bluuebunny/crossref_metadata_2025 huggingface dataset:
Adjuvant arthritis as a model of inflammatory cachexia
Authors: Roubenoff Ronenn , Freeman Lisa M. , Smith Donald E. , Abad Leslie W. , Dinarello Charles A. , Kehayias Joseph J.
Published: February 2007

Objective. To determine whether adjuvant arthritis (AA) leads to changes in body composition and cytokine production similar to those seen in patients with rheumatoid arthritis.

Methods. AA was induced in Lewis rats using Freund's complete adjuvant. Body cell mass was measured by determining the concentration of total exchangeable potassium using 42K gavage. Splenocyte production of interleukin‐1 (IL‐1) and tumor necrosis factor α (TNFα) was measured by bioassay. Weight and food intake were also measured.

Results. Animals that developed AA lost 6% of their body weight by the onset of clinically evident arthritis (day 14; P < 0.01) and lost 20% by the end of the inflammatory phase of AA (day 28; P < 0.0001). Body cell mass fell 24.7 ± 8.6% (mean ± SEM) in animals with AA, but did not change significantly in controls (increase of 6.3 ± 7.9%) (P < 0.03). Pair‐fed animals lost one‐fourth of the weight lost by the animals with AA (P < 0.01), indicating that anorexia alone does not explain inflammatory cachexia. Weight loss was correlated with TNFα production by spleen mononuclear cells (r = 0.68, P < 0.007), and a weaker correlation was seen with IL‐1 production (r = 0.45, P < 0.04).

Conclusion. AA in rats is a useful model of inflammatory cachexia that mimics the human pathophysiology in important ways, and is consistent with cytokine‐driven cachexia in chronic inflammatory arthritis.
Up‐regulation of class II major histocompatibility complex and intercellular adhesion molecule 1 expression on scleroderma fibroblasts and endothelial cells by interferon‐γ and tumor necrosis factor α in the early disease stage
Authors: Gruschwitz Matthias S. , Vieth Gisela
Published: February 2007

Objective. To investigate the expression patterns of interferon‐γ (IFNγ) and tumor necrosis factor α (TNFα), both of which are potent inducers of class II major histocompatibility complex (MHC) and intercellular adhesion molecule 1 (ICAM‐1) expression, and their codistribution with HLA—DR and ICAM‐1 in skin lesions, cultured fibroblasts, and peripheral blood mononuclear cells (PBMC) of systemic sclerosis (SSc) patients in different stages of disease.

Methods. Investigations were carried out using immunohistochemistry studies, reverse transcriptasepolymerase chain reaction, dot‐blot hybridization, and cytometric analysis. Serum levels of TNFα were determined by enzyme‐linked immunosorbent assay.

Results. In the early inflammatory stage of SSc, class II MHC and ICAM‐1 expression could be detected on most endothelial cells and on fibroblasts located especially in perivascular areas surrounded by infiltrating lymphocytes, which belong to the T helper 1 phenotype expressing IFNγ and TNFα. In this early disease stage, an enhanced expression of TNFα on cultured dermal fibroblasts and PBMC, as well as elevated serum titers of soluble TNFα, could be found.

Conclusion. These data suggest that class II MHC antigens and ICAM‐1 on fibroblasts and endothelial cells are induced by IFNγ and TNFα in an early stage of SSc after the influx of mononuclear cells, and may be important in the putative autoimmune response and in the perpetuation of fibrotic processes in SSc.
Endothelial cells as target for antiphospholipid antibodies. Human Polyclonal and Monoclonal Anti‐β2‐Glycoprotein I Antibodies React In Vitro with Endothelial Cells Through Adherent β2‐Glycoprotein I and Induce Endothelial Activation
Authors: Papa N. Del , Guidali L. , Sala A. , Buccellati C. , Khamashta M. A. , Ichikawa K. , Koike T. , Balestrieri G. , Tincani A. , Hughes G. R. V. , Meroni P. L.
Published: February 2007

Objective. To investigate the ability of human anti‐β2‐glycoprotein I (anti‐β2GPI) antibodies to recognize the cofactor adherent on endothelial cells (EC) and to modulate endothelial functions.

Methods. Six human affinity‐purified polyclonal anti‐β2GPI IgG and 2 IgM monoclonal antibodies (MAb) were obtained from patients with the antiphos‐pholipid syndrome. The antibodies were tested for their ability to 1) bind to endothelial monolayers through the adherent β2GPI and 2) modulate endothelial adhesion molecule expression and interleukin‐6 (IL‐6) and 6‐keto‐prostaglandin F1α (6‐keto‐PGF1α) secretion.

Results. The affinity‐purified IgG and the MAb with anti‐β2GPI activity, but not the respective controls, displayed EC binding, which declined on cells incubated in serum‐free medium and was restored in a dose‐dependent manner by exogenous human β2GPI. After EC binding, both polyclonal and monoclonal antibodies up‐regulated adhesion molecule expression. Anti‐β2GPI MAb also significantly increased IL‐6 and 6‐keto‐PGF1α secretion.

Conclusion. These findings support the hypothesis that anti‐β2GPI antibodies bind and activate EC through the adherent cofactor β2GPI, likely leading to a procoagulant state.
Suppression of cartilage matrix gene expression in upper zone chondrocytes of osteoarthritic cartilage
Authors: Aigner T. , Vornehm S. I. , Zeiler G. , Dudhia J. , von der Mark K. , Bayliss M. T.
Published: February 2007

Objective. To evaluate the anabolic activity of osteoarthritic chondrocytes in situ by investigating the messenger RNA (mRNA) expression of 3 major cartilage components, type II collagen, aggrecan, and link protein.

Methods. In situ hybridization experiments and histochemical analysis for proteoglycan content were performed on parallel sections of normal and osteoarthritic (OA) cartilage specimens.

