bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential for glomerular C4d as an indicator of thrombotic microangiopathy in lupus nephritis
Authors: Cohen Danielle , Koopmans Marije , Kremer Hovinga Idske C. L. , Berger Stefan P. , van Groningen Marian Roos , Steup‐Beekman Gerda M. , de Heer Emile , Bruijn Jan Anthonie , Bajema Ingeborg M.
Published: August 2008

Objective

In patients with systemic lupus erythematosus (SLE) and lupus nephritis, the presence of antiphospholipid antibodies (aPL) is considered to be an indication of increased risk of thrombotic microangiopathy, a serious complication of SLE. Previous studies have demonstrated a critical role for activation of the classical pathway of complement that leads to thrombotic injury in the presence of aPL. This study was undertaken to investigate whether C4d deposition in lupus nephritis is related to circulating aPL and the presence of renal microthrombi.

Methods

Deposition patterns of C4d in 44 renal biopsy samples obtained from 38 patients with biopsy‐proven lupus nephritis were determined by staining with a polyclonal anti‐C4d antibody. A phosphotungstic acid–hematoxylin stain was used to identify fibrin microthrombi. Clinical data (serum creatinine levels and presence or absence of aPL) were obtained and correlated with findings in the renal biopsy specimens. Patients were categorized as having aPL (n = 20) or not having aPL (n = 18).

Results

A strong relationship between the intensity of glomerular C4d staining and the presence of microthrombi was found (P < 0.002). Intense glomerular C4d deposition was present in 7 of 8 biopsy samples showing renal microthrombi. Neither C4d deposition nor the presence of microthrombi was correlated with aPL status.

Conclusion

Our findings suggest that activation of the classical pathway of complement plays a pathogenic role in the development of renal tissue injury leading to thrombosis, irrespective of the type of circulating antibodies present. Immunodetection of glomerular C4d deposition in renal biopsy samples could be a convenient method of identifying patients at risk of thrombotic microangiopathy.
Potential novel biomarkers of disease activity in rheumatoid arthritis patients: CXCL13, CCL23, transforming growth factor α, tumor necrosis factor receptor superfamily member 9, and macrophage colony‐stimulating factor
Authors: Rioja Inmaculada , Hughes Fiona J. , Sharp Catriona H. , Warnock Linda C. , Montgomery Doug S. , Akil Mohammed , Wilson Anthony G. , Binks Michael H. , Dickson Marion C.
Published: August 2008

Objective

To determine whether the plasma levels of a range of inflammatory proteins have utility as biomarkers of disease activity in rheumatoid arthritis (RA) patients.

Methods

Plasma proteins (n = 163) were profiled in 44 patients with RA diagnosed according to the American College of Rheumatology 1987 criteria (22 with active and 22 with quiescent disease) and in 16 age‐ and sex‐matched healthy controls. The utility of a subset of differentially expressed proteins as predictors of RA disease activity was investigated using partial least‐squares discriminant analysis, and their response to therapeutic intervention was evaluated in plasma from an additional cohort of 16 patients with active RA treated with anti–tumor necrosis factor α (anti‐TNFα).

Results

The protein profiling study identified 25 proteins that were differentially expressed in plasma samples from patients with active RA (P for the false discovery rate ≤ 0.01) compared with those with quiescent RA, including the previously described interleukin‐6 (IL‐6), oncostatin M, and IL‐2, and the 5 less‐established markers macrophage colony‐stimulating factor (M‐CSF), tumor necrosis factor receptor superfamily member 9, CCL23, transforming growth factor α, and CXCL13. Systemic levels of these 5 markers correlated with the C‐reactive protein level, erythrocyte sedimentation rate, rheumatoid factor level, tender joint count in 68 joints, and Disease Activity Score in 28 joints (DAS28), and their combined plasma levels were shown to be good predictors of disease activity (κ = 0.64). In anti‐TNFα–treated RA patients, plasma levels of CXCL13 were reduced after 1 and 7 days of therapy, and levels of CCL23, M‐CSF, and CXCL13 showed a statistically significant positive correlation with the DAS28 score.

Conclusion

This exploratory study for biomarker discovery led to the identification of several proteins predictive of RA disease activity that may be useful in the definition of disease subphenotypes and in the measurement of response to therapy in clinical studies.
Abetimus sodium for renal flare in systemic lupus erythematosus: Results of a randomized, controlled phase III trial
Authors: Cardiel Mario H. , Tumlin James A. , Furie Richard A. , Wallace Daniel J. , Joh Tenshang , Linnik Matthew D.
Published: August 2008

Objective

To investigate whether treatment with abetimus delays renal flare in patients with lupus nephritis. Secondary objectives included evaluation of the effect of abetimus on C3 levels, anti–double‐stranded DNA (anti‐dsDNA) antibody levels, use of high‐dose corticosteroids and/or cyclophosphamide, and major systemic lupus erythematosus (SLE) flare.

Methods

We conducted a randomized, placebo‐controlled study of treatment with abetimus at 100 mg/week for up to 22 months in SLE patients. Three hundred seventeen patients with a history of renal flare and anti‐dsDNA levels >15 IU/ml were randomized to a treatment group (158 abetimus, 159 placebo); 298 (94%) were enrolled in the intent‐to‐treat (ITT) population (145 abetimus, 153 placebo), based on the presence of high‐affinity antibodies for the oligonucleotide epitope of abetimus at baseline screening.

