bluuebunny/crossref_metadata_2025 huggingface dataset:
Regression of bone and cartilage loss in adjuvant arthritic rats after treatment with cyclosporin a
Authors: Del Pozo E. , Graeber M. , Elford P. , Payne T.
Published: February 2007

To test the effect of cyclosporin A (CsA) on arthritis‐related bone resorption, we studied 30 female rats with adjuvant‐induced arthritis (AIA). The animals were randomly assigned to 5 groups of 6 animals each; they received daily oral doses of 3, 5, 10, or 15 mg/kg CsA or placebo for 10 days. The parameters studied were (a) caliper measurements of hindpaw swelling, (b) radiometric densitometry of caudal vertebrae, (c) quantitative histomorphometry of radiographed vertebrae, and (d) glycosaminoglycan measurements in femoral condyles. A significant dose‐dependent regression of articular swelling occurred in rats given 5, 10, and 15 mg/kg CsA, and this was concomitant with improvement in bone density. These results correlated with those of quantitative bone morphometry. Thus, trabecular volume was significantly reduced in AIA rats, but restoration to virtually normal values occurred with CsA doses between 5 and 15 mg/kg. The protective effect of CsA on articular damage was supported by the dose‐dependent progressive improvement in total femoral condyle glycosaminoglycan content. The favorable effect of CsA on AIA is likely due to a blockade of T cell activation via an inhibition of production of lymphokines such as interleukin‐2 and γ‐interferon. The consequent cessation of the immune reaction would lead to a reduction in the release of cytokines, such as interleukin‐1, that are likely to be the mediators of the pathologic bone and cartilage breakdown that is characteristic of arthritic disease.
Dissociation of immune responses to the ss‐a (ro) 52‐kd and 60‐kd polypeptides in systemic lupus erythematosus and sjögren's syndrome
Authors: Ben‐Chetrit Eldad , Fox Robert I. , Tan Eng M.
Published: February 2007

The cellular RNA particle SS‐A (Ro) is a target of autoimmune response in many patients with Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE). Recent immunologic, biochemical, and DNA cloning studies have shown that the SS‐A particle consists of at least 2 polypeptide components, of 52 kd and 60 kd. Immunodiffusion analysis of 60 sera from patients with primary SS revealed 47 (78%) to be SS‐A precipitin positive. Western blotting studies of the sera showed 3 groups of reactivities: 22 (47%) possessed autoantibodies against both the 60‐kd and the 52‐kd polypeptides, 19 (40%) reacted only with the 52‐kd protein, and 6 (13%) were nonreactive in Western blots although positive in immunodiffusion. Fifty‐one of 90 SLE sera (57%) were SS‐A precipitin positive by immunodiffusion. In Western blots, 24 (47%) possessed antibodies against both the 60‐kd and the 52‐kd antigens, while 9 (18%) reacted only with the 60‐kd protein. Eighteen (35%) were nonreactive by Western blot, although positive by immunodiffusion. Antibody to the 52‐kd antigen without concomitant antibody to the 60‐kd antigen was seen only in patients with primary SS, whereas antibody to the 60‐kd antigen without concomitant antibody to the 52‐kd antigen was seen only in SLE patients. Although antibodies to SS‐A are detected in both SS and SLE, our findings show that there is dissociation of immune responses to the 2 component antigens of the particle, which may be evidence of different events initiating the autoimmune process in these diseases.
Lupus‐inducing drugs alter the structure of supercoiled circular dna domains
Authors: Zacharias Wolfgang , Koopman William J.
Published: February 2007

We analyzed the effects of procainamide (PROC), hydralazine (HYD), N‐acetylprocainamide (NAPA), and L‐canavanine (CAN) on circular supercoiled plasmids as models for chromosomal loop domains. The supercoil‐dependent B‐Z equilibrium in recombinant plasmids was used as an indicator of structural changes induced in circular DNA. Twodimensional gel electrophoresis showed that PROC and HYD strongly inhibited supercoil‐induced Z‐DNA formation, whereas NAPA caused less pronounced changes in the B‐Z equilibrium, and CAN had no effect. Gel retardation assays showed that the binding of a Z‐DNA‐specific autoimmune antibody to a Z‐DNA‐containing plasmid was strongly perturbed by HYD, but not influenced by CAN. Both PROC and NAPA showed moderate inhibition of antibody binding. Our results demonstrate the different potentials of these 4 drugs to interact with DNA and to alter the tertiary topology of DNA domains. It is conceivable that the in vivo capacity of PROC and HYD to induce antinuclear antibodies may be related to their ability to influence structural features in chromosomal DNA domains or nucleosomes, thus liberating antigenic structural epitopes in DNA and/or DNA‐associated proteins.
Associations between clinical status questionnaire scores and formal education level in persons with systemic lupus erythematosus
Authors: Callahan Leigh F. , Pincus Theodore
Published: February 2007

In a study of 124 systemic lupus erythematosus patients, clinical status, according to 5 questionnaire scales, was poorer in patients with ⩽11 years versus those with ⩾12 years of formal education. These results were statistically significant when adjusted for age, race, sex, and disease duration, though results on some scales were not significant when adjusted for multiple comparisons. These findings further support observations that formal education level is associated with clinical status in rheumatic and other chronic diseases.
Rapidly progressive charcot arthropathy following minor joint trauma in patients with diabetic neuropathy
Authors: Slowman‐Kovacs Sally D. , Braunstein Ethan M. , Brandt Kenneth D.
Published: February 2007

