bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammation‐induced cartilage degradation in female rodents. protective role of sex hormones
Authors: Da Silva Joséa. P. , Colville‐Nash Paul , Spector Tim D. , Scott David L. , Willoughby Derek A.
Published: February 2007

Objective. To investigate the effects of physiologic levels of sex steroids on inflammation and cytokine production and their consequential cartilage degradation.

Methods. We used an in vivo model of inflammation‐induced cartilage degradation in female mice to study the effects of ovariectomy and hormone treatment, and in vitro culture systems to examine the influence of sex steroids on cartilage metabolism, interleukin‐1 (IL‐1) production by granulomatous tissue, and its effects on female mouse articular cartilage.

Results. Ovariectomy resulted in accelerated cartilage breakdown associated with increased production of IL‐1 by granulomatous tissue. The effects of ovariectomy on cartilage were reversed by treatment with estradiol and androgen, but not by progesterone treatment. Estradiol and progesterone reduced both spontaneous and IL‐1–induced cartilage degradation in vitro. Testosterone antagonized the effects of IL‐1 on both proteoglycan loss and proteoglycan synthesis.

Conclusion. These data suggest that sex steroids have an important influence on inflammation‐induced cartilage breakdown in female animals, with protective effects of both estradiol and androgens. Multiple mechanisms may be involved, and they are likely to include direct immunomodulatory effects as well as interactions with the effects of cytokine and of the glucocorticoid response to inflammation.
Rheumatoid arthritis and mortality. A longitudinal study in pima indians
Authors: Jacobsson LENNART T. H. , Knowler William C. , Pillemer Stanley , Hanson Robert L. , Pettitt David J. , Nelson Robert G. , Puente Antonio Del , Mccance David R. , Charles Marie‐Aline , Bennett Peter H.
Published: February 2007

Objective. To determine the effect of rheumatoid arthritis (RA) on mortality rates.

Methods. Longitudinal analyses of data from a cohort of Pima Indians from the Gila River Indian Community in Arizona, who were followed up during the period February 1965 through December 1989.

Results. Among 2,979 study subjects aged ≤25 years, there were 858 deaths, 79 of which occurred in subjects with RA (36 men, 43 women). Age and sex‐adjusted mortality rates were slightly higher in subjects with RA than in those without (mortality rate ratio 1.28, 95% confidence interval [95% CI] 1.01–1.62). Among those with RA, mortality rates were higher in older subjects (mortality rate ratio 1.51 per 10‐year increase in age, 95% CI 1.22–1.88), in male subjects (mortality rate ratio 2.23, 95% CI 1.44–3.45, adjusted for age), and in subjects with proteinuria (mortality rate ratio 1.88, 95% CI 1.02–3.46, adjusted for age and sex). Mortality rate ratios for these risk factors were similar in subjects without RA. In addition, among subjects with RA, rheumatoid factor (RF) positivity was predictive of death (mortality rate ratio 1.94, 95% CI 1.10–3.43), and the excess mortality was found primarily among subjects who were seropositive. The death rate from cardiovascular disease (mortality rate ratio 1.77, 95% CI 1.10–2.84) and from liver cirrhosis or other alcohol‐related disease (mortality rate ratio 2.52, 95% CI 1.06–6.01) was increased in persons with RA.

Conclusion. The results of this population‐based study suggest that although the risk of mortality in subjects with RA is significantly higher than in those without RA, the risk ratio is in the lower range of that described previously in studies of clinic‐based cohorts. RF positivity as a predictor of early death among subjects with RA indicates that the immunologic processes in seropositive RA may contribute to the events that eventually lead to early death.
Antineutrophil cytoplasmic antibodies in rheumatoid arthritis. characterization and clinical correlations
Authors: Mulder A. H. L. , Horst G. , Van Leeuwen M. A. , Limburg P. C. , Kallenberg C. G. M.
Published: February 2007

Objective. To study the prevalence, interrelationships, and target antigens of antineutrophil cytoplasmic antibodies (ANCA) in rheumatoid arthritis (RA) and to relate their presence to disease duration and to the occurrence of extraarticular manifestations, including vasculitis.

Methods. Sera from 94 patients with RA (31 with recent‐onset disease, 35 with longstanding disease but without extraarticular manifestations, and 28 with extraarticular disease) were studied for the presence of ANCA by indirect immunofluorescence. All sera were tested by enzyme‐linked immunosorbent assay (ELISA) for the presence of antibodies to proteinase 3, myeloperoxidase (MPO), elastase, lactoferrin (LF), and cathepsin G (CG), and by Western blotting for antibodies to neutrophil proteins.

Results. Seventy percent of the 94 sera showed staining of the nuclei of ethanol‐fixed neutrophils; 32% of the 94 were proven to have ANCA, as manifested by their cytoplasmic staining pattern on paraformaldehyde‐fixed neutrophils. In the ELISA, 19 sera reacted with LF, 1 with MPO, and 1 with CG. By Western blotting, 21 sera reacted with LF, and 15 reacted with previously unknown polypeptides (7 sera with a 67/66‐kd doublet and 8 with a 63/54‐kd doublet). Neither of these antibodies was associated with a particular subset of the disease, but the prevalence of the antibodies tended to increase among patients with longstanding disease.

