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ID PMID Title PublicationDate abstract
9227228 A comparison between 111In-anti-E-selectin mAb and 99Tcm-labelled human non-specific immun 1997 May We have developed and validated a method for imaging inflammation using a monoclonal antibody (1.2B6) against E-selectin, an endothelial-cell specific adhesion molecule. This study was undertaken to compare 111In-1.2B6 with 99Tcm-labelled non-specific IgG (99Tcm-HIG) in the detection of synovitis in 11 patients with rheumatoid arthritis (RA). Imaging was performed 4 h and 20-24 h post-injection (pi) of 555 MBq 99Tcm-HIG and 15 MBq 111In-1.2B6. Scintigraphic results were compared with clinical scores of joint involvement. Joint uptake was semiquantitated. The scintigraphic appearances with both tracers correlated well, although 111In-1.2B6 at 24 h showed the highest detection rate. Taking joint tenderness or swelling as evidence of clinical activity, the sensitivity of 111In-1.2B6 at 4 h and 24 h was 69% and 82%, respectively, compared with 69% and 62% for 99Tcm-HIG. 111In-1.2B6 also displayed abnormal activity over a number of joints that appeared silent on clinical examination. Joint-to-soft tissue ratios were higher for 111In-1.2B6 at 24 h (4.0 +/- 1.9; p < 0.0001 vs all) than at 4 h (2.4 +/- 1.4) or than for 99Tcm-HIG at 4 h and 24 h (1.6 +/- 0.5 and 2.3 +/- 0.7, respectively). Net 111In counts over joints increased significantly between 4 h and 24 h (mean change: 54 +/- 40%). This study demonstrates that 111In-1.2B6 scintigraphy is a sensitive method by which to assess RA activity and that targeting is more intense and specific than using 99Tcm-HIG. However, the optimum time for 111In-1.2B6 scintigraphy is 24 h whereas good results are already obtained with 99Tc-HIG at 4 h pi. Current efforts are directed at developing 99Tcm-labelled 1.2B6 for imaging endothelial activation.
11141325 CXCR3 and CCR5 ligands in rheumatoid arthritis synovium. 2001 Jan The pathogenesis of rheumatoid arthritis (RA) may be mediated by Th1-type T cells. Since chemokine receptors CXCR3 and CCR5 are preferentially expressed on Th1 cells, we tested the expression and regulation of several chemokines, including those that signal through CXCR3 (interferon-gamma-inducible protein of 10 kDa, IP-10, CXCL10; and monokine induced by interferon-gamma, Mig, CXCL9) and CCR5 (macrophage inflammatory protein (Mip)-1 alpha, CCL3; and Mip-1 beta, CCL4) in RA synovial fluids, synovial tissues, and blood. Synovial fluid (SF) protein levels of IP-10 (32.1 +/- 10.5 ng/ml), Mig (15.0 +/- 6.4 ng/ml), Mip-1 beta (0.7 +/- 0.3 ng/ml), and Mip-1 alpha (0.8 +/- 0.1 ng/ml) were 100-, 50-, 25-, and 2-fold elevated in RASF compared to control SF (P < 0.001, P < 0.001, P < 0. 001, and P < 0.02, respectively). Tissue levels of IP-10, Mig, and Mip-1 beta were significantly higher in RA than in OA (P < 0.01). Serum levels of IP-10 (3.1 +/- 1.2 ng/ml) were higher in patients with seropositive RA compared to controls (1.2 +/- 0.2 ng/ml) (P < 0.02). There was a gradient of IP-10, Mig, Mip-1 alpha, and Mip-1 beta from the blood into the synovial fluid in RA. Infiltrating T cells around high endothelial venules in RA synovium and 90 +/- 3% of SF CD3(+)CD4(+) T cells expressed CXCR3, and 85 +/- 2% of SF CD3(+)CD4(+) T cells expressed CCR5. Chemokines, including IP-10, Mig, Mip-1 alpha, and Mip-1 beta, may participate in the selective recruitment of CCR5(+)CXCR3(+) T cells to the inflamed synovium.