Neuropathic (Charcot) arthropathy is a slowly progressive, chronic, destructive form of joint degeneration seen in patients with a neurosensory deficit. Attempts to produce neuropathic joint disease experimentally with a variety of deafferentation procedures have generally been unsuccessful. However, if the knee is rendered unstable by anterior cruciate ligament transection (ACLT), breakdown of the joint occurs rapidly in dogs that have previously undergone dorsal root ganglionectomy (DRG) for deafferentation of the ipsilateral limb. In contrast, ACLT in neurologically intact dogs produces only nonprogressive changes that are characteristic of mild osteoarthritis. This report describes 3 patients with longstanding insulin‐dependent diabetes mellitus in whom neuropathic arthropathy developed within weeks after minor trauma to the foot or ankle. In these patients, diabetic neuropathy served as the functional equivalent of dorsal root ganglionectomy, and the minor trauma served as the functional equivalent of ACLT. Together, they illustrate the phenomenon of neurogenic acceleration of joint degeneration in humans.
T Cell Receptor Expression And Activation Of Synovial Lymphocyte Subsets In Patients With Rheumatoid Arthritis
Authors: Réme Thierry , Portier Marielle , Frayssinoux Florence , Combe Bernard , Miossec Pierre , Favier François , Sany Jacques
Published: February 2007

Two‐color flow cytometry analysis of peripheral blood and synovial lymphocytes from rheumatoid arthritis patients was performed using monoclonal antibodies directed against T cell subsets, T cell activation markers, and T cell receptors. The results showed an abnormally high percentage (>15%) of CD3+, CD4−, and CD8− T cells expressing a specific receptor containing a γ chain. Phenotypic analysis of lymphocytes infiltrating both knee joints of individual rheumatoid arthritis patients revealed very similar subset distribution and activation levels, despite strong differences in the clinical status between the 2 sites.
Estrogen use and radiographic osteoarthritis of the knee in women
Authors: Hannan Marian T. , Felson David T. , Anderson Jennifer J. , Naimark Allan , Kannel William B.
Published: February 2007

Female participants of the Framingham Osteoarthritis Study (n = 831, mean age 73, age range 63–93) were evaluated for osteoarthritis with weight‐bearing radiographs of the knee during 1983–1985. At each biennial examination (1963–1981), the women were asked about their use of estrogen during the previous 2 years. We categorized estrogen use as no use reported, use reported at 1 examination, or use reported at 2 or more examinations. We found no positive association of estrogen use with radiographic knee osteoarthritis after controlling for age, body mass index, age at menopause, physical activity, history of knee injury, and smoking. In fact, a modest but nonsignificant protective effect for both radiographic osteoarthritis (odds ratio 0.71, 95% confidence interval 0.42, 1.20) and severe radiographic osteoarthritis (odds ratio 0.66, 95% confidence interval 0.33, 1.32) was seen in women who reported estrogen use at 2 or more examinations. Subgroup analyses also showed no association between estrogen use and radio‐graphic knee osteoarthritis. We conclude that estrogen use in women is not associated with an increased risk of radiographic knee osteoarthritis.
Serum activity that confers acid lability to α‐interferon in systemic lupus erythematosus: its association with disease activity and its independence from circulating α‐interferon
Authors: Yee Arthur M. F. , Yip Yum K. , Fischer Harry D. , Buyon Jill P.
Published: February 2007

We conducted a longitudinal evaluation of a patient with systemic lupus erythematosus who constitutively exhibited elevated levels of circulating α‐interferon (α‐IFN). This study demonstrated that the serum levels of an activity that renders the endogenous α‐IFN acid labile are positively correlated with disease activity. This IFN acid lability‐inducing activity can also be found in the sera of systemic lupus erythematosus patients who have active disease but who do not have circulating α‐IFN.
Elevated levels of interleukin‐6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system invol vement
Authors: Hirohata Shunsei , Miyamoto Terumasa
Published: February 2007

Paired serum and cerebrospinal fluid (CSF) specimens from 14 patients with systemic lupus erythematosus (SLE) and central nervous system (CNS) involvement were studied for interleukin‐6 (IL‐6) activity using the IL‐6‐dependent murine hybridoma, MH60.BSF2. We also studied 23 patients with noninflammatory neurologic diseases, and 9 SLE patients without CNS involvement. CSF IL‐6 activity was elevated only in SLE patients with CNS involvement, although there was no significant difference in serum IL‐6 activity among the 3 groups. CSF IL‐6 activity was not correlated with either the CSF‐serum albumin quotient (Q albumin; an indicator of blood‐brain barrier function) or serum IL‐6 activity in SLE patients with CNS involvement. The CSF IL‐6 activity decreased significantly when CNS manifestations subsided after successful treatment. These results indicate that determination of CSF IL‐6 activity may be useful in the evaluation of CNS disease activity in SLE. Moreover, the data confirm the presence of immune system activation within the CNS in patients with SLE‐associated CNS disease.
Homologous type ii collagen—induced arthritis in rats
Authors: Larsson Per , Kleinau Sandra , Holmdahl Rikard , Klareskog Lars
Published: February 2007

