bluuebunny/crossref_metadata_2025 huggingface dataset:
Antibodies in rabbits immunized with cationized IgG react with histones H3 and H4
Authors: Suzuki Takahiro , Burlingame Rufus W. , Cavalot Franco , Andres Giuseppe , Kashiwazaki Sadao , Tan M.
Published: February 2007

Objective. Rabbits immunized with cationized rabbit IgG develop antinuclear antibodies. This study was aimed at identifying the reactive antigens.

Methods. Rabbits were immunized with homotypic or allotypic IgG that were physicochemically altered to produce positively charged dimethylpropanamide (polycationic) side chains.

Results. Seven of 11 rabbits injected with cationized IgG produced antinuclear antibodies detected by indirect immunofluorescence. By enzyme‐linked immunosorbent assay, these were IgG antibodies reacting with histone (H3–H4)2 tetramer and with individual histone polypeptides H3 and H4. The antihistone antibodies were absorbed by cationized IgG but not by normal IgG.

Conclusion. Cationized IgG appears to possess antigenic determinants of sufficient similarity to produce antibody responses cross‐reactive with histones H3 and H4.
The intrinsic migratory capacity of memory T cells contributes to their accumulation in rheumatoid synovium
Authors: Cush John J. , Pietschmann Peter , Oppenheimer‐Marks Nancy , Lipsky Peter E.
Published: February 2007

Objective. Mechanisms controlling the infiltration of T cells into rheumatoid synovium have not been fully characterized. These studies were undertaken to investigate the relationship between T cell phenotype and migratory capacity, so as to elucidate mechanisms that might contribute to the accumulation of T cells at inflammatory sites.

Methods. The characteristics of in vivo migrating cells were studied by dual‐immunofluorescence FACS (fluorescence‐activated cell sorter) analysis of rheumatoid synovial and peripheral blood T cells. Migratory cells were also characterized using a recently developed in vitro assay, wherein peripheral blood T lymphocytes (PBTL) with the capacity to migrate through endothelial cell monolayers were retrieved and assessed.

Results. Migratory CD4+ T cells from rheumatoid arthritis (RA) and normal individuals were characterized as being CD45RA‐, CD29bright, CD11abright, L‐selectin‐, CD54+, and CD58+. Migrating RA PBTL (compared with normal PBTL), however, were significantly enriched in activated HLA—DR+ T cells. RA synovial tissue lymphocytes exhibited a similar phenotype, but with decreased surface density of CD4 and an increase in HLA‐DR and VLA‐1. RA synovial lymphocytes exhibited a 2–3‐fold increase in migratory capacity over normal and RA PBTL.

Conclusion. These studies demonstrate the inherent migratory proficiency of CD4+ T cells that express a memory phenotype (CD29bright, CD11abright, and CD58+). In addition, enhanced transendothelial migration was observed for CD4+ T cells that were CD54+ and L‐selectin—. These studies demonstrate that the migratory patterns of circulating lymphocytes may be correlated with their surface phenotype and that the intrinsic migratory capacity of memory T cells is one component contributing to their accumulation in the rheumatoid synovium.
Association of dry eyes and dry mouth with anti—Ro/SS‐A and anti—La/SS‐B Autoantibodies in normal adults
Authors: Jacobsson Lennart , Hansen Bjarne U. , Manthorpe Rolf , Hardgrave Kathy , Neas Barbara , Harley John B.
Published: February 2007

Objective. To evaluate the extent to which seemingly healthy, mature adults with mild symptoms of dry eyes or dry mouth share the immunologic features found in patients with Sjögren's syndrome.

Methods. Of 705 subjects in Malmö, Sweden (age range 52–72 years) who responded to a questionnaire, 35% reported some symptoms of dry eyes or mouth. A random subgroup of the symptomatic subjects (n = 77) and an age‐ and sex‐matched control group from among the asymptomatic subjects (n = 32) were evaluated objectively by serologic testing and by various measures of exocrine gland function.

Results. The symptomatic subjects had relatively impaired exocrine gland function and elevated levels of anti‐Ro and anti‐La (1.54–2.88‐fold increase compared with the asymptomatic subjects, 95% confidence interval [CI] 1.41, 4.03). The 2 autoantibodies correlated with each other (r = 0.64, 95% CI 0.49, 0.78) as well as with selected clinical measures of glandular function.

Conclusion. The association between self‐reported symptoms of dry eyes or dry mouth and anti‐Ro and anti‐La, found in more than one‐third of mature adults in this study, suggests that the immune abnormalities and exocrine gland dysfunction found in Sjögren's syndrome affect a substantial proportion of the general population.
Interactions of synovial fluid immunoglobulins with chondrocytes
Authors: Takagi Toshitaka , Jasin Hugo E.
Published: February 2007

Objective. To study the interaction of synovial fluid (SF) immunoglobulins with living chondrocytes, and to evaluate the relative contribution of type II collagen (CII) antibodies.

Methods. SF of patients with rheumatoid arthritis (RA), osteoarthritis (OA), and gout were incubated with isolated bovine articular chondrocytes. Ig binding was measured by flow cytometry and by quantitation with 125I‐labeled anti‐IgG and anti‐IgM. Complement‐dependent cytotoxicity was determined by 51Cr release. Immunoglobulin binding and cytotoxicity were compared between chondrocytes obtained from the superficial and from the deep cartilage zones.

Results. Significantly greater IgG and IgM binding was found with RA SF compared with OA or gout SF. Chondrocytes bound more Ig than did fibroblasts. The relative contribution of anti‐CII antibodies to Ig binding was studied following absorption of the SF with bovine CII, and by incubation with bacterial collagenase‐treated chondrocytes. There was a small but significant reduction in IgG and IgM binding with SF samples that were positive for anti‐CII. RA SF exhibited modest, but significantly greater complement‐dependent cytotoxicity than OA SF. Gel chromatography fractionation indicated that IgM antibodies were responsible for the cytotoxic activity. Additional studies showed that SF IgM antibodies bound preferentially to, and killed chondrocytes obtained from, the superficial layers of cartilage.