10229138 Circulating myeloperoxidase and anti-myeloperoxidase antibody in patients with vasculitis. 1999 To evaluate a role of myeloperoxidase (MPO) and antibody to myeloperoxidase (anti-MPO) in vasculitis, MPO and anti-MPO were determined by enzyme-linked immunosorbent assays in sera from 43 patients with vasculitis, 40 with rheumatoid arthritis, 36 with systemic lupus erythematosus (SLE), 23 with mixed connective tissue disease, 13 with systemic sclerosis, 22 with polymyositis/dermatomyositis, 18 with Sjögren's syndrome, and 30 normal controls. Kidney and lung sections from patients with vasculitis were stained for MPO. Anti-MPO titers were significantly higher (p<0.005) in the patients with vasculitis (mean+/- SD absorbance at 405 nm: 0.53 +/- 0.37) than in any other groups (0.15 +/- 0.04 to approximately 0.21 +/- 0.11). MPO levels in patients with vasculitis were comparable with those in patients with other diseases except SLE. In two patients with vasculitis, anti-MPO decreased sharply with simultaneous increases in MPO 1-2 weeks after they developed pulmonary hemorrhage. Numerous cells positive for MPO infiltrated the Bowman's spaces. These results indicate that MPO may contribute to the pathogenesis of vasculitis and a sudden fall in anti-MPO may predict a poor prognosis in some cases.
10365921 Antiperinuclear factor in psoriatic arthropathy. 1999 Jun BACKGROUND: Antiperinuclear factor (APF) is an autoantibody directed against (pro)-filaggrin molecules. OBJECTIVE: We evaluated whether APF determination is useful for the diagnosis of psoriatic arthritis (PA). METHODS: We determined APF titers in sera from patients with PA (n = 76), psoriasis vulgaris (n = 38), noninflammatory rheumatic diseases (NIRDs, n = 119), rheumatoid arthritis (RA, n = 159) both with negative (n = 36) and positive (n = 123) rheumatoid factor (RF) tests, as well as from 204 healthy controls. We used an indirect immunofluorescence test on epithelial cells from human buccal mucosa as a substrate. RESULTS: In patients with PA, 7.9% of the serum samples were APF-positive. The incidence was greater than in healthy controls (1.0%; P < .01), similar to those with uncomplicated psoriasis (2.6%; P = NS) and NIRDs (4.0%; P = NS), and lower than in RF-negative (52.7%; P < .001) and RF-positive (90.2%; P < .001) patients with RA. Three APF-positive patients with PA had symmetric joint involvement and 3 had pustulotic arthroosteitis. CONCLUSION: The APF test may be useful in differentiating PA from RA, and APF may be specific for two PA subgroups.
10583608 Histidine-rich glycoprotein prevents the formation of insoluble immune complexes by rheuma 1999 Nov In previous studies we have shown that histidine-rich glycoprotein (HRG), a relatively abundant plasma protein, can bind to immunoglobulin G (IgG) and inhibit the insolubilization of IgG-containing immune complexes (IC). It was of interest, therefore, to determine whether HRG can inhibit the formation of insoluble IC (IIC) resulting from the interaction of rheumatoid factor (RF) with human IgG-containing IC. Light scattering techniques were used to examine the effect of HRG on the formation of IIC between RF and IC containing human IgG according to three different models. In all three models physiological concentrations of HRG could block the formation of IIC induced by RF. Optical biosensor studies of the RF-IgG interaction also revealed that HRG can mask the epitopes on IgG recognized by RF. Additional studies examined whether HRG can solubilize already formed IIC and demonstrated that HRG can, in fact, partially solubilized IIC. These data indicate that HRG can regulate the formation of IIC induced by RF at three levels: namely by inhibiting the initial recognition of IgG containing IC by RF, by inhibiting the subsequent insolubilization of IgG containing IC by RF and by solubilizing already formed IIC. Collectively, these findings suggest that HRG may be an important inhibitor of the formation of pathogenic IC in diseases such as systemic lupus erythematosus and rheumatoid arthritis.
