bluuebunny/crossref_metadata_2025 huggingface dataset:
The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: A five‐year followup study
Authors: Kalden J. R. , Schattenkirchner M. , Sörensen H. , Emery P. , Deighton C. , Rozman B. , Breedveld F.
Published: June 2003

Objective

To investigate the efficacy and safety of leflunomide beyond 2 years in a multinational, open‐label extension of 2 phase III double‐blind studies.

Methods

Patients with rheumatoid arthritis (RA) who received leflunomide (100 mg/day for 3 days, 10 mg/day or 20 mg/day thereafter) in the 2 phase III studies and who completed 2 years of treatment were offered inclusion in the open‐label extension phase and were maintained on the same dosage of leflunomide. The American College of Rheumatology revised criteria for 20% improvement (ACR20), ACR50, and ACR70 response rates, the Stanford Health Assessment Questionnaire (HAQ) scores, and C‐reactive protein (CRP) levels were assessed. Safety measures included monitoring of adverse events and laboratory values.

Results

A total of 214 patients (mean age 57 years) were treated with leflunomide for >2 years; 74.8% of the patients were female. The mean disease duration was 4.1 years (range 0.1–26.6 years), and in 44% of patients, RA was first diagnosed within 2 years of entry into the phase III studies. The mean duration of leflunomide treatment was 4.6 years (range 2.8–5.8 years), and 32% of patients had received no previous treatment with disease‐modifying antirheumatic drugs. ACR20, ACR50, and ACR70 response rates and HAQ scores at 1 year were maintained through year 4 or until the end point. No new types of adverse events were observed, and liver function was normal at baseline and at the end point in the majority of patients.

Conclusion

The improvements in both functional ability and physician‐based efficacy measures seen with leflunomide after 1 year were maintained for up to 5 years (maximum treatment duration 5.8 years), demonstrating that the early efficacy of leflunomide in patients with RA is sustained long‐term, and that the long‐term safety profile of leflunomide is no different from that observed in phase III trials.
Six‐month results of a double‐blind, placebo‐controlled trial of etanercept treatment in patients with active ankylosing spondylitis
Authors: Brandt J. , Khariouzov A. , Listing J. , Haibel H. , Sörensen H. , Grassnickel L. , Rudwaleit M. , Sieper J. , Braun J.
Published: June 2003

Objective

There is increasing evidence that tumor necrosis factor α (TNFα) is centrally involved in the pathogenesis of ankylosing spondylitis (AS) and other spondylarthritides. This study was designed to investigate the efficacy of anti‐TNFα therapy with etanercept, a 75‐kd receptor fusion protein, in active AS.

Methods

This multicenter trial had 2 phases: an initial placebo‐controlled period of 6 weeks' duration and an observational phase lasting 24 weeks. Thirty patients with active AS were included. They were randomized into 2 groups, which received either etanercept (25 mg twice weekly) (n = 14) or placebo (n = 16) for 6 weeks. Then both groups were treated with etanercept. Nonsteroidal antiinflammatory drug (NSAID) treatment could be continued, but disease‐modifying antirheumatic drugs (DMARDs) and steroids had to be withdrawn prior to the study. All patients received etanercept for a total of 12 weeks and were followed up for at least 24 weeks. The Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index, Bath AS Metrology Index, pain level on a numeric rating scale, quality of life by the Short Form 36, and C‐reactive protein (CRP) level were assessed. The primary outcome parameter was a ≥50% improvement in the BASDAI.

Results

Treatment with etanercept resulted in at least a 50% regression of disease activity in 57% of these patients at week 6, versus 6% of the placebo‐treated patients (P = 0.004). After the placebo‐treated patients switched to etanercept, 56% improved. The mean ± SD BASDAI improved from 6.5 ± 1.2 at baseline to 3.5 ± 1.9 at week 6 in the etanercept group, with no improvement in the placebo group (P = 0.003 between groups). Similarly, pain, function, mobility, and quality of life improved with etanercept but not with placebo at week 6 (P < 0.05). Mean CRP levels decreased significantly with etanercept but not with placebo (P = 0.001). There was ongoing improvement in all parameters in both groups until week 12 and week 18, respectively (i.e., throughout the period of etanercept treatment). Disease relapses occurred a mean ± SD of 6.2 ± 3.0 weeks after cessation of etanercept. No severe adverse events, including major infections, were observed during the trial.

Conclusion

This study shows that on a short‐term basis (3 months), treatment with etanercept is clearly efficacious in patients with active AS who are receiving NSAID therapy but not DMARDs or steroids. After cessation of therapy, almost all patients experienced a relapse within a few weeks. Thus, it seems probable that etanercept must be administered continuously in most AS patients to achieve permanent inhibition of the inflammatory process.
Differential control of CD22 ligand expression on B and T lymphocytes, and enhanced expression in murine systemic lupus
Authors: Lajaunias Frédéric , Ida Akinori , Kikuchi Shuichi , Fossati‐Jimack Liliane , Martinez‐Soria Eduardo , Moll Thomas , Law Che‐Leung , Izui Shozo
Published: June 2003

Objective

CD22, a B cell–restricted transmembrane glycoprotein, regulates B cell antigen receptor signaling upon interaction with α2,6‐linked sialic acid–bearing glycans, which act as ligands and are expressed on B and T cells. In this study, we investigated how the expression of CD22 ligand (CD22L) is modulated following lymphocyte activation or during the course of systemic lupus erythematosus (SLE).