Arthritis was induced in Lewis and DA rat strains after immunization with native homologous type II collagen (CII). Differences were noted in the clinical signs of arthritis in the 2 rat strains, which were immunized with the same arthritogenic preparation of CII. DA rats showed disease onset characterized by symmetric involvement of the interphalangeal joints of the hind feet. Lewis rats showed disease onset characterized by involvement of only the ankle or knee joints. Moreover, the arthritis tended to be chronic (i.e., persistent and variable redness and swelling seen in interphalangeal joints) in DA rats, but not in Lewis rats. Analysis of the delayed‐type hypersensitivity reaction to CII and anti‐CII autoantibody production demonstrated the presence of T cell, as well as B cell, reactivity to rat CII in both strains of rat. A spontaneous T cell reactivity to CII, as measured by rat CII‐induced ear swelling, was observed in nonimmunized DA rats, but not in nonimmunized Lewis rats. The demonstration that clinical features of arthritis induced with identical arthritogenic stimuli are different depending on the genetic background of the affected animal may be relevant in understanding the heterogeneity of the clinical features of human inflammatory joint disease.
The igg, igm, and iga isotypes of anti‐topoisomerase i and anticentromere autoantibodies
Authors: Hildebrandt Sabine , Weiner Ethan , Senécal Jean‐Luc , Noell Steve , Daniels Leslie , Earnshaw William C. , Rothfield Naomi F.
Published: February 2007

We studied the expression of IgG, IgM, and IgA autoantibodies in the anti‐topoisomerase I and anticentromere immune responses by enzyme‐linked immunosorbent assay, immunoblotting, and immunofluorescence. While IgG autoantibodies were most common, IgA autoantibodies were also frequently found, but IgM autoantibodies were rare. This is the first report of IgA autoantibodies in scleroderma.
Dietary fish oil and olive oil supplementation in patients with Rheumatoid Arthritis clinical and immunologic effects
Authors: Kremer Joel M. , Lawrence David A. , Jubiz William , Digiacomo Ralph , Rynes Richard , Bartholomew Lee E. , Sherman Malcolm
Published: February 2007

Forty‐nine patients with active rheumatoid arthritis completed a 24‐week, prospective, double‐blind, randomized study of dietary supplementation with 2 different dosages of fish oil and 1 dosage of olive oil. Clinical evaluations were performed at baseline and every 6 weeks thereafter, and immunologic variables were measured at baseline and after 24 weeks of study. The 3 groups of patients were matched for age, sex, disease severity, and use of disease‐modifying antirheumatic drugs (DMARDs). Subjects continued receiving DMARDs and other background medications without change during the study. Twenty patients consumed daily dietary supplements of n3 fatty acids containing 27 mg/kg eicosapentaenoic acid (EPA) and 18 mg/kg docosahexaenoic acid (DHA) (low dose), 17 patients ingested 54 mg/kg EPA and 36 mg/kg DHA (high dose), and 12 patients ingested olive oil capsules containing 6.8 gm of oleic acid. Significant improvements from baseline in the number of tender joints were noted in the low‐dose group at week 24 (P = 0.05) and in the high‐dose group at weeks 18 (P = 0.04) and 24 (P = 0.02). Significant decreases from baseline in the number of swollen joints were noted in the low‐dose group at weeks 12 (P = 0.003), 18 (P = 0.002), and 24 (P = 0.001) and in the high‐dose group at weeks 12 (P = 0.0001), 18 (P = 0.008), and 24 (P = 0.02). A total of 5 of 45 clinical measures were significantly changed from baseline in the olive oil group, 8 of 45 in the low‐dose fish oil group, and 21 of 45 in the high‐dose fish oil group during the study (P = 0.0002). Neutrophil leukotriene B4 production decreased by 19% from baseline in the low‐dose fish oil group (P = 0.0003) and 20% in the high‐dose group (P = 0.03), while macrophage interleukin‐1 production decreased by 38.5% in the olive oil group (P not significant), 40.6% in the low‐dose group (P = 0.06), and 54.7% in the high‐dose group (P = 0.0005). Tritiated thymidine incorporation in peripheral blood mononuclear cells after stimulation with concanavalin A increased significantly in all 3 groups after 24 weeks, compared with baseline values. We conclude that the clinical benefits of dietary supplementation with omega‐3 fatty acids are more commonly observed in patients consuming higher dosages of fish oil for time intervals that are longer than those previously studied. Dietary supplementation with olive oil is also associated with certain changes in immune function, which require further investigation.
Noradrenergic and peptidergic nerves in the synovial membrane of the sprague‐dawley rat
Authors: Bjurholm A. , Kreicbergs A. , Ahmed M. , Schultzberg M.
Published: February 2007

This immunohistochemical study of nerves in the synovial tissue of Sprague‐Dawley rats demonstrated the occurrence of 4 neuropeptides and 2 enzymes that are involved in the synthesis of catecholamines. Substance P and calcitonin gene‐related peptide were colocalized in fibers that terminated as varicosal endings in the synoviocyte layer. Similarly, tyrosine hydroxylase and dopamine β‐hydroxylase, which reflect the presence of noradrenaline, were colocalized with neuropeptide Y. These fibers were predominantly found adjacent to and within blood vessel walls. Immunoreactivity to vasoactive intestinal polypeptide was seen in varicose nerve terminals in the synoviocyte layer. Many were localized in vessel walls. There is accumulating evidence of an involvement of substance P and noradrenaline in the pathogenesis of inflammatory joint disease and nociception. The role of these colocalized neuropeptides, namely, calcitonin gene‐related peptide and neuropeptide Y, in the pathophysiology of such conditions warrants further analysis.
Biliary elimination of low‐dose methotrexate in humans
Authors: Nuernberg Bernd , Koehnke Rachelle , Solsky Marilyn , Hoffman John , Furst Daniel E.
Published: February 2007