Conclusion. Anti‐CII antibodies contained in RA SF represent one of many antibody specificities reacting with chondrocyte membrane antigens. Chondrocyte‐reactive SF antibodies may play an important pathogenic role in the processes leading to irreversible cartilage damage in RA. These deleterious effects appear to be exerted particularly on chondrocytes located near the articular surface of cartilage.
Causes of death in systemic lupus erythematosus, long‐term followup of an inception cohort
Authors: Ward Michael M. , Pyun Elise , Studenski Stephanie
Published: February 2007

Objective. To describe the causes of death in a cohort of patients with systemic lupus erythematosus (SLE), and to determine if the major causes of death differ according to patient age, sex, race, socioeconomic status, and the duration of SLE.

Methods. We examined survival in a cohort of 408 patients with SLE. During a median of 11 years of followup, 144 patients died. The cause of death was determined for 134 patients (93%).

Results. SLE was the most common cause of death, occurring in 49 patients (34%), followed by in‐ fection (n = 32; 22%), cardiovascular disease (n = 23; 16%), cerebrovascular disease (n = 8; 6%), and cancer (n = 8; 6%). Deaths due to SLE and due to infections were more common among younger patients, and deaths due to cancer were more common among older patients. Although the risk of death due to SLE was greatest during the first 3 years after diagnosis, deaths due to SLE occurred throughout the course of disease.

Conclusion. In this study of patients with SLE who were followed up for an extended period of time beginning soon after diagnosis, SLE was the most common cause of death, and deaths due to SLE occurred throughout the course of illness.
Association of radiographically evident osteoarthritis with higher bone mineral density and increased bone loss with age. The rotterdam study
Authors: Burger Huibert , van Daele Paulus L. A. , Odding Else , Valkenburg Hans A. , Hofman Albert , Grobbee Diederick E. , Schütte Henry E. , Birkenhäger Jan C. , Pols Huibert A. P.
Published: February 2007

Objective. To investigate the relationship of osteoarthritis (OA) to bone mineral density (BMD) and rate of bone loss.

Methods. The study group consisted of 2,745 persons (1,624 women) from the general elderly population. Disability was assessed by the Health Assessment Questionnaire. Femoral neck BMD was measured at baseline and, in 1,723 subjects, after 2 years of followup. Knee and hip radiographic OA was assessed on anteroposterior radiographs.

Results. With the exception of knee radiographic OA in men, radiographic OA was associated with significantly increased BMD (3–8%). BMD increased significantly according to the number of affected sites and the Kellgren score. Radiographic OA was also associated with significantly elevated bone loss with age (in men, only for radiographic OA of the hip). A significant increase in relation to the number of affected sites and the Kellgren score (except with regard to knee OA in men) was found, independent of disability.

Conclusion. Radiographic OA is associated with higher BMD and increased rate of bone loss. This suggests a more pronounced difference in BMD earlier in life.
The presence of costimulatory molecules CD86 and CD28 in rheumatoid arthritis synovium
Authors: Liu Ming Fei , Kohsaka Hitoshi , Sakurai Hiroshi , Azuma Miyuki , Okumura Ko , Saito Ichiro , Miyasaka Nobuyuki
Published: February 2007

Objective. To investigate the expressions of costimulatory molecules CD86 (B7‐2, B70) and CD28 by cells obtained from the synovial tissues (ST) and synovial fluids (SF) of patients with rheumatoid arthritis (RA).

Methods. Monoclonal antibodies (MAb) against CD86 and CD28 were used for immunochemical study of synovia from 18 RA patients, 4 osteoarthritis (OA) patients, and 4 normal subjects. These MAb were also used for flow cytometry of isolated ST cells from 8 RA and 5 OA patients and of SF mononuclear cells from 5 RA and 5 OA patients.

Results. Immunohistochemical examination revealed that CD86+ cells occurred in 11 of the 18 RA synovia, but in none of the 4 OA or 4 normal synovia. Most of the positive cells had macrophage‐like morphology, and surrounded lymphoid aggregates. Most cells within lymphoid aggregates were stained positively for CD28. Flow cytometry showed that CD86+ cells comprised 2.9–33.4% (average 14.3%) of the total ST cells and 2.1–14.9% (average 6.1%) of the total SF mononuclear cells from RA patients. Approximately 40% of the CD86+ cells expressed CD14. A majority (mean 72%, range 57–89%) of the T cells in ST and SF expressed CD28. RA synovia expressed more CD86 molecules than did OA synovia (mean frequency of positive cells 14.3% versus 2.8%; mean fluorescence intensity 104.6 versus 40.9).

Conclusion. This study has shown that the expression of the CD86 molecule was up‐regulated in RA synovia. The CD86+ cells appeared macrophage‐like and surrounded CD28+ cells in lymphoid aggregates. The simultaneous presence and close localization of CD86+ and CD28+ cells in the RA synovial compartment suggests that their interaction potentially contributes to the sustained immune activation of RA.
Synovial tissue macrophage populations and articular damage in rheumatoid arthritis
Authors: Mulherin Diarmuid , Fitzgerald Oliver , Bresnihan Barry
Published: February 2007

Objective. To examine the relative contribution of individual synovial cell populations to polyarticular destruction in rheumatoid arthritis (RA).

Methods. Serial measurements of disease activity and articular destruction, obtained prospectively in 28 RA patients followed up for a mean of 5.8 years, were correlated with synovial cell populations quantified using immunohistochemical techniques.