Methods

The expression levels of CD22L on B and T cells in nonautoimmune mice were assessed by flow cytometric analysis using a soluble recombinant form of CD22, following stimulation with antigen or mitogen in vitro. In addition, the expression levels of CD22L on circulating lymphocytes were correlated with the progression of SLE in lupus‐prone mice.

Results

We observed a constitutive expression of CD22L on mature B cells, but not T cells, in nonautoimmune mice. However, CD22L levels were up‐regulated selectively on T cells (but not B cells) stimulated with antigens in vitro, while their expression levels on B cells was up‐modulated following polyclonal activation with lipopolysaccharide. Furthermore, expression of CD22L was increased on circulating B cells (and to a lesser extent on T cells) in parallel with progression of SLE in several different lupus‐prone mice and in a cohort of (C57BL/6 × [NZB × C57BL/6.Yaa]F1) backcross mice.

Conclusion

The expression of CD22L is differentially regulated in B and T cells, and high expression of CD22L on circulating B cells is a marker for development of severe SLE, suggesting a role for CD22–CD22L interactions in SLE as well as in the regulation of humoral immunity.
Effects of antiinflammatory drugs on arthritic cartilage: A high‐frequency quantitative ultrasound study in rats
Authors: Jaffré Britta , Watrin Astrid , Loeuille Damien , Gillet Pierre , Netter Patrick , Laugier Pascal , Saïed Amena
Published: June 2003

Objective

To evaluate the ability of 55‐MHz quantitative ultrasound (US) to detect the in vivo effects of experimental arthritis, as well as those of two antiinflammatory drugs, naproxen (NPX) and dexamethasone (DEX), on cartilage and subchondral bone.

Methods

Arthritis was induced in both knees of 108 rats by intraarticular injection of zymosan (ZYM). Two groups of arthritic rats (n = 36 per group) were treated daily with either NPX (10 mg/kg/day) or DEX (0.1 mg/kg/day). Using a 3‐dimensional US microscope, patellae were explored in vitro on days 5, 14, and 21 after injections. US assessment included the analysis of quantitative indices of local modifications involving cartilage and bone: integrated reflection coefficient (IRC) from the cartilage surface and apparent integrated backscatter from the cartilage internal structure (cartilage matrix) (AIBcartilage) and the cartilage–bone interface (AIBbone).

Results

ZYM induced articular surface fibrillation that resulted in a decrease in IRC at all times (P < 0.02) and in an increase in AIBbone on days 5 and 14 (P < 0.005). Fibrillation was not changed by NPX administration, while it disappeared following DEX treatment. Cartilage–bone interface alterations were prevented by DEX and partially compensated for by NPX. Cartilage matrix echogenicity decreased with time in all groups due to maturation (P < 0.05), except in DEX‐treated rats.

Conclusion

Quantitative 55 MHz US allowed detection of early cartilage and bone lesions due to experimental arthritis, and also allowed detection of the effects of antiinflammatory drugs. NPX seemed to have an effect on subchondral bone lesions, but not on cartilage. DEX appeared to repair articular surface and bone, but prevented animal growth and cartilage maturation.
Predicting mortality in patients with rheumatoid arthritis
Authors: Wolfe Frederick , Michaud Kaleb , Gefeller Olaf , Choi Hyon K.
Published: June 2003

Objective

A number of different variables have been proposed as risk factors for mortality in patients with rheumatoid arthritis (RA), but limited prospective information on the magnitude of their effects is available. This study was undertaken to evaluate the relative predictive strength and usefulness of a wide range of variables on the risk of mortality in a large, long‐term, prospectively studied cohort of patients with RA.

Methods

Over a 20‐year period of followup beginning in 1981, 1,387 consecutive RA patients were seen in a single clinic. A wide range of clinical and demographic assessments were recorded and entered into a computer database at the time of each clinical assessment. Assessment of predictive strength included determination of standardized and fourth‐versus‐first–quartile odds ratios (ORs), goodness‐of‐fit measures, and contributing fraction.

Results

The Health Assessment Questionnaire (HAQ) disability index was the strongest clinical predictor of mortality. A 1‐SD change in the HAQ resulted in a much larger increase in the odds ratio for mortality compared with a 1‐SD change in global disease severity, the next most powerful predictor of mortality (OR 2.31 versus 1.83). Considering the contributing fraction, mortality would be reduced by 50% for the HAQ and by 33% for global disease severity if patients in the fourth quartile for these variables could be switched to the first quartile. Global disease severity, pain, depression, anxiety, and laboratory and radiographic features were significantly weaker predictors. Disease duration, nodules, and tender joint count were clinical variables that provided very little predictive information. In multivariable analyses, HAQ and other patient self‐report measures were significantly better predictors than were radiographic and laboratory variables. A single baseline observation provided the least information, with substantially increasing predictive ability associated with 1‐year, 2‐year, and all–time point followup observations (time‐varying covariates).

Conclusion

In this large 20‐year study from routine clinical practice, the HAQ was the most powerful predictor of mortality, followed by other patient self‐report variables. Laboratory, radiographic, and physical examination data were substantially weaker in predicting mortality. We recommend that clinicians collect patient self‐report data, since they produce more useful clinical outcome information than other available clinical measures.
Delayed lupus onset in (NZB × NZW)F1 mice expressing a human C‐reactive protein transgene
Authors: Szalai Alexander J. , Weaver Casey T. , McCrory Mark A. , van Ginkel Frederik W. , Reiman Rachael M. , Kearney John F. , Marion Tony N. , Volanakis John E.
Published: June 2003

Objective

Human C‐reactive protein (CRP) binds apoptotic cells and alters blood clearance of injected chromatin in mice. To test whether CRP participates in the pathogenesis of systemic lupus erythematosus (SLE), we examined disease development in lupus‐prone (NZB × NZW)F1 (NZB/NZW) mice expressing a human CRP transgene (hCRPtg/BW).

