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ID PMID Title PublicationDate abstract
11350490 Acquired Factor VIII autoantibody: four cases demonstrating the heterogenous nature of thi 2001 Mar The development of an autoantibody to human Factor VIII is rare and presents many problems for diagnosis and treatment. We have seen several cases at our institution recently with widely heterogenous clinical and laboratory presentations. A wide range of treatment modalities were used in these cases with no gold standard of treatment or widely accepted guidelines existing. This has prompted us to examine all cases of this condition presenting at Fremantle Hospital over the last decade. We describe four cases which demonstrate the heterogeneity of this condition and its treatment and review the recent literature on the subject.
11892941 Cladribine. Ortho Biotech Inc. 2001 Dec Cladribine, an adenosine deaminase inhibitor, has been developed and launched by Ortho Biotech in collaboration with The Scripps Research Institute for the treatment of several neoplasms, including acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneos T-cell lymphoma, hairy-cell leukemia and non-Hodgkin's lymphoma. It was first launched in the US in February 1993. Ortho Biotech and The Scripps Research Institute have since been developing the compound for its potential use in multiple sclerosis (MS). In 1997, Ortho filed air NDA in the US for the use of cladribine in the treatment of relapsing-remitting and secondary progressive MS. An FDA drug advisory committee was planning to meet in January 1999 to discuss the NDA. However, Ortho cancelled the meeting. Following an FDA inspection during December 1998 and January 1999, the Scripps Clinic received a warning letter from the FDA in April 1999 regarding violations in the clinical studies of cladribine for MS, and Ortho withdrew the NDA after concluding that further clinical studies would be necessary. Cladribine has been known since the 1960s as an intermediate for the synthesis of 2-deoxynucleotides and its potential for the treatment of leukemia was disclosed in 1984. The Scripps Research Institute and the Johnson & Johnson group hold several patents claiming preparation methods (US 05208327), and additional indications, such as multiple sclerosis (WO-09316706) and rheumatoid arthritis (US-05310732). The associated patent, WO-09323508, is the only one among those patents that claims the use of unmodified cladribine for the treatment of leukemia, but it focuses particularly on a specific form of the disease, chronic myelogenous leukemia. Analysts at UBS Warburg predicted in October 2001, that the product would make US sales of $50 million in 2004 for its MS indication.
10513809 Treatment with sulfasalazine or sulfapyridine, but not 5-aminosalicyclic acid, inhibits ba 1999 Sep OBJECTIVE: Rheumatoid arthritis (RA) is characterized by leukocyte recruitment and angiogenesis. We investigated the effects of sulfasalazine (SSZ) and its metabolites, sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA), on components of angiogenesis, namely, endothelial cell (EC) chemotaxis and proliferation, as well as on EC chemokine and soluble adhesion molecule expression. METHODS: SSZ, SP, and 5-ASA were assayed for their effects on basic fibroblast growth factor (bFGF)-induced human dermal microvascular endothelial cell (HMVEC) chemotaxis and proliferation. EC were plated on Matrigel to assess the effect of SSZ on EC tube formation. Enzyme-linked immunosorbent assays were performed to determine changes in HMVEC production of interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), growth-related oncogene alpha (GROalpha), epithelial neutrophil-activating peptide 78 (ENA-78), soluble E-selectin (sE-selectin), and soluble intercellular adhesion molecule 1 (sICAM-1) upon treatment with SSZ or its metabolites. RESULTS: HMVEC incubated with SSZ or SP exhibited reduced bFGF-induced chemotaxis (59%, [n = 7] and 22%, [n = 3], respectively) (P<0.05). SSZ and SP decreased basal HMVEC proliferation, while 5-ASA increased proliferation (P<0.05; [n = 5]). SSZ decreased bFGF-induced HMVEC proliferation (P<0.05 [n = 5]). SSZ inhibited phorbol 12-myristate 13-acetate-induced HMVEC tube formation (P<0.05; [minimum n = 5]). Tumor necrosis factor alpha-stimulated HMVEC shedding of sICAM-1 was reduced by incubation with either SSZ (19%) or 5-ASA (23%) (P<0.05; [n = 6]). SP inhibited cytokine-stimulated HMVEC expression of IL-8 and MCP-1 (P<0.05; [n = 4]). Neither SSZ nor its metabolites had any effect on HMVEC production of sE-selectin, GROalpha, or ENA-78. CONCLUSION: These results demonstrate that SSZ and its metabolite SP may affect the pathogenesis of RA by inhibiting EC chemotaxis, proliferation, tube formation, and expression of sICAM-1, IL-8, and MCP-1.
