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ID PMID Title PublicationDate abstract
7983639 Synovial fibroblast-like cell transfection with the SV40 large T antigen induces a transfo 1994 Aug OBJECTIVE: To understand the intracellular signals leading to transformed-like growth of synovial fibroblast-like cells from patients with rheumatoid arthritis (RA). METHODS: Cell lines stably transfected with one or both of 2 complementary oncogenes, the SV40 large T antigen and the ras oncogene, were studied for phenotypic changes. RESULTS: Synovial fibroblast-like cells stably transfected with the SV40 large T antigen, but not the ras oncogene, showed high levels of growth factor independent proliferation, grew under anchorage independent conditions, expressed cathepsin L mRNA, and formed transient tumors in immunodeficient mice. Synovial fibroblast-like cells stably transfected with both oncogenes appeared phenotypically similar to synovial fibroblast-like cells transfected with the large T antigen alone. CONCLUSION: The SV40 large T antigen confers a phenotype on synovial fibroblast-like cells similar to that stimulated by growth factors, suggesting that it stimulates the same intracellular signalling pathway leading to cytokine induced, transformed synovial fibroblast-like cell growth. When injected into immunodeficient mice these transfected cells formed tumors characterized by rapid, transient growth, central necrosis, and neutrophil infiltration.
7939135 Expression of the components and regulatory proteins of the classical pathway of complemen 1994 We studied the synthesis of the classical pathway complement components in synovial membrane. Ribonucleic acid was extracted from the synovial membranes of patients with rheumatoid arthritis (RA) or osteoarthritis (OA), as well as from normal synovial membrane. Northern blot and dot blot analysis showed that the mRNAs for all classical pathway complement components (C1qA chain, C1qB chain, C1qC chain, C1r, C1s, C4 and C2) and the fluid-phase regulatory components (C1-inhibitor, C4-bp and factor I) were present in all three types of synovial membrane. Thus, all the components of the classical pathway were expressed in normal and diseased synovium. In an attempt to determine which components were synthesised by each cell type, monocytes (mononuclear phagocytes), human umbilical vein endothelial cells (HUVEC), synovial membrane fibroblasts (from normal, OA and RA synovial membrane) and peripheral blood lymphocytes were cultured in vitro and secretion rates of individual components were measured and total cellular RNA was analysed by Northern blotting. Monocytes secreted C1q, C1r, C1s, C4, C2, C1-inhibitor and C4-bp but not factor I. Fibroblasts secreted C1r, C1s, C2, C3, C1-inhibitor and factor I but not C1q, C4 or C4-bp. HUVEC secreted C1s, C2, C1-inhibitor and factor I but not C1q, C1r, C4 or C4-bp. Lymphocytes did not secrete any of these components. In three instances mRNA was detected in the absence of secreted protein: mRNAs for the C1qA and C1qC chains were detected in HUVEC, whereas the mRNA for the C1qB chain was not, and C4 mRNA was detected in both fibroblasts and HUVEC.(ABSTRACT TRUNCATED AT 250 WORDS)
