bluuebunny/crossref_metadata_2025 huggingface dataset:
Epitope patterns of Anti‐RNP antibodies in rheumatic diseases evidence for an antigen‐driven autoimmune response
Authors: Habets Winand J. , Hoet Margot H. , Venrooij Walther J.Van
Published: February 2007

Autoantibodies against small nuclear ribonucleo‐proteins (snRNP) are common in systemic lupus erythematosus and related disorders. The 3 categories, anti‐(U1)RNP, anti‐(U1,U2)RNP, and anti‐Sm, all contain a common antibody specificity directed against the U1 snRNP‐associated A protein. To determine the specificity of anti‐U1 snRNP A protein antibodies for various antigenic sites, we tested 26 different anti‐snRNP‐positive sera for reactivity with fragments of the U1 snRNP A protein, which was produced using recombinant DNA technology. Several different fragments were shown to contain autoimmune‐reactive epitopes, which indicates that the antibody response against the U1 snRNP A protein is polyclonal. Antibodies against a discontinuous or conformational epitope were found in most of the sera tested, regardless of whether they were classified as anti‐(U1)RNP, anti‐Sm, or anti‐(U1,U2) RNP. These results strongly support the hypothesis that the anti‐snRNP autoimmune response is antigen driven.
Proteoglycan‐induced polyarthritis and spondylitis adoptively transferred to naive (nonimmunized) BALB/c mice
Authors: Mikecz Katalin , Glant Tibor T. , Buzás Edit , Poole A.Robin
Published: February 2007

Mononuclear cells from BALB/c mice with progressive polyarthritis and spondylitis induced by injection of fetal human articular cartilage proteoglycan (PG) were used to transfer arthritis by intravenous injection into irradiated, nonimmunized syngeneic mice. Successful transfer of arthritis to BALB/c mice required the injection of lymphocytes from mice with arthritis, along with 50 m̈g of human fetal PG, or lymphocytes stimulated in vitro with either fetal human PG or with mouse cartilage PG. In addition, interleukin‐2 or immune sera from animals with arthritis significantly reduced the time to onset of transferred disease. The onset of adoptively transferred arthritis, using cells and antigen, from the time of the first injection (38.2 ± 18.2 days, mean ± SD) was shortened if lymphocytes from mice with transferred arthritis were reinjected (retransferred) into other, irradiated syngeneic mice (6.1 ± 2.6 days). The appearance of autoreactive antibodies to mouse cartilage PG in the sera of mice with adoptively transferred arthritis (secondary or tertiary) preceded the appearance of the first clinical symptoms by a few days. The transfer of arthritis was blocked by pretreatment of donor (arthritic) lymphocytes with either anti‐T cell or anti‐B cell antibodies and complement. Exposure of mononuclear cells from mice with arthritis to PG, and its removal prior to transfer, also resulted in transfer of the arthritis. PG‐induced arthritis was not transferred to nonirradiated mice, nor to irradiated mice injected with lymphocytes from animals with primary arthritis without chondroitinase ABC‐digested fetal human PG. Arthritis never developed after injection of immune sera from mice with arthritis (without cells), nor when cells of nonarthritic animals were used with chondroitinase ABC‐digested fetal human PG, with or without interleukin‐2.
Eosinophilia‐myalgia syndrome due to l‐tryptophan ingestion: report of four cases and review of the Maryland experience
Authors: Roubenoff Ronenn , Coté Timothy , Watson Rosemarie , Levin Michael L. , Hochberg Marc C.
Published: February 2007

Eosinophilia‐myalgia syndrome (EMS) is a recently described clinical entity that has been ascribed to taking over‐the‐counter preparations of the amino acid L‐tryptophan. We describe 4 patients with EMS, 3 of whom presented with eosinophilic fasciitis, and we review the epidemiology of EMS reported in Maryland and discuss the possible pathophysiology of the disease. EMS should be considered in the differential diagnosis of severe myalgia, eosinophilia, and eosinophilic fasciitis.
The effect of ethnicity on major histocompatibility complex complement allotypes and extended haplotypes in patients with systemic lupus erythematosus
Authors: Schur P. H. , Marcus‐Bagley D. , Awdeh Z. , Yunis E. J. , Alper C. A.
Published: February 2007

Previous studies of patients with systemic lupus erythematosus (SLE) have shown an increased frequency of certain major histocompatibility complex (MHC) markers, including HLA–DR2, DR3, and C4AQO (C4A‐null), in Caucasian patients. However, most of these studies were of randomly selected, unrelated patients; families were not included, and haplotypes were not determined. In order to define more accurately the possible role of MHC genes in lupus susceptibility, HLA–A, B, C, and DR, as well as BF, C2, C4A, C4B, and GLO, markers were determined in 62 Caucasian patients of known ethnic background, and in the members of their families. The distributions of extended haplotypes (fixed combinations of HLA–B, DR, and complotype alleles), fragments thereof, and individual alleles were determined in SLE patients and controls. The MHC distributions in all patients were compared with haplotypes in a normal Caucasian population. There were no statistically significant differences between the frequencies of any MHC marker, fragment, or extended haplotype in the patients compared with the controls. The patients were categorized into 2 groups of European ancestry (English/Irish; other Europeans), and each group was compared with a group of ethnically matched controls. There was a statistically significantly increased frequency of the alleles C4AQO and DR3 and the complotype SC01 in SLE patients of English/Irish descent as compared with ethnically matched controls. The increase in C4AQ0 and DR3 could be accounted for by the fact that they were part of the extended haplotype [HLA–B8;SC01;DR3] and/or its fragment (SC01;DR3). No increase in any MHC marker was observed in the other patients. Thus, our results suggest that SLE in patients of English/Irish ancestry is associated with an MHC extended haplotype and/or its DR‐containing fragment.
Human lupus‐type inclusions in umbilical cord blood mononuclear cells
Authors: Rich Steven A. , Gibbons William E.
Published: February 2007

