bluuebunny/crossref_metadata_2025 huggingface dataset:
Synoviocytes synthesize, bind, and respond to basic fibroblast growth factor
Authors: Melnyk Vera O. , Shipley Gary D. , Sternfeld Mark D. , Sherman Larry , Rosenbaum James T.
Published: February 2007

Rheumatoid arthritis (RA) is a systemic disease characterized by the destructive proliferation of synovial tissue. It has been suggested that this proliferative lesion resembles a malignancy. Although polypeptide growth factors have been implicated in malignant cell growth, their role in the pathogenesis of proliferative but non‐neoplastic diseases such as RA has not been extensively studied. We tested the hypothesis that the synoviocyte itself may be a source of growth factor activity. We demonstrated that culture supernatants from synoviocytes obtained from patients with RA, osteoarthritis, and traumatic joint disease contain mitogenic activity. This activity has biologic properties identical to those of basic fibroblast growth factor (bFGF). Specifically, the mitogenic activity is synergistic with insulin and binds to heparin‐agarose, but elutes with 2.0M NaCl. In addition, synoviocyte extracts contain a peptide with a molecular weight of ∼ 16,000, which reacts with antibody specific for bFGF. Cultured synoviocytes express the bFGF gene, express receptors for bFGF, and proliferate in response to bFGF. We conclude that bFGF derived from the synoviocytes themselves may play a role in stimulating their proliferation in an autocrine manner in disease states such as RA.
Rapid periarticular bone loss in rheumatoid arthritis
Authors: Sambrook P. N. , Shawe Deirdre , Hesp R. , Zanelli Joan M. , Mitchell Rhiannon , Katz D. , Gumpel J. M. , Ansell Barbara M. , Reeve J.
Published: February 2007

For approximately 2 years, bone loss was measured in women with early stages of rheumatoid arthritis (RA) and in control subjects, using serial computed tomography and dual photon absorptiometry. Rapid trabecular bone loss from the distal radius was observed in the RA patients but not the controls. The bone loss correlated with initial plasma levels of parathyroid hormone and 1,25‐dihydroxyvitamin D3 (calcitriol) concentrations. It has been suggested that these humoral factors may interact with cytokines or other mediators produced in the adjacent wrist joint. Losses of the cortical bone of the radial midshaft and the lumbar spine were modest and were comparable in the 2 groups. Indices relating to both bone formation and bone resorption predicted bone loss at these 2 sites, but changes in the parathyroid hormone and calcitriol concentrations did not.
Measurement of increases in anti‐double‐stranded dna antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus
Authors: Ter Borg E. J. , Horst G. , Hummel E. J. , Limburg P. C. , Kallenberg C. G. M.
Published: February 2007

To evaluate the predictive power of changes in levels of antibodies to double‐stranded DNA (anti‐dsDNA) as a predictor of disease exacerbations in systemic lupus erythematosus (SLE), we performed a prospective study on 72 unselected patients with SLE (mean duration of study 18.5 months, range 6–35 months). Patients were seen at least once every 3 months, and disease activity was scored according to a specific protocol. Plasma samples were obtained at least once every month and were assessed for anti‐dsDNA antibody (by the Crithidia luciliae assay, an enzymelinked immunosorbent assay [ELISA], and the Farr assay) and for complement components C3 and C4. Twenty‐seven of 33 disease exacerbations observed during the study period were accompanied by a positive test result for anti‐dsDNA antibody (27 by the Farr assay, 19 by the C luciliae assay, and 23 by the ELISA). Twenty‐four of these exacerbations were preceded by a significant increase in anti‐dsDNA antibody levels (23 by the Farr assay, 12 by the C luciliae assay, and 17 by the ELISA). The first observance of a significant increase in anti‐dsDNA antibody levels preceded the exacerbation by 8–10 weeks. Significant increases in anti‐dsDNA antibody levels not followed by an exacerbation were observed in 5 cases by the Farr assay, in 7 cases by the C luciliae assay, and in 3 cases by the ELISA; however, in 3 cases, 2 cases, and 1 case, respectively, these increases were followed by an increase in disease activity that did not fulfill the criteria for an exacerbation. Serial measurement of anti‐dsDNA antibody levels was more sensitive for predicting exacerbations than was measurement of C3 and/or C4 levels (P < 0.03). Serial assessment of anti‐dsDNA antibody levels, especially by the Farr assay, is a sensitive and reasonably specific method for predicting disease exacerbations in SLE.
Beneficial effect of fibronectin administration on chronic nephritis in rats
Authors: Quirós Javier , Gonzalez‐Cabrero Jesus , Egido Jesus , Herrero‐Beaumont Gabriel , Martinez‐Montero Juan C.
Published: February 2007

We studied the effect of fibronectin (FN) on the course of chronic nephritis (induced by daily injections of ovalbumin) and on the clearance and catabolism of immune complexes in Wistar rats. Rats with chronic nephritis were treated with FN (2.5 mg/kg/48 hours) for 15 days after proteinuria was first detected. In rats with untreated nephritis, urinary protein levels increased from 40 ± 22 mg/day (mean ± SD) to 339 ± 68 mg/day during the 15 days of the study (P < 0.0005). This statistically significant increase was not observed in rats treated with FN (mean ± SD 58 ± 46 mg/day to 124 ± 112 mg/day). Rats treated with FN showed a higher total serum protein level than did the untreated animals (mean ± SD 6.4 ± 0.3 gm/dl versus 5.1 ± 0.5 gm/dl; P < 0.0125), as well as a significant reduction in mesangial and glomerular basement membrane deposits. Untreated nephritic rats demonstrated delayed plasma clearance of 125I‐labeled aggregated IgG (plasma half‐life [T1/2] 3.03 ± 0.6 minutes) and less catabolism of these aggregates at 30 minutes (mean ± SD 15 ± 1.7%) than did the normal rats (T1/2 1.5 ± 0.2 minutes, 22 ± 2.8%, respectively; P < 0.0005). Both parameters were within normal limits in the FN‐treated rats (T1/2 1.6 ± 0.4 minutes, 22 ± 6%, respectively). In vitro, FN induced a significant increase in aggregated IgG catabolism by Kupffer cells and peritoneal macrophages from normal rats. These results show that FN reduces the proteinuria and histologic lesions of chronic nephritis in rats. These beneficial effects of FN could be due to the improved clearance of immune complexes, decreased glomerular deposition, and perhaps, to better renal processing of immune complexes.
Autoantibodies, ly‐1, and immunoglobulin v gene expression in hybridomas obtained from young and from old new zealand black mice
Authors: Fidanza Vincenzo , Mayer Raoul , Zaghouani Habib , Diliberti Mary Ann , Bona Constantin A.
Published: February 2007