We studied the pharmacokinetics of methotrexate (MTX) in a 64‐year‐old man with rheumatoid arthritis. After 6 months of treatment, acute clinical complications arose, requiring emergency laparotomy and cholecystotomy. A biliary tube was inserted, and this allowed for direct analysis of the bile. The pharmacokinetics of 2 separate doses of MTX (orally and intravenously) were assessed (dosage 10 mg/m2). No substantive differences in the pharmacokinetics were found between pre‐ and post‐cholecystotomy MTX treatment, including clearance rates, volumes of distribution, and terminal half‐lives. The results, however, demonstrated a change in the bioavailability of the drug (decreasing from 84.7% to 38.9%). Based on extrapolations of the data, with assumed rates of bile flow, the findings also suggest that there is substantial biliary elimination of MTX (8.7–26.0%) and its principal 7‐hydroxy metabolite (1.5–4.6%).
Hla‐dr alleles with naturally occurring amino acid substitutions and risk for development of rheumatoid arthritis
Authors: Gao Xiaojiang , Olsen Nancy J. , Pincus Theodore , Stastny Peter
Published: February 2007

To determine the HLA‐DR4 subtypes associated with rheumatoid arthritis (RA), we performed amplification of DR4 DRB1 genes by the polymerase chain reaction and dot‐blots with oligonucleotide probes. In 52 HLA‐DR4+ RA patients, Dw4 was the predominant subtype. This subtype was found in 45 of 52 patients (86.5%) compared with 33 of 59 DR4+ controls (55.9%; P < 0.001). In the whole population, Dw4 also gave the highest relative risk for RA (RR = 5.31). Relative risk was also associated with DR1.1, the common white DR1 (Dw1) type, which has a third hypervariable region amino acid sequence similar to some forms of DR4 and has glycine at position 86. Variants of DR1 (DR1.2) or DR4 (Dw14.1, Dw14.1) with valine at position 86 appeared less able to confer risk for RA. Substitution of residues in the third hypervariable region of the first domain of DRB1 appeared to correlate with relative risk for RA. Among subjects having 0–1 amino acid substitutions, RA developed in 53%, whereas in subjects with 2–4 amino acid changes, RA was present in only 17.4% (P < 0.00001). DQw7 (formerly DQw3.1) was slightly increased in DR4+ RA patients compared with controls, but a striking excess of Dw4,DQw7 homozygous patients was observed. The results suggest that DQw7 may have an additional effect, possibly with a recessive mechanism, since it was observed only in DR4 homozygous patients.
Altered immune response to glycine‐rich sequences of epstein‐barr nuclear antigen‐1 in patients with rheumatoid arthritis and systemic lupus erythematosus
Authors: Petersen Jorgen , Rhodes Gary , Roudier Jean , Vaughan John H.
Published: February 2007

Prior studies have shown that patients with rheumatoid arthritis (RA) have an increased number of circulating Epstein‐Barr virus–infected B lymphocytes and elevated titers of antibody to Epstein‐Barr nuclear antigen–1 (EBNA‐1), the major nuclear antigen expressed in latently infected B cells. However, it is not known whether antibodies from RA patients recognize the same epitopes as antibodies from normal subjects. Most of the anti–EBNA‐1 antibodies in normal subjects are directed at the glycine‐alanine repeating region of the molecule. Antibodies specific for this region are also somewhat more prevalent in RA patients than in normal subjects. A panel of synthetic peptides derived from EBNA‐1 was used to analyze the immune response to antigenic epitopes outside the glycine‐alanine region, using the peptides as solid‐phase antigen. Sera from RA patients and from systemic lupus erythematosus patients contained elevated levels of IgG antibodies to 2 non–glycine‐alanine peptides and to 3 non–glycine‐alanine peptides, respectively. Two of the 3 peptides are glycinerich, but antibodies that react with them are distinct from each other, as well as from those that react with the glycine‐alanine epitope. Eight other peptides from the C‐terminal portion of EBNA‐1 either do not react with sera or show no difference between normal subjects and patient groups. The antibodies to the glycine‐alanine peptide are enriched with k light chains, whereas antibodies to epitopes outside the glycinealanine region are not so restricted among k and λ light chains. Thus, RA patients and systemic lupus erythematosus patients have different antibody responses than do normal subjects, both quantitatively and qualitatively.
Long‐term disability and prolonged sick leaves as outcome measurements in ankylosing spondylitis: possible predictive factors
Authors: Guillemin Francis , Briançon Serge , Pourel Jacques , Gaucher Alain
Published: February 2007

Prognostic factors for the occurrence of longterm disability and prolonged sick leave were determined in 182 patients with ankylosing spondylitis. A significant relationship appeared between functional disability (determined by the Stanford Health Assessment Questionnaire) and sex, age at disease onset, and the number of peripheral joints involved. Using a life‐table approach, the probability of prolonged sick leaves was associated with peripheral joint involvement and work that involved carrying heavy loads. Long‐term disability was more frequent after work involving exposure to cold conditions (relative risk [RR] = 2.01) and prolonged standing postures (RR = 1.34), while sedentary work (RR = 0.35) and formal vocational rehabilitation programs (RR = 0.57) seemed to protect against long‐term disability.
Interleukin‐1α, interleukin‐2, and soluble interleukin‐2 receptors in polymyositis
Authors: Wolf Robert E. , Baethge Bruce A.
Published: February 2007