Results

Abetimus did not significantly prolong time to renal flare, time to initiation of high‐dose corticosteroid and/or cyclophosphamide treatment, or time to major SLE flare. However, there were 25% fewer renal flares in the abetimus group compared with the placebo group (17 of 145 abetimus‐treated patients [12%] versus 24 of 153 placebo‐treated patients [16%]). Abetimus treatment decreased anti‐dsDNA antibody levels (P < 0.0001), and reductions in anti‐dsDNA levels were associated with increases in C3 levels (P < 0.0001). More patients in the abetimus group experienced ≥50% reductions in proteinuria at 1 year, compared with the placebo group (nominal P = 0.047). Trends toward reduced rates of renal flare and major SLE flare were noted in patients treated with abetimus who had impaired renal function at baseline. Treatment with abetimus for up to 22 months was well tolerated.

Conclusion

Abetimus at 100 mg/week significantly reduced anti‐dsDNA antibody levels but did not significantly prolong time to renal flare when compared with placebo. Multiple positive trends in renal end points were observed in the abetimus treatment group.
Development of autoimmune hepatitis–like disease and production of autoantibodies to nuclear antigens in mice lacking B and T lymphocyte attenuator
Authors: Oya Yoshihiro , Watanabe Norihiko , Owada Takayoshi , Oki Mie , Hirose Koichi , Suto Akira , Kagami Shin‐Ichiro , Nakajima Hiroshi , Kishimoto Takashi , Iwamoto Itsuo , Murphy Theresa L. , Murphy Kenneth M. , Saito Yasushi
Published: August 2008

Objective

B and T lymphocyte attenuator (BTLA), a coreceptor expressed on lymphocytes, was recently described as an inhibitory coreceptor that negatively regulates lymphocyte activation. The purpose of this study was to investigate the role of BTLA in the regulation of immune homeostasis and the pathogenesis of autoimmunity.

Methods

We examined the levels of immunoglobulins and autoantibodies to nuclear antigens and the activation status of T cells in BTLA−/− mice. We also examined histopathologic changes in the organs of BTLA−/− mice.

Results

We observed that BTLA−/− mice gradually developed hypergammaglobulinemia, antinuclear antibodies, anti‐SSA antibodies, anti–double‐stranded DNA antibodies, and an increased number of activated CD4+ T cells in the periphery with age. Lack of BTLA led to spontaneous development of autoimmune hepatitis–like disease characterized by an elevation in the level of transaminases, interface hepatitis, and spotty necrosis of the liver. BTLA−/− mice also showed inflammatory cell infiltration of multiple organs, including the salivary glands, lungs, and pancreas; these features are similar to those of Sjögren's syndrome, which is a frequent complication of autoimmune hepatitis. Furthermore, the survival rate of BTLA−/− mice was significantly reduced after the age of 7 months.

Conclusion

Our results indicate that BTLA plays an important role in the maintenance of immune tolerance and the prevention of autoimmune diseases.
HLA class I deficiency syndrome mimicking Wegener's granulomatosis
Authors: Villa‐Forte Alexandra , de la Salle Henri , Fricker Dominique , Hentges Francois , Zimmer Jacques
Published: August 2008

Herein we report the case of a 20‐year‐old woman who presented with multiple skin ulcers on her legs, severe pansinusitis, and chronic lung disease. She was initially thought to have Wegener's granulomatosis (WG). However, serologic studies indicated an HLA class I deficiency, which was confirmed by flow cytometry. Complementation studies and reverse transcriptase–polymerase chain reaction followed by direct DNA sequencing revealed a mutation in the gene encoding subunit 1 of the peptide transporter associated with antigen processing (TAP1). This mutation, which has not been previously described in the literature, results in a stop codon in the catalytic domain of TAP1. Although TAP mutations are rare, clinicians may encounter them in the evaluation of patients with suspected WG. In patients with WG‐like symptoms it is important to consider this alternative genetic diagnosis as early as possible, not only so that appropriate antibiotic therapy can be initiated to prevent bronchiectasis, but also to avoid inappropriate immunosuppressive therapy that worsens the disease.
Rho‐associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts
Authors: Akhmetshina Alfiya , Dees Clara , Pileckyte Margarita , Szucs Gabriella , Spriewald Bernd M. , Zwerina Jochen , Distler Oliver , Schett Georg , Distler Jörg H. W.
Published: August 2008

Objective

Rho‐associated kinases (Rock) are the major cellular mediators of Rho GTPases and play an important role in the organization of the actin cytoskeleton. Inhibitors of Rock are currently being evaluated for the treatment of pulmonary arterial hypertension. This study was undertaken to analyze the role of Rock in the activation of fibroblasts in systemic sclerosis (SSc).

Methods

Rock signaling was inhibited using chemical inhibitors and small interfering RNA. The expression of extracellular matrix (ECM) proteins and α‐smooth muscle actin was analyzed by real‐time polymerase chain reaction, Western blotting, and SirCol assay. Metabolic activity was quantified by MTT assay. Cell viability was assessed by staining with annexin V and propidium iodide. The role of MAP kinases was investigated using selective inhibitors and Western blotting.

Results

Inhibition of Rock strongly reduced the synthesis of the major ECM proteins at the messenger RNA level as well as the protein level. Counterregulatory changes in the expression of tissue inhibitors of metalloproteinases and matrix metalloproteinases were not observed. Inhibition of Rock prevented myofibroblast differentiation. Transforming growth factor β activated ERK in a Rock‐dependent manner, and ERK mediated in part the stimulatory effects of Rock on myofibroblast differentiation. Toxic adverse effects of the inhibition of Rock were not observed.