We obtained a large number of hybridomas from 1‐month‐old and 16‐month‐old New Zealand black mice to study the fine specificities of the autoantibodies produced, the expression of Ly‐1, and the expression of the immunoglobulin V gene families in this autoimmune strain. Analysis of the autoantibody specificities yielded 2 major classifications: those specific for a single autoantigen and those that exhibited multispecific binding. Among the multispecific antibodies, 2 categories were found: an antigen‐inhibitable group and an antigennoninhibitable group. A large proportion of VHJ558 and VH7183 gene families was observed in hybridomas obtained from 1‐month‐old mice, and in hybridomas obtained from 16‐month‐old mice, there was a large proportion of VHJ558 and VH36–60 gene families. Among the autoantibody k chains secreted by the hybridomas, there was a higher frequency of the Vk1, Vk8, and Vk9 gene families. Autoantibodies were produced by both the Ly‐1+ and the Ly‐1‐B cell subsets.
Biochemical demonstration of calpains and calpastatin in osteoarthritic synovial fluid
Authors: Suzuki Kiichi , Shimizu Katsuji , Hamamoto Takashi , Nakagawa Yasuaki , Hamakubo Takao , Yamamuro Takao
Published: February 2007

Calpains (calcium‐dependent cysteine proteinases; optimum pH 7.0–7.5) have been regarded as intracellular proteinases. We examined the cell‐free components of synovial fluid from 14 patients with osteoarthritis and demonstrated the existence of calpains, as the caseinolytic activities of chromatographic fractions, together with calpastatin, the specific endogenous inhibitor of calpains. The presence of these calpains and calpastatin was verified by immunoblotting with their respective specific antibodies. Calpain fractions showed proteoglycan‐degrading activity. The results suggest that the calpain‐calpastatin system may contribute to the turnover of cartilage matrix components.
Depletion of high‐energy phosphates in the central nervous system of patients with systemic lupus erythematosus, as determined by phosphorus‐31 nuclear magnetic resonance spectroscopy
Authors: Griffey Richard H. , Brown Mark S. , Bankhurst Arthur D. , Sibbitt Randy R. , Sibbitt Wilmer L.
Published: February 2007

Systemic lupus erythematosus (SLE) can produce profound disturbances in the central nervous system, characterized by encephalopathy, focal neurologic deficits, cerebral infarction, psychosis, and seizures. We used 31P nuclear magnetic resonance (NMR) spectroscopy to determine the in vivo levels of high‐energy phosphates in the central nervous system of 10 patients with SLE and 10 age‐matched normal controls. 31P NMR spectroscopy was performed on a 1.5‐Tesla unit equipped with a dual‐tuned 1H‐31P surface coil and a software‐directed DRESS (depth resolved surface coil spectroscopy) pulse sequence. This procedure detected ADP, ATP, sugar phosphates, phosphocreatine (PCr), inorganic phosphate, phosphomonoesters, and phosphodiesters in the brain tissue of all study subjects. Levels of ATP in the deep white matter of 10 SLE patients were significantly decreased compared with the levels in 10 normal controls, as quantitated by the ratio of ATP:ATP + ADP (mean ± SD 0.81 ± 0.11 versus 0.91 ± 0.05; P < 0.02). In a subgroup of 4 patients, PCr levels were decreased to a greater extent than the ATP levels. NMR spectroscopic alterations were not related to obvious anatomic lesions, as determined by standard cranial proton magnetic resonance imaging. In 4 SLE patients with markedly abnormal 31P NMR spectra, treatment with prednisone (80 mg/day) normalized the levels of ATP and PCr. Restoration of a normal 31P profile was accompanied by an obvious improvement in the patients' mental status and clinical symptoms. 31P NMR spectroscopy is a powerful new technique for monitoring high‐energy phosphate metabolism, and may be particularly useful for characterizing central nervous system disease in patients with neuropsychiatric SLE.
Autoantibodies to lamins in rheumatoid arthritis
Authors: Lassoued Slim , Oksman Françoise , Fournie Bernard , Danon Françoise , Fournie Antoine , Lassoued Kaiss
Published: February 2007

The presence of autoantibodies reacting with lamins A and C was demonstrated in sera from 2 patients with rheumatoid arthritis (RA). One patient developed antilamin antibodies several years after being diagnosed as having RA; she was also found to have chronic active hepatitis. The second patient had severe nodular RA. We describe the other serologic findings in these 2 patients and discuss the relationships between antilamin antibodies and RA.
Biochemical characterization of amyloid derived from the variable region of the k light chain subgroup III
Authors: Picken Maria M. , Gallo Gloria R. , Pruzanski Waldemar , Frangione Blas
Published: February 2007