Cell‐mediated immunity has been implicated in the pathogenesis of polymyositis (PM). We conducted a prospective study in which serum levels of soluble interleukin‐2 receptors (IL‐2R), IL‐1α, and IL‐2 were correlated with creatine kinase (CK) levels and clinical disease activity. Cytokines and IL‐2R were quantitated in 133 serum samples from 14 patients by use of an enzyme‐linked immunosorbent assay. In patients with acute PM (9 patients), soluble IL‐2R and IL‐1α levels were elevated initially, but declined rapidly with therapy. A significant linear relationship was found between soluble IL‐2R levels and CK levels. IL‐2 was initially detectable in only 3 patients, and it disappeared with therapy in all 3. The levels of cytokines and IL‐2R were consistently normal in patients with inactive PM (2 patients). In patients with chronic PM (3 patients), the cytokines and soluble IL‐2R levels were normal despite persistently abnormal CK levels and/or muscle weakness. Cellular IL‐2R levels correlated positively with serum levels of soluble IL‐2R. Our studies substantiate a pathogenic role for cellular immunity in PM, with the finding of activation of lymphocytes. The finding of increased levels of IL‐1α demonstrates for the first time that there is monocyte activation in PM. Persistent elevation of CK levels after normalization of the levels of cytokines and IL‐2R may be prognostic of impending chronic disease. Serum soluble IL‐2R appear to be a sensitive indicator of improvement or exacerbation of disease activity in patients with PM.
Elevated substance p and accelerated cartilage degradation in rabbit knees injected with interleukin‐1 and tumor necrosis factor
Authors: O'Byrne Elizabeth M. , Blancuzzi Vincent , Wilson Douglas E. , Wong Mary , Jeng Arco Y.
Published: February 2007

Cytokines, interleukin‐1 (IL‐1), tumor necrosis factor α, and the neurotransmitter, substance P, have been implicated in the pathogenesis of arthritis because they stimulate synovial cells to secrete prostaglandin E2 and collagenase in vitro. We investigated in vivo changes in intraarticular substance P and the degradation of cartilage proteoglycan in response to intraarticular cytokine injections in rabbits. Twenty‐four hours after a single injection of 10 ng, 30 ng, or 100 ng of recombinant human IL‐1α (rHuIL‐1α) per joint, the mean ± SEM levels of substance P detected in the cell‐free joint lavage fluid were 250 ± 67 fmoles, 480 ± 60 fmoles, and 530 ± 130 fmoles (n = 4–5), respectively. The level of substance P in the contralateral knees injected with diluent was 58 ± 8 fmoles (n = 12). The level of substance P had increased by 2 hours after IL‐1 injection and remained elevated in the joint 48 hours after injection. Cytokineinduced proteoglycan depletion was also time‐ and dose‐dependent. Proteoglycan concentrations in articular cartilage dissected from the weight‐bearing condyles were calculated as the ratio of sulfated glycosaminoglycan measured using 1,9‐dimethylmethylene blue: hydroxyproline. After 48 hours, 10 ng, 30 ng, or 100 ng of rHuIL‐la per joint decreased proteoglycan levels by 9 ± 4%, 14 ± 4%, and 21 ± 3% (n = 8), respectively. Likewise, the injection of recombinant human tumor necrosis factor α induced depletion of intraarticular substance P and cartilage proteoglycan.
Metabolic and ultrastructural changes in articular cartilage of rats fed dietary supplements of omega‐3 fatty acids
Authors: Lippiello Louis , Fienhold Margery , Grandjean Carter
Published: February 2007

A “marginally deficient” essential fatty acid state was produced in male Sprague‐Dawley rats by dietary supplementation with Ω3 fatty acids. Animals fed diets containing the highest amounts of these fatty acids (10% menhaden fish oil) demonstrated a 70% maximum decrease in the linoleic and arachidonic acid content of articular cartilage, a 30–40% decrease in cartilage hexosamine content, with little effect on hydroxyproline levels, and a 32% inhibition of proteoglycan synthesis. Histologic analysis revealed an occasional surface irregularity and localized depletion of Safranin O and toluidine blue staining of articular cartilage on the femoral heads from animals taking the higher doses. Electron microscopic analysis revealed a marked decrease in “dark‐staining” chondrocytes relative to “light‐staining” cells in all animals fed menhaden fish oil. The cartilaginous changes noted in this study reflect a causal relationship between chondrocyte metabolism and an altered unsaturated fatty acid content. The observed responses of chondrocytes to Ω3 fatty acids may be similar to those commonly associated with the development of early osteoarthrosis. It is not known whether similar changes are induced in other species, including humans, but these observations suggest that some caution must be taken in the long‐term adminitration of menhaden fish oil or other Ω3 fatty acid‐containing preparations in rheumatoid arthritis patients.
MULTICENTRIC RETICULOHISTIOCYTOSIS IN A PATIENT WITH MALIGNANT MELANOMA: A RESPONSE TO CYCLOPHOSPHAMIDE AND A UNIQUE CUTANEOUS FEATURE
Authors: Kenik Jay G. , Huerter Christopher J. , Hurley John A. , Stanosheck James F.
Published: February 2007

We describe a patient with multicentric reticulohistiocytosis and a history of malignant melanoma. His widely disseminated disease did not affect the site of surgical removal of the malignant melanoma nor the donor site of a skin graft. The multicentric reticulohistiocytosis progressed while the patient was taking nonsteroidal antiinflammatory agents, but showed significant response during a 10‐month course of cyclophosphamide. While he was taking the cyclophosphamide, however, his melanoma recurred, and the patient subsequently died.
SCINTIGRAPHIC EVALUATION OF LUMBOSACRAL PAIN IN BRUCELLOSIS
Authors: Cordero‐Sánchez M. , Alvarez‐Ruiz S. , López‐Ochoa J. , Garcia‐Talavera J. R.
Published: February 2007

Low back pain is the most frequent rheumatologic manifestation of brucellosis. The diagnosis of brucellar sacroiliitis is hampered by the poor specificity of the clinical data and the poor sensitivity of the radiologic data. In this report, we show that scintigraphy not only increases the sensitivity but also allows an earlier diagnosis of disease and permits the detection of osteoarticular brucellar involvement in areas adjacent to the sacroiliac joint.
The longitudinal course of hand osteoarthritis in a male population
Authors: Kallman Douglas A. , Wigley Fredrick M. , Scott William W. , Hochberg Marc C. , Tobin Jordan D.
Published: February 2007