Results. Most chondrocytes in the deeper zones of OA cartilage showed an increase in mRNA expression, in particular, of type II collagen and to a lesser extent, aggrecan, compared with normal specimens. However, chondrocytes of the upper zone were largely negative for aggrecan or type II collagen mRNA. The expression of link protein mRNA was low in normal and OA specimens.

Conclusion. These observations suggest that suppression of the anabolic activity of chondrocytes in the upper zones contributes to the metabolic imbalance observed in OA cartilage. Stimulation of matrix anabolism in superficial chondrocytes might be a suitable target for therapeutic intervention.
Direct evidence for the expression of multiple endogenous retroviruses in the synovial compartment in rheumatoid arthritis
Authors: Nakagawa Kaku , Brusic Vladimir , McColl Geoffrey , Harrison Leonard C.
Published: February 2007

Objective. Circumstantial evidence links retroviruses (RVs) with human autoimmune diseases. The aim of the present study was to obtain direct evidence of RV gene expression in rheumatoid arthritis (RA).

Methods. Synovial samples were obtained from patients with RA, patients with osteoarthritis (OA), and normal control subjects. Reverse transcriptionpolymerase chain reaction (RT‐PCR) was performed using synovial RNA and primers to conserved sequences in the polymerase (pol) genes of known RVs.

Results. PCR products (n = 857) were cloned and sequenced. Multiple pol transcripts, many with open reading frames, were expressed in every sample. Sequences were aligned and classified into 6 families (F1‐F6) that contained 33 groups of known and unknown endogenous RVs (ERVs), each distinguished by a specific, deduced peptide motif. The frequency of sequences in each family was similar between RA, OA, and normal synovial tissue, but differed significantly in RA synovial fluid cells. F1 sequences (undefined, but related to murine and primate type C RVs) were lower in frequency, F2 (ERV‐9‐related), F4 (HERV‐K‐related), and F6 (HERV‐L‐related) sequences were higher in frequency, and F3 (RTVL‐H‐related) sequences were not detected, in the RA synovial fluid cells compared with the RA synovial tissues.

Conclusion. Multiple ERVs are expressed in normal and diseased synovial compartments, but specific transcripts can be differentially expressed in RA.
Soluble oligonucleosomal complexes in synovial fluid from inflamed joints
Authors: Yu Dan , Rumore Peter M. , Liu Qingli , Steinman Charles R.
Published: February 2007

Objective. To determine whether soluble oligonucleosomal DNA, typical of that released during apoptotic cell death, is present in synovial fluids from inflamed joints and, if so, whether it is present in sufficient concentrations to have pathophysiologic significance.

Methods. Fifty synovial fluid specimens from 46 patients were studied, 41 from joints with a variety of inflammatory disorders and 9 from osteoarthritic joints. DNA from freshly collected synovial fluid was isolated and quantitated by microfluorometry, and the oligonucleosomal fraction was measured by radiolabeling, gel electrophoresis, and autoradiography. Specific immunoprecipitation with monoclonal antihistone antibody, after DNA radiolabeling in whole synovial fluid, was used to detect histone binding.

Results. DNA with a typical oligonucleosomal ladder was observed in most specimens. The mean ± SD oligonucleosomal DNA concentration was 14.1 ± 18.5 μg/ml in synovial fluids from inflamed joints, considerably higher than that in osteoarthritic synovial fluids. Additionally, the DNA was shown to be complexed with histone, as would be expected. Control experiments were performed to show that the oligonucleosomal DNA was present in soluble form and did not arise due to in vitro artifact. The DNA concentrations were found to correlate significantly with the concentrations of synovial fluid leukocytes, most of which were neutrophils.

Conclusion. Synovial fluids from inflamed joints contain oligonucleosomal DNA typical of that released during apoptotic cell death. The probable source is fluid‐phase neutrophils undergoing apoptotic cell death, although this was not directly demonstrated. The concentrations are sufficient to have biologic activity similar to that shown in vitro, including lymphoproliferation and stimulation of interleukin‐6 secretion. A mechanism by which oligonucleosomal DNA may contribute to perpetuation of rheumatoid synovitis is proposed. If it is generalizable to other sites of inflammation, as seems probable, similar oligonucleosomal DNA release accompanying inflammation may play a pathogenetic role in other disorders, including systemic lupus erythematosus.
Cardiac expression of 52β, an alternative transcript of the congenital heart block‐associated 52‐kd SS‐A/Ro autoantigen, is maximal during fetal development
Authors: Buyon Jill P. , Tseng Chung‐E , Donato Francis Di , Rashbaum William , Morris Allan , Chan Edward K. L.
Published: February 2007

Objective. Congenital heart block (CHB), associated with antibodies to SS‐A/Ro and SS‐B/La, is most often detected between 18 and 24 weeks of gestation, yet the maternal heart is unaffected. We recently described an alternatively spliced 52‐kd SS‐A/Ro messenger RNA (mRNA) derived from the skipping of exon 4 which encodes a smaller protein, 52β (MW 45 kd), recognized by CHB maternal antisera. This study was designed to identify whether cardiac expression of 52β and fulllength 52α relates to the development of CHB.

Methods. Reverse transcriptase‐polymerase chain reaction was performed using primers flanking exon 4 and mRNA from 22 human fetal hearts (age 11–25 weeks) and 3 adult hearts. The brain, kidney, liver, lung, and spleen were similarly evaluated in a 15‐week, an 18‐week, and a 24‐week fetus.

Results. Expression of 52β was greatest and 52α lowest between 14 and 16 weeks of gestation. In fetal hearts ages 22–25 weeks and adult heart, the 52β transcript was markedly diminished and 52α clearly dominated. The 52β mRNA was observed in a 15‐week brain, kidney, lung, and spleen; however, its expression relative to 52α was greatest in the heart.