11316008 Naphthol-ASBI phosphate as a preferred substrate for tartrate-resistant acid phosphatase i 2001 Apr Tartrate-resistant acid phosphatase (TRAP) isoform 5b is a potential serum marker for osteoclastic activity. Biochemical assays for serum TRAP activity with para-nitrophenylphosphate (pNPP) have low specificity for bone because of hydrolysis by unrelated nontype 5 TRAPs of blood cells and by related isoform 5a. Our purpose was to increase the specificity of TRAP assay for osteoclastic activity by using naphthol-ASBI phosphate (N-ASBI-P) as a substrate for serum type 5 TRAP activity and heparin as an inhibitor of isoform 5a. TRAP activity in individual and pooled sera of normal subjects and patients with endstage renal disease (ESRD) and rheumatologic diseases was quantitated using pNPP and N-ASBI-P as substrate at pH 5.5 and 6.1. For some experiments, heparin (23U/ml) was added as a specific inhibitor of isoform 5a activity. Isoforms 5a and 5b were separated from serum pools by cation exchange chromatography and identified by nondenaturing polyacrylamide gel electrophoresis (PAGE). N-ASBI-P was selectively hydrolyzed by TRAP isoform 5b. TRAP assays with pNPP and N-ASBI-P correlated only in ESRD sera, which contained primarily isoform 5b. The two assays did not correlate in normal or rheumatic sera with significant amounts of 5a. Heparin inhibited isoform 5a activity approximately 50% but had little effect on isoform 5b activity. Biochemical assay of serum TRAP activity can be made specific for isoform 5b by using N-ASBI-P and heparin. This method can be adapted to simple microplate biochemical or immunochemical assays. This simplified method for assessment of osteoclastic TRAP 5b activity warrants a detailed investigation in diseases of bone metabolism.
10921508 Cytokine mRNA in the joints and draining lymph nodes of rats with adjuvant arthritis and e 2000 Oct TNF-alpha and IL-1beta promote leukocyte recruitment to arthritic joints and may contribute to cartilage degradation while regulatory cytokines such as IL-4 and IL-1RA may in part determine the course of arthritis. Here we report the pattern of TNF-alpha, IL-1beta, IL-6, IFN-gamma, IL-1RA, and IL-4 mRNA expression, detected by RT/PCR, in the talar joint and draining popliteal lymph node (PLN) of rats with adjuvant arthritis (AA). Levels of TNF-alpha and IFN-gamma mRNA were increased in the PLN before clinical signs of arthritis. This was followed by increases in IL-1beta and IL-1RA mRNA at d9 and IL-6 mRNA at d12. PLN IL-1RA mRNA levels were positively correlated with those of IL-1beta and TNF-alpha throughout d5-d20. IL-4 mRNA levels were highest on days 7 and 20. In the synovium, a small increase in TNF-alpha, IL-1beta, and IL-6 mRNA was detected on d5 then again on d12. Maximal synovial TNF-alpha levels were reached on d20, while IL-1beta peak expression was on d16 and IL-6 on d14. IL-4, IL-1RA, and IFN-gamma mRNA was undetectable in the synovium. Cyclosporin treatment for 4 days, initiated at the height of arthritis, rapidly decreased clinical disease, and decreased migration of neutrophils and T lymphocytes into the joints. Yet no significant effect of CyA was observed on inflammatory cytokine expression, although the correlation between PLN IL-1RA and IL-1beta or TNF-alpha was lost in treated animals. Thus there is a variable pattern of cytokine gene expression in rat AA, the undetectable IL-4 and IFN-gamma mRNA in synovium being analogous to human rheumatoid arthritis.