Results. The mean radiologic score worsened (from 37 to 86; P = 0.0001) despite significant improvement in disease activity. Synovial lining layer cell depth and sublining layer macrophage, but not lymphocyte, cell counts correlated significantly with radiologic course. Detailed analysis of 11 patients demonstrated reduced synovial lining expression of CD14 compared with CD68 (P = 0.003), whereas sublining expression of CD14 and CD68 was equivalent.

Conclusion. Synovial macrophage numbers correlated with articular destruction in RA. In addition, the study results provided further evidence that lining layer macrophages may represent a distinct subpopulation that is of importance in this process. These findings have implications for the development of new therapies for RA.
The antiinflammatory and antiviral effects of hydroxychloroquine in two patients with acquired immunodeficiency syndrome and active inflammatory arthritis
Authors: Ornstein Matthew H. , Sperber Kirk
Published: February 2007

Objective. To report the antiinflammatory and antiviral effects of hydroxychloroquine (HCQ) treatment in 2 patients with AIDS and inflammatory arthritis.

Methods. Two patients with AIDS and inflammatory arthritis were treated with HCQ, which was given in a loading dose of 600 mg/day. The maintenance dosage was calculated to remain below 6.5 mg/kg/day. Both patients had initial T cell subset studies; 1 patient, had serum and plasma collected before and after 1 year of HCQ treatment. Assays were performed for T cell subsets, recoverable human immunodeficiency virus type 1 (HIV‐1) RNA, mitogen‐ and antigen‐specific proliferation, and interleukin‐6 (IL‐6) levels. New studies on the use of HCQ as an anti–HIV‐1 agent are reviewed.

Results. Both patients had a dramatic decrease in their arthritis activity. Neither patient required immunosuppressive therapy or developed an opportunistic infection. In the patient who was studied after 1 year of therapy, there was a 1‐log decrease in recoverable HIV‐1 RNA, improved mitogen‐ and antigen‐specific immune responses, and a large decrease in the IL‐6 level while taking HCQ. Recent in vitro and in vivo assays in patients with HIV infection have shown similar antiviral and antiinflammatory effects from HCQ.

Conclusion. HCQ may exert simultaneous antiinflammatory and antiviral effects in patients with HIV infection and inflammatory arthritis. If larger studies confirm this observation, it may be the drug of choice in this population of patients.
Inhibition of lymphocyte adhesion to cytokine‐activated synovial fibroblasts by glucocorticoids involves the attenuation of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 gene expression
Authors: Tessier Philippe A. , Cattaruzzi Paola , McColl Shaun R.
Published: February 2007

Objective. The aim of this study was to evaluate the ability of glucocorticoids to inhibit lymphocyte adhesion to human synovial fibroblasts.

Methods. Adhesion of lymphocytes to cultured synovial fibroblasts was measured by counting the number of cells bound to fibroblasts. Surface expression of intercellular adhesion molecule 1 (ICAM‐1) was measured by enzyme‐linked immunosorbent assay, while vascular cell adhesion molecule 1 (VCAM‐1) surface expression was measured by flow cytometry. ICAM‐1 and VCAM‐1 messenger RNA (mRNA) levels were assessed by Northern blot analysis.

Results. Stimulation of synovial fibroblasts by the proinflammatory cytokines tumor necrosis factor α, interleukin‐1β, and interferon‐γ resulted in a dose‐dependent increase in lymphocyte adhesion to synovial fibroblasts. This response was inhibited by preincubation of the cells with the synthetic glucocorticoid dexa‐methasone. Since lymphocyte adhesion to synovial fibroblasts is known to be mediated by VCAM‐1 and ICAM‐1, we examined the modulation of VCAM‐1 and ICAM‐1 expression in these cells. All 3 cytokines stimulated VCAM‐1 and ICAM‐1 surface and mRNA expression. Dexamethasone inhibited both VCAM‐1 and ICAM‐1 surface and mRNA expression in a dose‐dependent manner, which correlated with the inhibition of lymphocyte adhesion.

Conclusion. Taken together, these results suggest that glucocorticoids may reduce inflammatory responses at extravascular sites by inhibiting the expression of these adhesion molecules, thereby reducing the adhesion of lymphocytes to connective tissue cells.
The systemic effect of intraarticular administration of corticosteroid on markers of bone formation and bone resorption in patients with rheumatoid arthritis
Authors: Emkey Ronald D. , Lindsay Robert , Lyssy Jane , Weisberg Jerome S. , Dempster David W. , Shen Victor
Published: February 2007

Objective. To assess the effects of intraarticular (IA) corticosteroid use on bone metabolism in patients with rheumatoid arthritis (RA).

Methods. Levels of the bone turnover markers, serum osteocalcin (BGP) and urinary pyridinoline (PYD), were monitored in RA patients for 4 weeks following a single IA administration of xylocaine alone or in combination with triamcinolone acetonide.

Results. Levels of the bone resorption marker, PYD, did not show any significant change, whereas BGP levels were drastically decreased 1 day after IA administration of corticosteroid, and then returned to pretreatment levels by day 14. The efficacy of IA corticosteroid treatment lasted for 4 weeks.

Conclusion. Our results suggest that IA administration of corticosteroid has no net effects on bone resorption and only a transient systemic effect on bone formation. IA corticosteroid administration may be better for bone metabolism than continuous use of orally administered corticosteroid.
Evaluating systemic lupus erythematosus disease activity using molecular markers of hemostasis
Authors: Inoh Masayukiinoh , Tokuda Michiaki , Kiuchi Hiroyuki , Kurata Noriyuki , Takahara Jiro
Published: February 2007

Objective. To determine the usefulness of measuring sensitive markers of the coagulation–fibrinolysis system (i.e., thrombin–antithrombin III complex [TAT], D dimer fragments [DD], and plasmin–α2‐plasmin inhibitor complex [PIC]) for evaluating disease activity in patients with systemic lupus erythematosus (SLE).