Conclusion

Our findings demonstrate that Rock potently stimulates the differentiation of resting fibroblasts into myofibroblasts and the production of ECM at biologically relevant concentrations without cell toxicity. These findings, along with the beneficial effects of Rock inhibition on vascular disease, indicate that inhibition of Rock might be an interesting novel therapeutic approach for the treatment of SSc.
Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus
Authors: Petri Michelle , Stohl William , Chatham Winn , McCune W. Joseph , Chevrier Marc , Ryel Jeff , Recta Virginia , Zhong John , Freimuth William
Published: August 2008

Objective

To determine the association of plasma B lymphocyte stimulator (BLyS) levels, immunosuppressive therapy, and other clinical parameters with disease activity in systemic lupus erythematosus (SLE).

Methods

Two hundred forty‐five SLE patients were evaluated prospectively over a 2‐year period at 4 centers. Assessments were performed every 3–6 months. Univariate analysis was used to determine the association among the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, serum anti–double‐stranded DNA (anti‐dsDNA), and plasma BLyS levels. A multivariate repeated‐measures model incorporating immunosuppressive therapy was utilized.

Results

Ninety‐two percent of the patients were female. Sixty‐seven percent were white, 31% African American, and 2% Asian (all of these groups may include Hispanic). Mean values at baseline were as follows: age 41.5 years, disease duration 8.1 years, SELENA–SLEDAI 3.3 (median 2, range 0–18), BLyS 5.57 ng/ml, IgG 1,439 mg/dl, C3 104.4 mg/dl, and C4 21.3 mg/dl; among those positive for anti‐dsDNA, the median titer was 1:40 (range 1:10–1:1,280). Univariate analysis showed that plasma BLyS levels were associated with anti‐dsDNA titers (P = 0.0465) and SELENA–SLEDAI scores (P = 0.0002). In multivariate analyses, a greater increase in the SELENA–SLEDAI score from the previous visit was associated with higher BLyS levels at the previous visit (P = 0.0042) and with a greater increase in the BLyS level from the previous visit (P = 0.0007).

Conclusion

The findings of association between a greater increase in the BLyS level from the previous visit and a greater increase in the SELENA–SLEDAI score at the subsequent visit, and between an elevated BLyS level at the previous visit and a greater SELENA–SLEDAI score at the subsequent visit, demonstrate a relationship between circulating BLyS levels and SLE disease activity. These results lend support to the notion that BLyS is a candidate for therapeutic targeting in SLE.
Validation of a prediction rule for disease outcome in patients with recent‐onset undifferentiated arthritis: Moving toward individualized treatment decision‐making
Authors: van Der Helm‐van Mil Annette H. M. , Detert Jacqueline , Cessie Saskia Le , Filer Andrew , Bastian Hans , Burmester Gerd R. , Huizinga Tom W. J. , Raza Karim
Published: August 2008

Objective

The decision to start disease‐modifying antirheumatic drugs in patients with recent‐onset undifferentiated arthritis (UA) is complicated by a varied natural disease course in which the disease in one‐third of patients progresses to rheumatoid arthritis (RA), whereas 40–50% of patients experience spontaneous remission. Recently, a prediction rule was developed to estimate the chance of progression to RA in individual patients presenting with UA. This study investigates the accuracy of this prediction rule in independent cohorts of patients with UA.

Methods

In 3 cohorts of patients with recent‐onset UA, from the UK, Germany, and The Netherlands, the prediction score and the corresponding chance of developing RA were calculated. These data were compared with the observed disease outcome after ≥1 year of followup. Positive predictive values (PPVs) and negative predictive values (NPVs) were calculated and the overall discriminative ability of the prediction rule was assessed using area under the receiver operating characteristic curves (AUCs).

Results

Since data on the severity of morning stiffness were not available in all validation cohorts, the prediction rule was rederived with the duration of morning stiffness as a substitute. The AUC for this rule was 0.88 (SEM 0.015). For each validation cohort, the AUC was 0.83 (SEM 0.041), 0.82 (SEM 0.037), and 0.95 (SEM 0.031) in the British, German, and Dutch cohorts, respectively. The NPV (for a prediction score ≤6) in these 3 cohorts was 83%, 83%, and 86%, respectively; the PPV (for a prediction score ≥8) was 100%, 93%, and 100%, respectively.

Conclusion

The recently derived prediction rule, when applied to 3 independent cohorts of patients with UA, has an excellent discriminative ability for assessing the likelihood of progression to RA. Application of this rule will allow individualized treatment decision‐making for patients with UA.
Power doppler ultrasonographic monitoring of response to anti–tumor necrosis factor therapy in patients with rheumatoid arthritis
Authors: Naredo Esperanza , Möller Ingrid , Cruz Ana , Carmona Loreto , Garrido Jesüs
Published: August 2008

Objective

To evaluate the validity, responsiveness, and predictive value of power Doppler ultrasonography (PDUS) monitoring of response to tumor necrosis factor (TNF) blocking agents in rheumatoid arthritis (RA).

Methods

Three hundred sixty‐seven RA patients were prospectively recruited at 25 Spanish centers; complete clinical, laboratory, and PDUS data were obtained on 278 patients. The patients underwent clinical, laboratory, and PDUS assessment at baseline and after 1, 3, 6, and 12 months of anti‐TNF treatment, and radiographic assessment of the hands and feet at baseline and 12 months. The Disease Activity Score in 28 joints (DAS28) was recorded at each visit. PDUS examination included 86 intraarticular and periarticular sites in 28 joints. US synovial fluid (SF), synovial hypertrophy (SH), and PD signal were scored in all synovial sites. US count and index for SF, SH, and PD signal were obtained. Sensitivity to change of the PDUS variables was assessed by estimating the smallest detectable difference (SDD) from the intraobserver variability.

