bluuebunny/crossref_metadata_2025 huggingface dataset:
T Cell Influence on Superantigen‐Induced Arthritis in MRL‐lpr/lpr Mice
Authors: Mountz John D. , Zhou Tong , Long Richard E. , Bluethmann Horst , Koopman William J. , Edwards Carl K.
Published: February 2007

Objective. To define the influence of the T cell receptor (TCR) and the lpr autoimmune gene on the induction and progression of superantigen‐induced arthritis in V β8 transgenic MRL‐lpr/lpr mice.

Methods. The time to onset and the extent of synovial hyperplasia after the induction of arthritis by intraarticular injection of staphylococcal enterotoxin B (SEB) were compared in mice having T cells that bear the V β8 transgene alone (V β8 TCR transgenic MRL‐+/+), the lpr gene without the V β8 gene (nontransgenic MRL‐lpr/lpr), both the V β8 gene and the lpr gene (V β8 transgenic MRL‐lpr/lpr), or neither gene (nontransgenic MRL‐+/+). Synovial hyperplasia was compared in SEB‐injected V β8 transgenic MRL‐lpr/lpr mice after treatment with cyclosporin A (CSA), anti‐V β8 and anti‐CD4 monoclonal antibodies, and in V β8 transgenic MRL‐lpr/lpr mice after injection of a non—V β8‐reactive superantigen, staphylococcal enterotoxin A (SEA).

Results. At day 30, increased synovial cells were observed in all SEB‐treated mice, but the increase was greatest in the V β8 transgenic MRL‐lpr/lpr mice. T cell involvement was indicated by the inability of either heat‐denatured SEB or SEA to induce severe arthritis, the reduction in the severity of the arthritis on systemic treatment with CSA or anti‐V β8, and the correlation of synovial hyperplasia with in vitro SEB reactivity of T cells.

Conclusion. These observations suggest that super‐antigens can induce chronic arthritis and that the induction and progression of the arthritis requires an underlying T cell defect in anergy induction in addition to exposure to the superantigen.
The Effects of Orally Administered Calcium Pentosan Polysulfate on Inflammation and Cartilage Degradation Produced in Rabbit Joints by Intraarticular Injection of a Hyaluronate—Polylysine Complex
Authors: Smith Margaret M. , Ghosh Peter , Numata Yukiko , Bansal Mohinder K.
Published: February 2007

Objective. To determine the antiinflammatory and cartilage‐protecting activities of orally administered calcium pentosan polysulfate (CaPPS) in a rabbit model of inflammatory arthritis.

Methods. A single intraarticular injection of a preformed polycation complex (PC) of poly‐D‐lysine and hyaluronan was used to induce joint inflammation; saline was injected into the contralateral joint as a control. Animals were killed 1, 4, 7, or 10 days post—PC injection. CaPPS, at 5 mg/kg, 10 mg/kg, or 75 mg/kg, was given every 48 hours commencing 7 days prior to PC injection. Serum interleukin‐6 (IL‐6), synovial fluid (SF) prostaglandin E2, cell numbers, and cartilage proteoglycan (PG) content, composition, and biosynthesis were determined for PC‐ and saline‐injected joints.

Results. In PC‐injected, non—drug‐treated animals, serum IL‐6 activity, SF leukocyte numbers, and prostaglandin E2 levels were elevated, while cartilage PG content and biosynthesis were reduced. CaPPS at 10 mg/kg, but not at 5 mg/kg, decreased serum IL‐6 levels but maintained cartilage PG concentration and biosynthesis. However, SF leukocyte counts and prostaglandin E2 levels (except on day 1) were not reduced.

Conclusion. The ability of CaPPS to attenuate serum IL‐6 levels and preserve cartilage PGs in inflamed rabbit joints suggests that this substance could be of value as an effective orally administered chondroprotective, antiarthritic drug.
Intermittent Spinal ischemia
Authors: Newcombe David S.
Published: February 2007

A woman who presented with leg claudication and neurologic dysfunctions is described. Aortic obstruction was defined by aortography, with large collateral vessels observed above the obstruction extending to the femoral arteries and small collaterals extending to the spinal cord. Aorto—femoral bypass surgery resulted in resolution of the patient's symptoms. Prompt recognition and treatment of spinal cord ischemia is essential if permanent and disabling neurologic damage is to be avoided.
Mechanisms of Methotrexate Action in Rheumatoid Arthritis
Authors: Firestein Gary S. , Paine Mary M. , Boyle David L.
Published: February 2007

Objective. To measure the effect of methotrexate (MTX) treatment in rheumatoid arthritis (RA) on the expression of synovial collagenase, stromelysin, and tissue inhibitor of metalloproteinase 1 (TIMP‐1) gene expression in a prospective study.

Methods. Serial percutaneous synovial biopsies (pretreatment and after 3–4 months) were performed on the knees of 8 patients (7 with RA, 1 with seronegative arthritis) who were beginning oral MTX therapy. Synovial gene expression was determined by quantitative in situ hybridization using computer‐assisted image analysis.

Results. After therapy, patients had decreased joint counts, morning stiffness, and erythrocyte sedimentation rates. Synovial inflammation in the biopsy tissues was slightly decreased after therapy. In situ hybridization on pretreatment and posttreatment frozen sections was performed to quantify synovial messenger RNA (mRNA) levels. Collagenase gene expression significantly decreased after MTX therapy (P = 0.006) even though cell density in the region was unchanged. TIMP‐1 and stromelysin mRNA levels were not changed by MTX therapy. To study the mechanism of MTX action in vitro, MTX‐treated and control fibroblast‐like synoviocytes were stimulated with interleukin‐1β (IL‐1β). MTX did not alter collagenase or TIMP‐1 mRNA levels after IL‐1 exposure.