Methods

Mortality was monitored, proteinuria was determined by dipstick, and serum levels of human CRP and anti–double‐stranded DNA (anti‐dsDNA) were determined by enzyme‐linked immunosorbent assay in NZB/NZW and hCRPtg/BW mice. Thin sections of kidneys were analyzed by immunofluorescence microscopy to compare deposition of IgG, IgM, C3, and human CRP, and electron microscopy was used to reveal differences in ultrastructure. In situ hybridization was performed to detect human CRP messenger RNA expression.

Results

The hCRPtg/BW mice had less proteinuria and longer survival than NZB/NZW mice. They also had lower IgM and higher IgG anti‐dsDNA titers than NZB/NZW mice, although the differences were transient and small. In hCRPtg/BW mice, accumulation of IgM and IgG in the renal glomeruli was delayed, reduced, and more mesangial than in NZB/NZW mice, while end‐stage accumulation of IgG, IgM, and C3 in the renal cortex was prevented. There was less glomerular podocyte fusion, basement membrane thickening, mesangial cell proliferation, and occlusion of capillary lumens in hCRPtg/BW mice, but dense deposits in the mesangium were increased. With disease progression in hCRPtg/BW mice, there was little rise in the plasma CRP level, but CRP in the kidneys became increasingly apparent due to local, disease‐independent, age‐related expression of the transgene.

Conclusion

In hCRPtg/BW mice, CRP protects against SLE by increasing blood and mesangial clearance of immune complexes and by preventing their accumulation in the renal cortex.
Clinical responses to tumor necrosis factor α antagonists do not show a bimodal distribution: Data from the Stockholm Tumor Necrosis Factor α Followup Registry
Authors: van Vollenhoven Ronald F. , Klareskog Lars
Published: June 2003

Objective

To study the distribution of clinical responses to treatment with the tumor necrosis factor α (TNFα) antagonists etanercept and infliximab, and in particular, to determine whether there is a biologically meaningful distinction between responders and nonresponders.

Methods

Among patients in the Stockholm TNFα Followup Registry, we analyzed the clinical responses to etanercept and infliximab, using the American College of Rheumatology (ACR) core set of outcome measures. For each parameter, the absolute change (value at baseline − current value) and the percentage change ([absolute change]/[value at baseline] × 100) from baseline were calculated. The results were plotted as histograms and inspected visually, and the distributions were statistically compared with computer‐generated normal distributions.

Results

Absolute and relative changes in outcomes on the ACR core set of measures in 406 patients receiving etanercept or infliximab were studied. All but a few of these analyses yielded normal or somewhat skewed distributions. The statistical analyses did not detect any non‐normal distributions, and visually, the distributions did not appear to be bimodal.

Conclusion

The clinical response to TNFα blockade displays a normal or skewed, but not bimodal, distribution. The frequently encountered perception that a clear distinction can be made between responders and nonresponders is not borne out. These relatively straightforward findings imply that the biologic mechanisms determining responsiveness to TNFα blockade are multifactorial and may also have important implications for regulatory guidelines pertaining to treatment with these biologic agents.
High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis
Authors: Pullerits Rille , Jonsson Ing‐Marie , Verdrengh Margareta , Bokarewa Maria , Andersson Ulf , Erlandsson‐Harris Helena , Tarkowski Andrej
Published: June 2003

Objective

To examine the potential role of high mobility group box chromosomal protein 1 (HMGB‐1) in the pathogenesis of arthritis.

Methods

Mice were injected intraarticularly with 1 μg or 5 μg of HMGB‐1. Joints were dissected on days 4, 7, and 28 after injection and were evaluated histopathologically and immunohistochemically. To investigate the importance of different white blood cell populations for the development of arthritis, in vivo cell depletion procedures were performed. In addition, spleen cells were cultured in the presence of HMGB‐1, and nuclear factor κB (NF‐κB) activation was detected by electrophoretic mobility shift assay.

Results

Injection of recombinant HMGB‐1 (rHMGB‐1) into different mouse strains resulted in an overall frequency of arthritis in 80% of the animals. The inflammation was characterized by mild to moderate synovitis and lasted for at least 28 days. The majority of cells found in the inflamed synovium were Mac‐1+ macrophages, whereas only a few CD4+ lymphocytes were detected. Pannus formation was observed in some cases 7 and 28 days after HMGB‐1 injection. No significant differences were found with respect to incidence and severity of arthritis between mice depleted of monocytes, granulocytes, or lacking T/B lymphocytes. However, combined removal of monocytes and neutrophils resulted in a 43% lower incidence of arthritis. Mice rendered deficient in the interleukin‐1 (IL‐1) receptor did not develop inflammation upon challenge with HMGB‐1. In vitro data corroborate this finding, showing that rHMGB‐1 activated NF‐κB, a major pathway leading to IL‐1 production.