Methods. We studied 57 SLE patients. Plasma concentrations of DD were measured by latex agglutination using monoclonal antibodies; TAT and PIC were determined by sandwich enzyme‐linked immunosorbent assay. Disease activity was determined by using the SLE Disease Activity Index (SLEDAI).

Results. Levels of TAT, DD, and PIC were higher in SLE patients than in healthy controls (P < 0.05). Levels of TAT and DD showed good correlations with SLEDAI scores (for TAT r = 0.66, P < 0.001; for DD r = 0.50, P < 0.001). Elevated levels of TAT, DD, and PIC were decreased following treatment.

Conclusion. These results strongly suggest that measurement of molecular markers of hemostasis is useful for evaluating disease activity in patients with SLE.
Interleukin‐10 inhibition of the progression of established collagen‐induced arthritis
Authors: Walmsley Marita , Katsikis Peter D. , Abney Erika , Parry Sarah , Williams Richard O. , Maini Ravinder N. , Feldmann Marc
Published: February 2007

Objective. Interleukin‐10 (IL‐10) is a potent inhibitor of the proinflammatory cytokines, including tumor necrosis factor α and IL‐1, which are considered important in the pathogenesis of rheumatoid arthritis (RA). The study was undertaken to establish whether IL‐10 can ameliorate arthritis in the collagen‐induced arthritis (CIA) model of RA.

Methods. DBA/1 mice were immunized with bovine type II collagen in adjuvant, and treated daily after disease onset with recombinant murine IL‐10 or with saline as a control. Mice were monitored for paw swelling and clinical score. Histologic analysis was also performed.

Results. IL‐10 treatment of established CIA inhibited paw swelling (P < 0.0001), as well as disease progression as defined by clinical score (P < 0.0002). Cartilage destruction, as assessed histologically, was reduced in IL‐10–treated mice compared with controls (P < 0.01).

Conclusion. IL‐10 suppresses established CIA, probably by inhibiting proinflammatory cytokine production. Our results, taken together with previously reported findings, indicate a potential therapeutic role for IL‐10 in RA.
Epstein‐Barr virus clonality in lymphomas occurring in patients with rheumatoid arthritis
Authors: van de Rijn Matthijs , Cleary Michael L. , Variakojis Daina , Warnke Roger A. , Chang Pearl P. , Kamel Onsi W.
Published: February 2007

Objective. A causative role for Epstein‐Barr virus (EBV) in the development of lymphoma in patients with rheumatoid arthritis (RA) has been proposed. We investigated the molecular features of EBV‐positive diffuse large cell lymphomas in 2 patients with RA.

Methods. Southern blot analysis for immunoglobulin gene rearrangements, terminal repeat analysis for clonality of the EBV genome, and double‐labeling of the lymphoma cells by in situ hybridization and immuno‐peroxidase staining were performed.

Results. In both cases, double‐labeling studies localized the EBV genome to the malignant B cells. Both neoplasms contained clonal immunoglobulin gene rearrangements and clonal EBV genomes.

Conclusion. Our data indicate that EBV infection was an early step in the development of these neoplasms. The findings further extend knowledge on the similarity of this subset of lymphomas to posttransplantation lymphomas and emphasize the role of immunosuppression in their genesis.
Enhancement of anti‐DNA topoisomerase I autoantibody response after lung cancer in patients with systemic sclerosis: A report of two cases
Authors: Kuwana Masataka , Fujii Takao , Mimori Tsuneyo , Kaburaki Junichi
Published: February 2007

Anti‐DNA topoisomerase I (anti–topo I) antibody profiles were compared before and after lung cancer in 2 patients with systemic sclerosis (SSc). Both patients developed adenocarcinoma of the lung late in the course of SSc and died of the cancer. Anti–topo I antibody levels, determined by double immunodiffusion and enzyme‐linked immunosorbent assay, increased markedly at the time of diagnosis of lung cancer. Furthermore, patients' sera obtained after lung cancer reacted with multiple epitopes on the entire topo I molecule, some of which had not previously been recognized. These results further support the concept that anti–topo I antibody production in SSc patients is due to an antigen‐driven process.
Cigarette smoking increases the risk of rheumatoid arthritis: Results from a nationwide study of disease‐discordant twins
Authors: Silman Alan J. , Newman Jason , Macgregor Alexander J.
Published: February 2007

Objective. To test the hypothesis that cigarette smoking is associated with susceptibility to rheumatoid arthritis (RA) by comparing smoking history between twins with RA and their unaffected co‐twins.

Methods. Interview questionnaires on smoking history were administered to 79 identical (monozygotic [MZ]) and 71 same‐sex nonidentical (dizygotic, [DZ]) twin pairs who were discordant for RA, recruited from the Arthritis and Rheumatism Council Twin Study. Results were expressed as odds ratios (OR) with 95% confidence intervals (95% CI).

Results. Although most twin pairs were concordant for smoking history, there was a strong association between ever smoking and RA in the MZ pairs (OR 12.0, 95% CI 1.78–513), with a similar trend observed in the DZ pairs (OR 2.5, 95% CI 0.92–7.87).

Conclusion. The discordance in cigarette smoking history for individuals who are at presumed identical genetic risk for RA supports other data suggesting the role of smoking in disease susceptibility.
Direct gene delivery to synovium: An evaluation of potential vectors in vitro and in vivo
Authors: Nita I. , Ghivizzani S. C. , Galea‐Lauri J. , Bandara G. , Georgescu H. I. , Robbins P. D. , Evans C. H.
Published: February 2007

Objective. To assess the abilities of various vectors to transfer genes to the synovial lining of joints.