Conclusion. Since expression of the alternative product 52β is maximal at the time of cardiac ontogeny when maternal antibodies gain access to the fetal circulation, just prior to the clinical detection of bradyarrhythmia, a role for 52β in the development of CHB is implicated. Although other fetal tissues express 52β, there may be differences in accessibility of antigen or regenerative capacities.
A major, novel systemic lupus erythematosus autoantibody class recognizes the E, F, and G Sm snRNP proteins as an E‐F‐G complex but not in their denatured states
Authors: Brahms Hero , Raker Veronica A. , van Venrooij Walther J. , Lührmann Reinhard
Published: February 2007

Objective. To determine whether the E, F, and G Sm proteins present antigenic determinants recognized by systemic lupus erythematosus (SLE) patient sera, and if so, whether the antigenicity depends on the native conformations of the polypeptides and/or is E‐F‐G complex restricted.

Methods. Radioimmunoprecipitation, epitope tagging, expression polymerase chain reaction, in vitro translation, in vitro reconstitution, and immunoblotting.

Results. Most of the anti‐Sm SLE patient sera tested reacted with one or more of the E, F, and G proteins in immunoprecipitation studies but not on immunoblots. All sera, however, highly efficiently immunoprecipitated the E‐F‐G complex. This complex recognition was detected exclusively in anti‐Sm patient sera but not in patient sera with other serotypes.

Conclusion. We demonstrate the presence of a novel and abundant anti‐Sm autoantibody class in SLE patient sera which exclusively or predominantly recognizes conformational Sm epitopes present on the E‐F‐G complex but not on the denatured proteins. This complex recognition is highly specific for sera of the anti‐Sm serotype and may be relevant for clinical diagnosis as well as for understanding the etiology of anti‐Sm auto‐antibody production.
Affinity columns containing anti‐DNA Id+ human myeloma proteins adsorb human epibodies from intravenous gamma globulin
Authors: Williams Ralph C. , Malone Christine C. , Fry Gentry , Silvestris Franco
Published: February 2007

Objective. To study eluates of intravenous gamma globulin (IVGG) prepared from affinity columns of human cationic IgG myeloma proteins bearing anti‐DNA idiotype (Id) markers 16/6, F4, 3I, and 8.12 for possible anti‐Id (combining site) blocking activity.

Methods. Anti‐DNA idiotypic antibody activity was studied in 3 preparations of IVGG containing high, medium, and low levels of IgG anti‐F(ab′)2, and in 4 other commercial IVGG preparations. Affinity‐purified IgG anti‐DNA (APAD) from systemic lupus erythematosus (SLE) patients was biotinylated, and binding to DNA coated on enzyme‐linked immunosorbent assay plates was used to measure anti‐DNA antibody activity. IVGG was adsorbed to Sepharose 4B affinity columns linked to a panel of cationic human IgG myeloma proteins positive for anti‐DNA Id markers 16/6, F4, 3I, and 8.12. Material adsorbing to such columns was eluted at low pH (2.5) and after neutralization, tested for its ability to inhibit biotinylated APAD reacting with DNA.

Results. Only 0.05–0.9% of IVGGs bound firmly to Id affinity columns. These IVGGs were then eluted, using pH 2.5 glycine‐saline and eluates neutralized to pH 7.4. Column flowthrough and eluate fractions were compared for their ability to block SLE APAD reacting with DNA. Significant inhibition of SLE APAD combining sites was observed with eluates from anti‐DNA Id affinity columns; however, no correlation between IVGG anti‐F(ab′)2 activity and true anti‐Id blocking of APAD was apparent. No residual anti‐Id activity remained in column flowthrough fractions. No anti‐Id blocking activity was recorded for IVGG eluates from human cationic myeloma columns devoid of the 4 anti‐DNA Id markers. DNase treatment of IVGG or Id column eluates did not affect anti‐Id blocking activity. Thus, all detectable anti‐DNA idiotypic antibody capable of blocking SLE anti‐DNA combining sites bound to Id+ affinity columns. Column eluates also showed some relative concentration of IgG anti‐DNA activity, which was of lower affinity for DNA than antibodies also present in eluates which blocked anti‐DNA combining sites.

Conclusion. The presence of both anti‐DNA and antiidiotypic (anti‐combining site) activity in human anti‐DNA Id column eluates indicates that epibodies from IVGG are relatively concentrated when this strategy is used. This approach may lead to a new strategy for treatment of SLE nephritis.
Expression OF membrane type 1 matrix metalloproteinase in human articular cartilage
Authors: Büttner Frank H. , Chubinskaya Susan , Margerie Daniel , Huch Klaus , Flechtenmacher Johannes , Cole Ada A. , Kuettner Klaus E. , Bartnik Eckart
Published: February 2007

Objective. To detect the message for membrane type 1 (MT1) matrix metalloproteinase (MMP) in articular cartilage and chondrosarcoma cells, to study its expression in osteoarthritis (OA), and to determine whether interleukin‐1β (IL‐1β) influences its expression.

Methods. Reverse transcription–polymerase chain reaction methods were used to detect message. Cloning and sequencing were applied to confirm the sequence. Northern blotting was used to quantify the message for MT1‐MMP and to compare its expression in OA cartilage with or without IL‐1β treatment. In situ hybridization was utilized to show MT1‐MMP transcripts in cartilage and to study the influence of IL‐1β.

Results. The results show that MT1‐MMP messenger RNA (mRNA) is expressed in chondrosarcoma cells and OA chondrocytes. Results of the in situ hybridization confirmed the expression in OA cartilage as well as in normal cartilage. The level of mRNA was not modulated following IL‐1β stimulation.

