bluuebunny/crossref_metadata_2025 huggingface dataset:
Emergence of oligoclonal t cell populations following therapeutic t cell depletion in rheumatoid arthritis
Authors: Jendro Michael C. , Ganten Tom , Matteson Eric L. , Weyand Cornelia M. , Goronzy JÖRg J.
Published: February 2007

Objective. To examine the compartment of CD4+ T cells in patients with rheumatoid arthritis (RA) who have developed persistent lymphopenia following antibody‐mediated T cell depletion and to investigate why T cell depletion is of limited therapeutic efficacy.

Methods. Circulating T lymphocytes from 10 patients with seropositive RA treated with the monoclonal antibody (MAb) CAMPATH‐1H were longitudinally monitored by fluorescence‐activated cell sorter analysis with MAb. To assess the molecular diversity of repopulating T cells, random samples of T cell clones from the peripheral blood of 3 patients were analyzed by sequencing the T cell receptor (TCR) β chains. At the time of recurring disease, the synovial tissue was examined by immunohistochemistry, and the repertoires of peripheral and synovial tissue T cells were compared by TCR β‐chain sequencing and by semiquantitative hybridization with oligonucleotides specific for the V–D–Jβ junctional region of selected clones.

Results. The reconstitution of the peripheral T cell compartment was very slow. A mean CD4+ T cell count of 105/μl was reached 34 weeks following MAb treatment. After treatment, the percentage of CD4+ T cells with the CD45RO+ phenotype was significantly increased (P = 0.001), indicating the expansion of antigen‐primed memory T cells. TCR β‐chain sequences revealed a marked restriction in the diversity of repopulating T cells with the emergence of dominant clonotypes. Despite the low counts of peripheral CD4+ T cells, the synovial tissue was infiltrated by CD4+ T cells to a similar extent as that in RA patients not treated with MAb. Selected clonotypes that had emerged in the peripheral blood compartment dominated the repertoire of tissue‐infiltrating T cells in the synovium.

Conclusion. In patients with RA, T cell depletion induces a long‐term imbalance in T cell homeostasis. Clonal proliferation of CD4+ T cells severely restricts the diversity of available T cell specificities and results in the emergence of dominant clonotypes, which accumulate in the synovial tissue despite peripheral lymphopenia.
Hematologic and cytofluorographic analysis of patients with feltyapos;s syndrome a hypothesis that a discrete event leads to large granular lymphocyte expansions in this condition
Authors: Bowman S. J. , Corrigall V. , Panayi G. S. , Lanchbury J. S.
Published: February 2007

Objective. To compare hematologic and cyto‐fluorographic features in Feltyapos;s syndrome (FS) patients with and without the large granular lymphocyte (LGL) syndrome.

Methods. Peripheral blood cells from FS patients and from 2 control groups (rheumatoid arthritis [RA] patients and subjects without symptoms of a rheumatic disease) were analyzed by hematologic and cytofluorographic techniques. A separate assessment of disease activity was performed.

Results. FS patients had reduced lymphocyte and platelet counts, with a parallel reduction in lymphocyte subsets examined. CD4 counts were reduced in all FS patients, including those with the LGL syndrome. Disease activity was lower in FS patients than in RA control patients. Treatment was similar in all patient groups. No direct association was seen between LGL numbers and duration of RA or neutrophil counts in RA groups.

Conclusion. Hematologic abnormalities in FS extend beyond neutropenia. Although similarities were seen between FS patients and FS patients with the LGL syndrome (e.g., CD4 lymphopenia), evidence for a gradation from FS to the LGL syndrome was not seen, thus favoring the hypothesis that a “transforming event” is required.
Heterogeneity in the expression of ro and la antigens in human skin
Authors: Niimi Yayoi , Ioannides Demetris , Buyon Jill , Bystryn Jean‐Claude
Published: February 2007

Objective. To determine whether there are variations in the expression of Ro and La antigens in human skin.

Methods. Levels of expression of Ro and/or La antigens in 26 specimens of normal human skin (11 sun‐exposed, 15 sun‐protected) were measured by indirect immunofluorescence with monospecific antisera.

Results. Levels of expression of both antigens varied by more than 2,000‐fold in the skin of different individuals. There usually was a correlation between the levels of expression of Ro and La antigens in the same skin specimen. There was no correlation found between the levels of Ro or La antigen expression and sun exposure, nor was there a correlation found between levels of antigen expression and location of the skin on the body.

Conclusion. There is a marked heterogeneity in the expression of both Ro and La antigens in the skin of different individuals. The present study findings suggest that the levels of expression of these antigens may play a role in the propensity of some individuals to develop anti‐Ro or anti‐La antibodies and/or skin lesions associated with the presence of these antibodies.
Effects of tenidap on canine experimental osteoarthritis i. morphologic and metalloprotease analysis
Authors: Fernandes Julio C. , Martel‐Pelletier Johanne , Otterness Ivan G. , Lopez‐Anaya Arturo , Mineau François , Tardif Ginette , Pelletier Jean‐Pierre
Published: February 2007

Objective. To examine the effects of tenidap and diclofenac on osteoarthritic lesions and metalloprotease activity in experimental osteoarthritis (OA).

Methods. The anterior cruciate ligament of the right stifle joint of 25 mongrel dogs was sectioned by a stab wound. Seven dogs received no treatment, 6 were treated with oral omeprazole (20 mg/day), another 6 were treated with diclofenac (0.25 mg/kg/twice daily) plus omeprazole (20 mg/day), and 6 received oral tenidap (3 mg/kg/twice daily) plus omeprazole (20 mg/day). The dogs received medication for 8 weeks; all dogs were killed at the end of this period. Eight normal dogs were used as controls. Lesions were evaluated macroscopically for the incidence and size of osteophytes and the area and grade of cartilage erosions on the condyles and plateaus, along with histologic evaluation of the severity of the cartilage lesions and synovial inflammation. Stromelysin and collagenase activities and the collagenase messenger RNA (mRNA) level were measured in cartilage and synovial membrane.