Conclusion. MTX therapy decreases collagenase gene expression but not TIMP‐1 or stromelysin gene expression in the synovium. This action is probably an indirect effect due to an alteration in the synovial cytokine milieu, rather than a direct effect on gene expression.
The Effect of Low‐Dose Methotrexate on Bone Metabolism and Histomorphometry in Rats
Authors: May Kimberly P. , West Sterling G. , Mcdermott Michael T. , Huffer William E.
Published: February 2007

Objective. To ascertain the effects of low‐dose methotrexate (MTX) on bone metabolism and histomorphometry in rats.

Methods. Female Sprague‐Dawley rats (6 months old, n = 42) were divided into the following 4 groups: intraperitoneal (IP) injections of MTX, with and without ovariectomy, and IP saline (controls), with and without ovariectomy. Injections were given for 16 weeks. The MTX dose was equivalent to a standard dose for rheumatoid arthritis in humans that would yield similar serum MTX levels (0.6 ± 0.1 μmoles).

Results. Bone formation (assessed by serum alkaline phosphatase and osteocalcin levels and histomorphometry) was significantly lower in the MTX groups, and bone resorption (assessed by urinary hydroxyproline levels and histomorphometry) was increased in the MTX groups. Bone mass was significantly diminished in the MTX groups.

Conclusion. Prolonged administration of lowdose MTX in rats causes significant osteopenia via suppression of osteoblast activity and stimulation of osteoclast recruitment, which results in increased bone resorption.
Impaired Glucocorticoid Induction of Mononuclear Leukocyte Lipocortin‐1 in Rheumatoid Arthritis
Authors: Morand Eric F. , Jefferiss Carolyn M. , Dixey Jonathan , Mitra Devashis , Goulding Nicolas J.
Published: February 2007

Objective. To investigate leukocyte lipocortin‐1 production in rheumatoid arthritis (RA).

Methods. Eight control and 8 RA subjects received 100 mg hydrocortisone intravenously. Leukocyte lipocortin‐1 was measured by enzyme‐linked immunosorbent assay.

Results. Hydrocortisone induced significant increases in lipocortin‐1 production by control mononuclear cells (MNC) (P = 0.006 versus baseline) but not by RA MNC (P = 0.44 versus baseline). Peak lipocortin‐1 levels in control MNC were significantly higher than those in RA MNC (P = 0.014).

Conclusion. These results indicate that glucocorticoid‐induced MNC lipocortin‐1 production is impaired in RA.
Differential Distribution of Intercellular Adhesion Molecules (ICAM–1, ICAM–2, and ICAM–3) and THE MS–1 Antigen in Normal and Diseased Human Synovia
Authors: Szekanecz Zoltan , Haines G. Kenneth , Lin Theodore R. , Harlow Lisa A. , Goerdt Sergij , Rayan Ghazi , Koch Alisa E.
Published: February 2007

Objective. Cellular adhesion and differentiation molecules (CAMs) may play a role in the recruitment and retention of inflammatory cells into rheumatoid arthritis synovial tissue (RA ST). In order to determine if certain CAMs are up‐regulated in RA ST compared with normal ST, we studied the distribution of intercellular adhesion molecules (ICAMs) 1, 2, and 3 in ST. We also studied the MS‐1 antigen since it is preferentially expressed on discontinuous endothelia, such as those found in RA ST; MS‐1 is also expressed differentially upon cytokine activation of cells in vitro or in pathologic conditions in situ. Thus, we postulated a possible similarity between MS‐1 and ICAM‐1 expression in inflamed ST.

Methods. Immunohistochemical analysis was used to determine the distribution of ICAMs and MS‐1 in ST from 10 patients with RA, 10 with osteoarthritis (OA), and 4 normal individuals.

Results. ICAM‐1 expression was found on significantly more RA ST endothelial cells compared with normal cells, as well as on RA ST macrophages and lining cells. ICAM‐2, also found on endothelial cells, showed no differential staining pattern. ICAM‐3 was present on RA ST macrophages and lining cells as well as on some RA and OA endothelial cells. The MS‐1 antigen was present on most RA and OA ST endothelia, lining cells, and macrophages. ICAM‐1 expression and MS‐1 expression in the lining layer were positively correlated in both RA and OA.

Conclusion. ICAM‐1, while found mainly on endothelial cells, is up‐regulated on RA ST macrophages and lining cells, suggesting a role for these cells in the infiltration and tissue damage seen in the RA ST. ICAM‐3, which is present mainly on normal resting leukocytes but not on normal endothelium, is expressed by some diseased ST leukocytes and endothelial cells. MS‐1 is also found on the RA ST specialized, fenestrated endothelium, on macrophages, and in the lining layer. These results suggest that the differential expression of ICAMs and MS‐1 in RA ST compared with normal ST might play a special role in the pathogenesis of RA.
Cytokine Combinations Increase p75 Tumor Necrosis Factor Receptor Binding and Stimulate Receptor Shedding in Rheumatoid Synovial Fibroblasts
Authors: Taylor David J.
Published: February 2007

Objective. To identify cytokines responsible for the increased levels of tumor necrosis factor receptor (TNFR) in the joints of patients with rheumatoid arthritis.

Methods. Antibodies to TNFR types were used both to inhibit ligand cell binding and to quantify released receptors in rheumatoid synovial fibroblasts.

Results. Binding by and shedding of the p75 TNFR was affected by interleukin‐1 (IL‐1), IL‐4, and interferon‐γ.

Conclusion. IL‐1 could cause increased TNFα binding and TNFR shedding in inflamed joints.
Cysteine Proteinase Inhibitors Decrease Articular Cartilage and Bone Destruction in Chronic Inflammatory Arthritis
Authors: Esser Ronald E. , Angelo Richard A. , Murphey Mark D. , Watts Lynnetta M. , Thornburg Larry P. , Palmer James T. , Talhouk Jamil W. , Smith Robert E.
Published: February 2007

Objective. To determine the effects of peptidyl fluoromethyl ketones on the in vitro activity of purified cathepsins B and L, on tissue cysteine proteinase activity, and on cartilage and bone destruction in experimental arthritis.