8239761 Oxidative DNA damage and cellular sensitivity to oxidative stress in human autoimmune dise 1993 Sep OBJECTIVES: To estimate the extent of genomic DNA damage and killing of lymphocytes by reactive oxygen intermediates in autoimmune diseases. METHODS: 8-Oxo-7-hydrodeoxyguanosine (8-oxodG), a promutagenic DNA lesion induced by reactive oxygen intermediates, was measured by high performance liquid chromatography, coupled with electrochemical detection, in hydrolysates of DNA which had been extracted from lymphocyte and polymorphonuclear leucocyte fractions of human blood. In addition, human primary blood lymphocytes stimulated by concanavalin A were assayed for cytotoxicity induced by hydrogen peroxide on day 0, by assessing cell proliferation during seven days of culture. RESULTS: Constitutive 8-oxodG was detectable (mean (2 SEM) moles 8-oxodG/10(6) moles deoxyguanosine) in DNA isolated from normal human blood lymphocytes (68 (8), n = 26) and polymorphonuclear leucocytes (118 (24), n = 24). Lymphocyte DNA from donors with the following inflammatory autoimmune diseases contained significantly higher levels of 8-oxodG than that from healthy donors: rheumatoid arthritis (98 (16)), systemic lupus erythematosus (137 (28)), vasculitis (100 (32)), and Behçet's disease (92 (19)). Lymphocyte 8-oxodG levels in non-autoimmune controls and patients with scleroderma were not significantly different from those of healthy controls. The levels of 8-oxodG were significantly higher in the DNA from normal polymorphonuclear leucocytes than in paired DNA samples from normal lymphocytes, but there were no differences between levels of 8-oxodG in polymorphonuclear leucocytes from normal subjects and the patients studied. Levels of 8-oxodG did not correlate with disease duration, disease severity, or age. Lymphocytes from patients with systemic lupus erythematosus and rheumatoid arthritis, but not those with scleroderma, also showed cellular hypersensitivity to the toxic effects of hydrogen peroxide. CONCLUSION: There was increased genomic DNA damage, and increased susceptibility to cytotoxic killing by hydrogen peroxide, in lymphocytes from patients with certain autoimmune diseases. These results might be explained by defective repair of DNA damage or by increased production of reactive oxygen intermediates in inflammation. Although more direct studies are needed, the evidence available favours the former explanation.
7510751 Rheumatoid synovium is enriched in mature antigen-presenting dendritic cells. 1994 Mar 1 Monocytes and dendritic cells (DC) can be purified from fresh peripheral blood (PB) based on their expression of CD33, CD13, and CD14. Whereas DC can be identified as CD33+ CD14dim or CD13+CD14dim cells, monocytes can be identified as CD33+CD14bright or CD13+CD14bright cells. Rheumatoid synovial fluid (SF) and synovial tissue (ST) non-T cells were found to be enriched in CD33+CD14dim cells compared with PB. Whereas 4 to 14% of normal or rheumatoid PB non-T cells were CD33+ and CD14dim, in rheumatoid SF or ST these cells comprised 20 to 45% of non-T mononuclear cells. Synovial CD33+CD14dim cells assumed a typical dendritic morphology on in vitro culture. Freshly isolated CD33+CD14dim PB DC precursors express low levels of HLA-DQ, CD40, and B7, which increase after in vitro incubation. In contrast, freshly isolated SF DC constitutively expressed these markers, and increased densities of HLA-DR and MHC class I molecules. Rheumatoid SF DC showed a specifically enhanced ability to stimulate autologous PB T cells compared with PB DC, or PB or SF monocytes. PB DC or monocytes preincubated in granulocyte-macrophage-CSF, TNF-alpha, or both cytokines exhibited enhanced expression of HLA-DR. Furthermore, DC preincubated in both granulocyte-macrophage-CSF and TNF-alpha were better stimulators of the autologous MLR than DC preincubated in medium, or in either cytokine alone. The data indicate that DC are enriched in rheumatoid SF and ST, and display a more differentiated phenotype than PB DC. These results suggest that PB DC accumulate in the synovium where they undergo phenotypic and functional differentiation in situ, which may be mediated by local cytokines. DC may play an important role in the ongoing presentation of antigen to autoreactive T cells in RA synovium.