We report the clinical data and results of biochemical studies of amyloid in a postpartum patient. The amyloidosis was not associated with myeloma, and immunopathologic examination of the amyloid deposits gave inconclusive results. Biochemical analysis of the deposits proved that the amyloid protein JUN was derived from the variable region of the k light chain subgroup III and is homologous to a rarely expressed protein POM, which was previously shown to have rheumatoid factor activity. The significance of this association and the diagnostic problems associated with certain cases of amyloid derived from immunoglobulin light chain (type AL) are discussed.
Decreased activity of reiter's syndrome after urethrectomy
Authors: Rubin Richard A. , Goldfarb Richard A. , Lidsky Martin D. , Abrams Jackie
Published: February 2007

Reiter's syndrome is a chronic rheumatic disease that develops after infective urethritis or gastroenteritis and has a strong association with the HLA‐B27 antigen. How these factors interact remains unclear. We present a patient with Reiter's syndrome who exhibited 2 novel features: unusually severe urethritis that produced strictures requiring surgery, and dramatic regression of his rheumatic manifestations following a urethrectomy.
Intravenous gamma globulin therapy in systemic juvenile rheumatoid arthritis
Authors: Silverman Earl D. , Laxer Ronald M. , Greenwald Mark , Gelfand Erwin , Shore Abraham , Stein Leonard D. , Roifman Chaim M.
Published: February 2007

Intravenous (IV) gamma globulin has been successfully used as replacement therapy for antibody‐deficient patients and, more recently, in the treatment of autoimmune diseases such as idiopathic thrombocytopenic purpura, myasthenia gravis, and Kawasaki disease. In view of the successful treatment of these diseases, we initiated a pilot study of the effect of IV gamma globulin in systemic juvenile rheumatoid arthritis (JRA). Eight patients with active systemic JRA that was unresponsive to first‐line agents, second‐line agents, and/or corticosteroids received this therapy monthly for 6 months. Outcome measures included changes in articular and extraarticular features, steroid dosage, and laboratory parameters. Following IV gamma globulin therapy, there was significant improvement in arthritis and/or morning stiffness in 5 of 8 patients, while extraarticular features significantly improved in 7 of 8 patients. At study entry, 6 of 8 patients were receiving prednisone; at study end, prednisone was discontinued in 3 patients and decreased by more than 50% in the other 3. Overall, there was an 80% reduction in the prednisone dosage. Initially, all patients had anemia, low levels of serum albumin, and an elevated erythrocyte sedimentation rate, while a thrombocytosis was seen in 7 of 8 patients. Serum IgG was initially elevated in 6 patients. IV gamma globulin therapy resulted in a significant increase in hemoglobin and albumin levels and a significant decrease in the mean serum IgG level, platelet count, and erythrocyte sedimentation rate. In only 1 patient did IV gamma globulin fail to significantly improve the clinical or laboratory features of the disease. We suggest that this therapy may be beneficial in the treatment of systemic JRA.
Structural characterization of the second major cross‐reactive idiotype group of human rheumatoid factors. Association with the VH4 Gene Family
Authors: Silverman Gregg J. , Schrohenloher Ralph E. , Accavitti Mary A. , Koopman William J. , Carson Dennis A.
Published: February 2007

Rheumatoid factors (RF) are the most common type of functional antibodies among naturally occurring human monoclonal IgM proteins. A large subset of these autoantibodies use structurally homologous light chains of the kIII subgroup, which bear the 6B6.6 cross‐reactive idiotype (CRI). Although antibody binding activity requires both heavy and light chains, information about the heavy chains used by these autoantibodies is limited. To investigate these proteins, the murine monoclonal antibodies, 5–14 and 6–10, were generated by immunization with the heavy chains of the 6B6.6 CRI‐positive RF, COR and LEW. These antiidiotypic antibodies reacted with 8 of 11 autoantibodies that coexpressed the 6B6.6 CRI. All 8 RF had heavy chains from the VH4 gene family, as assessed by reactivity with a VH4‐specific primary sequence‐dependent antibody. The same RF were also identified by the previously described murine monoclonal antiidiotype, LCI. Further experiments revealed that the LCI antibody delineates a subfamily of VH4 heavy chains that is preferentially used in KIII‐6B6.6 CRI‐positive IgM‐RF. The cumulative data suggest that 13–22% of RF express both the KIII‐6B6.6 and VH4‐LC1 CRI. These findings document that RF autoantibody activity requires specific VL‐VH pairing, and that a subset of idiotypically related VH4 heavy chains is commonly expressed in disease‐associated monoclonal IgM‐RF.
Cellular immune response toward human articular chondrocytes. T cell reactivities against chondrocyte and fibroblast membranes in destructive joint diseases
Authors: Alsalameh Saifeddin , Mollenhauer JÜRgen , Hain Norbert , Stock Klaus‐Peter , Kalden Joachim R. , Burmester Gerd R.
Published: February 2007

Articular cartilage is one of the major targets in destructive joint diseases in humans. We studied cellular immune reactions against cartilage cell‐surface membranes, because it has recently been suggested that these represent possible antigenic structures, based upon the observation of autoantibodies with this specificity in certain joint diseases. A striking T cell reactivity toward chondrocyte membranes was found both in blood and synovial tissue from patients with rheumatoid arthritis. This reactivity was strongly dependent on the presence of monocytes and had all the characteristics of an antigen‐driven process. Clonal analysis demonstrated high precursor frequencies in peripheral blood T cells that were reactive against chondrocyte membranes. This response to chondrocyte membranes greatly exceeded the T cell stimulation induced by membranes from other sources such as fibroblasts or epithelial cells. In contrast to patients with rheumatoid arthritis, individuals with osteoarthritis showed a strong peripheral blood and synovial fluid T cell response not only to chondrocyte membranes, but also to fibroblast membrane material. However, there was no reactivity to epithelial cell membranes. Normal donors generally did not show significant responses to any membrane preparation. These data indicate that there is a strong T cell reactivity toward chondrocyte membranes in destructive joint disorders, and this may significantly contribute to the pathogenetic processes that occur in these diseases.
Relationship of glucocorticoid dosage to serum bone gla‐protein concentration in patients with rheumatologic disorders
Authors: Kotowicz Mark A. , Hall Stephen , Hunder Gene G. , Cedel Sandra L. , Mann Kenneth G. , Riggs B. Lawrence
Published: February 2007