Results

A significant parallel improvement in DAS28 and PDUS parameters was found at followup assessment (P < 0.0005 for within‐subject between‐visit changes). The SDD for PDUS parameters was lower than the mean changes throughout followup. Time‐integrated values of US joint count for PD signal and rheumatoid factor (RF) showed predictive value in relation to progression of radiographic erosion (R = 0.64), and time‐integrated values of US joint count for PD signal, RF, and erythrocyte sedimentation rate were predictors of progression of the total radiographic score (R = 0.59).

Conclusion

These findings indicate that PDUS is a valid method for monitoring response to anti‐TNF therapy in RA; results obtained by PDUS are reproducible and sensitive to change. PDUS findings may have predictive value in relation to radiologic outcome.
Bone density, structure, and strength in juvenile idiopathic arthritis: Importance of disease severity and muscle deficits
Authors: Burnham Jon M. , Shults Justine , Dubner Sarah E. , Sembhi Harjeet , Zemel Babette S. , Leonard Mary B.
Published: August 2008

Objective

To identify determinants of musculoskeletal deficits (muscle cross‐sectional area [mCSA], trabecular volumetric bone mineral density [vBMD], and cortical bone strength [section modulus]) in patients with juvenile idiopathic arthritis (JIA) and to determine if cortical bone strength is appropriately adapted to muscle forces.

Methods

Peripheral quantitative computed tomography (pQCT) of the tibia was performed in 101 patients with JIA (79% female; 24 with oligoarticular JIA, 40 with polyarticular JIA, 18 with systemic JIA, and 19 with spondylarthritis [SpA]) and 830 healthy control subjects; all were ages 5–22 years. Outcomes of pQCT were expressed as sex‐ and race‐specific Z scores. Multivariable linear regression models assessed mCSA and bone status in JIA patients compared with controls and identified factors associated with musculoskeletal deficits in JIA.

Results

The median duration of JIA was 40 months; 29% of the JIA patients had active arthritis, and 28% had received glucocorticoid therapy during the previous year. Compared with the controls, the mCSA and section modulus Z scores were significantly lower in patients with polyarticular JIA and those with SpA. Trabecular vBMD Z scores were significantly lower in patients with polyarticular JIA, those with systemic JIA, and those with SpA. Significant predictors of musculoskeletal deficits included active arthritis in the previous 6 months (mCSA), temporomandibular joint disease (mCSA and section modulus), functional disability (mCSA and vBMD), short stature (vBMD), infliximab exposure (vBMD), and JIA duration (section modulus). The section modulus was significantly reduced relative to mCSA in patients with JIA after adjustment for age and limb length.

Conclusion

Marked deficits in vBMD and bone strength occur in JIA in association with severe and longstanding disease. Contrary to the findings of previous studies, bone deficits were greater than expected relative to the mCSA, which illustrates the importance of adjusting for age and bone length.
Efficacy and safety of rilonacept (interleukin‐1 trap) in patients with cryopyrin‐associated periodic syndromes: Results from two sequential placebo‐controlled studies
Authors: Hoffman Hal M. , Throne Martin L. , Amar N. J. , Sebai Mohamed , Kivitz Alan J. , Kavanaugh Arthur , Weinstein Steven P. , Belomestnov Pavel , Yancopoulos George D. , Stahl Neil , Mellis Scott J.
Published: August 2008

Objective

To assess the efficacy and safety of rilonacept (Interleukin‐1 [IL‐1] Trap), a long‐acting and potent inhibitor of IL‐1, in patients with cryopyrin‐associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS) and Muckle‐Wells syndrome (MWS).

Methods

Forty‐seven adult patients with CAPS, as defined by mutations in the causative NLRP3 (CIAS1) gene and pathognomonic symptoms, were enrolled in 2 consecutive phase III studies. Study 1 involved a 6‐week randomized double‐blind comparison of weekly subcutaneous injections of rilonacept (160 mg) versus placebo. Study 2 consisted of 9 weeks of single‐blind treatment with rilonacept (part A), followed by a 9‐week, randomized, double‐blind, placebo‐controlled withdrawal procedure (part B). Primary efficacy was evaluated using a validated composite key symptom score.

Results

Forty‐four patients completed both studies. In study 1, rilonacept therapy reduced the group mean composite symptom score by 84%, compared with 13% with placebo therapy (primary end point; P < 0.0001 versus placebo). Rilonacept also significantly improved all other efficacy end points in study 1 (numbers of multisymptom and single‐symptom disease flare days, single‐symptom scores, physician's and patient's global assessments of disease activity, limitations in daily activities, and C‐reactive protein and serum amyloid A [SAA] levels). In study 2 part B, rilonacept was superior to placebo for maintaining the improvements seen with rilonacept therapy, as shown by all efficacy parameters (primary end point; P < 0.0001 versus placebo). Rilonacept was generally well tolerated; the most common adverse events were injection site reactions.