Methods. The effects of the fluoroketones on cathepsins B and L in vitro and the effects of oral administration of fluoroketones on ex vivo cysteine proteinase activity in tissue homogenates were determined by measuring the inhibition of fluorogenic substrate cleavage. To determine the effects on arthritis, animals were injected with adjuvant or type II collagen, treated orally with the fluoroketones, and the severity of arthritis was assessed by clinical, histologic, and radiologic methods.

Results. All of the fluoroketones tested were potent inhibitors of purified cathepsins B and L activity. Oral administration of the fluoroketones reduced tissue cysteine proteinase activity by up to 77%. In addition, fluoroketone treatment significantly reduced the severity of clinical joint disease and decreased the destruction of articular cartilage and bone. Quantitative analysis of radiographic images indicated that treatment significantly reduced soft tissue changes, periosteal proliferation, and bone erosion, but only partially reduced juxtaarticular osteoporosis.

Conclusion. These studies suggest that cysteine proteinase inhibitors may limit tissue destruction in diseases such as rheumatoid arthritis.
Anticentromere Autoantibodies
Authors: Vázquez‐Abad Dolores , Wallace Susan , Senécal Jean‐Luc , Joyal France , Roussin Andre , Earnshaw William C. , Rothfield Naomi
Published: February 2007

Objective. To evaluate an enzyme‐linked immunosorbent assay (ELISA) for anticentromere autoantibodies (ACA).

Methods. Sera from 611 patients with scleroderma, CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias), Raynaud's disease, and connective tissue disease control patients were studied by ELISA using the fusion protein CENP‐B, by immunofluorescence on dividing HEp‐2 cells, and by immunoblotting on chromosomes and CENP‐B.

Results. Compared with immunofluorescence, the CENP‐B ELISA sensitivity was 94% and the specificity was 93%. In 19.7% of the cases, there was a probability of a false‐positive result and in 1.9%, a probability of a false‐negative result, yielding positive and negative predictive values of 0.80 and 0.98, respectively.

Conclusion. The CENP‐B ELISA is a sensitive and specific assay for ACA.
Assessment of Clinical Parameters Associated with Increased Frequency of Mutant T Cells in Patients with Systemic Lupus Erythematosus
Authors: Dawisha Sahar M. , Gmelig‐Meyling Frits , Steinberg Alfred D.
Published: February 2007

Objective. To determine the clinical features that contribute to an increased frequency of mutant T cells (FMC) in patients with systemic lupus erythematosus (SLE).

Methods. During in vivo T cell division, there are errors in replication which give rise to mutations throughout the genome. An estimate of such mutations may be obtained by focusing on mutations in the hprt gene, which can be screened by assessing relative growth of T cell clones in the presence and absence of 6‐thioguanine. In this study, peripheral blood T cell clones from 47 patients with SLE were assessed, and the frequency of mutant T cells (FMC) determined. An attempt was made to correlate the FMC with disease measures.

Results. Patients with SLE had a spectrum of FMC values, ranging from normal to almost 1,000 times normal. Total duration of active disease (rs = 0.94), past highest disease activity index (rs = 0.80), and number of lupus flares (rs = 0.76) correlated most strongly (P < 0.0001) with FMC by Spearman's rank order analysis. In contrast, current disease activity index and current anti‐DNA level did not correlate with FMC. Similar correlations between FMC and cumulative past lupus disease activity were found by linear regression analysis (rp = 0.89 for the correlation between the natural logarithm of FMC and cumulative duration of active disease). By both statistical tests, therapy was found to be only a minor contributor to FMC.

Conclusion. In our patient population, a high FMC value appears to reflect cumulative clinical lupus disease activity, involving both intensity and duration of past active disease.
Immunocytochemical Localization and Serologic Detection of Transforming Growth Factor β1
Authors: Higley H. , Persichitte K. , Chu S. , Waegell W. , Vancheeswaran R. , Black C.
Published: February 2007

Objective. To determine the presence of transforming growth factor β1 (TGFβ1) and inflammatory cell markers (HLA–DR and Factor XIIIa) and to compare these with the presence of type I procollagen, in clinically uninvolved and involved skin from patients with different subsets of systemic sclerosis (SSc), and to analyze circulating levels of TGFβ1 in SSc patients.

Methods. TGFβ1, HLA‐DR, Factor XIIIa, and type I procollagen were detected in skin biopsy sections using a biotin–streptavidin–peroxidase system. Levels of circulating TGFβ1 were measured using a capture enzyme‐linked immunosorbent assay technique.

Results. Patients with active diffuse cutaneous SSc (dcSSc) showed minimal TGFβ1 but significant type I procollagen staining in involved skin, while the clinically uninvolved skin of these patients showed moderate extracellular and intra‐epidermal TGFβ1 immunoreactivity. Patients with limited cutaneous SSc (IcSSc) showed elevated TGFβ1 staining in both involved and uninvolved skin, as well as procollagen staining. Significant TGFβ1 reactivity, HLA–DR and Factor XIIIa immunoreactivity, numerous inflammatory cells, and procollagen staining were seen in specimens from patients with morphea. Sequential biopsies suggested the presence of cytokine activity at the earliest stages of disease, which was not maintained with progression of sclerosis. Among the disease groups studied, elevated levels of circulating TGFβ1 were seen only in patients with morphea.