Methods. Vectors derived from retrovirus, adenovirus, and herpes simplex virus as well as cationic liposomes and naked plasmid DNA were evaluated. Each construct contained the lac Z marker gene; and one retroviral construct, and one plasmid also contained a gene encoding human interleukin‐1 receptor antagonist. Gene expression was under the control of the human cytomegalovirus promoter in all vectors except the retrovirus, where the endogenous 5′ long terminal repeat was retained as the promoter. Cultures of rabbit synovial fibroblasts were exposed to these vectors and stained with X‐gal to identify lac Z+ cells. Vectors were then injected directly into rabbits' knee joints, and gene transfer and expression were assessed by X‐gal staining and polymerase chain reaction (PCR).

Results. Adenovirus was a highly effective vector both in vitro and in vivo, with lac Z gene expression persisting for at least 28 days. However, an inflammatory response was noted in vivo. Cells infected in vitro and in vivo with herpes simplex virus also expressed the lac Z gene at high levels, but expression was limited by cytotoxicity. Retroviruses, in contrast, were effective only under in vitro conditions, permitting cell division. Liposomes gave variable in vitro results; when injected into joints in vivo, gene expression was low and was detectable for only a few days, even though a PCR signal persisted for at least 28 days. Unexpectedly, plasmid DNA was captured by the synoviocytes and expressed transiently following intraarticular injection.

Conclusion. None of the vectors was ideal for in vivo gene delivery to synovium, although adenovirus was clearly the most effective of those tested. Retroviruses, although poor vectors for in vivo gene delivery, are well suited for ex vivo gene transfer to the synovial lining of joints.
Enrichment of differentiated CD45RBdim, CD27 – memory T cells in the peripheral blood, synovial fluid, and synovial tissue of patients with rheumatoid arthritis
Authors: Kohem Charles L. , Brezinschek Ruth I. , Wisbey Heather , Tortorella Cosimo , Lipsky Peter E. , Oppenheimer‐Marks Nancy
Published: February 2007

Objective. To delineate in greater detail the phenotype of T cells that reside in the synovial tissue (ST) and synovial fluid (SF) of patients with rheumatoid arthritis (RA), in order to determine their precise differentiation status, and to determine whether the accumulation of these specific T cell subsets in these synovial compartments could be related to their capacity for transendothelial migration.

Methods. Lymphocytes from normal subjects or from the peripheral blood (PB), ST, and/or SF of RA patients were phenotypically analyzed by flow cytometry. Normal PB CD4+ T cells were also characterized using an in vitro assay of transendothelial migration.

Results. ST and SF were found to be enriched with memory (CD45RA‐, CD45RO+, CD11abright, CD44bright) and activated (CD69+) T cells. Moreover, ST and SF cells from RA patients were enriched in differentiated CD4+, CD45RBdim, CD27‐ T cells, a subset of mature memory T cells that develops after prolonged antigenic stimulation. In addition, PB of some RA patients contained an increased number of CD4+, CD45RBdim, CD27‐ T cells. The CD4+, CD11abright, CD44bright memory T cells, which included the CD45RBdim, CD27‐ more mature memory cells, exhibited an enhanced capacity for transendothelial migration that is likely to contribute to their enrichment in the rheumatoid synovium.

Conclusion. RA patients manifest an increased number of mature memory T cells in the SF and ST, and some also have an increased number of these cells in PB that is likely to reflect chronic antigenic stimulation. The enrichment of these cells in the SF and ST reflects, in part, an enhanced capacity to migrate from the vascular space into inflamed tissue.
A comparative study of HLA genes in HLA–B27 positive ankylosing spondylitis and HLA–B27 positive peripheral reactive arthritis
Authors: Westman Pia , Leirisalo‐Repo Marjatta , Partanen Jukka , Koskimies Saija
Published: February 2007

Objective. To determine whether HLA–B27 positive patients with ankylosing spondylitis (AS) and reactive arthritis (ReA) share additional HLA factors that confer disease susceptibility.

Methods. HLA class I antigens were typed serologically, and class II antigens molecularly, in samples taken from 33 patients with AS, 30 patients with ReA, and 55 healthy HLA–B27 positive controls.

Results. There was no major difference between the HLA alleles in AS and ReA patients, but deviations were observed when compared with healthy controls, especially between the antigens that were probably encoded by genes in the non‐B27 chromosome.

Conclusion. These results suggest that both HLA class I and class II genes may influence the pathogenesis of HLA–B27 positive ReA, whereas class I antigens seem to be the major additional genetic factors in HLA–B27 positive AS.
Why health care costs more in the US: Comparing health care expenditures between systemic lupus erythematosus patients in Stanford and Montreal
Authors: Gironimi Gail , Clarke Ann E. , Hamilton Vivian H. , Danoff Deborah S. , Bloch Daniel A. , Fries James F. , Esdaile John M.
Published: February 2007

Objective. Recent studies to identify the causes of higher health care expenditure in the US versus Canada have relied on population‐based measures of health care utilization and have restricted their analysis to one sector, such as physician or hospital expenditures. We present a detailed comparative analysis of the direct costs (health services utilized) of treating systemic lupus erythematosus (SLE) patients in Stanford, CA and Montreal, Quebec.

Methods. Using the self‐report Stanford Health Assessment Questionnaire, we assessed 6‐month direct costs incurred by 174 American and 164 Canadian SLE patients. We explored 3 potential reasons for the differential expenditure. These were 1) higher prices for health care inputs, 2) more severe disease in the patient case mix, and 3) greater resource utilization.

Results. The direct health care costs for the American SLE patients exceeded those for the Canadian patients by almost 2‐fold ($10,530 versus $5,271, expressed in 1991 US dollars). The higher direct costs were explained by the higher price of health services in the US and the more severe disease mix. In fact, for all health resource categories studied, Canadians utilized at least as many services as their American counterparts. Canadians had longer hospital stays, made more emergency room visits, and used more medications.