11469450 Splice variants VEGF121 and VEGF165 of the angiogenic peptide vascular endothelial cell gr 2001 Jul OBJECTIVE: To determine the expression of the angiogenic peptide vascular endothelial growth factor (VEGF, also known as vascular permeability factor, VPF) in the synovium of patients with rheumatoid arthritis (RA). METHODS: Expression of VEGF protein from the synovial tissue of 10 patients with RA was monitored by ELISA and visualized by immunocytochemistry, and by double-staining with the VEGFR-1/flt-1. VEGF mRNA and its splice variants were determined by reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: VEGF protein was strongly increased in rheumatoid synovium and localized at the synovial surface, whereas the VEGF receptor flt-1 (VEGFR-1) was visualized on microvessels in close vicinity. In synovial tissues from all 10 patients with RA, VEGF121 and VEGF165 were identified at the mRNA level as the only VEGF splice forms expressed. CONCLUSION: Since VEGF165 and VEGF121 are differently diffusible due to their opposite heparan sulfate-binding properties, they act at different distances. The presence of VEGF121 may explain induction of the VEGFR-1 on infiltrating blood vessels near the synovial surface.
9434799 Autoantibodies to a novel early endosome antigen 1. 1998 Jan Autoantibodies to EEA1, an antigen on early endosomes, were first reported in the serum of a patient with subacute cutaneous lupus erythematosus (SCLE). Here we have examined 38 sera selected for investigation of autoantibodies to EEA1 on the basis of cytoplasmic vesicle-like reactivity by immunofluorescence. Ten of the sera were reactive to a HeLa cell protein of approximately the same M(r) as human EEA1. Eight of these sera belonged to the IgG1 subclass. Five of the sera reacted with fusion proteins incorporating either the amino (from amino acids 1 to 209) or the carboxyl (incorporating the most C-terminal 300 amino acids) terminus of the human EEA1 protein. Antigens reactive with these 5 sera colocalized with internalized transferrin receptors, indicating their association with early endosomes. The other 5 sera which did not react to both fusion proteins did not colocalize with internalized transferrin receptors. We conclude that 5 of the 38 patients (13%) have autoantibodies to EEA1. None of these patients have SCLE, but have generalized joint pain, polyarthritis, rheumatoid arthritis, or circulating rheumatoid factors.
10211894 Pneumocystis carinii pneumonia in patients with connective tissue diseases: the role of ho 1999 Apr OBJECTIVE: Pneumonia due to Pneumocystis carinii has been increasingly reported in patients with connective tissue diseases, but the frequency of this complication is not known. We sought to determine the frequency of P carinii pneumonia (PCP) in patients with connective tissue diseases, and to determine the role that a hospital's acquired immunodeficiency syndrome (AIDS)-related experience may have in the diagnosis of PCP in these patients. METHODS: We used a state hospitalization registry to identify all patients with PCP and either rheumatoid arthritis, systemic lupus erythematosus, Wegener's granulomatosis, polymyositis, dermatomyositis, polyarteritis nodosa, or scleroderma who had an emergent or urgent hospitalization in California from 1983 to 1994. We compared patient and hospital characteristics between these patients and patients with connective tissue diseases hospitalized with other types of pneumonia. RESULTS: Two hundred twenty-three patients with connective tissue diseases were diagnosed with PCP in the 12-year study period. The frequency of PCP ranged from 89 cases/10,000 hospitalizations/year in patients with Wegener's granulomatosis to 2 cases/10,000 hospitalizations/year in patients with rheumatoid arthritis. Compared with 5,457 patients with connective tissue diseases and pneumonia due to other organisms, patients with PCP were more likely to be younger, to be male, to have private medical insurance, and to have systemic lupus erythematosus, Wegener's granulomatosis, inflammatory myopathy, or polyarteritis nodosa rather than rheumatoid arthritis, and were less likely to be African American. Hospital size, teaching status, urban/rural location, proportion of admissions due to AIDS or PCP, and proportion of patients with pneumonia undergoing bronchoscopy were each associated with the likelihood of diagnosis of PCP in univariate analyses, but only the number of patients with PCP being treated at a hospital (odds ratio [OR] 1.03 for each additional 10 cases/year, 95% confidence interval [95% CI] 1.01-1.05) was associated with the likelihood of diagnosis of PCP in multivariate analyses. Patients were also somewhat more likely to be diagnosed with PCP if there had previously been a case of PCP in a patient with a connective tissue disease at the same hospital (OR 135, 95% CI 0.98-1.85). In-hospital mortality was 45.7%, and was unrelated to hospital characteristics. CONCLUSION: PCP is an uncommon, but often fatal, occurrence in patients with connective tissue disease. A hospital's prior experience with patients with PCP is associated with the likelihood that this condition is diagnosed in patients with connective tissue diseases who present with pneumonia, suggesting that diagnostic suspicion is an important factor in the correct identification of affected patients.