Conclusion. The pattern of TGFβ1 staining in dermal sections from patients with dcSSc, IcSSc, and morphea suggests that this cytokine is important in the pathogenesis of scleroderma. Furthermore, the presence of TGFβ1 prior to the onset of fibrosis indicates an early involvement of this growth factor, possibly in the inflammatory stage of the disease.
Rapamycin Prolongs Survival and Arrests Pathophysiologic Changes in Murine Systemic Lupus Erythematosus
Authors: Warner Linda M. , Adams L. M. , Sehgal S. N.
Published: February 2007

Objective. To evaluate the effects of oral rapamycin (RAPA), a macrolide immunosuppressant that has been shown to interfere with T cell activation events, on the course of spontaneous disease progression in the MRL/MpJ/lpr/lpr (MRL/I) mouse model of lupus.

Methods. RAPA treatment (6, 12, or 25 mg/kg 3 times per week) was evaluated by monitoring survival rates, autoantibody levels, and urinary albumin levels. Additionally, concanavalin A responsiveness, interleukin‐2 (IL‐2) production, lymphoid organ size, and histopathology were evaluated ex vivo.

Results. RAPA prevented the typical rise in anti–double‐stranded DNA antibody and urinary albumin levels and prolonged survival. Spleen and lymph node sizes were significantly decreased, inflammatory changes in the lung, liver, kidney, spleen, lymph node, and thymus were significantly reduced, and T cell mitogen–stimulated splenocyte proliferation and IL‐2 production were restored.

Conclusion. Data from 3 independent experiments demonstrated that RAPA significantly reduced or prevented many pathologic features of lupus normally seen in the MRL/1 mouse, and suggest that RAPA may be useful as a therapeutic agent in SLE in humans.
CLINICAL RHEUMATOLOGY TRAINING IN AN UNCERTAIN FUTURE. Opinions of Recent and Current Rheumatology Fellows About an Extended Fellowship in Musculoskeletal Medicine
Authors: Mazzuca Steven A. , Brandt Kenneth D.
Published: February 2007

Objective. To estimate among recent and current rheumatology fellows the appeal of a 3‐year rheumatology fellowship emphasizing musculoskeletal medicine.

Methods. A survey of 348 trainee members of the American College of Rheumatology during 1990–1993, by mailed questionnaire.

Results. The response rate was 77.8% (n = 271). Both recent and current fellows indicated that they desired more experience in musculoskeletal medicine. Most notably, 50% of current fellows, and a significantly higher proportion of recent fellows (70%; P < 0.005), indicated that they would have opted for a 3‐year fellowship in musculoskeletal medicine had one been available to them at the completion of their residency.

Conclusion. Expertise in musculoskeletal medicine is desired by a sufficient proportion of recent and current rheumatology fellows to warrant the investment in another year of training.
Absence of Lentiviral and Human T Cell Leukemia Viral Sequences in Patients with Rheumatoid Arthritis
Authors: Giovine Francesco S. Di , Bailly Sabine , Bootman Janet , Almond Neil , Duff Gordon W.
Published: February 2007

Objective. The etiology of rheumatoid arthritis (RA) is unknown, and the possibility that an infectious agent is involved has not been excluded. Lentiviruses can cause chronic arthritis in humans and in animals and have been suggested as candidate agents in RA. We therefore tested for the presence of lentiviruses and also for human T cell leukemia virus type I (HTLV‐I)/ HTLV‐II in cells from patients with RA.

Methods. We used the polymerase chain reaction with degenerate primers designed to recognize highly conserved nucleotide sequences from 5 different pathogenic lentiviruses. This method allowed the detection of at least 1 infected cell/20,000 uninfected cells in control experiments.

Results. Testing of synovial cells and blood cells from patients with early RA and patients with established RA did not yield any specific viral product.

Conclusion. Our results do not support the presence of lentiviruses or HTLV‐like sequences in RA.
The Time‐Dependence of Long‐Term Prediction in Lupus Nephritis
Authors: Esdaile John M. , Abrahamowicz Michal , Mackenzie Todd , Hayslett John P. , Kashgarian Michael
Published: February 2007

Objective. To assess the clinical, laboratory, and renal biopsy predictors of long‐term outcome in lupus nephritis and to investigate the time‐dependence of these predictors.

Methods. Eighty‐seven lupus nephritis patients were studied retrospectively for the outcomes renal failure and fatality due to renal involvement. In addition to a conventional Cox model analysis, a new generalized time‐dependent analytic approach was developed and used to assess the time‐dependence of a predictor variable's importance.

Results. The mean followup time was 11.9 years. Renal failure (n = 19) was significantly predicted by measures of renal function (abnormal serum creatinine levels, proteinuria, duration of prior renal disease) and immunologic activity (elevated DNA binding, hypocomplementemia, and thrombocytopenia), by overall lupus disease activity measures (le Riche index, Lupus Activity Criteria Count), and by the activity index, the tubulointerstitial index, and the amount of subepithelial deposits on renal biopsy. In general, the laboratory predictors were significantly better prognostic markers in the early years after biopsy, the disease activity measures were best in the later years, and the biopsy variables were significant predictors over the entire observation period. In contrast to the renal failure outcome, the best predictors for death not directly related to lupus nephritis (n = 17) were the extent of comorbid diseases (principally vascular diseases), older age, and the chronicity index. All three predicted well over the extended observation period.

Conclusion. The major predictor variables for renal outcomes and nonrenal outcomes are distinct. The time‐dependence of the predictive ability of some variables may be important in managing individual patients. The new generalized time‐dependent analytic technique may have widespread application in studies to identify prognostic factors for established disease or risk factors for the development of disease.
Lymphocyte Antigens in Neuropsychiatric Systemic Lupus Erythematosus
Authors: Denburg Susan D. , Behmann Sharon A. , Carbotte Ramona M. , Denburg Judah A.
Published: February 2007

Objective. To examine the relationships among specific lymphocyte antigenic reactivities of lupus sera and central nervous system complications of systemic lupus erythematosus (SLE), lymphocytotoxic antibody (LCA) positivity, and specific cognitive impairment.