Results. Compared with the untreated or omeprazole‐treated OA groups, the dogs treated with tenidap exhibited significant reduction in the incidence (P < 0.001) and size (P < 0.0001) of osteophytes. Tenidap also significantly decreased the size and grade of cartilage macroscopic lesions, as well as the histologic severity of cartilage lesions on both condyles and plateaus. The histologic severity of synovial inflammatory reaction was also significantly reduced (P < 0.003) in the tenidap group. Tenidap markedly decreased stromelysin and collagenase activity in both cartilage (stromelysin P < 0.003; collagenase P < 0.01) and synovial membrane (stromelysin P < 0.003; collagenase P < 0.005). Moreover, tenidap also decreased the collagenase mRNA level in cartilage (P < 0.005) and synovial membrane (P < 0.002). Diclofenac slightly reduced the incidence and size of osteophytes and cartilage lesions, but these changes were not statistically significant. Diclofenac had no effect on the severity of synovial inflammation, metalloprotease activity, or collagenase expression.

Conclusion. This study showed that tenidap had a more potent anti‐osteoarthritic effect than diclofenac in this model. The effect of the drug in suppressing metalloprotease synthesis, a process known to play a major role in the pathophysiology of osteoarthritic lesions, may explain its mechanism of action.
Signal transduction through chondrocyte integrin receptors induces matrix metalloproteinase synthesis and synergizes with interleukin‐1
Authors: Arner E. C. , Tortorella M. D.
Published: February 2007

Objective. To study the role of signal transduction via integrin receptors in the production of metalloproteinase by rabbit articular chondrocytes.

Methods. Confluent, primary rabbit articular chondrocytes (RAC) were incubated for 72 hours in the presence of interleukin‐1 (IL‐1), Arg‐Gly‐Asp (RGD) peptide, or a combination of IL‐1 and RGD peptide. Media were analyzed for stromelysin enzymatic activity using a 3H‐labeled transferrin substrate, and for stromelysin and collagenase protein by Western analysis. Gelatinase activity was analyzed by gelatin zymography. IL‐1 receptor antagonist (IL‐1Ra) protein was used to determine the involvement of IL‐1 in mediating the effects of RGD peptide, and fluorescence‐activated cell sorter analysis (FACS) was used to examine the effect of IL‐1 on chondrocyte integrin subunit expression.

Results. RGD peptides induced chondrocyte synthesis of stromelysin, collagenase, and 92‐kd gelatinase B, and increased synthesis of the constitutively expressed 72‐kd gelatinase A. Further studies focusing on stromelysin demonstrated that this up‐regulation was concentration dependent and that RGD peptides synergized with IL‐1 in inducing stromelysin synthesis. RGD‐induced stromelysin production was inhibited by the IL‐1Ra in a concentration‐dependent manner, indicating that induction by RGD requires binding of IL‐1 to its receptor. FACS analysis of RAC showed that IL‐1 stimulation increased the expression of β1 and αv integrin subunits on the chondrocyte surface.

Conclusion. Our data demonstrate that signal transduction through chondrocyte integrin receptors up‐regulates metalloproteinase expression and that this is likely mediated through induction of IL‐1. They also suggest that the binding of adhesion molecules to their chondrocyte integrin receptors reduces the amount of IL‐1 required to induce stromelysin synthesis. Up‐regulation of chondrocyte integrin expression by IL‐1 may play a role in the synergistic effects seen with a combination of IL‐1 and RGD peptides. Since elevated levels of both IL‐1 and adhesion molecules are present in rheumatoid arthritis and osteoarthritis synovial fluid, our data suggest that this interaction may be important in mediating the cartilage destruction accompanying these diseases.
Tuberculous and foreign‐body granulomatous reactions involving a total knee prosthesis
Authors: Lusk Rodney H. , Wienke Eugene C. , Milligan Thomas W. , Albus Thomas E.
Published: February 2007

This case report describes loosening of a right knee prosthesis and represents the first report of the simultaneous occurrence of 2 granulomatous processes involving a prosthetic joint. Microscopic examination of the tissue revealed areas of foreign‐body granulomas and areas of necrotizing granulomas and caseation. Acid‐fast bacilli cultures were positive for Mycobacterium tuberculosis. The pathophysiology of implant loosening following an inflammatory reaction to components of prosthetic materials is discussed. Also discussed is the occurrence of infectious complications and rarity of tuberculous infections associated with prosthetic implants.
Glomerulonephritis associated with complete deficiency of the fourth component of complement response to intravenous immunoglobulin
Authors: Welch Thomas R. , McAdams A. James , Beischel Linda S.
Published: February 2007

A 15‐year‐old girl with complete C4 deficiency and a lupus‐like disorder developed evidence of nephritis after 4 years of followup. Renal biopsy demonstrated an immune complex glomerulonephritis, with deposits in the capillary loops, the paramesangium, and the mesangial matrix. Renal function was normal. The patient was treated with monthly infusions of intravenous immunoglobulin for 6 months. The treatment was well tolerated, and resulted in resolution of the rash and hematuria. Followup biopsy showed less proliferation and fewer loop deposits. In light of the serious risk of infections that is associated with complement deficiency, approaches to glomerulonephritis that do not include immunosuppression should be considered.
Hydatid disease an unusual cause of chronic monarthritis
Authors: Campoy E. , Rodriguez‐moreno J. , Del Blanco J. , Narvaez J. , Clavaguera T. , Roig‐escofet D.
Published: February 2007

We describe a patient with granulomatous synovitis secondary to osseus hydatid disease that manifested with chronic monarthritis, eosinophilia, and urticaria.
Special article the economic cost and social and psychological impact of musculoskeletal conditions
Authors: Yelin Edward , Callahan Leigh F. ,   THE NATIONAL ARTHRITIS DATA WORK GROUP
Published: February 2007

Objective. To provide an indication of the economic, social, and psychological impact of musculoskeletal conditions in the United States.

