bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of ultrasonographic assessment of synovitis and joint vascularity with radiographic evaluation in a randomized, placebo‐controlled study of infliximab therapy in early rheumatoid arthritis
Authors: Taylor P. C. , Steuer A. , Gruber J. , Cosgrove D. O. , Blomley M. J. K. , Marsters P. A. , Wagner C. L. , McClinton C. , Maini R. N.
Published: April 2004

Objective

To investigate sensitive ultrasonographic imaging methods for detection of synovial thickness and vascularity to discriminate between patients with early rheumatoid arthritis (RA) receiving infliximab + methotrexate (MTX) versus placebo + MTX over 18 weeks, and to compare the relationship between synovial thickening and vascularity at baseline and radiologic damage to joints of the hands and feet at 54 weeks.

Methods

Patients with early RA (duration <3 years) receiving stable dosages of MTX were randomly assigned to receive blinded infusions of 5 mg/kg infliximab (n = 12) or placebo (n = 12) at weeks 0, 2, 6, and then every 8 weeks until week 46. At baseline and week 18, clinical assessments were performed, and metacarpophalangeal joints were assessed by high‐frequency ultrasonography and power Doppler ultrasonography measurements. Radiographs of the hands and feet taken at baseline and at 54 weeks were evaluated using the van der Heijde modification of the Sharp method (vdH‐Sharp score).

Results

Using changes in the total vdH‐Sharp score over 54 weeks and changes in synovial thickening and joint vascularity at 18 weeks, we were able to distinguish those patients receiving infusions of infliximab + MTX from those receiving placebo + MTX. Sonographic measurements of synovial thickening and vascularity at baseline in the placebo + MTX group demonstrated clear relationships with the magnitude of radiologic joint damage at week 54. Infliximab + MTX treatment abolished these relationships.

Conclusion

The delay or reversal of inflammatory and joint‐destructive mechanisms in patients with early RA was already apparent following 18 weeks of treatment with infliximab + MTX and was reflected in radiologic changes at 54 weeks.
The role of subchondral bone remodeling in osteoarthritis: Reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model
Authors: Hayami Tadashi , Pickarski Maureen , Wesolowski Gregg A. , Mclane Julia , Bone Ashleigh , Destefano James , Rodan Gideon A. , Duong Le T.
Published: April 2004

Objective

It has been suggested that subchondral bone remodeling plays a role in the progression of osteoarthritis (OA). To test this hypothesis, we characterized the changes in the rat anterior cruciate ligament transection (ACLT) model of OA and evaluated the effects of alendronate (ALN), a potent inhibitor of bone resorption, on cartilage degradation and on osteophyte formation.

Methods

Male Sprague‐Dawley rats underwent ACLT or sham operation of the right knee. Animals were then treated with ALN (0.03 and 0.24 μg/kg/week subcutaneously) and necropsied at 2 or 10 weeks postsurgery. OA changes were evaluated. Subchondral bone volume and osteophyte area were measured by histomorphometric analysis. Coimmunostaining for transforming growth factor β (TGFβ), matrix metalloproteinase 9 (MMP‐9), and MMP‐13 was performed to investigate the effect of ALN on local activation of TGFβ.

Results

ALN was chondroprotective at both dosages, as determined by histologic criteria and collagen degradation markers. ALN suppressed subchondral bone resorption, which was markedly increased 2 weeks postsurgery, and prevented the subsequent increase in bone formation 10 weeks postsurgery, in the untreated tibial plateau of ACLT joints. Furthermore, ALN reduced the incidence and area of osteophytes in a dose‐dependent manner. ALN also inhibited vascular invasion into the calcified cartilage in rats with OA and blocked osteoclast recruitment to subchondral bone and osteophytes. ALN treatment reduced the local release of active TGFβ, possibly via inhibition of MMP‐13 expression in articular cartilage and MMP‐9 expression in subchondral bone.

Conclusion

Subchondral bone remodeling plays an important role in the pathogenesis of OA. ALN or other inhibitors of bone resorption could potentially be used as disease‐modifying agents in the treatment of OA.
Monitoring neutrophil activation in juvenile rheumatoid arthritis by S100A12 serum concentrations
Authors: Foell Dirk , Wittkowski Helmut , Hammerschmidt Inga , Wulffraat Nico , Schmeling Heinrike , Frosch Michael , Horneff Gerd , Kuis Wietse , Sorg Clemens , Roth Johannes
Published: April 2004

Objective

Phagocytes are extensively involved in the synovial inflammation associated with chronic arthritis. The aim of our study was to determine neutrophil activation in juvenile rheumatoid arthritis (JRA) by analyzing S100A12 (EN‐RAGE; calgranulin C), a proinflammatory protein secreted by human neutrophils.

Methods

S100A12 serum concentrations were determined in 124 patients with chronic active polyarticular‐, oligoarticular‐, or systemic‐onset JRA. S100A12 was also analyzed in synovial fluid obtained from 22 patients. Changes in S100A12 levels in response to anti–tumor necrosis factor α (anti‐TNFα) therapy, intraarticular injections of corticosteroids, and methotrexate (MTX) treatment were analyzed. Forty‐five patients were followed up after successful antiinflammatory treatment, for a mean period of 2.8 years.

Results

The mean serum level of S100A12 was 395 ng/ml in patients with active polyarticular JRA and 325 ng/ml in patients with active oligoarticular JRA (normal <120 ng/ml). The level of S100A12 was ∼10‐fold higher in synovial fluid than in serum, indicating release at sites of local inflammation. In patients with systemic‐onset JRA, the mean level of S100A12 was 3,700 ng/ml. Moreover, serum levels decreased in response to different antiinflammatory therapies (i.e., intraarticular injections of corticosteroids, MTX, or etanercept). S100A12 levels were elevated in 20 patients who experienced disease flares after the initial induction of remission, even weeks before the relapses became clinically apparent.