Mononuclear cells purified from umbilical cord blood activated oligoadenylate synthetase and formed human lupus‐type inclusions (LI) when cultured with the purified recombinant human leukocyte interferon, IFLrA. LI frequencies increased from 0% to a low of 0.75% and a high of 6.25% in 4‐day cultures with IFLrA (100 units/ml). These interferon‐induced responses in the mononuclear cells of neonates indicate that LI are solely an intrinsic product of normal cells, and not an exogenous virus or some other environmental agent.
Pseudotumor of the craniocervical junction during long‐term hemodialysis
Authors: Rousselin BenoǐT , Helenon Olivier , Zingraff Johanna , Delons Simone , Drueke Tilman , Bardin Thomas , Moreau Jean‐FrançOis
Published: February 2007

A systematic study of the upper cervical spine was performed using magnetic resonance imaging in 25 patients (15 men and 10 women) who had been undergoing hemodialysis for more than 10 years. Seven pseudotumors of the periodontoid soft tissue were disclosed, which were similar to the pannus recently described in rheumatoid arthritis. Bone cystic radiolucencies were observed in association with these pseudotumors in 5 patients. The radiolucencies were located in the atlas (1 in the lateral mass and 1 in the anterior branch) and in the axis (3 in the odontoid process and 1 in the vertebral body). No horizontal or vertical atlantoaxial subluxation was demonstrated. These features were observed only in patients who had amyloid arthropathy. They could be a frequent, yet thus far little‐recognized, feature of β2‐microglobulin amyloidosis.
The post‐occlusive hyperemic response in patients with systemic sclerosis
Authors: Wigley F. M. , Wise R. A. , Mikdashi J. , Schaefer S. , Spence R. J.
Published: February 2007

We investigated post‐ischemic hyperreactive cutaneous blood flow in patients with primary Raynaud's phenomenon and Raynaud's phenomenon secondary to systemic sclerosis (SSc). Reactive hyperemia was measured over a locally warmed area of skin, using a laser Doppler flowmeter, following 5 minutes of suprasystolic occlusion of blood flow. We found that patients with primary Raynaud's phenomenon had normal post‐ischemic blood flow compared with normal controls. In contrast, patients with SSc had reduced levels of baseline and peak blood flow compared with either the primary Raynaud's phenomenon patients or the normal subjects. Infusion of carbaprostacyclin, a potent prostacyclin analog vasodilator, did not increase blood flow in the SSc patients, nor did it restore the reactive hyperemic response. These findings are consistent with the hypothesis that patients with the nonvasoconstricted condition of SSc have fixed structural defects that limit cutaneous microvascular blood flow.
Type XI collagen‐degrading activity in human osteoarthritic cartilage
Authors: Yu Lucino P. , Smith Gerald N. , Brandt Kenneth D. , Capello William
Published: February 2007

Homogenates of 6 samples of human osteoarthritic cartilage were shown to degrade exogenous type XI collagen. On sodium dodecyl sulfate‐polyacrylamide gel electrophoresis, the cleavage products generated by each homogenate were similar, and they were identical to those obtained by cleavage of the substrate with purified gelatinase. Enzyme activity, which was inhibited by EDTA, was greater in extracts of fibrillated osteoarthritic cartilage than in extracts of grossly normal cartilage from the same joint or in extracts of cartilage from joints with osteonecrosis. Activation with APMA enhanced digestion, but breakdown was apparent in extracts of fibrillated osteoarthritic cartilage even without APMA. Enzymatic degradation of type XI collagen could play a significant role in the turnover of articular cartilage in health and disease states.
A subluxing arthropathy associated with the anti‐jo‐1 antibody in polymyositis/dermatomyositis
Authors: Oddis Chester V. , Medsger Thomas A. , Cooperstein Lawrence A.
Published: February 2007

Of 180 patients with polymyositis/dermatomyositis (PM/DM) seen at the University of Pittsburgh and affiliated hospitals since 1975, 21 of 100 tested positive for the anti‐Jo‐1 antibody. Sixteen of the 21 patients were women and 18 were white. Fifteen had adult PM, 4 had myositis in overlap with scleroderma, and 2 had adult DM. Evidence of interstitial lung disease was found in 12 of 18 anti‐Jo‐1 positive patients (67%), but in only 15 of 79 anti‐Jo‐1 negative patients (19%) (P > 0.0002). The 21 anti‐Jo‐1 positive patients were divided into 3 separate groups based on the observed articular findings. Four patients had a deforming, predominantly nonerosive arthropathy with subluxations of the distal interphalangeal joints, especially the thumbs. Eight patients had a nondeforming arthropathy primarily affecting the small joints of the hands, wrists, shoulders, and knees. Those with deformities had a longer duration of arthritis compared with those with nondeforming arthropathy (mean 14.5 years versus 3.3 years). Nine anti‐Jo‐1 positive patients had no joint arthropathy. Three of 4 patients with deformities have required articular reconstructive surgery for subluxation, with 2 having associated subcutaneous calcinosis.
Human rheumatoid factor cross‐idiotypes
Authors: Barnes Joye Lynn , Goni Fernando , Heyermann Hubert , Frangione Blas , Agnello Vincent
Published: February 2007

The BLA cross‐idiotype (XId) is present on a unique subset of rheumatoid factors (RF) that cross‐react with DNA‐histone. In this study, prototype Bla monoclonal RF was shown from serologic investigations and N‐terminal amino acid sequence analysis to have distinct k chains related to the Vk III subgroup and VH4 heavy chains. The amino terminus of the heavy chain was cyclized, rendering the protein resistant to Edman degradation and providing a possible investigator bias to the published Ig sequence data to date. This appears to be the first definitive report of a serum IgM that expresses the VH4 gene. RF with DNA cross‐reactivity have been reported to be produced by human and mouse cloned cells that have the VH4 or homologous mouse Vh36–60 gene.
Rescue of interleukin‐1 activity by leucovorin following inhibition by methotrexate in a murine in vitro system
Authors: Segal Rafael , Yaron Michael , Tartakovsky Boris
Published: February 2007