Conclusion. Despite significantly greater per capita health care expenditure in the US, our data show that Canadian SLE patients actually receive more medical services.
N‐[4‐hydroxyphenyl] retinamide in rheumatoid arthritis: A pilot study
Authors: Gravallese Ellen M. , Handel Malcolm L. , Coblyn Jonathan , Anderson Ronald J. , Sperling Richard I. , Karlson Elizabeth W. , Maier Agnes , Ruderman Eric M. , Formel Franca , Weinblatt Michael E.
Published: February 2007

Objective. To evaluate the efficacy and tolerability of N‐[4 hydroxyphenyl] retinamide (4‐HPR), a synthetic retinoid, in the treatment of rheumatoid arthritis (RA).

Methods. An uncontrolled, open clinical trial with synovial biopsy pre‐ and postmedication to evaluate the clinical effects of 4‐HPR as well as its effects on metalloproteinase gene expression.

Results. Twelve patients with severe, longstanding RA were enrolled in this study. Six patients withdrew before study completion, 2 because of drug toxicity, 2 because of a flare of RA, and 2 because of intercurrent medical problems. No patient met predetermined Paulus criteria for treatment response, and there was no improvement in the laboratory parameters, except for a modest decrease in C‐reactive protein. No decrease in messenger RNA for the metalloproteinases collagenase and stromelysin was seen in the 2 patients in whom paired synovial biopsies were obtained.

Conclusion. No beneficial clinical effect was observed with the retinoid 4‐HPR in the treatment of severe, longstanding RA at the 300 mg/day dosage studied. The use of higher dosages is precluded by the observed toxicities. The effect of this drug in patients with early or mild disease was not studied. Although this particular retinoid was not effective in this pilot study, the use of other retinoids in RA should still be considered.
Human synovial mast cells. I. Ultrastructural in situ and in vitro immunologic characterization
Authors: De Paulis Amato , Marinò Isabella , Ciccarelli Anna , De Crescenzo Gennaro , Concardi Monica , Verga Laura , Arbustini Eloisa , Marone Gianni
Published: February 2007

Objective. To examine the ultrastructure of human synovial mast cells in situ, to identify immunologic and nonimmunologic stimuli that activate these cells in vitro, and to quantify a number of preformed and de novo–synthesized mediators.

Methods. We conducted an ultrastructural study of synovial mast cells in situ and performed immunoelectron microscopy localization of tryptase and chymase. Isolated synovial mast cells were analyzed biochemically, immunologically, and functionally in vitro and compared with cells from human lung, heart, and skin.

Results. Ultrastructural study of synovial tissue revealed mast cells with homogeneously dense, scrolled, crystal, and mixed granules, and lipid bodies in the cytoplasm. A small percentage of mast cells showed evidence of degranulation. Immunoelectron microscopy demonstrated the subcellular localization of tryptase and chymase over granules of >90% of the mast cells, which were of the MCTC subtype. Isolated synovial mast cells released histamine in response to immunologic (anti‐IgE and anti‐Fcε receptor I [anti‐FcεRI]) and nonimmunologic (substance P, recombinant human stem cell factor, and 48/80) stimuli, but did not respond to recombinant human C5a in vitro. Synovial mast cells differed from those isolated from other human tissues, in a variety of immunologic and biochemical features. There was a linear correlation between the percentage of histamine secretion and tryptase release (r = 0.79, P < 0.001) induced by cross‐linking of FcεRI. Cross‐linking of IgE with anti‐IgE on synovial mast cells induced de novo synthesis of prostaglandin D2 (mean ± SEM 87.5 ± 4.9 ng/106 cells) and of leukotriene C4 (57.6 ± 17.8 ng/106 cells).

Conclusion. Mast cells ultrastructurally characterized in situ in synovial tissue were seen to differ from mast cells previously isolated from other human tissues. This raises the possibility that the local microenviroment influences their phenotype. Isolation of mast cells from human synovia can be useful for studying their role and their mediatrors in patients with arthritis.
Expression and function of CD80 and CD86 costimulator molecules on synovial dendritic cells in chronic arthritis
Authors: Summers Kelly L. , O'Donnell John L. , Williams Lisa A. , Hart Derek N. J.
Published: February 2007

Objective. To examine CD86 expression on dendritic cells isolated from the synovial fluid (SFDC) of patients with chronic arthritis, and to determine the importance of both CD80 and CD86 molecules in SFDC‐T lymphocyte interactions.

Methods. CD86 messenger RNA (mRNA) and surface expression were analyzed in SFDC using reverse transcriptase‐polymerase chain reaction and flow cytometry, respectively. The costimulator activity of the SFDC CD80 and CD86 molecules was determined by allogeneic mixed lymphocyte reaction (MLR). CD80 and CD86 induction on SFDC during in vitro culture was also examined.

Results. Fresh SFDC either lacked or showed very weak surface expression of CD86 molecules (as shown previously for CD80), yet contained CD86 mRNA. CD80 antibodies minimally inhibited an allogeneic MLR, whereas CD86 antibodies and CTLA‐4 Ig showed significant inhibition. Both CD80 and CD86 molecules were inconsistently induced on SFDC following culture in either media, interferon‐γ, or granulocyte‐macrophage colony‐stimulating factor.

Conclusion. SFDC may be defective antigen‐presenting cells in vivo. The ability of CD80 and CD86 molecules to be induced and become functional on SFDC in vitro implies the presence of a negative regulatory compound(s) in the synovial environment.
The effects of the phospholipase a2 inhibitor, manoalide, on cartilage degradation, stromelysin expression, and synovial fluid cell count induced by intraarticular injection of human recombinant interleukin‐1α in the rabbit
Authors: Schrier Denis J. , Flory Craig M. , Finkel Martin , Kuchera Susan L. , Lesch Mark E. , Jacobson Peer B.
Published: February 2007

Objective. To evaluate the effects of the phospho‐lipase A2 (PLA2) inhibitor manoalide on cartilage degradation, stromelysin expression, and inflammatory cell accumulation in rabbits treated intraarticularly with recombinant human interleukin‐1α (rHuIL‐1α).