11037979 CD97 isoform expression in leukocytes. 2000 Oct Different adhesive capacity in interactions with CD55 has been ascribed to the isoforms of the leukocyte CD97 antigen, CD97 (EGF 1,2,5), CD97 (EGF 1,2,3,5), and CD97 (EGF 1,2,3,4,5). In the study, coexpression of the three CD97 isoforms and predominance of CD97 (EGF 1,2,5) transcripts in leukocytes are demonstrated. The contribution of CD97 (EGF 1,2,3,5) and CD97 (EGF 1,2,3,4,5) to total CD97 levels varied among most cell types only slightly, although relatively higher mRNA levels of both isoforms were detected in U 937 cells and monocytes. In peripheral blood lymphocytes, CD97 isoforms did not show clear variation after PMA stimulation and were down-regulated equally after CD97 cross-linking. Moreover, the CD97 isoform pattern was not altered in monocytes after interferon-gamma stimulation and in synovial T cells from patients with rheumatoid arthritis. CD97 mRNA levels did not necessarily correspond to CD97 surface density. The findings suggest that adhesive activity of CD97 toward CD55 is unlikely to be regulated by differential CD97 isoform expression.
10882168 Production and characterization of monoclonal IgM autoantibodies specific for the T-cell r 2000 Jan Natural autoantibodies to the T-cell receptor (Tcr) have been identified in all human sera. However, titer, epitope specificity, and isotype vary with physiological conditions, autoimmune diseases, and retroviral infections. The levels of anti-Tcr autoantibodies in rheumatoid arthritis (RA) patients are significantly higher than in normal individuals, and the autoantibodies are typically IgM. To obtain detailed information on these autoantibodies, we generated B-cell heterohybridomas secreting monoclonal IgM autoantibodies (mAAbs) from the synovial tissue and peripheral blood of RA patients. We selected clones secreting mAAbs that bound a major Vbeta epitope defined by a synthetic peptide that contains the CDR1 region of the Vbeta 8.1 gene product. From these we isolated a subset of seven mAAbs that bound a recombinant single-chain Valpha/Vbeta construct containing the peptide epitope and, also to JURKAT cells which express Vbeta 8.1. The mAAbs produced by these clones were distinct from each other in their V-region sequences. However, all the V regions were essentially identical to germline sequences in both the heavy and light chains. Heavy-chain CDR3 segments ranged in length from 17 to 26 residues, did not correspond to any known autoantibodies, and showed extensive N-region diversity in the V(D)J junctions. Five monoclonal autoantibodies use VH 3 genes, while the remaining two utilized VH 4 sequences. Light-chain variable regions used were Vkappa3 (two), Vlambda3 (four), and one Vlambda2. These autoantibodies derived their unique features from their CDR3 segments that could not be aligned with any known sequences.
11219247 Oral contraceptives: current status. 2001 Mar During the past four decades, oral contraceptives have remained a safe and effective method of birth control. Reductions in the estrogen and progestin dosages have significantly decreased the incidence of cardiovascular complications. The association between oral contraceptives and breast cancer appears to be primarily because of detection bias or possibly a promotional effect. Despite the changes in formulation, the problems related to side effects have not been totally solved. Because compliance and successful use is strongly affected by side effects, improvement in this area is probably the biggest challenge faced by developers of oral contraceptives. It is also clear that there are a growing number of significant noncontraceptive benefits that accrue in oral contraceptive users. Unfortunately, many women do not know about these benefits. Thus, one of the issues that providers need to continue to address is how to provide better information about oral contraceptives and contraception in general to patients.
9832620 Establishment and characterization of a novel human rheumatoid fibroblast-like synoviocyte 1998 Dec 1 A novel immortalized rheumatoid fibroblast-like synoviocyte (FLS) line, MH7A, was established by stably transfecting FLS cells with SV40 T antigen gene. MH7A cells expressed SV40-specific small t and large T antigens as well as an elevated level of p53 protein. They have already reached over 150 population doublings through culture crisis, and have been growing rapidly compared with the parental FLSs. Constitutive activation of p42/p44 mitogen-activated protein (MAP) kinase was detected in MH7A cells. Serum requirements for the growth of MH7A were markedly decreased compared with those for the parental FLSs. MH7A cells were stained positively for interleukin (IL)-1R, intercellular adhesion molecule-1 (ICAM-1), CD16, CD40, CD80, and CD95. IL-1beta enhanced the production of IL-6 and stromelysin-1, and the surface expression of ICAM-1, in a manner similar to that in the parental FLSs. SB203580, a specific inhibitor of p38 MAP kinase, significantly inhibited IL-1beta-induced IL-6 and stromelysin-1 production by both parental FLSs and MH7A cells; although PD098059, an inhibitor of the p42/p44 MAP kinase pathway, did not affect it. Our results clearly indicate the usefulness of MH7A cells for investigating the regulation of rheumatoid FLSs and the IL-1 signal transduction pathway to develop future RA therapy.