7519955 High free and latent collagenase activity in psoriatic arthritis synovial fluids. 1994 Aug Collagenase activity has been studied intensively in SF from OA and RA patients. Less is known about collagenolytic activity in PsA SF. Therefore we examined collagenolytic activity in crude and trypsin treated SF as well as the alpha 1-antitrypsin and alpha 2-macroglobulin concentrations in 50 patients suffering from OA (n = 13), RA (n = 17), and PsA (n = 20). Free collagenolytic activity was low in the crude OA SF (1.80 +/- 1.35 micrograms released collagen/min/ml SF) and almost equally low in RA SF (2.35 +/- 1.80 micrograms released collagen/min/ml SF; P > 0.3). The PsA SF, however, exhibited a significantly higher free collagenolytic activity (5.63 +/- 5.69 micrograms released collagen/min/ml SF; P < 0.05 in comparison to OA and RA SF). The treatment of the SF with trypsin further activated collagenolytic activity in each group (OA 2.17 +/- 1.35 micrograms released collagen/min/ml SF; RA 6.48 +/- 6.73 micrograms released collagen/min/ml SF; PsA 11.24 +/- 5.02 micrograms released collagen/min/ml SF) and yielded significant differences between OA and RA, OA and PsA, and RA and PsA SF (P < 0.05). Concomitantly with the collagenolytic activity, the alpha 1-antitrypsin and alpha 2-macroglobulin concentrations of the SF were measured. In SF from patients with PsA (172.9 +/- 69.4 mg/100 ml) and RA (190.6 +/- 64.7 mg/100 ml) the alpha 1-antitrypsin was significantly higher than in those from OA SF (106.1 +/- 39.2 mg/100 ml).(ABSTRACT TRUNCATED AT 250 WORDS)
7876539 Immobilized anti-CD3 antibody activates T cell clones to induce the production of intersti 1995 Mar 15 In this study we have investigated whether direct cell to cell contact between activated paraformaldehyde-fixed T cell clones obtained from synovial tissue of patients with osteoarthritis (OA) or rheumatoid arthritis and target monocytic cells or dermal fibroblasts influenced the balance between interstitial collagenase and its specific inhibitor tissue inhibitor of metalloproteinases (TIMP) produced by the latter cell types. PHA/PMA-activated fixed T cell clones or their membranes strongly induced the production of collagenase both in monocytic THP-1 cells and in dermal fibroblasts. In contrast, only low levels of TIMP were induced in THP-1 cells and no change of TIMP expression was observed in fibroblasts as a result of stimulation with PHA/PMA-activated T cells or T cell membranes. Anti-CD3-activated T cell clones stimulated the production of collagenase both in THP-1 cells and fibroblasts, whereas TIMP levels were not influenced. Collagenase production in THP-1 cells induced by anti-CD3-activated T cell clones was 1) dependent on the dose of anti-CD3 used to stimulate the T cells, 2) initiated only when CD3 was cross-linked, and 3) inhibited when cyclosporin A was included during T cell activation. Our data collectively indicate that activated T cells in contact with monocytic cells or fibroblasts may alter the balance between interstitial collagenase and its specific inhibitor TIMP. This selective induction of a mediator profile representative of matrix breakdown as a result of target cell interaction with activated T cells may be an important factor in the local process of tissue destruction that characterizes osteoarthritis and rheumatoid arthritis.
8378689 Menstrual-associated sleep disorder: an unusual hypersomniac variant associated with both 1993 Aug A 42-year-old female presented with a history of hypersomnia associated with her menstrual periods. The menstrual periods abated coincident with the use of metoclopramide. The hypersomnolence, however, did not abate, but rather became more brief and erratic in its periodicity. The hypersomnolence was associated with marked elevations in the serum prolactin level.
8781124 H2-A polymorphism contributes to H2-Ebeta-mediated protection in collagen-induced arthriti 1996 Collagen-induced arthritis (CIA) is an animal model of auto-immune inflammatory polyarthritis which has features similar to rheumatoid arthritis (RA). Much like RA, susceptibility to mouse CIA is influenced by the major histocompatibility complex (MHC) and is restricted to the H2 haplotypes q and r. In previous experiments, we have found that the introduction of an H2-Ebd transgene in H2-Aq CIA-susceptible mice was able to protect these mice against disease development. More recently, we have proposed that the polymorphism of the first domain of the Ebeta molecule modulates this protection, and that the presentation of a peptide from the third hypervariable region of the Ebeta chain by the H2-Aq molecule plays an important role in this mechanism. In the present report, we investigated whether the H2-E-mediated protection is H2-Aq-specific and whether the source of collagen has any influence. While the source of collagen had no effect on the protection, our results showed that the H2-E molecule failed to protect B10.RIII (H2(r)) mice against CIA. Further, the H2 haplotype r exerted a negative effect on the Ebetad-mediated protection in H2-Aq-restricted disease. Our results provide additional proof that self-MHC-derived peptides, such as Ebeta peptides, may play an important role in the T-cell repertoire education and/or modulation of the T-cell response in the periphery.