In this prospective analysis of the natural history of osteoarthritis (OA) of the hand, the incidence and progression of various radiographic features of OA were examined in 177 men who participated in the Baltimore Longitudinal Study of Aging. Subjects who were less than 60 years old were selected based on the availability of at least 4 hand radiographs taken during at least 20 years of followup, while subjects who were age 60 or older were required to have had at least 4 hand radiographs taken during only 14 years of followup. Individual joints of the hands were graded for the presence and severity of 5 features of OA: osteophytes, joint space narrowing, subchondral sclerosis, lateral deformity, and cortical collapse. They were also graded according to the global Kellgren/Lawrence scale. The incidence and rate of progression of OA, as measured by all scales, increased in progressively older age groups. Cox's proportional hazards models showed that isolated doubtful osteophytes (Kellgren/Lawrence grade 1) and isolated joint space narrowing predicted the development of the radiographic features of OA. The rate of OA progression slowed as the severity increased. We conclude that, in men, the incidence of radiographic features of hand OA increases with age. Regardless of age, the earliest radiographic signs of OA are joint space narrowing and doubtful osteophytes.
Synovitis and osteoarthritic changes in canine articular cartilage after anterior cruciate ligament transection. Effect of surgical hemostasis
Authors: Myers Stephen L. , Brandt Kenneth D. , O'Connor Brian L. , Visco Denise M. , Albrecht Marjorie E.
Published: February 2007

Anterior cruciate ligament transection (ACLT) in the dog produces changes in the articular cartilage of the unstable knee that are consistent with those of osteoarthritis (OA). To determine whether the degrees of severity of OA cartilage changes, of synovitis, and of synovial iron deposition were related to adequacy of hemostasis at the time of ACLT, a modified surgical technique was devised, whereby electrocautery was used to obtain meticulous control of bleeding when the ligament was severed and irrigation was used to remove intraarticular blood before closure of the joint. When no particular attention was given to hemostasis, 69% of the dogs showed synovitis in the OA knee 10 weeks after ACLT; when electrocautery and irrigation were used to maintain hemostasis, synovitis was present in only 24% of the OA knees 10 weeks after ACLT (P < 0.01). Iron deposits were present in 75% of synovial samples obtained after routine ACLT, but in only 6% (P < 0.001) when attention was given to hemostasis.Hypertrophy of articular cartilage, chondrocyte cloning, fibrillation, and changes in tangential zone chondrocytes were less prominent in the OA knee when electrocautery and irrigation were used. However, the water content, uronic acid concentration, and rate of net 35S‐labeled glycosaminoglycan synthesis were similarly increased regardless of the surgical technique used, and presumably, these changes reflect the reaction of joint cartilage to mechanical instability in this model of OA.
Vitamin e status during dietary fish oil supplementation in rheumatoid arthritis
Authors: Tulleken Jacob E. , Limburg Pieter C. , Muskiet Frits A. J. , Rijswijk Martin H. Van
Published: February 2007

The primary objective of this study was to determine whether it is the fish oil itself or the α‐tocopherol that is added to the fish oil preparations (to prevent peroxidation) that is responsible for the beneficial effects of dietary supplementation with fish oil in patients with rheumatoid arthritis (RA). One group of RA patients took fish oil supplements and another group took α‐tocopherol‐enriched coconut oil supplements (placebo controls), both for 3 months. Clinical and laboratory indices of RA activity in relation to cellular and plasma vitamin E levels were assessed at the beginning and the end of the trial. The results of the study provide evidence that the beneficial effects of fish oil supplementation cannot be ascribed to the antioxidizing properties of the α‐tocopherol per se.
The analysis of antinuclear and antinucleolar autoantibodies of scleroderma by radioimmunoprecipitation assays
Authors: Kipnis Robert J. , Craft Joe , Hardin John A.
Published: February 2007

We have characterized autoantibodies to nuclear and nucleolar antigens in 112 patients with diffuse scleroderma, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias), scleroderma overlap syndromes, or primary Raynaud's phenomenon by indirect immunofluo‐rescence and radiolabeled immunoprecipitation assays. We noted for the first time that anti‐Th RNP antibodies represent a common antibody specificity in scleroderma (occurring in 13% of patients with scleroderma‐like illnesses) and that anti‐NOR 90 antibodies are quite rare in American patients (none found). In addition, we describe 3 new scleroderma‐associated autoantibodies.
The comparative efficacy and toxicity of second‐line drugs in rheumatoid arthritis results of two metaanalyses
Authors: Felson David T. , Anderson Jennifer J. , Meenan Robert F.
Published: February 2007

We performed 2 metaanalyses of placebo‐controlled and comparative clinical trials to examine the relative efficacy and toxicity of methotrexate (MTX), injectable gold, D‐penicillamine (DP), sulfasalazine (SSZ), auranofin (AUR), and antimalarial drugs, the second‐line drugs most commonly used to treat rheumatoid arthritis (RA). For the efficacy study, we applied a set of inclusion criteria and focused on trials which provided information on tender joint count, erythrocyte sedimentation rate, or grip strength. We found 66 clinical trials that contained 117 treatment groups of interest, and for each drug, we combined the treatment groups. For each outcome, results showed that AUR tended to be weaker than other second‐line drugs. The results of the 3 outcome measures were synthesized into a composite measure of outcomes, and AUR was significantly weaker than MTX (P = 0.006), injectable gold (P < 0.0001), DP (P < 0.0001), and SSZ (P = 0.009) and was slightly, but not significantly, weaker than antimalarial agents (P = 0.11). We also found heterogeneity among antimalarial agents, in that patients treated with chloroquine did better than those treated with hydroxychloroquine. We found little difference in efficacy between MTX, injectable gold, DP, and SSZ. A power analysis showed that a trial should contain at least 170 patients per treatment group to successfully differentiate between more effective and less effective (e.g., AUR) second‐line drugs. None of the reported interdrug comparative trials we reviewed were this large.