Conclusion

Treatment with weekly rilonacept provided marked and lasting improvement in the clinical signs and symptoms of CAPS, and normalized the levels of SAA from those associated with risk of developing amyloidosis. Rilonacept exhibited a generally favorable safety and tolerability profile.
Treatment of pulmonary fibrosis for twenty weeks with imatinib mesylate in a patient with mixed connective tissue disease
Authors: Distler Jörg H. W. , Manger Bernhard , Spriewald Bernd M. , Schett Georg , Distler Oliver
Published: August 2008

Interstitial lung disease, which is common in patients with mixed connective tissue disease (MCTD), can progress to severe pulmonary fibrosis. The tyrosine kinase inhibitor imatinib mesylate has recently been shown to prevent experimental pulmonary, dermal, and renal fibrosis. Our patient, a 64‐year‐old woman with MCTD and rapidly progressive pulmonary fibrosis, presented with rapid deterioration despite treatment with immunosuppressants. During 20 weeks of treatment with imatinib mesylate at 400 mg/day, our patient improved significantly according to several outcome measures, including New York Heart Association classification, diffusing capacity for carbon monoxide, 6‐minute walking distance, arterial oxygen pressure, and reduction of ground‐glass opacities seen on high‐resolution computed tomography. No adverse effects of imatinib mesylate were observed. These findings suggest that imatinib mesylate might be effective in patients with fibrotic diseases and warrant the initiation of larger clinical studies on the safety and efficacy of imatinib mesylate in connective tissue diseases.
Imatinib mesylate treatment of nephrogenic systemic fibrosis
Authors: Kay Jonathan , High Whitney A.
Published: August 2008

Objective

To examine the effectiveness of imatinib mesylate in the treatment of nephrogenic systemic fibrosis (NSF).

Methods

Two patients with stage 5 chronic kidney disease and NSF were treated with oral imatinib mesylate at a dosage of 400 mg/day. Skin thickening and tethering were assessed using the modified Rodnan skin thickness score (MRSS), and knee joint flexion contractures were measured with a goniometer.

Results

Each patient displayed progressive reduction of skin thickening and tethering, with a steady decrease in the MRSS, following the initiation of imatinib mesylate treatment. The patient who had knee joint contractures achieved increased knee extension with passive range‐of‐motion exercises once his skin thickening and tethering had begun to decrease. Within weeks of stopping imatinib mesylate, the skin changes recurred in each patient. Recurrent skin thickening and tethering again improved in the patient who resumed taking imatinib mesylate for longer than 2 weeks. Skin biopsies performed both before and after initial dosing of that patient revealed less fibrosis and less staining for type I procollagen after imatinib mesylate treatment, but essentially unchanged tissue gadolinium content.

Conclusion

Imatinib mesylate treatment decreases fibrosis and results in the relatively rapid and steady improvement of skin changes and knee joint contractures in patients with stage 5 chronic kidney disease and NSF, despite the persistence of gadolinium in the tissues. Because skin changes recurred after discontinuation of imatinib mesylate, the duration for which treatment may be required is undetermined.
Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate
Authors: Pannu Jaspreet , Asano Yoshihide , Nakerakanti Sashidhar , Smith Edwin , Jablonska Stefania , Blaszczyk Maria , ten Dijke Peter , Trojanowska Maria
Published: August 2008

Objective

Activation of Smad1 signaling has recently been implicated in the development of fibrosis. The goal of the present study was to gain further insights into activation of the Smad1 pathway in fibrosis in systemic sclerosis (SSc) and to determine whether this pathway is targeted by the antifibrotic drug imatinib mesylate.

Methods

Levels of phosphorylated Smad1 and total Smad1 were examined in SSc and control skin biopsy samples by immunohistochemistry and in cultured fibroblasts by Western blotting. Activity of the CCN2 promoter was examined by a luciferase reporter gene assay. Interactions of Smad1 with the CCN2 promoter were examined by in vitro and in vivo DNA binding assays. Expression of the nonreceptor tyrosine kinase c‐Abl and Smad1 was blocked using respective small interfering RNA.

Results

Total and phosphorylated Smad1 levels were significantly elevated in SSc skin biopsy samples and in cultured SSc fibroblasts and correlated with elevated CCN2 protein and CCN2 promoter activity. DNA binding assays demonstrated that Smad1 was a direct activator of the CCN2 gene. Small interfering RNA–mediated depletion of Smad1 in SSc fibroblasts normalized the production of CCN2 and collagen. Imatinib mesylate blocked activation of the Smad1 pathway in transforming growth factor β–stimulated control fibroblasts and reversed activation of this pathway in SSc fibroblasts. Likewise, blockade of c‐Abl abrogated activation of the Smad1 pathway in SSc fibroblasts.

Conclusion

Our findings demonstrate that activation of Smad1 signaling occurs in a subset of SSc patients and contributes to persistent activation of SSc fibroblasts. Demonstration that the Smad1/CCN2 pathway is blocked by imatinib mesylate further clarifies the mechanism of the antifibrotic effects of this compound. This study suggests that SSc patients with activated Smad1 signaling may benefit from imatinib mesylate treatment.
Comparison of duplex sonography and high‐resolution magnetic resonance imaging in the diagnosis of giant cell (temporal) arteritis
Authors: Bley T. A. , Reinhard M. , Hauenstein C. , Markl M. , Warnatz K. , Hetzel A. , Uhl M. , Vaith P. , Langer M.
Published: August 2008

Objective

To compare the diagnostic performance of high‐resolution magnetic resonance imaging (MRI) and color‐coded duplex sonography (CCDS) in patients with giant cell (temporal) arteritis (GCA).

Methods

Results of high‐resolution MRI and CCDS in 59 patients with suspected GCA were compared with the final clinical diagnosis (based on the American College of Rheumatology GCA criteria and a 6‐month followup study). Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for each method. In 41 of the patients, imaging results were also compared with the findings of a temporal artery (TA) biopsy.