Methods. Sera from 115 patients with SLE were examined for the presence of IgM‐ and IgG‐class auto‐antibodies binding to surface target antigens on lymphocytes, by immunoblotting and microdroplet lymphocytotoxicity studies. Seventy‐three of these patients also underwent detailed neuropsychological testing within the same time period.

Results. Significant associations were found between reactivities to several lymphocyte antigenic moieties and neuropsychiatric SLE (NPSLE) or cognitive impairment. Specifically, immunoblot reactivities to 31–32‐kd, 50–52‐kd, 54–56‐kd, and 97–98‐kd targets were associated with clinical NPSLE; there was a significant association between reactivity to the 50–52‐kd moiety in particular and cognitive impairment. There were also associations between LCA and immunoblot reactivity. Furthermore, the previously reported association between LCA positivity and specific visuospatial cognitive impairment was confirmed with data obtained from 2 different batteries of neuropsychological tests.

Conclusion. In some cases, specific antigenic targets of LCA‐containing sera may be implicated in the pathogenesis of NPSLE.
Up‐Regulation of Endothelial Cell Adhesion Molecules Characterizes Disease Activity in Systemic Lupus Erythematosus
Authors: Belmont H. Michael , Buyon Jill , Giorno Ralph , Abramson Steven
Published: February 2007

Objective. To test the hypothesis that during exacerbations of systemic lupus erythematosus (SLE), endothelial cells are activated to increase their expression of adhesion molecules.

Methods. Endothelial cell expression of E‐selectin, vascular cell adhesion molecule 1 (VCAM‐1), and intercellular adhesion molecule 1 (ICAM‐1) was quantitated immunohistochemically in 20 biopsy specimens from nonlesional, non‐sun‐exposed skin from 16 SLE patients. Disease activity was evaluated with the SLE Disease Activity Index (SLEDAI) and with measurements of complement components C3a desArg, C3, and C4.

Results. The mean expression of all 3 adhesion molecules was significantly elevated in patients with SLE versus healthy controls, as well as in patients with active versus inactive SLE. The mean C3a desArg level was significantly higher in patients with active SLE compared with those with inactive SLE. The SLEDAI scores correlated directly with C3a desArg levels and inversely with C3 and with C4 levels. Evaluation of serial biopsy specimens demonstrated loss of endothelial cell adhesion molecules and reduction of C3a levels with clinical improvement.

Conclusion. Our findings demonstrate up‐regulation of the surface expression of 3 distinct adhesion molecules, E‐selectin, VCAM‐1, and ICAM‐1, in patients with SLE. The abnormal expression of these endothelial cell adhesion molecules is most marked in patients with active disease characterized by significant elevations of the complement split product C3a desArg. We suggest that in certain SLE patients, excessive complement activation in association with primed endothelial cells induces leukocyte‐endothelial cell adhesion and leuko‐occlusive vasculopathy.
Antihistone Antibodies in Systemic Sclerosis
Authors: Sato Shinichi , Ihn Hironobu , Kikuchi Kanako , Takehara Kazuhiko
Published: February 2007

Objective. To determine the prevalence and clinical significance of antihistone antibodies (AHA) in systemic sclerosis (SSc).

Methods. Serum samples from patients with limited cutaneous SSc (n = 44), diffuse cutaneous SSc (dcSSc; n = 48), and other SSc‐related disorders (n = 22) were examined by enzyme‐linked immunosorbent assay and immunoblotting for AHA.

Results. AHA were demonstrated in 29% of the 92 SSc patients and in 44% of those with dcSSc. The presence of AHA correlated with severe pulmonary fibrosis in those with dcSSc. Immunoblotting revealed that the predominant antigen was histone H1.

Conclusion. AHA might be a serologic indicator of the severity of pulmonary fibrosis in SSc.
Treatment of Lupus Interstitial Lung Disease with Intravenous Cyclophosphamide
Authors: Eiser Arnold R. , Shanies Harvey M.
Published: February 2007

Intravenous pulse cyclophosphamide (IPC) was used to treat lupus interstitial lung disease in 2 patients. Vital capacity increased by 67–110% of baseline values with IPC treatment. Total lung capacity and diffusing capacity also improved. Dyspnea and other manifestations of lupus improved dramatically. This is the first report documenting the efficacy of the early use of IPC for acute and chronic interstitial lung disease associated with lupus.
Reduced joint counts in controlled clinical trials in rheumatoid arthritis
Authors: Fuchs Howard A. , Pincus Theodore
Published: February 2007

Results. The effect sizes of the joint scores derived using a reduced number of joints were similar to those of the original 60‐joint score. The reduced joint count scores revealed significant changes for clinical trials involving as few as 15 patients.

Conclusion. Reduced joint count scores may be used to evaluate the results of clinical trials without decreasing the ability to detect change over time. Quantitative assessment of a reduced number of joints may also facilitate assessment of responses to treatment in the routine care of patients with RA.

Objective. To determine if quantitative assessment of a reduced number of joints provides information equivalent to that obtained by the traditional 60‐joint evaluation in detecting changes in patients participating in clinical trials of rheumatoid arthritis (RA).

Methods. The changes in quantitative joint scores of patients from 3 previously reported clinical trials were compiled and compared with changes in quantitative scores derived using a reduced number of joints. Effect sizes were calculated (mean change in joint score/standard deviation of joint score) and compared for the different joint indices.
The mortality of rheumatoid arthritis
Authors: Wolfe Frederick , Mitchell Donald M. , Sibley John T. , Fries James F. , Bloch Daniel A. , Williams Catherine A. , Spitz Patricia W. , Haga May , Kleinheksel Sue M. , Cathey Mary Ann
Published: February 2007

Objective. To determine the risk and causes of death and to quantify mortality predictors in patients with rheumatoid arthritis (RA).