Methods. Review of the literature combined with estimates of data concerning health care utilization and acute and chronic disability due to musculoskeletal conditions, from the 1990–1992 National Health Interview Survey.

Results. The cost of musculoskeletal conditions was $149.4 billion in 1992, of which 48% was due to direct medical care costs and the remainder was due to indirect costs resulting from wage losses. This amount translates to ˜2.5% of the Gross National Product, a sharp rise since the prior studies, even if part of the increase is an artifact of improved accounting methods. Each year, persons with musculoskeletal conditions make 315 million physician visits, have more than 8 million hospital admissions, and experience ˜1.5 billion days of restricted activity. Approximately 42% of persons with musculoskeletal conditions–more than 17 million in all–are limited in their activities.

Conclusion. The economic and social costs of musculoskeletal conditions are substantial. These conditions are responsible for a sizable amount of health care use and disability, and they significantly affect the psychological status of the individuals with the conditions as well as their families.
Characterization of biologically active antineutrophil cytoplasmic antibodies induced in mice:pathogenetic role in experimental vasculitis
Authors: Tomer Yaron , Gilburd Boris , Blank Miri , Lider Ofer , Hershkoviz Rami , Fishman Perina , Zigelman Rosa , Meroni Piere‐Luigi , Wiik Alan , Shoenfeld Yehuda
Published: February 2007

Objective. To investigate the pathogenetic role of antineutrophil cytoplasmic antibodies (ANCA) in Wegener's granulomatosis (WG).

Methods. BALB/c mice were immunized with human IgG ANCA from a patient with WG. Control mice were immunized with normal human IgG. Levels of mouse ANCA and other autoantibodies were determined. Mouse ANCA were tested for their ability to induce adhesion and respiratory burst of neutrophils. The mouse lungs and kidneys were examined for the development of vasculitis.

Results. Mice immunized with human ANCA developed anti‐human ANCA and anti–anti‐human ANCA (mouse ANCA), while the controls did not develop these antibodies. Mouse ANCA were capable of inducing adhesion of neutrophils to fibronectin and activating the respiratory burst in neutrophils. Moreover, the mice that were immunized with human ANCA developed perivascular mononuclear cell infiltrates in the lungs, suggesting vasculitis.

Conclusion. The results suggest a pathogenic role of ANCA in WG, and may imply that activation of neutrophils is the initiating event in the development of vasculitis in WG.
Monoclonal anticardiolipin autoantibodies established from the (new zealand white x bxsb)f1 mouse model of antiphospholipid syndrome cross‐react with oxidized low‐density lipoprotein
Authors: Mizutani Hajime , Kurata Yoshiyuki , Kosugi Satoru , Shiraga Masamichi , Kashiwagi Hirokazu , Tomiyama Yoshiaki , Kanakura Yuzuru , Good Robert A. , Matsuzawa Yuji
Published: February 2007

Objective. Autoimmunity‐prone (New Zealand white X BXSB)F1 ([NZW X BXSB]F1) mice have been shown to be useful as a model of antiphospholipid syndrome with myocardial infarction. The aim of this study was to examine the cross‐reactivity of anticardiolipin antibody (aCL) derived from (NZW X BXSB)F1 mice with oxidized low‐density lipoprotein (ox‐LDL), which is closely associated with atherosclerosis.

Methods. Six monoclonal antibodies (MAb) against CL were established from (NZW X BXSB)F1 mice, and reactivity of aCL with ox‐LDL was examined by micro–enzyme‐linked immunosorbent assay.

Results. Higher titers of anti–ox‐LDL autoantibodies were found in adult (NZW X BXSB)F1 mice compared with other autoimmunity‐prone mouse strains (P < 0.01) or a control strain (P < 0.005). There was a significant positive correlation between titers of aCL and those of anti–ox‐LDL in (NZW X BXSB)F1 mice (r = 0.79, P < 0.001). Of the 6 MAb against CL, 2 clones that showed β‐glycoprotein 1–dependent reactivity also cross‐reacted with ox‐LDL. Binding of monoclonal aCL to solid‐phase cardiolipin was inhibited by ox‐LDL, but not by native LDL.

Conclusion. We confirmed that aCL derived from (NZW X BXSB)F1 mice can cross‐react with ox‐LDL. This result suggests that aCL, which is closely associated with lupus‐assocaited thrombosis, may also play an important role in atherosclerotic complications in patients with systemic lupus erythematosus.
The major dermatomyositis‐specific mi‐2 autoantigen is a presumed helicase involved in transcriptional activation
Authors: Seelig Hans Peter , Moosbrugger Isabelle , Ehrfeld Hans , Fink Thomas , Renz Manfred , Genth Ekkehard
Published: February 2007

Objective. To characterize the complementary DNA (cDNA) and protein sequences of autoantigens recognized by anti–Mi‐2 antibodies, using recombinant Mi‐2 proteins for improved autoantibody detection.