We have recently shown that methotrexate (MTX) inhibits interleukin‐1 (IL‐1) activity in vitro. This effect may play an important role in the rapid antiinflammatory action of MTX in rheumatoid arthritis. In the present study, we showed that the inhibition of IL‐1 activity in vitro by MTX is dependent on folate pathways since, after the addition of leucovorin, the inhibitory effect of MTX was abolished. These findings may shed more light on the mechanism of action of MTX in rheumatoid arthritis. They also point to the fact that some IL‐1 activities may be dependent on intracellular folate pathways.
Suppression of type II collagen–induced arthritis by monoclonal antibodies
Authors: Kobayashi Seiichi , Terato Kuniaki , Harada Yoshitada , Moriya Hideshige , Taniguchi Masaru
Published: February 2007

Some mouse monoclonal antibodies raised against chicken type II collagen suppressed or delayed the onset of chicken type II collagen–induced arthritis in DBA/1 mice. This was correlated with the suppression of anti–mouse type II collagen antibody responses following immunization with chicken type II collagen. The epitopes recognized by the suppressive antibodies were found to be present on cyanogen bromide (CB)—digested collagen peptides CB‐11 and CB‐12. This was also confirmed by the finding that administration of the CB‐11 or CB‐12 peptide suppressed the induction of arthritis.
Biologic effects of an interleukin‐1 receptor antagonist protein on interleukin‐1–stimulated cartilage erosion and chondrocyte responsiveness
Authors: Smith Robert J. , Chin Jia En , Sam Laurel M. , Justen James M.
Published: February 2007

Recombinant human interleukin‐1α (IL‐1α) and recombinant human IL‐1β stimulate matrix proteoglycan degradation and inhibit glycosaminoglycan synthesis in bovine nasal cartilage explants. A 17‐kd human recombinant IL‐1 receptor antagonist protein (IRAP) caused a concentration‐dependent (0.2–200 ng/ml) suppression of the effects of IL‐1α and IL‐1β in cartilage organ cultures. IRAP inhibited the binding of radiolabeled IL‐1α to rabbit articular chondrocytes. Matrix metalloproteinase (collagenase, gelatinase, and stromelysin) and prostanoid production by IL‐1–activated rabbit articular chondrocytes was also suppressed by IRAP. These results could have potential significance in the development of a new antiarthritis therapy based on an IRAP.
Down‐regulation of adoptive adjuvant‐induced arthritis by suppressor factor(s)
Authors: Nanishi Fumio , Battisto Jack R. , Nanishi Fumio , Battisto Jack R.
Published: February 2007

We recently described a method for inducing immunologic tolerance to trinitrochlorobenzene (TNCB), a hapten that generates suppressor cells capable of down‐regulating the efferent phase of TNP‐specific contact hypersensitivity in rats. Peritoneal exudate cells (PEC) of such tolerized rats, upon being triggered by specific hapten, suppressed contact hypersensitivity to another hapten elicited at the same time. This implied that cells that mediate delayed‐type hypersensitivity of any specificity might be down‐regulated, provided that the suppressor cells are activated with specific antigen and that the unrelated delayed‐type hypersensitivity is elicited in parallel. To rigorously test this possibility, we examined the ability of TNP‐specific suppressor lymphoid cell factors to affect cells that mediate adoptively transferable adjuvant‐induced arthritis (AIA) in rats. To induce arthritis, spleen cells from Freund's complete adjuvant‐injected rats were stimulated with concanavalin A and administered to naive recipients. Prior to adoptive transfer, the cells were exposed for brief intervals to supernatants of lymphoid cells from control and hapten‐tolerized rats. Supernatants of PEC and lymph node cells from hapten‐tolerized rats were found to markedly reduce the effectiveness of cells that mediate AIA. The hapten‐tolerized cells required reexposure to hapten prior to preparation of the supernatants. Supernatants of spleen cells from hapten‐tolerized rats that had been hapten‐painted as well as hapten‐triggered and supernatants of lymph node cells and of PEC from only hapten‐painted or hapten‐triggered rats were ineffective in altering the AIA. Thus, factors from suppressor cells induced toward hapten‐coupled self‐antigens have been found to adversely affect the function of lymphoid cells that mediate a totally unrelated inflammatory response, namely, AIA. The clinical implications of these findings are discussed.
The effect of nifedipine on myocardial perfusion and metabolism in systemic sclerosis. A positron emission tomographic study
Authors: Duboc Denis , Kahan André , Maziere Bernard , Loc'H Christian , Crouzel Christian , Menkès Charles J. , Amor Bernard , Strauch Georges , Guérin François , Syrota André
Published: February 2007

We assessed the effect of nifedipine on myocardial perfusion and metabolism in 9 patients with systemic sclerosis, using positron emission tomography with a perfusion tracer (potassium‐38) and a metabolic tracer (18F‐fluorodeoxyglucose [18FDG]). Nifedipine, 20 mg 3 times daily for 1 week, induced a significant increase in 38K myocardial uptake, a significant decrease in 18FDG myocardial uptake, and a significant increase in the myocardial 38K:18FDG ratio. These results indicate that the increase in myocardial perfusion is associated with modifications in myocardial energy metabolism, which probably result from a beneficial anti‐ischemic effect of nifedipine in patients with systemic sclerosis.
Activation of CD16+ effector cells by rheumatoid factor complex. Role of natural killer cells in rheumatoid arthritis
Authors: Hendrich Christian , Kuipers Jens G. , Kolanus Waldemar , Schmidt Reinhold E. , Hammer Michael
Published: February 2007