Conclusion. ANCA in RA patients are directed toward diverse cytoplasmic antigens of the neutrophil, in particular, LF and other, not yet fully characterized polypeptides. The antibodies are not a marker for a disease subset, but are probably a corollary of chronic inflammation.
Circulating soluble tumor necrosis factor receptors, interleukin‐2 receptors, tumor necrosis factor α, and interleukin‐6 levels in rheumatoid arthritis.
Authors: Barrera Pilar , Th. Boerbooms Agnes M. , Janssen Elly M. , Sauerwein Robert W. , Gallati H. , Mulder Jan , Boo Theo De , Demacker Pierre N. M. , Van De Putte Levinus B. A. , Van Der Meer JOS W. M.
Published: February 2007

Objective. To assess whether circulating concentrations of soluble tumor necrosis factor receptors (sTNFR; p55 and p75), soluble interleukin‐2 receptors (sIL‐2R), tumor necrosis factor α (TNFα), and interleukin‐6 (IL‐6) reflect clinical response and whether changes are dependent on the drug used in rheumatoid arthritis (RA) patients taking methotrexate (MTX) or azathioprine (AZA).

Methods. These cytokines and soluble receptors were assessed in 20 control subjects and serially for up to 48 weeks in 61 RA patients, by bioassay (IL‐6) and immunoassays (sTNFR, sIL‐2R, TNFα, and IL‐6).

Results. Concentrations of p55 and p75, sIL‐2R, and TNFα (but not IL‐6) were significantly higher in RA patients than in controls. Significant decreases in sIL‐2R and p55 concentrations were associated with clinical improvement and were observed in patients treated with MTX, but not AZA. Both treatments induced decreases in IL‐6 concentrations, but circulating AZA (or its metabolites) appears to interfere with the measurement of IL‐6 bioactivity. TNFα and p75 levels did not show significant changes.

Conclusion. Measurement of circulating sIL‐2R, p55, and IL‐6 may be useful in the evaluation of RA disease activity and response to therapy. Interference by circulating levels of drugs must be ruled out when bioassays are used to evaluate cytokine levels.
Detection of herpesviruses by polymerase chain reaction in lymphocytes from patients with rheumatoid arthritis
Authors: Zhang Lijuan , Nikkari Simo , Skurnik Mikael , Ziegler Thedi , Luukkainen Reijo , Möttönen Timo , Toivanen Paavo
Published: February 2007

Objective. To investigate the occurrence of herpesviruses, including Epstein‐Barr virus (EBV), herpes simplex viruses types 1 and 2 (HSV‐1; HSV‐2), and human herpes virus 6 (HHV‐6), in lymphocytes from patients with rheumatoid arthritis (RA) of less than 1 year's duration.

Methods. The polymerase chain reaction was applied to cells isolated from synovial fluid and peripheral blood. Indirect immunofluorescence and enzyme immunoassay techniques were used to detect antibodies against EBV and HSV, respectively.

Results. EBV DNA was present in synovial fluid lymphocytes from 19% (7 of 37) of the RA patients and 33% (5 of 15) of the patients with reactive arthritis (ReA). Peripheral blood lymphocytes harbored EBV DNA in 39% of the RA patients, 39% of the ReA patients, 27% of the patients with other arthropathies, and in 31% of the healthy control subjects. HSV‐1, HSV‐2, and HHV‐6 viral DNA was not detected in cells from the synovial fluid or peripheral blood.

Conclusion. Our findings do not support the participation of EBV, HSV‐1, HSV‐2, or HHV‐6 in the pathogenesis of RA. A role for the highly prevalent EBV cannot be excluded, however, since potential contributions may become manifest only when other necessary factors are involved. RA pathogenesis caused by an overproduction of the EBV virus is nevertheless highly unlikely.
Presence of estrogen‐binding sites on macrophage‐like synoviocytes and cd8+, cd29+, cd45ro+ t lymphocytes in normal and rheumatoid synovium
Authors: Cutolo Maurizio , Accardo Silvano , Villaggio Barbara , Clerico Paolo , Bagnasco Marcello , Coviello Domenico A. , Carruba Giuseppe , Casto Michele Lo , Castagnetta Luigi
Published: February 2007

Objective. To study the presence of estrogen‐binding sites (EBS) in the synovial tissues of male and female patients with rheumatoid arthritis (RA) and in age and sex‐matched healthy controls.

Methods. Both type 1 (high affinity, low binding capacity) and type 2 (reduced affinity, higher binding capacity) EBS were investigated in both soluble and nuclear fractions of homogenized synovial tissue samples by a dextran‐coated charcoal method. To determine what type of synovial cell was positive for EBS, cryosections of synovial tissues were immunostained with a specific monoclonal anti–estrogen receptor antibody (anti‐ER MAb) using both immunofluorescence and immunoperoxidase techniques. Double immunostaining with the anti‐ER MAb and with specific MAb to detect different macrophage antigens (Ber‐MAC3, MAC387, CD68) and CD8+ T cell subsets (CD29+, CD45RO+ and CD29–, CD45RO–) was performed.

Results. Higher affinity EBS were found mostly in nuclear cell fractions of either RA or control synovial tissues (28 of the 33). These EBS were present to a lesser extent in soluble cell fractions (11 of the 33). Immunostaining showed the estrogen receptor–positive cells to be the macrophage‐like synoviocytes and the CD8+, CD29+ T cells both in RA and in control synovial tissues. Higher nuclear content of EBS was consistent with more intense nuclear staining of synoviocytes and T cells.

Conclusion. It is conceivable that the immunomodulatory activity exerted by estrogens is at least partly mediated through their interaction with EBS that are present on macrophage‐like synoviocytes, functioning as antigen‐processing and antigen‐presenting cells, and on antigen‐experienced (memory) CD8+ T lymphocytes (CD29+, CD45RO+).
Increased levels of circulating intercellular adhesion molecule 1 in the sera of patients with rheumatoid arthritis
Authors: Cush John J. , Rothlein Robert , Lindsley Herbert B. , Mainolfi Elizabeth A. , Lipsky Peter E.
Published: February 2007

Objectdive. We sought to assess whether circulating levels of intercellular adhesion molecule 1 (ICAM‐1) in patients with rheumatoid arthritis (RA) are elevated and correlate with clinical measures of disease activity and whether this ICAM‐1 originates from the synovium.