Methods. A cDNA expression library was immunoscreened, and cDNA isolation, alignment, and sequence analysis were performed. Northern blotting and in situ hybridization techniques were used. A recombinant protein (rMi‐2) was synthesized. Immunoprecipitation of 35S‐methionine–labeled HEp‐2 cell proteins and immunoblotting of rMi‐2 and natural nuclear proteins were performed. Immunofluorescence studies were done with anti–Mi‐2 positive sera of dermatomyositis (DM) patients, and with human or rabbit antibodies specific for rMi‐2. Antibody screening of systemic lupus erythematosus, rheumatoid arthritis, DM, and antinuclear antibody–positive human sera was performed using an rMi‐2 protein enzyme‐linked immunosorbent assay (ELISA).

Results. A major antigen recognized by anti–Mi‐2 positive sera of DM patients was found to constitute a 218‐kd nuclear protein (218‐kd Mi‐2) encoded on chromosome 12 and to belong to the SNF2/RAD 54 helicase family. Human and rabbit antibodies that were affinity purified using the recombinant protein reacted with and precipitated a nuclear protein of similar size, which was also recognized by anti–Mi‐2 sera. Anti–218‐kd Mi‐2 antibodies detected by rMi‐2 protein ELISA seemed to be mainly restricted to sera from patients with DM.

Conclusion. The molecular characterization of the 218‐kd Mi‐2 antigen may contribute to our understanding of autoimmune phenomena in DM. The use of immunoreactive recombinant proteins allows structural and functional studies of the helicase and the development of sensitive and accurate antibody screening tests.
Alteration of chlamydia trachomatis biologic behavior in synovial membranes suppression of surface antigen production in reactive arthritis and reiter's syndrome
Authors: Nanagara Ratanavadee , Li Feng , Beutler Anna , Hudson Alan , Schumacher H. Ralph
Published: February 2007

Objective. To investigate the biologic state of Chlamydia and its surface antigen expression in the synovial membranes of patients with Chlamydia‐associated reactive arthritis/Reiter's syndrome (ReA/RS).

Methods. Expression of chlamydial lipopoly‐saccharide (LPS), major outer membrane protein (MOMP), and elementary body (EB) antigens was studied by gold labeling immunoelectron microscopy on 6 synovial membrane and 2 synovial fluid (SF) pellet samples from 6 patients with Chlamydia‐associated arthritis. The study findings were compared with 24‐hour cultures of HeLa cells infected with Chlamydia trachomatis EB.

Results. Persistent C trachomatis infection was found in all 6 synovial membrane samples from patients who had either early or chronic arthritis. The infection persisted despite antibiotic treatment, including a 1‐month course of doxycycline therapy. Most persistent organisms were atypical reticulate bodies (RBs) found in both fibroblasts and macrophages. Specific, but weak, immunogold staining for all 3 antibodies was found on both intracellular RBs and extracellular EBs. In the SF samples, Chlamydia surface antigens were detected only in phagosomes containing degraded electron‐dense materials.

Conclusion. The synovial membrane biopsies conducted in this study of Chlamydia‐associated ReA/RS revealed atypical RBs with diminished MOMP and LPS expression. Such altered organisms may escape immune surveillance and contribute to disease chronicity; moreover, these organisms may be difficult to detect and treat in some ReA/RS patients.
Antibodies to synovial antigens in recent‐onset rheumatoid arthritis
Authors: Mccol Geoffrey J. , Cram David S. , Harrison Leonard C.
Published: February 2007

Objective. To identify synovial antigens that bind to serum antibodies from subjects with recent‐onset rheumatoid arthritis (RA) (<6 months of synovitis).

Methods. Soluble and insoluble fractions of Triton X‐100 extracts of RA and normal synovial tissue, and normal spleen and placenta, were immunoblotted with sera from 27 patients with recent‐onset RA, 13 autoimmune disease control subjects, and 13 blood bank control donors. Bound immunoglobulin was probed with 125I‐labeled protein A.

Results. Antibodies in the sera of 20 (74%) patients with recent‐onset RA recognized at least 1 of 5 antigens in both a disease‐ and tissue‐specific and nonspecific manner. Anti‐La antibodies, usually associated with primary Sjögren's syndrome, were detected in 2 sera. Eight sera had increased reactivity to an IgG heavy and light chain dimer. There was strong binding of 8 sera with a 35‐kd doublet and of 3 sera with a 55‐kd species in RA and normal synovial lysates (insoluble fractions). Two sera uniquely recognized a 45‐kd protein only in the RA synovial lysate (soluble fraction).

Conclusion. IgG antibodies in the sera of patients with recent‐onset RA show positive immunoblots for 3 novel synovial antigens of 35‐kd, 55‐kd, and 45‐kd, as well as for 2 previously characterized antigens (La and IgG). Thus, a variety of synovial antigens appear to be recognized by B cells even early in the clinical course of RA.
Prediction of progression of radiologic damage in newly diagnosed rheumatoid arthritis
Authors: Heide Agnes Van Der , Remme Carol Ann , Hofman Dirk M. , Jacobs JOHANNES W. G. , Bijlsma JOHANNES W. J.
Published: February 2007

Objective. To investigate the extent to which early radiologic damage is predicted by joint inflammation in patients with newly diagnosed rheumatoid arthritis (RA).

Methods. Regression analysis was performed on 1‐year progression of total radiologic damage for baseline characteristics and cumulative disease activity measures, and the effects of continued joint inflammation on the progression of damage in separate joint groups were investigated.

Results. Odds ratios for progression of total damage were 12 for the presence of rheumatoid factor, 5 for the presence of damage at baseline, and 2 for cumulative joint inflammation. A positive association between continued joint inflammation and progression of damage was found to be statistically significant for most joint groups.