Results

Thirty‐six of the 59 patients (61%) were ultimately diagnosed as having GCA. Sensitivity of high‐resolution MRI and CCDS was 69% and 67%, respectively, specificity was 91% and 91%, PPV was 93% and 92%, and NPV was 66% and 64%, respectively. TA biopsy findings were positive in 24 of the 41 biopsied patients (59%). Sensitivity of high‐resolution MRI and CCDS compared with TA biopsy was 83% and 79%, respectively, specificity was 71% and 59%, PPV was 80% and 73%, and NPV was 75% and 67%, respectively. The differences between high‐resolution MRI and CCDS were not significant.

Conclusion

The diagnostic power of high‐resolution MRI and CCDS in detecting GCA was comparable. Either of these noninvasive techniques may have value in the evaluation of patients with suspected GCA, and decisions regarding which technique to use may depend on the clinical setting.
Small‐vessel vasculitis surrounding an uninflamed temporal artery: A new diagnostic criterion for polymyalgia rheumatica?
Authors: Chatelain Denis , Duhaut Pierre , Loire Robert , Bosshard Sylvie , Pellet Hélène , Piette Jean‐Charles , Sevestre Henri , Ducroix Jean‐Pierre
Published: August 2008

Objective

To assess the prevalence and clinical significance of small‐vessel vasculitis (SVV) surrounding an uninflamed temporal artery (TA) in patients diagnosed as having giant cell (temporal) arteritis (GCA) and/or polymyalgia rheumatica (PMR).

Methods

Patients with GCA and/or PMR (n = 490) were included in this multicenter prospective study. Slides of TA biopsy specimens were reviewed by 2 pathologists who were blinded with regard to clinical information. SVV was defined as aggregates of mononuclear inflammatory cells surrounding a capillary, distant from an uninflamed temporal artery. Clinical and biologic data of patients in the SVV group (n = 35) were compared with data of patients with biopsy‐proven GCA (n = 280) and with negative TA biopsy findings (n = 175).

Results

SVV was diagnosed in 18 women and 17 men (mean ± SD age 74.5 ± 9.4 years). The group of patients with SVV had a higher proportion of men than in the entire GCA series, had systemic symptoms, headache, jaw claudication, and an abnormal temporal artery less frequently at clinical examination, but had symptoms of PMR more often than patients in the biopsy‐proven GCA group (P = 2.6 × 10−7, odds ratio 9.17 [95% confidence interval 3.44–24.4]). Levels of inflammation markers were significantly lower in the SVV group. Patients in the SVV group had fever less frequently than patients in the group with negative TA biopsy findings, but otherwise shared the same clinical (including PMR symptoms) and biologic features. Eighteen of the 94 patients with pure PMR (19%) had SVV.

Conclusion

SVV is often neglected by pathologists, and appears to be strongly associated with PMR symptoms in patients with a clinical diagnosis of GCA and/or PMR. However, SVV as a new diagnostic criterion for PMR must be assessed in prospective studies.
Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: Support for the notion of a gene‐dose effect from the X chromosome
Authors: Scofield R. Hal , Bruner Gail R. , Namjou Bahram , Kimberly Robert P. , Ramsey‐Goldman Rosalind , Petri Michelle , Reveille John D. , Alarcón Graciela S. , Vilá Luis M. , Reid Jeff , Harris Bryan , Li Shibo , Kelly Jennifer A. , Harley John B.
Published: August 2008

Objective

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that predominantly affects women. Despite isolated reports of patients with coexisting Klinefelter's syndrome (47,XXY) and SLE, no association of Klinefelter's syndrome with SLE or any other autoimmune disease has been established. The present study was undertaken to investigate the prevalence of Klinefelter's syndrome in a large population of patients with SLE.

Methods

Sex chromosome genotyping was performed in 981 SLE patients, of whom 213 were men. A first group of 844 SLE patients from 378 multiplex families and a second group of 137 men with nonfamilial SLE were evaluated. In selected cases, chromosomes were enumerated by fluorescence in situ hybridization (FISH) and karyotyping in transformed B cell lines.

Results

Of 213 men with SLE, 5 had Klinefelter's syndrome (1 in 43). Four of them were heterozygous at X markers, and Klinefelter's syndrome was confirmed by FISH and karyotyping in the fifth. An overall rate of 47,XXY of 235 per 10,000 male SLE patients was found (95% confidence interval 77–539), a dramatic increase over the known prevalence of Klinefelter's syndrome in an unselected population (17 per 10,000 live male births). Asking men with SLE about fertility was highly sensitive (100%) for Klinefelter's syndrome. All 768 women with SLE were heterozygous at X.

Conclusion

The frequency of Klinefelter's syndrome (47,XXY), often subclinical, is increased in men with SLE by ∼14‐fold compared with its prevalence in men without SLE. Diagnostic vigilance for 47,XXY in male patients with SLE is warranted. These data are the first to show an association of Klinefelter's syndrome with an autoimmune disease found predominantly in women. The risk of SLE in men with Klinefelter's syndrome is predicted to be similar to the risk in normal women with 46,XX and ∼14‐fold higher than in men with 46,XY, consistent with the notion that SLE susceptibility is partly explained by an X chromosome gene‐dose effect.
Trends in out‐of‐pocket medical care expenditures for medicare‐age adults with arthritis between 1998 and 2004
Authors: Lurie Ithai Z. , Dunlop Dorothy D. , Manheim Larry M.
Published: August 2008

Objective

To provide estimates of the growth in out‐of‐pocket (OOP) medical expenditures for persons with arthritis.

Methods

OOP medical expenditures were estimated for 1998–2004 based on 7 panels of the Medical Expenditures Panel Survey, which provide nationally representative data. A simple simulation then extrapolated the data through 2006, for which the potential effects of Medicare Part D drug coverage were computed.