Methods. Circulating ICAM‐1 (cICAM‐1) levels were determined by sandwich enzyme‐linked immunosorbent assay of serum from 61 RA, 18 osteoarthritis (OA), and 11 inflammatory arthritis (IA) patients. In addition, paired serum and synovial fluid samples were collected from 17 RA, 9 OA, and 4 IA patients. The stability of cICAM‐1 was assessed by overnight incubation at 37°C. Finally, the potential degradative effects of synovial fluid proteases were assessed by incubation of recombinant soluble ICAM‐1 with patient synovial fluid.

Results. RA sera contained significantly greater (P < 0.001) levels of cICAM‐1 compared with RA synovial fluid and compared with sera or synovial fluid from the OA and IA patients. Circulating ICAM‐1 levels were unaffected by overnight incubation at 37°C and were unaffected by exposure to RA, OA, or IA synovial fluid. Serum levels of cICAM‐1 demonstrated a weak, but significant (P < 0.05) correlation with the joint score and erythrocyte sedimentation rate in 25 RA patients treated with nonsteroidal antiinflammatory drugs.

Conclusion. The greatest elevations of cICAM‐1 were seen in RA patient sera. In both RA and OA, synovial fluid cICAM‐1 levels were consistently lower than serum levels, suggesting that cICAM‐1 did not originate in the synovium. Because the production of cICAM‐1 can be increased by cytokines (e.g., interleukin‐1, tumor necrosis factor α), elevated levels of circulating ICAM‐1 in RA may be reflective of systemic exposure to elevated cytokine levels.
Integrin‐mediated attachment of articular chondrocytes to extracellular matrix proteins
Authors: Loeser Richard F.
Published: February 2007

Objective. To investigate the interactions between chondrocytes and their extracellular matrix (ECM). An attachment assay was used to determine the extent of integrin‐mediated attachment of chondrocytes to a variety of ECM proteins and the effect of monolayer culturing on attachment activity.

Methods. Bovine and human articular cartilage chondrocytes were grown in high‐density monolayer cultures for 3–21 days and used in the assays. Cell shape and production of 3H‐proline–labeled collagen were monitored to assess phenotypic changes with time in culture. Cultured chondrocytes were incubated in wells coated with purified proteins, with and without specific inhibitors of integrin‐mediated attachment, and cell attachment was determined.

Results. Compared with bovine serum albumin, chondrocytes showed significant attachment to fibronectin, matrix Gla protein (MGP), osteopontin, bone sialoprotein II (BSP II), vitronectin, and types II and VI collagen. A synthetic peptide containing the integrin‐recognition sequence Arg‐Gly‐Asp inhibited attachment to all the proteins tested, except types II and VI collagen. A monoclonal antibody (MAb) to the β1integrin subunit inhibited attachment to fibronectin, MGP, and type II collagen, and a MAb to the β3integrin subunit inhibited attachment to BSP II and osteopontin. An increase in cell attachment was seen with time in culture, and this increase was followed by a change in the chondrocytes to flattened, type I collagen–producing cells.

Conclusion. Chondrocytes can attach to a variety of cartilage and bone proteins; this attachment is mediated via integrins, including members of both the β1 and β3 subunit families. The modulation of the chondrocyte phenotype during monolayer culture may be related to activation or increased expression of integrins.
Correlation between serum levels of soluble tumor necrosis factor receptor and disease activity in systemic lupus erythematosus
Authors: Aderka Dan , Wysenbeek Arjeh , Engelmann Hartmut , Cope Andrew P. , Brennan Fionula , Molad Yair , Hornik Vered , Levo Yoram , Maini Ravinder N. , Feldmann Marc , Wallach David
Published: February 2007

Objective. To determine the value of measurement of serum soluble tumor necrosis factor receptor (sTNFR), compared with established parameters such as anti–double‐stranded DNA, in monitoring systemic lupus erythematosus (SLE) disease activity, and to determine whether serum sTNFR are bioactive and can effectively inhibit TNF bioactivity.

Methods. Fifty‐three consecutive ambulatory or hospitalized SLE patients and 140 consecutive healthy subjects were enrolled in a prospective cohort study. Serum levels of sTNFR were measured by a unique 2‐sided capture enzyme‐linked immunosorbent assay using mouse monoclonal antibodies and rabbit antisera against the sTNFR.

Results. The mean ± SD concentrations of both the p55 (type I) and p75 (type II) soluble receptors were significantly higher in a group of 46 SLE patients than in controls: 1.89 ± 0.89 ng/ml versus 0.77 ± 0.19 ng/ml and 7.25 ± 3.89 ng/ml versus 3.02 ± 0.57 ng/ml, respectively (P < 0.0001 for both). The incidence and the extent of the increase among the healthy subjects and these patients (as well as in 7 additional patients on whom sequential studies were performed) correlated with disease activity more than did the occurrence of serum anti‐DNA antibodies (correlation coefficients with disease activity 0.81 and 0.85 for p55 and p75 sTNFR, respectively, and 0.51 for anti‐DNA antibodies). The increase in sTNFR levels seems to reflect, largely, enhanced formation, and only to a minor extent, reduced clearance due to impairment of renal function. Sera of the SLE patients had a marked inhibitory effect on the in vitro cytocidal activity of TNF, and this was shown to result entirely from their higher sTNFR receptor concentration.