Methods. RA patients (n = 3,501) from 4 centers (Saskatoon n = 905, Wichita n = 1,405, Stanford n = 886, and Santa Clara n = 305) were followed for up to 35 years; 922 patients died.

Results. The overall standardized mortality ratio (SMR) was 2.26 (Saskatoon 2.24, Wichita 1.98, Stanford 3.08, Santa Clara 2.18) and increased with time. Mortality was strikingly increased for specific causes: infection, lymphoproliferative malignancy, gastroenterologic, and RA. In addition, as an effect of the SMR of 2.26, the expected number of deaths was increased nonspecifically across all causes (except cancer), with a large excess of deaths attributable to cardiovascular and cerebrovascular diseases. Independent predictors of mortality included age, education, male sex, function, rheumatoid factor, nodules, erythrocyte sedimentation rate, joint count, and prednisone use.
Induction of cyclooxygenase ii in human synovial microvessel endothelial cells by interleukin‐1
Authors: Szczepanski Andrew , Moatter Tariq , Carley William W. , Gerritsen Mary E.
Published: February 2007

Conclusion. IL‐1 treatment of HSE cells induces COX II, as demonstrated by both Northern blotting and immunoprecipitation. The induction of COX II expression provides, at least in part, a mechanism for the pronounced increase in prostanoid synthesis observed in HSE cells following incubation with IL‐1. The selective up‐regulation of HSE COX II by inflammatory cytokines such as IL‐1 suggests that development of specific pharmaceutical inhibitors for this novel isozyme may provide significant new therapeutic advantages in the treatment of RA.

Objective. To characterize the effects of inter‐leukin‐1α (IL‐1) on prostanoid biosynthesis by human rheumatoid synovium microvessel endothelium (HSE).

Methods. HSE cells were treated with cytokines, metabolic inhibitors, and steroids under various conditions, and prostaglandin biosynthesis was determined by radioimmunoassay. Newly synthesized cyclooxygenase (COX) was quantitated by immunoprecipitation of metabolically labeled HSE cell lysates. The effects of IL‐1 on levels of messenger RNA (mRNA) for COX II were also determined.

Results. IL‐1 induced an increase in COX activity (as assessed by prostaglandin E2 release) that was dose‐and time‐dependent and was blocked by cycloheximide, actinomycin D, and dexamethasone. IL‐1 induced a selective increase in COX II mRNA and biosynthesis of COX II protein that was blocked by dexamethasone.

Conclusion. Mortality rates are increased at least 2‐fold in RA, and are linked to clinical severity.
Association of tap2 polymorphism with rheumatoid arthritis is secondary to allelic association with hla–drb1
Authors: Marsal Sara , Hall Margaret A. , Panayi Gabriel S. , Lanchbury Jerry S.
Published: February 2007

Objective. To study polymorphisms of the newly described TAP2 locus in rheumatoid arthritis (RA) and to analyze their relationship with HLA–DRB1 alleles previously implicated in the development of the disease.

Methods. TAP2 polymorphic residues at 3 sites, Val/Ile‐379, Ala/Thr‐565, and Ala/Thr‐665, were characterized by amplification refractory mutation system polymerase chain reaction in 185 RA patients and 48 HLA–DR4 positive healthy controls. HLA‐DR4 subtypes were determined by sequence‐specific priming and oligonucleotide hybridization.

Results. The frequencies of Ile‐379, Thr‐565, and Thr‐665 were significantly increased in DR4 positive versus DR4 negative RA patients. TAP2 genotype distributions also differed between the patient groups stratified by DR4 status. However, no significant differences in TAP2 polymorphisms were observed between DR4 positive RA patients and DR4 positive controls, although relationships between specific DR4 subtypes and TAP2 variants were identified.

Conclusion. Particular TAP2 polymorphisms are associated with distinct HLA–DR specificities in both normal and RA populations. Thus, the prevalence of specific TAP2 residues and genotypes in RA appears to be secondary to the HLA–DR frequencies and genotypic combinations that are typical of RA.
Hla–drb1 alleles in polymyalgia rheumatica, giant cell arteritis, and rheumatoid arthritis
Authors: Weyand Cornelia M. , Hunder Naomi N. H. , Hicok Kevin C. , Hunder Gene G. , Goronzy Jörg J.
Published: February 2007

Objective. Immunogenetic analysis has demonstrated that giant cell arteritis (GCA) and rheumatoid arthritis (RA) are associated with 2 different domains of the HLA–DR4 molecule. The present study was undertaken to evaluate whether polymyalgia rheumatica (PMR) immunogenetically resembles GCA or RA and to determine whether expression of HLA‐DRB1 alleles can be used to detect heterogeneity among PMR patients.

Methods. Forty‐six patients with PMR, 52 with GCA, 122 with seropositive RA, and 72 normal individuals were genotyped for HLA‐DRB1 alleles by allele‐specific amplification and subsequent oligonucleotide hybridization.

Results. The HLA‐DRB1*04 allele was the most frequent among PMR patients (67%). While the expression of allelic variants of the HLA‐DR4 family was restricted to HLA‐DRB1*0401 and*0404/8 in RA patients, all HLA–DRB1*04 alleles, including B1*0402 and B1*0403, were represented in the PMR group. The distribution of HLA–DRB1 alleles among HLA–DRB1*04 negative patients was similar in those with PMR and those with GCA, and could be distinguished from that in RA patients. In particular, HLA–DRB1*01 alleles, which were found in most HLA–DRB1*04 negative RA patients, were underrepresented in patients with PMR and GCA.