Conclusion

S100A12 serum concentrations indicate neutrophil activation in JRA and correlate with disease activity. S100A12 may indicate synovial inflammation even when other signs of arthritis are absent. Its function as a proinflammatory factor secreted by activated neutrophils makes this protein a potential target for future therapies.
Signs of first‐degree heart block occur in one‐third of fetuses of pregnant women with anti–SSA/Ro 52‐kd antibodies
Authors: Sonesson Sven‐Erik , Salomonsson Stina , Jacobsson Lilly‐Ann , Bremme Katarina , Wahren‐Herlenius Marie
Published: April 2004

Objective

To prospectively investigate the development of fetal heart block in anti–SSA/Ro 52‐kd–positive women, and to evaluate the usefulness of serial Doppler echocardiography in detecting early signs of congenital heart block.

Methods

Twenty‐four women with anti–SSA/Ro 52‐kd antibodies and consequently increased risk for fetal heart block were followed up weekly, between 18 and 24 weeks of gestation, with two Doppler echocardiographic methods designed to estimate the time delay between hemodynamic events caused by atrial and ventricular depolarizations. Two hundred eighty‐four women with normal pregnancies served as controls. Anti–Ro 52‐kd, anti–Ro 60‐kd, and anti‐La antibodies were investigated by immunoblotting and enzyme‐linked immunosorbent assay using recombinant proteins.

Results

In anti–Ro 52‐kd–positive women, fetal atrioventricular (AV) time intervals were longer and heart rates were slightly lower compared with those in controls. Eight of 24 fetuses had signs of first‐degree block. One of these fetuses had progression to complete block, and another showed recovery from second‐degree block to first‐degree block with betamethasone treatment. In the remaining 6 fetuses, spontaneous normalization occurred before or shortly after birth. Fetuses with normal AV time intervals at 18–24 weeks had normal electrocardiographic results at birth.

Conclusion

Anti–Ro 52‐kd–positive pregnant women frequently carry fetuses with Doppler echocardiographic signs of first‐degree AV block. These blocks revert spontaneously in the majority of fetuses, but progression to a more severe degree of block may occur in some. Serial Doppler echocardiographic measurement of AV time intervals is suggested as a useful method for surveillance of these high‐risk pregnancies.
Musculoskeletal abnormalities of the forearm in patients with juvenile idiopathic arthritis relate mainly to bone geometry
Authors: Roth Johannes , Palm Christian , Scheunemann Ingo , Ranke Michael B. , Schweizer Roland , Dannecker Guenther E.
Published: April 2004

Objective

Alterations of the skeletal system, including reduced bone mineral density, increased frequency of fractures, and changes in markers of bone metabolism, have been described in juvenile idiopathic arthritis (JIA), but measurement of volumetric bone density and bone geometry is not possible with the techniques used in most studies. This study was undertaken to obtain a more detailed understanding of the musculoskeletal system in JIA by analyzing bone density, bone geometry, and muscle force as the most important factor in bone development.

Methods

The technique of peripheral quantitative computed tomography was used in a cross‐sectional study of 57 children with the oligoarticular, polyarticular, or systemic form of JIA. Density of trabecular and cortical bone as well as geometric parameters of bone and muscle were measured at the forearm.

Results

Children in all subgroups had significantly reduced muscle cross‐sectional area, which was strongly correlated with muscle force and abnormalities in geometric parameters of bone, including a significant reduction in cortical thickness. Trabecular density was affected only in the polyarticular JIA group, and cortical density was normal in all subgroups.

Conclusion

Our results suggest that an important problem in JIA is the lack of muscle mass and force, together with abnormal bone geometry. The thinned bony cortices might predispose to fractures even though cortical bone density itself is normal. These results might have implications with regard to therapeutic approaches to preserve musculoskeletal integrity in JIA.
Prolongation of the corrected QT interval in adult patients with anti‐Ro/SSA–positive connective tissue diseases
Authors: Lazzerini Pietro Enea , Acampa Maurizio , Guideri Francesca , Capecchi Pier Leopoldo , Campanella Valeria , Morozzi Gabriella , Galeazzi Mauro , Marcolongo Roberto , Laghi‐Pasini Franco
Published: April 2004

Objective

Newborns of mothers positive for anti‐Ro/SSA autoantibodies may develop a series of electrocardiographic (EKG) disturbances. Prolongation of the corrected QT (QTc) interval was recently reported in a significant proportion of children with maternally acquired anti‐Ro/SSA antibodies, with a concomitant disappearance of EKG abnormalities and acquired maternal autoantibodies during the first year, suggesting a direct, reversible electrophysiologic effect of anti‐Ro/SSA antibodies on the ventricular repolarization. On this basis, we investigated whether these antibodies may also affect cardiac repolarization in anti‐Ro/SSA–positive adult patients with connective tissue diseases.

Methods

Fifty‐seven patients with connective tissue diseases were selected: 31 had anti‐Ro/SSA antibodies and 26 did not (controls). In all subjects, we analyzed the QTc interval, heart rate variability, and signal‐averaged high‐resolution EKG recording.

Results

Anti‐Ro/SSA–positive patients showed a significant prolongation of the mean QTc interval compared with the controls (mean ± SD 445 ± 21 versus 419 ± 17 msec; P = 0.000005). Eighteen of the 31 anti‐Ro/SSA–positive patients (58%) and none of the 26 anti‐Ro/SSA–negative patients had QTc values above the upper limit of normal (440 msec). Both groups had a reduction in heart rate variability, with a prevalence for the sympathetic nervous system and a high incidence of ventricular late potentials; these values were not significantly different between the 2 groups.