Results

Median total OOP expenditures for persons with arthritis showed an increase of 52.4% between 1998 and 2004 (7.3% annually beyond inflation). Median OOP expenditures for prescription medication showed larger growth, at 72.0%. Medicare Part D was predicted to lower both total and prescription OOP expenditures and return them close to 2003 levels. Simulation limitations included exclusive use of the standard Medicare Part D benefit structure and the assumption of stable prescribing trends during this period.

Conclusion

High prescription drug expenditures are likely to continue to be an issue, both for individuals faced with increasing OOP burden and for policy makers faced with increasing budgetary shortfalls to fund increasing Medicare expenses.
Subgroup analyses to determine cardiovascular risk associated with nonsteroidal antiinflammatory drugs and coxibs in specific patient groups
Authors: Solomon Daniel H. , Glynn Robert J. , Rothman Kenneth J. , Schneeweiss Sebastian , Setoguchi Soko , Mogun Helen , Avorn Jerry , Stürmer Til
Published: August 2008

Objective

To explore the extent to which clinical characteristics influence the association between cyclooxygenase 2 inhibitors (coxibs) and/or nonselective nonsteroidal antiinflammatory drugs (NSAIDs) and increased cardiovascular disease (CVD) risk in specific patient subgroups. There is substantial concern regarding the potential cardiovascular adverse effects of selective coxibs and nonselective NSAIDs, but many patients with arthritis experience important clinical benefits from these agents.

Methods

The study population consisted of Medicare beneficiaries also eligible for a drug benefits program for older adults during the years 1999–2004. We calculated the relative risk (RR) for CVD events (myocardial infarction [MI], stroke, congestive heart failure, and cardiovascular death) among users of coxibs or nonselective NSAIDs in the prior 6 months compared with nonusers. We assessed biologic interaction between these medication exposures and important patient characteristics.

Results

In the primary cohort, we identified 76,082 new users of coxibs, 53,014 new users of nonselective NSAIDs, and 46,558 nonusers. Compared with nonusers, the adjusted RR of CVD events for new users of each agent increased for rofecoxib (RR 1.22, 95% confidence interval [95% CI] 1.14, 1.30) and decreased for naproxen (RR 0.79, 95% CI 0.67, 0.93). Several patient characteristics were found to increase the risk of CVD events among users of some agents in both the primary and secondary cohorts, including age ≥80 years, hypertension, prior MI, prior CVD, rheumatoid arthritis, chronic renal disease, and chronic obstructive pulmonary disease. Rofecoxib and ibuprofen appeared to confer an increased risk in multiple patient subgroups.

Conclusion

Many nonselective NSAIDs and coxibs are not associated with an increased risk of CVD events. However, several patient characteristics identify important subgroups that may be at an increased risk when using specific agents.
Validation of the Childhood Health Assessment Questionnaire in active juvenile systemic lupus erythematosus
Authors: Meiorin Silvia , Pistorio Angela , Ravelli Angelo , Iusan Silvia M. , Filocamo Giovanni , Trail Lucia , Oliveira Sheila , Cuttica Ruben , Espada Graciela , Alessio Maria , Mihaylova Dimitrina , Cortis Elisabetta , Martini Alberto , Ruperto Nicolino ,   Paediatric Rheumatology International Trials Organisation (PRINTO)
Published: August 2008

Objective

To validate the Childhood Health Assessment Questionnaire (C‐HAQ) as a measure of disability in patients with active juvenile systemic lupus erythematosus (SLE).

Methods

Of 557 patients with juvenile SLE included in the Paediatric Rheumatology International Trials Organisation (PRINTO) database, 504 (90.5%) were included in the present study and underwent C‐HAQ assessment at the time of a major therapeutic intervention and then after 6 months. Validation procedures, according to the Outcome Measures in Rheumatology Clinical Trials filter for outcome measures in rheumatology, included assessment of responsiveness, feasibility, internal consistency, construct validity, collinearity, and discriminative ability. Response to therapy was evaluated with the PRINTO/American College of Rheumatology (ACR) juvenile SLE definition of improvement.

Results

At baseline, patients showed a high level of disease activity (mean physician global 5.8) and moderate disability (mean C‐HAQ 0.83); both disease activity and disability improved after 6 months of treatment. The change in C‐HAQ score correlated moderately with the Systemic Lupus Activity Measure (rs = 0.42), parent's global assessment of pain and well‐being (rs = 0.55 and 0.53, respectively), and the physical summary score of the Child Health Questionnaire (rs = −0.61), and poorly with other clinical and laboratory parameters. The absolute change in C‐HAQ demonstrated a significant ability to discriminate between patients who improved and those who did not improve based on the PRINTO/ACR definition of improvement. Responsiveness of the C‐HAQ was moderate (standardized response mean 0.74). Internal consistency was excellent (Cronbach's α = 0.96).

Conclusion

The C‐HAQ showed moderate responsiveness to clinical change, construct validity, good feasibility, internal consistency, and discriminative ability. These findings demonstrate that the C‐HAQ represents a good measure to capture disability in patients with active juvenile SLE.
Use of nonbiologic disease‐modifying antirheumatic drugs and risk of infection in patients with rheumatoid arthritis
Authors: Lacaille Diane , Guh Daphne P. , Abrahamowicz Michal , Anis Aslam H. , Esdaile John M.
Published: August 2008

Objective

Rheumatoid arthritis (RA) is associated with increased frequency of and mortality from infections, which may be related to host factors, RA itself, inflammation, or medication side effects. This study was undertaken to determine the effect of nonbiologic disease‐modifying antirheumatic drugs (DMARDs) on infection risk in RA.