Conclusion. This study shows that MT1‐MMP is expressed by chondrocytes. The similarities in mRNA levels in OA and normal chondrocytes suggest that regulation of MT1‐MMP mRNA may not be a primary factor in OA.
Racial differences in scleroderma among women in Michigan
Authors: Laing Timothy J. , Gillespie Brenda W. , Toth Mary B. , Mayes Maureen D. , Gallavan Robert H. , Burns Carol J. , Johanns Jewel R. , Cooper Brenda C. , Keroack Brian J. , Wasko Mary Chester M. , Lacey James V. , Schottenfeld David
Published: February 2007

Objective.To examine racial differences in disease onset, extent, manifestations, and survival among women with scleroderma.

Methods.A retrospective cohort study of women with scleroderma, diagnosed in Michigan between 1980 and 1991, was conducted. Clinical, laboratory, and demographic data were abstracted from the patients' medical records.

Results.A total of 514 women with scleroderma were identified: 117 (23%) were black and 397 (77%) were white. Among black women, the mean age at diagnosis was lower (44.5 years versus 51.5 years;P< 0.001) and diffuse disease was more common (49.6% versus 24.9%;P< 0.001) than among white women. The overall incidence of scleroderma was 14.1 per million per year: 22.5 per million per year in black women versus 12.8 per million per year in white women (P< 0.001). Pericarditis (P= 0.009), pulmonary hypertension (P< 0.001), pleural effusions (P= 0.01), myositis (P= 0.02), and an erythrocyte sedimentation rate >40 mm/hour (P< 0.001) were more frequent among black women, while white women were more likely to have digital infarctions (P< 0.001). Survival at 7 years from diagnosis was 72.5% among black women and 77.6% among white women. Age‐adjusted survival was significantly reduced among black women (P= 0.033), most likely because of increased diffuse involvement. Survival among those with renal or pulmonary involvement was also significantly reduced.

Conclusion.Black women with scleroderma were significantly more likely than white women to develop diffuse disease, be diagnosed at a younger age, have a higher incidence of inflammatory features, and have a worse age‐adjusted survival rate.
Primary juvenile fibromyalgia. Psychological adjustment, family functioning, coping, and functional disability
Authors: Reid Graham J. , Lang Bianca A. , McGrath Patrick J.
Published: February 2007

Objectives. 1) To determine the importance of psychological adjustment and family functioning in primary juvenile fibromyalgia by assessing these factors in children with fibromyalgia and in their parents, compared with children with juvenile rheumatoid arthritis (JRA) and with pain‐free control children and their parents. 2) To examine which of these factors predict functional disability.

Methods. Fifteen children in each of the 3 study groups, and their parents, completed self‐report questionnaires and pain diaries. A medical evaluation of each child was performed, including assessment of tender points by palpation and by dolorimetry.

Results. All children in the fibromyalgia group met the Yunus and Masi criteria for fibromyalgia, and 11 met the American College of Rheumatology criteria. There were almost no significant group differences in the children's or parents' psychological adjustment, ratings of family functioning, or coping strategies. Significant group differences in functional disability, pain, fatigue, tender point threshold, and control point tolerance were found. A number of the psychological adjustment, pain, fatigue, and coping variables were significantly associated with functional disability.

Conclusion. The notion that fibromyalgia is a psychogenic condition is not supported by these results. Fibromyalgia is associated with disability of a magnitude comparable to that of other chronic pain conditions. Disability among children with fibromyalgia or JRA is a function of the children's psychological adjustment and physical state, and of the parents' physical state and method of coping with pain.
Non‐Hodgkin's lymphoma and other cancers among a cohort of patients with systemic lupus erythematosus
Authors: Mellemkjér Lene , Andersen Vagn , Linet Martha S. , Gridley Gloria , Hoover Robert , Olsen Jørgen H.
Published: February 2007

Objective. To investigate whether systemic lupus erythematosus (SLE) is associated with non‐Hodgkin's lymphoma or other malignant neoplasms.

Methods. Data on a cohort of 1,585 patients with SLE from the nationwide Danish Hospital Discharge Register were linked to information in the Danish Cancer Registry to determine the occurrence of cancer during up to 15 years of followup. The expected number of cancers was calculated from accumulated person‐years and national cancer incidence rates.

Results. There was a significant excess of non‐Hodgkin's lymphoma among the SLE patients, based on 8 cases observed against 1.5 expected (relative risk [RR] 5.2, 95% confidence interval 2.2–10.3). In addition, a significantly increased RR was found for cancer of the lung (RR 1.9; n = 15), the liver (RR 8.0; n = 5), and the vagina/vulva (RR 5.7; n = 3).

Conclusion. There seemed to be a positive association between SLE and non‐Hodgkin's lymphoma. Other cancers with a possible virus‐related etiology, such as liver and vaginal/vulva cancer, were also observed in excess. In addition, there was an indication of an increased risk of lung cancer among patients who were hospitalized for SLE.
Azathioprine in Behçet's syndrome. Effects on long‐term prognosis
Authors: Hamuryudan Vedat , Özyazgan Yilmaz , Hizli Nail , Mat Cem , Yurdakul Sebahattin , Tüzün Yalçin , Şlenocak Mustafa , Yazici Hasan
Published: February 2007

Objective. To assess the effect of azathioprine (AZA) treatment on long‐term prognosis in Behçet's syndrome.

Methods. Patients (all male) who took part in a double‐blind, placebo‐controlled trial of AZA a mean ± SD of 94 ± 10 months previously were reevaluated.