The role of natural killer (NK) cells in rheumatoid arthritis (RA) remains unclear. A pathogenetic function of rheumatoid factors (RF) also has not been defined. In the present studies, natural killer (NK) cells were examined as a model for Feγ receptor type III‐positive (Feγ RIII+) cells, with regard to their interaction with RF. NK cell antigen CD16 (FcγRIII) and CD56 expression and functional NK and antibody‐dependent cell‐mediated cytotoxicity (ADCC) activity were compared in peripheral blood lymphocytes and autologous synovial fluid lymphocytes (SFL) of RA patients. Peripheral blood lymphocytes and SFL showed normal CD56 expression. In contrast, both the frequency and the density of CD16 antigen were decreased in SFL. Furthermore, diminished NK cytotoxicity and a significant decrease in ADCC were observed in SF NK cells. In subsequent in vitro studies with normal fresh NK cells, it was demonstrated that IgG‐containing RF complexes from RA patients induced a modulation of FCγRIII structure from the NK cell surface, a decrease in NK activity, and a complete loss of ADCC. When purified RF was incubated with NK‐enriched cell lines from RA patients, increased transcription and subsequent production of interferon‐γ and tumor necrosis factor α were observed. These data suggest a direct involvement of RF complexes in the pathogenetic process of chronic inflammation in RA.
Diversity of rheumatoid synovial tissue T cells by T cell receptor analysis. Oligoclonal expansion in interleukin‐2–responsive cells
Authors: Cooper Sheldon M. , Dier Douglas L. , Roessner Karen D. , Budd Ralph C. , Nicklas Janice A.
Published: February 2007

The synovitis of rheumatoid arthritis (RA) is characterized by infiltrates of CD4+ T lymphocytes. To determine the clonal diversity of these cells, we cloned T cells with interleukin‐2 (IL‐2), alone or with phytohemagglutinin (PHA), directly from actively inflamed synovial tissue obtained at synovectomy. A total of 205 clones from 4 specimens was analyzed for T cell receptor (TCR) gene rearrangements using Hind III and Eco RI digests with β chain and γ chain complementary DNA probes. A comparison of the TCR rearrangements enabled us to determine if the T cell clones arose from the same or different precursor cells. Most of the T cell clones (92%) had distinct TCR gene rearrangement patterns, indicating a unique clonal origin. However, a few clones (1 quadruplicate and 6 pairs) with identical TCR rearrangements were identified, and these clonal multiples were most commonly found in clones selected with IL‐2 alone. Mass cultures were propagated with IL‐2, alone or with PHA, and at each passage, cells were removed for TCR analysis. The later passages of the lines selected with IL‐2 had oligoclonal TCR rearrangements, whereas no oligoclonal rearrangements were found in the PHA + IL‐2‐selected cell lines. The TCR rearrangements in the later passages of the IL‐2 mass cultures were often identical to the TCR rearrangements that were found in the IL‐2‐derived clonal multiples. These findings indicate that while the majority of CD4+ T cells within the actively inflamed rheumatoid joint have diverse clonal origins, small numbers of clonal multiples and oligoclonal populations are present, and these cells may be enriched in an IL‐2‐responsive T cell subset.
Systemic sclerosis associated with cutaneous exposure to solvent: Case report and review of the literature
Authors: Brasington Richard D. , Thorpe‐Swenson Amy Jo
Published: February 2007

Sclerodermatous skin changes and systemic sclerosis have been reported to occur as a result of contact with several different organic solvents. We describe a 41‐year‐old man who developed systemic sclerosis after working for 15 years in a foundry, where he had extensive cutaneous contact with multiple organic solvents (trichloroethane, xylene, trimethylbenzene, and naphthalene). Cutaneous exposure to organic solvents may be a factor in the etiology of some cases of systemic sclerosis.
Platelet‐derived growth factor potentiates cellular responses of articular chondrocytes to interleukin‐1
Authors: Smith Robert J. , Justen James M. , Sam Laurel M. , Rohloff Norman A. , Ruppel Patricia L. , Brunden Marshall N. , Chin Jia En
Published: February 2007

Recombinant human interleukin‐1α (IL‐1α) induced a time‐dependent (0–72 hours) and concentration‐dependent (0.01–10 ng/ml) production of metalloproteinases (collagenase, gelatinase, stromelysin) and prostaglandin E2 (PGE2) in rabbit articular chondrocytes (RAC). Exposure of RAC to recombinant human platelet‐derived growth factor homodimer BB (PDGF‐BB; 2–200 ng/ml) in the presence of stimulatory and substimulatory concentrations of IL‐1α resulted in a marked augmentation of metalloproteinase and PGE2 production. PDGF‐BB exerted no agonist effects on RAC responsiveness. PDGF‐BB up‐regulated the number of IL‐1 receptors per chondrocyte but had no effect on receptor affinity. Cycloheximide and actinomycin D caused a concentration‐dependent suppression of the PDGF‐BB–mediated potentiation of radiolabeled IL‐1α binding to RAC and cell responsiveness to IL‐1α. Similarly, IL‐1 increased the number of PDGF receptors on RAC without changing receptor affinity. These data are discussed within the context of cytokine–growth factor interactions as components of the pathogenesis of arthritic diseases.
PBC 95K, a 95‐kilodalton nuclear autoantigen in primary biliary cirrhosis
Authors: Evans Janine , Reuben Adrian , Craft Joe
Published: February 2007