Conclusion

Our results indicate that HMGB‐1 is not a mere expression of inflammatory responses, but on its own, it triggers joint inflammation by activating macrophages and inducing production of IL‐1 via NF‐κB activation.
Broad‐spectrum matrix metalloproteinase inhibitor marimastat–induced musculoskeletal side effects in rats
Authors: Renkiewicz Richard , Qiu Luping , Lesch Charles , Sun Xin , Devalaraja Radhika , Cody Theresa , Kaldjian Eric , Welgus Howard , Baragi Vijaykumar
Published: June 2003

Objective

To characterize the clinical and histopathologic changes in a rat model of broad‐spectrum matrix metalloproteinase (MMP)–induced musculoskeletal syndrome (MSS), and to facilitate research into the causes and treatments of MSS in humans.

Methods

Male Lewis rats weighing 150–180 gm were administered 10–30 mg of the broad‐spectrum MMP inhibitor marimastat over a 2‐week period via surgically implanted subcutaneous osmotic pumps. The animals were monitored and scored for the onset and severity of MSS, using clinical and histologic parameters.

Results

Marimastat‐treated rats exhibited various clinical signs, including compromised ability to rest on their hind feet, high‐stepping gait, reluctance or inability to move, and hind paw swelling. Histologically, marimastat‐treated rat joints were characterized by soft tissue and bone changes, such as increased epiphyseal growth plate, synovial hyperplasia, and increased cellularity in the joint capsule and extracapsular ligaments. The severity of MSS, as judged by clinical criteria (2 blinded observers using 3 clinical parameters), paw volume, and histologic score, was nearly identical. The observed changes were indistinguishable from those reported for primate models and mimic MSS in humans.

Conclusion

This simple and sensitive model of MSS is an attractive alternative for studying the pathology of MSS.
Asymmetric knee loading in advanced unilateral hip osteoarthritis
Authors: Shakoor Najia , Hurwitz Debra E. , Block Joel A. , Shott Susan , Case John P.
Published: June 2003

Objective

Subjects with unilateral end‐stage hip osteoarthritis (OA) who undergo total hip replacement (THR) preferentially require subsequent replacement of the contralateral knee compared with the ipsilateral knee. We investigated whether this nonrandom, preferential evolution of lower extremity OA from the hip to the contralateral knee joint may be related to asymmetries in dynamic joint loading at the knees, particularly the peak external knee adduction moment, which has been associated with the progression of knee OA.

Methods

Gait analysis was performed on 50 subjects who were preoperative for unilateral THR. Twenty‐two of these subjects were reevaluated postoperatively 10–23 months after undergoing successful THR. At each analysis, dynamic joint loads in the contralateral knee were compared with those in the ipsilateral knee.

Results

Prior to THR, the peak external knee adduction moment and peak medial compartment load were significantly higher in the contralateral knee. This asymmetry persisted after THR.

Conclusion

Subjects with unilateral end‐stage hip OA preferentially require subsequent replacement of the contralateral knee, as compared with the ipsilateral knee. Among patients with unilateral end‐stage hip OA, the contralateral knee is subjected to higher dynamic joint loads than is the ipsilateral knee, and this asymmetric loading persists long after subjects have undergone successful THR. Biomechanical factors appear to be involved in the multiarticular evolution of OA of the lower extremities.
Hsp70 prevents nitric oxide–induced apoptosis in articular chondrocytes
Authors: Terauchi Ryu , Takahashi Kenji A. , Arai Yuji , Ikeda Takumi , Ohashi Suzuyo , Imanishi Jiro , Mazda Osam , Kubo Toshikazu
Published: June 2003

Objective

To deliver and overexpress the hsp70 gene in cultured chondrocytes to investigate its effect on nitric oxide (NO)–induced apoptosis of chondrocytes.

Methods

Primary chondrocyte cultures were established from rabbit joints. The cells were transduced with an empty adenovirus vector (Ax1w) or an adenovirus vector harboring the hsp70 E‐tag fusion gene (AxSHEwt). Apoptosis was induced by sodium nitroprusside (SNP) dihydrate, which generates NO, or by staurosporine, which is a proapoptotic agent dependent upon Bax or Bak protein. Cell viability and apoptosis induction were estimated by lactate dehydrogenase (LDH) assay, Hoechst 33342 staining, or the TUNEL method. To study Hsp70, cytochrome c, and caspase 3, Western blot analyses were performed.

Results

The AxSHEwt‐transduced cells escaped apoptosis, as revealed by the LDH assay, Hoechst 33342 staining, and the TUNEL method. A massive amount of the tagged Hsp70 was demonstrated in the AxSHEwt‐transduced chondrocytes but not in control cells. Hsp70 did not affect the cytosolic cytochrome c level, but appeared to have obstructed the activation of caspase 3.

Conclusion

Experimentally overexpressed Hsp70 almost completely inhibited NO‐ or staurosporine‐induced apoptosis in primary chondrocytes.
Elevated levels of leukotriene B4 and leukotriene E4 in bronchoalveolar lavage fluid from patients with scleroderma lung disease
Authors: Kowal‐Bielecka Otylia , Distler Oliver , Kowal Krzysztof , Siergiejko Zenon , Chwiećko Justyna , Sulik Agnieszka , Gay Renate E. , Łukaszyk Anna Bodzenta , Gay Steffen , Sierakowski Stanisław
Published: June 2003

Objective

The leukotrienes are a family of arachidonic acid–derived lipid mediators with proinflammatory and profibrotic properties. The aim of this study was to analyze the role of leukotriene B4 (LTB4) and LTE4 in the pathogenesis of scleroderma lung disease (SLD).