10614885 Design and application of combined hip-knee intramedullary joint replacements. 1999 Dec Cases in which there is a total hip arthroplasty and a stemmed total knee arthroplasty in the same femur, with loosening of 1 or both components, with serious endosteal bone loss or even a fracture between the stems present a difficult reconstruction problem. We describe a reconstruction using a combined hip and stemmed knee, designed so that they could be rigidly connected during the surgical procedure. The advantages of this implant design are that the entire femur with its muscle attachments is preserved, and the inherent stability allows for immediate weight bearing. To determine the viability of the connection between the hip and the knee, a stress analysis was carried out using finite element analysis. Guidelines were thus provided for the required metal and cement thicknesses. Three case examples are presented with an average follow-up of 3 years. It was shown that the combined hip-knee implant could provide successful results for these difficult reconstructive problems in appropriately selected cases.
12768666 [A novel method for screening anti-inner ear autoantibody in patients with autoimmune dise 2000 Apr OBJECTIVE: To appraise the clinical value of a newly established method, rapid electric field immobilizing liquid phase molecule dot blot analysis (REILMD), for screening anti-inner ear autoantibody in patients with autoimmune diseases. METHODS: Seventy-one patients with 11 kinds of autoimmune diseases were chosen for the study. Both the general immunity and autoantibodies were tested. In the processes of detection of anti-inner ear autoantibody, REILMD was used for screening, and then the Western blot was used to define the molecular weight of inner ear antigen recognized by the positive autoantibody. RESULTS: Acceleration of erythrocyte sedimentation rate (ES), positive rheumatoid factor (RF), increases in C reactive protein (CRP), IgG and circulating immune complex (CIC) were found in most cases with rheumatoid arthritis (RA) and systemic lupus erythematodes (SLE). Some of these patients had increased IgA, IgM and C4. Two of 16 RA had anti-double-stranded DNA (dsDNA) and anti-mitochondria and 4/16 had anti-nucleus antibodies. Eleven of 16 SLE had antinucleus, 7/13 had anti-ribonucleoprotein (RNP), anti-Sjögren syndrome A (SSA) and anti-dsDNA, 3/13 had anti-smooth muscle (Sm) and 1/13 had anti-DNA topoisomerase I (Scl)-70, striated muscle and stomach acid cell antibodies. No autoantibody was detected in AS. Anti-inner ear autoantibody existed in 9 out of 71 patients (13%) with autoimmune diseases, in 2 of 21 patients (10%) with sudden deafness and only in 1 of 48 control subjects (2%, coronary heart disease). The anti-inner ear autoantibody was positive in 5 of 16 (31%) patients with SLE and 1 each in RA, AS, Behset's disease and streptococcus infection syndrome. In patients with positive anti-inner ear antibody, 67% had anti-nucleus antibody, 50% had anti-RNP and dsDNA antibody. The molecules recognized by the positive anti-inner ear antibody were defined as 52,000, 36,000, 31,000 and 15,000 molecules of inner ear antigen. CONCLUSION: REILMD is a feasible and easy method for screening anti-inner ear autoantibody. Several autoimmune diseases, particularly SLE, may be implicated in damage to the inner ear.