Conclusion

Adult patients with anti‐Ro/SSA–positive connective tissue diseases showed a high prevalence of QTc interval prolongation. This feature, with the concomitant abnormalities in the autonomic tone and ventricular late excitability observed in all patients studied, suggests that anti‐Ro/SSA–positive patients may have a particularly high risk of developing life‐threatening arrhythmias.
Potential strategies to reduce medial compartment loading in patients with knee osteoarthritis of varying severity: Reduced walking speed
Authors: Mündermann Anne , Dyrby Chris O. , Hurwitz Debra E. , Sharma Leena , Andriacchi Thomas P.
Published: April 2004

Objective

To determine whether reducing walking speed is a strategy used by patients with knee osteoarthritis (OA) of varying disease severity to reduce the maximum knee adduction moment.

Methods

Self‐selected walking speeds and maximum knee adduction moments of 44 patients with medial tibiofemoral OA of varying disease severity, as assessed by using the Kellgren/Lawrence grade, were compared with those of 44 asymptomatic control subjects matched for sex, age, height, and weight.

Results

Differences in self‐selected normal walking speed explained only 8.9% of the variation in maximum knee adduction moment for the group of patients with knee OA. The severity of the disease influenced the adduction moment–walking speed relationship; the individual slopes of this relationship were significantly greater in patients with less severe OA than in asymptomatic matched control subjects. Self‐selected walking speed did not differ between patients with knee OA, regardless of the severity, and asymptomatic control subjects. However, knees with more‐severe OA had significantly greater adduction moments (mean ± SD 3.80 ± 0.89% body weight × height) and were in more varus alignment (6.0 ± 4.5°) than knees with less‐severe OA (2.94 ± 0.70% body weight × height; and 0.0 ± 2.9°, respectively).

Conclusion

Patients with less‐severe OA adapt a walking style that differs from that of patients with more‐severe OA and controls. This walking style is associated with the potential to reduce the adduction moment when walking at slower speeds and could be linked to decreased disease severity.
Augmented production of chemokines by the interaction of type II collagen–reactive T cells with rheumatoid synovial fibroblasts
Authors: Min Do‐June , Cho Mi‐La , Lee Sang‐Heon , Min So‐Youn , Kim Wan‐Uk , Min Jun‐Ki , Park Sung‐Hwan , Cho Chul‐Soo , Kim Ho‐Youn
Published: April 2004

Objective

To determine the impact of type II collagen (CII)–reactive T cells on the production of chemokines in the joints of patients with rheumatoid arthritis (RA).

Methods

T cell proliferative responses to bovine CII were assayed in synovial fluid (SF) mononuclear cells and peripheral blood mononuclear cells. CII‐stimulated T cells were cocultured with fibroblast‐like synoviocytes (FLS). The expression of interleukin‐8 (IL‐8), monocyte chemoattractant protein 1 (MCP‐1), and macrophage inflammatory protein 1α (MIP‐1α) in the sera, SF, and supernatant of the CII‐stimulated T cells and FLS coculture was measured by enzyme‐linked immunosorbent assays.

Results

The levels of IL‐8, MCP‐1, and MIP‐1α in SF were significantly higher than those in paired sera of RA patients. IL‐8, MCP‐1, and MIP‐1α levels in SF were strongly correlated with T cell responses to CII. When FLS were cocultured with CII‐stimulated T cells, the production of IL‐8, MCP‐1, and MIP‐1α was significantly increased. This increase correlated well with the T cell proliferative response to CII. Chemokine production by coculture of CII‐stimulated T cells and FLS was mediated mainly by direct cell–cell contact through CD40 ligand–CD40 engagement.

Conclusion

Our data indicate that the presence of CII‐reactive T cells in RA joints can increase the production of chemokines such as IL‐8, MCP‐1, and MIP‐1α through interaction with FLS. This chemokine production is mediated by cell–cell contact, including CD40 ligand–CD40 engagement. These results suggest that CII‐reactive T cells play a crucial role in the amplification and perpetuation of the inflammatory process in the rheumatoid synovium.
Inhibition of antigen‐presenting cell function and stimulation of human peripheral blood mononuclear cells to express an antiinflammatory cytokine profile by the stress protein BiP: Relevance to the treatment of inflammatory arthritis
Authors: Corrigall Valerie M. , Bodman‐Smith Mark D. , Brunst Melanie , Cornell Hannah , Panayi Gabriel S.
Published: April 2004

Objective

The stress protein and endoplasmic reticulum chaperone, immunoglobulin binding protein (BiP), is an autoantigen in rheumatoid arthritis (RA). Stress proteins, however, may have extracellular functions, mediated via cell surface receptors, that may include immunomodulatory functions. We sought to determine whether cell‐free BiP is present in the synovial fluid (SF) of patients with RA and to further investigate the possible extracellular antiinflammatory and immunomodulatory properties of BiP in peripheral blood mononuclear cells (PBMCs) in vitro.

Methods

The presence of BiP in SF was established by Western blotting. PBMCs were stimulated with exogenous recombinant human BiP, and cytokine production and cell proliferation were measured in the presence and absence of cell signaling inhibitors or neutralizing anti–interleukin‐10 (anti–IL‐10) monoclonal antibody. Cytokine levels were quantified by enzyme‐linked immunosorbent assay, cell proliferation by tritiated thymidine uptake, and cell surface molecule expression by flow cytometry.