Methods

Nineteen systemic sclerosis (SSc) patients with SLD, 11 SSc patients without SLD, and 10 healthy controls were studied. Bronchoalveolar lavage (BAL) fluid was obtained during routine bronchoscopy of the right middle lobe in all study subjects. Levels of LTB4 and LTE4 were measured using enzyme immunoassay kits.

Results

Levels of LTB4 and LTE4 were significantly higher in SSc patients with SLD (251 ± 170 pg/ml and 479 ± 301 pg/ml, respectively), than those in patients without SLD (114 ± 86 and 159 ± 149 pg/ml) and those in normal controls (86 ± 49 and 110 ± 67 pg/ml). In the total group of patients with SSc, levels of both leukotrienes correlated positively with the total number of cells in the BAL fluid and correlated negatively with the forced vital capacity. After intravenous pulse therapy with cyclophosphamide in 6 patients, there was a significant reduction in the concentration of LTB4 (from 380 ± 196 pg/ml to 155 ± 123 pg/ml) but no significant difference in the levels of LTE4 (from 697 ± 325 pg/ml to 418 ± 140 pg/ml).

Conclusion

Our findings show that LTB4 and LTE4 levels are elevated in SSc patients with SLD and correlate with parameters of inflammation in the lungs. These results indicate that leukotrienes may contribute to the pathogenesis of SLD and may represent a new therapeutic target.
Informed consent in a clinical trial of a novel treatment for rheumatoid arthritis
Authors: Criscione Lisa G. , Sugarman Jeremy , Sanders Linda , Pisetsky David S. , St.Clair E. William
Published: June 2003

Objective

To evaluate the informed consent process for a clinical trial of intravenous doxycycline for rheumatoid arthritis.

Methods

Participants completed a self‐administered questionnaire about the consent process at baseline and 16 weeks following enrollment in a clinical trial.

Results

Respondents (n = 30) affirmed voluntary participation in the parent trial. Participants acknowledged hope and altruism as reasons for entering the trial more than expectation of personal benefit or outside influences. Many respondents did not understand randomization (14/30), placebos (15/30), or risks of study medications; 11/30 respondents believed that the study drug was completely safe.

Conclusion

Respondents generally understood the experimental nature of the trial and confirmed their participation was voluntary. However, gaps existed in participants understanding of trial design, raising the question of whether they were adequately informed about the research study prior to enrollment. Further education of potential participants in clinical trials may be required to achieve valid informed consent.
European Consensus Lupus Activity Measurement is sensitive to change in disease activity in childhood‐onset systemic lupus erythematosus
Authors: Brunner Hermine I. , Silverman Earl D. , Bombardier Claire , Feldman Brian M.
Published: June 2003

Objectives

To evaluate the European Consensus Lupus Activity Measurement (ECLAM) for responsiveness to change in disease activity when used in childhood‐onset systemic lupus erythematosus (cSLE). To confirm the construct validity and to characterize the measurement properties of the ECLAM by assessing its ability to predict damage and steroid requirements.

Methods

The disease courses of 66 newly diagnosed cSLE patients were reviewed. The ECLAM and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were scored for all clinic visits and hospitalizations. Damage was assessed at the end of the followup period using the Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index. Disease activity at the time of diagnosis, 6 months after diagnosis, at the time of first flare, and 6 months after first flare was used to estimate responsiveness of the measures. Responsiveness was measured by the effect size, the effect size index, the standardized response mean, and the relative efficiency index (REI). The measurement properties of the ECLAM and SLEDAI over time were examined by comparing the ability of both measures to predict damage and oral steroid requirement.

Results

The ECLAM and SLEDAI are both responsive to change in disease activity irrespective of the statistic used. The ECLAM is more sensitive than the SLEDAI using the REI (all >1.9). Cumulative disease activity as measured by the SLEDAI or the ECLAM are important predictors of damage. There are no statistically important differences between the 2 measures with regard to their ability to predict steroid requirements.

Conclusions

The ECLAM has construct validity in cSLE and, like the SLEDAI, is highly sensitive to clinically important change in disease activity. The ECLAM may be more responsive. The quantitative properties of the 2 measures are very similar. The SLEDAI likely remains the preferable disease activity measure for cSLE given its overall measurement properties and ease of use.
Changes in self‐efficacy and health status over 5 years: A longitudinal observational study of 306 patients with rheumatoid arthritis
Authors: Brekke Mette , Hjortdahl Per , Kvien Tore K.
Published: June 2003

Objective

To investigate changes in self‐efficacy and health status over 5 years in patients with rheumatoid arthritis (RA), the relationships between these changes, and the influence of baseline values on subsequent changes.

Methods

306 adult patients with RA, born in 1926 or later, were examined by questionnaire in 1994 and again in 1999. We analyzed data regarding pain (visual analogue scale [VAS], Arthritis Impact Measurement Scale [AIMS2] symptom scale, Short Form‐36 [SF‐36] pain scale), fatigue (VAS, SF‐36 vitality scale), mental distress (AIMS2 affect scale, SF‐36 mental health scale) and self‐efficacy (Arthritis Self‐Efficacy Scales for pain and for other symptoms).