7979578 Significance of anti-entactin antibodies in patients with systemic lupus erythematosus and 1994 Oct OBJECTIVES: To further evaluate the association of anti-entactin antibodies with clinical manifestations in patients with systemic lupus erythematosus (SLE) and related disorders. METHODS: Sera were analysed for anti-entactin antibodies from 79 patients with SLE, 38 patients with rheumatoid arthritis, 20 patients with progressive systemic sclerosis and five with Behçet's syndrome. Sera from 150 healthy blood donors and 20 patients with pneumonia were analysed as controls. To study the association of anti-entactin antibodies with severity and activity in SLE, 30 patients were assigned into three groups with 10 patients in each: (1) with mild manifestations; (2) severe disease without renal involvement and (3) frank lupus nephritis. Two blood samples from each patient were analysed, one from the active and the other from the inactive phase of the disease. Additionally, serial sera from 12 patients with SLE were also analysed. RESULTS: Thirty one patients with SLE (39%) had IgG, IgM or both anti-entactin antibodies. Twenty three of these patients (29%) had biopsy verified glomerulonephritis and 12 (50%) were positive for anti-entactin antibodies. Of the remaining 56 patients without apparent renal involvement, 18 (36%) were positive for anti-entactin antibodies. (chi squared = 2.77, p > 0.05). With the exception of rheumatoid arthritis where six patients (24%) had IgM anti-entactin antibodies, the antibodies were present much less frequently in other diseases (two patients with systemic vasculitis whilst none of the patients with PSS or Behçet's syndrome). Only one patient with pneumonia and none of the 150 sera from healthy blood donors had anti-entactin antibodies. Among Group 1, three (30%) were positive for IgG or IgM anti-entactin antibodies. Six (60%) patients in group 2, and five patients (50%) in group 3 were positive for anti-entactin antibodies. However, the difference between the presence of anti-entactin antibodies between group 1 and 2 or between group 1 and 3 was not significant (p = 0.15 and 0.19 respectively). There was no significant correlation between the titres of anti-entactin antibodies and total serum concentration of IgG (r = 0.141, p > 0.10) and IgM. (r = 0.130, p > 0.10). Furthermore, no significant correlation was observed between SLE disease activity index (SLEDAI) scores and the titres of IgG (r = 0.067, p > 0.10) or IgM (r = -0.033, p > 0.10) anti-entactin antibodies. CONCLUSION: The study demonstrates that anti-entactin antibodies are present in a significant number of patients with SLE and tend to be more common in those with severe disease, with or without nephritis, than in patients with mild disease manifestations. There is no correlation between the titre of anti-entactin antibodies and severity or activity of SLE.
8531375 [Sensory ataxic neuropathy associated with Sjögren's syndrome]. 1995 Oct One tenth of patients with Sjögren's syndrome (SS) is associated with peripheral neuropathy. Trigeminal neuropathy, mononeuropathy multiplex, sensory neuropathy, distal sensory neuropathy, ataxic sensory-autonomic neuropathy have been described as the neuropathy associated with SS. However, some of them secondary occur associated with the vasculopathy due to rheumatoid arthritis, systemic lupus erythematodes etc combined with SS. We demonstrated the clinico-patho-physiological features and spinal MRI findings of patients with primary SS in whom the sensory ataxia and autonomic dysfunctions were the predominant symptoms. The underlying pathology was lymphocytic (T cells) infiltration to the dorsal root ganglia with sensory neuronal degeneration. These findings have identified as association between SS and sensory ataxic neuropathy.