Results

PBMCs responded to BiP with secretion of an antiinflammatory profile of cytokines. Although BiP stimulated the early production of tumor necrosis factor α (TNFα), the major cytokine induced was IL‐10. Soluble TNF receptor II and IL‐1 receptor antagonist secretion was also increased. Addition of SB203580, the MAPK p38 pathway inhibitor, partially inhibited the production of IL‐10 and TNFα, whereas they were unaffected by the MAPK ERK‐1/2 inhibitor PD98059. BiP also inhibited the recall antigen response by PBMCs to tuberculin purified protein derivative. Further investigation showed that incubation of monocytes in the presence of either BiP or IL‐10 down‐regulated CD86 and HLA–DR expression. The effect observed with IL‐10 was transient compared with the long‐lasting reduction induced by BiP.

Conclusion

Extracellular BiP may stimulate immunomodulatory and antiinflammatory pathways, which are only partly due to the production of IL‐10. These properties may be of relevance for the treatment of diseases such as RA.
Inefficacy of infliximab in primary Sjögren's syndrome: Results of the randomized, controlled trial of remicade in primary Sjögren's syndrome (TRIPSS)
Authors: Mariette Xavier , Ravaud Philippe , Steinfeld Serge , Baron Gabriel , Goetz Joelle , Hachulla Eric , Combe Bernard , Puéchal Xavier , Pennec Yvon , Sauvezie Bernard , Perdriger Aleth , Hayem Gilles , Janin Anne , Sibilia Jean
Published: April 2004

Objective

There is no effective treatment for patients with primary Sjögren's syndrome (SS). Since tumor necrosis factor α (TNFα) could be a key element in the pathogenesis of primary SS, we conducted a multicenter, randomized, double‐blind, placebo‐controlled trial to evaluate the effect of infliximab in primary SS.

Methods

A total of 103 patients with primary SS were randomly assigned to receive infliximab infusions (5 mg/kg) or placebo at weeks 0, 2, and 6 and were followed up for 22 weeks. All patients fulfilled the new American‐European Consensus Group criteria for SS and had active disease as assessed by values >50 mm on 2 of 3 visual analog scales (VAS) (0–100 mm) that evaluated joint pain, fatigue, and buccal, ocular, skin, vaginal, or bronchial dryness. A favorable overall response was defined as the patient having ≥30% improvement between weeks 0 and 10 in the values on 2 of the 3 VAS. Secondary end points were values on each VAS separately, the number of tender and swollen joints, the basal salivary flow rate, results of the Schirmer test for lacrimal gland function, the focus score on labial salivary gland biopsy, the level of C‐reactive protein, and the erythrocyte sedimentation rate evaluated at weeks 0, 10, and 22, as well as quality of life evaluated by use of the generic Short Form 36 questionnaire administered at weeks 0, 10, and 22.

Results

At week 10, 26.5% of patients receiving placebo and 27.8% of patients treated with infliximab had a favorable overall response (P = 0.89), and at week 22, 20.4% of the placebo group and 16.7% of the infliximab group had a favorable response (P = 0.62). In addition, the 2 groups did not differ in any of the secondary end points over the 22 weeks of the trial. Severe adverse events reported in the infliximab group did not differ from those observed in previous studies.

Conclusion

This randomized, double‐blind, placebo‐controlled study of an anti‐TNF agent did not show any evidence of efficacy of infliximab in primary SS.
Early failures of total hip replacement: Effect of surgeon volume
Authors: Losina Elena , Barrett Jane , Mahomed Nizar N. , Baron John A. , Katz Jeffrey N.
Published: April 2004

Objective

To determine whether provider volume is associated with early failures following total hip replacement (THR) requiring revision.

Methods

Claims data were analyzed to follow a cohort of 57,488 Medicare beneficiaries who underwent elective primary THR in 1995–1996 in 3,044 hospitals in the US. Patients were followed through the end of 1999. Failure of primary THR was defined as a subsequent revision THR, as determined by International Classification of Diseases, Ninth Revision codes in hospital claims. Hospitals were stratified into 4 volume groups: low (<25 THRs/year), medium (26–50, 51–100 THRs/year), and high (>100 THRs/year). Low‐volume surgeons were defined as those surgeons performing <12 elective primary THRs annually in the Medicare population. Associations between the rates of revision and surgeon volume were determined by hazard ratios from a proportional hazard model, with adjustment for hospital volume, patient age, poverty status, sex, and comorbidities. We also examined whether the effect of surgeon volume on revision rates differed between the first 18 months postoperatively and later time periods.

Results

Among 57,488 patients who had elective primary THR in 1995–1996, 2,537 (4.4%) had at least 1 revision THR by the end of 1999, with 1,437 (56.6%) of these revisions occurring within the first 18 months after the index primary THR. Median followup time was 47 months (range 0–54). Patients of high‐volume surgeons were less likely to have revision THRs than patients of low‐volume surgeons, regardless of hospital volume stratum. Further analysis revealed that the effect of surgeon volume on revisions was striking in the first 18 months after surgery but was not evident in the subsequent years.