Results. The emergence of blindness (log rank χ2 = 5.6, P = 0.02) and a 2‐line drop in the visual acuity of the right eye (log rank χ2 = 5.9, P = 0.015) occurred significantly more frequently among the patients originally allocated to the placebo group compared with patients who originally received AZA, despite posttrial treatment for patients in both groups when needed. There was also a trend toward more frequent occurrence of extraocular complications in the placebo group. The beneficial effect of AZA was especially pronounced among patients who had eye involvement of short duration prior to their entry into the trial.

Conclusion. Early treatment with AZA tends to favorably affect the long‐term prognosis of Behçet's syndrome.
Treatment of acquired factor VIII inhibitor using intravenous immunoglobulin in two patients with systemic lupus erythematosus
Authors: Lafferty Thomas E. , Smith J. Bruce , Schuster Stephen J. , Dehoratius Raphael J.
Published: February 2007

Acquired inhibitors of factor VIII have rarely been reported in the presence of systemic lupus erythematosus (SLE). Treatment is usually corticosteroids, with or without immunosuppressive agents such as cyclophosphamide or azathioprine. We report here case histories of 2 patients, one with documented SLE, the other with a forme fruste of SLE. Both patients had inadequate responses to corticosteroids and immunosuppressive agents. Both responded to intravenous immunoglobulin, with a decrease in their titers of factor VIII inhibitor and significantly decreased frequency of bleeding episodes despite persistent low‐level inhibitor titers. Better control of their SLE symptoms and findings was also observed. Previously reported treatments of acquired factor VIII inhibitors in SLE are discussed.
In situ expression of B7 and CD28 receptor families in skin lesions of patients with lupus erythematosus
Authors: Denfeld Ralf W. , Kind Peter , Sontheimer Richard D. , Schöpf Erwin , Simon Jan C.
Published: February 2007

Objective. To examine the expression of costimulatory molecules of the B7 and CD28 receptor families in active skin lesions of patients with systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus (SCLE), and chronic discoid lupus erythematosus (CDLE).

Methods. The in situ expression of B7‐1, B7‐2, BB‐1, and CD28 was studied by immunohistochemistry, and B7‐1 and B7‐2 RNA expression was examined by reverse transcription‐polymerase chain reaction.

Results. Only in lesional skin from SLE, SCLE, and CDLE patients did dermal and epidermal antigenpresenting cells (APC) express B7‐1 and B7‐2, particularly when in apposition to CD28+ T cells. These B7‐1 + and B7‐2+ APC bound CTLA‐4 fusion protein. In lesional (but not in nonlesional) skin, keratinocytes expressed BB‐1. The majority of infiltrating T cells were CD28+. B7‐1 and B7‐2 RNA were expressed in lesional skin from SLE, SCLE, and CDLE patients; when dermis was separated from epidermis, only faint B7‐1 and B7‐2 RNA signals were detectable in the epidermis, indicating that dermal but not epidermal cells were the major source of B7‐1 and B7‐2 RNA. During treatment, both B7‐1 and B7‐2 protein and RNA expression were reduced.

Conclusion. These in situ findings suggest that costimulation via the B7‐CD28 pathway may be important for the generation and/or propagation of T cell activity in skin lesions of humans with lupus erythematosus. Thus, the manipulation of this pathway (e.g., by CTLA‐4 fusion protein) could be an important target for the development of future therapies for LE.
Repeat treatment of Rheumatoid Arthritis patients with a murine anti‐intercellular adhesion molecule 1 monoclonal antibody
Authors: Kavanaugh Arthur F. , Schulze‐Koops Hendrik , Davis Laurie S. , Lipsky Peter E.
Published: February 2007

Objective. To assess the safety and efficacy of a second course of treatment with a murine monoclonal antibody (MAb) to intercellular adhesion molecule 1 (ICAM‐1; CD54) in active rheumatoid arthritis (RA).

Methods. In an open‐label study, 8 patients who had previously received a course of anti‐ICAM‐1 MAb received a second course.

Results. The second course of therapy was associated with adverse effects suggestive of immune complex formation. Such adverse effects were not seen during the initial course of therapy. Clinical efficacy associated with the second course of therapy was less than that observed in the first course.

Conclusion. Repeated courses of therapy with a murine MAb to ICAM‐1 would probably not be a useful therapeutic strategy in patients with RA, probably because of its immunogenicity.
Polymorphism of the HLA‐DMA and DMB genes in Rheumatoid Arthritis
Authors: Pinet Valérie , Combe Bernard , Avinens Odile , Caillat‐Zucman Sophie , Sany Jacques , Clot Jacques , Eliaou Jean‐François
Published: February 2007

Objective. To determine whether the HLA‐DMA and DMB genes, whose encoded molecules are involved in HLA class II‐restricted antigen presentation, contribute to the genetic susceptibility to rheumatoid arthritis (RA).

Methods. One hundred ninety‐one RA patients, 147 control subjects, and 218 HLA‐DRBI genotypematched control subjects were oligotyped for DMA and DMB genes.

Results. DMA*0103 and DMB*0104 were significantly increased in the RA patients compared with the randomly selected and the matched controls, thus indicating a direct influence of the DM genes. After stratification of the patients and matched controls according to DRB1 genotypes, only DMA*0103 was increased in the RA patients with DRB1*01, as well as in the patients negative for the RA‐susceptibility DR alleles.

Conclusion. Our results suggest that DMA*0103 could play an additional role in the genetic susceptibility to RA.
Henoch‐Schönlein purpura in adulthood and childhood. Two different expressions of the same syndrome
Authors: Blanco Ricardo , Martínez‐Taboada Víctor M. , Rodríguez‐Valverde Vicente , García‐Fuentes Miguel , Gonzalez‐Gay Miguel A.
Published: February 2007

Objective. To assess the possible differences between children (⩽ 20 years) and adults (> 20 years) with Henoch‐Schönlein purpura (HSP).