We have identified a novel antinuclear antibody (ANA) in the sera of patients with primary biliary cirrhosis (PBC). Sera from 22 of 50 PBC patients stained the nuclei of HEp‐2 cells in a pattern of 5–20 discrete dots, on indirect immunofluorescence. Typically, the titers were higher than 1:1,280. This staining pattern was seen in only 4 of 1,240 ANA‐positive samples from patients with other connective tissue diseases, and in none of the ANA‐positive sera from 49 patients with other liver diseases. Sera which stained the nuclear dots bound a 95‐kd polypeptide in immunoblots of HeLa nuclei and in immunoprecipitates of 35S‐methionine–labeled HeLa extracts. Affinity‐purified antibodies from the 95‐kd protein reproduced the nuclear dot immunofluorescence staining pattern, demonstrating that this polypeptide is located in the nuclear dots. ANA of this type, therefore, occur in 44% of patients with PBC, and they appear to be specific for PBC. These antibodies bind a 95‐kd protein that is discrete and is scattered throughout the nucleus.
The pharmacokinetics of total and unbound concentrations of tenoxicam in synovial fluid and plasma
Authors: Day R. O. , Williams K. M. , Graham S. , Handel M.
Published: February 2007

Tenoxicam is a nonsteroidal antiinflammatory drug with an elimination half‐life of 60–80 hours; it is administered once daily. Tenoxicam concentrations were measured in plasma (10 samples) and synovial fluid (6 samples) over a 24‐hour dosage interval at steady state in 10 subjects with arthritis who had been taking the drug at a dosage of 20 mg/day for at least 2 weeks. Total tenoxicam concentrations in synovial fluid were always less than those in plasma, and there was little fluctuation in plasma or synovial concentrations over the dosage interval, although there was substantial inter‐subject variation in both concentrations. There was a significant relationship between the tenoxicam dosage when expressed as mg/kg of body weight and the average steady‐state total concentration of tenoxicam in plasma (r = 0.80, P = 0.006); this accounted for a substantial proportion of the intersubject variation. The mean ± SD steady‐state concentrations in synovial fluid and plasma were 3.9 ± 1.8 μg/ml and 9.2 ± 3.7 μg/ml, respectively, yielding a mean ± SD synovial fluid: plasma ratio of 0.43 ± 0.12. Synovial fluid:plasma ratios of total tenoxicam correlated with synovial fluid:plasma ratios of albumin (r = 0.71, P = 0.02). The synovial fluid:plasma ratio of unbound tenoxicam was 0.90 ± 0.3 (95% confidence interval 0.68–1.11), which was not significantly different from a value of 1 (t = −1.09, P = 0.31).
Serum hyaluronate level as a predictor of radiologic progression in early rheumatoid arthritis
Authors: Paimela Leena , Heiskanen Arja , Kurki Pekka , Helve Tapani , Leirisalo‐Repo Marjatta
Published: February 2007

Increased serum levels of hyaluronate (HA) have been found in patients with rheumatoid arthritis (RA). This probably reflects increased leakage of HA from the inflamed joints into the circulation. In a prospective study of 40 patients with early RA, we evaluated the relationship of serum HA to clinical, laboratory, and radiologic parameters of disease activity. The patients were followed for 12 months; all had active disease at study entry. We confirmed the previous finding of higher serum HA concentrations in RA patients compared with healthy controls. At study entry, the patients' serum HA levels correlated positively with clinical and laboratory parameters of acute inflammation. Despite marked clinical improvement during therapy with second‐line drugs, the serum HA levels increased during the followup period. At the end of 1 year, these levels correlated with the radiologic progression of joint lesions, whereas they showed a less pronounced correlation with clinical or laboratory parameters of inflammation. We conclude that, in early RA, serum HA levels may reflect ongoing joint destruction and may even predict subsequent joint damage.
Pregnancy in patients with a history of juvenile rheumatoid arthritis
Authors: Østensen Monika
Published: February 2007

The present investigation was undertaken to study the relationship between pregnancy and juvenile rheumatoid arthritis (JRA), with regard to possible reactivation of the disease, complications at delivery, and postpartum complications. Data on 76 pregnancies in 51 JRA patients were collected retrospectively. Comparison of pre‐pregnancy disease activity with the course during gestation showed that pregnancy did not cause reactivation of the symptoms of quiescent JRA. Patients with minor symptoms at conception and the majority of those with active inflammation experienced improvement or total remission in the second half of gestation. Four JRA patients with active anterior uveitis had active eye disease during pregnancy also. Seventy‐four of the pregnancies resulted in births of infants that were healthy and of normal birth weight; 1 infant had low birth weight and 1 was stillborn. Twenty children were delivered by cesarean section, and in 15 cases this was related to sequelae of JRA. A flare 3–6 months postpartum was reported after 45 pregnancies. However, in none of the patients whose disease was quiescent before or during pregnancy did this cause permanent reactivation of the JRA. Comparison of these 51 patients with 45 age‐matched female patients without children revealed that disease severity and functional impairment were the limiting factors in the decision for or against having children.
Long‐term preservation of renal function in patients with lupus nephritis receiving treatment that includes cyclophosphamide versus those treated with prednisone only
Authors: Steinberg Alfred D. , Steinberg Susan C.
Published: February 2007

The purpose of this study was to assess long‐term preservation of renal function in 111 patients with systemic lupus erythematosus and active glomerulonephritis who participated in a randomized treatment trial. Four different drug treatment programs, each of which allowed the use of low‐dose oral prednisone in addition to the study drug(s), were compared with a regimen consisting solely of high‐dose oral prednisone. Patients randomized to receive intravenous cyclophosphamide, oral cyclophosphamide, or oral azathioprine plus cyclophosphamide had significantly better preservation of renal function than did patients who were randomized to receive prednisone only. Results in the azathioprine group did not differ from those in the prednisone‐only group. Cyclophosphamide appears to have long‐term benefit in the delay or prevention of end‐stage renal disease in patients with lupus nephritis.
Modulation of interleukin‐1–induced alterations in cartilage proteoglycan metabolism by activation of protein kinase C
Authors: Arner Elizabeth C. , Pratta Michael A.
Published: February 2007