Serum bone Gla‐protein (BGP) measurements in 50 rheumatic disease patients receiving long‐term prednisone therapy revealed an inverse relationship (r = −0.71, P < 0.001) between serum BGP levels and prednisone dosage. Multiple regression analysis demonstrated significant relationships (R2 = 0.72, P < 0.001) between serum BGP1/2 and prednisone dosage, dosage2, serum creatinine, age, and an age‐creatinine interaction. This model predicts the suppression of serum BGP with low dosages of steroids and 50% suppression with dosages of 20–25 mg/day.
IgG and IgA antibodies to the collagen‐like region of C1q in rheumatoid vasculitis
Authors: Siegert C. E. H. , Daha M. R. , Van Voort E. A. M. Der , Breedveld F. C.
Published: February 2007

We investigated the presence of IgG and IgA antibodies to C1q in serum samples from 80 patients with rheumatoid arthritis (RA), 31 patients with rheumatoid vasculitis, and 80 healthy controls. IgG and IgA antibodies to C1q, as measured by enzyme‐linked immunosorbent assay, were found in <5% of the sera from RA patients and from healthy controls. In contrast, IgG and IgA antibodies to C1q were found in 29% and 61%, respectively, of the sera from patients with rheumatoid vasculitis. The occurrence of IgA antibodies to C1q has not been previously demonstrated. These results also demonstrate that IgG antibodies to C1q do not occur exclusively in systemic lupus erythematosus patients: Sera of patients with rheumatoid vasculitis frequently contain IgG or IgA antibodies to C1q, which contribute to immune complex formation.
Association of labial salivary gland histopathology with clinical and serologic features of connective tissue diseases
Authors: Shah Farah , Rapini Ronald P. , Arnett Frank C. , Warner Noranna B. , Smith Carolyn A.
Published: February 2007

Focal sialadenitis is now widely accepted as an objective criterion for the oral component of Sjögren's syndrome (xerostomia). We investigated the association between labial salivary gland histopathologic changes and the clinical and serologic features of 192 patients with suspected connective tissue disorders. A retrospective review of the medical records of all patients was performed, and historical, physical, laboratory, histologic, and roentgenographic data were abstracted. Each patient had undergone labial salivary gland biopsy as part of a rheumatologic evaluation. There were significant associations between positive findings on lip biopsy and the presence of keratoconjunctivitis sicca (P = 0.013), positive antinuclear antibodies (titer ≥1:80) (P = 2 x 10−8), and positive Ro antibodies (P = 1 x 10−8). However, sicca symptoms and glandular enlargement were not statistically associated with positive findings on lip biopsy. Features predictive of a positive lip biopsy included Ro antibodies (P = 0.914), keratoconjunctivitis sicca (P = 0.700), and positive antinuclear antibodies (P = 0.590).
Functional studies of soluble low‐affinity interleukin‐2 receptors in rheumatoid synovial fluid
Authors: Miossec Pierre , Elhamiani Majida , Edmonds‐Alt Xavier , Sany Jacques , Hirn Michel
Published: February 2007

Since abnormal regulation of interleukin‐2 (IL‐2) has been demonstrated in rheumatoid arthritis (RA), the functional role of low‐affinity soluble IL‐2 receptors (sIL‐2R) purified from RA synovial fluids (SF) was studied. Picomolar levels of sIL‐2R were detected in RA SF using an enzyme‐linked immunosorbent assay. Levels were higher in serum and SF from RA patients than in controls (P < 0.001) and higher in RA SF than in paired RA serum (P < 0.01). Soluble IL‐2R from RA SF had estimated molecular weights of 40‐50 kd and 80–100 kd by gel filtration analysis. The 80–100‐kd peak is likely to be a dimer of the 40–50‐kd peak, since a single 45‐kd peak was found after elution from sodium dodecyl sulfate‐polyacrylamide gels. Since inhibitory activity for lymphocyte proliferation was found in the 80–100‐kd range, the sIL‐2R were purified with an anti‐CD25 affinity column and further analyzed. The purified fractions did not interfere with the proliferation of mitogen‐stimulated lymphocytes or with the binding of radiolabeled IL‐2 to CTLL‐2 cells, although direct binding of IL‐2 was demonstrated. The affinity of sIL‐2R from RA SF for binding IL‐2 was in the range of 25 nM, which is similar to the affinity of sIL‐2R purified from a human T cell clone, indicating that both sIL‐2R are low‐affinity receptors for IL‐2. We conclude that the concentration and binding affinity of low‐affinity sIL‐2R purified from RA SF render them unable to interfere with IL‐2‐related activities.
Inhibition of interleukin‐1‐induced collagenase production in human articular chondrocytes in vitro by recombinant human interferon‐gamma
Authors: Andrews H. J. , Bunning R. A. D. , Plumpton T. A. , Clark I. M. , Russell R. G. G. , Cawston T. E.
Published: February 2007

The production of collagenase by human articular chondrocytes in response to interleukin‐1β is inhibited in a dose‐dependent manner by interferon‐γ (1–1,000 units/ml). The analysis of culture medium samples by Western blotting and the measurement of levels of tissue inhibitor of metalloproteinases suggest that the decrease in measurable collagenase activity is primarily due to the inhibition of procollagenase production. These results provide evidence of a role for interferon‐γ in limiting connective tissue degradation.
Yersinia Enterocolitica In the synovial membrane of patients with Yersinia‐induced Arthritis
Authors: Hammer Michael , Zeidler Henning , Klimsa Silvia , Heesemann JÜRgen
Published: February 2007