Conclusion

Patients of low‐volume surgeons have higher rates of revision THR than patients of high‐volume surgeons, particularly within the first 18 months postoperatively. Referring clinicians should consider including surgeon volume among the factors influencing their choice of surgeon for elective THR.
A pilot study of the use of 2‐[18F]‐fluoro‐2‐deoxy‐D‐glucose–positron emission tomography to assess the distribution of activated lymphocytes in patients with systemic lupus erythematosus
Authors: Nowak Miroslawa , Carrasquillo Jorge A. , Yarboro Cheryl H. , Bacharach Steven L. , Whatley Millie , Valencia Xavier , Takada Kazuki , Brust Douglas G. , Illei Gabor G.
Published: April 2004

Objective

The 2‐[18F]‐fluoro‐2‐deoxy‐D‐glucose–positron emission tomography (FDG‐PET) technique provides information on uptake and metabolism of glucose in various tissues. Compared with resting cells, activated lymphocytes take up radioactively labeled glucose analog at a higher rate, which makes it possible to identify lymphoid organs with higher concentrations of activated lymphocytes. This study was undertaken to compare the pattern of PET images and quantitative FDG uptake in lymphoid organs of patients with active systemic lupus erythematosus (SLE) versus patients with inactive SLE and to correlate these findings with peripheral blood lymphocyte phenotypes.

Methods

Ten patients with active SLE and 9 patients with inactive SLE were studied. FDG‐PET images were obtained from the inguinal region to above the ear, starting at 60 minutes after injection of FDG. Standardized uptake values using lean body mass were determined over areas of interest.

Results

Both patients with active lupus and those with inactive lupus had increased FDG uptake in lymph nodes when compared with healthy volunteers, and there was no statistically significant difference between the 2 groups of lupus patients. Thymic uptake was demonstrated in 5 of 10 patients with active lupus compared with 0 of 9 patients with inactive disease. Three of the 5 patients with active SLE who were over 29 years of age had thymic uptake. Of the activation markers tested, only the CD3/CD71 population of cells was significantly different between the patient groups, with an increased percentage in the active disease group (P = 0.0247).

Conclusion

Increased FDG uptake in lymph nodes of both patients with active SLE and patients with inactive SLE suggests that metabolic, and probably immunologic, activity is enhanced not only in active, but also in clinically quiescent, disease. The increased thymic uptake observed only in patients with active disease suggests that the thymus plays an important role during periods of disease activity.
Antibodies to microtubule‐associated protein 2 in patients with neuropsychiatric systemic lupus erythematosus
Authors: Williams Ralph C. , Sugiura Kazumitsu , Tan Eng M.
Published: April 2004

Objective

Microtubule‐associated protein 2 (MAP‐2), a cellular protein restricted to neurons, is important in the control of cytoskeletal integrity and other neuronal functions. We undertook this study to examine the presence of autoantibodies to MAP‐2 in neuropsychiatric systemic lupus erythematosus (NPSLE).

Methods

Sera from 100 patients with SLE, 74 patients with other neurologic disorders and injuries (including cerebrovascular accidents, brain trauma, brain tumors, and demyelinating disorders), and 60 normal controls were examined both by enzyme immunoassays and by Western immunoblotting for autoantibodies to MAP‐2. Sera designated positive for antibodies to MAP‐2 were required to be positive in both assays.

Results

Seventeen percent of SLE patients had autoantibodies to MAP‐2, in contrast to 4% of neurologic injury/disease control patients (P = 0.028) and 1.7% of normal controls. In SLE, anti–MAP‐2 positivity in both assays was associated with neuropsychiatric symptoms in 76.5% of patients, whereas the absence of anti–MAP‐2 was associated with neuropsychiatric symptoms in 19.7% of patients (P = 0.0002). The neuropsychiatric symptoms in the former group included psychosis, seizure, neuropathy, and cerebritis.

Conclusion

Autoantibodies to MAP‐2, a neuron‐restricted cytoskeletal protein, appear to be another immune marker for NPSLE.
Cyclooxygenase 2–derived prostaglandin E2 production by corticotropin‐releasing hormone contributes to the activated cAMP response element binding protein content in rheumatoid arthritis synovial tissue
Authors: McEvoy Alice N. , Bresnihan Barry , FitzGerald Oliver , Murphy Evelyn P.
Published: April 2004

Objective

To determine a mechanism by which corticotropin‐releasing hormone (CRH) promotes human inflammatory joint disease progression.

Methods

An ex vivo synovial tissue culture system was established to investigate the functional properties of CRH at peripheral sites of inflammation. CRH‐ and interleukin‐1β (IL‐1β)–induced prostaglandin E2 (PGE2) production from 10 fresh rheumatoid arthritis (RA) synovial tissue (ST) explants was quantified using a competitive enzyme‐linked immunosorbent assay. Modulation of PGE2 levels was further examined following selective and nonselective cyclooxygenase 2 (COX‐2) inhibition. Nuclear extracts were analyzed by electrophoretic mobility shift assays to determine functional cAMP response element binding protein (CREB) activity in response to CRH and PGE2 in isolated primary synovial cell populations. Western blot analysis measured levels of total and activated (phosphospecific) CREB/activating transcription factor (ATF) family members prior to and following stimulation.

Results

CRH, in a time‐ and dose‐dependent manner, significantly (P = 0.022) up‐regulated PGE2 production from 10 fresh RA ST explants. Costimulation of RA ST with CRH and IL‐1β significantly augmented (P = 0.036) the effects on PGE2 production additively over 24 hours. We demonstrated that selective COX‐2 inhibitors prevent the induction of PGE2 by both CRH and IL‐1β. Further, we provided evidence that CRH and PGE2 signal through the induction of CREB and phosphorylated CREB/ATF family members in RA ST and in isolated primary RA cell populations.

Conclusion

Our findings underscore the pathogenic role that CRH may play in modulating inflammatory joint disease and establish the CREB/ATF family of transcription factors as principal effector molecules of proinflammatory mediator action in RA.
Decreases in rates of hospitalizations for manifestations of severe rheumatoid arthritis, 1983–2001
Authors: Ward Michael M.
Published: April 2004

Objective

To determine whether the rates of hospitalization for 4 manifestations of severe rheumatoid arthritis (RA), which are used as indicators of long‐term health outcomes, have changed from 1983 to 2001.