Conclusion. An increase in serum levels of sTNFR may become a useful marker for SLE activity since it shows a stronger correlation than do any other laboratory or clinical parameters employed presently in the daily clinical setting. At the concentrations attained in the serum of SLE patients, sTNFR effectively inhibit the bioactivity of TNF and may thus be a significant determinant of the intensity of the manifestations of SLE.
Lymphoproliferation in primary sjögren's syndrome. evidence of selective expansion of a b cell subset characterized by the expression of cross‐reactive idiotypes
Authors: Shokri Fazel , Mageed Rizgar A. , Robert Maziak B. , Talal Norman , Amos Nicholas , Williams Bryan D. , Jefferis Roy
Published: February 2007

Objective. To evaluate the possibility that lymphoproliferation in primary Sjögren's syndrome (SS) arises within a subset of B cells.

Methods. A panel of monoclonal antibodies (MAb) specific for rheumatoid factor (RF)–associated cross‐reactive idiotypes (CRI) and anti‐VK and anti‐VH subgroup antibodies were used to define the clonality of B lymphocytes undergoing neoplastic transformation in 5 patients with primary SS. Anti‐CRI antibodies were also used to study longitudinal variations in serum paraprotein levels and in vitro regulation of IgM and IgM‐RF production by peripheral blood lymphocytes. The levels of CRI, IgM, and IgM‐RF were quantitated in serum and culture supernatants by enzyme‐linked immunosorbent assay. Heavy and light chain isotypes and VH subgroups of the paraproteins were determined by immunoelectrophoresis, immunofixation, and Western blotting.

Results. Paraproteins from all patients expressed an epitope associated with VKIIIb sub‐subgroup of light chains. Three of the paraproteins were cryoglobulins with RF activity, all of which expressed the VKIIIb‐associated CRI (detected by MAb 17–109) and the VHI‐associated CRI (detected by MAb G6 and G8). None of the paraproteins expressed the VHIII‐associated CRI (detected by MAb B6 and D12). The CRI were consistently expressed over a period of 5–6 years. The anti‐CRI and anti‐subgroup antibodies substantially inhibited spontaneous production of IgM‐RF and IgM by peripheral blood B lymphocytes from 3 of the SS patients.

Conclusion. These results suggest that lymphoproliferation in primary SS is highly selective, and that the anti‐CRI antibodies can be used as an aid to early diagnosis as well as for monitoring and modulating the lymphoproliferative process in primary SS.
Antihistone antibodies in patients with localized scleroderma
Authors: Sato Shinichi , Ihn Hironobu , Soma Yoshinao , Igarashi Atsuyuki , Tamaki Takeshi , Kikuchi Kanako , Ishibashi Yasumasa , Takehara Kazuhiko
Published: February 2007

Objective. To study the prevalence and antigen specificity of antihistone antibodies (AHA) in localized scleroderma.

Methods. Forty‐nine serum samples from patients with localized scleroderma were examined by an enzyme‐linked immunosorbent assay (ELISA) and by immunoblottin.

Results. By ELISA, AHA were demonstrated in 47% (23 of 49) of patients with localized scleroderma and in 87% (13 of 15) of patients with generalized morphea. Immunoblotting revealed that the predominant antigens were histones H1 and H3. The presence of AHA correlated with that of anti–single‐stranded DNA antibody.

Conclusion. Some of the major antigens for antinuclear antibodies in patients with localized scleroderma are histones.
The spectrum of vasculitis in human immunodeficiency virus–infected patients. a clinicopathologic evaluation
Authors: Gherardi Romain , Belec Laurent , Mhiri Chokri , Gray Francoise , Lescs Marie‐Claude , Sobel Alain , Guillevin Loïc , Wechsler Janine
Published: February 2007

Objective. To delineate the different types of inflammatory vascular diseases (IVD) occurring in patients with human immunodeficiency virus (HIV) infection.

Methods. Muscle, nerve, or skin biopsy specimens from 148 symptomatic HIV‐infected individuals were reviewed, and subgroups of vasculitis were identified using the American College of Rheumatology (ACR) 1990 clinicopathologic criteria for the classification of vasculitis.

Results. IVD was documented in 34 patients (23%) and included necrotizing arteritis (3 patients), non‐necrotizing arteritis (1 patient), neutrophilic IVD (7 patients), mononuclear IVD (17 patients), and other small vessel inflammatory changes (6 patients). According to the ACR criteria, 11 patients could be classified as having a distinct category of vasculitis, including polyarteritis nodosa (4 patients), Henoch‐Schönlein purpura (1 patient), and drug‐induced hypersensitivity vasculitis (6 patients), and 23 were classified in the group ‘other vasculitis, type unspecified.’ One patient had hepatitis B virus surface antigenemia, 2 had cryoglobulinemia, and 2 were coinfected by human T lymphotropic virus type I. Cytomegalovirus inclusions and antigens were found in endothelial cells in 1 patient. HIV antigens and genome were detected in perivascular cells of 2 of the 3 patients with necrotizing arteritis; in 1, HIV‐like particles were seen by electron microscopy. Immune deposits were found in small vessel walls in 5 skin biopsy samples showing small vessel vasculitis and in the muscle of the 3 patients with necrotizing arteritis.

Conclusion. A wide range of inflammatory vascular diseases may occur in HIV‐infected individuals. Vascular inflammation appears multifactorial and may result from HIV‐induced immunologic abnormalities and exposure to a variety of xenoantigens, such as HIV itself, other infectious agents, and drugs.
Comparison of naproxen and acetaminophen in a two‐year study of treatment of osteoarthritis of the knee
Authors: James Williams H. , Ward John R. , Egger Marlene J. , Neuner Rosemarie , Brooks Raye H. , Clegg Daniel O. , Field Elizabeth H. , Skosey John L. , Alarcón Graciela S. , Willkens Robert F. , Paulus Harold E. , Jon Russell I. , Sharp John T.
Published: February 2007

Objective. To compare the relative safety and efficacy of naproxen and acetaminophen in the treatment of osteoarthritis (OA) of the knee. The major outcome measures were radiographic progression and withdrawal from the trial due to lack of efficacy.

