rheumatologists (n = 239). The respondents were asked to consider 2 hypothetical scenarios, 1 describing undifferentiated arthritis and the other more suggestive of rheumatoid arthritis. They were then asked what diagnostic workup they would order. Costs for each study were determined in 2001 euros, according to the French public health system fee schedules.

Results

In total, 151 rheumatologists participated in the study (63%). The mean ± SD diagnostic costs were 406.5 ± 194.3 € for the case with no diagnostic clues, and 280.7 ± 154.3 € for the case suggestive of early RA. Responses were very heterogeneous. The 2 main sources of expenditure were immunology tests and imaging. Hospital staff physicians tended to order more expensive workups, and costs tended to vary inversely with physician experience. The most important predictor of cost was diagnostic doubt, as estimated by the number of diagnoses proposed by respondents in each case; each additional diagnosis cost an additional 19.1–26.1 €.

Conclusion

Diagnostic workups after a first medical visit for early polyarthritis result in substantial direct costs. This observation and the great variability observed in physicians' practices point out the need for consensus on the appropriate workups for these patients.