Using a monospecific rabbit antibody against Yersinia enterocolitica outer membrane protein 1, we examined synovial biopsy specimens from 7 patients with Yersinia‐induced arthritis. Yersinia were demonstrated in the synovial membrane by indirect immunofluorescence in 4 patients with Yersinia‐induced arthritis, but not in 6 control patients with Salmonella‐induced arthritis or with rheumatoid arthritis. These findings suggest the persistence of Yersinia in the joints of patients with Yersinia‐induced arthritis.
Catabolic effects of muramyl dipeptide on rabbit chondrocytes
Authors: Ikebe Tetsuro , Iribe Hideaki , Hirata Masato , Yanaga Fumi , Koga Toshitaka
Published: February 2007

Muramyl dipeptide, an essential structure for the diverse biologic activities of bacterial cell wall peptidoglycan, inhibited the synthesis of glycosaminoglycan/proteoglycan in cultured rabbit costal chondrocytes in a dose‐dependent manner. Muramyl dipeptide, as well as lipopolysaccharide and interleukin‐1α, also enhanced the release of 35S‐sulfate—prelabeled glycosaminoglycan/proteoglycan from the cell layer, which seems to reflect, at least partially, the increasing degradation of glycosaminoglycan/proteoglycan. Five synthetic analogs of muramyl dipeptide known to be adjuvant active or adjuvant inactive were tested for their potential to inhibit synthesis of glycosaminoglycan/proteoglycan and to enhance the release of glycosaminoglycan/proteoglycan in chondrocytes. The structural dependence of these synthetic analogs on chondrocytes was found to parallel that of immunoadjuvant activity. These results suggest that muramyl dipeptide is a potent mediator of catabolism in chondrocytes.
Inhibition of 5‐lipoxygenase product formation and polymorphonuclear cell degranulation by tenidap sodium in patients with rheumatoid arthritis
Authors: Blackburn Warren D. , Heck Louis W. , Loose Leland D. , Eskra J. D. , Carty T. J.
Published: February 2007

We studied the effect of tenidap sodium, a new antiinflammatory/antirheumatic drug (120 mg/day for 7 days), on eicosanoid production and neutrophil degranulation in patients with rheumatoid arthritis. Endogenous prostaglandin E2 levels and ex vivo production of leukotriene B4 (LTB4) were measured in synovial fluid samples obtained at baseline and 1 week later. We measured peripheral blood polymorphonuclear cell (PMN) degranulation following surface‐bound IgG stimulation, a possible 5‐lipoxygenase product–mediated event, by determining lactoferrin and elastase release into the culture fluid. We found decreased levels of endogenous prostaglandin E2 as measured by radioimmunoassay, and decreased ex vivo production of LTB4 by PMN as measured by high performance liquid chromatography, in synovial fluid samples from patients who took tenidap. Release of the granule proteins lactoferrin and elastase was decreased in PMN obtained from patients receiving tenidap, as well as in the PMN incubated in vitro with tenidap. Improvement in clinical measures paralleled the biochemical changes. The unique 5‐lipoxygenase inhibitory property of tenidap, as measured by LTB4 production and degranulation, suggests that it may have clinical activity which differentiates it from nonsteroidal antiinflammatory drugs.
Tenidap, in contrast to several available nonsteroidal antiinflammatory drugs, potently inhibits the release of activated neutrophil collagenase
Authors: Blackburn Warren D. , Heck Louis W. , Loose Leland D. , Chatham W. Winn
Published: February 2007

Neutrophils contain a collagenase that is stored in a latent form within the specific granule. With cellular activation, the latent enzyme is activated in association with the production of a variety of oxidants, including hypochlorous acid. We evaluated 4 nonsteroidal antiinflammatory drugs (NSAIDs) currently on the market and the new antiinflammatory/antirheumatic drug tenidap for their effects on the release of activated collagenase. In contrast to the 4 NSAIDs, tenidap profoundly inhibited the release of activated collagenase. This inhibition was predominantly due to interference with activation of the latent enzyme, rather than interference with enzyme release. The inhibition of collagenase activation was associated with a profound reduction in myeloperoxidase activity and in hypochlorous acid production. These observations demonstrate that tenidap has properties that set it apart from conventional NSAIDs and suggest that it may be a particularly useful agent in the treatment of inflammatory rheumatic disorders.
In vivo leukocyte migration in arthritis
Authors: Jones Anthony K. P. , Al‐Janabi Mazim A. , Solanki Kishor , Sobnack Ravin , Greenwood Allison , Doyle David V. , Britton Keith E. , Huskisson Edward C.
Published: February 2007

We quantitated in vivo migration of neutrophils into the knees of patients with rheumatoid arthritis (RA) and osteoarthritis, using 99mtechnetium–hexamethyl‐propylene‐amineoxime–labeled leukocytes and gamma scintigraphy. Significant neutrophil migration occurred in patients with RA irrespective of disease duration, and it was reduced by 60% following intraarticular steroid injection. The reduction in neutrophil migration correlated with reduction in pain. Leukocyte migration into osteoarthritic joints was also demonstrated, although it was much less than that seen in rheumatoid joints. No significant leukocyte migration into the joints of patients without arthritis was demonstrated. This technique appears to provide a sensitive method for quantitatively assessing the neutrophil component of inflammation in individual joints of patients with arthritis.
Amelioration of lapine osteoarthritis by treatment with glycosaminoglycan–peptide association complex (Rumalon)
Authors: Dean David D. , Muniz Ofelia E. , Rodriquez Ivette , Carreno Manuel R. , Morales Sara , Agundez Agueda , Madan Maria Elena , Altman Roy D. , Annefeld Marliese , Howell David S.
Published: February 2007