Results

On group level, all health status measures were numerically somewhat improved, and self‐efficacy slightly reduced. Changes in self‐efficacy and in corresponding health status measures were significantly correlated. For patients with above average educational level self‐efficacy for pain at baseline was positively correlated to improvement in pain measures. Good mental health at baseline was correlated to improvement in self‐efficacy for other symptoms, but only for patients with below average educational level.

Conclusion

Baseline self‐efficacy seems to influence future level of perceived pain and baseline mental health status seems to influence future self‐efficacy. These associations seem to be affected by level of education.
The effects of physician specialty and patient comorbidities on the use and discontinuation of coxibs
Authors: Patino Fausto G. , Allison Jeroan , Olivieri Jason , Mudano Amy , Juarez Lucia , Person Sharina , Mikuls Ted R. , Moreland Larry , Kovac Stacey H. , Saag Kenneth G.
Published: June 2003

Objective

To examine the effects of physician specialty and comorbidities on cyclooxygenase 2–selective nonsteroidal antiinflammatory drugs (NSAIDs; coxibs) utilization.

Methods

Medical records of 452 patients from a regional managed care organization with ≥3 consecutive NSAID prescriptions from June 1998 to April 2001 were abstracted. Multivariable adjusted associations between coxib initiation and discontinuation and patient and provider characteristics were examined.

Results

A total of 1,142 NSAID prescriptions were written over 9,398 total patient‐months of followup. Compared with patients seeing family or general practitioners, patients seeing rheumatologists (odds ratio [OR] 3.4, 95% confidence interval [95% CI] 2.1–5.7) and internists (OR 2.3, 95% CI 1.5–3.6) were significantly more likely to receive a coxib, as well as patients with a history of osteoarthritis (OR 2.6, 95% CI 1.7–3.8), gastrointestinal disease (OR 2.3, 95% CI 1.2–4.5), and congestive heart failure (OR 4.1, 95% CI 1.0–16.4). Although specialists were more likely than generalists to prescribe coxibs, only family or general practitioners were significantly more likely to selectively use coxibs among their patients with a history of gastrointestinal disease. Fifty‐four percent of NSAID prescriptions were discontinued, and coxibs were significantly less likely to be discontinued than were traditional NSAIDs (OR 0.6, 95% CI 0.5–0.8).

Conclusion

Our findings suggest significantly greater, but perhaps less selective use of coxibs among specialists, even after accounting for important covariates. The initiation and discontinuation of coxibs was influenced by physician specialty and by patient risk factors.
Vertebral deformities in 229 female patients with rheumatoid arthritis: Associations with clinical variables and bone mineral density
Authors: Ørstavik Ragnhild E. , Haugeberg Glenn , Uhlig Till , Falch Jan A. , Halse Johan I. , Høiseth Arne , Lilleås Finn , Kvien Tore K.
Published: June 2003

Objective

To examine the occurrence of vertebral deformities in female patients with rheumatoid arthritis (RA), and the relationship between vertebral deformities and bone mineral density (BMD) and between vertebral deformities and clinical variables.

Methods

Lateral radiographs of the spine were obtained in 229 female patients with RA (mean age 63.4 years, range 51.4–73.6 years) recruited from a county RA register. Vertebral deformities were measured semiquantitatively by an experienced radiologist. A clinical examination including core measurements of disease activity and severity was performed, and BMD was measured at the spine (L2–L4) and hip.

Results

According to the statistical analysis, 49 patients were considered to have relevant vertebral deformities. The occurrence of vertebral deformities was independently associated with age, long‐term corticosteroid use, and previous nonvertebral fracture, as well as reduced BMD. Our results failed to show any independent relationship between vertebral deformities and the activity or severity of disease.

Conclusion

Corticosteroid use is an important marker of established osteoporosis in patients with RA. Additionally, there seems to be a consistent relationship between BMD and vertebral deformities in this patient group.
The cost effectiveness of rofecoxib and celecoxib in patients with osteoarthritis or rheumatoid arthritis
Authors: Maetzel Andreas , Krahn Murray , Naglie Gary
Published: June 2003

Objective

To evaluate the cost effectiveness of the cyclooxygenase 2 (COX‐2) selective nonsteroidal antiinflammatory drug (NSAID) rofecoxib compared with naproxen and the COX‐2 NSAID celecoxib compared with ibuprofen and diclofenac.

Methods

Cost‐effectiveness analysis based on a 5‐year Markov model. Probability estimates were derived from detailed data of 2 randomized trials and a systematic search of the medical literature. Utility estimates were obtained from 60 randomly selected members of the general public. Cost estimates were obtained from Canadian provincial databases. Incremental cost‐effectiveness ratios were calculated for patients at average risk of upper gastrointestinal (UGI) events and for high‐risk patients with a prior history of a UGI event. Subjects were patients with osteoarthritis or rheumatoid arthritis (RA) where a decision has been made to treat with NSAIDs but who do not require low‐dose aspirin. Main outcome measures were proportion of patients with clinical or complicated UGI events, quality‐adjusted life expectancy, and life expectancy.

Results

Evaluation of rofecoxib versus naproxen in patients with RA at average risk resulted in costs per quality‐adjusted life year (QALY) gained of $Can271,188. Celecoxib was dominated by diclofenac in average‐risk patients. Both rofecoxib and celecoxib are cost‐effective in high‐risk patients. Analyses by age groups and assuming a threshold of Can$50,000 per QALY gained, suggest that rofecoxib or celecoxib would be cost‐effective in patients aged over 76 and 81, respectively, without additional risk factors.