Methods

Data on all patients with RA who were hospitalized with rheumatoid vasculitis or to undergo splenectomy for Felty's syndrome, cervical spine fusion for myelopathy, or total knee arthroplasty at hospitals in California were abstracted from a state hospitalization database. Changes in rates of hospitalization from 1983 to 2001 were examined in this serial cross‐sectional study.

Results

Rates of hospitalization for rheumatoid vasculitis and splenectomy in Felty's syndrome decreased progressively over time. The risk of hospitalization for rheumatoid vasculitis was one‐third lower in 1998–2001 than in 1983–1987. The risk of hospitalization for splenectomy in Felty's syndrome was 71% lower in 1998–2001 than in 1983–1987. There were no significant decreases in the rates of hospitalization for cervical spine surgery or total knee arthroplasty (primary and revision), although in 1998–2001 there was a reversal of the trend of increasing rates of total knee arthroplasty. The risk of hospitalization for primary total knee arthroplasty was significantly lower in 1998–2001 than in 1990–1993 (rate ratio 0.90, 95% confidence interval 0.86–0.95; P < 0.0001).

Conclusion

Rates of hospitalization for rheumatoid vasculitis and splenectomy in Felty's syndrome have decreased over the past 19 years, and there has been a recent decrease in the rates of primary total knee arthroplasty in patients with RA. Although several factors may account for these decreases, these findings suggest that since the early 1980s, the long‐term health outcomes of patients with RA have improved.
Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate
Authors: Maini R. N. , Breedveld F. C. , Kalden J. R. , Smolen J. S. , Furst D. , Weisman M. H. , St.Clair E. W. , Keenan G. F. , van der Heijde D. , Marsters P. A. , Lipsky P. E.
Published: April 2004

Objective

To evaluate the efficacy and safety of repeated administration of infliximab plus methotrexate (MTX) over a 2‐year period in patients with rheumatoid arthritis (RA) who previously experienced an incomplete response to MTX.

Methods

Four hundred twenty‐eight patients were randomly assigned to receive MTX plus placebo or infliximab at a dose of 3 or 10 mg/kg plus MTX for 54 weeks, with an additional year of followup. The protocol was later amended to allow for continued treatment during the second year. Of 259 patients who entered the second year of treatment, 216 continued to receive infliximab plus MTX for 102 weeks. Ninety‐four of these 259 patients experienced a gap in therapy of >8 weeks before continuing therapy. Infusions were administered at weeks 0, 2, and 6, followed by treatment every 4 weeks or every 8 weeks (alternating with placebo infusions in the interim 4‐week visits) at a dose of 3 or 10 mg/kg for a total of 102 weeks (including the gap in therapy). For safety and efficacy assessments, data on the patients who were randomized to receive treatment, irrespective of whether treatment was administered for 102 weeks, were evaluated using all actual observations available. The efficacy measures included the Health Assessment Questionnaire (HAQ) (physical function), Short Form 36 health survey (SF‐36) (health‐related quality of life), total radiographic scores (structural damage), and the American College of Rheumatology 20% improvement criteria (ACR20) (signs and symptoms).

Results

The infliximab plus MTX regimens resulted in significantly greater improvement in HAQ scores (P ≤ 0.006) and SF‐36 physical component summary scores (P ≤ 0.011) compared with the MTX‐only group. There also was stability in the SF‐36 mental component summary score among patients who received the infliximab plus MTX regimens. Median changes from baseline to week 102 in the total radiographic score were 4.25 for patients who received the MTX‐only regimen and 0.50 for patients who received the infliximab plus MTX regimen. The proportion of patients achieving an ACR20 response at week 102 varied from 40% to 48% for the infliximab plus MTX groups compared with 16% for the MTX‐only group.

Conclusion

Throughout 102 weeks of therapy, infliximab plus MTX provided significant, clinically relevant improvement in physical function and quality of life, accompanied by inhibition of progressive joint damage and sustained improvement in the signs and symptoms of RA among patients who previously had an incomplete response to MTX alone.
Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis
Authors: DeGroot Jeroen , Verzijl Nicole , Wenting‐Van Wijk Marion J. G. , Jacobs Kim M. G. , Van El Benno , Van Roermund Peter M. , Bank Ruud A. , Bijlsma Johannes W. J. , TeKoppele Johan M. , Lafeber Floris P. J. G.
Published: April 2004

Objective

Osteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting the elderly. Its etiology is largely unknown, but age is the most prominent risk factor. The current study was designed to test whether accumulation of advanced glycation end products (AGEs), which are known to adversely affect cartilage turnover and mechanical properties, provides a molecular mechanism by which aging contributes to the development of OA.

Methods

The hypothesis that elevated AGE levels predispose to the development of OA was tested in the canine anterior cruciate ligament transection (ACLT) model of experimental OA. Cartilage AGE levels were enhanced in young dogs by intraarticular injections of ribose. This mimics the accumulation of AGEs without the interference of other age‐related changes. The severity of OA was then assessed 7 weeks after ACLT surgery in dogs with normal versus enhanced AGE levels.

Results

Intraarticular injections of ribose enhanced cartilage AGE levels ∼5‐fold, which is similar to the normal increase that is observed in old dogs. ACLT surgery resulted in more‐pronounced OA in dogs with enhanced AGE levels. This was observed as increased collagen damage and enhanced release of proteoglycans. The attempt to repair the matrix damage was impaired; proteoglycan synthesis and retention were decreased at enhanced AGE levels. Mankin grading of histology sections also revealed more‐severe OA in animals with enhanced AGE levels.