The chondroprotective potential of glycosaminoglycan–peptide association complex (GP‐C) was examined in the medial meniscectomy model of lapine osteoarthritis (OA). Prophylactic treatment with increasing doses of intramuscular GP‐C (0.05–0.5 ml/kg) caused a significant reduction in OA lesion area and histologic scores, and the effect on disease activity appeared to be dose related. The DNA and uronic acid contents of OA tissue were unaffected by prophylactic treatment with GP‐C. However, levels of hydroxyproline in OA cartilage increased to near control levels with prophylactic treatment. Cartilage levels of active and total metalloproteinases that digest proteoglycans were elevated in rabbits with OA; prophylactic treatment with low‐dose GP‐C (0.05 ml/kg) produced a significant reduction in active, but not total, enzyme. Cartilage levels of tissue inhibitor of metalloproteinases in animals with OA were comparable with control levels, but rose with increasing doses of GP‐C. We also investigated GP‐C as a therapeutic treatment in animals that had already developed OA lesions. Carbon black retention and histologic score returned to near‐normal after therapeutic treatment with GP‐C. Uronic acid and hydroxyproline levels were decreased in OA cartilage. Therapeutic treatment with GP‐C had no statistically significant effect on uronic acid levels, but was associated with increased hydroxyproline content in the cartilage. The changes in metalloproteinase and metalloproteinase inhibitor were similar to those found in the studies of prophylactic treatment. The findings in this animal model may help explain some of the beneficial effects of GP‐C in human OA.
Restricted diversity of the variable region nucleotide sequences of the heavy and light chains of a human rheumatoid factor
Authors: Ezaki Ichiko , Shingu Masao , Nobunaga Masashi , Kanda Hidetoshi , Watanabe Takeshi , Sakai Kouko , Fukui Nobunori
Published: February 2007

The complete nucleotide sequences of the variable region genes of the heavy and light polypeptide chains of a human monoclonal rheumatoid factor (RF) produced from a human–mouse heterohybridoma were determined. The antibody, designated YES8c, contained V κIII, Jκ2, VH1, JH4, and a D gene segment of 9 amino acids. The nucleotide sequences and the deduced amino acid sequences of the light chain variable region were remarkably homologous (97–98%) to previously described RF of the Wa idiotypic family (PAY, GLO, CUR, FLO, and GAR) and to that of a VκIII germline gene (Humkv325). The YES8c heavy chain variable region gene was most closely related to the VH1 gene of the restricted human fetal repertoire, designated 51p1, and also to 3 rearranged VH1 genes that were recently isolated from patients with chronic lymphocytic leukemia. These results suggest that variable region genes of RFs are highly conserved and that YES8c VH, as well as Vκ, may be identical to heavy and light chains expressed during early B cell development.
A double‐blind randomized controlled trial of ketotifen versus placebo in early diffuse scleroderma
Authors: Gruber Barry L. , Kaufman Lee D.
Published: February 2007

To determine the efficacy of the mast cell‐stabilizing drug ketotifen in scleroderma, we conducted a 6‐month, randomized, prospective, double‐blind, placebo‐controlled trial in 24 patients. No significant improvement in the clinical paramenters, pulmonary function, global assessments, and mast cell releasability was noted. Pruritus tended to improve in the group taking the active drug. Six months of treatment with ketotifen (6 mg/day), therefore, produced no apparent benefit in patients with early scleroderma. We were unable to address the role of mast cells in scleroderma since mast cell suppression was not achieved.
Relationship between arthroscopic evidence of cartilage damage and radiographic evidence of joint space narrowing in early osteoarthritis of the knee
Authors: Fife Rose S. , Brandt Kenneth D. , Braunstein Ethan M. , Katz Barry P. , Shelbourne K. Donald , Kalasinski Lorrie A. , Ryan Sarah
Published: February 2007

We examined the relationship between articular cartilage degeneration, as visualized arthroscopically, and joint space narrowing (JSN) in standing anteroposterior knee radiographs of 161 patients with chronic knee pain. The majority of these patients had radiographic findings of mild osteoarthritis. Twenty‐five (33%) of the 76 patients in the series whose radiographs showed tibiofemoral JSN had grossly normal articular cartilage in both tibiofemoral compartments at arthroscopy (false‐positive). The specificity of medial JSN for the presence of medial compartment articular cartilage degeneration was 0.61, i.e., only 61% of patients with normal (grade 0) medial compartment cartilage had a normal medial joint space. Of 22 patients with >50% medial JSN, 9 (41%) had normal articular cartilage in the medial compartment at arthroscopy. Of 6 patients with >50% lateral JSN, 3 (50%) had normal lateral compartment articular cartilage at arthroscopy. Among 36 patients with >25% JSN who had neither medial nor lateral compartemnt articular cartilage degeneration, JSN was associated with articular caartilage degeneration, JSN was associated with articular cartilage degeneration in the patellofemoral compartemnt in 8 (22%), with meniseus degeneration in 18 (50%), and with both in 8 (22%). Thus, in these patients with chronic knee pain, radiographic evidence of JSN in the tibiofemoral compartment did not permit confident prediction of the status of the articular cartilage.
T cell proliferation induced by Borrelia burgdorferi in patients with lyme borreliosis. Autologous serum required for optimum stimulation
Authors: Krause Andreas , Kalden Joachim R. , Burmester Gerd R. , Brade Volker , Schoerner Christoph , Solbach Werner
Published: February 2007