Conclusion. Progression of radiologic damage in patients with newly diagnosed RA is independently associated with the presence of rheumatoid factor and damage at baseline and with cumulative joint inflammation.
Identification of patient subsets among those presumptively diagnosed with, referred, and/or followed up for systemic lupus erythematosus at a large tertiary care center
Authors: Calvo‐Alén Jaime , Bastian Holly M. , Straaton Karin V. , Burgard Sheila L. , Mikhail Isis S. , Alarcón Graciela S.
Published: February 2007

Objective. To identify different subsets of patients from a large tertiary care center who were presumptively referred for and/or diagnosed with systemic lupus erythematosus (SLE) (or followed up).

Methods. All patients who were referred, followed up, and/or diagnosed with SLE at our center, who had disease duration of ≤5 years, and who resided in Alabama, were identified and their charts reviewed and abstracted.

Results. Abstracted data were reviewed by 3 rheumatologists, and patients were assigned to 1 of 3 categories: 1) SLE by the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) criteria, 2) clinical SLE but not meeting 4 of the ACR criteria, or 3) fibromyalgia‐like manifestations with antinuclear antibody (ANA) positivity. There were 90 patients in the first group (criteria), 22 in the second group (clinical), and 37 in the third group (fibromyalgia‐like). Patients in all 3 groups were predominantly women. Only 50% of the fibromyalgia‐like group were African‐American, compared with 55–65% for the other 2 groups. Organ system involvement occurred with comparable frequency in the first 2 groups, but mucocutaneous and hematologic abnormalities were more frequent in the criteria group; in contrast, the patients with fibromyalgia‐like symptoms primarily presented with arthralgias/myalgias, fatigue, depression, and sleep disturbances, as well as mucocutaneous manifestations.

Conclusion. When the ACR criteria for SLE are used to determine eligibility for lupus studies, a group of patients with clinically unequivocal SLE are excluded. A group of patients with fibromyalgia‐like manifestations, who test positive for ANA and differ clinically and sociodemographically from the patients in the other 2 groups, very likely do not belong within the spectrum of SLE.
Presence of nucleosome‐restricted antibodies in patients with systemic lupus erythematosus
Authors: Chabre Henri , Amoura Zahir , Piette Jean‐Charles , Godeau Pierre , Bach Jean‐François , Koutouzov Sophie
Published: February 2007

Objective. To assess whether nucleosome‐restricted antibodies, i.e., antibodies that react with the whole nucleosome particle but not with its individual components (double‐stranded DNA [dsDNA] and his‐tones), are present in the sera of patients with systemic lupus erythematosus (SLE).

Methods. Antibodies were detected by enzyme‐linked immunosorbent assay using purified nucleo‐somes, dsDNA, or histones. These tests were applied to the sera of 40 patients with SLE. Protein G–purified IgGs of representative sera were sequentially adsorbed on dsDNA‐and histone‐conjugated solid‐phase supports and further assayed for their nucleosome, dsDNA, and histone reactivities.

Results. Of the 40 sera tested, 16 displayed anti‐dsDNA and/or antihistone antibody activity, which was always associated with significant antinucleosome reactivity. In addition, 3 sera showed antinucleosome activity that was not associated with concomitant anti‐dsDNA or antihistone activity. The presence of true nucleosome‐restricted antibodies was demonstrated, after solid‐phase adsorption, in representative SLE sera that showed anti‐dsDNA or antihistone antibody activity, and also in sera that did not show these activities.

Conclusion. Our results provide evidence for the presence of nucleosome‐restricted antibodies in patients with lupus. These nucleosome‐restricted antibodies, along with anti‐dsDNA and antihistone antibodies, appear to belong to a broad set of antinuclear antibodies, the antinucleosome family.
Lack of detection of enteroviral rna or bacterial dna in magnetic resonance imaging–directed muscle biopsies from twenty children with active untreated juvenile dermatomyositis
Authors: Pachman Lauren M. , Litt Deborah L. , Rowley Anne H. , Hayford Jennifer R. , Caliendo Janice , Heller Scott , Ticho Baruch S. , Christensen Mary , Patterson Bruce , Ytterberg Steven R. , Pallansch Mark
Published: February 2007

Objective. To investigate for the presence of increased titers of circulating antibody to putative infectious agents and for detectable viral RNA or bacterial DNA in children with active recent‐onset juvenile der‐ matomyositis (DM).

Methods. Magnetic resonance imaging–directed muscle biopsies were performed in 20 children with active, untreated, recent‐onset juvenile DM and in age‐matched children with neurologic disease. Sera were tested for complement‐fixing antibody to Coxsack‐ievirus B (CVB), influenza A and B, parainfluenza 1 and 3, Mycoplasma pneumoniae, mumps, respiratory syncytial virus, and Reovirus; and by immunofluorescence for IgG antibody to Toxoplasma gondii cytomegalovirus and IgM antibody to Epstein‐Barr virus. Muscle from juvenile DM patients and control children, CD‐1 Swiss mice with and without CVB1 infection, and viral stock positive for CVB1–6 were tested using reverse‐transcriptase polymerase chain reaction with 5 primer sets, 4 probes (1 Coxsackievirus, 3 Enterovirus), and universal primers for DNA.

Results. No increased antibody, viral RNA, or bacterial DNA was present in the juvenile DM patients or the control children.

Conclusion. Juvenile DM may be triggered by unidentified agent(s) in the genetically susceptible host.
The elusive search for geographic clusters of systemic lupus erythematosus.
Authors: Wallace Daniel J. , Quismorio Francisco P.
Published: February 2007

Objective. To ascertain whether there are any geographic clusters of systemic lupus erythematosus (SLE), and critically review 2 previous reports of these clusters.