Conclusion. The distribution of HLA–DRB1 alleles in PMR resembles that found in GCA. PMR and GCA share the associated sequence polymorphism encoded by the second hypervariable region (HVR) of the HLA–DRB1 gene. The HLA–DRB1 association of PMR and GCA can be distinguished from that of RA, which is linked to a sequence motif in the third HVR of DRB1 alleles. The differential role of distinct domains on HLA‐DR molecules suggests that multiple biologic functions are regulated by these molecules and that they contribute differently to disease mechanisms. The similarities in the distribution of HLA–DRB1 alleles in PMR and GCA indicates that HLA–DRB1 alleles are not predictive for progression of PMR to the vasculitic lesions that are pathognomonic for GCA.
Intraarticular injections of hyaluronan in patients with cartilage abnormalities and knee pain
Authors: Dahlberg Leif , Lohmander L. Stefan , Ryd Leif
Published: February 2007

Objective. To compare the effect of intraarticular injections of hyaluronan and placebo (vehicle, saline) in patients with knee pain on exertion and with joint cartilage abnormalities.

Methods. Fifty‐two patients with arthroscopically verified deep cartilage fissures and villus‐like flakes in the symptomatic knee were randomly assigned to receive intraarticular injections of 2.5 ml of either hyaluronan or vehicle, weekly for 5 weeks. The effect was evaluated by both primary and secondary parameters of efficacy at 2, 4, 13, 26, and 52 weeks.

Results. At the followup visits, both groups had improvement from baseline; however, there was no difference between the groups in any of the relevant variables at any time point.

Conclusion. The effects of intraarticular hyaluronan do not differ significantly from those of placebo in patients with knee pain and cartilage disease.
Integrin expression by human articular chondrocytes
Authors: Woods Virgil L. , Schreck Paul J. , Gesink Dirk S. , Pacheco Hector O. , Amiel David , Akeson Wayne H. , Lotz Martin
Published: February 2007

Objective. To perform a comprehensive analysis of the integrin forms expressed by normal human articular chondrocytes.

Methods. Cartilage sections and collagenase‐released chondrocytes were probed with a comprehensive panel of integrin isoform–specific monoclonal antibodies (MAb), using in situ immunohistochemistry techniques, indirect immunofluorescence and flow cytometry, and immunoprecipitation/sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS‐PAGE).

Results. Chondrocytes in cartilage sections reacted with MAb specific for the α5, αv, and β1 integrin subunits and the αvβ3 and αvβ5 heterodimers. They also reacted with a polyclonal antibody specific for the intracytoplasmic portion of the α1 subunit. MAb specific for the αv subunit reacted more strongly with chondrocytes near the articular surface than with those in deeper layers of cartilage, and the αvβ3‐specific MAb reacted exclusively with chondrocytes within the most superficial 30 μm of cartilage. Flow cytometric analysis and SDS‐PAGE analysis of immunoprecipitates prepared from extracts of cell‐surface radioiodinated chondrocytes confirmed the above observations, and additionally revealed the presence of the α3β1 integrin.

Conclusion. Normal human articular chondrocytes prominently display substantial quantities of the α1β1, α5β1, and αvβ5 integrin heterodimers, as well as lesser quantities of the α3β1 and αvβ3 heterodimers, The αv subunit–containing integrins are detected more readily on the more superficial chondrocytes than on chondrocytes deep within cartilage. These observations provide the basis for analysis of the role of chondrocyte integrins in cartilage homeostasis and in the pathogenesis of joint diseases.
Effect of low‐dose cyclosporin a on systemic lupus erythematosus disease activity
Authors: Tokuda Michiaki , Kurata Noriyuki , Mizoguchi Akihito , Inoh Masayuki , Seto Kunio , Kinashi Makoto , Takahara Jiro
Published: February 2007

Objective. To determine the effect of low‐dose cyclosporin A (CSA) treatment on disease activity in systemic lupus erythematosus (SLE).

Methods. All patients in the study had active disease as defined by at least the presence of a low CH50 level. Patients were initially given 3 mg/kg/day of CSA. Dosages were adjusted individually at every visit, according to both clinical and laboratory data.

Results. Eleven women with SLE were enrolled in the study; 10 were evaluable. After 20 weeks of CSA treatment, the mean score for disease activity on the SLE Disease Activity Index decreased significantly, from 10.6 to 3.8 (P = 0.02). The titer of antinuclear antibodies decreased in 8 patients and the level of anti‐DNA antibodies decreased in 5. Side effects included hypertension (40%), hypertrichosis (30%), gingival hypertrophy (10%), and a rise in the blood urea nitrogen level. Serum creatinine levels remained unchanged.

Conclusion. The favorable responses observed in our patients strongly suggest that low‐dose CSA can reduce the disease activity of SLE.
Kidney biopsy in systemic lupus erythematosus
Authors: Mclaughlin John R. , Bombardier Claire , Farewell Vernon T. , Gladman Dafna D. , Urowitz Murray B.
Published: February 2007

Objective. To examine the importance of renal biopsy as a predictor of death due to any cause in patients with systemic lupus erythematosus (SLE).

Methods. The study included 123 SLE patients who had a renal biopsy between 1970 and 1984 and were followed up as part of a prospective study. Data were initially analyzed to identify clinical and laboratory features that were significantly associated with the risk of dying. Renal biopsy variables were then examined to determine whether they contributed additional information about prognosis.

Results. The clinical and laboratory factors most closely associated with the risk of dying in multivariate analyses were the serum creatinine level and the SLE Disease Activity Index score. The presence of chronic renal lesions on biopsy contributed significantly to the prognostic information offered by clinical and laboratory factors in the subset of patients who had normal serum creatinine levels—the majority (85%) of patients in this study.