9462173 Intra-articular pressure profile of the knee joint in a spectrum of inflammatory arthropat 1997 Nov OBJECTIVES: The intra-articular pressure (IAP) rises significantly after isometric quadriceps contraction in patients with rheumatoid synovitis, a process that may temporarily impede synovial blood flow and cause oxidative injury. In acute traumatic knee effusions (ATE) pressure rises are trivial. This study compared the IAP profiles of patients with ATE with three different populations--an acute synovitis on the background of a chronic inflammatory arthropathy, a chronic low grade inflammatory arthropathy, and an acute intermittent inflammatory arthropathy. The study objective was to discover if the pressure profiles observed in these groups reflect an influence of the inflammatory process or time or both. METHODS: Thirty three patients were studied. These were divided into four subgroups; group 1: five acute traumatic knee effusions (ATE); group 2: acute effusions on the background of a chronic inflammatory arthropathy: seven rheumatoid arthritis (RA), five psoriatic arthritis (PsA); group 3: seven osteoarthritis (OA) and group 4: acute effusions on the background of an intermittent inflammatory arthropathy: seven pyrophosphate arthropathy (PA), one amyloid (AA), one Behcet's (B). IAP was measured (mm Hg) at rest and during isometric quadriceps contraction using the hand held portable 295-1 intra-compartmental pressure monitor system (Stryker UK). The volume of synovial fluid aspirated was recorded. RESULTS: Expressed as medians (inter-quartile range). Resting IAP was; ATE 6 (2-12), RA 8 (5-47), PsA 18 (11-31), OA 17 (7-21), PA 25 (9-29), AA 14, and B 12. IAP increased in all subjects during isometric contraction; ATE 9 (7-16), RA 56 (33-150), PsA 52 (43-85), OA 56 (20-116), PA 53 (41-65), AA 47, B 57 and the IAP rise was significant (p < 0.05) in all except the ATE group (p > 0.05). The volume of synovial fluid aspirated in groups 2, 3, and 4 correlated significantly with the magnitude of the IAP change (r = 0.45, p < 0.05). CONCLUSION: The IAP rise during isometric quadriceps contraction is a feature of all patients with an inflammatory based effusion irrespective of the duration of the effusion. This is not the case in patients with an ATE. In inflammatory synovitis the rise in intra-articular pressure with isometric quadriceps contraction relates to effusion volume. It is concluded that the inflammatory process prevents reflex muscle inhibition, a locally protective mechanism that minimises the potential for intermittent ischaemia/oxidative injury.
10529121 Nitric oxide synthase is expressed in the lymphomononuclear cells of synovial fluid in pat 1999 Oct OBJECTIVE: To investigate the expression of inducible nitric oxide synthase (iNOS) in subpopulations of peripheral blood and synovial fluid (SF) leukocytes in patients with rheumatoid arthritis (RA). METHODS: iNOS was detected in peripheral blood and SF samples after cell permeabilization, by 2 color immunofluorescence flow cytometry. Samples from 14 patients with RA and 8 with osteoarthritis (OA) were studied. Nitrite concentration was determined by Griess reaction, interleukin 1beta and tumor necrosis factor alpha by an immunoenzymatic assay, and C-reactive protein (CRP) by an immunonephelometric method. RESULTS: In SF, iNOS was detected in 11 of 14 patients with RA and 2 of 8 with OA. In blood cells, iNOS was detected in 8 of 14 patients with RA and none of the OA group. iNOS was consistently detected in monocytes and was not detected in granular cells. In RA, there was no correlation between the number of iNOS positive mononuclear cells and cytokine concentrations. CRP concentration was correlated with the number of iNOS positive mononuclear cells in RA SF samples. CONCLUSION: SF mononuclear cells from patients with RA express iNOS and are involved in NO production in the joint. The number of positive cells is correlated with CRP concentration, suggesting the implication of NO production in the inflammatory process.
9415631 Clinical characteristics of patients with rheumatoid arthritis and methotrexate induced pn 1997 Dec OBJECTIVE: To determine the clinical features of methotrexate (MTX) pneumonitis in patients treated for rheumatoid arthritis (RA). METHODS: The medical records of 284 patients with RA who had been treated with oral MTX (mean followup 33.2 mo) were reviewed retrospectively. RESULTS: MTX induced interstitial pneumonitis developed in 6 patients (2.1%). The affected patients were significantly older than those without MTX pneumonitis (67.3 +/- 9.8 vs 52.4 +/- 12.6 yrs, respectively; p < 0.005). The cumulative MTX dose ranged from 65 to 580 mg at the time pneumonitis developed. Five of the patients (83%) had preexisting interstitial abnormalities, while only 29 of the 278 patients without MTX pneumonitis (10%) had such abnormalities (p < 0.001). The frequency of adverse effects due to previous treatment with disease modifying antirheumatic drugs (DMARD) was 66.7% in MTX pneumonitis patients and 14.3% in the other 278 patients (p < 0.01). CONCLUSION: Advanced age, preexisting interstitial abnormalities, and previous adverse reactions to DMARD may be associated with MTX pneumonitis. Patients with these characteristics require careful monitoring during MTX therapy.