Conclusion

Both rofecoxib and celecoxib are economically attractive in high risk and elderly patients. They are not economically attractive in patients at average risk. Coprescription of proton‐pump inhibitors with COX‐2 NSAIDs is not economically attractive for patients at high risk.
US incidence of juvenile dermatomyositis, 1995–1998: Results from the National Institute of Arthritis and Musculoskeletal and Skin Diseases Registry
Authors: Mendez Eduardo P. , Lipton Rebecca , Ramsey‐Goldman Rosalind , Roettcher Phil , Bowyer Susan , Dyer Alan , Pachman Lauren M. ,   For the NIAMS Juvenile DM Registry Physician Referral Group
Published: June 2003

Objective

To estimate the incidence of juvenile dermatomyositis (juvenile DM) in the United States between 1995 and 1998.

Methods

Physician referrals to the National Institute of Arthritis and Musculoskeletal and Skin Diseases Juvenile Dermatomyositis Research Registry and the National Pediatric Rheumatology Disease Registry from Indiana University were utilized for a 2‐source capture‐recapture estimation of Juvenile DM annual incidence.

Results

For children 2–17 years of age, the estimated annual incidence rates from 1995 to 1998 in the US ranged from 2.5 to 4.1 juvenile DM cases per million children, and the 4‐year average annual rate was 3.2 per million children (95% confidence interval 2.9–3.4). Estimated annual incidence rates by race were 3.4 for white non‐Hispanics, 3.3 for African American non‐Hispanics, and 2.7 for Hispanics. During the 4‐year period of the study, completeness of ascertainment for the combined registries ranged from 56% to 86% and girls were affected more than boys (ratio 2.3:1).

Conclusion

This study provides evidence for sex, and possibly racial differences in the risk of juvenile DM in the US.
Exercise‐related goals and self‐efficacy as correlates of aquatic exercise in individuals with arthritis
Authors: Gyurcsik Nancy C. , Estabrooks Paul A. , Frahm‐Templar Melissa J.
Published: June 2003

Objective

To examine whether aquatic exercise–related goals, task self‐efficacy, and scheduling self‐efficacy are predictive of aquatic exercise attendance in individuals with arthritis. A secondary objective was to determine whether high attendees differed from low attendees on goals and self‐efficacy.

Methods

The sample comprised 216 adults with arthritis (mean age 69.21 years). Measures included exercise‐related goal difficulty and specificity, task and scheduling self‐efficacy, and 8‐week aquatic exercise attendance.

Results

Results of a multiple hierarchical regression analysis were significant (P< 0.01). Goal difficulty, specificity, and task self‐efficacy were independent predictors of attendance (P< 0.05). A significant multivariate analysis of variance (P< 0.01) indicated that high attendees had higher task and scheduling self‐efficacy and lower goal difficulty than did low attendees (P< 0.05).

Conclusion

Support for the importance of exercise‐related goal setting and self‐efficacy was demonstrated. Implications pertain to the design of interventions to impact aquatic exercise.
Anti–interleukin‐6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis
Authors: Nakahara Hideko , Song Jian , Sugimoto Masamichi , Hagihara Keisuke , Kishimoto Tadamitsu , Yoshizaki Kazuyuki , Nishimoto Norihiro
Published: June 2003

Objective

To investigate whether interleukin‐6 (IL‐6) is a regulator of vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA).

Methods

Serum VEGF levels in RA patients were assayed before and after 8 weeks or 24 weeks of maintenance therapy with humanized anti–IL‐6 receptor monoclonal antibody (anti–IL‐6R mAb). VEGF secreted by RA synovial fibroblasts cultured in the presence of IL‐6, IL‐1β, and/or tumor necrosis factor α (TNFα) was measured. The inhibitory effect of anti–IL‐6R mAb, recombinant IL‐1 receptor antagonist (IL‐1Ra), and anti‐TNFα mAb on VEGF production was also examined.

Results

Serum VEGF levels in RA patients before anti–IL‐6R mAb therapy were significantly higher than those in healthy controls (P < 0.0005). Treatment of RA patients with anti–IL‐6R mAb normalized serum VEGF levels. In the in vitro study, IL‐6 and IL‐1β each induced a slight amount of VEGF production in synovial cells, but TNFα did not. Although VEGF‐inducing activity of these cytokines was not remarkable when they were added alone, IL‐6 acted synergistically with IL‐1β or TNFα to induce VEGF production. There was no synergistic effect between IL‐1β and TNFα. In the presence of all of these cytokines, anti–IL‐6R mAb eliminated the synergistic effect of IL‐6, IL‐1β, and TNFα, while IL‐1Ra or anti‐TNFα mAb did not.

Conclusion

Anti–IL‐6R mAb therapy reduced VEGF production in RA. IL‐6 is the pivotal cytokine that induces VEGF production in synergy with IL‐1β or TNFα, and this may be the mechanism by which IL‐6 blockade effectively suppresses VEGF production in synovial fibroblasts.
Lymphoma subtypes in patients with rheumatoid arthritis: Increased proportion of diffuse large B cell lymphoma
Authors: Baecklund Eva , Sundström Christer , Ekbom Anders , Catrina Anca I. , Biberfeld Peter , Feltelius Nils , Klareskog Lars
Published: June 2003

Objective

Patients with rheumatoid arthritis (RA) have an increased risk of developing malignant lymphoma. It is not clear whether the increase is confined to certain subtypes of lymphomas. Immunosuppressive therapy and Epstein‐Barr virus (EBV) have been linked to the development of these lymphomas. To gain information about the baseline pattern of lymphoma subtypes in RA before the current widespread use of immunosuppressive drugs, we examined the distribution of lymphoma subtypes and the presence of EBV in a cohort of RA patients with a low frequency and duration of treatment with immunosuppressive drugs.