Methods. A literature review of all epidemiologic surveys relevant to SLE published since 1966 was undertaken. This included a search of abstracts and reports, in addition to peer‐reviewed publications.

Results. Two geographic clusters were identified in the literature. A report purporting that contaminated ground water in southwest Tucson, Arizona was associated with significantly increased symptoms of SLE was flawed since no patients were examined, discarded criteria were used, and incorrect definitions were employed by the nonrheumatologist authors. Another study, which identified a cluster in Nogales, Arizona, used generally valid methodology. However, the authors' conclusion that a 94/100,000 prevalence of SLE was evidence of an excessive increase in this 92% Hispanic/Native American community is not consistent with published surveys among Hispanic and Native American populations.

Conclusion. No valid claims of SLE geographic clusters have been published.
Double‐blind, placebo‐controlled multicenter trial using chimeric monoclonal anti‐cd4 antibody, cm‐t412, in rheumatoid arthritis patients receiving concomitant methotrexate
Authors: Moreland Larry W. , Pratt Parks W. , Mayes Maureen D. , Postlethwaite Arnold , Weisman Michael H. , Schnitzer Thomas , Lightfoot Robert , Calabrese Leonard , Zelinger David J. , Woody James N. , Koopman William J.
Published: February 2007

Objective. To evaluate the clinical response to and safety of single and repeat doses of a chimeric anti‐CD4 monoclonal antibody, cM‐T412, in patients with rheumatoid arthritis (RA) concomitantly treated with a stable regimen of low‐dose methotrexate.

Methods. Sixty‐four patients with refractory RA, who were already receiving stable doses of methotrexate, were randomized into a multicenter, double‐blind, placebo‐controlled trial to receive 3 monthly treatments with either a placebo, or 5, 10, or 50 mg cM‐T412, given intravenously.

Results. Using ≥50% improvement in swollen joint counts as a criterion for clinical response, 13%, 13%, 18%, and 13% of patients receiving 50, 10, or 5 mg cM‐T412, or the placebo, respectively, exhibited a clinical response at 3 months of therapy. Using ≥50% improvement in tender joint counts as a measure of clinical efficacy at 3 months, 19%, 13%, 12%, and 6% of patients receiving 50, 10, or 5 mg cM‐T412, or the placebo, respectively, exhibited a clinical response. “Flu‐like” symptoms (fever, chills, rigor) within 24 hours of the infusion occurred more frequently in the groups receiving 50‐mg (29%) and 10‐mg (31%) doses of cM‐T412 than those receiving 5 mg cM‐T412 (12%) or the placebo (13%). Significant CD4+ T cell depletion occurred in the 50‐mg group (mean of 353 CD4+ T cells/mm3 at 6 months versus 856 CD4+ T cells/mm3 at baseline). All patients were followed up for 12 months after the final treatment; no opportunistic infectious complications occurred.

Conclusion. Treatment with cM‐T412 in this cohort of RA patients who were also taking methotrexate was not associated with clinical efficacy or enhanced toxicity from infectious complications, despite significant peripheral CD4+ T cell depletion.
Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis
Authors: Mladenovic Vlastimir , Domljan Zlatko , Rozman Blaz , Jajic Ivo , Mihajlovic Dimitrije , Dordevic Jovan , Popovic Milan , Dimitrijevic Miroslava , Zivkovic Milutin , Campion Giles , Musikic Predrag , Löw‐Friedrich Iris , Oed Christine , Seifert Hildegard , Strand Vibeke
Published: February 2007

Objective. To assess the safety and effectiveness of leflunomide versus placebo in patients with active rheumatoid arthritis (RA) treated for 6 months.

Methods. Four hundred two patients were randomly assigned to receive placebo or leflunomide at 5 mg, 10 mg, or 25 mg daily. A washout period of 6–12 weeks from prior second‐line therapy was required.

Results. Statistically significant improvement in primary and secondary outcome measures, as well as by responder analyses, occurred in the 10‐mg and 25‐mg dosage groups compared to placebo. Twenty‐one patients (7.0%) in the active treatment groups withdrew due to adverse events (AEs). The incidence of AEs was higher with leflunomide than with placebo. Gastrointestinal symptoms, weight loss, allergic reactions, skin rash, and reversible alopecia were more common in the 10‐mg and 25‐mg dosage groups. The incidence of infections was similar between the treatment and placebo groupsno opportunistic infections were seen. Transient elevations in liver function studies were noted in a small number of patients.

Conclusion. Leflunomide is effective in daily doses of 10 mg and 25‐mg in patients with active RA. Improved efficacy at the 25‐mg dose was associated with a higher incidence of AEs. Randomized, placebocontrolled trials using daily doses of 10 mg and 20 mg are under way in the US and Europe to confirm these positive results.
Quantification of rheumatoid synovitis by magnetic resonance imaging
Authors: Gaffney Karl , Cookson John , Blake David , Coumbe Adam , Blades Selina
Published: February 2007

Objective. To develop a method for quantifying acute synovial inflammation in rheumatoid arthritis (RA), utilizing magnetic resonance imaging (MRI).

Methods. Gadolinium–diethylenetriamine pentaacetic acid‐enhanced MRI was performed in 21 patients with knee synovitis. Changes in synovial membrane signal intensity were identified and quantified by line profile analysis. Multiple synovial biopsies were obtained by a blind biopsy technique, and standard clinical and laboratory measurements of disease activity were recorded.

Conclusion. Dynamic MRI is a valuable technique for assessing acute synovial inflammation in RA.