10812500 IL-8 producing cells in patients with Behçet's disease. 2000 Mar OBJECTIVE: IL-8 is thought to be the principal chemokine responsible for neutrophil activation and tissue infiltration in patients with Behçet's disease (BD). In various studies serum levels of IL-8 were reported to be increased. METHODS: IL-8 mRNA was purified from both peripheral whole blood samples and separated lymphocytes, granulocytes and monocytes of patients with BD and compared to that from healthy (HC) and disease controls. IL-8 sequences were revealed by PCR amplification using appropriate sequence-specific primers. mRNA levels were determined semi-quantitatively using an image analyser in comparison with beta-actin. RESULTS: Although the differences did not reach statistical significance, BD patients tended to have higher IL-8 mRNA levels compared to HC in whole blood samples (2.0 +/- 1.4 vs 1.5 +/- 1.2) as well as in their lymphocytes (2.7 +/- 1.6 vs 1.5 +/- 0.9). No differences were observed between BD and HC in monocyte or granulocyte IL-8 mRNA levels. CONCLUSION: Our results suggest that the cellular source of IL-8 is diverse in BD with a possible major contribution by lymphocytes.
9366578 Interleukin-10 promotes activation-induced cell death of SLE lymphocytes mediated by Fas l 1997 Nov 15 Immune function in SLE is paradoxically characterized by active T cell help for autoantibody production, along with impaired T cell proliferative and cytokine responses in vitro. To reconcile these observations, we investigated the possibility that the accelerated spontaneous cell death of SLE lymphocytes in vitro is caused by an activation-induced cell death process initiated in vivo. 27 SLE patients, three patients with systemic vasculitis, seven patients with arthritis, and 14 healthy subjects were studied. Patients with clinically active SLE or systemic vasculitis had accelerated spontaneous death of PBMC with features of apoptosis at day 5 of culture. A prominent role for IL-10 in the induction of apoptosis was observed, as neutralizing anti-IL-10 mAb markedly reduced cell death in the active SLE patients by 50%, from 22.3 +/- 5.2% to 11.2 +/- 2.8%, and the addition of IL-10 decreased viability in the active SLE group, but not in the control group, by 38%. In addition, apoptosis was shown to be actively induced through the Fas pathway. The potential clinical relevance of T cell apoptosis in active SLE is supported by the correlation of increased apoptosis and IL-10 levels in vitro with low lymphocyte counts in vivo. We conclude that the spontaneous cell death observed in vitro in lymphocytes from patients with SLE and other systemic autoimmune disorders results from in vivo T cell activation, is actively induced by IL-10 and Fas ligand, and reflects pathophysiologically important events in vivo. Activation-induced cell death in vivo provides a pathogenic link between the aberrant T helper cell activation and impaired T cell function that are characteristic features of the immune system of patients with SLE.
9543564 Association of mast cells with fibrosis and fatty infiltration in the minor salivary gland 1998 Jan OBJECTIVE: To determine the distribution and density of mast cells in the minor salivary glands of patients with primary Sjögren's syndrome (pSS) and of normal controls. METHODS: Minor salivary gland biopsies were obtained from 19 patients with pSS, 9 with systemic lupus erythematosus, one each with rheumatoid arthritis, sarcoidosis, and Hodgkin's disease, and from 10 individuals who had subjective xerostomia with normal salivary gland biopsies. Biopsy specimens were evaluated for the degree of inflammation according to Tarpley's classification. Sections were analysed for staining with Toluidine blue and with the mast cell specific marker c-kit. The data obtained were correlated with the histological findings of fatty infiltration, fibrosis and lymphocytic infiltration. RESULTS: There was a significant correlation between the number of mast cells identified and the degrees of fibrosis and fatty infiltrates. There was no correlation between the intensity of lymphoid infiltration and the number of mast cells. c-kit staining showed a high correlation when compared to Toluidine blue staining. CONCLUSION: Mast cells in the minor salivary glands of patients with pSS are strongly associated with fibrosis and cell acid infiltration. However, there is no correlation with parameters of disease activity such as lymphoid infiltration.