Conclusion

These findings demonstrate increased severity of OA at higher cartilage AGE levels and provide the first in vivo experimental evidence for a molecular mechanism by which aging may predispose to the development of OA.
Low‐dose aspirin and prevention of cranial ischemic complications in giant cell arteritis
Authors: Nesher Gideon , Berkun Yaakov , Mates Michal , Baras Mario , Rubinow Alan , Sonnenblick Moshe
Published: April 2004

Objective

Cranial ischemic complications such as cerebrovascular accidents (CVAs) and acute visual loss are among the leading causes of giant cell arteritis (GCA)–related morbidity. In this retrospective study, we evaluated the effect of treatment with low‐dose aspirin on the incidence of cranial ischemic complications in GCA.

Methods

Charts of 175 consecutive patients in whom GCA was diagnosed between 1980 and 2000 were reviewed for medical data. Data for 166 patients who were followed up for at least 3 months were also available.

Results

At the time of the diagnosis of GCA, 36 patients (21%) had already been receiving low‐dose aspirin (100 mg/day). In all cases, the indication for this treatment was ischemic heart disease. There were no significant differences between the aspirin‐treated and non–aspirin‐treated groups regarding the mean age of patients, the male‐to‐female ratio, duration of GCA‐related symptoms, rates of headaches, systemic symptoms, and jaw claudication, and the mean erythrocyte sedimentation rate, hemoglobin count, and platelet count. Cerebrovascular risk factors (hypertension, hyperlipidemia, or diabetes mellitus) were more common in the aspirin‐treated group (38.9% versus 20%;P= 0.03). Cranial ischemic complications were diagnosed in 43 patients at presentation: 30 patients had acute visual loss, 11 had CVAs, and 2 had both conditions simultaneously. Only 3 of the aspirin‐treated patients (8%) presented with cranial ischemic complications, compared with 40 (29%) of the non–aspirin‐treated patients (P= 0.01). Despite the use of steroid therapy, cranial ischemic complications developed in 14 of the 166 patients followed up for 3 months or longer. However, cranial ischemic complications developed in only 3% of the aspirin‐treated patients, compared with 13% of the patients treated with prednisone only (P= 0.02).

Conclusion

These data suggest that low‐dose aspirin decreases the rate of visual loss and CVAs in patients with GCA.
Reappraisal of the epidemiology of giant cell arteritis in Olmsted County, Minnesota, over a fifty‐year period
Authors: Salvarani Carlo , Crowson Cynthia S. , O'Fallon W. Michael , Hunder Gene G. , Gabriel Sherine E.
Published: April 2004

Objective

To investigate time trends in the incidence and survival of giant cell arteritis (GCA) over a 50‐year period in Olmsted County, Minnesota.

Methods

Using the unified record system at the Mayo Clinic, we identified all incident cases of GCA first diagnosed between 1950 and 1999. Incidence rates were estimated and adjusted to the 1980 United States white population for age and sex. The annual incidence rates were graphically illustrated using a 3‐year centered moving average. Survival rates were computed and compared with the expected rates in the population.

Results

There were 173 incident cases of GCA during the 50‐year study period. Of these, 79% were women and the mean age at diagnosis was 74.8 years. The overall age‐ and sex‐adjusted incidence per 100,000 persons 50 years of age or older was 18.8 (95% confidence interval [95% CI] 15.9–21.6). Incidence was higher in women (24.4; 95% CI 20.3–28.6) than in men (10.3; 95% CI 6.9–13.6). Incidence rates increased significantly over the study period (P = 0.017); in particular, a progressive increase was observed from 1950 to 1979; subsequently, no substantial increases in incidence rates were observed. A cyclic pattern of annual incidence rates was apparent, with evidence of 6 peak periods. Survival among individuals with GCA was not significantly different from that expected in the population (P = 0.80).

Conclusions

The incidence of GCA increased over the first 3 decades of the study, then remained stable over the last 20 years. The previously observed cyclic pattern of annual incidence rates was still apparent over a 50‐year period. Overall survival in GCA was similar to that in the population.
The safety and efficacy of leflunomide in combination with infliximab in rheumatoid arthritis
Authors: Hansen K. E. , Cush J. , Singhal A. , A. Cooley D. , Cohen S. , Patel S. R. , Genovese M. , Sundaramurthy S. , Schiff M.
Published: April 2004

Objective

To report the safety and efficacy of leflunomide (LEF) in combination with infliximab (INF) for the treatment of rheumatoid arthritis.

Methods

In an open, multicenter, retrospective study, data were collected on the safety and efficacy of LEF and INF.

Results

Eighty‐eight patients received the combination of LEF and INF for an average of 6.6 months and a total exposure of 581 patient‐months. The mean duration of LEF was 17 ± 9 months (range 3–32 months; median 18.5 months) with an average of 4.8 INF infusions per patient. In all but 3 subjects, LEF was used initially and INF was added later. Infusion reactions occurred in 3 patients (0.7% of all infusions). A total of 34% of subjects experienced adverse events and in 6 (6.8% of the group) these were deemed serious. Ten infections occurred when patients were taking the combination; 9 patients recovered fully and 1 died of bacterial pneumonia. A lifetime smoker developed lung cancer and another patient was found to have colon cancer.