Methods

We performed a retrospective, longitudinal study of a population‐based RA cohort in British Columbia, Canada, followed from January 1996 to March 2003 using administrative data. We evaluated mild infections (requiring a physician visit or antibiotics) and serious infections (requiring or complicating hospitalization). Adjusted risk of mild and serious infections associated with DMARD exposure was estimated using generalized estimating equation extension of multivariate Poisson regression models, after adjusting for baseline covariates (age, sex, RA duration, socioeconomic status) and time‐dependent covariates (corticosteroids, comorbidity, prior infections).

Results

A total of 27,710 individuals with RA provided 162,710 person‐years of followup. Of these, 25,608 (92%) had at least 1 mild infection and 4,941 (18%) had at least 1 serious infection. Use of DMARDs without corticosteroids was associated with a small decrease in mild infection risk of statistical significance but unclear clinical significance (adjusted rate ratio [RR] 0.90, 95% confidence interval [95% CI] 0.88–0.93 relative to no corticosteroid or DMARD use). Use of DMARDs without corticosteroids was not associated with increased serious infection risk (adjusted RR 0.92, 95% CI 0.85–1.0). Use of corticosteroids increased the risk of mild and serious infections.

Conclusion

Our results indicate that use of nonbiologic DMARDs, including methotrexate, does not increase the risk of infection in RA, whereas use of corticosteroids does. This has important implications for counseling individuals with RA concerning risks and benefits of DMARDs.
Arthritis prevalence and associations in American Indian and Alaska native people
Authors: Ferucci Elizabeth D. , Schumacher M. Catherine , Lanier Anne P. , Murtaugh Maureen A. , Edwards Sandra , Helzer Laurie J. , Tom‐Orme Lillian , Slattery Martha L.
Published: August 2008

Objective

To investigate the prevalence of arthritis and associations with arthritis in American Indian and Alaska Native populations.

Methods

Data on self‐reported, doctor‐diagnosed arthritis from the baseline visit of 9,968 American Indian and Alaska Native adults from Alaska and the Southwest US were included. The prevalence of arthritis and univariate and multivariate associations between arthritis and demographic characteristics, health‐related factors, and treatment are described.

Results

The prevalence of self‐reported arthritis increased with age. The age‐sex adjusted prevalence was high in Alaska (26.1%) and low in the Southwest US (16.5%) as compared with the US population (21.5%). In both centers, arthritis was associated with age, lack of employment, chronic medical conditions, and poorer self‐reported overall health. Arthritis was associated with female sex in Alaska only, whereas education, marital status, and urban residency were associated with arthritis in the Southwest US. In both centers, self‐reported physical health measured by the Short Form 12 Health Survey was lower in people with arthritis, and mental health was not associated with arthritis. More frequent use of antiinflammatory medications was reported with arthritis in both centers, but increased use of traditional medicine and healers were associated with arthritis only in Alaska.

Conclusion

Compared with US rates, the prevalence of self‐reported arthritis was higher among Alaska Native people and lower in a Southwest American Indian population. Some factors associated with arthritis differ between the 2 populations.
Increased angiogenesis and cellular proliferation as hallmarks of the synovium in chronic septic arthritis
Authors: Pessler F. , Dai L. , Diaz‐Torne C. , Ogdie A. , Gomez‐Vaquero C. , Paessler M. E. , Einhorn E. , Chen L. X. , Schumacher H. R.
Published: August 2008

Objective

To characterize histologic alterations and inflammatory infiltrates in the synovium of patients with chronic septic arthritis (SeA).

Methods

Synovial membranes from patients with SeA (9 specimens; disease duration >4 weeks) were compared with specimens from patients with septic joint prosthesis loosening (septic total arthroplasty [SeTA]; 9 specimens), rheumatoid arthritis (RA; 25 specimens), osteoarthritis (25 specimens), and normal histology (10 specimens). Sections were stained with hematoxylin and eosin, tissue gram stain, and immunostains for von Willebrand factor (vWF; blood vessels), Ki‐67 (dividing cells), CD15 (neutrophils), CD3 (T cells), CD20 (B cells), CD38 (plasma cells), and CD68 (macrophages).

Results

Gram stains were positive in all SeA and SeTA specimens. Mixed polymorphonuclear and mononuclear infiltrates predominated in SeA and SeTA. SeA could be differentiated from RA by higher densities of CD15+ cells (SeA:RA ratio 6.5:1; P < 0.001) or Ki‐67+ cells (ratio 2.1:1; P = 0.012). The inflammatory infiltrate of SeTA was similar to SeA but contained fewer CD3+ cells (SeTA versus SeA 0.26:1; P = 0.009) and a tendency toward fewer CD20+ cells. Mean vascular density was strikingly increased in SeA (SeA:normal ratio 3.0:1; P < 0.001) and, to a lesser extent, in the vascularized areas of the SeTA specimens (SeTA:normal ratio 1.9:1). Ki‐67/CD31 double immunostains demonstrated proliferating endothelial cells in small subintimal blood vessels, suggesting angiogenesis. Receiver operating characteristic curve analysis identified higher densities of CD15+ and Ki‐67+ cells and vWF‐positive vessels as histologic markers that differentiated SeA from RA.

Conclusion

This first analysis of the synovium in patients with chronic pyogenic arthritis identified dramatic neovascularization and cell proliferation, accompanied by persistent bacterial colonization and heterogeneous inflammatory infiltrates rich in CD15+ neutrophils, as histopathologic hallmarks.