Interleukin‐1 (IL‐1) stimulates proteoglycan degradation and prostaglandin E2 (PGE2) release and inhibits proteoglycan synthesis by cartilage in organ culture. Addition of the protein kinase C (PKC) activator, mezerein, resulted in the concentration‐dependent inhibition of IL‐1 activity on proteoglycan metabolism. Similar effects were seen with other compounds which stimulated PKC, such as teleocidin B4 and phorbol dibutyrate (PDBu), but not with a phorbol analog that is inactive in stimulating PKC. Simultaneous addition of the PKC antagonist, staurosporine, blocked the mezerein‐induced inhibition of IL‐1 activity on both proteoglycan degradation and synthesis in a concentration‐related manner. In contrast to its inhibition of the effect of IL‐1 on proteoglycan metabolism, mezerein did not block the release of PGE2 by cartilage in response to IL‐1 but caused a synergistic stimulation of PGE2 release. Importantly, in cultures made deficient in PKC by prolonged incubation with PDBu, the effects of this PKC agonist on proteoglycan breakdown and PGE2 were blocked, while stimulation by IL‐1 persisted. These data indicate that the effects of IL‐1 on proteoglycan metabolism and prostaglandin production are mediated by an intracellular signal distinct from PKC and suggest that activation of PKC in chondrocytes may play a role in modulating the action of IL‐1 on proteoglycan metabolism.
Rheumatic Diseases Among Civil War Troops
Authors: Bollet Alfred Jay
Published: February 2007

There are extensive existing medical records of Federal Civil War troops. More than 160,000 cases of „acute rheumatism”︁ occurred among these soldiers, and acute rheumatic fever was known to be the main cause. Infectious arthritides were frequent but not understood; gout was rare. „Chronic rheumatism”︁ was diagnosed more than 246,000 times; prolonged rheumatic fever and reactive arthritis following dysentery were probably the major causes. Over 12,000 soldiers were discharged because of chronic rheumatism, many with „lumbago,”︁ which was probably spondylarthropathy.
The Prevalence of Antiphospholipid Antibodies in Women With Recurrent Spontaneous Abortion, Women With Successful Pregnancies, and Women Who Have Never Been Pregnant
Authors: Parke Ann L. , Wilson Daniel , Maier Donald
Published: February 2007

Antibodies to negatively charged phospholipids are associated with a predisposition to both arterial and venous thrombosis, recurrent fetal wastage, and thrombocytopenia. These associations have been reported in patients who do not fulfill criteria for connective tissue diseases. In this study, we determined the prevalence of antiphospholipid antibodies in 81 women who had had recurrent spontaneous abortion (3 or more fetal losses), in 88 women whose pregnancies were successful, and in 64 women who had never been pregnant. Antiphospholipid antibodies were found in 16% of women with recurrent spontaneous abortion, and at a statistically greater prevalence than in women who had successful pregnancies (7%) as well as those who had never been pregnant (3%). A false‐positive VDRL and IgG anticardiolipin antibodies were more specific for fetal wastage than was either the lupus anticoagulant or IgM anticardiolipin antibodies.
HLA and T Cell Receptor Polymorphisms in Pauciarticular‐Onset Juvenile Rheumatoid Arthritis
Authors: Nepom Barbara S. , Malhotra Uma , Schwarz David A. , Nettles James W. , Schaller Jane G. , Concannon Patrick
Published: February 2007

The immunogenetic basis of pauciarticular‐onset juvenile rheumatoid arthritis is unclear. We therefore analyzed the HLA and T cell receptor genes present in a clinically well‐defined group of patients. We found that the DR8 haplotype contributes most of the HLA‐associated risk, although alleles at other loci contribute independently. A candidate disease‐associated T cell receptor polymorphism, in contrast, was not identified in this population. Mechanistic implications of these findings are discussed.
The B Cell Repertoire in Rheumatoid Arthritis
Authors: Moynier Marinette , Abderrazik Mohamed , Didry Catherine , Sany Jacques , Brochier Jean
Published: February 2007

Objective. We sought to compare the frequencies of precursors producing IgM rheumatoid factors (IgM‐RFs) in synovial fluid and peripheral blood B cells from patients with rheumatoid arthritis (RA).

Methods. We used limiting‐dilution analysis of Epstein‐Barr virus—activated B cells from seropositive and seronegative patients. B cell precursors producing IgM against insulin, an irrelevant autoantigen, were also assessed for comparison.

Results. On average, IgM‐RF—producing precursors were 15‐fold higher in the synovial fluid than in the peripheral blood of seropositive RA patients, but not in seronegative RA patients. The frequency of B cell precursors producing IgM against insulin was lower in the synovial fluid than in the peripheral blood of both the seropositive and the seronegative patient groups; moreover, the concentrations were similar in both groups.

Conclusion. The findings provide evidence against a nonspecific accumulation of IgM‐producing cells in the synovial fluid, and suggest that there is an active attraction of the RF‐producing B cell precursors toward sites of inflammation in RA.
Interleukin‐1, Interleukin‐2, Interleukin‐4, Interleukin‐6, Tumor Necrosis Factor α, and Interferon‐γ Levels in Sera from Patients With Scleroderma
Authors: Needleman Barbara White , Wigley Fredrick M. , Stair Richard W.
Published: February 2007

Objective. To determine whether interleukin‐lα (IL‐1α), IL‐1β, IL‐2, IL‐4, interferon‐γ (IFNγ), IL‐6, and tumor necrosis factor α (TNFα) are detected more frequently in sera from scleroderma patients than in sera from controls.

Methods. Serum concentrations of these cytokines were measured in 78 scleroderma patients and 73 controls, using enzyme‐linked immunosorbent assay, radioimmunoassay, and bioassay techniques.