Methods. A retrospective study of an unselected population of patients with HSP who presented to our teaching hospital between 1975 and 1994. Patients were classified as having HSP according to the criteria proposed by Michel et al.

Results. Following the above‐mentioned criteria, 162 white patients (113 male and 49 female) were classified as having HSP; 46 of the patients were adults (mean ± SD age 53.2 ± 16.9 years) and 116 were children (6.9 ± 3.1 years). We were unable to identify any precipitating event in 72% of the adults and 66% of the children. The frequency of previous drug treatment, primarily antibiotics or analgesics, was similar in both groups, whereas previous upper respiratory tract infection was more frequent among the children (P < 0.02). At symptom onset, cutaneous lesions were the main clinical manifestation in both groups. However, adults had a lower frequency of abdominal pain (P < 0.008) and fever (P < 0.01), and a higher frequency of joint symptoms (P < 0.001). During the clinical course, adults had more frequent (P < 0.001) and severe renal involvement. An increased erythrocyte sedimentation rate was also more frequent in the adults (P < 0.001). Adults required more aggressive therapy, consisting of steroids (P < 0.002) and/or cytotoxic agents (P < 0.001).

The outcome was relatively good in both age groups, with complete recovery in 107 children (93.9%) and in 33 adults (89.2%) after a mean ± SD followup of 19.4 ± 27.7 (median 12) and 21.8 ± 33.5 (median 15) months, respectively.

Conclusion. In adulthood, HSP, as defined by the criteria proposed by Michel et al, represents a more severe clinical syndrome, with a higher frequency of renal involvement. However, the final outcome of HSP is equally good in patients of both age groups.
Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies
Authors: Lundberg Ingrid , Ulfgren Ann‐Kristin , Nyberg Pernilla , Andersson Ulf , Klareskog Lars
Published: February 2007

Objective. To study cytokine expression in muscle tissues of patients with inflammatory myopathies and to compare the profiles of patients with polymyositis (PM), inclusion body myositis (IBM), and dermatomyositis (DM).

Methods. We performed indirect immunohistochemistry studies of muscle tissue sections with a panel of 16 different cytokine‐specific monoclonal antibodies, directed against interleukin‐1α, (IL‐1α), IL‐1β, IL‐1 receptor antagonist (IL‐1ra), IL‐2, IL‐3, IL‐4, IL‐6, IL‐8, IL‐10, IL‐13, interferon‐γ (IFNγ), tumor necrosis factor α (TNFα), granulocyte‐macrophage colonystimulating factor (GM‐CSF), transforming growth factor β1 (TGFß1), TGFß2, and TGFß3 in 5 untreated patients each with PM, DM, and IBM and in 4 normal controls. Fresh frozen muscle tissue sections were fixed in formaldehyde before the procedure. The use of saponin as a detergent to permeabilize the cell membranes enabled identification of intracellular cytokine production.

Results. The most prominent finding was the expression of IL‐1α observed in all patients but in none of the normal controls. In all patients with PM, DM, and IBM, IL‐1α was expressed in endothelial cells of capillaries, arterioles, and venules in areas surrounded by inflammatory cells, and also in areas with no or scarce inflammatory cells in both endomysium and perimysium. Furthermore, IL‐1α was also expressed in mononuclear inflammatory cells in all 15 cases. IL‐1β was observed in inflammatory cells in 10 of the 15 patients but, in contrast to IL‐1α, it was not expressed in blood vessel walls. TGFß1, TGFß2, and TGFß3 were strongly positive in all 15 patients, but only scattered cells were positive in the normal controls. The remaining cytokines were observed only in relatively few cells and only in occasional patients (although the patients were selected for the presence of large infiltrates), and in none of the controls. The patterns were similar in PM, DM, and IBM.

Conclusion. Cytokine expression in muscle tissue of patients with inflammatory myopathy is dominated by IL‐1α, IL‐1β, and TGFß1–3. The predominant IL‐1α expression in the blood vessels indicates an importance of the endothelial cells in the inflammatory process in PM, IBM, and DM. A sustained, local release of T cell‐derived cytokines may not be a requirement for tissue injury in the inflammatory myopathies. There does not appear to be a qualitative difference in cytokine expression patterns in PM, IBM, and DM.
The outcome of bacterial arthritis. A prospective community‐based study
Authors: Kaandorp Carola J. E. , Krijnen Pieta , Moens Hein J. Bernelot , Habbema J. Dik F. , van Schaardenburg Dirkjan
Published: February 2007

Objective. To assess the outcome and adverse prognostic factors of bacterial arthritis (BA).

Methods. In a prospective community survey of BA, data were collected at the time of diagnosis and at a mean of 2 years later. A poor patient outcome was defined as death due to BA or severe overall functional deterioration. A poor joint outcome was defined as amputation, arthrodesis, prosthetic surgery, or severe functional deterioration. Possible prognostic factors were analyzed by univariate analysis.

Results. BA was diagnosed in 154 patients, 121 adults and 33 children. One‐half of the adults had a preexisting joint disease and 29% of the infected joints contained synthetic material. The patient outcome was poor in 21% of all patients, and the joint outcome was poor in 33% of the surviving patients. Adverse prognostic factors were an older age, preexisting joint disease, and an infected joint containing synthetic material. These factors were interrelated. There was no association between a poor outcome and young age, comorbidity, immunosuppressive medication, functional class, multiple infected joints, type of microorganism, or treatment delay.