11890355 Alicaforsen. Isis Pharmaceuticals. 2001 Oct Alicaforsen (ISIS-2302) is an RNase H-dependent antisense inhibitor of the intercellular adhesion molecule ICAM-1 under development by Isis Pharmaceuticals, for the potential treatment of a variety of inflammatory disorders [175741]. As of April 1997 it was in phase III trials for Crohn's disease (CD); however, the trial failed and, in December 1999, the company suspended development for this indication [352801]. In October 2000, the company re-initiated development in CD [384820] and new phase III trials had begin by May 2001 [409704]. In August 2000, phase II studies of alicaforsen in an enema formulation for ulcerative colitis and a topical formulation for psoriasis were ongoing [378715]. Development of the compound for the potential treatment of rheumatoid arthritis (RA) was discontinued in 1999 [347579]. By the end of 1998, alicaforsen was in phase II trials for kidney transplant rejection. At this time, these trials were expected to finish in mid-1999 [343460]. However, they were ongoing in September 1999, although no further development has been reported for this indication since that time [338672]. In February 1995, Isis Pharmaceuticals and Boehringer Ingelheim (BI) signed a collaborative agreement on cell adhesion inhibitors, including alicaforsen [174111]. By early 1999, Isis and BI were to decide on the next developmental step for alicaforsen following further analyses of its performance against CD [292915], [315439]. Their joint development agreement was terminated in 1999; Isis regained rights to the product and by September 1999 was in talks to license alicaforsen to another partner for CD [338672]. In June 2000, Cytogenix entered into a sponsored research agreement with Baylor College of Medicine at the Texas Medical Center Houston for the use of its ssDNA expression system for the development of antisense strategies directed against intercellular adhesion molecules for the purpose of reducing lung inflammation and injury in disease states and conditions [369677]. US-05514788, and other patents, cover antisense cell adhesion molecule inhibitors [212289], [234792].
10975769 Efficacy of pantoprazole in the prevention of peptic ulcers, induced by non-steroidal anti 2000 Apr AIM: To evaluate the efficacy of pantoprazole in preventing gastrointestinal lesions in patients with rheumatic diseases receiving continuous, long-term treatment with non-steroidal anti-inflammatory drugs. MATERIAL: This was a prospective, randomised, double-blind, unbalanced, placebo-controlled, parallel group study. Outpatients (n= 104, age range 22-80 years, mean age 59.5) with rheumatoid arthritis or osteoarthritis, requiring chronic intake of NSAIDs (at least 8 weeks prior to the start of the study), were randomised and enrolled to receive either 40 mg pantoprazole (n=70) or placebo (n=34) once daily, for 12 weeks. Patients had endoscopically confirmed gastric and duodenal lesions grade 0, 1 or 2 (Lanza classification grade 0: normal to hyperaemic mucosa; grade 1: 1 to 3 erosions, submucosal haemorrhage or petechiae, grade 2: 4 to 10 erosions, submucosal haemorrhages or petechiae). Clinical and endoscopic evaluations were performed at baseline, after 4, and 12 weeks. The primary end-point of the study was the incidence of gastric or duodenal ulcers after 4 and 12 weeks of treatment. RESULTS: Patients (n=95) were evaluated: 65 in the pantoprazole group and 30 in the placebo group. When considering all patients (those with Lanza score grade 0, 1, 2 at baseline), the overall proportion of patients in remission was 82% and 77% after 4 weeks, and 72% and 59% after 12 weeks in pantoprazole and placebo groups, respectively (cumulative survival analysis according to Kaplan-Meier). The difference between the treatment groups was even more marked when only those patients with normal mucosa at baseline (grade 0) were considered. After 12 weeks, the proportion of patients in remission was 82% (95% confidence limits 70% - 94% in the pantoprazole and 55% (95% confidence limits 33% - 77%) in the placebo treatment group, p=O.036. Adverse events were reported in 4% and 6% of patients in pantoprazole and placebo treatment groups, respectively CONCLUSIONS: Pantoprazole 40 mg once daily was well tolerated and is more effective than placebo in the prevention of peptic ulcers in patients with rheumatic diseases who require continuous, long-term, treatment with NSAIDs.
10985365 Sjögren's syndrome associated with multiple myeloma. 2000 Aug Sjögren's syndrome (SS) is a chronic autoimmune disease of unknown etiology characterized by lymphocytic infiltration of the exocrine glands and a polyclonal B-cell activation; it is demonstrated by the presence of multiple autoantibodies against organ- and non-organ-specific autoantigens. SS is associated with malignant lymphomas, Waldenstrom's macroglobulinemia and benign monoclonal gammopathy, while its relationship with multiple myeloma is extremely rare. The association between multiple myeloma and rheumatoid arthritis and other autoimmune diseases has been established, but it is not clear why a B-cell proliferation like myeloma occurs more rarely than other B-cell disorders in patients with SS. We describe a patient who presented with multiple myeloma and SS that might have existed for at least 2 years prior to the appearance of myeloma.