9038755 Differential regulation of leucocyte L-selectin (CD62L) expression in normal lymphoid and 1996 Sep AIMS: To study tissue expression of L-selectin, a leucocyte cell surface molecule that is considered to be involved in adhesion to certain endothelia, particularly in peripheral lymph nodes and during inflammation, and is shed upon leucocyte activation. METHODS: Leucocytes were examined by immunohistochemistry and double immunofluorescence staining in various lymphoid sites and normal and inflamed extralymphoid tissues. RESULTS: L-selectin was present on mantle zone B lymphocytes in different lymphoid sites, including in intestinal lymphoid tissue, but was absent on germinal centre B cells. Splenic white pulp B cells also expressed L-selectin. The proportion of T lymphocytes expressing L-selectin depended on the site under study, being greatest in peripheral lymph nodes (mean 48% of T cells positive), and lower in mucosal lymphoid sites and spleen (9 and 11% positive, respectively). Non-lymphocytic L-selectin staining was observed on follicular dendritic cells in tonsils and on macrophages in thymus. L-selectin positive leucocytes were rare in normal extralymphoid tissues, and relatively few were seen in most inflammatory settings. However, in rejecting renal transplants, a higher proportion (30%) of leucocytes expressed L-selectin. CONCLUSIONS: Overall, the results indicate how the degree of L-selectin expression by leucocytes in particular tissues may reflect a requirement for L-selectin expression for entry into those tissues and the activation state of leucocytes once localised there.
8759356 Identification, quantitation, and purification of a 36 kDa circulating protein associated 1996 Aug PURPOSE: To establish a correlation between the presence of a 36 kDa protein in the blood of patients with pars planitis and to characterize and purify this protein. METHODS: Blood samples were obtained from patients with pars planitis and other types of uveitis and from various controls. Samples were treated with polyethelene glycol and protein A and were analyzed on 10% SDS-PAGE for the presence of a 36 kDa protein. Quantitative estimation of the level of this protein was determined by densitometric tracing of the stained gels. Polyclonal antibodies were raised by immunizing New Zealand White rabbits with a mixture of the gel fragment containing the 36 kDa protein (p-36) and complete Freund's adjuvant. These antibodies were used in the immunoaffinity purification of this protein. RESULTS: The levels of p-36 were sixfold to eightfold higher in 81% of the patients with active pars planitis than in controls (P < 0.05). Furthermore, the levels of this protein correlated with disease activity. A partial amino terminal sequence analysis revealed that p-36 may be a novel protein. It has been purified from the patient's blood using affinity chromatography. CONCLUSIONS: A 36 kDa protein (p-36) is found in elevated concentrations in the blood of many patients with active pars planitis. Its putative role in the etiopathogenesis of pars planitis is unknown.
8832976 Suppression of human synovial fibroblast 85 kDa phospholipase A2 by antisense reduces inte 1996 Mar OBJECTIVE: To evaluate the relative roles of rheumatoid synovial fibroblast phospholipases A2 (PLA2) in interleukin- 1beta (IL-1 beta) stimulated prostaglandin E2 (PGE2) production. METHODS: The role of the cytosolic 85 kDa PLA2 in IL-1beta induced human rheumatoid synovial fibroblast PGE2 formation was directly evaluated using an antisense phosphorothioate oligonucleotide to the initiation site of the 85 kDa PLA2 mRNA. Contribution of the 14 kDa PLA2 was assessed using selective inhibitors or a neutralizing monoclonal antibody (Mab). RESULTS: Antisense, but not sense, decreased IL-1beta upregulation of 85 kDa PLA2 activity and protein levels. The antisense effect was specific, since it did not affect 14 kDa PLA2 activity released into the media or induced cyclooxygenase II protein levels over 24 h. Antisense, but not sense, reduced PGE2 formation in a concentration dependent manner. IL-1 beta significantly upregulated cell associated 14 kDa PLA2 and its subsequent release. Specific inhibition of this enzyme by a neutralizing Mab or selective inhibitors of 14 kDA PLA2 activity did not alter IL-1beta induced PGE2 levels. CONCLUSION: These data directly support a role for the 85 kDa PLA2, but not the 14 kDa PLA2, in IL- 1beta stimulated PGE2 production from human rheumatoid synovial fibroblast.