9566801 Differential inhibitory effects of indomethacin, dexamethasone, and interferon-gamma (IFN- 1998 Apr IL-11, a member of the IL-6 type cytokines, has some biological activity related to the joint destruction in rheumatoid arthritis (RA), such as induction of osteoclast differentiation. However, its expression and regulation in rheumatoid inflamed joints has not been clarified. In the present study we examined the capacity of fresh rheumatoid synovial cells (fresh RSC) to produce IL-11, and the effect of indomethacin, dexamethasone and IFN-gamma on IL-11 production. Fresh RSC obtained from eight patients with RA produced large amounts of IL-11, measured by ELISA, and showed strong expression of IL-11 mRNA, determined by Northern blotting. Indomethacin inhibited the production of IL-11 by about 55%. Prostaglandin E2 (PGE2) completely prevented the inhibition, suggesting that IL-11 production by fresh RSC was in part mediated by PGE2. Dexamethasone inhibited the production of IL-11 by more than 80%. Interestingly, the inhibition was not abolished by PGE2. IFN-gamma inhibited the production of IL-11 from IL-1alpha-stimulated cultured rheumatoid synovial fibroblasts, although IFN-gamma did not inhibit the production of IL-11 by fresh RSC. These results suggest that the production of IL-11 by rheumatoid synovia was differentially regulated by PGE2 and IFN-gamma, and that treatment with indomethacin or dexamethasone decreased the level of IL-11 at inflammatory joints in patients with RA.
11733367 Cathepsin k is a critical protease in synovial fibroblast-mediated collagen degradation. 2001 Dec Synovial fibroblasts (SFs) play a critical role in the pathogenesis of rheumatoid arthritis (RA) and are directly involved in joint destruction. Both SF-resident matrix metalloproteases and cathepsins have been implicated in cartilage degradation although their identities and individual contributions remain unclear. The aims of this study were to investigate the expression of cathepsin K in SFs, the correlation between cathepsin K expression and disease severity, and the contribution of cathepsin K to fibroblast-mediated collagen degradation. Immunostaining of joint specimens of 21 patients revealed high expression of cathepsin K in SFs in the synovial lining and the stroma of synovial villi, and to a lesser extent in CD68-positive cells of the synovial lining. Cathepsin K-positive SFs were consistently observed at sites of cartilage and bone degradation. Expression levels of cathepsin K in the sublining and vascularized areas of inflamed synovia showed a highly significant negative correlation with results derived from the Hannover Functional Capacity Questionnaire (r = 0.78, P = 0.003; and r = 0.70, P = 0.012, respectively) as a measure of the severity of RA in individual patients. For comparison, there was no correlation between Hannover Functional Capacity Questionnaire and cathepsin S whose expression is limited to CD-68-positive macrophage-like synoviocytes. The expression of cathepsin K was also demonstrated in primary cell cultures of RA-SFs. Co-cultures of SFs on cartilage disks revealed the ability of fibroblast-like cells to phagocytose collagen fibrils whose intralysosomal hydrolysis was prevented in the presence of a potent cathepsin K inhibitor but not by an inhibitor effective against cathepsins L, B, and S. The selective and critical role of cathepsin K in articular cartilage and subchondral bone erosion was further corroborated by the finding that cathepsin K has a potent aggrecan-degrading activity and that cathepsin K-generated aggrecan cleavage products specifically potentiate the collagenolytic activity of cathepsin K toward type I and II collagens. This study demonstrates for the first time a critical role of cathepsin K in cartilage degradation by SFs in RA that is comparable to its well-known activity in osteoclasts.