Methods. One hundred seventy‐eight patients with OA of the knee were enrolled in a 2‐year prospective, controlled, double‐blind multicenter trial and were randomly assigned to receive acetaminophen (ACT) or naproxen (NPX) treatment.

Results. After 6 weeks of treatment, modest improvement in pain on motion and in physician's global assessment was seen in both the ACT and the NPX groups, and the NPX group also had modest improvement in pain at rest and in 50‐foot walk time. Sixty‐two patients completed the 2‐year study. Among these patients, radiographic progression was similar in the 2 treatment groups. Withdrawal from the trial due to lack of drug efficacy was slightly more frequent among patients in the ACT group (22% versus 16%), but withdrawal due to adverse drug effects was slightly more common in the NPX group (23% versus 18%).

Conclusion. The efficacy of ACT treatment and NPX treatment was similar, although it was slightly better for NPX. The toxicity rate was slightly lower with ACT. However, the high rate of withdrawal in both treatment groups suggests that neither is satisfactory for the treatment of OA.
The structure of aggrecan fragments in human synovial fluid. evidence that aggrecanase mediates cartilage degradation in inflammatory joint disease, joint injury, and osteoarthritis
Authors: Stefan Lohmander L. , Neame Peter J. , Sandy John D.
Published: February 2007

Objective. To determine the proteolytic fragmentation patterns and N‐terminal sequence of aggrecan fragments in human synovial fluid from patients with inflammatory arthritides, joint injury, or osteoarthritis (OA).

Methods. Knee synovial fluid was obtained from patients with joint injury, OA, acute pyrophosphate arthritis (pseudogout), reactive arthritis, psoriatic arthritis, or juvenile rheumatoid arthritis. Chondroitin sulfate–substituted aggrecan fragments present in the fluid were purified by cesium chloride gradient centrifugation and enzymatically deglycosylated. Core protein species were determined by N‐terminal analysis and by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS‐PAGE) with electroblotting and detection with monoclonal antibody 3B3.

Results. Samples from patients with joint injury, OA, and inflammatory joint disease all showed a similar 3‐band pattern, with core sizes of approximately 200 kd, 170 kd, and 135 kd. In all samples, diffuse immuno‐reactive products were also seen, with an apparent size of >250 kd. N‐terminal analysis of core preparations of all samples showed a consistent single predominant sequence, beginning at alanine 374 of the human aggrecan core protein.

Conclusion. The aggrecan fragments present in joint fluids from patients with various inflammatory arthritides, joint injury, or OA result from a predominant cleavage of the human aggrecan core protein at the glutamate 373–alanine 374 bond within the interglobular domain, between the G1 and G2 domains. The consistent pattern of fragments seen on SDS‐PAGE and the single predominant N‐terminal sequence suggest a common degradative mechanism of aggrecan in these different joint conditions. The identity of the proteolytic agent (aggrecanase), however, remains unknown. These results appear to have important implications with regard to the development of therapies to protect cartilage from degradation in patients with joint disease.
Biased t cell receptor v gene usage in rheumatoid arthritis. oligoclonal expansion of t cells expressing vα2 genes in synovial fluid but not in peripheral blood
Authors: Bröker Barbara M. , Korthäuer Ulf , Heppt Peter , Weseloh Gerd , Camp RÜDiger De La , Kroczek Richard A. , Emmrich Frank
Published: February 2007

Objective. To analyze the T cell receptor (TCR) variable (V) region gene usage in the rheumatoid joint.

Methods. Monoclonal antibodies (MAb) were used to determine the prevalence of selected V elements on T cells in synovial fluid (SF) from rheumatoid arthritis (RA) patients and in peripheral blood (PB) from RA patients and normal controls. Vα2‐positive PB and SF T cells from 1 patient were cloned by immediated limiting‐dilution and analyzed by restriction mapping.

Results. In 9 of 14 RA patients, SF was enriched in at least 1 of the selected V elements, compared with PB. TCR genes of the Vα2 family were the most frequently overrepresented in the SF (4 patients). The expanded Vα2‐positive cells were oligoclonal in SF but heterogeneic in PB.

Conclusion. Our data showing biased and clonally restricted TCR elements in the rheumatoid joint indicate major histocompatibility complex–restricted antigen recognition, rather than a “superantigen,” in the pathogenesis of RA.
Reduction of leukocyte and interleukin‐1β concentrations in the synovial fluid of rheumatoid arthritis patients treated with methotrexate
Authors: Thomas Ranjeny , Carroll Graeme J.
Published: February 2007

Objective. To examine the effect of methotrexate (MTX) on the numbers of leukocytes in the peripheral blood (PB) and synovial fluid (SF) of patients with active rheumatoid arthritis (RA).

Methods. Twelve patients were treated with MTX; 5 patients not taking MTX served as controls. Samples of PB and SF were collected at 0, 1, 4, and 8 weeks of the study. Disease activity was scored, and total leukocytes, neutrophils, lymphocytes, and CD4+, CD8+, DR+, and CD25+ lymphocyte subsets were analyzed in PB and SF. Interleukin‐1β (IL‐1β) concentrations in SF were determined.

Results. Patients treated with MTX showed significant clinical improvement. No change in PB leukocytes or lymphocyte subsets was observed in either patient group over the 8‐week study period. In contrast, the number of leukocytes, the number and proportion of neutrophils, and the concentration of IL‐1β in the SF of patients treated with MTX were reduced. In addition, in MTX‐treated patients, there was an appreciable decrease in SF CD8+ lymphocytes, but not CD4+, DR+, or CD25+ lymphocytes.