1281554 Interleukin-8 as a macrophage-derived mediator of angiogenesis. 1992 Dec 11 Angiogenic factors produced by monocytes-macrophages are involved in the pathogenesis of chronic inflammatory disorders characterized by persistent angiogenesis. The possibility was tested that interleukin-8 (IL-8), which is a cytokine that is chemotactic for lymphocytes and neutrophils, is also angiogenic. Human recombinant IL-8 was potently angiogenic when implanted in the rat cornea and induced proliferation and chemotaxis of human umbilical vein endothelial cells. Angiogenic activity present in the conditioned media of inflamed human rheumatoid synovial tissue macrophages or lipopolysaccharide-stimulated blood monocytes was equally blocked by antibodies to either IL-8 or tumor necrosis factor-alpha. An IL-8 antisense oligonucleotide specifically blocked the production of monocyte-induced angiogenic activity. These data suggest a function for macrophage-derived IL-8 in angiogenesis-dependent disorders such as rheumatoid arthritis, tumor growth, and wound repair.
8070163 Improved in vitro models for assay of rheumatoid synoviocyte chemotaxis. 1994 May OBJECTIVES: (1) To define the optimal conditions for transwell assay of synoviocyte chemotaxis. (2) To develop a live cell imaging chemotaxis assay for synoviocytes. (3) To characterize the chemotaxis of rheumatoid synoviocytes (RAS). RESULTS: Optimal conditions for transwell assay of synoviocyte chemotaxis were 8 microns pore size filters coated with collagen I (C1), assayed for 24 hours. Without the C1 coating 2.9 x 10(3) RAS migrated to the lower chamber. This increased to 4.7 x 10(3) when 20 micrograms/ml fibronectin (Fn) was added. With the C1 coating 4.3 x 10(3) cells migrated through the filter without chemotactic stimulation compared to 12.8 x 10(3) with interleukin 1 beta (IL-1 beta) 5 ng/ml, 12.2 x 10(3) with granulocyte-macrophage colony stimulating factor (GM-CSF) 25 ng/ml, 11.7 x 10(3) with Fn 20 micrograms/ml, and 9.0 x 10(3) with transforming growth factor-beta 1 (TGF-beta 1) 20 ng/ml (all p < 0.01). In the imaging assay, 50.7% of the RAS migrated toward the C1 coating without bound chemoattract. The percentage of cells migrating toward each chemoattractant at its optimal concentration was 64.3% for IL-1 beta, 60.8% for IL-8, 64.7% for GM-CSF, 61.0% for Fn, 58.9% for IL-6, and 69.1% for TGF-beta 1 (all p < 0.01). All of these chemoattractants increased directed migration without changing the random migration. Indomethacin (100 ng/ml) and Dexamethasone (10 ng/ml) inhibited Fn-induced chemotaxis. CONCLUSION: We report two in vitro assays for synoviocyte chemotaxis adapted and optimized for the study of synoviocytes. The live cell imaging assay had the advantage that it could separate directed and random migration.