The cellular immune response to Borrelia burgdorferi was studied in 24 patients with seropositive and seronegative Lyme borreliosis, 30 patients with arthritides of different origin (non‐Lyme arthritides), and 20 normal blood donors. By far, the strongest T cell stimulation was induced by incubation with autologous serum; there was a significantly lower response or no response after incubation with allogeneic or heterologous sera. In patients with Lyme borreliosis, including seronegative patients, there was a strikingly elevated proliferation in response to whole B burgdorferi bacteria (mean 64,750 dpm) compared with that of normal donors (mean 19,700 dpm; P < 0.0001) and especially that of non‐Lyme arthritis patients (mean 11,600 dpm; P <0.0001). Levels of proliferation declined significantly in patients with Lyme borreliosis after successful antibiotic treatment. Parallel cultures using B burgdorferi and Treponema phagedenis as antigens showed that cells from patients with Lyme borreliosis responded significantly more to B burgdorferi than to T phagedenis, but this did not occur with cells from individuals with non‐Lyme arthritides. There was no correlation between disease stages and proliferation values. These data indicate that lymphocyte proliferation assays may provide an important tool for the diagnosis of Lyme borreliosis, most notably in patients with arthritides and in those who are seronegative. Conversely, the lack of reactivity appears to be a strong indicator of the absence of active Lyme disease. It seems to be crucial, howeveer, to use autologous sera in these assays.
The effects of cyclosporin a on eicosanoid excretion in patients with rheumatoid arthritis
Authors: Weinblatt M. , Helfgott S. , Coblyn J. , Spragg J. , Tumeh S. , Sperling R. , Maier A. , Uedelhoven W. M. , Lorenz R. , Weber P.
Published: February 2007

Alterations in renal eicosanoid levels have been postulated as a factor in cyclosporin A (CSA) nephro‐toxicity. The effects of CSA on renal eicosanoid excretion in rheumatoid arthritis were studied over a 24‐week period, during which treatment with nonsteroidal anti‐inflammatory drugs was discontinued. The initial dosage of CSA was 4 mg/kg/day; at week 24, the mean dosage of CSA was 3.9 mg/kg/day. At week 24, the mean (±SD) serum creatinine level (1.04 ± 0.24 mg/dl) was 32% above the baseline value; renal blood flow had decreased by 21% (P < 0.03) and the glomerular filtration rate had decreased by 16%. There was a significant increase (P < 0.03) in the 2,3‐dinor thromboxane B2 level at week 2, but there was no significant change in the levels of the other eicosanoids. This study demonstrates that after CSA treatment, there is a selective increase in a thromboxane metabolite that parallels an increase in renal vascular resistance, even in the absence of nonsteroidal antiinflammatory drugs, and with unimpaired formation of other vasodilator eicosanoids.
Morphologic and morphometric changes in synovial membrane associated with mechanically induced osteoarthrosis
Authors: Boyd R. D. , Walker E. R. , Wu D. D. , Lukoschek M. , Burr D. B. , Radin E. L.
Published: February 2007

We sought to determine whether synovial leukocytic inflammation is a primary event in mechanically induced osteoarthrosis. Repetitive impulse loading (50 ms duration at 60 Hz for 40 minutes each day) was applied to the right hindlimbs of 24 New Zealand white rabbits for 3, 6, or 9 weeks. The synovial membrane from the medial suprapatellar area was examined qualitatively using transmission electron microscopy and quantitatively using light microscopic morphometry. The results indicate that synovial inflammation is not a primary event in this mechanically induced osteoarthrosis, but synovial hyperplasia occurs prior to histologically evident cartilage destruction at 6–9 weeks.
Evidence for autoimmunity in the tight skin mouse model of systemic sclerosis
Authors: Bocchieri Maureen H. , Henriksen Paul D. , Jimenez Sergio A. , Kasturi Kuppuswamy N. , Muryoi Tai , Bona Constantin A.
Published: February 2007

The tight skin mouse strain has been proposed for use as an animal model of systemic sclerosis because this animal exhibits a condition that has biochemical and pathologic similarities to the human disease. To date, however, evidence of inflammatory and immunologic changes in the tight skin mouse has been scarce. We demonstrated the presence of antinuclear antibodies in approximately half of these mice ages 8 months and older. This suggests that there is an autoimmune component in their disease process. The antibodies were identified as anti–topoisomerase I by a characteristic staining pattern on HEp‐2 cells and by Western blot analysis. Except for a low incidence of anti‐DNA antibodies, none of the other parameters tested, including mitogen responses, lymphokine production, and anti‐erythrocyte antibodies, was indicative of immune system dysregulation.
T lymphocyte–synovial fibroblast interactions induced by mycobacterial proteins in rheumatoid arthritis
Authors: Holoshitz Joseph , Kosek Jon , Sibley Richard , Brown Daniel A. , Strober Samuel
Published: February 2007

An in vitro system was established in which single‐cell suspensions of lymphocytes and synovial cells from the joints of patients with rheumatoid arthritis were cultured and produced an outgrowth of an organized inflammatory tissue with an extracellular matrix and capsule. The tissue outgrowth, which had histologic features of pannus, required the addition of mycobacterial antigen and interleukin‐2 to the tissue culture medium and was dependent upon the presence of T lymphocytes and their interaction with synovial fibroblasts.
Autosomal dominant arthropathy in a french family
Authors: Gaucher Alain , Weryha Georges , Perrier Pascale , Moreau Paul , Pere Patrice , Gillet Pierre , Vu Vincent Dang
Published: February 2007

We studied a French family in which 18 adult members had destructive arthropathy and enthesopathic changes. In 16 patients, the diagnosis was verified radiologically, and in the 2 other patients, the clinical history was consistent with familial arthropathy. The disease predominantly affects the wrists, fingers, shoulders, and peripheral entheses, and its onset occurs after age 18. Genetic transmission is autosomal dominant, with 100% penetrance, and is not related to the HLA system. The clinical and radiologic features are strikingly similar in all patients in successive generations and different branches of the genealogic tree, and this suggests monogenic transmission.
Neutrophil chemotactic factors in synovial fluids of patients with lyme disease
Authors: Georgilis Kostis , Noring Richard , Steere Allen C. , Klempner Mark S.
Published: February 2007