Conclusion. BA had a poor outcome in almost one‐half of the patients. Patients who were older, had a preexisting joint disease, and/or had an infected joint containing synthetic material had the poorest prognosis.
Induction of apoptosis in peripheral blood lymphocytes following treatment in vitro with hydroxychloroquine
Authors: Meng Xue Wei , Feller John M. , Ziegler John B. , Pittman Sally M. , Ireland Christine M.
Published: February 2007

Objective. Defective regulation of apoptosis may be central to the development of autoimmune disorders. This study investigated the possibility that the antirheumatic effect of hydroxycholoroquine (HCQ) may be achieved by up‐regulation of apoptosis.

Methods. Peripheral blood lymphocytes collected from normal controls and patients with systemic lupus erythematosus (SLE) were cultured in the presence or absence of a range of concentrations of HCQ. Cells undergoing apoptosis were identified by several standard methods, including morphologic changes, DNA fragmentation, and flow cytometry. For some experiments, lymphocytes were simultaneously stained with antibodies to T cell surface markers and with propidium iodide for dual‐stain flow cytometric studies.

Results. HCQ was able to induce apoptosis in peripheral blood lymphocytes in a dose‐ and time‐dependent manner. HCQ induced these changes in all T cell subpopulations studied. There was no significant difference between the controls and patients with SLE in terms of the percentage of apoptotic cells detected following treatment with HCQ.

Conclusion. The present study demonstrated that HCQ induces apoptosis in peripheral blood lymphocytes, which leads to the speculation that HCQ may exert its antirheumatic effect through this mechanism.
The 52‐kd protein as a target of intermolecular spreading of the immune response to components of the SS‐A/Ro‐SS‐B/La complex
Authors: Tseng Chung‐E , Chan Edward K. L. , Miranda Eugenia , Gross Michael , Donato Francis Di , Buyon Jill P.
Published: February 2007

Objective. To determine whether immunization of healthy non‐autoimmune mice with 52‐kd SS‐A/Ro induces a secondary antibody response to other components of the 48‐kd SS‐B/La‐60‐kd SS‐A/Ro RNP complex and vice versa, since anti‐52‐kd antibodies have been invariably linked to these antigens in patients with Sjögren's syndrome and in mothers whose children have neonatal lupus.

Methods. Female BALB/c mice were immunized with 100 μg of 6 × His recombinant human 48‐kd SS‐B/La, 52‐kd SS‐A/Ro, or 60‐kd SS‐A/Ro proteins, or the 6 × His polypeptide control, each purified by Ni2+ affinity chromatography. Mice subsequently received booster injections with 50 μg of the same antigen every 10–21 days. Immune responses were measured by enzyme‐linked immunosorbent assay (ELISA), immunoblotting of recombinant antigens, and immunoprecipitation of 35S‐methionine‐labeled in vitro translation products.

Results. Immunization with 48‐kd SS‐B/La resulted in anti‐48‐kd SS‐B/La antibodies within 45 days, followed 10 days later by a secondary response to 52‐kd SS‐A/Ro, as measured by ELISA. Antibody spreading to 60‐kd SS‐A/Ro was not detected. Immunization with 52‐kd SS‐A/Ro resulted in rapid high‐titer anti‐52‐kd SS‐A/Ro responses within 27 days. Spreading to 48‐kd SS‐B/La occurred in only 1 mouse and 60‐kd SS‐A/Ro was detected in a minority of the mice after prolonged antigen exposure. Immunization with 60‐kd SS‐A/Ro led to anti‐60‐kd SS‐A/Ro responses within 37 days, followed 3 months later by low‐titer anti‐48‐kd SS‐B/La and anti‐52‐kd SS‐A/Ro antibodies. All primary immune responses were confirmed by immunoblotting and immunoprecipitation. While immunoblotting of the recombinant proteins revealed reciprocal intermolecular spreading in the majority of mice, immunoprecipitation clearly demonstrated that predominant spreading was generated after immunization with 48‐kd SS‐B/La, which consistently resulted in antibodies to 52‐kd SS‐A/Ro.

Conclusion. The murine responses observed in the present study, demonstrating reciprocal intermolecular spreading to 48‐kd SS‐B/La, 52‐kd SS‐A/Ro, and 60‐kd SS‐A/Ro, support the linkage of 52‐kd SS‐A/Ro with the other proteins, despite their as‐yet‐undetected association in vivo. The marked recruitment of anti‐52‐kd SS‐A/Ro responses elicited by 48‐kd SS‐B/La may provide a lead to exploring the physical interaction, direct or indirect, of 52‐kd SS‐A/Ro with the SS‐A/Ro‐SS‐B/La RNP particle and its presentation to the immune system. These data should facilitate the establishment of a murine model of neonatal lupus.
Multiple congenital anomalies associated with weekly low‐dose methotrexate treatment of the mother
Authors: Buckley Lenore M. , Bullaboy Charles A. , Leichtman Lawrence , Marquez Mariella
Published: February 2007

This report describes an infant with multiple congenital anomalies born to a 20‐year‐old mother with juvenile rheumatoid arthritis who had been taking weekly low‐dose methotrexate (MTX) during the first trimester of pregnancy. The abnormalities found were consistent with those associated with maternal ingestion of MTX at dosage levels used to induce abortions, i.e., the group of abnormalities referred to as the “aminopterin syndrome.” Although weekly low‐dose MTX has been associated with spontaneous abortions, this is, to our knowledge, the first case report describing multiple congenital abnormalities consistent with MTX embryopathy secondary to weekly low‐dose MTX treatment.
Changes in messenger rna and protein levels of proteoglycans and link protein in human osteoarthritic cartilage samples
Authors: Cs‐Szabó Gabriella , Melching Lee I. , Roughley Peter J. , Glant Tibor T.
Published: February 2007

Objective. To determine the steady‐state messenger RNA (mRNA) levels and corresponding protein contents of major matrix components in osteoarthritic (OA) cartilage.