7685226 Reduction of acute-phase proteins with tenidap sodium, a cytokine-modulating anti-rheumati 1993 Jun Four independent studies have investigated and compared the effects of tenidap sodium, naproxen and placebo on CRP in patients with active RA. One of these studies also investigated the effects of tenidap and naproxen on serum amyloid A (SAA) concentrations and ESR. The duration of the four studies ranged between 2 weeks and 24 weeks, and depending on the study, tenidap sodium was administered orally in doses of 40-120 mg/day and naproxen in doses of 1000 mg/day. In all four studies serum CRP concentrations in tenidap-treated patients had decreased significantly from baseline at the time of final assessment. The decrease in CRP concentration in tenidap-treated patients was observed as early as 1 week after initiation of therapy and was sustained for up to 6 months, the last assessment timepoint. CRP concentrations in naproxen-treated and placebo patients were essentially unchanged. The decreases from baseline observed in tenidap-treated patients were significantly greater than the changes observed in naproxen-treated or placebo patients. After 24 weeks of tenidap treatment the decrease in CRP was paralleled by significant decreases in SAA concentration and ESR. The finding that tenidap sodium rapidly, consistently and significantly lowered CRP serum concentrations differentiates tenidap sodium from the NSAID, naproxen. This could possibly have important therapeutic implications given that other long-term investigations have shown that reducing serum CRP and SAA concentrations correlates with a reduction in radiographically-assessed disease progression.
8495275 Differential effect of glucocorticoids on calcium absorption and bone mass. 1993 May Osteoporosis is one of the most serious side effects of glucocorticoid therapy and its development and severity are dependent on the particular glucocorticoid used. A short-term study (15 days) comparing the bone wasting effects and changes in calcium absorption induced by equiactive low and high doses of prednisone, deflazacort (DFZ) and betamethasone, revealed that low and high doses of betamethasone and high doses of prednisone induced a significant decrease in intestinal calcium absorption. No such changes were observed with DFZ. As 1,25-dihydroxycholecalciferol levels were maintained throughout the study, it appears that glucocorticoids impair calcium absorption through a mechanism not involving this hormone. A long-term study (1 year) of equipotent doses showed that all three glucocorticoids caused a decrease in calcium absorption and a progressive decrease in lumbar spine bone mineral content. However, the impairment of calcium absorption and decrease in bone mineral content was least with DFZ. Thus, DFZ appears to offer a degree of protection against both decreased calcium absorption and bone loss.
9003103 The prevalence and clinical associations of anticardiolipin antibodies in a large inceptio 1996 Dec PURPOSE: To determine the prevalence and clinical associations of anticardiolipin antibodies (aCL) in a blinded, controlled study of patients with a variety of connective tissue diseases (CTD) using a standardized aCL testing system. PATIENTS AND METHODS: Anticardiolipin antibodies (IgG, IgM, and IgA) were measured by direct enzyme-linked immunosorbent assay (ELISA) in the baseline serum samples of patients enrolled in a Cooperative Study of Systematic Rheumatic Diseases (CSSRD), National Institutes of Health (NIH) supported, 5-year inception-cohort, prospective study of early rheumatic diseases: rheumatoid arthritis (RA, n = 70), systemic lupus erythematosus (SLE, n = 70), scleroderma (PSS, n = 45), myositis (PM/DM, n = 36), and early undifferentiated connective tissue disease (EUCTD, n = 165). Diagnosis was based on standardized criteria and determined at the last study visit. A nested group of patients with Sjögren's syndrome (SJ, n = 44) was also defined. Serum from 200 blood donors (BB) served as controls. Additional patients with known antiphospholipid syndrome (APS, n = 33) and ANCA-related renal vasculitis (ANCA, n = 52) were also studied. Laboratory personnel were blinded to sample diagnostic group. RESULTS: The prevalence of either IgG or IgM aCL among each diagnostic group was RA 15.7%, SLE 15.76%, PSS 6.7%, PM/DM 8.3%, EUCTD 9.1%, SJ 6.8%, ANCA 3.8%, and BB controls 4.0%. Prevalence of aCL was significantly different for both the RA and SLE groups versus BB controls (P < 0.01) but not among other diagnostic groups. Only 2 study patients had positive tests for IgA aCL (1 with PM/DM and 1 with EUCTD) versus 15% of APS with positive IgA aCL. Study patients positive for IgG or IgM aCL were significantly more likely to have hemolytic anemia or a positive serologic test for syphilis and less likely to have Raynaud's phenomenon. However, no associations were found between aCL positivity and thrombocytopenia, seizures, renal insufficiency, presence of a positive antinuclear antibody or rheumatoid factor, subcutaneous nodules or digital ulcers. CONCLUSIONS: Based on results from this large CSSRD inception cohort, anticardiolipin antibodies are present in approximately 16% of patients with RA or SLE but are less common in patients with PSS, PM/DM, EUCTD, SJ, and ANCA vasculitis, where their prevalence approaches that in the normal population. Few consistent clinical association can be found among patients with CTD who are aCL positive. The complete diagnostic and prognostic importance and specificity of these antibodies remains to be fully determined.