For the toxicity study, our inclusion criteria captured RA trials which reported the proportion of patients who discontinued therapy because of drug toxicity and the total proportion who dropped out. We found 71 clinical trials that contained 129 treatment groups. The average proportion who dropped out and the average proportion who dropped out because of drug toxicity were computed for each drug. Overall, 30.2% of the patients in these trials dropped out; 50% of them did so because of drug toxicity. Injectable gold had higher toxicity rates (P < 0.05) and higher total dropout rates (P < 0.01) than any other drug; 30% of goldtreated patients dropped out because of side effects versus 15% of all trial patients. Antimalarial drugs and AUR had relatively low rates of toxicity; the rate for MTX was imprecise because of discrepancies between trials. Thus, of the commonly used second‐line drugs, AUR is the weakest, and injectable gold is the most toxic. Agents introduced in the future will be compared with these drugs. If a curative drug is not found, large multicenter trials or data synthesis from multiple drug trials may be necessary to identify new treatment regimens that have promise.
Imbalance between the mechanisms of activation and inhibition of metalloproteases in the early lesions of experimental osteoarthritis
Authors: Pelletier Jean‐Pierre , Mineau FrançOis , Faure Marie‐Pierre , Martel‐Pelletier Johanne
Published: February 2007

Levels of tissue inhibitor of metalloproteases (TIMP) and plasminogen activator (PA)/plasmin were measured and the distribution of PA was studied by immunohistochemical techniques in cartilage and synovium samples from dogs subjected to sectioning of the anterior cruciate ligament of their right knees and sham operation of their left knees (controls). Twenty‐three animals were divided into 3 groups and killed at 2, 4, or 8 weeks after surgery. The levels of PA and plasmin were found to be significantly elevated in the osteoarthritic (OA) knee cartilage and synovium at all times after surgery, except for levels of PA in the OA cartilage at 2 weeks. There was a positive correlation between the levels of PA and plasmin in the synovial membrane (r = 0.64, P < 0.001). In OA knees, the presence of high levels of total and active collagenase was detected in cartilage and in synovium. The levels of these 2 forms of collagenase showed a positive correlation both in cartilage (r = 0.65, P < 0.001) and in synovium (r = 0.77, P < 0.001). The levels of TIMP in cartilage from OA and sham operated knees were similar. Although the TIMP level was increased in the OA synovium, it was found only in trace amounts in cartilage. Immunohistochemical studies revealed that both forms of PA, urokinase‐type PA and tissue‐type PA, and TIMP were present in OA tissues. In the synovium, they were found mainly in monocyte/macrophages, synovial lining cells, and blood vessel cells. In OA cartilage, PA was present only at the superficial level in chondrocytes and in cartilage matrix, whereas TIMP was present in chondrocyte lacunae throughout the full thickness of the cartilage. TIMP was also detected in the superficial level of cartilage from sham operated knees. The results of this study indicate that in OA tissues, there are conditions that favor the synthesis and activation of metalloproteases. PA and plasmin are likely to play an important role in the physiologic activation of metalloproteases, although they are probably not the only system involved in this process. The lack of increased TIMP levels in the OA cartilage, in the presence of increased metalloprotease activity, is also a possible contributing factor in the enzymatic degradation of this tissue.
Specificity of antibodies to type II collagen in rheumatoid arthritis
Authors: Terato Kuniaki , Shimozuru Yasunori , Katayama Kou , Takemitsu Yoshiharu , Yamashita Izumi , Miyatsu Makoto , Fujii Katsuyuki , Sagara Mitsusada , Kobayashi Shiegeto , Goto Makoto , Nishioka Kusuki , Miyasaka Nobuyuki , Nagai Yutaka
Published: February 2007

To reassess the role of autoantibodies to type II collagen in the pathogenesis of diseases, we studied antibodies from patients with rheumatoid arthritis (RA) and from patients with relapsing polychondritis for species specificity and collagen type specificity, using an improved enzyme‐linked immunosorbent assay. Antibodies were found in the sera of 15% of the RA patients and 50% of the relapsing polychondritis patients, as well as in the cartilage of 69% of the RA patients examined. Reaction with both homologous and heterologous type II collagens was common. Analysis of 19 selected RA sera revealed that autoantibodies were generally associated with specific antibodies to some species of heterologous type II collagen. In contrast, antibodies found in 4% of the non‐RA controls were specific for either bovine or chick type II collagen. These findings indicate that autoantibody formation in RA and relapsing polychondritis may occur as a result of an immune response to heterologous type II collagen. However, since RA and relapsing polychondritis patient sera differed in their reactivity with the cyanogen bromide‐digested peptides, it is possible that the clinical manifestation of collagen autoimmunity might be influenced by the epitope specificity of the antibodies.
Use of molecular cloning methods to map the distribution of epitopes on topoisomerase I (Scl‐70) recognized by sera of scleroderma patients
Authors: D'Arpa Peter , White‐Cooper Helen , Cleveland Don W. , Rothfield Naomi F. , Earnshaw William C.
Published: February 2007