Results. The rate of synovial membrane enhancement correlated with histologic features of acute inflammation (r = 0.63, P < 0.01), but not with clinical or laboratory assessments.
Predictors of work disability in rheumatoid arthritis patients
Authors: Reisine Susan , Mcquillan Julia , Fifield Judith
Published: February 2007

Objective. To evaluate regression models that include social, attitudinal, work structure, health status, and family characteristics, with regard to their prediction of work disability in a national sample of patients with rheumatoid arthritis (RA).

Methods. Four hundred ninety‐eight employed RA patients were recruited from a national sample of private rheumatology practices. Three hundred ninety‐two remained in the study after 5 years. Data were collected from patients by telephone interview, and patients' physicians provided written clinical assessments. Only variables on which information was obtained in year 1 were used to predict work status in year 5, using hierarchical multiple logistic regression analysis.

Results. The significant predictors of work disability were age (odds ratio [OR] 1.04), number of deformed joints (OR 1.26), number of joints with flare (OR 1.23), the complexity of working with things at work (OR 0.88), and the desire to remain employed (OR 2.3). The risk of work disability increased with increasing age, more severe disease, greater complexity of involvement with things at work, reduced work hours, and desire to not be working outside the home.

Conclusion. The risk of becoming work disabled in 5 years was predicted more by clinical status at entry into the study than by work structure. These results, which contradict previous research on work disability in arthritis, prompt a rethinking of future studies of work disability in RA.
Corticosteroids plus pulse cyclophosphamide and plasma exchanges versus corticosteroids plus pulse cyclophosphamide alone in the treatment of polyarteritis nodosa and churg‐strauss syndrome patients with factors predicting poor prognosis
Authors: Guillevin Loïc , Lhote François , Cohen Pascal , Jarrousse Bernard , Lortholary Olivier , Généreau Thierry , Léon Anne , Bussel Annette
Published: February 2007

Objective. To define the most effective treatment for severe polyarteritis nodosa (PAN) and Churg‐Strauss syndrome (CSS) and to investigate the indication for plasma exchange treatment.

Methods. We conducted a prospective, randomized, multicenter trial in which 62 patients were randomly assigned to receive either prednisone plus cyclophosphamide (intravenous bolus) (group An = 28) or prednisone plus cyclophosphamide (intravenous bolus) plus plasma exchanges (group B; n = 34) as first‐line treatment for severe PAN or CSS. Factors predicting poor prognosis were renal symptoms, gastrointestinal tract involvement, cardiomyopathy, central nervous system involvement, weight loss > 10% of body weight, and age > 50 years old. Patients with hepatitis B virus‐related PAN were not included in this study. The end point of the study was control of the disease (recovery or remission) or death.

Results. Clinical symptoms and laboratory findings did not differ significantly in the 2 groups. Initial control of the disease was similar in both groups. Relapse after initial control of the disease was observed in 7 patients (4 in group A and 3 in group B). The mean ± SD followup period was 31.1 ± 20 months for group A and 35.9 ± 16.8 months for group B. At 5 years of followup, 38 patients (61.3%) were cured (16 in group A and 22 in group B), and 5 (8.1%) were in remission without treatment but had not yet completed the curedefining period of 18 months (3 in group A and 2 in group B). Eight (12.9%) (2 in group A and 6 in group B) were considered to be in clinical remission and required a maintenance regimen of low‐dose corticosteroids. Eleven patients died during the study period (7 in group A [25%], 4 in group B [11.8%]). Uncontrolled vasculitis was responsible for 4 deaths (2 in each group), and treatment side effects caused the death of 1 patient in group A. There was no significant difference between the 5‐year cumulative survival rates of the 2 groups (75% and 88%, respectively).

Conclusion. Based on our data, combined treatment with prednisone, cyclophosphamide, and plasma exchanges is not superior to treatment with prednisone and cyclophophamide alone, and plasma exchanges should not be systematically proposed for initial treatment of severe PAN or CSS.
Treatment of calcinosis with diltiazem
Authors: Palmieri Genaro M. A. , Sebes Jeno I. , Aelion Jacob A. , Moinuddin Mohamed , Ray Morris W. , Wood George C. , Leventhal Marvin R.
Published: February 2007

Objective. To test the hypothesis that the calcium antagonist diltiazem is effective in the treatment of calcinosis.

Methods. Diltiazem, 240–480 mg/day, was given to 4 patients with idiopathic or CREST‐related (calcinosis, Raynaud'S phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) calcinosis for 1–12 years. Serial radiographs of the affected areas, using identical technique, and clinical evaluations were obtained. A fifth patient, who did not tolerate diltiazem, received verapamil, 120 mg/day for 18 months.

Results. All patients taking diltiazem had a reduction or disappearance of the calcific lesions, with striking clinical improvement. One patient'S case was followed for 12 years. The response to diltiazem during the first 5 years of treatment has been previously reported in detail; however, over 7 years of additional treatment, there was further reduction of the lesions. One patient developed a large calcific lesion while receiving verapamil for hypertension, and after verapamil was replaced with diltiazem, there was a dramatic response. Verapamil was ineffective in the fifth patient, who did not tolerate diltiazem.

Conclusion. Long‐term treatment with diltiazem, but not verapamil, is effective in calcinosis.
Antibody reactivity to the hres‐1 endogenous retroviral element identifies a subset of patients with systemic lupus erythematosus and overlap syndromes
Authors: Perl Andras , Colombo Emanuela , Dai Huiliang , Agarwal Rajeev , Mark Kenneth A. , Banki Katalin , Poiesz Bernard J. , Phillips Paul E. , Hoch Sallie O. , Reveille John D. , Arnett Frank C.
Published: February 2007

Objective. To evaluate the correlation between the presence of antibodies to an endogenous retroviral element–encoded nuclear protein autoantigen, HRES‐1, and the presence of other antinuclear antibodies and HLA class II alleles in patients with systemic lupus erythematosus (SLE) and overlap syndromes.