Results. IL‐2, IL‐4, and IL‐6 were each detected more frequently in sera from scleroderma patients than in sera from controls. TNFα and IL‐1α were found with equal frequency in patient and control sera. IL‐1β and IFNγ were not detected in any sera.

Conclusion. IL‐2, IL‐4, and IL‐6 may be among the cytokines that contribute to the disease process in scleroderma patients. To our knowledge, this is the first report of elevated serum IL‐4 levels in human disease.
Autoantibody to U3 Nucleolar Ribonucleoprotein (Fibrillarin) In Patients with Systemic Sclerosis
Authors: Okano Yutaka , Steen Virginia D. , Medsger Thomas A.
Published: February 2007

To determine the clinical significance of serum antibodies to the U3 small nuclear ribonucleoprotein particle ([U3]snRNP), we studied sera from 416 patients with systemic sclerosis (SSc) and 264 controls, using immunofluorescence and immunoprecipitation assays. The presence of serum anti‐(U3)snRNP was highly specific to SSc, was found more frequently in blacks, and was associated with skeletal muscle disease and primary pulmonary arterial hypertension. These antibodies may identify one or more unusual clinical subsets of SSc.
The Effect of Local Heat and Cold Therapy on the Intraarticular and Skin Surface Temperature of the Knee
Authors: Oosterveld F. G. J. , Rasker J. J. , Jacobs J. W. G. , Overmars H. J. A.
Published: February 2007

Objective. To evaluate the effects of local application of ice chips, ligno‐paraffin, short‐wave diathermy, and nitrogen‐cold air on skin and intraarticular temperature.

Methods. Forty‐two healthy subjects were divided into 4 treatment groups. A temperature probe was inserted into the knee joint cavity and another placed on the overlying skin, and changes in temperature over 3 hours, by treatment group, were recorded.

Results. The mean skin surface temperature dropped from 27.9°C to 11.5°C after application of ice chips, and from 28.8°C to 13.8°C after application of cold air. The mean intraarticular temperature decreased from 31.9°C to 22.5°C and from 32.9°C to 28.8°C, respectively, after these 2 treatments. Short‐wave diathermy increased skin temperature by 2.4°C; intraarticular temperature was increased only 1.4°C by short‐wave diathermy. Treatment with ligno‐paraffin increased the skin surface temperature 8.9°C; the temperature in the joint cavity was increased 3.5°C.

Conclusion. The use of short‐wave diathermy and superficial heat packs in the treatment of patients with arthritis may potentially cause harm by increasing intraarticular temperature. This may have major implications regarding treatment policy for patients with arthritis.
Regulation of B Cell Function by Lobenzarit, A Novel Disease‐Modifying Antirheumatic Drug
Authors: Hirohata Shunsei , Shinohara Satoshi , Inoue Tetsufumi , Miyamoto Terumasa , Lipsky Peter E.
Published: February 2007

Objective. Lobenzarit (disodium 4‐chloro‐2,2'‐iminodibenzoate [CCA]) is a novel disease‐modifying drug for the treatment of rheumatoid arthritis (RA). Although its clinical efficacy has been demonstrated, its mechanism of action remains unclear. We therefore examined the effects of CCA on in vitro IgM and IgM rheumatoid factor (IgM‐RF) production by human B cells.

Methods. IgM and IgM‐RF production was induced from highly purified B cells from 8 healthy donors by stimulation with Staphylococcus aureus Cowan 1 (SAC) plus factors generated from mitogen‐activated T cells (TCF) or with immobilized anti‐CD3—activated CD4+ T cells.

Results. CCA suppressed the production of IgM‐RF as well as IgM at concentrations of 25—50 μg/ml (therapeutic serum concentrations of the drug), although the IgM‐RF production induced by SAC plus TCF was suppressed at lower concentrations of CCA (1—3 μg/ml). Whereas CCA suppressed interleukin‐2 (IL‐2) production by anti‐CD3—activated CD4+ T cells, its suppressive effects on B cells were not overcome by addition of IL‐2 or TCF. CCA did not inhibit the initial stages of B cell activation in either culture system, but rather, suppressed the maturation of previously activated B cells. Cell cycle analysis by acridine orange staining indicated that CCA‐mediated inhibition of B cell responsiveness induced by anti‐CD3—activated CD4+ T cells was the result of a block at the G1—S interphase.

Conclusion. These results indicate that CCA suppresses the production of IgM and IgM‐RF by directly inhibiting activated B cells. Thus, one of the actions of CCA in RA may be the suppression of the function of activated B cells.
Racial Differences in the Frequencies of Scleroderma‐Related Autoantibodies
Authors: Reveille John D. , Durban Egon , Goldstein Rose , Moreda Ramon , Arnett Frank C.
Published: February 2007

Objective. To determine demographic differences in scleroderma‐related autoantibodies.

Methods. One hundred fifty‐six patients with systemic sclerosis were prospectively examined for anticentromere antibodies (ACA), anti—topoisomerase I (anti—topo I, or Scl‐70), antinucleolar, and anti—U1 RNP autoantibodies.

Results. ACA was found in 36% of Caucasians and 4% of American blacks (P = 0.002, odds ratio [OR] 15). Anti—topo I was found in 37% of American blacks, compared with 17% of Caucasians (P = 0.04, OR 3). No significant differences in the frequencies of antinucleolar and anti—U1 RNP autoantibodies were found.

Conclusion. These data suggest important demographic differences in scleroderma‐associated autoantibodies.
Articular Cartilage Vesicles Generate Calcium Pyrophosphate Dihydrate‐Like Crystals in Vitro
Authors: Derfus Beth A. , Rachow John W. , Mandel Neil S. , Boskey Adele L. , Buday Michael , Kushnaryov Vladimir M. , Ryan Lawrence M.
Published: February 2007

Objective. To identify the morphology of a mineral‐forming fraction of adult porcine hyaline articular cartilage digest and characterize the mineral it forms.