We examined synovial fluid samples from 14 patients with Lyme arthritis for the presence of neutrophil chemotactic factors. Thirteen of the synovial fluids stimulated chemotaxis of normal human neutrophils. The chemotactic activity was heat‐sensitive and was not inhibited by antibody to C5a or antibody to interleukin‐8, or by a competitive inhibitor of the chemotactic peptide f‐Met‐Leu‐Phe. A culture supernatant of Borrelia burgdorferi also contained neutrophil chemoattractants. Chromatography demonstrated that the chemoattractants in the synovial fluid samples were different from those in the B burgdorferi culture supernatant. One of the major chemotactic factors in Lyme disease synovial fluid had a calculated molecular weight of 13,900. We conclude that a novel, host‐derived chemoattractant is present in the synovial fluid of patients with Lyme disease.
Expression of large quantities of rheumatoid factor major cross‐reactive idiotype in the serum of adults with seropositive rheumatoid arthritis
Authors: Wedgwood Josiah F. , Hatam Lynda , Bonagura Vincent R.
Published: February 2007

We quantified rheumatoid factor cross‐reactive idiotype (RF‐CRI) in whole serum from RF+ rheumatoid arthritis (RA) patients, using an inhibition enzymelinked immunosorbent assay which is not affected by the presence of IgG. Serum from 16 RF+ RA patients contained 2–252 μg/ml RF‐CRI (geometric mean */÷ SD 20.8 */÷ 5.2), while serum from 11 normal adults contained 1–16 μg/ml RF‐CRI (geometric mean */÷ SD 3.9 */÷ 2.3). Serum from 8 of the RF+ RA patients contained RF‐CRI at concentrations more than 2 standard deviations above the geometric mean in the normal subjects (>21 μg/ml). Our results indicate that some RF+ RA patients express high concentrations of RF‐RCRI and immunoglobulin molecules that express the RF‐CRI may not be RF.
Rheumatoid factors react with fab fragments of monoclonal antibodies to herpes simplex virus types 1 and 2 fcγ‐binding proteins
Authors: Tsuchiya Naoyuki , Malone Christine , Hutt‐Fletcher Lindsey M. , Williams Ralph C.
Published: February 2007

Human polyclonal IgM rheumatoid factors (RF) were tested in an enzyme‐linked immunosorbent assay with monoclonal antibodies (MAb) (II‐481 and B10/A8) to glycoprotein E (gE), the Fcγ‐binding protein of herpes simplex virus type 1 (HSV‐1), as well as with MAb 88‐S to gE of HSV‐2. Most of the RF reacted with II‐481 and 88‐S. Positive reactions were recorded for RF reacting with whole MAb II‐481 and 88‐S, as well as with their Fab, but not their Fc, fragments. Human monoclonal IgM RF isolated from mixed cryoglobulins showed a similar profile, with reactivity for both whole MAb II‐481 and 88‐S and for their Fab fragments. Reactivity with MAb to gE was observed regardless of the Gm specificity of the polyclonal RF and the crossreactive idiotypes (6B6, 17.109, or G6) of the monoclonal RF. No positive reactions were noted between protein A and Fab fragments of any of the anti‐gE MAb. These findings indicate that many RF may bear the internal image of the Fcγ‐binding regions of 2 different herpesviruses: HSV‐1 and HSV‐2.
Monocyte‐derived neutrophil chemotactic factor/interleukin‐8 is a potential mediator of crystal‐induced inflammation
Authors: Terkeltaub Robert , Zachariae Claus , Santoro Denise , Martin Jody , Peveri Paola , Matsushima Kouji
Published: February 2007

The physical interaction of particulates with resident mononuclear phagocytes is a consistent feature in certain forms of crystal‐induced inflammation. In this study, we observed that monosodium urate crystals stimulated the rapid release of neutrophil chemotactic activity from monocytes, and that this activity steadily increased over 24 hours. Because the release of monocyte‐derived neutrophil chemotactic activity was markedly diminished by pretreatment of the monocytes with cycloheximide, and was completely removed from conditioned media by adsorption to heparin‐agarose, we addressed the possibility that monocyte‐derived neutrophil chemotactic factor/interleukin‐8 (IL‐8), a heparin‐binding neutrophil‐activating polypeptide, might modulate these activities. Urate crystal‐induced IL‐8 secretion from monocytes was verified by radioimmuno‐assay. In addition, an IL‐8–specific antibody markedly inhibited the neutrophil‐activating capacity of the conditioned media from monocytes activated by urate crystals, as well as by inflammatory silica crystals. Last, IL‐8 was significantly increased in gouty synovial fluids (range 3.0–16.8 ng/ml, mean 8.4 ng/ml, n = 6) relative to osteoarthritic synovial fluids (range 1.1–1.7 ng/ml, mean 1.5 ng/ml, n = 6) (P = 0.006). We conclude that microcrystal‐induced secretion of IL‐8 by mononuclear phagocytes may mediate a number of forms of crystal‐induced inflammation.
Synovial fluid 5′‐nucleotidase activity. Relationship to other purine catabolic enzymes and to arthropathies associated with calcium crystal deposition
Authors: Wortmann Robert L. , Veum Judith A. , Rachow John W.
Published: February 2007

We measured 5′‐nucleotidase (5NT) activity in synovial fluid from 159 patients with various diagnoses. The activity of 5NT was compared with activities of nucleotide pyrophosphohydrolase, alkaline and neutral phosphatases, and adenosine deaminase, in the same samples. Higher levels of 5NT activity occurred in synovial fluid from osteoarthritic joints than from joints of patients with gout, pseudogout, or rheumatoid arthritis. The highest levels of 5NT activity were found in synovial fluid from patients with Milwaukee shoulder syndrome and from osteoarthritis patients in whom deposition of calcium‐containing crystals was also present.