Methods

By linking data from the Swedish Hospital Discharge Register and the Swedish Cancer Register, 42 cases of lymphoma were identified among 11,683 patients with RA in the Uppsala Health Care Region between 1964 and 1984. The medical records and paraffin‐embedded lymphoma tissues were collected, and the lymphomas were reclassified using the World Health Organization classification. In situ hybridization was used to detect EBV.

Results

Tissues from 35 patients were reviewed. Non‐Hodgkin's lymphoma (NHL) was found in 33 patients and Hodgkin's lymphoma in 2 patients. There was an increased frequency of diffuse large B cell lymphoma (DLBCL) (22 of 33 NHL patients, 67%) compared with that in the general population (30–40%). EBV was detected in 5 of 30 examined lymphomas from patients (17%). Twenty of the 22 DLBCL patients had RA with medium or high inflammatory activity, and 6 had been treated with a disease‐modifying antirheumatic drug for ≥1 year.

Conclusion

The findings of this study suggest an increased incidence of one specific lymphoma subtype, DLBCL, in RA patients, as well as a possible association with RA disease activity.
A public‐key based authentication and key establishment protocol coupled with a client puzzle
Authors: Lee M.C. , Fung Chun‐Kan
Published: June 2003

Network Denial‐of‐Service (DoS) attacks, which exhaust server resources and network bandwidth, can cause the target servers to be unable to provide proper services to the legitimate users and in some cases render the target systems inoperable and/or the target networks inaccessible. DoS attacks have now become a serious and common security threat to the Internet community. Public Key Infrastructure (PKI) has long been incorporated in various authentication protocols to facilitate verifying the identities of the communicating parties. The use of PKI has, however, an inherent problem as it involves expensive computational operations such as modular exponentiation. An improper deployment of the public‐key operations in a protocol could create an opportunity for DoS attackers to exhaust the server's resources. This paper presents a public‐key based authentication and key establishment protocol coupled with a sophisticated client puzzle, which together provide a versatile solution for possible DoS attacks and various other common attacks during an authentication process. Besides authentication, the protocol also supports a joint establishment of a session key by both the client and the server, which protects the session communications after the mutual authentication. The proposed protocol has been validated using a formal logic theory and has been shown, through security analysis, to be able to resist, besides DoS attacks, various other common attacks.
The myth of technological neutrality in copyright and the rights of institutional users: Recent legal challenges to the information organization as mediator and the impact of the DMCA, WIPO, and TEACH
Authors: Lipinski Tomas A.
Published: June 2003

This article discusses the accelerating trend of ownership rights in digital property, copyright, in specific. This trend is in contrast to the stated legislative purpose of copyright law to be neutral as to the technology that either owners employ to embody the copyrighted work or that others employ to facilitate access and use of the work. Recent legislative initiatives as well as interpretive court decisions have undermined this important concept. There is an ascendancy of digital ownership rights that threatens to undermine the concept of technological neutrality, which in essence guarantees that ownership and well as “use” rights apply equally to analog and digital environments. The result of this skewing is twofold: an unstable environment with respect to the access and use rights of individuals, institutions, and other users of copyrighted material, and the incentive of copyright owners to present works to the public in digital formats alone, where ownership rights are strongest. This article attempts to plot that digital ascendancy and demonstrate the undermining of neutrality principles.
A cast of thousands: Coauthorship and subauthorship collaboration in the 20th century as manifested in the scholarly journal literature of psychology and philosophy
Authors: Cronin Blaise , Shaw Debora , La Barre Kathryn
Published: June 2003

We chronicle the use of acknowledgments in 20th‐century scholarship by analyzing and classifying more than 4,500 specimens covering a 100‐year period. Our results show that the intensity of acknowledgment varies by discipline, reflecting differences in prevailing sociocognitive structures and work practices. We demonstrate that the acknowledgment has gradually established itself as a constitutive element of academic writing, one that provides a revealing insight into the nature and extent of subauthorship collaboration. Complementary data on rates of coauthorship are also presented to highlight the growing importance of collaboration and the increasing division of labor in contemporary research and scholarship.
Do nondomain experts enlist the strategies of domain experts?
Authors: Drabenstott Karen M.
Published: June 2003

User studies demonstrate that nondomain experts do not use the same information‐seeking strategies as domain experts. Because of the transformation of integrated library systems into Information Gateways in the late 1990s, both nondomain experts and domain experts have had available to them the wide range of information‐seeking strategies in a single system. This article describes the results of a study to answer three research questions: (1) do nondomain experts enlist the strategies of domain experts? (2) if they do, how did they learn about these strategies? and (3) are they successful using them? Interviews, audio recordings, screen captures, and observations were used to gather data from 14 undergraduate students who searched an academic library's Information Gateway. The few times that the undergraduates in this study enlisted search strategies that were characteristic of domain experts, it usually took perseverance, trial‐and‐error, serendipity, or a combination of all three for them to find useful information. Although this study's results provide no compelling reasons for systems to support features that make domain‐expert strategies possible, there is need for system features that scaffold nondomain experts from their usual strategies to the strategies characteristic of domain experts.