Methods. Electron microscopy, Fourier transform infrared (FTIR) spectroscopy, x‐ray microanalysis, compensated polarized light microscopy, and biochemical studies including 14C‐labeled UDPG pyrophosphohydrolase radiometric assay.

Results. This fraction of articular cartilage digest contained membrane‐limited vesicles resembling growth plate cartilage matrix vesicles and formed mineral after only 24 hours in physiologic salt solution containing 1 mM ATP. The mineral contained inorganic pyrophosphate, 95% of which derived from ATP, and phosphate, 93% of which derived from inorganic phosphate in the medium. The FTIR spectrum of this mineral closely resembled the spectrum of standard calcium pyrophosphate dihydrate (CPPD) crystals. Compensated polarized light microscopy showed positively birefringent, rod‐shaped crystals morphologically identical to CPPD. Ca:P ratios, defined by energy‐dispersive microanalysis, were also consistent with CPPD.

Conclusion. The articular cartilage vesicle fraction of porcine hyaline cartilage is capable of generating mineral that strongly resembles CPPD.
Effects of interleukin‐6 on the metabolism of connective tissue components in rheumatoid synovial fibroblasts
Authors: Ito Akira , Itoh Yoshifumi , Mori Yo , Sasaguri Yasuyuki , Morimatsu Minoru
Published: February 2007

Objective. High levels of interleukin‐6 (IL‐6) have been found in the synovial fluid of patients with rheumatoid arthritis (RA). We undertook the present study to investigate the role of IL‐6 in this disease.

Methods. We examined the effects of IL‐6, in comparison with IL‐1, on the biosynthesis of extracellular matrix macromolecules and of matrix‐degrading proteinases in rheumatoid synovial fibroblasts.

Results. In rheumatoid synovial fibroblasts, IL‐6 by itself enhanced the production of plasminogen activator, its inhibitor, and tissue inhibitor of metalloproteinases, whereas it did not modulate the biosynthesis of precursor of matrix metalloproteinase 1 (proMMP‐1) (tissue collagenase), proMMP‐3 (stromelysin), or connective tissue components. However, IL‐1–induced production of proMMP‐1 and proMMP‐3 was preferentially augmented by IL‐6.

Conclusion. These results suggest that in RA, IL‐6 may participate along with IL‐1 in fine tuning of the catabolism of connective tissue components, by modulating the balance between connective tissue–degrading enzymes and their inhibitors.
In vivo expression of stromelysin in synovium and cartilage of rabbits injected intraarticularly with interleukin‐1β
Authors: Hutchinson Nancy I. , Lark Michael W. , Macnaul Karen L. , Harper Coral , Hoerrner Lori A. , McDonnell Joseph , Donatelli Susan , Moore Vernon , Bayne Ellen Kahn
Published: February 2007

Objective. To examine the in vivo expression of the matrix metalloproteinase stromelysin in the synovium and articular cartilage of rabbits injected intraarticularly with recombinant human interleukin‐1β (IL‐1).

Methods. The direct isolation of messenger RNA (mRNA) from articular cartilage without the prior isolation of chondrocytes is described. The in vivo expression of stromelysin was examined at the mRNA level by Northern blot analysis, and at the protein level by in situ immunolocalization and by enzyme‐linked immunosorbent assay.

Results. In the synovium of IL‐1–injected joints, stromelysin mRNA levels were highest at 4 hours and declined to background levels within 24 hours. In the cartilage of IL‐1–injected joints, stromelysin mRNA was elevated at 4 hours and continued to increase until 8 hours, before declining. Stromelysin mRNA expression preceded a similar increase in stromelysin protein levels in both synovium and cartilage.

Conclusion. Intraarticular injection of IL‐1 induced the endogenous expression of stromelysin mRNA and protein in both synovium and cartilage. The kinetics of stromelysin expression correlated well with the accumulation of stromelysin and proteoglycan in synovial fluids. Therefore, the de novo synthesis of stromelysin in cartilage may have contributed to the loss of proteoglycan from that tissue.
Autoantibodies to glycyl–transfer RNA synthetase in myositis. Association with dermatomyositis and immunologic heterogeneity
Authors: Hirakata Michito , Suwa Akira , Takeda Yoshihiko , Matsuoka Yasuo , Irimajiri Shoichiro , Targoff Ira N. , Hardin John A. , Craft Joe
Published: February 2007

Objective. To elucidate the clinical significance and immunologic heterogeneity of anti–glycyl–transfer RNA (tRNA) synthetase antibodies in polymyositis/dermatomyositis (PM/DM).

Methods. Sera from 345 patients with rheumatic diseases, including 91 with myositis, were examined using immunoprecipitation assays. Autoantibodies to aminoacyl‐tRNA synthetases were further analyzed with 2‐dimensional RNA fractionation and via inhibition of in vitro aminoacylation.

Results. Serum from 1 patient with DM and interstitial lung disease immunoprecipitated glycyl‐tRNA synthetase along with only 1 of 4 associated tRNAs, in comparison with control anti–glycyl‐tRNA synthetase antibodies, which bound the enzyme along with all 4 associated tRNAs. Immunoblotting findings and a lack of in vitro inhibition aminoacylation of tRNAgly by serum from this patient also suggested differences between the epitope specificity of this serum and that of other sera with anti–glycyl‐tRNA synthetase antibodies.

Conclusion. This identification of antibodies to glycyl‐tRNA synthetase from a patient with DM underscores the association of this specificity with the disease. The finding that these antibodies bound an epitope outside the active site of the synthetase enzyme, in contrast to most anti–aminoacyl‐tRNA synthetases, emphasizes the immunologic heterogeneity of these autoantibodies.