We report the initial molecular characterization of the autoimmune response against DNA topoisomerase I (topo I; Scl‐70). Sera from 36 patients with scleroderma and 4 healthy control subjects were studied using 6 subcloned portions of topo I. Twenty‐three sera recognized at least 2 independent epitopes on the molecule. Therefore, anti‐topo I, like other non‐organ‐specific autoantibodies characterized to date, is polyclonal and multifocal. The cloned protein should prove suitable for sensitive early detection of anti‐topo I in the clinical setting.
Synergistic, additive, and antagonistic effects of interleukin‐1β, tumor necrosis factor α, and γ‐interferon on prostaglandin e, hyaluronic acid, and collagenase production by cultured synovial fibroblasts
Authors: Meyer Frank A. , Yaron Ilana , Yaron Michael
Published: February 2007

The effects of binary combinations of the recombinant human cytokines, interleukin‐1β (rHuIL‐1β), tumor necrosis factor α (rHuTNFα), and γ‐interferon (rHuγ‐IFN) on the production of prostaglandin E (PGE), hyaluronic acid (HA), and collagenase by human synovial fibroblasts in culture were investigated. All 3 were stimulated by rHuIL‐1β and rHuTNFα alone, but not by rHuγ‐IFN. Stimulation with rHuIL‐1β and rHuTNFα occurred at femtomolar and picomolar concentrations, respectively, and maximal stimulation by rHuIL‐1β was several times greater than that by rHuTNFã. Stimulation of PGE and collagenase production with rHuIL‐1β or rHuTNFα was depressed by rHuγ‐IFN, depending on the concentration used. In contrast, stimulation of HA production with rHuIL‐1β or rHuTNFα was unaffected or increased somewhat with rHuγ‐IFN. Combinations of rHuIL‐1β and rHuTNFα had marked synergistic effects on PGE and collagenase production. However, when rHuIL‐1β effects were maximal, rHuTNFα had an additive effect. These cytokines had only additive effects on HA production, however, and when rHuIL‐1β effects were maximal, rHuTNFα produced no further stimulation. These data suggest that the secretory activities of synovial fibroblasts can be influenced by a combination of cytokines and is dependent on the type of cytokine present and its concentration.
Alteration of the cellular fatty acid profile and the production of eicosanoids in human monocytes by gamma‐linolenic acid
Authors: Pullman‐Mooar Sally , Laposata Michael , Lem Diana , Holman Ralph T. , Leventhal Lawrence J. , Demarco Deborah , Zurier Robert B.
Published: February 2007

We administered borage seed oil (9 capsules/day) for 12 weeks to 7 normal controls and to 7 patients with active rheumatoid arthritis. The therapy provided 1.1 gm/day of γ‐linolenic acid (GLA). GLA administration resulted in increased proportions of its first metabolite, dihomo‐γ‐linolenic acid (DGLA), in circulating mononuclear cells. The ratios of DGLA to arachidonic acid and DGLA to stearic acid increased significantly in these cells. Significant reductions in prostaglandin E2, leukotriene B4, and leukotriene C4 produced by stimulated monocytes were seen after 12 weeks of GLA supplementation. The antiinflammatory effects of GLA administration observed in animal models, and the apparent clinical improvement experienced by 6 of 7 rheumatoid arthritis patients given borage seed oil in this open, uncontrolled study may be due in part to reduced generation of arachidonic acid oxygenation products.
Renal disease in chronic arthritis of childhood. A study of urinary N‐acetyl‐β‐glucosaminidase and β2‐microglobulin excretion
Authors: Malleson Peter N. , Lockitch Gillian , Mackinnon Murray , Mahy Marguerite , Petty Ross E.
Published: February 2007

Urinalyses of randomly obtained samples from children with various types of chronic arthritis revealed proteinuria in 2.3% of patients, hemoglobinuria in 3.5%, erythrocyturia in 4.1%, and leukocyturia in 5.3%; these frequencies are within the range found by screening school children. However, raised urinary levels of N‐acetyl‐β‐glucosaminidase and/or β2‐microglobulin (both sensitive measures of renal tubular damage) were found more frequently in children with chronic arthritis than in controls (P < 0.0001). Abnormalities of either N‐acetyl‐β‐glucosaminidase or β2‐microglobulin excretion were associated with active arthritis as measured by physician global estimate of disease activity, with a polyarticular onset of juvenile rheumatoid arthritis, and with the use of slow‐acting antirheumatic drugs or the concurrent use of more than 1 nonsteroidal antiinflammatory drug. Abnormal renal tubular function appears to be common in chronic arthritis of childhood. The long‐term consequences of this abnormality remain to be elucidated.
D‐penicillamine‐induced lupus erythematosus
Authors: Enzenauer Raymond J. , West Sterling G. , Rubin Robert L.
Published: February 2007

We describe a patient who presented with polyarthritis, pleurisy, rash, and a positive antinuclear antibody result after 5 years of D‐penicillamine therapy. D‐penicillamine‐induced antinuclear antibodies were mainly high‐titer IgG directed against the (H2A‐H2B)‐DNA complex. Weak IgM activity with H1 and H2B was also observed. Withdrawal of D‐penicillamine therapy resulted in improvement in clinical symptoms and gradual resolution of serologic abnormalities.
Amyloidosis in behçet's syndrome
Authors: Yurdakul Sebahattin , Tüzüner Nüket , Yurdakul Ibrahim , Hamuryudan Vedat , Yazici Hasan
Published: February 2007

We investigated the frequency of amyloidosis in 99 consecutive patients (65 men and 34 women) with Behçet's syndrome. Rectal biopsies performed on all patients showed no amyloidosis by polarizing microscopy. The results of urinalyses were normal in all patients. Among 1,130 patients registered in our Behçet's syndrome outpatient clinic, 5 were found to have systemic amyloidosis, all of the AA type.