Conclusion. These findings suggest that in RA, MTX acts, at least in part, by reducing the migration of leukocytes into the inflamed synovium. Local reduction of IL‐1β secretion may contribute to this effect.
Identification of mothers at risk for congenital heart block and other neonatal lupus syndromes in their children. comparison of enzyme‐linked immunosorbent assay and immunoblot for measurement of anti–ss‐a/ro and anti–ss‐b/la antibodies
Authors: Buyon Jill P. , Winchester Robert J. , Slade Seth G. , Arnett Frank , Copel Joshua , Friedman Deborah , Lockshin Michael D.
Published: February 2007

Objective. To identify the fine specificity patterns of maternal anti–SS‐A/Ro and anti–SS‐B/La antibodies that are associated with the birth of a child with transient or permanent manifestations of neonatal lupus syndromes, and to suggest a predictor algorithm for use in counseling.

Methods. Sera were obtained from 4 groups of mothers: 57 whose children had congenital heart block, 12 whose children had transient dermatologic or hepatic manifestations of neonatal lupus but no detectable cardiac involvement, 152 with systemic lupus erythematosus and related autoimmune diseases, who gave birth to healthy infants, and 30 with autoimmune diseases whose pregnancy resulted in miscarriage, fetal death, or early postpartum death unrelated to neonatal lupus. Antibodies to SS‐A/Ro and SS‐B/La were assessed by enzymelinked immunosorbent assay (ELISA) and by sodium dodecyl sulfate (SDS)‐immunoblot.

Results. Anti–SS‐A/Ro antibodies were identified by ELISA in 100%, 91%, 47%, and 43% of the mothers of infants with heart block, with transient neonatal lupus, healthy infants, and fetal death, respectively. High titers of anti–SS‐A/Ro antibodies were present more often in mothers of children with cardiac disease or transient neonatal lupus than in either of the other 2 groups. Maternal antibodies to SS‐B/La were detected by ELISA in 76% of the heart block group, 73% of the cutaneous neonatal lupus group, 15% of the group with healthy children, and 7% of the fetal death group. On SDS‐immunoblot, sera from 91% of the heart block group mothers who had antibodies to SS‐A/Ro but not to SS‐B/La recognized at least 1 SS‐A/Ro antigen, with significantly greater reactivity against the 52‐kd component. In contrast, only 62% of the anti–SS‐A/Ro positive, anti–SS‐B/La negative responders in the healthy group recognized the 52‐kd and/or the 60‐kd component. Although there was no profile of anti–SS‐A/Ro response unique to the mothers of children with heart block or cutaneous manifestations of neonatal lupus, only 1% of the healthy infants were born to mothers with antibodies directed to both the 52‐kd SS‐A/Ro and 48‐kd SS‐B/La antigens and not to the 60‐kd SS‐A/Ro antigen.

Conclusion. Women with antibodies to both SS‐A/Ro and SS‐B/La have an increased risk of giving birth to children with neonatal lupus, especially if the anti‐SS‐A/ Ro response identifies the 52‐kd component on SDS‐immunoblot. Women whose sera contain only anti‐SS‐A/Ro antibodies in low titer and only recognize determinants that are altered by conditions of SDS‐immunoblot have a low risk for giving birth to a child with neonatal lupus. Specific antibody profiles do not distinguish among the manifestations of the neonatal lupus syndromes.
Changes in the proteins coating monosodium urate crystals during active and subsiding inflammation. immunogold studies of synovial fluid from patients with gout and of fluid obtained using the rat subcutaneous air pouch model
Authors: Ortiz‐Bravo Esteban , Sieck Marie S. , Ralph Schumacher H.
Published: February 2007

Objective. In this in vivo study, we investigated changes in the proteins that coat monosodium urate (MSU) crystals in human synovial fluid samples and rat air pouch fluid samples obtained sequentially during periods of active and resolving inflammation, in order to evaluate whether in vivo findings are consistent with hypotheses on roles of protein coating based on in vitro findings.

Methods. Crystals from patients with gout were isolated from joint fluids with acute inflammation, and subsequently from the same joints at the time inflammation was resolving. Crystals were also obtained using the rat subcutaneous air pouch model. Immunogold was used to label proteins coating MSU crystals, for light microscopy (LM) and transmission electron microscopy (TEM) studies.

Results. Dense immunogold–silver labeling for IgG was observed under LM on crystals from fluid with acute inflammation, whereas other proteins (apolipoproteins [Apo], fibronectin, fibrinogen, albumin) were not labeled significantly. Apo B became strongly positive on crystals as the inflammation subsided, whereas other proteins were only weakly positive and IgG became absent or weakly positive. Quantitative TEM evaluation confirmed the LM observations.

Conclusion. This study provides the first in vivo evidence supporting the notion derived from previous in vitro studies that proteins coating MSU crystals change as inflammation evolves. Protein coatings may play an important role in the self‐limited nature of gouty inflammation. IgG coating MSU crystals may enhance the inflammation. As the inflammation subsides, Apo B could displace the IgG by competitively coating sites on crystals and could contribute in part to the resolution of the acute gouty arthritis.
Correlation of interleukin‐6 production and disease activity in polymyalgia rheumatica and giant cell arteritis
Authors: Roche Niall E. , Fulbright James W. , Wagner Annette D. , Hunder Gene G. , Goronzy Jörg J. , Weyand Cornelia M.
Published: February 2007

Objective. To explore the role of proinflammatory cytokines in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR), two clinically related syndromes characterized by an intense acute‐phase reaction. In particular, to determine plasma concentrations of interleukin‐6 (IL‐6) and tumor necrosis factor α (TNFα) and to correlate changes in plasma IL‐6 levels with clinical symptoms during corticosteroid therapy.