Methods. Rabbits were given an intraarticular injection of rHuIL‐1α. At various time points over a 24‐hour period, the rabbits were euthanized and the articular space was lavaged with sterile PBS. The proteoglycan content of the lavage fluid was measured using a dimethylmethylene blue assay. PLA2 activity and differential cell counts were also measured. The femur was removed and cartilage proteoglycan content determined. In some experiments, levels of synovial stromelysin messenger RNA (mRNA) were assessed. Manoalide or vehicle was administered 30 minutes before the rHuIL‐1α injection.

Results. The rHuIL‐1α‐induced arthritic response is characterized by significant accumulation of inflammatory cells, loss of proteoglycan from the condylar cartilage, and induction of mRNA for stromelysin. PLA2 activity was also elevated in synovial fluids from rHuIL‐1α‐injected joints. Pretreatment with manoalide (0.3 mg/joint) significantly inhibited PLA2 activity in the synovial fluid, prevented the loss of proteoglycan from the condylar cartilage, and reduced proteoglycan levels in lavage fluids. However, manoalide either had no effect on, or stimulated, cell accumulation. To assess the relationship between the induction of PLA2 and stromelysin, levels of stromelysin mRNA were measured in synovial tissue from manoalide‐ and vehicle‐treated joints. Stromelysin message levels were significantly suppressed in a dose‐dependent manner.

Conclusion. These studies demonstrate that manoalide is a potent inhibitor of inflammation and cartilage catabolism, and suggest that PLA2 is involved in the pathophysiology of rHuIL‐1α‐induced arthritis in rabbits.
Variation in the inflammatory properties of basic calcium phosphate crystals according to crystal type
Authors: Prudhommeaux Florence , Schiltz Corinne , Lioté Frédéric , Hina Ali , Champy Romuald , Bucki Barbara , Ortiz‐Bravo Esteban , Meunier Alain , Rey Christian , Bardin Thomas
Published: February 2007

Objective. To determine the inflammatory potential of basic calcium phosphate (BCP) crystals, which have been identified in human joints.

Methods. Hydroxyapatite, carbonate apatite, whitlockite, and octacalcium phosphate crystals were injected in rat air pouches. Volume and cellularity of the exudate were measured. Physicochemical properties of the injected BCP crystals were determined, and correlations with the magnitude of induced inflammatory responses were sought.

Results. Significant differences were observed among the volumes and white blood cell (WBC) counts of the pouch exudates, based on the various crystal types used to induce inflammation. A strong correlation was demonstrated between the specific surface (SS) area of the injected crystals and the area under the curve for induced WBC count versus time (R2 = 0.88, P = 0.05). This correlation was observed for SS area values below 50 m2/gm, but when SS area increased further, this parameter plateaued. Another parameter of inflammatory response was obtained by dividing the area under the curve figuring WBC counts versus time by the corresponding SS area for each crystal type. This parameter increased linearly with the Ca:P ratio (R2 = 0.97, P = 0.0003).

Conclusion. The inflammatory potential of BCP crystals appeared to vary according to crystal features. SS area and the Ca:P ratio (which correlates with crystal solubility) influenced inflammatory properties. These results could explain the variable clinical consequences of BCP deposits, and must be taken into account in the choice of apatite ceramics for use as biomaterials.
Risk factors for serious infection during treatment with cyclophosphamide and high‐dose corticosteroids for systemic lupus erythematosus
Authors: Pryor Betty D. , Bologna Saba G. , Kahl Leslie E.
Published: February 2007

Objective. To determine risk factors for serious infection during treatment with cyclophosphamide (CYC) and high‐dose corticosteroids in systemic lupus erythematosus (SLE).

Methods. Records of 100 SLE patients who had received CYC were examined for documentation of serious infections that occurred during CYC therapy and the subsequent 3 months.

Results. Infection occurred in 45 of 100 patients during CYC therapy. Patients with infection were more likely to have multiple organ disease (49% versus 29%; P = 0.04), a lower nadir in the white blood cell (WBC) count (2,818 versus 3,558 cells/μl; P = 0.02), and a higher maximum corticosteroid dose (195 versus 73 mg; P ≤ 0.01) than patients without infection. Infection occurred with equal prevalence in those who received intravenous (IV) (39%) or oral (40%) CYC, but was more common with use of sequential IV and oral therapy (68%). By multivariate analysis, the strongest association with infection was a WBC nadir ≤3,000 cells/μl (odds ratio [OR] 2.8, 95% confidence interval [95% CI] 1.4–5.5) and use of sequential IV and oral CYC (OR 2.3, 95% CI 1.2–4.3). Infection occurred in more CYC‐treated patients taking concomitant steroids than in those treated with high‐dose steroids alone (45% versus 12%; P = 0.001). Fatal and opportunistic infections during CYC therapy were associated with a low WBC nadir and a high maximum corticosteroid dose.

Conclusion. The risk of serious infection in patients with SLE is influenced by the inclusion of CYC in the treatment regimen. The likelihood of infection in this setting is enhanced by CYC‐induced reductions in the total WBC count <3,000 cells/μl and by sequential IV and oral therapy. Both of these factors may be indicators of aggressive cytotoxic treatment, underscoring the need for close observation during treatment to minimize the risk of serious infection.
Association of anti–ribosomal P protein antibodies with neuropsychiatric systemic lupus erythematosus
Authors: Isshi Kunio , Hirohata Shunsei
Published: February 2007

Objective. Although it has been reported that anti–ribosomal P protein antibodies (anti‐P) are highly specific for lupus psychosis, there have been discrepancies among the studies regarding the clinical correlation of these antibodies with systemic lupus erythematosus (SLE). The present study was therefore carried out to reappraise the association of anti‐P and neuropsychiatric SLE.