Conclusion. These results indicate that renal biopsy serves an important role in the assessment of prognosis in patients who do not have advanced renal disease.
Association between antiphospholipid antibodies and epilepsy in patients with systemic lupus erythematosus
Authors: Herranz M. Teresa , Rivier Gilles , Khamashta Munther A. , Blaser Klaus U. , Hughes Graham R. V.
Published: February 2007

Objective. To determine whether the occurrence of seizures is correlated with the presence of serum antiphospholipid antibodies (aPL) in systemic lupus erythematosus (SLE) patients.

Methods. The study included 221 unselected patients with SLE. Of these, 21 patients with epileptic seizures not attributed to any cause other than SLE were identified. Epilepsy was diagnosed by clinical history and electroencephalography. Blood samples were tested for the presence of antibodies to cardiolipin (aCL, IgG and IgM isotypes) and lupus anticoagulant (LAC).

Results. LAC was detected in 43.8% of the patients with epilepsy and in 20.8% of controls (P = 0.057). A statistically significant association was found between moderate‐to‐high titers of IgG aCL and the presence of seizures (P = 0.02). Brain computed tomography and/or magnetic resonance imaging scanning was performed in 14 patients. All patients with abnormal features found on these tests had positive aPL (P = 0.03). Nine patients (42.9%) had at least 1 of the classic features associated with the aPL syndrome.

Conclusion. We confirmed that epilepsy as a primary neuropsychiatric event is significantly associated with moderate‐to‐high titers of IgG aCL in SLE patients. Our results suggest that aPL could have a role in the etiopathogenesis of epilepsy in SLE.
Serum thrombomodulin
Authors: Boehme Michael W. J. , Nawroth Peter P. , Kling Elisabeth , Lin Jie , Amiral Jean , Riedesel Jutta , Raeth Ulrich , Scherbaum Werner A.
Published: February 2007

Objective. Soluble thrombomodulin (sTM), a proposed serum marker of endothelial cell injury, was investigated as a parameter of disease activity in patients with systemic lupus erythematosus (SLE).

Methods. Levels of sTM were determined by enzyme‐linked immunosorbent assay. Disease activity was assessed using 3 established scoring systems: the American College of Rheumatology (ACR), the New York Hospital for Special Surgery (NYHSS), and the Systemic Lupus Activity Measure (SLAM) systems.

Results. A close correlation was found between sTM levels and disease activity as assessed with all 3 scoring systems: r = 0.52 by the ACR, 0.75 by the NYHSS, and 0.82 by the SLAM.

Conclusion. We found that sTM is a sensitive serologic marker of organ involvement in patients with SLE. Furthermore, sTM may prove to be an important marker for vasculitis in general.
Treatment of glucocorticoid‐resistant or relapsing takayasu arteritis with methotrexate
Authors: Hoffman Gary S. , Leavitt Randi Y. , Kerr Gail S. , Rottem Menachem , Sneller Michael C. , Fauci Anthony S.
Published: February 2007

Objective. To identify the role of methotrexate (MTX) in the treatment of persistent or recurrent Takayasu arteritis that is refractory to treatment with glucocorticoids (GC) alone.

Methods. An open‐label pilot study of weekly low‐dose MTX + GC treatment was performed. Outcome was evaluated according to clinical characteristics, laboratory abnormalities, findings on routinely performed angiographic studies, and ability to withdraw GC and MTX therapy. Eighteen patients entered the study; 2 dropped out, and 16 were followed up for a mean period of 2.8 years (range 1.3–4.8 years).

Results. Weekly administration of MTX (mean stable dose of 17.1 mg) and GC resulted in remissions in 13 of 16 patients (81%). However, 7 patients (44%) had relapses as GC was tapered to or near discontinuation. Retreatment again led to remission, and 3 of 7 patients in this group have successfully stopped GC therapy. Of those patients who achieved remission, 8 (50%) have sustained remissions of 4–34 months (mean 18 months), and 4 of this group have not required GC or MTX therapy for 7–18 months (mean 11.3 months). Three patients experienced disease progression in spite of treatment.

Conclusion. About half of all Takayasu arteritis patients have chronic active disease for which GC therapy alone does not provide sustained remissions that allow withdrawal of treatment. Weekly low‐dose MTX is an effective means of inducing remission and minimizing GC therapy and toxicity in most of these patients. Further long‐term studies will be required to assess the durability of remission and the need for maintenance MTX therapy in this subset of Takayasu arteritis patients.
Reduction of mortality and lymphadenopathy in mrl‐lpr/lpr mice treated with nonmitogenic anti‐cd3 monoclonal antibody
Authors: Henrickson Michael , Giannini Edward H. , Hirsch Raphael
Published: February 2007

Objective. To evaluate the therapeutic efficacy of nonmitogenic anti‐CD3 monoclonal antibody (MAb) in a preexisting autoaggressive response, using the MRL‐lpr/lpr (MRL/I) murine model of autoimmune disease.

Methods. Female MRL/I mice, 8–10 weeks of age, were treated with nonmitogenic anti‐CD3 MAb or phosphate buffered saline and effects on mortality, lymphadenopathy, T cell phenotypes, anti‐DNA titers, and total IgG titers were measured.

Results. Nonmitogenic anti‐CD3 MAb treatment resulted in a dramatic reduction in lymphadenopathy and mortality, as well as an early reduction in α/β+, CD4–, CD8–, Thy+, B220+ (double‐negative) lymph node cells. No significant effects on anti‐DNA or IgG titers were observed. No morbidity was observed following administration of nonmitogenic anti‐CD3 MAb.

Conclusion. A short course of treatment with nonmitogenic anti‐CD3 MAb can suppress preexisting autoimmune responses without inducing the cytokinemediated toxicity characteristic of mitogenic forms of anti‐CD3 MAb. The use of nonmitogenic anti‐CD3 MAb may be efficacious in the clinical setting for the treatment of T cell–mediated autoimmune disorders.