11544312 T cell selection and differential activation on structurally related HLA-DR4 ligands. 2001 Sep 15 Plasticity of TCR interactions during CD4(+) T cell activation by an MHC-peptide complex accommodates variation in the peptide or MHC contact sites in which recognition of an altered ligand by the T cell can modify the T cell response. To explore the contribution of this form of TCR cross-recognition in the context of T cell selection on disease-associated HLA molecules, we have analyzed the relationship between TCR recognition of the DRB1*0401- and DRB1*0404-encoded HLA class II molecules associated with rheumatoid arthritis. Thymic reaggregation cultures demonstrated that CD4(+) T cells selected on either DRB1*0401 or DRB1*0404 could be subsequently activated by the other MHC molecule. Using HLA tetramer technology we identify hemagglutinin residue 307-319-specific T cells restricted by DRB1*0401, but activated by hemagglutinin residues 307-319, in the context of DRB1*0404. One such clone exhibits an altered cytokine profile upon activation with the alternative MHC ligand. This altered phenotype persists when both class II molecules are present. These findings directly demonstrate that T cells selected on an MHC class II molecule carry the potential for activation on altered self ligands when encountering Ags presented on a related class II molecule. In individuals heterozygous for these alleles the possibility of TCR cross-recognition could lead to an aberrant immune response.
10955327 Upper gastrointestinal tolerability of celecoxib, a COX-2 specific inhibitor, compared to 2000 Aug OBJECTIVE: To determine the upper gastrointestinal (GI) tolerability of celecoxib, naproxen, and placebo in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: An analysis of 5, 12-week, randomized, double blind, parallel group, placebo controlled clinical trials was conducted. In these trials, patients were randomized to: naproxen 500 mg bid (n = 1,099), placebo (n = 1,136), celecoxib 50 mg bid (n = 690) (subtherapeutic dose), celecoxib 100 mg (n = 1,131) or 200 mg bid (n = 1,125) (therapeutic dose), or celecoxib 400 mg bid (n = 434) (supratherapeutic dosage). The incidence and time until moderate to severe abdominal pain, dyspepsia, nausea, and any of the aforementioned 3 upper GI symptoms (composite endpoint) were determined using time-to-event analysis. RESULTS: The cumulative incidences of moderate to severe abdominal pain, dyspepsia, or nausea (composite endpoint) were: naproxen 500 mg (12.0%; 95% CI 9.9%-14.0%), celecoxib 50 mg bid (7.1%; 95% CI 5.0%-9.2%), celecoxib 100 mg bid (7.8%; 95% CI 6.0%-9.5%), celecoxib 200 mg bid (8.1%; 95% CI 6.4%-9.9%), celecoxib 400 mg bid (6.0%; 95% CI 3.6%-8.4%), and placebo (8.5%; 95% CI 6.5%-10.8%). After controlling for independent predictors of the composite endpoint, relative risks (RR) for the various treatments relative to naproxen 500 mg bid were: celecoxib 50 mg (RR 0.54; 95% CI 0.37-0.77; p < 0.001), celecoxib 100 mg (RR 0.60; 95% CI 0.45-0.80; p < 0.001), celecoxib 200 mg bid (RR 0.63; 95% CI 0.47-0.83; p = 0.001), celecoxib 400 mg bid (RR 0.56; 95% CI 0.35-0.89; p = 0.015), and placebo (RR 0.63; 95% CI 0.47-0.85; p = 0.002). After controlling for independent predictors of the composite endpoint, celecoxib treatment group patients did not differ from placebo patients when reporting the composite endpoint, with p values ranging from 0.40 to 0.96. CONCLUSION: The upper GI tolerability of celecoxib is superior to naproxen. A dose-response relationship between celecoxib and upper GI symptoms was not apparent.