Methods. Highly purified synthetic ribosomal P peptides of the carboxyl‐terminal 22‐amino acid sequence were conjugated to human serum albumin (HSA) with the use of glutaraldehyde. Anti‐P in sera from 75 patients with SLE (26 without central nervous system disease [non‐CNS], 28 with lupus psychosis, and 21 with nonpsychotic CNS involvement [nonpsychotic CNS lupus]) were analyzed with an enzyme‐linked immunosorbent assay (ELISA), using HSA–ribosomal P peptide conjugates as antigens. Anti‐P levels were quantitated by subtracting the nonspecific binding activities to HSA.

Results. The ELISA was found to be specific for anti‐P, as determined by comparison with the results of Western blotting using extracts of HEp‐2 cells. Serum anti‐P levels were significantly elevated in patients with lupus psychosis, including organic brain syndrome and nonorganic psychosis, compared with those with non‐CNS SLE or those with nonpsychotic CNS lupus. There were no significant differences in serum anti‐P levels between patients with organic brain syndrome and those with nonorganic psychosis. Anti–P antibodies were not detected in the cerebrospinal fluid of patients with either lupus psychosis or nonpsychotic CNS lupus.

Conclusion. Our results, obtained from the highly specific ELISA using HSA–ribosomal P peptide conjugates, confirm the correlation of serum anti‐P with lupus psychosis. The data also suggest that differences in the purity of the ribosomal P peptides used might be a major reason for the conflicting results in the literature regarding the association of anti‐P with lupus psychosis.
Phagocytic lining cells determine local expression of inflammation in type II collagen–induced arthritis
Authors: van Lent P. L. E. M. , Holthuysen A. E. M. , van den Bersselaar L. A. M. , van Rooijen N. , Joosten L. A. B. , van de Loo F. A. J. , van de Putte L. B. A. , van den Berg W. B.
Published: February 2007

Objective. To investigate the in vivo role of phagocytic synovial lining cells in the local expression of inflammation in type II collagen–induced arthritis (CIA) in DBA/1J mice.

Methods. On various days before arthritis induction (day 7, 5, or 2), phagocytic lining cells were selectively depleted from the synovial layer by injecting multilamellar liposomes containing clodronate (dichloromethylene diphosphonate) directly into the knee joints. As controls, either PBS or PBS‐laden liposomes were injected. CIA was induced by immunizing mice with heterologous bovine type II collagen in Freund's complete adjuvant. Arthritis onset was synchronized by a single intraperitoneal injection of lipopolysaccharide; arthritis was evaluated in hematoxylin and eosin–stained knee joint sections. Chemotactic activity in synovial washout samples was detected in a Transwell chemotactic assay. Interleukin‐1 (IL‐1) and tumor necrosis factor α (TNFα) protein levels were measured in NOB‐1 and L929 bioassays, respectively. IL‐1 messenger RNA (mRNA) in synovial specimens was measured by reverse transcriptase–polymerase chain reaction. IL‐1 was also detected immunohistologically in knee joint sections.

Results. In clodronate‐laden liposome–treated, lining‐depleted knee joints, there was significantly decreased inflammation compared with controls. Cell influx into the synovium was markedly decreased. Expression of IL‐1 mRNA in the synovium was significantly reduced. IL‐1 was detected only in some cells in the deeper synovial layer, in contrast to controls, in which large numbers of cells in the deeper synovial layer were stained. In synovial washouts from lining‐depleted knee joints, biologically active IL‐1 levels were reduced by 40% at 6 hours after arthritis induction. Most strikingly, chemotactic activity was highly decreased in these synovial washout samples. When IL‐1 or TNFα was injected into the knee joints of immunized mice in which arthritis was not yet expressed, arthritis was not induced in the lining‐depleted joints, whereas marked cell influx was found in control joints.

Conclusion. Our data indicate that phagocytic lining cells play a crucial role in the local expression of inflammation in systemically induced CIA. Phagocytic lining cells probably form an important source of chemotactic factors which are set free upon activation by IL‐1 or TNFα.
Nitric oxide production during adjuvant‐induced and collagen‐induced arthritis
Authors: Cannon Grant W. , Openshaw Scott J. , Hibbs John B. , Hoidal John R. , Huecksteadt Thomas P. , Griffiths Marie M.
Published: February 2007

Objective. To investigate the role of nitric oxide (NO) production and NO synthase (NOS) induction during adjuvant‐induced arthritis (AIA) and collagen‐induced arthritis (CIA) in Dark Agouti rats.

Methods. Urinary nitrate excretion and immune NOS (iNOS) messenger RNA (mRNA) expression were measured in the joint, lymph node, spleen, and liver tissues following the induction of either AIA or CIA.

Results. Urinary nitrate excretion and iNOS mRNA expression increased substantially during joint inflammation in both models of arthritis. However, the increases in urinary nitrate excretion and iNOS mRNA expression observed in the joint, liver, and spleen tissues during AIA were greater than those observed during CIA, although iNOS induction in the lymph nodes was similar for both models. A prior injection with Mycobacterium bovis heat‐shock protein resulted in suppression of arthritis and NO production in AIA, but not in CIA.

Conclusion. Differences in NO production during AIA versus CIA are a reflection of the fundamental pathophysiologic differences between these 2 models of arthritis. Thus, NO production in these 2 models could not be merely a nonspecific reaction to the adjuvant injection, nor simply a byproduct of local inflammation in the joint.