7685771 Interferon-alpha and interleukin 2 synergistically enhance basic fibroblast growth factor 1993 Jun To elucidate mechanisms underlying neovascularization that accompanies certain chronic immune/inflammatory disorders, the effects of interferon-alpha (IFN-alpha) and interleukin 2 (IL-2) on endothelial cell (EC) growth in vitro and angiogenesis in vivo were studied. Preincubation of cultured human ECs with IFN-alpha, followed by exposure to IL-2, resulted in effective stimulation of cell growth, whereas either cytokine alone had only a slight effect. The combination of IFN-alpha/IL-2 induced an angiogenic response in the rabbit cornea. IL-2 receptor expression was enhanced on IFN-alpha-treated ECs: p55 was increased and p70 was induced. 125I-IL-2 binding to ECs treated with IFN-alpha was enhanced (Kd from approximately 7 nM to approximately 260 pM with IFN-alpha), and anti-p55 IgG blocked 125I-IL-2/EC interaction as well as IL-2-mediated EC proliferation. Consistent with these findings in cell culture, immunohistologic studies demonstrated p55 and p70 antigen in the vasculature of rheumatoid joints, but not in normal joint tissue. Exposure of cultured ECs to IFN-alpha increased levels of intracellular EC basic fibroblast growth factor (bFGF), and subsequent addition of IL-2 led to bFGF release into the medium. The observation that anti-bFGF IgG largely blocked EC proliferation in response to IFN-alpha/IL-2 suggested that bFGF was a critical agent in this setting. These data suggest a mechanism rendering ECs responsive to IL-2 which may be relevant in immune/inflammatory disorders: IFN-alpha-mediated induction of functional EC receptors for IL-2, which drives cell proliferation by a mechanism dependent on increased synthesis and release of bFGF.
8618582 Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiin 1996 May 30 BACKGROUND: Acid suppression with famotidine, a histamine H2-receptor antagonist, provides protection against gastric injury in normal subjects receiving short courses of aspirin or naproxen. The efficacy of famotidine in preventing peptic ulcers in patients receiving long-term therapy with nonsteroidal antiinflammatory drugs (NSAIDs) is not known. METHODS: We studied the efficacy of two doses of famotidine (20 mg and 40 mg, each given orally twice daily), as compared with placebo, in preventing peptic ulcers in 285 patients without peptic ulcers who were receiving long-term NSAID therapy for rheumatoid arthritis (82 percent) or osteoarthritis (18 percent). The patients were evaluated clinically and by endoscopy at base line and after 4, 12, and 24 weeks of treatment. The evaluators were unaware of the treatment assignment. The primary end point was the cumulative incidence of gastric or duodenal ulceration at 24 weeks. RESULTS: The cumulative incidence of gastric ulcers was 20 percent in the placebo group, 13 percent in the group of patients receiving 20 mg of famotidine twice daily (P = 0.24 for the comparison with placebo), and 8 percent in the group receiving 40 mg of famotidine twice daily (P = 0.03 for the comparison with placebo). The proportion of patients in whom duodenal ulcers developed was significantly lower with both doses of famotidine than with placebo (13 percent in the placebo group, 4 percent in the low-dose famotidine group [P = 0.04], and 2 percent in the high-dose famotidine group [P = 0.01]). Both doses of famotidine were well tolerated. CONCLUSIONS: Treatment with high-dose famotidine significantly reduces the cumulative incidence of both gastric and duodenal ulcers in patients with arthritis receiving long-term NSAID therapy.