Conclusions

The adverse events noted within the combination therapy group were in keeping with the known risks of each drug when used individually. Limited data were available on efficacy, but a general improvement in disease control was noted with the combination of drugs, which for most patients involved the addition of INF to previous use of LEF.
The influence of peripheral arthritis on disease activity in ankylosing spondylitis patients as measured with the Bath Ankylosing Spondylitis Disease Activity Index
Authors: Heuft‐Dorenbosch Liesbeth , Van Tubergen Astrid , Spoorenberg Anneke , Landewé Robert , Dougados Maxime , Mielants Herman , Van Der Tempel Hille , Van Der Heijde Désirée
Published: April 2004

Objectives

To assess the differences in disease activity as measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) between patients with and without peripheral arthritis/enthesitis. To investigate whether scores on the BASDAI change by omitting the 2 questions on peripheral disease.

Methods

Disease activity was assessed on a 10‐cm visual analog scale and by BASDAI. Alternative BASDAIs were constructed by omitting the peripheral joints question and/or the enthesitis question. Correlations between the alternative BASDAIs and other measures of disease activity were calculated. Generalized estimating equations (GEE) were used to assess whether having peripheral arthritis influenced BASDAI and alternative BASDAI scores, and to assess whether peripheral arthritis influenced the score of the individual questions of the BASDAI.

Results

At baseline, the BASDAI was calculated in 214 patients. In patients with peripheral arthritis (n = 56), the mean (SD) BASDAI score was 4.4 (2.3) as compared with 3.1 (1.9) (P < 0.0001) in the patients without peripheral arthritis (n = 158). The relationship between arthritis and the BASDAI score appeared to be truly longitudinal (GEE regression coefficient β = 0.64; 95% confidence interval 0.28–1.00). Peripheral arthritis was significantly longitudinally associated with all separate item scores of the BASDAI. Omitting the peripheral joints and/or enthesitis question from the BASDAI questionnaire only partially explained the difference in BASDAI score between the 2 groups.

Conclusion

Disease activity measured by the BASDAI is higher in patients with concomitant peripheral disease compared with patients with disease restricted to the axial skeleton. The increased BASDAI score in patients with peripheral arthritis is partially explained by increased overall disease activity as well as by a disproportionate contribution of the peripheral joints question to the overall score.
Positive classic antineutrophil cytoplasmic antibody (C‐ANCA) titer at switch to azathioprine therapy associated with relapse in proteinase 3–related vasculitis
Authors: Slot Marjan C. , Tervaert Jan Willem Cohen , Boomsma Maarten M. , Stegeman Coen A.
Published: April 2004

Objective

To analyze disease‐free survival in patients with antineutrophil cytoplasmic antibody (ANCA)–associated small‐vessel vasculitis (AAV) treated with cyclophosphamide only or switched to azathioprine after 3 months of full remission while taking cyclophosphamide.

Methods

We analyzed disease‐free survival in all consecutive patients diagnosed with AAV between 1990 and 2000 at our center. Patients were treated with cyclophosphamide only (1990–1996) or switched to azathioprine after 3 months of remission while taking cyclophosphamide (1997–2000). All patients received at least 12 months of followup.

Results

Of the total 128 patients, 53 (41%) relapsed. Forty‐four of the 128 patients (34%) had been switched to azathioprine therapy. Disease‐free survival at 2 and 4 years was 76% and 65% in the cyclophosphamide group compared with 76% and 51% in the azathioprine group. In patients with proteinase 3 (PR3) classic ANCA (C‐ANCA)–associated vasculitis who were switched to azathioprine (n = 33), a positive C‐ANCA titer at the moment of treatment switch (n = 13) was significantly associated with relapse (RR 2.6, 95% confidence interval 1.1–8.0; P = 0.04). In patients with a negative ANCA titer at the time of switch to azathioprine, disease‐free survival at 2 and 4 years was 80% and 62%, which was identical to that for patients treated with cyclophosphamide only. In patients who were ANCA‐positive at the time of treatment switch, disease‐free survival at 2 and 4 years was only 58% and 17%.

Conclusion

Switching cyclophosphamide to azathioprine after induction of remission in patients with PR3‐ANCA‐associated vasculitis who are still ANCA‐positive at the time of treatment switch is associated with a high risk of relapse.
Prognosis and quality of life in patients with acute low back pain: Insights from a comprehensive inception cohort study
Authors: Coste Joël , Lefrançois Gérard , Guillemin Francis , Pouchot Jacques ,   For the French Study Group for Quality of Life in Rheumatology
Published: April 2004

Objective

To investigate the respective contribution of various biologic and psychosocial factors, especially initial health‐related quality of life (HRQOL), in the natural history of acute low back pain (LBP) and to evaluate the impact of this condition on HRQOL.

Methods

For 3 months, we assessed 113 patients consulting for nonspecific acute LBP of <72 hours duration at inclusion and treated with acetaminophen. Endpoints included pain, disability assessed by the Roland Disability Questionnaire, and HRQOL assessed by the Short Form 36 health survey (SF‐36).

Results

Seventy‐three percent of patients recovered within 2 weeks and 5% of patients developed chronic LBP. Prior low back surgery, higher initial disability questionnaire score, lower SF‐36 score, and temporary compensation status were independently associated with delayed recovery. The impact of the acute LBP episode on HRQOL was brief and moderate, except for patients with comorbidity, psychiatric disorders, those of foreign origin, unemployed, or with job dissatisfaction. The impact of compensation status, sick leave, and bed rest was more profound and lasting.

Conclusions

This study highlights the large contribution of work‐related factors, but also initial HRQOL, to the prognosis of LBP. It also suggests that LBP impairs HRQOL mainly through compensation and inappropriate medical care, and that, in turn, impaired HRQOL favors the condition becoming chronic. These findings have implications for future research into the management of LBP.