Methods. IL‐6 and TNFα concentrations were determined in plasma samples from patients with untreated PMR or GCA, and plasma IL‐6 levels were monitored in patients receiving long‐term therapy (14 months) with corticosteroids. To identify IL‐6–producing cells, the polymerase chain reaction was used to detect IL‐6 messenger RNA. In vitro production of IL‐6 and IL‐2 by peripheral blood mononuclear cells (PBMC) from treated and untreated patients was quantified using IL‐6– and IL‐2–specific bioassay systems.

Results. IL‐6 concentrations were increased in PMR and GCA patients, whereas TNFα concentrations were similar to those in normal donors. Administration of corticosteroids rapidly reduced the levels of circulating IL‐6 but did not correct the underlying mechanism inducing the increased IL‐6 production. In individual patients, changes in plasma IL‐6 levels and clinical manifestations during prolonged therapy were closely correlated. Short‐term withdrawal of corticosteroids, even after several months of treatment, was followed by an immediate increase in plasma IL‐6 concentrations. To identify the cellular source of plasma IL‐6, PBMC from treated and untreated patients with PMR or GCA were analyzed for their ability to secrete IL‐6 and the T cell–specific cytokine IL‐2. Polyclonal T cell stimulation caused a rapid release of IL‐6, which was shown to be derived exclusively from CD14+ cells.

Conclusion. Increased production of IL‐6, but not TNFα, is a characteristic finding in patients with PMR or GCA. Corticosteroids rapidly suppress IL‐6 production but do not correct the underlying mechanism inducing the increased IL‐6 production. The close correlation of plasma IL‐6 concentrations with clinical symptoms suggests a direct contribution of this cytokine to the disease manifestations and presents the possibility that monitoring IL‐6 levels would be useful in making decisions on adjustment of corticosteroid dosage in individual patients.
The effect of an interleukin‐1 receptor antagonist protein on type ii collagen–induced arthritis and antigen‐induced arthritis in mice
Authors: Wooley Paul H. , Whalen Janey D. , Chapman Darryl L. , Berger Ann E. , Richard Karen A. , Aspar Danielle G. , Staite Nigel D.
Published: February 2007

Objective. To investigate the anti‐arthritic effect of recombinant human interleukin‐1 receptor antagonist protein (IRAP) in two experimental models of arthritis.

Methods. Recombinant IRAP was administered daily to mice with type II collagen–induced arthritis (CIA) or with antigen‐induced arthritis (AIA) provoked by methylated bovine serum albumin (mBSA). Disease incidence and severity were assessed by a clinical index and histologic features. Serum antibody to type II collagen, spleen cell proliferation to mBSA, and anti‐IRAP antibodies were measured as indices of immune function.

Results. IRAP reduced the incidence and delayed the onset of CIA and suppressed the antibody response to type II collagen. In contrast, IRAP did not affect the pathogenesis of AIA and had no effect on either humoral or cellular immune responses to mBSA in arthritic mice.

Conclusion. These observations suggest that interleukin‐1 may play a prominent role in the development of some, but not all, forms of arthritis.
Concomitant development of chronic active hepatitis and antibodies to ribosomal p proteins in a patient with systemic lupus erythematosus
Authors: Koren Eugen , Schnitz William , Reichlin Morris
Published: February 2007

We describe a systemic lupus erythematosus (SLE) patient who for several years had typical SLE features and positive antinuclear antibodies (ANA), including anti–native DNA. Over the course of a year, 4 years after the SLE was diagnosed, the ANA disappeared and antibodies to cytoplasmic component ribosomal P protein (anti‐P) appeared. Associated with the appearance of anti‐P antibodies was the development of biochemical evidence of liver disease, later shown histologically to be chronic active hepatitis. The temporal relationship between the occurrence of anti‐P antibodies and the development of liver disease raises the possibility of a role for anti‐P antibodies in liver disease.
Detection of intraarticular abnormalities in osteoarthritis of the knee
Authors: Ike Robert W. , O'Rourke Kenneth S.
Published: February 2007

Objective. To determine whether intraarticular abnormalities in osteoarthritis (OA) of the knee can be detected as well by needle arthroscopy as by standard arthroscopy.

Methods. Needle arthroscopy followed by standard arthroscopy was performed on 10 patients with knee OA (diagnosed according to American College of Rheumatology criteria) whose symptoms were not entirely attributable to the OA and were therefore an indication for further evaluation. Each knee was assessed for abnormalities of the menisci, articular cartilage (6 sites), and synovium (6 sites).

Results. Evaluation of the 18 menisci visualized with both techniques yielded the same results: 6 abnormal and 12 normal. Among the 54 articular cartilage sites evaluable with both procedures, 16 were judged normal by both needle arthroscopy and standard arthroscopy. Of the 38 cartilage sites judged abnormal by standard arthroscopy, 34 (89%) were abnormal by needle arthroscopy. Both techniques indicated cartilage changes were the same at 42 (78%) of the 54 sites; changes at the other 12 sites were 1 grade higher by standard arthroscopy than by needle arthroscopy. Both needle arthroscopy and standard arthroscopy revealed 51 evaluable sites in the synovium. Of 34 areas judged abnormal by standard arthroscopy, 24 (71%) were also judged abnormal by needle arthroscopy; 17 areas were judged normal by both techniques. The 2 techniques assigned the same macroscopic score in 27 (53%) of 51 areas of the synovium, with a higher grade by standard arthroscopy in all but 1 of the other 16 areas.