10503730 Apoptosis of human T-cells: induction by glucocorticoids or surface receptor ligation in v 1999 Apr Activated T-cells are susceptible to induction of apoptosis or programmed cell death in response to ligation of several cell surface structures, including CD2, CD3, and CD95/Fas. These mechanisms may be important in the regulation of immune responses and in prevention of autoimmunity. We used flow cytometric quantitation of DNA strand breaks to detect T-cells committed to programmed cell death. Activated human peripheral blood T-lymphocytes, and freshly isolated human thymocytes underwent apoptosis when exposed to dexamethasone or to monoclonal antibodies directed at CD2 or CD3. Interleukin-2 reduced spontaneous or dexamethasone-induced apoptosis, but augmented apoptosis due to ligation of CD2. A neutralizing anti-Fas antibody reduced the amount of DNA strand breakage, not only in T-cells exposed to antibodies to CD2 or CD3, but also in dexamethasone-treated cultures. In vivo activated T-cells, from inflammatory synovial fluids, were sensitive to immediate induction of DNA strand breaks without prior in vitro activation by lectin and IL-2. Taken together, the results indicated that: 1. Human lymphocytes, like murine thymocytes, are sensitive to glucocorticoid-induced apoptosis, as well as to programmed cell death triggered through surface receptors; 2. The effects of IL-2 on T-cell apoptosis depend on the apoptotic stimulus; 3. Fas/Fas ligand interactions may be relevant for both membrane receptor and glucocorticoid-induced cell death; and 4. Induction of T-cell apoptosis may be important in therapeutic effects of glucocorticoids in human disease.
10799861 CD40 engagement on synovial fibroblast up-regulates production of vascular endothelial gro 2000 May 15 We tested the impact of CD40 engagement on the production of vascular endothelial growth factor (VEGF) from rheumatoid synovial fibroblasts. Fibroblast-like synovial cells (FLS) were prepared from the synovial tissues of rheumatoid arthritis patients and cultured in the presence of CD40 ligand-transfected (CD40L+) L cells. VEGF levels were determined in the culture supernatants by ELISA. Stimulation of FLS by CD40L+ L cells increased the production of VEGF by 4.1-fold over the constitutive levels of unstimulated FLS. The CD40L on activated T cells from rheumatoid synovial fluid also up-regulated VEGF production from FLS. Neither indomethacin nor Abs to IL-1beta, TNF-alpha, and TGF-beta did affect CD40L-induced VEGF production. Stimulation of FLS with TNF-alpha, IL-1beta, and TGF-beta increased VEGF production by 1.6-, 2.0-, and 5.2-fold, respectively, and displayed an additive effect on the production of VEGF by CD40L. VEGF mRNA expression was also up-regulated by the stimulation of FLS with membranes from the CD40L+ L cells. Dexamethasone completely abrogated CD40L-induced VEGF production. In addition, pyrrolidine dithiocarbamate partially down-regulated CD40L-induced VEGF production, showing that the NF-kappaB pathway was partly involved in the signaling of CD40L leading to VEGF production. Collectively, these results suggest that the interaction between CD40 on synovial fibroblasts and CD40L expressed on activated T lymphocytes may be directly involved in the neovascularization in rheumatoid synovitis by enhancing the production of VEGF.
9201311 Differential immunological aberrations in patients with primary and secondary Sjögren's s 1997 Jun The aim of the present study was to analyse possible differences in immunological features between patients with primary and secondary Sjögren's syndrome (SS). Ten patients with primary SS and 10 patients with secondary SS also suffering from rheumatoid arthritis, were identified according to established criteria for SS. Ten healthy, age-matched women served as controls. The authors analysed the phenotypic characteristics of lymphocytes in peripheral blood as well as in focal inflammatory infiltrates of minor salivary gland biopsies. Functional analyses of T lymphocytes were performed after stimulation with mitogens and antigen. B cell activity was determined at the single cell level by spontaneous and mitogen induced immunoglobulin production. Serum levels of IL-4, IL-6 and IFN-gamma were also analysed. Patients with primary SS displayed a significantly higher degree of salivary gland inflammation and reduced salivary flow than did patients with secondary SS. Decreased in vitro T cell responses to antigen and mitogens were evident in both patient groups. The CD4/CD8 ratios in both peripheral blood and salivary gland lesions were significantly lower in primary SS compared with secondary SS patients. Polyclonal B cell activation, measured as the frequency of spontaneous immunoglobulin producing cells, was most prominent in primary SS, whereas a diminished response to poke-weed mitogen (PWM), a T cell dependent B cell mitogen, was more pronounced in secondary SS. The results reveal certain immunological aberrations in the whole group of patients with SS. In addition, the authors demonstrated distinct differences in immune dysfunction between patients with primary and secondary SS, indicating that they may constitute separate entities.