11315917 Involvement of the nuclear orphan receptor NURR1 in the regulation of corticotropin-releas 2001 Apr OBJECTIVE: To examine the regulation and mode of action of peripheral corticotropin-releasing hormone (CRH) in human inflammatory arthritis. METHODS: CRH messenger RNA (mRNA) levels were measured in normal and inflamed synovial tissue and in primary synoviocytes prior to and following cytokine stimulation. Primary synoviocytes were transiently transfected with CRH promoter/reporter constructs, and promoter activity in response to cytokines was assessed. Immunohistochemical staining established CRH receptor expression, and Northern blot analysis confirmed that the nuclear transcription factors NUR77 and NURR1 contributed to synovial CRH receptor-mediated signaling. Primary synoviocytes were treated with pro- and antiinflammatory mediators, and the time course of NURR1 and NUR77 modulation was examined. Nuclear extracts were analyzed by electrophoretic mobility shift assay to determine NURR1 binding to the CRH promoter/enhancer. RESULTS: CRH mRNA was up-regulated in the synovial tissue in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and sarcoid arthritis, but not in normal synovium. Inflammatory cytokines, such as interleukin-1beta and tumor necrosis factor alpha, enhanced the transcriptional activity of the human CRH promoter and increased levels of CRH mRNA in primary synoviocytes. Synovial CRH functioned in a paracrine manner to induce NURR1 and NUR77. NURR1 was abundantly expressed in the inflammatory cells of both RA and PsA synovium. NURR1 and NUR77 were differentially regulated, and NURR1 was the major cytokine-regulated member of the NURR subfamily as well as the mediator of cytokine- and CRH-dependent inflammatory responses in synovium. Furthermore, glucocorticoids dramatically suppressed cytokine- and CRH-induced synovial NURR1 mRNA. CONCLUSION: These data demonstrate the involvement of the transcription factor NURR1 in the regulation of CRH expression and activity in human inflammatory arthritis.
10415593 Perturbations of hypothalamic-pituitary-gonadal axis and adrenal androgen functions in rhe 1999 Jun 22 Rheumatoid arthritis (RA) is a heterogeneous disease with a diverse spectrum of manifestations and course of illness. Multiple factors are believed to contribute to its etiology. Nevertheless, consistent features are observed across populations, which include (1) increased familial or immunogenetic risk in younger-onset disease; (2) female predisposition, particularly during child-bearing ages; (3) predictable clinical improvement during pregnancy and worsening postpartum; and (4) increased incidence with aging, which suggest that hormonal factors influence the disease. In 1974, serum was prospectively obtained from pre-RA cases, 4 to 20 (mean = 12.0) years prior to onset of disease and concurrently from controls (CN) matched (4 CN per 1 RA) on age (+/- 2 years), race (all Caucasians), and entry menopausal status (EMS). CN have no known rheumatic disease. Pre-RA were divided into subgroups, according to EMS, i.e., premenopausal vs. non-premenopausal (peri- or post-menopausal), and either age at entry in 1974 or age at onset of RA. For example, one 3-way subgrouping includes: I. Entry premenopausal and RA onset < age 50 years; II. Entry premenopausal and RA onset age 50+ years, and III. Entry postmenopausal. The 11 youngest pre-RA (I) had a mean entry age of 29 years and RA onset of 41 years. An alternative 4-way subgrouping (a, b, c, d) divided the female subjects into premenopausal (last menstrual period [LMP], 0-31 days) and non-premenopausal major groups, as well as younger vs. older subgroups within the major EMS categories. The younger premenopausal women in each subgrouping system, that is, I or a, overlap almost entirely. Assays (RIA) of the major sex hormones were performed, e.g., luteinizing hormone (LH); follicle stimulating (FSH); estradiol (E2); progesterone (P4); and total testosterone (T); as well as adrenal hormones, including androstenendione (A4); dehydroepiandrosterone (DHEA); its sulfate (DHEAS); and cortisol (C). A significantly lower entry mean serum DHEAS level (mumol/L) was found in the pre-RA subgroup I, than in the 43 CN (2.14 +/- 0.47 vs. 3.62 +/- 0.37, respectively, (p = 0.033). The 25 older pre-RA and 100 CN (subgroups II and III) showed close mean DHEAS levels (1.89 +/- 0.30 and 1.94 +/- 0.14, respectively, p = 0.45). The serum DHEAS levels in pre-RA vs. CN subgroups were validated in a second reference laboratory. Also, the youngest pre-RA subgroup (I) showed a significant dissociation between entry serum DHEAS and cortisol levels (r = -0.660, p = 0.027), which differed (p = 0.017) from its matched CN, and from the older pre-RA (p = 0.004). Analyses of results based upon subgroupings by EMS and entry age (a, b, c, d) showed similar results. No significant differences were found between pre-RA and CN groups in levels of serum cortisol, other adrenal steroids, or the sex hormones assayed. In a sample of younger premenopausal women, significantly low serum DHEAS levels were found 4 to 20 years prior to onset of RA. Dissociation of serum cortisol and DHEAS levels was also found in the youngest, but not older, pre-RA subjects. The data suggest that subtle adrenal cortical dysfunction, manifested mainly by adrenal androgen (AA) deficiency, may either predispose to younger-onset RA or be a long-term marker in a minority subgroup of women.