Conclusion. These pilot data suggest that in knee OA, needle arthroscopy can 1) accurately detect meniscal abnormalities, 2) detect cartilage abnormalities, but may underestimate the severity, and 3) detect most synovial abnormalities, but often underestimates the severity. Needle arthroscopy is a potentially valuable rheumatologic tool for the assessment of OA of the knee.
Radiographic assessment of disease progression in rheumatoid arthritis patients enrolled in the cooperative systematic studies of the rheumatic diseases program randomized clinical trial of methotrexate, auranofin, or a combination of the two
Authors: Méndez Ada López‐ , Daniel William W. , Reading James C. , Ward John R. , Alarcón Graciela S.
Published: February 2007

Objective. To determine the radiographic progression of disease in rheumatoid arthritis (RA) patients from the Cooperative Systematic Studies of the Rheumatic Diseases clinical trial of auranofin (AUR) versus methotrexate (MTX) versus a combination of the two.

Methods. Baseline (week‐0) and study‐end (week‐48) hand/wrist radiographs in 200 of the 211 patients who completed this multicenter trial (95%) were scored blindly by 2 readers for the presence of erosions and joint space narrowing (JSN). Both intraobserver reliability and interobserver reliability were 0.80 for erosions (P ≤ 0.001); intraobserver reliability and interobserver reliability were both 0.75 for JSN (P ≤ 0.001).

Results. Worsening erosion and JSN scores occurred in all 3 treatment groups, but the difference from baseline reached significance only in the AUR group.

Conclusion. Clinical improvement has been clearly documented in all 3 treatment groups in this trial. Radiographic deterioration occurs in RA even when clinical features improve, but progression of disease as determined radiographically may be slowed by treatment with MTX.
Effects of methotrexate on radiologic progression in juvenile rheumatoid arthritis
Authors: Harel Liora , Wagner‐Weiner Linda , Poznanski Andrew K. , Spencer Charles H. , Ekwo Edem , Magilavy Daniel B.
Published: February 2007

Objective. To assess the effects of methotrexate (MTX) therapy on radiologic progression in juvenile rheumatoid arthritis (JRA).

Methods. We evaluated serial wrist radiographs for carpal length in 23 JRA patients with bilateral wrist involvement, before and during MTX treatment. These carpal length measurements were compared with established norms for carpal length in a healthy pediatric population.

Results. Both clinical responders to MTX (17 of 23 patients) and nonresponders (6 of 23) had decreasing carpal length prior to initiation of the treatment. Eleven of the 17 clinical responders had improved carpal length after a mean of 2.5 years of MTX treatment. All 6 clinical nonresponders had progressive loss of carpal length.

Conclusion. MTX treatment resulted in radiologic improvement, as measured by carpal length, in the majority of children with JRA who had a clinical response to MTX.
Chimeric cd4 monoclonal antibody cm‐t412 as a therapeutic approach to rheumatoid arthritis
Authors: Lubbe Peter A. VanDer , Reiter Christian , Breedveld Ferdinand C. , Kr¨︁ger Klaus , Schattenkirchner Manfred , Sanders Martin E. , Riethm¨︁ller Gert
Published: February 2007

Objective. To investigate the effects of chimeric CD4 monoclonal antibody cM‐T412 treatment in patients with rheumatoid arthritis (RA).

Methods. Thirty‐two RA patients received daily doses of 10, 50, or 100 mg of cM‐T412 intravenously for 7 days.

Results. There was a sustained decrease in the number of CD4+ T lymphocytes in all patients. Those who received 50 mg and 100 mg of the antibody experienced significant reductions in disease activity.

Conclusion. Treatment with cM‐T412 appears to have a dose‐dependent beneficial effect in RA patients. The clinical effects of cM‐T412 are independent of the depressed numbers of circulating CD4+ T cells.
Hla‐linked susceptibility to rheumatoid arthritis
Authors: Taneja Veena , Mehra N. K. , Anand C. , Malaviya A. N.
Published: February 2007

Objective. To analyze segregation of rheumatoid arthritis (RA) with HLA–DR4 and/or other alleles in multicase RA families and to compare the segregation patterns among affected and unaffected sibs.

Methods. Forty‐one multicase families (22 multiplex and 19 simplex) of northern Indian origin were studied for HLA haplotype segregation.

Results. HLA haplotype sharing among affected sibs was observed more often than expected in families in which both parents were healthy (P < 0.05). RA cosegregated with a DR4 haplotype among offspring only in multiplex families in which both parents were unaffected (P < 0.05), while in simplex families, the disease segregated with DR4 only when the allele was from the affected DR4‐heterozygous parent. In DR4‐negative affected sib pairs, DR1, DR6, and DR10 were inherited from healthy parents more often than expected.

Conclusion. Dissimilar modes of inheritance are seen among multiplex and simplex RA families. The results of segregation analysis are compatible with the hypothesis that an epitope, rather than an individual DR antigen(s), is responsible for increased risk for development of RA.
Lupus and pregnancy studies
Authors: Urowitz Murray B. , Gladman Dafna D. , Farewell Vern T. , Stewart Jacqueline , Mcdonald Joanne
Published: February 2007

Objective. To examine factors prior to pregnancy in patients with systemic lupus erythematosus (SLE) that are prognostic for the occurrence of active disease during and shortly after pregnancy.

Methods. Case–control study of pregnant SLE patients and nonpregnant SLE controls, using logistic regression analyses to assess the role of prepregnancy disease activity as a prognostic factor for flare during pregnancy or the postpartum followup period.

Results. Lupus flares occurred frequently and in similar percentages of pregnant SLE patients and control SLE patients. Active lupus at study entry, both in control and in pregnant patients, was not predictive of flare. Inactive lupus at onset was not protective against flare in controls but was protective in pregnant lupus patients.

Conclusion. Inactive disease at the onset of pregnancy in SLE provides optimum protection against the occurrence of flare during pregnancy.