Methods. Steady‐state levels of gene‐specific mRNA (relative to GAPDH) were measured by quantitative polymerase chain reaction (PCR), and the relative levels of the corresponding proteins were determined by Western blotting.

Results. All mRNA levels and corresponding protein contents of aggrecan and versican (hyaluronan‐binding large proteoglycans), decorin, biglycan, fibromodulin, and lumican (small proteoglycans), and link protein were higher in OA cartilage samples than in age‐matched normal samples. The ratio of increase, however, was different for each component. The mRNA and protein levels of biglycan, decorin, and fibromodulin increased synchronously, whereas message for link protein and lumican were several‐fold higher than expected by their measured protein contents. Versican was also detected in OA cartilage; however, the versican protein content was associated with a relatively low mRNA level.

Conclusion. The expression of matrix components was increased in chondrocytes of OA cartilage, especially the expression of small proteoglycans, most likely due to the repair processes. A discoordinate gene expression accompanied with imbalanced accumulation of noncollagenous matrix components may contribute to the disorganization of the cartilage and the development of OA processes.
The influence of silicone implantation on type II collagen‐induced arthritis in mice
Authors: Schaefer Caralee J. , Whalen Janey D. , Knapp Terry , Wooley Paul H.
Published: February 2007

Objective. To determine whether silicone implantation exacerbates autoimmune disease in a murine experimental model of arthritis.

Methods. DBA/1 mice were implanted with silicone in the form of an elastomer, gel, or oil, and immunized with type II collagen. The influence of silicone implantation on collagen‐induced arthritis and the immune response to type II collagen were determined by comparison against control mice receiving sham implantation. Adjuvant effects of silicone implantation were examined by measuring cytokine levels in implanted animals and assessing autoantibodies against proteins extracted from recovered silicone implants.

Results. No adverse influence of silicone implantation on the clinical aspects of collagen‐induced arthritis was observed. Further, polydimethylsiloxane silicone oil failed to serve as an adjuvant in the immune or arthritogenic response to type II collagen in mice. Cytokine analysis indicated that tumor necrosis factor α levels were lower and interleukin‐2 levels were higher in silicone‐implanted mice. The development of arthritis increased protein binding to implanted elastomers and gel, and autoantibodies against silicone‐bound proteins were present in sera from arthritic mice and absent in sera from nonarthritic mice.

Conclusion. The data suggest that silicone implantation may result in autoantibodies against silicone‐bound proteins, and the presence of arthritis may either provoke or increase the level of such autoantibodies. However, silicone implantation did not increase the incidence or severity of disease compared with sham‐operated controls. Thus, it appears that autoantibodies against silicone‐bound proteins may not have pathologic significance in this experimental model of arthritis.
Paclitaxel selectively induces mitotic arrest and apoptosis in proliferating bovine synoviocytes
Authors: Hui A. , Kulkarni G. V. , Hunter W. L. , McCulloch C. A. G. , Cruz T. F.
Published: February 2007

Objective. Rheumatoid arthritis (RA) is characterized by chronic progressive destruction of joints involving several disease processes, such as villous hypertrophy, proliferation of synovial lining cells, and infiltration of inflammatory cells. Synovial cell activation and proliferation is thought to be a key step in the destruction of cartilaginous and bony tissues in RA joints. In view of the invasive properties of synoviocytes in RA, we conducted in vitro studies to determine the mechanism of action of paclitaxel (Taxol) on synoviocytes, which may account for the inhibition of joint destruction found when this agent is administered.

Methods. Cultured synovial cells were treated with various concentrations of paclitaxel and were evaluated by cell viability, fluorescence microscopy, flow cytometry of DAPI‐stained cells, and electron microscopy.

Results. The data indicated that paclitaxel inhibited synoviocyte proliferation by a G2/M phase block and was toxic to synoviocytes by inducing apoptosis. Confluent cells such as chondroyctes and synoviocytes were not affected by paclitaxel. Synchronization of synovioyctes at the G1/S boundary effectively abolished paclitaxel‐induced apoptosis.

Conclusion. The data indicate that induction of apoptosis in synoviocytes might be dependent on transit through the cell cycle, specifically through G2 and mitosis. Further, paclitaxel was selectively toxic to proliferating synoviocytes but spared nonproliferating synoviocytes and chondrocytes. These results demonstrate that paclitaxel can inhibit synovial cell proliferation and pannus formation in RA joints in vivo. We suggest that paclitaxel be considered as a prototypical compound for a new class of potential chondroprotective agents.
Soluble Fas (APO‐1, CD95) and soluble Fas ligand in rheumatic diseases
Authors: Nozawa Kazuhisa , Kayagaki Nobuhiko , Tokano Yoshiaki , Yagita Hideo , Okumura Ko , Hasimoto Hiroshi
Published: February 2007

Objective. To assess levels of soluble Fas (sFas) and soluble Fas ligand (sFas‐L) in sera from patients with various rheumatic diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), mixed connective tissue disease (MCTD), and Sjögren's syndrome (SS).

Methods. Levels of sFas and sFas‐L were determined by a sandwich enzyme‐linked immunosorbent assay.

Results. In SLE, PM/DM, MCTD, and SS, sFas levels were significantly higher compared with normal controls. Levels of sFas in the SLE patients were significantly higher than in patients with other rheumatic diseases. Levels of sFas‐L were significantly increased in SS patients. SLE and RA patients with high levels sFas‐L tended to have high levels of sFas, while sFas and sFasL levels did not correlate in patients with other diseases. In some of the SLE patients, sFas and sFas‐L levels decreased following steroid therapy.

Conclusion. Serum sFas and sFas‐L levels were significantly higher in some rheumatic disease patients. Since these changes are complex in these rheumatic diseases, it may be difficult to directly relate sFas and sFasL to their pathogenesis.