Methods. Antibody reactivities to native and recombinant proteins and synthetic peptides were assessed by counterimmunoelectrophoresis, enzyme‐linked immunosorbent assay, and Western blotting. HLA class II alleles were determined by oligonucleotide typing.

Results. Forty‐eight percent of the 153 patients with autoimmune disease, and 52% of the subgroup with SLE, had HRES‐1 antibodies. In contrast, 3.6% of 111 normal donors, and none of 42 patients with the acquired immunodeficiency syndrome or 50 asymptomatic human immunodeficiency virus 1–infected patients, had HRES‐1 antibodies. Chi‐square analyses revealed a significant association between anti–HRES‐1 and anti‐RNP and an inverse correlation between HRES‐1 and Ro/La autoantibodies in patients with SLE or overlap syndromes. Antigenic epitopes of HRES‐1 and the retroviral gag–related region of the 70‐kd protein component of U1 small nuclear RNP, which share 3 consecutive highly charged amino acids (Arg‐Arg‐Glu), an additional Arg, and functionally similar Arg/Lys residues, represent cross‐reactive epitopes between the two proteins. Selective removal of HRES‐1 antibodies from sera of HRES‐1‐seropositive/RNP‐seropositive patients by absorption on recombinant HRES‐1/glutathione‐S‐transferase‐conjugated agarose beads had no effect on anti‐RNP reactivities. A comparative multivariate analysis of HLA class II genes revealed a differential segregation of DQB1 alleles in HRES‐1‐seropositive versus HRES‐1‐seronegative patients (P = 0.04). While a relative increase of DQB1*0402 among HRES‐1‐seropositive patients was noted across ethnic groups (P = 0.02), a decrease of DQB1*0201 and DQB1*0301 was found in white HRES‐1‐seropositive patients (P = 0.04).

Conclusion. Autoantibodies to HRES‐1 are detectable in a distinct subset of patients with autoimmune disease, primarily in those who do not have antibodies to Ro and La. Anti–HRES‐1 and anti‐RNP reactivities are mediated by cross‐reactive but separate antibody molecules. HLA–DQB genes, rather than HLA–DRB or DQA genes, may have a more significant influence on generation of these antinuclear autoantibodies.
Association of hla‐b39 with hla‐b27‐negative ankylosing spondylitis and pauciarticular juvenile rheumatoid arthritis in japanese patients
Authors: Yamaguchi Akihiro , Tsuchiya Naoyuki , Mitsui Hiroshi , Shiota Michiko , Ogawa Atsuko , Tokunaga Katsushi , Yoshinoya Sadayoshi , Juji Takeo , Ito Koji
Published: February 2007

Objective. To investigate the characteristics of HLA‐B27 that render susceptibility to seronegative spondylarthropathies.

Methods. Serologic HLA class I typing of Japanese patients with ankylosing spondylitis (AS), juvenile rheumatoid arthritis (JRA), and healthy controls, was performed. HLA‐B39 subtypes were determined by polymerase chain reaction‐sequence‐specific oligohy‐bridization.

Results. HLA‐B27 was present in 40 of 48 patients with AS (83%), and in only 1 of 210 healthy controls (0.5%). Three of 8 patients (37.5%) who were negative for HLA‐B27 were positive for HLA‐B39, which was significantly higher compared with the HLA‐B27‐negative controls (6.2% P = 0.01). Significant association with HLA‐B39 was also noted in the JRA patients (16.7%; P < 0.01), especially in those patients with pauciarticular‐onset disease (33.3%; P < 0.01). Ten of 13 HLA‐B39‐positive patients had subtype B*3901 and 3 had B*3902.

Conclusion. Because HLA‐B27 and HLA‐B39 share Glu at position 45 and Cys at position 67, both of which constitute components of the peptide‐anchoring B pocket, and because they possess similar peptide‐ligand motifs, our results may support either the role of the peptides presented by class I antigens or the importance of Cys at position 67, in the development of spondylarthropathies and pauciarticular‐onset JRA.
Rheumatoid synovial fibroblast adhesion to human articular cartilage
Authors: Mccurdy Lewis , Winn Chatham W. , Blackburn Warren D.
Published: February 2007

Objective. To determine if preexposure of human articular cartilage to activated neutrophils alters rheumatoid synovial fibroblast adhesion to human articular cartilage.

Methods. Human articular cartilage was exposed to either activated neutrophils, interleukin‐1, or supernatants obtained from activated neutrophils that had been treated with different protease inhibitors. Radiolabeled rheumatoid synovial fibroblasts were then incubated with the cartilage and the number of counts associated with the cartilage was determined.

Results. Pretreatment of human articular cartilage with either activated neutrophils or supernatants obtained from activated neutrophils enhanced subsequent rheumatoid synovial fibroblast adhesion. In contrast, interleukin‐1 treatment of cartilage did not alter the adhesion of synovial fibroblasts. The enhanced adhesion could be attenuated by pretreatment of the neutrophil supernatants with either diisopropylfluoro‐phosphonate or EGTA and almost completely abolished by using both inhibitors.

Conclusion. This study demonstrates that adhesion of rheumatoid synovial fibroblasts to human articular cartilage can be enhanced by exposing the cartilage to proteases released by neutrophils. These results suggest that neutrophil products may play a role in enhancing adhesion of rheumatoid synovium to cartilage in vivo.