10719834 Vitamin D and autoimmunity: is vitamin D status an environmental factor affecting autoimmu 2000 Mar The environment in which the encounter of antigen with the immune system occurs determines whether tolerance, infectious immunity, or autoimmunity results. Geographical areas with low supplies of vitamin D (for example Scandinavia) correlate with regions with high incidences of multiple sclerosis, arthritis, and diabetes. The active form of vitamin D has been shown to suppress the development of autoimmunity in experimental animal models. Furthermore, vitamin D deficiency increases the severity of at least experimental autoimmune encephalomyelitis (mouse multiple sclerosis). Targets for vitamin D in the immune system have been identified, and the mechanisms of vitamin D-mediated immunoregulation are beginning to be understood. This review discusses the possibility that vitamin D status is an environmental factor, which by shaping the immune system affects the prevalence rate for autoimmune diseases such as multiple sclerosis, arthritis, and juvenile diabetes.
9836498 Levels of soluble Fas/APO-1 in patients with Behçet's disease. 1998 The aim of this study was to quantify soluble Fas/APO-1 (sFas/APO-1) protein in the serum of patients with Behcet's disease (BD) in active and inactive stages, compared with patients with systemic lupus erythematosus (SLE) and patients with rheumatoid arthritis (RA). Soluble Fas/APO-1 was quantified using a sandwich enzyme-linked immunosorbent assay. Increased serum sFas/APO-1 levels were observed in active BD, compared with inactive BD, RA patients and SLE patients. Increased serum sFas/APO-1 levels were correlated with the presence of neurologic manifestations or pulmonary involvement in active BD. In conclusion, increased levels of sFas/APO-1 occurred frequently and exclusively in active BD patients. Preliminary evidence suggested that elevated levels of sFas/APO-1 are associated with the clinical stage and clinical manifestations in BD.
11791644 European genetic study on rheumatoid arthritis: is there a linkage of the interleukin-1 (I 2001 Nov The genetic predisposition for rheumatoid arthritis (RA) is only partly explained by the HLA locus and most genetic factors involved in the susceptibility (and/or severity) of the disease await further identification. The first European genome scan in RA families provided suggestive evidence for linkage with a region (3.1/3q13) on chromosome 3, but many other potential RA susceptibility genes have yet to be analysed. AIMS: To perform a linkage analysis with microsatellite markers located in the vicinity of the interleukin-1 (IL-1) gene superfamily, the IL-10 gene and the IL-4 gene cluster which might be considered putative candidate loci for RA. METHODS: 107 Caucasoid European RA sibpairs from 90 nuclear families were genotyped for markers flanking the genes for the IL-1 superfamily, IL-10 and the IL-4 gene cluster. Linkage analysis based on the identity by descent (IBD) in affected siblings was analysed with the program SIBPALNA. Affected sibpairs were stratified according to the identity by state (IBS) for three markers in the HLA region (DRB1 oligotyping, D6S276 and TNFa microsatellites) and to the presence/absence of erosive disease on X-ray examination. RESULTS: Analysis of the whole family set showed an excess of allele sharing for markers of the IL-1 gene cluster (IBD 60%; P = 0.012) but not for IL-10 or IL-4. After stratification, the evidence of linkage to IL-1 was restricted to HLA concordant sibpairs (n = 32; IBD 70%; P = 0.006). Some evidence of linkage to IL-10 was also observed in HLA concordant sibpairs (IBD 66%; P = 0.03) and in sibpairs with erosive disease (n = 61; IBD 62%; P = 0.02). CONCLUSIONS: We found suggestive evidence of linkage of RA to the IL-1 locus. The increased linkage to IL-1 and IL-10 in HLA-identical sibs suggests a possible interaction between these cytokines and the HLA loci. Moreover IL-10 could interact with HLA factors in predisposing to erosive disease. These results need to be tested in additional families for consistency and replication.